JPH072655A - Agent for repairing or protecting denaturation of peripheral nerve - Google Patents

Abstract

PURPOSE:To provide the subject protecting agent containing a specified biphenyl derivative as the active component, capable of scavenging active oxygen species and useful, e.g. for improvement of traumatic neuropathy, diabetic neuropathy, etc. CONSTITUTION:The objective protecting agent contains, e.g. a biphenyl derivative represented by the formula [R<1> is H, a lower alkyl, a lower alkenyl, etc.; R<2> is a hydroxyl group, a lower alkanoyloxy, a (substituted) alkoxy, etc.; R<3> is hydroxyl group, a lower alkoxy, H, a (substituted) alkyl, etc.; R<4> is H, a (substituted) lower alkyl, a lower alkoxy, phenyl, etc.; R<5> is H, hydroxyl group, a lower alkyl group, etc.; R<6> is hydroxyl group, a lower alkenyloxy, etc.; RC is H or a lower alkyl] as the active component. In addition, this active component is administrated preferably in an amount of 0.2 to 200 mg/day kg weight.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a peripheral nerve cell degeneration repairing or protecting agent.

[0002]

DISCLOSURE OF THE INVENTION The peripheral nerve cell degeneration repairing or protecting agent of the present invention has the general formula (1):

[0003]

[Chemical 12]

[In the formula, R ¹ is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a phenyl group which may have a hydroxyl group, a lower alkyl group or a lower alkenyl group as a substituent on the phenyl ring, a cycloalkenyl group, a halogen. An atom or a lower alkanoyl group is shown. R ² is a hydroxyl group,
A lower alkanoyloxy group, a lower alkenyloxy group or a lower alkoxy group as a substituent, a tetrahydropyranyloxy group or an alkoxy group which may have a hydroxyl group is shown. R ³ has a hydroxyl group, a lower alkoxy group, a hydrogen atom, a lower alkoxy group as a substituent or a lower alkyl group which may have a hydroxyl group, a lower alkenyl group, a cycloalkenyl group, a phenyl group, a halogen atom, and a halogen atom as a substituent. A lower alkanoyl group, a thiazolyl group which may have a lower alkyl group as a substituent, a group -A-NR ⁷ R ⁸ (wherein A represents a lower alkylene group, R ⁷ and R ⁸ are the same or different) Represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group, and R ⁷ and R ⁸ together with the nitrogen atom to which they are bonded are a saturated 5- or 6-membered ring with or without a nitrogen atom or an oxygen atom. Or, it may form an unsaturated heterocycle, in which the amide group which may have a lower alkyl group as a substituent or An oxo group may be present) or a group -A-N ⁺ ( ^R7a ) ( ^R7b ) (R
^7c ) (R ^7a , R ^7b and R ^7c each represent a lower alkyl group, and A represents a lower alkylene group). R ⁴ is a hydrogen atom, a lower alkyl group which may have a hydroxyl group or a lower alkoxy group as a substituent, a lower alkoxy group,
Phenyl group, phenyl lower alkyl group, phenoxy group,
A lower alkenyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a halogen atom, a lower alkoxy lower alkyl group or a lower alkanoyl group is shown. R ⁵ may have a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkenyl group, a cycloalkenyl group, an amino lower alkyl group which may have a lower alkyl group as a substituent, and a halogen atom as a substituent. A lower alkanoyl group or a thiazolyl group which may have a lower alkyl group as a substituent is shown. R ⁶ is a hydroxyl group, a lower alkenyloxy group, a lower alkanoyloxy group or a lower alkoxy group as a substituent,
A tetrahydropyranyloxy group or an alkoxy group which may have a hydroxyl group is shown. R ^C represents a hydrogen atom or a lower alkyl group. ] A biphenyl derivative represented by the general formula (2)

[0005]

[Chemical 13]

[Wherein R ¹⁶ is a hydroxyl group, a lower alkenyloxy group, a cycloalkenyloxy group, a lower alkoxy group as a substituent, a tetrahydropyranyloxy group, a halogen atom, a lower alkanoyloxy group, a carboxy group, a hydroxyl group or a group -NR ¹⁰ R ¹³ (wherein R ¹⁰ and R ¹³ are the same or different and each represent a hydrogen atom, a lower alkyl group or a lower alkanoyl group. Further, R ¹⁰ and R ¹³ are bonded to each other via a nitrogen atom to which they are bonded. Or a 6-membered heterocycle may be formed), a lower alkylthio group, a lower alkoxycarbonyl group, a phenylthio group which may have a hydroxyl group or a lower alkyl group as a substituent on the phenyl ring, or a phthalimido group. Alkoxy group with

[0007]

[Chemical 14]

Alternatively,

[0009]

[Chemical 15]

(Wherein R ²⁰ represents a lower alkanoyloxy group). R ⁹ represents a lower alkenyl group. R ¹¹
Represents a hydrogen atom, a cycloalkenyl group or a lower alkenyl group, and R ¹² represents a hydroxyl group, a lower alkenyloxy group, a cycloalkenyloxy group or a lower alkanoyloxy group. R ¹² and R ¹⁶ may be bonded to each other to represent a lower alkylenedioxy group. R ¹⁷ is a hydrogen atom, a cycloalkenyl group, a lower alkenyl group or a group

[0011]

[Chemical 16]

Is shown. R ¹⁹ represents a lower alkenyl group.
However, R ¹⁷ is

[0013]

[Chemical 17]

R ¹² and R ¹⁶ are hydroxyl groups, R ¹¹
Is a hydrogen atom, and R ¹⁹ and R ⁹ are allyl groups. R ¹⁶ is based on

[0015]

[Chemical 18]

R ⁹ and R ¹⁹ are allyl groups and R
¹² is a hydroxyl group, and R ¹¹ and R ¹⁷ are hydrogen atoms. Furthermore, based on R ¹⁶

[0017]

[Chemical 19]

R ⁹ and R ¹⁹ are allyl groups and R
¹² is a lower alkanoyloxy group, and R ¹¹ and R ¹⁷ are hydrogen atoms. ] The compound represented by the general formula (3)

[0019]

[Chemical 20]

[In the formula, R ⁹ represents a hydrogen atom or a lower alkenyl group. R ¹⁴ represents a lower alkenyloxy group or a hydroxyl group. R ¹⁵ represents a hydrogen atom or a lower alkenyl group. R
^A represents a hydrogen atom or a lower alkenyl group. ] The compound represented by the general formula (4)

[0021]

[Chemical 21]

[In the formula, R ⁹ represents a hydrogen atom or a lower alkenyl group. R ¹⁸ represents a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower alkenyl group. R ²¹ and R ²⁴ represent a hydrogen atom or a lower alkenyl group. R ²² represents a hydrogen atom, a lower alkenyloxy group, a hydroxyl group or a lower alkenyl group. R ²³ represents a hydrogen atom, a lower alkenyl group, a lower alkenyloxy group or a hydroxyl group. R ^B represents a hydrogen atom, a lower alkyl group or a lower alkenyl group. However, R ²² and R ²³ must not be hydroxyl groups at the same time. R ^D represents a hydrogen atom or a lower alkyl group. ] The compound represented by
General formula (5)

[0023]

[Chemical formula 22]

[In the formula, R ^E , R ^F and R ^I each represent a lower alkyl group. R ^G and R ^H each represent a lower alkoxy group. ] It contains at least one selected from the group consisting of phenyl derivatives represented by the following and salts thereof as an active ingredient.

The compounds of the above-mentioned general formulas (1) to (5) and their production methods have already been described in JP-A-4-154737, and these compounds are useful as nerve cell degeneration repairing agents or protective agents. It is also known.

Nerve tissues are roughly classified into peripheral nerves and central nerves. When comparing the two from the viewpoint of nerve regeneration,
There is a big difference in the reproduction ability itself (Int. Rev. Bio
l. , 6,257-301, 1964), presence or absence of basement membrane (Brain Res., 288, 61-75, 198).
8), Differences between oligodendroglial and Schwann cell products (J. Neurosci., 8, 2381-23)
93, 1988, Trends Neurosci. ，
12, 1-3, 1989), etc., there are differences in the constituent tissues and produced substances involved in regeneration.

Compounds having a degenerative repairing action on both peripheral nerves and central nerves are known only for some biological factors such as NGF (nerve growth factor) and GM ₁ (ganglioside), and have been established as therapeutic agents. The current situation is that there are none.

The inventors of the present invention have conducted various studies to develop a peripheral nerve degeneration repairing agent.
It was found that the phenyl derivative represented by (5) or a salt thereof is useful as a peripheral nerve degeneration repairing or protecting agent, and the present invention has been completed here.

It has also been found that the phenyl derivatives represented by the above general formulas (1) to (5) or salts thereof further have an antioxidant action and are useful as an antioxidant.

The phenyl derivatives represented by the above general formulas (1) to (5) or salts thereof have a peripheral nerve degeneration repairing or protecting action and are useful as a peripheral nerve degeneration repairing or protecting agent, for example trauma. It is useful as an effective therapeutic drug for neuropathy caused by neuropathy, neuropathy caused by metabolic factors such as diabetic neuropathy, neuropathy caused by side effects of poisons or drugs, and peripheral neuropathy such as polyneuropathy.

For the living body, oxygen is indispensable for maintaining life such as energy production and metabolism. The oxygen becomes so-called active oxygen species such as oxygen anion radicals, peroxide ions and hydroxy radicals by the reaction in the energy production system, the oxygen reaction, the reaction by ultraviolet rays, the radiation and the like. The reactive oxygen species are useful for living organisms such as oxygenase and bactericidal action of leukocytes, but on the other hand, unsaturated substances that form phospholipids of biological membranes such as oleic acid, linoleic acid, linolenic acid and arachidonic acid which are abundant in living organisms. It promotes the peroxidation of fatty acids and forms lipid peroxides. This lipid peroxide causes generation of alkoxy radicals and hydroxy radicals like the above-mentioned active oxygen species, attacks biological membranes, and causes membrane damage and deactivation of various useful enzymes [Metabolism, 15 (10)]. , 1978 Special Feature Active Oxygen Reference]. However, there are enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, which are involved in the metabolic deactivation of the above reactive oxygen species in the living body, and α-tocopherol (vitamin E) and the like. There are various vitamins with antioxidative ability, and these actions normally maintain normal living body, but due to some reason, the appropriate defense mechanism by the above enzymes, vitamins, etc. is defective. Or, the generation of reactive oxygen species and the production and accumulation of lipid peroxides that exceed the capabilities of these defense mechanisms often occur. When such a defense mechanism deficiency occurs,
Serious disorders associated with peroxidative chain reaction, such as various diseases caused by platelet aggregation, inflammation, liver damage, arteriosclerosis,
Hemolysis, aging or senile dementia, retinopathy, lung disorder, cardiac and pulmonary disorders due to certain drugs, ischemic vascular disease and the like occur.

Compounds having the action of removing (scavenging) active oxygen species (radicals), which have been conventionally considered to be the main cause of various disorders, and preventing or reducing the production and accumulation of lipid peroxides in vivo, are generally Called an oxidizer,
In fact, many reports have been made on the preventive and therapeutic effects of the above-mentioned various diseases caused by its use. As the reported antioxidants, enzyme agents such as SOD described above [Superoxide and Medicine, Yoshihiko Oyanagi, 1981, Kyoritsu Publishing, 1
37-141] and butylhydroxytoluene (BH
T), butylhydroxyanisole (BHA), α-tocopherol (vitamin E), etc. [Mino Makoto, Tanaka Hidetaka, Pharmaceutical Journal, 19 (12), 1983, p2351.
2359 and Toshihiko Suematsu, Ibid., 19 (5), 198.
3 years, p909-914].

The compounds of the present invention scavenge reactive oxygen species,
It also has the effect of preventing or reducing the production of lipid peroxides in vivo.
Therefore, the compound of the present invention is used as a prophylactic and therapeutic agent for various disorders or diseases caused by excessive generation of reactive oxygen species, bioaccumulation of lipid peroxide, or lack of defense mechanism against these, for example, anti-arteriosclerotic agents, carcinogenic prevention. Agents, anti-inflammatory agents, analgesics, therapeutic agents for autoimmune diseases, platelet aggregation inhibitors, antihypertensive agents,
It is also useful as a drug such as a hyperlipidemic agent, a retinopathy of prematurity and a preventive and therapeutic agent for cataract. Furthermore, the compound of the present invention is effective not only as the above-mentioned pharmaceuticals but also as an antioxidant of fats and oils contained in processed foods and the like.

Among the phenyl derivatives represented by the above general formulas (1) to (5), the general formula is particularly preferable.

[0035]

[Chemical formula 23]

[Wherein R ^J is a hydrogen atom, a lower alkyl group,
A lower alkenyl group or a hydroxyl group is shown. R ^K represents a lower alkyl group. R ^L represents a hydrogen atom, a halogen atom or an imidazolyl lower alkyl group. R ^M represents a lower alkyl group or a lower alkenyl group. ] The compound represented by these is suitable.

More specifically, each group shown in the present specification is as follows.

As the lower alkyl group, for example, methyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl groups.

Examples of the lower alkenyl group include straight-chain or branched-chain alkenyl having 2 to 6 carbon atoms such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl and 2-hexenyl groups. A group can be mentioned.

The phenyl group which may have a hydroxyl group, a lower alkyl group or a lower alkenyl group as a substituent on the phenyl ring is, for example, phenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl or 4-vinyl. Phenyl, 3-allylphenyl,
2- (2-butenyl) phenyl, 4- (3-butenyl)
Phenyl, 3- (1-methylallyl) phenyl, 4-
(2-Pentenyl) phenyl, 2- (2-hexenyl)
Phenyl, 4-methylphenyl, 3-ethylphenyl,
2-propylphenyl, 4-n-butylphenyl, 3-
Pentylphenyl, 2-hexylphenyl, 2-hydroxy-3-allyl-5-ethylphenyl, 3,4,5-
Trimethylphenyl, 2,4,6-trihydroxyphenyl, 2,4-dihydroxyphenyl, 2,6-dimethylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl, 2-hydroxy-3-allylphenyl,
Hydroxyl group as a substituent on a phenyl ring such as 2-methyl-3-allylphenyl group, a linear or branched alkenyl group having 2 to 6 carbon atoms, or a linear or branched alkyl group having 1 to 6 carbon atoms A phenyl group which may have 1 to 3 groups can be exemplified.

As the halogen atom, for example, a fluorine atom,
Examples thereof include chlorine atom, bromine atom and iodine atom.

Examples of the lower alkanoyl group include straight-chain or branched-chain alkanoyl groups having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, tert-butylcarbonyl and hexanoyl groups.

Examples of the alkoxy group which may have a lower alkoxy group, a tetrahydropyranyloxy group or a hydroxyl group as a substituent include, for example, methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, hydroxymethoxy, 2-hydroxyethoxy, 1-hydroxyethoxy, 3-hydroxy. Propoxy, 4-hydroxybutoxy, 1,1-dimethyl-2-hydroxyethoxy, 5-
Hydroxypentyloxy, 6-hydroxyhexyloxy, 2-methyl-3-hydroxypropoxy, 7-hydroxyheptyloxy, 8-hydroxyoctyloxy, 9-hydroxynonyloxy, 10-hydroxydecyloxy, 11-hydroxyundecyloxy, 12
-Hydroxydodecyloxy, (2-tetrahydropyranyloxy) methoxy, 2- (3-tetrahydropyranyloxy) ethoxy, 1- (2-tetrahydropyranyloxy) ethoxy, 3- (3-tetrahydropyranyloxy) propoxy , 4- (2-tetrahydropyranyloxy) butoxy, 1,1-dimethyl-2- (4-tetrahydropyranyloxy) ethoxy, 5- (2-tetrahydropyranyloxy) pentyloxy, 6- (3-tetrahydro Pyranyloxy) hexyloxy, 2-methyl-3- (4-tetrahydropyranyloxy) propoxy, methoxymethoxy, 3-methoxypropoxy, 4-
Ethoxybutoxy, 6-propoxyhexyloxy, 5
-Isopropoxypentyloxy, 1,1-dimethyl-
2-butoxyethoxy, 2-methyl-3-tert-butoxypropoxy, 2-pentyloxyethoxy, hexyloxymethoxy group and the like, as a substituent, a linear or branched alkoxy group having 1 to 6 carbon atoms, tetrahydropyranyl 1 to 12 carbon atoms which may have an oxy group or a hydroxyl group
The straight chain or branched chain alkoxy group can be exemplified.

Examples of the cycloalkenyl group include cycloalkenyl groups having 3 to 8 carbon atoms such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl groups.

Examples of the lower alkylene group include methylene, ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, pentamethylene and hexamethylene. Number of carbon atoms such as 1
Examples of the straight-chain or branched-chain alkylene group of ~ 6 can be mentioned.

Examples of the amide group which may have a lower alkyl group include carbamoyl, methylamide, ethylamide, propylamide, isopropylamide, butylamide, tert-butylamide, pentylamide, hexylamide, dimethylamide, diethylamide, dipropylamide, Carbon number 1 such as dibutylamide, dipentylamide, dihexylamide, N-methyl-N-ethylamide, N-ethyl-N-propylamide, N-methyl-N-butylamide, N-methyl-N-hexylamide group
The amide group which may have 1-2 linear or branched alkyl groups of ~ 6 can be mentioned.

Examples of the 5- or 6-membered saturated or unsaturated heterocyclic group formed by R ⁷ and R ⁸ together with the nitrogen atom to which R ⁷ and R ⁸ are bound via a nitrogen atom or an oxygen atom are, for example, piperazinyl group and hyperidinyl group. Group, morpholino group, pyrrolidinyl group, imidazolyl group and the like.

Examples of the above-mentioned heterocyclic group substituted with an amide group which may have a lower alkyl group or an oxo group include 4-methylamido-1-piperazinyl, 4-ethylamido-1-piperidinyl and 2-dimethylamido-1-. Piperidinyl, 3-propylamidomorpholino, 3-tert
-Butylamido-1-piperidinyl, 3-pentylamido-1-pyrrolidinyl, 2-hexylamido-1-piperidinyl, 2-diethylamidomorpholino, 4-dipropylamido-1-piperidinyl, 2-dibutylamido-
1-pyrrolidinyl, 2-methylamido-1-pyrrolidinyl, 2-carbamoyl-1-pyrrolidinyl, 2-dipentylamido-1-pyrrolidinyl, 3-dihexylamido-1-pyrrolidinyl, 2- (N-ethyl-N-methylamido)- 1-pyrrolidinyl, 4- (N-ethyl-N-propylamido) -1-piperazinyl, 2-imidazolon-1-yl, 2-methylamido-1-imidazolyl, 2
1-2 linear or branched alkyl groups having 1 to 6 carbon atoms such as -oxo-1-pyrrolidinyl, 4-oxo-1-piperidinyl, 3-oxo-1-piperazinyl and 2-oxomorpholino groups Examples thereof include the above-mentioned heterocyclic groups substituted with an amide group or an oxo group.

Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. it can.

Examples of the phenyl lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl,
3-phenylpropyl, 4-phenylbutyl, 1,1-
Phenylalkyl in which the alkyl moiety such as dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, and 2-methyl-3-phenylpropyl group is a linear or branched alkyl group having 1 to 6 carbon atoms. A group can be mentioned.

Examples of the lower alkylthio group include linear or branched alkylthio groups having 1 to 6 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio and hexylthio groups.

Examples of the lower alkylsulfinyl group include straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms such as methylsulfinyl, ethylsulfinyl, isopropylsulfinyl, butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl and hexylsulfinyl groups. A sulfinyl group can be exemplified.

Examples of the lower alkylsulfonyl group include straight-chain or branched-chain alkyl having 1 to 6 carbon atoms such as methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl and hexylsulfonyl groups. A sulfonyl group can be exemplified.

The amino lower alkyl group which may have a lower alkyl group as a substituent is aminomethyl,
1-aminoethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl,
2-methyl-3-aminopropyl, methylaminomethyl, ethylaminomethyl, propylaminomethyl, isopropylaminomethyl, butylaminomethyl, tert-butylaminomethyl, pentylaminomethyl, hexylaminomethyl, dimethylaminomethyl, diethylaminomethyl, Dipropylaminomethyl, dibutylaminomethyl, dipentylaminomethyl, dihexylaminomethyl, N-methyl-N-ethylaminomethyl, N-ethyl-N-propylaminomethyl, N-methyl-N-butylaminomethyl, N-methyl -N-hexylaminomethyl, 2-methylaminoethyl, 1-ethylaminoethyl, 3-propylaminopropyl, 4-butylaminobutyl, 1,1-dimethyl-2-pentylaminoethyl,
5-hexylaminopentyl, 6-dimethylaminohexyl, 2-diethylaminoethyl, 1- (N-methyl-
N-hexylamino) ethyl, 3-dihexylaminopropyl, 4-dibutylaminobutyl, 2- (N-methyl-N-pentylamino) ethyl group or other straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms And a linear or branched alkyl group having 1 to 6 carbon atoms which has 1 to 2 amino groups as a substituent.

The cycloalkenyloxy group is, for example, a cycloalkenyloxy group having 3 to 8 carbon atoms such as cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy and cyclooctenyloxy groups. Can be mentioned.

The lower alkanoyloxy group includes, for example, formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy, and hexanoyloxy groups having 1 to 6 carbon atoms. Mention may be made of chain or branched alkanoyloxy groups.

The lower alkoxycarbonyl group is, for example, a straight chain having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl groups. Alternatively, a branched alkoxycarbonyl group can be exemplified.

As a substituent, a lower alkoxy group, a tetrahydropyranyloxy group, a halogen atom, a lower alkanoyloxy group, a carboxy group, a hydroxyl group, a group -NR ¹⁰ R ¹³ ,
A lower alkylthio group, a lower alkoxycarbonyl group, a phenylthio group which may have a hydroxyl group or a lower alkyl group as a substituent on the phenyl ring, or an alkoxy group which may have a phthalimido group include a lower alkoxy group as a substituent and a tetrahydro group. In addition to pyranyloxy or a lower alkoxy group which may have a hydroxyl group, aminomethoxy, 1-aminoethoxy, 2-
Aminoethoxy, 3-aminopropoxy, 4-aminobutoxy, 5-aminopentyloxy, 6-aminohexyloxy, 1,1-dimethyl-2-aminoethoxy, 2
-Methyl-3-aminopropoxy, methylaminomethoxy, ethylaminomethoxy, propylaminomethoxy,
Isopropylaminomethoxy, butylaminomethoxy,
tert-butylaminomethoxy, pentylaminomethoxy, hexylaminomethoxy, dimethylaminomethoxy, diethylaminomethoxy, dipropylaminomethoxy, dibutylaminomethoxy, dipentylaminomethoxy, dihexylaminomethoxy, N-methyl-N-ethylaminomethoxy, N- Ethyl-N-propylaminomethoxy, N-methyl-N-butylaminomethoxy, N-
Methyl-N-hexylaminomethoxy, 1-methylaminoethoxy, 2-ethylaminoethoxy, 3-propylaminopropoxy, 4-butylaminobutoxy, 1,1
-Dimethyl-2-pentylaminoethoxy, 5-hexylaminopentyloxy, 6-dimethylaminohexyloxy, 2-diethylaminoethoxy, 1- (N-methyl-N-hexylamino) ethoxy, 3-dihexylaminopropoxy, 4- Dibutylaminobutoxy, 2-
(N-methyl-N-pentylamino) ethoxy, formylaminomethoxy, acetylaminomethoxy, propionylaminomethoxy, butyrylaminomethoxy, isobutyrylaminomethoxy, pentanoylaminomethoxy,
tert-Butylcarbonylaminomethoxy, hexanoylaminomethoxy, 2-acetylaminoethoxy, 1-formylaminoethoxy, 3-acetylaminopropoxy, 4-butyrylaminobutoxy, 5-hexanoylaminopentyloxy, 6-pentanonoramino Hexyloxy, 2- (N-ethyl-N-acetylamino) ethoxy, 3- (N-methyl-N-acetylamino) propoxy, methylthiomethoxy, 2-methylthioethoxy, 1
-Ethylthioethoxy, 3-propylthiopropoxy,
4-isopropylthiobutoxy, 5-butylthiopentyloxy, 6-pentylthiohexyloxy, 1,1-
Dimethyl-2-hexylthioethoxy, 2-methyl-3
-Methylthiopropoxy, methoxycarbonylmethoxy, 2-ethoxycarbonylethoxy, 1-propoxycarbonylethoxy, 3-isopropoxycarbonylpropoxy, 4-butoxycarbonylbutoxy, 5-pentyloxycarbonylpentoxy, 6-hexyloxycarbonylhexyloxy, 4 -Ethoxycarbonylethoxy, phthalimidomethoxy, 2-phthalimidoethoxy, 1-phthalimidoethoxy, 3-phthalimidopropoxy, 4-phthalimidobutoxy, 5-phthalimidopentyloxy, 6-phthalimidohexyloxy group, fluorinated methoxy, 2-chloroethoxy, 6-Bromohexyloxy, 3-propoxy iodide, 1-chloroethoxy, 4-bromobutoxy, 5-pentyloxy iodide, 6-acetyloxy Hexyloxy, propionyloxymethoxy, 2-butyryloxyethoxy, 1-pentanoyloxyethoxy, 3-hexanoyloxypropoxy, 4-acetyloxybutoxy, 5-acetyloxypentyloxy, carboxymethoxy, 1-carboxyethoxy, 2 -Carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy,
6- (1-pyrrolidinyl) hexyloxy, 6- (1-
Imidazolyl) hexyloxy, 6- (3,5-di-t
-Butyl-4-hydroxyphenylthio) hexyloxy, (1-piperazinyl) methoxy, 2- (1-piperidinyl) ethoxy, 3-morpholinopropoxy, 4-
(1-pyrrolidinyl) butoxy, 5- (1-imidazolyl) pentyloxy, phenylthiomethoxy, 2- (4
-Methylphenylthio) ethoxy, 1- (2-hydroxyphenylthio) ethoxy, 3- (2,4-dihydroxyphenylthio) propoxy, 4- (2,6-dimethylphenylthio) butoxy, 5- (2-hydroxy -3-
a linear or branched alkoxy group having 1 to 6 carbon atoms, a tetrahydropyranyloxy group, a halogen atom, a linear or branched chain having 1 to 6 carbon atoms as a substituent such as t-butylphenylthio) pentyloxy group. Chain alkanoyloxy group, carboxyl group, hydroxyl group, group -NR ¹⁰ R ¹³ (R ¹⁰ and R ¹³ are the same or different, and are a hydrogen atom and a carbon number of 1 to 6).
Is a straight chain or branched chain alkyl group or a straight chain or branched chain alkanoyl group having 1 to 6 carbon atoms. Further, R ¹⁰ and R ¹³ are 5
Alternatively, a 6-membered heterocycle may be formed. ), Carbon number 1
6 straight-chain or branched-chain alkylthio groups, 1 to 1 carbon atoms
6 having a linear or branched alkoxycarbonyl group, a phenylthio group or a phthalimido group which may have a hydroxyl group or a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the phenyl ring A linear or branched alkoxy group having 1 to 6 carbon atoms can be exemplified.

Examples of the lower alkenyloxy group include vinyloxy, allyloxy, 2-butenyloxy, 3
-Butenyloxy, 1-methylallyloxy, 2-pentenyloxy, 2-hexenyloxy and the like having 2 to 2 carbon atoms
Mention may be made of straight-chain or branched alkenyloxy groups of 6.

Examples of the 5- or 6-membered heterocyclic group formed through the nitrogen atom to which R ¹⁰ and R ¹³ are bonded include a piperazinyl group, a piperidinyl group, a morpholino group, a pyrrolidinyl group and an imidazolyl group.

The phenylthio group which may have a hydroxyl group or a lower alkyl group as a substituent on the phenyl ring includes, for example, phenylthio, 2-hydroxyphenylthio, 3-hydroxyphenylthio, 4-hydroxyphenylthio and 4-methylphenyl. Thio, 3-ethylphenylthio, 2-propylphenylthio, 4-n-butylphenylthio, 3-pentylphenylthio, 2-hexylphenylthio, 4-hydroxy-3,5-di-t-butylphenylthio, Hydroxyl group or carbon as a substituent on the phenyl ring such as 3,4,5-trimethylphenylthio, 2,4-dihydroxyphenylthio, 2,6-dimethylphenylthio, 2-hydroxy-3-t-butylphenylthio group. 1 to 6 straight or branched chain alkyl groups
Examples thereof include phenylthio groups which may have 3 to 3.

Examples of the lower alkyl group which may have a lower alkoxy group or a hydroxyl group as a substituent include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl and 4- in addition to the above lower alkyl group. Hydroxybutyl, 1,1-dimethyl-
2-hydroxyethyl, 5-hydroxypentyl, 6-
Hydroxyhexyl, 2-methyl-3-hydroxypropyl, methoxymethyl, 1-ethoxyethyl, ethoxymethyl, 3-methoxypropyl, 4-ethoxybutyl,
Number of carbon atoms as a substituent such as 6-propoxyhexyl, 5-isopropoxypentyl, 1,1-dimethyl-2-butoxyethyl, 2-methyl-3-tert-butoxypropyl, 2-pentyloxyethyl, hexyloxymethyl group A straight-chain or branched-chain alkoxy group having 1 to 6 or a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms which may have a hydroxyl group can be exemplified.

Examples of the lower alkanoyl group which may have a halogen atom as a substituent include, for example, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl and 2-chloro in addition to the above lower alkanoyl group. Acetyl, 2-bromoacetyl, 2-fluoroacetyl, 2
-Iodoacetyl, 2,2-difluoroacetyl, 2,
2-dibromoacetyl, 3,3,3-trifluoropropionyl, 3,3,3-trichloropropionyl, 3-
Chloropropionyl, 2,3-dichloropropionyl,
As a substituent such as 4,4,4-trichlorobutyryl, 4-fluorobutyryl, 5-chloropentanoyl, 3-chloro-2-methylpropionyl, 6-bromohexanoyl, 5,6-dibromohexanoyl group 1 halogen atom
The straight-chain or branched-chain alkanoyl group having 1 to 6 carbon atoms which may have 3 to 3 can be mentioned.

Examples of the thiazolyl group which may have a lower alkyl group as a substituent include thiazolyl, 2-
Linear or branched chain having 1 to 6 carbon atoms as a substituent such as methylthiazolyl, 4-ethylthiazolyl, 5-propylthiazolyl, 2-n-butylthiazolyl, 4-pentylthiazolyl, 5-hexylthiazolyl group The thiazolyl group which may have a linear alkyl group can be mentioned.

Examples of the imidazolyl lower alkyl group include (1-imidazolyl) methyl, 2- (1-imidazolyl) ethyl, 1- (2-imidazolyl) ethyl, 3-
(4-Imidazolyl) propyl, 4- (1-imidazolyl) butyl, 1,1-dimethyl-2- (1-imidazolyl) ethyl, 5- (2-imidazolyl) pentyl, 6-
(4-Imidazolyl) hexyl, 2-methyl-3- (1
Examples thereof include an imidazolylalkyl group in which an alkyl moiety such as -imidazolyl) propyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.

The compounds of the present invention naturally include stereoisomers and optical isomers.

The phenyl derivatives represented by the general formulas (1) to (5) of the present invention can be easily converted into an acid addition salt by reacting with a pharmaceutically acceptable acid. It also includes addition salts. In the above, as the acid, for example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, malonic acid, methane Organic acids such as sulfonic acid and benzoic acid can be mentioned.

Among the biphenyl derivatives represented by the general formulas (1) to (5) of the present invention, the compound having an acidic group can easily form a salt by reacting with a pharmaceutically acceptable basic compound. You can Examples of the basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

Among the phenyl derivatives represented by the general formulas (1) to (5) of the present invention, the compound having an ammonium group is a pharmaceutically acceptable halogen anion (chlorine anion, bromine anion, fluorine anion). , Iodine anion)
And a salt can be easily formed.

The compounds of the present invention are usually used in the form of general pharmaceutical preparations. The preparation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. As this pharmaceutical preparation, various forms can be selected according to the therapeutic purpose,
Typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions,
Suspensions, etc.), ointments and the like. In the case of molding in the form of tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride,
Excipients such as glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate , Binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose , White sugar,
Disintegration inhibitors such as stearin, cocoa butter, hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Adsorbents, purified talc, stearates, boric acid powders, lubricants such as polyethylene glycol, etc. can be used. In addition, tablets are tablets with a normal coating, if necessary,
For example, a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multi-layer tablet can be used. When molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, Examples thereof include tragacanth powder, gelatin, a binder such as ethanol, a disintegrating agent such as laminaranthanthene, and the like. In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. When prepared as an injection, the solution, emulsion and suspension are preferably sterilized and isotonic with blood.
When formulating in the form of emulsions and suspensions, all those conventionally used in this field as diluents can be used, such as water, aqueous lactic acid solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoform. Stearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of sodium chloride, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. You may. Further, if necessary, a coloring agent, a preservative, a flavoring agent, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained in the pharmaceutical preparation. In the case of formulation in the form of paste, cream and gel, those conventionally known in this field can be widely used as the diluent, for example, white petrolatum, paraffin, glycerin, cellulose derivative, polyethylene glycol, silicone, bentonite and the like can be used.

The amount of the compound of the general formulas (1) to (5) of the present invention or a salt thereof to be contained in a pharmaceutical preparation is not particularly limited and may be appropriately selected within a wide range.
It is preferable to set the content to 70% by weight.

The administration method of the above-mentioned pharmaceutical preparation is not particularly limited, and it is administered according to various dosage forms, age, sex and other conditions of patients, degree of disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. Further, in the case of an injection, it is administered alone or mixed with an ordinary replenisher such as glucose and amino acid, and then intravenously administered, and if necessary, it is intramuscularly, intradermally, subcutaneously or intraperitoneally administered. Suppositories are administered rectally.

The dose of the above-mentioned pharmaceutical preparation is appropriately selected according to the usage, the age of the patient, the sex and other conditions, the degree of the disease, etc., but the dose of the compound of the general formula (1) to (5) which is an active ingredient is usually selected. The amount is about 0.2 to 200 m per 1 kg of body weight per day.
It is preferable to set it to about g.

[0074]

[Examples] Formulation examples and pharmacological test results are listed below.

Formulation Example 1 3,3'-Diallyl-2,4'-biphenyldiol 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets of the above composition were prepared in one tablet by a conventional method.

Formulation Example 2 3,3'-Diallyl-5-ethyl-5'-fluor-2,4'-biphenyldiol 150 mg Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g Corn starch 30 g Magnesium stearate 2 g Hydroxy Propyl methyl cellulose 10 g Polyethylene glycol-6000 3 g Castor oil 40 g Methanol 40 g The compound of the present invention, Avicel, corn starch and magnesium stearate are mixed and polished, and then tableted with a sugar coated R10 mm kine. The obtained tablets are coated with a film coating agent consisting of hydroxypropylmethyl cellulose, polyethylene glycol-6000, castor oil and methanol to produce film coated tablets.

Pharmacological test 1 (measurement of axon outgrowth in mouse dorsal root ganglion cell primary culture system) Cell adjustment was performed by Horie et al. [H. Horie. , FEB
S, 296, 23 (1990)]. That is, C5
7BL / 6 mice, male, 10-15 weeks old were used. Under ether anesthesia, exsanguination was performed and the spinal column from the cervical vertebra to the sacral vertebra was removed. Furthermore, in the F12 medium (flow) of ham, the capsule of the dorsal root ganglion after cutting the anterior root and the dorsal root was peeled off, and 37% with 0.25% collagenase (Worthington).
It was treated at 90 ° C. for 90 minutes. It was replaced with Hank's physiological buffer solution containing no calcium or magnesium, and treated with 0.25% trypsin (flow) at room temperature for 20 minutes. 100 μg / ml of trypsin inhibitor (Sigma) was added to stop the enzymatic reaction, and trituration was performed about 20 times with a tapered Pasteur pipette. Again, the medium was replaced with Ham's F12 medium and passed through a 150 μm nylon mesh to remove unseparated cell aggregates. N1 additive [Bottenstei
n, J. E. , Exp. Cell. Res. , 125,
183 (1980)] in Ham's F12 medium (60 μg / ml kanamycin added).

The culture was carried out at 37 ° C. for 3 hours at 10 μg / ml.
Laminin (Funakoshi) -coated polylysine-coated cell discs were placed in a 20-well dish and seeded with 5,000 to 10,000 nerve cells per dish. The test compound was dissolved in dimethylsulfoxide at a concentration of 0.01 mol / l, diluted with phosphate buffer, and added to the culture medium according to the final concentration. It was cultured at 37 ° C. in a gas phase of 5% CO ₂ -95% air for 7 days.

For the measurement of neurite outgrowth, on the 7th day of culture, the cell disk was washed with a phosphate buffer, fixed with 4% paraformaldehyde at 4 ° C. for 24 hours, and an anti-200 kD neurofilament antibody (Boehringer Mannh) was used.
Eim) using the Vecstatin ABC kit
Immunostaining was performed with (Funakoshi). Confined to the periphery of the cell disk and visually observed under a microscope, those with a large amount relative to the amount of neurofilament in the control well (total length per well) were positive (+), false positive (±), negative (-) in stages. ) Was evaluated. The results are shown in Table 1 below.

Test compound 1 3,3'-diallyl-5-ethyl-2,4'-biphenyldiol 2 3,3'-diallyl-5-ethyl-5'-fluoro-2,4'-biphenyldiol 3 3'-allyl-5-ethyl-2,3,4'-biphenyltriol 4,5 3,3'-diethyl-2,4'-biphenyldiol 5 3,3'-diallyl-2,4'-biphenyldiol 6 3 , 3'-dipropyl-5-ethyl-5 '-(1-
Imidazolyl) methyl-2,4'-biphenyldiol 7 5-ethyl-3'-allyl-2,4'-biphenyldiol 8 3,3'-diallyl-4,4'-biphenyldiol 9 2,4'-biphenyl Diol 10 5-methylthio-3 ', 5'-di-tert-butyl-2,4'-biphenyldiol

[0081]

[Table 1]

Pharmacological Test 2 (Measurement of Antioxidant Effect) Ascorbic acid-induced lipid peroxidation reaction [Shim
ada, O.D. and Yasuda, H .; BBA 48
9 , 163-172 (1977)] was used to measure the antioxidant effect.

Kato's method [J. Biochem. ，
59 , 574 (1966)], to obtain a microsomal fraction of liver of Wistar rat, which was added to 60 mM potassium phosphate buffer (containing 45 mM potassium chloride, 200 μM ascorbic acid and 20 μM ferrous sulfate) at 1 mg / m 2.
Then, the test compound was added (0.1% dimethylsulfoxide) and incubated at 37 ° C. for 15 minutes. An equal amount of 10% trichloroacetic acid was added, and after centrifugation, a part of the supernatant was taken and the amount of malondialdehyde (TBA value) by thiobarbituric acid was measured [Klaassen,
C. D. and Plaa, G .; L. Biochem.
Pharmacol. , 18 , 2019 (196
9)]. The inhibition rate was calculated by the following formula, and the 50% inhibition concentration
C ₅₀ ) is shown in Table 2.

Inhibition rate = {1- (TBA value of sample) / (TBA value of control)} × 100

[0085]

[Table 2]

[0086]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/425 9454-4C // C07D 277/22 (72) Inventor Osamu Hongo Okishima, Tokushima City, Tokushima Prefecture 50 Maison Kashihara No. 204 at 1-10 1 (72) Inventor Takao Nishi Nishi No. 28, 2 Taro Yasuma Taro Kitajima-cho, Itano-gun, Tokushima Prefecture

Claims (1)

[Claims] 1. A compound represented by the general formula (1): [In the formula, R ¹ is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a phenyl group which may have a hydroxyl group, a lower alkyl group or a lower alkenyl group as a substituent on the phenyl ring, a cycloalkenyl group, a halogen atom or a lower group. Indicates an alkanoyl group. R ² represents a hydroxyl group, a lower alkanoyloxy group, a lower alkenyloxy group or a lower alkoxy group as a substituent, a tetrahydropyranyloxy group or an alkoxy group which may have a hydroxyl group. R
³ has a hydroxyl group, a lower alkoxy group, a hydrogen atom, a lower alkoxy group as a substituent or a lower alkyl group which may have a hydroxyl group, a lower alkenyl group, a cycloalkenyl group, a phenyl group, a halogen atom, and a halogen atom as a substituent A lower alkanoyl group, a thiazolyl group which may have a lower alkyl group as a substituent,
.R ⁷ and R ⁸ groups -A-NR ⁷ R ⁸ (wherein A represents a lower alkylene group are the same or different, a hydrogen atom, a lower alkyl group or a lower alkanoyl group. Moreover this R ⁷ and R ⁸ may form a 5- or 6-membered saturated or unsaturated heterocycle with or without a nitrogen atom or an oxygen atom together with the nitrogen atom to which they are bound.
The heterocycle may have an amide group or an oxo group which may have a lower alkyl group as a substituent. ) Or the group —A—N ⁺ (R ^7a ) (R ^7b ) (R ^7c ) (R ^7a , R ^7b
And R ^7c each represents a lower alkyl group. A represents a lower alkylene group. ) Is shown. R ⁴ is a hydrogen atom, a lower alkyl group which may have a hydroxyl group or a lower alkoxy group as a substituent, a lower alkoxy group, a phenyl group, a phenyl lower alkyl group, a phenoxy group, a lower alkenyl group, a lower alkylthio group, a lower alkylsulfinyl group. , A lower alkylsulfonyl group, a halogen atom, a lower alkoxy lower alkyl group or a lower alkanoyl group. R ⁵ is a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkenyl group, a cycloalkenyl group,
An amino lower alkyl group which may have a lower alkyl group as a substituent, a lower alkanoyl group which may have a halogen atom as a substituent, or a thiazolyl group which may have a lower alkyl group as a substituent are shown. R ⁶ represents a hydroxyl group, a lower alkenyloxy group, a lower alkanoyloxy group or a lower alkoxy group as a substituent, a tetrahydropyranyloxy group or an alkoxy group which may have a hydroxyl group. R ^C represents a hydrogen atom or a lower alkyl group. ] A biphenyl derivative represented by the following general formula (2): [Wherein R ¹⁶ is a hydroxyl group, a lower alkenyloxy group, a cycloalkenyloxy group, a lower alkoxy group as a substituent,
Tetrahydropyranyloxy group, halogen atom, lower alkanoyloxy group, carboxy group, hydroxyl group, group -NR
¹⁰ R ¹³ (wherein R ¹⁰ and R ¹³ are the same or different and each represent a hydrogen atom, a lower alkyl group or a lower alkanoyl group. Further, R ¹⁰ and R ¹³ are bonded to each other via a nitrogen atom to which they are bonded. Or a 6-membered heterocycle may be formed), a lower alkylthio group, a lower alkoxycarbonyl group, a phenylthio group which may have a hydroxyl group or a lower alkyl group as a substituent on the phenyl ring, or a phthalimido group. An alkoxy group with a group Or the group (Wherein R ²⁰ represents a lower alkanoyloxy group). R ⁹ represents a lower alkenyl group. R ¹¹ is a hydrogen atom,
R ¹² representing a cycloalkenyl group or a lower alkenyl group
Represents a hydroxyl group, a lower alkenyloxy group, a cycloalkenyloxy group or a lower alkanoyloxy group. R ¹² and R ¹⁶ may be bonded to each other to represent a lower alkylenedioxy group. R ¹⁷ is a hydrogen atom, a cycloalkenyl group, a lower alkenyl group or a group Indicates. R ¹⁹ represents a lower alkenyl group. However, R ¹⁷ is a group In the case of, R ¹² and R ¹⁶ are hydroxyl groups, R ¹¹ is a hydrogen atom,
R ¹⁹ and R ⁹ are allyl groups. In addition, R ¹⁶ is a group , R ⁹ and R ¹⁹ are allyl groups, R ¹² is a hydroxyl group,
R ¹¹ and R ¹⁷ are hydrogen atoms. Further, R ¹⁶ is a group R ⁹ and R ¹⁹ are allyl groups, R ¹² is a lower alkanoyloxy group, and R ¹¹ and R ¹⁷ are hydrogen atoms. ] A compound represented by the general formula (3): [In the formula, R ⁹ represents a hydrogen atom or a lower alkenyl group. R
¹⁴ represents a lower alkenyloxy group or a hydroxyl group. R ¹⁵ represents a hydrogen atom or a lower alkenyl group. R ^A represents a hydrogen atom or a lower alkenyl group. ] The compound represented by
General formula (4) [In the formula, R ⁹ represents a hydrogen atom or a lower alkenyl group. R
¹⁸ represents a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower alkenyl group. R ²¹ and R ²⁴ represent a hydrogen atom or a lower alkenyl group. R ²² represents a hydrogen atom, a lower alkenyloxy group, a hydroxyl group or a lower alkenyl group. R ²³ represents a hydrogen atom, a lower alkenyl group, a lower alkenyloxy group or a hydroxyl group. R ^B represents a hydrogen atom, a lower alkyl group or a lower alkenyl group. However, R ²² and R ²³ must not be hydroxyl groups at the same time. R ^D represents a hydrogen atom or a lower alkyl group. ] A compound represented by the general formula (5): [In the formula, R ^E , R ^F and R ^I each represent a lower alkyl group. R ^G and R ^H each represent a lower alkoxy group. ] A peripheral nerve cell degeneration repairing or protecting agent containing as an active ingredient at least one selected from the group consisting of phenyl derivatives represented by the following and salts thereof.