Patent Grant
11958819
The present invention relates to novel compounds, particularly to compounds comprising a photoactive unit, said novel compounds being particularly suitable for ophthalmic devices as well as to ophthalmic devices comprising such compounds.
Cataract is a general term of an affection of the eye that leads to a loss of vision and in the extreme to blindness by clouding of the normally clear lens of the eye. It is the major cause of blindness in the world with it affecting more than 100 million people. Due to the fact that its major cause is age, it is expected that with the population's average age continuing to increase the number of cataracts will continue to increase substantially in the future.
Effective treatment of cataract is only possible by surgical intervention, whereby the natural lens of the eye is removed through an incision in the cornea and replaced with an artificial lens, often also referred to as “intraocular lens”. In preparation of surgery current state-of-the-art surgical methods employ methods for eye mapping so as to approximate the refractive power best suited to the respective patient.
Even though cataract surgery is one of the most widely used and safest surgical procedures it is not without specific post-surgery problems. It frequently happens that the refractive power of the implanted intraocular lens (IOL) is insufficient for restoring good vision. Such problems may, for example, be caused by changes in eye geometry in consequence of the surgery as well as irregular wound healing and positioning errors that result in the artificial lens not having the optimal optical properties. As a result the patient will still require corrective vision aids, e.g. glasses, to be able to see correctly. In some cases the resulting refractive power of the implanted artificial lens is so far removed from the required refractive power that further surgery will be required. Particularly for aged persons this is not desirable because the body's capability for healing are reduced with increasing age. Furthermore, there is the risk of attracting endophthalmitis, an inflammation of the eye, which can even lead to a complete loss of vision or worse, loss of the eye.
There is therefore a need in the health sector for optically active devices, and particularly artificial intraocular lenses, that would allow for non-invasive adjustment of refractive power after implantation of the lens, thereby preferably further reducing the need for post-surgery vision aids.
Some developments in this sense have already been made, as for example evidenced by WO 2007/033831 A1.
However, the compounds disclosed therein suffer from being too stiff and too brittle so that they can't be rolled or folded and are thus not fit to be implanted by state of the art cataract surgical methods, particularly by state of the art micro-incision cataract surgical methods.
Consequently, it is an objective of the present application to provide for novel compounds suitable for ophthalmic devices.
It is also an objective of the present application to provide for compounds, the optical properties of which may be changed, preferably by non-invasive techniques.
It is a further objective of the present application to provide for novel compounds that are more flexible than the currently known compounds, preferably in combination with being suitable for ophthalmic devices.
Further advantages and objectives of the compounds of the present application will be evident to the skilled person from the following detailed description as well as from the examples.
The present inventors have now surprisingly found that the above objects may be attained either individually or in any combination by the compounds and ophthalmic devices of the present application.
The present application therefore provides for a compound of formula (I)
The present application also provides for a composition comprising said compound as well as for an article comprising said composition.
In addition, the present application provides for a process of forming such article, said process comprising the steps of
a) providing a composition comprising said compound;
b) subsequently forming the article of said composition.
Furthermore, the present application provides for a process for changing the optical properties of such article, said process comprising the steps of
a) providing said article, and
b) subsequently exposing said article to irradiation having a wavelength of at least 200 nm and at most 1500 nm.
For the purposes of the present application an asterisk (“*”) denotes a linkage to an adjacent unit or group or, in case of a polymer, to an adjacent repeating unit or any other group.
For the purposes of the present application the term “organyl group” is used to denote any organic substituent group, regardless of functional type, having one free valence at a carbon atom.
For the purposes of the present application the term “organoheteryl group” is used to denote any univalent group comprising carbon, said group thus being organic, but having the free valence at an atom other than carbon.
For the purposes of the present application the term “carbyl group” includes both, organyl groups and organoheteryl groups.
As used herein, the term “carbyl group” will be understood to include any monovalent or multivalent organic radical moiety which comprises at least one carbon atom either without any non-carbon atoms (like for example —C≡C—), or optionally comprising one or more heteroatoms (for example carbonyl etc.).
The term “hydrocarbyl group” will be understood to mean a carbyl group that does additionally contain one or more H atoms and optionally contains one or more hetero atoms.
As used herein, the term “hetero atom” will be understood to mean an atom in an organic compound that is not a H- or C-atom, and preferably will be understood to mean N, O, S, P, Si, Se, As, Te or Ge, more preferably N, O, S, P and Si.
The compound of the present application is of the following formula (I)
wherein a, a′, R1, R2, R3, R4, R5, R6, Sp, X1, X2, X3 and X4 are as defined herein, provided that the compound of formula (I) comprises one group R6—Sp-[X1]a-* as defined herein. The expression “comprises one group R6—Sp-[X1]a-*” is to denote in this context that the compound of formula (I) comprises only one such group.
The compound of formula (I) is preferably a compound of formula (I′) or a compound of formula (I″).
a is 0 or 1. Preferably a is 1.
a′—if present—is 0 or 1.
R1, R2 and R3 are at each occurrence independently selected from the group consisting of H, F, Cl, Br, I, alkyl having from 1 to 20 carbon atoms, partially or completely halogenated alkyl having from 1 to 20 carbon atoms, aryl and heteroaryl. Most preferably, R1, R2 and R3 are all H.
One or both, preferably one of R4 and R5 is a group of formula (II)
with R10, R11, R12, R13 and R14 as defined herein. If only one of R4 and R5 is a group of formula (II), the other of R4 and R5 is selected from the group consisting of H, F, Cl, Br, I, alkyl having from 1 to 20 carbon atoms, partially or completely halogenated alkyl having from 1 to 20 carbon atoms, aryl, heteroaryl, and R6—Sp-[X1]a-*. Preferably R4 is H and R5 is a group of formula (II) as defined herein.
R10, R11, R12, R13 and R14 are at each occurrence independently of each other selected from the group consisting of H, F, Cl, Br, I, R6—Sp-[X1]a-* and R15 as defined herein. Preferably R10, R11, R12, R13 and R14 are at each occurrence independently of each other selected from the group consisting of H, F, and R15 as defined herein.
Preferably at least one (for example, two, three, four or all) of R10, R11, R12, R13 and R14, more preferably at least one (for example, two or all) of R10, R12 and R14, even more preferably at least one or all of R10 and R14, still even more preferably R10 only, and most preferably all of R10, R11, R12, R13 and R14 is/are H.
Preferably for the compound of formula (I′) one or both, preferably one, of R4 and R5 is a group of formula (II) with R10, R11, R12, R13 and R14 being at each occurrence independently of each other selected from the group consisting of H, F, Cl, Br, I, and R15 as defined herein and preferably with R10, R11, R12, R13 and R14 being at each occurrence independently of each other selected from the group consisting of H, F, and R15 as defined herein, wherein any two adjacent groups of R10, R11, R12, R13 and R14 that are R15 may also form a ring system; and if only one of R4 and R5 is a group of formula (II), the other of R4 and R5 is selected from the group consisting of H, F, Cl, Br, I, alkyl having from 1 to 20 carbon atoms, partially or completely halogenated alkyl having from 1 to 20 carbon atoms, aryl and heteroaryl.
For the compound of formula (I″) one of groups R10, R11, R12, R13 and R14 is R6—Sp-[X1]a-*. Thus, preferably for such compound one or both, preferably one, of R4 and R5 is a group of formula (II) with one of R10, R1, R12, R13 and R14 being R6-Sp-[X1]a-* and the others being at each occurrence independently of each other selected from the group consisting of H, F, Cl, Br, I, and R15 as defined herein, wherein any two adjacent groups of R10, R11, R12, R13 and R14 that are R15 may also form a ring system.
Alternatively, for the compound of formula (I″) one group R4 and R5 is R6—Sp-[X1]a-*. Thus, preferably for such compound one of R4 and R5 is R6—Sp-[X1]a-* and the other of R4 and R5 is a group of formula (II) with R10, R11, R12, R13 and R14 being at each occurrence independently of each other selected from the group consisting of H, F, Cl, Br, I, and R15 as defined herein and preferably with R10, R11, R12, R13 and R14 being at each occurrence independently of each other selected from the group consisting of H, F, and R15 as defined herein, wherein any two adjacent groups of R10, R11, R12, R13 and R14 that are R15 may also form a ring system.
R15 is at each occurrence independently selected from the group consisting of alkyl having from 1 to 20 carbon atoms and partially or completely halogenated (preferably fluorinated) alkyl having from 1 to 20 carbon atoms. More preferably, R15 is at each occurrence independently selected from the group consisting of partially or completely halogenated (preferably fluorinated) alkyl having from 1 to 20 (for example, from 1 to 10 or from 1 to 5, or from 1 to 3, or 1) carbon atoms. Most preferably, R15 is —CF3.
R15 is at each occurrence independently selected from the group consisting of alkyl having from 1 to 20 carbon atoms, partially or completely halogenated (preferably fluorinated) alkyl having from 1 to 20 carbon atoms, alkoxy having from 1 to 20 carbon atoms, partially or completely halogenated alkoxy having from 1 to 20 carbon atoms, thioalkyl having from 1 to 20 carbon atoms, and partially or completely halogenated thioalkyl having from 1 to 20 carbon atoms. More preferably, R15 is at each occurrence independently selected from the group consisting of partially or completely halogenated (preferably fluorinated) alkyl having from 1 to 20 (for example, from 1 to 10 or from 1 to 5, or from 1 to 3, or 1) carbon atoms. Most preferably, R15 is —CF3.
Any two adjacent groups of R10, R11, R12, R13 and R14 that are R15 may also form a ring system, preferably a six-membered ring system. Such ring system may be aromatic or non-aromatic. Such ring system, if non-aromatic, may be saturated or unsaturated, for example comprising a double bond. Optionally such ring system may be substituted, i.e. one or more of the hydrogens is replaced with H, F, Cl, Br, I, alkyl having from 1 to 20 carbon atoms, partially or completely halogenated alkyl having from 1 to 20 carbon atoms, aryl and heteroaryl.
R6 is a carbyl group for a′=1 and for a′=0 is selected from the group consisting of H, F, Cl, Br, I, alkyl having from 1 to 20 carbon atoms, partially or completely halogenated alkyl having from 1 to 20 carbon atoms, aryl and heteroaryl.
A carbyl or hydrocarbyl group comprising a chain of 3 or more C atoms may be straight-chain, branched and/or cyclic, including spiro and/or fused rings.
Preferred carbyl and hydrocarbyl groups include alkyl, alkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy and alkoxycarbonyloxy, each of which is optionally substituted and has 1 to 40, preferably 1 to 25, very preferably 1 to 18 C atoms, furthermore optionally substituted aryl or aryloxy having 6 to 40, preferably 6 to 25 C atoms, furthermore alkylaryloxy, arylcarbonyl, aryloxycarbonyl, arylcarbonyloxy and aryloxycarbonyloxy, each of which is optionally substituted and has 6 to 40, preferably 7 to 30 C atoms, wherein all these groups do optionally contain one or more hetero atoms, preferably selected from N, O, S, P, Si, Se, As, Te and Ge, more preferably N, O, S, P and Si.
The carbyl or hydrocarbyl group may be a saturated or unsaturated acyclic group, or a saturated or unsaturated cyclic group. Unsaturated acyclic or cyclic groups are preferred, especially aryl, alkenyl and alkynyl groups. Where the C1-C40 carbyl or hydrocarbyl group is acyclic, the group may be straight-chain or branched. The C1-C40 carbyl or hydrocarbyl group includes for example: a C1-C40 alkyl group, a C1-C40 fluoroalkyl group, a C1-C40 alkoxy or oxaalkyl group, a C2-C40 alkenyl group, a C2-C40 alkynyl group, a C3-C40 allyl group, a C4-C40 alkyldienyl group, a C4-C40 polyenyl group, a C2-C40 ketone group, a C2-C40 ester group, a C6-C18 aryl group, a C6-C40 alkylaryl group, a C6-C40 arylalkyl group, a C4-C40 cycloalkyl group, a C4-C40 cycloalkenyl group, and the like. Preferred among the foregoing groups are a C1-C20 alkyl group, a C1-C20 fluoroalkyl group, a C2-C20 alkenyl group, a C2-C20 alkynyl group, a C3-C20 allyl group, a C4-C20 alkyldienyl group, a C2-C20 ketone group, a C2-C20 ester group, a C6-C12 aryl group, and a C4-C20 polyenyl group, respectively.
The terms “aryl” and “heteroaryl” as used herein preferably mean a mono-, bi- or tricyclic aromatic or heteroaromatic group with 4 to 30 ring C atoms that may also comprise condensed rings and is optionally substituted with one or more groups L, wherein L is selected from halogen, —CN, —NC, —NCO, —NCS, —OCN, —SCN, —C(═O)NR0R00, —C(═O)X0, —C(═O)R0, —NH2, —NR0R00, —SH, —SR0, —SO3H, —SO2R0, —OH, —NO2, —CF3, —SF5, or carbyl or hydrocarbyl with 1 to 40 C atoms that is optionally substituted and optionally comprises one or more hetero atoms, and is preferably alkyl, alkoxy, thioalkyl, alkylcarbonyl, alkoxycarbonyl or alkoxycarbonyloxy with 1 to 20 C atoms that is optionally fluorinated, and R0, R00 and X0 have the meanings given above and below.
R0, R00 and R000 are at each occurrence independently of each other selected from the group consisting of H, F and hydrocarbyl having from 1 to 40 carbon atoms. Said hydrocarbyl preferably has at least 5 carbon atoms. Said hydrocarbyl preferably has at most 30, more preferably at most 25 or 20, even more preferably at most 20, and most preferably at most 12 carbon atoms. Preferably, R0, R00 and R000 are at each occurrence independently of each other selected from the group consisting of H, F, alkyl, fluorinated alkyl, alkenyl, alkynyl, phenyl and fluorinated phenyl. More preferably, R0, R00 and R000 are at each occurrence independently of each other selected from the group consisting of H, F, alkyl, fluorinated, preferably perfluorinated, alkyl, phenyl and fluorinated, preferably perfluorinated, phenyl.
It is noted that for example alkyl suitable as R0, R00 and R000 also includes perfluorinated alkyl, i.e. alkyl wherein all of the hydrogen are replaced by fluorine. Examples of suitable alkyls may be selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl (or “t-butyl”), pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl (—C20H41).
X0 is halogen. Preferably X0 is selected from the group consisting of F, Cl and Br.
Very preferred substituents L are selected from halogen, most preferably F, or alkyl, alkoxy, oxoalkyl, thioalkyl, fluoroalkyl and fluoroalkoxy with 1 to 12 C atoms or alkenyl and alkynyl with 2 to 12 C atoms.
Especially preferred aryl and heteroaryl groups are phenyl, phenyl wherein one or more CH groups are replaced by N, naphthalene, thiophene, selenophene, thienothiophene, dithienothiophene, fluorene and oxazole, all of which can be unsubstituted, mono- or polysubstituted with L as defined above. Very preferred rings are selected from pyrrole, preferably N-pyrrole, furan, pyridine, preferably 2- or 3-pyridine, pyrimidine, pyridazine, pyrazine, triazole, tetrazole, pyrazole, imidazole, isothiazole, thiazole, thiadiazole, isoxazole, oxazole, oxadiazole, thiophene, preferably 2-thiophene, selenophene, preferably 2-selenophene, thieno[3,2-b]thiophene, thieno[2,3-b]thiophene, furo[3,2-b]furan, furo[2,3-b]furan, seleno[3,2-b]selenophene, seleno[2,3-b]selenophene, thieno[3,2-b]selenophene, thieno[3,2-b]furan, indole, isoindole, benzo[b]furan, benzo[b]thiophene, benzo[1,2-b;4,5-b′]dithiophene, benzo[2,1-b;3,4-b′]dithiophene, quinole, 2-methylquinole, isoquinole, quinoxaline, quinazoline, benzotriazole, benzimidazole, benzothiazole, benzisothiazole, benzisoxazole, benzoxadiazole, benzoxazole, benzothiadiazole, all of which can be unsubstituted, mono- or polysubstituted with L as defined above.
An alkyl or alkoxy radical, i.e. where the terminal CH2 group is replaced by —O—, can be straight-chain or branched. It is preferably straight-chain (or linear). Suitable examples of such alkyl and alkoxy radical are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, ethylhexyl, undecoxy, dodecoxy, tridecoxy or tetradecoxy. Preferred alkyl and alkoxy radicals have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Suitable examples of such preferred alkyl and alkoxy radicals may be selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, ethylhexyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy and decoxy.
An alkenyl group, wherein one or more CH2 groups are replaced by —CH═CH— can be straight-chain or branched. It is preferably straight-chain, has 2 to 10 C atoms and accordingly is preferably vinyl, prop-1-enyl, prop-2-enyl, but-1-enyl, but-2-enyl, but-3-enyl, pent-1-enyl, pent-2-enyl, pent-3-enyl or pent-4-enyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl or hex-5-enyl, hept-1-enyl, hept-2-enyl, hept-3-enyl, hept-4-enyl, hept-5-enyl or hept-6-enyl, oct-1-enyl, oct-2-enyl, oct-3-enyl, oct-4-enyl, oct-5-enyl, oct-6-enyl or oct-7-enyl, non-1-enyl, non-2-enyl, non-3-enyl, non-4-enyl, non-5-enyl, non-6-enyl, non-7-enyl or non-8-enyl, dec-1-enyl, dec-2-enyl, dec-3-enyl, dec-4-enyl, dec-5-enyl, dec-6-enyl, dec-7-enyl, dec-8-enyl or dec-9-enyl.
Especially preferred alkenyl groups are C2-C7-1E-alkenyl, C4-C7-3E-alkenyl, C5-C7-4-alkenyl, C6-C7-5-alkenyl and C7-6-alkenyl, in particular C2-C7-1E-alkenyl, C4-C7-3E-alkenyl and C5-C7-4-alkenyl. Examples for particularly preferred alkenyl groups are vinyl, 1E-propenyl, 1E-butenyl, 1E-pentenyl, 1E-hexenyl, 1E-heptenyl, 3-butenyl, 3E-pentenyl, 3E-hexenyl, 3E-heptenyl, 4-pentenyl, 4Z-hexenyl, 4E-hexenyl, 4Z-heptenyl, 5-hexenyl, 6-heptenyl and the like. Alkenyl groups having up to 5 C atoms are generally preferred.
An oxoalkyl group, i.e. where one CH2 group is replaced by —O—, is preferably straight-chain 2-oxapropyl (=methoxymethyl), 2-(=ethoxymethyl) or 3-oxabutyl (=2-methoxyethyl), 2-, 3-, or 4-oxapentyl, 2-, 3-, 4-, or 5-oxahexyl, 2-, 3-, 4-, 5-, or 6-oxaheptyl, 2-, 3-, 4-, 5-, 6- or 7-oxaoctyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-oxanonyl or 2-, 3-, 4-, 5-, 6-,7-, 8- or 9-oxadecyl, for example. Oxaalkyl, i.e. where one CH2 group is replaced by —O—, is preferably straight-chain 2-oxapropyl (=methoxymethyl), 2-(=ethoxymethyl) or 3-oxabutyl (=2-methoxyethyl), 2-, 3-, or 4-oxapentyl, 2-, 3-, 4-, or 5-oxahexyl, 2-, 3-, 4-, 5-, or 6-oxaheptyl, 2-, 3-, 4-, 5-, 6- or 7-oxaoctyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-oxanonyl or 2-, 3-, 4-, 5-, 6-,7-, 8- or 9-oxadecyl, for example.
In an alkyl group wherein one CH2 group is replaced by —O— and one by —C(O)—, these radicals are preferably neighboured. Accordingly these radicals together form a carbonyloxy group —C(O)—O— or an oxycarbonyl group —O—C(O)—. Preferably this group is straight-chain and has 2 to 6 C atoms. It is accordingly preferably selected from the group consisting of acetyloxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, pentanoyloxymethyl, 2-acetyloxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 3-acetyloxypropyl, 3-propionyloxypropyl, 4-acetyloxybutyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, butoxycarbonylmethyl, 2-(methoxycarbonyl)ethyl, 2-(ethoxycarbonyl)ethyl, 2-(propoxycarbonyl)ethyl, 3-(methoxycarbonyl)propyl, 3-(ethoxycarbonyl)propyl, and 4-(methoxycarbonyl)-butyl.
An alkyl group wherein two or more CH2 groups are replaced by —O— and/or —C(O)O— can be straight-chain or branched. It is preferably straight-chain and has 3 to 12 C atoms. Accordingly it is preferably selected from the group consisting of bis-carboxy-methyl, 2,2-bis-carboxy-ethyl, 3,3-bis-carboxy-propyl, 4,4-bis-carboxy-butyl, 5,5-bis-carboxy-pentyl, 6,6-bis-carboxy-hexyl, 7,7-bis-carboxy-heptyl, 8,8-bis-carboxy-octyl, 9,9-bis-carboxy-nonyl, 10,10-bis-carboxy-decyl, bis-(methoxycarbonyl)-methyl, 2,2-bis-(methoxycarbonyl)-ethyl, 3,3-bis-(methoxycarbonyl)-propyl, 4,4-bis-(methoxycarbonyl)-butyl, 5,5-bis-(methoxycarbonyl)-pentyl, 6,6-bis-(methoxycarbonyl)-hexyl, 7,7-bis-(methoxycarbonyl)-heptyl, 8,8-bis-(methoxycarbonyl)-octyl, bis-(ethoxycarbonyl)-methyl, 2,2-bis-(ethoxycarbonyl)-ethyl, 3,3-bis-(ethoxycarbonyl)-propyl, 4,4-bis-(ethoxycarbonyl)-butyl, and 5,5-bis-(ethoxycarbonyl)-hexyl.
A thioalkyl group, i.e where one CH2 group is replaced by —S—, is preferably straight-chain thiomethyl (—SCH3), 1-thioethyl (—SCH2CH3), 1-thiopropyl (=—SCH2CH2CH3), 1-(thiobutyl), 1-(thiopentyl), 1-(thiohexyl), 1-(thioheptyl), 1-(thiooctyl), 1-(thiononyl), 1-(thiodecyl), 1-(thioundecyl) or 1-(thiododecyl), wherein preferably the CH2 group adjacent to the sp2 hybridised vinyl carbon atom is replaced.
A fluoroalkyl group is preferably perfluoroalkyl CiF2i+1, wherein i is an integer from 1 to 15, in particular CF3, C2F5, C3F7, C4F9, C5F11, C6F13, C7F15 or C8F17, very preferably C6F13, or partially fluorinated alkyl, in particular 1,1-difluoroalkyl, all of which are straight-chain or branched.
Alkyl, alkoxy, alkenyl, oxaalkyl, thioalkyl, carbonyl and carbonyloxy groups can be achiral or chiral groups. Particularly preferred chiral groups are 2-butyl (=1-methylpropyl), 2-methylbutyl, 2-methylpentyl, 3-methylpentyl, 2-ethylhexyl, 2-propylpentyl, in particular 2-methylbutyl, 2-methylbutoxy, 2-methylpentoxy, 3-methylpentoxy, 2-ethyl-hexoxy, 1-methylhexoxy, 2-octyloxy, 2-oxa-3-methylbutyl, 3-oxa-4-methyl-pentyl, 4-methylhexyl, 2-hexyl, 2-octyl, 2-nonyl, 2-decyl, 2-dodecyl, 6-meth-oxyoctoxy, 6-methyloctoxy, 6-methyloctanoyloxy, 5-methylheptyloxy-carbonyl, 2-methylbutyryloxy, 3-methylvaleroyloxy, 4-methylhexanoyloxy, 2-chloropropionyloxy, 2-chloro-3-methylbutyryloxy, 2-chloro-4-methyl-valeryl-oxy, 2-chloro-3-methylvaleryloxy, 2-methyl-3-oxapentyl, 2-methyl-3-oxa-hexyl, 1-methoxypropyl-2-oxy, 1-ethoxypropyl-2-oxy, 1-propoxypropyl-2-oxy, 1-butoxypropyl-2-oxy, 2-fluorooctyloxy, 2-fluorodecyloxy, 1,1,1-trifluoro-2-octyloxy, 1,1,1-trifluoro-2-octyl, 2-fluoromethyloctyloxy for example. Very preferred are 2-hexyl, 2-octyl, 2-octyloxy, 1,1,1-trifluoro-2-hexyl, 1,1,1-trifluoro-2-octyl and 1,1,1-trifluoro-2-octyloxy.
Preferred achiral branched groups are isopropyl, isobutyl (=methylpropyl), isopentyl (=3-methylbutyl), sec-butyl, tert-butyl, isopropoxy, 2-methyl-propoxy, 3-methylbutoxy, duryl and ethylhexyl
In a preferred embodiment, the hydrocarbyl groups are independently of each other selected from primary, secondary or tertiary alkyl or alkoxy with 1 to 30 C atoms, wherein one or more H atoms are optionally replaced by F, or aryl, aryloxy, heteroaryl or heteroaryloxy that is optionally alkylated or alkoxylated and has 4 to 30 ring atoms. Very preferred groups of this type are selected from the group consisting of the following formulae
wherein “ALK” denotes optionally fluorinated alkyl or alkoxy with 1 to 20, preferably 1 to 12 C-atoms, in case of tertiary groups very preferably 1 to 9 C atoms.
Sp is selected from the group consisting of alkanediyl, alkenediyl and alkyndiyl (*—C≡C—*).
Preferably said alkanediyl has at least 1 carbon atom, more preferably at least 2 or 3 carbon atoms, even more preferably at least 4 carbon atoms, still even more preferably at least 5 carbon atoms, and most preferably at least 6 carbon atoms. Preferably said alkenediyl has at least 2 carbon atoms, more preferably at least 3 carbon atoms, even more preferably at least 4 carbon atoms, still even more preferably at least 5 carbon atoms, and most preferably at least 6 carbon atoms.
Preferably said alkyndiyl has at least 3 carbon atoms, more preferably at least 4 carbon atoms, even more preferably at least 5 carbon atoms, and most preferably at least 6 carbon atoms.
Preferably said alkanediyl, alkenediyl or alkyndiyl has at most 20 carbon atoms, more preferably at most 19 or 18 carbon atoms, even more preferably at most 17 or 16 carbon atoms, still even more preferably at most 15 or 14 carbon atoms and most preferably at most 13 or 12 carbon atoms.
Preferably, Sp selected from the group consisting of alkanediyl, alkenediyl and alkyndiyl (*—C≡C—*), wherein at least one, preferably at least two hydrogen has/have been replaced with R16.
R16 may be selected from the group consisting of OH, alkyl having from 1 to 10 (preferably from 1 to 5) carbon atoms, partially or completely halogenated (preferably fluorinated) alkyl having from 1 to 10 (preferably from 1 to 5) carbon atoms, alkoxy having from 1 to 10 (preferably from 1 to 5) carbon atoms, and partially or completely halogenated (preferably fluorinated) alkoxy having from 1 to 10 (preferably from 1 to 5) carbon atoms. Preferably R16 is OH.
Sp may, for example, be represented by the following formula (III)
—[C(R7)(R8)]b— (III)
wherein b, R7 and R8 are as defined herein.
b is at least 1, preferably at least 2, more preferably at least 4, even more preferably at least 5. b is at most 20, preferably at most 19, more preferably at most 18, even more preferably at most 17, still even more preferably at most 16 and most preferably at most 15.
If b is at least two, two neighboring groups C(R7)(R8) may be replaced by an alkenediyl.
If b is at least three, two neighboring groups C(R7)(R8) may be replaced by an alkyndiyl.
R7 and R8 are independently of each other H or R16. Preferably at least one of the R7 and R8 present is R16. More preferably at least two of the R7 and R8 present are R16.
Alternatively Sp may, for example, be represented by the following formulae (III-a)
—[C(R7″)(R8′)]b1—[C(R7″)(R8″)]b2—[C(R7′″)(R8′″)]b3— (III-a)
wherein R7′, R8′, R7″, R8″, R7′″, R8′″, b1, b2 and b3 are as defined herein.
The sum of b1, b2 and b3 is b, i.e. b1+b2+b3=b. Preferably, at least one of b1 or b3 is at least 1 and b2 is 1. More preferably b1, b2 and b3 are all at least 1. Most preferably b1 and b3 are at least 1 and b2 is 1.
If b1 is at least two, two neighboring groups C(R7′)(R8′) may be replaced by an alkenediyl. If b2 is at least two, two neighboring groups C(R7″)(R8″) may be replaced by an alkenediyl. If b3 is at least two, two neighboring groups C(R7″)(R8″) may be replaced by an alkenediyl.
If b1 is at least two, two neighboring groups C(R7′)(R8′) may be replaced by an alkyndiyl. If b2 is at least two, two neighboring groups C(R7″)(R8″) may be replaced by an alkyndiyl. If b3 is at least two, two neighboring groups C(R7′″)(R8′″) may be replaced by an alkyndiyl.
Preferably R7′, R8′, R7′″ and R8′″— if present—are H and at least one of R7″ and R8″ is R16.
Suitable examples of Sp may be selected from the following formulae (III-1) to (III-10)
X1 and X2 are independently of each other selected from the group consisting of O, S and N—R17, with R17 as defined herein.
Preferably X1 is O.
Preferably X2 is O or S.
X3 is O or S.
R17 is at each occurrence independently selected from the group consisting of H, alkyl having from 1 to 20 carbon atoms, partially or completely halogenated alkyl having from 1 to 20 carbon atoms and aryl. Preferably R17 is H.
Preferably, the compound of formula (I) is an olefinic compound, wherein R6 comprises an olefinically unsaturated group. Preferably R6 is a group of formula (IV-A)
wherein X4, c, R20, R21 and R22 are as defined herein.
More preferably said olefinic compound comprises a group of formula (IV-A′)
wherein X1, a, Sp, X4, c, R20, R21 and R22 are as defined herein.
Preferred examples of such olefinic compounds may be represented by any one selected from the group consisting of formulae (I-A′), (I-A″-1), (I-A″-2), (I-A′″-1) and (I-A′″-2)
wherein one of R10, R11, R12, R13 and R14 is a group of formula R6—Sp-[X1]a-* and R6 is a group of formula (IV-A) as defined herein;
wherein one of R10, R11, R12, R13 and R14 is a group of formula R6-Sp-[X1]a-* an R6 is a group of formula (IV-A) as defined herein;
wherein R1, R2, R3, R4, R5, X1, X2, X3, X4, a, c, R20, R21 and R22 are as defined herein.
c is 0 or 1.
R20, R21 and R22 are carbyl. Preferably R20, R21 and R22 are at each occurrence independently of each other selected from the group consisting of H, F, alkyl having from 1 to 20 carbon atoms, partially or completely halogenated alkyl having from 1 to 20 carbon atoms, aryl and heteroaryl. More preferably R20, R21 and R22 are at each occurrence independently of each other selected from the group consisting of H, F, alkyl having from 1 to 20 carbon atoms, partially or completely halogenated alkyl having from 1 to 20 carbon atoms and aryl.
X4 is selected from the group consisting of O, S, C(═O), C(═O)O and N—R17, with R17 as defined herein. Preferably X4 is O.
It is noted that C(═O)O may be inserted in any direction, i.e. C(═O)O with the —O— group adjacent to Sp or OC(═O) with the —O— group adjacent to the olefinically unsaturated group.
The compounds of the present application may be synthesized by methods well known to the skilled person. An exemplary reaction sequence is shown in Scheme 1.
Preferably the compound of the present application is an oligomer or polymer, wherein R6 is the polymer backbone or wherein R6 is part of the polymer backbone. Preferably, such oligomer or polymer comprises a constitutional unit M0 of formula (IV-B), i.e. R6 is a group of formula (IV-B)
wherein X4, c, R20, R21 and R22 are as defined herein. More preferably, such oligomer or polymer comprises a constitutional unit M0 of formula (IV-B′)
Preferably, such oligomer or polymer comprises at least one constitutional unit M1 selected from the group consisting of the following formulae (I-B′), (I-B″-1), (I-B″-2), (I-B′″-1) and (I-B′″-2)
wherein one of R10, R11, R12, R13 and R14 is a group of formula R6—Sp-[X1]a-* and R6 is a group of formula (IV-B) as defined herein;
wherein one of R10, R11, R12, R13 and R14 is a group of formula R6-Sp-[X1]a-* and R6 is a group of formula (IV-B) as defined herein;
said at least one unit M1 being—if there are two or more, at each occurrence the same or different, wherein R1, R2, R3, R4, R5, X1, X2, X3, X4, a, c, R20, R21 and R22 are as defined herein.
The compound of formula (I) may be a copolymer, i.e. an oligomer or polymer comprising one or more constitutional unit M1 of formula (I-B), which may be the same or different from one another, and one or more constitutional units M2, which may the same or different from one another. Said one or more constitutional units M2 are chemically different from the units M1. Preferably, said one or more constitutional units M2 are derived by polymerization of one or more monomers selected from the group consisting of ethylene, propylene, acrylate, methacrylate and styrene.
Preferably the compound of formula (I) may be a homopolymer, i.e. an oligomer or polymer comprising one or more constitutional unit M1 of formula (I-B), wherein all constitutional units M1 are the same.
Exemplary compounds of formula (I) may be selected from the following formulae (M-1) to (M-63):
Exemplary oligomeric and polymeric compounds of formula (I) may be selected from the following formulae (P-1) to (P-63):
For the purposes of the present application the term “derived by polymerization” is used to indicate that a double bond is formally turned into a single bond and two linkages to other atoms, said linkages being indicated by the two asterisks:
Preferably said copolymer comprises the one or more constitutional units M1 in a molar ratio m1 and the one or more constitutional units M2 in a molar ratio m2, wherein the ratio m1:m2 is at least 0.01 and at most 100.
The present oligomers and polymers may be made by any suitable method. It is, however, preferred that the present oligomers and polymers are made by radical polymerization, wherein the polymerization reaction is started by means of a suitable radical polymerization initiator. For the purposes of the present application the type of radical polymerization initiator is not particularly limited and may be any suitable radical generating compound. Such compounds are well known to the skilled person. Suitable polymerization initiators may be selected from thermal initiators or photoinitiators, i.e. compounds that generate radicals by exposure to heat or irradiation with light of a suitable wavelength. Examples of suitable thermal polymerization initiators may be selected from the groups of compounds comprising one or more peroxide groups, i.e. compounds comprising a group —O—O—, and/or compounds comprising one or more azo groups, i.e. compounds comprising a group —N═N—.
Suitable polymerization initiators comprising one or more peroxide groups may, for example, be selected from the groups consisting of t-butyl(peroxy-2-ethyl-hexanoate), di-(tert-butylcyclohexyl)peroxydicarbonate and benzoylperoxide.
Suitable polymerization initiators comprising one or more azo groups may, for example, be selected from the group consisting of 1,1′-azobis(cyclohexancarbonitrile) and 2,2′azobis(cyclohexanecarbonitrile) (AIBN).
A suitable example of a photoinitiator is dimethylaminobenzoate/champherchinone
If a photoinitiator is used as polymerization initiator, it is preferred that the wavelength required to decompose said photoinitiator is different from the wavelength needed to irradiate the compound of the present application so as to change its optical properties.
Preferably, the radical initiators are used in an amount of at least 0.0001 eq and of at most 0.1 eq of the main monomer. Such radical initiators could be thermal initiators, e.g. azobisisobutyronitrile (AIBN) or photochemical initiators like dimethylaminobenzoate/champherchinone.
The present application also provides for a composition comprising the compound of formula (I). Depending upon the intended use such composition may comprise further different components. Such further components may, for example, be selected from the group consisting of UV absorbers, antioxidants and crosslinkers.
The UV absorber that may be used in the present composition is not particularly limited and can easily be selected from those generally known to the skilled person. Generally suitable UV absorbers are characterized by being unsaturated compounds, preferably compounds comprising one or more selected from group consisting of olefinic groups, aryl groups and heteroaryl groups; these groups may be present in any combination.
Suitable UV-absorbers for use in the present composition may, for example, be selected from those comprising a group selected from benzotriazole, benzophenone and triazine. Suitable UV-absorbers are, for example, disclosed in U.S. Pat. Nos. 5,290,892; 5,331,073 and 5,693,095.
Suitable crosslinkers may be used to impart elastomeric properties to the present composition and the articles produced therewith. Typically any suitable di- or tri-functional monomer may be used as crosslinker. Such monomers are generally well known to the skilled person.
The present compound of formula (I) is particularly well suited for use in optically active devices. Hence the present application also provides for optically active devices comprising the compound of formula (I). Preferred optically active devices are ophthalmic devices. Examples of such ophthalmic devices include lenses, keratoprostheses, and cornea inlays or rings. More preferably, said optically active device is a lens. Most preferably, such optically active device is an intraocular lens, which may, for example, be a posterior chamber intraocular lens or an anterior chamber intraocular lens.
The present optically active devices may be formed by a process comprising the steps of
a) providing a composition comprising the compound as defined herein; and
b) subsequently forming the article of said composition.
Intraocular lenses in accordance with the present application are believed to show particularly advantageous properties in that they are flexible enough so as to be rolled or folded and consequently requiring a much smaller incision for them to be inserted into the eye. It is believed that this will allow for improved healing of the eye, particularly in respect to the time for the eye to heal.
The type of intraocular lens is not limited in any way. It may, for example, comprise one or more optic and one or more haptic components, wherein the one or more optic components serve as lens and the one or more haptic components are attached to the one or more optic components and hold the one or more optic components in place in the eye. The present intraocular lens may be of a one-piece design or of multi-piece design, depending on whether the one or more optic components and the one or more haptic components are formed from a single piece of material (one-piece design) or are made separately and then combined (multi-piece design). The present intraocular lens is also designed in such a way that it allows to be, for example, rolled up or folded small enough so that it fits through an incision in the eye, said incision being as small as possible, for example, at most 3 mm in length.
Additionally, intraocular lenses in accordance with the present application allow for the non-invasive adjustment of the optical properties, particularly the refractive power, after implantation of the lens into the eye, thus reducing the need for post-surgery vision aids or reducing or totally avoiding follow-up surgery.
In order to change the optical properties and particularly the refractive power of the intraocular lens it is exposed to irradiation having a wavelength of at least 200 nm and of at most 1500 nm. Hence, the present application also provides for a process of changing the optical properties of an optically active article as defined herein, said process comprising the steps of
a) providing an article as defined herein; and
b) subsequently exposing said article to irradiation having a wavelength of at least 200 nm and at most 1500 nm.
Preferably, said irradiation has a wavelength of at least 250 nm or 300 nm, more preferably of at least 350 nm, even more preferably of at least 400 nm, still even more preferably of at least 450 nm, and most preferably of at least 500 nm. Preferably, said irradiation has a wavelength of at most 1400 nm or 1300 nm or 1200 nm or 1100 nm or 1000 nm, more preferably of at most 950 nm or 900 nm, even more preferably of at most 850 nm, still even more preferably of at most 800 nm and most preferably of at most 750 nm.
The following examples are intended to show the advantages of the present compounds in a non-limiting way.
Unless indicated otherwise, all syntheses were carried out under an inert atmosphere using dried (i.e. water-free) solvents. Solvents and reagents were purchased from Sigma-Aldrich or ABCR.
DCM is used to denote dichloromethane. DMF is used to denote dimethylformamide. EE is used to denote ethyl acetate. THF is used to denote tetrahydrofuran.
2 g (14.2 mmol) 2,4-Dihydroxy-benzaldehyde and 3.1 g (14.2 mmol) 4-bromophenylacetic acid were dissolved in 4.5 ml acetic anhydride and 4.4 ml pyridine. The batch is stirred at 135° C. for 72 h and is then cooled to room temperature. The solid which has precipitated out is filtered off with suction and rinsed neutral with water. The residue is dried at 40° C. in vacuo. The yield is 4.9 g (13.6 mmol) (96% of theory).
1H NMR (500 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.72-7.62 (m, 4H), 7.32 (d, J=2.1 Hz, 1H), 7.20 (dd, J=8.5, 2.2 Hz, 1H), 2.32 (s, 3H).
The following compounds 1a to 1q are prepared analogously:
Selected NMR Data:
Product 1a—1H NMR (500 MHz, Chloroform-d) δ 7.61 (s, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.40 (dd, J=8.3, 1.9 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.82 (m, 2H), 3.83 (s, 3H).
Product 1b—1H NMR (500 MHz, Chloroform-d) δ 7.66 (s, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.26 (dd, J=8.2, 1.9 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 7.03 (dd, J=8.4, 2.2 Hz, 1H), 2.28 (s, 3H).
Product 1c—1H NMR (500 MHz, Chloroform-d) δ 7.79 (d, J=2.1 Hz, 1H), 7.66 (s, 1H), 7.63 (dd, J=8.2, 2.2 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.13 (dd, J=8.5, 2.2 Hz, 1H), 2.39 (s, 3H).
Product 1e—1H NMR (500 MHz, Chloroform-d) δ 7.71 (dd, J=7.9, 1.2 Hz, 1H), 7.55 (t, J=7.7 Hz, 1H), 7.53 (s, 1H), 7.50 (d, J=1.9 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.38 (dd, J=8.2, 1.8 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H).
Product 1g—1H NMR (500 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.78 (t, J=7.5 Hz, 1H), 7.69 (t, J=7.7 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.38 (d, J=1.9 Hz, 1H), 7.23 (dd, J=8.4, 2.1 Hz, 1H), 2.34 (s, 3H).
Product 1h—1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.78 (m, 2H), 7.72 (d, J=7.4 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.01 (dd, J=8.6, 2.4 Hz, 1H), 3.89 (s, 3H).
Product 1i—1H NMR (500 MHz, Chloroform-d) δ 7.67 (d, J=2.2 Hz, 1H), 7.50 (s, 1H), 7.48 (dd, J=8.4, 2.2 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.2 Hz, 1H), 6.91 (s, 1H), 6.89 (d, J=9.5, 2.5 Hz, 1H), 3.84 (s, 3H).
Product 1j—1H NMR (500 MHz, Chloroform-d) δ 7.64 (s, 1H), 7.48 (m, 3H), 7.35 (d, J=8.5 Hz, 2H), 6.91-6.87 (m, 2H), 3.83 (s, 3H).
Product 1k—1H NMR (500 MHz, DMSO-d6) δ 8.23 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.79-7.74 (m, 2H), 7.60 (d, J=8.6 Hz, 1H), 7.38 (d, J=2.1 Hz, 1H), 7.24 (dd, J=8.4, 2.2 Hz, 1H), 2.34 (s, 3H).
Product 1l—1H NMR (500 MHz, DMSO-d6) δ 7.98 (d, J=1.3 Hz, 1H), 7.68 (dd, J=8.6, 1.4 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.22 (dd, J=8.2, 1.4 Hz, 1H), 7.07 (s, 1H), 7.01 (d, J=8.6 Hz, 1H), 3.89 (s, 3H), 2.57-2.46 (m, 2H), 1.09 (t, J=7.5 Hz, 3H).
Product 1m—1H NMR (500 MHz, DMSO-d6) δ 8.13 (m, 2H), 7.88 (d, J=7.8 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 7.04 (dd, J=8.6, 2.4 Hz, 1H), 3.91 (s, 3H).
Product 1n—1H NMR (500 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.58 (d, J=8.5 Hz, 1H), 7.32 (d, J=8.2 Hz, 2H), 7.19 (d, J=2.1 Hz, 1H), 7.12 (dd, J=8.4, 2.2 Hz, 1H), 2.38 (s, 3H).
Product 1o-1H NMR (500 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.53 (dd, J=7.8, 1.7 Hz, 1H), 7.51-7.45 (m, 1H), 7.42-7.38 (m, 2H), 7.20 (d, J=2.2 Hz, 1H), 7.12 (dd, J=8.4, 2.2 Hz, 1H), 2.38 (s, 3H).
Product 1p—1H NMR (500 MHz, Chloroform-d) δ 7.69 (s, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.42 (d, J=2.5 Hz, 1H), 7.26 (dd, J=8.6, 2.6 Hz, 1H), 6.94-6.89 (m, 2H), 3.93 (s, 3H).
Product 1q—1H NMR (500 MHz, Chloroform-d) δ 7.80 (d, J=2.0 Hz, 1H), 7.68 (s, 1H), 7.63 (dd, J=8.2, 2.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.51 (d, J=1.1 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.39 (dd, J=8.0, 1.6 Hz, 1H), 2.52 (s, 3H).
3.0 g (8.4 mmol) of acetic acid 3-(4-bromophenyl)-coumarin-7-yl ester, 1.0 g (8.8 mmol) of n-pentylboronic acid and 3.7 g (17.5 mmol) of tri-potassium phosphate trihydrate are dissolved in 80 ml of toluene and degassed. 171 mg (0.4 mmol) of 2-dicyclohexylphoshino-2′,6′-dimethoxy-1,1′-biphenyl and 47 mg (0.2 mmol) of palladium(II) acetate are added. The reaction mixture is subsequently stirred at 110° C. for 24 h under a protective-gas atmosphere. The cooled solution is diluted with ethyl acetate and washed with water, dried and evaporated. The product is purified by column chromatography on silica gel (heptane/ethyl acetate). Yield: 2.5 g (7.1 mmol), 85% of theory.
1H NMR (500 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.36 (d, J=2.2 Hz, 1H), 7.34 (d, J=8.3 Hz, 2H), 7.24 (dd, J=8.4, 2.2 Hz, 1H), 2.68 (t, J=7.6 Hz, 2H), 2.37 (s, 3H), 1.66 (p, J=7.5 Hz, 2H), 1.42-1.29 (m, 4H), 0.93 (t, J=7.0 Hz, 3H).
The following compounds 2a to 2g are prepared analogously:
Selected NMR Data:
Product 2a—1H NMR (500 MHz, Chloroform-d) δ 7.60 (s, 1H), 7.34 (d, J=9.2 Hz, 1H), 7.25-7.22 (m, 2H), 7.06 (d, J=8.7 Hz, 1H), 6.82-6.77 (m, 2H), 3.83 (s, 3H), 1.61-1.52 (m, 2H), 1.32-1.22 (m, 4H), 0.84 (t, J=6.8 Hz, 3H).
Product 2b—1H NMR (500 MHz, Chloroform-d) δ 7.65 (s, 1H), 7.47 (d, J=9.4 Hz, 1H), 7.39 (d, J=7.8 Hz, 2H), 7.14 (d, J=7.9 Hz, 2H), 6.90-6.84 (m, 2H), 3.82 (s, 3H), 2.56 (t, J=7.7 Hz, 2H), 1.62-1.52 (m, 2H), 1.31-1.24 (m, 4H), 0.83 (t, J=6.7 Hz, 3H).
Product 2c—1H NMR (500 MHz, Chloroform-d) δ 7.55 (s, 1H), 7.50 (d, J=1.7 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.23 (d, J=7.8 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.01 (dd, J=8.4, 2.2 Hz, 1H), 2.66-2.60 (m, 2H), 2.28 (s, 3H), 1.60 (p, J=7.4 Hz, 2H), 1.33-1.24 (m, 4H), 0.92-0.82 (m, 3H).
Product 2d—1H NMR (500 MHz, Chloroform-d) δ 7.60 (s, 1H), 7.57 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.27 (d, J=7.9 Hz, 1H), 7.00 (d, J=2.3 Hz, 1H), 6.98 (dd, J=8.6, 2.4 Hz, 1H), 3.93 (s, 2H), 2.75-2.62 (m, 2H), 1.69 (p, J=7.3 Hz, 2H), 1.39 (dt, J=7.2, 3.7 Hz, 4H), 0.95 (t, J=6.8 Hz, 3H).
Product 2e—1H NMR (500 MHz, Chloroform-d) δ 7.72 (s, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.23-7.15 (m, 2H), 6.98 (d, J=2.4 Hz, 1H), 6.86 (dd, J=8.5, 2.4 Hz, 1H), 6.01 (s, 1H), 2.71-2.66 (m, 2H), 1.67 (m, 2H), 1.38 (m, 4H), 0.94 (t, J=6.9 Hz, 3H).
Product 2f—1H NMR (500 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.69 (s, 1H), 7.63 (d, J=7.9 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.02 (dd, J=8.6, 2.4 Hz, 1H), 3.90 (s, 3H), 2.63 (q, J=7.5 Hz, 2H), 1.12 (t, J=7.5 Hz, 3H).
Product 2g—1H NMR (500 MHz, Chloroform-d) δ 7.60 (s, 1H), 7.59 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.23 (s, 1H), 7.18 (dd, J=8.1, 1.7 Hz, 1H), 3.03 (t, J=7.4 Hz, 2H), 2.74-2.65 (m, 2H), 1.75 (p, J=7.5 Hz, 2H), 1.69 (p, J=7.7, 7.3 Hz, 2H), 1.62-1.54 (m, 2H), 1.49 (p, J=7.2 Hz, 2H), 1.38 (p. J=3.7 Hz, 2H), 1.35-1.27 (m, 18H), 0.94 (t, J=6.8 Hz, 3H).
1.0 g (3.1 mmol) 3-(2,4-dichloro-phenyl)-7-methoxy-coumarin and 1.4 g (3.4 mmol) Lawesson's reagent are added to toluene (17 ml). The reaction vessel is heated to 100° C. for 24 h. The cooled reaction mixture is transferred to a separatory funnel, diluted ethyl acetate and extracted with water. The organic layer is dried over MgSO4, concentrated under reduced pressure and purified by column chromatography. 811 mg (2.4 mmol; 77% of theory) 3-(2,4-dichloro-phenyl)-7-methoxy-chromene-2-thione are isolated.
1H NMR (500 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.52 (dd, J=8.3, 2.1 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 7.12 (dd, J=8.7, 2.4 Hz, 1H), 3.94 (s, 3H).
The following compound 3a is prepared analogously:
161 mg (0.5 mmol) 3-(2,4-dichloro-phenyl)-7-methoxy-coumarin, 132 mg (1.5 mmol) isopropylboronic acid, 414 mg (3 mmol) potassium carbonate and 28.6 mg (0.05 mmol) methanesulfonato(tri-t-butylphosphino)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) are added to a flask. Degassed toluene (1 ml) and water (0.50 ml) are then added via syringe. The reaction vessel is heated to 100° C. for 24 h. The cooled reaction mixture is diluted with ethyl acetate, filtered, concentrated under reduced pressure, and purified by column chromatography. 128 mg (0.4 mmol; 76% of theory) 3-(2,4-Diisopropyl-phenyl)-7-methoxy-chromen-2-one are isolated.
1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.26 (s, 1H), 7.11 (s, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.6, 2.5 Hz, 1H), 3.88 (s, 3H), 2.94 (p, J=6.8 Hz, 1H), 2.81 (p, J=6.8 Hz, 1H), 1.25 (s, 6H), 1.24 (s, 6H).
The following compounds 4a to 4e are prepared analogously:
Selected NMR data:
Product 4b—1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.13 (s, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.06 (dd, J=7.9, 1.9 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.98 (dd, J=8.6, 2.4 Hz, 1H), 3.88 (s, 3H), 2.62-2.55 (m, 2H), 2.49-2.46 (m, 2H), 1.67-1.54 (m, 2H), 1.35-1.26 (m, 4H), 1.07 (t, J=7.5 Hz, 3H), 0.88 (t, J=7.0 Hz, 3H).
Product 4d—1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.16 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.09 (dd, J=7.8, 1.5 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 7.00 (dd, J=8.6, 2.4 Hz, 1H), 3.89 (s, 3H), 2.64 (q, J=7.6 Hz, 2H), 2.50 (q, J=7.2 Hz, 2H), 1.22 (t, J=7.6 Hz, 3H), 1.09 (t, J=7.5 Hz, 3H).
Product 4e—1H NMR (500 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.42 (d, J=1.4 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.28 (dd, J=7.8, 1.6 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 7.01 (dd, J=8.6, 2.4 Hz, 1H), 3.90 (s, 3H), 2.67 (q, J=7.6 Hz, 2H), 2.50 (q, J=7.2 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H), 1.09 (t, J=7.5 Hz, 3H).
1.4 g (4.3 mmol) of 7-Methoxy-3-(4-pentyl-phenyl)-thiocoumarin are dissolved in 50 ml of dichloromethane and cooled to 5° C. 0.4 ml (4.3 mmol) of boron tribromide are added dropwise to this solution over the course of 10 min, and stirring is continued overnight. Water is subsequently slowly added to the mixture, and the organic phase is diluted with ethyl acetate, washed three times with water, dried over MgSO4, evaporated in a rotary evaporator and purified by recrystallization from ethanol. Yield: 1.3 g (4 mmol), 94% of theory.
1H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.05 (s, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.25 (d, J=8.2 Hz, 2H), 6.97 (d, J=2.3 Hz, 1H), 6.93 (dd, J=8.6, 2.4 Hz, 1H), 2.61 (t, J=7.6 Hz, 2H), 1.61 (p, J=7.5 Hz, 2H), 1.39-1.26 (m, 4H), 0.88 (t, J=7.0 Hz, 3H).
The following compounds 5a to 5g are prepared analogously:
Selected NMR data:
Product 5a—1H NMR (S00 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.62 (s, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.01 (d, J=2.1 Hz, 1H), 6.94 (dd, J=8.6, 2.3 Hz, 1H), 2.74-2.68 (m, 2H), 1.63 (p, J=7.5 Hz, 2H), 1.40-1.24 (m, 4H), 0.89 (t, J=6.9 Hz, 3H).
Product 5c—1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.33 (d, J=8.3 Hz, 1H), 7.26 (s, 1H), 7.11 (s, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.6, 2.5 Hz, 1H), 2.94 (p, J=6.8 Hz, 1H), 2.81 (p, J=6.8 Hz, 1H), 1.25 (s, 6H), 1.24 (s, 6H).
Product 5d—1H NMR (500 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.13 (d, J=1.7 Hz, 1H), 7.11 (d, J=7.7 Hz, 1H), 7.06 (dd, J=7.8, 1.4 Hz, 1H), 6.82 (dd, J=8.4, 2.2 Hz, 1H), 6.77 (d, J=2.1 Hz, 1H), 2.63-2.55 (m, 2H), 2.50-2.45 (m, 2H), 1.60 (q, J=7.5 Hz, 2H), 1.38-1.28 (m, 4H), 1.08 (t, J=7.5 Hz, 3H), 0.89 (t, J=7.0 Hz, 3H).
Product 5e—1H NMR (500 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.86 (s, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.15 (s, 1H), 7.12 (d, J=7.7 Hz, 1H), 7.08 (dd, J=7.7, 1.8 Hz, 1H), 6.82 (dd, J=8.5, 2.3 Hz, 1H), 6.77 (d, J=2.3 Hz, 1H), 2.64 (q, J=7.6 Hz, 2H), 2.56-2.42 (m, 2H), 1.22 (t, J=7.6 Hz, 3H), 1.08 (t, J=7.5 Hz, 3H).
2.5 g (7.1 mmol) acetic acid 3-(4-pentyl-phenyl)-coumarin-7-yl ester are suspended in a mixture of 14 ml ethanol and 10 ml sulfuric acid (20%, aq.) and refluxed for 2 h. The batch is then cooled to room temperature, and the solid which has precipitated out is filtered off with suction and rinsed neutral with water. The yield is 2.2 g (7.1 mmol), 99% of theory.
1H NMR (500 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.12 (s, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.6 Hz, 1H), 7.25 (d, J=8.1 Hz, 2H), 6.83 (dd, J=8.5, 2.2 Hz, 1H), 6.76 (d, J=2.1 Hz, 1H), 2.61 (t, J=7.6 Hz, 2H), 1.60 (p, J=7.5 Hz, 2H), 1.37-1.36 (m, 4H), 0.88 (t, J=7.0 Hz, 3H).
The following compounds 6a to 6h were prepared analogously:
Selected NMR Data:
Product 6a—1H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 7.92 (s, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.75 (t, J=7.5 Hz, 1H), 7.66 (t, J=7.7 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 6.84 (dd, J=8.5, 2.3 Hz, 1H), 6.80 (d, J=2.2 Hz, 1H).
Product 6b—1H NMR (500 MHz, DMSO-d6) δ 10.64 (s, 1H), 7.86 (s, 1H), 7.80-7.75 (m, 2H), 7.70 (t, J=7.4 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.52 (d, J=7.3 Hz, 1H), 6.84 (dd, J=8.5, 2.3 Hz, 1H), 6.79 (d, J=2.2 Hz, 1H).
Product 6c—1H NMR (500 MHz, DMSO-d6) δ 10.63 (s, 1H), 7.89 (s, 1H), 7.63 (s, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 6.83 (dd, J=8.5, 2.2 Hz, 1H), 6.79 (d, J=2.2 Hz, 1H), 2.76-2.69 (m, 2H), 1.64 (p, J=7.5 Hz, 2H), 1.40-1.26 (m, 4H), 0.89 (t, J=6.9 Hz, 3H).
Product 6d—1H NMR (500 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.08 (s, 1H), 7.65 (d, J=8.9 Hz, 2H), 7.59 (d, J=8.5 Hz, 1H), 6.99 (d, J=8.9 Hz, 2H), 6.82 (dd, J=8.5, 2.3 Hz, 1H), 6.75 (d, J=2.2 Hz, 1H), 4.02 (t, J=6.5 Hz, 2H), 1.78-1.66 (m, 2H), 1.51-1.41 (m, 2H), 0.95 (t, J=7.4 Hz, 2H).
Product 6f—1H NMR (500 MHz, Chloroform-d) δ 7.77 (d, J=2.0 Hz, 1H), 7.61 (dd, J=8.4, 2.2 Hz, 1H), 7.60 (s, 1H), 7.40-7.36 (m, 2H), 7.28 (d, J=1.4 Hz, 1H), 7.18 (dd, J=8.1, 1.7 Hz, 1H), 3.80 (s, 1H).
Product 6g—1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.23 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.5 Hz, 1H), 7.45 (d, J=8.2 Hz, 2H), 6.85 (dd, J=8.5, 2.3 Hz, 1H), 6.78 (d, J=2.2 Hz, 1H).
Product 6h—1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.04 (s, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.57 (td, J=7.4, 1.7 Hz, 1H), 7.49 (dd, J=7.2, 1.3 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 6.85 (dd, J=8.5, 2.3 Hz, 1H), 6.80 (d, J=2.1 Hz, 1H).
2.37 g (7.7 mmol) 7-hydroxy-3-(4-pentyl-phenyl)-coumarin and 2.0 g (8.0 mmol) 11-bromo-1-undecanol are dissolved in 23 ml acetone and 4.3 g (30.7 mmol) potassium carbonate are added. The suspension is refluxed for 2 d. The hot reaction mixture is filtered, washed with hot acetone (2×). The filtrate is evaporated under reduced pressure. The remaining solid is purified by column chromatography (SiO2, heptane/ethyl acetate). 7-(11-Hydroxy-undecyloxy)-3-(4-pentyl-phenyl)-coumarin is isolated. The yield is 2.8 g (5.9 mmol) (76% of theory).
1H NMR (500 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.3 Hz, 2H), 7.01 (d, J=2.3 Hz, 1H), 6.97 (dd, J=8.6, 2.4 Hz, 1H), 4.29 (t, J=4.4 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H), 3.38 (q, J=6.4 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H), 1.75 (p, J=6.6 Hz, 2H), 1.61 (p, J=7.5 Hz, 2H), 1.48-1.37 (m, 4H), 1.37-1.21 (m, 16H), 0.88 (t, J=7.0 Hz, 3H).
The following compounds 7a to 7w are prepared analogously:
Selected NMR data:
Product 7a—1H NMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.86 (d, J=8.9 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.27-7.23 (m, 3H), 7.08 (dd, J=8.7, 2.5 Hz, 1H), 4.29 (t, J=5.2 Hz, 1H), 4.10 (t, J=6.5 Hz, 2H), 3.42-3.34 (m, 2H), 2.62 (t, J=7.6 Hz, 2H), 1.75 (p, J=6.6 Hz, 2H), 1.61 (p, J=7.5 Hz, 2H), 1.42 (h, J=6.9 Hz, 4H), 1.37-1.20 (m, 16H), 0.88 (t, J=7.0 Hz, 3H).
Product 7f—1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.14 (s, 1H), 7.13 (d, J=7.8 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 6.97 (dd, J=8.6, 2.4 Hz, 1H), 4.29 (t, J=5.1 Hz, 1H), 4.10 (t, J=6.5 Hz, 2H), 3.38 (q, J=6.5 Hz, 2H), 2.63-2.57 (m, 2H), 2.53-2.42 (m, 2H), 1.75 (p, J=6.6 Hz, 2H), 1.61 (p, J=7.4 Hz, 2H), 1.47-1.38 (m, 4H), 1.37-1.32 (m, 4H), 1.26 (s, 14H), 1.08 (t, J=7.5 Hz, 3H), 0.89 (t, J=6.9 Hz, 3H).
Product 7g—1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.16 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.09 (dd, J=7.8, 1.5 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 6.98 (dd, J=8.6, 2.4 Hz, 1H), 4.29 (t, J=5.2 Hz, 1H), 4.10 (t, J=6.5 Hz, 2H), 3.41-3.34 (m, 2H), 2.64 (q, J=7.6 Hz, 2H), 2.54-2.45 (m, 2H), 1.78-1.72 (m, 2H), 1.47-1.37 (m, 4H), 1.37-1.25 (m, 14H), 1.22 (t, J=7.6 Hz, 3H), 1.08 (t, J=7.5 Hz, 3H).
Product 7h—1H NMR (500 MHz, Chloroform-d) δ 7.68 (d, J=7.9 Hz, 1H), 7.54-7.48 (m, 2H), 7.43 (t, J=7.7 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.31 (d, J=9.0 Hz, 1H), 6.81-6.76 (m, 2H), 3.96 (t, J=6.5 Hz, 2H), 3.59-3.51 (m, 2H), 1.79-1.70 (m, 2H), 1.49 (p, J=6.7 Hz, 2H), 1.40 (p, J=7.1 Hz, 2H), 1.33-1.19 (m, 12H).
Product 7i—1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.80-7.75 (m, 2H), 7.72 (d, J=7.4 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.99 (dd, J=8.6, 2.4 Hz, 1H), 4.29 (t, J=5.2 Hz, 1H), 4.11 (t, J=6.5 Hz, 2H), 3.38 (q, J=6.5 Hz, 2H), 1.76 (p, J=6.6 Hz, 2H), 1.42 (dp, J=13.2, 6.9 Hz, 4H), 1.37-1.22 (m, 14H).
Product 7j—1H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.64 (s, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.98 (dd, J=8.6, 2.3 Hz, 1H), 4.29 (t, J=5.1 Hz, 1H), 4.10 (t, J=6.5 Hz, 2H), 3.38 (q, J=6.5 Hz, 2H), 2.75-2.67 (m, 2H), 1.75 (p, J=6.7 Hz, 2H), 1.64 (p, J=7.4 Hz, 2H), 1.46-1.39 (m, 4H), 1.37-1.23 (m, 18H), 0.89 (t, J=6.9 Hz, 3H).
Product 7k—1H NMR (500 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 6.98 (d, J=2.3 Hz, 1H), 6.91 (dd, J=8.6, 2.4 Hz, 1H), 4.22 (s, 1H), 4.03 (t, J=6.5 Hz, 2H), 3.31 (t, J=6.5 Hz, 2H), 2.68-2.60 (m, 2H), 1.68 (p, J=6.6 Hz, 2H), 1.56 (p, J=7.5 Hz, 2H), 1.42-1.32 (m, 4H), 1.32-1.18 (m, 10H), 0.82 (t, J=7.0 Hz, 3H).
Product 7n—1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.68-7.65 (m, 3H), 7.02-6.99 (m, 3H), 6.97 (dd, J=8.6, 2.4 Hz, 1H), 4.29 (s, 1H), 4.09 (t, J=6.5 Hz, 2H), 4.03 (t, J=6.5 Hz, 2H), 3.38 (t, J=6.6 Hz, 2H), 1.79-1.69 (m, 4H), 1.53-1.37 (m, 6H), 1.36-1.22 (m, 14H), 0.96 (t, J=7.4 Hz, 3H).
Product 7q—1H NMR (500 MHz, Chloroform-d) δ 7.78 (d, J=1.9 Hz, 1H), 7.62 (dd, J=8.0, 1.8 Hz, 1H), 7.61 (s, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.23 (s, 1H), 7.19 (dd, J=8.2, 1.5 Hz, 1H), 3.67 (q, J=6.4 Hz, 2H), 3.03 (t, J=7.4 Hz, 2H), 1.76 (p, J=7.5 Hz, 2H), 1.60 (p, J=7.2 Hz, 2H), 1.49 (p, J=7.2 Hz, 2H), 1.38-1.27 (m, 14H).
Product 7r—1H NMR (500 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.46 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 6.90 (dd, J=8.6, 2.3 Hz, 1H), 6.87 (d, J=2.1 Hz, 1H), 4.06 (t, J=6.5 Hz, 2H), 3.67 (t, J=6.6 Hz, 2H), 1.85 (p, J=6.7 Hz, 2H), 1.59 (p, J=6.7 Hz, 2H), 1.50 (p, J=7.1 Hz, 2H), 1.44-1.21 (m, 14H).
Product 7s—1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.81 (d, J=8.9 Hz, 1H), 7.65-7.61 (m, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 7.09 (dd, J=8.7, 2.5 Hz, 1H), 4.31 (t, J=5.2 Hz, 1H), 4.11 (t, J=6.5 Hz, 2H), 3.40-3.35 (m, 2H), 2.77-2.68 (m, 2H), 1.75 (p, J=6.6 Hz, 2H), 1.63 (p, J=7.5 Hz, 2H), 1.45-1.38 (m, 4H), 1.37-1.31 (m, 4H), 1.30-1.23 (m, 14H), 0.89 (t, J=7.0 Hz, 3H).
Product 7u—1H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.64 (d, J=1.2 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H), 6.98 (dd, J=8.6, 2.4 Hz, 1H), 4.29 (t, J=5.2 Hz, 2H), 4.10 (t, J=6.5 Hz, 2H), 3.42-3.35 (m, 2H), 2.75-2.67 (m, 2H), 1.75 (p, J=6.6 Hz, 2H), 1.64 (p, J=7.5 Hz, 2H), 1.45-1.23 (m, 24H), 0.89 (t, J=7.0 Hz, 3H).
Product 7v—1H NMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.62-7.55 (m, 2H), 7.53-7.45 (m, 2H), 7.06 (d, J=2.3 Hz, 1H), 7.00 (dd, J=8.6, 2.4 Hz, 1H), 4.11 (t, J=6.5 Hz, 2H), 3.38 (t, J=6.6 Hz, 2H), 1.81-1.70 (m, 4H), 1.51-1.37 (m, 4H), 1.37-1.22 (m, 12H).
Product 7w—1H NMR (500 MHz, Chloroform-d) δ 7.70 (s, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.22-7.16 (m, 2H), 6.92-6.87 (m, 2H), 4.06 (t, J=6.5 Hz, 2H), 3.67 (td, J=6.4, 3.8 Hz, 2H), 2.71-2.65 (m, 2H), 1.85 (p, J=6.6 Hz, 2H), 1.67 (p, J=7.5 Hz, 2H), 1.50 (p, J=7.0 Hz, 2H), 1.44-1.28 (m, 20H), 0.94 (t, J=6.9 Hz, 3H).
To an ice-cooled solution of 2.8 g (8.1 mmol) 7-Hydroxy-3-(4-pentyl-phenyl)-coumarin, 1.0 g (4E)-Octa-4,7-dien-1-ol (8.1 mmol), 2.4 g (11.6 mmol) triphenylphosphine in THF (18 ml), 2.32 ml (11.6 mmol) diisopropyl azodicarboxylate is added dropwise. After stirring at room temperature overnight, the reaction mixture was evaporated. The crude product is purified by column chromatography to give 2.25 g of 7-[((E)-Octa-4,7-dienyl)oxy]-3-(4-pentyl-phenyl)-coumarin (6.50 mmol, 67% of theory) as a white solid. For further purification, the product was recrystallized in EtOH.
1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.72 (d, J=7.2 Hz, 2H), 7.70 (d, J=8.6 Hz, 1H), 7.46 (t, J=7.4 Hz, 2H), 7.02 (d, J=2.3 Hz, 1H), 6.99 (dd, J=8.6, 2.4 Hz, 1H), 5.82 (ddt, J=16.7, 10.1, 6.4 Hz, 1H), 5.59-5.36 (m, 2H), 5.02 (dq, J=17.2, 1.7 Hz, 1H), 4.98 (dq, J=10.1, 1.3 Hz, 1H), 4.10 (t, J=6.4 Hz, 2H), 2.75 (t, J=5.7 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H) 2.17 (q, J=6.4, 5.9 Hz, 2H), 1.83 (p, J=6.5 Hz, 2H), 1.60 (p, J=7.5 Hz, 2H), 1.31-1.24 (m, 4H), 0.83 (t, J=6.7 Hz, 3H).
A Schlenk flask is charged with THF (0.5 ml) and 100 mg (0.24 mmol) 7-[((E)-octa-4,7-dienyl)oxy]-3-(4-pentyl-phenyl)-coumarin. The solution is cooled to 0° C. After 10 min, 0.48 ml (0.24 mmol) 9-BBN (0.5 M in THF) is added dropwise via syringe over 30 min. The reaction is stirred for 1 h at 0° C., then 1 h at 25° C. 0.34 ml (0.69 mmol) NaOH (aq, 2M) is added and the reaction cooled to 0° C. 0.20 ml (1.97 mmol) H2O2 (30% in water) is added dropwise over 10 min. The reaction is diluted with Et2O, filtered through Celite. The organic filtrate is concentrated to give 53 mg (0.15 mmol) crude 7-((E)-8-hydroxy-oct-4-enyloxy)-3-(4-pentyl-phenyl)-coumarin (50% of theory).
1H NMR (500 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.72 (d, J=7.4 Hz, 2H), 7.70 (d, J=8.7 Hz, 1H), 7.46 (t, J=7.5 Hz, 2H), 7.02 (d, J=2.2 Hz, 1H), 6.99 (dd, J=8.6, 2.3 Hz, 1H), 5.47 (dd, J=4.5, 2.9 Hz, 2H), 4.33 (t, J=5.2 Hz, 1H), 4.10 (t, J=6.4 Hz, 2H), 3.46-3.35 (m, 2H), 2.61 (t, J=7.6 Hz, 2H), 2.18-2.11 (m, 2H), 2.06-1.96 (m, 2H), 1.87-1.76 (m, 2H), 1.68 (p, J=6.8 Hz, 2H), 1.55-1.41 (m, 2H), 1.31-1.24 (m, 4H), 0.83 (t, J=6.7 Hz, 3H).
12 g (46 mmol) 11-Bromo-undecan-1-ol and 4.6 ml (51 mmol) 3,4-Dihydropyran in 45 ml THF are treated with 400 mg (2.32 mmol) p-toluenesulfonic acid and stirred overnight. The reaction mixture was filtered and washed with THF. The solvent was evaporated. The residual oil (9.6 g; 28.7 mmol), 547 mg (2.87 mmol), 1.1 mg (4.3 mmol) triphenylphosphine and 10.94 g (43.08 mmol) bis-(pinacolato)-diboron were added to a Schlenk tube equipped with a stir bar. The vessel was evacuated and filled with argon (three cycles). DMF (55.8 ml) was added under argon atmosphere. The resulting reaction mixture was stirred vigorously at 25° C. for 18 h. The reaction mixture was then diluted with EtOAc, filtered through silica gel with copious washings (EtOAc), concentrated, and purified by column chromatography. 2-[11-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-undecyloxy]-tetrahydro-pyran (7.66 g; 16.00 mmol) was received as oil, 55.7% of theory.
1H NMR (500 MHz, DMSO-d6) δ 4.53 (dd, J=4.4, 2.8 Hz, 2H), 3.73 (ddd, J=11.2, 8.1, 3.1 Hz, 2H), 3.60 (dt, J=9.7, 6.7 Hz, 2H), 3.46-3.37 (m, 2H), 3.35-3.30 (m, 2H), 1.77-1.67 (m, 2H), 1.64-1.57 (m, 2H), 1.54-1.41 (m, 9H), 1.36-1.22 (m, 8H), 1.18 (s, 12H).
155 mg (0.4 mmol) 7-Bromo-3-(2-trifluoromethyl-phenyl)-coumarin, 167 mg (0.4 mmol) 2-[11-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-undecyloxy]-tetrahydropyran, 120 mg (1.3 mmol) sodium tert-butylate and 12 mg (0.02 mmol) bis(dibenzylideneacetone)palladium(0) are added to a flask equipped with a stirbar. Degassed toluene (2.9 ml) is then added. The reaction vessel is heated to 100° C. for 24 h. The cooled reaction mixture is filtered and washed thoroughly with diluted HCl. The organic phase is concentrated under reduced pressure, and purified by column chromatography. 63 mg (0.1 mmol; 32% of theory) 3-(2-trifluoromethyl-phenyl)-7-(11-hydroxy-undecyl)-coumarin are isolated.
Acryloyl chloride (0.3 ml; 3.5 mmol) is slowly added to an ice-cooled solution of 1.4 g (2.9 mmol) 7-(11-hydroxy-undecyloxy)-3-(4-pentyl-phenyl)-coumarin in dry 10 ml THF and 1.6 ml (11.7 mmol) triethylamine. Afterwards, the reaction is stirred for 2 h at room temperature. The solid which has precipitated out is filtered off with suction and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography. 1.1 g (2.1 mmol; 71% of theory) Acrylic acid 11-[2-oxo-3-(4-pentyl-phenyl)-coumarin-7-yloxy]-undecyl ester are isolated.
1H NMR (500 MHz, Chloroform-d) δ 7.64 (s, 1H), 7.52 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.3 Hz, 2H), 6.78-6.75 (m, 1H), 6.74 (d, J=2.2 Hz, 1H), 6.31 (dd, J=17.4, 1.5 Hz, 1H), 6.04 (dd, J=17.3, 10.4 Hz, 1H), 5.72 (dd, J=10.3, 1.5 Hz, 1H), 4.07 (t, J=6.8 Hz, 2H), 3.93 (t, J=6.5 Hz, 2H), 2.58-2.43 (m, 2H), 1.73 (dt, J=14.5, 6.6 Hz, 2H), 1.58 (dq, J=15.4, 8.1, 7.4 Hz, 4H), 1.39 (p, J=7.0 Hz, 2H), 1.30-1.21 (m, 16H), 0.82 (t, J=6.9 Hz, 3H).
The following compounds 12a to 12z are prepared analogously:
Selected NMR Data
Product 12a—1H NMR (500 MHz, Chloroform-d) δ 7.66 (s, 1H), 7.54 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.3 Hz, 1H), 7.17 (d, J=8.2 Hz, 2H), 6.79 (d, J=8.2, 2.4 Hz, 1H), 6.77 (s, 1H), 6.02 (s, 1H), 5.47 (s, 1H), 4.07 (t, J=6.7 Hz, 2H), 3.95 (t, J=6.5 Hz, 2H), 2.60-2.51 (m, 2H), 1.87 (s, 3H), 1.75 (dt, J=14.5, 6.6 Hz, 2H), 1.59 (dp, J=15.7, 7.1 Hz, 4H), 1.40 (p, J=7.0 Hz, 2H), 1.34-1.18 (m, 16H), 0.85-0.82 (m, 3H).
Product 12b—1H NMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H), 7.25 (d, J=2.5 Hz, 1H), 7.08 (dd, J=8.7, 2.5 Hz, 1H), 6.32 (dd, J=17.3, 1.6 Hz, 1H), 6.17 (dd, J=17.3, 10.3 Hz, 1H), 5.93 (dd, J=10.3, 1.6 Hz, 1H), 4.10 (t, J=6.6 Hz, 4H), 2.62 (t, J=7.6 Hz, 2H), 1.75 (p, J=6.6 Hz, 2H), 1.61 (p, J=7.7, 7.0 Hz, 4H), 1.43 (p, J=6.8 Hz, 2H), 1.36-1.24 (m, 16H), 0.88 (t, J=7.0 Hz, 3H).
Product 12g—1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.14 (s, 1H), 7.12 (d, J=7.8 Hz, 1H), 7.07 (dd, J=7.8, 1.4 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 6.97 (dd, J=8.6, 2.4 Hz, 1H), 6.32 (dd, J=17.3, 1.5 Hz, 1H), 6.17 (dd, J=17.3, 10.3 Hz, 1H), 5.93 (dd, J=10.3, 1.5 Hz, 1H), 4.10 (t, J=6.6 Hz, 4H), 2.64-2.57 (m, 2H), 2.52-2.45 (m, 2H), 1.75 (p, J=6.7 Hz, 2H), 1.60 (q, J=6.3 Hz, 4H), 1.43 (p, J=6.7 Hz, 2H), 1.37-1.26 (m, 20H), 1.08 (t, J=7.5 Hz, 3H), 0.89 (t, J=6.9 Hz, 3H).
Product 12h—1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.64 (d, J=8.7 Hz, 1H), 7.16 (s, 1H), 7.13 (d, J=7.7 Hz, 1H), 7.09 (dd, J=7.8, 1.5 Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 6.98 (dd, J=8.6, 2.4 Hz, 1H), 6.32 (dd, J=17.3, 1.6 Hz, 1H), 6.17 (dd, J=17.3, 10.3 Hz, 1H), 5.93 (dd, J=10.3, 1.6 Hz, 1H), 4.10 (t, J=6.6 Hz, 4H), 2.64 (q, J=7.6 Hz, 2H), 2.51-2.47 (m, 2H), 1.75 (p, J=6.7 Hz, 2H), 1.61 (p, J=6.7 Hz, 2H), 1.43 (p, J=7.0 Hz, 2H), 1.36-1.25 (m, 14H), 1.22 (t, J=7.6 Hz, 3H), 1.08 (t, J=7.5 Hz, 3H).
Product 12i—1H NMR (500 MHz, Chloroform-d) δ 7.69 (d, J=7.9 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.50 (s, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.32 (d, J=9.3 Hz, 1H), 6.80-6.78 (m, 2H), 6.32 (dd, J=17.4, 1.5 Hz, 1H), 6.05 (dd, J=17.3, 10.4 Hz, 1H), 5.74 (dd, J=10.4, 1.5 Hz, 1H), 4.08 (t, J=6.8 Hz, 2H), 3.97 (t, J=6.5 Hz, 2H), 1.80-1.72 (m, 2H), 1.67-1.55 (m, 2H), 1.41 (p, J=7.1 Hz, 2H), 1.34-1.21 (m, 12H).
Product 12j—1H NMR (500 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.82-7.74 (m, 2H), 7.71 (t, J=7.7 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.54 (d, J=7.4 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 6.99 (dd, J=8.6, 2.4 Hz, 1H), 6.32 (dd, J=17.3, 1.6 Hz, 1H), 6.17 (dd, J=17.3, 10.3 Hz, 1H), 5.93 (dd, J=10.3, 1.6 Hz, 1H), 4.10 (td, J=6.5, 3.3 Hz, 4H), 1.75 (p, J=6.6 Hz, 2H), 1.61 (p, J=6.7 Hz, 2H), 1.43 (p, J=7.8, 7.1 Hz, 2H), 1.37-1.23 (m, 14H).
Product 12k—1H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.64 (s, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 6.98 (dd, J=8.6, 2.4 Hz, 1H), 6.31 (dd, J=17.3, 1.6 Hz, 1H), 6.16 (dd, J=17.3, 10.3 Hz, 1H), 5.92 (dd, J=10.3, 1.6 Hz, 1H), 4.10 (t, J=6.7 Hz, 4H), 2.76-2.68 (m, 2H), 1.75 (p, J=6.6 Hz, 2H), 1.68-1.56 (m, 4H), 1.43 (p, J=6.9 Hz, 2H), 1.38-1.22 (m, 20H), 0.89 (t, J=7.0 Hz, 3H).
Product 12m—1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.66 (m, 3H), 7.04-6.93 (m, 4H), 6.01 (s, 1H), 5.66 (s, 1H), 4.09 (t, J=6.6 Hz, 4H), 4.02 (t, J=6.5 Hz, 2H), 1.88 (s, 3H), 1.73 (q, J=8.1, 7.6 Hz, 4H), 1.64-1.58 (m, 2H), 1.50-1.40 (m, 4H), 1.29 (d, J=11.6 Hz, 12H), 0.96 (t, J=7.4 Hz, 3H).
Product 12n—1H NMR (500 MHz, Chloroform-d) δ 7.62 (s, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.32 (d, J=8.3 Hz, 1H), 6.87 (d, J=8.7 Hz, 2H), 6.80-6.72 (m, 2H), 6.32 (dd, J=17.4, 1.6 Hz, 1H), 6.05 (dd, J=17.3, 10.4 Hz, 1H), 5.73 (dd, J=10.4, 1.6 Hz, 1H), 4.08 (t, J=6.7 Hz, 2H), 3.94 (q, J=6.5 Hz, 4H), 1.73 (tt, J=14.7, 6.6 Hz, 4H), 1.59 (p, J=6.8 Hz, 2H), 1.48-1.35 (m, 4H), 1.34-1.17 (m, 14H), 0.91 (t, J=7.4 Hz, 3H).
Product 12s—1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.14 (s, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.07 (dd, J=7.7, 1.1 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 6.99 (dd, J=8.6, 2.4 Hz, 1H), 6.33 (dd, J=17.3, 1.5 Hz, 1H), 6.18 (dd, J=17.3, 10.3 Hz, 1H), 5.94 (dd, J=10.3, 1.5 Hz, 1H), 4.12 (t, J=6.6 Hz, 2H), 3.89 (s, 3H), 2.61 (t, J=7.7 Hz, 2H), 2.51-2.47 (m, 2H), 1.66-1.58 (m, 4H), 1.40-1.36 (m, 4H), 1.08 (t, J=7.5 Hz, 3H).
Product 12t—1H NMR (500 MHz, Chloroform-d) δ 7.59 (s, 1H), 7.58 (s, 1H), 7.44 (d, J=7.5 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.24 (d, J=1.4 Hz, 1H), 7.18 (dd, J=8.2, 1.7 Hz, 1H), 6.42 (dd, J=17.4, 1.5 Hz, 1H), 6.14 (dd, J=17.3, 10.4 Hz, 1H), 5.83 (dd, J=10.4, 1.4 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 3.03 (t, J=7.4 Hz, 2H), 2.79-2.64 (m, 2H), 1.76 (p, J=7.6 Hz, 2H), 1.69 (p, J=6.9 Hz, 4H), 1.49 (p, J=7.3 Hz, 2H), 1.39 (p, J=3.6 Hz, 4H), 1.33-1.28 (m, 14H), 0.97-0.92 (m, 3H).
Product 12u—1H NMR (500 MHz, Chloroform-d) δ 7.79 (s, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.2 Hz, 2H), 6.90 (dd, J=8.5, 2.4 Hz, 1H), 6.87 (d, J=2.2 Hz, 1H), 6.42 (dd, J=17.3, 1.4 Hz, 1H), 6.15 (dd, J=17.3, 10.4 Hz, 1H), 5.83 (dd, J=10.4, 1.4 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 4.06 (t, J=6.5 Hz, 2H), 1.70 (p, J=6.8 Hz, 2H), 1.50 (p, J=7.0 Hz, 2H), 1.43-1.28 (m, 16H).
Product 12v—1H NMR (500 MHz, Chloroform-d) δ 7.59 (s, 1H), 7.57 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 6.98 (d, J=2.3 Hz, 1H), 6.96 (dd, J=8.6, 2.4 Hz, 1H), 6.42 (dd, J=17.3, 1.4 Hz, 1H), 6.15 (dd, J=17.3, 10.4 Hz, 1H), 5.84 (dd, J=10.4, 1.4 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 4.06 (t, J=6.5 Hz, 2H), 2.74-2.66 (m, 2H), 1.85 (dt, J=14.4, 6.6 Hz, 2H), 1.69 (dq, J=10.2, 5.1, 3.6 Hz, 2H), 1.50 (p, J=7.0 Hz, 2H), 1.44-1.29 (m, 20H), 0.94 (t, J=6.9 Hz, 3H).
Product 12w—1H NMR (500 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.64 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H), 6.98 (dd, J=8.6, 2.4 Hz, 1H), 6.31 (dd, J=17.3, 1.6 Hz, 1H), 6.17 (dd, J=17.3, 10.3 Hz, 1H), 5.93 (dd, J=10.3, 1.6 Hz, 1H), 4.15-4.04 (m, 2H), 2.75-2.69 (m, 2H), 1.75 (p, J=6.6 Hz, 2H), 1.68-1.57 (m, 4H), 1.43 (p, J=6.9 Hz, 2H), 1.38-1.23 (m, 22H), 0.89 (t, J=7.0 Hz, 3H).
Product 12x—1H NMR (500 MHz, Chloroform-d) δ 7.61-7.57 (m, 2H), 7.43 (d, J=8.1 Hz, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 6.88 (d, J=6.7 Hz, 2H), 6.42 (dd, J=17.3, 1.3 Hz, 1H), 6.15 (dd, J=17.4, 10.4 Hz, 1H), 5.83 (dd, J=10.4, 1.3 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 4.06 (t, J=6.5 Hz, 2H), 2.75-2.67 (m, 2H), 1.85 (p, J=6.6 Hz, 2H), 1.69 (p, J=6.8 Hz, 4H), 1.50 (p, J=7.3 Hz, 2H), 1.44-1.25 (m, 22H), 0.94 (t, J=6.8 Hz, 3H).
Product 12y—1H NMR (500 MHz, Chloroform-d) δ 7.69 (s, 1H), 7.51 (dd, J=7.8, 1.8 Hz, 1H), 7.45-7.42 (m, 1H), 7.41 (d, J=8.3 Hz, 1H), 7.38-7.34 (m, 2H), 6.90-6.85 (m, 2H), 6.09 (s, 1H), 5.56-5.51 (m, 1H), 4.14 (t, J=6.7 Hz, 2H), 4.04 (t, J=6.5 Hz, 2H), 1.94 (t, J=1.2 Hz, 3H), 1.88-1.79 (m, 2H), 1.73-1.62 (m, 2H), 1.51-1.44 (m, 2H), 1.41-1.27 (m, 14H).
Product 12z—1H NMR (500 MHz, Chloroform-d) δ 7.70 (s, 1H), 7.43 (d, J=7.7 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.21-7.16 (m, 2H), 6.93-6.86 (m, 2H), 6.42 (dd, J=17.4, 1.4 Hz, 1H), 6.15 (dd, J=17.3, 10.4 Hz, 1H), 5.83 (dd, J=10.4, 1.4 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 4.06 (t, J=6.5 Hz, 2H), 2.71-2.65 (m, 2H), 1.91-1.79 (m, 2H), 1.74-1.63 (m, 4H), 1.53-1.47 (m, 2H), 1.43-1.29 (m, 18H), 0.94 (t, J=6.9 Hz, 3H).
1.00 g (1.83 mmol) 2-Methyl-acrylic acid 11-[3-(4-pentyl-phenyl)-coumarin-7-yloxy]-undecyl ester is dissolved in DMF (11 ml). The solution is degassed by three freeze-pump-thaw cycles. 12 mg (0.07 mmol) azobisisobutyronitrile are added to the solution and the reaction vessel is then placed in a 65° C. preheated oil bath for 3 d. At the end of the reaction, the mixture is poured into cold methanol (1 l). The precipitated polymer is collected by filtration and yielded 698 mg (70% of theory).
The following polymers 13a to 13r are prepared analogously:
A solution of 5-Hexenol (1.00 ml; 8.35 mmol) in anhydrous 15 ml THF under argon at room temperature was treated dropwise with 9-Borabicyclo[3.3.1]nonane (0.5 M in THF) (20.04 ml; 10.02 mmol). The reaction was then heated 30 min at 90° C. The resulting solution was then transferred into a stirred mixture of 3-(4-Bromo-2-ethyl-phenyl)-7-methoxy-coumarin (750.00 mg; 2.09 mmol) and Tripotassium phosphate monohydrate (2.12 g; 9.19 mmol) in anhydrous Dimethylformamide (3.90 ml; 50.11 mmol) and Water (0.79 ml; 43.85 mmol) under argon. After bubbling argon through the reaction for 5 min at room temperature, Tetrakis(triphenylphosphine)palladium(0) (120.63 mg; 0.10 mmol) was added. Then the reaction mixture was heated to 80° C. for 12 h. The cooled reaction mixture was then concentrated in vacuo, diluted with DCM and aqueous ammonia solution, the organic phase separated, washed with brine, dried over MgSO4 and concentrated in vacuo. Chromatography Heptane/EtOAc gave 3-[2-Ethyl-4-(6-hydroxy-hexyl)-phenyl]-7-methoxy-coumarin (774.00 mg; 2.03 mmol; 97.4%).
1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.15-7.11 (m, 2H), 7.06 (m, 2H), 6.99 (dd, J=8.6, 2.5 Hz, 1H), 3.88 (s, 3H), 3.40 (q, J=6.4 Hz, 2H), 2.60 (t, J=7.7 Hz, 2H), 2.50 (m, 2H), 1.63-1.57 (m, 2H), 1.47-1.39 (m, 2H), 1.37-1.30 (m, 4H), 1.08 (t, J=7.5 Hz, 3H).
| Number | Date | Country | Kind |
|---|---|---|---|
| 15182029 | Aug 2015 | EP | regional |
| Number | Name | Date | Kind |
|---|---|---|---|
| 3351482 | Raue | Nov 1967 | A |
| 3420835 | Wolf-Dieter et al. | Jan 1969 | A |
| 4103256 | Hammond et al. | Jul 1978 | A |
| 4230850 | Briet et al. | Oct 1980 | A |
| 4349619 | Kamoshida et al. | Sep 1982 | A |
| 4785004 | Von Sprecher et al. | Nov 1988 | A |
| 5077335 | Schwabe et al. | Dec 1991 | A |
| 5290892 | Namdaran et al. | Mar 1994 | A |
| 5331073 | Weinschenk et al. | Jul 1994 | A |
| 5585385 | Natsugari et al. | Dec 1996 | A |
| 5693095 | Freeman et al. | Dec 1997 | A |
| 5968952 | Venet et al. | Oct 1999 | A |
| 6143766 | Kaltenbronn et al. | Nov 2000 | A |
| 6201087 | Herr et al. | Mar 2001 | B1 |
| 6331562 | Bhagwat et al. | Dec 2001 | B1 |
| 6887269 | Hampp et al. | May 2005 | B1 |
| 7247646 | McKie et al. | Jul 2007 | B2 |
| 7399767 | Zhang et al. | Jul 2008 | B2 |
| 7642364 | Liu et al. | Jan 2010 | B2 |
| 8247511 | Mentak | Aug 2012 | B2 |
| 8329842 | Ritter et al. | Dec 2012 | B2 |
| 8329849 | Iji et al. | Dec 2012 | B2 |
| 8366963 | Goto et al. | Feb 2013 | B2 |
| 8592007 | Goetz et al. | Nov 2013 | B2 |
| 9315496 | Zhang et al. | Apr 2016 | B2 |
| 9580653 | Archetti et al. | Feb 2017 | B2 |
| 9823492 | De Sio et al. | Nov 2017 | B2 |
| 10386653 | Beaton et al. | Aug 2019 | B2 |
| 10457658 | Dobelmann-Mara et al. | Oct 2019 | B2 |
| 10723713 | Dobelmann-Mara et al. | Jul 2020 | B2 |
| 10829451 | Dobelmann-Mara et al. | Nov 2020 | B2 |
| 10875833 | Kumar et al. | Dec 2020 | B2 |
| 11001576 | Dobelmann-Mara et al. | May 2021 | B2 |
| 11014900 | Dobelmann-Mara et al. | May 2021 | B2 |
| 11014901 | Schraub et al. | May 2021 | B2 |
| 11040990 | Dobelmann-Mara et al. | Jun 2021 | B2 |
| 11078177 | Dobelmann-Mara et al. | Aug 2021 | B2 |
| 11111226 | Dobelmann-Mara et al. | Sep 2021 | B2 |
| 20050054586 | Bartels et al. | Mar 2005 | A1 |
| 20050176763 | Boy et al. | Aug 2005 | A1 |
| 20060147840 | Ishidai | Jul 2006 | A1 |
| 20070037876 | Liu et al. | Feb 2007 | A1 |
| 20070053831 | Barrio et al. | Mar 2007 | A1 |
| 20070218567 | Tanaka et al. | Sep 2007 | A1 |
| 20080004610 | Miller et al. | Jan 2008 | A1 |
| 20090143858 | Knox et al. | Jun 2009 | A1 |
| 20090157178 | Hampp | Jun 2009 | A1 |
| 20100160482 | Nachbaur | Jun 2010 | A1 |
| 20100227273 | Hatakeyama et al. | Sep 2010 | A1 |
| 20100228345 | Bille | Sep 2010 | A1 |
| 20100324165 | Ritter et al. | Dec 2010 | A1 |
| 20110021522 | Wells et al. | Jan 2011 | A1 |
| 20110028667 | Ritter et al. | Feb 2011 | A1 |
| 20110092612 | Miki et al. | Apr 2011 | A1 |
| 20110205482 | Goetz et al. | Aug 2011 | A1 |
| 20110215334 | Quinn | Sep 2011 | A1 |
| 20110245919 | Pettit | Oct 2011 | A1 |
| 20120305843 | Klasen-memmer et al. | Dec 2012 | A1 |
| 20130033975 | Gindre et al. | Feb 2013 | A1 |
| 20130114010 | Goetz et al. | May 2013 | A1 |
| 20150048276 | Goebel et al. | Feb 2015 | A1 |
| 20150274885 | Joy | Oct 2015 | A1 |
| 20160081852 | Peyman | Mar 2016 | A1 |
| 20160159763 | Taugerbeck et al. | Jun 2016 | A1 |
| 20160262872 | De Sio et al. | Sep 2016 | A1 |
| 20160363784 | Beaton et al. | Dec 2016 | A1 |
| 20170306121 | Brust et al. | Oct 2017 | A1 |
| 20180086725 | Kumar et al. | Mar 2018 | A1 |
| 20180237410 | Dobelmann-Mara et al. | Aug 2018 | A1 |
| 20180243082 | Zheleznyak et al. | Aug 2018 | A1 |
| 20190389827 | Dobelmann-Mara et al. | Dec 2019 | A1 |
| 20200002304 | Dobelmann-Mara et al. | Jan 2020 | A1 |
| 20200038549 | Stoy et al. | Feb 2020 | A1 |
| 20200332041 | Dobelmann-Mara et al. | Oct 2020 | A1 |
| 20220202566 | Schraub et al. | Jun 2022 | A1 |
| 20230084690 | Gerstenecker | Mar 2023 | A1 |
| 20230203214 | Riedmueller et al. | Jun 2023 | A1 |
| Number | Date | Country |
|---|---|---|
| 102532015 | Oct 2013 | CN |
| 104656272 | May 2015 | CN |
| 106810559 | Jun 2017 | CN |
| 105753837 | Apr 2018 | CN |
| 106810560 | Mar 2019 | CN |
| 111040202 | Apr 2020 | CN |
| 111378138 | Jul 2020 | CN |
| 111378159 | Jul 2020 | CN |
| 111378160 | Jul 2020 | CN |
| 111378163 | Jul 2020 | CN |
| 111378165 | Jul 2020 | CN |
| 111378168 | Jul 2020 | CN |
| 10147238 | Apr 2003 | DE |
| 0155177 | Sep 1985 | EP |
| 0354179 | Aug 1994 | EP |
| 2698369 | Jul 1997 | EP |
| 1342770 | May 2006 | EP |
| 1926454 | Mar 2010 | EP |
| 1958945 | Nov 2014 | EP |
| 1683792 | Oct 2016 | EP |
| 3133065 | Feb 2017 | EP |
| 2837671 | Oct 2017 | EP |
| 3363791 | Aug 2018 | EP |
| 2118191 | Jul 1972 | FR |
| 1212174 | Nov 1970 | GB |
| S52122371 | Oct 1977 | JP |
| 57035850 | Feb 1982 | JP |
| 57035850 | Feb 1982 | JP |
| 3275681 | Dec 1991 | JP |
| H03275681 | Dec 1991 | JP |
| 5263072 | Oct 1993 | JP |
| H05263072 | Oct 1993 | JP |
| H063761 | Jan 1994 | JP |
| H08301849 | Nov 1996 | JP |
| F08337583 | Dec 1996 | JP |
| 02876129 | Mar 1999 | JP |
| H11514635 | Dec 1999 | JP |
| 2004203751 | Jul 2004 | JP |
| 2007505835 | Mar 2007 | JP |
| 2007510674 | Apr 2007 | JP |
| 2011505932 | Mar 2011 | JP |
| 2012506878 | Mar 2012 | JP |
| 2012124297 | Jun 2012 | JP |
| 108383 | Mar 1999 | PL |
| 308658 | Apr 2009 | TW |
| 9924420 | May 1999 | WO |
| 0008026 | Feb 2000 | WO |
| 0118079 | Mar 2001 | WO |
| 0197217 | Dec 2001 | WO |
| 2005028472 | Mar 2005 | WO |
| 2005065689 | Jul 2005 | WO |
| 2006078834 | Jul 2006 | WO |
| 2007001407 | Jan 2007 | WO |
| 2007033831 | Mar 2007 | WO |
| 07066755 | Jun 2007 | WO |
| 2007082178 | Jul 2007 | WO |
| 2007132948 | Nov 2007 | WO |
| 2007136125 | Nov 2007 | WO |
| 2008013950 | Jan 2008 | WO |
| 08096673 | Aug 2008 | WO |
| 2008094476 | Aug 2008 | WO |
| 2009032754 | Mar 2009 | WO |
| 09074520 | Jun 2009 | WO |
| 09074521 | Jun 2009 | WO |
| 2009156182 | Dec 2009 | WO |
| 2010049044 | May 2010 | WO |
| 2010049269 | May 2010 | WO |
| 2010049270 | May 2010 | WO |
| 20100086484 | Aug 2010 | WO |
| 2011057942 | May 2011 | WO |
| 2011090224 | Aug 2011 | WO |
| 2011117195 | Sep 2011 | WO |
| 2012034719 | Mar 2012 | WO |
| 2012097858 | Jul 2012 | WO |
| 2012150550 | Nov 2012 | WO |
| 2012167124 | Dec 2012 | WO |
| 2013130689 | Sep 2013 | WO |
| 2014059350 | Apr 2014 | WO |
| 2014090362 | Jun 2014 | WO |
| 2015003095 | Jan 2015 | WO |
| 2016146583 | Sep 2016 | WO |
| 20160200401 | Dec 2016 | WO |
| 2017032442 | Mar 2017 | WO |
| 2017032443 | Mar 2017 | WO |
| 2017032444 | Mar 2017 | WO |
| 2017221068 | Dec 2017 | WO |
| 2018149850 | Aug 2018 | WO |
| 2018149852 | Aug 2018 | WO |
| 2018149853 | Aug 2018 | WO |
| 2018149855 | Aug 2018 | WO |
| 2018149856 | Aug 2018 | WO |
| 2018149857 | Aug 2018 | WO |
| 2018171688 | Sep 2018 | WO |
| 2019097232 | May 2019 | WO |
| Entry |
|---|
| Inal (2013), Temperature-Regulated Fluorescence Characteristics of Supramolecular Assemblies Formed By a Smart Polymer and a Conjugated Polyelectrolyte. Macromol. Chem. Phys., 214: 435-445. https://doi.org/10.1002/macp.201200493 (Year: 2013). |
| Inal “Temperature-Regulated Fluorescence and Association of an Oligo(ethyleneglycol)methacrylate-Based Copolymer with an Conjugated Polyelectrolyte—The Effect of Solution lonic Strength”, J. Phys. Chem. B 2013, 117, 14576-14587 (Year: 2013). |
| Australian Examination report in corresponding AU application 2016312305 dated Nov. 4, 2020 (pp. 1-9). |
| Report with CAS Registry No. 376382-75-1 ( STN dale Dec. 18, 2001), CAS Registry No. 376380-44-8 ( STN date Dec. 18, 2001), CAS Registry No. 376378-98-2 ( STN dale Dec. 18, 2001). |
| Aroldi, A., et al., Analogues of Phytoalexins. Syntheis of Some 3-Phenylcoumarins and Their Fungicidal Activity, J_\gric. Food Chem., (1986), vol. 34, No. 2, pp. 185-188. |
| Kurosawa et al., “Analysis of stereoisomeric C27-bile acids by high performance liquid chromatography with uorescence detection” Journal of Pharmaceutical and Biomedical Analysis, 1997, 15, 1375-1382. |
| Parenti et al., “Three-Dimensional Quantitative Structure-Activity Relationship Analysis of a Set of Plasmodium falciparum Dihydrofolate Reductase Inhibitors Using a Pharmacophore Generation Approach”; Journal of Medicinal Chemistry, 2004, 47, 17, 4258-4267 plus Suppl. Material. |
| Matos et al., “Insight into the Interactions between Novel Coumarin Derivatives and Human A3 Adenosine Receptors” ChemMedChem, 2014, 9, 2245-2253. |
| You et al., “Discovery of novel osthole derivatives as potential anti-breast cancer treatment”; Bioorganic & Medicinal Chemistry Letters, 2010, 20, 7426-7428. |
| First Office action in corresponding JP appl. 2018-509835 dispatched Jul. 7, 2020 (pp. 1-4). |
| Intemational Search Report PCT/EP2016/001341 dated Sep. 22, 2016. |
| Carrer, Adv Synth Catal, vol. 355, 2013, 2044-2054. {Year: 2013). |
| Wu, Chem Lett, vol. 34(4), 550-551, 2005. {Year: 2005). |
| Wang, Adv Synth Catal, vol. 349, 1943-1948,2007. {Year: 2007). |
| Cheng, Bioort & Med Chem Lett, vol. 14, 2411-2415, 2004. {Year: 2004). |
| International Search Report PCT/EP2016/001340 dated Sep. 23, 2016. |
| Liao, J.H. et al.: “Anti-UVC Irradiation and Metal Chelation Properties of 6-Benzoyl-5,7-dihydroxy-4-phenyl-chromen-2-0ne: An Implication for Anti-Cataract Agent”, Int. J_ Mol. Sci., vol. 12, 2011, pp. 7059-7076, KP002761569. |
| Intemational Search Report PCT/EP2016/001339 dated Oct. 6, 2016. |
| E. Tang et al: “A Convenient Solid-Phase Synthesis of Coumarins by TMSOTf-Catalyzed Intramolecular Seleno-I \rylation ofTethered Alkenes”, SYNLETT, vol. 23, No. 06, Mar. 15, 2012 (Mar. 15, 2012), DE, pp. 907-912, KP055241177, ISSN: 0936-5214. |
| Odovico Lunazzi et al: “Stereomutation of Axially Chiral Aryl Coumarins”, The Journal of Organic Chemistry, vol. 75, No. 17, Sep. 3, 2010 (Sep. 3, 2010), US, pp. 5927-5933, XP055241172, ISSN: J022-3263, DOI: 10.1021/jo101261k. |
| Kiao-Feng Wu et al: “A General Palladium-Catalyzed Carbonylative Synthesis of Chromenones from Salicylic I Aldehydes and Benzyl Chlorides”, Chemistry—A European Journal., vol. 19, No. 37, Sep. 9, 2013 Sep. 9, 2013), Weinheim, DE, pp. 12245-12248, XP055241154, ISSN: 0947-6539. |
| Neiying Lin et al: “Through-Bond Energy Transfer Cassettes with Minimal Spectral Overlap between the Donor Emission and Acceptor Absorption: Coumarin-Rhodamine Dyads with Large Pseudo-Stokes Shifts and Emission Shifts”, Angewandte Chemie International Edition, vol. 49, No. 2, Jan. 8, 2010 (Jan. 8, 2010), DE, pp. 375-379, XP055241144, ISSN: 1433-7851. |
| Filipenko et al: “Effect of intermolecular interactions on the formation of mesophases in 3-aryl-7-substituted Coumarins, and the crystal structure of 3-(4?-butyl)- and (4?-heptylphenyl)-7-propoxycoumarins”, Bulletin of the I Cademy of Sciences of the USSR, Division of Chemical Sciences., vol. 38, No. 10, Oct. 1, 1989 Oct. 1, 1989), US, pp. 2073-2079, XP055241135, ISSN: 0568-5230. |
| Dolores Vina et al: “8-Substituted 3-Arylcoumarins as Potent and Selective MAO-B Inhibitors: Synthesis, Pharmacological Evaluation, and Docking Studies”, Chemmedchem, vol. 7, No. 3, Mar. 5, 2012 {Mar. 5, 2012), DE, pp. 464-470, XP055241043, ISSN: 1860-7179. |
| Kiaoping Chen et al: “Synthesis of Novel Polymer/Urea Peptoid Conjugates Using RAFT Polymerization”, Macromolecules, vol. 43, No. 3, Feb. 9, 2010 {Feb. 9, 2010), US, pp. 1341-1348, XP055241030, ISSN: 024-9297. |
| Sebastien L. Degorce et al: “Investigation of { E )-3-[4-{2-Oxo-3-aryl-chromen-4-yl)oxyphenyl]acrylic Acids as Oral Selective Estrogen Receptor Down-Regulators”, Journal of Medicinal Chemistry, vol. 58, No. 8, Apr. 23, J015 {Apr. 23, 2015), US, pp. 3522-3533, XP055240905, ISSN: 0022-2623. |
| Arnaz Jafarpour et al: “Palladium-Catalyzed Decarboxylative Cross-Coupling Reactions: A Route for Regioselective Functionalization of Coumarins”, The Journal of Organic Chemistry, vol. 78, No. 7, Apr. 5, J013 {Apr. 5, 2013), US, pp. 2957-2964, XP055240707, ISSN: 0022-3263. |
| Na Gordeeva et al: “Photochemical Reactions of 7-Aminocoumarins. 8*. Reaction of 3-Iodo-4-Methyl-7-Diethylaminocoumarin With Monosubstituted Benzenes”, Chemistry of Heterocyclic Compounds, Jan. 1, 1990 {Jan. 1, 1990), pp. 976-980, XP055240705, Retrieved from the ntemet [retrieved on Jan. 12, 2016]. |
| Schraub Martin et al: “Photoinduced refractive index changes of 3-phenyl-coumarin containing polymers for Jphthalmic applications”, European Polymer Journal, Pergamon Press Ltd. Oxford, GB, vol. 51, Dec. 1, 2013 {Dec. 1, 2013), pp. 21-27, XP028810223, ISSN: 0014-3057. |
| Schraub Martin et al: “Smart polymers containing substituted coumarin side groups enable photo-induced uning offocal length of intraocular lenses”, Ophthalmic Technologies XXI, SPIE, 1000 20th St. Bellingham WA 98225-6705 USA, vol. 7885, No. 1, Feb. 10, 2011 {Feb. 10, 2011), pp. 1-11, XP060005764. |
| Kapoor et al., “Synthesis of coumarins”, Labdev {Kanpur, India), 1966, 4(1),27-29 {Year: 1966). |
| Trager et al., “Polymers for in vivo Tuning of Refractive Properties in Intraocular Lenses”, Macromol. Biosci. 2008, 8, 177-183 {Year: J008). |
| Schraub et al. “Smart polymers containing substituted coumarin side groups enable photo-induced tuning of focal ength of intraocular lenses”, Proc. SPIE 7885, Ophthalmic Technologies XXI, 78851Z, Feb. 11, 2011; doi: 10.1117/12.873814. {Year: J011). |
| Asif, “Overview of Diverse Pharmacological Activities of Substituted Coumarins” Compounds with Therapeutic Potentials, American Journal of Current Organic Chemistry, vol. 1, Issue 1, Jan. 21, 2015, 16 pages. {Year: 2015). |
| Search report in corresponding EP application No. 17156321 dated May 2, 2017 (1 Page). |
| Search report in corresponding EP application No. 17156327 dated May 2, 2017 (2 Pages). |
| Search report in corresponding EP application No. 17156324 dated Apr. 27, 2017 (2 Pages). |
| Search reports in corresponding EP application No. 17156329 and No. 17156326 dated Mar. 22, 2017 (3 Pages each). |
| J.-M. Legeais, J_ Cataract. Refract. Surg., 1998, 24, 371-379. |
| Search report in corresponding EP application No. 17156331 dated Mar. 24, 2017 (2 Pages). |
| N. K. Sangwan et al., Indian Journal of Chemistry, 1990, vol. 29B, pp. 294-296. |
| NASU; J_ Maler. Chem., 2010, 20, 6688-6695. |
| Schmidt: Pure Appl. Chem. 1971, 27, 647-678. |
| Mi Sun Lee et al., Journal of Applied Polymer Science, 2012, vol. 124, 4339-4345. |
| Jenkins; Pure Appl. Chem. 1996, vol. 68, No. 12; 2287-1231. |
| Krauch et al., Chemische Berichte Jahrg. 99, 1966, 1723. |
| Buquet et al., Tetrahedron, 1981, vol. 37, 75 to 81. |
| David L. Oldroyd et al., Tetrahedron Letters, 1993, vol. 34, No. 7, 1087-1090. |
| J. M. G. Cowie, Polymers: Chemistry & Physics of Modern Materials, Blackie, Glasgow, 1991. |
| Truong et al, JACS, 2014, vol. 136, No. 24, p. 8568-8576. |
| P_L. Beaulieu et al., Journal of Medicinal Chemistry, 2012, vol. 55, No. 17, p. 7650-7666. |
| Busch A.P., et al., “Two-Photon-Absorption Triggered Release of 5-Fluorouracil from Isomer-Pure Polymer Bound Syn-Head-to-Head Dimers for Novel Intraocular Lenses,” International Journal of Drug Delivery, 2015, vol. 7, pp. 174-190. |
| Helmstetter S., et al., “High-refractive Quinolinone-based Polymers for Ophthalmic Devices,” Journal of Polymer Research, 2016, vol. 23 (12), 14 pages. |
| Johnston P., et al., “Topochemical Photo-reversible Polymerization of a Bioinspired Monomer and its Recovery and Repolymerization After Photo-depolymerization,” Chemical Science, 2012, vol. 3 (7), pp. 2301-2306. |
| Lohse B., et al., “N1-Alkylated Pyrimidine Films as a New Potential Optical Data Storage Medium,” Chemistry of Materials, 2006, vol. 18 (20), pp. 4808-4816. |
| Lohse B., et al., “Photodimerization in Pyrimidine-substituted Dipeptides,” Journal of Peptide Science, 2005, vol. 11 (8), pp. 499-505. |
| Lohse B., et al., “UV-photodimerization in Uracil-substituted Dendrimers for High Density Data Storage,” Journal of Polimer Science, 2007, vol. 45 (19), pp. 4401-4412. |
| Matharu A.S., et al., “Photochromic Polymers for Optical Data Storage: Azobenzenes and Photodimers,” In N. S. Allen, Photochemistry and Photophysics of Polymeric Materials, 2010, pp. 209-234. |
| Patel M.P., et al., “Polymerization Shrinkage of Methacrylate Esters,” Biomaterials, 1987, vol. 8 (1), pp. 53-56. |
| Ramanujam P.S., et al., “Photochromic Processes for High Density Optical Storage,” SPIE Proceedings, 2003, vol. 5069, pp. 57-63. |
| Setlow R.B., “Cyclobutane-type Pyrimidine Dimers in Polynucleotides,” Science, 1996, vol. 153 (3734), pp. 379-386. |
| Theis A., “Synthesis and Kinetic Studies on the Photochemical Behavior of Polymeric Mesoions from Novel Methacrylic Monomers and of Mesoionic Copolymers with Liquid Crystalline Properties,” Macromolecules, 2003, vol. 36 (20), pp. 7552-7559. |
| Behm H., et al., “NOTE Crystal and Molecular Structure of a Photo Dimer of 1 ,2-dihydro 3-phenylnaphthalene, C32H28,” Journal of Crystallographic and Spectroscopic Research, 1988, vol. 18(4), pp. 471-475. |
| Billeret D., et al., “Convenient Synthesis of 5-Azacoumarins,” Journal of Heterocyclic Chemistry, 1993, vol. 30, pp. 671-674. |
| Bonnetaud D, et al., “Synthesis of Formyl-3 Hydroxy-2 Pyridine and 2H-Pyrano[2,3-b] Pyridines One-2 (1),” Journal Heterocycl. Chemistry, Feb. 1972, vol. 9 (1), pp. 165-166. |
| Bozukova D., et al., “Polymers in Modem Ophthalmic Implants—Historical Background and Recent Advances,” Materials Science and Engineering R, 2010, vol. 69(6), pp. 63-83. |
| Bratcher M.S., et al., “Synthesis of Bifunctional Photorefreactive Polymers with Net Gain: Design Strategy Amenable to Combinatorial Optimization,” Journal of the American Chemical Society, 1998, vol. 120, pp. 9680-9681. |
| Brufola G., et al., “Efficient One-Pot Synthesis of 7-Azacoumarins by Knoevenagel Reaction Using Water as Reaction Medium,” Heterocycles, 1997, vol. 45 (9), pp. 1715-1721. |
| Database Registry, STN International CAS Registry No. 1105244-13-0, Mar. 13, 2010. |
| Database Registry, STN International CAS Registry No. 1211903-13-0, Mar. 19, 2010. |
| Database Registry, STN International CAS Registry No. 1211936-26-3, Mar. 19, 2010. |
| Database Registry, STN International CAS Registry No. 1212764-88-9, Mar. 21, 2010. |
| Database Registry, STN International CAS Registry No. 1212785-02-8, Mar. 21, 2010. |
| Desai S.M., et al., “Synthesis of 3-Substituted-aminopropoxy-2-hydroxycoumarin Derivatives as Possible B-Blockers,” Journal of the Indian Chemical Society, Jun. 1989, vol. 66 (6), pp. 415-417. |
| Duguet E., et al., “New Cyclodisilazane Monomers,” Journal of Organometallic Chemistry, 1993, vol. 458(1-2), pp. 9-12. |
| Fang J., et al., “Synthesis and Photodimerization in Self-assembled Monolayers of 7-(8-trimethoxysilyloctyloxy) Coumarin,” Journal Materials Chemistry, 2001, vol. 11, pp. 2992-2995. |
| Federal Register, vol. 76 (27), Feb. 9, 2011, pp. 7166. |
| Garazd M.M., et al., “Modified Coumarins. I. Synthesis of 5-phenyl-7h-furo[2, 3-g]chromen-7-ones and 9-phenyl-7h-furo-[2, 3-f]chromen-7-ones,” Chemistry of Natural Compounds, 2000, vol. 36 (5), pp. 478-484. |
| Garazd M.M., et al., “Modified Coumarins. 29. Synthesis of Structural Analogs of Natural 6-arylfuro[3,2-g]chromen-7-ones,” Chemistry of Natural Compounds, 2009, vol. 45 (2), pp. 158-163. |
| Garazd M.M., et al., “Modified Coumarins. 8. Synthesis of Substituted 5-(4-methoxyphenyl)-7h-furo[3,2-g]chromen-7-ones,” Chemistry of Natural Compounds, 2002, vol. 38 (6), pp. 539-548. |
| Ikeda M., et al., “Effect of Microcrystalline Cellulose on the Stability of Oxazolam in Solid State,” Journal of Pharmaceutical Science and Technology, 1987, vol. 47 (4), pp. 204-210. |
| Iupac, Glossary of Basic terms in polymer Science, Pure and Applied Chemistry, 1996, vol. 68, pp. 2291. |
| Kano S., et al., “A Facile Synthesis of 4-Phenylcarbostyrils and 4-Phenylisocarbostyril Involving Photocyclization of Benzo [b]thiophene-2-carboxanilidines and 2-Benzoylamino-3-chlorobenzo[b]thiophene,” Heterocycles, 1979, vol. 12 (4), pp. 489-492. |
| Keijzer F., et al., “Photoacoustic Determination of the Photostability of 3-phenyl-1 ,2-dihydronaphthalene,” Journal of Photochemistry and Photobiology A: Chemistry, 1990, vol. 50(3), pp. 401-406. |
| Kienast A., et al., “Influence of a New Surface Modification of Intraocular Lenses With Fluoroalkylsilan on the Adherence of Endophthalmitis-causing Bacteria in Vitro,” Graefe's Archive for Clinical and Experimental Ophthalmology, 2006, vol. 244(9), pp. 1171-1177. |
| Korchia L., et al., “UV-Responsive Amphiphilic Graft Copolymers based on Coumarin and Polyoxazoline,” Soft Matter, Jan. 2017, vol. 13(25), pp. 4507-4519. |
| Krejcoves J., et al., “The Use of Coumarin Derivatives in the Preparation of Fluorescence-labelled Poly [N-(2-hydroxypropyl)methacrylamide],” Collection of Czechoslovak Chemical Communications, 1980, vol. 45(3), pp. 727-731. |
| Lamberts J.J.M., et al., “The Photochemistry of 1-3- and 4-phenyl-substituted 1,2 Dihydronaphthalenes,” Recueil, Journal of the Royal Netherlands Chemical Society, 1984, vol. 103(4), pp. 131-135. |
| Li M., et al., “Evaluation of Vinylsulfamides as Sulfhydryl Selective Alkylation Reagents in Protein Modification,” A Bioorganic & Medicinal Chemistry Letters, 2003, pp. 383-386. |
| Miyata A., et al., “Clinical and Experimental Observations of Glistening in Acrylic Intraocular Lenses,” Japanese Journal of Ophthalmology, 2001, vol. 45(6), pp. 564-569. |
| Miyata A., et al., “Equilibrium Water Content and Glistenings in Acrylic Intraocular Lenses,” Journal of Cataract and Refractive Surgery, 2004, vol. 30(8), pp. 1768-1772. |
| Moffett R.B., et al., “Azacoumarins,” Journal of Organic Chemistry, 1970, vol. 35 (11), pp. 3596-3600. |
| Qin et al., Polymer International, 1999, vol. 48, pp. 491-494. |
| Rampazzo E., et al., “Surface Modification of Silica Nanoparticles: a New Strategy for the Realization of Self-organized Fluorescence Chemosensors,” Journal of Materials Chemistry, 2005, vol. 15 (27-28), pp. 2687-2696. |
| Sato Y., et al., “Studies on New-adrenergic Blocking Agents. I. Syntheses and Pharmacology of Coumarin Derivatives,” Chemical and Pharmaceutical Bulletin, 1972, vol. 20 (5), pp. 905-917. |
| Schraub M., et al., “Smart Polymers Containing Substituted Coumarin Side Groups Enable Photo-induced Tuning of Focal Length of Intraocular Lenses,” Ophthalmic Technologies, 2011, vol. 7885, pp. 1-11. |
| Schwartz D.M., et al., “Light-adjustable Lens: Development of in Vitro Nomograms,” Transactions of the American Ophthalmological Society, Dec. 2004, vol. 102, pp. 67-74. |
| Skowronski L., et al., “Optical Properties of Coumarins Containing Copolymers,” Optical Materials, Sep. 2015, vol. 47, pp. 18-23. |
| Smith L.E., et al., “Synthesis and Properties of Functional Poly(vinylpyrrolidinone) Hydrogels for Drug Delivery ,” Polymers for Biomedical Applications, 2008, vol. 977, pp. 196-203. |
| Sohn E., et al., “Tuning Surface Properties of Poly(Methyl Methacrylate) Film Using Poly(Perfluoromethyl Methacrylate)s With Short Perfluorinated Side Chains,” Langmuir: the ACS journal of surfaces and colloids, 2016, vol. 32 (38), pp. 9748-9756. |
| Suratwala T., et al., “Photostability of Silylated Coumarin Dyes in Polyceram Hosts,” Journal of Sol-Gel Science and Technology, 1997, vol. 8(1), pp. 973-978. |
| Trecourt F., et al., “Improved Synthesis of 2,3-disubstituted Pyridines by Metallation of 2-chloropyridine: a Convenient Route to Fused Polyheterocycles,” Journal of the Chemical Society, Perkin Transactions, 1990, vol. 1 (9), pp. 2409-2415. |
| Trivedi R.H., et al.,“Post Cataract-interocular Lens (IOL) Surgery Opacification,” Eye, 2002, vol. 16(3), pp. 217-241. |
| Wang D, et al., “Strategic Approach to 8-Azacoumarins,” Organic Letters, 2017, vol. 19 (5), pp. 984-987. |
| Wolfbeis O.S, et al., “Darstellung Pyronokondensierter 2-Pyridone, Cumarine and 2-Chinolone mit Hilfe der Kappe-Mayer-Variante der von Pechmann-Reaktion,” Monatshefte fur Chemie, 1982, vol. 113, pp. 365-370. |
| Zhang J., et al., “Enantioselective Phosphine-Catalyzed Allylic Alkylations of Mix-Indene with MBH Carbonates”, Organic Letters, 2017, vol. 19(22), pp. 6080-6083. |
| Waldmann H., et al., “Reagent-Controlled Domino Synthesis of Skeletally-Diverse Compound Collections,” Chemical Communications, 2008, vol. 10, pp. 1211-1213. |
| Number | Date | Country | |
|---|---|---|---|
| 20210363122 A1 | Nov 2021 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16560265 | Sep 2019 | US |
| Child | 17390029 | US | |
| Parent | 15753192 | US | |
| Child | 16560265 | US |
