JPS62164661A - Aromatic thioether - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides that the sulfur atom is optionally substituted with an aromatic group or a heteroaromatic group (M), e.g.
and/or is bonded to a phenyl group fused to a 6-membered heterocyclic ring, and is bonded to a linear group (L) having at least 11 carbon atoms by the other valence, and this linear group is On one side of the side chain there is a hydroxyl group in the α-position relative to the sulfur atom, preferably in the trans-configuration relative to the S-atom, and on the other side - or more double bonds and - The present invention relates to a novel asymmetric α-hydroxythioether which may have/or a phenylene ring.

The present invention particularly relates to the general formula (I): OR0 R"-B"-A-C-C-B'-R' (I)
H [wherein the common symbols have the following definitions, i.e. R
o represents hydrogen or an alkanoyl group having 1 to 7 carbon atoms; R1 represents an alkyl group having 1 to 3 carbon atoms, which may be substituted with one or more halogen atoms having an atomic number of up to 17; R2 represents an aliphatic group having 5 to 15 carbon atoms, A represents a single bond, an ethylene group or a vinylene group,
13' represents an alkylene group or a phenylene group having 1 to 7 carbon atoms, B2 represents a single bond, an ethylene group, or a phenylene group, and M is a subformula: 111. ．． 1□ (The symbols in the formula have the following definitions, that is, R3 represents hydrogen or an alkyl group having 1 to 4 carbon atoms, and X represents a single bond when NHlo, S or R4 represents hydrogen. , one of the symbols R4 and R5 represents hydrogen, and the other represents the group -Co-R'
or R4 and R5 together represent the group -Co-C(R6)=C(R')- or -Co-C(R
7) =C(R6)-, or R4 and RS together with X represent the group -N=C(R')-C(R')=CH-, and R
1' is =(CH2)b-COOR3 (in the formula b-0~
2), R7 represents hydrogen or an alkyl group having 1 to 4 carbon atoms, and R8 represents hydrogen, a methyl group, a methoxy group, or a halogen) and has salt-forming properties. It relates to a salt of the compound.

〇1 atom of hydroxy group is Royal Susu- to S- atom
Said general formula (I) for preferred compounds having the configuration
The steric configuration is as follows. The symbol of the first line is above the plane and the symbol of the third line is therefore below the plane (or vice versa), which according to the ahn-Ingold-Prelog convention, with respect to the formula shown. It corresponds to the relative configuration of two central carbon atoms (also S)-(S and).

The present invention further provides a method for producing the compound according to the present invention,
and pharmaceutical compositions containing these compounds as active ingredients,
and to a corresponding manufacturing method for manufacturing such compositions in a non-chemical manner. The present invention further provides for the use of the aforementioned compounds and pharmaceutical compositions, in particular in the alleviation and cure of medical conditions in which the significant leukotriene antagonistic and/or phospholipase-inhibiting activity of the compounds of the present invention may be utilized, e.g. It relates to therapeutic use in the case of allergies, in particular in the case of asthma and in particular in the case of inflammation of the skin and mucous membranes.

It was established several years ago that leukotrienes, particularly leukotrienes C and D, probably cause bronchoconstriction in asthma as the primary cause of the hypersensitivity reactions that directly lead to attacks (H, R8 Morris et al., Nature 285, 1045-1106). May 1980) and O
erning, S., trammerström and B.
, Samuelsson: Proc.

Natl, Acad, Sci, USA
Eie (4), 2014-2017 (I980
)reference〕.

In general, the basic structural skeleton of leukotrienes is as shown in the formula below for the most important representative example:
Linear icosanoic acid with a large number of unsaturated bonds and characteristic substituents at the 5- and 6-positions.
d) formed by

LTC-4: I? '=110COC11(Nll□
)CII□CIl□C0-1R2= -NIICII□
C00I+ 1, TD-4: R'=H-2R2--NIICII
□COO11LTIE-4: R'-11-1I?
2=-011 [In the formula, the steric configuration is as follows. The entire niolefin chain is in the plane of the paper, the valence bond line shown as an arrow extends above the paper, and the dashed line extends below the paper. . Leukotrienes are generally characterized in their physiological properties by causing significant contractions of a wide variety of smooth muscle types. From a health point of view, such effects are generally undesirable and the search for suitable leukotriene antagonists has therefore been the focus of research in this field.

In the compounds of the general formula (I) according to the invention, the basic linear structure of the known leukotrienes is retained as a general rule, and in general the structure present in aromatic compounds and in particular heteroaromatic compounds having a blood coagulation inhibitory effect. characteristics in combination through the sulfur atom. Surprisingly, the new compound has a clear leukotriene antagonism in various tests in vitro.

For example, the compound according to the invention may be about 0.1 to 25 μl
In the test concentration range of IO1/1, leukotriene-Da
(LTD4 - see discussion above)-induced smooth muscle contraction. This so-called 1,TD4-antagonism is demonstrated experimentally, for example, in the following way:
Synthetic leukotriene-DJ was incubated in an organ bath with a 1 g load in Tyrode's solution at 38° C. while bubbling with a mixture of 95% oxygen and 5% carbon dioxide.
(in the form of potassium salts) to cause contractions and record isotonic lines. After pre-incubation for 2 minutes, the degree of inhibition by the test substance was confirmed, and tCS was performed. , ie the concentration that reduces the test shrinkage by 50%. LTD, antagonism can also be demonstrated in vivo using aerosol administration by a standard bronchoconstriction test on guinea pigs. (Explanation of the test method can be found in Japanese Patent Application Laid-Open No. 61-1875.
6, pages 165-170) Surprisingly, the compounds of general formula (I) also have a pronounced inhibitory effect on other physiologically important enzyme systems. for example,
Inhibition of phospholipase A2 from human leukocytes was approximately 0.
．． It was observed in the experimental concentration range of 5 to 50 μmol/l (the experimental method for this measurement is described in
(Refer to Publication No.-18756).

Similarly, inhibition of phospholipase C from human platelets was observed in a tested concentration range of approximately 1 = 100 II mol/1 (experimental methods are described in JP-A-61-18
(See Publication No. 756).

The anti-allergic and anti-inflammatory effects shown in vitro by these methods are also confirmed in vivo in animal tests. For example, local anti-inflammatory activity may include, for example, G, Tone
lli and Th1baulL (Endocrinology 77.625,
(I965)) can be demonstrated by inhibiting croton oil-induced edema in the ears of normal rats at doses ranging from about 1 to about 100 mg/rn1.

Because the compounds of general formula (I) according to the present invention have these useful pharmacological effects, they can be used therapeutically in all cases where the allergenic effect of leukotrienes causes pathological conditions and this should be alleviated or eliminated. I can do it. Thus, these compounds may be used, for example, in the treatment of allergic conditions, such as asthma in particular, but also in the treatment of hay fever and obstructive pulmonary diseases, including cystic fibrosis. Similarly, these compounds possess anti-inflammatory activity and therefore can be used as anti-inflammatory agents, especially as external (topical) skin anti-inflammatory agents, to treat any type of inflammation such as mild skin hypersensitivity, contact dermatitis, rashes and burns. It is suitable for the treatment of sexually transmitted dermatoses and, as a mucosal anti-inflammatory agent, for the treatment of inflammation of the mucous membranes, such as the eyes, nose, lips, mouth and genital or anal area. These compounds are
Sunburn can also be used as an inhibitor. Furthermore, the high inhibitory activity against various blood factors is due to the general formula (
This suggests the possibility of using the compounds of I) in the treatment of thrombosis and blood coagulation.

As mentioned above, there are inter alia the adjacent S-
There is a general similarity in the preferred trans configuration of one atom and the linear structure of the group (L). However, the compounds according to the invention differ from leukotrienes in that the linear group (L) has no specific terminal carboxy group or is substituted with a varying number of halogen atoms.

Also, unlike leukotrienes, the number, character and spatial arrangement of multiple bonds in the group (L) are not limiting as the compounds of the invention may be free of them or may be substituted with phenylene groups. . Furthermore, the overall length of the group (L) is, within wide limits, contingent on the activity, and both the absolute and relative configuration of the two aforementioned asymmetric carbon atoms is, for example, active 5 (R) .

It is not limiting in terms of activity, as evidenced by the 6 (S)-epimer, which, compared to the natural leukotrienes, has a reverse absolute configuration of the carbon atoms in the 5 and 6 positions of the hydrocarbon chain (L).

-IflQ formula (among the preferred definitions of Ro during the day, mention may be made in particular of hydrogen and also of alkanoyl groups having 1 to 4 carbon atoms, such as the acetyl group).

In the general formula (I) above, the symbol R1 represents an unsubstituted alkyl group, such as an ethyl group, a propyl group and especially a methyl group, or a similar alkyl group in which the terminal carbon atom is substituted with chlorine or especially fluorine, such as chloromethyl or a fluoromethyl group, a 2-fluoroethyl group or a 3-fluoropropyl group or a perfluoroalkyl group, such as especially a trifluoromethyl group.

Aliphatic groups represented by the symbol R2 are linear groups, such as alkyl groups having 5 to 15 carbon atoms, preferably 7 to 12 carbon atoms, such as especially heptyl, nonyl, undecyl and dodecyl groups, or Corresponding mono- or polyunsaturated groups having 1, 2 or 3 multiple bonds, such as triple bonds and especially double bonds, in the cis- or trans-configuration, optionally in any combination. is preferable. These multiple bonds are preferably present as close as possible to the sulfur atom, that is, in the α-, β-positions relative to the sulfur-bearing carbon atom, or conjugated with the vinylene group represented by A. Preferred groups R2 of this type are
For example, 1-alkenyl, 1,3-alkagenyl and 1,3,6-alkagenyl, such as especially l-hebutenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl and l-dodecenyl group, 1,3-octagenyl group, 1.3-decajenyl group, 1.3-dodecadenyl group, and l,3゜6-dozocatrienyl group, in which all double bonds are independent of each other. can be present in the cis- or trans-configuration and can also form any combination.

The vinylene group represented by the symbol A in general formula (I) may be present in the cis- or trans-configuration.

-a When the symbol B1 in formula (I) represents an alkylene group having 1 to 7 carbon atoms, the group has the subformula -(cttz),
- (wherein a is 1 to 7, preferably 2 to 4) is preferred. Furthermore, when the symbol B1 represents a phenylene group, the group is preferably an m-phenylene group. Ignoring the group R', B1 may be substituted with one or more C1-C4 alkyl groups, in particular methyl groups (total number of carbon atoms up to 6), but may also be unsubstituted. It is preferable to have one.

-i 82 in formula (I) is preferably a single bond or a phenylene group, such as, in particular, a 〇- or p-phenylene group; as in the case of the symbol Bl, the phenylene group further comprises a total of carbon atoms It may have six or less alkyl groups, but is preferably unsubstituted. When B2 represents a phenylene group, A preferably represents a single bond or a vinylene group.

The symbol R3 as defined in the general formula (I) above preferably represents a methyl group and especially hydrogen as a constituent of the symbol R6, while as a substituent on the phenyl ring it represents a hydrogen or a propyl group. is preferred.

The aromatic group of subformula (M), i.e., the phenyl group is m-
or the back of these groups having an aliphatic substituent at the p-position,
R3 and Ra each represent hydrogen, X represents a single bond, R5 represents a group CO(CH2)b-COOR' (in the formula, preferably represents 2, and R9 represents a methyl group, an ethyl group or preferably hydrogen ), and in particular R1 and R5
each represents hydrogen, X represents a group -NH-, and R4
is the group -CO-(CI(2)b-COOR9 (in the formula O
12 or preferably l and R9 represents a methyl group, an ethyl group or preferably a hydrogen group, i.e.
Partial formula: [In the formula, R and R9 represent the above-described groups].

In addition to the heteroaromatic group of sub-formula (M), 4)' is an oxygen-containing group derived from chromene, especially sub-formula (M')
: free or sub-formula (M4)2(J(JR') [wherein R3 represents the above, preferably a propyl group or especially hydrogen, R9 represents an ethyl group or especially a methyl group and preferably hydrogen The following groups are mentioned.

Among the heteroaromatic groups of sub-formula (M), derived from quinoline, sub-formula (M'): [wherein R9 represents an ethyl group or in particular a methyl group or hydrogen and RIG represents a halogen, such as in particular chlorine or More particularly, mention may be made of nitrogen-containing groups having the 1-oxy group.

The above-mentioned compounds furthermore include, with particular preference, compounds in which the carboxy group is present in the form of a salt, especially an alkali metal salt.

The remaining compounds of the -C formula ([) can also exist in the form of salts, depending on their individual properties. Compounds with suitable acidity, such as especially those with free carboxyl groups, are capable of forming salts with bases, especially inorganic bases, preferably physiologically acceptable alkali metal salts, especially sodium and potassium salts. I can do it. Compounds of general formula (I) with suitable basicity, such as those of the subformula (
The esters of the quinoline derivatives of M3) can be present in the form of acid addition salts with customary pharmaceutically acceptable acids, in particular physiologically acceptable salts. Among the inorganic acids, mention may be made in particular of the hydrohalic acids, such as hydrochloric acid and sulfuric acid and of phosphoric or pyrophosphoric acid; among the organic acids, mention may be made in particular of the sulfonic acids, such as aromatic sulfonic acids, such as benzenesulfonic acid, p-toluenesulfonic acid. , embonic acid and sulfanilic acid, or lower alkanesulfonic acids such as methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid and ethylenedisulfonic acid, as well as aliphatic, cycloaliphatic,
aromatic or heterocyclic carboxylic acids such as formic acid, acetic acid,
Propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, hydroxymaleic acid, oxalic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p -hydroxybenzoic acid, salicylic acid and p-aminosalicylic acid, and ascorbic acid. Compounds of general formula (r) containing basic and acidic functional groups, such as quinoline derivatives of subformula (M3) with free carboxy groups,
It may be in the form of an inner salt.

Among the compounds of general formula (I) according to the invention, the symbols have the following definitions, namely, Ro represents an alkanoyl group having 1 to 4 carbon atoms or preferably hydrogen, and R1 represents a methyl group, a chloromethyl group. or represents a trifluoromethyl group, and R2 is a linear alkyl group having 7 to 15 carbon atoms or 2
．． represents a corresponding group having 3 or preferably 1 double bond, such as the group mentioned above, 8 represents a cis- or trans-vinylene group, and Bl has 2 to 5 carbon atoms, preferably a carbon atom represents a number 2 or 3 cotton-like al-1-lene group, B2 represents a single bond, M is a subformula (M2), (
M3) and preferably compounds having the definitions listed under (Ml), and among these compounds, in particular, compounds having a free carboxyl group and their pharmaceutically acceptable salts, e.g. Alkali metal salts include sodium and potassium salts.

Furthermore, the symbols have the following definitions: Ro represents an alkanoyl group having 1 to 4 carbon atoms or preferably hydrogen, R1 represents a methyl group, a tetramethyl group or a trifluoromethyl group, and R2 represents a linear alkyl group having 7 to 15 carbon atoms, preferably 8 to 12 carbon atoms, such as the group mentioned above, A represents a single bond or a vinylene group in cis- or trans-configuration, and B1 represents a carbon atom number 2-5,
Preferably represents a linear alkylene group having 2 or 3 carbon atoms, B2 represents a phenylene group, in particular a 〇- or p-phenylene group, M represents subformulas (M2), (M3) and preferably (Ml ) General formula (I) with the definitions listed below
Among these compounds, mention may be made in particular of compounds with free carboxy groups and their pharmaceutically acceptable salts, such as the alkali metal salts, such as the sodium salts and the calylum salts.

In particular, the symbols have the following definitions: Ro represents an alkanoyl group having 1 to 4 carbon atoms or preferably hydrogen, R1 represents a methyl, chloromethyl or trifluoromethyl group, and R2 represents a carbon represents a linear alkyl group having 7 to 15 atoms or a corresponding group having 2.3 or preferably 1 double bond, such as the group mentioned above, A represents a cis- or trans-vinylene group, B1 represents a phenylene group, in particular an m-phenylene group, B2 represents a single bond, M represents subformulas (M2), (M3) and preferably (Ml
), and among these compounds, in particular, compounds having a free carboxyl group and their pharmaceutically acceptable salts, such as alkali metal salts, Examples include sodium salts and potassium salts.

Furthermore, in particular, the symbol has the following definition: R
o represents an alkanoyl group having 1 to 4 carbon atoms or preferably hydrogen, R1 represents a methyl group, chloromethyl group or trifluoromethyl group, and RZ has 7 to 15 carbon atoms
, preferably a linear alkyl group having 8 to 12 carbon atoms, such as the groups mentioned above, A is a single bond or especially a vinylene group in the cis- or trans-configuration, and B1 is a phenylene group, especially m-phenylene. a general formula (]) in which B2 represents a phenylene group, in particular a 0- or p-phenylene group, and M has the definitions given under the subformulas (M2), (M3) and preferably (Ml); Among these compounds, mention may be made in particular of the compounds having free carboxy groups and their pharmaceutically acceptable salts, such as the alkali metal salts, such as the sodium and potassium salts.

Furthermore, particular mention may be made of the compounds of the general formula (I) described in the Examples.

The thioethers according to the invention can be prepared in a manner known per se, for example in the following manner: having up to 11 carbon atoms and corresponding to the groups (L) mentioned at the outset,
In particular, partial formula (■): / \ (II) R2-B" -A-CH-CH-Bl -R1 [in the formula A
, B', B2, R' and R2 represent the above, preferably the two hydrogen atoms of the oxirane ring are mutually in trans-configuration], or preferably trans- The epoxide is reacted with a mercapto derivative or a salt thereof corresponding to the group (M) of the general formula (■): H-3-M (III) [wherein M represents the above], and if necessary, Then, the obtained compound of general formula (I) in which Ro represents hydrogen is referred to as R
o represents an alkanoyl group having 1 to 7 carbon atoms, is acylated to the corresponding compound and/or hydrolyzes the compound present in the form of an ester into a free acid or a salt, and/or has salt-forming properties; The resulting free compound is converted into a salt and/or the compound is adducted from the corresponding salt form.

This reaction is carried out under conditions known per se from about -20°C to about +5°C.
At a temperature of 0 °C, preferably at room temperature, in particular in a basic medium, e.g.
(e.g. triethylamine or ethyldiisopropylamine), dialkylbenzylamine (e.g. N, N-
dimethylbenzylamine), N,N-dialkylaniline (eg N,N-dimethylaniline) or N-methyl- or N-ethyl-piperidine or N.

Performed in the presence of No-dimethylpiperazine. Usually the reaction is carried out in an inert organic solvent, such as a lower alkanol, such as methanol or ethanol.

Acylation of the hydroxy group formed in the main step may be carried out later, and is a reaction that yields a compound of general formula (I) in which Ro represents an alkanoyl group having 1 to 7 carbon atoms,
In a manner known per se, the primary product, for example in which Ro represents hydrogen, is converted to the desired acid, such as formic acid, or a suitable reactive acid derivative, in particular a halide (preferably a chloride), a symmetrical anhydride, a mixed anhydride (in particular This can be carried out by treatment with trifluoroacetic acid (anhydride) or ketene.

As reaction medium, e.g. diethyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane), acid esters (e.g. ethyl acetate) and acid amides (e.g. acetamide, dimethylformamide), and optionally various basic non-acylatable organic bases, e.g. heteroaromatics. family bases (e.g. pyridine, colicin, quinoline)
, tertiary amines (e.g. triethylamine, N-ethylpiperidine, N-methylmorboline, N,N'-dimethylpiperidine) or 1,5-diazabicyclo(5,4,
0)-undec-5-ene can be used. The operation is also carried out using advantageous combinations of all these solvents. The reaction temperature may range from about -70°C to the boiling temperature of the mixture, preferably from about -20°C to about 30°C.

For the main reaction (condensation with epoxide), the general formula (Ill)
The mercapto component is used in particular in the form of its alkyl ester having from 1 to 4 carbon atoms (eg methyl ester or ethyl ester). If it is desired that the Rh'4 product according to the invention is in the form of M discrete or its salts, the resulting ester must be hydrolyzed. Hydrolysis is carried out under customary conditions, for example using alkali metal carbonates (e.g. sodium carbonate or potassium carbonate) or dilute alkali metal hydroxides (e.g. sodium hydroxide or potassium hydroxide). It is carried out in the presence of water in a water-miscible solvent such as a lower alkanol (for example methanol or ethanol) or a cyclic ether (for example tetrahydrofuran or dioxane) at about 0 to 80°C, preferably at room temperature. In the case of particularly sensitive compounds, milder conditions may be used, e.g. at particularly low temperatures (preferably below room temperature).
, using stoichiometric equivalents of alkali, using short reaction times, and optionally with analytical monitoring, e.g. by thin-layer chromatography, the ester group can be removed while retaining the less alkali-stable groups. However, during the course of this operation the acylated hydroxy group in the group R0 is generally removed at the same time.

The starting materials for the condensation step according to the invention are known per se or can be obtained in a known manner by analogous known methods. For example, important mercapto compounds of the -11 formula (II[) have been described (see e.g. EP-A-0123543) and other similar acids have been prepared starting from the corresponding known starting materials. can be obtained in the same way.

The cis- or preferably trans-epoxides used as starting materials, such as the epoxides of the one-limited formula (TI) mentioned above, can in particular be prepared using the same methods as used for the synthesis of leukotrienes. For example, in a typical general synthesis method, R1-substituted henzaldehyde or general formula (■): 0=CH(CHz)-R' (IV) [
A saturated aliphatic aldehyde (alkanal) in which a and R1 are as defined above is used.

This compound is condensed with formylmethylenetriphenylphosphorane (or an equivalent reagent) to form the corresponding α of the general formula (V): in which BI is as defined above.

A β-unsaturated aldehyde, ie, a 2-trans-alkenal, is produced. This compound is then epoxidized in a manner known per se, preferably under weakly alkaline conditions (e.g. in the presence of an alkali metal carbonate), using an aqueous hydrogen peroxide solution to give the tranoxide eboxide, i.e. the general formula (■). : [In the formula, 81 represents the above] 2
(Shakudan).

3(SR)-epoxy-alkanal is produced.

In a similar manner, aldehydes with cis-double bonds are
2 (R3), giving rise to the corresponding cis-epoxy configuration in the 3 (R3)-epoxyaldehyde. The epoxyaldehyde is condensed with the corresponding known benzylidene or alkylidene triphenylphosphorane to form the desired trans-unsaturated epoxide,
For example, it can be an epoxide of the general formula (n) where 8 represents a vinylene group. For polyunsaturated epoxides, such as those of general formula (II) in which R2 has one or more double bonds, there is an indirect alternative. That is, instead of the Winotech reaction with ylidenephosphorane having an unsaturated bond in its chain, the aldehyde of general formula (IV) is first reacted with γ-triphenylphosphoranylidenebutyraldehyde (4-triphenylphosphoranylidenebutyraldehyde). 4 (R3), 5 (R3)-epoxy-
The 2-alkenal alone is condensed with a single saturated alkylidene triphenylphosphorane or with a less complex henzylidene or alkenylidene triphenylphosphorane to give the desired epoxide, such as the epoxide of general formula (II). In the case of an epoxide of the general formula (II) in which A represents a single bond and B2 represents a phenylene group, the aldehyde of the general formula (IV) is reacted with the corresponding benzylidene triphenylphosphorane and then epoxidized. However, in this case usually a mixture of cis- and trans-styrene derivatives is formed, which has to be separated into two individual isomers, or a mixture of two isomeric epoxides is formed. , from which four stereoisomers can then be formed in the main step.

If individual diastereomers are desired, at any stage individual diastereomers of the starting materials can be used, or from racemic or optically inactive starting materials, stereoselective reaction conditions or optical Diastereomers are formed preferentially by active reagents, or racemic diastereomeric mixtures are separated optically into individual diastereomers by physical separation methods, optionally using optically active auxiliaries. It is advantageous to separate the

However, from a stereochemical point of view, the condensation of the product components of the general formulas (II) and (III) and the preparation of the starting materials according to the invention in particular use stereochemically homogeneous starting materials in each case; The reaction is carried out as stereoselectively as possible, for example by using optically active reagents and/or auxiliaries, and by isolating the stereochemically homogeneous product from the reaction mixture immediately after the reaction. for example,
In preparing the unsaturated starting materials, the isomers with possible cis- and trans-double bonds are immediately separated from each other, and for this purpose the customary physical separation methods, e.g. Chromatography is suitable. For the main reaction, in particular, the epoxides of the general formula (II) are used as individual trans-stereoisomers, but also in racemic form (as is customary by epoxidation of olefins). If the mercapto moiety of general formula (III) is optically active, it is preferably used in the form of the individual optical enantiomer. This makes it possible to separate the two optically active diastereomers formed from each other simply by conventional physical methods, such as chromatography. When using optically inactive mercap[ components, the individual optically active products can be obtained by cleavage into the enantiomers using optically active auxiliaries, e.g. optically active bases. It is absolutely necessary to use a method of forming salts with. All suitable separation methods are known per se;
They can be repeated or suitably combined with each other.

Since there is a close relationship between the free form of the new compound and its salt form, in the above and below descriptions, the free compound or its salt also means the corresponding salt or free compound, respectively. shall be.

The invention further provides that the compounds obtained as intermediates at any stage of the process are used as starting materials to carry out the remaining steps or that the starting materials are used in salt form or under the reaction conditions. It also relates to embodiments for forming.

The invention also relates to the process according to the invention and the new starting layer t4 and medium 1111 bodies produced in its initial stages.

The starting materials and reaction conditions are preferably selected in such a way that the compounds mentioned above as particularly preferred are obtained.

The invention furthermore relates to pharmaceutical compositions and medicaments comprising one compound of general formula (I) or a pharmaceutically acceptable salt thereof according to the invention. The pharmaceutical compositions according to the invention are especially prepared for topical administration to mammals, especially humans, and especially for inhalation administration, for example in the form of an aerosol, a finely divided powder or a finely sprayed solution, containing the active ingredient. Alone or together with a pharmaceutically acceptable carrier material.

Pharmaceutical preparations for external and topical use include, for example, for skin treatment, lotions and creams, including liquid or semisolid oil-in-water or wood-in-oil emulsions, and ointments, preferably containing preservatives. be. Preparations suitable for the treatment of the eye include eye drops containing the active compound in aqueous or oily solution;
and an eye ointment preferably manufactured under sterile conditions. Suitable formulations for nasal treatment include aerosols and sprays (similar to those described below for treatment of the respiratory tract), coarse powders administered by rapid inhalation through the external nostrils, and, in particular, active compounds. This is a nasal spray containing the following in an aqueous or oily solution.

Agents suitable for topical treatment of the oral cavity include oral agents containing the active compound in a composition formed from -1i1Q, sugar and acacia or tragacanth (optionally flavored) and, for example, gelatin and glycerin or Included are soft lozenges containing the active ingredient in an inert composition consisting of sugar and gum acacia.

Pharmaceutical compositions suitable for administration in the form of an aerosol or spray may include, for example, a suitable pharmaceutically acceptable solvent,
For example, solutions, suspensions or emulsions of active ingredients of general formula (I), especially in ethanol and water or mixtures of such solvents. If desired, the composition may contain other pharmaceutical auxiliaries, such as nonionic or anionic surfactants, emulsifiers and stabilizers, as well as other types of active ingredients, and propellant gases, such as pressurized an inert gas or, in particular, a readily volatile liquid, preferably boiling below normal atmospheric pressure and below normal room temperature (e.g. from about -30°C to +10°C), such as an at least partially fluorinated polyhalogen; It is particularly advantageous to mix with lower alkanes or mixtures of such liquids. Such pharmaceutical compositions, which are used primarily as intermediates or stock mixtures for the manufacture of the corresponding drug in finished form, usually contain from about 0.1 to about io% by weight of active ingredient, especially about 0.0% by weight. 3 to about 3% by weight
of? Included in solubility. To produce a finished drug,
Such pharmaceutical compositions are placed in suitable containers, such as small bottles and pressure bottles (equipped with a spray device or valve suitable for the purpose). Preferably, the valve is configured as a metered valve which, when operated, releases a predetermined amount of liquid corresponding to a predetermined dose of active ingredient. When producing a finished drug, the corresponding repellent pharmaceutical composition in the form of a stock solution and the propellant can also be placed separately in a container and then mixed. The amount and frequency of administration of the active ingredient of general formula (I) to be administered will depend on the specific activity and duration of action of the individual compound, the severity of the disease to be treated and its symptoms, and the sex of the mammal to be treated; Depends on age, weight and individual responsiveness.

The recommended daily dose of a compound of general formula (I) according to the invention for a mammal (especially a human) weighing 75 kg is:
On average about 25B to about 500mg, preferably about 25B
~250 mg, as needed.
Advantageously, it is administered several times a day.

The invention further provides a general formula according to the invention for the alleviation or cure of pathological conditions and/or symptoms in the body of mammals, in particular humans, which are due to the allergenic action of leukotrienes and which occur in particular in the case of asthma. Concerning the use of the active ingredient of (I). This use and the corresponding method of treatment involves treating the infected body or body part with an antiallergic effective amount of a compound of the invention (alone or in the form of a medicament, especially a pharmaceutical composition prepared for inhalation). Characterized by treatment. "Anti-allergic effective amount" means an amount of active ingredient sufficient to significantly inhibit the contractions caused by leukotrienes.

The following examples illustrate the invention in further detail:
It is not intended to limit the scope of the invention.

All temperatures are given in degrees Celsius.

Example C] ■Soil: 3-[5(S,), 6(R)-5-hydroxy-7-cis-pentadecen-6-ylthiocombalonanilic acid methyl ester and its 5(R),
6(S)-stereoisomer methanol 10-5(S), 6(S)
5゜To a solution of 1.1 g of 6-nipoxy-7-cis-pentadecene was added triethylamine 6.2- and 3-mercaptomaloneanilinic acid methyl ester (European Patent Application Publication No. 0).
123543) are added, the whole is stirred for 16 hours at room temperature, concentrated to dryness by evaporation in vacuo and the residue is chromatographed on silica gel with hexane/ethyl acetate (3:2). The title compound is obtained in the form of a pale yellow oil.

[α] 30=+3.3±1.6° (c=0.62%,
(in Chloroporum).

In a similar manner, the corresponding 5 (R), 6 (
R) -Epoxide to stereoisomer 3-(5(R)
, 6(S)-5-hydroxy-7-cis-pentadecen-6-ylthiocombalonanilic acid methyl ester is obtained.

5 (S), 6 (S) used as starting materials
) -5,6-Eboxy-7-cis-pentadecene is
For example, it is prepared in the following way: a) 16.9 g of 2-heptenol in 200 ml of 2-trans-heptenol ether
is added dropwise to a solution of 10 g of lithium aluminum hydride in 400 ml of ether at 0° C. within 30 minutes without stirring, and the resulting reaction mixture is boiled under reflux overnight. Excess LiA11ln is destroyed by adding 40-ethyl acetate while cooling in an ice-water bath, and the resulting reaction mixture is taken between ether and cold IN sulfuric acid. Acidic (pH2
) the aqueous layer is extracted again with ether, the combined organic extracts are dried over magnesium sulphate and concentrated by evaporation in vacuo. When the residue (I8 g) was distilled under reduced pressure, 13.2 g of 2-trans-heptenol was obtained with a boiling point of 71.5-72
It is obtained in the form of a colorless oil of ”C/13 mbar.

Under anhydrous conditions, a stirred solution of 66.3- and 38.51 ml of tetraisopropyl orthotitanate and D-(-)-tartrate diethyl ester in 1.11 methylene chloride was added to
At 3°C, 2-trans-heptenol (see previous section) 25
．． 7 g and 140 ml of a 3.2 M solution of jet-butyl hydroperoxide in toluene are added in succession, the whole is kept at -20° C. for 16 hours, and at -23° C. 55 ml of an aqueous solution of L-tartaric acid with a concentration of 10% are added dropwise. . After another 30 minutes,
The mixture is warmed to +20° C. and stirred further until the organic layer is clearly separated. The organic layer was treated with sulfite at a concentration of 1%.
- Stir for 1 hour with 1 liter of aqueous lithium solution, separate, wash with water, dry over 1-lium sulfate and concentrate in a water pump vacuum. The residue was dissolved in 1.61 liters of diethyl ether, cooled to 0°C and dissolved in 615 ml of N sodium hydroxide solution.
ml is added dropwise and the whole is stirred at O''C for 30 min 1,2. The separated organic layer is washed with saturated sodium chloride solution, dried and concentrated to give 2 ( r2
), 3 (R)-2,3-epoxyheptanol is obtained, which is processed directly in the next step.

2(S), 2.3 of 3(S)-epimer
-Epoxyheptanol can also be obtained in the following way: in a solution of 5.94 g of tetraisopropyl orthotitanate and 4.12 g of L-(+)-diethyl tartrate in 210 mff1 of methylene chloride at -20°C. , 2-trans-heptenol in 1719 ml of methichloride 2.28
g (20 mmol), then 4.1 M of tert-butyl hydroperoxide in 1,2-dichloroethane.
9.75 mIt of solution are added in succession. The resulting reaction mixture is left at -20°C overnight. dimethyl sulfide 8m
After addition of 1 liter, the whole was stirred at -20°C to -23°C for 45 minutes, then 50 ml of 1°-(+)-tartaric acid aqueous solution with a concentration of 10% was added, and the whole was further stirred at -20°C. Stir for 30 minutes and 60 minutes without cooling. The organic phase is separated, then washed with too much water, dried over magnesium sulfate and then evaporated under reduced pressure. The residue is dissolved in 150 ml of ether and stirred for 30 minutes at 0° C. with 60 ml of 1N sodium hydroxide solution, the aqueous phase is separated off and extracted again with ether, and the combined organic extracts are shaken with sodium chloride solution. Drying the organic portion over magnesium sulfate and removing the solvent in vacuo yields 2(S), 3
(S>-2.3 g of 2,3-epoxyheptanol are obtained in the form of a colorless unstable oil, which is processed directly in the next step.

c) 2(S),3(R)-2,3-Epoxyhebucnal PA of 110.1 g of pyridinium chlorochromate and 41.9 g of sthorium acetate in 500 ml of methylene chloride.
I↑2(R) in suspension in 100 Wdl of methylene chloride.

3 (R)-2,3-epoxyheptanol 13.3
The solution of g is completed within 30 minutes, maintaining the temperature at 25° C. with gentle cooling. After 3 hours, the reaction mixture is diluted with 500 ml of diethyl ether and passed on silica gel. The oral fluid is washed with p118 phosphate buffer, dried over sodium sulfate and concentrated by evaporation. The residue was purified on silica gel with petroleum ether (boiling point 30-45°C) and diethyl ether (3:2). Chromatography using the R compound results in 2 (S), 3 (R)-2
, 3-epoxyheptanal is obtained in the form of a colorless liquid. The product has similar spectral properties to its 2 (R), 3 (S) monoenantiomer (see below j, il).

The 2(R),3(S)-epimer can also be obtained in the following way: A freshly prepared solution of 5.5 g of chromium trioxide and 8.76 g of pyridine in 10 ml of methylene chloride is added with 28 g of methylene chloride at room temperature. - Middle 2 (S), 3 (S) -
A solution of 1.2 g of 2,3-epoxyheptanol is added and the resulting reaction mixture is stirred for a further 30 minutes.

The dark reaction mixture is decanted from the precipitated material, which is washed with 160 ml of methylene chloride, and the combined organic portions are washed with 80 mL of phosphate buffer, pH 8.0.

After drying over magnesium sulfate and concentration by evaporation under reduced pressure, the remaining crude product was added to 90 g of Merck.
ck) Toluene and ethyl acetate on silica gel 60 (
4;1) Chromatography using the mixture. 2
464 mg of (R),3(S)-2,3-epoxyheptanal are obtained in the form of a colorless oil. (α
] Oto = +101° ±l.

(1.225% in C11C1j) i I R (CIl
□C1z): 2950.2925.2860.28
15.2730.1722.1462.1432.13
80.1360.1230.1156.850cm-'
.

Tetrahydrofuran 4. To a solution of 370 mg of octyltriphenylphosphonium fluorite in 1 ml and 26-ml of hexamethylphosphoric triamide, add 20% of butyllithium in hexane at -78°C under alcohol.
Add 0.31mff1 of liquid 8 dropwise and heat the resulting solution to -78°.
Stir for an additional 30 minutes at C. 1. Add tetrahydrofuran to the resulting triphenylphosphoranylidene octene solution. O
A solution of 1 ml of 2 (S), 3 (R)-2,3-epoxyheptanal in 100 ml is prepared at -78 DEG C. and the resulting reaction mixture is stirred at -78 DEG C. for a further 30 minutes. For work-up, the reaction mixture was mixed with ether 100d and pH 8.0.
of phosphate buffer 1ffE30- and then the two phases are extracted again with ether and buffer respectively.

Dry the combined ethereal portion over magnesium sulfate,
Concentration by evaporation in vacuo gives the oily crude product 421
mg is obtained. This is stirred with 2-3 ml of a 11 mixture of hexane and ether, the triphenylphosphine oxide precipitated in the form of crystals is separated off, and the oral liquid is concentrated by evaporation. The resulting residue (95 mg I) is chromatographed using the same eluent on an aluminum oxide column (I0 g) prepared in hexane containing 65% triethylamine. 90.6 mg of the title compound are obtained in the form of a viscous yellowish oil. can get.

Epimer 5 (R), 6 (R) -5,,
6-Evogysy 7-cis-pentadecene is obtained in a similar manner from epimeric 2(R),3(S)-2,3-epoxyheptanol.

Hitsugi Rho N=3-[5(R),6(S)-5-hydroxy-7=cis-icosen-6-ylthio]-malonanilic acid methyl ester 5(R),6(R)-5,6- In a similar manner as described in Example 1, but starting from eboxy 7-cis-icosene and 3-mercaptomaloneanilic acid methyl ester, the title compound is obtained in the form of an oil.

5 (R), 6 (R) used as starting materials
) -5,6-Eboxy-7-cis-icosene is 2(
R), 3 (S)-2,3-epoxyheptanal as described in Example 1d by reacting with triphenylphosphoranylidene tridecene (prepared from tridecyltriphenylphosbonium bromito and butyllithium) Obtained in a similar manner.

Example 1B: 3-[5(S),6(R)-5-hydroxy-7=
Cis-icosene-6-ylthiocombalonanilic acid methyl ester 5 (S), 6 (S) -5,6-eboxy 7-cis-icosene (2(S), 3 (R) -2,3
The title compound is obtained in a similar manner to that described in Example 1, but starting from Example IA) and 3-mercaptomaloneanilinic acid methyl ester.

IR(CIl□Cl2): 2930.2850.
1725.1690.1590.1535.1350c
m -1° spot I near-(5(S),6(R)-5-hydroxy-7-cis-pentadecen-6-ylthio]-4-oxo 4H
-chromene-2-carboxylic acid methyl ester and its 5
(R), 6 (S)-stereoisomer [α) Bo
=-9,s±1.6° (C-0,63 in chloroform
%) of the title compound or its 5(R).

The 6(S)-stereoisomers are 5(S) and 6(S), respectively.
)- or 5 (R) , 6 (R) -5,6-nipoxy-7-cis-superpecitadecene and 7-mercabuto 4-oxo-4H-chromene-2-carboxylic acid methyl ester (European Patent Application No. 0123543) It is obtained in a similar manner to that described in Example 1, starting from the publication).

1 person: ? -(5(R),6(S)-5-hydroxy-7-
cis-icosen-6-ylthio]-4-oxo-4H-
From chromene-2-carboxylic acid methyl ester 5(R),6(R)-5,6-eboxy-7-cis-icosene (see Example IA) and 7-mercabuto 4-oxo-4H-chromene-2-carboxylic acid methyl ester Starting in a similar manner to that described in Example 1, the title compound is obtained in the form of a yellowish oil.

Advance 1nia -(5(S), 6(R)-5-hydroxy-7-cis-icosen-6-ylthio]-4-oxo-41(-chromene-2-carboxylic acid methyl ester 5(S), 6 (S)-5,6-epoxy-7-cis-icosene (prepared analogously to Example IA using 2(S),3(R)-2,3-epoxyheptanal) and 7-mercabuto-4-oxo- 4H-chromene-2-
The title compound is obtained in a similar manner to that described in Example 1, but starting from the carboxylic acid methyl ester.

I R (C112CI2): 2930.2860.
1750.1660.1600.1415 cm-'.

Carbon main near-(5(S),6(R)-5-hydroxy-7-
trans,9-cis-icosadien-6-ylthio]-
4-oxo-48-chromene-2-carboxylic acid methyl ester 5 (S), 6 (S) -5,6-epoxy-futrans, 9-cis-icosadiene and 7-mercapto-4-oxo-4H- In a similar manner as described in Example 1 using chromene-2-carboxylic acid methyl ester,
The title compound is obtained.

[α] to 8 = -97.4 ± 0.9° (C-1,1% in chloroform) 5 (S), 6 (S) used as starting materials
-5,6-Eboxy7-1-lance,9-cis-icosadiene is produced, for example, as follows: 2 (R), 3 in 350 ml of chloroborum.
10 g of (S)-epoxyheptanal (see Example 1c) and 23.7 g of formylmethylenetriphenylphosphorane
The solution is heated to reflux under argon for 1.5 hours.

Remove the solvent from the cooled solution in vacuo at room temperature and wash the residue with ether/hexane (4:1).

Concentrate the extract in vacuo and transfer the residue onto silica gel in hexane/ethyl acetate (5:l, containing 1% triethylamine).
Chromatography is performed using ζ.

The title compound is obtained in the form of a colorless oil.

The title compound was prepared in a manner similar to that described in Example 1d by reacting 4(S),5(S)-4,5-epoxy-2-trans-nonenal with undecyltriphenylphosphonium bromide. can get.

Example 3A: 3-(5(S),6(R)-5-hydroxy-7=trans,9-cis-icosadien-6-ylthio]-malonanilic acid methyl ester 5(S), 6
Example 1, but starting from (S)-5,6-epoxy-futrans, 9-cis-icosadiene (see Example 3b) and 3-mercaptomaloneanilic acid methyl ester
The title compound is obtained in a similar manner as described in .

Get↓Nia-(5(R),6(S)-5-hydroxy-7゜9
-trans-11-cis-icosatrien-6-ylthio]-4-oxo-4H-chromene-2-carboxylic acid methyl ester 5 (R), 6 (R) -5,6-epoxy-
7゜9-trans-11-cis-icosatriene and 7
In a similar manner to that described in Example 1 starting from -mercabuto 4-oxo-4H-chromene-2-carboxylic acid methyl ester, the title compound is obtained.

[α)gO=+198.9±2.7° (CIICIf
f, C-0,38%), UV (CIlCI3
) :λ□X(ε)=268(34100);322
(I1900) nm.

5 (R), 6 (
R) -5,6-epoxy-7,9-1-lance-11
- Cis-icosatriene is prepared, for example, in the following way: 2 (S), 3 in 250 ml of methylene chloride
A solution of 6.7 g of (R)-2,3-epoxyhebutanal (see Example 1c) was added with T in 200 ml of methylene chloride.
-Triphenylphosphoranylidenechlor 1 to aldehyde 1
' 20.85 g of the solution is stirred at 20°C over 1 hour and the whole is stirred for a further 1 hour at 20°C. The reaction mixture was diluted with 2/l0ml of hequinane and 120ml of ethyl acetate, filtered through silica gel, and concentrated. The residue is taken up in equal volumes of hexane and ethyl acetate, stirred for 15 minutes, passed through silica gel again and concentrated.

For isomerization, the resulting oily mixture of cis, trans- and trans, trans-isomers was diluted with 200 ml of methanol.
1 and then 220 mg of iodine are added and the whole is left at 20° C. for 3 hours. After washing with aqueous sodium thiosulfate and water and drying over sodium sulfate, the solution is concentrated and the residue is chromatographed on silica gel. Elution with hexane/ethyl acetate (4:1) yields the desired 6(R), ? (R)-6,7-epoxy-2,
4-trans-undecadienal is obtained in the form of a yellowish oil. [α] Furnace = -21.1 ± 1.3° (c in chloroform = 0.75% w/v), λ, , = 276 nm
, t-29900; IR (CIlzClz):
2950.2920.2850.2800.2720.
1678.1640.1600.1460.1163.
1120.1007.985 cm-'.

To a stirred solution of 5.15 g of nonyltriphenylphosphonium bromide in 5 Q ml of tetrahydrofuran, cooled to −78° C., 6.85 ml of a 1.6 M solution of butyllithium in toluene are added under argon. -78°
After 30 minutes at C, the mixture was sequentially treated with hexamethylphosphoric triamide l5. lg and tetrahydrofuran lQml
6 (R), 7 (R)-6,7-eboxy 2.
4-Trans-Undecajenal! , 52 g of the solution was added, the whole was kept at -78°C for an additional 15 minutes, and then heated to 0°C.
Warm to. Add 9% salt buffer (pH 8) to the reaction mixture.
and extracted with ether. The combined ethereal extracts are stabilized with a few drops of triethylamine, dried over sodium sulfate and freed from easily volatile components at 20° C. in vacuo. The residue is stirred with a small amount of ether and the solid triphenylphosphine oxide that precipitates out is removed by filtration. Triphenylphosphine oxide is completely removed from the column by washing with a silica gel column previously prepared by washing with a (4:1) mixture of ether/hexane mixed with 2% triethylamine. Removal of the solvent from the solution by vaporization gives the desired product in the form of pale yellow crystals with a melting point of 31-32°C.

Example j: 1.2 g of 3-(5(S),6(R)-5-hydroxy-7-cis-pentadecen-6-ylthiocombalonanilinic acid methyl ester of the title compound (see Example 1) Dissolve in 3 Q ml of methanol and add 27 ml of 0.IN sodium hydroxide solution.
Stir for 0 h and concentrate by evaporation in vacuo. The residue was purified on silica gel with dichloromethane/methanol (9:1).
remove the eluent from the eluent in vacuo,
The residue is dissolved in water and acidified with IN hydrochloric acid. The aqueous phase was extracted with ether, the extract was dried over magnesium sulfate,
Pass through the mouth and concentrate by evaporation. The title compound is obtained in the form of a white resin. Optical rotation of sodium salt: [α)'O=
+17.2±1.6° (C-〇, 65% in methanol
) body, I'7 white bud hashigi: 3- (5(S), 6(R)-5-hydroxy-7-
trans,9-cis-icosadien-6-ylthio]-
Malonanilic acid The title compound is obtained from the corresponding methyl ester (see Example 3A) in a similar manner as described in Example 5: (
αBo=-z, 2±0.9° (c=1.
16%), UV (methanol): λ1llaX(ε)=
210 (sh); 240 (37240)n
m-.

Anal-(5(S),6(R)-5-hydroxy-7-cis-pentadecen-6-ylthiocou 4-oxo-4+
1-Chromene-2-carboxylic acid The title compound is obtained in a similar manner to that described in Example 5 starting from the corresponding methyl ester. [α),;0=+2.1±1.
5° (methanol 41c = 0.68%) f! LL: ? -(5(S),6(R)-5-Hydroxy-7゜9-trans-11-cis~icosatrien-〇-ylthio]-4-oxo-4H-chromene-2-carboxylic acid sodium salt of the title 1.1 g of the methyl ester of the compound was mixed with 3 methanol
0-, dissolved in 0. lN Na0II 21 ml
Add. The whole was stirred at room temperature for 10 hours, the solution was concentrated in vacuo, and the solution was concentrated on a reverse phase column (Merck pre-prepared column RP-
8) with methanol/water (3:l). The title compound is obtained in the form of a white resin.

[α] Otsu 0 = +145.8 ± 2,6° (C-O in methanol, 38%), IJV (methanol): λmaX (
ε)=206 (23500); 225 (2336
0);267 (34340);285 (sh);
324 (I0040) nm.

Example 7A: 3-(5(R), 6(S)
The sodium salt of -5-H1,1:1-C-7-cis-bentadecen-6-ylthio]-malonanilic acid The title compound is the corresponding methyl ester (see Example 1).
obtained in a similar manner to that described in Example 7. [α
)go=+13.8±2.8° (c=0 in methanol
．． 36%), UV(me'))-/L/).

λ,,X(ε)−223(sh); 246
(I8200) nm.

Example Yu”-: ? -(5(R),6.(S)-5-hydroxy-7-cis-pentadecen-6-ylthio]-4-oxo-4H
- Sodium salt of chromene-2-carboxylic acid The title compound is the corresponding methyl ester (see Example 2)
obtained in a similar manner to that described in Example 7. Melting point 2
46~249℃; [α] Otsu0=1.1±3.7° (
C in methanol = 0.27%), UV (methanol)
:λ□X(ε)=206(22200);223(I
9800);260(sh);267 (I4100)
;324 (I1000) nm.

Flame↑tania-(5(R), 6(S)-5-hydroxy-7-cis-icosen-6-ylthio]-4-oxo-4H-triCl-2-carboxylic acid sodium The title compound is the corresponding (α) from the methyl ester (see Example 2A) in a similar manner as described in Example 7.
8 = 11.3 ± 3.8° (c in methanol = 0.2
7%) Example 7D = 3 (5(R), 6(S) 5-hydroxy-
Salt of 7-cis-icosen-6-ylthio]-malonanilic acid The title compound is obtained in a similar manner to that described in Example 7 from the corresponding methyl ester (see Example IA). [
α) 30=-15,5±2.3° (c in methanol
= 0.43%), UV (Meta/-L): λ, , (ε
) = 223 (sh); 246 (I8100
) nm.

The title compound is the sodium salt of 7-(5(S),6(R)-5-hydroxy-7-cis-icosen-6-ylthio]-4-oxo-4H-chromene-2-carboxylic acid. (see Example 2B) in a similar manner as described in Example 7.
(methanol): λwax(ε)=324 (I05
60) i266 (I3320), 223 (I8
640) nm.

■1L: 3-(5(S),6(R)-5-hydroxy-7-
Storium salt of cis-icosen-6-ylthio]-malonanilic acid The title compound is obtained in a manner analogous to that described in Example 7 from the corresponding methyl ester (see Example IB). [
α)'O=+23°9±2.8° (c in methanol
= 0.36%) So1LL = 7-[5(S),6(R)-5-hydroxy-7-trans,9-cis-icosadien-6-ylthio]-4-oxo-4H-chromene- Sodium salt of 2-carphonic acid The title compound is obtained in a similar manner to that described in Example 7 from the corresponding methyl ester.

[α) + SO = 91.6 ± 1” (C-0,8% in methanol) Example” -Nia-(4(R),5(S)-1,1,17 trifluoro-4-hydroxy-6 ,10-cis,8-trans-nonadecatrien-5-ylthio]-4~oxo4
H-chromene-2-carboxylic acid methyl ester 4 (R),5 (R)-4゜5-epoxy-1,1,1-)refluoro-6゜10- in 10 ml of methanol
To a solution of 0.67 g of cis,8-trans-nonadecatriene was added 0.74 g of triethylamine and then 7-
Mercabuto 4-oxo-411-chromene-2-carboxylic acid methyl ester is added with stirring under argon. The brown-red solution is stirred at 20° C. for 16 hours and concentrated by evaporation.

The residue was purified on silica gel with hexane/ethyl acetate (7:3).
The title compound is obtained in the form of yellow crystals.

I R (C112C12): 3020.2970.
2940.2860.1750.1670, 1610
．． 1420.1150cm-'.

4 (R), 5 (R) used as starting materials
), -4,5-epoxy-1,1,1-1-lifluoro-6,1O-cis,8-1-lans-nonadecatriene is produced, for example, as follows: J, A
m, Chem, Soc, 104U, 3527-2
9 (I982), 3.42 g (I0 mmol) of CO□(CO)a in 5 Qml of mesitylene was reduced to 0.
．． Place it in a 31 autoclave at 0℃, 3,3.31
0.5 mol of refluoropropene is introduced and then, at room temperature, 65 bar of carbon monoxide and 65 bar of hydrogen are added in succession. The reaction mixture was heated to 110°C and treated with CO for one summer.
The pressure is kept constant at 130 bar by adding a (I: 1) mixture (V/V).

1 JIL in which the theoretical amount of CO/H2 mixture was absorbed (
5 hours), the whole is cooled to 0° C. and the autoclave is returned to normal pressure. After rinsing the crude mixture with a small amount of mesitylene, 156.8 g of ethoxycarbonylmethylenetriphenylphosphorane in 600 d of methylene chloride (
0.45 mol) solution is added gradually. After the mildly exothermic reaction has stopped, the whole is stirred at room temperature for 2z hours and then concentrated by evaporation. The residue was diluted with pentane (approximately 100.n
Step f) is made into a slurry, the precipitated triphenylphosphine compound is removed, and one distillation is carried out under reduced pressure. The desired ester is a colorless oil (boiling point 78-82℃/26+nl1
g) with a yield of 50%.

b) 6.6. 6.6-1-Refluoro-2-trans-hexenoic acid ethyl ester in 70 ml of lotrifluoro-2-tra 4-nihexenol diethyl ether (>log solution was cooled to 0-5 °C, At this temperature 102 Inl of 1M diisobutylaluminum hydride solution in hexane is added.Then the reaction mixture is
Stir at ℃ for 5 minutes and add about 200ml of 6N hydrochloric acid! Hydrolyze carefully. The organic phase is separated one time and the aqueous phase is extracted three more times with ether. The combined organic phases were dried over MgOa,
Concentrate by evaporation.

The residue was purified on silica gel with hexane/ethyl acetate (7=3).
Chromatography gives the title compound in the form of a colorless liquid.

Under absolutely anhydrous conditions, 6.38 ml of tetraisopropyl orthotitanate and D-(
-)-Tartrate diethyl ester 4.5 ml? 8?
&, is cooled to -70°C. At this temperature, 6,6. Lotrifluoro-2-trans-hexenol (above) 6
．． 3 g and 30.15 ml of a 2.74 M tert-butyl hydroperoxide solution in toluene are added.

The temperature is raised to 0° C. within 2 hours and a solution of 27 g of iron sulphate (It) and 11 g of tartaric acid in 110 ml of water is added. After stirring for 30 min at 10 °C, the organic phase was separated, the aqueous phase was extracted twice with ether, and the combined organic phases were purified with NazSO
，Dry on and by evaporation? ;Shrink. The residue was taken up in 120 mff1 of ether, cooled to 0-5°C and dissolved in saturated NaC.
1? A suspension of 4.2 g of Na0Il in 110 ml of 'fl fluid is added. The mixture is stirred for 1 hour at 0-5°C, the organic phase is separated and the aqueous phase is extracted three times with ether. The combined organic phases are dried over Na, SO and concentrated by evaporation. The resulting title compound can be further processed without further purification.

C112CI! Oxalyl chloride 3.3 in 40 ml
ml of the solution was cooled to -70°C and the C112CI215
7 ml of dimethyl sulfoxide per ml, making sure that the temperature does not exceed 160°C. After stirring for 10 min at -70°C, 2 in 40 ml of C1hC1z
(R), 3 (R)-2,3-epoxy-6,6
, rottrifluorohexanol (manufactured by C)6.
Completely request 95g within 15 minutes. 30 more at -70°C
After a few minutes, add 28.7 ml of triethylamine and raise the temperature to 0°C. The reaction mixture was diluted with phosphate buffer (pH 8)
The aqueous phase is extracted twice with C1hC1z, the combined organic phases are washed with water, dried over Na, SO, and concentrated by evaporation. The resulting title compound is further worked up directly.

e) 6 (R),? (R)-6,7-! Hoxy 10
．． 10. 10-to 1 fluoro 2-tra 4 people.

4-trans-decajenal and 6(R), 7enal CIIzClz 2(S), 3(
CIIzCIz 150 to a solution of 6.87 g of R)-2゜3-epoxy-6,6,6-dolifluorohexanal.
A solution of 14.87 g of 4=triphenylphosphoranylidenecrotonaldehyde in d is added dropwise within 60 minutes.

The reaction mixture is stirred for a further hour at 20° C. and concentrated by evaporation. The residue is taken up in hexane/ethyl acetate (I:1) and passed through silica gel. Oral speech is concentrated by evaporation,
The residue was purified on silica gel with hexane/ethyl acetate (4:1).
Chromatography using Concentration of the first fraction by evaporation gives the 2-trans,4-cis-isomer of the title compound. Subsequent fractions contain the 2-trans, 4-trans-isomer of the title compound. Both products are tan oils.

f) 4(R),5(R)-4,5-epoxy-1°1.1-trifluoro-6-cis,8-trans.

A stirred solution of 1.25 g of nonyltriphenylphosphonium bromide in 1Q ml of tetrahydrofuran was heated to 78°C.
Cool to 50°C and add, under argon, 1.66 m of a 1,6 M butyllithium solution in hexane.

After 30 minutes at -78°C, 4g of hexamethylphosphoric acid triamide
and 6(R) in tetrahydrofuran for pocket money.

A solution of 0.45 g of (R)-6,7-epoxy-10,10,10-trifluoro-2-trans,4-cis-decajenal is added dropwise. The whole was stirred for an additional 15 minutes at -78°C, the temperature was allowed to rise to 0°C, and phosphate buffer (
pH 8) and extracted with ether. The combined organic phases were washed three times with phosphate buffer (pH 8) and treated with Na, SO,
Dry on top and concentrate by evaporation. The residue is suspended in a small amount of ether, the precipitated triphenylphosphine oxide is removed by filtration and concentrated again by evaporation.

The resulting title compound is further processed directly in the main step.

-27-(4(R),5(S)-1,1,1-trifluoro-4-hydroxy-6,8-1-lance.

10-cis-nonadecatrien-5-ylthio]-4-
Oxo4. H-chromene-2-carboxylic acid methyl ester 4 (R), 5 (R) -4,5-epoxy-
1.1.1, l-Trifluoro-6,81 lance, 10-cis-nonadecatriene and 7-mercabuto 4-oxo-40-chromene-2-carboxylic acid methyl ester to prepare the title title in a similar manner as described in Example 9. The compound is obtained. I R (C112C1t): 3Q2Q, 297
0, 2940.2860.1750.1665.161
0.1420.1390, 1150c+n-' 4 (R), 5 (R
) -4,5-Epoxy-1,l,1-1-lifluoro-6,8-) lance, 10-cis-nonadecatriene is prepared, for example, by the following method =a) obtained in Example 9C 6 (R), 7 1)-6゜7-Eboxy 10
．． 10. to-1-lifluoro-2-trans,4-cis-decajenal was reacted and worked up in the same manner as described in Example 9f to give 4 (R), 5 (R
) -4,5-epoxy-1,1,1-1-refluoro-6,8-1-lance.

10-cis-nonadecatriene is obtained.

■Earthwork Ni-(4(S),5(R)-1,1,1-)lifluoro-4-hydroxy-6,10-cis,8-trans-nonadecatrien-5-ylthio]-4-oxo 4
H-chromene-2-carboxylic acid methyl ester 4 (S), 5 (S)-4,5-epoxy-1゜1.
1-trifluoro-6,10-cis, 8-1-lans-
Nonadecatriene and 7-mercabuto 4-oxo-4
Example 9 from 8-chromene-2-carboxylic acid methyl ester
The title compound is obtained in a similar manner as described in .

4(S), 5(S) used as starting materials
) -4,5-epoxy-1,1,1-4 refluoro-
6,10-cis,8-trans nonadecatriene is
For example, the title compound is obtained in cell-free form in a similar manner to that described in Example 9C, except that =D-(+)-tartrate diethyl ester prepared in the following manner is acted upon.

Example 9
Work-up in a manner similar to that described under d gives the title compound.

2 (R) , 3 (S) −2, from enal example 11b
3-Epoxy-6,6,6-trifluorohexanal was treated in a manner similar to that described in Example 9e to obtain an isomer mixture which was chromatographically separated from the 2-trans, 4-cis-isomer. and is separated into 2-trans and 4-trans isomers.

6 (S), ? (S) -6,7-nipoxy 10゜10.10-) refluoro-2-trans, 4-
The title compound is obtained in a similar manner to that described in Example 9f by reacting cis-decajenal.

Example 12: ? -(4(S),5(R)-1,1,1''-)refluoro-4-hydroxy-6,8-1-lance.

10-cis-nonadecatrien-5-ylthio]-4-
Oxo-4II-chromene-2-carboxylic acid methyl ester 7-mercabuto 4-oxo-4H-chromene-2-carboxylic acid methyl ester and 4(S).

5(S)-4,5-epoxy-1,1,1-trifluoro-6,8-)lance, 10-cis-nonadecatriene(6(S),?(S)-6,7-epoxy-
10,10,10-trifluoro-2-trans,4-
trans-decajenal (see Example 11C) to Example 9f
The title compound is obtained in a manner analogous to that described in Example 9.

Flaming 182 3- (4(R),5(S)-1,1,1-1-refluoro-4-hydroxy-6-cis-icosene-5-
ylthio]-malonanilic acid methyl ester 3-mercaptomalonanilic acid methyl ester and 2 (S), 3 (R) -2 as in Example 9f.
4 (R), 5' (R)-4゜5-epoxy- obtained by reacting ,3-epoxy-6,6,rotrifluorohexanol with tetradecylbosphonium bromide
The title compound is obtained in a manner analogous to that described in Example 9 from 1,1,1-)lifluoro-6-cis-icosene.

General engineer: ? -(4(R),5(S)-1,1,1-1-lifluoro-4-hydroxy-6-cis-icosen-5-ylthio]-4-oxo-4II-chromene-2-carboxylic acid methyl ester 7- Mercabuto 4-oxo-4H-chromene-2-carboxylic acid methyl ester and 2(S).

3 (R)-2,3-Evogysy 6.6. The title compound is obtained in a similar manner to that described in Example 9 from 6.6-1-lifluorohexanol.

Charcoal ± main ni-(4(R),5(S)-1,1,l-trifluoro-4-hydroxy-6-cis-icosen-5-ylthio]-2-methoxyquinoline-3-carboxylic acid methyl ester 7 -Merkabuto 2-methoxyquinoline-3-carboxylic acid methyl ester and 2(S), 3(R)-
The title compound is obtained in a manner analogous to that described in Example 9 from 2,3-epoxy-6,6,rotrifluorohexanol.

Blood ±1 = 7-(4(R),5(S)-1,1,14lifluoro-4-hydroxy-6,10-cis,8-trans-nonadecatrien-5-ylthio]-4-oxo4
0.35 g of the corresponding methyl ester of H-chromene-2-carboxylic acid (see Example 9) is dissolved in 40 ml of methanol, cooled to 0°C and 118 ml of 0,4N Na0 is added slowly. Once the addition was complete, the whole was warmed to room temperature and stirred for an additional 45 minutes. Methanol is evaporated at room temperature, water and CIl□Ch are added to the residue and the whole is acidified with cold 2N hydrochloric acid.

The aqueous phase was separated and then extracted twice with C1lzC12,
The combined organic phases are dried over Mg5O and concentrated by evaporation. The title compound is obtained in the form of a yellow-brown consistency. I R (C1lzC12): 3040.2950
．． 2870.1750.1670.1640.1610
．． 1425.1150cu+-'.

Based on the above-mentioned (4(R),5(S)-1,1,1-trifluoro-4-hydroxy-6,8-1-lance).

IO-cis-nonadecatrien-5-ylthio]-4-
The title compound is obtained in a manner analogous to that described in Example 13 from the corresponding methyl ester of oxo-4H-chromene-2-carboxylic acid (see Example 10).

ILLi: ? -(4(S),5(R)-1,1,1-trifluoro-4-hydroxy-6,lO-cis,8-trans-nonadecatrien-5-ylthio]-4-oxo4
The title compound is obtained in a manner similar to that described in Example 13 from the corresponding methyl ester of H-chromene-2-carboxylic acid (see Example 11).

LL! =? -(4(S),5(R)-1,1,1-trifluoro-4-hydroxy-6,8-1-lance.

10-cis-nonadecatrien-5-ylthio]=4-
The title compound is obtained in a similar manner to that described in Example 13 from the corresponding methyl ester of oxo 4H-chromene-2-carboxylic acid (see Example 12).

Local: 3-(4(R),5(S)-1,1,1-1-refluoro-4-hydroxy-6-cis-icosene-5-
The title compound is obtained in a manner analogous to that described in Example 7 from the sodium salt of ylthio]-malonanilic acid and the corresponding methyl ester (see Example 12A). [
α] to 8=-10,0±2.0° (0,5%, methanol) -Hydroxy-6-cis-icosene-5-
Example 7 from the corresponding methyl ester (see Example 12 B)
The title compound is obtained in a similar manner as described in . Melting point 243-245°C pH6c: ? -C4 (R), 5 (S) -1,1,1-)
Refluoro-4-hydroxy-6-cis-icosene-5
-ylthio]-2-methoxyquinoline-3-carboxylic acid sodium salt The title compound is obtained in a similar manner as described in Example 7 from the corresponding methyl ester (see Example 12C). U
V (methanol): λmaX(ε)-332 (9300
), 293 (7380), 22G (37960
), [α)'0=-21,0±1O00° (0.1% in methanol) J! ! LLT: ? -(I(R3),2(SR)-2-hydroxy-1
-(2-nonylphenyl)-hexylthio-4-oxo-4H-chromene-2-carboxylic acid methyl ester 1 (R3), 2 (R3)-1,2-epoxy-1
-(2-nonylphenyl)-hexane 2.42 g, 7
A mixture of 1.11 g of -merkabuto 4-oxo-4II-chromene-2-carboxylic acid methyl ester, 3 ml of triethylamine 1F and 3 Q ml of methanol is stirred at room temperature under argon for 22 hours. The reaction mixture is then concentrated by evaporation under reduced pressure at room temperature and the residue is purified by chromatography on silica gel with CIl□C1z/acetone (9B, 5:1.5). 'l-
(I(R5),2(SR)-2-hydroxy-1
-(2-nonylphenyl)-hexylthio]-4-oxo-4H-chromene-2-carboxylic acid methyl ester is obtained in the form of a pale yellow solid with a melting point of 65-68°C.

IR (CII□Cl2): 3580.2930.2
860.1745.1655.1600.1415.1
240.1140cu+-'.

1 (R3), 2 (R3) used as starting materials
)-1,2-epoxy-1-(2-nonylphenyl)-
Hexane is obtained in the following way: a) l-(2-nonylphenyl)-1-hexanal Into a stirred mixture of 1.1 g of magnesium dust, 8 ml of tetrahydrofuran and 3 drops of carbon tetrachloride under an argon atmosphere, 1/3 of a solution of 1 g of 2-nonylbromobenzene (EP 0 123 543) in 15% tetrahydrofuran is added and the whole is heated under reflux for 30 min.
Heat to boil for minutes. The remainder of the solution of 2-nonylbromobenzene is then poured in over 30 minutes and the reaction mixture is kept under reflux for 2 hours. After dilution with 15 ml of tetrahydrofuran, the suspension is cooled to -10 DEG C. and added portionwise to a solution of 4.6 g of hexanal in 12 ml of tetrahydrofuran, cooled to -70 DEG. After stirring at -70°C for 1 hour, the reaction mixture was added with 2 ml of saturated ammonium chloride aqueous solution.
Add 00mff1, separate the organic layer and extract the aqueous layer three times with ether. The combined ethereal extract was dried,
The residue remaining after concentration by evaporation is purified by chromatography on silica gel with increasing amounts of a mixture of methylene chloride and petroleum ether,
The desired 1-(2-nonylphenyl)-1-hexanol is obtained in the form of a colorless oil. I R (C1l□C1z)
:3600.2960.2925.2855.146
5. J-',.

b) 1-(2-nonylphenyl), -1-) lance-
Hexene 1-(2-nonylphenyl)-1-hexanol 14.
4 g of toluene-4-sulfonic acid monohydrate and 250 ml of toluene are heated under reflux for 3 hours using a water separator. After cooling, the reaction mixture was reduced to a concentration of 10%.
(W/V) twice with sodium bicarbonate solution and twice with water.
Wash twice. The organic phase is dried over sodium sulfate, concentrated by evaporation in vacuo and the residue is purified by chromatography on silica gel using hexane as eluent. The desired 1-(2-nonylphenyl)-trans-hexene is obtained in pale yellowish form. r R
(C1l□C1z): 2960.2930.285
5.1465.970 cm-'.

3.6 g of 1-(2-nonylphenyl)-1-1-lans-hexene in 350 ml of methylene chloride? 3-chloroperbenzoic acid with a concentration of 85% as guest performer 15.2
g and the whole is stirred at room temperature for 3 hours. The reaction mixture is diluted with methylene chloride and washed twice each with saturated sodium bicarbonate solution and water. The semisolid residue remaining after drying the organic phase and concentrating by evaporation is suspended in hexane, filtered, and concentrated by evaporation under reduced pressure. The crude product is purified by chromatography on silica gel with hexane/ether (97:3) to give the desired l(R3),2(R3)-1,2-
Epoxy-1-(2-nonylphenyl)-hexane is obtained in the form of a colorless oil. IR(CIl*Ch):
2960.2930.2B60.1470cm-'.

■Earthworker: ? -(I(R3), 2 (SR)-1-(2-dodecylphenyl)-2-hydroxypentylthiogo 4
-oxo-4H-chromene-2-carboxylic acid methyl ester 1 (R3), 2 (R3) -1-(2-dodecylphenyl)-1,2-epoxypencune and 7-mercabuto 4-oxo-4H-chromene The title compound is obtained in a similar manner to that described in Example 17, but starting from -2-carboxylic acid methyl ester. Melting point 77
~78℃. I R (CIIzC1□): 3580,2
960.2925.2855.1745.1655.1
600°1415cm-'.

1 (R3), 2 (R3) used as starting materials
-1-(2-dodecylphenyl)-1,2-epoxy pencune can be prepared by the method described in Example 17a-c as follows: = 1 from 2-dodecylphenylmagnesium bromide and pentanal -(2-dodecylphenyl)-pentanol is produced, which is dehydrated to produce 1-(2-dodecylphenyl)-pentene, which is converted to the desired epoxide using 3-chloroperbenzoic acid ( Colorless oil, IR, C1l□C1z: 29
60.2920.2850.1460cm-').

Flaming 11 Near-(I(R3), 2 (SR)-2-hydroxy-1
-(2-pentadecylphenyl)-pentylthiogo 4
-oxo-4H-chromene-2-carboxylic acid methyl ester 1 (R3), 2 (R3)-1,2-epoxy=1
The title compound was prepared in a manner similar to that described in Example 17, but starting from -(2-pentadecylphenyl)-penkune and 7-mercabuto 4-oxo-41(-chromene-2-carboxylic acid methyl ester). is obtained in solid form (from petroleum ether), melting point 68-69°C, IR
(CIl□C1□)=3580.2960.2930.
2860.1745.1655.1600.1415c
m-' 1 (R3), 2 (
R3)-1,2-Epoxy=1-(2-pentadecylphenyl)-pentane by the method described in Examples 17a-C, as below! ! ! 1-(2-pentadecylphenyl)-pentanol can be produced from 2-pentadecylphenylmagnesium, bromide and pentanal, which is dehydrated to produce 1-(2-pentadecylphenyl)-pentene. which is converted to the desired epoxide using 3-chloroperbenzoic acid.

Once in flames, near (I(R3), 2 (Sr2)-1-(2-
dodecylphenyl)-2-hydroxypentylthio]-
4-oxo-8-propyl-4H-chromene-2-carboxylic acid methyl ester 1 (r2s), 2 (R3)-1-(2-dodecylphenyl)-1,2-epoxypencune (see Example 17A) and 7-Mercabuto 4-oxo-8-propyl-
In a similar manner to that described in Example 17, but starting from 4H-chromene-2-carboxylic acid methyl ester, the title compound is obtained in the form of a viscous oil. [R(C112C
I□): 3580.2960.2930.2860
．． 1745.1655.1590.141011250
cm −'.

7- (I(R3), 2 (SR)-2-hydroxy-
1-(2-nonylphenyl)-hexylthio]-2-methoxyquinoline-3-carboxylic acid methyl ester 1 (R3), 2 (R3)-1,2-epoxy-1
-(2-nonylphenyl)-hexano (see Example 17C)
In a similar manner to that described in Example 17, but starting from 2-methoxyquinoline-3-carboxylic acid methyl ester and 7-mercabuto, the title compound is obtained in the form of a pale yellow honey.

I R(CH2Ch): 3580.2950.29
20.2850.1725.1610.1480.14
50.1400.1340.1190.108108O
'Appendix 178: ? -(I(R3), 2 (SR)-1-(2-dodecylphenyl)-2-hydroxypentylthio]-2
-Methoxyquinoline-3-carboxylic acid methyl ester 1 (R3), 2 (R5) -1-(2-dodecylphenyl)-1,2-epoxypencune and 7-mercabuto 2-methoxyquinoline-3-carboxylic acid methyl ester In a similar manner to that described in Example I7, but starting from the ester, the title compound is obtained in the form of a viscous oil.

[R(CIl□Cl2): 3580.2960.2
925.2860.1730.1610.1480.1
455.1400.1345.1190.1080cm
-'.

±"Yu"den? -(I(R3),2(SR)-2-human°roxy-
1-(2-pentadecylphenyl)-pentylthio]-
2-methoxyquinoline-3-carboxylic acid methyl ester] (R3), 2 (R3)-1,2-epoxy-1
The title compound was prepared as a viscous oil in a manner similar to that described in Example 17, but starting from -(2-pentadecylphenyl)-pentane and 7-mercabuto 2-methoxyquinoline-3-carboxylic acid methyl ester. obtained in the form of

IR(CIl□C1z): 3580.2960.
2925.2850.1730.1610.1480.
1455.1400.1340.108108O'.

Once on a plate El (R3), 2 (SR) 2-Hydroxy-1-(2-nonylphenyl)-pentylthiocou 4-oxo-4H-chromene-2-carboxylic acid methyl ester 1 (R3), 2 (R3)-1,2-epoxy-1
In a similar manner as described in Example 17, but starting from -(2-nonylphenyl)-pentane and 7-mercabuto 4-oxo-4H-chromene-2=carboxylic acid methyl ester, the title compound was obtained. It will be done. IR(CI
(zcI□): 2930.2860.1745.1
660.1605.1240cm-'.

1 (R3), 2 (R3) used as starting materials
)-1,2-epoxy=1-(2-nonylphenyl)-
Pentane can be prepared analogously to Examples 17a-c starting from 2-nonylbromobenzene and pentanol.

± soil owner = 7- (I(R3), 2 (SR)-2-hydroxy-
1-(2-nonylphenyl)-hexylthio]-4-oxo 4H-chromene-2-carboxylic acid Example 17-7
- (I(R3),2 (SR)-2-hydroxy-1
A mixture of 2.5 g of -(2-nonylphenyl)-hexylthio]-4-oxo-4H-lysyl 1-men-2-carboxylic acid methyl ester, 100 mf of methanol, and 55 kg of an O,1 N aqueous sodium hydroxide solution was prepared at room temperature. Stir for 18 hours. The reaction mixture was concentrated by evaporation under reduced pressure at room temperature;
The residue is partitioned between methylene chloride and 0.2N hydrochloric acid.

The organic phase is washed with water, dried over sodium sulfate and the solvent is removed under reduced pressure at room temperature. Recrystallization of the solid residue from nythyl/hexane gives the title compound in the form of a pale yellow crystalline solid. Melting point 72-75℃, IR(
KBr) 23420 (wide), 2955.2925
．． 2855.1735.1635.1595.1420
．． 1235.1150.960.905.760 cr
n-'.

Set up: ? -C1,(R3),2 (SR)-1-(2-dodecylphenyl)-2-hydroxypentylthio2-4-
Oxo-4H-chromene-2-carboxylic acid Corresponding methyl ester (Example 17)
A) gives the title compound. Melting point 111-1
16℃.

IR (CIl□C1Z): 3580.3450.2
960.2930.2860.1740.1655, ■
600.1420c+n-'.

In II 1 8 B near-(I(R3), 2 (SR)-2-hydroxy-1
-(2-pentadecylphenyl)-pentylthiocou 4
-Silium salt of oxo-48-chromene-2-carboxylic acid The title compound is obtained in solid form from the corresponding methyl ester (see Example 17B) in a manner analogous to that described in Example 18F below. It will be done. Melting point 238-240°C (decomposition), I
R (Br): 2960.2925.2855.1
635.161O11420c111-'.

Tan ± ldan: ? -(I(R3), 2 (SR)-1-(2-dodecylphenyl)-2-hydroxypentylthio2 4
Sodium salt of -oxo-8-propyl-411-chromene-2-carboxylic acid The title compound is prepared in solid form from the corresponding methyl ester (see Example 17c) in a manner analogous to that described in Example 18F below. can get. Melting point 247-249℃ (decomposition),
IR (CIIZC12): 2960.293
0.2860.1635.1415.1365cm-'
.

``Flame'''' J 7- (I(R3), 2 (SR)-2-hydro; 1
-C1-(2-nonylphenyl)-hexylthio-2-methoxyquinoline-3-carboxylic acid? −(I(R3
), 2 (SR)-2-hydroxy-1-(2-nonylphenyl)-hexylthio-2-methoxyquinoline-3-carboxylic acid methyl ester (see Example 17D)1.
A mixture of 1 g, 35 methanol and 2.5 ml of 2N aqueous sodium hydroxide solution is stirred at room temperature under argon for 14 hours and then concentrated under reduced pressure at 45°C. Residue 0. Acidify with IN hydrochloric acid and take up in methylene chloride. Dry the organic extract over sodium sulfate and concentrate in vacuo.

The residue is chromatographed on silica gel, eluting with increasing amounts of methanol in ether. After evaporating the solvent, the title compound is obtained as a pale yellow honey. I
R(CIl□01□): 3580.3320.296
0.2930.2860.1745.1610.148
5.1390.1340 cm-'.

Kando Kodan: ? -[1(R3), 2 (SR)-1-(2-dodecylphenyl)-2-hydroxypentylthio]-2
-Methoxyquinoline-3-carboxylic acid The corresponding methyl ester (Example 17
The title compound is obtained in the form of a yellowish resin.

I R (CIIzClz): 3580.3320.
2960.2930.2860.1745.1610.
1485.1390.1340cm-'.

Example 18F=7-(I(R3),2(SR)-2-hydroxy-
1-(2-pentadecylphenyl)-pentylthio]-
Sodium salt of 2-methoxyquinoline-3-carboxylic acid 7-(I(R3),2(SR)-2-hydroxy-1-(2-pentadecylphenyl)-pentylthio-2-methoxyquinoline-3-carvone To a mixture of acid methyl ester (0.81 g), 15 ml of methanol and 5 ml of tetrahydrofuran was added 1.3 mN of IN aqueous sodium hydroxide solution and the whole was heated under argon at room temperature for 12 min.
Stir for an hour. The easily volatile constituents are removed under reduced pressure at 45°C and the residue is triturated with carbon tetrachloride. Evaporation of the volatile components in vacuo gives the title compound in the form of a colorless solid with a melting point above 250°C. I R (KBr
): 2960.2925.2855.1635.1
610.1585.1390.1240 cm-'.

Kodan Nukijo: ? -(I(R3),2(SR)-2-hydroxy-1
-(2-nonylphenyl)-pentylthio]-4-oxo-4H-chromene-2-carboxylic acid'corresponding methyl ester (see Example 17G) In a similar manner as described in Example 18, the title compound was prepared. can get. Melting point 124-1
26℃ [LL: ? -(I(R3),2(SR)-2-hydroxy-1
-(4-nonylphenyl)-hexylthio]-4-oxo-41! -chromene-2-carboxylic acid methyl ester 1 (RS), 2 (R3) -1,2-epoxy-
0.85 g of 1-(4-nonylphenyl)-hexane is dissolved in 20 ml of methanol under argon, 0.86 g of triethylamine and then methyl 7-mercabuto 4-oxo-4H-chromene-2-carboxylate. 0.85 g of ester is added and the whole is stirred at room temperature for 22 hours.

The precipitate that separates is filtered through a suction port and washed with a small amount of methanol and hexane. The title compound obtained is 135-1
Melt at 36°C.

1 (R3), 2 (
R3)=1,2-epoxy-1-(4-nonylphenyl)-hexane is prepared, for example, in the following way: A suspension of 13.9 g of pentyltriphenylphosphonium bromide in 150 d of tetrahydrofuran is heated with argon. The mixture was cooled to -20°C and 21.2 ml of a 1,6 M butyllithium solution in fuxanes was added within 5 minutes, and the whole was heated to 0-20°C.
Stir for an additional 30 minutes at 10°C.

To the mixture cooled to -60°C to -70°C was added 6 g of 4-nonylbenzaldehyde in 40% of tetrahydrofuran.
Please take your time and pray. The reaction mixture is allowed to warm to 0-10° C., stirred for a further 45 minutes at this temperature and concentrated by evaporation. The residue was taken up in hexane/ethyl acetate (I: 1) and
Pass by mouth on silica gel. By giving an oral presentation? 7:im
and chromatograph on silica gel with hexane. The title compound (mixture of cis- and trans-isomers) is obtained in the form of a colorless oil, which is used directly in the next step.

1-( from the previous step in 150 mA' of dichloromethane)
A solution of 6.32 g of 4-nonylphenyl)-hex-1-ene (mixture of cis- and trans-isomers) was added with 6.76 g of m-chloroperbenzoic acid (90% content) in 100 ml of dichloromethane. Add with cooling to ~5°C and stir the whole at 20°C for 20 hours. The reaction mixture was diluted with 10% (w/v) sodium sulfite solution, 5%
Wash three times successively with (W/V) sodium carbonate solution and water, dry over sodium sulfate and concentrate by evaporation.

The residue was purified on silica gel with hexane/ethyl acetate (I9:1).
), sequential trans-
(I(R3), 2 (R3)-) and cis-(I(R3)
), 2 (SR)-)-isomer is obtained in the form of a colorless oil.

Example 19A: 3 C1 (R3) , 2 (Sr2) 2-
! :=l''roxy-1-(4-nonylphenyl)-hexylthiocombalonanilic acid methyl ester 1 (R3), 2 (R3)-1,2-epoxy-1
The title compound is obtained in a similar manner as described in Example 19, but starting from -(4-nonylphenyl)-hexane and 3-mercaptomaloneanilic acid methyl ester as the mercapto component.

-(LLifl: ?-(I(R3), 2 (SR)-2-hydroxy-
1-(4-nonylphenyl)-hexylthio]-2-methoxyquinoline-3-carboxylic acid methyl ester 1 (R3), 2 (R3)-1,2-epoxy-1
-(4-nonylphenyl)-hexane and 3-mercapto-2-meth as the himercapto component; in a similar manner as described in Example 19, but starting from 1-shiquinoline-3-carboxylic acid methyl ester, the title A compound is obtained.

J! ! ! LLL=? -[1(R5),2(R3)-2-hydroxy-1
-(4-nonylphenyl)-hexylthio]-4-oxo-4H-chromene-2-carboxylic acid methyl ester corresponding l (R3),2 (SR)-1,2-epoxy-1-(4-nonyl phenyl)-hexane (Example 1
After chroma I-graphy on silica gel and eluting with hexane/ethyl acetate (3:2) in a similar manner as described in Example 19, but starting from The title compound is obtained in crystalline form.

Example 20A = 7-[l (R3),2 (SR)-2-hydroxy-1-(4-nonylphenyl)-pentylthio24
-oxo-4H-chromene-2-carboxylic acid methyl ester 1 (R3), 2 (R5)-1,2-epoxy-1
In a similar manner as described in Example 19, but starting from (4-nonylphenyl)-pentane and 7-medoxy 4-oxo-4H-chromene-2-carboxylic acid methyl ester, the title compound was prepared with a melting point of 136 Obtained in the form of yellow crystals at ~138°C.

1 (R3), 2 (R3) used as starting materials
-1,2-Epoxy-1-(4-nonylphenyl)-pentane can be prepared analogously to Examples 17a-c starting from 4-nonylbromobenzene and pentanal. I R (C1l□Cl2): 2890.2
820.1500.1445cnn-'.

Coal amount: ? -(I(R5),2(SR)-2-hydroxy-
1-(4-nonylphenyl)-hexylthio]=4-oxo-4II-chromene-2-carboxylic acid sodium salt in a similar manner as described in Example 7 from the corresponding methyl ester (see Example 19). The title compound is obtained in solid form. Melting point: 267°C (decomposed).

Processed below El'1 Example 22 Near-C1(R5),2(SR)-2-hydroxy-1
-(4-nonylphenyl)-hexylthiocomalonanilic acid Natowau 11 salt The title compound was prepared from the solid monohydrate in a similar manner as described in Example 7 from the corresponding methyl ester (see Example 19Δ). It is obtained in the form of ゛. Melting point 168-169°C side ii near-(I(R5), 2 (SR)-2-hydroxy=
Sodium salt of 1-(4-nonylphenyl)-hexylthiocou 2-methoxyquinoline-3-carboxylic acid Corresponding methyl ester (see Example 19B) Color Example 18F
In a similar manner as described in , the title compound is obtained in solid form. Melting point 268-270 Example 24 Near-, (I(R3), 2 (R3)-2-hydroxy-
Sodium salt of 1-(4-nonylphenyl)-hexylthio]-4-oxo-4II-chromene-2-carboxylic acid Corresponding methyl ester (see Example 20) in a similar manner as described in Example 7. The title compound is obtained.

MiiA Near-N (R3),2 (SR)-2-HiFO$-C1-(4-nonylphenyl)-pentylthio2-4-
The title compound is obtained in a manner analogous to that described in Example 18 from the oxo-4H-chromene-2-carboxylic acid corresponding methyl ester (see Example 20A). Melting point 98-1
00℃ -mNia-(I(R3),2(SR)-1-hydroxy-1
-(m-tolyl)-3-trans-5-cis-pentadecadien-2-ylthio]-4-oxo 4H-chromene-2-carboxylic acid methyl ester tetrahydrofuran 4〇-1 (R3), 2
(R3)-1,2-epoxy-1-(m-1lyl)-3
-trans-5-cis-pentadecadiene 2.2 g, 7
-Merkabuto 4-oxo-4H-chromene-2-carboxylic acid methyl ester 2.0 g and triethylamine 3
．． The mixture of 4- is stirred at room temperature for 20 hours and the volatile components are removed by vacuum distillation. The residue was purified on silica gel using a 3:2 mixture of hexane/ethyl acetate (v/v) as eluent.
) gives the title compound in the form of a red-yellow resin.

1 (R3), 2 (R3) used as starting materials
-1,2-epoxy-1-(m-)lyl)-3-trans-5-cis-pentadecadiene can be prepared by the following method: m-tolyl aldehyde 56,6 in 670 mf toluene
A total of 152-1 tc of formylmethylenetriphenylphosphorane is added in several portions to the boiling solution of 4.4 under reflux, and the whole is then heated to boiling for 16 hours. The volatile constituents are distilled off, the residue is dissolved in a 4:l mixture of ether/hexane (V/V) and filtered through silica gel. The solvent is removed from the mouth by distillation and distilled in a high vacuum. The title compound is obtained in the form of a colorless oil. Boiling point 87-9
2°C/3 mbar.

A solution of 25.32 g of m-methylcinnamaldehyde (above) in 400 ml of methanol was prepared at 20-25° C. with 136 mff1 of hydrogen peroxide at a temperature of 30% and 1200 mf of water.
A vigorously stirred mixture of 54 g of sodium bicarbonate in ml is stirred for 45 minutes and the whole is stirred for a further 2 hours. The reaction mixture is extracted several times with methylene chloride. The organic portion is washed once with sodium sulfite solution, dried over sodium sulfate and the solvent is removed by evaporation. Chromatography of the residue on silica gel, eluting with a 3:l mixture of hexane/ethyl acetate (v/v) gives the title compound in the form of a colorless oil.

c) 4 (R3), 5 (R3) 4
．． 5-Evokyno-5-(m-)lyl)-2-) 2 (R3), 3 (
9.56 g of SR)-2,3-epoxy-(m-tolyl)-propionaldehyde (see b)? A solution of 18.63 g of formylmethylenetriphenylphosphorane in 70 ml of methylene chloride is added at room temperature under an argon atmosphere and the whole is stirred at room temperature for 20 hours.

The reaction mixture is concentrated, diluted with a mixture of hexane and ethyl acetate in a volume ratio of 1:1 and filtered onto silica gel. Once the solvent has evaporated, the residue is chromatographed on silica gel. Elution with hexane/ether (I: 1) and removal of the solvent by cooling gives the title compound in the form of a colorless oil.

1 of butyllithium in hexane under an argon atmosphere
．． Add 17.3 ml of 6M solution to 120 ml of tetrahydrofuran.
Add to a stirred solution of 13.39 g of decyltriphenylposbonium bromide in Inl cooled to -78°C. The temperature of the mixture is briefly allowed to rise naturally to 0°C, and then the solution is cooled again to -78°C. With stirring and cooling, 4 (R
3), 5 (R3)-4,5-epoxy-5-(m-)
-Ryl)-21 lance-pentenal (see C) 7.0
2g? We sincerely hope that the guest performance will not exceed 170 degrees Celsius. The reaction mixture is allowed to warm to +10° C. and concentrated in vacuo.

The residue was dissolved in 4:1 (v/V) of ether/hexane.
) Take the mixture and pass through a silica gel column previously washed with the same solvent mixture to which 1% triethylamine has been added. Concentrate the 0 solution in vacuo to obtain the title compound in the form of a colorless viscous oil.

3 7- (I(R3), 2 (R3)-1-hydroxy-
1-(4-methylphenyl)-3-cis-hexadecen-2-ylthio]-4-oxo-48-chromene-2-
Carboxylic acid methyl ester 1 (R3), 2 (R3
)-1,2-epoxy-1-(4-methylphenyl)-
In a similar manner as described in Example 25, but starting from 3-cis-hexadecene and 7-mercabuto 4-oxo-4I]-chromene-2-carboxylic acid methyl ester, the title compound was prepared with a melting point of 133-135. Obtained in the form of yellow crystals at °C.

1 (R3), 2 (R3) used as starting materials
)-1,2-epoxy-1-(4-methylphenyl)-
3-cis-hexadecene was prepared in Examples 25a, b as below.
It can be manufactured by the method described in and d.

p-methylcinnamaldehyde is produced from p-)lyraldehyde and formylmethylenetriphenylphosphorane, and this is reacted to produce 2 (R3).

3 (SR)-2,3-epoxy-3-(p-tolyl)-propionaldehyde is formed which is converted to the desired product with tridecyltriphenylbosboniumbutomide. IR (C1I□C1g): 2880.2
810, 1490.1445 cm-'.

Charcoal 1] Tania-(I(S), 2(I)-1-human-1-roxy1-(3-)lifluoromethylphenyl)-4-(
3-nonylphenyl)-3-cis-buten-2-ylthio]-4-oxo 4H-chromene-2-carboxylic acid methyl ester and its trans-isomer 1 (S), 2 (S)-1-(3 -trifluoromethylphenyl)-4-(3-nonylphenyl)-1,
Similar procedures as described in Example 1, but starting from 2-epoxy-3-butene (cis/trans-isomer mixture) and 7-mercabuto-4-oxo-4N (-chromene-2-carboxylic acid methyl ester) In the process, the title compound is obtained in the form of a mixture of cis-/trans-isomers.The isomers are separated by chromatography on silica gel with hexane/ethyl acetate (7:3).cis-
Isomer [α], qo = +33.6 ± 8.0° (0.125% in chloroform) to trans-isomer [α] 8 - -183.0 ± 7.4° (0.125% in chloroform). 1
35%).

1 (S), 2 (S) used as starting materials
) -1-(3-1-lifluoromethylphenyl)-4
-(3-nonylphenyl)-1,2-epoxy-3-butene can be produced, for example, as follows.

88.9 g of ethoxycarbonylmethylenetriphenylphosphorane are added with cooling to a solution of 34.0 g of 3-trifluoromethylhenzaldehyde in 400 mf1 of dichloromethane. The reaction mixture is stirred for 1 hour at room temperature, the solvent is evaporated in vacuo and the residue is filtered onto silica gel using ether/hexane (4:1). Concentration of the eluent by evaporation gives the title compound in the form of white crystals. Melting point 40-41'C0 3-(3-1-lifluoromethylphenyl)-2=trans-propenoic acid ethyl ester l+Reduction in the manner described in I9b gives the title compound in colorless form. I R (C112C12): 3550.282
0.1310.1140.1100 cm-'.

Epoxidation of nor-3-(3-1-lifluoromethylphenyl)-2-trans-propenol as described in Example 9C, but using L-(+)-tartrate diethyl ester, yielded the title compound. Obtained in colorless form. I
R(CHzCI□): 3500.2820.13
30.1170S1125.1070crn-1゜nor2(S),3(S)-2,3-epoxy-3-(3
-trifluoromethylphenyl)-propatool Example 9
Oxidation as described in d gives the title compound in colorless form. IR(CIl□Cl2): 282
0.1730.133 (L, 1170.1125.10
7107O'.

(romethylphenyl)-4-(3-nonylphenyl)2
(R),3 (S)-2,3-Epoxy-3-(3-trifluoromethylphenyl)-propatur and 3-nonylbenzyltriphenylphosphonium bromide as described in Example 1d. In a similar manner, a mixture of cis-/trans-isomers of the title compound is obtained in pale yellowish form.

Seishishi Lq; 7- (I(S), 2 (R)-1-hydroxy-1-
(3-Trifluoromethylphenyl)-4-(3-nonylphenyl)-3-buten-2-ylthio]-2-methoxyquinoline-3-carboxylic acid methyl ester (cis-/trans-isomer mixture) 1 (S) , 2 (S)-1-(3-trifluoromethylphenyl)-4-(3-nonylphenyl)-1,
2-Epoxy-3-butene (cis/1-lance-isomer mixture) and 7-mercabuto-2-methoxyquinoline-
In a similar manner to that described in Example 1, but starting from 3-carboxylic acid methyl ester, the title compound is obtained in colorless form.

UV (chloroborum): λ, one (ε) = 340 (I1
000) nm.

Teisha Kodan: ? -(I(S),2(R)-1-hydroxy-1-(
3-)lifluoromethylphenyl)-4-(4-nonylphenyl)-3-cis-buten-2-ylthio]-4-
Oxo-40-chromene-2=carboxylic acid methyl ester and its trans-isomer 1 (S),2 (S)-1-(3-)lifluoromethylphenyl)-4-(4-nonylphenyl)-1 ，
Similar procedure as described in Example 1, but starting from 2-epoxy-3-butene (cis/trans-isomer mixture) and 7-mercabuto 4-oxo-4H-chromene-2-carboxylic acid methyl ester The title compound is obtained in the form of a mixture of cis-/trans-isomers. The isomers are separated by chromatography on silica gel with hexane/ethyl acetate (7:3). The cis-isomer [α]′0=+91.3±8.7° (0.115% in chloroform) is the trans-isomer [α]′0=+91.3±8.7°
87.4±7.4° (0.135% in chloroform)
Earlier? It will be stored.

1 (S), 2 (S) used as starting materials
) -1-(I-trifluoromethylphenyl)-4-
(4-nonylphenyl)-1,2-epoxy-3-butene is 2(R),3(S)-2,3-epoxy-3-(3-,)lifluoromethylphenyl)-propanol and It is obtained in a pale yellowish form in a similar manner to that described in Example 1d, but starting from 4-nonylbenzyltriphenylphosphonium bromide.

Shushu Tatsutania-(I(S), 2 (R)-1-hydroxy-1=(
3-trifluoromethylphenyl)-4-(4-nonylphenyl)-3-buten-2-yl 1,000]-2-methoxyquinoline-3-carboxylic acid methyl ester (cis/
trans-isomer mixture) 1 (S), 2 (S)-1-(3-trifluoromethylphenyl)-4-(4-nonylphenyl)-1,
Similar procedure as described in Example 1, but starting from 2-epoxy-3-butene (cis-/l-lance-isomer mixture) and 7-mercabuto 2-methoxyquinoline-3-carboxylic acid methyl ester. The title compound is obtained in the form of a colorless oil.

UV (chloroform): λ#1mX(ε)=340(I
2400), 300 (I0000) nm.

±Yu''-27- (I(S), 2 (R)-1-hydroxy-1
-(3-1-lifluoromethylphenyl)-3-trans-5-cis-hexadecadien-2-ylthio]-4
-Oxo 414-chromene-2-carboxylic acid methyl ester 1 (S), 2 (S)-1,2-epoxy-1-(
3-trifluoromethylphenyl)-3-trans-5
The title compound was prepared in the form of a colorless oil in a similar manner as described in Example 1, but starting from -cis-hexadecadiene and 7-mercabuto 4-oxo-4H-chromene-2-carboxylic acid methyl ester. It can be obtained with [αBo=-
+-t9. t±10” (0.099% in chloroborm
) 1 (S), 2 (S) used as starting materials
) -1,2-epoxy-1-(3-trifluoromethylphenyl)-3-) lance-5-cis-hexadecadiene is 2(R),3(S)-2,3-epoxy-3 -(3-1-lifluoromethylphenyl)-propatur (see Example 25B).

This was vinylized (νinylog
ize) and react as in Example 25d to form the required epoxide, except that undecyltriphenylphosphonium bromide is used.

Example 26: 7-(I(R3),2(SR)-1-hydroxy-
1-(m-)lyl)-1-)lanth-5-cis-pentadecadien-2-ylthio]-4-oxo-4H-chromene-2-carboxylic acid tetrahydrofuran 5Qmj! 0, I to a solution of 3.02 g of the methyl ester of the title compound (see Example 25) in
6.6 - of N aqueous sodium hydroxide solution is added and the whole is stirred at 20° C. for 2 hours and concentrated under reduced pressure.

The residue is dissolved in water, brought to pH 1 with IN hydrochloric acid and extracted with ether. The organic extracts are washed twice with saturated l-IJium chloride solution, dried over magnesium sulfate and the solvent is removed in vacuo. After chromatography of the residue on silica gel and evaporation of the solvent from the fractions eluted with methylene chloride/methanol (5:1), the title compound is obtained in the form of an orange powder. Melting point: 66-67℃ ■Main craftsman: ? -(I(R3),2(SR)-1-hydroxy-
1-(4-methylphenyl)-3-cis-hexadecen-2-ylthio]-4-oxo-4H-chromene-2-
The title metal compound is obtained in a manner analogous to that described in Example 18F from the corresponding methyl ester of the sodium salt of the carboxylic acid (see Example 25A). Melting point: 255-257°C.
3-1-Lifluoromethylphenyl)-4-(3-nonylphenyl)-3-cis-buten-2-ylthio)-4
-Oxo-4H-chromene-2-carboxylic acid In a similar manner as described in Example 5 starting from the corresponding methyl ester, the title compound is obtained in the form of a beige solid. Melting point: 253°C (decomposed).

Associate! 126 C nia-(I(S),,2(R)-1-hydroxy-1-
(3-1-Lifluoromethylphenyl)-4-(3-nonylphenyl)-3-1-lans-buten-2-ylthio-2-4-oxo-4H-chromene-2-carboxylic acid Starting from the corresponding methyl ester In a similar manner to that described in Example 5, the title compound is obtained in the form of a pale yellow solid. Melting point: 253°C (decomposed).

Example" 2 [here: ? -(I(S),2(R)-1-hydroxy-1-(
3-trifluoromethylphenyl)-4=(3-nonylphenyl)-3-buten-2-ylthio]-2-methoxyquinoline-3-carboxylic acid (cis-/trans-isomer mixture) cis-/trans-isomer mixture of the corresponding methyl ester In a similar manner to that described in Example 5 starting from the trans-isomer mixture, the title compound is obtained in the form of a white solid. Melting point: 81-82℃ General temperature: ? -(I(S),2(R)-1-hydroxy-1-(
3-)Lifluoromethylphenyl)-4-(4-nonylphenyl)-3-cis-buten-2-ylthio2-4-
In a similar manner to that described in Example 5 starting from the corresponding methyl ester of oxo-4H-chromene-3-carboxylic acid, the title compound is obtained in solid form.

Melting point 69-70℃ side 26 days Ni-(I(S), 2(R)-1-hydroxy-1-(
Starting from the corresponding methyl ester of 4-oxo-chromene-2-carboxylic acid In a similar manner to that described in Example 5, the title compound is obtained in solid form.

Melting point: 70-71'C Pan-26-(I(S),2(R)-1-hydro-1-cy-1-(3-1-lifluoromethylphenyl)-4-(4
-nonylphenyl)-3-buten-2-ylthio]-2
-Methoxyquinoline-3-carboxylic acid (cis/trans isomer mixture) In a similar manner as described in Example 5 starting from the cis/trans isomer mixture of the corresponding methyl ester, the title compound was prepared as a white solid. Obtained in form. Melting point 91-92
°C base・, 171 days 2 side ratio: ? -(I(R3),2(SR)-1-hydroxy-1
-(3-trifluoromethylphenyl)-3-trans-5-cis-hexadelene-2-ylthio]-4-
The title compound is obtained in a similar manner as described in Example 18 from the corresponding methyl ester of oxo-4H-chromene-2-carboxylic acid (see Example 25F).

IR (C112CI: 3620.2930,X
650.1605.1330.1130cm-'.

Example 27: 7-(I(S),2(R)-2-hydroxy-1-
(3-nonylphenyl)-hexylthio-4-oxo-48-chromene-2-carboxylic acid methyl ester 1 (R3), 2 (R3)-1,2-epoxy-1
In a similar manner as described in Example 17, but starting from methylnystyl -(3-nonylphenyl)-hexane and 7-mercabuto-4-oxo-4H-chromene-2-carboxylate, the title compound was prepared with a melting point of 92 Obtained in the form of a yellowish powder at ~93°C.

1 (R3), 2 (R3) used as starting materials
-1,2-epoxy-1-(3-nonylphenyl)-hexane starting from 3-nonylbromobenzene in Example 1
It can be manufactured in the same manner as 7a-c.

Example 27A Near-(I(R3),2(R3)-2-hydroxy-1
-(3-nonylphenyl)-pentylthio]=4-oxo-4H-chromene-2-carboxylic acid methyl ester 1 (R3), 2 (SR)-1,2-epoxy-1
The title compound was prepared in a similar manner as described in Example 17, but starting from -(3-nonylphenyl)-pentane and 7-merkab 1--4-oxo-4H-chromene-2-carboxylic acid methyl ester. The compound is obtained in the form of pale yellow crystals with a melting point of 84-86°C.

1 (R3), 2 (R3) used as starting materials
-1,2-Epoxy-1-(3-nonylphenyl)-pentane can be prepared analogously to Examples 17a-c starting from 3-nonylbromobenzene and pentanal. IR(C1lzC1z): 2930.2
850.1610.1460cm-'.

Ti: 3- (I(R3), 2 (SR)-2-hydroxy-
1-(3-nonylphenyl)-hexylthiocombalonanilic acid methyl ester 1 (R3), 2 (R3)-1,2-epoxy-1
In a similar manner to that described in Example 1, but starting from -(3-/nylphenyl)-hexane (see Example 27) and 3-mercaptomaloneanilic acid methyl ester, the title compound was obtained in colorless form. can get.

JI! L2i near-[1(R3),2(SR)-2-hydroxy-1
-(3-nonylphenyl)-hexylthio]-4-oxo-4H-chromene-2-carboxylic acid sodium salt In a similar manner as described in Example 7 from the corresponding methyl ester (see Example 27), the title The compound is obtained in solid form. Melting point: 185℃ (decomposition) Flame Yu” No Taku? -(I(R3),2(SR)-2-hydroxy-1
-(3-nonylphenyl)-pentylthio]-4-oxo 4H~chromene-2-carboxylic acid corresponding methyl ester (Example 27 A compound is obtained. Melting point 13
4-136℃.

,ii! ! LLL: 3-(I(R3),2(SR)-2-hydroxy-
Sodium salt of 1-(3-nonylphenyl)-hexylthiocomalonanilic acid Corresponding methyl ester (see Example 28) In a similar manner as described in fp17, the title compound is obtained in solid form. Melting point: 150-152°C.

Example 31 Near-(3(R3),4(SR)-4-hydroxy-1
-(2-nonylphenyl)-1-) lance-octene-
3-ylthio]-4-oxo 48-chromene-2-carboxylic acid methyl ester 3 (R3), 4 CR3)-
3,4-epoxy-I-(2-nonylphenyl)-1
-1-Lance-octene and 7-mercabuto 4-oxo-4H-chromene-2-carboxylic acid methyl ester in the same manner as described in Example 17, reacted for 60 hours at room temperature and After working up by process, the title compound is obtained in the form of a viscous oil.

s R (C1lzC1z): 3590.2960.
2930.2860.1750°1655.1600.
According to H-NMR analysis, the product contains approximately 10% of the corresponding cis-isomer.

3 (R3), 4 (R5) used as starting materials
-3,4-epoxy-1-(2-nonylphenyl)-1
-Trans-octene can be produced by the following method.

a) 2-nonylbenzaldehyde of 22 g of 2-nonylbromobenzene in 35 ml of tetrahydrofuran? Add 1/3 of the 8 liquid to 3.4 g of magnesium scraps.
g, 25 mβ of tetrahydrofuran and 3 drops of carbon tetrachloride are added to a stirred mixture under an argon atmosphere and the whole is heated to boiling under reflux for 30 minutes. The remainder of the 2-nonylbromobenzene solution is then added dropwise over a period of 1 hour and the reaction mixture is kept under reflux for 2 hours. Tetrahydrofuran 4
After dilution with Q mR, the whole is cooled to about 5° C. in a water bath and a solution of 11.6 dimethylformamide in 20 W dl of tetrahydrofuran is added dropwise over 15 minutes. After stirring for 1 hour at room temperature, 250 g of saturated ammonium chloride solution is added to the reaction mixture, the organic layer is separated and the aqueous layer is extracted three times with ether. The combined ethereal extracts are dried and the residue remaining after concentration by evaporation is purified by chromatography on silica gel with increasing amounts of a mixture of methylene chloride and petroleum ether.
The desired 2-nonylbenzaldehyde is obtained in the form of a pale yellow liquid. I R (C1l□CI□): 2920.
2850.1695.1600c+a −'.

b) 22/nylhensyl alcohol methanol 150mm! 0.57 g of sodium borohydride to a stirred solution of 9.3 g of 2-nonylbenzaldehyde in
Add g in portions over 15 minutes. After stirring for a further 30 minutes, the reaction mixture is concentrated by evaporation under reduced pressure and the residue is taken up in ether. The organic phase is washed with water-cooled 0.2N hydrochloric acid and water, dried over 1-helium sulfate and concentrated by evaporation in vacuo. Purification of the residue by chromatography on silica gel with increasing amounts of a mixture of ether and petroleum ether gives the desired 2-nonylhensyl alcohol in the form of a pale yellow liquid. [R(
C112C12): 3600.2925.2855
．． 1465.1000cm fence.

C) 2-nonylbenzyl bromide 6.6 g of 2-nonylbenzyl alcohol and 5 benzene
10 ml of phosphorus tribromide in 50 ml of benzene to a stirred mixture
g solution is added dropwise over 15 minutes. The reaction mixture is heated under reflux for 30 minutes and after cooling ice water and ether are added. The organic phase is separated, washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. Purification of the residue by chromatography on silica gel with petroleum ether gives 2-nonylbenzyl bromide in colorless form. I R (CIIzClz): 2
920.285o, 1470.1210cII+-'.

d) 2-Nonylhensyltriphenylphosphonium bromide A mixture of 7.2 g of 2-nonylbenzyl bromide, 5.77 g of triphenylphosphine and 60 g of toluene was heated under reflux for 4 hours, cooled and diluted with 8 Q ml of ether. Dilute. The precipitated 2-nonylbenzyltriphenylphosphonium bromide is filtered off, washed with ether and dried in vacuo.

Melting point l14-176°C.

5.6 g of octene 2-nonylhensyltriphenylphosphonium bromide and 50 ml of anhydrous tetrahydrofuran at 5°C.
6.4 ml of a 1.6 M solution of butyllithium in hexane are added to the cooled and stirred mixture under an argon atmosphere. After another 10 minutes, 15 m of Te1-rahydrofuran
A solution of 2 (R3), 3 (R3)-2,3-epoxyheptaryol in 1 is added dropwise within 3 minutes. The mixture is stirred for a further 1 hour at 5°C and 15 minutes at room temperature. is added and extracted three times with ether. The organic phase is dried over sodium sulfate and concentrated. The residue is suspended in hexane, filtered and the mouth plate is concentrated by evaporation under reduced pressure. The residue is purified on silica gel. Purification by chromatography above and elution with a 97:3 mixture of petroleum ether/ether (V/V) yielded 3 (RS), 4 (R3)-3,4-epoxy-1-(2-nonylphenyl). -1-trans-octene is obtained.IR(C1l.Cl2): 296
0.2930.2860, I470.870c+n-'
.

'According to H-NMR analysis, the product contains approximately 10% of the corresponding cis-isomer.

SeLL2-2? −(3(R3), 4(SR
) -4-human +=l-cy1-(2-nonylphenyl)-1-1-lans-octen-3-ylthio]-2-methoxyquinoline-3-carboxylic acid methyl ester 3 (R3), 4 (R3)-3,4-x Hoxy 1-
In a similar manner as described in Example 17, but starting from (2-nonylphenyl)-1-trans-octyne (see Example 31e) and 7-mercabuto 2-methoxyquinoline-3-carboxylic acid methyl ester, The title compound is obtained in pale yellowish form. I R (C112CI2)
: 3580.2960.2925.2860.173
0.1615.1485.1460.1400.134
5cm-'.

'H-NMR analysis shows that the product is the corresponding cis-
Contains about 10% isomer.

Example 33 Near-(3(R3),4(SR)-4-hydroxy-
1-(2-nonylphenyl)-1-1-lans-octen-3-ylthio]=4-oxo48-chromene-2-carboxylic acid from the corresponding methyl ester (see Example 31) as described in Example 18. In a similar manner, the title compound is obtained in the form of yellow honey. I R (CIl□Ch): 3580.3
450.2960.2925.2860.1740.1
According to 655.1600.1415.1240cIII-1°'II-NMR analysis, the product contains about lθ% of the corresponding cis-isomer.

Mii: ? -(3<R8'), 4 (SR) -4-Hydroxy-1-(2-nonylphenyl)-1-trans-octen-3-ylthio-2-m-1-xyquinoline-3-carboxylic acid corresponding methyl ester (see Example 32) in a manner analogous to that described in Example 18D, the title compound is obtained in crystalline form. Melting point 65-69℃, 11R (CIItClz
): 3580.3320.2960.2930.2
860.1745.1615.1485.1390.1
340.1245cm-'.

'H-NMR analysis shows that the product is the corresponding cis-
Contains about 10% isomers.

劃J”罎3-(3(R3),4(SR)-4-hydroxy-
1-(4-octylphenyl)-1-octen-3-ylthiocombalonanilic acid methyl ester (shu/
mixture of trans-isomers) 3 (R3), 4 (R3
)-3,4-epoxy-1-(4-octylphenyl)
-1-octene (mixture of phu/trans-isomers)
In a similar manner as described in Example 19A, but starting from 3-mercaptomalonanilic acid methyl ester as mercapto component, the title compound (mixture of shu/trans-isomers) is obtained.

a) 3 (R5), 4 used as starting materials
(R3)-3,4-Epoxy-1-(4-octylphenyl)-1-octene is obtained by the method described in Example 31G using 4-octylbenzyltriphenylphosphonium bromide.

■ Main i: 3-[3(R3), 4 (SR)-4-hydroxy-1
Sodium salt of -(4-octylphenyl)-1-octen-3-ylthio]-malonanilic acid (mixture of cis-/trans-isomers) corresponding methyl ester (mixture of cis-/1-trans-isomers) (e.g. 35) in a manner analogous to that described in Example 7, the title compound is obtained in semisolid form.

Hikiuni7- (3(R3), 4 (Slma)-4-hydro=
1-cy1-(4-octylphenyl)-1-octen-3-ylthiocou4-oxo-4H-chromene=2-
Carboxylic acid methyl ester (individual cis- and trans-isomers) 3 (R3), 4 (R5)-3,4-epoxy-1-
Starting from (4-octylphenyl)-1-octene (see Example 35a) and 7-mercabuto 4-oxo-4H-chromene-2-carboxylic acid methyl ester,
In a similar manner to that described in Example 19, the title compound is obtained in the form of an isomer mixture.

The product can be separated into individual components by chromatography on silica gel, first by elution with a 7:3 mixture of hexane/ethyl acetate (V/V).
The cis-isomer and then the trans-isomer are obtained.

劃J”罎? -(3(R3),4(SR)-4-hydroxy-1
-(4-octylphenyl)-1-trans-octen-3-ylthio2-4-oxo-411-chromene-2
- Sodium salt of carboxylic acid corresponding methyl ester (
The title compound is obtained in a similar manner to that described in Example 7 from the trans-isomer (see Example 37).

■Main uni 7-[・3 (RS), 4 (SR)-4-hydroxy-17(4-octylphenyl)-1-cis-octen-3-ylthio)-4-oxo-4H-chromene-2-
The title compound is obtained in a similar manner to that described in Example 7 from the sodium salt of the carboxylic acid and the corresponding methyl ester (cis-isomer, see Example 37).

Charcoal Ni-(I(RS),2(SR)-4-chloro-2-hydroxy-1-(2-nonylphenyl)-butylthio)
-4-oxo-4H-chromene-2-carboxylic acid methyl ester 1 (R3), 2 (R3) -4-chloro-1,2
-Epoxy-1-(2-nonylphenyl)-butane and 7-mercabuto-4-oxo-41(-chromene-2-
Example 17 except starting from carboxylic acid methyl ester
In a similar manner as described in , the title compound is obtained in the form of pale yellow crystals (from ether/petroleum ether). Melting point 69-73°C1I R(CHzCh): 358
0.2960.2930.2860.1745.165
5.1605.1420cI11-'.

1 (R3), 2 (R3) used as starting materials
-4-chloro-1,2-epoxy-1-(2-nonylphenyl)-butane can be produced as follows.

a) 4-chloro-1-(2-nonylphenyl)-butanol Example 1, but starting from 4-chlorobutyraldehyde
In a similar manner as described under 7a, the title compound is obtained in colorless form from 2-nonyl-bromobenzene. I
R (C112C12): 3600.2960.29
30.2860.1470.1055 mark.

In a similar manner as described in Example 17b, 4-chloro-1
-(2-nonylphenyl)-phthanol (above),
The title compound is obtained in colorless form. I R(C1l
□ch): 2960.2930.2860.146
5.970 an-'.

In a similar manner as described in Example 17C, 4-chloro-1
From -(2-nonylphenyl)-1-trans-butene (above), the title compound is obtained in colorless form. [R
(CHzClz): 2930.2860.1465
．． 1450cm-'.

Endo master: ? -(I(R3),2(SR)-4-chloro-2-hydroxy-1-(2-nonylphenyl)-phthylthio]
-2-methoxyquinoline-3-carboxylic acid methyl ester 1 (R3),:? (R3)-4-chloro-1,2
The title compound was prepared in a similar manner as described in Example 40, but starting from =epoxy-1-(2-nonylphenyl)-butane and 7-mercabuto 2-methoxyquinoline-3-carboxylic acid methyl ester. can get. I.R.
(C112CI□): 3580.2960.293
5.2860.1730.1615.1485.108
108O'.

Endo Kodan: ? -[1(R5),2(SR)-6-chloro-2-hydroxy-1-(2-nonylphenyl)-hexylthio]-4-oxo-4H-chromene-2-carboxylic acid methyl ester 1 (T ?S), 2 (R3)-6-chloro-1,
2-epoxy-1-(2-/nylphenyl)-hexane and 7-mercabuto 4-oxo-4H-chromene-2
- Example 4, but starting from carboxylic acid methyl ester
0, the title compound is obtained. melting point 60-62 °C l used as starting material
(R5),2 (R3)-6-Chloro-1,2-epoxy-1-(2-nonylphenyl)-hexane may be prepared by the method described in Example 4 Q a - c as follows: = 1-(2-nonylphenyl)-6-chlorohexanol is produced from 2-nonylphenylmagnesium bromite and 6-chlorohexanol, which is dehydrated to form 1-(2-nonylphenyl)-6-chloro hexene, which is converted to the desired epoxide with 3-chloroperbenzoic acid. IR (C112C12): 29
30.2860.1460.1220.900crn
-'.

Back±ldan: ? -(I(R3), 2 (SR)-6-chloro-2-hydroxy-1-(2-nonylphenyl)-hexylthio]-2-methoxyquinoline-3-carboxylic acid methyl ester 1 (R3), 2 (R3)-6-chloro-1,2-
In a similar manner as described in Example 40, but starting from eho-t-cy 1-(2-nonylphenyl)-hexane and 7-mercabuto 2-meI xyquinoline-3-carboxylic acid methyl ester. The title compound is obtained.

IR(C112CI□): 3580.29602
930.2860.1730.1615.1485.1
195.1080c+n-'.

Example” - History■-: ? -(I(R3),2(SR)-6-fluoro-2
-Hydroxy-1-(2-nonylphenyl)-hexylthio-4-oxo-4H-chromene-2-carboxylic acid methyl ester 1 (R3), 2 (R3)-6-fluoro-1°2-epoxy-1- (2-nonylphenyl)-hexane and 7-mercabuto 4-oxo-4H-chromene-2
- Example 4, but starting from carboxylic acid methyl ester
0, the title compound is obtained. Melting point 60-62°C.

1 (R3), 2 (R5) used as starting materials
)-1,2-epoxy-6-fluoro-1-(2-nonylphenyl)-hexane can be produced, for example, as follows.

Lidium aluminum hydride 2 was added to a stirred solution of 34.4 g of 6-(2-nonylphenyl)-5-hexenoic acid methyl ester (EP 0 123 543) in 300% tetrahydrofuran under a nitrogen atmosphere.
．． Add 8g little by little over 1 hour. After a further 30 minutes, 30 ml of ethyl acetate and 3 Qml of water are added dropwise. The reaction mixture is acidified with IN hydrochloric acid and extracted several times with ethyl acetate. The combined extracts are dried over sodium sulphate, concentrated by evaporation and chromatographed on silica gel with dichloromethane. The title compound is obtained in pale yellowish form. I R (C1l□Cl2): 3620.29
30.2850.

1470.970 cm-'.

8.17 g of 6-(2-nonylphenyl)-5-trans-hexenol in 20 ml of dichloromethane;
The mixture is added dropwise over 20 minutes to a stirred mixture of 4.68 g of diethylamino-sulfur trifluoride in 20 ml of dichloromethane under an argon atmosphere while cooling with ice. The whole is stirred at room temperature for 14 hours, water is added and the organic layer is separated and washed with saturated sodium bicarbonate solution and water. After drying and concentration in one shot, the crude product is purified by flash chromatography on silica gel with petroleum ether. The title compound is obtained in the form of a colorless oil. IR(CIl□Ch): 2930.285
0.1465.970 cm-'.

Hexane 6-Fluoro-1-(2-nonylphenyl)-1-trans-hexene is reacted with 3-chloroperbenzoic acid in the manner described in Example 17C to give the title compound in the form of a colorless oil. I R (CIl□CIri: 2920.2
850.1455 cm-'.

I (R3), 2 (SR)-6-Fluoro-2
-Hydroxy-1-(2-nonylphenyl)-hexylthio-2-methoxyquinoline-3-carboxylic acid methyl ester 1 (R3), 2 (R3)-6-fluoro-1゜2
The title compound was prepared in a manner similar to that described in Example 40, but starting from -epoxy-1-(2-nonylphenyl)-hexane and 7-mercabuto 2-methoxyquinoline-3-carboxylic acid methyl ester. can get. IR
(C1l□CI□): 3580.2925.286
0.1730.1615.1485.1195.108
108O'.

Charcoal↓yo: ? -[1(R3),2(SR)-4-chloro-2-hydroxy-1-(2-nonylphenyl)-butylthio]
-4-Oxo-4H-chromene-2-carboxylic acid The title compound is obtained in a similar manner to that described in Example 18 from the corresponding methyl ester (see Example 40) in the form of pale yellow crystals. Melting point 136-138℃, IR (C1l□
Ch): 3580.3430.2925.2860
．． 1735.1645.1600.1420em-'.

Charcoal: ? -(I(R3),2(SR)-4-chloro-2-hydroxy-1-(2-nonylphenyl)-butylthio]
- Sodium salt of 2-methoxyquinoline-3-carboxylic acid From the corresponding methyl ester (see Example 40A) to Example 18F
The title compound is obtained in a similar manner as described in . Melting point: 187-192°C.

Jl'LAi: ? -(I(R3),2(SR)-6-chloro-2-hydroxy-1-(2-nonylphenyl)-hexylthio-4-oxo-4H-chromene-2-carboxylic acid corresponding methyl ester (Example 40B The title compound is obtained in a manner analogous to that described in Example 18.

Melting point 135-139°C.

Example 44 Near-(I(R3),2(SR)-6-chloro-2-hydroxy-1-(2-nonylphenyl)-hexylthio-2-methoxyquinoline-3-carboxylic acid corresponding methyl ester (Example 40C In a similar manner to that described in Example 18, the title compound is obtained.

I R (CIIZCI2): 3570.3300.
29Go, 2920.2850.1740.161O1
1480,1240cm-'.

Example 45: ? -(I(R3),2(SR)-6-fluoro-2
-Hydroxy-1-(2-nonylphenyl)-hexylthio-4-oxo-4H-chromene-2-carboxylic acid The corresponding methyl ester (see Example 40D) was prepared from the title A compound is obtained.

I R (CtlzCh): 3580.2900
(wide), 2960.2930.1740.1660
．． 1630.1600.1420cm-'.

Example 46: ? -(I(R3),2(SR)-6-fluoro-2
-1-nitroxy-1-(2-nonylphenyl)-hexylthio-2-methoxyquinoline-3-carboxylic acid The title compound was prepared in a similar manner as described in Example 18 from the corresponding methyl ester (see Example 40E). can get.

I R (CIIzClz): 3580.296o,
293o, 2820.1745.1615.1490.
1390.1340.1245c+n −'.

Glue earthwork: ゛'l-(I(S), 2(R)-1-hydroxy-1-(rn-1-lyl)-11-lans-5-cis-pentadecadien-2-ylthio]-4 -Oxo 4
H-chromene-2-carboxylic acid methyl ester and its 1 (R), 2 (S)-diastereomers except starting from pure diastereomeric epoxides.
The title compound is obtained in a similar manner to that described in Example 25. 1 (S), 2 (R)-diastereomer, [αBo--so, 9 ± 9° (0.11% in chloroform), and 1 (R), 2 (S)-
Diastereomer, [α]O=+ss, t±8.9° (0.1125% in methanol).

1 (S), 2 (S) used as starting materials
) -1,2-epoxy-1-(m-tolyl)-3-trans-5-cis-pentadecadiene and its 1(R)
, 2 (R)-diastereomer is the corresponding pure diastereomeric aldehyde, i.e. 2 (R), 3
(S)-2,3-epoxy-3-(m-tolyl)-
Property tools and part 2 (S).

Obtained analogously to Example 25C and d, but using the 3 (R)-stereoisomer. Example 25B (a-
Obtained in the same manner as d).

1:? -(I(S),2(R)-1-hydroxy-1-(
m-tolyl)-31lanse-5-cis-pentadecadien-2-ylthio]-4-oxo-4H-chromene-
2-Carboxylic acid and its 1 (R).

2 (S)-Diastereomer - The title compound is obtained in a similar manner as described in Example 18 from the corresponding methyl ester. 1 (S), 2 (
R)-diastereomer, [α]60= −54,8±
8.7° (0.115% in methanol), and 1
(R), 2(S)-diastereomer, I R
(CII2Ch): 3340.2880.1615
．． 1590.1400.1340cm-'.

and the corresponding drug in finished form In the following, the term "active ingredient" refers to the compounds of the general formula () according to the invention, in particular the compounds described as products in Examples 1 to 41. means.

Variegation; inhalation suspension forming a solid aerosol containing propellant and O, 1% by weight of active ingredient 1"2% by weight of finely divided active ingredient 0.1 sorbitan trioleate 0.5 propellant A ( I-
(dichlorotrifluoroethane) 4.1 Propellant B (dichlorodifluoromethane and 15.01.
2-Dichlorotetrafluoroethane) 80.0 Residue: Using a regular homogenizer, while removing moisture,
The active ingredient is suspended in trichlorotrifluoroethane supplemented with sorbitan trioleate, the suspension is introduced into an aerosol container fitted with a metering valve, the container is sealed and the propellant B is filled under pressure.

±l: an aqueous solution at a temperature of about 2% of the active ingredient in the form of the sodium or potassium salt, suitable for inhalation; and: active ingredient (K or Na salt) 2000 m
g Ethylenediaminetetraacetic acid nilytriuno, salt 10m
g Henzalkonium chloride 10 mg freshly distilled water Total volume 100 mlRemoval: Dissolve the active ingredient in approx. 59 rnl of freshly distilled water and add the stabilizer (nitrithorium salt of ethylenediaminetetraacetic acid) and the preservative (henzalkonium chloride). .Once all ingredients are completely dissolved, the resulting solution is loo
ml, put it into a small pressurized bottle, and seal it airtight. The required amount of propellant is added in pressurized gas or liquid form.

Grass 1. i.7” (Japanese)

Claims (1)

[Claims] 1. General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^0 represents hydrogen or an alkanoyl group having 1 to 7 carbon atoms, and R ^1 represents an alkyl group having 1 to 3 carbon atoms optionally substituted with one or more halogen atoms having an atomic number of up to 17; R^2 represents an alkyl group having 5 to 3 carbon atoms;
15 aliphatic groups, A represents a single bond, ethylene group or vinylene group, B^1 represents an alkylene group or phenylene group having 1 to 7 carbon atoms, B^2 represents a single bond, ethylene group or Represents a phenylene group, M is a partial formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(M) (In the formula, R^3 represents hydrogen or an alkyl group having 1 to 4 carbon atoms, and X is NH, O , S or R^4 represents hydrogen, it represents a single bond, one of the symbols R^4 and R^5 represents hydrogen, and the other represents the group -CO-R^6, or R ^4 and R^5 together represent the group -CO-C(R^6)=C(R^7)- or -CO-C
(R^7)=C(R^6)- or R^4 and R^5 together with X represent the group -N=C(R^8)-C(R^6)=CH- represents a group, R^6 is -(CH_2)_b-COOR^3 (in the formula b
=0 to 2), and R^7 is hydrogen or carbon number 1 to 4
represents an alkyl group, and R^8 represents hydrogen, a methyl group, a methoxy group, or an aromatic group of halogen)] and salts of the compounds having salt-forming properties. 2. The compound according to claim 1, wherein in the general formula (I), the O-atom of the hydroxy group exists in a trans-configuration with respect to the S-atom. 3. The compound according to claim 1, wherein in the general formula (I), R^1 represents a trifluoromethyl group. 4. In the general formula (I), B^1 is the partial formula -(CH
_2) The compound according to claim 1, which represents a linear alkylene group of _a- (in the formula, a represents an integer of 1 to 7). 5. The compound according to claim 1, wherein in the general formula (I), B^1 represents an unsubstituted phenylene group. 6. The compound according to claim 1, wherein in the general formula (I), R^0 represents hydrogen. 7. In general formula (I), R^2-B^2-A together represent o- or p-(C_5_-_1_5-alkyl)-
Claim 1 representing a phenyl group or -styryl group
Compounds described in Section. 8. In general formula (I), R^2 has 8 to 8 carbon atoms
8. A compound according to claim 7, which represents 12 linear alkyl groups. 9. In the general formula (I), R^1 represents a trifluoromethyl group, and R^2-B^2-A together represent a linear 1-alkenyl group having 10 to 16 carbon atoms, 1,3- represents an alkadienyl group or a 1,3,6-alkatrienyl group,
The compound according to claim 1, wherein B^1 represents a group -(CH_2)_a- (in the formula, a represents an integer of 3 to 6). 10. In general formula (I), M represents a phenyl group, R^3 represents hydrogen in this group, R^4 represents hydrogen together with X, and R^5 represents a group -CO-(CH_2) _b-COOR^9 (in the formula, b is 2
and R^9 represents a methyl group, ethyl group or hydrogen)
The compound according to any one of claims 1 to 9, which represents 11, M represents a phenyl group, R^3 and R^5 each represent hydrogen, X represents a group -NH-, and R^4 represents a group -CO-(CH_2)_b-COOR^9 (In the formula, b is 1
and R^9 represents a methyl group, ethyl group or hydrogen)
The compound according to any one of claims 1 to 9, which represents 12. In the general formula (I), M is a partial formula: ▲ Formula,
There are chemical formulas, tables, etc.▼(M^1) Claim 1 representing the group [in the formula, R^3 represents a propyl group or hydrogen, and R^9 represents an ethyl group, methyl group, or hydrogen] The compound according to any one of Items 1 to 9. 13. In the general formula (I), M is a partial formula: ▲ Formula,
There are chemical formulas, tables, etc.▼(M^4) [In the formula, R^9 represents an ethyl group, a methyl group, or hydrogen] Any one of claims 1 to 9 Compounds described. 14. In the general formula (I), M is a partial formula: ▲ Formula,
There are chemical formulas, tables, etc.▼(M^3) [In the formula, R^9 represents an ethyl group, a methyl group, or hydrogen, and R
The compound according to any one of claims 1 to 9, wherein ^1^0 represents a halogen or methoxy group. 15. In the general formula (I), R^0 represents hydrogen,
R^1 represents a methyl group, chloromethyl group or trifluoromethyl group, R^2 represents a linear alkyl group having 7 to 15 carbon atoms or a corresponding group having 1 to 3 double bonds, A represents a cis- or trans-vinylene group, and B^
1 represents a linear alkylene group having 2 or 3 carbon atoms,
B^2 represents a single bond, M represents claim 11,
A compound or a salt thereof according to claim 1 having the definition set forth in claim 12 or 14. 16. In the general formula (I), R^0 represents hydrogen,
R^1 represents a methyl group, chloromethyl group or trifluoromethyl group, R^2 represents a linear alkyl group having 8 to 12 carbon atoms, and A is a single bond or a cis- or trans-configured vinylene group , B^1 represents a linear alkylene group having 2 or 3 carbon atoms, B^2 represents an unsubstituted phenylene group, and M represents Claim 11, 12 or 14. A compound or a salt thereof according to claim 1 having the definition set forth in claim 1. 17. In the general formula (I), R^0 represents hydrogen,
R^1 represents a methyl group, chloromethyl group or trifluoromethyl group, R^2 represents a linear alkyl group having 7 to 15 carbon atoms or a corresponding group having 1 to 3 double bonds, A represents a cis- or trans-vinylene group, and B^
1 represents an unsubstituted phenylene group, B^2 represents a single bond, and M has the definition described in claim 11, 12 or 14; Compound or its salt. 18. In the general formula (I), R^0 represents hydrogen, R^1 represents a methyl group, chloromethyl group, or trifluoromethyl group, and R^2 has a carbon atom number of 8 to
12 represents a linear alkyl group, A represents a single bond or a vinylene group in cis- or trans-configuration, B^1 represents an unsubstituted phenylene group, B^2 represents an unsubstituted phenylene group, and M represents A compound or a salt thereof according to claim 1 having the definitions set forth in claim 11, 12 or 14. 19. In the general formula (I), R^1 represents hydrogen,
R^1 represents a methyl group, chloromethyl group or trifluoromethyl group, R^2 represents a linear alkyl group having 8 to 12 carbon atoms, A represents a trans-double bond, and B^1
represents an unsubstituted m-phenylene group, B^2 represents an unsubstituted phenylene group, and M represents the subformula (M^1) listed in claim 12. Claim 1 Compounds or salts thereof described in Section 1. 20. The compound or alkali metal salt thereof according to any one of claims 1 to 19, which has a free carboxy group. 21. Physiologically acceptable salts of the compounds according to any one of claims 1 to 20. 22, the compound according to claim 1 described in any one of Examples 1 to 41. 23. Claims 1 to 22 for use as a leukotriene antagonist and/or for inhibiting phospholipase
A compound according to any one of paragraphs. 24. General formula (I): ▲Mathematical formula, chemical formula, table, etc.▼(I) [In the formula, R^0 represents hydrogen or an alkanoyl group having 1 to 7 carbon atoms, and R^1 represents a maximum of 17 represents an alkyl group having 1 to 3 carbon atoms which may be substituted with one or more halogen atoms having an atomic number of
15 aliphatic groups, A represents a single bond, ethylene group or vinylene group, B^1 represents an alkylene group or phenylene group having 1 to 7 carbon atoms, B^2 represents a single bond, ethylene group or Represents a phenylene group, M is a partial formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(M) (In the formula, R^3 represents hydrogen or an alkyl group having 1 to 4 carbon atoms, and X is NH, O , S or R^4 represents hydrogen, it represents a single bond, one of the symbols R^4 and R^5 represents hydrogen, and the other represents the group -CO-R^6, or R ^4 and R^5 together represent the group -CO-C(R^6)=
C(R^7)- or -CO-C(R^7)=C(R^6
)-, or R^4 and R^5 together with X represent the group -N=C(R^8)-C(R^6)=CH-, and R^6 represents -( CH_2)_b-COOR^3 (b in the formula
=0 to 2), and R^7 is hydrogen or carbon number 1 to 4
represents an alkyl group of formula (II ): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, A, B^1, B^2, R^1 and R^2 represent the above] epoxide is expressed as general formula (III) : H-S-M(III) [In the formula, M represents the above] is reacted with a mercapto derivative, and if necessary, the general formula (where R^0 represents hydrogen) is reacted.
Acylation of the obtained compound of I) to the corresponding compound in which R^0 represents an alkanoyl group having 1 to 7 carbon atoms and/or hydrolysis of the compound present in the form of an ester to the free acid or salt. and/or having salt-forming properties, converting the obtained free compound into a salt and/or liberating the compound from the corresponding salt form,
A method for producing the compound of I) and a salt of the compound having salt-forming properties. 25. The method according to claim 24 for producing the compound according to any one of claims 2 to 23. 26. Claims 1 to 23 as active ingredients together with at least one pharmaceutically acceptable carrier substance.
A pharmaceutical composition comprising at least one compound according to any one of paragraphs. 27. A pharmaceutical composition according to claim 26 in the form of a finished drug. 28. A pharmaceutical composition according to claim 26 or 27, suitable for administration by inhalation. 29. Claims 1 to 23 as active ingredients together with at least one pharmaceutically acceptable carrier substance
In order to produce a pharmaceutical composition containing at least one compound according to any one of the paragraphs, the corresponding ingredients are processed by non-chemical methods and, if the finished drug is desired, the individual dosages A method for producing a pharmaceutical composition, characterized in that it is divided into portions or placed in measured amounts in suitable containers. 30. Use of a compound according to any one of claims 1 to 23 for the manufacture of a pharmaceutical composition. 31. Use of a compound according to any one of claims 1 to 23 for the reduction or elimination of pathological conditions or symptoms in mammals caused by the allergenic action or inflammation of leukotrienes. 32. An effective amount of the compound according to any one of claims 1 to 23 for reducing or eliminating a medical condition or symptom in a mammal due to the allergenic effect or inflammation of leukotrienes. A method of treatment, characterized in that it is administered alone or in the form of a pharmaceutical composition according to any one of claims 26 to 28. 33. The therapeutic method according to claim 32, which treats humans.