JP5098011B2 - Wound healing promoter - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a wound-healing accelerator having an effect of accelerating the regeneration capacity of a living body by cell migration. <P>SOLUTION: This wound-healing accelerator contains a 2-benzazepine derivative expressed by general formula (I) and 2-isoquinoline derivative or any of their pharmaceutically acceptable salts as an active ingredient. <P>COPYRIGHT: (C)2008,JPO&amp;INPIT

Description

  The present invention relates to a wound healing promoter used for damage of epithelial cell tissue. The present invention relates to a wound healing promoter that promotes cell migration in epithelial cells such as skin, cornea and conjunctiva.

  Epithelial cell tissue damage includes damage to the skin, cornea, conjunctiva, etc., and skin damage is a wound of epidermal cells such as a surgical incision, skin ulcer, burn, laceration, abrasion, pressure ulcer. The corneal damage is corneal epithelial tissue damage caused by corneal ulcer, corneal epithelial detachment, keratitis, and dry eye. As a treatment method for wounds, it is common to disinfect or suture the wounded part and wait for the wounded part to heal by the natural recovery force of the living body itself. However, such natural healing requires a long time to recover, and the pain of patients including pain is not normal. Therefore, it is desired to actively and directly promote healing without relying on natural healing. Since wound healing generally depends on the formation of new connective and epithelial tissues by cell proliferation, drugs that stimulate or promote the differentiation and proliferation processes of cells involved in wound healing have been considered effective. As a drug for stimulating or promoting the differentiation / proliferation process of cells, peptide compounds (Patent Document 1), imidazole compounds (Patent Document 2), cis-6-hexadecenoic acid extracted from natural products (Patent Document 3), and novel drugs Peptides (Patent Document 4) and the like have been reported.

  Other methods of engraftment of extracellular matrix such as collagen, chitin, chitosan, engraftment of artificial skin, and production substances effective for wound healing rather than direct administration of cytokines, cell growth factors, etc. There is also a report of a medical material in which a cell that produces a cell growth factor, which is a kind of the above, is incorporated (Patent Document 5).

  Moreover, regarding the benzazepine derivative, the manufacturing method and the use as a pharmaceutical are disclosed. As an antibacterial drug (Patent Document 6), as a fibrinogen antagonist that is a blood coagulation factor (Patent Document 7), for antiarrhythmia (Patent Document 8), or by antagonizing the receptor of vitronectin as a cell adhesion factor, inflammation, cancer It has also been clarified that it is effective for treating cardiovascular disorders and osteoporosis (Patent Document 9). However, the wound healing effect by the cell migration promoting effect is not disclosed.

On the other hand, as the use of isoquinoline derivatives as pharmaceuticals, tetrahydroisoquinoline derivatives have an inhibitory action on the expression of ERas gene, which is an oncogene, and are therefore useful as antitumor agents (Patent Document 10), and bone formation. There is a report (Patent Document 11) of promoting. However, it was unclear that 2-isoquinoline derivatives have a wound healing promoting effect.
JP 2003-231695 A Japanese Patent No. 3038519 JP 2005-179190 A Japanese Patent No. 3673305 JP-A-8-198763 JP 2004-536079 A Japanese Patent No. 3497164 Japanese National Patent Publication No. 9-501405 JP-T-2001-501936 JP 2006-036671 A JP 2006-508051 A

  The above wound healing promoter is not considered to be sufficiently satisfactory from the viewpoints of healing effect, stability and practical use. In view of these points, the main object of the present invention is to provide a more useful wound healing promoter for wounds by promoting the regenerative ability of the living body by cell migration.

  The present inventors have found that 2-benzazepine derivatives and 2-isoquinoline derivatives have an effect of promoting wound healing against skin and cornea damage, and have completed the present invention.

That is, the present invention provides the following (3) to (5).

(1) General formula (I)

［式中、Ｒ^１は水素原子、ヒドロキシル基、アミノ基、カルバモイル基、アルキルチオール基、置換又は無置換の炭素数１〜６のアルキル基、置換又は無置換の炭素数２〜８のアルケニル基、置換又は無置換の炭素数２〜８のアルキニル基、置換又は無置換の炭素数１〜８のアルコキシ基、置換又は無置換の炭素数２〜８のカルボニル基、置換又は無置換の炭素数５〜８のアリール基、置換又は無置換の炭素数３〜８のシクロアルキル基、あるいは置換又は無置換の炭素数３〜８のシクロヘテロアルキル基を表し、Ｒ^２、Ｒ^３、Ｒ^４は、それぞれ独立して、水素原子、ハロゲン原子、ヒドロキシル基、チオール基、アミノ基、カルバモイル基、置換又は無置換の炭素数１〜６のアルキル基、置換又は無置換の炭素数２〜８のアルケニル基、置換又は無置換の炭素数２〜８のアルキニル基、置換又は無置換の炭素数１〜８のアルコキシ基、置換又は無置換の炭素数２〜８のカルボニル基、置換又は無置換の炭素数５〜８のアリール基、置換又は無置換の炭素数３〜８のシクロアルキル基、あるいは置換又は無置換の炭素数３〜８のシクロヘテロアルキル基を表し、Ｘは２つの水素原子又は１つの酸素原子、Ｎは０または１である］で表される化合物または医薬上許容される塩を有効成分として含有する創傷治癒促進剤。

[Wherein, R ¹ represents a hydrogen atom, a hydroxyl group, an amino group, a carbamoyl group, an alkylthiol group, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted alkenyl group having 2 to 8 carbon atoms. Substituted or unsubstituted alkynyl group having 2 to 8 carbon atoms, substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, substituted or unsubstituted carbonyl group having 2 to 8 carbon atoms, substituted or unsubstituted carbon number 5-8 aryl group, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms or a substituted or unsubstituted cycloheteroalkyl group having 3 to 8 carbon ^{atoms,, R 2, R 3,} R 4 is , Each independently, a hydrogen atom, a halogen atom, a hydroxyl group, a thiol group, an amino group, a carbamoyl group, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 8 carbon atoms Base A substituted or unsubstituted alkynyl group having 2 to 8 carbon atoms, a substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, a substituted or unsubstituted carbonyl group having 2 to 8 carbon atoms, a substituted or unsubstituted carbon number 5 Represents an aryl group of ˜8, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, or a substituted or unsubstituted cycloheteroalkyl group having 3 to 8 carbon atoms, and X represents two hydrogen atoms or one oxygen A wound healing promoter comprising a compound represented by the formula [Atom, N is 0 or 1] or a pharmaceutically acceptable salt as an active ingredient.

(2) R ^{1 in the} general formula (I) is a hydrogen atom, hydroxyl group, amino group, carbamoyl group, alkylthio group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 2, 2, 2-trifluoroethyl group, hydroxyethyl group, benzyl group, (4-trifluoromethylbenzyl) aminomethyl group, vinyl group, allyl group, propenyl group, isopropenyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group , Ethynyl group, propynyl group, butynyl group, methoxy group, ethoxy group, hydroxyethoxy group, 2-propenyloxy group, propoxy group, butoxy group, pentyloxy group, hexyloxy group, heptyloxy group, octyloxy group, (2 -Hydroxyoctyl) oxy, isonononaoxy, benzyloxy , Or pyridylaminopropoxy group, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, hexanoyl group, methacryloyl group, carboxy group, methoxycarbonyl group, benzoxy group, hydroxycarbonyl group, acetoxy group, cyclohexanecarbonyl group, benzoyl group Cinnamoyl group, phenyl group, tolyl group, chlorophenyl group, cyclohexyl group, cyclopentyl group, piperidine group, morpholinyl group, pyrrolidinyl group, etc., and R ² , R ³ , and R ⁴ are each independently a hydrogen atom , Halogen atom, hydroxyl group, alkylthio group, amino group, carbamoyl group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 2,2,2-trifluoroethyl group, hydroxy group Group, benzyl group, (methoxycarbonyl) methyl group, (ethoxycarbonyl) methyl group, (dimethylaminocarbonyl) methyl group, (4-trifluoromethylbenzyl) aminomethyl group, vinyl group, allyl group, propenyl group, iso Propenyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group, ethynyl group, propynyl group, butynyl group, methoxy group, ethoxy group, hydroxyethoxy group, 2-propenyloxy group, propoxy group, butoxy group, pentyloxy group, Hexyloxy group, heptyloxy group, octyloxy group, (2-hydroxyoctyl) oxy group, isononoxy group, benzyloxy group, pyridylaminopropoxy group, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, hexanoyl group, Me Acryloyl group, carboxy group, methoxycarbonyl group, benzoxy group, hydroxycarbonyl group, acetoxy group, cyclohexanecarbonyl group, benzoyl group, cinnamoyl group, phenyl group, tolyl group, chlorophenyl group, cyclohexyl group, cyclopentyl group, piperidine group, morpholyl group Or the wound healing promoter as described in said (1) which is chosen from a pyrrolidinyl group etc., X is an oxygen atom, and N is 0 or 1.

(3) N- (2,2,2-trifluoroethyl) -4-methyl-8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N- (2,2,2-trifluoroethyl) -4-methyl-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N-ethyl-4-methyl-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N-methyl-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N-methyl-4-methyl-8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N-ethyl-4-methyl-8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3 -one,
N- (2,2,2-trifluoroethyl) -4- (ethoxycarbonyl) methyl-8-hydroxy-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N- (2,2,2-trifluoroethyl) -4- (ethoxycarbonyl) methyl-8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N- (2,2,2-trifluoroethyl) -4- (methoxycarbonyl) methyl-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N- (2,2,2-trifluoroethyl) -8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N- (2,2,2-trifluoroethyl) -4-methyl-7-methoxy-1,2,4,5, tetrahydro-2 (1H) -isoquinolin-3-one,
Or the wound healing promoter containing these pharmaceutically acceptable salt as an active ingredient .

(4) The wound healing promoter according to (3) above, wherein the wound treatment is by promoting cell migration.

(5) The wound healing promoter according to (3) or (4) above , wherein the wound treatment is for skin and / or corneal damage.

  ADVANTAGE OF THE INVENTION By this invention, the wound healing promoter which has the effect which accelerates | stimulates wound healing by promoting the reproduction | regeneration ability of the biological body by cell migration can be provided.

  The present invention provides a wound healing promoter containing a 2-benzazepine derivative and / or a 2-isoquinoline derivative as an active ingredient.

  The wound healing promoter for promoting cell migration of the present invention is a drug that exhibits a wound healing effect by promoting cell migration by the following mechanism. That is, when a wound occurs, growth factors and migration factors are released from the broken platelets, and are attracted to these factors, neutrophils and macrophages migrate to the wound, and epidermal cells begin to migrate and divide. Will be played. Next, fibroblast migration and division occur, collagen and other fibers are produced, and the dermis layer is repaired to heal the wound.

  The compound serving as an active ingredient of the wound healing promoter of the present invention is one or more compounds selected from 2-benzazepine derivatives and 2-isoquinoline derivatives represented by the general formula (I).

R ^{1 in the} general formula (I) is a hydrogen atom, a hydroxyl group, an amino group, a carbamoyl group, an alkylthio group, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted carbon atom having 2 to 8 carbon atoms. Alkenyl group, substituted or unsubstituted alkynyl group having 2 to 8 carbon atoms, substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, substituted or unsubstituted carbonyl group having 2 to 8 carbon atoms, substituted or unsubstituted It represents an aryl group having 5 to 8 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, or a substituted or unsubstituted cycloheteroalkyl group having 3 to 8 carbon atoms.

The alkyl group having 1 to 6 carbon atoms represented by R ¹ in the general formula (I) may be linear or branched, and may be substituted. Preferred substituents are a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, a carbonyl group, and an alkoxy group, or an aryl group having 5 to 8 carbon atoms, an aryloxy group having 5 to 8 carbon atoms, and 5 carbon atoms. -8 arylamino groups, 5-membered or 6-membered cycloalkyl groups, or cycloheteroalkylheterocycles, and the like, which may be further substituted. Specific examples of the alkyl group represented by R ¹ include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 2,2,2-trifluoroethyl group, hydroxyethyl group, benzyl group, Or (4-trifluoromethylbenzyl) aminomethyl group is mentioned.

The alkenyl group having 2 to 8 carbon atoms represented by R ¹ in the general formula (I) may be linear or branched, and may be substituted. Preferred substituents are a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, a carbonyl group, and an alkoxy group, or an aryl group having 5 to 8 carbon atoms, an aryloxy group having 5 to 8 carbon atoms, and 5 carbon atoms. -8 arylamino groups, 5-membered or 6-membered cycloalkyl groups, or cycloheteroalkylheterocycles, and the like, which may be further substituted. Specific examples of the alkenyl group represented by R ¹ include a vinyl group, an allyl group, a propenyl group, an isopropenyl group, a butenyl group, a pentenyl group, a hexenyl group, and a heptenyl group.

The alkynyl group having 2 to 8 carbon atoms represented by R ¹ in the general formula (I) may be linear or branched, and may be substituted. Preferred substituents are a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, a carbonyl group, and an alkoxy group, or an aryl group having 5 to 8 carbon atoms, an aryloxy group having 5 to 8 carbon atoms, and 5 carbon atoms. -8 arylamino groups, 5-membered or 6-membered cycloalkyl groups, or cycloheteroalkylheterocycles, and the like, which may be further substituted. Specific examples of the alkynyl group represented by R ¹ include an ethynyl group, a propynyl group, and a butynyl group.

The alkoxy group having 1 to 8 carbon atoms represented by R ¹ in formula (I), may be branched may be linear, or may be substituted. Preferred substituents are halogen atoms, hydroxyl groups, amino groups, carbamoyl groups, carbonyl groups, or aryl groups having 5 to 8 carbon atoms, aryloxy groups having 5 to 8 carbon atoms, and 5 to 8 carbon atoms. Examples thereof include an arylamino group, a 5-membered or 6-membered cycloalkyl group, or a cycloheteroalkylheterocycle, and these may be further substituted. Specific alkoxy groups represented by R ¹ include methoxy group, ethoxy group, hydroxyethoxy group, 2-propenyloxy group, propoxy group, butoxy group, pentyloxy group, hexyloxy group, heptyloxy group, octyloxy Group, (2-hydroxyoctyl) oxy group, isononoxy group, benzyloxy group, or pyridylaminopropoxy group.

The carbonyl group having 2 to 8 carbon atoms represented by R ¹ in the general formula (I) may be linear or branched, and may be substituted. Preferred substituents are halogen atoms, hydroxyl groups, amino groups, carbamoyl groups, alkoxy groups, or aryl groups having 5 to 8 carbon atoms, aryloxy groups having 5 to 8 carbon atoms, and 5 to 8 carbon atoms. Examples thereof include an arylamino group, a 5-membered or 6-membered cycloalkyl group, or a cycloheteroalkylheterocycle, and these may be further substituted. Specific examples of the carbonyl group represented by R ¹ include formyl group, acetyl group, propionyl group, butyryl group, valeryl group, hexanoyl group, methacryloyl group, carboxy group, methoxycarbonyl group, benzoxy group, hydroxycarbonyl group, acetoxy Group, cyclohexanecarbonyl group, benzoyl group, cinnamoyl group and the like.

The aryl group having 5 to 8 carbon atoms represented by R ¹ in the general formula (I) may be substituted. Preferred substituents include a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, a carbonyl group, An alkoxy group, an aryl group having 5 to 8 carbon atoms, an aryloxy group having 5 to 8 carbon atoms, an arylamino group having 5 to 8 carbon atoms, a 5- or 6-membered cycloalkyl group, or cycloheteroalkyl Heterocycle etc. are mentioned, These may be further substituted. Specific examples of the aryl group represented by R ¹ include a phenyl group, a tolyl group, and a chlorophenyl group.

The cycloalkyl group having 3 to 8 carbon atoms represented by R ¹ in the general formula (I) may be substituted, and examples of the substituent include a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, a carbonyl group, An alkoxy group, an aryl group having 5 to 8 carbon atoms, an aryloxy group having 5 to 8 carbon atoms, an arylamino group having 5 to 8 carbon atoms, a 5- or 6-membered cycloalkyl group, or cycloheteroalkyl Heterocycle etc. are mentioned, These may be further substituted. Specific examples of the cycloalkyl group represented by R ¹ include a cyclohexyl group and a cyclopentyl group.

The C3-C8 cycloheteroalkyl group represented by R ¹ in the general formula (I) may be substituted, and examples of the substituent include a halogen atom, a hydroxyl group, an amino group, a carbamoyl group, and a carbonyl group. , An alkoxy group, or an aryl group having 5 to 8 carbon atoms, an aryloxy group having 5 to 8 carbon atoms, an arylamino group having 5 to 8 carbon atoms, a 5- or 6-membered cycloalkyl group, or cyclohetero Examples thereof include alkyl heterocycles, and these may be further substituted. Specific examples of the cycloheteroalkyl group represented by R ¹ include a piperidine group, a morpholinyl group, and a pyrrolidinyl group.

In general formula (I), R ² , R ³ and R ⁴ each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a thiol group, an amino group, a carbamoyl group, a substituted or unsubstituted carbon number of 1 to 6 Alkyl group, substituted or unsubstituted alkenyl group having 2 to 8 carbon atoms, substituted or unsubstituted alkynyl group having 2 to 8 carbon atoms, substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, substituted or unsubstituted A carbonyl group having 2 to 8 carbon atoms, a substituted or unsubstituted aryl group having 5 to 8 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, or a substituted or unsubstituted carbon group having 3 to 8 carbon atoms. Represents a cycloheteroalkyl group.

In R ² , R ³ and R ⁴ of the general formula (I), a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 8 carbon atoms, or a substituted or unsubstituted group The alkynyl group having 2 to 8 carbon atoms, the substituted or unsubstituted alkoxy group having 1 to 8 carbon atoms, and the substituted or unsubstituted carbonyl group having 2 to 8 carbon atoms are the same as in R ^{1 and} are linear. It may be branched or branched, and may be substituted. Specific alkyl groups represented by R ² , R ³ and R ⁴ include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 2,2,2-trifluoroethyl group, hydroxy group Examples include an ethyl group, a benzyl group, an (ethoxycarbonyl) methyl group or a (dimethylaminocarbonyl) methyl group, or a (4-trifluoromethylbenzyl) aminomethyl group. Examples of the alkenyl group include a vinyl group, an allyl group, and a propenyl group. , Isopropenyl group, butenyl group, pentenyl group, hexenyl group, heptenyl group, etc., alkynyl group includes ethynyl group, propynyl group, butynyl group, etc., and alkoxy group includes methoxy group, ethoxy group, Hydroxyethoxy group, 2-propenyloxy group, propoxy group, butoxy group A pentyloxy group, a hexyloxy group, a heptyloxy group, an octyloxy group, a (2-hydroxyoctyl) oxy group, an isononoxy group, a benzyloxy group, or a pyridylaminopropoxy group, and a carbonyl group includes a formyl group, an acetyl group, Examples include propionyl group, butyryl group, valeryl group, hexanoyl group, methacryloyl group, carboxy group, methoxycarbonyl group, benzoxy group, hydroxycarbonyl group, acetoxy group, cyclohexanecarbonyl group, benzoyl group, cinnamoyl group and the like.

In R ² , R ³ and R ⁴ of the general formula (I), a substituted or unsubstituted aryl group having 5 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a substituted or unsubstituted carbon atom having 3 to 3 carbon atoms. The cycloheteroalkyl group of 8 is the same as in R ¹ and may be substituted. Specific aryl groups represented by R ² , R ³ and R ⁴ include a phenyl group, a tolyl group, and a chlorophenyl group. Examples of the cycloalkyl group include a cyclohexyl group, a cyclopentyl group, and a cycloheteroalkyl group. , Piperidine group, morpholinyl group, pyrrolidinyl group and the like.

  Preferable examples of the 2-benzazepine derivative and 2-isoquinoline derivative represented by the general formula (I) which are active ingredients of the wound healing promoter of the present invention include N- (2,2,2-trifluoroethyl) -4. -Methyl-8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3-one (compound 1), N- (2,2,2-trifluoroethyl) -4-methyl-1,2 , 4,5, tetrahydro-2-benzazepin-3-one (compound 2), N-ethyl-4-methyl-1,2,4,5, tetrahydro-2-benzazepin-3-one (compound 3), N -Methyl-1,2,4,5, tetrahydro-2-benzazepine-3-one (compound 4), N-methyl-4-methyl-8-methoxy-1,2,4,5, tetrahydro-2-benzazepine -3 ON (compound 5), N-ethyl-4-methyl-8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3-one (compound 6), N-butyl-4- (methoxycarbonyl) Methyl-8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3-one (compound 7), N-isopropyl-4-methyl-8-methoxy-1,2,4,5, tetrahydro- 2-benzazepin-3-one (compound 8), N- (2,2,2-trifluoroethyl) -4- (ethoxycarbonyl) methyl-8-hydroxy-1,2,4,5, tetrahydro-2- Benzazepin-3-one (Compound 9), N- (2,2,2-trifluoroethyl) -4- (ethoxycarbonyl) methyl-8-methoxy-1,2,4,5, tetrahydro-2-ben Azepine-3-one (Compound 10), N- (2,2,2-trifluoroethyl) -4- (methoxycarbonyl) methyl-1,2,4,5, tetrahydro-2-benzazepin-3-one ( Compound 11), N- (2,2,2-trifluoroethyl) -8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3-one (Compound 12), N- (2,2 , 2-trifluoroethyl) -4-methyl-7-methoxy-1,2,4,5, tetrahydro-2 (1H) -isoquinolin-3-one (compound 13).

  The compound used in the present invention may be a pharmacologically acceptable salt thereof. In the case of a basic compound, for example, a salt with an organic acid, an inorganic acid or the like, and in the case of an acidic compound, for example, an alkali metal. And salts with alkaline earth metals, organic bases and the like. Examples of organic acids include acetic acid, adipic acid, benzoic acid, citric acid, fumaric acid, aspartic acid, lactic acid, malic acid, palmitic acid, salicylic acid, tartaric acid, benzenesulfonic acid, camphorsulfonic acid, toluenesulfonic acid, and inorganic acid. Examples thereof include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like. Examples of the alkali metal, alkaline earth metal, organic base and the like include lithium, sodium, potassium, calcium, magnesium, barium, tetramethylammonium, tetrabutylammonium and the like.

  The compounds used in the present invention include optically active substances, racemates, diastereomers, or mixtures of diastereomers, and all enantiomers to mixtures of enantiomers.

  In the present invention, a series of compounds represented by the above general formula can be prepared by the method of Uemura et al. (Akio Kamimura et al. J. Org. CHem., 2003; 68: 4996-4998, Akio Kamimura et al. TetraHedroN Lett., 2004). ; 45: 2335-2337), but is not limited to these methods.

  The wound healing promoter of the present invention can be administered orally or parenterally, and the dosage form can be arbitrarily selected according to the purpose. Specifically, ointments, jellies, creams, aerosols, In addition to external preparations such as sprays, poultices, and eye drops, preparations such as injections, tablets, granules, fine granules, powders, and capsules can be used. When a series of compounds represented by the above general formula is formulated as an active ingredient, it is mixed with a pharmaceutically acceptable additive in consideration of an administration route and an administration method.

  For example, ointments, jellies and creams are white petrolatum, yellow petrolatum, lanolin, white beeswax, cetanol, stearyl alcohol, stearic acid, hardened oil, gelled hydrocarbon, polyethylene glycol, liquid paraffin, squalane, etc. , Fatty acids and fatty acid esters such as oleic acid, isopropyl myristate, glyceryl triisooctanoate, crotamiton, diethyl sebacate, diisopropyl adipate, hexyl laurate, fatty alcohols, vegetable oils and solubilizers, tocopherol derivatives, L -Antioxidants such as ascorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, preservatives such as parahydroxybenzoic acid ester, moisturizing such as glycerin, propylene glycol, sodium hyaluronate Agent, polyoxyethylene derivative, glycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, surfactant such as lecithin, carboxyvinyl polymer, xanthan gum, carboxymethylcellulose, carboxymethylcellulose sodium salts, hydroxypropylcellulose, Thickeners and stabilizers such as hydroxypropylmethylcellulose, preservatives, absorption promoters, and other suitable additives can be blended.

  In particular, the eye ointment can be prepared using hydrocarbon bases such as white petrolatum, liquid paraffin, wax, macrogol, cetanol, higher fatty acid esters and the like.

  In the case of poultices, tackifiers such as polyacrylic acid and polyacrylic acid copolymers, cross-linking agents such as aluminum sulfate, potassium aluminum sulfate, aluminum chloride, magnesium metasilicate aluminate, dihydroxyaluminum acetate, polyacrylic acid Sodium, polyvinyl alcohol, polyvinylpyrrolidone, gelatin, sodium alginate, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and other thickeners, glycerin, polyethylene glycol (macrogol), propylene glycol, 1,3- Polyhydric alcohols such as butanediol, surfactants such as polyoxyethylene derivatives, perfumes such as l-menthol, parahydroxybenzoic acid Preservatives such as esters, purified water, or other suitable additives can be blended.

  For example, in the case of eye drops, isotonic agents such as glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol, boric acid, sodium borate, potassium tetraborate, potassium metaborate, phosphoric acid, phosphorus Buffers such as sodium oxyhydrogen, sodium dihydrogen phosphate, potassium dihydrogen phosphate, hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium bicarbonate PH adjusters such as polysorbate 80, polyoxyethylene hydrogenated castor oil 60, surfactants such as macrogol 4000, cellulose polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, thickeners such as polyvinyl alcohol and polyvinylpyrrolidone And dispersants, para Stabilizers such as sodium, edetic acid, sodium edetate, sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and other flavoring or cooling agents Various additives such as an agent may be appropriately selected, and one or more additives may be used in combination.

  Furthermore, in this case, it is necessary to adjust the osmotic pressure and pH within a range acceptable for the living body. The osmotic pressure is preferably 100 to 1200 mOsm, preferably 100 to 600 mOsm, particularly preferably about 150 to 400 mOsm, and the pH is usually preferably pH 4.0 to 10.0, preferably 4 .5 to 9.0, particularly preferably 5.0 to 8.5.

  Oral preparations such as tablets, capsules, granules, powders, etc. are bases such as lactose, crystalline cellulose, starch, vegetable oil, lubricants such as magnesium stearate and talc, hydroxypropyl cellulose, polyvinyl Necessary binders such as pyrrolidone, disintegrating agents such as carboxymethyl cellulose and low-substituted hydroxypropyl methyl cellulose, coating agents such as hydroxypropyl methyl cellulose and silicone resin, and coating agents such as gelatin film And can be prepared as required.

  The dose of this compound can be appropriately selected depending on symptoms, age, dosage form, etc., but when used as an external preparation, it is usually about 0.01 to 5000 mg, preferably about 0.1 to 1000 mg, more preferably 1 per day. About 100 mg can be administered in 1 to several divided doses. In particular, in the case of eye drops, the volume per day is usually in the range of 0.0001 to 10% (w / v), preferably 0.001 to 3% (w / v). . For oral preparations, 0.01 to 5000 mg per day, preferably 0.1 to 1000 mg, may be administered in 1 to several divided doses.

  Below, the Example about the wound healing promotion effect of typical 2-benzazepine derivative and 2-isoquinoline derivative is shown.

<Effects on skin epidermal cell spreading>
Using HaCat cells, an immortalized cell line of human skin epidermal cells, the effect on epidermal cell spreading was examined by the following method.

[Method] A 96-well plate was seeded with 2.5 × 10 ⁴ HaCat cells per well, and cultured in DMEM medium containing 10% FBS until the entire surface was covered. A cell-free region having a width of 1 mm was prepared using a 200 μL pipette plastic tip, washed with DMEM medium, and then cultured in DMEM medium containing 50 μM of a test compound under conditions of 37 ° C. and 5% CO ₂ for 24 hours. . Photographs were taken before the test compound was added, and the area of the cell-free area was measured. The effect on the spread of HaCat cells was examined by comparing with the area 24 hours after addition of the test compound. As a control, the same culture in a culture solution containing no test compound was used.

  [Test Compound] The compounds used in the experiment are Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, and Compound 8. FIG. 1 shows the structural formula.

  [Results] The results are shown in Table 1. The HaCat cell extension in the table is the average value and standard error of each of the six cases calculated with reference to the cell extension of the control (100%). * And ** indicate statistical significance at P <0.05 and P <0.01, respectively. As shown in Table 1, when culturing in a culture solution containing Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, or Compound 6, an excellent promoting effect on HaCat cell expansion was observed.

<Action on skin wound healing>
Using BALB / c male mice, the effect on skin wound healing was examined by the following method.

  [Method] Mice were anesthetized by inhalation with diethyl ether, the back hair was shaved with a clipper, and the hair was removed with a hair removal cream. Using a 5 mm diameter skin biopsy trepan, three full-thickness wounds of the epidermis and dermis were created on the back skin at regular intervals, and after confirmation of hemostasis, 30 μL of physiological saline containing 50 μM of the test compound was administered 2 times a day. Was applied to the affected area every 12 hours. Before the test compound was applied, the back wound of the mouse was photographed and the area was measured. The skin wound healing effect was examined by comparing the wound area after application of the test compound. As a control, physiological saline containing no test compound was applied to the affected area.

  [Test Compound] The compounds used in the experiment are Compound 1, Compound 2, and Compound 7 used in Example 1.

  [Results] Table 2 shows the experimental results. In addition, the remaining wound area in the table is an average value ± standard error of each 6 mice 6 days after wound creation, which was calculated using the area immediately after wound creation as a reference (100%). ** indicates statistical significance at P <0.01 relative to control. As shown in Table 2, when Compound 1 and Compound 2 were applied, an excellent skin wound healing promoting effect was recognized.

<Action on corneal epithelial extension>
Using corneas of male Japanese white rabbits, using the cornea epithelial length in a tissue culture system of cornea pieces as an index according to the method of Nisida et al. (J. Cell. Biol., 97, 1653-1657 (1983)). The effect on epithelial extension was examined.

[Method] A corneal block (six per group) cut out from a rabbit corneal slice was cultured under conditions of 37 ° C and 5% CO _{2 in} a culture solution (TC-199) containing a test compound of 50 µM as a final concentration. Incubate for hours. After the culture, the corneal block was fixed in a mixed solution of ethanol-glacial acetic acid (volume ratio 95: 5) and embedded in paraffin to prepare a section. The sections were deparaffinized and then stained with hematoxylin-eosin, and the spread of epithelial cell running was measured under a microscope. As a control, the same culture in a culture solution containing no test compound was used.

  [Test Compound] The compounds used in the experiment are Compound 1, Compound 2, Compound 7, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13. FIG. 1 shows the structural formula.

  [Results] The results are shown in FIG. In addition, the extension rate in a figure is the average value and standard error of each 6 examples calculated on the basis of the extension length of a control group (100%). * And ** indicate statistical significance at P <0.05 and P <0.01, respectively. As shown in FIG. 2, when the cells were cultured in a culture medium containing Compound 1, Compound 2, Compound 9, Compound 10, Compound 11, Compound 12, or Compound 13, significant corneal epithelial extension was observed.

  INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide external preparations and oral preparations such as ointments, jellies, creams, aerosols, sprays, poultices, eye drops and the like useful as therapeutic agents for promoting wound healing.

It is a figure which shows structural formula of the 2-benzazepine derivative and 2-isoquinoline derivative which were used in the Example. It is a figure which shows the result of the effect | action with respect to epidermal epithelial elongation.

Claims (3)

N- (2,2,2-trifluoroethyl) -4-methyl-8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N- (2,2,2-trifluoroethyl) -4-methyl-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N-ethyl-4-methyl-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N-methyl-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N-methyl-4-methyl-8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N-ethyl-4-methyl-8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N- (2,2,2-trifluoroethyl) -4- (ethoxycarbonyl) methyl-8-hydroxy-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N- (2,2,2-trifluoroethyl) -4- (ethoxycarbonyl) methyl-8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N- (2,2,2-trifluoroethyl) -4- (methoxycarbonyl) methyl-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N- (2,2,2-trifluoroethyl) -8-methoxy-1,2,4,5, tetrahydro-2-benzazepin-3-one,
N- (2,2,2-trifluoroethyl) -4-methyl-7-methoxy-1,2,4,5, tetrahydro-2 (1H) -isoquinolin-3-one,
Or the wound healing promoter containing these pharmaceutically acceptable salt as an active ingredient. The wound healing promoter according to claim 1, wherein the wound treatment is by promoting cell migration . The wound healing promoter according to claim 1 or 2 , wherein the wound treatment is for skin and / or cornea damage .

Images