PATENT HIGHLIGHT pubs.acs.org/acsmedchemlett
Sulfonamide Derivatives and Pharmaceutical Applications Thereof Benjamin Blass* Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, Pennsylvania 19140, United States Title:
Sulfonamide derivatives and pharmaceutical applications thereof
Patent Application Number: WO2015158313A1
Publication date:
October 22nd, 2015
Priority date:
April 19th, 2014
Priority Application:
CN 201410159273.0
Inventors:
Zhang, Y.; Jin, C.; Zhong, W.; Xie, H.; Zhang, J.
Assignee Company:
Sunshine Lake Pharma Company
Disease Area: Summary:
CNS Biological Target: 5-HT6 The neurotransmitter serotonin, also known as 5-hydroxytrptamine (5-HT), plays a key role in a wide range of biological processes. Its actions are mediated by a family of G-protein-coupled receptors (GPCRs) referred to as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. It has been previously demonstrated that the 5-HT6 receptor is highly expressed in the brain, which suggests that this receptor may play a key role in a number of CNS diseases and disorders. As such, it has been hypothesized that compounds that modulate 5-HT6 receptor activity may be useful for the treatment of a variety of conditions such as anxiety, depression, manic depressive disorder, psychoses, schizophrenia, epilepsy, obsessive compulsive disorder, migraine, panic attacks, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), sleep disorders, anorexia, bulimia, Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease. The present disclosure describes a series of sulfonamides capable of binding to the 5-HT6 receptor and their method of use for the treatment of CNS disease and disorders.
Important Compound Classes:
Definitions:
k is 0, 1, 2, or 3; m is 0, 1, 2, 3, or 4; n is 1, 2, 3, or 4; Each X is independently CH or N, and at most two X are N; Each Y is independently CH or N; Each Rl and R3 is independently H, D, F, CI, Br, I, CN, NO2, OH, NH2, Cl C3
8 cycloalkyl, Cl‑6 haloalkyl, Cl
C(dO)R9b,
C(dO)OR9C,
6 alkoxy, Cl
6 haloalkoxy, Cl
6
6 alkylthio, Cl
alkyl, C2
6
alkynyl,
9a 9 6 alkenylthio, R R N Cl
6 alkyl,
6
alkenyl, C2
C(dO)NR9R9a, R9R9aN S(dO)2 , R9bS(dO)2 , R9bS(dO) Cl‑6 alkyl,
R9R9aN C(dO)-Cl 6 alkyl, C6 10 aryl, C6 10 arylamino, 5- to 12-membered heteroaryl, (C3 8 cycloalkyl) (Cl‑6 alkyl) , (3- to 12-membered heterocyclyl) (Cl‑6 alkyl) , (C6 10 aryl) (Cl‑6 alkyl) , (5- to 12-membered heteroaryl) (Cl‑6 alkyl)- or 3- to 12-membered heterocyclyl; Each R2 is independently H, D, F, CI, Br, I, CN, OH, NH2, Cl Cl‑6 haloalkyl, Cl
6
alkoxy, Cl‑6 haloalkoxy or C6
10
6
alkyl, C2
6
alkenyl, C2
6
alkynyl, C3
8
cycloalkyl,
aryl; or two adjacent R2, together with the carbon atoms to
which they are attached, form a substituted or unsubstituted 5- to 7-membered carbocyclic ring, 5- to 7-membered heterocyclic ring, benzene ring, or 5- to 6-membered heteroaromatic ring; R4 is H, D, Cl
6
alkyl, Cl
6
haloalkyl, C3
8
cycloalkyl,
C(dO)R9b,
C(dO)NR9R9a, C2
6
alkenyl or C2
6
alkenyl, C2
6
alkynyl; Each of R5, R6, R7, and R8 is independently H, D, F, CI, Br, I, CN, NO2, OH, NH2, Cl‑6 alkyl, C2 alkynyl, 3- to 12-memerbered heterocyclyl, C3
8
cycloalkyl,
C(dO)R9b, or
6
C(dO)NR9R9a;
or R5 and R6, or R7 and R8, together with the carbon atom to which they are attached, independently form a substituted or unsubstituted 3- to 8-membered carbocyclic ring or 3- to 8-membered heterocyclic ring;
Received:
r XXXX American Chemical Society
A
December 6, 2015
dx.doi.org/10.1021/acsmedchemlett.5b00466 | ACS Med. Chem. Lett. XXXX, XXX, 000–000
ACS Medicinal Chemistry Letters
PATENT HIGHLIGHT
R10 is 3- to 12-membered heterocyclyl, C3
8
cycloalkyl, C6
optionally each of 3- to 12-membered heterocyclyl, C3
10
aryl or 5- to 12-membered heteroaryl, and wherein
8 cycloalkyl, C6 10 aryl, and 5- to 12-membered heteroaryl
is independently substituted with 1, 2, 3, or 4 substituents independently selected from H, D, F, CI, Br, I, CN, oxo (dO), C(dO)R9b, C(dO)OR9C, C(dO)NR9R9a, Cl 6 alkyl, C3 8 cycloalkyl, Cl 6 haloalkyl, Cl Cl 6 haloalkoxy, (C6 10 aryl) (Cl‑6 alkyl) or (5- to 12-membered heteroaryl) (Cl‑6 alkyl) ; and Each R9, R9a, R9b, and R9c is independently H, D, 3- to 12-membered heterocyclyl, C3 heterocyclyloxy, C3
8
OH, Cl
8 cycloalkyl, (C6 10 aryl)
cycloalkoxy, C6
10
6
alkyl, Cl
6
haloalkyl, Cl
(Cl‑6 alkyl) , C6
6
alkoxy, C6
6 alkoxy,
10
aryl,
10 aryloxy, 3- to 12-memebered
arylamino, 3- to 12-membered heterocyclylamino, C3
8
cycloalkylamino
or 5- to 12-membered heteroaryl; or R9 and R9a, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted 3- to 8-membered ring. Key Structures:
B
dx.doi.org/10.1021/acsmedchemlett.5b00466 |ACS Med. Chem. Lett. XXXX, XXX, 000–000
ACS Medicinal Chemistry Letters Recent Review Articles:
PATENT HIGHLIGHT
1. Bali, A.; Singh, S. Serotonergic 5-HT6 Receptor Antagonists: Heterocyclic Chemistry and Potential Therapeutic Significance. Curr. Top. Med. Chem. 2015, 15 (17), 1643 1662. 2., Karila, D.; Freret, T.; Bouet, V.; Boulouard, M.; Dallemagne, P.; Rochais, C. Therapeutic Potential of 5-HT6 Receptor Agonists. J. Med. Chem. 2015, 58 (20), 7901 7912. 3. , Marazziti, D.; Baroni, S.; Borsini, F.; Picchetti, M.; Vatteroni, E.; Falaschi, V.; Catena-Dell’Osso, M. Serotonin Receptors of Type 6 (5-HT6): From Neuroscience to Clinical Pharmacology. Curr. Med. Chem. 2013, 20 (3), 371 377.
Biological Assay:
5-HT6 Receptor binding assay: 32 μg membrane proteins of CHO cell expressing human 5-HT6 receptor, 2 nM radioactive marker [3H]LSD, a compound of the present invention having different test concentrations, 100 μM 5-HT (5-HT was used to eliminate nonspecific binding sites), and a buffer solution were mixed uniformly. Then the resulting mixture was incubated at 37 °C for 120 min in which the buffer solution comprised 50 mM Tris-HCl (pH 7.4), 10 mM MgCl2, 0.5 mM EDTA, 10 μM pargyline, and 20 mg/L protease inhibitor. After incubation, the resulting mixture was filtered by a fiberglass filter in vacuo (GF/B, Packard), and the filter membrane of the fiberglass filter was preimpregnated with 0.3% PEl before the filtering and washed with 50 mM of Tris-HCI for several times after the filtering. After the filter membrane was dried, the radioactivity of filter membrane was determined by liquid scintillation counting by using a scintillometer (Top count, Packard). The reference standard was 5-HT, and IC50 values were calculated by competitive inhibition curves plotted based on several inhibition ratios and the corresponding compound concentrations.
Biological Data:
Claims:
24 Total claims 15 Composition of matter claims 9 Method of use claims
’ AUTHOR INFORMATION Corresponding Author
*Tel: 215-707-1085. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
C
dx.doi.org/10.1021/acsmedchemlett.5b00466 |ACS Med. Chem. Lett. XXXX, XXX, 000–000
