WO2011022207A1 - Bis-sulfonamide derivatives, compositions, and methods of use - Google Patents

Bis-sulfonamide derivatives, compositions, and methods of use Download PDF

Info

Publication number
WO2011022207A1
WO2011022207A1 PCT/US2010/044387 US2010044387W WO2011022207A1 WO 2011022207 A1 WO2011022207 A1 WO 2011022207A1 US 2010044387 W US2010044387 W US 2010044387W WO 2011022207 A1 WO2011022207 A1 WO 2011022207A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
sulfonamide
benzothiophene
group
alkyl
Prior art date
Application number
PCT/US2010/044387
Other languages
French (fr)
Inventor
Robert Carl Andrews
Anitha Hari
Original Assignee
High Point Pharmaceuticals, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by High Point Pharmaceuticals, Llc filed Critical High Point Pharmaceuticals, Llc
Publication of WO2011022207A1 publication Critical patent/WO2011022207A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • L 1 , L 2 and L 3 are independently selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -S-, -S(O)-, and -SO 2 -; provided that, when at least one of Ar 2 and Ar 3 is not formula (If), or when Ar 1 is not a thiophene group, at least one of the following two conditions are met:
  • Embodiment 27 A compound according to embodiment 26, wherein R y is -L 1 - Ci_3 alkyl.
  • Embodiment 29 A compound according to embodiment 28, wherein R y is -L 1 -
  • Embodiment 42 A compound according to any one of embodiments 37 through
  • Embodiment 45 A compound according to any one of embodiments 1 through 44, wherein R 11 is selected from the group consisting of -C 1-6 alkyl, -C 1-6 haloalkyl, -L 2 - Ci_6 alkyl, and -L 2 -Ci_6 haloalkyl.
  • Embodiment 47 A compound according to embodiment 46, wherein R 11 is -C 1-3 alkyl.
  • Embodiment 56 A compound according to any one of embodiments 52 through 54, wherein L 2 is -O-.
  • Embodiment 72 A compound according to any one of embodiments 1 through
  • R 2 , R 3 , R 4 , R 5 are independently selected from the group consisting of
  • Embodiment 80 A compound according to embodiment 79, wherein R x is selected from the group consisting of methyl and ethyl.
  • Embodiment 86 A compound according to any one of embodiments 75 through 76, wherein R x is haloalkyl.
  • Embodiment 87 A compound according to embodiment 86, wherein R x is -L 1 -
  • Embodiment 89 A compound according to any one of embodiments 84 through 87, wherein L 1 is -S-.
  • Embodiment 118 A compound according to embodiment 117, wherein R 1 is -L 2 - C 1-3 alkyl.
  • Embodiment 119 A compound according to embodiment 110, wherein R 1 is -L 2 -
  • Embodiment 120 A compound according to embodiment 119, wherein R 1 is -L 2 - Ci_3 haloalkyl.
  • Embodiment 129 A compound according to embodiment 125, wherein R 11 is -
  • Embodiment 149 A compound according to embodiment 148, wherein at least one of R 2 , R 3 , R 4 , R 5 is -L 3 -Ci_ 3 alkyl.
  • Embodiment 150 A compound according to embodiment 140, wherein at least one of R 2 , R 3 , R 4 , R 5 is -L 3 -Ci_ 6 haloalkyl.
  • Scheme 4 describes the preparation of a sulfonyl chloride (8).
  • R52 is a substituent such as but not limited to alkyl, aryl, alkoxy, or -alklylaryl.
  • parenteral includes subcutaneous injections, intravenous, intramuscular, intracisternal injection, or by infusion techniques.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • the tablets may also be coated by the techniques described in U.S. Patent Numbers 4,356,108; 4,166,452; and 4,265,874, to form osmotic therapeutic tablets for controlled release.
  • treatment of such disorders including alleviation or reduction of one or more symptoms of such disorders may be affected by the administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound. It is contemplated within the scope of the invention these compounds and pharmaceutical compositions comprising such compounds may be formulated to treat disorders that are not associated with binding of galanin (or lack thereof) to the GaIRl receptor but where the symptoms of the disorder may be mediated by a GaIRl agonist.
  • the pharmaceutical composition is in the form of an oral dosage. In another embodiment, the pharmaceutical composition is in the form of a parenteral dosage unit. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.
  • the present invention provides a method comprising: administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, the compound may be administered as part of a pharmaceutical composition.
  • the present invention provides a method comprising: administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject having a condition ameliorated by the activation of a GaIRl receptor in an amount sufficient to increase activity of GaIRl in the subject.
  • the compounds of the present invention may be administered at a dosage level at or below 1000 mg/kg of the body weight of the subject being treated. In another embodiment, the compounds of the present invention may be administered at a dosage level at or below 100 mg/kg. In another embodiment, the compounds of the present invention may be administered at a dosage level at or below 10 mg/kg of body weight per day. In another embodiment, the compounds of the present invention may be
  • the compounds and pharmaceutical compositions of the present invention may be useful in treating neuropathic pain.
  • the compounds of the present invention may be capable of binding to at least one peripheral GaIRl while being substantially unable to cross the blood-brain barrier. Partial or complete exclusion of a compound of Formula (I) or a pharmaceutically acceptable salt thereof from the brain may reduce the risk or severity of one or more centrally-mediated side effect associated with the administration of the compound to a subject.
  • LC-MS data was obtained using gradient elution on a parallel ML, r X n; system., running four Waters 1525 binary HPLC pumps, equipped with a Mux-UV 2488 multichannel UV- Vis detector (recording at 215 and 254 nM) and a Leap Technologies HTS PAL Auto sampler using a Waters Xterra MS Cl 8 4.6x50 mm column. A three minute gradient was run from 25% B (97.5%acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100% B. The system is interfaced with a Waters Micromass ZQ mass spectrometer using electrospray ionization. All MS data was obtained in the positive mode unless otherwise noted. IH NMR data was obtained on a Varian 400 MHz spectrometer.
  • LC-MS/MS analysis was conducted with either an Applied Biosystems (Foster City, CA, USA) APB 000 triple quadrupole mass spectrometer with an Turbo Ion Spray interface, Agilent (Foster City, CA, USA) 1100 series HPLC system, Shimadzu
  • Applied Biosystems mass spectrometer was operated in positive electrospray ion mode. Instrument conditions: gases were set at Nebulizer: 3 units, Curtain: 10 units, Collision: 12 units; Temperature: 500 0 C; ion spray 4.25kV. Automatic Quantitative Optimization of the product ion, declustering potential (DP) and collision energy (CE) was accomplished by infusion utilizing Analyst 1.4.

Abstract

Embodiments of the present invention provide bissulfonamide derivtives and pharmaceutical compositions comprising bissulfonamide derivatives. Methods of use of such compounds and compositions to reduce neuropathic pain in a subject are also provided.

Description

Bis-Sulfonamide Derivatives, Compositions, and Methods of Use
STATEMENT OF RELATED APPLICATIONS
The present application claims the benefit of priority to United States Provisional Patent Application No. 61/234,495, filed August 17, 2009.
FIELD OF THE INVENTION
The present invention relates to bissulfonamide derivatives, compositions comprising bissulfonamide derivatives, methods of use of such compounds and compositions including the use of such compounds and compositions to alleviate or reduce pain.
BACKGROUND
Pain is a sensation and a perception that is comprised of a complex series of mechanisms. In its most simple construction, pain is a signal from the firing of nociception, touch and pressure receptors in the periphery that is transmitted to the spinal cord and finally to lower and higher centers of the brain. However, this signal can be modified in a multitude of ways at each level of the pain pathway.
Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurons and is exclusively activated by noxious stimuli via peripherally transducing mechanisms. These sensory fibres are known as nociceptors and are characterized by smaller diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration, and quality of noxious stimulus. Nociceptors also encode the location of the stimulus by virtue of their topographically organized projection to the spinal cord. The nociceptors are found on nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated). The activity generated by nociceptor input is transferred after complex processing in the dorsal horn, either directly or via brain stem relay nuclei to the ventrobasal thalamus and then on to the cortex where the sensation of pain is generated. There are primarily three types of pain. Acute pain, termed nociception, is the instantaneous onset of a painful sensation in response to a noxious stimulus. It is considered to be adaptive because it can prevent an organism from damaging itself. For example, removing a hand from a hot stove as soon as pain is felt will prevent serious burns.
The second type of pain is persistent pain. Unlike acute pain, it usually has a delayed onset but can last for hours to days. It is predominately considered adaptive because the occurrence of persistent pain following injury can prevent further damage to the tissue. For example, the pain associated with a sprained ankle will prevent the patient from using the foot thereby preventing further trauma and aiding healing.
The final category of pain is chronic pain. It has a delayed onset and can last for months to years. In contrast to acute and persistent pain, chronic pain is considered maladaptive and is associated with conditions such as arthritis, nerve injury, AIDS and diabetes.
Chronic or neuropathic pain occurs in a variety of forms including spontaneous pain (painful sensation without an external stimulus), allodynia (painful sensation in response to a normally innocuous stimulus) and hyperalgesia (strong painful sensation to a mildly painful stimulus). It may be this diversity of symptoms that has made this condition difficult to treat clinically. In fact, current treatments are predominately off label use of antidepressants and anticonvulsants. Both antidepressants and
anticonvulsants may present problems for a patient.
Tricyclic antidepressants have the longest history of use in the treatment of neuropathic pain. Such drugs typically target the serotonergic and noradrenergic systems and increase the available extracellular levels of both serotonin and norepinephrine. It has been proposed that the postsynaptic activation of alpha2-adrenoceptors by
norepinephrine may be the mechanism through which these compounds alleviate neuropathic pain. Since antidepressants may readily cross the blood-brain barrier, their ability to increase the levels of serotonin and norepinephrine may cause the undesired activation of other receptors leading to the high risk of centrally mediated side effects. Side effects of antidepressants may range from mild but irritating symptoms such as dry mouth and sedation to severe life threatening side effects such as postural hypotension and cardiac arrythmias. The elderly, who represent a large number of neuropathic patients, can be particularly vulnerable to the more serious side effects of antidepressants.
The effectiveness of anticonvulsants in the treatment of various pain states, including neuropathic pain, has recently been evaluated. Similar to antidepressants, side effects may frequently occur with these medications.
Due to the common occurrence of side effects with antidepressants and anticonvulsants and the limitations these side effects may place on the use of these compounds, there is a need for a treatment for neuropathic pain that may avoid centrally mediated side effects.
Galanin is a 30 amino acid neuropeptide in humans (29 amino acids in rodents) that is widely distributed in tissues including brain, spinal cord, and gut. Galanin regulates numerous processes including nociception, nerve regeneration, feeding, memory, neuroendocrine release, gut secretion and contractility. Three galanin receptor subtypes (GaIRl, GalR2, and GalR3) have been cloned and belong to the superfamily of G protein-coupled 7-transmembrane receptors. These receptors have been shown to couple to various G-protein systems that modulate second messenger activity. Galanin stimulation of GaIRl is sensitive to pertussis toxin, consistent with coupling to Gi/o -type G proteins.
All three galanin receptor subtypes are expressed in the dorsal root ganglia (DRG) and the spinal cord. The anatomical location of both galanin and its receptors, and the upregulation of galanin in response to nerve damage suggest that the galanin-GalR pathway may play a key role in the regulation of spinal nociceptive transmission.
Intrathecal dosing of galanin enhanced the spinal anti-nociceptive response to morphine and reduced the physical signs of opiate withdrawal. GaIRl may be a key galanin receptor for anti-nociceptive transmission. Intrathecal administration of a galanin peptide analog with GaIRl selectivity improved pain threshold in a neuropathic pain model.
In recent studies, the expression, mitogenic function, and signaling mechanism of GaIRl were investigated in normal and malignant oral epithelial cells. Upon competitive inhibition of GaIRl, proliferation was upregulated in immortalized and malignant keratinocytes. Studies also demonstrated that activation of GaIRl inhibits proliferation in immortalized and malignant keratinocytes by inactivating the MAPK pathway. SUMMARY OF INVENTION
The present invention provides bissulfonamide derivatives as described herein.
In another embodiment, the present invention also provides methods for the preparation of bissulfonamide derivatives.
The present invention also provides pharmaceutical compositions comprising a bissulfonamide derivative.
In another embodiment, the present invention provides methods for the preparation of pharmaceutical compositions comprising a bissulfonamide derivative. The pharmaceutical compositions may further comprise a pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof.
In another embodiment, the present invention provides methods for the use of a bissulfonamide derivative and for the use of pharmaceutical compositions comprising a bissulfonamide derivative. The compounds and pharmaceutical compositions of the present invention may be used for the treatment of human or animal disorders.
In another embodiment, the present invention provides a pharmaceutical composition comprising a bissulfonamide derivative in an amount sufficient to increase activity of a GaIRl receptor in a subject. In another embodiment, the pharmaceutical composition comprises a bissulfonamide derivative in an amount sufficient to stimulate GaIRl in a subject.
In another embodiment, the present invention provides a method comprising administering to a subject having a disorder ameliorated by the activation of a GaIRl receptor, a pharmaceutical composition comprising a bissulfonamide derivate in an amount sufficient to increase activity of GaIRl in a subject. For example, the compounds and pharmaceutical compositions of the present invention may be useful in treating neuropathic pain or pain associated with cancer. Further, at doses for which an analgesic effect may be observed, the compounds of the present invention may be capable of binding to at least one peripheral GaIRl while substantially unable to cross the blood- brain barrier. Partial or complete exclusion of the compounds of the present invention from the brain may reduce the risk of or severity of one or more centrally mediated side effects typically associated with compounds or pharmaceutical compositions having analgesic effects that are able to substantially cross the blood-brain barrier.
Additional features of the present invention will be described hereinafter. It is to be understood that the invention is not limited in its application to the details set forth in the foregoing or following description but is capable of other embodiments and of being practiced or carried out in various ways.
DETAILED DESCRIPTION
Embodiment 1 : In a first embodiment, the present invention provides a compound of Formula (I):
Ar2-SO2NH-ArI-NHSO2-Ar3 (I), or a pharmaceutically acceptable salt thereof, wherein
Ar1 is either
Figure imgf000006_0001
or
Ar2 and Ar3 are independently selected from the group consisting of the following formulas (Ic), (Id), (Ie) and (If):
Figure imgf000007_0001
Figure imgf000007_0002
wherein at least one OfAr2 and Ar3 comprise (Ic), (Id) or (If);
Rx and Ry are selected independently from the group consisting of
a) hydrogen;
b) -halogen;
c) -Ci_6 alkyl;
d) -C1-6 haloalkyl;
e) -cyano;
f) -iΛCi-e alkyl; and
g) -iΛCi-e haloalkyl;
or Rx and Ry are bonded through either a -O-(CH2)2-O- or a -0-CH2-O- group to form a benzodioxine or a benzodiozane ring, respectively;
Rw and Rz are selected independently from the group consisting of
a) hydrogen;
b) -halogen;
c) -C1-6 alkyl; d) -Ci_6 haloalkyl;
e) -cyano;
f) -L^C1-6 alkyl; and
g) -L^C1-6 haloalkyl;
R1 and R11 are selected independently from the group consisting of
a) -hydrogen;
b) -Ci-6 alkyl;
c) -Ci_6 haloalkyl;
d) -L2- C i_6 alkyl; and
e) -L2-Ci_6 haloalkyl;
R2, R3, R4, R5, R12, R13 and R14are selected independently from the group consisting of a) -hydrogen;
b) -halogen;
c) -Ci-6 alkyl;
d) -Ci-6 haloalkyl;
e) -L3- Ci_6 alkyl; and
f) -L3-Ci_6 haloalkyl; wherein
L1, L2 and L3 are independently selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -S-, -S(O)-, and -SO2-; provided that, when at least one of Ar2 and Ar3 is not formula (If), or when Ar1 is not a thiophene group, at least one of the following two conditions are met:
1) at least one of R1 and R11 is a group other than hydrogen, and
2) at least one of R2, R3, R4, R5, R12, R13 and R14 is a group other than hydrogen; and
provided that, if one OfAr2 and Ar3 has the structure of formula (Ie), then the other of
Ar2 and Ar3 has the structure of formula (Ic) and R1 is not hydrogen. Embodiment 2: A compound according to embodiment 1, wherein at least one of Ar2 and Ar3 has the structure of formula (Ie).
Embodiment 3 : A compound according to embodiment 1 , wherein at least one of Ar2 and Ar3 is (Ic).
Embodiment 4: A compound according to embodiment 3, wherein Ar2 has the structure of formula (Ic) and Ar3 has the structure of formula (Ic).
Embodiment 5: A compound according to any one of embodiments 1 through 3, wherein Ar1 has the structure of formula (Ic).
Embodiment 6: A compound according to any one of embodiments 1 through 5, wherein Rw and Rz are hydrogen.
Embodiment 7: A compound according to any one of embodiments 1 through 6, wherein Rx is selected from the group consisting of chloro and fluoro.
Embodiment 8: A compound according to any one of embodiments 1 through 6, wherein Rx is -C1-6 alkyl.
Embodiment 9: A compound according to embodiment 8, wherein Rx is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and sec- butyl.
Embodiment 10: A compound according to embodiment 9, wherein Rx is selected from the group consisting of methyl and ethyl.
Embodiment 11 : A compound according to any one of embodiments 1 through 6, wherein Rx is -C1-6 haloalkyl.
Embodiment 12: A compound according to embodiment 11, wherein Rx is -C1-3 haloalkyl.
Embodiment 13: A compound according to embodiment 12, wherein Rx is -CF3.
Embodiment 14: A compound according to any one of embodiments 1 through 6, wherein Rx is -L^C1-6 alkyl. Embodiment 15: A compound according to embodiment 14, wherein Rx is -L1- Ci_3 alkyl.
Embodiment 16: A compound according to any one of embodiments 1 through 6, wherein Rx is
Figure imgf000010_0001
haloalkyl.
Embodiment 17: A compound according to embodiment 16, wherein Rx is -L1-
Ci_3 haloalkyl.
Embodiment 18: A compound according to any one of embodiments 1 through 17, wherein Ry is selected from the group consisting of -halo, -Ci_6 alkyl, -Ci_6 haloalkyl, -iΛCi-e alkyl, and -L^C1-6 haloalkyl.
Embodiment 19: A compound according to embodiment 18, wherein Ry is selected from the group consisting of chloro and fluoro.
Embodiment 20: A compound according to embodiment 18, wherein Ry is -C1-6 alkyl.
Embodiment 21 : A compound according to embodiment 18, wherein Ry is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.
Embodiment 22: A compound according to embodiment 19, wherein Ry is selected from the group consisting of methyl and ethyl.
Embodiment 23: A compound according to embodiment 18, wherein Ry is -C1-6 haloalkyl.
Embodiment 24: A compound according to embodiment 23, wherein Ry is -C1-3 haloalkyl.
Embodiment 25: A compound according to embodiment 24, wherein Ry is selected from the group consisting of -CF3.
Embodiment 26: A compound according to embodiment 18, wherein Ry is -L1-
C1-6 alkyl. Embodiment 27: A compound according to embodiment 26, wherein Ry is -L1- Ci_3 alkyl.
Embodiment 28: A compound according to embodiment 18, wherein Ry is -L1- Ci_6 halo alkyl.
Embodiment 29: A compound according to embodiment 28, wherein Ry is -L1-
Ci_3 halo alkyl.
Embodiment 30: A compound according to any one of embodiments 1 through 29, wherein R1 is selected from the group consisting of -Ci_6 alkyl, -Ci_6 haloalkyl, -L2- Ci_6 alkyl, -L2-Ci_6 haloalkyl, and -L2-Ci_6 perhaloalkyl.
Embodiment 31 : A compound according to embodiment 30, wherein R1 is -Ci_6 alkyl.
Embodiment 32: A compound according to embodiment 31, wherein R1 is -Ci_3 alkyl.
Embodiment 33: A compound according to embodiment 32, wherein R1 is methyl.
Embodiment 34: A compound according to embodiment 30, wherein R1 is -Ci_6 haloalkyl.
Embodiment 35: A compound according to embodiment 34, wherein R1 is -Ci_3 haloalkyl.
Embodiment 36: A compound according to embodiment 35, wherein R1 is selected from the group consisting of -CF3.
Embodiment 37: A compound according to embodiment 30, wherein R1 is -L2- C1-6 alkyl.
Embodiment 38: A compound according to embodiment 37, wherein R1 is -L2- C1-3 alkyl.
EEnmbodiment 39: A compound according to embodiment 30, wherein R1 is -L2- Ci_6 haloalkyl. Embodiment 40: A compound according to embodiment 39, wherein R1 is -L2- Ci_3 haloalkyl.
Embodiment 41 : A compound according to any one of embodiments 37 through 40, wherein L2 is -O-.
Embodiment 42: A compound according to any one of embodiments 37 through
40, wherein L2 is -S-.
Embodiment 43: A compound according to any one of embodiments 37 through 40, wherein L2 is -S(O)-.
Embodiment 44: A compound according to any one of embodiments 37 through 40, wherein L2 is -SO2-.
Embodiment 45 : A compound according to any one of embodiments 1 through 44, wherein R11 is selected from the group consisting of -C1-6 alkyl, -C1-6 haloalkyl, -L2- Ci_6 alkyl, and -L2-Ci_6 haloalkyl.
Embodiment 46: A compound according to embodiment 45, wherein R11 is -C1-6 alkyl.
Embodiment 47: A compound according to embodiment 46, wherein R11 is -C1-3 alkyl.
Embodiment 48: A compound according to embodiment 47, wherein R11 is methyl.
Embodiment 49: A compound according to embodiment 48, wherein R11 is -C1-6 haloalkyl.
Embodiment 50: A compound according to embodiment 49, wherein R11 is -C1-3 haloalkyl.
Embodiment 51 : A compound according to embodiment 50, wherein R11 is selected from the group consisting of -CF3.
Embodiment 52: A compound according to embodiment 45, wherein R , 11 is -L - C1-6 alkyl. Embodiment 53: A compound according to embodiment 52, wherein R11 is -L2- Ci_3 alkyl.
Embodiment 54: A compound according to embodiment 45, wherein R11 is -L2- Ci_6 halo alkyl.
Embodiment 55: A compound according to embodiment 54, wherein R11 is -L2-
Ci_3 halo alkyl.
Embodiment 56: A compound according to any one of embodiments 52 through 54, wherein L2 is -O-.
Embodiment 57: A compound according to any one of embodiments 52 through 54, wherein L2 is -S-.
Embodiment 58: A compound according to any one of embodiments 56 through 54, wherein L2 is -S(O)-.
Embodiment 59: A compound according to any one of embodiments 56 through 54, wherein L2 is -SO2-.
Embodiment 60: A compound according to any one of embodiments 1 through
59, wherein at least one of R2, R3, R4, R5, R12, R13 and R14 is selected from the group consisting of -halo, -Ci_6 alkyl, -Ci_6 haloalkyl, -L - Ci_6 alkyl, and -L -Ci_6 haloalkyl.
Embodiment 61 : A compound according to embodiment 60, wherein at least one of R2, R3, R4, R5, R12, R13 and R14 is selected from the group consisting of chloro and fluoro.
Embodiment 62: A compound according to embodiment 60, wherein at least one of R2, R3, R4, R5, R12, R13 and R14 is -C1-6 alkyl.
Embodiment 63: A compound according to embodiment 62, wherein at least one of R2, R3, R4, R5, R12, R13 and R14 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.
Embodiment 64: A compound according to embodiment 63, wherein at least one of R2, R3, R4, R5, R12, R13 and R14 is selected from the group consisting of methyl and ethyl. Embodiment 65: A compound according to embodiment 60, wherein at least one of R2, R3, R4, R5, R12, R13 and R14 is -C1-6 haloalkyl.
Embodiment 66: A compound according to embodiment 65, wherein at least one of R2, R3, R4, R5, R12, R13 and R14 is -C1-3 haloalkyl.
Embodiment 67: A compound according to embodiment 66, wherein at least one of R2, R3, R4, R5, R12, R13 and R14 is selected from the group consisting of -CF3.
Embodiment 68: A compound according to embodiment 60, wherein at least one of R2, R3, R4, R5, R12, R13 and R14 is -L3-Ci_6 alkyl.
Embodiment 69: A compound according to embodiment 60, wherein at least one of R2, R3, R4, R5, R12, R13 and R14 is -L3-Ci_6 haloalkyl.
Embodiment 70: A compound according to any one of embodiments 1 through
69, wherein Ar1 is a thiophene group.
Embodiment 71 : A compound according to any one of embodiments 1 through
70, wherein both Rx and Ry are a group other than hydrogen.
Embodiment 72: A compound according to any one of embodiments 1 through
71, wherein at least one of R1 and R11 is a group other than hydrogen.
Embodiment 73 : A compound according to any one of embodiments 1 through 71, wherein both R1 and R11 are a group other than hydrogen.
Embodiment 74: A compound according to any one of embodiments 1 through 73, wherein at least one of R2, R3, R4, R5, R12, R13 and R14 is a group other than hydrogen.
Embodiment 75 : The present invention further provides bissulfonamide derivative of Formula (II):
Figure imgf000015_0001
(H)
wherein,
Rx and Ry are selected independently from the group consisting of
a) hydrogen;
b) -halogen;
c) -C1-6 alkyl;
d) -Ci_6 haloalkyl;
e) -cyano;
f) -L^C1-6 alkyl; and
g) -iΛCi-e haloalkyl;
or Rx and Ry are bonded through either a -O-(CH2)2-O- or a -0-CH2-O- group to form a benzodioxine or a benzodiozane ring, respectively; Rw and Rz are selected independently from the group consisting of
a) hydrogen;
b) -halogen;
c) -C1-6 alkyl;
d) -C1-6 haloalkyl;
e) -cyano;
f) -L^C1-6 alkyl; and
g) -L^C1-6 haloalkyl;
R1 is selected from the group consisting of
a) -hydrogen; b) -Ci_6 alkyl;
c) -Ci_6 haloalkyl;
d) -L2- Ci_6 alkyl; and
e) -L2-Ci_6 haloalkyl;
R2, R3, R4, R5 are independently selected from the group consisting of
a) -hydrogen;
b) -halogen;
c) -C1-6 alkyl;
d) -C1-6 haloalkyl;
e) -L3- Ci_6 alkyl; and
f) -L3-Ci_6 haloalkyl;
R11 is selected from the group consisting of
a) -hydrogen;
b) -Ci-6 alkyl;
c) -C1-6 haloalkyl;
d) -L4-Ci_6 alkyl; and
e) -L4-Ci_6 haloalkyl;
R12, R13, R14, R15 are independently selected from the group consisting of
a) -hydrogen;
b) -halogen;
c) -Ci-6 alkyl;
d) -Ci-6 haloalkyl;
e) -L5-Ci_6 alkyl; and
f) -iΛCi-e haloalkyl;
wherein
L2, L3, L4, and L5 are independently selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -S-, -S(O)-, and -SO2-; and
wherein at least one of Rx and Ry is a group other than hydrogen;
at least one of R1 and R11 is a group other than hydrogen, and
at least one of R2, R3, R4, R5, R12, R13, R14, and R15 is a group other than
hydrogen,
or a pharmaceutically acceptable salt thereof.
Embodiment 76: A compound according to embodiment 75, wherein Rw and Rz are hydrogen.
Embodiment 77: A compound according to any one of embodiments 75 through 76, wherein Rx is selected from the group consisting of chloro and fluoro.
Embodiment 78: A compound according to any one of embodiments 75 through 76, wherein Rx is -C1-6 alkyl.
Embodiment 79: A compound according to embodiment 78, wherein Rx is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.
Embodiment 80: A compound according to embodiment 79, wherein Rx is selected from the group consisting of methyl and ethyl.
Embodiment 81 : A compound according to any one of embodiments 75 through 76, wherein Rx is -C1-6 haloalkyl. Embodiment 82: A compound according to embodiment 81, wherein Rx is -C1-3 haloalkyl.
Embodiment 83: A compound according to embodiment 82, wherein Rx is selected from the group consisting of -CF3.
Embodiment 84: A compound according to any one of embodiments 75 through 76, wherein Rx is -L^C1-6 alkyl. Embodiment 85: A compound according to embodiment 84, wherein Rx is -L1- Ci_3 alkyl.
Embodiment 86: A compound according to any one of embodiments 75 through 76, wherein Rx is
Figure imgf000018_0001
haloalkyl. Embodiment 87: A compound according to embodiment 86, wherein Rx is -L1-
Ci_3 haloalkyl.
Embodiment 88: A compound according to any one of embodiments 84 through 87, wherein L1 is -O-.
Embodiment 89: A compound according to any one of embodiments 84 through 87, wherein L1 is -S-.
Embodiment 90: A compound according to any one of embodiments 84 through 87, wherein L1 is -S(O)-.
Embodiment 91 : A compound according to any one of embodiments 84 through 87, wherein L1 is -SO2-. Embodiment 92: A compound according to any one of embodiments 75 through
76, wherein Rx is hydrogen.
Embodiment 93: A compound according to any one of embodiments 75 through 92, wherein Ry is selected from the group consisting of -halo, -Ci_6 alkyl, -Ci_6 haloalkyl, -iΛCi-e alkyl, and -L^C1-6 haloalkyl. Embodiment 94: A compound according to embodiment 93, wherein Ry is selected from the group consisting of chloro and fluoro.
Embodiment 95: A compound according to embodiment 93, wherein Ry is -C1-6 alkyl. Embodiment 96: A compound according to embodiment 95, wherein Ry is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.
Embodiment 97: A compound according to embodiment 96 wherein Ry is selected from the group consisting of methyl and ethyl.
Embodiment 98: A compound according to embodiment 93, wherein Ry is -C1-6 haloalkyl.
Embodiment 99: A compound according to embodiment 98, wherein Ry is -C1-3 haloalkyl. Embodiment 100: A compound according to embodiment 99, wherein Ry is selected from the group consisting Of -CF3.
Embodiment 101 : A compound according to embodiment 93, wherein Ry is -L1- C1-6 alkyl.
Embodiment 102: A compound according to embodiment 101, wherein Ry is -L1- C1-3 alkyl.
Embodiment 103: A compound according to embodiment 93, wherein Ry is -L1- Ci_6 haloalkyl.
Embodiment 104: A compound according to embodiment 103, wherein Ry is -L1- Ci_3 haloalkyl. Embodiment 105: A compound according to any one of embodiments 101 through 104, wherein L1 is -O-.
Embodiment 106: A compound according to any one of embodiments 101 through 104, wherein L1 is -S-.
Embodiment 107: A compound according to any one of embodiments 101 through 104, wherein L1 is -S(O)-. Embodiment 108: A compound according to any one of embodiments 101 through 104, wherein L1 is -SO2-.
Embodiment 109: A compound according to any one of embodiments 75 through 91, wherein Ry is hydrogen. Embodiment 110: A compound according to any one of embodiments 75 through
109, wherein R1 is selected from the group consisting of -C1-6 alkyl, -C1-6 haloalkyl, -L2- Ci_6 alkyl, -L2-Ci_6 haloalkyl, and -L2-Ci_6 perhaloalkyl.
Embodiment 111 : A compound according to embodiment 110, wherein R1 is -C1- 6 alkyl.
Embodiment 112: A compound according to embodiment 111, wherein R1 is -C1-
3 alkyl.
Embodiment 113: A compound according to embodiment 112, wherein R1 is methyl. Embodiment 114: A compound according to embodiment 110, wherein R1 is -
Ci_6 haloalkyl.
Embodiment 115: A compound according to embodiment 114, wherein R1 is - Ci_3 haloalkyl.
Embodiment 116: A compound according to embodiment 115, wherein R1 is selected from the group consisting of -CF3.
Embodiment 117: A compound according to embodiment 110, wherein R1 is -L2- C1-6 alkyl.
Embodiment 118: A compound according to embodiment 117, wherein R1 is -L2- C1-3 alkyl. Embodiment 119: A compound according to embodiment 110, wherein R1 is -L2-
Ci_6 haloalkyl. Embodiment 120: A compound according to embodiment 119, wherein R1 is -L2- Ci_3 haloalkyl.
Embodiment 121 : A compound according to any one of embodiments 117 through 120 wherein L2 is -O-. Embodiment 122: A compound according to any one of embodiments 117 through 120, wherein L2 is -S-.
Embodiment 123: A compound according to any one of embodiments 117 through 120, wherein L2 is -S(O)-.
Embodiment 124: A compound according to any one of embodiments 117 through 120, wherein L2 is -SO2-.
Embodiment 125: A compound according to any one of embodiments 1 through 124, wherein R11 is selected from the group consisting of -C1-6 alkyl, -C1-6 haloalkyl, -L4- C1-6 alkyl, and -L4-Ci_6 haloalkyl.
Embodiment 126: A compound according to embodiment 125, wherein R11 is - C1-6 alkyl.
Embodiment 127: A compound according to embodiment 126, wherein R11 is - C1-3 alkyl.
Embodiment 128: A compound according to embodiment 127, wherein R11 is methyl.
Embodiment 129: A compound according to embodiment 125, wherein R11 is -
Ci_6 haloalkyl.
Embodiment 130: A compound according to embodiment 129, wherein R11 is - Ci_3 haloalkyl.
Embodiment 131 : A compound according to embodiment 130, wherein R11 is selected from the group consisting of -CF3. Embodiment 132: A compound according to embodiment 125, wherein R11 is
L4-Ci_6 alkyl.
Embodiment 133: A compound according to embodiment 132, wherein R11 is - L4-Ci_3 alkyl. Embodiment 134: A compound according to embodiment 125, wherein R11 is -
L4-Ci_6 haloalkyl.
Embodiment 135: A compound according to embodiment 134, wherein R11 is - lACi_3 haloalkyl.
Embodiment 136: A compound according to any one of embodiments 132 through 135, wherein L4 is -O- .
Embodiment 137: A compound according to any one of embodiments 132 through 135, wherein L4 is -S-.
Embodiment 138: A compound according to any one of embodiments 132 through 135, wherein L4 is -S(O)-. Embodiment 139: A compound according to any one of embodiments 132 through 135, wherein L4 is -SO2-.
Embodiment 140: A compound according to any one of embodiments 75 through 139, wherein at least one of R2, R3, R4, R5 is selected from the group consisting of -halo, - Ci_6 alkyl, -Ci_6 haloalkyl, -L3- Ci_6 alkyl, and -L3-Ci_6 haloalkyl.
Embodiment 141 : A compound according to embodiment 140, wherein at least one of R2, R3, R4, R5 is selected from the group consisting of chloro and fluoro.
Embodiment 142: A compound according to embodiment 140, wherein at least one of R2, R3, R4, R5 is -C1-6 alkyl. Embodiment 143: A compound according to embodiment 142, wherein at least one of R2, R3, R4, R5 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.
Embodiment 144: A compound according to embodiment 143, wherein at least one of R2, R3, R4, R5 is selected from the group consisting of methyl and ethyl.
Embodiment 145: A compound according to embodiment 140, wherein at least one of R2, R3, R4, R5 is -C1-6 haloalkyl.
Embodiment 146: A compound according to embodiment 145, wherein at least one of R2, R3, R4, R5 is -C1-3 haloalkyl. Embodiment 147: A compound according to embodiment 146, wherein at least one of R2, R3, R4, R5 is selected from the group consisting of -CF3.
Embodiment 148: A compound according to embodiment 140, wherein at least one of R2, R3, R4, R5 is -L3-Ci_6 alkyl.
Embodiment 149: A compound according to embodiment 148, wherein at least one of R2, R3, R4, R5 is -L3-Ci_3 alkyl.
Embodiment 150: A compound according to embodiment 140, wherein at least one of R2, R3, R4, R5 is -L3-Ci_6 haloalkyl.
Embodiment 151 : A compound according to embodiment 150, wherein at least one of R2, R3, R4, R5 is -L3-Ci_3 haloalkyl. Embodiment 152: A compound according to any one of embodiments 148 through 151, wherein L is -O- .
Embodiment 153: A compound according to any one of embodiments 148 through 151, wherein L3 is -S-.
Embodiment 154: A compound according to any one of embodiments 148 through 151, wherein L3 is -S(O)-. Embodiment 155: A compound according to any one of embodiments 148 through 151, wherein L is -SO2-.
Embodiment 156: A compound according to any one of embodiments 75 through 155, wherein at least one of R12, R13, R14, R15 is selected from the group consisting of - halo, -C1-6 alkyl, -C1-6 haloalkyl, -L5-Ci_6 alkyl, and -L5-Ci_6 haloalkyl.
Embodiment 157: A compound according to embodiment 156, wherein at least one of R12, R13, R14, R15 is selected from the group consisting of chloro and fluoro.
Embodiment 158: A compound according to embodiment 156, wherein at least one of R12, R13, R14, R15 is -C1-6 alkyl.
Embodiment 159: A compound according to embodiment 158, wherein at least one of R12, R13, R14, R15 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and sec-butyl.
Embodiment 160: A compound according to embodiment 159, wherein at least one of R12, R13, R14, R15 is selected from the group consisting of methyl and ethyl.
Embodiment 161 : A compound according to embodiment 156, wherein at least one of R12, R13, R14, R15 is -C1-6 haloalkyl.
Embodiment 162: A compound according to embodiment 161, wherein at least one of R12, R13, R14, R15 is -C1-3 haloalkyl. Embodiment 163: A compound according to embodiment 162, wherein at least one of R12, R13, R14, R15 is selected from the group consisting of -CF3.
Embodiment 164: A compound according to embodiment 156, wherein at least one of R12, R13, R14, R15 is -L5-Ci_6 alkyl.
Embodiment 165: A compound according to embodiment 164, wherein at least one of R12, R13, R14, R15 is -L5-Ci_3 alkyl. Embodiment 166: A compound according to embodiment 155, wherein at least one of R12, R13, R14, R15 is -L5-Ci_6 haloalkyl.
Embodiment 167: A compound according to embodiment 166, wherein at least one of R12, R13, R14, R15 is -L5- C1-3 haloalkyl. Embodiment 168: A compound according to any one of embodiments 156 through 167, wherein L5 is -O-.
Embodiment 169: A compound according to any one of embodiments 156 through 167, wherein L5 is -S-.
Embodiment 170: A compound according to any one of embodiments 156 through 167, wherein L5 is -S(O)-.
Embodiment 171 : A compound according to any one of embodiments 156 through 167, wherein L5 is -SO2-.
Embodiment 172: A compound according to any one of embodiments 75 through 171, wherein the compound of Formula (I) is C2 symmetric. Embodiment 173: A compound according to any one of embodiments 75 through
171, wherein the benzothiophene substituent groups R1, R2, R3, R4, and R5 are the same as the benzothiphene substituent groups R11, R12, R13, R14, and R15.
Embodiment 174: A compound according to any one of embodiments 75 through 171, wherein the benzothiophene substituent groups are different. Embodiment 175: A compound according to any one of embodiments 1 through
171, wherein
at least one of R2, R3, R4, and R5 is a group other than hydrogen, and at least one of R12, R13, R14, and R15 is a group other than hydrogen.
Embodiment 176: A compound according to embodiment 1, wherein
Rw and Rz are hydrogen, Rx and Ry are independently selected from the group consisting of hydrogen, chloro, fluoro, -C1-4 alkyl, and -C1-2 haloalkyl, wherein at least one of Rx and Ry is not hydrogen;
R1 and R11 are independently selected from the group consisting of methyl and ethyl; R3 and R13 are independently selected from the group consisting of hydrogen, chloro, fluoro, -C1-4 alkyl, and -C1-2 haloalkyl, wherein at least one of R3 and R13 is not hydrogen.
Embodiment 177: A compound according to embodiment 176, wherein R2, R4, R5, R12, R14, and R15 are hydrogen. Embodiment 178: A compound according to any one of embodiments 176 to 177, wwhheerreeiinn RR33 aanndd RR1133 aarree iinnddeeppeennddeennttllyy f selected from the group consisting of chloro, fluoro, -C1-4 alkyl, and -C1-2 haloalkyl.
Embodiment 179: A compound according to embodiment 178, wherein R3 and
R , 13 are independently selected from the group consisting of chloro and fluoro. Examples of compounds of Formula (I) of the present invention are shown in
Table 1 and in the Examples section.
Table 1
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Example 13 N,Λ/"-(4-chlorobenzene- 1 ,2-diyl)bis(5- fluoro-3 -methyl- 1 -benzothiophene-2-
Figure imgf000029_0001
sulfonamide)
5-bromo-N-(2-{[(3,4-
Example 14 dichlorophenyl)sulfonyl]amino}phenyl)
-3 -methyl- 1 -benzothiophene-2-
Figure imgf000029_0002
sulfonamide
N,Λ/"-(4,5-dichlorobenzene-l ,2-
Example 15 diyl)bis(5 -chloro-3 -methyl- 1 - benzothiophene-2-sulfonamide)
Figure imgf000029_0003
N,Λ/"-(4-cyanobenzene- 1 ,2-diyl)bis(5-
Example 16 chloro-3 -methyl- 1 -benzothiophene-2- sulfonamide)
Figure imgf000029_0004
methyl 3, 4-bis{ [(5 -chloro-3 -methyl- 1-
Example 17 benzothiophen-2- yl)sulfonyl]amino } benzoate
Figure imgf000029_0005
Figure imgf000030_0001
N,Λ/"-(4-chlorobenzene- 1 ,2-diyl)bis(5-
Example 23 bromo-3 -methyl- 1 -benzothiophene-2- sulfonamide)
Figure imgf000031_0001
N,Λ/>-(4-trifluoromethylbenzene- 1 ,2-
Example 24 diyl)bis(5 -chloro-3 -methyl- 1 - benzothiophene-2-sulfonamide)
Figure imgf000031_0002
5-chloro-N-(2-{[(5-fluoro-3-methyl-l-
Example 25 benzothiophen-2- yl)sulfonyl] amino } phenyl)-3 -methyl- 1■
Figure imgf000031_0003
benzothiophene-2-sulfonamide
N,Λ/'-(4,5-dichlorobenzene-l ,2-
Example 26 diyl)bis(5 -fluoro-3 -methyl- 1 - benzothiophene-2-sulfonamide)
Figure imgf000031_0004
Λ/,Λ/"-(4-chloro-5-fluorobenzene-l,2-
Example 27 diyl)bis(5 -fluoro-3 -methyl- 1 - benzothiophene-2-sulfonamide)
Figure imgf000031_0005
Figure imgf000032_0001
Unless indicated otherwise, the structures of the Examples having vacant connectivity for heteroatoms, such as oxygen and nitrogen, are assumed to have a hydrogen atom attached thereto.
DEFINITIONS
The following definitions are meant to clarify, but not limit, the terms defined. If a particular term used herein is not specificially defined, such term should not be considered indefinite. Rather, terms are used within their accepted meanings.
As used herein the term "Ci_6 alkyl" refers to a straight or branched chain hydrocarbon having one to six carbon atoms, which may be optionally substituted as herein further described, with multiple degrees of substitution being allowed. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, isopentyl, and n-pentyl. As used throughout this specification, the number of atoms, such as carbon atoms in an alkyl group, for example, will be represented by the phrase "Cx-Cy alkyl," or "Cx-y alkyl," which refer to an alkyl group, as herein defined, containing from x to y, inclusive, carbon atoms. Similar terminology will apply for other terms and ranges as well.
As used herein the term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.
As used herein the term "haloalkyl" refers to an alkyl group, as defined herein, that is substituted with at least one halogen. Examples of branched or straight chained
"haloalkyl" groups as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens, for example, fluoro, chloro, bromo, and iodo. The term "haloalkyl" should be interpreted to include groups such as -CF3 , -CH2-CF3, and -CF2Cl .
As used herein, the term "substituted" refers to substitution of one or more hydrogens of the designated moiety with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated, provided that the substitution results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature from about -80° C to about +40° C, in the absence of moisture or other chemically reactive conditions, for at least a week, or a compound which maintains its integrity long enough to be useful for therapeutic administration to a subject.
As used herein the terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable diluent", and "pharmaceutically acceptable excipient" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
As used herein the term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, human, or subject that is being sought by a researcher, veterinarian, medical doctor, patient or other clinician, which includes reduction or alleviation of the symptoms of the disease or condition being treated. When the active compound (i.e., active ingredient) is administered as the salt, references to the amount of active ingredient are to the free acid or free base form of the compound.
As used herein, "Subjects" include, for example, horses, cows, sheep, pigs, mice, dogs, cats, primates such as chimpanzees, gorillas, rhesus monkeys, and, humans. In an embodiment, a subject is a human. In another embodiment, a subject is a human in need of activation of GaIRl .
The compounds of Formula (I) may be prepared according to the following reaction Schemes (in which variables are as defined before or are defined in the Schemes and Examples). In these reactions, it is also possible to make use of variants that are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.
Scheme 1 describes the preparation of a compound of formula (2). In this scheme Ar1 and Ar3 have the same meaning as for formula (I). R51 represents a substituent such as but not limited to alkyl, aryl, heteroaryl, alkoxy or halogen.
Scheme 1
Figure imgf000034_0001
Bissulfonamides (2) may be prepared by treatment of a phenylenediamine (1) with an aryl or heteroaryl sulfonyl chloride in presence of a base such as pyridine or triethylamine in an aprotic solvent such as dichloromethane or DMF at a temperature of from O 0C to 100 0C.
Scheme 2 describes a synthesis of a compound of formula (4). Scheme 2
Figure imgf000035_0001
Phenylenediamine (1) may be monosulfonated with an aryl or heteroaryl sulfonyl chloride in presence of a base such as pyridine or triethylamine in an aprotic solvent such as but not limited to dichloromethane or DMF at a temperature of from 0 0C to 100 0C to afford sulfonamidoanilines (3). Such a monosulfonylation may take place preferentially when 0.5 to 1.5 molar equivalents of the sulfonyl chloride are employed. The sulfonamidoaniline (3) obtained may be further sulfonated with an aryl or heteroaryl sulfonyl chloride in the presence of a base such as pyridine or triethylamine in an aprotic solvent such as dichloromethane or DMF at a temperature of from 0 0C to 100 0C to provide the bissulfonamide (4).
Scheme 3 describes an alternative synthesis of a compound of formula (4).
Scheme 3
Figure imgf000035_0002
2-Nitroanilines (5), either unsubstituted or substituted with a substituent Rs1, may be sulfonylated with an aryl or heteroaryl sulfonyl chloride in pyridine as solvent, optionally in a aprotic cosolvent like DMF or acetonitrile in the presence of a base such as pyridine or triethylamine, at a temperature of from 0 0C to 100 0C, to afford a 2- sulfonamidonitroaryl intermediate. The 2-sulfonamidonitroarene thus obtained may be reduced using methods such as but not limited to hydrogenation with a noble metal catalyst such as palladium on carbon, or reduction with SnCl2 in EtOH (alternatively with LiAlH4) to provide 2-sulfonamidoanilines (6). The aniline (6) may be sulfonylated as described previously to afford (4).
Scheme 4 describes the preparation of a sulfonyl chloride (8). R52 is a substituent such as but not limited to alkyl, aryl, alkoxy, or -alklylaryl.
Scheme 4
CISO3H
R52 Ar4 ». R52 Aq— SO2CI
(7) (8) The sulfonyl chloride (8) may be prepared by reacting an arene or heteroarene (7) with chlorosulfonic acid in a solvent such as DCM or DCE at a temperature of from 0 0C to 100 0C, to afford the desired sulfonyl chloride (8).
Scheme 5 describes an alternate synthesis of a sulfonyl chloride (8). X is Br or I.
M is -MgX or Li.
Scheme 5
M I ) SO2
.X Mg or RLi ,SO2CI
R X52— π Arl 5 *• R^9 Ar1- R1--— Ar1- κ" Afc 52 5 2) NCS or SO2CI2 52 5
(9) (10) (8)
An arene or heteroarene with a halogen substituent (9) may be metallated by
treatment with magnesium metal in a solvent such as ether or THF, at a temperature of from - 20 0C to 100 0C, to afford the organometallic reagent (10) where M is -MgX.
Alternately, treatment of (9) with n-butyllithium under inert atmosphere in a solvent such as ether or THF, at a temperature of from - 78 0C to 0 0C affords (10) where M is Li.
Alternately, treatment of (9) with 2 equivalents of tert-butyllithium under inert atmosphere in a solvent such as ether or THF, at a temperature of from - 78 0C to 0 0C, affords (10) where M is Li. The metalloarene or metalloheteroarene intermediate (10) thus formed may be treated with sulfur dioxide in an ethereal solvent such as THF to afford a sulfϊnate salt that is subsequently treated with N-chlorosuccinimide or sulfuryl chloride to provide the desired sulfonyl chloride (8).
The present invention also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of Formula (I) along with methods for the preparation of compounds of Formula (I).
The below Procedures A, B and C may describe general conditions for making bissulfonamides according the the above reaction Schemes.
Procedure A (symmetrical bissulfonamides)
To a solution of o-phenylenediamine (1 mmol) in and DCM (4 mL) pyridine (1 mL) at 0 0C, arylsulfonyl chloride (2.2 mmol) was added at 0 0C in small portions at 0 0C. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. In some cases, the reaction is allowed to proceed overnight to ensure completion and/or may be aided by adding catalytic amount of DMAP. The reaction mixture was then diluted with DCM (5 mL).
The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc system to obtain the requisite bissulfonamide. Procedure B
To a solution of o-phenylenediamine (1 mmol) in and DCM (4 mL) pyridine (1 mL) at 0 0C, arylsulfonyl chloride (1.1 mmol) is added at 0 0C in small portions at 0 0C. The reaction mixture is then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture is then diluted with DCM (5 mL). The organic phase is washed with water (2X5 mL) and 5 mL of brine. The organic phase is dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained is purified by flash column chromatography eluting with DCM/EtOAc system to obtain the sulfonamide.
The monosulfonamide (1 mmol) obtained as above is dissolved in DCM (2 mL) and pyridine (2 mL). Arylsulfonyl chloride (1.1 mmol) is then added at RT and the reaction mixture is then allowed to stir at RT overnight or until the reaction is complete as determined by TLC or LC-MS. In some cases, the reaction is allowed to proceed overnight to ensure completion and/or may be aided by adding catalytic amount of DMAP. The reaction mixture is then diluted with DCM (5 mL). The organic phase is washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase is dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained is purified by flash column chromatography eluting with
DCM/EtOAc system to obtain the requisite bissulfonamide.
Procedure C
To a stirred solution of nitroaniline (2 mmol) in pyridine (4 mL) at RT, sulfonyl chloride (2.2 mmol) is added and the resulting reaction mixture is then heated at 100 0C until the reaction is complete as determined by TLC or LC-MS. The reaction mixture is diluted with EtOAc (20 mL) and washed with 10% aq. HCl (2x10 mL), H2O (2x10 mL) and brine (10 mL). The product may be used without further purification or may be purified on a silica gel column chromatography using EtOAc/hexane as eluant.
Hydrogenation is carried out in MeOH using 10% Pd/C (wet) under 1 atm.
Alternatively, when hydrogenation is not compatible, reduction is performed using Fe/ AcOH as follows: Sulfonamide from above (2 mmol) in AcOH (2 mL) is added with Fe powder (20 mmol). The reaction mixture is then heated at 100 0C until the reaction is complete as determined by TLC or LC-MS. The reaction mixture is then cooled to RT and diluted with EtOAc (20 mL) with vigorous stirring. The suspension is then filtered on a Celite pad and the filtrate is then concentrated in vacuo to remove most of the acetic acid. The residue obtained is redissolved in EtOAc (20 mL), washed with saturated aqueous bicarbonate solution (20 niL), followed by water (20 mL) and brine (20 mL). The product may be used for further transformation without any purification.
The monosulfonamide (1 mmol) obtained as above is dissolved in DCM (2 mL) and pyridine (2 mL). Arylsulfonyl chloride (1.1 mmol) is then added at RT and the reaction mixture is then allowed to stir at RT overnight or until the reaction is complete as determined by TLC or LC-MS. In some cases, the reaction is allowed to proceed overnight to ensure completion and/or may be aided by adding catalytic amount of DMAP. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase is dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained is purified by flash column chromatography eluting with DCM/EtOAc system to obtain the requisite bissulfonamide.
The term "pharmaceutical composition" is used herein to denote a composition that may be administered to a mammalian host, e.g. , orally, topically, parenterally, by inhalation spray, or rectally, in unit dosage formulations that may contain conventional pharmaceutically acceptable carriers, diluents, adjuvants, vehicles and the like.
The term "parenteral" as used herein, includes subcutaneous injections, intravenous, intramuscular, intracisternal injection, or by infusion techniques.
The pharmaceutical compositions containing a compound of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous, or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. The tablets may also be coated by the techniques described in U.S. Patent Numbers 4,356,108; 4,166,452; and 4,265,874, to form osmotic therapeutic tablets for controlled release.
Formulations for oral use may also be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl-eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alchol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring, and coloring agents may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil- in- water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectible aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as solvent or suspending medium. For this purpose, any bland fixed oil may be employed using synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compositions may also be in the form of suppositories for rectal
administration of the compounds of the invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols, for example. For topical use, creams, ointments, jellies, solutions of suspensions, etc., containing the compounds of the invention are contemplated. For the purpose of this application, topical applications shall include mouth washes and gargles.
The compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Pharmaceutically acceptable salts of the compounds of the present invention, where a basic or acidic group is present in the structure, are also included within the scope of the invention. The term "pharmaceutically acceptable salts" refers to salts of the compounds of this invention which are not biologically or otherwise undesirable. Such pharmaceutically acceptable salts may be prepared generally by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. Representative salts include the following salts: Acetate,
Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Methanesulfonate, Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,
Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide, Trimethylammonium and Valerate. When an acidic substituent is present, such as-COOH, there can be formed the ammonium, morpholinium, sodium, potassium, barium, calcium salt, and the like, for use as the dosage form. When a basic group is present, such as amino or a basic heteroaryl radical, such as pyridyl, an acidic salt, such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxlate, maleate, pyruvate, malonate, succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethanesulfonate, picrate and the like, and include acids related to the pharmaceutically- acceptable salts listed in the Journal of Pharmaceutical Science, 66, 2 (1977) p. 1-19.
Other salts that are not pharmaceutically acceptable may be useful in the preparation of compounds of the invention and these form a further aspect of the invention.
As used herein, the term "analgesia" isused to describe pain reduction including the reduction of pain associated with neuropathic pain, as well as allodynia often associated with neuropathic pain.
As used herein, a compound that is "substantially unable to cross the blood- brain barrier" or "partially or completely excluded from the brain" is a compound that diffuses across the blood-brain barrier at a lower rate than the rate of diffusion in the periphery of a subject.
In an embodiment, at dose levels that are able to stimulate GaIRl receptors in the periphery of a subject, a compound that is "substantially unable to cross the blood- barrier" or "partially or completely excluded form the brain" may be present in the brain of a subject at or below the limit of detection.
In another embodiment, at dose levels in which an analgesic effect is observed in a subject, a compound that is "substantially unable to cross the blood-brain barrier" or "partially or completely excluded from the brain" may be present in the brain of a subject at or below the limit of detection.
As used herein, a GaIRl agonist comprises compounds: 1) that are capable of binding to a GaIRl receptor and inhibiting forskolin induced cAMP production in Bowes cells that express the human GaIRl receptor; and 2) that do not inhibit forskolin induced cAMP production in cell lines that do not express the GaIRl receptor. In an embodiment, a GaIRl agonist is a compound that exhibits greater efficacy in a functional assay in comparison to no ligand.
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, diluent, or mixture thereof. In another embodiment, the present invention also provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof in an amount sufficient to increase activity of a GaIRl receptor in a subject. In another embodiment, the pharmaceutical composition comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof in an amount sufficient to stimulate GaIRl in a subject.
In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount comprises an amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof capable of at least partially activating the GaIRl receptor in a subject, or an amount capable of at least partial amelioration of at least one GaIRl mediated disease. Diseases or disorders that may be ameliorated by a GaIRl agonist may include a seizure disorder, a neuroendocrine disorder, a gastrointestinal disorder, a musculoskeletal disorder, psychotic behavior such as schizophrenia, migraine, morphine tolerance, drug addiction, particularly opiate addiction, pain, particularly neuropathic pain, inflammatory pain, chronic pain, a sleep disorder, eating/body weight disorders such as bulimia, bulimia nervosa, and anorexia nervosa, metabolic wasting disorders such as cachexia, neuropathological disorders, diabetes, dyslipidimia, hypertension, memoryloss, depression, anxiety, cerebral hemorrhage, diarrhea, and one or more cancers such as, but not limited to, squamous cell carminoma. Accordingly, treatment of such disorders including alleviation or reduction of one or more symptoms of such disorders may be affected by the administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound. It is contemplated within the scope of the invention these compounds and pharmaceutical compositions comprising such compounds may be formulated to treat disorders that are not associated with binding of galanin (or lack thereof) to the GaIRl receptor but where the symptoms of the disorder may be mediated by a GaIRl agonist.
In another embodiment, the pharmaceutical composition is in the form of an oral dosage. In another embodiment, the pharmaceutical composition is in the form of a parenteral dosage unit. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In another embodiment, the pharmaceutical composition may further comprise one or more therapeutic agents selected from the group consisting of biologic response modifiers, analgesics, NSAIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides, acarbose, PPAR agonists, DPP-IV inhibitors, GK activators, insulin, insulin mimetics, insulin secretagogues, insulin sensitizers, GLP- 1, GLP-I mimetics, cholinesterase inhibitors, antipsychotics, antidepressants,
anticonvulsants, HMG CoA reductase inhibitors, cholestyramine, and fibrates. In another embodiment, the pharmaceutical composition may further comprise one or more therapeutic agents such as anticancer agents: such as, but not limited to, cyclophosphamide, nitrosoureas, carboplatin, cisplatin, procarbazine, Bleomycin, Daunorubicin, Doxorubicin, Methotrexate, Cytarabine, Fluorouracil, Vinblastine, Vincristine, Etoposide, Paclitaxel, Tamoxifen, Octreotide acetate, Finasteride, Flutamide, Interferons, Interleukins, and anti-tumor antibodies and antiangiogenic compounds and proteins.
In another embodiment, the present invention provides a method comprising: administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The methods wherein a compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject, the compound may be administered as part of a pharmaceutical composition.
In another embodiment, the present invention provides a method comprising: administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject having a condition ameliorated by the activation of a GaIRl receptor in an amount sufficient to increase activity of GaIRl in the subject. Conditions that may be treated with a GaIRl agonist include seizure disorders, neuroendocrine disorders, gastrointestinal disorders, musculoskeletal disorders, psychotic behavior such as schizophrenia, migraine, morphine tolerance, drug addiction, particularly opiate addiction, pain, particularly neuropathic pain, inflammatory pain, chronic pain, sleep disorders, eating/body weight disorders such as bulimia, bulimia nervosa, and anorexia nervosa, metabolic wasting disorders such as cachexia, neuropathological disorders, diabetes, dyslipidimia, hypertension, memoryloss, depression, anxiety, cerebral hemorrhage, diarrhea, and one or more cancers such as, but not limited to, squamous cell carminoma.
In an embodiment, the present invention provides a method comprising:
administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt so as to induce an analgesic effect in the subject.
In another embodiment, the present invention provides a method comprising: administering to a subject suffering pain a compound of Formula (I) or a
pharmaceutically acceptable salt thereof so as to induce an analgesic effect in the subject. In another embodiment, the present invention provides a method comprising: administering to a subject suffering from neuropathic pain a compound of Formula (I) or a pharmaceutically acceptable salt thereof so as to induce an analgesic effect in the subject. In another embodiment, the present invention provides a method comprising: administering to a subject suffering from allodynia a compound of Formula (I) or a pharmaceutically acceptable salt thereof so as to induce an analgesic effect in the subject.
In another embodiment, the compounds and pharmaceutical compositions of the present invention may be useful to increase a subject's pain threshold. Thus, in another embodiment, the present invention provides a method comprising: administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof, so as to increase the subject's pain threshold. In a further embodiment, the subject is suffering from neuropathic pain. In a further embodiment, the subject is suffering from allodynia or hyperalgesia. In a further embodiment, the subject is suffering from pain associated with having cancer.
The compounds of the present invention may be administered at a dosage level at or below 1000 mg/kg of the body weight of the subject being treated. In another embodiment, the compounds of the present invention may be administered at a dosage level at or below 100 mg/kg. In another embodiment, the compounds of the present invention may be administered at a dosage level at or below 10 mg/kg of body weight per day. In another embodiment, the compounds of the present invention may be
administered at a dosage level at or above 0.01 mg/kg of body weight per day. In another embodiment, the compounds of the present invention may be admistered at a dosage level at or above 0.5 mg/kg of body weight per day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain 1 mg to 2 grams of a compound of Formula (I) with an appropriate and convenient amount of carrier material that may vary from 5 to 95 percent of the total composition. Dosage unit forms will generally contain between from 5 mg to 500 mg of active ingredient. The dosage may be individualized by the clinician based on the specific clinical condition of the subject being treated. Thus, it will be understood that the specific dosage level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
In another embodiment, the pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered to a subject in combination with one or more therapeutic agents selected from the group consisting of biologic response modifiers, analgesics, NSAIDs, DMARDs,
glucocorticoids, sulfonylureas, biguanides, acarbose, PPAR agonists, DPP-IV inhibitors, GK activators, insulin, insulin mimetics, insulin secretagogues, insulin sensitizers, GLP- 1, GLP-I mimetics, cholinesterase inhibitors, antipsychotics, antidepressants,
anticonvulsants, HMG CoA reductase inhibitors, cholestyramine, and fibrates.
In another embodiment, a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered to a subject in combination with one or more therapeutic agents selected from the group consisting of anticancer agents such as, but not limted to, Cyclophosphamide, nitrosoureas, carboplatin, cisplatin, procarbazine,
Bleomycin, Daunorubicin, Doxorubicin; Methotrexate, Cytarabine, Fluorouracil;
Vinblastine, Vincristine, Etoposide, Paclitaxel; Tamoxifen, Octreotide acetate,
Finasteride, Flutamide, Interferons, Interleukins, and anti-tumor antibodies and antiangiogenic compounds and proteins.
Neuropathic pain may be ameliorated, at least in part, by a GaIRl agonist binding to the peripheral GaIRl receptors in a subject. Where a GaIRl agonist is partially or completely prevented from passing through the blood-brain barrier, the risk of inducing centrally mediated central nervous system (CNS) side effects may be reduced or avoided. In an embodiment, the present invention provides a method of treating neuropathic pain in a subject that may avoid or reduce the risk of centrally mediated side effects in the subject. This method may be practiced with a compound of Formula (I) or a
pharmaceutically acceptable salt thereof that is substantially unable to cross the blood- brain barrier. Because peripheral GaIRl receptors in neuropathic pain may be associated with allodynia, this provides a useful method of treating a subject in need of relief from allodynia by administering to the subject a compound of Formula (I) or a
pharmaceutically acceptable salt thereof that is substantially unable to cross the blood- brain barrier. This method of treating allodynia may reduce or eliminate the risk of one or more centrally mediated CNS side effects.
For example, the compounds and pharmaceutical compositions of the present invention may be useful in treating neuropathic pain. Further, at doses for which an analgesic effect may be observed, the compounds of the present invention may be capable of binding to at least one peripheral GaIRl while being substantially unable to cross the blood-brain barrier. Partial or complete exclusion of a compound of Formula (I) or a pharmaceutically acceptable salt thereof from the brain may reduce the risk or severity of one or more centrally-mediated side effect associated with the administration of the compound to a subject.
In another embodiment, the present invention provides a method comprising: administering to a subject suffering from neuropathic pain a compound of Formula (I) or a pharmaceutically acceptable salt thereof so as to induce an analgesic effect in the subject. In a further embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is capable of stimulating peripheral GaIRl receptors in the subject. In a further embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is partially or completely excluded from the brain.
In another embodiment, the present invention provides a method comprising: administering to a subject suffering from allodynia a compound of Formula (I) or a pharmaceutically acceptable salt thereof so as to induce an analgesic effect in the subject. In a further embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is capable of stimulating peripheral GaIRl receptors in the subject. In a further embodiment, the compound is substantially unable to cross the blood-brain barrier at doses for which an analgesic effect is observed in the subject.
In another embodiment, the present invention provides a method comprising: administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject suffering from neuropathic pain and modulating peripheral GaIRl receptors in the subject at the level of the dorsal root ganglia (DRG). In a further embodiment, the compound is substantially unable to cross the blood-brain barrier in the subject at doses for which an analgesic effect is observed in the subject.
In another embodiment, the present invention provides a method of treatment comprising: administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject suffering from cancer, wherein the cancer cell proliferation is inhibited in the subject. In another embodiment of the treatment, the compound is administered in an amount effective to inhibit or inactivate the MAPK pathway in cancer cells in the subject.
EXAMPLES
LC-MS data was obtained using gradient elution on a parallel ML,rXn; system., running four Waters 1525 binary HPLC pumps, equipped with a Mux-UV 2488 multichannel UV- Vis detector (recording at 215 and 254 nM) and a Leap Technologies HTS PAL Auto sampler using a Waters Xterra MS Cl 8 4.6x50 mm column. A three minute gradient was run from 25% B (97.5%acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100% B. The system is interfaced with a Waters Micromass ZQ mass spectrometer using electrospray ionization. All MS data was obtained in the positive mode unless otherwise noted. IH NMR data was obtained on a Varian 400 MHz spectrometer.
Abbreviations that may be used in the Examples are as follows:
DCM = dichloromethane
DMAP = dimethylaminopyridine DMF = N, N-dimethylformamide
DMSO= dimethylsulfoxide
EDTA = ethylenediamine tetraacetic acid ether = diethyl ether
EtOAc = ethyl acetate
g = gram
h = hour
Hz = hertz
i.v. = intravenous
L = liter
M = molar
m/z = mass to charge ratio
MeOH = methanol
mg = milligram
min = minute
mL = milliliter
mM = millimolar
mmol = millimole
mol = mole
mp = melting point
MS = mass spectrometry
NMR = nuclear magnetic resonance spectroscopy
PBS = phosphate buffered saline solution ppm = parts per million
rt = room temperature
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = thin layer chromatography
Tr = retention time
Example 1 : To a solution of benzene-1, 2-diamine (0.5 mmol) in and DCM (2 mL) pyridine (0.5 mL) at 0 0C, 5-methyl-benzo [b] thiophene-2-sulfonyl chloride (l.lmmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with
EtOAc/hexane (15-25%) to obtain 186 mg N, N'-benzene-l, 2-diylbis (5 -methyl- 1- benzothiophene-2-sulfonamide). LC: MS: 530.3 (M+2)+. 1H NMR (CDCl3, 400 MHz): δ 7.7 (m, 2H), 7.6 (s, 4H), 7.3 (m, 2H), 7.1 (m, 4H), 2.4 (s, 6H) ppm.
Example 2:
To a solution of benzene-1, 2-diamine (0.5 mmol) in and DCM (2 mL) pyridine
(0.5 mL) at 0 0C, 5-phenyl-thiophene-2-sulfonyl chloride (l.lmmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (15- 25%) to obtain 202 mg Λ/,Λ/"-benzene-l,2-diylbis(5-phenylthiophene-2-sulfonamide). LC: MS: 554.1 (M+2)+. 1U NMR (CDCl3, 400 MHz): δ 7.6 (m, 4H), 7.4 (m, 8H), 7.2 (m, 6H) ppm.
Example 3 :
To a solution of benzene-1, 2-diamine (0.5 mmol) in and DCM (2 mL) pyridine (0.5 mL) at 0 0C, 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (l.lmmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC- MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with
EtOAc/hexane (15-25%) to obtain 190 mg N,Λ/'-benzene-l,2-diylbis(5-chloro-3-methyl- l-benzothiophene-2-sulfonamide). LC: MS: 598.0 (M+2)+. 1U NMR (CDCl3, 400 MHz): δ 7.7 (m, 4H), 7.4 (m, 2H), 7.0-7.1 (m, 4H), 2.3 (s, 6H) ppm.
Example 4:
To a solution of benzene-1, 2-diamine (0.5 mmol) in and DCM (2 mL) pyridine (0.5 mL) at 0 0C, 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (l.lmmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC- MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with
EtOAc/hexane (15-25%) to obtain 185 mg NJΨ-benzene- 1 ,2-diylbis(5-fluoro-3-methyl- l-benzothiophene-2-sulfonamide). LC: MS: 565.8 (M+2)+. 1U NMR (CDCl3, 400 MHz): δ 7.7 (m, 2H), 7.4 (m, 2H), 7.0-7.1 (m, 6H), 2.3 (s, 6H) ppm.
Example 5 :
To a solution of 4-chloro-benzene-l, 2-diamine (0.5 mmol) in and DCM (2 mL) pyridine (0.5 mL) at 0 0C, 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (l.lmmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 rnL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (30-40%) to obtain 240 mg N,7V-(4-chlorobenzene-l,2- diyl)bis(5-chloro-3-methyl-l-benzothiophene-2-sulfonamide. LC: MS: 630.0 (M)+. 1H NMR (CDCl3, 400 MHz): δ 7.78 (s, IH), 7.75 (m, 3H), 7.5 (m, 2H), 7.2-7.3(m, IH), 7.0 (m, IH), 6.8 (m, IH), 2.5 (s, 3H), 2.3 (s, 3H) ppm.
Example 6:
To a solution of 4-fluoro-benzene-l,2-diamine (0.5 mmol) in and DCM (2 mL) pyridine (0.5 mL) at 0 0C, 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (1.1 mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (30-40%) to obtain 212 mg N,7V-(4-fluorobenzene-l,2- diyl)bis(5-chloro-3-methyl-l-benzothiophene-2-sulfonamide. LC: MS: 615.0 (M+ 1)+. 1H NMR (CDCl3, 400 MHz): δ 7.6-7.8 (m, 4H), 7.4 (m, 2H), 7.2 (m, IH), 6.7 (m, 2H), 2.5 (s, 3H), 2.2 (s, 3H) ppm.
Example 7:
To a solution of o-phenylenediamine (4 mmol) in DCM (20 mL) and pyridine (4 mL) at 0 0C, 3,4-dichlorobenzenesulfonyl chloride (4.4 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with water (2 x 20 mL) and 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 760 mg of N-(2-amino-phenyl)-3,4- dichloro-benzenesulfonannide. LC: Tr 0.98 min, MS: 317.0 (M+l ) +; 1H NMR (CDCl3, 400 MHz): δ 4.95 (bs, 2H), 6.45(t, IH), 6.11 (d, IH), 6.72 (d, IH), 6.92 (t, IH), 7.59 (dd, IH), 7.80 (d, 3H) ppm .
The monosulfonamide (0.5mmol) obtained as above was dissolved in DCM (2 mL) and pyridine (1 mL). 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.6 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mX). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL), and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with
EtOAc/hexane (30-40%) to give 202 mg of 5-chloro-N-(2-{[(3,4- dichlorophenyl)sulfonyl] amino } phenyl)-3 -methyl- 1 -benzothiophene-2-sulfonamide. LC : MS: 560.8 (M+l) +; 1H NMR (DMSO-d6, 400 MHz): δ 8.0-8.1 (m, 2H), 7.9 (s, IH), 7.8 (m, IH), 7.5-7.6 (m, 2H), 6.9-7.1 (m, 4H), 2.3 (s, 3H) ppm.
Example 8:
To a solution of o-phenylenediamine (4 mmol) in DCM (20 mL) and pyridine (4 mL) at 0 OC, 3,4-dichlorobenzenesulfonyl chloride (4.4 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with water (2 x 20 mL) and 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 760 mg of N-(2-amino-phenyl)-3,4- dichloro-benzenesulfonannide. LC: Tr 0.98 min, MS: 317.0 (M+l ) +; 1H NMR (CDCl3, 400 MHz): δ 4.95 (bs, 2H), 6.45(t, IH), 6.11 (d, IH), 6.72 (d, IH), 6.92 (t, IH), 7.59 (dd, IH), 7.80 (d, 3H) ppm. The monosulfonamide (0.5mmol) obtained as above was dissolved in DCM (2 niL) and pyridine (1 mL). 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.6 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mX). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL), and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with
EtOAc/hexane (30-40%) to give 194 mg of 5-fluoro-iV-(2-{[(3,4- dichlorophenyl)sulfonyl] amino } phenyl)-3 -methyl- 1 -benzothiophene-2-sulfonamide. LC : MS: 544.9 (M+l) +; 1H NMR(DMSO-d6, 400 MHz): δ 8.1 (m, IH), 7.9 (s, IH), 7.7-7.8 (m, 2H), 7.6 (m, IH), 7.4 (m, IH), 6.9-7.1 (m, 4H), 2.3 (s, 3H) ppm.
Example 9:
To a solution of benzene-1, 2-diamine (0.5 mmol) in and DCM (2 mL) pyridine (0.5 mL) at 0 0C, 6-chloro-imidazo[2,l-b]thiazole-5-sulfonyl chloride (l.lmmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with
EtOAc/hexane (40-50%) to obtain 105 mg N,Λ/'-benzene-l,2-diylbis(6- chloroimidazo[2,l-6][l,3]thiazole-5-sulfonamide. LC: MS: 550.2(M+2)+. 1H NMR (CDCl3, 400 MHz): δ 7.6 (m, 2H), 7.1-7.2(m, 4H), 7.0 (m, 2H) ppm.
Example 10:
To a solution of thiophene-3,4-diamine (0.25 mmol) in and DCM (1 mL) pyridine (0.25 mL) at 0 0C, Benzo[b]thiophene-2-sulfonyl chloride (0.6mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (30- 40%) to obtain 90mg N,Λ/'-thiene-3,4-diylbis(l-benzothiophene-2-sulfonamide). LC: MS: 506.1(M)+. 1H NMR (CDCl3, 400 MHz): δ 7.8 (m, 4H), 7.7 (s, 2H), 7.4-7.5 (m, 4H), 7.0 (s, 2H) ppm.
Example 11 :
To a solution of thiophene-3,4-diamine (0.25 mmol) in and DCM (1 mL) pyridine (0.25 mL) at 0 0C, 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.6 mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC- MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with
EtOAc/hexane (30-40%) to obtain 102 mg N,Λ/'-thiene-3,4-diylbis(5-chloro-3 -methyl- 1- benzothiophene-2-sulfonamide). LC: MS: 602.3 (M)+. 1U NMR (CDCl3, 400 MHz): δ 7.7 (m, 4H), 7.4 (m, 2H), 6.9 (s, 2H), 2.3 (s, 6H) ppm.
Example 12:
To a solution of 4-fluoro-benzene-l,2-diamine (0.5 mmol) in and DCM (2 mL) pyridine (0.5 mL) at 0 0C, 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride
(1.1 mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (30-40%) to obtain 216 mg N,7V-(4-fluorobenzene-l,2- diyl)bis(5-fluoro-3-methyl-l-benzothiophene-2-sulfonamide). LC: MS: 582.3 (M)+. 1H NMR (DMSO-d6, 400 MHz): δ 8.0-8.1 (m, 2H), 7.8 (m, 2H), 7.4 (m, 2H), 7.1 (m, 2H), 6.98 (m, 3H), 2.42 (s, 3H), 2.3 (s, 3H) ppm.
Example 13:
To a solution of 4-chloro-benzene-l,2-diamine (0.5 mmol) in and DCM (2 mL) pyridine (0.5 mL) at 0 0C, 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride
(1.1 mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (30-40%) to obtain 221 mg N,7V-(4-chlorobenzene-l,2- diyl)bis(5-fluoro-3-methyl-l-benzothiophene-2-sulfonamide). LC: MS: 598.1 (M)+. 1H NMR (DMSO-d6, 400 MHz): δ 8.0-8. l(m, 2H), 7.8 (m, 2H), 7.4 (m, 2H), 7.1 (m, 2H), 7.0 (m, IH), 2.4 (s, 3H), 2.3 (s, 3H) ppm.
Example 14:
To a solution of o-phenylenediamine (4 mmol) in DCM (20 mL) and pyridine (4 mL) at 0 0C, 3,4-dichlorobenzenesulfonyl chloride (4.4 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with water (2 x 20 mL) and 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 760 mg of N-(2-amino-phenyl)-3,4- dichloro-benzenesulfonannide. LC: Tr 0.98 min, MS: 317.0 (M+l )+; 1H NMR (CDCl3, 400 MHz): δ 4.95 (bs, 2H), 6.45(t, IH), 6.11 (d, IH), 6.72 (d, IH), 6.92 (t, IH), 7.59 (dd, IH), 7.80 (d, 3H) ppm.
The monosulfonamide (0. lmmol) obtained as above was dissolved in DCM
(0.5mL) and pyridine (0.25 mL). 5-bromo-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.11 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (4 mX). The organic phase was washed with 10% aqueous HCl (4 mL), water (4 mL), and brine (4mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with
EtOAc/hexane (30-40%) to give 42 mg of 5-bromo-JV-(2-{[(3,4- dichlorophenyl)sulfonyl] amino } phenyl)-3 -methyl- 1 -benzothiophene-2-sulfonamide. LC : MS: 606.1 (M+l) +; 1H NMR (DMSO-d6, 400 MHz): δ 8.1 (s, IH), 8.0 (m, IH), 7.9 (m, IH), 7.8 (m, IH), 7.6-7.7 (m, 2H), 7.1 (m, IH), 7.0 (m, 2H), 6.9 (m, IH), 2.3 (s, 3H) ppm.
Example 15:
To a solution of 4,5-dichloro-benzene-l,2-diamine (0.5 mmol) in and DCM (2 mL) pyridine (0.5 mL) at 0 0C, 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (1.1 mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (50-60%) to obtain 250 mg N,Λ/'-(4,5-dichlorobenzene-l,2- diyl)bis(5 -chloro-3 -methyl- 1 -benzothiophene-2-sulfonamide). LC: MS: 666.0 (M+2)+.JH NMR (DMSO-d6, 400 MHz): δ 8.02 (m, 2H), 8.0 (s, 2H), 7.6 (m, 2H), 7.1 (s, 2H), 2.4 (s, 6H) ppm. Example 16:
To a solution of 3,4-diamino-benzonitrile (0.25 mmol) in and DCM (1 niL) pyridine (0.3 rnL) at 0 0C, 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (O.βmmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (30-40%) to obtain 125 mg N,7V-(4-cyanobenzene-l,2- diyl)bis(5-chloro-3-methyl-l-benzothiophene-2-sulfonamide). LC: MS: 622.9 (MH)-K1H NMR (CDCl3, 400 MHz): δ 7.81 (s, 2H), 7.79 (m, 3H), 7.4-7.6 (m, 3H), 6.7 (m, IH), 2.5 (s, 6H) ppm.
Example 17:
To a solution of 3,4-diamino-benzoic acid methyl ester (0.25 mmol) in and DCM (1 mL) pyridine (0.3 mL) at 0 0C, 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.6 mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (30-40%) to obtain 136 mg methyl 3,4- bis{[(5-chloro-3-methyl-l-benzothiophen-2-yl)sulfonyl]amino}benzoate. LC: MS: 656.5 (M+2)+.1H NMR (CDCl3, 400 MHz): δ 7.8 (m, IH), 7.6-7.7 (m, 4H), 7.4 (m, 4H), 3.7 (s, 3H), 2.5 (s, 3H), 2.2 (s, 3H) ppm. Example 18:
To a solution of o-phenylenediamine (1 mmol) in DCM (4 niL) and pyridine (1 rnL) at 0 0C, 3-methanesulfonyl-benzenesulfonyl chloride (1.1 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with water (2 x 10 mL) and 10 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give N-(2-amino-phenyl)-3- methanesulfonyl-benzenesulfonamide .
The monosulfonamide (O.lmmol) obtained as above was dissolved in DCM (0.5mL) and pyridine (0.25 mL). 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.11 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (4 mL). The organic phase was washed with 10% aqueous HCl (4 mL), water (4 mL), and brine (4mL). The organic phase was dried over anhydroixs sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with
EtOAc/hexane (30-40%) to give 46 mg of 5-chloro-3-methyl-iV-[2-({[3- (methylsulfonyl)phenyl]sulfonyl} amino)phenyl]- 1 -benzothiophene-2-sulfonamide. LC : MS: 570.3 (M) +; 1H NMR (CDCl3, 400 MHz): δ 8.4 (s, IH), 8.1 (m, IH), 8.0 (m, IH), 7.7 (m, 3H), 7.4 (m, IH), 7.3 (m, IH), 7.2 (m, IH), 7.0 (m, IH), 6.8 (m, IH), 3.1 (s, 3H), 2.2 (s, 3H) ppm.
Example 19:
To a solution of 2,3-dihydro-benzo[l,4]dioxine-6,7-diamine (0.1 mmol) in and
DCM (1 mL) pyridine (0.3 mL) at 0 0C, 5-chloro-3-methyl-benzo[b]thiophene-2- sulfonyl chloride (0.22mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 niL) and 5 niL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (40-60%) to obtain 48 mg
Figure imgf000062_0001
l,4-benzodioxine-6,7-diylbis(5-chloro-3-methyl-l-benzothiophene-2-sulfonamide). LC: MS: 654.1 (M)+.1H NMR (CDCl3, 400 MHz): δ 7.7 (m, 4H), 7.4 (m, 2H), 6.8 (bs, 2H), 6.6 (s, 2H), 4.2(s, 4H), 2.4(s, 6H) ppm.
Example 20:
To a solution of 4-chloro-5-fluoro-benzene-l,2-diamine (0.25 mmol) in and DCM (1 mL) pyridine (0.3 mL) at 0 0C, 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.6mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (50-60%) to obtain 150 mg N,Λ/'-(4-chloro- 5-fluorobenzene-l,2-diyl)bis(5-chloro-3-methyl-l-benzothiophene-2-sulfonamide). LC: MS: 648.0 (M)+.1H NMR (CDCl3, 400 MHz): δ 7.7-7.8 (m, 4H), 7.5 (m, 2H), 7.19 (m, IH), 6.9 (m,lH), 2.5 (s, 3H), 2.3 (s, 3H) ppm.
Example 21 :
To a solution of 4-chloro-5 -methyl-benzene- 1,2-diamine (0.25 mmol) in and DCM (1 mL) pyridine (0.3 mL) at 0 0C, 5-chloro-3-methyl-benzo[b]thiophene-2- sulfonyl chloride (0.6mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (40-60%) to obtain 142 mg N,Λ/'-(4-chloro- 5 -methylbenzene-l,2-diyl)bis(5-chloro-3 -methyl- l-benzothiophene-2-sulfonamide). LC: MS: 644.0 (M)+.1H NMR (DMSO-d6, 400 MHz): δ 8.1 (m, 2H), 8.0 (s, 2H), 7.6 (m, 2H), 7.0 (s, 2H), 2.4 (s, 6H), 2.1 (s, 3H) ppm.
Example 22:
To a solution of 4-methoxy-benzene-l,2-diamine (0.25 mmol) in and DCM (1 mL) pyridine (0.3 mL) at 0 0C, 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.6mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (30-40%) to obtain 134 mg JV,iV-(4-methoxybenzene-l,2- diyl)bis(5-chloro-3 -methyl- l-benzothiophene-2-sulfonamide). LC: MS: 626.0 (M)+.JH NMR (DMSO-d6, 400 MHz): δ 8.0-8.1 (m, 4H), 7.5-7.6 (m, 2H), 6.8 (m, IH), 6.6 (m, 2H), 3.6 (s, 3H), 2.4 (s, 3H), 2.3 (s, 3H) ppm.
Example 23 :
To a solution of 4-chloro-benzene-l,2-diamine (0.1 mmol) in and DCM (1 mL) pyridine (0.3 mL) at 0 0C, 5-bromo-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.22mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by
TLC or LC-MS. The reaction mixture was then diluted with DCM (4 mL). The organic phase was washed with 10% HCl aqueous solution (4 mL), water (4 mL) and 4 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (30-40%) to obtain 56 mg N,7V-(4-chlorobenzene-l,2- diyl)bis(5-bromo-3 -methyl- l-benzothiophene-2-sulfonamide). LC: MS: 722.1 (M+2)+.1H NMR (CDCl3, 400 MHz): δ 7.9 (m, 2H), 7.6-7.7 (m, 4H), 7.3 (m, IH), 7.0 (m, IH), 6.8 (m, IH), 2.4 (s, 3H), 2.2 (s, 3H) ppm.
Example 24:
To a solution of 4-trifluoromethyl-benzene-l,2-diamine (0.25 mmol) in and DCM (1 mL) pyridine (0.3 mL) at 0 0C, 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.6mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (30-40%) to obtain 142 mg N,JST-(4- trifluoromethylbenzene- 1 ,2-diyl)bis(5 -chloro-3 -methyl- 1 -benzothiophene-2- sulfonamide). LC: Tl-1.18 min; MS: 666.2 (M+2)+.1H NMR (CDCl3, 400 MHz): δ 7.6- 7.8 (m, 4H), 7.5 (m, 2H), 7.4 (m, 2H), 7.1 (s, IH), 2.42 (s, 3H), 2.2 (s, 3H) ppm.
Example 25:
To a solution of o-phenylenediamine (1 mmol) in DCM (4 mL) and pyridine (1 mL) at 0 0C, 5 -chloro-3 -methyl-benzo[b]thiophene-2-sulfonyl chloride (1.1 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with water (2 x 5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 5 -chloro-3 -methyl- benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide. The monosulfonamide (0.1 mmol) obtained as above was dissolved in DCM (0.5mL) and pyridine (0.25 mL). 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.11 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (4 mX). The organic phase was washed with 10% aqueous HCl (4 mL), water (4 mL), and brine (4 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with
EtOAc/hexane (15-25%) to give 39 mg of 5-chloro-N-(2-{[(5-fluoro-3-methyl-l- benzothiophen-2yl)sulfonyl] amino } phenyl)-3 -methyl- 1 -benzothiophene-2-sulfonamide . LC: MS: 582.1 (M+2) +; 1H NMR (DMSO-d6, 400 MHz): δ 8.0 (m, 3H), 7.7 (m, IH), 7.6 (m, IH), 7.4 (m, IH), 7.0-7.1 (m, 4H), 2.3 (s, 3H), 2.2 (s, 3H) ppm.
Example 26:
To a solution of 4,5-dichloro-benzene-l,2-diamine (0.25 mmol) in and DCM (1 mL) pyridine (0.3 mL) at 0 0C, 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.6mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (50-60%) to obtain 145 mg N,7V-(4,5-dichlorobenzene-l,2- diyl)bis(5-fluoro-3-methyl-l-benzothiophene-2-sulfonamide). LC: MS: 632.2 (M)+.1H NMR (CDCl3, 400 MHz): δ 7.7-7.8 (m, 2H), 7.4 (m, 2H), 7.3 (m, 2H), 7.2 (s, 2H), 2.4 (s, 6H) ppm.
Example 27:
To a solution of 4-chloro-5-fluoro-benzene-l,2-diamine (0.25 mmol) in and DCM (1 mL) pyridine (0.3 mL) at 0 0C, 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (O.βmmol) was added at O 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (50-60%) to obtain 136 mg N,Λ/'-(4-chloro- 5 -fluorobenzene-l,2-diyl)bis(5-fluoro-3 -methyl- l-benzothiophene-2-sulfonamide). LC: MS: 616.2 (M)-K1H NMR (CDCl3, 400 MHz): δ 7.78 (m, 2H), 7.4 (m, 2H), 7.3 (m, 2H), 7.1 (m, IH), 6.9 (m, IH), 2.5 (s, 3H), 2.3 (s, 3H) ppm.
Example 28:
To a solution of 4-chloro-5 -methyl-benzene- 1,2-diamine (0.25 mmol) in and DCM (1 mL) pyridine (0.3 mL) at 0 0C, 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.6mmol) was added at 0 0C in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction is complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% HCl aqueous solution (5 mL), water (5 mL) and 5 mL of brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc/hexane (40-60%) to obtain 128 mg N,Λ/'-(4-chloro- 5 -methylbenzene-l,2-diyl)bis(5-fluoro-3 -methyl- l-benzothiophene-2-sulfonamide). LC: MS: 612.4 (M)+.1H NMR (CDCl3, 400 MHz): δ 7.78 (m, 2H), 7.4 (m, 2H), 7.3 (m, 2H), 7.0 (m, 2H), 2.4 (s, 3H), 2.38 (s, 3H), 2.2 (s, 3H) ppm.
Example 29:
To a solution of 4,5-dichloro-benzene-l,2-diamine (4 mmol) in DCM (20 mL) and pyridine (4 mL) at 0 0C, 3,4-dichlorobenzenesulfonyl chloride (4.4 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with water (2 x 20 mL) and 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give N-(2-Amino-4,5-dichloro- phenyl)-3,4-dichlorobenzenesulfonamide.
The monosulfonamide (0.25 mmol) obtained as above was dissolved in DCM (1 mL) and pyridine (0.5 mL). 5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.6 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% aqueous HCl (5 mL), water (5 mL), and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with
EtOAc/hexane (40-60%) to give 130 mg of 5-chloro-iV-(4,5-dichloro-2-{[(3,4- dichlorophenyl)sulfonyl] amino } phenyl)-3 -methyl- 1 -benzothiophene-2-sulfonamide. LC : MS: 630.2 (M+2) +; 1H NMR (CDCl3, 400 MHz): δ 7.85 (s, IH), 7.75-7.78 (m, 2H), 7.6 (m, 2H), 7.5 (m, IH), 7.2 (s, IH), 7.02 (s, IH), 2.38 (s, 3H) ppm.
Example 30:
To a solution of 4,5-dichloro-benzene-l,2-diamine (4 mmol) in DCM (20 mL) and pyridine (4 mL) at 0 0C, 3,4-dichlorobenzenesulfonyl chloride (4.4 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with water (2 x 20 mL) and 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give N-(2-Amino-4,5-dichloro- phenyl)-3,4-dichlorobenzenesulfonamide. The monosulfonamide (0.25mmol) obtained as above was dissolved in DCM (1 niL) and pyridine (0.5 rnL). 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonyl chloride (0.6 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% aqueous HCl (5 mL), water (5 mL), and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with
EtOAc/hexane (40-60%) to give 126 mg of iV-(4,5-dichloio-2-{[(3,4- dichlorophenyl)sulfonyl] amino } phenyl)-5 -fluoro-3 -methyl- 1 -benzothiophene-2- sulfonamide. LC: MS: 614.2 (M+2) +; 1H NMR (CDCl3, 400 MHz): δ 7.9 (s, IH), 7.7 (m, IH), 7.4-7.6 (m, 3H), 7.3 (m, IH), 7.2 (s, IH), 7.0 (s, IH), 2.3 (s, 3H) ppm.
Comparative Example 1 :
Figure imgf000068_0001
Comparative Example 1 may be synthesized as described in U.S. Patent
Publication 2006/0106089 (Example 33).
Comparative Example 2:
Figure imgf000068_0002
Comparative Example 2 may be synthesized as described in U.S. Patent
Publication 2006/0106089 (Example 26). Biological Assays
GaIRl Binding Assay
The affinity of compounds for GaIRl were studied in an [ 125I] galanin
displacement binding assay. Bowes melanoma cell membranes were used in the GaIRl binding assay. Compound was diluted in 40% DMSO/ water. The final assay
concentration ranging from 0.1 nM to 10 uM in 4% final DMSO concentration was used. The final binding assay conditions were 25 mM Tris-HCL, pH 7.4 buffer containing 10 mM MgCl2 ,1 - 10 ug membrane, 300 pM [125I]galanin (SA=2200 Ci/mmoL, (Perkin Elmer part no. NEX333), and compound in final DMSO concentration of 4% (final assay volume of 100 uL). Positive control wells (C+) lacked compound, and negative control wells (C-) lacked compound and contained cold excess galanin (1 micromolar). The reaction was carried out at room temp for 60-90 min. Membrane containing bound
[125I] galanin ligand was isolated following filtration onto Unifilter-96 GF/C filter plates (PerkinElmer part no. 6005177) using a cell harvester instrument. Plates were washed 5 times with cold 25 mM Tris-HCL, pH 7.5 containing 0.05% bovine serum albumin (BSA). Following filtration, 5OML of Microscint PS (Packard part no. 6013631) was added, plates were sealed with TopSeal-A adhesive seals (Packard part no. 6005185). 125I isotope bound to the Unifilter-96 GF/C plates was counted using a TopCount instrument (Packard).
Data Analysis
Percent inhibition of [125I]galanin binding was calculated according to the equation [100 x l-{(Samplecpm - C-cpm)/C+cpm - C-cpm)}]. Percent inhibition of
[125I] galanin binding (Y) vs compound concentration (X) data were generated.
The IC50 values were calculated by fitting the data using parameters for a sigmoidal dose response, variable slope nonlinear regression (GraphPAD Prizm, San Diego, CA) according to the equation: Y=Bottom + (Top-Bottom)/(l+10Λ((LogEC50- X)*HillSlope)); X is the logarithm of concentration. Y is the response; Y starts at Bottom and goes to Top with a sigmoid shape. This is identical the the "four parameter logistic equation." The compounds of Formula (I) in Table 1 showed a Human GaIRl Binding IC50 of less than or about 350 nanomolar in the binding assay described above. Specific IC50 data is shown in Table 2, below.
Table 2 - IC-50 Data
Figure imgf000070_0001
Functional cell-based assay
The agonist functional activity of compounds in Bowes cells was determined by measuring forskolin-stimulated intracellular cAMP. cAMP was quantitated using cAMPFire™ fluorescence polarization cAMP detection kit (Perkin Elmer). Bowes cells were grown minimum essential medium eagle containing Earle's salts, L-glutamine and sodiumk bicarbonate, supplemented with 10% fetal bovine serum. Cells were harvested by incubating cell monolayers in 15 mL PBS (Ca2+, Mg2+ - free) for 20 min in humidified 370C incubator containing 95% O2, 5% CO2. Gentle tapping of flasks dislodged cells, and cell suspensions were centrifuged 600xg for 5 min (40C). Cells were counted using a hemocytometer and diluted in stimulation mix (containing anti-cAMP antibody and isobutyl methyl xanthine) to a final cell density of 1- to 5xlO6 cell/mL. Typically, assays used between 10,000 and 50,000 of cells per well. Compound was diluted in 1% DMSO/ PBS to final assay concentration ranging from 0.1 nM to 10 uM, and 5 uL was dispensed in Costar black 384-well plates. Forskolin was filuted in 1% DMSO/PBS. Galanin was diluted in PBS containing complete protease inhibitor cocktail (Complete Mini, EDTA- free, Roche Diagnostics). Cells (10 uL) were pre -incubated with compound for 15 min, and then forskolin (5 to 20 uM) and galanin (0.1 to 10 nM) were added to a final assay volume of 20 uL. Following 30 min incubation of cells in a humidified 370C incubator with 95% O2, 5% CO2, Alexa Fluor 594-cAMP detection mix was added (20 uL), and plates were incubated at room temp with shaking for 1 hr. The degree of fluorescence polarization (expressed as mP units) was measured using an Envision (Perkin Elmer) fluorescence plate reader. Standard curves of c AMP (1 - 100 nM) were used to quantitate the amount of cAMP.
The compounds of Formula (I) in Table 1 showed an EC50 of less than or about 10 micromolar in the functional cell based assay described above and were determined to be GaIRl agonists.
Behavioral Assessment
Animals
Male Sprague Dawley rats (100-150 g for nerve ligation) were purchased from
Charles River (Portage, Mich.). Prior to surgery, animals were group-housed and maintained in a temperature regulated environment (lights on between 7:00 a.m. and 8:00 p.m.). Two weeks after surgery, experimentation began when animals were between 250-350 g. Rats had access to food and water ad libitum. For the assessment of neuropathic pain, mechanical allodynia in the affected paw of animals who had undergone sciatic nerve ligation was evaluated using von Frey filaments. As described previously (Chaplan et al, Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Meth, 1994; 53:55-62), two weeks following surgery, rats were acclimated to the testing box which was constructed of plexiglass with a wire mesh floor to allow access to the planter surface of the hind paws. Using the Dixons Up- Down method, a baseline level of allodynia was taken with allodynia defined as a withdrawal threshold of less than 4 g. Test compounds were then administered and subsequent withdrawal thresholds were determined. When dosed in the range between about 15 to 100 mg/kg with compounds in Table 1, the withdrawal thresholds of the animals with sciatic nerve injury increased was compared to the withdrawal threshold of vehicle treated animals with sciatic nerve injury.
Metabolic Stability Chemicals and reagents
Human, mixed gender, mouse (CD-I, male) liver microsomes and 0.5 M potassium phosphate buffer were from BD Biosciences (Bedford, MA). Verapamil, propranolol hydrochloride, R-S-warfarin, magnesium chloride, DMSO and reduced nicotinamide adenine dinucleotide phosphate tetrasodium salt (NADPH) were from Sigma (St. Louis, MO). Dog (Beagle, male), rat (Sprague-Dawley, male) and monkey (Cynomolgus, male) liver microsomes were from Xenotech (Kansas City, KS). HPLC- grade water, methanol, acetonitrile and formic acid were from Fisher (St. Louis, MO).
Incubation conditions
Incubations were performed in duplicate in 96-well deep well plates in a total volume of 0.20 mL. Incubations contained 0.5 mg/mL of microsomal protein, 1 μM of test compound (< 0.5% DMSO) in 67 mM potassium phosphate buffer (pH 7.4) with 3.3 mM MgCl2. Samples were pre -incubated at 37 0C for 5 min. Reactions were initiated by the addition of 10 μL 26 mM NADPH. Reactions were terminated at various time points (30, 60 or 120 min) by adding 200 μL of the appropriate internal standard at 1 μg/mL (TTP-3644 for controls) in acetonitrile to the reaction mixture. 0 min reactions were quenched prior to the addition of NADPH.
The samples were centrifuged at 3000 rpm for 10 minutes to remove precipitated protein. Following centrifugation, the plates was loaded into CTC HTS 96-well plate autosampler and ready for injection. 20 μL of supernatant was injected into LC-MS/MS for analysis. Percent remaining was calculated by comparing the peak area response signal after incubation with that of 0 minute incubation. Analytical Conditions
Instrumentation
LC-MS/MS analysis was conducted with either an Applied Biosystems (Foster City, CA, USA) APB 000 triple quadrupole mass spectrometer with an Turbo Ion Spray interface, Agilent (Foster City, CA, USA) 1100 series HPLC system, Shimadzu
(Columbia, MD, USA) SIL5000 autosampler and Analyst 1.4software for system operation and data processing or a Waters System (Milford, MA, USA) consisting of a Waters 1525μ HPLC pump, Leap-CTC (Carrboro, NC) autosampler and a Waters Quattro Micro triple quadrupole mass spectrometer with an electrospray interface and Mass Lynx 4.1 software for system operation and data processing.
Chromatographic conditions
Sample separation was conducted on a Zorbax Extend C-18 5μ column, 50mm x
2.2 mm (Agilent, Palo Alto, CA) with guard column cartridge. HPLC solvent mobile phase A was 0.5% (v/v) formic acid in methanol: water 20:80 (v/v), while mobile phase B was methanol with 0.5% formic acid. The HPLC flow rate was 0.25 mL/min.
Gradient elution on the Applied Biosystems (5 min. runtime) was as follows: the mobile phase was adjusted from 20% B to 100% B with a linear gradient over 1 minute; maintained at 100% B for 2.5 minute and then re-equilibrated at 20% B for 1.5 minute.
Gradient elution on the Waters (4 min. runtime) was as follows: the mobile phase was adjusted from 0% B to 95% B with a linear gradient over 1 minute; maintained at 95% B for 1.5 minute and then re-equilibrated at 0% B for 1.5 minute.
Mass spectrometric conditions
Applied Biosystems mass spectrometer was operated in positive electrospray ion mode. Instrument conditions: gases were set at Nebulizer: 3 units, Curtain: 10 units, Collision: 12 units; Temperature: 5000C; ion spray 4.25kV. Automatic Quantitative Optimization of the product ion, declustering potential (DP) and collision energy (CE) was accomplished by infusion utilizing Analyst 1.4.
Waters mass spectrometer was operated in negative ion mode. Capillary voltage was set to 4 kV. The extractor voltage was set at 3 V. Source and desolvation temperatures were set to 15O0C and 35O0C respectively. Nitrogen was used as both the desolvation and cone gas at 600 and 200 L/hr respectively. Argon was used as the collision gas. Optimization of the product ion, cone voltage (CV) and collision energy (CE) was accomplished with Mass Lynx Quant Opt module by injecting 0.5μM methanol: water 1 :1 solution.
Control and Internal Standard mass spec conditions (Waters)
Figure imgf000074_0001
Mass spec conditions
Figure imgf000075_0001
Results
Table 3 below shows the % of the test compound (identified by Example No. or Comparative Example No.) remaining after 1 hour incubation in liver microsomes of various species. Table 3 - Stability of Test Compounds in Liver Microsomes (% Remaining after 1 hr)
Figure imgf000076_0001
As can be seen from the data above, compounds of the present invention may exhibit microsome stability greater than 7% in humans, typically greater than 8% in humans, and often greater than 20% in humans. Compounds of general formula (II) of the present invention typically exhibit microsome stability greater than 40% in humans.
While the invention has been described and illustrated with reference to certain embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the invention. For example, effective dosages other than the dosages as set forth herein may be applicable as a consequence of variations in the responsiveness of the mammal being treated. Likewise, the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention.

Claims

We claim:
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof
Ar2-SO2NH-ArI-NHSO2-Ar3 (I), wherein
Aτi is either
Figure imgf000078_0001
Ar2 and Ar3 are independently selected from the group consisting of the following formulas (Ic), (Id), (Ie) and (If):
Figure imgf000078_0002
Figure imgf000078_0003
wherein at least one of Ar2 and Ar3 comprise an oxygen atom or sulfur atom vicinal or geminal to the point of attachment to the -NHSO2- group; Rw, Rx, Ry and Rz are independently selected from the group consisting of a) -hydrogen;
b) -halogen;
c) -Ci_6 alkyl;
d) -Ci_6 haloalkyl;
e) -cyano;
f) -L^C1-6 alkyl; and
g) -L^CL6 haloalkyl;
or Rx and Ry are bonded through either a -O-(CH2)2-O- or a -0-CH2-O- group to form a benzodioxine or a benzodiozane ring, respectively;
R1 and R11 are selected independently from the group consisting of
a) -hydrogen;
b) -Ci_6 alkyl;
c) -Ci_6 haloalkyl;
d) -L2- C i_6 alkyl; and
e) -L2-Ci_6 haloalkyl; R2, R3, R4, R5, R12, R13 and R14are selected independently from the group consisting of a) -hydrogen;
b) -halogen;
c) -C1-6 alkyl;
d) -Ci_6 haloalkyl;
e) -L3- C i_6 alkyl; and
f) -L3-Ci_6 haloalkyl; wherein
L2 and L3 are independently selected from the group consisting of -O-, -C(O)-, -C(O)-O-, -S-, -S(O)-, and -SO2-; provided that, when at least one OfAr2 and Ar3 is not formula (If), or when Ar1 is not a thiophene group, at least one of the following two conditions are met:
1) at least one of R1 and R11 is a group other than hydrogen, and
2) at least one of R2, R3, R4, R5, R12, R13 and R14 is a group other than hydrogen; and
provided that, when one OfAr2 and Ar3 has the structure of formula (Ie), the other of Ar2 and Ar3 has the structure of formula (Ic) and R1 is not hydrogen.
2. The compound of claim 1, wherein Ar1 is,
Figure imgf000080_0001
3. The compound of claim 2, wherein at least one OfAr2 and Ar3 has the structure of formula (Ic).
4. The compound of claim 3, wherein both Ar2 and Ar3 have the structure of formula (Ic).
5. The compound of claim 3, wherein at least one of R1 and R11 is methyl.
6. The compound of claim 4, wherein both R1 and R11 are methyl.
7. The compound of claim 3, wherein at least one of R2, R3, R4, R5, R12, R13,
R , 14 and . r R, 15 is selected from the group consisting of -C1-3 alkyl and halogen.
8. The compound of claim 7, wherein at least one of R2, R3, R4, R5, R12, R13,
R14 and R15 is selected from the group consisting of methyl and halogen.
9. The compound of claim 2, wherein at least one of Rx and Ry is selected from the group consisting of halogen, -L^C1-3 alkyl, -cyano, -C1-3 alkyl and -C1-3 haloalkyl.
10. The compound of claim 9, wherein at least one one of Rx and Ry is halogen.
11. The compound of claim 1 , wherein the compound is a compound selected from the group consisting of
N,Λ/'-benzene-l,2-diylbis(5-methyl-l-benzothiophene-2-sulfonamide);
N,Λ/'-benzene-l,2-diylbis(5-chloro-3-methyl-l-benzothiophene-2-sulfonamide);
N,Λ/I-benzene-l,2-diylbis(5-fluoro-3-methyl-l-benzothiophene-2-sulfonamide);
N,Λ/'-(4-chlorobenzene-l,2-diyl)bis(5-chloro-3 -methyl- l-benzothiophene-2-sulfonamide);
N,Λ/'-(4-fluorobenzene-l,2-diyl)bis(5-chloro-3-methyl-l-benzothiophene-2-sulfonamide); 5 -chloro-jV-(2- { [(3 ,4-dichlorophenyl)sulfonyl] amino } phenyl)-3 -methyl- 1 - benzothiophene-2-sulfonamide;
N-(2- { [(3 ,4-dichlorophenyl)sulfonyl]amino } phenyl)-5 -fluoro-3 -methyl- 1 - benzothiophene-2-sulfonamide;
N5A/1 -thiene-3,4-diylbis(5-chloro-3 -methyl- 1 -benzothiophene-2-sulfonamide);
N,Λ/'-(4-fluorobenzene- 1 ,2-diyl)bis(5 -fluoro-3 -methyl- 1 -benzothiophene-2-sulfonamide);
N,Λ/'-(4-chlorobenzene-l,2-diyl)bis(5 -fluoro-3 -methyl- 1 -benzothiophene-2-sulfonamide);
5 -bromo-iV-(2- { [(3 ,4-dichlorophenyl)sulfonyl] amino } phenyl)-3 -methyl- 1 - benzothiophene-2-sulfonamide;
N,Λ/'-(4,5-dichlorobenzene- 1 ,2-diyl)bis(5-chloro-3 -methyl- 1 -benzothiophene-2- sulfonamide);
N,Λ/'-(4-cyanobenzene- 1 ,2-diyl)bis(5-chloro-3 -methyl- 1 -benzothiophene-2-sulfonamide);
Methyl 3 ,4-bis { [(5 -chloro-3 -methyl- 1 -benzothiophen-2-yl)sulfonyl] amino } benzoate;
5 -chloro-3 -methyl-JV-[2-( { [3 -(methylsulfonyl)phenyl] sulfonyl} amino)phenyl] - 1 - benzothiophene-2-sulfonamide;
N,Λ/'-2,3-dihydro-l,4-benzodioxine-6,7-diylbis(5-chloro-3-methyl-l-benzothiophene-2- sulfonamide); //,^-(4-ChIoIO-S -fluorobenzene- 1 ,2-diyl)bis(5-chloro-3 -methyl- 1 -benzothiophene-2- sulfonamide);
//,^-(4-ChIoIO-S -methylbenzene-l,2-diyl)bis(5-chloro-3 -methyl- l-benzothiophene-2- sulfonamide);
Λ/,Λ/'-(4-methoxybenzene-l,2-diyl)bis(5-chloro-3 -methyl- 1-benzothiophene -2- sulfonamide);
N,Λ/'-(4-chlorobenzene-l,2-diyl)bis(5-bromo-3 -methyl- l-benzothiophene-2- sulfonamide);
N,Λ/'-(4-trifluoromethylbenzene- 1 ,2-diyl)bis(5-chloro-3 -methyl- 1 -benzothiophene-2- sulfonamide);
5 -chloro-jV-(2- { [(5 -fluoro-3 -methyl- 1 -benzothiophen-2-yl)sulfonyl]amino } phenyl)-3- methyl- 1 -benzothiophene-2-sulfonamide;
JV,iV-(4,5-dichlorobenzene- 1 ,2-diyl)bis(5 -fluoro-3 -methyl- 1 -benzothiophene-2- sulfonamide);
JV,JV-(4-chloro-5 -fluorobenzene- 1 ,2-diyl)bis(5 -fluoro-3 -methyl- l-benzothiophene-2- sulfonamide);
N,Λ/'-(4-chloro-5-methylbenzene-l,2-diyl)bis(5 -fluoro-3 -methyl- l-benzothiophene-2- sulfonamide);
5-chloro-N-(4,5-dichloro-2-{[(3,4-dichlorophenyl)sulfonyl]amino}phenyl)-3-methyl-l- benzothiophene-2-sulfonamide;
N-(4,5 -dichloro-2- { [(3 ,4-dichlorophenyl)sulfonyl]amino } phenyl)-5 -fluoro-3 -methyl- 1 - benzothiophene-2-sulfonamide;
N,Λ/'-benzene-l,2-diylbis(6-chloroimidazo[2,l-δ][l,3]thiazole-5-sulfonamide);
N,7V-thiene-3 ,4-diylbis( 1 -benzothiophene-2-sulfonamide); and
Λ/,Λ/" -thiene-3,4-diylbis(5-chloro-3 -methyl- 1 -benzothiophene-2-sulfonamide);
or a pharmaceutically acceptable salt thereof.
12. A compound of formula (II)
Figure imgf000083_0001
(H)
wherein,
Rw, Rx, Ry, and Rz are independently selected from the group consisting of a) -hydrogen;
b) -halogen;
c) -Ci_6 alkyl;
d) -Ci_6 haloalkyl;
e) -cyano;
f) -L^C1-6 alkyl; and
g) -L^C1-6 haloalkyl; R1 is selected from the group consisting of
a) -hydrogen;
b) -Ci-6 alkyl;
c) -Ci_6 haloalkyl;
d) -L2- C i_6 alkyl; and
e) -L2-Ci_6 haloalkyl;
R2, R3, R4, R5 are independently selected from the group consisting of a) -hydrogen;
b) -halogen;
c) -Ci-6 alkyl; d) -Ci_6 haloalkyl;
e) -L3- Ci_6 alkyl; and
f) -L3-Ci_6 haloalkyl; R11 is selected from the group consisting of
a) -hydrogen;
b) -Ci-6 alkyl;
c) -Ci_6 haloalkyl;
d) -L4-Ci_6 alkyl; and
e) -L4-Ci_6 haloalkyl;
R12, R13, R14, R15 are independently selected from the group consisting of
a) -hydrogen;
b) -halogen;
c) -Ci-6 alkyl;
d) -Ci-6 haloalkyl;
e) -L5-Ci_6 alkyl; and
f) -L5-Ci_6 haloalkyl;
wherein
L1, L2, L3, L4, and L5 are independently selected from the group consisting of -O-,
-C(O)-, -C(O)-O-, -S-, -S(O)-, and -SO2-; and
wherein
at least one of Rx and Ry is a group other than hydrogen;
at least one of R1 and R11 is a group other than hydrogen, and
at least one of R2, R3, R4, R5, R12, R13, R14, and R15 is a group other than
hydrogen,
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
14. A method comprising administering to a subject a compound of claim 1, so as to induce an analgesic effect in the subject.
15. The method of claim 14, wherein the subject is suffering from pain.
16. The method of claim 15, wherein the subject is suffering from neuropathic pain.
17. A method comprising administering to a subject a compound of claim 1 , so as to increase the subject's pain threshold.
18. The method of claim 17, wherein the subject is suffering from neuropathic pain.
19. The method of claim 17, wherein the subject is suffering from allodynia or hyperalgesia.
20. The method of claim 17, wherein the subject is suffering from pain associated with having cancer.
PCT/US2010/044387 2009-08-17 2010-08-04 Bis-sulfonamide derivatives, compositions, and methods of use WO2011022207A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US23449509P 2009-08-17 2009-08-17
US61/234,495 2009-08-17

Publications (1)

Publication Number Publication Date
WO2011022207A1 true WO2011022207A1 (en) 2011-02-24

Family

ID=43607280

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/044387 WO2011022207A1 (en) 2009-08-17 2010-08-04 Bis-sulfonamide derivatives, compositions, and methods of use

Country Status (1)

Country Link
WO (1) WO2011022207A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014096864A1 (en) * 2012-12-21 2014-06-26 University Of Sunderland Enzyme inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060106089A1 (en) * 2004-10-21 2006-05-18 Mjalli Adnan M Bissulfonamide compounds as agonists of GalR1, compositions, and methods of use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060106089A1 (en) * 2004-10-21 2006-05-18 Mjalli Adnan M Bissulfonamide compounds as agonists of GalR1, compositions, and methods of use

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014096864A1 (en) * 2012-12-21 2014-06-26 University Of Sunderland Enzyme inhibitors
US9856230B2 (en) 2012-12-21 2018-01-02 University Of Sunderland Enzyme inhibitors

Similar Documents

Publication Publication Date Title
KR101472248B1 (en) Treatment of duchenne muscular dystrophy
ES2835553T3 (en) Indazole Inhibitors of the Wnt Signaling Pathway and Their Therapeutic Uses
EP1711184B1 (en) (3-oxo-3,4-dihydro-quinoxalin-2-yl-amino)-benzamide derivatives and related compounds as glycogen phosphorylase inhibitors for the treatment of diabetes and obesity
EP1991544B1 (en) Substituted imidazole derivatives and their use as ptpase inhibitors
AU2019337703B2 (en) Aryl cyclopropyl-amino-isoquinolinyl amide compounds
US9855267B2 (en) Histone deacetylase inhibitors and compositions and methods of use thereof
WO2014159214A1 (en) Histone deacetylase inhibitors and compositions and methods of use thereof
US6448259B1 (en) Substituted cycloalkyl-4-oxonicotinic carboxamides; GABA brain receptor ligands
ES2640638T3 (en) Substituted phenyl-hexahydropyran [3,4-d] [1,3] thiazin-2-amine compounds
JP2023158113A (en) Aromatic derivative, preparation method for the same, and medical applications thereof
US7582673B2 (en) Bissulfonamide compounds as agonists of GalR1, compositions, and methods of use
US9650366B2 (en) Heterocycle-substituted pyridyl benzothiophenes as kinase inhibitors
WO2011022207A1 (en) Bis-sulfonamide derivatives, compositions, and methods of use
TW201726671A (en) N-[2-(3-amino-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,2,4-thiadiazin-5-yl)-1,3-thiazol-4-yl] amides
CN102807574B (en) New pyridine sulphur nitrogen seven-membered ring derivative as antitumor drug, and its preparation method and application
BRPI0717873A2 (en) 3-AMINO-PIRAZOL-4-CARBOXAMIDE DERIVATIVE AS PROTEIN KINASE INHIBITORS
BRPI0710843A2 (en) thiazolyl dihydro indazoles
KR100636515B1 (en) Novel type condensed pyridazinone compounds
US11932639B2 (en) Fused ring heteroaryl compounds as ALK4/5 inhibitors
EA023336B1 (en) 1,2,4]thiadiazine 1,1-dioxide compounds for lowering serum uric acid
JP2023547529A (en) 2-[(thiophen-2-yl)formamide]-N-(phenyl)-2-methylpropanamide derivatives and their use as pharmaceuticals
KR101459720B1 (en) Novel 5-sulfonylamino-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one compounds having inhibitory activity of serotonine 5-HT6

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10810368

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10810368

Country of ref document: EP

Kind code of ref document: A1