JP6628252B2 - 虚血性眼疾患の処置用の医薬組成物 - Google Patents
虚血性眼疾患の処置用の医薬組成物 Download PDFInfo
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- JP6628252B2 JP6628252B2 JP2016505296A JP2016505296A JP6628252B2 JP 6628252 B2 JP6628252 B2 JP 6628252B2 JP 2016505296 A JP2016505296 A JP 2016505296A JP 2016505296 A JP2016505296 A JP 2016505296A JP 6628252 B2 JP6628252 B2 JP 6628252B2
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- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
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- 235000005985 organic acids Nutrition 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical class O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
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- 239000003380 propellant Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
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- 230000009467 reduction Effects 0.000 description 1
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- 125000006413 ring segment Chemical group 0.000 description 1
- 238000005185 salting out Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001760 tenon capsule Anatomy 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 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
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
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- 239000001993 wax Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
-
- 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
-
- 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
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Ophthalmology & Optometry (AREA)
- Urology & Nephrology (AREA)
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Description
また、高眼圧による動脈の圧迫に起因する眼虚血により、視神経疾患または視神経障害が生じる場合がある。
Raはそれぞれ独立して、ハロ、ヒドロキシ、アルキル、ハロ置換アルキル、アリール、ハロまたはアルキル置換アリール、アルコキシ、ヒドロキシまたはカルボキシ置換アルコキシ、アリールオキシ、ハロまたはアルキル置換アリールオキシ、CHO、C(O)−アルキル、C(O)−アリール、C(O)−アルキル−カルボキシル、C(O)−アルキレン−カルボキシエステルおよびシアノから成る群から選択され、
mは0〜4から選択される整数である〕
の化合物またはそのオキシド、エステル、プロドラッグ、薬学的に許容される塩もしくは溶媒和物(以下、本発明の化合物と称する)を提供する。
特に具体的な定めのない限り、本明細書で使用される用語は、有機化学、医学、薬学、分子生物学、微生物学等の分野における当業者に一般に理解されるとおりの意味を有する。以下にいくつかの本明細書で使用される用語についての定義を記載するが、これらの定義は、本明細書において、一般的な理解に優先する。
「アリールオキシ」は、−O−アリール(ここで、アリールは本明細書に定義されている)の基を意味し、例えばフェノキシおよびナフトキシを含む。
「カルボキシル」または「カルボキシ」は−COOHまたはその塩を意味する。
「カルボキシルエステル」または「カルボキシエステル」は、−C(O)O−アルキル(ここで、アルキルは本明細書に定義されている)の基を意味する。
「ハロ」または「ハロゲン」はフルオロ、クロロ、ブロモおよびヨードを意味する。
「ヒドロキシ」または「ヒドロキシル」は−OHの基を意味する。
本発明のある実施態様では、少なくとも1種の式(I)の化合物を、単独でまたはさらなる薬剤とともに含み、ヒトまたは動物対象への投与に適した薬学的に許容される担体を含む、虚血性眼疾患の処置用の医薬組成物が提供される。
化合物32:4−アミノ−3−[6−(4−フルオロ−2−メチルフェニル)ピリジン−3−イルアゾ]ナフタレン−1−スルホン酸ナトリウム塩の合成
2−クロロ−5−ニトロピリジン(5.0g、31.5mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0.35g、0.3mmol)を1,2−ジメトキシエタン(50ml)に加え、減圧下で脱気、窒素置換を3回行った。窒素雰囲気下、室温で20分間撹拌後、4−フルオロ−2−メチルフェニルボロン酸(31.5mmol)、2M炭酸ナトリウム水溶液(31.5ml)を注加し、80℃に昇温した。80℃で3時間反応後、室温まで冷却し酢酸エチルと水を加えて抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。カラムクロマトグラフィーで精製し、表題化合物を得た。
エタノール(20ml)と水(5ml)を混合し、鉄粉を加え70−80℃に加熱した。塩化アンモニウム(0.1g、2.1mmol)を加え、次いで(i)で得られた2−(4−フルオロ−2−メチルフェニル)−5−ニトロピリジン(10.0mmol)を加え、70−80℃で1時間反応を行った。反応終了後、鉄粉をセライトで熱時ろ過し、ろ液を減圧下濃縮した。残渣をイソプロピルアルコールに溶解し、水を加え晶析・ろ過し、表題化合物を得た。
(ii)で得られた6−(4−フルオロ−2−メチルフェニル)ピリジン−3−イルアミン(58.9mmol)を99%酢酸(50ml)に溶解し、35%塩酸(25g)を加え塩酸塩とした。氷冷下、36%亜硝酸ナトリウム水溶液(12g、62.5mmol)を0−5℃で滴下し、約15分間反応を行った。アミド硫酸を加え、更に5分間反応を行い、ジアゾ液を得た。4−アミノ−1−ナフタレンスルホン酸(13.0g、58.4mmol)を水(130ml)に懸濁し、10%水酸化ナトリウム水溶液でpH8−9に調整した。5−10℃まで冷却し、得られたジアゾ液を5−10℃で滴下した。その際、pH7−9を維持するよう10%水酸化ナトリウム水溶液で調整した。滴下終了後、5−10℃で1時間反応を行い、その後室温まで昇温した。飽和食塩水で塩析し、析出した結晶を吸引ろ過した。カラムクロマトグラフィーで精製し、表題化合物を得た。
1H-NMR δ[ppm]=9.22 (1H, d, J=2.4Hz), 8.76 (1H, d, J=8.1), 8.49-8.44 (2H, m), 8.34 (1H, s), 7.82 (2H, bs), 7.67-7.47 (4H, m), 7.21-7.11 (2H, m), 2.41 (3H, s)
13C-NMR (DMSO-d6) δ[ppm]=163.5, 160.3, 158.2, 147.1, 146.7, 145.4, 138.8, 138.7, 136.1, 136.1, 132.4, 132.1, 131.8, 131.7, 129.2, 128.6, 128.3, 127.2, 125.1, 124.6, 124.2, 124.0, 117.3, 117.1, 116.6, 112.9, 112.6, 20.4, 20.4
網膜虚血ラットモデルの作成
Washington University より分与された Thy1-GFP ラット(Magill CK et al. Arch Facial Plast Surg 2010)を使用して、網膜虚血(I/R)ラットモデルを作成した。8〜10週齢の雄のラットを、ケタミン(80mg/体重kg)およびキシラジン(5mg/体重kg)の筋肉内注射により麻酔し、眼球の前房内に33G注射針を刺入した後に、生理食塩水を灌流し、眼圧を150mmHgまで上昇させた。眼底観察で網膜動脈の虚脱を確認した後、高眼圧を60分間維持し、網膜虚血ラットモデルを作成した。
網膜虚血ラットにおける網膜電位の測定
化合物32を経口投与した網膜虚血ラットで網膜電位図(ERG)を測定した。
I/R施行3日前から、生理食塩水に溶解した化合物32(50mg/kg)を、1日1回、胃ゾンデによりラットに経口投与した。対照ラットには、同じ方法で生理食塩水のみを投与した。I/R施行の開始前および7日後に、網膜電位図(ERG)を測定した。ERG測定24時間前からラットを暗順応させ、全身麻酔(80mg/kgケタミン+5mg/kgキシラジン筋注)、散瞳下(0.5%フェニレフリン、5%ネオシネジン)で検査を行った。暗順応下にて、ガンツフェルト全視野ERGで3cds/m2で刺激し、角膜に装用したコンタクトレンズ型電極で波形を記録した。結果を図1に示す。
網膜虚血ラットにおける網膜電位の測定
化合物32を腹腔内投与した網膜虚血ラットで網膜電位図(ERG)を測定した。
I/R施行3日前から、生理食塩水に溶解した化合物32(50mg/kg)を、腹腔内注射により、1日1回ラットに投与した。対照ラットには、同じ方法で生理食塩水のみを投与した。I/R施行の開始前および7日後に、網膜電位図(ERG)を測定した。ERG測定24時間前からラットを暗順応させ、全身麻酔(80mg/kgケタミン+5mg/kgキシラジン筋注)、散瞳下(0.5%フェニレフリン、5%ネオシネジン)で検査を行った。暗順応下にて、ガンツフェルト全視野ERGで3cds/m2で刺激し、角膜に装用したコンタクトレンズ型電極で波形を記録した。結果を図2に示す。
網膜虚血ラットにおける網膜電位の測定
実施例4と同様に、化合物32を腹腔内投与した網膜虚血ラット(N=11)および対照ラット(N=11)で網膜電位図(ERG)を測定した。結果を表2および図3に示す。
Claims (14)
- 虚血性眼疾患の処置用の、式(I):
〔式中、
Raはハロ、ヒドロキシ、C1−6アルキル、ハロ置換C1−6アルキル、C1−6アルコキシ、ヒドロキシまたはカルボキシ置換C1−6アルコキシ、CHO、C(O)−C1−6アルキル、C(O)−C1−6アルキル−カルボキシル、C(O)−C1−6アルキレン−カルボキシエステルおよびシアノから成る群から選択され、
mは0〜4から選択される整数である〕
の化合物またはその薬学的に許容される塩もしくは溶媒和物を含む医薬組成物、但し、虚血性眼疾患は正常眼圧緑内障ではない。 - Raが、それぞれ独立して、ハロ、ヒドロキシ、C1−6アルキル、ハロ置換C1−6アルキルおよびC1−6アルコキシから成る群から選択される、請求項1に記載の医薬組成物。
- Raが、それぞれ独立して、ハロおよびC1−6アルキルから成る群から選択される、請求項1または請求項2に記載の医薬組成物。
- Raが2個存在し、一方がハロであり、他方がC1−6アルキルである、請求項1ないし請求項3のいずれかに記載の医薬組成物。
- 化合物が、4−アミノ−3−[6−(4−フルオロ−2−メチルフェニル)ピリジン−3−イルアゾ]ナフタレン−1−スルホン酸またはその薬学的に許容される塩もしくは溶媒和物である、請求項1ないし請求項4のいずれかに記載の医薬組成物。
- 虚血性眼疾患が急性虚血性眼疾患である、請求項1ないし請求項5のいずれかに記載の医薬組成物。
- 虚血性眼疾患が虚血再灌流障害を伴うものである、請求項1ないし請求項6のいずれかに記載の医薬組成物。
- 虚血性眼疾患が、網膜中心動脈閉塞症、網膜動脈分枝閉塞症、虚血性視神経症、網膜中心静脈閉塞症、網膜静脈分枝閉塞症、糖尿病性網膜症または高眼圧症に基づく視神経疾患もしくは視神経障害である、請求項1ないし請求項7のいずれかに記載の医薬組成物。
- 虚血性眼疾患が、網膜中心動脈閉塞症、網膜動脈分枝閉塞症または虚血性視神経症である、請求項1ないし請求項8のいずれかに記載の医薬組成物。
- 虚血性眼疾患が網膜中心動脈閉塞症または網膜動脈分枝閉塞症である、請求項1ないし請求項9のいずれかに記載の医薬組成物。
- 局所投与用の請求項1ないし請求項10のいずれかに記載の医薬組成物。
- 硝子体投与用の請求項1ないし請求項11のいずれかに記載の医薬組成物。
- 経口投与用の請求項1ないし請求項10のいずれかに記載の医薬組成物。
- 虚血性眼疾患の処置用の医薬組成物を製造するための、請求項1に記載の式(I)の化合物またはその薬学的に許容される塩もしくは溶媒和物の使用。
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