IE860745L - Phenol derivatives - Google Patents

Phenol derivatives

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Publication number
IE860745L
IE860745L IE860745A IE74586A IE860745L IE 860745 L IE860745 L IE 860745L IE 860745 A IE860745 A IE 860745A IE 74586 A IE74586 A IE 74586A IE 860745 L IE860745 L IE 860745L
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IE
Ireland
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formula
group
same meaning
compound
hydrogen
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IE860745A
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IE58359B1 (en
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Gruenenthal Chemie
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Publication of IE860745L publication Critical patent/IE860745L/en
Publication of IE58359B1 publication Critical patent/IE58359B1/en

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    • G—PHYSICS
    • G05—CONTROLLING; REGULATING
    • G05D—SYSTEMS FOR CONTROLLING OR REGULATING NON-ELECTRIC VARIABLES
    • G05D23/00—Control of temperature
    • G05D23/01—Control of temperature without auxiliary power
    • G05D23/13—Control of temperature without auxiliary power by varying the mixing ratio of two fluids having different temperatures
    • G05D23/1393—Control of temperature without auxiliary power by varying the mixing ratio of two fluids having different temperatures characterised by the use of electric means
    • G—PHYSICS
    • G05—CONTROLLING; REGULATING
    • G05D—SYSTEMS FOR CONTROLLING OR REGULATING NON-ELECTRIC VARIABLES
    • G05D23/00—Control of temperature
    • G05D23/185—Control of temperature with auxiliary non-electric power
    • G05D23/1858—Control of temperature with auxiliary non-electric power by varying the mixing ratio of fluids having different temperatures

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  • Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Automation & Control Theory (AREA)
  • Power Engineering (AREA)
  • Multiple-Way Valves (AREA)
  • Domestic Plumbing Installations (AREA)
  • Control Of Temperature (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Bidet-Like Cleaning Device And Other Flush Toilet Accessories (AREA)
  • Domestic Hot-Water Supply Systems And Details Of Heating Systems (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The domestic water mixing tap includes valves for the control of the admission of hot and cold water into the mixing chamber. The valves are electromechanically or electromagnetic operated, but may be shut down by use of stored energy. The energy required for shut down may be stored in torsion springs or stored electrically in an accumulator, capacitor or inductance. When operated, the hot water supply is cut off more rapidly than the cold supply. The water temperature is controlled by a triple action device responding to a comparison of the mixer outlet water temperature with a preset value to produce a difference signal value. [FR2582418A1]

Description

8.3 5 9 2 Polyunsaturated higher fatty acids,, such as e.g. arachidonic acid, serve in the metabolism of humans and of mammals as substrates for the enzymatically catalysed formation of physiologically important eicosanoids, such e.g. prostaglandins and leukotrienes, a class of substances which is also known 5 by the name "slow reacting substance of anaphylaxis" (SRS-A). Prostaglandin formation is catalysed here by cyclo-oxygenase (also called "prostaglandin synthetase"), and leukotriene formation by 5-lipoxygenase.
Whereas prostaglandins di splay a number of desi rable actions in the ■ organism, it is known that leukotrienes or SRS-A are responsible for the 1 0 development of allergic reactions, bronchoconstri cti ons, inflammations, asthma and a large number of other undesirable effects. It would therefore be desirable to be able to have available chemically and metaboli cal ly stable compounds which leave prostaglandin formation in the organism uninfluenced, but at the same time inhibit 5-lipoxygenase as selectively or 15 specifically as possible and in this way prevent the formation of undesirable leukotrienes. It has now been found that certain phenol derivatives which carry an unsaturated 11-hydroxyalkyl radical in the 4-posi ti on are suffi ciently stable chemi cal ly and metabolicaIly for therapeuti c use and have a speci fi c inhibiting action against 5~ 20 lipoxygenase.
These new phenol derivatives correspond to the general formula R- «2 c 9 or (ch9), 2 o in which A and B are i denti cal or di fferent and each represent one of the groups ~C=C-> cis~CH=CN~ or trans~CH=CH-> R-j denotes hydrogen or a straight-chain alkyl radical with 1 to 6 carbon atoms, or 3 a 5- to 7-membered cycloalkyl groups or a group of the fortaula ~(CH2)m~0-R7, wherein n represents one of the numbers 1, 2 or 3 and Ry represents methyl or ethyls or a group of the formula 1 # ^8'n wherein X represents a single bond,, a -CHg- group or a -CHgO™ group and Rg denotes a hydrogen/, chlorine or fluorine aton or a methyl,, nethoxy or trifluoromethyl group and n represents one of the numbers 1 or 2, Rp represents hydrogen, methyl or ethyl, R~ denotes hydrogen or an acetyl or propionyl radical, R/ represents hydrogen, an acetyl or propionyl radical or a straight-chain or branched alkyl radical with 1 to 4 carbon atoms,.
Rg represents a group of the formula -COOR-jq, wherein R^q is a hydrogen atom, a pharmaceutical^ tolerated cation, in particular a monovalent cation, a straight-chain or branched alkyl radical with 1 to 6 catbon 15 atoms or the group -CCH^p-N-CCCh^p-CH^Dg/- ™ which p represents zero or one of the numbers 1 to 5, and of (sic) pharmaceuti cal ly tolerated salts of these basic esters with acids, or represents a group of the formula ,r„, -c0-n ^ k12 wherein R^ and R^ are identical or different and represent hydrogen, the alkyl radical Rg or 2-hydroxyethyl, or one of these radicals denotes a hydroxy I group and the other denotes hydrogen, or R-j-j and R.^ taken together represent the group -CC^q-V in which q represents one of the numbers 4, 5 or 6, or 4 represents a group of the formula ; /(CH2>P-CH3 ,-CO-N' i '0r13 wherein R-j- represents hydrogen, ~(CH2)p'"CH3J, carboxymethyl, acetyl or propionyl and p in each case has tha same meaning as above, or represents a group of the formula -CO-NH-CCH^Jp-NCCHjJg,, wherein r represents one of the numbers 2 or 3, or pharmaceuti cally tolerated salts thereof with acids,, or represents a group of the formula -co-n y \ / 1 0 in which Y denotes an oxygen atom or the group ^N-CH^, or if appropriate pharmaceutical^ tolerated salts thereof with acids,, or represents a nitri le radical,, or represents a hydroxy I, acetoxy or propionyloxy group,, an alkoxy group ORp or - taken together with OR^ - represents the methylenedioxy group and R^ represents hydrogen, a hydroxy I, acetoxy or propi onyloxy group, the alkyl radical Rg or an alkoxy group OR^, wherein R^ in each case has the same meaning as above.
If R-j and R2 do not have the same meaning, a centre of asymmetry occurs on 20 the carbon atom carrying these radi cals. In these cases, the invention * 1 0 relates both to the racemates and to the optically active forms of the compounds of the formula I- Xn preferred compounds of the formula I, the groups A and 8 each have the same meaning and represent, in particular, -C=C- or cis~CH=CH~. If A and 8 represent different groups, B preferably denots -C=C-. preferably represents a hydrogen atom., These preferred groups of compounds of the formula I can be represented by the following structural formulae: 1) If A and B represent the group ~C=C~ '6 2) If A and B represent the group -cis~CH=CH- '6 oh i" 3) If A and Q are different and B represents the group ~C=C~ 1 C e wherein, in each case, R-j to R3, R5, and A have the sane meaning as © above.
In particularly preferred compounds of the formula I or compounds of the formulae IV X" and I'"', R? and R~ represent hydrogen, whereas in these compounds preferably denotes hydrogen, a straight-chain alkyl radical with 1 to 6 carbon atoms or a phenyl or cyclohexyl radical. i /Rn Preferred meanings of R^ are the groups -CO-N 3 \ /(CH2>p-CH3 /" R,Z ' -co-M » -CO-N y , 0Rq . . D _ _ ^ f 9 wherein Rq, R^-j, R.p, R^~ 0R13 and Y represent the same radicals as above, wherein Rq in particular represents methyl and R,^ represents hydrogen) and the hydroxyL group™ As already mentioned above, the compounds of the formula 1 have a specific inhibiting action against 5-lipoxygenase, which has been determined by in vitro experiments.
To determine the 5-lipoxygenase inhibition, basophilic leukaemic leucocytes from the rat were cultured in vitro and, when a cell density of about 10^ 15 cells per ml was reached, were centrifuged off from the nutrient medium at 400 g. The residue was suspended in 50 siM potassium phosphate buffer of pH 7-4 so that the cell count was 1.5 x 10^ cells per ml.
Indomethacin (10 pM) and calcium chloride (2mM) were added to 1 ml portions of this suspension and the portions were incubated in the presence or 20 absence of ona of the test substances with radioactively labelled arachidonic acid and the calcium ionophor A 23 187 at room temperature for 5 minutes,, After acidification to pH 5, the arachidonic acid metabolites formed under the influence of the 5-lipoxygenase were extracted with ethyl acetate and separated by thin layer chromatography using a mobile phase 25 mixture suitable for the leukotrienes Cc.f, Jakschik et al. Biochem-Biophys. Res. Com mun. 102, 624 (1981)3. The distribution of the radioactivity amongst the various metabolites was measured with the aid of a thin layer scanner. If the percentage amounts of 6-lipoxygenase products 7 formed (5-HETE and LTB^) are related to the amount or concentration of the total radioacti vi ty employed or the test substance of the formula I, the "ic^q value X" (i.e. the concentration which effects 50% inhibition of the * 5-lipoxygenase) can be determined- The influence of the compounds of the formula I on cyclooxygenase activity was investigated with the aid of sheep seminal vesicle microsones suspended in potassium phosphate buffer (50 mM, pH 7-5) by incubation with the test substance and 1 ^C-labelied arachidonic acid for 10 minutes at room temperature™ After addition of glacial acetic acid, the mixture was 10 extracted with ethyl acetate and the concentrated extract was separated on silica gel thin layer plates using ether/hexane/glacial acetic acid (50:50:1). The di st ri buti on of the radioactivity amongst the prostaglandins formed and the unchanged arachidonic acid were determined and the ,sXCgg value II'5' (for 50% i nhi bi ti on of the eye looxygenase) was 15 determined therefrom for the particular substance.
Thus, for example, for the products of the examples mentioned in the following table, the particular ic«jq values quoted were found, from which IC50II the quotient can be calculated. "so1 Example ICijqCjjM] for inhibition of Quotient -lipoxygenase (I) cyclooxygenase (II) 7 0.15 38 253.3 9 0.31 28 90.3 13 0.35 31 88.6 14 0.21 119.1 0-32 >100 >320.0 16 0-28 37 132.1 18 0-1 38 380.0 22c 2.9 130 44.8 22d 2.8 180 64.3 8 This table shows that the IC^g values for the cyclooxygenase inhibition are usually more than 50 times higher than the values for the 5-lipoxygenase inhibition, i„e„ that the test substances very specifically cause only inhibition of the 5-lipoxygenase activity.
On the basis of this favourable influence on the metabolization of polyunsaturated fatty acids, in particular inhibiting action on the formation of arachidonic acid metabolites of 5-1ipoxygenase, such as 5" hydroxyperoxyeicosatetraenoi c acid (5-HPETE), 5-hydroxyeicosatetraenoic acid (5-HETE) and SRS-A, the compounds of the formula X according to the invention cause numerous physiologically useful effects in the organisra of humans and mammals, such as e.g. antiallergic, antianaphylactic, antiinflammatory, antiasthmatic, antihypertensive and circulation-promoting (coronary and cerebraI ci rculation) actions, reduction in leucocyte aggregation and the formation of leucocyte thrombi etc.
These therapeutically useful properties can be demonstrated, for example, by the following results obtained in animal experiments: An oedema is induced in Sprague-Dawley rats by subplantar injection of 0.1 ml of a kaolin suspension (100 mg/l) and the paw volume is measured hourly by plethysmoraetry.
Three hours after inducement of the oedema, the particular test substance, suspended in 5 ml 1% sodium carboxymethy Icellulose solution per kg body weight of the experimental animals, is administered intraperitoneally. The change in paw volume by oedema inhibition under the action of the substance in comparison with the volume measured immediately before administration of the substance can be seen from the following table (values above 100% indicate a decrease in the oedema volume to below the starting value): Product of Dose % Inhibition Time after example (mg/kg) maximum value administration of substance (hours) 7 46»4 65 1 100.0 164 1 14 46-4 68 1 100.0 127 2 100.0 73 2 16 100.0 54 1 If the administration of the test substance takes place at the same time as the kaolin administration by injection of 1 mg substance per paw, dissolved in 0.1 ml 1% sodium carboxymethy Ice llulose solution,, the following maximum values of oedema inhibition or formation of the oedema are measured: Product of % Inhibition Time after example (maximum value) administration of substance (hours) 7 36 2 61 3 14 4o 2 64 16 45 7 This table also shows (c.f. in particular the maximum values of the action observed after 5 and 7 hours for the products of examples 15 and 16) that 1 0 the compounds of the formula I according to the invention are quite stable towards metabolic breakdown and therefore remain active for a long period of time.
On the basis of these useful properties in respect of stability and action, 5 the compounds of the formula I are suitable e.g. as anti a I lergi cs,, antianaphylacti cs, antiinflammatories, antiasthmatics, antihypertensives, antithrombotic agents, agents for the prophylaxis or therapy of ischaemi c cardiac infarction, disturbances in the coronary and/or cerebral arteries etc- The compounds according to the invention have only a low toxicity, which manifests itself only at dosages which are far higher than those to be used therapeutically or prophylactically. They can therefore be administered as such in suitable pharmaceutical formulations to humans or animals.
The invention accordingly also relates to medicaments which contain one or 15 more of the compounds of the formula I according to the invention as the active compound. The amount of active compound to be administered to the patient varies according to e.g. the weight of the patient, the administration route, the indication and the severity of the iIIness. Taking into account these factors, the active compound content per 2° individual dose is in general about 0.01 - 50 mg, and in particular in formulation forms for parenteral admi ni strati on 0-01 to 10 mg, and in formulations for oral or rectal administration about 0.1 to 50 mg.
Medicaments for parenteraI administration can be either solutions or suspensions, and dry formulations which are easy to reconstitute are also 25 possible- Sprays for intranasal or oral administration or for administration of the substances vi a the bronchi are also parti cularly sui tab le administration forms.
Formulation forms of the compounds of the formula I for oral use, such as 30 tablets, coated tablets, capsules, granules, drops and elixirs or syrups, • ■ i i and also suppositories and percutaneous administration formulations (such as e.g. plasters or the like containing the active compounds in a depot in dissolved form, if appropriate with (addition of agents which promote penetration of the skin) are also advantageously suitable for many 5 prophylactic or therapeutic uses. These formulation forms for oral, rectal or percutaneous use are advantageously prepared such that the active compound is released therefrom in a delayed manner, in order thus to guarantee a uniform supply of the active compound to the patient over a prolonged period of time (for example 24 hours).
All the abovementioned pharmaceutical formulation forms are known per se, and since the compounds of the formula I according to the invention are quite stable chemically, their incorporation into these formulation forms presents no problems at all to the expert. The usual care in selection of auxiliaries, such as carrier materials, dyestuffs, flavour correctants, 15 binders, tablet disintegrating agents etc., must of course be taken in this preparation according to the invention of these medicaments, and in particular in the preparation of formulation forms for parenteral use, sterility and - if they are in liquid form - isotonicity should be ensured.
The preparation according to the invention of the compounds of the formula 2 0 I can be carried out by a procedure in which A) a compound of the general formula II in which A, B, and R? have the same weaning as in formula I, represents the alkyl radical R^ or a protective group which can be split 25 off under oi Id conditions, such as a tetrahydropyran-2~yl radical or in particular a tert-butyldiraethyl or -diphenylsilyl group, represents the group 0R^/ or has the same meaning as Rj, with the provi so that in this radical r-jq cannot represent a cation and the basic groups which may be present in Rj cannot be in salt form, or R^, taken together with i 2 the group OR^represents a methylenedioxy group, R^ denotes a hydrogen atom or one of the groups or OR-] 4 and is a protective group which can be split off under mild conditions (such as e.g. one of those mentioned in the definition of R-j^)/- 1) is prepared by reaction of a compound of the formula :■ *17 r, — c — c — c — me " lu i i or, wherein R-j, and have the same meaning as above and He represents a lithium,, sodium or potassium atom or one of the radicals -HgBr or -Mgl, with a compound of the formula r1£~*(ch2)5" "™0r^ iv in which 8 and R^ to have the same meaning as above and R18 represents a bromine or an iodine atom,, if appropri ate in the presence of catalyti c amounts of copper(I) 1 5 ha li des, copper (I) cyanide or other copper salts. Inert solvents, such as aliphatic hydrocarbons or, preferably, anhydrous ethers, such as diethyl or diisopropyl ether, tetrahydrofuran, dioxane etc., are used as the solvent. If Me represents a lithium atom in particular, a solution of the compound of the formula IV in hexamethylphosphoric 20 acid tri amide, 1,3-di methyl-tetrahydro-2-(1H)-pyri midinone, 1,3- di fflethyl-2-imidazoLidinone or e.g. in N,N,N',N'-tetraethy Isulphami de or appropriately dipolar aprotic cosolvents is advantageously slowly added to a solution of the compound of the formula III in one of the solvents mentioned. 1 3 The reaction is carried out at temperatures of about -80° to +75°C, arid preferably, if He is a lithium, sodium or potassium atom, at -80° to 0°C, and if He denotes a radical -MgBr or -Hgl, at -5° to *25°C.
If the radical R15 represents the group 0R14, in particular, the 5 addition of polar cosolvents can be dispensed with and the reaction can be carried out at a higher temperature, such as e.g. at the boiling point of the solvent used. 2) If the radical in the compound of the formula IV represents the group 0R.jthe preparation of the compound of the formula II can 10 also be effected by reaction thereof with a compound of the formula ?2 r c — c ^ c — me' ilia I f • 0R17 wherein R^ R, and have the same meaning as above and He' represents a lithium, sodium or potassium atom, in liquid ammonia. 1 5 3) The compound of the formula II can also be obtained by a process in which a compound of the formula ?2 • — c (CH?)s — Rm |f or,, in which A, R,, R^-. and R^g have the same meaning as above, is reacted with a compound of the formula Me" ~ C = C y 0R|4 Vl R16 wherein R^ to have the same meaning as above and He" represents one of the groups He or Me* defined above™ under the conditions mentioned above for 1 and 2. 4) Compounds of the formula II in which A represents ~CH=CH~ can also be obtained by a process in which a strong anhydrous base, such as n-buty I lithium,, potassium tert-butylate or e.g. sodium bis-Ctri methyl-si lyOamide, is allowed to act on a compound of the formula in which R ) Analogously to the procedure described above for A,,4), compounds of the formula II in which B represents -CH=CH- are obtained by reaction of a phosphorane formed from a compound of the formula h VI A J R1-?-W-(CH2)7-p(W:i-,!.9 0R17 1 0 wherein A,, R^e» R7/. R^ and have the same saeaning as above by the action of a base, with an aldehyde of the formula 0. ^c_// y_0R,4 • xn H / ^ Rlfi ; w or by reaction of the phosphorane obtained by the action of a base on the compound of the foroule o ! ,—/ 15 I R19 ~ CC6H5)3P - CH2 0R14 XIII1 4 ^-R.j 16 I s wherein to and have the same meaning as above ui th an aldehyde of the formula ; : §2 ^ ,ri_c..(a^(ch2)6-cv OR,, r. 0 xiv h in which A, R-j, R? and R^j have the same meaning as above under the conditions mentioned for A4 The protective groups contained in R^/ to 8-y are then split off from the resulting compound of the formula XI in a manner which is known per se, which can also be effected selectively because of the various possible methods for splitting off. Thus, e tetrahydropyran-2-yl group 1° can preferably be split off in raethanolic or ethanolic solution at about 50° - 60°C by addition of catalytic amounts of pyridinium toluene-4-sulphonate. If e.g. the tert-butyldimethyl or -diphenylsilyl group are present ars protective groups, this group can preferably be split off by the action of tetra-n-butylaramonium fluoride in an inert solvent, such 15 as tetrahydrofuran, dioxane, diethyl ether, methylene chloride etc., or of hydrogen chloride, dissolved in methanol, on the compound of the formula II at room temperature.
If at least one of the radicals Rg or R^ is to represent acetyl or propionyl or at least one of the radicals Rg and R^ is to represent 20 acetoxy or propionyloxy, the acid radical in question is then introduced in the customary manner, for example by treatment with a solution of acetic or propi oni c anhydride in pyri di ne or by reacti on of acetyl or propionyl chloride in the presence of an acid-binding agent- B) In a preferred process for the preparation of compounds of the formula 25 I, a compound of the formula XV wherein A, R^ and Rg have the same meaning as above and *20 represents a hydrogen atoia or has the same meaning as R^ is reacted in the presence of a secondary or tertiary amine which is Liquid at about -10° to +80oC^ in particular a dialkyl- or trialkylamine with 2 or 3 carbon atoms in each of the alkyl radicals, pyrrolidine or piperidine, with the addition of catalytic amounts (by these there to be understood amounts of about 0.01 to 1 per cent per mol compound of the formula XV employed) of a complex palladium catalyst, in particular bis-(triphenyIphosphine)-palladium(II) chloride or acetate or tetrakis-(triphenylphosphine)-palladium^. and if appropriate with the addition of catalytic amounts of copper(Ij) iodide at about 0° to 75°C, with e compound of the formula wherein R^g has the same meaning as above, R^-j denotes a hydrogen atom, an alkyl radical rq or a protective group which can be split off under mild conditions (such as e.g. one of those mentioned for ^), represents the group or has the same meaning as R^, with the proviso that in this radical R^g cannot represent a cation and the basic groups which may be present in Rj cannot be in salt form,, or taken together with the group OR^, represents a methylenedioxy group and R^g has the same meaning as R^ or represents a hydroxyl group.
A compound of the formula XVI R. - lR21 XVII i 8 is thus obtained^, from which the protective groups contained,, if appropriate^. in R^q to R^g are split off in the manner described for the conversion of the compound of the formula II into the compound of the formula I, it also being possible for this to be carried out selectively here,, if appropriate. If at least one of the radicals Rg or R4 is to represent the acetyl or propionyl radical or at least one of the radicals R«j and is to represent the acetoxy or propionyloxy radical, this radical is then introduced in the customary wanner, for example as described above for A).
C) Compounds of the formula I can furthermore also be obtained by a process in which a compound of the formula R me — c = c — (ch^)- —(b 7% or 14 xvii] 18 wherein Me, 0 and to have the same meaning as above, are reacted with a compound of the formula R2 0 = C / \ xix Rj in which and R7 have the same taeaning as above in the presence of an inert solvent, such as tetrahydrofuran, diethyl ether or e.g. n-hexane, at about -80° to +30°C, to give a compound of the formula R2 ~G)~ CCH2}6 oh .—r 14 W A A wherein A, B, R-j, Rp and to R^ have the same meaning as above i o J are 6 arid the protective groups contained, if appropriate,* in to R^o split off in the manner described above., If at least one of the radicals R~ and R^ or R^ and R^ in the compound of the formula I is to represent or contain an acetyl or propionyl radicals this is then introduced in the customary wanner.
D) To prepare compounds of the formula I in which is other than hydrogen,, a procedure can be followed in which a compound of the formula 'r, (ck2)6^ xxi 0 ~ - in which A, B and R^ to R1(j have the same meaning as above and R)j has 10 the same meaning as R.j, with the exception of hydrogen, is first prepared by a process in which Da compound of the formula !CH3(CH2)p"°32 - P - CH2 - C - Rj XXII 0 0 wherein p and R| have the same meaning as above, p preferably 15 representing zero, is treated with an anhydrous base, such as sodium hydride or n-butyI lithium, in an "inert solvent, such tetrahydrofuran, dimethoxyethane, n-hexane or toluene, and the product is then reacted with a compound of the formula VIII at temperatures of about -10°C to 20 +35°C, preferably 0°C to 10°C, or 2) a compound of the formula 2 0 r h-C=c — (ch2)6 14 XXIII in which 0 and to R^ have the same weaning as above. is reacted with a compound of the formula xxiv wherein and have the same meaning as above in the presence of a tertiary amine which boils above about +80°C, in particular a trialkylaraine with 2 or 3 carbon atoms in each of the alkyl radicals, under the conditions described in B for the reaction between the compounds of the formula XV and XVI.
The corresponding compound of the formula I (in which R^ and if appropriate R^ cannot represent hydrogen) is then obtained from the compound of the formula XXI prepared by this route by reduction or by reaction with a compound of the formula RJ#-Me, wherein Me has the same meaning as above and Rjhasthe same meaning as Rg,? with the exception of hydrogen, subsequent splitting off of protective groups present in R^ to and if appropriate - if at least one of the radicals Rg and R^ or Rij and R^ is to represent or contain an acetyl or propionyl radical -acylation, which can be carried out before or after the protective groups are split off from R^ - R^.
The reduction of the compound of the formula XXI is carried out with metal borohydrides^, such as sine borohydride or in particular sodium borohydride, preferably with addition of cerium(III) chloride, in methanol, ethanol or dimethoxyethane, with addition of water, at temperatures of about -20° to +30°C, preferably at about +20°C. 2 1 I 1 0 1 5 If desired, triple bonds (in A, and/or B) present in the compounds of the formula I obtained according to A, B, C or D can be hydrogenated to double bonds. This hydrogenation is in general carried out with catalytically excited hydrogen under normal pressure at room temperature usi ng, in particular, palladium catalysts, preferably "Lindlar catalysts", such as e.g. palladium poisoned with lead on calcium carbonate. Solvents which are used here in a manner which is known per se are e.g. n~hexane, methanol, ethanol, ethyl acetate, benzene, toluene and di i sopropyl ether, advantageously with addition of 0.1 - 2% quinoline or pyridine, or pure pyri dine.
If the radical R5 in the compound of the formula I obtained represents the group C00R If the radical Rg in a compound of the formula I obtained by one of the 10 above routes contains a basic group, this can easily be converted by neutralization with a suitable acid in a manner which is known per se into a pharmaceutical^ tolerated salt with this acid. If this salt formation has taken place in a solvent in which the salt formed is soluble,, this is advantageously isolated by freeze-drying, although precipitation by 15 addition of suitable liquids which are miscible with the solvent and in which the salt is insoluble can of course also be used to isolate the salt-Preferably, however, the free base is dissolved in an anhydrous agent of low polarity, such as e.g. diethyl ether, an ethereal solution of the acid is added and if appropriate n-hexane or petroleum ether, for example,, is 20 added in order to start the crysta I li zati on. On the other hand, in this case also isolation of the salt by evaporation, preferably in vacuo, is of course possible. Suitable acids for this salt formation are e.g. hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, w formic acid, acetic acid, benzoic acid, salicylic acid, benzenesuIphonic 25 acid and other aci ds customary for the preparation of pharnaceuti caIly usable salts.
Other conversion possibilities for the radical R^ are obvious to the expert. For example, the free carboxyl groups can easily be converted into the carboxymethyI or carboxyethyl group by treatment with di azoaethane or 30 di azoethane (especially if Rg and R/ are other than hydrogen and R^ does 2 3 not represent a hydroxyl group).
In the synthesis processes described in the contest of this Application, in each case those starting materials in which any double bonds present are already in the configuration desired in the end product are advantageously used. Isomer resolution in cases where a further double bond is introduced in the last stage but is not obtained with a uniform configuration is in this way facilitated., The isomer resolution can be carried out in a manner which is known per se, e.g. by column chromatography.
If R-j and Rg differ from one another, any raeeraate resolution desired can be carried out in the customary manner. E.g. if Rg contains a basic group or represents a free carboxyl group, this can be achieved by salt formation with optically active acids or bases in a manner which is known per se.
The starting compounds for the procedures described above for the preparation of the compounds of the formula I are in all cases prepared in 15 a manner which is known per se. The routes to be considered for these are chosen, in particular, by also taking into account the various meanings of A and B.
I E.g. the compounds of the formula VI and from these those of the formula IV can be obtained by a procedure in which chloromethy lene-20 triphenyl-phosphorane (produced in situ from chloromethyItriphenylphos- phonium chloride by the action of e.g. n-buty I li thium /di methyl su I ph-oxide in tetrahydrofuran) is allowed to act on an aldehyde of the forsnula XII and hydrogen chloride is then split off from the compound formed, e.g. with n-butyllithium. The resulting phenylacetylene 25 derivative is then converted into the compound of the formula VI by reaction e.g. with butyllithium, sodium hydride, potasium hydride or ethylmagnesium bromide or iodide. Reaction thereof with 1,6-dibromo-or 1,6-diiodohexane, e.g. in diethyl ether or tetrahydrofuran, preferably in the presence of an aprotic dipolar solvent, at about ~ 30 80°C and later at 0°C, then gives the compound of the formula IV.
II A compound of the formula V in which A represents -C=C- is obtained 2 4 e.g, by reaction of a compound of the formula III with 1^6-dibromo- or 1,6-di i odo-hexane under the conditions described above in I for the reaction of the compound of the formula VI with one of these halogen compounds- III The compound of the formula VIII is obtained by reaction of a compound of the formula VI with a compound of the formula a O - 0 -CH2 — (CH2)6 R18 aaV under the conditions described above in I, splitting off of the tetrahydropyran-2-yl group and oxidation of the resulting alcohol of 10 the formula ^*"t5 : HO - CH2 - If the hydroxyl group in the compound of the formula XXVI is replaced by a bromine atom, e.g- by reaction with carbon tetrabromide in the 15 presence of triphenylphosphine, and the product is then reacted with triphenyIphosphine (for examoiple by boiling in acetonitrile under reflux for 12 to 24 hours), a compound of the formula IX in which R-j9 represents bromine is obtained.
IV If a compound of the formula III is reacted with 1^7'~dibromoheptane 20 under th# conditions mentioned in I and the resulting compound of the formula k Ri ? c- C—(CH2)7—Br XXV!I OR,7 is treated with triphenylphosphine (e.g* heating in acetonitrile), the corresponding compound of the forsnula XI in which represents bromine is obtained, V To prepare a compound of the formula XIV in which A represents -C=C-, e 5 compound of the formula III in which should not represent the tetrahydropyran-2-yI group is first reacted with a compound of the formula XXV under the condi ti ons described in I and the tetrahydropyran-2-yl group is split off,, an alcohol of the formula ?2 R1 — c - C s c ~ (CH,)6 - CH2 - OH xxviii ' " °ri7 being obtained- On oxidation (e.g. with pyridinium dichromate in dimethylformamide or methylene chloride), this gives the compound of the formula XIV.
VI A compound of the formula XV in which A represents -C=C- End represents hydrogen can be obtained by reaction of a compound of the formula hc = c- (CH2)6-Cs C-Me xxix with a compound of the formula XIX in anhydrous ethers, such as tetrahydrofuran, at temperatures of about ™80°C to +65°C.
VII To prepare compounds of the formula XVIII, the aldehyde of the formula* 20 VIII is used as the starting substance and the desired compound of the formula XVIII is obtained therefrom by reaction with chlororaethylene-triphenylphosphorane, followed by splitting off of hydrogen chloride from the resulting product in accordance with the method described in I and subsequent reatment of the resulting compound of the formula XXIII 25 with butyllithiurn, sodium hydride, potassium hydride or e.g. ethyl- 2 6 magnesium bromide or iodide.
The compound of the formula XXIII is also accessible on the other hand from the compound of the formula XV by reaction with lithium acetylide-ethylenediamine complex in dimethylsulphoxide or dimethylformamide at 5 about 5° to 25°C„ Other routes for the preparation of starting compounds for the process according to the invention are obvious to the expert. Moreover, the starting materials are in some case also known from the literature or commercially available.
The following examples further illustrate the process according to the invention and the preparation of new starting materials and intermediate products. In carrying them out, no emphasis has been placed on achieving maximum yields. All the temperature data are uncorrected.
The products are in the form of oils, unless other data is given in an 15 individual case.
The ^H-NMR spectra were recorded at 60 MHz. The chemical shift of the spectroscopic resonance data was measured in ppm.
The n-butyllithium solution used in the examples contained - dissolved in n-hexane - 1.6 mol n-buty I lithium/litre. However, it is of course also 20 possible to employ solutions of other concentrations and/or with solvents other than n-hexane.
Unless stated otherwise, the ether used in the examples is diethyl ether, and the petroleum ether is that with a boiling range of 50° - 70°C.
For the chromatography and column chromatography - unless mentioned 25 otherwise - silica gel 60 (0.040 ~ 0.063 mm) from Machery-NageI was used as as the stationary phase. For the HPLC, a silica gel marketed by the same company under the name "iMucleosil C 18 (10 fjm)" was employed as the stationary phase. •) 7 Monitoring of the course of the reaction by thin layer chromatography was performed with "HPTLC pre-coated plates, silica gel 60 F 254" from E. Merck, Darmstadt. The mobile phase used is stated in the examples in each case by gB(TLCs „»„)"* The mixing ratios of the mobile phases for all the chromatographic analyses are always stated in volume/volume.
Enantiomer mixtures obtained in the examples were not separated - unless mentioned otherwise. In such cases, the data quoted thus relate to the enantiomer mixtures.
Example 1 1-(4'-Hydroxy-5 '--fflethoxycarbonylphenyl)-11~hydroxy--undeea--1,9-di ine a) Undeca~2,10-diin-1~ol 59,4 ml n-butyllithium solution are added dropwise to 13,42 g deca-1,9-diine in 300 ml absolute tetrahydrofuran at -40°C in the course of one 15 hour, while stirring and passing over dry nitrogen. The mixture is subsequently stirred for one hour, during which the temperature is allowed to rise to 0°C, 6.0 g paraformaldehyde are then added and the mixture is heated under reflux. (TLC: petroleum ether/ether - 3:2). After the end of the reaction^, the mixture is broken down with saturated 20 ammonium chloride solution and extracted several times with ether, and the extract is dried over sodium sulphate and evaporated in vacuo. Column chromatography of the residue with petroleum ether/ether (3:2) gives 8.27 g title compound as a liquid which gradually solidifies in a refrigerator. 1H-NMR (CDCl3): 1-2 - 1.80 Cm, 9 H); 1.85 - 2.00 Example 2 1-(3'-Carboxy-4'-hydroxyphenyl)~11~hydroxy-undeca-1,9-diine 3.24 ml of an aqueous solution of lithium hydroxide (1 mol/l) are added to 0.20 g product from example 1, di ssolved in 2 ml methanol and 2 ml tetrahydrof uran- (TLC: petroleum ether/ether/glacial aceti c acid : 3:6:0-1)-After 20 hours,, the mixture is evaporated in vacuo, the residue is diluted with 3 ml water and the mi xture is acidified to pH 3 with hydroch lori c 20 acid, while cooli ng with i ce~water. It is extracted th ree times with ether, washed with water, dried with sodium sulphate and evaporated, 0-172 g title compound being obtained. 1H-NMR (CDClg): 1,07 - 1-93 (m, 8 H); 2.00 - 2.70 (m, 4 H); 3.97 - 4.30 (m, 2 H); 6.63 - 7.93 (m, 3 H).
Example 3 1-(3'-Carbamoyl-4"-hydroxyphenyl)-11-hydroxy-undeca"1,9"diine 0,180 g ester obtained obtained in example 1 are dissolved in 5 ml of a 2 9 methanol! c solution of ammoi ni a <11% NH~)» (TLC: petroleum ether/ether/ glacial acetic acid - 3:6:0.1). When the reaction has ended,, the mixture is evaporated in vacuo. Column chromatography of the residue with petroleum ether/ether/glacial acetic acid (3:6:0.1) gives 0.132 g title 5 compound in the form of white crystals. 1H-NMR (CDCI3): 1.07 - 1.97 (m, 8 H); 2.01 - 2.67 (m, 4 H); 3-90 ~ 4.23 (m, 2 H); 6.56 - 7.77 (m, 3 H).
Example 4 1-(4'-Acetoxy~38~methoxycarbonylphenyl)-11~ac8toxy-undeca"'1/g9-diine 1 0 0.10 g ester obtained in example 1 are dissolved in 1 mI absolute tetra-hydrofuran and 0.255 ml absolute pyridine,* and 0.268 ml acetic anhydride is added dropwise, while cooling with ice-water. The mixture is allowed to warm to room temperature and, after 20 hours, is evaporated in vacuo. Column chromatography of the residue with petroleum sther/ethyl acetate 15 G:2) gives 0.120 g title compound. 1H~NMR (CDCIj): 1.20 - 1.93 (m, 8H); 1.97 - 2-70 (m, 4 H); 2.10 (s, 3 H); 2.33 (s, 3 H); 3.87 (s, 3 H); 4.47 - 4.73 (m, 2 H); 6.80 - 8.03 (m, 3 H).
Example 5 1 l-Hydroxy-l-^'-hydroxy-S 'wmethoxyphenyl)~undeca-1,«9-di ine) a) 3-Hethoxy-4-(tetrahydropyran-2'"yloxy)-bensaldehyde 0.20 g p-toluenesulphonic acid monohydrate is added in 3 portions to a solution of 20 g vani I li n and 14.28 ml 3,4-di hydro-2H-pyran in 320 ml methylene chloride- After 60 minutes, 3 g anhydrous potasssium 25 carbonate are added to the reaction mixture, the mixture is stirred in an ice-water bath for 30 minutes and 20 ml water are then added. The methylene chloride phase is washed twice with saturated sodium chloride 3 0 solution, dried over sodium sulphate and evaporated- The crude product is purified by column chromatography with petroleum ether/ether (2:1). 22.26 g title compound are obtained as an oil, which gradually soli di fes to white crystals, which melt at 43°C, in a refrigerator. 1H-NMR CCDCI3): 1.33 - 2.27 ; 9.70 - c) 3-Methoxy~4~(tetrahydropyran~-2e~yIoxy)-phenylacetylene .47 g product obtained in example 5b are dissolved in 28 sal absolute tetrahydrofuran, and 27.8 ml n-butyIlithium solution are added dropwise at 0°C. The mi xture is stirred at 0°C for a further 3 hours and then broken down with saturated ammonium chloride solution and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated- Column chromatography of the residue with petroleum ether/ether (2:1) gives 3.81 g title compound. 3 I 1H-NMR (CDCL3): 1.40 - 2-20 (m, 6 H); 2.95 (s, 1 H); 3.37 - 4.16 (m, 2 H); 3.87 (s, 3 H); 5.20 - 5.50 Cm, 1 H); 6.80 - 7.10 Cm, 3 H). 1 ~C5'-Methoxy-4Ctet r ahydropy ran-2"-yloxy)-pheny 13-11~Ctetrahydropy ran-2'-yloxy)"undeca-1/.9"di ine 1.31 g product from example 5c are dissolved in 9.5 ml absolute tetrahydrofuran, and 3.51 ml n-butyllithium solution are added dropwise at -78°C to -70°C, while sti rri ng and passi ng over dry ni trogen. The mixture is sti rred in a cold bath for a further 60 minutes and a solution of 1.72 g 1-bromo~9-(tetrahydropyran-2"-yloxy)~non~7~ine in 5.3 ml absolute hexamethylphosphoric acid triamide is then added dropwise. After about 4 hours, the cold bath is removed. As soon as the reaction mixture has reached 0°C, it is broken down with saturated ammonium chloride solution and extracted three times with ether. The combined ethereal extracts are washed twice with saturated ammonium chloride solution and once with water, dried over sodium sulphate and then evaporated in vacuo. Column chromatography of the residue with petroleum ether/ether (2:1) gives 1-72 g title compound. 1H-NMR (CDClj): 1,07 - 2-07 (m, 20 H); 2.10 - 2-60 (m, 4 H); 3.27 - 4.07 (m, 4 H); 3.86 (s, 3 H); 4.13 - 4.37 (m, 2 H); 4-67 - 4.91 (m, 1 H); -33 - 5.51 (m, 1 H); 6-67 - 7.07 (m, 3 H).
The 1-bromo~9~(tetrahydropyran-29~yloxy)~non-7-ine used in example 5d as one of the starting compounds is obtained as follows: -0 g 3~(tetrahydropyran-2!~y loxy)~prop~1-i ne are dissolved in 70 mI absolute tetrahydrofuran, and 22.31 ml n-butyllithium solution are added dropwi se at -78°C to -70°C, while sti rring and passing over dry ni t rogen. The mi xture is sti rred in a cold bath for a further 60 m i nutes and 16.3 ml 1,6-di bromohexane are then added dropwise in the course of 5 mi nutes, followed by 30 mI absolute hexamethylphosphoric acid triamide in the course of 25 minutes- After 4 hours, the cold bath .3 2 is removed and the mixture is worked up analogously to example 5d^ but the ether extracts are washed with saturated sodium chloride solution-The crude product gives 8.23 g title compound by column chromatography with n-hexane/ether (10:1)- 1H-NMR (CDCl3): 1-16 - 2.43 (m, 16 H); 3-20 - 4.05 (m, 4 H); 4.10 - 4.33 (m, 2 H); 4.61 - 4.90 (m, 1 H). f) 11-Hydroxy-(4'-hydroxy-3'-methoxyphenyl)--undeca"1^,9~diine 1.71 g product obtained in example 5d and 0.08 g pyridinium toluene-4-sulphonate are dissolved in 34 ml absolute ethanol and the solution is stirred under dry nitrogen at a bath temperature of 55°C to 60°C for 3 hours and then evaporated in vacuo at a bath temperature of 20° to 25°C. Column chromatography of the residue with petroleum ether/ethyl acetate (3:4) gives 0-726 g title compound,, which slowly turns into crystaIs which melt at 71°C. 1H-NMR (CDCI3): 1.16 - 1-83 (m, 8 H); 1-91 - 2-53 (m, 4 H); 3.87 (s„ 3 H); 4-20 - 4-37 (m^, 2 H); 6-60 - 7-01 (m^ 3 H)„ Example 6 11-Acetoxy-1-(4"-acetoxy-3"-methoxyphenyl)-undeca~1^.9"di ine 0-20 g product from example 5 are reacted in 2 ml absolute tetrahydrofuran with 0.60 ml absolute pyri dine and 0-63 ml acetic anhydride analogously to example 4, 0.273 g title compound being obtained. 1H-NMR (CDCI3): 1.20 - 2.53 (m, 12 H); 2.05 (s, 3 H); 2.25 (s, 3 H); 3-70 (si? 3 H); 4.43 - 4.60 (nv 2 H); 6.60 - 7-10 (m, 3 H).
Example 7 1~(5 ',4;-Dihydroxyphenyl)-11-hydroxy-undeca-1,9-diine a) 3,4-Bis-(tetrahydropyran-2"-yloxy)"ben^aldehyde A suspensi on "of 25 g 3,4~di hydroxybenz aldehyde in 125 fill methylene chloride is reacted with 39.5 rail 3,4-dihydro-2H-pyran under the catalytic action of 0-05 g p-toluenesuIphonic acid monohydrate analogously to example 5a and the mi xtxure is then worked up- Column chromatography with petroleum ether/ether (3:2) gives 38.42 g title compound, which partly solidifies after some time in a refrigerator- 1H-NMR (CDClg): 1.33 ~ 2-27 (m, 12 H); 3-20 - 4-23 (m, 4 H); 5-23 - 5-63 (m, 2 H); 6-93 - 7.70 (m, 3 H); 9-70 (s, 1 H). b) 1^,2-Bi s-(tetrahydropyran-2"-yloxy)-4-(2''chlorovinyl)-benzene The procedure is analogous to example 5b to give^. from 20.0 g ch loromethyItriphenyIphosphonium chloride, 6-46 g potassium tert-butylate and 11.8 g product from example 7a, after column chromatography with petroleum ether/ether (2:1), 10.56 g title compound. 1H-NMR (CDCl3): 1-40 - 2.40 (m, 12 H); 3.27 - 4-27 Cm, 4 H); 5-20 - 5.63 (m, 2 H); 5-97 - 7-56 Cm, 5 H). c) 5,4-Bis-(tetrahydropyran-2'~yloxy)~phenylacetylene The procedure is analogous to example 5c to give, from 4.0 g chlorovinyl compound prepared in example 7b and 16.24 ml n-butyllithium solution, after column chromatography with petroleum ether/ether C5:1), 2-96 g title compound, which gradually solidifies to a white crystalline mass with a melting range of 58° - 70°C- 3 4 1H-NMR (CDCL3): 1-37 - 2.33 (m, 12 H): 2-90 (s, 1 H); 3.33 - A.23 (m, 4 H); .23 - 5-56 Example 8 11~Acetoxy-1--(5'/.4''-diacetoxyphenyl)-undeca-1,r9--diine The title compound is obtained by acetylation of the product obtained in example 7 using the procedure described in example 4. 1H-NMR (CDCI3): 1.20 ~ 1-83 (m, 8 H); 1-93 - 2.50 Cm, 13 H); 4.40 ~ 4.60 Cm,. 2 H); 6.73 - 7*20 (m, 3 H). 1 5 Example 9 1-(3%4"~&ihydroxypheny l)-11~hydroxy-undeca-1Z.,9Z~diene 0.545 g product obtained in example 7, dissolved in 20 ml absolute ethanol containing 0-1 ml freshly distilled qui noli ne,, are hydrogenated at room temperature under atmospheric pressure over 0.136 g pa I ladiura-on-ca leium 20 carbonate (5% Pd; "Lindlar catalyst" poisoned with lead). After uptake of the theoretical amount of hydrogen.,, the catalyst is filtered off and the filtrate is.evaporated in vacuo. The residue is purified by HPLC with methanol/water (60:40),, 0.416 g title compound being obtained. 1H-NMR (CDCI3): 1-15 - 1.75 (m, 8 H); 1.70 - 2.53 (m, 4 H); 4-07 -5.23 - 6.37 (m, 4 H); 6.47 - 6.90 (m, 3 H). 4.33 (nv 2 H); 3 6 Example 10 The procedure is as in example 9 to give 11-hydroxy-1-C4'~hydroxy-3!~ methoxyphenyl)-undeca-1Z,9Z-diene from the product of example 5- 1H-NMR (CDCl3): 1.10 - 1.70 Cm, 8 H); 1.72 - 2.50 Cm, 4 H); 3.77 Cm, 3 H); 3.80 - 4.13 Cm, 2 H); 5.13 - 6.30 Cm, 4 H); 5.53 Cs, 1 H); 6.37 ~ 6.73 Cm, 3 H).
Example 11 1-C3',4'-Dimethoxyphenyl)-11-hydroxy-undeca~1,9-diine a) l-C3!\y4"-Dimethoxyphenyl)"11-Ctetrahydropyran--2*-yloxy)-undeca-1<,9-di ine The procedure is analogous to example 5d to give,, from 0.75 g 3,4-di methoxyphenyI acetylene, 2.88 ml n-butyllithium solution, 1.29 g 1-iodo-9-Ctetrahydropyran-2"-yloxy)-non~7-i ne and 4 ml absolute hexamethylphosphoric acid triamide, after column chromatography with 15 petroleum ether/ether C2s1), 1*17 g title compound 1H-NMR CCDClj): 1.25 - 1.93 Cm., 14 H); 2.03 - 2.53 Cm, 4 H); 3.30 - 4.00 Cm, 2 H); 3.83 Cs, 6 H); 4.13 - 4.27 Cm, 2 H); 4.67 - 4.87 Cm, 1 H); 6.57 - 7-00 Cm, 3 H). b) 1-C5',4°-Dimethoxyphenyl)-11-"hydroxy-undeca"1,9-di ine The procedure is analogous to example 5f to give, from 1-15 g product from example 11a, 30 ml absolute ethanol and 0.075 g pyridinium toluene-4-suIphonate, after column chromatography with n-hexane/ether C1:1), 0.78 g title compound in the form of whits crystals which melt at 39° -25 41 °C. njfc flj 1H-NMR (CDCLj): 1.25 - 1.85 (m, 9 H); 2.05 - 2-55 (m, 4 H); 3.83 (s, 6 H); 4.07 - 4.33 (m, 2 H); 6.57 - 7-00 (m, 3 H).
Example 12 11~Hydroxy-1-(3",4'-methylenedioxyphenyl)-undeca-1,9-di ine a) 1-(3'^4'i~Hethylenedioxyphenyl)-11"(tetrahydropyran"2'"yloxy)-undeca-1^9-diine The procedure is analogous to example 5d to give,, from 1.61 g 3,4-methylenedioxyphenylacetylene, 6,9 ml n-butyllithium solution, 3.08 g 1-iodo-9-(tetrahydropyran~2,~yloxy)-non-7-ine and 10 ml absolute hexa-methylphosphoric acid triamide, after column chromatography with petroleum ether/ether (10:1), 2.60 g title compound. 1H-NMR (CDCl3): 1.20 - 1.90 (m, 14 H); 2.03 - 2.53 (m, 4 H); 3.23 - 4.00 («, 2 H); 4.13 - 4.30 (m, 2 H); 4.65 - 4.85 (m, 1 H); 5.85 (s, 2 H); 6.50 - 6.93 (m, 3 H). b) 11-Hydroxy-1- (38, 4 s -methy lenedi oxypheny I )-undeca-1, 9-di i ne The procedure is analogous to example 5f to give, from 2.51 g product obtained in example 12a, 70 ml absolute ethanol and 0-17 g pyridinium toluene-4-sulphonate, after column chromatography with n-hexane/ether G:2), 1.41 g title compound in the form of white crystals which melt at 45° - 46°C. 1H-NMR (CDClg): 1-25 - 1.80 (m, 9 H); 2.03 - 2.53 (m, 4 H); 4.07 - 4-33 (ra, 2 H); .85 (s, 2 H); 6.50 - 6.93 (m, 3 H). 38 Example 15 1-(3%49-Dihydroxyphenyl)-11-hydroxy~11-methyl-dodec3-1,9-diine a) 1-Bromo~9~methy l-9-(tet rahydropyran-2,;-y loxy)-dec-?'-i ne .05 g 3~methy l~3~(tetrahydropyran-2!'-y loxy)-but-1-i ne, 18-3 ml n-5 butyl lithium solution, 13.9 ml 1,6-di bromohexane and 10 ml absolute hexamethylphosphoric acid triamide are reacted analogously to example 5e. (TLCs petroleum ether/ether - 20:1)- After 6 hours, the cold bath is removed- As soon as the reaction mixture has reached 0°C, it is worked up analogously to example 5e. Column chromatography with 10 petroleum ether/ether (20:1) gives 6-08 g title compound. 1H-NMR (CDCl3): 1.20 - 2-37 (m, 22 H); 3-23 - 4.13 (m, 4 H); 4.90 - 5.10 (m, 1 H). b) 1"C3"<.4'-Bi s~(tetrahydropyran-2"-yloxy)-phenyU-11-methyl~11"(tetra-hydropyran-2"yloxy)-dodeca-1,9-di ine The procedure is analogous to example 5d to give, from 1-51 g 3,4-Bis- (tetrahydropyran~2fi-yloxy)-phenylacetylene, 3-13 ml n~butyI lithium solution, 1.33 g product obtained in example 13a and 4.5 ml absolute hexa me thy I phosphor i c acid tri am i de, after column chromatography with petroleum ether/ether (5:1), 1-81 g title compound, 1H-NMR (CDCI3): 1.25 - 2.50 (m, 36 H); 3.27 - 4.17 (m, 6 H); 4-90 - 5.10 (m, 1 H); 5.23 - 5.43 (m, 2 H); 6.87 - 7.13 (m, 3 H). c) 1-(3 %4"-&ihydroxyphenyl)-11-hydroxy-11-methyl-dodeea-1,9-di ine The procedure is analogous to example 5f to give, from 1.75 g product 25 from example 13b, 30 ml absolute ethanol and 0.08 g pyri di nium toluene- 4-sulphonate, after column chromatography with petroleum ether/ether (1:3) and recrysta I lization from n-hexane/ethyI acetate, 0.69 g title compound in the form of white crystals which melt at 71°C to 73°C. 1h-nmr (cdci3): 1.25 » 1.73 (m, 14 H>; 1.97 - 2,50 (m, 5 H); 5.40 (s.„ 1 H); .90 Example 14 1~(3',4'~Dihydroxyphenyl)-11-hydroxy-hexadeca-1,9-di ine a) 1-0% 4'~Bi s-(tetrahydropyran~2"-yloxy)~phenylI3"8"bromo~oet~1~ing 6.9 ml n-butyllithium solution are added dropwise to a solution of 3-33 g 3,4~Bis-(tetrahydropyran-2"-yloxy)-phenylacetylene in 20 ml absolute tetrahydrofuran at -78° to -70°C in the course of 45 minutes, under dry nitrogen, the mixture is stirred in a cold bath for a further hour and 5.1 ml 1,6-dibromohexane are then added,* followed by dropwise addition of 7 ml absolute 1,3-di methy 1-3,4, 5,6-tetrahydro-2(1H)~pyri mi di none. The mixture is stirred for 20 hours,, allowed to warm to 0°C and worked up analogously to example 5e» Column chromatography with toluene/diisopropylether (10:1) gives 3.55 g title compound. 1H-NMR (CDCI3): 1.20 ~ 2.56 (m, 22 h); 3.23 - 4.23 (m, 6 H); 5.25 - 5.53 (m, 2 h); 6.73 - 7.20 (rn, 3 H). b) 1~C3f,4'-Bi s- (tetrahydropyran~28'~yloxy)-phenyl3~H"(tert~butyldi phenyl" si lyloxy)~hexadeea--1„,9-diine The procedure followed is according to the process described in example 5d to give, from 1.82 g 3-(tert-buty Idi phenyl si ly loxy)-oct~1~i ne, 3.13 ml n-butyllithium solution, 1.86 g product from example 14a and 4.5 ml absolute hexamethyIphosphoric acid triamide, after column chromatography with petroleum ether/ether (4:1), 2.26 g title compound. 40 1H-NMR (CDCl3): 0.67 - 2.50 (m, 35 H); 1.07 (s^ 9 H); 3.33 - 4»45 (m, 5 H); .23 ~ 5.43 (m, 2 H); 6.85 - 7.80 (m, 13 H).
To prepare the 3-(tert-butyIdiphenylsilyloxy)-oct-1-ine used in example 14b as one of the starting compounds, 5 ml tert-butyldiphenyIchloro-si lane are added dropwise to a solution of 2-03 g oct-l-in-3-ol and 132 g imidazole in 20 ml absolute dimethyIformamide at 0°C, while stirring and passing over dry nitrogen^, and the miture is subsequently stirred at room temperature for 3 hours,, diluted with 100 ml methylene chloride and washed in succession in each case once with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over sodium sulphate and evaporated in vacuo. Column chromatography of the residue with petroleum ether/toluene (8:1) gives 5.34 g title compound. 1H-NMR (cdci3): 0.63 - 1.87 (m, 11 H); 1.10 (s^ 9 H); 2.28 (d, 1 H); 4.13 - 4.43 (m, 1 H); 7.15 ~ 7.80 (m, 10 H). 1-C3%4"-Bis-(tetrahydropyran-2"~yloxy)-phenyl3-11-hydroxy--hexadeca~1,j,9-diine 9 ml of a solution of tetra~n~buty I ammonium fluoride in tetrahydrofuran (1 mol/l) are added dropwise to a solution of 2-23 g product obtained in example 14b in 30 ml absolute tetrahydrofuran at 0° - 5°C^ while stirring and passing over dry nitrogen,, and the mixture is then allowed to warm to room temperature. (TLC; petroleum ether/ether - 3:2). After four hours, the reacti on is complete. Saturated ammonium chloride solution is added and the mixture is worked up analogously to example 5e. Column chromatography of the crude product with n-hexane/ether G:2) gives 1.42 g title compound. 1h-nmr (cdci3): 0-67 - 2.53 (m, 36 H); 3.33 - 4-43 (m, 5 H); 5.20 - 5.43 (m, 2 H); 6.80 - 7.15 (nv 3 H)„ 4 1 e) 1~(3%4'-Pihydroxyphenyl)-11~hydroxy-hexadeca-1,»9-diine The procedure is analogous to example 51 to give,, from 1„40 g product from example 14d^ 30 ml absolute ethanol and 0-07 g pyridinium toluene-4-sulphonate^ after column chromatography with petroleum ether/ether 5 (1:3), 0.73 g title compound in the form of crystals which melt at 46° - 48°C» 1H-NMR (CDCl3): 0.67 - 1.93 (m, 19 H); 2.00 - 2.50 (m, 4 H); 4.17 ~ 4.57 (m, 3 H); 6.50 - 7.00 (mt. 3 H). 1 0 Example 15 1-(3%4'-&ihydroxyphenyl)-11-hydroxy-11-phenyL"undeca-1^.9"di ine a) 1~C3'^4'-Bi s-(tetrahydropyran-2"-yloxy)~phenyU-deca-1,,9-diine 2-1 ml absolute dimethylsulphoxide are poured over 0-237 g lithium acetylide-e thy lenedi am ine complex (95%) and the mixture is sti r red at -| 5 room temperature for 30 minutes under dry nitrogen. A solution of 1-0 g 1-C3%4'~bis-(tetrahydropyran-2"~yloxy)~phenyU~8-bromo~oct-1 -i ne in 1.5 ml absolute dimethylsulphoxide is carefully added dropwise to the mixture,, cooled to h-8°C^ at a temperature of 8° - 9°C„ The cooling bath is removed and the mixture is subsequently stirred at room temperature 20 for 3 hours. It is then broken down with saturated ammonium ch lori de solution and worked up analogously to example 5e. Column chromatography of the crude product with petroleum ether/ether (4:1) gives 0.689 g title compound. 1H-NMR (CDClj): 1.30 - 2.55 (m, 25 H); 3.33 - 6.83 - 7-15 (m, 3 H). 4.20 (m, 4 H); 5.23 - 5.47 (m, 2 H); 4 2 b) 1-C3", 4 ll!-Bis-(tetrahydropyran--2"--yloxy)-phenylIM 1-oxo-11-phenyl-undeca-1,9-di i ne 0-64 g product from example 15a is dissolved in 10 ml absolute triethylamine, and first 0.18 ml benzoyl chloride and then 0.032 g bis-(triphenylphosphine)-palladium(II) chloride and 0.015 § copper(I) iodide are added,, while stirring and passing over dry nitrogen- (TLC: petroleum ether/ether - 2:1), When the reaction has ended^ the mixture is diluted with 50 ml ether and filtered and the filtrate is evaporated in vacuo. Column chromatography of the oily residue with petroleum ether/ether (3:1) gives 0,66 g title compound. 1H-NMR (cdci3): 1.25 - 2.10 (m, 20 H); 2.15 - 2.67 (m, 4 H); 3.30 - 4.20 (ra, 4 H); 5.23 - 5.47 and 0-48 ml cyclohexanealdehyde is then added dropwise- The mixture is kept for in each case a further hour at -10°C and then at room temperature- It is then broken down with 5 ml 20 saturated ammonium chloride solution and worked up analogously to example 5e. Column chromatography of the crude product with petroleum ether/ether (2:1) gives 0-94 g title compound. 1H-NMR (CDCl3): 0-70 - 2.50 (m, 36 H); 3.26 - 4-20 (m, 5 H); 5.23 - 5.43 (m, 2 H); 2 5 6-83 - 7-15 (HI, 3 H). b) 11"Cyclohexyl-1-(5%4"-dihydroxyphenyl)-11-hydroxy~undsca-1t„9-diine By the procedure desc ri bed in example 5f, 0-91 g product obtai ned in 4 4 example 16a,, 18 ml absolute ethanol and 0.04 g pyridinium toluene-4-sulphonate give, after column chromatography with n-hexane/ether (2:5), 0.44 g title compound. 1h-nmr (coci3): 0.70 - 2.50 (m, 24 H); 3-95 - 4.20 (m, 1 H); 5.43 (s, 1 H); .87 (s, 1 H); 6.50 - 6.90 Example 17 11-Hydroxy"1"(3B<,4" j,58-trimethoxyphenyl)-undeca-1^9-di ine a) 5-(2'-Chlorovinyl)"1,,2^.3-trimethoxy-benzene 21.5 ml n-butyllithium solution are added dropwise to a suspension of 11.94 g chloromethyl-triphenylphosphonium chloride in 85 ml absolute dimethylsulphoxide and 170 ml absolute tetrahydrofuran at 0°C, while stirring and passing over dry nitrogen, the mi xture is subsequent ly stirred for 30 minutes, 5.48 g 3,4,5-tri methoxybenzaldehyde, dissolved in 20 ml absolute tetrahydrofuran, are added dropwise to the resulting solution and the mixture is stirred at 0°C for a further 30 minutes and then allowed to warm to room temperature. After about 4 hours, it is uorked up analogously to example 5e. Column chromatography of the crude product with petroleum ether/ether (2:1) gives 4.64 g title compound. 1h-nmr (cdci3): 3.83 (s, 9 H); 6-05 - 6.93 (m, 4 H). b) 5,4,,5-Trimethoxyphenylacetylene Using the procedure described in example 5c, 4.60 g product from example 17a and 28-2 mI n-butyIli thium soluti on give 3.47 g crude product. Recrystallization from n-hexane gives 3-09 g title compound in the form of white crystals which melt at 68° - 70°C- 4 5 1H-NMR (COCLj): 2.97 Cs, 1 H); 3.77 Cs, 9 H); 6.60 Cs, 2 H). c) 11-CTetrahydropyran-2!'--yloxy?~1-C3%,4!',,.5a-'trimethoxyphenyl)'-undeca~1,9-di ine The procedure is analogous to example 5d to gi ve, from 1.73 g product from example 17b, 5-65 sal n~butyl lithium solution, 2-10 g 1-i odo-9- (tetrahydropyran-2IB-yloxy)~non-7-ine and 7.5 ml absolute hexamethylphosphoric acid triamide, after column chromatography with petroleum ether/ether C2:1), 1,94 g title compound, 1H-NMR CCDCI3): 1-30 - 1.93 (m^ 14 H); 2-05 - 2,53 Cm. 4 H); 3.27 - 4.03 Cm, 2 H); 3.80 Cs, 9 H); 4.13 - 4.27 Cm, 2 H); 4-67 - 4.83 Cm, 1 H); 6.53 Cs, 2 H). d) 11-Hydroxy-"1"(5 V4'.,5l!'"trimethoxyphenyl)~undeca"1^9'-diine The procedure is analogous to example 5f to give, from 1.91 g product obtained in example 17c, 40 ml absolute ethanol and 0.09 g pyridinium toluene-4-sulphonate, after column chromatography with n-hexane/ether (1:1), 1,38 g title compound. 1H-NMR (cdci3): 1.33 - 1.83 Cm, 9 H); 2.05 - 2.57 Cm, 4 H); 3.80 Cs, 9 H); 4.10 - 4.30 Cm, 2 H); 6.53 Cs, 2 H).
Example 18 H 1 — C5 ■ ,5'-Dimethoxy-4'-hydroxyphenyl)-11"hydro«y-undeca-l,9-di ine a) 4-Ctert-ButyIdimethyI silyloxy?~3,5"dimethoxy~benzaldehyde 2.05 g 3,5-di methoxy-4-hydroxybens:aldehyde and 0.91 g imidazole in 15 ml absolute di methylformamide are reacted with 2.05 g tert-butyldi methyl- chlorosilane under the conditions described in example 14c. The crude product is purified by chromatography on silica gel 60 (0.063 - 0.200 mm) with petroleum ether/ether (1:1), 2.91 g title compound being obtained in the form of crystals which melt at 68°C. 1h-nmr (cdcl3): 0.20 (s, 6 H); 1.03 (s, 9 H); 3.83 (s, 6 H). 7.00 (s, 2 H); 9.67 (s, 1 H). 2-(tert-Butyldimethylsilyloxy)-5-(2'~chlorovinyl)"-1,3-dimethoxy-benzene The procedure is ana logous to example 17a to gi ve, from 2.90 g product obtai ned in example 18a, 4.08 g chloromethyItriphenyIphosphonium chloride and 7.4 ml n-butyllithium solution, after column chromatography with petroleum ether/ether (3:1), 2.74 g title compound. 1h-nmr (CDClg)s 0.13 (s, 6 H); 1.03 (s, 9 H); 3.75 (s. 6 H); 5.97 - 6.83 (m, 4 H). 4-(tert"Butyldimethylsilyloxy)-3,5"dimethoxy-phenyIacetylene The procedure is ana logous to example 5c to gi ve, from 2.72 g product from example 18b and 11.65 m I n-but yllithium soluti on, after purification by chromatography on si lica gel 60 (0.063 - 0-200 mm) with petroleum ether/ether (4:1)^, 1.89 g title compound in the form of crystals which melt at 35° - 38°C. 1H-NMR (cdci3): 0.15 (s, 6 H); 1.03 (s, 9 H); 2.95 (s, 1 H); 3.75 (s, 6 H); 6.63 (s, 2 H). 1-C4'~(tert-butyldimethylsilyloxy)-3',5'-dimethoxyphenyl]-11-(tetra- hydropyran-2'!-y loxy)-undeca-1,9-di ine The procedure is analogous to example 5d to give, from 1.85 g product obtained in example 18c, 3.95 ml n-butyllithium solution, 1.48 g 1~iodo- 4 ? 9-(tetrahydropyran~2E-yloxy)~non-7-ine and 5-3 ml absolute hexamethylphosphoric acid triamide, after column chromatography with petroleum ether/ether (3:1), 1-22 g title compound. 1H-NMR (COClg): 0.13 (s, 6 H); 1.03 (s, 9 H); 1-23 - 1.97 (m, 14 H); 2.00 - 2-50 (m, 4 H); 3-25 - 3.95 (m, 2 H); 3.75 (s, 6 H); 4.13 - 4.30 (m, 2 H); 4.67 - 4.87 (m, 1 H); 6.53 (s, 2 H). e) 1 ~ (38 * 5' -Di methoxy-4»-hydroxypheny I) -11 -hydroxy-undec a-1, 9~di i ne ml of a methanolic solution of hydrogen chloride (3%) are poured, under dry nitrogen, over 1.19 g product obtained in example 18d and the mixture is stirred at room temperature, the compound employed gradually dissolving. (TLC: n-hexane/acetone - 3:2)- When the reaction has ended, the reacti on mixture is poured careful ly into 50 m I saturated sodium bicarbonate solution. It is extracted several times with 30 ml ether each time and the extracts are washed in each case once with saturated sodium bicarbonate solution and sodium chloride solution and dried over sodium sulphate. The crude product obtained by evaporation in vacuo is first pre-purified by column chromatography with n-hexane/acetone (3:2)- HPLC with methanol/water (70:30) then gives 0.428 g title compound. 1H-NMR (CDCl3): 1.23 - 1.83 (m„ 9 H); 2.00 - 2.53 (m, 4 H); 3.80 (s, 6 H); 4-05 - 4.30 (m, 2 H); 5-45 (s, 1 H); 6-53 (s, 2 H).
Example 19 1*i-Hydroxy-1-(3'-hydro3;y-4li"methoxyphenyl)'-undeca"1,,9"di ine a) 4~Bethoxy-3"(tetrahydropyran-2!'--yloxy)-ben^aldehyde .0 g i sovani lli n, suspended in 320 ml methylene chloride^, are reacted with 14.28 ml 3,4-dihydro~2H~pyran in the presence of 0..20 g p-toluene- 4 d sulphonic acid monohydrate analogously to example 5a and the mixture is then worked up. Column chromatography of the crude product with petroleum ether/ether (1:1) gives 24.85 g title compound. 1H-NMR (CDCl3): 1.40 ~ 2.27 (m, 6 H); 3.26 - 4.10 (m, 2 H); 3.87 (s, 3 H); .20 - 5-47 (m, 1 H); 6.60 - 7.56 (m, 3 H); 9.54 (s, 1 H). b) 4~(2t'-Chloroyinyl)-2-(tgtrahydropyran-j2'~yloxy)-anisole The procedure is analogous to example 5b to give,? from 20.0 g chloro-methyItriphenylphosphonium chloride, 6.46 g potassium tert-butylate and 10 9.0 g product obtained in example 19a, after column chromatography with petroleum ether/ether (1:1), 8.43 g title compound. 1H-NMR (cdci3): 1.37 - 2.10 (m, 6 H); 3.30 - 4.13 (m, 2 H); 3.82 - 3.83 (s,s 3 H); 5.11 - 5-37 (m, 1 H); 5-80 - 7.43 (m, 5 H). 1 5 c) 4-f}ethoxy-3-(tetrahydropyran-2'-yloxy)-phenylacetylene The procedure is analogous to example 5c to give, from 2.92 g chloro-v i nyI compound prepared in example 19b and 14-73 m I n-butyllithium solution, after column chromatography with petroleum ether/ethyl acetate (2:1), 2.02 g title compound. 1H-NMR (CDClg): 1.37 - 2.05 (rn, 6 H); 2.87 (s, 1 H); 3.25 - 4.05 (m, 2 H); 3.80 (s, 3 H); 5.07 - 5.33 (m, 1 H); 6.40 - 7.20 (n», 3 H). d) 1-C4'-Methoxy~3"-(tetrahydropyran-2"-yloxy)-pheny13-11-(tetrahydropyran-2E-yIoxy)-unde c a-1,9-di i ne By the process described in example 5d, 1.90 g product from example 19c, 5.11 ml n-butyllithium solution, 2.47 g 1-bromo~9-(tetrahydropyran-2u-y loxy)-non-7-i ne and 5.70 ml 1,3-di methy 1-3,4, 5,6-tetrahydro-2-(1 H)- 4 9 pyri mi di none gi ve, after column chromatography with petroleum ether/ ether (2:1),. 3.14 g title compound. 1H-NMR (CDCl3): 1.20 - 2.53 (m, 24 H); 3.16 - 4.10 (m, 4 H); 3.83 (s^ 3 H); 5 4.13 - 4.27 (m, 2 H); 4.56 - 4.80 (in, 1 H); 5-16 - 5.37 (m, 1 H); 6.43 - 7.07 (m, 3 H). s) 11-Hydroxy-1-(3'-hydroxy-4' -methoxyphenyI)-undeca-1,9~di i ne The procedure is analogous to example 5f to give,. from 3.0 g product from example 19d^. 60 ml absolute ethanol and 0-150 g pyridinium toluene-10 4~sulphonate, after column chromatography with ethyl acetate/petroleum ether (4:3),. 1-61 g title compound in the form of colourless crystals which melt at 77°C to 78°C. 1H-NMR (CDCl5): 1.20 - 1-87 (m, 8 H); 1.98 15 3,93 - 4.23 (m, 2 H); 6.50 Example 20 The procedure is analogous to example 1, but instead of the methyl 5-iodosalicylate a) n-propyl S-iodosalicylate or 20 b) 5-iodosalicylic acid piperidide are used, to give in this way a) 1~(4f-hydroxy-3'-n-propoxycarbonyl~phenyl)-11-hydroxy-undeca~1,.9-diine 1H-NMR (CDCI3): 0.77 - 2.53 (m, 17 H); 5-77 - 4.37 (■», 4 H); 6.40 - 7-53 in, 3 H); 2 5 10.47 (sf 1 H)„ - 2-53 (m^ 4 H); 3-80 isr 3 H); - 7.02 (m, 3 H). and 0 b) l-CA'-hydroxy-S'-CN^N-pantamethylenecarbamoyl)-pheny13-11-hydroxy-undeca-1^9-diine. 1H-NMR CCDCI3): 1.25 - 1.95 (m, 15 H); 1.95 - 2.50 (m, 4 H); 3.35 - 3.70 (m, 4 H); 5 4.05 - 4.23 (m, 2 H); 6.57 - 7.23 (m, 3 H).
Example 21 The procedure is as in example 3r but instead of the ammonia,? 2-amino-ethanol is used to give,, from the ester shown in example 1^, 1~C3"-(2"-* hydroxyethy l-carbamoyl)-4"-hydroxyphenyl3~11-hydroxy-undeca-1/.9-diine. 1H-NMR (CDCI3): 1-16 - 2.53 (m, 12 H); 3.27 - 4.23 (», 6 H); 6.52 - 6.83 Example 22 Usi ng the cor respondi ng start i ng materials, the procedures described^, in 15 particular those explained in more detail in examples 1 - 21, gives a) 11-eye lohexyl~1~ (4"-hydroxy-3"-methoxypheny I )-11-hy droxy-undeca-1, 9- diine; 1H-NMR CCDCI3): 0.71 - 2.73 (m, 23 H); 3.90 - 4.27 (m, 1 H); 3-91 (s, 3 H>; 20 5.63 (s, 1 H); 6.60 - 7.07 (m, 3 H). b) 11-eyclohexyl~1-(3:l,f5"-dimethoxy-4"-hydroxyphenyl)-11-hydroxy-undeea-1,9-diine; 1H-NMR (CDCI3): 0.90 - 1-97 (m, 20 H); 1.95 - 2.47 (m„ 4 H); 3.80 (s, 6 H); 3.80 - 4.17 (m, 1 H); 5.43 (s„ 1 H); 6.47 (s, 2 H). c) 11-cyclohejcyL-1"(3%4'-dihydro>(yphen>'L>"11-hydroxy-undec-9E-en-1~i ne 1H-NMR (CDCI3): 0.85 - 2.53 (m, 24 H); 3.57 - 3-93 (m^ 1 H); 5.10 - 5.80 («, 3 H); 6.13 (s,, 1 H); 6-47 - 6.83 (ra, 3 H>... and from these, by hydrogenation analogously to example 9, d) 11-cyclohexyl-1-(3,/.4,-dihydroxyphenyl)-11-hydroxy-undeca-1Z,9£-diene; 1H-NMR (CDCl-): 0.85 - 2.45 (ra, 23 H); 3.50 - 3-83 (m, 1 H); 5-05 - 6.80 (m, 7 H). e) 1-(4"-hydroxy-5"l-methoxy-3l! -methoxycarbonyl-phenyU-ll-hydroxy-undeca-1,9-diine; 1H-NMR (CDCl^): 1.23 - 2-53 (m, 12 H>; 3-80 (s, 3 H); 3.87 (s, 3 H); 3,93 - 4.23 (m, 2 H); 6.60 - 6.83 (d, 1 H); 7.10 - 7.33 (d, 1 H); .60 (s, 1 H).
Example 23 1 - (3, 4' -Pi hydroxypheny I) -11 -hydroxy-undee-1 Z-en-9-i ne a) 1-(tert-Butyldiphenylsilyloxy)-prop-2-ine 2.9 ml 2-propi n-1-ol, 15.6 ml te rt-butyldiphenylchlorosi lane and 4.1 g imidazole are reacted analogously to example 14c- Chromatography of the crude product over si li ga gel 60 (0.063 - 0.200 mm) with petroleum ether/diisopropyl ether (20:1) gives 13.3 g title compound in the form of crystals which melt at 55 - 58°C. 1H-NMR (CDCl^): 1.07 (s, 9 H); 2.30 - 2.43 (t, 1 H); 4.20 - 4.37 (d, 2 H); 7.15 - 7-75 (n>, 10 H).
EC *> b) 1-Bromo"10-(tert-butyldiphenylsilyloxy)-dec~8~ine The procedure is analogous to example 5e to give,? using 7.36 g product from example 23 a, 15,63 ml n-butyllithium solution, 12,8 ml 1,7-dibromo-heptane and 22 ml absolute hexamethylphosphoric acid triamide,? afer column chromatography with n-hexane/toluene (3:1), 6,96 g title compound. 1H-NMR (C0Cl3): 1.07 (s, 9 H); 1,10 - 2.27 (m, 12 H); 3.20 - 3,50 (t, 2 H); 4.17 - 4-35 (nv 2 H); 7.17 - 7,75 (m, 10 H). c) C10-(tert~Butyldiphenylsi lyloxy)-dec-8-in-1~yU-triphenylphosphonium bromide A solution of 5,66 g product from example 23b and 3.45 g triphenyl-phosphine in 36 ml absolute acetonitrile is heated under reflux for 6 days. It is then evaporated in vacuo and the residue is extracted by shaking five times with diethyl ether and dried over phosphorus pentoxide. 7,44 g title compound are obtained in the form of a hygroscopic solid. 1H-NMR (CDCI3): 1.07 (s, 9 H); 1.05 - 1.83 (m, 10 H); 1.85 - 2.15 (m, 2 H); 3,40 - 3.95 (m,? 2 H); 4-10 - 4-30 (nv 2 H); 7.00 - 7-87 (m, 25 H). d) 1-C3',4"-Bi s~(tert~butyldimethylsilyloxy)-pheny13-11-(tert-butyldiphenylsi lyloxy)-undec"1Z-en~9~ine 4.7 ml n-butyllithium solution are added dropwise to a solution of 5,50 g product from example 23c in 40 ml absolute dimethylsulphoxide and 80 ml absolute tetrahydrofuran at -10°C, while stirring and passing over dry nitrogen. The mixture is subsequently stirred for 15 minutes and a solution of 1.84 g 3,4-bis-(tert-butyIdimethyIsi lyloxy)-benzaldehyde in 5 ml absolute tetrahydrofuran is then added dropwise. After stirring at ~10°C for 1 hour, the mixture is allowed to warm to room temperature and is broken down after a further 4 hours with 20 mI saturated ammonium chloride solution- The crude product obtained during working up (analogously to example 5e) is purified by column chromatography with petroleum ether/toluene (8:1), 1.94 g title compound being obtained. 1H-NMR (CDCIj): 0.20 (s, 12 H>; 0.70 - 1.55 Cm, 35 H); 1.90 - 2.45 (m, 4 H); 4.13 - 4.30 (m, 2 H) ; 4.90 - 6.25 (m, 2 H); 6.50 - 6.80 (m, 3 H); 7.05 - 7-65 (m, 10 H). e) To prepare the 3,4-bis-(tert~butyldimethylsi lyloxy)-benzaldehyde used in example 23d,* 2.14 g 3,4~dihydroxybenzaldehyde, 5.83 g tert-butyl-dimethyIchlorosilane and 2.58 g imidazole ere reacted analogously to example 14c to give^ after chromatography with petroleum ether/ether (6:1), 3.57 g title compound in the form of crystals which melt at 44° -46°C. 1H-NMR (CDCl3): 0.20 (s, 12 H); 0.90 (s, 18 H); 6.60 - 7.20 (m, 3 H); 9.47 (s, 1 H). f) 1 - (3' ,4'-Pi hydroxyphenyI)~11-hydroxy-undec-1Z-an-9-ine The procedure is analogous to example 14d to give, from 3.52 g product from example 23d and 42.8 ml of a solution of tetra-n-butyl-ammonium fluoride in tetrahydrofuran (1 mol/l), after column chromatography with petroleum ether/ethyl acetate (1:1) and HPLC purification with methanol/water (6:4), 1.29 g title compound. 1H-NMR (CDCl3): 1.10 - 1.67 (bi, 8 H); 1.90 - 2.45 (m, 5 H): 4.07 - 4.30 (ra, 2 H); 5.15 - 6.83 (m, 7 H).
Example 24 1-(45-Hydroxy~3'-methoxyphenyl)~11-hydroxy-hexadeca-1,9~diine 2-70 g product from example 5c are reacted with 1,6-dibromohexane analogously to example 13a, the resulting 8-bromo-1-C3s-methoxy-4'-(tetra- hydropyran-2,e-yloxy)-phenyl!!~oct"1"ine is reacted with lithium acetylide- ethylenediamine complex analogously to example 15a, the product is then reacted with n-hexanaI analogously to example 16a and finally the protective group is split off, analogously to example 5f, from the 11-hydroxy-1-C3l"-methoxy~4"-(tetrahydropyran-2"'-yloxy)-phenyU-hexadeca-1,9-10 diine thus obtained. Column chromatography of the crude product with ether/petroleum ether (1:1) gives the pure title compound. 1H-NMR (CDCl3): 0.56 - 2.55 (m, 23 H); 3.77 (s, 3 H); 3.97 - 4.40 (m, 1 H); -43 (s, 1 H); 6.51 - 6.77 (tn, 3 H). 1 5 Example 25 11-Cyclohexyl-1-(3*',5'J"dimethoxy"49"hydroxyphenyl)"11"hydroxy-undec-9E-en-1-i ne 4-(tert"butyldiphenylsilyloxy)-3,5-dimethoxy-phenylacetylene Using 3,5-di methoxy-4-hydroxybenzaIdehyde and tert-butyldi pheny Ich loro-20 si lane and the other starting materials mentioned in examples 18a - c and the procedures described therein, the title compound is obtained in the form of crystals which melt at 83° - 85°C. 1H-NMR (CPCI3): 1.07 (s, 9 H); 2.83 (s, 1 H); 3.33 (s, 6 H); 6.40 (s, 2 H); 25 6.97 - 7.60 (m, 10 H)„ b) 1-C4'~(tert-ButyLdiphenylsi lyloxy)-3V5'J-dimethoxyphenyl3~9-(tetra-hydropyran-2"-yloxy)-non-1-ine Ths procedure is analogous to example 5d to give,? from 14.58 g product from example 25a, 21.9 sal n-butyllithium solution,. 6.98 g l-bromo-7-(tetrahydropyran-S'-yloxy)~heptane and 55 ml absolute hexamethyIphos-phoric acid triamide,, after column chromatography with petroleum ether/ ether (5:1), 10.27 g title compound. 1H-NMR (CDCI-): 0.75 - 1-90 (m, 16 H); 1.07 (s, 9 H); 2.10 - 2.47 (m, 2 H); 3.07 - 3.97 Cm,- 4 H); 3.35 (s, 6 H); 4.37 - 4.57 (m, 1 H); 6.30 (s, 2 H); 6-97 - 7.65 (m, 10 H). c) 1-C4'-(tert-Butyldiphenylsi lyloxy)-5 VS'-dimethoxyphenyU-Q-hydroxy-non-1-ine From 10.22 g product obtained in example 25b, 130 ml absolute ethanol and 038 g pyridinium toluene*-4~sulphonate, analogously to example 5 f and after column chromatography with petroleum ether/ethyl acetate (1:1), 70.98 g title compound are obtained- 1H-NMR (CDCl3): 1.07 (s, 9 H); 1-15 - 1.80 (m, 11 H); 2.10 - 2.50 (mt? 2 H); 3.33 (s, 6 H); 3.35 - 3.70 (m, 2 H); 6.30 (s, 2 H); 6.97 - 7.65 (m, 10 H). d) 1-C4'-(tert-Butyldiphenylsilyloxy)-3',5'-diroethoxyphenyl3-non~1~in-9-al 0.37 g anhydrous sodium acetate and then, in portions, 0.75 g pyridinium ch lorochromate are added to a solution of 1.20 g product obtained in example 25c in 22.5 ml absolute methylene chloride at room tewperature, while sti rri ng and passi ng over dry ni trogen. The reacti on has ended after about 2 hours. (TLC: petroleum ether/ether - 1:1). The mixture is f i Itered, the filtrate is concentrated to a volume of about 2 ml and the concentrate is chromatographed with petroleum ether/ether (3:2), 6 0.87 g title compound being obtained. 1H-NMR (CDCl3): 1.07 (s, 9 H); 1.15 - 1-83 (m, 8 H); 2.10 - 2.57 (m, 4 H); 3.33 (s, 6 H); 6.30 (s(, 2 H); 6,97 - 7.67 (m, 10 H); 5 9.57 - 9.70 (t, 1 H). e) 1-C4'-(tert-Butyldiphenylsilyloxy)~3',5'-di methoxypheny13-11-cyclo~ hexy 1-11-oxo-undec--9E-en-i-ine 1.15 ml n-butyllithium solution are added dropwise to a solution of 0.45 g dimethyl (2-cyclohexyl-2-oxoethyl)-phosphonate in 15 ml absolute tetrahydrofuran, while stirring and passing over dry nitrogen, such that the internal temperature remains below 5°C. The mixture is subsequently stirred for 15 minutes and a solution of 0.85 g product from example 25d in 7.5 m I absolute 1,2~di methoxy ethane is then added dropwise at the same temperature. The reaction mixture is stirred for a further 2 hours, during which it is allowed to warm to room temperature^ and is then broken down with saturated ammonium chloride solution and worked up analogously to example 5e. Column chromatography of the crude product with petroleum ether/ether (5:1) gives 0-78 g title compound. 1H-NMR (CDCl3): 0-90 - 2.50 (m, 23 H); 1.07 (s, 9 H); 3.33 (s, 6 H); .83 - 6-95 (m, 2 H); 6-30 (s, 2 H); 7.00 - 7-67 (m, 10 H). f) 1-C4s-(tert-Butyldiphenylsilyloxy)-3',5'-dimethoxypheny13-11-cyclohexy 1-11 -hydroxy-undec-9E-en"1 -ine The procedure is analogous to example 15c to give, from 0.74 g product 25 from example 25e in 3 ml of a soluti on of cerium (III) chloride in methanol (0.4 mol/l) with 0.049 g sodium borohydri de, after column chromatography with petroleum ether/ether (2:1), 0.70 g title compound. 1h-nmr (cdci3): 0.80 - 2-45 (m, 24 H); 1.07 (s, 9 H); 3.33 (s, o H); 1 0 .7 3-50 - 3.83 (in, 1 H); 5.05 - 5.60 (m, 2 H); 6.30 Cs,, 2 H): 6.97 - 7-67 (m, 10 H). g) n~Cyclohexyl~1~(5',5'-dinethoxy~4'~hydroxyphenyl)-n-hydroxy~undec-9E-- en-1-ine The procedure is analogous to example 14d but is carried out at room temperature to give, from 0.64 g product from example 25f with 3 ml of a solution of tetra-n-buty lammonium fluoride in tetrahydrofuran,, after column chromatography with petroleum ether/ethyl acetate G:E), 0-36 g title compound. 1H-NMR (CDCI-): 0.75 - 2.53 (m, 24 H); 3-55 - 3.90 (m, 1 H); 3-80 (s, 6 H); -07 - 5.70 (m, 3 H); 6.47 (s, 2 H).
Example 26 1-(3',4'~Dimethoxyphenyl)"1i"hydroxy~undec-1E-en-9"ine and the 1 5 corresponding 1Z-Isomer a) 10-(tertH3utyldiphenylsilyloxy)-dec~8-in-l-al Using 8-87 g product from example 23a, 118.8 ml n-butyllithium solution, 6.73 g 1~bromo-7-(tetrahydropyran-2s~ylQxy)-heptane and 28-5 ml absolute hexamethylphosphoric acid triamide, 8.92 g 1-(tert-butyldiphenylsi lyl-20 oxy)"10~{tetrahydropyran-2s--yloxy)"dec-2-ine are obtained analogously to example 5d, from which the protective group is split off analogously to example 5f. The 1-(tert~butyIdi phenyl-si lyloxy)-l0~hydroxy-dec-2-ine thus obtai ned is then oxidised analogous ly to example 25d to give the title compound, which is purified by chromatography with petroleum 25 ether/ether (2:1). 1H-NMR (CDCI3); 1.07 (s, 9 H); 1.10 - 1.77 (ra, 8 H); 1.93 - 2-53 (m, 4 H>; 4.10 ~ 4.27 (t, 2 H); 7.05 - 7.63 (m, 10 H); 9.40 - 9.55 (t, 1 H). 58 11"(tert-ButyIdiphenylsi lyloxy)~1~(3 '<.4'"dimethoxyphenyl?-undec-1E<,Z"-en-9-i ne 0.392 g potassium tert-butylate is added in portions to a suspension of 1.571 g 3„4-di methoxybenzyItriphenylphosphonium chloride in 8 ml absolute tetrahydrofuran at 2 to 5°C, while stirring and passing over dry nitrogen™ The mixture is stirred for 30 m i nutes, a solution of 0.841 g product from example 26a in 3 ml absolute tetrahydrofuran is added dropwise in the course of 5 minutes and after a further 60 minutes the mixture is diluted with about 15 ml ethyl acetate. The mixture is washed in each case once with saturated solutions of ammonium chloride or sodium chloride and then dried over sodium sulphate and evaporated. Column chromatography with ether/petroleum ether (1:10) gives 0.698 g title compound. 1H-NMR (CDCg): 0.12 - 2.43 (m, 21 H); 3-77 (s, 6 H); 4.03 - 4.23 (m, 2 H); .11 - 6.73 (tn, 5 H); 6.91 ~ 7.67 (m, 10 H). 1-(3E^4e"0i methoxyphenyl)-'11"hydroxy"undec-1E^Z"en-9"ine and the corresponding 1E" and IZ-i somer The procedure is analogous to example 14d to give,, from 0.452 g product from example 26b with 1-26 ml of a soluti on of tetra-n-buty lammonium fluori de in tetrahydrofuran, after column chromatography with ether/ petroleum ether (2:1), 0.223 g title compound. 1H-NMR (CDCl3): 1.13 - 2.51 (m, 12 H); 3.80 (s, 6 H); 3-94 - 4.23 (m„ 2 H); .10 - 6.37 (m, 2 H); 6-43 - 6-73 (m^ 3 H).
The isomer mixture obtained in the synthesis of the title compound can be resolved by HPLC with methanol/water (7;3) to isolate the IE- and the 1Z—isomer: 9 1E-Isomer: 1H-NMR (CDClj): 1.10 - 2.50 Cm, 3.87 - 4-27 Cm, 6.40 ~ 6.75 Cm, IZ-Isoiner: 1H-NMR CCDCL): 1.10 - 2.50 Cm, 12 H); 3.73 Cs, 6 H); 3.90 - 4.20 Cm, 2 H); .10 - 6.30 Cm, 2 H; : 11 Hz); 6.37 - 6.70 Cm, 3 H).
Example 27 1-C3',5'-Dimethoxy-4'~hydroxyphenyl)--11-hydroxy-undec~9Z-en-1-ine a) 9-Bromo~1-C4"--Ctert"butyLdiphenylsi lyloxy)-3",5'~diit)ethoxyphenyl]~non-1-ine 6.74 g carbon tetrabromide are added in portions to a solution of 6.11 g product from example 25c and 5.33 g triphenylphosphine in 230 ml absolute methylene chloride at 0°C, whi le stirring and passing over dry nitrogen. After the mixture has been sti rred for two hours, it is evaporated in vacuo and 240 ml petroleum ether and 12 ml ether are added to the residue. The mixture is filtered, the fiItrate is evaporated and the residue is purified by column chromatography with petroleum ether/ ether C20:1), 6.47 g title compound being obtained. 1H-NMR CCDCl3): 1.07 Cs, 9 H); 1.20 - 2-03 Cm, 10 H); 2.15 - 2.50 Cm, 2 H); 3-17 - 3.47 Cm, 2 H); 3-33 Cs, 6 H); 6.30 Cs, 2 H); 7.00 - 7.65 Cm, 10 H). 12 H); 3.73 Cs, 3 H); 3.77 Cs, 3 H); 2 H); 5.53 - 6.33 Cm, 2 H, 3J : 15 Hz); 3 H). 2~(tert"Butyldiphenylsi lyloxy)"-acet aldehyde .15 g glyclolaldehyde and 26.78 ml tert-butyIdiphenylchlorosi Lane are reacted in the presence of 7»61 g imidazole and 26 ml absolute dimethyL-formamide under the conditions described in example 14c to give,, after column chromatography with ether/petroleum ether (1:2), 21-26 g title compound, 1H-NMR (C0C13): 1.10 (s, 9 H); 4.07 (d, 2 H); 6.73 ~ 7.56 (m, 10 H); 9.30 (t, 1 H). 11-(tert."ButyIdiphenylsilyloxy)-1-C4'~(tert.,-buty ldiphenylsilyloxy)-5 ",5B~dimethoxyphenyLII--undec-9Z"en-1-ine 6*38 g product from example 27a and 3.13 g triphenylphosphine are reacted analogously to example 23c and 3.42 g resulting product are then reacted with 2.5 ml n-butyllithium solution and 0.90 g aldehyde shown in example 27b analogously to example 23d. Column chromatography ui th petroleum ether/ether (20:1) gives 1.74 g title compound. 1H-NMR (cdci3): 0.75 ~ 2.45 (m, 30 H); 3-33 (s, 6 H); 4.05 - 4-23 (m, 2 H); .13 - 5.63 (m, 2 H); 6-30 (s, 2 H); 6.97 - 7.67 (m, 20 H). 1~(3a,5-Dimethoxy-4s-hydroxyphenyl)-11-hydroxy-undec-9Z--en-1-ine Splitting off of the protective group from 1.71 g product obtai ned in example 27c with 12,.9 ml of a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 mol/l) analogously to example 14d gives, after column chromatography with petroleum ether/acetone (1:1), 0.625 g title compound, which melts at 74° - 76°C. 1h-nmr (cdci3) : 0.95 - 2-50 (m, 13 H); 3-80 (s, 6 H); 3.93 0 4.23 (m, 2 H); .15 - 5.70 (m, 3 H); 6.50 (s, 2 H)-

Claims (1)

CLAIMS; 1) Phenol derivatives of the general formula or c -(a)- (cH2)s ~ '3 1 in which A and B are identical or different and each represent one of the groups -C=C-> cis-CH-CH- or trans-CH=CH-> R.j denotes hydrogen or a straight-chain alkyl radical with 1 to 6 carbon atoms,, or a 5- to 7-membered cycloalkyl group, or a group of the formula ~CCH2>m~0-R^ wherein m represents one of the numbers 2 or 3 and R^ represents methyl or ethyl, or wherein X represents a single bond, a -CHg- group or a -CHjQ- group and Rg denotes a hydrogen,, chlorine or fluorine atom or a methyl,, methoxy or trifluoromethyI group and n represents one of the numbers 1 or 2, Rg represents hydrogen, methyl or ethyls Rj denotes hydrogen or an acetyl or propionyl radical, R4 represents hydrogen,, an acetyl or propionyl radical or a straight-chain or branched alkyl radical Rq with 1 to 4 carbon atoms, a group of the formula 6 2 Rg represents a group of the formula -COOR-jq, wherein R-j q is a hydrogen atom,, a pharmaceutically tolerated cation, in particular a monovalent cation,, a straight-chain or branched alkyl radical with 1 to 6 catbon atoms or the group -(CHgJp-M-CCCF^Jp-CHgll?, in which 5 p represents zero or one of the numbers 1 to 3, and of (sic) pharmaceutical^ tolerated salts of these basic esters with acids,, or represents a group of the formula /R11 -co - n 12 10 wherein R^ and R^j> are identical or different and represent hydrogen,, the alkyl radical Rq or 2-hydroxyethyI, or one of these radicals denotes a hydroxyl group and the other denotes hydrogen, or R-j-j and taken together represent the group -(CHjOq"? in which q represents one of the numbers 4, 5 or 6, or 15 represents a group of the formula .Cch2)p-ch3 or, /^"2'P ■co — n 13 wherein R^ represents hydrogen,, "(CHgJp-CH^ carboxymethy I,, acetyl or propionyl and p in each case has the same meaning as above,, or represents a group of the formula wherein r 20 represents one of the numbers 2 or 3, or pharmaceuti cally tolerated salts thereof with acids, or represents a group of the formula - co - n in which V denotes an oxygen atom or the group ^N-CHj, or if appropriate pharmaceuti cally tolerated salts thereof with acids, or represents a nitrile radicaI, or represents a hydroxyl, acetoxy or propi onyloxy group,, an alkoxy group OR9, in which Rq has the same meaning as above, or - taken together with OR* - represents the methylenedioxy group and R^ represents hydrogen, a hydroxyl, acetoxy or propionyloxy group, the alkyl radi cal Rq of «*n alkoxy group ORq, wherein Rq in each case has the same meaning as above- Phenol derivatives of the formula R2 ^ R5 -c-csc—(CH,)rCHC-/_V-OH ,, or, c 3 ~FL wherein to R3 and Rg and have the same meaning as in claim 1. Phenol derivatives of the formula k h h h h y—rc^s |2 j 1 ii c ~ c = c ^ /c~c \_/°h j" 0r3 (ch2)s wherein R-j to R- and Rg and have the same meaning as in claim 1. Phenol derivatives of the formula 8 4 2 Ri — C —C^)— ~ ^ 2 '6 OR. wherein R-j to Rg and R^ and A have the same meaning as in claim 1, Phenol derivatives of the general formula R1 ~~ ?H ^CH2^6 oh wherein R-p R4 to R^, A and B have the same meaning as in claim 1. Phenol derivatives of the formula r1 — ch 1 1 oh in which R-j denotes a hydrogen atom, a straight-chain alkyl radical with 1 to 6 carbon atoms or a phenyl or eyelohexyI radical and R,. to ■+ have the same meaning as in claim 1„ Phenol derivatives according to claims 1 to 6f in which represents a hydrogen atom or a methoxy group. (CH2)5-CSC Phenol derivatives according to claims 1 to 7, in which R^ represents /(CH2VCH3 one of the groups -OH,, -oro*- -co-n „ -CO-N or \ ' \ 12 ^13 •co-n wherein R^ R-j-j to P and Y have the same meaning as in claim 1. 8 5 9) Phenol derivatives according to claims 1 to 8, in which R5 represents /CH3 one ot the cjroups "OH^ •"•OCH's or -co-n \ oh 10) Medicament, characterised in that it contains as the active ingredient at least one of tha phenol derivatives corresponding to claims 1 to 9 5 and is suitable for parenteral, oral, intranasal, percutaneous or rectal administration., 11) Medicament according to claim 10, characterized in that it contains as the active ingredient 0.01 to 50 rag of a phenol derivative corresponding to claims 1 to 9 per individual dose. 10 12) Medicament according to claims 10 and 11, characterized in that is is suitable for parenteral administration and contains 0.01 to 10 mg of a phenol derivative corresponding to claims 1 to 9. 13) Medicament according to claims 10 and 11, characterized in that it is suitable for oral administration and contains 0-1 to 50 mg of a phenol 15 derivative corresponding to claims 1 to 9- 14) f-iedi cement according to claim 15 for oral admi ni strati on, characterised in that it is in the form of tablets, coated tablets or capsules,, if appropriate with delayed release of the active ingredient. 20 15) Medicament accor di ng to claim 10 for intranasal, oral or peroral administration of a phenol derivative corresponding to claims 1 to 9 in spray form. 16) Medicament accordi ng to claim 10 for percutaneous admini strati on, consi sting of a reservoir which is to be applied to the ski n and 25 contai ns a phenol derivative correspondi ng to claims 1 to 9 in dissolved form, preferably with the addition of agents which promote penetration of the skin- b o 10 17) Process for the preparation of the medicaments according to claims 10 to 16*. characterised in that the phenol derivatives corresponding to claims 1 to 9 are processed in the customary manner with excipient materials, solvents and/or diluents and if appropriate binders, tablet disintegrating agents and other customary auxiliaries and the individual dosage forms are produced from the resulting mixture. 18) Process for the preparation of the phenol derivatives of the formula I from claim I, characterised in that A) a compound of the general formula II L OR, 2 ri ~ ? ~(Ey (ch2' 17 in which A, B, and Rg have the same meaning as in formula I, represents the alkyl radical R0 or a protective group which can be r split off under mild conditions, represents the group OR^ or has the same meaning as R5, with the proviso that in this radical 15 R-jg cannot represent a cation and the basic groups which may be present in R5 cannot be in salt form, or R-j 5, taken together with the group OR^, represents a methy lenedi oxy group, R^ denotes a hydrogen atom or one of the groups Rq or 0R-|4 and 7 is a protective group which can be split off under mild conditions, is 20 prepared 1) by reaction of a compound of the formula h R C—C^C — Me in • 1 0R17 wherein R^, R^ and R-jy have the same meaning as above and Me represents a lithium, sodium or potassium atom or one of the 25 radicals -MgBr or 0 7 with a compound of the formula '"l5 r,8-(Ch2)6H ^0R14 iv in which B and to have the same meaning as above and R^g represents a bromine or an iodine atom, 5 at temperatures of about -80° to +75°C in an inert, aprotic solvent, if appropriate in the presence of catalytic amounts of a copper salt, or 2) by reaction of a compound of the formula IV, in which R^-represents the group OR^, with a compound of the formula r2 10 R1~?~C = C - Me" Ilia OR,? wherein R^, R2 and R^j have the same meaning as above and Me' represents a lithium, sodium or potassium atom, in liquid ammonia at temperatures of about ~80°C to -35°C, or 3) by reaction of a compound of the formula 15 R,-f-®-6-R18 V OR,? in which A, R-j, Rg, R-j^ and R^g have the same meaning as above, with a compound of the formula /r^C R*5 Me" — C ^ C —(f X>—0R14 VI 16 wherein R-^ to R-j^ have the same meaning as above and He" represents one of the groups He or Me" defined above,, under the conditions mentioned above for 1 or 2r or (if the group A in the compound of the formula II represents -CH=CH~) i) by treatment of a compound of the formula ?2 r, ~ c — ch2 _ p(c6hs)3 — r19 vii 0R17 in which R^ Rj and have the same meaning as above and R7 ix wherein B, u to R16 and R^o have the same meaning as above, HR^ being split off,, with an aldehyde of the formula Ro .0 i2 # R. — C —C X ' i \ 0R17 H 5 wherein R-j, R2 end R17 have the same meaning as' above,. at temperatures of about ~80°C to +30°C in the presence of an inert solvent, or 5) Ci f the group B in the compound of the formula II represents -CH=CH~> 1 0 i) by reaction of a phosphorane formed from the compound of the formula _R9 Rl —C —(TV-(ch2)7 — P(c6H5)3 — Rig XI
1. ori7 wherein A, R-j^ R?, and have the same meaning as above 15 by the action of a base and splitting off of HR^y, with an aldehyde of the formula wherein R-j/ to R-.^ have the same meaning as above 70 at temperatures of about -80°C to +30°C in the presence of an inert solvent, or ii) by reaction of the phosphorane obtained by the action of a base on the compound of the formula /r^rRl5 R19~(C6H5)3?~CH2 •~\==/"0RU Xm r.„ 1o wherein to and have the same meaning as above with an aldehyde of the formula R9 >.0 R1 _ (ch2)6 - C\ xrv or, 7 « in which A, R-j, Rg and R-j^ have the same meaning as above 10 at temperatures of about ~80°C to +30°C in the presence of an inert solvent and the protective groups contained in R^ to R^ are split off from the resulting compound of the formula II in a manner which is known per se and if appropriate - if at 15 least one of the radicals Rg and R4 or R5 and R^ is to represent or contain an acetyl or propionyl radical - one or more acetyl or propionyl group(s) is/are introduced^ or 8) a compound of the formula R? ~ ^2^6 ^ SCH XV OR20 7 1 wherein A, R-j and Rg have the same meaning as above and R2q represents a hydrogen atom or has the same meaning as is reacted, in the presence of a secondary or tertiary amine which is liquid at about -10°C to +80°C and catalytic amounts of a 5 complex palladium catalyst and if appropriate catalytic amounts of copper(I) iodide at about 0°C to 75°C, with a compound of the formula wherein R^g has the same meaning as above,*, R2-j denotes a hydrogen 10 atom,, the alkyl radi cal R9 or a protective group which can be split off under mi Id conditions, R22 represents the group 0R21 or has the same meaning as R5, with the provi so that in this radi cal R«g cannot represent a cation and the basic groups which may be present in R5 cannot be in salt form, or R^ taken tc/gether with the group 15 ORg-j^ represents a niethylenedioxy group and R2^ has the same meaning as R^ or represents a hydroxyl group, and the protective groups contained, if appropriate,, in R2q to R2g are split off from the resulting compound of the formula R9 / n22 R1 - f-Q- 6-CSC -f_V 0R21 XVII . ^ r23 20 and if appropriate - if at least one of the radicals Rj and RA or R5 and is to represent or contain an acetyl or propionyl radi cal - one or more acetyl or propionyl group(s) is/are introduced, or C) a compound of the formula 7«> Me — C — C (CH„), v 2D XVIII wherein Me, B and to R^ have the same meaning as above,. is reacted in the presence of an inert solvent at about -80°C to +30°C with a compound of the formula 0 ~ C /R2 R„ XIX in which R-j and R2 have the same meaning as above to give a compound of the formula / vv aa wherein A, B, R-j, R2 and R-j* to have the same meaning as above 10 and the protective groups contained, if appropriate^ in R-j^ to R^ are split off from the reaction product and - if at least one of the radicals Rg and R* or Rg and is to represent or contain an acetyl or propionyl radical ~ one or more acetyl or propionyl groups is/are introduced^, or 15 d) a compound of the formula Rj — C ~(T)~ (CH2)6-(7j 0 XXI in which A, B and R^ to R-j^ have the same meaning as above and RJ| 7 3 has the same meaning as R-j, with the exception of hydrogen, is prepared 1) by treatment of a compound of the formula tCH3(CH2V°]2 " « " CH2 ~ J " Ri XXII 0 0 wherein p and R| have the same meaning as above, with an anhydrous base in an inert solvent and subsequent reaction with a compound of the formula VIII at temperatures of about -10°C to +35% or 10 2) by reaction of a compound of the formula XXIII in which B and R-ja to have the same meaning as above, in the presence of a tertiary amine with a boiling point above about -rS0°C and catalytic amounts of a complex palladium 15 catalyst and if appropriate catalytic amounts of copper(I) iodide at about 0°C to 75°C, with a compound of the formula R-io — C — R°( XXIV jy u s wherein RJj and R<|q have the same meaning as above, 20 and this compound of the formula XXI is converted into the corresponding compound of the formula I (in which R<| and if r> A 4 *3 appropriate R2 are other than hydrogen) by reduction with a metal borohydride or by reaction with a compound of the formula R 2~ M e, wherein He has the same meaning as above and has the same meaning as R2<» with the exception of hydrogen^ subsequent splitting 5 off of protective groups present in R^ to R-j^ and if appropriate - if at least one of the radicals R^ and R^ or R^ and R^ is to represent or contain an acetyl or propionyl radical -introduction of one or more acetyl or propionyl groups,*. and the radicals and R^ or R22 in the compounds obtained 10 according to A., B, C or D are converted into the desired group Rg and/or if appropriate triple bonds present therein are hydrogenated cata lyti ca I ly to give double bonds,. 19) Process according to claim 18,. characterised in that the protective groups represented by R^ R^ R2q or R21 or contained in R^ and R22 15 are identical or different representatives from the group comprising the tetrahydropyran-2~yl radical^ the tert„~butyldimethylsilyl radical and the tert„-butyIdiphenyIsilyl radical- 20) Process according to claims 18 and 19^ characterised in that procedures A1 and A3 are carried out in the presence of a dipolar 20 aprotic solvent and a copperCl) salt™ 21) Process according to claims 18 and 19, characterized in that n-butyllithium, potassium tert.-butylate or sodium bis-Ctrimethylsilyl)-amide is employed as the anhydrous base for the phosphorane formation by splitting off HR^ in procedures A4 and A5» 25 22) Process according to claims 18 and 19, characterized in that bi s- (triphenylphosphine)~palladium(II) chloride or acetate or tetrakis-(triphenyIphosphine)-paIladium are employed as the complex palladium catalyst in procedures B and D2 and these procedures are carried out in the presence of a triaIkylamine with 2 or 3 carbon atoms in each of 30 the alkyl radicals,., with a compound of formula I in which Rg represents a) an esterified carboxylic group -C00R.(q wherein R^g is the alkyl group Rg or the group -(CH^t(CHg)p~CH3]2s or b) an unsubstituted carboxylic group COOH, said reaction being performed in presence of an agent capable to split off water, or with an intermediately formed reactive functional derivative of the carboxylic group- 23 )A phenol derivative of the general formula I given and defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, substantially as hereinbefore described with particular reference to the accompanying Examples. 24 )A process for the preparation of a phenol derivative of the general formula I given and defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof p substantially as hereinbefore described with particular reference to the accompanying Examples. 25)A phenol derivative of the general formula I given and defined in claim 1 or a pharmaceutically acceptable acid addition salt thereoff whenever prepared by a process claimed in a preceding claim. 26) A medicament according to claim 10,, substantially as hereinbefore described. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.
IE74586A 1985-05-23 1986-03-21 New phenol derivatives, pharmaceutical compositions containing these compounds and processes for the preparation of these compounds and compositions IE58359B1 (en)

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