US2011021772A1PendingUtilityA1
New heterocyclic compounds, their preparation and their use as medicaments, in particular as anti-bacterial agents
Est. expiryAug 1, 2020(expired)· nominal 20-yr term from priority
A61P 31/04A61P 31/00A61P 9/10A61P 11/00A61P 17/00C07D 487/08C07D 471/08
53
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Claims
Abstract
The invention relates to new heterocyclic compounds of general formula (I), and their salts with a base or an acid: The invention also relates to a process for the preparation of these compounds as well as their use as medicaments, in particular as anti-bacterial agents.
Claims
exact text as granted — not AI-modified1 . Compound of general formula (I), or one of its salts with a base or an acid:
in which:
R 1 represents a hydrogen atom, a COOH, CN, COOR, CONR 6 , R 7 , (CH 2 ) n′ R 5 or
radical,
R is selected from the group consisting of an alkyl radical containing from 1 to 6 carbon atoms, optionally substituted by a pyridyl or carbamoyl radical, a
—CH 2 -alkenyl radical containing at the most 3 to 9 carbon atoms, aryl containing from 6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon atoms, the ring of the aryl or aralkyl radical being optionally substituted by an OH, NH 2 , NO 2 , alkyl radical containing from 1 to 6 carbon atoms, an alkoxy radical containing from 1 to 6 carbon atoms or by one or more halogen atoms,
R 6 and R 7 being identical or different, are selected from the group consisting of a hydrogen atom, an alkyl radical containing from 1 to 6 carbon atoms, an aryl radical containing from 6 to 10 carbon atoms and an aralkyl radical containing from 7 to 11 carbon atoms, optionally substituted by a carbamoyl, ureido or dimethylamino radical, and an alkyl radical containing from 1 to 6 carbon atoms substituted by a pyridyl radical,
n′ is equal to 1 or 2,
R 5 is selected from the group consisting of a COOH, CN, OH, NH 2 , CO—NR 6 R 7 , COOR, OR, OCOH, OCOR, OCOOR, OCONHR, OCONH 2 , NHR, NHCOH, NHCOR, NHSO 2 R, NH—COOR, NH—CO—NHR ou NHCONH 2 , R, R 6 and R 7 being as defined above;
R 2 represents a hydrogen atom or a (CH 2 ) n′1 R 5 group, n′ 1 being equal to 0, 1 or 2 and R 5 being as defined above;
R 3 represents a hydrogen atom or an alkyl radical containing from 1 to 6 carbon atoms;
A represents a bond between the two carbon carriers of R 1 and R 2 or a
group, R 4 representing a hydrogen atom or a (CH 2 ) n′1 R 5 group, n′ 1 and R 5 being as defined above, the dotted line representing an optional bond with one or other of the carbon carriers of the substituents R 1 and R 2 ;
n is equal to 1 or 2;
X represents a divalent —C(O)—B— group attached to the nitrogen atom by the carbon atom,
B represents a divalent —O—(CH 2 ) n″ — group attached to the carbonyl by the oxygen atom, an —NR 8 —(CH 2 ) n″ — or —NR 8 —O— group attached to the carbonyl by the nitrogen atom, n″ is equal to 0 or 1 and R 8 is selected from the group consisting of a hydrogen atom, an OH, R, OR, Y, OY, Y 1 , OY 1 , Y 2 , OY 2 , Y 3 , OCH 2 CH 2 SO m R, OSiR a R b R c and SiR a R b R c radical, R a , R b and R c individually representing a linear or branched alkyl radical containing from 1 to 6 carbon atoms or an aryl radical containing from 6 to 10 carbon atoms, R being as defined above and m being equal to 0, 1 or 2;
Y is selected from the group consisting of the COH, COR, COOR, CONH 2 , CONHR, CONHOH, CONHSO 2 R, CH 2 COOH, CH 2 COOR, CH 2 CONHOH, CH 2 CONHCN, CH 2 tetrazole, protected CH 2 tetrazole, CH 2 SO 3 H, CH 2 SO 2 R, CH 2 PO(OR) 2 , CH 2 PO(OR)(OH), CH 2 PO(R)(OH) and CH 2 PO(OH) 2 radicals,
Y 1 is selected from the group consisting of the SO 2 R, SO 2 NHCOH, SO 2 NHCOR, SO 2 NHCOOR, SO 2 NHCONHR, SO 2 NHCONH 2 and SO 3 H radicals,
Y 2 is selected from the group consisting of the PO(OH) 2 , PO(OR) 2 , PO(OH)(OR) and PO(OH)(R) radicals,
Y 3 is selected from the group consisting of the tetrazole radicals, tetrazole substituted by the R radical, squarate, NH or NR tetrazole, NH or NR tetrazole substituted by the R radical, NHSO 2 R and NRSO 2 R, R being as defined above;
it being understood that when n is equal to 1 and A represents a
group in which R 4 is a hydrogen atom and
either X represents the —C(O)—O—(CH 2 ) n″ group in which n″ is 0 or 1, or X represents the —CO—NR 8 —(CH 2 ) n″ group in which n″ is 1 and R 8 is the isopropyl group, or X represents the —CO—NR 8 —(CH 2 ) n″ group in which n″ is 0 and R 8 is hydrogen or phenyl,
so all three of R 1 , R 2 and R 3 cannot represent a hydrogen atom at the same time.
2 . Compound according to claim 1 , wherein n is equal to 1.
3 . Compound according to claim 1 , wherein A represents a
group.
4 . Compound according to claim 3 , wherein R 4 represents a hydrogen atom.
5 . Compound according to claim 1 , wherein X represents a divalent —CO—B— group in which B represents a —NR 8 —(CH 2 ) n″ group.
6 . Compound according to claim 5 , wherein n″ is 0 and the R 8 group is a Y 1 or OY 1 group, in which Y 1 is selected from the group consisting of SO 2 R, SO 2 NHCOR, SO 2 NHCOOR, SO 2 NHCONHR, SO 3 H wherein R is as defined in claim 1 .
7 . Compound according to claim 1 , wherein R 1 is CONR 6 , R 7 .
8 . Compound according to claim 1 , wherein R 2 is H.
9 . Compound according to claim 1 , wherein R 3 is H.
10 . A compound selected from the group consisting of:
trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts, trans-7-oxo-N-(phenylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts, trans-7-oxo-N-(4-pyridinyl methyl)-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts, trans-7-oxo-N-(3-pyridinyl methyl)-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts, trans-7-oxo-N-(2-amino 2-oxo ethyl)-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts, and phenylmethyl trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxylate.
11 . Compound of general formula (I), or one of its salts with a base or an acid:
in which:
R 1 represents a hydrogen atom, a COOH, CN, COOR, CONR 6 , R 7 , (CH 2 ) n′ R 5 or
radical,
R is selected from the group consisting of an alkyl radical containing from 1 to 6 carbon atoms, optionally substituted by a pyridyl or carbamoyl radical, a
—CH 2 -alkenyl radical containing at the most 3 to 9 carbon atoms, aryl containing from 6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon atoms, the ring of the aryl or aralkyl radical being optionally substituted by an OH, NH 2 , NO 2 , alkyl radical containing from 1 to 6 carbon atoms, an alkoxy radical containing from 1 to 6 carbon atoms or by one or more halogen atoms,
R 6 and R 7 being identical or different, are selected from the group consisting of a hydrogen atom, an alkyl radical containing from 1 to 6 carbon atoms, an aryl radical containing from 6 to 10 carbon atoms and an aralkyl radical containing from 7 to 11 carbon atoms, optionally substituted by a carbamoyl, ureido or dimethylamino radical, and an alkyl radical containing from 1 to 6 carbon atoms substituted by a pyridyl radical,
n′ is equal to 1 or 2,
R 5 is selected from the group consisting of a COOH, CN, OH, NH 2 , CO—NR 6 R 7 , COOR, OR, OCOH, OCOR, OCOOR, OCONHR, OCONH 2 , NHR, NHCOH, NHCOR, NHSO 2 R, NH—COOR, NH—CO—NHR ou NHCONH 2 , R, R 6 and R 7 being as defined above;
R 2 represents a hydrogen atom or a (CH 2 ) n′1 R 5 group, n′ 1 being equal to 0, 1 or 2 and R 5 being as defined above;
R 3 represents a hydrogen atom or an alkyl radical containing from 1 to 6 carbon atoms;
A represents a
group, R 4 representing a hydrogen atom, or a (CH 2 ) n′1 R 5 group, n′ 1 and R 5 being as defined above, the dotted line representing an optional bond with one or other of the carbon carriers of the substituents R 1 and R 2 ;
n is equal to 1;
X represents a divalent —C(O)—B— group attached to the nitrogen atom by the carbon atom,
B represents an —NR 8 —(CH 2 ) n″ attached to the carbonyl by the nitrogen atom, n″ is equal to 0 or 1 and R 8 is selected from the group consisting of a hydrogen atom, an OH, R, OR, Y, OY, Y 1 , OY 1 , Y 2 , OY 2 , Y 3 , OCH 2 CH 2 SO m R, OSiR a R b R c and SiR a R b R c radical, R a , R b and R c individually representing a linear or branched alkyl radical containing from 1 to 6 carbon atoms or an aryl radical containing from 6 to 10 carbon atoms, R being as defined above and m being equal to 0, 1 or 2;
Y is selected from the group consisting of the COH, COR, COOR, CONH 2 , CONHR, CONHOH, CONHSO 2 R, CH 2 COOH, CH 2 COOR, CH 2 CONHOH, CH 2 CONHCN, CH 2 tetrazole, protected CH 2 tetrazole, CH 2 SO 3 H, CH 2 SO 2 R, CH 2 PO(OR) 2 , CH 2 PO(OR)(OH), CH 2 PO(R)(OH) and CH 2 PO(OH) 2 radicals,
Y 1 is selected from the group consisting of the SO 2 R, SO 2 NHCOH, SO 2 NHCOR, SO 2 NHCOOR, SO 2 NHCONHR, SO 2 NHCONH 2 and SO 3 H radicals,
Y 2 is selected from the group consisting of the PO(OH) 2 , PO(OR) 2 , PO(OH)(OR) and PO(OH)(R) radicals,
Y 3 is selected from the group consisting of the tetrazole radicals, tetrazole substituted by the R radical, squarate, NH or NR tetrazole, NH or NR tetrazole substituted by the R radical, NHSO 2 R and NRSO 2 R, R being as defined above;
it being understood that when n is equal to 1 and A represents a
group in which R 4 is a hydrogen atom and
either X represents the —C(O)—O—(CH 2 ) n″ group in which n″ is 0 or 1, or X represents the —CO—NR 8 —(CH 2 ) n″ group in which n″ is 1 and R 8 is the isopropyl group, or X represents the —CO—NR 8 —(CH 2 ) n″ group in which n″ is 0 and R 8 is hydrogen or phenyl,
so all three of R 1 , R 2 and R 3 cannot represent a hydrogen atom at the same time.
12 . Compound according to claim 11 , wherein R 4 represents a hydrogen atom.
13 . Compound according to claim 11 , wherein in group B, n″ is 0 and the R 8 group is a Y 1 or OY 1 group, in which Y 1 is selected from the group consisting of SO 2 R, SO 2 NHCOR, SO 2 NHCOOR, SO 2 NHCONHR, SO 3 H wherein R is as defined in claim 11 .
14 . Compound according to claim 11 , wherein R 1 is CONR 6 , R 7 .
15 . Compound according to claim 11 , wherein R 2 is H.
16 . Compound according to claim 11 , wherein R 3 is H.
17 . Compound of general formula (I), or one of its salts with a base or an acid:
in which:
R 1 represents CONR 6 R 7 ,
R 6 and R 7 being identical or different, are selected from the group consisting of a hydrogen atom, an alkyl radical containing from 1 to 6 carbon atoms, an aryl radical containing from 6 to 10 carbon atoms and an aralkyl radical containing from 7 to 11 carbon atoms, optionally substituted by a carbamoyl, ureido or dimethylamino radical, and an alkyl radical containing from 1 to 6 carbon atoms substituted by a pyridyl radical,
R 2 represents a hydrogen atom;
R 3 represents a hydrogen atom;
A represents a
group,
R 4 representing a hydrogen atom, or a (CH 2 ) n′1 R 5 group, n′ 1 is equal to 1 or 2 and R 5 is selected from the group consisting of a COOH, CN, OH, NH 2 , CO—NR 6 R 7 , COOR, OR, OCOH, OCOR, OCOOR, OCONHR, OCONH 2 , NHR, NHCOH, NHCOR, NHSO 2 R, NH—COOR, NH—CO—NHR ou NHCONH 2 ; R is selected from the group consisting of an alkyl radical containing from 1 to 6 carbon atoms, optionally substituted by a pyridyl or carbamoyl radical, a —CH 2 -alkenyl radical containing at the most 3 to 9 carbon atoms, aryl containing from 6 to 10 carbon atoms or aralkyl containing from 7 to 11 carbon atoms, the ring of the aryl or aralkyl radical being optionally substituted by an OH, NH 2 , NO 2 , alkyl radical containing from 1 to 6 carbon atoms, an alkoxy radical containing from 1 to 6 carbon atoms or by one or more halogen atoms;
R 6 and R 7 being as defined above, the dotted line representing an optional bond with one or other of the carbon carriers of the substituents R 1 and R 2 ;
n is equal to 1;
X represents a divalent —C(O)—B-group attached to the nitrogen atom by the carbon atom,
B represents an —NR 8 —(CH 2 ) n″ — attached to the carbonyl by the nitrogen atom, n″ is equal to 0 or 1 and R 8 is selected from the group consisting of a hydrogen atom, an OH, R, OR, Y, OY, Y 1 , OY 1 , Y 2 , OY 2 , Y 3 , OCH 2 CH 2 SO m R, OSiR a R b R c and SiR a R b R c radical, R a , R b and R c individually representing a linear or branched alkyl radical containing from 1 to 6 carbon atoms or an aryl radical containing from 6 to 10 carbon atoms, R being as defined above and m being equal to 0, 1 or 2;
Y is selected from the group consisting of the COH, COR, COOR, CONH 2 , CONHR, CONHOH, CONHSO 2 R, CH 2 COOH, CH 2 COOR, CH 2 CONHOH, CH 2 CONHCN, CH 2 tetrazole, protected CH 2 tetrazole, CH 2 SO 3 H, CH 2 SO 2 R, CH 2 PO(OR) 2 , CH 2 PO(OR)(OH), CH 2 PO(R)(OH) and CH 2 PO(OH) 2 radicals,
Y 1 is selected from the group consisting of the SO 2 R, SO 2 NHCOH, SO 2 NHCOR, SO 2 NHCOOR, SO 2 NHCONHR, SO 2 NHCONH 2 and SO 3 H radicals,
Y 2 is selected from the group consisting of the PO(OH) 2 , PO(OR) 2 , PO(OH)(OR) and PO(OH)(R) radicals,
Y 3 is selected from the group consisting of the tetrazole radicals, tetrazole substituted by the R radical, squarate, NH or NR tetrazole, NH or NR tetrazole substituted by the R radical, NHSO 2 R and NRSO 2 R, R being as defined above;
18 . Compound according to claim 17 , wherein R 4 represents a hydrogen atom.
19 . Compound according to claim 17 , wherein in group B n″ is 0 and the R 8 group is a Y 1 or OY 1 group, in which Y 1 is selected from the group consisting of SO 2 R, SO 2 NHCOR, SO 2 NHCOOR, SO 2 NHCONHR, SO 3 H wherein R is as defined in claim 17 .
20 . Pharmaceutical compositions comprising, as active ingredient, at least one product according to claim 1 and a pharmaceutical acceptable carrier.
21 . Pharmaceutical compositions comprising, as active ingredient, at least one product according to claim 10 and a pharmaceutical acceptable carrier.
22 . Pharmaceutical compositions comprising, as active ingredient, at least one product according to claim 11 and a pharmaceutical acceptable carrier.
23 . Pharmaceutical compositions comprising, as active ingredient, at least one product according to claim 17 and a pharmaceutical acceptable carrier.
24 . Process for the preparation of a compound according to claim 1 , wherein it comprises:
a) a stage during which a compound of formula (II) is reacted with a carbonylation agent, if appropriate in the presence of a base:
in which:
R′ 1 represents a hydrogen atom or a CN, protected COOH COOR′, (CH 2 )n′R′ 5 , CONR 6 , R 7 or protected
radical;
n′, R 6 and R 7 being as defined in claim 1 and R′ and R′ 5 having the definitions of R and R 5 respectively of claim 1 , in which the reactive functions optionally present are protected;
R′ 2 represents a hydrogen atom or a (CH 2 )n′ 1 R′ 5 , group n′ 1 being defined as in claim 1 and R′ 5 being as defined above;
R 3 is as defined in claim 1 ;
A′ represents a bond between the two carbon carriers of R′ 1 and R′ 2 or a
group, R′ 4 representing a hydrogen atom or a (CH 2 )n′ 1 R′ 5 group, n′ 1 and R′ 5 being as defined above, the dotted line representing an optional bond with one or other of the carbon carriers of the substituents R′ 1 and R′ 2 ;
n is as defined in claim 1 ;
HZ represents an HO—(CH 2 )n″-, HNR′ 8 —(CH 2 ) n″ — or HNR′ 8 —O— group, n″ being as defined previously and R′ 8 representing a hydrogen atom, protected OH, an R′, OR′ radical, a Y′ or OY′ radical, Y′ being selected from COH, COR′, COOR′, CONH 2 , CONHR′, protected CONHOH, CONHSO 2 R′, protected CH 2 COOH, CH 2 COOR′, protected CH 2 CONHOH, CH 2 CONHCN, CH 2 tetrazole groups substituted by R′, CH 2 SO 2 R′, CH 2 PO(OR′) 2 , protected CH 2 SO 3 , protected CH 2 PO(OR′)OH, protected CH 2 PO(R′)OH, protected CH 2 PO(OH) 2 , a Y′ 1 or OY′ 1 radical, Y′ 1 being selected from the SO 2 R′, SO 2 NHCOH, SO 2 NHCOR′, SO 2 NHCOOR′, SO 2 NHCONH 2 , SO 2 NHCONHR′ and protected SO 3 H groups, a Y′ 2 or OY′ 2 radical, Y′ 2 representing a protected PO(OH) 2 , protected PO(OH)(OR′), protected PO(OH)(R′) or PO(OR′) 2 group, or a Y′ 3 radical, Y′ 3 being selected from the protected tetrazole, tetrazole substituted by the R′ radical, NH or NR′ protected tetrazole, NH or NR′ tetrazole substituted by the R′ radical, NHSO 2 R′ and NR′SO 2 R′ groups, R′ being as defined above;
with a view to obtaining an intermediate compound of formula:
in which:
R′ 1 , R′ 2 , R 3 , A′ and n have the same meanings as above and either X 1 is a hydrogen atom and X 2 represents a —Z—CO—X 3 group, X 3 representing the remainder of the carbonylation agent, or X 2 is a —ZH group and X 1 represents a CO—X 3 group, X 3 being as defined above;
b) a stage during which the intermediate obtained previously is cyclized in the presence of a base;
and in that:
c) optionally, stage a) is preceded by and/or stage b) is followed by one or several of the following reactions, in an appropriate order:
protection of the reactive functions,
deprotection of the reactive functions,
esterification
saponification,
sulphation,
phosphation
amidation,
acylation,
sulphonylation;
alkylation;
introduction of a double bond;
formation of a urea group;
introduction of a tetrazole group;
reduction of carboxylic acids;
dehydration of amide to nitrile;
salification;
ion exchange;
splitting or separation of diasterisomers;
sulphide oxidation to sulphoxide and/or sulphone.
25 . Process according to claim 24 , wherein the carbonylation agent is selected from the group consisting of phosgene, diphosgene, triphosgene, aryl chloroformates, aralkyle chloroformates, alkyl chloroformates, alkenyl chloroformates, alkyl dicarbonates, carbonyl-diimidazole and their mixtures.
26 . Process according to claim 24 , wherein the carbonylation reaction takes place in the presence of base.
27 . Process according to claim 26 , wherein the base is an amine.
28 . Process according to claim 24 , wherein in stage b the base is selected from the group consisting of amines, hydrides, alcoholates, amides or carbonates of alkali or alkaline-earth metals.
29 . Process for the preparation of a compound according to claim 11 , wherein it comprises:
a) a stage during which a compound of formula (II) is reacted with a carbonylation agent, if appropriate in the presence of a base:
in which:
R′ 1 represents a hydrogen atom or a CN, protected COOH COOR′, (CH 2 )n′R′ 5 , CONR 6 , R 7 or protected
radical;
n′, R 6 and R 7 being as defined in claim 11 and R′ and R′ 5 having the definitions of R and R 5 respectively of claim 11 , in which the reactive functions optionally present are protected;
R′2 represents a hydrogen atom or a (CH2)n′1R′5, group n′1 being defined as in claim 11 and R′5 being as defined above;
R 3 is as defined in claim 11 ;
A′ represents a bond between the two carbon carriers of R′ 1 and R′ 2 or a
group, R′ 4 representing a hydrogen atom or a (CH 2 )n′ 1 R′ 5 group, n′ 1 and R′ 5 being as defined above, the dotted line representing an optional bond with one or other of the carbon carriers of the substituents R′ 1 and R′ 2 ;
n is as defined in claim 11 ;
HZ represents an HO—(CH2)n″-, HNR′8-(CH2)n″- or HNR′8-O— group, n″ being as defined previously and R′8 representing a hydrogen atom, protected OH, an R′, OR′ radical, a Y′ or OY′ radical, Y′ being selected from COH, COR′, COOR′, CONH2, CONHR′, protected CONHOH, CONHSO2R′, protected CH2COOH, CH2COOR′, protected CH2CONHOH, CH2CONHCN, CH2tetrazole groups substituted by R′, CH2SO2R′, CH2PO(OR′)2, protected CH2SO3, protected CH2PO(OR′)OH, protected CH2PO(R′)OH, protected CH2PO(OH)2, a Y′1 or OY′1 radical, Y′1 being selected from the SO2R′, SO2NHCOH, SO2NHCOR′, SO2NHCOOR′, SO2NHCONH2, SO2NHCONHR′ and protected SO3H groups, a Y′2 or OY′2 radical, Y′2 representing a protected PO(OH) 2 , protected PO(OH)(OR′), protected PO(OH)(R′) or PO(OR′)2 group, or a Y′3 radical, Y′3 being selected from the protected tetrazole, tetrazole substituted by the R′ radical, NH or NR′ protected tetrazole, NH or NR′ tetrazole substituted by the R′ radical, NHSO2R′ and NR′SO2R′ groups, R′ being as defined above;
with a view to obtaining an intermediate compound of formula:
in which:
R′ 1 , R′ 2 , R 3 , A′ and n have the same meanings as above and either X 1 is a hydrogen atom and X 2 represents a —Z—CO—X 3 group, X 3 representing the remainder of the carbonylation agent, or X 2 is a —ZH group and X 1 represents a CO—X 3 group, X 3 being as defined above;
b) a stage during which the intermediate obtained previously is cyclized in the presence of a base;
and in that:
c) optionally, stage a) is preceded by and/or stage b) is followed by one or several of the following reactions, in an appropriate order:
protection of the reactive functions,
deprotection of the reactive functions,
esterification
saponification,
sulphation,
phosphation
amidation,
acylation,
sulphonylation;
alkylation;
introduction of a double bond;
formation of a urea group;
introduction of a tetrazole group;
reduction of carboxylic acids;
dehydration of amide to nitrile;
salification;
ion exchange;
splitting or separation of diasterisomers;
sulphide oxidation to sulphoxide and/or sulphone.
30 . Process according to claim 29 , wherein the carbonylation agent is selected from the group consisting of phosgene, diphosgene, triphosgene, aryl chloroformates, aralkyle chloroformates, alkyl chloroformates, alkenyl chloroformates, alkyl dicarbonates, carbonyl-diimidazole and their mixtures.
31 . Process according to claim 29 , wherein the carbonylation reaction takes place in the presence of a base.
32 . Process according to claim 31 , wherein the base is an amine.
33 . Process according to claim 29 , wherein in stage b the base is selected from the group consisting of amines, hydrides, alcoholates, amides or carbonates of alkali or alkaline-earth metals.
34 . Process for the preparation of a compound according to claim 17 , wherein it comprises:
a) a stage during which a compound of formula (II) is reacted with a carbonylation agent, if appropriate in the presence of a base:
in which:
R′ 1 represents a hydrogen atom or a CN, protected COOH COOR′, (CH 2 )n′R′ 5 , CONR 6 , R 7 or protected
radical;
n′, R 6 and R 7 being as defined in claim 17 and R′ and R′ 5 having the definitions of R and R 5 respectively of claim 17 , in which the reactive functions optionally present are protected;
R′ 2 represents a hydrogen atom or a (CH 2 )n′ 1 R′ 5 , group n′ 1 being defined as in claim 17 and R′ 5 being as defined above;
R 3 is as defined in claim 17 ;
A′ represents a bond between the two carbon carriers of R′ 1 and R′ 2 or a
group, R′ 4 representing a hydrogen atom or a (CH 2 )n′ 1 R′ 5 group, n′ 1 and R′ 5 being as defined above, the dotted line representing an optional bond with one or other of the carbon carriers of the substituents R′ 1 and R′ 2 ;
n is as defined in claim 17 ;
HZ represents an HO—(CH 2 )n″-, HNR′ 8 —(CH 2 ) n″ — or HNR′ 8 —O— group, n″ being as defined previously and R′ 8 representing a hydrogen atom, protected OH, an R′, OR′ radical, a Y′ or OY′ radical, Y′ being selected from COH, COR′, COOR′, CONH 2 , CONHR′, protected CONHOH, CONHSO 2 R′, protected CH 2 COOH, CH 2 COOR′, protected CH 2 CONHOH, CH 2 CONHCN, CH 2 tetrazole groups substituted by R′, CH 2 SO 2 R′, CH 2 PO(OR′) 2 , protected CH 2 SO 3 , protected CH 2 PO(OR′)OH, protected CH 2 PO(R′)OH, protected CH 2 PO(OH) 2 , a Y′ 1 or OY′ 1 radical, Y′ 1 being selected from the SO 2 R′, SO 2 NHCOH, SO 2 NHCOR′, SO 2 NHCOOR′, SO 2 NHCONH 2 , SO 2 NHCONHR′ and protected SO 3 H groups, a Y′ 2 or OY′ 2 radical, Y′ 2 representing a protected PO(OH) 2 , protected PO(OH)(OR′), protected PO(OH)(R′) or PO(OR′) 2 group, or a Y′ 3 radical, Y′ 3 being selected from the protected tetrazole, tetrazole substituted by the R′ radical, NH or NR′ protected tetrazole, NH or NR′ tetrazole substituted by the R′ radical, NHSO 2 R′ and NR′SO 2 R′ groups, R′ being as defined above;
with a view to obtaining an intermediate compound of formula:
in which:
R′ 1 , R′ 2 , R 3 , A′ and n have the same meanings as above and either X 1 is a hydrogen atom and X 2 represents a —Z—CO—X 3 group, X 3 representing the remainder of the carbonylation agent, or X 2 is a —ZH group and X 1 represents a CO—X 3 group, X 3 being as defined above;
b) a stage during which the intermediate obtained previously is cyclized in the presence of a base; and in that:
c) optionally, stage a) is preceded by and/or stage b) is followed by one or several of the following reactions, in an appropriate order:
protection of the reactive functions,
deprotection of the reactive functions,
esterification
saponification,
sulphation,
phosphation
amidation,
acylation,
sulphonylation;
alkylation;
introduction of a double bond;
formation of a urea group;
introduction of a tetrazole group;
reduction of carboxylic acids;
dehydration of amide to nitrile;
salification;
ion exchange;
splitting or separation of diasterisomers;
sulphide oxidation to sulphoxide and/or sulphone.
35 . Process according to claim 34 , wherein the carbonylation agent is selected from the group consisting of phosgene, diphosgene, triphosgene, aryl chloroformates, aralkyle chloroformates, alkyl chloroformates, alkenyl chloroformates, alkyl dicarbonates, carbonyl-diimidazole and their mixtures.
36 . Process according to claim 34 , wherein the carbonylation reaction takes place in the presence of a base.
37 . Process according to claim 36 , wherein the base is an amine.
38 . Process according to claim 34 , wherein in stage b the base is selected from the group consisting of amines, hydrides, alcoholates, amides or carbonates of alkali or alkaline-earth metals.
39 . Compound of general formula (III) or one of its salts with an acid, in particular its hydrochloride:
in which R′ 1 , R′ 2 , R 3 , A′, n, X 1 and X 2 have the same meanings as in claim 24 .Join the waitlist — get patent alerts
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