JP5923161B2 - 鉄欠乏症状および鉄欠乏性貧血の治療および予防のための鉄(iii)錯体化合物 - Google Patents
鉄欠乏症状および鉄欠乏性貧血の治療および予防のための鉄(iii)錯体化合物 Download PDFInfo
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- JP5923161B2 JP5923161B2 JP2014501593A JP2014501593A JP5923161B2 JP 5923161 B2 JP5923161 B2 JP 5923161B2 JP 2014501593 A JP2014501593 A JP 2014501593A JP 2014501593 A JP2014501593 A JP 2014501593A JP 5923161 B2 JP5923161 B2 JP 5923161B2
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- iron deficiency
- deficiency anemia
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- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/02—Iron compounds
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- C07D239/72—Quinazolines; Hydrogenated quinazolines
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Description
−「ピリミジン−2−オール−1−オキシド」、
−「ピリミジン−2−オール−1−オキシド化合物」または
−「ピリミジン−2−オール−1−オキシド」配位子
は、対応する鉄(III)錯体化合物中に存在する、対応するヒドロキシ出発化合物:
の少なくとも1つの、好ましくは二座ピリミジン−2−オール−1−オキシド配位子を含む、錯体化合物を包含する。
矢印はそれぞれ、1個のまたは異なる鉄原子への配位結合を表し、ならびに
R1、R2、R3は、同じかまたは異なっていてもよく、および
−水素、
−置換されていてもよいアルキル、
−ハロゲン、
−置換されていてもよいアルコキシ、
−置換されていてもよいアリール、
−置換されていてもよいアルコキシカルボニル、
−置換されていてもよいアミノ、および
−置換されていてもよいアミノカルボニル
から成る群より選択されるか、または
R1とR2もしくはR2とR3は、それらが結合している炭素原子と共に、1もしくはそれ以上のヘテロ原子を含有してもよい、置換されていてもよい飽和もしくは不飽和5員もしくは6員環を形成する]
の少なくとも1つの、好ましくは3個の同じかまたは異なる、好ましくは同じ配位子、またはその医薬的に許容される塩を含有する。
矢印はそれぞれ、1個のまたは異なる鉄原子への配位結合を表し、ならびに
R1、R2、R3は、同じかまたは異なっていてもよく、
−水素、
−置換されていてもよいアルキル、
−ハロゲン、
−置換されていてもよいアルコキシ、
−置換されていてもよいアリール、
−置換されていてもよいアルコキシカルボニル、および
−置換されていてもよいアミノカルボニル
から成る群より選択されるか、または
R1とR2もしくはR2とR3は、それらが結合している炭素原子と共に、1もしくはそれ以上のヘテロ原子を含有してもよい、置換されていてもよい飽和もしくは不飽和5員もしくは6員環を形成する]
の少なくとも1つの配位子、またはその医薬的に許容される塩を含有するこれらの鉄(III)錯体化合物に関する。
R1、R2、R3は、同じかまたは異なっていてもよく、
−水素、
−置換されていてもよいアルキル、および
−ハロゲン
から成る群より選択される]
の少なくとも1つの配位子を含有するこれらの鉄(III)錯体化合物に関する。
1〜8個、好ましくは1〜6個の炭素原子を有する直鎖もしくは分枝アルキル、3〜8個、好ましくは5もしくは6個の炭素原子を有するシクロアルキル、またはシクロアルキルで置換された、1〜4個の炭素原子を有するアルキル、ここで、これらのアルキル基は置換されていてもよい、
を包含する。
R1とR2またはR2とR3が一緒になって、好ましくは、それぞれ1個のメチレン基(−CH2−)が−O−、−NH−または−NR4−[式中、R4は上記で定義したとおりである]で置換されていてもよい、プロピレン(−CH2−CH2−CH2−)またはブチレン(−CH2−CH2−CH2−CH2−)基を表し、ここで、R1とR2またはR2とR3によって形成される基は、それぞれ、ヒドロキシ、オキソ、C1−C4アルコキシ、アミノおよびモノ−またはジ−(C1−C4アルキル)アミノから成る群より選択される1〜3個の置換基によってさらに置換されていてもよい、
化合物が含まれる。
−水素
−好ましくは上記で示した、C1−6−アルキル、
−好ましくは上記で示した、ハロゲン、
−好ましくは上記で示した、C3−6−シクロアルキル、
−好ましくは上記で示した、C3−6−シクロアルキル−C1−4−アルキル、
−好ましくは上記で示した、C1−4−アルコキシ−C1−4−アルキル、
−好ましくは上記で示した、C1−4−アルコキシカルボニル、
−好ましくは上記で示した、C1−4−モノまたはジアルキルアミノカルボニル、
−それぞれアミノカルボニルまたはカルバモイル(H2NCO−)、
−好ましくは上記で示した、ヒドロキシ−C1−4−アルキル、および
−好ましくは上記で示した、ハロゲン−C1−4−アルキル
から選択される。
(本発明において、「1−6C」中の数字1−6または「1−4C」もしくは「C1−4」中の数字「1−4」等は、各々の場合に、それに続く指定名称の炭化水素基の炭素原子の数を意味する)。
−水素、
−ハロゲン、
−モノまたはジ(1−6C−アルキル)アミノ、
−1−6C−アルキル(すなわち1〜6個の炭素原子を有するアルキル)、
−3−6C−シクロアルキル、
−3−6C−シクロアルキル−1−4C−アルキル、
−1−4C−アルコキシ−1−4C−アルキル、
−ヒドロキシ−1−4C−アルキル、
−フルオロ−1−4C−アルキル
から成る群より選択されるか、または
R1とR2は一緒になって、プロピレン(−CH2−CH2−CH2)、ブチレン(−CH2−CH2−CH2−CH2−)、アザブチレンまたはオキサブチレン基を形成するか、または
R2とR3は一緒になって、プロピレン(−CH2−CH2−CH2−)、ブチレン(−CH2−CH2−CH2−CH2−)、アザブチレンまたはオキサブチレン基を形成するか、または
R1とR2は、それらが結合している炭素原子と共に、1またはそれ以上のさらなるヘテロ原子を含有してもよい不飽和環を形成するか、または
R2とR3は、それらが結合している炭素原子と共に、1またはそれ以上のさらなるヘテロ原子を含有してもよい不飽和環を形成するか、または
その医薬的に許容される塩である。
1−6C−アルキルは、好ましくは1〜6個の炭素原子を有する直鎖または分枝アルキル基を包含する。その例は、したがって、メチル、エチル、n−プロピル、イソ−プロピル、n−ブチル、イソ−ブチル、sec−ブチル、tert−ブチル、n−ペンチル、イソ−ペンチル、ネオ−ペンチル、n−ヘキシル、イソ−ヘキシルおよびネオ−ヘキシルであり得る。
R1、R2およびR3は、
−水素、
−ハロゲン、
−1−6C−アルキル、
−1−4C−アルコキシ−1−4C−アルキル、
−ヒドロキシ−1−4C−アルキル、
から成る群より選択されるか、または
R1とR2は一緒になって、プロピレン(−CH2−CH2−CH2)、ブチレン(−CH2−CH2−CH2−CH2−)、アザブチレンまたはオキサブチレン基を形成するか、または
R2とR3は一緒になって、プロピレン(−CH2−CH2−CH2)、ブチレン(−CH2−CH2−CH2−CH2−)、アザブチレンまたはオキサブチレン基を形成するか、または
R1とR2は、それらが結合している炭素原子と共に、さらなるヘテロ原子を含有してもよい不飽和環を形成するか、または
R2とR3は、それらが結合している炭素原子と共に、さらなるヘテロ原子を含有してもよい不飽和環を形成する。
R1、R2およびR3は、
−水素、
−1−6C−アルキル、
−1−4C−アルコキシ−1−4C−アルキル
から成る群より選択されるか、または
R1とR2は一緒になって、プロピレン(−CH2−CH2−CH2)またはブチレン(−CH2−CH2−CH2−CH2−)基を形成するか、または
R2とR3は一緒になって、プロピレン(−CH2−CH2−CH2)またはブチレン(−CH2−CH2−CH2−CH2−)基を形成するか、または
R1とR2は、それらが結合している炭素原子と共に、1個のさらなる窒素原子を含有してもよい不飽和環を形成するか、または
R2とR3は、それらが結合している炭素原子と共に、1個のさらなる窒素原子を含有してもよい不飽和環を形成する。
驚くべきことに、発明者らは、本発明の主題であって、特に一般構造式(II)によって表される鉄(III)ピリミジン−2−オール−1−オキシド錯体化合物が、安定な生物学的に利用可能な鉄錯体であり、鉄欠乏症状およびそれらに伴う症状である鉄欠乏性貧血の治療および予防のための薬剤として使用するのに適することを見出した。
配位子の指定は、Advanced Chemistry Development Inc.によるACD/名称プログラム、バージョン12.01と共にIUPAC命名法に従って実施した。
s 一重項 t 三重項
d 二重項 q 四重項
dd ダブル二重項 m 多重項
(ブロード/多重)
L 配位子
出発化合物:
A.ピリミジン−2−オール−1−オキシド塩酸塩
IR(物質中、cm−1):3114、3082、2995、2935、2837、2776、2718、2467、1734、1575、1492、1421、1363、1314、1232、1176、1123、1100、1073、911、861、773、733、689、574(2回目の画分)。
CN元素分析:C、32.29;N、18.98(1回目の画分);C、32.41;N、18.98(2回目の画分)。
塩化物含量:24.6%(m/m)(1回目の画分)、23.6%(m/m)(2回目の画分)
LC−MS:113(M+H)。
1H−NMR(DMSO−d6,400MHz).δ[ppm]=9.05(dd,1H),8.55(dd,1H),6.74(t,1H)。
IR(物質中、cm−1):3102、3034、2926、2841、2730、2657、2531、1741、1650、1602、1581、1518、1456、1374、1302、1184、1131、1110、1037、977、888、821、780、734、697、603(3回目の画分)。
CHN元素分析:C、37.48;H、4.33;N、17.12(3回目の画分);C、37.12;H、4.30;N、17.08(4回目の画分)。
LC−MS:127(M+H)。
1H−NMR(DMSO−d6,400MHz):δ[ppm]=8.97(d,1H),6.73(d,1H),2.49(s,3H)。
IR(物質中、cm−1):3077、3052、2938、2855、2796、2521、1740、1610、1564、1509、1423、1368、1316、1215、1163、1141、1089、1049、1026、997、975、852、775、741、695、626、601(1回目の画分)。
CHN元素分析:C、40.74;H、5.03;N、15.78(1回目の画分);C、27.75;H、5.87;N、18.98(2回目の画分)。
塩化物含量:19.9%(m/m)(1回目の画分)、33.4%(m/m)(2回目の画分)
LC−MS:141(M+H)。
1H−NMR(DMSO−d6,400MHz):δ[ppm]=6.78(s,1H);2.53(s,3H);2.43(s,3H)(1.fraction)。
IR(物質中、cm−1):3116、3024、2804、2687、2628、1996、1746、1603、1572、1512、1443、1394、1297、1213、1156、1082、1061、963、901、861、814、745、700。
CHN元素分析:C、22.71;H、6.94;N、19.99。
塩化物含量:42.9%(m/m)
LC−MS:169(M+H)。
1H−NMR(DMSO−d6,400MHz):δ[ppm]=6.75(s,1H),2.86(q,2H),2.70(q,2H),1.21(t,3H),1.20(t,3H)。
IR(物質中、cm−1):3106、3011、2963、2576、1834、1740、1604、1567、1514、1467、1446、1403、1371、1321、1280、1234、1209、1149、1104、1070、1032、1010、915、861、820、774、750、712、680、644、615、580。
CHN元素分析:C、28.68;H、6.93;N、18.33。
塩化物含量:37.6%(m/m)
LC−MS:183(M+H)。
1H−NMR(DMSO−d6,400MHz):δ[ppm]=6.76(s,1H),2.72(d,2H),2.44(s,3H),2.13(m,1H),0.91(d,6H)。NMRスペクトルから、生成物は約2%の位置異性体、6−メチル−4−(2−メチルプロピル)ピリミジン−2−オール−1−オキシド塩酸塩を含有すると推定された。
IR(物質中、cm−1):3112、2997、2934、2850、2796、2629、2544、1734、1612、1582、1513、1472、1392、1373、1309、1247、1215、1152、1132、1093、1014、945、896、803、777、742、707、630、603、558、528、500。
CHN元素分析:C、36.31;H、6.16;N、16.28(2回目の画分)。
塩化物含量:25.9%(m/m)(2回目の画分)
LC−MS:155(M+H)。
1H−NMR(DMSO−d6,400MHz):δ[ppm]=2.56(s,3H),2.47(s,3H),2.05(s,3H)。NMRスペクトルから、生成物は約9%の4,6−ジメチルピリミジン−2−オール−1−オキシド塩酸塩を副産物として含有すると推定された。
IR(物質中、cm−1):3115、2900、2667、2516、1745、1577、1505、1378、1310、1194、1135、1102、1049、973、900、835、737、674、578。
塩化物含量:40.1%(m/m)
LC−MS:175(M+H)。1H−NMR(DMSO−d6,400MHz):δ[ppm]=2.49(s,3H),2.37(s,3H)。
1H−NMR(DMSO−d6、400MHz):δ[ppm]=4.74(t,1H)、3.23(s,6H)、2.70(d,2H)、2.45(q,2H)、0.90(t,3H)(表題化合物、生成物混合物中62%m/m);δ=7.69(d,1H)、5.61(d,1H)、3.69(s,3H)、2.48(q,2H)、0.96(t,3H)((1E)−1−メトキシペント−1−エン−3−オン、生成物混合物中38%)。
ヒドロキシ尿素0.388mol(25.9g)を2M HCl 195mlに溶解し、メタノール80mlを添加して、1,1−ジメトキシペンタン−3−オン(生成物混合物中62%含量)0.388mol(56.7g)を、内部温度を−6〜−7℃に維持しながら冷却下で滴下した。溶液を氷浴中で室温まで解凍し、1時間撹拌して、その後蒸発乾固させた。残留物をアセトン100mlで懸濁させ、混合物を氷/エタノール浴中で0℃以下に冷却して、固体をろ取し、少量の氷冷アセトンで洗浄した。乾燥後、粗生成物32.6gを得た。粗生成物をエタノール200mlで沸騰するまで加熱し、熱時ろ過して、−18℃まで緩やかに冷却した。沈殿した固体をろ取し、少量のエタノールで洗浄して、乾燥した。表題化合物11.7gを得た。
IR(物質中、cm−1):3115、3038、2936、2678、2518、1753、1606、1585、1516、1465、1403、1381、1301、1229、1184、1134、1109、1053、1002、896、803、769、736、680、605、540、513、494、474。
CHN元素分析:C、40.72;H、5.03;N、15.32。
LC−MS:141(M+H)。
1H−NMR(DMSO−d6,400MHz):δ[ppm]=8.92(d,1H),6.70(d,1H),2.73(q,2H);1.19(t,3H)。1H−NMR(DMSO−d6,400MHz):δ[ppm]=6.76(s,1H),2.72(d,2H),2.44(s,3H),2.13(m,1H),0.91(d,6H)。NMRスペクトルから、生成物は<3%の位置異性体、6−エチルピリミジン−2−オール−1−オキシド塩酸塩を含有すると推定された。
IR(物質中、cm−1):3093、2997、2945、2679、2555、1805、1741、1601、1571、1508、1435、1401、1370、1327、1290、1253、1213、1157、1103、1049、903、849、811、766、742、701、669、626、607、582、512、494。
LC−MS(m/z):155.7(M+H)。
1H−NMR(DMSO−d6,400MHz):δ[ppm]=6.78(s,1H),2.88(q,2H),2.46(s,3H),1.21(t,3H)。1H−NMR(DMSO−d6,400MHz):δ[ppm]=6.76(s,1H),2.72(d,2H),2.44(s,3H),2.13(m,1H),0.91(d,6H)。NMRスペクトルから、生成物は約6.6%の位置異性体、4−エチル−6−メチルピリミジン−2−オール−1−オキシド塩酸塩を含有すると推定された。
IR(物質中、cm−1):3133、3042、2841、2751、2480、1730、1613、1590、1493、1404、1374、1314、1289、1221、1134、1062、1044、1020、972、938、894、868、822、740、707、637、575、552、525、509。
LC−MS(m/z):167.5(M+H)。
CHN元素分析:C、43.93;H、6.07;N、13.41。
塩化物含量:21.7%(m/m)
1H−NMR(DMSO−d6,400MHz):δ[ppm]=3.22(t,2H),2.82(t,2H),2.42(s,3H),2.13(quintett,2H)。NMRスペクトルから、生成物は約6%の位置異性体、4−メチル−6,7−ジヒドロ−5H−シクロペンタ[d]ピリミジン−2−オール−3−オキシド塩酸塩を含有すると推定された。
IR(物質中、cm−1):3135、3044、2937、2875、2805、2706、2426、1743、1572、1501、1443、1403、1345、1288、1260、1235、1150、1122、1086、1041、908、883、824、740、707、669、643、605、546、514。
CHN元素分析:C、43.63;H、6.08;N、14.66。
塩化物含量:22.2%(m/m)
NMRスペクトルから、生成物は約5%の位置異性体、1H−NMR(DMSO−d6,400MHz):δ[ppm]=2.76(m,2H),2.53(s,3H),2.49(m,2H),1.70(m,4H)。4−メチル−5,6,7,8−テトラヒドロキナゾリン−2−オール−1−オキシド塩酸塩を含有すると推定された。
IR(物質中、cm−1):2971、2585、1815、1748、1598、1572、1513、1463、1390、1305、1230、1186、1163、1132、1049、986、934、901、815、773、749、719、681、616、582、518、498、484、478。
CHN元素分析:C、43.54;H、6.10;N、14.50
LC−MS(m/z):155.5(M+H)。
1H−NMR(DMSO−d6,400MHz):δ[ppm]=8.88(d,1H),6.68(d,1H),3.02(heptett,1H);1.20(d,6H)。
IR(ニート、cm−1):3077、2853、2685、2550、1745、1608、1568、1514、1461、1416、1370、1323、1304、1249、1211、1160、1142、1104、1069、1028、994、936、887、849、767、746、707、685、625、599、567、525、500。
LC−MS(m/z):155(M+H)。
1H−NMR(DMSO−d6,400MHz):δ[ppm]=6.83(s,1H),2.70(q,2H),2.55(s,3H),1.20(t,3H)。NMRスペクトルから、生成物は約13%の位置異性体、1H−NMR(DMSO−d6,400MHz):δ[ppm]=2.76(m,2H),2.53(s,3H),2.49(m,2H),1.70(m,4H)。6−エチル−4−メチル−ピリミジン−2−オール−1−オキシド塩酸塩を含有すると推定された。
IR(ニート、cm−1):2850、2482、1758、1605、1565、1517、1494、1467、1389、1377、1310、1264、1190、1118、1086、887、828、751、730、703
1H−NMR(DMSO−d6,400MHz):δ[ppm]=8.66(d,1H),6.61(d,1H),1.27(s,9H)。
IR(ニート、cm−1):2569、2539、1726、1628、1589、1503、1453、1378、1336、1255、1220、1157、1141、1120、1021、919、828、755、734、713
1H−NMR(DMSO−d6,400MHz):δ[ppm]=8.98(s,1H);2.50(s,3H);2.08(s,3H)。
IR(ニート、cm−1):2591、2536、2477、1770、1736、1608、1580、1311、1194、1185、1130、1115、1082、1001、904、892、823、787、736、680
1H−NMR(DMSO−d6,400MHz):δ[ppm]=8.98(d,1H),6.75(d,1H),2.74(t,2H),1.69(hextett,2H),0.93(t,3H)。
IR(物質中、cm−1):3082、3054、1596、1506、1431、1366、1278、1197、1136、1108、1055、907、798、765、613、554、513。
CHN元素分析:C、35.77;H、2.78;N、20.23。
ESI−MS:278.3(FeL2 +);390.4(M+H+);412.4(M+Na+)。
鉄含量:13.61%[m/m]
IR(物質中、cm−1):3400、3074、1602、1545、1503、1425、1378、1339、1249、1201、1145、1110、1032、954、805、762、645、600。
CHN元素分析:C、38.42;H、4.10;N、18.11。
ESI−MS:306.4(FeL2 +);432.4(M+H+)。
鉄含量:12.15%[m/m]
IR(物質中、cm−1):3596、3441、3077、1604、1551、1511、1441、1393、1380、1360、1320、1153、1097、1029、875、856、798、651、564、524、486。
CHN元素分析:C、44.27;H、4.22;N、17.35。
ESI−MS:334.4(FeL2 +);474.5(M+H+);496.6(M+Na+)。
鉄含量:11.33%[m/m]
融点なし、約230℃で発熱分解が始まる。
IR(物質中、cm−1):3593、3378、3087、2969、2934、2880、1602、1549、1510、1460、1406、1328、1255、1235、1146、1108、1073、1027、964、903、863、807、764、701、672、645、619、578、522。
CHN元素分析:C、49.23;H、6.03;N、14.43。
鉄含量:10.05%[m/m]
IR(物質中、cm−1):2959、2929、2872、1598、1549、1513、1462、1434、1400、1355、1289、1233、1151、1122、1102、1034、990、928、879、853、799、769、701、648、606、575。
CHN元素分析:C、53.71;H、6.40;N、13.92。
鉄含量:9.29%[m/m]
IR(物質中、cm−1):3424、2925、1593、1510、1439、1377、1234、1188、1160、1109、999、935、869、803、763、720、657、613、561。
CHN元素分析:C、45.43;H、5.80;N、14.12。
鉄含量:10.68%[m/m]
IR(物質中、cm−1):2929、2363、1688、1589、1509、1431、1390、1375、1196、1169、1092、1016、968、847、759、694、667、553。
CHN元素分析:C、37.01;H、2.83;N、14.47。
鉄含量:9.88%[m/m]
IR(物質中、cm−1):3083、2974、2936、2876、1596、1543、1511、1460、1428、1313、1249、1194、1143、1107、1079、1056、991、948、811、770、748、696、639、598、531、502。
CHN元素分析:C、44.67;H、4.52;N、17.36。
鉄含量:11.40%[m/m]
IR(物質中、cm−1):3515、3080、2974、2938、1598、1550、1516、1461、1427、1401、1317、1257、1229、1149、1104、1060、1035、985、918、851、813、768、681、651、557、522。
CHN元素分析:C、47.48;H、5.44;N、15.81。
鉄含量:10.32%[m/m]
塩化物含量:0.0%[m/m]
IR(物質中、cm−1):2918、2361、2326、1599、1571、1499、1429、1382、1359、1311、1279、1232、1208、1173、1100、1067、1043、1013、970、945、904、881、836、761、733、663、566、528、499。
CHN元素分析:C、50.36;H、4.98;N、14.88。
鉄含量:9.71%[m/m]
塩化物含量:1.05%[m/m]
IR(物質中、cm−1):2932、2859、1586、1510、1446、1421、1377、1348、1308、1267、1229、1189、1168、1100、1079、1057、1030、969、889、846、824、762、704、654、614、571、507。
CHN元素分析:C、53.25;H、5.49;N、13.76。
鉄含量:9.03%[m/m]
塩化物含量:0.0%[m/m]
IR(物質中、cm−1):3071、2965、2930、2871、1594、1540、1510、1467、1428、1373、1309、1239、1204、1152、1132、1108、1049、970、931、881、834、809、777、733、712、645、599、552、514。
CHN元素分析:C、47.53;H、5.01;N、15.84。
鉄含量:10.86%[m/m](ICP)
塩化物含量:0.60%[m/m]
IR(ニート、cm−1):2970、2936、2876、1750、1685、1601、1552、1511、1462、1441、1404、1386、1362、1308、1231、1196、1154、1106、1056、1034、984、846、807、790、770。
CHN元素分析:C、42.43;H、5.43;N、14.03。
鉄含量:9.5%[w/w]
IR(ニート、cm−1):2965、1589、1512、1450、1375、1228、1181、1100、1057、1011、958、863、768、716、685、664。
CHN元素分析:C、49.67;H、5.83;N、14.52。
鉄含量:9.54%[w/w]
塩化物含量:0.0%[w/w]
IR(ニート、cm−1):2965、1598、1535、1506、1477、1419、1364、1339、1273、1238、1217、1159、1122、1025、967、829、810、779、717、701。
鉄含量:10.15%[w/w]
塩化物含量:0.65%[w/w]
IR(ニート、cm−1):3409、1613、1518、1443、1403、1361、1241、1221、1202、1177、1094、1007、880、762、714。
CHN元素分析:C、40.77;H、4.95;N、15.85。
鉄含量:10.68%[w/w]
塩化物含量:1.1%[w/w]
IR(ニート、cm−1):3072、2961、1594、1541、1507、1460、1426、1380、1337、1246、1141、1108、1088、979、870、838、799、768、733、691。
鉄含量:10.74%[w/w]
塩化物含量:0.0%[w/w]
IR(ニート、cm−1):3287、2975、1620、1588、1531、1490、1448、1381、1344、1283、1254、1178、1156、1096、1066、1014、826、784、754、708
鉄含量:11.03%[w/w]
塩化物含量:0.47%[w/w]。
本発明による鉄錯体を通して達成できる優れた鉄利用能を、以下のマウスモデルを用いて測定した。
=[(Hb2(3) *BW9(14)−Hb1 *BW4)*0.000238−(Hb2(3)対照 *BW9(14)対照−Hb1対照 *BW4対照)*0.000238]*100/Fe Dos。
=(Hb2(3) *BW9(14)−Hb1 *BW4−Hb2(3)対照 *BW9(14)対照+Hb1対照 *
BW4対照)*0.0238/Fe Dos。
0.07=体重(BW)kg当たりの血液70mlについての係数
0.0034=0.0034g鉄/g Hbについての係数
Hb1=1日目のヘモグロビンレベル(g/l)
Hb2(3)=8日目(または15日目)のヘモグロビンレベル(g/l)
BW4=1日目の体重(g)
BW9(14)=8日目(または15日目)の体重(g)
Hb1対照=対照群における1日目の平均ヘモグロビンレベル(g/l)
Hb2(3)対照=対照群における8日目(または15日目)の平均ヘモグロビンレベル(g/l)
BW4対照=対照群における1日目の平均体重(g)
BW9(14)対照=対照群における8日目(または15日目)の平均体重(g)
Fe Dos.=5日間または10日間にわたる全投与鉄(mg鉄)
Fe ut.=(Hb2(3) *BW9(14) Hb1 *BW4)*0.07*0.0034(mg鉄)
Δ利用能=食餌から利用された、総鉄利用量(試験群)−Fe ut.対照群(mg鉄)
Claims (12)
- 鉄(III)−ピリミジン−2−オール−1−オキシド錯体化合物またはその医薬的に許容される塩を含む、鉄欠乏症および鉄欠乏性貧血ならびにそれらに関連する症状の治療および予防のための医薬組成物であって、
前記鉄(III)錯体化合物が、下記式:
矢印はそれぞれ、1個のまたは異なる鉄原子への配位結合を表し、ならびに
R 1 、R 2 、R 3 は、同じかまたは異なっていてもよく、および
−水素、
−置換されていてもよいアルキル、
−ハロゲン、
−置換されていてもよいアルコキシ、
−置換されていてもよいアリール、
−置換されていてもよいアルコキシカルボニル、
−置換されていてもよいアミノ、および
−置換されていてもよいアミノカルボニル
から成る群より選択されるか、または
R 1 とR 2 もしくはR 2 とR 3 は、それらが結合している炭素原子と共に、1もしくはそれ以上のヘテロ原子を含有してもよい、置換されていてもよい飽和もしくは不飽和5員もしくは6員環を形成する]
の配位子を3つ含有する、医薬組成物。 - 前記鉄(III)錯体化合物が、式(I):
矢印はそれぞれ、1個のまたは異なる鉄原子への配位結合を表し、ならびに
R1、R2、R3は、同じかまたは異なっていてもよく、および
−水素、
−置換されていてもよいアルキル、
−ハロゲン、
−置換されていてもよいアルコキシ、
−置換されていてもよいアリール、
−置換されていてもよいアルコキシカルボニル、および
−置換されていてもよいアミノカルボニル
から成る群より選択されるか、または
R1とR2もしくはR2とR3は、それらが結合している炭素原子と共に、1もしくはそれ以上のヘテロ原子を含有してもよい、置換されていてもよい飽和もしくは不飽和5員もしくは6員環を形成する]
の配位子を3つ含有する、請求項1に記載の、鉄(III)−ピリミジン−2−オール−1−オキシド錯体化合物またはその医薬的に許容される塩を含む医薬組成物。 - 前記鉄(III)錯体化合物が、式(I):
矢印はそれぞれ、1個のまたは異なる鉄原子への配位結合を表し、
R1、R2、R3は、同じかまたは異なっていてもよく、ならびに水素、アルコキシによって置換されていてもよいアルキル、およびハロゲンから成る群より選択されるか、または
R1とR2もしくはR2とR3は一緒になって、プロピレン(−CH2−CH2−CH2−)、ブチレン(−CH2−CH2−CH2−CH2−)、アザブチレンもしくはオキサブチレン基を形成する]
の配位子を3つ含有する、請求項1〜3のいずれか一項に記載の、鉄(III)−ピリミジン−2−オール−1−オキシド錯体化合物またはその医薬的に許容される塩を含む医薬組成物。 - 式中、R1、R2、R3は同一かまたは異なっており、ならびに水素およびアルキルから成る群より選択され、ただし、置換基R1、R2およびR3の少なくとも1つはアルキルである、請求項1〜4のいずれか一項に記載の、鉄(III)−ピリミジン−2−オール−1−オキシド錯体化合物またはその医薬的に許容される塩を含む医薬組成物。
- 式中、R2は水素であり、ならびにR1およびR3は各々同じかまたは異なっており、およびアルキルから選択される、請求項1〜5のいずれか一項に記載の、鉄(III)−ピリミジン−2−オール−1−オキシド錯体化合物またはその医薬的に許容される塩を含む医薬組成物。
- 症状が、疲労、倦怠感、集中力の欠如、認知効率の低下、正しい言葉を見つけることの困難さ、健忘症、異常な青白さ、過敏性、心拍数の加速(頻拍)、舌のただれまたは腫脹、肥大脾、奇妙な食物に対する欲求(異食)、頭痛、食欲不振、易感染性の増大、抑うつ気分を包含する、請求項1〜6のいずれか1項に記載の、鉄(III)−ピリミジン−2−オール−1−オキシド錯体化合物またはその医薬的に許容される塩を含む医薬組成物。
- 妊婦における鉄欠乏性貧血、小児および青年における潜在性鉄欠乏性貧血、胃腸障害に起因する鉄欠乏性貧血、血液喪失による鉄欠乏性貧血、消化管出血による鉄欠乏性貧血、潰瘍による鉄欠乏性貧血、癌による鉄欠乏性貧血、痔核による鉄欠乏性貧血、炎症性疾患による鉄欠乏性貧血、アセチルサリチル酸の摂取による鉄欠乏性貧血、月経に起因する鉄欠乏性貧血、損傷に起因する鉄欠乏性貧血、脱毛症(スプルー)による鉄欠乏性貧血、低い食事性鉄摂取による鉄欠乏性貧血、選択的摂食の小児および青年における、低い食事性鉄摂取による鉄欠乏性貧血、鉄欠乏性貧血に起因する免疫不全、鉄欠乏性貧血に起因する脳機能障害、鉄欠乏性貧血に起因する不穏下肢症候群、癌の症例における鉄欠乏性貧血、化学療法に起因する鉄欠乏性貧血、炎症(AI)によって誘発される鉄欠乏性貧血、うっ血性心不全(CHF;うっ血性心不全)の症例における鉄欠乏性貧血、第3〜5病期の慢性腎不全(CKD 3〜5;慢性腎疾患第3〜5病期)の症例における鉄欠乏性貧血、慢性炎症(ACD)によって誘発される鉄欠乏性貧血、関節リウマチ(RA)の症例における鉄欠乏性貧血、全身性エリテマトーデス(SLE)の症例における鉄欠乏性貧血および炎症性腸疾患(IBD)の症例における鉄欠乏性貧血の治療のための、請求項1〜6のいずれか1項に記載の、鉄(III)−ピリミジン−2−オール−1−オキシド錯体化合物またはその医薬的に許容される塩を含む医薬組成物。
- 経口的に投与される、請求項1〜8のいずれか一項に記載の、鉄(III)−ピリミジン−2−オール−1−オキシド錯体化合物またはその医薬的に許容される塩を含む医薬組成物。
- 丸剤、錠剤、腸溶錠、フィルム錠、多層錠、徐放製剤、デポー製剤、糖衣錠、坐剤、粒剤、マイクロカプセル、マイクロ製剤、ナノ製剤、カプセル、腸溶カプセルおよび散剤を包含する固体製剤、または飲用に適した製剤、シロップ剤、エリキシル剤、溶液、懸濁液およびジュースを包含する液体製剤を投与する、請求項9に記載の、鉄(III)−ピリミジン−2−オール−1−オキシド錯体化合物またはその医薬的に許容される塩を含む医薬組成物。
- 少なくとも1つの生理的に適合性の担体または賦形剤をさらに含有する、請求項1〜10のいずれか1項に記載の、鉄(III)−ピリミジン−2−オール−1−オキシド錯体化合物またはその医薬的に許容される塩を含む医薬組成物。
- 鉄代謝に作用する少なくとも1つのさらなる薬剤と組み合わせた、請求項1〜11のいずれか1項に記載の、鉄(III)−ピリミジン−2−オール−1−オキシド錯体化合物またはその医薬的に許容される塩を含む医薬組成物。
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US4788281A (en) | 1984-01-04 | 1988-11-29 | Tosoni Anthony L | Dextran hexonic acid derivative, ferric hydroxide complex and method manufacture thereof |
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