JPS5841861A - Improvement of organic compound - 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 relates to alkanoic acids.

The present invention provides compounds having the following general formula It- in the free acid form. That is, provided that H8 in the general formula I is.

(41 aliphatic, unsaturated hydrocarbyl groups with up to 20 Fc atoms, unsubstituted or unsubstituted, hydroxyl groups, alkoxy groups having 3 to 6 carbon atoms, carbon Schiff alkyl group with 3 to 6 children, ant □
the cycloalkyl, aryl or Fi heteroaryl group is unsubstituted or substituted with at least one substituent selected from the group consisting of the cycloalkyl, aryl or the hydroxyl group. , a halogeno atom, and a carbon atom number iot, which is substituted with an alkenyl or alkynyl group;
゛(Noodles) Unsubstituted or substituted with an alkyl, alkenyl or alkynyl group of up to #i atomic number / 6, a cycloalkyl group having 3 to 4 carbon atoms; or a hydroxyl group, an alkoxy group, a halogeno atom, or an aryl or aryl group substituted with an alkyl, alkenyl or alkynyl group having up to 76 carbon atoms;夛, and R1 is (1) an unsubstituted substitute having up to IO carbon atoms.
A group selected from the group consisting of -alkyl group, alkyl group, halogen atom, xyl group, NHR, and COx is substituted with more substituents such as alkyl, cycloalkyl, or Alkenyl group, where R, is H
1 number of carbon atoms/~tei alkyl group, ryoryl group, aono m**1* is 46 in COX, ; Straddle □ (Ml unsubstituted bottle or alkyl group with carbon number / ~ tei, alkoxy group with vertical prime number 7 ~ tei, acyl group with carbon number 2 ~ S,
Halo□gun atom, hydroxyl group, car-xyl group, 2)D group,)lihalomethyl group, phenyl group, number of carbon atoms/~
The azilaino group NHR', (however, R4
(determined by water bulk atom or number of carbon atoms/~da alkynyl group)
Y is an aryl group monosubstituted with one or more substituents or an aryl group selected from the group consisting of -S-1-so- or -so,
− is. where -YR, is glutathionyl, cysteinyl or cysteinylglycinyl, KU,
R, is unpupillated alkadetraenyl t having 72 to 6 carbon atoms
or a group other than an alkali-4-anthaenyl group. Preferred compounds have the above general formula! In , R is carbon number S
``Unsubstituted monoalkyl group in 1 or number of carbon atoms/co~/6
The unrIIt-substituted alkatrienyl, alkatetraenyl, and alkataenyl also have the condition that L<fl4 other than the alkadiengenyl group.
-CO: A compound in which Y is as described above.

In the above formula, the compound is #l! Shown in acid play. They also exist in lactone, filtrate and ester forms, and these forms fall within the scope of the present invention. As can be understood, the lactone form is expressed by the following formula.

It is preferable that the salt form is a type of tomb that is used for pharmaceutical purposes, such as alkali and alkaline earth metal salt forms, ammonium and amine salt forms, and alkali metal salt forms. Particularly preferred are the sodium and potassium silane shapes.

The ester form is preferably a pharmaceutically applicable ester form, such as alkyl, silyl, cycloalkyl, cycloalkyl alkyl, and aralkyl ester forms, and alkyl esters with a carbon number/~tei. It is particularly preferable that

-ff Compounds of formula 1 ri/ can contain more cal-17rll groups and are therefore so-called partial salts and partial esters, i.e. compounds in which not all cal-17 acid groups are in salt or ester form. is possible,
It is actually a combined salt/ester form.

formula! In the compound Ytl! -5- or -5O3
- It is preferable to do this.

When R□ is an unsubstituted aliphatic group or a saturated hydrocarbyl group, it is preferably a straight chain or monobranched alkyl group having a carbon number of - to /g1, preferably S to /6; It is preferable to be able to do it. When R is a substituted aliphatic or aliphatic saturated hydrocarbyl group, and the substituent is a halogen atom ('alkyni group t+ is a hydroxyl group, similarly, if the number of carbon atoms is -~/g1, preferably j~/6), A straight-button or branched alkyl group is preferred, and a straight-chain alkyl group is even more preferred. R is a substituted aliphatic saturated carbyl group, and the substituent is cycloalkyl, When it is an aryl group or an aryl group, it is preferably an alkyl group of groups a to b, and the alkyl group is preferably a linear cycloalkyl, aryl or hetero When the ring aryl substituent is itself substituted, the preferred substituent is an alkyl, alkenyl or alkynyl group with up to ri carbons/4, and the alkenyl and alkynyl groups have up to ri carbon-carbon double Preferred aryl groups containing a bond or triple bond are phenyl and L pinaphthyl groups, preferred compound aryl groups are pyridyl, and thiophene groups. The most preferred substituents are alkyl and alkenyl groups, with the former being preferred among aryls and heteroaryls.

When Ro is an aliphatically unsaturated hydrocarbyl group, this may be an alkenyl or alkynyl group, containing lt or more, preferably up to 54a, at any position along its length. Carbon-carbon double or triple bonds can exist, in fact a mixture of double and triple bonds, and can be branched or branched. When unsubstituted and substituted with a halogen atom, alkoxy or human xyl group, the unsaturated hydrocarbyl group preferably has a carbon number of ~/1% 19
Preferably it is riS~/6. When substituted with an aryl or heterocyclic aryl substituent, the alkenyl or alkynyl group preferably has an IR nest number a to b,
Preferred aryl groups and cyclic aryl groups and preferred substituents in these groups are the same as those given for the case where R8 is an alkyl group. Among the unsaturated hydrocarbyl groups as R, up to 5 carbon-
Alkenyl groups containing a carbon double bond are preferred, and unsubstituted ones of this unsubstituted group are also preferred for lI/. When R is aliphatic unsaturated, the following formula = R -
The type represented by CH=C- is most preferred, and in the general formula teR,t! Phenyl, benzyl, naphthyl or 3 carbon atoms
It is an alkyl or monoalkenyl group of ˜4I, and the R, tll hydrogen atomic ratio is the number of carbon atoms/˜tei alkyl group.

When R is a cycloalkyl group having 3 to g carbon atoms, it is preferably a cycloglobyl, cyclopentyl or cyclopentyl group, lI a cycloalkyl group, an alkyl group -alkenyl group or an alkynyl group. Any of the groups preferably has a carbon number of /Jt, and any alkynyl group or alkynyl substituent has/or more carbon atoms, preferably S to R elements. A double bond or a triple bond can be included.

Examples of R8, aryl and multiple aryl groups, include phenyl, naphthyl, pyrinol and thiophene groups. Among the aryl and heterocyclic aryl groups, the former is preferred! ! F aryl or ri complex aryl group is, for example, a hydroxyl group,
/% lil carbon atom or carbon number ""i'"""""group, te"':"group can be substituted with an alkynyl group. ff Any alkyl, alkenyl or alkynyl group on an aryl or heterocyclic aryl group preferably has a carbon number as small as 1 and the alkenyl or alkynyl substituent has/or more carbon atoms, preferably up to Film. The carbon-carbon double bond can have a triple bond. In the first half of the substituted aryl and heteroaryl groups as R, the Il substituent is preferably an alkyl, alkenyl or alkynyl group; Most preferably the phenyl group is a naphthyl group, and when the group is substituted, it preferably has a single carbon alkyl group or Fi-phenyl group.

R1 is an -it-substituted acyalkyl group,
If R3 is cycloalkyl or substituted with a cycloalkyl group, it is preferable that they have a carbon number of λ to S, preferably a straight chain or a branched chain. , wrinkled cycloalkyl group ri vertical element 3-II
Preferably, R3 has, for example,
group, /I-rory atom, hydroxy, + group, NHR,
O LU: C0 vertices, substituted or unsubstituted with/or more substituents left over from
o*, an alkyl or alkenyl group). R
The alkyl group as 1 is preferably a phenyl group as any aryl substituent that can be placed on the alkenyl group, and when the R group is a substituted alkyl or alkenyl group, the preferred substituent is NHRI or L. and COX, R theory is H1 alkyl, aryl, amino acid residue with 7 to 7 carbon atoms, or COx, and xriost or amino acid residue. R8 also as X, preferred amino acid residues are glycine, glutaic acid, alanine and phenylalanine residues;
Relatedly, this is to be understood to also include protected W (protected with known groups). R3
For alkyl and alkenyl groups, the former is preferred; preferred -YR groups for 41 are glutathionyl, cysteinyl and cysteinyl dalicinyl iptide residues, each having the following formula: %.

When Rm; df71J-, it is preferably phenyl, an alkyl group whose substituent is returned to the prime number /~d, carbon X
The substituent is preferably an electron-withdrawing group, preferably an alkoxy group, a halogen atom, a hydroxyl group, a carboxyl group, and the substituents are preferably electron-withdrawing groups, such as 1, a nido group, a trihalomethyl group, especially a trifluoro group. It can be a methyl group or an acyl group having -5 carbon atoms.

Rihani X or Oku I as a hapgun in general 5cl
R is preferred, and the former is particularly preferred.

Particularly preferable R1 is the following 9.

a) Unsubstituted carbon *! ;-/+ alkyl group +r
Unsubstituted alkenyl group containing double condensation at sstst, b) Number of carbon atoms λ to j monosubstituted with phenyl (7)
Alkyl group, C) Unsubstituted phenyl or naphthyl group, d) R, -CH, -C-17t fe L R@
jj 7 x = ruhenzyl, naphthyl or an alkylmodyl hamonoalkenyl group having 3 to 1 carbon atoms,
R. is a hydrogen atom or an alkyl group with carbon number/~.

Particularly preferred R1 groups are as follows.

a) Glutathionyl, cysteinyl glycinyl, or cysteinylglycinyl groups containing a sulfur atom as the -5R1 group, b) Alkyl with a carbon number of /~, alkoxy with a carbon number of ~, a halogen atom, or a hytoxyl group. A phenyl group selected from the group consisting of xyl groups and substituted with a group of 7t/ to 3Illl or unsubstituted.

As will be understood, the compound of general formula
has a chiral center at , and therefore a stereoisomer, j
'R,i;ts%As;,iR,45 35%6R
exists in Other enantiomers IL/ are possible depending on the nature of the substituents R1 and R1, leading to further chamber isomers. I
I! When a compound contains an alkenyl substituent, for example at R, cis-trans isomers may exist; however, the present invention is not intended to be limited to any particular isomer.

Further examples of preferred groups of compounds are as follows.

a) General formula: However, R is an alkyl group having up to 70 carbon atoms, a cycloalkyl group, an aryl, a cycloalkyl halogen,
hydroxy, NHR, and cox (where “s#iH
% return prime number l-da alkyl, aryl, amino acid residue,
or cox, and X is OH, alkyl of carbon number/~, NHL or az) acid residue, optionally substituted directly with nl or more substituents, 4 may be unsubstituted, and Rm has 3 to 4 carbon atoms.

Alkyl is an alkenyl group, and an alkenyl group has the formula: R, Cl==CH-, where Hl is an alkyl, phenyl, or naphthyl with a prime number of 1 to 1. is an alkyl group having 1 to 2 carbon atoms, and thus compounds, lactones, salts and esters thereof.

R, is preferably an alkyl group with an IR prime number of 70-/d, particularly a CSS alkyl, or a FiR-ma CH=CH- (wherein R1 is an alkyl group with a carbon number of 1 to 1), and t
The structure of R at the carbon atom can be a FiE structure, and 2 is preferred.

R, Fi can be a wide range of groups, preferably carbon number - ~ j
alkyl of NHRs and C0x (herein R
j is h or an amino acid residue or COx, and
FiO)l, alkyl having carbon number/-1, N8 or an amino acid residue) is preferably substituted with one or more substituents, and as a 7-anoic acid residue, Those derived from darisin and alanine are preferable.
A preferred general formula for R is as follows: RdH is an alkyl with a carbon number of 7 to 7, and n
Ha/~3, XtiOH17? :, tlOH! and Rs are Hl and FiCUR (R is alkyl having 1-carbon atoms, preferably methyl).

Thus, particularly preferred sub-general groups are those of the following.

However, it is denoted by R,ri and 1. where R is H or carbon, :IR number/~V alkyl 6, nri/~J,
- alkyl, preferably methyl group).

-R, examples of groups are -CH@Ch, C0OH.

-(CHr)・C0OH, -CI-1,C)I(NH,
) COOH.

including.

lbl General formula: However, 81'Fi substituted calligraphy is unsubstituted phenyl or naphthyl or has the formula R, -C'H,,,CH- (where R
m B is a phenyl, benzyl or naphthyl group), RIri is a modified or substituted phenyl group, compounds represented by -. .

If R, is substituted, the number of substitutions, lk, Fi, 3
Alkyl, preferably carbon number/~q, carbon number,
/~Tei flukoxy, -R prime number-~4-5 acyl (R
The alkyl-co), haofon, human-kin, carboxy, 2)'',) U halomethyl and carbon 3I number l-da azyl-a, ino are widely used, most preferably halogen. , Tri-Full 1st Me,, f ; Clear or nitro.

% of the single-general formula with 1 #f attached (7 g).

OH However, R1 is naphthyl 1. , @■0-substituted phenyl is preferably a phenyl group substituted with #li/-J number of i-logon, nitro or trifluoromethyl groups.

(c) General formula:.

OH However, R, 71 formula R, CH=CH-17'triR
, CHICH, - (where R, d phenyl) is 6
”), Rm is unsubstituted or substituted alkyl having 1-d carbon atoms and unsubstituted or substituted phenyl.
・1. ton, salt arrangement (ester type compound, substituents on the 7-enyl nucleus are listed in (b) above)
Get one of the items listed above.

The present invention #4 also provides a method for producing the compound of the present invention l), which method consists of the following steps.
, .

a) A compound of free acid in which Y is -5-7 in the general formula 0 is obtained as the following 15, that is, al) stratified with free acid;
″ ゛−
2, where R1 is as defined above, and a sulfenyl chloride having formula 2: R,Sα carbonate are reacted in an inert solvent, and then the resulting lactone type compound of formula 1 is Isolate or hydrolyze the obtained lactone to obtain the compound 2 in the free acid form, a. b) reacting a compound having the formula V: RISHV with a thiol having the formula I in the free acid form, where R1 is as defined above, where Y is -5O-
or -5OI-) in the corresponding compound, ie, free acid form, of the above formula
C) In the free acid form, a compound having the above formula
− is)), a compound having the formula ■: R1-C)(, −
5O,R, straight, R1, R,ri is as above, and in the free Al form, the formula ■: /\71\
■ 0) React with a compound having 1c C0OH, and if necessary, release the resulting compound! #! It is prepared by isolating it in , lactone, salt or ester form.

Step al) Lri preferably a base, e.g.
is preferably carried out in the presence of a tertiary organic ion, such as a trialkyl ion, for example triethyl ion. The reaction is carried out in an inert solvent, for example an ether such as zoethyl ether, and in a hydrogenated hydrocarbon, such as a carbonated hydrocarbon. The reaction fIA degree was 1600 to +60
°C, preferably -20 °C to +-°C. The initial product of this process is the lactone form of the compound of general formula, which can be hydrolyzed to the acid form using, for example, basic hydrolysis. This step al) is not preferred when the ri compound contains other double or triple bonds, for example when R is an alkenyl group. Otherwise, a competitive side reaction involving the addition reaction of sulfenyl chloride to C at a position other than the heavy bond would occur. For such compounds step ail) is preferred.

In order to keep in mind that the sulfenyl chloride of formula (2) is relatively unpopular, this reagent can be used on the spot with a comparable thiol (RISH) or a preferentially corresponding di-sulfide (R@ Lcm to chlorinate S-5Rs)
Preferably, the chlorination is carried out using molecular chlorine or sulfuryl chloride as the chlorination agent, and the temperature -
It is carried out at 600 DEG to +20 DEG C. in an inert solvent, for example carbon tetrachloride.

Compound I is preferably used in free form.

The superposition of C in the compound box can be cis (Z) or trans (E), giving final compounds that are different diastereomers.

Step ai) Fi is preferably carried out in the presence of a trialkyl ion with a strong base (pKa ), such as triethylamine, in an inert slow-burning solvent such as an alcohol, such as methanol. The suitable reaction temperature is / 00 ~
j0°C, preferably rich. This reaction is catalyzed by adsorption of a thiol of formula V onto an activated alkaline metal.

In step 1m), it is preferable to use compound (1) in the form of an ester, particularly in the form of an alkyl ester having a carbon number of 1 to 1, and in particular in the form of a methyl ester.The compound obtained by the present invention is therefore initially in the corresponding ester form. Manufactured in

In this reaction, isomerized S-thio-6-hydroxy compounds can be produced according to the given S-human tetraxy-6-thio compounds of formula (1).

After the isomerization by-product is lactonized, only the 5-hydroxy compound that undergoes lactonization can be extracted from the mixture by forming the acid type compound, for example by heating in an inert solvent such as toluene.

Process b) can be carried out according to known methods of converting sulfides to sulfoxides or sulfones, for example using /oxyacids as oxidizing agents. A particularly preferred saponifying agent is rim-perbenzoic acid. This reaction t'i/'-carbohydrate can advantageously be carried out in an inert fIFr medium such as methylene chloride. The above formula (■) in which sulfoxide, that is, Y is -5O-
If you want to obtain a compound of formula! Preferably, 7 moles of sulfide ai*b and 1 mole of m-a-perbenzoic acid are used at about θ°C. Sulfone i.e. Y is -5O1-
When the compound of the above formula is to be prepared, it is preferable to use an excess of m-wa perbenzoic acid in a room.

In Jin's method, it is preferred to use a sulfide starting material of formula I in the lactone form and first prepare the corresponding sulfone or sulfoxide in the lactone form.

In process c) it is preferred to use the compound of formula (1) in ester form, the preferred ester form being the methyl ester form. That is, it is most preferred to use methyldarhol 2-rubutyrate, so that the resulting formula
The compound is initially in the corresponding ester form. This reaction is preferably carried out in the presence of a base such as magnesium bromide and in an inert solvent such as an aromatic hydrocarbon such as benzene. High reaction temperatures are preferred, for example it is preferably carried out under reflux.

The compounds obtained according to the invention can be isolated and purified according to known methods.

Among the various forms of the compounds of the invention, e.g. salts, free acids,
Interconversion between lactones and esters - can be carried out according to known methods, for example in the ester form, in pM? It can be converted to the p1 salt form by evaporation with an appropriate aqueous dilute base at ~lθ. The salt form can be converted to the free acid form for aqueous oxidation. The free acid form can be converted to the KL silactyl form by iron treatment at pBO lower than 3, and the salt tfCri free base 4 can be converted to the base or RI acid catalyzed ester using an appropriate alcohol. The compound KL can be converted to the quester form.

The intermediates used in the above methods a) to C) are of the known type 4, or according to known methods,
It can be obtained from available starting materials.

For example, a compound of formula 2 is a compound of the formula ■near, where ph is a phenyl group,
and the following formula: R, Cl-10, where 81 is as described above, can be obtained by Wlttig reaction with an aldehyde of It is carried out in the presence of potassium tert-butoxide, etc., and a suitable reaction temperature is in the range of 0 to 700°C, preferably Fi 10 to 30''O.

The second sulfenyl chloride can be produced as described above. That is, the corresponding thiol or h disulfide can be obtained by the reaction of the corresponding thiol or h-disulfide, as shown in step W#, which is discussed in step-:).

The chemical oxide used in the above step (1) can be prepared by oxidation of a compound of the formula C, preferably in the ester form, for example, using rim-chlorine perbenzoate or aqueous peroxide as the oxidizing agent. use. m- as an oxidizing agent
If chlorine perbenzoate is used, the oxidation can be carried out in chloroform, and preferably in methanol, where aqueous peroxide is conveniently used.

Particularly valuable are compounds with 2 in the free S acid form,
In the free acid form, the new group is 2.1: However, R1' is the same as the above R1, but is a group other than alkatetraenyl or an alkatetraenyl group having from /co to /6 carbon atoms. It is something that you have.

The preferred breakdown of R11 is the formula: %Formula%) However, Rx is an aliphatic saturated or unsaturated hydrocarbyl group with 7tt carbon atoms, which may be monosubstituted with a phenyl or naphthyl group, or may be unsubstituted. <, Shaphenylte is naphthyl monosubstituted with an alkyl group, alkenyl group, or alkynyl group with a base prime number of 10t,
or is an unsubstituted group represented by the following, but Rx is other than an unsubstituted alkatorienyl or alkato7'traenyl group having 10 to 1 carbon atoms.

Another preferred intermediate group H1' has the formula: %Formula%, where R- is an alkyl or alkenyl group having 3 to 10 carbon atoms, and the alkenyl group has the formula R, CH==CH-
(However, R1 is alkyl, phenyl, or naphthyl having a carbon number of /~/2),
I is H or an alkyl group having 7 to 7 carbon atoms.

PK and other preferred intermediate groups are those in which R1' is a substituted or unpupillated phenyl group or a naphthyl group.

The compound of formula η used in method C) has the following formula X: R, CHI B r
X However, 81 is the above-mentioned definition.
can be prepared by reacting a nulphinate having the above definition, preferably in dimethylformamide at room temperature.

Compounds of the invention, i.e. compounds bearing the above formula 1 in free acid form, are pharmacologically active and/or of the tests shown below.
It is 5R3-antagonistic as shown above. (115chi lcl method (Brlt,
J, Pharm, , , 2, /97-λ06(/
9117> ), / On &-!;Osf
In vitro tests on guinea pig ileum segments at a concentration of p till Au5t.
(GuineaPlg Pulmonar)
y Function Te5t; J, Cl1n
.

Invest, ,! ; J, / Ih? ? −／
Aj! (/?71I)), which is 0.0
! f s9~SJ) Intravenous administration of misaki/noodles;
(ill) 2! ;--〇〇M9/h4 improvement in dosage @Herxhe1mer' test, the @He
rxhe1mer ”The test is based on allergic bronchospasm induced in guinea pigs.
The asthma-like symptoms seen in humans are very similar to RA. The mediators that produce bronchospasm are very similar to those released when sensitized human lung tissue is challenged with the antigen KL. In a modified test used for compounds of the invention, animals were treated with the Vistaon antagonist, Mevila 2, at 0.05 min. ! ;q/* with an intraperitoneal dose. This improvement hides the oxidative effect and makes the 5R3-A effect even more pronounced.

Therefore, the compounds of the present invention have pharmacological use in the treatment of allergic conditions in the pulmonary artery system, in which
R5-^ is thought to be a mediator of bronchospasm. IID, allergic lung disease,
He is involved in extrinsic asthma and mulberry asthma, such as farmer's lung (1 and 7%), as well as other allergic/inflammatory or pulmonary diseases in which KsR5-^ is thought to be a mediator. It has therapeutic uses in, for example, allergic skin diseases, metastatic and atopic eczema, psoriasis, contact hypersensitivity, pharyngeal hydroedema, bronchitis, and fibrosis.

The compounds of the invention may be administered in the free acid form, the lactate form or the sterically acceptable salt or ester form.

They can be administered by a variety of routes, such as oral, rectal, topical or parenteral, such as injection, and are usually used in the form of preparative compositions.

Such compositions form part of the present invention and may be prepared by methods well known in the pharmaceutical art and typically contain a diluent or r that is pharmaceutically formulated with a viscous compound of at least σ.
In making the compositions of the present invention containing in combination with an i carrier, the active ingredient is usually mixed with the carrier or diluted in the carrier and/or encapsulated within the ri carrier; 6) in the form of, for example, a container, a bag, a container, or another container. When the carrier functions as a dispensing agent, it can be a solid substance or a liquid material, which acts as a vehicle for the active ingredient and as a medium for the excipients.

The compositions are tablets, preparations, cachets,
elixirs jlJ, II suspensions, knee w sols (111 bodies or in liquid medium), e.g. ointments containing up to 70% by weight of the active compound, soft and hard gelatin capsules,
It may take the form of suppositories, injectable solutions and suspensions, and sterile powders.

Special configurations made by D4 for administration by inhalation include Enisol, a) yib-L and evaporator.

Lactose, dextrose, nuclose, sorbitol, i-nitol, starch, to name a few examples of carriers that have been passed through
Gum acacia, calcium phosphate, alginate, tragacanth, gelatin, sheets! , methyl cellulose, methyl- and gouvyl-hydroxybenzoates, Merck, magnesium stearate, mineral oil, etc. The compositions of the present invention are presently known to have a rapid-acting effect after administration to a patient. It is also possible to formulate a sea urchin that releases the active ingredient in a slow or delayed manner.

When the composition of the invention is formulated in four unit doses, each unit dose contains 10w5i to /II. The term "unit dosage form" shall mean a quantitatively discrete unit of Km unit dosage for humans as well as for animals. Each such substance contains a predetermined amount of active ingredient calculated to provide the desired therapeutic effect, together with the necessary pharmaceutical carriers.

The active compounds of the invention are effective over a wide range of administration;
And for example / daily dose @r1 usually 0,! ; ~3
00q/Kg, more generally 5~1O
Cape O/is within the range of 4. However, the dosage should be determined by the physician in light of the husband's circumstances, including the condition to be treated, the choice of compound to be administered, and the remaining route of administration.
It will be understood that the
(It should be understood that the above dosage ranges are not intended to limit the scope of the invention in any way.

The following six examples illustrate the present invention.

In some examples ijm, pm or tz b, p,
Although it has not been possible to satisfy the requirements, all compounds of the present invention have been described in a practical manner.

Example/Sodium hydride (/1.0g, !fO- in oil
dispersion) of anhydrous dimethyl sulfoxy)' (/00-
) was heated to 70 to 7 g O for 170 minutes under a nitrogen atmosphere, and the dark colored liquid was cooled to confirm that the Butyltriphenylphosphonium bromide C1,31
1> solution was added over a period of 10 minutes at 20.degree. Temperature 30~
j! ! 3-phenyl-f-ropionaldehyde (/2.5 sd) was added while cooling to a constant temperature.
The mixture was stirred for an additional hour at room temperature.

The mixture was then poured into ice water and washed with chloroform. The aqueous phase was made hostile and extracted with chloroform. The extract was washed with water, dried and exposed to IIA. ! ! II
The distillate was distilled under reduced pressure to obtain the indicated product t*b,
p, / 347 A- / 39”C10,07■.

”CNMRx (/) leMl'iKLF) approx.
It was found that the El-isomer of Is exists.

Following the procedure described above and using the appropriate starting materials, 5-heguchi/acid, 5-landecenoic acid, was similarly prepared. These are b, p, b g~7/'O/0.
3 wa, fj sac IZl otechhi/, 1-IGtEl
(by CNMR) alignment Kb, p-10j~104
°Q/0. /■,901NZlOxUlolElr
h*.

/, J, C, 51(C), λ/ri(/?6g)ko, J,O,S,, II3.17317(197g>(
b) (bar-hexadecenoic acid stirred, bromide-cal-xybutyl-triphenylphosphonium (+ '1.t g) in benzene (co-o)
The ow>ffi liquid was dried by heating under a water trap for 10 minutes. The mixture was cooled and solid potassium t'ert-butoxide (J
4',0Ii) was added and the stirred suspension was heated to reflux for 1S min. Unr Sil Alr Hit (, LO, twg)
of anhydrous benzene (-〇-) bath solution was added to the mixture cooled to 10-21''O. After mixing for */hour, the mixture was diluted with ether and extracted with sodium chloride solution. Aqueous extraction The solution was acidified and extracted with ether, and the ether extract was dried and evaporated.
A product with 9θ% (Zl and 10% (ε)) in NMR was obtained ft* (Chem, ^bl, g!
: /jwo3(1/ and Chem.

Phys, Lipids, LA, J/j (/q76)
).

The carbon tetrachloride (10wt) bath solution of sodium chloride (0,99>) was mixed with the carbon tetrachloride (-
〇-) solution at a temperature of θ to -5C, the yellow solution was then stirred at 0℃ for 70 minutes, and then the yellow solution prepared as in δ1 (Zl-ff-phenyl-5- Ok f
7 densities (/, 11 kg) and triethyl chloride (0
,9,3m) and a bath solution of carbon tetrachloride (JOm) at θ~-
Addition was made at 5°C. The mixture was stirred at room temperature for several hours and then evaporated under reduced pressure.

The residual ether bath was washed with dilute sulfuric acid, then with dilute sodium hydroxide solution, dried and evaporated to give a pale oil.

A mixture of the crude neutral product and lO-sodium carbonate solution was heated to reflux for 2 hours, cooled, washed with ether, and 11
! The extract was dried and evaporated, and the remaining acid solution in toluene was heated under a water trap for 30 minutes to give the crude lactone. This was further cleaved by q-madography with silica glue in to# Neil petroleum spirit (/:3) to obtain the pure product.

The 6-(3-phenyl-/-phenylthio-7''a-bil)-tetrahydrogen monomer prepared as described above in (cl)
A stirred mixture of pyran-coon (2,7-1> and /θ-carbonate <5OW) was heated to reflux for 2 hours, cooled, diluted with sodium chloride solution and ether Washed with water, acidified and extracted with ether. The extract was dried and evaporated without heating to give the product as a pale oil.

The above-mentioned S-hydroxy-phenyl-6-phenylthiooctanoic acid (/, 4j#) in ethanol (SO 1 ml/) fg solution was mixed with 1 mol of sodium methoxide in methanol (!, /TId). Make it basic with the solution and ##! The liquid was evaporated to dryness under reduced pressure. The residue was crystallized from inglononol-petroleum spirit, m.
The title product of p, about iso:c was obtained.

The lactones shown below were prepared according to the method described in Examples C to C), using the appropriate starting material 11 and omitting the hydrolysis and lactonization. Purification of the product was carried out only by chromatography.

R1-uni n-cl@)'ml
phPh(C)Is)i Ph cholera lactone was hydrolyzed as described in Example/(di) and converted to the sodium salt shown below in the manner described in Example/1e).

H”C1@H1l Ph Freeze-drying
-Ph(CHs)4 Ph Methanol/Isopro/Gnol - Practical IfA Example S Darkalxybutyltriphenylphosphonium B1
A solution of penzene (3t, -9) was stirred and dried by heating it under a water trap for 20 minutes.The mixture was cooled and solid potassium was added. Jert-butoxide (co9.Ol) was added under a nitrogen atmosphere and the stirred suspension was heated to reflux for 1S minutes.

Anhydrous penyan (coO) of benzaldehyde (f, ri3-)
-) Add the solution to the mixture cooled to 10-10°C,
! After stirring for 1 hour, the mixture was diluted with ether and extracted with IJum solution. After the aqueous extraction was acidified and re-extracted with a needle, the ether extract was dried and evaporated. To evaporate the residue!, 9, (21 and 1)
Mixture of El-4-phenyl-5-hexenoic acid, b, p
.

/3 da~l Dako''010-1 m was obtained.This mixture was mixed with thick sulfuric acid (0,lIme)-containing methanol (250
) for 2 hours under reflux. The mixture was evaporated and the residue was dissolved in ether, washed with sodium bicarbonate solution, dried and re-evaporated. The wm product is distilled in a rotating band apparatus to give b-p-/-1~/koJ'O/0
．． 3 wm mel 121-4-7 x nil-5-
Hexanoate treatment, p, / 33℃/0',
E) Isomers of J m were separated.

Methyl 121-j-phenyl-5-hexanoate (
Co, lj) dioxane (-〇-) # solution and 10% sodium carbonate solution (-〇-) closure! Heat to reflux for an hour and evaporate to low volume, dilute the residue with water and
The mixture was washed with ether, acidified, and extracted with ether.

The extract was dried and evaporated to give α)-A-phenyl-3.
--J-I prayed for xenoic acid.

E)-isomer was similarly hydrolyzed (J, 0°C, a3t, /390 (/944>).

Chlorine (/, jAF) four-base carbon <2311 Biao liquid,
IjR, wood (jOm/) ill of stirred diphenyl dinulphide (France 01) at a temperature of 5-10 °C.
added to the liquid. The yellow bath was stirred for 70 minutes at 5-10°C and then added to +21-4-phenyl-5-hexene (,
T,! 7) and triethylamino (,3,t sg)
A solution of Osig tetrachloride (!-Osig) at 5-10℃
Added under. The mixture was stirred at room temperature for 2 hours and then evaporated under reduced pressure. The residual ether bath was washed with dilute hydrochloric acid, followed by dilute hydroxylation), washed with IJ bath, dried, and concentrated to give 7-phenyl-6- at rr+, p, 144°C. To obtain 4-horned crystals, the mother liquor was evaporated and the residue was chromatographed on silica gel in ethyl acetate:petroleum spirits (/:J) to obtain an oil. Ta. This was crystallized from ether to give m and p.

Zako~I II ℃norel -(l, R, αR)-
4-(α-phenylthiobenzyl)-P) Rahido fermentation-,
IH-biran-coon was obtained.

04-(α-phenylthiopennor)-r)9hi)'
A solution of a-, IH-pyran-kion (/, -g) in dioxane (10m> and 10-*fll sodium (-0-) was stirred, heated to reflux for 1 hour, then evaporated.

The residual aqueous fFr solution was washed with ether, acidified, and extracted with ether. The extract was dried and evaporated, and the residual ethanol*(jOm)#[ was made basic with 1M solution of 1M sodium methoxide in methanol (3,1+/) and evaporated to dryness under vacuum. , m, p, -7oC.

This compound, m, p, approximately /90°C, was prepared as in Example S. However, the corresponding old-isomer was used as starting material. After applying the
The crude 6-membered ring lactone was hydrolyzed to L in Example J (bl) and then heated in toluene under a water trap to re-lactonize it. The toluene-vinegar solution was evaporated. The residual ethyl acetate bath was washed with S-sodium carbonate solution, dried and evaporated.

The residue was crystallized from ether to m5ps/coro °C.
Pure r-(hR,α5)-4-(α-phenylthiobenzyl)-detrahydro-biran-coon t- was obtained.

Examples lal Methyl+21- g-phenyl-5-octanoate 7l-t-fz 2Jl/-, (-octa7r11(
/ Ko, 4,! i+1 (Refer to Example/(a)) A mixture of concentrated sulfuric acid (O, /*) and methanol (300yd>fN) was heated under reflux for one hour. The liquid was evaporated and the residue was distilled under reduced pressure. Then, b, p, /10~//3°C10
,/wm of ester was obtained.

(bl/+le S, 6-oxido-za-phenyl octanoate solid m-re aa pass benzoin (10,711, purity ff
01g)t,/! ; at -20°C, lfk(z-g-phenyl-5-octanoate<l1011; the above (al
The mixture was stirred at room temperature for an hour and filtered.

The OS* was washed with bicarbonate solution, dried, evaporated and the residue was distilled under reduced pressure, b, p.

lko0-/ko! ? "Olo, 0!-Product t-obtained.

Ethanethiol (, t, A-) is dissolved in an activated alkaline solution in stirred, dry ether (/1O-).
grade; isog> was added to the suspension. The suspension was stirred at room temperature for S min, then methyl j,6-oxidoj-phenyl-octanoate (4t, II
The ether (da θ-) solution of the above (see BL) was added. The mixture was stirred for 7 hours and diluted with methanol (/j
) and pour the residue into a mixture of methyl 6-nitylthio S-hydroxy-g-phenyl octanoate and methyl S-ethylthio-6-hydroxy-g-phenyloctanoate by diluting the mixture into a pale color. Obtained as oil.

This oil and 10-sodium carbonate INI liquid (DaSII/
), heat the stirred mixture to reflux for an hour, cool,
Washed with ether, acidified and extracted with ether. The extract was dried, evaporated and the residue toluene (S-)
The bath liquid was heated under a water trap for one hour, diluted with ether, washed with sodium hydroxide solution, dried and evaporated. This residual lactone was stirred with 10-sodium carbonate #solution (20-) for 1 hour while heating under reflux. The solution was washed with ether, acidified and extracted with ether, and the extracts were dried and evaporated to give the title compound as a pale oil.

Example t This compound was prepared by repeating the method described in Example tcl using thioenol in place of ethanethiol.

Example 9 1al Methyl5. ! IEI Oxydo? 121
/Natecenote Bromide Dodecyltriphenylphosphonilla 5 (/7.99)
is dissolved in dry tetrahydrofuran <200 watts),
- Stirred under elementary atmosphere and cooled to -7g°C. Butyl lithium (7,6 molar hequinane bath solution, co3-) was slowly added to give a deep orange color. After stirring for 20 minutes at -7g°C, methyl 5. AIE + oxidocouquinheptanoate (1,6,9) Te) j He)' 07 run (
20m>The bath liquid was added rapidly. The solution becomes thinner in color and lasts about 7 hours! The temperature was raised to the turtle. Most of the solvent was evaporated under reduced pressure and the residue was dissolved in triethylaquine (
, 3x30-) containing ether/hexane 50/!
; Extracted at θv/y. The combined extracts were evaporated under reduced pressure to a small volume using the same mixed solvent.
The mixture containing the title compound was chromatographed on silica gel and evaporated under reduced pressure to give the title product as a colorless oil at room temperature.

After storage at -10°C, the product solidifies.

Methyl, t, AEI oxide-7 (z) ) and triethyl chloride (co, Od) in anhydrous methanol (3.0 m2) were reacted at room temperature for 3 days. The solution was evaporated under reduced pressure and extracted with dicouple methane/methanol as solvent. j/j-v/v t41
chromatography on silica gel gave the cysteinyl derivative of the title compound as a pale yellow oil in which the 6-position of the methi-editated ester was completely preserved. This product (/
,,t,F) was dissolved in methanol (#7m) and a solution of anhydrous sodium carbonate (01g) in water (S-) was added with stirring. Additional amount of water was carefully added to obtain a cloudy 9#l solution, which was stirred at room temperature for 3 days. 91A obtained
The clear liquid of 10 was evaporated under reduced pressure to remove methanol and the aqueous residue was brought to a pH of approximately 5.3 with dilute hydrochloric acid.
Approximately 3 M'-sections of pu were made with 15 L and then glacial acetic acid. This mixture was extracted with Nag"504
The above dried extract was evaporated under reduced pressure to give the title compound as a viscous colorless oil, which was heated at -2θ°C.
It solidified rapidly when stored.

Examples 70-/'S The procedure of Example 9(b) was repeated. However, appropriate corresponding starting materials were used. In this way, a compound of J or less was obtained.
! Doroki, Sea &-(S, F(J(2-Cal?xyethyl7theo,), -7iZl-/?De.

Heptanoic acid; ,.

j-(R,S)-hydroxy-6-(S, RJ-5
-(N, acetylcysteinyl) -7(Zl-nonadecene #nij-(R,S)-hydroxy, -4-'(S,R),
-pencylthio-1 (El -9(El / (zl
-/, /Eb-/121-eicosate, enone-1 acid; ~j-(R,S)-hydroxy-+-(s
,s,)-(,coaZnoethyl,3thio)-7(E
1-(R,,S,)-human tetraxy-4-(S,,,
Fl)-ethylthio-7(El-9(El/
(zl -1zl-/ 4A121-eicosatetraenoic acid.

(al (Zl-za-f:, Enyl-S, -octenoic acid sodium hydride, ram (/2-q 9 #!Fθ-
Oil content 4-part dispersion anhydrous, methyl sulfoxide <10
0 wt). am, add 1. ia basic song,
The mixture was heated to 70 to 5° C. for θ minutes under air. Cool the dark solution, cool the solution, add anhydrous dimethyl phosphatide of a chloride, siebutyl trif, enylphosphonium (,tJ,p,) <ioo,t) pm, and add the solution to 20~2 pm.
If! for 20 minutes at 5℃! , and the resulting multiliquid was stirred for 2 minutes over 5 minutes at a time. 3-phenyl 6-no,
Add ROBIONA, RHITO (/Jj-) with cooling, keeping the temperature at 30~jj'0° at a time, stir the mixture at W temperature for 1 hour, then add ice, water ( 400d) and washed with p-form. The aqueous phase is made acidic and
Extracted with Rojo and Lum. Extraction [j Wash with water, dry,
Evaporated.

The residual oil is vaporized under reduced pressure under 1, b, ρ, i, tii~/
The title compound of 39''CIo, 07- was obtained.
CNMRK! If 1. (E) - It was shown that about 5 different sex 9 bodies exist. .

−/′-phenylthioglobil)-tetrahuman chlorine (0
,9&> of diphenyl disulfide (2,2!i) was stirred in a carbon tetrachloride (10 m/) bath solution.

A carbon tetrachloride (-0gIt) solution was heated at θ to -5°C. The yellow solution was stirred at 0° C. for 70 min and then mixed with (Zl-g-phenyl-5-octenoic acid <i,ysp> and triethylamine [) prepared as described above (al), 93
A solution of carbon tetrachloride (mg) in carbon tetrachloride (CO011) was added at θ to -5°C. The mixture was stirred at room temperature for an hour and then evaporated under reduced pressure. The ethereal solution of the residue was washed with dilute hydrochloric acid. The mixture was washed with dilute hydroxide solution, dried and evaporated to give a pale oil.

The crude neutral product was heated to reflux in 10 fR sodium chloride solution for 1 hour, cooled, washed with ether, acidified, and extracted with ether.

Dry and evaporate the extract, and remove the remaining acid from the toluene layer.
Heat under a water trap for 30 minutes to evaporate.
A crude lactone was obtained. This was further chromatographed on silica gel in ethyl acetate dipetroleum spirits (/:J) to obtain the pure product. A dichloromethane (100wi) solution of purity) was added to a stirred rel
-(AR,/'R) -1s -(3'-phenyl-/
'-phenylthioglobil)-gtrachthu-co-H-pyran-co-one (da, -g) in dichloro-methane (co00
1) It was added to the bath solution at 5 to 10°C.

After standing at room temperature for a few hours, precipitate (m-claw benzoin #)
The white solid was filtered. Wash Part F with aqueous/sodium sulfite, aqueous sodium S-carbonate and saturated sodium chloride, dry over anhydrous sodium sulfate, filter,
Evaporate to give rel-(AR,/'R)-6-(/
'-Phenylsulfonyl-3'-phenylp4-
Tetrahydro-λH--ran-coon was obtained as a colorless viscous oil, which was chromatographed (silica 5 orbsil U j O) as a 4-hydro-4 compound.
) x f am, p, 13°C, ground in Rue-fle.

wrinkled tetramodropyran-coon derivative (/, 1.3I
) and 10 chronic aqueous sodium carbonate fall (llO*) was heated to reflux for 7 hours. Cool this # along,
The mixture was washed with diethyl ether, acidified to approximately pH 2), and extracted with diethyl ether (SOt). The extract was washed with saturated aqueous sodium chloride solution, dried, FA and evaporated to give a colorless oil. This was ground with diethyl ether and crystallized to obtain the title compound as a white solid.
-1) -700~/θ℃.

Example / A bath solution of ethylmagnesium dibromide (7.7 w, / JM diethyl ether) was stirred and then phenyl 3-phenylglopylsulfone (2.6 g of anhydrous benzene
-) added to the solution. The mixture was heated to reflux for 772 hours, then cooled to room temperature. Upon addition of methylformylbutylate (3Ii), a white precipitate began to form; the bales were left at room temperature for one hour, ice water (70m> and -Molar salt #(Od) was added), and the product was dissolved in diethyl ether. Extract and then pour over ``Matodarafui'' (5 or
bsll Ll j O silica) to give the title compound as a colorless viscous oil.

Example/l Methyl-1-hydroxy-Z-7H-6-phenylsulfonyl octaate was hydrolyzed with aqueous sodium carbonate in the hydrolysis step of Example/6 to give the title compound as a viscous oil. .

Example/? -,2/ The following compounds were prepared as described in Example 7.

S-Hydroxy-4-(!-chlorophenyl)sulfonyl-za-phenyl-octanoic acid;
-(dermethylphenyl)sulfonyl-za-phenyl-octanoic acid; S-human-xy-6-phenylsulfonyl-g-phenyl-7-octenoic acid.

Example-11 A dimethylformamide (coO-) bath solution of /-(cou-methyl)-naphthalene (/ri, 69) was mixed with a stirred dimethyl of sodium benzenesulfinate (/A, eI). Added to the suspension in formamide (tO1'j). After standing at room temperature for 20 hours, the mixture was diluted with water and the white precipitate that formed was filtered.

Recrystallization from ethyl acetate-petroleum ether at 60 to 9°C gave the title compound with m, ρ, and 9°C.

A solution of ethylmagnesicum chloride bromide (3M ethyl ether solution) was added to the above stirred solution (I14 in al).
It was added to a solution of the prepared (/-naphthyl)-methyl-7enyl sulfone (g, llA, SF) in dry tetrahydrofuran (tOwd>) at -0°C. After 7 hours, it was heated to -1θ°C. The mixture was warmed to 0° C. over 7 hours, poured into ice and hydrochloric acid, and extracted into dichloromethane to give methyl S-hydroxy-&(/-naphthyl)-. A-phenylmelphonylhexanoate was obtained as a colorless viscous oil.

This methyl ester was hydrolyzed by heating with dioxane (jOm), water (daj-), and an aqueous salt of comol #(/-) for 1 hour to give the crude title compound. Ta. This product can be lactonized, hydrolyzed (L)
Purified by forming Q-rim salt. m,
p, about /70°C (isoglobil alcohol).

Example 23 4 ml cinnamyl ethyl sulfone hydrogen peroxide (JO* w/w, 0.comole) was added to stirred cinnamyl ethyl sulfide (/6.g
Jil) in acetic acid <1oo-> solution. The mixture rose to temperature (approximately IfO 0 C, exothermic reaction) and was then heated to 700 0 C for 2 hours. # The mixture was then cooled, diluted with water, and the precipitate was filtered and recrystallized from tetanized backstone, oil ether at to-to °C to give the title compound, 6 m-p. -/00℃.

The above compound was prepared from cinnamyl ethyl sulfone by the method described in Example 2(b)K, m-p-
The temperature was approximately 730°C.

Example Kodacinnaelectrothioglobion #l (m, p, 7°C) was prepared from cinnamylb+2 odo and mercagtogoubionic acid, which was oxidized according to the method described in Example Koj (alK) to give m, p, / 40° C. was obtained. This acid was mixed with stirred lithium aluminum hydride (co-equivalent) of tetrahedral hydroxide.
The resulting product was isolated by ethyl acetate and m
, p, 6° C. Cinnal 3-hydroxyglopylsururine was obtained. A dichloromethane solution of lannaol 3-human xyclovir sulfone, p-1' luenesulfone il & (catalytic) and pyran (-equivalent) was left at room temperature for 21 hours and evaporated. The title compound was obtained at 5° C. by condensation from diethyl ether.

Nyl-co-glopenyl]-tetrahydro-co-h-bilane-coon was prepared from co(cinnylsulfoelglopyroxy)-tetrahydrobyran by the method described in Example 1--lbl, which was converted into the sodium salt of the title compound. force n water decomposition friend, m, p, /jj”o.

A-[/-(Hydroxyglobilsulfonyl)-3-phenyl-Korg! 2(Nil) ~ Gutrahydro 2H-pyran-kion (! IIl! See Example-DA, /, 09)
A mixed paste of pyridium zokutetramate (Da, 6'7 g) and dimethylformamide (10d) was stirred at room temperature for 20 hours. The mixture was diluted with water and extracted with ethyl acetate to give l, -CI-(car-xyethylsulfonyl)
-3-phenyl-2-7''benyl]-tetrahydro-2H-pyran-coon was obtained as an oil. The lactone was hydrolyzed to prepare the sea urchin disodium salt in Example Coco (bl) with m, p, approx. The title compound at 03°C was obtained as the cysodium salt.

Example 26 (E) / +21-nonaderyonic acid methyl ester methylfolyl butyrate (13 g) and /-)liphenylphosphoranylidene-copropanone <3/, IIfl) were dissolved in toluene (20011 Minutes - Fast flowing 0
The toluene was then evaporated, ether was added to the residue, and the solution was stirred for 1 minute at room temperature. The suspended triphenylphosphine oxide was separated by F and further washed with 100-ether. The combined ether solutions were evaporated to dryness to give a yellow oil, which was
0 using the hr device 111e (air bath temperature/da 0°C)
．． Distillation at 716 g gave 7-oxo-S-octenoic acid methyl ester as a colorless oil.

Sodium dehydrogenate <sg>' was dissolved in water (100 ml), and KSO-aqueous hydrogen peroxide (S-) was added thereto.
To this solution was added methanol (/(7WI) of cuoxo-5-octenoic acid methyl ester (3,111) at room temperature.
After 700 minutes of addition of the tl# solution, the resulting clear liquid was extracted with dichloromethane 9 times (daXjO-). Extract S, dry (MgSO4) and evaporate to give 7-okino5. /, El-oxide-5-octenoic acid methyl ester was obtained.

n-dodecyl-triphenyl-phosphonium bromide (/
7.0-g) was dissolved in anhydrous tetrahydro 7ran (1001) and cooled to -7g°C with stirring.

n-Butyllithium (/3..3-, hexa797.5
7-oxo-! mol) was added to obtain an orange colored ylide 111#, which was stirred at -7g°C for 70 minutes, and then added to this 7-oxo-! A solution of 61E)-oxido-5-octenoic acid methyl ester (3,7 g) in anhydrous tetrahydrofuran (201) was then added to the reaction mixture, which was then warmed to room temperature over 7 hours. Evaporate and add ether (-00d) to the oily solid./R
After stirring for a while, remove the ether by decantation,
This process was repeated one more time. The ether extracts I& were combined and evaporated to dryness to give a pale yellow oil, which was chromatographed on a silica column and leached with 1 hexane:ether (/:/) solvent to give the comethyl-3 ,A
(Two isomers of El-oxide-7-nonadecenoic acid methyl ester were obtained.

DL-N-acetyl-β-mercazotoinoleucine methyl ester (2/de) was dissolved in anhydrous methanol (CO), and triethyl aquine (-) was added. Coumethyl-3゜41El-oxide-7-nonadecenoic acid methyl ester (,3Jtq) was added to
A pale yellow solution was obtained which was left at 50° C. for S days. The solution was then evaporated to give a pale yellow oil, which was subjected to chromatography on a t7 column and eluted with ether to give 5(9-hydroxy-AIRI-[(,2
-(N-acetyla Z])-comethoxyol? Niru7-xfru/-methylethyl)-f]-ri(Z)
/(E)-Methyl-nonadecenoic acid methyl ester and its j-R,A S-isomer was obtained as a colorless oil. Next, this diester was dissolved in methanol (g-) and
．． Hydrolyzed by addition of 7 molar aqueous potassium carbonate solution (/cod), the resulting cloudy water bath solution was then stirred at room temperature until clear (76 hours). Furthermore, p
h was diluted with aqueous-molar hydrochloric acid and the resulting solution was extracted twice (4'x10+/) with dichloromethane. The extracts were combined and evaporated to dryness, and the resulting oil was loaded onto a silica column KL and evaporated with solvent to remove the title compound. The sodium salt of this was prepared by reacting the free acid with 7 equivalents of an aqueous solution.

Lithium Salt Example Corro's half ester (100 tt) was dissolved in t2M lithium hydride (3-) and the solution was heated to room rmK for 16
The pH of the bath solution was adjusted to 3 and extracted with dichloromethane three times (3 x 10 ml).The extracts were combined and dried over MgSO4.
It was then evaporated to give a viscous oil which was azeotroped with benzene for 2 hours to give the lactone of the title compound.

This lactone was then subjected to a 1-cyclodehyde reaction on a silica column with dichloromethane:methanol:acetic acid (?
0:? :/)! It was eluted with medium. Finally, the lactone was treated with a coequivalent amount of aqueous sodium bicarbonate solution to yield the title compound.

Example 2g The title compound was prepared following the method described in Example/(C).

Potassium salt The lactone of 1al above was hydrolyzed as in Example/(dl. The ether extract was neutralized with a 1 molar solution of potassium hydroxide in ethanol and the resulting lactone was evaporated. The water bath solution was lyophilized to give the title compound as a rubber.

Boron tri7tide (3,Ot) was dissolved in a stirred rel-
(4R. cooled dichloromethane (manufactured by
The temperature was adjusted to 10θ-) solution. The resulting dark solution was stirred at room temperature for 7 hours and then treated with water (30-). #!
The medium layer was dried and evaporated, and the ether solution of the residue was extracted with IJ Umu Biaking. The aqueous extract was acidified, apricot extracted with ether, and the Neagle extract # was dried.
1 mol sodium methoxytome)tanol (7-Oml
) Neutralized with Mllf and evaporated. The residual gum was treated with In7'a panol-petroleum spirit to give the title compound as a solid.

Example 30 1al Methyl(E)-za-phenyl-5-octanony]! A solution of bromine (11.3 mg) in dichloromethane (tOe) was added to a stirred solution of triphenylphosphine (cog).
The temperature of the dichloromethane (100ml) solution was adjusted, and the resulting pale yellow liquid was evaporated, and the remaining solid was suspended in anhydrous benzene (300ml). Me, Chill 5.4-
Oxide-3-phenyl octanoate <t9.01;
The mixture was stirred for an hour and then evaporated.
0t), the extract was evaporated again and the methyl re
l, + (jR, AR) -5,6-dipromo g-
Phenyl octanoate is obtained as an oil.

The zinc powder bed (koku, da!i) was mixed with the dibromo compound (core, II9) and stirred vinegar H (2301) 114
added to the liquid. The mixture was stirred for 3θ min and water (7!;0
-) and extracted with petroleum spirit (3xlloo-).
). The extract was washed with sodium bicarbonate solution, dried, evaporated and the residue was distilled under reduced pressure to give the title compound, b,p,iio~//3°C 10. To),
The results of 1-IPLc analysis contained the 121-isomer of ios.

-A, at t'O, chlorine gas was added to methyl (Zl-g-phenyl-5-olinoate (/1.Al) in stirred dichloromethane (co5o
b) Passed through the solution. This solution was heated to 120℃,
This was then poured into ice/sodium metabisulfite solution. The solvent layer was washed with water, then with sodium bicarbonate solution, dried and evaporated to give methyl rel.
-(!;Hr Is 5)-s,b-dichloro-za-
Phenyl octanoate was obtained as a pale oil.

This dichloro compound and sodium iodide (1001) were stirred in anhydrous zomethylformide (300yd>
The solution was heated to 9°C for 2L hours, poured into ice/water and extracted with ether.

Extraction fIit - washed with sodium metabisulfite solution, then with sodium chloride solution, dried and evaporated. The residue was distilled under reduced pressure to give the title compound. It contained about 10 rZl-isomers.

Stirred methyl IEI-za-phenyl-5-tp thenoate (/3.411) nooxane (/J!fgIt
) and 10-sodium carbonate dissolved (/2.tsg) were heated under reflux for 7 hours and then evaporated. The water bath residue was washed with ether, acidified and extracted with ether, and the extract was dried and evaporated.

The residue was distilled under reduced pressure to #i, o, p, /! ;0~15
The title compound of 3'O/0 was obtained.

Stirred bromide, triphenylphosphoniu, &(II!;,71), methanol (,300-)
The mixture of Oyoko M sodium hydroxide solution was heated at 30° C. for 3 hours and then concentrated under reduced pressure until the oily product solidified. The resulting solid was washed with water, dried and reconsolidated from petroleum spirits to give m, p, 6? Diphenyl-undecylphosphine oxide of C was obtained as follows.

/, 1s M n-butyllithium in hexane (5AI
I/)? @The solution was stirred with phosphine oxyto (3/,
01/) in anhydrous tetrahydrofuran (DA00t) at -1IO to -95°C under a phonetic atmosphere. The orange solution was stirred for 70 minutes at SO<0>C and then a solution of valerolactone (9.0 g) in anhydrous tetrahydrofuran was added. Raise the temperature along the light color #l to room temperature,
Poured onto ice and extracted with ether. The extract was dried, evaporated and the residue was crystallized from Neegro petroleum spirit, m, p.

/-(j-hydroxypentanoyl)-unf at 70°C
I attended siluzophenylphosphine oxyto.

Stirred mixture of this compound (/9. IEI and sodium borohydride (/, OI) in ethanol (200
-t) The solution was heated to reflux for 2 hours. The solution was evaporated and the aqueous residue was extracted with ether. The extract was dried and evaporated and the residue was crystallized from nityl petroleum spirit, m, p.

Erythro/-(/, 5-dihydrocybentyl)-undecyldiphenyl-phosphine oxide was obtained.

A stirred mixture of the diol (/1..2 g), sodium hydride (/, 7i, gos oil dispersion), and anhydrous dimethylformamide (200 wt) was heated to SO ~ 52 °C for an hour. Cooled, diluted with ice/water and extracted with ether. The extract was washed with a sodium chloride bath, dried and evaporated to give IEI-
, 5-1-hexadecenol t-4fc, which solidifies to a waxy solid at riO<0>C.

A solution of alcohol (9,99) in aqueous chromium/sulfuric acid (Jone sulfuric acid) was prepared at 20°C.
S reagent). The mixture was poured onto ice and extracted with ether. The extract was dried and evaporated and the residue was distilled under reduced pressure to give b, p, /15 to /1. ．． 0℃10. The compound described in ① was obtained.

(・1 Lactone The following lactones were prepared according to the method described in Example/(C1), IE of the compound of the general name)-isomer (said 1al, (bl, (7)) ).

Ph (CHI)1 n-Cs Hzvn-c
The lactone of Example 30 was hydrolyzed as described in Example hd) and converted to the sodium salt as shown below as described in Example ce).

oH Pfi (CH,), n-C, H,.

n-cll”ml　　　’ph Example 1 hexenoic acid Stirred water volumized sodium (Koda, oti, s.

-Oil dispersion) Anhydrous dimethyl sulfoxide (200-)
The dispersion was heated under a threatening atmosphere for 7 hours.

The dark solution was cooled to 20° C. and the anhydrous zomethyl sulfoxide of decaldaxybutyl tripheelphosphonium bromide (1041/) C coθ0-f) #! was added and the mixture was stirred for 70 min. 2-Naturaldehyde <3
Anhydrous Nomethy A/, The mixture was then poured into ice-water (Zl''jK) and washed with awz form. The aqueous phase was clarified and extracted with ether.

The extract was dried and evaporated to give (Z)-Okobi (El-
A-(,2-naphthyl)-S-hexene # was obtained and this was used as an example! ; lal Kika's method KL is esterified,
The mixture of methyl esters was partially separated by fractional distillation under reduced pressure.

The partially separated ester was hydrolyzed in Example 51 al.
crystallize from m, p, 41. tZl in °C, -'b
-(cornaphthyl)-,! --hexenoic acid, m, p,
(El-6-(-1naphthyl)-5-hexenoic acid at 93°C was obtained.

(bl Methyl Cεl-4-(λ-naphthyl 1-5-
Hexenoate (produced as described above in 41) (ZlO1)
and (ε) methyl ester at 750 to 140°C for 20 hours. Ropionic acid C number l1lli
) to obtain primarily the (El-isomer) and the product was distilled under reduced pressure.b,p,/!rO~/
62'O/0. /w*m-p-b 9°C methyl IEI-4-(Q-biphenyl)=S-hexenoate was prepared in a similar manner.

lcl methyl IEI-4-(/-naphthyl)-5-
Hexenoate (Zl- and (El-A-(/-naphthyl)-5-hexenoic acid mixture) was prepared and esterified according to the method described in Example (b) above. 1 isomerized, b, p, / Aθ~16
Olo, 1m of the title compound was obtained.9.

/ +ru(El-4-(II-octylphenyl)-5
-hexenoate (b, p, / A 0-77g"0
10.1m) also had moldy remains.

Stirred copromomethyl-6-methylnaphthalene (?,+#'I) and triphenylphosphine (g
, 3#) in <200ml> of toluene was heated under reflux for 3 hours. The solid product, (O-methyl-conaphthyl)-methyl-triphenylphosphonium bromide, was separated from P and washed with ether.

m, p, core 0°C.

7.4 mol butyl lithium hexane (1,,7wt) 1
The phosphonium salt (j, anhydrous tetrahydrofuran y < s
owt) was added to the suspended liquid. The dark solution was cooled to -5θ°C, and methylderformylpetillet (/, 5#) was added dropwise. The light colored solution was stirred for 30 min at approximately -60°C and -i
The temperature was raised to 9°C, poured into an ice-sodium chloride bath and extracted with ether. The extract was washed with dilute hydrochloric acid, dried and evaporated, and the residue was extracted with petroleum spirits and extracted with 12+- or The IEI-isomer mixture was obtained as an oil (2J, Ri.

The above lbl K &: isomerization method was carried out, m
, p.

A ζ compound (K, /, 9) was obtained at 50°C.

(el methikA-(2-naphthyl)-!r, lh-
Oki solid m-kuro yanasu anfung, incense fl(/!;,, 31.
(purity) was added to a stirred solution of methyl+El-4-(,2-naphthyl)-5-hexanoate (1 g, Og) in a 150 m/ml solution. The mixture was stirred at room temperature for 2 hours and filtered. P solution is sodium bicarbonate #! Washed with liquid, dried, evaporated and the residue was crystallized from ether.

The other oxides shown below were added to the above 1al~(di
) was produced in the same manner using ester. In neither case did the product crystallize.

Rt to OIMeR1m,p,
("Q) Rlm, p, ("C!1 Methyl trans-
A mixture of 5,6-oxide-6-(--naphthyl)-hexanoate (0,=711, thiophenol (0,λ-) and triethylamine (0,5-)' was heated to room temperature under nitrogen atmosphere. The clear solution was evaporated and stirred for 76 hours.
As a developing acid /: / ether and petroleum spirit to remove the residue with silica glue! The title compound of m, p, 90'O was obtained by subjecting to roughy.

Example 36~. 11I The following esters were prepared using the VCL method described in Example 35.

6th RI Hl RIR.

Rt R1 methyl ester (0,309, produced as described in Working Force 35),
A stirred mixture of 10-sodium carbonate #i (10 m) and methanol (10 mk) was heated to reflux for 1 hour. The methanol was evaporated under reduced pressure and the residue was diluted with water, washed with ether, acidified and diluted with ether. The extract was dried, evaporated and the ethanol bath of residual acid was made basic with a 7M solution of sodium methoxide in methanol (0.75m) and evaporated again.

The residue was solidified with Impro I4nol-petroleum spirit to give the title compound.

Examples 56-7 The esters of Examples 36-3 were hydrolyzed according to the method described in Example S5 to yield the sodium salts shown below.

R Otori R.

R,R.

RI HsR,R.

Example 7 J rel-(/'R,2'S)-
3-7'-Force example! Diester of ≠ (/ 00 W
), 1O-sodium carbonate solution (Jl) and methanol (Jd) were stirred at room temperature for 21 hours. The mixture was diluted with water, washed with ether, and pig 44.0
The mixture was acidified and extracted with ethyl acetate. Dry the extract,
Evaporation gave the title compound as a white solid.

- Zoeste N (7Jwg, see Example ←), methanol (J
gj) and 1 m (/d) of 1M potassium carbonate was stirred in a kiln at room temperature for 20 hours, diluted with water, washed with dichloromethane, acidified, and extracted with dichloromethane. The extract was dried and evaporated to give the title compound as a pale solid.

Example 7j Ethyl chloroformate (17,/Jd), '0L-
N-acetyl-J-mecaptoinleucine (o, -2
-/
(7CK"C was added. This bath solution was heated to room temperature,
Wash with dilute hydrochloric acid, then bicarbonate) IJum #11
Washed with 1, dried and evaporated to give J-acetamido-ethyl-methyl-corchetanone as a pale oil.

Solid glycine methyl ester hydrochloride (0, Jjf) and triethylamine (0, Jjf, 4) were added to this solution of thiolactone in dichloromethane (j-), and the mixture was stirred for 14 hours. The clear layer was washed with dilute hydrochloric acid and then with a sodium bicarbonate bath, dried, evaporated and the residue was extracted from methanol-water to m, p, /74
The title compound C was obtained.

(1)) j(S)-hydroxy-≦(R)-[(J methyl j, 4(F)-o, cyto-7(z)-nonaderonoate (/4), DL-N- Anhydrous tanol (10
0 μl) #I solution was reacted with joC for ``CJ-- days.

After removing the methanol with a stream of nitrogen, transfer the residue to diethyl ether/n-#t:/j O/j Ov/v
The mixture was diluted with #jl and subjected to chromatography using silica dal. When developed with the same warm solvent, one unreacted aquid was first collected. Dichloromethane/methanol de J/Iv/v warm moat further KJ! Upon extraction, the desired dimethyl ester was obtained, but it was a pale yellow oil contaminated with a small amount of free thiol.

The dimethyl ester was then dissolved in KfI in methanol (Jd).
The full solution was returned by adding a sodium carbonate bath solution (/, jd) and a few drops of water. Hydrolysis was allowed to continue for 3 days at room temperature, and the resulting almost clear S* was carefully adjusted to pil J,j (using dilute hydrochloric acid) and extracted with dichloromethane. The combined extracts were washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give the title compound as a very pale yellow viscous oil.

Monoethyl ester/I/(I) of Example 7I was dissolved in tetrahydrofuran (Li-), JM lithium hydroxide $111 (/m) was added, and water (J-) was added. A homogeneous solution was obtained, and this was heated in #IC for several days. Tetrahydrofuran was then removed from K by evaporation under reduced pressure and the residue was dissolved in dichloromethane and water (pl
J, adjust with dilute hydrochloric acid). The dichloromethane extract was dried over magnesium sulfate and evaporated in a stream of nitrogen to give the desired dicaroon soap as a colorless viscous oil.

Examples 77-II (a) Form a thiol intermediate as follows and convert it by the method of Example P (b) to (b) K
The friend is converted into the final product.

N-1 Lifluoroacetyl-cystine acid chloride (
i, of) fO, IIO mole ammonia submerged solution ocv
Treated for c″CJO minutes. Excess ammonia was removed,
Transparent WII [fk] Dilute with a small amount of water and shake with diethyl ether. The obtained white solid was separated from P and dried.

This solid (0219) was mixed with dimethoxy7ethane/water (j/
2. Triphenylphosphine (5, Jjf) was added and the mixture was stirred at room temperature for 1 hour. The S* was evaporated to dryness under reduced pressure, leaving a residue of diethyl ether/ethyl acetate (2d.

Deo/lov/v) Kfn was purified by chromatography on silica l'kK using the same #111 system to return the desired thio-A/ as a white crystalline solid.

Dithiozoacetic acid (/1.cof) anhydrous zenerite N (
/rowt)cfllj, stirred, and cooled. Oxolyl chloride (tl, zwl)'xMA was added (also, zomethyformamide 2/li&-flooded to catalyze the reaction). The steady-state fIItfk of the force is produced, the mixture is stirred for 1 hour in yoCr, then the chamber flK
Teml! The mixture was stirred for 7 hours. The pale yellow solution was evaporated under reduced pressure to a constant weight to obtain the chloride as a straw colored liquid that gradually darkened.

Anhydrous tetrahydrofuran (J, JP) of the acid chloride (J, JP)
DL-alanine methyl ester (j, Jf) in anhydrous tetrahydrofuran (77-
A grade 1 liquid WCOCK was added dropwise. A precipitate gradually formed and the mixture was stirred and allowed to react overnight at room temperature. The white precipitate IkF was separated and evaporated under reduced pressure to give the desired nosulfide straw-colored oil.

Dissolve this product in dimethoxyethane (coOd),
This was added to a stirred nomethoxyethane/water (20/10-) #I solution of triphenylphosphine (Jyof). The reaction was allowed to complete at room temperature for a period of time, and the mixture was evaporated under reduced pressure to give a light straw-colored oil. This product contains a small amount of nochloromethane! The excess triphenylphosphine was removed by chromatography on silica gel using dichloromethane as the solvent. The column ratio was adjusted with ethyl acetate and the eluate was evaporated to give the desired thiol pale yellow oil.

Koaminoethanetheol Hanawa saken salt (ri, ott) was stirred vigorously in ether (100 td), cooled to jC,
j 096 w/v sodium hydroxide solution was added. methylchloroforme) (A, -tsZl.

It was added gradually while maintaining the temperature at a low temperature. At the time the chloroformate intermediate was added, sodium hydroxide solution 11 (3,000 t/d water) was added simultaneously with the remaining chloroformate.

The mixture was stirred for 1 hour and then the ether phase was separated. The aqueous phase was further extracted with ether, the ether extracts were combined, washed with water and dried (4SO, )L.
, evaporated under reduced pressure to give the title thiol as a pale straw colored oil.

This Thio-〃 is the first German patent. ! /I, No. 7J- (Ch
emlcal ＾b$tracts 7ri:ρ /J
7jO17p ) Dlarnalt AG (8aye
rJeln F, etc.HC&! It was manufactured by the method described above.

(1))○j-(R,S)-Human 0 Naka C4-(S,R
)-8-benicilla miniroof (z)-nonadecenoic acid (the final hydrolysis was carried out at 10C for 3 days); −(z
-(r4-(car-oxymethyl)-caloxyamide]
-ethelthio)-7(Z)-nonadecenoic acid;
lohexylmethyltinor 7(Z)-nonadecenoic acid (the final hydrolysis was allowed to proceed for 71 hours in IOC); ○j-(R,S,)-hydroxy-4-(S,R)-(
j-car is xypentylthio) -7(Z)-nonadecenoic acid (initial process/-?sitohthiol reaction is zoC″′C
0z-(R,S)-hydroxy-4-(S,R)-(
(J-amino-cocal?medium-thia-zeta)-ethelthio,
)-7(Z)-nonadecenoic acid; at-(R,S)-human 4-(S,R)-
N-ethylcar-xyamide))-ethylthio)-7(
Z)-nonadecenoic acid;
s-(N-force A/&xamide)-7 Steini tv-7
(Z)-nonadecenoic acid; 0l-(R,S)-hydroxy-4-(S,R)-
[Co(N-methoxycaryl)-aminoethylthio]
-7(Z)-nonadecenoic acid; Oj -(R,S)-hydro-4-(S,R)-
(N-(/-cargaxyether)-triru&?cyamizomethylthio)-7(Z)-nonadecenoic acid.

Examples 14 and 17 Decyltriphenylphosphonium bromide (-021f)t
'anhydrous? )9hi Pa7? The mixture was weighed in Kl (AOsg), stirred under nitrogen atmosphere, and cooled to -71CK. Gradual addition of butyl lithium (key F/#*% 4.J- to 4M) produced a deep orange-yellow S* product.

-7 IC after stirring for 20 minutes -1 (E)
-Oh, Shito, -? -Onakane-7(E)-Nonenoate (
1,101) in tetrahydrofuran (1 m) It was rapidly added. The color of both solutions became pale and the temperature was raised to room temperature over 1 hour. Work-up was continued as in Example (a) to give the title compound as a colorless oil. The product became a solid upon storage with -COOC.

Example of using this 4-oxide and a moderate amount of thiol (1)
) The reaction under the conditions yielded the compounds described below.

07-(R,S)-hydroxy-4-(S,R)-ethelthio-7(E),de(Z)-nonadecagenonic acid; 0j-(R,S)-hydroxy-4-(S,R) -8
-cysteinyl-7,2-nonadecagenonic acid.

Example 11 Benzyltriphenylphosphonium chloride (7j, -7t
) of stirred anhydrous tetrahydrofuran (400 ml)
To the suspension, n-butyllithium (j#-17,4
M hexane bath solution] addition friend. Immediately, a deep orange color developed. This mixture was stirred for 5 minutes at 70 Cvc. Then, a solution of methyl j,4-(E)-o*71'-4-formyl-hequinanoate (/u, It) in anhydrous tetrahydrofuran (JOd) was added, and the reaction mixture was gradually added.
The temperature was raised to 11 degrees (after which, the ylide coloring partially disappeared and the color finally became straw yellow). Stir at room temperature for 11 hours! Then, at this point, the reaction started with tlc,
It was shown that the project was completed.

The reaction mixture was evaporated under reduced pressure and diluted with noretherether.
Extracted once. The extract was evaporated under reduced pressure to give an amber oil, which was mixed with 7 liters of water. 'Extracting and purification by column chromatography using # (#I output is 0, / @ Et5N
The title compound was obtained as a pale yellow oil by dilution of hexane containing 0.0% diethyl ether (111).

(b) j-(S,R)-Hydroxy-4-(R,S) Methyl prepared as in (a) above under nitrogen atmosphere! , 4-oxide l-phenyl-7 (E, Z
) - #Couti/knee1 <0.41) k and traces of hydroquinone, also under nitrogen atmosphere, triethylamine (0,!df) and nomethylmel force! A mixture of tosuccinate (0,179) and anhydrous methanol was added.

This mixture was allowed to stand at room temperature for λ hours, and then a volume of air was blown into the solution. Residual oil column chromatography (silica;
The eluate was diluted with dichloromethane containing 1qh acetic acid to give the trimethyl ester of the title compound as a pale oil.

The oil (JJOq) is mixed with methanol/&/(u Od ) and o
, stirred for 71 h at room temperature in iM potassium carbonate solution (/J 4 m) and traces of hydroquinone.
The reaction mixture was acidified with glacial acetic acid and extracted with ethyl acetate to obtain an oil, which was further purified by chromatography to obtain the final K(R) compound as a yellow oil.

This compound was prepared by the method of Example rrK, using furfuryl mercagtan instead of zometermercagutosuccinate and λH sodium carbonate instead of (7,/M potassium succinate). .

Example: Under a nitrogen atmosphere at -70°C, a stirred solution of 7-termederutrifenylphosphonium chloride (47/, 371) was dissolved in anhydrous tetrahydrofuran (700-1). Butyllithium (!f?wi, /bM hexane #I solution) was added. The development of a deep orange color was observed immediately. After stirring the mixture for /j minutes at -70°C, methyl!, 6-■ -oxide-6-formyl-hequinanoe) (/A,,2JJF) of anhydrous tetrahydro7rane (
! rOt) solution was added, and the reaction 1 mixture was gradually heated to 1 temperature (IriP's threatening color partially disappeared and finally became straw yellow), and stirred with electric current for another 90 minutes. continue,
At this point, it can be shown that the reaction is complete.

The reaction mixture was evaporated under reduced pressure and diluted with noether ether 3.
1 extracted. Evaporation of the extract gave an amber oil, which was chromatographed (silica, using diethyl ether in hexane) to give the gold compound as a yellow oil. Ta.

Cl00~) triethylamine (/Q3μ and dark chlorodeophenol Cl00■), which is also under the phoneme '# atmosphere, and anhydrous methanol <ioo
Add a mixture of µl) to the circles.

The reaction mixture was incubated at rich temperature for 1 hour, blown with a heavy stream of air, and the residual oil was purified by chromatography (silica; dichloromethane as extractant) to give the methyl ester of the title compound as a yellow oil. Nine.

The above oil <SO> was stirred in methanol (Jsg) with 2M sodium carbonate solution (0.35sg) and a trace amount of hydroquinone for 71 hours at rich temperature, then further stirred at 2°C for 7 hours. Stir for hours. This reaction 1 compound is 7
Acidified with M hydrochloric acid and extracted with chloroform to obtain an oil, which was purified by chromatography (silica; chloroform in 10-methanol as eluent).
The title compound was obtained as a pale yellow oil.

Thenic acid This compound is the compound of Example 90(a) with the 4-oxide and methyl-
3-Mercaptogropionate, Ii JII
Produced according to the method described in iPI17t (b).

EXAMPLE 1 This compound was prepared by the method described in Example 90 using 7-methylmethyltriphenylphosphonium chloride.

This compound is the compound of (a) above. The sample was prepared according to the method of Example 0(b) using 100% carbon dioxide.

This compound was produced according to the method of Example It f (b) using Example 9 (--(-)-methyl-N-)-lyfluoroacetylcysteine and omitting the hydrolysis step. Shie.

This compound is Example 93O compound, Example t t (
b) can be prepared by hydrolysis according to the method described.

Example tS (-Methyl 5.6-(t)-oxide-9-phenylene) This compound was prepared using phenylethyltriphenylphosphonicum bromide by the method described in Example DeQ (-).
I did l1l.

The ζO compound was prepared from the skin by the method described in Example 5) using the compound oxide of Example 5(a) and dark chlorothiophenol.

The ζO compound was produced by the method of Example t (b) using Example Dej (a) O Process III.

EXAMPLE 3 The ζO compound was prepared by the method of Example t(a) using phenylhexyltriphenyl sulfonicum bromide.

Using the compound of (a) above and dark chlorodeophenol, and according to the method described in Example 1 (b), the corresponding acid of the title compound O was prepared in an amount of mpL 9, however, this age is fleeting. /, resulting in the following om
It was found that it was converted to the sodium salt according to Procedure II.

j-(SsR)-hydroxy, -4-(R%5)-(4
(-chlorophenylthio)-/3-7-■-tridecene iron, citow> in sodium bicarbonate solution <iv
After addition of K, the mixture was treated with heat treatment and allowed to stand at room temperature for one hour to obtain the title compound as water St.

- phenyl-tri, decene, sodium salt This compound was prepared using 1 #AH9 oxide (-0) and heated according to the method of Example ff f (b), followed by Example fIi 9 (b). ) P is produced by converting K to 2 and converting it to its sodium salt.

In this compound, Example 97 Ca) CJ Engineering IIt and methyl-N-)lifluoroacetyl cysteine were
I and prepared by the method of Example gt(b).

Enon This thiol is compatible! From droxy compound -p
4avtnan a to arnes method (J,Q(,,
,7/,.

3910-da(/94&)K can therefore be manufactured.

Co, 4I-dihydrodiacetophenone-C4t, 4I
l), potassium carbonate (6 g, ?/j) and dimederthiocarpayl chloride (Aj, AjJI) in anhydrous 77 tons (/200 dti) at linear temperature.
The reaction mixture was stirred for an hour and then RILed overnight in water C.
I! The mixture was poured into FOO1), stirred, filtered, and dried under reduced pressure to obtain 0-(4t-ade7deru-3-hydroxyphenyl)-N,N-dimethylthiocarbamate as a white solid. m, μ750~/32°C.

The above compound was added in powder form at once with boiling diphenyl ether (/400 st) and reflux was continued for an additional 20 minutes under a smoky atmosphere. The diphenyl ether was evaporated under reduced pressure and the residue was boiled over carbon tetrachloride ψ with decolorizing charcoal for 30 minutes.

Filter, evaporate P solution, and obtain 5-(e-7 ceteru 3-
and Resiphenyl-N,N-dimethylthiocarbamate in Pa was obtained as a light brown crystalline solid.

Tortoise p, /= 三〜l−Meng℃.

The above compound was heated to boiling in 10-sodium hydroxide solution, and the milky Hρ/ρh,o mixture was distilled off until all the diphenyl ether was removed.The mixture was then cooled and methanol ( Add X)00-), a
M solution was flushed overnight. Evaporate the methanol under reduced pressure,
The aqueous layer was extracted once with diethyl ether and the extract was discarded), and then acidified with KjNHα (,71IOsdl).
The acidic aqueous layer was then extracted twice with diethyl ether,
The combined extracts were washed with water, dried on bar S04, filtered and evaporated. Residue t column black! Togelaphi (7 lica; 100-Ck-4α, as eluent)
Purification with charcoal decolorization in boiling carbon tetrachloride gave the title compound as a yellowish crystalline solid, 0 mμ7.
0~2℃.

This thiol is co,4I-dihydroxy-3-n-f
W: Use the I pill-acetophenone to remove the above CmO.
I was disappointed with the method and manufactured it.

Is this compound an example? j(a)'s oxidation and 1-hydroxy-3-n-10 biru-tei-mel force! It was prepared according to the method of Example 7g (b) using toacetophenone (prepared in the same manner as in (a) above).

Neneic acid This compound is a mixture of epoxides and monohydrocarbons of Cedarmercagtorr and tophenone (synthesis I).
Prepared by the method of jl [Example t t (b)) by replacing oo<a>

This compound was obtained from Example q7 (ω's process/Nakasito and Example 1).
Example g Prepared according to method S-0 using -monohydroxydermercaptoacetophenone from 0θ(a).

Example 103 (RR,SS) A-(/-7) prepared as in Example/(υ)
was recognized using an equivalent amount of a retardant (m-chloroperbenzoic acid) as described in Example 4, resulting in a viscous oil (yield: 1 (RR, 55)). -(/-Phenylsulfinyl-3-phenylpropyl)-tetohydrocoH-III#rancoon was obtained.

Using #A modified metal products/9 or more of the present invention, a typical cormorant product was created as follows.

Example 10 Active ingredient jJ! Motile starch -0OW silicone oil 1 drop, 2/OWv The active ingredient is mixed with part of the starch, then pre-mixed with silicone oil and the remaining part of the starch, -1 cell of silicone oil. ni Hikari 111 friends.

Example IO5 Tablets Tablets tII Ingredients 1oay humid silica 50■ Mycelium crystalline cellulose CoooMI? Vinylpyrrolidone λ09 Sodium carboxymethyl starch Coθ ~ Stearine Magnesium 6Iv304 First, mix the humid silica and the active ingredient, and knead 1. Microcrystalline cellulose is added to the mixture, the whole of this 4 is soaked with an aqueous solution of polyvinylpyrrolitone, briefly passed through the liquid, dried, adjusted to size, and sodium calkyne methyl starch and Mixed with compact magnesium stearin and then compressed in a tablet making machine to a weight of 3.
Generate 06 drops of tablets.

Active Ingredients S-danium caloxymethyl cellulose 10OQ sucrose /, Co5iI
p-hydroxybenzoate 0. Required amount Dye Required amount Ice making Dissolve sucrose in some water and add sodium caloxymethylcellulose to form a smooth paste. Circle, some water Kp-hydroxybenzoate and dye are dissolved, and this is added to the sucrose solution, circle,
The active ingredient is poured into the aqueous #11', and perfume and sufficient water are added to make up the desired volume.

Example 107 Aerosol active ingredient 5ml t Ethanol 30wt Propellant 11/114 Required amount Active ingredient was dissolved in ethanol, quenched in glass v7, sealed with pulp and CO
(O/-) and fill with warming propellant.

Continuing from page 1 ■Int, C1, 3 identification code Office serial number C0
7C149/10 7162-4
H149/26 7162-4H
-149/30 7162-4H
C07D 303/40 704
3-4C307/38 7043
-4 C309/30 7169
-4 C Priority Claim ■May 7, 1982■) United Kingdom (GB) ■13211 (0 Inventor William Botsfay Jameson, UK Surrey Working Horsell Kettlewell Close 31 Invuarchitp0 Inventor William James Ross 8 Kessick Drive, Lightwater, Surrey, UK Inventor Aritzk Todd 366 Gum Barkham Road, Walkin, Berkshire, UK

Claims (1)

[Scope of Claims] (C) A compound represented by the following general formula in a free acid state: Where, R is (+1) and (9) is a halogen atom, a hydroxyl group, or an alkoxy group having 3 to 3 carbon atoms. , aliphatic, saturated, having up to 7 carbons X number - 0, substituted with at least /S substitution or substituent selected from the group consisting of a cycloalkyl group having 3 to 6 carbon atoms, an aryl group or a heterocyclic aryl group or an unsaturated hydrocarbyl group; the cycloalkyl group, aryl group or compound aryl group is unsubstituted,
or hydroxyl group, /10rn atom and 7 carbon atoms
1i1 unsubstituted or di-substituted with an alkyl, alkenyl or d-alkynyl group having up to 16 carbon atoms; , a cycloalkyl group having 3 to 7 carbon atoms, or (11p unsubstituted or substituted xyl group, 7 carbon atoms)
～Tei alkoxy group, halogen atom or carbon number/6
an aryl group or a aryl group substituted by an alkyl, alkenyl or alkynyl group up to and R,ri A is unsubstituted, or an aryl group, a cytaloalkyl group
■Gun atom, human adPV group, NHR. and an alkyl, alkenyl or Schiftetraalkyl group having up to 10 carbon atoms, substituted with/or more substituents selected from COx;
is an alkyl group, an aryl group, or an aino-identical residue t+-(ncOX-1", xho+,
An alkyl group with a carbon number of ~da, NH, fi, or an amino acid residue, or (Ill unsubstituted, or an alkyl group with a carbon number of l-da, an alkoxy group with a carbon number of ~da, a carbon number of ~S acyl group, halogen atom, human xyl group, carboxyl group,
Nidomi group, trihalomethyl group, phenyl group, number of carbon atoms/~
i) group and NHR, and R4 is a hydrogen atom or rijl! ! It is an alkyl group of cumulative number/~da,
an aryl group or a heteroaromatic group substituted with one or more substituents selected from When -YR is glutathionyl, cysteinyl or cysteinyl, R is a group other than an unsubstituted alkatetraenyl or alkapentaenyl group having 7 to 1 carbon atoms. (J11! The compound according to Claim No. (C) which is a pharmaceutically acceptable salt.
A compound according to claim C4. vIl lactone type, Toru, Claim S (
Section 3: - Compounds of thieves. (2) The compound according to claim 1 (c), which is in the free acid form. An alkynyl group-substituted or unsubstituted aryl or alkynyl aryl group, J is 111 unsubstituted or aryl group, ismf atom, human wdP syl group, NHR, and C0x (however, R , flH, an alkyl group with carbon number/-4', an aryl group, an acid residue group or COx, and X is a CH group or an amino acid residue) or more substituents. an alkyl or alkenyl group with 101 carbon atoms or (ill unsubstituted, preferably an alkyl group with a carbon number of up to 10 carbon atoms, an alkyl group with a carbon number of up to 100 carbon atoms; an xy group,) s * f 7 atoms , L droxyl group, carboxyl group 1 and NHR, (7t, R4 is a hydrogen atom or an alkyl group with a carbon number of up to 1) aryl substituted with/or more substituents Also r
The compound according to claim 1h, which is a heteroaryl aryl group. (71Y is -S- or -so,-,
゛ψ The compound according to claim 17), which is represented by the following general formula and is in the form of a salt or an ester: Aryl group, Schiff-alkyl group, halogen atom, hydroxy i group, NHR and cox (here, R514Hs alkyl group with carbon number/-1, aryl group, acrylic acid residue t*acOX 61, XriOH% [Ea/~da alkyl group, N~
or an amino acid residue); t) Substituted group, alkyl or cycloalkyl with 10 carbon atoms;
, J is an alkyl or alkenyl group having 3 to 4 carbon atoms, and the alkenyl group has the formula is a naphthyl group), and R, F
iH is an alkyl group with carbon number/~. ? ) R1 is an alkyl group having 10 to 1 carbon atoms;
The compound according to claim 1f1, wherein CH-CH-1, where R is an alkyl group having 1 to 1 carbon atoms. (Claims Series J in which lυR1 is represented by shi, xrio+. R3 is R4 9 is C0R (however, R is an alkyl group of number/~da). (The compound described in claim j) represented by the following formula: However, R3 is represented by the formula, and in the formula, each R is H or carbon #7 to
is an alkyl group, n is an integer/number of / to 3,
X is oHl or OR, R3 is Hl or Ill1cOR
(R is an alkyl group with carbon number/~da). (/J The compound according to claim 1C, which is represented by the following formula, and its lactone, ester and ester forms: H, where R is a substituted or unsubstituted phenyl or naphthyl group, or a formula R, -CH =C day-1 is R. Fi is a group represented by phenyl, benzyl or naphthyl group, JFi is a substituted or unsubstituted 7-enyl group. (/j) R, is a 7-ethyl group and 9, R, is a phenyl group substituted with 7 to 3 hydroxyl groups, nido eat or trifluoro a) 1 thyl group,
2) Compound described in 114. (/lI) A compound according to claim V) of the following formula, and in its lactone, salt and ester form: SO,R, R, -CM-CH -MaiaR, -C
) I, CH, - (ζ- and R8 is a phenyl group), and R8 is an unsubstituted or substituted alkyl group or a substituted phenyl group having 1 to 2 carbon atoms. (/6) A pharmaceutical composition containing the compound according to any one of the claims 7 above, together with a diluent or a biphasic compound to be used as a pharmaceutical. The compound according to any one of Claims No. (c) to (/+). (/7) In the free acid state, the compound according to claim No. There it is,
・ (a), ai) General formula in the state of play + wagt:
However, R1 is as defined above, and a compound having the general formula ■: R, SCj 厘However, R8 is as defined above, is reacted with a sulfenyl chloride represented by in an entirely inert solvent, The resulting lactone form of the compound f of formula (2) is released, but if F'i the lactone form is hydrolyzed to obtain the compound of general formula (2) in the released acid form, t or a. 'M) In the free acid form, the general formula ■: However, RIFi is as described above, and the compound represented by 11, and the general formula ■: R, S day ■ However, R, ri is as described above. , in particular to obtain compounds of the formula 1 in the free acid form, in which Y is -S-, or to obtain compounds with the general formula and then obtain a compound with )lcl general formula vi: R, -CI-1, -5O,l'? , vl, R and R are as defined above, and by reacting a compound represented by formula I with a compound having the formula I in the free acid form, . -1 to obtain a compound in which Y is 15O1-, and if necessary, the step of separating the obtained compound in free form, 111m form, lactone form, salt form or ester form,
A method for producing the above compound. (/l) A compound that commands the following formula 11F1 in the free III acid state: However, R□' has the same meaning as R given in the claim (C), but only the number of carbon atoms. /co to /6 other than the furcatetraenyl or alcapentaenyl group.