JPH11322612A - Attractant for hepatocyte growth factor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare the subject attractant attracting a hepatocyte growth factor which has a strong protecting action on nervous system-constituting cells in central and peripheral nerves and a nerve-attracting action, by including a prostanoic acid derivative. SOLUTION: This attractant is prepared by including as an active principle a prostanoic acid derivative which is pref. prostaglandine A, B, C, D, E, F, G, H, T or J derivative and is esp. pref. 4,8-inter-m-phenyleneprostaglandine I2 , derivative of formula [wherein, R<1> is COOR<2> (wherein, R<2> is H, a 1-12C straight chain alkyl, or the like), CH2 OH, or the like; A is (CH2 )m , C≡C, or the like; Y is H, Cl, nitro, or the like; B is X-C(R<11> ) (R<12> )OR<13> (wherein, R<11> is H or a 1-4C alkyl; R<13> is H, a 1-14C acyl, or the like; X is CH2 -CH2 , C≡C, or the like; R<12> is a 1-12C straight chain alkyl or the like); E is H or OR<18> (wherein, R<18> is a 1-12C acyl or the like)] or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a hepatocyte growth factor attractant containing a prostanoic acid derivative as an active ingredient.

[0002]

2. Description of the Related Art Hepatocyte growth factor (HGF)
th Factor) was initially identified as an entity of liver regeneration factor, but recent studies have shown that it is a pleiotropic functional factor that primarily promotes proliferation, motility, and morphogenesis of epithelial cells. In the nervous system, this hepatocyte growth factor acts as a nerve attractant to guide the axons of motor nerves to the limbs, and as a strong neurotrophic factor, it promotes the survival of nerve cells in the central and motor nerves. Was.

[0003] Therefore, hepatocyte growth factor is expected to be an effective therapeutic agent for various intractable nervous system diseases accompanied by neurodegeneration. However, this factor is administered by a usual administration route such as oral or injection. However, it is difficult to reach a target site in a sufficient amount, and many problems remain in clinical adaptation, particularly adaptation to the brain region.

On the other hand, in recent years, various cerebrovascular diseases have been increasing with the progress of an aging society. Cerebrovascular disease is aging,
It is thought to be caused by hypertension, arteriosclerosis, hyperlipidemia, etc., and is generally called a stroke. Causes of stroke include cerebral infarction (cerebral thrombosis, cerebral embolism), cerebral hemorrhage, subarachnoid hemorrhage, transient cerebral ischemia, hypertensive encephalopathy and the like. These causative diseases cause damage and necrosis of nervous system constituent cells in ischemia and the surrounding area, and manifest local psychiatric / neurological symptoms such as cerebrovascular dementia. In recent years, Alzheimer's disease has been increasing as a representative of presenile dementia. Alzheimer's disease is a representative disease of presenile dementia, and impaired memory, spatial and temporal disorientation,
Occasionally, there are symptoms such as aphasia, apraxia and agnosia. This disease is characterized by impaired overall brain function, with advanced dementia at the end of life and death due to general weakness. Pathologically, extensive brain atrophy is observed, and it is known that Alzheimer's neurofibrillary tangles and senile plaques are observed.

[0005] As described above, drugs for improving cerebral circulation and cerebral function have been used for the purpose of improving neuropsychiatric symptoms associated with cranial nerve disorders and senile dementia, but none of these drugs show sufficient effects.

[0006] Peripheral neuropathy is also called polyneuritis and neuritis, and is caused by various causes such as inheritance, trauma, poisoning, inflammation, metabolic abnormalities such as diabetes, malignant tumors, and peripheral nerve tumor compression. Symptoms include sensory impairment, motor impairment, hypotonia,
Loss of reflexes, autonomic nervous disorder, etc. are seen, and the electromyogram shows a neurogenic pattern, with a decrease in peripheral nerve conduction velocity.
Pathological findings are nonspecific changes such as axonal degeneration, nodal demyelination, and Waller degeneration. Treatment is with rehabilitation
Steroids, vitamins, anti-inflammatory drugs, analgesics, etc. are used, but the therapeutic effect is not enough.

[0007] In the above-mentioned various pathological conditions, the causes are various, but finally the cells constituting the nervous system become suicidal,
Since shedding or dysfunction occurs, various mental symptoms including dementia, sensory disorders, movement disorders, autonomic nervous disorders and the like are caused. Therefore, if the nerve cells can be strongly protected, the disorder can be reduced and the symptoms can be expected to be improved. Furthermore, it has been revealed that nerve constituent cells other than nerve cells, such as the above-mentioned glial cells, play an extremely important role in maintaining the function of nerve cells, and reducing the damage of glial cells is effective in maintaining the function of nerve cells. is there.

[0008] Prostanoic acid derivatives are known to have various physiological activities, but are divided into several groups by modifying the 5-membered ring portion consisting of C-8 to C-12. Among these, a compound in which the carbon atoms at the 6-position and the 9-position are bonded via an oxygen atom is called PGI, and prostaglandin I ₂ (PGI ₂ , prostacyclin) is known as a typical example. This PGI ₂ is known as a substance having a strong platelet aggregation inhibitory action and a peripheral vasodilatory action (see Nature 268: 688, 1976).

PGI derivatives having a skeleton obtained by converting the structure of the exoenol ether portion, which is a characteristic structure of PGI ₂ , to an inter-m-phenylene type are particularly preferred as compounds which have greatly improved the instability of PGI _2. Fairness 2-12
Announcement of 226, Announcement of Tokuhei 2-57548, Announcement of Tokuhei 1
It is described in the -53672 publication. In addition to PGI derivatives in which the carbon atoms at the 6th and 9th positions are oxygen, PGI derivatives in which this oxygen atom is substituted with a carbon atom or another hetero atom are known. Examples include Ataprost, Iloprost, Clinprost, Cyprosten, Naxaprosten, Taprosten, Cicaprost, Pimilprost, CH-169, CS570, SM10902 (Review of Prostaglandin No. 1 12 of Hyundai Medical Co., Ltd.).
Page 3, 1994, Tomorrow's New Drug 15-IV-185, page 19
1996, tomorrow's new drug 15-III-551, 1996). However, it is not known at all that these prostanoic acid derivatives induce hepatocyte growth factor in nervous system constituent cells.

[0010]

DISCLOSURE OF THE INVENTION The present invention provides a powerful protection for nervous system constituent cells by inducing hepatocyte growth factor having a strong protective action and a nerve-inducing effect on nervous system constituent cells in central and peripheral nerves. As a result, it is effective as an excellent preventive or therapeutic agent for central and peripheral neuropathy caused by cerebrovascular disorder, cerebral nerve cell disorder, ischemic encephalopathy, dementia, diabetes, etc. It is another object of the present invention to provide a prophylactic or therapeutic agent which is effective for nerve damage due to trauma such as a surgical operation or a traffic accident, and promotion of nerve fiber extension to a relevant site in transplantation operation.

[0011]

SUMMARY OF THE INVENTION The above-mentioned object is to provide a prostanoic acid derivative, preferably prostaglandins A, B,
It is achieved by a hepatocyte growth factor attractant containing a C, D, E, F, G, H, I or J derivative, more preferably a prostaglandin I derivative as an active ingredient.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The prostanoic acid derivatives of the present invention include prostaglandins A, B, C, D, E, F,
Any of the G, H, I, or J derivatives or salts thereof may be used, but a prostaglandin I derivative or a salt thereof is preferably used.

More preferably, the following general formula (I)

[0014]

Embedded image Wherein R ¹ is (A) COOR ² where R ² is 1) hydrogen or a pharmacologically acceptable cation, 2) linear alkyl having 1 to 12 carbons or 3 to 1 carbons.
4) branched alkyl of 3) -ZR ³ wherein Z is a valence bond or a linear or branched alkylene represented by C _t H _2t , t is an integer of 1 to 6, and R ³ is carbon A cycloalkyl of the formulas 3 to 12 or R ⁴
Wherein R ⁴ is hydrogen or alkyl having 1 to 5 carbon atoms, 4) — (CH ₂ CH ₂ O) _n CH _3, wherein n is an integer of 1 to 5, 5) -Z-Ar ^1, wherein Z is the same as defined above, and Ar ¹ is phenyl, α-naphthyl, β-naphthyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, α-furyl, β-furyl, α-thienyl, β-thienyl or substituted phenyl wherein the substituent is at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, Alkyl, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidobenzamide, -CH = N-NH-C (= O) -NH
₂ , -NH-C (= O) -Ph, -NH-C (= O)-
CH ₃ or -NH-C (= O) as a _{-NH 2), 6) -C t} H 2t COOR 4 wherein C _t H _2t, R ⁴ is as defined above, 7) -C _t H _2t N (R ⁴ ) ₂ where C _t H _2t and R ⁴ are the same as defined above; 8) —CH (R ⁵ ) —C (＝ O) —R ⁶ where R ⁵ is hydrogen or benzoyl, and R ⁶ is Phenyl,
p- bromophenyl, p- chlorophenyl, p- biphenyl, p- nitrophenyl, p- benzamide phenyl, _{2-naphthyl, 9) -C P H 2P -W} -R 7 wherein, W is -CH = CH-, —CH ＝ CR ⁷ — or —C 3 C—, and R ⁷ is hydrogen or a carbon number 1 to
30 is a linear or branched alkyl or aralkyl, p is an integer of 1 to 5, or 10) —CH (CH ₂ OR ⁸ ) ₂ where R ⁸ is alkyl or acyl having 1 to 30 carbon atoms; ) —CH ₂ OH (C) —C (＝ O) N (R ⁹ ) ₂ where R ⁹ is hydrogen, straight-chain alkyl having 1 to 12 carbons, branched alkyl having 3 to 12 carbons, and 3 to 12 carbons. 12 cycloalkyl, cycloalkylalkylene having 4 to 13 carbon atoms, phenyl, substituted phenyl (the substituent is the same as in the case of the above (A) 5), aralkyl having 7 to 12 carbon atoms or -SO ₂ R ¹⁰ Wherein R ¹⁰ has 1 to ¹⁰ carbon atoms
Alkyl, cycloalkyl having 3 to 12 carbons, phenyl, substituted phenyl (substituents are as defined in the above (A) 5), and aralkyl having 7 to 12 carbons.
R ⁹ may be the same or different, but one is -S
When R ₂ represents O ₂ R ¹⁰ , the other R ⁹ is not —SO ₂ R ¹⁰ , or (D) is —CH ₂ OTHP (THP is a tetrahydropyranyl group), and A is 1) — _{(CH 2) m - 2)} -CH = CH-CH 2 - 3) -CH 2 -CH = CH- 4) -CH 2 -O-CH 2 - 5) -CH = CH- 6) -O-CH ₂ or 7) -C3C-, wherein m represents an integer of 1 to 3, Y is hydrogen, alkyl having 1 to 4 carbons, chlorine, bromine, fluorine, formyl,
Methoxy or nitro, and B is —X—C (R ¹¹ ) (R ¹² ) OR ^13, wherein R ¹¹ is hydrogen or alkyl having 1 to 4 carbons, R ¹³ is hydrogen, 1 carbons ~ 14 acyl, 6 carbon atoms
15 aroyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl or t- butyl, X _{is, 1) -CH 2 -CH 2 -} 2) -CH = CH- 3) -C three C- in R ¹² is: 1) straight-chain alkyl having 1 to 12 carbons, branched alkyl having 3 to 14 carbons, or 2) -Z-Ar ² where Z is the same as defined above, Ar ² is phenyl, α -Naphthyl, β-naphthyl, or at least one chlorine,
Bromine, fluorine, iodine, trifluoromethyl, carbon number 1
To 4 alkyl, represents nitro, cyano, methoxy, phenyl or phenoxy substituted phenyl, _{or, 3) -C t H 2t OR} 14 wherein C _t H _2t is as defined above, R ¹⁴ is 1 to carbon atoms 6
Linear alkyl, branched alkyl having 3 to 6 carbon atoms, phenyl, at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, alkyl having 1 to 4 carbon atoms, nitro,
Represents cyano, methoxy, phenyl or phenoxy-substituted phenyl, cyclopentyl, cyclohexyl, or cyclopentyl or cyclohexyl substituted with 1 to 4 straight-chain alkyl having 1 to 4 carbon atoms, or 4) -ZR ³ Wherein Z and R ³ are the same as defined above, or 5) —C _t H _2t —CH ＝ C (R ¹⁵ ) R ¹⁶ where C _t H _2t is the same as defined above, and R ¹⁵ and R ¹⁶ are hydrogen ,
Methyl, ethyl, propyl or represents a butyl, or, 6) -C _u H _2u -C three C-R ¹⁷ wherein u is an integer of 1-7, the C _u H _2u is straight or branched alkylene R ¹⁷ represents a straight-chain alkyl having 1 to 6 carbons, E represents hydrogen or —OR ^18, wherein R ¹⁸ represents an acyl having 1 to 12 carbons and 7 to 15 carbons
Aroyl or R ² (where R ² is the same as defined above)
And the general formula represents d-form, l-form or dl-form]
A 4,8-inter-m-phenylene prostaglandin I ₂ derivative represented by the following formula or a pharmaceutically acceptable salt thereof is used.

Preferred prostaglandin I _{2 of the} present invention
Specific examples of the derivative, beraprost represented by the following formula or a salt thereof,

[0016]

Embedded image Iloprost, Clinprost, Ataprost, Cyprosten, Naxaprosten, Taprosten, Cicaprost, Pimilprost, CH-169, CS570, SM
-10902 and the like, but not particularly limited thereto.

The prostanoic acid derivative of the present invention can be produced by a known method. For example, the compound represented by the general formula (I) can be produced by the method described in Japanese Patent Publication No. 1-53672. can do.

The nervous system constituent cells in the present invention include nerve cells in the brain, glial cells such as oligodendrocytes, astrocytes, microglia, ependymal cells, neurosecretory cells, and nerve cells and Schwann cells in the peripheral nerve. Including mantle cells and paraneurons, the hepatocyte growth factor attractant of the present invention is effective for these cells, and is particularly effective for glial cells and nerve cells.

The prostanoic acid derivative of the present invention has an excellent hepatocyte growth factor-inducing ability, is effective as an excellent preventive or therapeutic agent for central and peripheral neuropathy, and further has an effect on the nerve fiber to the relevant site. It is also an effective agent for promoting extension. Specifically, it is effective as an excellent preventive or therapeutic agent for central and peripheral neuropathy caused by cerebrovascular disorder, cerebral nerve cell disorder, ischemic encephalopathy, dementia, diabetes, etc. It can also be used as an effective prophylactic or therapeutic agent for nerve damage due to trauma such as an accident, promotion of nerve fiber extension to the site in transplantation surgery, and the like.

The prostanoic acid derivative of the present invention has a remarkable ability to attract hepatocyte growth factor when administered orally or parenterally. In the present invention, the dose of the prostanoic acid derivative is 0.01 to 100 mg / adult for an adult.
Humans are administered 1-3 times daily.

As the hepatocyte growth factor attractant of the present invention, one or several prostanoic acid derivatives or salts thereof may be used as they are, but tablets, dragees, powders, granules, troches, capsules, pills Orally administered as a pharmaceutical composition in a commonly used dosage form such as a syrup.
Such dosage forms are prepared using the following additives commonly used in the pharmaceutical field.

Examples of additives include excipients such as starches, lactose, sucrose, glucose, mannitol, calcium carbonate, calcium sulfate, etc .; binders such as starches, dextrin, gum arabic, tragacanth, methylcellulose, gelatin, polyvinyl Pyrrolidone, polyvinyl alcohol, etc .: Disintegrants, for example, starches, polyvinylpyrrolidone, crystalline cellulose, etc., lubricants, for example, magnesium stearate, talc, etc .: coloring agents, fragrances and the like.

The hepatocyte growth factor attractant of the present invention can be applied to a wide range of parenteral administration methods such as various injections and suppositories, in addition to the oral preparations described above. The injection is prepared by dissolving, suspending, or emulsifying the prostanoic acid derivative or a salt thereof used in the present invention in a sterile aqueous or oily liquid commonly used for injections. Aqueous liquids to be used include water for injection, physiological saline, glucose solution, etc., and oily liquids include sesame oil, soybean oil, etc., and dissolution aids, suspending agents, isotonic agents, buffers, respectively. , A preservative, a soothing agent and the like may be used in combination. The suppository is prepared by mixing the prostanoic acid derivative or a salt thereof used in the present invention with an ordinary suppository base and molding.

[0024]

EXAMPLES The present invention will be specifically described below with reference to examples. Hepatocyte growth factor inducing effect for Example 1 Culture Isolation microglial cells: using rat fetal-derived microglial cells, was examined hepatocyte growth factor inducing effect of prostaglandin E _2.

The cerebral cortex was aseptically removed from the 20-day-old embryon rat, and the cells were dispersed by treatment with papain and DNase, followed by planting in a 16 cm x 13 cm (uncoated) polystyrene flask for culture. For each fetus, flask 1 /
This is the ratio of two sheets. 10 until culture is confluent
The cells were cultured at 37 ° C. in air containing 5% carbon dioxide and saturated water vapor using a D-MEM culture solution containing inactivated fetal bovine serum. Hereinafter, the cultured cells were cultured under the same conditions as above, except as otherwise noted. Microglial cells were isolated by shaking, and seeded at a density of 600,000 cells / cm ^{2 on} a 6-well chamber slide or a 100 mm polystyrene dish for culture. After culturing for 24 hours, the reactivity to prostaglandin was examined. Incorporation of DiI-labeled acetyl into cultured cells and staining experiments using anti-CD11 antibody revealed that at this stage the microglia ratio was at least 99% of the total cells in culture, and anti-glial acidic fiber antibodies and , Anti-nerve specific enolase antibody, anti-OX-
No contamination of cells showing a positive result in the staining experiment using the 21 antibody was observed. The prostaglandin E ₂ used is 1 m
A solution dissolved in ethanol at a concentration of M was dispensed in 10 μl aliquots, stored at −20 ° C. until use, and all had been used within 2 minutes of opening at the latest.

1. By immunochemical methods, it is detected that the prostaglandin E ₂ induces hepatocyte growth factor in cultured microglia cells. To isolate microglial cells prepared on chamber slides were added prostaglandin E _2. Prostaglandin E ₂ was used, the dispensing liquid was diluted with D-MEM medium containing 10% fetal bovine serum was added to the cells at a concentration of 1 [mu] M. 0.1% as control group
Microglial cells treated with a D-MEM culture solution containing 10% ethanol and 10% fetal calf serum were used. After 8 hours and 16 hours, the cells were fixed with a 4% paraformaldehyde solution containing 1 M phosphate buffer, and finally diamino acid was added using an ABC (Avidin-Biotin Complex) method using an anti-hepatocyte growth factor antibody. Color was developed with benzine. As a result, while the control group was observed at all reactions, the prostaglandin E ₂ dose group, all cells are uniformly stained.

2. Western blotting shows that prostaglandin E ₂ induces hepatocyte growth factor in cultured microglial cells, and that the amount of hepatocyte growth factor in the cells is maximized 16 hours after the start of prostaglandin E ₂ treatment. Was detected. To isolate microglial cells adjusted on 100mm culture dishes, it was added prostaglandin E _2. Prostaglandin E ₂ was used, the dispensing liquid was diluted with D-MEM medium containing 10% fetal bovine serum, 1 [mu] M
At a concentration of. After 8, 16, and 24 hours, the cells were scraped, collected by centrifugation, electrophoresed on a 15% polyacrylamide gel, and the separated proteins were transferred to a nitrocellulose membrane. Using an anti-hepatocyte growth factor antibody, a signal finally emitted by the enhanced chemiluminescense (ECL) method was exposed to an X-ray film. Signal strength was image analyzed on a Macintosh computer using NIH-image 1.57. The result of quantifying the signal intensity in each group is shown in FIG. Compared to non-treated group, when cultured in ₂ coexistence prostaglandin E, 4.5-fold after 8 hours showed 12 times higher hepatocyte growth factor production after 16 hours.

Example 2 Hepatocyte growth factor-inducing effect of isolated microglial cells in culture:
The effect of prostaglandin I2 derivative, beraprost, on the induction of hepatocyte growth factor was examined using microglial cells derived from rat fetuses.

The cerebral cortex was aseptically removed from the 20-day-old rat, and the cells were dispersed by treatment with papain and DNase, followed by planting in a 16 cm × 13 cm (uncoated) polystyrene flask for culture. For each fetus, flask 1 /
This is the ratio of two sheets. 10 until culture is confluent
37% using D-MEM containing inactivated fetal bovine serum.
The cells were cultured at 5 ° C. in air containing 5% carbon dioxide and saturated steam. Hereinafter, the cultured cells after isolation were cultured using serum-free D-MEM under the same conditions except as otherwise specified. Isolation of microglia is performed by shaking and 20 to 300,000 cells / c
The cells were planted in uncoated 48-well multiwell plates (Iwaki) made of polystyrene at a density of m2. After culturing for 24 hours, the reactivity to beraprost was examined. Uptake of DiI-labeled acetyl into cultured cells and anti-C
According to the staining experiment using the D11 antibody, at this stage, the ratio of microglia to all cells in the culture was 99% or more, and anti-glia acidic fiber antibody, anti-nerve specific enolase antibody, and anti-OX-21 antibody were used. No contamination of cells showing a positive result in the staining experiment used was observed.

The used prostaglandin I2 derivative, beraprost, was previously dissolved in distilled water at a concentration of 10 mM (similar to mol / litter) and stored at −20 ° C.
PG by ELIZA kit for rat HGF (Special Immune Research Institute)
It was detected that the I2 derivative beraprost induced HGF in cultured microglia. Beraprost was added to the isolated microglial cells prepared on an uncoated 48-well multiwell plate (Iwaki). The used beraprost was diluted in serum-free D-MEM and added to cells at a concentration of 1 μM and 10 μM. After 22 hours, the HGF in the culture supernatant was
It was measured using a ZA kit.

As a result, when culturing in the coexistence of beraprost with respect to the solvent-added group, the 1 μM coexisting group was 2.6 times as large.
The 10 μM coexisting group showed 3-fold higher HGF production.

[0032]

EFFECTS OF THE INVENTION The hepatocyte growth factor-inducing agent of the present invention has an excellent hepatocyte growth factor-attracting effect on cells constituting the nervous system, whether orally or parenterally administered. It is effective as an excellent preventive or therapeutic agent for central and peripheral neuropathy caused by cell damage, ischemic encephalopathy, dementia, diabetes, etc., and furthermore, nerve damage due to trauma such as surgery or traffic accident, transplant surgery It is also an effective agent for promoting the extension of nerve fibers to the site in the above.

Claims (7)

[Claims] (1) A hepatocyte growth factor attractant, wherein the prostanoic acid derivative acts on cells constituting the nervous system. 2. The hepatocyte growth factor attractant according to claim 1, wherein the prostanoic acid derivative is a prostaglandin A, B, C, D, E, F, G, H, I or J derivative. 3. The hepatocyte growth factor attractant according to claim _{2, wherein the} prostaglandin I derivative is a prostaglandin I ₂ derivative. 4. A prostaglandin I ₂ derivative represented by the following general formula (I): Wherein R ¹ is (A) COOR ² where R ² is 1) hydrogen or a pharmacologically acceptable cation, 2) linear alkyl having 1 to 12 carbons or 3 to 1 carbons.
4) branched alkyl of 3) -ZR ³ wherein Z is a valence bond or a linear or branched alkylene represented by C _t H _2t , t is an integer of 1 to 6, and R ³ is carbon A cycloalkyl of the formulas 3 to 12 or R ⁴
Wherein R ⁴ is hydrogen or alkyl having 1 to 5 carbon atoms, 4) — (CH ₂ CH ₂ O) _n CH _3, wherein n is an integer of 1 to 5, 5) -Z-Ar ^1, wherein Z is the same as defined above, and Ar ¹ is phenyl, α-naphthyl, β-naphthyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, α-furyl, β-furyl, α-thienyl, β-thienyl or substituted phenyl wherein the substituent is at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, Alkyl, nitro, cyano, methoxy, phenyl, phenoxy, p-acetamidobenzamide, -CH = N-NH-C (= O) -NH
₂ , -NH-C (= O) -Ph, -NH-C (= O)-
CH ₃ or -NH-C (= O) as a _{-NH 2), 6) -C t} H 2t COOR 4 wherein C _t H _2t, R ⁴ is as defined above, 7) -C _t H _2t N (R ⁴ ) ₂ where C _t H _2t and R ⁴ are the same as defined above; 8) —CH (R ⁵ ) —C (＝ O) —R ⁶ where R ⁵ is hydrogen or benzoyl, and R ⁶ is Phenyl,
p- bromophenyl, p- chlorophenyl, p- biphenyl, p- nitrophenyl, p- benzamide phenyl, _{2-naphthyl, 9) -C P H 2P -W} -R 7 wherein, W is -CH = CH-, —CH ＝ CR ⁷ — or —C 3 C—, and R ⁷ is hydrogen or a carbon number 1 to
30 is a linear or branched alkyl or aralkyl, p is an integer of 1 to 5, or 10) —CH (CH ₂ OR ⁸ ) ₂ where R ⁸ is alkyl or acyl having 1 to 30 carbon atoms; ) —CH ₂ OH (C) —C (＝ O) N (R ⁹ ) ₂ where R ⁹ is hydrogen, straight-chain alkyl having 1 to 12 carbons, branched alkyl having 3 to 12 carbons, and 3 to 12 carbons. 12 cycloalkyl, cycloalkylalkylene having 4 to 13 carbon atoms, phenyl, substituted phenyl (the substituent is the same as in the case of the above (A) 5), aralkyl having 7 to 12 carbon atoms or -SO ₂ R ¹⁰ Wherein R ¹⁰ has 1 to ¹⁰ carbon atoms
Alkyl, cycloalkyl having 3 to 12 carbons, phenyl, substituted phenyl (substituents are as defined in the above (A) 5), and aralkyl having 7 to 12 carbons.
R ⁹ may be the same or different, but one is -S
When R ₂ represents O ₂ R ¹⁰ , the other R ⁹ is not —SO ₂ R ¹⁰ , or (D) is —CH ₂ OTHP (THP is a tetrahydropyranyl group), and A is 1) — _{(CH 2) m - 2)} -CH = CH-CH 2 - 3) -CH 2 -CH = CH- 4) -CH 2 -O-CH 2 - 5) -CH = CH- 6) -O-CH ₂ or 7) -C3C-, wherein m represents an integer of 1 to 3, Y is hydrogen, alkyl having 1 to 4 carbons, chlorine, bromine, fluorine, formyl,
Methoxy or nitro, and B is —X—C (R ¹¹ ) (R ¹² ) OR ^13, wherein R ¹¹ is hydrogen or alkyl having 1 to 4 carbons, R ¹³ is hydrogen, 1 carbons ~ 14 acyl, 6 carbon atoms
15 aroyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl or t- butyl, X _{is, 1) -CH 2 -CH 2 -} 2) -CH = CH- 3) -C three C- in R ¹² is: 1) straight-chain alkyl having 1 to 12 carbons, branched alkyl having 3 to 14 carbons, or 2) -Z-Ar ² where Z is the same as defined above, Ar ² is phenyl, α -Naphthyl, β-naphthyl, or at least one chlorine,
Bromine, fluorine, iodine, trifluoromethyl, carbon number 1
To 4 alkyl, represents nitro, cyano, methoxy, phenyl or phenoxy substituted phenyl, _{or, 3) -C t H 2t OR} 14 wherein C _t H _2t is as defined above, R ¹⁴ is 1 to carbon atoms 6
Linear alkyl, branched alkyl having 3 to 6 carbon atoms, phenyl, at least one chlorine, bromine, fluorine, iodine, trifluoromethyl, alkyl having 1 to 4 carbon atoms, nitro,
Represents cyano, methoxy, phenyl or phenoxy-substituted phenyl, cyclopentyl, cyclohexyl, or cyclopentyl or cyclohexyl substituted with 1 to 4 straight-chain alkyl having 1 to 4 carbon atoms, or 4) -ZR ³ Wherein Z and R ³ are the same as defined above, or 5) —C _t H _2t —CH ＝ C (R ¹⁵ ) R ¹⁶ where C _t H _2t is the same as defined above, and R ¹⁵ and R ¹⁶ are hydrogen ,
Methyl, ethyl, propyl or represents a butyl, or, 6) -C _u H _2u -C three C-R ¹⁷ wherein u is an integer of 1-7, the C _u H _2u is straight or branched alkylene R ¹⁷ represents a straight-chain alkyl having 1 to 6 carbons, E represents hydrogen or —OR ^18, wherein R ¹⁸ represents an acyl having 1 to 12 carbons and 7 to 15 carbons
Aroyl or R ² (where R ² is the same as defined above)
And the general formula represents d-form, l-form or dl-form]
Hepatocyte growth factor attractant according to claim 3, wherein 4,8-a inter -m- phenylene prostaglandin I ₂ derivative or a pharmacologically acceptable salt thereof represented in. 5. A prostaglandin I ₂ derivative comprising beraprost, ataprost, iloprost, clinprost, cyprosten, naxaprosten, taprosten, cicaprost, pimiprost, CH-169, CS570,
The hepatocyte growth factor attractant according to claim 3, which is SM10902 or a salt thereof. 6. The hepatocyte growth factor attractant according to claim 1, wherein the nervous system constituent cells are glial cells or nerve cells. 7. The hepatocyte growth factor attractant according to claim 1, wherein the disease is central or peripheral neuropathy.