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    • 专利摘要:
    The invention describes new analogous maa photoprotective compounds which generally have the formula 1: {image-01} And its acceptable salts and solvates; In which: R1 is selected from the group consisting of alkyl c1-6, s-alkyl c1-6 and O-alkyl c1-6; R2 are each selected from the group consisting of h and alkyl c1-6; R3 are each selected from the group consisting of {image-02}; N is an integer selected from the group consisting of 0, 1 and 2. The invention also describes methods of synthesizing such compounds as well as compositions comprising them. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2550374A1
    申请号:ES201500508
    申请日:2015-06-30
    公开日:2015-11-06
    发明作者:Diego SAMPEDRO RUIZ；Raúl LOSANTOS CABELLO；Ignacio FUNES ARDOIZ
    申请人:Universidad de La Rioja；
    IPC主号:
    专利说明:

    Field of the Invention
    The present invention relates to the field of protection against solar radiation, and more specifically to new MAA analog compounds
    (mycosporine type amino acids) for protection against solar radiation.

    Background of the invention
    The compoundsamino acidsfromkindmycosporin
    ("Mycosporine-like Not meAcids ",MAA)bethey findfrom
    shape ubiquitousindifferentpartsfromthephysiologyfrom
    multitude of different species, in totally different ecosystems, from the tropics to Antarctica. At the biological level, these compounds have been associated with various types of processes, one of the most interesting being to act as photoprotective compounds that protect organisms against sunlight.
    Virtually all methods known in the prior art for obtaining MAA are based on the extraction thereof from their natural sources, that is, the processing of algae or fish roe to produce extracts containing MAA.
    However, obtaining the compounds by extraction from their natural sources is not practical from an industrial point of view due to the low yield of the extraction, which increases their economic cost.
    On a commercial level, a number of compounds have been approved for use as an ultraviolet filter in commercial formulations (see EU Cosmetic Directive
    76/768 / EEC, Annex VII). Most of these compounds share their chemical structure and, therefore, their mechanism of action and their properties. However, several of these known compounds other than MAA (for example, avobenzone, octyl cinnamate, benzophenone derivatives ...) have poor photostability, that is, these compounds decompose as they absorb sunlight. This lack of photostability involves two main problems, on the one hand they lose their photoprotective properties as they receive the light so their duration of action is relatively short. On the other hand, the decomposition of these compounds can lead to the production of harmful by-products.
    For example, WO 0239974 discloses personal care compositions comprising MAA type compounds. All the compounds disclosed in that document are of natural origin and not enough information is provided to obtain them synthetically. In addition, these known natural compounds of the MAA type have limited photostability properties that reduce their duration of action.
    Therefore, there is a need in the art for new MAA analog photoprotective compounds that exhibit increased photostability with respect to the compounds
    from MAAnaturalacquaintances,Ythatalsocanget
    by viasyntheticwithyieldsacceptablesincehe
    point of view of Industrial application
    Summary of the invention
    To solve the problems described above, in a first aspect the present invention discloses new MAA analog photoprotective compounds having the formula 1: : "IN I
    R,
    n ; trN, R3
    R2
    R2 H
    Formula 1 as well as its acceptable salts and solvates; in which:
    R1 is selected from the group consisting of Cl6 alkyl, S-Cl-6 alkyl and O-Cl-6 alkyl; R2 are each selected from the group consisting of H and Cl-6 alkyl; R3 are each selected from the group consisting of
    ~ OH
    ~ ) J.
    Mr
    and
    n is an integer selected from the group consisting of O, 1 and 2. In a second aspect, the present invention gives
    5 knowing a synthesis process to obtain the compounds according to the first aspect of the present invention. Said process comprises reacting a compound of formula 2A, 2B or 2C with a compound of formula 3
    Formula 3 in which R3 is as defined in the first aspect of the present invention;
    25 in a suitable solvent and in the presence of an acid
    suitable X-OH in which X is selected from the group consisting of TSO-, Cl-, AcO-, CF3COO- and CF3S03-.
    Depending on the value of the substituent R 1 that is desired in the compound of formula 1, the process comprises reacting the compound of formula 3 with a compound
    of formula So, 3 is done
    2A, 2B or 2C. when Rl is Cl-6 alkyl, the compound of formula reacts with a compound of formula 2A
    When Rl is reacted
    15 When Rl is reacted ~ R1R2 ~ O
    R2 Formula 2A. O-Cl-6 alkyl, the compound of formula 3 with a compound of formula 2B
    Formula 2B S-Cl-6 alkyl, the compound of formula 3 with a compound of formula 2C
    ~ R1R2 ~ N .. 3
    R2 H
    Formula 2C
    According to a third aspect, the present invention gives
    20 knowing a sun radiation protection composition comprising an effective amount of at least one compound according to the first aspect of the present invention.
    BRIEF DESCRIPTION OF THE FIGURES The present invention will be better understood with reference to the accompanying drawings, in which:
    Figure 1 shows UV-Vis spectra of some compounds synthesized according to the present invention as well as three commercial compounds for comparison.
    5Detailed description of the preferred embodiments
    As will be appreciated by the person skilled in the art, some compounds according to the present invention may have various stereoisomeric forms such as
    0 diastereoisomers (due to the presence of double bonds). Although not specifically mentioned in each case, it is intended that the mention of a compound according to the present invention includes all possible stereoisomeric forms thereof.
    As mentioned above, the present invention discloses new MAA analog photoprotective compounds which generally have the formula
    one:
    20 as well as its acceptable salts and solvates; wherein: R 1 is selected from the group consisting of Cl 6 alkyl, S-Cl-6 alkyl and O-Cl-6 alkyl;
    R2 are each selected from the group consisting of H and Cl-6 alkyl; R3 are each selected from the group consisting of
    ~ OH
    ~ J :Y
    Br
    Y ; and n is an integer selected from the group consisting of 0, 1 and 2. According to a preferred embodiment of the present
    The invention, n is equal to 1, so that the compounds are aminocyclohexenimines of formula lA:
    R ~ R1 R2 ~ N .. R3
    R2 H Formula lA. According to a preferred embodiment of the present
    In the invention, Rl is selected from the group consisting of Me, Et, SMe, OMe and OEt, more preferably from the group consisting of Me, Et and OEt, most preferably Rl is Me. According to another preferred embodiment of the present
    Invention, R2 is selected from the group consisting of H and Me, more preferably R2 is H. Most preferably, both R2 groups are identical. According to another preferred embodiment of the present invention, R3 is selected from the group consisting of
    0, ~
    '-'
    J
    I ~
    20, ~ and Br,
    more preferably, R3 is selected from the group consisting of
    0 '
    J
    I ~ Br
    Y
    Most preferably, both R3 groups are identical.
    According to another preferred embodiment of the present invention, the compound of formula 1 is presented as a salt according to formula lB:
    and
    x
    in which
    X- is selected from the group consisting of TsO-, Cl-,
    AcO-, CF3COO- and CF3S03-, preferably from the group
    10 constituted by TsO- and Cl-, more preferably X-is TsO-. The compounds of the present invention analogous to
    MAA present several differences with respect to the MAA obtained from natural sources, which provide them with a series of substantial advantages over the latter.
    First, the Rl substituent is generalized from the OMe group that appears in naturally occurring MAA type compounds to a wide range of substituents
    20 such as Cl-6 alkyl groups, sulfur groups (Salquilo Cl-d and oxygenated groups (O-Cl-6 alkyl). This difference mainly affects the absorption wavelength, the solubility of the compounds in different solvents and even the stability of the compounds a
    25 once incorporated into a complex formulation (which will depend on its final use, whether for plastics, creams, varnishes, ...). In general, the change of this Rl substituent implies the generalization of the base structure providing the same general properties of
    photoprotection, but allowing adjustment of other useful practical properties to adapt the compound to a specific use or subsequent formulation conditions.
    The R2 substituent in naturally occurring MAA type compounds takes the values of OH (for one of them) and CH20H (for the other). According to the present invention, the R2 substituents are selected from the group consisting of H and Cl-6 alkyl, preferably H and Me. This change in the value of the R2 substituent does not substantially affect the photoprotective properties of the compound, and yet allows it to be obtained synthetically with good yields, which was not possible according to the prior art. According to the preferred embodiment of the present invention in which both R2 groups are identical, the synthesis performance of the resulting compounds is further improved.
    The specific value for the R3 substituent according to the
    Present inventionIt allowsto easethesynthesisfromthe
    compounds finalsSohowmodulartheproperties
    photophysics (byexample,theabsorption)of thecompoundin
    function of said substituent.
    The change of the carbonyl group c = o in position 1 of compounds of type MAA of natural origin by an imino group C = N increases the stability (both thermal and photochemical), absorption and properties as a photoprotector of the final compound. Indeed, the energy absorbed from light by the compounds of the present invention dissipates in the form of heat, and then the compounds recover their initial chemical structure. Thus, the compounds of the invention have higher photostability than known naturally occurring MAA-type compounds, thus providing a duration of
    longer action and being safer (since they do not degrade to give by-products possibly harmful to the environment or to health).
    The present invention also discloses
    5 compositions for protection against solar radiation comprising an effective amount of at least one compound of the present invention, as defined above. The formulation of said compositions will depend on the intended end use thereof, by
    10 examples, such as paints or varnishes for surface protection, such as sunscreen creams for use on the skin of an animal, etc. As used herein, the term "animal" refers to anyone in which it may be desirable to protect the skin from solar radiation, preferably a mammal, more preferably a human being. In the case of a composition for application on the skin of an animal, for example a human being, said composition comprises an effective amount of a compound
    20 of the present invention in the form of a physiologically acceptable salt according to formula IB:
    and
    x : 3't ~ R,
    neither R i):
    I ..... N, R3
    R2 H
    Formula lBin which
    X-is selected from the group consisting of TsO- and Cl-¡and Rl, R2 and R3 are as defined above. Furthermore, according to a preferred embodiment, the composition according to the present invention further comprises the
    less a second protective agent against solar radiation in combination with at least one compound according to the present invention. The second protective agent may also be a compound according to the present invention, a compound of naturally occurring MAA type or any other compound against sun radiation known to the person skilled in the art, such as for example a microfine titanium dioxide, Microfino zinc oxide, boron nitride, iron oxides, talcs, paraaminobenzoic acids, esters and derivatives thereof, methoxycinnamate esters, benzophenones, dibenzoi methanes, acid 2
    Pheni-benzimidazo-S-su1phonic and its salts, alkyl 13,13 diphenyl acrylates, triazines, camphor derivatives, sunscreen agents based on organic pigments, sunscreen agents based on silicon and salicylates.
    The present invention also discloses methods for the synthesis of the compounds of the present invention described above. He
    process fromthePresentinventionunderstandsdo
    react acompoundfromformula2A,2Bor2 Cwitha
    compound formula3
    R3NH2
    Formula 3 in which R3 is as defined above in the present invention; in a suitable solvent and in the presence of an acid
    suitable X-OH in which X is as defined hereinbefore.
    The use of a compound of formula 2A, 2B or 2C in the process of the present invention depends on the substituent R 1 that is desired in the compound of formula 1
    final according to the present invention. Thus, when R 1 is Cl-6 alkyl, the compound of formula 3 is reacted with a compound of formula 2A ~ R1 R2 ~ O
    R2 5 Formula 2A. When R 1 is O-Cl-6 alkyl, the compound of formula 3 is reacted with a compound of formula 2B
    Formula 2B When Rl is S-Cl-6 alkyl, the compound of formula 3 is reacted with a compound of formula 2C ~ R1R2 "~ N, R3
    R2 H Formula 2C. In all cases, R1 and R3 are as defined hereinbefore.
    The process of the present invention is preferably carried out using toluene as a solvent, and under reflux conditions.
    Specific examples of
    20 compounds according to the present invention, as well as intermediate products necessary for obtaining said compounds according to the present invention.
    Synthesis of intermediates 25 2-Alkoxy-aminocyclohexenones
    R1 = OMe, OH, OBz, H R1 = OEt, OH, OBz, H
    The synthesis of this great variety of compounds is carried out following the route described by M. Adler, K. Schank,
    V. Schmidt, Chem. Ber. 1979, 112, 2314-2323 and M. Adler, K. 5 Schank, V. Schmidt, Chem. Ber. 1979, 112, 2324-2331.
    R2 = H, H Y Me, Me
    For the first stage a mixture of morpholine (20 mmol), 1,3-cyclohexadione or 5,5-dimethyl-1,310 cyclohexanedione (20 mmol) and p-toluenesulfonic acid (pTsOH, 0.02 mmol) is prepared in 50 ml of anhydrous toluene. Once all is added, the mixture is refluxed in toluene overnight. After that time, the mixture is brought to room temperature and the toluene is evaporated at
    15 reduced pressure. The reaction crude consists of the practically pure final enaminone. The second stage is carried out by gradually adding a solution of benzoyl peroxide onto a suspension.
    or dissolution of the above derivative in acetonitrile. The mixture is allowed to stir at 55 ° C for 16 h in the case of
    compound with R2 = H, H, Y for 24 h in the case of the compound with R2 = Me, Me.
    Once it is found that no peroxide remains by thin layer chromatography using ethyl acetate as eluent, the mixture is cooled and cold water is added, a brown oil is decanted or filtered if it is solid. The mixture of acetonitrile and filtered water is extracted four times with diethyl ether. The combination of extracts is washed with a saturated NaHC03 solution, and the organic phase is dried with anhydrous sodium sulfate and the solvent is evaporated under reduced pressure, obtaining a brown oil in the case of the compound with R2 = H, H (30 % yield) and an orange / brown solid with R2 = Me, Me
    (45% yield).
    Deprotection of the benzoyl ester is carried out by the addition of 1 equivalent of NaH on a solution of the entire compound obtained in the previous stage in morpholine at GO ° C. Once the addition in small fractions is finished, the mixture is heated at 120 ° C until the total disappearance of the starting compound verified by thin layer chromatography (3-4 h) is allowed to cool to evaporate the morpholine under reduced pressure.
    For both compounds the treatment is the same, water is added and neutralized using 1M HCl. Once in neutral medium, it is extracted 4 times with CH2C12 and the combination of extracts is dried with sodium sulfate and the solvent is removed under pressure. reduced The compound is purified by column chromatography with ethyl acetate as eluent.
    The last stage involves a small modification since EtI is used instead of EtBr, which is the reagent used in the aforementioned literature. The reaction is carried out by adding on a THF solution of the
    compound at 45 ° C an equivalent of t-BuOK, 100 mg of NBnEt3Cl and an equivalent of either p-toluenesulfonic acid methyl ester or ethyl iodide, depending on whether it is desired to methylate or ethylate the OH group.
    After 4 or 5 hours have elapsed, respectively, it is filtered by washing the solid with THF, and the filtrate is evaporated under reduced pressure to give the compound expected for both cases.
    10 Aminocyclohexenones with other substituents at position 2
    ~ R1
    A
    , R3 H R1 = 1, SMe, SC5H11, SePh, H
    R3 = as defined above The synthesis of this group of compounds is performed
    15 as described by Héctor Felipe González Cruz, Doctoral Thesis, University of La Rioja, 2013, although with some modifications such as the change in the amine that forms the enaminone and the irradiation conditions, thus optimizing the synthesis.
    or or
    R3NH2; 0.01 Eq, TsOH & ) lR1
    ------- ... I
    hv, CH3CN U
    O Toluene, reflux N, R3
    , R3N
    H
    H R1 = SePh, SMe, SCSHll
    For the first stage a mixture of amine (20 mmol), 1,3-cyclohexadione (20 mmol) and ptoluenesulfonic acid (0.02 mmol) in 50 ml of anhydrous toluene is prepared. 25 Once all is added, the mixture is refluxed in toluene overnight. After that time, it
    Bring the mixture to room temperature and evaporate the toluene under reduced pressure. The reaction crude consists of practically pure enaminone.
    The second reaction is carried out by dissolving one mmol of bis (pyridine) -iodonium (I) tetrafluoroborate in
    fifteen mefromdichloromethane,totemperatureambient.TO
    continuation beAddonemmolfromenaminoneYbelet
    evolve thereactionduring3hoursYhalf.
    Past thatweather,befilter,bewashwith10mefrom
    Saturated sodium bicarbonate solution and extracted with dichloromethane (3 x 10 ml). The organic phases are combined, dried with sodium sulfate and evaporated under reduced pressure, obtaining practically pure iodoenaminone (> 95%) •
    Irradiation of iodoenaminones is carried out
    using a 400 W medium pressure mercury lamp with a Pyrex filter (A> 290 nm). A 3-5 mM solution of iodinated compound in about 100 ml of anhydrous acetonitrile is prepared in the immersion reactor, 20 equivalents of radical trap are added and the mixture is deoxygenated by bubbling argon for fifteen minutes before lighting the lamp and maintaining Argon flow throughout irradiation to increase agitation. As the radical scavenger, dimethyl disulfide, dipentyl disulfide or diphenyl disselenide are used. It is irradiated for 2 h in the case of sulfur trappers and for 1 h for selenium, following the reaction by TLC using Hex: AcOEt (1: 2) as eluent in the case of sulfur compounds and Hex: AcOEt (1: 4) for the compound with selenium. Once the reaction is over, the solvent is evaporated under reduced pressure and the crude is purified by column chromatography using in each case the eluent described above.
    Synthesis of compounds of the present invention
    Compound 1 (4-Methoxy-N- (3- (45-methoxyphenylamino) -2-methylcyclohex-2-enyliden) benzeneminium) (4-methylbenzenesulfonate)
    I
    T80- ~ o
    (±) ~ p-Anisidine, H ~ I
    TsOH (6: 1) eX 'ÚO --------··eleven
    Toluene, reflux ~ N ::::: "" H
    The reaction is refluxed in anhydrous toluene in the presence of 1 equivalent of ptoluenesulfonic acid and 6 equivalents of p-anisidine, which is
    10 added in this order on 2-methyl-1,3-cyclohexanedione obtained from commercial sources. Reflux is maintained for two days. After this time, toluene is evaporated and a small amount of dichloromethane and hexane is added to the reaction crude to precipitate both the
    15 amine as the compound. The black precipitate obtained is filtered on a filter plate, washed once with hexane to drag remains that remain in the flask and subsequently numerous washes with dichloromethane, until the total disappearance of the amine that allows to see the color
    Pale yellow of the compound. This compound is very insoluble and no special precaution in handling or subsequent purification is necessary.
    lH-NMR '(400 MHz, MeOD) 8 7.69 (d, J = 8, O Hz, 2H),7.21 (d, J = 8.8 Hz, 6H), 7.02 (d, J = 8.8 Hz, 4H), 3.8325 (s, 6H), 2.52 (t, J = 5.8 Hz, 4H), 2.36 (s, 3H), 2.07 (s,
    3H), 1.87-1.67 (m, 2H).
    13C-NMR '(101 MHz, MeOD) 8 160.90 (s), 143.67 (s), 141.58 (s), 131.15 (s), 129.77 (s), 128.92 ( s), 126.96 (s), 115.71 (s), 100.45 (s), 56.06 (s), 28.69 (s), 21.57 (s),
    21.30 (s), 9.52 (s).
    uv-vis (CH3CN): A (nm) = 341 (6 = 32410 M-1cm-1).
    ES-MS (+) (C21H2SN202 + H): 337,1911.
    5 Compound 2 (4-methylbenzenesulfonate of N- (2-ethyl-3- (4-methoxyphenylamino) cyclohex-2-enylidene) -4-methoxybenzenamine)
    N02
    I. I
    O EtOOC COOEt TsO- ~ O I I O ® ~ ) J ~
    O ~ ~ Et p-Anisidi ~ a, H ~ IAt 0.01 Eq. Proliné! U TsOH (6.1). ~ Et ~ O
    U CH2CI2 O Toluene, reflux U'N ~
    or
    H
    The reaction is carried out to form the 2-ethyl-1,3-cyclohexanedione derivative analogously to that described by D. B. Ramachary, M. Kishor, J. Org. Chem. 2007, 72, 5056-5068, the acetaldehyde being coupled to the cyclohexanedione giving the 2-ethyl-1,3-cyclohexanedione derivative which is purified as described in said article. Diimine formation is carried out in the
    15 same conditions as for compound 1 above, keeping the mixture of 6 equivalents of p-anisidine and 1 of p-toluenesulfonic acid at reflux in anhydrous toluene for two days. The subsequent treatment is the same, evaporate toluene and precipitate with hexane and wash with
    20 cold dichloromethane (from the freezer), since compound 2 is slightly soluble, and partly creeps when washing many times.
    lH-NMR (400 MHz, MeOD) 8 ppm 7.70 (d, J = 8.1 Hz, 2H), 7.24-7.18 (m, 6H), 7.03 (d, J = 8, 8 Hz, 4H), 3.84 (s, 25 6H), 2.62 (q, J = 7.4 Hz, 2H), 2.50 (t, J = 6.3 Hz, 4H), 2, 36 (s, 3H), 1.81 -1.71 (m, 2H), 1.18 (t, J = 7.5 Hz,
    3H).
    13C-NMR (101 MHz, MeOD) 8171.36 (s), 160.96 (s), 143.65 (s), 141.60 (s), 131.11 (s), 129.78 (s) , 129.04 (s), 126.97 (s), 115.74 (s), 106.93 (s), 56.06 (s), 28.73 (s), 21.74 (s), 21.29 (s), 16.85 (s), 12.17 (s).
    uv-vis (CH3CN): A. (nm) = 340 (e = 33030 M-1cm-1).ES-MS (+) (C22H27N202 + H): 351,2067.
    From the synthesis of this compound you can extrapolate the synthesis of analogs that have two methyl in position 5 as well as the presence of linear carbon chains of up to 4 to 6 carbon atoms, since the
    The synthesis of intermediate products is described in the previous article and the imination stage can be carried out in the same way for all of them.
    I
    TsO ~ O
    (f) ~ H R ~ 6 '~ ~
    PNH
    R = Et, Pr, Bu, Pe, ...
    Compound 3 (4-butoxy-N- (3- (4-butoxyphenylamino) -2-methylcyclohex-2-enyliden) benzenamine) 3 (4-methylbenzenesulfonate)
    n-B ~ O ~
    0u TsO-r7Y
    (f) ~
    O ~ NH2 H ~ TsOH (6: 1) C) :: '.., OO ~
    ((---- ~~~: I O Toluene, reflux ~ N ~ H
    The reaction is refluxed in anhydrous toluene in the presence of 1 equivalent of p20 toluenesulfonic acid and 6 equivalents of p-butoxyaniline, which are added in this order on 2-methyl-1,3-cyclohexanedione obtained from commercial sources. Reflux is maintained for two days. After this time, toluene is evaporated and a small oil is added to the reaction crude
    amount of dichloromethane and purified by column chromatography using mixtures of CH2C12 / MeOH (14/1) by gradient increasing the proportion of methanol. As a byproduct, compound 4 is obtained which is
    5 shown below in this document.
    lH-NMR (400 MHz, MeOD) 8 7.25 (d, 1H), 7.18 (d, J = 8.8 Hz, 4H), 6.99 (d, J = 8.8 Hz, 4H) , 6.70 (d, J = 8.8 Hz, 1H), 3.99 (t, J = 6.4 Hz, 4H), 2.50 (t, J = 6.1 Hz, 4H), 2 , 05 (s, 5H), 1.81 -1.67 (m, 6H), 1.57 -1.42 (m, 4H),
    10 0.98 (t, J = 7.4 Hz, 6H). 13C-NMR (101 MHz, MeOD) 8 169.92 (s), 158.98 (s), 153.97 (s), 130.32 (s), 129.60 (s), 127.48 (s ), 121.93 (s), 114.83 (s), 114.78 (s), 99.00 (s), 67.71 (s), 31.01 (s), 27.30 (s) , 22.09 (s), 20.17 (s), 20.17 (s), 18.87 (s), 15 12.74 (s). UV-vis (CH3CN): (nm) = 340 (e = 42700 M-1cm-1).
    "
    ES-MS (+) (C27H37N202 + H): 421.2850.
    Compound 4 (4-methylbenzenesulfonate of (4- (3- (4
    Hydroxyphenyliminium) -2-methylcyclohex-1-ylamino) phenyl) oxonium)
    n-BuO TsO- ~ OH O ~ H ~~
    6 :: TsO '~ NH2 Ó (~
    TsOH (6: 1) "ÚOH2
    ---- ~~~ 1 I
    Or Toluene. reflux: "'N ~ H
    This compound, which is the byproduct described above in the synthesis of compound 3, is isolated
    25 increasing the proportion of methanol in the column. The compound is a yellow solid. The compound has two tosylate groups for each molecule, which is in accordance with the protonation of one of the two free OHs in the molecule.
    lH-NMR (400 MHz, MeOD) 8 7.67 (d, J = 8.1 Hz, 4H),
    7.19 (d, J = 8, O Hz, 4H), 7.05 (d, J = 8.7 Hz, 4H), 6.82 (d, J = 8.7 Hz, 4H), 2, 46 (t, J = 6.0 Hz, 4H), 2.32 (s, 6H), 2.01 (s, 3H), 1.75 -1.62 (m, 2H).
    5 13C-NMR (101 MHz, MeOD) 8 171.97 (s), 158.67 (s), 143.39 (s), 141.75 (s), 129.98 (s), 129.80 ( s), 128.90 (s), 126.94 (s), 116.97 (s), 100.15 (s), 28.61 (s), 21.55 (s), 21.30 (s ), 9.46 (s).
    UV-Vis (CH3CN): A (nm) = 339 (e = 8420 M-1cm-1).
    ES-MS (+) (C19H21N202 + H): 309.1598.
    Compound 5 (4- methylbenzenesulfonate of N- (3- (butylamino)
    2-methylcyclohex-2-eniliden) butan-1-aminium)
    TsO
    @ / '.. /' ..
    HN- ~ "p-TsOH ----_. Ó (I
    '"
    n-BuNH2 • reflux I ~ N ~ H
    The reaction is carried out at reflux of n-butylamine and 1 equivalent of p-toluenesulfonic acid in the presence of 2-methyl-1,3-cyclohexanedione. Reflux is maintained for two days. After this time, the butylamine is evaporated and to the reaction crude is added 3 ml of
    20 dichloromethane and hexane is added to precipitate the compound. The precipitate obtained is filtered on a filter plate and washed numerous times with hexane, which allows the removal of the amine residues and other by-products. This compound is very insoluble and a
    25 subsequent purification.
    1 H-NMR (300 MHz, CDC13) 8 7.70 (s, 2H), 7.24 (s, 2H),
    2.89 (s, 4H), 2.60 (s, 4H), 2.37 (s, 6H), 1.94 -1.62 (m,
    2H), 1.61 (s, 4H), 1.39 (s, 4H), 0.96 (s, 6H).
    13C-NMR (75 MHz, MeOD) 8 170.06 (s), 143.50 (s),
    141.74 (s), 129.82 (s), 126.92 (s), 79.41 (s), 40.51 (s), 33.13 (s), 30.56 (s), 26 , 21 (s), 21.29 (s), 20.61 (s), 13.83 (s), 8.87 (s).
    uv-vis (CH3CN): A (nm) = 324 (e = 4200 M-1cm-1).ES-MS (+) (ClsH29N2 + H): 237.2325.
    Compound 6 (4-methylbenzenesulfonate of 2-bromo-N- (3- (2-bromophenylamino) -2-methylcyclohex-2-enyliden) benzenamine)
    ~ mr sr;: o
    ~ TsO · ® ~ I
    NH2 HN p-TsOH (6:!) Ó (: '1 -9 '", I
    toluene, reflux N, ...... H Sr 10 The reaction is refluxed in anhydrous toluene in the presence of 1 equivalent of ptoluenesulfonic acid and 6 equivalents of o-bromoaniline, which are added in this order on 2- methyl-1,3-cyclohexanedione obtained from commercial sources. Reflux 15 is maintained for one day. After this time, the precipitate obtained is filtered and filtered on a filter plate, washed with abundant toluene to carry remains that remain in the flask and the excess amine from the reaction. The compound is a light gray solid. This compound is very insoluble and does not require further purification. The only precaution is not to add any excess p-toluenesulfonic acid, since it would form a salt insoluble in toluene that would remain with the compound. lH-NMR (300 MHz, MeOD) 8 7.82 (d, J = 7.9 Hz, 2H), 25 7.70 (d, J = 8.1 Hz, 2H), 7.57-7.37 (m, 8H), 7.23 (d, J = 7.8 Hz, 2H), 2.40 (t, J = 6.6 Hz, 4H), 2.37 (s, 3H), 2.15 (s, 3H), 1.88 -1.75 (m, 2H). 13C-NMR (75 MHz, MeOD) 8 173.49 (s), 143.60 (s),
    141.62 (s), 137.56 (s), 134.79 (s), 131.85 (s), 130.76 (s), 130.76 (s), 130.20 (s), 129 , 79 (s), 126.96 (s), 123.43 (s), 101.44 (s), 28.53 (s), 21.30 (s), 21.14 (s), 9, 63 (s).
    UV-Vis (CH3CN): A (nm) = 330 (e = 27610 M-1cm-1).5 ES-MS (+) (C19H19Br2N2 + H): 432.9910.
    Compound 7 (4-methylbenzenesulfonate of N- (3 (mesylamino) -2-methylcyclohex-2-enyliden) -2,4,6-trimethylbenzenamine) Yl (-fj
    O and NH2 TsO '® ~
    lx:
    p-TsOH (6: 1! H , _ O 10luono, reflux ~ -P
    The reaction is refluxed in anhydrous toluene in the presence of 1 equivalent of ptoluenesulfonic acid and 6 equivalents of 2,4,6-trimethylaniline, which are added in this order on 2-methyl-1,3
    15 cyclohexanedione obtained from commercial sources. Reflux is maintained for two days. After this time, the solvent is evaporated and the crude is dissolved with a few drops of dichloromethane and hexane is added. Instead of a precipitate, a viscous oil is obtained that adheres
    20 to the walls, hexane is decanted and the process is repeated 2 times, after this it is washed with hexane twice and dried in a vacuum pump to obtain the compound that can crystallize as a brown solid. The compound is isolated but hydrolysed very easily, so it has not
    25 fully characterized. ES-MS (+) (C2sH33N2 + H): 361.2638.
    Compound 8 (4-methylbenzenesulfonate of N- (3 (cyclohexylamino) -2-methylcyclohex-2eniliden) cyclohexanedaminium)
    T50 <t> Ú
    & D
    N H
    The reaction is carried out at 120 ° C in cyclohexylamine
    5 in the presence of 1 equivalent of p-toluenesulfonic acid which is added over 2-methyl-1,3-cyclohexanedione obtained from commercial sources. Reflux is maintained for two days. After this time, the amine is evaporated and the crude is dissolved with a few drops of dichloromethane and
    10 add hexane. Instead of a precipitate, a viscous oil is obtained that adheres to the walls. Hexane is decanted and the process is repeated twice, after this it is washed with hexane twice and dried in the vacuum pump to obtain the compound that can crystallize as a
    15 solid brown.
    lH-NMR (300 MHz, MeOD) B 7.71 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 4.62 (s, 2H) , 2.66 (t, J = 6.3 Hz, 4H), 2.38 (s, 3H), 2.05-1.59 (m, 15H), 1.34 (m, 10H).
    13C-NMR (75 MHz, MeOD) B 169.34 (s), 143.55 (s),
    20 141.68 (s), 129.80 (s), 126.94 (s), 97.89 (s), 51.53 (s), 33.97 (s), 32.01 (s), 26.33 (s), 26.12 (s), 25.88 (s), 25.34 (s), 21.29 (s), 20.90 (s), 9.06 (s).
    UV-Vis (CH3CN): ') .. (nm) = 327 (e = 14500 M-1cm-1).
    ES-MS (+) (C19H33N2 + H): 289.2638.
    Compound 9 (4-methoxy-N- (3- (4-methoxyphenylamino) -2- (methylthio) cyclohex-2-enylidene) benzenamine) (4-methylbenzenesulfonate)
    I '' d 'TSO · {JIO
    O I I P-AnlSI na, Ef) O TsOH (4: 1) HN ~ - :: • I, / I
    OCs I NO LOL, .oo., OO'lo rYS {J0
    H U ~ I
    N
    H
    The synthesis of the starting aminocyclohexenone was described above herein. The reaction is carried out to form compound 9 therein.
    5 conditions than the above compounds (compounds 1 to 8) but for 3 and a half days. There are two possibilities of purification, the first is to do the same as for compounds 1 and 2 but, being more soluble, quite a compound is lost and the yield is lower. Thus,
    It is preferred to dissolve all the crude in dichloromethane and make a silica gel filtration using dichloromethane as eluent until all the amine residues and other compounds are carried away, as it is eluted a yellow color is observed on the silica front, which creeps using
    Dichloromethane: methanol (1: 1), obtaining the pure compound.
    lH-NMR (400 MHz, MeOD) 8 ppm 7.70 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.9 Hz, 4H), 7.22 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.9 Hz, 4H), 3.84 (s, 6H), 2.64 (t, J = 6.2 Hz, 4H), 2.36 (s, 3H), 2.27 (s, 3H), 1.89 -1.75 (m, 2H).
    20 13C-NMR (101 MHz, MeOD) 8 ppm 174.63 (s), 161.14 (s), 143.72 (s), 141.55 (s), 130.56 (s), 129.77 (s), 128.82 (s), 126.96 (s), 115.77 (s), 98.26 (s), 56.09 (s), 29.06 (s), 21.30 ( s), 21.07 (s), 17.23 (s).
    uv-vis (CH3CN): "A, (nm) = 336 (s = 29240 M-1cm-1).
    ES-MS (+) (C21H2SN202S + H): 369.1631.
    Compound 10 (4-Methoxy-N- (2-methoxy-3- (4-methoxyphenylamino) cyclohex-2-ylidene) benzeneminium) 10 (4-methylbenzenesulfonate)
    I T50-0 °
    ° p-Anisidine, @ I TsOH (6: 1) HN ~ I
    0 '• I O "" "" °
    I dOlueoo • efflux OCNO
    H
    The synthesis of the starting aminocyclohexenone was described above herein. The reaction is carried out to form compound 10 in the
    5 same conditions as for compounds 1 and 2. In this case, the purification is carried out by gel filtration of the crude dissolved in dichloromethane, eluting until only the compound remains and dragging with a mixture of dichloromethane: methanol (1: 1) to get the compound pure.
    10 lH-NMR (400 MHz, MeOD) 8 ppm 7.70 (d, J = 8, O Hz, 2H),
    7.28 -7.15 (m, 6H), 7.03 (d, J = 8.6 Hz, 4H), 3.83 (s, 6H), 3.78 (s, 3H), 2.62 (t, J = 5.8 Hz, 4H), 2.36 (s, 3H), 1.89 -1.73 (m, 2H).
    13C-NMR (101 MHz, MeOD) 8 ppm 164.84 (s), 160.84 (s),
    15 143.67 (s), 141.59 (s), 130.43 (s), 129.77 (s), 129.16 (s), 128.40 (s), 126.97 (s), 115.70 (s), 60.21 (s), 56.06 (s), 27.43 (s), 21.49 (s), 21.29 (s).
    uv-vis (CH3CN): A (nm) = 353 (s = 31120 M-1cm-1).
    ES-MS (+) (C21H2SN203 + H): 353.1860.
    20 Compound 11 (4-methylbenzenesulfonate of 2-bromo-N- (3- (2-bromophenylamino) -2-ethoxy-5,5-dimethylcyclohex-2-enylidene) benzenamine) <~ NH2 TSo r ~ or - ~~
    PO ~ TsOH (6: 1) H ~ :::: "" I - Ao ~ oTaluena, reflux ~~ j)
    Br
    The synthesis of the starting aminocyclohexenone was described above herein. The reaction is carried out to form compound 11 in the
    5 same conditions as for compound 6. In this case, the purification is carried out completely differently, since the compound is soluble in toluene. Once the reaction is over, the toluene is evaporated and ethyl acetate is added to dissolve the maximum amount of
    10 compound, the supernatant is discarded and, after multiple washes, a crystalline solid is filtered and dried by suction, thus obtaining the pure compound as a yellow solid.
    lH-NMR (400 MHz, MeOD) 8 7.82 (d, J = 7.8 Hz, 2H),
    15 7.70 (d, J = 8.0 Hz, 2H), 7.57-7.48 (m, J = 7.4 Hz, 2H), 7.44 (d, J = 7.8 Hz, 2H), 7.42-7.38 (m, J = 7.3 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 4.17 (sa, 2H), 2, 37 (s, 3H), 2.35 (sa, 4H), 1.57 (sa, 3H), 1.04 (s, 6H).
    13C-NMR (101 MHz, MeOD) 8 165.22 (s), 143.63 (s),
    20 141.59 (s), 136.74 (s), 134.77 (s), 131.90 (s), 130.63 (s), 130.17 (s), 129.77 (s), 127.16 (s), 126.95 (s), 123.21 (s), 69.71 (s), 40.62 (s), 32.96 (s), 28.00 (s), 21 , 29 (s), 15.27 (s). UV-vis (CH3CN): f ... (nm) = 340 (8 = 35880 M-1cm-1).
    ES-MS (+) (C21H2SN203 + H): 491.0328.
    Compound 12 (4, methylbenzenesulfonate of N, N '- (2
    methylcyclopent-1-en-1-yl-3-ylidene) bis (4-methoxybenzenamine))
    0 I 0
    TsOH- ~ "ffi p-Anisidine, HN ~
    TsOH (6: 1)
    •
    Toluene, reflux
    °
    The reaction is carried out to form compound 12 under the same conditions as for compounds 1 and 2. In this case, 2-methyl-1,3-cyclopentanedione is used as the starting material. The mixture is refluxed for two days. After this time has elapsed at reflux, toluene is evaporated and a small amount of dichloromethane and hexane is added to precipitate the compound.
    Finally, it is purified by filtration to give a yellow solid.
    lH-NMR (400 MHz, MeOD) 8 7.70 (d, J = 7.9 Hz, 2H), 7.26 (d, J = 8.6 Hz, 4H), 7.22 (d, J = 7.8 Hz, 2H), 7.01 (d, J = 8, 6 Hz, 4H), 3, 82 (s, 6H), 2, 79 (s, 4H), 2, 36 (s,
    15 3H), 1.97 (s, 3H).
    13C-NMR (101 MHz, MeOD) 8180.54 (9), 160.54 (9), 143.67 (9), 141.57 (9), 131.91 (s), 129.77 (9) , 127.46 (9), 126.94 (s), 115.74 (s), 106.86 (s), 56.04 (s), 29.14 (s), 21.30 (s), 7.28 (s).
    20 UV-Vis (CH3CN): A (nm) = 328 (E = 34560 M-1cm-1) • ES-MS (+) (C2oH23N202 + H): 323.1754.
    Compound 13 (4-methylbenzenesulfonate of N, N '- (cyclohept-1-1-yl-3-ylidene) bis (4-methoxybenzenamine))
    The reaction is carried out to form compound 13 under the same conditions as for compounds 1 and 2. In this case, 1,3-cycloheptanedione is used as the starting material. The mixture is refluxed for one day and the toluene is evaporated.
    Synthesis of compounds with different counterions
    TsO-counterion substitution was carried out in some of the synthesized compounds as described above. Substitution was carried out by means of an anion exchange resin, Amberlite IRA
    420.
    To condition the resin, it is kept in a 1 M NaOH bath for 20 minutes. After that time, pass through a filter plate, washing with plenty of water. The resin is introduced in a 1 M HCl bath for 20 minutes and, after elapsing, it is filtered on a plate washing with plenty of water until the filtrate ceases to have an acidic character. Suction is maintained for 30 minutes and placed in the oven at 50 ° C for two hours to remove excess moisture. After this it is stored at room temperature in a desiccator.
    Once the activated resin is obtained, the exchange is carried out, adding the activated resin on a solution of any of the compounds of the present invention described above. After stirring for one hour, the total substitution of the tosylate anion with chloride occurs. It is filtered to remove the resin and the corresponding compound is obtained with the new counterion.
    Next, the new compound having the chloride can be treated as a counterion with a soluble silver salt on a cold solution in water. In this way the precipitation of silver chloride and the
    exchange for the anion of the silver salt used. This procedure has been carried out by changing the counterion to acetate, trifluoroacetate and triflate anions.
    Characterization of the compounds of the invention
    The photophysical and photochemical characterization of representative examples of the synthesized compounds was carried out, studying their behavior against artificial UV light and sunlight.
    UV-Vis spectra were obtained using acetonitrile as solvent. Figure 1 shows the absorption spectrum of some of the compounds synthesized according to the present invention (solid line) as well as the spectra of some commercial compounds (dotted line) by way of comparison.
    Some relevant characteristics are: absorption in the area of interest (ultraviolet A and B), the possibility of modulation of the absorption wavelength depending on the substituents (maximum of the UV spectrum between 325 and 360 nm), a very high absorption intense (in the case of compound 10 greater than any of the commercial products tested).
    Comparatively, the comparative compounds of the prior art have an absorption centered at longer energy wavelengths, with a maximum absorption between 275-300 nm, while the range covered by the compounds of the present invention ranges from 320 up to 350 nm, although due to the width of the band the range between 300 and 400 nm can be covered efficiently.
    Table 1 shows the absorption data obtained for some of the compounds synthesized according to the present invention as well as for commercial compounds.
    and intermediate products for comparison. Stability data of these same compounds are also presented, obtained by analysis by 1 H-NMR to determine the decomposition of the compounds after irradiation with a
    5 medium pressure mercury lamp 400 W.
    Table 1. Absorption and photostability data
    o ó () lp ~ N / H 968874
    As can be seen in Table 1, all synthesized compounds show zero decomposition from the 1 H-NMR data, while the compounds
    5 commercials experience decomposition in relatively short times. To verify said behavior of the compounds of the present invention, they were irradiated for 16 hours, without observing any apparent change by 1 H-NMR (data not shown).
    In Table 1 above it can also be seen that all aminocyclohexenones (intermediates used in the process of the present invention) have photodecomposition on a smaller time scale than the compounds of the present invention. In the first
    For example, a total decomposition is observed very quickly (even after only 1 h) And in the others it occurs gradually, being somewhat less in the compounds that have a heteroatom in position 2. These results clearly indicate that MAA analog compounds according to
    The present invention is much more photostable than its aminocyclohexenone analogs. It was also found that there is no possibility of radiant deactivation, since the quantum fluorescence performance for all the compounds of the present
    The invention under test is less than 1% (detection limit of the measuring equipment, measured in solutions at S * 10E-S M in acetonitrile and using a Jobin-Yvon Horiba Fluorolog 3-11 Tau-3 device). A study of the solubility of the
    compounds of the present invention, since at the time of a possible industrial / commercial application it is necessary to know in which means it is possible to dissolve the compound to know in what type of formulations they can be compatible. Qualitative tests were carried out with a multitude of solvents, but dichloromethane, methanol and water were chosen for semi-quantitative tests, since they cover the range of organic solvents, alcohols and biological media. Table 2 shows the results.
    10 obtained.
    Table 2. Solubility data
    Compound CH2C12 (g / L)MeOH (g / L)H20 (g / L)
    one 1.1124<0.0003
    1 Cl 31061.48
    6 0.8114.5<0.001
    12 23. 4. ::. 0,001
    Avobenzone 2406.310.0022
    Octinoxate --0.00016
    Benzophenone-3 108022.310.069
    As shown in Table 2, the compounds
    15 synthesized according to the present invention have a high solubility in methanol. The solubility in halogenated solvents varies significantly depending on the compound while the solubility in water remains more
    or less constant, increasing a little for the
    Compound 12. In the pair of compounds 1 and 1 Cl (compound 1 with Cl-as counterion) it is observed that the solubility in dichloromethane increases while the increase when using methanol is much more drastic, the solubility being practically an order of magnitude greater than
    for 1. Moreover, in the case of this pair of compound 1 and 1 Cl, the water solubility is increased by four orders of magnitude which allows to use a much greater amount than for the rest of compounds of this
    5 invention or commercials used as a comparison. For commercial compounds it can be seen that they are practically insoluble in water. The melting points of some compounds of the present invention were also measured, observing in all
    10 they do not melt but always decompose at temperatures above 200 ° C. In table 3, the decomposition temperatures for these compounds are provided.
    15 Table 3. Decomposition temperatures
    Compound Decomposition temperature (OC)
    one 270
    2 245
    6 210
    9 255
    10 210
    eleven 205
    12 217
    From the results provided in Table 3, it can be seen that the compounds of the present invention are thermally very stable, which facilitates their
    20 use in a very wide range of temperatures.
    权利要求:
    Claims (22)
    [1]
    1. MAA analog photoprotective compound having formula 1:
    : N
    'I R, n I
    R2-trN, R3
    R2 H
    5 Formula 1 and its acceptable salts and solvates; wherein: R 1 is selected from the group consisting of Cl 6 alkyl, S-Cl-6 alkyl and O-Cl-6 alkyl;
    10 R2 are each selected from the group consisting of H and Cl-6 alkyl; R3 are each selected from the group consisting of
     (Y0H
    ~
     JI) ((f.
    Br
    and
    15 n is an integer selected from the group consisting of O, 1 and 2.
    [2]
    2. Compound according to claim 1, characterized in that n is equal to 1, and therefore has the following formula lA:
    ~ R1
     R2 ~ N, R3
    R2 H
    20 Formula lA.
    [3]
    3. Compound according to any of the claims
    above, characterized in that Rl is selected from the group consisting of Me, Et, SMe, OMe and OEt.
    [4]
    Four. Compound according to claim 3, characterized in that Rl is selected from the group consisting of Me, Et and OEt.
    [5]
    5. Compound according to claim 4, characterized in that Rl is Me.
    G. Compound according to any of the preceding claims, characterized in that each is selected from the group consisting of H and Me.
    [7]
    7. Compound according to claim G, characterized in that each R2 is H.
    [8]
    8. Compound according to any of the preceding claims, characterized in that both groups R2 are identical.
    [9]
    9. Compound according to any of the preceding claims, characterized in that each is selected from the group consisting of
     (Y ~ J
     ~, ~ and Mr
    [10]
    10. Compound according to claim 9, characterized in that each R3 is selected from the group consisting of
    J7
    Mr
    [11]
    eleven. Compound according to any of the preceding claims, characterized in that both R3 groups are identical.
    [12]
    12. Compound according to any of the preceding claims, characterized in that it is presented in the form of a salt according to formula lB:
    and
    x
    Formula lB in which X-is selected from the group consisting of TsO-, Cl-,
    5 AcO-, CF3COO- and CF3S03-.
    [13]
    13. Compound according to claim 12, characterized in that X-is selected from the group consisting of TsO- and Cl-.
    [14]
    14. Compound according to claim 13, characterized in that X-is TsO-.
    [15]
    15. Method of synthesis of a compound according to any one of claims 1 to 14, wherein R 1 is Cl-6 alkyl; which comprises reacting a compound of formula 2A
     ~ R1 R2 ~ O
    R2 Formula 2A wherein Rl is Cl-6 alkyl and R2 is as defined in claims 1 to 14; with a compound of formula 3 20
    wherein R3 is as defined in claims 1 to 14; in a suitable solvent and in the presence of a suitable acid X-OH in which X is as defined in the
    claims 12 to 14.
    [16]
    16. Synthesis process of a compound according to any one of claims 1 to 14, wherein R 1 is O-Cl-6 alkyl; which comprises reacting a compound of formula 2B
    Formula 2B
    in thethatRlisO-alkylCl-6YR2issuchhowbe
    define inclaims 1to14;
    10 with acompoundformula 3
    in whichR3issuchhowbedefine inthe
    fifteen claims 1to14;
    in asolventsuitableY inpresencefromaacid
    suitable X-OH inthe one that X issuchhowbedefineinthe
    claims 12 to14.
    [17]
    17. Processfromsynthesisfromacompoundaccording
    twenty anyonefromtheclaimsoneto14,inhethat
    R1 isS-Cl -6 alkyl;thatunderstand reacta
    compound formula2 C
    ~ R1
    Ri ~~ N, R3R2 H
    Formula 2C
    25 inthethatRlisS-alkylCl-6,R2issuchhowbe
    define inclaims 1to14YR3issuchhow
    be defineinclaims 1to14;
    with a compound of formula 3
    R3NH2
    Formula 3 wherein R3 is as defined in claims 1 to 14; in a suitable solvent and in the presence of a suitable acid X-OH in which X is as defined in claims 12 to 14.
    [18]
    18. Process according to any of claims 15 to 17, wherein the reaction is carried out in toluene as solvent and at reflux.
    [19]
    19. Composition for protection against solar radiation comprising an effective amount of at least one compound according to any of claims 1 to
    [14]
    14.
    [20]
    twenty. Composition for protection against solar radiation according to claim 19 for application on the skin of an animal, characterized in that the compound is in the form of a physiologically acceptable salt of formula lB.
    [21]
    twenty-one. Composition according to claim 20, characterized in that the X-counterion in formula 1B is selected from the group consisting of TsO- and el-o
    [22]
    22 Composition according to any of claims 19 to 21, characterized in that it further comprises at least a second protective agent against solar radiation in combination with the at least one compound according to any one of claims 1 to 14.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3622621A|1967-12-18|1971-11-23|Searle & Co|2-alkyl-n-aryl-3-arylimino-1-cyclopenten-1-ylamine salts|
    AU1529188A|1987-04-28|1988-11-03|Australian Institute Of Marine Science|Ultra violet light absorbing materials|
    WO2013181741A1|2012-06-04|2013-12-12|Elkimia|Imino compounds as protecting agents against ultraviolet radiations|WO2021148426A1|2020-01-22|2021-07-29|Basf Se|Analogues of mycosporine-like amino acid and use thereof as sunscreens|
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