JP2012516285A - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
- Publication number
- JP2012516285A JP2012516285A JP2011531691A JP2011531691A JP2012516285A JP 2012516285 A JP2012516285 A JP 2012516285A JP 2011531691 A JP2011531691 A JP 2011531691A JP 2011531691 A JP2011531691 A JP 2011531691A JP 2012516285 A JP2012516285 A JP 2012516285A
- Authority
- JP
- Japan
- Prior art keywords
- dihydro
- pyrrolo
- pyrimidine
- oxo
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000008194 pharmaceutical composition Substances 0.000 title description 7
- 150000003230 pyrimidines Chemical class 0.000 claims abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
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- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims abstract description 4
- 239000006096 absorbing agent Substances 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims abstract description 4
- 239000002537 cosmetic Substances 0.000 claims description 13
- 230000006750 UV protection Effects 0.000 claims description 8
- 239000011814 protection agent Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 abstract description 27
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- 239000003223 protective agent Substances 0.000 abstract description 12
- 239000003112 inhibitor Substances 0.000 abstract description 11
- 150000003839 salts Chemical class 0.000 abstract description 11
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- IVIDDMGBRCPGLJ-UHFFFAOYSA-N 2,3-bis(oxiran-2-ylmethoxy)propan-1-ol Chemical compound C1OC1COC(CO)COCC1CO1 IVIDDMGBRCPGLJ-UHFFFAOYSA-N 0.000 description 2
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- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 description 1
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
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- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- QURCVMIEKCOAJU-UHFFFAOYSA-N trans-isoferulic acid Natural products COC1=CC=C(C=CC(O)=O)C=C1O QURCVMIEKCOAJU-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
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- RNWHGQJWIACOKP-UHFFFAOYSA-N zinc;oxygen(2-) Chemical class [O-2].[Zn+2] RNWHGQJWIACOKP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/16—Emollients or protectives, e.g. against radiation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/18—Antioxidants, e.g. antiradicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Ophthalmology & Optometry (AREA)
- Toxicology (AREA)
- Birds (AREA)
- Epidemiology (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Cosmetics (AREA)
Abstract
新たな紫外線吸収剤、紫外線防護剤及び/又はメラニン産生抑制剤を提供する。式(1)の2-置換-6-アルキル-5-オキソ-5,6-ジヒドロ(7H)ピロロ[3,4-d]
ピリミジン類化合物、または式(2)の2-置換-7-アルキル-6-オキソ-5,6-ジヒドロ(7H)ピロロ[2,3-d]ピリミジン類化合物またはその薬学的に許容される塩類を有効成分とする紫外線吸収剤、紫外線防護剤及び/又はメラニン産生抑制剤。
〔式(1)または式(2)において、R1からR8は独立に水素または低級アルキル基、−CH2CH2OCH3、−CH2COR9(R9=CH3、C2H5、NH2)、−CH2−OCOC2H5を;Xは−N(R10)−(R10=CH3、C2H5、Ph、−CH2Ph、−CH(Ph)2、−COCH3、−COOCH3、−SO2CH3)、−CH2−、−CH(CH3)−、−CH(C2H5)−、−O−、−S−を;示す。但しPhはフェニル基である〕A new ultraviolet absorber, ultraviolet protective agent and / or melanin production inhibitor is provided. 2-substituted-6-alkyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] of the formula (1)
Pyrimidine compounds, or 2-substituted-7-alkyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine compounds of formula (2) or pharmaceutically acceptable salts thereof UV-absorbing agent, UV-protecting agent and / or melanin production inhibitor containing as an active ingredient.
[In Formula (1) or Formula (2), R1 to R8 are independently hydrogen or a lower alkyl group, —CH2CH2OCH3, —CH2COR9 (R9═CH3, C2H5, NH2), —CH2—OCOC2H5; X is —N ( R10)-(R10 = CH3, C2H5, Ph, -CH2Ph, -CH (Ph) 2, -COCH3, -COOCH3, -SO2CH3), -CH2-, -CH (CH3)-, -CH (C2H5)-, -O- and -S- are shown. Where Ph is a phenyl group]
Description
本発明は新規な紫外線吸収剤、新規な皮膚科用剤、化粧品用剤、詳しくは皮膚を紫外線障害から守る、紫外線防護剤、紫外線障害防護剤あるいは、皮膚のしみ、そばかす、炎症等のもとであるメラニンの産生系の抑制剤又は調整剤、ないしメラノサイト、ケラチノサイト等皮膚細胞の機能・活動の抑制剤又は調整剤に関する。 The present invention is a novel ultraviolet absorber, novel dermatological agent, cosmetic agent, specifically, protects the skin from UV damage, UV protective agent, UV protective agent, or skin stains, freckles, inflammation, etc. It is related with the inhibitor or regulator of the production system of melanin which is, or the inhibitor or regulator of the function / activity of skin cells such as melanocytes and keratinocytes.
皮膚におけるしみ、そばかすの生成等色素異常、日やけ、日光やけど後の色素沈着は、ひとそれぞれ、体質による程度の違いがあるが、皮膚組織に存在する色素細胞(メラノサイト)の、日光等光被曝に対する生体防御的活動によるメラニン合成の結果の表現である。しみ、そばかすや日やけ後の色素沈着は、でき易い人とでき難い人がおり、でき易い人にとっては、大きな悩みであり、紫外線曝露に対する、効果的な紫外線防護方法を取り入れることが求められている。 Pigment abnormalities such as spots on the skin, freckle formation, pigmentation after sunburn, sunburn, etc., differ in degree depending on the constitution, but exposure of pigmented cells (melanocytes) present in skin tissue to sunlight, etc. It is an expression of the result of melanin synthesis by the body defense activity against. Blots, freckles, and pigmentation after sunburn are both easy and difficult to do. For those who are easy to do, it is a big problem, and it is necessary to incorporate effective UV protection methods against UV exposure. Yes.
フロンガス等による上空の成層圏にあるオゾン層破壊のため、より強力な紫外線の被曝などによる遺伝的影響、発癌作用等により癌患者の増加が懸念されている。人間の皮膚は280〜320nmの波長の紫外線に敏感で、特に305〜310nmの領域の紫外線が皮膚癌を起こすという。この波長域の紫外線を吸収するオゾン層の破壊は地上に降り注ぐ紫外線を増加させ、上記のように皮膚癌の増大につながることが論議されているが、かような放射線被曝の障害を、予防・治療する薬剤を開発することも重要な課題となってきている。 Due to the destruction of the ozone layer in the stratosphere above by chlorofluorocarbons, etc., there is a concern that the number of cancer patients will increase due to genetic effects, carcinogenic effects, etc. due to exposure to stronger ultraviolet rays. Human skin is sensitive to ultraviolet rays with a wavelength of 280 to 320 nm, and especially ultraviolet rays in the region of 305 to 310 nm cause skin cancer. It has been argued that the destruction of the ozone layer that absorbs ultraviolet rays in this wavelength range increases the amount of ultraviolet light that falls on the ground, leading to an increase in skin cancer as described above. Developing drugs to treat has also become an important issue.
現代は、紫外線被曝によるしわ形成などの皮膚の老化や、メラノーマ、皮膚がんの発病や白内障の発症等の予防・治療から、頭頚部や衣服非着用部・皮膚露出部における美容上の問題の改善までを目的として、より効力があり、望ましい紫外線防護剤や紫外線防護化粧料の必要性が、より高まっている。紫外線吸収剤や紫外線遮断剤や紫外線散乱剤をまとめて、紫外線防護剤というなら、二酸化チタン類、酸化亜鉛類、桂皮酸誘導体類、ベンゾフェノン誘導体類などの物質が従来、使用されてきた。また、色素異常や色素沈着等の皮膚美容上のトラブルを回避・防止し、又は改善する目的で、アスコルビン酸類、過酸化水素、ハイドロキノン類、アルブチン、フェルラ酸、コウジ酸、グルタチオン類、美白性生薬のエキス等を配合した、いわゆる美白剤と言われる皮膚外用剤が化粧品として生産され、日常的に使用されてきた。 In modern times, skin aging such as wrinkle formation due to UV exposure, prevention and treatment of melanoma, skin cancer and cataracts, etc. For the purpose of improvement, there is a growing need for more effective and desirable UV protection agents and UV protection cosmetics. When UV absorbers, UV blockers, and UV scattering agents are collectively referred to as UV protective agents, substances such as titanium dioxides, zinc oxides, cinnamic acid derivatives, and benzophenone derivatives have been conventionally used. In addition, ascorbic acids, hydrogen peroxide, hydroquinones, arbutin, ferulic acid, kojic acid, glutathione, whitening crude drug for the purpose of avoiding, preventing or improving skin cosmetic problems such as pigment abnormalities and pigmentation Skin external preparations, so-called whitening agents, containing the above-mentioned extracts and the like have been produced as cosmetics and used daily.
本発明者は、メラノサイトの良性腫瘍であるホクロに科学的関心があり、「アレルギー疾患抵抗性・感受性とほくろの多・無とのリンク」即ち、「ほくろ(形成能)は、花粉症等アレルギー疾患抵抗性の表現形質(素因)である」という報告等々を行ってきており、メラノサイトのメラニン合成・代謝系活性化等、皮膚状態の活性化を通した、疾患の発症や進展の予防・治療方法を提案してきた(非特許文献1、2および特許文献1)。 The present inventor has a scientific interest in moles, which are benign tumors of melanocytes, and `` links between resistance to allergic diseases / sensitivity and number of moles '', that is, `` mole (formation ability) is an allergy such as hay fever. It has been reported that it is a phenotypic characteristic (predisposition) of disease resistance, etc., and prevention and treatment of disease onset and progression through activation of skin conditions such as melanin synthesis and metabolic system activation of melanocytes A method has been proposed (Non-Patent Documents 1 and 2 and Patent Document 1).
本発明者はその研究の延長で、本発明者らが以前から検討してきた一群の合成ピリミジン化合物の、紫外線防護剤として、美白剤としての生物活性を検討することに想い到った。これら合成ピリミジン化合物は、特許文献2〜7および非特許文献3〜5に示すように、元来、神経細胞の再生、修復効果を有する、末梢神経の障害疾患や中枢神経の障害疾患へ適用しうる神経疾患用治療薬であり、また、学習記憶の改善・回復効果を有し、痴呆等脳疾患へ適用しうる治療薬であり、また創傷を治癒する創傷治療剤として開発が期待されている化合物である。 As an extension of the study, the present inventor has come up with the idea of investigating the biological activity of a group of synthetic pyrimidine compounds that have been studied by the present inventors as a UV protective agent and as a whitening agent. As shown in Patent Documents 2 to 7 and Non-Patent Documents 3 to 5, these synthetic pyrimidine compounds are originally applied to peripheral nerve disorders and central nerve disorders, which have nerve cell regeneration and repair effects. It is a therapeutic agent for neurological diseases, has an effect of improving and recovering learning memory, is a therapeutic agent that can be applied to brain diseases such as dementia, and is expected to be developed as a therapeutic agent for wound healing A compound.
本発明は、従来にない新たな化学構造式を持つ、有用な紫外線吸収剤、紫外線防護剤及び/又はメラニン産生抑制剤を提供することを課題とする。 It is an object of the present invention to provide a useful ultraviolet absorber, ultraviolet protective agent and / or melanin production inhibitor having a new chemical structural formula that has not existed before.
本発明者らは、この目的で、本発明者らが以前に見出した式(1)または式(2)のピリミジン類化合物またはその薬学的に許容される塩類について、新たに紫外線防護活性やメラニン産生抑制活性のスクリーニングを行い、期待通り本発明の化合物が優れた生物活性を有することを見出すことにより、所期の目的を達成し、本発明を完成した。即ち、本発明は、式(1)または式(2)のピリミジン類化合物またはその薬学的に許容される塩類を有効成分とする紫外線吸収剤、紫外線防護剤及び/又はメラニン産生抑制剤を提供するものである。
本発明は、上記の式(1)または式(2)のピリミジン類化合物またはその薬学的に許容される塩類を有効成分とする紫外線吸収剤、紫外線防護剤及び/又はメラニン産生抑制剤を提供する。 The present invention provides an ultraviolet absorber, an ultraviolet protective agent and / or a melanin production inhibitor comprising the pyrimidine compound of the above formula (1) or formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient. .
本発明によりこれら剤として提供できる合成ピリミジン系化合物としては、特許文献2〜7や非特許文献3〜5などに記載のある2−置換−6−アルキル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン類化合物および2−置換−7−アルキル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン類化合物またはその塩である。より具体的には上記の式(1)あるいは式(2)に表わす化合物である。〔式(1)または式(2)において、R1からR8は独立に水素または低級アルキル
基、−CH2CH2OCH3、−CH2COR9(R9=CH3、C2H5、NH2)、−CH2−OCOC2H5を;Xは−N(R10)−(R10=CH3、C2H5、Ph、−CH2Ph、−CH(Ph)2、−COCH3、−COOCH3、−SO2CH3)、−CH2−、−CH(CH3)−、−CH(C2H5)−、−O−、−S−を;示す。但しPhはフェニル基である〕
Synthetic pyrimidine compounds that can be provided as these agents according to the present invention include 2-substituted-6-alkyl-5-oxo-5,6-dihydro compounds described in Patent Documents 2 to 7, Non-Patent Documents 3 to 5, and the like. 7H) pyrrolo [3,4-d] pyrimidine compounds and 2-substituted-7-alkyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine compounds or salts thereof. . More specifically, it is a compound represented by the above formula (1) or formula (2). [In Formula (1) or Formula (2), R1 to R8 are independently hydrogen or a lower alkyl group, —CH2CH2OCH3, —CH2COR9 (R9═CH3, C2H5, NH2), —CH2—OCOC2H5; X is —N ( R10)-(R10 = CH3, C2H5, Ph, -CH2Ph, -CH (Ph) 2, -COCH3, -COOCH3, -SO2CH3), -CH2-, -CH (CH3)-, -CH (C2H5)-, -O- and -S- are shown. Where Ph is a phenyl group]
(式(1)または式(2)において、R1からR8は独立に水素または低級アルキル基、CH3OCH2CH2−、−CH2CONH2、−COCH3、−COC2H5、−CH2OCOC2H5を、Xは>NH、>N−CH3、>N−C2H5、>N−ph、>N−CH2−ph、>N−CH−ph2、>N−COCH3、>N−COOC2H5、>N−SO2CH3、>CH2、>CHCH3、>CHC2H5、−O−、−S−を示す。ただし、phはフェニル基を示す。)なお、低級アルキル基としては炭素数が1から7の低級アルキル基が好ましい。 (In Formula (1) or Formula (2), R1 to R8 are independently hydrogen or a lower alkyl group, CH3OCH2CH2-, -CH2CONH2, -COCH3, -COC2H5, -CH2OCOC2H5, X is> NH,> N-CH3, > N-C2H5,> N-ph,> N-CH2-ph,> N-CH-ph2,> N-COCH3,> N-COOC2H5,> N-SO2CH3,> CH2,> CHCH3,> CHC2H5, -O -, -S-, where ph represents a phenyl group.) The lower alkyl group is preferably a lower alkyl group having 1 to 7 carbon atoms.
式(1)の代表的化合物を以下に例挙する。2−ピペラジノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−(4−メチルピペラジノ)−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−(4−エチルピペラジノ)−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−ピペリジノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−(4−メチルピペリジノ)−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−(4−エチルピペリジノ)−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−モルホリノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−チオモルホリノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−ピペラジノ−6−エチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、 Representative compounds of formula (1) are listed below. 2-piperazino-6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2- (4-methylpiperazino) -6-methyl-5-oxo-5,6- Dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2- (4-ethylpiperazino) -6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2- Piperidino-6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2- (4-methylpiperidino) -6-methyl-5-oxo-5,6-dihydro ( 7H) pyrrolo [3,4-d] pyrimidine, 2- (4-ethylpiperidino) -6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2-morpholino- 6-Methyl-5-o So-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2-thiomorpholino-6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine 2-piperazino-6-ethyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine,
2−ピペラジノ−6−イソプロピル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−ピペラジノ−6−n−ブチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−ピペラジノ−6−sec−ブチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−ピペラジノ−6−t−ブチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−ピペラジノ−4,6−ジメチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−ピペラジノ−6,7−ジメチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−ピペラジノ−6,7,7−トリメチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−ピペリジノ−4,6−ジメチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−ピペリジノ−6,7,7−トリメチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−ピペラジノ−7−メチル−6−エチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン、2−ピペラジノ−4−メチル−6−エチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジン。 2-piperazino-6-isopropyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2-piperazino-6-n-butyl-5-oxo-5,6-dihydro ( 7H) pyrrolo [3,4-d] pyrimidine, 2-piperazino-6-sec-butyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2-piperazino-6 t-butyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2-piperazino-4,6-dimethyl-5-oxo-5,6-dihydro (7H) pyrrolo [ 3,4-d] pyrimidine, 2-piperazino-6,7-dimethyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2-piperazino-6,7,7- Trimethyl-5-oxo-5, -Dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2-piperidino-4,6-dimethyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2-piperidino -6,7,7-trimethyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2-piperazino-7-methyl-6-ethyl-5-oxo-5,6 -Dihydro (7H) pyrrolo [3,4-d] pyrimidine, 2-piperazino-4-methyl-6-ethyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine.
式(2)の代表的化合物を以下に例挙する。2−ピペラジノ−7−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−(4−メチルピペラジノ)−7−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−(4−エチルピペラジノ)−7−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−(4−N−アセチルピペラジノ)−7−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペリジノ−7−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−(4−メチルピペリジノ)−7−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−(4−エチルピペリジノ)−7−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−モルホリノ−7−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−チオモルホリノ−7−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペリジノ−7−エチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペリジノ−7−n−プロピル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペリジノ−7−イソプロピル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、 Representative compounds of formula (2) are listed below. 2-piperazino-7-methyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2- (4-methylpiperazino) -7-methyl-6-oxo-5,6- Dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2- (4-ethylpiperazino) -7-methyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2- (4-N-acetylpiperazino) -7-methyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2-piperidino-7-methyl-6-oxo-5 , 6-Dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2- (4-methylpiperidino) -7-methyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine , 2- (4-Ethylpiperidino) 7-methyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2-morpholino-7-methyl-6-oxo-5,6-dihydro (7H) pyrrolo [2, 3-d] pyrimidine, 2-thiomorpholino-7-methyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2-piperidino-7-ethyl-6-oxo-5 , 6-dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2-piperidino-7-n-propyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2 -Piperidino-7-isopropyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine,
2−ピペリジノ−7−n−ブチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペリジノ−7−t−ブチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペリジノ−5−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペラジノ−5−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペラジノ−4,7−ジメチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペリジノ−5,7−ジメチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペリジノ−5,5,7−トリメチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペラジノ−5,7−ジメチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペラジノ−5,5,7−トリメチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペリジノ−4メチル−7−エチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン、2−ピペリジノ−5−メチル−7−エチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジン。 2-piperidino-7-n-butyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2-piperidino-7-t-butyl-6-oxo-5,6- Dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2-piperidino-5-methyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2-piperazino-5 Methyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2-piperazino-4,7-dimethyl-6-oxo-5,6-dihydro (7H) pyrrolo [2, 3-d] pyrimidine, 2-piperidino-5,7-dimethyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2-piperidino-5,5,7-trimethyl- 6-oxo-5,6-dihydro ( H) pyrrolo [2,3-d] pyrimidine, 2-piperazino-5,7-dimethyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2-piperazino-5 5,7-trimethyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine, 2-piperidino-4methyl-7-ethyl-6-oxo-5,6-dihydro (7H ) Pyrrolo [2,3-d] pyrimidine, 2-piperidino-5-methyl-7-ethyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine.
本発明のピリミジン化合物類は、下記のような、様々なインビトロ、インビボ実験系で検討され、紫外線障害過程に効果的に作用し、紫外線防護及び/又はメラニン産生抑制活性を持つことが明らかにされた。即ち、280-320nmのUVBに対する防護効果は、ヒト表皮ケラチノサイトHaCaT細胞培養液に、0-500mMの本発明化合物をUVB照射前又は照射後に添加し、UVB(50, 100mJ/cm2)を曝露して、UVB曝露12, 24時間後の細胞生存率を、細胞外へのLDH漏出量の測定、DNA断片化の検出(TUNEL染色、アガロースゲル電気泳動法)により評価した。また、炎症性サイトカインであるTNF-αの産生量を、ELISA法にて測定した。本発明の化合物により、UVB曝露による細胞生存率の減少、アポトーシスの誘導が濃度依存的に抑制され、またUVB誘発性のTNF-α産生も有意に抑制される結果を得た。更にHaCaT細胞の増殖に対する本発明化合物の作用を調べたところ、本発明化合物は一般に細胞増殖を増加させることが分かった。 The pyrimidine compounds of the present invention have been studied in various in vitro and in vivo experimental systems as described below, and have been shown to effectively act in the process of UV damage and have UV protection and / or melanin production-inhibiting activities. It was. That is, the protective effect against UVB of 280-320 nm is obtained by adding 0-500 mM of the present compound before or after UVB irradiation to human epidermal keratinocyte HaCaT cell culture medium and exposing UVB (50, 100 mJ / cm2). The cell viability after 12 and 24 hours after UVB exposure was evaluated by measuring the amount of LDH leakage outside the cell and detecting DNA fragmentation (TUNEL staining, agarose gel electrophoresis). In addition, the production amount of TNF-α, which is an inflammatory cytokine, was measured by ELISA. With the compound of the present invention, the cell viability decrease and the induction of apoptosis by UVB exposure were suppressed in a concentration-dependent manner, and UVB-induced TNF-α production was also significantly suppressed. Further, when the effect of the compound of the present invention on the proliferation of HaCaT cells was examined, it was found that the compound of the present invention generally increases cell proliferation.
一方、メラニン産生抑制効果のスクリーニングは、マウスB16メラノーマ細胞を、100μMを中心に様々な濃度の本発明化合物の存在下で、72時間培養する実験系で行った。細胞内メラニン産生量を、アルカリ条件下でメラニンを可溶化し、その吸光度を測定することにより評価した。またメラニン産生に関与する細胞内Mitfおよびチロシナーゼ発現量への本発明化合物の影響を、Westernblot法にて検討した。本発明の化合物により、B16細胞のメラニン産生量が有意に抑制され、更に本発明化合物は細胞内Mitfおよびチロシナーゼの発現量を減少させる結果が得られた。マウスB16メラノーマ細胞に対する本発明の化合物の細胞毒性を、MTT法で調べたが、本発明化合物は一般に毒性は弱く、安全性の高い化合物であった。 On the other hand, screening for the melanin production inhibitory effect was performed in an experimental system in which mouse B16 melanoma cells were cultured for 72 hours in the presence of various concentrations of the compound of the present invention, mainly at 100 μM. Intracellular melanin production was evaluated by solubilizing melanin under alkaline conditions and measuring its absorbance. In addition, the influence of the compound of the present invention on the expression level of intracellular Mitf and tyrosinase involved in melanin production was examined by the Westernblot method. The compound of the present invention significantly suppressed the amount of melanin produced in B16 cells, and the compound of the present invention further reduced the expression levels of intracellular Mitf and tyrosinase. The cytotoxicity of the compound of the present invention against mouse B16 melanoma cells was examined by the MTT method. The compound of the present invention was generally low in toxicity and was a highly safe compound.
マウスやラットやモルモット等の背中の体毛を剃り、紫外線照射を行い、本発明化合物の紅斑、浮腫(発赤、湿疹、かぶれ)等の皮膚反応に対する作用を肉眼で観察し、紫外線防護作用を調べたところ、インビボでの効果が顕著に見られた。 The back hair of mice, rats, guinea pigs, etc. was shaved and irradiated with ultraviolet rays, and the effects of the compound of the present invention on skin reactions such as erythema and edema (redness, eczema, rash) were observed with the naked eye, and the ultraviolet protective effect was examined. However, the effect in vivo was noticeable.
このようにして、本発明の式(1)および式(2)のピリミジン類化合物は、UVB防護作用、及び/又は、細胞内Mitfおよびチロシナーゼの発現抑制を介したメラニン産生抑制作用を有することが示され、紫外線防護剤及び/又はメラニン産生抑制剤として有用であることが明らかにされた。 Thus, the pyrimidine compounds of the formulas (1) and (2) of the present invention have a UVB protective action and / or a melanin production inhibitory action through suppression of intracellular Mitf and tyrosinase expression. It was shown that it is useful as an ultraviolet protective agent and / or a melanin production inhibitor.
式(1)および式(2)のピリミジン類化合物またはその薬学的に許容される塩類は、通常医薬組成物や化粧品製剤の形で用いられ、皮膚透過、皮下、筋肉内、経口、静脈内、鼻内、経気管支、経肺及び直腸経路といった種々の経路により投薬される。 The pyrimidine compounds of formula (1) and formula (2) or pharmaceutically acceptable salts thereof are usually used in the form of pharmaceutical compositions and cosmetic preparations, and are percutaneous, subcutaneous, intramuscular, oral, intravenous, It is dosed by various routes such as intranasal, transbronchial, transpulmonary and rectal routes.
本発明の紫外線防護剤及び/又はメラニン産生抑制剤を含む医薬組成物あるいはしみやそばかす用化粧品や、日やけ、日光やけど後の色素沈着止め化粧料は、式(1)または式(2)の本発明の化合物に加えて、必要に応じて本発明の効果を損なわない範囲で、医薬組成物あるいは化粧品に、一般に用いられる製薬学的に許容される充填剤、結合剤、滑沢剤、湿潤剤、崩壊剤等々の賦形剤、添加剤、希釈剤あるいは担体と混合することができる。これら成分として、例えば、界面活性剤、酸化防止剤、増粘剤、防腐剤、保湿剤、界面活性剤、防腐剤、酸化防止剤、殺菌剤、香料、色素、粉末成分、油脂、ロウ類、炭化水素油、高級脂肪酸、高級アルコール、合成エステル油、シリコーン等を配合することができる。 The pharmaceutical composition containing the UV protective agent and / or the melanin production inhibitor of the present invention, the cosmetic for freckles and freckles, and the anti-pigmentation cosmetic after sunburn and sunburn are represented by the formula (1) or the formula (2). In addition to the compounds of the present invention, pharmaceutically acceptable fillers, binders, lubricants, and moisturizers that are generally used in pharmaceutical compositions or cosmetics as long as the effects of the present invention are not impaired as necessary. It can be mixed with excipients, additives, diluents or carriers such as agents and disintegrants. Examples of these components include surfactants, antioxidants, thickeners, preservatives, moisturizers, surfactants, antiseptics, antioxidants, bactericides, fragrances, dyes, powder components, fats and oils, waxes, Hydrocarbon oils, higher fatty acids, higher alcohols, synthetic ester oils, silicones and the like can be blended.
本発明は製薬的に許容される担体と活性成分としての式(1)および式(2)の化合物もしくはその薬学的に許容される塩を含有する製薬調合物を包含する。本発明の式(1)および式(2)の化合物の薬学的に許容しうる塩類としては、例えば、塩酸塩、臭化水素酸塩、硫酸塩、重硫酸塩、リン酸塩、酸性リン酸塩、酢酸塩、マレイン酸塩、フマル酸塩、コハク酸塩、乳酸塩、酒石酸塩、安息香酸塩、クエン酸塩、グルコン酸塩、糖酸塩、メタンスルホン酸塩、p−トルエンスルホン酸塩、ナフタレンスルホン酸塩などの薬学的に許容しうるアニオンを有する非毒性酸付加塩を形成する酸から形成される塩類もしくはそれらの水和物、並びに第4級アンモニウム(又はアミン)塩類もしくはそれらの水和物があげられる。 The present invention includes pharmaceutical formulations containing a pharmaceutically acceptable carrier and a compound of formula (1) and formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient. Examples of the pharmaceutically acceptable salts of the compounds of formula (1) and formula (2) of the present invention include hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, and acidic phosphoric acid. Salt, acetate, maleate, fumarate, succinate, lactate, tartrate, benzoate, citrate, gluconate, saccharide, methanesulfonate, p-toluenesulfonate , Salts formed from acids that form non-toxic acid addition salts with pharmaceutically acceptable anions such as naphthalene sulfonate, or hydrates thereof, and quaternary ammonium (or amine) salts, or their Hydrates.
本発明の組成物は、例えば軟膏、無菌注射液、乳濁液、乳液、懸濁液、エアロゾル、成形パップ、錠剤、カプセル、散剤、顆粒、トローチ、カシエー、エリキシル、シロップ、軟質及び硬質ゼラチンカプセル、alzet(登録商標)pumpカプセル、ペレット、坐薬及び無菌包装粉末などの形にすることができる。
経口投与の場合、式(1)および式(2)の化合物は、担体又は希釈剤と混合され、錠剤、カプセル剤などの形に調製される。非経口投与の場合、活性成分は10%ブドウ糖水溶液、等張食塩水、無菌水あるいは類似の液体に溶解され、静脈内に点滴または注射により、あるいは筋肉内注射により投与されるべくバイアル又はアンプルに密閉される。有利には、溶解補助剤や局所麻酔剤、保存剤及び緩衝剤も媒体中に含有させることもできる。安定性を増すために、本組成物をバイアル又はアンプルに注入した後に、凍結乾燥することも可能である。非経口投与の他の製剤としては、例えば軟膏剤、パップ剤などの経皮的に投与される製剤がある。この場合成型パップやテープ剤が有利である。また障害局所、組織、骨などの中に直接埋め込むペレット剤やalzet(登録商標)pumpカプセル剤などもある。ペレット作製に用いる樹脂としては、ポリ(2−ハイドロキシエチルメタアクリレート)や、エチレンビニルアセテートコポリマーなどが挙げられる。本組成物は、また患者に投薬の後、活性成分が急速に、持続的に又は遅延的に放出されるように調製することができる。
Compositions of the present invention include, for example, ointments, sterile injections, emulsions, emulsions, suspensions, aerosols, molded pops, tablets, capsules, powders, granules, troches, cashiers, elixirs, syrups, soft and hard gelatin capsules , Alzet® pump capsules, pellets, suppositories and sterile packaging powders.
For oral administration, the compounds of formula (1) and formula (2) are mixed with a carrier or diluent and prepared in the form of tablets, capsules and the like. For parenteral administration, the active ingredient is dissolved in 10% aqueous glucose solution, isotonic saline, sterile water, or a similar liquid and placed in a vial or ampoule to be administered intravenously by infusion or injection, or by intramuscular injection. Sealed. Advantageously, solubilizers, local anesthetics, preservatives and buffering agents can also be included in the medium. To increase the stability, the composition can be lyophilized after injection into a vial or ampoule. Other preparations for parenteral administration include preparations administered transdermally such as ointments and poultices. In this case, a molded patch or tape is advantageous. In addition, there are pellets and alzet (registered trademark) pump capsules that are directly embedded in damaged regions, tissues, bones, and the like. Examples of the resin used for pellet production include poly (2-hydroxyethyl methacrylate) and ethylene vinyl acetate copolymer. The composition can also be prepared so that the active ingredient is released rapidly, sustained or delayed after dosing to the patient.
製薬的に許容される担体(又は希釈剤)の例は、乳糖、ブドウ糖、蔗糖、ソルビトール、マンニトール、とうもろこし澱粉、結晶セルロース、アラビアゴム、リン酸カルシウム、アルギン酸塩、ケイ酸カルシウム、微結晶セルロース、ポリビニルピロリドン、トラガカントゴム、ゼラチン、シロップ、メチルセルロース、カルボキシメチルセルロース、メチルヒドロキシ安息香酸エステル、プロピルヒドロキシ安息香酸エステル、タルク、ステアリン酸マグネシウム、不活性なポリマー類、水又は鉱油などである。 Examples of pharmaceutically acceptable carriers (or diluents) are lactose, glucose, sucrose, sorbitol, mannitol, corn starch, crystalline cellulose, gum arabic, calcium phosphate, alginate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone Tragacanth gum, gelatin, syrup, methylcellulose, carboxymethylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, inert polymers, water or mineral oil.
本組成物は、単位投薬量形状にあたり一般に0.1ないし2000mg、好ましくは0.5ないし1000mgの活性成分を含有する。式(1)および式(2)の化合物は広い投薬量範囲にわたって有効である。例えば、1日あたりの投薬量は普通0.03mg/kgないし100mg/kgの範囲である。実際に投与される化合物の量は、投与される化合物により、また個々の患者の年令、体重、反応、症状の程度、投与経路等により、医者により決定される。従って、上記の投薬量範囲は本発明の範囲を限定するものではない。1日あたりの好適な投薬回数は通常1〜6回、好ましくは1〜4回である。また、本発明化合物は美白効果を併せ持つ新規紫外線防護剤として期待され、クリーム、ローション、軟膏、パック、パウダーあるいは化粧水、乳液などの形態の皮膚外用剤、化粧品製剤として、当該技術分野で周知の調製方法で、調製される。1日あたりの好適な塗布回数は、医薬組成物に準じると良い。 The compositions generally contain from 0.1 to 2000 mg, preferably from 0.5 to 1000 mg of active ingredient per unit dosage form. The compounds of formula (1) and formula (2) are effective over a wide dosage range. For example, the daily dosage is usually in the range of 0.03 mg / kg to 100 mg / kg. The amount of compound actually administered will be determined by the physician depending on the compound being administered and on the age, weight, response, severity of symptoms, route of administration, etc. of the individual patient. Accordingly, the above dosage ranges do not limit the scope of the invention. The preferred number of doses per day is usually 1-6 times, preferably 1-4 times. Further, the compound of the present invention is expected as a novel ultraviolet protective agent having a whitening effect, and is well known in the art as a skin external preparation or cosmetic preparation in the form of cream, lotion, ointment, pack, powder or skin lotion, emulsion, etc. Prepared by the preparation method. The preferred number of applications per day may be in accordance with the pharmaceutical composition.
式(1)および(2)の化合物は、それ自体で有効な紫外線防護剤及び/又はメラニン産生抑制剤であるが、必要ならば1種又はそれ以上の他の同効剤と組合せて投薬ないしは塗布することもできる。そのような付加的な薬剤には上記のような紫外線防護剤やメラニン産生抑制剤があげられる。
本発明の治療薬に用いる式(1)および式(2)の化合物の製造例は既に、本発明者らが特許出願および論文発表をしているので、それらを参考としたい(特許文献2〜7や非特許文献3および4)。
以下に、本発明を実施例および実験例をもってより詳細に説明するが、本発明はこれらに限定されるものではない。
The compounds of formulas (1) and (2) are effective UV protection agents and / or melanin production inhibitors per se, but may be administered in combination with one or more other synergists if necessary. It can also be applied. Examples of such additional drugs include UV protection agents and melanin production inhibitors as described above.
Since the present inventors have already filed patent applications and published papers for the preparation examples of the compounds of formula (1) and formula (2) used in the therapeutic agent of the present invention, we would like to refer to them (Patent Documents 2 to 2). 7 and Non-Patent Documents 3 and 4).
Hereinafter, the present invention will be described in more detail with reference to examples and experimental examples, but the present invention is not limited thereto.
実施例1
活性成分10mgを含有する錠剤は以下のようにして製造される。
錠剤当り
活性成分 10mg
トウモロコシデンプン 55mg
結晶セルロース 35mg
ポリビニルピロリドン(10%水溶液として) 5mg
カルボキシメチルセルロース・カルシウム 10mg
ステアリン酸マグネシウム 4mg
タルク 1mg
───────────────────────────────
合計 120mg
活性成分、澱粉および結晶セルロースを80メッシュふるいを通し、完全に混合する。得られた粉末にポリビニルピロリドン溶液を混合し造粒した後、18メッシュのふるいを通す。このように製造した顆粒を50〜60℃で乾燥し、再度18メッシュのふるいにより整粒する。前もって80メッシュのふるいにかけておいたカルボキシメチルセルロースカルシウムおよびステアリン酸マグネシウムおよびタルクを顆粒に加え、混合した後、製錠機により各々120mgの重量の錠剤を製造する。
Example 1
A tablet containing 10 mg of the active ingredient is produced as follows.
Per tablet
Active ingredient 10mg
Corn starch 55mg
Crystalline cellulose 35mg
Polyvinylpyrrolidone (as 10% aqueous solution) 5mg
Carboxymethylcellulose calcium 10mg
Magnesium stearate 4mg
Talc 1mg
───────────────────────────────
120mg total
The active ingredient, starch and crystalline cellulose are passed through an 80 mesh screen and mixed thoroughly. The resulting powder is mixed with a polyvinylpyrrolidone solution and granulated, and then passed through an 18-mesh sieve. The granules thus produced are dried at 50-60 ° C. and sized again with an 18 mesh screen. Carboxymethylcellulose calcium and magnesium stearate and talc, previously screened through an 80 mesh screen, are added to the granules, mixed, and then tableted into tablets weighing 120 mg each.
実施例2
活性成分200mgを含有する錠剤は以下のようにして製造される。
錠剤当り
活性成分 200mg
トウモロコシデンプン 50mg
結晶セルロース 42mg
軽質無水ケイ酸 7mg
ステアリン酸マグネシウム 1mg
───────────────────────────────
合計 300mg
上記成分を80メッシュふるいを通し、完全に混合する。得られた粉末を圧縮成形し、重量300mgの錠剤を製造する。
Example 2
A tablet containing 200 mg of the active ingredient is produced as follows.
Per tablet
Active ingredient 200mg
Corn starch 50mg
Crystalline cellulose 42mg
Light anhydrous silicic acid 7mg
Magnesium stearate 1mg
───────────────────────────────
300mg total
The ingredients are passed through an 80 mesh screen and mixed thoroughly. The obtained powder is compression-molded to produce a tablet having a weight of 300 mg.
実施例3
活性成分100mgを含有するカプセル剤は以下のようにして製造される。
カプセル当り
活性成分 100mg
トウモロコシデンプン 40mg
乳糖 5mg
ステアリン酸マグネシウム 5mg
───────────────────────────────
合計 150mg
上記成分を混ぜ合せ、80メッシュふるいを通し、完全に混合する。得られた粉末を150mgずつカプセルに充填する。
Example 3
Capsules containing 100 mg of active ingredient are produced as follows.
Per capsule
Active ingredient 100mg
Corn starch 40mg
Lactose 5mg
Magnesium stearate 5mg
───────────────────────────────
150mg total
Mix the above ingredients and pass through 80 mesh sieve and mix thoroughly. 150 mg of the obtained powder is filled into a capsule.
実施例4
活性成分5mgを含有するバイアル入り用時溶解注射剤は以下のようにして製造される。
バイアル当り
活性成分 5mg
マンニトール 50mg
用時、注射用蒸留水1mlを用いて溶解し、使用する。
Example 4
A vial-in-solution injection containing 5 mg of the active ingredient is produced as follows.
Per vial
Active ingredient 5mg
Mannitol 50mg
At the time of use, dissolve and use 1 ml of distilled water for injection.
実施例5
活性成分50mgを含有するアンプル入り注射剤は以下のようにして製造される。
アンプル当り
活性成分 50mg
塩化ナトリウム 18mg
注射用蒸留水 適量
───────────────────────────────
合計 2ml
Example 5
An ampoule-containing injection containing 50 mg of the active ingredient is produced as follows.
Per ampoule
Active ingredient 50mg
Sodium chloride 18mg
Distilled water for injection ───────────────────────────────
2ml total
実施例6
活性成分17.5mgを含有する粘着性貼付製剤は以下のようにして製造される。ポリアクリル酸アンモニウム10部を水60部に溶解する。一方グリセリンジグリシジルエーテル2部を水10部に加熱しつつ溶解する。更にもう一方でポリエチレングリコール(グレード400)10部、水10部、活性成分1部を撹拌溶解する。ついでポリアクリル酸アンモニウムの水溶液を撹拌しつつ、グリセリンジグリシジルエーテルの水溶液及びポリエチレングリコールの活性成分含有水溶液を添加混合した薬物含有含水ゲル用溶液を、柔軟性のあるプラスチックフィルムに活性成分が平方センチメートル当り0.5mgとなるように塗布し、表面を剥離紙で覆い35平方センチメートルに切断し、製剤とした。
Example 6
An adhesive patch preparation containing 17.5 mg of the active ingredient is produced as follows. 10 parts of ammonium polyacrylate are dissolved in 60 parts of water. On the other hand, 2 parts of glycerin diglycidyl ether is dissolved in 10 parts of water while heating. On the other hand, 10 parts of polyethylene glycol (grade 400), 10 parts of water, and 1 part of active ingredient are stirred and dissolved. Then, while stirring the aqueous solution of ammonium polyacrylate, the aqueous solution of drug-containing gel containing an aqueous solution of glycerin diglycidyl ether and an active ingredient of polyethylene glycol was added and mixed into a flexible plastic film with an active ingredient per square centimeter. It was applied to 0.5 mg, and the surface was covered with release paper and cut into 35 square centimeters to prepare a preparation.
実施例7
活性成分10mgを含有する粘着性貼付製剤は以下のようにして製造される。ポリアクリル酸ナトリウム100部、グリセリン100部、水150部、トリエポキシプロピルイソシアヌレート0.2部、エタノール100部、ミリスチン酸イソプロピル25部、プロピレングリコール25部及び活性成分15部の混合水溶ゾル液を調製した。次にこのゾル液をレーヨン不織物とポリエチレンフィルムとからなる複合フィルムの不織布面に100μm厚に塗布して薬剤含有の粘着剤層を形成した。この層中に含まれる放出補助物質(ミリスチン酸イソプロピルとプロピレングリコール)の含量は約20重量%であった。その後25℃で24時間架橋し、上記粘着剤界面に剥離フィルムを貼り合せ、更にこれを35平方センチメートルに切断し製剤とした。
Example 7
An adhesive patch preparation containing 10 mg of the active ingredient is produced as follows. A mixed aqueous sol solution of 100 parts of sodium polyacrylate, 100 parts of glycerin, 150 parts of water, 0.2 part of triepoxypropyl isocyanurate, 100 parts of ethanol, 25 parts of isopropyl myristate, 25 parts of propylene glycol and 15 parts of active ingredient Prepared. Next, this sol solution was applied to a nonwoven fabric surface of a composite film composed of a rayon nonwoven fabric and a polyethylene film in a thickness of 100 μm to form a drug-containing pressure-sensitive adhesive layer. The content of release auxiliary substances (isopropyl myristate and propylene glycol) contained in this layer was about 20% by weight. Thereafter, it was cross-linked at 25 ° C. for 24 hours, a release film was bonded to the pressure-sensitive adhesive interface, and this was further cut into 35 square centimeters to obtain a preparation.
実施例8
ポリ(2−ハイドロキシエチルメタアクリレート)(Polysciences, Inc.)の粗い砂状結晶を、すり鉢に入れ、すりこぎを用いて、クリーンベンチ内で無菌的に粉末状に細かく砕いた。滅菌シャーレーにこの粉末10mgをとり、99%エチルアルコールを10μlと活性成分0.5mgを含む水溶液10μlとを加え、よく攪拌して糊状の塊とした後、乾燥させた。
Example 8
Coarse sandy crystals of poly (2-hydroxyethyl methacrylate) (Polysciences, Inc.) were placed in a mortar and finely pulverized aseptically in a clean bench using a pestle. 10 mg of this powder was taken in a sterile petri dish, 10 μl of 99% ethyl alcohol and 10 μl of an aqueous solution containing 0.5 mg of the active ingredient were added, stirred well to form a paste-like lump, and then dried.
実施例9
水中油クリーム作製用の基剤成分として用いるモノステアリン酸グリセリン10%重量、流動パラフィン10%重量、POE(30)セチルエーテル2%重量、 セチルアルコール5%重量、ワセリン4%重量およびγ−トコフェロールに活性成分1%重量を加えて各成分を混合し、80℃に加熱した。一方、精製水 56%重量と1,3−ブチレングリコール10%重量を混合し、80℃に加熱した。両方の混合物を混ぜて、撹拌して乳化させ、その後35℃にまで冷却して、水中油クリームを製造した。
Example 9
10% by weight of glyceryl monostearate, 10% by weight of liquid paraffin, 2% by weight of POE (30) cetyl ether, 5% by weight of cetyl alcohol, 4% by weight of petrolatum and γ-tocopherol used as a base component for the preparation of oil-in-water cream 1% by weight of the active ingredient was added and the ingredients were mixed and heated to 80 ° C. On the other hand, 56% by weight of purified water and 10% by weight of 1,3-butylene glycol were mixed and heated to 80 ° C. Both mixtures were mixed and stirred to emulsify, then cooled to 35 ° C. to produce an oil-in-water cream.
実施例10
実施例9同様の各種成分を用い、親水性化合物を固体状態で油脂性基剤に溶解させ、油相へ封入するSolid in Oil技術を応用して、経皮製剤を製造した。
Example 10
Using the same various components as in Example 9, a transdermal preparation was produced by applying the Solid in Oil technique in which a hydrophilic compound was dissolved in an oily base in a solid state and encapsulated in an oil phase.
実施例11
紫外線曝露されたHaCaT細胞に対する本発明化合物の作用
DMEM培地で40mmディシュに培養されたHaCaT細胞にUVB照射を行った。50ないし100mJ/cm2のUVB照射前後に様々な濃度の本発明化合物を添加して、24時間培養後、上清のLDH(乳酸脱水素酵素)含有量を測定した。対照は、UVBを照射せず、本発明化合物を加えていない細胞の培養後の上清のLDH含有量とした。LDH含有量をもとに、細胞生存率%を求め、本発明化合物の効果を下記に示す。UVB照射のみ群の細胞生存率に対する有意差を( )内に示す。無処置群の細胞生存率は、91.39±0.32%であった。UVB50mJ/cm2照射のみ群の細胞生存率は59.91±2.50%であり、UVB100mJ/cm2照射のみ群の細胞生存率は52.19±2.07%であった。
Example 11
Effects of compounds of the present invention on HaCaT cells exposed to ultraviolet light
HaB cells were irradiated on HaCaT cells cultured in 40 mm dish in DMEM medium. Various concentrations of the compound of the present invention were added before and after UVB irradiation of 50 to 100 mJ / cm 2, and after incubation for 24 hours, the LDH (lactate dehydrogenase) content of the supernatant was measured. As a control, the LDH content of the supernatant after culturing of cells not irradiated with UVB and not added with the compound of the present invention was used. Based on the LDH content, the cell viability% was determined, and the effects of the compound of the present invention are shown below. The significant difference with respect to the cell viability of the UVB irradiation only group is shown in parentheses. The cell survival rate of the untreated group was 91.39 ± 0.32%. The cell survival rate of the UVB50mJ / cm2 irradiation only group was 59.91 ± 2.50%, and the cell survival rate of the UVB100mJ / cm2 irradiation only group was 52.19 ± 2.07%.
2−ピペラジノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジンマレイン酸塩を添加した場合、50mJ/cm2のUVB照射前添加の場合、50、250、500μMそれぞれ、66.34±1.72%(p<0.05)、76.55±2.76%(p<0.005)、83.31±0.54%(p<0.005)であった。50mJ/cm2のUVB照射後添加の場合、50、250、500μMそれぞれ、64.35±3.29%、66.61±3.44%、70.81±2.67%(p<0.01)であった。100mJ/cm2のUVB照射前添加の場合、50、250、500μMそれぞれ、57.59±1.35%(p<0.05)、61.62±4.71%(p<0.005)、71.89±1.09%(p<0.005)であった。100mJ/cm2のUVB照射後添加の場合、50、250、500μMそれぞれ、49.93±4.99%、59.43±1.97%(p<0.01)、55.07±3.08%であった。このように、本発明化合物によってUVBによる細胞死が濃度依存的に、有意に抑制されることが明らかにされた。 When 2-piperazino-6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine maleate is added, 50 mJ / cm 2 before UVB irradiation is added; They were 66.34 ± 1.72% (p <0.05), 76.55 ± 2.76% (p <0.005), and 83.31 ± 0.54% (p <0.005), respectively. In the case of addition after 50 mJ / cm 2 UVB irradiation, the values were 64.35 ± 3.29%, 66.61 ± 3.44%, and 70.81 ± 2.67% (p <0.01), respectively. When added to 100 mJ / cm2 before UVB irradiation, they were 57.59 ± 1.35% (p <0.05), 61.62 ± 4.71% (p <0.005), and 71.89 ± 1.09% (p <0.005), respectively. . In the case of addition after 100 mJ / cm 2 UVB irradiation, they were 49.93 ± 4.99%, 59.43 ± 1.97% (p <0.01), and 55.07 ± 3.08%, respectively. Thus, it was clarified that cell death by UVB is significantly suppressed by the compound of the present invention in a concentration-dependent manner.
実施例12
HaCaT細胞のUVB照射による細胞のクロマチン凝集およびDNA断片化に対する本発明化合物の効果
HaCaT細胞培養に、50ないし100mJ/cm2のUVB照射前に、500μMの2−ピペラジノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジンマレイン酸塩を添加した場合、12時間後の細胞生存率は、約250個の細胞をカウントしたが、UVB照射非添加群が、無処置群に比べ70%に落ちたのに対して、ほぼ無処置群程度に回復した(p<0.005)。また、UVB照射による12時間後のクロマチン凝集が、本発明化合物添加により抑制されることが、Hoechst33342を用いて細胞核を染色し、アポトーシス細胞特異的な核の形態変化の蛍光顕微鏡観察で示された。一方、HaCaT細胞のUV照射DNA断片化が、本発明化合物の添加により抑制されることが、Tunel染色による蛍光顕微鏡観察で示された。
また、細胞溶解後の抽出DNA断片をアガロースゲル電気泳動して、Ethidium bromide染色によるDNAの蛍光を、UVトランスイルミネーターを用いて検出することによっても、UV照射DNA断片化は、本発明化合物の添加により抑制されることが明らかにされた。
Example 12
Effects of the compounds of the present invention on cell chromatin aggregation and DNA fragmentation by UVB irradiation of HaCaT cells
HaCaT cell culture was subjected to 500 μM 2-piperazino-6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine maleate prior to 50-100 mJ / cm 2 UVB irradiation. The cell viability after 12 hours counted about 250 cells, but the UVB-irradiated group dropped to 70% compared to the untreated group, while the almost untreated group It recovered to the extent (p <0.005). In addition, the addition of the compound of the present invention inhibits the aggregation of chromatin after 12 hours due to UVB irradiation by staining cell nuclei with Hoechst33342, which was shown by fluorescence microscope observation of apoptotic cell-specific nuclear morphological changes. . On the other hand, it was shown by fluorescence microscope observation by Tunel staining that UV irradiation DNA fragmentation of HaCaT cells was suppressed by the addition of the compound of the present invention.
Further, UV-irradiated DNA fragmentation can be achieved by subjecting the extracted DNA fragment after cell lysis to agarose gel electrophoresis and detecting the fluorescence of DNA by Ethidium bromide staining using a UV transilluminator. It was clarified that the addition was suppressed.
実施例13
HaCaT細胞へのUVB照射によるTNF-α産生に対する本発明化合物の効果
TNF-α特異的なELISA測定系で、HaCaT細胞の培養上清のTNF-α含量の測定を行ったところ、50mJ/cm2のUVB照射24時間後のTNF-α量は3.62±0.37pg/mlであり、100mJ/cm2のUVB照射24時間後のTNF-α量は4.98±0.31pg/mlであり、無処置群は、2.67±0.47pg/mlであった。2−ピペラジノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジンマレイン酸塩を50mJ/cm2照射前に添加した場合、50、250、500μMそれぞれ、TNF-α量は2.02±0.88pg/ml、1.31±0.57pg/
ml(p<0.01)0.61±0.57pg/ml(p<0.005)であった。( )内は、50mJ/cm2のUVB照射群との有意差検定のp値である。2−ピペラジノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジンマレイン酸塩を100mJ/cm2照射前に添加した場合、50、250、500μMそれぞれ、 TNF-α量は4.21±0.27pg/ml(p<0.05)、3.00±0.80pg/ml(p<0.05)、2.67±0.47pg/ml(p<0.005)であった。( )内は、100mJ/cm2のUVB照射群との有意差検定のp値である。本発明の化合物添加により、UVB誘発性のTNF-α産生も有意に抑制されることが明らかにされた。
Example 13
Effect of the compound of the present invention on TNF-α production by UVB irradiation to HaCaT cells
When TNF-α content of the culture supernatant of HaCaT cells was measured using a TNF-α-specific ELISA measurement system, the amount of TNF-α after UVB irradiation at 50 mJ / cm2 was 3.62 ± 0.37 pg / ml The amount of TNF-α after 24 hours of UVB irradiation at 100 mJ / cm 2 was 4.98 ± 0.31 pg / ml, and the untreated group was 2.67 ± 0.47 pg / ml. When 2-piperazino-6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine maleate was added before 50 mJ / cm 2 irradiation, 50, 250, 500 μM, TNF-α amount is 2.02 ± 0.88pg / ml, 1.31 ± 0.57pg / ml
ml (p <0.01) 0.61 ± 0.57 pg / ml (p <0.005). The values in parentheses are p-values for a significant difference test with the 50 mJ / cm 2 UVB irradiation group. When 2-piperazino-6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine maleate was added before 100 mJ / cm 2 irradiation, 50, 250, 500 μM, The amounts of TNF-α were 4.21 ± 0.27 pg / ml (p <0.05), 3.00 ± 0.80 pg / ml (p <0.05), and 2.67 ± 0.47 pg / ml (p <0.005). The values in parentheses are p-values for a significant difference test with the 100 mJ / cm 2 UVB irradiation group. It was revealed that UVB-induced TNF-α production was also significantly suppressed by the addition of the compound of the present invention.
実施例14
HaCaT細胞培養に50μM、250μM、500μMの2−ピペラジノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジンマレイン酸塩を添加し、6時間培養後、1μCi/ディシュの3H-チミジンを加え18時間後、細胞増殖に対する本発明化合物の作用を調べたところ、濃度依存的に細胞増殖を増加させることが分かった。
Example 14
50 μM, 250 μM and 500 μM 2-piperazino-6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine maleate was added to the HaCaT cell culture and cultured for 6 hours. After adding 1 μCi / dish of 3H-thymidine and examining the effect of the compound of the present invention on cell proliferation 18 hours later, it was found that cell proliferation was increased in a concentration-dependent manner.
実施例15
B16メラノーマ細胞におけるメラニン産生に対する本発明化合物の作用
B16メラノーマ細胞を6ウェルプレートに1×105 cells/wellでD-MEM培地にまいて、24時間培養し、新しい培地に換え、この時、PBSに溶解した本発明化合物を加えて全量を2mlとした(培地1.8ml+本発明化合物/PBS 200μl)。ついで、72時間培養を続けた後、細胞を洗い、EDTA0.025%を600μl/well加え、細胞をはがしこみ1.5ml チューブに回収した。そしてチューブを700gで5分間遠心した。ついで、細胞を含む50μlほどを残して、上清を捨て、1N NaOH を100μl/チューブ加えた。これを80℃で1時間保温した。それから、ウェルプレートに100μl/ウェル移し、波長405nmで吸光度を測定した。100μMの2−ピペラジノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジンマレイン酸塩を添加した場合、タンパク質量補正後の、メラニン産生量は、対照に比べて、62.7%(P<0.005)となり、本発明化合物のメラニン産生抑制作用が顕著であった。
Example 15
Effects of the compounds of the present invention on melanin production in B16 melanoma cells
B16 melanoma cells are spread in a 6-well plate at 1 x 105 cells / well in D-MEM medium, cultured for 24 hours, replaced with fresh medium, and at this time, the compound of the present invention dissolved in PBS is added to make a total volume of 2 ml. (1.8 ml of medium + 200 μl of the present compound / PBS). Subsequently, after culturing for 72 hours, the cells were washed, EDTA 0.025% was added at 600 μl / well, and the cells were peeled off and collected in a 1.5 ml tube. The tube was then centrifuged at 700 g for 5 minutes. Then, leaving about 50 μl containing cells, the supernatant was discarded, and 100 μl / tube of 1N NaOH was added. This was kept at 80 ° C. for 1 hour. Then, it was transferred to a well plate at 100 μl / well, and the absorbance was measured at a wavelength of 405 nm. When 100 μM 2-piperazino-6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine maleate is added, the amount of melanin produced after protein amount correction is Compared to the control, it was 62.7% (P <0.005), and the melanin production inhibitory action of the compound of the present invention was remarkable.
実施例16
B16メラノーマ細胞におけるMitfおよびチロシナーゼの発現量に対する本発明化合物の作用
60mmディシュで80%コンフルエント程度で培養したB16細胞を溶解後、本発明の化合物の添加が、72時間後、細胞内Mitfおよびチロシナーゼの発現量にどう影響するかwestern blot法により検討したところ、10μM、50μM、100μMの2−ピペラジノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジンマレイン酸塩を添加した場合、濃度依存的に、Mitfおよびチロシナーゼの発現量を減少させる結果が得られた。
Example 16
Effects of the compounds of the present invention on the expression levels of Mitf and tyrosinase in B16 melanoma cells
After lysing B16 cells cultured at about 80% confluence in a 60 mm dish, the effect of addition of the compound of the present invention on the expression level of intracellular Mitf and tyrosinase after 72 hours was examined by Western blot. , 50 μM, 100 μM 2-piperazino-6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine maleate in a concentration-dependent manner, Mitf and tyrosinase The result which decreased the expression level of was obtained.
実施例17
B16メラノーマ細胞に対する本発明化合物の細胞毒性をMTTアッセイで測定した。2−ピペラジノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジンマレイン酸塩を添加し、72時間インキュベート後の場合、5〜100μMの濃度範囲では、ほぼ90%の細胞生存率であり、毒性が弱い物質であることが示された。
Example 17
The cytotoxicity of the compounds of the present invention against B16 melanoma cells was measured by MTT assay. When 2-piperazino-6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine maleate is added and incubated for 72 hours, in the concentration range of 5-100 μM The cell viability was almost 90%, indicating that the substance is weakly toxic.
実施例18
5〜8週齢ICR雄マウスを用い、マウス背中の体毛をバリカンで剃毛した後、少なくも半日〜1日経過した皮膚に、20μlの100μM、250μMないし500μMの2−ピペラジノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジンマレイン酸塩、2−(4−メチルピペラジノ)−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジンマレイン酸塩、2−ピペラジノ−7−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジンマレイン酸塩、2−ピペリジノ−7−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジンマレイン酸塩、2−(4−エチルピペリジノ)−7−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジンマレイン酸塩等本発明の化合物を塗布した。塗布部はドライヤーを用いて冷風乾燥した後、50 mJ/cm2の照射強度のUVB紫外線照射を行った。本発明の化合物を塗布後2週間を通して、毎日観察したが、発赤、湿疹、かぶれ等の皮膚の異常反応は、非塗布部分に比べ検出されなかった。また、体重増加は、対照群マウスと同様の増加推移をたどり、特に異常所見は認められなかった。
Example 18
Using 5 to 8 week-old ICR male mice, the hair on the back of the mice was shaved with a clipper, and then 20 μl of 100 μM, 250 μM to 500 μM 2-piperazino-6-methyl- 5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine maleate, 2- (4-methylpiperazino) -6-methyl-5-oxo-5,6-dihydro (7H) pyrrolo [3,4-d] pyrimidine maleate, 2-piperazino-7-methyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine maleate, 2-piperidino-7 -Methyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine maleate, 2- (4-ethylpiperidino) -7-methyl-6-oxo-5,6-dihydro ( 7H) Pirolo [2, -d] was applied compound pyrimidine maleate salt present invention. The coated part was dried with cold air using a dryer, and then irradiated with UVB ultraviolet rays having an irradiation intensity of 50 mJ / cm2. When the compound of the present invention was observed every day for 2 weeks after application, abnormal skin reactions such as redness, eczema and rash were not detected as compared with the non-application area. In addition, the body weight gain followed the same increasing trend as in the control group mice, and no abnormal findings were observed.
実施例19
UV吸収スペクトル:本発明化合物の50μMのそれぞれの水溶液を石英セル(光路長1cm)に入れ、UV吸収能を紫外線分光光度計で測定したところ、2−ピペラジノ−6−メチル−5−オキソ−5,6−ジヒドロ(7H)ピロロ〔3,4−d〕ピリミジンマレイン酸塩は、272.6nmに最大値を持ち、2−ピペラジノ−7−メチル−6−オキソ−5,6−ジヒドロ(7H)ピロロ〔2,3−d〕ピリミジンマレイン酸塩は、301.0nmに最大値を持つことが示された。
Example 19
UV absorption spectrum: 50 μM of each aqueous solution of the compound of the present invention was placed in a quartz cell (optical path length: 1 cm), and UV absorption was measured with an ultraviolet spectrophotometer. 2-piperazino-6-methyl-5-oxo-5 , 6-Dihydro (7H) pyrrolo [3,4-d] pyrimidine maleate has a maximum at 272.6 nm and is 2-piperazino-7-methyl-6-oxo-5,6-dihydro (7H) pyrrolo [2,3-d] pyrimidine maleate was shown to have a maximum at 301.0 nm.
実施例20
トリオクタン酸グリセリル5%、スクアラン5%、グリセリン5%、 液状ラノリン3%、ステアリルアルコール2%、トリオクタン酸トリメチロールプロパン 2%、モノオレイン酸グリセリル2%、モノステアリン酸ポリオキシエチレン(20モル)ソルビタン1%、トリエタノールアミン1%、カルビキシビニルポリマー0.2%、p-アミノ安息香酸 0.1%、ビタミンC 0.1%を用いて、有効成分1%と、それぞれ重量比で、混合した。
更に香料少量、重硫酸ナトリウム少量、防腐剤少量、蒸留水残りを加えて乳液が調製された。
Example 20
Glyceryl trioctanoate 5%, squalane 5%, glycerin 5%, liquid lanolin 3%, stearyl alcohol 2%, trimethylolpropane trioctanoate 2%, glyceryl monooleate 2%, polyoxyethylene monostearate (20 mol) sorbitan 1%, 1% triethanolamine, 0.2% carboxyvinyl polymer, 0.1% p-aminobenzoic acid, 0.1% vitamin C were mixed with 1% active ingredient in a weight ratio.
Further, a milky lotion was prepared by adding a small amount of perfume, a small amount of sodium bisulfate, a small amount of preservative, and the remaining distilled water.
実験例1
本発明の化合物を雄性ddy系5週令マウスおよび雄性ウィスター系8週令ラットに経口投与し、24時間後に毒性を判定したが、それぞれの化合物はマウスにおいて、LD50値が、>1000mg/kgないし550〜1000mg/kgであり、ラットにおいても>1700mg/kgないし550〜1000mg/kgであり、一般に毒性が弱い、安全性の高い薬剤と考えられた。個々の値については既に公開ないし登録された本発明者らの特許出願した明細書に記載されている。
Experimental example 1
The compounds of the present invention were orally administered to male ddy-type 5-week-old mice and male Wistar-type 8-week-old rats, and toxicity was determined after 24 hours. Each compound had an LD50 value of> 1000 mg / kg or less in mice. It was 550 to 1000 mg / kg, and it was also> 1700 mg / kg to 550 to 1000 mg / kg in rats, and it was generally considered to be a highly safe drug with low toxicity. The individual values are described in the specification of the patent application already filed or registered by the present inventors.
以上のように本発明により見い出された化合物は紫外線吸収剤、紫外線防護剤及び/又はメラニン産生抑制剤としての用途に優れ、安全性の高い医薬組成物あるいは、しみやそばかす用化粧品や、日やけ、日光やけど後の色素沈着止め化粧料、美肌作用化粧料として有用である。紫外線障害とされている、メラノーマ、皮膚がん等悪性腫瘍や、皮膚炎症、皮膚のしわ形成や白内障等の発症の予防・抑制にも効果を示すと考えられる。 As described above, the compounds found by the present invention are excellent in use as ultraviolet absorbers, ultraviolet protective agents and / or melanin production inhibitors, and are highly safe pharmaceutical compositions, stains and freckles cosmetics, sunscreens, and the like. It is useful as an anti-pigmentation cosmetic after sunburn, and as a beautifying cosmetic. It is considered to be effective in preventing and suppressing the onset of malignant tumors such as melanoma and skin cancer, skin inflammation, skin wrinkle formation, and cataracts, which are considered to be UV damage.
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