WO2008124524A2 - Composés de sulfonamide d'aryle comme modulateurs de récepteur cck2 - Google Patents

Composés de sulfonamide d'aryle comme modulateurs de récepteur cck2 Download PDF

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WO2008124524A2
WO2008124524A2 PCT/US2008/059292 US2008059292W WO2008124524A2 WO 2008124524 A2 WO2008124524 A2 WO 2008124524A2 US 2008059292 W US2008059292 W US 2008059292W WO 2008124524 A2 WO2008124524 A2 WO 2008124524A2
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Prior art keywords
bromo
phenyl
piperidine
methyl
carbonyl
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PCT/US2008/059292
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WO2008124524A3 (fr
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Brett D. Allison
Michael H. Rabinowitz
Mark D. Rosen
Craig R. Woods
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Janssen Pharmaceutica N.V.
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Publication of WO2008124524A3 publication Critical patent/WO2008124524A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
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    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
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    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • 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
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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 ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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 ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

  • the present invention relates to certain aryl sulfonamide compounds, pharmaceutical compositions containing them, and methods of using them for the treatment of disease states, disorders, and conditions mediated by the cholecystokinin 2 (CCK2) receptor.
  • CCK2 cholecystokinin 2
  • gastrins and cholecystokinins are structurally related neuropeptides that exist in gastrointestinal tissue, gastrinomas and, in the case of the cholecystokinins, the central nervous system (Walsh, J. H. Gastrointestinal Hormones, L. R. Johnson, ed., Raven Press, New York, 1994, p. 1 ).
  • Natural cholecystokinin is a 33 amino acid peptide (CCK-33), the C-terminal five amino acids of which are identical to those of gastrin.
  • Gastrin acts on CCK2 receptors (otherwise known as gastrin or CCK-B receptors) and cholecystokinin acts on both CCK2 and CCK1 receptors (otherwise known as cholecystokinin or CCK-A receptors).
  • Gastrin and cholecystokinin are key regulators of gastrointestinal function.
  • Gastrin is one of three primary stimulants of gastric acid secretion.
  • gastrin has a trophic effect on the gastrointestinal mucosa and is implicated as a trophic hormone of several adenocarcinomas, including pancreatic, gastric, colorectal, esophageal and small cell lung carcinomas.
  • Cholecystokinin stimulates intestinal motility, gallbladder contraction, and pancreatic enzyme secretion, inhibits gastric emptying, and is known to have trophic actions on the pancreas through increasing pancreatic enzyme production.
  • Cholecystokinin also has various effects in the central nervous system, including regulation of anxiety, satiety, and pain.
  • CCK2 receptor antagonists have undergone evaluation for the treatment of advanced pancreatic cancer or pancreatic adenocarcinoma (JB95008 (gastrazole) from the James Black Foundation and Janssen Pharmaceutica N. V.), pain (L-365,260 (Colycade) from ML Laboratories and Panos), gastro-esophageal reflux disease (GERD) (YF-476 from Yamanouchi and Ferring Research Institute), gastroduodenal ulcers and reflux esophagitis (Z-360 from Zeria Pharmaceuticals), and anxiety disorders, cancer (particularly colon cancer) and peptic ulcer (CR 2945 (itriglumide) from Rotta).
  • JB95008 gastrazole
  • Pain L-365,260 (Colycade) from ML Laboratories and Panos
  • GERD gastro-esophageal reflux disease
  • Z-360 from Zeria Pharmaceuticals
  • anxiety disorders cancer (particularly colon cancer) and peptic ulcer (CR 2945 (itriglumide) from Rotta).
  • CCK2 receptor modulators are useful for the treatment of certain cancers, gastro-intestinal disorders, anxiety, eating disorders, and pain.
  • Various aryl sulfonamides have been reported in: WO2002/087568,
  • the invention relates to a compound of the following Formula (I):
  • R 1 is one of the following moieties:
  • R a is H or methyl;
  • R is H, fluoro, chloro, or bromo; and
  • R c is fluoro, chloro, or bromo;
  • R 2 is chloro or bromo; and Ar is a phenyl, furanyl, thiophenyl, pyrazolyl, benzo[1 ,3]dioxolyl, 3,4-dihydro-2H- benzo[b][1 ,4]dioxepinyl, benzo[b]thiophenyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl, benzotriazolyl, benzo[1 ,2,5]thiadiazol-5-yl, or imidazo[2,1-b]thiazolyl group, each unsubstituted or substituted with one, two, or three R d substituents; where each R d substituent is independently selected from the group consisting of methyl, fluoro, chloro, trifluoromethyl, bromo, methoxycarbonyl, nitro, cyano, 2- methylsulfanyl-pyrimidin-4-yl, 2-methyl-thiazol
  • the invention relates to pharmaceutical compositions each comprising: (a) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; and (b) a pharmaceutically acceptable excipient.
  • the invention is directed to a method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by CCK2 receptor activity, comprising administering to the subject in need of such treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof.
  • the disease, disorder, or medical condition is selected from: cancer, gastro-intestinal disorders, anxiety, eating disorders, and pain.
  • alkyl refers to a straight- or branched-chain alkyl group having from 1 to 12 carbon atoms in the chain.
  • alkyl groups include methyl (Me, which also may be structurally depicted by the symbol, 7"), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples.
  • cycloalkyl refers to a saturated or partially saturated, monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from 3 to 12 ring atoms per carbocycle.
  • Illustrative examples of cycloalkyl groups include the following entities, in the form of properly bonded moieties:
  • heterocycloalkyl refers to a monocyclic ring structure that is saturated or partially saturated and has from 4 to 7 ring atoms per ring structure selected from carbon atoms and up to two heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the ring structure may optionally contain up to two oxo groups on sulfur ring members.
  • Illustrative entities, in the form of properly bonded moieties include:
  • heteroaryl refers to a monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle.
  • Illustrative examples of heteroaryl groups include the following entities, in the form of properly bonded moieties: ose skilled in the art will recognize that the species o cyclo heterocycloalkyl, and heteroaryl groups listed or illustrated above are not exhaustive, and that additional species within the scope of these defined terms may also be selected.
  • halogen represents chlorine, fluorine, bromine or iodine.
  • halo represents chloro, fluoro, bromo or iodo.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In cases where a specified moiety or group is not expressly noted as being optionally substituted or substituted with any specified substituent, it is understood that such a moiety or group is intended to be unsubstituted.
  • any formula given herein is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
  • compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof, are considered within the scope of the formula.
  • any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof.
  • certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers.
  • any formula given herein is intended to embrace hydrates, solvates, and polymorphs of such compounds, and mixtures thereof.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds, lsotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, 36 CI, 125 I, respectively.
  • Such isotopically labeled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or 11 C labeled compound may be particularly preferred for PET or SPECT studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the moiety for the variable appearing elsewhere.
  • the choice of the species from a specified list is independent of the choice of the species for the same variable elsewhere in the formula.
  • R 1 is R : where R a , R b , and R c are as defined in Formula (I).
  • R a is methyl.
  • R b and R G are each independently fluoro or chloro.
  • R is
  • R 2 is bromo
  • Ar is 2,4-difluorophenyl, 2,6-difluorophenyl, 2-methyl- 2H-benzotriazol-5-yl, 2-methyl-2H-benzotriazol-4-yl, 1-methyl-1 H-benzotriazol-4-yl, 2- methyl-benzothiazol-7-yl, 3H-benzoimidazol-4-yl, benzothiazol-4-yl, benzothiazol-6-yl, benzothiazol-7-yl, benzooxazol-4-yl, benzo[1 ,3]dioxol-4-yl, 6-chloro-imidazo[2,1- b]thiazol-5-yl, 2-chloro-4-thfluoromethyl-phenyl, 3-bromo-5-chloro-thiophen-2-yl, 3- methoxycarbonyl-2-methyl-furan-5-yl, 2-methoxycarbonyl-thiophen-3-yl
  • the compound of Formula (I) is selected from the group consisting of:
  • the invention includes also pharmaceutically acceptable salts of the compounds of Formula (I), preferably of those described above and of the specific compounds exemplified herein, and methods of treatment using such salts.
  • a “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented by Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S. M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley- VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
  • a compound of Formula (I) may possess a sufficiently acidic group, a sufficiently basic group, or both types of functional groups, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzo
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an inorganic acid, such as hydrochloric acid,
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other base and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.
  • Suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines, such as benzylamines, pyrrolidines, piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • the invention also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I), and treatment methods employing such pharmaceutically acceptable prodrugs.
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)).
  • a “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, covalently joined through an amide or ester bond to a free amino, hydroxy, or carboxylic acid group of a compound of Formula (I).
  • amino acid residues include the twenty naturally occurring amino acids, commonly designated by three letter symbols, as well as 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
  • amides include those derived from ammonia, primary Ci ⁇ alkyl amines and secondary di(Ci- 6 alkyl) amines. Secondary amines include 5- or 6-membered heterocycloalkyl or heteroaryl ring moieties. Examples of amides include those that are derived from ammonia, Ci ⁇ alkyl primary amines, and di(Ci- 2 alkyl)amines.
  • esters of the invention include Ci -7 alkyl, C 5-7 cycloalkyl, phenyl, and phenyl(Ci- 6 alkyl) esters.
  • Preferred esters include methyl esters.
  • Prodrugs may also be prepared by derivatizing free hydroxy groups using groups including hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, following procedures such as those outlined in Adv. Drug Delivery Rev. 1996, 19, 115. Carbamate derivatives of hydroxy and amino groups may also yield prodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters of hydroxy groups may also provide prodrugs.
  • acyloxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester, optionally substituted with one or more ether, amine, or carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, is also useful to yield prodrugs.
  • Prodrugs of this type may be prepared as described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including ether, amine, and carboxylic acid functionalities.
  • the present invention also relates to pharmaceutically active metabolites of the compounds of Formula (I), which may also be used in the methods of the invention.
  • a "pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula (I) or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini, et al., J. Med. Chem. 1997, 40, 2011-2016; Shan, et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dei/. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res.
  • the compounds of Formula (I) and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of the present invention are useful as modulators of the CCK2 receptor in the methods of the invention.
  • the compounds may act as antagonists, agonists, or inverse agonists.
  • “Modulators” include both inhibitors and activators, where “inhibitors” refer to compounds that decrease, prevent, inactivate, desensitize or down-regulate CCK2 receptor expression or activity, and “activators” are compounds that increase, activate, facilitate, sensitize, or up-regulate CCK2 receptor expression or activity.
  • treat or “treating” as used herein is intended to refer to administration of an active agent or composition of the invention to a subject for the purpose of effecting a therapeutic or prophylactic benefit through modulation of CCK2 receptor activity. Treating includes reversing, ameliorating, alleviating, inhibiting the progress of, lessening the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such disease, disorder or condition mediated through modulation of CCK2 receptor activity.
  • subject refers to a mammalian patient in need of such treatment, such as a human.
  • the invention relates to methods of using the compounds described herein to treat subjects diagnosed with or suffering from a disease, disorder, or condition mediated by CCK2 receptor activity, such as: cancer, gastro-intestinal disorders, anxiety, eating disorders, and pain. Symptoms or disease states are intended to be included within the scope of "medical conditions, disorders, or diseases.”
  • Cancer includes, for example, pancreatic cancer (such as pancreatic adenocarcinoma), esophageal cancer, gastric cancer, colorectal cancer, and colon cancer, and small cell lung carcinoma.
  • Gastro-intestinal disorders include those in which lower gastric activity or lower acid secretion is desirable. Examples of gastro- intestinal disorders include gastro-esophageal reflux disease (GERD), gastrointestinal ulcers, gastroduodenal ulcers, peptic ulcers, reflux esophagitis, Barrett's esophagus, antral G cell hyperplasia, pernicious anaemia, and Zollinger-Ellison syndrome.
  • GDD gastro-esophageal reflux disease
  • gastrointestinal ulcers gastroduodenal ulcers
  • peptic ulcers peptic ulcers
  • reflux esophagitis Barrett's esophagus
  • Barrett's esophagus antral G cell hyperplasia
  • pernicious anaemia and Zollinger-Ellison
  • the compounds of the present invention are useful in the treatment or prevention of gastro-espohageal reflux disease, pancreatic cancer, colon cancer, pain, and anxiety.
  • an effective amount of at least one compound according to the invention is administered to a subject suffering from or diagnosed as having such a disease, disorder, or condition.
  • An "effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic or prophylactic benefit in patients in need of such treatment for the designated disease, disorder, or condition.
  • Effective amounts or doses of the compounds of the present invention may be ascertained by routine methods such as modeling, dose escalation studies or clinical trials, and by taking into consideration routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder, or condition, the subject's previous or ongoing therapy, the subject's health status and response to drugs, and the judgment of the treating physician.
  • An example of a dose is in the range of from about 0.001 to about 200 mg of compound per kg of subject's body weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID, QID).
  • a suitable dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about 2.5 g/day.
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease. Patients may, however, require intermittent treatment on a long- term basis upon any recurrence of symptoms.
  • the compounds of the invention may be used in combination with additional active ingredients in the treatment of the above conditions.
  • additional active ingredients are those that are known or discovered to be effective in the treatment of conditions, disorders, or diseases mediated by CCK2 receptor activity or that are active against another target associated with the particular condition, disorder, or disease, such as CCK1 receptor modulators.
  • the combination may serve to increase efficacy (e.g., by including in the combination a compound potentiating the potency or effectiveness of a compound according to the invention), decrease one or more side effects, or decrease the required dose of the compound according to the invention.
  • a pharmaceutical composition of the invention comprises: (a) an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof; and (b) a pharmaceutically acceptable excipient.
  • a "pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a compound of the invention and that is compatible therewith.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • compositions containing one or more dosage units of the compounds of the invention may be prepared using suitable pharmaceutical excipients and compounding techniques now or later known or available to those skilled in the art.
  • the compositions may be administered in the inventive methods by oral, parenteral, rectal, topical, or ocular routes, or by inhalation.
  • the preparation may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories.
  • the compositions are formulated for intravenous infusion, topical administration, or oral administration.
  • the compounds of the invention can be provided in the form of tablets or capsules, or as a solution, emulsion, or suspension.
  • the compounds may be formulated to yield a dosage of, e.g., from about 0.05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about 0.1 to about 10 mg/kg daily.
  • Oral tablets may include a compound according to the invention mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, compounds of the invention may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the compound of the invention with water, an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • an oil such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate
  • compositions may be formulated for rectal administration as a suppository.
  • parenteral use including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the compounds of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms will be presented in unit-dose form such as ampules or disposable injection devices, in multi-dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses may range from about 1 to 1000 ⁇ g/kg/minute of compound, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • the compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • a pharmaceutical carrier for topical administration, may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the compounds of the invention may utilize a patch formulation to affect transdermal delivery.
  • Compounds of the invention may alternatively be administered in methods of this invention by inhalation, via the nasal or oral routes, e.g., in a spray formulation also containing a suitable carrier.
  • isatoic anhydrides A2 are commercially available or are prepared from commercially available anthranilic acids A1. Reaction with amines R 1 H provides benzamides A3. Alternatively, coupling of anthranilic acids A1 with amines R 1 H under peptide coupling conditions provides benzamides A3 in one step.
  • Benzamides A3 are reacted with sulfonyl chlorides ArSO 2 CI in the presence of a base, such as triethylamine or pyridine, to form compounds of Formula (I).
  • a base such as triethylamine or pyridine
  • Sulfonyl chlorides ArS ⁇ 2 CI are commercially available or are prepared using methods known in the art.
  • Compounds of Formula (I) may be converted to their corresponding salts using methods known to those skilled in the art.
  • compounds of Formula (I) may be treated with a base such as NaOH in a solvent such as methanol (MeOH) or water to provide the corresponding sodium salt forms.
  • a base such as NaOH
  • a solvent such as methanol (MeOH) or water
  • Compounds prepared according to the schemes described above may be obtained as single enantiomers, diastereomers, or regioisomers, by enantio-, diastero-, or regiospecific synthesis, or by resolution.
  • Compounds prepared according to the schemes above may alternately be obtained as racemic (1 :1 ) or non-racemic (not 1 :1) mixtures or as mixtures of diastereomers or regioisomers.
  • single enantiomers may be isolated using conventional separation methods known to one skilled in the art, such as chiral chromatography, recrystailization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation, or enzymatic transformation.
  • chiral chromatography recrystailization
  • diastereomeric salt formation a compound formed from diastereomeric adducts
  • biotransformation e.g., enzymatic transformation
  • enzymatic transformation e.g., single isomers may be separated using conventional methods such as chromatography or crystallization.
  • reaction mixtures were magnetically stirred at room temperature (rt). Where solutions were “dried,” they were generally dried over a drying agent such as Na 2 SO 4 or MgSO 4 . Where mixtures, solutions, and extracts were “concentrated”, they were typically concentrated on a rotary evaporator under reduced pressure.
  • Mass spectra were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. The calculated (calcd.) mass corresponds to the exact mass.
  • HRMS High resolution mass spectra
  • Nuclear magnetic resonance (NMR) spectra were obtained on Bruker model DRX spectrometers.
  • the format of the 1 H NMR data below is: chemical shift in ppm downfield of the tetramethylsilane reference (multiplicity, coupling constant J in Hz, integration). Rotameric broadening was observed in the spectra.
  • Example 1 2-Methyl-2H-benzotriazole-5-sulfonic acid F5-bromo-2-(piperidine-1- carbonvD-phenyll-amide.
  • Example 3 i-Methyl-I H-benzotriazole-4-sulfonic acid f5-bromo-2-(piperidine-1- carbonyP-phenyll-amide.
  • Example 4 2-Methyl-benzothiazole-7-sulfonic acid [5-bromo-2-(piperidine-1-carbonyl)- phenyli-amide.
  • the titled compound was prepared from 2-methylbenzothiazole-7-sulfonyl chloride (0.10 g, 0.35 mmol) and (2-amino-4-bromo-phenyl)-piperidin-1-yl-methanone as described in Example 1. Purification by FCC provided the titled compound as a solid (0.13 g, 75%). MS: calcd. for C 20 H 20 BrN 3 O 3 S 2 , 494.4; found, m/z 495.8 [M+Hf. 1 H
  • Example 5 3H-Benzoimidazole-4-sulfonic acid f5-bromo-2-(piperidine-1-carbonyl)- phenyli-amide.
  • Example 6 Benzothiazole-4-sulfonic acid [5-bromo-2-(piperidine-1-carbonyl)-phenyl1- amide.
  • the titled compound was prepared from benzothiazole-4-sufonyl chloride (0.12 g, 0.53 mmol) and (2-amino-4-bromo-phenyl)-piperidin-1-yl-methanone as described in Example 1. Purification by FCC provided a solid (0.12 g, 91%). MS: calcd. for C 19 H 18 BrN 3 O 3 S 2 , 480.4; found, m/z 482.0 [M+H] + .
  • Example 7 Benzothiazole-6-sulfonic acid F5-bromo-2-(piperidine-1-carbonyl)-phenyl '
  • the titled compound was prepared from benzothiazole-6-sulfonyl chloride (0.12 g, 0.53 mmol) and (2-amino-4-bromo-phenyl)-piperidin-1-yl-methanone as described in Example 1. Purification by FCC afforded a solid (0.12 g, 93%). MS: calcd. for Ci 9 Hi 8 BrN 3 O 3 S 2 , 480.4; found, m/z 482.0 [M+H] + .
  • Example 8 Benzothiazole-7 -sulfonic acid F5-bromo-2-(piperidine-1-carbonyl)-phenv ⁇ - amide.
  • the titled compound was prepared from benzothiazole-7-sulfonyl chloride (0.12 g, 0.53 mmol) and (2-amino-4-bromo-phenyl)-piperidin-1-yl-methanone as described in Example ! Purification by FCC provided a solid (0.13 g, 100%). MS: calcd. for Ci 9 Hi 8 BrN 3 O 3 S 2 , 480.4; found, m/z 482.0 [M+Hf .
  • Example 9 Benzooxazole-4-sulfonic acid [5-bromo-2-(piperidine-1-carbonyl)-phenyll- amide.
  • Step A Diethylthiocarbamic acid O-benzooxazole-4-yl ester.
  • a mixture of A- hydroxybenzooxazole (1.0 g, 7.4 mmol), ⁇ /, ⁇ /-diethylthiocarbamoyl chloride (1.34 g, 8.9 mmol), finely ground H ⁇ CO 3 (5.1 g, 38 mmol), and DMF (20 ml_) was rapidly stirred for 16 h. The mixture was partitioned between 1 M NaOH and Et 2 ⁇ , and the ethereal solution was collected, dried, and concentrated. The residue was purified by FCC to provide a tan solid (1.1 g, 59%).
  • Step B Diethylthiocarbamic acid S-benzooxazole-4-yl ester. Neat diethylthiocarbamic acid O-benzooxazole-4-yl ester (0.90 g, 3.6 mmol) was heated at 240 0 C for 1 h, then allowed to cool to rt. The crude product was isolated by FCC to give a solid (0.83 g, 92%).
  • Step C Benzooxazole-4-sulfonic acid r5-bromo-2-(piperidine-1-carbonvD- phenyll-amide.
  • a rapidly stirring mixture of diethylthiocarbamic acid S-benzooxazole-4- yl ester (0.20 g, 0.80 mmol), DCM (10 mL), formic acid (5 ml_), and H 2 O (5 ml_) was cooled to 0 0 C, and chlorine gas was bubbled through the reaction mixture for 5 min.
  • the mixture was diluted with EtOAc, washed successively with H 2 O, stad. aq. Na 2 S 2 O 3 , and satd. aq.
  • Example 10 BenzoM ,31dioxole-4-sulfonic acid f5-bromo-2-(piperidine-1-carbonyl)- phenyli-amide.
  • the titled compound was prepared from benzo[1 ,3]dioxole-4-sulfonyl chloride (0.018 g, 0.080 mmol) and (2-amino-4-bromo-phenyl)-piperidin-1-yl-methanone as described in Example 1.
  • the crude product was purified by trituration with Et 2 O to give a solid (0.0082 g, 24%).
  • Example 11 N-
  • the mixture was treated with trisamine polystyrene resin [tris-(2-aminoethyl)aminoethyl polystyrene (Aldrich), 200 mg, 0.88 mmol, 4.4 mmol/g loading], shaken for 1 h, and filtered to remove the resin.
  • the filtrate was treated with TBD-methyl polystyrene resin [1 ,5,7-triazabicyclo[4.4.0]dec-5- ene polystyrene (Nova Biochem), 325 mg, 0.88 mmol, 5 equiv., 2.7 mmol/g loading] and shaken for 1 h to sequester product.
  • the resin was collected by filtration, washing with DCM.
  • Example 12 6-Chloro-imidazof2,1-b1thiazole-5-sulfonic acid [5-bromo-2-(piperidine-1- carbonvP-phenyli-amide.
  • Example 13 N-F5-Bromo-2-(piperidine-1 -carbonyl)-phenyl1-2-chloro-4-trifluoromethyl- benzenesulfonamide.
  • Example 14 3-Bromo-5-chloro-thiophene-2-sulfonic acid f5-bromo-2-(piperidine-1- carbonvD-phenyli-amide.
  • Example 15 5-[5-Bromo-2-(piperidine-1 -carbonyl)-phenylsulfamov ⁇ -2-methyl-furan-3- carboxylic acid methyl ester.
  • Example 16 3-[5-Bromo-2-(piperidine-1-carbonyl)-phenylsulfamoyl1-thiophene-2- carboxylic acid methyl ester.
  • Example 17 N-f5-Bromo-2-(piperidine-1-carbonyl)-phenyll-4-methyl-3-nitro- benzenesulfonamide.
  • Example 18 3,4-Dihydro-2H-benzo[b1H ,41dioxepine-7-sulfonic acid f5-bromo-2- (piperidine-i-carbonyl)-phenyll-amide.
  • Example 20 5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonic acid l " 5-bromo-2- (piperidine-1-carbonvO-phenyli-amide.
  • Example 21 5-(2-Methyl-thiazol-4-vD-thiophene-2-sulfonic acid f5-bromo-2-(piperidine- i-carbonvO-phenyli-amide.
  • Example 22 5-f5-Bromo-2-(piperidine-1 -carbonyl)-phenylsulfamoyll-4-methoxy- thiophene-3-carboxylic acid methyl ester.
  • Example 24 N-F5-Bromo-2-(piperidine-1 -carbonyl)-phenv ⁇ -3-cyano- benzenesulfonamide.
  • Example 25 5-(5-Trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonic acid [5-bromo-2- (piperidine-i-carbonyl)-phenyli-amide.
  • Example 27 N-(5-f5-Bromo-2-(piperidine-1 -carbonyl)-phenylsulfamoyll-thiophen-2-ylj- benzamide.
  • Example 28 3-[5-Bromo-2-(piperidine-1 -carbonyl)-phenylsulfamoyr
  • Example 29 ⁇ -Methyl-i-phenyl-I H-pyrazole ⁇ -sulfonic acid f5-bromo-2-(piperidine-1- carbonyiy-phenyli-amide.
  • Example 30 N-r5-Bromo-2-(piperidine-1 -carbonyl)-phenyl1-3-(5-methyl- f1 ,3,41oxadiazol-2-yl)-benzenesulfonamide.
  • Example 31 N-r5-Bromo-2-(piperidin-1-ylcarbonyl)phenvn-2,4- difluorobenzenesulfonamide.
  • Example 32 4-Chloro-2-(r(2.4-difluorophenyl)sulfonyllamino>-N-ri -(A- fluorophenvDethv ⁇ benzamide.
  • Example 33 N-[5-Chloro-2-(piperidin-1-ylcarbonyl)phenyll-2,4- difluorobenzenesulfonamide.
  • Example 34 N-f5-Chloro-2-(piperidin-1-ylcarbonyl)phe ⁇ yl1-2,6- difluorobenzenesulfonamide.
  • Example 35 N-f5-Chloro-2-(morpholin-4-ylcarbonyl)phenyl1-2,6- difluorobenzenesulfonamide.
  • Example 36 N-f5-Bromo-2-(morpholin-4-ylcarbonyl)phenyl1-2,6- difluorobenzenesulfonamide.
  • Example 37 4-ChloiO-N-KI R)-1-(2,4-difluorophenvnethvn-2-ffl2.6- difluorophenyl)sulfonyl1amino>benzamide.
  • Example 38 4-Bromo-N-r(1 R)- 1 -f 2,4-difluorophenyl)ethyll-2-ff(2.6- difluorophenyl)sulfonv ⁇ amino)benzamide.
  • Example 39 4-Chloro-N-r(1 R)-1-(2,4-dichlorophenyl)ethyl1-2- ⁇ r(2,6- difluorophenvOsulfonyliaminolbenzamide.
  • Example 40 4-Bromo-N-r(1 R)-1 -(2.4-dichlorophenyl)ethvn-2-ff(2.6- difluorophenyl)sulfonvnamino)benzamide.
  • Example 41 N-[5-Chloro-2-(pyrrolidin-1-ylcarbonyl)phenyl1-2,6- difluorobenzenesulfonamide.
  • Example 42 4-Chloro-N-K4-chlorophenv ⁇ methvn-2-fK2.6- difluorophenyl)sulfonyl]amino)benzamide.
  • Example 43 4-Chloro-N-r(2,4-dichlorophenyl)methyll-2- ⁇ [(2,6- difluorophenyl)sulfonyllamino)benzamide.
  • Example 44 4-Chloro-N-f(2,4-difluorophenvnmethyl1-2- ⁇ r(2,6- difluorophenvDsulfonyliaminojbenzamide.
  • Example 45 N-[(1 R)-1-(4-Bromophenyl)ethyll-4-chloro-2-(f(2,6- difluorophenvDsulfonyliaminojbenzamide.
  • Example 46 N4(1S)-1-(4-BromophenyltethylH-chloro-2-ff(2.6- difluorophenyl)sulfonyl]amino)benzamide.
  • Example 47 4-Bromo-N-f(2.4-dichlorophenv0methyl1-2-(f(2,6- difluorophenvDsulfonyl1amino)benzamide.
  • Example 48 4-Bromo-N-r(2.4-difluorophenyl)methvn-2-(r(2.6- difluorophenyl)sulfonyl1amino ⁇ benzamide.
  • Zinc Finger Proteins specific for the CCK2R gene were identified by Sangamo Biosciences.
  • the ZFP domain was fused with the herpes simplex virus VP16 activation domain, and the fusion protein was subsequently cloned into the pcDNA3 mammalian expression vector (Invitrogen, San Diego, CA).
  • Tet-inducible cell lines expressing the coding region from the ZFP vector were created using the T-REx-293TM cell line (Invitrogen). After 2 weeks of selection in culture medium containing 400 mg/mL Zeocin (Invitrogen), sixty drug-resistant stable clones were isolated and analyzed for ZFP expression as well as CCK2R induction upon addition of doxycycline to the culture medium.
  • the cell line with the most appropriate CCK2R ZFP construct was used in all further assays and was termed the HEKZFP cell line.
  • HEKZFP cells were grown in DMEM supplemented with L-glutamine (2 mM), penicillin (50 units/mL) and streptomycin (50 ⁇ g/mL) and 10% FBS (v/v).
  • HEKZFP cells were treated with 2 mM doxycycline (Sigma-AIdrich, MO; USA) for 2 days to de-repress the tet-regulated expression of the CCK2 receptor selective zinc finger proteins and were harvested using a rubber cell scraper.
  • c) Membrane Preparation Membranes were prepared from the HEKZFP cells after induction. Frozen cell pellets (-40 0 C) were thawed in 14 ml.
  • buffer A (10 mM HEPES, 130 mM NaCI, 4.7 mM KCI, 5 mM MgCI, 1 mM EGTA and 15.4 mg/100mL bacitracin at pH 7.2), adapted from Harper, E. A. et al. (Br. J. Pharmacol. 1996, 118(7), 1717-1726).
  • the thawed pellets were homogenized using a Polytron PT-10 (7 X 1 s). The homogenates were centrifuged for 5 min at 1500 rpm (600 X g), and the resulting pellets were discarded.
  • the supematants were re-centrifuged in order to collect the receptor-membrane pellets (25 min 15,000 rpm; 39,800 X g), which were re-suspended in buffer A. d) Incubation Conditions
  • Non-specific binding of [ 125 I]-BH-CCK-8S was determined in the presence of 15 ⁇ L of 10 ⁇ M YF476, a CCK-2 receptor selective antagonist that is structurally unrelated to the radioligand [ 125 I]-BH- CCK-8S.
  • the assay preparation was incubated for 1 h at 21 ⁇ 3 0 C, and then the assay was terminated by rapid filtration of the preparation under reduced pressure.
  • the loaded filters were washed three times using undiluted PBS (100 ⁇ L), and then 100 ⁇ L of scintillation fluid was added to the filter plate. Bound radioactivity was determined using a Topcount (Packard BioScience, Meriden, CT) with a count time of 1 min.

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Abstract

Certains composés de sulfonamide d'aryle comme modulateurs de récepteur CCK2, utiles pour le traitement de maladies dont la médiation est assurée par ce type de récepteur.
PCT/US2008/059292 2007-04-03 2008-04-03 Composés de sulfonamide d'aryle comme modulateurs de récepteur cck2 WO2008124524A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010141680A2 (fr) * 2009-06-03 2010-12-09 The Board Of Trustees The Leland Stanford Junior University Antagonistes de la voie hedgehog et méthodes d'utilisation afférentes
WO2012168162A1 (fr) 2011-06-06 2012-12-13 F. Hoffmann-La Roche Ag Acide acétique de benzocylcoheptène
US10709714B2 (en) 2013-11-22 2020-07-14 Clifton Life Sciences LLC Gastrin antagonists for treatment and prevention of osteoporosis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030114499A1 (en) * 2001-06-12 2003-06-19 Joachim Brendel Anthranilamides with heteroarylsulfonyl side chain, process of preparation, and use
WO2008008374A2 (fr) * 2006-07-14 2008-01-17 Chemocentryx, Inc. Inhibiteurs de ccr2 et leurs procédés d'utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030114499A1 (en) * 2001-06-12 2003-06-19 Joachim Brendel Anthranilamides with heteroarylsulfonyl side chain, process of preparation, and use
WO2008008374A2 (fr) * 2006-07-14 2008-01-17 Chemocentryx, Inc. Inhibiteurs de ccr2 et leurs procédés d'utilisation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BRETT D. ALLISON ET AL: "Identification and Optimization of Anthranilic Sulfonamides as Novel, Selective Cholecystokinin-2 Receptor Antagonists" J. MED. CHEM., vol. 49, 2006, pages 6371-6390, XP002488484 *
ROSEN M D ET AL: "Discovery of potent cholecystokinin-2 receptor antagonists: Elucidation of key pharmacophore elements by X-ray crystallographic and NMR conformational analysis" BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 16, no. 7, 1 April 2008 (2008-04-01), pages 3917-3925, XP022593500 ISSN: 0968-0896 [retrieved on 2008-02-05] *
WOODS ET AL: "Synthesis and solid-phase purification of anthranilic sulfonamides as CCK-2 ligands" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 17, no. 24, 10 November 2007 (2007-11-10), pages 6905-6909, XP022339597 ISSN: 0960-894X *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010141680A2 (fr) * 2009-06-03 2010-12-09 The Board Of Trustees The Leland Stanford Junior University Antagonistes de la voie hedgehog et méthodes d'utilisation afférentes
WO2010141680A3 (fr) * 2009-06-03 2011-03-31 The Board Of Trustees The Leland Stanford Junior University Antagonistes de la voie hedgehog et méthodes d'utilisation afférentes
WO2012168162A1 (fr) 2011-06-06 2012-12-13 F. Hoffmann-La Roche Ag Acide acétique de benzocylcoheptène
US10709714B2 (en) 2013-11-22 2020-07-14 Clifton Life Sciences LLC Gastrin antagonists for treatment and prevention of osteoporosis

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