Water-soluble myosin 2 inhibitors for the treatment of neurological, neuropathic or psychiatric diseases

Patent metadata

Field	Value
Publication number	US-10858357-B2
Application number	US-201716073597-A
Country	US
Kind code	B2
Filing date	Jan 27, 2017
Priority date	Jan 29, 2016
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

Abstract

The present invention relates to highly soluble, non-fluorescent and photostable myosin inhibitors; especially, for in vivo inhibition of the ATPase activity of neuronal non-muscle myosin 2 of formula (II): wherein Q 1 , Q 2 , Q 3 , Q 4 , R 1 , R 2 , R 4 and R 5 are as defined in claim 1 . The invention also relates to pharmaceutical compositions or medicaments comprising the compounds of the invention and processes for manufacturing these compounds and their intermediates.

First claim

The invention claimed is:

1. A compound of general formula (II):

and pharmaceutically acceptable salts and/or solvates thereof, wherein:
Q 1 , Q 2 , Q 3 and Q 4 are each independently selected from H, halogen, alkyl, heteroalkyl, halogenoalkyl, halogenoheteroalkyl, nitro, hydroxyl, thiol and alkoxy;
R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from phosphonic acid, phosphoryl, hydrogen, halogen, alkyl, heteroalkyl, halogenoalkyl, halogenoheteroalkyl, hydroxyl, nitro, thiol, alkoxy, amino, alkylamino, halogenoalkylamino, imido, alkylimido, halogenoalkylimido, hydroxylamino, alkylhydroxyamino, sulfonyl, alkylsulfonyl, halogenoalkylsulfonyl, carboxyl, carbonyl, ester, alkyloxycarbonyl, halogenoalkyloxycarbonyl, amido, alkylamido, halogenoalkylamido, formyl, alkylcarbonyl, halogenoalkylcarbonyl, formylaminocarbonyl and carboxylic acid isostere, wherein the carboxylic acid isostere is selected from the group consisting of

wherein R is selected from hydrogen, alkyl, halogenoalkyl, hydroxyl, thiol, alkoxy, heteroalkyl, halogenoheteroalkyl, sulfonyl, alkylsulfonyl, halogenoalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, halogenoalkylaminosulfonyl, amidosulfonyl, alkylamidosulfonyl, halogenoalkylamidosulfonyl, formyl, alkylcarbonyl, halogenoalkylcarbonyl alkyloxycarbonyl, halogenoalkyloxycarbonyl, carboxyl and phosphoryl; and

represents the point of attachment of the moiety to the rest of the molecule; and
wherein at least one of R 2 , R 3 and R 4 are a hydrophilic group selected from phosphonic acid, phosphoryl, hydroxyl, amino, carboxyl and ester having a C1-C4 alkyl chain or any charged groups thereof; and
* stands for the (R)-enantiomer, the (S)-enantiomer, the racemate or the non-racemic mixture of (R) and (S) enantiomers of the corresponding formula (II).

2. The compound according to claim 1 , which is the (S)-enantiomer.

3. The compound according to claim 1 , wherein Q 3 is methyl and Q 1 , Q 2 , Q 4 , R 1 , R 2 , R 4 and R 5 are hydrogen; and R 3 is a hydrophilic group selected from phosphonic acid, phosphoryl, hydroxyl, amino, carboxyl and ester having a C1-C4 alkyl chain.

4. The compound according to claim 1 , wherein the compound is selected from:
1-(4-aminophenyl)-3a-hydroxy-6-methyl-3,3a-dihydro-1H-pyrrolo[2,3-b]quinolin-4(2H)-one;
3-(3a-hydroxy-6-methyl-4-oxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-b]quinolin-1-yl)benzoic acid;
4-(3a-hydroxy-6-methyl-4-oxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-b]quinolin-1-yl)benzoic acid;
3a-hydroxy-1-(3-hydroxyphenyl)-6-methyl-3,3a-dihydro-1H-pyrrolo[2,3-b]quinolin-4(2H)-one;
3a-hydroxy-1-(4-hydroxyphenyl)-6-methyl-3,3a-dihydro-1H-pyrrolo[2,3-b]quinolin-4(2H)-one;
1-(3-aminophenyl)-3a-hydroxy-6-methyl-3,3a-dihydro-1H-pyrrolo[2,3-b]quinolin-4(2H)-one; and
(4-(3a-hydroxy-6-methyl-4-oxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-b]quinolin-1-yl)phenyl)phosphonic acid.

5. The compound according to claim 1 , wherein the compound is selected from:

6. A pharmaceutical composition comprising at least one of a compound and pharmaceutically acceptable salts and/or solvates thereof according to claim 1 , and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.

7. A medicament comprising at least one of a compound and pharmaceutically acceptable salts and/or solvates thereof according to claim 1 .

8. A method of treating or preventing a myosin 2 mediated disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one of a compound of general formula (II) and pharmaceutically acceptable salts and/or solvates thereof according to claim 1 .

9. The method of claim 8 , wherein the myosin 2 mediated disease is a neurological, neuropathic and/or psychiatric disease or trauma.

10. The method of claim 8 , wherein the myosin 2 mediated disease is selected from schizophrenia, cerebral ischemia, stroke, neuropathic pain, spinal cord injury, Alzheimer's disease, Parkinson's disease, addiction, brain cancer and multiple sclerosis.

11. The method of claim 8 , wherein the compound of general formula (II) inhibits the effects of cannabinoid receptor activation.

12. The method of claim 8 , wherein the compound of general formula (II) inhibits neuronal actomyosin contractility.

13. The method of claim 12 , wherein the compound inhibits neuronal actomyosin contractility in vivo.

14. The pharmaceutical composition of claim 6 , wherein the compound is the (S)-enantiomer.

15. The pharmaceutical composition of claim 6 , wherein Q 3 is methyl and Q 1 , Q 2 , Q 4 , R 1 , R 2 , R 4 and R 5 are hydrogen; and R 3 is a hydrophilic group selected from phosphonic acid, phosphoryl, hydroxyl, amino, carboxyl and ester having a C1-C4 alkyl chain.

16. The pharmaceutical composition of claim 6 , wherein the compound is selected from:
1-(4-aminophenyl)-3a-hydroxy-6-methyl-3,3a-dihydro-1H-pyrrolo[2,3-b]quinolin-4(2H)-one;
3-(3a-hydroxy-6-methyl-4-oxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-b]quinolin-1-yl)benzoic acid;
4-(3a-hydroxy-6-methyl-4-oxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-b]quinolin-1-yl)benzoic acid;
3a-hydroxy-1-(3-hydroxyphenyl)-6-methyl-3,3a-dihydro-1H-pyrrolo[2,3-b]quinolin-4(2H)-one;
3a-hydroxy-1-(4-hydroxyphenyl)-6-methyl-3,3a-dihydro-1H-pyrrolo[2,3-b]quinolin-4(2H)-one;
1-(3-aminophenyl)-3a-hydroxy-6-methyl-3,3a-dihydro-1H-pyrrolo[2,3-b]quinolin-4(2H)-one; and
(4-(3a-hydroxy-6-methyl-4-oxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-b]quinolin-1-yl)phenyl)phosphonic acid.

17. The medicament of claim 7 , wherein the compound is the (S)-enantiomer.

18. The medicament of claim 7 , wherein Q 3 is methyl and Q 1 , Q 2 , Q 4 , R 1 , R 2 , R 4 and R 5 are hydrogen; and R 3 is a hydrophilic group selected from phosphonic acid, phosphoryl, hydroxyl, amino, carboxyl and ester having a C1-C4 alkyl chain.

19. The medicament of claim 7 , wherein the compound is selected from:
1-(4-aminophenyl)-3a-hydroxy-6-methyl-3,3a-dihydro-1H-pyrrolo[2,3-b]quinolin-4(2H)-one;
3-(3a-hydroxy-6-methyl-4-oxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-b]quinolin-1-yl)benzoic acid;
4-(3a-hydroxy-6-methyl-4-oxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-b]quinolin-1-yl)benzoic acid;
3a-hydroxy-1-(3-hydroxyphenyl)-6-methyl-3,3a-dihydro-1H-pyrrolo[2,3-b]quinolin-4(2H)-one;
3a-hydroxy-1-(4-hydroxyphenyl)-6-methyl-3,3a-dihydro-1H-pyrrolo[2,3-b]quinolin-4(2H)-one;
1-(3-aminophenyl)-3a-hydroxy-6-methyl-3,3a-dihydro-1H-pyrrolo[2,3-b]quinolin-4(2H)-one; and
(4-(3a-hydroxy-6-methyl-4-oxo-2,3,3a,4-tetrahydro-1H-pyrrolo[2,3-b]quinolin-1-yl)phenyl)phosphonic acid.

20. The method of claim 8 , wherein the compound is the (S)-enantiomer.

21. The method of claim 8 , wherein Q 3 is methyl and Q 1 , Q 2 , Q 4 , R 1 , R 2 , R 4 and R 5 are hydrogen; and R 3 is a hydrophilic group selected from phosphonic acid, phosphoryl, hydroxyl, amino, carboxyl and ester having a C1-C4 alkyl chain.

22. The method of claim 8 , wherein the compound is selected from:
1-(4-aminophenyl)-3a-hydroxy-6-methyl-3,3a-dihydro-1H-pyrrolo[2,3-b]quinolin-4(2H)-one;
3-(3a-hydroxy-6-methyl-4-oxo-2

Assignees

• Paris Sciences Lettres Quartier Latin
• Centre Nat Rech Scient
• Inst Nat Sante Rech Med
• Printnet Ltd

Inventors

• Lenkei Zsolt
• Málnási Csizmadia András
• Képiró Miklós
• Várkuti Boglárka

Classifications

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title