Azetidinimines as carbapenemases inhibitors
11174226 · 2021-11-16
Assignee
Inventors
- Robert Dodd (Paris, FR)
- Kevin Cariou (Paris, FR)
- Corinne Minard (Aulnay sous Bois, FR)
- Bogdan-Iuliu Iorga (Antony, FR)
- Thierry Naas (Clamart, FR)
Cpc classification
A61K45/06
HUMAN NECESSITIES
C07D205/085
CHEMISTRY; METALLURGY
Y02A50/30
GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
C07D401/04
CHEMISTRY; METALLURGY
C07D205/06
CHEMISTRY; METALLURGY
International classification
C07D205/06
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
A61K45/06
HUMAN NECESSITIES
C07D205/085
CHEMISTRY; METALLURGY
Abstract
The present application relates to novel azetidinimine of formula (I). Wherein R.sub.1-R.sub.6 are as defined in claim 1. The azetidinimine of the invention are useful as antibiotics and as inhibitors of a carbapenemases. The present invention thus further relates to their use in antibiotic therapies and their methods of synthesis. ##STR00001##
Claims
1. Compound of formula (I): ##STR00150## wherein: R.sub.1 represents a chemical moiety chosen in the group consisting of hydrogen, cyano, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.10 alkoxy, C.sub.1-C.sub.10 haloalkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-haloalkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.10 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.10 alkylsulfinyl, C.sub.1-C.sub.10 haloalkylsulfinyl, C.sub.1-C.sub.10 haloalkylsulfonyl, C.sub.3-C.sub.10 trialkylsilyl, C.sub.1-C.sub.10 alkylsulfonyl, C.sub.5-C.sub.12 arylsulfonyl, formyl, C.sub.2-C.sub.10 alkylcarbonyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.2-C.sub.10 alkenyloxy, C.sub.2-C.sub.10 alkynyloxy, C.sub.2-C.sub.10 alkenylthio, C.sub.2-C.sub.10 alkynylthio, C.sub.1-C.sub.10 haloalkyl, C.sub.2-C.sub.10 haloalkenyl, C.sub.2-C.sub.10 haloalkynyl, C.sub.2-C.sub.10 haloalkylcarbonyl, C.sub.1-C.sub.10 haloalkylthio, C.sub.2-C.sub.10 haloalkenyloxy, C.sub.2-C.sub.10 haloalkynyloxy, C.sub.2-C.sub.10 haloalkenylthio, C.sub.2-C.sub.10 haloalkynylthio, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl ester or a mono or polycyclic C.sub.5-C.sub.12 aryl or mono or polycyclic C.sub.3-C.sub.12 heteroaryl fragments, wherein the aryl or heteroaryl fragments are optionally substituted by one or several halogen atoms, hydroxyl (OH), nitro, cyano, formyl, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, amino-C.sub.1-C.sub.10 alkoxy, (carboxylic acid)-C.sub.1-C.sub.10 alkoxy, (carboxylic (C.sub.1-C.sub.6)alkyl ester)-C.sub.1-C.sub.10 alkoxy, (1,2 diol)-C.sub.2-C.sub.10 alkoxy, —O—(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-OH, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.2-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkoxy alkyl, C.sub.2-C.sub.6 haloalkylcarbonyl, C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.3-C.sub.6 trialkylsilyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.2-C.sub.6 haloalkynyloxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.2-C.sub.6 alkenylthio, C.sub.2-C.sub.6 alkynylthio, C.sub.2-C.sub.6 haloalkenylthio, C.sub.2-C.sub.6 haloalkynylthio and/or a C.sub.1-C.sub.6 alkoxy optionally substituted by a mono or polycyclic C.sub.5-C.sub.12 aryl group, and/or a bridging group of formula —O—CH.sub.2—O— or —O—CH.sub.2CH.sub.2—O—; R.sub.2, R.sub.3, R.sub.4 and R.sub.5, independently one from each other, represent a chemical moiety chosen in the group consisting of hydrogen, halogen, nitro, cyano, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.10 alkoxy, C.sub.1-C.sub.10 haloalkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-haloalkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.10 thioalkyl, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl ester, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.10 alkylsulfinyl, C.sub.1-C.sub.10 haloalkylsulfinyl, C.sub.1-C.sub.10 haloalkylsulfonyl, C.sub.3-C.sub.10 trialkylsilyl, C.sub.1-C.sub.10 alkylsulfonyl, C.sub.5-C.sub.12 arylsulfonyl, formyl, C.sub.2-C.sub.10 alkylcarbonyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.2-C.sub.10 alkenyloxy, C.sub.2-C.sub.10 alkynyloxy, C.sub.2-C.sub.10 alkenylthio, C.sub.2-C.sub.10 alkynylthio, C.sub.1-C.sub.10 haloalkyl, C.sub.2-C.sub.10 haloalkenyl, C.sub.2-C.sub.10 haloalkynyl, C.sub.2-C.sub.10 haloalkylcarbonyl, C.sub.1-C.sub.10 haloalkylthio, C.sub.2-C.sub.10 haloalkenyloxy, C.sub.2-C.sub.10 haloalkynyloxy, C.sub.2-C.sub.10 haloalkenylthio, C.sub.2-C.sub.10 haloalkynylthio, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl or a mono or polycyclic C.sub.5-C.sub.12 aryl or mono or polycyclic C.sub.3-C.sub.12 heteroaryl fragments, wherein the aryl or heteroaryl fragments are optionally substituted by one or several halogen atoms, nitro, cyano, formyl, COOH, —COO(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 N.sub.3-substituted alkyl, C.sub.1-C.sub.6 NH.sub.2-substituted alkyl, C.sub.1-C.sub.6 alcohol, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.2-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkoxy alkyl, C.sub.2-C.sub.6 haloalkylcarbonyl, C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.3-C.sub.6 trialkylsilyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.2-C.sub.6 haloalkynyloxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.2-C.sub.6 alkenylthio, C.sub.2-C.sub.6 alkynylthio, C.sub.2-C.sub.6 haloalkenylthio, C.sub.2-C.sub.6 haloalkynylthio, a monocyclic C.sub.5-C.sub.6 aryl group optionally substituted by a C.sub.1-C.sub.6 alkyloxy group and/or a COO(C.sub.1-C.sub.6 alkyl) group wherein the alkyl is substituted by NH.sub.2 or NHCOO(C.sub.1-C.sub.6)alkyl or NHCOO(C.sub.1-C.sub.6)alkyl(mono or polycyclic C.sub.5-C.sub.12)aryl; R.sub.6 represents a mono or polycyclic C.sub.5-C.sub.12 aryl fragment, wherein the aryl fragment is optionally substituted by one or several halogen atoms, cyano, formyl, nitro, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.2-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkoxy alkyl, C.sub.2-C.sub.6 haloalkylcarbonyl, C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.3-C.sub.6 trialkylsilyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.2-C.sub.6 haloalkynyloxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.2-C.sub.6 alkenylthio, C.sub.2-C.sub.6 alkynylthio, C.sub.2-C.sub.6 haloalkenylthio, C.sub.2-C.sub.6 haloalkynylthio fragments, and/or a monocyclic C.sub.5-C.sub.6 aryl group optionally substituted by a C.sub.1-C.sub.6 alkyloxy group; or a solvate or a salt thereof; provided that at least two of R.sub.3, R.sub.4 and R.sub.5 represent a hydrogen atom and R.sub.2 or R.sub.3 is different from hydrogen.
2. The compound according to claim 1 characterized in that R.sub.6 represents a R.sub.6 represents a mono or polycyclic C.sub.5-C.sub.12 aryl fragment, optionally substituted by one or several halogen atoms, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkoxy.
3. Compound according to claim 1 or 2, characterized in that R.sub.1 represents a monocyclic aryl fragment optionally substituted by one or several OH, C.sub.1-C.sub.6 thioalkyl, halogen, amino-(C.sub.1-C.sub.10 alkoxy), (carboxylic acid)-(C.sub.1-C.sub.10 alkoxy), (carboxylic (C.sub.1-C.sub.6)alkylester)-C.sub.1-C.sub.10 alkoxy, (1,2 diol)-C.sub.2-C.sub.10 alkoxy, —O—(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-OH, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl ester, nitro and/or a C.sub.1-C.sub.6 alkoxy group optionally substituted by a mono or polycyclic C.sub.5-C.sub.12 aryl group, and/or a bridging group of formula —O—CH.sub.2—O— or —O—CH.sub.2CH.sub.2—O—.
4. The compound according to claim 1, wherein R.sub.2 and/or R.sub.3 represent a monocyclic aryl, monocyclic heteroaryl or polycyclic aryl fragment optionally substituted by one or several halogen atoms, COOH, —COO(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 N.sub.3-substituted alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alcohol, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 acyl, nitro, cyano and/or a COO(C.sub.1-C.sub.6 alkyl) group wherein the alkyl is substituted by NH.sub.2 or NHCOO(C.sub.1-C.sub.6)alkyl or NHCOO(C.sub.1-C.sub.6)alkyl(mono or polycyclic C.sub.5-C.sub.12)aryl fragment.
5. The compound according to claim 1, wherein R.sub.3, R.sub.4 and R.sub.5 represent hydrogen atoms.
6. A compound selected from the group consisting of: ##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162## a solvate or a salt thereof.
7. The compound according to claim 1, wherein R.sub.1 represents a monocyclic aryl fragment optionally substituted by one or several C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 thioalkyl, halogen, amino-(C.sub.1-C.sub.10 alkoxy), (carboxylic acid)-(C.sub.1-C.sub.10 alkoxy), (1,2 diol)-(C.sub.2-C.sub.10 alkoxy), (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl ester and/or nitro fragments.
8. The compound according to claim 1 wherein R1 represents a phenyl fragment, a 4-hydroxyphenyl, a 4-methoxyphenyl, a 2-methoxyphenyl, a 3-methoxyphenyl, a 3,4-dimethoxyphenyl, a 3,4,5-trimethoxyphenyl, a 4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-benzyloxy-phenyl, a 1 ,3-benzodioxole, a 1 ,4-benzodioxane, a 4-[(2,3 diol)-propoxy]-phenyl, a 4-phenoxyacetic acid, a tert-butyl 4-(phenoxy)acetate, a 4-(bis(2-hydroxyethyl)ether)phenyl or a 4-iodo-phenyl.
9. The compound according to claim 1 wherein R1 represents a 4-hydroxyphenyl.
10. The compound according to claim 1 wherein R2 and/or R3 represent a fragment chosen from the group consisting of phenyl, 4- methoxy phenyl, 4-formylphenyl, 4-nitro phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, naphthyl, indolyl, furanyl, pyridyl, and thiophenyl.
11. The compound according to claim 1 wherein R2 represents a 2,4-dichlorophenyl.
12. The compound according to claim 1 wherein R6 represents a phenyl group, optionally substituted by 1 to 3 halogen atoms, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkoxy.
13. The compound according to claim 1 wherein R6 represents a phenyl group, optionally substituted by 1 to 3 iodine atoms.
14. The compound according to claim 1 wherein R1 represents a 4-hydroxyphenyl, R2 represents a 2,4- dichlorophenyl, R6 represents a phenyl group, optionally substituted by 1 to 3 iodine atoms, and R3, R4 and R5 represent hydrogen atoms.
15. A composition comprising a combination of a compound of formula (I) as defined in claim 1 and an antibiotic.
16. The composition according to claim 15 wherein said antibiotic is effective on bacteria chosen from gram-negative bacteria.
17. The composition according to claim 16, wherein said gram-negative bacteria is selected from the group consisting of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii.
18. A pharmaceutical composition comprising at least one compound of formula (I) as defined in claim 1, and a pharmaceutically acceptable carrier.
19. The pharmaceutical composition of claim 18, wherein it comprises a second active substance.
20. The pharmaceutical composition according to claim 19, wherein said second active substance is an antibiotic.
21. A method for inhibiting a carbapenemase enzyme wherein a compound of formula (I) as defined in claim 1 is used as a carbapenemase enzyme inhibitor.
22. The method according to claim 21, wherein the carbapenemase enzyme, is a NDM-1 type, OXA-48 type or a KPC-type enzyme.
23. A method of therapeutical treatment comprising the administration of a compound of formula (I) as defined in claim 1 as a drug.
24. The method of claim 23, wherein the drug is an antibiotic.
25. A kit comprising: at least one first container containing a first therapeutically active compound of formula (I) as defined in claim 1 and mixtures thereof, and at least one second container containing a second therapeutically active substance which is an antibiotic, as a combination product for simultaneous, sequential and separate use.
26. The kit according to claim 25, as a combination product for simultaneous, sequential and separate use in antibiotherapy.
27. A method to prepare a compound of formula (I): a. to a compound of formula (II): ##STR00163## wherein: R.sub.1 represents a chemical moiety chosen in the group consisting of hydrogen, cyano, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.10 alkoxy, C.sub.1-C.sub.10 haloalkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6) -haloalkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.10 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.10 alkylsulfinyl, C.sub.1-C.sub.10 haloalkylsulfinyl, C.sub.1-C.sub.10 haloalkylsulfonyl, C.sub.3-C.sub.10 trialkylsilyl, C.sub.1-C.sub.10 alkylsulfonyl, C.sub.5-C.sub.12 arylsulfonyl, formyl, C.sub.2-C.sub.10 alkylcarbonyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.2-C.sub.10 alkenyloxy, C.sub.2-C.sub.10 alkynyloxy, C.sub.2-C.sub.10 alkenylthio, C.sub.2-C.sub.10 alkynylthio, C.sub.1-C.sub.10 haloalkyl, C.sub.2-C.sub.10 haloalkenyl, C.sub.2-C.sub.10 haloalkynyl, C.sub.2-C.sub.10 haloalkylcarbonyl, C.sub.1-C.sub.10 haloalkylthio, C.sub.2-C.sub.10 haloalkenyloxy, C.sub.2-C.sub.10 haloalkynyloxy, C.sub.2-C.sub.10 haloalkenylthio, C.sub.2-C.sub.10 haloalkynylthio, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl ester or a mono or polycyclic C.sub.5-C.sub.12 aryl or mono or polycyclic C.sub.3-C.sub.12 heteroaryl fragments, wherein the aryl or heteroaryl fragments are optionally substituted by one or several halogen atoms, hydroxyl (OH), nitro, cyano, formyl, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, amino-C.sub.1-C.sub.10 alkoxy, (carboxylic acid)-C.sub.1-C.sub.10 alkoxy, (carboxylic (C.sub.1-C.sub.6)alkyl ester)-C.sub.1-C.sub.10 alkoxy, (1,2 diol)-C.sub.2-C.sub.10 alkoxy, —O—(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-OH, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.2-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl,C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkoxy alkyl, C.sub.2-C.sub.6 haloalkylcarbonyl, C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.3-C.sub.6 trialkylsilyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.2-C.sub.6 haloalkynyloxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.2-C.sub.6 alkenylthio, C.sub.2-C.sub.6 alkynylthio, C.sub.2-C.sub.6 haloalkenylthio, C.sub.2-C.sub.6 haloalkynylthio and/or a C.sub.1-C.sub.6 alkoxy optionally substituted by a mono or polycyclic C.sub.5-C.sub.12 aryl group, and/or a bridging group of formula —O—CH.sub.2—O— or —O—CH.sub.2CH.sub.2—O—; R.sub.2, R.sub.3, R.sub.4 and R.sub.5, independently one from each other, represent a chemical moiety chosen in the group consisting of hydrogen, halogen, nitro, cyano, C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.10 alkoxy, C.sub.1-C.sub.10 haloalkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-haloalkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.10 thioalkyl, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl ester, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.10 alkylsulfinyl, C.sub.1-C.sub.10 haloalkylsulfinyl, C.sub.1-C.sub.10 haloalkylsulfonyl, C.sub.3-C.sub.10 trialkylsilyl, C.sub.1-C.sub.10 alkylsulfonyl, C.sub.5-C.sub.12 arylsulfonyl, formyl, C.sub.2-C.sub.10 alkylcarbonyl, C.sub.2-C.sub.10 alkenyl, C.sub.2-C.sub.10 alkynyl, C.sub.2-C.sub.10 alkenyloxy, C.sub.2-C.sub.10 alkynyloxy, C.sub.2-C.sub.10 alkenylthio, C.sub.2-C.sub.10 alkynylthio, C.sub.1-C.sub.10 haloalkyl, C.sub.2-C.sub.10 haloalkenyl, C.sub.2-C.sub.10 haloalkynyl, C.sub.2-C.sub.10 haloalkylcarbonyl, C.sub.1-C.sub.10 haloalkylthio, C.sub.2-C.sub.10 haloalkenyloxy, C.sub.2-C.sub.10 haloalkynyloxy, C.sub.2-C.sub.10 haloalkenylthio, C.sub.2-C.sub.10 haloalkynylthio, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl or a mono or polycyclic C.sub.5-C.sub.12 aryl or mono or polycyclic C.sub.3-C.sub.12 heteroaryl fragments, wherein the aryl or heteroaryl fragments are optionally substituted by one or several halogen atoms, nitro, cyano, formyl, COOH, —COO(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 N.sub.3-substituted alkyl, C.sub.1-C.sub.6 NH.sub.2-substituted alkyl, C.sub.1-C.sub.6 alcohol, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.2-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkoxy alkyl, C.sub.2-C.sub.6 haloalkylcarbonyl, C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.3-C.sub.6 trialkylsilyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.2-C.sub.6 haloalkynyloxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.2-C.sub.6 alkenylthio, C.sub.2-C.sub.6 alkynylthio, C.sub.2-C.sub.6 haloalkenylthio, C.sub.2-C.sub.6 haloalkynylthio, a monocyclic C.sub.5-C.sub.6 aryl group optionally substituted by a C.sub.1-C.sub.6 alkyloxy group and/or a COO(C.sub.1-C.sub.6 alkyl) group wherein the alkyl is substituted by NH.sub.2 or NHCOO(C.sub.1-C.sub.6)alkyl or NHCOO(C.sub.1-C.sub.6)alkyl(mono or polycyclic C.sub.5-C.sub.12)aryl; R.sub.6 represents a mono or polycyclic C.sub.5-C.sub.12 aryl fragment, wherein the aryl fragment is optionally substituted by one or several halogen atoms, cyano, formyl, nitro, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.2-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkoxy alkyl, C.sub.2-C.sub.6 haloalkylcarbonyl, C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.3-C.sub.6 trialkylsilyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.2-C.sub.6 haloalkynyloxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.2-C.sub.6 alkenylthio, C.sub.2-C.sub.6 alkynylthio, C.sub.2-C.sub.6 haloalkenylthio, C.sub.2-C.sub.6 haloalkynylthio fragments, and/or a monocyclic C.sub.5-C.sub.6 aryl group optionally substituted by a C.sub.1-C.sub.6 alkyloxy group, provided that at least two of R.sub.3, R.sub.4 and R.sub.5 represent a hydrogen atom and R.sub.2 or R.sub.3 is different from hydrogen; said method comprising the following steps: a. to a compound of formula (II): ##STR00164## wherein R.sub.4 and R.sub.6 are as defined in said compound of formula (I) and R.sub.7 represents a leaving group, optionally, R.sub.6—N—R.sub.7 may form at least one ring wherein R.sub.6 and R.sub.7 directly linked one to each other and wherein said ring comprises from 3 to 12 atoms chosen from C, N, O, S, B and P, substituted by at least one hydrogen, oxygen, nitrogen, hydroxyl, thiol, amine, cyano, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-haloalkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.3-C.sub.6 trialkylsilyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.5-C.sub.12 arylsulfonyl, formyl, C.sub.2-C.sub.6 alkylcarbonyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.2-C.sub.6 alkenylthio, C.sub.2-C.sub.6 alkynylthio, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.2-C.sub.6 haloalkylcarbonyl, C.sub.1-C.sub.6 haloalkylthio, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.2-C.sub.6 haloalkynyloxy, C.sub.2-C.sub.6 haloalkenylthio, C.sub.2-C.sub.6 haloalkynylthio, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl or a mono or polycyclic C.sub.5-C.sub.12 aryl or mono or polycyclic C.sub.3-C.sub.12 heteroaryl fragments, wherein the aryl or heteroaryl fragments are optionally substituted by one or several halogen atoms, nitro, cyano, formyl, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.2-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkoxy alkyl, C.sub.2-C.sub.6 haloalkylcarbonyl, C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.3-C.sub.6 trialkylsilyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.2-C.sub.6 haloalkynyloxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.2-C.sub.6 alkenylthio, C.sub.2-C.sub.6 alkynylthio, C.sub.2-C.sub.6 haloalkenylthio, C.sub.2-C.sub.6 haloalkynylthio and/or nitro fragments; is added a compound of formula (III): ##STR00165## wherein R.sub.1, R.sub.2 and R.sub.3 are as defined in said compound of formula (I) in the presence of a base; b. an optional addition step of R.sub.5 as defined in claim 1 through a nucleophilic addition to the compound obtained in step a., and, c. retrieving the compound of formula (I) as defined in claim 1.
28. The method according to claim 27, wherein R.sub.1 is an electro-donating group and/or R.sub.2 and/or R.sub.3 are electron-withdrawing groups.
29. The method according to claim 27, wherein R.sub.7 represents a leaving group selected from the group consisting of amides, sulfonyl, and_oxy-carbonyls.
30. The method according to claim 27, wherein the nucleophilic addition to the compound obtained in step a. is performed with R5-X, wherein X is a halogen atom in the presence of a base.
31. The method according to claim 27, wherein step (a) is carried out under microwaves.
32. The method according to claim 27, wherein step (a) is carried out under pressure and/or at a temperature above 50° C.
33. The method according to claim 27, wherein step (a) is carried out without the presence of a metal compound, whether it is in its metallic or one of its oxidized or reduced forms.
Description
DETAILED DESCRIPTION
(1) The subject matter of the present invention concerns a compound as presently defined characterized in that R.sub.6 represents a chemical moiety chosen in the group consisting of C.sub.2-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 alkylthio, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, (C.sub.1-C.sub.6)-haloalkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.3-C.sub.6 trialkylsilyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 alkylcarbonyl, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.2-C.sub.6 alkenylthio, C.sub.2-C.sub.6 alkynylthio, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.2-C.sub.6 haloalkylcarbonyl, C.sub.1-C.sub.6 haloalkylthio, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.2-C.sub.6 haloalkynyloxy, C.sub.2-C.sub.6 haloalkenylthio, C.sub.2-C.sub.6 haloalkynylthio, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl, mono or polycyclic C.sub.5-C.sub.12 aryl or mono or polycyclic C.sub.3-C.sub.12 heteroaryl fragment optionally substituted by one or several halogen atoms, nitro, cyano, formyl, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.2-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, (C.sub.5-C.sub.12)-arylsulfonyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkoxy alkyl, C.sub.2-C.sub.6 haloalkylcarbonyl, C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.3-C.sub.6 trialkylsilyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.2-C.sub.6 haloalkynyloxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.2-C.sub.6 alkenylthio, C.sub.2-C.sub.6 alkynylthio, C.sub.2-C.sub.6 haloalkenylthio, C.sub.2-C.sub.6 haloalkynylthio and/or nitro fragments, or a monocyclic C.sub.5-C.sub.6 aryl group optionally substituted by a C.sub.1-C.sub.6 alkyloxy group preferably R.sub.6 represents a mono or polycyclic C.sub.5-C.sub.12 aryl or heteroaryl fragment (preferably a phenyl fragment), wherein the aryl (phenyl) fragment is optionally substituted by one or several (notably 1 to 3) halogen atoms, cyano, formyl, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.2-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkoxy alkyl, C.sub.2-C.sub.6 haloalkylcarbonyl, C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.3-C.sub.6 trialkylsilyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.2-C.sub.6 haloalkynyloxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.2-C.sub.6 alkenylthio, C.sub.2-C.sub.6 alkynylthio, C.sub.2-C.sub.6 haloalkenylthio, C.sub.2-C.sub.6 haloalkynylthio and/or nitro fragments, or a monocyclic C.sub.5-C.sub.6 aryl group optionally substituted by a C.sub.1-C.sub.6 alkyloxy group, such as a phenyl group optionally substituted by a C.sub.1-C.sub.6 alkyloxy group, in particular a (4-)methoxyphenyl group. Even more preferably, R.sub.6 represents a mono or polycyclic C.sub.5-C.sub.12 aryl fragment (such as a phenyl group), optionally substituted by one or several (notably 1 to 3) halogen atoms, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkoxy. More preferably, R.sub.6 is a monocyclic aryl fragment such as a phenyl group, optionally substituted by one or several (notably 1 to 3) halogen atoms, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkoxy such as Cl, I, F, Br, CF.sub.3 or OMe, especially for the method of preparation of the compound of formula (I) according to the present invention.
(2) The subject matter of the present invention concerns a compound as presently defined, characterized in that R.sub.1 represents an aryl or heteroaryl fragment, wherein the aryl or heteroaryl fragments are optionally substituted by one or several halogen atoms, hydroxyl (OH), nitro, cyano, formyl, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, amino-C.sub.1-C.sub.10 alkoxy, (carboxylic acid)-C.sub.1-C.sub.10 alkoxy, (carboxylic (C.sub.1-C.sub.6)alkyl ester)-C.sub.1-C.sub.10 alkoxy, (1,2 diol)-C.sub.2-C.sub.10 alkoxy, —O—(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-OH, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.2-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkoxy alkyl, C.sub.2-C.sub.6 haloalkylcarbonyl, C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.3-C.sub.6 trialkylsilyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.2-C.sub.6 haloalkynyloxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.2-C.sub.6 alkenylthio, C.sub.2-C.sub.6 alkynylthio, C.sub.2-C.sub.6 haloalkenylthio, C.sub.2-C.sub.6 haloalkynylthio and/or a C.sub.1-C.sub.6 alkoxy optionally substituted by a mono or polycyclic C.sub.5-C.sub.12 aryl group, and/or a bridging group of formula —O—CH.sub.2—O— or —O—CH.sub.2CH.sub.2—O—.
(3) In a particular embodiment, R.sub.1 represents an aryl or heteroaryl fragment optionally substituted by one or several (notably 1 to 3) C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 thioalkyl, halogen, amino-C.sub.1-C.sub.10 alkoxy, (carboxylic acid)-C.sub.1-C.sub.10 alkoxy, (1,2 diol)-C.sub.2-C.sub.10 alkoxy, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl ester and/or nitro fragments, especially for the method of preparation of the compound of formula (I) according to the present invention. Preferably, R.sub.1 is an electro-donating group, especially for the method of preparation of the compound of formula (I) according to the present invention.
(4) Preferably, the compounds of the present invention are characterized in that R.sub.1 represents a monocyclic aryl fragment optionally substituted by one or several (notably 1 to 3) OH, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 thioalkyl, halogen, amino-(C.sub.1-C.sub.10 alkoxy), (carboxylic acid)-(C.sub.1-C.sub.10 alkoxy), (carboxylic (C.sub.1-C.sub.6)alkyl ester)-C.sub.1-C.sub.10 alkoxy, (1,2 diol)-C.sub.2-C.sub.10 alkoxy, —O—(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-OH, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl ester, nitro and/or a C.sub.1-C.sub.6 alkoxy group optionally substituted by a mono or polycyclic C5-C12 aryl group, and/or a bridging group of formula —O—CH.sub.2—O— or —O—CH.sub.2CH.sub.2—O—,
especially for the method of preparation of the compound of formula (I) according to the present invention.
(5) More preferably, the compounds of the present invention are characterized in that R.sub.1 represents a monocyclic aryl fragment optionally substituted by one or several (notably 1 to 3): OH, C.sub.1-C.sub.6 thioalkyl, in particular SCH.sub.3, C.sub.2-C.sub.6 alkenyl, such as —CH═CH.sub.2 (vinyl group), halogen, such as iodine, (carboxylic acid)-(C.sub.1-C.sub.10 alkoxy), such as OCH.sub.2COOH, (carboxylic (C.sub.1-C.sub.6)alkyl ester)-C.sub.1-C.sub.10 alkoxy, such as OCH.sub.2COOCH.sub.3, OCH.sub.2COOCH.sub.2CH.sub.3 or OCH.sub.2COOC(CH.sub.3).sub.3, in particular OCH.sub.2COOC(CH.sub.3).sub.3, (1,2 diol)-C.sub.2-C.sub.10 alkoxy, such as OCH.sub.2CHOHCH.sub.2OH, —O—(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-OH, such as OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OH, and/or C.sub.1-C.sub.6 alkoxy group optionally substituted by a mono or polycyclic C.sub.5-C.sub.12 aryl group, such as OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2Ph, and/or a bridging group of formula —O—CH.sub.2—O— or —O—CH.sub.2CH.sub.2—O—,
(6) even more preferably, R.sub.1 represents a monocyclic aryl fragment optionally substituted by one or several (notably 1 to 3) OH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 thioalkyl, halogen, amino-(C.sub.1-C.sub.10 alkoxy), (carboxylic acid)-(C.sub.1-C.sub.10 alkoxy), (carboxylic (C.sub.1-C.sub.6)alkyl ester)-C.sub.1-C.sub.10 alkoxy, (1,2 diol)-C.sub.2-C.sub.10 alkoxy, —O—(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-OH, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl ester, nitro and/or a C.sub.1-C.sub.6 alkoxy group optionally substituted by a mono or polycyclic C.sub.5-C.sub.12 aryl group, and/or a bridging group of formula —O—CH.sub.2—O— or —O—CH.sub.2CH.sub.2—O—,
especially for the method of preparation of the compound of formula (I) according to the present invention.
(7) More preferably, the compounds of the present invention are characterized in that R.sub.1 represents a monocyclic aryl fragment optionally substituted by one or several (notably 1 to 3): OH, C.sub.1-C.sub.6 thioalkyl, in particular SCH.sub.3 halogen, such as iodine, (carboxylic (C.sub.1-C.sub.6)alkyl ester)-C.sub.1-C.sub.10 alkoxy, such as OCH.sub.2COOCH.sub.3, OCH.sub.2COOCH.sub.2CH.sub.3 or OCH.sub.2COOC(CH.sub.3).sub.3, in particular OCH.sub.2COOC(CH.sub.3).sub.3, (1,2 diol)-C.sub.2-C.sub.10 alkoxy, such as OCH.sub.2CHOHCH.sub.2OH, —O—(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-OH, such as OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OH, and/or C.sub.1-C.sub.6 alkoxy group optionally substituted by a mono or polycyclic C.sub.5-C.sub.12 aryl group, such as OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2Ph, and/or
a bridging group of formula —O—CH.sub.2—O— or —O—CH.sub.2CH.sub.2—O—,
especially for the method of preparation of the compound of formula (I) according to the present invention.
(8) For instance, the compounds of the present invention are characterized in that R.sub.1 represents a monocyclic aryl fragment optionally substituted by one or several C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 thioalkyl, halogen, amino-(C.sub.1-C.sub.10 alkoxy), (carboxylic acid)-(C.sub.1-C.sub.10 alkoxy), (1,2 diol)-C.sub.2-C.sub.10 alkoxy, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl ester and/or nitro fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(9) In a particular embodiment, the compounds of the present invention are characterized in that R.sub.1 represents a phenyl fragment optionally substituted by one or several C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 thioalkyl, halogen, amino-C.sub.1-C.sub.10 alkoxy, (carboxylic acid)-C.sub.1-C.sub.10 alkoxy, (2,3 diol)-propoxy, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl ester and/or nitro fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(10) In a particular embodiment, the compounds of the present invention are characterized in that R.sub.1 represents an aryl fragment substituted by one or several iodine atoms, methoxy, methylthio, ethyloxy, amino-C.sub.1-C.sub.10 alkoxy, (carboxylic acid)-C.sub.1-C.sub.10 alkoxy, (2,3 diol)-propoxy, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl ester and/or nitro fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(11) Yet in a particular embodiment, the compounds of the present invention are characterized in that R.sub.1 represents an aryl fragment substituted by one or three methoxy groups, one methylthio group, one ethoxy group, one iodine atom, one (2,3 diol)-propoxy group and/or nitro fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(12) In a preferred embodiment, the compounds of the present invention are characterized in that R.sub.1 represents a phenyl fragment substituted by one or three methoxy groups, one methylthio group, one ethoxy group, one iodine atom, one (2,3 diol)-propoxy group and/or nitro fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(13) In a particular embodiment, the compounds of the present invention are characterized in that R.sub.1 represents a phenyl fragment, a 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a 4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a 4-nitro phenyl or a 4-[(2,3 diol)-propoxy]-phenyl fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(14) In another embodiment, the compounds of the present invention are characterized in that R.sub.1 represents a monocyclic aryl fragment optionally substituted by one or several halogen atoms, C.sub.1-C.sub.6 alkoxy and/or C.sub.1-C.sub.6 thioalkyl fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(15) Preferably, the compounds of the present invention are characterized in that R.sub.1 represents a phenyl fragment optionally substituted by one or several halogen atoms, C.sub.1-C.sub.6 alkoxy and/or C.sub.1-C.sub.6 thioalkyl fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(16) In a particular embodiment, the compounds of the present invention are characterized, the compounds of the present invention are characterized in that R.sub.1 represents an aryl fragment substituted by one or several iodine atoms, methoxy, methylthio and/or ethyloxy fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(17) In a particular embodiment, the compounds of the present invention are characterized, the compounds of the present invention are characterized in that R.sub.1 represents an aryl fragment substituted by one iodine atom, one or three methoxy groups, one methylthio group and/or one ethoxy group, especially for the method of preparation of the compound of formula (I) according to the present invention.
(18) In a preferred embodiment, the compounds of the present invention are characterized in that R.sub.1 represents a phenyl fragment substituted by one iodine atom, one or three methoxy groups, one ethoxy group, one benzyloxy group, one OCH.sub.2COOH group, one OCH.sub.2COOC(CH.sub.3).sub.3 group, one OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OH group, one OH group, one OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OH group, one methylthio group and/or one bridging group of formula —O—CH.sub.2—O— or —O—CH.sub.2CH.sub.2—O—, even more preferably, by one iodine atom, one or three methoxy groups, one ethoxy group, one benzyloxy group, one OCH.sub.2COOC(CH.sub.3).sub.3 group, one OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OH group, one OH group, one OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2OH group, one methylthio group and/or one bridging group of formula —O—CH.sub.2—O— or —O—CH.sub.2CH.sub.2—O—, especially for the method of preparation of the compound of formula (I) according to the present invention.
(19) In a preferred embodiment, the compounds of the present invention are characterized in that R.sub.1 represents a phenyl fragment substituted by one iodine atom, one or three methoxy groups, one methylthio group and/or one ethoxy group, especially for the method of preparation of the compound of formula (I) according to the present invention.
(20) In a particularly preferred embodiment, the compounds of the present invention are characterized in that R.sub.1 represents a phenyl fragment, a 4-hydroxyphenyl, a 4-methoxyphenyl, a 2-methoxyphenyl, a 3-methoxyphenyl, a 3,4-dimethoxyphenyl, a 3,4,5-trimethoxyphenyl, a 4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-benzyloxy-phenyl, a 1,3-benzodioxole, a 1,4-benzodioxane, a 4-[(2,3 diol)-propoxy]-phenyl, a 4-phenoxyacetic acid, a tert-butyl 4-(phenoxy)acetate, a 4-(bis(2-hydroxyethyl)ether)phenyl or a 4-iodo-phenyl, even more preferably, R.sub.1 represents a phenyl fragment, a 4-hydroxyphenyl, a 4-methoxy phenyl, a 2-methoxy phenyl, a 3-methoxy phenyl, a 3,4-dimethoxyphenyl, a 3,4,5-trimethoxyphenyl, a 4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-benzyloxy-phenyl, a 1,3-benzodioxole, a 1,4-benzodioxane, a 4-[(2,3 diol)-propoxy]-phenyl, a tert-butyl 4-(phenoxy)acetate, a 4-(bis(2-hydroxyethyl)ether)phenyl or a 4-iodo-phenyl, especially for the method of preparation of the compound of formula (I) according to the present invention.
(21) In another particularly preferred embodiment, the compounds of the present invention are characterized in that R.sub.1 represents a phenyl fragment, a 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a 4-methylthio-phenyl, a 4-ethoxy-phenyl or a 4-iodo-phenyl, especially for the method of preparation of the compound of formula (I) according to the present invention.
(22) The subject matter of the present invention also concerns a compound as defined presently, characterized in that R.sub.2 and/or R.sub.3 represent a C.sub.1-C.sub.6 haloalkyl, a C.sub.1-C.sub.6 alkoxy, a C.sub.1-C.sub.6 thioalkyl, a C.sub.1-C.sub.6 acyl, nitro and/or a cyano fragments, a mono or polycyclic aryl or heteroaryl fragment optionally substituted by one or several halogen atoms, nitro, cyano, formyl, COOH, —COO(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7 cycloalkyl, C.sub.1-C.sub.6 N.sub.3-substituted alkyl, C.sub.1-C.sub.6 NH.sub.2-substituted alkyl, C.sub.1-C.sub.6 alcohol, C.sub.1-C.sub.6 alkoxy, (C.sub.1-C.sub.6)-alkoxy-(C.sub.1-C.sub.6)-alkyl, C.sub.2-C.sub.6 alkylcarbonyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 thioalkyl, (C.sub.1-C.sub.6)-alkylthio-(C.sub.1-C.sub.6)-alkyl, C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 haloalkoxy alkyl, C.sub.2-C.sub.6 haloalkylcarbonyl, C.sub.1-C.sub.6 haloalkylthio, C.sub.1-C.sub.6 haloalkylsulfinyl, C.sub.1-C.sub.6 haloalkylsulfonyl, C.sub.3-C.sub.6 trialkylsilyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 haloalkenyloxy, C.sub.2-C.sub.6 haloalkynyloxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.2-C.sub.6 alkenylthio, C.sub.2-C.sub.6 alkynylthio, C.sub.2-C.sub.6 haloalkenylthio, C.sub.2-C.sub.6 haloalkynylthio, a monocyclic C.sub.5-C.sub.6 aryl group optionally substituted by a C.sub.1-C.sub.6 alkyloxy group and/or a COO(C.sub.1-C.sub.6 alkyl) group wherein the alkyl is substituted by NH.sub.2 or NHCOO(C.sub.1-C.sub.6)alkyl or NHCOO(C.sub.1-C.sub.6)alkyl(mono or polycyclic C.sub.5-C.sub.12)aryl (preferably the alkyl in the COO(C.sub.1-C.sub.6 alkyl) group is substituted by NHCOO(C.sub.1-C.sub.6)alkyl or NHCOO(C.sub.1-C.sub.6)alkyl(mono or polycyclic C.sub.5-C.sub.12)aryl), especially for the method of preparation of the compound of formula (I) according to the present invention.
(23) In particular, R.sub.2 and/or R.sub.3 represent a C.sub.1-C.sub.6 haloalkyl, a C.sub.1-C.sub.6 alkoxy, a C.sub.1-C.sub.6 thioalkyl, a C.sub.1-C.sub.6 acyl, nitro and/or a cyano fragments, a mono or polycyclic aryl or heteroaryl fragment optionally substituted by one or several halogen atoms, especially for the method of preparation of the compound of formula (I) according to the present invention.
(24) Preferably R.sub.2 (and/or R.sub.3) is an electron-enricher group, i.e. an electron donating group, especially for the method of preparation of the compound of formula (I) according to the present invention. Specifically, in one embodiment of the present invention, the compounds of the present invention are characterized in that R.sub.2 and/or R.sub.3 represent at least one electron-withdrawing group chosen in the list consisting of a para-halogenophenyl, a CF.sub.3, a phenyl, a fragment comprising a carbonyl such as an acyl, a cyano, a 3-pyridyl, a 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a 4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a 4-nitro phenyl or a 4-[(2,3 diol)-propoxy]-phenyl fragment.
(25) Preferably, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent a monocyclic aryl, monocyclic heteroaryl or polycyclic aryl fragment optionally substituted by one or several (notably 1 to 3) halogen atoms, C.sub.1-C.sub.6 NH.sub.2-substituted alkyl, COOH, —COO(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 N.sub.3-substituted alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alcohol, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 acyl, C.sub.2-C.sub.6 alkenyl, nitro, cyano, a monocyclic C.sub.5-C.sub.6 aryl group optionally substituted by a C.sub.1-C.sub.6 alkyloxy group (such as a phenyl group substituted by a C.sub.1-C.sub.6 alkyloxy group, preferably a methoxy group) and/or a COO(C.sub.1-C.sub.6 alkyl) group wherein the alkyl is substituted by NH.sub.2 or NHCOO(C.sub.1-C.sub.6)alkyl or NHCOO(C.sub.1-C.sub.6)alkyl(mono or polycyclic C.sub.5-C.sub.12)aryl, fragments (preferably the alkyl in the COO(C.sub.1-C.sub.6 alkyl) group is substituted by NHCOO(C.sub.1-C.sub.6)alkyl or NHCOO(C.sub.1-C.sub.6)alkyl(mono or polycyclic C.sub.5-C.sub.12)aryl), especially for the method of preparation of the compound of formula (I) according to the present invention.
(26) Preferably, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent a monocyclic aryl, monocyclic heteroaryl or polycyclic aryl fragment optionally substituted by one or several halogen atoms, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 acyl, nitro and/or cyano fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(27) For example, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent a phenyl fragment, a pyridyl fragment, or a naphthalene fragment, optionally substituted by one or several (notably 1 to 3) halogen atoms, COOH, —COO(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 N.sub.3-substituted alkyl, C.sub.1-C.sub.6 NH.sub.2-substituted alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alcohol, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 thioalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 acyl, nitro, cyano, a monocyclic C.sub.5-C.sub.6 aryl group optionally substituted by a C.sub.1-C.sub.6 alkyloxy group (such as a phenyl group substituted by a C.sub.1-C.sub.6 alkyloxy group, preferably a methoxy group) and/or a COO(C.sub.1-C.sub.6 alkyl) group wherein the alkyl is substituted by NH.sub.2 or NHCOO(C.sub.1-C.sub.6)alkyl or NHCOO(C.sub.1-C.sub.6)alkyl(mono or polycyclic C.sub.5-C.sub.12)aryl, fragments (preferably the alkyl in the COO(C.sub.1-C.sub.6 alkyl) group is substituted by NHCOO(C.sub.1-C.sub.6)alkyl or NHCOO(C.sub.1-C.sub.6)alkyl(mono or polycyclic C.sub.5-C.sub.12)aryl), especially for the method of preparation of the compound of formula (I) according to the present invention.
(28) In particular, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent a phenyl fragment, a pyridyl fragment, or a naphthalene fragment, optionally substituted by one or several halogen atoms, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 acyl, nitro and/or cyano fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(29) More preferably, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent an aryl fragment substituted by one or several chlorine atoms, fluorine atoms, methoxy, COOH, COOCH.sub.3, COOC(CH.sub.3).sub.3, COOCH.sub.2CH.sub.2NH.sub.2, COOCH.sub.2CH.sub.2NHCOOC(CH.sub.3).sub.3, CH.sub.2OH, CH.sub.2N.sub.3, CH.sub.2NH.sub.2, CH.sub.2Cl, vinyl, nitro, 4-methoxyphenyl, and/or cyano fragments, even more preferably by one or several chlorine atoms, fluorine atoms, methoxy, COOH, COOCH.sub.3, COOC(CH.sub.3).sub.3, COOCH.sub.2CH.sub.2NHCOOC(CH.sub.3).sub.3, CH.sub.2N.sub.3, CH.sub.2Cl, nitro and/or cyano fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(30) Even more preferably, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent an aryl fragment substituted by one or several chlorine atoms, fluorine atoms, methoxy fragments, nitro and/or cyano fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(31) Yet more preferably, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent an aryl fragment optionally substituted by one, two or three methoxy groups, one methylthio group, one ethoxy group, one iodine atom, one fluorine atom, one or two chlorine atom, one (2,3 diol)-propoxy group, one COOH group, one vinyl group, one COOCH.sub.3 group, one COOC(CH.sub.3).sub.3 group, one COOCH.sub.2CH.sub.2NH.sub.2 group, one COOCH.sub.2CH.sub.2NHCOOC(CH.sub.3).sub.3 group, one CH.sub.2OH group, one CH.sub.2N.sub.3 group, one CH.sub.2NH.sub.2 group, one CH.sub.2Cl group, one 4-methoxyphenyl, and/or nitro fragments, even more preferably by one, two or three methoxy groups, one methylthio group, one ethoxy group, one iodine atom, one fluorine atom, one or two chlorine atom, one (2,3 diol)-propoxy group, one COOH group, one COOCH.sub.3 group, one COOC(CH.sub.3).sub.3 group, one COOCH.sub.2CH.sub.2NHCOOC(CH.sub.3).sub.3 group, one CH.sub.2N.sub.3 group, one CH.sub.2Cl group, and/or nitro fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(32) Yet more preferably, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent an aryl fragment substituted by one or three methoxy groups, one methylthio group, one ethoxy group, one iodine atom, one (2,3 diol)-propoxy group and/or nitro fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(33) Yet more preferably, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent: a phenyl fragment optionally substituted by one methoxy group, one fluorine atom, one or two chlorine atoms, one vinyl group, one COOH group, one COOCH.sub.3 group, one COOC(CH.sub.3).sub.3 group, one COOCH.sub.2CH.sub.2NH.sub.2 group, one COOCH.sub.2CH.sub.2NHCOOC(CH.sub.3).sub.3 group, one CH.sub.2OH group, one CH.sub.2N.sub.3 group, one CH.sub.2NH.sub.2 group, one CH.sub.2Cl group and/or one 4-methoxyphenyl, preferably a phenyl fragment optionally substituted by one methoxy group, one fluorine atom, one or two chlorine atoms, one COOH group, one COOCH.sub.3 group, one COOC(CH.sub.3).sub.3 group, one COOCH.sub.2CH.sub.2NHCOOC(CH.sub.3).sub.3 group, one CH.sub.2N.sub.3 group, and/or one CH.sub.2Cl group, a naphthalene fragment, or a pyridine fragment,
especially for the method of preparation of the compound of formula (I) according to the present invention.
(34) In a more preferred embodiment, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent an phenyl fragment substituted by one or three methoxy groups, one methylthio group, one ethoxy group, one iodine atom, one (2,3 diol)-propoxy group and/or nitro fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(35) In a preferred embodiment, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent a phenyl fragment, a 2-naphthalenyl fragment, a 3-pyridyl fragment, a 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a 4-(hydroxymethyl)-phenyl, a 4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a 4-fluoro-phenyl, a 4-chloro-phenyl, a 3,5-dichloro-phenyl, a 4-nitro phenyl a 4-[(2,3 diol)-propoxy]-phenyl, a 4-(chloromethyl)-phenyl, a 4-(azidomethyl)-phenyl, a 4-(aminomethyl)-phenyl, a 4-carboxylic acid-phenyl (i.e a
(36) ##STR00016##
group), a methyl 4-carboxylate-phenyl (i.e a
(37) ##STR00017##
group), a tert-butyl 4-carboxylate-phenyl (i.e a
(38) ##STR00018##
group), a
(39) ##STR00019##
group (especially as the ammonium salt, such as the corresponding trifluoroacetate ammonium salt) or a
(40) ##STR00020##
group, a 4-vinylphenyl group
(41) ##STR00021##
or a 4-(4-methoxyphenyl)-phenyl group,
(42) ##STR00022##
preferably a phenyl fragment, a 2-naphthalenyl fragment, a 3-pyridyl fragment, a 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a 4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a 4-fluoro-phenyl, a 4-chloro-phenyl, a 3,5-dichloro-phenyl, a 4-nitro phenyl a a 4-[(2,3 diol)-propoxy]-phenyl, a 4-(chloromethyl)-phenyl, a 4-(azidomethyl)-phenyl, a 4-carboxylic acid-phenyl (i.e a
(43) ##STR00023##
group), a methyl 4-carboxylate-phenyl (i.e a
(44) ##STR00024##
group), a tert-butyl 4-carboxylate-phenyl (i.e a
(45) ##STR00025##
group), or a
(46) ##STR00026##
group, especially for the method of preparation of the compound of formula (I) according to the present invention.
(47) In a preferred embodiment, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent a phenyl fragment, a 3-pyridyl fragment, a 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a 4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a 4-nitro phenyl or a 4-[(2,3 diol)-propoxy]-phenyl, especially for the method of preparation of the compound of formula (I) according to the present invention.
(48) In another preferred embodiment, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent a phenyl fragment, a 2-naphthalenyl fragment, a 3-pyridyl fragment, a 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a 4-(hydroxymethyl)-phenyl, a 4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a 4-fluoro-phenyl, a 4-chloro-phenyl, a 3,5-dichloro-phenyl, a 4-(chloromethyl)-phenyl, a 4-(azidomethyl)-phenyl, a 4-(aminomethyl)-phenyl, a 4-vinylphenyl group, a 4-(4-methoxyphenyl)-phenyl group, a 4-carboxylic acid-phenyl, a methyl 4-carboxylate-phenyl, a tert-butyl 4-carboxylate-phenyl a
(49) ##STR00027##
group (especially as the ammonium salt, such as the corresponding trifluoroacetate ammonium salt) or a
(50) ##STR00028##
fragment, preferably a phenyl fragment, a 2-naphthalenyl fragment, a 3-pyridyl fragment, a 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, a 4-methylthio-phenyl, a 4-ethoxy-phenyl, a 4-iodo-phenyl, a 4-fluoro-phenyl, a 4-chloro-phenyl, a 3,5-dichloro-phenyl, a 4-(chloromethyl)-phenyl, a 4-(azidomethyl)-phenyl, a 4-carboxylic acid-phenyl, a methyl 4-carboxylate-phenyl, a tert-butyl 4-carboxylate-phenyl or a
(51) ##STR00029##
fragment, especially for the method of preparation of the compound of formula (I) according to the present invention.
(52) Preferably, R.sub.2 (and/or R.sub.3) is an electron-withdrawing group and R.sub.1 is an electro-donating group, especially for the method of preparation of the compound of formula (I) according to the present invention.
(53) In another embodiment, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent monocyclic aryl, monocyclic heteroaryl or polycyclic aryl fragments optionally substituted by one or several halogen atoms and/or C.sub.1-C.sub.6 alkoxy fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(54) More preferably, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent a phenyl fragment optionally substituted by one or several halogen atoms and/or C.sub.1-C.sub.6 alkoxy fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(55) Even more preferably, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent a monocyclic aryl, monocyclic heteroaryl or polycyclic aryl substituted by one or several chlorine atoms, fluorine atoms and/or methoxy fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(56) Yet more preferably, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent a phenyl or pyridyl fragment optionally substituted by one or several chlorine atoms, fluorine atoms and/or methoxy fragments, especially for the method of preparation of the compound of formula (I) according to the present invention.
(57) In a more preferred embodiment, the compound of the present invention is characterized in that R.sub.2 and/or R.sub.3 represent a phenyl, a 3-pyridyl, a 4-methoxy phenyl, a 4-fluoro-phenyl, a 4-chloro phenyl, or a 3,5 dichlorophenyl, especially for the method of preparation of the compound of formula (I) according to the present invention.
(58) Preferably, R.sub.1 is an electro-donating group and R.sub.2 (and/or R.sub.3) is an electron-withdrawing group, especially for the method of preparation of the compound of formula (I) according to the present invention.
(59) The subject matter of the present invention also concerns a compound as presently defined, characterized in that at least one of R.sub.3, R.sub.4 and R.sub.5 represents a hydrogen atom, especially for the method of preparation of the compound of formula (I) according to the present invention.
(60) Preferably, the compound of the present invention is characterized in that at least two of R.sub.3, R.sub.4 and R.sub.5 represent a hydrogen atom, especially for the method of preparation of the compound of formula (I) according to the present invention.
(61) Preferably, the compound of the present invention is characterized in that R.sub.3, R.sub.4 and R.sub.5 represent hydrogen atoms, especially for the method of preparation of the compound of formula (I) according to the present invention. In this embodiment, R.sub.2 preferably represents a monocyclic aryl, monocyclic heteroaryl or polycyclic aryl fragment optionally substituted by one or several (notably 1 to 3) halogen atoms, COOH, —COO(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 N.sub.3-substituted alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alcohol, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 thioalkyl, C.sub.1-C.sub.6 acyl, nitro, cyano and/or a COO(C.sub.1-C.sub.6 alkyl) group wherein the alkyl is substituted by NH.sub.2 or NHCOO(C.sub.1-C.sub.6)alkyl or NHCOO(C.sub.1-C.sub.6)alkyl(mono or polycyclic C.sub.5-C.sub.12)aryl, fragments, especially for the method of preparation of the compound of formula (I) according to the present invention. In particular, R.sub.2 represents: a phenyl fragment optionally substituted by one methoxy group, one fluorine atom, one or two chlorine atoms, one COOH group, one COOCH.sub.3 group, one COOC(CH.sub.3).sub.3 group, one COOCH.sub.2CH.sub.2NH.sub.2 group, one COOCH.sub.2CH.sub.2NHCOOC(CH.sub.3).sub.3 group, one CH.sub.2OH group, one CH.sub.2N.sub.3 group, and/or one CH.sub.2Cl group, preferably a phenyl fragment optionally substituted by one methoxy group, one fluorine atom, one or two chlorine atoms, one COOH group, one COOCH.sub.3 group, one COOC(CH.sub.3).sub.3 group, one COOCH.sub.2CH.sub.2NHCOOC(CH.sub.3).sub.3 group, one CH.sub.2N.sub.3 group, and/or one CH.sub.2Cl group, a naphthalene fragment, or a pyridine fragment.
(62) In this embodiment, R.sub.6 represents a mono or polycyclic C.sub.5-C.sub.12 aryl fragment, optionally substituted by one or several (notably 1 to 3) halogen atoms, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkoxy, more preferably, R.sub.6 is a monocyclic aryl fragment such as a phenyl group, optionally substituted by one or several (notably 1 to 3) halogen atoms, C.sub.1-C.sub.6 haloalkyl or C.sub.1-C.sub.6 alkoxy such as Cl, I, F, Br, CF.sub.3 or OMe. Even more preferably, in this specific embodiment, the compounds of the present invention are preferably characterized in that R.sub.1 represents a monocyclic aryl fragment optionally substituted by one or several (notably 1 to 3) OH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 thioalkyl, halogen, amino-(C.sub.1-C.sub.10 alkoxy), (carboxylic acid)-(C.sub.1-C.sub.10 alkoxy), (carboxylic (C.sub.1-C.sub.6)alkyl ester)-C.sub.1-C.sub.10 alkoxy, (1,2 diol)-C.sub.2-C.sub.10 alkoxy, —O—(C.sub.1-C.sub.6)alkyl-O—(C.sub.1-C.sub.6)alkyl-OH, (C.sub.5-C.sub.12)-aryl-(C.sub.1-C.sub.6)-alkyl ester, nitro and/or a C.sub.1-C.sub.6 alkoxy group optionally substituted by a mono or polycyclic C.sub.5-C.sub.12 aryl group, and/or a bridging group of formula —O—CH.sub.2—O— or —O—CH.sub.2CH.sub.2—O—.
(63) The subject matter of the present invention moreover concerns a compound as presently defined, especially for the method of preparation of the compound of formula (I) according to the present invention, characterized in that: R.sub.1 represents a fragment chosen from the group consisting of phenyl, 4-methoxy phenyl, 4-ethoxy-phenyl, 4-nitro phenyl, 3,4,5-trimethoxyphenyl, 4-methylthio-phenyl, 4-iodo-phenyl; and R.sub.2 and/or R.sub.3 represent a fragment chosen from the group consisting of phenyl, 4-methoxy phenyl, 4-formylphenyl, 4-nitro phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, naphtyl, indolyl, furanyl, pyridyl, thiophenyl.
(64) The subject matter of the present invention preferably concerns a compound as presently defined, especially for the method of preparation of the compound of formula (I) according to the present invention, characterized in that: R.sub.1 represents a fragment chosen from the group consisting of phenyl, 4-methoxy phenyl, a 3,4,5-trimethoxyphenyl, 4-methylthio-phenyl, 4-ethoxy-phenyl or 4-iodo-phenyl R.sub.2 and/or R.sub.3 represent a fragment chosen from the group consisting of phenyl, 4-methoxy phenyl, 4-formylphenyl, 4-nitro phenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, naphtyl, indolyl, furanyl, pyridyl, thiophenyl.
(65) It is understood that the present invention concerns any combination of particular and/or preferred embodiments of R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6.
(66) In a particular embodiment, especially for the method of preparation of the compound of formula (I) according to the present invention, the subject matter of the present invention concerns the molecules of the following structure:
(67) ##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041##
salts or solvates thereof.
(68) More specifically, especially for the method of preparation of the compound of formula (I) according to the present invention, the subject matter of the present invention concerns the molecules of the following structure:
(69) ##STR00042## ##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050##
salts or solvates thereof.
(70) In particular, especially for the method of preparation of the compound of formula (I) according to the present invention, the subject matter of the present invention concerns the molecules of the following structure:
(71) ##STR00051## ##STR00052## ##STR00053## ##STR00054##
salts or solvates thereof.
(72) The subject matter of the present invention thus also concerns a method to prepare a compound of formula (I) as defined above, including the explicitly excluded compounds above, implicating a compound of formula (II):
(73) ##STR00055##
(74) wherein R.sub.4, R.sub.6 and R.sub.7 are as defined above.
(75) Preferably, R.sub.4 and R.sub.6 have the same definitions in formula (II) as in the case of formula (I) with, if need be, protecting groups on the reacting functions thereof.
(76) R.sub.7 preferably is an electron-withdrawing group such as chosen in the group consisting of carbamates, a sulphonamide, amides and sulfonyles.
(77) More preferably, R.sub.7 is chosen in the group consisting of Boc (i.e. tert-butyloxycarbonyl), acetamide, mesylate or tosylate.
(78) In a particular embodiment of the present invention, R.sub.6—N—R.sub.7 forms at least one ring, comprising e.g. lactames, oxazolidinone, or even sultames. More specifically, R.sub.6—N—R.sub.7 forms 2 or even 3 rings wherein at least one of the rings is a hydrocarbon ring, which can be saturated, unsaturated or aromatic.
(79) The compound(s) of the present invention can be produced, and used in the form of mixtures of enantiomers and/or diasteroisomers.
(80) The expression “mixtures of enantiomers” in the present invention means any mixture of enantiomers. The mixtures can be racemic, i.e. 50/50% of each enantiomer in weight (w/w), or non-racemic, i.e. enriched in one or the other of the enantiomer so that the ratios w/w are between 50/50% and 75/25%, between 75/25% and 90/10% or above 95% of one enantiomer in comparison with the other.
(81) The expression “mixtures of diastereoisomers” in the present invention means any mixture of diastereoisomers in any proportions.
(82) Moreover, the subject matter of the present invention concerns at least one compound of formula (I) for its use as an antibiotic or for its use in combination with an antibiotic characterized in that the antibiotic is effective on bacteria chosen from gram-negative bacteria such as Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, preferably drug resistant forms of gram-negative bacteria to one or several classes of antibiotics comprising β-lactams by production of a β-lactamase.
(83) In a particular embodiment, the present invention concerns a composition of several compounds of formula (I), in particular for its use as a drug (antibiotic), in the form of a mixture of enantiomers and/or diasteroisomers of formula (I).
(84) In another particular embodiment, the present invention concerns a composition of several compounds of formula (I), in particular for its use in combination with at least one known antibiotic as defined hereunder, in the form of a mixture of enantiomers and/or diasteroisomers of formula (I).
(85) The subject matter of the present invention thus also concerns a compound of formula (I) (in its different variants) for its use as a potentiating agent, preferably of an antibiotic.
(86) Indeed, the combination of at least one compound of formula (I) with at least one antibiotic advantageously provides a potentiating effect, i.e. by “potentiating effect/action” it is meant according to the present invention that at least one of the active compounds acts either as a “suicide molecule” as explained above enabling the other active ingredient to be active (i.e. antibiotic), and/or increases the activity of at least one of the other compounds present in term of biological (i.e. antibiotic) activity through e.g. a synergistic effect.
(87) Therefore, said compounds of formula (I) according to the present invention can be used alone, or in combination with each other, or at least one other antibiotic already known. The derivatives thereof, if they have antibiotic activity, can also be used.
(88) Examples of known antibiotics already used as medicaments specific in this field which can be used in combination with at least one compound of the present invention, and whose effect may be potentiated by the compound(s) of formula (I) of the present invention, can belong to at least one of the families consisting of the beta-lactam family (such as an amoxicillin and/or ampicillin), the cephalosporin family (such as cephazolin), the tetracycline family (such as chlortetracycline), the rifamycin family (such as rifampicin), the peptide family (such as a polymyxin), the aminoside family (such as streptomycin), the phenicol family (such as chloramphenicol), the macrolide family (such as erythromycin).
(89) Preferably, the combination comprises at least one known beta-lactam antibiotic. Examples of beta lactams preferentially used according to the present invention comprise carbapenems such as imipenem, meropenem, ertapenem and the compound commonly known as “PZ-601”.
(90) In yet another embodiment, the known antibiotic(s) is/are selected from the group consisting of the amoxicillin, ampicillin, carbapenems, cephazolin the cephalosporins, the glycopeptides, the polymyxins, the gramicidins, tyrocidin, the aminosides, the macrolides, the lincosamides, the synergistins, the phenicols, the tetracyclines, fusidic acid, the oxazolidinones, the rifamycins, the quinolones, the fluoroquinolones, the sulfamides, trimethoprim, and the mixtures thereof.
(91) More preferably, the known antibiotic is selected from the group consisting of the penicillins, oxacillin, cloxacillin, ampicillin, meropenem, ertapenem, PZ-601, amoxicillin, bacampicillin, metampicillin, pivampicillin, azlocillin, mezlocillin, piperacillin, ticarcillin, pivmecillinam, sulbactam, tazobactam, imipenem, cephalexin, cephydroxii, cephaclor, cephatrizine, cephalotin, cephapirin, cephazolin, cephoxitin, cephamandole, cephotetan, cephuroxime, cephotaxime, cephsulodin, cefepime, cephoperazone, cephotiam, cephtazidime, cephtriaxone, cephixime, cephpodoxime, cephepime, colistin, latamoxef, aztreonam, vancomycin, vancocin, teicoplanin, polymyxin B, colistin, bacitracin, tyrothricin, streptomycin, kanamycin, tobramycin, amikacin, sisomycin, dibekacin, netilmycin, spectinomycin, spiramycin, ceftazidime, erythromycin, josamycin, roxithromycin, clarithromycin, azithromycin, lincomycin, clindamycin, virginiamycin, pristinamycin, dalfopristine-quinupristine, chloramphenicol, thiamphenicol, tetracycline, doxycycline, minocycline, fusidic acid, linezolide, rifamycin, rifampicin, nalidixic acid, oxolinic acid, pipemidic acid, flumequin, pefloxacin, norfloxacin, ofloxacin, ciprofloxacin, enoxacin, sparfloxacin, levofloxacin, moxifloxacin, nitroxolin, tilboquinol, nitrofurantoin, nifuroxazide, metronidazole, ornidazole, sulfadiazine, sulfamethisol, trimethoprim, isoniazide and the derivatives and mixtures thereof. Said antibiotics, and more particularly amoxicillin, can optionally be used in association with yet at least one another antibiotic activity enhancer such as clavulanic acid.
(92) The present invention thus also relates to a pharmaceutical composition comprising at least one compound of formula (I) as presently disclosed and to the (medical) use(s) of said composition, advantageously as an antibiotic. Preferably the pharmaceutical composition of the present invention comprises only two therapeutically active substances, at least one of which is a compound of formula (I) as presently disclosed.
(93) In particular embodiment of the present invention, the pharmaceutical composition comprises at least two compounds of formula (I) as presently disclosed.
(94) Moreover, the second therapeutically active substance comprised in the pharmaceutical composition of the invention can be an antibiotic which is already known as such and already used as medicament specific in this field and whose activity is potentiated.
(95) Preferably, the pharmaceutical composition of the present invention comprises at least two therapeutically active substances, one of which exerts a potentiating action on the other(s).
(96) Examples of known antibiotics already used as medicaments specific in this field (such as those cited above) can be used in the pharmaceutical composition of the invention, said known antibiotics' effect may be potentiated by the first therapeutically active substance (i.e. compound of formula (I) according to the present invention, including the excluded compound thereof), as explained above.
(97) Of course, the pharmaceutical composition according to the invention is not restricted to the use of only those antibiotics mentioned above. In fact, considering the potentiating effect exerted by the compound defined in the invention of formula (I), other known or future antibiotics can also be successfully used.
(98) These pharmaceutical compositions can be administered orally, rectally, parenterally, intramuscularly or locally by topical application on the skin and the mucosa. In all cases, the pharmaceutical form of the pharmaceutical composition of the invention shall be adapted to its use. For example, it can be used in the form of a solution, suspension, tablet . . . for oral administration. The compositions for parenteral administration are generally pharmaceutically acceptable sterile solutions or suspensions which can optionally be prepared immediately before use. The aqueous solutions may be suitable for intravenous administration in so far as the pH is properly adjusted and they are made isotonic, for example by adding a sufficient amount of sodium chloride or glucose.
(99) The compositions according to the present invention can be solid or liquid and present in pharmaceutical forms in current use in human medicine or veterinary use such as, for example, simple or coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods.
(100) The active principle or principles can be incorporated in the excipients usually used in these pharmaceutical compositions, such as cellulose derivatives (HPMC, HPC, microcrystalline cellulose, etc.), talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or other media, fatty bodies of animal or plant origin, paraffin derivatives, glycols, different wetting, dispersing or emulsifying agents, preservatives. These compositions can notably take the form of a lyophilisate designed to be dissolved as required in an appropriate solvent, for example pyrogen free sterile water.
(101) The compound(s) and/or pharmaceutical composition(s) according to the invention can be formulated so as to be suitable for a simultaneous or sequential administration of said at least one compound of formula (I) according to the invention and known antibiotic agent(s) as defined above.
(102) The pharmaceutical composition of the invention thus enables the treatment of local or systemic infections caused by resistant microorganisms using doses of the compound of formula (I) the present invention, or combinations thereof eventually with known antibiotic agent(s) as defined above.
(103) In the case of such a combination, the active substance are preferably lower than the doses required for treating the same infections due to susceptible microorganisms with one or the other of these same said compound of formula (I) according to the invention and known antibiotic agent as defined above alone.
(104) The result is to offer a treatment which has at least the following advantages: effectiveness at very low doses against nonresistant microorganisms, effectiveness against microorganisms resistant to at least one therapeutic agent, control of recurrence phenomena, and/or control of phenomena of resistant microorganisms selection.
(105) Advantageously, there is a notable reduction in the risks of toxicity and/or adverse effects (well known to the person of the art for the known antibiotics), thanks to the potentiation which enables the administration of very low doses.
(106) The pharmaceutical compositions of the invention are a simple and efficient means to combat the problems related to microbial agents in general which comprise mainly resistance to therapeutic agents and toxicity of the latter resulting from the use of high doses.
(107) A method according to the present invention for treating patients having a bacterial infection consists in administering to said patients the dose, determined by the physician, of the pharmaceutical composition of the invention comprising suitable doses of at least one compound of formula (I) according to the invention, combined with suitable doses of at least one said known antibiotic agent(s) as defined above.
(108) In a particular embodiment of the present invention, the compositions thus include at least two active principles, one of which at least is a compound of formula (I) as defined presently, which can be administered simultaneously, separately or spread over time. They can for example be provided in kit form, allowing the administration of a compound of general formula (I) and that of another antibacterial compound separately.
(109) The present invention also proposes a kit characterized in that it comprises at least one first container containing a first therapeutically active compound of formula (I) (including all variants, such as the excluded compounds above) and mixtures thereof, and at least one second container containing a second therapeutically active substance which is an antibiotic, in particular as defined above. The kit of the invention preferably contains instructions for use. Said kit enables health care personnel to prepare on demand either a mixture of suitable doses of the desired first therapeutic substance(s) and of the desired antibiotic(s), for a simultaneous administration, or to sequentially and separately administer the suitable dose of at least one said first therapeutically active substance, followed by the suitable dose of at least one said second therapeutically active substance, that is, the suitable antibiotic, or vice versa. However, a mixture for simultaneous use shall be preferred for ease of administration.
(110) Therefore the present invention in particular concerns a kit comprising: at least one first container containing a first therapeutically active compound of formula (I) as defined in any one of claims 1 to 6 or as defined in claim 7 and mixtures thereof, and at least one second container containing a second therapeutically active substance which is an antibiotic, as a combination product for simultaneous, sequential and separate use, in particular in antibiotherapy.
(111) The dose administered of the compounds of formula (I) can vary depending on the severity and nature of the condition being treated, the particular subject, the administration route and the other antibacterial product involved. It can be, for example, between 0.1 mg and 1 g per kg per day, by oral route in humans or for veterinary purposes, or between 0.05 mg and 0.5 g per kg per day by intramuscular or intravenous route in humans or for veterinary purposes. The dose of the known antibacterial compound can also vary depending on the condition being treated, the particular subject, the administration route and the product involved, but generally follows the typical doses prescribed by practitioners, for example for human administration as described in the French reference Vidal. This dose can range up to 10 g per day per patient, or even more. Nevertheless, as a result of the potentiation provided by the compounds of general formula (I) to the known antibacterial compound(s), doses of the latter as part of the combination can be reduced compared to standard doses. The inventive combinations can also be used as disinfectants for surgical instruments.
(112) Another subject matter of the present invention concerns the method to prepare a compound of formula (I) of the present invention which comprises in a first step (a) the addition of a compound of formula (II) as defined above with a compound of formula (III),
(113) ##STR00056##
wherein fragments R.sub.1, R.sub.2, R.sub.3 have the same definitions as in the case of formula (I) with, if need be, protecting groups on the reacting functions thereof.
(114) In a preferred embodiment, at least one of the fragments of R.sub.2 or R.sub.3 in formula (III) is an electron-withdrawing group.
(115) Preferably “electron-withdrawing group”, in the context of the present invention, especially for the method of preparation of the compound of formula (I) according to the present invention, means that none of R.sub.2 or R.sub.3 in formula (III) is a mesomeric attracting fragment.
(116) In another preferred embodiment, especially for the method of preparation of the compound of formula (I) according to the present invention, the fragment R.sub.1 in formula (III) is an electro-donating group (equivalent to “electro-enriching group”).
(117) R.sub.1 may be for example p-methoxyphenyl. The article “Tetrahedron Lett. 2006 47, 8109” shows how to cut off the p-methoxyphenyl moiety and thus liberate the secondary amine, which in turn can be substituted by another R.sub.1. This can of course be applicable to other types of R.sub.1.
(118) In a more preferred embodiment, the fragment R.sub.1 in formula (II) is an electro-donating group, and at least one of the fragments of R.sub.2 or R.sub.3 in formula (II) is an electron-withdrawing group, especially for the method of preparation of the compound of formula (I) according to the present invention. Therefore, in yet a more preferred embodiment, at least one of the fragments of R.sub.2 or R.sub.3 in formula (II) is an inductive attracting fragment such as a para-halogenophenyl, and the fragment R.sub.1 in formula (II) is an electro-donating group, whilst none of R.sub.2 or R.sub.3 in formula (III) is a mesomeric attracting fragment, especially for the method of preparation of the compound of formula (I) according to the present invention.
(119) Preferably compound of formula (II) is added to compound of formula (III) with an excess of compound of formula (II). The excess of compound (II) is preferably superior to 1.5 equivalents (i.e. in moles) of compound (III). More preferably, the excess of compound (II) is comprised between 2 equivalents and 10 equivalents of compound (III).
(120) The addition of step (a) is completed in the presence of a base B1.
(121) Preferably, B1 is a tert-butanolate salt, such as t-BuONa, t-BuOLi, t-BuOK or t-BuONa. Preferably B1 is t-BuOLi.
(122) In yet another embodiment, step (a) comprises an excess of base B1 proportionally to compound (II) in relation to compound (III). The excesses of compound (II) and B1 are preferably superior to 1.5 equivalents (i.e. in moles) of compound (III) (i.e. 1.5 equivalents of compound (II) and 1.5 equivalent of B1 in respect to compound (III)). More preferably, the excesses of compound (II) and B1 are comprised between 2 equivalents and 10 equivalents of compound (III).
(123) The addition of step (a) may also be conducted in the presence of a polar solvent, such as dimethylformamide (“DMF”), preferably with a content of water inferior to 5% molar, more preferably with a content of water inferior to 1% molar (i.e. “dry”), yet in a more preferable embodiment without substantially any water (i.e. “extra dry”). In the most preferred embodiment, step (a) comprises dry or extra dry DMF.
(124) Furthermore the addition of step (a) may be conducted under microwaves, preferably for a period of time comprised between 1 minute and 24 hours, more preferably between 5 minutes and 5 hours, even more preferably between 10 minutes and 1 hour, such as around (±5 minutes) 20 minutes, 30 minutes, 40 minutes or 50 minutes.
(125) In a preferred embodiment, step (a) also comprises silicagel, preferably between 0.5 and 5 equivalents in reference to the imine of formula (III). More preferably, step (a) comprises silicagel between 0.8 and 2 equivalents in referenced to the imine (III). In yet a more preferred embodiment, step (a) comprises around (±0.1 equivalent) 1 equivalent of silicagel.
(126) Moreover, the reaction of step (a) can be made under pressure and/or at a temperature above 50° C.
(127) Preferably the pressure is greater than 1.5 bar, more preferably greater than 2 bars, even more preferably greater than 3 bars.
(128) The temperature of the reaction of step (a) is preferably greater than 60° C., more preferably greater than 75° C., even more preferably greater than 85° C. In a particular preferred embodiment of the present invention, the temperature of step (a) is fixed at around 100° C., i.e. 100° C.±5° C.
(129) Moreover, the method of preparation of the compound of formula (I) as defined above can be characterized in that the reaction of step (a) is made without the presence of a metal compound, such as copper, whether it is in its metallic or one of its oxidized or reduced forms.
(130) In a particular embodiment of the present invention, the method to prepare a compound of formula (I) of the present invention thus comprises in its first step (a), the addition of a compound of formula (II) with a compound of formula (III) as defined above, in the presence of a base B1 which can be a tert-butanolate salt or an equivalent base thereof, such as phenolates, methanolates or hydroxides, wherein said addition of the compounds is made in a polar solvent such as dry or extra dry DMF.
(131) In a preferred embodiment of the present invention, the method to prepare a compound of formula (I) of the present invention comprises in its first step (a) the addition of a compound of formula (II) with a compound of formula (III) as defined above, in the presence of a base B1 which can be a tert-butanolate salt or an equivalent base thereof, said addition of the compounds is made in dry or extra dry DMF wherein the reaction of step (a) is made under pressure and/or at a temperature above 50° C., preferably greater than 75° C., such as 85° C.±5° C. or 100° C.±5° C.
(132) In yet a preferred embodiment of the present invention, the method to prepare a compound of formula (I) of the present invention comprises in a first step (a) the addition of a compound of formula (II) with a compound of formula (III) as defined above, in the presence of a base B1 which is a tert-butanolate salt or an equivalent base thereof, said addition of the compounds is made in dry or extra dry DMF, and wherein the reaction of step (a) is made under microwaves and under pressure and/or at a temperature above 50° C., preferably greater than 75° C., such as 85° C.±5° C. or 100° C.±5° C.
(133) In an even more preferred embodiment of the present invention, the method to prepare a compound of formula (I) of the present invention comprises in its first step (a) the addition of a compound of formula (II), wherein at least one of R.sub.2 or R.sub.3 is an electron-withdrawing group, with a compound of formula (III) as defined above, in the presence of a base B1 which is a tert-butanolate salt or an equivalent base thereof, said addition of the compounds is made in dry or extra dry DMF, and wherein the reaction of step (a) is made under microwaves and under pressure and/or at a temperature above 50° C., preferably greater than 75° C., such as 85° C.±5° C. or 100° C.±5° C.
(134) In an even more preferred embodiment of the present invention, the method to prepare a compound of formula (I) of the present invention comprises in its first step (a) the addition of a compound of formula (II), wherein R.sub.1 is an electro-donating group, with a compound of formula (III) as defined above, in the presence of a base B1 which is a tert-butanolate salt or an equivalent base thereof, said addition of the compounds is made in dry or extra dry DMF, and wherein the reaction of step (a) is made under microwaves and under pressure and/or at a temperature above 50° C., preferably greater than 75° C., such as 85° C.±5° C. or 100° C.±5° C.
(135) In an even more preferred embodiment of the present invention, the method to prepare a compound of formula (I) of the present invention comprises in its first step (a) the addition of a compound of formula (II), wherein R.sub.1 is an electro-donating group and at least one of R.sub.2 or R.sub.3 is an electron-withdrawing group, with a compound of formula (III) as defined above, in the presence of a base B1 which is a tert-butanolate salt or an equivalent base thereof, said addition of the compounds is made in dry or extra dry DMF, and wherein the reaction of step (a) is made under microwaves and under pressure and/or at a temperature above 50° C., preferably greater than 75° C., such as 85° C.±5° C. or 100° C.±5° C.
(136) It is another subject matter of the present invention to propose several imines of formula (III). The obtaining of imines is well documented in the art. Two methods have been used to obtain these compounds. These two methods (“Condition A” and “Condition B”) both use the substitution of the oxygen atom of a carbonyl by the nitrogen atom of an amine:
(137) ##STR00057##
R.sub.1, R.sub.2, R.sub.3 are as defined above, with adequate protecting groups if need-be.
(138) The conditions A comprise silica (1 equivalent) in ethanol as solvent. Preferably ultra sounds are used at ambient temperature (20-25° C.). The time left for the reaction to proceed can for example be comprised between 1 min and 10 hours, preferably around one hour (±20 minutes).
(139) The conditions B comprise toluene as solvent at reflux, for example using a Dean-Stark apparatus. Water appears as a sub product due to the condensation, and thus may be trapped by any convenient means, if need-be. The time left for the reaction to proceed can for example be comprised between 1 hour and 2 days, preferably around one day (±1 hour).
(140) The method of preparation of the compound of formula (I) according to the present invention can furthermore comprise an optional step (b) of addition of R.sub.5 as defined above in the case of formula (I), R.sub.5 being conveniently protected if need-be, through a nucleophilic addition to the compound obtained in step (a).
(141) Preferably the nucleophilic addition can be conducted with R.sub.5—X, wherein X is a halogen atom in the presence of a base B2. Preferably B2 is a non-nucleophilic base, such as N,N-diisopropylethylamine (“DIPEA”), 1,8-diazabicycloundec-7-ene (“DBU”), triethylamine, 2,6-di-tert-butylpyridine, phosphazene bases such as t-Bu-P.sub.4, lithium diisopropylamide (“LDA”), silicon based amides such as sodium or potassium bis(trimethylsilyl)amide (“NaHMDS” and “KHMDS”), 1-Lithio-2,2,6,6-tetramethylpiperidine (“LiTMP” also called “harpoon base”), sodium hydride, potassium hydride, or even sodium butoxide, potassium butoxide or lithium butoxide.
(142) The method of preparation of the compound of formula (I) according to the present invention finally comprises a step (c) of retrieving the compound of formula (I) as defined presently.
(143) By “retrieving” it is understood according to the present invention that the products obtained are extracted by techniques common in the art, e.g. by means of a two-phase washing comprising for example an organic solvent and water; alternatively, it is possible to recover the products in suspension (either in the form of crystals or amorphous solids) in the liquid that contains them, by filtration or drainage. Another way to recover the products may simply evaporate or freeze dry the solvent that contains them. This recovery phase may further contain a purification step by washing the obtained solid or to pass the compounds on a chromatography column.
EXAMPLES
(144) The invention shall become clearer in the following examples describing different embodiments, which are given for purposes of illustration and not by way of limitation.
Example 1: Reaction Conditions Establishment
(145) Different operating conditions involving imines, ynamides and at least a base were tested in order to prepare azetidinimine feature (Table 1).
(146) ##STR00058##
(147) TABLE-US-00001 TABLE 1 Reaction conditions establishment Entry # Base Solvent T(° C.) Heating Time Adjuvant Observations 1 t-BuONa DMF AT — 24 h — imine + ynamide AT — 1 h DMAP No evolution 40 .Math. 16 h — No evolution AT — 72 h Indole cat. No evolution (5 mol %) 2 t-BuONa DMF AT — 24 h Indole cat. imine + ynamide (5 mol %) 3 NaOH DMF AT — 24 h — imine + ynamide 40 .Math. 24 h — imine + ynamide + unknown 4 MeONa DMF AT — 24 h — imine + ynamide (30% 40 .Math. 16 h — No evolution MeOH) 70 .Math. 16 h — No evolution 5 MeONa DMF AT — 24 h — imine + ynamide (solid) 40 .Math. 16 h — No evolution 70 .Math. 16 h — No evolution 6 NaOH DMF AT — 24 h — imine + ynamide + (dried) reduced imine 40 .Math. 16 h — imine + ynamide, no evolution 70 .Math. 16 h — imine + ynamide, no evolution 7 LiOH DMF AT — 24 h — imine + ynamide (dried) 40 .Math. 16 h — No evolution 70 .Math. 16 h — No evolution 8 KOH DMF AT — 24 h — imine + ynamide (dried) 40 .Math. 16 h — No evolution 70 .Math. 16 h — No evolution 9 Cs.sub.2CO.sub.3 DMF AT — 24 h — imine + ynamide 40 .Math. 16 h — No evolution 70 .Math. 16 h — No evolution 10 NaOH dry AT — 24 h — imine + ynamide + (dried) DMF reduced imine 60 .Math. 16 h — imine + ynamide, no evolution 11 t-BuONa dry AT — 24 h — imine + ynamide + DMF azetidinimide 60 .Math. 16 h — No evolution 55% isolated 12 TBAF dry AT — 24 h — imine + ynamide + 1M THF DMF reduced imine TBAF dry 60-80 .Math. 48 h — imine + ynamide, 1M THF DMF no evolution 13 t-BuONa dry AT — 24 h Yb(OTf).sub.3 imine + ynamide + DMF reduced imine 60-80 .Math. 48 h — No evolution 14 TBAF dry AT — 24 h Yb(OTf).sub.3 imine + ynamide + 1M THF DMF reduced imine 60-80 .Math. 48 h — No evolution 15 DBU dry AT — 24 h — imine + ynamide + DMF imine réduite 60-80 .Math. 48h — No evolution
(148) Different conditions of reaction were produced using bases, solvents, adjuvants at different reaction temperatures and times. In the conditions set in this first study (i.e. particular chemical structures of imine and ynamide), the type of base “tert-butoxide” seemed required as well as the use of extra dry DMF (sold in a bottle with septum containing a sieve in the DMF) (entry 11). The method of preparing a compound of formula (I) according to the present invention thus is preferably conducted with a step (a) comprising less than 5% mol of water, relative to the solvent, more preferably less than 3% mol, or less than 1% mol of water, relative to the solvent. In the most preferred embodiment of the method of the invention, no water is present in step (a) of said method. The method of preparing a compound of formula (I) according to the present invention thus is preferably conducted with a step (a) comprising a base B1 which is a tert-butoxide.
Example 2: Optimization of the Reaction Conditions
(149) After having verified the possibility to access the desired compound, the previously determined method was optimized by studying the best reaction conditions (Table 2)
(150) TABLE-US-00002 TABLE 2 optimization of the method Entry # Base Solvent T (° C.) Heating Time Adjuvant Observations 11 t- dry DMF AT — 24 h — imine + ynamide + BuONa azetidinimide 1 t- dry DMF 60 .Math. 16 h — No evolution BuONa 2 t- dry DMF 25 MW 10 min — imine + azetidinimide BuONa (ratio crude NMR 97/3: imine/azet.) 80 MW 30 min — imine + azetidinimide (ratio crude NMR 90/10: imine/azet.) 80 MW 1 h — imine + azetidinimide (ratio crude NMR 80/20: imine/azet.) 3 t- THF 57 MW 1 h — imine + ynamide BuONa (distilled) 4 t-BuOK dry DMF 80 MW 1 h — imine + azetidinimide (ratio crude NMR 48/52: imine/azet.) 46% isolated 5 t-BuOK dry DMF 80 MW 1 h No imine + azetidinimide (ratio molecular crude NMR 45/55: sieve* imine/azet.) 6 t-BuOLi dry DMF 80 MW 1 h — imine + azetidinimide (ratio crude NMR 50/50: imine/azet.) 7 t-BuOK dry DMF 80 MW 1 h 2 eq. of imine + azetidinimide (ratio ynamide crude NMR 37/63: imine/azet.) 45% isolated 8 t-BuOK Toluene 100 MW 1 h — imine - no more ynamide - no azetidinimine 9 t-BuOK dry DMF 80 .Math. 1 h Slow MS - no reaction addition of ynamide at 80° C. 16 h MS - no reaction - no evolution 10 t-BuOK dry DMF AT .Math. 1 h-4 d — MS - no reaction 11 t-BuOK dry DMF 80 MW 1 h 2 eq. of No improvement base 12 t-BuOLi dry DMF 80 MW 1 h No No improvement molecular sieve - 2 eq. of base 13 t-BuOLi dry DMF 80 MW 1 h With No improvement - seems molecular cleaner sieve - 2 eq. of base 14 t-BuOLi dry DMF 80 MW 1 h With No improvement - seems molecular more dirty sieve - 10 eq. of base 15 t-BuOLi N- 80 MW 1 h — MS - no reaction methylacetamide 16 t-BuOLi ACN 65 MW 1 h — MS - no reaction 17 t-BuOLi dry DMF 80 .Math. 1 h Round MS - no reaction bottom flask + refrigerant 16 h No improvement 48 h No improvement 18 t-BuOLi dry DMF 80 .Math. 1 h sealed Traces of azetidinimine tube 16 h No improvement 48 h No improvement 19 t-BuOLi dry DMF 80 MW 2 h — No improvement 1 h 1 equiv. No improvement of ynamide added 20 t-BuOLi dry DMF 80 MW 1 h 10 mol % MS - no reaction of t-BuOLi 21 t-BuOLi dry DMF 80 MW 1 h More Traces of azetidinimine concentrated - 0.16M vs. 0.33M 22 t-BuOLi dry DMF 80 MW 1 h less MS - no reaction concentrated - 0.66M vs. 0.33M 23 t-BuOLi dry DMF 80 MW 1 h Smaller No improvement tube MW 100 1 h — conversion improved 24 t-BuOLi dry DMF 120 MW 1 h smaller Degradation product tube MW 150 1 h No more degradation product 25 t-BuOLi dry DMF 100 MW 1 h silicagel Clear improvement added 2.5 eq. 26 t-BuOLi dry DMF 100 MW 1 h silicagel Formation of a secondary added 2.5 supplementary product eq. + 2 eq. of base 27 t-BuOLi dry DMF 100 MW 1 h silicagel Same as entry 4-1.0 eq. added 1.0 seems to be enough eq. 28 t-BuOLi dry DMF 100 MW 1 h silicagel Formation of a secondary added supplementary product 10.0 eq. 29 t-BuOLi dry DMF 100 MW 1 h Alumina Same as entry 4 added 1.0 eq. 30 t-BuOLi dry DMF 100 MW 1 h Addition No improvement of 10 mol % 31 t-BuOLi dry DMF 100 MW 1 h 3 eq. of Conversion of the imine ynamide clearly improved but the reaction is more dirty 32 t-BuOLi dry DMF 100 MW 1 h 3 eq. of No improvement, on the ynamide 3 contrary times with 20 min interspace *3A molecular sieve being present in other cases in order to avoid parasite reactions with water. (wherein MW = microwave)
(151) This study showed that the use of lithium tert-butoxide was particularly favorable to the reaction conditions previously set. The method of preparing a compound of formula (I) according to the present invention thus is preferably conducted with a step (a) comprising a base B1 which is lithium tert-butoxide. Furthermore, the reaction time could be reduced to 1 hour by use of microwaves to an optimized temperature of 100° C. The method of preparing a compound of formula (I) according to the present invention thus is preferably conducted with a step (a) comprising microwaves for a period of time stretching up e.g. up to 24 hours, preferably around 1 hour (±15 minutes), at a temperature above 80° C., preferably around 100° C. (±10° C.). It was therefore determined that the use of e.g. microwaves makes it possible to obtain in a significant quantity the desired product.
(152) Other parameters were also studied. The most relevant parameter was the addition of silicagel which proved to be particularly favorable to the reaction. Indeed, the use of 1 equivalent of Silicagel was sufficient to significantly increase the conversion of the starting imine. The method of preparing a compound of formula (I) according to the present invention thus is preferably conducted with a step (a) comprising silicagel, preferably in a quantity of around 1 equivalent (±0.1 eq) in respect of the product at the lowest quantity engaged in the reaction, e.g. the imine. Finally it was also found that the conversion of the imine could be improved with the use of an excess of ynamide (2 equiv.) accompanied by a proportional base B1 excess (2 equiv.). The method of preparing a compound of formula (I) according to the present invention thus is preferably conducted with a step (a) comprising an excess of ynamide, e.g. around 2 eq. (±0.1 eq.) in respect of the imine. The method of preparing a compound of formula (I) according to the present invention thus is preferably conducted with a step (a) comprising an excess of base B1, e.g. around 2 eq. (±0.1 eq.) in respect of the imine. More preferably, the method of preparing a compound of formula (I) according to the present invention thus is conducted with a step (a) comprising an excess of ynamide, e.g. around 2 eq. (±0.1 eq.) in respect of the imine, accompanied by a proportional base B1 excess, e.g. around 2 eq. (±0.1 eq.) in respect of the imine.
(153) Multiple optimization tests were summarized in Table 2. The conditions adopted for the rest of the study were as follows: ynamide (2 eq.); imine (1 eq.); t-BuOLi (2 eq.); Silicagel (1 eq.); extra dry DMF; 100° C., 1 h, micro-waves. The method of preparing a compound of formula (I) according to the present invention thus is preferably conducted with a step (a) comprising around 2 equivalents of ynamide, around 1 equivalent of imine, around 2 equivalents of t-BuOLi, around 1 equivalent of silicagel in extra dry DMF at around 100° C., for 1 h, under micro-waves.
Example 3: Variation of the Imine
(154) An aromatic imine family was first prepared using mainly two methods (Table 3).
(155) ##STR00059##
(156) TABLE-US-00003 TABLE 3 imine syntheses Entry R.sub.2 R.sub.1 method R(%) 1 C.sub.6H.sub.5 4-(OMe)C.sub.6H.sub.4 1 86 2 4-(OMe)C.sub.6H.sub.4 C.sub.6H.sub.5 1 82 3 4-(NO.sub.2)C.sub.6H.sub.4 4-(OMe)C.sub.6H.sub.4 1 86 4 4-(OMe)C.sub.6H.sub.4 4-(OMe)C.sub.6H.sub.4 1 88 5 4-(F)C.sub.6H.sub.4 4-(OMe)C.sub.6H.sub.4 1 94 6 4-(CN)C.sub.6H.sub.4 4-(OMe)C.sub.6H.sub.4 1 67 7 C.sub.6H.sub.5 3,4,5-(OMe).sub.3C.sub.6H.sub.2 1 72 8 C.sub.6H.sub.5 4-(NO.sub.2)C.sub.6H.sub.4 2 57 9 4-(Cl)C.sub.6H.sub.4 4-(OMe)C.sub.6H.sub.4 1 80 10 2-(F)C.sub.6H.sub.4 4-(OMe)C.sub.6H.sub.4 1 10 11 2,4-(Cl).sub.2C.sub.6H.sub.3 4-(OMe)C.sub.6H.sub.4 1 89 12
(157) These imines were then engaged in the conditions to produce azetidinimine starting from ynamide as previously established (Table 4).
(158) ##STR00066##
(159) TABLE-US-00004 TABLE 4 Preparation of azetidinimines by imine variation Entry # R.sub.2 R.sub.1 R(%) 1 C.sub.6H.sub.5 4-(OMe)C.sub.6H.sub.4 55 2 4-(OMe)C.sub.6H.sub.4 C.sub.6H.sub.5 46 3 4-(NO.sub.2)C.sub.6H.sub.4 4-(OMe)C.sub.6H.sub.4 0 4 4-(OMe)C.sub.6H.sub.4 4-(OMe)C.sub.6H.sub.4 40 5 4-(F)C.sub.6H.sub.4 4-(OMe)C.sub.6H.sub.4 83 6 4-(CN)C.sub.6H.sub.4 4-(OMe)C.sub.6H.sub.4 0 7 C.sub.6H.sub.5 3,4,5-(OMe).sub.3C.sub.6H.sub.2 54 8 C.sub.6H.sub.5 4-(NO.sub.2)C.sub.6H.sub.4 0 9 4-(Cl)C.sub.6H.sub.4 4-(OMe)C.sub.6H.sub.4 86 10 2-(F)C.sub.6H.sub.4 4-(OMe)C.sub.6H.sub.4 0 11 2,4-(Cl).sub.2C.sub.6H.sub.3 4-(OMe)C.sub.6H.sub.4 53 12
(160) The application of the method was verified, i.e. the desired compounds were generally obtained in good yields. As previously mentioned, the study showed that the reaction was promoted when the imine was substituted by an electro donating group R.sub.1 and/or an electron-withdrawing group in position R2 (and/or R3 according to formula (I) of the present invention).
(161) Moreover, the p-methoxyphenyl group is a particular good choice for R.sub.1, because of its electron donor character and various procedures described in literature (see e.g. Tetrahedron Lett. 2006 47, 8109) show how to cut off the p-methoxyphenyl moiety and thus liberate the secondary amine.
(162) Moreover, the use of para-halophenyl as R.sub.2 fragment proved particularly effective with excellent yields of up to 86%. The attractor inductive character of these derivatives could be the cause of such success. However, when electron-withdrawing mesomeric derivatives were used as R.sub.2 fragments, it was rarely possible to observe the desired product in significant quantities.
Example 4: Biological Tests
(163) These tests were conducted by comparing UV absorbance slope measurements of impenem alone, and then imipenem with the concerned azetidinimines at given concentrations in the presence of the enzyme. It was thus possible to monitor the hydrolysis of imipenem. Lower the value of the slope, the higher is the percentage of inhibition of the enzyme.
(164) ##STR00073##
(165) Stability tests of imipenem with increasing concentrations of tested molecules of the present invention (T4#1, i.e. compound #1 of table 4; T4#7 i.e. compound #7 of table 4; T4#9 i.e. compound #9 of table 4; T4#2 i.e. compound #2 of table 4) were also conducted (Table 2).
(166) TABLE-US-00005 TABLE 5 Stability tests Slope Slope Slope Slope Entry C (μM) T4#1 T4#7 T4#9 T4#2 1 100 506 174 390 321 2 10 50 10 38 30 3 1 9 0 2 3
Moreover, the different biology test results made on the compounds of the present invention are summarized in the table 6.
(167) TABLE-US-00006 TABLE 6 Biology tests results summary NDM-1 Enzyme OXA-48 Enzyme KPC Enzyme C Inhibition IC.sub.50 C Inhibition IC.sub.50 C Inhibition IC.sub.50 Structures (μM) % (μM) (μM) % (μM) (μM) % (μM)
Example 5: Experimental Section
(168) 1. General Remarks
(169) Melting points were measured in capillary tubes on a Büchi B-540 apparatus and are uncorrected. Infrared spectra were recorded on a Perkin Elmer Spectrum BX FT-IR spectrometer. Proton (1H) and carbon (13C) NMR spectra were recorded on Bruker spectrometers: Avance 300 MHz (QNP—13C, 31P, 19F—probe or Dual 13C probe) and Avance 500 MHz (BB0—ATM probe or BBI—ATM probe). Carbon NMR (13C) spectra were recorded at 125 or 75 MHz, using a broadband decoupled mode with the multiplicities obtained using a JMOD or DEPT sequence. NMR experiments were carried out in deuterochloroform (CDCl3), chemical shifts (δ) are reported in parts per million (ppm) with reference to CDCl3 (1H: 7.26; 13C: 77.00). The following abbreviations are used for the proton spectra multiplicities: s: singlet, bs: broad singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br: broad. Coupling constants (J) are reported in Hertz (Hz). Mass spectra were obtained either with a LCT (Micromass) instrument using electrospray ionization (ES), or from a Time of Flight analyzer (ESI-MS) for the high resolution mass spectra (HRMS). Elemental analyses were performed on a Perkin Elmer CHN 2400 analyzer with detection by catharometry. Thin-layer chromatography was performed on silica gel 60 F254 on aluminium plates (Merck) and visualized under a UVP Mineralight UVLS-28 lamp (254 nm) and with ninhydrin and phosphomolybdic acid in ethanol. Flash chromatography was conducted on Merck silica gel 60 (40-63 μm) at medium pressure (300 mbar) or on CombiFlash apparatus (Serlabo Technologies), using standard settings. Chiral High Pressure Liquid Chromatography (HPLC) was performed on a Waters 2695 Separations Module equipped with a diode array UV detector (254 nm) and with a Daicel CHIRACEL IA column (4.6*250 nm, 5 mm). Data are reported as follows: column temperature, eluent, flow rate, retention time. Microwaves irradiation experiments were carried out in an Anton Paar Monowave 300 instrument with internal optic-fiber- or IR temperature control.
(170) All reagents were obtained from commercial suppliers unless otherwise stated. Where necessary, organic solvents were routinely dried and/or distilled prior to use and stored over molecular sieves under nitrogen commercial DMF (anhydrous DMF was purchased from Sigma-Aldrich in Sure/Seak™ Bottles. Organic extracts were dried over magnesium sulfate (MgSO.sub.4).
(171) 2. General Procedures
(172) General Procedure A: Imine Formation
(173) Aldehyde (1.0 equiv.), aniline (1.0 equiv.) and silica (1.0 equiv.) are successively added in a round bottom flask followed by the addition of ethanol (0.7M). The mixture is then placed in an ultrasound unit for 5-10 minutes (monitored by TLC) and filtered to remove silica. After concentration under reduced pressure, the crude imine is recrystallized in absolute ethanol.
(174) General Procedure B: Azetidinimine Formation
(175) Imine (1.0 equiv.), ynamide (2.0 equiv.), t-BuOLi (2.0 equiv.) and silica (1.0 equiv.) are successively added in a microwave sealed tube placed under argon before the addition of extra dry DMF (0.3M). The sealed tube is caped and placed in a microwave apparatus for 1 h at 100° C. After cooling, the crude material is transferred in a round bottom flask, concentrated under reduced pressure and purified by flash chromatography or preparative TLC on silica gel with appropriated solvents.
(176) General Procedure C: Formation of Carboxylic Acids from Tert-Butyl Esters Under Acidic Hydrolysis Conditions
(177) A solution of the corresponding tert-butyl ester in DCM (1 mL/30 mg of tert-nutyl ester) is cooled to 0° C. then TFA (trifluoroacetic acid, 1 mL, excess) is added. After 1 h (thin layer chromatography (TLC) monitoring), the mixture is cooled to 0° C. then a saturated aqueous solution of NaHCO.sub.3 is added dropwise until pH 7. The aqueous layer is extracted once with DCM (dichloromethane). The organic layers are washed with water and brine, dried over sodium sulfate, filtered then evaporated under reduced pressure. The resulting residue is purified by automated flash chromatography using a gradient of MeOH in DCM (MeOH 0%.fwdarw.40% over 20 min).
(178) General Procedure D: Demethylation or the t-Butyl Ester Hydrolysis with BBr.sub.3
(179) An argon-flushed and stirred solution of azetidinimine in anhydrous dichloromethane (DCM) (at a concentration of around 0.1 M) is cooled at −78° C., then BBr.sub.3 (1M solution in DCM, 4 equiv.) is added dropwise. The solution is further stirred at −78° C. for 2 h then allowed to warm to room temperature. Once the reaction completed (TLC monitoring), the reaction mixture is carefully quenched at −78° C. with a 1:1 mixture of MeOH/DCM (10 mL). After warming to room temperature, the solvents are evaporated then the crude residue is resolubilized in DCM, washed with saturated aqueous NaHCO.sub.3 and water. The organic layer is dried on sodium sulfate, filtered then evaporated under reduced pressure. The resulting residue is subsequently purified by automated flash chromatography using a gradient of AcOEt in heptane (AcOEt 0%.fwdarw.60% over 30 min).
(180) 3. Analytical Data for some Azetidinimines Products According to the Present Invention
E)-N-(1-(4-methoxyphenyl)-4-phenylazetidin-2-ylidene)aniline
(181) ##STR00111##
(182) C.sub.22H.sub.20N.sub.2O—Exact Mass: 328,1576; .sup.1H NMR (300 MHz, CDCl.sub.3): (ppm) 7.37-7.16 (m, 9H), 6.99-6.92 (m, 3H), 6.72 (d, J=9.1 Hz, 2H), 5.07 (dd, J=6.1, 2.9 Hz, 1H), 3.66 (s, 3H), 3.42 (dd, J=14.6, 6.1 Hz), 2.86 (dd, J=14.6, 2.9 Hz). .sup.13C NMR (75 MHz, CDCl.sub.3): (ppm) 154.8 (C), 154.1 (C), 148.6 (C), 139.4 (C), 133.7 (C), 129.1 (2CH), 128.9 (2CH), 128.3 (CH), 125.9 (2CH), 122.8 (CH), 122.2 (2CH), 117.5 (2CH), 114.2 (2CH), 58.2 (CH), 55.5 (CH.sub.3), 40.5 (CH.sub.2). HRMS (ESI): calc. for C.sub.22H.sub.21N.sub.2O [M+H] m/z 328.1576, found m/z 329.1658. IR (neat): 2993, 2931, 2894, 1668, 1592, 1510, 1486, 1390, 1256, 1241, 1162, 1035 cm.sup.−1.
(E)-N-(4-phenyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-ylidene)aniline
(183) ##STR00112##
(184) C.sub.24H.sub.24N.sub.2O.sub.3—Exact Mass: 388,1787; .sup.1H NMR (300 MHz, CDCl.sub.3): (ppm) 7.51-7.26 (m, 7H), 7.12-7.01 (m, 3H), 6.78 (s, 2H), 5.16 (dd, J=6.0, 2.9 Hz, 1H), 3.79 (s, 3H), 3.73 (s, 6H), 3.54 (dd, J=14.8, 6.0 Hz, 1H), 3.00 (dd, J=14.8, 2.9 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3): (ppm) 153.4 (2C), 148.0 (C), 136.2 (C), 132.8 (C), 129.1 (2CH), 129.0 (2CH), 128.5 (CH), 127.6 (C), 126.0 (2CH), 123.0 (CH), 122.2 (C), 122.1 (CH), 94.2 (2CH), 92.6 (C), 60.9 (CH), 58.6 (CH.sub.3), 56.0 (2CH.sub.3), 40.4 (CH.sub.2). HRMS (ESI): calc. for C.sub.24H.sub.25N.sub.2O.sub.3 [M+H] m/z 389.1787, found m/z 389.1871
(E)-N-(4-(4-chlorophenyl)-1-(4-methoxyphenyl)azetidin-2-ylidene)aniline
(185) ##STR00113##
(186) C.sub.22H.sub.19ClNO.sub.2—Exact Mass: 362,1186; .sup.1H NMR (300 MHz, CDCl.sub.3): (ppm) 7.34-7.25 (m, 6H), 7.24-7.16 (m, 2H), 6.73 (d, J=9.1 Hz, 2H), 5.04 (dd, J=6.0, 2.8 Hz, 1H), 3.67 (s, 3H), 3.42 (dd, J=14.6, 6.0 Hz, 1H), 2.81 (dd, J=14.6, 2.8 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3): (ppm) 155.0 (C), 153.6 (C), 148.4 (C), 138.0 (C), 134.1 (C), 133.4 (C), 129.3 (2CH), 129.0 (2CH), 127.3 (2CH), 123.0 (CH), 122.2 (2CH), 117.5 (2CH), 114.3 (2CH), 57.5 (CH), 55.5 (CH.sub.3), 40.5 (CH.sub.2). HRMS (ESI): calc. for C.sub.22H.sub.20.sup.35ClNO.sub.2 [M+H] m/z 363.1186, found m/z 363.1246; calc. for C.sub.22H.sub.20.sup.37ClNO.sub.2 [M+H] m/z 365.1156, found m/z 365.1251
(E)-N-(4-(4-methoxyphenyl)-1-phenylazetidin-2-ylidene)aniline
(187) ##STR00114##
(188) C.sub.22H.sub.20N.sub.2O—Exact Mass: 328,1576; .sup.1H NMR (300 MHz, CDCl.sub.3): (ppm) 7.38 (d, J=8.3 Hz, 2H), 7.32-7.11 (m, 6H), 7.01-6.93 (m, 3H), 6.92-6.80 (m, 3H), 5.06 (dd, J=6.0, 2.8 Hz, 1H), 3.73 (s, 3H), 3.41 (dd, J=14.8, 6.0 Hz, 1H), 2.84 (dd, J=14.8, 2.8 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3): (ppm) 159.6 (C), 154.5 (C), 149.3 (C), 139.9 (C), 131.3 (C), 128.9 (2CH), 128.8 (2CH), 127.2 (2CH), 123.0 (CH), 122.2 (2CH), 122.1 (CH), 116.4 (2CH), 114.5 (2CH), 57.8 (CH), 55.3 (CH.sub.3), 40.5 (CH.sub.2). HRMS (ESI): calc. for C.sub.22H.sub.21N.sub.2O [M+H] m/z 329.1576, found m/z 329.1638.
(E)-N-(1,4-bis(4-methoxyphenyl)azetidin-2-ylidene)aniline
(189) ##STR00115##
(190) C.sub.23H.sub.22N.sub.2O.sub.2—Exact Mass: 358,1681; .sup.1H NMR (300 MHz, CDCl.sub.3): (ppm) 7.42-7.25 (m, 6H), 7.05-6.96 (m, 3H), 6.88 (d, J=8.6 Hz, 2H), 6.78 (d, J=8.9 Hz, 2H), 5.08 (dd, J=5.6, 3.0 Hz, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 3.45 (dd, J=14.7, 5.6 Hz, 1H), 2.90 (dd, J=14.7, 3.0 Hz, 1H). .sup.13C NMR (75 MHz, CDCl.sub.3): (ppm) 159.3 (C), 154.5 (C), 148.1 (C), 133.2 (C), 131.0 (C), 129.1 (CH), 127.4 (CH), 126.9 (C), 123.0 (CH), 122.5 (CH), 117.8 (CH), 114.7 (CH), 114.4 (CH), 58.1 (CH), 55.7 (CH.sub.3), 55.5 (CH.sub.3), 40.8 (CH.sub.2). HRMS (ESI): calc. for C.sub.23H.sub.23N.sub.2O.sub.2 [M+H] m/z 359.1681, found m/z 359.1752.
(E)-4-(4-chlorophenyl)-N-(4-iodophenyl)-1-(4-methoxyphenyl)azetidin-2-imine
(191) ##STR00116##
(192) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.57 (d, J=8.4 Hz, 2H), 7.36-7.33 (m, 6H), 6.82 (d, J=9.3 Hz, 2H), 6.78 (d, J=8.7 Hz, 2H), 5.14 (dd, J=6.0, 3.0 Hz, 1H), 3.76 (s, 3H), 3.49 (dd, J=14.7, 6.0 Hz, 1H), 2.87 (dd, J=14.7, 3.0 Hz, 1H). HRMS: [M+H].sup.+ m/z 489.0230, found 489.0240.
(E)-N-(4-iodophenyl)-1-(4-methoxyphenyl)azetidin-2-imine
(193) ##STR00117##
(194) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.58 (d, J=8.4 Hz, 2H), 7.41-7.36 (m, 7H), 6.81 (d, J=4.5 Hz, 2H), 6.79 (d, J=4.2 Hz, 2H), 5.15 (dd, J=5.6, 3.0 Hz, 1H), 3.75 (s, 3H), 3.48 (dd, J=14.7, 6.0 Hz, 1H), 2.93 (dd, J=14.7, 3.0 Hz, 1H). HRMS: [M+H].sup.+ m/z 455.0542, found 455.0624.
(E)-4-(4-chlorophenyl)-N-(4-chlorophenyl)-1-(4-methoxyphenyl)azetidin-2-imine
(195) ##STR00118##
(196) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.37-7.23 (m, 8H), 6.94 (d, J=8.7 Hz, 2H), 6.81 (d, J=9.0 Hz, 2H), 5.15 (dd, J=6.0, 3.0 Hz, 1H), 3.76 (s, 3H), 3.50 (dd, J=14.7, 6.0 Hz, 1H), 2.89 (dd, J=14.7, 6.0 Hz, 1H). HRMS: [M+H].sup.+ m/z 398.0874, found 398.0898.
(E)-4-N-(4-chlorophenyl)-1-(4-methoxyphenyl)azetidin-2-imine
(197) ##STR00119##
(198) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.41-7.23 (m, 9H), 6.97 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 5.16 (dd, J=5.9, 2.7 Hz, 1H), 3.75 (s, 3H), 3.49 (dd, J=14.7, 5.9 Hz, 1H), 2.92 (dd, J=14.7, 2.7 Hz, 1H). HRMS: [M+H].sup.+ m/z 363.1264, found 363.1268.
(E)-4-(4-chlorophenyl)-N-(4-trifluoromethylphenyl)-1-(4-methoxyphenyl)azetidin-2-imine
(199) ##STR00120##
(200) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.42-7.27 (m, 8H), 7.18 (d, J=7.8 Hz, 2H), 6.82 (d, J=9.0 Hz, 2H), 5.17 (dd, J=6.0, 2.7 Hz, 1H), 3.77 (s, 3H), 3.53 (dd, J=14.7, 6.0 Hz, 1H), 2.91 (dd, J=14.7, 2.7 Hz, 1H). HRMS: [M+H].sup.+ m/z 431.1138, found 431.1131.
(E)-1-(4-ethoxyphenyl)-N-(4-methoxyphenyl)-4-(naphthalen-2-yl)azetidin-2-imine
(201) ##STR00121##
(202) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.89-7.83 (m, 2H), 7.56-7.43 (m, 7H), 7.02 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.79 (d, J=9.0 Hz, 2H), 5.30 (dd, J=6.0, 3.0 Hz, 1H), 3.95 (q, J=13.8, 6.9 Hz, 2H), 3.80 (s, 3H), 3.57 (dd, J=14.7, 6.0 Hz, 1H), 2.99 (dd, J=14.7, 3.0 Hz, 1H), 1.37 (t, J=13.8, 6.9 Hz, 2H). HRMS: [M+H].sup.+ m/z 423.1993, found 423.1987.
(E)-1-(4-ethoxyphenyl)-N-(4-iodophenyl)-4-(naphthalen-2-yl)azetidin-2-imine
(203) ##STR00122##
(204) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.89-7.40 (m, 7H), 6.82 (d, J=8.4 Hz, 2H), 6.79 (d, J=9.0 Hz, 2H), 5.32 (dd, J=5.7, 2.7 Hz, 1H), 3.95 (q, J=5.7, 2.7 Hz, 2H), 3.54 (dd, J=14.4, 6.0 Hz, 1H), 2.99 (dd, J=14.4, 2.7 Hz, 1H), 1.36 (t, J=6.0, 2.7 Hz, 2H). HRMS: [M+H].sup.+ m/z 519.0944, found 519.0941.
(E)-4-(3,5-dichlorophenyl)-N-(4-iodophenyl)-1-(4-methoxyphenyl)azetidin-2-imine
(205) ##STR00123##
(206) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.56 (d, J=8.7 Hz, 2H), 7.45 (d, J=1.8 Hz, 2H), 7.37-7.21 (m, 3H), 6.86 (d, J=9.3 Hz, 2H), 6.75 (d, J=8.4 Hz, 2H), 5.49 (dd, J=6.3, 3.0 Hz, 1H), 3.78 (s, 3H), 3.60 (dd, J=14.7, 6.3 Hz, 1H), 2.93 (dd, J=14.7, 3.0 Hz, 1H). HRMS: [M+H].sup.+ m/z 538.9968, found 538.9920.
(E)-1-(4-(benzyloxy)phenyl)-N-4-diphenylazetidin-2-imine
(207) ##STR00124##
(208) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.49-7.20 (m, 14H), 7.11-6.98 (m, 3H), 6.93-6.81 (m, 2H), 5.15 (dd, J=6.0, 2.9 Hz, 1H), 5.00 (s, 2H), 3.5 (dd, J=14.6, 6.0 Hz, 1H), 2.94 (dd, J=14.6, 2.9 Hz, 1H). HRMS-EI (m/z) calcd for C.sub.28H.sub.25N.sub.2O [(M+H).sup.+] 405.1967, found 405.1952.
(E)-1-(3,4-dimethoxyphenyl)-N-4-diphenylazetidin-2-imine
(209) ##STR00125##
(210) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.52 (d, J=2.3 Hz, 1H), 7.48-7.22 (m, 7H), 7.06-6.99 (m, 3H), 6.72 (d, J=8.6 Hz, 1H), 6.64 (dd, J=8.6, 2.3 Hz, 1H), 5.15 (dd, J=6.1, 2.9 Hz, 1H), 3.8 (2 overlaps s, 6H), 3.52 (dd, J=14.6, 6.1 Hz, 1H), 2.97 (dd, J=14.7, 2.9 Hz, 1H). HRMS-EI (m/z) calcd for C.sub.23H.sub.23N.sub.2O.sub.2 [(M+H).sup.+] 359.1760, found 359.1763.
(E)-1-(benzo[d][1,3]dioxol-5-yl)-N,4-diphenylazetidin-2-imine
(211) ##STR00126##
(212) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.46-7.22 (m, 8H), 7.12-6.97 (m, 3H), 6.77 (dd, J=8.4, 2.1 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 5.88 (dd, J=2.7, 1.4 Hz, 2H), 5.12 (dd, J=6.1, 2.9 Hz, 1H), 3.50 (dd, J=14.7, 6.1 Hz, 1H), 2.93 (dd, J=14.7, 2.9 Hz, 1H). HRMS-EI (m/z) calcd for C.sub.22H.sub.19N.sub.2O.sub.2 [(M+H).sup.+] 343.1448, found 343.1453.
(E)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-4-diphenylazetidin-2-imine
(213) ##STR00127##
(214) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.49-7.22 (m, 7H), 7.08-6.98 (m, 4H), 6.95 (dd, J=8.7, 2.5, 1H), 6.74 (d, J=8.7 Hz, 1H), 5.11 (dd, J=6.1, 2.9 Hz, 1H), 4.27-4.13 (m, 4H), 3.48 (dd, J=14.7, 6.1 Hz, 1H), 2.92 (dd, J=14.7, 2.9 Hz, 1H). HRMS-EI (m/z) calcd for C.sub.23H.sub.21N.sub.2O.sub.2 [(M+H).sup.+] 357.103, found 357.1588.
(E)-1-(3-methoxyphenyl)-N,4-diphenylazetidin-2-imine
(215) ##STR00128##
(216) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.45-7.21 (m, 8H), 7.14 (t, J=8.1 Hz, 1H), 7.09-7.00 (m, 3H), 6.96-6.89 (m, 1H), 6.53 (ddd, J=8.1, 2.5, 0.8 Hz, 1H), 5.17 (dd, J=6.2, 3.0 Hz, 1H), 3.75 (s, 3H), 3.51 (dd, J=14.8, 6.2 Hz, 1H), 2.95 (dd, J=14.8, 3.0 Hz, 1H). HRMS-EI (m/z) calcd for C.sub.22H.sub.20N.sub.2O [(M+H).sup.+] 329.1654, found 329.1658.
(E)-4-(4-chlorophenyl)-1-(3-methoxyphenyl)-N-phenylazetidin-2-imine
(217) ##STR00129##
(218) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.38-7.23 (m, 6H), 7.23-6.97 (m, 5H), 6.88 (dd, J=8.0, 1.0 Hz, 1H), 6.54 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 5.14 (dd, J=6.2, 3.0 Hz, 1H), 3.76 (s, 3H), 3.52 (dd, J=14.8, 6.2 Hz, 1H), 2.90 (dd, J=14.8, 3.0 Hz, 1H). HRMS-EI (m/z) calcd for C.sub.22H.sub.20ClN.sub.2O [(M+H).sup.+] 363.1264, found 363.1250.
(E)-4-(4-chlorophenyl)-1-(2-methoxyphenyl)-N-phenylazetidin-2-imine
(219) ##STR00130##
(220) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.31-8.23 (m, 1H), 7.28-7.14 (m, 6H), 7.00-6.86 (m, 5H), 6.69-6.64 (m, 1H), 5.52 (dd, J=6.0, 2.8 Hz, 1H), 3.48 (s, 3H), 3.44 (dd, J=14.7, 6.0 Hz, 1H), 2.80 (dd, J=14.7, 2.8 Hz, 1H). HRMS-EI (m/z) calcd for C.sub.22H.sub.20ClN.sub.2O [(M+H).sup.+] 363.1264, found 363.1273.
Methyl (E)-4-(1-phenyl-4-(phenylimino)azetidin-2-yl)benzoate
(221) ##STR00131##
(222) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.06 (d, J=8.7 Hz, 2H), 7.5 (d, J=8.7 Hz, 2H), 7.42 (d, J=8.7 Hz, 2H), 7.33-7.22 (m, 4H), 7.08-6.95 (m, 4H), 5.24 (dd, J=6.3 Hz, 3.0 Hz, 1H), 3.92 (s, 3H), 3.55 (dd, J=14.8, 6.3 Hz, 1H), 2.93 (dd, J=14.8, 3.0 Hz, 1H). HRMS-ESI (m/z) calcd for C.sub.23H.sub.21N.sub.2O.sub.2 [(M+H).sup.+] 357.1603, found 357.1589.
(E)-N-(1,4-diphenylazetidin-2-ylidene)aniline
(223) ##STR00132##
(224) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.48-7.23 (m, 12H), 7.08-6.95 (m, 3H), 5.19 (dd, J=6.4, 2.8 Hz, 1H), 3.52 (dd, J=14.8, 6.4 Hz, 1H), 2.96 (dd, J=14.8, 2.8 Hz, 1H). HRMS-ESI (m/z) calcd for C.sub.21H.sub.19N.sub.2 [(M+H).sup.+] 299.1548, found: 299.1563.
(E)-tert-butyl 4-(1-(4-methoxyphenyl)-4-(phenylimino)azetidin-2-yl)benzoate (MBG132 MBG135)
(225) ##STR00133##
(226) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.03 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.40-7.29 (m, 5H), 7.06 (m, 3H), 6.82 (d, J=8.0 Hz, 1H), 5.21 (dd, J=15.0, 6.0 Hz, 1H), 3.77 (s, 3H), 3.55 (dd, J=15.0, 6.0 Hz, 1H), 2.94 (dd, J=15.0, 3.0, 1H), 1.61 (s, 9H). HRMS-ESI (m/z) calcd for C.sub.27H.sub.29N.sub.2O.sub.3 [(M+H).sup.+] 429.2178, found: 429.2187.
tert-butyl (E)-4-(1-phenyl-4-(phenylimino)azetidin-2-yl)benzoate
(227) ##STR00134##
(228) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.00 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H), 7.44-7.20 (m, 6H), 7.08-6.93 (m, 4H), 5.23 (dd, J=6.2, 3.0 Hz, 1H), 3.54 (dd, J=14.7, 6.2 Hz, 1H), 2.92 (dd, J=14.7, 3.0 Hz, 1H), 1.58 (s, 9H); HRMS-ESI (m/z) calcd for C.sub.26H.sub.27N.sub.2O.sub.2 [(M+H).sup.+] 399.2073, found 399.2111.
(E)-2-(2-(4-(2-phenyl-4-(phenylimino)azetidin-1-yl)phenoxy)ethoxy)ethan-1-ol
(229) ##STR00135##
(230) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.47-7.22 (m, 9H), 7.09-6.96 (m, 3H), 6.89-6.65 (m, 3H), 5.15 (dd, J=6.1, 2.9 Hz, 1H), 4.37-4.19 (m, 2H), 4.15-4.01 (m, 2H), 3.92-3.70 (m, 4H), 3.50 (dd, J=14.7, 6.1 Hz, 1H), 2.93 (dd, J=14.7, 2.9 Hz, 1H); HRMS-ESI (m/z) calcd for C.sub.25H.sub.27N.sub.2O.sub.3 [(M+H).sup.+] 403.2022, found 403.2008.
(E)-tert-butyl 2-(4-(2-(4-chlorophenyl)-4-(phenylimino)azetidin-1-yl)phenoxy)acetate
(231) ##STR00136##
(232) To a stirred solution of azetidinimine 1 (30 mg, 0.086 mmol, see below for structure), and potassium carbonate (13 mg, 0.095 mmol, 1.1 equiv.) in dimethylformamide (DMF) (500 μL) is added t-butyl bromoacetate (18.5 mg, 14 μL, 0.095 mmol, 1.1 equiv.). The reaction mixture is stirred at 60° C. overnight (thin layer chromatography (TLC) monitoring) then purified by automated flash column chromatography using a gradient of AcOEt in heptane (AcOEt 0%.fwdarw.20% over 20 min). Orange wax. (31 mg, 78%).
(233) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.37-7.26 (m, 8H), 7.06 (m, 3H), 6.83-6.79 (m, 2H), 5.12 (dd, J=6.2, 2.8 Hz, 1H), 4.44 (s, 2H), 3.50 (dd, J=14.5, 6.2 Hz, 1H), 2.90 (dd, J=14.5, 2.8 Hz, 1H), 1.47 (s, 9H). HRMS-ESI (m/z) calcd for C.sub.27H.sub.28ClN.sub.2O.sub.3 [(M+H).sup.+] 463.1788, found: 463.1793.
(E)-tert-butyl 2-(4-(2-phenyl-4-(phenylimino)azetidin-1-yl)phenoxy)acetate
(234) ##STR00137##
(235) To a stirred solution of azetidinimine 2 (36 mg, 0.115 mmol), and potassium carbonate (32 mg, 0.095 mmol, 2 equiv.) in DMF (400 μL) is added t-butyl bromoacetate (34 mg, 25 μL, 0.095 mmol, 1.5 equiv.). The reaction mixture is stirred at 100° C. overnight (TLC monitoring) then purified by automated flash column chromatography using a gradient of AcOEt in heptane (AcOEt 0%.fwdarw.20% over 20 min). Orange wax. (30.7 mg, 62%).
(236) .sup.1H NMR (300 MHz, CDCl.sub.3): δ .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.43-7.26 (m, 10H), 7.02 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.4 Hz, 2H), 5.14 (dd, J=6.0, 3.0 Hz, 1H), 4.44 (s, 2H), 3.50 (dd, J=15.0, 6.0 Hz, 1H), 2.93 (dd, J=6.0, 3.0 Hz, 1H), 1.47 (s, 9H). HRMS-ESI (m/z) calcd for C.sub.27H.sub.29N.sub.2O.sub.3 [(M+H).sup.+] 429.2178, found: 429.2182.
(E)-4-(1-phenyl-4-(phenylimino)azetidin-2-yl)benzoic acid 4
(237) ##STR00138##
(238) This compound was obtained using general procedure C as a white foam in 96%.
(239) .sup.1H NMR (300 MHz, MeOD): δ 8.03 (d, J=8.2 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.31-7.21 (m, 4H), 7.06-6.94 (m, 4H), 5.36 (dd, J=6.0, 3.0 Hz, 1H), 3.59 (dd, J=15.0, 6.0 Hz, 1H), 2.89 (dd, J=15.0, 3.0 Hz, 1H). One proton missing due to chemical exchange with CD.sub.3OD. HRMS-ESI (m/z) calcd for C.sub.22H.sub.19N.sub.2O.sub.2 [(M+H).sup.+] 343.1447, found 343.1430.
(E)-2-(4-(2-(4-chlorophenyl)-4-(phenylimino)azetidin-1-yl)phenoxy)acetic acid
(240) ##STR00139##
(241) This compound was obtained using general procedure C as a white foam in 69%.
(242) .sup.1H NMR (300 MHz, MeOD): δ 7.44-7.27 (m, 8H), 7.08-7.05 (m, 3H), 6.87 (d, J=9.3 Hz, 2H), 5.31 (dd, J=5.7, 2.9 Hz, 1H), 4.46 (s, 2H), 3.58 (dd, J=14.7, 5.7 Hz, 1H), 2.95 (dd, J=14.7, 2.9 Hz, 1H). HRMS-ESI (m/z) calcd for C.sub.23H.sub.19ClN.sub.2O.sub.3 [(M+H).sup.+] 407.1162, found 407.1159.
(E)-2-(4-(2-phenyl-4-(phenylimino)azetidin-1-yl)phenoxy)acetic acid
(243) ##STR00140##
(244) This compound was obtained using general procedure C as a white foam in 65%.
(245) .sup.1H NMR (300 MHz, MeOD): δ 7.43-7.25 (m, 10H), 7.04-6.99 (m, 3H), 6.84 (d, J=9.4 Hz, 2H), 5.23 (dd, J=6.0, 2.8 Hz, 1H), 4.34 (s, 2H), 3.53 (dd, J=14.6, 6.0 Hz, 1H), 2.85 (dd, J=14.6, 2.8 Hz, 1H). HRMS-ESI (m/z) calcd for C.sub.23H.sub.21N.sub.2O.sub.3 [(M+H).sup.+] 373.1552, found 373.1545.
(E)-4-(2-phenyl-4-(phenylimino)azetidin-1-yl)phenol 2
(246) ##STR00141##
(247) This compound was obtained using general procedure D as a yellow oil in 38%.
(248) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.41-7.23 (m, 10H), 7.07-7.03 (m, 3H), 6.68 (d, J=8.9 Hz, 2H), 5.16 (dd, J=6.0, 2.9 Hz, 1H), 3.50 (dd, J=14.7, 6.0 Hz, 1H), 2.92 (dd, J=14.7, 2.9 Hz, 1H), OH signal missing. HRMS-ESI (m/z) calcd for C.sub.21H.sub.19N.sub.2O [(M+H).sup.+] 315.1497, found 315.1503.
(E)-4-(2-(4-chlorophenyl)-4-(phenylimino)azetidin-1-yl)phenol 1
(249) ##STR00142##
(250) This compound was obtained using general procedure D as a yellow foam in 60%.
(251) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.34-7.26 (m, 8H), 7.07-7.00 (m, 3H), 6.71 (d, J=9.0 Hz, 1H), 5.13 (dd, J=6.0, 3.0 Hz, 1H), 3.50 (dd, J=14.8, 6.2 Hz, 1H), 2.90 (dd, J=14.8, 3.0 Hz, 1H), OH signal missing. HRMS-ESI (m/z) calcd for C.sub.21H.sub.18ClN.sub.2O [(M+H).sup.+] 349.1108, found 349.1092.
(E)-4-(1-(4-methoxyphenyl)-4-(phenylimino)azetidin-2-yl)benzoic acid 3
(252) ##STR00143##
(253) This compound was obtained using general procedure D as a yellow foam in 29%.
(254) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.04 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 7.31-7.23 (m, 5H), 7.07-7.02 (m, 3H), 6.72 (d, J=8.0 Hz, 2H), 5.22 (dd, J=15.0, 3.0 Hz, 1H), 3.91 (s, 3H), 3.54 (dd, J=15.0, 6.0 Hz, 1H), 2.92 (dd, J=15.0, 3.0 Hz, 1H), carboxylic proton missing. HRMS-ESI (m/z) calcd for C.sub.23H.sub.21N.sub.2O.sub.3 [(M+H).sup.+] 373.1552, found: 373.1546.
(E)-2-((tert-butoxycarbonyl)amino)ethyl 4-(1-phenyl-4-(phenylimino)azetidin-2-yl)benzoate 5
(255) ##STR00144##
(256) To an argon-flushed and stirred solution of compound 4 in DCM (0.5 mL) is added triethylamine (1.2 mg, 2 μL, 0.07 mmol, 1 equiv.), CDI (11.7 mg, 0.07 mmol, 1 equiv.) and tert-butyl (2-hydroxyethyl)carbamate (11.7 mg, 0.07 mmol, 1 equiv.). The reaction mixture is stirred 16 h at rt then purified by automated flash column chromatography using a gradient of AcOEt in heptane (AcOEt 0%.fwdarw.50% over 30 min) to afford a white foam. (14 mg, 38%).
(257) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.06 (d, J=9.0 Hz, 2H), 7.51 (d, J=9.0 Hz, 2H), 7.41 (d, J=9.0 Hz, 2H), 7.33-7.23 (m, 4H), 7.08-6.96 (m, 4H), 5.25 (dd, J=6.0, 3.0 Hz, 1H), 4.82 (m, 1H), 4.38 (t, J=5.0, 2H), 3.60-3.52 (m, 3H), 2.93 (dd, J=15.4, 3.0 Hz, 1H), 1.43 (s, 9H). HRMS-ESI (m/z) calcd for C.sub.29H.sub.32N.sub.3O.sub.4 [(M+H).sup.+] 486.2393, found 486.2375.
(E)-2-((4-(1-phenyl-4-(phenylimino)azetidin-2-yl)benzoyl)oxy)ethanaminium 2,2,2-trifluoroacetate
(258) ##STR00145##
(259) To a solution of azetidinimine 5 (19 mg, 0.038 mmol) in DCM (100 μL) is added TFA (trifluoroacetic acid, 100 μL, excess). The reaction mixture is stirred at room temperature for 16 h then at 40° C. for 24 h. Subsequent evaporation of solvents furnished the title compound in the form of a TFA salt (19 mg, quant.).
(260) .sup.1H NMR (300 MHz, MeOD): δ 8.03 (d, J=8.3 Hz, 2H), 7.55-7.47 (m, 4H), 7.42-7.40 (m, 1H), 7.34-7.30 (m, 2H), 7.03-6.97 (m, 2H), 6.58-6.53 (m, 3H), 4.94 (dd, J=8.0, 6.0 Hz, 1H), 4.54-4.50 (m, 2H), 3.35 (t, J=5.7 Hz, 2H), 2.90 (dd, J=15.2, 8.0 Hz, 1H), 2.79 (dd, J=15.2, 6 Hz, 1H). Three protons missing due to chemical exchange with MeOD. .sup.19F NMR (282 MHz, MeOD): δ −76.87 (s, 3F). HRMS-ESI (m/z) calcd for C.sub.24H.sub.24N.sub.3O.sub.2 [(M+H).sup.+] 386.1869, found: 386.1862.
(E)-(4-(1-phenyl-4-(phenylimino)azetidin-2-yl)phenyl)methanol 6
(261) ##STR00146##
(262) A solution of azetidinimine 4 (40 mg, 0.2 mmol) under argon in anhydrous THF (terahydrofuran, 0.6 mL) is cooled to 0° C. then LiAlH.sub.4 (23 mg, 0.6 mmol, 3 equiv.) is added. The reaction mixture is stirred 3 h at room temperature (TLC monitoring) then AcOEt and a saturated aqueous solution of Na.sub.2SO.sub.4 are carefully added to quench the reaction. The resulting slurry is filtrated through a pad of celite and washed with additional AcOEt. The organic layer is dried over sodium sulfate, filtered then evaporated. Automated flash column chromatography using a gradient of AcOEt in heptane (AcOEt 0%.fwdarw.30% over 20 min) furnished the title compound as a white foam (51.2 mg, 79%).
(263) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.48-7.38 (m, 6H), 7.34-7.23 (m, 4H), 7.09-6.95 (m, 4H), 5.20 (dd, J=6.0, 3.0 Hz, 1H), 4.70 (s, 2H), 3.52 (dd, J=14.7, 6.0 Hz, 1H), 2.93 (dd, J=14.7, 3.0 Hz, 1H), OH proton missing. HRMS-ESI (m/z) calcd for C.sub.22H.sub.21N.sub.2O [(M+).sup.+] 329.1654, found: 329.1643.
(E)-N-(4-(4-(chloromethyl)phenyl)-1-phenylazetidin-2-ylidene)aniline
(264) ##STR00147##
(265) A solution of azetidimine 6 (22 mg, 0.068 mmol) and triethylamine (14 mg, 19 μL, 0.135 mmol, 2 equiv.) in DCM and under argon is cooled to 0° C. then MsCl (mesyl chloride, 8.5 mg, 6 μL, 0.074 mmol, 1.1 equiv.) is added. The reaction mixture is stirred at rt overnight. Afterwards, additional DCM (10 mL) is added then the reaction mixture is washed twice with water, dried over sodium sulfate and evaporated. Automated flash column chromatography using a gradient of AcOEt in heptane (AcOEt 0%.fwdarw.20% over 25 min) furnished the title compound as a colorless oil (19.2 mg, 70%).
(266) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.45-7.39 (m, 6H), 7.32-7.23 (m, 4H), 7.08-6.95 (m, 4H), 5.19 (dd, J=6.0, 3.0 Hz, 1H), 4.59 (s, 2H), 3.51 (dd, J=14.6, 6.0 Hz, 1H), 2.92 (dd, J=14.6, 3.0 Hz, 1H). HRMS-ESI (m/z) calcd for C.sub.22H.sub.20ClN.sub.2 [(M+H).sup.+] 347.1315, found: 347.1310.
(E)-N-(4-(4-(azidomethyl)phenyl)-1-phenylazetidin-2-ylidene)aniline
(267) ##STR00148##
(268) Step 1: A solution of 6 (148 mg, 0.45 mmol) and triethylamine (50 mg, 70 μL, 0.5 mmol, 2 equiv.) in DCM and under argon is cooled to 0° C. then MsCl (mesyl chloride, 57 mg, 39 μL, 0.5 mmol, 1.1 equiv.) is added. The reaction mixture is stirred at rt overnight. Afterwards, additional DCM (10 mL) is added and the reaction mixture is washed twice with water. The aqueous layer is extracted with DCM then the organic layer is dried over sodium sulfate and evaporated to afford the crude benzylic chloride intermediate. Step 2: To the previous crude residue is added DMF (0.5 mL), NaN.sub.3 (33 mg, 0.5 mmol, 1.1 equiv.) and KI (8 mg, 0.045 mmol, 10 mol %). The reaction mixture is stirred overnight at 50° C. under air. Automated flash column chromatography using a gradient of AcOEt in heptane (AcOEt 0%.fwdarw.20% over 25 min) furnished the title compound as a colorless oil (98 mg, 62%).
(269) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.49-7.47 (m, 4H), 7.37-7.26 (m, 6H), 7.10-6.98 (m, 4H), 5.21 (dd, J=6.0, 3.0 Hz, 1H), 4.37 (s, 2H), 3.53 (dd, J=15.0, 6.0 Hz, 1H), 2.95 (dd, J=15.0, 3.0, 1H). HRMS-ESI (m/z) calcd for C.sub.22H.sub.20N.sub.5 [(M+H).sup.+] 354.1719, found: 354.1727.
(E)-N-(1-phenyl-4-(4-((prop-2-yn-1-yloxy)methyl)phenyl)azetidin-2-ylidene)aniline
(270) ##STR00149##
(271) To a stirred solution of 6 (100 mg, 0.3 mmol) in anhydrous DMF and under argon is added NaH (13 mg, 0.33 mmol, 1.1 equiv.). After 10 min, a 70% wt. propargyl chloride solution in toluene (35 mg, 37 μL, 0.33 mmol, 1.1 equiv.) is added. The reaction mixture is stirred overnight. Automated flash column chromatography using a gradient of AcOEt in heptane (AcOEt 0%.fwdarw.20% over 25 min) furnished the title compound as a colorless oil (26 mg, 24%).
(272) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.46-7.37 (m, 6H), 7.33-7.22 (m, 4H), 7.08-6.95 (m, 4H), 5.19 (dd, J=6.0, 3.0 Hz, 1H), 4.61 (s, 2H), 4.20 (d, J=2.0 Hz, 2H), 3.51 (dd, J=15.0, 6.0 Hz, 1H), 2.92 (dd, J=15.0, 3.0 Hz, 1H), 2.48 (t, J=2.0, 1H). HRMS-ESI (m/z) calcd for C.sub.25H.sub.23N.sub.2O [(M+H).sup.+] 367.1810, found: 367.1799.