JPH05507716A - leukotriene antagonist - 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] leukotriene antagonist Background of the invention [Anaphylaquine slow-reacting substance J (SR5-A) mainly acts on mast cells and is a very powerful airway constrictor released from basophilic cells and basophil cells upon antigen challenge. It has been shown that 5R5-A is a major mediator in human asthma It is proposed that In addition to its pronounced effects on lung tissue, 5R5-A has change the transparency of It may also be involved in acute skin allergic reactions. do not have. Furthermore, 5RS-A reduces ventricular contraction and suppresses the cardiovascular effects of histamine. It has been shown to have a potentiating effect.

The discovery of naturally occurring leukotrienes and their association with 5R3-A There has been increasing interest in 5RS-A and other arachidonic acid metabolites. Ma 5R8-A from mice, rats, guinea pigs and humans all Leukotriene-C4 (LTC4), Leukotriene-D4 (LTD, ) and Leukotriene-D4 (LTD) It has been identified as a mixture of En-R4 (LTE4), and their structural formula is the following formula: It is expressed as

LTD4　R”　1=　Cys-GlyLTE4　R11=　Cys Leukotrienes are produced from arachidonic acid metabolism via the lipokingenase pathway. It is a group of eicosanoids. These lipid derivatives are derived from LTA, , there are two types: (1) those containing sulfide-peptide side chains ( LTC4, LTD, and LTE, ), and (2) non-peptidic (LT E4).

Leukotrienes are important contributors to the pathogenesis of diverse inflammatory and ischemic disorders Consists of a group of naturally occurring substances that have potential. Pathophysiology of leukotrienes Its physical role has been the focus of intense research in recent years.

LTC, LTD4 and LTE4 or end organs, e.g. airway smooth muscle compounds of the invention and by antagonizing the effects of other mediators that are active in and pharmaceutical compositions for treating leukotrienes in patients, including humans or animals. It has value in the treatment of certain diseases.

Summary of the invention The present invention has the structural formula (1) [In the formula, q is 0.1 or 2; R, is (L), -(CHz)-(T)c-B (wherein a is 0 or 1° b is 3~14° C is O or 1: L and T are independently oxygen, sulfur or CH2 (where q is 1 or 2) , L and T are not sulfur]: B is Cl-4 alkyl, ethynyl, trifluor olomethyl, isopropenyl, furanyl, chenyl, cyclohexyl, or Br5CL　CF3, Cl-4 alkyl, C1-4 alkoxy, methyl as desired phenyl optionally substituted with thio or trifluoromethylthio): R 2 and A are independently HSCF3, C2-4 alkyl, C1-4 alkoxy, F, C1, Br, L　OH, No2 or NH2: or R1 and A is Hl and Rz is (L), -(CH2)-(T)-B (wherein a, b, cSL.

T and B have the same meanings as above): Y is COR3 or (CHX), (CH2)-Z (wherein R3 is ○H, NH, Aryloxy or Cl-6 alkokene; p is 0 or 1: X is HloH, C, alkyl, C1-4 alkokene or F: and Z is CO R3 or tetrazolyl).

(In the formula, m is O~6, provided that when W is imidazole, m is 1~6: m is not O, R4 and R5 are independently hydrogen or Cl-4 alkyl. and may be in any position: W is unsubstituted or of the formula (wherein R4 and R5 have the same meanings as above; j is 0 to 6; and (2) is hydrogen, Cl-4 alkyl, CORs, So, H, So, H, So.

NH2, COCH20H, CHOHCH20H or tetrazolyl, and R3 has the same meaning as above) Tetrazolyl, thiazolyl, triazo substituted with 1 to 3 groups represented by Lyle, chenyl, furyl, oxacylyl, thiadiazolyl, pyrrolyl, imidazo is a 5-membered heteroaryl group selected from lyl or pyrazolyl) The present invention relates to the represented compound or a pharmaceutically acceptable salt thereof.

Furthermore, the invention relates to ester or diester derivatives of compounds of formula (I). Ru.

The present invention includes all stereoisomers, racemates or mixtures thereof. example For example, W is 1. 2. 3-triazole, 1.3.4-triazole, 1.　 2. 3-thiadiazole, 1. 3. 4-thiadiazole and other present It may also be a stereoisomer.

Additionally, the present invention provides a pharmaceutical carrier or diluent and a non-toxic amount of a compound of formula (1). The present invention relates to a pharmaceutical composition. The composition inhibits the action of leukotrienes and It is useful for treating diseases caused by leukotrienes.

Additionally, the present invention provides a pharmaceutical carrier or diluent and a non-toxic amount of a compound of formula (I) or and a histamine H1 receptor antagonist. The composition The drug is useful in suppressing antigen-induced respiratory anaphylaxis.

Furthermore, the present invention relates to a method of inhibiting the action of leukotrienes. Also, books The invention provides an antigen-induced respiratory anaphylaxis comprising administering an effective amount of the above pharmaceutical composition. Concerning how to suppress lacunae.

Detailed description of the invention The compounds of the present invention have the following general structural formula (I) [wherein, q is 0, 1 or 2. R, is (L). -(CH2). -(T), -B (where a is 0 or 1. b is 3-14. C is O or 1: L and T are independently oxygen, sulfur or CH2 (where q is 1 or 2) , L and T are not sulfur): B is C1-4 alkyl, ethynyl, trifluγ Methyl, isobropenyl, furanyl, chenyl, chlorohexyl, or as desired Br, Cl, CF. , C1-4 alkyl, C1-4 alkokino, methylthi (phenyl optionally substituted with 1 or trifluoromethylthio): R2 and A are independently H, CF3, C1-4 alkyl, C1-4 alkoxy, F 1C1, Br, L selected from OH, No2 or NH2: or R, and A is H1 and R2 is (L). -(CH2). -(T)e-B (wherein a, b, c, L, T and B have the same meanings as above). Y is COR3 or (CHX)-(CH2)-Z (wherein, R is OH, NH2 , aryloxy or C1-6 alkoxy: p is O or 1: X is H10H, Cl-4 alkyl, C1-4 alkoxy or F: and Z is C oR3 or tetrazolyl) R is (In the formula, m is 0 to 6, When m is not O, R and R are independently hydrogen or C,-4 alkyl. Yes, and may be in any position: (wherein, ' is 0 to 6: and ■ is hydrogen, 01-4 alkyl, COR3, SO3H, S○2H, S? 2NH2, COCH20H, CHOHCH20H or tetrazolyl, and R3 is as above Same meaning) is chenyl substituted with 1 to 3 groups represented by The present invention relates to a compound or a pharmaceutically acceptable salt thereof.

The present invention includes all stereoisomers, racemates or mixtures thereof. example For example, W is 1,2,3-triazole, 1,3. 4- Triazole, 1.　 2. 3-thiadiazole, 1. 3. 4-thiadiazole and other present It may also be a stereoisomer.

Furthermore, the compounds of the invention include ester and diester derivatives of compounds of formula (I). Consists of the body.

Preferred compounds of the present invention are m: 0, 1 or 2: chenyl is λ, [In the formula, j is 0 or 1, R4 and R5 are hydrogen, and v is CoR3, S○3 H%S○2H, So■NH2, COCH20H, CHOHCH20H or Tetrazolyl, R3 has the same meaning as above] Substituted with one of the groups represented by, or a pharmaceutically acceptable salt thereof Ru.

A subgroup of these compounds is the compound represented by the structural formula (1) where Y is C○2H. It is a compound. Particular examples of this subgroup include the following compounds: : (1) 2-(2-dodecylphenyl)-2-[(1-carpoquinmethyl-5-te trazolyl]thio]acetic acid, (2) 2-(2-dodecyl phenyl)-2-[[1-(3-carpoquine probi l)-5-tetrazolyl]thio]acetic acid, (3) 2L(2-dodecylphenyl)-2-[(1-sulfomethyl-5-tetra zolyl)thio]acetic acid, (4) 2-(2-dodecylphenyl)-2-[(1-methyl-5-tetrazolyl) ) thio]acetic acid, (5) 2-[2-(8-phenyloctyl)phenylco 2-[[1-(3- Carpoxyprovir)-5-tetrazolyl]thio]acetic acid, (6) 2-[2betet rasol-5-yl)ethylthioco-2-(2-dodecylphenyl)acetic acid, and Beauty (7) 2-(2-dodecylphenyl)-2-(5-carpoxy 4-methyl-2 -thiazolylthio)acetic acid.

A second subgroup of these compounds has structural formula (1) where Y is CH2COOH. It is a compound represented by This subgroup includes, in particular, the following compounds: is exemplified: (1) 3-(2-dodecylphenyl)-3-[[1-(3-carpoxyprobyl) )-5-tetrazolyl]propanoic acid, (2) 3-[2-(8-phenyloctyl)phenyl]-3-[(1-carpoky dimethyl-5-tetrazolyl)thio]propanoic acid, and (3) 3-[2-(8 -Phenyloctyl)phenylco3-[[1-(3-carboxyprobyl)- 5-tetrazolyl]thiocobropanoic acid.

A third subgroup of these compounds has the structural formula where Y is CH(OH)COOH This is a compound represented by (I). This sub-concept group includes, in particular, the following concepts: Examples of compounds include: (1) 3-[2-(8-phenyloctyl)phenyl]-3-[[1-(3- Carpoxybrovir)-5-tetrazolyl]thioco-2-hydroxybutyl acid, (2) 3-[2-(8-phenyloctyl)phenyl]-3-[(1-cal poxymethyl)-5-tetrazolyl)thio]-2-hydroxypropanoic acid, (3 )2-Hydroxy-3-[2-(8-phenyloctyl)phenyl]-3-[[ 1-(2-carboxypropyl)-5-thenylmethyl]thiocopropanoic acid, ( 4) 2-hydroxy-3-[2-(8-phenyloctyl)phenyl]-3-V , (2-carpoxychen-5-ylmethyl)sulfonyl]propanoic acid, and (5) 2-hydroxy-3-[2-(8-phenyloctyl)phenyl]-3- [(2-Carpoxychen-5-ylmethyl)thiocoprobanic acid.

Furthermore, another preferred group of compounds is that Y is CHXCOOH or derivatives of this acid. conductors, such as esters, amides and salts thereof, where X is CI C4 alkokene , especially those that are metkin. Examples include the following compounds.

3-[2-(8-phenyloctyl)phenylco3-[[1-(3-carboxyl) cypropyl)-5-tetrazolyl]thio]-2-methoxypronogonic acid, 3-[ 2-(8-phenyloctyl)phenyl]-3-[(1-carboxymethyl-5 -tetrazolyl)thioko-2-methoxypropanoic acid, 2-methoquino-3-C2- CB-phenyloctyl)phenylco-3-[[1-(2-carboquinepropyl) )-5-chenylmethyl]thio]propanoic acid, 2-methoxy-3-[2-(8- phenyloctyl)phenyl]-3-[(2-carpoxychen-5-ylmethylene) ) sulfonyl]propanoic acid, and 2-methquine-3-[2-(8-phenyl) octyl)phenyl]-3-[(2-carboxythien-5-ylmethyl)thio ] Propanoic acid.

Some compounds of formula (I) contain one or two asymmetric centers.

Therefore, there may be two or four stereoisomers for each compound. There is. The present invention covers all such stereoisomers, racemates or mixtures thereof. including. Depending on their structure, the compounds of the invention can be prepared by methods well known in the art. Therefore, salts can be formed with known pharmaceutically acceptable bases. such allowance Vine bases include inorganic and organic bases such as ammonia, arginine, organic amines , including alkaline earth and alkali metal bases. Di-acid compound of formula (I) Potassium, magnesium, calcium, diammonium, zinc, piveazine, Particularly useful are tylene diamine and the disodium salt.

The compound of formula (1) in which Y is Co)2H has the following formula (II) [wherein ASR, and R2 are as defined above]. Iodide A compound of formula (II) is converted to trimethylsilyl in an inert solvent in the presence of zinc at low temperature. /anide to form a trimethylsilyl protected cyanohydrin. this was treated with hydrogen chloride gas in methanol to induce methyl 2-hydroxyacetate. This is converted to 2-chloroacetate with thionyl chloride.

This valuable intermediate is then reacted with an appropriate thiol of choice to form the ester. After removal of the protecting group, the desired product of formula (I) is obtained.

Y is CH(X)CO,H (wherein, X is H, Cl-4 alkyl or C1-4 alkyl) Compounds of formula (I) which are and esterified bromoacetates (preferably t-butyl bromoacetate). , diethylaluminium chloride, zinc dust and a catalytic amount of cuprous bromide. The esterified 3-hydroxy-propyl- nato derivatives, which are reacted directly with substituted thiols in trifluoroacetic acid. . Alternatively, use a mixture of trimethyl borate and zinc in tetrahydrofuran. A 3-hydroxypropionate derivative may also be produced. In the above reaction , the use of esterified 2-promopropionate with aldehyde (II) A compound of formula (I) in which Y is CH(CH3)C02H is obtained.

Aruiha, Y is CH(X)CO2H (wherein, XI; tH, C, -4furkyl, C I-4 flucoquine or fluoro), the compound of formula (1) has the following structure: Formula (IV) [In the formula, A, R, and R2 have the same meanings as above, and R1゜ is a normal ter protecting group, e.g. t-butyl or C1-4 alkyl, and RI+ is hydrogen , C,-, alkyl, C1-.

Produced from propionate precursors that are alcoquines or fluoro. formula( IV) with an alkali metal alkoxide (e.g. sodium methoxide) or After removal of the ester protecting group by reaction with a suitable thiol, the desired formula (I) of the product is obtained.

The propionate precursor of formula (IT) can be prepared from the corresponding aldehyde of formula (II) by General methods, e.g. with alkyl (triphenylphosphoranylidene) acetates reaction or modification of the above aldehyde to a 3-hydroxypropionate derivative. obtained by formation of a double bond by conversion and subsequent elimination reaction. In addition, the professional The pionate precursor is a 3-methanesulfonyloxypropionate derivative, Obtained by treatment with triethylamine.

The compound of formula (I) in which Y is CH(○H)(CHz), C02H has the following structure Formula (V) [ASR and R2 have the same meanings as above, p is 0.1 or 2 and R1 2 is a conventional ester protecting group, such as t-butyl or C1-4 alkyl (e.g. ethyl or ethyl)]. The compound of formula (V) is , in an inert solvent, with triethylamine and a suitable thiol of choice. After removal of the ester protecting group, the desired product of formula (I) is obtained.

The epoxide precursor of formula (V) in which p is 2 is a bromobenzene compound of formula (VI) The reaction of the Grignard derivative of the compound with acrolein leads to the corresponding enol derivatization. obtained, which was reacted with trialkylorthoacetate and then m-chlorofiltrate. Obtained by epoxidation using benzoic acid.

The epoxide precursor of formula (V) in which p is 1 is a compound in which p is O and Rl2 is H. Produced by Aruntoistilt homologation of compounds can be built.

The epoxide precursor of formula (V) where p is 0 can be prepared in a suitable solvent (e.g. diethyl nitsch). aldehyde of formula (II) in dichloromethane or methylene chloride). reacts with tartates and alkali metal alkoxides (e.g. sodium methoxide). Manufactured by

The compound of formula (I) (7) in which Y is (CH2)3CO2H has the following structural formula (V II) [wherein A, R, and R2 are tetrahydro-4H- having the same meanings as above Obtained from pyran-2-one precursor. A compound of formula (VII) is dissolved in iodine in an inert solvent. with a mixture of zinc uride and substituted thiols or in trifluoroacetic acid. to obtain the product of formula (1) after removal of all ester protecting groups. .

The tetrahydro-4H-pyran-2-one precursor of formula (VII) is a tetrahydro-4H-pyran-2-one precursor of formula (VI) Grignard derivatives of bromobenzene compounds are mixed with chlorotitanium triisopropylene. poxide and then with 5-oxovalerate alkyl ester. Manufactured by

Aldehydes of formula (II) are known or readily prepared using the following general methods. Manufactured in

Compounds of formula (1) in which R1 is an alkyl group containing e.g. 8 to 13 carbon atoms The aldehyde precursor to the appropriate 2-alkylphenyl-4-14-dimethyl produced from oxazoline [Meyers et al., Journal of ・Org・Chemistry〇、Org、Chem、）　43　137 2 (1978)].

Compounds of formula (I) in which R1 is an alkoxy group containing e.g. 7 to 12 carbon atoms The aldehyde precursor of It is produced by O-alkylation of aldehyde with the corresponding alkylating agent.

The thioalkyl containing aldehyde precursor of the compound of formula (I) can be prepared using standard methods. 0-haloalkylthiobenzene optionally substituted by, for example, formula (eeee) [wherein X is halo and R is alkyl] Manufactured by reaction with methylformamide.

The phenylthioalkyl containing aldehyde precursor of the compound of formula (I) may optionally be Substituted haloalkylbenzaldehydes with thiophenol and triethyl acetate It is produced by reacting with min.

The heteroaryl mercaptan precursor required to produce the compound of formula (D) is known in the art. compounds, advantageously prepared using standard chemical reactions. of these precursors Mercapto derivatives are produced by known methods. For example, 5-(2-mercapto ethyl)tetrazole converts β-merceptprobionitrile into tetrahydrofuran made by adding it to a mixture of sodium azide and aluminum chloride in a can be built. Production of tetrazolethiol compounds with various substituents No. 4.048.311, U.S. Pat. No. 4.22 to Berges. No. 0°644, and No. 4.286.089. various substituents The production of triazole thiols and thiadiazole thiols with Berges, U.S. Pat. Nos. 3.868.369 and 3.989.6. No. 94 teaches. These mercaptans were reacted as described above. A compound of formula (I) is obtained.

By suitably modifying the general methods disclosed, the methods described in the Examples below may also be used. As a result, various compounds defined by formula (1) are obtained.

The leukotriene antagonist activity of the compounds of the invention has been demonstrated in guinea pig airway tissue. Measured by the compound's ability to inhibit leukotriene-induced contractions in vitro . The following method was used.

In vitro: Guinea pig (adult male Alpino Hartley) Hartley system) Spiral strip of trachea (cross section width 2-3cm, length 3.5cm) s+ size) in a jacketed 10-1 tissue bath. The cells were submerged in modified Krebs buffer and continuously aerated with 95% CO2 and 15% CO2.

A displacement transducer is used to replace the tissue with a braided thread. er) and the isointense tension was recorded. The tissue was allowed to equilibrate for 1 hour and then Meclofenamic acid (IM) for 15 minutes Pretreatment to remove endogenous prostaglandin reactions, followed by further test compound or or vehicle control for 30 minutes. Continuous increase in bath concentration of LTD4 A cumulative concentration-response curve for LTD4 on tissues in triplicate was obtained by adding It was.

To minimize tissue-to-tissue variation, LTD4-induced contractions were compared to control normalized as a percentage of the maximal response obtained to carbachol (IOM) did.

Calculations: Triple LTD, concentration-reaction, both in the presence and absence of the test compound. The average response curve was plotted on logarithmic graph paper. Carbachol-induced yield The LTD required to induce 30% of contractions was measured at 411 degrees, EC. defined as Ta.

The 1 og K@ value for the test compound was determined by the following formula.

2, K, = concentration of test compound/(X-1) The compound of the present invention contains leukotrienes It has biologically important antagonist activity against species. Representative embodiment of the present invention The antagonist activity of the compounds is shown in Table 1 below (other data are shown in the Preparation Examples). ). Calculate the -1ogL value from the test protocol above. Try a compound more than once The values shown here represent the most recent average data.

Table 1 0 Ikotriene antagonist activity -W　m　-(C)tRJ5V　R,Y　-LogKe5-tetrazolyl 0 1-C1hSO3EI C+ 21125 C02H6,45-tetrazolyl 0 1-CH3C+□H25CO2H5,85-tetrazolyl 0 1-(CI I2) 3COOHC1□H25C02 days 7.45-tetrazolyl 0 1-( CH2)3COOH(C1l[2)gPh COJ 6.05-tetrazolyl 0 1 (C112), C00Ill C1□Hzs CH2C0□H6,65- Tetrazolyl 0 1-CHtCOOE (C1lz)sPh CH2C0□H 6,35-tetrazole 0 1-(CH2), cOoday (CBz)sPh CH2C0□■6,05-tetrazolyl 2 1-HCIJ25 COJ 6. 55-Tetrazolyl 0 1 (C1+2)icOOH(CHz)sPh C1' 1(OH)CO2H7,05-tetrazolyl 0 1-CF2COOH(CH2 ), ph CH (OTI) COJ 7.02-thiazolyl 0 4 < l1ls, 5-C0OHC+dhs COO[16,7 optionally -(C) rR4R5 -V, R2 and A are Hl and q is 0] .

The pharmaceutical compositions of the invention are suitable for use with a pharmaceutical carrier or diluent and with symptoms of asthma and other sensitivities. an amount of formula (I) sufficient to inhibit the effects of leukotrienes such as sexually transmitted disease symptoms; or a pharmaceutically acceptable salt, such as an alkali metal salt thereof.

When the pharmaceutical composition is used in the form of a solution or suspension, a suitable pharmaceutical carrier or Examples of diluents include water for aqueous systems; ethanol, glycerin, and plastic for non-aqueous systems. Lopylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid powder Raffins and their mixtures with water: solid systems include lactose, kaolin and mannitol; and dichlorodifluoromethane, chlorotrif for aerosol systems. Includes fluoroethane and compressed carbon dioxide propellants. In addition, the pharmaceutical carrier or In addition to diluents, the composition may contain other ingredients such as stabilizers, antioxidants, preservatives, etc. It may contain agents, lubricants, suspending agents, viscosity modifiers, etc. However, the additive The ingredients do not have a deleterious effect on the therapeutic action of the composition. .

Of course, the nature of the composition and pharmaceutical carrier or diluent will depend on the intended route of administration. i.e. parenterally, topically, orally or by inhalation).

Generally, particularly for the prophylactic treatment of asthma, the compositions will be in a form suitable for administration by inhalation. It is. Therefore, the composition can be prepared by dissolving the active ingredient in water by means of a conventional nebulizer. administration suspension or solution. Alternatively, the composition can be placed in a pressurized aerosol container. A suspension or solution of the active ingredient in a conventional liquefied propellant or compressed gas administered from Consists of liquid. The composition may also be diluted with a solid diluent for administration from a powder inhalation device. It consists of solid active ingredients. In the above compositions, the amount of carrier or diluent may vary. Preferably, suspensions or solutions of the active ingredient account for the majority. Melt. If the diluent is a solid, it may be less, equal to or more than the solid active ingredient. May exist.

For parenteral administration, the pharmaceutical preparation may be in sterile injectable liquid form, e.g. liquid or aqueous or non-aqueous suspension.

For topical administration, the pharmaceutical formulation is in the form of a cream or ointment.

Typically, the compound of formula It is administered to animal patients, including humans, as a separate composition. Used in this way when administering the composition, the dosage of the composition is readily determined by one of ordinary skill in the art and generally Selected from the range of 350 mg to 700 IIg of active ingredient. For your convenience, every day Select the daily dose from about 350 mg to about 2800 mg and administer equal doses 1 to 4 times. do.

The above pharmaceutical formulations can be manufactured by the ordinary skill of a medicinal chemist appropriate to the desired end product. Ru.

A therapeutically effective amount of a compound of formula I to produce said inhibition is preferably included in a pharmaceutical composition. A method for suppressing the symptoms of an allergic reaction comprising administering to an animal subject are within the scope of this disclosure. The administration may be in appropriately spaced dosage units or as needed. Single dose as needed. Typically, this method is used specifically to alleviate allergic symptoms. Do this in certain cases. However, usually the method is also carried out as a continuous or prophylactic treatment.

The effective dose to be administered will depend on factors such as the degree of severity of the allergic condition being treated. It is determined by routine experiments from the above dose range, taking into account the It is within the skill of the field.

The compounds of the invention, alone and together with histamine H, receptor antagonists, Antigen-induced contractions of isolated and sensitized guinea pig trachea (model of respiratory anaphylaxis) ).

As mentioned above, the pharmaceutical compositions of the present invention also include a pharmaceutical carrier or diluent and the formula (■ ) or its pharmaceutically acceptable salt to inhibit antigen-induced respiratory anaphylaxis. In combination with a sufficient amount of histamine H, a receptor antagonist, Become. Examples of histamine H1 receptor antagonists include mevilamine, 2 -[4-(5-bromo-3-methyl-pyrid-2-yl)butylamino]-5- [(6-Methyl-pyrid-3-yl)methylio4-pyrimidone and other known H1 receptor antagonists. The above administration of a compound of formula at known effective doses of histamine H1 receptor antagonists for the purpose of done advantageously. Regarding combination with histamine H1 receptor antagonist Similarly, the single active ingredient administration method described above can be used.

The following examples illustrate the preparation of compounds of the invention and their incorporation into pharmaceutical formulations. However, as such, it does not limit the invention as set forth in the claims appended hereto. It's not a thing.

Example 1 2-(2-dobnorphenyl)-2-[(1-methyl-5-tetrazolyl)1,000 】Vinegar fermentation (a) 2-(2-dobnorphenyl)-4,4-dimethyloxazoline distilled tetate Freshly prepared dodecylmagnesium bromide in lahydrofuran (50ml) (30.13 mmol of dodecyl bromide and 26.2 On+mol of Mag 2-(2-methkinf) in tetrahydrofuran (30 ml). phenyl)-4,4-dimethyloxazoline [A.I. Meyers (A.I., Meyers et al., Journal of Organic Chemistry (J, Org, Chet), 43. 1372 (1978)] (17,88+ mol). The resulting yellow solution was stirred for 20 minutes under argon at ambient temperature. did. The solution was cooled in an ice bath and diluted with an aqueous ammonium chloride solution (100 ml). I was pissed. The reaction product was extracted into diethyl ether (100ml) and the organic layer was washed with saturated sodium chloride solution (50 ml), followed by anhydrous magnesium sulfate. It was dried. The organic layer was evaporated to give a colorless oil, which was purified on silica gel in hexane. Purified by flash chromatography using 5% ethyl acetate as eluent. The desired product was obtained as a pale yellow oil.

Elemental analysis, calculated value as C23H31No: C, 80, 41: H, 10, 85 ;N.

4, 08. Actual value: C, 80,22; H, 10,56; N, 3.87° (b)2 -(2-dobnorphenyl)-3,4,4-trimethyloxazolinium iodine -Sito Solution of the compound of Example 1(a) (17.2 mmol) in methyl iodide (20 ml) was refluxed under argon for 18 hours. The volatiles were removed under vacuum and the solid residue was dissolved in acetic acid. Trituration with ethyl (25 ml) gave the desired product as white crystals (mp 78- Compound of Example 1(b) (10,0 mmo) in methanol (50+1) (84°C) A small amount of sodium borohydride (10.0 mmol) was added to the water-cooled solution of I added it over a period of time.

The reaction mixture was stirred for 30 minutes and then quenched with 5% sodium hydroxide (50 ml). I punched it. The reaction mixture was extracted with diethyl ether (2X50ml) and the extract was washed with brine (50 ml) and dried over anhydrous magnesium sulfate. The extract Evaporation gave an oil, which was dissolved in acetone (50 ml) and 3N hydrochloric acid (10 ml). ) was added.

The mixture was flushed with argon and stirred at ambient temperature for 16 hours. volatile substances was removed under vacuum and the residue was dissolved in diethyl ether (50ml) and water (50ml). ) was distributed between. The aqueous layer was further extracted with diethyl ether (50n+1). If The combined organic layer was washed with brine (50 ml) and dried over anhydrous magnesium sulfate. . Evaporation of the organic layer gave an oil, which was eluted with 2% ethyl acetate in hexane. The desired product was purified by flash chromatography on silica gel. Obtained as colorless old.

Elemental analysis, CHH300, calculated value: C, 83, 15: H, 11, 02 actual measurement Value: C, 82,59; H, 10,65° (d) Methyl 2-(2-dodecylphenyl)-2-hydroxyacetate Example Compound 1(C) (17,2 city o1) was dissolved in methylene chloride (20 ml), and 0 Stirred at <RTIgt;C</RTI> under argon. Add zinc iodide (1.87 mmol), then chloride Trimethylsilyluanide (2,45111) dissolved in methylene (30111) 1,18,3 mmol) was added dropwise. After 1 hour at 0°C, the water bath was removed and the mixture was Stirred for 1 hour at room temperature. After the solvent was removed and the residue cooled in a water bath, methanol (10 0 ml) was added. Excess hydrogen chloride is removed from the solution while the mixture is stirred at water bath temperature. Bubble occurred in the liquid. The water bath was then removed and the mixture was stirred at room temperature for 18 hours. water (20ml) was added and the mixture was stirred for 2 hours. Evaporate the solvent and leave the aqueous residue. Extracted with ethyl acetate.

The combined organic layers were dried over anhydrous sodium sulphate, filtered and evaporated. crude product Flash chromatography on silica gel, 20% ethyl acetate/hexyl Elution with xane gave the product as a clear colorless liquid.

(e) Methyl 2-chloro-2-(2-dodecylphenyl)acetate Example 1 ( The compound of d) (12 mmol) was stirred under argon in a water bath and thionyl chloride ( 20 ml) were added in batches. The water bath was removed and the mixture was stirred for 18 hours under argon. Ta. The solvent was removed and the residue was purified on 200 grams of silica gel with 20% methylene chloride/tetra The product was purified by fluorocarbon chromatography using carbon chloride as the eluent. Obtained as a clear liquid.

(f) Methyl 2-(2-dodecylphenyl)-2-C(1-methyl-5-tetra zolyl)thio]acetate 0.7 g (0,002 mo1) of the compound of Example 1(e) was mixed with 0.37 g ( 0,0027 mol) of 5-mercapto-1-methyltetrazole sodium salt , 1 ml of triethylamine and 20+111 methylene chloride. Applicable The mixture was stirred at ambient temperature under argon for 3 days. Wash the reaction mixture with water and It was dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum to give 0.7 g of raw A product was obtained.

(g) 2-(2-dobnorphenyl)-2”-[(1-methyl-5-tetrazoli )thio]acetic acid 7 g (0,0016 mol) of the compound of Example 1(f) was added to 5 ml of methanol. Mix with 0.4 g (0.01 mol) of sodium hydroxide, Stir for a while. The reaction mixture was concentrated under vacuum and the residual oil was redissolved in 5 ml of water.

The pH of the solution was adjusted to 48 or until a precipitate formed. Filter the precipitate and redissolved in methylene chloride, washed with flavored water, dried over anhydrous magnesium sulfate, and filtered. and concentrated under vacuum. 0.3 g of the produced oil was transferred onto silica gel, methylene chloride, Flash chromatography using 0.05% methanol and 0.001% formic acid as eluent. Matography yielded 0.18 g of oil, which was solidified into a low-melting wax. Ta.

Similarly, 2-(2-methoxyphenyl)-4,4-dimethyloxazoline and and the appropriate alkyl halide, the following compounds were prepared by the general method of Example 1. Manufactured: 2-(2-tetradenulfenyl)-2-[(1-methyl-5-tetrazolyl) -thiocoacetic acid and 2-(2-octylphenyl)-2-[(I-methyl-5-tetrasilinolithio) ] Acetic acid.

The compound of Example 1(e) (352 mg, 1 city 01), triethylamine (0,2 1ml1.1.5mmol) and 5-mercapto-1-carbetoquinomethyltet Mix rasol (250 mg, 1°33 mmol) in 25 ml of methylene chloride do. The mixture was stirred at ambient temperature for 2 days under argon. Remove the solvent and remove the residue. was subjected to flash chromatography on 50 grams of silica gel at 15% Elution with ethyl acetate/hexane yielded the product (500 mg, 99%) as a clear colorless liquid. I got it as a body.

The compound of Example 2(a) (260 mg, 0.52 mmol) was added to 4.2 ml of Dissolved in ethanol and stirred in an argon water bath. IN solution of sodium hydroxide (2.1 ml, 2.1 mmol) was added. Remove the water bath and leave the mixture for 1 hour. Stir at ambient temperature.

During this time a white precipitate formed. Evaporate the methanol and add another 4 ml of water. A slightly cloudy mixture was obtained which was stirred overnight at ambient temperature. Dilute the mixture with salt Acidified with acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated. I let it happen. The crude product was recrystallized from ethyl acetate/hexane to give the desired product (20 4 mg, 86%) was obtained as a white crystalline solid (melting point 147-148°C).

Elemental analysis, calculated value as Cz3Hs4N404S: C, 59, 72; H, ? , 41;N.

12, 11. Actual value: C, 59, 61: H, 7, 27; N, 12.15° Example 3 2-(2-dodecylphenyl)-2-[CI-(3-carboxypropyl)-5 -Te Compound of Example 1 (e) (325 mg, 1 m + 5 ol), triethyl acetate (0.42 mL 3 mmol) and 5-mercapto-1-(3-carboxy propyl)tetrazole (250 mg, 1.33 mmol) and 25 ml of The methylene chloride was combined and stirred under argon at ambient temperature overnight. removing the solvent, The residue was flash chromatographed on 50 grams of silica gel, The desired product (411 mg, 82%).

The compound of Example 3(a) (411 mg, o, 82 mmol) was added to 10 ml of Dissolved in ethanol and stirred in an argon water bath. IN solution of sodium hydroxide (3,2i1.3,2 mmol) was added dropwise, the water bath was removed and the mixture was kept at ambient temperature. Stir overnight. The solvent was removed and the residue was acidified with dilute hydrochloric acid at water bath temperature. crude product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated. residue was subjected to flash chromatography on 50 grams of silica gel for 30 days. A0:1 (ethyl acetate hexane:formic acid), followed by 50:50:1 (ethyl acetate, hexane:formic acid) :hexane:formic acid). Recrystallize from ethyl acetate/hexane to obtain the desired product. The product (285 mg, 71%) was obtained as a white crystalline solid (melting point 86-88 °C). Ta.

Elemental analysis, calculated value as C2C25H3'LOaS: C, 61, 20; H, 7 , 81:N.

11.42; S, 6.53. Actual value: C, 61, 43+H, 7, 83+N, 11 ．． 59; 2-(2-dodecylphenyl)-2-[(1-sulfomethyl-5-te Torazolyl) Compound of Example 1(e) (20Qmg, o, 57mmol) and 5-mercapto-1-sulfomethyltetrazole disodium salt (136m g, 0.57 mmol) in 4 ml of dimethylformamide, and The mixture was stirred overnight. The solvent was pumped off and the residue was dissolved in 5 ml of water. IN water Sodium oxide solution (2ml 1.2mmol) was added at 0°C and the mixture was brought to ambient temperature. The mixture was stirred overnight. The solvent was pumped off and the residue was filtered onto 50 grams of silica gel. Rush chromatography was performed using 6:3.1 (methylene chloride, ethanol). ・Eluted with ammonium hydroxide). Remove the solvent, take up the residue in water and freeze dry. The desired product (180 mg, 58%) was obtained as an amorphous white solid.

Elemental analysis, C2□H, IN 40 s S 22 N Hs 3 / 2 Hz As O, calculated values: C, 47°21; H, 7,74; N, 15.01.　 Actual value: C, 47,57; H, 7,39; N, 12-[2-(8-phenyl oc thyl)phenyl]-2-[[1-(3-carboxypropyl)-5-tetrazoly Production of 2-(8-phenyloctinol) dipotassium thio]acetate hydrate (a) Benzaldehyde 8-phenyloctyl bromide was added to 8-phenyl chloride in methylene chloride. Made from nyloctatool, carbon tetrabromide and triphenylphosphine. 8 -Nub-dried tetrahydrofurane of phenyl octanoic acid (19,8111101) (5 ml) solution was diluted with tetrahydrofuran (30 ml, 29° C.) for 4 hours at 20°C. , 1 mmol) to give 8-phenyloctatool. Applicable Octatool (approximately 19,8 imol) and carbon tetrabromide (21,98 mmol) l) in methylene chloride (50 ml) was added to a water-cooled methylene chloride (50 ml) solution of of triphenylphosphine (22.30 mmol) was added and the resulting solution was diluted with 2. Stirred for 5 hours. The volatiles were evaporated and the residue was taken up in ether (100ml). The mixture was cooled in water and filtered. The filtrate was evaporated and distilled to give 8-phenyloctylpropylene. Lomid was obtained as an oil. 8-Fe in distilled tetrahydrofuran (40IIll) Niloctyl bromide and 21.27a+a+ol of magnesium 2-(2-methoxyphenyl)-4,4-dimethy in hydrofuran (20ml) Luoxazoline (17.10 mmol) was added. After 24 hours of stirring, reaction mixture The material was similarly worked up to give 2-[2-(8-phenyloctyl)phenyl]-4 ,4-dimethyloxazoline was obtained as an oil. The oxazoline (11,58mm A solution of ol) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Volatile The corresponding 3,4.4-trimethyloxazolinium iodine after removing the The product was obtained as a white solid (melting point 76°5-78°C). The iodide (9.46 mm To a water-cooled methanol (35 ml) solution of ol) was added sodium borohydride (9 , 20 mmol) was added in portions. The reaction mixture was treated as in Example 1(C). The desired product was isolated as an oil.

Elemental analysis, calculated value as CzrH2aO: C, 85,67; H, 8,90, actual Measured value: C, 85, 12, 85, 22; H, 8, 94, 8, 96° (b) 2-( Alternative method for the production of 8-phenyloctyl)benzaldehyde 5-hexynyl alcohol A solution of pyridine (150+al) of 102ma+o was heated to 0°C under argon. It was cooled and p-toluenesulfonyl chloride (204 mmol) was added. the reaction The mixture was kept at about 4° C. for 18 hours, poured into ice water and then taken up in ether. The said d The ether extract was washed with cold 10% hydrochloric acid, water and brine. Dry the organic layer and Concentration in air gave 5-hequinyl p-toluenesulfonate.

A solution of phenylacetylene (97 mmol) in tetrahydrofuran (200 liters) (containing traces of triphenylmethane) was cooled to 0°C and then n-butyl Lithium (37.3 ml of 2.611101 in hexane) was added dropwise. generate The solution was stirred at 0°C for 10 minutes, and hexamethylphosphoramide (2III) was added dropwise. did. After stirring for 10 minutes, 5-hexynyl p-h luenesulfonate (97, 1mm. A solution of 1) in tetrahydrofuran (200 ml) was added. the reaction mixture Stir at room temperature for 18 hours, dilute with ether and wash the organic layer with water and brine. Ta. Concentrate the dry organic solution and purify the product by flash chromatography. 1-phenylocta-1,7-diyne was obtained. Triethylamine (100 ml) of the compound (43 mm.

1), 2-bromobenzaldehyde (35.8 mmol), cupric iodide (0 , 5ma+ol) and bis(triphenylphosphine)palladium(II) A mixture of loride (0.7 mmol) was heated in an oil bath (95° C.) for 1 hour. anti The reaction mixture was cooled to 0° C., filtered, and the filtrate was evaporated. Dissolve the residue in ether, Washed with 10% hydrochloric acid, water and saline. Dry and concentrate the organic layer to obtain the product; This was purified by flash chromatography and 2-(8-phenyl-1, 7-octadiynyl)benzaldehyde was obtained. The compound (24.1 mmol) A solution of ethyl acetate (100 ml) and 10% palladium on charcoal (1 g) were prepared at room temperature. Hydrogenation (hydrogen 4 Qpsi) was carried out for 15 minutes. Filter the catalyst and concentrate the filtrate to 2 -(8-phenyloctyl)benzaldehyde was obtained.

(C) Methyl 2-[2-(8-phenyloctyl)phenylco-2-hydroxy acetate The compound of Example 5(a) or 5(b) (10 amol) was added to methylene chloride (10 ml) and stirred at 0°C under argon. Add zinc iodide (1.1wol) Then, trimethyluryl cyanide (1 ml) dissolved in methylene chloride (20 ml) , 47ml1.11ma+ol) was added dropwise. After 1 hour at 0°C, remove the water bath and The mixture was stirred at room temperature for 1 hour. Remove the solvent and add methanol (60 ml) to water bath temperature. Added in degrees. Excess hydrogen chloride was bubbled into the solution while stirring. except for bathing , the mixture was stirred at room temperature for 18 hours. Add water (12 ml) and stir the mixture for 2 hours. Stir for a while. The solvent was evaporated and the residue was extracted with ethyl acetate and anhydrous sodium sulfate. dried, filtered and evaporated. Crude product on 200 grams of silica gel, 20% Flash chromatography using ethyl acetate/hexane as eluent; The product was mixed with a colorless transparent liquid and the compound of Example 5(c) (6.8 mmol) in a water bath. Stir under medium argon and add thionyl chloride (15 ml) in portions. except for bathing , the mixture was stirred for 18 hours.

Remove the solvent and transfer the residue onto 100 grams of silica gel, 20% methylene chloride/tetrachloride. Flash chromatography using carbon as eluent produces a colorless and transparent product. It was obtained as a liquid.

(e) Methyl 2-[2-(8-phenyloctyl)phenyl]-2-[[1-( 3-carboxypropyl)-5-tetrazolylcothiocoacetate Example 5 (d ) compound (7441g, 2mmol) was dissolved in methylene chloride (25IIll). and stirred at room temperature under argon. 5-Mercapto-1-(3-carboxypropyl) ) Tetrazole (376 mg, 2.1) and triethylamine (0.84 m1.6 mmol) was dissolved in methylene chloride (25 ml), and the reaction mixture of Example 5(d) was prepared. added to the compound solution. The mixture was stirred under argon for 24 hours. excluding the solvent, The residue was purified on 100 grams of silica gel in 70:30:1 hexane:ethyl acetate. : Flash chromatography using formic acid as eluent yields the desired product ( 830 mg, 79%) was obtained.

(f) 2-[2-(8-phenyloctyl)phenyl]-2-[[1-(3-cal) Luboquinpropyl)-5-tetrazolyl]thio]acetic acid Example 5(e) Compound ( 524 mg, 1 mmol) was dissolved in methanol (12 ml) and heated under argon. Stir in water bath. Drop IN sodium hydroxide solution (4IIl, 4 mmol) The water bath was removed and the mixture was stirred at room temperature overnight. Remove the solvent and place the residue in a water bath. Cool and acidify with dilute hydrochloric acid. The crude product was extracted with ethyl acetate and diluted with anhydrous sodium sulfate. um, filtered and evaporated. The crude product was filtered onto 70 grams of silica gel. Rush chromatography was performed using 30 nia 0:1 ethyl acetate:hexane: Elution with formic acid, then 50:50:1 ethyl acetate:hexane, formic acid yields the desired product. (495 mg: 97%) was obtained.

(g) 2-[2-(8-phenyloctyl)phenyl]-2”-[[1-(3 -carboxypropyl)-5-tetrazolyl]thio]acetic acid, dipotassium salt, hydrated The compound of Example 5(f) (495 mg 50.97 mmol) was added under argon. Treated with a solution of potassium carbonate (415 mg, 3 mmol) in water (10 ml) at water bath temperature. I understood. The water bath was removed and the mixture was stirred at room temperature for 15 minutes. Then, the solution was converted to C1 Chromatography on one column, eluting with water to remove excess base; It was eluted with 1:1 (acetonitrile:water). The desired compound ( 524 mg, 92%) was obtained as a white hygroscopic solid.

Elemental analysis, C27HszN4ChS 2K H2O and shite, calculated value: C, 53, 62:H.

5.67; N, 9.26, actual value: C, 53,81; H, 5,51: N, 9.3 6゜Similarly, 2-(2-methoxyphenyl)-4,4-dimethyloxazoli and the appropriate alkyl halide, the following compounds were prepared by the general method of Example 5. Manufactured something: 2-[2-(4-phenylbutyl)phenyl]-2-4[1-(3-carboquine) propyl)-5-tetrazolyl]thio]acetic acid, dipotassium salt, hydrate and 2- [2-(10-phenyldenyl)phenyl]-2-[[1-(3-carboxypyl) Lopyl)-5-tetrazolyl]thio]acetic acid, dipotassium salt, hydrate.

Example 6 3-(2-dodecylphenyl)-3-[[1-(3-carboxypropyl)-5 -Production of tetrazolyl]thio]propanoic acid (a) t-Butyl 3-hydroxy-3-(2-dodecylphenyl)propionani Up Under argon and stirring at 20°C, diethylaluminum chloride (54°7 mmol) of hexane solution in anhydrous tetrahydrofuran (300 ml). Lead dust (74,5 mff1 ol) and a catalytic amount of copper(I) bromide (2,5 m mol) was added to the slurry. The resulting mixture was then placed in an ice-methanol bath. Cooled to 0°C. t-Butyl bromoaceter 1-(49,8 unit o1) and implementation Anhydrous tetra of 2-dodecylbenzaldehyde (54.7 mmol) of Example 1(C) Hydrofuran solution was added slowly over 60 minutes. Stir the reaction for about 24 hours. , slowly warmed to room temperature. The mixture was filtered to remove zinc, concentrated and diluted with 3N hydrochloric acid. The mixture was acidified with water and extracted with ether.

The organic extracts were dried over magnesium sulphate, filtered and evaporated to give the crude product. One This material was then flashed onto silica using 8% ethyl acetate in hexane. Chromatography gave the desired product in 79% yield.

(b) 3-(2-dodecylphenyl-3-[[1-(3-carboxypropyl) )-5-tetrazolyl J thio J propanoic acid A 3-day 100 ml round bottom flask equipped with a thermometer and stir bar was placed on dry ice. It was cooled to -30°C using an acetone bath and then an ice-methanol bath. the flask trifluoroacetic acid (20111), then 5-mercapto-1-(3-carbo Add (xypropyl)tetrazole (0,00128 mol, 0.1923 g) Ta. The mixture was cooled under argon for 10 minutes. To this, methylene chloride (5i 1) Add the compound of Example 6(a) (0,001282 mol, 0.5 g) Ta. The reaction was stirred at 15° C. for 2 hours and allowed to warm to ambient temperature. trifluoroacetic acid The resulting oil was evaporated and the resulting oil was dissolved in 20% water in methanol over a Cl11 bag. Chromatography using 0% formic acid gave the desired product.

Elemental analysis, as CzsH4oN40nS, total) [fa: (0.5 mol Hz O +:) C.

60.81; H, 7, 79; N, 10.92, actual value: C, 60, 24: H, 7 ,79;N,10.62° Similarly, the following compounds were prepared according to the general method of Example 6.

3-(2-tetradecylphenyl)-3-[[1-(3-carboxypropyl) -5-tetrazolylcothiocoprobanic acid and 3-(2-octylphenyl)- 3-[[1-(3-carboxypropyl)-5-tetrazolylcothiocobroban acid.

Example 7 3-[2-(8-phenyloctyl)phenyl]-3-[(1-carboxine methyl Preparation of (5-tetrazolyl)1,000]propanoic acid (a) t-butyl 3-hydroxy C-3-[2-(8-phenyloctyl)phenyl]propionate Diethylaluminum chloride (0,00 A hexane solution of 82 mo1.8.2 m1) was added to anhydrous tetrahydrofuran (40 m l) Zinc dust (0,0111mol1.0.7248g) and catalytic amount of odor It was added to a slurry of copper(I) chloride (0,0004 mol, 0.0585 g). unintentionally The resulting mixture was then cooled to -20°C in a water-methanol bath. t-butylbutylene Lomoacetate (0°0082mol1.1.32ml) and Example 5(a) or (b) 2-(8-phenyloctyl)benzaldehyde (0,0O82m ol, 2.3969 g) in anhydrous tetrahydrofuran was slowly added over 60 minutes. added. The reaction was stirred overnight and slowly warmed to room temperature. The mixture was filtered and The lead was removed, concentrated and azeotroped with methylene chloride. Then, the obtained oil is Flash chromatography using 5% ethyl acetate in hexane with 0.5% formic acid The desired product was obtained by chromatography.

(b) 3-[2-(8-phenyloctyl)phenyl]-3-[(1-carboxyl Thermometer and stirring rod A 100m1 round bottom flask of Milo was placed in a dry ice-acetone bath, then ice- It was cooled to -30°C using a methanol bath. Trifluoroacetic acid (1 0 ml), then 5-mercapto-1-carboxine methyltetrazole (0,0 (124 mol, 0.2 g) was added. Cool the mixture under argon for 10 minutes did. To this mixture was added the compound of Example 7(a) (0 , OO113mol1.0.4634g) was added. Stir the reaction at -15°C for 2 hours. Stir and then warm to room temperature. Evaporate trifluoroacetic acid and combine with methylene chloride. I let it boil. The resulting oil was treated with 30% ethyl acetate in hexane with 0.5% formic acid. The desired product (yield: 26%) was obtained by chromatography.

Elemental analysis, Cx s H32N 404S, calculated value as 3/4HtO: C, 61,21;H.

6.32; N, 10.98; S, 6.29, actual value: C, 61,22; H, 6, 47:N.

11.87; S, 6.38° Similarly, the following compounds were prepared according to the general method of Example 7.

3-[2-(4-phenylbutyl)phenyl]-2-[(1-carboxypropyl) -5-tetrazolyl)thio]propanoic acid and 3-[2-(10-phenylde sil)phenyl]-2-[(1-carboxypropyl-5-tetrazolyl)thio Cobrobanic acid.

Example 8 3-[2-(8-phenyloctyl)phenylto 3-[[1-(3-carboxy Propyl)-5-tetrazolyl]thio]propanoic acid production thermometer and stirring rod Place the attached Milo 10011 round bottom flask in a dry ice-acetone bath, then put it on ice. - Cooled to -30°C using a methanol bath. Add trifluoroacetic acid ( 20a+1), then 5-mercapto-1-(3-carboxypropyl)tetra Sol (0.OO24 mol, 0.4574 g) was added. The mixture was The mixture was cooled for 10 minutes under an oven. To this was added Example 7(a) in methylene chloride (5 ml). The compound (0.OO24mol, area 9069g) was added. The reactants were heated to -15°C. Stirred for 2 hours then warmed to room temperature. Evaporating trifluoroacetic acid produced oil in 20% water in methanol with 0.5% formic acid on reverse phase cps backing. The desired product was obtained in 26% yield.

Elemental analysis, CzsH3sN404S, calculated value as 1/2H20: C, 63, 02;H.

6.80; N, 10.5; Actual value: C, 63.08; H, 6.74; N, 10. 4゜Example 9 2-(2-undecyloxyphenyl)-2-[(1-carboxinemethyl-5- Te (a) 2-undecyloxybenzaldehyde pre-washed with petroleum ether, Sodium hydride (10, Om mol) of dimethyl salicylaldehyde (101a + mol). Formamide solution was added dropwise. Then undecylp was added to the reaction mixture. Romid (1 mol 10,0II) was added and the mixture was heated with nitrogen at ambient temperature for 16 hours. Stir at the bottom. The mixture was taken up in hexane (50 ml) and diluted with 10% sodium hydroxide. (2×50 ml) and saturated sodium chloride (50 ml).

The organic layer was dried over anhydrous magnesium sulfate and charcoal. evaporate volatile substances A colorless liquid was obtained which was purified on silica gel using 2% ethyl acetate in hexane as eluent. Purification by flash chromatography provided the desired product as an oil.

Elemental analysis, calculated value as C+5HzsOz: C, 78,21; H, 10,21 :, Actual value・C, 77,92; H, 9,95° (b) 2-(2-undecyl) xyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio] vinegar acid Using the general method of Example 1(d)-1(g), the compound of Example 9(a) was convert to the desired product.

A suitably substituted hydroxybenzaldehyde and a suitable alkyl halide The following compound is prepared according to the general method described above: 2-(2-heptyloxy Cyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]acetic acid , 2-(2-dodecyloxyphenyl)-2-[(1-carboxymethyl-5-te trazolyl)thio]acetic acid, 2-(5-methoxy-2-dodecyloxyphenyl)-2-[(1-carboxy Methyl-5-tetrazolyl)thio]acetic acid, 2-(5-methyl-2-dodecyloxy) Cyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]acetic acid , 2-(5-fluoro-2-dodecyloxyphenyl)-2-[(1-carboxy Methyl-5-tetrazolyl)thio]acetic acid, 2-(5-chloro-2-dodecylox Cyphenyl)-2-[(1-carboxymethyl-5-tetrazolyl)thio]acetic acid , 2-(5-iodo-2-dodecyloxyphenyl)-2-[(1-carboxyme thyl-5-tetrazolyl)thio]acetic acid, 2-(5-bromo-2-dodecyloxyphenyl)-2-[(1-carboxyme thyl-5-tetrazolyl)thio]acetic acid, 2-(5-hydroxy-2-dodecyloxyphenyl)-2-[(1-carboxy methyl-5-tetrazolyl)thio]acetic acid, 2-(5-nitro-2-dodecyl) xyphenyl'l-2-[(1-carboxymethyl-5-tetrazolyl)thio] acetic acid, 2-(5-amino-2-dodecyloxyphenyl)-2-[(1-carboxyme thyl-5-tetrazolyl)thio]acetic acid, and 2-(5-trifluoromethyl- 2-dodecyloxyphenyl)-2-[(1-carboxymethyl-5-tetrazo lyl)thio]acetic acid.

2-(2-dodecylthiophenyl)-2-[(1-carboxymethyl-5-tetate) Lazolyl)thio]acetic acid is prepared from 2-(dodecylthio)benzaldehyde.

2-(2-hebutylthiophenyl)-2-[(1-carboxymethyl-5-tetate) Lazolyl)thio]acetic acid is prepared from 2-(heptylthio)benzaldehyde.

Example 10 2-[2-6-phenylhexyloxy)phenyl]-2-[[1-(3-cal Production of boquinpropyl-5-tetrazolyl)thio]acetic acid (a) 2-(6-phenylene) hexyloxy)benzaldehyde 6-phenylhexanoic acid (19,8amo A solution of 1) in sieve-dried tetrahydrofuran (5 ml) was added to tetrahydrofuran for 4 hours at 0°C. Reduction with diborane in hydrofuran (30ffil, 29, 1 + uol), 6-phenylhexanol was obtained. Hexanol (approximately 19°8 wol) and In a water-cooled methylene chloride (50+el) solution of carbon bromide (21.98 mmol) , triphenylphosphine (22,30mmol in methylene chloride (30a+1) l) was added and the resulting solution was stirred for 2.5 hours. Evaporate the volatiles and leave a residue was taken up in ether (100at1), cooled in water and filtered. Evaporate the filtrate , to give 6-phenylhexyl bromide as an oil. dimethylformamide The promide (8,00 mmol) in 10 ml of salicylaldehyde ( 8,19 o1) and potassium carbonate (9,33 mmol) were heated to 100°C. , and kept at this temperature for 1 hour.

The cooled reaction mixture was taken up in hexane (50111) and diluted with 5% sodium hydroxide. (50ml) and saturated sodium chloride (50ml). Anhydrous organic layer Dry with magnesium sulfate and charcoal. A cell-free product is obtained by evaporation, and this is converted into silica. Flux chromatography on gel, eluting with 5% ethyl acetate in hexane. Purification by filtration gave the desired product as an oil.

Elemental analysis, calculated value as C19H2202: C, 80, 82; H, 7, 85; , Actual measurement C, 80, 62; H, 7, 72° (b) 2-C2-(6-phenylhexyloxy)phenyl]-2-[[1-( 3-Carboquinpropyl)-5-tetrazolyl]thio]acetic acid from Example 5(C) 5(g) - Using the membrane force method, the compound of Example 10(a) was converted to the desired product. Ru.

From an appropriately monosubstituted phenylalkyloxybenzaldehyde, the general method described above According to the following, the following compounds are produced.

2-[2-(3-phenylpropyloxy)phenyl]-2-[[1-(3-carboxylic acid) ruboquinpropyl)-5-tetrazolyl)thiocoacetic acid and 2-[2-(9-ph) phenylnonyloxy)phenyl]-2-[[1-(3-carboquinepropyl)- 5-tetrazolyl)thiocoacetic acid.

Example 11 2-Methyl-3-(2-dodecylphenyl)-3-[(1-carbodimethyl- Production of 5-tetrazolyl)thio]propanoic acid (a) Methyl 2-methyl-3-hydride Roxy-3-(2-dodecylphenyl)propanoate Zinc dust (15 mmol) and bromide t! Steaming of 4 (I) (3 mmol) Diethyl aluminum chloride ( 10a+mol) was added at 25°C. The mixture was stirred for 5 minutes and then poured with ice-meth. It was cooled to 0°C in a nord. Compound of Example 1(C) (10a+mol) and and methyl dl-2-promobu oral pioner h (10 mmol) in tetrahydrofu Run (10 ml) solution was added dropwise to the cooled suspension. The resulting mixture was heated at 25°C. Stirred for 3 hours. The reaction mixture was filtered, the filtrate was washed with water, and magnesium sulfate was added. The product was obtained after drying and evaporation.

(b) Methyl 3-(2-dodecylphenyl)-3-[(1-carbethoxymethyl -5-tetrazolyl)thio]propanoate trifluoroacetic acid (15+111) and 5-mercapto-1-carbetoquin methyltetrazole (2,4ml). , the compound of Example 11(a) was added at 0°C. The reaction mixture was stirred for 3 hours and evaporated. I let it emanate. The resulting residue was subjected to flash chromatography on silica, Elution with 20% ethyl acetate in hexane gave the product.

(C) 2-Methyl-3-(2-dodecylphenyl)-3-[(1-carboxyme methyl-5-tetrazolyl)thio]propanoic acid 10% sodium hydroxide (50ml ) solution, methanol (12 ml) and ethylene glycol dimethyl ether. , the compound of Example 12(b) (93.9 mmol) is added. The mixture was heated to 25°C. Stir for 24 hours. The reaction mixture was then cooled to 0°C in an ice-methanol bath. acidified to pH 3.5 with hydrochloric acid, extracted with diethyl ether, and extracted with magnesium sulfate. dry in a vacuum, filter and evaporate. The resulting isomer mixture was flashed onto silica. Chromatography to give the product, eluting with 30% ethyl acetate in hexane. get.

Example 12 2-(2-dodecylphenyl)-2-[2-(tetrazol-5-yl)ethylthi Oco(a) 5”(2-mercaptoethyl)tetrazoletetrahydro7:/1 00Iil, aluminum chloride (6.65g, 0.05mol) and azide Sodium (9.75 g, 0.15 IBol) was added at 0°C. this mixture The temperature was brought to 22°C and stirred for 30 minutes. β-Mercaptopropionitrile (4.35g , Q, 5 mol of Q) were added, and the mixture was heated to reflux for 24 hours. the mixture Cool, carefully acidify with excess 15% aqueous hydrochloric acid, and remove solvent under reduced pressure. did. The residue was extracted with ethyl acetate, the extract was washed with water, dried and the solvent was evaporated. I set it. The residue was recrystallized from 1,2-nochloroethane to give 5-(2-mercaptoethyl 3.7 g (57%) of tetrazole was obtained.

(b) Methyl 2-(2-dodecylphenyl)-2-[2-(tetrazol-5-yl) )ethylthio]acetate Methyl 2-chloro-2-(2-dodecylphenyl) in methylene chloride (20 ml) ) acetate (0,615g, 1.75mmol), 5 (2-mercapto ethyl)tetrazole (0,227g, 1,75 mmol) and triethyl A mixture of Ruamine (0.48ml 1.3°5mmol) was stirred at 22°C for 18 hours. , the solvent was evaporated. The residue was taken up in diethyl ether, washed with IN hydrochloric acid and dried. Dry and remove solvent. The residue was chromatographed on a silica gel column. Ta. Impurities were eluted with ethyl acetate/hexane (1:3), and the product was eluted with methanol. /ethyl acetate (1:19).

Evaporation of the solvent from these fractions gave the desired product (0.570 g, 73% ).

(c) 2-(2-dodecyl)2-2-[2-(tetrazol-5-yl)ethyl] Chilthio] acetic acid Methyl 2-(2-dodecylphenyl )-2-[2-(tetrazol-5-yl)ethylthiocoacetate (0,57g , 1.28mm.

The stirred suspension of l) was treated with 2.5N sodium hydroxide 3I111 at 70°C. . After 30 minutes at 70° C., the mixture was cooled, diluted with 10 μl of water and filtered. filtrate Acidified and extracted with ethyl acetate, the extracts were dried and the solvent was evaporated. Remove the residue Recrystallization from tanol gave the desired product (0.415g, 74%). N.M. R (CDCIs/MezCO): 10, 23-11.70 (broad, 2H ), 7.52-7.62 (i, IH), 7.27 (s, 3B), 5 ．． 04 (s, kH), 3.0-3.44 (a , 4H), 2.63-2.92 (t, 2H), 1.12-1.84 (i, 2 0111), 0.62-1.02 (t, 3H).

Example 13 3-C2-(8-phenyloctyl)phenylco3-[[1-(3-carboxyl) Production of (cypropyl)-5-tetrazolyl]thio]-2-hydroxypropanoic acid ( a) 2-(8-phenyloctyl)benzaldehyde Example 5(a) or (b) ) 2-(8-phenyloctyl)benzaldehyde was produced in the same manner as described in did.

(b) Methyl 3-[2-(8-phenyloctyl)phenyl]-2,3-dipoxy Empropionato The compound of Example 7(a) (2.94 g, 10 u+ol) was dissolved in diethyl ether ( 25+1) and the solution was stirred at 0° C. under argon. Methyl chloroacetate Tart (1632ml 1.15mmol) was added, then sodium methoxide ( 810 mg, 15 mmol) was added. The mixture was stirred in a water bath for 2.5 hours. did. Add a small amount of water, separate the ether layer, dry with anhydrous sodium sulfate, and filter. Filtered and evaporated. The residue was purified on 80 grams of silica gel from 5 to 30% ethyl acetate/hexyl acetate. Flash chromatography eluting with xane gave the product.

(c) Methyl 3-[2-(8-phenyloctyl)phenyl]-3-[[1-( 3-carboxypropyl)-5-tetrazolyl]thio]-2-hydroxybropy on honor The compound of Example 13 (c) (549 g, 1.5 o1) was dissolved in 2% triethyl The amine was dissolved in methanol (6 ml) and the solution was heated at room temperature under argon. Stirred.

5-mercapto-1-(3-carboxypropyl)tetrazole (282 mg, 1°5 mmol) and triethylamine (0,84Ilt, 5n+mol) was dissolved in methanol (9 ml), added dropwise to the reaction mixture, and then stirred at room temperature for 5 days. Stirred. The solvent was removed and the residue was purified on 50 grams of silica gel at 70:30:1 (hexyl). Flash chromatography eluting with ethyl acetate (formic acid) The desired product was obtained.

The compound of Example 13(d) (554 mg, 11011101) was dissolved in methanol (1 5+1) and stirred at water bath temperature under argon. Sodium hydroxide IN The solution (4 ml, 4 mmol) was added dropwise, the water bath was removed and the mixture was stirred at room temperature overnight. did. The methanol was removed and the residue was acidified with dilute hydrochloric acid. Extract with ethyl acetate and dried over anhydrous sodium sulfate, filtered and evaporated to obtain the crude product, which was on gram silica gel, eluting with 50:50:1 (ethyl acetate:hexane:formic acid) Flash chromatography gave the desired product.

Example 14 3-[2-(8-phenyloctyl)phenyl]-3-[(1-carboxine methyl - 2-(8-Phenyloctyl) prepared as in Example 5(a) or (b) ) Benzaldehyde (15 g) was added to methylene chloride at 25°C under an argon atmosphere. (58 ml). Add methyl chloroacetate (6.2 ml) in one portion. Ta. The resulting solution was cooled to -28°C using a dry ice/isopropanol bath. Rejected.

Then, sodium methoxide (1 3.5 ml) was slowly added. The reaction mixture was then stirred for 45 minutes and slowly The mixture was then warmed to 0°C. The reaction was then stirred for 1.5 hours at 0°C. the reaction mixture was quenched with aqueous buffer solution (pH 7, 117 ml) and hexane 117 ml. . The layers were separated and the aqueous portion was filtered and washed with hexane. combined organic extract was dried over sodium sulfate, filtered and concentrated. Flash-clean the residue on silica. Chromatography and elution with 3.97 ethyl acetate/hexane yielded the desired product. I got something.

(b) Methyl 2-hydroxy-3-[(1-carboxymethyl-5-tetrazolyte) ru) Chio] Propano Art Methyl 2,3-epoxy-3-[2-(8-phenyloctyl) of Example 14(a) phenyl]propanoate (0.4 g) was dissolved in 2% Tolieopropane under an argon atmosphere. Dissolved in 5 ml methanol containing thylamine. The reaction mixture was placed on ice/meth. Cooled using a Knoll bath. 5-Mercapto-1-carbethoxymethyltetrazo 205 g of 2% triethylamine and 51 ml of triethylamine Q A methanol (5 ml) solution containing . Remove the layer and bring the reaction to room temperature. Warmed. The reaction was concentrated onto silica and eluted with 20% ethyl acetate/hexane. The desired product was obtained by flux chromatography.

Earthworks engineer ``2n3M striped giant three decoys'' Thiocoke-hydroxypropanic acid Example 14(b) of methyl 2-hydroxo- 3-[(1-carboxymethyl-5-tetrazolyl)thio]propatazur) (0 , 45 g) in methanol (6.6 ml) and cooled in an ice and methanol bath. A 4% solution of sodium hydroxide (3.3 ml) was added thereto. except for the layer , the reaction was allowed to warm to room temperature overnight. (In a palanquin, remove methanol and dilute the residue with dilute hydrochloric acid.) diluted with Extracted with ethyl acetate, dried over magnesium sulfate in LX, filtered. Evaporated. flash chromatography of the crude product on silica; Elute with 30-50% ethyl acetate/hexane. The column was washed with 100% methanol. Washed with. 40 mg of desired product was recovered.

Compound of Example 1(e) (0.53g, O,OO15a+a+oL), methyl 4-Methyl-2-mercaptothiazole-5-carboxilade (0.39 g, 0.00195 mol), triethylamine (0.23 g, 0.0023 m ol) and methylene chloride (lQml) at room temperature under argon for 48 hours. Stir for a while. The reaction mixture was treated with three times 5 ml of 5% sodium carbonate solution and then with water. , dried over magnesium sulfate, filtered and concentrated under vacuum. The oily residue , flash chromatography using hexane-5% ethyl acetate, 0.58g of oil was obtained.

(b) 2-(2-dodenulfenyl)-2-(5-carboxy-4-methyl-2 -thiazolylthio)acetic acid Compound of Example 15(a) (0.24 g, O,OO46 mol), sodium hydroxide Lithium (0.11g, O,OO28mol), methanol (lQml) and A mixture of water and water (1 ff 1 l) was stirred at room temperature under argon for 2 days. the reaction mixture The material was concentrated under vacuum and the residual oil was redissolved in 5 ml of water. The aqueous solution was adjusted to pH 3.8. 3 or until a cloudy solution is obtained, then 10 ml of vinegar. Extracted three times with ethyl acid. The extract was washed with 5 ml of water, and then washed with magnesium sulfate. Dry, filter and concentrate. The resulting oily residue was triturated with petroleum ether. desired The product (0,054 g) was obtained as a powder with a melting point of 88-91°C.

Elemental analysis, CtsHssNo4S2, calculated value: C, 62, 86: H, 7, 38; N, 2.93° Actual measurement C, 62, 59: H, 7,47; N, 2.88° Example 16 2-[2-(8-phenyloctyl)phenylco2-C[2-carboxy-5 -(1,3,4-thianazolyl)]thio]acetic acid production (a) Methyl 2-[2- (8-phenyloctyl)phenylco-2-[[2-carbetoxy-5-(1, 3,4-Thiadiazolyl)]thio]acetate Example 5(d) Compound (744 mg, 2II1 mO1) in 25 ml of methylene chloride and heated to room temperature under argon. Stir with Ethyl 5-mercapto-1,3,4-thiadiazole-2-carbo Xylard (380 mg, 2II 1 mol) and triethylamine (0,8 Example 5 (d) was dissolved in 25 ml of methylene chloride. ) to the solution of the metal compound. The mixture is stirred under argon for 48 hours. solvent Evaporate and flash chromatograph the residue on silica gel with acetic acid. Elution with ethyl/hexane gives the product.

Example 16 (a) 0) Compound (526 mg, l major) was added to lQml Dissolve in methanol and stir in a water bath under argon. IN hydroxide) IJ Add '7mm solution (4ff11.4a+mol). Remove the water bath and pour the mixture into Stir at room temperature for 24 hours. The solvent was evaporated, the residue cooled in a water bath and acidified with dilute hydrochloric acid. extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated. Get the product.

The compound of Example 5(d) (744 mg, 2 mmol) was added to methylene chloride from 25 companies. and stir at room temperature under argon. 5-mercaptomethylfuric acid (316 mg, 2 mmol) and triethylamine (0.84 m 1.5 m + mol) Dissolve in 25 ml of methylene chloride and add to the solution of the compound of Example 5(d). Applicable The mixture is stirred under argon for 48 hours. Evaporate the solvent and place the residue on silica gel, Subjected to flux chromatography and eluted with ethyl acetate/hexane/formic acid. to obtain the product.

The compound of Example 17(a) (494 mg, 1 mmol) was dissolved in methanol (1Qa +1) Dissolve and stir in a water bath under argon. IN sodium hydroxide solution Add (411,4a+mo1). Remove the water bath and stir the mixture for 24 hours at room temperature. Stir. The solvent was evaporated and the residue was cooled in a water bath, acidified with dilute hydrochloric acid and diluted with ethyl acetate. The product is extracted with water, dried over anhydrous sodium sulfate, filtered and evaporated.

Example 18 3-[2-(6-thiofynoxyhexylthio)phenyl]-3-[[1-(3 -carboxypropyl)-5-tetrazolyl]thio]-2-hydroxypropane acid production (a) Production of 2-(6-thiophenoxyhexylthio)benzoic acid Thiosalicylic acid (1°2g1008+*ol) and 6-thiophninoquinohexyl bromide (2.5 g, 0-009 mol) was dissolved in dimethylformamide (50 ml). , the solution is stirred under argon. Potassium carbonate (15g, 0.011mol) to the reaction carefully. After addition is complete, slowly warm the mixture to 100°C do. The solvent was evaporated and the residue was dissolved in water, acidified with dilute hydrochloric acid and extracted with ethyl acetate. Remove, dry over anhydrous sodium sulfate, filter and evaporate. Transfer the residue onto silica gel. Flash chromatography gives the desired product.

(b) Production of 2-(6-thiophenoxyhexylthio)benzyl alcoholHydrogen Tetrahydrof lithium aluminum oxide (0,292g, O,OO7mol) Add 2-(6-thiophenoxyhexylthio)an to the furan (30 ffll) suspension. Zozoic acid (2°42g, 0.007mol) in tetrahydrofuran (30ml) Add solution. This reaction is carried out in the same manner as in Example 1(b).

(c) Production of 2-(6-thiophenoxyhexylthio)benzaldehyde dioxide Suspension of manganese (11.78 g, 0.135 mol) in ethyl acetate (30 ml) 2-(6-thiophethoxyhexylthio)benzyl alcohol 0 0 3 7 mol) of ethyl acetate (20111) solution is added. This reaction is shown in Example 1 (C) Do it in the same way.

(d) Methyl 3-[2-(6-thiophenoxyhexylthio)phenyl]-2. 3-Epoxy propionate Example 18 The compound (c) (10 mmol) was added to diethyl ether (25 ml). ) and stir the solution at 0°C under argon. Methyl chloroacetate (15 mmol) was slowly added, and then sodium methoxide (15 mmol) was added slowly. Add l). The mixture is stirred for 2.5 hours at water bath temperature. Add a small amount of water and The ether layer is separated, dried over anhydrous sodium sulfate, filtered and evaporated. 8 residue Flash chromatography on 0g silica gel, 5-30% Elution with ethyl acetate/hexane gives the product.

(e) Methyl 3-[2-(6-thiophenoxyhexylthio)phenyl]-3- [[1-(3-carboxypropyl-5-tetrazolylcothioco-2-hydroxy) cypropionate The compound of Example 18(d) (1.5 mmol) was added to 2% triethylamine. The solution was stirred at room temperature under argon. Ru. 5-mercapto-1-(3-carboxypropyl)tetrazole (l, 5 mmol) and triethylamine (5 mmol) in methanol <9 11), added dropwise to the reaction mixture, and then stirred at room temperature for 5 days. Remove solvent The residue was flash chromatographed on 50 grams of silica gel. , 70:30:1 (hexane:ethyl acetate, formic acid) to give the desired product. Ru.

(e) 3-[2-(6-thiophethoxyhexylthio)phenyl]-3-[[ 1-(3-carboxypropyl-5-tetrazolyl]thio]-2-hydroxyp The compound (1 mmol) of ropanic acid Example 18(e) was added to methanol (15 ml). and stir at water bath temperature under argon. IN sodium hydroxide solution (9 4 mmol) dropwise, the water bath is removed and the mixture is stirred at room temperature overnight. methano Remove the filtrate and acidify the residue with dilute hydrochloric acid. Extraction with ethyl acetate followed by anhydrous sulfur Drying over sodium chloride, filtration and evaporation gave the crude product, which was divided into 25 g Flash chromatography on ram silica gel, 50:50:1 Elute with (ethyl acetate:hexane:formic acid) to obtain the desired product.

Example 19 Methyl 2-hydroxy-3-mercapto-3-[2-(8-phenyloctyl) Production of phenyl propionate (a) Methyl 2-hydroxy-3-(4-methoxyphenylmethylthio)-3- [2-(8-Phenyloctyl)phenylcobropionate triethylamine 1 ．． The epoxy of Example 13(b) in a mixture of 7 ml and 20 ml methanol. Stell 4. 5.4g (12.4mmol) and p-methoxybenzylmethane lucaptan 1. A solution of 91 g (12.4 mmol) was stirred for 42 hours, and the solution The medium was evaporated. The residue was dissolved in diethyl ether and washed with 0.1N HCl . The organic layer was dried and the solvent was evaporated. Chromatograph the residue on an alumina column I attached it to the ee.

Impurities and undesired regioisomers were removed using hexane/ethyl acetate/methanol (60: It eluted at 40:1). The desired product is hexane/ethyl acetate/methanol It was eluted at 40.60 mm. 2. 6g (40%), NMR ( CDC13) + 7.68 (1.IH), 7.20 (m.10H), 6.8 2 (d.2H), 4.58 (t.LH), 4.45 (d.IEI), 3. 82 (s.3H), 3.72is. 2H), 2.

66 (s.3H), 3.14 (d.IH), 2.24-2.72 (+*, 4 H), 1, 10-1. 72 (m. 12H).

(b) Methyl 2-hydroxy-3-mercapto-3-[2-(8-phenyloc) Chyl) phenyl propionate Compound 1 of Example 19(a). 1g (2.12mmol) of 25ml Add the tanol solution to 2.mercuric acetate. 0.2g (6.35mmol) of Treated with tanol (100ml) solution. After stirring for 16 hours, filter the white precipitate. and washed with diethyl ether. Add this mercuric salt to 251111 hot dimethic acid Dissolve in chloroformamide, add 5Qml of methanol, and add 3Qml of H,S to the solution. Bubbled for 0 minutes. Filter the black precipitate, concentrate the filtrate, dilute with water and dilute with diethyl Extracted with ether. Wash the diethyl ether layer thoroughly with water, dry, and evaporate the solvent. I let it emanate. The residue was subjected to silica gel column chromatography, and the product was purified with acetic acid ether. Elution was carried out with a mixture of chill/hexane (40:60). 370 mg (44%).

NilR (CDC1a/DtO): 7.02-7.78 (m.9H), 4.6 2 (s.2H), 3.

70 (s, 3H), 2.50-2.88 (a+.4■), 1.20-1.8 2 (m.12H).

Example 20 [R-(R units.8 units)]-]2-methquine-3-2-(8-phenyloctyl- 3-(2-carpoxychen-5-ylmethyl)sulfonyl)propanoic acid 20 (a) Methyl 2(S)-methoxy-3(R)-(4-methoxyphenylmethyl )thio-3-(2-(8-phenyloctyl)cobropionate tetrahydrof Methyl 2(S)-hydrogen in 150 ml run and 50 ml dimethylformamide. Droxy-3(R)-(4-methoxyphenylmethyl)thio-3-[2-(8- Phenyl octyl) phenyl] propionate 5. 5 8g (0.01 1 mol) (produced as described in EPo Publication Application No. 88305188.0) ) and 0.67 ml of iodomethane were added to 430 mg of 60 % NaH dispersion. The water bath was removed and the reaction was stirred at 23°C for 2 hours and cooled. The mixture was poured into 0.5N HCl aqueous solution and extracted with diethyl ether. Wash the extract with water , dried and evaporated.

The residue was subjected to silica gel column chromatography and the product was chromatographed at 20% in hexane. Eluted with % ethyl acetate. NMR (CDCI,): δ7.09-7-54 ( m. 11H), 6.80 (d.2H), 4.37 (d.IH), 4.11 (d.LH), 3.75 (s, 3H), 3.73 (s, 3H), 3.63 (d.LH), 3.52 (d,hH), 3.28 (s.3H), 2.60 (t.2B), 2.42 (t.2H), 1.23 -1.68 (+w.12H).

20(b) Methyl [R-(R*.8)]-]3-mercapto-2-methoxy -2(8-phenyloctyl)phenylpropanoatomethyl 2(S)-methoxy C-3(R)-(4-methoxyphenylmethyl)thio-3-[2-(8-phenylmethyl) (octyl) phenyl] propionate 3. 4 2g lQQml methanol The solution was treated with 5.3 g of Hg(○AC)2 and stirred overnight. Remove the solvent and The residue was stirred with a mixture of 25% diethyl ether in hexane. Remains after crushing The resulting solid was dissolved in 100 ml methanol, and H2S was bubbled in for 1 hour. HgS was filtered off and the filtrate was evaporated. The residue was subjected to silica gel chromatography and the raw The product was eluted with a mixture of 30% ethyl acetate in hexane.

NMR (CDC13): δ7.12-7.46 (*.911), 4.52 (t.LH), 4.16 (d.LH), 3.74 (s, RH), 3.3 1 (s.3tl), 2.55-2.78 (m.4H), 2. 10 (d. 1 ■), 1.28-1.69 (a+, 1211).

20 (c) Methyl [R-(R*.Ss)]-]2-methoxy3-2-(8 -phenyloctyl)phenyl]-3-(2-carpomethoxychen-5-yl) methyl) sultetrahydrofuran 6011 and dimethylformamide 30ml Methyl [R-(R units, 8 units)]-]3-mercapto-2-methoxy in a mixture of 2-(8-phenyloctyl)phenylpropanoate 1.42g (3,43 mmol) was treated with 137 mg of a 60% dispersion of NaH in mineral oil at 0 °C. Ta. Once salt formation is complete, methyl 5-bromomethylchenyl-2-carboxyl 806 mg of chloride was added. Stirring was continued at 0°C for 2 hours and then at 23°C for 1 hour.

The reaction was poured into H2O and extracted with diethyl ether. Extract H! Wash with ○ Cleaned, dried and solvent removed. Partial purification of intermediate products was performed using a silica gel column. Chromatography was performed, eluting with 20% ethyl acetate in hexane. crude methi [R-(R*, 8)]-β-[(5-carboxymethyl-2-chenylmethylene) ) Thiokol α-methoxy-2-(8-phenyloctyl)benzenepropanoa 85% m-chloroperbenzoic acid was dissolved in 100 ml of CH2Cl2. 0.833 g was treated at 23''. After 1172 hours, the reaction was dissolved in NazCOs water. Washed repeatedly with solution. The organic layer was dried and the solvent was evaporated. Silicage the residue The product was subjected to column chromatography with 30% ethyl acetate in hexane. It was eluted and collected from the eluate.

NMR (CDCh): 67.98 (m, LH), 7.62 (d, IH), 7.40-7.06 (m, 8H), 6.90 (d, 11P1), 5 10 (d, LH), 4.82 (d, LH), 4.62 (d, 111), 4 ．． 27 (d, LH), 3.86 (s, 3H), 3.64is, 3H), 3 ゜ 57 (s, 3B), 2.92-2.40 (m, 4■), 1.82-1. 02 (m, 12H).

20 (d) [R-(R pieces, 8 pieces)]-]2-methoxy 3-C2-8-phene phenyl]-3-(2-carboxycecy-5-ylmethyl)su Ruhonil) Prodo 2 Awakening Dimethyl ester from 19(a) in 20 ml glacial acetic acid and 8 ml concentrated MCI A solution containing 0.98 gm of water was refluxed for 6 hours. The reaction was cooled, poured into water, and CHC Extracted with l3. Wash the CHCl3 repeatedly with H2O, dry and remove the solvent. , 082 g of product was obtained. NMR (CDC13-Me2CO-Do)68.0 3 (m, IH), 7.63 (d, IEt), 7.40-7.10 (mB 8B), 7.00 (d, 1 [f), 6.63 (broad s, 2H), 5.20 (d, 1 [1), 4.82 (d, IH), 4. V2 (d, LH), 4 33 (d, IB), 3.67 (s, 3H), 2.46-2.96 (a+ , 4H), 1.10-1.76 (m, 12H) Example 21 [R-(R units, 8 units)]-]2-hydroxy-3-2-(8-phenyloctyl ]-3-(2-carpoxychen-5-ylmethyl)thio)propanoic acid tetra Methyl in a mixture of hydrofuran 3011 and dimethylformamide 2011 2(S)-hydroxy-3(R)-mercapto-3-[2-(8-phenyloc) methyl) phenyl] propionate mercapto 1. 2 6g (3. 1 7+ A solution of 3. mol) of NaH was added. It was treated with 17 mmol. Complete anion 3. methyl 5-bromomethylchenyl-2-carboxilade is produced.　 5.2 gmol was added, the water bath was removed, and the reaction was stirred for 2 hours. The mixture was heated with H2 Pour into O and extract with diethyl ether, wash the extract with H2O, dry and remove the solvent. was removed. The residue was subjected to silica gel column chromatography, and the product was Elution with a 30% ethyl acetate mixture in Sun gave the title compound after removal of the solvent.

NMR (CDC13) 67, 65 (d. IH), 7.32-7. 1 0 (m. 9FI), 6. 91 (d. LH), 4. @6-4.　55( m. 2B).

3, 97 (d.LH), 3.88 (s.3H), 3.81 (d.LH), 3.66 (s.3H), 3.00 (d.IH), 2.6Q (t.2B).

2, 48 (m.21'ri, 1.62 (m, 2H), 1.50-1.26 (+ m. 10B).

21 (b) [R-(R book.S zero)]-]2-hydroxy-3-2-(8-F phenyloctyl)phenyl]-3-(2-carboxycecy-5-ylmethyl) Thio) Propagia Awakening The above diester in a mixture of 3 ml of tetrahydrofuran and 2 ml of ethanol. A solution of 145 mg of Li was treated with excess LiOH in H2O. 3 hours at 23″ Afterwards, the solution was diluted with water and filtered. The filtrate was acidified and extracted with ethyl acetate. Lottery The output was washed with H2O, dried and the solvent was evaporated to give the title compound.

NMR (CDC13) 67, 58 (d.LH), 6.8.8 (d.IH), 4.57-4.42 (m.2H), 3.94 (d.LH) A 3.7 3 (d. IH).

Example 22 Specific examples of the composition of the present invention include the following. Active ingredients, e.g. The compound of Example 4, 13 or 14 was added to isoerosive saline solution at a concentration of 1 to 10 mg/ml. aerosolization (aerosol) from a nabulizer that is dissolved in olized) to deliver the desired weight of aerosolized drug.

Example 23 Furthermore, the following are listed as specific examples of the composition of the present invention. Active ingredients, e.g. 100 to 1000 mg of the compound of Example 4, 13 or 14 is added to a suitable carrier or is combined with 4 mg of chloropheniramine maleate along with additives.

abstract The present invention provides phenyl and heterogeneous compounds useful as leukotriene antagonists. Alkanoic acid compound having an arylthio substituent and a pharmaceutical composition containing the compound Regarding products. The present invention also provides for administering an effective amount of the above compound or composition. relates to a method for treating diseases caused by leukotrienes.

international search report −Rei−−＾−−−ms, K Ryo/ji91103922 Force United States Pennsylvania Old 9085, Villa Tsuno (, Brospek No. 154)

Claims (11)

[Claims] 1. Formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼I [In the formula, q is 0, 1 or 2; R1 is (L)a-(CH2)b-(T)c-B (wherein a is 0 or 1; b is 3-14; c is 0 or 1; L and T are independently oxygen, sulfur or CH2 (where q is 1 or 2) , L and T are not sulfur); and B is C1-4 alkyl, ethynyl, tri- Fluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl, and is optionally Br, Cl, CF3, C1-4 alkyl, C1-4 alkoxy, metal. phenyl optionally substituted with methylthio or trifluoromethylthio) ; R2 and A are independently H, CF3, C1-4 alkyl, C1-4 alkoxy selected from C, F, Cl, Br, I, OH, NO2 or NH2; or R1 or and A is H, and R2 is (L)a-(CH2)b-(T)c-B (wherein a, b , c, L, T and B have the same meanings as above); Y is COR3 or (CHX)n(CH2)p-Z (wherein R3 is OH, NH2 , aryloxy or C1-6 alkoxy; n is 0 or 1; p is 0 or 1; X is H, OH, C1-4 alkyl, C1-4 alkoxy or F; and Z is C OR3 or tetrazolyl); R is ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, m is 0 to 6; When m is not 0, R4 and R5 are independently hydrogen or C1-4 alkyl. , and may be in any position; W is the formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (wherein j is 0 to 6; and V is hydrogen, C1-4 alkyl, COR3, SO3H, SO2H, SO2NH2, COCH2OH, CHOHCH2OH or tetrazolyl, and R3 is as above Same meaning) is thienyl substituted with 1 to 3 groups represented by A compound or a pharmaceutically acceptable salt thereof. 2. q is 0, j is 0 or 1, m is 1, V is COR3, and Y is COR3. 2. The compound according to claim 1. 3. R2 is hydrogen, A is hydrogen, and R1 is dodecyl or 8-phenyloctyl The compound according to claim 2. 4. q is 0, j is 0 or 1, V is COR3, and Y is -CH2COR3 2. The compound according to claim 1. 5. R2 is hydrogen, A is hydrogen, and R1 is dodecyl or 8-phenyloctyl 5. The compound according to claim 4. 6. q is 0, j is 0 or 1, V is COR3, and Y is -CH(OH)COR 3. The compound according to claim 1, which is 7. R2 is hydrogen, A is hydrogen, and R1 is dodecyl or 8-phenyloctyl 7. The compound according to claim 6. 8.2-Hydroxy-3-[2-(8-phenyloctyl)phenyl]-3-[ (2-carboxythien-5-ylmethyl)thio]propionic acid or its pharmaceutical 8. The compound according to claim 7, which is an acceptable salt of the above. 9. q is 0 or 2, j is 0 or 1, V is COR3, and Y is -CH(OC 2. The compound according to claim 1, which is H3)COR3. 10. R2 is hydrogen, A is hydrogen, and R1 is dodecyl or 8-phenyloctyl 10. The compound according to claim 9, which is 11. q is 2, the compound 2-methoxy-3-[2-(8-phenyloctyl)phene Nyl]-3-[(2-carboxythien-5-ylmethyl)sulfonyl]propyl 11. The compound according to claim 10, which is an onic acid or a pharmaceutically acceptable salt thereof.