DD259192A5 - PROCESS FOR PREPARING 7-OXABICYCLOHEPTAN SUBSTITUTED DIAMIDES - Google Patents

Abstract

The invention relates to a process for the preparation of 7-oxabicycloheptane-substituted diamides of the general formula I and their stereoisomers, where the radicals have the meaning given in the invention. The compounds prepared according to the invention are valuable drugs for the treatment of thrombosis, bronchoconstriction and ischemic diseases of the heart muscle. Formula (I)

Description

and then reduced to the corresponding compound in which A is a - (CH ₂ ) ₂ group.

2. The method according to item 1, characterized in that reacting the compounds obtained with LiN (iC ₃ H ₇ ) ₂ and then with oxoperoxymolybdenum (pyridine) - (hexamethylphosphoric triamide) to give a compound in which Q is a -CH- group.

OH

3. The method according to item 1, characterized in that the compounds obtained with a compound of the general formula HNR ⁴ R ⁵ , in the R ⁴ and R ⁵ neither a hydroxyl group

represent an alkoxy radical, converted into a compound which R is a radical q _ ^ - r ⁴ -r ⁵ .

4. The method according to item 1, characterized in that the resulting compounds in which R is a CO ₂ alkyl radical, reduced to a compound in which R is a CH ₂ OH group.

5. The method according to item 1, characterized in that one hydrolyses the resulting compounds in which R is a CO ₂ alkyl radical to a compound in which R is a COOH group.

6. The method according to item 1, characterized in that the compounds obtained with a compound of general formula

- ₅ , OR ·.

HN. BCl

^ R ⁴ . .Q--

umυ a compound in which R is the radical C-N-QR.

R 'Field of the invention

The. Use of the present invention is in the field of drugs for the treatment of thrombosis, bronchoconstriction and ischemic diseases of the heart muscle.

Characteristic of the known technical solutions

Publications which underlie the present invention as prior art are currently unknown.

Object of the invention

The aim of the invention is to provide new drugs for the treatment of thrombosis, bronchoconstriction and ischemic diseases of the heart muscle.

Explanation of the essence of the invention

It is an object of the present invention to provide novel drugs which inhibit arachidonic acid induced platelet aggregation and also act as selective thromboxane A ₂ receptor antagonists and synthetase inhibitors and thus as drugs for the treatment of thrombosis, bronchoconstriction and ischemic Diseases of the heart muscle are suitable.

The invention accordingly relates to a process for the preparation of 7-oxabicycloheptane-substituted diamides of the general formula (I)

(CH.) -N-C- (CH) -NCR ^{3 x} ^ ρ ι -, ii 2 q ι _? μ

R ¹ O ΈΓ O

and their stereoisomers, where m is 0 to 4; A is a -CH = CH- or-CH ₂ -CH ₂ group; η is 1 to 5; Q is a -CH = CH-, -CH ₂ -;

OH Halo Halo Halo -

Group or a single bond, R represents a CO ₂ H group, a CO ₂ alkyl group, a CGyAlkalimetall-, a CO ₂ Polyhydroxyaminsalz, a group

-CNR ⁴ R ⁵

means in that.

R ⁴ and R ^{5 are the} same or different and represent a hydrogen atom, a lower alkyl radical, a hydroxyl group, a lower alkoxy or an aryl radical, where at least one of the two radicals R ⁴ and R ^{5 is} a hydroxyl group "and no lower alkoxy radical, ρ is the value 1 to 4 has R ¹ is a hydrogen atom or a ¹ lower alkyl; q is 1 to 12 has, R ² represents a hydrogen atom or a Niederalkyirest and R ³ is a hydrogen atom, a lower alkyl, lower alkenyl, Niederalkynyl-, aryl -, Arylalkyl-, lower alkoxy, arylalkyloxy or an aryloxy, an amino group, an alkylamino, Arylalkylamino- or Arylaminorest, or a radical

f W? η · i?

alkyl-S-, aryl-S-, arylalkyl-S-, aryl-S-alkyl-,

alkyl-S-alkyl, arylalkyl-S-alkyl

wherein n 'is 0.1 or 2, is an alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or an arylalkoxyalkyl radical, characterized in that

A) if Q is a -CH ₂ group or a single bond, a compound of general formula (VIA) "7CH ₂ T _n -A- (CH _{2) n} -Q-C0 ₂ Alky 1

(VIA)

CH-NHR ¹ ...

with a compound of general formula VII

O RO

Ii II

OH-C (CH ₀₎ -NC -R "

to a compound of the general formula

(VLI)

CH-A- (CHJ-Q-CO _ alkyl 2 2 η 1

\ CH _n -NC (CHJ -NCR

« ² I ₁ ^2q M

R RO.

and B) if Q is -CH = CH- group and Aeine-CH = CH- group, a compound of general formula (XX)

(CHJ -CHO 2 m

O RO .RO

with a compound of the general formula (C ₆ H ₅ ) 3 P = CH- (CH ₂ ) _n -CH = CHCO ₂ H

to a compound of general formula IJ

(CHJ -A- (CH) -CH = CH-CO H 2 m 2 η

(CH) -N-C- (CHJ -N-C-R "

² P Il Il ^{2 q} I ₂ Ο

R ¹ OR

and C) if Q is a -CH-

, Halo

or a halo halo

(XX)

(U)

Group and

A is a -CH = CH group, a compound of general formula XX

(CHJ -CHO 2 m

with a compound of the general formula

(C ₆ H ₅ ) ₃ P = CH- (CH ₂ ) _n -C-CO ₂ ^E

(halo) _x

where X is 1 or 2, to a compound of general formula IK

(XX)

(hala) _x

(CH ₂ ) _p -Hj> (CH ₂ ) _q -NCR R ¹ O RO

(IK)

and D) if R ^{3 is} an NH ₂ group, a compound of the general formula VIA

(CH ₂ ) _m -A- (CH ₂ ) _n -Q-CO ₂ alkyl

with a compound of the general formula

HO ₀ C-CH ₀ -NC-NH ₉

O and then converted to a compound of general formula IT

(CH) -A- (CH) -Q-R 2 m 2 η

2 η

1 ^(CH 2 ^ -f "i- ^ J _q - _fr C-NH ₂

o ho ro '

hydrolyzed, and E) if R is a group

N N

N N

and A is a -CH = CH group, a compound of general formula HC

(CHJ _m -CH = CH- (CH ₂ ) _n -Q _ ^ | J

N N

(VIA)

(IT)

(MC)

with a compound of the general formula

II H

HO-C- (CHJ-N -C-

to a compound of general formula IN

(CHJ -CH = CH- (CHJ -Q 2 m 2 η

(CH) -Ν- C- (CH 1 -N-C-

² PI 1 II ^{2 q} I 2 H

RO RO

N N

'N- N H

(IN)

and then reduced to the corresponding compound in which A is a - (CH ₂ ^ - group.

The subject matter of the invention is also the said method with the special feature that the compounds obtained are reacted with LiN (i-C3H ₇ ) ₂ and then with oxoperoxymolybdenum (pyridine) (hexamethylphosphoric triamide) to give a compound in which Q is a CHOH group ,

The invention also provides the said process with the particular feature that the compounds obtained are reacted with a compound of the general formula HNR ₄ R ₅ in which R ₄ and R _{5 represent} neither a hydroxyl group nor an alkoxy radical, to give a compound in which R a rest

"45

-CNR * R

The invention also provides the said method with the particular feature that the compounds obtained, in

wherein R is a -CO ₂ -AIkyIrest, reduced to a compound in which R is a -CH ₂ OH group.

The invention also provides the said method with the particular feature that the compounds obtained, in

wherein R is a -CO ₂ -AIkylrest hydrolyzed to a compound in which R is a-CO ₂ H group.

The subject matter of the invention is also the abovementioned process with the special feature that the obtained

Compounds with a compound of the general formula

HtT. HCl

converts to a compound, in the R the rest

"45 '·.

-CNR OR - - -

The term "lower alkyl" or "alkyl" used either alone or as part of a larger group refers to both branched and unbranched carbon chains of 1 to 12 carbon atoms in the main chain, preferably of 1 to 7 carbon atoms, such as methyl, Ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl , Nonyl, decyl, undecyl or dodecyl groups, their branched isomers and groups having a halogen substituent, such as a fluorine, bromine, chlorine or iodine atom or the 'group CF ₃ , an alkoxy, an aryl, an alkylaryl, a haloaryl, a cycloalkyl, an alkylcycloalkyl substituent, a hydroxyl group, an alkylamino, an alkanoylamino, an arylcarbonylamino, a nitro, a cyano, a thiol or an alkylthio substituent.

The term "cycloalkyl", used either alone or as part of a larger group, means saturated cyclic hydrocarbons of 3 to 12 carbon atoms, preferably of 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , Cyclooctyl, cyclodecyl or cyclododecyl groups optionally with 1 or 2 halogen atoms, 1 or 2 lower alkyl radicals, 1 or 2 lower alkoxy radicals, 1 or 2 hydroxyl groups, 1 or 2 alkylamino radicals, 1 or 2 alkanoylamino radicals, 1 or 2 arylcarbonylamino radicals, 1 or 2 Amino groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 thiol groups and / or 1 or 2 alkylthio radicals. The term "aryl radical" or "Ar" used either alone or as part of a larger group means monocyclic or Bicyclic aromatic groups having 6 to 10 carbon atoms in the ring, for example, a phenyl, naphthyl, substituted phenyl or substituted Naphthyl group in which the respective substituents of the phenyl or naphthyl optionally 1 or 2 lower alkyl radicals, halogen atoms such as chlorine, bromine or fluorine atoms, 1 or 2 lower alkoxy, 1 or 2 hydroxyl groups, 1 or 2 alkylamino radicals, 1 or 2 Aikanoylaminoreste, 1 or 2 arylcarbonylamino radicals, 1 or 2 amino groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 thiol groups and / or 1 or 2 alkylthio radicals. The term "aralkyl group", "arylalkyl group" or "aryl lower alkyl group" used either alone or as part of a larger group means one of the above-described lower alkyl groups having an aryl substituent, for example, a benzyl group.

The term "lower alkoxy", "alkoxy", "aryloxy" or "aralkoxy" used either alone or as part of a larger group means a lower alkyl, alkyl, aralkyl or aryl group bonded to an oxygen atom.

The term "lower alkylthio radical", "alkylthio radical", "arylthio radical" or "aralkylthio radical" used either alone or as part of a larger group means a lower alkyl, alkyl, aralkyl or aryl radical bonded to a sulfur atom as described above.

The term "lower alkylamino radical", "alkylamino radical", "arylamino radical" or "arylalkylamino radical", used either alone or as part of a larger group, means a lower alkyl, alkyl, aryl or arylalkyl radical attached to a nitrogen atom.

The term "alkanoyl" used as part of a larger group means a lower alkyl group attached to a carbonyl group.

The term "lower alkylene" used either alone or as part of a larger group means a branched or unbranched carbon chain having 2 to 12 atoms, preferably having 2 to 6 atoms in the main chain, which contains a double bond in the main chain, such as a 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, or 4-dodecenyl.

• -9- 259

The term "lower alkynyl" used either alone or as part of a larger group means a branched or unbranched carbon chain having 2 to 12 atoms, preferably having 2 to 6 atoms in the main chain, which contains a triple bond in the main chain, e.g. B. is 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4 Heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, or a 4-dodecynyl group.

By the term (CH ₂ ) _m , (CH ₂ J _n and (CH ₂ ) _P , branched or unbranched chains having 0 to 4 carbon atoms in the main chain ((CH ₂ ) _m ), 1 to 5 carbon atoms in the main chain (( CH ₂ J _n ) or 1 to 4 carbon atoms in the main chain ((CH ₂ ) _P ). Optionally these chains contain one or more lower alkyl and / or halogen substituents Examples of the groups (CH ₂ ) _m , (CH ₂ ) _n and (CH ₂ ) _P are the groups

ρττ PtJ

^ - El- Uli

Cl j -CH ₂ -CHr-, -CH-, A ι CH ₂ CH ₃ , -CH ₂ CH- -CH-, -C-, 5 C ₂ H ₅ -CHCH ₀ 2 CH ₃ ( CH ₀ ) _o ^H 5 FJ -C- CH ₂ CH ₂ , -CH ₂ -CH- CH- C ₂ H - ( 1 CH ₃ -CHCH ₂ -, ) C- ^CH 3 - (CH CH ₃ , - (CH ₂ ) ^, ^CH 2 ^} 5 ' - ( <= 2 F CH ₃ -CHCH- I -C-CH ₂ -, 2> 3 CH ₂ C CH ₃ J ₂ -CH-, -CH CH ₃ ^{CH3 : H3} CH ₃ or 2 ~ ^€ Γ ' ₂ -CH- CH ₃ , - (CH i CH ₃ -CH ₂ -CH ₀ -CH-CH-CH ₃ CH -CH-CH ^CH 3

The term (CH ₂ ) _q denotes branched or unbranched chains having 1 to 12 carbon atoms in the main chain. Examples of the group (CH ₂ ) _q are the groups mentioned above as examples of the groups (CH ₂ ) _m , (CH ₂ I _n and (CH ₂ ) _P and the group (CH ₂ I ₆ , (CH ₂ I ₇ , (CH ₂ J ₈ , (CH ₂ ) _g , (CH ₂ ) i ₀ , (CH ₂ ) n or (CH ₂ ) i ₂ ) These groups are optionally substituted by one or more halogen groups, hydroxyl groups, alkoxy radicals, amino groups, alkylamino radicals, Arylamino, amide, thioamide, Thiolgrup.pen, alkylthio, arylthio, cyano or nitro substituted.

The term "amide" means the group in which R ⁶ and R ^{7 are} independently a hydrogen atom, -CN, represent a lower alkyl or aryl. \ Η

The term "polyhydroxyamine salt" means a glucamine salt or tris- (hydroxymethyl) -aminomethane The term "halogen atom" means a chlorine, bromine, fluorine or iodine atom or the group CF ₃ , preferably a chlorine or fluorine atom.

Preference is given to compounds of the general formula I in which m is 1 or 2, A is -CH = CH- group, η is 1 or 4, Q is a single bond or the group-C (F ₂ ) -,

OH

I t

-CH-

(CH ₂ J ₂ or -CH = CH, R is CO ₂ H or CH ₂ OH group, ρ is 1, R ^{1 is} hydrogen, (CH ₂ ) _{q is} -CH ₂ - group R ^{2 represents} a hydrogen atom or a CH ³ group and in which R ^{3 is} a lower alkyl radical, eg a pentyl, hexyl or heptyl group, a lower alkoxy radical, eg a pentoxy group, a lower alkylamino radical, eg a pentylamino group, or an arylthioalkyl radical For example, a phenylthiomethyl group The preferred compounds of general formula I are listed below.

1. The compounds of general formula I in which R ^{3 is} an alkyl, alkoxy or Arylthioalkylrest.

2. The compounds of the general formula I in which A is a -CH = CH group. ,

3. The compounds of general formula I in which m is 1 and η is 1 to 4.

4. The compounds of the general formula I in which ρ has the value 1 and q has the value 1.

5. The compounds of general formula I in which Q is a single bond or a -CH ₂ group.

6. The compounds according to claim 1, in which is pure CO ₂ alkyl radical or a -CO ₂ H group.

7. The compounds of the general formula I in which R ^{1 is} a hydrogen atom and R ^{2 is} a hydrogen atom or a CH ₂ group.

8. The compounds of the general formula I in which m has the value 1, η has the value 2 to 4, Q a -CH ₂ -GrUpPe, a single bond, a -CH = CH group or the group OH

-CH-

halo halo. ,

_R Rein is a pure CO ₂ alkyl radical _r a -CO ₂ H group, a -CH ₂ OH group or moiety

H 4 5

CNR R

is, ρ is 1, R ^{1 is} hydrogen, q is 1, R ^{2 is} hydrogen or alkyl, and R ^{3 is} alkyl, alkoxy or phenylthiomethyl.

9. [1S- [Iβ, 2a (5Z), 3a4β]] - 7- [3 - [[[[(1-oxohexyl) amino] acetyl] amino] methyl] -7-oxobicycio [ 2.2.1] hept-2-yl] -5-heptenoic acid or its esters and stereoisomers.

10. [1S- [1β, 2a (5Z), 3a, 4β]] - 7- [3 - [[[[[[(butylamino) carbonyl] amino] acetyl] amino] methyl] -7- oxabicycloE2.2.1] hept-2-yl] -5-heptenoic acid or its esters and stereoisomers.

11. [IS-α, β-α, β, β] -II-tert-butyl-d-oxohexyl-D-amino-1-yl-aminol-methyl-1-yl-oxabicyclo) -he-3-heptyl-B-heptenoic acid or their esters and stereoisomers.

12. [1S- [1β, 2a (5Z), 3a, 4β]] - 7- [3 - [[[[([butoxycarbonyi) amino] acetyl] amino] methyl] -7-oxabicyclo [2.2. 1] hept-2-yl] -5-heptenoic acid or its esters and stereoisomers.

13. [1S- [1β, 2a (5Z), 3a (R), 4β]] - 7- [3 - [[[1-Oxo-2 - [(1-oxohexyl) -amino] -propyl] -amino ] -methyl] -7-oxabicyclo [2.2.1] hept-2-y!] - 5-heptenoic acid or its esters and stereoisomers.

14. nS-Tiss ^ alBzl ^ aiSl ^ ßll ^ -is-itii-oxo ^ -KI-oxohexyD-amine oil-propyl-aminol-methyll ^ -oxabicyclo ^^. H-hept ^ -yil-B-heptenoic acid or its esters and stereoisomers.

15. [1S- [1β, 2a (5Z), 3a, 4β]] - 7- [3 - [[[[(1-oxo-4-phenyl) -butyl] -amino] -acetyl] -amino] -methyl] -7-oxabicycio [2.2.1] hept-2-yl] -5-heptenoic acid or its esters and stereoisomers.

16. · [1S- [1a, 2β (Z), 3β, 4a]] - 7- [3 - [[[[[[[(phenylthio) acetyl] amino] acetyl] amino] methyl] -7-oxabicyclo [2.2.1] -hept-2-yl] -5-heptenoic acid or its esters and stereoisomers.

17. [1S- [1a, 2β (Z), 3β, 4a]] - 7 - [[[[[3- (4-hydroxyphenyl) -1-oxopropyl] -amino] -acetyl] -amino] -methyl] -7-oxabicyc! O [2.2.1] hept-2-yl] -5-heptenoic acid or its esters and stereoisomers.

18. [1S- [1a, 2β (Z), 3β, 4a]] - 7- [3 - [[[[(phenoxyacetyl) amino] acetyl] amino] methyl] -7-oxabicyclo [2.2 .1] -hept-2-yl] -5-heptenoic acid or its esters and stereoisomers.

19. [1S- [1a, 2β (5Z), 3β, 4a]] - 7- [3 - [[[[(1-oxo-3-phenylpropyl) amino] acetyl] amino] methyl] - 7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid or its esters and stereoisomers.

20. [1S- [1a, 2β (5Z), 3β, 4a]] - 7- [3 - [[[[(1-oxo-5-phenyl-pentyl) -amino] -acetyl] -amino] -methyl] - 7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid or its esters and stereoisomers.

21. [1S- [1a, 2β (Z), 3β, 4a]] - 7- [3 - [[[[(4-cyclohexyl-1-oxo-butyl) -amino] -acetyl] -amino] -methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid or its esters and stereoisomers.

22. [IS-iia-ßlZl ^ ß ^ all ^ -IS-ttltii-oxo-S-IPhenylthio 5-heptenoic acid or its esters and stereoisomers.

23. [IS-iia-βlZJ.Sß ^ all ^ -P-t-n-phenyl-phenyl-methyl-thi-heptenoic acid or their esters and stereoisomers.

24. [1S- [1a, 2β (Z), 3β, 4a]] - 7- [3 - [[[[[[(butylthio) acetyl] amino] acetyl] amino] methyl] -7- oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid or its esters and stereoisomers.

25. [1S- [1a, 2β (Z), 3β, 4a]] - 7- [3 - [[[[[[[(cyclohexylmethyl) -thio] -acetyl] -amino] -acetyl] -amino] - methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid or its esters and stereoisomers.

26. [IS-Iia] ßfZl ^ ß ^ all ^ -IS-ItllliPhenylsulfinyD-acetyl-aminol-acetyl-aminol-methyll ^ -oxabicyclo ^^. Ilhept ^ -yll-S-heptenoic acid or their esters and stereoisomers.

27. [1S- [1a, 2ß (Z), 3R, 4a]] - 7- [3 - [[[[[(phenylsulfonyl) acetyl] amino] acetyl] amino] -methyl] -7 oxabicycio [2.2.1] hept-2-yl] -5-

heptenoic acid or its esters and stereoisomers. The compounds of general formula I can be prepared as described below.

A. ρ and m are 1, Q is a -CH ^ group or a single bond, and R ¹ is a hydrogen atom

, alkyl

CIIOIl

reduction

(in: the A is a -CH = CH group _H / _pd / _c

is)

II

(in which A is a - (CH ₉ J -group ΙΙΛ ^zz )

tosylation

• ^: ->

TsCl / Pyr.idln-

^ f CII ₂ -A- (CH ₂ J _n -Q-CO ₂ alkyl _K -N

Displacement reaction; DMSO 90-100 ° e

CH ₀ -A- (CH) -Q-CO alkyl

Selective hydrolysis

CH -A- (CIl> -Q-CO alkyl

2 η O || HOC- (CH) -N-Ci-R / THF VII

Carbonyldiimidazole (CDI)

coupling reaction

CtI-A- (CIi ₂ ) -Q-CO alkyl

O CH -NH-Cr (CH) -N-C-R "

ro cn ω

A ¹ . If ρ and m are 1, Q is a -CH group or a single bond and R is an alkyl radical.

CH-O OCII

³ / VI HC-N (CH)

CH ₂ -A- (CH) -Q-COalkyl I) R OS-CF

CH-N = CHN (CH)

VI '

HA- (CH ₀ ) -Q-CO

2 η

\ CH-NHR

VIA

Il

HOC- (CH) 2 q

R ² O

I 'I

-N-C-R / TIIF

VII

CDI

coupling reaction

CH ₂ -A- (CH ₂ J _n -Q-CO ₂ alkyl

O CH -NC (CH) -Ν-CR ³

° ² I ₁ ² * I ₂ 1!

R R

IA ¹

N) oil CO

B- If Q is a CH group or a single bond, ρ is 2 to 5,

m is 1, and R is hydrogen >

or HA

Collins oxidation

alkyl

Ciio

III or IHA

III (in which A is a -CH = CH group)

IIIA (where A is a - (CH) -group)

Wittig

(C H) P = CHOCIK ο D 3 3

VIII

-A- (CH ₂ ) _n -Q-CO ₂ . alkyl

3.

VIII

IX

alkyl

(p-1 fold repetition)

reduction

NaBIi

CH ₂ -A- (CH ₂ J _n -alkyl

tosylation

TsCl / pyridine -

IXA

^iCil 2 ^] (PI)

ii

displacement reaction

DMSO 90-100 ° C

CH -A- (CH J -Q-CO _n alkyl

_o l (αΐ ₂ ) -μ

XI

Selective hydrolysis

¹ O ₂ -A- (CII ₂ J _n -Q-CO ₂ alkyl HOC- (CH) -NCR ³ ZTIIF (VII)

XII q

CDI

coupling reaction

CH-A- (CII J -Q-CO alkyl

0 Il

(CH NH J-C- (CH ₀₎ -N-CR

^P · ^q I II-

'I

IB

B ¹ . If Q is a -CH- group or a single bond, ρ is 2 to 5, m is 1 and R is alkyl.

3/3

1) HC-N (CH ₃ ) ₂

(Ν, Ν-dimethylformamide dimethyl

1) R O-L'-CF.

CII -A- (ClI) -Q-CO alkyl £ 2 η 2

(CH)

2) HC1 / CHOH

XII '

CH-A- (CH) -O-CO, alkyl 2 2 η "

XIIA

OR ² O.

HOC- (CII ₂ ) -Ν-CR ³ / THF

VII

CDI

coupling reaction

CH -A- (CII) -Q-CO ί 2 η 2

) -T-N-C- (CH) -N-C-I P Ij 2 qj μ

Il Η I ₂ 'I

RO RO

IB ¹

C. If m is 2, ρ is 1, A is -CH = CH, and Q is CH, or a single bond

OH

Wittig (1)

(Alkoxymethyl) Ph P shark

XIII

Repetition of the Wittig

Reason n. " (1)

XIV

Wittig reaction (2)

CIi ₂ -CII = CH- (CII) _n -Q-CO H esterification

CH-OHXV

CH ₂ CH ₂ -CII = CH- (CH ₂ ) -Q-CO, alkyl

CII Oll

XVI

-Q-CO alkyl

CH-N-C- (CIK) -Ν-C-ίΓ

Ii il ² ι I ₂ II

RO R 0

TC

D. If m is 2, ρ is 1, A is a -CH-CH group, Q is CH ^ or a single bond

reduction

H ₂ / Pd / C

CH CH -CH, -ClI, - (CII) -Q-CO alkyl ZZ Z λ 2 η

\ CH OH O ²

XVIA

CH CH - (CH) - (CH) -Q-CO, alkyl AZ ZZ Zn ζ

ι CII-NC- (CH _n) -N-CR "

² I ₁ H ^2q l ₂ ll

RO RO

ID

E. If m is 3 or 4, ρ is 1, A is -CH-CH and Q is CH or a single bond

Repetition of the Wittig reaction (1)

1 time, if m has the value 3 and

2 times, if m is 4 ··

(CI) -CHO 2 m

I CIl OH

Wittig

reaction ^

(2)

CH) -CH = CH- (CH) -Q-CO-H m 2 η ²

XVII xviir

esterification

_{m is} -CH = CH- (CH ₂ ) -O-CO.: alkyl

(CH) -CH = CH- (CH) -Q-CO alkyl

2 m

2 η '· ~~ 2' 3

j -CiI ₂ -NC- (CH ₂ ) -Ν-CR

l O

I ₂ Il

R

IE

ro cn u>

F. If m is 3 or 4, ρ is 1, A is CII GH, and Q is CH, or a single bond.

reduction

H ₂ / Pd / C

- (CH ₂ ) _n -Q-CO ₂ ; alkyl

OH

XIXA

) _m - (CII ₂ ) ₂ - (CH ₂ ) _n -Q-CO ₂ . alkyl

CH-NC- (ClI) -NCR " ² I ₁ I! ² II ₉ II. RO R" 0

IF

G. If m has the value O, A is a -CH = CH group, ρ is 1 and Q is a CH group or a bond

Wittig reaction carboxyalkyl-Ph ₃ PHaI)

XIII

H = CM- (CH) -COO, -alkyl 2 η

IXB

CH = CH- (CH) -Q-CO. Alkyl 2 η 2 -

CH-Ν-C- (Ol) -Ν-C-R

IG

H. If m is O, A is a - (CH) group, ρ is 1 and Q is CH or a single bond

Reduction \

H ₂ / Pd / C

₂ - (CU ₂ ) -Q-COO .. alkyl

CII OH

IXC

^{: H} 2 ~ ^CH 2 ~

HN-C- (CII _n ) -NCR ' ² Il II ² <UI RO

NC

₂ Il

RO

IH

I. If Q is a -CH = CH group

IA, IB, IC, IE, IG

Ozonolysis.

(CH) -CHO 2 m

(CH) -N-C- (Cll) -N-C-R

P Ii Il ² <3 I ₂ Ii

RO. RO

XX

Wittig - reaction

(CM _1. ) .P = CII- (CiL) -CH = CH-CO H 6 5 3 2 η

(CH) -A- (CIL) -CII = CII-CO "H m 2 η 2

(CH) -Ν-C- (CII) -Ν-C-R

^Ρ Il Il ² * I ₂ (I

RO R 0

(in which A represents a CH = CH group) IJ

N) OI (O

Halo

J. If Q is a -CH-

halo halo or a -C group

Wittig reaction

(Halo)

(where A is a -CH = CH group and χ has the value 1 or)

OH

K. If Q is a -CH- group

(halo) _x .

(CH) -A- (CHl -C-CO H m 2 η

'(CHl -N-C- (CH,) -H-C-R "

^P Il Ii ^λ * YOU

Il Ii RO

IK

I ₂ H RO

IB, IC, ID, IE, IF, IG, IH

1)

2) MoO PyHMPA

OH

(Chi) -A- (CH) -CH-CO-alkyl ra 2 η

(CH) -N-C- (CH) -N-C-R

P II H ² 1 I ₂ H RO

Il RO

₂ RO

IL

"45 4 5

L. If R is a CNR R radical in which R and R have no hydroxyl group and no

Alkoxy mean

IA, IB, IC, ID, IE, IF, IG, IH,

HNR ⁴ R ⁵

(CH ₂ ) _m -A- (CH ₂ ) -Q-CNR R

-Q-b

.4 5

RO

N-N

M. If R is a group and A is a -CH = CH group

' H

(CH ₀ ) CHO

OH

XVII Wittig reaction

^(C 6 ^H 5 ⁾ 3 ^PBr " ^CH 2 ^(CH 2 ⁾ n ^Q

N-N

N-N H

N N

(CH) -CH = CH- (CH) -Q_ / 11

2 m 2 η V. ||

N N

CHOH ^H

nc

nc

) _m -CH = CH-

₀₎ -NC- (CH ₀₎ -NCR "

P Il II ^{2 q} I ₂ I

RO RO

N N

ii

'N - N H

IN

If R is a

group

Ν-Ν

// jj is and A'is a (CH) group

N N

Reduction,

H ₂ / Pd / C

N - N H

(CH) -N-C- (CH) -N-C-

IO

O. If R is a "... CH OH group

IA to IH IL,

or ester_ of

  IJ and IK

NaBH

or

LiBH,

(CH) -A- (CH) -Q-CHOH 2 m 2 η 2

(CH) -Ν-C- (CH) -N-C-R

² P Il Il ^{2 q} I ₂ H

RO RO

P. If R is a CO Η group

IA to IH Oydrolyse :. \ IL LiOH, HCl

(CH) -A- (CH ₀₎ -Q-CO "H 2 m 2 η 2

(CH) -Ν-C- (CH_) ^{2 P} I l ^{2 q}

^{2 p}

Il Il RO

I ₂ U RO

(IQ, where A is a -CH = CH group)

(IR, where A is a - (CH) -group)

Q. -If R is a CN-OR group R ⁴

IQ hydroxamate formation

or 1) ClCOCOCl, -Benzol N, R.T. IR

cat. DMF>.

5 V

OR

2) HN. HCl / (C It) N \ 4 - - j

₇ ) _m -A- (CII ₂ ) ^ -Q-

₇ ) _m

(CH ₀₎ -Ν-C- (CII ₀₎ -Ν-CR ~

² PI ₁ H ² 9 I ₂ Il

O RO RO

IS

(in which R is a hydrogen atom or an alkyl radical)

R. If R is an NH group

VI, VIA or XII

1) carbonyldiimidazole + HO ₂ C-CH ₂ -NH-C-NH ²⁾ hydrolysis

Il

(Hydantoic acid) S ₁

IT

N) oil (O

-K (O N)

It can be seen from reaction sequence A above that the compounds of the invention in which Q is a -CH ₂ group or a single bond, ρ is 1, R is CO ₂ alkyl and R ^{1 is} hydrogen

(IA) -

(GH ₂ J _1n -A- (CH ₂ ) _n -Q-CO ₂ alkyl-1

Μ 3

NH-C- (CH ₂ ) _σ -Ν-CR

! ²

by tosylation of the hydroxymethyl group-containing lower alkyl ester of structural formula II or HA described in U.S. Patent 4,134,305. For this purpose, a compound of structural formula II or HA is reacted with tosyl chloride in the presence of pyridine to give the corresponding tosylate IV. This is subjected to a displacement reaction whereby it is dissolved in dimethyl sulfoxide and heated to 90 to 100 ^° C. in the presence of potassium phthalimide. There is obtained the phthalimide V, which is subjected to selective hydrolysis. For this purpose, it is dissolved in methylene chloride and ethanol under a protective gas, such as argon, and treated with anhydrous hydrazine to the amine Vl

(CH ₂ I ₁₁₁ -A- (CH ₂ ) _n -Q-CO ₂ alkyl

(Vl)

implemented.

From the reaction sequence Ä 'it can be seen that the alkylation reaction, if R ^{1 is} a lower alkyl, after

M.J. O'Donnell et al., Tetrahedron Lett 25 (1984), pp. 3651-3654. The connection becomes VIA

^(CH 2 ⁾ m " ^A ~ ^(CH 2 ⁾ n ~ ^Q " ^CO 2 ^A y y ¹

(VIA)

-NHR ^J

receive. The amine IV or VIA is then subjected to a CDI coupling reaction by reacting with an acid of the structural formula

O RO

Il IH-

HO-C- (CH-) -N-C-R "2 q

in the presence of an inert organic solvent, such as tetrahydrofuran, and of carbonyldiimidazole under an inert gas, such as argon, at a molar ratio of compound VkCompound VII of from about 1: 1 to about 1: 1.2 to the amide ester compound of general formula IA or IA 'of the invention.

(CH ₂ ) _m -A-

) _n -O-CO ₂ .Alkyl

CH_-NC- (CH) -N-CR ³ .

2 I ₁ 2 q, _, ι J

R ¹ -IT O

in which R ^{1 represents} a hydrogen atom (IA) or a lower alkyl radical (IA ').

The reaction sequences B and B 'are used for the preparation of compounds of the invention in which Q is a -CH ₂ -GrUpPe or a single bond, ρ is 2 to 5 and in which R is a C ₂ alkyl radical

- ^A - ^(CH

il · 3 ·

(CH-) -N-C- (CH-) -Ν-C-R

² P ι ι ² <3 I τ (I,

R _ R ^ O *

in which R ^{1 is} a hydrogen atom (IB) or an alkyl radical (IB ').

The compound II or IIIIA is used to prepare the aldehyde III in which A is -CH = CH- or the compound HIA in which A represents a (CH ₂ ) 2 group.

To prepare the aldehyde III in which A is a -CH = CH group, the compound Ii is subjected to Collins oxidation, for example by reaction with chromium trioxide in pyridine. To prepare the aldehyde INA, in which A is a (CH 2) 2 group, the compound II is reduced, for example with hydrogen in the presence of palladium on carbon as a catalyst. Thereby, the hydroxymethyl compound HA is obtained in which A is a - (CH ₂ ) ₂ - group. This is converted by Collins oxidation into the aldehyde IHA in which A is a - (CH ₂ I _{2 group} .) The aldehydes ill or IHA are used to prepare the aldehyde IX in which ρ is 2 to 5 For this they are subjected to a homologation, for example a Wittig reaction with (C ₆ H ₅ IaP = CHOMe followed by a (p-1) -fold hydrolysis: the aldehyde IX in which ρ has the value 2 to 5 converted by reduction into the compounds of the invention, in which ρ has the value 2 to 5

(CH ₂ ) _m -A- (CH ₂ J _n -Q-CQ alkyl

(CH) -NC- (CH) -Ν-CR ³ ^ Pl ₁ 2 qj H

R ¹ R ² O

The aldehyde IX is reduced with a reducing agent such as sodium borohydride, the alcohol IXA

(IXA)

The alcohol IXA is then tosylated as described above. There is obtained the tosylate X, which is converted into the phthalimide XI by a displacement reaction with potassium phthalimide as described above. The phthalimide IX is finally subjected to selective hydrolysis as described above. It becomes the amine XII

(CH ₂ ) _m -Ä-

lkyl

(CH ₂ ) _p NH ₂

^x O received.

From reaction sequence B 'it can be seen that the alkylation reaction is carried out according to O'Donnell et al (supra) if R ^{1 is} a lower alkyl radical. It will be the connection XIIA

[CH-) -A- (CH_) -Q-CC 2 m 2 η

(CH ₂ ) _p -NH

receive. The amine XIII or XIIA is then reacted with the acid VII in a CDI coupling reaction as described above to form the amide ester compound of the formula IB or IB 'according to the invention.

(CH) -NC- (CH) -Ν-CR ³ 2 ρ I ₁ 2 q ι ₉ ι,

R RO *

in which R ^{1 is} a hydrogen atom (IB) or a lower alkyl radical (IB ') is reacted.

The compounds according to the invention in which m has the value 2, A is a -CH = CH group, ρ has the value 1 and Q is a CH ₂ group or a single bond, can be obtained according to reaction sequence C. In this case, the starting compound XIII in a Wittig reaction (1) designated Wittig reaction with Alkoxymethyltriphenylphosphoniumhalogenid, such as (methoxymethyl) -triphenylphosphoniumchlorid, reacted to compound F. This reaction is described, for example, in Example 4 of US Patent 4143054. The Wittig reaction (1) is repeated with compound F. It will get the aldehyde XIV. This is in a Wittig reaction (2) with a Carboxyalkyltriphenylphosphoniumhalogenid, z. B. Carboxypentyltriphenylphosphoniumbromid reacted to Hydroxymethylverbindung XV. Compound XV is esterified, ζ. B. by reaction with diazomethane. The ester XVI is obtained. This is then used instead of the compound II in the reaction sequence A. There is obtained the compound of the invention IC.

After the reaction sequence D compounds of the invention are obtained in which m is 2, A is a-CH ₂ -CH ₂ group, ρ is 1 and in the UE is a -CH ₂ group or a single bond. In this case, the hydroxymethyl compound XVI is reduced to the compound XVIA, which is used in the reaction sequence A instead of the compound HA. There is obtained the compound of the invention ID.

Following reaction sequence E, the compounds of the present invention are obtained in which m is 3 or 4, A is -CH = CH, ρ is 1 and in Q is -CH ₂ - or a single bond. Here, the aldehyde XIV in a simple Wittig reaction (1), if m is 3, or in a two-fold Wittig reaction (1), if m is 4, converted to aldehyde XVII. The aldehyde XVII is converted in a Wittig reaction (2) to the acid XVIII, which is esterified to the ester XIX. This is used in place of compound II in reaction sequence A. The compound IE according to the invention is obtained. '

In the reaction sequence F, the compounds according to the invention are obtained in which m has the value 3 or 4, A is a -CH ₂ -CH ₂ -GrUpPe, ρ has the value 1 and in the Q is a -CH ₂ - group or a single bond means. In this case, the hydroxymethyl compound XIX is reduced to the compound XIXA, which is reacted instead of the compound II in the reaction sequence A to the inventive compound IF.

Thus, the compounds of the invention in which m is 0, 2, 3 or 4 and ρ is 2, 3 or 4 can be prepared by using the hydroxymethyl compounds XVI, XVIA, XiX or XIXA through reaction sequences A and B. In the reaction sequence G, the compounds according to the invention in which m has the value 0, A is a -CH = CH group, ρ has the value 1 and in which Q denotes a -CH ₂ group or a single bond are obtained. Compound XIII of Example 3 described in Example 3 of a Wittig reaction described, for example, in Example 6 (c) of US Pat. No. 4,134,354 is reacted with a carboxyalkyltriphenylphosphonium halide, such as carboxypentyltriphenylphosphonium bromide, to give hydroxymethyl compound IXB. This is used to prepare the ester IG, which can be hydrolyzed to the corresponding acid.

In the reaction sequence H, the compounds according to the invention are obtained in which m has the value 0 and is aeine (CH ₂ ) ₂ group. In the process, the hydroxymethyl compound IXB is reduced with hydrogen in the presence of palladium-on-carbon as the hydroxymethyl compound IXC catalyst. From this the ester IH is obtained, which can be hydrolyzed to the corresponding acid

 In the reaction sequence I, the compounds of the formula IJ

(CH ₂ ) _m -A- (CH ₂ ) _n -CH = CH-CO ₂ H

(U)

(CH,) -N-C- (CH,) -N-CR ³

RO R ^z O

in which Q is -CH = CH- group. The esters IA, IB, IA ', IB', IC, IE or IG at -78 ° C in methylene chloride and methanol with ozone to aldehyde XX

(CH ₂ ) _m -CHO

(XX)

(CH) -Ν-C-CH-Ν-C-2-Pι -, ii 2 q, _ ι,

RO RO

ozonolysis. This is in a Wittig reaction with (C ₆ H ₅ ) ₃ P = CH- {CH ₂ ) _n -CH = CH-CO ₂ ^e _f

in which A is a (-CH = CH -) group, converted to compound IJ.

In the reaction sequence J, the compounds according to the invention are obtained in which Q is a

hai -CH-

Halo

Halo

-Gruppeist.

For this purpose, the aldehyde XX is a Wittig reaction with the compound C

(Halo)

C ₅ H ₅ ) ₃ P = CH- (CH ₂

(C)

in the Aeine CH = CH group and X has the value 1 or 2, to the compound IK according to the invention

(Halo)

(CH ₂ ) _m -A- (CH ₂ ) _n -C-CO ₂

{CH) -N-C- (CE ₀₎ -NC 2 PI -, κ 2 q, -, ι

R ^x OR ^z o

implemented.

In the reaction sequence K, the compounds of the structural formula II

• I (CH ₂ ) -A- (CH ₂ ) -CH-C

(CH ₀

I-C- (CH-) -N-CR-1 / 2'q- ₁

ro o ro

(IK)

(IL)

obtained in which Q a

, OH

-CH group

The esters IA to IH are reacted with lithium diisopropylamide in the presence of an inert solvent, such as tetrahydrofuran, at temperatures of less than -5O ⁰ C and then with oxodiperoxymolybdenum (pyridine) / (hexamethylphosphoric triamide) (IVIoO ₅ PyHMPA).

In the reaction sequence L, the compounds of the structural formula IM according to the invention,

(CH ₂ ) _m -A- (CH ₂ ) _n -Q-CNR ⁴ R ⁵

(IN THE)

CH_) -N-C- (CH-) -NC-IT ² Pl ₁ H 2 q,

RO RO

in which R ⁴ and R ⁵ independently of one another denote a hydrogen atom, an alkyl or an aryl radical, by reacting the esters IA to IH or IL or the esters of the compounds IJ or Ik with an amine of the structural formula E

4 _D 5

HNR ⁴ R

receive. ,

In the reaction sequence M, the compounds according to the invention in which R is a tetrazole radical

N-N

\ ϊ -Ν

'H is and A is a -CH = CH group, obtained. In this case, the obtained according to US Patent 4143054 alcohol XVII

"(CH ₂ J _n CHO -

(XVII)

CH ₂ OH

with the Wittig reagent of structural formula G

(C Hg) ₃ PBr-CH ₂ - (CH ₂ J _n -Q

N N

N N

in the presence of a base such as potassium tert-butoxide or sodium hydride dimethylsulfoxide at a molar ratio of XVII: G of from about 1: 1 to about 0.2: 1 to the hydroxymethyl compound MC

"N N

(CH ₂ ) _m -CH = CH- (CH ₂ ) _n -Q

N N

(NC)

implemented. This can be in the reaction sequences A and B to the compounds of formula IN, .in the Aeine -CH = CH group, or the formula I0, in which A is a - (CH ₂ ) 2 group

-A- (CH ₂

N N

N N

(IN or ΙΟ)

(CH-) -Ν-C- (CH,) -Ν-C-2'ρ I ₁ , I 2 q _I? H

RO RO

realize.

In addition, the compound IO duich reduction of the compound IN can be obtained with hydrogen in the presence of palladium-on-charcoal as a catalyst.

The compounds of the present invention wherein R is a tetrazole group and A is a -CH = CH group can also be prepared by reacting the aldehyde XX as described above with a Wittig reagent of Structural Formula G in the presence of a base such as potassium tert-butoxide or sodium hydride dimethylsulfoxide in the reaction sequence I.

In the reaction sequence 0, the compounds of the general formula IP

< ^CH 2 ^> m " ^A " ^(CH 2 ⁾ n " ^Q " ^CH 2 ^OH

(CH) -NC- (CH,) -NCR ³ 2 P 1, Il 2'q, "

R ¹ OR ² O. -

in which R is a CH ₂ OH group, obtained by reduction of the esters IA to IH and IL and the ester of the compounds J and K with sodium borohydride or lithium borohydride.

In the reaction sequence P, the compounds of the formula IQ according to the invention, in which A is a-CH = CH group, or the formula IR, in which A is a - (CH ₂ ) 2 group

(CH ₂ ) _m -A- (CH ₂ ) _n -Q-CO ₂ H

-NH-C- (

I ₂ Π R ^Z O

by reacting the esters IA, IA ', IB, IB' to IH and IL with a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide to the corresponding Al kali meta lisa Iz and by subsequent neutralization with an acid such as dilute hydrochloric acid or oxalic acid

 In the reaction sequence Q, the compounds of the formula I according to the invention are obtained, in which R is a radical

OOR ⁵ '. ,

Il /

CN

in which R ⁵ 'is a hydrogen atom or an alkyl radical. A solution of the acid in an organic solvent such as benzene is treated with oxalyl chloride and a catalytic amount of dimethylformamide (DMF). The mixture is stirred under nitrogen as a protective gas at room temperature. The formed acid chloride is dissolved in an inert organic solvent such as tetrahydrofuran. Then, a cold solution of amine hydrochloride H

OR "

HN.

HCl

in which R ⁵ 'is a hydrogen atom or an alkyl group, and triethylamine in aqueous tetrahydrofuran is added dropwise with the solution obtained above. The molar ratio of acid chloride: Compound H is about 0.3: 1 to about 1: 1 and preferably about 0.5: 1. It becomes the hydroxamate IS

(CH ₂ ) _m -A- (CH ₂ J _n -Q-CON

CH ₀₎ -NC- (CH ₀₎ -Ν-CR ² q ² PMH ι ο ι /

R- ¹ OR ^ 0

receive. "

In the reaction sequence R, the compounds of the invention are the general IT

(IS)

(IT)

obtained in which R ^{3 is} an NH ₂ group.

In this case, the amine Vl, VIA or XII is reacted with hydantoic acid in the presence of Carbonyiiimidazol and then hydrolyzed to the inventive compound IT.

The tris (hydroxymethyl) aminomethane salts of the acids of general formula I according to the invention are obtained by reacting a solution of the acid in an inert solvent such as methanol with tris (hydroxymethyl) aminomethane. After subsequent evaporation of the solvent left behind the desired salt.

The sulfinyl and / or sulfonyl analogues of the compounds of the formula I according to the invention in which R ^{3 is} an -S-alkyl, -S-aryl, -S-alkylaryl, -alkyl-S-aryl, -alkyl-S- alkyl or an alkyl-S-alkylaryl group, can be obtained by oxidation with sodium periodate or potassium monopersulfate (oxone) in the presence of methanol. Mixtures of the compounds can be separated by chromatography or other known separation methods.

The acid used as starting material VII

R ² O

m i

-N-C-

can be achieved by reaction of the amino acid J

O R

Il - 1

HOC- (CH ₂ ) -NH

or its acid chloride with the acid chloride K

"3

Cl-C-R

(J)

(K)

or its acid, if the acid chloride of J is used, in the presence of a strong base such as NaOH and water.

The compounds of the invention have four asymmetric centers, which are indicated in the general formula I by asterisks. Also, the not separately asterisked above formulas have these asymmetric centers. The invention relates to all stereoisomeric forms of said compounds.

The various stereoisomeric forms of the compounds according to the invention, namely the cis-exo, cis-endo and all trans forms and stereoisomeric pairs can be prepared according to the examples described below and with the starting compounds and processes mentioned in US Pat. No. 4,134,354.

Examples of the stereoisomers are described below: '-A- (CH ₂ ) _n -QR

(CH ₉ JNC- (CH,) -N-CR-R ¹ IT

la

O H

(Cis-endo)

-A- (CH ₂ ) _n -QR

O (CH ₉ ) -NC- (OL,) -Ν-CR- ^ Pl ₁ ^ 1 ι, II

R R ^ 0

ib

(Cis-exo)

(CH-) -N-C- (CH,) -Ν-C-R "2 ρ ι, 2 q ι" κ

R ²

O.H

ic

(Trans)

(CH ₂ ) _m -A- (CH ₂ ) _n -QR

--Ή

RO

id

For ease of understanding, the backbone of the compounds of the invention will be described as either

or as

shown.

The compounds which can be prepared according to the invention are valuable drugs with cardiovascular action. They inhibit platelet aggregation, such as arachidonic acid-induced platelet aggregation. Therefore, they can be used in the treatment of thrombosis, such as coronary thrombosis or brain thrombosis.

Furthermore, they are selective thromboxane A2 receptor antagonists and synthetase inhibitors and have e.g. Legs

vasodilatory effect suitable for the treatment of ischemic diseases of the heart muscle, such as angina pectoris

The compounds which can be prepared according to the invention can be combined with an inhibitor of the cyclic AMP phosphodiesterase (PDE) such as theophylline or papaverine in the preparation and storage of platelet concentration

use.

The compounds which can be prepared according to the invention can be administered orally or parenterally. The effective dose is in the range of about 1 to 100 mg / kg, preferably about 1 to 50 mg / kg, and more preferably in the range of about 2 to

25 mg / kg for a single or 2 to 4 divided daily dose regimen.

The active ingredient is z. B. as a tablet, capsule, solution or suspension administered with about 5 to 500 mg per dosage unit. As the active ingredient, a compound or mixture of compounds of general formula I can be used in conventional dosage forms such as tablets, capsules, solutions or suspensions containing about 5 to 500 mg of the compound or compounds per dosage unit. In this case, the compounds of the invention in customary, for example, with a physiologically acceptable carrier material, with an excipient, a binder, preservative, stabilizing or flavoring compound. As already stated above, certain compounds which can be prepared according to the invention can be prepared as intermediates for the preparation of other compounds which can be prepared according to the invention

Use connections.

The compounds which can be prepared according to the invention can also be administered locally for the treatment of peripheral vascular diseases

use. For this they are optionally formulated as a cream or ointment.

Ausführungsbeispieie example 1

[1S- [1ß, 2a (5Z), 3a, 4SS]] - 7- [3 - [[[i (1-oxohexyl) amino] acetyl] amino] -methyl!] - 7-oxabicyclo [2.2 .1] hept-2-yl] -5-heptensäurernethylester

A. M-hexanoyl glycine

7, '5 g (10OmMoI) glycine are dissolved in a solution of 8 g NaOH and 50 ml of water and the solution is cooled to 0 ° C. 50 ml of diethyl ether are added and then 13.4 g (10OmMoI) n-Hexanoylchiprid are added dropwise with vigorous stirring at 0 ⁰ C within 60 minutes. The reaction mixture is allowed to stand until it has reached room temperature and stirred for 1 hour. 10 ml of 1 N NaOH solution are added and the phases are separated. The aqueous phase is washed twice with 20 ml of diethyl ether. The combined diethyl ether phases are washed with 20 ml of 1 N NaOH solution. extracted. The combined aqueous phases are adjusted to pH 2 with concentrated hydrochloric acid and the products are extracted three times with 100 ml of diethyl ether each time. The combined diethyl ether phases are washed with 50 ml brine and dried over magnesium sulfate. Filtration and evaporation of the solvent yield 16.2 g of a colorless solid. This is recrystallized from 60 ml of ethyl acetate. There are obtained 10.9 g (63 mmol, 63% dTH) of colorless, needle-shaped crystals of mp 93 to 96 ° C. Thin layer chromatography: silica gel; methanol; CH ₂ Cl ₂ : HCOOH; 10, 89.5: 0.5; PMA R, = 0.45.

B. [1S- [1β, 2α (5Ζ), 3α, 4β]] - 7- [3- (tosyloxymethyl) -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid methyl ester

3g (11.2 mmol) [1 S- [1β, 2α (5Ζ), α, 4β]] - 7- [3- (hydroxymethyl) -7-oxabicyclo [2.2.1] hept-2-yl] -5 -heptensäuremethylester, hergesteJIt according to US Patent 4143054, in 30 ml of pyridine is mixed with stirring at 0 ⁰ C was treated dropwise with a solution of 4,256g (22,4mMol) of tosyl chloride in 30 ml CH ₂ CI. ₂ The mixture is then warmed to room temperature and stirred overnight. Then, the reaction mixture is poured into ice / water and stirred for 30 minutes. The products are extracted three times with 80 ml of ethyl acetate each time. The combined Äthylacetatphasen be three times with 40 ml of 3 N HCl, with saturated

NaHCO ₃ solution and washed with brine. Then they will. dried over magnesium sulfate. Filtration and evaporation of the solvent gives a white solid. This is recrystallized from isopropyl ether. 4.23 g (89% of theory) of the title compound are obtained as needle-like crystals of mp 68 ° C. to 70 ° C.

C. [1S- [1β, 2α (5Z), 3α, 4β]] - 7 - [(3- (aminomethyl) -7-oj-abicyclo [2.2.1] hept-2-yl] - 5-heptenoic

The tosylate obtained according to B is subjected to a Gabriel synthesis. In this case, the corresponding amino compound is obtained as described below.

The potassium phthalimide used is first purified. For this purpose, 5 g are boiled with 9 ml of acetone for 15 minutes, the hot solution is filtered and washed with 5 ml of acetone. The residual solid is dried under reduced pressure for 6 hours at 10 pX.

8.11 g (19,2ml) of the tosylate obtained in accordance with B and 6.4 g (34,6mMol) 1,8Äquiv) purified potassium phthalimide in 70 ml of dimethylsulfoxide are heated for 2 hours at 90 to 100 V2 ⁰ C. Then it is checked by thin layer chromatography with diethyl ether of 2: 1 in the ratio 2: 1, if no tosylate is left. After cooling the reaction mixture to room temperature, 90 ml of water are added. It begins to form a precipitate. The mixture is poured into about 350 ml of ice water and stirred for 30 minutes. The straw-colored solid is separated by filtration and washed again with water. The solid is dissolved in 150 ml of warm ethyl acetate, washed three times with 50 ml of water each time, dried over magnesium sulfate, filtered and the solvent is evaporated under reduced pressure. There remain behind 7.88 g of solid, which are recrystallized from about 150 ml of isopropyl ether. There are obtained 6.35 g (83% of theory) of the corresponding phthalimides.

TLC: silica gel; Diethyl ether: hexane = 2: 1, UV + vanillin; R _f = 0.38, track 0.09. 5.5 g (13.8 mmol) of the phthalimides obtained above are dissolved in 24 ml of distilled CH ₂ Cl ₂ and 104 ml of distilled ethanol under argon as inert gas. There are added 0.78 ml (25.6 mmol) of anhydrous hydrazine. The solution is stirred at room temperature. After 8 hours, another 0.2 ml of hydrazine are added and the mixture is stirred for another 15 hours at room temperature. A white solid is filtered off and washed with CH ₂ Cl ₂ . Under reduced pressure, the filtrate is evaporated to dryness.

80 ml of a cold 0.5N HCl solution is added. A small amount of a white solid is filtered off and washed again with 80 ml of 0.5 N HCl solution. The acidic solution is washed twice with 100 ml of diethyl ether each time and made alkaline with solid K ₂ CO ₃ . The amine is extracted three times with 100 ml each of CHCl ₃ , dried over magnesium sulfate, and the solvent is evaporated under reduced pressure. There remains a yellow oil to which 100ml of diethyl ether are added. Part of the solid is insoluble. After cooling in an ice bath, the solid is filtered off. The solvent is removed from the filtrate under reduced pressure. There are left behind 2.441 g (71% of theory) of the title compound as a pale yellow oil. Small impurities are detected by NMR spectrum and thin layer chromatography. The resulting compound is used further without additional purification.

D. [1S- [1β, 2a (5Z), 3a, 4β]] - 7- [3 - [[[[(1-oxohexyl) -amino] -acetyl] -amino] -methyl] -7-oxabicyc! o [2.2.l] hept-2-yl] -5-heptenoic acid methyl ester

260 mg (1.5 mmol) of the compound obtained according to A are dissolved in 12 ml of distilled TH F under argon as inert gas. After cooling in an ice bath, 243 mg (1.5 mmol) of carbonyldiimidazole (CDI) are added. The cold mixture is stirred for 1 hour. The mixture is then stirred again for 1 hour at room temperature. The solution is cooled to 0 ° C and a solution of 401 mg (1.5 mmol) of the amine obtained according to C in 3 ml of THF is added. The mixture is stirred overnight at room temperature. The solvent is evaporated under reduced pressure and the residue is dissolved in 50 ml of CHCl ₃ . It is then washed with 20 ml of 1N HCl, 2M NaOH and 20 ml of H ₂ O, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. It leaves behind a viscous oil. The oil is rapidly chromatographed on 30 g of silica gel. By. Elution with ethyl acetate and 1% methanol in ethyl acetate 425 mg of the title compound (67% of theory) are obtained as an oil. *

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ , vanillin; R _f = 0.48.

Example 2

[1S- [1β, 2a (5Z), 3α, 4β]] - 7- [3 - [[[[(1-oxo-hydroxy-D-aminol-acetyl-aminol-methyl] -oxabicyclo-U-1-heLhep-y-yl. B-heptenoic acid 420 mg (0.994 mmol of the methyl ester obtained according to Example 1 is dissolved in 40 ml of distilled THF and 8 ml of water under argon as protective gas 9.5 ml of a 1 N LiOH solution are added and the mixture is stirred for 3 ³ hours at room temperature. After neutralization with 9.5 ml of 1 N HCl, solid potassium chloride is added and the phases are separated, the aqueous phase is extracted three times with 50 ml of CHCl ₃ each time, the combined organic phases (THF + CHCl ₃ ) are washed twice with 25 ml of saturated NaCl each time Solution, which is evaporated under reduced pressure, leaving behind a very viscous oil, which is rapidly chromatographed on 30 g of silica gel, eluting with 4% methanol in CH ₂ Cl ₂ . 88% of theory) of a compound which consists of about 10 Is recrystallized from acetonitrile. In this case, 248 mg (61% of theory) of the title compound of mp 119-121 ⁰ C are obtained. Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ , vanillin; R _f = 0.37.

calc .: C H N C ₂₂ H ₃₆ O ₅ N _2; gel: 64.68 8.88 6.86 64.67 8.87 6.86

Example 3

[1S- [1β, 2a (5Z), 3α, 4β]] - 7- [3 - [[[[[[(butylamino) carbonyl] amino] acetyl] amino] methyl] -7- oxabicyclo [2.2.1 Jhept-2-y!] - 5-

heptenoic

A. N-f-butylaminol-carbonyl-glycine ethyl ester

5.58 g (40 mmol) of glycine ethyl ester · HCl are suspended in 20 ml of distilled CH ₂ Cl ₂ . After cooling in an ice bath, 6.13 ml (44 mmol) of distilled Et ₃ N are added. Then 4.95 ml (44 mmol) of distilled n-butyl isocyanate are added. The

Ice bath is removed and the mixture is stirred overnight at room temperature. Another 3.05 ml of Et ₃ N are added and the mixture is stirred again for 3 hours. After dilution with CH ₂ Cl ₂ , the solution is washed with 50 ml of water, 50 ml of 1 N HCl, 50 ml of saturated NaHCO ₃ solution and with 50 ml of water. It is dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There remain behind 7.641 g (94% of theory) of the title compound, which crystallizes out slowly. This will continue to be used without additional purification.

N - [(butylamino) carbonyl] glycine

3.373 g (16.7 mmol) of the ethyl ester obtained according to A are dissolved in 100 ml of distilled THF and treated with 40 ml of 1 N LiOH solution. It is stirred overnight at room temperature and acidified with concentrated HCl. Then solid KCl is added and the phases are separated. The aqueous phase is extracted three times with 50 ml of ethyl acetate each time. The combined organic phases (THF and ethyl acetate) are washed with 25 ml of saturated NaCl solution, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There are left behind 2.81 g (97% of theory) of the title compound.

C. [1S- [1β _/ 2a (5Z) _/ 3a, 4β]] - 7- [3 - [[[[[[(butylamino) carbonyl] amino] acetyl] amino] methyl] -7- oxybicyclo [2.2.1] hept-2-yl] -5-heptenoic acid methyl ester

174.2 g (1 mmol) of the compound obtained according to B are partially dissolved in 8 ml of distilled THF under argon as inert gas. After cooling in an ice bath, 162 mg (1 mmol) of carbonyldiimidazole (CDI) are added. The cold mixture is stirred for 1 hour. It is then stirred for 1 h at room temperature to give a clear solution. The solution is cooled in an ice-bath and treated with a solution of 267 mg (1 mmol) of the chiral amine obtained according to Example 1, Part C in 3 ml of THF. The ice bath is removed and the mixture is stirred overnight at room temperature. The solvent is evaporated under reduced pressure. The residue is mixed with 35 ml of CHCl ₃ . The solution is washed with 15 ml of 1N HCl, 15 ml of 1 N NaOH and with 15 ml of H ₂ O, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There are 340mg of very viscous oil behind. This is rapidly chromatographed on 20g silica gel. It is eluted with ethyl acetate and 5% methanol in ethyl acetate. This gives 212 mg (15% of theory) of the title compound as a viscous oil

Thin layer chromatography: silica gel; 5% methanol in ethyl acetate, vanillin; R _f = 0.23.

Example 4

[1S- [1β, 2α (5Z), 3α, 4β]] - 7- [3 - [[[[[[(Bu tylaminol-carbonylaminol-acetoxy-aminol-methyne] -oxabicyclic acid. a.ijhept-a-yU-S-

heptenoic

208 mg (0.491 mmol of the methyl ester obtained according to Example 3 are dissolved in 20 ml of distilled THF and 4.8 ml of water under argon as protective gas 4.9 ml of a 1N LiOH solution are added and the mixture is stirred for 5 hours at room temperature neutralized with 4.9 ml of 1N HCl solution and solid potassium chloride is added, the phases are separated, and the aqueous phase is extracted three times with 25 ml of CHCl ₃ each time, the combined organic phases (THF and CHCl ₃ ) being saturated with 15 ml NaCl solution, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There remains behind an oil. This was chromatographed on 18g of silica gel. As Elutionsmitte! is 4% methanol in CH ₂ CI _{2 was} used. There are 158 mg (78.2 % of theory) of the title compound as a white foam

Thin layer chromatography on silica gel; 10% methanol in CH ₂ Cl ₂ , vanillin; Rf = 0.28.

CHN

C ₂ H H ₃₅ O ₆ N ₃ -O ₁ IH ₂ O: calc .: 61.32 8.63 10.21

F .: -.61.15 8.74 10.23

Example 5.

[1S- [1β, 2α (5Z), 3α, 4β]] - 7- [3 - [[[[[Μβ ^ νΙ- (1-οχοΙΐ6χγΙ) -3Γηίηο] -3οβίγΙ] -3ηιϊηο] -ΓηβίΗνΙ] -7-οχ3ΒϊονοΙο] 2.2.1] -hept-2-yl] -5-

heptenoic

A. N-hexanoyl-N-methylglycine

1.88 g (20 mM) of sarcosine are dissolved in 40 ml of 1 N NaOH solution and 40 ml of diethyl ether are added. After cooling in an ice-bath, a solution of 3.1 ml (22 mmol) of hexanoyl chloride in 10 ml of diethyl ether is added dropwise. The mixture is stirred for 1 hour while cooling. Then the pH is adjusted to about 8 with about 3 ml of 1 N NaOH solution and the mixture is stirred for 45 minutes at room temperature. It is then adjusted to pH 9-10 with NaOH solution. The phases are separated and the aqueous phase is washed with 50 ml of diethyl ether. After acidification of the aqueous phase with concentrated HCl and saturation with solid KCl, the product is extracted three times with 70 ml each of CHCl ₃ . The combined CHCl ₃ extracts are washed with 25 ml of saturated NaCl solution, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There are 3.78 g (quant.) Of the title compound remaining which are used without additional purification. '

For example, [IS-fi

heptenoic

187 mg (1 mmol) of the compound obtained according to A are dissolved in 8 ml of distilled THF under argon as protective gas and cooled in an ice bath. 162 mg (1 mmol) of carbonyldiimidazole (CDI) are added and the mixture is stirred for 1 h in cold dsr and then at room temperature for 1 h. After cooling in an ice bath, a solution of 267 mg (1 mmol) of the obtained according to Example Ί, Part C, chiral amine in 3 ml of THF is added. The ice bath is removed and the mixture is stirred overnight at room temperature. The solvent is evaporated under reduced pressure. To the residue 35 ml of CHCl _{3 are} added. The solution is washed with 15 ml of 1N HCl, 15 ml of 1 N NaOH solution and with 15 ml of water, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There are 424mg left behind

Oil. This is rapidly chromatographed on 20 mg silica gel. It is eluted with ethyl acetate and 2% methanol in ethyl acetate. There are obtained 252 mg (57.7% of theory) of the title compound as an oil

Thin layer chromatography: silica gel; 5% methanol in ethyl acetate, vanillin; R _f = 0.46.

Example 6

[1 S- [1β, 2α (5Ζ), 3a, 4β]] - 7- [3 - [[[[methyl- (1-oxohexyl) -amino] -acety!] - amino] -methyl] -7 -Oxabicyclo [2.2.1] hept-2-yl] -5-

heptenoic

248 mg (0.568 mmol) of the methyl ester obtained according to Example 5 are dissolved in 25 ml of distilled THF and 5 ml of water under argon as Schutegas. A 1N LIOH solution is added and the mixture is stirred for 4 hours at room temperature. After neutralization with 5.6 ml of 1 N HCl solution and addition of solid KCl, the phases are separated. The aqueous phase is extracted three times with 25 ml CHCl ₃ each time. The combined organic phases (THF + CHCl ₃ ) are washed with 15 ml of saturated NaCl solution, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There are left behind 242mg of an oil. This is rapidly chromatographed on 20g silica gel. It is eluted with 4% methanol in CH ₂ Cl ₂ . There are 191.8 mg (79.9% of theory) of the title compound as a viscous oil! receive. Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ , vanillin, R _f = 0.46.

calc .: C H N C ₂₃ H ₃₈ O ₅ N ₂ ; Found .: 65.37 9.06 6.63 65,50 9.10 ^% 6.74

Example 7 '[Ιβ-ΙΊβ, Ζ heptenoic acid methyl ester

A. IM-f-Butoxycarbonyl-O-glycine ethyl ester

3.5 g (25mMo!) Glycine ethyl ester HCl are dissolved in 25 ml of distilled CH 2 Cl 2 under argon as inert gas. After cooling to -40 ⁰ C 7.65 ml (55 mmol) of Et ₃ N are added. The resulting solution is then added dropwise with a solution of 3.2 ml (about 25 mmol) of distilled n-butyl chloroformate in 10 ml of CH ₂ Cl ₂ . The mixture is stirred for 1 hour at -40 ° C and allowed to stand overnight at -5 ° C in the refrigerator. The mixture is then stirred at -5 to -1O ⁰ C for 1 hour. Add CH ₂ Cl ₂ followed by 50 ml of water. The phases are separated. The organic phase is washed with 50 ml of 1 N HCl, 50 ml of saturated NaHCO ₆ solution and 50 ml of water, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There are 3.199g of the product left behind. These are combined with the product from a batch of 5 mmol and rapidly chromatographed on 100 g of silica gel. It is eluted with diethyl ether / hexane in the ratio 1: 1. There are obtained 3.196 g (52.5%) of the title compound as an oil. Thin layer chromatography: silica gel; Diethyl ether: hexane = 1: 1, PMA; R _f = 0.34.

B. N- (butoxycarbonyl) -glycine

3.14 g (15.47 mmol) of the ethyl ester obtained according to A are dissolved in 100 ml of distilled THF and treated with 40 ml of 1 N LiOH solution. The mixture is stirred overnight at room temperature. After acidification with concentrated HCl and addition of solid KCl, the phases are separated. The aqueous phase is extracted three times with 50 ml of ethyl acetate. The combined organic phases (THF + ethyl acetate) are washed with 25 ml of saturated NaCl solution, dried over magnesium sulfate and the solvent evaporated under reduced pressure. There remain behind 2.78 g (quant.) Of the title compound, which crystallized slowly.

C. [1S-t1β, 2a (5Z), 3-heptenoic acid methyl ester

175.2 mg (1 mmol) of the acid obtained according to B are dissolved in 8 ml of distilled THF under argon as inert gas. After cooling in an ice bath, 162 mg (1 mmol) of carbonyldiimidazole (CDI) are added. The mixture is stirred in the cold for 1 hour and then at room temperature for 1 hour. The mixture is again cooled in an ice bath and a solution of 267 mg (1 mmol) of the chiral amine obtained according to Example 1, part C in 3 ml of THF is added. The ice bath is removed and the mixture is stirred overnight at room temperature. The solvents are distilled off under reduced pressure. 35 ml of CHCl ₃ are added. The solution is washed with 15 ml of 1N HCl, 15 mM of NaOH and 15 ml of water, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There remains behind 433 mg of an oil, which is rapidly chromatographed on 20 g of silica gel. Is eluted with ethyl acetate. There are obtained 291 mg of a partially purified product. These are chromatographed again on 20 g of silica gel, eluting with diethyl ether and 2% methanol in diethyl ether. There are obtained 172 mg (40.5%) of the title compound as an oil. Another 57 mg (13.4%) of the resulting compound is contaminated with a small amount of a slower running product. Thin layer chromatography: silica gel; 5% methanol in diethyl ether, vanillin, R _f = 0.32.

Example 8

[1S- [1β, 2α (5Ζ), 3α, 4β]] - 7- [3 - [[[[([butoxycarbonyi) amino] acetyl] amino] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid 168 mg (0.396 mmol) of the methyl ester obtained according to Example 7 are dissolved in 16 ml of distilled THF and 3.8 ml of water under argon as protective gas and 3.9 ml of 1 N LIOH solution added. The mixture is stirred at room temperature for 5 hours and then neutralized with 3.8 ml of 1N HCl solution. After adding solid KCl, the phases are separated. The aqueous phase is extracted three times with 25 ml CHCl ₃ each time. The combined organic phases (THF + CHCl ₃ ) are washed with 15 ml of saturated NaCl solution, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There are 150mg of an oil left behind. This is rapidly chromatographed on 10 g silica gel. It is eluted with 4% methanol in CH ₂ Cl ₂ . There are obtained 67 mg of a product which is pure in thin layer chromatography on silica gel with 10% MeOH in CH ₂ Cl ₂ and with vanillin at an R _f value of 0.43 is pure. When left to stand for several days in the refrigerator, the product partially crystallized. Digestion with diethyl ether gives 58.5 mg (36% of theory) of the title compound of

-40-F. 104 ° C to 106 ⁰ CaIs of white solid.

calc .: C H N C ₂₁ H ₃₄ O ₆ N ₂ : Found .: 61.44 8.35 6.82 61,50 8.37 6.98

Example 9

[1S- [1ß, 2a (5Z), 3a, 4SS]] - 2,2-difluoro-7- [3 - [[[[(1-oxohexyl) amino] acetyl] amino] methyl] - 7-oxabicyclo [2.2.1] hept-2-yl] -5-

heptenoic

A. [1S- [Iβ, 2α, 3α, 4β]] - 2- [3 - [[[[[[{1-oxohexyl) -amino] -acety! -Amino] -hiethyne-7-oxabicyclo [2.2 .1] hept-2-yl] -acetaldehyde

A solution of 211 mg (0.5 mmol) of the compound obtained according to Example 1 [1S- (1β, 2a (5z), 3ci, 4β]] - 7- [3 - [[[[(1-oxohexyl) -amino] -acetyl] -amino] -methyl] -7-oxybicyclo [2.2.1] -hept-2-yl] -5-heptenoic acid methyl ester in CH ₂ Cl ₂ : MeOH in the ratio 10 ml: 10Ml of solvent is at -78 ⁰ C is bubbled in. Ozone is bubbled through until the solution has a blue color, then excess ozone is removed in a stream of nitrogen and 1 ml (CH ₃ I ₂ S added) The reaction mixture is warmed to room temperature and poured into 50 ml CH ₂ Cl ₂ and 10 ml H ₂ O molded. The products are extracted with CH ₂ Cl _2. The aqueous phase is separated and extracted once more with 30 ml of CH ₂ CI _2. The combined CH ₂ CI ₂ phases are washed with 10ml brine and dried over magnesium sulfate. filtration and evaporating the solvent, a crude product is obtained which is purified by column chromatography on silica gel received.

B. (4-carboxy-3,3-difluoro-butyl) -triphenylphosphonium bromide

1. MethyltetrahydrofuroEit

, 75 g (0.595 mol) of methyl furoate are dissolved in 150 ml of methanol and poured into a Parr flask. The air is exchanged with an argon atmosphere and 2.5 g of 10% palladium on carbon is added as a catalyst. Hydrogen is introduced and hydrogenated at 2.76 bar for 48 hours.

The reaction mixture is filtered through a bed of diatomaceous earth, which is washed with diethyl ether. The filtrate and the washing solution are combined and the solvent is distilled off. There remain behind 71 g (0.546 mol, 92% of theory) of the title compound, mp 59 ° C at 5.1 mm Hg as a colorless liquid.

2. Methyl ^ -acetoxy-B-bromopentanoate

Hydrogen bromide gas is introduced for 2 hours at 0 ° C in 200ml Ac ₂ O until the specific gravity is 1.4. The solution is stirred at ⁰ ° C. with 70 g (0.538 mol) of the methyltetrahydrofuroa obtained according to Part 1). The reaction mixture is warmed to room temperature. It is stirred over N eight, the reaction mixture is carefully poured into 1 200 ice and allowed to stand for 30 minutes with occasional whirling. The products are extracted twice with 600 ml and once with 300 ml of diethyl ether. The combined diethyl ether phases are washed with dilute (about 0.5%) NaOH solution until the wash solution is alkaline. The diethyl ether phase is then washed with H ₂ O, dried over Na ₂ SO ₄ and filtered. The filtrates are evaporated and distilled. There are 116 g (0.458 mol, 85% of the title compound of F. 103 at 1 mm Hg obtained as a colorless liquid.

3. Methyi-5-bromo-i-hydroxypentanoate

100 ml of Mg (OMe) ₂ distilled Methanoi are saturated at 0 ⁰ C with hydrogen bromide gas. 60 g (0.237 mol) of the compound obtained according to 2) in 200 ml of Mg (OMe) ₂ distilled methanol are added. The mixture is warmed to room temperature and stirred overnight. The reaction mixture is evaporated under reduced pressure. 200 ml of toluene are added to the resulting liquid and the Reaktionsgeraisch is evaporated. This process is repeated twice. The resulting liquid is washed in 2,000 ml of ethyl acetate and washed with 0.5% NaOH and brine, and dried over Mag nesi u msu If at. After filtration and evaporation of the solvent, 44.8 g of a straw-colored oil are obtained. By distillation, 34 g (0.161 mol, 68% of theory) of the title compound as a colorless liquid ^ rnaIten.

4) Methyl 5-bromo-oxopentanoate

A solution of 12.53 g (59.3 mmol) of the compound obtained according to 3) in 150 ml of acetone is stirred at room temperature and washed with Jones reagent (CrO ₃ : 9.58 g, H ₂ SO ₄ : 8.47 ml, H ₂ O: 36.8 ml). The temperature is kept below 35 ° C. After complete addition, the reaction mixture is stirred at room temperature for 45 minutes. 30 ml of isopropanol are added and stirring is continued for a further 30 minutes. The reaction mixture is then diluted with 500 ml of water and the products are extracted with 1 liter of CH ₂ Cl ₂ . The CH ₂ Cl ₂ phase is washed three times with in each case 100 ml of saline solution and dried over magnesium sulfate. Filtration and evaporation of the solvents give 11.4 g [54.5 mmol] 92% of theory of the title compound as a colorless liquid.

5) Methyl 5-bromo-2,2-difluoropentanoate

6.8 ml (55.7 mmol) of C ₂ H ₅ J ₂ NSF ₃ (DAST) are added dropwise at room temperature to 11.4 g (54.5 mmol) of the compound obtained according to 4). The flask used in 4) is rinsed with 20 ml of CH ₂ Cl ₂ , which are also added to the reaction mixture. The reaction mixture is stirred for 1 hour at room temperature and poured into 80 ml of H ₂ O.

The products are extracted three times with 40 ml each of CH ₂ Cl ₂ . The combined CH ₂ Cl ₂ phases are washed three times with 20 ml H ₂ O each time and dried over magnesium sulfate. By filtration and evaporation of the solvent, 10.8 g of a straw-colored liquid are obtained. This is distilled. There are obtained 8.4 g (36.3 mmol, 67% of theory) of the title compound of mp 41 ° C at 0.015 mm Hg as a colorless liquid.

6) 5-bromo-2,2-difluoropentanoic acid

In 100 ml of a 48% solution of hydrogen bromide in water, hydrogen bromide gas is introduced while cooling occasionally in an ice bath until the weight is 180 g. Then, 8.4 g (36.3 mmol) of that obtained in 5)

-41- 253 192

Compound at room temperature with a hydrogen bromide solution and the reaction mixture is stirred for 5 hours at room temperature. The reaction mixture is cooled to 0 ° C and poured into 900ml diethyl ether in an ice bath. The products are extracted into the diethyl ether phase. The aqueous phase is extracted again with 200 ml and with 100 ml of diethyl ether. The combined diethyl ether phases are washed with 200 ml of water. The washing solution is then washed with 100 ml of diethyl ether. The combined diethyl ether phases are dried over magnesium sulfate. Filtration and evaporation of the solvent yield 7.8 g (quant.) Of the title compound as a colorless liquid.

7) (4-carboxy-3,3-difluorobutyl) -triphenylphosphonium-rhomide

A mixture of 6.7 g (25.7 mmol) and 4.6 g (21.2 mmol) of the compound obtained according to 6) is admixed with 23 ml of acetonitrile. The solution is stirred for 30 hours while heating under gentle reflux. Then 46 ml of toluene are added and the reaction mixture is briefly refluxed. The reaction mixture is cooled to 5 ⁰ C and allowed to stand overnight. The resulting white precipitates were collected, washed with a cold solution of AcetönitrikToluol in the ratio 1: 2, and washed in a 6O ⁰ C oven under reduced pressure (about 5 mm Hg). There are obtained 9.8 g (20.4 mmol, 96.5% of theory) of the title compound as a white solid.

C. [1 ¹ I SI ß, 2a (5Z), 3a, 4SS]] - 2,2-Dif fluoro-7- [3 -! [[[[(1-oxohexyl) amino] -acety] - amino] -mBthyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid

1.7 g of the compound (4-carboxy-3,3-difluorobutyl) -triphenylphosphonium bromide obtained according to B are suspended in 15 ml of THF. 3 ml of a 1.7 M solution of KOt-amylate in toluene are added at room temperature. The reaction mixture is stirred for 4 hours. 177.1 mg of the Aerdehen aldehyde in 10 ml of THF are added dropwise at 0 ° C with the solution obtained above. The reaction mixture is warmed to room temperature and stirred for 15 hours. 25 ml of saturated NH ₄ Cl-LOSU ng are added and the products are extracted three times with 40 ml of ethyl acetate. The combined organic phases are washed with 30 ml of brine and dried over magnesium sulfate. Filtration and evaporation of the solvents gives a brownish oil. This is purified by column chromatography on silica gel. It will get the title connection.

Example 10

[1S- [1β, 2a (2E, 5Z), 3a, 4β1] -7- [3 - [[[[(1-oxohexyl) -amino] -acetyl] -amino] -methyl] -7-oxabicycio [2.2.13} iept-2-yl3-2,5-

heptadienoic acid

1.13 g of (4-carboxy-2-butenyl) -triphenylphosphonium bromide are dissolved in 15 ml of THF. At room temperature, 3 ml of 1.7 M KOt-amylate in toluene are added. The mixture is stirred for 4 hours. 177.1 mg of the obtained according to Example 9, Part A aldehyde in 1OmITHF be "added dropwise the solution obtained above at 0 ⁰ C. The reaction mixture is warmed to room temperature and stirred for 15 hours. 25 ml of saturated NH ₄ CI solution are added and the products are extracted three times with 40 ml of ethyl acetate each time, the combined organic phases are washed with brine (30 ml) and dried over magnesium sulphate, followed by filtration and evaporation of the solvent to give a crude product which is purified by column chromatography over silica gel to give the title compound ,

Example 11.

[1S- [1β, 2a (5Z), 3a, 4β]] - 2-hydroxy-7- [3 - [[[[[(1-oxohexyl) amino] acetyl] amino] methyl] -7- oxabicyclo [2.2.1] hept-2-yl] -5-

heptenoic

First, lithium diisopropylamine (LDA) is prepared under argon atmosphere. For this purpose, 0.89 ml (6.44 mg, 6.36 mmol) of diisopropylamine are dissolved in 30 ml of THF at ⁰ ° C. Then, 2.55 ml (5.1 mmol) of a solution of 2N n -BuLi in hexane are added dropwise. It is stirred for 30 minutes at 0 ⁰ C. The LDA solution is cooled to -78 ° C. 767 mg (1.8 mmol) of the ester obtained in Example 1 in 10 ml of THF are added. The reaction mixture is stirred for 1 hour at -78 ^0C. 2.76 g (6.36 mmol) of oxodiperoxymolybdenum (pyridine) (hexamethylphosphortriamide) (MoOPH) are added all at once. The mixture is stirred for 30 minutes at -78 ⁰ C and 1 hour at -30 ⁰ C to -4o C. The reaction is stopped ⁰ ₃ solution by the addition of 200 ml of saturated NaHSO and warmed to room temperature. It is stirred for 30 minutes at room temperature, then water is added. Thus, 2 phases are obtained, which are separated. The aqueous phase is extracted three times with 100 ml of ethyl acetate. The combined organic phases are washed twice with 50 ml of 1N HCl each time and twice with 20 ml of brine and dried over magnesium sulfate. By filtration and evaporation of the solvent, a crude product is obtained. This is purified by column chromatography on silica gel. The title compound is obtained.

Example 12

[1S- [1β, 2a (5Z), 3α, 4β]] - 2-ΗναΓΓχγ-7- [3 - [[[[(1-ΟχοΗβχν!) - 3ΓΠίηο] -3θβίγΠ-3Γηϊηο] -ΓηείΗγΙ] -7- οχ3 ^ ογοΙο [2.2.1] Ηβρί-2-νΙ] -5-heptenoic acid '

According to Example 2, but using the ester of Example 11, the title compound is obtained.

Example 13

[1S- [1β, 2a (5Z), 3a, 4β]] - 7- [3 - [[[[(1-oxohexyl) amino] acetyl] amino] methyl] -7-oxabicyclo [2.2. 1] hept-2-yl] -5-hepten-1,2-diol A solution of 438 mg of the obtained according to Example 11 hydroxy ester is added at 0 ⁰ C with stirring with 185 mg of NaBH ₄ . As soon as the hydrogen evolution moderates, the reaction mixture is allowed to come to room temperature and stirred for 16 hours overnight. 10 ml of saturated NH ₄ Cl solution are added. The mixture is then stirred for 1 hour. Most of the methanol is evaporated at reduced pressure. The residue is separated into 50 ml of ethyl acetate and 10 ml of saline in phases. The aqueous phase is extracted twice with 40 ml of ethyl acetate each time. The combined organic phases are washed with 30 ml of brine and dried over magnesium sulfate. Filtration and evaporation of the solvent give a crude product. This is purified by column chromatography on silica gel. It will get the title connection.

Example 14

heptenamide

A solution of 153 mg of the ester obtained in Example 1 in 14 ml of THF is added at room temperature with stirring with 2ml of 40% MeNH ₂ in H ₂ O. It is stirred overnight (17 hours) at room temperature. The reaction mixture is evaporated under reduced pressure to give a crude product, which is purified by column chromatography on silica gel. The title compound is obtained.

Example 15

[1S- [1β, 2a (5Z), 3a (R), 4β]] - 7- [3 - [[[1-Oxo-2 - [(1-oxohexyl) -amino] -propyl] -amino ] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-

heptenoic

A. (2R) -2- (hexanoylamino) -propionic acid

According to the procedure of Example 5, Part A, 2OmMoI D-alanine be reacted with 22mMol hexanoyl chloride. After recrystallization from 20 ml of isopropyl ether, 2.45 g (65% of theory) of the title compound of melting point 82 ° C. to 95 ° C. are obtained as a white, crystalline material.

[18- [1β, 2α (5Ζ), 3α (Β), 4β]] - 7- [3 - [[[1-Οχο-2 - [(1-!ο! ΙβκγΙ) -3Γηΐηο] -ρΐΌργΙ] -3Γηϊηο] -ΓηβίΐΊγΙ] -7-οχ30! ογοΙο [2.2.13Ηβρί-2-γΙ] -5-heptenoic

As described in Example 5, Part B, 1 mmol of the acid obtained according to A is coupled with 1 mmol of the amine obtained according to Example 1, Part C. The crude product is chromatographed from the silica gel. It is eluted with 2 to 4% methanol in Diäthyläthereliert. The eluate is digested with diethyl ether. There are obtained 217 mg (50% of theory) of the title compound as a white solid

 Thin layer chromatography: silica gel; 5% methanol in diethyl ether, vanillin; Rf = 0.47.

Example 16

[1S- [1β, 2a (5Z) _/ 3a (R), 4β]] - 7- [3 - [[[1-oxo-2 - [(1-oxohexyI) -amino] -propyl] -amino] - methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-

heptenoic

215 mg (0.49 mmol) of the methyl ester obtained according to Example 15 are hydrolyzed with a LiOH solution in a THF-water mixture as described in Example 6. The viscous product is dissolved in about 2 to 3 ml of ethyl acetate. Upon standing, a crystal-like product precipitates. This is filtered off and washed with diethyl ether. There are obtained 166.6mg (80% of theory) of the title compound of mp. 101 ⁰ C to 103 ⁰ C.

calc .: C H N C ₂₃ H ₃₈ O ₅ N ₂ :. Found .: 65.37 9.06 6.63 65,30 9.16 6.46

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ , vanillin; R _f = 0.48. [a] _D: +25.5 ⁰ C (c, 1.37 in methanol).

Example 17 _:

[18- [1β, 2α (5Ζ), 3α (5), 4β]] - 7- [3 - [[[1-Οχο-2 - [(1-οχοΗβχγ1) -3Γηϊηο] -ρΓοργΙ] -3Γηίηο] - Γηβΐ1ιγΙ] -7-οχ30ίογοΙο [2.2.1] Ηβρί-2-γΙ] -5-heptenoic acid methyl ester

A. (2S) -2- {hexanoylarnino) -propionic acid

Following the procedure described in Example 5, part A, 10 mM of L-alanine are reacted with 11 mmol of hexanoyl chloride. After recrystallization from 6 ml of isopropyl ether, 1.091 g (58% of theory) of the title compound are obtained as a white, crystalline material.

B. [1 S- [Iβ, 2a (5Z), 3a (S), 4β]] - 7- [3 - [[[1-oxo-2 - [(1-oxohexyl) -amino] -propyl] amino] -methyl] - 7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid methyl ester

As described in Example 5, Part B, ImMoI of the compound from A is coupled with 1 mmol of the chiral amine obtained according to Example 1, Teii C using 1 mmol of CDI. The crude product is rapidly chromatographed on silica gel. It is eluted with 2% methanol in diethyl acetate. In this case, 178 mg (41% of theory) of the title compound in pure form and 129mg (29% of theory) with a slower in thin-layer chromatography running material title compound

receive.

Thin layer chromatography: silica gel; 5% methanol in diethyl ether, vanillin; R _f = 0.55.

The Rr value of the slower migrating impurity is 0.34.

Example 13

[1S- [1β, 2α (5Z), 3α (S), 4β]] - 7- [3 - [[[1-oxo-2 - [(1-oxohexyl) -amino] - propyl] amino] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-

heptenoic

As described in Example 6, 175mg (0.4OmMoI) of the methyl ester obtained in Example 17 are hydrolyzed with LiOH in a THF-water mixture. The viscous products are dissolved in 2 ml of ethyl acetate. Upon standing, a crystal-like product precipitates. This is filtered off and washed with cold diethyl ether. There are obtained 129mg (76% of theory) of the title compound of F. 104 ⁰ C to 106 ⁰ C.

calc .: C H N C ₂₃ H ₃₈ O ₅ N ₂ : Found .: 65.37 9.06 6.63 65.53 9.26 6.50

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cla, vanillin, R f = 0.48. [a] _D: -40 ⁰ C (c, 1.29 in methanol).

Example 19

[1S- [1β, 2a (5H), 3a, 4β]] - 7- [3 - [[[2-Methyl-2 - [(1-oxohexy!) -Amino] -1-oxopropyl] -amino ] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -

5-heptenoic

A. 2- {hexanoylamino) -2-methylpropionic acid

Following the procedure described in Example 5, part A, 2.0 g (19.4 mmol) of 2-aminoisobutyrylic acid with 3.0 g (22.4 mmol) of n-hexanoyl chloride in the presence of 1.6 g (40 mmol) NaOH in a diethyl ether / water Implemented. By recrystallization from benzene the title compound, melting at 141 ⁰ C to 143 ° C are 1,90g (49% d.Th.) Was obtained.

yl] -5-heptenoic acid methyl ester

Following the procedure described in Example 1, Part D, 1 mmol of the compound obtained in Ä is reacted with 1 mmol of CDI and then with 1 mmol of the chiral amine obtained according to Example 1, Part C. The crude product is rapidly chromatographed on 25 g of silica gel. It is eluted with 2% methanol in diethyl ether. There are obtained 235 mg (52% of theory) of the title compound as white crystals

 Thin layer chromatography: silica gel; 5% methanol in diethyl ether, vanillin; Rf = 0.46.

Example 20

[1S- [1β _/ 2α (5Z), 3α _/ 4β]] - 7- [3 - [[[2-ethyl-2 - [(1-oxohexyl) -amino] -1-oxo-propyl] -amino] -methyl ] -7-oxabicyclo [2.2.1l · hept 2-yl] -

5-heptenoic

According to Example 6, 231 mg (0.51 mmol) of the methyl ester obtained according to Example 19 are hydrolyzed with LiOH in a water-THF mixture. The product is crystallized from about 4 ml of ethyl acetate. There are 154,2mg (69% d.Th.) Of

Title compound obtained from F. 81 ° C to 87 ° C.

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ , vanillin; Rf = 0.42.

[a] _D : -10.1 ° C (c, 1.63 in methanol) -

CHN C ₂₄ H ₄₀ O ₆ N _2: 'calc .: 66.02 9.24. 6.42

gel: 65.92 9.37 6.46.

Example 21

[1S- [1ß, 2a (5Z), 3a, 4SS]] - 7- [3 - [[[[(1-oxoheptyl) -arriino] acetyl] amino] methyl] -7-oxabicyclo [2.2. 1] hept-2-yl] -5-

heptenoic

A. 2- (heptanoylarnino) acetic acid

Following the procedure described in Example 5, 1.5 g (20 mmol) of glycine are reacted with 22 mmol of heptanoyl chloride in the presence of 40 mM MoOH in a water / diethyl ether mixture. The crude product is crystallized from 30 ml of ethyl acetate. There are 2.71 g (72.% of theory) of the title compound of F. 98 to 100 ⁰ C obtained.

For example, [1S- [1β, 2a (5Z), 3a, 4β]] - 7-C3 - [[[[(1-oxoheptyl) amino} acetyl] amino] methyl] -7-oxabicyclo [2.2 .1] hept-2-yl] -5-heptenoic acid methyl ester

Following the procedure described in Example 5, Part B, 1 mmol of the compound obtained according to A is reacted with 1 mmol of CDI and then with 1 mmol of the chiral amine obtained according to Example 1, Part C. The crude product is rapidly chromatographed on 25 g of silica gel. It is eluted with ethyl acetate and 2% methanol in ethyl acetate. This 270mg (62% of theory) of the title compound are obtained as an oil

Thin Layer Chromatography: Kiesel; 5% methanol in ethyl acetate, vanillin; R _f = 0.45.

Example 22

[1S- [1β, 2a (5Z), 3α, 4β] l · 7- [3 - [[t [(1-oxoheptyl) -amiπo] -acetyl] -aΓnino] -methyl] -7-oxabicyclo [ 2.2.1] -hept-2-yl] -5-heptenoic acid As described in Example 6, 265 mg (0.607 mmol) of the methyl ester obtained according to Example 21 are hydrolyzed with LiOH in a water-THF mixture. The crude product is crystallized from 4 ml of ethyl acetate. There are 204 mg (80% of theory) of

Title compound obtained from F. 114 ⁰ C to 116 ° C.

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ , vanillin; Rf = 0.40 [a] _D : -6.6 ° C (c, 1.15 in methanol).

C ₂₃ H ₃₈ O ₅ N ₂ :

Example 23

[1S- [1β, 2a, 3α, 4β)] - 7- [3 - [[[[(1-oxoheptyl) aminol · acetyl] amino] methyl ^ 7-oxabicyclo [2.2.1 ^ hept-2 -yll · 5-heptenoic

A. [1S- [1β, 2α, 3α, 4β)] - 7- [3- (hydroxymethyl) -7-oxabicyclo [2.2.1] hept-2-yl] -heptanoic acid methyl ester

800 mg (3, OmMoI) [1S- [1β, 2a (Z), 3a, 4β]] - 7- [3-hydroxymethyl] -7-oxabicyclo [2.2.1] -hept-2 (1) -5- heptensäuremethylestergelöst

in 120 ml of ethyl acetate are under Aronatmosphäre with 160mg 5% palladium-on-carbon as a catalyst

C H N calc .: 65.37 9.06 6.42 Found .: 65.38 9.01 6.64

- «ft - 4.-J ^ J

added. The argon atmosphere is exchanged for hydrogen, which is under a slightly positive pressure. The mixture is stirred at 25 ^° C. for 8 hours, filtered through a plug of diatomaceous earth, and the solvents are evaporated. There are 730 mg (90% of theory) of the title compound.

For example, [IS-dss ^ a.S

heptanoic

According to Example 1, but using the alcohol ester of A, the title compound is obtained.

Example 24

[1S- [1β, 2α (5Z), 3α _/ 4β]] - 7- [3 - [[[(1-oxo-3 - [(1-oxopentyl) amino] acetyl] -amiπo] -methyl] -7-oxabicyclo [2.2.1] hept-2-yl ^ 5-

heptenoic

A. 3- (pentanoyl amino) -propionic acid

After the procedure described in Example 5 2OmMoI ß-alanine be reacted with 22 mmol of valeric chloride in the presence of 4OmMoI NaOH in a mixture of water and diethyl ether. There are obtained 2.75 g (79% of theory) of a crystalline crude product which is crystallized from 150 ml of isopropyl ether and 10 ml of ethyl acetate. There are obtained 1.51 g (44% of theory) of the title compound of mp 73 ⁰ C to 76 ° C.

B. [1S41β, 2α (5Z) _/ 3α, 4β]] - 743 - [[I! 1-oxo-3-t (1-c) xopenty!) - amino] -acetyl] amino-3-methyll-7 oxabicyclo [2.2.'l ^ hept-2-yΠ-5-heptenoic

VmMoI of the acid obtained according to A with 1 mmol of carbonyldiimidazole and then'mit 1 mmol of the compound obtained according to Example 1, Part C, compound [1 S- [I ß, 2a (5Z), 3a, 4ß]] - 7- [3 - (aminomethyl) -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptensäuremethylester implemented. The crude product is rapidly chromatographed on 25 g of silica gel. It is eluted with 5 to 10% methanol in diethyl ether. There are obtained "304mg (72% of theory) of the title compound as a white solid. Thin layer chromatography: silica gel; 10% methanol in diethyl ether, vanillin; R _f = 0.47.

Example 25

[1 S- [1β, 2α (5 Z), 3α, 4β]] - 7- [3 - [[[(1-oxo-3 - [(1-oo-ω-πΓγΟ-αΓηϊηοΙ-ίρΓοργΠ-θΓηίποΙ- ΓηβίΗνΠ ^ ^ -οχΒ ογοΙο ^ ^ .Σ.ΙΙ-Ηβρί -νΠ-Β-

heptenoic

As described in Example 6, 301 mg (0.71 mmol) of the methyl ester obtained according to Example 24 are hydrolyzed with LiOH in a THF-H ₂ O mixture to give 249 mg of a white solid. This is recrystallized from about 4 ml of ethyl acetate. There are obtained 218 mg (75% of theory) of the title compound, mp. 113 ° C to 115 ° C. Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ ; vanillin; R _f = 0.28.

calc .: C H N C ₂₂ H ₃₆ O ₅ N _2: 'gel: 64.68 8.88 6.86 64.65 8.85 6.87

[a] _D : -8.4 ⁰ C (c, 1.0 in methanol).

Example 26

[1S- [1β, 2a (5Z), 3a, 4β]] - 7- [3 - [[[[[(4-phenylbenzoyl) -amino] -acet] -amino] -methyl] -7-oxabicyclo [2.2. 1] hept-2-yl] -5-

heptenoic

A. 2 - [(4-phenylbenzoyl) -amino] -acetic acid

Following the procedure described in Example 5, 5 mmol of glycine is reacted with about 5 mmol of 4-biphenylcarbonyl chloride in the presence of 10 ml of a 1 N NaOH solution, 21 ml of diethyl ether and 2 ml of THF. After acidification of the aqueous phase during work-up, most of the reaction product precipitates out as a solid. This is relatively insoluble in CHCl ₃ and ethyl acetate. It is largely dissolved in 35ml CH ₃ CN. The insoluble material is filtered off. Upon cooling, 0.81 g (63% of theory) of crystalline title compound of F. 207 ⁰ C to 218 ⁰ C (dec.) From.

B. [1S- [1ß, 2a (5Z), 3a, 4SS]] - 7- [3 - _{[[[[(4-PhenylbenzoyO-amino]} acetyl] amino] -rnethyl] -7-oxabicyclo [2.2 .1] hept-2-yl] -5-heptenoic acid methyl ester

According to Example 1, Part C, 1 mmol of the acid obtained according to A with 1 mmol of carbonyldiimidazole and then with 1 mmol of [1 S- [1 ß, 2a (5Z), 3a, 4ß]] - 7- [3 - [-. (aminomethyl) -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptensäuremethylester implemented. It is stirred overnight at room temperature. A large part of the solid has still not gone into solution and by thin layer chromatography is found that the reaction is not complete. 3 ml of DMF are added. An almost clear reaction mixture is obtained which is stirred for a further 24 hours. After the usual workup, the viscous product is rapidly chromatographed on 30 g of silica gel. It is eluted with 2% methanol in CH ₂ Cl ₂ . The product thus obtained is crystallized from 2 ml of ethyl acetate. There are obtained 143 mg (28% of theory) of the title compound a Is white solid

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ , UV + vanillin; R _f = 0.51.

Example 27

[1S- [1β, 2a (5Z), 3α, 4β]] - 7- [3 - [[[[(4-phenylbenzoyl) amino] acetyl] amino] methyl] -7-oxabicyclo [2.2.1] -hept-2-yl] -5-

heptenoic

According to the method described in Example 6, 141 mg (0.279 mmol) of methyl ester obtained according to Example 26 are hydrolyzed with LiOH. A white solid is obtained. This is digested with ethyl acetate. This gives 118 mg (86% of theory) of the title compound of mp 227-229 ° C (dec.).

bee: C H N C ₂₉ H ₃₄ O ₅ N _2: Found .: 71.00 6.99 5.71 70,90 6.91 5.65

Example 27 A

[1S- [1β, 2α, 3a, 4β)] - 7-t3 - [[[[[(2-methyl-2 - [(1-oxohexyl) amino] -1-oxopropyl-3-amino] -methyl] - 7-oxabicyclo [2.2.1] hept-2-yl] -5-

heptanoic

According to Example 2, but using the acid obtained in Example 19, Part A, the title compound is obtained.

Example 28

[1 S- [beta I, 2a (5Z), 3 α, 4 ß]] - 7- [3 - [[[[(1 -Oxoheptyi) -amino] -acety!] - amino] -iTiethyl] - 7-oxabicyclo [2.2.1] -hept-2-y!] - 5-heptenoic acid

According to Example 1 and 2, but using propanoyl chloride, the title compound is obtained.

Example 28A

[1S- [1β, 2a! 5Z), 3a, 4β]] - 7- [3-t [[[i1-oxoethyl] -amino] -acetyl] -amino] -methyl] -7-oxabicyclot2.2.1] hept-2-yl] -5-heptenoic acid

According to Example 1 and 2, but using acetyl chloride, the title compound is obtained.

Example 29

[1S- [1β, 2a (5Z), 3a, 4β]] - 7- [3 - [[[[(1-ω-2-υββγγ) -3Γηϊπο] -3θΘίνΙ] -3Γηϊηο] -ΓηβίΗγΙ] -7- οχ.3ΜογοΙο [2.2.1] - ηβρί-2-ν] - 5-

heptenoic

According to Example 1 and 2, but using 2-butenoyl chloride, the title compound is obtained.

Example 29A

[1S- [1β, 2a (5Z), aa, 4β] 3-7- [3- [t [[(1-oxo-3-butynyl) amino] acetyl] amino] methyl] - 7-oxabicyclo [2.2.1] hept-2-yl] -5-

heptenoic

According to Example 1 and 2, but using 3-butynoyl chloride, the Titeiverbindung is obtained.

Example 30

[1S-Hβ, 2a (52), 3a, 4β]] - 7- [3 - [[[[[[[(penylarnino) -carbonyl] -amino] -acetyl] -arnino] -methyl] -7-oxabicyclo [2.2 .1] hept-2-yl] -5-

heptenoic acid.

According to Examples 3 and 4, but using N-pentyl isocyanate, the title compound is obtained.

Example 3OA

[1S- [1β, 2α (5Z), 3α, 4β]] - 7- [3 - [[[[[[(phenylamino) carbonyl] amino] acetyl] amino] methyl ] -7-oxabicyclo [2.2.1] -hept-2-yl] -5-

heptenoic

According to Example 3 and 4, but using phenyl isocyanate, the title compound is obtained.

Example 31

[1S- [1β, 2α (5Z), 3α, 4β]] - 7- [3 - [[[[(phenoxy carbonyl) amino] acetyl] amino] methyl] - 7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid

According to Example 1 and 2, but using benzoyl chloride, the title compound is obtained.

Example 32 · .. "'

[1S- [1β, 2α (5Ζ), 3α, 4β]] - 7-t3 - [[[1-Oxo-3- [ethyl] (phenylcarbonyl) amino] propyl] amino] methyl] -7 -Oxabicyclo [2.2.1] hept-2-

yl] -5-heptenoic acid

According to Example 5 and 6, but using 3- (ethylamino) propionic acid and benzoyl chloride, the title compound is obtained.

Example 33

[1S- [1β, 2a {5Z), 3a, 4β]] - 7- [3 - [[[[(Benzyloxycarbonyl-amino] -acetyl] -amino] -methyl] -7-oxabicyclo [2.2.1 ] hept-2-yl] -5-

heptenoic

According to Example 7 and 8, but using benzyl chloroformate, the title compound is obtained.

Example 34

[1S- [1β, 2a, 3a, 4β]] - 7- [3 - [[IC (1-oxobutyl) amino] acetyn-amino] methyl] -7-oxabicyclo [2.2.1] - hept-2-yl] -5-heptanoic acid

According to Example 23, but using butanoyl chloride, the title compound is obtained.

Example 35

[1S- [1β, 2a, 3a, 4β]] - 7- [3 - [[[[i1-Oxo-2-propenyl) -amino] -acetyl] -amino] -rnethyl] - 7-oxabicyclo [2.2.1] -hept-2-yl] -5-heptanoic acid According to Example 23, but using propenyl chloride, the title compound is obtained.

Example 36

[1S- [1β, 2α, 3α, 4β3l-7- [3- [I [[(1-oxo-4-pentynyl) -amino3-acetyl] -amino] -methyl] -7-oxabicyclo [2.2.13- hept-2-yl] -5-heptanoic acid

According to Example 23, but using 4-pentynoyl chloride, the title compound is obtained.

Example 37

[1S- [1β, 2a, 3a, 4β] 3-7- [3 - [[[[[[(phenylamino) -carbonyl] -amino3-acetyl-3-amino] -methyl] -7-oxabicyclo [2.2.13-hept -2-yl3-5-

heptanoic

According to Example 23 and Example 3, but using phenyl isocyanate, the title compound is obtained.

Example 38

[1S- [1β, 2α, 3α, 4β]] - 7- [3 - [[[[[(1-O)] o-4- [propyl (1-oxobenzyl) amino] butyl] amino] methyl] -7-oxab! cyclo [2.2.1] hept-2-yl ^ 5

heptanoic

According to Example 23 and Example 5, but using 4- (propylamino) butanoic acid, the title compound is obtained.

Example 39

[1S- [1β, 2a, 3a, 4β]] - 7-f3 - [[[[(benzyloxycarbonyl) amino] acetyl] amino] methyl] -7-oxabicyclo [2.2.1] hept-2 -yl] -5-heptanoic acid According to Example 23 and Example 7, but using benzoyl chloroformate, the title compound is obtained.

Example 40

[1S- [1β, 2a (52), 3a, 4β]] - 7- [3 - [[[[(1-oxoheptyl) amino] acetyl] amino] ethyl] -7-oxabicyclo [2.2.1] hept-2-yl-3-5-heptenoic

A. [1S- [1β, 2a (2), 3a, 4β]] - 7- [3- (2-oxo) ethyl-7-oxabicyclo [2.2.1] hept-2-yl] -5 -heptensäuremethylester

A dry 100 ml three-necked round-bottomed flask equipped with a stirrer is charged with 12.9 g (37.7 mmol) of methoxymethyltriphenylphosphonium chloride

(C ₆ H ₅ I ₃ P ⁺ -CH ₂ OCH ₃ Cr) and distilled toluene kept with molecular sieves (235 ml) and the resulting suspension is stirred in an ice bath under an argon atmosphere until cold. 28.3 mMöl) dropwise. 1.55m added to a solution of potassium tert-ämylat in toluene It forms a bright red Lösung.Diese is stirred for 35 minutes at 0 ⁰ C. then a solution of 4,97g (18 , 8 mmol) of [1-5β, 2a (5Z), 3a, 4β]] - 7- [3-formyl-7-oxabicyclo [2.2.1] -hept-2-yl] -5-heptenoic acid methyl ester in 60 ml Toiuol is added dropwise within 35 minutes with a dropping funnel, the ice bath is allowed to stand, the reaction is stopped by adding 2.3 g (39 mmol) of acetic acid in 5 ml of diethyl ether, the reaction mixture immediately turns pale yellow and immediately becomes 200 ml of saturated NH ₄ Cl solution The mixture is then extracted four times with 200 ml of diethyl ether each time, and the combined diethyl ether phases are washed with a saturated solution of diethyl ether washed NaCl solution and dried over Magnesiumsu If at. After evaporation, a yellow oil is obtained in a white, crystalline solid (phosphine oxide). The white solid is digested with ethyl acetate and the cermet is purified by chromatography on an LPS-1 silica gel column. The following fractions are obtained:

(A) [1S- [1β, 2a (Z), 3a, 4β]] - 7- [3- (2-oxo) -ethyl-7-oxabicyclo [2.2.1] hept-2-yl] -5 -heptensäuremethylester,

(B) [1S- [1β, 2α (Ζ), 3α, 4β]] - 7- [3- (2-methoxy) -äthenyl-7-oxabicyclo [2.2.1] hept-2-yl] -5 methylheptenate, and

(C) [1S- [1β, 2a (Z), 3a, 4β]] - 7- [3- (2,2-dimethoxy) -ethyl-7-oxabicyclo [2.2.1] hept-2-yl ] -5-heptenoic. The compounds (B) and (C) are each converted with trifluoroacetic acid to the compound (A).

B. [1S- [1β, 2a (52), 3a, 4β] 3-7- [3- (2-hydroxyethyl) -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid methyl ester

1.4 g (5 mmol) of the aldehyde obtained in A in 50 ml of methanol are treated with 0.19 g (5 mmol) of NaBH ₄ at ⁰ ° C. under an argon atmosphere. The mixture is stirred for 1 hour at ^{0 0} C and the reaction is stopped by adjusting the pH to 2 with 2 N HCl. The methanol is evaporated under reduced pressure and the reaction mixture is taken up in diethyl ether. The diethyl ether solution is washed with saturated KHCO ₃ solution and saturated NaCl solution and dried over magnesium sulfate. Diethyl ether is evaporated. It leaves behind the title compound.

C. [1S- [1β, 2a (Z), 3a, 4β]] - 7- [342 - [[[(1-oxohexy!) - arnino] -acetyl] -arnino] -äthy!] - 7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid

According to Example 1 and 2, but using the alcohol obtained according to B, the title compound is obtained.

Example 41

[1S- [1β, 2c, 3a, 4β)] - 7- [3- [2 [[[(1-oxohexyl) amino] -acetyl] -amino] -ethyl] -7-oxabicyclo [2.2.13 ^! -hept-2-yl] -hepianic acid According to Example 40 and Example 1 but using [1S- (1β, 2α, 3a, 4β) -7- [3-formyl-7-oxybicyclo [2.2.1 ] -hept-2-yljheptanoic acid methyl ester, the title compound is obtained.

Example 42

[1S- [Iβ, 2a (5Z), 3a, 4β]] - 7- [3- [2 - [[[(1-oxopropyl) amino] acetyl] amino] ethyl] -7- oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid

According to Example 40, but using propionyl chloride, the title compound is obtained.

Example 43

(1β, 2a, 3a, 4β) -7- [3- [2 - [[[(1-oxo-2-butenyl) amino] -acetyl] -amino] -ethyl] -7-oxabicyclo [2.2. 1] hept-2-yl] -5-heptanoic acid

According to Example 40 and 23, but using 2-butenoyl chloride, the title compound is obtained.

Example 44

[1S- [1β, 2α (5Z), 3α, 4β] l · 7 · [3- [2 - [[[[(phenylamino) -carbonyl] -amino-acetyl] -aΓnino] -ethyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] -5-

heptenoic

According to Example 40 and Example 3, but using phenyl isocyanate, the title compound is obtained.

Example 45 i

2-yl] -5-heptenoic acid

According to Example 40 and Example 5, but using 3- (ethylamino) propionic acid and benzoyl chloride, the title compound is obtained.

Example 46

[1S- [1β, 2α (5Ζ), 3α, 4β]] - 7- [3- [4 - [[[(1-oxohexyl) amino] acetyl] amino] -butyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid

A. [1S- [Iβ, 2α (5Ζ), 3α, 4β]] - 7- [3 - [(3-oxo) -propyl] -7-oxabicyclo [2.2.1] -hept-2 -y] - 5-heptenoic

According to Example 40, Part A, but using [1 S- [I ß, 2a (Z), 3a, 4ß]] - 7- [3- (2-oxo) -ethyl-7-oxabicyclo [2.2.1 ] -hept-2-yl] -5-heptenoic acid methyl ester, the title compound is obtained.

For example, [1S- [1β, 2a (5Z), 3a, 4β]] - 7- [3 "[(4-oxo) -butyl-7-oxabicyclo [2.2.1] -hept-2-y! ] -5-heptensäuremethyiestef

According to Example 40, part A, but using the aldehyde obtained according to A above, the title compound is obtained.

C. [1S- [1β, 2a (Z), 3a, 4β]] - 7- [3- {4-hydroxybutyl) -7-oxabicyclo [2.2.1] hept-2-yl] - 5-heptenoic

According to example 40, part B, but using the aldehyde obtained under B above, the title compound is obtained.

D. [1S- [1β, 2a (Z), 3a, 4β]] - 7- [3- [4 - [[[(1-oxohexyl) -amino] -acetyl] -amino] -butyl] -7 -oxabicyc! o [2.2.1] hept-2-yl] -5-heptens3ure

According to Example 1 and Example 2, but using the above-obtained alcohol, the title compound is obtained.

Step Example! 47

[1S- [1β, 2a (5Z), 3a, 4β]] - 8- [3 - [[[[(1-oxohexy! 5-amino] -acetyl] -arniro] -methyl] -7-δ-bicyclo [2.2.1] hept-2-yl] -5-octenoic acid

A. [IS-i ^^ a ^

A slurry of 1,09kg (3.18 mol) of methoxymethyltriphenylphosphonium chloride in 3 liters after Burdick and Jackson sieve-dried tetrahydrofuran is rapidly cooled to 0 ⁰ C and added dropwise within 20 minutes with 1 910ml (2,67mMol) a potassium 1,4Μ tert-amylate in toluene. A dark red solution is obtained, which is stirred for 1 hour at ⁰ ° C. The mixture is then treated slowly over 5 minutes with 200 g (1.28 mmol) of solid hemiacetaline prepared according to Example 3 of US Patent 4143054 (see Compound XIII in Reaction C). The temperature rises slowly to 23 ° C. The mixture is stirred vigorously for 90 minutes at room temperature. The reaction mixture is then cooled rapidly to ⁰ ° C. and treated slowly with 124 ml (2.2 mol) of acetaldehyde within 10 minutes. The mixture is diluted with 2500 ml of water and adjusted to pH 7 with 10% hydrochloric acid. Then, the reaction mixture is extracted seven times with 2 liters of diethyl ether. The combined ether extracts are dried over magnesium sulfate, filtered and the filtrates are evaporated under reduced pressure. The resulting mixture is mixed with 4 liters of isopropyl ether and stirred overnight. The mixture is rapidly cooled to -1O ⁰ C, allowed to stand for 90 minutes at this temperature and then filtered off. The solids are washed thoroughly with isopropyl ether. After evaporation of the filtrate under reduced pressure, 460 g of an oily residue are obtained. This Äiige residue is mixed with 4000 ml of water and stirred vigorously for 2 hours. The aqueous phase is decanted off and the oily residue is again treated twice with 1 liter of water. After the third wash, the residue solidifies and it is filtered off. The combined aqueous solutions are concentrated under reduced pressure to a volume of 3.5 liters. The turbid mixture is filtered through a bed of diatomaceous earth. The filtrates are concentrated again to a volume of 2.3 liters. The turbid solution is quenched in an ice bath and slowly added with 683 ml of concentrated hydrochloric acid. Then the mixture is stirred for 3 hours at room temperature. Thereafter, the solution is neutralized by the slow addition of 720 g of solid ammonium bicarbonate. The mixture is filtered through a bed of diatomaceous earth and finally extracted four times with 2 liters of hexane each time and ten times with 2 liters each of ethyl acetate. The combined Äthyiacetatextrakte are dried magnesium sulfate and evaporated under reduced pressure. The solid residue is triturated with 1 liter of hexane, filtered and dried under reduced pressure. There are 220 g (100% d.Th.j of the reaction sequence CaIs hemiacetal F designated compound of F. 104 ^D C to 105 ⁰ C.

[ct] _D : + 27 ° C (c, 1% in methanol). '

Thin layer chromatography on silica gel; ethyl acetate; R _f = 0.3; Ce (SO ₄ ) ₂ .

The Wittig reaction described above is repeated with the hemiacetal F instead of the hemiacetal XII. The title compound is obtained.

E. [1S- [1β, 2a (Z), 3a, 4β]] - 8- [3- (hydroxymethyl) -7-oxabicyclo [2.2.1] hept-2-yl] -5-octenoic acid methyl ester

Compared to calcium nitrite dried dimethyl sulfoxide is a Wittig reagent by dropwise addition of a solution of 5.32 g (12 mmol) of 4-carboxybutyltriphenylphosphonium bromide in 100ml dimethyl sulfoxide with a by heating 600 mg of sodium hydride in 60 ml of dimethyl sulfoxide at 75 ⁰ C, that is until the evolution of hydrogen finished, prepared Natriummethylsulfinylrnethid solution prepared. Once the organic color of the Ylid solution for the first time longer than 10. Seconds, one equivalent of base is added. The resulting deep orange solution is treated with 1.02 g (6 mmol) of the aldehyde obtained in A in 20 ml of dimethyl sulfoxide and the resulting mixture is stirred for 45 minutes at room temperature. The reaction is completed by adding 24mMo! Acetic acid is broken off, the mixture is poured into 300 ml of brine and extracted three times with 200 ml diethyl ether. After evaporation of the solvents, an oil is obtained. This is stirred with saturated sodium carbonate solution until crystalline triphenylphosphine oxide forms in the mixture. The mixture is then washed with benzene and acidified with 10% hydrochloric acid. The aqueous phase is saturated with salt and extracted with diethyl ether. After drying over sodium sulfate and evaporation of the solvents, 2.43 g of crude product are obtained. The mixture is stirred for 24 hours with 10% aqueous sodium hydroxide solution and isolated again by acidification and diethyl ether extraction. The reaction product is purified on 70 g of silica gel. The eluent used is ethyl acetate: hexane in the ratio 50:50. There are obtained 1.1 g of the acid. After treating the acid with diazomethane (CH ₂ N ₂ ) in diethyl ether, the title compound is obtained.

C. [1S- [1β, 2a (Z), 3a, 4β]] - 8- [3 - [[[[(1-oxohexyl) amino] acetyl] amino] methyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] -5-octenoic acid According to Example 1 and Example .2, but using the ester obtained according to B, the title compound is obtained.

Step Example! 48

[1S-i1β, 2α {Z}, 3α, 4βj] -8 [34 [[{1-oxohexyamino] -acetoyl] -aminotrine trlyl] -7-oxabicyclo [2.2.1] hept-2-yl ] - ^ (1H-ltetrazol-5-yl] -4-

A. [1S- [1β, 2a (Z), 3a, 4β]] - 6-l3-hydroxymethyl-7-oxabicyclo [2.2.1] hept-2-yl] -1- (1H-tetrazoyl) 5-yl] -4-hexenoic

5.5 g (11.8 mMgI) triphenyl-4- (1 H-tetrazol-5-yl) -butylphosphoniumbromid in 100ml of tetrahydrofuran (THF) at 0 C with ^c 2,78g (23,6mMol) of potassium tert butoxide added. The mixture is stirred for 30 minutes at 25 ⁰ C and 2g (11,8mMol) according to US-PS 4,143,054 produced (exo) -octahydro-5,8-epoxy-1H-benzopyran-3-ol in 30 ml THF are added. The reaction mixture is stirred for 2 hours and the reaction is stopped by adding dilute, aqueous hydrochloric acid. The aqueous phase is extracted with 250 ml of ethyl acetate. The combined organic phases are evaporated under reduced pressure, diluted with 500 ml of 5% NaHCGyLösung, washed with 100 ml of diethyl ether, the pH is adjusted to 3 with dilute hydrochloric acid and finally extracted three times with 500ml of ethyl acetate. The combined organic solutions are dried over anhydrous magnesium sulfate. These products are then purified by chromatography on silica gel. It is eluted with 5% methanol in methylene chloride. 2 g of the title compound are obtained.

For example, [1S- [1β, 2a (5Z), 3a, 4β]] - 6- [3 - [[[(1-oxohexy!) - amino] acetyl] -arnino] -methyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] -1- {1H-tetrazol-5-yl] -4-hexenoic

According to Example 1 and Example 2, but using the compound obtained according to A, the Titeiverbindung is obtained.

Example 49

[1S- [1β, 2α (5Z), 3α, 4β] l · 7- [3 - [[[[(1-oxohexyl) -arnino-acetyl-amino] -m-8-ethyl] -7-oxabicyclo [2.2.1 ] hept-2-yll · N-hydroxy-N-

methyl-5-heptenamide

To a solution of 0.82 mmol of the acid obtained according to Example 2 in 5 ml of anhydrous benzene is added 1 ml (11.24 mmol, 13.7 equiv.) Of oxalyl chloride and 1 drop of DMF and stirred for 2 hours at room temperature under a nitrogen atmosphere. Excess oxalyl chloride and solvent are removed with a stream of nitrogen, the mixture being heated in a water bath. The oily residue is dried under reduced pressure (oil pump) for 1 hour. It leaves behind the acid chloride. This is dissolved in 1.5 ml of anhydrous tetrahydrofuran and 139.8 mg of sodium in an ice bath to 0 ⁰ C cooled solution of 98% (1,64mMol, 2 equiv.) Of methylhydroxylamine hydrochloride and 0,34ml (2.46 mmol, 3 equiv.) Triethylamine in 2 ml of tetrahydrofuran and 2 ml of water was added dropwise. The mixture is stirred under nitrogen atmosphere for 30 minutes at 0 ° C and 5.5 hours at room temperature, diluted with 10 ml of water and extracted twice with 50 ml of dichloromethane. The organic extracts are washed with 10 ml of 1 M HCl, 5 ml of 5% NaHCO ₃ solution with 10 ml of water, dried over anhydrous magnesium sulfate, filtered off and evaporated to dryness. A crude product is obtained, which is purified by column chromatography on silica gel. It will get the title connection.

Example 50

[1S- [1ß, 2a (6Z), 3a, 4SS]] - 7- [3 - [[[I (1-oxohexyl) -arnino] -acety!] - aniiiio] -rnethyl]! -7-o oxabicyc [2.2.1] hept-2-yn-6-heptenoic acid

A. [1S- [1β, 2a (6Z), 3a, 4β]] - 7- [3-hydroxymethyl) -7-oxabicyclo [2.2.1] hept-2-yl] -heptenoic acid methyl! A slurry of carboxypentyltriphenylphosphonium bromide in THF is cooled in an ice bath and treated dropwise with 1.4 M KOt-Arnylat in toluene. Then the reaction mixture is allowed to rise slowly to room temperature and stirred for 6 hours. The reaction mixture is added dropwise with stirring within 30 minutes with a solution of the obtained according to Example 3 of US Patent 4143054 hemiacetal in THF dropwise (see reaction sequence G). The reaction mixture is then stirred for 15 hours overnight. Then it is cooled in an ice bath and the reaction is stopped by addition of HOAc. The solvent is evaporated under reduced pressure, the residue is taken up in saturated NaCl solution and extracted with chloroform. The chloroform phases are then extracted with saturated NaHCO3 solution. The aqueous extracts are adjusted to about pH 3.5 by addition of an aqueous HCl solution and extracted several times with chloroform. After evaporation of the combined chloroform extracts under reduced pressure, a crude product is obtained. This is esterified with an excess of a solution of diazomethane in diethyl ether at 0 ⁰ C and then purified by chromatography on silica gel. It will get the title connection.

[1S- [1β, 2a (8Z), 3a, 4β]] - 7- [3 - [[[[(1-oxohexyl) -amino] -acoxy] -amino] -metbyl] -7-oxabicyclo [ 2.2.1] hept-2-yl] -6-heptenoic acid

According to Example 1, but using the ester obtained according to A, the title compound is obtained.

Example 51 '

[1S- [1ß, 2a (2E), 3a, 4SS]] - 7- [3 - [[[[(1-oxohexyl) amino] acetyl] amino] methyl] -7-oxabicyclo [2.2. 1] hept-2-yl] -2-heptenoic acid

A. [1S- [1β, 2a, 3a, 4β)] - 5- [3- (hydroxymethyl) -7-oxabicyclo [2.2.1] hept-2-yl] -pentanal

According to Example 47, Part A, but using [1 S- [1β, 2a, 3a, 4β)] - 3- [3- (hydroxymethyl) -7-oxabicyclo [2.2.1] hept-2-yl] -propionaldehyde in place of the hemiacetal XIII (see reaction sequence Coder E), the compound [1 S- [1β, 2α, 3α, 4β)] - 4- [3- (hydroxymethyl) -7-oxabicyclo [2.2.1] hept -2-yl] -butanol. This is repeated according to Example 47, Part A, proceed. It will get the title connection.

B. [1S- [1β _/ 2a (2E), 3a, 4β]] - 7- [3- (hydroxymethyl) -7-oxabicyclo [2.2.1] hept-2-yl] - 2-heptenoic acid methyl ester

A solution of the aldehyde obtained in A in methanol is treated with carbomethoxymethyltriphenylphosphorane. Then it is stirred for 24 hours at room temperature under argon atmosphere. After evaporation of the solvent under

reduced pressure, a viscous oil is obtained, which is digested with diethyl ether. It precipitates triphenylphosphine oxide, which is removed by filtration. The filtrate is concentrated under reduced pressure. In this case, a mixture of (E) and (Z) esters is obtained. The pure title compound is obtained by chromatography.

C. [1S- [1β, 2a (2E), 3a, 4β]] - 7- {3 - [[[[(- (- oxohexyl) amino] acetyl] amino] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -2-heptenoic acid According to Example 1, but using the ester obtained according to B, the title compound is obtained.

Example 52

[1S- [1β, 2a (5Z), 3a, 4β]] - 7- [3 - [(methylamino) -methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid methyl ester

1 mmol of Example 1, Part C obtained in Chi rales Am in and 1.5 mmol N, N-di methyl If ormamid-di methyl acetate are dissolved in 6 ml of CH ₂ Cl ₂ . The mixture is stirred at room temperature overnight. The solvent and the excess reactants are evaporated under reduced pressure. There remains behind a crude amidine, which is dissolved in 5 ml of CH ₂ Cl ₂ . 2 mmol of trifluoromethanesulfonate are added at room temperature. Then it is stirred for 1 hour at room temperature. The organic solvents and the excess reactants are evaporated under reduced pressure and the residue is treated with a solution of hydrogen chloride in methanol at room temperature overnight. The reaction mixture is evaporated under reduced pressure and the residue is dissolved in 1N HCl. The aqueous phase is washed with diethyl ether and made alkaline with saturated NaHCO ₃ solution. The aqueous phase is extracted with diethyl ether dried over magnesium sulfate. After filtration and evaporation of the solvent, a crude product is obtained, which is purified by column chromatography on silica gel. The title connection is obtained. The title verbin du ng is then used instead of the chiral amine used in Example 1, Part C for the preparation of compounds of the invention in which R ^{1 represents} a CH ₃ group.

Step Example! 53

[1S- [1β, 2α (5Z), 3α, 4β33-7- [3 - [[[ί (r-oxononyl) -arnino] -acetyl] aιτιino ^ n · lethyΠ-7-oχ.abϊcyclo [2. .. ^] hept-2-yl] -5-heptensäurernethylester

A. N-imanoanoyl glycine

According to Example 1, Part A 2OmMoI glycine are reacted with 22 ml of nonanoyl chloride in the presence of 40mM NaOH in a mixture of water and diethyl ether. There are obtained 4.25 crystal-like crude product, which is recrystallized from 40 to 50 ml of ethyl acetate. 3.42 g (79.5% of theory of the title compound of mp 106 to 109 ⁰ C are obtained.

For example, [1S- [1β _/ 2a (5Z), 3a, 4β]] - 7- [3 - [[[[(i) oxononyl) amino] acetyl] amino] methyl] -7- oxabicyclo [2.2.1] hept-2-yl] -5-heptensäuiemethylester

According to Example 1, Part D, 1 mmol of the compound obtained according to A is reacted with 1 mmol of carbonyldiimidazole and then with the obtained from Example 1, Part C chiral Ami η. The crude product is rapidly chromatographed on 30 g of silica gel. It is eluted with ethyl acetate and 2% methanol in ethyl acetate. This gives 305 mg (65.6% of theory) of the title compound as a colorless oil. '.

Thin layer chromatography: silica gel; 2% methanol in ethyl acetate, vanillin; R _f = 0.39.

Example 54

[1S- [1ß, 2a (5Z), 3d, 4ß3] -7- [3 - [[[l (1-oxononyl) -arnino] acetyl] amino] methyl] -7-oxabicyclo [2.2.1lhept 2-yl] -5-hep: ene acid According to Example 2, 302 mg (6, SmMoI) of the methyl ester obtained according to Example 53 are hydrolyzed with LiOH in a THF-H ₂ O mixture. There is obtained a crystal-like product. This is recrystallized from about 8 ml of ethyl acetate. It will be

233 mg (79.5% of theory) of the title compound vom.F. 121 to 127 ° C obtained; [a] _D : -6.0 ⁰ C (c, 1 in methanol).

Thin Layer Chromatography: Silica gel; 10% methanol in CH ₂ Cl ₂ ; vanillin; Rf = 0.44.

CHN

C ₂₆ H ₄₂ O ₅ N ₂ : calc .: 66.64 9.39 6.22

F .: 66.27 9.32 6.28

Example 55 heptenoic acid methyl ester

A. N-octanoylglycine

According to Example 1, Part A 2OmMoI glycine are reacted with 22 mmol of octanoyl chloride in the presence of 4OmMoI NaOH in a mixture of water and diethyl ether. There are obtained 3.06 g (76% of theory) of a crystal-like crude product. This is crystallized from 15 ml of ethyl acetate to. There are obtained 1.11 g (28% of theory) of the title compound of mp 105 to 107 ⁰ C.

For example, [1S- [1β, 2a {5Z), 3a, 4β]] - 7- [3 - [[[[[(oxooctyl) -amino] -acetyl] -amino] -ethyl] -7-oxabicyclo [2.2 .1] hept-2-yl] -5-heptenoic acid methyl ester

According to Example 1, Part D, 1 mmol of the compound obtained according to A is reacted with 1 mmol of carbonyldiimidazole and then with 1 mmol of the obtained according to Example 1, Part C, chiral amine. The crude product is rapidly chromatographed on 30g silica gel. It is eluted with ethyl acetate and 2% methanol in ethyl acetate. This 330mg (73% of theory) of the title compound are obtained as a colorless oil

Thin layer chromatography: silica gel; 2% methanol in ethyl acetate, vanillin; R _f = 0.26.

Example 55A

[1S- [1ß, 2a 5Z), 3a, 4SS!]] - 7- [3 - [[[t (1-oxooctyl) amino] -acetY] - amino] -meihyl] -7-oxabicycIo [2.2 According to Example 2, 327 mg (0.726 mmol) of the methyl ester obtained according to Example 55 are hydrolyzed with LiOH in a mixture of THF-H ₂ O. 306 g of a white solid are obtained This is recrystallized from 10 ml of ethyl acetate.

In this case, 362 mg (83% of theory) of the title compound, melting at 129 to 131 ⁰ C are obtained.

[a] _D : -6.0 ⁰ C (c, 0.96% in methanol).

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ ; Vanillin, R _f = 0.44.

calc .: C H N C ₂₄ H ₄₀ O ₅ N _2: Found .: 66.02 9.24 6.42 66.02 9.16 6.39

Example 56

[1S- [1β, 2a (5Z) _/ 3a, 4β]] - 7- [3 - [[[[[{1-oxo-4-phenyl) -butyl-3-arnino-3-acetyl] -arnino] -methyl] - 7-oxabicyclot2.2.1] hept-2-yl] -5-

heptenoic

A. 4-phenylbutanoylglycine ethyl ester

2,46 g (15 mmol) of 4-phenylbutyric acid are dissolved in 70 ml of distilled THF under argon as protective gas. After cooling in an ice bath, 2.43 g (1.5 mmol) of carbonylidiimidazole (CDI) are added and the mixture is stirred in the cold for 1 hour and at room temperature for 1 hour. The mixture is then cooled again and 2.09 g (1SmMoI) glycine ethyl ester · HCl and 2.1 mL (1 SmMoI) distilled Et ₃ N are added. The mixture is stirred at room temperature overnight. After evaporation of the solvents under reduced pressure, 200 ml of diethyl ether are added. The solution is washed with 70 ml of 1 N HCl, 70 ml of 0.5 N NaOH solution, dried over magnesium sulfate and the solvents are evaporated under reduced pressure. 3.13 g (84% of theory) of the title compound are left behind as a white, crystal-like material

Thin layer chromatography: silica gel; Diethyl ether, UV; R _f = 0.58.

B. 4-pherryibutanoylglycine

3.07 g (12.3 mmol) of the ester obtained according to A are hydrolyzed with 5 g (12 .mu.moles) of NaOH in 60 ml of water. It is stirred for 6 hours at room temperature. By washing twice with 50 ml of diethyl ether, a neutral product is obtained. The aqueous solution is then acidified with concentrated HCl solution. The product is extracted three times with 60 ml CHCl ₃ each time, dried over magnesium sulphate and the solvent is removed under reduced pressure. It leaves behind a white solid. This is recrystallized from 10 ml of ethyl acetate. There are 2.18 g (80% of theory) of the title compound, melting at 99 to 101 of ⁰ C obtained.

C. [1S- [1β, 2a {5Z), 3a, 4β]] - 7- [3 - [[[[(1-oxo-4-phenyl) -buyl] amino} -acety!] - amino] methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid methyl ester

According to Example 5, Part B, 1 mmol of the acid obtained according to B with 1 mmol of CDI and then with. 1 mmol of the obtained according to Example 1, Part C chiral amine. The crude product is rapidly chromatographed on 26 g of silica gel. It is eluted with ethyl acetate and 2% methanol i η ethyl acetate. There are obtained 337 mg (72% of theory) of the title compound as an oil. Thin layer chromatography: silica gel; 2% CH ₃ OH in ethyl acetate, Ce (SO ₄ ); R _f = 0.40.

D. [is-Liten heptensäure

According to Example 6, 336 mg (0.71 mmol) of the methyl ester obtained according to C are hydrolyzed with LiOH in a water-THF mixture. There are obtained 300 mg of a crystal-like crude product. After recrystallization from a methanol / ethyl acetate mixture 247.8mg (76% of theory) of the title compound, mp. 114-116 ⁰ C are obtained; [a] _D : -5.3 ° (c, 1.7% in methanol).

Thin layer chromatography: silica gel; 2% methanol in ethyl acetate, Ce (SO ₄ J ₂ ; R _f = 0.20.

calc .: C H N C ₂₆ H ₃₆ N ₂ O ₅ : Found .: 68,40 7.95 6.14 68.45 8.03 6.11

Example 57

[1S-i1a, 2SS (Z), 3R, 4a]] - 7- [3 - [[[[[(phenylthio) -ACE tyl] -arnino] acetyl] amino] -methyl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid

A. (phenylthioJ-acetylglycine ethyl ester)

According to Example 56, Part A, the title compound is prepared from 15 mMol thiophenoxyacetic acid and the ethyl ester of glycine HCl with carbonyidiimidazole (CDI). 2.95 g (78% of theory) of the title compound are obtained as a solid.

B. (Phenylthio) acetylglycine According to Example 56, Part B, the ethyl ester obtained according to A is hydrolyzed with aqueous NaOH solution. There are 1.041 g (92% of theory) of the title compound as a crystalline Materia! receive.

C. [1S- [1a, 2ß (Z), 3R _r 4a]] - 7- [3 - [[I [[[phenylthio) -acetyl3-amino] acetyl] amino] methyl] -7-oxabicyclo ] -2.2.1] hept-2-yl] -5-heptenoic acid methyl ester

According to example 5, part B, 1, SmMoI of the acid obtained according to B are reacted with 1.5 mmol of CDI and then with 1.5 mmol of the chiral amine obtained according to example 1, part C. The crude product obtained is rapid on 30 g of silica gel

chromatogrephiert. It is eluted with ethyl acetate and 2% methanol in ethyl acetate. This 523 mg (73% d.Th.) Of

Title compound obtained as a solid.

Thin layer chromatography: silica gel; 5% methanol in ethyl acetate, UV + vanillin; R _f = 0.48.

D. [IS-ti heptenoic acid

According to Example 6, 467 mg (0.9 μmol) of the methyl ester obtained according to C are hydrolyzed with 1 N LiOH (2 equivalents). The crude product is recrystallized from 10 ml of ethyl acetate. There are 419 mg (93% d.Th.) Of the title compound, melting at 126 ⁰ C 128 bi obtained; [a] _D : -5.4 ° (c, 0.8% in methanol)

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ + HOAc (3 drops per 10 ml), UV + vanillin; R _f = 0.51.

calc .: C H N S C ₂₄ H ₃₂ O ₅ N ₂ S: Found .: 62.58 7.00 6.08 6.96 62.49 7.14 6.02 6.91

Example 58

[1S- [1a, 2ß Z), 3ß, 4a!]] - 7- [3 - [[[[t3- 4-hydroxyphenyl) -! 1-oxopropyl] -arnmo] acetyl] amino] -methyl !] - 7-oxabicyclo [2.2.1] hept-2-yl] -

5-heptenoic

A. 3- (4-hydroxypheny!) - propanoyl glycine: hy! Es1: er

According to Example 56, Part A, 2.49 g (ISmMoI) 3- (4-hydroxypheny]) - propionic acid with glycine ethyl ester hydrochloride in the presence of CDI and Et ₃ N the residue obtained after evaporation of the solvent is dissolved in CHCl ₃ and with 1 N HCI, "saturated NaHCO ₃ solution and washed with saturated NaCl solution. It is dried over magnesium sulphate and the solvents are evaporated under reduced pressure. In this case, 2,44g of the title compound are obtained as a viscous oil. According to NMR the reaction product contains a Main impurity, but it will continue to be used without additional purification.

B. 3- (4-hydroxyphenyl) propanoyl glycine

According to Example 56, Part B, the crude ethyl ester obtained according to A is hydrolyzed with NaOH in water. There are obtained 1.37 g of a white solid. This is recrystallized from ethyl acetate and methanol. Thereby, 0.98 g {29% of the initial ma'teria! used acid).

C. [1S41α, 2β (Z), 3β, 4α]] - 7- [3 - [[[[¢ 3- (4-Hydr (5x-phenyl) -1-oxopropyl-ar-1-amino] -acety!] -Arynino-3-methyl -7-oxabicyc! O [2.2.1] hept-2-yl] -5-heptenoic acid met hy ester

401 mg (1.5 mmol) of Example 1, Part C obtained chiral amine are dissolved in 20 ml of distilled THF under argon as inert gas. The solution is mixed with 346 mg (1.55 mmol) of B acid obtained. The mixture is cooled in an ice bath. It is mixed with 319 mg (1.55 mmol) of dicyclohexylcarbodiimide (DCC) and stirred for 20 minutes in the cold and overnight at room temperature. Then, 4 drops of 1N HCl are added, and after stirring for 10 minutes, the solvent is evaporated under reduced pressure. The residue is taken up in 8 ml of ethyl acetate. After cooling in an ice bath, the solid is filtered off and washed with about 10 ml of ethyl acetate. The filtrate is evaporated under reduced pressure and the residue is rapidly chromatographed on 35 g of silica gel. It is eluted with ethyl acetate and 3% methanol in ethyl acetate. This gives 243 mg (34% of theory) of the title compound as a viscous material. Thin layer chromatography: silica gel; 8% methanol in ethyl acetate, UV + vanillin; R _f = 0.45.

D. [1S- [1a, 2β (Z), 3β, 4a]] - 7- [3 - [[[[3- (4-hydroxyphenyl) -1-oxo-propyn-amino] -acetyl] -amino] - methyl-7- oxabioyclo [2.2.1] hept-2-yl] -5-heptenoic acid.

243 mg (0.51 mmol) of the methyl ester obtained according to C are dissolved in 20 ml of distilled THF and 2 ml of water under an argon atmosphere and treated with 2 ml of 1N LiO H solution. According to Du η η Schichtchromatograph ie the reaction is complete after only 1 hour. After 2 hours, the reaction mixture is worked up according to Example 6. It will

212 mg (90% of theory) of the title compound as a brittle foam which does not crystallize out; [a] _D : -5.7 ° (c, 0.65, in methanol).

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ + HOAc (3 drops per 10 ml), UV + vanillin; R _f = 0.32.

calc .: C H N C ₂₅ H ₃₄ O ₅ N ₂ : Found .: 65.48 7.47 6.11 65.34 7.59 6.09

Example 59

[1S- [1a, 2ß (2), 3ß, 4a]] - 7- [3 - [[[[(Phenoxyac3t.yl) amino] acetyl] amino] methyl] -7-oxabicyclo [2.2. 1] hept-2-yl] - 5-hepiensäure

A. Phenoxyacetylglycine

According to Example 5, Part A, 2OmMoI glycine are reacted with 22 mMoI distilled phenoxyacetyl chloride in the presence of 4OmMoI NaOH with a mixture of water and diethyl ether. The crude product is recrystallized from 15 ml of ethyl acetate. There are obtained 2.38 g (57% of theory) of the title compound.

heptenoic.

According to example 5, part B, 1.5 mmol of the acid obtained according to A are reacted with 1, SmMoI CDI and then with 1.5 mmol of the chiral amine obtained according to example 1, part C. The crude product is rapidly chromatographed on 25 g of silica gel. It is eluted with ethyl acetate and 2% methanol in ethyl acetate. 463 mg (67% of theory) of the title compound are obtained.

-52 _Γ 259

Thin layer chromatography: silica gel; 5% methanol in ethyl acetate, UV + vanillin; R _f = 0.53.

C. [ΐε-ΙΙ ^

According to Example 6, 463 mg (1.01 mmol) of the methyl ester obtained according to B are hydrolyzed with 2 equivalents of 1 N LiOH in a THF-H ₂ O mixture. The product is crystallized from 20 ml of ethyl acetate with a few drops of methanol. It will

380 mg (84.6% of theory) of the title compound; [a] _D : -5.9 ° (c, 0.68 in methanol).

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ + HOAc (3 drops / 10 ml), UV + vanillin; R _f = 0.57.

calc .: C H N C ₂₄ H ₃₂ O ₆ N _2: Found .: 64.85 7.26 6.30 64.94 7.34 6.26 Step Example! 60 heptenoic -ammo

A. 3-phenylpropanoyloglycine

According to Example 5, Part A, 1.5 g (20 mM) glycine and 3.37 g (22 mmol) hydrocinnamoyl chloride are reacted in the presence of 40 mM NaOH in a mixture of water and diethyl ether. The crude product is extracted with chloroform, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There are left behind 3.53 g (85% of theory) of a white solid. This is recrystallized from 13 ml of ethyl acetal. There are 2.66 g (64% of theory) as a solid from mp 112 to 114 ⁰ C.

B. [1S- [1a, 2β (5Z), 3β, 4a]] - 7- [3 - [[[[(1-oxo-3-phenylpropyl) amino] -acetyl] -amino] -methYl] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid methyl ester

In accordance with Example 5, Part B, 1 mmol of the acid obtained according to A is reacted with 1 mmol of CDI and then with 1 mmol of the amine chiral amine obtained according to Example 1, Part C. The crude product is rapidly chromatographed on 25 g of silica gel. It is eluted with 2% methanol in ethyl acetate. This gives 330 mg (72% of theory) of the title compound as an oil. Thin layer chromatography: silica gel, 2% methanol in ethyl acetate, vanillin; Rf = 0.29.

heptenoic

According to Example 6, 330 mg (0.72 mmol) of the methyl ester obtained in B are hydrolyzed with LiOH in a water-THF mixture. The crude product is recrystallized from 12 ml of ethyl acetate. There are obtained 264 mg (82.8% of th.) Of the title compound, mp 119-122 ° C; [a] _D : -5.9 ° (c, 1.1 in methanol)

Thin layer chromatography: silica gel; 8% methanol in CH ₂ Cl ₂ , UV + vanillin; R _f = 0.29.

calc .: C H N C ₂₆ H ₃₄ O ₅ N _2: Found .: 67.85 7.74 6.33 3P λ _η "π τ r-3 rrr 67.62 7.65 6.22 Example 61 5 ρ, ^ * ujj "/" i "5'LLL heptenoic nönyipsntyi ) -Ammo]

A. 5-Pheny! Pentanoy! Giycinäthy! Ester

According to Example 56, Part A, 2.67 g (15 mmol) of 5-phenyl valeric acid in distilled THF are reacted with 15 mMolCDI and then with 15 mmol of glycine ethyl ester · HCl and 15 mmol (C ₂ Hg) ₃ N. 3.25 g (82% of theory) are obtained. This will continue to be used without additional purification.

B. 5-phenylpentanoyiglycine

According to Example 56, Part B 12.34mMoI of the ester obtained according to A are hydrolyzed with NaOH in water. The crude product is recrystallized from 12 ml of ethyl acetate. There are 2.39 g (82% of theory) of the title compound, mp 93 to 96 ° C.

C. [IS-Ci heptensäuremethyl ester.

According to example 5, part B, 1 mmol of the compound obtained according to B is reacted with 1 mmol of CDI and then with 1 mmol of the chiral amine obtained according to example 1, part C. The crude product is rapidly chromatographed on 25 g of silica gel and eluted with 2% methanol in ethyl acetate. This gives 363 mg (75% of theory) of the title compound as an oil. Thin layer chromatography: silica gel; 2% methanol in ethyl acetate, vanillin; R _f = 0.33.

D. [1S- [1a, 2β, 5Z), 3β, 4a]] - 7- [3- [i [[(1-oxa-5-phenyl-peniyl) -amino] -acetyl] -amino] -methyl3 -7-oxabicyclo [2.2.1] hept-2-yl3-5-heptenoic acid ...

According to Example 6, 362 mg (0.749 mmol) of the methyl ester obtained according to C are hydrolyzed with LiOH in a water-THF mixture. The crystal-like crude product is recrystallized as 10 ml of ethyl acetate containing a few drops of methanol. There are 278mg (79% of theory) of the title compound from mp 129 to 131 ⁰ C; [a] _D : -5.5 ° (c, 0.9 in CH ₃ OH). Thin layer chromatography: silica gel; 8% methanol in CH ₂ Cl ₂ , vanillin; Rf = 0.31).

calc .: C H N C ₂₇ H ₃₃ O ₅ N ₂ : Found .: 68.91 8.14 5.95 68.82 8.02 5.88 Example 62 rfi4 - C * vclohpx heptenoic

A. 4-Cyclohexyl butanoic acid

4-Phenylbutanoic acid prepared according to Example 56, Part A is dissolved in 25 ml of glacial acetic acid. The solution is mixed with 0.1 g of platinum oxide. The solution is hydrogenated in a Parr shaker for 6.5 hours at up to 3.8 bar until the hydrogen uptake decreases. The catalyst is filtered off and the acetic acid is removed under reduced pressure. The residue is recrystallized from 20 ml of diethyl ether. This gives the title compound, melting at 85 to 88 ⁰ C. 1.18 g (77% of theory).

For example, [1S- [1a, 2β (Z), 3β, 4a]] - 7- [3 - [[[[(4-cyclohexyl-1-oxobutyl) amino] -acety!] - amino] -rnethyl! ] -7-oxabicyclo [2.2.1] hept-2-yl] -5-heptenoic acid methyl ester

341 mg (1.5 mmol) of the acid obtained according to A is dissolved in 10 ml of CHCl ₃ under an argon atmosphere. The solution is cooled in an ice bath and treated with 2,43 mg (1.5 mmol) of carbonyldiimidazole. The mixture is stirred in the cold for 30 minutes and at room temperature for 1 hour. 456 mg (1.5 m Mo I) of the hydrogen chloride of the chi fa I en amine prepared in Example 1, Part C are added. The solution is cooled in an ice-bath and treated with 0.36 ml (2.78 mg, 1.5 mmol) of tri-n-β-amine. The mixture is stirred overnight at room temperature. It is then mixed with 40 ml of CHCl ₃ and washed with 20 ml of 1 N HCl, 20 ml of saturated NaHCO ₃ solution and with 20 ml of saturated NaCl solution. After drying over magnesium sulfate, the solvent is evaporated under reduced pressure. The product obtained is mixed with 30g of kieselge! rapidly chromatographed. It is eluted with 1% methanol in ethyl acetate. This 661 mg (92.5% of theory) of the title compound are obtained as an oil which auskristalüsiert slowly

Thin layer chromatography: silica gel; 2% methanol in ethyl acetate, vanillin; R _f = 0.26.

C. [liHi

  heptenoic acid.

According to Example 6, 661 mg (1.39 mmol) of the methyl ester obtained according to B are hydrolyzed with LiOH. The crude product is recrystallized from 15 ml of ethyl acetate and 1 ml of methanol. There are obtained 542 mg (84% of theory) of the title compound, mp 141 to 143 ⁰ C; [a] _D : -6.0 ° (c, 0.96 in methanol)

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ , vanillin; Rf = 0.51.

calc .: C H N C ₂₆ H ₄₂ O ₅ N ₂ : Found .: 67,50 9.15 6.06 3 / IiT Π "7 Γ *? Π 67.58 9.24 6.05 Example 63 Π (Ϊ fin 9 Ql ~ 7 \ '? F LI o- (. I U. ,, C p \ <; J, o I heptenoic acid ienylthio) -pi

A. 3- (phenylthio) -propanoic acid methyl ester

440 mg (4 mmol) of thiophenol and 70 μΐη (0, SmMoI) of Et ₃ N are dissolved in 5 ml of CH ₂ Cl ₂ . The solution is added dropwise with 412 mg (4.8 mmol) of methyl acrylate. The reaction is exothermic. It is stirred for 30 minutes at room temperature. Then the excess methyl acrylate is removed under reduced pressure.

Thin layer chromatography: silica gel; Diethyl etherhexane = 1: 2, UV; R, = 0.58. The crude product is used without additional purification.

B. 3- (phenylthio) -propanoic acid

About 4 m of the M et hy ester obtained according to Part A are treated with 10 ml of 1 N NaOH and 5 ml of THF. It is stirred for 3 hours at room temperature. Then, 30 ml of diethyl ether are added. The phases are separated and the diethyl ether phase is again extracted with 10 ml of 1 N NaOH solution. The combined aqueous phases are washed with 20 ml of diethyl ether and then acidified with concentrated HCl. The product is extracted twice with 30 ml each of CHCl ₃ . The chloroform extracts are washed twice with 20 ml each of saturated NaCl solution, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. The title compound remains as a white solid (quant). This will continue to be used without additional purification.

'C. 3- (phenylthio) -propanoylglycine ethyl ester

According to Example 56, Part A, 0.740 g (4.06 mmol) of the acid obtained according to B are reacted with 4.06 mmol of carbonylimidazole and then with 4.06 mmol of glycine ethyl ester HCl. There is obtained 1.00 g (92% of theory) of the title compound as a crystal-like material.

D. S-iPhenylthiol-propanoylglycine

According to Example 56, Part B, 0.96 g (3.6 mmol) of the ethyl ester obtained after C are hydrolyzed with NaOH. A white solid is obtained. This is digested with diethyl ether. There are obtained 0.75 g (87% of theory) of the title compound.

E. [TS41a, 2β (Z), 3β, 4a]] - 7- [34t [i [1-oxo-3-phenylthio) -propyl] -amino] -acety!] - am! No] -methyi] -7-oxafaicyc! o [2.2.1] hept-2-y-5

heptenoic acid methyl ester.

According to Example 62, Part B, 359 mg (1.5mMoi) of the acid obtained after D with 1, BmMoI carbonyldiimidazole and then reacted with the hydrochloride of the obtained according to Example 1, Part C chiral amine. The crude product is chromatographed on 30g silica gel. It is eluted with 1% methanol in ethyl acetate. This gives 623 mg (85% of theory) of the title compound of the oil. , ·

Thin layer chromatography: silica gel; 2% methanol in ethyl acetate, LJV + vanillin; R _f = 0.21.

C H N S calc. 63.27 7.22 5.90 6.76 Found .: 63.41 7.28 5.94 6.63

heptenoic

623 mg (1.285 mmol) of the methyl ester obtained according to E are dissolved in 25 ml of THF and 2.5 ml of H ₂ O under an argon atmosphere and treated with 2.6 ml of a 1 N LiOH solution. The mixture is stirred for 5 hours at room temperature and then worked up according to Example 6. The crude product is chromatographed on 20g silica gel. It is eluted with 5% methanol in CH ₂ Cl ₂ . There are obtained 436 mg (71% of theory) of an oil which crystallized on standing. It is recrystallized from 10 ml of ethyl acetate. This gives 136.5 mg (22% of theory) of the title compound, mp. 95 to 97 ° C; [ci] _D : -5.3 ° (c, 0.88 in

Methanol).

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ ; Rf = 0.50.

C ₂₅ H ₃₁₁ O ₅ M ₂ S :.

Example 64

[1S- [1α, 2β, z) _/ 3β, 4α]] - 7- [3 - [[[[[[[(pheny! Methyl) thiol · acetylamino] acetyl] -aΓnino] -methyl] -7 -oxabicyclo [2.2.1] hep ^ -2-y]] - 5-heptenoic acid:

A. Chloroacetylglycine "i. ,

1.5 g (2OmMoI) of glycine are dissolved in 25 ml (5OmMoI) 2 N NaOH and treated with 20 ml Diäthyläthsr. This solution is added dropwise at 0 ° C with 2.26 g of chloroacetyl chloride in 20 ml of diethyl ether. The mixture is stirred at 0 ^° C. for 30 minutes and at room temperature for 1 hour. The phases are separated and the aqueous phase is washed twice with 20 ml of diethyl ether. The aqueous phase is then adjusted to CH ₂ with concentrated HCl and the products are extracted three times with 50 ml of ethyl acetate each time. The combined ethyl acetate extracts are washed with brine, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There are obtained 2.56 g (84% of theory) of the title compound as a solid, which is used further without additional purification.

B. (Benzylihio) -8cety! G! Ycine

1.28 g (8.4 mMo) of the acid obtained according to A are dissolved in 10 ml of methanol and cooled in an ice bath. Then, 10.8 g (2OmMoI) of sodium methoxide are added and finally 1.25 g (10.08 mmol) of benzyl mercaptan are added dropwise. It is stirred overnight at room temperature. Thereafter, 10 ml of a 1 N NaOH solution are added. The neutral products will be removed raw twice with jewei! S40ml diethyl ether. The aqueous phase is then adjusted to pH 2 with concentrated HCl. The product is extracted three times with 50 ml portions of diethyl ether, washed with brine, dried over magnesium sulphate and the solvent is evaporated under reduced pressure. It leaves behind a white solid. This is recrystallized from benzene. There are obtained 1.28 g (64% of theory) of the title compound.

hepterssäuremethylesier

According to Example 62, 359 mg (1.5 mmol) of the acid obtained according to B are reacted with 1.5 mmol of carbonyldiimidazole and then with 1.5 mmol of the chiral amine obtained according to Example 1 part C in HCl. The crude product is rapidly chromatographed on a 30 g silica gel. It is eluted with 1% methanol in ethyl acetate. This gives 625 mg (85% of theory) of the title compound. ,

Thin layer chromatography: silica gel; 2% methanol in ethyl acetate, UV + vanillin; Rf = 0.30.

D. tiS- [1a, 2ß (Z), 3ß, 4a]] - 7- [3 - [[[[[[[(phenylmethyl) -thio] -acety!] - amJno] -acety!] - arnino] - methyl] - [7-oxabicyc o 2.2.1] hept-2-yl] -5!

heptenoic

According to Example 5, Part B, 625 mg (1.28 mmol) of the methyl ester obtained according to C are hydrolyzed with 2.6 ml of a 1N LiOH solution in a THF-water mixture. The reaction mixture is worked up after 5 hours and 20 minutes. The crude product is recrystallized from 15 ml of ethyl acetate. There are 427 mg (77.7% of theory) of the title compound, melting at obtain 98 to 101 ⁰ C; [a] _D : -5.7 ° (c, 0.95 in methanol). , '

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ , UV + vanillin; R _f = 0.4.

C ₂₅ H ₃₄ O ₅ N ₂ S:

C H N S calc. 63.27 7.22 5.90 6.76 gef. 63.53 7.42 5.91 6.77

Step Example! 65 [1S- [1a, 2β (Z), 3β, 4a]] - 7- [34 [[[[[(Butylthio) -aceiyi] -amino] -acetyl] -amino] -nathyl] -7-o; < abicyc! o [2,2.1] HSPT-2-yI] -5-heptensäiii-e

A. (butanethio) acetylglycine. ,

According to Example 64, 1.28 g (8.4 mmol) of the acid obtained according to Example 64, Part A, are reacted with 1-butanethio. The crude product is crystallized from Etv / a 10 ml of diisopropyl ether. 0.55 g (32% of theory) of the title compound are obtained.

B. [1S41a, 2ß {Z), 3ß, 4a]] - 7- [3 - [[[i [(Buiy! Thio) -aoeiyi-am! No] -acaiy] -amino] -rnethy!] - 7-oxabioyc! o [2.2.1] hepi-2-yl] -5-hsptensäuremetbyiester

According to Example 62, 308 mg (1.5 mmol) of the acid obtained according to A are reacted with 1.5 mmol of carbonyldiimidazole and then with 1.5 mmol of the hydrochloride of the chiral amine obtained according to Example 1, Part C. The crude product is rapidly chromatographed on 30 silica gel. In this case, 1% methanol in ethyl acetate sluiert. There are obtained 53 $ mg (79% of theory) of the title compound as an oil

Thin layer chromatography: silica gel; 2% methianol in ethyl acetate, UV + vanillin; R _f = 0.29.

C. [1 S- [I ct, 2 ß (Z), 3 ß, 4a]] - 7- [3 - [[[[[(Buty! Th! O) -ac8ty!] - arn5no] -ac8ty! !] amino] -methyl] - 7-oxafaicyc o [2.2.13hept-2-yI] -5-heptenoic!

According to Example 5, Part B, 533 mg (1.13 mmol) of the methyl ester obtained according to B are hydrolyzed with 2.4 ml of a 1 N LiOH solution in a THF-water mixture. The reaction mixture is worked up after 5 hours. The crude product is crystallized from 20 ml of ethyl acetate. This gives 444 mg (85.4 of theory) of the title compound of mp 114 to 116 ° C; [a] _D : -6.0 ° (c, 0.9 in methanol)

Thin-layer chromatography: Kiese !; 10% methanol in CH ₂ Cl ₂ , UV + vanillin; R _f = 0.3.

calc .: C H N S C ₂₂ H ₃₆ O ₆ N ₂ S: Found .: 59.97 8.24 6.36 7.28. 59.77 8.31 6.30 7.27.

^Example:;

[1S- [1α, 2β (Z), 3β, 4α]] - 7 »[3- [I [[[[[(cyclohexylmethyl) thioacetyl! Amino-acetyl-amino] methyl] - 7 -oxabicycio [2.2.1] hep ^ 2-yI] -

5-heptensJiure

A. Gydohexyimethylthioacetate

1.92 g (10 mol) of cyclohexylmethyl mesylate and 1.25 g KSCOCH ₃ are dissolved in distilled THF. The reaction mixture is heated at reflux for 3 hours. Another 1.25 g of KSCOCH3 and 9 ml of THF are added and the mixture is heated under reflux for a further 3 hours. 100 ml of diethyl ether are added and the mixture is washed with 30 ml of brine. The aqueous phase is extracted again with 30 ml Diäthy lather. The combined organic phases are washed with 15 ml of brine, dried over magnesium sulfate and then the solvent is evaporated under reduced pressure.

It leaves behind 1.8 g of a straw-colored oil. This is rapidly chromatographed on 50 g of silica gel. It is eluted with 2% diethyl ether in hexane. 1.199 g (69% of theory) of the title compound are obtained as an oil. Thin layer chromatography: silica gel; 10% diethyl ether in hexane, UV and J ₂ ; Rf = 0.48.

For example, [(Cyc! Ohexy! Meihy!) - ihio] -ac8tyig! Ycine

According to example 64, part B, 6 mmol of the compound of A and 6 mmol of the compound from example 54 ^! , Part A used in the presence of 17mM NaOMe. The crude product is crystallized from diisopropyl ether. 516 mg (35% of theory) of the title compound are obtained.

C. [IS-ii y!] - 5-hepi: enoic acid methyl ester

According to Example 62, Part B, 368 mg (1.5 mmol) of the compound obtained according to B are mixed with 456 mg (1, SmMoI) of the crude amine Am in -HCl obtained in Example 1, TeIa C. In the presence of 1.5M M carbonyldiimidazole ( CDI). The crude product is chromatographed on 30 g of silica gel. It is eluted with 1% methanol in ethyl acetate. This gives 542 mg (73% of theory) of the title compound as an oil

Thin Layer Chromatography: Kieseigel; 2% methanol in ethyl acetate, UV + vanillin; R _f = 0.38.

D. [1S41a, 2βiZ), 3β, 4a]] - 7- [3- [ti [[i (cyclohexyl! Methyl) thio] acetyl] -arnino] -acatyl] -amirio] -methy!] -7-oxabicyclo [2.2.1] hept-2-y!] - 5-heptenoic acid -

According to Example 6, 542 mg (1.09 mmol) of the methyl ester obtained according to C are hydrolysed with 4 ml of 1 N LiOH solution in a mixture of THF and water. The crude product is recrystallized from 30 ml of ethyl acetate. 439 mg (83% of theory) of the title compound of melting point 131 to 133 ° C. are obtained; [a] _D : -5.0 ° (c, 0.95 in methanol). Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ , UV + vanillin; R _f = 0.56.

C ₂₅ H ₄₀ N ₂ O ₅ S: calc .:

_gef. ^ _

Example 67.

[1S- [1Q, 2β (Z), 3β, 4α] ^ 7- [3 - [[[[[[(phenylsulfinyl) -acetic] -amino-acyl] aminomethyl] -7-oxabicyclo [2.2.1] hep ^ 2 yl] -5-

heptenoic

385 mg (1.8 mmol) of powdered NaJO ₄ are dissolved in 12 ml of water. This solution is treated with a solution of 2.76 mg (0.6 mmol) of the acid obtained in Example 57 in 20 ml of methanol. The mixture is stirred overnight at room temperature. Most of the methanol is distilled off under reduced pressure. There are 50 ml of saturated NaCl solution

C H N S 62.47 8.39 5.83 6.67 62.37 3.46 5.77 6 60

259

added. The product is extracted three times with 50 ml each of CHCl ₃ . The combined chloroform extracts are washed with 20 ml of MaCl solution, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. There is an oil left behind. This is rapidly chromatographed on 4g silica gel. It is eluted with 5% methanol in CH ₂ Cl ₂ . This gives 254 mg of a foam which gives very broad maxima in the ¹ H NMR spectrum. This material is dissolved in 100 ml of CHCl ₃ , washed twice with 25 ml of 1N HCl solution and twice with 20 ml of saturated H.CI solution each time, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure. It. leave 213 mg (74% of theory) of the title compound as a white foam; [a] _D : -9.7 ° (c, 0.7 in methanol)

Thin layer chromatography: silica gel; 10% methanol in CH ₂ Cl ₂ , UV + vanillin, R _f = 0.14.

C ₂₄ H ₃₂ N ₂ O ₆ S · 0.2 H ₂ O

Example 68

-743-ί [[[[(Phenyl-sulfonyl) 7 - [iS41α, ßίZ), 3R, 4α3.?] -! FiceΐyΠ-am ^^ o] l -acety · amino] -methyl]! -C) xabicyc o [2.2.1] hept-2-yl] -! 5-

hepisnsäure

44.5 mg (0.9 mmol) of the acid obtained according to Example 57 are dissolved in 10 ml of methanol and cooled in an ice bath. 810 mg (about 2.7 m M oil) of oxone in 10 ml of water are added. The mixture is stirred for 4 hours at room temperature and then diluted with 30 ml of water. The product is extracted three times with 35 ml of CHCl ₃ . The combined CHCl ₃ extracts are washed twice with 20 ml each of saturated NaCl solution, dried over magnesium sulphate and the solvent is evaporated under reduced pressure. It leaves behind 430ml of an oil. This is chromatographed on 10g silica gel. It is eluted with 5% methanol in CH ₂ Cl ₂ . This gives 165rng (37% of theory) of the title compound. Thin Layer Chromatography: Kieseigel; 10% methanol / CH 2, UV + vanillin; R _f = 0.27.

C H N S calc .: 60.02 6.80 5.83 6.68 Found .: 59,95 6.83 5.78 6.53

C ₂₄ H ₃₂ O ₇ N ₂ S-0.5H ₂ O:

ber .: gef .:

57.46 57.27

6.63 6.44

5.59 5.55

Examples 69-104

According to the method explained in the description and in the above embodiments, the following are

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Claims (2)

A process for the preparation of 7-oxabicycloheptane substituted diamides and the related prostanglandin analogs of general formula I. (CH-) -NC- (CH-JNCR " ³ 2 P ι τ Μ 2'σ, - ji O R "O RO and their stereoisomers, where m is 0 to 4; A is a-CH = CH-or-CH ₂ -CH ₂ group; η is 1 to 5; Q one OH halo halo halo -CH = CH-, -CH "-, -CH-, -CH-, -C- '. '' R represents a CO ₂ H group, a CO ₂ alkyl radical, a CO ₂ -alkali metal salt, a C0 ₂ polyhydroxyamine salt, a group, or a single bond "45 or the rest CNR'R \ N-N wherein R ⁴ and R ^{5 are the} same or different and represent a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy or an aryl group, wherein at least one of R ⁴ and R ^{5 is} not a hydroxyl group and a cermet alkoxy group; ρ is 1 to 4; R ^{1 is} a hydrogen atom or a lower alkyl group; q has the value 1 to 12; R ^{2 represents} a hydrogen atom or a lower alkyl, lower alkenyl, lower alkyl, aryl, arylalkyl, lower alkoxy, arylalkyloxy or aryloxy, amino, alkylamino, arylalkylamino or arylamino radical, or a radical _t fl'n alkyl-S, aryl-S, arylalkyl-S, aryl-S-alkyl-, alkyl-S-alkyl, arylalkyl-S-alkyl wherein η 'is 0.1 or 2, is an alkylaminoalkyl, arylaminoalkyl, arylalkylaminoalkyl, alkoxyalkyl, aryloxyalkyl or an arylalkoxyalkyl radical, characterized in that A) if Q is a CH ₂ group or a single bond, a compound of the general formula -Q-C0 ₂ alkyl ^ CH-NHR ^ Ό ' with a compound of general formula VII CH-NHR 0 R ² O 0 * 4- (CH ₂ ), -. SS - to a compound of the general formula CH _n -A- (CHJ -Q-CO alkyl 2 2 η <L CH-N-C (CHJ -N-C-2 ι 2 σ ι η ti ² 1 implements, and B) if Q is a -CH = CH group and A is a -CH = CH group, a compound of the general formula (XX) (CHJ -CHO , (CHJ -N-C- (CHJ -N-C-R ² PI ₁ Il ² 1 I ₂ Il , 'O RO .RO with a compound of the general formula (C ₆ H ₅ ) ₃ P = CH- {CH ₂ ) _n -CH = CHCO ₂ H to a compound of general formula IJ (CHJ -A- (CHJ-CH = CH-CO _n H 2 m, 2 η 2 (CH ₂ ) -Ν-C- (CHJ-Ν-CR "O ¹ R ¹ 0 R ' implements, and C) if Q is one -CH- Halo' or a halo halo -G- (XX) (U) Group and Aeine-CH = CH group is a compound of general formula XX (CHj -CHO 2 m ι ^ic Vp - ;; - '' ^(c Vfi7ir η RO .RO (XX) with a compound of the general formula (halo) _x . ί in which X has the value Toder 2, to a compound of general formula IK (halo) _x (CH.) -A- (CH) -C-COH Zm 2 η 2 (CH 1 -Ν-C- (CH) -N ^2Ρ Μ ² * 1 (IK) implements, and
D) if R ^{3 is} an NH ₂ group, a compound of general formula VIA (CH.) -A-iCH.J ^ -Q-CO-alkyl 2 m 2 η (VIA) with a compound of the general formula HO ₂ C-CH ₂ -NC-NH ₂ Il and then to a compound of general formula IT "CH J -A- (CH.) -Q-R. (IT) (CH) -N-C- (CH) -N - C-NH, RO RO hydrolyzed, and
E) if R is a group - N ^X N H . and A is a CH = CH group, a compound of the general formula HC (CH) -CH = CH- (CH) -Q // \\ 2 m, 2 η \ Ij CH M N (HC) with a compound of the general formula Il 11 3 OH-C- (CH-) -N-CR
2 q I, to a compound of general formula IN (CH ₂ ) _m -CH = CH- (CH ₂ ) _n -Q - ^ jj N N ' N - N. H (CH) -Ν-C- (CH.) -Ν-CR ³ (IN) ^{2 Ρ} I 1 II ^{2 q} I 2 Κ RO RO