WO2006084835A1 - N-(3-(imidazo[1,5-a]pyrimidin-4-yl)phenyl]sulfonamides et n-[3-(imidazo[1,5-a]pyrimidin-4-yl)phenyl]carboxamides et leur utilisation en tant que modulateurs des recepteurs gabaa - Google Patents

N-(3-(imidazo[1,5-a]pyrimidin-4-yl)phenyl]sulfonamides et n-[3-(imidazo[1,5-a]pyrimidin-4-yl)phenyl]carboxamides et leur utilisation en tant que modulateurs des recepteurs gabaa Download PDF

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WO2006084835A1
WO2006084835A1 PCT/EP2006/050705 EP2006050705W WO2006084835A1 WO 2006084835 A1 WO2006084835 A1 WO 2006084835A1 EP 2006050705 W EP2006050705 W EP 2006050705W WO 2006084835 A1 WO2006084835 A1 WO 2006084835A1
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phenyl
imidazo
pyrimidin
methyl
benzoyl
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Luis Anglada
Albert Palomer
Antonio Guglietta
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Ferrer Internacional, S. A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics

Definitions

  • This invention is directed to agents with affinity for GABAA receptor, specifically to N- [3-(8-substituted-imidazo[1 ,5-a]pyrimidin-4-yl)-phenyl]-sulfonamide and N-[3-(8- substituted-imidazo[1 ,5-a]pyrimidin-4-yl)-phenyl]-carboxamide compounds.
  • GABAA receptor ( ⁇ -aminobutyric acid A ) is a pentameric protein which forms a membrane ion channel. GABAA receptor is implicated in the regulation of sedation, anxiety, muscle tone, epileptogenic activity and memory functions. These actions are due to defined subunits of GABAA receptor, particularly the ⁇ r and ⁇ 2 -subunits.
  • Sedation is modulated by the ⁇ r subunit.
  • Zolpidem is characterized by a high affinity for the oci-receptors and its sedative and hypnotic action is mediated by these receptors in vivo.
  • the hypnotic action of zaleplon is also mediated by the ⁇ r receptors.
  • the anxiolytic action of diazepam is mediated by the enhancement of GABAergic transmission in a population of neurons expressing the 0C 2 -receptors. This indicates that the 0C 2 -receptors are highly specific targets for the treatment of anxiety.
  • Muscle relaxation in diazepam is mainly mediated by acceptors, since these receptors exhibit a highly specific expression in spinal cord.
  • diazepam The anticonvulsant effect of diazepam is partly due to ⁇ r receptors.
  • diazepam a memory-impairing compound, anterograde amnesia is mediated by oci-receptors.
  • GABAA receptor and its ⁇ r and 0C 2 -subunits have been widely reviewed by H. M ⁇ hler et al.(J. Pharmacol. Exp. Then, 300, 2-8, 2002); H. M ⁇ hler et al.(Curr. Opin.
  • Diazepam and other classical benzodiazepines are extensively used as anxiolytic agents, hypnotic agents, anticonvulsants and muscle relaxants. Their side effects include anterograde amnesia, decrease in motor activity and potentiation of ethanol effects.
  • the compounds of this invention are ligands of ⁇ r and OC 2 -GABAA receptor for their clinical application in sleep disorders, preferably insomnia, anxiety and epilepsy.
  • Insomnia is a highly prevalent disease. Its chronicity affects 10% of the population and 30% when transitory insomnia is computed as well. Insomnia describes the trouble in falling asleep, staying asleep or waking up too early, experiencing a non- refreshing sleep, and is associated with next-day hangover effects such as weariness, lack of energy, low concentration and irritability. The social and health impact of this complaint is important and results in evident socioeconomic repercussions.
  • non- benzodiazepine hypnotics such as pyrrolo[3,4- ⁇ ]pyrazines (zopiclone), imidazo[1 ,2- a] pyridines (Zolpidem) and, finally, pyrazolo[1 ,5-a] pyrimidines (zaleplon).
  • pyrrolo[3,4- ⁇ ]pyrazines imidazo[1 ,2- a] pyridines
  • Zolpidem imidazo[1 ,2- a] pyridines
  • zaleplon pyrazolo[1 ,5-a] pyrimidines
  • two new pyrazolo[1 ,5-a] pyrimidines, indiplon and ocinaplon have entered into development, the latter with rather anxiolytic action. All these compounds show a rapid sleep induction and have less next-day hangover effects, lower potential for abuse and lower risk of rebound insomnia than benzodiazepines.
  • Zolpidem is disclosed in US 4382938. Some other related hypnotic imidazo[1 ,2- a]pyridines have been disclosed in FR 2593818, US 4650796 and EP 172096. In US 4626538 (zaleplon), US 4654347, US 6399621 (indiplon), EP 129847 (ocinaplon), ES 200301746 and ES 200301747 hypnotic pyrazolo[1 ,5-a]pyrimidines are disclosed.
  • the present invention is directed to new imidazo[1 ,5-a]pyrimidine compounds which are active versus GABAA and, particularly, versus its ⁇ r and ⁇ 2 -subunits. Consequently, the compounds of this invention are useful in the treatment and prevention of all those diseases mediated by GABAA receptor ⁇ r and ⁇ 2 -subunits.
  • Non-limitative examples of such diseases are sleep disorders, preferably insomnia, anxiety and epilepsy.
  • Non-limitative examples of the relevant indications of the compounds of this invention are all those diseases or conditions, such as insomnia or anesthesia, in which an induction of sleep, an induction of sedation or an induction of muscle relaxation are needed.
  • the present invention relates to novel N-[3-(8-substituted-imidazo[1 ,5- a]pyrimidin-4-yl)-phenyl]-sulfonamides and N-[3-(8-substituted-imidazo[1 ,5- a]pyrimidin-4-yl)-phenyl]-carboxamides of formula (I)
  • Ri is selected from the group consisting of alkyl(CrC 6 ), alkenyl(C 2 -C 6 ), ⁇ , ⁇ , ⁇ -trifluoroalkyl(Ci-C 6 ), cycloalkyl(C 3 -C 6 ), cycloalkyl(C3-C 6 )alkyl(Ci-C 6 ), - O-alkyl(CrC ⁇ ), -NH-alkyl(C r C 6 ), -N(dialkyl(C r C 6 )), alkyl(C r C 6 )-O-alkyl(Ci- C 6 ), alkyl(Ci-C 6 )-NH-alkyl(Ci-C 6 ), alkyl(Ci-C 6 )-N(dialkyl(Ci-C 6 )), phenyl, monosubstituted phenyl, disubstituted phenyl, phenylalkyl(CrC 6
  • n is an integer 1 , 2 or 3 inclusive;
  • R 3 is selected from the group consisting of hydrogen, halogen, alkyl(CrC 6 ), cycloa Iky I (C 3 -C 6 ), alkenyl(C 2 -C 6 ), alkynyl(C 2 -C 6 ), -O-alkyl(C r C 6 ), halo- alkyl(CrC 6 ), -CN, -NO 2 , -SO 2 -R 4 , -SO-R 4 , -SO 2 -NH-R 4 , -SO 2 -NR 4 R 5 , -SO 2 -
  • R 4 and R 5 are independently selected from the group consisting of alkyl(d-
  • R 6 is selected from the group consisting of hydrogen, alkyl(CrC 6 ), alkenyl(C 2 -
  • R 7 is selected from the group consisting of alkyl(CrC 6 ), cycloalkyl(C 3 -C 6 ), -
  • R 8 is selected from the group consisting of hydrogen, alkyl(CrC 6 ), cycloa Iky I (C 3 -C 6 ), aryl and substituted or unsubstituted heteroaryl.
  • X can be a carbonyl or a sulfonyl group.
  • novel compounds can be prepared following the reaction sequence in scheme 1.
  • R 1 , R 2 and R 3 are as described above and Q is an appropriate leaving group consisting of N(dialkyl(C r C 6 )), alkylthio(C r C 6 ) and alkoxy(C r C 6 ).
  • Q is selected from the group consisting of dimethylamino, methylthio or methoxy.
  • reaction of aminoimidazole of general formula (III) with appropriately substituted 1-aryl-2-propen-1-one (II) is carried out in an inert polar protic or aprotic solvent such as glacial acetic acid, ethanol, methanol, dimethylformamide or dimethylsulfoxide at a temperature ranging from 50° to 13O 0 C. After elapsing several hours (reaction time), the solvent is removed and the residue obtained is partitioned between an aqueous solution of sodium bicarbonate and dichloromethane.
  • an inert polar protic or aprotic solvent such as glacial acetic acid, ethanol, methanol, dimethylformamide or dimethylsulfoxide
  • the crude resulting from evaporating the organic layer to dryness may be purified by one of the following methods: (a) silica gel chromatography using ethyl acetate or dichloromethane /methanol as eluent; or (b) crystallization in a suitable solvent (ethyl acetate, ethanol, methanol, etc.).
  • sulfonamides of formula (IV), wherein X is a sulfonyl group are prepared according to the method described by R. H. Uloth et al (J. Med. Chem. 9, 88- 96, 1966).
  • the enaminones of formula (Vl), wherein X is a sulfonyl group, are prepared according to general synthetic procedures of enamines described by J. M. Domagala et al (J. Heterocyclic Chem., 26(4), 1147-58, 1989); and K. Sawada et al (Chem. Pharm. Bull., 49(7), 799-813, 2001 ) by reacting an acetophenone with N,N-dimethylformamide dimethylacetal (DMFDMA) or Bredereck's reagent (tert-butoxybis(dimethylamino) methane).
  • DMFDMA N,N-dimethylformamide dimethylacetal
  • Bredereck's reagent tert-butoxybis(dimethylamino) methane
  • the carboxamides of formula (Vl), wherein X is a carbonyl group and Q is dimethylamino, are obtained by reaction between the corresponding acetophenone and ⁇ /, ⁇ /-dimethylformamide dimethylacetal or Bredereck's reagent (tert-butoxybis(dimethylamino)methane) as described by J. M. Domagala et al (J. Heterocyclic Chem., 26(4), 1147-58, 1989); and K. Sawada et al (Chem. Pharm. Bull., 49(7), 799-813, 2001 ).
  • the 5-carbonitrile of formula X can be converted to an 5-aryl or heteroaryl carbonyl-3/-/-imidazol-4-yl-amine by reaction with an appropriate Grignard reagent prepared from an aryl or heteroaryl bromide compound.
  • the pharmacological activity of the compounds of the present invention has been determined as shown below.
  • Ligand-binding assays Determination of the affinity of test compounds for OLI- and ⁇ 2 - GABA A receptor. Male Sprague-Dawley rats weighing 200-250 g at the time of experiment were used. After decapitation of the animal, the cerebellum (tissue that mostly contains oci-GABA A receptor) and spinal cord (tissue that mostly contains ⁇ 2 - GABA A receptor) were removed. The membranes were prepared according to the method by J. Lameh et al.(Prog. Neuro-Psychopharmacol. Biol.
  • Centrifugation speed was 1000 g and the supernatant was centrifuged at 20000 g and resuspended twice more under the same conditions describe above for cerebellum. On the next day, the process was repeated until the final pellet was resuspended at a ratio of 1 :10 (v/v) in the case of cerebellum and at a ratio of 1 :5 (v/v) in the case of spinal cord.
  • Affinity was determined by competitive tests using radiolabeled flumazenil as ligand. The tests were performed according to the methods described by S. Arbilla et al. (Eur. J. Pharmacol., 130, 257-263, 1986); and Y. Wu et al. (Eur. J. Pharmacol., 278, 125-132, 1995) using 96-well microtiter plates. The membranes containing the study receptors, flumazenil (radiolabeling at a final concentration of 1 nM) and ascending concentrations of test compounds (in a total volume of 230 ⁇ l in 50 mM [ph 7.4] Tris-HCI buffer) were incubated.
  • the membranes were only incubated with the radiolabeled flumazenil (total binding, 100%) and in the presence of an elevated concentration of unradiolabeled flumazenil (non-specific binding, % estimation of radiolabeled ligand).
  • the reactions started on adding the radiolabeled ligand followed by incubation for 60 minutes at 4 0 C.
  • 200 ⁇ l of reaction were transferred to a multiscreen plate (Millipore) and filtered using a vacuum manifold and then washed three times with cold test buffer.
  • the multiscreen plates were equipped with a GF/B filter that retained the membranes containing the receptors and the radiolabeled ligand which had been bound to the receptors. After washing, the plates were left till dry. Once dried, scintillation liquid was added and left under stirring overnight. The next day the plates were counted using a Perkin- Elmer Microbeta scintillation counter.
  • X amount of bound ligand for every concentration of compound.
  • T total binding, maximum amount bound to the radiolabeled ligand.
  • N non-specific binding, amount of radiolabeled ligand bound in a nonspecific way irrespective of the receptor used.
  • mice The in vivo effects of these compounds were assessed by a predictive sedation-hypnosis test in mice (D. J. Sanger et al., Eur. J. Pharmacol., 313, 35-42, 1996; and G. Griebel et al., Psychopharmacology, 146, 205-213, 1999).
  • mice Groups of 5-8 male CD1 mice, weighing 22-26 g at the time of test, were used.
  • the test compounds were administered in single equimolecular intraperitoneal doses, suspended in 0.25% agar with one drop of Tween in a volume of 10 ml/kg. Control animals received the vehicle alone.
  • a Smart System Panlab, S. L., Spain
  • the traveled distance in cm is recorded for each mouse at 5-min intervals during a period of 30 minutes after dosing.
  • Example 5 N-[3-(8-cyano-imidazo[1 ,5-a]pyrimidin-4-yl)-phenyl]-N-ethyl- methanesulfonamide
  • 0.036 g (0.34 mmol) of 5-amino-1 H-imidazole- 4-carbonitrile and 0.1 g (0.34 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2- propenyl]phenyl]-N-ethyl-methanesulfonamide were reacted under reflux and the crude obtained was chromatographied (silica gel) using ethyl acetate as eluent to produce 71 mg (yield 62%) of N-[3-(8-cyano-imidazo[1 ,5- a]pyrimidin-4-yl)-phenyl]-N-ethyl-methanesulfonamide.
  • Example 1 0.040 g (0.37 mmol) of 5-amino-1 H-imidazole- 4-carbonitrile and 0.1 g (0.37 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2- propenyl]phenyl]-N-prop-2-ynyl-acetamide were reacted under reflux and the crude obtained was chromatographied (silica gel) using ethyl acetate as eluent to produce 58 mg (yield 50%) of N-[3-(8-cyano-imidazo[1 ,5- a]pyrimidin-4-yl)-phenyl]-N-prop-2-ynyl-acetamide.
  • Example 10 General procedure for the preparation of benzoyl-imidazo[1 ,5- a]pyrimidines of general formula (I) following Scheme 1 N-[3-(8-benzoyl-imidazo[1 ,5-a]pyrimidin-4-yl)-phenyl]-N-methyl- methanesulfonamide
  • Part A A solution of phenylmagnesium bromide was prepared from 1.0 g ( 42 mmol) of magnesium and 6.6 g (42 mmol) of bromobenzene in 40 ml of dry tetrahydrofuran.
  • Part B 0.1 g (0.53 mmol) of (5-amino-1 H-imidazol-4-yl)-phenyl-methanone and 0.15 g (0.53 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl- methanesulfonamide were dissolved in 10 ml of glacial acetic acid. After refluxing for 4 hours, the solvent was removed by reduced pressure distillation. To the resultant residue 10 ml of dichloromethane and 10 ml of a saturated solution of sodium bicarbonate were added. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane.
  • Example 19 General procedure for the preparation of (thiophene-2- carbonyl)-imidazo[1 ,5-a]pyrimidines of general formula (I) following Scheme 1. N-[3-[8-(thiophene-2-carbonyl)-imidazo[1 ,5-a]pyrimidin-4-yl]-phenyl]-N- methyl-methanesulfonamide
  • Part A A solution of thiophen-2-yl magnesium bromide was prepared from 1.0 g ( 42 mmol) of magnesium and 6.94 g (42 mmol) of 2-bromo-thiophene in 40 ml of dry tetrahydrofuran.
  • Example 27 N-[3-[8-(thiophene-2-carbonyl)-imidazo[1 ,5-a] pyrimidin-4-yl]- phenyl]-N-prop-2-ynyl-acetamide
  • 0.045 g (0.24 mmol) of (5-amino-1 H- imidazol-4-yl)-thiophen-2-yl-methanone and 0.064 g (0.24 mmol) of N-[3-[3- (dimethylamino)-1-oxo-2-propenyl]phenyl]-N-prop-2-ynyl-acetamide were reacted under reflux and the crude obtained was chromatographied (silica gel) using dichloromethane-methanol as eluent to produce 20 mg (yield 21%) of N-[3-[8-(thiophene-2-carbonyl)-imidazo [1 ,5-a]pyrimidin-4-yl
  • Example 28 General procedure for the preparation of 4-methyl-benzoyl- imidazo[1 ,5-a]pyrimidines of general formula (I) following Scheme 1 N-[3-[8-(4-methyl-benzoyl)-imidazo[1 ,5-a]pyrimidin-4-yl]-phenyl]-N-methyl- methanesulfonamide
  • a solution of 4-methyl-phenyl magnesium bromide was prepared from 1.0 g ( 42 mmol) of magnesium and 7.2 g (42 mmol) of 1 -bromo-4-methyl-benzene in 40 ml of dry tetrahydrofuran.
  • a mixture of 1 g (9.3 mmol)of 5-amino-1 H-imidazole-4-carbonitrile and 20 ml of dry tetrahydrofuran was slowly added with stirring. After standing at room temperature for 2 hours, the mixture was cooled and decomposed by adding, with stirring, 40 ml of 3M hydrochloric acid.
  • Part B 0.075 g (0.35 mmol) of (5-amino-1 H-imidazol-4-yl)-p-tolyl-methanone and 0.1 g (0.35 mmol) of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl- methanesulfonamide were dissolved in 10 ml of glacial acetic acid. After refluxing for 4 hours, the solvent was removed by reduced pressure distillation. To the resultant residue 10 ml of dichloromethane and 10 ml of a saturated solution of sodium bicarbonate were added.
  • Example 32 N-[3-[8-(4-methyl-benzoyl)-imidazo[1 ,5-a] pyrimidin-4-yl]- phenyl]-N-ethyl-methanesulfonamide
  • 0.071 g (0.34 mmol) of (5-amino-1 H- imidazol-4-yl)-p-tolyl-methanone and 0.1 g (0.34 mmol) of N-[3-[3- (dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-methanesulfonamide were reacted under reflux and the crude obtained was chromatographied (silica gel) using ethyl acetate as eluent to produce 62 mg (yield 42%) of N-[3-[8-(4- methyl-benzoyl)-imidazo[1 ,5-a]pyrimidin-4-y
  • Example 37 General procedure for the preparation of 4-methoxy-benzoyl- imidazo[1 ,5-a]pyrimidines of general formula (I) following Scheme 1.
  • Example 38 N-[3-[8-(4-methoxy-benzoyl)-imidazo[1 ,5-a] pyrimidin-4-yl]- phenyl]-N-methyl-ethanesulfonamide
  • Example 40 N-[3-[8-(4-methoxy-benzoyl)-imidazo[1 ,5-a] pyrimidin-4-yl]- phenyl]-N-prop-2-ynyl-ethanesulfonamide
  • Example 46 General procedure for the preparation of 4-fluoro-benzoyl- imidazo[1 ,5-a]pyrimidines of general formula (I) following Scheme 1. N-[3-[8-(4-fluoro-benzoyl)-imidazo[1 ,5-a]pyrimidin-4-yl]-phenyl]-N-methyl- methanesulfonamide Part A A solution of 4-fluoro-phenyl magnesium bromide was prepared from 1.0 g ( 42 mmol) of magnesium and 7.9 g (42 mmol) of 1-bromo-4-fluoro-benzene in 40 ml of dry tetrahydrofuran.
  • Example 46 0.069 g (0.34 mmol) of (5-amino-1 H- imidazol-4-yl)-(4-fluoro-phenyl)-methanone and 0.1 g (0.34 mmol) of N-[3-[3- (dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl-ethanesulfonamide were reacted under reflux and the crude obtained was chromatographied (silica gel) using ethyl acetate as eluent to produce 67 mg (yield 45%) of N-[3-[8-(4- fluoro-benzoyl)-imidazo[1 ,5-a]pyrimidin-4-yl]-phenyl]-N-methyl- ethanesulfonamide.
  • Example 48 N-[3-[8-(4-fluoro-benzoyl)-imidazo[1 ,5-a] pyrimidin-4-yl]-phenyl]- N-ethyl-methanesulfonamide
  • Example 46 0.066 g (0.32 mmol) of (5-amino-1 H- imidazol-4-yl)-(4-fluoro-phenyl)-methanone and 0.1 g (0.32 mmol) of N-[3-[3- (dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-ethanesulfonamide were reacted under reflux and the crude obtained was chromatographied (silica gel) using ethyl acetate as eluent to produce 30 mg (yield 21%) of N-[3-[8-(4- fluoro-benzoyl)-imidazo[1 ,5-a]pyrimidin-4-yl]-phenyl]-N-ethyl- ethanesulfonamide.
  • Example 46 0.079 g (0.38 mmol) of (5-amino-1 H- imidazol-4-yl)-(4-fluoro-phenyl)-methanone and 0.1 g (0.38 mmol) of N-[3-[3- (dimethylamino)-i -oxo-2-propenyl]phenyl]-N-ethyl-acetamide were reacted under reflux and the crude obtained was chromatographied (silica gel) using ethyl acetate as eluent to produce 34 mg (yield 22%) of N-[3-[8-(4-fluoro- benzoyl)-imidazo[1 ,5-a]pyrimidin-4-yl]-phenyl]-N-ethyl-acetamide.
  • Example 54 N-[3-[8-(4-fluoro-benzoyl)-imidazo[1 ,5-a] pyrimidin-4-yl]-phenyl]- N-prop-2-ynyl-ethanesulfonamide
  • Example 46 0.064 g (0.31 mmol) of (5-amino-1 H- imidazol-4-yl)-(4-fluoro-phenyl)-methanone and 0.1 g (0.31 mmol) of N-[3-[3- (dimethylamino)-1-oxo-2-propenyl]phenyl]-N-prop-2-ynyl-ethanesulfonamide were reacted under reflux and the crude obtained was chromatographied (silica gel) using ethyl acetate as eluent to produce 108 mg (yield 75%) of N- [3-[8-(4-fluoro-benzoyl)-imidazo[1 ,5-a]pyrimidin-4-yl]-phenyl]-N-prop-2-ynyl- ethanesulfonamide.

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Abstract

La présente invention concerne des composés répondant à la formule (I), dans laquelle R1, R2, R3 et X sont conformes à la définition indiquée dans les revendications. Les composés ont une affinité spécifique pour le récepteur GABAA et sont donc utiles dans le traitement et la prévention des maladies modulées par les récepteurs GABAA 1 et 2.
PCT/EP2006/050705 2005-02-10 2006-02-06 N-(3-(imidazo[1,5-a]pyrimidin-4-yl)phenyl]sulfonamides et n-[3-(imidazo[1,5-a]pyrimidin-4-yl)phenyl]carboxamides et leur utilisation en tant que modulateurs des recepteurs gabaa WO2006084835A1 (fr)

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JP2019510794A (ja) * 2016-04-06 2019-04-18 リソソーマル・セラピューティクス・インコーポレイテッドＬｙｓｏｓｏｍａｌ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． イミダゾ［１，５−ａ］ピリミジニルカルボキサミド化合物および医学的障害の処置におけるその使用

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