JP6860677B2 - グローコカリキシンa誘導体、その医薬的に許容できる塩または医薬組成物、およびこれらの乾癬治療用医薬の調製における使用 - Google Patents
グローコカリキシンa誘導体、その医薬的に許容できる塩または医薬組成物、およびこれらの乾癬治療用医薬の調製における使用 Download PDFInfo
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- JP6860677B2 JP6860677B2 JP2019537224A JP2019537224A JP6860677B2 JP 6860677 B2 JP6860677 B2 JP 6860677B2 JP 2019537224 A JP2019537224 A JP 2019537224A JP 2019537224 A JP2019537224 A JP 2019537224A JP 6860677 B2 JP6860677 B2 JP 6860677B2
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
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- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Description
同時に、CN104761460AおよびCN104887652Aには、グローコカリキシンA環外二重結合を修飾した化合物が開示され、研究によると、グローコカリキシンAの水溶性が悪い問題をある程度で克服したが、このようなグローコカリキシンA誘導体化合物は、一般的に安定性が悪く、水溶液および血漿でグローコカリキシンAに加水分解して結晶析出しやすく、その有効性と安全性に大きく影響を及ぼし、同様に抗乾癬医薬として直接使用するのに不適であることが分かった。
特に断りのない限り、本願に使用される以下の用語は以下の意味を有する。1つの特定の用語は、特に定義されていない場合、不確定または不明と見なされるべきではなく、本分野の一般的な意味で理解すべきである。本文に商品名が現れると、それに対応する商品またはその活性成分を指すことを意味する。
本実施例では、本願のグローコカリキシンA誘導体およびその医薬的に許容できる塩のヒトのケラチノサイトの増殖に対する影響を考察し、本実施例において、表1に示すグローコカリキシンA誘導体を医薬として考察を行い、方法は以下のとおりである。
例えば、CN1541643AにグローコカリキシンAが開示されている。化合物32におけるジメチルアミノグローコカリキシンA塩酸塩誘導体(CN104761460Aに開示された)の構造は、
本実施例において、グローコカリキシンAの誘導体およびその医薬的に許容できる塩のヒトのケラチノサイトの細胞増殖に対する抑制率と医薬濃度との関係を考察し、表1における化合物23を例示的な化合物とし、考察方法は以下のとおりである。
本実施例において、グローコカリキシンAの誘導体およびその医薬的に許容できる塩のキシレンによるマウス耳腫脹に対する抑制作用を考察し、化合物23を例示的な医薬とし、考察方法は以下のとおりである。
本実施例において、グローコカリキシンAの誘導体およびその医薬的に許容できる塩のConAにより誘導されたマウス脾臓リンパ細胞の増殖への影響を考察し、化合物23をそれぞれ例示的な医薬とし、考察方法は以下のとおりである。
本実施例において、化合物23および化合物24の急性毒性を考察し、方法は以下のとおりである。
Claims (13)
- R1およびR2は独立して、水素、アミノ基、メチル基、エチル基、n−プロピル基、イソプロピル基、ブチル基、ピリジル基、ヘキシル基、アリル基、シクロヘキシル基、フェニル基またはベンジル基である、請求項1に記載の使用。
- 前記医薬的に許容できる塩は、前記グローコカリキシンA誘導体の有機酸塩または無機酸塩であり、
好ましくは、前記有機酸塩は、酒石酸塩、ステアリン酸塩、シュウ酸塩、クエン酸塩、乳酸塩、ソルビン酸塩、アロマレイン酸塩、ギ酸塩、酢酸塩、安息香酸塩、ベンゼンスルホン酸塩、エタンスルホン酸塩、樹脂酸塩、トリフルオロ酢酸塩、マレイン酸塩、メタンスルホン酸塩、フマル酸塩、アミノ酸塩またはニコチン酸塩から選ばれるいずれか1つまたは少なくとも2つの組み合わせであり、
好ましくは、前記無機酸塩は、ヨウ素酸塩、リン酸塩、硫酸塩、ヨウ化水素酸塩、臭化水素酸塩、硝酸塩、臭素酸塩、または塩酸塩から選ばれるいずれか1つまたは少なくとも2つの組み合わせである、請求項1〜3のいずれか1項に記載の使用。 - 前記医薬組成物は、医薬的に許容できる補助材料を更に含み、
好ましくは、前記医薬組成物の剤形は、経口製剤、腸胃外投与製剤、または外用剤である、請求項1〜4のいずれか1項に記載の使用。 - 前記乾癬は、尋常性乾癬、関節症性乾癬、膿疱性乾癬、または紅皮症性乾癬から選ばれる、請求項1〜5のいずれか1項に記載の使用。
- 前記R1およびR2は独立して、メチル基、エチル基、プロピル基、イソプロピル基、n−ブチル基、ピリジル基、ヘキシル基、アリル基、シクロヘキシル基、フェニル基、またはベンジル基である、請求項7に記載のグローコカリキシンA誘導体。
- 請求項7〜9のいずれか1項に記載のグローコカリキシンA誘導体の医薬的に許容できる塩であって、前記医薬的に許容できる塩は、前記グローコカリキシンA誘導体の有機酸塩または無機酸塩である、ことを特徴とするグローコカリキシンA誘導体の医薬的に許容できる塩。
- 前記有機酸塩は、酒石酸塩、ステアリン酸塩、シュウ酸塩、クエン酸塩、乳酸塩、ソルビン酸塩、アロマレイン酸塩、ギ酸塩、酢酸塩、安息香酸塩、ベンゼンスルホン酸塩、エタンスルホン酸塩、樹脂酸塩、トリフルオロ酢酸塩、マレイン酸塩、メタンスルホン酸塩、フマル酸塩、アミノ酸塩、またはニコチン酸塩から選ばれるいずれか1つである、請求項10に記載のグローコカリキシンA誘導体の医薬的に許容できる塩。
- 前記無機酸塩は、ヨウ素酸塩、リン酸塩、硫酸塩、ヨウ化水素酸塩、臭化水素酸塩、硝酸塩、臭素酸塩、または塩酸塩から選ばれるいずれか1つである、請求項10に記載のグローコカリキシンA誘導体の医薬的に許容できる塩。
- 請求項7〜9のいずれか1項に記載のグローコカリキシンA誘導体の調製方法であって、2−臭素化グローコカリキシンAとN,N−ジアルキルチオ尿素とを反応させ、式I’に示すグローコカリキシンA誘導体を得ることを含む、調製方法。
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