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  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
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  • C09B23/00—Methine or polymethine dyes, e.g. cyanine dyes
  • C09B23/0066—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)
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  • C09B23/02—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups
  • C09B23/08—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines
  • C09B23/086—Methine or polymethine dyes, e.g. cyanine dyes the polymethine chain containing an odd number of >CH- or >C[alkyl]- groups more than three >CH- groups, e.g. polycarbocyanines more than five >CH- groups
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  • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

• the present invention relates to heptacarbonated or nonacarbonated carboxonium salts and streptocyanines, their preparation process, and their use as biological markers. 5 Chemical, chromatographic or spectroscopic methods have long been poorly suited to the detection of molecules in the field of nano and " subnanograms", for reasons of insufficient sensitivity.
• radioactive iodine 125 I
• endogenous and exogenous substances hormones, bacteria, viruses, toxins, etc.
• Cyanines are interesting compounds for coupling with biological molecules and can be used as markers because of their triple character: positively charged, lipophilic and fluorescent. It is known to use certain cyanines as
• ⁇ 5 markers in combination with antibodies, DNA, proteins, polysaccharides and other biological molecules, for the assay, in vivo and in vitro monitoring of active substances or for the diagnosis of various diseases. So that a compound can be used as
• the 30 biological marker it must have an absorption and emission domain moved towards the near infrared so as not to interfere with the autofluorescence zone of the substrate. It must also be able to be grafted onto the target molecule by covalent bond or by complexation.
• Cyanines which have five methine groups between the indole groups of ends) and which have a wavelength ⁇ max of the order of 680 nm has been described by the same authors. Cyanines of this type, called Cy5, are also sold by the company Amersham Life Science.
• the pentacarbonated carboxonium salt is obtained by reaction of an arylmethylketone with triethoxymethane and perchloric acid. This process is related
• streptocyanines obtained however have a wavelength ⁇ max which remains below a value of the order of 600 nm, which limits their use as a marker in the near infrared.
• the cyanines can be
• the first type of bisaldehyde is a glutaconaldehyde salt corresponding to the formula:
• the corresponding Schiff base corresponds to the formula:
• the second bisaldehyde is of the 2-Q-1-formyl-3-hydroxy ethylene cyclohexene type in which Q is most often
• the aim of the present invention is to provide new functionalized cyanines having a high absorption wavelength, which can be used in particular as markers.
• the subject of the invention is salts in which the cation comprises a group 1,7- or 1 / 9- . diarylpolymethine, as well as a process for their preparation, and their use as biological markers.
• a compound according to the invention corresponds to the following formula (I):
• n 0 or 1
• G and G 'independently of one another represent an OEt group, an amino group, a phosphaimino group, an amidino group, a guanidino group, a hydrazino group, a hydrazono group, or a multivalent radical linked to at least one of its other ends to a radical corresponding to formula (I 1 ) below
• G represents an OEt group, an amino group, a phosphaimino group, an amidino group, a guanidino group, a hydrazino group, a hydrazono group, or a multivalent radical;
• R 1 to R 5 independently of one another represent a hydrogen, a halogen, an alkyl radical, an alkyloxy radical having from 1 to 15 carbon atoms or an acetamido group CH 3 C (0) HN-;
• Z represents H or a halogen
• the anion is preferably chosen from BF 4 " , CF 3 S0 3 " , CIO4 ' , I " , Br “ and Cl " .
• G, G' or G" represents a multivalent radical, it is preferably chosen from -NH-E-NH- groups in which E is - (CH 2 ) n -, 3 ⁇ n ⁇ 9, or - (CH 2 ) 2 0 (CH 2 ) 2 0 (CH 2 ) 2 -.
• R 1 to R 7 , n, Q and Z have the meaning given above, and represents an ethyl group.
• n 0 and R 6 represents H, they correspond to the following formula (II A ).
• a compound (HA) according to the present invention can be prepared from an aryl ketone Ar-C (O) R '(hereinafter referred to as AC) in which Ar represents a phenyl radical bearing the substituents R 1 to R 5 defined above and R ′ S represents an alkyl radical having from 1 to 5 carbon atoms, preferably a methyl.
• TEM 1, 3, 3-triethoxypropene
• TEP 1, 3, 3-triethoxypropene
• the inert atmosphere is advantageously obtained by operating under argon.
• the process is preferably carried out at room temperature.
• the TEP / TEM ratio is preferably equal to 1 and the AC / TEM + TEP ratio is preferably equal to 1 to avoid the formation of by-products
• the strong acid is chosen from HBF 4 , CF 3 S0 3 H, HC10 4 , HI, HBr or HC1.
• the compound obtained in the reaction medium can be recovered by precipitation, filtering, washing and drying.
• the precipitation can be carried out in a solvent such as
• ⁇ 5 ether a hydrocarbon or a non-polar solvent.
• ethyl ether THF
• pentane hexane
• cyclohexane cyclopentane
• carbon tetrachloride a hydrocarbon or a non-polar solvent.
• the inventors found that, surprisingly, the addition of triethoxymethane to the reaction medium made it possible to obtain the expected compound (H A ), with the secondary product, the pyrylium salt (when TEM / TEP ⁇ 1) or the pentacarbonated carboxonium salt (when TEM / TEP> 1).
• Triethoxymethane is a commercially available compound under the name ethyl orthoformate.
• a compound (II B ) according to the present invention can be prepared from an aryl ketone ArC (O) R '(hereinafter referred to as AC) in which Ar represents a phenyl radical bearing the substituents R 1 to R 5 defined ci -above and R 'represent-
• Ar represents a phenyl radical bearing the substituents R 1 to R 5 defined ci -above and R 'represent-
• the process for the preparation of a compound (II B ) is characterized in that it consists in reacting ... aryl ketone (AC) with a mixture of triethoxymethane (TEM) and a bisaldehyde (BA) in presence of a strong acid,
• AC ... aryl ketone
• TEM triethoxymethane
• BA bisaldehyde
• CFHMCH 2-chloro-1-formyl-3-hydroxymethylenecyclohexene
• FHMCH l-formyl-3-hydroxymethylenecyclohexene
• CFHMCP 2-chloro-1-formyl-3-hydroxymethylenecyclopentene
• FHMCP 1-formyl-3-hydroxymethylenecyclopentene
• the inert atmosphere is advantageously obtained by operating under argon.
• the process is preferably carried out at room temperature.
• the BA / TEM ratio is preferably equal to 1/4 and the AC / TEM + BA ratio is preferably equal to 2/5 to limit the formation of undesirable by-products.
• the strong acid is chosen from HBF 4 , CF 3 S0 3 H, HC10 4 , HI, HBr or HC1.
• the compound (II B ) obtained in the reaction medium can be recovered by precipitation, filtering, washing and drying.
• the precipitation can be carried out in a solvent such as an ether, a hydrocarbon or a non-polar solvent.
• a solvent such as an ether, a hydrocarbon or a non-polar solvent.
• a compound according to the invention can also be a streptocyanine corresponding to formula (III) below:
• R B , R, R 10 and R 11 are chosen independently of each other from:
• - phenyl radicals optionally carrying substituents chosen independently of one another from H, halogens, alkyl or alkyloxy radicals having 1
• the heptacarbon streptocyanines of type (III) are represented by the following formula (III A ):
• the non-carbonaceous streptocyanines are represented by the following formula (III B ):
• a compound of the invention can also be a streptocyanine corresponding to the following formula (IV):
• R 1 to R 7 , n, Q and Z have the meaning given above -; • X and X 'independently of one another represent R “ 3 P, R" 2 N (R') C, (R “ 2 N) 2 C or NR" 2 , R "representing an alkyl preferably having from 1 to 4 carbon atoms, or a phenyl.
• the streptocyanines (IV) are symmetrical when the substituents X and X 'are identical.
• a heptacarbon streptocyanine of type (IV) is represented by the following formula (IV A ):
• a non-carbonaceous streptocyanine of type (IV) is represented by the following formula (IV B ):
• a compound of the present invention can also be D a macrocyclic dicationic compound corresponding to the following formula (V):
• R 1 to R 7 , n, Q and Z have the meaning given above
• a dicationic macrocyclic compound (V) in which each cationic group is heptacarbon corresponds to the following formula (V A ):
• a macrocyclic dicationic compound (V) in which each cationic group is nonacarbon corresponds to the following formula (V B ):
• a compound according to the invention may be a diaryl hemicarboxonium salt corresponding to the following formula (VI):
• a salt of type (VI) heptacarbone corresponds to the following formula (VI A ):
• a salt of the nonacarbon type (VI) corresponds to the following formula (VI B ):
• a compound according to the invention may also be a diaryl hemicarboxonium salt corresponding to the following formula (VII):
• a salt of type (VII) heptacarbone corresponds to the following formula (VH A ):
• a nonacarbon type salt (VII) corresponds to the following formula (VII B ):
• a compound according to the invention can also be a non-macrocyclic polycationic compound (VIII) when one of the substituents G or G 'is a multivalent group linked at each of its ends to a group corresponding to the formula (I') defined above .
• the process for the preparation of a symmetrical streptocyanine (III) of the invention consists in reacting a salt (H) with a nitrogenous compound, using at least two equivalents of nitrogenous compound for one equivalent of salt, said nitrogenous compound being chosen among amines, hydrazines and hydrazones.
• a heptacarbon salt (II A ) makes it possible to obtain a streptocyanine corresponding to the formula (III A ).
• a nonacarbon salt (II B ) makes it possible to obtain a streptocyanine corresponding to the formula (III B ).
• the process for the preparation of a symmetrical streptocyanine (IV) of the invention consists in reacting a compound (II) with a nitrogenous compound, using at least two equivalents of nitrogenous compound for an equivalent of salt, said nitrogenous compound being chosen among the guanidines, the phospha- imines and amidines.
• a heptacarbon salt (H A ) makes it possible to obtain a streptocyanine corresponding to the formula (IV A ).
• a nonacarbon salt (H B ) makes it possible to obtain a streptocyanine corresponding to the formula (IV B ).
• a macrocyclic dicationic compound (V) is obtained by reacting a compound (II) with a diamine H 2 NE-NH 2 , using a molar ratio (II) / diamine of 1/1.
• the use of a salt heptacarbone (H A) provides a streptocyanine of formula (V A).
• the use of a nonacarbon salt (II B ) makes it possible to obtain a streptocyanine corresponding to the formula (V B ).
• the process for preparing a hemicarboxonium salt (VI) or (VII) consists in reacting a compound (II) with a nitrogenous compound, using an equivalent of nitrogenous compound for an equivalent of compound (II).
• the nitrogenous compound is chosen from amines, hydrazines, hydrazones for a compound (VI) or from guanidines, phosphaimines and amidines for compounds (VII).
• the use of a heptacarbon salt (H A ) makes it possible to obtain a heptacarbon hemicarboxonium salt corresponding respectively to the formula (VI A ) or (VIIj).
• the use of a nonacarbon salt (H B ) makes it possible to obtain a nonacarbon hemicarboxonium salt corresponding respectively to the formula (VI B ) or (VII B ).
• a hemicarboxonium (VI) salt can advantageously be used for the preparation of asymmetric streptocyanines (III), by reaction of an equivalent of compound (VI) with an equivalent of a nitrogenous compound chosen from amines, hydrazines , hydrazones different from that used for the preparation of said compound (VI) from compound (II).
• a salt (VI A ) makes it possible to obtain an asymmetric cyanine (III A )
• a salt (VI B ) makes it possible to obtain an asymmetric streptocyanine (III B ).
• a hemicarboxonium salt (VII) can advantageously be used for the preparation of asymmetric streptocyanines (IV), by reaction of an equivalent of compound (VII) with an equivalent of a nitrogen compound chosen from guanidines, phosphaimines and the amidines different from that used for the preparation of said compound (VII) from compound (II).
• a salt (VII A ) allows to obtain an asymmetric streptocyanine (IV A )
• a salt (VH B ) allows to obtain an asymmetric streptocyanine (IV B ).
• a hemicarboxonium salt (VI) can also be used for the preparation of non macrocyclic dicationic compounds (VIII), by reaction of n equivalents of salt (VI) with an equivalent of a primary or secondary polyamine.
• n equivalents of salt (VI) with an equivalent of a primary or secondary polyamine.
• di-, tri-, tetra- or polycationic ' may be obtained by reacting two, three, four or n equivalents (n> 4) salt (VI) respectively with a diamine, a triamine, a tetramine or a polyamine.
• the hemicarboxonium (VI) salts can be grafted onto a substrate carrying nitrogenous functions, via the OEt function.
• the streptocyanines (III B ) of the invention in which Z is a halogen can be functionalized by replacing the halogen atom with a group -M- ⁇ -A. The compound then meets the formula
• M can be an oxygen or sulfur atom
• streptocyanines of the present invention corresponding to formulas (III), (IV), (VI) or (VII) can be advantageously used as markers for various biological molecules such as for example antibodies, DNA, proteins, polysaccharides .
• Another object of the present invention is a method for labeling biological molecules, characterized in that it uses a streptocyanine according to the present invention.
• the present invention is illustrated in more detail with the aid of a few examples to which it is not however limited.
• the bisaldehyde used in Example 14 is 2-chloro-1-formyl-3-hydroxymethylenecyclohexene CFHMCH. It was prepared according to the method described by GA Reynolds, KH Drexhage, J. Org. Chem. 1977, 42, 885. This is a simple reaction, fast, and implementing the 'DMF, dichloromethane, cyclohexanone and the oxide ID trichlorophosphore all of which are commercial reagents.
• the summary diagram is summarized as follows:
• Bisaldehyde CFHMCH is in the form of an orange-yellow crystalline powder. Its characteristics are as follows:
• Example 3 The procedure described in Example 3 was used for the preparation of compound 2a, but using the compound lb obtained in Example 2.
• the compound corresponding to the following formula was obtained in the form of pink crystals , with a yield of 73%.
• salt 3a was thus isolated in the form of purple flakes with blue-green reflections, with a yield of 56%. It corresponds to the following formula:
• Salt 5a was thus isolated in the form of a green-blue powder, with a yield of 12%.
• salt la was dissolved in about 50 ml of dry acetonitrile.
• An equivalent of diethylamine (0.11 ml / 1.08 mmol) was then added. After twelve hours of reaction, the acetonitrile was evaporated. The residue was washed with pentah and then dried under vacuum. Salt 6a corresponding to the following formula was isolated in the form of an orange-red powder.
• Example 10 The procedure described in Example 10 was used for the preparation of compound 6a, but using the compound lb obtained in Example 2.
• the compound corresponding to the following formula was obtained in the form of a 5 shiny black powder, with a yield of 92%.
• hemicarboxonium salt 7a was dissolved in 15 ml of dry acetonitrile. 0.04 ml
• Salt 8a corresponding to the following formula, was thus isolated, in the form of a dark blue crystalline powder, with a yield of 37%.
• the characteristics of the diketonic compound (9a ′) are the following:
• IR (KBr pellet)

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