Substituted 4-methyl-pyrrolo[1,2-a]pyrimidine-8-carboxamide compounds and uses thereof for modulating glucocerebrosidase activity

Patent metadata

Field	Value
Publication number	US-10442812-B2
Application number	US-201916252053-A
Country	US
Kind code	B2
Filing date	Jan 18, 2019
Priority date	Jul 1, 2015
Publication date	Oct 15, 2019
Grant date	Oct 15, 2019

Abstract

Disclosed are new small molecules having a 4-methylpyrrrolo[1,2-a]pyrimidine-8-carboxamide core structure and the uses thereof for modulating glucocerebrosidase activity. Also disclosed are pharmaceutical compositions comprising the small molecules which may be administered in methods of treating diseases or disorders associated with glucocerebrosidase activity, including neurological diseases and disorders such as Gaucher's disease and Parkinson's disease. The small molecules may contain a fluorophore or may be conjugated to a fluorophore in order to prepare a fluorescent probe for use in high throughput screening methods to identify new modulators of glucocerebrosidase activity via fluorescence polarization.

First claim

We claim:

1. A compound or a salt or solvate thereof having a formula:

wherein:
n is 0-2; and
X is selected from hydrogen, alkyl, halo, haloalkyl, phenyl optionally substituted with alkyl or halo, alkylamino, N-pyrrolidinyl, alkyl-N-piperidinyl, 4-N,N-dialkylamino-N-piperidinyl, N-piperazinyl, N-alkyl-N-piperazinyl, N-benzyl-N-piperazinyl, N-morpholinyl, azido, hydroxyl, alkylhydroxyl, alkynylphenyl, phenoxy, oxophenyl, and oxyalkylcarboxyl.

2. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutical carrier.

3. A method for treating Gaucher's disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 2 to the subject.

4. A method for treating Parkinson's disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 2 to the subject.

5. The compound of claim 1 covalently attached to glucocerebrosidase.

6. A pharmaceutical composition comprising: (i) the compound of claim 1 covalently attached to glucocerebrosidase; and (ii) a pharmaceutical carrier.

7. A method for treating Gaucher's disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 6 to the subject.

8. A method for treating Parkinson's disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 6 to the subject.

9. A compound or a salt or solvate thereof having a formula:

wherein:
n is 0-2; and
X is selected from the group consisting of:

10. A pharmaceutical composition comprising the compound of claim 9 and a pharmaceutical carrier.

11. A method for treating Gaucher's disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 10 to the subject.

12. A method for treating Parkinson's disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 10 to the subject.

13. The compound of claim 9 covalently attached to glucocerebrosidase.

14. A pharmaceutical composition comprising: (i) the compound of claim 9 covalently attached to glucocerebrosidase; and (ii) a pharmaceutical carrier.

15. A method for treating Gaucher's disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 14 to the subject.

16. A method for treating Parkinson's disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 14 to the subject.

17. A compound having a formula selected from:

18. A pharmaceutical composition comprising the compound of claim 17 and a pharmaceutical carrier.

19. The compound of claim 17 covalently attached to glucocerebrosidase.

20. A pharmaceutical composition comprising: (i) the compound of claim 17 covalently attached to glucocerebrosidase; and (ii) a pharmaceutical carrier.

Assignees

• Univ Northwestern

Inventors

• Krainc Dimitri
• Silverman Richard B
• Zheng Jianbin

Classifications

• C09B11/24

  Phthaleins containing amino groups {; Phthalanes; Fluoranes; Phthalides; Rhodamine dyes; Phthaleins having heterocyclic aryl rings; Lactone or lactame forms of triarylmethane dyes} · CPC title

• A61K9/10

  Dispersions; Emulsions · 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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/5355

  Non-condensed oxazines and containing further heterocyclic rings · CPC title