JP2007238458A - Novel isoquinoline derivative and medicine containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound having a high wound-healing effect and to provide a medicine containing the same. <P>SOLUTION: Provided is a compound represented by formula (1), its acid-addition salt, or its solvated product (wherein R<SP>1</SP>is an alkyl group; R<SP>2</SP>is a hydrogen atom or a hydroxy group; and ring A is a five- to seven-membered heterocyclic group which may have one nitrogen or oxygen atom as a ring-constituting heteroatom in addition to the nitrogen atom bonded to the sulfonyl group or may have alkyl group(s) as substituent(s)). <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a novel isoquinoline derivative and a medicament containing the same.

  In the treatment of skin ulcers and pressure sores, substances that promote granulation and epidermal regeneration while removing necrotic tissue and suppressing bacterial growth with antibacterial agents are used in clinical settings. In recent years, various cell growth factors and the like have been developed as wound healing agents along with the progress of basic research on wound healing. For example, patients with various diseases such as diabetes and elderly people have a problem that ulcers and pressure ulcers tend to occur and are difficult to cure. Therefore, administration of purified cell growth factor, genetically modified cell growth factor, etc. has been devised, and for example, genetically modified basic fibroblast growth factor has been developed.

  Skin wound healing involves interactions between keratinocytes, fibroblasts, vascular endothelial cells and inflammatory cells, and in normal wound healing the acute inflammatory phase, the extracellular matrix and collagen synthesis phase, and the remodeling phase (e.g. , See Non-patent Document 1). That is, in the acute inflammatory phase, inflammation occurs around the wound, increased permeability of capillaries and lymph vessels, migration of leukocytes and macrophages, phagocytosis and removal of bacteria and necrotic substances, and fibrin deposition begin. In the extracellular matrix and collagen synthesis phase, granulation and blood vessels are born by migration and proliferation of fibroblasts and synthesis and deposition of extracellular matrix such as collagen. In the remodeling phase, re-epithelialization and remodeling from type III collagen to type I collagen occurs (see, for example, Non-Patent Document 2).

Collagen is abundant in blood vessels, skin, and bones and plays an important role in the formation and construction of these tissues as a scaffold for cells and occupies about 1/3 of in vivo proteins. In addition, various wound covering materials such as collagen membranes have been developed for the treatment of shallow burns, which are used as a substrate for various cells in vitro, etc., and in which epidermal cells remain in burns and the like. Thus, collagen plays an important role not only in normal tissues but also in the wound healing process. Collagen is produced by fibroblasts, and it is known that TGFβ promotes production. However, to date, no low molecular weight compound has been developed as a wound healing promoter that promotes collagen production in fibroblasts and exhibits wound healing effects.
Peacock, E .; E. , Jr. , Wound Repair, 2nd edition, WB Saunders, Philadelphia (1984). Clark, R.A. A. F. , J .; Am. Akak. Dermatol 13: 701 (1985)

  An object of this invention is to provide the compound which has a high wound healing promotion effect, and the pharmaceutical containing this.

  In order to solve the above problems, the present inventors have intensively studied, and as a result, the compound represented by the following general formula (1), an acid addition salt thereof, and a solvate thereof promote the collagen production of strong fibroblasts. The present invention was completed by finding that it has an action, and further has a strong granulation renewal promoting action at the wound site, and has a wound healing promoting effect.

  That is, the present invention provides the following general formula (1)

[Wherein R ¹ represents an alkyl group, R ² represents a hydrogen atom or a hydroxy group, and ring A represents a nitrogen atom or oxygen atom as a hetero atom constituting the ring in addition to a nitrogen atom bonded to a sulfonyl group. And a 5- to 7-membered heterocyclic group which may have an alkyl group as a substituent. ]
Or an acid addition salt thereof or a solvate thereof.

  Moreover, this invention provides the pharmaceutical which contains the said compound, its acid addition salt, or those solvates as an active ingredient.

  Furthermore, the present invention provides the above-mentioned medicament which is a wound healing promoter and the above-mentioned medicament which is a medicament for treating skin ulcer or pressure ulcer.

  The compounds of the present invention represented by the general formula (1), acid addition salts thereof and solvates thereof have strong fibroblast collagen production promoting action, and further have strong granulation renewal promoting action at the wound site. Therefore, it is useful as an active ingredient of a medicine, and can be suitably used as an active ingredient of a wound healing promoter, or as an active ingredient of a medicine for treating skin ulcer or pressure ulcer.

In the general formula (1), examples of the alkyl group represented by R ¹ include C ₁ -C ₆ linear or branched alkyl groups such as methyl, ethyl, n-propyl, and iso-propyl. Group, n-butyl group, iso-butyl group, tert-butyl group, pentyl group, hexyl group and the like. Of these, a methyl group and an iso-propyl group are preferable.

In general formula (1), ring A is bonded to the sulfonyl group through a nitrogen atom. Ring A may have one nitrogen atom or oxygen atom as a heteroatom constituting the ring, in addition to the nitrogen atom bonded to the sulfonyl group, and may have an alkyl group as a substituent. Represents a 7-membered heterocyclic group, and such heterocyclic groups may be saturated or unsaturated, but are preferably saturated. Examples of the 5- to 7-membered heterocyclic group include pyrrolidinyl group, pyrazolidinyl group, imidazolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, homopiperazinyl group, and the like in the present invention. Group, piperazinyl group, morpholinyl group, and homopiperazinyl group are preferred, and the degree of promoting collagen production in fibroblasts is excellent, and the degree of promoting granulation at the wound site is particularly preferred, and homopiperazinyl group is particularly preferred. The alkyl group which may have on the heterocyclic group, the bond include C ₁ -C ₆ alkyl group such as methyl group, ethyl group, etc. n- propyl group. Onto the heterocycle The position is arbitrary. Examples of the 5- to 7-membered heterocyclic group having an alkyl group in the compound of the present invention include a methyl homopiperazinyl group and an ethyl piperazinyl group. A methyl homopiperazinyl group is preferable, and a 2-methylhomo A piperazinyl group is particularly preferred.

  Preferred ring A in the compound of the present invention includes pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, homopiperazinyl group, and methylhomopiperazinyl group.

  The acid addition salt of the compound (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of the acid addition salt include hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate. Acid addition salts of mineral acids such as: benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartrate, Examples include acid addition salts of organic acids such as citrate and acetate.

  Moreover, although this invention compound (1) may exist in the form of the solvate represented by the hydrate, the said solvate is also included by this invention.

  The compound (1) of the present invention can be produced according to the following method.

[Wherein R ¹ , R ² and ring A have the same meaning as described above, and X represents a halogen atom such as a chlorine atom. In the case where Ring A has two nitrogen atoms on the ring, the nitrogen atoms that are not reacted with the sulfonyl group are benzyloxycarbonyl group, tert-butoxycarbonyl group, 9-fluorenylmethoxycarbonyl group, formyl group, It protects suitably with suitable protecting groups, such as a fluoroacetyl group and a trityl group. ]

The 4-substituted benzaldehyde (2) which is a starting material is converted into the isoquinoline derivative (3) by a known method, for example, a method as described in JP-T-10-511893. Nitration of this compound (3) by a known method easily gives the 5-position nitro compound (4), which can be obtained by a known method such as catalytic reduction in the presence of palladium carbon or reduction with tin chloride. Converted to the 5-position amino form (5). A compound obtained by diazotizing compound (5) by a known method can be easily derived into a sulfonyl halide (6) by a known method, and this compound (6) is compounded with compound (7) by coupling with an amine. Led to. Compound (7) corresponds to compound (1) of the present invention in which R ² is a hydrogen atom when ring A has no protecting group. When ring A has a protecting group, the present compound (1) can be obtained by further deprotecting compound (7) by a known method. The compound (1) of the present invention in which R ² is a hydroxy group converts the compound (7) into an N-oxide (8) by using a known reagent such as m-chloroperbenzoic acid. Later, it can be obtained by introducing a hydroxy group into the 1-position of isoquinoline by a known method.

  The compound (1) of the present invention can be obtained by the above-described method, and can be further purified by a usual purification means such as a recrystallization method or column chromatography, if necessary. If necessary, the desired salt or solvate described above can be obtained by a conventional method.

  The medicament of the present invention comprises the compound of the present invention represented by general formula (1), an acid addition salt thereof or a solvate thereof as an active ingredient. As shown in Examples below, the compounds of the present invention, their acid addition salts and their solvates have a strong fibroblast collagen production-promoting action, and further have a strong granulation-promoting action at the wound site. Therefore, the medicament of the present invention can be suitably used as a wound healing promoter, in particular, a medicament for treating skin ulcers, pressure ulcers and the like.

  The administration form of the medicament of the present invention is not particularly limited and can be appropriately selected depending on the purpose of treatment. For example, when used as a wound healing promoter, when used as an external preparation, it is desirable to formulate it into a liquid, cream, patch, gel or the like and apply it directly to the wound site. These preparations are prepared using known techniques and can contain acceptable ordinary carriers, excipients, binders, stabilizers, and the like. Examples of the form for oral administration include tablets, capsules, pills, granules, powders, liquids, syrups, and suspensions. Further, when used in an injection form, an acceptable buffer, solubilizing agent, isotonic agent and the like can be added.

  The dose of the active ingredient of the medicament of the present invention varies depending on the subject to be treated, the patient's age, sex, body weight, symptom, dosage form, number of administrations, etc., for example, as a wound healing promoter or treatment of skin ulcer or pressure ulcer When it is used in the form of an external preparation as a medicine for the above, it is preferable to administer 0.001 to 300 mg, preferably 0.1 to 100 mg per day, in one or several divided doses.

  Specific examples of the compound included in the present invention include the following compounds. However, specific examples of these compounds are for illustrative purposes, and the present invention is not limited thereto.

[Production Example 1]
Synthesis of 6-methylisoquinoline:

p-Tolualdehyde (3.36 g) and aminoacetaldehyde dimethyl acetal (3.12 g) were dissolved in toluene (40 mL) and refluxed at 140 ° C. overnight. The mixture was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL), and ethyl chlorocarbonate (3.04 g) was added. After stirring at room temperature for 1 hour, trimethyl phosphite (4.44 g) was added, and the mixture was further stirred at room temperature for 20 minutes. The mixture was concentrated under reduced pressure, the residue was dissolved in dichloromethane (10 mL), titanium chloride (31.9 g) was added, and the mixture was stirred at 65 ° C. for 42 hr. The reaction solution was neutralized with an aqueous potassium hydroxide solution, and the precipitate was removed by filtration. The filtrate was acidified with concentrated hydrochloric acid, washed with chloroform, and the pH of the aqueous layer was made alkaline again with potassium hydroxide and extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound as a crystalline powder.
Yield: 1.93 g (48%)

[Production Example 2]
Synthesis of 6-methyl-5-nitroisoquinoline:

6-Methylisoquinoline (1.72 g) was added to concentrated sulfuric acid (30 mL) under ice cooling, followed by potassium nitrate (2.3 g). The mixture was stirred at 0 ° C. for 70 minutes and poured into water. The mixture was made alkaline with concentrated potassium hydroxide, and the deposited precipitate was collected by filtration.
Yield: 2.32 g (100%)

[Production Example 3]
Synthesis of 5-amino-6-methylisoquinoline:

6-Methyl-5-nitroisoquinoline (2.31 g) was dissolved in a mixed solvent of concentrated hydrochloric acid (25 mL) and acetic acid (50 mL), and tin (II) chloride (23.1 g) was added. The mixture was stirred overnight at room temperature, and the precipitate was collected by filtration and dissolved in water (100 mL). The mixture was made alkaline with an aqueous potassium hydroxide solution, extracted with chloroform, and concentrated under reduced pressure to give the title compound as pale tan crystals.
Yield: 1.51 g (78%)

[Production Example 4]
Synthesis of 5-chlorosulfonyl-6-methylisoquinoline:

5-Amino-6-methylisoquinoline (0.80 g) was dissolved in concentrated hydrochloric acid (10 mL), and sodium nitrite (0.52 g) dissolved in water (2 mL) was added dropwise. The mixture was stirred under ice-cooling for 50 minutes and added dropwise to a mixture of copper chloride dihydrate (0.28 g), water (1.4 mL), and 64% sulfite acetic acid solution (6.3 g). After the reaction solution was stirred at 5 ° C. for 80 minutes, the pH was adjusted to 3 with an aqueous potassium hydroxide solution, and chloroform was added. Further, a potassium hydroxide solution was added, and when the pH reached 5, chloroform extraction was performed three times. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound as a brown crystalline powder.
Yield: 0.12 g (10%)

[Example 1]
Synthesis of 6-methyl-5- (1-pyrrolidinesulfonyl) isoquinoline hydrochloride:

5-Chlorosulfonyl-6-methylisoquinoline (100 mg) was added to a solution of pyrrolidine (150 mg) and triethylamine (210 mg) in tetrahydrofuran (10 mL). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 4: 1 → hexane-ethyl acetate = 3: 1) and then concentrated under reduced pressure. The obtained oil was dissolved in methanol, and 4M hydrochloric acid in ethyl acetate was added to obtain a hydrochloride, whereby the title compound was obtained as pale orange pink crystals.
Yield: 110 mg (85%)
M / Z: 276 [M ⁺ ]

[Example 2]
Synthesis of 6-methyl-5- (1-piperidinesulfonyl) isoquinoline hydrochloride:

5-Chlorosulfonyl-6-methylisoquinoline (100 mg) and piperidine (180 mg) were reacted in the same manner as in Example 1 to obtain the title compound as light brown crystals.
Yield: 70 ng (52%)
M / Z: 290 [M ⁺ ]

[Example 3]
Synthesis of 6-methyl-5- (4-morpholinesulfonyl) isoquinoline hydrochloride:

5-Chlorosulfonyl-6-methylisoquinoline (150 mg) and morpholine (275 mg) were reacted in the same manner as in Example 1 to obtain the title compound as light brown crystals.
Yield: 30 mg (15%)
M / Z: 292 [M ⁺ ]

[Production Example 5]
Synthesis of 5- [1- (4- (tert-butoxycarbonyl) homopiperazine) sulfonyl] -6-methylisoquinoline:

5-chlorosulfonyl-6-methylisoquinoline (0.11 g) and 1- (tert-butoxycarbonyl) homopiperazine (0.30 g) were reacted in the same manner as in Example 1. Thereafter, work-up was performed to obtain the title compound as a pale yellow oil without converting to hydrochloride.
Yield: 0.20 g (34%)

[Example 4]
Synthesis of 6-methyl-5- (1-homopiperazinesulfonyl) isoquinoline dihydrochloride:

5- [1- (4- (tert-Butoxycarbonyl) homopiperazine) sulfonyl] -6-methylisoquinoline (190 mg) is dissolved in dioxane (2.5 mL), and 4M hydrochloric acid in dioxane (2.5 mL) is added. It was. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was dissolved in water. The mixture was neutralized with an aqueous sodium hydrogen carbonate solution, extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (chloroform → chloroform-methanol = 50: 1 → chloroform-methanol = 25: 1 → chloroform-methanol = 10: 1), and 4M hydrochloric acid in ethyl acetate was added. The hydrochloride was obtained to give the title compound as colorless needle crystals.
Yield: 138 mg (79%)
M / Z: 305 [M ⁺ ]

[Production Example 6]
Synthesis of (S) -2-[(benzyloxycarbonyl) amino] -N- (3-hydroxypropyl) propylamine:

(S) -2-[(Benzyloxycarbonyl) amino] -1-propanol (4.96 g) and triethylamine (5.0 mL) were dissolved in chloroform (50 mL), and methanesulfonyl chloride (2.7 mL) was cooled with ice. ) Was added dropwise. The reaction solution was returned to room temperature and stirred for 30 minutes, and water was added to separate the organic layer. The aqueous layer was further extracted with chloroform, and the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 mL), 3-amino-1-propanol (8.90 g) was added, and the mixture was refluxed overnight. The mixture was concentrated under reduced pressure, water and chloroform were added, and the organic layer was separated. The aqueous layer was further extracted with chloroform, and the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol = 9: 1 → chloroform-ammonia saturated methanol = 9: 1) to obtain the desired product as a colorless oil.
Yield: 3.76 g (60%)

[Production Example 7]
Synthesis of (S) -2-[(benzyloxycarbonyl) amino] -N- (tert-butoxycarbonyl) -N- (3-hydroxypropyl) propylamine:

(S) -2-[(Benzyloxycarbonyl) amino] -N- (3-hydroxypropyl) propylamine (3.76) and triethylamine (2.4 mL) were dissolved in chloroform (20 mL), and di-tert- Butyl dicarbonate (3.70 g) was added and stirred at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure, ethyl acetate and water were added to the residue, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 10: 1 → hexane-ethyl acetate = 1: 1) to obtain the desired product as a colorless oil.
Yield: 4.38 g (85%)

[Production Example 8]
Synthesis of (S) -2-amino-N- (tert-butoxycarbonyl) -N- (3-hydroxypropyl) propylamine:

(S) -2-[(benzyloxycarbonyl) amino] -N- (tert-butoxycarbonyl) -N- (3-hydroxypropyl) propylamine (4.38 g) was dissolved in methanol (20 mL) and 10% Catalytic reduction was performed in a hydrogen stream in the presence of palladium-activated carbon (440 mg). After completion of the reaction, the catalyst was removed and the filtrate was concentrated under reduced pressure to obtain the desired product as a colorless oil.
Yield: 2.77 g (100%)

[Production Example 9]
Synthesis of (S) -N- (tert-butoxycarbonyl) -N- (3-hydroxypropyl) -2-[(2-nitrobenzenesulfonyl) amino] propylamine:

(S) -2-amino-N- (tert-butoxycarbonyl) -N- (3-hydroxypropyl) propylamine (1.53 g) and triethylamine (923 μL) were dissolved in chloroform (10 mL), and 2-nitrobenzenesulfonyl was dissolved. Chloride (1.46 g) was added. The mixture was stirred for 1 hour and extracted by adding water and chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (hexane-ethyl acetate = 1: 1 → ethyl acetate) to give the title compound as a colorless oil.
Yield: 1.89 g (69%)

[Production Example 10]
Synthesis of (S) -1- (2-nitrobenzenesulfonyl) -4- (tert-butoxycarbonyl) -2-methylhomopiperazine:

(S) -N- (tert-butoxycarbonyl) -N- (3-hydroxypropyl) -2-[(2-nitrobenzenesulfonyl) amino] propylamine (1.87 g) and triphenylphosphine (1.78 g). It melt | dissolved in anhydrous tetrahydrofuran (50 mL), and the 40% toluene solution (2.96g) of diethyl azo carbonate was dripped. The mixture was stirred overnight under an argon atmosphere and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product proceeded to the next reaction without purification.
Yield: 2.59g

[Production Example 11]
Synthesis of (S) -1- (tert-butoxycarbonyl) -3-methylhomopiperazine:

(S) -1- (2-Nitrobenzenesulfonyl) -4- (tert-butoxycarbonyl) -2-methylhomopiperazine (1.33 g) was dissolved in acetonitrile (15 mL), and potassium carbonate (0.92 g) and thiol were dissolved. Phenol (0.69 mL) was added. The mixture was stirred at room temperature for 5 hours and concentrated in vacuo. Water and chloroform were added to the residue, and the chloroform layer was further washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (chloroform → chloroform-methanol = 30: 1 → chloroform-methanol = 10: 1) to obtain the title compound as a colorless oil.
Yield: 0.41 g (58%)

[Production Example 12]
Synthesis of (S) -6-methyl-5- [1- (4- (tert-butoxycarbonyl) -2-methylhomopiperazine) sulfonyl] isoquinoline:

5-chlorosulfonyl-6-methylisoquinoline (135 mg) and (S) -1- (tert-butoxycarbonyl) -3-methylhomopiperazine (180 mg) were reacted in the same manner as in Example 1. Thereafter, work-up was performed to obtain the title compound as a pale yellow oil without converting to hydrochloride.
Yield: 70 mg (30%)

[Example 5]
Synthesis of (S) -6-methyl-5- [1- (2-methylhomopiperazine) sulfonyl] isoquinoline dihydrochloride:

(S) -6-methyl-5- [1- (4- (tert-butoxycarbonyl) -2-methylhomopiperazine) sulfonyl] isoquinoline (70 mg) was treated in the same manner as in Example 4 to give the title compound as white crystals. Obtained as a powder.
Yield: 31 mg (46%)
M / Z: 319 [M ⁺ ]

[Production Example 13]
Synthesis of 6-isopropylisoquinoline:

4-Isopropylbenzaldehyde (20.9 g) was treated in the same manner as in Production Example 1 to obtain the title compound as a brown crystalline powder.
Yield: 16.2 g (67%)

[Production Example 14]
Synthesis of 6-isopropyl-5-nitroisoquinoline:

6-Isopropylisoquinoline (5.14 g) was treated in the same manner as in Production Example 2 to obtain the title compound.
Yield: 4.79 g (74%)

[Production Example 15]
Synthesis of 5-amino-6-isopropylisoquinoline:

6-Isopropyl-5-nitroisoquinoline (2.0 g) was treated in the same manner as in Production Example 3 to give the title compound as a pale brown oil.
Yield: 0.74 g (43%)

[Production Example 16]
Synthesis of 5-chlorosulfonyl-6-isopropylisoquinoline:

5-Amino-6-isopropylisoquinoline (0.72 g) was treated in the same manner as in Production Example 4 to obtain the title compound as a light brown crystalline powder.
Yield: 0.65 g (62%)

[Production Example 17]
Synthesis of 5- [1- (4- (tert-butoxycarbonyl) homopiperazine) sulfonyl] -6-isopropylisoquinoline:

5-Chlorosulfonyl-6-isopropylisoquinoline (0.20 g) and 1- (tert-butoxycarbonyl) homopiperazine (0.45 g) are reacted in the same manner as in Production Example 5 to obtain the title compound as a pale yellow oil. It was.
Yield: 0.12 g (37%)

[Example 6]
Synthesis of 6-isopropyl-5- (1-homopiperazinesulfonyl) isoquinoline dihydrochloride:

5- [1- (4- (tert-Butoxycarbonyl) homopiperazine) sulfonyl] -6-isopropylisoquinoline (0.12 g) was treated in the same manner as in Example 4 to obtain the title compound as a pale yellow crystalline powder. .
Yield: 60 mg (54%)
MZ: 333 [M ⁺ ]

[Production Example 18]
Synthesis of 5- [1- (4- (tert-butoxycarbonyl) homopiperazine) sulfonyl] -6-isopropyl-2-oxoisoquinoline:

5- [1- (4- (tert-Butoxycarbonyl) homopiperazine) sulfonyl] -6-isopropylisoquinoline (169 mg) is dissolved in chloroform (5 mL), m-chloroperbenzoic acid (200 mg) is added and the mixture is stirred overnight. did. A 10% aqueous sodium thiosulfate solution (4 mL) was added, and the mixture was stirred at room temperature for 1 hr, and extracted with chloroform. The organic layer was washed with saturated sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (developing solvent; chloroform-methanol = 15: 1) to obtain the title compound as a light brown oil.
Yield: 129 mg (88%)

[Production Example 19]
Synthesis of 5- [1- (4- (tert-butoxycarbonyl) homopiperazine) sulfonyl] -1-hydroxy-6-isopropylisoquinoline:

To a solution of 5- [1- (4- (tert-butoxycarbonyl) homopiperazine) sulfonyl] -6-isopropyl-2-oxoisoquinoline (108 mg) in chloroform (3 mL) was added n-butylammonium chloride (135 mg) and potassium acetate ( 71 mg) in water (3 mL) was added, and a solution of benzoyl chloride (61 mg) in chloroform (1 mL) was added at room temperature with stirring. The mixture was stirred at room temperature for 1 hour and chloroform and water were added. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (chloroform → chloroform-methanol = 20: 1) to obtain the title compound as a pale yellow oil.
Yield: 84 mg (78%)

[Example 7]
Synthesis of 1-hydroxy-6-isopropyl-5- (1-homopiperazinesulfonyl) isoquinoline hydrochloride:

5- [1- (4- (tert-Butoxycarbonyl) homopiperazine) sulfonyl] -1-hydroxy-6-isopropylisoquinoline (90 mg) was treated in the same manner as in Example 4 to obtain the title compound as colorless needle crystals. It was.
Yield: 46 mg (60%)
M / Z: 349 [M ⁺ ]

[Production Example 20]
Synthesis of 5- [1- (4- (tert-butoxycarbonyl) piperazine) sulfonyl] -6-isopropylisoquinoline:

5-Chlorosulfonyl-6-isopropylisoquinoline (165 mg) and 1- (tert-butoxycarbonyl) piperazine (136 mg) were reacted in the same manner as in Production Example 5 to obtain the title compound as a pale yellow oil.
Yield: 183 mg (73%)

[Example 8]
Synthesis of 6-isopropyl-5- (1-piperazinesulfonyl) isoquinoline dihydrochloride:

5- [1- (4- (tert-Butoxycarbonyl) piperazine) sulfonyl] -6-isopropylisoquinoline (183 mg) was treated in the same manner as in Example 4 to obtain the title compound as a pale yellow crystalline powder.
Yield: 132 mg (77%)
M / Z: 319 [M ⁺ ]

[Example 9]
Synthesis of 6-isopropyl-5- (4-morpholinesulfonyl) isoquinoline hydrochloride:

5-Chlorosulfonyl-6-isopropylisoquinoline (0.20 g) and morpholine (0.33 g) were reacted in the same manner as in Example 1 to obtain the title compound as colorless needle crystals.
Yield: 52 mg (85%)
M / Z: 320 [M ⁺ ]

[Test Example 1]
(Evaluation of the effect of Example compounds on collagen production by incorporation of ³ H-Proline)
Normal human skin fibroblasts were seeded at 6000 cells / 100 μL / well (96 well-plate) and cultured at 37 ° C. overnight. Thereafter, the medium of Example was replaced with 100 μL of the compound of Example at a concentration of 1 μM or 10 μM, and further 50 μL of 1.5 μCi ³ H-Proline (Amersham Bioscience) dissolved in the medium was added at 37 ° C. Culture was performed for 48 hours. After cultivation, 100 μL of a Pepsin (Sigma) solution dissolved in cold 1M acetic acid at 1 mg / mL was added, and the mixture was allowed to stand at 4 ° C. overnight. Thereafter, 800 μL of neutral soluble collagen (KOKEN) dissolved in 0.5 M acetic acid at 100 μL / mL was added and mixed, and centrifuged at 4 ° C., 13,000 g for 15 minutes, and the supernatant was collected. To this supernatant was added 250 μL of a 25% NaCl 0.5M acetic acid solution, which was then allowed to stand at room temperature for 2 hours, and then centrifuged at 4 ° C., 13,000 g for 15 minutes to obtain a precipitate. The obtained precipitate was dissolved in 150 μL of a 0.15 M NaCl-50 mM Tris-HCl (pH 7.5) solution, added with a 4.5 M NaCl 50 mM Tris-HCl (pH 7.5) solution, mixed, and mixed at room temperature. Let stand for hours. Thereafter, the precipitate (collagen fraction) is obtained by centrifugation at 4 ° C., 13,000 g for 15 minutes, and the precipitate is added with 1 mL of 20% ethanol and centrifuged at 4 ° C., 13,000 g for 15 minutes. Washed. The washed collagen fraction was dissolved in 250 μL of 0.5 M acetic acid, 5 mL of liquid scintillator was added, and the amount of radioactivity derived from ³ H-Proline incorporated by a liquid scintillation counter was measured. The obtained value was calculated by the following formula to evaluate the test substance. In addition, what performed the experiment operation with respect to the thing which does not contain a test substance at the time of a cell culture was handled as control, and what performed the experiment operation with respect to the thing which does not contain a cell and a test substance was handled as background. . The results are shown in Table 1.
(Test substance added sample value−background value) / (control value−background value) × 100 (%)

(result)
As shown in Table 1, all of the compounds of Example 4, Example 6, and Example 7 have a collagen production promoting action, and the compound of the present invention is used as an active ingredient of a wound healing promoter and for skin ulcers or pressure ulcers. It turned out that it can be conveniently used as an active ingredient of a medicine for treatment.

[Test Example 2]
(Animal experiment using rabbit ear skin defect wound model)
A male Japanese white rabbit (body weight: 2.0 kg) was anesthetized inside the auricle and was dissolved in phosphate buffer solution with the compound of Example 6 in four 6 mm diameter wounds made on cartilage every day for 4 days. .01, 0.1, 1.0% 10 μL of the test drug was applied. The deficient wound was covered with a waterproof film, and then rolled gauze was sandwiched between the pinna and the pinna was fixed with a stretchable adhesive tape. 14 deficient wounds were used per group, and untreated were used as controls. The concentration of bFGF used as a control was set to 100 μg / mL. After 5 days, anesthesia was killed, the auricles were removed, and formalin was fixed. Thereafter, a section including the center of the defect wound was prepared by embedding in paraffin. After staining with hematoxylin and eosin, the image under the microscope was taken into a computer and the granulation area was measured. The results are shown in FIG.

(result)
As shown in FIG. 1, it can be seen that the test drug containing the compound of Example 6 as an active ingredient exhibits a strong granulation renewal promoting action at the wound site, and the compound of the present invention is used as an active ingredient of a wound healing promoter and the skin. It has been found that it can be suitably used as an active ingredient of a medicine for treating ulcers or pressure ulcers.

It is a figure which shows the intensity | strength of the granulation neoplasia promoting effect of the test drug in Test Example 2.

Claims (6)

The following general formula (1)
[Wherein R ¹ represents an alkyl group, R ² represents a hydrogen atom or a hydroxy group, and ring A represents a nitrogen atom or oxygen atom as a hetero atom constituting the ring in addition to a nitrogen atom bonded to a sulfonyl group. And a 5- to 7-membered heterocyclic group which may have an alkyl group as a substituent. ]
Or an acid addition salt or solvate thereof. In the general formula (1), R ¹ is a C ₁ -C ₆ linear or branched alkyl group, and the heterocyclic group represented by the ring A is a saturated heterocyclic group. The described compounds, their acid addition salts or their solvates. In general formula (1), R ¹ is a methyl group or an iso-propyl group, and ring A is a pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, homopiperazinyl group, or methylhomopiperazinyl group. 3. The compound according to 1 or 2, an acid addition salt thereof or a solvate thereof.   The pharmaceutical which contains the compound of any one of Claims 1-3, its acid addition salt, or those solvates as an active ingredient.   The medicament according to claim 4, which is a wound healing promoter.   The medicament according to claim 4, which is a medicament for treating skin ulcer or pressure ulcer.