Patent Application
20080193398
The present invention is related to the cosmetic, dermatological and pharmaceutical fields. In particular, the present invention relates to new derivatives of heptaazaphenalene which, due to their physicochemical properties, are useful as protecting agents against UV radiation, together with their use for manufacturing cosmetic, dermatological, veterinary and pharmaceutical formulations that protect the skin, lips, nails and hair against UV radiation.
Sunlight, and ultraviolet radiation in particular, can under certain circumstances provoke harmful effects on skin, giving rise to pathological manifestations such as sunburns, photodermatosis and photoageing, among others.
The main factor responsible for such pathological manifestations is ultraviolet radiation, whose energy is inversely proportional to its wavelength. Thus, the shorter the wavelength the more energetic the radiation is. Ultraviolet radiation can be classified into UV-C, UV-B and UV-A, with UV-C being the most harmful, although it is absorbed by the ozone layer.
To counteract the damage that UV-A and UV-B radiation can cause, people's skin has various natural protection systems that either absorb or reflect the radiation, such as melanin, hair, the fatty layer of the skin, etc.
Solar filters and/or sunscreens are currently used in this respect in order to reduce the effects of solar radiation. Such UV filters are compounds that are applied to the skin, lips, nails or hair and that can be found included in cosmetic, dermatological and pharmaceutical formulations and in other cosmetic preparations to protect against solar radiation, preventing the decomposition of active substances or components sensitive to radiation.
Research has been carried out in recent years to obtain compounds whose physicochemical properties would be more effective as UV filters.
Despite the wide diversity of solar filters, there exists a need for new compounds whose physicochemical properties make them suitable UV filters to protect against UV-A radiation, UV-B radiation or simultaneously against UV-A and UV-B radiation.
A first aspect of the invention comprises an heptaazaphenalene derivative of general formula (I):
where
R1, R2 and R3 are the same as or different from each other and represent an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; an —OR4 radical; or an —NR5R6 radical;
R4 represents hydrogen, an optionally substituted saturated or unsaturated linear or branched alkyl radical that contains from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 14 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S;
R5 and R6 are the same as or different from each other and represent hydrogen; an optionally substituted, saturated or unsaturated, linear or branched radical having from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S;
or R5 and R6 are fused to form together with the nitrogen a saturated, unsaturated or aromatic mono- or polycyclic ring system having from 4 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from N, O and S
or a pharmaceutically, dermatologically or cosmetically acceptable salt, tautomer, isomer or solvate thereof.
In a preferred embodiment, if R1, R2 and R3 are identical they may not be a phenyl, methylphenyl, dimethylphenyl, trimethylphenyl, and 2,3,5,6-tetramethylphenyl.
In another preferred embodiment if R1, R2 and R3 are the same and are OR4, then R4 is different from hydrogen.
In another preferred embodiment if R1, R2 and R3 are the same and are OR4, then R4 is different from n-butyl, ethyl, phenyl, benzyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,2,3,3,4,4,4-heptafluorobutyl, 2,2,3,3,3-pentafluoropropyl, 2,2,2-trifluoroethyl and hydroxymethyl.
In another preferred embodiment when R1, R2 and R3 are the same and are OR4, if R4 is ethyl for two of the radicals R1, R2 and R3, then R4 is different from hydrogen for the third R1, R2 and R3 radical.
In another preferred embodiment when R1, R2 and R3 are the same and are NR5R6, R5 and R6, being the same, are different from hydrogen.
In another preferred embodiment when R1, R2 and R3 are the same and are NR5R6, R5 and R6, being the same, are different from ethyl, n-butyl, benzyl, n-heptyl, phenyl, cyclohexyl, 2-pyridyl or hydroxymethyl.
In another preferred embodiment when R1, R2 and R3 are the same and are NR5R6, if one of R5 or R6 is hydrogen, the other radical R5 or R6 is different from n-butyl, (optionally unsubstituted) phenyl, hydroxymethyl, 4-methoxy-9,10-dihydro-9,10-dioxoanthracene-1-yl, 9,10-dihydro-9,10-dioxoanthracene-1-yl, 9,10-dihydro-9,10-dioxoanthracene-2-yl, or 5-benzoylamino-9,10-dihydro-9,10-dioxoanthracene-1-yl.
In another preferred embodiment when R1, R2 and R3 are the same and are NR5R6, if one of R5 or R6 is phenyl, the other R5 or R6 radical is different from methyl.
In another preferred embodiment when R1, R2 and R3 are NR5R6, if R5 and R6 are the same for two of the radicals R1, R2, R3, and represent n-heptyl, and for the third radical of R1, R2, R3, being NR5R6, R5 or R6 is phenyl, then the other R5 or R6 is different from phenyl.
In another preferred embodiment when R1, R2 and R3 are NR5R6, if R5 and R6 are the same for two of the radicals R1, R2, R3, and represent phenyl, and for the third radical of R1, R2, R3, being NR5R6, R5 or R6 is n-heptyl, then the other R5 or R6 is different from n-heptyl.
In a preferred embodiment 6,6′,6″-(1,3,4,6,7,9,9b-heptaazaphenalene-2,5,8-triyltriimino)tris[[(4-acetamido-2-sulfophenyl)azo]-4-hydroxy-2-naphthalenesulfonic acid is disclaimed.
R1, R2 and R3 are the same as or different from each other and represent an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; an —OR4 radical; or an —NR5R6 radical;
R4 represents hydrogen, an optionally substituted saturated or unsaturated linear or branched alkyl radical that contains from 1 to 18 carbon atoms; a C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 14 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S;
with the condition that if R1, R2 and R3 are the same, then R4 is different from hydrogen;
with the condition that if R1, R2 and R3 are the same, then R4 is different from n-butyl, ethyl, phenyl, benzyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,2,3,3,4,4,4-heptafluorobutyl, 2,2,3,3,3-pentafluoropropyl, 2,2,2-trifluoroethyl and hydroxymethyl; and
with the condition that if R4 is ethyl for two of the radicals R1, R2 and R3, then R4 is different from hydrogen for the third radical;
R5 and R6 are the same as or different from each other and represent hydrogen; an optionally substituted, linear or branched radical having from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; or R5 and R6 are fused to form together with the nitrogen a saturated, unsaturated or aromatic mono- or polycyclic ring system having from 4 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from N, O and S;
with the condition that when R1, R2 and R3 are the same, R5 and R6, being the same, are different from hydrogen, ethyl, n-butyl, benzyl, n-heptyl, phenyl, cyclohexyl, 2-pyridyl or hydroxymethyl;
with the condition that when R1, R2 and R3 are the same, if R5 or R6 is hydrogen, the other radical R5 or R6 is different from n-butyl, phenyl, hydroxymethyl, 4-methoxy-9,10-dihydro-9,10-dioxoanthracene-1-yl, 9,10-dihydro-9,10-dioxoanthracene-1-yl, 9,10-dihydro-9,10-dioxoanthracene-2-yl, or 5-benzoylamino-9,10-dihydro-9,10-dioxoanthracene-1-yl;
with the condition that when R1, R2 and R3 are the same, if R5 or R6 is phenyl, the other R5 or R6 radical is different from methyl;
with the condition that if R5 and R6 are the same for two of the radicals R1, R2, R3, and represent n-heptyl, and for the third radical of R1, R2, R3, R5 or R6 is phenyl, then the other R5 or R6 is different from phenyl;
with the condition that if R5 and R6 are the same for two of the radicals R1, R2, R3, and represent phenyl, and for the third radical of R1, R2, R3, R5 or R6 is n-heptyl, then the other R5 or R6 is different from n-heptyl;
or a pharmaceutically, dermatologically or cosmetically acceptable salt, tautomer, isomer or solvate thereof;
In the present invention, “optionally substituted”—if not defined otherwise—means a radical that can be substituted in at least one position, by a linear or branched alkyl radical that contains from 1 to 8 carbon atoms; a C3-C6 cycloalkyl radical; C2-C6 alkenyl; C2-C6 alkenyl-COOR7; C2-C6 alkenyl-aryl; C1-C8 alkoxide; aryl; saturated, unsaturated or aromatic heterocyclic group containing from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; a —COOR7 radical; a —CONR8R9 radical; a —COR10 radical; an hydroxyl radical; an NR8R9 radical; a sulfur-containing radical; a nitro radical; an halogen such as chlorine or fluorine; a C1-C8 alkoxide; an optionally substituted linear or branched alkyl chain radical having from 1 to 6 carbon atoms, wherein the alkoxide or the alkyl radical can be substituted by at least one hydroxyl group, an —SO3M radical, a —N(R11)2 radical, an —N(R11)3+ radical, or a group of general formula (II):
where
m=0 or 1;
p=0, 1, 2, 3 or 4
R12, R13, R14, R15 and R16 are the same as or different from each other and represent an optionally substituted alkyl radical having from 1 to 6 carbon atoms, an alkoxide radical having from 1 to 6 carbon atoms, an optionally substituted aryl radical or an —OSi(R17)3 radical;
R17 represents an alkyl radical having from 1 to 6 carbon atoms, an alkoxide radical having from 1 to 6 carbon atoms or an optionally substituted aryl radical;
M is H, Na or K;
R7, R8 and R9 are independently selected from hydrogen; an optionally substituted linear or branched alkyl radical having from 1 to 18 carbon atoms; a substituted or unsubstituted ary radical; a saturated, unsaturated or aromatic heterocycle having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; a C3-C12 cycloalkyl radical; or
R8 and R9 can be fused, forming together with the nitrogen a mono- or polycyclic saturated, unsaturated or aromatic ring system having from 5 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from O, N and S;
R10 is an optionally substituted alkyl radical, or an optionally substituted aryl radical, or R10 is fused to form a mono- or polycyclic saturated, unsaturated or aromatic ring system having from 5 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from O, N and S;
R11 is an optionally substituted alkyl radical.
Any of the above mentioned groups could also be optionally substituted in at least one position.
The term “salt” means any form of the active compound (of general formula (I)) in accordance with the invention in which the latter has an ionic form or it is charged and it is bound to a contra-ion (a cation or an anion) or it is in solution. Also are included complexes of the active compound with other molecules and ions, and in particular complexes that are linked by ionic interactions.
In a preferred meaning the term “salt” is to be understood as meaning any form of the active compound used according to the invention in which it assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution. By this are also to be understood complexes of the active compound with other molecules and ions, in particular complexes which are complexed via ionic interactions. It especially includes physiologically, dermatologically or cosmetically acceptable salts, which is to be used equivalently to pharmacologically, dermatologically or cosmetically acceptable salts.
The term “pharmaceutically, dermatologically or cosmetically acceptable salt” means, in the context of this invention, the salt formed with a) a pharmaceutically, dermatologically or cosmetically acceptable acid or b) a pharmaceutically acceptable base. This means, especially, salts of the active compound, in particular with inorganic or organic acids that are pharmaceutically, cosmetically and dermatologically acceptable—especially if used on humans and/or mammals—or with at least one cation, preferably inorganic, which is pharmaceutically, cosmetically and dermatologically acceptable—especially if used on humans and/or mammals.
In a preferred meaning the term “pharmaceutically, dermatologically or cosmetically acceptable salt” means, in the context of this invention, the salt formed with a) a pharmaceutically, dermatologically or cosmetically acceptable acid or b) a pharmaceutically, dermatologically or cosmetically acceptable base. This means, especially, salts of the active compound, in particular with inorganic or organic acids that are pharmaceutically, cosmetically and dermatologically acceptable—especially if used on humans and/or mammals—or with at least one cation, preferably inorganic, which is pharmaceutically, cosmetically and dermatologically acceptable—especially if used on humans and/or mammals.
The term “solvate” means, in the context of this invention, a compound formed by the combination of molecules of solvent with molecules or ions of the solute of general formula (I).
In a preferred meaning the term “solvate” according to this invention is to be understood as meaning any form of the active compound according to the invention in which this compound has attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcoholates, e.g. methanolate.
In a preferred embodiment, the heptaazaphenalene derivative has any of the following general formulas:
wherein R′1, R′2 and R′3 are the same as or different from each other and represent an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can optionally contain 1, 2 or 3 heteroatoms selected from O, N and S;
R′4, R″4 and R′″4 represent independently of each other hydrogen, an optionally substituted saturated or unsaturated linear or branched alkyl radical that contains from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 14 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S;
R′5, R″5, R′″5, R′6, R″6 and R′″6 are identical or different from each other and represent hydrogen; an optionally substituted, saturated or unsaturated, linear or branched alkyl radical having from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; or R′5, R″5, R′″5, R′6, R″6 and R′″6 are fused to form together with the nitrogen a saturated, unsaturated or aromatic mono- or polycyclic ring system having from 4 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from N, O and S.
In another preferred embodiment of the first aspect of the invention, the heptaazaphenalene derivative has general formula (IA):
where R′4, R″4 and R′″4 represent independently of each other a cycloalkyl radical having from 3 to 12 carbon atoms; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical containing from 5 to 14 atoms that can optionally contain 1, 2 or 3 heteroatoms selected from O, N and S.
In another preferred embodiment of the first aspect of the invention, the heptaazaphenalene derivative has general formula (IA):
where R4 represents a cycloalkyl radical having from 3 to 12 carbon atoms; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical containing from 5 to 14 atoms that can optionally contain 1, 2 or 3 heteroatoms selected from O, N and S.
In a preferred embodiment when R1, R2, R3 are the same, R4 is different from phenyl, benzyl, 2,6-dimethylphenyl or 3,5-dimethylphenyl.
In a more preferred embodiment, R4 as well as optionally R′4, R″4 and R′″4 represent an aryl group that can be substituted in at least one position, with said substituent being an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted C2-C6alkenyl radical; an optionally substituted aryl; an optionally substituted saturated, unsaturated or aromatic heterocycle having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; a —COOR7 radical; a —CONR8R9 radical; a —COR10 radical; an hydroxyl radical; an halogen such as chlorine or fluorine; C1-C8 alkoxide; an optionally substituted linear or branched alkyl chain radical having from 1 to 6 carbon atoms, wherein the alkoxide or the alkyl radical can be substituted by at least one hydroxyl group, an —SO3M radical, a —N(R11)2 radical, an —N(R11)3+ radical, or a group of general formula (II):
where
m=0 or 1;
p=0, 1, 2, 3 or 4
R12, R13, R14, R15 and R16 are the same as or different from each other and represent an optionally substituted alkyl radical having from 1 to 6 carbon atoms, an alkoxide radical having from 1 to 6 carbon atoms, an optionally substituted aryl radical or an —OSi(R17)3 radical;
R17 represents an alkyl radical having from 1 to 6 carbon atoms, an alkoxide radical having from 1 to 6 carbon atoms or an optionally substituted aryl radical;
M is H, Na or K;
R7, R8 and R9 are independently selected from hydrogen; an optionally substituted or unsubstituted aryl; an optionally substituted linear or branched alkyl radical having from 1 to 18 carbon atoms; a saturated, unsaturated or aromatic heterocycle having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; a C3-C12 cycloalkyl radical; or
R8 and R9 can be fused, forming together with the nitrogen a mono- or polycyclic saturated, unsaturated or aromatic ring system having from 5 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from O, N and S;
R10 is an optionally substituted alkyl radical, or an optionally substituted aryl radical, or R10 is fused to form a mono- or polycyclic saturated, unsaturated or aromatic ring system having from 5 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from O, N and S;
R11 is an optionally substituted alkyl radical.
In another preferred embodiment, R4 represents an aryl group that can be substituted in at least one position, with said substituent being a C3-C12 cycloalkyl radical; a C2-C6 alkenyl; aryl; saturated, unsaturated or aromatic heterocycle having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; a —COOR7 radical; a —CONR8R9 radical; a —COR10 radical; an hydroxyl radical; an halogen such as chlorine or fluorine; C1-C8 alkoxide; a linear or branched alkyl chain radical having from 1 to 6 carbon atoms, wherein the alkoxide or the alkyl radical can be substituted by at least one hydroxyl group, an —SO3M radical, a —N(R11)2 radical, an —N(R11)3+ radical, or a group of general formula (II)
where
m=0 or 1;
p=0, 1, 2, 3 or 4
R12, R13, R14, R15 and R16 are the same as or different from each other and represent an optionally substituted alkyl radical having from 1 to 6 carbon atoms, an alkoxide radical having from 1 to 6 carbon atoms, an optionally substituted aryl radical or an —OSi(R17)3 radical;
R17 represents an alkyl radical having from 1 to 6 carbon atoms, an alkoxide radical having from 1 to 6 carbon atoms or an optionally substituted aryl radical;
M is H, Na or K;
R7, R8 and R9 are independently selected from hydrogen; an optionally substituted linear or branched alkyl radical having from 1 to 18 carbon atoms; a saturated, unsaturated or aromatic heterocycle having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; a C3-C12 cycloalkyl radical; or
R8 and R9 can be fused, forming together with the nitrogen a mono- or polycyclic saturated, unsaturated or aromatic ring system having from 5 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from O, N and S;
R10 is an optionally substituted alkyl radical, or an optionally substituted aryl radical, or R10 is fused to form a mono- or polycyclic saturated, unsaturated or aromatic ring system having from 5 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from O, N and S;
R11 is an optionally substituted alkyl radical.
In another preferred embodiment R4 represents 4-methoxyphenyl, naphthyl, cyclopentyl, cyclohexyl;
with the condition that when R1, R2 and R3 are the same, R4 is different from phenyl, benzyl, 2,6-dimethylphenyl and 3,5-dimethylphenyl.
In another preferred embodiment of the first aspect of the invention, the heptaazaphenalene derivative has general formula (IB):
wherein the radicals within each radical pair R′5R′6, R″5R″6, and R′″5R′″6 are different from each other and represent hydrogen; an optionally substituted linear or branched alkyl radical having from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can optionally contain 1, 2 or 3 heteroatoms selected from O, N and S;
or the radical pairs R′5R′6, R″5R″6, or R′″5R′″6 are fused and form together with the nitrogen a saturated, unsaturated or aromatic mono- or polycyclic ring system having from 4 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from N, O and S.
In another preferred embodiment of the first aspect of the invention, the heptaazaphenalene derivative has general formula (IB):
R5 and R6 are different from each other and represent hydrogen; an optionally substituted linear or branched alkyl radical having from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can optionally contain 1, 2 or 3 heteroatoms selected from O, N and S;
or R5 and R6 are fused and form together with the nitrogen a saturated, unsaturated or aromatic mono- or polycyclic ring system having from 4 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from N, O and S.
In a preferred embodiment if one of the radicals within each radical pair R′5R′6, R″5R″6, and R′″5R′″6 is hydrogen, the other radical is different from n-butyl, unsubstituted phenyl, hydroxymethyl, 4-methoxy-9,10-dihydro-9,10-dioxoanthracene-1-yl, 9,10-dihydro-9,10-dioxoanthracene-1-yl, 9,10-dihydro-9,10-dioxoanthracene-2-yl, or 5-benzoylamino-9,10-dihydro-9,10-dioxoanthracene-1-yl.
In another preferred embodiment if one of the radicals within each radical pair R′5R′6, R″5R″6, and R′″5R′″6 is phenyl, the other radical is different from methyl.
In a more preferred embodiment one radical of the pair R5R6 or optionally one radical of the pairs R′5R′6, R″5R″6 or R′″5R′″6 represents an aryl group that can be substituted in at least one position, with said substituent being a C3-C12 cycloalkyl radical; an optionally substituted C2-C6 alkenyl radical; an optionally substituted aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocycle having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; a —COOR7 radical; a —CONR8R9 radical; a —COR10 radical; an hydroxyl radical; an halogen such as chlorine or fluorine; C1-C8 alkoxide; an optionally substituted linear or branched alkyl radical having from 1 to 6 carbon atoms, where the alkoxide radical or the alkyl radical can be optionally substituted by at least one —SO3M group, an —N(R11)2 radical, an —N(R11)3+ radical, or a group of general formula (II):
where
m=0 or 1;
p=0, 1, 2, 3 or 4
R12, R13, R14, R15 and R16 are the same as or different from each other and represent an optionally substituted alkyl radical having from 1 to 6 carbon atoms, an alkoxide radical having from 1 to 6 carbon atoms, an optionally substituted aryl radical or a —OSi(R17)3 radical;
R17 represents an alkyl radical having from 1 to 6 carbon atoms, an alkoxide radical having from 1 to 6 carbon atoms or an optionally substituted aryl radical;
M is H, Na or K;
R7, R8 and R9 are independently selected from hydrogen; an optionally substituted aryl radical; an optionally substituted linear or branched alkyl radical having from 1 to 18 carbon atoms; an optionally substituted saturated, unsaturated or aromatic heterocycle having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; a C3-C12 cycloalkyl radical; or
R8 and R9 can be fused to form together with the nitrogen a mono- or polycyclic saturated, unsaturated or aromatic ring system having from 5 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from O, N and S;
R10 is an optionally substituted saturated or unsaturated, linear or branched alkyl radical having from 1 to 6 carbon atoms, or an optionally substituted aryl radical, or R10 is fused to form a mono- or polycyclic saturated, unsaturated or aromatic ring system having from 5 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from O, N and S;
R11 is an optionally substituted alkyl radical.
In another preferred embodiment R5 or R6 represent an aryl group that can be substituted in at least one position, with said substituent being a C3-C12 cycloalkyl radical; a C2-C6alkenyl; an aryl; a saturated, unsaturated or aromatic heterocycle having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; a —COOR7 radical; a —CONR8R9 radical; a —COR10 radical; an hydroxyl radical; an halogen such as chlorine or fluorine; C1-C8 alkoxide; a linear or branched alkyl radical having from 1 to 6 carbon atoms, where the alkoxide radical or the alkyl radical can be substituted by —SO3M group, an —N(R11)2 radical, an —N(R11)3+ radical, or a group of general formula (II):
where
m=0 or 1;
p=0, 1, 2, 3 or 4
R12, R13, R14, R15 and R16 are the same as or different from each other and represent an optionally substituted alkyl radical having from 1 to 6 carbon atoms, an alkoxide radical having from 1 to 6 carbon atoms, an optionally substituted aryl radical or a —OSi(R17)3 radical;
R17 represents an alkyl radical having from 1 to 6 carbon atoms, an alkoxide radical having from 1 to 6 carbon atoms or an optionally substituted aryl radical;
M is H, Na or K;
R7, R8 and R9 are independently selected from hydrogen; an optionally substituted linear or branched alkyl radical having from 1 to 18 carbon atoms; a saturated, unsaturated or aromatic heterocycle having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; a C3-C12 cycloalkyl radical; or
R8 and R9 can be fused to form together with the nitrogen a mono- or polycyclic saturated, unsaturated or aromatic ring system having from 5 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from O, N and S;
R10 is an optionally substituted saturated or unsaturated, linear or branched alkyl radical having from 1 to 6 carbon atoms, or an optionally substituted aryl radical, or R10 is fused to form a mono- or polycyclic saturated, unsaturated or aromatic ring system having from 5 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from O, N and S;
R11 is an optionally substituted alkyl radical.
In another preferred embodiment, the heptaazaphenalene derivative has general formula (IC)
wherein R′1, R′2 and R′3 are the same as or different from each other and represent an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can optionally contain 1, 2 or 3 heteroatoms selected from O, N and S.
In a preferred embodiment, if R′1, R′2 and R′3 are identical they may not be a phenyl, methylphenyl, dimethylphenyl, trimethylphenyl, and 2,3,5,6-tetramethylphenyl.
In a yet more preferred embodiment R1, R2, R3 as well as optionally R′1, R′2, R′3 are the same as or different from each other and represent naphthyl, pyrrole, thiophene, indole, pyrazole, imidazole, triazole, benzothiophene, benzimidazole, benzopyrazole, oxazole, isoxazole, benzofuran, all of them optionally substituted, or else a radical of general formula (III)
R18 represents an hydrogen; or an hydroxyl radical; an —OR22 radical; an optionally substituted saturated or unsaturated linear or branched alkyl radical that contains from 1 to 18 carbon atoms; or an optionally substituted linear or branched chain C1-C18 alkoxyde radical;
R19 represents an hydrogen; an hydroxyl radical; an optionally substituted aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can optionally contain 1, 2 or 3 heteroatoms selected from O, N and S; a —COOR7 radical; a —CONR8R9 radical; an —OR22 radical; an optionally substituted —COR10 radical; a C3-C6 cycloalkyl radical; an optionally substituted, saturated or unsaturated linear or branched alkyl radical that contains from 1 to 18 carbon atoms, optionally substituted by at least one hydroxyl radical, an —SO3M, —N(R11)2 or —N(R11)3+ group, or else by a group of general formula (II):
wherein
m=0 or 1;
p=0, 1, 2, 3 or 4;
R22 represents an optionally substituted aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can optionally contain 1, 2 or 3 heteroatoms selected from O, N and S; an optionally substituted —COR10 radical; a C3-C12 cycloalkyl radical; a saturated or unsaturated linear or branched alkyl radical that contains from 1 to 18 carbon atoms, optionally substituted at least by one hydroxyl radical, a —SO3M, —N(R11)2 or —N(R11)3+ group or else by a group of general formula (II):
wherein
m=0 or 1;
p=0, 1, 2, 3 or 4;
where R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are as defined above;
R20 and R21 can be the same or different and represent hydrogen; an optionally substituted saturated or unsaturated linear or branched alkyl radical that contains from 1 to 6 carbon atoms; an optionally substituted C1-C6 alkoxide radical; or an —SO3M radical, where M is as defined above.
In another more preferred embodiment R5 and R6 are different from each other and represent hydrogen, cyclopropyl, cyclohexyl, cyclobutyl, cycloheptyl, cyclopentyl, 4-(hydroxycarbonyl)phenyl, 4-(butoxycarbonyl)phenyl, 4-(2-ethylhexyloxycarbonyl)phenyl, 4-(2-butyloctyloxycarbonyl)phenyl, 4-(2-hexyldecyloxycarbonyl)phenyl, 4-(3,3,5-trimethylcyclohexyloxycarbonyl)phenyl, 4-(3,3,5-trimethylhexyloxycarbonyl)phenyl, 4-(octadecyloxycarbonyl)phenyl, 4-(hexadecyloxycarbonyl)phenyl, 4-(docecyloxycarbonyl)phenyl, 4-((2-ethylhexyl)carbamoyl)phenyl, 4-(L-menthyloxycarbonyl)phenyl, 4-styrylphenyl, 3-styrylphenyl, 3-((E)-3-(2-ethylhexyloxy)-3-oxoprop-1-enyl)phenyl, 4-((E)-3-(2-ethylhexyloxy)-3-oxoprop-1-enyl)phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-nitrophenyl phenyl, biphenyl-4-yl, 4-(imidazo[1,2-a]pyridin-2-yl)phenyl, 4-(4,5,6,7-tetrahydro-2,6,6-trimethyl-4-oxoindol-1-yl)phenyl, 4-(1H-benzo[d]imidazol-2-yl)phenyl, hydroxymethyl, pyridine, heptyl, butyl, ethyl, 2-ethylhexyl, 4-(1,3,3-trimethylbicyclo[2.2.1]heptan-2-yloxy)phenyl, 1H-indol-5-yl, 4-((3,7-dimethyloctyloxy)carbonyl)phenyl, 2-amino-4,5-dimethylphenyl or n-propyl.
In another more preferred embodiment R4 represents 4-methoxyphenyl, naphthyl, cyclopentyl, cyclohexyl.
In still another more preferred embodiment when R1, R2 and R3 are the same, R4 is different from phenyl, benzyl, 2,6-dimethylphenyl and 3,5-dimethylphenyl.
In another preferred embodiment R7 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, 2-ethylhexyl, L-menthyl, 3,3,5-trimethylcyclohexanyl, 3,3,5-trimethylhexanyl, dodecyl, 2-butyloctyl, 2-hexyldecyl, octadecyl, 3,7-dimethyloctyl, 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl, optionally substituted benzyl radical or an optionally substituted phenyl radical.
In another preferred embodiment R8 and R9, are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl 2-ethylhexyl, L-menthyl, 3,3,5-trimethylcyclohexanyl, 3,3,5-trimethylhexanyl, dodecyl, 2-butyloctyl, 2-hexyldecyl, 3,7-dimethyloctyl, 1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl or octadecyl.
In another preferred embodiment of the first aspect of the invention R10 represents methyl, ethyl, n-propyl, n-butyl, tert-butyl or phenyl.
In another preferred embodiment R12 to R16 represent methyl, ethyl, methoxy, ethoxy or phenyl.
In another preferred embodiment R17 represents methyl, ethyl, methoxy, ethoxy or phenyl.
In another preferred embodiment of the first aspect of the invention, R18 represents hydrogen, an hydroxyl radical, a methyl radical, a methoxy radical or an acyloxy radical.
In another preferred embodiment R19 represents an hydrogen, a hydroxyl radical, an acyloxy radical, a linear or branched chain, saturated or unsaturated alkoxide radical such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, 2-ethylhexyloxy, phenoxide, optionally substituted by at least one —SO3M or —N(R11)3+ group.
In another preferred embodiment of the first aspect of the invention R20 and R21 are independently selected from hydrogen, a hydroxyl radical, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, n-pentoxy, hexyloxy or 2-ethylhexyloxy, optionally substituted by at least one —SO3M group, where M is as defined above.
Preferably the heptaazaphenalene derivative of general formula (I) is selected from the group that consists in:
Other possible examples for compounds of general formula (I) are shown in Table (II):
Other possible examples for compounds of general formula (I) are shown in Table (III):
Other possible examples for compounds of general formula (I) are shown in Table (IV):
Other possible examples for compounds of general formula (I) are shown in Table (V):
Other possible examples for compounds of general formula (I) are shown in Table (VI):
Other possible examples for compounds of general formula (I) are shown in Table (VII):
Surprisingly, the inventors of the present invention have found that the heptaazaphenalene derivatives of general formula (I) absorb in the ultraviolet radiation range of both type A and type B, said derivatives therefore being useful as UV radiation absorbents. In addition to protect against UV-A radiation and UV-B radiation they can be simultaneously effective in protecting against UV-A and UV-B radiation being still preferably as UV-A radiation protectors and showing a very good UV-A/UV-B ratio (meaning a comparatively high value for UV-A compared to for UV-B).
In addition the heptaazaphenalene derivatives of general formula (I) seem to show very good toxicity profile, good solubility and water improved resistance among other properties that made this compounds became very useful from a formulation point of view.
Another aspect of the present invention are the methods for preparing a heptaazaphenalene derivative in accordance with the first aspect of the invention.
The heptaazaphenalene derivatives of general formula (I) in accordance with the first aspect of the invention can be obtained according to the known procedures (e.g. Shroeder, H.; Kober, E. J. Org. Chem. 1962, 27, 4262). Schematically:
Therefore, in a second aspect the present invention relates to a method for obtaining a heptaazaphenalene derivative of general formula (I) according to the first aspect of the invention,
wherein R1, R2 and R3 are the same and represent —NR5R6, where R5 and R6 are as defined above, which comprises reaction of the 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene derivative of formula (IV) with a derivative of general formula (V)
in a solvent comprising 1,4-dioxane, tetrahydrofuran, toluene, xylene (mixture of isomers), N,N-dimethylformamide, N-methylpyrrolidone or acetone, at a temperature that ranges between 0° C. and the boiling temperature of the solvent, preferably between room temperature and the boiling temperature of the solvent, and more preferably between 50° C. and the boiling temperature of the solvent, optionally in the presence of an organic base comprising diisopropylethylamine, triethylamine or pyridine, or an inorganic base comprising potassium carbonate, sodium hydroxide, sodium carbonate, cesium carbonate or sodium bicarbonate.
The process described in the abovementioned second aspect has shown very good possibilities in order to obtain industrial quantities of compounds and leading also to compounds of general formula (I) that show a very good stability and will also give a very good protection against UV-A and UV-B radiation, especially UV-A radiation.
Any of the steps described in the above procedures can also be carried out in a microwave oven, employing a typical procedure of MAOS (microwave assisted organic synthesis). The present invention provides processes of efficiently preparing these compounds in a short time by using microwave irradiation. Microwave assisted chemistry is relatively new compared to some other techniques, however, it has become well established and accepted. Microwave assisted chemical synthesis refers to the use of electromagnetic radiation within the microwave frequencies to provide the energy required to initiate, drive, or accelerate certain chemical reactions. As chemists have long been aware, the application of heat energy is one of the most significant factors in increasing the rate of a wide variety of chemical reactions. Microwave assisted reactions can be completed in a much shorter period of time than conventional thermal-treatment techniques requiring long reaction time. In each of the reactions discussed or illustrated above, pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 5 atmospheres are generally acceptable, and ambient pressure, i.e. about 1 atmosphere, is preferred as a matter of convenience. Under microwave-assisted heating, sealed reactors are indicated, resulting in high-pressure reactions up to as much as 350 psi.
Common microwave equipment may be used in preparation processes according to the present invention. The microwave irradiation may be performed at a power level of 1 to 1600 W, preferably 1 to 300 W, and particularly preferably about 70 W. The duration for the microwave irradiation may vary according to conditions such as the amount or reactant but may be in the range from 20 seconds to 60 minutes, preferably from 1 minute to 20 minutes. The reaction can be carried out at a temperature of 50-280° C., preferably 80-200° C., and more preferably 120-150° C., with of without solvent, under microwave irradiation. A presently preferred microwave furnace is commercially available from CEM, Inc., as model Discover®. The Discover® System incorporates temperature and pressure feedback systems, for example, an infrared temperature sensor positioned below the reaction vessel, for complete control of the reaction. As described above, according to the present invention, heptaazaphenalene derivatives can be prepared within a very short time, i.e. several seconds to several minutes, by microwave irradiation, unlike conventional techniques requiring about 12-50 hours for preparation of compounds for general formula I.
In a third aspect, the present invention relates to a method for obtaining a heptaazaphenalene derivative of general formula (I) according to the first aspect of the invention:
where
where R5 and R6 are as defined above, in a solvent comprising 1,4-dioxane, tetrahydrofuran, toluene, xylene (mixture of isomers), N,N-dimethylformamide, N-methylpyrrolidone or acetone, at a temperature that ranges between 0° C. and the boiling temperature of the solvent, preferably between room temperature and the boiling temperature of the solvent, and more preferably between 50° C. and the boiling temperature of the solvent; optionally in the presence of an organic base comprising diisopropylethylamine, triethylamine or pyridine, or an inorganic base comprising potassium carbonate, sodium hydroxide, sodium carbonate, cesium carbonate or sodium bicarbonate; and
Any of the steps described above can be conducted trough MAOS (microwave assisted organic synthesis)
In a fourth aspect, the present invention relates to a method for obtaining a heptaazaphenalene derivative of general formula (I) according to the first aspect of the invention:
wherein
where R5 and R6 are as defined above, in a solvent comprising 1,4-dioxane, tetrahydrofuran, toluene, tetrahydrofuran, xylene (mixture of isomers), N,N-dimethylformamide, N-methylpyrrolidone or acetone, at a temperature that ranges between 0° C. and the boiling temperature of the solvent, preferably between room temperature and the boiling temperature of the solvent and more preferably between 50° C. and the boiling temperature of the solvent; optionally in the presence of an organic base comprising diisopropylethylamine, triethylamine or pyridine, or an inorganic base comprising potassium carbonate, sodium hydroxide, sodium carbonate, cesium carbonate or sodium bicarbonate;
NHR5R6 (V)
where one of R5 and R6 are as defined above, and submitting to reflux; and
NHR5R6 (V)
where R5 and R6 are as defined above.
Any of the steps described above can be conducted trough MAOS (microwave assisted organic synthesis).
Under a fifth aspect, the present invention relates to a method for obtaining a heptaazaphenalene derivative of general formula (I) according to the first aspect of the invention:
wherein R1, R2 and R3 are the same and represent a derivative of general formula (III)
that includes making the 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene derivative of formula (IV) react with a heterocyclic derivative or a compound of general formula (VI)
where R18, R19, R20 and R21 are as defined above, in the presence of a Lewis acid comprising, FeCl3, BF3, in particular aluminium trichloride, in an inert solvent comprising toluene, 1,1,2,2-tetrachloroethane, tetrahydrofuran, 1,2-dichlorobenzene, nitrobenzene or benzene and at a temperature that ranges between 60° C. and the boiling temperature of the solvent.
Any of the steps described above can be conducted trough MAOS (microwave assisted organic synthesis).
Under a sixth aspect, the present invention relates to a method for obtaining a heptaazaphenalene derivative of general formula (I) according to the first aspect of the invention:
wherein:
one of the radicals R1, R2 and R3 represents an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; and
the other two radicals are the same and represent —NR5R6, where R5 or R6 are as defined in claim 1, which includes the reaction of a derivative of general formula (VII) with a derivative of general formula (V):
where R1 is an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; and
The derivative of general formula (VII) is obtained by reaction of the 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene derivative of general formula (V) with an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S,
Any of the steps described above can be conducted trough MAOS (microwave assisted organic synthesis).
Under a seventh aspect, the present invention relates to a method for obtaining a heptaazaphenalene derivative of general formula (I) according to the first aspect of the invention:
wherein:
two of the radicals R1, R2 and R3 are the same and represent an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; and
the third of the radicals R1, R2 and R3 represents —NR5R6, where R5 or R6 are as defined above,
where R5 and R6 are as defined above, in a solvent comprising 1,4-dioxane, tetrahydrofuran, toluene, xylene (mixture of isomers), N,N-dimethylformamide, N-methylpyrrolidone or acetone, at a temperature that ranges between 0° C. and the boiling temperature of the solvent, preferably between room temperature and the boiling temperature of the solvent, and more preferably between 50° C. and the boiling temperature of the solvent, optionally in the presence of an organic base such as diisopropylethylamine, triethylamine or pyridine, or an inorganic base comprising potassium carbonate, sodium hydroxide, sodium carbonate, cesium carbonate or sodium bicarbonate to obtain a compound of general formula (VIII),
said derivative of general formula (VIII) reacts with a compound of general formula (VI):
in the presence of a Lewis acid comprising, FeCl3, BF3, in particular aluminium chloride, in an inert solvent comprising toluene, xilene, 1,1,2,2-tetrachloroethane, tetrahydrofuran, 1,2-dichlorobenzene, nitrobenzene or benzene and at a temperature between 60° C. and the boiling temperature of the solvent;
Any of the steps described above can be conducted trough MAOS (microwave assisted organic synthesis).
The compounds of general formula (I), wherein R20 is —SO3M, where M is as defined above, can be obtained by carrying out, for example, the methods disclosed in U.S. Pat. No. 6,090,370, in particular column 5, line 59-column 6, line 8.
The compounds of general formula (I), wherein an —SO3M group, where M is as defined above, has been introduced into an alkylic chain, can be obtained according to the methods described in Lewin, G. et al., J. Nat. Prod., 58 (1995) 12, 1840-1847.
The compounds of general formula (I), wherein an —N(R11)3+ group, where R11 is as defined above, has been inserted into an alkylic chain, can be obtained for example by following the methods described in Sharma, M. L. et al., J. Indian Chem. Soc., 74(1997)4, 343-344.
As indicated above, the heptaazaphenalene derivatives of general formula (I) according to the first aspect of the present invention have physicochemical properties such as the absorption of ultraviolet light that allow them to be used as protective agents against UV radiation.
Any of the steps described above can be conducted trough MAOS (microwave assisted organic synthesis).
Also object of the present invention, therefore, are cosmetic, dermatological, veterinary or pharmaceutical formulations or a medicament that include one or more derivatives of general formula (I), according to the first aspect of the invention, and at least one cosmetically, dermatologically or pharmaceutically acceptable carrier or excipient.
A preferred embodiment is a dermatological formulation comprising a compound according to general formula (I)
wherein
R1, R2 and R3 are identical or different from each other and represent an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; an —OR4 radical; or an —NR5R6 radical;
R4 represents hydrogen, an optionally substituted saturated or unsaturated linear or branched alkyl radical that contains from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 14 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S;
R5 and R6 are identical or different from each other and represent hydrogen; an optionally substituted, saturated or unsaturated, linear or branched alkyl radical having from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; or R5 and R6 are fused to form together with the nitrogen a saturated, unsaturated or aromatic mono- or polycyclic ring system having from 4 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from N, O and S.
Another preferred embodiment is a cosmetic formulation comprising a compound according to general formula (I):
wherein
R1, R2 and R3 are identical or different from each other and represent an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; an —OR4 radical; or an —NR5R6 radical;
R4 represents hydrogen, an optionally substituted saturated or unsaturated linear or branched alkyl radical that contains from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 14 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S;
R5 and R6 are identical or different from each other and represent hydrogen; an optionally substituted, saturated or unsaturated, linear or branched alkyl radical having from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; or R5 and R6 are fused to form together with the nitrogen a saturated, unsaturated or aromatic mono- or polycyclic ring system having from 4 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from N, O and S.
Another preferred embodiment is a pharmaceutical formulation comprising a compound according to general formula (I):
wherein
R1, R2 and R3 are identical or different from each other and represent an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; an —OR4 radical; or an —NR5R6 radical;
R4 represents hydrogen, an optionally substituted saturated or unsaturated linear or branched alkyl radical that contains from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 14 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S;
R5 and R6 are identical or different from each other and represent hydrogen; an optionally substituted, saturated or unsaturated, linear or branched alkyl radical having from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; or R5 and R6 are fused to form together with the nitrogen a saturated, unsaturated or aromatic mono- or polycyclic ring system having from 4 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from N, O and S.
wherein
R1, R2 and R3 are identical or different from each other and represent an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; an —OR4 radical; or an —NR5R6 radical;
R4 represents hydrogen, an optionally substituted saturated or unsaturated linear or branched alkyl radical that contains from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 14 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S;
R5 and R6 are identical or different from each other and represent hydrogen; an optionally substituted, saturated or unsaturated, linear or branched alkyl radical having from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; or R5 and R6 are fused to form together with the nitrogen a saturated, unsaturated or aromatic mono- or polycyclic ring system having from 4 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from N, O and S.
wherein
R1, R2 and R3 are identical or different from each other and represent an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; an —OR4 radical; or an —NR5R6 radical;
R4 represents hydrogen, an optionally substituted saturated or unsaturated linear or branched alkyl radical that contains from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 14 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S;
R5 and R6 are identical or different from each other and represent hydrogen; an optionally substituted, saturated or unsaturated, linear or branched alkyl radical having from 1 to 18 carbon atoms; an optionally substituted C3-C12 cycloalkyl radical; an optionally substituted mono- or polycyclic aryl radical; an optionally substituted saturated, unsaturated or aromatic heterocyclic radical having from 5 to 10 atoms that can contain 1, 2 or 3 heteroatoms selected from O, N and S; or R5 and R6 are fused to form together with the nitrogen a saturated, unsaturated or aromatic mono- or polycyclic ring system having from 4 to 10 atoms that can optionally contain 1 or 2 heteroatoms selected from N, O and S.
are excluded and thus are not heptaazaphenalene compounds comprised in the formulation.
In a preferred embodiment, said cosmetic, dermatological or pharmaceutical formulation further includes at least one organic, micronized organic or inorganic filter against solar radiation.
In another preferred embodiment said compound according to formula (I) is micronized.
In another preferred embodiment, said formulation further includes at least one active substance.
Said cosmetic, dermatological or pharmaceutical formulation can be adapted for application thereof on the skin and lips in the form of: a non-ionic vesicular dispersion, emulsion, cream, lotion, gel, aerosol, cream-gel, gel-cream, suspension, dispersion, ointment, powder, solid stick, foam, spray, oil, pomade and fluid, among others.
Similarly, said formulation can be adapted for applying it on the hair in the form of a shampoo, lotion, gel, fluid, lacquer, foam, dye, emulsion, cream, spray, among others, and on the nails in the form of a nail varnish, oil and gel, among others.
The organic, micronized organic and inorganic filters are selected from those acceptable under the country's legislation.
The organic filters, for example, can be selected from those approved by the Council of the European Communities (revised text of European Directive 76/768/EEC Annex-7, pages 76-81, published on Oct. 15, 2003) and by the U.S. Food and Drug Administration (see, for example, “Food and Drugs, Sunscreen drug products for over the counter human use”, title 21, volume 5 of Code of Federal Regulations, revised 1 Apr. 2004), such as: anthranilates; camphor derivatives; dibenzoylmethane derivatives; benzotriazole derivatives; diphenylacrylate derivatives; cinnamic derivatives; salycylic derivatives; triazine derivatives such as those disclosed in patents EP-863145, EP-517104, EP-570838, EP-796851, EP-775698 and EP-878469, benzophenone derivatives; benzalmalonate derivatives; benzimidazole derivatives, imidizolines; p-aminobenzoic acid derivatives; polymeric and silicone filters.
The inorganic filters can be selected from a group that includes: metallic oxides as pigments, nanopigments, treated and untreated, such as the dioxide of titanium (amorphous or crystalline), iron, zinc, zirconium or cerium. Moreover, alumina and/or aluminium stearate are conventional coating agents, while examples of untreated metallic oxides as (uncoated) inorganic filters are those described in patents EP518772 and EP518773.
The cosmetic, dermatological and pharmaceutical formulations of the present invention can additionally contain additives and adjuvants that can be selected from fatty acids, organic solvents, thickening agents, softening agents, antioxidants, opacifiers, stabilisers, emollients, hydroxyacids, anti-foaming agents, moisturizing agents, vitamins, fragrances, preservatives, surfactants, sequestering agents, polymers, propellants, acidifying or basifying agents, colorants, dyes, dihydroxyacetone, insect repellent or any other ingredient that is commonly used in cosmetic formulations, and particularly in the production of photoprotective compositions.
Examples of substances/fatty acids include, among others, oils or waxes or mixtures thereof and can include fatty acids, fatty alcohols and fatty acid esters. The oils are advantageously selected from animal and vegetable oils, mineral or synthetic oils, and in particular from liquid petrolatum, liquid paraffin, volatile silicone oils, isoparaffins, polyalphaolefins or fluorated or perfluorated oils. Similarly, the waxes are advantageously selected from animal and vegetable waxes, mineral or synthetic waxes known to skilled in the art.
Examples of organic solvents include short alcohols and polyols.
The thickeners are selected, advantageously, from among acrylic-acid crosslinked polymers, modified and unmodified carob bean rubbers, celluloses and xanthane rubbers, such as hydroxypropylated carob bean rubber, methylhydroxyethylcellulose, hydroxypropylmethylcellulose or hydroxyethylcellulose.
When choosing the excipients, adjuvants, etc., an expert in the subject will ensure that they do not affect the activity of the heptaazaphenalene derivatives of general formula (I) in accordance with the invention.
Under an eighth aspect, the present invention relates to the use of a derivative according to the first aspect of the invention in a cosmetic, dermatological, pharmaceutical or veterinary formulation as a UV radiation filtering agent.
Under a ninth aspect, the present invention relates to the use of a derivative or mixture of derivatives according to the first aspect of the invention for manufacturing a formulation to protect the skin, lips and/or related tissues of a mammal against solar radiation.
Under a tenth aspect, the present invention relates to the use of at least one derivative or mixture of derivatives according to the first aspect of the invention for manufacturing a formulation for preventive use, as a coadjuvant in the treatment of pathologies caused by ultraviolet radiation on the skin, lips and/or related tissues of a mammal, such as polymorphous light eruptions, photoageing, actinic keratasis, vitiligo, urticaria solar, chronic actinic dermatitis and xeroderma pigmentosum. Preferably, said formulation is applied topically.
In a preferred embodiment said mammal is a human.
The properties of the heptaazaphenalene derivatives of general formula (I) mean that said compounds are also useful as photostabilisers of polymers and as solar filters for textile fibres.
In the present invention, “polymers” means chemical compounds of natural or synthetic origin and generally of high molecular weight made up of structural units (monomers) linked to each other by means of covalent bonds. Examples of polymers include but are not limited to proteins, polysaccharides, cellulose, natural rubber, nucleic acids, polyethylene, polycarbonates, silicone polymers, polyurethanes, polyesters, polyamides and acrylic polymers, among others.
There follow some examples where the UV λmax and εmax have been measured according to general methods known for the person skilled in the art by way of non-restrictive illustration of the present invention.
A mixture of 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene (50 mg, 0.18 mmol) and butyl 4-aminobenzoate (210 mg, 1.08 mmol) in toluene (2 mL) is refluxed for 30 minutes. The resulting solid is filtered by porous plate and washed with toluene (10 mL), to yield 2,5,8-tris-(4-(butoxycarbonyl)phenylamino)-1,3,4,6,7,9,9b-heptaazaphenalene (130 mg, 0.17 mmol, 96%).
M.P. 289-290° C.
1H NMR (300 MHz, DMSO-d6): δ 0.95 (t, J=7.2 Hz, 9H), 1.41 (m, 6H), 1.65 (m, 6H), 4.20 (m, 6H), 7.92 (m, 12H), 10.80 (m, 3H).
MS-EI (m/z): 747 (M+1).
UV λmax=325 nm; εmax=100000 M−1 cm−1 (CHCl3—EtOH).
A mixture of 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene (50 mg, 0.18 mmol) and 2-ethylhexyl 4-aminobenzoate (270 mg, 1.08 mmol) in toluene (2 mL) is refluxed for 1 hour. The solvent is evaporated in vacuo and the crude product is purified by silica gel column chromatography, eluting with hexane/ethyl acetate 2/1. 2,5,8-tris-(4-(2-ethylhexyloxycarbonyl)phenylamino)-1,3,4,6,7,9,9b-heptaazaphenalene is obtained (160 mg, 0.17 mmol, 97%).
M.P. 183-186° C.
1H NMR (300 MHz, DMSO-d6): δ 0.93 (m, 18H), 1.30 (m, 24H), 1.62 (m, 3H), 4.18 (d, J=5.4 Hz, 6H), 7.95 (m, 12H), 10.85 (m, 3H).
MS-EI (m/z): 916 (M+1).
UV: λmax=326 nm; εmax=95000 M−1 cm−1 (CHCl3).
A mixture of 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene (25 mg, 0,09 mmol), 4-(H-imidazo[1,2-a]pyrridin-2-yl)benzenamine (114 mg, 0.54 mmol) and diisopropylamine (155 μL, 0.9 mmol) in toluene (2 mL) is refluxed for 1 hour. N-methylpyrrolidone (0.2 mL) is added and heated to 120° C. for 2 hours. The system is then allowed to cool. The solid is filtered by a porous plate and purified by silica gel column chromatography, eluting with mixtures of ethyl acetate/methanol. This yields 2,5,8-tris-(4-(imidazo[1,2-a]pyrridin-2-yl)-phenylamino)-1,3,4,6,7,9,9b-heptaazaphenalene (31 mg, 0.03 mmol, 22%).
1H NMR (300 MHz, DMSO-d6): δ 6.90 (m, 3H), 7.30 (m, 3H), 7.60 (m, 3H), 7.90 (m, 12H), 8.38 (s, 3H), 8.55 (m, 3H), 10.65 (m, 3H).
MS-EI (m/z): 795 (M+1).
UV: λmax=353 nm; εmax=75000 M−1 cm−1 (DMSO).
A mixture of 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene (50 mg, 0.18 mmol) and 1-(4-aminophenyl)-6,7-dihydro-2,6,6-trimethyl-1H-indol-4(5H)-one (291 mg, 1.08 mmol) in toluene (2 mL) is refluxed for 4 hours. The system is then allowed to cool. The solid is filtered by a porous plate and washed with HCl 1N (10 mL), H2O (10 mL) and Et2O (10 mL). The crude product obtained is purified by silica gel column chromatography, eluting with mixtures of hexane/ethyl acetate. This yields 2,5,8-tris-(4-(4,5,6,7-tetrahydro-2,6,6-trimethyl-4-oxoindol-1-yl)phenylamine)-1,3,4,6,7,9,9b-heptaazaphenalene (98 mg, 0.1 mmol, 56%).
1H NMR (300 MHz, CDCl3): δ 1.05 (s, 18H), 2.10 (s, 9H), 2.38 (m, 12H), 6.40 (s, 3H), 7.20 (m, 6H), 7.80 (m, 9H).
MS-EI (m/z): 973 (M+1).
UV: λmax=314 nm; εmax=103000 M−1 cm−1 (EtOH).
A mixture of 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene (50 mg, 0.18 mmol) and 4-aminobiphenyl (183 mg, 1.08 mmol) in toluene (2 mL) is refluxed for 2 hours. The system is then allowed to cool. The solid is filtered by a porous plate and washed with HCl 1N (10 mL), H2O (10 mL) and Et2O (10 mL). This yields 2,5,8-tris-(biphenyl-4-ylamino)-1,3,4,6,7,9,9b-heptaazaphenalene.
M.P.>310° C.
1H NMR (300 MHz, DMSO-d6): δ 7.25 (m, 3H), 7.40 (m, 6H), 7.65 (m, 12H), 7.80 (m, 6H), 10.60 (m, 3H). MS-EI (m/z): 675 (M+1).
Following the method described on example 1. Yield: 90%. M.P.>310° C.
1H NMR (300 MHz, DMSO-d6): δ 7.25 (m, 3H), 7.40 (m, 6H) 7.65 (m, 12H), 7.80 (m, 6H), 10.60 (s, 3H)
MS-EI (m/z): 675 (M+1).
UV λmax=333 nm; εmax=103000 M−1 cm−1 (DMSO).
A mixture of 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene (50 mg, 0.18 mmol) and 4-(1H-benzo[d]imidazol-2-yl)phenylamine (227 mg, 1.08 mmol) in toluene (2 mL) is refluxed for 5 hours. The system is then allowed to cool. The solid is filtered by a porous plate and washed with HCl 1N (10 mL), H2O (10 mL), MeOH (10 mL) and Et2O (10 mL). This yields 2,5,8-tris-(4-(1H-benzo[d]imidazol-2-yl)phenylamino)-1,3,4,6,7,9,9b-heptaazaphenalene.
NMR1H (300 MHz, DMSO-d6): δ 7.40 (m, 6H), 7.65 (m, 6H), 8.05 (m, 6H), 8.30 (m, 6H). EM-IE (m/z): 795 (M+1).
UV λmax=358 nm); εmax=107000 M−1 cm−1 (CHCl3-MeOH).
Following the method described on example 1. Yield: 82%.
M.P.>275° C.
1H NMR (300 MHz, DMSO-d6): δ 7.40 (m, 6H), 7.65 (m, 6H), 8.05 (m, 6H), 8.30 (m, 6H), 10.90 (m, 3H).
MS-EI (m/z): 795 (M+1).
UV λmax=358 nm; εmax=107000 M−1 cm−1 (CHCl3-MeOH)
A mixture of 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene (50 mg, 0.18 mmol) and butyl 4-aminobenzoate (38 mg, 0.19 mmol) in toluene (2 mL) is refluxed for 1 hour. The mixture is then cooled, 4-aminobiphenyl (122 mg, 0.72 mmol) is added and heated again at reflux for a further 1 hour. The solid is filtered by a porous plate and washed with toluene (10 mL), to yield 2,5-bis-(biphenyl-4-ylamino)-8-(4-(butoxycarbonyl)phenylamino)-1,3,4,6,7,9, 9b-heptaazaphenalene.
MS-EI (m/z): 699 (M+1).
A mixture of 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene (50 mg, 0.18 mmol) and butyl 4-aminobenzoate (38 mg, 0.19 mmol) in THF (2 mL) is refluxed for 1 hour. The mixture is then cooled, 2-ethylhexyl aminobenzoate (50 mg, 0.19 mmol) is added and heated at reflux for a further 3 hours. The mixture is then cooled, 4-aminobiphenyl (122 mg, 0.72 mmol) is added and it is again heated at reflux for a further 3 hours. The resulting solid is filtered by porous plate and washed with MeOH (10 mL), to yield 2-(biphenyl-4-ylamino)-5-(4-(butoxycarbonyl)phenylamino)-8-(4-(2-ethylhexyloxycarbonyl)phenylamino)-1,3,4,6,7,9,9b-heptaazaphenalene.
MS-EI (m/z): 779 (M+1).
A mixture of 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene (50 mg, 0.18 mmol), resorcinol (66 mg, 0.59 mmol) and aluminium trichloride (79 mg, 0.59 mmol) in THF (2 mL) is heated at reflux. After 5 hours, the system is cooled and HCl 1N (2 mL) is added and left under stirring for 10 minutes. The solvent is evaporated in vacuo and extracted with AcOEt (3×10 mL). The combined organic phases are washed with saturated solution of NaCl (1×10 mL), dried over Na2SO4 and the solvent eliminated in vacuo. This yields 2,5,8-tris-(2,4-dihydroxyphenyl)-1,3,4,6,7,9,9b-heptaazaphenalene.
Yield: 67%.
1H NMR (300 MHz, DMSO-d6): δ 6.31 (d, J=2 Hz, 3H), 6.49 (dd, J=9, 2 Hz, 3H), 8.13 (d, J=9 Hz, 3H), 10.90 (s, 3H), 12.97 (m, 3H).
HPLC-MS (m/z): 497 (M+).
UV: λmax=394 nm; εmax=56000 M−1 cm−1 (DMSO).
A mixture of 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene (50 mg, 0.18 mmol) and 1-methylpyrrol (16 μL, 0.18 mmol) in toluene (2 mL) is refluxed for 4 hours. The system is then left to cool. The solid is filtered by porous plate and washed with dry toluene (10 mL). This yields 2,5-dichloro-8-(1-methyl-1H-pyrrol-2-yl)-1,3,4,6,7,9,9b-heptaazaphenalene (41 mg, 0.12 mmol, 71%).
1H NMR (300 MHz, CDCl3): δ 4.10 (s, 3H), 6.38 (m, 1H), 7.15 (m, 1H), 7.65 (m, 1H).
MS-EI (m/z): 319 (M−2).
A mixture of 2,5-dichloro-8-(1-methyl-1H-pyrrol-2-yl)-1,3,4,6,7,9,9b-heptaazaphenalene (41 mg, 0.12 mmol), butyl 4-aminobenzoate (98 mg, 0.51 mmol) and diisopropylethylamine (110 μL, 0.63 mmol) in N-methylpyrrolidone (0.5 mL) is heated for 7 hours at 120° C. The system is then left to cool and H2O (5 mL) is added. The solid is filtered by porous plate and washed with Et2O (10 mL). This yields 2,5-bis-(4-(butoxycarbonyl)phenylamino)-8-(2-(1-methyl-1H-pyrrol-2-yl)-1,3,4,6,7,9,9b-heptaazaphenalene (62 mg, 0.09 mmol, 76%).
M.P. 195-196° C.
1H NMR (300 MHz, CDCl3): δ 0.90 (m, 6H), 1.85 (m, 8H), 3.80 (s, 3H), 4.25 (m, 4H), 6.10 (m, 1H), 6.85 (m, 1H), 7.65 (m, 4H), 7.90 (m, 1H), 7.95 (m, 4H), 8.30 (m, 2H).
MS-EI (m/z): 635 (M+1).
A mixture of 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene (50 mg, 0.18 mmol) and butyl 4-aminobenzoate (38 mg, 0.19 mmol) in toluene (2 mL) is refluxed for 1 hour. The mixture is then cooled, aluminium trichloride (48 mg, 0.36 mmol) is added and heated again at reflux. After 3 hours, H2O (5 mL) is added and left at reflux for 30 minutes. The system is cooled and the resulting solid is filtered by porous plate. The part insoluble in CH2Cl2 corresponds to 2-(4-(carboxy)phenylamino)-5,8-bis-(4-methylphenyl)-1,3,4,6,7,9,9b-heptaazaphenalene.
MS-EI (m/z): 489 (M+1).
Following the method described in example 1. Yield: 93%.
M.P. >270° C.
1H NMR (300 MHz, DMSO-d6): δ 7.45 (m, 6H), 7.65 (m, 15H), 7.90 (m, 6H), 10.90 (m, 3H).
MS-EI (m/z): 759 (M+1).
UV: λmax=339 nm; εmax=112000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 81%.
M.P. 224-227° C.
1H NMR (300 MHz, DMSO-d6): δ 6.50 (s, 3H), 7.80 (m, 15H), 8.40 (s, 3H), 10.60 (s, 3H).
MS-EI (m/z): 645 (M+1).
UV λmax=330 nm; εmax=99000 M−1 cm−1 (DMSO).
Following the method described in example 9.
MS-EI (m/z): 666 (M+1).
A mixture of 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene (50 mg, 0.18 mmol), naphthalene-2-amine (155 mg, 1.08 mmol) and diisopropylamine (247 μL, 1.44 mmol) in 1,4-dioxane (2 mL) is heated at 120° C. for 10 minutes in a MW oven. The system is cooled. The solid is filtered by a porous plate and washed with 1,4-dioxane and methanol. This yields 2,5,8-tris-(naphthalen-2-ylamino)-1,3,4,6,7,9,9b-heptaazaphenalene (85 mg, 79%).
M.P.>275° C.
1H NMR (300 MHz, DMSO-d6): δ 7.40 (m, 6H), 7.50 (m, 6H), 7.90 (m, 12H), 8.35 (m, 6H), 10.70 (m, 3H).
MS-EI (m/z): 597 (M+1).
UV: λmax=279 nm; εmax=89000 M−1 cm−1; λmax=331 nm; εmax=75000 M−1 cm−1 (DMSO).
Following the method described in example 11. Yield: 84%.
MS-EI (m/z): 685 (M+1).
UV: λmax=337 nm; εmax=65000 M−1 cm−1 (DMSO).
Following the method described in example 16. Yield: 79%.
1H NMR (300 MHz, DMSO-d6): δ 7.25 (m, 6H), 7.35 (m, 3H), 7.45 (m, 6H), 7.65 (m, 12H).
MS-EI (m/z): 678 (M+1).
UV: λmax=262 nm; εmax=81000 M−1 cm−1 (DMSO).
Following the method described in example 16. Yield: 82%.
M.P.>275° C.
1H NMR (300 MHz, DMSO-d6): δ 3.75 (s, 9H), 6.64 (d, J=7 Hz, 3H), 7.45 (m, 6H), 10.35 (m, 3H).
MS-EI (m/z): 537 (M+1).
UV: λmax=312 nm; εmax=62000 M−1 cm−1 (MeOH).
Following the method described in example 16. Yield: 75%.
1H NMR (300 MHz, DMSO-d6): δ 3.72 (s, 9H), 6.89 (d, J=8.4 Hz, 6H), 7.64 (d, J=8.4 Hz, 6H), 10.20 (m, 3H).
MS-EI (m/z): 537 (M+1).
UV: λmax=324 nm; εmax=59000 M−1 cm−1 (DMSO).
Following the method described in example 16. Yield: 76%.
M.P.>275° C.
1H NMR (300 MHz, DMSO-d6): δ 1.25 (m, 9H), 4.20 (m, 8H), 6.55 (m, 3H), 7.60 (m, 3H), 7.65 (m, 6H), 7.80 (m, 6H), 10.70 (m, 3H).
MS-EI (m/z): 741 (M+1).
UV: λmax=359 nm; εmax=135900 M−1 cm−1 (DMSO).
Following the method described in example 16. Yield: 66%.
1H NMR (300 MHz, DMSO-d6): δ 3.80 (s, 9H), 7.90 (m, 24H), 10.80 (m, 3H).
MS-EI (m/z): 849 (M+1).
UV: λmax=346 nm; εmax=99000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 59%.
M.P. 288-291° C.
1H NMR (300 MHz, DMSO-d6): δ 3.70 (s, 9H), 7.92 (m, 12H)
UV: λmax=329 nm; εmax=116000 M−1 cm−1 (DMSO).
Following the method described in example 9.
MS-EI (m/z): 444 (M+1).
UV: λmax=327 nm; εmax=86000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 44%.
1H NMR (300 MHz, DMSO-d6): δ 7.20 (s, 9H), 7.60 (m, 9H), 7.90 (m, 3H), 13.20 (m, 3H).
MS-EI (m/z): 842 (M).
UV: λmax=354 nm, εmax=122000 M−1 cm−1; εmax=368 nm; εmax=123000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 94%.
1H NMR (300 MHz, DMSO-d6): ε 6.77 (m, 6H), 7.00 (m, 9H), 7.15 (m, 6H), 7.55 (m, 6H), 8.01 (s, 3H), 10.20 (m, 3H).
MS-EI (m/z): 720 (M+1).
UV: λmax=360 nm, εmax=60000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 76%. M.P.>270° C.
1H NMR (300 MHz, DMSO-d6): δ 7.20 (m, 9H), 7.35 (m, 6H), 7.60 (m, 12H), 7.80 (m, 6H), 10.60 (m, 3H).
UV: λmax=367 nm; εmax=163000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 57%.
1H NMR (300 MHz, DMSO-d6): δ 0.90 (m, 18H), 1.35 (m, 24H), 1.60 (m, 3H), 3.30 (m, 6H).
UV: λmax=265 nm; εmax=92000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 49%.
M.P. 202-206° C.
1H NMR (300 MHz, DMSO-d6): δ 0.72 (d, J=7 Hz, 9H), 0.85 (m, 21H), 1.10 (m, 6H), 1.50 (m, 6H), 1.70 (m, 6H), 1.82 (m, 3H), 2.00 (m, 3H), 4.88 (dt, J=6.5, 4.2 Hz, 3H), 7.90 (m, 12H), 10.90 (m, 3H).
UV: λmax=326 nm; εmax=118000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 92%.
M.P.>275° C.
1H NMR (300 MHz, DMSO-d6): δ 0.90 (d, J=7.2 Hz, 18H), 1.01 (m, 15H), 1.20 (m, 3H), 1.30 (m, 3H), 1.70 (m, 6H), 2.00 (m, 3H), 4.88 (m, 3H), 7.88 (m, 12H), 10.85 (m, 3H).
UV: λmax=329 nm; εmax=143000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 90%.
M.P. 213-216° C.
1H NMR (300 MHz, DMSO-d6): δ 0.86 (t, J=7.2 Hz, 18H), 1.27 (m, 32H), 1.57 (m, 3H), 4.04 (d, J=4.7 Hz, 6H), 6.54 (d, J=16 Hz, 3H), 7.54 (d, J=16 Hz, 3H), 7.67 (d, J=8 Hz, 6H), 7.84 (d, J=8 Hz, 6H), 10.73 (m, 3H).
UV: λmax=358 nm; εmax=154000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 73%.
M.P. 206-210° C.
1H NMR (300 MHz, DMSO-d6): δ 0.86 (m, 18H), 1.27 (m, 32H), 1.59 (m, 3H), 4.04 (m, 6H), 6.53 (d, J=16 Hz, 3H), 7.45 (m, 9H), 7.80 (m, 6H), 10.53 (m, 3H).
UV: λmax=290 nm; εmax=126000 M−1 cm−1 (DMSO).
Following the method described in example 7.
1H NMR (300 MHz, DMSO-d6): δ 0.86 (m, 18H), 1.27 (m, 32H), 1.34 (m, 3H), 4.04 (m, 6H), 6.55 (m, 3H), 7.60 (m, 15H), 10.74 (m, 3H).
UV: λmax=288 nm; εmax=66000 M−1 cm−1; λmax=354 nm; εmax=113000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 76%.
1H NMR (300 MHz, DMSO-d6): δ 7.58 (t, J=8 Hz, 3H), 7.87 (d, J=7 Hz, 3H), 8.05 (d, J=7 Hz, 3H), 8.75 (s, 3H), 10.95 (m, 3H).
UV: λmax=308 nm; εmax=113000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 85%. M.P. 215-222° C.
1H NMR (300 MHz, DMSO-d6): δ 0.88 (m, 18H), 1.28 (m, 48H), 1.76 (m, 3H), 4.21 (m, 6H), 7.70 (m, 6H), 7.99 (6H).
MS-EI (m/z): 1084 (M+1).
UV: λmax=326 nm; εmax=119000 M−1 cm−1 (CHCl3).
Following the method described in example 1. Yield: 57%.
1H NMR (300 MHz, DMSO-d6): δ 7.39 (m, 12H), 7.67 (m, 15H), 7.89 (m, 6H), 10.62 (m, 3H).
UV: λmax=316 nm; εmax=167000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 87%.
M.P. 141-144° C.
1H NMR (300 MHz, DMSO-d6): δ 0.88 (m, 18H), 1.28 (m, 72H), 1.76 (m, 3H), 4.21 (m, 6H), 7.70 (m, 6H), 7.99 (m, 6H).
MS-EI (m/z): 1252 (M+1).
UV: λmax=324 nm; εmax=121000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 86%.
1H NMR (300 MHz, DMSO-d6): δ 0.87 (s, 27H), 0.95 (d, J=6.3 Hz, 9H), 1.09 (m, 3H), 1.24 (m, 3H), 1.54 (m, 3H), 1.68 (m, 6H), 4.26 (m, 6H), 7.90 (m, 12H), 10.88 (s, 3H).
MS-EI (m/z): 957 (M+).
UV: λmax=326 nm; εmax=126000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 61%.
1H NMR (300 MHz, DMSO-d6): δ 0.87 (t, J=6.8 Hz, 9H), 1.25 (m, 80H), 1.43 (bs, 10H), 1.76 (m, 6H), 4.30 (m, 6H), 7.68 (m, 6H), 8.03 (6H).
UV: λmax=324 nm; εmax=117000 M−1 cm−1 (DMSO).
Following the method described in example 11. Yield: 47%.
1H NMR (300 MHz, DMSO-d6): δ 3.74 (s, 6H), 4.00 (s, 3H), 6.18 (m, 1H), 6.66 (m, 2H), 7.23 (m, 6H), 7.47 (s, 2H), 10.48 (s, 2H).
MS-EI (m/z): 494 (M+).
UV: λmax=352 nm; εmax=57000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 91%.
M.P. 252-255° C.
1H NMR (300 MHz, DMSO-d6): δ 0.87 (t, J=6.8 Hz, 9H), 1.25 (m, 80H), 1.75 (m, 6H), 4.30 (m, 6H), 7.70 (m, 6H), 8.06 (m, 6H).
MS-EI (m/z): 1252 (M+1).
UV: λmax=324 nm; εmax=125000 M−1 cm−1 (DMSO).
Following the method described on example 1. Yield: 50%.
1H NMR (300 MHz, DMSO-d6): δ 0.85 (m, 18H), 1.25 (m, 24H), 1.53 (m, 3H), 3.16 (m, 6H), 7.81 (m, 12H), 8.24 (m, 3H), 10.85 (m, 3H).
MS-EI (m/z): 912 (M+).
UV: λmax=326 nm; εmax=118000 M−1 cm−1 (CHCl3).
Following the method described in example 1. Yield: 87%.
1H NMR (300 MHz, DMSO-d6): δ 0.87 (t, J=6.8 Hz, 9H), 1.26 (m, 54H), 1.76 (m, 6H), 4.30 (m, 6H), 7.70 (m, 6H), 7.80 (bs, 3H), 8.05 (m, 6H).
UV: λmax=326 nm; εmax=87000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 89%.
1H NMR (300 MHz, DMSO-d6): δ 0.83 (s, 9H), 1.11 (s, 9H), 1.18 (s, 9H), 1.40-1.70 (m, 21H), 4.60 (s, 3H), 7.72 (m, 6H), 8.09 (m, 6H).
MS-EI (m/z): 988 (M+1).
UV: λmax=330 nm; εmax=150000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 53%.
1H NMR (300 MHz, DMSO-d6): δ 6.38 (m, 3H), 7.32 (m, 9H), 8.06 (m, 3H), 10.19 (s, 3H), 11.03 (s, 3H). MS-EI (m/z): 564 (M+1).
UV: λmax=331 nm; εmax=46000 M−1 cm−1 (DMSO).
Following the method described in example 1. Yield: 74%.
1H NMR (300 MHz, DMSO-d6): δ 0.83 (d, J=6.6 Hz, 18H), 0.92 (d, J=6.4 Hz, 18H), 1.12-1.75 (m, 36H), 4.30 (m, 6H), 7.92 (bs, 12H), 10.90 (s, 3H).
UV: λmax=329 nm; εmax=125000 M−1 cm−1 (DMSO). Example 48
Following the method described in example 1. Yield: 77%.
1H NMR (300 MHz, DMSO-d6): δ 2.20 (s, 18H), 7.20 (m, 6H).
MS-EI (m/z): 576 (M+1).
UV: λmax=270 nm; εmax=44000 M−1 cm−1 (DMSO).
A mixture of 2,5,8-trichloro-1,3,4,6,7,9,9b-heptaazaphenalene (50 mg, 0.18 mmol) and aluminium trichloride (79 mg, 0.59 mmol) in benzene (2 mL) is heated at reflux. After 6 hours, HCl 1N (2 mL) is added and left at reflux for 30 minutes. The system is allowed to cool and the solid is filtered by porous plate and washed with HCl 6N (3×10 mL) and H2O ((3×10 mL). This yields 2,5,8-triphenyl-1,3,4,6,7,9,9b-heptaazaphenalene.
MS-EI (m/z): 402 (M+1).
The following examples by way of non-restrictive illustration of the present inventions will lead to final products trough the methods of general knowledge by a person skilled in the art.
| Number | Date | Country | Kind |
|---|---|---|---|
| P 200501746 | Jul 2005 | ES | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2006/064201 | 7/13/2006 | WO | 00 | 1/11/2008 |
