JP5818905B2 - エリスロポエチン産生促進剤 - Google Patents
エリスロポエチン産生促進剤 Download PDFInfo
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- JP5818905B2 JP5818905B2 JP2013538526A JP2013538526A JP5818905B2 JP 5818905 B2 JP5818905 B2 JP 5818905B2 JP 2013538526 A JP2013538526 A JP 2013538526A JP 2013538526 A JP2013538526 A JP 2013538526A JP 5818905 B2 JP5818905 B2 JP 5818905B2
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- JP
- Japan
- Prior art keywords
- therapeutic
- erythropoietin
- anemia
- prophylactic agent
- group
- Prior art date
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- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
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- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- YUMLNTJCWGYGQU-UHFFFAOYSA-N zinc azane Chemical compound N.N.[Zn+2] YUMLNTJCWGYGQU-UHFFFAOYSA-N 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
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- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
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- FUTVBRXUIKZACV-UHFFFAOYSA-J zinc;3-[18-(2-carboxylatoethyl)-8,13-bis(ethenyl)-3,7,12,17-tetramethylporphyrin-21,24-diid-2-yl]propanoate Chemical compound [Zn+2].[N-]1C2=C(C)C(CCC([O-])=O)=C1C=C([N-]1)C(CCC([O-])=O)=C(C)C1=CC(C(C)=C1C=C)=NC1=CC(C(C)=C1C=C)=NC1=C2 FUTVBRXUIKZACV-UHFFFAOYSA-J 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
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- A61K31/28—Compounds containing heavy metals
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- A61K31/28—Compounds containing heavy metals
- A61K31/295—Iron group metal compounds
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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- A—HUMAN NECESSITIES
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Description
本発明は、また、エリスロポエチン産生能低下に起因する貧血、典型的には腎性貧血に対する治療剤及び/又は予防剤に関する。より詳しくは、本発明は、ALA類を含む、貧血の治療剤及び/又は予防剤に関する。
1)腎性貧血の診断が確定し、投与基準を満たす場合にはESA(赤血球造血刺激因子製剤)療法を開始すべきである(積極的推奨)。
2)造血に必要な鉄剤の投与を併用すべきである(積極的推奨)。
3)維持血液透析(hemodialysis:HD)患者では、透析液の清浄化に努め、十分な透析を行う(積極的推奨)。
4)栄養障害や炎症を伴う患者に対しては、これらに対する積極的な治療を行うべきである(積極的推奨)。
しかしながら、腎性貧血患者の一部は、ESA療法に対して抵抗性を示すことが知られている。ESA療法に対する低い反応性を生じるメカニズムについては、いまだ不明な点が多い。このようなESA療法に対する低い反応性の原因の一つとして、TNF−αやIL−6などの炎症性サイトカイン血中濃度の増加が積極的な原因であると考えられている。炎症性サイトカインとは、生体内における様々な炎症症状を引き起こす原因因子である。また、炎症性サイトカインは、赤血球寿命を短縮することが知られている。また、炎症性サイトカインは、エリスロポエチン産生細胞によるエリスロポエチンの産生を低下させることが知られている。したがって、炎症性サイトカインは、貧血を引き起こす原因物質として考えられる。
上述のように、腎性貧血は、典型的な、エリスロポエチンの産生の低下に起因する貧血、すなわち、腎臓内のエリスロポエチン産生細胞によるエリスロポエチンの産生が低下することにより生じる病態である。よって、以下、エリスロポエチンの産生の低下に起因する貧血を代表する貧血として、「腎性貧血」について述べるが、本発明の対象とする貧血は、腎性貧血に限定されるものではない。
本発明は、腎性貧血のより根本的な原因に対する治療を可能とするものである。
すなわち、本発明者らは、ALA類にがん性貧血の改善効果を見出している。しかし、これはがん特異的な溶血反応の抑制であると考えられている。また、本発明者らは、ALA類に慢性腎臓病の改善・予防効果を見出している。しかし、これは、腎臓の濾過能力を直接的に改善するものであり、エリスロポエチン産生細胞によるエリスロポエチンの産生の低下を抑制するという本発明のメカニズムとは全く関係がない。また、本発明者らは、ALA類に敗血症の治療・予防効果を見出している。しかし、これは、炎症性サイトカインの産生自体を抑制する効果に基づくものであり、エリスロポエチン産生細胞によるエリスロポエチンの産生の低下を抑制するという本発明のメカニズムとは全く関係がない。
エリスロポエチン産生促進剤であって、
下記式(I)で示される化合物
又はその塩
を含むエリスロポエチン産生促進剤に関する。
治療上有効量の、下記式(I)で示される化合物
又はその塩
を対象に投与する
ことを特徴とするエリスロポエチンの産生を促進する方法に関する。
下記式(I)で示される化合物
又はその塩
を含むエリスロポエチンの産生の低下に起因する貧血の治療剤及び/又は予防剤に関する。
R1は、水素原子、炭素数1〜8のアルカノイル基、及び、炭素数7〜14のアロイル基からなる群から選択されることができ、また、
R2は、水素原子、直鎖又は分岐状の炭素数1〜8のアルキル基、炭素数3〜8のシクロアルキル基、炭素数6〜14のアリール基、及び、炭素数7〜15のアラルキル基からなる群から選択されることができる。
すなわち、本発明は、腎性貧血の治療剤及び/又は予防剤を提供する。
なお、本発明において、治療とは、腎性貧血を完全に完治することのみならず、腎性貧血の症状を改善することをも含む。予防についても、同様に、腎性貧血の症状を完全に生じさせないことのみならず、本発明の予防剤を投与しなければ生じるであろう腎性貧血の症状をより穏やかなものとすることを含む。
このように、本発明は、ESA(赤血球造血刺激因子製剤)等の対症療法的な薬剤とは別の新しいアプローチにより、腎性貧血を治療及び/又は予防する方法を提供するものである。
さらに、本発明の腎性貧血の治療剤及び/又は予防剤は、ESA療法の代わりに、またはESA療法と併用して使用することでき、そうすることにより、ESA療法単独の場合による副作用を低減させることができる。
本発明のエリスロポエチン産生促進剤の使用により、エリスロポエチン産生細胞によるエリスロポエチンの産生を促進させることができる。
本明細書において、ALAは、5−アミノレブリン酸を意味する。ALAは、δ−アミノレブリン酸ともいい、アミノ酸の1種である。
エリスロポエチン産生細胞を低酸素下で培養し、エリスロポエチンを人為的に産生させた状態で、炎症性サイトカイン、または、尿毒症の毒素を添加することによりエリスロポエチン産生細胞のエリスロポエチン産生能を低下させた。
Claims (8)
- エリスロポエチンの産生の低下に起因する貧血の治療剤及び/又は予防剤であって、
下記式(I)で示される化合物
又はその塩
を含むエリスロポエチンの産生の低下に起因する貧血の治療剤及び/又は予防剤。 - 請求項1に記載の貧血の治療剤及び/又は予防剤であって、
R1が、水素原子、炭素数1〜8のアルカノイル基、及び、炭素数7〜14のアロイル基からなる群から選択され、
R2が、水素原子、直鎖又は分岐状の炭素数1〜8のアルキル基、炭素数3〜8のシクロアルキル基、炭素数6〜14のアリール基、及び、炭素数7〜15のアラルキル基からなる群から選択される
ことを特徴とする治療剤及び/又は予防剤。 - 請求項1又は2に記載の貧血の治療剤及び/又は予防剤であって、
前記治療剤及び/又は予防剤が、さらに一種又は二種以上の金属含有化合物を含有することを特徴とする治療剤及び/又は予防剤。 - 請求項3に記載の貧血の治療剤及び/又は予防剤であって、
前記金属含有化合物が、鉄、マグネシウム、及び、亜鉛からなる群から選択される金属を含有する化合物である
ことを特徴とする治療剤及び/又は予防剤。 - 請求項3に記載の貧血の治療剤及び/又は予防剤であって、
前記金属化合物が、鉄を含有する化合物である
ことを特徴とする治療剤及び/又は予防剤。 - 請求項1に記載の貧血の治療剤及び/又は予防剤であって、
前記エリスロポエチンの産生の低下が、炎症性サイトカイン又は尿毒症毒素により引き起こされるものである
ことを特徴とする治療剤及び/又は予防剤。 - 請求項1〜6のいずれか1項に記載の貧血の治療剤及び/又は予防剤であって、
前記貧血が、腎性貧血である
ことを特徴とする治療剤及び/又は予防剤。 - 請求項7に記載の腎性貧血の治療剤及び/又は予防剤であって、
前記化合物又はその塩が、エリスロポエチンの産生を促進することにより、前記腎性貧血が治療及び/又は予防される
ことを特徴とする治療剤及び/又は予防剤。
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