-Alkoxvacrvlates against malaria The invention relates to compounds of the general formulae wherein R1 is lower alkyl X isNorCH R in LA is Ial wherein Y is S or 0 and A1 is phenyl, which may be substituted by one or more substituents, selected from halogen, lower alkoxy, lower alkyl, CF3, NO2, NH2, phenoxy or CF3- phenoxy; naphthyl; isothiazol-3-yl; thiazol-2-yl, optionally substituted by lower alkoxyalkoxyalkyl, lower alkyl, lower alkoxycarbonyl or lower acetoxyalkyl; thiadiazol-2-yl, optionally substituted by lower alkylthio, lower alkinylthio, cycloalkyl- alkylthio, CF3 or -NHC6H4CF3; quinoxalin-2-yl, optionally substituted by halogen or lower alkyl; benzoxazol-2-yl; benzotriazine, optionally substituted by an oxo-group; and quinolin-2-yl; wherein

R2 is hydrogen, lower alkoxycarbonyl, CF3, lower alkyl, cycloalkyl, lower alkoxyalkyl, lower alkylthioalkyl or lower alkoxy and A2 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, CF3, halogen, lower alkylthio, lower alkoxy or NO2; -C(O)C6Hs; -C(CH3)=CH-C6H4-lower alkyl; -CH=CH-C6H5; pyridin-2-yl; pyridin-3-yl; pyridin- 4-yl; thiazol-5-yl, optionally substituted by lower alkyl; thien-3-yl, optionally substituted by lower alkyl; thien-2-yl, optionally substituted by halogen; quinolin- 2-yl; naphthyl, benzo[b]thiophen-2-yl, optionally substituted by lower alkyl or halogen; or benzo[b]furan-2-yl; wherein W is S, O, NH or CH2; R3 is hydrogen or lower alkyl and A3 is 5-acetoxy-6-acetoxymethyl-5,6-dihydro-2H- pyran or phenyl, which may be substituted by one or more substituents, selected from halogen, CF3 or lower alkyl; wherein A4 is phenyl, which may be substituted by one or more substituents, selected from NO2, lower alkoxy, halogen, CF3,phenyloxy, styryl-phenyl or (2-CF3- or Cl-phenyl)-furan-2-yl; benzo[1,3]dioxol- 5-yl, optionally substituted by halogen; isoxazol-4- yl, optionally substituted by phenyl or lower alkoxyalkoxy; quinolin-3-yl; pyridin-2-yl; pyridin- 3-yl, pyridin-4-yl; furyl; thien-2-yl; thien-3-yl; -C=-C-C(CH3)3; -C=-C-C6H5; indolizin-2-yl, optionally substituted by lower alkyl; benzofuran-

2-yl; benzopyran-3-yl or dihydrobenzo [b] thiophen- 5-yl; wherein R4 is hydrogen or lower alkyl; and A5 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, lower alkoxy, NO2, halogen, cyano or CF3; pyridin-2-yl; pyridin-4-yl; quinolin-2-yl; quinolin-3-yl; naphthyl; pyrrol-2-yl, optionally substituted by lower alkyl; furan-2-yl, furan-3-yl; thien-2-yl; thien-3-yl, optionally substituted by halogen and lower alkyl; thiazol-2-yl, optionally substituted by C6H4Cl; thiazol-4-yl, optionally substituted by phenyl; benzo[b]thiophen-2-yl, optionally substituted by halogen; or benzo [b]thiophen-3-yl; wherein A6 is phenyl, optionally substituted by CF3; wherein A7 is phenyl, optionally substituted by CF3; or -(CH2)n-A8 Ia8 wherein n is 4 and A8 is phenyl, which may be substituted by one or more substituents, selected from CF3, halogen or -CH=N-OCH2-CO-OCH3; naphthyl or pyridin-4-yl; wherein A9 is phenyl, optionally substituted by CF3; and wherein in formula IB R6-R8 are hydrogen, lower alkyl or lower alkoxy and

Z is hydrogen; lower alkoxy; lower alkyl; or halogen wherein V is O, -N(CH3)-, -S- and B1 is phenyl, optionally substituted by halogen or alkyl; quinolin-8-yl; pyrimidin-2-yl; -CH(CH3)- C6H5; or -CH2-C6H5; wherein m is 0 or 1; and B2 is phenyl, optionally substituted by halogen, lower alkyl or CF3; or benzo[b]thiophen-5-yl; wherein B3 is phenyl, optionally substituted by CF3; wherein R5 is hydrogen, lower alkyl or lower alkoxyalkyl and B4 is phenyl, optionally substituted by CF3; pyridin- 2-yl; or thiazolin-5-yl, optionally substituted by lower alkyl; wherein B5 is phenyl; -C=-C-C(CH3)3; or thien-3-yl; as well as pharmaceutically acceptable salts of compounds of formulae IA and IB. All possible stereoisomers as well as their racemates are included in formulae IA and IB.

It has now surprisingly been found that compounds of the present invention are useful against malaria. Every year, between 300 and 500 million people develop malaria. Close to 3 million people die as a result

of this disease, most of them children and nearly all of them living in tropical Africa. Fifty years ago, many people thought that malaria could be completely eradicated. But over the past twenty years, malaria has been making a comeback. For years, chloroquine has been the standard treatment, but in some areas the malaria parasite is resistant to chloro- quine and to cocktails of almost all the older antimalarials. Around 40% of the world's population now live in areas where malaria is found.

The compounds of the invention have the property that they are active not only against chloroquine-sensitive, but also against chloroquine-resistant malaria pathogens. For this reason they are very well suited for the prophylaxis and treatment of malaria, especially in cases where the malaria pathogens are resistant to chloroquine.

Most of the above described -alkoxyacrylates and their salts are known compounds. They are described in the following documents EP 379 098, EP 299 694, WO 9007493, EP 278 595, EP 463 488, EP 370 629, EP 475 158, EP 474 042, EP 178 826, DE 3 519 280, EP 433 233, EP 460 575 and EP 254 426 as compounds with fungicidal activity for use in agriculture.

The following compounds of formula IA5 are novel: wherein R1 is lower alkyl, X is N or CH, R4 is hydrogen or lower alkyl and A5 is phenyl, which may unsubstituted or substituted by one or more substituents, selected from lower alkyl, lower alkoxy, NO2, halogen, cyano or CF3; pyridin-2-yl; pyridin-4-yl; quinolin-2-yl; quinolin-3-yl; naphthyl; pyrrol-2-yl, optionally substituted by lower alkyl; furan-2-yl, furan-3-yl; thien-2-yl; thien-3-yl, optionally substituted by halogen and lower

alkyl; thiazol-2-yl, optionally substituted by C6H4Cl; thiazol-4-yl, optionally substituted by phenyl; benzo[b]thiophen-2-yl, optionally substituted by halogen; or benzo [b]thiophen-3-yl; as well as their pharmaceutically acceptable salts.

Objects of the present invention are the use of the mentioned compounds of formulae IA and IB and their pharmaceutically acceptable salts thereof against chloroquine-sensitive and chloroquine resistant malaria pathogens, the use of these compounds for manufacture of corresponding medicaments, medicaments, containing these compounds and their salts as well as new compounds of formula IA5 per se.

The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.

As used herein, the term "lower alkyl" denotes a straight or branched-chain alkyl group containing from 1-4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- butyl and the like.

The term "halogen" denotes chlorine, iodine, fluorine or bromine.

The term "lower alkoxy" denotes an alkyl group, as defined earlier which is attached via an oxygen atom. The term "cycloalkyl" denotes saturated cyclic hydrocarbon residues containing 3 to 6 carbon atoms.

The present invention embraces all possible racemates and their optical antipodes.

Preferred compounds of formula IA are especially those of formula IA5,

in which R1 is methyl, X is CH, R4 is hydrogen and A5 is phenyl, substituted by one or more substituents, selected from CF3, bromine, chlorine, methoxy, NO2 or lower alkyl; or naphthyl or thienyl.

Compounds of formula IA2 in which R1 is methyl, X is CH, R2 is hydrogen or lower alkyl and A2 is phenyl, substituted by CF3, chloro, fluoro, methyl, t-butyl or SCH3 are also preferred.

Another group of preferred compounds is the following: in which R1 is methyl, X is CH, Y is O or S and A1 is phenyl, optionally substituted by methyl, isopropyl, t-butyl, bromo, chloro, CF3 or methoxy; naphthalenyl; or thiadiazolyl, optionally substituted by thiomethyl or propynylthiocyclopropyl.

The following intermediates which are used in the process for preparation of compounds of formulae IA4 show also a pharmaceutical activity against malaria pathogens: The compounds of formulae IA and IB can be prepared as described in the documents cited above.

In addition, compounds of formulas IA1-IA9 and IB1-IB5, can be prepared in accordance with schemes 1-14.

Scheme 1 wherein the substituents have the significances described above.

Scheme 2

wherein the substituents have the signifcances described above.

Scheme 3 R ooR1 oR1 R3 R1 X R:0 n nia R1 ,X + <S OTHP ¼;oTHP j)Br n vm THP=tetrahydropyran 0 0o OR3 A3 R1% 0X 0 R0X RX oXe 3 W >° R>4° R3 A3WH < =Br ~ tOH IA3 xII xI wherein the substituents have the significances described above.

Scheme 4

wherein the substituents have the significances described above.

Scheme 5 wherein the substituents have the significances described above. Scheme 6 wherein the substituents have the significances described above.

Scheme 7

wherein the substituents have the significances described above.

Scheme 8 wherein the substituents have the significances described above. R 0X Scheme R X Scheme 9 R1 R1 o' o 0 H2S04 0 os A9 A9 \\ ½ Na2S XXI IA9 wherein the substituents have the significances described above.

Scheme 10 wherein the substituents have the significances described above.

Scheme 11 wherein the substituents have the significances described above.

Scheme 12 wherein the substituents have the significances described above.

Scheme 13 wherein the substituents have the significances described above.

Scheme 14 wherein the substituents have the significances described above.

The novel compounds of formula IA5 can be prepared in accordance with scheme 5 and by Examples 164-206.

As mentioned earlier, the -alkoxyacrylates of general formulae IA and IB in accordance with the invention and their pharmaceutically usable salts have valuable pharmaceutical properties.

In particular, they have a very good activity against malaria pathogens. Their activity is equally good against chloroquine-resistant strains of the pathogen as against chloroquine-sensitive strains.

Accordingly, the present compounds can also be used for the prophylaxis and cure of malaria even in those cases where the pathogen does not respond to chloroquine.

In the following table are described the tested compounds: R1 X Y A1 Expl.No. CH3 -CH S ;AIci 1 CI CH3 CH S / 2 CH3 -CH S ) l 3 CI CH3 -CH S )33 4 CH3 -CH S 5 cl CH3 -CH S ri\\ 6 6 CH3 CH S y 7 CH3 -CH S o9CF3 8 NO, CH3 CH S )3oBr 9 CH3 CH S y 10 CH3 CH S F>zgF 11 I CH3 CH S ;icr)O 12 CH3 CH S AK 13 CH3 CH S ¼ 14 CH3 CH S J9FS 15 CF CH3 CH S ,CF3 16 CH3 CH S (CH,)2-O(CH2)rOCH no 1717 /t (CH2)2-o-(CHz)2 oCH3 CH3 CH S S- 18 sy CH3 CR S tNY5N/YS H N 19 CH3 CH a CR3 CH S w SS 20 NUN CH3 CH S Y /SCF3 21 N, CR3 CR S 22 CH3 H CF3 CH3 CH S S C, 23 X CR3 CH S WNI W 24 CR3 CH S Ye 0Y ~ ~ CH3 CR S A9 26 CH3 CH O NIX 27 0 CH3 CH O )()½r)Br 28 CH3 CH O AN4Br 29 CH3 CH 0 ¼]) 30 CH3 CH O J(NS 31 CH3 CH 0 N>) 32 CH3 CH O » 33 A CEI3 CH O NCI R CR3 CH O ¼ 35

Preferred compounds are also those of formula IAl wherein R1 is methyl, X is CH, Y is S or O, Al is phenyl, which may be substituted by one or more substituents, selected from hal, lower alkoxy, lower alkyl, CF3, NO2, NH2, phenoxy, or CF3-phenoxy. Such compounds can be prepared according to the procedure set in example 1 of EP 278595, like the following specific compounds: (E)-2-[2-(2-Bromo-phenoxymethyl)-phenyl]-3-methoxy-acrylic acid methyl ester; (E)-3-methoxy-2- [2-(4-phenoxy-phenoxymethyl)-phenyl]-acrylic acid methyl ester; (E)-3-methoxy-2-[2- [4-(4-trifluoromethyl-phenoxy)-phenoxy- methyl]-phenyl]-acrylic acid methyl ester; (E)-3-methoxy-2- [2-(4-methoxy-2-nitro-phenoxymethyl)-phenyl] - acrylic acid methyl ester; (E)-2-[2-(2 ,4-dibromo-phenoxymethyl)-phenyl] -3-methoxy-acrylic acid methyl ester; (E )-2-[2-(2-chloro-4-methyl-phenoxymethyl)-phenyl]-3-methoxy- acrylic acid methyl ester; (E)-2-[2-(2-chloro-4-trifluoromethyl-phenoxymethyl)-phenyl] -3 - methoxy-acrylic acid methyl ester; (E)-3-methoxy-2-(2-pentafluorophenyloxymethyl-phenyl)-acryli c acid methyl ester; (E)-2-[2-(2,4-dichloro-phenylsulfanylmethyl)-phenyl]-3-metho xy- acrylic acid methyl ester; (E )-2-[2-(2-amino-4-trifluoromethyl-phenylsulfanylmethyl)- phenyl]-3-methoxy-acrylic acid methyl ester; (E)-2- [2-(2-amino-4-methoxy-phenoxymethyl)-phenyl]-3-methoxy- acrylic acid methyl ester; (E)-2-[2-(4-tert-butyl-2-chloro-phenoxymethyl)-phenyl]-3-met hoxy- acrylic acid methyl ester. R1 X R2 A2 Expl.No. CH3 CH -C(O)OCH3 93 36 CF CH3 CH CF3 cm3 37 CI CHS CH CH3 38 CH3 CH a 40 CF3 CH3 CR < 41

CH3 CR -CR2OCR3 42 CH3 CH CH3 ), 43 CH3 CH CH3 4113 44 CH3 CH H 45 CH3 CR CH2CH3 MW 46 CH3 CH CH3 ¼) 47 CF3 CR3 CR CR3 JJ os 48 CH3 CH CH2CH3 )01 49 CH3 CH CR2CR3 bs 50 CN3 CH CH2CH3 IflBr 51 CE-I3 CH CH3a 52 CH3 CH CH3 53 CR3 CH CR3 CF3 54 CH3 CH CH3 AF 54 CH3 CH CH3 X 55 CH3 CR CR3 F 56 CH3 CR CH2CH3 F 57 CH3 CH CH2CH3 Q 58 A CH3 CH CH2CH3 AK 59 CH3 CR CR2SCR3 ½!) 60 CH3 CH CH3 O~ 61 CH3 CH H AK 62 CH3 CH H X 63 CH3 CH H 10 64 CH3 CH H DBr 65 CH3 CH H g C, 66 CH3 CH CH2CH3 67 CH3 CH H /OZNO2 68 CH3 CH CR3 AK 69 CH3 CR CH3 AK 70 CH3 CH H JQ 71 CH3 CH H J j 72 CH3 CH CH3 )cki) 73 CF3 CH3 CH CH3 )Ai) 74 Br CR3 CR CR3 75 NO2 CH3 CR CR3 CH, 76 CH3 CH CH3 S 77 CH3 CH CH3 )i£y/CH3 78 CH3 CR CH3 CI 79 CH3 CH f CR3 J<a 80 CH3 CH CH3 n 81 CH3 CH CH3 ¼)) 82 CH3 CR CR3 ¼ 83 CH3 CH CH3 CH3cl 84 CH3 CH CH3 N99 85 CH3 CH CH3 °s 86 CH3 CH H act 87 CH3 CR CH3 s 88 CH3 CH CH3 )CI 89 CH3 CH CH2CH3 %rCI 90 CH3 CH (CH2)2CH3 ½') 91 CH3 CR < 92 CH3 CH CH3 y 93 CH3 CR CR3 Mis 94 CH3 CH H /oCF3 95 CH3 CH CF3 93 96 CH3 CH CH3 N03 97 CH3 CH H J3 98 CH3 CH H 3 99 CH3 CR H JCN 100 CH3 CH CH3 \ 03 101 CH3 CH H c c, 102 CH3 CH H ¼) 103 CH3 CH CH3 ) 104 CH3 CH CH3 )& CF3 105 ½ CF3 CH3 CH CH3 F) \ 106 CH3 CH CH3 )?i$FF 107 CH3 CH CR3 F ; 108 CH3 CH CR3 )ArF 109 CH3 N CH3 Ak) 110 CF3 CH3 N CH3 CF3 111 \CF3 CH3 N CF3 )3 112 CH3 N CH3 - NO2 113 CH3 N CH3 Ak 114 Br CH3 N CH3 °s 115 CH3 N CbS ArC 116 CH3 ~~ N Cur3 117 R1 X R3 | W A3 Expl.No. CH3 CH H2 S F 118 CH3 CH H2 S ) 119 CH3 CH H2 S J9F, 120 CF CF3 CH3 CH H2 S 121 CH3 CH R2 NH o'3 123 CH3 CH H2 NH jCF3 124 CH3 CH CH3 CH2 ) 125

Preferred compounds are also those of formula IA3 wherein R1 is methyl, X is CH-, R3 is H2, W is S, O, A3 is phenyl, which may be substituted by one or more substituents, selected from hal, CF3, lower

alkyl or is 5-acetoxy-6-acetoxymethyl-5,6-dihydro-2H-pyran. Such <BR> <BR> <BR> compounds can be prepared according to the procedure set out in<BR> <BR> <BR> <BR> <BR> <BR> example 118, like the following additional compounds:<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (E)-2-[2-[(E)-3-(5-Acetoxy-6-acetoxymethyl-5,6-dihydro-2H-py ran- <BR> <BR> <BR> <BR> <BR> <BR> 2-yloxy)-propenyl]-phenyl]-3-methoxy-acrylic acid methyl ester,<BR> <BR> <BR> <BR> <BR> <BR> (E)-2-[2-[(E )-3-(2-chloro-phenylsulfanyl)-propenyl]-phenyl]-3- methoxy-acrylic acid methyl ester, <BR> <BR> <BR> (E)-2-{2-{(E)-3-(2-chloro-4-methyl-phenoxy)-propenyl]-phenyl ]-3- <BR> <BR> <BR> <BR> <BR> <BR> <BR> methoxy-acrylic acid methyl ester, and<BR> <BR> <BR> <BR> <BR> (E)-2- [2- [(E)-3-(2-chloro-4-trifluoromethyl-phenoxy)-propenyl]- phenyl]-3-methoxy-acrylic acid methyl ester. R1 X A4 Expl.No. CH3 CH 126 NO2 CH3 CH O) 127 E/Z NO2 CH3 CH )%)Ct 128 NO2 E/Z CH3 CH )7 129 NO2 E/E CH3 CH 4, 130 CI CH3 CH 131 NOI E/E NO2 CH3 CH » 133 cl CH3 CH C 4, Cl 134 C C CH C, C, ISD CI CH3 CH S O~ 136 cl CH3 CH X 137 CI CH3 CH e 138 CH3 CH VCF3 139 CF3 CH3 CH - 140 CF3 CH3 CH X or 141 Wo ow CH3 CH A OX 142 CH3 CH CF3 CH3 CH D O > 144 CH3 CH ¼ARNO2 145 CH3 CH 47 E/E 146 NO2 E/E CH3 CH 47 147 NO, E/Z CH3 CH Ak) C, 148 CF3 CH3 CH g O> 149 CH3 CH ½iD) 150 CH3 CH X 151 CH3 CH X 152 CR3 CH 5¼) 153

CH3 CR %)O/ 154 CH3 CH X 155 CH3 CH = ( 156 CH3 CH X 157 CH3 CH MN7/ 158 CH3 CH s 159 CH3 CH S 160 CH3 CH 161 CH3 CH 162 CR3 CH ¼)) 163 Preferred compounds are also those of formula IA4 wherein R1 is methyl, X is CH, and A4 is phenyl, which may be substituted by one or more substituents, selected from hal, lower alkoxy, NO2, styryl-phenyl, <BR> <BR> <BR> or (2-CF3-, or Cl-phenyl)-fiiran-2-yl. Such compounds can be prepared<BR> <BR> <BR> <BR> according to the procedure set in example 126 (EP-475158 A2 920318), like: <BR> <BR> <BR> <BR> <BR> (E)-3-Methoxy-2-[2-[(E)-2-[5-(2-trifluoromethyl-phenyl)-fura n-2-yl]- <BR> <BR> <BR> <BR> vinyl]-phenyl]-acrylic acid methyl ester,<BR> <BR> <BR> <BR> <BR> (E)-2-[2-[(E)-2-(2-chloro-3,4-dimethoxy-6-nitro-phenyl)-viny l]- phenyl]-3-methoxy-acrylic acid methyl ester, (E)-2-[(E)-2-[5-(2-chloro-phenyl)-furan-2-yl]-vinyl]-phenyl] -3- methoxy-acrylic acid methyl ester and (E)-3-methoxy-2-[2-[(E)-2-[(E)-4-styryl-phenyl]-vinyl]-pheny l]- acrylic acid methyl ester. R1 R4 A5 X Expl.No. CH3 H Wo CH 164 CH3 H )%)CI CH 165 CI CH3 H ) CH 166 CH3 H ) ,Xcl CH 167 CH3 H )yF CH 168 CH3 H ) CH 169 CH3 H p CH 170 CR3 H CR 171 ½)iN,

CH3 H XN CH 172 CH3 H CH 173 CH3 H CH 174 CH3 H ¼ CH 175 CH3 H NW CH 176 CH3 H DCF3 CH 177 CH3 H D CR 178 CH3 H OB CH 179 I CH3 H CH 180 CH3 H ACF3 CH 181 CF3 CH3 H £)IO, CH 182 CH3 H Wi C CH 183 CH3 H 9 CH 184 CH3 H 47 CH 185 CF3 CH3 H J<F CH 186 CH3 H CH 187 CH3 H C CH 188 CH3 H \Br CH 188 CH3 H D CH 189 CH3 H CH 190 CH3 H CH 191 CH3 H CH 191 CH3 H )ws, CH 192 CH3 H CH 193 CH3 H 4¼)) CH 194 CH3 H CH 195 CH3 H CH 196 CH3 H 3 CH 197 CH3 H CF3 CH 198 ½ CF,

CH3 H AK CF, CH 199 CF, CH3 H )3sBr CH 200 CH3 H )3zC' CH 201 CH3 H CI CR 202 CH3 H 47 CH 203 Br CH3 H o I CH 0 204 bX° CH3 CH3 CH 205 CH3 H 47 N 206 CF, Preferred compounds are also those of formula IA5 wherein R1 is methyl, X is CH, R4 is H and A5 is phenyl, which may be substituted by one or more substituents, selected from lower alkyl, lower alkoxy, NO2, hal, cyano, or CF3. Such compounds can be prepared according to the procedure set out in example 164, like: <BR> <BR> (E)-2-[2-[(1E ,3E)-4-(2-Chloro-3,4-dimethoxy-phenyl)-buta-1,3- <BR> <BR> <BR> <BR> dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester,<BR> <BR> <BR> <BR> (E)-2-[2-[( lE,3E)-4-(2-bromo-4,5-dimethoxy-phenyl)-buta-i,3- <BR> <BR> <BR> <BR> dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester,<BR> <BR> <BR> <BR> (E)-2-[2-[( lE,3E)-4-(2-cyano-phenyl)-buta-1,3-dienyl]-phenyl]-3- methoxy-acrylic acid methyl ester, (E)-3-methoxy-2-[2-[(1E,3E)-4-(3-methoxy-2-nitro-phenyl)-but a-1,3-

dienyl]-phenyl]-acrylic acid methyl ester,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (E)-2-[2-[(1E ,3E)-4-(4-fluoro-2-trifluoromethyl-phenyl)-buta- 1,3- <BR> <BR> <BR> <BR> <BR> <BR> <BR> dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (E)-2- [2- [( lE,3E)-4-(4-tert-butyl-phenyl)-buta- 1,3-dienyl]-phenyl]- <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3-methoxy-acrylic acid methyl ester,<BR> <BR> <BR> <BR> <BR> <BR> <BR> (E)-2-[2-[(1E ,3E)-4-(2-chloro-4-fluoro-phenyl)-buta- 1,3-dienyl] - <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> phenyl]-3-methoxy-acrylic acid methyl ester,<BR> <BR> <BR> <BR> <BR> <BR> <BR> (E)-2-[2-[( lE,3E)-4-(2,4-difluoro-phenyl)-buta-1,3-dienyl]-phenyl]-3- <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> methoxy-acrylic acid methyl ester,<BR> <BR> <BR> <BR> <BR> <BR> <BR> (E)-2-[2-[( lE,3E)-4-(2-chloro-4-methyl-phenyl)-buta-1,3-dienyl]-<BR& gt; <BR> <BR> <BR> <BR> <BR> <BR> <BR> phenyl]-3-methoxy-acrylic acid methyl ester,<BR> <BR> <BR> <BR> <BR> <BR> <BR> (E)-2-[2-[(1E ,3E)-4-(2,4-dimethyl-phenyl)-buta-1,3-dienyl]-phenyl]- <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3-methoxy-acrylic acid methyl ester and<BR> <BR> <BR> <BR> <BR> <BR> <BR> (E)-2-[2-[(1E,3E)-4-(2-fluoro-4-trifluoromethyl-phenyl)-buta -1,3- dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester. R1 X A6 Expl.No. CH3 N 47 207 CF, CR3 N AK CF, 208 CF, Rl X L A7 2 Expl.No. ci, n J9F, 209 CF,

R1 X 7 A8 Expl.No. CH3 CH 47 210 CF CH3 CH AK CF, 211 CF, CH3 CR )frICI 212 CI CR3 CR b 213 CH3 CH J 214 CH3 N 47 215 CF, CH3 N ) 216 ~ . ~ /0s MyV0 R1 X A9 Expl.No. CR3 N 47 217 CF, Rl V B1 X Expl.No. CH3 0- -O- CR 218 CH3 -O- i Br CH 219 CH3 -N(CH3)- AK CH 220 CH3 -N(CH3)- mo) CR 221 CH3 -N(CHs) Cll CR 222 CH3 -N(CH3)- '¼ CH 223 CH3 -S ¼) CH 224 J(N1 R1 B2 X m Expl.No. CH3 D C, CH 1 225 CH3 47 CH 0 226 CH3 X CH 0 227 CH3 X, CH 1 228 CH30 CH 1 229 CH3 5¼) CH 1 230 CH3 ga CH 1 231 CH3 + CH 1 232 CH3 )7 CR 1 233 CI CR3 CI CR 0 234 CI CR3 )CF3 CR 1 235 / CH3 j CH | O / 234 / CH3 1 CF3 / CH | 1 1 235 / R1 | B3 | X | Expl.No. R t oFs L R1 | R5 | B4 | X | Expl.No. CH3 O AkCF, CH 237 CH3 CR3 AkCF, cH 238 CH3 CH3 4 CH 239 CH3 H ,5 CH 240 R1 \ B5 x X \ ExplSo. CH3 \ CH ll 241 CH3 f CH \ 242 CH3 CM CH \ 243

R1 Z Z \ R6 \ R7 \ R8 \ ExplSo. C113 \ ,o H H \ H l H l 244 CH3 CH3 II H H \ CH3 \ 245 C113 Br II H H 246 I ! l CH3 i" H | -OCH i" H 247

CH3 H H -OCR3 H 248 CH3 Cl H H H 249 CH3 H H H CH3 250 The activity of the compounds against not only chloroquine- resistant, but also chloroquine-sensitive malaria pathogens shows itself in a strong, in vitro measurable growth inhibition of various strains of the human-pathogenic Plasmodium falciparum, as set forth in Table 1 hereinafter. The ratio of the growth inhibition of a strain which is especially resistant to chloroquine and of a strain which is sensitive to chloroquine gives as the "resistance index" a measurement for the <BR> <BR> <BR> absence or presence of a cross-resistance with chloroquine. Since, for all<BR> <BR> <BR> <BR> <BR> <BR> novel compounds the resistance index lies between 0.7 and 2.5, they inhibit the growth of sensitive as well as resistant strains of the malaria pathogen equally effectively. They are accordingly also suitable for the prophylaxis of a malaria disease and also for the treatment of a malaria disease even when chloroquine is ineffective.

The good activity against malaria pathogens is also shown in animal experiments. The effective doses measured after oral and subcutaneous <BR> <BR> <BR> administration to mice infected with malaria pathogens are shown in<BR> <BR> <BR> <BR> <BR> <BR> Table 2 hereinafter.

Test method for the determination of the activity against Plasmodium falciparum in vitro The preparations are tested on intraerythrocytary stages of Plasmodium falciparum from asynchronous cultures according to the method of Desjardin et al. (Desjardins, R.E. et al: Quantitative assessment of antimalarial activity in vitro by a semiautomated <BR> <BR> <BR> microdilution technique. Antimicrob. Agents Chemother. 16, 710-718,<BR> <BR> <BR> <BR> <BR> <BR> (1979)).<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> The culture medium consists of RPMI 1640 with the addition of<BR> <BR> <BR> <BR> <BR> 25 mM HEPES, 25 mM NaHC03, 100 pLg/ml neomycin and 10% human serum (A+). Human-A+ erythrocytes are used as the Plasmodium

falciparum host cells. The parasites are maintained at 37OC in an atmosphere of 3% 02, 4% CO2, 93% N2 and 95% relative humidity.

In order to determine the activity, the preparations are dissolved in DMSO, pre-diluted in the culture medium to a suitable starting concentration and subsequently titrated-out on to microtitre plates in <BR> <BR> <BR> the 2nd stage over 6-7 steps. After the addition of the parasite culture<BR> <BR> <BR> <BR> <BR> <BR> <BR> (0.7% parasitemia in 2.5% erythrocyte suspension) the test plates are<BR> <BR> <BR> <BR> <BR> <BR> incubated under the conditions given above for 72 h. The parasite growth in the different preparation concentrations is determined using [G-3H]-hypoxanthin incorporation compared to untreated control cultures on the same test plates. The 50% growth inhibition (IC50) is calculated according to logit regression analysis from the resulting dosage-activity curve.

The preparations are tested on at least one chloroquine-resistant and one chloroquine-sensitive Plasmodium falciparum strain.

Additional sensitive and resistant strains are included for futher characterization.

Test method for the determination of the activity against Plasmodium berehei in vivo The preparations are tested on mice infected with malaria <BR> <BR> <BR> pathogens (Plasmodium berghei). Male albino mice (IBM:MORO(SPF),<BR> <BR> <BR> <BR> <BR> <BR> <BR> FUELLINSDORF) weighing about 25 g are used as the test animals.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>They are kept in climatized rooms at 21-22°C in groups of 5 animals per<BR> <BR> <BR> <BR> <BR> <BR> cage. They receive ad libitum a diet feed with a low PABA content<BR> <BR> <BR> <BR> <BR> <BR> <BR> (NAFAG FUTTER " No. 9009 PAB-45, PABA content 45 mg/kg) and drinking water. On the first day of the test (DO) the test animals are infected with Plasmodium berghei (strain ANKA). For this there is used heparinized blood of a donor mouse with about 30% parasitemia, <BR> <BR> <BR> which is diluted with physiological saline such that it contains 108<BR> <BR> <BR> <BR> <BR> <BR> parasitized erythrocytes per ml. 0.2 ml of this suspension is injected intravenously (i.v.) into the mice to be treated and into the control mice.

In untreated control animals the parasitemia normally reaches 30-40% on the third day after the infection (D+3) and the test animals die between days +5 and +7.

The substances to be tested are dissolved or suspended in distilled<BR> <BR> <BR> <BR> <BR> <BR> water or in a mixture of 7% Tween 80, 3% alcohol (96%) and water.<BR> <BR> <BR> <BR> <BR> <BR> <P>Usually, 0.25 ml of this solution or suspension is administered once<BR> <BR> <BR> <BR> <BR> <BR> <BR> subcutaneously and perorally to groups of 5 test animals. Treatment is effected 24 hours after the infection. 10 control animals are treated in the same manner with solvent or suspension medium per test.

All substances are tested in a first test in a single dosage of 100 or 10 mg/kg. Only those substances which in this test (10 mg/kg) have shown a parasitaemia reduction of more than 90% are used for the titration. Suitable dilutions of the test substance can be used to obtain an accurate titration of the activity.

48 hours after the treatment (D+3) blood smears are prepared from all animals using blood from tail veins and are stained with giemsa. The average erythrocyte infection rate (parasitemiea in %) in the control groups as well as in the groups which have been treated with the test compounds is determined by counting under a microscope.

The difference in the average values of the infection rates of control group (100%) and treated groups is calculated and expressed as a percentage reduction (GI%). The ED50 or ED90 is determined mathematically by means of the JMP programme (nonlinear fit). The ED50 (ED90) in mg/kg is that dose which after single administration reduces the average erythrocyte infection rate by 50% (90%) in comparison to the control group.

Table 1 Values measured in vitro (IC50 values in ,ug/ml) for the grouth inhibition of the human-pathogenic Plasmodium falciparum strain NF54 as an example of a chloroquine-sensitive strain and of the human-pathogenic Plasmodium flaciparum K1 as an example of a chloroquine-resistant strain. Formula Example No. in vitro strain NF 54 strain K1 IC50 72 h IC50 72 h IA1 11 1.17 4.9 IA1 28 17.7 19.1 IA2 105 0.21 1.01 IA2 110 20 65.8 IA2 111 1.6 4.3 IA3 120 1.75 2.51 IA4 126 1.2 3.3 IA4 136 1.04 2.9 IA5 185 0.06 0.15 IA5 199 0.06 0.13 IA5 203 0.07 0.28 IA5 206 0.4 1.4 IA6 207 10.8 25.8 IA7 209 3.21 5.7 IA8 210 0.85 1.35 IA8 211 0.33 1.34 IA9 217 23.7 60.8 IB1 222 22,6 64.3 IB4 238 17.5 40.9 IB5 241 1.4 7.4 IB5 243 6.7 22.6 IB 244 147.3 419.2 IB 250 184.4 550.3 IB2 233 29.5 67.3 IB3 236 44.2 174.7 III 251 64.9 111

Table 2 Activity measured in vivo against Plasmodium berghei in mice in percentage reduction of the parasitemia after a perorally (po) or subcutaneously (sc) administered dose of 100 (10) mg/kg of test substance, ED50 is the effective administered dose of test substance Formula Example No. in vivo po act. % Sc act. % IA1 11 80 tox IA3 120 46 91 IA4 126 79 76 IA4 136 40 tox

IA5 185 99.0 (10 mg/kg) 99.95 IA5 199 100 (10 mg/kg) 99.97 IA5 203 76 (10 mg/kg) 90 IA5 206 46 44 IA8 210 82 99 IA8 211 59 (10 mg/kg) 92 III 251 40 74 The compounds of formula IA or IB and the pharmaceutically acceptable acid addition salts of the compounds of formula IA or IB can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions, or nasally.

The compounds of formula IA or IB and the pharmaceutically acceptable acid addition salts of the compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, drawees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils and the like.

Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain still other therapeutically valuable substances.

Medicaments containing a compound of formula LA or IB or a pharmaceutically acceptable acid addition salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their manufacture which comprises bringing one or more compounds of formula IA or IB and/or pharmaceutically acceptable acid addition salts thereof into a galenical administration form together with one or more therapeutically inert carriers.

In accordance with the invention compounds of general formula IA or IB as well as their pharmaceutically acceptable acid addition salts can be used for the treatment or prevention of malaria and, respectively, for the production of corresponding medicaments. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In the case of oral administration the dosage lies in a range of about 10 mg to about 2.5 g per day of a compound of general formula IA or IB or the corresponding amount of a pharmaceutically acceptable acid addition salt thereof, although the upper limit can also be exceeded when this is found to be indicated.

In the following Examples, which illustrate the present invention but are not intended to limit its scope in any manner, all temperatures are given in degrees Celsius. The 250 MHz-1H-NMR spectra were measured at room temperature; chemical shifts 5(pom) relative to o(TMS) = 0.0 ppm.

The novel compounds of formula IA5 can be prepared as described below. All temperature are given in "C.

Example 164 (E)-2- [2-(1E,3E )-4- [4 5-Dimethoxv-2-nitro-phenvl)-buta- 1 .3-dienvll- phenvll-3-methoxv-acrvlic acid methvl ester a) At room temperature, NaOCH3 (335 mg, 6.19 mmol) was added to a solution of 1,3-dioxan-2-ylmethyltributylphosphoniumbromide (C.

Spangler; R. McCoy, Synthetic communications, 18, 51, (1988)) (5.17 ml, 1M in DMF, 5.71 mmol) and 4,5-dimethoxy-2-nitro-benzaldehyde (1.25 g, 4.76 mmol) in DMF (20 ml). After heating the mixture at 50° for overnight, the mixture was poured over water, and extracted with ether, washed with brine and dried over MgSO4. The solvent was evaporated and the residue was dissolved in THF (100 ml) and treated with 2N HCl (50 ml). After stirring the mixture at room temperature for 2 h, the THF was evaporated, and the yellow solid was filtered, and suspended in ether/ethylacetate 4:1. The suspension stirred at room temperature for 1 h, filtered and washed with ether to afford (E)-3-(4,5- dimethoxy-2-nitro-phenyl)-propenal (624 mg, 55%) as a yellow solid, m.p. 103-105°. IR (KBr): 1689, 1605 cm-l. MS (EI): 237 (M). b) At 0°, NaH (40 mg, 0.954 mmol) was added to a solution of (E)-2- [2-(dimethoxy-phosphorylmethyl)-phenyl] -3-methoxy-acrylic acid methyl ester (EP-203606) (250 mg, 0.79 mmol) in THF (5 ml). The mixture was stirred at room temperature for 30 min and treated with (E)-3-(4,5-dimethoxy-2-nitro-phenyl)-propenal (189 mg, 0.79 mmol) in CH2Cl2 (2 ml). After the mixture was stirred at room temperature for 3 h and refluxed for 1.5 h, the reaction mixture was cooled to room temperature and treated with CH3CO2H (1 ml). After stirring for 10 min at room temperature, the reaction mixture was extracted with ethylacetate, washed with NaRCO3 solution, brine, water, and dried over MgSO4. Evaporation of the solvent and chromatography (hexane/ethylacetate 1:1) gave (E)-2- [2-( 1E ,3E)-4- [4,5-dimethoxy-2- nitro-phenyl)-buta- 1, 3-dienyl] -phenyl] -3-methoxy- acrylic acid methyl ester (116 mg, 34%) as white solid, m.p. 198-200°. IR (KBr): 1710, 1630 cm-1. MS (EI): 425 (M).

According to the procedure set forth in the preceding example, the following compounds were prepared:

Example 165 (E)-2-[2-[(1E,3E)-4-(2,4-Dichloro-phenyl)-buta-1,3-dienyl]-p henyl]-3- methoxv-acrylic acid methvl ester m.p. 143-145° IR (KBr): 1707, 1629 cm-1, MS (EI): 388 (M).

Example 166 Methvl (E and/or Z)-3-methoxy-2-[o-[(all-E)-4-(2-pyridyl)-1,3- butadienvll phenyll acrvlate m.p. 106-108° Example 167 Methvl (E and/or Z)-2-fo-F(all-E)-4-(2 3-dichlorophenvl)-1.3-butadiensll- phenvll -3-methoxyacrylate m.p. 141-145° Example 168 Methvl (E and/or Z)-2-fo-[(all-E)-4-(2.3-difluorophenvl)-1.3-butadienvll- phenyl]-3-methoxyacrylate m.p. 142-144° Example 169 Methvl (E and/or Z)-3-methoxy-2-[o- r(all-E)-4-(2-auinolinvl)-1.3- butadienyl]phenyl]acrylate m.p. 137-138° Example 170 Methvl (E and/or Z)-3-methoxy-2-[o-[(all-E)-4-(1-naphthyl)-1,3- butadienvll phenyll acrvlate m.p. 138-140°

Example 171 Methvl (E and/or Z)-3-methoxv-2- to- [(all-E)-4-(1-methylpyrrol-2-yl)-1,3- butadienvll phenvll acrvlate m.p. 139-142° Example 172 Methvl (E and/or Z)-3-methoxy-2-[o-[(all-E)-4-(4-pyridyl)-1,3- butadienyl]phenyl]acrylate m.p. 175-177° Example 173 Methvl (E and/or Z)-2-[o-[(all-E)-4-(2-furyl)-1,3-butadienyl]phenyl]-3- methoxvacrvlate m.p. 136-137° Example 174 Methvl (E and/or Z)-3-methoxy-2-[o-[(all-E)-4-(2-thienyl)-1,3- butadienyl]phenyl]acrylate m.p. 142-145° Example 175 Methvl (E and/or Z )-3-methoxv-2- to- t(all-E and/or Z)-4-(3-thienyl)-1,3- butadienvll phenyll acrvlate m.p. 194-195° Example 176 Methvl (E and/or Z)-3-methoxv-2-Fo-[(all-E)-4-(3-quinolinvl)-1.3- butadienvll Bhenvll-3 -methoxvacrvlate m.p. 173-175°

Example 177 Methyl (E)-3-methoxy-2-[o-[(all-E)-4-(alpha,alpha,alpha-trifluoro-p - tolyl)- I 3-butadienvfl phenvll acrvlate m.p. 190-191° Example 178 Methyl (E)-2-[o-[(all-E)-4-(p-fluorophenyl)-1,3-butadienyl]phenyl]- 3- methoxvacrvlate m.p. 156-157° Example 179 Methvl (E)-2- to- [(all-E)-4-(o-ethoxyphenyl)-1,3-butadienyl]phenyl]-3- methoxvacrvlate m.p. 152-153° Example 180 Methvl (E)-2- to- [(all-E)-4-(2-chloro-6-fluorophenyl)-1,3- butadienvll phenvll acrvlate m.p. 165° Example 181 Methvl (E)-3-methoxv-2- to- [(all-E)-4-(alpha,alpha,alpha-trifluoro-m- tolyl)-1,3-butadienyl]phenyl]acrylate m.p. 152-153° Example 182 Methyl (E)-2-[o-[(all-E)-4-(3-furyl)-1,3-butadienyl]phenyl]-3- methoxvacrvlate m.p. 174-175°

Example 183 Methvl (E)-2- to- [(all-E)-4- r2-(p-chloro-phenvl)-4-thiazolvll -1.3- butadienyl]phenyl]-3-methoxyacrylate m.p. 167-171° Example 184 Methvl (E )-2- to- [(all-E)-4-(o-chlorophenyl)- 1.3- butadiensll phenvll acrvlate m.p. 158-162° Example 185 Methyl (E)-3-methoxy-2-[o-[(all-E)-4-(alpha,alpha,alpha-trifluoro-t olyl)- 1.3-butadienvll phenvll acrvlate m.p. 148-149° Example 186 Methyl (E)-2-[o-[(all-E)-4-(m-fluorophenyl)-1,3-butadienyl]phenyl]- 3- methoxvacrvlate IR (KBr): 1705, 1628 cm-1, MS (EI): 338 (M) Example 187 Methyl (E)-3-methoxy-2-[o-[(all-E)-4-(5-phenyl-4-thiazolyl)-1,3- butadienyl]phenyl]acrylate m.p. 167° Example 188 Methyl (E)-2-[o-[(all-E)-4-(5-bromo-2-thienyl)-1,3-butadienyl]pheny l]-3- methoxvacrvlate m.p. 160-161°

Example 189 Methyl (E)-3-methoxy-2-[o-[(all-E)-4-(p-methoxyphenyl)-1,3-butadien yl]- phenvll acrvlate m.p. 164-166° Example 190 Methyl (E)-3-methoxy-2-[o-[(all-E)-4-[3-methoxybenzo[b]thiophen-2-y l]- 1.3-butadienvll phenvll acrvlate m.p. 202-203° Example 191 Methvl (E)-3-methoxv-2- to- [(all-E)-3-(2-thiazolvl)-1,3- butadienyl]phenyl]acrylate m.p. 131-133° Example 192 Methyl (E)-3-methoxy-2-[o-[(all-E)-4-(5-methyl-2-thienyl)-1,3- butadienvll phenyli acrvlate m.p. 131-133° Example 193 Methvl (E)-3-methoxv-2- [o- T(all-E )-4-(3-methvl-2-thienvl)- 1.3- butadienyl]phenyl]acrylate m.p. 168° Example 194 Methyl(E)-3-methoxy-2-[o-[4-(2-naphthyl)-1,3- butadienyl]phenyl]acrylate m.p. 172°

Example 195 Methyl (E)-2-[o-[(all-E)-4-benzo[b]thiophen-2-yl-1,3-butadienyl]phe nyl]- 3-methoxy-acrylate m.p. 223-225° Example 196 Methyl (E)-2-[o-[(all-E)-4-benzo[b]thiophen-3-yl-1,3-butadienyl]phe nyl]- 3-methoxv-acrvlate m.p. 157° Example 197 Methyl (E)-3-methoxy-2-[o-[(all-E)-4-phenyl-1,3- butadienyl]phenyl]acrylate m.p. 165-167° Example 198 (E)- or (Z)-2-[2-[4-(3,5-bis-trifluoromethyl-phenyl)-buta-1,3- dienvll phenvll-3-methoxv-acrvlic acid methvl ester IR (KBr): 1703, 1630 cm-1 MS (EI): 456 (M) Example 199 (E)- or (Z)-2- [2- [4-(2.4-bis-trifluoromethvl-phenvl)-buta- 1.3- dienyl]phenyl]-3-methoxy-acrylic acid methvl ester m.p. 176-177° IR (KBr): 1703, 1630 cm-1 MS (EI): 456 (M)

Example 200 Methyl-2-[o-[(all-E)-4-(m-bromophenyl)-1,3-butadienyl]phenyl ]-3- methoxvacrvlic IR (KBr): 1701, 1626 cm-1 MS (EI): 399 (M) Example 201 Methyl (E)-2-[o-[(all-E)-4-(p-chlorophenyl)-1,3-butadienyl]phenyl]- 3- methoxvacrvlate m.p. 209° Example 202 Methvl (E)-2- to- [(all-E)-4-(m-chlorophenyl)-1,3-butadienyl]phenyl]-3- methoxvacrvlate m.p. 121-122° Example 203 Methyl (E)-2-[o-[(all-E)-4-(o-bromophenyl)-1,3-butadienyl]phenyl]-3 - methoxvacrvlate m.p. 150-151° Example 204 Methyl (E)-3-methoxy-2-[o-[(all-E)-4-(3,4,5-trimethoxyphenyl)-1,3- butadienyl]phenyl]acrylate m.p. 98-102° Example 205 Methyl (E)-2-[o-[(all-E)-4-(p-tert-butylphenyl)-3-methyl-1,3-butadi enyl]- phensll 3-methoxvacrvlate IR (KBr): 1709, 1632 cm-1 MS (EI): 390 (M)

Example 206 (Z)- or (E)-Methoxyimino-[2-[(1E,2E)-4-(2-trifluoromethylphenyl)-but a- 1.3-diensll-phenyll-acetic acid methyl ester a) At 24°, Bu3SnH (0.56 ml, 2.1 mmol) was added to a solution of (2-ethynyl-phenyl)-methoxyimino-acetic acid methyl ester (151 mg, 0.7 mmol) and AIBN (cat.) in toluene (0.5 ml). After the mixture was stirred at 80° for 3.5 h, solvent was evaporated under reduced pressure and chromatography (hexane/ethylacetate 9:1) gave methoxyimino- [2-(E ,Z)- (2-tributylstannanyl-vinyl)-phenyl]-acetic acid methyl ester (1:1 mixture) (155 mg, 44%) as a yellowish liquid. IR (KBr): 1731, 1600 cm-1.

MS (EI): 508 (M). b) A solution of 1-(2,2-dibromo-vinyl)-2-trifluoromethyl-benzene (989 mg, 3 mmol), and (Et)2POH (0.75 ml, 6 mmol) in Et3N (0.83 ml, 6 mmol) was stirred at 5° for 4 h. Hexane was added, and stirred for further 10 min. The mixture was extracted with hexane, washed with brine and dried over Na2 SO4. Evaporation of the solvent and chromatography (hexane) gave 1-(2-bromo-vinyl)-2-trifluoromethyl- benzene (674 mg, 90%) as a colorless liquid. IR (KBr): 1600, 940 cm-1.

MS (EI): 251 (M). c) At 24°, Pd[PPh3]4 (21 mg, 0.02 mmol) was added to a solution of 1- (1-bromo-vinyl)-2-trifluoromethyl-benzene (151 mg, 0.6 mmol) and methoxyimino-[2-(E,Z)-(2-tributylstannanyl-vinyl)-phenyl]-ac etic acid methyl ester (304 mg, 0.6 mmol) in toluene (5 ml). The mixture was stirred at 110° for 5 h, cooled to room temperature, extracted with toluene, washed with brine, and dried over Na2SO4. Evaporation of the solvent and chromatography (hexanel ethylacetate 3:2) gave (Z)- or (E)- methoxyimino- [2- [( 1E,2E)-4-(2-trifluoromethylphenyl)-buta- 1 ,3-dienyl] - phenyl]-acetic acid methyl ester (48 mg, 21%) as brown oil. IR (KBr): 1734, 1610 cm-1. MS (EI): 389 (M).

Example 251 (III) (E)-3-Methoxy-2-{(E)-2-[(R)- and (S)-3-(tetrahydro-pyran-2-yloxy}- propenyl]-phenyl}-acrylic acid methvl ester (active intermediate) At 24°, Pd[PPh3]4 (58 mg, 0.05 mmol) was added to a solution of (E)-tributyl-[3-(R)- and (S)-(tetrahydro-pyran-2-yloxy)-propenyl] - stannane (2.2 g, 5.1 mmol) (E.J. Corey; J.W. Suggs, J. Org. Chem. 40, 2554, (1975)) and (E)-2-(2-bromo-phenyl)-3-methoxy-acrylic acid methyl ester (1.38 mg, 5.1 mmol) (EP 0307101 A2 890315) in toluene (20 ml).

The mixture was stirred at 110° for 2 days, cooled to room temperature, extracted with toluene, washed with brine, and dried over Na2SO4.

Evaporation of the solvent and chromatography (hexane/ethylacetate 9:1) gave (E)-3-methoxy-2-[(E)-2-[(R)- and (S)-3-(tetrahydro-pyran-2- yloxy)-propenyl]-phenyl]-acrylic acid methyl ester (884 mg, 52%) as a white solid, m.p. 66-68°. IR (KBr): 1711, 1633 cm-1. MS (EI): 216 (M- MeOH-Dihydropyrane).

Example 252 (IV) (E)-2-f2-(3-Hvdroxv-propensl)-phensll-3-methoxY-acrYlic acid methvl ester (active intermediate) At 24°, toluene-4-sulfonic acid monohydrate (1.11 g, 0.4 mmol) was added to a solution of(E)-3-methoxy-2-[(E)-2-[(R)- and (S)-3-(tetrahydro- pyran-2-yloxy)-propenyl]-phenyl]-acrylic acid methyl ester (4.866 g, 14 mmol) in ethanol (70 ml). After the mixture was stirred for 6 h and neutralized with K2CO3 solution, the solvent was evaporated and the crude was dissolved in ethylacetate, washed with brine, water, and dried over Na2SO4. Evaporation of the solvent gave (E)-2-[2-(3-hydroxy- propenyl)-phenyl]-3-methoxy-acrylic acid methyl ester (3.4 g, 93%) as a white solid, m.p. 78-80°. IR (KBr): 1683, 1619 cm-1. MS (EI): 216 (M- MeOH).

Example A (E)-2-[2-(1E,3E)-4-[4,5-Dimethoxy-2-nitro-phenyl)-buta-1,3-d ienyl]- phenyl]-3-methoxyacrylic acid methyl ester can be formulated as the active ingredient according to methods known per se to give pharmaceutical preparations of the following composition:

1. 500 mg tablets Active ingredient 500 mg Powd. lactose 149 mg Polyvinylpyrrolidone 15 mg Dioctyl sodium sulphosuccinate 1 mg Na carboxymethylstarch 30 mg Magnesium stearate 5 m&t 700 mg 2. 50 mg tablets Active ingredient 50 mg Powd. lactose 50 mg Microcrystalline cellulose 82 mg Na carboxymethylstarch 15 mg 200 mg 3. 100 mg capsules Active ingredient 100.0 mg Powd. lactose 104.7 mg Corn starch 70.0 mg Hydroxypropylmethylcellulose 10.0 mg Dioctyl sodium sulphosuccinate 0.3 mg Talc 12.0 mg Magnesium stearate 3.0 mg 300.0 mg 4. 500 mg suppositories Active ingredient 500 mg Suppository mass ad 2000 mg 5. 100 mg soft gelatine capsules Active ingredient 100 mg Medium chain triglyceride 300 mg 400 mg