Sulfonamide Derivatives and Pharmaceutical Applications Thereof

Title:	Sulfonamide derivatives and pharmaceutical applications thereof
Patent Application Number:	WO2015158313A1	Publication date:	October 22nd, 2015
Priority Application:	CN 201410159273.0	Priority date:	April 19th, 2014
Inventors:	Zhang, Y.; Jin, C.; Zhong, W.; Xie, H.; Zhang, J.
Assignee Company:	Sunshine Lake Pharma Company
Disease Area:	CNS	Biological Target:	5-HT6
Summary:	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–6 alkyl, C2–6 alkenyl, C2–6 alkynyl, C3–8 cycloalkyl, Cl-6 haloalkyl, Cl–6 alkoxy, Cl–6 haloalkoxy, Cl–6 alkylthio, Cl–6 alkenylthio, R9aR9N–Cl–6 alkyl, −C(=O)R9b, −C(=O)OR9C, −C(=O)NR9R9a, R9R9aN–S(=O)2–, R9bS(=O)2–, R9bS(=O)–Cl-6 alkyl, R9R9aN–C(=O)-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–6 alkyl, C2–6 alkenyl, C2–6 alkynyl, C3–8 cycloalkyl, Cl-6 haloalkyl, Cl–6 alkoxy, Cl-6 haloalkoxy or C6–10 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(=O)R9b, −C(=O)NR9R9a, C2–6 alkenyl or 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, C2–6 alkenyl, C2–6 alkynyl, 3- to 12-memerbered heterocyclyl, C3–8 cycloalkyl, −C(=O)R9b, or −C(=O)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;
	R10 is 3- to 12-membered heterocyclyl, C3–8 cycloalkyl, C6–10 aryl or 5- to 12-membered heteroaryl, and wherein optionally each of 3- to 12-membered heterocyclyl, C3–8 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 (=O), −C(=O)R9b, −C(=O)OR9C, −C(=O)NR9R9a, Cl–6 alkyl, C3–8 cycloalkyl, Cl–6 haloalkyl, Cl–6 alkoxy, 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, −OH, Cl–6 alkyl, Cl–6 haloalkyl, Cl–6 alkoxy, C6–10 aryl, 3- to 12-membered heterocyclyl, C3–8 cycloalkyl, (C6–10 aryl)–(Cl-6 alkyl)–, C6–10 aryloxy, 3- to 12-memebered heterocyclyloxy, C3–8 cycloalkoxy, C6–10 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:
Recent Review Articles:	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-HT6Receptor 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

The authors declare no competing financial interest.