FI94342B - Process for the preparation of new alkanophenones - Google Patents

Abstract

Substituted alkanophenones of the general formula <IMAGE> in which R1 denotes optionally fluorinated lower alkyl, R2 represents hydrogen, optionally fluorinated lower alkyl or lower alkenyl, X denotes lower alkylene, oxy, thio or a direct bond, alk represents lower alkylene, n stands for 1 or 2, R3 denotes phenyl which is unsubstituted or substituted by optionally fluorinated lower alkyl, etherified or esterified hydroxyl, optionally lower alkylated amino and/or optionally esterified or amidated carboxyl or denotes lower alkyl which is optionally fluorinated or substituted by optionally esterified or amidated carboxyl, R4 represents optionally esterified or amidated carboxyl or 5-tetrazolyl and R5 stands for hydrogen or lower alkyl, have leukotriene-antagonist properties and can be used as antiallergic pharmaceutical active compounds. The process for their preparation is characterised in that an epoxide of the formula <IMAGE> in which R1, R2, X, alk, n and R3 have the above meanings, is reacted with a thiol of the formula <IMAGE> in which R4 and R5 have the above meanings, or a salt thereof and, if desired, a compound obtainable according to the process is converted into another compound of the formula I, a stereoisomer mixture obtainable according to the process is resolved into the components and/or a free compound obtainable according to the process is converted into a salt or a salt obtainable according to the process is converted into the free compound or into another salt.

Description

Q A 7. A n y η ο δ.

Process for the preparation of new alkanophenones For the preparation of new alkanophenones

The invention relates to a process for the preparation of novel general formula I.

2

/ \ / \ QH

R1 i -H-X-alk- (CH = CH) -CH-CH-R3 (I), »'Y" 1 AA, k; i. Substituted alkanophenones according to rRu • · · ^ \ / • · ö and their to prepare salts wherein C 1 -C 4 alkyl or fluorinated C 1 -C 4 alkyl, R 2 represents hydrogen, C 1 -C 4 alkyl or fluorinated C 1 -C 4 alkyl, X represents branches or thioa represents C 1 -C 4 alkyl. -C 1-6 alkylene, n is 1 or 2, R 3 represents unsubstituted or substituted by C 1-4 alkyl, fluorinated C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl and / or halogen, or R3 represents C1-C7-alkyl, ω, ω, ω-trifluoro-C1-C7-alkyl, carboxy-C1-C4-alkyl or C1-C4-alkoxycarbonyl-C1-C4-alkyl and R4 represents carboxy, C1- C4 alkoxycarbonyl or N- (benzenesulfonyl) carbamoyl.

The state representation of the above formula I is to be understood for the preferred compounds in which the o atom of the hydroxyl group is in relative trans configuration with the S atom, so that the symbols in the first row are above the representation level, the symbols in the third row are below it (or vice versa). , which corresponds to the opposite configuration (RS) - (SR) for the formula shown in the Kahn-In- · gold-Prelog agreement on a carbon atom (CS-) connected to a sulfur atom and a carbon atom containing a hydroxy group (C-OH). In this case, when n is 2, enantiomers of the S (CS -), R (C-OH) configuration are highly preferred, and when n is 1, R (CS -), S (C- Enantiomers having the OH) configuration. In the vinylene or vast, buta-1,3-dienylene residue represented by the symbol - (CH = CH) n, a double bond or a double bond from the C atom attached to the butadiene residue of alk, but preferably in the cis configuration, is preferably, though not necessarily, present, conventionally denoted by the symbol (Z), the second double bond then preferably, though not necessarily, having the trans configuration, conventionally denoted by the symbol (E).

Optionally fluorinated C 1 -C 4 alkyl is C 1 -C 4 alkyl or mono-, di- or polyfluoro-C 1 -C 4 alkyl.

C1-C7-alkyl is in particular straight-chain C1-C4-alkyl, such as methyl, ethyl, propyl, isopropyl, butyl or sec-butyl. but it may also be branched C1-C4 alkyl, such as isobutyl or tert-butyl or a pentyl, hexyl or heptyl residue. C1-C4-alkyl is, for example, methyl, C1-C4-alkyl R2 is, for example, propyl, and C1-C4-alkyl R3 is in particular C3-C7-alkyl, e.g. propyl, butyl or pentyl.

Mono-, di- or polyfluoro-C1-C4-alkyl has, for example, up to 5 fluorine atoms and is, for example, mono-, di- or trifluoro-C1-C4-alkyl, in particular ω-fluoro or ω, ω, ω-trifluoro -C 1 -C 4 alkyl such as trifluoromethyl, 2,2,2-trifluoroethyl or 3,3,3-trifluoropropyl. Fluorinated C 1 -C 4 alkyl R 1 and the substituent of phenyl R 3 are in particular trifluoromethyl and fluorinated C 1 -C 7 alkyl R 3 is in particular ω, ω, ω-trifluoro-C 2 -C 4 alkyl, e.g.

3.3.3-trifluoropropyl.

C 1 -C 6 alkylene is, for example, straight-chain, the residue alk being in particular C 2 -C 6 alkylene, such as ethylene, 1,3-propylene, 1,4-butylene, further 1,5-pentylene or 1,6-hex. syleeni.

94342 3 C1-C4-Alkoxy is, for example, methoxy.

C1-C4-Alkoxycarbonyl is, for example, methoxy, ethoxy, propyleneoxy or butyloxycarbonyl.

Halogen is, for example, halogen having an order number of up to 35, such as fluorine, chlorine or bromine.

Most of the compounds of formula I may also exist in the form of salts according to their individual nature. Those with sufficient acidity, such as in particular those having carboxyl, tetrazolyl or sulfamoyl groups, can also form salts with bases, in particular with inorganic bases, in particular physiologically acceptable alkali metal salts, in particular sodium or potassium salts. However, ammonium salts formed with ammonia or physiologically tolerable organic amines, such as mono-, di- or tri (hydroxyalkyl) amines, such as tris- (hydroxymethyl) methylamine or D-glucosamine, can also be used.

The compounds of formula 1 and their salts have advantageous pharmacological properties, in particular excellent leukotriene antagonism.

Thus, for example, they inhibit leukotriene D4 (LTD4) -induced smooth muscle contraction in vitro in the concentration range of about 0.001 to 1.0 μπ »οο1ΐβ / 1: η. This so-called LTD4 antagonism is demonstrated experimentally, e.g., as follows:! The segments taken from the ileum of a guinea pig weighing 300 to 400 g and incubated in an organ bath in Tyrode's solution at 38 ° C and gassing with a mixture of 95% oxygen and 5% carbon dioxide at a load of 1 g are triggered with synthetic leukotriene D4 ( potassium salt) contractions (contractions) and recorded isoto- 4 g Ait19 s -tu η Δ.

cally. The amount of inhibition induced by the test substance is determined after pre-incubation for 2 minutes and evaluated as IC 50, i.e. at a concentration that reduces test contraction by 50%. The compounds of formula I are also very effective in vivo. In addition, they have a specific and therapeutically very significant advantage over a relatively long period of action. Thus, a clear LTD4 antagonistic effect could be demonstrated in an in vivo standard bronchoconstriction test in a guinea pig by aerosolizing a solution containing 0.001 to 1% by weight of the test substance. (An explanation of the test method is given below).

Surprisingly, several compounds of the formula I also have a clear inhibitory effect on other physiologically important enzyme systems. Thus, inhibition of human leukocyte-derived phospholipase A2 was observed in the tested concentration range of about 0.5-50 .mu.mol / l. (The experimental setup for this assay is described in more detail below).

PHARMACOLOGICAL TEST METHODS

Guinea pig bronchoconstriction test in vivo, aerosol):

Male guinea pigs weighing 400-700 g are anesthetized intraperitoneally with 1.4 g / kg urethane and a polyethylene cannula is introduced into the jugular vein (Vena jugularis). The second polyethylene cannula is directed into the trachea. An esophageal cannula connected to a Statham pressure transducer records esophageal pressure. The animal is placed in an airtight plexiglass chamber connected to Fleisch tube Nr. 000 and Validyne- ·

Transducer for MP 45-1. This device measures the flow (Flow).

After surgical preparation of the experimental animals, it is expected. prescribed time for lung function to stabilize.

5 q a i λ o y n

The test compound is then administered according to the following schedule. The experimental animals are exposed for one minute to a 1% aerosol solution (w / v) or distilled water (for control) of the test compound. For all test compounds administered by inhalation, a Monaghan ultrasonic nebulizer (Model 670) with a particle size of 1 to 8 microns and a majority of 3 microns is used.

Aqueous solutions are always prepared fresh and directed with an on-stream drug vial into the chamber of the sprayer. The spray mist produced is administered to the experimental animals through a glass chamber containing 65 ml and connected by cannula to the trachea. At the end of the treatment time, LTD4 (0.3 μg / ml) is administered for 2 minutes using a second Monaghan ultrasonic nebulizer (model 670) and through the same glass chamber.

Read the decrease in compliance at 3 minutes after administration of LTD4 and compare the mean of the three animals with the mean of the three control animals and calculate the percentage inhibition of compliance according to the following formula: (100 - compliance preparation). 100% esto = 100 - (100 - compliance check)

If different concentrations of active substance are examined, then for each concentration the percentage inhibition is denoted, namely the log concentration for the abscissa and the percentage inhibition for the ordinate. The IC50 is then determined by linear regression analysis.

6 94342

In vitro assay to determine inhibition of human leukocyte-derived phospholipase A2

Neutrophilic squamous human leukocytes are isolated from coagulated blood plasma ("Buffy coats") by multi-stage fractional sedimentation and deep-frozen. Phospholipase A2 is extracted from the cell suspension by homogenization by adding ice-cold 0.36 N H 2 SO 4 in 2N NaCl and centrifuged at 10,000 x g, after which the resulting supernatant is dialyzed against sodium acetate buffer, pH 4.5.

To determine enzyme activity, the enzyme (10-30 μg protein) is incubated for 1 hour at 37 ° in 0.1 M Tris / HCl buffer pH 7 by adding 1 mM CaCl 2 and a substrate consisting of biosynthetically 14C-oleic acid radiolabeled Escherichia coli phospholipids. of them (2 μΚ). The reaction is stopped by the addition of Dole reagent (isopropanol / heptane / 1N H 2 SO 4 40: 10: 1, v / v) and the 14C-oleic acid selectively released by phospholipase A2 is extracted. Likewise, the co-extracted substrate is completely removed by filtering the extract through a silica gel column.

The 14C-oleic acid in the eluate is determined by radiometry.

To determine the inhibitory effect of the test substances on phospholipase A2, these are added as solutions in water, dimethyl sulfoxide (final batch concentration up to 5% v / v) or ethanol (final batch concentration up to 2.5% v / v) to the incubation product. The potency of the test substances is expressed as the IC50 value, i.e. at a concentration that results in a 50% inhibition of control activity. The IC50 is determined graphically by plotting the percentage inhibition for the ordinate and the log concentration (μΜ) for the abscissa.

II

• 7 g / 17/10 J ‘τ o * t ά

Under the experimental conditions shown, mepacrine inhibits phospholipase A2 with an IC50 of 1600 μΜ.

In vitro assay to determine inhibition of phospholipase C from human thrombocytes

Human platelets are produced from coagulated blood plasma (Buffy coats) by fractional centrifugation and then deep-frozen. Phospholipase C is released by sonication of the cell suspension and, after ultracentrifugation (150,000 x g for one hour), is present in soluble form in the supernatant.

To determine enzyme activity, the enzyme (20-100 μg protein) is incubated at 37 ° for 5 minutes in 0.025 M Tris / maleate buffer, pH 6, with the addition of 0.2 mM CaCl 2 and 0.02 mM radiolabeled substrate, phosphatidyl [14 C]. inositol. The reaction is quenched by shaking with CHCl 3 / CH 3 OH 2: 1 (v / v). In this case, the unused substrate is extracted into the organic phase, while the reaction product * 4C-inositol phosphate remains in the aqueous phase and can be measured from the sample by radiometry.

Inhibitory effect of test substances on phospholipase C. to determine this, these are added as solutions in water, dimethyl sulphoxide (final batch concentration up to 5% v / v) or ethanol (final batch concentration up to 2.5% v / v) to the incubation batch. The potency of the effect of the test substances is expressed as the IC50 value, i.e. at a concentration that results in a 50% inhibition of control activity. The IC50 is expressed graphically by plotting the percentage inhibition for the ordinate and the log concentration (μΜ) for the abscissa.

Under the experimental conditions shown, mepacrine inhibits phospholipase C with an IC50 of 20 μΜ.

8 q, i ~ i /. 9

7uiZ

Table: Pharmacological test results, in vitro LTD „antagonism

Compound example- In vitro requirement for LTD4- No. No. No. antagonism, guinea pig ileum, pre-incubation time: 2 min IC50 [MM] 43 2 0.0027 45 3 0.00096 73 0.0042 102/2 0, 0030 103/2 4 0.0019 102/1 0.0045 102/3 5 0.0013 2 0.013 4 0.025 10 0.0073 16 -0.0072 «53 0.028 67 0.02 71 0.015 75 -0.015 51 0.016 0 / 7/10 S'TulZ 9

Inhibition of phospholipase C from human platelets was also observed in the tested concentration range of about 1 to 100 .mu.mol / l.

Due to these valuable pharmacological properties, the compounds of the formula I according to the invention can be used wherever the action of leukotrienes leads to pathological conditions and must be alleviated or eliminated. Thus, they can be used, for example, for the treatment of allergic conditions and diseases, in particular asthma, but also hay fever and obstructive pulmonary diseases, including cystic fibrosis. They are also suitable for their anti-inflammatory properties as anti-inflammatory agents, in particular as external (topical) dermatologists for the treatment of all types of inflammatory dermatoses, such as mild skin irritations, ocular inflammation, nasal congestion, mucosal infections, rashes and burns. for the treatment of the lips, mouth and genitals, the anal area. Furthermore, they can be used as sunscreens. The high inhibitory effect on various blood factors further suggests the possibility of therapeutic use of the compounds of formula I in the indication region for thrombosis and blood clotting.

The invention relates in particular to the preparation of, for example, compounds of the formula I and their salts, in particular pharmaceutically acceptable salts, in which R 3 represents C 1 -C 4 alkyl, R 2 represents optionally fluorinated C 1 -C 4 alkyl and the radicals X, R 3 and R 4 has the meanings given above.

10 g. z a 9 In this case, the group X is preferably in the para position with respect to the group R (C (O)), i.e. the formula of the compounds is fl »/ \ / \ 1 i 11

He / XX-alk-fCH = CH 2 -CH-? H-RJ (Ia) I nT Ud '' \ / \ / ° \ i 5 Γ \ / \ / * fi where the radicals R1f R2, X, alk, n , R 3 and R 4 are as defined above, but in particular R 1 is C 1 -C 4 alkyl, R 2 is optionally fluorinated C 1 -C 4 alkyl and / or phenyl R 3 is, in particular, substituted as described above.

The invention relates in particular to the preparation of compounds of the formula Ia and their salts, in particular their pharmaceutically usable salts, in which R 3 represents C 1 -C 4 alkyl, such as methyl, R 2 represents C 1 -C 4 alkyl, such as propyl, X represents ox, C 2 -C 6 alkylene, such as ethylene, 1,3-propylene or 1,4-butylene, n is 1 or especially 2, R 3 represents C 1 -C 4 alkyl, such as methyl, C 1 -C 4 alkylene, alkoxy, such as nitroxy, halogen having an order of 35 or less, such as chlorine, trifluoromethyl or phenyl substituted with C 1-4 alkoxycarbonyl, such as methoxycarbonyl, C 3 -C 5 alkyl, such as propyl or butyl, ω, ω, trifluoro-C3-C5-alkyl, such as 3,3,3-trifluoropropyl or 4,4,4-trifluorobutyl, or C1-C4-alkoxycarbonyl-C1-C4-alkyl, such as 3-methoxycarbonylpropyl or 4-methoxycarbonylbutyl and R 4 represents carboxy, wherein when n is 1, the chain C- in particular, the chain C atom attached to the hydroxy group has the (S) configuration or, when n is 2, the chain C atom attached to the sulfur atom has, in particular, the chain C atom containing the (S) and hydroxy group. the atom has in particular the (R) configuration and the double bond attached to the residue alk 94342 11 occurs especially in the cis configuration and any additional double bond present occurs especially in the trans configuration.

The invention relates in particular to the preparation of compounds of the formula Ia and their salts, in particular pharmaceutically acceptable salts, in which R 1 represents C 1 -C 4 alkyl, such as methyl, R 2 represents O 2 to 4 alkyl, such as propyl, X represents branches, alk represents C 2 -C 6 alkylene, such as ethylene or 1,4-butylene, n is 1 or especially 2, R 3 represents a group of the formula -A-R 3 ', in which -A- represents O 2 to 4 alkylene, such as ethylene, or phenylene, in particular m-phenylene and R 3 'denotes O 4 -O 4 -alkyl, such as methyl, trifluoromethyl or O-O 4 -31-coxycarbonyl, such as methoxycarbonyl, and R 4 denotes carboxy or N- (benzenesulphonyl) carbamoyl, where, when n is 1, the chain C atom has in particular (R) - and the chain C atom attached to the hydroxy group has in particular the (S) configuration or, when n is 2, the chain C atom attached to the sulfur atom has in particular (S) - and the chain C atom containing a hydroxy group has e however, the (R) -configuration and the double bond attached to the residue alk occur especially in the cis configuration and any additional double bond present may occur in the pre-; also in the trans configuration.

The invention relates in the first instance to the preparation of compounds of the formula Ia and their salts, in particular pharmaceutically acceptable salts, in which R 2 represents O 2 to 4-alkyl, such as methyl, R 2 represents Δ 4 -O-4-alkyl, such as propyl, X represents branches, alk represents C 2 -C5-alkylene, such as ethylene, 1,3-propylene or 1,4-butylene, n is 2, R3 denotes O2-4alkyl, such as methyl, trifluoromethyl or O2-4-alkoxycarbonyl, such as methoxycarbonyl, in particular phenyl, C3-C5-alkyl, such as propyl or butyl, ω, ω, ω-trifluoro-C3-C5-alkyl, such as 3,3,3-trifluoropropyl or 4,4,4-trifluorobutyl, or C1-C4-alkoxycarbonyl-C2-C4-alkyl, such as 3-methoxycarbonylpropyl or 4-methoxycarbonylbutyl, and R4 represents carboxy, the chain C atom attached to the sulfur atom having in particular the chain group attached to the (S) and hydroxy group. In particular, the C atom has the (R) -configuration The double bond bonded to the residue and the residue alk occurs especially in the cis configuration and the second additional double bond occurs especially in the trans configuration.

The invention relates in particular to the preparation of the compounds of the formula I mentioned in the examples and their salts, in particular their pharmaceutically usable salts.

The process according to the invention for the preparation of the compounds of the formula I and their salts is based on processes known per se and is characterized in that

_ A A A

R1 is 4H-X-alkfCH = CH) -CH-CH-R1 (II).

• · n

h / Y

An epoxide according to Λ2 *, in which the radicals R1 # R2, X, alk, n and R3 have the meanings given above, is reacted with the formula

HSx, \ A A

iaa (m), • · · ^ \ / • · li, wherein the residue R4 has the meaning given above, or a salt thereof and, if desired, converting a compound obtained by the process into another compound of formula I, separating the stereoisomeric mixture obtained according to the process into its components and / or I, α / 7 / ΐη / τ JtZ 13 is converted to a free compound obtained by the method into a salt or a salt obtained by the method to a free compound or to another salt.

The reaction of the epoxides II with the thiols III takes place by exchanging the configuration with the thio group on the C-atom forming the bond and maintaining the configuration on the C-atom containing the hydroxy group. In order to obtain the preferred compounds having the opposite configuration on both of these C atoms, it is therefore preferable to start from the corresponding trans epoxides II. In this case, starting from R, R-epoxides II, compounds I having the S (CS -), (R (C-OH) configuration) are obtained, or starting from S, S-epoxides II, R (CS), S (C-OH) - The reaction takes place under conditions known per se at about -20 to about + 50 ° C, preferably at room temperature, i.e. 18 to 25 ° C, and preferably in a basic environment, for example in the presence of an amine, in particular a tertiary aliphatic, arylaliphatic or a saturated heterocyclic amine such as trialkylamine (e.g. triethylamine or ethyl-diisopropylamine), dialkylbenzylamine (e.g. N, N-dimethylbenzylamine), Ν, Ν-dialkylaniline (e.g. N, N-dimethylaniline) in the presence of N-methyl or N-ethyl piperidine or * N, N'-dimethylpiperazine, respectively The reaction is usually carried out in an inert (weakly reactive) organic solvent such as lower alkanol, e.g. methanol or ethanol.

In a preferred embodiment, starting from components II and III, wherein R 4 represents esterified carboxy or tetrazolyl and the residue R 3 has the meaning given above and represents, for example, esterified carboxy or optionally fluorinated lower alkyl, R 4 is hydrolyzed (optionally selectively) to carboxy and optionally converted to amidated carboxy.

14 94342

The starting materials for the process according to the invention are either known per se or can be prepared according to known methods of analogy in a manner known per se.

The epoxide of formula II defined above as starting material can be advantageously prepared according to the same methods as are also used in the synthesis of leukotrienes. A typical general synthetic procedure for compounds II where n is 1 starts from, for example, an aldehyde of the formula 0 = CH-R3 (IV) in which the residue R3 has the meaning given above, the optional free carboxyl group R3 being present as an ester in protected form, e.g. lower alkyl. This compound is condensed with formylmethylenetriphenylphosphorane (or equivalent reagent) to form the corresponding trans-3-R3-prop-2-enal of formula ° = C \ / \, (v). This compound is then epoxidized in a manner known per se, in particular under temporal conditions (e.g. in the presence of early carbonates) with aqueous hydrogen peroxide to give the formula

0 = CWH

/ z — cv (VI)

B

according to trans-, i.e. (2 RS), 3 (R) -epoxy-3-R3-propanal. Epoxyaldehyde VI can be reacted by condensing 94342 15 l of phosphonium halide

R

R1 '\ -HX-alk-CH2-PCCtH5) jHal® (VII) ηο'Ύ' wherein R1f R2 and alk have the meanings given and Hal represents a halogen atom, in particular bromine, and with a base, e.g. sodium amide in tetrahydrofuran, to the corresponding epoxide II, wherein R4 is esterified carboxy and n is 1.

Compounds VII are prepared in a conventional manner, in particular by reacting the corresponding compound of formula R / X / X-alkyl-CH2-Hal (VIII)

Hc / y compound to react with triphenylphosphine. The compounds Vili in which X represents branches or thio are obtained, for example, by condensing the corresponding compounds of the formulas R '\ ^ \ 1 I # -XH (IX) and Hal-alk-CHj-Hal (X) «/ y« 2. in the usual way.

In another process for the preparation of compounds II of formula HOCHj, CH.

trans-3-R3-prop-2-enol according to claim 1, wherein the residue R3 is

Λ Λ 7/1 O

16 above, is epoxidized with, for example, tert-butyl hydroperoxide, titanium tetraisopropanolate and D- or resp. In the presence of an L-tartaric acid diaeaalkyl ester, in which case the D-tartaric acid ester is used primarily to give 2R, 3R-epoxy-3-R3-propanol Xlla or, in the case of the L-tartaric acid ester, the corresponding 2S, 3S-epoxy-3 * R3-H This is then oxidized, for example by treatment first with oxalyl chloride / dimethyl sulphoxide and then with triethylamine to give the corresponding epoxaldehyde VI, which can then be reacted with the corresponding phosphonium salt VII to give the corresponding epoxide II, where R 3 is esterified carboxy and 1.

In this case, mainly epoxides II are obtained, in which the double bond has the preferred cis stereotaxis. If a D-tartaric acid ester is used, as mentioned, mainly compounds II are obtained in which the epoxy group has the R, R configuration, or the like. S, S enantiomers when the reaction is carried out in the presence of L-tartaric acid esters.

The preparation of epoxides II in which n is 2 takes place, for example, in such a way that the epoxy alcohol Xlla or resp. X11b is converted by first treatment with Ν, Ν'-dicyclohexylcarbodiimide and dimethyl sulfoxide in the presence of trifluoroacetic acid and pyridine and then with triphenylphosphoranylidene acetaldehyde to give the corresponding compounds of formulas i i 17 94 342

Xllla or resp. XIII b

0 = HC-CH = CH 2 H 0 = HC-CH = CH 0 H

To 4R, 5R or 4S, 5S-4,5-epoxy-5-R3-pent-2-enal according to V— "c (XIIIa) or (XII1b) * / ', which is then further reacted to give -phonium halide VII to the corresponding epoxide in which n is 2. This gives in particular compounds in which the double bond attached to the residue alk has the cis configuration and the double bond connected to the oxirane ring has the trans configuration.

The compounds obtained according to the process can be converted, if desired, into other compounds of the formula I.

For example, esterified or amidated carboxy groups can be hydrolyzed to the free hydroxy, preferably under basic conditions, e.g. in the presence of sodium hydroxide and preferably in a water-miscible organic solvent such as tetrahydrofuran, dioxane or a lower alkanol such as methanol or ethanol. Starting from compounds I in which R 4 represents an esterified carboxy, such as lower alkoxycarbonyl and R 3 contains such a substituent, the hydrolysis can be controlled by selectively hydrolyzing only R 4 or the lower alkoxycarbonyl substituent of both R 4 and the residue R 3 to carboxy. If equimolar sodium hydroxide is used and mild reaction conditions are selected, e.g.

Stirring for 0.5-2 hours at room temperature, practically hydrolyzes only alkoxycarbonyl R4, while under drastic conditions, e.g. using longer reaction times or heating, both R4 and the residue R3 are hydrolyzed to alkoxycarbonyl carboxy.

94342 18

On the other hand, the carboxy R4 and the carboxy substituent of the residue R3 can be esterified in a conventional manner.

The free or esterified carboxy R4 and such a substituent on the residue R3 can be further amidated in a conventional manner, for example by treatment with ammonia or a mono- or dialkylalkylamine. For example, carboxy R4 can be converted to the corresponding N-benzenesulfamidoylcarbamyl groups in a conventional manner with an optionally substituted benzenesulfonamide, e.g. a carbodiimide salt, e.g. N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide hydrochloride and 4-dimethylaminopyridine.

Of course, the resulting diastereomeric mixture can also be separated into the individual components based on the different physical properties of the components and / or the resulting enantiomeric mixture can be separated into the individual enantiomers according to conventional racemate separation methods.

When individual diastereomers are desired, the individual diastereomer of the starting material may be used in an arbitrary step, or the diastereomer may be formed from the starting material preferably in the form of a diastereomer by stereoselective reaction conditions or optically active reagents, or by racemic diastereomeric mixtures. , optically as individual diastereomers.

However, in a stereochemical ratio, both the condensation of components II and III according to the invention and the preparation of the starting materials are carried out primarily by using stereotactically uniform starting materials in each case, the reactions being carried out, if possible, by stereoselective

II

19

q Λ ZAO

/ e.g., using stereotactically uniform, optically active reagents and / or excipients, and isolating stereotactically uniform products from the reaction mixtures immediately after the reaction. Thus, for example, any cis and trans isomers formed in the preparation of unsaturated starting materials are immediately separated from one another, for which purpose conventional physical separation methods, such as chromatography in particular, are suitable. The main reaction uses primarily stereomeric epoxide II, which has a preferred double bond stereotaxis for the final product, specifically in racemic form (as is often formed in the epoxidation variant of compound V with hydrogen peroxide) or especially as an individual diastereomer with a preferred C With the S atom in the oxirane C atom forming a bond.

Likewise, the salts obtained can be converted into the free acids, for example, by treatment with an acid or, inter alia, the free acids obtained can be converted into salts by treatment with a base.

Due to the close relationship between the new compounds in free form and in salt form, the above and following free compounds or their salts also suitably mean the corresponding salts or free compounds.

The invention also relates to those embodiments of the process which proceed at some stage in the process starting from the intermediate compound and carrying out the missing steps or using the starting material in the form of a salt or under reaction conditions.

The novel starting materials and intermediates present in the processes of the invention and their precursors form; as well as the subject of the invention.

94342 20

Preferably, such starting materials are used and the reaction conditions are selected to give the highly preferred compounds set forth above.

The compounds obtained according to the method are used for the preparation of pharmaceutical compositions and medicaments.

Pharmaceutical compositions containing the compounds of the invention as active ingredient are in particular those intended for topical use and in particular for inhalation, e.g. in the form of an aerosol, powdered powder or finely divided solution for mammals, in particular humans, and containing the active ingredient alone or in combination with a pharmaceutically acceptable carrier. with the substance.

Pharmaceutical preparations for topical or topical use include, for example, liquid skin creams and ointments containing a liquid or semi-solid oil-in-water or water-in-oil emulsion, and ointments (preferably containing a preservative). Suitable eye treatments are eye drops containing the active compound in aqueous or oily solution, and eye ointments, which are preferably prepared in sterile form. Aerosols and sprays suitable for the treatment of the nose (same as those subsequently described for the treatment of the respiratory tract), coarse powders which are inhaled rapidly through the nose, and in particular nasal drops containing the active compound in aqueous or oily solution; also suitable for the topical treatment of the oral cavity are lozenges containing the active compound in a mass generally composed of sugar and gum arabic or tragacanth, to which flavorings may be added, and lozenges containing the active ingredient in an inert mass, e.g. gelatin and glycerol or sugar and gum arabic.

li 94 342 21

Suitable pharmaceutical compositions for use in the form of an aerosol or spray are, for example, solutions, suspensions or emulsions of the active compound of the formula I according to the invention in a suitable pharmaceutically acceptable solvent, in particular ethanol and water or a mixture of such solvents. They may also contain, if necessary, other pharmaceutical excipients, such as nonionic or anionic surfactants, emulsifiers and stabilizers and other active ingredients, and are in particular suitably mixed with a propellant such as an inert gas under elevated pressure or especially in a volatile atmospheric atmosphere. with a boiling liquid such as at least partially fluorinated polyhalogenated lower alkane or a mixture of such liquids below a conventional room temperature (e.g. between about -30 ° C and + 10 ° C). Such pharmaceutical compositions, which are used primarily as intermediates or stock mixtures for the preparation of the corresponding medicaments in finished form, usually contain the active ingredient n.

0.1 to about 10, especially about 0.3 to about 3% by weight. In order to prepare medicaments in ready-to-use form, such a pharmaceutical composition is filled into suitable containers, such as bottles or pressure bottles, equipped with a spray device or valve suitable for such purposes. The valve is preferably formed as a metering valve which, in use, releases a predetermined amount of liquid according to a predetermined dose of active ingredient. In preparing the finished dosage form, it is also possible to proceed in such a way that the corresponding amounts of the pharmaceutical composition and the propellant present as a stock solution are filled separately into the containers and only mix in them. The dosage and frequency of use of the active ingredient of the formula I to be used depend on the particular potency or response of each individual compound, the duration of action, the severity of the disease being treated, the severity of its symptoms and the sex, age, weight and individual responsiveness of the mammal being treated. On average, the recommended daily dose of a compound of formula I according to the invention for a mammal weighing 75 kg (primarily a human) is probably about 10 to n.

In the range of 500, preferably about 25 to about 250 mg, in which case the administration may conveniently take place in several doses per day as required.

The active compounds of the formula I according to the invention are used for alleviating or eliminating the symptoms of mammalian conditions, and in particular human diseases, and / or resistance, which are due to the action of leukotrienes and occur in particular in asthma. This use or the corresponding method of improvement is characterized in that the diseased body or body part is treated with an antiallergically effective amount of a compound of the formula I alone or in the form of a medicament, in particular in the form of a pharmaceutical composition for inhalation. The term "antiallergically effective amount" means an amount of active substance sufficient to significantly inhibit leukotriene-induced contractions (contractions).

The following examples further illustrate this invention without limiting its scope. All temperatures are in degrees Celsius.

Example 1; (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) - dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid methyl ester

To a solution of 0.93 g of (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) octa -3 (E), 5 (Z)-diene in 25 ml of methanol, 0.80 g of triethylamine and 0.62 g of 7-mercaptochromone-2-carboxylic acid methyl ester are added under argon, stirred for 20 hours at room temperature and evaporated. 7/1 o 7 -ron report 23. The residue is dissolved in ethyl acetate and filtered through silica gel. The filtrate is washed once with 2N hydrochloric acid and 3 times with brine, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on silica gel with hexane / ethyl acetate (1: 1) to give the title compound, m.p. 62-63 °, [α] 20 D (methanol, 0.135%) = 103 + 7.4e, UV (methanol): λmax (ε) 1,216 (50,000), 235 / sh, 271 (27,940), 285 / sh, 325 (12,900).

The starting material is prepared, for example, as follows: a) (2R, 3R) -2,3-epoxy-3- (3-trifluoromethylphenyl) -propanol

Under absolutely anhydrous conditions and an argon atmosphere, a solution of 4.62 ml of tetraisopropyl orthotitanate in 100 ml of methylene chloride is cooled to -70e, 3.2 ml of D (-) - tartaric acid diethyl ester and 5.45 g of 3- With (3-trifluoromethylphenyl) -prop-2 (E) -eno in a small amount of methylene chloride. Stir for 10 minutes at -70 ° and then add 21.5 ml of a 3 molar solution of tert-butyl hydroperoxide in toluene, raising the temperature to -60 °. The temperature is allowed to rise to 0e within 2 hours, then the yellow solution formed is slowly poured into a solution of 14.5 g of ferrous sulphate and 5.8 g of L (+) - tartaric acid in 60 ml of water (cooling! Exothermic). and stirred for 30 minutes at 5-10 °. The aqueous phase is separated and extracted with ether. The combined organic extracts are dried over sodium sulfate and evaporated. The residue is dissolved in 90 ml of ether, cooled to 0-5e, a suspension of 2.32 g of sodium hydroxide in 60 ml of brine is added and stirred for 1 to 5e. The aqueous phase is separated and extracted with ether. The combined ether phases are dried over sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with hexane / ethyl acetate (3: 2). The title compound is obtained as a colorless oil. IR (CH 2 Cl 2): 3550, 3430, 2950, 2880, 2830, 1310, 1150, 1110, 1050 cm -1. [α] 20 D (methanol, 0.175%) = 42.3 + 5.7e, Rf = 0.30 (hexane / ethyl acetate 3: 2).

b) (4R, 5R) -4,5-Epoxy-5- (3-trifluoromethyl-phenyl) -pent-2 (E) -enal

To a solution of 4.5 g of (2R, 3R) -2,3-epoxy-3- (3-trifluoromethylphenyl) propanol in 105 ml of dimethyl sulfoxide is added 1.7 ml of pyridine under argon. , 77 ml of trifluoroacetic acid and 12.75 g of N, N-dicyclohexylcarbodiimide, and stirred for 6 hours at room temperature. 8.25 g of formylmethylenetriphenylphosphorane are added and then the mixture is further stirred for 20 hours at room temperature, 320 ml of ethyl acetate are added and, after 10 minutes, poured into 320 ml of brine. The resulting suspension is stirred for 5 minutes and then filtered. The aqueous phase in the filtrate is extracted twice with ethyl acetate. The combined organic phases are washed 3 times with brine, dried over sodium sulfate and evaporated. The residue is filtered through silica gel with ether / hexane (4: 1). The filtrate is evaporated and the residue is chromatographed on silica gel with hexane / ethyl acetate (3: 1). The title compound is thus obtained as a pale yellow oil. IR (CH 2 Cl 2): 2780, 2695, 1670, 1620, 1305, 1145, 1105 cm -1. Rf = 0.31 (hexane / ethyl acetate 3: 1). [α] 20 D (chloroform, 0.245%) = 144.5 + 4, le.

• • · 25 0/7/10

j * tZ

c) 3- (4-Acetyl-3-hydroxy-2-propylphenoxy) propyl triphenylphosphonium bromide

To a solution of 27 g of 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propyl bromide in 50 ml of toluene is added 21.85 g of triphenylphosphine, and then heated under reflux for 20 hours. The resulting suspension is cooled to room temperature, 200 ml of ether are added and the mixture is stirred for one hour. The colorless precipitate is filtered off with suction, washed with ether and dried. The title compound sp. is 211 - 212 *.

d) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) - diene

To a suspension of 5.55 g of 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propyl triphenylphosphonium bromide in 80 ml of tetrahydrofuran are added 0.78 g of NaNH2 and 60 mg of potassium tert-butanolate and stirred. under argon for 1 hour at room temperature, cooled to 0-5e, 1.7 g of (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) -pent-2 (E) - enal in 20 ml of tetrahydrofuran and stirred for 2 hours at room temperature. The resulting suspension is poured into phosphate buffer (pH 7) and extracted with ether. The combined ether extracts are washed with phosphate buffer pH 7, dried over sodium sulfate and evaporated. The residue is taken up in hexane / ethyl acetate / triethylamine (24: 71: 5) and filtered through silica gel prewashed with this solvent mixture; Iin through. The filtrate is evaporated to give the title compound as a pale yellow oil. Rf = 0.75 (hexane / ethyl acetate-3: 2).

26 Q /, 7 Λ n 7t J'ti.

Example 2: (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt 0.7 g of (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl) -okta-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic the acid methyl ester is dissolved in 20 ml of tetrahydrofuran under an argon atmosphere, 5.1 ml of 0.2N sodium hydroxide are added and the mixture is stirred for 1 hour at room temperature. Evaporate the residue and purify by chromatography on a reverse phase silica gel column (Reversed Phase-Kieselgel column, e.g. Merck Lichroprep® RP-8) with methanol / water (3: 1) to give the title compound, m.p.

207-209e, [α] 20 D (0.54%, methanol) = 96.3 + 1.9 °. UV (methanol): λ max (ε) = 220 (488840), 235 / sh, 267 (25940), 285 (22900), 324 / sh.

Example 3: (1S, 2R) -1-Hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-karboksyylihappometyyliesteri_

The title compound is prepared according to Example 1) * (1S, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E ), From 5 (Z)-diene, m.p. 68 - 69 *.

The starting material is prepared, for example, as follows: li 94342 27 a) (2S, 3S) -2,3-epoxy-3- (3-trifluoromethylphenyl) -propanol

The title compound is prepared as described in Example 1a) using L (+) - tartaric acid diethyl ester, colorless oil. IR (CH 2 Cl 2): 3590, 3480, 2920, 2870, 1330, 1165, 1125, 1070 cm -1; ta] 2 D (methanol, 0.175%) = -41.7 + 5.7®, Rf = 0.34 (hexane / ethyl acetate 1: 1).

b) (4S, 5S) -4,5-Epoxy-5- (3-trifluoromethyl-phenyl) -pent-2 (E) -enal

The title compound is prepared according to Example Ib) from the epoxy alcohol of a) as a pale yellow oil. IR (CH 2 Cl 2): 2780, 2695.1670, 1620, 1305, 1145, 1110 cm -1, [α] 20 D (chloroform, 0.15%) = -158.0 + 6.7®, Rf = 0.4 (hexane / ethyl acetate 4: 1).

c) (1S, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) - dieenl

The title compound is prepared according to Example Id) from the epoxy aldehyde of b) as a light brown oil.

Rf s 0.61 (hexane / ethyl acetate 3: 2).

Example 4: (1S, 2R) -1-Hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 3, m.p. 210 -212®, [α] 20 D (MeOH, 0.18%) = -86.1 ± 5.6®, UV (MeOH):

Xmax (e) = 220 (42820), 235 / sh, 267 (26660), 285 (23760), 320 (15800).

• 28,94542

Example 5: (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic syylihappometyyliesteri_

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) - of ene, a pale yellow tough oil. [α] 20 D (MeOH, 0.115%) * 57.4 ± 8.7e, UV (MeOH): λmax (ε) = 220 / sh, 271 (5280), 285 / sh, 320 (2800).

The starting material is prepared, for example, as follows: a) (2S, 3R) -2,3-epoxy-3- (3-trifluoromethylphenyl) -propanal

A solution of 1.1 g of oxalyl chloride in 15 ml of methylene chloride is cooled to -65-70 ° under an argon atmosphere and then 1.5 g of dimethyl sulfoxide in 5 ml of methylene dichloride are added over 2 minutes. Stir for 10 minutes at -65 to -70 ° and then add dropwise 1.7 g of (2R, 3R) -2,3-epoxy-3- (3-trifluoromethyl-phenyl) -propanol in 15 ml of methylene chloride. Stirring is continued for 30 minutes and then 4 g of triethylamine are added dropwise, bringing the temperature to -40 °. The temperature is allowed to rise to 0 ° and then the reaction mixture is poured into phosphate buffer (pH 8). The organic phase is separated and the aqueous phase is extracted with methylene chloride. The combined organic extracts are washed twice with filtration. water, dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel with hexane / ethyl acetate (7: 3) to give the title compound as a colorless oil. IR (methylene chloride): 2820, 1730, 1330, 1165, 1125, 1070 cm-1. Rf = 0.36 (hexane / ethyl acetate 3: 2). [α] 20 D (chloroform, 0.20%) = -17.5 ± 5e.

»1/17/10 29 b) (1R, 2R) -1,2-Epoxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 ( Z) -ene

The title compound is prepared according to Example Id) from the epoxy aldehyde of a) as a pale yellow oil. Rf = 0.69 (hexane / ethyl acetate 3: 2).

Example 6: (1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic syyllhappo-natrlumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 5, m.p. 222-224 °. [α] 20 D (MeOH, 0.135%) - 62.2 ± 7.4 °. UV (MeOH): λmax (ε) = 267 (22060), 285 (21140), 318 / sh.

Example 7: (1S, 2R) -1-Hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic syylihappometyyllesterl_

The title compound is prepared according to Example 1 from (1S, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -ene, colorless powder, m.p. 69-71 °.

The starting material is prepared, for example, as follows: a) (2R, 3S) -2,3-epoxy-3- (3-trifluoromethylphenyl) -propanal

The title compound is prepared according to Example 5a) in (2S, 3S) -2,3-epoxy-3- (3-trifluoromethylphenyl) -propano-liquid, pale yellow liquid. IR (CH 2 Cl 2): 2820, 1730, 30

Q /. 7 A O JiZ

1330, 1165, 1130, 1070 cm -1; ta] 2 ° D (chloroform, 0.20%) = 0.0 ± 5 °, [α] 20365 (chloroform, 0.20%) = 475.0 ± 5.0 °, Rf = 0.44 (hexane / ethyl acetate 7: 3).

b) (1S, 2S) -1,2-Epoxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -ene

The title compound is prepared according to Example Id) from the corresponding epoxy aldehyde according to a), a pale yellow oil. Rf = 0.43 (hexane / ethyl acetate 3: 2).

Example 8: (1S, 2R) -1-Hydroxy-1- (3-trifluoromethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid-natrlumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 7, m.p. 239-241 °, [α] 20 D (methanol, 0.15%) = -60.7 ± 6.7e, UV (methanol): λmax (ε) = 216 (44080), 268 (22520), 285 (21640), 320 / sh.

Example 9: (1R, 2S) -1-hydroxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -dien -2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic happometyyliesteri_

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 ( Z)-diene, pale yellow powder, m.p. 71 - 72e. [α] 20 D = 81.7 ± 8.7 * (MeOH, 0.115%), UV (MeOH): λmax (ε) = 217 (53680), 235 / sh, 271 (29120), 285 / sh, 325 ( 13200).

The starting material is prepared, for example, as follows: 94342 31 a) (2R, 3R) -2,3-epoxy-3- (3-methylphenyl) -propanol

The title compound is prepared according to Example 1a) from 3- (3-methylphenyl) -prop-2 (E) -enol, a colorless, viscous oil.

IR (CH 2 Cl 2): 3560, 3410, 2880, 2830, 1590, 1050 cm -1 Rf = 0.39 (hexane / ethyl acetate 1: 1), [α] 2 ° π = 38'9 ± 5'3 ° (chloroform, 0.19%).

b) (4R, 5R) -4,5-Epoxy-5- (3-methylphenyl) -pent-2 (E) -enal

The title compound is prepared according to Example 1b) from the epoxy alcohol according to a), a pale yellow powder, m.p. 60 - 61e. IR (CH 2 Cl 2): 2920, 2820, 2740, 1690, 1640, 1610, 1155, 1130 cm -1, Rf = 0.34 (hexane / ethyl acetate 4: 1).

c) (1R, 2R) -1,2-epoxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) - diene

The title compound is prepared according to Example Id) from the epoxy aldehyde of a) as a pale yellow oil. Rf = 0.63 (hexane / ethyl acetate 3: 2).

Example 10: (1R, 2S) -1-hydroxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -dien -2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natrlumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 9, beige powder, m.p. 217 ° (dec.). [α] 20 D (methanol, 0.15%) = 71.3 ± 6.7 °, UV (methanol): λmax (e) - 219 (51520), 234 / sh, 267 (26460), 284 (23280) , 322 / sh.

32 Q / 7/1 O 7 -r o n <£.

Example 11: (1S, 2R) -1-Hydroxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -dien -2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic happometyyliesteri_

The title compound is prepared according to Example 1 (1S, 2S) -1,2-epoxy-1- (m-tolyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 ( Z) -diene. [α] 25 D (MeOH, 0.148%) = -75.7 ± 6.8 °, UV (MeOH): λmax (ε) = 217 (51760), 240 / sh, 271 (27860), 290 / sh, 328 (12600).

The starting material is prepared, for example, as follows: a) (2S, 3S) -2,3-epoxy-3- (3-methylphenyl) propanol

The title compound is prepared according to Example 1a) from 3- (3-methylphenyl) -prop-2 (E) -enol using L (+) - tartaric acid diethyl ester, colorless oil. IR (CH 2 Cl 2): 3550, 3470, 2940, 2880, 2830, 1590, 1050 cm -1; Rf = ° '31 (hexane / ethyl acetate 3: 2).

b) (4S, 5S) -4,5-Epoxy-5- (3-methylphenyl) -pent-2 (E) -enal. The title compound is prepared according to Example Ib) from the epoxy alcohol according to a), a pale yellow oil. . IR (CH 2 Cl 2): 2920, 2820, 2740, 1690, 1640, 1610, 1155, 1130, 1085 cm -1, Rf = 0.29 (hexane / ethyl acetate 4: 1).

c) (1S, 2S) -1,2-epoxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) - diene

The title compound is prepared according to Example Id) from the epoxy aldehyde of b) as a pale yellow oil. Rf = 0.51 (hexane / ethyl acetate 7: 3). 1 li · · 33 0/7/10 7 -f o n £.

Example 12: (1S, 2R) -1-Hydroxy-1- (3-methylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene -2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natriumsuola_

The title compound is prepared according to Example 1 from the corresponding methyl ester of Example 11, m.p. 197-198 *, [α] 20 D (MeOH, 0.14%) = -72.1 ± 7.1 °, UV (MeOH):

Amax (ε) = 218 (50700), 235 / sh, 267 (25780), 285 (22600), 321 (15000).

Example 13; (1R, 2S) -1-Hydroxy-1- (3-methylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl-7-thio -4-oxo-4H-l-benzopyran-2-carboxylic acid metyyliesteri_

The title compound is prepared according to Example 1 from (1R, 2R) -1,2-epoxy-1- (3-tolyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -ene, colorless powder, m.p. 136 - 138 *. [α] 20 D = 28.1 ± 7.4 ° (methanol, 0.135%), UV (methanol): xmax (ε) = 271 (26020), 282 / sh, 323 (13700).

The starting material is prepared, for example, as follows: a) (2S, 3R) -2,3-epoxy-3- (3-methylphenyl) -propanal

The title compound is prepared according to Example 5a) from (2R, 3R) -2,3-epoxy-3- (3-methylphenyl) propanol, a pale yellow oil. IR (methylene chloride): 2920, 2820, 1730, 1640, 1140, 1070 cm-1, Rf = 0.49 (hexane / ethyl acetate 3: 2).

34

Q A ~ l A O 7 -T jnZ

b) (1R, 2R) -1,2-Epoxy-1- (3-methylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -ene

The title compound is prepared according to Example Id) from the epoxy aldehyde of a) as a pale yellow oil. Rf = 0.73 (hexane / ethyl acetate 3: 2).

Example 14: (1R, 2S) -1-Hydroxy-1- (3-methylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -2-yl-7- thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 13, beige powder, m.p. 238 - 240®. [α] 20 D (methanol, 0.135%) = 31.1 ± 7.4®, UV (methanol): λmax (ε) = 268 (21800), 285 (20860), 322 / sh.

Example 15: (1R, 2S) -1-Hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-karboksyylihappometyyliesteri_

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 ( Z) -diene. [α] 2 D (methanol, 0.14%) = 27.9 ± 7.1®, UV (methanol):? max (ε) = 221 (53560), 234 / sh, 270 (28980), 285 / sh, 326 (13860).

The starting material is prepared, for example, as follows: 94342 35 a) (2R, 3R) -2,3-epoxy-3- (3-methoxycarbonylphenyl) -propanol

The title compound is prepared according to Example 1a) from (E) -3-methoxycarbonylcinnamic alcohol, a slightly yellowish oil. Rf = 0.3 (hexane / ethyl acetate 1: 1).

b) (4R, 5R) -4,5-Epoxy-5- (3-methoxycarbonylphenyl) -pent-2 (E) -enal

The title compound is prepared according to Example Ib) from the corresponding epoxy alcohol, a pale yellow oil. Rf = 0.35 (hexane / ethyl acetate 3: 2).

c) (1R, 2R) -1,2-Epoxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) - dieenl

The title compound is prepared according to Example Id) from the corresponding epoxy aldehyde according to b), a tough yellow oil. Rf = 0.50 (hexane / ethyl acetate 3: 2).

Example 16: (1R, 2S) -1-Hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -dien -2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid A-natriumsuola_

The title compound is prepared according to Example 2 (1R, 2S) -1-hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (D) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester (e.g. 15), light brown powder, m.p. 181 ° (dec.). [α] 20 D (methanol, 0.15%) = 32.0 ± 6.7e, UV (methanol): Xmax (e) = 222 (51600), 232 / sh, 267 (24160), 284 (22940), 320 / sh, 400 / sh.

36 9 4342

Example 17: (1S, 2R) -1-Hydroxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-karboksyylihappometyyliesteri_

The title compound is prepared according to Example 1 (1S, 2S) -1,2-epoxy-1- (3-methoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 ( From Z) diene, m.p. 77-78e (colorless powder), [α] 20 D (methanol, 0.15%) = -52.7 ± 6.7e, UV (methanol): λ max (ε) = 221 (57420), 235 / sh, 271 (29980), 288 / sh, 326 (14320).

The starting material is prepared, for example, as follows: a) (2S, 3S) -2,3-epoxy-3- (3-methoxycarbonylphenyl) -propanol

The title compound is prepared according to Example 1a)! From (E) -methoxycarbonylcinnamic alcohol using L (+) - tartaric acid diethyl ester, colorless oil. Rf = 0.48 (hexane / ethyl acetate 1: 1).

b) (4S, 5S) -4,5-Epoxy-5- (3-methoxycarbonylphenyl) -pent-2 (E) -enal ** The title compound is prepared according to Example Ib) from the corresponding epoxy alcohol, colorless oil. IR (methylene chloride): 3050, 2990, 2945, 2820, 2730, 1725, 1695, 1640, 1290 1255 cm-1; Rf = ° 34 (hexane / ethyl acetate 3: 2).

(c) (1S, 2S) -1,2-epoxy-1- (3-meoxycarbonylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 ( Z) - dienenl

The title compound is prepared according to Example Id) from the epoxy aldehyde of b) as a pale yellow oil. = 0.54 (hexane / ethyl acetate 3: 2).

37 94342

Example 18: (1S, 2R) -1-Hydroxy-1- (3-methoxycarbonyl-phenyl-8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) diene -2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 17, beige powder, m.p. 174-176 °. [α] 20 D (methanol, 0.155%) -80.6 ± 6.5®, UV (methanol): xmax (ε) 223 (59300), 235 / sh, 267 (27300), 284 (24800), 321 ( 16200).

Example 19: (1R, 2S) -1-Hydroxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2- yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic syylihappometyvliesteri_

The title compound is prepared according to Example 1 from (1R, 2R) -1,2-epoxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -ene, colorless oil. [α] 20 D (methanol, 0.11%) = 24.5 ± 9.1 °, UV (methanol): xmax (e) - 270 (22400), 322 (12000).

The starting material is prepared, for example, as follows: a) (2S, 3R) -2,3-epoxy-3- (3-methoxycarbonylphenyl) -propanal

The title compound is prepared according to Example 5a) as a (2R, 3R) -2,3-epoxy-3- (3-methoxycarbonylphenyl) propano list, pale yellow oil. IR (methylene chloride): 2950, 2820, 1725, 1610, 1590, 1430, 1290, 1255 cm -1; Rf = ° 33: (hexane / ethyl acetate 3: 2).

♦ · I

· Q at. λ o 38 7 1τ o -r ^ b) (1R, 2R) -1,2-epoxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -ene

The title compound is prepared according to Example Id) from the epoxy aldehyde of a) as a pale yellow oil. Rf = 0.39 (hexane / ethyl acetate 3: 2).

Example 20: (1R, 2S) -1-Hydroxy-1- (3-methoxycarbonyl-phenyl-6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) en-2-yl- 7-Thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt (A) and (1R, 2S) -1-hydroxy-1- (3-carboxyphenyl) -6- (4- Acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid disodium salt (B)

To a solution of 0.5 g of (1R, 2S) -1-hydroxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 according to Example 19 ) -en-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester in 20 ml of tetrahydrofuran, 7.5 ml of 0.2 N sodium hydroxide are added and the mixture is stirred under an argon atmosphere. for one hour at room temperature. The residue is purified by chromatography on Lichroprep® RP-8 (Merck) with methanol / water (3: 1) to give fractions 2-5 to give the title compound B, m.p. 262 - 264β. [α] 2 ° ο (methanol, 0.105%) = 17.1 ± 9.5 °, UV (methanol): Xmax (ε) 1 268 (19680), 284 (19060), 325 / sh. Fractions 8-12 give the title compound A, m.p. 155e (dec.). [α] 20 D (methanol, 0.12%) = 22.5 ± 8.3e, UV (methanol): λmax (ε) = 268 (26200), 286 (29220), 325 / sh.

i 1 • · 39

0/7/10 x -r o 1t Z

Example 21: (1S, 2R) -1-Hydroxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) 2-yl-7 thio-4-oxo-4H-l-benzopyran-2-carboxylic happometyyliesteri_

The title compound is prepared according to Example 1 from (1S, 2S) -1,2-epoxy-1- (3-carboxymethylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -ene, colorless oil which solidifies in the refrigerator, m.p. 90-91 °.

[α] 20 D a -41.5 ± 5.7 ° (0.13%, methanol), UV (methanol): λmax U) = 271 (25120), 322 (13280).

The starting material is prepared, for example, as follows: a) (2R, 3S) -2,3-epoxy-3- (3-methoxycarbonylphenyl) -propanal

The title compound was prepared according to Example 5 from (2S, 3S) -2,3-epoxy-3- (3-methoxycarbonylphenyl) propano-colored oil. IR (methylene chloride): 2910, 2780, 1705, 1590, 1570, 1415, 1270, 1235 ΟϊΓ1; Rf = ° 36 (hexane / ethyl acetate 3: 2).

b) (1S, 2S) -1,2-Epoxy-1- (3-methoxycarbonylphenyl) -6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -enyl

The title compound is prepared according to Example Id) from the corresponding epoxy aldehyde according to a), a colorless oil which has not been further characterized.

• · • · 40 Q /: 7/10 7 t O t ^

Example 22: (1S, 2R) -1-Hydroxy-1- (3-methoxycarbonyl-phenyl-6- (4-acetyl-3-hydroxy-2-propylphenoxy) -hex-3 (Z) -en-2-yl -7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid-natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 21, beige powder, m.p. 208-210 °. [α] 20 D (methanol, 0.12%) = -41.7 ± 8.3 °, UV (methanol): xmax (ε) = 268 (21060), 285 (21540), 325 / sh.

Example 23: (4R, 5S) -1,1,1-Trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E), 8 (Z) -dien -5-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic happometyyliesterl_

The title compound is prepared according to Example 1 (4R, 5R) -4,5-epoxy-1,1,1-trifluoro-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E), 8 (Z)-diene, beige powder, m.p. 64 - 66 *. [α] 20 D (methanol, 0.15%) = 147.3 ± 6.7e, UV (methanol): xmax (e) = 220 (48960), 270 (28500), 283 / sh, 325 (13400).

The starting material is prepared, for example, as follows: a) (2R, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanol

The title compound is prepared according to Example 1a)! 6,6,6-Trifluoro-hex-2 (E) -enol, colorless oil. [α] 20 D (chloroform, 0.17%) = 35.9 ± 5.9 °, IR (methylene chloride): 3550, 3420, 2950, 2890, 2830, 1125 cm-1.

»| · · ·

II

41 O "2/10 y ^ ά.

b) (4R, 5R) -4,5-Epoxy-8,8,8-trifluoro-oct-2 (E) -enal

The title compound is prepared according to Example ib) from the corresponding epoxy alcohol of a), a pale yellow oil. IR (CH 2 Cl 2): 3050, 2980, 2930, 2820, 2730, 1695, 1645, 1450, 1150, 1100 cm -1 Rf = ° '41 (hexane / ethyl acetate 3: 2).

c) (4R, 5R) -4,5-Epoxy-1,1,1-trifluoro-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E), 8 (Z) - diene

The title compound is prepared according to Example Id) from the epoxy aldehyde of b) as a pale yellow oil. Rf = 0.48 (hexane / ethyl acetate 3: 2).

Example 24: (4R, 5S) -1,1,1-Trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E), 8 (Z) -dien -5-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natrlumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 23, beige powder, m.p. 198 - 200β. [α] 20υ (methanol, 0.15%) = 127.3 ± 6.7 ", UV (methanol): λ max (ε) = 221 (48820), 230 / sh, 267 (25440), 285 (23080 ), 322 / sh.

• ·

Example 25: (4S, 5R) -1,1,1-Trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E), 8 (Z) -dien -5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The title compound is prepared according to Example 1 (4S, 5S) -4,5-epoxy-1,1,1-trifluoro-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E), 8 (Z)-diene, colorless powder, m.p. 69-71 °. [α] 20 D = -153.3 ± 6.7 "(methanol, 0.15%), UV (methanol):) (max (ε) = 220 (49560), 235 / sh,.: 270 (29220) , 285 / sh, 325 (12990).

• · The starting material is prepared, for example, as follows: 42

Q 4 7/1 O

7 * t O * T L · a) (23,33) -2,3-epoxy-6,6,6-trifluoro-hexanol

The title compound is prepared according to Example 1a) from 6,6,6-trifluoro-hex-2 (E) -enol using L (+) - tartaric acid diethyl ester, colorless oil. [α] 20 D (chloroform, 0.17%) = -25.9 ± 5.9 °, IR (methylene chloride): 3550, 3430, 2940, 2880, 2830, 1125 cm-1.

b) (4S, 5S) -4,5-Epoxy-8,8,8-trifluoro-oct-2 (E) -enal

The title compound is prepared according to Example Ib) from the corresponding epoxy alcohol of a) as a pale yellow oil. IR (methylene chloride): 3050, 2990, 2930, 2820, 2730, 1695, 1645, 1450, 1150, 1100 cm-1. Rf = 0.36 (hexane / ethyl acetate 3: 2).

c) (4S, 5S) -4,5-Epoxy-1,1,1-trifluoro-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E), 8 (Z) - diene

The title compound is prepared according to Example Id) from the epoxy aldehyde according to b), a pale yellow oil *

Example 26: (4S, 5R) -1,1,1-Trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 (E), 8 (Z) -dien -5-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 25, beige water, m.p. 201-203 °. [α] 20 D (methanol, 0.15%) = -117.3 ± 6.7 °, UV (methanol): xmax (ε) 222 (48320), 233 / sh, 267 (26440), 285 (24440) , 330 / sh.

»·. .. · · * 43 S4342

Example 27: (4R, 5S) -1,1,1-Trifluoro-4-hydroxy-9- (4-acetyl-3-hydroxy-2-propylphenoxy) -non-6 (Z) -en-5- yl-7-thio-4-oxo-4H-l-benzopyran-2-karboksyylihappometyylies-terl_

The title compound is prepared according to Example 1 (4R, 5R) -4,5-epoxy-1,1,1-trifluoro-9- (4-acetyl-3-hydroxy-2-propylphenoxy) -non-6 (Z) - enen, colorless, tough oil. IR (methylene chloride): 3530, 2920, 2890, 2820, 1720, 1640, 1605, 1585 cm-1.

The starting material is prepared, for example, as follows: a) (2S, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanal

The title compound is prepared according to Example 5a) from (2R, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanol, colorless liquid, b.p. 80 - 81V26 mbar. [α] 20 D (chloroform, 0.15%) = -10.7 ± 6.7e.

b) (4R, 5R) -4,5-Epoxy-1,1,1-trifluoro-9- (4-acetyl-3-hydroxy-2-propylphenoxy) -non-6 (Z) -ene

The title compound is prepared according to Example Id) from the epoxy aldehyde according to a), a pale yellow oil.

Example 28: (4R, 5S) -1,1,1-Trifluoro-4-hydroxy-9- (4-acetyl-3-hydroxy-2-propylphenoxy) -non-6 (Z) -en-5-yl- Li-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 27, pale yellow powder, m.p. 204-206 °. [c *] 20D (methanol, 0.15%) «» · * 44

G A ~ L A O

Jlt ε = 42.7 ± 6.7 °, UV (methanol): λ max (ε) = 218 (36920), 268 (20280), 285 (20180), 325 / sh.

Example 29: (5R, 6S) -5-Hydroxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -dodec-7 (Z) -en-6-yl-7-thio-4- oxo-4H-l-bentsopyraanl-2-karboksvvlihappometvvliesteri_

The title compound is prepared according to Example 1 from (5R, 6R) -5,6-epoxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -dodec-7- (Z) -ene, pale yellow oil. Rf = 0.37 (hexane / ethyl acetate 1: 1).

The starting material is prepared, for example, as follows: a) 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyl-triphenylphosphonium bromide

The title compound is prepared according to Example 1e) from 5- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyl bromide, colorless crystals, m.p. 82 - 851.

b) (2S, 3R) -2,3-epoxy-heptanal

The title compound is prepared according to Example 5a) from • (2R, 3R) -2,3-epoxyheptanol. [α] 20 D 1 -99.4 ± 0.1 °.

1% c) (5R, 6R) -5,6-Epoxy-12- (4-acetyl-3-hydroxy-2-propyl-1-phenoxy) -dodec-7- (Z) -enyl

The title compound is prepared according to Example id). of epoxy aldehyde according to dan a), pale yellow oil · li ·

Example 30; (5R, 6S) -5-hydroxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -dodec-7 (Z) -en-6-yl-7-thio-4-oxo-4H -1-Benzopyran-2-carboxylic acid sodium salt_45 QA 1 AO y T vj 't

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 29, m.p. 192-194 °. [α] 2 D (methanol, 0.125%) = + 5.6 ± 8.0 e, UV (methanol): λ max (ε) = 218 (38000), 268 (22040), 285 (21120), 325 / sh.

Example 31: (5S, 6R) -5-Hydroxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -dodec-7 (Z) -en-6-yl-7-thio-4- oxo-4H-l-benzopyran-2-karboksyyllhappometyyliesteri_

The title compound is prepared according to Example 1 from (5S, 6S) -5,6-epoxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -dodec-7- (Z) -ene, pale yellow oil, Rf = 0.41 (hexane / ethyl acetate 1: 1).

The starting material is prepared, for example, as follows: a) (2R, 3S) -2,3-epoxy-heptanal

The title compound is prepared according to Example 5a) from (2S, 3S) -2,3-epoxy-heptanol. [α] 20 D = +104.3 ± 0.4 °.

b) (5S, 6S) -5,6-Epoxy-12- (4-acetyl-2-hydroxy-2-propyl-phenoxy) -dodec-7 (z) -ene

The title compound is prepared according to Example Id) from the epoxy aldehyde of a) as a pale yellow oil. Rf = 0.42 (hexane / ethyl acetate 3: 2).

'·

Example 32: (5S, 6R) -5-Hydroxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -dodec-7 (z) -en-6-yl-7-thio-4- oxo-4H-1-benzopyran-2-carboxylic acid sodium salt_ 46 Q Λ 7. Λ O yt «jn L.

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 31, m.p. 192 -194 '. [α] 2 D (methanol, 0.145%) = 0 ± 6.9 °, UV (methanol): λmax (ε) = 218 (37060), 268 (21760), 286 (20520), 325 / sh .

Example 33: (4R, 5S) -1,1,1-Trifluoro-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undek-6 (Z) -en-5-yl- 7-thio-4-oxo-4H-l-benzopyran-2-karboksyylihappome-tyyliesterl_

The title compound is prepared according to Example 1 (4R, 5R) -4,5-epoxy-1,1,1-trifluoro-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undek-6 (Z) - of ene, a pale yellow oil. Rf = 0.47 (hexane / ethyl acetate 1: 1).

The starting material is prepared, e.g., according to Example Id) from (2S, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanal, a pale yellow oil.

Example 34: (4R, 5S) -1,1,1-Trifluoro-4-hydroxy-11- (4% acetyl-3-hydroxy-2-propylphenoxy) -undek-6 (Z) -en-5-yl -li-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natriumsuola_

The title compound is prepared according to Example 2. only from the methyl ester of Example 33, m.p. 193-195 °. [Α] 20 D (methanol, 0.135%) - +16.3 ± 7.4 «, UV (MeOH): λmax (ε) = 218 (37380), 267 (21380), 286 (21020), 325 / sh.

0/7/10

Example 35: (5R, 6S) -5-hydroxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) -dec-7 (Z) -en-6-yl-7-thio-4- oxo-4H-1-benzopyran-2-carboxylic acid methyl ester_47

The title compound is prepared according to Example 1 from (5R, 6R) -5,6-epoxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) -dec-7- (Z) -ene, pale yellow oil. [α] 20 D (methanol, 0.135%) = +48.9 ± 7.4 °, UV (methanol): Amax (e) = 216 (38140), 271 (24040), 285 sh, 322 (12700).

The starting material is prepared, e.g., according to Example Id) from (2S, 3R) -2,3-epoxy-heptanal, a pale yellow oil.

Rf = 0.45 (hexane / ethyl acetate 7: 3).

Example 36: (5R, 6S) -5-hydroxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) -dec-7 (Z) -en-6-yl-7-thio-4- oxo-4H-1-benzopyran-2-carboxylic acid

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 35 and converted to the free acid with hydrochloric acid, m.p. 58-60 °. [α] 20 D (methanol, 0.130%) = +36.2 ± 7.7 *, UV (methanol):? max (ε) - 218 (35240), 269 (20760), 283 (19800), 330 sh.

Example 37: (5S, 6R) -5-Hydroxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) -dec-7 (Z) -en-6-yl-7-thio -4-Oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The title compound is prepared according to Example 1

(5S, 6S) -5,6-epoxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) -dec-7 (Z) -ene, pale yellow oil. [A] 20 D

(methanol, 0.115%) = -50.4 ± 8.7 °, UV (MeOH): λmax (ε) = 217 (38000), 271 (24100), 285 sh, 321 (12800).

The starting material is prepared, e.g., according to Example Id) from (2R, 3S) -2,3-epoxy-heptanal, a light brown oil. Rf = 0.52 (hexane / ethyl acetate 7: 3).

Example 38: (5S, 6R) -5-Hydroxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) -dec-7 (Z) -en-6-yl-7-thio-4- oxo-4H-1-benzopyran-2-carboxylic acid sodium salt-48 gaaaoy-rose

The title compound is prepared according to Example 2 from the corresponding methyl ester of Example 37, m.p. 224-226 °. [α] 20 D (methanol, 0.145%) = -29.0 ± 6.9e, UV (methanol): λmax (ε) = 219 (38760), 268 (21880), 285 (21260), 325 sh.

Example 39: (5S, 6R) -5-Hydroxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) -dec-7 (Z) -en-6-yl-7-thio-4- oxo-4H-1-benzopyran-2- (N-benzenesulfonamidyl) carboxamide

To a solution of 0.20 g of (5S, 6R) -5-hydroxy-10- (4-acetyl-3-hydroxy-2-propylphenoxy) -dec-7 (Z) -en-6-yl-7 -thio-4-oxo-4H-1-benzopyran-2-carboxylic acid in 10 ml of methylene chloride, 60 mg of benzenesulfonamide, 44 mg of 4-dimethylaminopyridine and 70 mg of N-ethyl-N '- (3-dimethylaminopropyl) are added. ) -carbodiimide hydrochloride, and stirred under argon for 24 hours at room temperature. The resulting solution is diluted with 30 ml of methylene chloride, washed twice with 1N hydrochloric acid and twice with brine, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica. in a pogel with methylene chloride / methanol (9: 1) to give the title compound, m.p. 140 - 142 *.

Example 40: (4RS, 5SR) -1-Methoxycarbonyl-4-hydroxy-9- (4-acetyl-3-hydroxy-2-propylphenoxy) -non-6 (Z) -en-5-yl-7-thio- 4-oxo-4H-l-benzopyran-2-carboxylic acid metyyliesteri_

The title compound is prepared according to Example 1 (4RS, 5RS) -4,5-epoxy-1-methoxycarbonyl-9- (4-acetyl-3-49 0/7/0 s -r-Ί- έ.

hydroxy-2-propylphenoxy) -non-6 (Ζ) -ene, colorless oil. [α] 20 D (methanol, 0.125%) = 0.0 ± 8.0 °, UV (methano-H): Xmax (ε) = 270 (24000), 340 (13200).

The starting material is prepared, e.g. according to Example Id), from 5,6-epoxy-6-formyl-hexanoic acid methyl ester, a pale yellow oil. Rf = 0.35 (hexane / ethyl acetate 3: 2).

Example 41: (4RS, 5SR) -1-Carboxy-4-hydroxy-9- (4-acetyl-3-hydroxy-2-propylphenoxy) -non-6 (z) -en-5-yl-7- thio-4-oxo-4H-1-benzopyran-2-carboxylic acid disodium salt_ 0.24 g of the methyl ester of Example 40 are dissolved in 15 ml of tetrahydrofuran under argon, 3.8 ml of 0.2N sodium hydroxide are added and the mixture is stirred. For 20 hours at room temperature. Evaporation and chromatography of the residue on a reverse phase silica gel column (e.g. Merck Lichroprep® RP-8) with methanol / water (7: 3) affords the title compound, m.p. 248-250 ° (dec.). uv (methanol): xmax (e) = 218 (33900), 268 (18580), 284 (18240), 330 sh.

Example 42: (1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z ) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-karboksyyllhappometyyllesterl_

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) - diene, pale yellow oil. [Α] 20 D (CHCl 3, 0.363%) = 46.6 ± 2.8 °, UV (CHCl 3): (ε) = 270 (26500), 285 (24240), 322 (15200).

The starting material is prepared, for example, as follows: 50 0/7/10 y * τ o * i · £.

a) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) - diene

The title compound is prepared according to Example Id) from 5- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentyltriphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) - pent-2 (E) -enal (Example Ib), light brown oil. [(CHCl 3, 0.224%) = 70.8 ± 10 °, Rf = 0.50 (hexane / ethyl acetate 1: 1), IR (CH 2 Cl 2): 2960, 2930, 2865, 1735, 1625, 1330, 1125 cm -1 .

Example 43: (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) -dien -2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natrlumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 42), m.p. 217 - 219 ".

[α] 20 D (MeOH, 0.160%) * 145.6 ± 6.3 ·, UV (MeOH): λmax (ε) = 220 (50480), 230 (sh), 267 (26240), 284 (23000), 320 (Sh).

Example 44: (1R, 2S) -1-Hydroxy-1- (3-methylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (z) -dien -2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic happometyyliesterl_

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-methylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 ( From Z) diene, m.p.

59-60 °. [α] 20 D (CHCl 3, 0.163%) = 31.9 ± 6.1 °, UV (CHCl 3):? max (ε) - 241 (31420), 286 (23060).

Additional Q / 7/10 The starting material is prepared, for example, as follows: a) (1R.2R) -1,2-Epoxy-1- (3-methylphenyl-10-M-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E) .5fZ) -diene

The title compound is prepared according to Example Id) from 5- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentyltriphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-5- (3-methylphenyl) - from pent-2 (E) -enal (Example 9b), pale yellow oil. [α] 20 D (CHCl 3, 0.273%) = 118.7 ± 3.7®, Rf = 0.62 (hexane / ethyl acetate 3: 2).

Example 45: (1R, 2S) -1-Hydroxy-1- (3-methylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) -dien -2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 44), m.p. 208-210 °. [ck] 20d (MeOH, 0.30%) = 50.7 ± 3.3®, UV (MeOH): (e) = 219 (52420), 230 (sh), 267 (26620), 285 (23520) , 325 (sh).

Example 46: (1S, 2R) -1-Hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-karbokswlihappometwliesteri_

The title compound was prepared according to Example 1 (1S, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 ( Z) diene, tough mass. Rf * 0.48 (hexane / ethyl acetate 1: 1).

The starting material is prepared, for example, as follows: 52 g of A 7/10 7 no L · a) (1S / 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy -2-propylphenoxy) -deca- (3 (E), 5 (Z) - diene

The title compound is prepared according to Example Id) from 5- (4-acetyl-3-hydroxy-2-propylphenoxy) -pentyltriphenylphosphonium bromide (Example 29a) and (4S, 5S) -4,5-epoxy-5- (3-trifluoromethylphenyl) - from pent-2 (E) -enal (Example 3b), pale yellow oil. [α] 20 D (chloroform, 0.454%) = -86.8 ± 2.2 °, Rf = 0.46 (hexane / ethyl acetate 1: 1), IR (methylene chloride): 2960, 2930, 1730, 1625, 1330, 1130 cm-1.

Example 47: (1S, 2R) -1-Hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) -dien -2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natrlumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 46), m.p. 168-170 °.

Cet] 20d (methanol, 0.150%) = -66.7 ± 6.7e, UV (MeOH): * max (ε) = 220 (49640), 230 (sh), 266 (25640), 285 (22140), 320 (Sh).

Example 48: (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) phenoxy] -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The title compound is prepared according to Example 1: (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) - phenoxy] -octa-3 (E), 5 (Z)-diene, pale yellow oil, Rf = 0.34 (hexane / ethyl acetate 1: 1).

i: 53 The starting material is prepared, for example, as follows: g Λ 7 A 9

Ji Z

(a) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) phenoxy] octa-3 ( E), 5 (Z)-dienes

The title compound is prepared according to Example Id) from 3- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) phenoxy] propyltriphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) -pent-2 (E) -enal (Example Ib), pale yellow oil. [α] 2 D (chloroform, 0.406%) = -58.6 ± 2.5®, Rf = 0.45 (hexane / ethyl acetate 7: 3), IR (methylene chloride): 2945, 1670, 1610, 1310, 1055 cm-1.

b) 3- [4-Acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) -phenoxy] propyl] triphenylphosphonium bromide

The title compound is prepared according to Example 1e) from 3- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) -phenoxy] -propyl bromide, m.p. 184 - 185®.

Example 49: (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) phenoxy] -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 48), m.p. 238 - 240®.

[α] 20 D (methanol, 0.150%) = 208 ± 6.6®, UV (MeOH): λmax :: (ε) = 216 (50040), 230 (sh), 267 (28960), 280 (sh), 320 (16020).

• · 54 q /, / '/ 1 o ✓ -r Δ.

Example 50: (1R, 2S) -1-Hydroxy-1- (3-methylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) phenoxy] octa -3 (E), 5 (Z) -Dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-methylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) phenoxy] -octa-3 (E), 5 (Z)-diene, pale yellow viscous oil. Rf = 0.41 (hexane / ethyl acetate 1: 1). [α] 20 D (chloroform, 0.155%) - 32.3 ± 6.5 °, UV (chloroform): λ ^ χ (e) = 271 (32320), 318 (16100).

The starting material is prepared, for example, as follows: a) (1R, 2R1 -1,2-epoxy-1- (3-methylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) -phenoxy] -octa- 3 m 5 (Z) -Diene

The title compound is prepared according to Example Id) from 3- (4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) -phenoxy] -propyltriphenylphosphonium bromide (Example 48b) and (4R, 5R) -4,5-epoxy- 5- (3-Methylphenyl) -pent-2 (E) -enaa-list (Example 9b), pale yellow oil, Rf = 0.38 (hexane / ethyl acetate 3: 2).

Example 51: (1R, 2S) -1-Hydroxy-1- (3-methylphenyl) -8- [4-acetyl-3-hydroxy-2- (3,3,3-trifluoropropyl) phenoxy] octa -3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzo-pyran-2-carboxylic acid natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 50), m.p. 233-235 °.

[or] 20D (methanol, 0.195%) = 69.7 ± 5.1 °, UV (MeOH): λ ^ χ (6) = 218 (52320), 230 (sh), 267 (29040), 280 (sh ), 320 (16000).

li g / 17/10 y * T O -f L. 55

Example 52: (1R, 2S) -1-Hydroxy-1- (2-trifluoromethylphenyl-8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z ) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-karboksyylihappometyyliesteri_

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -diene, m.p. 66-68 °. Rf = 0.23 (hexane / ethyl acetate 3: 2), [α] 20 D (methanol, 0150%) = 22.0 ± 6.7 ", UV (MeOH): Xmax (ε) = 216 (50,000), 238 (sh), 271 (27860), 285 (sh), 324 (13900).

The starting material is prepared, for example, as follows: a) (1R, 2R) -1,2-epoxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 ( E), 5 (Z) -dleeni

The title compound is prepared according to Example Id)! 3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) -propyltriphenylphosphonium bromide (Example 1e) and (4R, 5R) -4,5-epoxy-5- (2-trifluoromethylphenyl) -pent- 2 (E) -enal, light brown oil. [α] 20 D (chloroform, 0.207%) = -5.8 ± 4.8e, Rf = 0.25 (hexane / ethyl acetate 4: 1).

b) (4R, 5R) -4,5-Epoxy-5- (2-trifluoromethyl-phenyl) -pent-2 (E) -enal

The title compound is prepared according to Example Ib); (2R, 3R) -2,3-Epoxy-3- (2-trifluoromethyl-phenyl) -propanol, yellow crystals. Rf = 0.36 (hexane / ethyl acetate 4: 1), [α] 2 D (methanol, 0.165%) = 23.0 ± 6, UV, MeOH: ^ ax (ε) = 216 (14400) , 235 (17240).

Q /. 7/1 O

7 T J 166 c) (2R, 3R) -2,3-Epoxy-3- (2-trifluoromethylphenyl) -propanol

The title compound is prepared according to Example 1a) from 3- (2-trifluoromethylphenyl) -prop-2 (E) -enol, colorless crystals. Rf = 0.38 (hexane / ethyl acetate 3: 2). IR (methylene chloride): 3600, 3050, 2990, 2920, 2870, 1610, 1585, 1320, 1170, 1125 cm-1.

Example 53: (1R, 2S) -1-hydroxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 52), m.p. 155 - 157®.

[α] 20 D (methanol, 0.180%) = 12.8 ± 5.6®, UV (MeOH): λmax (ε) = 219 (48400), 230 (sh), 266 (25480), 284 (22540), 325 (sh).

Example 54: (1S, 2R) -1-Hydroxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester 9

The title compound is prepared according to Example 1 (1S, 2S) -1,2-epoxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl) -3-hydroxy-2-propyl) -octa-3 (E) , 5 (Z)-diene, m.p. 71 - 73®. Rf = 0.25 (hexane / ethyl acetate 3: 2), [α] 20 D (methanol, 0.170%) = -27.1 ± 5.9e, UV (MeOH): x max (e) = 216 (51040), 235 (sh), 271 (28140), 285 (sh), 324 (13500).

The starting material is prepared, for example, as follows: li 57 Q Λ 7/0 y -f vj -e l.

a) (1S, 2S) -1,2-Epoxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z ) -dieenl

The title compound is prepared according to Example Id) from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propyl-triphenylphosphonium bromide (Example 1e) and (4S, 5S) -4,5-epoxy-5- (2-Trifluoromethylphenyl) -pent-2 (E) -enal, reddish oil. [α] D (chloroform, 0.207%) = 5.4 ± 4.8 °,

Rf = 0.29 (hexane / ethyl acetate 4: 1).

b) (4S, 5S) -4,5-Epoxy-5- (2-trifluoromethyl-phenyl) -pent-2 (E) -enal

The title compound is prepared according to Example Ib) as yellow crystals of (2S, 3S) -2,3-epoxy-3- (2-trifluoromethylphenyl) propano. Rf = 0.38 (hexane / ethyl acetate 4: 1), [α] 20 D (meth anole, 0.180%) = -25.0 ± 5.6e, UV (MeOH): λmax (ε) = 215 (13960) , 236 (17060).

c) (2S, 3S) -2,3-Epoxy-3- (2-trifluoromethylphenyl) -propanol 1

The title compound is prepared according to Example 1a from 3- (2-trifluoromethylphenyl) -prop-2 (E) -enol, colorless crystals. Rf = 0.35 (hexane / ethyl acetate 3: 2), IR (methylene chloride): 3600, 3050, 2990, 2920, 2870, 1610, 1585, 1320, 1170, 1125 cm-1.

58

Q A T / 1 O y -r o -r Z

Example 55: (1R, 2S) -1-Hydroxy-1- (2-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natrlumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 54), m.p. 182 - 184 *.

[α] 20 D (methanol, 0.205%) = -16.6 ± 4.9e, UV (MeOH): λmax (e) = 219 (47680), 235 (sh), 266 (24960), 284 (22100), 330 (sh).

Example 56: (1R, 2S) -1-Hydroxy-1- (4-trifluoromethylphenyl-8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z ) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-karboksyylihappometyyliesteri_

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E ), From 5 (Z)-diene, m.p. 68-70 °. Rf = 0.16 (hexane / ethyl acetate 3: 2), [α] 20 D (methanol, 0155%) = 110.3 ± 6.5 ", UV (MeOH): λmax (ε)" 217 (52880), 236 (Sh), 270 (28880), 285 (sh), 326 (13700).

The starting material is prepared, for example, as follows: a) (1R, 2R) -1,2-epoxy-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 ( E), 5 (Z) -dlene. The title compound is prepared according to Example Id)! 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propyl-triphenylphosphonium bromide (Example 1e) and (4R, 5R) -4,5-epoxy-5- (4-trifluoromethyl-phenyl) - pent-2 (E) -enal, yellow oil. [α] 20 D (chloroform, 0.220%) = 6.5 ± 4.5 ", Rf = 0.35 (hexane / ethyl acetate 4: 1).

li 94342 59 b) (4R, 5R) -4,5-Epoxy-5- (4-trifluoromethyl-phenyl) -pent-2 (E) -enal

The title compound is prepared according to Example 1b) (2R, 3R) -2,3-epoxy-3- (4-trifluoromethylphenyl) -propanol, yellow crystals, m.p. 67-70 °. Rf = 0.24 (hexane / ethyl acetate 4: 1), [α] 20 D (methanol, 0.150%) = 171.3 ± 6.7e, UV (MeOH): λ max (ε) = 237 (19660) .

c) (2R, 3R) -2,3-Epoxy-3- (4-trifluoromethyl-phenyl) -propanol.

The title compound is prepared according to Example 1a) from 3- (4-trifluoromethylphenyl) -prop-2 (E) -enol, colorless crystals. Rf = 0.25 (hexane / ethyl acetate 3: 2). IR (methylene chloride): 3550, 3010, 2950, 2880, 2830, 1605, 1310, 1150, 1110, 1050 cm-1.

Example 57: (1R, 2S) -1-Hydroxy-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid A-natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 56), m.p. 229-231 °.

; ; [α] 20 D (methanol, 0.160%) = 118.8 ± 6.3e, UV (MeOH): λmax (ε) = 220 (53060), 235 (Sh), 267 (27280), 284 (23880), 320 (16300).

60 94342

Example 58: (1S, 2R) -1-Hydroxy-1- (4-trifluoromethyl-phenyl) -8- (4-acetyl-3-hydroxy-3-propyl-phenoxy) -octa-3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-karboksyylihappometyyliesteri_

The title compound is prepared according to Example 1 (1S, 2S) -1,2-epoxy-1- (4-trifluoromethylphenyl) -8- (4-acetyl) -3-hydroxy-2-propylphenoxy) -octa-3 (E) , 5 (Z) -diene, m.p. 67 - 69e. Rf 0, 0.13 (hexane / ethyl acetate 3: 2), [α] 20 D (methanol, 0.155%) = -109.7 ± 6.5 °, UV (MeOH): λmax (ε) = 217 (52640), 235 (Sh), 270 (28660), 285 (sh), 326 (13680).

The starting material is prepared, for example, as follows: a) (1S, 2S) -1,2-epoxy-1- (4-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 ( E), 5 (Z) -diene

The title compound is prepared according to Example Id) from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -propyl-triphenylphosphonium bromide (Example 1c) and (4S, 5S) -4,5-epoxy-5- (4-Trifluoromethylphenyl) -pent-2 (E) -enal, reddish oil. [α] 20 D (chloroform, 0.199%) = -5.4 ± 5.0 *,

Rf = 0.23 (hexane / ethyl acetate 4: 1).

»« • <b) (4S, 5S) -4,5-Epoxy-5- (4-trifluoromethyl-phenyl) -pent-2 (E) -enal

The title compound is prepared according to Example 1b) (2S, 3S) -2,3-epoxy-3- (4-trifluoromethylphenyl) -propanol, yellow crystals, m.p. 67-69 °. Rf = 0.18 (hexane / ethyl acetate 4: 1), [α] 20 D (methanol, 0.150%) = -180.0 ± 6.7 °, UV (MeOH): (ε) = 236 (19740).

«0/17/10 61 c) (2S, 3S) -2,3-epoxy-3- (4-trifluoromethylphenyl) propanol

The title compound is prepared according to Example 1a from 3- (4-trifluoromethylphenyl) -prop-2 (E) -enol, colorless crystals. Rf = 0.23 (hexane / ethyl acetate 3: 2), IR (methylene chloride): 3550, 3010, 2950, 2880, 2830, 1605, 1310, 1150, 1110, 1050 CT1T1.

Example 59: (1S, 2R) -1-Hydroxy-1- (4-trifluoromethyl-phenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natrlumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 58), m.p. 228-230 °.

[α] 20 D (methanol, 0.175%) = -99.4 ± 5.7 ·, UV (MeOH): λmax (ε) * 220 (49800), 235 (sh), 267 (25320), 284 (22200) , 320 (15600).

Example 60: (1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl-8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z ) -en-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-karboksyyllhappometyyllesterl_

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E ), 5 (Z) -ene, colorless oil. Rf = 0.41 (hexane / ethyl acetate 1: 1), [α] OD (chloroform, 0.150%) = 46.7 ± 6.7 °, UV (MeOH): λmax (ε) δ 271 (22760), 288 ( 20060), 270 (28880), 324 (14460).

The starting material is prepared, for example, as follows: 62 g of A 9 7 (trans) L (a) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy -2-propyl-phenoxy) -octa-3 (E), 5 (Z) -ene

The title compound is prepared according to Example Id) from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (2S, 3R) -2,3-epoxy-3- ( 3-Trifluoromethylphenyl) propanal (Example 5a), pale yellow oil. [α] 20 D (chloroform, 0.221%) = 25.3 ± 4.5 *, Rf * 0.56 (hexane / ethyl acetate 3: 2).

Example 61: (1R, 2S) -1-Hydroxy-1- (3-trifluoromethyl-phenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) en-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid A-natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 60), m.p. 231 - 233 *.

[α] 20 D (ethanol, 0.190%) = 51.1 ± 5.3 *, UV (MeOH): λmax (ε) = 215 (42320), 267 (22220), 286 (20800), 320 (sh).

Example 62: (1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl-9- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -nona-3 (E), 5 (Z ) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-karboksyylihappometyyliesteri_

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (E), 5 ( Z) diene, pale yellow, viscous oil. [α] 2 D (chloroform, 0.155%) = 44.5 ± 6.5 °, Rf = 0.50 (hexane / ethyl acetate 1: 1), UV (CHCl 3): λ max (ε) = 270 ( 26800), 284 (23100), 323 (14480).

The starting material is prepared, for example, as follows: l! 63 q ai An a) 3- (4-Acetyl-3-hydroxy-2-propyl-phenoxy) butyl-triphenylphosphonium bromide

The title compound is prepared according to Example 1c) from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) butyl bromide, m.p. 167-169 °.

b) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (E), 5 (Z) - diene

The title compound is prepared according to Example Id) from 5- (4-acetyl-3-hydroxy-2-propylphenoxy) butyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) -pent -2 (E) -enal (Example 1b), pale yellow oil. [α] 20 D (chloroform, 0.308%) = 40.7 ± 3.2e, Rf = 0.70 (hexane / ethyl acetate 3: 2), IR (methylene chloride): 2950, 2860, 1625, 1325, 1120 cm -1.

Example 63: (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -9- (4-acetyl-3-hydroxy-2-propylphenoxy) -nona-3 (E), 5 (Z) -dien 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt, The title compound was prepared according to Example 2 from the corresponding methyl ester (Example 62), m.p. 204-2061. [Α] 20 D (chloroform, 0.289%) = 8.0 ± 3.5e, [α] 20 D (methanol, 0.155%): 55.5 ± 6.5 °, UV (methanol): λ max (ε) = 219 (49320), 232 (Sh), 266 (25800), 285 (22060), 330 (Sh).

»64 C Λ ~ ζ λ o S * Τ U‘ t Δ.

Example 64: (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -11- (4-acetyl-3-hydroxy-2-propylphenoxy) -unde-3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -11- (4-acetyl) -3-hydroxy-2-propylphenoxy) -undeca-3 (E), 5 (Z) -Dadiene, light yellow viscous oil. [α] 20 D (chloroform, 0.160%) = 48.1 ± 6.3e, Rf <0.50 (hexane / ethyl acetate 1: 1), UV (CHCl 3): * max (ε) = 270 (27120) , 286 (23300), 323 (14740).

The starting material is prepared, for example, as follows: a) 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) hexyl-triphenylphosphonium bromide

The title compound is prepared according to example le)! 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) hexyl bromide, the compound crystallizes very slowly.

b) (1R, 2R) -1,2-Epoxy-1- (3-trifluoromethylphenyl-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-3 (E), 5 (Z)-diene «

The title compound is prepared according to Example Id) from 5- (4-acetyl-3-hydroxy-2-propylphenoxy) hexyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) -pent-2 (E) -enal (Example Ib), horizontal; lean yellow oil. [α] 20ρ (chloroform, 0.450%) = 41.1 ± 2.2 ", Rf = 0.66 (hexane / ethyl acetate 3: 2), IR (methylene chloride): 2960, 2860, 1625, 1325, 1120 cm-1.

94342 65

Example 65: (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -11- (4-acetyl-3-hydroxy-2-propylphenoxy) -unde-3 (E), 5 ( Z) -Dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 64), m.p. 216 - 218 *.

[α] 20 D (chloroform, 0258%) = 34.9 ± 3.9 *, [α] 20 D = 73.8 ± 6.3 * (methanol, 0.160%), UV (methanol): Xmax (ε) = 219 (50140), 232 (sh), 266 (26120), 286 (22460), 320 (15600).

Example 66: (1R, 2S) -1-Hydroxy-1-phenyl-8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -dien-2 -yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1-phenyl-8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) of diene, light yellow foam. Rf = 0.41 (hexane / ethyl acetate 1: 1), [α] 20 D = 47.3 ± 2.6 * (chloroform, 0.385%).

The starting material is prepared, for example, as follows: a) (1R, 2R) -1,2-epoxy-1-phenyl-8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -diene

The title compound is prepared according to Example Id)! 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propyl triphenylphosphonium bromide (Example 1e) and (4R, 5R) -4,5-epoxy; from si-5-phenyl-pent-2 (E) -enal, pale yellow oil.

Rf = 0.60 (hexane / ethyl acetate 3: 2).

66 Q A 7/10 7 τ vJ n b) (4R, 5R) -4,5-Epoxy-5-phenyl-pent-2 (E) -enal

The title compound is prepared according to Example 1b) from (2R, 3R) -2,3-epoxy-3-phenylpropanol, a yellow oil which crystallizes on standing. Rf = 0.38 (hexane / ethyl acetate 3: 2), [α] 20 D = 185 ± 5.0 ° (chloroform, 0.200%).

c) (2R, 3R) -2,3-Epoxy-3-phenyl-propanol

The title compound is prepared according to Example 1a) from 3-phenyl-prop-2 (E) -enol, a colorless oil which crystallizes on cold. Rf 0.49 (hexane / ethyl acetate 1: 1), IR (methylene chloride): 3590, 3040, 2980, 2920, 2870, 1605, 1080, 1070 cm-1. [α] D (chloroform, 0.279%) = 47.4 ± 3.6 °.

Example 67: (1R, 2S) -1-Hydroxy-1-phenyl-8- (4-acetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -dien-2-yl - 7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 66), m.p. 219-221 °.

[α] 20 D (chloroform, 0.160%) = 103.1 ± 6.3 °, UV (methanol): λmax (ε) = 221 (51180), 232 (sh), 267 (27040), 284 (23840), 321 (16200), UV (chloroform): * max (ε) = 274 (26080), 286 (sh), 330 (sh).

Example 68: (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (3-acetyl-4-hydroxy-5-propylphenoxy) -octa-3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-: carboxylic acid methyl ester

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (3-acetyl-4-hydroxy-5-propylphenoxy) -octa-3 (E ), From 5 (Z)-diene, Rf = 0.21 (hexane / ethyl acetate, 3: 2).

The starting material is prepared, for example, as follows: 0/7/10 / ή J ί ii 67 a) 3- (3-Acetyl-4-hydroxy-5-propyl-phenoxy) -propyl bromide

To a solution of 5.8 g of 2,5-dihydroxy-3-propylacetophenone and 6.1 ml of 1,3-dibromopropane in 60 ml of methyl ethyl ketone are added 6.2 g of potassium carbonate and 0.5 g of potassium iodide. The reaction mixture is heated to reflux for 24 hours. It is then poured into 300 ml of ice-water, acidified with hydrochloric acid and extracted with dichloromethane (3 x 150 ml). The combined extracts are washed with 50 ml of water and dried over sodium sulfate. Filter and evaporate in vacuo, then chromatograph the residue on 400 g of silica gel with dichloromethane. The first fractions elute the title compound, which precipitates after evaporation as pale yellow crystals, m.p. 69 - 70 ".

b) 3- (3-Acetyl-4-hydroxy-5-propyl-phenoxy) propyl-triphenylphosphonium bromide

The title compound is prepared according to Example 1e) from 3- (3-acetyl-4-hydroxy-5-propyl-phenoxy) propyl bromide and triphenylphosphine, m.p. 103 - 105 ".

* <• «c) (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (3-acetyl-4-hydroxy-5-propylphenoxy) -octa-3 (E) , 5 (Z)-dienes; The title compound is prepared according to Example Id) from 3- (3-acetyl-4-hydroxy-5-propylphenoxy) propyl triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) pent -2 (E) -enal, Rf = 0.54 (hexane / ethyl acetate, 2: 1).

68 0/7/10 y t o "t e.

Example 69: (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (3-acetyl-4-hydroxy-5-propylphenoxy) -octa-3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natriumsuola_

The title compound is prepared according to Example 2 by (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (3-acetyl-4-hydroxy-5-propylphenoxy) -octa-3 (E), From 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester, yellow foam. 1 H-NMR (CD 3 OD): δ = 7.91, 7.76 - 7.56, 7.50, 7.36, 7.05, 6.82, 6.41, 6.00, 5.75, 5.47, 5.12, 4.45, 3.78, 2.65 - 2.35, 1.88, 1.58, 0.94 ppm.

Example 70: (1R, 2S) -1-Hydroxy-1- (3-chlorophenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic happometyyliesterl_

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-chlorophenyl) -8- (4-acetyl) -3-hydroxy-2-propylphenoxy) -octa-3 (E) , 5 (Z)-diene, m.p.

76 - 77e. [α] 20 D (chloroform, 0.215%) = 51.2 ± 4.7e, UV (chloroform): * max (ε) = 271 (28160), 285 (sh), 321 (15380.

«The starting material is prepared, for example, as follows: a) (1R, 2R) -1,2-epoxy-1- (3-chlorophenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -dienes •

The title compound is prepared according to Example Id) from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide (Example 1e) and (4R, 5R) -4,5-epoxy-5- ( 3-Chloro-phenyl) -pent-2 (E) -enal, pale yellow oil. [α] 20 D (chloroform, 0.541%) = 63.9 ± 1.8 *.

94342 69 b) (4R, 5R) -4,5-Epoxy-5- (3-chlorophenyl) -pent-2 (E) -enal

The title compound is prepared according to Example 1b) from (2R, 3R) -2,3-epoxy-3- (3-chlorophenyl) propanol, a dark yellow oil. Rf = 0.23 (hexane / ethyl acetate 4: 1), [α] 2 D (chloroform, 0.30%) = 184.7 ± 3.3.

c) (2R, 3R) -2,3-Epoxy-3- (3-chlorophenyl) -propanol

The title compound is prepared according to Example 1a) from 3- (3-chlorophenyl) -prop-2 (E) -enol, a pale yellow oil. Rf = 0.22 (hexane / ethyl acetate 7: 3), IR (methylene chloride): 3580, 3040, 2980, 2910, 2860, 1600, 1570, 1070 cm-1, [α] 20 D (chloroform, 0.334%) : 47.3 ± 3.0 °.

Example 71: (1R, 2S) -1-Hydroxy-1- (3-chlorophenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 70), m.p. 217-219 °.

[α] 20 D (methanol, 0.160%) = 107.5 ± 6.3e, UV (methanol): Vax (ε) 219 (55060), 235 (sh), 267 (27340), 284 (23920), 320 ( 16500).

Example 72: (1R, 2S) -1-Hydroxy-1- (3-chlorophenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-chlorophenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z)-diene, m.p. 61 - 62β. [α] 20 D (chloroform, 0.170%) = 52.9 ± 5.9 °, UV

70 Q A 7/1 o 7 n u n L · (chloroform): λmax (ε) = 271 (27120), 286 (24800), 322 (15400).

The starting material is prepared, for example, as follows: a) (1R, 2R) -1,2-epoxy-1- (3-chlorophenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 ( E), 5 (Z) -diene

The title compound is prepared according to Example Id) from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-5- ( From 3-chlorophenyl) -pent-2 (E) -enal (Example 70b), pale yellow oil. [α] 20 D (chloroform, 0.391%) = 61.4 ± 2.5 °.

Example 73: (1R, 2S) -1-hydroxy-1- (3-chlorophenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid-natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 72), m.p. 204-206 °.

[α] 20 D (methanol, 0205%) = 58.5 ± 4.9 °, UV (MeOH): λmax (ε) = 218 (27940), 267 (13140), 285 (11600), 320 (sh).

•

Example 74: (1R, 2S) -1-Hydroxy-1- (3-methoxyphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester: The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-methoxyphenyl ) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z)-diene, m.p.

65 - 67 *. UV (chloroform): λmax (e) = 271 (30360), 285 (sh), 323 (16600).

t li g A ~ LA o 71 The starting material is prepared, for example, as follows: a) (1R, 2R) -1,2-epoxy-1- (3-methoxyphenyl) -8- (4-acetyl-3-hydroxy-2-propyl phenoxy) -okta-3 (E), 5 (Z) -diene

The title compound is prepared according to Example Id) from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide (Example 1e) and (4R, 5R) -4,5-epoxy-5- ( 3-methoxyphenyl) -pent-2 (E) -enal, pale yellow oil. [α] 20 D (chloroform, 0.315%) * 78.4 ± 3.2.

b) (4R, 5R) -4,5-Epoxy-5- (3-methoxyphenyl) -pent-2 (E) -enal

The title compound is prepared according to Example Ib) from (2R, 3R) -2,3-epoxy-3- (3-methoxyphenyl) -propanol, yellow oil. Rf = 0.41 (hexane / ethyl acetate 3: 2), [α] 20 D (chloroform, 0.567%) = 168.9 ± 1.8e.

c) (2R, 3R) -2,3-Epoxy-3- (3-methoxyphenyl) propanol

The title compound is prepared according to Example 1a) from 3- (3-methoxyphenyl) -prop-2 (E) -enol, a pale yellow oil.

Rf = 0.31 (hexane / ethyl acetate 3: 2), IR (methylene chloride): 3550, 2890, 1580, 1565, 1465, 1445, 1130 cm-1,

Example 75: (1R, 2S) -1-Hydroxy-1- (3-methoxyphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 74), m.p. 206-208 °.

[α] 20 D (methanol, 0.293%) * 99.7 ± 3.4e, uv (methanol): Xmax (ε) 221 (57840), 235 (sh), 268 (29360), 282 (26400), 320 ( 16800).

I «72 94342

Example 76: (1R, 2S) -1-Hydroxy-1- (3-methoxyphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E), 5 (Z) dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic happometyyliesterl_

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-methoxyphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z)-diene, m.p.

53e (partially sublimed). UV (chloroform): λ max (ε) = 272 (29920), 285 (sh), 323 (15540), [α] 20 D (chloroform, 0.180%): 44.4 ± 5.6 °.

The starting material is prepared, for example, as follows: a) (1R, 2R) -1,2-epoxy-1- (3-methoxyphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 ( E), 5 (Z) -diene

The title compound is prepared according to Example Id)! 3- (4-acetyl-3-hydroxy-2-propylphenoxy) pentyl triphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-5- (3-methoxyphenyl) pent -2 (E) -enal (Example 74b), pale yellow oil. [α] 20 D (chloroform, 0.375%) = 72.5 ± 2.7e.

Example 77: (1R, 2S) -1-hydroxy-1- (3-methoxyphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 (E), 5 (Z) dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid-natriumsuola_

The title compound is prepared according to Example 2 against the corresponding; only from methyl ester (Example 76), m.p. 187 - 188®.

[α] 20 D (methanol, 0.150%) = 72.0 ± 6.7 °, UV (methanol):

Amax = 222 (55780), 268 (27820), 282 (25200), 321 (16200).

• · 73 0/7/0 7 * τ ^ * t ίϋ

Example 78: (1R, 2S) -1-Hydroxy-1- (3-trifluoromethyl-phenyl) -8- (4-trifluoro-acetyl-3-hydroxy-phenoxy) -octa-3 (E), 5 (Z) -dien -2-yl-7-thio-4-oxo-4H-l-benzopyran-2-karboksyylihappometyyliesteri_

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl-3-hydroxyphenoxy) -octa-3 (E), 5 ( Z) -dieenis-s. Rf = 0.23 (hexane / ethyl acetate 3: 2).

The starting material is prepared, for example, as follows: a) 3- (4-trifluoroacetyl-3-hydroxy-phenoxy) propyl bromide

The title compound is prepared according to Example 68a) from 2,4-dihydroxytrifluoroacetophenone and precipitates as a pale yellow oil. IR (dichloromethane): 3150, 2940, 1645, 1625, 1380, 1210, 1150, 1125, 1020, 940 cm-1.

b) 3- (4-Trifluoroacetyl-3-hydroxy-phenoxy) propyl-triphenylphosphonium bromide

The title compound is prepared according to Example 1e) from 3- (4-: trifluoroacetyl-3-hydroxy-phenoxy) propyl bromide and triphenylphosphine, m.p. 125-130 °.

c) (1R, 2R) -1,2-Epoxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl-3-hydroxy-phenoxy) -octa-3 (E), 5 (Z)-diene

The title compound is prepared according to Example Id) from 3- (4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy) -propyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethyl-phenyl) -pent-2 (E) -enal, Rf = 0.56 (hexane / ethyl acetate 2: 1).

74 g /, 7 / ίο

Example 79: (1R, 2S) -1-Hydroxy-1- (3-trifluoromethyl-phenyl) -8- (4-trifluoro-acetyl-3-hydroxy-phenoxy) -octa-3 (E), 5 (Z) -dien 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt in a cooled solution of 708 mg of the methyl ester of the title compound (cf. Example 78) in 25 ml of tetrahydrofuran, 10 ml of 0.1 N aqueous sodium hydroxide are added. The reaction mixture is stirred for 24 hours at room temperature, the solvent is released in vacuo and the residue is taken up in water. After clarification, the solution is lyophilized. The title compound is obtained as an olive-green, amorphous powder. 1 H-NMR (CD 3 OD): δ = 7.94, 7.78 - 7.46, 7.36, 6.90, 6.36, 6.04, 5.74, 5.42, 5.12, 4.42, 3.86 ppm.

Example 80: (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzo-pyran-2-karboksvvlihappometvvliesterl_

The title compound is prepared according to Example 1 (1R, 2R) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl) -3-hydroxy-2-propylphenoxy) octa- ; 3 (E), 5 (Z) -diene. Rf = 0.18 (toluene / ethyl acetate 5: 1).

The starting material is prepared, for example, as follows: a) 3- (4-Trifluoroacetyl-3-hydroxy-2-propyl-phenoxy) -propyl bromide

The title compound is prepared according to Example 68a)! 2,4-dihydroxy-3-propyl-trifluoroacetophenone and precipitates as a yellow oil. IR (dichloromethane): 3150, 2950, 2860, 1640, 1620, 1500, 1295, 1210, 1150, 1120, 1070 cm-1.

75

>. 'i A ~ l fI O JtZ

b) 3- (4-Trifluoroacetyl-3-hydroxy-2-propyl-phenoxy) -propyl-triphenylphosphonium bromide

The title compound is prepared according to Example 1e) from 3- (4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy) -propyl bromide and triphenylphosphine, m.p. 170 - 190®.

c) (1R, 2R) -1,2-Epoxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 (Z ) -diene

The title compound is prepared according to Example Id) from 3- (4-trifluoroacetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethyl-phenyl) -pent-2 (E) -enal, Rf = 0.55 (hexane / ethyl acetate 2: 1).

Example 81: (1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl) -8- (4-trifluoroacetyl-3-hydroxy-2-propylphenoxy) -octa-3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt in a cooled solution of 500 mg of the methyl ester of the title compound (cf. Example 80) ) 20 ml of tetra-:: hydrofuran, 6.6 ml of 0.1 N aqueous sodium hydroxide are added. The reaction mixture is stirred for 1 hour at 10 °, then liberated in vacuo from tetrahydrofuran and the remaining solution is lyophilized. The title compound is obtained as a yellow-green amorphous powder. 1 H-NMR (CD 3 OD): δ = 7.93, 7.77 - 7.60, 7.50, 7.36, 6.92, 6.43, 6.04, 5.73, 5.47, 5.13, 4.47, 4.00, 2.50, 2.38, 0.72 ppm.

94342 76

Example 82: (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenylthio) -octa-3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-ni-karboksvylihappometyyliesteri_

The title compound is prepared according to Example 1 (1R, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -octa-3 (E ), 5 (Z) -diene. Rf = 0.19 (hexane / ethyl acetate 3: 2).

The starting material is prepared, for example, as follows: a) 3- (4-Acetyl-3-hydroxy-2-propyl-phenylthio) propyl bromide

The title compound is prepared according to Example 68a) from 2-hydroxy-4-mercaptoacetophenone, a pale yellow oil.

b) 3- (4-Acetyl-3-hydroxy-2-propyl-phenylthio) propyl-triphenylphosphonium bromide

The title compound is prepared according to Example 1) from 3- (4-acetyl-3-hydroxy-2-propyl-phenylthio) propyl bromide and triphenylphosphine.

c) (1R, 2S) -1,2-Epoxy-1- (3-trifluoromethylphenyl) -8- (4-acetyl-3-hydroxy-2-propylphenylthio) -octa-3 (E), 5 (z ) -diene

The title compound is prepared according to Example Id) from 3- (4-acetyl-3-hydroxy-2-propylphenylthio) propyltriphenylphosphonium bromide and (4R, 5R) -4,5-epoxy-5- (3-trifluoromethylphenyl) pent-2 (E) -enaalista.

94342 77

Example 83: (1R, 2S) -1-Hydroxy-1- (3-trifluoromethyl-phenyl) -8- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -octa-3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-nl-2-carboxylic acid-natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 82).

Example 84: {1R, 2S) -1-Hydroxy-1- (3-trifluoromethyl-phenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenylthio) -deca-3 (E), 5 ( Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-nl-karboksvvllhappometyyllesteri_

The title compound is prepared according to Example 1 by (1R, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenylthio) -octa-3 (E), 5 (Z)-diene. Rf = 0.17 (hexane / ethyl acetate 3: 2).

The starting material can be prepared, for example, as follows: a) 5- (4-acetyl-3-hydroxy-2-propyl-phenylthio) pentyl bromide

The title compound is prepared according to Example 68a) from 2-hydroxy-4-mercaptoacetophenone, a pale yellow oil.

b) 5- (4-Acetyl-3-hydroxy-2-propyl-phenylthio) pentyl-triphenylphosphonium bromide

The title compound is prepared according to Example 1) from 5- (4- • acetyl-3-hydroxy-2-propyl-phenylthio) pentyl bromide and triphenylphosphine.

* · 78 94342 c) (1R, 2S) -1,2-epoxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenylthio) -deca-3 (E) , 5 (Z) -diene

The title compound is prepared according to Example Id) from 5- (4-acetyl-3-hydroxy-2-propyl-phenylthio) pentyl-triphenylphosphonium bromide and (4R / 5R) -4,5-epoxy-5- (3-trifluoromethyl-phenyl) -pent. -2 (E) -enolista.

Example 85: (1R, 2S) -1-Hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenylthio) -deca-3 (E), 5 (Z) dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-ne-2-carboxylic acid natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 84).

Example 86: (5R, 6S) -1,1,1-Trifluoro-5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) dien-6-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic lihappometyyliesterl_

The title compound is prepared according to Example 1 (5R, 6R) -5,6-epoxy-1,1,1-trifluoro-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E ), 9 (Z)-diene, pale yellow foam. Rf = 0.24 (hexane / ethyl acetate 3: 2).

The starting material is prepared, for example, as follows: a) (2R, 3R) -2,3-epoxy-7,7,7-trifluoro-heptanol

The title compound is prepared according to Example 1a) from 7,7,7-trifluoro-hept-2 (E) -enol, a pale yellow oil.

Rf = 0.38 (hexane / ethyl acetate 3: 2). [α] 2 D (chloroform, <· · 1 μg λ τ / 1 o / n jtZ 79 0.490%) = 15.3 ± 2.0 ", IR (methylene chloride): 3550, 3430, 2900, 1180, 1125 cm-1.

b) (4R, 5R) -4,5-Epoxy-9,9,9-trifluoro-non-2 (E) -enal

The title compound is prepared according to Example ib) from (2R, 3R) -2,3-epoxy-7,7,7-trifluoro-heptanol: an oil which crystallizes in the refrigerator. Rf = 0.63 (hexane / ethyl acetate 1: 1), [α] 20 D (chloroform, 0.210%) = 19.5 ± 4.8 ".

c) (5R, 6R) -5,6-Epoxy-1,1,1-trifluoro-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z ) -diene

The title compound is prepared according to Example Id)! 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propyltriphenylphosphonium bromide (Example 1e) and (4R, 5R) -4,5-epoxy-9,9,9-trifluoro-non-2 (E ) -anal, yellow oil. Rf * 0.56 (hexane / ethyl acetate 3: 2).

Example 87: (5R, 6S) -1,1,1-Trifluoro-5-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) dien-6-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 86), m.p. 190 - 191e. [α] 20 D (methanol, 0.268%) = 105.2 ± 3.7 °, UV (methanol): λmax 222 (48800), 235 (Sh), 267 (25920), 285 (22920), 320 (16000).

«80 g · 7/1 o y * T O" t i.

Example 88: (4R, 5S) -1,1,1-Trifluoro-4-hydroxy-13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -trideca-6 (E), 8 (Z) dien-5-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic happometyyliesterl_

The title compound is prepared according to Example 1 (4R, 5R) -4,5-epoxy-1,1,1-trifluoro-13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -trica-6 (E ), From 8 (Z)-diene, yellow oil.

The starting material is prepared, for example, as follows: a) (4R, 5R) -4,5-Epoxy-8,8,8-trifluoro-oct-2 (E) -enal

The title compound is prepared according to Example Ib)! (2R, 3R) -2,3-epoxy-6,6,6-trifluoro-hexanol, a pale yellow oil which crystallizes in the refrigerator. Rf = 0.53 (hexane / ethyl acetate 3: 2). [α] 20 D (chloroform, 0.290%) = 21.7 ± 3.4e, IR (methylene chloride): 3050, 2980, 2930, 2810, 2730, 1690, 1640, 1145 cm-1.

b) (4R, 5R) -4,5-Epoxy-1,1,1-trifluoro-13- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -trideca-6 (E), 8 (Z ) -diene

The title compound is prepared according to Example id) from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-8, 8,8-Trifluoro-oct-2 (E) -enal, yellow oil. Rf = 0.69 (hexane / ethyl acetate 3: 2).

φ • · 81 94342

Example 89: (4R, 5R) -1,1,1-Trifluoro-4-hydroxy-13- (4-acetyl-3-hydroxy-2-propylphenoxy) -trideca-6 (E), 8 (Z) -diene -5-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid-natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 88), m.p. 150-152 °.

[α] 20 D (methanol, 0.265%) = 72.5 ± 3.8 °, UV (methanol): λmax (ε) * 221 (44680), 231 (sh), 266 (22560), 285 (20560), 330 (Sh).

Example 90: (4R, 5S) -1,1,1-Trifluoro-4-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-6 (E), 8 (Z) dien-5-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic happometyyliesteri_

The title compound is prepared according to Example 1 (4R, 5R) -4,5-epoxy-1,1,1-trifluoro-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-6 (E ), From 8 (Z)-diene, pale yellow oil. Rf = 0.31 (hexane / ethyl acetate 3: 2).

The starting material is prepared, for example, as follows: a) (4R, 5R) -4,5-epoxy-1,1,1-trifluoro-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-6 ( E), 8 (Z) -diene

The title compound is prepared according to Example Id)! 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) butyl-triphenylphosphonium bromide (Example 62b) and (4R, 5R) -4,5-epoxy-8,8-trifluoro-oct-2 From the (E) -enal (Example 88a), which is an oil. Rf * 0.64 (hexane / ethyl acetate 3: 2).

• · · 82 QA I / IQ 7 -r ^ 1Λ ά.

Example 91: (4R, 5S) -1,1,1-Trifluoro-4-hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-6 (E), 8 (Z) dien-5-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester S (Example 90), m.p. 180-182 °.

[α] 20 D (methanol, 0.292%) = 77.1 ± 3.4 °, UV (methanol):

Xrnax (ε) = 222 (47480), 231 (sh), 267 (24840), 285 (22120), 321 (15800).

Example 92: (5R, 6S) -5-Hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) -dien-6-yl -7-Thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The title compound is prepared according to Example 1 from (5R, 6R) -5,6-epoxy-12- (4-acetyl-3-hydroxy-5-propyl-phenoxy) -dodeca-7 (E), 9 (Z)-diene. Rf = 0.43 (hexane / ethyl acetate 1: 1), [α] 20 D (methanol, 0.150%) = 22.0 ± 6.7 °, IR (methylene chloride): 3580, 2950, 1745, 1655, 1625, 1600 cm-1.

The starting material is prepared, for example, as follows: • a) (4R, 5R (-4,5-epoxy-non-2 (E) -enal)

The title compound is prepared according to Example Ib) from (2R, 3R) -2,3-epoxy-heptanol, yellow oil. Rf 1 0.29 (hexane / ethyl acetate 4: 1), [α] 20 D (Q, chloroform, 0.390%) = 21.3 ± 2.6e, IR (methylene chloride): 2950, 2920, 2860, 1690, 1640, 1100, 970 cm-1.

B) (5R, 6R) -5,6-epoxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) -diene 83 94342

The title compound is prepared according to Example Id) from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide (Example 1c) and (4R, 5R) -4,5-epoxy-non-2 (E) -enal, pale yellow oil. [α] 20 D (chloroform, 0.650%) = 23.7 ± 1.5β.

Example 93: (5R, 6S) -5-Hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) -dien-6-yl -7-Thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 92), m.p. 205 - 207e.

[α] 20 D (methanol, 0.278%) = 115.1 ± 3.6 °, UV (methanol): Amax (e) = 222 (50960), 235 (sh), 267 (27400), 285 (24000), 321 (16400).

Example 94: (5R, 6S) -5-Hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) -dien-6-yl -7-Thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The title compound is prepared according to Example 1 • from (5S, 6S) -5,6-epoxy-12- (4-acetyl-3-hydroxy-2-propylphenoxy) -dodeca-7 (E), 9 (Z)-diene, colorless foam.

[α] 20 D (methanol, 0.260%) = 136.2 ± 3.8 ·, UV (methanol): λmax (ε) 1221 (48040), 271 (28320), 327 (13200).

The starting material is prepared, for example, as follows: • · a) (4S, 5S) -4,5-epoxy-non-2 (E) -enal

The title compound is prepared according to Example Ib) from (2S, 3S) -2,3-epoxy-heptanol, yellow oil. Rf = 0.27 • * · 94342 84 (hexane / ethyl acetate 5: 1), [α] 20 D (chloroform, 0.325%) = 23.1 ± 3.0 °.

b) (5S, 6S) -5,6-Epoxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z)-diene

The title compound is prepared according to Example id) from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) propyl-triphenylphosphonium bromide (Example 1c) and (4S, 5S) -4,5-epoxy-non-2 (E) -enal, pale yellow oil. [α] 20 D (chloroform, 0.600%) = 24.6 ± 1.6e.

Example 95: (5S, 6R) -5-Hydroxy-12- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -dodeca-7 (E), 9 (Z) -dien-6-yl -7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium suola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 94), m.p. 204 - 206®.

[α] 20 D (methanol, 0.570%) = 121.1 ± 1.8®, UV (methanol):

Xmax (e) = 222 (51240), 235 (sh), 267 (27360), 284 (21400), 320 (16400).

Example 96: (5R, 6S) -5-Hydroxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -dien-6- 7-thio-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid methyl ester

The title compound is prepared according to Example 1 from (5R, 6R) -5,6-epoxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z)-diene , light yellow tough oil. [α] 20 D (chloroform, 0.424%) = 66.5 ± 2.4®, UV (chloroform): λ max (ε) = 270 (28560), 288 (sh), 325 (15240). 1 Li φ «• ·« 94342 85 The starting material is prepared, for example, as follows: a) (5R, 6R) -5,6-Epoxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca -7 (E), 9 (Z) -diene

The title compound is prepared according to Example id) from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-non-2 (E) -enal (Example 92a), pale yellow oil. [α] 2 D (chloroform, 0.441%) = 20.6 ± 2.3 °.

Example 97: (5R, 6S) -5-Hydroxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -dien-6-yl -7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium suola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 96), m.p. 193-195 °.

[α] 20 D (methanol, 0.284%) = 71.1 ± 3.5e, UV (methanol): Xjnax (ε) - 222 (49320), 232 (sh), 267 (25520), 286 (22680), 321 (16000).

Example 98: (5S, 6R) -5-Hydroxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -dien-6-yl -7-thio-4-oxo-4H-l-benzopyran-2-karboksyylihappometyyli-esteri_

The title compound is prepared according to Example 1 from (5S, 6S) -5,6-epoxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z)-diene. [α] 20 D (chloroform, 0.463%) = 79.0 ± 2.2e, UV (chloroform):? max (ε) 1270 (27120), 288 (sh), 326 (14960).

The starting material is prepared, for example, as follows: · (a) (5S, 6S) -5,6-epoxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -diene 86 94342

The title compound is prepared according to Example Id) from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (4S, 5S) -4,5-epoxy-non-2 (E) -enal, pale yellow oil. [α] 2 D (chloroform, 0.472%) = 18.8 ± 2.1 °.

Example 99: (5S, 6R) -5-Hydroxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (z) -dien-6-yl -7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium suola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 98), m.p. 193-195 °.

[α] 20 D (methanol, 0.296%) = 65.9 ± 3.4 °, UV (methanol): λmax (ε) = 222 (49760) / 232 (sh), 267 (25800), 285 (22520) , 320 (16000).

Example 100: (5R, 6S) -1,1,1-Trifluoro-5-hydroxy-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) dien-6-yl-7-thio-4-oxo-4H-l-benzopyran-2-karboksyyllhappometyyliesteri_

The title compound was prepared according to Example 1 (5R, 6R) -5,6-epoxy-1,1,1-trifluoro-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E ), From 9 (Z)-diene, pale yellow oil. Rf = 0.32 (hexane / ethyl acetate 3: 2).

• The starting material is prepared, for example, as follows: («(a) (5R, 6R) -5,6-epoxy-1,1,1-trifluoro-14- (4-acetyl-3-hydroxy-2-propyl-phenoxy) - tetradeca-7 (E), 9 (Z) -diene 0 A ~ ZAO 87

The title compound is prepared according to Example id) from 3- (4-acetyl-3-hydroxy-2-propyl-phenoxy) pentyl-triphenylphosphonium bromide (Example 29a) and (4R, 5R) -4,5-epoxy-9.9 , 9-trifluoro-non-2- (E) -enal (Example 86b), yellow oil. Rf = 0.72 (hexane / ethyl acetate 3: 2).

Example 101: (5R, 6S) -1,1,1-Trifluoro-5-hydroxy-14- (4-acyl-3-hydroxy-2-propyl-phenoxy) -tetradeca-7 (E), 9 (Z) -dien-6-yl-7-thio-4-oxo-4H-l-benzopyran-2-karboksyvlihappo-natriumsuola_

The title compound is prepared according to Example 2 from the corresponding methyl ester (Example 100). UV (methanol): λmax (6) = 222 (48800), 235 (sh), 267 (25920), 320 (16000).

Example 102: In a similar manner to that described in Examples 1-77, (1R, 2S) -1-hydroxy-1-phenyl-10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deca-3 ( E), 5 (Z) -dien-2-yl-7-thio-4-oxo- [4H-1-benzopyran-2-carboxylic acid sodium salt; mp

197-198 °, α20 £) (1% in methanol) = 49.2 ° 10 * (1R, 2S) -1-hydroxy-1- (3-fluorophenyl) -10- (4-acetyl-3-hydroxy- 2-propyl-phenoxy) -deca-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt; mp 226-228 °, α 2 O 2 (0.5% in methanol) = 59.8 ° ± 1.5 °.

(1R, 2S) -1-hydroxy-L- (3-methoxycarbonylphenyl) -10- (4-acetyl-3-hydroxy-2-propyl-phenoxy) -deka-3 (E), 5 (Z) -dien- 2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt; mp 172-174 °, α20D (0.45% in methanol) = 53.9 ° ± 2.2 °.

(1R, 2S) -1-hydroxy-1- (3,4-dichlorophenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) - dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid salt of NAT; mp 209-211 °, α20D (0.35% in methanol) = 69.9 ° ± 2.8 °.

(1R, 2S) -1-hydroxy-1- (2,4-dichlorophenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) - dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid salt of NAT; mp 204-206 °, α20D (0.21% in methanol) = 3.3 ° ± 4.8 °.

Example 103: In a similar manner to that described in Examples 1 to 101, the following compounds can be further prepared: (1R, 2S) -1-hydroxy-1- (3-bromophenyl) -8- (4-acetyl-3-hydroxy-2- propyl-phenoxy) -okta-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid sodium salt; mp 221-223 °, α20D (0.53% in methanol) = 91.3 ° ± 1.9 °.

* (1R, 2S) -1-hydroxy-1- (3-bromophenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca-3 (E), 5 (Z) -dien -2-yl-7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid salt of NAT; mp 202-204 °, α20D (0.18% in methanol) = 55.6 ° ± 5.6 °.

(5R, 6S) -1,1,1-trifluoro-5-hydroxy-15- (4-acetyl-3-hydroxy-2-propyl) -pentadeka-7 (E), 9 (Z) -dien- 6-yl-. 7-thio-4-oxo-4H-l-benzopyran-2-carboxylic acid salt of NAT; mp 140 °, ar 2 O (0.26% in CHCl 3) = 58.8 ° ± 3.8 °.

ti 8 9

Q h Λ O

(5R, 6S) -5-hydroxy-15- (4-acetyl-3-hydroxy-2-propylphenyl, for recourse) -pentadeka-7 (E), 9 (Z) -dien-6-yl-7-thiol 4-Oxo-4H-1-benzopyran-2-carboxylic acid sodium salt, (4R, 5S) -1-carboxy-4-hydroxy-11- (4-acetyl-3-hydroxy-2-propylphenoxy) -undeca-6 ( E), 8 (Z) -Dien-6-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid disodium salt, (4R, 5S) -1-carboxy-4-hydroxy- 12- (4-Acetyl-3-hydroxy-2-propylphenoxy) -dodeca-6 (E), 8 (Z) -dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2- carboxylic acid disodium salt, (4R, 5S) -1-carboxy-4-hydroxy-13- (4-acetyl-3-hydroxy-2-propylphenoxy) -trideca-6 (E), 8 (2) -dien-5- Yyl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid disodium salt, (4R, 5S) -1-carboxy-4-hydroxy-14- (4-acetyl-3-hydroxy-2-propylphenoxy ) -tetradeca-6 (E), 8 (Z) -dien-5-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid disodium salt.

• · I

Claims (5)

A process for the preparation of therapeutically active substituted alkanophenones of the general formula I r -J 1 -X-alk- (CH = CH) -CH-CH 3 -R 3 (I) T XX / "· o and their salts, wherein C 1 -C 4 alkyl or fluorinated C 1 -C 4 alkyl, R 2 represents hydrogen, C 1 -C 4 alkyl or fluorinated C 1 -C 4 alkyl, X represents oxy or thioa alk represents C 1 -C 4 alkylene, n is 1 or 2 , R3 is unsubstituted or substituted by C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl and / or halogen, or R3 is C1-C7-alkyl, ω, ω-trifluoro-C 1 -C 4 -alkyl, carboxy- (C 1-4 -alkyl or C 1 -C 4 -alkoxycarbonyl-C 1 -C 4 -alkyl and R 4 denotes carboxy, C 1 -C 4 -alkoxycarbonyl or N- (benzenesulfonyl) -carbamoyl, characterized in that the epoxide of the formula II O / O--4-X-alk- (CH = CH) -CH-CH-FL (Π) R2, in which R1f R2, X, alk. , n and R3 have the meanings given above, reacting a thiol of formula III (III) 91 g / 17 / io / '' t HS I, or the mixture of stereoisomers obtained according to the process is separated into its components and / or the free compound obtained according to the process is converted into a salt or the salt obtained according to the process into the free compound or another salt. Process according to Claim 1, characterized in that (1R, 2S) -1-hydroxy-1- (3-trifluoromethylphenyl) -10- (4-acetyl-3-hydroxy-2-propyl) is prepared. Phenoxy) -deca-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid or its sodium salt. Process according to Claim 1, characterized in that (1R, 2S) -1-hydroxy-1- (3-methylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) is prepared. Deca-3 (E), 5 (Z) -dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid or its sodium salt. Process according to Claim 1, characterized in that (1R, 2S) -1-hydroxy-1- (3-bromophenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) -deca- 3 (E), 5 (Z) -Dien-2-yl-7-thio-4-oxo-4H-1-benzopyran-2-carboxylic acid or its sodium salt. Process according to Claim 1, characterized in that (1R, 2S) -1-hydroxy-1- (3-methoxycarbonylphenyl) -10- (4-acetyl-3-hydroxy-2-propylphenoxy) deca- 3 (E), 5 (Z) -Dien-2-yl-7-thio-4-oxo-92,943,400-4H-1-benzopyran-2-carboxylic acid or its sodium salt.