JPWO2020163268A5 - - Google Patents

Description

（式中、Ｒ１は、

であり、
Ｒ２はＨまたはＯＨである）
の化合物、またはその薬学的に許容される塩。
［２］
Ｒ１が、

である、［１］に記載の化合物、またはその薬学的に許容される塩。
［３］
Ｒ２がＯＨである、［２］に記載の化合物、またはその薬学的に許容される塩。
［４］
メタノール中で（＋）旋光度を有する単一の鏡像異性体を含む式：

の、［３］に記載の化合物、またはその薬学的に許容される塩。
［５］
メタノール中で（－）旋光度を有する単一の鏡像異性体を含む式：

の、［３］に記載の化合物、またはその薬学的に許容される塩。
［６］
Ｒ２がＨである、［２］に記載の化合物、またはその薬学的に許容される塩。
［７］
Ｒ１が、

である、［１］に記載の化合物、またはその薬学的に許容される塩。
［８］
Ｒ２がＨである、［７］に記載の化合物、またはその薬学的に許容される塩。
［９］
Ｒ２がＯＨである、［７］に記載の化合物、またはその薬学的に許容される塩。
［１０］
式：

の、［９］に記載の化合物、またはその薬学的に許容される塩。
［１１］
式：

の、［９］に記載の化合物、またはその薬学的に許容される塩。
［１２］
［１］～［１１］のいずれか一項に記載の化合物、またはその薬学的に許容される塩を１種または複数の薬学的に許容される担体、希釈剤または賦形剤と共に含む医薬組成物。
［１３］
運動ニューロン興奮性の変化によって引き起こされる疾患を処置する方法であって、必要とする患者に有効量の［１］～［１１］のいずれか一項に記載の化合物、またはその薬学的に許容される塩を投与するステップを含む、方法。
［１４］
運動ニューロン興奮性の変化によって引き起こされる前記疾患がＡＬＳである、［１３］に記載の方法。
［１５］
運動ニューロン興奮性の変化によって引き起こされる疾患を処置する方法であって、必要とする患者に［１２］に記載の医薬組成物を投与するステップを含む、方法。
［１６］
運動ニューロン興奮性の変化によって引き起こされる前記疾患がＡＬＳである、［１５］に記載の方法。
［１７］
治療での使用のための、［１］～［１１］のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
［１８］
運動ニューロン興奮性の変化によって引き起こされる疾患の処置での使用のための、［１］～［１１］のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
［１９］
運動ニューロン興奮性の変化によって引き起こされる前記疾患がＡＬＳである、［１８］に記載の使用のための化合物、またはその薬学的に許容される塩。
［２０］
運動ニューロン興奮性の変化によって引き起こされる疾患の処置のための医薬を製造するための、［１］～［１１］のいずれか一項に記載の化合物またはその薬学的に許容される塩の使用。
［２１］
運動ニューロン興奮性の変化によって引き起こされる前記疾患がＡＬＳである、［２０］に記載の化合物またはその薬学的に許容される塩の使用。
［２２］
医薬組成物を調製するための方法であって、［１］～［１１］のいずれか一項に記載の化合物、またはその薬学的に許容される塩を１種または複数の薬学的に許容される担体、希釈剤、または賦形剤と混合するステップを含む、方法。
［２３］
式：

の化合物またはその薬学的に許容される塩。
［２４］
メタノール中で（＋）旋光度を有する単一の鏡像異性体を含む式：

の化合物、またはその薬学的に許容される塩。
［２５］
式：

の化合物、またはその薬学的に許容される塩。 There is a significant difference in time and time*treatment interactions (two-way RM ANOVA; time effect F(26,312)=13.18, p=<0.0001; time*treatment interaction F(78,312) ) = 2.888, p < 0.0001.Bonferroni multiple comparison test showed that 30 mg/kg of Example 1 significantly elevated the absolute threshold (decreased excitability) compared to vehicle. XE-991 was able to reverse this elevation (increase excitability).
The present invention can include the following aspects.
[1]
formula:

(Wherein, R1 is

and
R2 is H or OH)
or a pharmaceutically acceptable salt thereof.
[2]
R1 is

The compound according to [1], or a pharmaceutically acceptable salt thereof.
[3]
The compound according to [2], or a pharmaceutically acceptable salt thereof, wherein R2 is OH.
[4]
Formula containing a single enantiomer with (+) optical rotation in methanol:

, the compound according to [3], or a pharmaceutically acceptable salt thereof.
[5]
Formula containing a single enantiomer with (−) optical rotation in methanol:

, the compound according to [3], or a pharmaceutically acceptable salt thereof.
[6]
The compound according to [2], wherein R2 is H, or a pharmaceutically acceptable salt thereof.
[7]
R1 is

The compound according to [1], or a pharmaceutically acceptable salt thereof.
[8]
The compound of [7], wherein R2 is H, or a pharmaceutically acceptable salt thereof.
[9]
The compound of [7], or a pharmaceutically acceptable salt thereof, wherein R2 is OH.
[10]
formula:

, the compound according to [9], or a pharmaceutically acceptable salt thereof.
[11]
formula:

, the compound according to [9], or a pharmaceutically acceptable salt thereof.
[12]
A pharmaceutical composition comprising the compound according to any one of [1] to [11], or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients thing.
[13]
A method of treating a disease caused by altered motor neuron excitability, comprising an effective amount of the compound of any one of [1] to [11], or a pharmaceutically acceptable administering a salt that
[14]
The method of [13], wherein said disease caused by altered motor neuron excitability is ALS.
[15]
A method of treating a disease caused by altered motor neuron excitability, comprising administering to a patient in need thereof the pharmaceutical composition of [12].
[16]
The method of [15], wherein said disease caused by altered motor neuron excitability is ALS.
[17]
A compound according to any one of [1] to [11], or a pharmaceutically acceptable salt thereof, for use in therapy.
[18]
A compound according to any one of [1] to [11], or a pharmaceutically acceptable salt thereof, for use in treating a disease caused by altered motor neuron excitability.
[19]
A compound, or a pharmaceutically acceptable salt thereof, for use according to [18], wherein said disease caused by altered motor neuron excitability is ALS.
[20]
Use of the compound according to any one of [1] to [11] or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of diseases caused by altered motor neuron excitability.
[21]
Use of the compound of [20] or a pharmaceutically acceptable salt thereof, wherein the disease caused by altered motor neuron excitability is ALS.
[22]
A method for preparing a pharmaceutical composition, wherein the compound according to any one of [1] to [11], or a pharmaceutically acceptable salt thereof, is added to one or more pharmaceutically acceptable mixing with a carrier, diluent, or excipient.
[23]
formula:

or a pharmaceutically acceptable salt thereof.
[24]
Formula containing a single enantiomer with (+) optical rotation in methanol:

or a pharmaceutically acceptable salt thereof.
[25]
formula:

or a pharmaceutically acceptable salt thereof.

Claims (21)

formula:

(Wherein, R1 is

and
R2 is H or OH)
or a pharmaceutically acceptable salt thereof. R1 is

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is 3. The compound of Claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is OH. Formula containing a single enantiomer with (+) optical rotation in methanol:

or a pharmaceutically acceptable salt thereof, according to claim 3. Formula containing a single enantiomer with (−) optical rotation in methanol:

or a pharmaceutically acceptable salt thereof, according to claim 3. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is H. R1 is

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R2 is H. 8. The compound of Claim 7, or a pharmaceutically acceptable salt thereof, wherein R2 is OH. formula:

or a pharmaceutically acceptable salt thereof, according to claim 9. formula:

or a pharmaceutically acceptable salt thereof, according to claim 9. formula:

or a pharmaceutically acceptable salt thereof. Formula containing a single enantiomer with (+) optical rotation in methanol:

or a pharmaceutically acceptable salt thereof. formula:

or a pharmaceutically acceptable salt thereof. 15. A pharmaceutical composition comprising a compound according to any one of claims 1-14 , or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients. 15. A compound according to any one of claims 1 to 14 , or a pharmaceutically acceptable salt thereof, for use in therapy. A compound according to any one of claims 1 to 14 , or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases caused by altered motor neuron excitability. 18. A compound, or a pharmaceutically acceptable salt thereof, for use according to claim 17 , wherein said disease caused by altered motor neuron excitability is ALS. 16. A pharmaceutical composition according to claim 15 for the treatment of diseases caused by altered motor neuron excitability. 20. The pharmaceutical composition according to claim 19, wherein said disease caused by altered motor neuron excitability is ALS. A method for preparing a pharmaceutical composition comprising a compound according to any one of claims 1 to 14 , or a pharmaceutically acceptable salt thereof, in one or more pharmaceutically acceptable carriers , a diluent, or an excipient.