JPWO2021071965A5 - - Google Patents

Description

またはそれらの塩から選択される、項目３に記載の方法。
（項目５）
前記アルドースレダクターゼ阻害剤が、化合物Ｂまたはその塩である、項目１～４のいずれか一項に記載の方法。
（項目６）
前記アルドースレダクターゼ阻害剤が、式（ＩＩ）の化合物またはその塩である、項目１～２のいずれか一項に記載の方法。
（項目７）
前記アルドースレダクターゼ阻害剤が、以下のもの

またはそれらの塩から選択される、項目６に記載の方法。
（項目８）
前記アルドースレダクターゼ阻害剤が、化合物Ａまたはその塩である、項目７に記載の方法。
（項目９）
前記アルドースレダクターゼ阻害剤が、式（Ｉ）～（ＶＩ）のいずれか１つの化合物またはその塩である、項目１～２のいずれか一項に記載の方法。
（項目１０）
前記被験体がヒトである、項目１～９のいずれか一項に記載の方法。
（項目１１）
ＰＭＭ２－ＣＤＧの処置において使用するための、アルドースレダクターゼ阻害剤。
（項目１２）
処置が、ＰＭＭ２－ＣＤＧを有する被験体におけるＰＭＭ２酵素活性を増大させる、項目１１に記載の使用。
（項目１３）
前記アルドースレダクターゼ阻害剤が、式（ＩＩＩ）の化合物またはその塩である、項目１１～１２のいずれか一項に記載の使用。
（項目１４）
前記アルドースレダクターゼ阻害剤が、以下のもの

またはそれらの塩から選択される、項目１３に記載の使用。
（項目１５）
前記アルドースレダクターゼ阻害剤が、化合物Ｂまたはその塩である、項目１１～１４のいずれか一項に記載の使用。
（項目１６）
前記アルドースレダクターゼ阻害剤が、式（ＩＩ）の化合物またはその塩である、項目１１～１２のいずれか一項に記載の使用。
（項目１７）
前記アルドースレダクターゼ阻害剤が、以下のもの

またはそれらの塩から選択される、項目１６に記載の方法。
（項目１８）
前記アルドースレダクターゼ阻害剤が、化合物Ａまたはその塩である、項目１７に記載の方法。
（項目１９）
前記アルドースレダクターゼ阻害剤が、式（Ｉ）～（ＶＩ）のいずれか１つの化合物またはその塩である、項目１１～１２のいずれか一項に記載の方法。 Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described in the preceding paragraphs. Additionally, the materials and methods are illustrative only and not intended to be limiting. All US patents and published or unpublished US patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are incorporated by reference. All published references, documents, manuscripts, scientific literature cited herein are incorporated by reference. All identifiers and accession numbers for scientific databases (eg, PUBMED, NCBI, GENBANK, EBI) referenced herein are incorporated herein by reference.
In one embodiment, for example, the following items are provided:
(Item 1)
A method of treating PMM2-CDG comprising administering to a subject in need thereof a therapeutically effective amount of an aldose reductase inhibitor.
(Item 2)
A method of increasing PMM2 enzyme activity in a subject having PMM2-CDG, the method comprising administering to said subject a therapeutically effective amount of an aldose reductase inhibitor.
(Item 3)
The method according to any one of items 1 to 2, wherein the aldose reductase inhibitor is a compound of formula (III) or a salt thereof.
(Item 4)
The aldose reductase inhibitor is one of the following:

or a salt thereof.
(Item 5)
5. The method according to any one of items 1 to 4, wherein the aldose reductase inhibitor is Compound B or a salt thereof.
(Item 6)
The method according to any one of items 1 to 2, wherein the aldose reductase inhibitor is a compound of formula (II) or a salt thereof.
(Item 7)
The aldose reductase inhibitor is one of the following:

or a salt thereof.
(Item 8)
8. The method according to item 7, wherein the aldose reductase inhibitor is Compound A or a salt thereof.
(Item 9)
The method according to any one of items 1 to 2, wherein the aldose reductase inhibitor is a compound of any one of formulas (I) to (VI) or a salt thereof.
(Item 10)
The method according to any one of items 1 to 9, wherein the subject is a human.
(Item 11)
An aldose reductase inhibitor for use in the treatment of PMM2-CDG.
(Item 12)
The use according to item 11, wherein the treatment increases PMM2 enzyme activity in a subject with PMM2-CDG.
(Item 13)
The use according to any one of items 11 to 12, wherein the aldose reductase inhibitor is a compound of formula (III) or a salt thereof.
(Item 14)
The aldose reductase inhibitor is one of the following:

or a salt thereof, the use according to item 13.
(Item 15)
The use according to any one of items 11 to 14, wherein the aldose reductase inhibitor is Compound B or a salt thereof.
(Item 16)
The use according to any one of items 11 to 12, wherein the aldose reductase inhibitor is a compound of formula (II) or a salt thereof.
(Item 17)
The aldose reductase inhibitor is one of the following:

or a salt thereof.
(Item 18)
18. The method according to item 17, wherein the aldose reductase inhibitor is Compound A or a salt thereof.
(Item 19)
The method according to any one of items 11 to 12, wherein the aldose reductase inhibitor is a compound of any one of formulas (I) to (VI) or a salt thereof.

Claims (18)

A composition for treating PMM2-CDG in a subject in need thereof , the composition comprising an aldose reductase inhibitor. A composition for increasing PMM2 enzyme activity in a subject having PMM2-CDG, the composition comprising an aldose reductase inhibitor. The aldose reductase inhibitor is a compound of formula (III) :

or its salt ;
During the ceremony,
R ¹ is CO ₂ R ² ;
R ² is H, (C ₁ -C ₆ )-alkyl, (C ₁ -C ₆ )-hydroxyalkyl or (C ₁ -C ₆ )-aminoalkyl;
X ¹ is H or halogen;
X ² is H or halogen;
Y is a bond, C=O, C=S, C=NH or C=N(C ₁ -C ₄ )-alkyl;
Z is

And;
A ¹ is NR ⁷ , O, S or CH ₂ ;
A ² is N or CH;
A ³ is NR ⁷ , O or S;
R ³ to R ⁶ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C ₁ -C ₄ )-alkyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )-alkylthio, (C ₁ -C ₄ )-alkylsulfinyl or (C ₁ -C ₄ )-alkylsulfonyl; and
Composition according to claim 1 or 2 , wherein R ⁷ is hydrogen, C ₁ -C ₄ alkyl or C(O)O-(C ₁ -C ₄ )-alkyl . R ² is H or (C ₁ -C ₆ ) - alkyl;
Y is C=O;
A ¹ is NR ⁷ , O or S;
A ² is N;
A ³ is O or S; and
R ³ ～R ⁶ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C ₁ -C ₄ )-alkyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )-alkylthio, (C ₁ -C ₄ )-alkylsulfinyl or (C ₁ -C ₄ )-alkylsulfonyl; and
R ⁷ is hydrogen, C ₁ -C ₄ Alkyl or C(O)O-(C ₁ -C ₄ )-alkyl. Z is

The composition according to claim 3 or 4, which is a salt thereof. R ² is H or (C ₁ -C ₆ ) - alkyl;
X ¹ is H;
X ² is H;
Y is C=O;
A ¹ is S;
A ² is N; and
R ³ ～R ⁶ A composition according to any one of claims 3 to 5, wherein is independently hydrogen, halogen or haloalkyl. Z is

or a pharmaceutically acceptable salt or solvate thereof. R ² is hydrogen or (C ₁ -C ₆ ) - alkyl;
Y is C=O;
R ³ ～R ⁶ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C ₁ -C ₄ )-alkyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )-alkylthio, (C ₁ -C ₄ )-alkylsulfinyl or (C ₁ -C ₄ )-alkylsulfonyl; and
R ⁷ is hydrogen, C ₁ -C ₄ Alkyl or C(O)O-(C ₁ -C ₄ )-alkyl. The aldose reductase inhibitor is

The composition according to any one of claims 3 to 6 , selected from the group consisting of and salts thereof. The aldose reductase inhibitor is compound B :

or a salt thereof, the composition according to any one of claims 1 to 6 . The aldose reductase inhibitor is a compound of formula (I):

or a salt thereof, in the formula:
R ¹ is H, (C ₁ -C ₆ )-alkyl, (C ₁ -C ₆ )-hydroxyalkyl or (C ₁ -C ₆ )-aminoalkyl;
X ¹ is N or CR ³ And;
X ² is N or CR ⁴ And;
X ³ is N or CR ⁵ And;
X ⁴ is N or CR ⁶ and, however, X ¹ ,X ² ,X ³ or X ⁴ two or three of them are N;
Y is a bond, C=O, C=S, C=NH or C=N(C ₁ -C ₄ ) - alkyl;
Z is

And;
A ¹ is NR ¹¹ , O, S or CH ₂ And;
A ² is N or CH;
A ³ is NR ¹¹ , O or S;
R ³ ～R ¹⁰ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C ₁ -C ₄ )-alkyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )-alkylthio, (C ₁ -C ₄ )-alkylsulfinyl or (C ₁ -C ₄ )-alkylsulfonyl; or R ³ ～R ⁶ two or R ⁷ ～R ¹⁰ Both (C ₁ -C ₄ )-alkylenedioxy; and
R ¹¹ is hydrogen, C ₁ -C ₄ Alkyl or C(O)O-(C ₁ -C ₄ )-alkyl, the composition according to claim 1 or 2. R ¹ is H or (C ₁ -C ₆ ) - alkyl;
X ¹ and X ⁴ is N;
X ² is CR ⁴ And;
X ³ is CR ⁵ And;
Y is C=O;
A ¹ is NR ¹¹ , O or S;
A ² is N;
A ³ is O or S;
R ³ ～R ¹⁰ are each independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, (C ₁ -C ₄ )-alkyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )-alkylthio, (C ₁ -C ₄ )-alkylsulfinyl or (C ₁ -C ₄ )-alkylsulfonyl; and
R ¹¹ is hydrogen, C ₁ -C ₄ Alkyl or C(O)O-(C ₁ -C ₄ )-alkyl. R ³ ～R ¹⁰ 13. A composition according to claim 11 or 12, wherein each is independently hydrogen, halogen or haloalkyl. Z is

The composition according to any one of claims 11 to 13, which is The aldose reductase inhibitor is a compound of formula (II) :

or its salt ;
R ¹ is H, (C ₁ -C ₆ )-alkyl, (C ₁ -C ₆ )-hydroxyalkyl or (C ₁ -C ₆ )-aminoalkyl;
Y is a bond, C=O, C=S, C=NH or C=N(C ₁ -C ₄ )-alkyl; and
R ⁷ to R ¹⁰ are independently hydrogen, halogen, cyano, acyl, haloalkyl, haloalkoxy, haloalkylthio, trifluoroacetyl, (C ₁ -C ₄ )-alkyl, (C ₁ -C ₄ )-alkoxy, (C ₁ -C ₄ )-alkylthio, (C ₁ -C ₄ )-alkylsulfinyl or (C ₁ -C ₄ )-alkylsulfonyl; or both R 7 ^to R ¹⁰ are (C ₁ -C ₄ )-Alkylenedioxy , the composition according to any one of claims 1 , 2 or 11 to 14 . The aldose reductase inhibitor is one of the following:

The composition according to any one of claims 1, 2 or 11-15, selected from the group consisting of and salts thereof. The aldose reductase inhibitor is compound A :

or a salt thereof, according to any one of claims 1, 2 or 11 to 16 . The composition according to any one of claims 1 to 17 , wherein the subject is a human.