CA2189337A1 - Compounds containing a michael-acceptor, especially maleimide or maleic acid derivatives, directly or indirectly linked to a chromophore and their use in long lasting sunscreen compositions - Google Patents

Abstract

The present invention relates to compounds which are useful as sunscreens. The compounds persists on the skin for much longer than conventional sunscreens because they comprise a Michael acceptor linked directly or indirectly to a chromophore. The Michael acceptor is capable of undergoing a conjugate addition reaction with thiol groups present in cysteine residues of keratin and thus the compound is chemically bound to the skin and will not be removed by immersion in water.

Description

2 1 Q~ 9 3 3 7 W095l30646 ~ ' ' ` r~ .s i ~

COMPOUNDS CONTAINING A MICHAEL-ACCEPTOR, ESPECIALLY MALEIMIDE OR MALEIC ACID
DERIVATIVES, DIRECTLY OR IND~RECTLY LINKED TO A CHROMOPHORE AND THEIR USE
IN LONG LASTING S~l lS~`~P~N COMPOSITIONs The present invention relates to novel c u~-ds which are useful as sunscreens and to water resistant and long lasting sunscreen compositions.
n skin comprises two main layers; the outer cP~ l Ar layer is termed the epidermis and the inner layer, which is mainly non-cellular is known as the dermis. The dermis cnnt=;"R structural proteins such as collagen and elastin. The outer layer of the epidermis is a non-living keratin layer known as the stratum corneum and is derived from keratinocytes of which the ~pi fiprm; q is mainly ~ re~ . The other types of cell in the epidermis are melanocytes which synthPqi ce melanin and r =n~Prh~nc cells which presen~ antigens to the systemic immune system.
Solar ultra violet radiation (UVR) ranges in wavelength from about 290 nm to 400 nm. Radiation of 280 to 320 nm is known as UV~3 and r~ tion of 320 to 400 nm is termed WA. Light of wavelength 100 to 280 nm is known as WC.
Solar UVR is known to have various photobiological effects on the skin and these include acute effects such as erythema ( sunburn) and tanning as well as longer term effects such as skin cancer and premature aging. The precise me~h=niqmq of the rP=t-t;onq of sunlight on the skin are not fully understood but it seems clear that the initial event is likely to be a photochemical reaction i~
which a chromophore present in the skin is modified after absorption of UV~. Known chromophores in the skin include urocanic acid, which is a tiP~m;n=t;nn product of histidine and is present in large quantities in the _ WO 95130646 2 1 8 9 3 3 7 ~Cr/GB95101035 .
stratum corneulr, nucleic acids, aromatic amino acids and mol ~n;n~ which are complex pigments producea by the melanocytes .
~3ecause of the well known damaging effects of sunlight on the skin, sunscreens have been in use f or many years .
Sunscreens are ciassified by their sun protection factor against simulated solar r~ tir-n which is defined by the following eS[uation [MED24h with sunsc~een at 2~1/cm2]
SPE [M~D24h without sunsc~een]
Until recently, most of the adverse effec~s of sunlight on the ski~ as well as tanning have been attributed to the effects of W~3 but there is now an increasing body of evidence which suggests that WA is likely to be responsible :~ for some of the aging and carcinogenic effects of ~=sunlight. In particular, it has been suggested that WA could be a cause of malignant l~nt~
in humans (Setlow et al, Proc. Natl. Acad. Sci. 90, 6666-6670 ) . For this reason, until relatively recently most of the sunscreens were designed only to protect from W~3 and offered little or no protection from WA. ~learly, this can be ~dangerous to the wearer of the sunscreen since protection from erythema caused by WB encourages longer exposure to the sun and conse~uently to WA from which the wearer of the sunscreen is not protected. It is therefore widely accepted that it is desirable for sunscreen formulations to offer protection from both WA
and UVB.
There are two conventional modes of action of sunscreens.

WO9S/30646 ~ ,r ~ s 2 l ~9 3 37 ~ .035 ~he first of these lS to prevent ~lVR from reaching the sRin which can be àone by covering the skin with a pigment which wiil scatter UVR. Pigments which are used in sunscreens include inorganic substances sucll a6 titanium dioxide and zinc oxide and some sunscreens also include melanin, The other strategy for providing a sunscreen ~ s to cover the skin with a substance ~ossessing a chromophore which absorbs light of the appropriate wavelength. Substances with suitable chromophores i~clude anthranilates, bPn7nnnPnnnPC, camphor derivatives, ,-- nnAr-tpc-, dibenzoylmethanes, p-cm;nnhPn7oic acid (PABA) and its derivatives and salicylates. Broad spectrum ~rotection from WR can be achieved by combining WA and WB absorbing substances such as 2-ethylhexyl-4~-methoxycinn~r~te (~max = 308 nm) and 4-'butyl-4 ' -methoxydibenzoylmethane (~max = 355 nm) .
There are, however, several problems with Conv~nt-nn~l sunscreens and one of the most serious is that they generally remain on the skin for only for a relatively short period of time. This can be dangerous as many users do not realise that their sunscreen will protect them for perhaps as little as 30 to 60 minutes when the sunlight is very intense. The problem is particularly acute for swimmers and other participants in water sports since many of the most effective sunscreens are highly soluble in water and, as water is ineffective at filtering out WR, the user may be completely unprotected soon after entering the water. Water resistant sunscree~s are available but the water resistance often arises from the way in which the compounds are formulated although water resistant sunscreens comprising a W
absorbing ~, nnt attached to a polymeric h~rkhnnp have also been proposeà. Even with these so called water ;~ 218933~ ` ~'7 ---resistant sunscreens, however, it is still necessary for the user to reapply them f requently and this can be inconvenient in many water sports situations.
One approach to providing long lasting protection from UVR has been the so called "active sunscreen"
formulation which includes low concentrations of the photosensitiser 5-methoxypsoralen (5-MOP) which i9 capable of ; nt~ ; ng a tan which provides superior and la persistent photoprotection against DNA damage. However, the use of 5-MOP has proved controversial as it photobinds to DNA and has been shown to be a photomutagen and a photocarcinogen.
There is thus a need for a sunscreen which is capable of providing long lasting protection to the user even in the water. The present invention solves this problem by providing a completely new approach to the production of sunscreens . It is; ntPnr1pd that the sunscreen compounds o~ the invention, instead of merely forming a protective layer on top of the skin, will be capable of interacting chemically with the epidermis and will thus be much more persistent than the creams and lotions which form the~
state of the art. The keratinised cells of the stratum corne~ are cnn~;n~lA11y shed by the process of desquamation and the stratuzn corneum renews itself approximately every four days and therefore a sunscreen which is chemically attached to it would be likely to persist for about that time.
JP-A-59-204171 discloses maleimide derivatives for use as reagents for determining S}~-cnn~;n;n~ compounds.
EP-A-0407932 discloses compounds for use as sunscreens ,, , ~ o , . o o o o 4a which are polymers of n~ethacrylates carrying chromophores such as hydroxylated ben20phPn, nPc.
In a first aspect of the present invention, therefore, AMEN~E~ SHEET ~ ~

WO 95/30646 , ~ 035 there is provided a compound for use as a sunsc_een and comprising a W chromophore attached to a grou~ which is ca~able of chemical binding to r^-r~ n skin.
Although the intention of the present inventors is to design a sunscreen wnich is chemically attachea to the skin, it is important that it is not suf~iciently absorbed for it to interact with the livi~g cell layers of the epidermis. For this reason, it is greatly 1~ preferred that the compounds of the present inven~ion are designed to react with the keratin of which cel`~ s of the stratu~z~ corneum are mainly composed. It is also greatly pref erred that reaction of the sunscreen agent with the keratin should be relatively rapid so that penetration of unreacted compound into the skin is minimal.
The components of keratin are proteins which have a relatively high ratio of cysteine to other amino acids.
Although the keratin present in the epidermis rnnt~inc:
somewhat lower quant ties of cysteine than the keratin of the hair and nails, there are still sufficient cysteine residues, and thus thiol groups, for them to be used as a point of att~rhr~nt of a WR absorbing substance.
2ri Thiols are able to react with ~ unsaturated carbonyl compounds or similar agents in conjugate addition reactions and this route of atti~r' t to the skin has been found to be particularly useful.

3 0 Theref ore, in a second aspect of the present invention, there is provided a compound for use as a sunscreen and comprising a W chromophore attached directly or indirectly to a Michael acceptor.

( P 5 . ~ C 2 1 8 9 W095/30646 ` 337 r ,. 1035 In the context of the present lnvention the phrase "attached directly or indirectlyn means that the W
cnL. h~re can be either directly linked to the Michael acceptor via some part of the chromophoric entity.
Alternatlvely, there may be indirect attachment whereby the chromophore is attached to a linker such as an alkyl or alkenyl chain which is in turn linked to the Michael acceptor .
In the context of the present invention, the term "Michael acceptor'~ refers to any ~"~-unsaturated compound which is capable of reacting with a n~ enph; 1~ in a conjugate addition reaction such as the so called Michael addition. Strictly speaking, the term Michael addition refers to a particular conjugate addition reaction in which a carbanion is reacted with an S!, ~-unsaturated compound whereas the present invention is primarily concerned with the situation when the nucleophile is a thiol group. However, the same groups which would undergo the Michael reaction will also react with thiols and therefore they have been termed "Michael acceptors~
throughout the pregent spe~; f; c~t i nn .
Examples o~: Michael acceptors are well known and any 1 ~ r~ of this type is suitable for use in the present invention. Michael acceptors include o~ -unsaturated esters, amides, carboxylic acids, nitriles, aldehydes and ketones. Specific examples include derivatives of ~uinone:

W0 95/30646 ' ~ ' ~ ' 2 1 8 9 ~ 3 7 P~
o ¢

Quinone maleic and acryiic acids, and their esters a~à other deriva~ives:
O O
11~ o H ¢~N H
maleic acid maleimide ~OH
acrylic acid and other electron de~icient alkenes such as acrylonitrile:
N
~1 acrvlonitrile Wo 95/30646 ~ S 2 1 8 9 3 3 7 PCr/GB95/01035 _t has been found rhat maleic acid, maleamic acid and maleimide and their derivatives are particularl~y suitable for use as the Michael acceptor since they react gently yet quickly with thiol groups and thus would be unlikely to cause unpleasant side effects when applied to the s kin .
The reaction = of a maleimide derivative with the ethyl ester of cysteine can be represented by the ollowing equation:
E~--51~ + ¢ ~NR ~ ~NR
Other Michael acceptors react with the thiol group of cysteine in an analogous manner.
The Michael acceptorq nr j nn~l specifically above are well known to those skilled in the art and are either commercially available or can be prepared by methods known to those skilled in the art.
A further advantage of attaching the chromophoric group to a Michael acceptor is that the Michael acceptors are able to bind not only to free thiol groups on cysteine residues but also to other nucleophiles which are likely to be present in the skin. For example, they can react with ~-amino groups which are present at the N-t~rm; n~lc of proteins ~:and peptides and on the slde chain of the amino acid lysine to form covalently linked ~ in1m;de 8q337 Wo 95/30646 . ~ 03~

~erivatives. It has also been suggested =hat the mi ~A701 f~ group of histi!~ine will react with ~ m; r~P~
~he W chromophore may ~e selected f rom any one of a number of well known chromophores. It will of ~ourse be chosen so that the Amax _s within either the ~iVA or the W;3 wavelength range according to the particular type of ~rotection which is desired.
Exampies include derivatives of cinnamic acid and benzylidene which are UV}3 absorbers and various substituted benz~rphPnnnP and dibenzoylmethane de-ivatives which are WA absorbers.
The present invention re I ates in a third aspect ~o novel compounds of general formula I:
X-R (I) wherein X is a Michael acceptor;
R is Z, Cl CB alkyl-YZ, C_CB alkenyl-YZ or C2-Cg alkynyl-YZ;
Y is o, NR4, S(O)nl C=o or CH~ and n is an integer from o to 2;
wherein R4 is H, Cl-Cg alkyl or C2-C9 alkenyl; and Z is a chromophore group;

with the proviso that when X represents:

8 9 3 3 7 ^--wo 9s/30646 o . ~1,~,., . . ~
o then Z is not ~11~
Pre~erahly, X represents one of the following groups:
O O
R4)~0-- 4J~ NH~ N--H2C~o-- Cl~`OH [~/

wherein R4 is H, C~~Cg alkyl or CA~-Ce alkenyl;
and Z is rrPf~r~hl Y a ~:11LI , hr~re group:

W095/30646 , ,~,,t~ 21 89337 T~

Rl R2 1O ~ 1~ r ~ ~

wherein Rl and R2 may be the same or diffe_ent and represent:
-H, -ORs, -NRsR~, -S03s~, chloro, fluoro, bromo, iodo, Cl-Ca alkyl, C.-C3 alkenyl, C3-c9 alkynyl, phenyl, -Cl-Ca alkylphenyl, - C2 - C8 alkenylphenyl, - C2 - Ct alkynylphenyl, -CooR3, -CoR3, -Cl-Ca alkylCORi, -C2-Cg alkenylCOR3, -C2-C8 alkynylCOR3, -Cl-C8 alkylCOOR3, -C2-C8 alkenylCOOR3 or -C2-C8 alkynylCOOR3;
alternatively, either or both of Rl and R3 may be replaced by a group C,-C, alkyl-YZ, C2~Cq alkenyl-YZ
or C2-C8 alkynyl-YZ wherein Y and Z are as defined above;
R3 is H, C.-Cg alkyl, C.-Cg alkenyl, phenyl, C~-Cl2 cycloalkyi, C~-Cl2 cyr~ konyl, C~-C10 W095/30646 ~ t C 2 ~ ~9337 .~

cyclnA7kPn~nf~ Qr C~-C.2 cy~l~Alk~n-~nf~;
Rs and R; may be the same or different and represent H or C. - Cq alkyl .
s It can be seen that all o~ the above compounds conform to the general pattern of a Michael acceptor linked to a chromophore or to a pair of unconjugated chromophores.
In the present invention the term "Cl-C8 alkyl" -efers to a straight or branched chain alkyl group having from one to eight carbon atoms. Examples of such groups include methyl, ethyl, n-butyl, ~-butyl and n-hexyl.
In the present invention, the term ~C2-C8 alkenyl" refers to a straight or branched chain alkenyl group having from two to eight carbon atoms. Examples o~ SUGh groups include ethenyl, propenyl, 1-butenyl and 2-butenyl.
In the present invention, the terms "C~-C~2 cycloalkyl" and "C~-C.~ cycloalkenyl" refer respectively to substi~uted or unsubstituted cyclic alkyl and alkenyl groups having from

4 to 12 carbon atoms. Such groups include cyclobutyl, cyclohexyl, cyl~ h~ onyl and more complex ring systems such as norbornyl and norbornylene It is pre~erred that the group X represents either a malelmido group or a maleamic acid residue since cu~ .,ullds based on these Michael acceptors are particularly easy to 5ynth,sq; q~ and react reaaily yet mildly with thiols.
t has been ~ound that good results are obtained when the roup R is a subs~ituted phenyl group, a h~n7nphl~n~n~ or WO s5/30646 ` ~ ' 2 1 8 9 3 3 7 ~ 0~5 substituted benzophenone or a cinnamic acid derivative.
The following compounds of general formula I are particularly useful:

N- ~4-carboxyphenyl)maleamic acid;
N- ( 4 - carboxyphenyl ) maleimide;
N- (4-benzoylphenyl)maleamic acid;
N- (4-benzoylphenyl)maleimide;
N- [4 - ( 2 -carboxy- ( ~) -ethenyl) phenyl] maleamic acid;
N- [4- (2-carboxy- (E~) -ethenyl) phenyl] maleimide;
N- [4- (2-carboxy- (Z) -ethenyl)phenyl]maleamic acid;
N- [4 - (2 -carboxy- ( Z) -ethenyl ) phenyl] maleimide;
N- (4-methoxycarbonylphenyl)maleamic acid;
N- ( 4 -methoxycarbonylphenyl ) maleimide;
N- (4-n-butyloxycarbonylphenyl)maleamic acid; and N- (4-n-butyloxycarbonylphenyl)maleimide.
It has been found that the W characteristics of the chromophores used in the compounds of the invention are changed s/ ~ on directly attaching a Michael acceptor and subsequently reac~ing the product with a thiol.
Generally, it has been found that the Amax of the chromophore falls slightly on attaching the Michael receptor with a rather larger fall on reaction of the product with cysteine . This can s~ - t i ~ be a problem since if the change in ~max is too great, the chromophore may no longer absorb light in the WA or W}3 wavelength range .
An example of this change is 4-aminobenzophenone which has a )~max of 318 nm which is in the W3 range. When the amino group is replaced by a maleamic acid group, the ;~max of the chromophore shifts to 306 nm which is still e~ 2~893 wo 95/30646 3 7 1 ~ . . L

within the u~s range but when the amino sroup is replaced by a maleimide resldue, the Amax falls to 25B nm. This is ou~side ~he range of W~3 although there is a restoration of W.3 activity when the maleimide is reacted with cysteine as it would be when applied to the skin lAmax = 293 nm). The changes are easily rationalised on the basis of conjugative effects but the effects of attaching Michael acceptors to the various chromophores which may be used cannot always easily be predicted.
This problem can be overcome to a large extent simply by g~r~r~tin~ the chromophore from the Michael acceptor using a spacer. Particularly useful oJ~ ds therefore include those in which the group R is Cl-C8 alkyl-YZ, C~-C6 alkenyl-YZ or C2-C8 alkynyl-YZR and especially those in which Y is O~ Compounds in which a hexyloxy linker is used (that is, R is (C~I~) 6Z) are especially preferred.
Examples o~ compounds of general f ormula I with a spacer between the Michael acceptor and the ChL~ , hnre include the ~ollowing:
N- [6- (4-be~zoylphenoxy) hexyl] -maleamic acid;
N- [6- (4-benzoyl-3-hydroxy-phenoxy) -hexyl] -maleamic 2 5 acid;
N - { 6 - [ 4 - ( 2 ', 4 ' - dihydroxybe~zoyl ) - 3 - hydroxy -phenoxyl]-hexyl}-maleamic acid;
N- [6- (4-benzoylphenoxy) hexyl] -maleimide;
N- [6- (4-benzoyl-3-hydroxy-phenoxy) -hexyl] -maleimide;
N- { 6- [4 ~ - (2 ', 4 ~ -dihydroxybenzoyl ) -3 -hydroxy-r i~ }r ~ 2 i ~) 9337 W095l30646 ~ ` ~f ~

phenoxy] - hexyl } - mal e imide;
N-{6-l [4' - (2"-ethylhexyloxy) -carbonyl- (Z) -ethenyl] -phenoxy} -hexyl } -maleamic acid;
N-{6-{ [4' - (2"-e~hylhexyloxy) -carbonyl- (Z) -ethenyl] -phenoxy} -hexyl} -maleimide;
N-{6-{ [4~- (2"-ethylhexyloxy) -carbonyl- (E) -ethenyl] -phenoxy} -hexyl } -maleamic acid;
N-{6-{ [ (4' - (2"-ethylhexyloxy) -carbonyl- (E) -ethenyl] -phenoxy~ - hexyl ~ -maleimide;
N- { 6 - [ (4 ' -ethoxycarbonyl- (Z) -ethenyl) -phenoxy] -hexyl ~ -maleamic acid;
N-{6- [ (4~ -ethoxycarbonyl- (Z) -ethenyl) -phenoxy] -hexyl } -maleimide;
N- { 6 - [ ( 4 ~ -ethoxycarbonyl - (E) -ethenyl ) -phenoxy] -hexyl } -maleamic acid;
N-{6-[(4'-ethoxycarbonyl-(E)-ethenyl)-phenoxy]-hexyl~-maleimide;
[4- (2' ,2~ -dimethylethyl) -benzoyl] - [4- (ethenedioic acid mnnn~m; rf~-N-6-hexyloxy) -benzoyl] -methane;
[4- (2 ~, 2 ~ -dimethylethyl) -benzoyl] - [4- (6-maleimidohexyloxy) -benzoyl] -methane .
The pre~erred compounds according to the present invention are, unlike many conventional sunscreens, not WO95/30646 2~ 89337 ,~I~ 5. l~s irritating to the skin and they will there~ore be particularly welcome to the large section of the population who have sensitive skin and are therefore not able to use conv~nt;nn~l sunscreens without a considerable degree of discomfort. In addition, on testing ~or mutagenicity it was surprisingly found that, unlike many known N-alkylmaleimides the compounds of the present invention do not seem to be mutagenic and they also have very low toxicity .

Compounds of general formula I in which X is a maleamic acid residue:
~OH
1~ N H--o can be prepared by reaction of maleic anhydride with a compound of general ~ormula II or III.
RNH~ II

wherein R is as defined in general formula I in an inert solvent such as dinhl orn~othane and in the presence of a tertiary amine such as triethylamine.
Compounds of general formula I in which X is a maleimide res idue:

WO95/30646 ~'?~ .; 2~89337 ~ 0~5 o O

can be prepared from the correspondi~g maleamic acid compound of general formula I by reaction with a dehydrating agent such as acetic acid in sodium acetate.
Compounds of general formulae II and III can both be prepared from a compound of general formula IV
o ~ N--R
o IV
wherein R is as def ined in general f ormula I .
In order to obtain a compound of general formula II, the compound of formula IV can be treated with hydrazine whilst, if a compound of general formula III is required, the rhth~ ;de residue can be cleaved in the presence of acid .
Whether the compound of formula I is synthesised via a compound of formula II or formula III will depend upon the nature of the group R . I f it is stable in acid but unstable in alkali, then the compound of formula IV will be converted with acid to a compound of formula III
whereas if the group R is unstable in acid, the route via WO 95~30646 r ~ s 5~ ~ ~ 2 1 8 9 3 3 7 1 ~ l oln~

a c~ ,ul~d of formula II will be used.
A compound of general formula IV can be prepared from a compound of ~general formula V:

R-Br V
wherein R is as def ined in yeneral f ormula I by reaction with:

N K+
(potassium phthalimide) in a polar solvent such as dimethylformamide (DM~). This route for the conversion of compounds of general formula V to compounds of general formula II is known as the Gabriel synthesis and preferred reaction times and conditions are familiar to those skilled in the art. The Gabriel Synthesis is particularly useful when R is a bpn7orh~on~n~o or similar derivative .
An alternative method for the preparation of a ,- ~1 of general ~ormula III is by reaction of a ~ ' of general formula VI:
R-N (MelSi~ 2 V
wherein R is as defined in general formula I. ~his reaction is carried out in the presence of aqueous acid and is useful when the group R is one which is suscep~ible to nucleophilic attack in a site other than Wo 95/30646 PCTIGB95/0103 the one to be coupled to the Micnael acceptor.
Compounds of general formula VI can be prepared from c u,..,Juul-ds of general formula V by reaction with ~a~N~(SiMe3)2.
Compounds of general formula V are well known in the art and/or can be prepared by methoas known to those sk ' lled in the ar~.
A third way of preparing compounds of general formula III
lS by reac~ion of a compound of general formula VII
R-NHCOO'Bu VII
wherein R is as defined in general formula I, with trif luoroacetic acid to remove the t-butyloxycarbonyl (Boc) protecting group.
Protected amines of general formula VII can be produced from amines similar to those of ~eneral formula II. This rou~e is of ten used when R is a reactive group such as a cinnamic acid derivative. For example, an aryl group can be introduced into a protected amine to give a compound of general formula VII, following which the protectiny group can be removed to give a compound of general formula III.
Compounds of general formula I in which X is a maleic acid ester residue:

` ~ ~ir. . ~ 2t ~9337 WO g5/30646 'I ~I~

o ~OH
~0 can be prepared by reaction of a compound of general formula VIII:
R-OE~ VIII
wherein R is as defined in general formula I with maleic anhydride in an acid catalysed ester~ t i nn reaction .
Alcohol derivatives of general formula VIII are well known or can be prepared by methods known to those skilled in ~he art, for example from bromides of general formula v.
Compounds o~ general formula I in which X is a quinone derivat iYe:

and R is a group Z can be prepared by the reaction of qui~one with a ~-~rnrolln~ of general formula IX:
ArN2~ IX
under the canditions described in Org. Synth. Coll. Vol.

Wo 95/30646 .. i ~ ; 2 1 8 q3 3 7 PCr/GBsS/0l035 4, 15 (1963) . For compounds of general formula I in which X is a quinone and R is a substituted Z group such as Z-O (CH2) n/ a suitable synthetic route is the reaction of a compound of general formula X:
z-o (CH2) nC02H X
wherein Z is as defined in general formula I with quinone under the conditions described in Org, Synth., Coll. Vol.
6, 890 (1988).
Compounds of general formulae IX and X are known in the art or may be prepared by methods familiar to those skilled in the art.
Compounds of general formula I in which X is an acrylic acid residue:
o 2 0 ~ O H
may be prepared by heating a compound of general formula XI:
R- CH=C ( C02Et ) 2 XI
in aqueous acid.
A ,~,,mrolln~ of general formula XI may be obtained by reac~ion of a compound of general formula XII:
RCHO XI I

WO 95/30646 ~ ? ~ C; 2 t a 9 3 3 7 with diethyl proF~np~i~i c ester [ (EtO2C) zCE2] in the presence of pyrimidine.
Compounds o~ general f ormulae XII are known in the art and may be prepared by methods known to those skilled in the art.
An alternative method for the synthesis of a compound of general formula I in which X is an acrylic acid residue is via the Perkin reaction. In this method, a of general formula XIII:
RCEO XI I I
is reacted with acetic anhydride in the presence of sodium acetate. This is a particularly suitable method when R is an aryl group.
Again, aldehydes of general formula XIII are well known 2 0 in the art .
The processes f or preparing the compounds of general formula I form a part of the present invention and therefore in another aspect of the invention there is provided a process for the preparation of a compound of general formula I, the process comprising:
a. when X is a maleamic acid _esidue, reacting maleic anhydride with a compound of general ~ormula II or general formula III in an inert solvent such as dichloromethane, optionally in the presence of an amine such as triethylamine;
b. when X ls a r-l,=;m;~l~ residue, reacting the compound Wos~/30646 ; ~ ri~t~ 2 1 89337 PCr/GB95101035 of general formula I produced in step ~a) with a dehydrating agen~ such as acetic acid and sodium acetate;
c. when X is a maleic acid ester residue, reacting a S compound of general formula VIII with maleic anhydride;
d. when X is a quinone residue, reacting quinone with a compound of general formula IX or general formula X; or e. when ~ is an acrylic acid residue, heating a compound of general formula XI in aqueous acid conditions or reacting an aldehyde of general formula XIII with acetic anhydride;
wherein general formulae II, III, VIII, IX, X, XI and XIII are as defined above.
The compounds of the present invention may be fULI ~ ~t~
as creams, lotions or oils for topical administration to the skin. Conv~nti~n;~ )1 ogically acceptable excipients are well known to those skilled in the art and include fats, paraff~n, emollien~s etc.
Thus, in a further aspect of the invention, there is provided a sunscreen formulation comprising a compound of the present invention together with a dermatologically accep~able ,~ ;ni~nt or carrier.
In a further aspect of the invention, there is provided a process for screening the skin from the sun, comprising applying to the skin a sunscreen compound as described above .
Because of their ability to screen the skin ~rom the sun _ _ W0 9~130646 ~ 2 ~ 8 9 3 3 ~

for prolonge-d periods of time, the compounds of the invention will be of cLssistance in preventing dermatological cnntlitin-nR arising from exposure to sunlight, for example erythema, premature aging, skin cancers and other conditions caused by prolonged exposure to sunlight.
Therefore, in a further aspect of the invention there is provided a compound of the invention for use in the prevention of dermatological rnn~i tinnq related to exposure to sunlight.
The invention also comprises a method for the preventiOn of a dermatQlogical condition arising from exposure to sunlight, the method comprising administering to a patient an effective amount of a ~ ULld as described above .
In an ;~ ;tirn~l aspect of the invention there is provided the use of a compound as described above in the preparation of an agent for t~Le prevention of rl,-r~tnl ogical conditions arising from exposure to sunlight .
The invention will now be further illustrated by refere~ce to the following examples and to the drawings in which:
FIGURE 1 is a plot showing the change in the absorption spectrum of hair keratin after reaction with N-phenylmaleimide j and FIGURE 2 is a plot showing the change in the absorption spectrum of horn-hoof keratin after W0 95/30646 ~ 2 1 8 9 3 3 7 P l . ~1035 reaction with ~-~henylmaleimide.
Exam~le

5 N- (4-carboxyphenyl)~ c acid o 11~ NH~ COOH
4-Aminobenzoic acid (17.24 g, 0.1257 mol) was added to a stirred solut~on of maleic anhydride (12.33 g, 0.1257 mol) in L,~upc...ulle (300 ml). Stirring was nnntin~a~l at room temperature f or 3 hours . The product, which separated as a yellow solid, was collected by suction filtration and ~ried on the filter: ~p 217-219C. ~Ref:
20 K C Liu, IJ. Chin. Che~. Soc., 1973, 20, 163) .
Exam~le 2 N- (4-carboxyphenyl)maleimide 2~
¢~N~COOH

The product --om Example 1 (20 . 00 g, 0 . 0852 mol) was added to a stir~ed solution of anhydrous sodium ethanoate (4 . oo g) in ethanoic anhydride (200 ml) and the mixture WO 9s/30646 ~ 3 3 7 PCT/GB95l0l035 heated with s~irrIng at 90-95C until ~l;qcoll~tion was complete. The solution was allowed to cool to room temperature, with stirri~g and, af~er a further 2 hours, poured slowly into an ice-59~ aqueous sodiu~ bicarbonate solution (2 L). The precipitate was filtered at the pump, wa8hed with diethyl ether (3 x 30 ml) and air dried. ~urification of the product by flash chromatography using chloroform as eluent yielded the maleamic acid (Ref: K C Liu, J. Chin. Chem. Soc., 1973, 20, 163 ) .
Examole 3 N- (4-~enzoylphenyl)male ic acid o 1~ NH~
O
4_r--i nf h~n70phenone (10 . oo g, o . 0507 mol) was added to a stirred q~ ti~n of maleic anhydride (4.98 g, 0.0508 mol) in dirhl~ thane (200 ml). After 10 minutes of stirring at ~oom temperature, yellow precipitate was formed. Stirring was ~-~7nt;nl-~d for a rurther 3 hours, following which the solid was collected, wa8hed with dichl~ th~n~ (3 x 30 ml) and diethyl ether (2 x 30 ml) and finally air dried to yield the maleamic acid.
(Found: C, 68.74; H, 4.57; N, 4.41%. CI~HI3NO~ requires ~, 69.15; H, 4.44; N, 4.7496) H.p.l.c (KrOmaZil Clhl 49.9596 MeOH, 49.959~ H2O, 0.19~ CF3CO2H): 99.7~ x 306 nm;
~ 20560. I~-n.m.r (DMSO): ~ 10.62 (lH, s, NH); 7.8 - 7.5 W0 95/30646 'i r~ 2 1 8 q 3 3 7 pcllGB95lolo3s (9H, m, phenyl); 5.45 (lH, d; CH = CH); 6.31 (lM, d, CH
CH); 3 . 3 8 ~ 1~ , S , CO.H) .
Exam~le 4 N- (4-benzoylphenyl)maleimide ¢~N~cO~
o The method of Example 2 was employed, but, in place of the product of 3xample 1 the maleamic acid from Example 3 (15 . O g, O . 0508 mol) and anhydrous sodium eth~nr~atP
(3 . oo g) in ethanoic anhydride (150 ml) were used. The maleimide was obtained. lH-n.m.r (DMSO): ~ 7.91 ~4H, m, N-Ph); 7.52 (5H, m, Ph); 6.89 (2H, s, CH = C~), H.p.l.c.
10096.
Exam~le 5 ~- [4- (2-carhoxy- ( ) -ethenyl)phenyl]maleamic acid ~OH ~OH
o o The me~hod of Example l was employed using 4-W095/30646 `; ~ 1 8 9337 I~l.. 1035 ~minnninni~mtC acid hydrochloride (10.0 g, 0.0501 mol) and maleic anhydr~ de 15 . 00 g, 0 . 0509 mol) . Triethylamine (7.00 ml, 0.0502 mol) in dichloromethane ~100 ml) was added to gerera~e the f~ee amine. The yellow maleamic 5acid was obtained. H.p.l.c. 100~. IH-n.m.r. ~DMSO): ~
10.51 ~lH, s, 2~H); 7.65 ~4H, bs, ar H's); 7.55 ~lH, d, pH
- CH); 6.44 ~2H, t, HO.C CH = CH; CO, PhCH = CH); 6.30 ~lH,d,HO2C CX = C~ CO) .
10~m~le 6 N- [4- (2-carboxy- (E) -ethenyl)phenyl]malei ide i5 ¢~N~ ` OH
o This preparation was carried out as for the method described for Example 2 using the produc~ from Example 5 ~10.0 g, 0.038 mol). Purification was carried out by flash column C~1L~ ~n~raphy with 10~ methanol - 90 chloroform as eluent. The maleimi~e was obtained.
H~p.l c. 99_8196. lX-n.m.r. (CDCl,): ~ 7.80 (2H, d, 2, 6H
on phenyl); 7 . 61 (lH, d, CH = CH CO2H); 7 .38 (2H, d, 3 , 5-H
on phenyl); 7.20 (2H, s, CH = C~); 6.57 (lH, d, CH =
CXCOzH) .

Wo 9~/30646 ~ ~ ' 2 ~ ~ 9 3 3 7 . ~1 103~

Example 7 N- ( 4 -methoxycarbonylphenyl ) mal eamic acid 1~
NH~OMe The method described in Example 5 wa6 employed using methyl 4-~1n; nnh-~n7n~te hydrochloride (10 . O g, 0 . 053 mol) .
the maleamic acid was obtained. (Found C, 57.60; H, 1~ 4.55; N, 5.52%. Cl2H.lNOs reS~uires C, 57.83; H, 4.45; N, 5.62%) lH-n.m.~. (DMSO): ~ 10.65 (lH, 5, NH); 7.91 (2H, d, 2,6-H of phenyl); 7.75 (2H, d, 3,5-H of phenyl); 6.51 (lH, d, CH = CH); 6 32 (lH, d, CH = C~); 3.82 (3H, 8, CH3) . H.p.l.c. 99.31%. A,""~ 294 nm: ~ 16013.
Exam~le 8 N- (4-meth~" y~ ",ylphenyl)r~ ;m;ti~
2 5 ¢~N~ OMe o The me~hod descr bed in Example 2 was employed using the product from Exam~le 7 (10.0 g, 0.04 mol) . The maleimide wa6 obtained as a golden yellow solid. ~Found C, 61.77;
H, 4.06; N, 5.899s. Cl2H9NO~ 0.1 H20 re~uires C, 61.86; H, 3.98; N, 6.01%~ . H.p.l.c. 99.73%. -H-n.m.r. (CDCl3):

WO 95130646 t ~ ~ ~ 8 9 3 3 7 J ~ L~ ~

8.06 (2H, d, 2,6-H on phenyl); 7.42 ~2H, d, 3,5-H on phenyl); 6.81 (2H, g, C~ = CH) 3.85 (3H, s, CEI,) . A","~ 245 nm, E 15844.
~mnle 9 N- ( 4 -n -butyloxycarbonylphenyl ) m ~ l e~m; r acid o I C~ NH~<On~U

The maleamic acid was prepared using the method described in Exam.ple 7 but butyl ester (12.20 g, 0.053 mol) was used in place of the methyl ester. The product was obtained as an o~-white solid. (Found C, 61.71; H, 5.74; N, 4.67~6. C,sHl~NOs re~uire6 C, 61.85; X, 5.88; N, 4.8150). H.p.l.c. gg go~ iH-n.m.r. (DMSO): ~ 10.61 (lH, s, NH); 7.85 (2H, d, 2,6-H o~ phenyl); 7.73 (2H, d, 3,5H
o~ phenyl); 6.45 (lH, d, CH = CH); 6.32 (lH, d, CH = C~);
4.21 (2H, m, CH2); 1.52 (2H, m, CH2) . A",," 294 m:l, E
15806.

Wo9sl306~6 ~ r~ 2 ~ 8933 7 r~

E~xam~le 10 N- (4-n-butyloxycarbonylphe~yl)maleimide ~N~oO~Bu The maleimide was prepared as in Example 8 using the product from Examcle 8 (10 . O g, O . 034 mol) i~ place of the methyl ester. ~he product was ootained as an off- : _ white solid. (Found C, 65.70; H, 5.69; N, 5.0556.
C.sHlsNO4 requires C, 65.93; H, 5.53; N, 5.13~). H.p.l.c.
99.89~. 1E-n.m.r. (CDC13) 8.11 (2H, d, 2,6H of phenyl);
7.46 (2H, d, 3,5H of phenyl~; 6.83 (2H, 5, CN = CH); 4.29 (2H, t, CLY1CH2O); 1.71 (2H, m, CLY2 CH2O~; 1.44 (3H, m, CH3, C~2); 0.94 (3H, t, CH3). A,~.x 245, ~ 15563.
~Y~ le 11 N- [6- (4-benzoylphenoxy) -hexyl] -maleamic acid 1 J~OH
1~ ~ NH (CH2)6--(}~co~3 The steps for the preparation of this c(....~uulLd were as follows .

W0 9S/30646 ' ~ t ~ 1 8 9 ~ 3 7 PCr/GB95101035 A. Preparation o~ 4- (6-b~, Ayy1oY,y) _b~n~A~rh_nAn_ To a solution of sodium ethoxide, prepared by dissolving sodium (1.3D g, 0.055 mol) in absolute e~hanol (150 ml), was slow;y added 1-benzoyl-4-hydroxy-benzene (10 g, 0.05 mol) . The resulting solution was added dropwise to a stirred solution of 1,6-dibrnmnh~ n_ ~36.6 g, 0.15 mol) in ethanol heated under reflux. Stirring and heating were Annt i n~ l for 8 hours during which time sodium bromide was formed as a crystalline precipitate.
Removal of the sodium bromide by filtration and evaporation of the filtrate in vac~Ao gave a white solid which was washed with ethanol ( 3 0 ml ) . The ethanol washings were rA~ ntra~ed to 10 ml and the product isolated by flasn column chromatography using chloroform as eluent to yield the bromohexvl deArivative as white crvstals. (Found: C, 63.12; H, 6.18~. ClgH2~BrO2 requires C, 63.17; H, 5.86%) . FA~ ms 362 and 360 (MH ) .
H-n.m.r. (DMSO) ~ 7.3 - 6.9 (9H, m, aromatic); 4.02 (2H, t, CH2); 3.41 (2H, m, CH2); 1.99-1.80 (2 x CH2); 1.50 (2 20 x CH,) .
B. Preparation of N- [6- (4-~Anzoylp_enoYy) -hexyl] -rhi h~l ;m;~i_ Potassium ~hth~l imide (5.75 g, 0.031 mol) was added to a solution of the product from A (10.2 g, 0.028 mol) in dimethylformamide ~250 ml). The reaction mixture was heated at 60C for 16 hours. Chloroform (300 ml) was added and the mixture poured into distilled wa~er ( 1. 4 L). The chloroform layer was separated and the a~ueous layer extracted with chloroform (2 x 75 ml). The combined chloroform layers were washed successively with 0.2 M sodium hydroxide ~150 ml) and water (150 mi), dried over anhydrous magnesium sulphate and evaporated to yield a gum which produced white crystals of the desired Wo 95/30646 ~ 1~ f~ ' 2 t ~ 9 3 3 7 r~l.. Clu~

nhth~ ;mide derivative and its hydrate on trituration with diethyl ether. (Found: C, 74.37; H, 5.96; N, 3.24~.
C2,H2sNO~ 0.5 H2O requires C, 74.29; H, 6.00; N, 3.21~).
rAB ms 428 (MH ) . lH-n.m.r. (CDCl3) ~ 7.8 - 7.6 (6H, m, - aromatic); 7 . 5 (2X, m, aromatic); 7 . 4 (3X, m, aromatic);

6.7 (2X, m, aromatic); 4.0 (2X, t, C~2N); 3.7 (2H, t, C~2O); 1.8 - 1.4 (8X, m, 4 x CX2). I3C-n.m.r. (CDCl3) 168.49 (C = O); 168.38 (CON); 162.68 - 113.91 (aromatic);
67.96 (CXz); 37.79 (CX2); 28.86 (CX~); 28.44 (CX2); 26.48 (CX2); 25 . 55 (CX2) .
C. 4- (6- ; oh~Yyloxy) -bon~u~h~ ~ chloride The product from B (above) (9.00 g, 0.021 mol) was added to a mixture of ethanoic acid (200 ml) and rnnn~ntrated hydrochloric acid ( 2 0 0 ml ) and the mixture heated under reflux for 36 hours with further additions of 1:1 ethanoic acid and hydrochloric acid (100 ml) after 4 and 24 hours. The resulting solution was treated with charcoal, filtered and the filtrate washed into an evaporating flask with chloro~orm. Evaporation yielded the hydrochloride as an of ~-white solid on trituration with diethyl ether. (Found: C, 60.33; H, 6.67; N, 3.7496. ClgH2~NCl03 0.45 CHCl3 requires C, 60.28; H, 6.36;
N, 3.61~ H-n.m.r. (CDCl3) ~ 7.9 (3X, bs, N'X3); 7.6 -

7.5 (9H, m, aromatic); 4.2 (2X, t, CX2N); 2.8 (2H, t, CX2o); 1.8 - 1.4 (sX, m, 2 x CX2); 1.4 - 1.2 (4X, m, 2 x CH2 ) .
D. 1-3e~zoyl-4- (e~n~; oir acid - ~-N-hexy1-6-30 oxy)-benzene (Example 11) The product from C (above) (5 . 00 g, 0 . 015 mol) was treated as for Example 5 using maleamic acid (1.47 g, 0.015 mol~ . Column chromatography on silica gel with lO9o MeOH, 905O chloroform yield the pure title compou~2d as its W0 95/30646 ` ' ~ ~ l 8 9 3 3 7 , ~ ., ~ ~ c l~35 hydrate r~p 114 - 6C. (Found: C, 6B.97; H, 5.31; N, 3.39%. C23X,5NOs 0.4 H20 re~uires C, 68.61; H, 6.46; N, 3.4836) FA~3 ms 396 (MH ) . lH-n.m.r. (CDCl3) ~ 8.2 ~lH, bs, NH), 7.8 - 7.4 (7H, m, aromatic~, 6.9 ~2H, d, aromatic), - 6.4 (lH, d, CH = C), 6.2 ~lH, d, CH = C), 3.8 ~2H, m, CH2N), 3.3 ~2H, m, CH20), 1.8 - 1.3 (8H, m, 4 x CHz). A,,,~,~
(CH3Cl2) 285 nm, ~ 16047. H.p.l.c. 99.7%.
ExamPle 120 N- [ 6 - (4 -benzoylphenoxy) -he~cyl] -T '- l F.; Tn; .1~-[~N--(CH7)6--~CC~
The compound can be prepared from N- [6- (4-benzoylphenoxy)-hexyl]-maleamic acid from Example ll by reacting with acetic acid and sodium acetate according to the method described in Example 2. The desired maleimide was i qnl;~te~i as its monohyarate by ~lash column ~ L to~raphy. Mp 84 - 6C. (Found: C, 72.78; H, 6.28; N, 3.58%. C23H23NO3, H20 reauires C, 73.19; H, 6.65;
N, 3.69~) . H.p.l.c. lD0%. FA3 ms 378 ~MH~) . lH-n.m.r.
~CDCl3) ~ 6.9 ~2H, m, aromatic), 6.6 ~2H, d, CH = CH), 3.9 (2H, m, CH2), 3.5 (2H, m, CH2), 1.8 (2H, m, CH2), 1.6 ~2H, m , CH2 ), 1 . 5 ~ 2H , m , CH2 ), 1 . 3 ~ 2H , m , CH3 ) . A,,,,,c ( CH2Cl2 ) 286 nm, ~ 16590.

WO9S/30646 ~ 2 1 8933 7 rxam~le 13 N- [6 - (4-benzoyl-3 -hydroxy-phenoxy) -hexyl] -r- 1 o1 m; C' acid NH (CH2)6_o~C~3 ~his compound can be prepared according to the f ollowing method .
~. 4- (6-L., h~Yyloxy) -2-hydroxy-~on7~h~n~no The preparative method employed was analogous to that in Example 10 A uæing 2,4-dih-yd,~,~yL,~lzophe~one (20.00 g, 0 . 08B mol~ in place of benzophenone. The product was isolated as of ~-white crystals and was used without further purification in s (below).
B. N- [6- (4-benzoyl-3-hydroxy-pheuoxy) -hexyl] -Fhl h~l ;ri~lP
The product f rom A was treated in an analogous manner to that described in Example 10 B (above), and the product was isolated i~l 42.57~ yield by column rhro~trrraphy (sio, gel - 10~ ethyl ethanoate in hexane).
C. 4- (6-ammo::Liohexyloxy) -2 -hydroxy-benzophenone 3 o hydrochloride The product from B (3 . 00 g, 0 . 00676 mol) was treated as for Example 10 C (above). The product hydrochloride was obtained as a tan-coloured solid.

Wo 9S/30646 ~ C 2 1 8 9 3 3 7 pCrlGB9510103~ ~

D. N- [6- (4-benzoyl-3-hydroxy-phenoxy) -hexyl] ~ m;C
acid ~he product ~rom C ~1.00 g, 0.00286 mol~ was reacted with maleic anhydride as descri~ed in Example 13 D and the ~ure tltle compound as i~s monohydrate was isolated as a tan-coloured solid. (Found: C, 64.66; H, 6.04; N, '.34%. C23Hl~jNO~ H30 reqllires C, 64.32; H, 6.34; N, 3.26) .p.l.c. 99_~%. FA3 ms 412 (ME~ H-n.m.r. (CDCl3) ~
L2.8 (lH, bs, NH), 7.8 - 7.2 (8H, m, aromatic), 5.5 - 6.1 (3H, d+s, CH = CH, OH), 4.1 (2H, m, CH2), 3.3 (2H, m, CH~), 1.9 - 1.2 (9H, m, 4 x CH3 + OH).
P~ le 14 X- [6- (4-benzoyl-3-l~y~ ~,.yyhcnoxy) -hexyl] -~ .;m~
O OH
¢~ ( 2 ) 6 ~ C
O
~his compound was prepared from the product o~ Example 13 using the method o~ Example 2.
~n order to demonstrate that the compounds of the invention are capable o~ binding to keratin, the Collowing experiments were carried out S.: 2 ~ 8933 7 W0 95~30646 r~

''xaml~le 15 N-{6- [4- (2' ,4' -Di~y~Lu~Lyb_ ~uyl) -3-hy~Lu~yy}i_~u~y]}lexyl}
~ Am; f~ acid OH O OH
HO ~' `~ O(CH~)6--HN

o A. 4-[6-(N-t-Butyloxycarbonyl)~ nh~Yyloxy]-2,2',4'-tril~yd. u~y~ rh~nnn~
Sodium (3 . 48 g, 152 mmole) was dissolved in absolute ethanol (500 ml). The mixture was purged with nitrogen and 2,2' ,4,4' -tetrahydroxybenzophenone (37.5 g, 152 mmole) added. Methane sulphonic acid 6- (~-t-butyloxycarbonyl)~minnh,~yl ester (15 g, 50 mmole) was added. The mixture was refluxed for 27 h, then filtered.
The filtrate was crnr~ontrated to dryness and redissolved in chlorof orm . An oil which so1; fi; f i .o~l, separated and was removed by filtration. The filtrate was concentrated to dryness and the process repeated twice. The final filtrate was crnr~ntrated to dryness and c_romatographed over silica gel using chloroform/methanol 9:1 to give the product (20.14 g, 8996) NMR (d6-DMSO): ~ 11.48 (lH, s, OH), 11.1 (lH, s, OH), 10.3 (lH, s, OH), 7.25-7.15 (2H, m, ArCH), 6.44-6.48 (2H, m, ArCH), 6.29-6.36 (2H, m, ArCH), 3.93-4.0 (2H, m, OCH.), 2.83-2.89 (2H, m, NCH~), 1.34-1.69 (17H, m, t-butyl, 4 x CH7). m/e: 446 (M + 1; 6~6), 346 (30~), 137 (1006~).

2 1 8 93~ 7 Wo95/30646 B. 4-(6_r inh~yyloxy-)-4~2~2~-triLy~u~yL~ orh~nA~r chloride 4- (6- (N-t-Butyloxycarbonyl) aminohexyloxy) -2, 2 ~, 4 ' -trihydroxybenzophenone (18 g) was dissolved i~ methanol (250 ml) and cooled on ice. Concentrated hydrochloric acid (50 ml) was added dropwise. After 15 minutes, cnnr~n~rated hydrochloric acid (25 ml) was addea and the mixture stirred at room temperature overnight. The solvent was removed and the residue crystallised from ethanol/ether to yield the title compound (7.9 g, 56.696) .
NMR(d6-DMSO): ~ 7.15-7.26 ~2H, m, ArCH), 6.44-6.49 (2H, m, ArCX), 6.28-6.33 (2H, m, ArCX), 3.95-4.03 ~2X, m, OCH2), 2.71-2.79 (2H, m, NCE~2), 1.33-1.73 (8H, m, 4 x CH.) . m/e 346 (M~ + l; 86% 253 (10096), C. N- {6 - [4 - (2 ~, 4 ' -Dihydroxybeuzoyl) -3 -~yd~u,-y~henoxy] hexyl}-~ m; r~ ;lcid 4 - (6 _pmj nnh~ cyloxy) 4 ~ 2, 2 ' -tri~lydL~,~y'u~ zophenone (1 g, 2 . 6 mmole) and maleic anhydride (255 mg, 2 . 6 mmole~ were suspended in methylene chloride (50 ml) and triethylamine (265 mg, 2 . 6 mmole) added. The mixture was stirred at room temperature for 2.5 days. Triethylamine (265 mg, 2 . 6 mmole) was added and the mixture stirred for a further 18 h. It was filtered, the filtrate concentrated and the residue redissolved in chl oroform (50 ml) . This solution was treated with a~Iueous XCl (25 ml, 1. 2 M) whereupon a precipitate formed. This was filtered off and dried (*40 mg, 38',;) I~MR (d6-DMSO) ~ 11.49 (lH, s, OH), 11.14 (lH, s, OH), 10.35 (lH, s, OH), 7.17-7.24 (2H, m, ArCX), 6.21-6.48 (6H, m, 4 x ArC~, 2 x CH of acid), 3.97-4.03 (2H, t, CH.O), 3.15-3.20 (2X, m, NCH2), ;.69-1.72 (2El, m, OE~2), 1.31-1 5~ ~6H, m, 3 x CX~) m/e: 444 ~M- + 1, 40~), 176 ~10096).

,,,. 21~q337 ~ W095raO646 ' ~ .,, S'~lOa~

rxaml~le 16 N-{6- [ (4' -Ethoxycarbonyl- (Z) -ethenyl)phenoxy]hexyl}-__ 7 ~ m; ~r acid A. Ethyl 4- [6- (N-t-butyloxycarbonyl) -s~m; nrh--Yyloxy] phenylethenoate ~thyl 4-hydroxyrinn~-~te (2.0 g) was dissolved ~n dry THF
(20 ml), potassium hydroxide (1.17 g) was added and the mixture stirred for 1 hour. A solution of 6- (N-t-butyloxycarbonyl)amino-hexanol methaneslllrhnnAte (3.07 g) in THF ( 12 ml ) was added dropwise during 3 o min and the mixture stirred for 3 h in a vessel protec~ed by a calcium chloride guard tube. The solution was heated under re~lux for l . 25 h, cooled, and the gel-like precipitate removed by filtration. rr,nr~ntration of the filtrate gave the title ~ ~ as a pale yellow oil which cryst~ll;q~ on standing (4.47 g, 110~ as solvate) lH nmr (CDCl~ 7.62(1H, d, ArCF~=CH), 7.44(2H, d, Ar-m-H) 6.86(2H,d,Ar-o-H), 6.28(1X, d, =CHCO), 4.5(1H, br, NH), 4 .23 (2H, q, CH2CH3), 3 .9 (2H, t, CH2O), 3 .7(2H, t, CE2CH2O), 3.1(4H, m, 2 x CH2), 1-7-1.9(4H, m, 2 x CH2), 1.~2 (9H, s, (CH3) 3C), 1.27 (3H, t, CH3) .
s. Ethyl 6- ; rh~Yyloxy) phenyl ethenoz~te chloride The product from A (2.0 g) was dissolved in ethanol (27.5 ml ) and the solution cooled to oC . Conc . hydrochl oric acid ( 5 . 5 ml ) was added dropwise over 10 min and the solution allowed to warm to room temperature with stirring. A further addition of conc. hydrochloric acid (2.7 ml) was made after 1 h and stirring crntin~ for a further 23 hours. Evaporation in vacuo yielded a white crystalline solid which was dried by co-evapora~ion with ethanol (15 ml). Recrystallisation from ethanol gave the _ . _ _ _ Wo 95/30646 ~ ~ g 9 3 3 7 ~ 5 title compound as white platelets (1.4 g, 84~).
M . s (FB) M 292 .
C. N-{6- [ (4~ -Ethoxycarbonyl- (Z) -ethenyl)phenoxy]hexyl}-5 ~ nTn; r acid Maleic anhydride ( 1. 5 g) was dissolved in acetonitrile (15 ml) and a suspension of the product from B above (1 g) in acetonitrile (15 ml) was added. The suspension was stirred and triethylamine was added dropwise. The resulting clear solution was stirred for 1 h, 1.2 M
hydrochloric acid (25 ml) was added and stirring cnntinll~rl for a further 1.5 h. The precipitate which formed was collected, washed with 1.2 M hydrochloric acid (3 ml) and dried by suction on the filter to yield the title c,u.. ~uulld as a white powder (0.33 g, 28~6) mp 135.5-136.5C. Hplc (80:20 MeOH:X2O), m.6 (FAB) MH 390. NMR (d6-DMSO) ~ 9.13-9.14 ~IH, bm, NH), 7.53-7.67 (3H, m, 2 x ArCH, alkenyl CH), 6.94-6.97 (2~, d, 2 x ArCH), 6.23-6.49 (3X, m, alkenyl CH), 4.14-4.20 (2H, ~, CH2CH2), 3.99-4.03 20 (2H, t, CH.CH2O), 3.16-3.22 (2H, ~, CH2N), 1.70-1.75 (2H, m, CH~), 1.32-1.54 (6H, m, 3 x CH2), 1.23-1.27 (3~, t, CH ) 3 ' Exam~le 17 Reactior. o r ~Laleimide derivatives with L-cysteir~e ethyl es ter In order to underpin the pri~ciple of reaction of maleimido derivatives with the cysteine thiol groups, two model reactions were studied. Thus the r~ rtirnc between L-cysteine ethyl ester and N-phenylmaleimide and N- (4-benzoylphenyl)maleimide were carried out. In each case, the reaction produced the diastereoisomeric product W0 9s/30646 ~ 1035 ~lxtures in reasonable yields at room temperature. All s~arting maleimides had reacted within 30 minu~es ~tlc).
~e two products were isolated and characterised.
~he mildness and rapidity of these reactions indicate that the maleimido groups confer the ability for reaction with the nucleophilic groups of keratin.
~xam~le l 8 Substantivity te~t~ with ker~tin ~~ order to demonstrate that the maleimides are capable of binding to keratin, the following tests were carried out using N-phenylmaleimide as a model ~ lu~d.
Initial tests were conducted with human hair sp~ 11 y cleaned and prepared to provide as near to a standard substrate as possible. The method adopted utilised the reduction in ultra-violet absorptivity in the supernatant ~olution in contact with hair when the compound under ~est was absorbed into the hair surface. Standard and control solutions were employed. It was found that the s~andardisation of hair, coupled with the difficulty of h~n~l ing a readily static-charged material, was impossible to achieve. Nevertheless, all results showed that substantivity was a feature of the N-phenylmaleimide used as a model compound, considerable reduction in absorptivity being observed. Similar tests with hair have been ~uoted in the patent literature as evidence, and as a standard test, for substantivity of sunscreens and other cosmetics.
Xeratin prepared from the horns and hooves of various _ _ _ _ _ . . . .. . . . . , _ WogS/30646 ~ 8 9 3 3 i L ~ iO3~ ~

animals is commercially available, and this was used in a similar ~ay to the hair (above). The keratin was f inely powdered and stirred with a solution of the maleimido compound and its substantivity estima~ed by uv absorptivity mea~uL~ tq The results were ound to parallel those obtained with hair (Table 2 and Figures 3 and ~ ) TA~3~E 1 Results o~ substa~tivity teE~ts on N-pheny~ ;m;~ with hair and horn-proof keratin W Wt ~l-~d~ dd d Wt aul-l-~d- ~b-orb-d Sub~tLvlty 15 t Or ~ uv ~ y) 1 0000 0 ~520 0 0~17 '8 5 1 0000 0 4670 0 1421 30 i ~v~r~c~ 0 1125 c 24 ~' Wt o~ Wt l~l-LsLd- ~dd~d Wt r~l-~d- ub~orb-d Sub~tuatl~ ty Ic-r-t1r 1 0000 0 il60 0 0968 '2 Z
1 0000 0 47il 0 1001 21 1 Av~r~c- 0 0985 C 21 7't The results indicate that the incorporation of a maleimido residue resulted in chemico-~hysical in~eractions~ with the keratin component of hair and the hard tissues of the epldermis. The method is ex~ensively used to establish substantivity and the measurements are an indirect lndication of persistence of the molecules on the hair or skin.

q337 -- W0 95/30646 ' ~ 5~ /c Examl~l e 19 ~iolo~ 71 results: mutagenicity and toxicity studies Among the important criteria for topically applied sunscreens, safety in use has the highest priority. It was thus n~cP~s~ry to investigate the mutagenicity of the maleimide and maleamic acid derivatives of sunscreens.
Six compounds of the present invention were chosen as representative of the main classes of sunscreen and submitted for Ames tests. The results are summarised in Table 2. The tests demonstrated that none of the compounds were mutagenic below toxic levels, with or without the presence of rat liver ~Pt~h~ activation system S9, that the maleamic acid derivatives showed only slight toxicity and that the maleimides were mildly toxic .

W0 95/30646 2 1 8 9 3 3 7 ~ 0103~ ~, ~-ABLE .2 Toxici~ arld mur~n; ~ ty test results E~AMPLE FORMULA TOXICITY/IlG plate ~utagenicitv +S9 -S9 3 ~Co~ ; 25~ 25~ es~ative O
4 C~_~Co~ 100 ~o o CO.~ -,, CO.H 5 ooo . suou o CO.H 500 5 0 0 5 ~ 2 5000 50~00 ,, o 6 ~jN~co2H 200 200 o 2H 6~ C~ 2500 2500 o 1 2) 12 ~N(CH2)6~co~ soo 200 O I ~
~I N~-~ S0 25 ~ ht-'~~( . oot statis~icallv o s i~2ni f icant

Claims (17)

1. The use of a compound comprising a UV chromophore attached to a group which is capable of covalently binding to mammalian skin, in the preparation of a sunscreen composition.

2. The use as claimed in claim 1 wherein the group capable of covalently binding to mammalian skin is a Michael acceptor attached directly or indirectly to the UV chromophore.

3. The use as claimed in claim 2 wherein the Michael acceptor is maleic acid, maleamic acid or maleimide, or a derivative of one of these.

4. The use of claim 2 or claim 3 wherein the Michael acceptor is separated from the chromophore by a spacer.

5. A compound of general formula I:
X-R I
wherein X is a Michael acceptor;
R is C1-C8 alkyl-YZ, C2-C8 alkenyl-YZ or C2-C8 alkynyl-YZ;
Y is O, NR4, S(O)n or C=O and n is an integer from 0 to 2;
wherein R4 is H, C1-C8 alkyl or C2-C8 alkenyl; and Z is a chromophore group;
with the following provisos:

that when X represents:
then Z is not or that the compound is not wherein n is 2 and R is methoxy or n is 6 and R is methoxy, ethoxy, pentoxy or hexyloxy;
or that the compound is not N-phenacylmaleinmonoamide, 1-p-Aminophenoxy-5-maleimidopentane, 2-hydroxy-4-(beta-hydroxyethoxy) benzophenone maleic acid, 2-hydroxy-4-(beta-hydroxyethoxy) benzophenone maleic acid ester, 2-(Phenoxymethyl)-1,4-benzoquinorle, 2-hydroxy-4-(2-methacryloyloxyethoxy) benzophenone, 4-(Methacryloyloxy) hexyloxy-bipheryl, N-phenyl ethanolamine methacrylate, N-(2-methylphenyl) ethanolamine methacrylate, 4-(Acrylocyloxyhexyloxy) cinnamic acid or N[6-(4-(2-hydroxy)-benzoylphenoxy)-propyl] maleimide.

6. A compound as claimed in claim 5, wherein X
represents one of the following groups:

wherein R4 is H, C1-C8 alkyl or C2-C8 alkenyl;
R is C1-C8 alkyl-YZ, C2-C8 alkenyl-YZ or C2-C8 alkynyl-YZ;
Y is O, NR4, S (O) n or C=O and n is an integer from 0 to 2; and Z is a group:

wherein R1 and R2 may be the same or different and represent:
-H, -OR5, -NR5R6, -SO3H, chloro, fluoro, bromo, iodo, C1-C8 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, phenyl, -C1-C9 alkylphenyl, -C2-C8 alkenylphenyl, -C2-C8 alkynylphenyl, -COOR3, -COR3, -C1-C3 alkylCOR3, -C2-C8 alkenylCOR3, -C2-C9 alkynylCOR3, -C1-C8 alkylCOOR3, -C2-C8 alkenylCOOR3 or -C2-C8 alkynylCOOR3;
alternatively, either or both of R1 and R2 may be replaced by a group C1-C8 alkyl-YZ, C2-C8 alkenyl-YZ
or C2-C8 alkynyl-YZ wherein Y and Z are as defined above;
R3 is H, C1-C9 alkyl, C2-C8 alkenyl, phenyl, C4-C12 cycloalkyl, C4-C12 cycloalkenyl, C4-C10 cyclcoalkenone or C4-C12 cycloalkenone;
R5 and R6 may be the same or different and represent H or C1-C8 alkyl.

7. A compound as claimed in claim 5 or claim 6, wherein R is a substituted phenyl group, a benzophenone or substituted benzophenone or a cinnamic acid derivative.

8. A compound as claimed in any one of claims 5 to 7, wherein the group R is (CH2)6OZ.

9. N-[6-(4-benzoylphenoxy)hexyl]-maleamic acid;
N-[6-(4-benzoyl-3-hydroxy-phenoxy)-hexyl]-maleamic acid;
N-{6-[4-(2',4'-dihydroxybenzoyl)-3-hydroxy-phenoxyl]-hexyl}-maleamic acid;
N-[6-(4-benzoylphenoxy)hexyl]-maleimide;
N-[6-(4-benzoyl-3-hydroxy-phenoxy)-hexyl]-maleimide;
N-{6-[4'-(2',4'-dihydroxybenzoyl)-3-hydroxy-phenoxy]-hexyl}-maleimide;
N-{6-{[4'-(2"-ethylhexyloxy)-carbonyl-(Z)-ethenyl]-phenoxy}-hexyl}-maleamic acid;
N-{6-{[4'-(2"-ethylhexyloxy)-carbonyl-(Z)-ethenyl]-phenoxy}-hexyl}-maleimide;
N-{6-{[4'-(2"-ethylhexyloxy)-carbonyl-(E)-ethenyl]-phenoxy}-hexyl}-maleamic acid;
N-{6-{[(4'-(2"-ethylhexyloxy)-carbonyl-(E)-ethenyl]-phenoxy}-hexyl}-maleimide;

N-{6-[(4'-ethoxycarbonyl-(Z)-ethenyl)-phenoxy]-hexyl}-maleamic acid;
N-{6-[(4'-ethoxycarbonyl-(Z)-ethenyl)-phenoxy]-hexyl}-maleimide;
N-{6-[(4'-ethoxycarbonyl-(E)-ethenyl)-phenoxy]-hexyl}-maleamic acid;
N-{6-[(4'-ethoxycarbonyl-(E)-ethenyl)-phenoxy]-hexyl}-maleimide;
[4-(2',2'-dimethylethyl)-benzoyl]-[4-(ethenedioic acid monoamide-N-6-hexyloxy)-benzoyl]-methane;
[4-(2',2'-dimethylethyl)-benzoyl]-[4-(6-maleimidohexyloxy)-benzoyl]-methane.

10. The use as claimed in any one of claims 1 to 4 wherein the compound is of the formula I (a):

X-R I(a) wherein X is a Michael acceptor;
R is Z, C1-C8 alkyl-YZ, C2-C8 alkenyl-YZ or C2-C8 alkynyl-YZ;
Y is O, NR4, S(O)n, C=O or CH2 and n is an integer from 0 to 2;
wherein R4 is H, C1-C8 alkyl or C2-C8 alkenyl; and Z is a chromophore group;

in the preparation of a sunscreen composition.

11. The use of a compound of the formula I(a) X-R I(a) wherein X is a Michael acceptor;
R is Z, C1-C8 alkyl-YZ, C2-C8 alkenyl-YZ or C2-C8 alkynyl-YZ;
Y is O, NR4, S(O)n, C=O or CH2 and n is an integer from 0 to 2;
wherein R4 is H, C1-C8 alkyl or C2-C8 alkenyl; and Z is a chromophore group;
in the preparation of an agent for the prevention of dermatological conditions related to exposure to sunlight.

12. The use as claimed in claim 10 or claim 11 wherein the compound is modified by any one or more of the features of claims 6 to 9.

13. The use as claimed in any one of claims 1 to 4 wnerein the compound is:
N-(4-carboxyphenyl)maleamic acid;
N-(4-carboxyphenyl)maleimide;
N-(4-benzoylphenyl)maleamic acid;
N-(4-(2-carboxy-(E)-ethenyl)phenyl]maleamic acid;
N-[4-(2-carboxy-(E)-ethenyl)phenyl]maleimide;

N-[4-(2-carboxy-(Z)-ethenyl)phenyl]maleamic acid;
N-[4-(2-carboxy-(Z)-ethenyl)phenyl] maleimide;
N-(4-methoxycarbonylphenyl)maleamic acid;
N-(4-methoxycarbonylphenyl)maleimide;
N-(4-n-butyloxycarbonylphenyl)maleamic acid; or N-(4-n-butyloxycarbonylphenyl)maleimide.

14. A process for the preparation of a compound of general formula I, the process comprising:
a. when X is a maleamic acid residue, reacting maleic anhydride with a compound of general formula II or general formula III:

RNH3+ III
in an inert solvent such as dichloromethane, optionally in the presence of an amine such as triethylamine;
b. when X is a rraleimide residue, reacting the compound of general formula I produced in step (a) with a dehydrating agent such as acetic acid and sodium acetate;
c. when X is a maleic acid ester residue, reacting a compound of general formula VIII:
R-OH VIII
with maleic anhydride;
d. when X is a quinone residue, reacting quinone with a compound of general formula IX:

ArN2+ IX
or general formula X:

Z-O(CH2)nCO2 X
or;
e. when X is an acrylic acld residue, heating a compound of general formula XI:
R-CH=C(CO2Et)2 XI
in aqueous acid conditions or reacting an aldehyde of general formula XIII:
RCHO XIII
with acetic anhydride.

15. A sunscreen formulation comprising a compound as defined in any one of claims 5 to 10, or claim 13 together with a dermatologically acceptable excipient or carrier.

16. A process for screening the skin from the sun, comprising applying to the skin a sunscreen compound as defined in any one of claims 5 to 10, or claim 13.

17. A compound as defined in any one of claims 5 to 10, or claim 13, for use in the prevention of dermatological conditions related to exposure to sunlight.