WO2008124518A1 - Composés de sulfonamide d'oxo-dihydroisoindole comme modulateurs de récepteur cck2 - Google Patents

Composés de sulfonamide d'oxo-dihydroisoindole comme modulateurs de récepteur cck2 Download PDF

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Publication number
WO2008124518A1
WO2008124518A1 PCT/US2008/059286 US2008059286W WO2008124518A1 WO 2008124518 A1 WO2008124518 A1 WO 2008124518A1 US 2008059286 W US2008059286 W US 2008059286W WO 2008124518 A1 WO2008124518 A1 WO 2008124518A1
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WO
WIPO (PCT)
Prior art keywords
bromo
difluoro
acid
isoindol
pharmaceutically acceptable
Prior art date
Application number
PCT/US2008/059286
Other languages
English (en)
Inventor
Brett D. Allison
Michael H. Rabinowitz
Original Assignee
Janssen Pharmaceutica N.V.
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 Janssen Pharmaceutica N.V. filed Critical Janssen Pharmaceutica N.V.
Publication of WO2008124518A1 publication Critical patent/WO2008124518A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D417/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • 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.
  • 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 "/"), 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.
  • 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.
  • Such liquid compositions may optionally contain: pharmaceuticaliy-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 gel and the like
  • non-aqueous vehicles e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water
  • Step A Methyl 4.5-dibromo-2-furoate.
  • Neat methyl 2-furoate (20.0 g, 158 mmol) was stirred as AICI 3 (45.0 g, 337 mmol) was carefully added in several portions.
  • Neat Br 2 (54.0 g, 338 mmol) was then added carefully via dropping funnel over 30 min, giving a very thick, partially solid mixture. The thick mixture was allowed to stir for 30 min after addition was complete.
  • the reaction was cooled in an ice bath as the AICI 3 was quenched by careful addition of crushed ice.
  • the resulting mixture was extracted with Et 2 ⁇ (3x). The combined organic extracts were washed with 10% aq. Na 2 S 2 ⁇ 3 , dried and concentrated to give a yellow solid.
  • Step B 4,5-Dibromo-2-furoic acid.
  • a suspension of methyl 4,5-dibromo-2- furoate (26.19 g, 92.2 mmol) in THF (60 mL) was added LiOH (3 M in water, 60 mL, 180 mmol).
  • the biphasic mixture was stirred for 4 h.
  • the reaction mixture was poured into 1 N HCI and extracted with DCM (4x). The combined organic layers were dried and concentrated to provide 24.59 g (99%) of the acid as an off-white solid.
  • 1 H NMR (CD 3 OD) 7.30 (s, 1 H).
  • Step B S-(S)-2-Methyl-propane-2-sulfinic acid 1-(f?H1-(2,4-difluoro-phenyl)- ethylj-amide.
  • Step H (R)-Benzo ⁇ ,2.51thiadiazole-4-sulfonic acid (6-bromo-2-H-(2,4-difluoro- phenyl)-ethyll-1 ,3-dioxo-2,3-dihvdro-1 H-isoindol-4-yl)-amide.

Abstract

Certains composés de sulfonamide d'oxo-dihydroisoindole de formule (I): R1 et R2 sont chacun indépendamment fluoro ou chloro; R3 est H ou méthyle; R4 est chloro ou bromo; soit X soit Y est carbonyle, l'autre étant carbonyle ou -CH2-; Il peut s'agir également d'un sel pharmaceutiquement acceptable, d'un médicament pharmaceutiquement acceptable, ou d'un métabolite pharmaceutiquement actif de ces composés, qui agissent en tant que modulateurs de récepteur CCK2 pour le traitement de maladies dont la médiation est assurée par ce type de récepteur.
PCT/US2008/059286 2007-04-03 2008-04-03 Composés de sulfonamide d'oxo-dihydroisoindole comme modulateurs de récepteur cck2 WO2008124518A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US90982007P 2007-04-03 2007-04-03
US60/909,820 2007-04-03

Publications (1)

Publication Number Publication Date
WO2008124518A1 true WO2008124518A1 (fr) 2008-10-16

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Family Applications (1)

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WO (1) WO2008124518A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9969687B2 (en) 2013-12-23 2018-05-15 Norgine B.V. Compounds useful as CCR9 modulators
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
WO2005012275A2 (fr) * 2003-03-28 2005-02-10 Janssen Pharmaceutica, N.V. Composes benzo[1,2,5]thiadiazole
WO2005016896A1 (fr) * 2003-08-08 2005-02-24 Janssen Pharmaceutica, N.V. Composes de 2- (quinoxaline-5-ylsulfonylamino) -benzamide utilises en tant que modulateur du recepteur cck2

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012275A2 (fr) * 2003-03-28 2005-02-10 Janssen Pharmaceutica, N.V. Composes benzo[1,2,5]thiadiazole
WO2005016896A1 (fr) * 2003-08-08 2005-02-24 Janssen Pharmaceutica, N.V. Composes de 2- (quinoxaline-5-ylsulfonylamino) -benzamide utilises en tant que modulateur du recepteur cck2

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ALLISON BRETT D ET AL: "Identification and Optimization of Anthranilic Sulfonamides as Novel, Selective Cholecystokinin-2 Receptor Antagonists", JOURNAL OF MEDICINAL CHEMISTRY., vol. 49, no. 21, 19 October 2006 (2006-10-19), US, AMERICAN CHEMICAL SOCIETY. WASHINGTON., pages 6371 - 6390, XP002488978 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10709714B2 (en) 2013-11-22 2020-07-14 Clifton Life Sciences LLC Gastrin antagonists for treatment and prevention of osteoporosis
US9969687B2 (en) 2013-12-23 2018-05-15 Norgine B.V. Compounds useful as CCR9 modulators

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