JP5719985B2 - Diphenylmethyl piperazine derivatives - Google Patents

Description

Detailed Description of the Invention

  The present invention relates to a diphenylmethyl heterocyclic derivative suitable for pharmaceuticals, and more particularly to a diphenylmethyl heterocyclic derivative useful for scar treatment.

Extracellular matrix such as collagen fibers plays an important role in wound healing, etc., but sometimes in the wound healing process, excessive production of these extracellular matrix occurs and this forms a scar. It is said.
Such overproduction has been pointed out to involve TGF-b and TGF-b type II receptors, and suppression of TGF-b signaling that contributes to the overproduction of this extracellular matrix suppresses scarring. It is considered to be important for suppression of generation or disappearance of the generated scar (see, for example, Patent Document 1 and Patent Document 2). Thus, since the scar generated by the enhancement of the TGF-b and TGF-bII type receptors gives an unpleasant appearance, attempts have been made to suppress the action of TGF-b. Such substances that suppress the action of TGF-b, or substances that suppress the formation of scars include thyroid hormone-like substances, pyrazolone derivatives, biaryl derivatives such as furancarboxylate (see, for example, Patent Document 3). Etc. are known. Although these substances certainly suppress excess production of the extracellular matrix, the present situation is that the scar has not yet been suppressed, and further improvement of the effect has been desired.

  On the other hand, diphenylmethyl heterocyclic derivatives such as diphenylmethyl piperazine are known to have dopamine reuptake inhibitory action (see, for example, Patent Document 4), ACAT inhibitory action (see, for example, Patent Document 5), and the like. It is known that the diphenylmethylpiperazine skeleton is useful as a skeleton of an active ingredient of a medicine. Moreover, what has an elastase inhibitory effect is known as an active ingredient of a skin external preparation (for example, refer patent document 6). However, diphenylmethyl heterocyclic derivatives such as diphenylmethylpiperazine have a TGF-bII type receptor inhibitory action, and only a morin derivative is known to have a scar inhibitory action (for example, Patent Documents) 2).

JP 2003-335671 A JP 2007-84446 A JP 2000-26410 A JP-A-10-218867 JP-A-10-120644 JP 2003-55133 A

  The present invention has been made under such circumstances, and an object of the present invention is to provide a compound having a TGF-bII type receptor inhibitory action in order to suppress scar formation.

In view of such a situation, the present inventors have sought for a compound having a TGF-bII type receptor inhibitory action and, as a result of intensive research efforts, have found that at least two aromatic groups have a hetero atom. A diphenylmethyl heterocyclic derivative in which a part A connected by an aliphatic group and a part B formed of a condensed heteroaromatic group are bonded by a heteroaliphatic ring has such an action. The headline and invention were completed. That is, the present invention is as follows.
<1> A part formed by connecting an aliphatic group, which may have a hetero atom with at least two aromatic groups, and a part B formed by a condensed heteroaromatic ring group are bonded by a heteroaliphatic ring. Diphenylmethyl heterocyclic derivatives and / or salts thereof.
<2> The diphenylmethyl heterocyclic derivative and / or the diphenylmethyl heterocyclic derivative according to <1>, wherein the diphenylmethyl heterocyclic derivative is a diphenylmethylpiperazine derivative represented by the following general formula (1): salt.

（但し、式中Ｘ、Ｙはメチレン基、窒素原子、硫黄原子又は原子が存在しない場合を表し、Ｒ１は、水素原子、水素原子又は炭素原子が窒素で置換されていても良いアルキル基又はアルケニル基を表し、Ｒ２はハロゲン原子、アミノ基又はヒドラジニル基を表し、Ｒ３は置換基を有していても良い炭素数５〜１８の芳香族基を表す。）

(Wherein, X and Y represent a methylene group, a nitrogen atom, a sulfur atom or a case where no atom exists, and R 1 represents an alkyl group or alkenyl in which a hydrogen atom, a hydrogen atom or a carbon atom may be substituted with nitrogen. R2 represents a halogen atom, an amino group or a hydrazinyl group, and R3 represents an aromatic group having 5 to 18 carbon atoms which may have a substituent.

<3> The diphenylmethyl piperazine according to <2>, wherein the compound represented by the general formula (1) is a compound represented by the following general formula (2) or (3) Derivatives and / or salts thereof.

（但し、式中Ｒ１は、水素原子、水素原子又は炭素原子が窒素で置換されていても良いアルキル基又はアルケニル基を表し、Ｒ２はハロゲン原子、アミノ基又はヒドラジニル基を表し、Ｒ３は置換基を有していても良い炭素数５〜１８の芳香族基を表す。）

(In the formula, R1 represents a hydrogen atom, a hydrogen atom or an alkyl group or an alkenyl group in which a carbon atom may be substituted with nitrogen, R2 represents a halogen atom, an amino group or a hydrazinyl group, and R3 represents a substituent. Represents an aromatic group having 5 to 18 carbon atoms which may have

（但し、式中Ｒ１は、水素原子、水素原子又は炭素原子が窒素で置換されていても良いアルキル基又はアルケニル基を表し、Ｒ２はハロゲン原子、アミノ基又はヒドラジニル基を表し、Ｒ３は置換基を有していても良い炭素数５〜１８の芳香族基を表す。）

(In the formula, R1 represents a hydrogen atom, a hydrogen atom or an alkyl group or an alkenyl group in which a carbon atom may be substituted with nitrogen, R2 represents a halogen atom, an amino group or a hydrazinyl group, and R3 represents a substituent. Represents an aromatic group having 5 to 18 carbon atoms which may have

<4> A TGF-b (transforming growth factor beta) type II receptor inhibitor comprising the diphenylmethyl heterocyclic derivative and / or a salt thereof according to any one of <1> to <3>.
<5> A medicament for treating scars, which comprises the TGF-bII type receptor inhibitor of <4> as an active ingredient.
<6> The medicament according to <5>, which is an external preparation for skin.

ADVANTAGE OF THE INVENTION According to this invention, the compound which has a TGF-bII type receptor inhibitory effect can be provided.

<1> Compound of the Present Invention The compound of the present invention comprises at least two aromatic groups, which may have a hetero atom, an A part that is connected by an aliphatic group, and B that is a condensed heteroaromatic ring group. It is characterized in that it is a diphenylmethyl heterocyclic derivative and / or a salt thereof in which the moiety is bonded with a heteroaliphatic ring.

  Here, at least two aromatic groups constituting part A may be the same or different, and some or all of the hydrogen atoms may be substituted with substituents. As such an aromatic group, a heteroaromatic ring is also allowed, and the number of carbon atoms constituting the ring is preferably 3 to 12, and more preferably 4 to 10. Specifically, for example, a phenyl group, a pyridinyl group, an imidazolyl group, a triazolyl group, a pimidinyl group and the like can be preferably exemplified. At least 2, preferably 4 or less, more preferably 3 or less of these are bonded with an aliphatic group to form part A, and the aliphatic group for bonding is a cyclic condensed with the aromatic group. An aliphatic group, a branched or straight chain aliphatic group, which may have 1 to 5 unsaturated bonds, and the aliphatic group has a hydrogen atom or a carbon atom, an oxygen atom, a nitrogen atom It may be substituted with an atom, sulfur atom, halogen atom or the like. Specific examples of such A part include diphenylmethyl group, bis (4-fluorophenyl) methyl group and the like, diphenylmethyl group, diphenylacetyl group, bis ( 4-fluorophenyl) diphenylalkylcarbonyl group, dibenzosuberanyl group, dibenzo [b, e] thiepinyl group, dibenzo [b, e] azepinyl group, etc., in which hydrogen atoms may be substituted with halogen such as methylcarbonyl group Can be suitably exemplified. In the A part, part or all of the hydrogen atoms can be substituted with a substituent.

  The B part bonded to the A part via the heteroaliphatic ring is composed of a condensed heteroaromatic ring group, and the condensed heterocyclic group may have a part or all of its hydrogen atoms substituted with substituents. good. As a hetero atom which comprises a heterocyclic group, a nitrogen atom, an oxygen atom, a sulfur atom etc. can be illustrated suitably, for example. Examples of such a condensed heterocyclic group include a 6-membered ring and a 6-membered condensed ring, a 6-membered ring and a 5-membered condensed ring, and a 5-membered ring and a 5-membered condensed ring. Pyridopyridine, pyrimidopyrimidine, pyrazolopyridine, pyrazolopyrimidine, imidazolopyridine, imidazolopyrimidine, oxazolopyridine, oxazolopyrimidine, pyrazolopyrazole and the like can be preferably exemplified. Particularly preferred are those having a pyrazolopyrimidine skeleton.

  The heteroaliphatic ring for bonding the A part and the B part has a structure in which at least one carbon of the aliphatic cyclic compound is substituted with the heteroatom, and a part or all of the hydrogen atoms are substituents. It may be replaced with. As such a heteroaliphatic ring, for example, a piperidine residue, a piperazine residue, a homopiperazine residue, a morpholine residue and the like can be preferably exemplified, and a piperazine residue is particularly preferable.

  Examples of the substituent include a halogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms or an alkenyl group, an alkyloxy group having 1 to 4 carbon atoms, and an alkyl group having 1 to 4 carbon atoms. Amino group, aminocarbonyl group, amyridino group, guanidino group, carboxyl group, alkylcarbonyl group having 1 to 4 carbon atoms, phenyl group, naphthyl group, halogenophenyl group, halogenonaphthyl group, alkylphenyl group, alkyl Preferred examples include a naphthyl group, an alkyloxyphenyl group, an alkyloxynaphthyl group, a hydroxyphenyl group, a hydroxynaphthyl group, a nitrophenyl group, and a nitronaphthyl group.

  Diphenylmethyl in which at least two aromatic groups, which may have a hetero atom, are connected by a heteroaliphatic ring and an A portion connected by an aliphatic group and a B portion consisting of a condensed heteroaromatic ring group. As the heterocyclic derivatives, those represented by the following general formula (1) can be particularly preferably exemplified.

（但し、式中Ｘ、Ｙはメチレン基、窒素原子、硫黄原子又は原子が存在しない場合を表し、Ｒ１は、水素原子、水素原子又は炭素原子が窒素で置換されていても良いアルキル基又はアルケニル基を表し、Ｒ２はハロゲン原子、アミノ基又はヒドラジニル基を表し、Ｒ３は前記置換基を有していても良い炭素数５〜１８の芳香族基を表す。）

(Wherein, X and Y represent a methylene group, a nitrogen atom, a sulfur atom or a case where no atom exists, and R 1 represents an alkyl group or alkenyl in which a hydrogen atom, a hydrogen atom or a carbon atom may be substituted with nitrogen. R2 represents a halogen atom, an amino group or a hydrazinyl group, and R3 represents an aromatic group having 5 to 18 carbon atoms which may have the substituent.

  As the compound represented by the general formula (1), a compound represented by the following general formula (2) and a compound represented by the general formula (3) are particularly preferable.

（但し、式中Ｒ１は、水素原子、水素原子又は炭素原子が窒素で置換されていても良いアルキル基又はアルケニル基を表し、Ｒ２はハロゲン原子、アミノ基又はヒドラジニル基を表し、Ｒ３は前記置換基を有していても良い炭素数５〜１８の芳香族基を表す。）

(Wherein, R1 represents a hydrogen atom, a hydrogen atom or an alkyl group or an alkenyl group in which a carbon atom may be substituted with nitrogen, R2 represents a halogen atom, an amino group or a hydrazinyl group, and R3 represents the above-mentioned substituent. Represents an aromatic group having 5 to 18 carbon atoms which may have a group.)

（但し、式中Ｒ１は、水素原子、水素原子又は炭素原子が窒素で置換されていても良いアルキル基又はアルケニル基を表し、Ｒ２はハロゲン原子、アミノ基又はヒドラジニル基を表し、Ｒ３は置換基を有していても良い炭素数５〜１８の芳香族基を表す。）

(In the formula, R1 represents a hydrogen atom, a hydrogen atom or an alkyl group or an alkenyl group in which a carbon atom may be substituted with nitrogen, R2 represents a halogen atom, an amino group or a hydrazinyl group, and R3 represents a substituent. Represents an aromatic group having 5 to 18 carbon atoms which may have

  As specific compounds represented by these general formulas (1) to (3), the following compounds 1, 2 and 3 can be preferably exemplified.

化合物１： １−ジフェニルメチル−４−（６−ヒドラジノ−１−フェニル−１Ｈ−ピラゾロ［３，４−ｄ］ピリミジン−４−イル）ピペラジン（化合物コードＰＰ１３０５８）

Compound 1: 1-diphenylmethyl-4- (6-hydrazino-1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazine (Compound code PP13058)

化合物２： １−（ジベンゾ［ｂ．ｅ］チエピン−１１−イル）−４−（６−アミジノ−１−フェニル−１Ｈ−ピラゾロ［３，４−ｄ］ピリミジン−４−イル）ピペラジン（化合物コードＰＰ１３０５８−７６）

Compound 2: 1- (Dibenzo [b.e] thiepin-11-yl) -4- (6-amidino-1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazine (Compound code) PP13058-76)

化合物３： １−（ジベンゾ［ｂ．ｅ］チエピン−１１−イル）−４−（６−アミジノ−１−（４−メトキシフェニル）−１Ｈ−ピラゾロ［３，４−ｄ］ピリミジン−４−イル）ピペラジン（化合物コードＰＰ１３０５８−９１）

Compound 3: 1- (Dibenzo [b.e] thiepin-11-yl) -4- (6-amidino-1- (4-methoxyphenyl) -1H-pyrazolo [3,4-d] pyrimidin-4-yl ) Piperazine (Compound code PP13058-91)

  Such a diphenylmethyl heterocyclic derivative is obtained by using, as a raw material, a compound in which a hydroxyl group or a halogen is introduced at the site corresponding to the bond in the A part, and in the case of a hydroxyl group, the hydroxyl group is substituted with a halogen using a halogenating reagent such as thionyl chloride. A compound obtained by condensing a heterocyclic aliphatic compound such as dimethylformamide (DMF) in the presence of an alkali with heating as a solvent and halogenating a compound having a hydroxyl group at the site corresponding to the bond in part B in the same manner. It can be obtained by condensation in the presence of alkali.

  The diphenylmethyl heterocyclic derivative thus obtained can be used as it is for a medicine or the like, or can be treated with an acid and used as a salt. Preferred examples of the salt include mineral acid salts such as hydrochloride, sulfate, nitrate, carbonate and phosphate, and organic acid salts such as citrate, tartrate and oxalate.

  Since the diphenylmethyl heterocyclic derivative and / or salt thereof of the present invention has an excellent TGFβIIR inhibitory effect, scar formation can be suppressed by containing it in a topical skin preparation and administering it. Scar formation inhibition means content including an action for preventing the already formed scar from further development and an action for preventing the scar that will be generated from occurring. In order to achieve such an effect, it is preferable that 0.1 to 50% by mass of such a compound is contained in an external preparation for skin and an appropriate amount is transdermally administered once to several times a day.

  Such external preparations for skin can contain optional components usually used in external preparations for skin, in addition to the diphenylmethyl heterocyclic derivative of the present invention. Examples of such optional ingredients include macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil, liquid lanolin, and hardened coconut oil. Oil, wax, oils such as beeswax, molasses, hydrogenated castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax; , Hydrocarbons such as microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, undecylenic acid; cetyl alcohol, stearyl alcohol, isostearyl Higher alcohols such as alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, cetostearyl alcohol; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, di-2-ethylhexyl sebacate, cetyl lactate, malic acid Diisostearyl, di-2-ethylhexanoic acid ethylene glycol, dicaprate neopentyl glycol, di-2-heptylundecanoic acid glycerin, tri-2-ethylhexanoic acid glycerin, tri-2-ethylhexanoic acid trimethylolpropane, tri Synthetic ester oils such as trimethylolpropane isostearate and pentane erythritol tetra-2-ethylhexanoate; dimethylpolysiloxane, methylphenylpoly Linear polysiloxanes such as oxane and diphenylpolysiloxane; cyclic polysiloxanes such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, and dodecamethylcyclohexanesiloxane; amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxane, Oil agents such as silicone oils such as modified polysiloxanes such as fluorine-modified polysiloxanes; Anionic surfactants such as fatty acid soap (sodium laurate, sodium palmitate, etc.), potassium lauryl sulfate, triethanolamine ether of alkyl sulfates; Cationic surfactants such as stearyltrimethylammonium, benzalkonium chloride, laurylamine oxide; imidazoline-based amphoteric surfactants (2-cocoyl-2-imida Zolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.), and amphoteric surfactants such as acylmethyltaurine; sorbitan fatty acid esters (sorbitan) Monostearate, sorbitan sesquioleate, etc.), glycerin fatty acids (eg, glyceryl monostearate), propylene glycol fatty acid esters (eg, propylene glycol monostearate), hardened castor oil derivatives, glycerin alkyl ethers, POE sorbitan fatty acid esters (POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.), POE sorbite fatty acid esters (POE-sorbitol monolaurate, etc.), POE glycerin fatty acid ester Tells (POE-glycerol monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl) Ethers, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronics, POE castor oil / hardened castor oil derivatives (POE castor oil, POE hardened castor oil, etc.), Nonionic surfactants such as sucrose fatty acid ester and alkyl glucoside; polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, maltitol, propylene Polyhydric alcohols such as recall, dipropylene glycol, diglycerin, isoprene glycol, 1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol, 1,2-octanediol; sodium pyrrolidonecarboxylate Moisturizing ingredients such as lactic acid and sodium lactate; powders such as mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, anhydrous silicic acid (silica), aluminum oxide, barium sulfate, etc. whose surface may be treated Body, the surface may be treated, inorganic pigments such as bengara, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, bitumen, titanium oxide, zinc oxide; surface may be treated, mica Pearl agents such as titanium, fish phosphorus foil, bismuth oxychloride; red 202 which may be raked, red Color 228, Red 226, Yellow 4, Blue 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Blue 1 No., green 201, purple 201, red 204, etc .; organic powders such as polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer; para-aminobenzoic acid UV absorbers; anthranils Acid UV absorbers; salicylic acid UV absorbers; cinnamic acid UV absorbers; benzophenone UV absorbers; sugar UV absorbers; 2- (2′-hydroxy-5′-t-octylphenyl) benzo UV absorbers such as triazole and 4-methoxy-4′-t-butyldibenzoylmethane; low such as ethanol and isopropanol Alcohols; vitamin A or derivatives thereof, vitamin B6 hydrochloride, vitamin B6 tripalmitate, vitamin B6 dioctanoate, vitamin B2 or derivatives thereof, vitamin B such as vitamin B12, vitamin B15 or derivatives thereof; α-tocopherol, β- Vitamin E such as tocopherol, Y-tocopherol, vitamin E acetate, vitamin D, vitamin H, pantothenic acid, panthetin, pyrroloquinoline quinone and the like; and antibacterial agents such as phenoxyethanol are preferred.

<2> TGF-bII type receptor inhibitor of the present invention The TGF-bII type receptor inhibitor of the present invention comprises the diphenylmethyl heterocyclic derivative of the present invention and / or a salt thereof. Such an inhibitor fits into the keyhole of the TGF-bII type receptor and is thought to inhibit the occurrence of signal transduction due to the binding of TGF-b. Such an action can be confirmed by the following procedure.

<Measurement of TGFβIIR inhibitory activity>
A 96-well plate coated with 0.5 ng of rhTGF-b sRII / Fc Chimera (manufactured by R & D systems) was added 0.01 BSA-containing buffer (128 mM NaCl, 5 mM KCl, 5 mM MgSO ₄ , 1.3 mM CaCl ₂ , 50 mM HEPES). 90 μL was dispensed. After adding 5 μL of DMSO solution of a compound prepared in a 3-fold dilution series from 2 × 10 ⁻³ M (control is DMSO), 5 μL of 10 μg / mL biotinylated rhTGF-s (manufactured by R & D systems) was added. Stir for hours. After completion of the stirring, the plate was washed with Wash Concentrate (manufactured by Perkin Elmer) diluted 25 times, and 200 μL of 1000-fold diluted Eu-Labeled streptavidin (manufactured by Perkin Elmer) was added and stirred for 30 minutes. After stirring, wash with Wash Concentrate (manufactured by Perkin Elmer) diluted 25-fold under ice-cooling, add 200 μL of enhancement solution (manufactured by Perkin Elmer), stir for 5 minutes, and then measure the fluorescence intensity of each well did. In addition, for the purpose of examining non-specific reactions, reactions using rhTGF-β (manufactured by R & D systems) that were not biotinylated were performed together.
The result was calculated by the following formula as an inhibition rate at each compound concentration.
Binding rate (%) = (fluorescence intensity of well added compound-fluorescence intensity of non-specific reaction) / (fluorescence intensity of control well-fluorescence intensity of non-specific reaction) × 100
IC ₅₀ was calculated by fitting the obtained binding rate to a logistic model. The results are shown in Table 1.

  Hereinafter, the present invention will be described in more detail with reference to examples.

  Dissolve 2.64 g of diphenylmethylpiperazine, 2.65 g of 4,6-dichloro-1-phenyl-1H-pyrazolo [3,4-d] pyrimidine and 1.06 g of triethylamine in 500 ml of ethyl acetate, and heat to reflux for 5 hours. After washing three times with water, the ethyl acetate phase was concentrated under reduced pressure, and purified on a silica gel column using chloroform: methanol (10: 0 → 9: 1) as an elution solvent to give 1-diphenylmethyl-4- (6-chloro- 4.72 g of 1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazine was obtained.

0.76 g of 1-diphenylmethyl-4- (6-chloro-1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-yl) piperazine was dissolved in 8 ml of anhydrous tetrahydrofuran, and 2 mL of absolute ethanol was dissolved therein. Add 1.58 g of hydrazine dissolved in 4 hours, and heat to reflux for 4 hours. After cooling to room temperature, extract with 100 ml of water and 20 mL of methylene chloride, take the methylene chloride phase, and add the aqueous phase extracted with 10 mL of methylene chloride. This was washed with 100 mL of water, concentrated under reduced pressure, and recrystallized from ethanol to obtain 0.73 g of Compound 1.
Melting point: 224-227 ° C
¹ H-NMR (δ ppm): 7.21 to 8.20 (16H, m), 6.04 (1H, s), 4.28 (1H, t), 3.92 to 3.98 (5H, m ), 2.53-2.56 (4H, m), 1.22-1.26 (1H, m)

Chlorination was performed by adding 2 mL of methylene chloride to 0.27 g of 11-hydroxydibenzo [b, e] thiepine, and this was concentrated under reduced pressure, 50 mL of acetonitrile was added, 0.56 g of piperazine was added thereto, and the mixture was heated for 2 hours. The mixture was refluxed and concentrated under reduced pressure to obtain 0.52 g of 11-chlorodibenzo [b, e] thiepine. Thereafter, the same operation as in Example 1 was carried out to obtain Compound 2.
¹ H-NMR (δ ppm): 7.00 to 7.60 (17H, m), 4.90 to 4.30 (5H, bs), 3.30 to 3.60 (1H, bs), 2.43 ~ 2.72 (4H, bs)

  According to the following formulation, a pharmaceutical composition for external use as a pharmaceutical composition of the present invention was prepared. That is, the prescription ingredients were kneaded with a kneader to obtain a skin external pharmaceutical composition 1.

According to the following formulation, a pharmaceutical composition for external use as a pharmaceutical composition of the present invention was prepared. That is, the prescription ingredients were kneaded with a kneader to obtain a skin external pharmaceutical composition 2.

The present invention can be applied to a medicine such as a skin external medicine.

Claims (4)

A diphenylmethylpiperazine derivative and / or a salt thereof, which is a compound represented by the following general formula (2) or (3).

(In the formula, R1 represents a hydrogen atom, a hydrogen atom or an alkyl group or an alkenyl group in which a carbon atom may be substituted with a nitrogen atom, R2 represents an amidino group, and R3 has a substituent. Represents a good aromatic group having 5 to 18 carbon atoms.)

(However, in the formula, R1 represents a hydrogen atom, a hydrogen atom or an alkyl group or an alkenyl group in which a carbon atom may be substituted with a nitrogen atom, R2 represents an amidino group, and R3 may have a substituent. Represents a good aromatic group having 5 to 18 carbon atoms.) A TGF-b (transforming growth factor beta) type II receptor inhibitor comprising the diphenylmethyl heterocyclic derivative according to claim 1 and / or a salt thereof. A medicament for treating scar comprising the TGF-bII type receptor inhibitor of claim 2 as an active ingredient. The medicine according to claim 3, which is an external preparation for skin.