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HK1152038B - Azetidine derivatives, their preparation and their application in therapy - Google Patents

Azetidine derivatives, their preparation and their application in therapy Download PDF

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Publication number
HK1152038B
HK1152038B HK11106128.9A HK11106128A HK1152038B HK 1152038 B HK1152038 B HK 1152038B HK 11106128 A HK11106128 A HK 11106128A HK 1152038 B HK1152038 B HK 1152038B
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HK
Hong Kong
Prior art keywords
methyl
azetidin
bis
methanesulfonylamino
chlorophenyl
Prior art date
Application number
HK11106128.9A
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Chinese (zh)
Other versions
HK1152038A1 (en
Inventor
Jean-François SABUCO
Original Assignee
赛诺菲-安万特
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
Priority claimed from FR0708830A external-priority patent/FR2925051B1/en
Priority claimed from FR0802492A external-priority patent/FR2930941B1/en
Application filed by 赛诺菲-安万特 filed Critical 赛诺菲-安万特
Priority claimed from PCT/FR2008/001748 external-priority patent/WO2009106708A2/en
Publication of HK1152038A1 publication Critical patent/HK1152038A1/en
Publication of HK1152038B publication Critical patent/HK1152038B/en

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Description

Azetidine derivatives, their preparation and their use in therapy
The present invention relates to azetidine derivatives, to their preparation and to their therapeutic use in the treatment or prevention of diseases in which the cannabinoid CB1 receptor is involved.
The invention relates to compounds corresponding to formula (I)
Wherein:
r is (C)1-C6) Alkyl or halo (C)1-C6) An alkyl group;
r' is a NR4R5 OR8 group;
a and B, if they are present, are each independently of the other 1 or 2 carbon atoms which are substituted by 1 or more hydrogens or (C)1-C6) Alkyl substitution; the(C1-C6) Alkyl is optionally substituted with 1 or more of the following groups: hydroxy (C)1-C6) Alkoxy, halo (C)1-C6) Alkyl radical (C)1-C6) An alkyl S (O) p, NR4R5 or CONR4R5 group;
a + B is at most two carbons;
r1 is hydrogen atom or (C)1-C6) An alkyl group;
r2 and R3 are each independently a hydrogen atom or (C)1-C6) An alkyl group; the (C)1-C6) Alkyl is optionally substituted with 1 or more of the following groups: hydroxy (C)1-C6) Alkoxy, halo (C)1-C6) Alkyl radical (C)1-C6) An alkyl S (O) p, NR4R5 or CONR4R5 group;
r4 and R5 are each independently a hydrogen atom or (C)1-C6) Alkyl, or together with the nitrogen atom bearing them, form the following heterocycle: azetidine, pyrrolidine, piperidine, azepane, piperazine, homopiperazine, morpholine, thiomorpholine S-oxide or thiomorpholine S-dioxide, optionally substituted by (C)1-C6) Alkyl substitution;
r6 and R7 are each phenyl, optionally substituted with 1 or more atoms or groups selected from: a hydrogen atom, a halogen atom, and (C)1-C6) Alkyl, halo (C)1-C6) Alkyl radical (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy or cyano;
y is a hydrogen atom, halogen, or (C)1-C6) Alkyl, halo (C)1-C6) Alkyl radical (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy group, (C)1-C6) Alkyl S (O) p or cyano;
r8 is hydrogen atom, (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, allyl or phenyl (C)1-C6) Alkyl, the phenyl group being optionally substituted by 1 or 2O-methyl groups;
p is an integer selected from 0, 1 or 2;
the compounds are in the form of bases or of addition salts with acids or with bases.
The compounds of formula (I) may contain one or more asymmetric carbon atoms. They may thus exist in enantiomeric or diastereomeric forms. These enantiomers and diastereomers, as well as mixtures thereof, including racemic mixtures, also form part of the invention.
In the compounds of formula (I) which are the subject of the present invention, a first group of compounds comprises the following compounds,
wherein:
r' is NR4R5 OR OR 8;
r is methyl;
a and B, if they are present, are each independently of the other-CH2-；
R1 is a hydrogen atom;
r2 and R3 are each independently a hydrogen atom or (C)1-C6) An alkyl group; the (C)1-C6) Alkyl optionally substituted with hydroxy;
r4 and R5 are each independently of the other a hydrogen atom or a methyl group, or together with the nitrogen atom which carries them form morpholine;
r6 and R7 are each phenyl, optionally substituted at the para position with 1 or more atoms or groups selected from: halogen, and (C)1-C6) Alkyl, halo (C)1-C6) Alkyl radical (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy or cyano;
r8 is hydrogen atom or (C)1-C6) An alkyl group;
y is hydrogen, halogen, (C)1-C6) An alkoxy group;(C1-C6) An alkyl group; a cyano group; or halo (C)1-C6) An alkyl group;
the compounds are in the form of enantiomers or diastereomers or as mixtures of these forms;
the compounds are in the form of bases or of addition salts with acids or with bases.
In the compounds of formula (I) which are the subject of the present invention, a second group of compounds comprises the following compounds,
wherein:
r' is NR4R5 OR OR 8;
r is methyl;
a and B, if they are present, are each independently of the other-CH2-；
R1 is a hydrogen atom;
r2 and R3 are each independently a hydrogen atom or (C)1-C6) An alkyl group; the (C)1-C6) Alkyl optionally substituted with hydroxy;
r4 and R5 are each independently of the other a hydrogen atom or a methyl group, or together with the nitrogen atom which carries them form morpholine;
r6 and R7 are each in the para position bound by a chlorine, fluorine or bromine atom or Me, OMe, CN, CF3Or OCF3Phenyl substituted with a group;
r8 is hydrogen atom or (C)1-C6) An alkyl group;
y is hydrogen, halogen, (C)1-C6) An alkoxy group; (C)1-C6) An alkyl group; a cyano group; or halo (C)1-C6) An alkyl group;
the compounds are in the form of enantiomers or diastereomers or as mixtures of these forms;
the compounds are in the form of bases or of addition salts with acids or with bases.
Among the compounds of formula (I) which are the subject of the present invention, the third group of compounds comprises the following compounds,
wherein:
r' is NR4R5 OR OR 8;
r is methyl;
a and B, if they are present, are each independently of the other-CH2-；
R1 is a hydrogen atom;
r2 and R3 are each independently a hydrogen atom or (C)1-C6) An alkyl group; the (C)1-C6) Alkyl optionally substituted with hydroxy;
r4 and R5 are each independently of the other a hydrogen atom or a methyl group, or together with the nitrogen atom which carries them form morpholine,
r6 and R7 are each phenyl, optionally substituted at the para position with 1 or more atoms or groups selected from: halogen, and (C)1-C6) Alkyl, halo (C)1-C6) Alkyl radical (C)1-C6) Alkoxy, halo (C)1-C6) Alkoxy or cyano;
r8 is hydrogen atom or (C)1-C6) An alkyl group;
y is a hydrogen, chlorine, fluorine or bromine atom or Me, OMe, CN or CF3A group;
the compounds are in the form of enantiomers or diastereomers or as mixtures of these forms;
the compounds are in the form of bases or of addition salts with acids or with bases.
In the compounds of formula (I) which are the subject of the present invention, the fourth group of compounds comprises the following compounds, in which:
r' is NR4R5 OR OR 8;
r is methyl;
a and B, if they are present, are each independently of the other-CH2-；
R1 is a hydrogen atom;
r2 and R3 are each independently a hydrogen atom or (C)1-C6) An alkyl group; the (C)1-C6) Alkyl optionally substituted with hydroxy;
r4 and R5 are each independently of the other a hydrogen atom or a methyl group or together with the nitrogen atom bearing them form morpholine;
r6 and R7 are each in the para position bound by a chlorine, fluorine or bromine atom or Me, OMe, CN, CF3Or OCF3Phenyl substituted with a group;
r8 is hydrogen atom or (C)1-C6) An alkyl group;
y is a hydrogen, chlorine, fluorine or bromine atom or Me, OMe, CN or CF3The radical(s) is (are),
the compounds are in the form of enantiomers or diastereomers or as mixtures of these forms;
the compounds are in the form of bases or of addition salts with acids or with bases.
Within the scope of the invention:
the term "halogen" means: fluorine, chlorine, bromine or iodine;
term "(C)1-C6) Alkyl "means: a cyclic, branched or straight chain saturated aliphatic group, which may be optionally substituted with a cyclic alkyl group. As examples, there may be mentioned methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl and the like groups;
the term "halo (C)1-C6) Alkyl "means: as defined above (C)1-C6) An alkyl group, one or more hydrogen atoms of which are substituted by halogen atoms. AsBy way of example, mention may be made of CF3，CH2CF3，CHF2Or CCl3A group;
term "(C)1-C6) Alkoxy "means: -O- (C)1-C6) Alkyl group of which (C)1-C6) Alkyl is as defined above;
the term "halo (C)1-C6) Alkoxy "means: halo (C)1-C6) alkyl-O-group, wherein the halo (C)1-C6) Alkyl is as defined above;
the term "allyl" refers to CH2-CH ═ CH 2.
The compounds of formula (I) may be present in the form of a base or an acid or a salt. These addition salts form part of the present invention.
These salts may be prepared using pharmaceutically acceptable acids, but salts of other acids useful, for example, in the purification or isolation of compounds of formula (I) also form part of the invention.
The compounds of formula (I) may also exist in the form of hydrates or solvates, i.e. in combination or association with one or more water molecules or solvents. Such hydrates and solvates also form part of the present invention.
Among the compounds of formula (I) which are the subject of the present invention, the following compounds may be mentioned in particular; the nomenclature used corresponds to the IUPAC nomenclature.
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N-carbamoylmethyl-5-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((R) -1-carbamoylethyl) -5-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((R) -1-carbamoylethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- (2-carbamoylethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- (2-morpholin-4-yl-2-oxoethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-3-methylbutyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -5-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) -5-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- (methylcarbamoylmethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- (carbamoylmethyl) benzamide
(S) -tert-butyl 2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) benzoylamino ] propanoate
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) benzoylamino ] propanoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) benzoylamino acetic acid tert-butyl ester
4- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoylamino ] butanoic acid tert-butyl ester
(S) -tert-butyl 2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoylamino ] propionate
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-methoxybenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-dimethylcarbamoylethyl) benzamide
4- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) benzoylamino ] butyric acid tert-butyl ester
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoylamino ] propanoic acid and its sodium salt
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluoro-N- ((S) -1-methylcarbamoylethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((1S, 2R) -1-carbamoyl-2-hydroxypropyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- (3-carbamoylpropyl) -5-fluorobenzamide
[3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) benzoylamino ] acetic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -2-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -2-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -6-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -6-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -6-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -6-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -4-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N-carbamoylmethyl-5-methylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-methylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-methylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -5-methylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -5-methylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) -5-methylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-chlorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-chlorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -5-chlorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -5-chlorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) -5-chlorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-bromobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-bromobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -5-bromobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -5-bromobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) -5-bromobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N-carbamoylmethyl-5-trifluoromethylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-trifluoromethylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-trifluoromethylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -5-trifluoromethylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -5-trifluoromethylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) -5-trifluoromethylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-cyanobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-cyanobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -5-cyanobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -5-cyanobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) -5-cyanobenzamide
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -6-fluorobenzoylamino ] propionic acid and its trifluoroacetate salt
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-methylbenzoylamino ] propionic acid and its trifluoroacetate salt
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-chlorobenzoylamino ] propanoic acid and its trifluoroacetate salt
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-bromobenzoylamino ] propionic acid and its trifluoroacetate salt
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -3-trifluoromethylbenzoylamino ] propionic acid and its trifluoroacetate salt
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-cyanobenzoylamino ] propionic acid and its trifluoroacetate salt
3- ({1- [ bis (4-bromophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide
3- ({1- [ bis (4-trifluoromethylphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide
3- ({1- [ bis (4-cyanophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide
3- ({1- [ bis (4-methoxyphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide
3- ({1- [ bis (4-fluorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide
(S) -methyl 2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoylamino ] propanoate
3- ({1- [ bis (4-methylphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-fluorobenzamide
3- ({1- [ bis (4-bromophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -5-fluorobenzamide
(S) -2- [3- ({1- [ bis (4-bromophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoylamino ] propanoic acid
(S) -ethyl 2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoylamino ] propionate
3- ({1- [ bis (4-trifluoromethoxyphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-fluorobenzamide
Optical isomers thereof and pharmaceutically acceptable salts thereof.
A subject of the invention is also the use of a compound of formula (I) according to the invention for the preparation of a medicament for the treatment or prevention of diseases in which the CB1 receptor is involved.
A subject of the present invention is also the use of a compound of formula (I) according to the invention for the preparation of a medicament for the treatment or prevention of the following diseases: psychiatric disorders, substance dependence and withdrawal (withdry), tobacco withdrawal, cognitive and attention disorders and acute and chronic neurodegenerative disorders; metabolic, desire (appetence) disorders, appetite disorders, obesity, diabetes (type I and/or type II), metabolic syndrome, dyslipidemia, sleep apnea; pain, neuropathic pain, anticancer drug-induced neuropathic pain; gastrointestinal disorders, emesis, ulcers, diarrheal disorders, bladder and urinary disorders, disorders of endocrine origin (disorders of endocrine origin), cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, liver disease, chronic cirrhosis, fibrosis, nonalcoholic steatohepatitis (NASH), steatohepatitis (steatohepatitis) and hepatic steatosis (hepatosteatosis), regardless of the etiology of these conditions (alcohol, drugs, chemical products, autoimmune diseases, obesity, diabetes, congenital metabolic diseases); immune system diseases, rheumatoid arthritis, demyelination, multiple sclerosis, inflammatory diseases; alzheimer's disease, parkinson's disease, schizophrenia, cognitive disorders associated with diabetes, cognitive disorders associated with obesity or cognitive disorders associated with metabolic syndrome; asthma, chronic obstructive pulmonary disease, Raynaud's syndrome, glaucoma, fertility disorders; infectious and viral diseases such as encephalitis, stroke, Guillain-barre syndrome, osteoporosis and sleep apnea, and drugs for anticancer chemotherapy; diseases associated with antipsychotic treatment (weight gain, metabolic disorders).
According to the present invention, the compounds of general formula (I) can be prepared according to the method described in scheme 1:
scheme 1
The mesylation of compounds 1 to 2 can be carried out according to methods known to the person skilled in the art or as described in t.w. green, Protective Group in Organic Synthesis, third edition. The reaction can be carried out in a chlorinated solvent such as dichloromethane, in the presence of a base such as pyridine and in the presence of a mesylated derivative such as methanesulfonyl chloride at a temperature of-10 ℃ to 40 ℃.
Derivative 1 is commercially available or synthesized from suitable commercially available precursors according to methods known to those skilled in the art; r' is a group R8 except for a hydrogen atom.
Derivative 4 can be obtained by reacting mesylate (mesylate)2 with azetidine 3. This step is preferably carried out under an inert atmosphere in an inert solvent such as 4-methyl-2-pentanone in the presence of an inorganic base such as potassium carbonate under reflux of the reaction mixture.
The synthesis of azetidine 3 is described in patent application WO 01064634.
The hydrolysis of the ester 4 to the acid 5 is carried out according to methods known to the person skilled in the art and more particularly in a mixture of a polar solvent such as tetrahydrofuran and water in the presence of a base such as lithium hydroxide hydrate at a temperature of around 20 ℃.
The formation of the compound of formula (I) can be carried out according to pathway a by reaction of acid 5 and amino derivative 6. The reaction may be carried out in an inert solvent such as tetrahydrofuran or a chlorinated solvent (e.g. dichloromethane), in the presence or absence of a base such as a trialkylamine (e.g. triethylamine) and a coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, in the presence or absence of an additive such as 1-hydroxybenzotriazole for preventing any racemisation, and in the presence or absence of a reagent for facilitating peptide synthesis by formation of a mixed anhydride such as isobutyl chloroformate, at a temperature from-20 ℃ to the boiling point of the solvent. The reaction can also be carried out in an inert solvent in the presence of a coupling agent and optionally an additive for preventing racemization, the isolated product optionally being converted into an addition salt with an acid.
Derivatives 6 are commercially available or synthesized from suitable commercially available precursors according to methods known to those skilled in the art.
The formation of the compound of formula 8 can proceed according to pathway B by reaction of acid 5 and amino derivative 7. This reaction can be carried out according to the conditions described above for obtaining the compound of formula (I) from acid 5 and amino derivative 6.
Derivatives 7 are commercially available or synthesized from suitable commercially available precursors according to methods known to those skilled in the art.
The hydrolysis of the ester 8 to the acid 9 is carried out according to methods known to the person skilled in the art.
The formation of the compound of formula (I) may be carried out by a reaction between an acid 9 and an amine 10. This reaction can be carried out according to the conditions described above for obtaining the compound of formula (I) from acid 5 and amino derivative 6.
Derivatives 10 are commercially available or synthesized from suitable commercially available precursors according to methods known to those skilled in the art.
Compounds of formula (I) may be converted to other compounds of formula (I) by altering the CHR6R7 group by debenzmethylation using methods known to those skilled in the art, followed by alkylation with a CHXR6R7 group in the presence of a base, X being a leaving group (e.g. halogen).
The compounds of formula (I) can be purified by generally known methods, such as crystallization, chromatography or extraction.
Enantiomers of compounds of formula (I) can be obtained by resolution of the racemic mixture, for example by chromatography on a chiral column according to W.H. PIRKLE et al, Asymmetric Synthesis, Vol.1, Academic Press (1983) or by salt formation or by Synthesis from chiral precursors. The diastereoisomers may be prepared according to generally known methods (crystallization, chromatography, or from chiral precursors).
The invention also relates to a method for preparing the intermediate.
According to another aspect, one subject of the invention is also the compounds of formulae 4 and 5. These compounds are useful as intermediates in the synthesis of compounds of formula (I).
Intermediates used in the synthesis of compounds of formula (I) are shown below in a non-limiting manner:
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid methyl ester
3- ({1- [ bis (4-fluorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid methyl ester
3- ({1- [ bis (4-fluorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-bromophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid ethyl ester
3- ({1- [ bis (4-bromophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-trifluoromethylphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid ethyl ester
3- ({1- [ bis (4-trifluoromethylphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-methoxyphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid ethyl ester
3- ({1- [ bis (4-methoxyphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-methylphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid methyl ester
3- ({1- [ bis (4-methylphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-cyanophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid ethyl ester
3- ({1- [ bis (4-cyanophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-trifluoromethoxyphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid methyl ester
3- ({1- [ bis (4-trifluoromethoxyphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -2-fluorobenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -2-fluorobenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -4-fluorobenzoic acid ethyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -4-fluorobenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -6-fluorobenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -6-fluorobenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-methoxybenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-methoxybenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-methylbenzoic acid allyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-methylbenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-chlorobenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-chlorobenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-bromobenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-bromobenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-trifluoromethylbenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-trifluoromethylbenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-cyanobenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-cyanobenzoic acid.
The compounds of formulae 4 and 5 are prepared in the form of a powder or oil, in the form of a base. Table 1A gives some physicochemical data for these intermediates.
TABLE 1A
The following examples describe the preparation of some compounds according to the invention. These examples are not intended to be limiting but merely to illustrate the invention. The numbering of the compounds listed refers to those given in the table below, which illustrate the chemical structure and physical properties of some of the compounds according to the invention.
Example 1: 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) benzamide (Compound No. 1)
67mg of 1-hydroxybenzotriazole, 0.4cm3Triethylamine and 228mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added continuously to 500mg of 3- [ {1- [ bis (4-chlorophenyl) methyl ] carbodiimide hydrochloride]Azetidin-3-yl } (methylsulfonyl) amino]Benzoic acid and 150mg L-alaninamide hydrochloride at 20cm3In tetrahydrofuran solution. The reaction mixture was stirred at a temperature around 20 ℃ overnight. After concentration of the reaction medium to dryness under reduced pressure, the resulting pale yellow-white powder is dissolved in dichloromethane. The organic phase was washed with water. After separation by standing, the aqueous phase was extracted with dichloromethane.The crude reaction product obtained after concentrating the organic phase to dryness under reduced pressure is purified by flash chromatography on a Merck 30g silica column (elution gradient: 100/0 to 95/5 dichloromethane/methanol). After concentration of the fractions under reduced pressure, a white powder was obtained, which was washed with diethyl ether and dried in vacuo. Thus, 430mg of 3- ({1- [ bis (4-chlorophenyl) methyl ] methyl-was obtained as a white solid]Azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) benzamide.
Mp.：229℃
1H NMR Spectrum(300 MHz; (delta, ppm); (DMSO-d 6); (reference 2.50 ppm): 1.34(d, J ═ 7.1Hz, 3H); 2.71(t, J ═ 6.8Hz, 2H); 2.97(s, 3H); 3.26-3.38(m partial mask, 2H); 4.38(s, 1H); 4.42(m, 1H); 4.73 (quintuple, J ═ 6.8Hz, 1H); 6.98 (width s, 1H); 7.31(d, J ═ 8.5Hz, 4H); 7.36(d, J ═ 8.5Hz, 4H); 7.39 (width s, 1H); 7.44-7.54(m, 2H); 7.80 (width s, 1H); 7.89(m, 1H); 8.50(d, J ═ 7.4Hz, 1H)
Mass spectrometry：ES m/z＝575(MH+Base peak), m/z 235 (C)13H9Cl2 +)，m/z＝573(MH-)
Elemental analysis：
Calculated values: c: 56.35% -H: 4.90% -N: 9.73% -S: 5.57 percent
Measurement values: c: 56.72% -H: 4.99% -N: 9.50% -S: 5.65 percent
Optical rotation：αD＝+10.3+/-0.6(c＝0.428，MeOH)
Example 2: 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -N-carbamoylmethyl-5-fluorobenzamide (Compound No. 2)
2a: 3-fluoro-5-methanesulfonylaminobenzoic acid ethyl esterEsters
2.65cm in length3Pyridine was added to 4g of ethyl 5-amino-3-fluorobenzoate stirred under argon at 100cm3In dichloromethane. The reaction medium is cooled to a temperature of about 0 ℃ by means of an ice bath and then added dropwise to 1.78cm3Methanesulfonyl chloride at 2cm3Solution in dichloromethane. The resulting orange solution was brought back to a temperature around 20 ℃ and stirred at this temperature for 20 hours. Adding 40cm of the mixture3Distilled water and 50cm3After dichloromethane is separated by standing, the organic phase is continued over 35cm3Distilled water and 40cm3Washed with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered through sintered glass and then concentrated to dryness under reduced pressure to give 5.8g of an orange solid. The crude reaction product was purified by flash chromatography on a Merck 400g silica column (particle size: 15-40 μm; eluent: 98/2 dichloromethane/methanol). After concentrating the fractions under reduced pressure, 5.09g of ethyl 3-fluoro-5-methanesulfonylaminobenzoate were obtained as a white solid.
Mass spectrometry：EI m/z＝261(M+.Base peak), M/z 233[ (M-C)2H4)+.]，m/z＝216[(M-OC2H5)+]，m/z＝182[(M-SO2CH3)+]，m/z＝138[(m/z＝182-OC2H4)+]
2b: 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid ethyl ester
3.97g of potassium carbonate was added to 3.7g of 1- [ bis (4-chlorophenyl) methyl group]Azetidin-3-yl methanesulfonate and 3.5g ethyl 3-fluoro-5-methanesulfonylaminobenzoate at 130cm34-methyl-2-pentanone. The reaction medium is stirred at reflux for 7 hours and then brought back to a temperature of around 20 ℃ for 16 hours. 50cm in length3Distilled water and 100cm3Ethyl acetate was added to the resulting milky suspension. After stirring for 30 minutes, the aqueous phase was separated by standing and the volume of the aqueous phase was 100cm3Extraction with ethyl acetateTwice. The combined organic phases took 80cm3The saturated aqueous sodium chloride solution was washed, dried over sodium sulfate, filtered through sintered glass and then concentrated to dryness under reduced pressure to give 7.2g of an orange residue. The crude reaction product was purified by flash chromatography on a Merck 400g silica column (particle size: 15-40 μm; elution gradient: 98/2 to 95/5 dichloromethane/methanol). After concentrating the fractions under reduced pressure, 4.03g of 3- ({1- [ bis (4-chlorophenyl) methyl ] methyl-1 are obtained in the form of a white foam]Azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid ethyl ester.
1H NMR Spectrum(400 MHz; (delta, ppm); (DMSO-d 6); (reference 2.50 ppm): 1.32J ═ 7.2Hz, 3H); 2.73(t, J ═ 7.3Hz, 2H); 2.98(s, 3H); 3.35(m, 2H); 4.34(q, J ═ 7.2Hz, 2H); 4.43(s, 1H); 4.77(m, 1H); 7.31(d, J ═ 8.8Hz, 4H); 7.37(d, J ═ 8.8Hz, 4H); 7.56(dt, J ═ 9.8; 2.4Hz, 1H); 7.66 (width d, J ═ 9.1Hz, 1H); 7.70 (Width s, 1H)
Mass spectrometry：ES m/z＝551(MH+)，m/z＝235(C13H9Cl2 +.Radical peak)
2c: 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
To a solution of 2.5g of 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid ethyl ester contained 34cm3Tetrahydrofuran and 9cm30.222g of lithium hydroxide was added in two portions to the solution in the water mixture, and the mixture was stirred under an argon atmosphere. The reaction medium is stirred for 24 hours at a temperature of about 20 ℃. Then 100cm of the solution was added3Saturated aqueous sodium hydrogen phosphate to bring the pH to 5. The aqueous phase was used for 200cm3Extracted four times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered through sintered glass and then concentrated to dryness under reduced pressure to give a foam which was used for 150cm3The ether was absorbed twice. After concentration under reduced pressure, 2.3g of 3- ({1- [ bis (4-chlorophenyl) methyl ] methyl-was obtained as a white solid]Azetidin-3-yl } methanesulfonylamino) -5-fluorobenzeneFormic acid.
1H NMR Spectrum(400 MHz; (delta, ppm); (DMSO-d 6); (reference 2.50 ppm): 2.74(t, J ═ 6.9Hz, 2H); 2.98(s, 3H); 3.33(m masked, 2H); 4.43(s, 1H); 4.76 (quintuple, J ═ 6.9Hz, 1H); 7.31(d, J ═ 8.8Hz, 4H); 7.36(d, J ═ 8.8Hz, 4H); 7.51(dt, J ═ 9.4; 2.0Hz, 1H); 7.64(dt, J ═ 8.9; 2.0Hz, 1H); 7.70(t, J ═ 2.0Hz, 1H); 13.25 (very wide m, 1H)
Mass spectrometry：ES m/z＝523(MH+)，m/z＝235(C13H9Cl2 +.Radical peak)
2d: 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -N-carbamoylmethyl-5-fluorobenzamide (Compound No. 2)
0.115cm3Isobutyl chloroformate was added to 0.4g of 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid and 0.245cm3Triethylamine at 5cm3In tetrahydrofuran solution. Precipitation occurred and the reaction medium was stirred for 30 minutes at a temperature of around 20 ℃ and then 0.101g glycinamide and 1cm were added in a single step3Tetrahydrofuran. The resulting white suspension was stirred at a temperature around 20 ℃ for 20 hours. The reaction medium is filtered through sintered glass, using 50cm3And (5) rinsing with tetrahydrofuran. The filtrate was concentrated to dryness in vacuo to give 0.55g of a yellow foam which was purified by flash chromatography on a Merck 70g silica column (particle size: 15-40 μm; eluent: 98/2 dichloromethane/methanol). After concentration of the fractions under reduced pressure, a foam is obtained, which is taken up in diethyl ether, filtered and then dried under vacuum at a temperature of around 50 ℃. The solid thus obtained took 20cm3The pentane was absorbed and left in pentane overnight. After filtration, the product was dried under vacuum. 0.222g of 3- ({1- [ bis (4-chlorophenyl) methyl-l-phenyl) is then obtained in the form of a pale yellow solid]Azetidin-3-yl } methanesulfonylamino) -N-carbamoylmethyl-5-fluorobenzamide.
Mp.：154-156℃
1H NMR Spectrum(400 MHz; (delta, ppm); (DMSO-d 6); (reference 2.50 ppm): 2.73(t, J ═ 7.0Hz, 2H); 3.00(s, 3H); 3.36(m, 2H); 3.81(d, J ═ 5.9Hz, 2H); 4.40(s, 1H); 4.72(m, 1H); 7.04 (width s, 1H); 7.31(d, J ═ 8.8Hz, 4H); 7.35(d, J ═ 8.8Hz, 4H); 7.37-7.47(m, 2H); 7.60-7.73(m, 2H); 8.84(t, J ═ 5.9Hz, 1H)
Mass spectrometry：ES m/z＝579(MH+Base peak), m/z 235 (C)13H9Cl2 +.)
Elemental analysis：
Calculated values: c: 53.89% -H: 4.35% -N: 9.67% -S: 5.53 percent
Measurement values: c: 53.88% -H: 4.71% -N: 9.16% -S: 5.66 percent
Example 3: 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide (Compound No. 3)
Mixing 0.1cm3Isobutyl chloroformate was added to 0.35g of 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid and 0.214cm3Triethylamine at 5cm3In tetrahydrofuran solution. The reaction medium is stirred for 1 hour 10 minutes at a temperature of about 20 ℃ and then 0.113g L-alaninamide hydrochloride and 2cm are added in one portion3Tetrahydrofuran. The resulting white suspension was stirred at a temperature around 20 ℃ for 48 hours. The reaction medium is filtered through sintered glass and rinsed with tetrahydrofuran. The filtrate was concentrated to dryness in vacuo to give 0.5g of a white foam which was purified by flash chromatography on a Merck 70g silica column (particle size: 15-40 μm; eluent: 97/3 dichloromethane/methanol). After concentration of the fractions under reduced pressure, a foam is obtained which is taken up in diethyl ether, filtered, thenThen dried under vacuum at a temperature of about 50c to give 0.307g of a white solid. The solid was recrystallized from an ethanol/water mixture under hot conditions and dried under vacuum at a temperature around 45 ℃. Thus 0.213g of 3- ({1- [ bis (4-chlorophenyl) methyl ] methyl-3- ({1- [ bis (4-chlorophenyl) methyl ] is obtained in the form of a white solid]Azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide.
Mp.：228-230℃
1H NMR Spectrum(400 MHz; (delta, ppm); (DMSO-d 6); (reference 2.50 ppm): 1.33(d, J ═ 7.3Hz, 3H); 2.73(t, J ═ 6.8Hz, 2H); 3.00(s, 3H); 3.24-3.43(m partial mask, 2H); 4.34-4.48(m, 2H); 4.72 (quintuple, J ═ 6.8Hz, 1H); 6.99 (width s, 1H); 7.31(d, J ═ 8.5Hz, 4H); 7.37(d, J ═ 8.5Hz, 4H); 7.39-7.45(m, 2H); 7.67 (width s, 1H); 7.74 (width d, J ═ 8.8Hz, 1H); 8.61(d, J ═ 7.3Hz, 1H)
Mass spectrometry：ES m/z＝593(MH+Base peak), m/z 637 (MH)-+HCO2H)，m/z＝591(MH-Radical peak)
Elemental analysis：
Calculated values: c: 54.64% -H: 4.59% -N: 9.44% -S: 5.40 percent
Measurement values: c: 54.09% -H: 4.66% -N: 9.34% -S: 5.43% -H2O：1.71％
Optical rotation：αD＝+11.3+/-0.7(c＝0.365，MeOH)
Example 4: 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -N- ((R) -1-carbamoylethyl) -5-fluorobenzamide (Compound No. 4)
Mixing 0.1cm3Isobutyl chloroformate was added to 0.35g of 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl methanesulfonateAcylamino) -5-fluorobenzoic acid and 0.216cm3Triethylamine at 7cm3In tetrahydrofuran solution. Precipitation occurred. The reaction medium is stirred for 1 hour and 25 minutes at a temperature of about 20 ℃ and then 0.108g D-alaninamide hydrochloride and 2cm are added in one portion3Tetrahydrofuran. The resulting white suspension was stirred at a temperature in the region of 20 ℃ for 24 hours. The reaction medium is filtered through sintered glass and rinsed with tetrahydrofuran. The filtrate was concentrated to dryness in vacuo to give 0.5g of a white foam which was purified by flash chromatography on a Merck 70g silica column (particle size: 15-40 μm; eluent: 97/3 dichloromethane/methanol). After concentration of the fractions under reduced pressure, a foam is obtained, which is taken up in diethyl ether, filtered and then dried under vacuum at a temperature of around 50 ℃ to give a solid. The solid was recrystallized from an ethanol/water mixture under hot conditions and dried under vacuum at a temperature around 45 ℃. Thus 0.095g of 3- ({1- [ bis (4-chlorophenyl) methyl ] methyl-was obtained as a white solid]Azetidin-3-yl } methanesulfonylamino) -N- ((R) -1-carbamoylethyl) -5-fluorobenzamide.
Mp.：219-221℃
1H NMR Spectrum(400 MHz; (delta, ppm); (DMSO-d 6); (reference 2.50 ppm): 1.33(d, J ═ 6.8Hz, 3H); 2.73(t, J ═ 7.1Hz, 2H); 3.00(s, 3H); 3.35(m, 2H); 4.35-4.45(m, 2H); 4.73 (quintuple, J ═ 6.8Hz, 1H); 6.99 (width s, 1H); 7.31(d, J ═ 8.8Hz, 4H); 7.37(d, J ═ 8.8Hz, 4H); 7.39-7.45(m, 2H); 7.68(t, J ═ 1.7Hz, 1H); 7.74(dt, J ═ 9.0; 1.7Hz, 1H); 8.62(d, J ═ 7.8Hz, 1H)
Mass spectrometry：ES m/z＝593(MH+Base peak), m/z 235 (C)13H9Cl2 +.)
Elemental analysis：
Calculated values: c: 54.64% -H: 4.59% -N: 9.44% -S: 5.40 percent
Measurement values: c: 54.44% -H: 4.54% -N:9.48％-S：5.36％-H2O＜0.1％
optical rotation：αD＝-23.3+/-0.7(c＝0.476，DMSO)
Example 5: 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -N- ((R) -1-carbamoylethyl) benzamide (Compound No. 5)
67mg of 1-hydroxybenzotriazole, 0.4cm3Triethylamine and 228mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added continuously to 500mg of 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylaminobenzoic acid and 150mg D-alaninamide hydrochloride at 20cm3In tetrahydrofuran solution. The reaction mixture was stirred at a temperature around 20 ℃ overnight. After concentration of the reaction medium to dryness under reduced pressure, the resulting pale yellow-white powder is dissolved with dichloromethane. The organic phase was washed with water. After separation by standing, the aqueous phase was extracted with dichloromethane. The crude reaction product obtained after concentrating the organic phase to dryness under reduced pressure is purified by flash chromatography on a Merck 30g silica column (elution gradient: 100/0 to 95/5 dichloromethane/methanol). After concentration of the fractions under reduced pressure, the product is obtained, which is washed with diethyl ether and dried in vacuo. Thus 220mg of 3- ({1- [ bis (4-chlorophenyl) methyl ] methyl-salt was obtained in the form of white crystals]Azetidin-3-yl } methanesulfonylamino) -N- ((R) -1-carbamoylethyl) benzamide.
Mp.：235℃
1H NMR Spectrum(300 MHz; (delta, ppm); (DMSO-d 6); (reference 2.50 ppm): 1.34(d, J ═ 7.3Hz, 3H); 2.71(t, J ═ 6.8Hz, 2H); 2.97(s, 3H); 3.32 (width m, 2H); 4.38(s, 1H); 4.42(m, 1H); 4.74 (quintuple, J ═ 6.8Hz, 1H); 6.98 (width s, 1H); 7.31(d, J ═ 8.8Hz, 4H); 7.36(d, J ═ 8.8Hz, 4H); 7.39 (width s, 1H); 7.45-7.54(m, 2H); 7.80 (width s, 1H); 7.88(m, 1H); 8.50(d, J ═ 7.6Hz, 1H)
Mass spectrometry：ES m/z＝575(MH+Base peak), m/z 235 (C)13H9Cl2 +.)
Elemental analysis：
Calculated values: c: 56.35% -H: 4.90% -N: 9.73% -S: 5.57 percent
Measurement values: c: 56.84% -H: 5.17% -N: 9.56% -S: 5.51 percent
Optical rotation：αD＝-6.6+/-0.5(c＝0.493，DMSO)
Example 6: 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) benzamide (Compound No. 6)
0.114cm3Isobutyl chloroformate was added to 0.4g of 3- ({1- [ bis (4-chlorophenyl) methyl ] methyl ester stirred at a temperature of-10 to-15 deg.C]Azetidin-3-yl } methanesulfonylamino) benzoic acid and 0.253cm3Triethylamine at 5cm3In tetrahydrofuran solution. Precipitation occurred. The reaction medium is stirred for 1 hour 15 minutes at a temperature below 0 ℃ and then 0.166g L-sersamine hydrochloride and 3cm are added3Tetrahydrofuran while maintaining the temperature of the reaction medium between-10 and-15 ℃. The resulting white suspension was stirred overnight at a temperature around 20 ℃. The reaction medium is cooled again and maintained at a temperature of-10 ℃ to-15 ℃, then: 22. mu.l triethylamine, 21. mu.l isobutyl chloroformate and 22.2mg L-serine amide hydrochloride in 2cm3Solution in tetrahydrofuran. After stirring for 3 hours at a temperature of around 20 ℃, the reaction medium is filtered through sintered glass and rinsed with dichloromethane. The filtrate was concentrated to dryness under reduced pressure to give 0.726g of a white foam which was purified by flash chromatography on a Merck 70g silica column (particle size: 15-40 μm; elution gradient: 99/1 to 98/2 ethyl acetate/methanol). After concentration of the fractions under reduced pressure, a white residue was obtained,it has an absorption of 35cm3In ether, filtered and then dried under vacuum at a temperature of around 40 ℃. 6cm for this operation3The ether was repeated once more. Thus 0.21g of 3- ({1- [ bis (4-chlorophenyl) methyl ] methyl-3- ({1- [ bis (4-chlorophenyl) methyl ] is obtained in the form of a white solid]Azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) benzamide.
Mp.：245-247℃
1H NMR Spectrum(400 MHz; (delta, ppm); (DMSO-d 6); (reference 2.50 ppm): 2.71(t, J ═ 6.9Hz, 2H); 2.97(s, 3H); 3.33(m masked, 2H); 3.71(m, 2H); 4.38(s, 1H); 4.44(m, 1H); 4.75 (quintuple, J ═ 6.9Hz, 1H); 4.93 (width t, J ═ 5.9Hz, 1H); 7.10 (width s, 1H); 7.31(d, J ═ 8.8Hz, 4H); 7.36(d, J ═ 8.8Hz, 4H); 7.41 (width s, 1H); 7.45-7.55(m, 2H); 7.81 (width s, 1H); 7.88(m, 1H); 8.30(d, J ═ 7.8Hz, 1H)
Mass spectrometry：ES m/z＝591(MH+Base peak), m/z 235 (C)13H9Cl2 +.)
Elemental analysis
Calculated values: c: 54.83% -H: 4.77% -N: 9.47% -S: 5.42 percent
Measurement values: c: 53.60% -H: 5.04% -N: 9.00% -S: 4.90% -H2O＝1.45％
Optical rotation：αD＝+30.9+/-0.8(c＝0.412，DMSO)
Example 7: 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -N- (2-carbamoylethyl) benzamide (Compound No. 7)
Will be 0.142cm3Isobutyl chloroformate was added to 0.5g of 3- ({1- [ bis (4-chlorophenyl) methyl ] methyl ester stirred at a temperature of-10 to-20 deg.C]Azetidin-3-yl methanesulfonateAcylamino) benzoic acid and 0.317cm3Triethylamine at 6cm3In tetrahydrofuran solution. Precipitation occurred. The reaction medium is stirred for 2 hours at a temperature below 0 ℃ and then 0.184g of beta-alaninamide hydrochloride and 2cm are added3Tetrahydrofuran while maintaining the temperature of the reaction medium between-10 and-20 ℃. The resulting white suspension was stirred at a temperature of about 20 ℃ for 3 hours. The reaction medium is cooled again and maintained at a temperature of-10 ℃ to-20 ℃, then: 27.5. mu.l triethylamine, 25.8. mu.l isobutyl chloroformate and 24.6mg beta-alaninamide hydrochloride at 2cm3Solution in tetrahydrofuran. After stirring for 15 hours at a temperature of around 20 ℃, the reaction medium is filtered through sintered glass and rinsed with dichloromethane. The filtrate was concentrated to dryness under reduced pressure to give 1g of a white foam which was purified by flash chromatography on a Merck 70g silica column (particle size: 15-40 μm; eluent: 98/2 ethyl acetate/methanol). After concentration of the fractions under reduced pressure, a white residue is obtained which absorbs at 35cm3In ether, filtered and then dried under vacuum at a temperature of around 40 ℃. Thus 0.429g of 3- ({1- [ bis (4-chlorophenyl) methyl ] methyl-was obtained as a white solid]Azetidin-3-yl } methanesulfonylamino) -N- (2-carbamoylethyl) benzamide.
Mp.：190-192℃
1H NMR Spectrum(400 MHz; (delta, ppm); (DMSO-d 6); (reference 2.50 ppm): 2.35(t, J ═ 7.1Hz, 2H); 2.69(t, J ═ 6.9Hz, 2H); 2.95(s, 3H); 3.34(t, J ═ 6.9Hz, 2H); 3.44(m, 2H); 4.37(s, 1H); 4.73 (quintuple, J ═ 6.9Hz, 1H); 6.81 (width s, 1H); 7.31(d, J ═ 8.8Hz, 4H); 7.35 (s-masked, 1H); 7.36(d, J ═ 8.8Hz, 4H); 7.41-7.52(m, 2H); 7.74 (width s, 1H); 7.80(m, 1H); 8.58(t, J ═ 5.6Hz, 1H)
Mass spectrometry：ES m/z＝575(MH+Base peak), m/z 235 (C)13H9Cl2 +.)
Elemental analysis：
Calculated values: c: 56.35% -H: 4.90% -N: 9.73% -S: 5.57 percent
Measurement values: c: 56.36% -H: 5.10% -N: 9.46% -S: 5.29% -H2O＝0.34％
Example 8: 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -N- (2-morpholin-4-yl-2-oxoethyl) benzamide (Compound No. 8)
67mg of 1-hydroxybenzotriazole, 0.14cm3Triethylamine and 270mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added successively to 500mg of 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino]Benzoic acid and 215mg of 2-amino-1-morpholin-4-ylethanone hydrochloride at 15cm3In tetrahydrofuran solution. The reaction mixture was stirred at a temperature of about 20 ℃ overnight. After concentration of the reaction medium to dryness under reduced pressure, the residue obtained is taken up in dichloromethane. The organic phase was washed with water, dried and concentrated to dryness under reduced pressure to give the crude reaction product which was purified by flash chromatography on a Merck 30g silica column (elution gradient: 100/0 to 95/5 dichloromethane/methanol). After concentration of the fractions under reduced pressure, a white foam was obtained which crystallized upon trituration with diethyl ether. After filtration and drying with a vane pump, 470mg of 3- ({1- [ bis (4-chlorophenyl) methyl ] p-toluenesulfonate were obtained in the form of white crystals]Azetidin-3-yl } methanesulfonylamino) -N- (2-morpholin-4-yl-2-oxoethyl) benzamide.
Mp.：176℃
1H NMR Spectrum(400 MHz; (delta, ppm); (DMSO-d 6); (reference 2.50 ppm): 2.71(t, J ═ 6.9Hz, 2H); 2.97(s, 3H); 3.34(t, J ═ 6.9Hz, 2H); 3.48(m, 4H); 3.58(m, 4H); 4.13(d, J ═ 5.5Hz, 2H); 4.37(s, 1H); 4.74 (quintuple, J ═ 6.9Hz, 1H); 7.31(d, J ═ 8.8Hz, 4H); 7.35(d, J ═ 8.8Hz, 4H); 7.47-7.55(m, 2H); 7.78 (width s, 1H); 7.85(m, 1H); 8.66(t, J ═ 5.5Hz, 1H)
Mass spectrometry：ES m/z＝631(MH+Base peak), m/z 235 (C)13H9Cl2 +.)
Elemental analysis：
Calculated values: c: 57.05% -H: 5.11% -N: 8.87% -S: 5.08 percent
Measurement values: c: 57.29% -H: 4.96% -N: 8.29% -S: 4.93 percent
Example 9: 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) benzamide (Compound No. 9)
Route A
0.113cm3Isobutyl chloroformate was added to 0.4g of 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) benzoic acid and 0.256cm3Triethylamine at 4cm3In tetrahydrofuran, under an inert atmosphere at a temperature of-10 to-20 ℃. Precipitation occurred. The reaction medium is stirred for 1 hour at a temperature below 0 ℃ and then 0.143g L-alanine methylamide hydrochloride and 2cm are added3Tetrahydrofuran while maintaining the temperature of the reaction medium between-10 and-20 ℃. The resulting white suspension was stirred at a temperature around 20 ℃ for 18 hours. The reaction medium is cooled again and maintained at a temperature of-10 ℃ to-20 ℃, then: 22. mu.l triethylamine, 20.6. mu.l isobutyl chloroformate and 22mg L-alanine methyl amide hydrochloride in 2cm3Solution in tetrahydrofuran. After stirring for 24 hours at a temperature in the region of 20 ℃, the reaction medium is filtered through sintered glass and rinsed with dichloromethane. The filtrate was concentrated to dryness under reduced pressure to give 0.684g of a white foam which was purified by flash chromatography on a Merck 70g silica column (particle size: 15-40 μm; eluent: 98/2 ethyl acetate/methanol). After concentration of the fractions under reduced pressure, a white residue was obtained which was obtained from anhydrousRecrystallization from an ethanol/water mixture. The resulting solid was filtered through sintered glass and dried under vacuum at a temperature in the region of 40 ℃. Thus 0.128g of 3- ({1- [ bis (4-chlorophenyl) methyl-) -methyl was obtained as a white solid]Azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) benzamide.
Mp.：171-173℃
1H NMR Spectrum(400 MHz; (delta, ppm); (DMSO-d 6); (reference 2.50 ppm): 1.32(d, J ═ 7.0Hz, 3H); 2.59(d, J ═ 4.9Hz, 3H); 2.71(t, J ═ 7.6Hz, 2H); 2.97(s, 3H); 3.33(t, J ═ 7.6Hz partial mask, 2H); 4.38(s, 1H); 4.44(m, 1H); 4.74(m, 1H); 7.31(d, J ═ 8.5Hz, 4H); 7.35(d, J ═ 8.5Hz, 4H); 7.44-7.52(m, 2H); 7.80(s, 1H); 7.83-7.91(m, 2H); 8.59(d, J ═ 7.8Hz, 1H)
Mass spectrometry：ES m/z＝589(MH+Radical peak)
Elemental analysis：
Calculated values: c: 57.05% -H: 5.13% -N: 9.50% -S: 5.44 percent
Measurement values: c: 55.49% -H: 5.50% -N: 9.14% -S: 5.10% -H2O＝2.57％
Optical rotation：αD＝+25.4+/-0.7(c＝0.427，DMSO)
Route B
Pathway B-a: (S) -tert-butyl 2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonyl-amino) benzoylamino ] propanoate
0.345cm3Triethylamine was added to 0.5g of 3- ({1- [ bis (4-chlorophenyl) methyl]Azetidin-3-yl } methanesulfonylamino) benzoic acid at 9cm3Stirring the solution in anhydrous tetrahydrofuran at a temperature of about-50 ℃ under an inert atmosphere. The reaction medium is stirred for 5 minutes and then 0.140cm is added at the same temperature3Isobutyl chloroformate. After stirring at about-50 ℃ for 1 hour, 0.270g of (S) -tert-butyl 2-aminopropionate hydrochloride and 6cm of3Tetrahydrofuran. The reaction medium is stirred for 10 minutes at a temperature of about-50 ℃ and then brought back to a temperature of about 20 ℃. After stirring for 3 hours, the medium is cooled to a temperature of-20 ℃ to-30 ℃ over a period of 10cm3Water was hydrolyzed and then stirred at a temperature of about 20c for 15 minutes. The aqueous phase was used for 25cm3Extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered through sintered glass and concentrated to dryness under reduced pressure to give 0.815g of crude product, which was purified by flash chromatography on a Merck 70g silica column (particle size: 15-40 μm; eluent: 99/1 ethyl acetate/methanol). After concentration of the fractions under reduced pressure, 0.418g of a white foam is obtained, which is taken up in pentane. Insoluble material was filtered off through sintered glass and then dried under vacuum at a temperature of 40 ℃. Thus 0.364g of (S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] is obtained in the form of a white solid]Azetidin-3-yl } methanesulfonylamino) benzoylamino]Tert-butyl propionate.
1H NMR Spectrum(400 MHz; (delta, ppm); (DMSO-d 6); (reference 2.50 ppm): 1.38(m masked, 3H); 1.39(s, 9H); 2.71(m, 2H); 2.97(s, 3H); 3.34(m partially masked, 2H); 4.35(m, 1H); 4.37(s, 1H); 4.74(m, 1H); 7.30(d, J ═ 8.5Hz, 4H); 7.34(d, J ═ 8.5Hz, 4H); 7.43-7.55(m, 2H); 7.79 (width s, 1H); 7.86(m, 1H); 8.72(d, J ═ 7.3Hz, 1H)
Mass spectrometry：ES m/z＝632(MH+Radical peak)
Optical rotation：αD＝+3.6+/-0.5(c＝0.448，DMSO)
Pathway B-B: (S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonyl-amino) benzoylamino ] propanoic acid
2.72cm3Trifluoroacetic acid was added dropwise to 0.5g of (S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] acetate stirred at a temperature of about 20 ℃ under an inert atmosphere]Azetidin-3-yl } methanesulfonylAmino) benzoylamino]T-butyl propionate at 11cm3In dichloromethane. The reaction medium is stirred for 19 hours at a temperature of around 20 ℃ and then concentrated to dryness under reduced pressure. To remove excess trifluoroacetic acid, 15cm was used3Toluene was azeotroped 2 times. The residue obtained was dissolved in 10cm3And (3) water. The aqueous phase was basified with 3 drops of 1M aqueous sodium hydroxide solution at pH 7 and then with 20cm3Dichloromethane was extracted three times. The combined aqueous phases were dried over magnesium sulfate, filtered through sintered glass and concentrated to dryness under reduced pressure to give 0.43g of a pale yellow foam which was purified by flash chromatography on a Merck 25g silica column (particle size: 15-40 μm; eluent: 100 ethyl acetate). After concentration of the fractions under reduced pressure, 0.207g of product is obtained, which is triturated in a minimum of pentane. After concentration to dryness under reduced pressure and drying, 0.169g of (S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] methyl) was obtained as a white powder]Azetidin-3-yl } methanesulfonylamino) benzoylamino]Propionic acid.
1H NMR Spectrum(400 MHz; (delta, ppm); (DMSO-d 6); (reference 2.50 ppm): 1.39(d, J ═ 7.3Hz, 3H); 2.71(m, 2H); 2.97(s, 3H); 3.23-3.45(m masked, 2H); 4.38(s, 1H); 4.39(m, 1H); 4.74(m, 1H); 7.30(d, J ═ 8.3Hz, 4H); 7.35(d, J ═ 8.3Hz, 4H); 7.44-7.56(m, 2H); 7.80 (width s, 1H); 7.86(m, 1H); 8.70(d, J ═ 7.3Hz, 1H)
Mass spectrometry：ES m/z＝576(MH+Radical peak)
Elemental analysis：
Calculated values: c: 56.25% -H: 4.72% -N: 7.29% -S: 5.56 percent
Measurement values: c: 55.68% -H: 4.99% -N: 6.89% -S: 5.01% -H2O＝0.82％
Optical rotation：αD＝+10(c＝0.195，DMSO)
Pathway B-c: 3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) benzamide (Compound No. 9)
60mg of 1-hydroxybenzotriazole, 200mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.700cm32M methylamine in tetrahydrofuran, 0.370cm3Triethylamine and 8cm3Tetrahydrofuran is continuously added to 0.5g of (S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] 2- [3, stirred at a temperature of around 20 ℃ under an inert atmosphere]Azetidin-3-yl } methanesulfonylamino) benzoylamino]Propionic acid at 15cm3In tetrahydrofuran solution. The reaction medium is stirred for 18 hours at a temperature of about 20 ℃. After concentration to dryness under reduced pressure, the residue was dissolved in 30/15cm3Dichloromethane/water mixture. Standing for separation, and collecting water phase with a length of 15cm3The dichloromethane was extracted twice. The organic phases were combined over a 15cm frame3Saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness to give 0.415g of crude product, which was purified by flash chromatography on a Merck 25g silica column (particle size: 15-40 μm; eluent: 100 ethyl acetate). After concentration of the fractions under reduced pressure, 0.293g of product is obtained, which is triturated in a minimum of pentane. After filtration, concentration to dryness under reduced pressure and drying gave 0.247g of solid cream. 147mg of this solid cream was injected onto a 6cm diameter column containing 700g of Chiralpak IA 20. mu.M chiral stationary phase. At 80cm3Elution was performed per minute and the mobile phase consisted of 95% acetonitrile and 5% dichloromethane. The dextrorotatory enantiomer elutes at the second position. After concentration of the mobile phase, 105mg of 3- ({1- [ bis (4-chlorophenyl) methyl ] methyl) are obtained in the form of an amorphous white powder]Azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) benzamide.
Table 1 below illustrates the chemical structure (I) and physical properties of some examples of compounds of the present invention (table 1A).
In this table:
the Na salt corresponds to the sodium salt; "Me" corresponds to methyl; "Et" corresponds to ethyl; "iPr" corresponds to isopropyl; "iBu" corresponds to isobutyl; "tBu" corresponds to tert-butyl; "Ph" is phenyl;
-R is methyl;
TABLE 1
TABLE 1A
The compounds according to the invention are the subject of pharmacological tests to determine the activity with respect to the human cannabinoid CB 1-type receptor. The efficacy of the compounds of formula (I) was determined in a functional test measuring the activity of the cannabinoid CB1 receptor (intracellular cyclic AMP test). Assays for detection of intracellular cyclic AMP in U373MG cells naturally expressing the human CB1 receptor were performed as described in the literature: boubauoula et al, 1995, j.biol.chem.270: 13973-13980. CisBio's HTRF cAMP Dynamic Kit was used to quantify intracellular cyclic AMP. In this test, the IC50The value is 0.001. mu.M to 2. mu.M.
For example, compound numbers 1, 3, 4, 6, 12, 36, 56, 68, 70 and 79 show IC50Values of 0.043, respectively; 0.009; 0.284; 0.020; 0.009; 0.952; 0.041; 0.024; 0.031 and 0.070. mu.M.
Other tests were performed which included measuring the in vivo activity of the compounds of the invention. The antagonistic activity of the compounds was also shown by a hypothermia model induced in mice by a cannabinoid CB receptor agonist (racemic CP55, 940(1RS, 3RS, 4RS) -3- [ hydroxy-2- (1, 1-dimethylheptyl) phenyl ] -4- (3-hydroxypropyl) cyclohexan-1-ol) at a dose of 1.25mg/kg, according to the method described in R.G.Pertwein Marijana 84, Harvey D.J.eds, Oxford IRL Press, 263-ion 277 (1985). Rectal temperature was measured in male CD1 mice at a time of 0 minutes prior to injection of the test product. At 30 minutes, the rectal temperature of the mice was further measured and racemic CP55, 940 agonist (1RS, 3RS, 4RS-3- [ hydroxy-2- (1, 1-dimethylheptyl) phenyl ] -4- (3-hydroxypropyl) cyclohexan-1-ol) (1.25mg/kg i.p. in 10% cremophor) was administered. At 90 minutes, rectal temperature was measured again. Results are expressed as% relative to control batch (minimum temperature) injected with CP55, 940 and vehicle batch (maximum temperature) not treated with CP55, 940. For example, compound numbers 1, 38, 55, and 57 show the percent inhibition of temperature drop induced by oral administration of 3mg/kg agonist as 5%, 17%, 28%, and 21%, respectively.
The antagonistic activity of the compounds was also determined by racemic CP55, 940(1RS, 3RS, 4RS-3- [ hydroxy-2- (1, 1-dimethylheptyl) phenyl)]-4- (3-hydroxypropyl) cyclohexan-1-ol) induced inhibition of gastrointestinal transit (gastrointestinal transit) in mice was shown according to the method described by Rinaldi-Carmona et al, J.Pharmacol.Exp.Ther.2004, 310, 905-914. Briefly, male CD1 mice received the test product orally, and after 30 minutes or 2 hours, racemic CP55, 940 agonist (1RS, 3RS, 4RS-3- [ hydroxy-2- (1, 1-dimethylheptyl) phenyl) was administered]-4- (3-hydroxypropyl) cyclohexan-1-ol) (0.15mg/kg ip in 10% cremophor). After an additional 30 minutes, the animals received charcoal briquettes (charcola) orally. After 30 minutes, animals were euthanized by euthanasia (CO)2/O2) The intestine was sacrificed and dissected. The development of the char mass in the intestine is expressed as a percentage of the total length of the intestine.
For example, compound numbers 1, 3, 16, 55, 57 and 68 showed percent inhibition at 1mg/kg of 39.2%, 49%, 18%, 74%, 78% and 7%, respectively, 3 hours after administration of the product.
Thus, the compounds of formula (I) of the present invention are in vitro and in vivo cannabinoid CB 1-type receptor antagonists. Some compounds are active in vivo in both the low temperature test and the pass test, while some compounds show separate activity between the low temperature test and the pass test.
Accordingly, the compounds according to the invention are useful for the treatment or prevention of diseases in which the cannabinoid CB1 receptor is involved.
For example and in a non-limiting manner, the compounds of formula (I) are useful as psychopharmaceuticals, in particular for the treatment of psychiatric disorders including anxiety, depression, mood disorders (mood disorders), insomnia, delirium disorders (delirium disorders), obsessive-compulsive disorders, psychosis in general (psychoses in general), schizophrenia, Attention Deficit Hyperactivity Disorder (ADHD) in children with hyperactivity disorder (MBD), and also for the treatment of disorders associated with the use of psychotropic substances, including alcohol dependence and nicotine dependence and withdrawal disorders, in particular in the case of substance abuse and/or substance dependence. The compounds of formula (I) according to the invention are useful as medicaments for the treatment of migraine, stress, diseases of psychogenic origin, panic attacks, epilepsy, movement disorders, in particular dyskinesia (dyskinsia) or parkinson's disease, tremor and dystonia.
The compounds of formula (I) according to the invention can also be used as medicaments for skin cancer and skin protection.
The compounds of formula (I) according to the invention are also useful as medicaments for the treatment of memory disorders, cognitive disorders, in particular cognitive disorders associated with senile dementia, with alzheimer's disease, with schizophrenia and with neurodegenerative diseases, and for the treatment of attention or consciousness disorders.
Furthermore, the compounds of formula (I) are useful as neuroprotective agents, in the treatment of ischemia and cranial wounds and in the treatment of neurodegenerative diseases: including Huntington's disease and Tourrette's syndrome.
The compounds of formula (I) according to the invention are useful for the treatment of pain: neuropathic pain, acute peripheral pain, chronic pain and pain of inflammatory origin.
The compounds of formula (I) according to the invention are useful as medicaments for the treatment of the following diseases: appetite disorders, desire disorders (preference for sugars, carbohydrates, drugs, alcohol or any appetite-promoting substance) and/or eating disorders, in particular for the treatment of bulimia (boulemia) and for the treatment of type II diabetes or non-insulin dependent diabetes mellitus and for the treatment of dyslipidemia and metabolic syndrome. The compounds of formula (I) according to the invention are therefore useful for the treatment of obesity and obesity-related risks, in particular cardiovascular risks.
Furthermore, the compounds of formula (I) of the present invention are useful as medicaments for the treatment of the following diseases: gastrointestinal disorders, diarrheal disorders, ulcers, emesis, bladder and urinary disorders, disorders of endocrine origin (disorders of endocrine origin), cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, cirrhosis, liver fibrosis, steatohepatitis and hepatic steatosis, regardless of the cause of these disorders: in particular, viruses, alcohol, drugs, chemical products, autoimmune diseases, obesity, diabetes, congenital metabolic diseases (hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's disease, etc.), chronic liver cirrhosis, fibrosis, nonalcoholic steatohepatitis (NASH), asthma, chronic obstructive pulmonary disease, raynaud's syndrome, glaucoma, fertility disorders, inflammatory phenomena, inflammatory diseases, diseases of the immune system, in particular autoimmune or neuroinflammatory diseases, such as rheumatoid arthritis, reactive arthritis, diseases leading to demyelination, multiple sclerosis, infectious and viral diseases such as encephalitis, cerebral stroke, can also be used as medicaments for anticancer chemotherapy, for the treatment of guillain-barre syndrome and for the treatment of osteoporosis and sleep apnea.
According to one aspect, the present invention relates to the use of compounds of formula (I), their pharmaceutically acceptable salts, and solvates or hydrates thereof, for the treatment of the disorders and diseases indicated above.
According to another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention as an active ingredient. These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt of said compound, and at least one pharmaceutically acceptable excipient.
The excipients are selected from the usual excipients known to the person skilled in the art, depending on the pharmaceutical form and the desired administration method.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical (topocal), local (local), intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above or a salt thereof may be administered in unit dosage form or in admixture with conventional pharmaceutical excipients for the treatment of the disorders or diseases mentioned above.
Suitable unit administration forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, administration forms by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms, and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.
By way of example, a unit administration form in the form of a tablet of a compound according to the invention may comprise the following ingredients:
compound according to the invention 50.0mg
Mannitol 223.75mg
Croscarmellose sodium 6.0mg
Corn starch 15.0mg
Hydroxypropyl methylcellulose 2.25mg
Magnesium stearate 3.0mg
There may be specific cases where higher or lower doses are appropriate; such dosages do not depart from the scope of the present invention. According to common practice, the dosage appropriate for each patient is determined by the physician according to the method of administration and the weight and response of the patient in question.
According to another aspect, the invention also relates to a method for treating the pathologies described above, which comprises administering to a patient an effective dose of a compound according to the invention or of a pharmaceutically acceptable salt thereof.

Claims (21)

1. A compound of formula (I)
Wherein:
r' is NR4R5 OR OR 8;
r is methyl;
a and B, if they are present, are each independently of the other-CH2-；
R1 is a hydrogen atom;
r2 and R3 are each independently a hydrogen atom or (C)1-C6) An alkyl group; the (C)1-C6) Alkyl optionally substituted with hydroxy;
r4 and R5 are independently from each other a hydrogen atom or a methyl group;
r6 and R7 are each in the para position bound by a chlorine, fluorine or bromine atom or Me, OMe, CN, CF3Or OCF3Phenyl substituted with a group;
r8 is hydrogen atom or (C)1-C6) An alkyl group;
y is a hydrogen, chlorine, fluorine or bromine atom or Me, OMe, CN or CF3The radical(s) is (are),
the compounds are in the form of enantiomers or diastereomers or as mixtures of these forms;
the compounds are in the form of bases or of addition salts with acids or with bases.
2. A compound of formula (I) according to claim 1, selected from:
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N-carbamoylmethyl-5-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((R) -1-carbamoylethyl) -5-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((R) -1-carbamoylethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- (2-carbamoylethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-3-methylbutyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -5-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) -5-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- (methylcarbamoylmethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- (carbamoylmethyl) benzamide
(S) -tert-butyl 2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) benzoylamino ] propanoate
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) benzoylamino ] propanoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) benzoylamino acetic acid tert-butyl ester
4- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoylamino ] butanoic acid tert-butyl ester
(S) -tert-butyl 2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoylamino ] propionate
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-methoxybenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-dimethylcarbamoylethyl) benzamide
4- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) benzoylamino ] butyric acid tert-butyl ester
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoylamino ] propanoic acid and its sodium salt
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluoro-N- ((S) -1-methylcarbamoylethyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((1S, 2R) -1-carbamoyl-2-hydroxypropyl) benzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- (3-carbamoylpropyl) -5-fluorobenzamide
[3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) benzoylamino ] acetic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -2-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -2-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -6-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -6-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -6-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -6-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -4-fluorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N-carbamoylmethyl-5-methylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-methylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-methylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -5-methylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -5-methylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) -5-methylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-chlorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-chlorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -5-chlorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -5-chlorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) -5-chlorobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-bromobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-bromobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -5-bromobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -5-bromobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) -5-bromobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N-carbamoylmethyl-5-trifluoromethylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-trifluoromethylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-trifluoromethylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -5-trifluoromethylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -5-trifluoromethylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) -5-trifluoromethylbenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-cyanobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-cyanobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-methylpropyl) -5-cyanobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -5-cyanobenzamide
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoyl-2-hydroxyethyl) -5-cyanobenzamide
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -6-fluorobenzoylamino ] propionic acid and its trifluoroacetate salt
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-methylbenzoylamino ] propionic acid and its trifluoroacetate salt
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-chlorobenzoylamino ] propanoic acid and its trifluoroacetate salt
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-bromobenzoylamino ] propionic acid and its trifluoroacetate salt
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -3-trifluoromethylbenzoylamino ] propionic acid and its trifluoroacetate salt
(S) -2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-cyanobenzoylamino ] propionic acid and its trifluoroacetate salt
3- ({1- [ bis (4-bromophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide
3- ({1- [ bis (4-trifluoromethylphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide
3- ({1- [ bis (4-cyanophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide
3- ({1- [ bis (4-methoxyphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide
3- ({1- [ bis (4-fluorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylethyl) -5-fluorobenzamide
(S) -methyl 2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoylamino ] propanoate
3- ({1- [ bis (4-methylphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-fluorobenzamide
3- ({1- [ bis (4-bromophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-methylcarbamoylethyl) -5-fluorobenzamide
(S) -2- [3- ({1- [ bis (4-bromophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoylamino ] propanoic acid
(S) -ethyl 2- [3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoylamino ] propionate
3- ({1- [ bis (4-trifluoromethoxyphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -N- ((S) -1-carbamoylpropyl) -5-fluorobenzamide
Optical isomers thereof and pharmaceutically acceptable salts thereof.
3. Medicament, characterized in that it comprises a compound of formula (I) as defined in claim 1 or 2.
4. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) as defined in claim 1 or 2.
5. Use of a compound of formula (I) as defined in claim 1 or 2 in the manufacture of a medicament for the treatment or prevention of psychiatric disorders, substance dependence and withdrawal, tobacco withdrawal, cognitive and attention disorders, and acute and chronic neurodegenerative disorders.
6. Use of a compound of formula (I) as defined in claim 1 or 2 for the manufacture of a medicament for the treatment or prophylaxis of metabolic disorders, desire disorders, appetite disorders, obesity, diabetes, metabolic syndrome, dyslipidemia and sleep apnea.
7. Use of a compound of formula (I) as defined in claim 1 or 2 in the manufacture of a medicament for the treatment or prevention of pain.
8. The use of claim 7, wherein the pain is neuropathic pain.
9. The use of claim 7, wherein the pain is anticancer drug-induced neuropathic pain.
10. Use of a compound of formula (I) as defined in claim 1 or 2 in the manufacture of a medicament for the treatment or prophylaxis of: gastrointestinal disorders, emesis, ulcers, diarrheal disorders, bladder and urinary disorders, disorders of endocrine origin, cardiovascular disorders, hypotension, hemorrhagic shock, septic shock, liver disease, chronic cirrhosis, fibrosis, non-alcoholic steatohepatitis, steatohepatitis and hepatic steatosis, which are induced by alcohol, drugs, chemical products, autoimmune diseases, obesity, diabetes, congenital metabolic diseases, regardless of the etiology of these conditions.
11. Use of a compound of formula (I) as defined in claim 1 or 2 in the manufacture of a medicament for the treatment or prophylaxis of immune system disorders, rheumatoid arthritis, demyelination, multiple sclerosis and inflammatory diseases.
12. Use of a compound of formula (I) as defined in claim 1 or 2 for the manufacture of a medicament for the treatment or prevention of alzheimer's disease, parkinson's disease, schizophrenia and cognitive disorders associated with schizophrenia, cognitive disorders associated with diabetes, cognitive disorders associated with obesity or cognitive disorders associated with metabolic syndrome.
13. Use of a compound of formula (I) as defined in claim 1 or 2 in the manufacture of a medicament for the treatment or prophylaxis of asthma, chronic obstructive pulmonary disease, raynaud's syndrome, glaucoma and fertility disorders.
14. Use of a compound of formula (I) as defined in claim 1 or 2 for the preparation of a medicament for the treatment or prevention of infectious and viral diseases, guillain-barre syndrome, osteoporosis and sleep apnoea, and for anticancer chemotherapy.
15. The use of claim 14, wherein the infectious and viral disease is encephalitis or stroke.
16. A process for the preparation of a compound of formula (I),
wherein R' is NR4R5, the other groups being as defined in claim 1,
acid derivative 5 and amino derivative 6 are reacted in an inert solvent in the presence of a coupling agent and optionally an additive for preventing racemization, and the product is isolated and optionally converted into an addition salt with an acid.
17. A process for the preparation of a compound of formula (I),
wherein R' is OR8, the other groups being as defined in claim 1,
acid derivative 5 and amino derivative 7 are reacted in an inert solvent in the presence of a coupling agent and optionally an additive for preventing racemization, and the product is isolated and optionally converted into an addition salt with an acid.
18. A process for the preparation of a compound of formula (I),
in formula (I) R' is OR8 and R8 is H, the other groups are as defined in claim 1,
by hydrolysis of an OR8 functional group, wherein R8 is (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, allyl or phenyl (C)1-C6) Alkyl, the phenyl group being optionally substituted by 1 or 2O-methyl groups; the product of such hydrolysis is isolated and optionally converted into an addition salt with a base.
19. A process for the preparation of a compound of formula (I),
wherein R' is NR4R5, the other groups being as defined in claim 1,
by reacting a compound of formula (I), wherein R' is OR8 and R8 is H, with the amino derivative HNR4R5 in the presence of a coupling agent and optionally an additive for preventing racemization in an inert solvent, and isolating and optionally converting the product into an addition salt with an acid.
20. A process for preparing a compound of formula 5,
wherein Y, R, R6 and R7 are as defined in claim 1, by hydrolyzing an ester functional group of a compound of formula 4, wherein Y, R, R6 and R7 are as defined in claim 1 and R "is (C)1-C6) Alkyl, halo (C)1-C6) Alkyl, allyl or phenyl (C)1-C6) Alkyl, the phenyl being optionally substituted by 1 or 2O-methyl groups
21. Intermediates useful in the synthesis of compounds of formula (I),
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid methyl ester
3- ({1- [ bis (4-fluorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid methyl ester
3- ({1- [ bis (4-fluorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-bromophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid ethyl ester
3- ({1- [ bis (4-bromophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-trifluoromethylphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid ethyl ester
3- ({1- [ bis (4-trifluoromethylphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-methoxyphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid ethyl ester
3- ({1- [ bis (4-methoxyphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-methylphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid methyl ester
3- ({1- [ bis (4-methylphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-cyanophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid ethyl ester
3- ({1- [ bis (4-cyanophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-trifluoromethoxyphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid methyl ester
3- ({1- [ bis (4-trifluoromethoxyphenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-fluorobenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -2-fluorobenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -2-fluorobenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -4-fluorobenzoic acid ethyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -4-fluorobenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -6-fluorobenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -6-fluorobenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-methoxybenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-methoxybenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-methylbenzoic acid allyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-methylbenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-chlorobenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-chlorobenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-bromobenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-bromobenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-trifluoromethylbenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-trifluoromethylbenzoic acid
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-cyanobenzoic acid methyl ester
3- ({1- [ bis (4-chlorophenyl) methyl ] azetidin-3-yl } methanesulfonylamino) -5-cyanobenzoic acid.
HK11106128.9A 2007-12-18 2008-12-16 Azetidine derivatives, their preparation and their application in therapy HK1152038B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
FR0708830 2007-12-18
FR0708830A FR2925051B1 (en) 2007-12-18 2007-12-18 AZETIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR0802492 2008-05-06
FR0802492A FR2930941B1 (en) 2008-05-06 2008-05-06 AZETIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
PCT/FR2008/001748 WO2009106708A2 (en) 2007-12-18 2008-12-16 Azetidine derivatives, their preparation and their application in therapy

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HK1152038A1 HK1152038A1 (en) 2012-02-17
HK1152038B true HK1152038B (en) 2015-01-30

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