CA1050042A - Polyene compounds - Google Patents
Polyene compoundsInfo
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- CA1050042A CA1050042A CA234,206A CA234206A CA1050042A CA 1050042 A CA1050042 A CA 1050042A CA 234206 A CA234206 A CA 234206A CA 1050042 A CA1050042 A CA 1050042A
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- C07F9/5456—Arylalkanephosphonium compounds
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- C07C205/07—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms
- C07C205/11—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings
- C07C205/12—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by halogen atoms having nitro groups bound to carbon atoms of six-membered aromatic rings the six-membered aromatic ring or a condensed ring system containing that ring being substituted by halogen atoms
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- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/20—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings
- C07C205/21—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups and hydroxy groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C205/22—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to carbon atoms of six-membered aromatic rings having nitro groups and hydroxy groups bound to carbon atoms of the same non-condensed six-membered aromatic ring having one nitro groups bound to the ring
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- C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
- C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/045—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis by substitution of a group bound to the ring by nitrogen
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
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- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
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- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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- C07C45/515—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an acetalised, ketalised hemi-acetalised, or hemi-ketalised hydroxyl group
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- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
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Abstract
ABSTRACT
Disclosed are polyene compounds of the general formula
Disclosed are polyene compounds of the general formula
Description
~AN 4060/67 1050~42 The present invention r~lates to polye~e compound~, More particularly, the inventio~ concerned with pol;~ene compou~ds, a process for the manufacture thereof ~nd pharmaceutical prepRration~ containing same.
. ~
The polyene compourld~ provided by the present invention are compound~ o~ the general ~or~ula.
R3 ~R6 ( I
R~
, wherein one of the ~ymbols Rl and R2 rQpr~8entB 8 halo~;en ~tom or 8 lower al3~rl e;roup a~d the other s ymbol repre-Bents 6 halogen ato~ or a lower ~lkoxy group, the symbol~ R3 and R5 each r~pre-sent a h;~roge2~ or ~sloge~ atom ~r a low~r alk;srl group with the proYisD tha~
on~ o~ the symbols R3 ~d R5 reprefient~
other than a h~logen atom, the s; rmbol R4 represents a lower alkoxy qrol~p and the symbol ~6 represents a ~s/l. 8. 1975 ~1 io~sao42 carboxyl, lower alkoxycar~onyl, or mono(lower alkyl)carb~moyl group, and salt8 thereof.
The afo~ementioned lower ~lkyl groups prefer~bly . ~
contain up to 6 carbon atoms such a8 the methyl, ethyl, propyl, isopropyl or 2-methylpropyl group. The lower alkoxy groups likewi~e prefersbly contain up to 6 carbon atoms such as the methoxy, etho~ or isopropo~y group.
Of the halogen ~toms, rluorine and chlorine are preferred.
. ~he amino group can be mo~osubstituted or di-substituted by straight-chai~ or br~nched-chai~ lower ~lkyl' groups~ e.g, by ~eth~l, ethyl or isopropyl. ~.
The alkox~methyl and alkoxycarbonyl groups prefer~bly contain alkoxy groups ~aving up to 6 carbon atoms. The6e csn be straight-chain or branched-chain such ~s, ~or ex~mple.
the methoxy, ethoxy or isopropoxy group. However, the alkoxy groupR c~n also be higher ~lkoxy group~ containin~
from 7 to 20 carbon ~toms. e6peci~11y ~he ce~yloxy group.
The ~ia alkox~ ~roup~ can be substituted b~ functionsl groupE; for exA~ple. by nitrog~n-cont~inin~ group~ 6uch a~ a~ optionally al~yl-substituted ~ino or morpholino ~roup.
or b~ 2 piperidyl or pyridyl group.
5~ ~ ~2 ~ he alkenoxycarbonyl and alkynoxycarbonyl groups also pre~erably contain alkenoxy and alkynoxy groups con-taining up to 6 carbon atoms such a~, for ex~mple, the allyloxy or propargyloxy ~roup.
~he alkanoylgroups present in the ~lk~noyloxymethyl groupR are prefer~bly deri~ed from lower alka~ecarbox~lic acid~ containing from 1 to 6 carbo~ atoms (e,~, acetic acid, propionic acid or pi~lic acid),but they m~ al30 be asrived from higher alkanecsrboxylic acids containing from 7 to 20 carbon atoms (e,g. p~lmitic acid or ~te~ric acid).
~he carbamoyl group can be mono~ubstituted or di-substituted by ~trai~ht-chain or branched-chain lower alkyl groups (e.g. meth~l, ethyl or isopropyl). Example~ of such substituted carb~moyl groups are the meth~lcarbamo~l, dimethyl-carbamo~l ~nd diethylcarb~moyl ~roups.
~he N-heterocyclyl portion of the ~-heteroc~cl~lcar-bonyl ~roups i~ pre~er~bly a 5-membered or 6-m~mbered heterocyclic group wh~ch, in addition to the nitrogen ~tom, may al80 contain an oxy~sn or sulphur atom or a further nitroge~ atom. ~xamples thereof are the piperldi~o, morpholinos thiomor~holino or pyrrolidino group, Examplss o~ compound~ of formula I ~r~:
9-(6-chloro-4-methoxy-2,3-dimethyl-phenyl)-3,7-dimethyl--nona-2,4~6,8-tetraen-1-oic acid ethyl ester, 9-(~-chloro-4-methoxy-2,5-dimethyl-phenyl~-3,7-dimethyl--nona-2,~.6,8-tetraen-1-oic acid ethyl ester, ~ 05004Z
9-(2-chloro-4-methoxy-~,5,6-trimethyl-phenyl)-3,7-dimethyl--rlona-2,4,6,8-tetraen-1-oic acid et~yl ester, 9-(5-chloro-2,4-dimethoxy-6-methyl-phenyl)-3,7-dim~thyl--nona-2,4,6,8-tetraen-1-oic acid ethyl ester, 9-(2,6-dichloro-4-methoxy-phen~1)-3,7-dimethyl-nona-
. ~
The polyene compourld~ provided by the present invention are compound~ o~ the general ~or~ula.
R3 ~R6 ( I
R~
, wherein one of the ~ymbols Rl and R2 rQpr~8entB 8 halo~;en ~tom or 8 lower al3~rl e;roup a~d the other s ymbol repre-Bents 6 halogen ato~ or a lower ~lkoxy group, the symbol~ R3 and R5 each r~pre-sent a h;~roge2~ or ~sloge~ atom ~r a low~r alk;srl group with the proYisD tha~
on~ o~ the symbols R3 ~d R5 reprefient~
other than a h~logen atom, the s; rmbol R4 represents a lower alkoxy qrol~p and the symbol ~6 represents a ~s/l. 8. 1975 ~1 io~sao42 carboxyl, lower alkoxycar~onyl, or mono(lower alkyl)carb~moyl group, and salt8 thereof.
The afo~ementioned lower ~lkyl groups prefer~bly . ~
contain up to 6 carbon atoms such a8 the methyl, ethyl, propyl, isopropyl or 2-methylpropyl group. The lower alkoxy groups likewi~e prefersbly contain up to 6 carbon atoms such as the methoxy, etho~ or isopropo~y group.
Of the halogen ~toms, rluorine and chlorine are preferred.
. ~he amino group can be mo~osubstituted or di-substituted by straight-chai~ or br~nched-chai~ lower ~lkyl' groups~ e.g, by ~eth~l, ethyl or isopropyl. ~.
The alkox~methyl and alkoxycarbonyl groups prefer~bly contain alkoxy groups ~aving up to 6 carbon atoms. The6e csn be straight-chain or branched-chain such ~s, ~or ex~mple.
the methoxy, ethoxy or isopropoxy group. However, the alkoxy groupR c~n also be higher ~lkoxy group~ containin~
from 7 to 20 carbon ~toms. e6peci~11y ~he ce~yloxy group.
The ~ia alkox~ ~roup~ can be substituted b~ functionsl groupE; for exA~ple. by nitrog~n-cont~inin~ group~ 6uch a~ a~ optionally al~yl-substituted ~ino or morpholino ~roup.
or b~ 2 piperidyl or pyridyl group.
5~ ~ ~2 ~ he alkenoxycarbonyl and alkynoxycarbonyl groups also pre~erably contain alkenoxy and alkynoxy groups con-taining up to 6 carbon atoms such a~, for ex~mple, the allyloxy or propargyloxy ~roup.
~he alkanoylgroups present in the ~lk~noyloxymethyl groupR are prefer~bly deri~ed from lower alka~ecarbox~lic acid~ containing from 1 to 6 carbo~ atoms (e,~, acetic acid, propionic acid or pi~lic acid),but they m~ al30 be asrived from higher alkanecsrboxylic acids containing from 7 to 20 carbon atoms (e,g. p~lmitic acid or ~te~ric acid).
~he carbamoyl group can be mono~ubstituted or di-substituted by ~trai~ht-chain or branched-chain lower alkyl groups (e.g. meth~l, ethyl or isopropyl). Example~ of such substituted carb~moyl groups are the meth~lcarbamo~l, dimethyl-carbamo~l ~nd diethylcarb~moyl ~roups.
~he N-heterocyclyl portion of the ~-heteroc~cl~lcar-bonyl ~roups i~ pre~er~bly a 5-membered or 6-m~mbered heterocyclic group wh~ch, in addition to the nitrogen ~tom, may al80 contain an oxy~sn or sulphur atom or a further nitroge~ atom. ~xamples thereof are the piperldi~o, morpholinos thiomor~holino or pyrrolidino group, Examplss o~ compound~ of formula I ~r~:
9-(6-chloro-4-methoxy-2,3-dimethyl-phenyl)-3,7-dimethyl--nona-2,4~6,8-tetraen-1-oic acid ethyl ester, 9-(~-chloro-4-methoxy-2,5-dimethyl-phenyl~-3,7-dimethyl--nona-2,~.6,8-tetraen-1-oic acid ethyl ester, ~ 05004Z
9-(2-chloro-4-methoxy-~,5,6-trimethyl-phenyl)-3,7-dimethyl--rlona-2,4,6,8-tetraen-1-oic acid et~yl ester, 9-(5-chloro-2,4-dimethoxy-6-methyl-phenyl)-3,7-dim~thyl--nona-2,4,6,8-tetraen-1-oic acid ethyl ester, 9-(2,6-dichloro-4-methoxy-phen~1)-3,7-dimethyl-nona-
-2,4,6,8-tetr3en-l-oic acid ethyl ester, 9-(2,5,6-trichloro-4-methoxy-phen~ 3,7-dlmethyl-nona--2,4,6,8-tetraen-1-oic acid ethyl e9ter D
9-(6-methyl-2,4-dimethoxy-phenyl)-3,7-dimethyl-~ona--2,4,6,8 tetraen-1-oic acid ethyl ester and 9-(2,4-dimethox~-3,6-dimethyl-phen~ 3,7-dime~hyl--nona-2,4,6,8-tetr~en-1-oic ~cîd ethyl ester.
According to the process provided by the pre~ent invention, the compounds of formula I hereinbefore and their 8alt8 are ma~u~actured by reacting a compound of the ge~eral ~ormula R3 ~ A
R~ ~Rl ~ II
with a co~pound of the ge~eral formula 5~
~ ~ III
wherein thc s~mbol m standc for zcro and the symbol n stands for 1, or the symbol m stands for 1 and the sgmbol n stands for zero 7 one of the symbols A
and B repre~ents the for~yl group and the other symbol repres~nts eithe~ a triarylpho~phoniummethyl group of the formul~ -CH2-Pt~3 , in which the symbol X represe~ts an aryl group and the symbol Y repres~nt~
th~ anion of an or~a~ic or inorganic ~cid, or a dialkoxyphosphinyl~ethyl group of the formula -CH2-~Z]2-o in which the symbol Z represents an al~oxy group; or one of the symbols A
a~d B represents a halomethyl~ alkyl-~sulphonylox~methyl or arylsulphonyloxy-methyl group and the other symbol repre~
sents a sulphonylmethyl group of the formula -CH2~ ~ , in which the symbol repre~ents an aryl or aralkenyl group which may carry one or more electron--repelling to electron-weakly attracting lalSO~Z
substituents; the symbol~ Rl, R2, R3 9 R4, and R5 have the significance given earlier; and the symbol R7 represents a carboxyl, alkoxycarbonyl, alXenoxycarbon~yl, alkynoxycarbonyl, di(lower alkyl)carbamoyl or N-hetero~
cyclylcarbonyl group; or the symbol R7 also represent~ ~n alkoxymethyl or alkanoyloxyme~h~l group when the ~ymbol B
represents the formyl group; or the cymbol R7 also represen~s a for~yl, alkox~m~t~yl or alkanoyloxymethyl group when the symbol B repr~sents ~ halomethyl.
alkyl~ulphonylsx~methyl or arylsulphonyl-o~methyl group; or the symbol R7 also represents a formyl group when the symbol ` B represents a triarylphosphoniummethyl group, a dial~ox~phosphinylmeth~l group or a sulphonylmethyl group, and clea~ing off a sulphone group which may be pre~ent in the reaction product to form an ~dditional carbon-carbon bo~d, a~d, if desired, converting an acid obtained or sn amine obtainsd into a salt, or converting a carboxylic acid of formula I into a carbo~ylic acid ester of formula I or into an amide of formula I, or converting a carbox~lic acid ester of formula I into a carboxylic acid of formula I or i~to ~n amide of formula I, or r~ducing a carboxylic acid of formul~ I or a carboxylic acid ester of formula I to the corresponding alcohol of formula I and if d0sired ethcrifying or esterifying said alcohol, or saponifying a~
lOS~O~Z
alcohol ester of formula I, or oxidising ~n ~lcohol or alcohol ester of fo~mula I to the corresponding carbo~ylic acid.
~he aryl groups denoted by the ~ymbol X in the triarylphosphoniummethyl groups formulated earlier include all generally known aryl group~. How~verf the aryl group~ are preferably mononuclear aryl groups such as phenyl or (lower alXyl)- or (lower alkoxy)-fiub~tituted phenyl groups (e~g. tolyl, xylyl. mesityl and p-methoxgphe~yl). Of the inorganic acid anions denoted by the symbol Y, th~ chlorine, bromine or iodine ion or the hydrosulphate ion is preferred.
Of the organic acid anio~s, the to~yloxy ion i~ preferred.
~he alkoxy groups denoted by the ~gmbol Z in the dialkoxypho~phinylmethyl ~roups formulated ~arlier are preferably lower alkoxy groups containing from 1 to 6 carbon atoms, especially methoxy and ethoxy group~.
Example~ of aryl or aralkenyl groups, which ma~
carry one or more electron-repelling to electron-weakly attr~cting ~ubstitue~ts, denoted by the symbol E i~ the ~0 sulphon~lmethyl group~ formulated earlier are phenyl and styryl, both of which may be ~ubstituted in the o-, m- or p-position by methoxy, phenoxy, acetoxy;
dimethylamino, phenylmethylamino, scetylamino;
thiomethyl, thiophenyl, thioacetyl, chloro, bromo;
cyano; or nitro in th~ m-position.
0 5~ 0 ~ 2 ~ he starting materi~ls of formula II are, in part, novel and such novel starting materials al~o form par~ of this invention. The~ can be prepared. far example, i~
the followlng manner:
Compounds of formula II in which the ~mbol m stands for zero and the s~mbol A representa a triar~lpho~pho~ium-meth;yl group [ IIaJ or a dialkoxyphosphinylmethyl group ~IIc] can be prepared, for example, by treating a corre~pon-ding (Rl-R5)-benzene with formaldeh~de in the presence of a h;~rdrohalic acid (e.~;. in the prosence of concentr~tea hyaro-chloric acia optionally in a solvent, e~peci~lly in a glacial acetic acid) and reacting the resulting (Rl-R5)-benzyl halide ~a halide of formula II in which the ~ymbol m stand~ for zero and the symbol A represent~ a halomethyl group (IIi)] in a manner known per ~e with a triarylphosphine in a sol~ent, preferabl~ with triphenylphosphine in toluene or benzene, or with trlalkylpho~phite, e~peci~lly with triethylpho~phite.
A~ alkoxy group can be introduced into the ~fore-D~ontioned (Rl-R5)-benzene b r, for example, alkyl~tion of a h~dro~y group alroaay pre~ent. For ex~mple, the corresponding ph~nol, preferAbly in a sol~ent (e.g. an al~anol) and in the presence of a base (e.g. potas~ium carbonate) can be r~acted with an alkyl halide (e.g. meth~l iodide) or dimsth~lsulphate.
Compounds of the formula II in which the sgmbol m 6ta~d6 for 1 and the s;s~mbol R repre~ents a triar;ylpho~phonium--methyl group ~IIb~ or a di~lkoxypho~phinylmethyl group (IId) can be prepared, for example, in the following msnner: A
corro6ponding (Rl-R5)-benze~e is fir~t subaected to ~ 05004Z
formylation; for example, by allowi~g a form~lating age~t to act on said (Rl-R5)-benzene~ This can be carried out, for example, by carrying out the form~lation in the prese~ce of a Lewis acid. As fo~mylating agents, there ma~ be mentioned, in particular, orthoformic acid esters, ~ormyl chloride ana dimethylform~mide. Especîall~ ~uitable l~wi8 acid~ are the halides o~ zinc. ~luminium, tit~nium, ti~ and iron, such as zinc chloride, aluminium trichlorid~, titanium tetr~chloride, tin tetrachloride ~nd ion trichloride, as well as the h~lides of inorganic and or~an~c acids such as, for example, phosphoruc oxychloride a~d metha~e~ulphon~l chloride.
If the form~lati~g agent i~ pre~ent in exces~, the form~lation ma~ be carried out without the addition of a furt~er solvent. Howe~2r, it i~ generally recommended to carry out the formylstion in an inert solvent (e.g.nitroben.ene or ~ chl~rinated hydrocarbo~ such as methyle~e chloride~. The formylation can be carried out at temperature between 0C and the boiling point of the for2ylatio~ ~ixture, The (~l-R5)-benzaldeh~de obtAi~ed can be subsequently con~erted in a manner known per ~e by condensation with ace-tone in the cold (i.e. ~t ~ temper~ture of Rbout 0-30~ in the pre~ence o~ alk~ .g. dilute aqueous sodium h~droxide) into ~ (Rl-R5)-phen~l-but-3-en-2-one which can be cQnverted into a corresponding (Rl-R5)-phenyl~3-methyl-3-hydroxy-penta--4-en-1-yne in a ma~ner known per ~e by means of ~n organo-metallic reaction (e,g, a Grignard reaction with the addition of acetylene), The reeultin~ tertiary acetylenic carbinol is subs~quentl~ partially hydrogenated in a manner ~nown per se uaing ~ partl~ deactivated noble metal catalyst (Lindlar ~ os~
cataly~t). The resulting tertiary ethylenic carbinol c~n subsequently be converted into the desired phosphonium salt of formula IIb in which the symbol m stands for 1 under allylic rearr~ngement ~y treatment with a triarylphosphine, especially triphenylpho~phine, in the presence of a mineral acid (e,g. a hydrogen halide ~uch a~ hydrogen chloride or hydrogen bromide or sulphuric acid) in a solvent (e,g.bonzene), ~he tertiary ethylenic carbinol can also be halogenated to give a halide of the formula II i~ which the symbol m stand~
for 1 and the symbol A repre~ents a halomethyl group (IIk) a~d the halide can be converted with a tri~lkylphosphite (e.g. triethylpho~phite) into a corresponding phosphonate of the formul~ IId.
Compou~ds of formuls II in which the symbol m stands for zero and the s~mbol A represents a sulphonylmethyl group E IIe car. be pr~parcd, for example, by dissolving a (Rl-R5)-phenol or a corresponding halobenæene in a polar solvent (e,g, a~
alka~ol such as metha~ol, ethanol or isopropanol, tetrahydro--furan, dimethylform~mide or gl~cial acetic acid) and treating the solution at room temper~ture with a sulphinic acid of t~e formula Ho~ -E~ in ~hich the symbol ~ has the significance given earlier. or with an alkali salt of said sulphinic acid.
~he sulphone can be isolated from the reaction mixture by, for example, making the re~ction mi~ture ~eutral by the addition of an agueous sodium bicarbonate solution and ex-tracting the ~ulphone with an organic solvent (e.g, ethyl acetate or ether~, Compou~ds of formula II in which the s;ymbol m stands ~ 0 50 ~ ~ Z
for 1 and the symbol A repre~ent~ a sulphonylmeth~l group [IIf] can be prepared ln ~n ~nalogous mæ~ner b~ reactin~ a (Rl-R5)-phenyl-3-meth~yl-pe~ta-2~4-dien-l-ol or ~ corre~ponding halide with a previ~u~ly de~cribea sulphinic ~cia or with ~n alkali metal salt thereof.
Compound6 of formula II in which the symbol m stands for z~ro and the s~mbol A represents the formyl group ~II]
can be prepared, for example, by formylating a (Rl-R5)-benzene in the ~annor prev_ously describ0d. I~ this m~n~er, there i~
obtained directly the (Rl-R5~-benzaldehyde, Compound~ of formuld II i~ which the symbol m ~tands for ~ ~d the ~ymbol A represents the form~l group ~IIh~ can be prep~red~ for ex~mple, by reacting a (21-~5)-phenyl-~ut-
9-(6-methyl-2,4-dimethoxy-phenyl)-3,7-dimethyl-~ona--2,4,6,8 tetraen-1-oic acid ethyl ester and 9-(2,4-dimethox~-3,6-dimethyl-phen~ 3,7-dime~hyl--nona-2,4,6,8-tetr~en-1-oic ~cîd ethyl ester.
According to the process provided by the pre~ent invention, the compounds of formula I hereinbefore and their 8alt8 are ma~u~actured by reacting a compound of the ge~eral ~ormula R3 ~ A
R~ ~Rl ~ II
with a co~pound of the ge~eral formula 5~
~ ~ III
wherein thc s~mbol m standc for zcro and the symbol n stands for 1, or the symbol m stands for 1 and the sgmbol n stands for zero 7 one of the symbols A
and B repre~ents the for~yl group and the other symbol repres~nts eithe~ a triarylpho~phoniummethyl group of the formul~ -CH2-Pt~3 , in which the symbol X represe~ts an aryl group and the symbol Y repres~nt~
th~ anion of an or~a~ic or inorganic ~cid, or a dialkoxyphosphinyl~ethyl group of the formula -CH2-~Z]2-o in which the symbol Z represents an al~oxy group; or one of the symbols A
a~d B represents a halomethyl~ alkyl-~sulphonylox~methyl or arylsulphonyloxy-methyl group and the other symbol repre~
sents a sulphonylmethyl group of the formula -CH2~ ~ , in which the symbol repre~ents an aryl or aralkenyl group which may carry one or more electron--repelling to electron-weakly attracting lalSO~Z
substituents; the symbol~ Rl, R2, R3 9 R4, and R5 have the significance given earlier; and the symbol R7 represents a carboxyl, alkoxycarbonyl, alXenoxycarbon~yl, alkynoxycarbonyl, di(lower alkyl)carbamoyl or N-hetero~
cyclylcarbonyl group; or the symbol R7 also represent~ ~n alkoxymethyl or alkanoyloxyme~h~l group when the ~ymbol B
represents the formyl group; or the cymbol R7 also represen~s a for~yl, alkox~m~t~yl or alkanoyloxymethyl group when the symbol B repr~sents ~ halomethyl.
alkyl~ulphonylsx~methyl or arylsulphonyl-o~methyl group; or the symbol R7 also represents a formyl group when the symbol ` B represents a triarylphosphoniummethyl group, a dial~ox~phosphinylmeth~l group or a sulphonylmethyl group, and clea~ing off a sulphone group which may be pre~ent in the reaction product to form an ~dditional carbon-carbon bo~d, a~d, if desired, converting an acid obtained or sn amine obtainsd into a salt, or converting a carboxylic acid of formula I into a carbo~ylic acid ester of formula I or into an amide of formula I, or converting a carbox~lic acid ester of formula I into a carboxylic acid of formula I or i~to ~n amide of formula I, or r~ducing a carboxylic acid of formul~ I or a carboxylic acid ester of formula I to the corresponding alcohol of formula I and if d0sired ethcrifying or esterifying said alcohol, or saponifying a~
lOS~O~Z
alcohol ester of formula I, or oxidising ~n ~lcohol or alcohol ester of fo~mula I to the corresponding carbo~ylic acid.
~he aryl groups denoted by the ~ymbol X in the triarylphosphoniummethyl groups formulated earlier include all generally known aryl group~. How~verf the aryl group~ are preferably mononuclear aryl groups such as phenyl or (lower alXyl)- or (lower alkoxy)-fiub~tituted phenyl groups (e~g. tolyl, xylyl. mesityl and p-methoxgphe~yl). Of the inorganic acid anions denoted by the symbol Y, th~ chlorine, bromine or iodine ion or the hydrosulphate ion is preferred.
Of the organic acid anio~s, the to~yloxy ion i~ preferred.
~he alkoxy groups denoted by the ~gmbol Z in the dialkoxypho~phinylmethyl ~roups formulated ~arlier are preferably lower alkoxy groups containing from 1 to 6 carbon atoms, especially methoxy and ethoxy group~.
Example~ of aryl or aralkenyl groups, which ma~
carry one or more electron-repelling to electron-weakly attr~cting ~ubstitue~ts, denoted by the symbol E i~ the ~0 sulphon~lmethyl group~ formulated earlier are phenyl and styryl, both of which may be ~ubstituted in the o-, m- or p-position by methoxy, phenoxy, acetoxy;
dimethylamino, phenylmethylamino, scetylamino;
thiomethyl, thiophenyl, thioacetyl, chloro, bromo;
cyano; or nitro in th~ m-position.
0 5~ 0 ~ 2 ~ he starting materi~ls of formula II are, in part, novel and such novel starting materials al~o form par~ of this invention. The~ can be prepared. far example, i~
the followlng manner:
Compounds of formula II in which the ~mbol m stands for zero and the s~mbol A representa a triar~lpho~pho~ium-meth;yl group [ IIaJ or a dialkoxyphosphinylmethyl group ~IIc] can be prepared, for example, by treating a corre~pon-ding (Rl-R5)-benzene with formaldeh~de in the presence of a h;~rdrohalic acid (e.~;. in the prosence of concentr~tea hyaro-chloric acia optionally in a solvent, e~peci~lly in a glacial acetic acid) and reacting the resulting (Rl-R5)-benzyl halide ~a halide of formula II in which the ~ymbol m stand~ for zero and the symbol A represent~ a halomethyl group (IIi)] in a manner known per ~e with a triarylphosphine in a sol~ent, preferabl~ with triphenylphosphine in toluene or benzene, or with trlalkylpho~phite, e~peci~lly with triethylpho~phite.
A~ alkoxy group can be introduced into the ~fore-D~ontioned (Rl-R5)-benzene b r, for example, alkyl~tion of a h~dro~y group alroaay pre~ent. For ex~mple, the corresponding ph~nol, preferAbly in a sol~ent (e.g. an al~anol) and in the presence of a base (e.g. potas~ium carbonate) can be r~acted with an alkyl halide (e.g. meth~l iodide) or dimsth~lsulphate.
Compounds of the formula II in which the sgmbol m 6ta~d6 for 1 and the s;s~mbol R repre~ents a triar;ylpho~phonium--methyl group ~IIb~ or a di~lkoxypho~phinylmethyl group (IId) can be prepared, for example, in the following msnner: A
corro6ponding (Rl-R5)-benze~e is fir~t subaected to ~ 05004Z
formylation; for example, by allowi~g a form~lating age~t to act on said (Rl-R5)-benzene~ This can be carried out, for example, by carrying out the form~lation in the prese~ce of a Lewis acid. As fo~mylating agents, there ma~ be mentioned, in particular, orthoformic acid esters, ~ormyl chloride ana dimethylform~mide. Especîall~ ~uitable l~wi8 acid~ are the halides o~ zinc. ~luminium, tit~nium, ti~ and iron, such as zinc chloride, aluminium trichlorid~, titanium tetr~chloride, tin tetrachloride ~nd ion trichloride, as well as the h~lides of inorganic and or~an~c acids such as, for example, phosphoruc oxychloride a~d metha~e~ulphon~l chloride.
If the form~lati~g agent i~ pre~ent in exces~, the form~lation ma~ be carried out without the addition of a furt~er solvent. Howe~2r, it i~ generally recommended to carry out the formylstion in an inert solvent (e.g.nitroben.ene or ~ chl~rinated hydrocarbo~ such as methyle~e chloride~. The formylation can be carried out at temperature between 0C and the boiling point of the for2ylatio~ ~ixture, The (~l-R5)-benzaldeh~de obtAi~ed can be subsequently con~erted in a manner known per ~e by condensation with ace-tone in the cold (i.e. ~t ~ temper~ture of Rbout 0-30~ in the pre~ence o~ alk~ .g. dilute aqueous sodium h~droxide) into ~ (Rl-R5)-phen~l-but-3-en-2-one which can be cQnverted into a corresponding (Rl-R5)-phenyl~3-methyl-3-hydroxy-penta--4-en-1-yne in a ma~ner known per ~e by means of ~n organo-metallic reaction (e,g, a Grignard reaction with the addition of acetylene), The reeultin~ tertiary acetylenic carbinol is subs~quentl~ partially hydrogenated in a manner ~nown per se uaing ~ partl~ deactivated noble metal catalyst (Lindlar ~ os~
cataly~t). The resulting tertiary ethylenic carbinol c~n subsequently be converted into the desired phosphonium salt of formula IIb in which the symbol m stands for 1 under allylic rearr~ngement ~y treatment with a triarylphosphine, especially triphenylpho~phine, in the presence of a mineral acid (e,g. a hydrogen halide ~uch a~ hydrogen chloride or hydrogen bromide or sulphuric acid) in a solvent (e,g.bonzene), ~he tertiary ethylenic carbinol can also be halogenated to give a halide of the formula II i~ which the symbol m stand~
for 1 and the symbol A repre~ents a halomethyl group (IIk) a~d the halide can be converted with a tri~lkylphosphite (e.g. triethylpho~phite) into a corresponding phosphonate of the formul~ IId.
Compou~ds of formuls II in which the symbol m stands for zero and the s~mbol A represents a sulphonylmethyl group E IIe car. be pr~parcd, for example, by dissolving a (Rl-R5)-phenol or a corresponding halobenæene in a polar solvent (e,g, a~
alka~ol such as metha~ol, ethanol or isopropanol, tetrahydro--furan, dimethylform~mide or gl~cial acetic acid) and treating the solution at room temper~ture with a sulphinic acid of t~e formula Ho~ -E~ in ~hich the symbol ~ has the significance given earlier. or with an alkali salt of said sulphinic acid.
~he sulphone can be isolated from the reaction mixture by, for example, making the re~ction mi~ture ~eutral by the addition of an agueous sodium bicarbonate solution and ex-tracting the ~ulphone with an organic solvent (e.g, ethyl acetate or ether~, Compou~ds of formula II in which the s;ymbol m stands ~ 0 50 ~ ~ Z
for 1 and the symbol A repre~ent~ a sulphonylmeth~l group [IIf] can be prepared ln ~n ~nalogous mæ~ner b~ reactin~ a (Rl-R5)-phenyl-3-meth~yl-pe~ta-2~4-dien-l-ol or ~ corre~ponding halide with a previ~u~ly de~cribea sulphinic ~cia or with ~n alkali metal salt thereof.
Compound6 of formula II in which the symbol m stands for z~ro and the s~mbol A represents the formyl group ~II]
can be prepared, for example, by formylating a (Rl-R5)-benzene in the ~annor prev_ously describ0d. I~ this m~n~er, there i~
obtained directly the (Rl-R5~-benzaldehyde, Compound~ of formuld II i~ which the symbol m ~tands for ~ ~d the ~ymbol A represents the form~l group ~IIh~ can be prep~red~ for ex~mple, by reacting a (21-~5)-phenyl-~ut-
-3-en-2-one (de~cribed hereinbefore in connection with the prepar~tion of compou~ds o~ formula IIb) under the conditions of a Wittig rcaotio~ with ethoxycarbonyl-methylene-triphe~
-phosphorane or with diethyl-phosphonacetic acid ethyl e~ter~
Thé re~ulting (Rl-R5~-phen~1-3-methyl-penta-2,4-aie~-1-oic acid eth~l ester i~ ~ub~equentl~ reduced in the cold by me~n~
of a mixed met~l hydride, especially lithium alumi~ium hydride, in a~ organic 801ve~t (eOg. ether or tetrahydrofur~n) to give a (Rl-R5)-phenyl-3-methyl-penta-2,4-dien-1-ol. This alcohol i8 then oxidised by treatment with an oxidising agent (e,g.
m~ng~nese dioxide in an or~anic colverLt 3uch as acetone or meth~lene chloride) at a temper~ture between 0C and the boilin~ point of the oxidation mixture to gi~e the desired (Rl-R5)-phe~yl-3-methyl-pentfl-2,4-dien-1-al of for~ula IIh, ~os~
~he co~pounds of the formula III are. in part, nov~l.
Compounds of formula III in which the symbol n stanas for zero ~nd the sgmbol B r~presents a tri~rylphosphoni~m-methyl group ~IIIa] or ~ dialkoxyphosphi~ylm~thyl group tIIIc] csn be readily prepared by xescting a 4-halo-3-methyl--crotonic acid~ which ~ay be esterified, or an etheri~ied
-phosphorane or with diethyl-phosphonacetic acid ethyl e~ter~
Thé re~ulting (Rl-R5~-phen~1-3-methyl-penta-2,4-aie~-1-oic acid eth~l ester i~ ~ub~equentl~ reduced in the cold by me~n~
of a mixed met~l hydride, especially lithium alumi~ium hydride, in a~ organic 801ve~t (eOg. ether or tetrahydrofur~n) to give a (Rl-R5)-phenyl-3-methyl-penta-2,4-dien-1-ol. This alcohol i8 then oxidised by treatment with an oxidising agent (e,g.
m~ng~nese dioxide in an or~anic colverLt 3uch as acetone or meth~lene chloride) at a temper~ture between 0C and the boilin~ point of the oxidation mixture to gi~e the desired (Rl-R5)-phe~yl-3-methyl-pentfl-2,4-dien-1-al of for~ula IIh, ~os~
~he co~pounds of the formula III are. in part, nov~l.
Compounds of formula III in which the symbol n stanas for zero ~nd the sgmbol B r~presents a tri~rylphosphoni~m-methyl group ~IIIa] or ~ dialkoxyphosphi~ylm~thyl group tIIIc] csn be readily prepared by xescting a 4-halo-3-methyl--crotonic acid~ which ~ay be esterified, or an etheri~ied
4-h~10-3-meth;yl-crotyl alcohol with a triar;ylpho~phi~e i~ a 801v~nt~ pref~rably with triphe~ylpho~phine in toluene or benzene, or with a trialkylpho~phit~,especiall~ with triethyl-10 phosphite.
Compounds o~ formul~ III in which the symbol n ~t~nd~for 1 ~nd the sgmbol B rQpresents ~ triarylphosphoniummethyl ~roup ~IIIb3 or a dial~oxypho~phinylmethyl ~roup ~IIId~ can be prep~red, for example, by reducing the for~yl group i~ an aldehgde of formula III, in which the symbol ~ stands for 1 and the ~gmbol B repr~s~nts the formyl group ~IIIh3 to th~
hgdroxymethyl group using a mstal hydride such a~ ~odiu~
boro~ydride in an fil~nol (e.g. sthanol or i~opropa~ol).
th~ r~ulting ~lcohol c~n be halogenated using a cust~mary h~logenating ~gent (e.g.pho~porous o~ychloride) and the resulting 8-halo-3,7-dimethyl-oet~-2,4,6-triene-1-carboxylic acid, ~ halide of formul~ III in which the ~mbol n st~nd~
for 1 a~d the symbol B represen~ 8 h~lomethyl group ~IIIi~, or a deriv~tive thereof can be co~verted with a triarylphos--phi~e i~ a solvo~t, preferably triphenylpho~phine,in tolusne or benzene, or wit~ a trialkylphosphite, especially triethylphosphite, i~to a desired pho~pho~ium salt of for~ula IIIb or pho~phonate of formula IIId.
~5~
Compounds of formula III in which the symbol n stand~
for zero and the symbol B represents a ~ulpho~lmethyl group ~IIIe3 ca~ be prepared, for exa~ple, by reacting 4-hydroxy -3-mathyl-but-2-e~-1-al or the acetat~ thereof or the corre~-po~di~g bromide in a polar 801~ent ( e.g, isoprop~nol orn-butanol) in the m~n~er pre~iou~ly describ~d with an ~ore mentioned ~ulphinic Acid or wi~h an alkali met~l ~alt th~reof~
Compounds of formula III i~ which the symbol n ~tanas for 1 and the ~ymbol B repre~ents 8 ~ulphon~lmethyl group tIII~ can be prepared in a ma~ner analogous to th~t previousl~
described by the re~ction of, for example~ 8-hydroxy-3,?--dimethyl-octa_2,4,6-trien-l~oic acid or the acetate thereo~
or a corresponding bromide with a~ ~foremention~d sulphinic acid.
Compounds o~ formula III in which the ~ymbol n ~tand~
for zero and the agmbol B r~present~ the form~l group [IIIg]
can be prepared, for oxa~ple, by oxidatively clea~ing an optionally e~terified t~rtaric acid (e,g. uæing l~ad tetra -acetate at room te~perature in an organic solvent such as ben~ene), ~he ~lyoxalic ~cid deriv~tive obtainsd is 6ub-eque~tly condeneed i~ a manner known per se. co~eniently i~ th0 pre~enoe of an ami~e, wlth propio~aldeh~de a~ an el~vated temperature ~e.g. a temper~ture betwee~ 60C a~d llO~C) with 10~9 of water to ~ive a desired 3-formyl-crot~l slcohol deri~ati~s.
Compound~ of for~ula III in which the ~mbol n stand6 for 1 and the symbol B represents the formyl group ~IIIh~
-- 1~
~500~2 c~n be prepared, for example, by allowing phosgene to aot on 4,4 dimethoxy-3-m~thyl-but-1-en-3-ol in the cold9 preferabl~
at -10C to -20C, i~ the pre~e~ce of a tertiary amine ~uch a~ pyridi~e ~nd condensing the re~ulting 2-formyl-4-chloro--but-2-ene under the coud~tion~ o~ ~ Wittig reaction with 3-formyl-croto~ic acid, which ma~ be ssterified9 or with a 3-formyl-crotyl ~lcohol, which m~ be esterified, to give the desired aldehyde of formula IIIh.
In accord~nce with the process provided by the pre~e~t invention, a pho~pho~ium salt of formula IIa or IIb is reacted with an alde~yde of formula IIIh or IIIg, or a phosphonium ~alt of formula IIIa or IIIb is reacted with an aldehyde of ~ormula IIh or IIg, or a phosphonate of ~ormula IIc or IId i8 reacted with an ~ldehyde of formula IIIh or IIIg 9 or a phosphonate of formula IIIc or IIId is re-acted. with an alaehyde of formula IIh or IIg, or a sulphone of formul~ IIe or IIf i8 reacted with a halide o~ formula IIIk or ITIi or a ~ulphone of formula IIIe or III~ is reacted with a halide of for~ula IIk or IIi.
According to the Wittig procedure, the compo~ents are reacted with one another iu the presence of an acid-binding agent ~e.g, an alkali metal alc~hol~te 5uc~ as sodium methylate or a~ alkylene oxide which may be alkyl-substituted, e~pecially ethylene oxid~ or 1,2 but~lene oxide), or if desir~d in a ~olvent (e.g. a chlorinated h~drocarbon such as meth~lene chloride~ or dimeth~lform~mide), at a temperature between room temperature and the boil~ng point of the reaction mixture, ~S0042 According to th~ Horner procedure, the compo~ents are reaeted to~3ether u~i~ag a ba~ and pr~f0rably in'the pr~er~ce o~ an inert organic 801ve~nt9 ~or ex~mple sodium h;rdrid~ i~
benzene, toluene, dimeth;ylfornamide, t~trah;ydrofura~ or 1,2-dimethox;s~ethane, or alao sodium methylate in ~thanol, at a temperature between 0C ~nd the boiling point of the reaction mixtur¢.
According to l;he Julia procedure, th~ comporLents ~re reacted ~ith o~e a~other u8i~g a cond~naation agc~t, con-veniorltly in the pres~no~ of a polar solvent. ~u~table solv~nts are, for e3~ample, dimeth~l~Grm~mide, dimct}~l sulp}:loxide, dimethyl~cetamideg tetr~h~dro~ur~ a~d hexs--meth;~lpho~phoric acid triamid~ a~ well as ~lcohol~ ~uch a8 metha~ol, isopropano~ or terbutanol~, Of the stro~g b~0es which are particul~rl~ use~ 18 the co~densatio~ ag~nts there ca~ be mentioncd, for exam~le, allc~li mat~l and alkaline ~arth metal carbonate~, ~specially sodium carbonato. alkali ~etal hardroxides ~uch a~ pot~sium h~rdroxide or sodium h;~rdroxide, alkali metal and ~lk~line earth metal alcohol~tes 8UCb a~l sodium Dleth~late and, eapeci~lly, potassium tert--butylete, alkali met~l hydrides such as sodium ~dride, alkyl-magne~ium halides ~uch a~ methyl-magnesium bromide snd ~lkali metal amides ~uch ~8 ~od~um ~mide, The resction USirlg this proeedure i~ pr~ferably carried out st a low temper~ture, e~pecially at a temp~rature below the freezing point (e,g, betwee~-5C)C and -80C).
It has boen ~ound to be con~Tenient in cert~in case~ to carry out the aforementio~ed re~ctions in situ; th~t is to :1~50042 say, without i~olating the particular phoQphonium ~alt, phosphonate or sulphone from the medium in which it i8 prepared .
A carboxylic ac~d of ~ormula I can be co~erted in a mann~r known per ~e (e,æ, by treatment with thion~l chloridet preferabl~ in pyridine3 into ~n acid chloride which c~n be co~verted into an ester by resction with an alka~ol a~d into an amide by re~ction with 8mmonia, A carboxylic acid ester of formula I can be h~drolysed to a c~rboxylic acid in a man~er known per se, for example, by treatment with an alkali, especially uqueous-alcoholic ~odium h~droxide or potassium hydroxide at a temperature betwee~ room temperature and th~ boiling point of the mixture, - ~he re~ulting carbo~ylic ~cid c~ then be amidated via an acid h~lide. Alternati~el~, a carboxylic acid ester ca~ be directly amid~ted a~ de~cribed herein~fter.
A carbo~ylic acid ester o~ formula I c~n be converted dir~ctly into a corresponding amide by treatment with lithium amide. ~his treatment 1~ advanta~eously carried out at roo~
temper~ture.
A cfirboxylic ~cid or a carboxylic acia ester o~ formula I can be reduced to a corresponding alcohol of formula 1 in a manner X~own per se. ~he reducticn i~ advantageou~ly carried out using a metal ~ydride or alkyl metal hydride in an inert solvent. Examples of hydride~ which h~ve proved to be particularly suitable are mixed metal hydride~ such A~ lithium ~ os~4~
aluminiu~ h~dride and bis-~methoxy-ethylenoxy~-sodium ~lu-minium hydride. Suit~ble inert ~olven~ are, int~r alia 9 ether, tetrahydrofuran or dioxane when lithium aluminium h~dride is used and ether, hexane~ benzene or toluene when diisobutylaluminium hydride or bi~-~methoxy-ethyle~oxy~--sodium aluminium ~ydride is usedO
An alcohol of formula I can be etherified with an alkyl h~lid~ (e,g. eth~l iodide), for example in the presence of a ba~e, preferably ~odium hydride, in an organic solv~nt such 0 ~8 dioxane, tetrahydrofuran, 1,2-dimethsxyetha~or dimethyl-formamide, or in the presence o~ an alkali metal alcoholate in an alka~ol, at a temperature betwee~ 0C and room te~-peratureS
An alcohol o~ formul~ I can ~180 be esterified b~
treatment with an alkano~l halide or anh~dride, expedientl~
in th~ prcssnce of e bas~ (e,g. pyr~dine or triethyl~mine) at ~ t~mperhture betwee~ room temperature and the boili~g point of the mixtur~.
An alcohol e~ter obtained can be saponified in a ~anner kno~ per se; for example in the man~er previou~ly describcd in connection with the saponification of a carbox~lic acid ester, An ~lcohol of formula I or ~n ester thereof can be oxidised in a maDner known per ~e to give a corre~ponding acid of formula I. The oxidation is ad~antageou~ly carried out U8ihg ~ er ~I) oxide and an alkali in w~ter or in a ~05Q04'~
water-miscible organic 801vent st a temper6ture between room temperature and the boiling point of the mixture.
An amine of formula I ~orms acid addition salts with inorganic acids (e,g, hydrohalic acids, especially hydrochloric acid or hydrobromic acid, and sulphuric acid) a~d with orga~ic acids (e,g, benzoic acid, acetic acid. citric aoid ana l~ctic acid), A carboxylic acid of formula I form~ ~alts with b~se~, e~pecially with alkali met~l hydroxidc~ and particularly with sodium h~droxide and pot~s3ium h~droxid~.
10The compounds of formul~ I can occur a~ a ci~/trans mixture which m~y be ~eparated in a manner known per s~ into the ci~ ~nd trans compone~t~ or isomeri~ed in a manner known per se to the all-tran~ compounds.
~hc present polye~e compounds ~re pharmacod~namically valuable. They can be usea for the topical ana 9y8temic:
therapy of benign and malignant neoplasia and of premalignant lesions as well ~8 for the systemic and topical proph~laxis of these conditionc. ~hey are al80 suit~ble for the topical and ~y~temic therspy of acne, ~coriacis and other dermatoses 20 accompanied by an increased or patholo~ically altcred corni-fication, and for the treatment of infl~mmatory and allergic dermatological condition~, ~he present pol~ene compounds ca~ al~o bs used for comb~ttin~ mucous membrane disea~es with inflammatory or de~enerative or metaplastic alterations.
25The toxicity of the pre~ent polyene compounas is slight.
For example, when 9-(2-chloro-4-methoxy-3,5,6-trimethyl-~os~04z -phenyl)-3~7-dimethyl-~ona 2,4~6,8-tetrRen l-oic acia i~
adminiætered intraperitone~lly to mice weighing ~0 g i~ a daily dosage of 200 mg/kgf then no indication OI an A-h~per-vitaminosis become~ evident ~fter 14 days ~ total of 10 ~d-ministration days~
~ he first indic~tio~s of a slight A-hypervitaminosis in mice appears at a daily do~age of 400 mg/kg after 14 d~ys Ztotal of 10 administratio~ dP~] This ma~ife~ts it6elf in a weight decrease of 20~, a moderate h~ir loss and slight flaking of the skin.
The tumour-inhibiting ~CtiYity of the pre68nt polyene compound~ i8 significantr In the papilloma te~t, tumours induced with di~ethylbenzanthracene and crot~n oil regreas.
~he dia~eter of the papilloma~ within 2 weeks after the intraperitoneal administr~tion of 9-(2-chloro-4-methoxy-3,5,6--trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid eth~l ester decre~se3 by 61~ at a dos~ge of 400 ~g/kg/week and by 45~ at a dosage of 200 mg/kg/week.
The polyene compounds of fo~mula I and their salts can therefore be used as medicaments; or example, in the form of pharmaceutical preparation~ which contain them in association with a c~mpatible phar~aceutical carrier, ~ he pharmaceutical preparations for systemic adminis-tratio~ can be prepar~d f for ~xample, by adding a polyene compound as the active ingredient to no~-toxic inert solid or liquid carriers which are usual in such preparations.
~ ~0 ~ ~ 2 The pharmaceutical preparations can be administered enterally or parenterally. Suitable preparations for enteral administration are, for example, tablets, csp~ules, dra~ées 9 8yrup~, suspensio~ olutions ~nd ~uppositories and suitsble preparation~ for parenteral administrati~n are infusion and in~ection solutions, The aosage~ in which the polyene compound~ of this invention are adminiRtered can b~ varied according to the mode and route of admini~tration ~nd according to the requir~ments of the patient, ~he polyene co~pound~ of this in~e~tion can be adminis-tered in amount~ of from 5 mg to 200 mg daily i~ one or more dosage~. Capsules containing ca 10 mg to ca 100 mg of a polyene compound of thi~ inventio~ represent a proferred form o~ administr~tion.
~he pharmaceutical preparations ca~ contain i~ert or pharm~cod~namically acti~e additi~es, Tablet6 or granules, for ex~mple, ccn conta~n a æerie~ of binders, fillers, c~rrier materials or diluents, Liquid preparations can, for example, take the form of a 8t9rile WBter-mi~Cible 801utio~. C~psule~
can co~t~ filler or thiekener, ~urthermore, flavour--improvi~g additi~es and ~ubstances commonly usea a~ pre~er~
~ative~, stabili6ers, moisture-retainers or emulsifier69 salts for var~ing the os20tic pressure ~ buffers aIld other additives can al80 be present in the pharmaceutical prep~r&-tions .
~soo~z ~ he aforementioned c~rrier ma~erial3 ~nd diluQnt~ ca~
be organic or inor~anic ~ubatances ~uch a~ wst6r, ~el~tin, lactose, ~tarch, magnesium ~tearate, talc, gum arabic, poly-alkylenegl~col~ and th~ like, It i~, of cource~ a pre-requisite that Rll ad~uvants used in the preparation o~ thepharmaceutical preparations are no~-toxic.
For topic~l ~d~inistr~tio~, the pre~ent pol~ene com-pounds are expedientl~ mede up in the form or ointment~, tinctures, cream~, 801ution8 ~ lotion~, sprays, ~uspe~sion~
and the like. Ointm~t~, crssms and ~olutions sre pr~ferred.
These pharmaceutical preparation~ for topic~l ad~inistration ca~ be prepared by mixing the pol~ne compou~dst a~ the active ingredie~t, with no~ toxic insrt ~olid or liquid carriers which are cuatomary i~ su~h prep~r~tions and which are suitable for topic~l treatm~nt~
Expedient for topic~l ad~i~istration are ca 0.10% to ca 003%, pre~erably O.OZ% to 0.1%~ solution~ ~nd ca 0.05% to ca 5%, preferably ca 0.1% to ca 2.~%, ointments or creams.
An antioxiaant (e.~ tocopher~ metbyl-~-tocophera-mine, butyl~ted hydroxy~nisole or but~latod hydroxytoluene)can ~180 be present in the pharmaceutic~l prepar~tion~, ~L050042 The following ~xamplas illu~tr~te the process provided by the present invention:
9,9 g of 2-chloro-4-methox~-3,5,6-trimethyl-benzyl--tr~phenylphosphonium chlor~de sre dissolved in 50 ml of d$meth~1formamide, A~ter the addition of 4~16 g of 7-formyl--3-methyl-octa-2,4,6-trien-1-oic acid cthyl ester. the solution is treated dropwise at 20~ with 10 ml of ~ solution of sodium ethylate frefi~ly prep~red from 0.460 g of sodium and 10 ml of ab~olute ethanol, The mixture i~ stirred ~t room tomperature for 12 houra, then introduced into 100 ml o~ w~ter and extracted with hexane. ~he hexane ~xtract is shaken out three times with methanol/water, dried over soAium sulphate and evaporated under rcduced pressure. ~he residue i9 purifiad by ~bsorption on ~ilica gel using meth~lene chloride/hex~ne (8:2) for the elution. The 9-(2-chloro-4--methoxy-3,5,6-trimethyl-phenyl)-3,7-dimet~yl-octa-2,4,6,8--tetraen-l-oic acid ethyl ester obt~ined from the eluate ~elts at 90C ~fter recr~3t~11is~tion from hexane.
~he 2-chloro-4-methox~-3,5,6~trimeth~1-benzyl--triphenylphosphoniu~ chloride uced as the st~rting material can b~ prepared, for examplQ, a~ follows:
189 g of 3-chloro-4,6-dimethyl-benzyl chloride are introduced into 1500 ml of 5-~ sodium hydroxid~, ~he mixture is treated while stirring with 195 g of zinc dust within 2 hours, The temperature of the reaction, which takes place 1C~S~04Z
exothermic~llg~ i8 maint~in~d at 70 C by cooling, ~he mixture i~ stirred for a further 12 hours ~t 50~C end sub~quently filtered. ~he filtrate i~ extractsd three time~ with 800 ml of ethyle~e chloride, ~he meth~le~ chloride extract i8 washed neutral with water, dried o~er sodium ~ulphate and evaporated. The re~ual 2-chloro-3~5,6-trimethyl-benzene i~ purified by adsorpt~on on ~ilica gel u8ing hexane/m~th~l~ne chloride ~9;1) for the elution. Th~ compound boils ~t 81~9 Torr~
70 g of 2-chloro-3,5~6-trimethyl-be~ene are ada~d dropwi~e within 30 minutes wh~le Bt~rrin~ to 400 ml of nitric acid t70% v~v] pr~-cooled to O~C. ~he mixture i8 ~tirred for a ~urth~r 4 hours at a ~low}~ increasin4 te~peraturc up to +20~G, then introduced ~n~o ic0-water a~d thoroughly extract~d with ether. ~e ether extract i~ washed 8iX time~
wit~ 1000 ml of wat~r, dri~d over ~oaium ~ulphate and ev~porst0d under reduced prec~ure. ~he r~cidual 2-chloro-4-nitro-3,5,6--trimethyl-be~zen~ i~ purifi~d b~ adsorption o~ ~ilica g21 u8ing hexan~/benze~e (3:7) ~or the elution. ~he co~po ~elts at 79-C after recrystalli~ation ~rom low-boil$ng petroleum ethor.
114,5 g of 2-chloro-4-nitro-~,5,6-trimethyl-benzene are di~olved in ~00 ml of ethyl ~cet~te. The 601ution i~
diluted with 300 ml of ethanol and, sfter the ~ddition o~
20 ml of Ra~ey-nickeli hydro~enated u~der no~mal con~it~ons.
~fter th~ uptak~ of 43 litr~s of hydrogen, the hydrogen~tion is tarminated, ~he catel~ iB filtered off while gassing with carbo~ dioxlde and washed with ~tha~ol, The combined ~os~o~z filtrates are e~aporated under reduced pres~ure, ~he re~idual 4-amino-2-chloro-3,5,6-trimethyl-benze~e melt~ ~t 93~C after recrystallisation from hexa~e.
65 g of 4-amino-2-chloro-3,5,6-trimethyl-ben~ene are gradually introduced into 250 ml of concentrated sulphuric acid while ~tirring a~d cooling. In ~o doi~g, the tempera-ture ri~es to ~60C. ~he mixture i~ cooled to 0C by the gr~dual addition of 75Q g of ice a~d then tre~ted dropwi~e within 3 hours with a solution of 26.4 g of sodium ~itrite in 80 ml of water, The mixture is ~tirred for a further 90 minutes Qt 0C to +10C and sub~eQuently filtered, ~he filtrat~ i8 ~ub~ect~d to a steam di~till~tio~ while adding dropwi8e 600 ml of sulphuric ~cid ~50 vol %~, The aistill~te i~ extracted threz tim~ with 1000 ml of methylene chloride, The meth~lene chlorid~ extract i8 dried o~er ~odium sulphate ~n~ e~aporated, ~he re~idual 2-chloro-4-hydro~y 3,5 96--trim~thyl-benzene melts ~t 97-C after recryst~llisation from hexane.
After t~e a~dition of 400 ml ~f methanol and 85,5 ~1 of dimeth~l sulphate, 76 g of 2-chloro-4-hydroxy-3,5,6--trimethyl-benzene are treated dropwise while stirring with 265,5 ml of potassium hydroxlde ~25~ g/v]~ The mixture, which thereb~ heat~ to boiling, i8 stirred for ~ further 4 hour~ under reflux conditions and ~ubsequently evaporated.
~he residue i8 taken up in 600 ml of water. ~he aqueous ~olutio~ i8 extr~cted three time~ with 600 ml of ether. ~he ether extract i~ wa~hed neutr~l with ~ater, dried over ~odium ~ulphate ~nd ev~por~ted under reduced preææure~ The re~idual 10~042 oily 2-chloro-4-methoxy-3,5,6-trimeth~l benzene boils ~t 77 -79 C/l ~orr~
65.35 g of 2-chloro-4-methoxy-3,5Y6-trimethyl-benzene are mixed with 235 ml of acetic ac~d, 446 ml of hydrochloric acid [37 g~v~ ~d 107 ml of formaldehyde ~35%), The mixture is ~tirred at 70 C for ~ hour~ and, after cooli~g, i~troduced into 2~00 ml of water~ The aqueous solution is extracted three times with 1000 ml of meth~lene chloride. The meth~-lene chloride extract i~ wa~hed three times with 1~00 ml of water, dried over ~odium sulphate a~d evaporated. The residual 2-chloro-4-methox~-3,5,6-trimethyl-ben~yl chloride is purified ~yadsorption o~ 6ilica gel u~in~ low boiling petroleum ether for the elutio~, The compound melt~ at 59-63C after recrystalli~ation from low boili~g petroleum ether.
70.8 g of ~-chloro~4-methox~-3,5,6-trimethyl-benzyl chloride are dis~olved in 500 ml of toluene. The solution i8 treated with 77 g of triphenylpho~phinç a~d stirred at 100C for 18 hour~. The 2-chloro-4-methoxy-3.5,6-trimethyl--be~zyl-triphenylphospho~ium chloride which separate~ in the form o~ white cr~tal~ ic washed with ether and dried in vacuo. The phospho~ium ~alt m~lts at 215JC.
~he 7-formyl-3-methyl-oct~-2,~,6~trien-1-oic acid eth~l ester u~ed as the starting material can be prepared, for exampl~, as follows:
After the addition of a 6mall amount o:E ion ~ III) -- 26 ~
nitrate, 2700 ml of liquid ammonia are treated portionwise with 169.5 g of potassium ~hile stirring and cooling. A~
soon as the initially blue colour has di~app~ared (i,e. ~fter about 30-45 minutes), ac~tylene gaa i~ introduced in a stream of three litre~ per minute until th~ d~rk colour of tha mixture becomes lighter. Thsn the ga~ ~tre~m i~ reduced to two litre~
per minuke ~nd the mixture treated aropwise with a solutio~ of 500 g of methylglyoxal dim~thylacetal in 425 ml of ab~olute ether. ~he g~ing with acetylene i~ continu~d for a ~urther 1 hour while stirring. ~he ~ixture i8 su~sequently treated portionwise with 425 g of ammonium chloride, gradua?l~ warmed to 30~C within 12 hour~ wh~le evaporating the a~monia ~nd extracted with 1600 ml of ether. The ether extract i~ dried ov~r ~odium sulphate ~nd e~por~ted under r~duced pre~sure.
The residual 4,4-dimethox~-3-meth~l-but-1-yne-3-ol boils, af~er rectification, ~t 33C/0.03 ~orr; ~ 5 ~ 1.4480.
198 g of 4,4-dimethox~-3-methyl-but-1-yne-3-ol ~re di~sol~ed in 960 ml of high boiling petroleum ether and, Qfter the additio~ of 19~3 g of 5% palladium cat~ly~t qnd 19.~ g of quinoline, hydrogenated under normal condition~. After the upta~e of 33.5 litres of hydrogen, the hydro~enation i~ ter-minated, The catal~st i8 filtered off. ~he ~iltrate is evaporated under reduced pres3ure. ~he residual 4,4-dimethoxg--3-meth~l-but-1-e~-3-ol boils, ~fter rectification, at 70-72~C~18 ~orr.
195 ml of pho~gene are introduced into 1570 ml of carbon tetr~chloride st -10C, After the ~ddition of 213 g of pyridine, the ~slution ia tre~ted dropwise with 327 g of 4,4-dimethoxy~3-methyl-but-1-en-~-ol at a temperature of -10C
10$0042 to -20C. The mixture i5 ~lowly warmed to 25 C while 3tirring, stirred for a ~lrther 3 hours at room temp~rature 9 cooled to 15~C and trea~ed with 895 ml of water~ ~he aqueou~ pha~e i~
separated a~d discarded. After standing for 12 hour~ in the cold, the orga~ic ph~e i9 treated with 448 ml of 5~ ~ulphuric acid, stirrea for 5 hours, th~n w~hed with water, dried over ~odium ~ulphate and ev~porated u~der reduced pres~ure, ~he re~idual 2-formyl-4-chloro-but-2-ene boils, ~fter rectif~cation, at 37-40C/1.8 ~orr; n25 ~ 1,48950 lQ 165,7 g of 2-form~l-4-chl~ro-but-2-ene are dissolved in 84Q ml of benzene and treated with 367 g of triphenylpho~phine.
~he mixture i8 he~ted to boiling under reflux conditions for 12 hour~ while ga~ing with nltrogen Rna then cooled to 20C.
The precipitsted 2-formyl-but-2-ene-~-triphe~ylphosphonium chloride melts at 250-252~C ~fter wa~hi~g with benzene and dr~ing.
212.6 ~ of 2-form~ ut-2-ene-4-triphe~ylpho~phonium chloride and 95 g of 3-formyl crotonic acid ethyl e3ter are ;ntroduced into 1100 ml of butanol ~nd tr~ated at 5C with ~
s~lu~ion of 57 g of triethylami~e in 60 ml of butanol. The mixture i~ subsequently stirred for 6 hours ~t 25C, then cooled, i~troduced into water and thoroughl~ extracted with he~a~e. ~he hexane pha~e i~ ~ir~t wa~hed repeatedly with metha~ol/water (6:4), then wanhed with water, dried o~er sodium sulphate and ~ilterad, Th~ ~$1trate i~ i~omeri~ed b~
shaking with iodine for 12 hour~, The iodine is romo~ed b~
the addition of ~odium thiosulphate, The filtrate i~ washed with w~ter again, dried and 0vaporated under reduced pre~ure.
~he residual 7-form~1-3-me~hyl-octa-2~4,6-trien-1-oic acid ethyl ester c~n be used in the process without ~urther purification~
39 ~ o~ 2 ,6-dichloro-4-methoxy-bellzyl-triphenylpho~-phonium chloride a~d 16 g o$ 7-fo~myl-~-met~yl-octa-2,4,~--trien-l-oic acid ethyl ester are heated at 82~-85C under reflux co~aitions while gtirring ~or 2 hours &f~er the addition of 40 g of 1,2-butylene oxiae. The mixture i8 then thoroughly extr~ctaa with h~xsna. ~he ~exa~e extract is washed several times with meth~nol/wster (60:40), aried over sodium ~ulph~te and e~por~ted und~r reducad pressure. ~he residue is puri-fied b~ ~dsorption on silica gel u~in~ hexd~e for the elution.
~he 9-(2,6-dichloro-4-m~thox~ phen~l)-3,7-d~methyl-octa-2,4.6,8--tetr~e~-l oic acid ~hyl egter obtained from the eluate melts at 117-118~C after recry~tallisation from hexane, ~he 2,6-dichloro-4-methoxy-benzyl-triphen~lphospho~ium chloride used a~ the starting material can be prepQrea. for example, a~ follow~:
77 g of 3,5-dich1oro-~nisole are di~sol~ed in 250 ml o~ ether, After the addition of 70 ml of formaldehyde r35% g/~], the ~olution i~ g~sscd with hydrogen chloride at room t~mperature while ~tirring for 8 ~ours, ~he solu~ion is subsequentl~ pourea on to ice and thoroughly ex*racted with ether, The ether extract i8 washed neutral with water, dried over ~odium ~ulph~te ~nd evaporsted under reduced ~ 29 -~ 05~4Z
pressure, ~he residual oily 2,6-dichloro-4-methox~ benzyl chloride has a refractive index of nD4 = 1.5730~
23,7 g of 2,6-dichloro-4-methoxy-benzyl chloride, 26.2 ~ of triphenylphosphine ~nd 150 ml o~ absolute benzene are hested for 12 hours under reflux conditions. The 2,6-dichloro-4-m~thoxy benzyl-triphenylpho~phonium chloride which precipitates on cooling is dried in vacuo be~ore beinK
u~ed in the process.
~.~, In a m~nner anologouc to that described in ~xa~ples 1 and 2, by reacting 2-chloro-4-m~thoxy-5,6~dimethyl-benzyl--triphenylpho~phonium chloride with 7-f~rmyl-3-methyl-octa--2,~,6-trien-1-oic acid ethyl ester there is obtained 9 (2--chloro-4-methoxy-5,6-dimethyl-phenyl)-3,7 dimethyl-nona-2,4,6,8-tetraen-1-oic a~.id ethyl ester, a yellow-red oil.
~he 2-chloro-4-methoxy-5,6-dimeth~l-benz~l-triphenyl-pho~phonium chlorido used a~ th~ startin$ ma~erial can be preparea i~ a ma~ner a~alogou~ to that described in Ex~mple~
1 and 2 starting, for example 9 from 2,3-dimeth~1-aniline and proceeding Tia 2,3-dimethy1-5-nitro-~niline, 2.3-dimothyl-5--nitro-phenol, 2,3-dimethyl-5-nitro~anisole, 2~3-dimethyl-5--amino-a~isole, 2,3-dimethy1-5-chloro-anisole ~nd 2 chloro-4--methoxy-5,6-dimethyl-benzyl chloride.
1~50042 In a m~nner analogous to that de3cribed in ~xamp~es 1 ~nd 2, by reacting 2,3,6-trichloro-~-methoxy-benæyl-triphenyl -pho~phonium chloride with 7-formyl-3-methyl-octa-?,4,6 trien--l-oic acid ethyl e~ter there i8 obtained 9-(2,3,6-trichloro-~ -methoxy-phen~ 3,7-dimethyl-~ona-~,4~6,8-tetr~en-1-oic acid ethyl ester o~ melting poin~ 126-128C.
The 2,3,6-trichloro-4-methoxy-benzyl-triphenylpho~pho-nium chloride used as the starting material can be prepared in a manner ~nalogous to th~t de~cribed in Example~ 1 asd 2 starting, for ex~mple, from ~,3,5-trichloro phenol and pro-ceeding ~ia 2,3,5-trichloro-ani6010 and 2,3,6-trichloro-4--methoxy-benz~l chloride.
Example 5 15 I~ a manner analogous to that de~crib~d in Examples 1 ~nd 2, by re~cting 2,4-aimethoxy-~,6-aimet~yl-benzyl-triphenyl--pho3pho~ium chloride with 7-formyl-3-methyl-octa-2,4,6-trien--l-oic ~cid ethyl ester there i~ obt~i~ed 9-(2~4-dimethoxy-- 3 ~6-aimethyl-phen~ 3,7-dimethyl-~on~-2 14 9 6,8-tetr~en-1-oic ~cid eth~l estor, ~ he 9-(2,4-dimethoxy-3,6-dimethyl~phenyl)-3,7-dimethyl--nona-2,4,6,a-tetraen-1-oic-acid obtained by saponifying the foregoi~g ester ~elts at 214-215G.
The 2,4-dimethoxy-3,6-dimethyl-benzyl-triphenylphosphonium chloride use as the stArting materi~l can be prepared in ~
m~nner ~n~logous to that described in Examples 1 and 2 starting, for example, ~ro~ orcin (3,5 dih~drox~-tolu~n~ ~n~ proce~di via 2-ace~ 3,5-dihydroxy-toluene, 2-~cetyl-3,5~dih~drox~--p-xylol, 2,6-dihydroxy-p-xylol, 2,6-dimethoxy-p-x~lol and 2,4-dimethoxy-3,6-dimethyl-benzyl chloride, x~mple~j6 In ~ manner analogous to that de~cribed in Ex~mpl~ 1 and 2, by re~cting 6-chloro-4-methox~-2,5-dimeth~l-ben~
Dtriphenylphosphonium chloride with 7-for~yl-3-methyl-oct~-2.4,6-trien-1-oic acid ethyl e~tsr there i~ obtained 9-(6--chloro-4-methoxy-2,5-dimeth~l-phenyl)-3,7-di~ethyl-nona--2,4,6,8-tetr~en-1-oic 8Ci~ ethyl ester o~ meltiDs point 106-107^C.
The 6-chloro-4-methoxy-2,5-dimethyl-benzyl-triphenyl--phosphonium c~loride use~ as the stsr~ing materi~l can be prep~rea in a manner analogous to th~t de~cribed in Examples 1 and 2 starting, for example, ~rom 3-chloro-2,5-dimethyl--~itrob~n~ene and ~roceedi~g ~a 3-chloro-2,5-di~ethyl--aniline, 3-chloro-?,5-dimethyl-phenol, 3-chloro-2,5-dimethyl--a~i~ole-a~d 6-chloro-4-methoxy-2,5-dimethyl-benzyl chloride, ~ea~Z
41 g of 9-(6-chloro-4-methoxy-2,5-dimethyl-phenyl)--3,7-dimethyl-nona-2,4,6,8-tetraen l-olc acid ethyl ester are di~solved in 750 ml of ethanol, ~he 601ution i6 treated with 41 g o~ potaææ~um hydroxide in 63 ml of water, heated - ~2 -1C~5004Z
to boiling for 30 minute~ under ~ nitrogen atmo~phere 9 cooled 9 introduced into water and ~cidified with h~drochloric acid, The precipitated 9-(6-chloro-4-methox~-2,5-di~ethyl-phenyl)--3,7-dimeth71-nons-2,4,6,8-tetraen-1-oic acid melts at 231-234C.
15 g of 9-(6-chloro-~-methoxy-2,5-dimethyl-phenyl)--3,7-dimathyl-nona-2,4,6,8-tetraen-1-oic acid are di~olved in 750 ml of tetrahydrofuran. ~he solution obtained i~
treated with 2,64 ml (0,7 mol) of phosphoru~ trichloride, concentrated after 12 hours to half of its volume at 30C
under reduced pressure and added dropwiae at 0-5 C to a tetrahgdrofuran solution containi~g 14.6 g of eth~lamine.
The mixture i8 stirrea for 1 hour at room temperature, introduced into a ~sturated squeou~ sodium chloride solution and extracted with methyl0ne chloride, ~he extr~ct is w~shed with an aqueous sodium chloride solution, dried and ~vaporated under reduced pressure. ~he residual 9-(6-chloro-4-methoxy-2,
Compounds o~ formul~ III in which the symbol n ~t~nd~for 1 ~nd the sgmbol B rQpresents ~ triarylphosphoniummethyl ~roup ~IIIb3 or a dial~oxypho~phinylmethyl ~roup ~IIId~ can be prep~red, for example, by reducing the for~yl group i~ an aldehgde of formula III, in which the symbol ~ stands for 1 and the ~gmbol B repr~s~nts the formyl group ~IIIh3 to th~
hgdroxymethyl group using a mstal hydride such a~ ~odiu~
boro~ydride in an fil~nol (e.g. sthanol or i~opropa~ol).
th~ r~ulting ~lcohol c~n be halogenated using a cust~mary h~logenating ~gent (e.g.pho~porous o~ychloride) and the resulting 8-halo-3,7-dimethyl-oet~-2,4,6-triene-1-carboxylic acid, ~ halide of formul~ III in which the ~mbol n st~nd~
for 1 a~d the symbol B represen~ 8 h~lomethyl group ~IIIi~, or a deriv~tive thereof can be co~verted with a triarylphos--phi~e i~ a solvo~t, preferably triphenylpho~phine,in tolusne or benzene, or wit~ a trialkylphosphite, especially triethylphosphite, i~to a desired pho~pho~ium salt of for~ula IIIb or pho~phonate of formula IIId.
~5~
Compounds of formula III in which the symbol n stand~
for zero and the symbol B represents a ~ulpho~lmethyl group ~IIIe3 ca~ be prepared, for exa~ple, by reacting 4-hydroxy -3-mathyl-but-2-e~-1-al or the acetat~ thereof or the corre~-po~di~g bromide in a polar 801~ent ( e.g, isoprop~nol orn-butanol) in the m~n~er pre~iou~ly describ~d with an ~ore mentioned ~ulphinic Acid or wi~h an alkali met~l ~alt th~reof~
Compounds of formula III i~ which the symbol n ~tanas for 1 and the ~ymbol B repre~ents 8 ~ulphon~lmethyl group tIII~ can be prepared in a ma~ner analogous to th~t previousl~
described by the re~ction of, for example~ 8-hydroxy-3,?--dimethyl-octa_2,4,6-trien-l~oic acid or the acetate thereo~
or a corresponding bromide with a~ ~foremention~d sulphinic acid.
Compounds o~ formula III in which the ~ymbol n ~tand~
for zero and the agmbol B r~present~ the form~l group [IIIg]
can be prepared, for oxa~ple, by oxidatively clea~ing an optionally e~terified t~rtaric acid (e,g. uæing l~ad tetra -acetate at room te~perature in an organic solvent such as ben~ene), ~he ~lyoxalic ~cid deriv~tive obtainsd is 6ub-eque~tly condeneed i~ a manner known per se. co~eniently i~ th0 pre~enoe of an ami~e, wlth propio~aldeh~de a~ an el~vated temperature ~e.g. a temper~ture betwee~ 60C a~d llO~C) with 10~9 of water to ~ive a desired 3-formyl-crot~l slcohol deri~ati~s.
Compound~ of for~ula III in which the ~mbol n stand6 for 1 and the symbol B represents the formyl group ~IIIh~
-- 1~
~500~2 c~n be prepared, for example, by allowing phosgene to aot on 4,4 dimethoxy-3-m~thyl-but-1-en-3-ol in the cold9 preferabl~
at -10C to -20C, i~ the pre~e~ce of a tertiary amine ~uch a~ pyridi~e ~nd condensing the re~ulting 2-formyl-4-chloro--but-2-ene under the coud~tion~ o~ ~ Wittig reaction with 3-formyl-croto~ic acid, which ma~ be ssterified9 or with a 3-formyl-crotyl ~lcohol, which m~ be esterified, to give the desired aldehyde of formula IIIh.
In accord~nce with the process provided by the pre~e~t invention, a pho~pho~ium salt of formula IIa or IIb is reacted with an alde~yde of formula IIIh or IIIg, or a phosphonium ~alt of formula IIIa or IIIb is reacted with an aldehyde of ~ormula IIh or IIg, or a phosphonate of ~ormula IIc or IId i8 reacted with an ~ldehyde of formula IIIh or IIIg 9 or a phosphonate of formula IIIc or IIId is re-acted. with an alaehyde of formula IIh or IIg, or a sulphone of formul~ IIe or IIf i8 reacted with a halide o~ formula IIIk or ITIi or a ~ulphone of formula IIIe or III~ is reacted with a halide of for~ula IIk or IIi.
According to the Wittig procedure, the compo~ents are reacted with one another iu the presence of an acid-binding agent ~e.g, an alkali metal alc~hol~te 5uc~ as sodium methylate or a~ alkylene oxide which may be alkyl-substituted, e~pecially ethylene oxid~ or 1,2 but~lene oxide), or if desir~d in a ~olvent (e.g. a chlorinated h~drocarbon such as meth~lene chloride~ or dimeth~lform~mide), at a temperature between room temperature and the boil~ng point of the reaction mixture, ~S0042 According to th~ Horner procedure, the compo~ents are reaeted to~3ether u~i~ag a ba~ and pr~f0rably in'the pr~er~ce o~ an inert organic 801ve~nt9 ~or ex~mple sodium h;rdrid~ i~
benzene, toluene, dimeth;ylfornamide, t~trah;ydrofura~ or 1,2-dimethox;s~ethane, or alao sodium methylate in ~thanol, at a temperature between 0C ~nd the boiling point of the reaction mixtur¢.
According to l;he Julia procedure, th~ comporLents ~re reacted ~ith o~e a~other u8i~g a cond~naation agc~t, con-veniorltly in the pres~no~ of a polar solvent. ~u~table solv~nts are, for e3~ample, dimeth~l~Grm~mide, dimct}~l sulp}:loxide, dimethyl~cetamideg tetr~h~dro~ur~ a~d hexs--meth;~lpho~phoric acid triamid~ a~ well as ~lcohol~ ~uch a8 metha~ol, isopropano~ or terbutanol~, Of the stro~g b~0es which are particul~rl~ use~ 18 the co~densatio~ ag~nts there ca~ be mentioncd, for exam~le, allc~li mat~l and alkaline ~arth metal carbonate~, ~specially sodium carbonato. alkali ~etal hardroxides ~uch a~ pot~sium h~rdroxide or sodium h;~rdroxide, alkali metal and ~lk~line earth metal alcohol~tes 8UCb a~l sodium Dleth~late and, eapeci~lly, potassium tert--butylete, alkali met~l hydrides such as sodium ~dride, alkyl-magne~ium halides ~uch a~ methyl-magnesium bromide snd ~lkali metal amides ~uch ~8 ~od~um ~mide, The resction USirlg this proeedure i~ pr~ferably carried out st a low temper~ture, e~pecially at a temp~rature below the freezing point (e,g, betwee~-5C)C and -80C).
It has boen ~ound to be con~Tenient in cert~in case~ to carry out the aforementio~ed re~ctions in situ; th~t is to :1~50042 say, without i~olating the particular phoQphonium ~alt, phosphonate or sulphone from the medium in which it i8 prepared .
A carboxylic ac~d of ~ormula I can be co~erted in a mann~r known per ~e (e,æ, by treatment with thion~l chloridet preferabl~ in pyridine3 into ~n acid chloride which c~n be co~verted into an ester by resction with an alka~ol a~d into an amide by re~ction with 8mmonia, A carboxylic acid ester of formula I can be h~drolysed to a c~rboxylic acid in a man~er known per se, for example, by treatment with an alkali, especially uqueous-alcoholic ~odium h~droxide or potassium hydroxide at a temperature betwee~ room temperature and th~ boiling point of the mixture, - ~he re~ulting carbo~ylic ~cid c~ then be amidated via an acid h~lide. Alternati~el~, a carboxylic acid ester ca~ be directly amid~ted a~ de~cribed herein~fter.
A carbo~ylic acid ester o~ formula I c~n be converted dir~ctly into a corresponding amide by treatment with lithium amide. ~his treatment 1~ advanta~eously carried out at roo~
temper~ture.
A cfirboxylic ~cid or a carboxylic acia ester o~ formula I can be reduced to a corresponding alcohol of formula 1 in a manner X~own per se. ~he reducticn i~ advantageou~ly carried out using a metal ~ydride or alkyl metal hydride in an inert solvent. Examples of hydride~ which h~ve proved to be particularly suitable are mixed metal hydride~ such A~ lithium ~ os~4~
aluminiu~ h~dride and bis-~methoxy-ethylenoxy~-sodium ~lu-minium hydride. Suit~ble inert ~olven~ are, int~r alia 9 ether, tetrahydrofuran or dioxane when lithium aluminium h~dride is used and ether, hexane~ benzene or toluene when diisobutylaluminium hydride or bi~-~methoxy-ethyle~oxy~--sodium aluminium ~ydride is usedO
An alcohol of formula I can be etherified with an alkyl h~lid~ (e,g. eth~l iodide), for example in the presence of a ba~e, preferably ~odium hydride, in an organic solv~nt such 0 ~8 dioxane, tetrahydrofuran, 1,2-dimethsxyetha~or dimethyl-formamide, or in the presence o~ an alkali metal alcoholate in an alka~ol, at a temperature betwee~ 0C and room te~-peratureS
An alcohol o~ formul~ I can ~180 be esterified b~
treatment with an alkano~l halide or anh~dride, expedientl~
in th~ prcssnce of e bas~ (e,g. pyr~dine or triethyl~mine) at ~ t~mperhture betwee~ room temperature and the boili~g point of the mixtur~.
An alcohol e~ter obtained can be saponified in a ~anner kno~ per se; for example in the man~er previou~ly describcd in connection with the saponification of a carbox~lic acid ester, An ~lcohol of formula I or ~n ester thereof can be oxidised in a maDner known per ~e to give a corre~ponding acid of formula I. The oxidation is ad~antageou~ly carried out U8ihg ~ er ~I) oxide and an alkali in w~ter or in a ~05Q04'~
water-miscible organic 801vent st a temper6ture between room temperature and the boiling point of the mixture.
An amine of formula I ~orms acid addition salts with inorganic acids (e,g, hydrohalic acids, especially hydrochloric acid or hydrobromic acid, and sulphuric acid) a~d with orga~ic acids (e,g, benzoic acid, acetic acid. citric aoid ana l~ctic acid), A carboxylic acid of formula I form~ ~alts with b~se~, e~pecially with alkali met~l hydroxidc~ and particularly with sodium h~droxide and pot~s3ium h~droxid~.
10The compounds of formul~ I can occur a~ a ci~/trans mixture which m~y be ~eparated in a manner known per s~ into the ci~ ~nd trans compone~t~ or isomeri~ed in a manner known per se to the all-tran~ compounds.
~hc present polye~e compounds ~re pharmacod~namically valuable. They can be usea for the topical ana 9y8temic:
therapy of benign and malignant neoplasia and of premalignant lesions as well ~8 for the systemic and topical proph~laxis of these conditionc. ~hey are al80 suit~ble for the topical and ~y~temic therspy of acne, ~coriacis and other dermatoses 20 accompanied by an increased or patholo~ically altcred corni-fication, and for the treatment of infl~mmatory and allergic dermatological condition~, ~he present pol~ene compounds ca~ al~o bs used for comb~ttin~ mucous membrane disea~es with inflammatory or de~enerative or metaplastic alterations.
25The toxicity of the pre~ent polyene compounas is slight.
For example, when 9-(2-chloro-4-methoxy-3,5,6-trimethyl-~os~04z -phenyl)-3~7-dimethyl-~ona 2,4~6,8-tetrRen l-oic acia i~
adminiætered intraperitone~lly to mice weighing ~0 g i~ a daily dosage of 200 mg/kgf then no indication OI an A-h~per-vitaminosis become~ evident ~fter 14 days ~ total of 10 ~d-ministration days~
~ he first indic~tio~s of a slight A-hypervitaminosis in mice appears at a daily do~age of 400 mg/kg after 14 d~ys Ztotal of 10 administratio~ dP~] This ma~ife~ts it6elf in a weight decrease of 20~, a moderate h~ir loss and slight flaking of the skin.
The tumour-inhibiting ~CtiYity of the pre68nt polyene compound~ i8 significantr In the papilloma te~t, tumours induced with di~ethylbenzanthracene and crot~n oil regreas.
~he dia~eter of the papilloma~ within 2 weeks after the intraperitoneal administr~tion of 9-(2-chloro-4-methoxy-3,5,6--trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid eth~l ester decre~se3 by 61~ at a dos~ge of 400 ~g/kg/week and by 45~ at a dosage of 200 mg/kg/week.
The polyene compounds of fo~mula I and their salts can therefore be used as medicaments; or example, in the form of pharmaceutical preparation~ which contain them in association with a c~mpatible phar~aceutical carrier, ~ he pharmaceutical preparations for systemic adminis-tratio~ can be prepar~d f for ~xample, by adding a polyene compound as the active ingredient to no~-toxic inert solid or liquid carriers which are usual in such preparations.
~ ~0 ~ ~ 2 The pharmaceutical preparations can be administered enterally or parenterally. Suitable preparations for enteral administration are, for example, tablets, csp~ules, dra~ées 9 8yrup~, suspensio~ olutions ~nd ~uppositories and suitsble preparation~ for parenteral administrati~n are infusion and in~ection solutions, The aosage~ in which the polyene compound~ of this invention are adminiRtered can b~ varied according to the mode and route of admini~tration ~nd according to the requir~ments of the patient, ~he polyene co~pound~ of this in~e~tion can be adminis-tered in amount~ of from 5 mg to 200 mg daily i~ one or more dosage~. Capsules containing ca 10 mg to ca 100 mg of a polyene compound of thi~ inventio~ represent a proferred form o~ administr~tion.
~he pharmaceutical preparations ca~ contain i~ert or pharm~cod~namically acti~e additi~es, Tablet6 or granules, for ex~mple, ccn conta~n a æerie~ of binders, fillers, c~rrier materials or diluents, Liquid preparations can, for example, take the form of a 8t9rile WBter-mi~Cible 801utio~. C~psule~
can co~t~ filler or thiekener, ~urthermore, flavour--improvi~g additi~es and ~ubstances commonly usea a~ pre~er~
~ative~, stabili6ers, moisture-retainers or emulsifier69 salts for var~ing the os20tic pressure ~ buffers aIld other additives can al80 be present in the pharmaceutical prep~r&-tions .
~soo~z ~ he aforementioned c~rrier ma~erial3 ~nd diluQnt~ ca~
be organic or inor~anic ~ubatances ~uch a~ wst6r, ~el~tin, lactose, ~tarch, magnesium ~tearate, talc, gum arabic, poly-alkylenegl~col~ and th~ like, It i~, of cource~ a pre-requisite that Rll ad~uvants used in the preparation o~ thepharmaceutical preparations are no~-toxic.
For topic~l ~d~inistr~tio~, the pre~ent pol~ene com-pounds are expedientl~ mede up in the form or ointment~, tinctures, cream~, 801ution8 ~ lotion~, sprays, ~uspe~sion~
and the like. Ointm~t~, crssms and ~olutions sre pr~ferred.
These pharmaceutical preparation~ for topic~l ad~inistration ca~ be prepared by mixing the pol~ne compou~dst a~ the active ingredie~t, with no~ toxic insrt ~olid or liquid carriers which are cuatomary i~ su~h prep~r~tions and which are suitable for topic~l treatm~nt~
Expedient for topic~l ad~i~istration are ca 0.10% to ca 003%, pre~erably O.OZ% to 0.1%~ solution~ ~nd ca 0.05% to ca 5%, preferably ca 0.1% to ca 2.~%, ointments or creams.
An antioxiaant (e.~ tocopher~ metbyl-~-tocophera-mine, butyl~ted hydroxy~nisole or but~latod hydroxytoluene)can ~180 be present in the pharmaceutic~l prepar~tion~, ~L050042 The following ~xamplas illu~tr~te the process provided by the present invention:
9,9 g of 2-chloro-4-methox~-3,5,6-trimethyl-benzyl--tr~phenylphosphonium chlor~de sre dissolved in 50 ml of d$meth~1formamide, A~ter the addition of 4~16 g of 7-formyl--3-methyl-octa-2,4,6-trien-1-oic acid cthyl ester. the solution is treated dropwise at 20~ with 10 ml of ~ solution of sodium ethylate frefi~ly prep~red from 0.460 g of sodium and 10 ml of ab~olute ethanol, The mixture i~ stirred ~t room tomperature for 12 houra, then introduced into 100 ml o~ w~ter and extracted with hexane. ~he hexane ~xtract is shaken out three times with methanol/water, dried over soAium sulphate and evaporated under rcduced pressure. ~he residue i9 purifiad by ~bsorption on ~ilica gel using meth~lene chloride/hex~ne (8:2) for the elution. The 9-(2-chloro-4--methoxy-3,5,6-trimethyl-phenyl)-3,7-dimet~yl-octa-2,4,6,8--tetraen-l-oic acid ethyl ester obt~ined from the eluate ~elts at 90C ~fter recr~3t~11is~tion from hexane.
~he 2-chloro-4-methox~-3,5,6~trimeth~1-benzyl--triphenylphosphoniu~ chloride uced as the st~rting material can b~ prepared, for examplQ, a~ follows:
189 g of 3-chloro-4,6-dimethyl-benzyl chloride are introduced into 1500 ml of 5-~ sodium hydroxid~, ~he mixture is treated while stirring with 195 g of zinc dust within 2 hours, The temperature of the reaction, which takes place 1C~S~04Z
exothermic~llg~ i8 maint~in~d at 70 C by cooling, ~he mixture i~ stirred for a further 12 hours ~t 50~C end sub~quently filtered. ~he filtrate i~ extractsd three time~ with 800 ml of ethyle~e chloride, ~he meth~le~ chloride extract i8 washed neutral with water, dried o~er sodium ~ulphate and evaporated. The re~ual 2-chloro-3~5,6-trimethyl-benzene i~ purified by adsorpt~on on ~ilica gel u8ing hexane/m~th~l~ne chloride ~9;1) for the elution. Th~ compound boils ~t 81~9 Torr~
70 g of 2-chloro-3,5~6-trimethyl-be~ene are ada~d dropwi~e within 30 minutes wh~le Bt~rrin~ to 400 ml of nitric acid t70% v~v] pr~-cooled to O~C. ~he mixture i8 ~tirred for a ~urth~r 4 hours at a ~low}~ increasin4 te~peraturc up to +20~G, then introduced ~n~o ic0-water a~d thoroughly extract~d with ether. ~e ether extract i~ washed 8iX time~
wit~ 1000 ml of wat~r, dri~d over ~oaium ~ulphate and ev~porst0d under reduced prec~ure. ~he r~cidual 2-chloro-4-nitro-3,5,6--trimethyl-be~zen~ i~ purifi~d b~ adsorption o~ ~ilica g21 u8ing hexan~/benze~e (3:7) ~or the elution. ~he co~po ~elts at 79-C after recrystalli~ation ~rom low-boil$ng petroleum ethor.
114,5 g of 2-chloro-4-nitro-~,5,6-trimethyl-benzene are di~olved in ~00 ml of ethyl ~cet~te. The 601ution i~
diluted with 300 ml of ethanol and, sfter the ~ddition o~
20 ml of Ra~ey-nickeli hydro~enated u~der no~mal con~it~ons.
~fter th~ uptak~ of 43 litr~s of hydrogen, the hydrogen~tion is tarminated, ~he catel~ iB filtered off while gassing with carbo~ dioxlde and washed with ~tha~ol, The combined ~os~o~z filtrates are e~aporated under reduced pres~ure, ~he re~idual 4-amino-2-chloro-3,5,6-trimethyl-benze~e melt~ ~t 93~C after recrystallisation from hexa~e.
65 g of 4-amino-2-chloro-3,5,6-trimethyl-ben~ene are gradually introduced into 250 ml of concentrated sulphuric acid while ~tirring a~d cooling. In ~o doi~g, the tempera-ture ri~es to ~60C. ~he mixture i~ cooled to 0C by the gr~dual addition of 75Q g of ice a~d then tre~ted dropwi~e within 3 hours with a solution of 26.4 g of sodium ~itrite in 80 ml of water, The mixture is ~tirred for a further 90 minutes Qt 0C to +10C and sub~eQuently filtered, ~he filtrat~ i8 ~ub~ect~d to a steam di~till~tio~ while adding dropwi8e 600 ml of sulphuric ~cid ~50 vol %~, The aistill~te i~ extracted threz tim~ with 1000 ml of methylene chloride, The meth~lene chlorid~ extract i8 dried o~er ~odium sulphate ~n~ e~aporated, ~he re~idual 2-chloro-4-hydro~y 3,5 96--trim~thyl-benzene melts ~t 97-C after recryst~llisation from hexane.
After t~e a~dition of 400 ml ~f methanol and 85,5 ~1 of dimeth~l sulphate, 76 g of 2-chloro-4-hydroxy-3,5,6--trimethyl-benzene are treated dropwise while stirring with 265,5 ml of potassium hydroxlde ~25~ g/v]~ The mixture, which thereb~ heat~ to boiling, i8 stirred for ~ further 4 hour~ under reflux conditions and ~ubsequently evaporated.
~he residue i8 taken up in 600 ml of water. ~he aqueous ~olutio~ i8 extr~cted three time~ with 600 ml of ether. ~he ether extract i~ wa~hed neutr~l with ~ater, dried over ~odium ~ulphate ~nd ev~por~ted under reduced preææure~ The re~idual 10~042 oily 2-chloro-4-methoxy-3,5,6-trimeth~l benzene boils ~t 77 -79 C/l ~orr~
65.35 g of 2-chloro-4-methoxy-3,5Y6-trimethyl-benzene are mixed with 235 ml of acetic ac~d, 446 ml of hydrochloric acid [37 g~v~ ~d 107 ml of formaldehyde ~35%), The mixture is ~tirred at 70 C for ~ hour~ and, after cooli~g, i~troduced into 2~00 ml of water~ The aqueous solution is extracted three times with 1000 ml of meth~lene chloride. The meth~-lene chloride extract i~ wa~hed three times with 1~00 ml of water, dried over ~odium sulphate a~d evaporated. The residual 2-chloro-4-methox~-3,5,6-trimethyl-ben~yl chloride is purified ~yadsorption o~ 6ilica gel u~in~ low boiling petroleum ether for the elutio~, The compound melt~ at 59-63C after recrystalli~ation from low boili~g petroleum ether.
70.8 g of ~-chloro~4-methox~-3,5,6-trimethyl-benzyl chloride are dis~olved in 500 ml of toluene. The solution i8 treated with 77 g of triphenylpho~phinç a~d stirred at 100C for 18 hour~. The 2-chloro-4-methoxy-3.5,6-trimethyl--be~zyl-triphenylphospho~ium chloride which separate~ in the form o~ white cr~tal~ ic washed with ether and dried in vacuo. The phospho~ium ~alt m~lts at 215JC.
~he 7-formyl-3-methyl-oct~-2,~,6~trien-1-oic acid eth~l ester u~ed as the starting material can be prepared, for exampl~, as follows:
After the addition of a 6mall amount o:E ion ~ III) -- 26 ~
nitrate, 2700 ml of liquid ammonia are treated portionwise with 169.5 g of potassium ~hile stirring and cooling. A~
soon as the initially blue colour has di~app~ared (i,e. ~fter about 30-45 minutes), ac~tylene gaa i~ introduced in a stream of three litre~ per minute until th~ d~rk colour of tha mixture becomes lighter. Thsn the ga~ ~tre~m i~ reduced to two litre~
per minuke ~nd the mixture treated aropwise with a solutio~ of 500 g of methylglyoxal dim~thylacetal in 425 ml of ab~olute ether. ~he g~ing with acetylene i~ continu~d for a ~urther 1 hour while stirring. ~he ~ixture i8 su~sequently treated portionwise with 425 g of ammonium chloride, gradua?l~ warmed to 30~C within 12 hour~ wh~le evaporating the a~monia ~nd extracted with 1600 ml of ether. The ether extract i~ dried ov~r ~odium sulphate ~nd e~por~ted under r~duced pre~sure.
The residual 4,4-dimethox~-3-meth~l-but-1-yne-3-ol boils, af~er rectification, ~t 33C/0.03 ~orr; ~ 5 ~ 1.4480.
198 g of 4,4-dimethox~-3-methyl-but-1-yne-3-ol ~re di~sol~ed in 960 ml of high boiling petroleum ether and, Qfter the additio~ of 19~3 g of 5% palladium cat~ly~t qnd 19.~ g of quinoline, hydrogenated under normal condition~. After the upta~e of 33.5 litres of hydrogen, the hydro~enation i~ ter-minated, The catal~st i8 filtered off. ~he ~iltrate is evaporated under reduced pres3ure. ~he residual 4,4-dimethoxg--3-meth~l-but-1-e~-3-ol boils, ~fter rectification, at 70-72~C~18 ~orr.
195 ml of pho~gene are introduced into 1570 ml of carbon tetr~chloride st -10C, After the ~ddition of 213 g of pyridine, the ~slution ia tre~ted dropwise with 327 g of 4,4-dimethoxy~3-methyl-but-1-en-~-ol at a temperature of -10C
10$0042 to -20C. The mixture i5 ~lowly warmed to 25 C while 3tirring, stirred for a ~lrther 3 hours at room temp~rature 9 cooled to 15~C and trea~ed with 895 ml of water~ ~he aqueou~ pha~e i~
separated a~d discarded. After standing for 12 hour~ in the cold, the orga~ic ph~e i9 treated with 448 ml of 5~ ~ulphuric acid, stirrea for 5 hours, th~n w~hed with water, dried over ~odium ~ulphate and ev~porated u~der reduced pres~ure, ~he re~idual 2-formyl-4-chloro-but-2-ene boils, ~fter rectif~cation, at 37-40C/1.8 ~orr; n25 ~ 1,48950 lQ 165,7 g of 2-form~l-4-chl~ro-but-2-ene are dissolved in 84Q ml of benzene and treated with 367 g of triphenylpho~phine.
~he mixture i8 he~ted to boiling under reflux conditions for 12 hour~ while ga~ing with nltrogen Rna then cooled to 20C.
The precipitsted 2-formyl-but-2-ene-~-triphe~ylphosphonium chloride melts at 250-252~C ~fter wa~hi~g with benzene and dr~ing.
212.6 ~ of 2-form~ ut-2-ene-4-triphe~ylpho~phonium chloride and 95 g of 3-formyl crotonic acid ethyl e3ter are ;ntroduced into 1100 ml of butanol ~nd tr~ated at 5C with ~
s~lu~ion of 57 g of triethylami~e in 60 ml of butanol. The mixture i~ subsequently stirred for 6 hours ~t 25C, then cooled, i~troduced into water and thoroughl~ extracted with he~a~e. ~he hexane pha~e i~ ~ir~t wa~hed repeatedly with metha~ol/water (6:4), then wanhed with water, dried o~er sodium sulphate and ~ilterad, Th~ ~$1trate i~ i~omeri~ed b~
shaking with iodine for 12 hour~, The iodine is romo~ed b~
the addition of ~odium thiosulphate, The filtrate i~ washed with w~ter again, dried and 0vaporated under reduced pre~ure.
~he residual 7-form~1-3-me~hyl-octa-2~4,6-trien-1-oic acid ethyl ester c~n be used in the process without ~urther purification~
39 ~ o~ 2 ,6-dichloro-4-methoxy-bellzyl-triphenylpho~-phonium chloride a~d 16 g o$ 7-fo~myl-~-met~yl-octa-2,4,~--trien-l-oic acid ethyl ester are heated at 82~-85C under reflux co~aitions while gtirring ~or 2 hours &f~er the addition of 40 g of 1,2-butylene oxiae. The mixture i8 then thoroughly extr~ctaa with h~xsna. ~he ~exa~e extract is washed several times with meth~nol/wster (60:40), aried over sodium ~ulph~te and e~por~ted und~r reducad pressure. ~he residue is puri-fied b~ ~dsorption on silica gel u~in~ hexd~e for the elution.
~he 9-(2,6-dichloro-4-m~thox~ phen~l)-3,7-d~methyl-octa-2,4.6,8--tetr~e~-l oic acid ~hyl egter obtained from the eluate melts at 117-118~C after recry~tallisation from hexane, ~he 2,6-dichloro-4-methoxy-benzyl-triphen~lphospho~ium chloride used a~ the starting material can be prepQrea. for example, a~ follow~:
77 g of 3,5-dich1oro-~nisole are di~sol~ed in 250 ml o~ ether, After the addition of 70 ml of formaldehyde r35% g/~], the ~olution i~ g~sscd with hydrogen chloride at room t~mperature while ~tirring for 8 ~ours, ~he solu~ion is subsequentl~ pourea on to ice and thoroughly ex*racted with ether, The ether extract i8 washed neutral with water, dried over ~odium ~ulph~te ~nd evaporsted under reduced ~ 29 -~ 05~4Z
pressure, ~he residual oily 2,6-dichloro-4-methox~ benzyl chloride has a refractive index of nD4 = 1.5730~
23,7 g of 2,6-dichloro-4-methoxy-benzyl chloride, 26.2 ~ of triphenylphosphine ~nd 150 ml o~ absolute benzene are hested for 12 hours under reflux conditions. The 2,6-dichloro-4-m~thoxy benzyl-triphenylpho~phonium chloride which precipitates on cooling is dried in vacuo be~ore beinK
u~ed in the process.
~.~, In a m~nner anologouc to that described in ~xa~ples 1 and 2, by reacting 2-chloro-4-m~thoxy-5,6~dimethyl-benzyl--triphenylpho~phonium chloride with 7-f~rmyl-3-methyl-octa--2,~,6-trien-1-oic acid ethyl ester there is obtained 9 (2--chloro-4-methoxy-5,6-dimethyl-phenyl)-3,7 dimethyl-nona-2,4,6,8-tetraen-1-oic a~.id ethyl ester, a yellow-red oil.
~he 2-chloro-4-methoxy-5,6-dimeth~l-benz~l-triphenyl-pho~phonium chlorido used a~ th~ startin$ ma~erial can be preparea i~ a ma~ner a~alogou~ to that described in Ex~mple~
1 and 2 starting, for example 9 from 2,3-dimeth~1-aniline and proceeding Tia 2,3-dimethy1-5-nitro-~niline, 2.3-dimothyl-5--nitro-phenol, 2,3-dimethyl-5-nitro~anisole, 2~3-dimethyl-5--amino-a~isole, 2,3-dimethy1-5-chloro-anisole ~nd 2 chloro-4--methoxy-5,6-dimethyl-benzyl chloride.
1~50042 In a m~nner analogous to that de3cribed in ~xamp~es 1 ~nd 2, by reacting 2,3,6-trichloro-~-methoxy-benæyl-triphenyl -pho~phonium chloride with 7-formyl-3-methyl-octa-?,4,6 trien--l-oic acid ethyl e~ter there i8 obtained 9-(2,3,6-trichloro-~ -methoxy-phen~ 3,7-dimethyl-~ona-~,4~6,8-tetr~en-1-oic acid ethyl ester o~ melting poin~ 126-128C.
The 2,3,6-trichloro-4-methoxy-benzyl-triphenylpho~pho-nium chloride used as the starting material can be prepared in a manner ~nalogous to th~t de~cribed in Example~ 1 asd 2 starting, for ex~mple, from ~,3,5-trichloro phenol and pro-ceeding ~ia 2,3,5-trichloro-ani6010 and 2,3,6-trichloro-4--methoxy-benz~l chloride.
Example 5 15 I~ a manner analogous to that de~crib~d in Examples 1 ~nd 2, by re~cting 2,4-aimethoxy-~,6-aimet~yl-benzyl-triphenyl--pho3pho~ium chloride with 7-formyl-3-methyl-octa-2,4,6-trien--l-oic ~cid ethyl ester there i~ obt~i~ed 9-(2~4-dimethoxy-- 3 ~6-aimethyl-phen~ 3,7-dimethyl-~on~-2 14 9 6,8-tetr~en-1-oic ~cid eth~l estor, ~ he 9-(2,4-dimethoxy-3,6-dimethyl~phenyl)-3,7-dimethyl--nona-2,4,6,a-tetraen-1-oic-acid obtained by saponifying the foregoi~g ester ~elts at 214-215G.
The 2,4-dimethoxy-3,6-dimethyl-benzyl-triphenylphosphonium chloride use as the stArting materi~l can be prepared in ~
m~nner ~n~logous to that described in Examples 1 and 2 starting, for example, ~ro~ orcin (3,5 dih~drox~-tolu~n~ ~n~ proce~di via 2-ace~ 3,5-dihydroxy-toluene, 2-~cetyl-3,5~dih~drox~--p-xylol, 2,6-dihydroxy-p-xylol, 2,6-dimethoxy-p-x~lol and 2,4-dimethoxy-3,6-dimethyl-benzyl chloride, x~mple~j6 In ~ manner analogous to that de~cribed in Ex~mpl~ 1 and 2, by re~cting 6-chloro-4-methox~-2,5-dimeth~l-ben~
Dtriphenylphosphonium chloride with 7-for~yl-3-methyl-oct~-2.4,6-trien-1-oic acid ethyl e~tsr there i~ obtained 9-(6--chloro-4-methoxy-2,5-dimeth~l-phenyl)-3,7-di~ethyl-nona--2,4,6,8-tetr~en-1-oic 8Ci~ ethyl ester o~ meltiDs point 106-107^C.
The 6-chloro-4-methoxy-2,5-dimethyl-benzyl-triphenyl--phosphonium c~loride use~ as the stsr~ing materi~l can be prep~rea in a manner analogous to th~t de~cribed in Examples 1 and 2 starting, for example, ~rom 3-chloro-2,5-dimethyl--~itrob~n~ene and ~roceedi~g ~a 3-chloro-2,5-di~ethyl--aniline, 3-chloro-?,5-dimethyl-phenol, 3-chloro-2,5-dimethyl--a~i~ole-a~d 6-chloro-4-methoxy-2,5-dimethyl-benzyl chloride, ~ea~Z
41 g of 9-(6-chloro-4-methoxy-2,5-dimethyl-phenyl)--3,7-dimethyl-nona-2,4,6,8-tetraen l-olc acid ethyl ester are di~solved in 750 ml of ethanol, ~he 601ution i6 treated with 41 g o~ potaææ~um hydroxide in 63 ml of water, heated - ~2 -1C~5004Z
to boiling for 30 minute~ under ~ nitrogen atmo~phere 9 cooled 9 introduced into water and ~cidified with h~drochloric acid, The precipitated 9-(6-chloro-4-methox~-2,5-di~ethyl-phenyl)--3,7-dimeth71-nons-2,4,6,8-tetraen-1-oic acid melts at 231-234C.
15 g of 9-(6-chloro-~-methoxy-2,5-dimethyl-phenyl)--3,7-dimathyl-nona-2,4,6,8-tetraen-1-oic acid are di~olved in 750 ml of tetrahydrofuran. ~he solution obtained i~
treated with 2,64 ml (0,7 mol) of phosphoru~ trichloride, concentrated after 12 hours to half of its volume at 30C
under reduced pressure and added dropwiae at 0-5 C to a tetrahgdrofuran solution containi~g 14.6 g of eth~lamine.
The mixture i8 stirrea for 1 hour at room temperature, introduced into a ~sturated squeou~ sodium chloride solution and extracted with methyl0ne chloride, ~he extr~ct is w~shed with an aqueous sodium chloride solution, dried and ~vaporated under reduced pressure. ~he residual 9-(6-chloro-4-methoxy-2,
5-dimethyl-phe~yl)-3,7-dimeth~l-nona-2,4,6,8-tetraen-1-oic acid ethyl amide i8 purified by adsorption on ~ilica ~el using methylene chloride/methanol (90:10) for the elution, After recryst311is~tion from ethyl ~cetste, this ethyl amide melts at ?o2o-2o~oc.
- ~3 -4;~
: The following ~xamples illu3trate typical ph~rmaceutical prepar~tions provided by this invention.
A capsule can contai~ the ~ollowing ingredient~:
9-(2-Chloro~-methoxy-3,5,6--trimethyl-phenyl~-3,7-dimethyl--non~-2l4,6,8-tetraen-1-oic ~cid 10 mg ethyl ester Wax mixture 41.5 mg Vegetable oil 98,0 mg ~risodium ~alt of ethylenedi~ine-tetraacetic acid 0.5 mg Individual weight of a capsule150 mg Active ingredient co~tent of a capcule 10 mg Example B
A 6~1ve cont~ining 2~0% of Qctive ingredient can be prepQred U6i~g the following ingredients:
9-(2-Chloro-4-methox~-3,5,6--trimeth~l-phenyl)-3,7-di~ethyl--~ona-2,4,6,8-tetraen-1-oic açid eth~l ester 2.0 g Cetyl alcohol 2. 7 g L~nolin 6.0 ~
Petroleum ~elly 15.0 g Distilled w~ter q.s ad 100 0 g ~ 34 --
- ~3 -4;~
: The following ~xamples illu3trate typical ph~rmaceutical prepar~tions provided by this invention.
A capsule can contai~ the ~ollowing ingredient~:
9-(2-Chloro~-methoxy-3,5,6--trimethyl-phenyl~-3,7-dimethyl--non~-2l4,6,8-tetraen-1-oic ~cid 10 mg ethyl ester Wax mixture 41.5 mg Vegetable oil 98,0 mg ~risodium ~alt of ethylenedi~ine-tetraacetic acid 0.5 mg Individual weight of a capsule150 mg Active ingredient co~tent of a capcule 10 mg Example B
A 6~1ve cont~ining 2~0% of Qctive ingredient can be prepQred U6i~g the following ingredients:
9-(2-Chloro-4-methox~-3,5,6--trimeth~l-phenyl)-3,7-di~ethyl--~ona-2,4,6,8-tetraen-1-oic açid eth~l ester 2.0 g Cetyl alcohol 2. 7 g L~nolin 6.0 ~
Petroleum ~elly 15.0 g Distilled w~ter q.s ad 100 0 g ~ 34 --
Claims (26)
1. Process for the manufacture of polyene compounds of the general formula (I) ,wherein one of the symbols R1 and R2 represents a halogen atom or a lower alkyl group and the other symbol repre-sents a halogen atom or a lower alkoxy group, the symbols R3 and R5 each repre-sent a hydrogen or halogen atom or a lower alkyl group with the proviso that one of the symbols R3 and R5 represents other than a halogen atom, the symbol represents a lower alkoxy group and the symbol R6 represents a carboxyl, lower alkoxy-carbonyl, or mono(lower alkyl)carbamoyl group, and of salts thereof, which process comprises reacting a compound of the general formula (II) with a compound of the general formula (III) , wherein the symbol m stands for zero and the symbol n stands for 1 or the symbol m stands for 1 and the symbol n stands for zero, one of the symbols A
and B represents the formyl group and the other symbol represents either a triarylphosphoniummethyl group of the formula -CH2-P[X]3?Y?
, in which the symbol X represents an aryl group and the symbol Y represents the anion of an organic or inorganic acid, or a dialkoxyphosphinylmethyl group of the formula , in which the symbol Z represents an alkoxy group; or one of the symbols A
and B represents a halomethyl, alkyl--sulphonyloxymethyl or arylsulphonyloxy-methyl group and the other symbol repre-sents a sulphonylmethyl group of the formula , in which the symbol E represents an aryl or aralkenyl group which may carry one or more electron--repelling to electron-weakly attracting substituents; the symbols R1, R2, R3, R4, and R5 have the significance given above and the symbol R7 represents a carboxyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, di(lower alkyl)carbamoyl or N-hetero-cyclylcarbonyl group; or the symbol R7 also represents en alkoxymethyl or alkanoyloxymethyl group when the symbol B
represents the formyl group; or the symbol R7 also represents a formyl, alkoxymethyl or alkanoyloxymethyl group when the symbol B represents a halomethyl, alkylsulphonyloxymethyl or arylsulphonyl-oxymethyl group; or the symbol R7 also represents a formyl group when the symbol B represents a triarylphosphoniummethyl group, a dialkoxyphosphinylmethyl group or a sulphonylmethyl group, and cleaving off a sulphone group which may be present in the reaction product to form an additional carbon-carbon bond, and, where a compound of formula I is required, wherein R6 is lower alkyl carbamoyl, converting a carboxylic acid of formula I into a lower alkyl amide, or, where a carboxylic acid of formula I is required and a carboxylic acid ester was obtained as the reaction product, converting the carboxylic acid ester of formula I into the corresponding carboxylic acid.
and B represents the formyl group and the other symbol represents either a triarylphosphoniummethyl group of the formula -CH2-P[X]3?Y?
, in which the symbol X represents an aryl group and the symbol Y represents the anion of an organic or inorganic acid, or a dialkoxyphosphinylmethyl group of the formula , in which the symbol Z represents an alkoxy group; or one of the symbols A
and B represents a halomethyl, alkyl--sulphonyloxymethyl or arylsulphonyloxy-methyl group and the other symbol repre-sents a sulphonylmethyl group of the formula , in which the symbol E represents an aryl or aralkenyl group which may carry one or more electron--repelling to electron-weakly attracting substituents; the symbols R1, R2, R3, R4, and R5 have the significance given above and the symbol R7 represents a carboxyl, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, di(lower alkyl)carbamoyl or N-hetero-cyclylcarbonyl group; or the symbol R7 also represents en alkoxymethyl or alkanoyloxymethyl group when the symbol B
represents the formyl group; or the symbol R7 also represents a formyl, alkoxymethyl or alkanoyloxymethyl group when the symbol B represents a halomethyl, alkylsulphonyloxymethyl or arylsulphonyl-oxymethyl group; or the symbol R7 also represents a formyl group when the symbol B represents a triarylphosphoniummethyl group, a dialkoxyphosphinylmethyl group or a sulphonylmethyl group, and cleaving off a sulphone group which may be present in the reaction product to form an additional carbon-carbon bond, and, where a compound of formula I is required, wherein R6 is lower alkyl carbamoyl, converting a carboxylic acid of formula I into a lower alkyl amide, or, where a carboxylic acid of formula I is required and a carboxylic acid ester was obtained as the reaction product, converting the carboxylic acid ester of formula I into the corresponding carboxylic acid.
2) A process according to claim 1, wherein a phosphonium salt of formula II or III is reacted with an aldehyde of formula III or II in the presence of an epoxide, the reaction being carried out in a solvent if desired.
3) A process according to claim 1, wherein a phosphonate of formula II or III is reacted with an aldehyde of formula III
or II in an inert organic solvent in the presence of a base.
or II in an inert organic solvent in the presence of a base.
4) A process according to claim 2, wherein there is used a starting material of formula II in which R1 represents a chlorine atom, R2 represents a chlorine atom or the methyl group, R3 and R5 each represent a hydrogen atom or the methyl group and R4 represents the methoxy group.
5) A process according to claim 2, wherein there is used a starting material of formula II
in which R1 represents a chlorine atom, R2 and R3 each repre-sent a chlorine atom or the metal group, R4 represents the methoxy group and R5 represents a hydrogen atom.
in which R1 represents a chlorine atom, R2 and R3 each repre-sent a chlorine atom or the metal group, R4 represents the methoxy group and R5 represents a hydrogen atom.
6) A process according to claim 2, wherein there is used a starting material of formula II in which R1 represents the methyl or methoxy group, R2 represents a chlorine atom or the methyl group, R3 and R5 each represent a hydrogen atom or the methyl group and R4 represents the methoxy group.
7) A process according to claim 1, 2 or 4, wherein a 2-chloro-4-methoxy-3,5,6-trimethyl-benzyl-triphenylphosphonium halide or a 2,6-dichloro-4-methoxy-benzyl-triphenylphosphonium halide is reacted wlth 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid or an alkyl ester thereof.
8) A process according to claim 1, 2 or 4, wherein 2-chloro-4-methoxy-3,5,6-trimethyl-benzaldehyhde or 2,6-dichloro-4-methoxy-benzaldehyde is reactad with a 1-(carboxy or alkoxy-carbonyl)-2,6-dimethyl-hepta-1,3,5-triene-7-triphenylphos-phonium halide.
9) A process according to claim 1, 2 or 5, wherein a 2-chloro-4-methoxy-5,6-dimethyl-benzyl-triphenylphosphonium halide or 2,3,6-trichloro-4-methoxy-benzyl-triphenylphosphonium halide is reacted with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid or an alkyl ester thereof.
10) A process according to claim 1, 2 or 5, wherein 2-chloro-4-methoxy-5,6-dimethyl-benzaldehyde or 2,3,6-trichloro-4-methoxy-benzaldehyde is reacted with a 1-(carboxy or alkoxy-carbonyl)-2,6-dimethyl-hepta-1,3,5-triene-7-triphenylphos-phonium halide.
11) A process according to claim 1, 2 or 5, wherein a 4-methoxy-2,5-dimethyl-6-chloro-benzyl-triphenylphosphonium halide or a 2,4-dimethoxy-3,6-dimethyl-benzyl-triphenylphos-phonium halide is reacted with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid or an alkyl ester thereof.
12) A process according to claim 1, 2 or 6, wherein 4-methoxy-2,5-dimethyl-6-chloro-benzaldehyde or 2,4-dimethoxy 3,6-dimethyl-benzaldehyde is reacted with a 1-(carboxy or alkoxycarbonyl)-2,6-dimethyl-hepta-1,3,5-triene-7-triphenyl-phosphonium halide.
13) A process according to claim 1, wherein a carboxylic acid of formula I is converted into a halide and this halide is reacted with ammonia or with a mono(lower alkyl)amine or with a di(lower alkyl)amine.
14) A process according to claim 1, wherein a 6-chloro-4-methoxy-2,3-dimethyl-benzyl-triphenylphosphonium halide is reacted with an ethyl ester of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid.
15) A process according to claim 1, wherein a 2-chloro-4-methoxy-3,5,6-trimethyl-benzyl-triphenylphosphonium halide is reacted with an ethyl ester of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid.
16) A process according to claim 1, wherein a 2,6-dichloro-4-methoxy-benzyl-triphenylphosphonium halide is reacted with an ethyl ester of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid.
17) A process according to claim 1, wherein a 2,5,6-trichloro-4-methoxy-benzyl-triphenylphosphonium halide is reacted with an ethyl ester of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid.
18) A process according to claim 1, wherein a 2,4-dimethoxy-3,6-dimethyl-benzyl-triphenylphosphonium halide is reacted with an ethyl ester of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid.
19) A process according to claim 1, wherein a 4-methoxy-2,5-dimethyl-6-chloro-benzyl-triphenylphosphonium halide is reacted with an ethyl ester of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid.
20) Polyene compounds of the general formula (I) ,wherein one of the symbols R1 and R2 represents a halogen atom or a lower alkyl group and the other symbol repre-sents a halogen atom or a lower alkoxy group, the symbols R3 and R5 each repre-sent a hydrogen or halogen atom or a lower alkyl group with the proviso that one of the symbols R3 and R5 represents other than a halogen atom, the symbol R4 represents a lower alkoxy group and the symbol R6 represents a carboxyl, lower alkoxycarbonyl, or mono(lower alkyl)car-bamoyl group, and salts thereof, whenever prepared by the process as claimed in any one of claims 1-3, or by an obvious chemical equivalent thereof.
21) 9-(6-Chloro-4-methoxy-2,3-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester, whenever prepared by the process as claimed in claim 14 or by an obvious chemical equlvalent thereof.
22) 9-(2-Chloro-4-methoxy-3,5,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester, whenever prepared by the process as claimed in claim 15 or by an obvious chemical equivalent thereof.
23) 9-(2,6-Dichloro-4-methoxy-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester, whenever prepared by the process as claimed in claim 16 or by an obvious chemical equivalent thereof.
24) 9-(2,5,6-Trichloro-4-methoxy-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester, whenever prepared by the process as claimed in claim 17 or by an obvious chemical equlvalent thereof.
25) 9-(2,4-Dimethoxy-3,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester, whenever prepared by the process as claimed in claim 18 or by an obvious chemical equivalent thereof.
26) 9-(6-Chloro-4-methoxy-2,5-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-oic acid ethyl ester, whenever prepared by the process as claimed in claim 19 or by an obvious chemical equlvalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1303274A CH605562A5 (en) | 1974-09-26 | 1974-09-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1050042A true CA1050042A (en) | 1979-03-06 |
Family
ID=4388688
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA234,206A Expired CA1050042A (en) | 1974-09-26 | 1975-08-26 | Polyene compounds |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS5951531B2 (en) |
| AR (1) | AR212858A1 (en) |
| AT (1) | AT346311B (en) |
| BE (1) | BE833784A (en) |
| BR (1) | BR7506154A (en) |
| CA (1) | CA1050042A (en) |
| CH (1) | CH605562A5 (en) |
| CU (1) | CU34345A (en) |
| DD (1) | DD122072A5 (en) |
| DE (1) | DE2542612A1 (en) |
| FR (1) | FR2285864B1 (en) |
| GB (1) | GB1514975A (en) |
| HU (1) | HU172958B (en) |
| IE (1) | IE41801B1 (en) |
| IL (1) | IL47929A (en) |
| LU (1) | LU73452A1 (en) |
| NL (1) | NL177913C (en) |
| NZ (1) | NZ178425A (en) |
| PH (1) | PH12883A (en) |
| SU (1) | SU623515A3 (en) |
| YU (1) | YU40124B (en) |
| ZA (1) | ZA755208B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4201727A (en) | 1976-11-14 | 1980-05-06 | Hoffmann-La Roche Inc. | Fluorinated aromatic polyenes |
| US4338253A (en) | 1975-11-14 | 1982-07-06 | Hoffmann-La Roche Inc. | Fluorinated aromatic polyenes |
| US4335248A (en) | 1975-11-14 | 1982-06-15 | Hoffmann-La Roche Inc. | Fluorinated polyenes |
| US4321209A (en) | 1975-11-14 | 1982-03-23 | Hoffmann-La Roche Inc. | Fluorinated aromatic polyenes |
| US4395575A (en) | 1975-11-14 | 1983-07-26 | Hoffmann-La Roche, Inc. | 5(Halophenyl)-2-fluoro-pentadienals |
| US4299995A (en) | 1979-05-10 | 1981-11-10 | Hoffmann-La Roche Inc. | Fluorinated polyenes |
| US4375563A (en) | 1975-11-14 | 1983-03-01 | Hoffmann-La Roche Inc. | Fluorinated aromatic polyenes |
| US4266073A (en) * | 1975-11-14 | 1981-05-05 | Hoffmann-La Roche Inc. | Fluorinated aromatic polyenes |
| CA1111441A (en) * | 1976-12-20 | 1981-10-27 | Werner Bollag | Polyene compounds |
| US4200647A (en) * | 1977-12-21 | 1980-04-29 | Hoffmann-La Roche Inc. | Vitamin A compositions to treat rheumatic disease |
| US4642318A (en) * | 1982-11-17 | 1987-02-10 | Klaus Wolff | Method for decreasing radiation load in PUVA therapy |
| ZA854828B (en) * | 1984-07-27 | 1986-03-26 | Hoffmann La Roche | Phenyl nonatetraenoic acid derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1109671B (en) * | 1958-10-17 | 1961-06-29 | Basf Ag | Process for the production of ª ‡, ª ‰ -unsaturated carboxylic acid esters or the free acids |
-
1974
- 1974-09-26 CH CH1303274A patent/CH605562A5/xx not_active IP Right Cessation
-
1975
- 1975-08-13 ZA ZA00755208A patent/ZA755208B/en unknown
- 1975-08-15 IL IL47929A patent/IL47929A/en unknown
- 1975-08-19 NZ NZ178425A patent/NZ178425A/en unknown
- 1975-08-26 CA CA234,206A patent/CA1050042A/en not_active Expired
- 1975-09-10 YU YU2287/75A patent/YU40124B/en unknown
- 1975-09-12 NL NLAANVRAGE7510778,A patent/NL177913C/en not_active IP Right Cessation
- 1975-09-12 AR AR260364A patent/AR212858A1/en active
- 1975-09-16 PH PH17579A patent/PH12883A/en unknown
- 1975-09-18 CU CU7534345A patent/CU34345A/en unknown
- 1975-09-23 JP JP50114373A patent/JPS5951531B2/en not_active Expired
- 1975-09-24 LU LU73452A patent/LU73452A1/xx unknown
- 1975-09-24 FR FR7529226A patent/FR2285864B1/en not_active Expired
- 1975-09-24 HU HU75HO00001839A patent/HU172958B/en unknown
- 1975-09-24 DE DE19752542612 patent/DE2542612A1/en active Granted
- 1975-09-24 BR BR7506154*A patent/BR7506154A/en unknown
- 1975-09-25 SU SU752178997A patent/SU623515A3/en active
- 1975-09-25 DD DD188555A patent/DD122072A5/xx unknown
- 1975-09-25 AT AT734775A patent/AT346311B/en not_active IP Right Cessation
- 1975-09-25 BE BE160342A patent/BE833784A/en not_active IP Right Cessation
- 1975-09-25 IE IE2098/75A patent/IE41801B1/en unknown
- 1975-09-26 GB GB39545/75A patent/GB1514975A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| BR7506154A (en) | 1976-08-03 |
| IE41801L (en) | 1976-03-26 |
| AR212858A1 (en) | 1978-10-31 |
| HU172958B (en) | 1979-01-28 |
| IL47929A0 (en) | 1975-11-25 |
| GB1514975A (en) | 1978-06-21 |
| AT346311B (en) | 1978-11-10 |
| JPS5951531B2 (en) | 1984-12-14 |
| NL7510778A (en) | 1976-03-30 |
| PH12883A (en) | 1979-09-28 |
| YU228775A (en) | 1983-01-21 |
| CH605562A5 (en) | 1978-09-29 |
| JPS51125233A (en) | 1976-11-01 |
| SU623515A3 (en) | 1978-09-05 |
| ATA734775A (en) | 1978-03-15 |
| CU34345A (en) | 1979-09-08 |
| DD122072A5 (en) | 1976-09-12 |
| DE2542612C2 (en) | 1987-09-10 |
| BE833784A (en) | 1976-03-25 |
| IE41801B1 (en) | 1980-03-26 |
| LU73452A1 (en) | 1977-05-16 |
| NL177913C (en) | 1985-12-16 |
| ZA755208B (en) | 1976-07-28 |
| YU40124B (en) | 1985-08-31 |
| IL47929A (en) | 1978-07-31 |
| FR2285864A1 (en) | 1976-04-23 |
| NZ178425A (en) | 1978-03-06 |
| AU8418775A (en) | 1977-02-24 |
| FR2285864B1 (en) | 1980-03-28 |
| DE2542612A1 (en) | 1976-04-22 |
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