DD299186A5 - PHENYLENE-7-OXABICYCLOHEPTYL-SUBSTITUTED HETEROCYCLOAMIDE-PROSTAGLANDINANALOGA - Google Patents

Abstract

There are provided phenylene-7-oxabicycloheptyl-substituted heterocycloamide prostaglandin analogs of general formula (I) wherein m is 1, 2 or 3; n has the value 0, 1, 2, 3 or 4; Y represents an oxygen atom, a vinyl group or a single bond, with the proviso that when n is 0, Y represents a single bond; R is the group CO2H, the radicals CO2-alkali metal or CO2-lower alkyl, the group CH2OH, the radicals CONHSO2R3 or CONHR3a or a 5-tetrazolyl group, with the proviso that when R is a 5-tetrazolyl group, n is not 0 ; X represents an oxygen or sulfur atom or an NH group; R 1 represents a hydrogen atom, a lower alkyl, cycloalkylalkyl, saturated-heterocyclic, aromatic-heterocyclic-alkyl or amide radical, each of which is optionally substituted by an alkyl, aryl, cycloalkyl or cycloalkylalkyl radical; and R 2 represents a hydrogen atom, a lower alkyl, aryl or aralkyl group, or R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- to 8-membered ring, R 3 represents a lower alkyl, aryl or aralkyl group and R 3a represents a hydrogen atom, a lower alkyl, aroyl or aralkyl radical. These compounds are useful in the treatment of thrombotic and vasospastic disorders. Formula (I) {prostaglandin analogs; 7-oxabicycloheptane compounds; thrombotic diseases; vasospastic disorders}

Description

The present invention relates to phenylen-7-oxablcycloheptyl-substituted heterocycloamide prostaglandin analogs useful as drugs having an effect on the cardiovascular system, e.g. B. in the treatment of thrombotic and vasospastic diseases are suitable, which show a good in vivo stability and a good duration of action. The invention relates to the compounds of general formula I.

(I)

X *

and all stereoisomers thereof, in

m is 1,2 or 3;

η is 0,1,2,3 or 4;

Y represents an oxygen atom, a vinyl group or a single bond, with the proviso that when η is 0, Y is a single bond;

R is the group CO ₂ H, the radicals CO ₂ -alkali metal or CO ₂ -lower alkyl, the group CH ₂ OH, the radicals CONHSO ₂ R ³ or CONHR ³ ', or a 5-tetrazolyl group, with the proviso that when R is a tetrazolyol group, η does not have the value O; X represents an oxygen or sulfur atom or the group NH;

R ^{1 represents} a hydrogen atom, a lower alkyl, lower alkenyl, lower alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, saturated-heterocyclic, saturated-heterocyclic-alkyl, aromatic-heterocyclic, aromatic-heterocyclic-alkyl or amide radical wherein each radical is optionally substituted by an alkyl, aryl, cycloalkyl or cycloalkylalkyl radical;

R ^{2 represents} a hydrogen atom, a lower alkyl, aryl or aralkyl group, or R ¹ and R ² together with the nitrogen atom to which they are attached form a 5- to 8-membered ring;

R ^{3 is} lower alkyl, aryl or aralkyl; and

R ^{3i represents} a hydrogen atom, a lower alkyl, aroyl or aralkyl radical.

The invention thus relates to the compounds of the general formulas IA, IB and IC:

(IA)

η R ^- Il / C-N \ R ²

The invention also relates to a process for the preparation of the compounds of the general formula I in which compounds of the general formula Γ

Y- (CH.,) -R

in which R is not the group CO ₂ H or their alkali metal salts, are converted into their acid halide form and then the acid halides are reacted with an amine of the formula HNR ₁ R ₂ in a manner known per se to give products in which R is not CO ₂ H- Group, or to their alkali metal salts, and, if R is a lower-alkyl CO ₂ , be hydrolysed to obtain hydrolyzed products in which R is a CO ₂ H group and formed therefrom in a conventional manner alkali metal salts. The invention also relates to processes for the preparation of compounds of the general formulas IA, IB and IC.

The individual process steps for the preparation of these compounds are set out below.

The term "lower alkyl" or "alkyl" as used herein means straight and branched chain radicals of up to 12 carbon atoms, more preferably of 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert, butyl -, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-fynmethylpentyl, nonyl, decyl, undecyl, or dodecyl, the various branched-chain isomers thereof and the like, and such groups having 1,2 or 3 halogen substituents, an aryl substituent, an alkylaryl substituent, a haloaryl substituent, a cycloalkyl substituent or an alkylcycloalkyl substituent.

The term "cycloalkyl radical" includes saturated cyclic hydrocarbon radicals having from 3 to 12 carbon atoms, especially from 3 to 8 carbon atoms, including the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl groups may be substituted by halogen atoms, lower alkyl and / or lower alkoxy.

The terms "aryl radical" or "Ar" refer to monocyclic or bicyclic aromatic radicals having from 6 to 10 carbon atoms in the ring moiety, such as the phenyl or naphthyl group. The terms aryl (or Ar), phenyl or naphthyl include substituted aryl, substituted phenyl or substituted naphthyl radicals, where 1 or 2 substituents may be present on the phenyl or naphthyl radical, e.g. Niec! 'Alkylrestfi, trifluoromethyl, Halogenatorr: a (Cl, Br or F), Niederaikoxy-, alkylthio, alkylsulfinyl and / or Alkylsulfonylreste.

The terms "aralkyl radical", "arylalkyl radical" or "aryl lower alkyl radical" refer to lower alkyl radicals of the kind discussed above having an aryl substituent such as a benzyl group.

The terms "non-alkoxyalkoxy", "alkoxy" or "aralkoxyrost" include any of the foregoing lower alkyl, alkyl or aralkyl radicals which are attached to an oxygen atom.

The term "haloionatom" refers to chlorine, bromine, fluorine or iodine, with chlorine being preferred.

The term "saturated heterocycle" refers to a 5-, 6- or 7-membered saturated ring comprising 1 or 2 heteroatoms, such as nitrogen, oxygen and / or sulfur atoms, such as

O-

and the like.

The term "aromatic heterocyclic" or "heteroaromatic" refers to a 5- or 6-membered aromatic ring comprising 1 or 2 heteroatoms, such as nitrogen, oxygen or sulfur atoms, such as N,

and the like.

Preference is given to compounds of the general formula I in which m is 1 and η is 2, Y is a single bond, X is an oxygen atom, R is a COjH group, R ^{1 is} a substituted alkyl radical and R ^{2 is} a hydrogen atom or is an alkyl radical and Y- (C ^) _n -R is in the ortho or meta position.

The compounds of the general formula I in which Y is a single bond, η is 1,2,3 or 4 and X is an oxygen atom, can be prepared by using as starting compounds bromophenylalkylalkcholes of the general formula A

(A)

in which η is 1,2,3 or 4, is treated with a protecting group such as tert-butylchlorodiphenylsilane in the presence of an amine base such as triethylamine and an inert solvent in a manner known per se, thereby yielding the protected bromophenylalkyl compounds the general formula B

(CH-)

2'- N + l

-OPro

(B)

in which Pro represents a protecting group.

Protective group-forming compounds useful in the reaction with bromophenyl alcohol A include, for example

CH, CH, CH,

l 3/3 ι 3

Cl-Si-C CH

I II

CH ₃ CH ₃ CH ₃

(Chlordimethylthexylsilan)

CH, CH-I 3 ι 3

Cl-Si-CCH

II CH ₃ CH ₃

(Chloro-dimethyltert.-butylsilane)

(Tert-butylchlorodiphenylsilane).

The provided with a protective group Compound B is then mbtalliert by treatment with t-C ₄ H ₉ Li or ^ C ₄ H ₉ Li in the presence of diethyl ether or tetrahydrofuran at about 100 ⁰ C to about ⁰ ° C or a Grignard reaction by Subjected to treatment with magnesium in the presence of an inert organic solvent such as tetrahydrofuran (THF) or diethyl ether. Subsequently, with (exo) octa, hydro-5,8-epoxy-1 H-benzopyran-3-ol or (exo) octahydro-4, T-epoxyisoben7ofuran-1-ol (which is prepared according to US Patent 4,143,054) of the general formula C

- O

condensed, wherein the molar ratio of C: B in the range of about 1: 2 to about 1: 4, in the presence of an inert organic solvent such as THF at a temperature in the range of about -78 to about 0 ° C. The condensed 7-oxabicycloheptane compounds of the general formula II are obtained

CH ₂ OH

The condensed compound II is then hydrogenated by treatment with hydrogen in the presence of a catalyst such as palladium hydroxide on charcoal in acetic acid or an inert organic solvent such as ethyl acetate. Alcohols of the general formula III are obtained

^(CH 2 ⁾ n ₊ r ^0Pro

CH ₂ OH

When the protecting group (Pro) in the compounds of general formula III is a thexyldimethylsilyl or tert-butyldimethylsilyl group, in an alternative process the alcohol III may be acetylated by treatment with acetyl chloride in the presence of pyridine and methylene chloride to acetylate the free alcohol. The acetate thus formed becomes

treated with hydrofluoric acid in the presence of acetonitrile. Cleavage of the silyl protecting group thus gives a compound of general formula IHA

-OH

(CH ₂ )

< ^CH 2> n ₊ 1

OCCH.

The compounds of general formula III A are treated with a protecting group-forming compound such as tert-butyldiphenylsilyl chloride in the presence of 4-dimethylaminopyridine and triethylamine and methylene chloride to form the protecting group. The acetate group is removed by reaction with aqueous hydroxide in tetrahydrofuran or methyllithium in the presence of an inert solvent such as diethyl ether. Compounds of the general formula HIB are obtained,

^(CH 2> m

CH ₂ OH

in which Pro is a tert-butyldipidylsilyl group.

The deprotected alcohol Hl or III B is then subjected to Jones oxidation to give a solution of the deprotected alcohol III or III B in acetone cooled from about -10 to about 25 ^° C with Jones. Reagents (CrO ₃ , dissolved or suspended in aqueous sulfuric acid, prepared according to Fieser & Fieser, "Reagents for Organic Synthesis", Vol 1 [1967], p 142) is reacted to give the acids of general formula IV

^(CH 2> n ₊ l- ° ^Pro

The acid IV is subjected to a carbodiimide coupling reaction in an inert organic solvent, such as tetrahydrofuran, with amine hydrochlorides of the general formula D

Ii λ HCl-H-N-CH-C-OR

> 2 HO

wherein R ^{4 represents} a lower alkyl group such as a methyl or ethyl group or an arylalkyl group such as a benzyl group in the presence of dicyclohexylcarbodiimide (DCC) or (3-dimethylaminopropyl) -3-ethylcarbodiimide (WSC) and 1-hydroxybenzotriazole and triethylamine under one inert atmosphere, such as argon. A molar ratio of D: IV of about 1.2: 1 to about 1: 1 is used to obtain hydroxyamides of the general formula V

^(CH 2> n ₊ r ^OPro

O

CN-CH-COR ^ OH CH ₂ OH

The hydroxyamide V is then subjected to a cyclizing condensation in which a solution of compounds of general formula V in an inert organic solvent such as tetrahydrofuran, acetonitrile or chloroform under an inert atmosphere such as argon with triphenylphosphine (in a molar ratio of compounds of general formula V: Tiiphenylphosphine from about 1: 1 to about 5: 1) and tetrachloromethane in the presence of an amine base such as triethylamine or diisopropylethylamine. Oxazolines of the general formula VI are obtained

(Vl)

Oxazoline VI is oxidized with manganese dioxide or preferably nickel peroxide. Oxazoles of the general formula VII are obtained

(VII)

The oxazole VII is converted to the corresponding acid by the addition of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide to form the corresponding alkali metal salt. Then neutralized with an acid such as dilute hydrochloric acid or oxalic acid and receives the acids of general formula VIII

^(CH 2

(VIII)

The acid VIII is converted to the corresponding acid chloride by reaction with oxalic acid chloride, optionally in the presence of catalytic amounts of dimethylformamide and a nonpolar solvent such as benzene, toluene or methylene chloride. The acid chloride thus formed is cooled in an inert solvent such as methylene chloride or toluene to a temperature in the range of about -1O ⁰ C to about + 1O ⁰ C. An amine base such as triethylamine or pyridine and amines of general formula E are added

"1

(E)

or a salt thereof in a molar ratio of E: VIII ranging from about 1.1: 1 to about 1.5: 1. Oxazoles of general formula IX are obtained

(CH.

(IX)

The silyl ether IX is then deprotected by reaction with hydrofluoric acid in the presence of acetonitrile and methylene chloride and subjected to Jones oxidation using the methods described above. Oxazoles of the general formula ID of the invention are obtained

In an alternative method, compounds of general formula I in which Y is a single bond and X is an oxygen atom are prepared starting from alcohol III by treating its hydroxyl group by treatment, for example with a solution of acetic anhydride, pyridine and 4-dimethylaminopyridine with a Protective group provides. Obtained with a protective group alcohols of general formula X.

^(CH 2> m

<CH ₂ ) _{n + 1} -oPro

CH ₂ OCCH ₃

As a further possibility, the compounds of the general formula II can be provided with a protective group by addition of, for example, a solution of acetic anhydride and pyridine. Compounds of general formula XI are obtained,

which are then hydrogenated as above. The compounds of general formula X are obtained.

The deprotected alcohol X is subjected to Jones oxidation according to the methods described above. This gives a crude acid which is freed from the protective group by reaction with aqueous hydroxide solution in the presence of an inert organic solvent such as THF and then z. By esterification with a diazoalkane such as diazomethane or with an acidified alcohol such as HCI in methanol. The esterified alcohols of general formula XII are obtained

CO alkyl

CH ₂ OH

Subsequently, the esterified alcohol XII is subjected to Jones oxidation. The acids of general formula XIII are obtained

< ^CH 2> m

(CH ₂ ) _n -CO ₂ alkyl

(XlIl)

The acid XIII is then subjected to a carbodiimide coupling reaction with the amine hydrochloride D (as in coupling the acid IV) as described above, in which R ^{4 is} a benzyl group. Amides of the general formula XIV are obtained

(CH ₂ ) _n -CO ₂ alkyl

C-N-CH - COR

Il I I

0 H CH ₂ -OH

The amide XIV is subjected to a cyclizing condensation (by the method similar to the cyclizing condensation of amide V). Oxazolines of general formula XV are obtained

( ^C H ₂ ) _n -CO ₂ alkyl

which are subjected to oxidation with manganese dioxide or preferably nickel peroxide. Oxazoles of the general formula XVI are obtained

(CH ₂ ) _n -CO ₂ alkyl

The oxazole XVI is then deprotected by R ⁴ , for example by treatment with palladium hydroxide on charcoal and hydrogen in the presence of an inert solvent such as ethyl acetate. The corresponding acids of the general formula XVII are obtained

alkyl

(XVII)

CO ₂ H

The acid XVII is then converted to the corresponding acid chloride, using a method similar to that described above for the acid VIII. The resulting acid chloride is treated with the amine E (molar ratio ErXVII) by a method; wherein the process and the above in the case of the acid VIII are similar to those described above for the acid Viii. The esters are given the general formula IE

(CH ₂ ) _n -co ₂ alkyl

O-

The ester IE can be hydrolyzed by addition of an alkali metal base followed by addition of aqueous acid. The corresponding acid ID is obtained.

The compounds of the general formula I in which Y is an oxygen atom and X is an oxygen atom can be prepared by reacting a bromophenol A ¹

with a protecting group-forming compound such as chloro-tert-butyldimethylsilan, benzyl bromide or bromomethyl methyl ether, preferably benzyl bromide or bromomethyl methyl ether for ortho-bromophenol in a conventional manner. The protected bromophenyl compound B ^{1 is obtained} ,

Opro

where Pro means a protecting group.

For example, compounds useful in the reaction with bromophenol A ¹ include the compounds listed above in the case of providing alcohol A with protecting groups.

The deprotected compound B ¹ is then metalated by a method similar to the method of metalating B using n-butyllithium in THF. The condensed 7-oxabicycloheptane compounds of the general formula XXII are obtained

(XXII)

The condensed compound XXII is then hydrogenated by treatment with hydrogen in the presence of a catalyst such as palladium on charcoal in acetic acid. If Pro is a silyl or methoxymethyl ether protecting group, alcohols of general formula XXIII are obtained. If Pro is a benzyl group, the compounds of general formula XXIV are obtained directly

^<CH 2> m

ΟΓνο

(XXlIl)

CH ₂ OH

When Pro is a shyl protecting group, Compound XXIII is deprotected by addition of, for example, a solution of acetonitrile with hydrofluoric acid. The deprotected alcohols of the general formula XXIV

(CH.)

2 'm

(XXIV)

CH ₂ OH

Alcohol XX.V wi. d followed by addition of a solution \ on alcohol XXIV in tetrahydrofuran with a molar equivalent of sodium hydride or 1 to 4 equivalents of a carbonate base such as potassium carbonate. A phenolate solution is obtained which is obtained by addition of a haloalkanoic ester of the general formula F

Hal- (CH ₂ ) _n -CO ₂ alkyl

1 is displaced in the opposite Wait an inert organic solvent such as THF or dimethylformamide or dimethoxyethane: in a Molve ^r ratio of F: XXIV of from about 1: 1 to approximately 3 minutes. This gives esters of the general formula XXV

Ö (CH ₂ ) _n -co alkyl

CH ₂ OH

As another option, when the protecting group in the general formula XXIII is methoxymethyl, the free hydroxyl group is provided with a benzyl ether protecting group. The methoxymethyl protecting group is removed by addition of aqueous acid. The resulting phenol is alkylated with ethyl bromoacetate as described above in the alkylation of compounds of general formula XXIV. The benzyl protecting group is then removed by hydrogenation with palladium hydroxide and hydrogen. Compounds of general formula XXV are obtained.

An alternative preparation of alcohol ester starting compounds of general formula XXV is described in US Pat. No. 4,536,513.

The alcohol ester of the general formula XXV is subjected to Jones oxidation as described above in the oxidation of the alcohol III. Acids of the general formula XXVI are obtained

^(CH 2> m

⁰ (CH ₂ ) _a -CO ₂ alkyl

(XXVI)

COOH

The XXVI acid is used to prepare compounds of the general formulas IF and IG according to the procedures described above for the conversion of acid XIII into the ester IF and the acid IG.

O- (CH ₂ ) _n -co alkyl

0- (CHJ-COH

The compounds of the formula I in which Y represents a single bond or an oxygen atom and X is a sulfur atom can be prepared starting from acid XIiI or XXVI by reacting the acid XIII or XXVI with oxalyl chloride, optionally in the presence of catalytic amounts of dimethylformamide in methylene chloride , The corresponding acid chloride is obtained, which is converted by reaction with ammonia into the amide of the general formula XXVII.

< ^CH 2> m

Y- (CH ₂ ) _n -CO ₂ alkyl

(XXVIl)

Another possibility is the reaction of the acids XIII or XXVI with an alkyl chloroformate in the presence of an amine, such as triethylamine. The mixed anhydride is obtained, which is converted by reaction with a solution of ammonia in methanol into the amides of the general formula XXVII.

The amide XXVII is then treated with phosphorus pentasulfide (PjS ₆ ) or Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide). The corresponding thioamides of the general formula XXVIII are obtained,

^(CH 2> m

(XXVIII)

CNH, O S

soft with pyruvic acid

(Br-CH ₂ -C -CO ₂ H)

in a polar solvent such as dimethylformamide in the presence of a base such as K ₂ CO ₃ , using a molar ratio of XXVIII to bromine pyruvic acid of from about 1: 1 to about 1: 1.5. Thiazolines of general formula XXIX are obtained

Y- (CH ₂ ) _n -CO ₂ alkyl

(XXlX)

The thiazoline XXIX is then dehydrated by adding a sulfonyl chloride such as methanesulfonyl chloride in the presence of a base such as triethylamine. Thiazole acids of the general formula XXX are obtained

) _n -CO ₂ alkyl

(XXX)

CO H O s "

then a carbodiimide coupling reaction with an amine of the general formula E.

HN-R ¹ Π ²

in the presence of DCC or WSC under an inert atmosphere, such as argon, using a molar ratio of E: XXX of from about 1: 1 to about 2: 1. Amides of the general formula IH are obtained

) _n -CO ₂ alkyl

Alternatively, the acid XXX may be activated by conversion to the corresponding acid chloride by treating the acid XXX with oxalyl chloride in a non-polar solvent such as benzene. The acid chloride is then linked with the amine E with an amine base, such as triethylamine or pyridine to give compounds of the general formula IH

The compounds of general formula I in which Y is a single bond or oxygen atom and X is NH are prepared starting from amide XXVII, which is dehydrated by heating at about 80 to 120 ^° C. in the presence of pyridine, oxalic chloride and dimethylformamide. Nitriles of the general formula XXXI are obtained

) _n -co ₂ alkyl

(XXXl)

CN

The nitrile XXXI is subjected to an addition reaction by addition of hydrochloric acid and methanol. The corresponding imino ether salts of the general formula XXXII are obtained

<y

Y- (CH

alkyl

(XXXlI)

The imino ether XXXII is reacted with amines of the general formula G in the presence of a tertiary amine base such as triethylamine, diisopropylethylamine and the like.

H ₂ NCH ₂ C-OPm · HCI

where Pro is a protecting group such as a -CH ₂ CH ₂ Si (CH ₃ I ₃ - or -CH ₂ OCH ₂ CH ₂ Si (CH ₃ ) ₃ group to give esters of general formula XXXIII

Y- (CH ₂ ) _n -CO ₂ alkyl

(XXXMl)

N-CH ₀ -CO ₀ PrO // 2 2

CI OCH ₀

which are mixed with a basic salt, such as potassium, potassium tert-butoxide or sodium ethoxide in the presence of ethyl formate. Ester salts of the general formula XXXIV are obtained

(CH ₀ )

Y- (CH ₂ ) _n -CO ₂ alkyl

N-C-CO ₀ PrO 11 2

C CH

OCH ₃ OK The ester XXXIV is dissolved in ammonia. Imidazoles of the general formula XXXV are obtained

(XXXIV)

(XXXV)

The imidazole XXXV is deprotected by treatment with tetra-n-butylammonium fluoride. The acid XXXVI is obtained

Y- (CH ₂ ) _n -CO ₂ alkyl

(XXXVl)

HCl

The XXXVI acid is subjected to a coupling reaction by converting the compound of general formula XXXVI into the acid chloride (following the procedure used to convert compounds of general formula XVII to compounds of general formula IE) followed by amine E in Presence of an amine base such as pyridine or triethylamine under an inert atmosphere, such as argon, using a molar ratio of E: XXXVI of from about 0.8: 1 to about 1.2: 1. Amides of the general formula IJ are obtained

) _n -co ₂ alkyl

CNR ^J OR ²

The compound of the general formula I in which η has the value 0 and Y is a single bond, namely benzoic acids or their derivatives of the general formula IK

can be prepared by reacting bromobenzyl alcohol of the formula A ²

OH

starting, which is reacted with a protecting group-forming compound such as tert-butylchlorodiphenylsilane in the presence of 4-dimethylaminopyridine and an amine base such as triethylamine and an inert solvent such as methylene chloride in a conventional manner. Obtained with a protective group Brombenzylverbindungen the general formula B ^2nd

CH ₂ -OPrO

where Pro means a protecting group.

Examples of suitable protective group-forming compounds correspond to the compounds listed above in the reaction with bromophenylalkyl alcohol A.

The protected compounds of the general formula B ² are then metallated by addition of tert-C ₄ HgLi or nC ^ gLi in the presence of diethyl ether or tetrahydrofuran at a temperature of about -100 ° to about ⁰ ° C. (or a Grignard reagent). Subjecting the reaction to magnesium in the presence of an inert organic solvent such as tetrahydrofuran (THF) or diethyl ether). It is then condensed with (exo) octahydro-5,8-epoxy-

1 H-benzopyran-3-ol or (exo) octahydro-4,7-epoxyiso-benzofuran-1-oil (prepared according to the procedure described in US Pat. No. 4,143,054) of the general formula C.

(CH

(C)

wherein a molar ratio of C: B ² of about 1: 2 to about 1: 4 is used. The reaction is carried out in the presence of an inert organic solvent such as THF at a temperature of about -78 to about ⁰ ° C. The condensed 7-oxabicycloheptane compounds of the general formula II A are obtained

CH, -OPro

OH

CH ₂ OH

The compounds of the general formula IIA are provided with a protective group by addition of, for example, a solution of acetic anhydride and pyridine in the presence of 4-dimethylaminopyridine. Compounds of the general formula XIA are obtained

^H ^ · CH ₂ -OPrO

^(CH 2> rn-1- ^C

/ A

OCCH

(XIA)

CH-OCCH-

ö ο

The deprotected alcohol XIA is subjected to Jones oxidation by methods described above. A crude acid is obtained, which is freed from the protective group by reaction with aqueous hydroxide in the presence of an organic solvent, such as THF, and then, for. B. is esterified by treatment with diazoalkane, such as diazomethane or acidified alcohol. The alcohol esters of the general formula XIIA are obtained.

O-alkyl

OH

(XIIa)

CH ₂ OH

The alcohol ester is then subjected to hydrogenation as described above, whereby the hydroxyl group is split off. Alcohol esters of the general formula XIIB are obtained

(XIIB)

Then the alcohol ester XIII is subjected to a Jones oxidation. The acid of general formula XIIIA is obtained

CO ₂ alkyl

(XlIlA)

The acid XIIIA is then used in place of the acid XIII to produce the corresponding benzoic acids of the general formulas IK, including IL, IM and IN.

co ₂ alkyl

co ₂ alkyl

C0 ₂ alkyl

The esters IE, IF, IH ₁ IJ ₁ IL ₁ IM and IN can be converted into the (acid speaking, the general formula IO

Y- (CH,) -COOH ζ η

by adding the esters with a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide. The corresponding alkali metal salts are obtained. Then neutralized with uiner acid, such as dilute hydrochloric acid or oxalic acid. The acids of general formula 10 are obtained

The compounds of the general formula I in which R is CONHSO ₂ R ³ , ie compounds of the general formula IP

) _n -CONHSO ₂ R ³

can be prepared by reacting the acid IO with a sulfonamide of the general formula H

H ₂ N ^ -R ₃ O

in the presence of a coupling agent such as carbonyldiimidazole or WSC in the presence of an amine such as dimethylaminopyridine under an inert atmosphere such as argon, using a molar ratio of H: IK of from about 0.8: 1 to about 1.2: 1. Sulfonamides of the general formula IP are obtained.

The compounds of general formula I in which R represents a 5-tetrazolyl group and Y represents a single bond, d. H. Compounds of general formula IQ in which Y represents a single bond,

Ν-Ν

'Ν-Ν H

(IQ)

can be prepared by subjecting the esters IE, IH, IJ, IL, IM or IN to reduction with a hydride reagent such as lithium borohydride or sodium borohydride. Alcohols of the general formula XXXVII are obtained

Y- (CH ₂ ) _n -OH

(XXXVII)

which are converted to the bromides by treatment with triphenyiphosphonium bromide in an inert solvent such as toluene. The bromides are then converted to nitriles of general formula XXXVIII by addition of an alkali metal cyanide in a polar solvent such as methanol / water.

Y- (CH ₂ J _n -C = N

m \

(XXXVlIl)

X.

C-N

The compounds of general formula I in which R represents a 5-tetrazolyl group and Y represents an oxygen atom, i. Compounds of the general formula IQ in which Y represents an oxygen atom can be prepared by dissolving the

Alcohol XXIII converted into ethers of the general formula XXXIX, by methods which are described above in the conversion of compounds of general formula XII in the esters IE, IH and IJ

(XXXIX)

into the nitrile XXXVIII by deprotection, e.g. with hydrofluoric acid, and subsequent alkylation with the halogenonitriles of the general formula J

X- (CH ₂ I _n -CN

in the presence of a base such as sodium hydride or potassium carbonate.

The nitrile is then subjected to a cycloaddition reaction by reacting compounds of the general formula XXXVIII with sodium azide in the presence of ammonium chloride, dimethylformamide and lithium chloride at ainer temperature of about 100 ⁰ C to about 13O ⁰ C. The compounds of the general formula IQ are obtained.

The Bromphenylalkylalkohol A, from which one starts, can be prepared by reacting aldehydes of the general formula M

CHO

a Wittig reaction with (Ce

subjects. This gives esters of the general formula N.

CH = CH ₂ CO ₂ CH ₃

br

which are then subjected to a reduction dv double bond by addition of hydrogen in the presence of a rhodium on alumina catalyst in the presence of methanol. Ester of the general formula O is obtained

(CH ₂ ) _n -CO ₂ CH ₃

The ester O is then reduced by adding diisobutylaluminum hydride in the presence of toluene as the solvent.

The alcohol is obtained A.

The compounds of the general formula I have four asymmetric centers which are indicated by the stars in the general formula I. However, it is apparent that the individual formulas given above in which no stars are included represent all possible stereoisomers. All different stereoisomeric forms fall under dun

Scope of the invention.

The various stereoisomeric forms of the compounds of the general formula I, namely the cis-exo, cis-endo and all trans forms and the stereoisomeric pairs can be prepared using starting compounds and according to the processes of US Pat. No. 4,143,054. Examples of such stereoisomers are listed below:

(Cis-endo)

(Cis-exo)

(Trans)

Y- (CH ₂ J _n -R

(Ib)

(lc) (ld)

(trans) The nucleus in the individual compounds of general formula I is used for convenience as

played. It should be noted that the nucleus of the compounds of the general formula I also as ^ O

can be played.

The compounds of general formula I are thromboxane receptor antagonists and, as such, are valuable inhibitors of thromboxane-receptor mediated effects. The term "thromboxane receptor antagonist" includes compounds which are the so-called thromboxane A ₂ receptor antagonists, thromboxane A ₂ antagonists, thromboxane A ₂ / prostaglandin endoperoxide antagonists, TP receptor antagonists. Antagonists or thromboxane antagonists.

The compounds of general formula I are also suitable as inhibitors of platelet function, i. H. for the prevention and treatment of disorders by thrombotic occlusions which are either complete or partial, e.g. Arterial thrombosis, including coronary, cerebral, ophthalmic, hepatic, mesentoral, renal and peripheral arteries or vascular or organ transplants, unstable angina, transient ischemic attacks or intermittent claudication. They are valuable for preventing thrombosis due to vascular injury in diagnostic or therapeutic procedures such as endarterectomy or angiography. The compounds are useful in the therapy or prophylaxis of disorders characterized by platelet consumption and / or activation, including platelet activation, dysfunction and / or extracorporeal circulation loss, the use of radiographic contrast agents, thrombotic thrombocytopenia purpura, disseminated intravascular coagulation, purpura fulminans, haemolytic transfusion reactions or hemolytic uremic syndrome. The compounds can be used to treat venous thrombosis or embolism, including pulmonary embolism, deep venous thrombosis, hepatic venous thrombosis, and renal vein thrombosis. The compounds of the general formula I are suitable as inhibitors of arterial or venous vasoconstriction. Accordingly, they are useful in the prevention of vasoconstriction associated with unstable angina, chronic stable angina and variants or with Prinzmetall angina, Raynaud's syndrome, migraine headache, vasospasm of the coronary, cerebral, ophthalmic, hepatic, mesenteric, renal and peripheral arteries Vascular grafts or vascular injuries associated with surgical or traumatic events. High pressure in pregnancy, hepatorenal syndrome and pulmonary hypertension are further examples of vasoconstrictive disorders that can be treated with the compounds of the invention.

The compounds of the invention are useful as inhibitors of bronchoconstriction, i. Hypersensitivity of the respiratory tract, allergic bronchospasm, asthma and bronchoconstrictive reactions to environmental stimuli, infectious, harmful or mechanical stimuli.

The compounds of general formula I are useful as inhibitors of ischemic and reperfusion injury to various tissues, including myocardium, skin, brain, intestine or kidney, alone or in combination with other agents intended to restore blood flow. For example, these compounds can be used to improve postischemic myocardial function and reduce the size of myocardial infarction. Ischemia caused by decreased blood flow during diagnostic or therapeutic procedures can be successfully treated with these compounds, for example, they reduce myocardial stunning observed after bypass surgery. Furthermore, they may be useful for reducing the gum damage caused by a stroke.

The compounds of general formula I may also be useful for the prophylaxis or therapy of other conditions including burns, diabetic retinopathy and tardive dyskinesis. The compounds may also be useful for enhancing diuretic-induced diuresis.

Further, the thromboxane receptor antagonists of general formula I can be used with a thrombolytic agent such as t-PA, streptokinase, urokinase, prourokinase or anisoylated plasminogen streptokinase activator-KomDiex (APSAC) within 6 hours after a myocardial infarction. In such a case, the thrombolytic agent may be used in amounts conventionally employed, as described, for example, in the Physicians' Desk Reference for reducing post-ischemic myocardial injury.

The compounds of general formula I may be administered orally or parenterally to various mammalian species suffering from such diseases as humans, cats, dogs and the like in an effective amount in the dosage range of from about 0.1 to about 100 mg / kg, preferably about 0, 2 to about 50 mg / kg, and more preferably about 0.5 to about 25 mg / kg (or about 1 to about 2500 mg and preferably about 5 to about 2000 mg) in a single dose or in 2- to 4-fold divided daily. Poses are administered.

The active ingredient may be used in a composition such as tablets, capsules, solutions or suspensions containing from about 5 to about 500 mg per unit dose of a compound or mixture of compounds of general formula I or in topical wound healing form (0.01 to 5 wt % of the compound of general formula 1.1 to 5 treatments daily). The compounds of general formula I may be prepared conventionally with a physiologically acceptable vehicle or carrier, diluent, excipient, preservative, stabilizer, flavoring agent and the like, or with a topical carrier such as Plastibase (mineral oil gelled with polyethylene) such as that introduced corresponds to pharmaceutical practice. As already discussed above, various compounds also serve as intermediates for other compounds of general formula I.

The compounds of general formula I may also be administered topically to treat peripheral vascular diseases. In such cases, they can be made into a cream or ointment. The following examples represent preferred embodiments of the invention. Unless otherwise indicated, all temperatures are based on ⁰ C.

embodiments

example 1

[1S- (1a, 2a, 3a, 4a)] - 2 - [[3- [4 - [[(4-cyclohexylbutyl) -amlno] carbonyl] -2-oxazolyl] -7-oxablcyclo [2.2.1] hept-2-yl] -r.iethyl] -phenylpropansäure

A. 3- (2-Bromophenyl) -2-propoic acid methyl ester

A suspension of 46.8 g of (14OmMoI) methyl triphenylphosphoranylidene acetate (ex Aldrich) in 250 ml of dry tetrahydrofuran (THF) distilled over potassium / benzophenone was added dropwise with stirring at room temperature for 30 minutes at room temperature with 25.0 g (135 mmol) 2-bromobenzaldehyde. The reaction was mildly exothermic and the mixture became homogeneous. The resulting solution was stirred for 18 hours and then evaporated under reduced pressure. An oily solid was obtained. This was slurried with 250 mL of hexane and filtered to remove solid triphenylphosphine oxide. The filtrate was evaporated under reduced pressure and the resulting oil was passed through a silica gel layer (Merck silica gel).

of 9.5 x 2.0 cm and eluted with ethyl acetate / petroleum ether 1: 4. The eluent was evaporated under reduced pressure. An oil was obtained. The crude oil was purified by a bulb-to-bulb distillation at 125-135 ° C and about 0.5mm. 32.0 g (133 mmol, 98%) of the title acrylate were obtained as a pale yellow liquid.

B. 2-Bromphanylpropansäure methyl ester

A mixture of 14.0 g (58.1 mmol) of the acrylate of Section A and 750 mg of catalyst of 5% rhodium on alumina (MCB) in 150 ml of methanol (from Burdick and Jackson) was stirred for 3 hours under a hydrogen atmosphere (balloon) until the starting compound was used up (DC). The reaction mixture was passed through a 4 μηπ polycarbonate membrane and the filtrate was evaporated under reduced pressure. An orange oil was obtained. The oil was dissolved in 100 ml of diethyl ether, washed with 50 ml of saturated sodium bicarbonate solution and 50 ml of brine, dried over magnesium sulfate and evaporated under reduced pressure. 13.7 g (56.4 mmol, 97%) of the title compound were obtained as a pale yellow liquid.

C. 2-bromophenylpropanol

A solution of 13.6 g (56, OmMoI) of the compound of Section B in 75 mL of molecular sieve-dried toluene (from Burdick and Jackson) was incubated at -78 ° C with 118 mL (118 mmol) of a 1.0 M diisobutyaluminum hydride solution in toluene ( from Aldrich). The mixture was stirred at -78 ⁰ C for 2 hours and heated for 2 hours to ⁰ ° C. The orange solution was slowly added with 10 ml of 6N HCl and then faster with 100 ml of 6 N HCl. The mixture was stirred for a further 10 minutes and placed in 50 ml of diethyl ether. The organic phase was separated with 2x 100 mL 1NHCl and 100 mL brine, dried over magnesium sulfate and evaporated under reduced pressure. This gave 12.0 g (55.8 mmol, 100%) of the title compound as a colorless oil.

D. 1-Bromo-2- [3 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] propyl] benzene

A solution of 12.0 g (55.8 mmol) of the compound of Section C, 15.3 (55.8 mmol) of tert-butylchlorodiphenylsilane (ex Aldrich) and 8.6 ml (82 mmol) of calcium hydride distilled triethylamine in 100 ml 200mg (1.6 mmol) of 4-dimethylaminopyridine (ex Aldrich) was added to dry methylene chloride distilled over phosphorus pentoxide. The reaction mixture was stirred for 4 hours at room temperature and then treated with 100 ml of hexane. The resulting slurry was filtered to remove triethylamine hydrochloride. The filtrate was concentrated under reduced pressure and the resulting oil was purified by flash chromatography through 12 x 9 cm Kieselgol of Morck with diethyl ether / hexane 1:19. This gave 23.2 g (51.2 mmol, 92%) of the title compound as a colorless oil.

dimethanol

A solution of 23,0g (50,8 mmol) of the compound from Part D in 75ml of potassium / benzophenone-dried diethyl ether, which was cooled to ⁰ -10o C, was about 20 minutes dropwise with 54 ml (92 mmol) of 1 , 7 M tert-butyllithium solution in pentane (from Aldrich). The reaction mixture was stirred for 15 minutes at -100 ⁰ C and warmed to O ⁰ C for 30 minutes. The resulting solution was cooled to -78 ⁰ C, with 40 ml of dry, distilled from ketyl THF and then a solution of 3,40g (21,8mMol) [3aR- (3aa, 4a7ß, 7aa)] - octahydro-4,7- epoxyisobenzofuran-1-ol in 20% dry THF for 5 minutes. The reaction mixture was warmed to ⁰ ° C., stirred for 1 hour, treated with 10 ml of water and partitioned between 200 ml of water and 100 ml of ethyl acetate. The organic phase was separated and the aqueous phase extracted again with 100 ml of ethyl acetate. The combined organic extracts were washed with brine (200 ml) and dried over magnesium sulfate. An oil was obtained. The crude oil was purified by flash chromatography through Merck 11 x 12cm silica gel with ethyl acetate / petroleum ether 1: 4 and then ethyl acetate / petroleum ether 4: 1. This gave 9.81 g (18.5 mmol, 85%) of the title compound as an oil.

F. [I methanol

A mixture of 8.5 g (16 mmol) of the compound of Section E and 15 g of wet palladium hydroxide, 20% on carbon (from Aldrich) in 100 mL of reagent grade ethyl acetate, was shaken for 42 hours in a Parr apparatus under 50 psi of hydrogen pressure. The resulting mixture was passed through a Buchner funnel and then through a Buchner funnel

Filtered 4 pm polycarbonate membrane filter. The filtrate was evaporated under reduced pressure and the resulting oil was purified by flash chromatography through 10χ 15cm Merck silica gel with ethyl acetate / petroleum ether 1: 2. This gave 2.07 g (4.03 mmol, 25%) of the title compound as a colorless oil.

G. tlS- (1a, 2a, 3a4a)] - 2 - [[2- [3 - [[(1,1-dimethylmethyl) diphenylsilyl] oxy] propyl] phenyl] methyl] -7-oxabicyclo - [2.2.1] heptane-3-carboxylic acid

A solution of 2.07 g (4,03mMol) of the compound from Part F was cooled in 20 mL of reagent grade acetone to ⁰ ° C and (with 3.5ml 2.6M Jones reagent see. For the preparation of Fieser and Fieser, "Reagents for Organic 1, page 142. The mixture was stirred for 1.5 hours, added with 2 ml of isopropanol and stirred for 15 minutes The resulting green slurry was filtered through a pad of celite and the filtrate was concentrated under reduced pressure The residue was partitioned between 30 mL of water and 30 mL of diethyl ether, the organic layer was separated, washed with brine (30 mL), dried over magnesium sulfate and evaporated under reduced pressure to give 2.10 g (3.98 mmol, 99%) of the crude Title compound as a colorless oil.

H. [1S- (1α, 2α, 3α, 4α)] - 2- [t [2 - [[2- [3 [[(1,1-dimethylthyl) diphenylsilyl] oxy] propyl] phenyl] -mθthvl] -7 · oxabicyclo [2.2.1] hθpt · 3-yl] carbonyl] -amlno] -3-hydroxy propane-acid methylester

A solution of 2.00 g (3.79 mmol) of the crude Compound G compound in 30 mL of dry Ketyl-distilled THF was successively charged at ⁰ ° C. with 512 mg (3.79 mmol) of 1-hydroxybenzotriazole hydrate (ex Aldrich). , 590 mg (3.79 mmol) of L-serine methyl ester hydrochloride (ex. Aldrich), 1.1 ml (8.6 mmol) of triethylamine distilled over calcium hydride and after

Added 781 mg (3.79 mmol) of dicyclohexylcarbodiimide (ex Aldrich) for 5 minutes. The mixture was stirred at ⁰ ° C. for 3 hours, warmed to room temperature for 16 hours and admixed with 15 ml of ethyl acetate. The resulting slurry

was filtered and the filtrate was evaporated under reduced pressure. An oil was obtained. The crude product was purified by flash chromatography through 15 x 5cm Merck silica gel with ethyl acetate. This gave 1.98 g (3.15mMoi, 83%) of the title compound as a white foam.

I. [1S * (1α _(2α, 3α, 4α)] - 2- [2 - [[2 [3 · _{[[(1/1-DImethylethvl)} dlphenvl8ilv)] · oxv] · propvl] · phenvl] · Methyl ] -7 · oκablcyclo · [2.2.1] hept · 3 · yl] -4,5-dlhydro-4-oxazolecarboxylic acid methylaster

A mixture of 1.91 g (2.96 mmol) of the compound of Section H and 2.33 g (8.88 mmol) of triphenylphosphine (ex AlcHch) in 15 mL of molecular sieve-dried acetonitrile (ex Burdick and Jackson) was stirred until homogeneous and then first with 1.5 ml (8.6 mmol) of diisopropylethylamine (ex Aldrich) and then with 0.86 ml (8.9 mmol) of carbon tetrachloride. The reaction was mildly exothermic and was cooled by a room temperature water bath. The resulting solution was stirred for 16 hours at room temperature, treated with 50 ml of ethyl acetate and then 50 ml of saturated aqueous sodium bicarbonate solution. That is, the organic layer was separated, washed with 20 ml of brine, dried over sodium sulfate and evaporated under reduced pressure. You got a dark oil. The crude product was purified by flash chromatography through 20 x 5 cm Merck silica gel with ethyl acetate / petroleum ether 2: 1. 1.24 g (2.03 mmol, 69%) of the title compound was obtained as a yellow oil.

J. Nickel peroxide oxidate solvent

The nickel peroxide oxidizing agent was prepared according to K. Nakagawa and co-workers, in J. Org. Chem., Vol. 27 (1962), p. 1597. A solution of 139 g (0.40 mol) of nickel (II) sulfate. Hexahydrate (ex Aldrich) in 240 mL of water was added dropwise over 45 minutes to a solution of 360 mL of aqueous, at least 5% sodium hypochlorite solution (ex Aldrich) containing 42 g of sodium hydroxide. The reaction was slightly exothermic. The temperature was maintained at between 20 and 25 ° C with a cold water bath. The oxidizer was formed on addition as a fine black precipitate. The reaction mixture was stirred for a further 2 hours and then split into two centrifuge bottles. The black solid was spun down at 2500 rpm for 10 minutes and the centrifugate was decanted. The solid in each bottle was slurried with 400 ml of ice-cold water and centrifuged. This wash was repeated 4 additional times (pH = 'O). Then the obtained black solid was filtered on a Buchner funnel with a latex filter. 144g of solid cake were placed in a vacuum oven at 1 mm and 25 ° C for 2 days. The obtained 56.5 g were crushed and then dried for 24 hours on a vacuum apparatus at 0.1 mm. 48.3 g (0.53 mol, 108%) of active oxidizing agent was obtained as a black powder.

K. [1S- (1a, 2a, 3a, 4a)] - 2- [2 - [[2- [3 - [[(1,1-dimethylmethyl) -diphenyl-1-butyl] -oxy] -propyl] -phenyl ] methyl] -7-oxablcyclo [2.2.1] hept-3-YLM-oxazolcarbons &-acid methylester

A solution of 1.20 gm (1.96 mmol) of the oxazoline of Section I in 30 mL of phosphorus pentahydric-distilled methylene chloride was added at room temperature with 2.4 g of the nickel peroxide oxidizer of Section J. The reaction mixture was stirred for 45 minutes (a TLC control gave approximately half the conversion), an additional 2.4 g of oxidant was added and stirred for a further 45 minutes. The mixture was diluted with 100 ml of ethyl acetate and 50 ml of 3 molar aqueous bisulfite solution and then stirred rapidly for 30 minutes. The obtained green emulsion ^! was added to 100 ml of 1M aqueous citrate solution. The organic layer was separated and the aqueous layer was extracted with a further 100 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained. The crude product was purified by flash chromatography through 20 x 3 cm Merck silica gel with ethyl acetate / petroleum ether 1: 2. 582 mg (0.96 mmol, 49%) of title oxazole were obtained as a colorless oil.

L, cyclohexylbutylamine monohydrochloride

A solution of 10.6 g (71.1 mmol) of 4-phenylbutylamine (ex Aldrich) in 100 ml of glacial acetic acid was added under stirring in an argon atmosphere with 1.06 g of 87% PtO (10 wt% calculated for 4-phenylbutylamine). The editorial mixture was hydrogenated for 4 hours at room temperature and 54 psi. The catalyst was filtered through a 2 "layer of Celite, the filtrate was evaporated under reduced pressure, the residue was diluted with 200 ml of diethyl ether, 100 ml of CH 3 OH and 8 ml of concentrated HCl, which was evaporated under reduced pressure and digested in diethyl ether , 1 g (97%) of the desired amine · HCl.

M. [1S- (1a, 2a, 3a, 4a)] - N- (4-cyclohexylbutyl) -2- [2 - [[2- [3 - [[(1 _/ 1-dimethylethyl) -diphenylsilyl] - oxy] propyl] phenyl] methyl] -7-oxabicyclo [2.2.1] hept-3-yl] -4-oxazolecarboxamide

A solution of 290 mg (0.48 mmol) of the oxazole of Section K and 40 mg (0.95 mmol) of lithium hydroxide monohydrate (before Aldrich) in 4 mL THF / water 3: 1 was rapidly stirred at room temperature for 1.5 hours. The reaction mixture was acidified with 2 ml of 1M hydrochloric acid and partitioned between 20 ml of diethyl ether and 20 ml of water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The crude acid was obtained as an oil. To a solution of the crude acid in 5 ml of molecular sieve-dried benzene (ex Burdick and Jackson) was added a small drop of dimethylformamide (DMF) followed by 60 μΙ (0.69 mmol) of oxalic chloride (ex Aldrich). The mixture was stirred for about 30 minutes until gas evolution ceased and then evaporated under reduced pressure. The crude acid chloride was obtained as a yellow oil.

A solution of the crude acid chloride in 5 mL of phosphorus pentoxide distilled dry methylene chloride was cooled to ⁰ ° C. and treated with 165 μL (1.2 mmol) of triethylamine distilled over calcium hydride followed by 110 mg (0.57 mmol) of cyclohexylbutylamine hydrochloride of Section L. The reaction mixture was warmed to room temperature, stirred for 1 hour and partitioned between 20 ml of ethyl acetate and 20 ml of 1 M hydrochloric acid. The organic phase was separated, dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained. The crude oil was purified by flash chromatography through 15% silica gel from Merck with ethyl acetate / petroleum ether 2: 3. This gave 277 mg (0.38 mmol, 79%) of the title compound as a white foam,

N. [1S- (1a, 2a, 3a, 4a)] - 2 - [[3- [4 - [[(4-cyclohexylbutyl) -amino] -carbonyl] -2-oxazolyl] -7-oxa-cyclo [2.2 .1] hept-2-yl] methyl] phenylpropanoic acid

To a solution of 270 mg (0.17 mmol) of the compound of Section M in 6 mL acetonitrile / methylene chloride 2: 1 was added 0.60 mL of 48% hydrofluoric acid at room temperature. The reaction mixture was stirred rapidly for 2 hours and diluted with 20 ml of diethyl ether. The reaction was stopped by the slow addition of 10 ml of saturated aqueous bicarbonate solution. The resulting mixture was added to 20 ml of water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The crude alcohol was obtained as an oil. To a solution of the crude alcohol in 6 ml acetone / methylene chloride 5: 1 was added 0.35 ml (2.6M Cr ^{+ 6} in water) of Jones reagent. The reaction mixture was stirred for 20 minutes. Then the reaction was stopped by adding 0.5 ml of isopropanol. After 10 minutes, 20 ml of diethyl ether and 20 ml of 3 M aqueous sodium bisulfite solution were added and the mixture was stirred for a further 15 minutes. The organic phase was separated, dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained. The crude product was purified by flash chromatography through 15 x 1 cm silica gel from Merck with ethyl acetate and then methanol / methylene chloride 1: 9. This gave 75 mg (0.15 mmol), 41%) of the title compound as a white foam

IR (KBr): 3413, 2920,1721,1644,1601,1522,1447cm " ¹ extract of 270MHz ¹ H NMR (CDCl ₃ ):

2.20 (dd, 1H) 2.34 (t, 1H) 2.55 (t, J = 8, 2H) 2.91 (t, J = 8, 2H), 3.40 (m , 3H) 4.40 (d, J = 4.1H) 4.98 (d, J = 4.1H) 7.14 (m, 5H) 8.14 (s, 1H)

67.5MHz ¹³ CNMR (CDCI ₃ ):

24,2,26,4,26,7,27,4,28,9,29,9,32,4,33,3,34,7,37,1,37,5,39,2,47, 0.50, 7.78, 7.9, 7.126, 6.16, 1.7, 129.0, 129.7, 166, 117, 118, 138, 141, 16, 16, 16, 16, 16, 76,

MS (CI): 509 (M + H) ⁺

TLC: R ₁ (silica gel, methanol / methylene chloride 1:19) = O, ammonium molybdate / ceric sulfate, UV. C ₃₀ H ₄₀ N ₂ O ₆ + 0.42 H ₂ O; CHN

Calculated: 69.80 7.97 5.43

gel .: 69.83 7.90 5.40

Example 2

[1S- [1a, 2a, 3a, 4a)] - 2 - [[3- [4 - [([4- (4-chlorophenyl) -butyl] -amino] -carbonyl] -2-oxazolyl] -7- oxabicyclo [2.2.1] hept-2-yl] methyl] phenylpropanoic acid

A. 1-Bromo-2- [3 - [[Dibrethyl- (1,1,2-trimethyl-propyl) -silyl] -oxy] -propyl] -ben-.ol

A solution of 29.0 g (135 mmol) of the crude alcohol of Example 1, Section C and 24.1 g (135 mmol) of thexyldimethylchlorosilane (from Petrarch) in 200 mL of dry, phosphorus pentoxide-distilled methylene chloride was allowed to react at room temperature with 20 mL (143 mmol) Calcium hydride distilled triethylamine and then with 200mg (164 mmol) of 4-dimethylaminopyridine (from Aldrich). The reaction mixture was stirred at room temperature for 18 hours. The resulting slurry was diluted with 100 mL of hexane, cooled to ⁰ ° C with stirring for 15 minutes, and filtered to remove solid triethylamine hydrochloride. The filtrate was evaporated under reduced pressure. An oil was obtained. The crude oil was purified by flash chromatography through Merck 15x10cm silica gel with ethyl acetate / petroleum ether 1: 9. This gave 45.5 g (127 mmol, 94%) of the title compound as a colorless liquid.

[1S- (1a, 2a, 3a, 4a)] - [2- [3 - [(dimethyl- (1,1,2-trimethyl-propyl) -sl-yl] -oxy] -propyl] -phenyl] -7- oxablcyclo [2.2.1] heptane-2,3-dlmethanol

A solution of 5.00 g (14.0 mmol) of the compound of Section A in 30 mL of dry ketyl-distilled diethyl ether was cooled to -100 ° C and 15 mL was added dropwise with 15 mL of 1.7 M tert-butyllithium in pentane (25 mmol , from Aldrich). The reaction mixture was stirred for 15 minutes at -100 ⁰ C and then 15 minutes at ⁰ ° C. The resulting pale yellow anion solution was cooled to -78 ° C and then first with 30 ml of dry, ketyl-distilled THF and then rapidly with a solution of 875 mg (5.61 mmol) of | 3aR- (3aa, 4β, 7β, 7aa) octahydro -4,7-epoxyisobenzofuran-1-oil in 10 ml of THF. The reaction mixture was warmed to ⁰ ° C., stirred for 1 hour, admixed with 5 ml of water and then partitioned between 100 ml of water and 25 ml of ethyl acetate. The organic layer was separated and the aqueous layer was extracted with another 25 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained. The crude oil was purified by flash chromatography through 12 χ 5cm Merck silica gel with ethyl acetate / petroleum ether 1: 4 and then ethyl acetate / petroleum ether 4: 1. 2.35 g (5.41 mmol, 97%) of the diastereomeric title alcohols were obtained as a colorless oil.

C. [1S- (1a, 2a, 3a, 4a)] - 2 - [(2- [3 - [(Dlmethyl (1,1,2-trimethyl-propyl) -sl-yl] -oxy] -propyl] -phenyl] - methyl] -7-oxoblcyclo [2.2.1] heptane-3-methanol

A mixture of 1.9 g (4.38 mmol) of the diastereomeric alcohols of Section B and 1.9 g of 20% palladium hydroxide on carbon catalyst (<50% water content, by Aldrich) in 60 mL of glacial acetic acid was added in a hydrogen atmosphere (Balloon ) Stirred for 5 hours quickly. The reaction mixture was filtered through a 4 μm polycarbonate membrane and the filtrate was evaporated under reduced pressure in a room temperature bath. The residue was partitioned between 50 ml of water and 50 ml of ethyl acetate. The organic phase was separated, washed with 50 ml of 1M sodium hydroxide solution, dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained. The crude product was purified by flash chromatography through 12 x 5 cm Merck silica gel with ethyl acetate / petroleum ether 1: 2. 1.03 g (2.39 mmol, 55%) of the titol compound was obtained as a colorless oil. Further, 573 mg (1.37 mmol, 30%) of the starting compound of Section C was recovered as a single diastereomer.

D. [1S- (1a, 2a, 3a, 4a)] - 2 - [[3- (hydroxymethyl) -7-oxaflulo- [2,2,1] hept-2-yl] -methyl] -phenylpropanoic acid methyl ester A solution of 1.00 g (2.39 mmol) of the compound of Section D and 50 mg (0.41 mmol) of 4-dimethylaminopyridine (ex Aldrich) in 6 mL of dry pyridine / acetic anhydride 1: 1 was stirred for 2 hours at room temperature. The

The reaction mixture was evaporated under reduced pressure and the residue was partitioned between 25 ml of ethyl acetate and 20 ml of 1M hydrochloric acid. The organise.ie phase was separated, washed with 20ml 1M sodium hydroxide solution and then with 20ml brine, dried over magnesium sulfate and evaporated under reduced pressure. The crude acetate was obtained as an oil.

A solution of the crude acetate in 15 ml of analytically pure acetone was rapidly reacted with 3.3 ml (2.6 M of Cr ⁺⁶ ) Jones reagent at 0 ° C. (compare to the preparation of Fieser & Fieser "Reagents for Organic Synthesis", Vol. The reaction mixture was stirred for 2 hours, the reaction was quenched by adding 1 ml of isopropanol and stirring was continued for a further 30 minutes The resulting green slurry was filtered through a celite pad The filtrate was evaporated under reduced pressure and concentrated The residue was partitioned between 25 ml of diethyl ether and 25 ml of water

separated and evaporated under reduced pressure. The acetate acid was obtained as an oil.

A solution of the crude acetate acid in 15 ml 1M sodium hydroxide / THF 2: 1 was stirred for 30 minutes at room temperature. The reaction mixture was cooled in an ice bath. The reaction was stopped by adding 15 ml of 1 M hydrochloric acid.

Thereafter, it was extracted with 2x25 ml of diethyl ether.

The combined ether extracts were mixed with 25 ml saline! washed and evaporated under reduced pressure. you

got the raw alcohol acid as an oil.

A solution of the crude alcohol-acid in 10 ml of acidified methanol (prepared by addition of 0.5 ml of acetyl chloride to 10 mL of dry methanol at ⁰ ° C) was stirred for 2 hours at O ⁰ C and then evaporated under reduced pressure. The resulting oil was purified by flash chromatography through 15 x 3.0 cm silica gel from Merck with ethyl acetate.

526 mg (1.76 mmol, 74% of the compound from Section C) of the title compound were obtained as a colorless oil.

E. [1S- (1a, 2a, 3a, 4a)] - 2 - [[3-carboxy-7-oxabicyclo [2.2.1] hept-2-yl] -methyl] -phenylpropanoic acid methyl ester

A solution of 495 mg (1.63 mmol) of the compound of Section D in 5 ml of reagent grade acetone was rapidly spiked with 2.0 ml (2.6 M of Cr ⁺⁶ ) Jones reagent at ⁰ ° C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was stopped by adding about 1 ml of isopropanol. After 15 minutes, the resulting green slurry was filtered through a celite pad. The filtrate was partitioned between 20 mL of diethyl ether and 20 mL of water. The organic phase was separated and the aqueous phase was extracted with another 20 ml of diethyl ether. The combined ether extracts were dried over magnesium sulfate and evaporated under reduced pressure. 560 mg (1.59 mmol, 98%) of the crude title compound were obtained as a colorless oil.

F. [1S- (1a, 2a, 3a, 4a)] - 2 - [[3 - [[1- (hydroxymethyl) -2-oxo-2- (phenylmethoxy) ethyl] amino] carbonyl] -7 -oxablcyclo [2.2.1] hept-2-yl] methyl-phenyl-propanoic-methyl ester

A solution of 490 mg (1.54 mmol) of the acid of Section E in 10 ml of dry ketyl-distilled THF was dissolved at ⁰ ° C with 392 mg (1.69 mmol) L-serine benzyl ester hydrochloride (ex Sigma), 228 mg (1.69 mmol). 1-hydroxybenzotriazole hydrate (ex Aldrich) and 530μΙ (3.8 mmol) triethylamine distilled over calcium hydride. The mixture was stirred for 5 minutes followed by the addition of 348 mg (1.69 mmol) of dicyclohexylcarbodiimide (ex Aldrich) all at once. The mixture was stirred with OX for 3 hours and then kept at room temperature for 16 hours. The resulting slurry was diluted with 10 ml of ethyl acetate for 15 minutes, cooled to ⁰ ° C. and then filtered. The filtrate was evaporated under reduced pressure. An oil was obtained. The crude product was purified by flash chromatography through 15 x 3 cm silica gel from Merck with ethyl acetate. 540 mg (1.09 mmol, 71%) of the title compound were obtained as a white solid.

G. [1S- (1a, 2a, 3a, 4a)] - 2 - [[3-t4,5-dihydro-4 - [(phonylmethoxy) carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2 .1] hept-2-yl] methyl] · phenylpropanoic acid methyl ester

A solution of 525 mg (1.06 mol) of the compound of Section F, 843 mg (3.1 mol%) of triphenylphosphine (ex Aldrich) and 540 μΙ (3.1 mmol) of diisopropylethylamine (ex Aldrich) in 6 ml of dry acetonitrile / methylene chloride 5: 1 was added at room temperature with 300μΙ (3.1 mmol) of analytically pure tetrachloromethane (by Mallinckrodt). The reaction mixture was stirred for 2 hours and then diluted with 15 ml of ethyl acetate and then slowly with 15 ml of saturated aqueous sodium bicarbonate solution. The resulting mixture was stirred for 5 minutes and then partitioned between 20 ml of ethyl acetate and 20 ml of water. The organic phase was separated, washed with 20 ml brine, dried over sodium sulfate and evaporated under reduced pressure. A yellow, oily solid was obtained. The crude product was purified by flash chromatography through 20 χ 3 cm Merck silica gel with ethyl acetate / petroleum ether 2: 1. 380 mg (0.8 mmol, 75%) of title oxazoline were obtained as a pale yellow solid.

H. [1S- (1a, 2a, 3a, 4a)] - 2 - [[3- [4 - [(phenylmethoxy) carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-one yl] methyl] -phenylpropansäure-methylestbr

A solution of 375 mg (0.79 mmol) of oxazoline from Section G in 10 mL of dry phosphoric pentoxide-distilled methylene chloride was added with 750 mg of nickel peroxide oxidizer of Example 1, Section J at room temperature. The reaction mixture was stirred for 1 hour and then treated with a further 190 mg of oxidizing agent. After 30 minutes, the reaction mixture was diluted with 20 ml of ethyl acetate and then treated with 10 ml of 3M aqueous sodium bisulfite solution. The resulting mixture was stirred rapidly for 20 minutes and then treated with 10 ml of water. The organic phase was separated and the aqueous phase extracted with a further 20 ml of ethyl acetate. The combined organic phases were washed with 25 ml of 1M aqueous sodium citrate solution, dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained. The crude product was purified by flash chromatography through 15 x 15 cm silica gel from Merck with ethyl acetate / petroleum ether 2-3. This gave 180 mg (0.38 mmol, 48%) of title oxazole as an oil.

I. 4- (4-chlorophenyl) -butylamines

(a) 3- (4-chlorophenyl) -propanol

A solution of 5.0 g (27 mmol) of 3- (4-chlorophenyl) -propanoic acid in 30 ml of tetrahydrofuran was added dropwise at ⁰ ° C. while stirring with 30 ml (30 μmol) borane-tetrahydrofuran complex. The reaction mixture was stirred for 15 hours and then evaporated under reduced pressure. The residue was added with water and partitioned between diethyl ether and saturated sodium bicarbonate solution. The organic phase was separated and the aqueous phase was washed twice with 40 ml

Extracted diethyl ether. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. This gave 3.9 g of a colorless oil. ' ³ C NMR (CDCl ₃ , 67.8 MHz) δ: 140.0, 131.0, 129.9, 129.0, 116.0, 132.5, 131.0

(b) 3- (4-chlorophenyl) -propyl-bromide

A solution of 4.15 g (15.8 mmol) of triphenylphosphine in 100 ml of toluene was added dropwise at ⁰ ° C. while stirring with 1.51 ml (15.8 mmol) of bromine. This mixture was stirred for 3 hours and then treated with a solution of 3.90 g (22.86 mmol) of the alcohol of section (a) and 1.63 mL (15.8 mmol) of pyridine in 20 mL of toluene. A mixture of 25 mL of hexane and 25 mL of diethyl ether was added and a brown mass formed. The liquid was decanted and evaporated under reduced pressure. The residue was digested with hexylvacetic acid ethyl ester and triphenylphosphine oxide was precipitated. The solid was filtered off and the filtrate was evaporated. One received a yellow oil. The oil was purified by flash chromatography. This gave 1.8 g (7.72 mmol, 49%) of the desired product. ¹³ C NMR (CDCl ₃ ) δ: 138.7, 131.6, 129.6, 128) 3.33, 7, 33, 0, 32, 5.

(c) 4- (4-chlorophenyl) -butyrronitrile

A solution of 3.10 g (13, SmMoI) of the bromide of section (b) in 36 ml of ethanol was stirred under argon at room temperature and treated with a solution of 4.26 g (65.4 mmol) of potassium cyanide in 12 ml of water. The reaction was incomplete according to TLC after 5 hours. The reaction mixture was mixed with 4 ml of THF and 4 ml of water, thereby becoming homogeneous. After stirring for 12 hours, water and diethyl ether were added. The organic phase was separated and the aqueous phase extracted with 2 χ 50ml diethyl ether. The combined organic phases were washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained. The oil was purified by flash chromatography with hexane / ethyl acetate 90: 1. This gave 1.80 g (10.1 mmol, 76%) of titanium nitrile as a clear oil

¹³ C NMR (CDCl ₃ ) δ: 138.0, 132.1, 129.6, 128.6, 33.5, 26.6, 16.2.

(d) 4- (4-Chlorophenyl) -butylamine

A solution of 1.80g (1OmMoI) nitrile from part (c) in 70ml diethyl ether was added boei O ⁰ C with stirring in an argon atmosphere with 0.38 g (1OmMoI) lithium aluminum hydride. It developed a gas. After 20 minutes, the reaction mixture was mixed with 0.4 ml of water, then 0.4 ml of 1 N NaOH and finally 1.2 ml of water, wherein after each addition a few minutes, ι was stirred. The white precipitate was filtered off and the filtrate was evaporated. 1.5 g (8.2 mmol, 82%) of titalamine were obtained as a clear oil

¹³ C NMR (CDCl ₃ ) δ: 140.7, 131.2, 129.5, 128.2, 41, 8.4, 9.33, 0.28, 4.

J. [S- (1a, 2a, 3a, 4a)] - 2 - [[3- [4 - [[[4- (4-chlorophenyl) -butyl] -amino] -carbonyl] -2-oxazolyl] - Methyl 7-oxa-cyclo [2.2.1] hept-2-yl] -methyl] · phenylpropanoate

A mixture of 175 mg (0.37 mmol) of oxazole from Section H and 30 mg of 20% palladium hydroxide on carbon, as catalyst (wet <50% water, from Aldrich) in 5 ml of in-lysine pure ethyl acetate was added under a hydrogen atmosphere (balloon) 1 Hour stirred. The catalyst was filtered off with a 4 μm polycarbonate membrane. The filtrate was evaporated under reduced pressure. This gave 141 mg (0.37 mmol, 100%) of the crude acid as a white solid, mp 156-158 ° C.

A solution of 135 mg (0.35 mmol) of the crude acid in 3 ml of dry, phosphorus pentoxide-distilled methylene chloride was added at room temperature with a small drop of DMF and then 40 μΙ (0.46 mmol) of oxalic acid chloride (ex Aldrich). The reaction mixture was stirred for 30 minutes and evaporated under reduced pressure. The crude acid chloride was obtained as a yellow solid. The acid chloride was dissolved in 3 ml of dry methylene chloride, cooled to ⁰ ° C. and treated with a solution of 84 mg (0.46 mmol) of Armin from Section I and 70 μΙ (0,5ηηΜοΙ) of triethylamine distilled over calcium hydride

1 ml of dry methylene chloride quickly added. The reaction mixture was stirred for 30 minutes and then partitioned between 25 ml of ethyl acetate and 15 ml of 1 M hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with another 10 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. A yellow solid was obtained. The crude product was purified by flash chromatography through 18 χ 1.5 cm silica gel from Merck with ethyl acetate / petroleum ether 3: 1. This gave 161 mg (0.29 mmol, 83%) of the title compound as a white solid, mp 140-142 ° C.

K. [1S- (1a, 2a, 3a, 4a)] - 2 - [[3- [4 - [[[4- (4-chlorophenyl) -butyl] -amino] -carbonyl] -2-oxazolyl] - 7-oxabicyclo [2.2.1] hept-2-yl] methyl] -phenylpropansäure

A solution of 158 mg (0.29 mmol) of the compound of Section J and 25 mg (0.60 mmol) of lithium hydroxide monohydrate (ex Aldrich) in 6 mL of THF / water 2: 1 was rapidly stirred for 1.5 hours at room temperature. The mixture was purified by adding

Acidified 2 ml of 1M hydrochloric acid and then partitioned between 20 ml of ethyl acetate and 20 ml of water. The organic phase was separated, washed with 20 mL brine, dried over magnesium sulfate and evaporated under reduced pressure. 152mg (0.28 mmol, 98%) of the title compound were obtained as a white solid foam.

IR (KBr): 3413,2940,1724,1652,1602,1522,1491,1203,1175,1105cm " ¹

Extract of 270MHz NMR (CDCI ₃ ):

δ 2.19 (dd, 1H), 2.32 (t, J = 11.1H), 2.55 (m, 5H), 2.89 (t, J = 8, 2H), 3, 39 (m, 3H), 4.39 (d, J = 4.1H), 4.96 (d, J = 4.1H), 7.12 (m, 9H), 8.14 (s, 1H).

67.5MHZ ¹³ CNMr (CDCI ₃ ):

δ 27.4.28, 5.2, 8.29, 8.2, 9.32, 4.34, 7.38, 8.6, 9.50, 7.78, 7.9, 7, 12.5, 5.26 , 7,128.4,129.0,129.7,131,4,135,8,137,7,138,4,140.5, 141,1,160,9,163,9,176.5.

MS (CI): 537, 539 (M + H) ⁺

OR: [a] _D = + 9.9 ° (c = 1.0 in methanol) closed opening.

TLC: R | (Silica gel, methanol / methylene chloride 1: 9) - 0.50, ammonium molybdate / cerium sulfate and UV, homogeneous. C ₃₀ H ₃₃ CIN ₂ O ₆ ; CHN Cl

bar .: 67.09 6.19 5.22 6.60

F .: 67.33 6.35 5.13 6.45

Example 3

[^ IS-da.aa.Sa all-the-tia - ^ - ^ td CyclohexylbutyD-amlnol-carbonyU ^ -oxazolyll-y-oxablcyclo ^^ ^ Hhept Yu-methyl.] Phenylacetic acid

A. (3-Bromophenethyl) oxythexyldimethylsilane

A solution of 55.8 g (26 μmol) of 3-bromophenylacetic acid (from Aldrich) was added dropwise at 0 ° C. under argon for 1 hour with 300 ml (30 μmol) of a 1M solution of diborane in tetrahydrofuran (THF). This mixture was stirred for 5.5 hours at 0 ° C and then slowly added to water uas resulting mixture was evaporated under reduced pressure and the residue between 300ml of saturated NaHCO ₃ solution and 4x 40ml diethyl ether distributed. The combined ether extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure. 51.7 g of crude alcohol were obtained. A solution of this alcohol and 75 ml (538 mmol) of triethylamine in 500 ml of dry CH ₂ Cl ₂ was added under stirring in an argon atmosphere at ⁰ ° C. over 15 minutes with 56.2 ml (286 mmol) of thexyldimethylsilyl chloride. The reaction mixture was allowed to stand for 75 minutes O ⁰ C and then stirred for 15 hours at room temperature. This mixture was diluted with 500 ml of diethyl ether and the precipitate was filtered off. The solid was washed with 3x 300 ml diethyl ether. The filtrate was evaporated under reduced pressure and partitioned between 300 ml of saturated NhUCI solution and 4 × 300 ml of diethyl ether. The combined ether extracts were dried over magnesium sulfate and evaporated under reduced pressure. This crude product was distilled. 76,9g (87%) title compound, F. 148-154 ⁰ C (about 0.5 mm) was obtained.

B. [1S * (1α, 2α, 3α, 4α)] 2 [3 [[3-hydroxymethyl) 7 oxaplocyclo [2.2.1] hept-2-ylhydroxymethyl] -phosphinyl] ethoxy] -dimethyl- (1 , 1,2-irimethylpropyD-silane

A solution of 10.0 g (29.1 mmol) of precursor of portion A in 60 mL of dry diethyl ether was added dropwise over 15 minutes at -78 ° C with 30 mL (1.7 M in pentane, 51 mmol) tert-butyllithium solution (ex Aldrich). The reaction mixture was stirred for 15 minutes at -78 ⁰ C and then 30 minutes at ⁰ ° C. The anion solution was cooled to -78 ⁰ C, treated with 40 ml of dry tetrahydrofuran and then with a solution of 1.87 g (12 mmol) of [3aR- (3aa, 4SS, 7.beta., 7aa) | - octahydro-4,7- epoxyisobenzofuran-1-ol in 20 ml of tetrahydrofuran was added dropwise. After 15 minutes the mixture was warmed to ⁰ ° C. The mixture was kept for a further hour at ⁰ ° C. and then admixed with 5 ml of water. The mixture was then extracted into 200 ml of water and with 2 × 75 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained. The crude oil was purified by flash chromatography through 23 χ 5cm Merck silica gel with ethyl acetate / petroleum ether 1: 4 and then with ethyl acetate. This gave 4.1 g (10.1 mmol, 85%) of the title compound as a colorless oil.

C. [IS-d

UlmethylpropyO-silane

A mixture of 4.05 g (10, OmMoI) compound of Section B and 5.5 g of 10% palladium on charcoal (ex Aldrich) in 80 mL of glacial acetic acid was shaken in a hydrogen atmosphere (40 psi) in a Parr apparatus for 24 hours. The resulting mixture was passed through a polycarbonate filter to remove the catalyst. The filtrate was evaporated under reduced pressure. An oil was obtained. The crude oil was partitioned between 100 ml of ethyl acetate and 100 ml of water. The organic phase was separated, dried over magnesium sulfate and evaporated under reduced pressure. This gave 3.72 g (9.6 mmol, 96%) of title alcohol as a colorless oil.

D. [IS-lia ^

A solution of 4.56 g (11.3 mmol) of Section C alcohol and 1.3 mL (16 mmol) of pyridine (ex Burdick and Jackson) in 50 mL of dry, phosphorus pentoxide-distilled methylene chloride was added dropwise at 0 ° C with a 1.0 mL solution (14mMole) acetyl chloride (from Mallinckrodt) in 3ml methylene chloride. The reaction mixture was stirred for 30 minutes and then treated with 50 ml of 1 N hydrochloric acid. The organic phase wurtio separated, washed with 50ml 1M sodium hydroxide solution, dried over magnesium sulfate and evaporated under reduced pressure. This gave 5.05 g (11.4 mmol, quantitative) of acetate as a colorless oil. A solution of the crude acetate in 30 ml of acetonitrile (by Burdick and Jackson) was added at ⁰ ° C with 1.5 ml of 48% hydrofluoric acid. The mixture was stirred for 1 hour. Thereafter, the reaction was stopped by adding 20 ml of saturated aqueous sodium bicarbonate solution. The resulting mixture was poured into 100 ml of water and extracted with 2x50 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained. The crude product was purified by flash chromatography through 20 χ 5cm Merck silica gel with ethyl acetate. This gave 3.01 g (9.9 mmol, 88%) of the title alcohol as a colorless oil.

E. [1S- (1a, 2a, 3a, 4a)] - 2 - [[3- [2 - [[(1 ', 1-dimethylmethyl) diphenylsilyl] oxy] ethyl] phenyl] methyl] -7-oxabicyclo [2.2.1] heptane-3-methanol

A solution of 3.0 g (9.87 mmol) of the alcohol of Section D and 2.75 g (10, OmMoI) of tert-butyl-chloridiphenylsilane (from Petrarch) in 50 mL of dry, phosphorus pentoxide-distilled methylene chloride was added at ⁰ ° C with 1.7 ml (12 mmol) of triethylamine distilled over calcium hydride and then with 200 mg (1.6 mmol) of 4-dimethylaminopyridine (ex Aldrich). The reaction mixture was warmed to room temperature, stirred for 2 hours, and the resulting slurry was washed with 50 ml of 1M hydrochloric acid, then with 50 ml of water, dried over magnesium sulfate and evaporated under reduced pressure. The crude silyl ether was obtained as an oil. A solution of the crude silyl ether in 50 ml of anhydrous diethyl ether (from Mallinckrodt) was added dropwise at -78 ° C for 15 minutes with 20 ml of 1.4M methyllithium in diethyl ether (28 mmol, from Aldrich). After 5 minutes, the mixture was treated with 1 ml of methanol, to room temperature

warmed up and distributed between 50ml diethyl ether and 100ml water. The organic phase was separated, washed with 50 mL brine, dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained. The crude product was purified by flash chromatography through 20 x 5 cm Merck silica gel with ethyl acetate / petroleum ether 1: 1. 4.41 g (8.32 mmol, 89%) of the title alcohol were obtained as a colorless glass.

F. [IS-da] aaa carboxylic acid

A solution of 1.75 g (3.5 mmol) of the alcohol from part A 25 ml reagent grade acetone was 5 minutes at ⁰ ° C with 3.5 ml of Jones reagent (2.6 M, see FIG. Fieser and Fieser, Vol 1, p. 142) was added dropwise. The mixture was stirred at ⁰ ° C for 1.5 hours. Thereafter, the reaction was stopped by adding about 1 ml of isopropanol. The mixture was stirred for 30 minutes and the resulting green slurry filtered through a celite pad. The filtrate was partitioned between 100 ml of water and 75 ml of ethyl acetate. The organic phase was separated, washed with 100 ml of water, then with 50 ml of brine, dried over magnesium sulfate and evaporated under reduced pressure. 1.82 g (3.54 mmol, 101%) of crude acid was obtained as a solid white foam.

yl] carbonyl] -amino3-3-hydroxypropanoic acid-methylester

A solution of 1.86 g (3.72 mmol) of the acid of Section F, 577 mg (3.72 mmol) of L-serine methyl ester hydrochloride (ex Aldrich) and 502 mg (3.72 mmol) of 1-hydroxybenzotriazole hydrate ( from Aldrich) in 20 mL of dry THF distilled from potassium / benzophenone was dissolved at ⁰ ° C with 1.1 mL (7.8 mmol) triethylamine distilled over calcium hydride and after 5 minutes with 766 mg (3.72 mmol) IS-dicyclohexylcarbodiimide (ex Aldrich). added. The reaction mixture heated to room temperature was stirred for 16 hours and filtered from the resulting sludge. The filtrate was evaporated under reduced pressure. An oil was obtained. The crude product was purified by flash chromatography through 15x15cm silica gel from Merck with ethyl acetate. This gave 1.75 g (2.84 mmol, 76%) of the title amide as a white foam.

H. [1S- (1a, 2A3a, 4a)] - 2- [2 - [[3- [2 - [[d, 1-dimethyl-ethyl) -diphenyl-3-yl-1-yl] -ethyl] -phenyl] -methyl] - 7-oxablcyclo [2.2.1] hept-3-yl] -4,5-dihydro-4-oxazolecarboxylic acid-methylester

A solution of 1.65 g (2.76 mmol) of the amide of Section G and 2.89 g (11, OmMoI) triphenylphosphine (ex Aldrich) in 40 mL of molecular sieve-dried acetonitrile (ex Burdick and Jackson) was mixed with 0.7 mL (7 , 2 mmol) of carbon tetrachloride and then treated with 1.1 ml (7.8 mmol) of calcium hydride triethylamine distilled. The solution was heated at 65 ° C for 30 minutes, then cooled to room temperature, and the resulting dark solution was partitioned between 120 mL of saturated aqueous bicarbonate solution and 50 mL of ethyl acetate. The organic phase was separated and the aqueous phase was extracted with a further 50 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated under reduced pressure. One received a dark oil. The crude product was purified by flash chromatography through 20 x 5 cm Merck silica gel with acetone / hexane 1: 2. 515 mg (0.86 mmol, 31%) of the title oxazoline were obtained as a yellow oil.

I. [1S.fwdarw.1α, 2α, 3α, 4α)]. 2- [2 - [[3- [2 - [[(1,1-dimethylethylthyl) diphenylsilyl] oxy] ethyl] phenyl ] Methyl-7-oxa-cyclo [2.2.1] hept-3-yl. 4-oxazolecarboxylic acid, methyl ester

A solution of 505 mg (0.85 mmol) of oxazoline from Section H in 20 ml dry phosphorus pentoxide-distilled methylene chloride was added at room temperature with 1.1 g of the nickel peroxide of Example 1, Section J at once. The reaction mixture was stirred for 1 hour and treated with another portion of 1.0 g of nickel peroxide. The mixture was stirred for a further hour and then treated with 40mi ethyl acetate and then with 25ml aqueous sodium bisulfite solution. The mixture was stirred rapidly for 20 minutes. The resulting blue-green emulsion was added with 50 ml of 1M aqueous sodium citrate solution. The mixture was stirred for a further 20 minutes. Thereafter, the organic phase was separated and the aqueous phase extracted with 25 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained. The crude oil was purified by flash chromatography through Merck 15x3cm silica gel with 1: 1 ethyl acetate / petroleum ether. 247 mg (0.42 mmol) of the title oxazole was obtained as a colorless oil.

J. (1S-da, 2a, 3a, 4a)] - N- (4-cyclohexylbutyl) -2- [2 - [[3- [2 - [[(1,1-dimethylethyl) -diphenylsilyl] -oxy] ethyl] phenyl] methyl] -7-oxablcyclo [2.2.1] hept-3-yl] -4-oxazolcarbons8ureamld

A solution of 240 mg (0.4 mmol) of the oxazole of Section I and 34 mg (0.81 mmol) of lithium hydroxide monohydrate (ex Aldrich) in 5 mL of THF / water 4: 1 was vigorously stirred at room temperature for 1.5 hours. The reaction mixture was acidified with 2 ml of 1M hydrochloric acid, then added to 20 ml of water and extracted with 2x20 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. The crude acid is obtained as an oil. The acid was dissolved in toluene and evaporated under reduced pressure to remove residual water. The residual oil was treated with 5 ml of molecular sieve-dried toluene (ex Burdick and Jackson), a small drop of DMF, and then 50 ml (0.52 mmol) of oxalic acid chloride (ex Aldrich) dropwise at room temperature. The reaction mixture was stirred for 1 hour, then evaporated under reduced pressure. The crude acid chloride was obtained as an oil. A solution of the crude acid chloride in 50 ml of dry, distilled over Kaiium / benzophenone THF was at ^{0 0} C with 95mg (0.5 mmol) cyclohexylbutylamine hydrochloride and then with 170μΙ (1.2 mmol) over calcium hydride distilled triethylamine. The mixture was stirred for 1 hour, then poured into 20 ml of 1 M hydrochloric acid and extracted with 2 x 20 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained, which was purified by flash chromatography through 20 χ 3 cm Merck silica gel with ethyl acetate / petroleum ether 2: 3. This gave 238 mg (0.33 mmol, 83%) of the title oxazole as a colorless oil.

K. [1S- (1a, 2a, 3a, 4a)] - 3 - [[3- [4 - [[(4-cyclohexylbutyl) amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2. 1] hept-2-yl] methyl] phenylacetic acid

A solution of 235 mg (0.33 mmol) of the oxazole of Section J in 7.5 ml of acetonitrile / methylene chloride 2: 1 was added at room temperature with 35 ml of 48% hydrofluoric acid. The reaction mixture was stirred for 2 hours and then to 20ml

saturated aqueous sodium bicarbonate solution. It was then extracted with 20 ml of ethyl acetate and 20 ml of methylene chloride. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained which was purified by flash chromatography through 15 x 3cm silica gel from Merck with ethyl acetate. This gave 147 mg (0.31 mmol, 94%) of the alcohol as a white solid.

A solution of 135 mg (0.28 mmol) of the above-prepared alcohol in 5 ml of analytically pure acetone was treated at room temperature with 0.35 ml (2.6M of Cr ⁺⁶ , see Fieser & Fieser, Vol. Reagent added. The reaction mixture was stirred for 45 minutes and then sotted with a few drops of isopropanol. After 15 minutes, 20 ml of ethyl acetate and then 20 ml of 3 M aqueous sodium bisulfite solution were added. The mixture was stirred rapidly for 15 minutes, then the organic phase was separated and the aqueous phase extracted with 20 ml of methylene chloride. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure to a volume of about 10 ml. The resulting solution was cooled to ⁰ ° C. and an excess of diazomethane in ether was added,

until the solution remained yellow. The excess of diazomethane was quenched with glacial acetic acid and the solution was evaporated under reduced pressure. An oil was obtained which was purified by flash chromatography through 15 x 1.5 cm Merck silica gel with ethyl acetate / petroleum ether 3: 2. This gave 63 mg (0.12 mmol, 43%) of methyl ester of title acid as a white foam.

A solution of 60 mg (0.12 mmol) methyl ester and 20 mg (0.48 mmol) lithium hydroxide monohydrate (ex Aldrich) in 2.5 mL THF / water 4: 1 was stirred for 3 hours at room temperature. The mixture was acidified by adding 1 ml of 1 M hydrochloric acid and then partitioned between 2C ml of ethyl acetate and 20 ml of water. The organic phase was separated, dried over magnesium sulfate and evaporated under reduced pressure. 58 mg (0.58 mmol, 100% based on methyl ester) of the title compound were obtained as a solid white foam.

IR (KBr): 3409 (broad), 2923,1712,1649,1604,1513cm " ¹

Extract of 270MHz ¹ H NMR (CDCl ₃ ):

δ2.20 (m, 1H) 2.40 (t, J = 10.1H) 2.62 (ni, 1H) 3.32 (d, J = 9.1H) 3.36 (m, 2 H) 3.56 (s, 2H) 4.39 (d, J = 4.1 H) 4.90 (d, J = 4.1 H) 6.90-7.30 (m, 4H) 8 , 04 (s, 1H)

67.5MHz ¹³ CNMR (CDCI ₃ ):

δ 24,2,26,3,26,7,29,0, 29,7, 29,8,33,3,35,9,37,0,37,5, 39,2,41,0,46 , 6, 50,6,79,2,79,9,127,2,127,3,128,6,129,7,133,9,135,7, 140,0,140,8,161,0,163,9,175,0.

MS (CI): 495 (M + H) ⁺

TLC: Rf (silica gel, methanol / methylene chloride 1: 9) = 0.38, ammonium molybdate / ceric sulfate, UV.

C ₂₉ H ₃₈ N ₂ O _5: CHN

Calc .: 70.42 7.74 5.67

F .: 70.54 7.78 5.57

Example 4

[1S- (1a, 2a, 3a, 4a)] - 2 - [[3- [4 - [[(4-cyclohexylbutyl) -amlno] -carfaonyl] -2-thlazolyl] -7-oxablcyclo [2.2.1] hept-2-yl] methyl] phenylpropanoic acid

A. [1S- (1a, 2a, 3a, 4a)] - 2 - [[3- (aminocarbonyl) -7-oxabicyclo [2.2.1] hept-2-yl] -methyl] -phenylpropanoic acid methyl ester A solution of 9.13 mmol of the acid of Example 2, Section E in 100 ml of dry benzene is treated dropwise with 0.96 ml (11 mmol) of oxalic acid chloride for 10 minutes. The mixture is stirred for 5 hours, evaporated under reduced pressure, dissolved in 10 ml of dry THF and added dropwise in 5 minutes to 3 ml of concentrated ammonium hydroxide solution in 100mL THF at ⁰ ° C. The mixture is then evaporated under reduced pressure. The solid residue is then partitioned between 150 ml of ethyl acetate and 25 ml of 0.25M K ₂ CO ₃ . The aqueous phase is extracted with 25 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated under reduced pressure. The residue is suspended in 100 ml of boiling diethyl ether and admixed with about 10 ml of ethyl acetate to dissolve it. The mixture is evaporated on a steam bath to about 50 ml, cooled to room temperature, seeded with seed crystals and cooled overnight. The title amide is obtained by filtration.

B. [IS-da ^ aa

A solution of 0.999 mmol of the amide of Section A in 10 mL of dry toluene is added at 60 ° C with 222 mg (0.55 mmol) of Lawesson's reagent. The mixture is stirred for 30 minutes at 60 ⁰ C, with 50 ml of diethyl ether veraünnt washed 2x with 5 ml half-saturated NaHCO _3. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The residue is passed through a short layer of silica gel using 50% ethyl acetate / hexane. The title thioamide is obtained.

C. [1S- (1a, 2a, 3a, 4a)] - 2 - [[3- (4-carboxy2-thiazolyl) -7-oxablCyclo [2.2.1] hept-2-yl] -methyl] - phenylpropanoic acid methyl ester A solution of 1.41 mmol of the thioamide of Section Bund 390 mg (2.82 mmol) of anhydrous K ₂ CO ₃ powder in 10 mL of dry DMF is taken in several portions with 295 mg (169 mmol) of pyruvic acid (die 0, 4 moles of water / mole of bromic acid). The mixture is stirred for 30 minutes at room temperature. Thereafter, an additional 29.5 mg of pyruvic acid are added. After a further hour, the solvent is evaporated off under reduced pressure below 30 ° C. The residue is suspended / dissolved in 10 ml of methylene chloride. Thereafter, 0.59 ml (4.2 mmol) of triethylamine and then, dropwise, 0.33 ml (4.2 mmol) of methanesulfonyl chloride are added. The mixture is stirred for 5 minutes and then diluted with 40 ml of diethyl ether. The organic phase is extracted with 9x 10 ml 0.5 MK ₂ CO ₃ . The combined aqueous phases are adjusted to pH 1.5 with 6N HCl and extracted with 6x 25 ml diethyl ether. The organic phases are dried over sodium sulfate and evaporated under reduced pressure.

D. [1S- (1a.2a, 3a, 4a)] - 2-t [3 - [<- [[(4-cyclohexylbutyl) amino] carbonyl] -2-thiazolyl] -7-oxabicyclo [2.2. 1] hept-2-yl] methyl] -phenylpropansäure-methyl easter

To a solution of 0.12 mmol of the acid of Section C in 1 ml of dry DMF is added 20.3 mg (0.125 mmol) of 1,1'-carbonyldiimidazole. The mixture is stirred for 1 hour and then treated with a solution of 23.4 mg (0.131 mmol) of cyclohexylbutylamine hydrochloride and 0.02 ml (0.14 mmol) of triethylamine in 0.5 ml of dry DMF. The mixture is

Stirred for 1 hour and evaporated to remove DMF. The residue is taken up in 20 ml of diethyl ether and 5 ml of 0.5 N HCl. The organic phase is dried over sodium sulfate and evaporated under reduced pressure. The title ester is obtained after chromatography through silica gel with ethyl acetate / hexane.

phenylpropanoic

To a solution of the amide of Section D in 1 ml of methanol is added 0.3 ml of 2N KOH. The mixture is stirred for 2 hours. Another 0.3 ml of KOH are added. After an additional hour, the mixture is evaporated to remove methanol. The residue is dissolved in 1 ml of water and adjusted to pH 2 with 1N HCl. The mixture is extracted with 3x 5 ml of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated under reduced pressure. The title compound is obtained.

Example 5

[1S- (1a, 2a, 3a, 4a)] - 2 - [[3- [4 - [[(4-cyclohexylbutyl) -amlno] carbonyl] -1H-lmldazol-2-yl] -7-oxabicyclo [ 2.2.1] hept-2-yl] methyl] phenylpropanoic acid

A solution of 1 mmol DMF in acetonitrile is added at 0 ° to prepare a Vilsmeier reagent with 1 mmol oxalic acid chloride. The reagent is added with 1 mmol of the amide ^r of Example 4, section A. After 45 minutes, 2 mmol of pyridine are added. The mixture is then partitioned between diethyl ether and 1N HCl. After drying and evaporation of the organic phase, the title nitrile is obtained.

B. [IS-da ^ a.Sa ^ all ^ -KS-dminomethoxymethyO-y-oxablcyclo ^^. Ilhept ^ -yU'methyll-phenylpropanes & uro-methyl ester hydrochloride

Gaseous HCl is introduced into a solution of ImMoI of the nitrile of Section A and 2 mmoles of methanol in 10 ml of diethyl ether for 5 minutes at 0 ° C. The mixture is stored for 7 days at ^{0 0} C and then evaporated. The title compound is obtained.

C. [1S- {1a, 2a, 3a, 4a)] - 2-t [3- [methoxy - [[2-oxo-2- [2- (trimethylsilyl) -ethoxy] -ethyl] -imino] -methyl ] -7-oxablcyclo-t2.2.1] hept-2-yl] methyl] -phenylpropansäure-methylester

1 mmol of the imino ether of Section B is suspended in 10 ml of THF and stirred with glycine, 2 mmol of 2- (trimethylsilyl) ethyl ester hydrochloride and 2 mmol of triethylamine. After 1 hour, the organic phase is diluted with diethyl ether, washed with NaHCO ₃ solution, dried and evaporated. The title tester is obtained, which is used for the subsequent step.

D. [1S- (1α, 2α, 3α, 4α)] - 2 · [[3 · [[[1 - (hydroxymethylene) -2-oxo-2- [2- (tri-methylsilyl) -ethoxy] -ethyl] -im! no] -methoxymethyl-7-oxa-cyclo [2.2.1] hept-2-yl] -methyl] -phenylpropanoic acid; methylester monopotassium salt

A solution of 2 mMol potassium methoxide is added dropwise at 0 ° to a solution of 4 mM of ethyl formate and 1 mM of C ester. After 3 hours, the potassium salt is filtered off and used immediately in the next step.

E. [I phenylpropansfiure methyl ester

The ester of Section D w ^! dissolved in concentrated ammonia. After 3 hours, the solution is bubbled with N ₂ to drive off excess NH ₃ . The residue is neutralized with 1 N HCl. The mixture is extracted with CH ₂ Cl ₂ . The organic phases are dried and evaporated under reduced pressure. The title imidazole is obtained.

F. [1S- (1α, 2α, 3α, 4α)] - 2 - [[3- (4-carboxy-1H-imidazol-2-yl) -7-oxyblcyclo [2.2.1] hept-2-yl] methyl) -phenylpropansäuremethylester

To a solution of 1 mmol of imidazole from section E in 10 ml of THF is added 1.1 ml of 1M tetra-n-butyl-ammonium fluoride in THF. The mixture is stirred for 1 hour, evaporated, diluted with water, adjusted to pH 7 with 1N HCl and extracted with methylene chloride. The organic phase is dried and evaporated. The title acid is obtained.

G. [1S- (1a, 2a, 3a, 4a)] - 2- [3 - [[(4-Cyclohexylbutyl) -amino] -carbonyl] -1H-imidazol-2-yl] -7-oxabicyclo [2.2.1] hept-2-yl] methyl] -phenylpropansäure-methylester

A mixture of 1, OmMoI the acid of Section F, 1 mmol of 4-cyclohexylbutylamine hydrochloride and 1, OmMoI 1-hydroxybenzotriazole in 10ml of dry dimethylformamide is added with stirring at ^{0 0} C under argon with 1.5 mmol of triethylamine. The mixture is treated for 10 minutes at 0 ° C with 1 mmol of 1-O-dimethylaminopropyl-S-ethylcarbodiimide hydrochloride. The reaction mixture is stirred for 24 hours at 23 ⁰ C and evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with saturated NaHCO ₃ , dried over MgSO ₄ , filtered and evaporated under reduced pressure. The title amide is obtained.

H. [1S- (1a, 2a, 3a, 4a)] - 2 - [[3- [4 - [[(4-cyclohexylbutyl) amino] carbonyl] -1H-imidazol-2-yl] -7- oxabicyclo [2.2.1] hept-2-yl] methyl] -phenylpropansäure

To a solution of 1 mmol of the amide of Section G in 10 ml of methanol is added 2 ml of 2N KOH. The mixture is stirred for 4 hours and then evaporated to remove methanol. The residue is diluted with water and adjusted to pH 2 with 1N HCl. The mixture is evaporated and the residue is extracted with methanol. The methanol is evaporated and the residue is extracted with chloroform / methanol 5: 1. The organic phases are evaporated. The crude title acid is obtained, which can be purified by chromatography with silica gel and ethyl acetate / pyridine / acetic acid / water.

Example β

[1S> (1a, 2a, 3a, 4a)] - 2- [3- [4 - hept [[(4-cyclohexylbutyl) -amlno] carbonyl] -2-oxazolyl] '7-oxablcyclo [2.2.1] -2-yl] -N- (phenylsulfonyD-phenylpropar. & Ureamld

To a mixture of 1.0 mmol of 1-O-dimethylaminopropyl O-S-ethyl-carbodiimide hydrochloride and 1 mmol of 4-dimethylaminopyridine in 8 ml of dimethylformamide is added 1 mmol of benzenesulfonamide and 2 mmol of triethylamine followed by 1 mmol of the title acid of Example 1. This mixture is stirred for 48 hours at room temperature and evaporated under reduced pressure. The residue is partitioned between water and ethyl acetate. The aqueous phase is acidified and extracted with ethyl acetate. The combined ethyl acetate phases are evaporated under reduced pressure. The title sulfonamide is obtained.

Example 7

[1S- (1a, 2a _< 3a, 4a)] - 3 - [[3- [4 - [[[4- (4-chlorophenyl) -butyl] -amino] -carbonyl] -2-oxazolyl] -7- oxablcyclo [2.2.1] hept-2-yl] methyl] benzoic acid

A. 3-bromobenzyl alcohol

A solution of 50 g (0.25 mol) of 3-bromobenzoic acid (from Alderich) in 100 ml of dry tetrahydrofuran (THF) is slowly added at ⁰ ° C. with 100 ml of 1 M borane-tetrahydrofuran complex (10 μmol, from Aldrich). The mixture is stirred for 1 hour at 0 ° C and then for 18 hours at room temperature. The reaction is stopped by dropwise addition of water. The mixture is evaporated under reduced pressure to remove the solvent. The residue is partitioned between diethyl ether and 1M hydrochloric acid. The organic phase is separated with 1M sodium hydroxide solution and then washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The title compound is obtained.

For example, 3-bromo-1 - [[[di (diethyl-1-yl-ethyl) -yl)] yl] -ben / ol

A solution of 25.2g (135mmol) of the crude alcohol of Section A and 24.1g (135mmol) of the thexyldimethylchlorosilane (from Petrarch) in 200ml dry phosphoric pentoxide distilled methylene chloride is distilled at room temperature with 20ml (143mmol) over calcium hydride Triethylamine and then 200mg (1.64 mmol) of 4-dimethylaminopyridine (ex Aldrich). The reaction mixture is stirred for 18 hours at room temperature. The resulting slurry is diluted with 100 mL of hexane, stirred at ⁰ C for 15 minutes, and filtered from the solid triethylamine hydrochloride. The filtrate is evaporated under reduced pressure. A crude oil is obtained which is purified by flash chromatography on silica gel from Merck. The title compound is obtained.

C. [IS-d dimethanol

A solution of 4.61 g (14 mmol) of the compound of Section B in 30 ml of dry, ketyl-distilled diethyl ether is 15 minutes at -100 ⁰ C dropwise with 1E τιΙ (25mMol) 1, 7 M tert-butyllithium in pentane (from Aldrich). The reaction mixture is for 15 minutes at -100 ⁰ C and then stirred for 15 minutes at ⁰ ° C. The anion solution is cooled to -78 ⁰ C and treated with 30 ml of dry, distilled from ketyl THF and then quickly with a solution of 875mg (5.61 mmol) l3aR- (3aa, 4SS, 7.beta., 7aa)] - Octahydro4,7- epoxyisobenzofuran-1-ol in 1OmITHF added. The reaction mixture is warmed to ⁰ ° C., stirred for 1 hour, admixed with 5 ml of water and partitioned between 100 ml of water and 25 ml of ethyl acetate. The organic phase is separated off and the aqueous phase is extracted with a further 25 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate and evaporated under reduced pressure. You get an oil. The crude oil is purified by flash chromatography on silica gel from Merck. The diastereomeric title alcohols are obtained.

D. [1S- (1α, 2α, 3α.4α) l • [3 [[[Dimethylsilyl (1,1,2-trimethylpropyl)] oxyj-ethyl] phenyl] -7-oxabicyclo [2.2.1] hθptan-2,3-dimethanol diacetate

A solution of 2.2 g (5.41 mmol) of the diol of Section C and 50 mg (0.41 mmol) of 4-dimethylaminopyridine (ex Aldrich) in 10 mL of acetic anhydride / pyridine 1: 1 is stirred for 6 hours at room temperature. The crude mixture is evaporated under reduced pressure and the residue is partitioned between 25 ml of ethyl acetate and 25 ml of 1M hydrochloric acid. The organic phase is separated, washed with 25 ml of 1M sodium hydroxide solution, dried over magnesium sulfate and evaporated under reduced pressure. The title compound is obtained.

E. [1S- (1a, 2a, 3a, 4a)] - 3- [hydroxy- [3- (hydroxymethyl) -7-oxeblcyclo [2.2.1] hept-2-yl] -methyl] -benzoic acid methyl ester

A solution of 1.1 g (2.24 mmol) of the diacetate of Section D in 15 mL of analytically pure acetone is rapidly added at 0 ° C with 3.3 mL of Jones reagent (2.6 M of CR ⁺⁶ , for preparation see Fieser et al 1, page 142. The reaction mixture is stirred for 2 hours, the reaction is stopped by addition of 1 ml of isopropanol and the mixture is stirred for a further 30 minutes Celite layer is filtered, the filtrate is evaporated at reduced pressure and the residue is partitioned between 25 ml of diethyl ether and 25 ml of water The organic phase is separated and evaporated under reduced pressure to give the crude diacetate acid as an oil crude diacetate acid in 15 ml 1M sodium hydroxide solution / THF 2: 1 is stirred for 90 minutes at room temperature The reaction mixture is cooled in an ice bath, mixed with 15 ml of 1 M hydrochloric acid and then extracted with 2x 25ml diethyl ether Purified ether extracts are washed with brine (25 ml) and evaporated under reduced pressure. The crude diol acid is obtained.

A solution of the crude diol acid in 10 ml of diethyl ether is added to diazomethane in ether at O'C and then evaporated under reduced pressure. The resulting oil is purified by flash chromatography with Kieselgol from Merck. The title compound is obtained.

F. [1S- (1a, 2a, 3a, 4a)] - 3 - [[(3-hydroxymethyl) -7-oxa -cyclo- [2.2.1] hept-2-yl] -methyl] -benzoic acid methyl ester

A mixture of 450 mg (1.54 mmol) of the diol of Section E and 450 mg of 10% palladium on carbon catalyst (from Aldrich) in 10 ml of glacial acetic acid is shaken for 24 hours under a hydrogen atmosphere of 50 psi. The mixture is

filtered and the filtrate is evaporated under reduced pressure. You get an oil. The crude product is purified by flash chromatography on silica gel from Merck. You get the title product.

G, [1S- (1a, 2a, 3a, 4a)] - 3 - [[3-carboxy-7-oxa-cycloplo [2.2.1] -hept-2-yl] -methyl] -benzoic acid methyl ester A solution of 450 mg (1.63 mmol) of the alcohol of Section F in 5 ml of reagent grade acetone is added rapidly at ⁰ ° C with 2.0 ml of Jones reagent (2.6 molar of Cr ⁺⁶ ). The reaction mixture is warmed to room temperature and stirred for 2 hours. The reaction is stopped by adding about 1 ml of isopropanol. After 15 minutes, the resulting green slurry is filtered through a celite pad. The filtrate is partitioned between 20 ml of diethyl ether and 20 ml of water. The organic phase is separated off and the aqueous phase is extracted with a further 20 ml of diethyl ether. The combined ether extracts are dried over magnesium sulfate and evaporated under reduced pressure. The crude title acid is obtained.

H. [IS-da ^

yl] methyl] -benzoes8ure-methylester

A solution of 447 mg (1.54 mmol) of the acid of Section G in 10 ml of dry ketyl-distilled THF is added at ⁰ ° C with 392 mg (1.69 mmol) of L-serine benzyl ester hydrochloride (ex Sigma), 228 mg (1.69 mmol) of 1-hydroxybenzotriazole hydrate (ex Aldrich) and 530 μΙ (3.8 mmol) of calcium hydride-distilled triethylamine. The mixture is stirred for 5 minutes and then treated with 348 mg (1.69 mmol) of dicyclohexylcarbodiimide (ex Aldrich) all at once. The mixture is stirred at ⁰ ° C. for 3 hours and then at room temperature for 16 hours. The resulting slurry is diluted with 10 ml of ethyl acetate, cooled to ⁰ ° C. for 15 minutes and then filtered. The filtrate is evaporated under reduced pressure. You get an oil. The crude product is purified by flash chromatography on silica gel from Merck. You get the title tester.

I. [IS-ti

benzoesSure-methylester

A solution of 495 mg (1.06 mmol) of the ester of Section H, 843 mg (3.1 mmol) of triphenyphosphine (ex Aldrich) and 540 μΙ (3.1 mmol) of diisopropylethylamine (ex Aldrich) in 6 mL of dry acetonitrile / methylene chloride 5: 1 is added Room temperature with 300 .mu.l (3.1 mmol) of analytically pure tetrachloromethane (from Mallinckrodt). The reaction mixture is stirred for 2 hours, then diluted with 15 ml of ethyl acetate and finally mixed slowly with 15 ml of saturated aqueous sodium bicarbonate solution. The resulting mixture is stirred for 5 minutes and then partitioned between 20 ml of ethyl acetate and 20 ml of water. The organic phase is separated, washed with 20 ml brine, dried over sodium sulfate and evaporated under reduced pressure. The crude product is determined by F! purified by silica gel chromatography from Merck. The title oxazoline is obtained.

J. [1S- (1a, 2a, 3a, 4a)] - 3 - [[3- [4 - [(phenylmethoxy) -; arbonyl] -2-oxazolyl] -7-oxab; cyclo-t2.2.1] hept-2-Yl] -methyl] -benzoic acid · methyl ester

A solution of 355 mg (0.79 mmol) of the oxazoline of Section I in 10 ml of dry, phosphorus pentoxide-distilled methylene chloride is added with 750 mg of nickel peroxide oxidant (prepared according to Example 1, Abstitu, J) at room temperature. The reaction mixture is stirred for 1 hour and then with 750 mg further Oxidationsmitte! added. After 30 minutes, the reaction mixture is diluted with 20 ml of ethyl acetate and then treated with 10 ml of 3M aqueous sodium bisulfite solution. The resulting mixture is stirred rapidly for 20 minutes and then treated with 10 ml of water. The organic phase is separated off and the aqueous phase is extracted with a further 20 ml of ethyl acetate. The combined organic extracts are washed with 25 ml of 1M aqueous sodium nitrate solution, dried over magnesium sulfate and evaporated under reduced pressure. You get an oil. The crude product is purified by flash chromatography on silica gel from Merck. The title oxazole is obtained.

K. [1S- (1a, 2a, 3a, 4a)] l-3 - [[3- [4 - [[[4- (4-chlorophenyl) -butyl] amino] carbonyl] -2-oxazolyl] - 7-oxabicyclo [2.2.1] hept-2-yl] -mothyl] -benzoic acid methylester

A mixture of 165 mg (0.37 mmol) of oxazole from Section J and 30 mg of 20% palladium hydroxide on carbon catalyst (wet, <50% water, from Aldrich) in 5 ml of reagent grade ethyl acetate is stirred in a hydrogen atmosphere (balloon) for 1 hour. The catalyst is filtered off through a 4 \ in the polycarbonate membrane. The filtrate is evaporated under reduced pressure. A crude acid is obtained.

A solution of 125 mg (0.35 mmol) of the crude acid in 3 ml of dry, phosphorus pentoxide-distilled methylene chloride is added at room temperature with a small drop of dimethylformamide (DMF) and then 40 .mu.l (0.46 mmol) of oxalic acid chloride (ex Aldrich). The reaction mixture is stirred for 30 minutes and then evaporated under reduced pressure. The crude acid chloride is obtained. The acid chloride is dissolved in 3 ml of dry methylene chloride and cooled to 0 ° C. Then, a solution of 84 mg (0.46 mmol) 4-chlorophenylbutylamine and 70 μ l (0.5 mmol) is added via calcium hydride-distilled triethylamine in 1 ml of dry methylene chloride. The reaction mixture is stirred for 30 minutes and then between 25ml Essigsäureethyi ster and 15m! 1M hydrochloric acid distributed. The organic phase is separated off and the aqueous phase is extracted with a further 10 ml of ethyl acetate. The combined organic extracts are dried over magnesium sulfate and evaporated under reduced pressure. The crude product is purified by flash chromatography on silica gel from Merck. You get the title tester.

L. [1S- (1a, 2a, 3a, 4a)] - 3 - [[3-t4 - [[[4- (4-chlorophenyl) -butyl] -amino] -carbonyl] -2-oxazolyl] -7 -Oxabicyclo [2.2.1] hept-2-yl] methyl] benzoic acid

A solution of 151 mg (0.29 mmol) ester of Section K and 25 mg (0.6 mmol) of lithium hydroxide monohydrate (ex Aldrich) in 6 mL of THF / water 2: 1 is stirred vigorously for 1.5 hours at room temperature. The mixture is acidified by adding 2 ml of 1 M hydrochloric acid and partitioned between 20 ml of ethyl acetate and 20 ml of water. The organic phase is separated, washed with 20 ml brine, dried over magnesium sulfate and evaporated under reduced pressure. You get the title item.

Example 8

[1S * (1α, 2α, 3α, 4α}] - 5 × [[3 · [4 · [[(4 · Cvclohθxylbutyl) · amlno] · carbonyl] -2-oxazolvll · 7.oxablcyclo [2.2.1] hept · 2.vl] · mθthvll · phenvl] · niethyl] -1H-tetrazole

A. [1S- (1a ₁ 2a, 3a, 4a)] - 3 - [[3- [4 - [[(4-cyclohexylbutyl) -amino] -carbonyl] -2-oxazolyl] -7-oxa-cyclo [2.2. 1] hept-2-yl] methyl] phenylacetonitrile

To a solution of 1 mmol of the ester of Example 7, Section K in 10 ml of tetrahydrofuran is added 2 mmol of lithium borohydride. The reaction mixture is stirred boi 23 ⁰ C for 1 hour. The reaction is then stopped by the addition of 1 M hydrochloric acid. The aqueous phase is extracted with ethyl acetate. The organic phases are dried, filtered and evaporated under reduced pressure. The raw alcohol is obtained. This alcohol is converted to the title nitrile according to the procedures of Example 2, Section i (b) and I (c).

For example, [IS-d

phonyll-methyl] -1H-tetrazole

A mixture of 300 mg (0.81 mmol) of Section A, 85 mg (1, OmMoI) sodium azide, 53 mg (1, OmMoI) ammonium chloride and 42 mg (1, OmMoI) lithium chloride in 5 ml dry dimethylformamide is heated to 125 ° C for 24 hours. The mixture is cooled and filtered, the filtrate is evaporated under reduced pressure and the residue is partitioned between water and ethyl acetate The aqueous phase is adjusted to pH 2 with 1M hydrochloric acid The organic phase is separated, dried over magnesium sulphate and evaporated under reduced pressure The crude product is purified by flash chromatography on silica gel from Merck to give the title compound.

Example S

[1 £ - (1a, 2a, 3a, 4a)] - [2 - [[3- [4 - [[(4.Cyclohexylbutyl) amino] carbonyl] -2-üxazolyl] -7-oxablcyclo [2.2. 1] hept-2-yl] methyl] phenoxyl acetic acid

A. 1 Bromo-2- (methoxymethoxy) benzene

4.5 g (112 mmol) of sodium hydride dispersion (60% in oil, ex Aldrich) was removed by washing with 3x 20 mL of hexane to remove the oil. The residue was covered with 75 ml of dimethylformamide (ex Burdick and Jackson). The resulting mixture was heated to about 5O ⁰ C and 15 minutes with 18.1 g (105 mmol) of 2-bromophenol (Aldrich) was added dropwise. A vigorous evolution of gas was observed. The mixture was stirred for a further 30 minutes. The resulting gray-brown solution was cooled to ⁰ ° C. and treated dropwise with 9.6 ml (117 mmol) of bromomethyl methyl ether (ex Aldrich) for 15 minutes. The reaction mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 16 hours. The resulting slurry was partitioned between 200 mL of 1M sodium hydroxide solution and 150 mL of hexane / diethyl ether 4: 1. The aqueous layer was separated and extracted with further 100 ml of hexane / diethyl ether 4: 1. The combined organic phases were washed with 2 x 200 ml of water, dried over magnesium sulphate and concentrated under reduced pressure; evaporated. This gave 22.2 g (102 mmol, 97% of the title compound as a pale yellow liquid.

B. [la-iiü.Ga.S

A L: 'ung ^ of 16.7 g (77 OmMoI) aryl bromide from Part A in 150 mL of dry, distilled from potassium / benzophenone THF was added at -78 ⁰ C was added dropwise 48 ml (77 mmol) of 1.6 M n- Butyllithium in hexane (from Aldrich) in 30 minutes dropwise. The Reektionsgemisch was stirred for 1 hour at -78 ^0C. The resulting white slurry of the anion was dried in 30 ml with a solution of 4.8 g (30.8 mmol) of | 3aR- (3aa, 4β, 7β, 7aa)] - octahydro-4,7-epoxyisobenzofuran-1-ol in 30 ml THF added. The reaction mixture was warmed to ⁰ ° C. while being homogeneous, stirred for 2 hours, admixed with 5 ml of methanol and evaporated under reduced pressure. The residue was partitioned between 100 ml of brine and 100 ml of ethyl acetate. Thereafter, an additional 50 ml of water was added. The aqueous phase was separated and extracted with 100ml Essigsäureethyloster. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained. The crude product was purified by flash chromatography through 22x 5cm silica gel from Merck with ethyl acetate / petroleum ether 1: 2 and then with ethyl acetate. 8.49 g (28.9 mmol, 94%) of title diol oeI were obtained.

C. [1S- (1n, 2a, 3a, 4a)] - 2 - [[2- (methoxymethoxy) -phinyl] -methyl] -7-oxacyclo [2.2.1] heptane-3-methanol

A mixture of 8.4 g (28.6 mmol) of the diol of Section B and 8.0 g of 10% palladium carbon on catalyst (from Aldrich) in 75 mL of glacial acetic acid was stirred for 18 hours in a hydrogen atmosphere (balloon). The resulting mixture was filtered with a Buchner funnel and passed through a 4 μm polycarbonate membrane. The filtrate was evaporated under reduced pressure (oil pump vacuum). An oil was obtained. The oil was partitioned between 75 ml of ethyl acetate and 100 ml of 1M sodium hydroxide solution (pH of the aqueous phase = 12). Then, 100 ml of saline was added. The aqueous phase was separated and extracted with a further 50 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. This gave 7.56 g (27.2 mmol, 95%) of the title alcohol as a colorless oil.

D. [Ilyypyyphenyl 552 mg (13.8 mmol) of sodium hydride dispersion (60% in Aldrich oil) was stripped of oil by washing three times with petroleum ether. The residue was covered with 15 ml of dry THF distilled from potassium / benzophenone. The mixture was heated to about 50 ⁰ C and then treated with a solution of 3.5 g (12.6 mmol) of alcohol from Part C in 15 mL of dry THF dropwise. You watched a fierce gaspick! The mixture was stirred for a further »30 minutes and then cooled to ⁰ ° C. The resulting anion solution was treated with 465 mg (1.26 mmol) of tetra-n-butylammonium iodide (ex Fluka) followed by dropwise addition of 1.6 mL (14 mmol) of benzyl bromide (ex Aldrich). The mixture was stirred at ⁰ ° C. for 2 hours and then at room temperature for 16 hours. The resulting mixture was admixed with 5 ml of water and then partitioned between 100 ml of 1M hydrochloric acid and 50 ml of ethyl acetate. The aqueous phase was separated and extracted with a further 50 ml of ethyl acetate. The combined organic phases were washed with 100 ml of 1M sodium hydroxide solution, dried over magnesium sulfate and evaporated under reduced pressure. This gave 4.55 g (12.4 mmol, 98%) of the crude title compound as a yellow oil.

E, [IS-lia.aa.Sa ^ Qll ^ -IO-HPhanylmethoxyl-methyll-y-oxablcycloia.a.ilhept ^ -yn-methyl-phenol

A solution of 4.53 g (12.3 mmol) of the title compound of Section D in 12 ml of dioxane (ex Burdick and Jackson) was mixed at room temperature with 30 ml of concentrated HCl / methanol 1: 4. The mixture was stirred for 5 hours and then evaporated under reduced pressure. The residue was partitioned between 50 mM hydrochloric acid and 75 ml of ethyl acetate and then admixed with 50 ml of saline. The organic phase was separated, dried over magnesium sulfate and evaporated under reduced pressure. An orange oil was obtained. The crude oil was purified by flash chromatography through Merck 12 x 5cm silica gel with ethyl acetate / methylon chloride / hexane. This gave 3.46 g (10.7 mmol, 87%) of title phenol as a pale yellow glass.

F. [Iyyypyphenyl 420 mg (11 mmol) sodium hydride dispersion (60% in oil, ex Aldrich) was freed of oil by washing three times with hexane. Subsequently, 15 ml of dry potassium / ezophenone-distilled THF was added. The resulting mixture was added dropwise with stirring at room temperature for about 15 minutes to a solution of 3.3 g (10.2 mmol) of phenol from Section E in 120 mL of dry THF. A vigorous evolution of gas was observed. The mixture was stirred for a further 30 minutes, cooled to ⁰ ° C. and treated dropwise with a solution of 1.75 g (10.5 mmol) of ethyl bromoacetate (ex Aldrich) in 2 ml of THF. The reaction mixture was stirred for 1.5 hours and then treated with 50 ml of 1M hydrochloric acid. The resulting mixture was added to 50 ml of brine and extracted with 75 ml of ethyl acetate /. The organic extract was dried over magnesium sulfate and evaporated under reduced pressure. One kept an oil. The crude oil was purified by flash chromatography through Merck 12x 5cm silica gel with 1: 2 ethyl acetate / hexane. This gave 3.87 g (9.44 mmol, 93%) of the title ester as a pale yellow oil.

Q. [1S- (1a, 2a, 3a, 4a)] - [2 - [[3- (hydroxymethyl) -7-oxaflulo- [2.2.1] hept-2-yl] -methyl] -phenoxv'j- Ethyl e8slate A mixture of 3.6 g (8.78 mmol) of the ester of Section F and 180 mg of 20% palladium hydroxide on carbon catalyst (wet, from Aldrich) in 25 mL of ethyl acetate was stirred under hydrogen atmosphere (balloon) for 2 hours. until the DC showed a weak reaction. The mixture was washed with 12 ml of absolute ethanol and then with 0.3 ml of concentrated hydrochloric acid. , 3tzt. The mixture was stirred for 2 hours (TLC showed a weak reaction), then an additional 360 mg of catalyst was added. The mixture was stirred for 20 hours, filtered through a Buchner funnel and then through a 4 μm polycarbonate membrane. The filtrate was evaporated under reduced pressure. An oil was obtained. The crude oil was purified by flash chromatography through 15 x 5cm Merck silica gel with ethyl acetate-Hoxan 2.1. This gave 1.2 g (3.75 mmol, 43%) of the desired title alcohol as an oil and 1.48 g (4.09 mmol, 47%) of the corresponding acetic acid ester as an oil.

H. [1S- (1a, 2a, 3a, 4a)] - [2 - [[3-carboxy-7-oxablcyclo [2.2.1] -hept-2-yl] -methyl] -phenoxy] -sulfurate ethyl ester A solution of 1.17 g (3.66 mmol) of Section G alcohol in 15 mL of reagent grade acetone was rapidly added at ⁰ ° C to 2.5 mL (6.5 mmol) of Jones reagent (2.6M on Cr ⁺⁶ , for preparation, cf. Fioser & Fieser, Vol. 1, page 142). The mixture was mixed for 1 hour at 0 ° C and then 30 minutes at Raumtemperatur'gerührt, the mixture was cooled to ^{0 °} C, treated with 2 ml isopropanol and stirred for an additional 30 minutes. The resulting green slurry was filtered through a celite pad. The filtrate was evaporated under reduced pressure and the residue was partitioned between 20 ml of 1M hydrochloric acid and 20 ml of ethyl acetate. The organic extract was separated, washed with 20 ml of brine, dried over magnesium sulfate and evaporated under reduced pressure. 1.19 g (3.56 mmol, 97%) of the title acid were obtained as an oil.

I. t1S- (1a, 2a, 3a, 4a)] - [2 - [[3 - [[[1- (hydroxymethyl) -2-oxo-2- (phosphinylmethoxy) ethyl] amino] carbonyl] - 7-oxablcyclo-t2.2.1] hept-2-yl] - msthy] 'phenoxy] -essigsSure-ethyl estar!

A solution of 1.19 g (3.69 mmol) of portion H crude acid in 15 mL of dry potassium / benzophenone distilled THF was dissolved at ⁰ ° C. with 540 mg of (4, OmMoI) 1-hydroxybenzotriazole hydrate (ex Aldrich). , 928 mg (4, OmMoI) L-serine benzyl ester hydrochloride (from Sigma) and then treated with 1.2 rnl (8.5 mmol) triethylamine distilled over calcium hydride. The slurry was stirred for 5 minutes followed by the addition of 824 mg of (4, OmMoI) dicyclohexylcarbodiimide (ex Aldrich). The reaction mixture was stirred at ⁰ ° C. for 3 hours and then at room temperature for 16 hours. The resulting slurry was diluted with 5 ml of ethyl acetate and then filtered. The filtrate was evaporated under reduced pressure. An oil was obtained. The crude product was purified by flash chromatography through 12 χ 5cm Merck silica gel with ethyl acetate. This gave 1.33 g (2.6 mmol, 73%) of the title amide as a solid.

J. [1S- {1α, 2α, 3α, 4α) 1 · (2 - [[3 · [4,5 · dihydro · 4-phenylpropethoxy) carbonyl] 2-oxa-olyl] -7-oxa -cyclo- [2.2.1] hθp ^ 2-yl] mθthyl] · phenoxyj-oleic acid othylosite

A solution of 1.32g (2.58 mmol) amide from section 1,1.02g (3.9 mmol) of triphanylphosphine (ex Aldrich) and 0.7 ml (4, OmMoI) diisopropylethylamine (ex. Aldrich) in 12 ml dry acetonitrile / methylonchloride 380 ml (3.9 mmol) of analytically pure tetrachloromethane were added at room temperature to 5: 1. The mixture was stirred for 2.5 hours and then treated with 30 ml of ethyl acetate and 30 ml of saturated sodium bicarbonate solution. The organic phase was separated, washed with 30 ml brine, dried over sodium sulfate and evaporated under reduced pressure. An oily solid was obtained. The crude product was purified by flash chromatography through 1b x 5cm silica gel from Merck with ethyl acetate / hexane 4: 1. This gave 883 mg (1.79 mmol, 69%) of title oxazoline as an oil.

K. [1S- (1α, 2α, 3α, 4α)] • [2 [[3- [4 - [(P1-ynylmethylthioxy-carbonyl] 2-oxazolyl] 7-oxa -cyclo [2.2.1] hept2-yl ] ethyl] ethylphosphate] acetate

A solution of 860 mg (1.74 mmol) of oxazoline from section J in 15 ml of dry phosphorus pentoxide-distilled methylene chloride was added at room temperature with 1.7 g of nickel peroxide oxidizer (for preparation see Example 1, Section J) all at once. The mixture was stirred for 45 minutes. A TLC indicated that the reaction was incomplete and another 1.7 g of oxidant was added. After 45 minutes, another 0.85 g of oxidizing agent was added. The reaction mixture was stirred for 45 minutes. A TLC showed that the starting compound was reversed. 50 ml of ethyl acetate and then 100 ml of 3M aqueous sodium bisulfite solution were added. The mixture was

Stirred vigorously for 30 minutes. The green emulsion was then added with 50 ml of 1 M aqueous sodium citrate solution. After 15 minutes of stirring, two phases formed. The organic phase was separated and the aqueous phase was extracted with a further 50 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. An oil was obtained. The crude product was purified by flash chromatography through 15 x 3 cm Merck silica gel with ethyl acetate / hexane 2: 3. 390 mg (0.79 mmol, 45%) of the title oxazole were obtained as a foam.

L. [1S- (1a, 2a, 3a, 4a)] - [2 - [[3- (4-carboxy-2-oxazolyl) -7-oxabicyclo [2.2.1] hept-2-vl] -methyl] A mixture of 385 mg (0.78 mmol) of oxazole from Section K and 38 mg of 20% palladium hydroxide on carbon as catalyst (wet, from Aldrich) in 10 ml of ethyl acetate was stirred vigorously under a hydrogen atmosphere (balloon) for 1.5 hours and then mixed with magnesium. The reaction mixture was passed through a 4 μιτι polycarbonate membrane. The filtrate was evaporated under reduced pressure. This gave 314 mg (0.78 mmol, 100%) derTiteloxazolsäure as a white solid, mp 151-154 ⁰ C.

M. [1S- (1a, 2a, 3a, 4a)] - [2 - [(3- [4 - [[(4-cyclohexylbutyl) -amino] -carbonyl] -2-oxazolyl] -7-oxa-cyclo [2.2 .1] hept-2-yl] methyl]. Phenoxyl-ethyl acetate.

A solution of 310mg (0.77mmol) of the oxazolic acid of Section L in 5ml of dry, phosphorus pentoxide distilled methylene chloride was added to a small drop of dimethylformamide followed by 90μΙ (1, OmMoI) oxalic chloride (ex Aldrich). The mixture was stirred for about 30 minutes until gas evolution ceased and evaporated under reduced pressure. The crude acid chloride was obtained as a yellow foam. The acid chloride was dissolved in 3 ml of dry methylene chloride, cooled to ⁰ ° C. and admixed dropwise with a solution of 192 mg (1, OmMoI) cyclohexylbutylamine hydrochloride and 280 μl (2, OmMoI) of triethylamine distilled over calcium hydride in 5 ml of dry methylene chloride. The reaction mixture was stirred for 15 minutes and then partitioned between 15 ml of 1 M hydrochloric acid and 25 ml of ethyl acetate. The organic phase was separated, washed with 15 mL brine, dried over magnesium sulfate and evaporated under reduced pressure. A solid was obtained. The crude product was purified by flash chromatography through 10 χ 3 cm Merck silica gel with ethyl acetate / hexane 1: 1. This gave 332 g (0.62 mmol, 80%) of the title oxazolamide as a white solid, mp 135-136 ° C.

N. [1S- (1a, 2a, aa, 4a)] - [2 - [[3- [4 - [[(4-cyclohexylbutyl) -amino] -carbonyl] -2-oxazolyl] -7-oxa-cyclo [2.2 .1] hept-2-yl] -methyl] -phenoxy! -Acetic acid

A mixture of 295 mg (0.55 mmol) of the ester of Section M and 46 mg (1.1 mmol) of lithium hydroxide monohydrate (ex Aldrich) in 2.5 mL of THF / w / r 4: 1 was added for 1.5 hours Room temperature stirred. The reaction mixture was acidified with 2.2 ml of 1M hydrochloric acid and partitioned between 20 ml of ethyl acetate and 20 ml of water. The organic phase was separated, dried over magnesium sulfate and evaporated under reduced pressure. This gave 281 mg (0.55 mmol, 100%) of the title compound as a white solid, mp 190-191 ⁰ C.

IR (KBr): 3416,2921,1741,1644,1602,1520,1492cm ¹ . '27OMHz ¹ HNMR (CDCI ₃ ):

0.70-1.90 (m, 22H) 2.18 (dd, 1H) 2.37 (dd, J = 12.12H) 2.70 (m, 1H) 3.40 (m , 3H) 4,53 (d, J = 15,1 H) 4,67 (d, J = 15,1 H) 5,04 (d, 1 H) 6,76 (d, J = 8,1 H ) 6.93 (dd, J = 7.7.1H) 7.15 (m, 3H) 8.17 (s, 1H) 67.5MHz ¹³ CNMR (CDCl ₃ ):

170,4,164,2,161,1,155,4,141,2,135,7,131,0,128,8,127,7,121,7,111,3,80,0,78,9,65,1,49,2,46,9,39,3,37, 5,37,1,33,3,30,7,29,9, 29,8,28,7,26,7,26,4,24,2

MS (CI): 511 (M + H) ⁺ OR: Ia] _O = + 41.8 ° (c = 1.0 in chloroform)

TLC: R ₁ (silica gel, acetic acid / methanol / methylene chloride 1:10:90) = 0.46, ammonium molybdate / cerium sulfate and UV, homogeneous. C ₂₉ H ₃₈ N ₂ O _6: CHN

calculated: 68.21 7.50 5.49

Filled: 68.35 7.81 5.42

Example 10

[1S- (1a, 2a, 3a, 4a)] - 2 - [[3- [4-t [7,7-Dimethylot- [yl) amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] methyl] phenylpropanoic acid

A. 7,7-D! Methyl-1-aminooctane

(1) 3,3-dimethylbutanal

A solution of 9.4 ml (107 mmol) of oxalyl chloride in 500 ml dry CH ₂ CI ₂ was 10 minutes at -60 ⁰ C with a solution of 15,4ml (18.5 g, 235 mmol) of dimethyl sulfoxide in 25 ml CH ₂ CI ₂ dropwise added. The reaction mixture was stirred for 10 minutes and then slowly added with 10 g (98 mmol) of 3,3-DimethyM-b'jianol (ex Aldrich). The reaction mixture was stirred for a further 20 minutes and treated with 68.1 ml (489 mmol) of triethylamine. Thereafter, the reaction mixture was allowed to warm to room temperature. 50 ml of water were added, the organic phase was separated off and the aqueous phase was extracted with 30 ml of CH ₂ Cl ₂ . The combined organic phases were washed successively with 1% hydrochloric acid, saturated aqueous sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated under reduced pressure. This gave 3.3 g (33%) of the title compound as a volatile yellow oil.

(2) (S-carboxypropyl-triphenylphosphonyl bromide

A mixture of 100 g (599mMol) of 4-bromobutyric acid (Aldrich) and 157g (599mMol) Triphenylphosnhin (from Aldrich) was heated at 13O ⁰ C for 2 hours and then cooled to room temperature. The resulting solid was dissolved in 250 ml of hot chloroform and diluted with 200 ml of diethyl ether. The mixture was cooled to room temperature and then to ⁰ ° C. The resulting solid was filtered off and dried under reduced pressure. 240 g (599 mmol), 93%) of the title compound were obtained.

(3) 7,7-Dimethyl-4-octenoic acid

A solution of 13.7 g (31.9 mmol) of the phosphonium bromide from Part A (2) in 60 ml of dry THF, under argon, for 10 minutes at -15 ⁰ C was added dropwise with 32mi (57,9mMol) 1.72 M potassium tert-amylate solution (from Callery Chem.). The mixture was stirred for 0.5 hours. Thereafter, the resulting orange reaction mixture was treated slowly with a solution of 2.0 g (19.9 mmo!) Of the aldehyde from Part A (D in 5 mL THF, The reaction was for 1 hour at -15 ⁰ C and then 20 hours at room temperature The reaction was quenched with 12 ml of glacial acetic acid, the resulting solution was evaporated under reduced pressure and the residue was partitioned between 100 ml of ethyl acetate and 100 ml of saturated NaHCO _3. The organic phase was separated and the aqueous phase was extracted with 2 × 100 ml of ethyl acetate The combined organic phases were washed successively with 1% hydrochloric acid, water, saturated aqueous NaHCO ₃ , water and brine, dried over magnesium sulfate and evaporated under reduced pressure The residue was purified by flash chromatography through Merck silica gel, gradient from 1% to 100 % Ethyl acetate in hexane, purified with 0.3% glacial acetic acid 1.75g (51%) of the title compound.

(4) 7,7-Dlmethyloctanoic acid

A solution of 1.2 g (7, OmMoI) of the compound of Section A (3) in 8 ml of glacial acetic acid was added while stirring with 0.2 g of platinum oxide catalyst. The mixture was stirred for 14 hours under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a pad of celite and the filtrate was evaporated under reduced pressure. The residue was diluted with öOmlToluol and re-evaporated. This process was repeated. 1.2 g (100%) of the title compound were obtained as an oil.

(5) 7,7'dimethyloctansfiureamid

To a solution of 1.21 g (7.02 mmol) of the compound of Section A (4) in 50 mL toluene was added 3 mL (134 mmol) oxalic acid chloride with stirring. The reaction mixture was stirred under argon at room temperature for 1 hour and then evaporated under reduced pressure. The residue was diluted with 20 ml of toluene and re-evaporated. The process was repeated to remove traces of oxalic acid chloride. The residue of the crude acid chloride was stirred in 5 mL methanol and treated with 1.17 mL (8.43 mmol) triethylamine and 2 mL (18 mmol) 9M ammonia in methanol under argon at room temperature. The reaction mixture was stirred for 16 hours and then partitioned between 3 ml of water and 20 ml of ethyl acetate. The organic phase was separated and the aqueous phase was extracted twice with 20 ml of ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. A semisolid product is obtained which crystallizes upon digestion with hexane. 0.5 g (42%) of the title compound was obtained as a solid.

(6) 7,7-Dimethylamino-octane

A solution of 0.45 g (2.62 mmol) of the compound of Part A (5) in 50 ml of dry diethyl ether was added under stirring in an argon atmosphere at 0 ⁰ C with 0.11 g (2.9 mmol) lithium aluminum hydride. There was a gas evolution. The reaction mixture was stirred for 4 days at room temperature. The reaction was stopped with vigorous stirring by careful sequential addition with 0.02 ml of water, 0.02 ml of 157o sodium hydroxide solution, 0.072 ml of water and 1 ml of diethyl ether. It formed a white precipitate. The mixture was stirred for 0.5 hours and filtered. The filtrate was evaporated under reduced pressure. 0.4 g (89%) of a yellow oil was obtained which crystallized to title amine by trituration with hexane and CHCl ₃ .

For example, [1S- (1a, 2a, 3a, 4a)] - 2 - [[3- [4 - [[(7,7-dimethyloctyl) -amino] -carbonyl] -2-oxBZolyl] -7-oxah! cyclo [2.2.1] hept-2-yl) -n ethyl] -phenylpropanoic acid methylene

A solution of 140 mg (0.36 mmol) of [1S- (1a, 2a, 3a, 4a)] - 2 - [[3- [4- (carboxy) -2-oxazolyl] -7-oxabicyclo [2.2.1] hept 2-yl] -methylphenylpropanoic acid prepared according to Example 2, Section J, first paragraph, in 4 ml of dry phosphoric pentoxide-distilled CH ₂ Cl j was treated with a small drop of dimethylformamide and then with 40 μΙ (0.46 mmol) oxalic acid chloride (ex Aldrich The mixture was stirred for about 20 minutes until gas evolution ceased, then the gomic was evaporated under reduced pressure to give the crude acid chloride as a pale yellow fecistoff.

A solution of the crude acid chloride in 3 ml of dry, phosphorus pentoxide-distilled CH ₂ Cl ₂ was added at ⁰ ° C with 63 mg (0.32 mmol) of the amine of Section A (80%, corresponding to 51 mg of pure amine) followed by a solution of 65 μΙ (0.46 mmol) triethylamine distilled over calcium hydride in 1 ml dry CH ₂ Cl ₂ . After 30 minutes, the reaction mixture was partitioned between 15 mL of CH ₂ Cl ₂ and 15 mL of water. The organic phase was separated and the aqueous phase was extracted with another 15 ml of CH ₂ Cl ₂ . The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. A crude solid was obtained which was purified by flash chromatography through Merck 12 x 2.5cm silica gel with 1: 1 ethyl acetate / hexane. 135 mg (0.26 mmol, 81%) of the title amine were obtained as a white solid.

C. [1S- (1a, 2a, 3a, 4a)] - 2 - [[3- [4-t [(7,7-dimethyl-octyl) -amino] -carbonyl] -2-osazolyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] methyl] -phenylpropansäure

A mixture of 134 mg (0.26 mmol) of the amide of Section B in 4 mL THF / 1 mL water was added with 22 mg (0.51 mmol) of lithium hydroxide monohydrate (ex Aldrich). The mixture was stirred at room temperature for 2.5 hours. Thereafter, the reaction was stopped by adding 1 ml of 1M hydrochloric acid. The mixture was partitioned between 20 ml of water and 20 ml of ethyl acetate. The organic phase was separated, dried over magnesium sulfate and evaporated under reduced pressure. A white crude solid was obtained which was recrystallised from hot ethyl acetate / hexane. This gave 100 mg (0.2OmMoI, 77%) of the title acid as a white solid, mp 151-153 ° C. IR (KBr): 3409.2950,2932,1726,1649,1603,1520cm " ¹ 270 MHz NMR (CDCl ₃ ) δ

8.15 (s, 1H) 7.27 (s, 1H) 7.10 (m, 4H) 4.98 (d, 1H) 4.39 (d, 1H) 3.38 (m, 3H) 2 , 90 (t, 2H) 2.55 (t, 3H) 2.34 (t, 1H) 2.20 (dd, 1H) 1.90-1.00 (m, 14H) 0.81 (s , 9H)

67.5MHz ¹³ CNMR (CDCI ₃ ) S:

176,2,163,9,160,8,141,0,138,5,137,8,136,0,129,7,129,0,126,7,126,5,7S, 7,78,7,50,0,47,0,44,2,39,2,34, 7,32,5,30,3,29,9,29,6, 29,4,28,9,27,4,27,0,24,5

MS (CL): 511 (M + H) ⁺

TLC: Rf (silica gel, methanol / methylene chloride 1: 9) = 0.2, ammonium molybdate / cersuifate and UV, homogeneous C ₃₀ H ₄₂ N ₂ O ₆ : CHN

Calculated: 70.56 8.29 5.50

F .: 70.44 8.42 5.50

In the following, further embodiments of the invention are listed:

2 3

m \ ^ * X \ / Γ X / O R- Il / R R ¹ r or. Cp. ^ 1 \ O 0 Y (position) C-N V COOM 1-piperidyl-4-butyl Example no. 1 η 0 - (2) R ² COOH 4-OH-phenylbutyl D.212 11th 1 2 0 - (2) H COOH propyl 165-168 12th 1 2 0 - (2) H COOH pentyl 136-139 13th 1 2 0 - (2) H COOH cyclohexylethyl 158-161 14th 1 2 0 - (2) H COOH t-butylbutyl 147-149 15th 1 2 0 - (2) H COOH 4-methoxyphenylbutyl 125-127 16th 1 2 0 - (2) H COOH 4-cyclohexylbuten-2-yl 167-169 17th 1 2 0 - (2) H COOH 5-cyclohexylpenten-4-yl 145-147 18th 1 2 0 - (2) H COOH heptyl 134-137 19th 1 2 0 - (2) H COOH cyclohexyl 58-62 20th 1 2 0 - (2) H COOH isopropyl 57-63 21st 1 2 0 - (2) H COOH cyclohexyloctyl 148-149 21st 1 2 0 - (2) H COOH 4-methylsulfonylphenylbutyl 159-161 23rd 1 2 0 - (2) H COOH 4-methylmercaptophenylbutyl 155-158 24th 1 2 0 - (2) H COOH phenyl 170-172 25th 1 2 0 - (2) H COOH p-biphenyl 204-206 26th 1 2 0 - (2) H COOH 4-phenylbutyl 148-150 27th 1 2 0 - (2) H COOH 4-benzyloxyphenyl 192-193 28th 1 2 0 - (2) H COOH 4-hydroxyphenyl 185-186 29th 1 2 0 - (2) H COOH 3-iodo-propen-2-yl 142-145 30th 1 2 0 - (2) H COOH 4- (m-0H, p-iodophenyl) -butyl 84-91 31st 1 2 0 - (2) H COOH Λ-cyclohexylbutyi 274-275 32nd 2 - (2) H (Na salt) 33rd 1 2 0 H COOH p-methoxyphenyl foam 1 0 - (2) COOH p-chlorophenyl 220-221 34th 1 2 0 - (2) H COOH l-imidazolylpropyl 215-216 35th 1 2 0 - (2) H COOH p-chlorophenethyl 187-138 36th 1 2 0 - (2) H COOH t-butyl 155-156 37th 1 2 0 - (2) H COOH 1,1, dimethylpropyl 128-132 38th 1 2 0 - (2) H COOH nC ₈ H ₃₇ 135-136 39th 1 2 0 - (2) H COOH ö-tN-cyclohexyO-pentamido 168-169 40th 1 2 0 - (2) H COOH 5-hydroxy-5-methylhexyl 149-150 41st 1 2 0 - (2) H COOH ö-carboxy-ö-methylnexyl 123-125 42nd 1 2 0 - (2) H COOH H > 200 43rd 1 2 0 - (2) H COOH p-F-phenylbutyl 141-143 44th 1 2 - (2) H COOH CirjC ₂ i 145-147 45th 2 0 - (2) H 46th 2 H

Example no. m η X Y (position) H R R ¹ Ep- ⁰ C 47th 1 2 0 - (2) H COOH 2,2-dimethylbutyl _ 48th 1 2 0 - (2) H COOH 2,2-dlmethylpropyl - 49th 1 2 0 - (2) H COOH 3,3-dimethylbutyl 160-162 50th 1 2 0 - (2) H COOH 2- (4-fluoro-phenyl-ethyl 187-189 51st 1 2 0 - (2) H COOH 2-phenyethyl 181-183 52nd 1 2 0 - (2) H -CONHC ₂ H ₆ cyclohexylbutyl 155-156 53rd 1 2 0 - ( ') H -CONH ₂ cyclohexylbutyl 174-175 54th 1 2 0 -Π H -CO ₂ C ₂ H ₆ cyclohexylbutyl 130-131 55th 1 2 0 - (2) CH ₃ -CH ₂ OH cyclohexyl butyl 119-121 56th 1 2 0 - (2) H COOH pentyl oil 57th 1 2 0 - (2) CH ₃ -CONHSO ₂ CH ₃ cyclohexylbutyl 154-156 58th 1 2 0 - (2) H COOH cyclohexylbutyl 60-65 59th 2 1 0 - (2) H COOH cyclohexylbutyl 58-63 60th 2 1 • 0 - (3) H COOH cyclohexylbutyl 50-58 61st 2 2 0 - (2) H COOH cyclohexylbutyl oil 62nd 1 0 0 - (2) H COOH cyclohexylbutyl 139-141 63rd 1 1 0 - (2) H COOH cyclohexylbutyl 130-132 64th 2 0 0 - (3) H COOH cyclohexylbutyl 160-162 65th 1 2 N - (2) H COOH cyclohexylbutyl 229-232 66th 1 2 0 vinyl (2) H COOH cyclohexylbutyl 210-211 67th 1 2 0 - (2) COOH 6-heptynyl -

Claims (27)

and all their stereoisomers in which
m is 1,2 or 3;
η is 0,1,2,3 or 4; Y represents an oxygen atom, a vinyl group or a single bond, with the proviso that when η is 0, Y represents a single bond; R is the group CO ₂ H, the radicals CO ₂ -alkali metal or CO ₂ -lower alkyl, the group CH ₂ OH, the radicals CONHSO ₂ R ³ or C0NHR ^3a or a 5-tetrazolyl group, with the proviso that when R is a 5-tetrazolyl group, η is not 0;
X represents an oxygen or sulfur atom or an NH group; R ^{1 represents} a hydrogen atom, a lower alkyl, lower alkenyl, lower alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, saturated-heterocyclic, saturated-heterocyclic-alkyl, aromatic-heterocyclic, aromatic-heterocyclic-alkyl or amide radical wherein each radical is optionally substituted by an alkyl, aryl, cycloalkyl or cycloalkylalkyl radical; and R ^{2 represents} a hydrogen atom, a lower alkyl, aryl or aralkyl group, or R ¹ and R ² together with the nitrogen atom to which they are attached form a 5- to 8-membered ring; R ^{3 represents} a lower alkyl, aryl or aralkyl radical and R ^{3a represents} a hydrogen atom, a lower alkyl, aroyl or aralkyl radical. 2. Compounds according to claim 1, characterized in that the compounds have the general formula IA (IA) respectively. 3. Compounds according to claim 1 or 2, characterized in that m is 1 and η is 2. 4. Compounds according to claim 1, characterized in that the compounds have the general formula IC (IC) respectively. 5. Compounds according to claim 1, characterized in that the compounds have the general formula IB (IB) respectively. 6. Compounds according to one of claims 1 to 5, characterized in that R is the group CO ₂ H, the radical CONHSO ₂ R ³ or a 5-tetrazolyl group. 7. Compounds according to claim 2, characterized in that R is the group CO ₂ H is. 8. Compounds according to claim 1, which is [1, S- (1α, 2α, 3α, 4a)] - 2 - [[3- [4 - [[(4-cyclohexylbutyl) amino] carbonyl] -2- oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] -methyl] -phenylpropanoic acid or its esters or salts. 9. Compounds according to claim 1, which is [1S- (1α, 2a, 3a, 4a)] - 2 - [[3- (4 - [([4-chlorophenyl) -butyl] -amino] -carbonyl] - 2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] -methyl] -phenylpropanoic acid or its esters or salts. Compounds according to claim 1, which is [1S- (1α, 2a, 3a, 4a)] - 3 - [[3- [4 - [[(4-cyclohexylbutyl) amino] carbonyl] -2-oxazolyl] - 7-oxabicyclo [2.2.1] hept-2-yl] methyl] phenylacetic acid or its Esters or salts. Compounds according to claim 1, which is [1S- (1α, 2a, 3a, 4a)] - [2 - [[3- [4 - [[(4-cyclohexylbutyD-amino) carbonyl] -2-oxazolyl] - 7-oxabicyclo [2.2.1] hept-2-yl] methyl] phenoxy] -essigsäureoder their esters or salts. 12. Compounds according to claim 1, which is [1S- (1α, 2α, 3α, 4a)] - 2 - [[3- [4 - [[(7,7-dimethyloctyD-amino] carbonyl] -2- oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] -methyl] -phenylpropanoic acid or its dead or salts. 13. Process for the preparation of compounds of general formula I. (D and all their stereoisomers in which m is 1,2 or 3; η has the value 1,2,3 or 4; Y represents an oxygen atom, a vinyl group or a single bond, with the proviso that when η is 0, Y represents a single bond; R is the group CO ₂ H, the radicals CO ₂ -alkali metal or CO ₂ -lower alkyl, the group CH ₂ OH, the radicals CONHSO ₂ R ³ or CONHR ³ "or a 5-tetrazolyl group, with the proviso, Jaß, if R is a 5-tetrazolyl group, η does not have the value O; X represents an oxygen or sulfur atom or an NH group; R ^{1 represents} a hydrogen atom, a lower alkyl, lower alkenyl, lower alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, saturated-heterocyclic, saturated-heterocyclic-alkyl, aromatic-heterocyclic, aromatic-heterocyclic-alkyl or amide radical wherein each radical is optionally substituted by an alkyl, aryl, cycloalkyl or cycloalkylalkyl radical; and R ^{2 represents} a hydrogen atom, a lower alkyl, aryl or aralkyl group, or R ¹ and R ² together with the nitrogen atom to which they are attached form a 5- to 8-membered ring; R ^{3 is} a lower alkyl, aryl or aralkyl radical and R ^{3n is} a hydrogen atom, a lower alkyl, aroyl or aralkyl radical, characterized in that compounds of the general formula Γ (Π CO ₂ H in which R is not the group CO ₂ H or their alkali metal salts, converted into their Säurehalogenidform and then reacting the acid halides with an amine of the formula in a conventional manner to products in which R is not a CO ₂ H group, or to the Alkali metal salts, and, if R is a CO ₂ -Niederalky! Rest hydrolyzed to obtain hydrolyzed products in which R is a CO ₂ H group and forms thereof in a conventional manner alkali metal salts. 14. The method according to claim 13, characterized in that compounds of the general formula IA (CH ₂ ) (IA) manufactures. 15. The method according to claim 13 or 14, characterized in that m has the value 1 and η is 2. 16. The method according to claim 13, characterized in that compounds of the general formula IC "^ Ό" ^Y " (Ic) manufactures. 17. The method according to claim 13, characterized in that compounds of the general formula IB (IB) manufactures. 18. The method according to any one of claims 13 to 17, characterized in that R is the group CO ₂ H, the radical CONHSO ₂ R ³ or a 5-tetrazolyl group. 19. The method according to claim 14, characterized in that R is the group CO ₂ H. 20. The method according to claim 13, characterized in that the compound [1 S- (1 α, 2α, 3α, 4a)] - 2 - [[3- [4 - [[(4-cyclohexylbutyl) amino) - carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] -methyl] -phenylpropanoic acid or its esters or salts. 21. The method according to claim 13, characterized in that the compound [1 S- (1 α, 2a, 3a, 4a)] - 2 - [[3- [4 - [[[4-chlorophenyl) -butyl] - amino] carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] -methyl-1-phenylpropanoic acid or esters or salts thereof. 22. The method according to claim 13, characterized in that the compound [1 S- (1 α, 2α, 3α, 4a)] - 3 - [[3- [4 - [[4-cyclohexylbutyl) amino] carbonyi ] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] methyll-phenylacetic acid or its esters or salts. 23. The method according to claim 13, characterized in that the compound [1 S- (1 α, 2 α, 3 α, 4a)] - i2 - [[3- [4 - [[(4-cyclohexylbutyl) amino ] carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-ylmethyl] phenoxy] acetic acid or its esters or salts. 24. The method according to claim 13, characterized in that the compound [1 S- (1 α, 2a, 3a, 4a)] - 2 - [[3- [4 - [[(7,7-dimethyloctyl) amino ] -carbonyl] -2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl! -methyl-1-phenylpropanoic acid or its esters or salts. A pharmaceutical composition comprising compounds according to any one of claims 1 to 12 in a pharmaceutically effective amount, together with pharmaceutically acceptable carriers. Use of the compounds according to any one of claims 1 to 12 for the inhibition of platelet aggregation and bronchoconstriction. Use of the compounds according to any one of claims 1 to 12 for the inhibition of bronchoconstriction which occurs in association with asthma. Use of the compounds according to any one of claims 1 to 12 for the improvement of the postischemic dysfunction of the myocardium. Use of the compounds according to any one of claims 1 to 12 for the treatment of toxemia during pregnancy. 30. Use of the compounds according to any one of claims 1 to 12 for the prevention or reduction of venous thrombosis. 31. Use of the compounds according to any one of claims 1 to 12 for the prevention or reduction of the loss of platelets in extracorporeal circulation. 32. Use of the compounds according to any one of claims 1 to 12 for combating burn injuries and / or promoting wound healing. 33. Use of the Vorbindungen according to any one of claims 1 to 12 together with a thrombolytically active agent for reducing myocardial injury after a myocardial infarction. 34. Use according to claim 33 of the compounds according to any one of claims 1 to 12, characterized in that the thrombolytically active agent is t-PA, streptokinase, urokinase, prourokinase or an anisoylated plasminogen streptokinase activator complex.