11-OXO-10,11-dihydrodibenzo[B,F][1,4]thiazepine S-oxide derivatives and their use as dopamine D2 receptor antagonists

Patent metadata

Field	Value
Publication number	US-9550742-B2
Application number	US-201414908271-A
Country	US
Kind code	B2
Filing date	Jul 29, 2014
Priority date	Jul 29, 2013
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

The disclosure includes compounds and pharmaceutically acceptable salts of Formula (I). Certain compounds and salts of Formula (I) are selective inhibitors of the Dopamine D 2 receptor. The variables R 1 -R 4 , n, and L are defined herein. The disclosure also provides methods of synthesizing compounds of Formula (I) and pharmaceutical compositions containing compounds of Formula (I). Additionally the disclosure provides methods or treating patients suffering from central nervous system disorders, including Tourette's syndrome, bipolar disorder, hyperprolactinemia, tardive dyskinesia, Huntington's chorea, psychosis, depression, or schizophrenia.

First claim

What is claimed is:

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein
L is —NHC(O)—, —C(O)NH—, —OC(O)— or —C(O)O—;
n is and integer from 1 to 4 and

 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy;
R 1 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (mono- or di-C 1 -C 4 alkylamino)C 1 -C 4 alkyl, or (mono- or di-C 1 -C 4 alkylamino)C 1 -C 4 alkoxy;
R 2 is mono-, bi-, or tricyclic carbocyclic or aromatic heterocylic group, a (mono- or di-C 1 -C 4 alkylamino)C 2 -C 4 alkyl group, or C 4 -C 8 alkyl, each of which R 2 is unsubstituted or substituted with one more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —OR 11 , —(CH 2 ) 0-4 C(O)R 11 , —(CH 2 ) 0-4 NR 11 R 12 , —(CH 2 ) 0-4 C(O)NR 11 R 12 , —(CH 2 ) 0-4 N(R 11 )C(O)(R 12 ), —(CH 2 ) 0-4 C(O)OR 11 , —(CH 2 ) 0-4 OC(O)R 11 , —(CH 2 ) 0-4 C(S)R 11 , —(CH 2 ) 0-4 S(O) a R 11 , —(CH 2 ) 0-4 S(O) b NR 11 R 12 , —(CH 2 ) 0-4 N(R 11 )S(O) b R 12 , and (phenyl)C 0 -C 2 alkyl, where a is 0, 1, or 2, and b is 1 or 2,
R 11 and R 12 are independently chosen at each occurrence from hydrogen and a C 1 -C 6 aliphatic group;
each of R 11 , and R 12 is unsubstituted or substituted with one or more substituents independently chosen from: halogen, hydroxyl, vinyl, allenyl, oxo, cyano, amino, —COOH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 2 alkyl, C 1 -C 6 alkylester, C 1 -C 6 alkylthio, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
R 3 and R 4 are 0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 2 -C 4 alkanoyl, (mono- and di-C 1 -C 4 alkylamino)C 0 -C 2 alkyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
with the proviso that when R 1 is ethyl, the group

is not 4-methoxybenzyl-NHC(O)—, pyridin-2-ylmethyl-NHC(O)—, 3-(morpholin-1-yl)propyl-NHC(O)—, 3-(azepan-1-yl)propyl-NHC(O)—, 2-(azepan-1-yl)ethyl-NHC(O)—, 3-(pyrrolidin-1-yl)propyl-NHC(O)—, 3-(4-methylpiperazin-1-yl)propyl-NHC(O)—, 3-(piperidin-1-yl)propyl-NHC(O)—, di-isopropylaminopropyl-NHC(O)—, di-propylaminopropyl-NHC(O)—, di-butylaminopropyl-NHC(O)—, or 3-(butyl(ethyl)amino)propyl-NHC(O)—.

2. A compound or salt of claim 1 , of the formula

3. A compound or salt of claim 1 , of the formula

4. A compound or salt of claim 1 , of the formula

5. A compound or salt of claim 1 , wherein
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl.

6. A compound or salt of claim 5 wherein R 1 is C 1 -C 6 alkyl.

7. A compound or salt of claim 1 , wherein
R 1 is methyl or ethyl, and R 3 and R 4 are both 0 substituents.

8. A compound or salt of claim 1 , wherein
R 3 and R 4 are both 0, 1, or 2 substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.

9. A compound or salt of claim 1 , wherein n is 1, 2, or 3 and

is unsubstituted or substituted with one C 1 -C 4 alkyl substituent or one trifluoromethyl substituent.

10. A compound or salt of claim 9 , wherein n is 1 or 2 and

is unsubstituted or substituted with one methyl substituent.

11. A compound or salt of claim 9 , wherein
R 2 is C 3 -C 7 cycloalkyl, phenyl, naphthyl, phenyl fused to a 5- or 6-membered heterocyclic ring containing 1 or 2 oxygen atoms, pyridyl, pyrimidinyl, pyrazinyl, thienyl, furanyl, thiazolyl, indolyl, or imidazolyl, each of which R 2 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, (mono- and di-C 1 -C 4 alkylamino)C 0 -C 2 alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.

12. A compound or salt of claim 11 , wherein
R 2 is phenyl, naphthyl, benzo[d][1,3]dioxolyl, pyridyl, thienyl, furanyl, indolyl, imidazolyl, or thiazolyl, each which is substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, (mono- and di-C 1 -C 4 alkylamino)C 0 -C 2 alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.

13. A compound or salt of claim 11 , wherein
R 2 is phenyl, naphthyl, benzo[d][1,3]dioxolyl, pyridyl, or thienyl, each which is substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, methylthio, methylsulfonyl, trifluoromethyl, and trifluoromethoxy.

14. A compound or salt of claim 3 , wherein
R 1 is C 1 -C 6 alkyl, or (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl;
n is 1, 2, or 3 and

 is unsubstituted or substituted with one C 1 -C 4 alkyl substituent or one trifluoromethyl substituent; and
R 2 is phenyl, naphthyl, benzo[d][1,3]dioxolyl, pyridyl, thienyl, furanyl, indolyl, imidazolyl, or thiazolyl, each which is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, (mono- and di-C 1 -C 4 alkylamino)C 0 -C 2 alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; and
R 3 and R 4 are both 0 substituents.

15. A compound or salt of claim 14 , wherein
R 2 is thienyl, which is unsubstituted or substituted with one or more substituents independently chosen from halogen, C 1 -C 2 alkyl, or C 1 -C 2 alkoxy.

16. A compound or salt of claim 14 , wherein
R 2 is phenyl which is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, (mono- and di-C 1 -C 4 alkylamino)C 0 -C 2 alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.

17. A compound or pharmaceutically acceptable salt thereof, wherein the compound is
10-Ethyl-N-(4-methoxybenzyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide 5-oxide;
10-Ethyl-N-(3-methoxybenzyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide 5-oxide;
10-Ethyl-N-(2-methoxybenzyl)-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide 5-oxide;
N-Benzyl-10-ethyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide 5-oxide;
10-Ethyl-11-oxo-N-(1-phenylethyl)-10,11-d

Assignees

• The Us Secretary Dept Of Health And Human
• Us Health

Inventors

• Marugan Juan Jose
• Xiao Jingbo
• Ferrer Marc
• Southall Noel Terrence
• Free R Benjamin
• Sibley David Robert

Classifications

• A61P25/18

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

• C07D281/16 Primary

  [b, f]-condensed · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P25/24

  Antidepressants · CPC title