Aryl methyl benzoquinazolinone M1 receptor positive allosteric modulators

Patent metadata

Field	Value
Publication number	US-9708273-B2
Application number	US-201514828216-A
Country	US
Kind code	B2
Filing date	Aug 17, 2015
Priority date	Nov 20, 2008
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

The present invention is directed to benzoquinazilinone compounds of formula (I)

which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimer's disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.

First claim

What is claimed is:

1. A method of treating Alzheimer's disease, or schizophrenia in a patient in need thereof, wherein treating consists of ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the disease, comprising administering to the patient a therapeutically effective amount of a compound selected from
rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]-quinazolin-4(3H)-one,
3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one,
rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3)-one,
3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-isopropylpyridin-3-yl)methylbenzo[h]quinazolin-4(3H)-one,
rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(hydroxymethyl)pyridine-3-yl]methyl}benzo[h]-quinazolin-4(3H)-one,
or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein the pharmaceutically acceptable salt is selected from the group consisting of acetate, trifluoroacetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, and para-toluenesolfonate.

3. The method of claim 1 where the compound is rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof.

4. The method of claim 3 wherein the pharmaceutically acceptable salt is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride.

5. The pharmaceutically acceptable salt according to claim 4 which is fumarate.

6. The method of claim 1 where the compound is 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof.

7. The method of claim 6 wherein the pharmaceutically acceptable salt is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride.

8. The pharmaceutically acceptable salt according to claim 7 which is fumarate.

9. The method of claim 1 where the compound is rac-3-[trans-2-hydroxycyclohexyl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof.

10. The method of claim 9 wherein the pharmaceutically acceptable salt is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride.

11. The pharmaceutically acceptable salt according to claim 10 which is fumarate.

12. The method of claim 1 where the compound is 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-isopropylpyridin-3-yl)methylbenzo[h]quinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof.

13. The method of claim 12 wherein the pharmaceutically acceptable salt is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride.

14. The pharmaceutically acceptable salt according to claim 13 which is fumarate.

15. The method of claim 1 where the compound is rac-3-[trans-2-hydroxycyclohexyl]-6-{[6-(hydroxymethyl)pyridine-3-yl]methyl}benzo[h]-quinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof.

16. The method of claim 15 wherein the pharmaceutically acceptable salt is selected from the group consisting of acetate, trifluoroacetate, fumarate, and hydrochloride.

17. The pharmaceutically acceptable salt according to claim 16 which is fumarate.

18. A compound which is: 6-bromo-3-[(1S,2S)-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one.

19. The compound of claim 18 represented by structural formula

Assignees

• Merck Sharp & Dohme

Inventors

• Kuduk Scott D
• Beshore Douglas C
• Dimarco Christina Ng
• Greshock Thomas J

Classifications

• 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

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/18

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

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title