Description 5

The development of resistance against chemotherapeutic agents is

< a major reason for the frequent failure in the clinical cancer therapy. Depending on the cancer cell-type, different molecular • mechanisms counteract chemotherapeutic agents. The phrase Multi-

10 Drug-Resistant (subsequently abbreviated as MDR) phenotype (S. Kuzmich et al., Med.Res.Rev. 1991, 11, 185) has ^' been coined for a phenotype which has been selected for resistance to a single cy- totoxic agent, but is found to exhibit cross-resistance to a va¬ riety of structurally and mechanistically unrelated compounds.

15 The MDR-phenotype is observed upon treatment with vinca alkalo¬ ids, anthracyclines, and epipodophyllotoxins. A positive correla¬ tion exists between the DRl-gene product P-glycoprotein of 170 KDalton molecular weight (subsequently abbreviated as P170) and the occurance of MDR (J. Bell, et al., Cancer Invest.

20 1991,9,563). P170 acts as an ATP-powered efflux-pump, which ex¬ ports cytotoxic compounds from the endoplas in a rather nonspe- cifc manner. In recent years, different classes of compounds were found to modulate MDR. Such compounds are : verapamil (E. Pomme- renke et al., Arzneim.-Forsch. 1991, 41 (II), 855), niguldipine

25 (A. Reymann et al., Arch.Pharmacol. 1991,343, Suppl. R50), cyclo- sporine A, and quinine (E. Solary et al., Cancer 1991, 68, 1714). As all of these compounds were developed for clinical applica¬ tions other than MDR-modulation, they possess severe side effects (e.g. lowering blood pressure or suppression of the immune sy-

30 stem) . This makes it difficult to use the compounds as MDR-modu- lators in routine cancer therapy. Therefore, new modulators with reduced side effects or toxicity are required.

The present invention describes the preparation and use of 35 l-amino-3-phenoxy-propane-derivatives that are effective in modu¬ lating the resistance of tumor cells against chemotherapeutic agents like vincristine, vinblastine, adriamycine and etoposide.

40 i

45

The present invention provides novel l-amino-3-phenoxy -propane- derivatives of formula 1

R A-B

in which

X represents H, OH, OCORi, OCOORi, OCONHRi, ORi, OS0 ₃ -, OP0 ₃ 2- wherein R ¹ means linear or branched alkyl; hydroxyalkyl; aminoalkyl; or phenyl, or pyridyl, both of which may be substituted by up to three substituents which may independently be selected from the group consisting of alkyl, alkoxy, halogen, nitro, CF ₃ , NR'R'', wherein R' and R' ' are either hydrogen or linear or branched alkyl; or phenylalkyl, wherein the alkyl moiety may be substitu¬ ted by a hydroxy- or amino-group and the phenyl group may be sub- stituted by up to three substituents which may independently be selected from the group consisting of linear or branched alkyl, alkoxy, halogen, nitro, CF ₃ , NR'R'', wherein R' and R' ' are defined as above;

Z represents the aminoheterocycles:

Z-l Z-2 Z-3 Z-4

wherein

m is 2 or 3;

R ² and R ³ independent from each other are hydrogen (provided that

R ² and R ³ are not hydrogen at the same time), cycloalkyl; or phenyl, or phenylalkyl, or pyridyl, where the rings may be substituted by up to three substituents which are independently selected from the group consisting of linear or branched alkyl, alkoxy, alkylenedioxy, halogen, nitro, CF ₃ , NR'R'', wherein R' and

R' ' are as defined above;

or the residues:

wherein

R ⁴ is hydrogen, hydroxy or cycloalkyl; R ^s is hydrogen or cycloalkyl, and R ⁶ is cycloalkyl; or Ri, Rs and R ⁶ are independently selected from the group of phenyl, or phenylalkyl, or pyridyl, which all may be substituted by up to three substituents which may independently be selected from the groups consisting of linear or branched alkyl, alkoxy, alkylenedioxy, halogen, nitro, CF ₃ , NR'R'', wherein R' and R' ' are as defined above;

Y means a carbonyl- or a (CH ₂ ) _n -πιoiety, with n being 0, 1,2 or 3, W means oxygen, sulfur, a group represented by the formula NR ¹¹ (wherein Rπ may be hydrogen or linear or branched alkyl) , a carbonyl moiety, or one of the following moieties:

-0-(CH ₂ ) _q -,-CH=CH-, -(CH ₂ ) _P -, -NH-CHj-, -N=CH-, -(C=0)-NR", and with q being 0, 1 or 2 and p being 0,1 or 2.

A represents the structures

wherein R ^β means hydrogen, linear or branched alkyl, allyl, alkoxy, benzyl, or CF ₃ .

a is 1, 2, 3 or 4, u and v are 0, 1 or 2 (with the proviso that the sum of u and v is not larger than three) , w and x are 0, 1 or 2 (with the proviso that the sum of w and x is not larger than three), y and z are independently from each other 0, 1 or 2.

B represents a ring system selected from the group consisiting of:

phenyl (with the proviso, that B is not phenyl, when A is - 0-CH-) , pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, naphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, indanyl, benzofuranyl, benzothienyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, naphthyridinyl, . or cyclopentadienyl, which all may be substituted by up to three substituents selected from the group consisting of linear or branched alkyl, alkoxy, methoxyalkyl, trifluoromethoxyalkyl, car- bonylalkoxy, CF ₃ halogen, cyano, nitro, NR'R'', wherein R' and R' ' are as defined above, alkyl-NR'R' ' , wherein R'and R' ' are de¬ fined as above; or 1,3,5-triazinyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, which all may be substituted by up to two substituents selected from the group consisting of linear or branched alkyl, alkoxy, methoxyalkyl, trifluoromethoxyalkyl, car- bonylalkoxy, CF ₃ , halogen, cyano, nitro, NR'R' ' , wherein R' and R' ' are as defined above, alkyl-NR'R'', wherein R'and R' ' are de¬ fined as above; or indolyl, benzimidazolyl, pyrrolyl, i idazolyl, or pyrazolyl, which all may be substituted at carbon by up to three substi¬ tuents selected from the group consisting of linear or branched alkyl, alkoxy, methoxyalkyl , trifluoromethoxyalkyl, carbonylal- koxy, CF ₃ , halogen, cyano, nitro, NR'R'' or alkyl-NR'R'', wherein R' and R' ' are as defined above, and which may be substituted at their nitrogen atoms by a substituent selected from a group con¬ sisting of linear or branched alkyl, phenylalkyl, acylalkyl, phe- nylacylalkyl, or phenylacyl; or 1,2,3-triazolyl, or 1,2,4-triazolyl, which may be substituted at their carbon atoms by a substituent selected from the group consisting of linear or branched alkyl, alkoxy, methoxyalkyl, trifluoromethoxyalkyl, carbonylalkoxy, CF ₃ , halogen, cyano, nitro, NR'R'' or alkyl-NR'R'', wherein R' and R' ' are as defined above, phenyl, benzyl (wherein these two residues may independently be substituted by up to two substituents selected from halogen, alkyl, alkoxy, CF ₃ ) , and which may be substituted at their nitro¬ gen atoms by a substituent selected from the group consisting of linear or branched alkyl, phenylalkyl, acylalkyl, phenylacylal- kyl, or phenylacyl; or 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,5-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2, 5-thiadiazolyl, or 1,3,5-thiadiazolyl, which may be substitu- ted by a substituent selected from the group consisting of linear or branched alkyl, alkoxy, methoxyalkyl, trifluoromethoxyalkyl, carbonylalkoxy, CF ₃ , halogen, cyano, nitro, NR'R'' or alkyl-

NR'R'', wherein R' and R' ' are as defined above, phenyl, benzyl (wherein these two residues may independently be substituted by up to two substituents selected from halogen, alkyl , alkoxy,

CF ₃ ); or 1,2,3,4-oxatriazolyl, or 1,2,3, 5-oxatriazolyl;

R and R ^χ each mean a substituent selected independently from the group consisting of hydrogen, hydroxy, linear or branched alkyl, alkoxy, halogen, nitro, CF ₃ , NR'R'', wherein R'and R' ' are as de¬ fined above, or a carbo- or heterocycle, annellated to the phenyl moiety of formula 1, thus forming a bicyclic ring system selected from the group consisting of naphthalene, tetrahydronaphthalene, tetramethyltetrahydronaphthalene, indene, indole, benzofurane, benzothiophene, benzimidazole, each of them optionally substitu¬ ted at their carbon atoms by up to three substituents indepen- dently selected from the group consisting of linear or branched alkyl, alkoxy, nitro, CF ₃ , halogen, nitro, NR'R'', wherein R' and R' ' are as defined above.

It is to be understood that the compounds of formula 1 can con- tain various stereogenic centers and that all possible stereo- and regioisomers of foresaid compounds including all possible mixtures of isomers are covered by this claim. Enantiomerically pure material of compounds of formula 1 containing one or more stereogenic centers can be obtained by the following procedures : use of enantiomerically pure starting materials, fractional cry¬ stallisation of diastereoisomeric salts formed with optically active acids, chromatographic separation using a chiral statio¬ nary phase.

The l-amino-3-phenoxy-propane-derivatives of formula 1 can be used as free bases or pharmaceutically suitable salts thereof. Preferred acids for the formation of salts are: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane- sulfonic acid, 4-toluenesulfonic acid, fumaric acid, malic acid, oxalic acid, malonic acid, citric acid, tartaric acid, propionic acid, acetic acid, formic acid, benzoic acid and other physiolo¬ gically tolerated acids (as described for example in J. Pharm. Sci., Vol 66, No.l, p.1-17 (1977)).

As used herein, the terms used above have the following preferred meanings:

halogen means fluoro, chloro, bromo or iodo; alkyl means a methyl-, ethyl-, propyl- or butyl-group, or their positional isomers;

NR'R'' means an amino-, methylamino-, ethylamino-, propylamino-, isopropylamino-, butylamino-, tert.butylamino-, dimethylamino-, diethylamino-, methylethylamino-, dipropylamino-, diisopropyl- amino-group; alkoxy means a methoxy-, ethoxy-, propoxy-, butoxy-group or their positional isomers; hydroxyalkyl means a 2-hydroxyethyl-, 2-hydroxypropy1-, 2-hydroxybutyl-grou ; aminoalkyl means a 1-aminomethyl-, 1-aminoethyl-, 1-amino- methyl-propyl-group; phenylalkyl means a phenylmethyl-, 2-(phenyl)-ethyl,

3- (phenyl)-propyl-group or their positional isomers, which addi¬ tionally may be substituted by up to three substituents which may be independently selected from the groups consisting of linear or branched alkyl (preferably C _ι _ ₄ ) , hydroxy, alkoxy (preferably Cι_ ₄ ), halogen, nitro, CF ₃ , NR'R'', wherein R' and R' ' are as defined above; alkylenedioxy means methylenedioxy, ethylenedioxy; Z means a substituted aminoheterocycle such as piperazine, homo- piperazine, piperidine, homopiperidine, or an annelated bicycle such as in 6- and/or 7-position substituted exo-3-aza- bicyclo-[3.2.0]-heptanes.

Examples of R ² and R ³ , which are part of Z, include the following groups: hydrogen- (provided that R ² and R ³ are not hydrogen at the same time) ; phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-tert.butylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 4-dimethylaminophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-tert.butylphenyl, 3-methoxy- phenyl, 3-trifluoromethylphenyl, 3-dimethylamino-phenyl, 2-fluo- rophenyl, 2-chlorophenyl, 2-tert.butylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 2-dimethylamino-phenyl, 3,4-dimethoxy- phenyl, 2,3,4-trimethoxyphenyl, 3,4, 5-trimethoxyphenyl, 3,4-me- thylenedioxy-phenylphenylmethyl, (4-fluorophenyl)-methyl, (4-chlorophenyl)-methyl, (4-tert.butylphenyl)-methyl, (4-methoxy- phenyl)-methyl, (4-trifluoromethylphenyl)-methyl, (4-dimethyl- aminophenyl)-methyl, (3-fluorophenyl)-methyl, (3-chlorophe- nyl)-methyl, (3-tert.butylphenyl)-methyl, (3-methoxy- phenyl)-methyl, (3-trifluoromethylphenyl)-methyl, (3-dimethyl- aminophenyl)-methyl, (2-fluorophenyl)-methyl, (2-chlorophe- nyl)-methyl, (2-tert.butylphenyl)-methyl, (2-methoxy- phenyl)-methyl, (2-trifluoromethylphenyl)-methyl, (2-dimethyl- aminophenyl)-methyl, (3,4-dimethoxyphenyl)-methyl, (2,3,4-trime- thoxyphenyl)-methyl, (3,4, 5-trimethoxyphenyl)-methyl, (3,4-methy- lenedioxypheny1)-methylphenylethyl, (4-fluorophenyl)-ethyl, (4-chlorophenyl)-ethyl, (4-ter .butylphenyl)-ethyl, (4-methoxy- phenyl)-ethyl, (4-trifluoroethylphenyl)-ethyl, (4-dimethylamino- phenyl)-ethyl, (3-fluorophenyl)-ethyl, (3-chlorophenyl)-ethyl,

(3-tert.butylphenyl)-ethyl, (3-methoxyphenyl)-ethyl, (3-trifluo- romethylphenyl)-ethyl, (3-dimethylamino-phenyl)-ethyl, (2-fluoro¬ phenyl)-ethyl, (2-chlorophenyl)-ethyl, (2-tert.butylphenyl)- ethyl, (2-methoxyphenyl)-ethyl, (2-trifluoromethylphenyl)-ethyl, (2-dimethylaminophenyl)-ethyl, (3,4-dimethoxyphenyl)-ethyl, (2,3,4-trimethoxyphenyl)-ethyl, (3,4,5-trimethoxyphenyl)-ethyl, (3,4-methylenedioxyphenyl)-ethyl, (3,4-dimethoxyphenyl)-ethyl, (2,3,4-trimethoxyphenyl)-ethyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, • (2-pyridyl)-methyl, (3-pyridyl)-methyl, (4-pyridyl)-methyl, (2-pyridyl)-ethyl, (3-pyridyl)-ethyl, (4-pyridyl)-ethyl, diphenylmethyl, bis (4-fluorophenyl)-methyl, bis(4-chlorophenyl)- methyl, bis (4-tert.butylphenyl)-methyl, bis(4-methoxyphenyl)- methyl, bis (4-trifluoromethylphenyl)-methyl, bis (4-dimethylamino- phenyl)-methyl, bis (3,4-dimethoxyphenyl)-methyl, bis (2,3,4-tri- methoxypheny1)-methyl, bis (3,4, 5-trimethoxyphenyl)-methyl, bis (2-pyridyl)-methyl, bis (3-pyridyl)-methyl, bis (4-pyridyl)- methyl, 2,2-diphenylethyl, 2,2-bis(4-fluorophenyl)-ethyl, 2,2-bis (4-chlorophenyl)-ethyl, 2,2-bis (4-tert.butylphenyl)-ethyl, 2,2-bis (4-methoxyphenyl)-ethyl, 2,2-bis (4-trifluoromethylphe- nyl)-ethyl, 2,2-bis(4-dimethylaminophenyl)-ethyl, 2,2-bis (3,4-di¬ methoxyphenyl)-ethyl, 2,2-bis (2,3,4-trimethoxyphenyl)-ethyl, 2,2-bis (3,4, 5-trimethoxyphenyl)-ethyl, 2,2-bis (2-pyridyl)-ethyl, 2,2-bis(3-pyridyl)-ethyl, 2,2-bis(4-pyridyl)-ethyl, triphenylme- thyl, phenyl-(2-pyridyl)-methyl, phenyl-(3-pyridyl)-methyl, phenyl-(4-pyridyl)-methyl, 2-phenyl-2-(2-pyridyl)-ethyl,

2-phenyl-2-(3-pyridyl)-ethyl, 2-pheny1-2-(4-pyridyl)-ethyl, cy- clohexyl-phenyl-methyl, 2-cyclohexyl-2-phenyl-ethyl, cyclo- hexyl- (2-pyridyl)-methyl, cyclohexyl-(3-pyridyl)-methyl, cyclo- hexyl-(4-pyridyl)-methyl, 2-(cyclohexyl)-2-(2-pyridyl)-ethyl, 2-cyclohexyl-2-(3-pyridyl)-ethyl, 2-cyclohexyl-2-(4-pyridyl)- ethyl, 3,3-diphenylpropyl, 3,3,3-triphenylpropyl, phenylacetyl, 2-(4-fluorophenyl)-acetyl, 2-(4-chlorophenyl)-acetyl, 2-(4-tert.butylphenyl)-acetyl, 2-(4-methoxyphenyl)-acetyl, 2-(4-trifluoroacetylphenyl)-acetyl, 2- (4-dimethylamino-phenyl)- acetyl, 2-(3,4-dimethoxyphenyl)-acetyl, 2-(2,3,4-trimethoxyphe- nyl)-acetyl, 2- (2-pyridyl)-acetyl, 2- (3-pyridyl)-acetyl, 2-(4-pyridyl)-acetyl, 2,2-diphenylacetyl, 2,2-triphenylacetyl, 2,2-bis(4-fluorophenyl)-acetyl, 2,2-bis(4-chlorophenyl)-acetyl, 2,2-bis (4-tert.butylphenyl)-acetyl, 2,2-bis(4-methoxyphenyl)- acetyl, 2,2-bis (4-trifluoroethylphenyD-acetyl, 2,2-bis(4-dime- thylamino-phenyl)-acetyl, 2,2-bis(3,4-dimethoxyphenyl)-acetyl, 2,2-bis (2,3,4-trimethoxyphenyD-acetyl, 2,2-bis (2-pyridyl)- acetyl, 2,2-bis (3-pyridyl)-acetyl, 2,2-bis (4-pyridyl)-acetyl, 2-phenyl-2-(2-pyridyl)-acetyl, 2-phenyl-2- (3-pyridyl)-acetyl, 2-phenyl-2-(4-pyridyl)-acetyl, 2-cyclohexyl-2-phenyl-acetyl, 2-cyclohexyl-2- (2-pyridyl)-acetyl, 2-cyclohexyl-2- (3-pyridyl)- acetyl, 2-cyclohexyl-2-(4-pyridyl)-acetyl,5-fluorenyl, 5-dibenzo-

suberanyl, 5-dibenzosuberenyl, 5-dibenzosuberanyliden, 5-dibenzo- suberenyliden, 9,10-dihydroanthracenyl, 9-xanthenyl, 9-thio- xanthenyl, 6, 11-dihydrobenz [b,e]oxepin-11-yl, dibenzo- [b,f]azepin-5-yl, 10,ll-dihydrodibenzo[b,f]azepin-5-yl, fluo- rene-5-carbonyl, dibenzosuberone-5-carbonyl, dibenzosuberene- 5-carbonyl, 9, 10-dihydroanthracene-carbonyl, xanthene-9-carbonyl, 9-thioxanthencarbonyl, 6,11-dihydrobenz[b,e]oxepin-11-carbonyl, dibenzo[b,f] zepin-5-carbonyl, 10,11-dihydrodibenzo[b,f]azepin- 5-carbonyl.

A means one of the following residues:

(E)-vinylene, (Z)-vinylene, (E)-l-methyl-vinylene, (E)-l-ethyl- vinylene, (E)-1-propyl-vinylene, (E)-1-butyl-vinylene, (E)-l-iso- propyl-vinylene, (E)-1-tert.butyl-vinylene, (Z)-l-methyl-viny- lene, (Z)-l-ethyl-vinylene, (Z)-l-propyl-vinylene, (Z)-l-butyl- vinylene, (Z)-l-isopropyl-vinylene, (Z)-1-tert.butyl-vinylene, (E)-2-methyl-vinylene, (E)-2-ethyl-vinylene, (E)-2-propyl-viny- lene, (E)-2-butyl-ethynyl, (E)-2-isopropyl-vinylene, (E)-2-tert.butyl-vinylene, (Z)-2-methyl-vinylene, (Z)-2-ethyl-vi- nylene, (Z)-2-propyl-vinylene, (Z) -2-butyl-vinylene, (Z)-2-iso- propyl-vinylene, (Z)-2-tert.butyl-vinylene, (E)-l-trifluorome- thyl-vinylene, (Z)-1-trifluoromethyl-vinylene; (E)-l-methoxy-vinylene, (E)-l-ethoxy-vinylene, (E)-l-propoxy-vi- nylene, (E)-1-butoxy-vinylene, (E)-l-isopropoxy-vinylene,

(E)-1-tert.butoxy-vinylene, (E)-2-methoxy-vinylene, (E)-2-ethoxy- vinylene, (E)-2-propoxy-vinylene, (E)-2-butoxy-vinylene, (E)-2-isopropoxy-vinylene, (E)-2-tert.bu oxy-vinylene, (Z)-l-methoxy-vinylene, (Z)-l-ethoxy-vinylene, (Z)-1-propoxy-vi- nylene, (Z)-1-butoxy-vinylene, (Z)-l-isopropoxy-vinylene,

(Z)-1-tert.butoxy-vinylene, (Z)-2-methoxy-vinylene, (Z)-2-ethoxy- vinylene, (Z)-2-propoxy-vinylene, (Z)-2-butoxy-vinylene, (Z)-2-isopropoxy-vinylene, (Z)-2-tert.butoxy-vinylene; e inylene; methylene, dimethylene, trimethylene, tetramethylene; carbonyl, carbonylmethylene, methylenecarbonyl, carbonyldimethy- lene, methylenecarbonylmethylene, dimethylenecarbonyl, carbonyl- trimethylene, trimethylenecarbonyl, methylenecarbonyldimethyl, dimethylenecarbonylmethylene; oxy, oxymethylene, oxy imethylene, methyleneoxy, dimethyleneoxy, methyleneoxymethylene, methyleneoxydimethylene, dimethyleneoxyme- thylene, dimethyleneoxydimethylene; carbonylimino, methylenecarbonylimino, N-methyl-carbonylimino, N-methyl-methylenecarbonylimino, iminocarbonyl, iminocarbonylme- thylene, N-methyl-iminocarbonyl, N-methyl-iminomethylenecarbonyl, N-dimethylenecarbonylimino, N-ethyl-dimethylenecarbonylimino, N-ethyl-iminocarbonyl, N-ethyl-iminodimethylene, N-propyl-carbo-

nylimino, N-propyl-dimethylenecarbonyl, N-propyl-iminocarbonyl, N-propyl-iminomethylencarbonyl, N-isopropyl-carbonylimino, N-iso- propyl-methylenecarbonyli ino, N-isopropyl-iminocarbonyl, N-iso- propyl-iminomethylenecarbonyl, carbonyliminomethylen, di- methylenecarbonyliminomethylene, carbonyl-N-methyl-imino- methylene, carbonyl-N-ethyl-iminomethylene, carbonyl-N-propyl- iminomethylene, carbonyl-N-isopropyl-iminomethylene, dimethylene- carbonyl-N-methyl-iminomethylene, dimethylenecarbonyl-N-ethyl- iminomethylene, dimethylenecarbony1-N-propyl-iminomethylene, di- methylenecarbonyl-N-isopropyl-iminomethyl; methylideneaza, azamethylidene, methylenmethylideneaza, dimethy- lenemethylideneaza, trimethylenemethylideneaza, (methyl)-methyli- deneaza, (isopropyl)-methylideneaza, (tert.butyl)-methylideneaza, (trifluoromethyl)-methylideneaza, azamethylidenmetnylene, azame- thylidenedimethylene, azamethylidenetrimethylene, aza-(methyl)- methylidene, aza-(tert.butyl)-methylidene, aza- (trifluorome¬ thyl)-methylidene, (methoxy)-methylideneaza, (ethoxy)- methylideneaza, (propoxy)-methylideneaza, (butoxy)-methylide¬ neaza, (isopropoxy)-methylideneaza, (tert.butoxy)-methylideneaza, aza-(methoxy)-methylidene, aza-(ethoxy)-methylidene, aza-(pro¬ poxy)-methylidene, aza-(butoxy)-methylidene, aza-(isopropoxy)- methylidene, aza-(tert.butoxy)-methylidene; cyclopropylene, 3-methyl-cyclopropylene, 3,3-dimethyl-cyclopropy- lene, 3-ethyl-cyclopropylene, 3-propyl-cyclopropylene, 3-butyl- cyclopropylene, 3-isopropyl-cyclopropylene, 3-ter .butyl-cyclo- propylene, 3-fluoro-cyclopropylene, 3-chloro-cyclopropylene, oxiranylene.

X means one of the following residues:

hydrogen, hydroxy, methoxy, ethoxy, propoxy, butoxy, isopropoxy, tert.butoxy, phenoxy, benzyloxy, phenethoxy, formyloxy, acetyl- oxy, propionyloxy, 2-hydroxy-propionyloxy, 2-amino-acetyloxy, 2-amino-propionyloxy, 2-amino-3-methyl-propionyloxy, benzoyloxy, 2-pyridoyl, 3-pyridoyl, 4-pyridoyl, 2-phenyl-acetyloxy, 2-phenyl- acetyloxy, 2-hydroxy-2-phenyl-acetyloxy; methylaminocarbonyloxy, phenylaminocarbonyloxy.

R and Rx each mean up to two residues which can independently be selected from the following groups: methyl, ethyl, n-propyl, butyl, isopropyl, tert.-butyl, tri- fluoromethylmethoxy, ethoxy, propoxy, butoxy, isopropoxy, tert.- butoxy, fluoro, chloro, bromo, nitro, amino, methylamino, ethyl- amino, propylamino, isopropylamino, butylamino, tert.butylcimino, dimethylamino, diethylamino, methylethylamino, dipropylamino, di- isopropylamino;

or R and R ^χ together with the phenyl residue they are attached to form a bicyclic ring system selected from the group consisting of: naphtalene, tetrahydronaphtalene, tetramethyltetrahydronaphta- lene, indene, indole, benzofurane, benzothiophene, benzimidazole.

Examples for B include structures such as:

T ⁱ H, F, Cl, Br, I, CH ₃ , CH ₂ CH ₃ , OH, OCH ₃ , CF ₃ , OCH ₂ CH ₃ CN, N0 ₂ , NH ₂ , N(CH ₃ ) ₂ , COOCH ₃ , COOCH ₂ CH ₃

T ² = H, F, Cl, Br, I, CH ₃ , CH ₂ CH ₃ , OH, OCH ₃ , CF ₃ , OCH ₂ CH ₃ CN, N0 ₂ , NH ₂ , N(CH ₃ ) ₂ , COOCH ₃ , COOCH ₂ CH ₃

T3 = H, F, Cl, Br, I, CH ₃ , CH ₂ CH ₃ , OH, OCH ₃ , CF ₃ , OCH ₂ CH ₃ CN, N0 ₂ , NH ₂ , N(CH ₃ ) ₂ , COOCH ₃ , COOCH ₂ CH ₃

T!,T ,T ³ independent from each other as described above (provided that only one of these residues may be N0 ₂ )

T ⁴ = H, F, Cl, Br, I, CF ₃ , CH ₃ , OH, OCH ₃ , N0 ₂ ,

CN, NH ₂ , N(CH ₃ ) ₂

⁵ = H, F, Cl, Br, I, CF ₃ , CH ₃ , OH, OCH ₃ , N0 ₂ ,

CN, NH ₂ , N(CH ₃ ) ₂

T ⁶ = H, methyl, ethyl, n-propyl, n-butyl, isopropyl, tert.-butyl, CF ₃

? = H, methyl, ethyl, n-propyl, n-butyl, isopropyl, tert.-butyl, CF ₃

U = H, CH ₃ , C ₂ H ₅ , formyl, acetyl, phenyl, benzyl

T ⁹ for all mentioned residues =

H, F, Cl, Br, I, methyl, ethyl, n-propyl, n-butyl, isopropyl, tert.bu¬ tyl, CF ₃ , OCH ₃ , N0 ₂ , COOCH ₃ , COOCH ₂ CH ₃

ie = methyl, ethyl, propyl, butyl, benzyl

.CH ₃ ,CH ₃

CH ₃

.CF ₃ CF ₃

CF ₃

.N_

N

I

-N r- N I

Ti, τ ² , T ³ independent from each other as described above (provided that only one of these residues is N0 ₂ )

Specific examples of formula 1 include the following structures, classified according to the type of amino heterocycle Z _

(the indication of listed compounds and examples with roman num¬ bers, e. g. III, refers to the classification of compounds shown in the reaction schemes III to VIII) :

Specific examples of type III with Z=Z-1 include:

Specific examples of type III with Z=Z-2 include:

Specific examples of type III with Z=Z-1 include:

Specific examples of type III with Z=Z-2 include:

Specific examples of type III with Z=Z-3 include :

R A-B

Specific examples of type III with Z=Z-4 include :

R A-B

Specific examples of type IV with Z=Z-1 include:

Specific examples of type IV with Z=Z-2 include:

R A-B

Specific examples of type V with Z=Z-1 include:

Specific examples of type V with Z=Z-2 include:

Specific examples of type VI with Z=Z-1 include:

R A-B

Specific examples of type VI with Z=Z-2 include:

Specific examples of type VI with Z=Z-3 include:

Specific examples of type VII with Z=Z-1 include:

Specific examples of type VIII with Z=Z-1 include:

Specific examples of type VIII with Z=Z-2 include:

Specific examples of type VIII with Z=Z-3 include:

Specific examples of type VIII with Z=Z-4 include:

Specific examples of type IX with Z=Z-1 include:

Specific examples of type IX with Z=Z-2 include:

The compounds of the present invention were prepared according to the following schemes and descriptions:

Scheme I)

a) A compound represented by the general formula £ (with A, B, Z, R and Rx in the meaning as defined above; X= OH) is prepared by reaction of an amine Z-H (Z in the meaning as described above) with a glycidether of formula Jfi in a suitable solvent, if neces¬ sary in the presence of a base.

Suitable solvents are organic solvents such as aliphatic alcohols (like methanol, ethanol, n- and isopropanol) ; linear dialkyl- and dialkylglycolethers (like diethylether, methy1-tert. utylether) , cyclic ethers (such as tetrahydrofuran, dioxane) ; aliphatic and aromatic hydrocarbons or their halogenated derivatives (pentane, hexane, heptane, cyclohexane, dichloromethane, trichloromethane, benzene, toluene, xylene, chlorobenzene) ; aliphatic ketones (ace- tone, methylethylketone, methylisobutylketone); dialkylform- and dialkylacetamides (such as dimethylformamide, dimethylacetamide) , dimethylsulfoxide, cyclic ureas (such as 1,3-dimethyl-tetrahy- dro-2[lH]-pyrimidone) , acetonitrile, H ₂ 0 and mixtures of the here mentioned solvents. The reaction can be run at room temperature or elevated temperature preferably at the boiling point of the applied solvent or solvent system. The above mentioned base can be an alkalimetal-hydroxide, -carbonate, -hydrogencarbonate, -al- coholate (especially -methylate, -ethylate and -tert.butylate) , or a tertiary amine like a trialkylamine, N-alkylmorpholine, pyridine, dimethylaminopyridine or diazabicycloundecane.

Amines like Z-H (with Z in the meaning as defined above) are ge¬ nerally known, and are either commercially available or can be prepared according to standard methods described in the litera- ture (e.g. EP 363 212) .

Compounds represented by the general formula I are prepared from glycidethers Ifi by reaction with equimolar amounts or excess up to two equivalents of an amine Z-H in a polar aprotic solvent, preferably in alcohols, especially preferred are ethanol or iso¬ propanol, if necessary in the presence of a base, especially po¬ tassium carbonate or N-methylmorpholin, and under stirring at elevated temparatures.

Glycidethers of the general formula la (with A, B, R , Rx in the meaning as described above) are obtained by alkylation of the corresponding phenols I (with A, B, R in the meaning as descri-

bed above) with epihalohydrins (e.g. epibromo-, epichloro-, epiiodohydrine) , 1,3-dihalogen-2-propanols (e.g. 1,3-dibromo- or l,3-dichloro-2-propanol) , or the corresponding glycidtosylates or -mesylates, in the presence of a base.

These reactions are carried out at 0°C or elevated temperatures up to 120°C at atmospheric pressure or elevated pressure in an auto¬ clave. Suitable solvents for these reactions are aliphatic ketones (like acetone, methylethylketone, methylisobutylketone), aliphatic alcohols (like methanol, ethanol, n- and isopropanol) , aliphatic dialkylethers or cyclic ethers (like diethylether, tetrahydrofuran, dioxane) , polar aprotic solvents like dialkyl¬ form- or -acetamides (e.g. dimethylformamide, dimethylacetamide) , dimethylsulfoxide, nitromethane, hexamethylphosphoric triamide, cyclic ureas (such as l,3-dimethyl-tetrahydro-2[lH]-pyrimidone) ; mixtures of the above mentioned solvents or an excess of the al¬ kylating agent. The reaction should be carried out in the pre¬ sence of base as acid scavenger, e.g. alkalimetal-carbonates (preferably from sodium or potassium), -hydrogencarbonates, -hy- droxides, -hydrides, -alcoholates; basic oxides like aluminum- or calcium-oxide; basic ion exchange resins; tertiary amines such as trialkylamines, N-alkylmorpholines or piperidine. The addition of a crown ether (like 18-crown-6) or a phase transfer catalyst (like "Aliquat 336* or triethylbenzylaπflrioniumchloride) may be useful to increase the yield of the reaction as well as addition of a catalytic amount of alkalimetall iodide (especially sodium or potassium iodide) .

Compounds represented by the general formula Ja are obtained pre- ferably by reaction of the corresponding phenols I with equmolar amounts or in excess with up to two equivalents of epibromo- or epichlorohydrine and 1.0-1.3 equivalents of sodium hydride or po¬ tassium tert.butylate in tetrahydrofuran or dimethylformamide, 1-2 equivalents of potassium carbonate in acetone, methylisobu- tylketone or dimethylformamide at a temperature of 0°C up to ele¬ vated temperatures like 100°C.

b) An alternative method for the synthesis of compounds repre¬ sented by formula ∑ is the reaction of phenols Ife (with A, B, R, Rx in the meaning as defined above) with a compound represented by formula Zs. (where Z is an amine residue as defined above) , whe¬ rein D means the residues [-CH ₂ -(CH)-0-(CH ₂ ) ] or [-CH ₂ -CHOH-CH ₂ -E] , wherein E means a general "leaving group". The reaction can be carried out using the same reaction conditions as described above for the conversion of .la to ∑. The leaving group E in formula Is. can mean a halogen radical like chloro, bromo, iodo, an aromatic or aliphatic sulfonic acid residue (like p-toluenesulfonate,

p-bromo- or p-nitrobenzenesulfonate, methanesulfonate or trifluo- romethanesulfonate) . In order to prepare compounds represented by the general formula ∑j_ the precursor Is. can also be used as a mixture of the corresponding epoxides and epihalohydrines, if the preparation of Is. affords such mixtures.

c) A compound represented by formula Is. (with Z, D, E in the meaning as described above) is obtained by reaction of an amine Z-H with an epihalohydrine (e.g. epibromo-, epichloro-, epiiodo- hydrine) , l,3-dihalogen-2-propanols (e.g. 1,3-dibromo- or

1,3-dichloro-2-propanol) , or the corresponding glycidtosylates or -mesylates, optionally in the presence of an additional base. The reaction conditions applicable to this step are generally known and are described for example in U.S. 4,980,351.

d) The compounds represented by formula (with A, B, Z, R, Rx in the meaning as definded above; X=OH) are converted into their corresponding esters Id (with A, B, R, Rx, Z in the meaning as described above, X is OC(=0)R ¹ , wherein Ri is defined as in gene- ral formula 1) by reaction of compound I with an acid derivative RiCO-G Ifi. G can be a general leaving group, preferably a halogen radical (like chlorine, bromine, iodine) or an azide. I& may also represent a symmetric or asymmetric anhydride with G in the mea¬ ning of RiCOO or R^COO respectively (with R ¹ * in the meaning of lower alkyl); an "active ester" (with G in the meaning of N-hy- droxysuccinimidyl-, i idazolidyl-, N-hydroxybenzotriazolyl-, pen- tafluorphenyl-residue; examples are given in M.Bodanszky's "Prin¬ ciples of Peptide Synthesis", p. 28-35, Springer Verlag 1984). In case of G in the meaning of OH the use of a dehydrating agent is necessary, such as a carbodiimide (e.g. dicyclohexylcarbodiimide, N,N-diisopropyl-ethylaminocarbodiimide) , or other suitable agents generally used for ester formation. The reaction is usually run in an inert organic solvent, the addition of a base might be ne¬ cessary depending on the nature of the leaving group G. The reaction conditions applicable to this step are generally known and described for example in J. March's "Advanced Organic Chemistry", 3rd edition, p.348-353, (John Wiley and Sons) and the literature cited therein. Precursors and other reagents are com¬ mercially available or can be prepared by known methods.

Scheme II)

a) Compounds represented by the general formula II (with A, B, Z, R, R in the meaning as described above) are prepared by reaction of an amine Z-H (Z in the meaning as described above) with a compound represented by formula Ila (with A, B, R, R in the meaning as described above) in a suitable solvent in the pre-

sence of a base. The leaving group E in formula iia can be a ha¬ logen radical like chlorine, bromine or iodine, an aromatic or aliphatic sulfonic acid residue (like p-toluenesulfonate, p-bromo- or p-nitrobenzenesulfonate, methanesulfonate or trifluo- romethanesulfonate) .

Suitable solvents are organic solvents such as aliphatic alcohols (like methanol, ethanol, n- and isopropanol) ; linear dialkyl- and dialkylglycolethers ^' (like diethylether, methy1-tert.butylether) , cyclic ethers (such as tetrahydrofuran, dioxane) ; aliphatic and and aromatic hydrocarbons or their halogenated derivatives (such as pentane, hexane, heptane, cyclohexane, dichloromethane, trich- loromethane, benzene, toluene, xylene, chlorbenzene) ; aliphatic ketones (acetone, methylethylketone, methylisobutylketone) ; dial- kylform- and dialkylacetamides (such as dimethylformamide, dime- thylacetamide) , dimethylsulfoxide, nitromethane, hexamethylphosp- horic triamide, cyclic ureas (such as 1,3-dimethyl-tetrahy- dro-2[lH]-pyrimidone) , water and mixtures of the above mentioned solvents. The reaction should be carried out in the presence of base as acid scavenger, e.g. alkalimetalcarbonates (preferably sodium or potassium carbonate) , -hydrogencarbonates, -hydroxides, hydrides, alcoholates; basic oxides like aluminum- or calcium- oxide; basic ion exchange resins, tertiary amines such as trial- kylamines, N-alkylmorpholines or piperidine. The addition of a crown ether (like 18-crown-6) or a phase transfer catalyst (like "Aliquat 336" or triethylbenzylammoniumchloride) may be useful to increase the yield of the reaction as well as addition of a catalytic amount of alkalimetall iodide (especially sodium or po¬ tassium iodide) . The reaction can be carried out at a temperature of -10°C or elevated temperatures up to the boiling point of the solvent or solvent system.

Compounds represented by the general formula II are preferably prepared by reaction of compounds Iia (with A, B, R, R with the meaning as described above and E preferably in the meaning of a halogen radical like chlorine, bromine, iodide) with an amine Z-H (with Z in the meaning as described above) at a temperature range from 0°C up to 80°C using equimolar amounts or an excess of potas¬ sium carbonate or N-methylmorpholin as base, in an alcohol, pre- ferably ethanol or isopropanol, or dimethylformamide as solvent.

Compounds represented by formula Iia (with A, B, R, R. E in the meaning as described above) are obtained by alkylation of phenol lb with 1,3-dihalopropanes (such as 1,3-dibromo-, 1,3-dichloro or l-bromo-3-chloropropane) or their corresponding tosylates or me- sylates (such as 3-halo-propyltosylate or -mesylate) in the pre¬ sence of a base using a suitable solvent. The reaction is carried

out according to the alkylation of Ha to ∑∑ applying similar reaction conditions (solvents, base, additives and temperatur range) .

Compounds represented by the general formula Iia are preferably prepared from compounds lb (with A, B, R, Rx in the meaning as described above) by alkylation with equimolar amounts or an ex¬ cess of 1,3-dibromopropane or 1,3-dichloropropane and 1.0-1.3 equivalents of sodium hydride or potassium tert.butylate in tetrahydrofuran or dimethylformamide, 1-2 equivalents of potas¬ sium carbonate in acetone, methylisobutylketone or dimethylforma¬ mide at a temperature range from 0°C or elevated temperatures up to 70°C.

b) Another method for the preparation of compounds represented by formula I (with A, B, Z, R, Rx in the meaning as described above) is the reductive alkylation of an aldehyde lib (with A, B, R, Rx in the meaning as described above) with an amine Z-H (with Z in the meaning as described above) in the presence of a reducing agent like hydrogen (or any hydrogen source such as ammonium-for¬ mate, hydrazine, diimine) and a hydrogenation catalyst (heteroge- nous or homogeneous) , sodium cyanoborohydride, sodium borohydride or formic acid. This type of reaction is well known, the reagents and reaction conditions applicable are described for example in J. March's "Advanced Organic Chemistry", 3rd edition, p.798-800, (John Wiley and Sons) and the literature cited therein.

Aldehydes represented by general formula b (with A, B, R, R ^χ in the meaning as described above) is obtained by alkylation of phe- nols Ik (with A, B, R, R in the meaning as described above) with a compound E-(CH ₂ ) ₂ -CHO in the presence of a base in a suitable solvent (with E in the meaning of a general leaving group as men¬ tioned above, preferably a halogen radical like chlorine and bro¬ mine) . The reaction can be carried out according to the synthesis of Ha.

c) A third method for the preparation of compounds represented by formula II (with A, B, Z, R, R in the meaning as described above) can be the reaction of a phenol lb (with A, B, R, R in the meaning as described above) with a compound represented by for¬ mula lie (with Z in the meaning as defined above) in a suitable solvent. In case that E means a general leaving group like a ha¬ logen radical (such as chlorine, bromine, iodine), an aromatic or aliphatic sulfonic acid residue (like p-toluenesulfonate, p-bromo- or p-nitrobenzenesulfonate, methanesulfonate or trifluo- romethanesulfonate) , the conversion represents a simple alkyla¬ tion of phenol lb which has been mentioned and described above.

If E means a hydroxy group, the reaction is carried out by using dehydrating agents (for example according to the so-called "Mitsunobu" reaction, using triphenylphosphine and a dialkylazo- dicarboxylate, preferably diethyldiazocarboxylate; a description of the reaction and the conditions applicable is given for example in Synthesis 1981, p.1-28 and the literature cited the¬ rein), at a temperature in the range of 0°C to room temperature. Compounds represented by formula lie (with Z, E in the meaning as mentioned above) are prepared by alkylation of an amine Z-H (with Z as above) with 1,3-dihalopropanes such as 1,3-dichloro-,

1,3-dibromo- or l-bromo-3-chloro-propane, which are commercially available, in the presence of a base using a suitable solvent. The reaction is run according to the synthesis of H from Iia ap¬ plying the same reaction conditions as described above.

Scheme III)

a) Compounds represented by the general formula in (with B, Z, R, Rx, Re as described for formula 1; X= OH) are prepared according to the methods already described above (scheme I) for the synthe¬ sis of compounds such as formula I using intermediates like Ilia or I iσ as precursor. Compounds of formula l σ are already known and are prepared as described in DE 30 06 351.

Compounds represented by the general formula Ilia (with B, R, Rx, R ⁸ in the meaning as described above) are already known and can be prepared by a Wittig or a Wittig-Horner reaction of heterocyclic phosphonates Hie (with Rs= aryl, O-alkyl) or heterocyclic phosp- honiumylides IIIc' (with R9= aryl) with the corresponding carbonyl compounds represented by formula Illb (with R, Rx, R" in the mea¬ ning as described above) . Both types of reaction are generally known and are carried out according to standard methods, for example the Wittig-Horner reactions using a phosphonate like IIIc according to Houben-Weyl's " ethoden der Organischen Che ie", Vol. 5/lb, p.395-401, the Wittig reaction using a phosphoniumylide such as IIIc' according to Houben-Weyl's "Methoden der Organischen Chemie", Vol. 5/lb, p. 383-394. Examples for the preparation of compounds represented by formula III with R ^β = H are given in DE 30 06 351, compounds with R ^β = alkyl can be prepared according to these methods.

The compounds represented by formula Ilia are usually obtained as mixtures of the corresponding Z- and E-isomers referred to the C=C double bond, the E/Z-ratio usually depends on the method applied (Wittig or Wittig-Horner reaction) . The isomers can be separated by column chromatography on silica gel or crystalliza¬ tion in appropriate solvents. Generally Z-isomers, or E/Z-mixtu-

res, can be isomerized photochemically or by treatment with catalytic amounts of iodine in a suitable solvent to afford the pure E-isomers. The reaction is run at a temperature in the range from 0°C or at elevated temperature up to the boiling point of the 5 solvent applied. Suitable solvents are inert organic solvents such as aliphatic and cyclic ethers (diethylether, diisopropyl- ether, methy1-tert. utylether, tetrahydrofuran, dioxane) ; aliphatic and aromatic hydrocarbons or their halogenated deriva- . tives (like pentane, hexane, heptane, cyclohexane, dichlorome- 10 thane, trichloromethane, benzene, toluene, xylene, chlorbenzene) .

E/Z-mixtures were pereferably converted into pure E-isomers by treating them with catalytic amounts of iodine, preferably using an aliphatic ether like diethylether, methyl-tert.butylether or 15 an aliphatic hydrocarbon like hexane or heptane at a temperature ranging from room temperature to the boiling point of the solvent applied.

Heterocyclic phosphonates such as compound IIIc (Rs= aryl/ O-al- 20 kyl) are generally known in the literature and can be prepared by- standard methods converting the corresponding halogenmethylhete- rocycles according to Arbusov- or Michaelis-Becker conditions, as for example described in Houben-Weyl's "Methoden der Organischen Chemie", Vol. 12, p.433-453 (special examples are given in EP 25 34754, DE 30 06 35) . Heterocyclic phosphoniumylides such as com¬ pound IIIc'are generally known in the literature and can be prepa¬ red according to Houben-Weyl's "Methoden der Organischen Chemie", Vol. 12, p.79-90. The halogenmethylheterocycles applied are gene¬ rally known and either commercialy available or can be prepared 30 according to standard methods described in the literature (exam¬ ples are given e.g. in DE 27 54 832).

Compounds represented by formula Illb (with R, R ^χ , R« in the mea¬ ning as described above) are usually obtained by alkylation of

35 the corresponding phenols according to the methods described for the preperation of glycidethers such as formula la- Especially the various (2,3-epoxypropoxy)-substituted benzaldehydes and ace- tophenones are known from the literature (e.g. Angew. Makro- ol.Chemie, 1968, p.168-169; DE 32 10 061) and can be prepared

40 according to the methods described therein.

Compounds represented by the general formula IHb are preferably obtained by reaction of the corresponding phenols with equimolar amounts or excess of of epibromo- or epichlorohydrine with 45 1.0-1.3 equivalents of sodium hydride or potassium tert.butano- late in tetrahydrofuran or dimethylformamide, 1-2 equivalents of

potassium carbonate in acetone, methylisobutylketone or dimethyl¬ formamide at a temperature ranging from 0°C to 70°C.

b) Another method for the synthesis of compounds represented by formula III is by Wittig or Wittig-Horner reaction of a carbonyl compound IHf (with X, Z, R, R ^χ , R ⁸ in the meaning as described above) with a heterocyclic phosphonate or phosphoniumylide like ∑∑∑S. or Hid according to standard methods as described above. Compounds represented by formula IHf are known in the literature and can be prepared for example as described DE 22 37 228 or DE 23 27 270.

c) Another method for the preparation of compounds represented by formula Ilia (with B, R, R ^χ in the meaning as described above) , wherein R ⁸ is hydrogen, is the reaction of a formylheterocycle B- CHO (with B in the meaning as described above) with phosphonate Hid (with R in the meaning as described above; R ⁹ = O-alkyl) ac¬ cording to Wittig-Horner conditions described above. Foππylhete- rocycles such as B-CHO are either commercially available or can be synthesized by using standard methods generally known.

Compounds Ilia (with B, R, Rx in the meaning as described above) , wherein R ⁸ is hydrogen, are preferably prepared by reaction of a compound B-CHO (with B in the meaning as described above) and a phosphonate Hid (with R, Rx in the meaning as described above; R ⁹ = O-alkyl) in the presence of a 1-1.3 equivalents of a base such as sodium hydride or potassium tert.butylate at a temperature ranging from 0°C to elevated temperatures such as 50°C, using po¬ lar aprotic solvents like dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, dimethylpropyleneurea or mixtures of the above mentioned solvents.

Compounds represented by general formula Hid (with R, R ^χ in the meaning as described above; R ⁹ = O-alkyl) are prepared by alkyla- tion of the corresponding phenol Hie (with R ⁹ in the meaning as described above) applying the same methods as described above for several other glycidethers like la and Hb.

Compounds represented by formula His are obtained by Arbusov- reaction of the corresponding hydroxybenzylalcohols with a tri- alkylphosphite such as triethylphosphite at elevated temperatures in an inert organic solvent according to the literature mentioned above.

Compounds like Hie are preferably prepared by reaction of a hy- droxybenzylalcohol with excess of trialkylphosphite, such as triethylphosphite, at elevated temperatures ranging from 100° to

140°C in a polar aprotic solvent like dimethylformamide, dimethyl- sulfoxide, or l,3-dimethyl-tetrahydro-2 [IH]-pyrimidone.

d) Another method for the preparation of compounds Hi (with B, X, Z, R, Rx in the meaning as described above, R ⁸ = H) is a

Wittig-Horner reaction of a compound such as Hlh (with X, Z, R, R and R ⁹ in the meaning as described above) with an aldehyde B- CHO (B in the meaning as mentioned above) according to the methods already mentioned above.

Compounds such as Hlh (with X, Z, R, Rx and R ⁹ in the meaning as described above) are prepared by reaction of a glycidether such as ∑∑∑s (with R, Rx and R ⁹ in the meaning as described above) with an amine Z-H (with Z in the meaning as definded above) according to the methods already described above.

Scheme IV

a) Compounds represented by formula IV (with B, Z, R, Rx, R ⁸ in the meaning as described above; X = H) are prepared by standard methods already described for the synthesis of compounds II (scheme II) . Compounds represented by the general formula His (with B, R, Rx, R ⁸ in the meaning as defined above) are already known and described for example in DE 30 06 351.

Scheme V

a) Compounds represented by general formula Y (with B, X, Z, R, Rx, y, z as described above) are prepared according to the methods already described for compounds I and II (scheme I and scheme II) using precursors Xa and Vb.

Compounds Vb (with B, R, R*, R ¹⁰ , y, z in the meaning as described above) are obtained by alkylation of the corresponding alcohols with halogenmethylheterocycles in the presence of a base in a suitable organic solvent according to standard procedures gene¬ rally known.

Compounds Vb (wherein R ¹⁰ means hydrogen, y=0 and z=l) are known and can be synthesized by direct alkylation of the corresponding catechols without the need for any additional protecting group, as described for example in DE 20 45 050 and DE 21 29 803.

Compounds like 3_b (with B, R, R ^χ , y, z as described above) are prepared by alkylation of benzylalcohols like VS/ wherein Rio means a protecting group suitable for phenols or catechols like an ether (such as methyl-, methoxymethyl-, tetrahydropyranyl-,

allyl-, isopropyl-, trimethylsilyl-, tert.butyldi ethyl-ether) or an ester (such as acetyl-, benzoyl-ester) . Application and clea¬ vage of such protecting groups as well as the preparation of pro¬ tected phenols is generally known in the literature, see for example in T.W. Greene, P.G. Wuts, "Protective Groups in Organic Synthesis", p. 143-174, 2nd Edition (J. Wiley and Sons,1991).

Scheme VI)

a) Compounds represented by the general formula YI (with B, Z, R, R as defined for formula I; X = OH; a = 0-4) are prepared ac¬ cording to the methods already described above (scheme I) using glycidethers Via or phenols Vlb (with a, B, R, Rx as defined above) as precursors.

b) Compounds represented by the general formula ¥∑ (with B, Z, R, R as defined for formula I ; X = OH; a = 2) are obtained by hydrogenation of unsaturated compounds such as HI (with B, Z, X, R, Rx as defined before, cf. scheme III, and R ⁸ = H) or VII (with B, Z, X, R, R as defined, cf. scheme VII) in a suitable solvent and in the presence of a homogeneous or heterogeneous ca¬ talyst at atmospheric pressure or elevated pressure in an auto¬ clave. The source of hydrogen can be hydrogen itself, hydrides such as boron hydrides, aluminum hydrides, tin hydrides or tri- alkyl- or triphenylsilanes or diimine, preferably hydrogen gas. Suitable solvents for the hydrogenation with hydrogen gas are po¬ lar solvents such as aliphatic alcohols (such as methanol, ethanol, isopropanol) , linear, branched or cyclic ethers (e.g. diethylether, methyl tert. butyl ether, tetrahydrofuran, dio- xane) , aliphatic or aromatic hydrocarbons and their halogenated derivatives (e.g. heptane, benzene, toluene, dichloromethane) , aliphatic ketones (e.g. acetone, methylethylketone), dialkylfor- mamides and dialkylacetamides (e.g. dimethylformamide) , dimethyl- sulfoxide, linear and cyclic amines (e.g. triethylamine, morpho- line) , acetonitrile, water and mixtures of the here mentioned solvents. The reaction can be catalyzed by homogeneous catalysts such as Wilkinson catalyst, rhodium or iridium salts or by hete¬ rogeneous catalysts such as rhodium on aluminum oxide or on char¬ coal, platinoxide or palladium on charcoal. The reaction can be carried out at temperatures between room temperature and 300°C, preferably between room temperature and 100°C. High pressure can be applied in the range of 1 - 1000 bar, preferably between 1 - 10 bar. Methods for hydrogenation of such compounds are described in P.N. Rylander, "Hydrogenation Methods", Academic Press, New York (1985) .

c) Compounds represented by the general formula V a (with a = 0

- 4, B, Z, R, R in the meaning as described above) are prepared from the corresponding phenols Vlb (with a = 0 - 4, B, Z, R, Rx as defined above) according to the methods already described for compounds la (scheme I) or Hlb (scheme III).

d) Compounds represented by the general formula V b (with a = 0

- 4, B, Z, R, Rx in the meaning as described above) are obtained . by cleavage of the hydroxy-protecting group Rio (with Rio in the meaning as described, cf. scheme V) from the compounds VTc (with a = 0 - 4, B, Z, R, Rx, Rio in the meaning as described above) by the methods already described for the synthesis of compounds Yb (cf. scheme V) .

e) Compounds represented by the general formula V c (with a = 0

- 4, B, Z, R, Rx, Rio in the meaning as described above; a = 0 - 4) are prepared by cycloaddition reactions of unsaturated compounds Yld ( with a = 0 - 4, J = carbon-carbon double or triple bond, carbon-nitrogen double or triple bond) , thus generating the heterocycles B such as isoxazoles or oxadiazoles. Suitable sol¬ vents for the cycloaddition are organic solvents such as aliphatic alcohols (e.g. methanol, ethanol, isopropanol), linear, branched or cyclic ethers (e.g. diethylether, methyl tert. butyl ether, tetrahydrofuran, dioxane) , aliphatic or aromatic hydrocar- bons or their halogenated derivatives (e.g. heptane, benzene, to¬ luene, dichloromethane) , aliphatic ketones (such as acetone, me¬ thylethylketone) , alkyl ester (e.g. ethyl acetate) , dialkylforma- mides and dialkylacetamides (e.g. dimethylformamide) , dimethyl- sulfoxide, acetonitrile, water and mixtures of the above mentio- ned solvents. Isoxazoles are usually prepared by the reaction of in situ generated nitriloxides and substituted alkynes in the above mentioned solvents at temperatures ranging from -50°C to 150°C preferably between -20°C and 40°C. The nitriloxides are ge¬ nerated by deny rohalogenation of the corresponding α-halo-oximes with bases such as amines (like triethylamine) or alkali carbona¬ tes and hydrogen carbonates (sodium carbonate, potassium hydrogen carbonate) or by treatment of nitro-methyl-derivatives with iso¬ cyanates (Mukaiyama reaction) , as described in Houben-Weyl, "Me¬ thoden der organischen Chemie", Vol.E5, p. 1591, Thieme Verlag, Stuttgart. Furthermore one-pot-conversion of oximes to isoxazoles are achieved by using a system of halogenation agent and suitable base such as N-chlorosuccinimide/sodium or potassium hydrogen- carbonate or sodium hypochlorite/sodium hydroxide in the presence of the unsaturated compound ϊld in an inert solvent such as dich- loromethane, ethyl acetate or water. Generation of nitriloxides and their conversion to isoxazoles are described in K.B.G. Tor-

sell, "Nitrile Oxides, Nitrones and Nitronates in Organic Synthe¬ sis", Verlag Chemie, 1988.

The compounds Yld are commercially available or can be prepared according to literature procedures as described e.g. in F.-T. Luo et al., J. Org. Chem. 1992, 57, 2213.

f) Another approach to compounds represented by the general formula Vic (with a = 0 - 4, B, Z, R, Rx, R" in the meaning as described above) is the catalyzed or uncatalyzed cross-coupling reaction between an organometallic compound Vie or Vlo (with Met = boron, lithium, magnesium, sodium, potassium, zinc, tin, cop¬ per) and an electrophilic compound such as organic halide, tosy- late, mesylate or triflate in an inert solvent. Suitable solvents are polar aprotic solvents such as linear, branched or cyclic ethers (e.g. diethylether, methyl tert. butyl ether, tetrahydro¬ furan, dioxane, dimethoxyethane) , aliphatic or aromatic hydrocar¬ bons and their halogenated derivatives (e.g. heptane, benzene, toluene, chloroform) , dimethylsulfoxide, amides (e.g. di ethyl- formamide, N-methylpyrrolidone, hexamethyl-phosphoric triamide) , cyclic ureas (e.g. l,3-dimethyl-tetrahydro-2 [lH]-pyrimidinon) , acetonitrile or mixtures thereof. For less reactive organo¬ metallic compounds catalysis of the reaction is required using catalysts such as palladium (e.g. palladium acetate or tetrakis- triphenylphosphinepalladium) , copper (e.g. dilithiumtetrachloro- cuprate) or nickel reagents (e.g. bis (cyclooctadienyl)nickel) . The reaction is usually carried out in the case of reactive organometallic compounds at low temperatures between -100°C and 50°C, preferably between -78°C and room temperature, in the case of less reactive compounds between 0°C and 200°C, preferably between room temperature and 150°C or at the boiling point of the solvent. General methods for such, often transition metal-cataly¬ zed (Ni, Pd, Cu) reactions are described in "Comprehensive Organic Chemistry", Vol. 3, Chapter 2; Ed. B.M. Trost, (1991).

Thus, metallated phenyl-derivatives Vie (with aa = 0; R, R ^χ , Ri°, Met in the meaning as described above ) or benzyl-derivatives 3Qs (with aa = 1; R, Rx, Ri°, Met in the meaning as described above ) react with heterocyclic derivatives VIf (with ab = 0 or 1; E, B in the meaning as described above and E in the meaning of a gene¬ ral leaving group as defined before) to Vic in an above mentioned solvent. Correspondingly, metallated heterocycles V q (with ad = 0; B and Met in the meaning as described above ) or methylhetero- cycles Ylff (with ad = 1; B, Met in the meaning as described above) react with phenylalkyl-derivatives Ylb (with ac = 0 or 1; R, Rx, R in the meaning as described above, E in the meaning of a general leaving group as described before) to ic under the

conditions described above. The metallation of methylheterocycles has been reported for isoxazoles and other cycles with N, S and 0 as heteratom by R.G. Micetich et al., Heterocycles, 1985, 23, 585 (isoxazoles) or B.C.Lipshutz and R.W.Hungate, J. Org. Chem. 1981, 46, 1410 (oxazoles) . Furthermore the metallated compounds are conveniently synthesized from the corresponding halides by methods as described in Houben-Weyl "Methoden der organischen Chemie", saturated E 13/1-8, Thieme Verlag, Stuttgart. A conve¬ nient approach to 5-tributylstannylisoxazoles Via (B as isoxa- zole, ad = 0; Met as tributylstannyl) is the [2+3]-dipolar cyclo¬ addition of nitriloxides to tributylstannylacetylen as described e.g. by Y. Kondo et al., Tetrahedron Lett.1989, 30, 4249 or K. Gothelf et al., Acta Chemica Scand. 1992, 46, 494. Other 5-metal- lated isoxazoles can be obtained from the stannyl compounds by transmetallation reactions as described e.g. by Seyferth, D. et al. J. Org. Chem. 1959, 1395 or J. Am. Chem .Soc. 1962, 84, 361.

g) The compounds represented by formula YI (with a, B, Z, R, Rx as defined above; X = OH) are converted into their corresponding esters Yli (with a, B, Z, R, Rx, R in the meaning as described above) using the same methods as described in scheme I for the transformation of I to Id.

Scheme VII)

a) Compounds represented by the general formula VH (with B, Z, R, R as defined for formula I; X = OH) are prepared according to the methods already described above (scheme I) using compounds Vila or VHb as precursors.

b) Compounds represented by the general formula Vila (with B, R, Rx in the meaning as described above) are prepared from the corresponding phenols VHb (with B, R, Rx in the meaning as des¬ cribed above) by the same methods already described for the syn- thesis of compounds l (scheme I) .

c) Compounds represented by the general formula YHb (with B, R, R in the meaning as described above) are obtained by cleavage of the hydroxy-protecting group R° (Ri° in the meaning as descri- bed above, cf. scheme V) from the compounds Vic (with B, R, Rx, Rio in the meaning as described above) by the same methods already described for the synthesis of compounds Yb (scheme V) .

d) Compounds represented by the general formula YHs (with B, R, Rx, Rio in the meaning as described above) are prepared by cata¬ lyzed or uncatalyzed cross-coupling reactions of alkinyl-deriva- tives with organic electrophiles such as halides, triflates, to-

sylates or mesylates in the presence of a base in a suitable sol¬ vent. Suitable solvents for the cross-coupling reaction are organic solvents such as aliphatic alcohols (such as methanol, ethanol, isopropanol), linear, branched or cyclic ethers (e.g. diethylether, methyl-tert.butylether, tetrahydrofuran, dioxane) , aliphatic or aromatic hydrocarbons or their halogenated derivati¬ ves (e.g. heptane, benzene, toluene, dichloromethane) , aliphatic ketones (e.g. acetone, methylethylketone), amines (e.g. triethy¬ lamine, diethylamine ^' , dicyclohexylamine) alkyl ester (e.g. ethyl acetate) , heteroaromates (e.g. pyridine) , dialkylform- and dial- kylacetamides (e.g. dimethylformamide), dimethylsulfoxide or ace- tonitrile and mixtures thereof. The liquid amines such as trie¬ thylamine, diethylamine, morpholine or pyridine can serve as sol¬ vent and base at the same time. Other bases used for neutraliza- tion of acid, generated during the reaction are alkali carbonates or hydrogencarbonates, phosphates or metal alcoholates. The reaction may be run at temperatures between -20°C and 200°C, pre¬ ferably at temperatures between room temperature and 150°C or at the boiling point of the solvent. The reaction is catalyzed by transition metal catalysts such as palladium acetate or bis(tri- phenylphosphine)palladium dichloride. Furthermore, if necessary, salts as copper halides or nickel halides are added. Instead of the alkynyl-derivatives also the metallated alkynes can be used (with Met = Li, Mg, Zn, Cu) .

The compounds VHe (with R, Rx, R° as described above) are either commercially available or can be prepared acording to published procedures.

Thus, phenyl-ethinyl-derivatives VHe (with R, R ^χ _# R° as defined above) react with compounds VIf (with ab = 0; B as defined be¬ fore, E as a general leaving group as defined before ) in a cross-coupling reaction under the conditions described above. The starting phenyl-ethinyl-derivatives YII__ (with R, Rx, Ro as des- cribed above) are obtained by a similiar catalyzed or uncatalyzed cross-coupling reaction of phenyl-derivatives VHd (with R, R ^χ , R ¹⁰ in the meaning as described before, E as a general leaving group as described before) with trimethylsilylacetylene and subsequent desilylation with potassium fluoride or carbonate or with silver nitrate/cyanide. This reaction is carried out as described above. Methods for the cleavage of the silyl group from the triple bond are described in e.g. M. Jung et al., J. Org. Chem. 1987, 52, 1888.

e) Another approach to compounds represented by the general formula VHe (with B, R, R ^χ , R° in the meaning as described above) is the formal dehydration of ketones YHIS. (with w = 0, x = 1 or

w = 1, x = 0 and B, R, Rio in the meaning as described above) , which are prepared according to scheme VIII. Several two-step procedures are known (R.C. Larock, "Comprehensive Organic Reactions", Verlag Chemie (1989), chapter alkynes, p.289 and re- 5 ferences) for the conversion of ketones to alkynes, for example via the corresponding enol phosphate. Mukaiyama et al. report an one-step-procedure for the conversion of aryl-methylen-ketones to phenyl-alkynes (Chem. Lett. 1979, 481) using 2-chloro-3-ethylben- zoxazolium salts and a base in an inert solvent such as dichloro-

10 methane. Thus, alkynes Vile are obtained from the ketones VIIIc by treatment with 2-halo-3-alkyl benzoxazolium salts and two or more equivalents of base such as triethylamine. The reaction is carried out in an inert solvent such as linear, branched or cy¬ clic ethers (such as diethylether, methyl tert. butyl ether,

15 tetrahydrofuran, dioxane) , aliphatic or aromatic hydrocarbons or their halogenated derivatives (such as heptane, benzene, toluene, dichloromethane or chloroform) at temperatures between -30°C and 100°C, preferably in a range from room temperature to 80°C or at the boiling point of the solvent. 0 f) A reliable method for the preparation of compounds represen¬ ted by the general formula VTIc (with B, R, Rx, Ri in the meaning as described above) is the double elimination of HL (L = I, Br, Cl) from the dihalocompounds YHl (with L = I, Br, Cl and B, R,

25 Rx, Ri in the meaning as described above) . The dehydrohalogenation can be carried out with basic reagents such as alkali amides (e.g. sodium or potassium amide) , alkali hydroxides (e.g. potas¬ sium or sodium hydroxide) , or alkali fluorides such as potassium fluoride on aluminum(III)oxide. Addition of crown-ethers such as

30 18-crown-6 may improve the yield of the reaction. Furthermore, the reaction can be carried out in a two-phase-system of water and an organic solvent as aromatic or nonaromatic hydrocarbons or their halogenated derivatives (e.g. heptane, benzene, toluene, dichloromethane or chloroform) or ethers (e.g. diethylether) un-

35 der phase transfer catalysis. Suitable catalysts are e.g. tetra- alkylammonium halides such as tetrabutylammonium chloride or benzyl trimethylammonium chloride. A survey of methods can be found in R.C. Larock, "Comprehensive Organic Reactions", Verlag Chemie (1989), chapter alkynes, p.289.

40

The dihalocompounds VHf are easily obtained by addition of halo¬ gen to the alkenes HI (with B, R, R" in the meaning as described above), which are prepared according to scheme III. Methods for halogenation of alkenes are found in H.O. House, "Modern Synthe-

45 tic Methods", 2nd ed, W.A. Benjamin (1972), p. 422.

g) The compounds represented by formula VTI (with B, Z, R, R ^χ as defined above; X = OH) are converted into their corresponding esters VIIh (with B, Z, R, Rx, Ri as defined above) using the same methods as described in scheme I for the transformation of I to Ifl.

Scheme VIII)

a) Compounds represented by the general formula VIII (with w, x = 0 - 2 and provided that w + x is not exceeding 3 and B, Z, R, R as defined for formula I ; X = OH) are prepared from compounds Villa or VIIlb according to the methods already described above (scheme I) .

b) Compounds represented by the general formula Villa (with w, x, B, R, R in the meaning as described above) are prepared from the corresponding phenols Vlllb (with w, x, B, R, R in the mea¬ ning as described above) by the same methods already described for the synthesis of compounds a (scheme I).

c) Compounds represented by the general formula YHIb (with w, x, B, R, Rx in the meaning as described above) are obtained by cleavage of the hydroxy-protecting group R" (R° in the meaning as described in scheme V) from the compounds YHIG (with w, x, B, R, Rx, Rio in the meaning as described above) using the same methods already described for the synthesis of compounds Yb (scheme V) .

d) Compounds represented by the general formula YHIfi (with w, x, B, R, Rx, Rio in the meaning as described above) are prepared by catalyzed or uncatalyzed coupling reactions of carboxyl deriva¬ tives VIIId or VHIf with organometallic compounds VIHe or VHIq (with metals such as boron, lithium, magnesium, aluminum, sodium, potassium, zinc, tin, copper) in an inert solvent. Suitable sol¬ vents are polar aprotic solvents such as linear, branched or cy- clic ethers (such as diethylether, methyl tert. butyl ether, tetrahydrofuran, dioxane, dimethoxyethane) , aliphatic or aromatic hydrocarbons or their halogenated derivatives (such as heptane, benzene, toluene, chloroform) , dimethylsulfoxide, amides (such as dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide), cyclic ureas (such as 1,3-dimethyl-tetrahy- dro-2 (lH)-pyrimidinon) or acetonitrile. For less reactive organo¬ metallic compounds catalysis of the reaction is required using catalysts such as palladium (e.g. palladium acetate or tetrakis- triphenylphosphinepalladiu ) , copper (such as dilithiumtetrachlo- rocuprate) or nickel reagents (such as bis(cycloocta- dienyl)nickel) . The reaction is usually carried out for reactive organometallic compounds at low temperatures between -100°C and

50°C, preferably between -78°C and room temperature, for less reactive compounds between 0°C and 200°C, preferably between room temperature and 150°C or at the boiling point of the solvent.

5 Thus, carboxyl derivatives VIlid (with x, B in the meaning as described above) react with organometallic compounds VHle (with w, Met, R, Rx, Rio as defined above) with or without catalysts in a solvent mentioned above to give the ketones YHIs (with w, x, B, R, Rx, Rio in the meaning as described above) . M is a general lea- 0 ving group, preferably alkoxy (e.g. methoxy or ethoxy) , halogen (e.g. chlorine, bromide or iodide) , tosylate, mesylate or tri- flate.

Furthermore, the reaction of compounds such as Yiiif (with w, M, 15 R, Rx, Ro in the meaning as described above) and VHIσ (with x = 0 - 2 and B, Met in the meaning as described above) provides the ketones VIHe (with w, x, B, R, Rx, R ¹⁰ in the meaning as described above) .

20 dl) Stille et al. reported the palladium-catalyzed cross- coupling reaction of acylchlorides with organotin compounds (J. Org. Chem. 1983,48, 4634). Thus, the above described reactions for VIIIe or VIIIσ (with Met = trialky1starmy1 and B, R, Rx, Ri° in the meaning as described above) with acid chlorides YHI-i (with M

25 = Cl and x, B in the meaning as described above) or vπif (with M = Cl and w, R, Rx, Ri in the meaning as described above) were car- ried out under palladium-catalysis in solvents such as tetra¬ hydrofuran, chloroform or N-methylpyrrolidone at temperatures in a range from 0°C to 200°C, preferably from room temperature to 30 150°C or at the boiling point of the solvent. Commercially availa¬ ble palladium catalysts such as tetrakistriphenylphosphinepalla- dium or benzyl-bis (triphenylphosphine)palladium(II)chloride can be used as catalysts for these reactions.

35 The acid chlorides VHle or VHlf (with M = Cl and B, R, Rx, R" in the meaning as described above) are prepared from the correspon¬ ding acids by reaction with chlorinating agents, e.g thionyl chloride or phosphorous trichloride as such or in inert solvents such as diethyl ether. Methods for the synthesis of acid chlori-

40 des are found in Houben-Weyl, "Methoden der organischen Chemie", Vol.E5, p. 587, Thieme Verlag, 1985. The acids are either commer¬ cially available or prepared according to published procedures.

The organometallic compounds vine or YIHff are prepared using 45 the same methods already for the synthesis of the corresponding compounds Vie or V£σ (cf. scheme VI) .

d2) The reaction of protected hydroxy benzoates with lithiated methylheterocycles has been described by N.A. Meanwell et al. (J. Med. Chem. 1992, 35, 3483). Thus, hydroxy protected benzoates YHIf (with M = alkoxy and w, R, R ^χ , R" in the meaning as descri- bed above) were converted into the corresponding ketones V Hc (with w, x, B, R, Rx, Rio in the meaning as described above) by reaction with compounds Vlllσ (with Met = Li and x, B in the mea¬ ning as described above) . The organolithium compounds YHI2 are prepared using the same methods as for the synthesis of the cor- responding compounds Via (cf. scheme VI). Low temperatures between -100°C and 0°C were used for the coupling reaction to avoid side reactions, preferably -78°C to -20°C. Suitable sol¬ vents are polar aprotic solvents as tetrahydrofuran, diethyl ether, dimethoxyethane, hexamethylphosphoric triamide, 1,3-dime- thyl-tetrahydro-2 [lH]-pyrimidone or mixtures thereof.

e) The compounds represented by formula VTII (with w, x, B, Z, R, R ^x as defined before; X = OH) are converted into their corres¬ ponding esters VTIlh (with w, x, B, Z, R, Rx, Ri as defined be- fore) using the same methods already described in scheme I for the transformation of I to Id.

Scheme IX)

a) Compounds represented by the general formula IX (with B, Z, R, R as defined for formula I ; X = OH; A in the meaning of the following amide linkage: (CH ₂ ) _u -CO-NR ⁸ -(CH ₂ ) _V or (CH ₂ ) _u -NR ⁸ -CO-(CH ₂ ) _v with u, v = 0 - 2, independently from each other, but u + v not exceeding three, and R ⁸ as defined before) are prepared according to the methods already described above (scheme I) using glycide¬ thers IXa or phenols ixb as precursors.

b) Compounds represented by the general formula IXa (with B, R, Rx in the meaning as described above and A as amide linkage as de- fined above) are prepared from the corresponding phenols ixb (with B, R, Rx in the meaning as described before and A as amide linkage as defined above) by the same methods already described for the synthesis of compounds la (scheme I) .

c) Compounds represented by the general formula IXb (with B, R, Rx in the meaning as described before and A as amide linkage as defined above) are obtained by cleavage of the hydroxy-protecting group Rio (in the meaning as described above, cf. scheme V) from the compounds iXc (with B, R, Rx, R in the meaning as described above and A as amide linkage as defined above) by the same methods already described for the synthesis of Yb (scheme V) .

dl) Compounds represented by the general formula !_____. (with B, R, Rx, Ro in the meaning as described above and A as amide linkage as defined above) are prepared by the reaction of amines ixd (with u, R, Rx, Ro, R ⁸ in the meaning as described above) with the compounds IXfi (with v and B in the meaning as described above and Q in the meaning of a general leaving group such as hydroxy, alkoxy, halogen (e.g. Cl, Br, I), tosylate, mesylate or tri- flate) , if necessary in presence of a base or a carboxyl group activating agent. Suitable bases are tertiary amines (e.g. trie- thylamine) , heteroaromates such as pyridine or inorganic bases such as potassium carbonate, sodium hydroxide. Carboxyl group ac¬ tivating agents for the coupling of acids with amines are for example carbodiimide such as cyclohexylcarbodiimide or phosphorus reagents such as N,N'-bis(2-oxo-3-oxazolidinyl)-phosphorylchlo- ride. The reactions are carried out in an inert solvent at tem¬ peratures between -50°C and 160 ^Oc . Suitable solvents for the amide fomation are organic solvents such as linear, branched or cyclic ethers (e.g. diethylether, methyl tert. butyl ether, tetrahydro¬ furan, dioxane) , aliphatic or aromatic hydrocarbons or their halogenated derivatives (e.g. heptane, benzene, toluene, dichlo¬ romethane) ,- aliphatic ketones (e.g. acetone, methylethylketone), tertiary amines (e.g. triethylamine), alkyl ester (e.g. ethyl acetate) , heteroaromates (e.g. pyridine) , dialkylform- and dial- kylacetamides (e.g. dimethylformamide) , dimethylsulfoxide, aceto- nitrile, alcohols, water and mixtures thereof.

A direct route to compounds IXb (with B, R, Rx in the meaning as described before and A as amide linkage as defined above) is the reaction of the non-protected phenol-derivatives IXd (with u, R, Rx, R ⁸ in the meaning as described above and Ri°= H with the compounds iXe (with v and B in the meaning as described above and Q in the meaning of a general leaving group such as hydroxy, alkoxy, halogen (e.g. Cl, Br, I) , tosylate, mesylate or tri- flate) , using the same methods for the formation of the amide bond as described before.

The synthesis of amides is described in Houben-Weyl, "Methoden der organischen Chemie",Vol. E5, Thieme Verlag, 1985.

d2) Compounds represented by the general formula IXe (with B, R, ,R ^χ , Rio in the meaning as described above and A as amide lin¬ kage as defined above) are prepared by the reaction of amines IXg (with v, B, R ⁸ in the meaning as described above) with the compounds IXf (with u, R, R ^χ , Ri° in the meaning as described above and Q in the meaning of a general leaving group such as hydroxy, alkoxy, halogen (e.g. Cl, Br, I), tosylate, mesylate or

triflate) , if necessary in presence of a base or a carboxyl group activating agent, using the same methods as described before.

e) The compounds represented by formula IX (with B, Z, R, Rx as defined above and A as amide linkage as defined above; X = OH) are converted into their corresponding esters IXh (with B, Z, R, R and R ¹ in the meaning as described before and A as amide lin¬ kage as defined above) by the same methods as described in scheme I for the transformation of I to Id.

Generally the compounds of the present invention can be prepared according to standard procedures of organic chemistry. he applied methods should be familiar and available to those who are skilled in the art.

66

Scheme II

lb lib

t \

Scheme VII

Scheme VIII

Scheme IX

R ^x

The present invention is further illustrated by the following examples:

5 III-l fE -l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- piperazin-1-yl]-3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)- ethenyl]-phenoxy}-propan-2-ol

lg of (E) -5- {2- [2- (2,3-epoxypropoxy)-phenyl]-ethenyl}-3- (methoxy- 10 methyl)-isoxazole (precursor IIIa-1) and 0.97g of (10,11-di- hydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperazine were refluxed in 10ml ethanol. After completion of the reaction the mixture was stirred at room temperature until a white solid precipitated. Re- cristallisation of the precipitate from ethanol afforded 1.36g of 15 the title compound as a white solid.

Mp. :118-121°C

¹³ C-NMR [CDC1 ₃ ; δ (ppm) ] : 31.8, 51.8, 58.8, 60.7, 65.4, 71.0, 79.0, 100.2, 112.6, 113.9, 121.3, 124.8, 125.5, 127.7, 127.8, 130.3, 20 130.8, 139.2, 139.7, 156.9, 161.7, 169.9

III-2 (E)-l- [4-(Bi.s (4-methoxphenyl) }-methyl]-piperazin-l-yl]- 3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]- phenoxy}-propan-2-ol 25

The reaction was carried out according to the synthesis of III-l using bis(4-methoxyphenyl)-methy1-piperazine and precursor

IIIa-1.

30 Mp.: 123-126°C

^! H-NMR [DMSO, δ (ppm)]: 2.10-2.80 (m, 10H) , 3.28 (s, 3H) , 3.65 (s, 6H), 3.92-4.20 (m, 4H) , 4.45 (s, 2H) , 4.80-5.10 (s, IH) , 6.63 (s, IH), 6.85 (m, 4H) , 6.95-7.15 (m, 2H) , 7.20-7.40 (m, 6H) , 7.55-7.70 ( , 2H) 35

III-3 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{4-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]- phenox }-propan-2-ol

40 The reaction was carried out as described for III-l using 4-(di¬ phenyl-methyl)-piperazine and (_?J-5-{2-[4-(2,3-epoxypropoxy)- phenyl]-ethenyl)-3-(methoxymethyl)-isoxazole (precursor IIIa-3) .

45

Mp.: 139-141°C ι ³ C-NMR [CDC1 ₃ ; δ (ppm)]: 52.0, 53.7, 58.5, 60.4, 65.5, 65.9, 70.5, 76.2, 99.9, 111.1, 115.0, 127.0, 128.0, 128.5, 128.6, 134.6, 142.7, 159.7, 161.7, 169.2 5

II 1-4 (\Ej-l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- piperazin-1-yl] -3-{4- [2- (3-methoxymethyl-isoxazol-5-yl) - ethenyl ] -phenoxy } -propan-2-ol

10 The reaction was run according to example III-l using 10,11-di- hydro-5H-dibenzo[a,d]cyclohepten-5-yl-piperazine and precursor IIIa-3.

Mp.: 146-147°C 15 ¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 31.8, 52.0, 53.8, 58.5, 60.4, 65.5,

65.9, 70.5, 79.1, 99.9, 111.1, 115.0, 126.5, 127.8, 128.6, 130.8, 134.6, 139.2, 139.7, 159.8, 161.7, 169.2

III-5 fs;-l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- 20 piperazin-1-yl]-3-{2-[2-(3-methyl-isoxazol-5-yl)- ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- 25 hepten-5-yl-piperazine and (_.)-5-{2-[2-(2,3-epoxypro- poxy)-phenyl]-ethenyl}-3-(methyl)-isoxazole.

Mp.: 167-168°C

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 11.4, 31.8, 51.9, 53.7, 60.7, 65.5, 30 79.1, 101.8, 112.6, 114.1, 121.2, 125.1, 125.5, 127.8, 129.9, 130.1, 130.8, 139.2, 139.7, 156.9, 160.0, 168.9

III-6 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2-[2-(3-methyl-isoxazol-5-yl)-ethenyl]-phenoxy}- 35 propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(diphenyl-methyl)-piperazine and C_.J-5-.2-_2- (2,3-epoxypropoxy)-phenyl]-ethenyl}-3-(methyl)-isoxa- 40 zole.

Mp.: 128-130°C

¹³ C-NMR [CDC1 ₃ ; δ (ppm)] : 11.5, 52.0, 53.6, 60.7, 65.4, 71.0, 76.2, 101.8, 112.5, 114.1, 121.3, 125.0, 127.0, 127.8, 128.5, 45 129.8, 130.1, 142.7, 156.9, 160.0, 168.9

III-7 ( ^/ _. -l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- piperazin-l-yl]-3-{2-[2-(3-carbethoxy-isoxazol-5-yl)- ethenyl]-phenoxy}-propan-2-ol

5 The reaction was carried out according to example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl-piperazine and (E)-3-(carbethoxy)-5-{2-[2-(2,3-epoxypro- poxy)-phenyl]-ethenyl}-isoxazole.

0 Mp. : 142-144°C

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 14.2, 31.8, 52.0, 53.7, 60.5, 62.1, 71.0, 79.1, 101.1, 112.6, 113.3, 121.3, 124.5, 125.5, 127.7, 129.1, 130.7, 130.8, 131.6, 139.2, 139.7, 156.7, 157.1, 160.1, 171.1 5

III-8 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2-[2-(3-carbethoxy-isoxazol-5-yl)-ethenyl]- phenoxy}-propan-2-ol

0 The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(diphenyl-methyl)-piperazine and (E)-3-(carbethoxy)-5-{2-[2-(2,3-epoxypropoxy)-phenyl]-etheny l}- isoxazole.

5 Mp. : 122-123°C

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 14.2, 52.0, 53.6, 60.7, 62.1, 65.3, 71.0, 76.2, 101.1, 112.5, 121.2, 124.5, 127.0, 128.0, 128.1, 128.5, 130.6, 131.7, 142.7, 156.7, 160.1, 171.1

0 III-9 .£;-l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- piperazin-l-yl]-3-{3-[2-(3-methoxymethyl-isoxazol-5-yl)- ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 35 bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and epoxide IIIa-2.

Mp.: 109-110°C

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 31.8, 51.9, 58.5, 60.4, 65.5, 65.8, 40 70.5, 79.1, 100.7, 113.1, 113.5, 120.2, 125.5, 127.8, 129.9, 130.8, 134.8, 137.0, 139.2, 139.7, 159.3, 161.8, 168.8

III-10 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{3-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]- 45 phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(diphenyl-methyl)-piperazine and epoxide IIIa-2.

5 ¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 45.8, 48.7, 53.4, 58.6, 60.3, 64.4,

65.8, 70.0, 73.2, 75.2, 101.0, 112.9, 113.6, 115.4, 120.5, 127.5, 127.7, 128.9, 130.0, 134.5, 137.1, 141.4, 158.6, 161.8, 168.7, 174.4, 179.3

0 III-ll .£)-l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- piperazin-1-yl]-3-{2-[2-(3-isopropyl-isoxazol-5-yl)- ethenyl]phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 5 bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and (E)-5-{2- [3-(2,3-epoxypropoxy)- phenyl]-ethenyl}-3-(isopropyl)-isoxazole.

Mp.: 160-162°C 0 "C-NMR [CDC1 ₃ ; δ (ppm)]: 21.8, 26.5, 31.8, 52.0, 53.7, 60.6,

65.4, 71.0,-79.1, 99.2, 112.5, 114.3, 121.2, 125.1, 125.5, 127.7, 129.7, 130.0, 130.7, 130.8, 139.2, 139.7, 156.9, 168.7, 169.6

111-12 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]- 5 3-{2-[2-(3-phenyl-isoxazol-5-yl)-ethenyl]-phenoxy}- propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(diphenyl-methyl)-piperazine and 30 (E)-5-{2-[3-(2,3-epoxypropoxy)-phenyl]-ethenyl}-3-(phenyl)-i soxa¬ zole.

Mp.: 129-132°C

"C-NMR [CDC1 ₃ ; δ (ppm)]: 52.0, 53.6, 60.7, 65.5, 71.0, 76.2,

35 99.0, 112.6, 114.0,, 121.2, 124.9, 126.8, 127.0, 127.9, 128.5,

128.9, 129.3, 129.9, 130.3, 142.7, 157.0, 162.7, 169.7

111-13 (£J-l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- piperazin-1-yl]-3-{2-[2-(3-phenyl-isoxazol-5-yl)- 40 ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out according to example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl-piperazine and (E)-5- {2- [3- (2,3-epoxypropoxy)-phenyl]-ethenyl}-3- (phenyl)-isoxa- 45 zole.

Mp.: 148-150°C

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 31.8, 52.0, 53.7, 60.6, 65.4, 71.0, 79.1, 99.0, 112.6, 114.0, 121.2, 125.5, 126.8, 127.7, 127.8, 128.9, 129.3, 130.3, 130.8, 139.2, 139.7, 157.0, 162.7, 169.7

5 111-14 CJ?;-l-t4-{Bis(4-fluorphenyl)-methyl}-piperazin-l-yl]- 3-{2-[2-(3-methoxy-methyl-isoxazol-5-yl)-ethenyl]- phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 10 bed for example III-l using epoxide IIIa-1 and bis (4-fluorophe¬ ny1)-methy1-piperazine.

Mp.: 110-112°C

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 51.8, 53.6, 58.5, 60.7, 65.5, 65.9, 15 71.0, 100.2, 112.5, 113.9, 115.3, 115.6, 123.3, 124.9, 127.8, 129.2, 129.3, 130.3, 138.2, 156.9, 160.6, 161.7, 163.1, 169.9

111-15 (Z)-l-[4-(Cyclohexyl-phenyl)-methyl]-piperazin-1-yl]- 3-{2-[2-(3-isopropyl-isoxazol-5-yl)-ethenyl]- 20 phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(cyclohexyl-phenyl)-methyl-pipera- zine and fZJ-5-.{2-[3-(2,3-epoxypropoxy)-phenyl]-ethenyl)-3-(iso- 25 propyl)-isoxazole.

¹³ C-NMR [ DMSO; δ (ppm)] (citrate) : 21.4, 25.4, 25.5, 26.3, 29.6,

29.6, 30.4, 36.3, 38.8, 43.5, 47.0, 52.9, 59.5, 63.0, 64.6, 70.8,

71.7, 73.4, 100.1, 112.7, 113.9, 121.0, 124.0, 126.9, 127.4,

30 127.7, 128.70, 129.0, 130.3, 136.2, 136.2, 156.3, 168.1, 169.2, 171.2, 175.8

111-16 ( ^, ZJ-l-[4-(2-Hydroxy-3-{2-[2-(3-isopropyl-isoxa- zol-5-yl)-ethenyl]-phenoxy}-propyl)-piperazin-1-yl]- 35 2,2-diphenyl-ethanone

The reaction was carried out following the same procedure descri¬ bed for example III-l using .Z)-5-{2-[3-(2,3-epoxypro- poxy)-phenyl]-ethenyl}-3-(isopropyl)-isoxazole and 2,2-diphenyl- 40 acetyl-piperazine.

¹³ C-NMR [ DMSO; δ (ppm)] (citrate) : 23.6, 28.0, 43.2, 45.0, 47.0, 54.6, 54.9, 55.2, 62.4, 68.0, 73.3, 74.2, 102.1, 114.8, 116.0, 122.9, 126.0, 128.6, 129.7, 130.2, 130.3, 130.9, 132.4, 142.1, 45 158.6, 170.2, 171.4, 171.5, 173.3, 177.1

111-18 f_-;-l- tl0 , ll-Dihydro-5H-dibenzo [a, d] cyclohepten-5-yl] - piperazin-1-yl]-3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)- ethenyl]-phenoxy}-propan-2-ol

5 The reaction was carried out following the same procedure descri¬ bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and the crude epoxide III-15a.

¹³ C-NMR [DMSO; δ (ppm) ^' ] (citrate): 30.9, 43.5, 49.7, 52.7, 57.8, 10 59.3, 64.7, 64.8, 70.7, 71.7, 77.2, 102.4, 112.1, 114.6, 120.2, 124.5, 125.5, 127.7, 129.3, 130.1, 130.4, 131.7, 138.7, 161.0, 167.4, 171.2, 175.8

111-19 (Z)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]- 15 3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]- phenoxy}-propan-2-ol

The reaction was run according to example III-l using 4-(diphe¬ nyl-methyl)-piperazine and the crude epoxide Ill-15a.

20

¹³ C-NMR [CDClj; δ (ppm)] (citrate): 44.5, 48.5, 58.6, 64.2, 65.7, 70.1, 73.1, 75.2, 101.9, 112.1, 115.9, 121.2, 124.9, 127.6, 127.8, 129.8, 130.3, 132.1, 141.1, 155.2, 161.4, 168.3, 173.9, 179.0

25

111-20 CE)-l-[5H-Dibenzo[a,d]cyclohepten-5-yl]-piperazin-l-yl]- 3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]- phenoxy}-propan-2-ol

30 The reaction was carried according to example III-l using 5H-di- benzo[a,d]cyclohepten-5-yl-piperazine and epoxide IIIa-1.

Mp.: 115-116°C

¹³ C-NMR [DMSO; δ (ppm)]: 51.1, 57.8, 60.8, 64.8, 66.2, 71.5, 35 100.9, 112.5, 113.6, 120.6, 123.8, 126.9, 127.6, 127.9, 129.3, 129.6, 129.8, 130.2, 130.4, 133.9, 137.8, 156.7, 161.5, 168.8

111-21 f£;-l-[4-(2-Hydroxy-3-{3-[2-(3-methoxymethyl-isoxa- zol-5-yl)-ethenyl]-phenoxy)-propyl)-piperazin-1-yl]- 40 cyclohexyl-phenyl-ethanone

The reaction was carried according to example III-l using 4-(cy¬ clohexyl-phenyl)-methyl-piperazine and epoxide IIIa-2.

45

¹³ C-NMR [DMSO; δ (ppm)] (citrate) : 25.5, 25.6, 26.0, 29.8, 31.6, 40.6, 42.9, 44.4, 52.4, 52.8, 53.4, 60.1, 64.8, 65.7, 70.7, 72.1, 101.3, 112.7, 113.6, 115.6, 119.9, 126.5, 128.2, 128.3, 129.8, 134.3, 136.7, 138.8, 158.9, 161.6, 168.3, 170.7, 171.2, 174.9 5

111-22 (E ) -!- [4-(Cyclohexyl-phenyl)-methy1-piperazin-l-yl]-

3-{2-[2-(3-methoxy-methyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

10 The reaction was carried according to example III-l using 4-(cy¬ clohexyl-phenyl)-methyl-piperazine and epoxide IIIa-1.

¹³ C-NMR [DMSO; δ (ppm) ] (citrate; mixture of E- and Z-Isomers 7:3): 25.4, 25.5, 26.3, 29.6, 30.4, 36.4, 43.7, 47.1, 52.9, 53.1, 15 57.9, 59.4, 59.7, 64.7, 64.9, 65.0, 70.6, 71.0, 71.6, 73.5, 101.0, 102.4, 112.2, 112.7, 113.7, 114.6, 120.3, 120.9, 123.9, 124.5, 126.8, 127.6, 129.0, 129.4, 130.1, 130.5, 131.7, 136.4, 155.9, 156.4, 161.0, 161.6, 167.4, 168.8, 171.2, 176.1

20 111-23 (E)-l-[4-(Cyclohexyl-phenyl)-methyl-piperazin-1-yl]- 3-{2-[2-(3-phenyl-isoxazol-5yl)-ethenyl]-phenoxy}- propan-2-ol

The reaction was carried according to example III-l using 4-(cy- 25 clohexyl-phenyl)-methyl-piperazine and .\_?J-5-{2-[3-(2,3-epoxypro- poxy)-phenyl]-ethenyl}-3-(phenyl)-isoxazole.

¹³ C-NMR [CDC1 ₃ ; δ (ppm)] (citrate; mixture of E- and Z-Isomers 1:1) : 26.3, 26.5, 26.9, 29.7, 29.7, 31.2, 37.7, 49.6, 53.9, 30 60.9, 65.5, 71.1, 99.0, 112.6, 114.1, 121.2, 125.0, 125.3, 126.8,

127.2, 127.7, 128.0, 128.3, 128.9, 129.1,129.3, 129.4, 129.9,

130.3, 130.4, 137.8, 157.0, 162.7, 169.8

111-24 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]- 35 3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]- phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(diphenyl-me hyl)-piperazine and 40 epoxide IIIa-1.

¹³ C-NMR [DMSO, δ (ppm) ] (citrate) : 43.5, 49.8, 52.7, 57.8, 59.6, 64.8, 71.0, 71.7, 74.4, 101.0, 112.7, 113.6, 120.9, 123.8, 126.9,

127.4, 127.5, 128.5, 129.3, 130.5, 142.3, 156.4, 161.5, 168.8, 45 171.2, 175.7

11-25 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]-4,5-di- methoxy-phenoxy}-propan-2-ol

5 The reaction was carried out following the same procedure descri¬ bed for example III-l using 4- (diphenyl-methyl)-piperazine and IIIa-12.

Mp.: 114-115.5°C 10 "C-NMR [CDC1 ₃ ; δ (ppm)]: 52.0, 53.6, 56.1, 58.5, 60.6, 65.5,

65.9, 72.6, 76.2, 99.4, 99.5, 109.9, 111.5, 126.99, 128.0, 128.5, 129.8, 142.5, 144.0, 151.1, 152.2, 161.7, 169.9

111-26 (E)-l-[4- (Diphenyl-methyl)-piperazin-l-yl]- 15 3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]- 5-N,N-diethylamino]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(diphenyl-methyl)-piperazine and 20 epoxide IIIa-13.

¹³ C-NMR [DMSO; δ (ppm)] (citrate): 12.5, 43.5, 43.7, 49.9, 52.8, 57.8, 59.9, 64.8, 64.9, 65.2, 70.8, 71.7, 74.4, 95.3, 98.7, 104.5, 107.6, 111.2, 126.9, 127.5, 128.5, 129.0, 130.2, 142.3, 25 149.5, 158.3, 161.3, 170.1, 171.2, 175.7

111-27 .£)-l-[10,ll-Dihydro-5H-dibenzo[a,d]cycloheρten-5-yl]- piperazin-1-yl]-ethenyl]-4,5-dimethoxy-phenoxy}- propan-2-ol 30

The reaction was carried out following the same procedure descri¬ bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and epoxide IIIa-12.

35 Mp.: ^' 130-132.5°C

¹³ C-NMR [CDC1 ₃ ,' δ (ppm)]: 31.8, 52.0, 56.1, 56.3, 58.2, 60.5, 65.6, 65.9, 72.6, 89.1, 99.4, 99.5, 109.9, 111.5, 117.0, 125.5, 127.7, 129.8, 130.9, 139.4, 139.7, 144.0, 151.1, 152.2, 161.7, 169.9 40

111-28 C_?;-l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- piperazin-l-yl]-3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)- ethenyl]-5-N,N-diethylamino]-phenoxy}-propan-2-ol

45

The reaction was carried out following the same procedure descri¬ bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and epoxide IIIa-13.

5 ¹³ C-NMR [DMSO; δ (ppm)] (citrate): 12.5, 30.9, 43.5, 43.7, 44.6, 50.0, 52.9, 57.8, 64.9, 65.3, 70.9, 71.7, 77.3, 95.3, 98.7, 104.5, 107.6, 111.2, 115.4, 127.7, 129.0, 130.2, 130.4, 130.6, 138.8, 149.5, 161.3, 170.1, 171.1, 175.8

10 111-29 (E)-l-[4-(Cyclohexyl-phenyl)-methyl-piperazin-1-yl]-

3-{2-[2-(3-methoxy-methyl-isoxazol-5-yl)-ethenyl]-4,5-di- methoxy-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 15 bed for example III-l using 4- (cyclohexyl-phenyl)-methyl-pipera¬ zine and epoxide IIla-12.

¹³ C-NMR [DMSO; δ (ppm)] (citrate) : 25.4, 25.5, 26.3, 29.6, 30.4, 36.4, 43.6, 46.6, 53.0, 55.7, 56.0, 57.8, 59.5, 64.9, 71.6, 72.0, 20 73.4, 99.2, 100.0, 110.0, 111.0, 115.6, 126.8, 127.6, 129.0, 136.3, 143.3, 150.9, 151.6, 161.4, 169.3, 171.2, 176.0

111-30 (E)-l-[4-(Cyclohexyl-phenyl)-methyl-piperazin-1-yl]- 3-{2-[2-(3-methoxy-methyl-isoxazol-5-yl)-ethenyl]- 25 5-N,N-diethylamino-phenoxy)-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(cyclohexyl-phenyl)-methyl-pipera¬ zine and epoxide IIIa-13. 30

Mp: 56-80°C

111-31 f£)-l-[4-(2-Hyσ_roxy-3-{2-[2-(3-methoxymethyl-isoxa- zol-5-y1)-ethenyl]-4,5-dimethoxy-phenoxy)-propyl)- piperazin-1-yl]-2,2-diphenyl-ethanone 35

The reaction was carried out following the same procedure descri¬ bed for example III-l using 2,2-diphenyl-acetyl-piperazine and epoxide IIla-12.

40 Mp: 55-71°C

111-32 CJ?;-l-[4-(2-Hydroxy-3-{2-[2-(3-methoxymethyl-isoxa- zol-5-yl)-ethenyl]-phenoxy)-propyl)-piperazin-1-yl]- 2,2-diphenyl-ethanone

45

The reaction was carried out following the same procedure descri¬ bed for example III-l using 2,2-diphenyl-acetyl-piperazine and epoxide Illa-l.

5 ¹³ C-NMR [DMSO ; δ (ppm)] (citrate) : 41.1, 42.9, 44.9, 52.5, 52.8,

53.1, 57.8, 53.1, 57.8, 60.4, 64.7, 64.8, 65.9, 71.2, 72.1, 101.0, 112.7, 113.6, 120.7, 123.8, 126.5, 127.6, 128.1, 128.2, 128.8, 129.4, 130.5, 140.0, 156.6, 161.6, 168.8, 169.4, 171.2, 175.0

10

111-35 (E) -l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2-[2-(3-isopropyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

15 The reaction was carried out according to example III-l using 4-(diphenyl-methyl)-piperazine and (E)-5-{2- [2- (2,3-epoxypro- poxy)-phenyl]-ethenyl}-3-(isopropyl)-isoxazole.

Mp.:145-146°C 20 ¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 21.8, 26.5, 52.0, 53.6, 60.7, 71.0,

76.2, 99.2, 112.5, 114.3, 121.2, 125.1, 126.9, 127.7, 127.9, 128.5, 129.7, 130.1, 142.7, 156.9, 168.7, 169.6

111-36 (E) -l-[4 _^ (Diphenyl-methyl)-piperazin-1-yl]- 25 3-{2-[2-(3-methyl-isoxazol-5-l)-ethenyl]-phen¬ oxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(diphenyl-methyl)-piperazine and 30 (E)-5-{2-[2-(2,3-epoxypropoxy)-phenyl]-ethenyl)-3-(methyl)-i soxa¬ zole.

Mp: 174-175°C (hydrochloride)

35 111-37 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2-[-2-(2-(4-methoxxphenyl)-l,3-oxazol-4-yl)-ethenyl]- phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 40 bed for example III-l using 4-(diphenyl-methyl)-piperazine and epoxide IIIa-10.

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 52.0, 53.7, 55.3, 60.8, 65.7, 71.1, 76.2, 112.6, 114.2, 117.6, 120.3, 121.2, 125.7, 126.5, 126.9, 45 127.2, 127.9, 128.3, 128.5, 128.7, 134.6, 140.9, 142.7, 156.4, 161.5, 161.8

111-38 .i. -l-[4-(10,ll-Dihydro-5H-dibenzo[a,d]cyclohep- ten-5-yl)-piperazin-1-yl]-3-{2-[2-(2-(4-methoxy- phenyl)-1,3-oxazol-4-yl)-ethenyl]-phenoxy}- propan-2-ol 5

The reaction was carried out following the same procedure descri¬ bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and epoxide Illa-10.

10 ¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 31.7, 52.0, 53.8, 55.4, 60.7, 65.7,

71.1, 79.1, 112.6, 114.1, 117.7, 120.3, 121.2, 125.5, 125.7, 126.5, 127.3, 127.7, 128.3, 128.7, 130.8, 134.6, 139.3, 139.6, 140.9, 156.5, 161.5, 161.8

15 111-39 ( ^/ _? -l-[4-(10,ll-Dihydro-5H-dibenzo[a,d]cyclohep- ten-5-yl)-piperazin-1-yl]-3-{2-[2-(5-(4-methyl-phe¬ nyl)-1,3,4-oxadiazol-2-yl)-ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 20 bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and epoxide IIla-9.

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 21.7, 31.7, 52.0, 53.7, 60.6, 65.4, 71.0, 79.1, IIO..9., 112.6, 121.3, 124.2, 125.5, 126.9, 127.7, 25 128.5, 129.7, 130.7, 130.8, 131.0, 134.2, 139.2, 139.6, 142.1, 157.3, 164.0, 164.6

111-40 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2-[2-(5-(4-methy1-phenyl)-1,3,4-oxadiazol-2-yl)- 30 ethenyl]-phenox }-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(diphenyl-methyl)-piperazine and epoxide llia-9. 35

¹³ C-NMR [CDCI ₃ ; δ (ppm)]: 21.7, 52.0, 53.7, 60.8, 65.4, 70.9,

76.2, 110.9, 112.5, 121.3, 124.2, 126.9, 127.0, 127.9, 128.4, 128.5, 129.7, 131.0, 134.2, 142.2, 142.7, 157.2, 164.0, 164.6 ^J

40 111-42 C_? -l-[4-(Diphenyl)-methyl-piperazin-l-yl]-

3-{2-[2-(3,5-dimethyl-isoxazol-4-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

45

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(diphenyl-methyl)-piperazine and (E) -&-{2- [2-(2,3-epoxypropoxy)-phenyl]-ethenyl}-3,5-dimethyl- isoxazole. 5

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 11.7, 11.9, 52.0, 53.7, 60.8, 65.5,

70.8, 76.2, 112.4, 113.6, 117.0, 121.2, 125.0, 126.2, 126.7,

127.0, 127.9, 128.5, 128.8, 142.6, 155.9, 158.3, 165.5

10 111-43 C-- ⁾ -l-[4-(10,ll-Dihydro-5H-dibenzo[a,d]cyclohep- ten-5-yl)-piperazin-1-yl]-3-{2-[2-(3,5-dimethyl-isoxa- zol-4-yl)-ethenyl]-phenoxy)-propan-2-ol

The reaction was carried out following the same procedure descri- 15 bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and C_-)-4-.2-[2-(2,3-epoxypropoxy)- phenyl]-ethenyl}-3,5-dimethyl-isoxazole.

¹³ C-NMR [CDCI ₃ ; δ (ppm)]: 11.7, 11.9, 31.7, 52.0, 53.7, 60.7, 20 65.5, 70.8, 79.1, 112.4, 113.6, 116.9, 121.2, 125.0, 125.5,

126.1, 126.6, 127.8, 128.8, 130.8, 139.1, 139.7, 155.9, 158.3, 165.4

111-44 f£J-l-[4-{Bis (4-fluorophenyl)-methyl}-piperazin-l-yl]- 25 3-{2-[2-(3,5-dimethyl-isoxazol-4-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using bis (4-fluorophenyl)-methyl-piperazine 30 and (E)-5-{2-[2-(2,3-epoxypropoxy)-phenyl]-ethenyl)-3,5-dimethyl - isoxazole.

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 11.7, 11.9, 51.8, 53.6, 60.8, 65.4,

70.9, 74.5, 112.4, 113.6, 115.5 (d, J = 21 Hz), 116.9, 121.3, 35 125.0, 126.2, 126.7, 128.8, 129.2 (d, J = 8 Hz), 138.1, 155.9,

158.3, 161.9 (d, J = 245 Hz), 165.5

111-45 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2-[2-(2-methoxymethyl-l,3-thiazol-4-yl)-ethenyl]-phen- 40 oxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(diphenyl-methyl)-piperazine and epoxide IIIa-8. 45

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 52.0, 53.7, 59.0, 60.8, 65.7, 71.1, 71.7, 76.3, 112.6, 115.0, 121.2, 122.3, 126.4, 126.6, 127.0, 127.4, 128.5, 128.8, 142.7, 154.8, 156.5, 168.6

5 111-46 r_.;-l-[4-(10,ll-Dihydro-5H-dibenzo[a,d]cyclohep- ten-5-yl)-piperazin-1-yl]-3-{2-[2-(2-methoxy- methyl-l,3-thiazol-4-yl)-ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 10 bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and epoxide IIla-8.

¹³ C-NMR [CDCI3; δ (ppm)]: 31.7, 52.0, 53.7, 59.0, 60.7, 65.7, 71.1, 71.6, 79.1, 112.6, 115.0, 121.2, 122.3, 125.5, 126.4, 15 126.5, 127.3, 127.7, 128.8, 130.7, 139.2, 139.6, 154.8, 156.5, 168.6

111-47 (E)-l-[Bis-(4-fluorophenyl-methyl)-piperazin-1-yl]-

3-{2-[2-(2-methoxy-methyl-l,3-thiazol-4-yl)-ethenyl]- 20 phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using bis (4-fluoropheny1-methyl)-piperazine and epoxide llla-8. 25

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 51.9, 53.7, 59.0, 60.8, 65.8, 71.1,

71.7, 74.5, 112.6, 115.0, 115.4 (d, J = 21 Hz), 121.2, 122.3,

126.4, 126.6, 127.4, 128.8, 129.2 (d, J = 8 Hz), 138.2, 154.8,

156.5, 161.8 (d, J = 246 Hz), 168.6 30

111-48 .-.;-!-[4-(Diphenyl-methyl)-piperazin-l-yl]-3-{2-[2-(thio- phen-2-yl)-ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 35 bed for example III-l using 4-(diphenyl-methyl)-piperazine and (E) -2 - {2-[2-(2,3-epoxypropoxy)-phenyl]-ethenyl}-thiophen.

Mp: 131-132°C (hydrochloride)

40 111-49 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-3-{2-[2-(thio- phen-3-yl)-ethenyl]phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(diphenyl-methyl)-piperazine and 45 (E)-3-f2-[2-(2,3-epoxypropoxy)-phenyl]-ethenyl)-thiophen.

Mp: 188-189°C (hydrochloride)

111-50 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-3-{2-[2-(5-me- thyl-thia-3,4-diazol-2-yl)-ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 5 bed for example III-l using 4-(diphenyl-methyl)-piperazine and (E)-2-f2-[2-(2,3-epoxypropoxy)-phenyl]-ethenyl}-5-methy1- thia-3,4-diazol.

Mp: 223-234°C (hydrochloride) 0

111-51 .E)-l-[2-(3,4-Dimethoxyphenyl)-ethyl]-piperazin-l-yl]- 3-{2-[2-(3-methoxy-methyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

5 The reaction was carried out following the same procedure descri¬ bed for example III-l using l-[2-(3,4-dimethoxyphenyl)-ethyl]- piperazine and epoxide IIIa-1.

Mp.: 197-199°C 0 ^l3 C-NMR [DMSO; δ (ppm)] (oxalate) : 29.9, 50.5, 55.4, 57.1, 57.8, 59.4, 64.9, 65.8, 71.1, 101.1, 112.0, 112.5, 112.7, 113.7, 120.5, 120.9, 123.9, 127.6, 129.4, 130.2, 130.5, 147.5, 148.7, 156.6,

161.6, 162.6, 168.9 5

111-52 f£)-l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- piperazin-1-yl] -3-{2- [2- (3-methoxymethyl-isoxazol-5-yl) - ethenyl ] -4-ni tro-phenoxy } -propan-2-ol

30 The reaction was carried out according to example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl-piperazine and ep¬ oxide IIIa-16.

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 31.7, 51.9, 53.5, 58.6, 60.1, 65.1, 35 65.8, 71.7, 79.1, 101.7, 112.1, 116.3, 123.0, 125.5, 125.6,

127.7, 127.8, 130.8, 130.8, 139.1, 139.7, 141.8, 161.2, 161.8, 168.3

111-53 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]- 40 piperazin-l-yl]-3-{2-[2-(3-methoxymethyl-isoxa- zol-5-yl)-ethenyl]-4-nitro-phenoxy)-propan-2-ol

The reaction was carried out according to example III-l using 4- (diphenyl-methyl)-piperazine and epoxide IIIa-16. 45

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 51.9, 53.6, 58.6, 60.3, 65.2, 65.8, 71.7, 76.2, 101.7, 112.1, 125.0, 125.6, 127.0, 127.7, 127.9, 128.5, 141.7, 161.2, 161.9, 168.3.

5 111-54 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2-[2-(5-methoxymethyl-3-isoxazolyl)-ethenyl]-phen¬ oxy}-propan-2-ol

The reaction was carried out according to example III-l using 10 4-(diphenyl-methyl)-piperazine and epoxide IIIa-7.

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 51.9, 53.6, 58.8, 60.6, 65.3, 65.5, 71.2, 76.2, 99.9, 112.6, 116.5, 121.3, 125.2, 127.0, 127.4, 127.9, 128.5, 130.0, 131.1, 142.6, 156.6, 162.3, 168.9 15

111-55 f__y-l-[4-(10,ll-Dihydro-5H-dibenzo[a,d]cyclohep- ten-5-yl)-piperazin-1-yl]-3-{2-[2-(5-metho-_ymethyl-isoxa- zol-3-yl)-ethenyl]-phenoxy)-propan-2-ol

20 The reaction was carried out according to example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl-piperazine and ep¬ oxide IIIa-7.

¹³ C-NMR [CDCI3; δ (ppm)]: 31.7, 52.0, 53.7, 58.8, 60.6, 65.4, 25 65.5, 71.2, 79.0, 99.9, 112.7, 116.5, 121.3, 125.2, 125.5, 127.4, 127.7, 130.0, 130.7, 130.8, 131.1, 139.2, 139.6, 156.6, 162.3, 168.9

111-56 (E)-l-[Bis (4-methoxyphenyl)-methyl-piperazin-1-yl]- 30 3-{2-[2-(2-methoxy-methyl-l,3-thiazol-4-yl)-ethenyl]- phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using bis(4-methoxyphenyl)-methy1-pipera- 35 zine and epoxide IIIa-8.

¹³ C-NMR [CDCI3; δ (ppm)] (fumarate): 50.0, 52.9, 54.9, 58.3, 60.2, 65.3, 70.7, 71.0, 73.2, 112.6, 113.8, 116.5, 120.8, 122.1, 125.3, 125.3, 126.6, 128.4, 128.9, 134.4, 134.6, 153.8, 156.0, 40 158.0, 166.7, 168.4

111-57 C£)-l-[4-(Cyclohexyl-phenyl)-methyl-piperazin-1-yl]- 3-{2-[2-(pyridin-3-yl)-ethenyl]-phenoxy}-propan-2-ol

45

The reaction was carried out according to example 111-58 using precursor ll h-1, 3-pyridine aldehyde and potassium tert.butylate as base.

5 ¹³ C-NMR [DMSO ; δ (ppm)] (citrate) : 25.4, 25.5, 26.2, 29.5, 30.4, 36.3, 43.5, 52.7, 59.2, 64.5, 70.9, 71.7, 73.3, 112.5, 112.6, 121.0, 123.2, 123.7, 125.0, 125.3, 126.3, 126.6, 126.9, 127.7, 128.0, 129.0, 129.3, 132.7, 133.1, 135.2, 136.1, 148.1, 148.2, 149.3, 155.7, 171.3, ^' 175.8 0

111-58 (E)-l-[4-(Cyclohexyl-phenyl)-methyl-piperazin-1-yl]- 3-{2-[2-(pyridin-2-yl)-ethenyl]-phenoxy}-propan-2-ol

A suspension of 12.5 mmol sodium hydride in 20 ml absolute dime- 5 thylformamide was prepared under inert gas. A solution of 5 mmol of diethyl 2-{3-[4-(cyclohexyl-phenyl-methyl]-piperazin-1-yl]- 2-hydroxy-propoxy)-benzyl phosphonate (precursor lllh-1) in 30 ml absolute dimethylformamide was added dropwise at room temperature. The reaction mixture was stirred at room temperature 0 for 2 hours. Then a solution of 7 mmol 2-pyridine aldehyde in 10 ml absolute dimethylformamide was added dropwise. The reaction mixture was stirred at room temperature for another 12 hours. For work-up the reaction mixture was poured into 500ml of water and extracted with ether. The ether phase was washed once with water, 5 dried over sodium sulfate and filtered. The ether was removed un¬ der reduced pressure. The desired product was isolated as an oil (1.6g). The citrate of the product was prepared for analytical purposes by addition of 2 aliquot of citric acid dissolved in ether. 0 l ³ C-NMR [DMSO; δ (ppm)] (citrate) : 25.4, 25.5, 26.2, 29.6, 30.4, 36.3, 43.4, 52.8, 64.5, 70.7, 71.7, 73.3, 112.7, 121.0, 122.1, 122.3, 125.1, 126.7, 126.9, 127.0, 127.7, 128.5, 129.0, 129.5, 136.1, 136.7, 149.4, 155.3, 156.1, 171.2, 175.7

35

III-106 (E)-l-[4-(Cyclohexyl-phenyl)-methy1-piperazin-l-yl]- 3-{2-[2-(pyridin-4-y1)-ethenyl]-phenoxy}-propan-2-ol

Prepared according to the procedure given for compound 111-58 and 40 4-pyridine aldehyde.

¹³ C-NMR [DMSO ; δ (ppm)] (citrate) : 25.4, 25.5, 26.2, 29.6, 30.4, 36.3, 43.4, 52.8, 59.3, 64.6, 64.8, 70.5, 70.8, 71.8, 73.3, 112.5, 112.7, 120.4, 120.8, 121.0, 123.0, 124.7, 126.3, 126.9, 45 127.0, 127.3, 127.7, 129.0, 129.3, 129.5, 129.9, 136.2, 144.3, 144.7, 149.5, 149.9, 155.9, 156.0, 171.2, 175.7

III-107 (E)-l-[4-(Cyclohexyl-phenyl)-methyl-piperazin-1-yl]- 3-{2-[2-(N-methyl-pyrrol-2-yl)-ethenyl]-phenoxy}- propan-2-ol

5 The reaction was carried out according to example 111-58 using precursor lllh-1 and 2-(N-methyl)-pyrrol aldehyde.

Mp: 148-156°C

10 III-108 (E) -l-[4-(Diphenyl-methyl)-piperazin-1-yl]-3-{2-[2-(N-me- thyl-pyrrol-2-yl)-ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out according to example 111-58 using diethyl 2-{3-[4-(diphenyl-methyl]-piperazin-1-yl]-2-hydroxy-pro- 15 poxy}-benzyl phosphonate and 2-(N-methyl)-pyrrol aldehyde.

¹³ C-NMR [ DMSO ; δ (ppm)] (citrate) : 33.6, 43.4, 52.6, 59.6, 64.8, 65.0, 70.9, 71.7, 74.3, 106.1, 107.7, 112.4, 118.0, 119.4, 120.8, 123.6, 125.9, 126.4, 126.9, 127.4, 127.8, 128.5, 131.8, 20 142.2, 151.8, 155.2, 171.2, 175.6

III-109 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2-[2-(pyridin-4-yl)-ethenyl]-phenoxy}-propan-2-ol

25 The reaction was carried out according to example 111-58 using diethyl 2-{3-[4- (diphenyl-methyl]-piperazin-1-yl]-2-hydroxy-pro- poxy)-benzyl phosphonate and 4-pyridine aldehyde.

¹³ C-NMR [DMSO ; δ (ppm)] (citrate) : 43.3, 49.2, 52.5, 59.2, 30 63.0, 64.3, 64.6, 70.9, 71.9, 74.2, 112.5, 112.7, 120.4, 120.7,

121.0, 123.0, 124.7, 126.3, 127.0, 127.3, 127.4, 127.6, 128.5, 129.3, 129.6, 130.0, 142.1, 144.3, 144.7, 149.5, 149.8, 155.9,

156.1, 171.2, 175.5

35 III-110 l-[4-(Diphenyl-methyl)-piperazin-l-yl]-

3-{2-[2-(pyridin-3-yl)-ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out according to example 111-58 using diethyl 2-{3-[4-(diphenyl-methyl]-piperazin-1-yl]-2-hydroxy-pro- 40 poxy}-benzyl phosphonate and 3-pyridine aldehyde.

¹³ C-NMR [DMSO ; δ (ppm)] (citrate) : 43.4, 49.6, 52.6, 64.9, 71.1, 71.7, 74.3, 112.6, 120.9, 123.6, 125.1, 125.3, 126.3, 126.6, 126.9, 127.4, 128.5, 129.3, 132.6, 133.1, 142.2, 148.1, 148.2, 45 155.8, 171.2, 175.6

III-lll l-[4- (Diphenyl-methyl)-piperazin-l-yl]-

3-{2-[2-(pyridin-2-yl)-ethenyl]-phenox }-propan-2-ol

The reaction was carried out according to example 111-58 using 5 diethyl 2-{3-[4-(diphenyl-methyl]-piperazin-1-yl]-2-hydroxy-pro- poxy}-benzyl phosphonate and 2-pyridine aldehyde.

¹³ C-NMR [DMSO ; δ(ppm)] (citrate) : 43.4, 49.6, 52.7, 59.7, 64.9, . 71.0, 71.8, 74.3, 112.3, 112.7, 120.2, 120.9, 121.9, 122.1, 10 122.8, 123.1, 125.1, 125.2, 126.8, 126.9, 127.0, 127.4, 128.4, 128.5, 129.2, 129.5, 130.1, 135.8, 136.7, 142.2, 149.1, 149.3, 155.3, 155.6, 155.9, 156.2, 171.2, 175.6

III-112 f£j-[4-(2-Hydroxy-3-{2-[2-(3-methoxymethyl-isoxazol- 15 5-y1)-ethenyl]-phenoxy}propyl)-piperazin-1-yl]- (9H-xanthen-9-y1)-methanone

The reaction was carried out according to example III-l using precursor IIIa-1 and piperazin-1-yl- (9H-xanthen-9-yl)-methanone.

20

Mp: 120-123°C

III-113 (_?.-l-[4-(2-Hydroxy-3-{2-[2-(3-methoxymethyl-isoxa- zol-5-y1)-ethenyl]-phenoxy}-propyl)-piperazin-1-yl]- 25 cyclohexyl-phenyl-ethanone

The reaction was carried out according to example III-l using precursor IIla-1 and piperazin-1-yl-(9H-xanthen-9-yl)-methanone.

30 ¹³ C-NMR [DMSO ; δ (ppm)] (citrate) : 25.5, 29.8, 31.6, 40.6, 40.8, 42.9, 44.5, 52.4, 52.8, 53.0, 53.4, 53.5, 57.8, 60.2, 60.4, 64.7, 64.8, 71.2, 72.1, 101.0, 112.1, 112.6, 113.6, 120.8, 123.8, 126.5, 126.5, 127.6, 128.2, 129.4, 130.5, 138.8, 156.6, 161.0, 168.8, 170.6, 171.2, 175.0 35

III-114 (E)-l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- piperazin-1-yl]-3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)- ethenyl]-6-fluoro-phenoxy)-propan-2-ol

40 The reaction was carried out according to example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl-piperazine and ep¬ oxide IIIa-14.

Mp: 140-142°C 45

III-115 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2-[2-(3-methoxy-methyl-isoxazol-5-yl)-ethenyl]- 6-fluoro-phenoxy}-propan-2-ol

5 The reaction was carried out according to example III-l using 4-(diphenyl-methyl)-piperazine and epoxide IIIa-14.

¹³ C-NMR [DMSO ; δ (ppm)] (citrate) : 43.4, 49.9, 52.7, 57.8, 59.3, 64.8, 65.7, 71.7, 74.4, 76.7, 101.7, 115.3, 117.1 (d, J=19.2 Hz), 10 122.3, 124.2 (d, J=11.5 Hz), 126.9, 127.4, 127.8, 128.5, 130.3,

142.3, 144.3 (d, J=11.5 Hz), 153.9 and 156.4 (d, J=245.1 Hz), 161.6, 168.3, 171.2, 175.7

III-116 (i.)-l-[4-(10,ll-Dihydro-5H-dibenzo[a,d]cyclohep- 15 ten-5-yl)-piperazin-yl]-3-{2-[2-(4-dimethyl-l,3-oxa- zolin-2-yl)-ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out according to example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl-piperazine and ep- 20 oxide IIIa-11.

¹³ C-NMR [CDC1 ₃ ; δ (ppm)] (citrate): 27.8, 27.9, 31.9, 44.7,48.5, 54.8, 61.2, 64.2, 66.3, 70.1, 72.5, 77.9, 79.2, 112.1, 115.9,

121.4, 123.5, 128.3, 130.9, 131.2, 131.3, 132.4, 137.5, 139.3, 25 139.6, 157.4, 164.2, 173.4, 180.0

III-117 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2-[2-(4-dimethyl)-l,3-oxazolin-2-yl)-ethenyl]-phen¬ oxy}-propan-2-ol 30

The reaction was carried out according to example III-l using 4-(diphenyl-methyl)-piperazine and epoxide IIIa-11.

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 28.4, 52.0, 53.0, 60.6, 65.6, 67.2, 35 71.1, 76.2, 78.7, 112.5, 116.2, 121.2, 124.7, 127.0, 127.9,

128.5, 130.5, 134.7, 142.7, 156.9, 162.3

III-118 (E)-l-[4-(Diphenyl-methyliden)-piperidin-1-yl]-

3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]-phen- 40 oxy}-propan-2-ol

lg of .£)-5-{2-[3-(2,3-epoxypropoxy)-phenyl]-ethenyl}-3-(methoxy- methyD-isoxazole (precursor IIIa-1) , lg of 4- (diphenyl-methyli¬ den)-piperidine hydrochloride and 0.4ml of N-methylmorpholin were 45 refluxed in 10ml ethanol. After the reaction was completed the solvent was evaporated and the crude residue purified by

chromatography on silica gel. The obtained oily residue was trea¬ ted with diethylether for crystallisation.

Mp.: 132-133°C 5 ¹³ C-NMR [DMSO; δ (ppm)]: 31.2, 38.8, 39.0, 39.2, 39.9, 40.2, 55.4, 57.8, 60.9, 64.8, 66.5, 71.6, 100.9, 112.7, 113.6, 120.7, 123.8, 126.3, 127.7, 128.1, 129.3, 129.6, 130.5, 135.0, 135.2, 142.0, 156.8, 161.5, 168.9

10 III-119 fi_ -l-[4-(Diphenyl-methyliden)-piperidin-1-yl]-

3-{2-[4-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 15 bed for example III-118 using epoxide Illa-3.

Mp.: 120-122°C

"C-NMR [CDC1 ₃ ; δ (ppm)]: 31.7, 55.6, 58.4, 60.4, 65.7, 65.9, 70.6, 99.9, 111.1, 115.0, 126.5, 128.1, 128.6, 129.8, 134.6, 20 134.7, 136.6, 142.4, 159.8, 161.8, 169.2

III-120 (E)-l-[4-(Diphenyl-methyliden)-piperidin-1-yl]- 3-{2-[2-(3-methyl-isoxazol-5yl)-ethenyl]-phen¬ oxy}-propan-2-ol 25

The reaction was carried out following the same procedure descri¬ bed for example III-118 using C_.J-5-{2-[2- (2,3-epoxypropoxy)- phenyl]-ethenyl}-3-(methyl)-isoxazole.

30 Mp. : 155-157°C

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 11.5, 18.5, 31.8, 55.5, 60.7, 65.6, 71.1, 101.9, 112.5, 114.1, 121.2, 124.1, 126.4, 127.7, 128.0, 129.8, 130.1, 134.8, 136.5, 142.4, 156.9, 160.0, 168.9

35 III-121 (E)-l-[4-(Diphenyl-methyliden)-piperidin-1-yl]-

3-{2-[2-(3-carbethoxy-isoxazol-5yl)-ethenyl]-phen¬ oxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 40 bed for example III-118 using (E)-3-(carbethoxy)-

5-{2-[2-(2,3-epoxypropoxy)-phenyl]-ethenyl)-isoxazole.

Mp.: 124-125°C

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 14.2, 31.8, 55.5, 60.6, 62.1, 65.5, 45 71.0, 101.1, 112.6, 113.3, 121.3, 124.5, 126.4, 128.1, 129.8, 130.7, 131.6, 134.7, 136.5, 142.4, 156.7, 157.1, 160.1, 171.1

III-122 (E)-l-[4-(Diphenyl-methyliden)-piperidin-1-yl]-

3-{2-[3-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

5 The reaction was carried out following the same procedure descri¬ bed for example III-118 using epoxide IIIa-2.

"C-NMR [CDC1 ₃ ; δ (ppm)] (citrate): 28.2, 44.3, 55.0, 58.5, 60.1, . 64.5, 65.8, 69.8, 73.2, 101.1, 112.9, 113.6, 115.5, 120.6, 127.2, 10 128.3, 128.4, 129.3, 130.0, 134.6, 137.0, 139.8, 141.0, 158.6, 161.8, 168.7, 174.0, 178.9

III-123 (E)-l-[4-(Diphenyl-methyliden)-piperidin-1-yl]-

3-{2-[2-(3-isopropyl-isoxazol-5-yl)-ethenyl]-phen- 15 oxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-118 using (E)-5-{2- [2-(2,3-epoxypro- poxy)-phenyl]-ethenyl}-3-{isopropyl)-isoxazole.

20

Mp.: 156-157°C

¹³ C-NMR [CDC1 ₃ ; δ (ppm) ] : 21.8 , 26.5 , 31.8 , 55.6 , 60.7 , 65.2 , 71.1 , 99.3 , 112 .6 , 114 .3 , 121.2 , 125.1 , 126.4 , 127.7 , 128. 1 , 129.7 , 129. 8, 130 .1 , 134 .8 , 136.5 , 142 . 1 , 156.9 , 168.8 , 169.7

25

III-124 (E) -l-[4-(Diphenyl-methyliden)-piperidin-1-yl]- 3-{2-[2-(3-phenyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

30 The reaction was carried out following the same procedure descri¬ bed for example III-118 using C )-5-{2-[3- (2,3-epoxypro- poxy)-phenyl]-ethenyl}-3-(phenyl)-isoxazole.

Mp.: 155-157°C 35 "C-NMR [CDC1 ₃ ; δ (ppm)]: 31.6, 55.6, 60.8, 66.3, 71.5, 99.1, 112.6, 113.7, 121.0, 124.5, 126.4, 126.6, 127.8, 127.9, 128.8, 129.1, 129.6, 129.9, 130.3, 135.1, 135.9, 142.3, 157.0, 162.5, 169.7

40 III-125 (Z)-l-[4-(Diphenyl-methyliden)-piperidin-1-yl]-

3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 45 bed for example III-118 using the epoxy compound IIIa-15.

"C-NMR [CDCI ₃ ; δ (ppm)] (citrate): 31.8, 55.5, 60.5, 65.6, 65.8,

101.6, 112.1, 115.5, 120.8, 125.2, 126.4, 128.0, 129.8, 130.1,

131.9, 134.8, 136.4, 142.4, 156.2, 161.2, 168.3

5 III-127 (E)-1-[4-(Diphenyl-methyliden)-piperidin-1-yl]-

3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]- 5-N, -diethyl-amino]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 10 bed for example III-118 using epoxide IIIa-13.

"C-NMR [DMSO; δ (ppm)] (citrate): 12.4, 29.1, 43.6, 43.7, 54.0, 57.4, 59.3, 64.9, 70.6, 71.6, 95.2, 98.7, 104.6, 107.6, 111.1,

126.6, 128.2, 129.0, 129.2, 130.1, 136.6, 141.4, 149.5, 158.2, 15 161.3, 170.0, 171.2, 175.9

III-128 (E) -1- [ -(Diphenyl-methyliden)-piperidin-1-yl]-

3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]-4, 5-di- methoxy-phenoxy}-propan-2-ol 20

The reaction was carried out following the same procedure descri¬ bed for example III-118 using epoxide IIIa-12.

Mp.: 149-151°C 25 "C-NMR [CDCI ₃ ; δ (ppm)]: 31.7, 55.5, 56.1, 56.5, 58.5, 60.6,

65.7, 65.9, 72.7, 99.3, 99.6, 109.9, 111.5, 117.0, 126.4, 128.1, 128.2, 129.5, 128.8, 134.6, 136.6, 142.4, 144.0, 151.1, 152.2,

161.7, 169.9

30 III-130 (E)-l-[4-(Diphenyl-methyliden)-piperidin-1-yl]-

3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]-4-nitro- phenox }-propan-2-ol

The reaction was carried out following the same procedure descri- 35 bed for example III-118 using epoxide IIIa-16.

Mp.: 142-144°C

"C-NMR [CDC1 ₃ ; δ (ppm)]: 31.7, 55.5, 58.6, 60.2, 65.4, 71.8,

101.8, 112.1, 116.3, 123.0, 125.6, 126.5, 127.7, 128.1, 129.8, 40 134.5, 136.7, 141.7, 142.3, 161.3, 161.9, 168.3

III-131 (E)-1-[4-(Diphenyl-methyliden)-piperidin-1-yl]-

3-.2-[2-{3-methoxymethyl-isoxazol-5-yl)-ethenyl]- 6-fluoro-phenoxy)-propan-2-ol 45

The reaction was carried out following the same procedure descri¬ bed for example III-118 using epoxide IIIa-14.

Mp: 102-103°C 5 III-132 (_?)-3-{2-[2-(4-Dimethyl-l,3-oxazolin-2-yl)-l-[4-diphenyl- methylidene-piperidin-1-yl]-ethenyl]-phenoxy)-propan-2-ol

The reaction was carried out following the same procedure descri-. bed for example III-118 using epoxide IIIa-11. 10

"C-NMR [CDC1 ₃ ; δ (ppm)] (citrate): 27.8, 27.9, 28.4, 44.8, 55.9,

61.2, 64.4, 66.4, 70.2, 72.8, 79.1, 112.2, 115.9, 121.4, 123.6,

127.2, 128.4, 128.6, 129.4, 131.2, 131.6, 138.6, 139.6, 141.0,

157.2, 163.9, 173.9, 180.0 15

III-133 .£J-l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- piperazin-l-yl]-3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)- l-methyl-ethenyl]-6-fluoro-phenoxy)propan-2-ol

20 The reaction was carried according to example III-l using

10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl-piperazine and ep¬ oxide Illa-17.

"C-NMR [DMSO; δ (ppm)] (citrate): 20.3, 30.9, 43.3, 49.6, 52.6, 25 57.8, 64.8, 64.9, 70.8, 71.7, 77.1, 102.5, 112.6, 114.4, 120.7,

125.5, 127.7, 128.8, 129.4, 130.4, 130.6, 132.4, 138.6, 138.9,

143.6, 151.7, 155.4, 161.1, 168.1, 171.2, 175.7

III-134 f__ -l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- 30 piperazin-l-yl]-3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)- l-methyl-ethenyl]-6-fluoro-phenoxy)-propan-2-ol

The reaction was carried according to example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl-piperazine and ep- 35 oxide IIIa-17.

"C-NMR [CDC1 ₃ ; δ (ppm)]: 26.2, 31.8, 51.9, 53.6, 58.2, 60.4, 65.4, 65.7, 65.9, 70.7, 79.1, 101.8, 112.7, 114.0, 121.5, 125.5,

127.7, 128.7, 129.1, 129.4, 130.1, 130.7, 139.2, 139.7, 144.2, 40 154.8, 160.8, 168.9

III-135 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-1-methyl- ethenyl]-phenoxy}-propan-2-ol 45

The reaction was carried according to example III-l using 4-(di¬ phenyl-methyl)-piperazine and epoxide llla-17.

"C-NMR [DMSO; δ (ppm)] (citrate): 20.3, 43.4, 49.8, 52.7, 57.8, 5 59.7, 64.8, 64.9, 70.8, 71.7, 74.4, 102.5, 112.6, 114.4, 120.7, 126.9, 127.4, 128.5, 128.8, 129.4, 132.4, 142.3, 143.7, 155.4, 161.2, 168.1, 171.2, 175.7

III-137 (E) -l-[4-(Diphenyl-methyliden)-piperidin-1-yl]- 0 3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-l-methyl- ethenyl]-phenoxy}-propan-2-ol

The reaction was carried according to example III-118 using 4-(diphenyl-methyliden)-piperidin and epoxide IIIa-17. 15

"C-NMR [DMSO; δ (ppm)] (citrate): 20.3, 29.4, 43.6, 54.2, 57.8, 59.6, 64.8, 65.1, 70.9, 71.7, 102.6, 112.7, 114.5, 120.8, 126.6, 128.2, 128.9, 129.2, 129.5, 132.6, 136.4, 141.6, 143.7, 155.5, 161.2, 168.2, 171.2, 175.9 20

III-139 (E)-l-[exo-6,7-Diphenyl-3-azabicyclo[3.2.0]hept-3-yl]- 3-{2-[2-(3-methoxy-methyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

25 The reaction was carried according to example III-l using exo-6,7-diphenyl-3-azabicyclo[3.2.0]heptane and epoxide IIla-1.

"C-NMR [DMSO; δ (ppm)] (citrate; mixture of E- and Z-Isomers 7:3): 43.5, 46.2, 46.3, 57.4, 57.6, 57.8, 59.8, 60.0, 60.1, 64.7, 30 64.8, 66.4, 66.6, 70.8, 71.2, 71.8, 101.1, 102.4, 112.3, 112.9, 113.7, 114.6, 120.3, 120.9, 124.0, 124.6, 125.3, 126.4, 127.5, 127.6, 127.9, 128.3, 129.4, 130.2, 130.5, 131.8, 140.6, 140.7, 156.0, 161.0, 161.6, 167.5, 168.8, 171.3, 175.9

35 III-140 (__J-l-[exo-6-(4-Fluor-phenyl)-3-azabicyclo

[3.2.0]hept-3-yl]-3-{2-[2-(3-methoxy-methyl-isoxa- zol-5-yl)-ethenyl]-phenoxy)-propan-2-ol

The reaction was carried according to example III-l using 40 exo-6- (4-fluor-phenyl)-3-azabicyclo[3.2.0]heptane and epoxide IIIa-1.

"C-NMR [CDC1 ₃ ; δ (ppm)] (mixture of E- and Z-Isomers 7:3) : 34.1, 34.2, 37.0, 41.9, 42.2, 45.7, 46.2, 46.3, 57.6, 57.7, 57.8, 57.9, 45 58.4, 58.5, 59.4, 59.5, 61.3, 61.4, 61.5, 65.8, 65.9, 67.3, 70.9, 71.1, 100.2, 101.6, 112.2, 112.6, 13.9, 115.0, 115.2, 115.5, 120.8, 121.2, 124.9, 125.2, 127.7, 127.8, 128., 129.8, 130.1,

130. 3 , 130.4 , 132 .0 , 142 .4 , 156.3 , 157 .0 , 160. 0 , 161.2 , 161.7 ,

162 .4 , 168.3 , 169. 6

III-141 ( ^, _. -l-[exo-6-(4-Fluor-phenyl)-3-azabicyclo 5 [3.2.0]hept-3-yl]-3-{4-[2-(quinolin-2-yl)-ethyl]-phen¬ oxy}-propan-2-ol

The reaction was carried according to example III-l using exo-6-(4-fluor-phenyl)-3-azabicyclo[3.2.0]heptane and epoxide 10 IIIa-3.

Mp: 91-104°C

III-143 (E)-1-[4-Dipheny1-methyl)-piperazin-1-yl]-3-{2-[2-(3-tri- 15 fluoromethyl-isoxazol-5-yl)-ethenyl]-phenoxy)-propan-2-ol

The reaction was carried according to example III-l using 4-(di¬ phenyl-methyl)-piperazine and epoxide IIIa-4.

20 "C-NMR [CDC1 ₃ ; δ (ppm)] : 52.0, 53.6, 60.6, 65.3, 71.1, 76.2, 97.8, 112.6, 112.8, 119.8 (q, J = 271 Hz), 121.3, 124.2, 126.7, 127.9, 128.3, 128.5, 131.0, 132.6, 142.6, 155.7 (q, J = 38 Hz), 157.2, 171.7

25 III-144 (_.)-l-[4-(10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)- piperazin-l-yl]-3-{2-[2-(3-trifluoromethyl-isoxa- zol-5-yl)-ethenyl]-phenoxy)-propan-2-ol

The reaction was carried according to example III-l using 30 10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl-piperazine and ep¬ oxide IIIa-4.

"C-NMR [CDC1 ₃ ; δ (ppm)] (citrate): 31.7, 51.9, 53.2, 60.5, 65.3, 71.0, 79.0, 97.8, 112.6, 112.8, 119.8 (q, J = 276 Hz), 121.3, 35 124.2, 125.5, 127.5, 128.3, 130.8, 131.0, 132.6, 139.1, 139.7, 156.0 (q, J = 52 Hz), 157.2, 171.7

III-145 (E)-1-[Bis(4-fluorophenyl)-methyl-piperazin-1-yl]-

3-{2-[2-(3-isopropyl-isoxazol-5-yl)-ethenyl]-phenoxy}- 40 propan-2-ol

The reaction was carried out according to example III-l using bis(4-fluoro-phenyl)-methyl-piperazine and C_-)-5-{2-[2- (2,3-epoxypropoxy)-phenyl]-ethenyl}-3-(isopropyl)-isoxazole. 45

"C-NMR [CDC1 ₃ ; δ (ppm) ] (citrate) : 21.7, 26.5, 44.2, 48.2, 60.8, 65.8, 71.0, 73.4, 100.1, 112.7, 113.6, 115.7,115.9, 124.5, 126.9, 128.5, 129.0, 129.3, 156.0, 160.6, 161.9 168.2 (J = 244 Hz) , 169.8, 173.9, 178.6 5

III-146 (E)-1-[4- (2-Hydroxy-3-{2-[2-(3-isopropyl-isoxazol-5-yl)- ethenyl]-phenox }-propyl)-piperazin-1-yl]-2,2-diphenyl- ethanone

10 The reaction was carried out according to example III-l using 2,2-diphenyl-acetyl-piperazine and (E)-5-{2- [2-(2,3-epoxypro- pox )-phenyl]-ethenyl}-3-(isopropyl)-isoxazole.

¹³ C-NMR [DMSO; δ (ppm)] (citrate): 21.4, 25.8, 41.6, 45.4, 52.6, 15 53.1, 53.4, 60.8, 66.4, 71.3, 99.9, 112.6, 113.9, 120.6, 123.9, 126.5, 127.6, 128.1, 128.8, 128.9, 130.3, 140.1, 156.6, 168.1, 169.2, 169.3

III-147 (£)-l-[4-(10,ll-Dihydro-5H-dibenzo[a,d]cyclohep-

20 ten-5-yl)-piperazin-l-yl]-3-{2-[2-(3-methoxy-isoxa- zol-5-yl)-ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out according to example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperazine and ep- 25 oxide IlIa-5.

¹³ C-NMR [CDC1 ₃ ; δ (ppm)] : 31.7, 51.9, 53.8, 56.9, 60.5, 65.3, 71.0, 79.1, 91.8, 112.5, 114.3, 121.2, 124.8, 125.5, 127.7, 127.8, 130.0, 130.2, 130.7, 130.8, 139.2, 139.7, 156.9, 169.8, 30 172.6

III-148 (Z)-l-[4-(10,ll-Dihydro-5H-dibenzo[a,d]cyclohep- ten-5-yl)-piperazin-1-yl]-{2-[2-(3-methoxy-isoxa- zol-5-yl)-ethenyl]-phenoxy}-propan-2-ol 35

¹³ C-NMR [CDCI ₃ ; δ (ppm)] : 31.8, 51.9, 53.8, 56.9, 60.4, 65.3, 70.8, 79.1, 93.2, 112.1, 116.1, 120.8, 125.1, 125.5, 127.7, 127.8, 129.7, 130.7, 130.8, 132.0, 139.2, 139.7, 156.1, 168.5, 172.2 40

III-149 (E) -l- [ (4-Dipheny1-methyl)-piperazin-1-yl)]-

3-{2-[2-(3-methoxy-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

45 The reaction was carried out according to example III-l using 4- (diphenyl-methyl)-piperazine and epoxide IIIa-5.

¹³ C-NMR [CDC1 ₃ ; δ (ppm)] : 52.0, 5.6, 56.9, 60.7, 65.4, 71.0, 76.2, 91.8, 112.5, 114.3, 121.2, 124.8, 127.0, 127.8, 127.9, 128.5, 130.1, 130.3, 142.7, 156.9, 169.8, 172.6

5 III-150 ( Z) -l- l (4-Dipheny1-methyl)-piperazin-l-yl)- 3-{2-[2-(3-methoxy-isoxazol-5-yl)-ethenyl]- phenoxy}-propan-2-ol

¹³ C-NMR [CDC1 ₃ ; δ (ppm)] : 52.0, 53.6, 56.9, 60.5, 65.4, 70.8, 10 76.2, 93.2, 112.1, 116.1, 120.8, 125.2, 127.0, 127.8, 127.9, 128.5, 129.7, 132.0, 142.7, 156.1, 168.5, 172.2

III-151 (£.-1-[4-(Diphenyl-methylidene)-piperidin-l-yl]-

3-{2-[2-(5-methoxy-methyl-isoxazol-3-yl)-ethenyl]-phen- 15 oxy}-propan-2-ol

The reaction was carried out according to example III-118 using epoxide IlIa-5.

20 ¹³ C-NMR [CDCI ₃ ; δ (ppm)]: 31.7, 55.4, 58.9, 60.6, 65.4, 65.7, 71.2, 99.9, 112.6, 116.6, 121.3, 125.2, 126.4, 127.5, 128.0, 129.8, 130.0, 131.1, 134.8, 136.4, 142.4, 156.6, 162.3, 168.9

III-152 (J?)-3-{2-[2-(3,5-Dimethyl-isoxazol-4-yl)-ethenyl]-phen- 25 oxy}-l-[4-diphenyl-methylidene-piperidin-l-yl]- propan-2-ol

The reaction was carried out according to example III-118 using (E)—i-{2- [2- (2,3-epoxypropoxy)-phenyl]-ethenyl)-3, 5-dimethyl- 30 isoxazole.

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 11.7, 11.9, 31.7, 55.6, 60.8, 65.7, 70.9, 112.4, 113.6, 116.9, 121.2, 125.0, 126.2, 126.5, 126.6, 128.1, 128.8, 129.7, 134.6, 136.6, 142.3, 155.9, 158.3, 165.4 35

III-153 (E)-1-[exo-6,7-Diphenyl-3-azabicyclo[3.2.0] ept-3-yl]- 3-{2-[2-(3-isopropyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

40 The reaction was carried out according to example III-l using exo-6,7-diphenyl-3-azabicyclo[3.2.0]heptane and (E)-5-{2- [2- (2,3- epoxypropoxy)-phenyl]-ethenyl}-3-(isopropyl)-isoxazole.

45

¹³ C-NMR [DMSO; δ (ppm)] (citrate): 21.4, 25.8, 39.3, 39.7, 43.3, 46.0, 46.1, 57.5, 59.8, 60.1, 66.2, 68.5, 71.9, 100.1, 112.8,

114.0, 121.0, 124.0, 125.4, 127.5, 127.9, 128.3, 128.6, 128.7, 130.4, 140.4, 140.5, 156.4, 168.1, 169.2, 171.3, 175.6

5

III-154 ( E)-1-[exo-(6-tert.Buty1-phenyl)-3-azabicyclo

[3.2.0]hept-3-yl]-3-{2-[2-(5-methoxymethyl-isoxa- zol-3-yl)-ethenyl]-phenoxy}-propan-2-ol

10 The reaction was carried out according to example III-l using exo- (6-tert.butyl-phenyl)-3-azabicyclo[3.2.0]heptane and epoxide IIIa-7.

¹³ C-NMR [CDC1 ₃ ; δ (ppm)] (citrate): 31.4, 34.4, 44.5, 58.7, 58.9, 15 65.7, 65.9, 70.5, 73.1, 100.3, 112.7, 117.0, 121.5, 124.7, 125.5,

126.1, 128.5, 130.3, 131.9, 140.8, 149.4, 156.3, 162.2, 169.1, 174.1, 179.3

III-155 (E)-1-[4-(2,2-Diphenyl-acetyl)-piperazin-1-yl]- 20 3-{2-[2-(3-trifluoromethyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2ol

The reaction was carried out according to example III-l using 2,2-diphenyl-acetyl-piperazine and epoxide Illa-7.

25

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 42.2, 46.0, 53.2, 54.9, 60.5, 65.7, 70.9, 97.9, 112.6, 119.8 (q, J = 270Hz) , 121.4, 124.2, 127.1, 128.1, 128.6, 129.0, 131.0, 132.4, 139.3, 155.6 (q, J = 31Hz) , 157.1, 170.3, 171.6

30

III-156 (E)-l-[Bis(4-fluorophenyl)-methyl-piperazin-1-yl]-

3-{2-[2-(3-trifluoromethyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2ol

35 The reaction was carried out according to example III-l using bis(4-fluorophenyl)-methyl-piperazine and epoxide IIIa-7.

Mp.: 65-67°C

40 III-157 (E)-l-[4-(2,2-Diphenyl-acetyl)-piperazin-l-yl]-

3-{2-[2-(2-methylmethoxy-l,3-thiazol-4-yl)-ethenyl]-phen� � oxy}-propan-2-ol

The reaction was carried out according to example III-l using 45 2,2-diphenyl-acetyl-piperazine and epoxide IIIa-8.

Mp . : 89-90°C (citrate)

III-158 (E)-1-[10, ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)- piperazin-1-yl]-3-{2-[ (2-methoxymethyl-l,3,4-thia- 5 diazol-5-yl)-ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure as des¬ cribed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cy- clohepten-5-yl)-piperazine and epoxide IIIa-18. 0

Mp.: 100-102°C (the compound starts sintering from 80°C on)

III-159 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-3-{2-[ (2-meth- oxymethyl-1,3,4-thiadiazol-5-yl)-ethenyl]-phenoxy}- 5 propan-2-ol

The reaction was carried out following the same procedure as des¬ cribed for example III-l using 4-(diphenyl-methyl)-piperazine and epoxide IIIa-18. 0

¹³ C-NMR (DMSO; δ (ppm)] (citrate): 43.6, 50.2, 53.0, 58.2, 60.0, 65.3, 67.8, 71.2, 71.6, 74.5, 112.7, 118.2, 120.9, 123.5, 126.9, 127.1, 127.4, 127.5, 128.0, 128.5, 128.6, 131.0, 133.9, 141.7, 142.4, 151.7, 156.6, 166.7, 168.7, 171.2, 175.9 5

III-160 CJ?;-l-[4-(2,2-Diphenyl-acetyl)-piperazin-l-yl]-

3-{2-[ (2-methoxymethyl-l,3,4-thiadiazol-5-yl)-ethenyl]- phenoxy}-propan-2-ol

30 The reaction was carried out following the same procedure as des¬ cribed for example III-l using 2,2-diphenyl-acetyl-piperazine and epoxide IIIa-18.

¹³ C-NMR (CDC1 ₃ ; δ (ppm)] (citrate): 42.2, 46.0, 53.1, 53.2, 54.9, 35 59.0, 60.6, 69.0, 70.8, 112.6, 119.0, 121.8, 124.5, 127.1, 128.2, 128.6, 129.0, 130.8, 134.6, 139.4, 156.8, 166.7, 169.8, 170.3

III-161 .Z)-l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)- piperazin-1-yl]-3-{2-[ (2-methoxymethyl-l,3,4-thiadiazol- 40 5-yl)-ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure as des¬ cribed for example III-l using 10, ll-dihydro-5H-dibenzo[a,d]cy- clohepten-5-yl)-piperazine and epoxide IIIa-18. 45

¹³ C-NMR (DMSO;,. δ (ppm)] (citrate) : 30.9, 43.4, 49.5, 52.5, 58.2, 64.6, 67.6, 70.6, 71.8, 77.1, 112.7, 120.9, 123.9, 125.5, 127.8, 129.7, 130.4, 130.6, 135.1, 138.6, 139.0, 155.7, 164.6, 167.1, 171.3, 175.7 5

111-162 .-TJ-l-[4-(Diphenyl-methylidene)-piperidine-1-yl]- > 3-{2-[2-(3-trifluoromethyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

10 The reaction was carried out following the same procedure as des¬ cribed for example III-118 using epoxide IIIa-4.

¹³ C-NMR (CDC1 _3; δ (ppm)]: 31.7, 55.6, 60.6, 65.5, 71.1, 97.8, 112.7, 119.8 (q, J = 270Hz) , 121.3, 126.5, 128.2, 128.3, 129.4, 15 129.8, 131.0, 132.6, 134.5, 136.6, 142.3, 155.5 (q, J = 36Hz) , 157.2, 171.7

111-164 (E)-l-[4-(Diphenyl-methylidene)-piperidine-1-yl]- 3-{2-[ (2-methoxymethyl-l,3,4-thiadiazol-5-yl)- 20 ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure as des¬ cribed for example III-118 using and epoxide llla-18.

25 Mp.: 130-132°C

III-165 (E)-l-[4-(Diphenyl-methylidene)-piperidin-l-yl]-

3-{2-[ (3-methoxymethyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2-ol 30

The reaction was carried out following the same procedure as des¬ cribed for example III-118 using and epoxide Illa-l.

Mp.: 90-91°C 35

III-166 fZ)-l-[4-(Diphenyl-methylidene)-piperidin-1-yl]-

3-{2-[ (3-methoxymethyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan-2-ol

40 The reaction was carried out following the same procedure as des¬ cribed for example III-118 using and the crude epoxide IIIa-15.

¹³ C-NMR (DMSO; δ (ppm)] (citrate): 33.3, 43.5, 45.4, 51.0, 58.5, 60.7, 64.2, 65.6, 70.3, 73.4, 101.8, 112.1, 115.6, 121.0, 124.9, 45 126.7, 129.0, 129.7, 130.2, 131.9, 155.4, 161.2, 168.2, 175.6, 179.9

III-171 r_- -l- [4- ( 10 , ll-Dihydro-dibenzo [a, d] cyclohepten-

5-yliden)-piperidin-1-yl]-3-{2-[2-(3-methylmethoxy- isoxazol-5-yl)-ethenyl]-phenoxy}-propan-2-ol

5 The reaction was carried out following the same procedure as des¬ cribed for example III-l using 4-(10,ll-dihydro-dibenzo[a,d]cy- clohepten-5-yliden)-piperazine and epoxide IIIa-1.

¹³ C-NMR (CDC1 ₃ ; δ (ppm)]: 31.0, 31.1, 32.5, 54.8, 55.9, 58.5, 10 60.6, 65.6, 65.9, 71.0, 100.2, 112.5, 113.9, 121.2, 124.9, 125.5, 126.9, 127.9, 128.8, 129.3, 130.3, 130.4, 133.6, 135.1, 138.0, 140.7, 157.0, 161.7, 169.6

III-179 (E)-l-[4-(10,11-Dihydro-dibenzo[a,d]cyclohepten- 15 5-yliden)-piperidin-1-yl]-3-{2-[2-(2-methoxymethy1- 1,3-thiazol-4-y1)-ethenyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure as des¬ cribed for example III-l using 4-(10,ll-dihydro-dibenzo[a,d]cy- 20 clohepten-5-yliden)-piperazine and epoxide IIIa-8.

¹³ C-NMR (CDCI ₃ ; δ (ppm)]: 30.9, 31.0, 32.5, 54.9, 56.0, 59.0, 60.6, 65.9, 71.1, 71.6, 112.5, 115.0, 121.1, 122.1, 125.5, 126.9, 127.2, 128.1, 128.8, 129.3,, 133.7, 134.9, 137.9, 140.6, 154.7, 25 156.4, 168.7

IV-1 (E)-l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)-ethenyl]-phen¬ oxy}-propan

30 a) 1.13g of sodium hydride (60% in mineral oil) were washed with pentane to remove the mineral oil, and dry dimethylformamide (30ml) was added. 4g of (E)-5-[{2-hydroxy-phenyl]-ethenyl}- 3-(methoxymethyl)-isoxazole -dissolved in 20ml of dimethylform-

35 amide- were added slowly through a dropping funnel ^' , and after gas evolution had ceased the mixture was stirred for another 15min. at 40°C. After cooling to 4°C 6.95g of 1,3-dibromopropane were ad¬ ded slowly. The mixture was stirred at room temperature until the reaction was finished.

40

Afterwards the reaction mixture was diluted with cold water, ex¬ tracted with ethyl acetate, the organic phase washed with satura¬ ted sodium chloride solution and then dried with magnesium sul¬ fate. Evaporation of the solvent and chromatography on silica gel

45 afforded 4.3g of C_?;-3-{2-[2-(3-methoxymethyl-isoxazol-5-yl)- ethenyl]-phenoxy}-propanylbromide as oil.

b) 1.2g of 4-(diphenyl)-methyl-piperazine, lg of the above men¬ tioned bromide and 0.3ml N-methylmorpholine were refluxed in 10ml ethanol. After the reaction was finished the solvent was evapora¬ ted and the crude product purified by chromatography on silica- 5 gel. The pure product was obtained as an oily residue which was precipitated as corresponding citrate.

"C-NMR [DMSO; δ (ppm)] (citrate): 24.7, 43.5, 49.7, 52.0, 53.7, . 57.8, 64.8, 65.8, 71.7, 74.2, 101.1, 112.6, 113.6, 120.8, 123.7, 10 126.9, 127.5, 127.6, 128.5, 129.1, 130.5, 142.2, 156.3, 161.5, 168.4, 171.2, 175.7

IV-2 (£J-l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- piperazin-1-yl]-3-{2-[2-(3-methoxymethyl-isoxazol- 15 5-yl)-ethenyl]-phenoxy}-propan

The reaction was carried out following the same procedure descri¬ bed for example IV-1 using 10,ll-dihydro-5H-dibenzo[a,d]cyclohep- ten-5-yl-piperazine and (E) -3-{2- [2-(3-methoxymethyl-isoxa- 20 zol-5-yl)-ethenyl]-phenoxy}-propanylbromide.

¹³ C-NMR [DMSO; δ (ppm)] (citrate): 24.7, 30.9, 38.8, 43.5, 49.7, 52.0, 53.5, 57.8, 64.8, 71.7, 101.2, 112.6, 113.6, 120.1, 123.7, 125, 5, 127.6, 127.8, 129.1, 130.4, 130.5, 130.6, 138.6, 139.0, 25 156.3, 161.5, 168.6, 171.2, 175.7

IV-3 (E)-l-[4-(Diphenyl-methyli¬ den)-piperidin-1-yl]-3-{2-[2-(3-methoxymethy1-isoxa- zol-5-yl)-ethenyl]-phenoxy}-propan

30

The reaction was carried out following the same procedure descri¬ bed for example IV-1 using 4-(diphenyl-methyliden)-piperidine- hydrochloride, (E) -3-{2- [2-(3-methoxymethyl-isoxazol-5-yl)- etheny1]-phenoxy}-propanylbromide.

35

Mp.: 205-207°C (hydrochloride)

"C-NMR [DMSO; δ (ppm)] (hydrochloride): 23.5, 27.8, 52.3, 52.9, 57.8, 64.8, 65.4, 101.3, 112.6, 113.8, 123.7, 126.9, 127.6, 40 128.3, 129.1, 130.5, 137.8, 141.1, 156.1, 161.5, 168.6

V-l 1-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- piperazin-1-yl]-3-{2-[ (3-methoxymethyl-isoxa- zol-5-yl)-methoxy]-phenoxy)-propan-2-ol 45

The reaction was carried out following the same procedure descri¬ bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and 5-{ [2-(2,3-epoxypropoxy)-phenyl]- methoxy}-3-(methoxymethyl)-isoxazole.

Mp.: 99.5-102°C

¹³ C-NMR [CDC1 ₃ ; δ (ppm)]: 31.8, 52.0, 53.7, 58.5, 60.4, 63.2, 65.7, 72.0, 79.1, 102.6, 115.0, 116.6, 121.7, 123.2, 125.5, 127.7, 130.7, 139.2, 139.7, 147.8, 149.7, 161.4, 168.7

V-2 1-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]- piperazin-1-yl]-3-{2-[ (3-methoxymethyl-isoxazol- 5-yl)-methoxymethyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and 5-{ [2-(2,3-epoxypropoxy)-phenoxy]- methoxymethyl}-3-(methoxymethyl)-isoxazol (precursor Va-1) .

Mp.: 145-146°C (hydrochloride)

iH-NMR [CDC1 ₃ ; δ (ppm)] (hydrochloride): 2.20-2.63 (m, 10H) , 2.72-2.88 (m, 3H) , 3.39 (s, 3H) , 3.45-3.60 (m, 2H) , 3.78-4.08 (m, 4-5H) , 4.55 (s, 2H) , 4.65 (s, 2H) , 5.17 (s, 2H) , 6.38 (s, IH) , 6.88-7.45 (m, 12H)

V-3 l-[4- (Diphenyl-methyl)-piperazin-l-yl]-3-{2-[ (3-methoxy- methyl-isoxazol-5-yl)-methoxymethyl) ]-phenoxy}-propan- 2-ol

The reaction was carried out according to example III-l using 4- (diphenyl-methyl)-piperazine and precursor Va-1.

Mp.: 123-125°C (oxalate)

iH-NMR [DMSO; δ (ppm)] (oxalate): 2.40-2.75 (m, 8H) , 3.05-3.35 (m, 7H) , 3.35-3.55 (m, 2H) , 4.10 (m, IH) , 4.44 (s, IH) , 4.49 (s, 2H) , 4.52 (s, 2H) , 5.35 (s, 2H) , 6.65 (s, IH) , 7.0 (m, IH) , 7.10-7.48 (m, 13H)

V-4 l-[4- (Diphenyl-methyl)-piperazin-l-yl]-3-{2-[ (3-methoxy- methyl-isoxazol-5-yl)-methoxy]-phenoxy)-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(diphenyl-methyl)-piperazine and 5-{ [2-(2,3-epoxypropoxy)-phenyl]-methoxy}-3-(methoxymethyl)-iso ¬ xazole. 5

Mp.: 117.5-119°C

"C-NMR [CDClj; δ (ppm)]: 52.0, 53.6, 58.5, 60.5, 63.2, 65.7, 72.0, 76.2, 102.6, U5.0, 116.6, 121.7, 123.2, 127.0, 128.0, 10 142.7, 147.9, 149.7, 161.4, 168.7

V-5 1-[4-(Cyclohexyl-phenyl)-methy1-piperazin-l-yl]-

3-{2-[ (3-methoxymethyl-isoxazol-5-yl)-methoxy]-phen¬ oxy}-propan-2-ol

15

The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(cyclohexyl-phenyl)-methyl-pipera¬ zine and 5-{ [2-(2,3-epoxypropoxy)-phenyl]-methoxy}-3-(methoxy¬ methyl)-isoxazole.

20

¹³ C-NMR [DMSO; δ (ppm)] (citrate) : 25.4, 25.5, 26.3, 29.5, 29.6,

30.4, 36.4, 43.7, 46.6, 52.9, 57.9, 59.5, 61.4, 64.6, 64.7, 71.4,

71.5, 73.4, 103.5, 114.5, 115.5, 121.2, 122.4, 126.8, 127.7, 129.0, 136.3, 147.1, 148.6, 151.8, 161.1, 168.2, 171.2, 176.2

25

V-6 l-[4-Diphenyl-methyl-piperazin-l-yl]-3-{2-[ (3-methyl-iso- xazol-5-yl)-methoxy]-phenoxy)-propan-2-ol

The reaction was carried out following the same procedure descri- 30 bed for example III-l using 4-(diphenyl)-methyl-piperazine and 5-{ [2- (2,3-epoxypropoxy)-phenyl]-methoxy}-3-(methoxymethyl)-iso¬ xazole.

Mp: 102-105°C (hydrochloride)

35

V-53 1-[4- (Diphenyl-methyliden)-piperidin-1-yl]-

3-{2-[ (3-methoxymethyl-isoxazol-5-yl)-methoxy¬ methy1]-phenoxy}-propan-2-ol

40 The reaction was carried out following the same procedure descri¬ bed for example III-118 using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and precursor Va-1.

¹³ C-NMR [CDC1 ₃ ; δ (ppm)] (citrate): 31.7, 55.5, 58.6, 60.6, 61.7, 45 65.7, 66.4, 68.2, 73.2, 102.5, 111.7, 121.9, 126.4, 127.5, 128.0, 128.8, 129.4, 129.8, 135.1, 136.2, 142.5, 155.4, 161.5, 168.4

V-54 l-[4-(Diphenyl-methyliden)-piperidin-1-yl]-3-{2-[3-meth- oxymethyl-isoxazole-5-yl-methoxy]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri- 5 bed for example III-118 using 5-{ [2-(2,3-epoxypropoxy)-phenyl]- methoxy}-3-(methoxmethyl)-isoxazole.

"C-NMR [CDC1 ₃ ; δ (ppm)] (citrate): 31.7, 55.5, 58.6, 60.6, 61.7, - 65.7, 66.4, 68.2, 73.2, 102.5, 111.7, 121.9, 126.4, 127.5, 128.0, 10 128.8, 129.4, 129.8, 135.1, 136.2, 142.5, 155.4, 161.5, 168.4

VI-1 (3-{2-[2-(4,5-Dimethyl-l,3-oxazol-2-yl)-ethyl]-phen- oxy}-l-(4-diphenyl-methyl-piperazin-l-yl)-propan-2-ol

15 3ml of a IN solution of tetrabutylammonium fluoride in tetra¬ hydrofuran were added to a solution of 1 g of 2-[2-(2-tert.butyl- dimethy1siloxy-phenyl)-ethyl]-4, 5-dimethyl-oxazole in 20 ml tetrahydrofuran. After stirring for 3h the reaction mixture was given into 20ml 0.1 N HCl and the solution extracted with ether.

20 After drying over sodium sulfate the solvent was removed in va- cuo. The residue was dissolved in 20 ml butanol. 0.4g potassium carbonate and 0.92g 4-diphenylmethyl-l-(2,3-epoxypropyl)- piperazine were added and the mixture refluxed for 2 hours. The solvent was removed in vacuo, the residue dissolved in saturated

25 ammonium chloride and extracted with ethyl acetate. After drying of the organic phase over sodium sulfate the solvent was removed in vacuo and the residue purified by flash chromatography to give 0.66g of (3-{2-[2-(4,5-dimethyl-l,3-oxazol-2-yl)-ethyl]-phenoxy}- 1- (4-diphenylmethyl-piperazin-l-yl)-propan-2-ol. The correspon-

30 ding citrate was obtained by treatment of a solution of the alco¬ hol with citric acid.

¹³ C-NMR [CDCI3; δ (ppm)] (citrate): 9.8, 10.4, 28.1, 28.6, 44.5, 48.6, 53.4, 60.3, 64.5, 69.8, 72.9, 75.2, 111.5, 121.2, 127.6, 35 127.8, 128.0, 128.5, 128.9, 129.2, 130.0, 141.1, 143.0, 156.1, 162.3, 173.6, 179.2

VII-6 l-[ (4-Diphenyl-methyl-piperazin-l-yl]-3-{2-[ (3-methyl- isoxazol-5-yl)-ethinyl]-phenoxy]-propan-2-ol

40

3.9ml of a IN tetrabutylammonium fluoride in tetrahydrofuran were added to a solution of l.lg of 2-(3-methyl-isoxazol-5-yl-ethi- nyl)-pheny1-tert.butyldimethylsilyl-ether (precursor VJJc) in 10ml of tetrahydrofuran. After stirring at room temperature over-

45 night the solution was poured into IN HCl, then extracted with ethylacetate. After drying the organic phase and evaporation of the solvent the residue was dissolved in acetonitrile. Then 0.6g

of potassium carbonate and 0.6g of epibromohydrine were added and the reaction mixture refluxed for 2h. 'After cooling the salts were filtered off, the filtrate evaporated, the obtained residue dissolved in ethylacetate and washed with water. The organic 5 phase was dried over magnesium sulfate. After evaporation of the solvent the residue was dissolved in anhydrous ethanol, l.lg of diphenylmethyl-piperazine added and refluxed for 2h. After coo¬ ling and evaporation of the solvent the residue was purified by - chromatography on silica gel to give 0.36g of the product. 10

"C-NMR [CDC1 ₃ ; δ (ppm)] 11.4, 51.9, 53.6, 60.4, 65.5, 71.0, 76.2, 79.7, 94.8, 108.2, 110.9, 112.5, 121.0, 126.9, 127.9, 128.5, 131.4, 133.4, 142.7, 153.5, 159.8

15 VIII-I l-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)- piperazin-l-yl]-3-{2-[ (3-methoxymethyl-isoxazol- 5-yl)-carbonyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure as des- 20 cribed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cy- clohepten-5-yl)-piperazine and epoxide Vllla-l.

"C-NMR (DMSO; δ (ppm)] (citrate): 30.9, 43.0, 48.9, 58.0, 63.9, 64.5, 70.6, 79.0, 109.1, 113.2, 120.9, 125.5, 126.4, 127.8, 25 129.7, 130.4, 130.6, 134.0, 138.4, 140.0, 156.7, 162.0, 166.2, 171.2, 175.0, 182.3.

VIII-2 l-[4- (Diphenyl-methyl)-piperazin-l-yl]-3-{ [2-(3-methoxy- methyl-isoxazol-5-yl)-carbonyl]-phenoxy}-propan-2-ol 30

The reaction was carried out following the same procedure as des¬ cribed for example III-l using 4-(diphenylmethyl)-methyl-pipera¬ zine and epoxide VTIla-1.

35 "C-NMR (DMSO; δ (ppm)] (citrate): 43.4, 49.8, 52.6, 58.0, 59.3, 64.5, 64.6, 70.8, 71.7, 74.4, 109.0, 113.2, 120.8, 126.4, 126.9, 127.4, 128.5, 129.6, 134.0, 142.3, 156.8, 161.9, 166.2, 171.2, 175.6, 182.4

40 VIII-3 l-[ (2,2-Diphenyl-acetyl)-piperazin-l-yl]-

3-{2-[ (3-methoxymethyl-isoxazol-5-yl)-carbonyl]-phen¬ oxy}-propan-2-ol

The reaction was carried out following the same procedure as des- 45 cribed for example III-l using 2,2-diphenyl-acetyl-piperazine and epoxide VTIIa-1.

"C-NMR (DMSO; δ (ppm)] (citrate): 41.0, 42.8, 44.8, 52.5, 52.6, 52.9, 58.0, 59.9, 64.5, 65.5, 71.0, 72.1, 108.9, 113.1, 120.7, 126.5, 128.0, 128.8, 129.6, 134.0, 140.0, 157.0, 161.9, 166.3, 169.4, 171.2, 174.9, 182.5 5

VIII-5 1-[4-(Diphenyl-methyliden)-piperidin-1-yl]-

3-{ [2-(3-methoxymethyl-isoxazol-5-yl)-carbonyl]-phen¬ oxy}-propan-2-ol

10 The reaction was carried out following the same procedure as des¬ cribed for example III-l using 4- (diphenyl-methyliden)-piperidine and epoxide Vllla-1.

"C-NMR (DMSO; δ (ppm)] (citrate): 29.1, 43.4, 53.9, 58.0, 59.0, 15 64.4, 64.5, 70.7, 71.7, 109.1, 113.2, 120.8, 126.4, 126.6, 128.2, 129.2, 129.7, 134.0, 136.5, 141.4, 151.8, 156.7, 162.0, 166.2, 171.2, 175.7, 182.3

VIII-25 l-[2-{3-[4-(10,ll-Dihydro-dibenzo[a,d]cyclohepten-5-yl)- 20 piperazin-1-yl]-2-hydroxy-propoxy}-phenyl]-3-phenyl-pro- pan-1-one

The reaction was carried out according to example III-l using 10,11-dihydro-dibenzo[a,d]cyclohepten-5-yl)-piperazine and 25 1-[2-(2,3-epoxypropoxy)-phenyl]-propan-1-one.

"C-NMR (CDC1 ₃ ; δ (ppm)]: 30.2, 31.8, 51.9, 60.8, 65.1, 70.8, 79.0, 112.6, 121.0, 125.5, 125.9, 127.7, 128.2, 128.4, 130.5, 130.7, 133.5, 139.1, 139.2, 139.6, 141.6, 157.8, 201.1 30

VIII-26 l-[2-{3-[4- (Diphenyl-methyl)-piperazin-1-yl]-2-hydroxy- propoxy}-phenyl]-3-phenyl-propan-l-one

The reaction was carried out according to example III-l using 35 4-(diphenyl-methyl)-piperazine and l-[2-(2,3-epoxypropoxy)- phenyl]-propan-1-one.

"C-NMR (CDCI ₃ ; δ (ppm)]: 30.3, 45.7, 52.9, 53.4, 60.8, 65.2, 70.9, 76.1, 112.6, 121.0, 125.9, 127.0, 127.9, 128.3, 128.4, 40 128.5, 130.5, 133.5, 141.7, 142.6, 142.7, 157.8, 201.2

VIII-27 l-[2-{3-[4-Bis(4-fluorophenyl-methyl)-piperazin-

1-yl]-2-hydroxy-propoxy}-phenyl]-3-phenyl-propan-l-one

45

The reaction was carried out according to example III-l using bis (4-fluorophenyl)-methyl-piperazine and 1-[2-(2,3-epoxypro- poxy)-phenyl]-propan-1-one.

5 "C-NMR (CDC1 ₃ ; δ (ppm)]: 30.3, 45.6, 51.8, 53.4, 60.7, 65.3, 70.9, 74.4, 112.7, 115.4 (d, J = 20Hz) , 121.1, 125.9, 128.4, 129.3, 130.4, 133.4, 138.1, 141.7, 157.8, 161.8 (d, J = 245Hz) , 201.2

10 VIII-68 l-[2-{3-[4-(2,3,4-Trimethoxyphenyl)-methyl)-piperazin-

1-yl]-2-hydroxy-propoxy}-4,5-dimethoxy-pheny1]-3-phenyl- propan-1-one

5.2g of 2-[ (2,3-epoxypropoxy)-4,5-dimethoxy]-3-phenyl-propanone 15 (epoxide VlIIa-2) and 6.7g of 4-(2,3,4-trimethoxypheny1)-methyl)- piperazine were refluxed in 60ml of isopropanol. After the reaction was completed the solvent was evaporated and the obtai¬ ned residue purified by cromatography on silica gel yielding 8.8g of pure product. 20

Mp.: 217-218°C

"C-NMR [CDC1 ₃ ; δ (ppm)]: 30.5, 45.8, 53.0, 56.0, 56.5, 60.8, 61.2, 65.3, 71.8, 97.7, 107.0, 112.6, 119.8, 124.1, 125.8, 128.4, 25 128.5, 142.1, 143.3, 152.7, 153.0, 153.8, 154.4, 198.6

According to the preparation of compound VIII-68 the following compounds were prepared:

30 VIII-69 l-[2-{3-[4-(Diphenyl-methyl)-piperazin-l-yl]-2-hydroxy- propoxy}-4, 5-dimethoxy-pheny1]-3-phenyl-propan-l-one

Mp.: 149-150°C

35 VIII-70 l-[2-{3-[4-(2,2-Diphenyl-acetyl)-piperazin-l-yl]- 2-hydroxy-propoxy}-4,5-dimethoxy-pheny1]-3-phenyl- propan-1-one

Mp.: 128-129°C 40

VIII-73 l- [2-{3- [4-Bis (4-fluorophenyl)-methyl) -piperazin-l-yl] - 2-hydroxy-propoxy }-4 , 5-dimethoxy-pheny 1 ] -3-phenyl-pro- pan-1-one

45 Mp . : 152-153°C

VIII-81 l- [2-{3- [4- (4-Trifluoromethyl-phenyl) -piperazin-l-yl] - 2-hydroxy-propoxy}-4 , 5-dimethoxy-pheny 1 ] - 3 -phenyl -pr o- pan-1-one

5 Mp . : 140-142°C

VIII-86 1-[2-{3-[4-(3,4,5-Trimethoxy-phenyl)-piperazin-1-yl]- 2-hydroxy-propoxy}-4,5-dimethoxy-pheny1]-3-phenyl-pro- pan-1-one 0

Mp.: 148-149°C

VIII-97 l-[2-{3-[4-(4-tert.Butylphenyl)-methyl]-piperazin-1-yl]- 2-hydroxy-propoxy}-4,5-dimethoxy-phenyl]-3-pheny1-pro- 5 pan-1-one

Mp.: 120-121°C

VIII-98 1-[2-{3-[4-(3,4-Methylendioxy-phenyl)-methyl]- 0 piperazin-1-yl]-2-hydroxy-propoxy}-4,5-dimethoxy- phenyl]-3-phenyl-propan-l-one

Mp.: 129-130°C

25 Vlll-99 1-[2-{3-[10,ll-Dihydro-5H-dibenzo[a,d]-cycloheρten-5-yl]- piperazin-1-yl]-2-hydroxy-propoxy}-4,5-dimethoxy-phenyl]- 3-pheny1-propan-1-one

"C-NMR [DMSO; δ (ppm)] (citrate): 197.6, 175.6, 171.2, 154.1, 30 153.7, 142.6, 141.6, 139.0, 138.6, 130.4, 128.2, 128.0, 127.8, 125.5, 125.4, 118.0, 112.0, 98.4, 77.1, 71.8, 64.8, 59.8, 55.9, 52.3, 49.7, 44.9, 43.4, 30.9, 29.9

VIII-1001-[2-{3-[4-(3,4,5-Trimethoxyphenyl)-methyl]- 35 piperazin-1-yl]-2-hydroxy-propoxy}-4,5-dimethoxy- phenyl]-3-phenyl-propan-l-one

Mp.: 126-127 ⁰ C

40 VIII-109 l-[2-{3-[2-(2,3-Dimethoxy-phenyl)-ethyl]-piperazin-l-yl] -2-hydroxy-propoxy}-4,5-dimethoxy-phenyl]-3-phenyl-pro- pan-1-one

Mp.: 104-105°C 45

VIII-117 l-[2-{3-[4- (Diphenyl-methyliden)-piperazin-1-yl]-

2-hydroxy-propoxy}-4,5-dimethoxy-phenyl]-3-phenyl-pro- pan-1-one

5 Mp.: 142-143°C

VIII-118 l-[2-{3-(Exo-6,7-diphenyl-3-aza-bicyclo[3.2.0]-heptan- 3-yl)-2-hydroxy-propoxy)-4,5-dimethoxy-pheny1]-3-phenyl- propan-1-one 0

Mp.: 134-135°C

VIII-119 l-[2-{3-(Exo-6-ρhenyl-3-aza-bicyclo[3.2.0]-heptan-3-yl)- 2-hydroxy-propoxy}-4,5-dimethoxy-pheny1]-3-phenyl-pro- 5 pan-1-one

Mp.: 134-135°C (HCl-salt)

VIII-1331-[2-{3-(4,4-Diphenyl-piperidin-l-yl)-2-hydroxy- 0 propoxy}-4,5-dimethoxy-pheny1]-3-phenyl-propan-l-one

Mp.: 152-154°C

VIII-1411-[2-{3-[10,11-Dihydro-dibenzo[a,d]-cyclohepten- 25 5-yliden]-piperidin-1-yl]-2-hydroxy-propoxy}-4,5-di- methoxy-phenyl]-3-phenyl-propan-l-one

¹³ C-NMR [DMSO; δ (ppm)] (citrate): 28.6, 29.9, 31.6, 43.5, 44.9, 53.6, 54.1, 55.7, 55.9, 59.7, 64.8, 71.7, 98.4, 112.0, 118.0, 30 125.4, 127.1, 128.0, 128.2, 128.3, 129.4, 135.0, 137.6, 139.8, 141.6, 142.7, 153.7, 154.1, 171.2, 175.9, 197.7

VIII-142 l-[2-{3-[4-(Phenyl-methyl)-piperazin-l-yl]-2-hydroxy- propoxy}-4,5-dimethoxy-phenyl]-3-phenyl-propan-l-one

35

Mp.: 103-104°C

IX-9 1-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)- piperazin-1-yl]-3-{2-(2-[3-methoxymethyl-isoxa- 40 zol-5-yl]-aminocarbonyl)-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure descri¬ bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and epoxide IXa-2.

45

Mp: 122-124°C

IX-10 l-[4-(Diphenyl-methyl)-piperazin-1-yl]-

3-{2- (2-[3-methoxymethyl-isoxazol-5-yl]-amino- carbonyl)-phenoxy}-propan-2-ol

5 The reaction was carried out following the same procedure descri¬ bed for example III-l using 4-(diphenyl-methyl)-piperazine and epoxide IXa-2.

Mp: 160-161°C 0

IX-13 1-[10,ll-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)- piperazin-1-yl]-3-{2-[2-(3-methoxymethyl-isoxa- zol-5-yl)-2-N-methyl-aminocarbonyl]-phenoxy}- propan-2-ol 5

The reaction was carried out following the same procedure as des¬ cribed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]- cyclohepten-5-yl-piperazine and epoxide IXa-3.

0 "C-NMR (DMSO; δ (ppm)] (citrate; mixture of rotameres) : 30.9,

36.6, 43.4, 49.7, 52.6, 57.6, 59.0, 64.3, 64.6, 65.0, 70.4, 70.8, 71.8, 77.1, 105.5, 105.6, 113.3, 113.5, 121.1, 125.5, 127.7, 128.8, 130.0, 130.4, 130.6, 130.9, 138.6, 139.0, 153.7, 153.8, 157.5, 160.7, 162.9, 171.2, 175.7 5

IX-14 l-[4- (Dipheny1-methyl)-piperazin-l-yl]-

3-{2-(2-[3-methoxymethyl-isoxazol-5-yl)-2-N-methyl-amino� � carbonyl]-phenoxy}-propan-2-ol

30 The reaction was carried out following the same procedure as des¬ cribed for example III-l using 4-(diphenyl-methyl)-piperazine and epoxide IXa-3.

"C-NMR (DMSO; δ (ppm)] (citrate; mixture of rotameres): 36.6, 35 43.4, 49.7, 52.7, 57.6, 59.3, 64.3, 64.6, 65.0, 70.4, 70.8, 71.8, 74.4, 105.5, 105.6, 113.3, 113.5, 121.6, 126.9, 127.4, 128.5,

128.8, 130.0, 130.8, 130.9, 142.3, 153.7, 153.8, 157.5, 160.7,

162.9, 171.2, 175.7

40 ιχ-15 l-[4-(2,2-Diphenyl-acetyl)-piperazin-l-yl]-

3-{2-(2-[3-methoxymethyl-isoxazol-5-yl)-2-N-methyl-amino� � carbonyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure as des- ⁴⁵ cribed for example III-l using 2,2-diphenyl-acetyl-piperazine and epoxide IXa-3.

"C-NMR (DMSO; δ (ppm)] (citrate; mixture of rotameres): 36.6, 42.8, 44.7, 52.5, 53.0, 57.6, 60.0, 64.2, 65.4, 65.8, 70.4, 70.9, 72.1, 105.4, 113.3, 113.5, 121.0, 126.5, 128.1, 128.9, 130.0, 130.9, 140.0, 153.0, 157.5, 160.6, 162.9, 169.4, 171.2, 174.8 5

IX-17 N-(5-Methyl-isoxazol-3-yl)-2-[3-{ (4-diphenyl-met yl)- piperazin-1-yl)-2-hydroxy-propoxy]-benzamide

The reaction was carried out following the same procedure descri- 10 bed for example III-l using 4-(diphenyl)-methyl-piperazine and epoxide IXa-1.

"C-NMR [DMSO; δ (ppm)] : 12.0, 51.5, 53.4, 60.6, 65.9, 71.9,

75.1, 96.7, 113.7, 120.9, 122.0, 126.7, 127.4, 128.4, 130.7, 15 133.4, 142.8, 156.5, 157.8, 163.5, 169.4

IX-18 N-(5-Methyl-isoxazol-3-yl)-2-{3-[4-(10,ll-dihydro-5H-di- benzo-[a,d]cyclo-hepten-5-yl)-piperazin-1-yl]-2-hydroxy- propoxy}-benzamide 20

The reaction was carried out following the same procedure descri¬ bed for example III-l using 10,ll-dihydro-5H-dibenzo[a,d]cyclo- hepten-5-yl-piperazine and epoxide IXa-1.

25 ¹³ _C -NMR [DMSO; δ (ppm)] : 12.6, 31.7, 51.9, 54.0, 59.9, 65.1,

71.2, 79.0, 97.1, 113.3, 121.3, 121.9, 125.5, 127.7, 130.7, 130.8, 132.5, 133.8, 139.3, 139.6, 157.1, 158.5, 163.3, 169.4

IX-19 N-(5-Methyl-isoxazol-3-yl)-2-{3-[4-(bis(4-fluorophenyl- 30 methyl)-piperazin-1-yl]-2-hydroxy-propoxy}-benzamide

The reaction was carried out following the same procedure descri¬ bed for example III-l using bis(4-fluoro-phenyl)-methyl-pipera¬ zine and epoxide IXa-1. 35

"C-NMR [CDC1 ₃ ; δ (ppm)]: 12.6, 51.8, 53.4, 60.0, 65.2, 71.1, 74.5, 97.1, 113.3, 115.4 (J = 21 Hz), 121.3, 121.9, 129.2 (J = 8 Hz), 132.5, 133.8, 138.3, 157.1, 158.5, 161.8 (J = 246 Hz), 163.3, 169.4 40

IX-22 1-[4-(Diphenyl-methyliden)-piperidin-1-yl]-

3-{2-[3-methoxymethyl-isoxazol-5-yl]-aminocarbony1}- propan-2-ol

45 The reaction was carried out following the same procedure descri¬ bed for example III-118 using epoxide IXa-2.

Mp: 126.5-127.5°C

IX-23 l-[4-(Diphenyl-methyliden)-piperidin-1-yl]-

3-{2- (2-[3-methoxymethyl-isoxazol-5-yl)-2-N-methyl-amino- 5 carbonyl]-phenoxy}-propan-2-ol

The reaction was carried out following the same procedure as des¬ cribed for example III-l using 4-(diphenyl)-methyliden-piperidine and epoxide lXa-3.

10

"C-NMR (DMSO; δ (ppm)] (citrate; mixture of rotameres): 29.3, 36.6, 43.4, 54.0, 57.6, 59.0, 59.2, 64.3, 64.5, 64.9, 70.4, 70.8, 71.6, 105.6, 113.4, 113.5, 121.2, 126.6, 128.1, 128.8, 129.2, 130.0, 130.9, 136.4, 141.5, 153.6, 153.8, 157.5, 160.7, 162.9,

15 171.2, 175.9.

Pre ^p fl..atipn of the starting cς>mpς>w.is

Epoxides of type Ill-a 20

IIIa-1 (E)-5-{2- [2-(2,3-Epoxypropoxy)-phenyl]-ethenyl}-3-(meth¬ oxymethyl)-isoxazole

4.6g of sodium hydride (60% in mineral oil) were washed with 25 pentane to remove the mineral oil, then 200ml of dry dimethylfor¬ mamide added. 28.7g of diethyl (3-methoxymethyl-5-isoxazolyl)- methyl phosphonate -dissolved in 50ml of dimethylformamide- were added dropwise, after gas evolution had ceased the mixture was stirred at 40°C for another 15min. At 4°C 18.6g of 2-(2,3-epoxy- 30 propoxy)-benzaldehyde -dissolved in 40ml dimethylformamide- were added slowly, then the mixture was stirred at room temperature. After the reaction was completed the liquid was diluted with cold water and extracted with ethylacetate. The organic phase was was¬ hed with saturated sodium chloride-solution and dried with 35 magnesium sulfate. After evaporation of the solvent the crude product was purified by chromatography on silica gel affording 19.26g of the title compound as an oil.

iH-NMR [CDC1 ₃ ; δ (ppm)]: 2.8 (dd, IH) , 2.9 (dd, IH) , 3.4 (m 4H) , 40 4.1 (dd, IH) , 4.30 (dd, IH) , 4.5 (s, 2H) , 6.30 (s, IH) , 6.8-7.1 ( , 3H) , 7.3 (m, IH) , 7.5 (m, IH) , 7.7 (d, IH)

The following compounds were prepared in analogous manner:

45 IIIa-2 (E )-5-{2-[3-(2,3-Epoxypropoxy)-phenyl]-ethenyl)-3-(meth¬ oxymethyl)-isoxazole

ⁱ H-NMR [CDC1 ₃ ; δ (ppm)] : 2.8 (dd, IH) , 2.9 (dd,lH), 3.25-3.40 (m, 4H), 3.9 (dd, IH), 4.3 (dd, IH) , 4.6 (s, 2H) , 6.3 (s, IH) , 6.85-7.4 ( , 6H)

IIIa-3 (E)-5-{2- [4- (2, 3-Epoxypropoxy) -phenyl] -ethenyl}-3- (meth¬ oxymethyl ) -isoxazole

ⁱ H-NMR [CDC1 ₃ ; δ (ppm)]: 2.75 (dd, IH) , 2.90 (dd, IH) , 3.4-3.5 (m, 4H), 4.0 (dd, IH) , 4.30, (dd, IH) , 4.6 (s, 2H) , 6.3 (s, IH) , 6.90 (d, IH) , 6.95 (d, 2H) , 7.4 (d, IH) , 7.6 (d, 2H)

IIIa-4 (_?)-5-{2-[2-(2,3-Epoxypropoxy)-phenyl]-ethenyl)-3-tri- fluoromethyl-isoxazole

iH-NMR [CDCI3; δ(ppm)]: 2.8 (dd, 1 H) , 3.0 (dd, 1 H) , 3.4-3.5 (m,

1 H), 4.1 (dd, 1 H) , 4.3 (dd, 1 H) , 6.5 (s, 1 H) , 6.9-7.2 (m,

2 H), 7.1(d, 1 H) , 7.3-7.4 (m, 1 H) , 7.5 (d, 1 H) , 7.7 (d, 1 H)

IIIa-5 (E) -5-{2- [2- (2 , 3-Epoxypropoxy ) -phenyl] -ethenyl }- 3-methoxy-isoxazole

iH-NMR [CDCI ₃ ; δ(ppm)]: 2.8 (dd, 1 H) , 3.0 (dd, 1 H) , 3.4-3.5 (m, 1 H) , 4.0 (s, 3 H) , 4.1 (dd, 1 H) , 4.3 (dd, 1 H) , 5.9 (s, 1 H) , 6.9-7.1 (m, 3 H) , 7.3-7.4 (m, 1 H) , 7.5 (d, 1 H) , 7.6 (d, 1 H)

IIIa-6 (Z)-5-{2-[2-(2,3-Epoxypropoxy)-phenyl]-ethenyl)- 3-methoxy-isoxazole

ⁱ H-NMR [CDC1 ₃ ; δ(ppm)]: 2.8 (dd, 1 H) , 2.9 (dd, 1 H) , 3.3-3.4 (m, 1 H), 4.0 (s, 3 H) , 4.1 (dd, 1 H) , 4.3 (dd, 1 H) , 5.6 (s, 1 H) , 6.4 (d, 1 H), 6.9-7.1 (m, 2 H) , 7.3-7.4 (m, 2 H) , 7.4 (d, 1 H),

IIIa-7 (E)-3-{2-[2-(2,3-Epoxypropoxy)-phenyl]-ethenyl)-5-meth- oxymethyl-isoxazole

iH-NMR [CDCI3; δ(ppm)]: 2.8 (dd, 1 H) , 2.9 (dd, 1 H) , 3.4 (s, 3 H) , 3.7-3.8 (m, 1 H) , 4.0 (dd, 1 H) , 4.3 (dd, 1 H) , 4.6 (s, 2 H) , 6.5 (s, 1 H), 6.9 (d, 1 H) , 7.0 (dd, 1 H) , 7.2 (d, 1 H) , 7.2-7.3 (m, 1 H) , 7.5 (d, 1 H) , 7.6 (d, 1 H)

IIIa-8 ( E) -4- { 2- [2- ( 2 , 3-Epoxypropoxy ) -phenyl ] -ethenyl } -2 -meth¬ oxymethy 1-1 , 3-thiazole

ⁱ H-NMR [CDC1 ₃ ; δ(ppm)]: 2.8 (dd, 1 H) , 2.9 (dd, 1 H) , 3.4-3.5 (m, 1 H), 3.5 (S, 3 H) , 3.9-4.1 (m, 1 H) , 4.3 (dd, 1 H) , 4.8 (s, 2 H) , 6.0 (s, 1 H), 6.9 -7.3 ( , 4 H) , 7.6 (d, IH) , 7.7 (d, 1 H)

IIIa-9 (£")-2-{2-[2-(2,3-Epoxypropoxy)-phenyl]-ethenyl}- 5- (4-methyl-phenyl) -1, 3 , 4-oxadiazole

ⁱ H-NMR [CDCI3; δ(ppm)]: 2.4 (s, 3 H) , 2.8 (dd, 1 H) , 3.0 (dd, 1 . H) , 3.4-3.5 (m, 1 H), 4.1 (dd, 1 H) , 4.6 (dd, 1 H) , 7.0 (d, 1 H), 7.0 (d, 1 H), 7.2 (d, 1 H) , 7.3 ( 2 H) , 7.3 (dd, 1 H) , 7.6 (d,l H) , 7.9 (d, 1 H), 8.0 (d, 2 H)

IIIa-10 (E) -4-{2- [2- (2 , 3-Epoxypropoxy) -phenyl] -ethenyl}- 2- (4-methoxy-phenyl)-l,3-oxazole

ⁱ H-NMR [CDCI3; δ(ppm)]: 2.8 (dd, 1 H) , 3.0 (dd, 1 H) , 3.4-3.5 (m, 1 H), 3.9 (s, 3 H) , 4.1 (dd, 1 H) , 4.3 (dd, 1 H) , 6.8-7.0 (m, 4 H) , 7.0 (d, 1 H) , 7.2 (dd, 1 H) , 7.6 (d, 1 H) , 7.7 (m, 2 H) , 7.9 (d, 1 H), 8.0 (d, 1 H)

IIIa-11 (£)-2-{2-[2-(2,3-Epoxypropoxy)-phenyl]-ethenyl)- 4-dimethyl-l,3-oxazoline

iH-NMR [CDCI3; δ(ppm)]: 1.4 (s, 6 H) , 2.8 (dd, 1 H) , 3.0 (dd, 1 H) , 3.4 (m, 1 H) , 4.1 (dd, 1 H) , 4.1 (s, 2 H) , 4.3 (dd, 1 H) ,

6.7 (d, 1 H) , 6.9 (dd, 1 H) , 7.0 (dd, 1 H) , 7.3 (dd, 1 H) , 7.5 (dd, 1 H) , 7.7 (dd, 1 H)

IIIa-12 (E)-5-{2-[2-(2,3-Epoxypropoxy)-4,5-dimethoxy-phe- nyl]-ethenyl}-3-(methoxymethyl)-isoxazole

Mtp.: 75-77°C

ⁱ H-NMR [CDC1 ₃ ; δ (ppm)]: 2.8 (dd, IH) , 2.9 (dd, IH) , 3.40 (s, 3H) , 3.9 (s, 6H) , 4.0 (dd, IH) , 4.4 (dd, IH) , 4.5 (s, 2H) , 6.30 (s, IH), 6.6 (s, IH), 6.9 (d, IH) , 7.1 (s, IH) , 7.6 (d, IH) .

IIIa-13 (E)-5-{2-[2-(2,3-Epoxypropoxy)-5-N,N-diethylamino-phe- nyl]-ethenyl}-3-(methoxymethyl)-isoxazole

iH-NMR [CDC1 ₃ ; δ (ppm)]: 1.2 (t, 6H) , 2.8 (dd, IH) , 2.9 (dd, IH) , 3.4 (m, 5H), 4.1 (dd, IH) , 4.3 (dd, IH) , 4.6 (s, 2H) , 6.15 (d, IH), 6.2 (s, IH), 6.8 (d, IH) , 7.35 (d, IH) , 7.55 (d, IH)

IIIa-14 .E)-5-{2-[2-(2,3-Epoxypropoxy)-6-fluoro-phenyl]-ethenyl}- 3-(methoxymethyl)-isoxazole

The compound was prepared following the same procedure as descri¬ bed for the synthesis of intermediate Illa-l. The obtained E/Z- mixture was refluxed in heptane with a catalytic amount of io¬ dine. Then the liquid was diluted with ethyl acetate, washed with 5 Na ₂ S ₂ 0 ₃ -solution and dried with magnesium sulfate. Filtration through a silica gel column afforded the pure E-isomere.

iH-NMR [CDClj; δ (ppm)]: 2.70 (dd, IH) , 2.8 (dd, IH) , 3.4 (m, 4H) , 4.1 (dd, IH) , 4.35 (dd, IH) , 4.55 (s, 2H) , 6.40 (s, IH) , 7.0-7.15 10 (m, 3H) , 7.35 (d, IH) , 7.65 (d, IH) .

IIIa-15 CZ/£;-5-{2-[2-(2,3-Epoxypropoxy)-phenyl]-ethenyl}- 3- (methoxymethyl)-isoxazole

15 12g of 3-(Methoxymethyl-isoxazol-5-yl)-methyl-triphenylphosphoni- um-bromide and 5.6g of 2-(2,3-epoxypropoxy)-benzaldehyde were dissolved in 90ml tetrahydrofuran.. At -10°C 3.2g of potassium tert.butylate were added, and the mixture stirred at the same temperature for 15min. Then the reaction mixture was diluted with

20 cold water, extracted with ethyl acetate, the organic phase was¬ hed with saturated sodium chloride-solution and dried with magnesium sulfate. After evaporation of the solvent the crude product was purified by chromatography on silica gel affording 6.4g of a yellow oil which according to ¹ H-NMR consisted of a mix-

25 ture of the Z-and the E-isomere. This mixture was used for the further reactions.

IIIa-16 C£j-5-{3-[2-(2,3-Epoxypropoxy)-4-nitro-phenyl]-ethenyl}- 3-(methoxymethyl)-isoxazole 30

Mp.: 116-117.5°C ⁱ H- MR [(CDC1 ₃ ; δ (ppm)]: 2.8 (dd, IH) , 3.0 (dd, IH) , 3.4 (s, 3H) , 3.45 (m, IH) , 4.1 (dd, IH) , 4.5 (dd, IH) , 4.55 (s, 2H) , 6.4 (S, IH) , 7.0 (d, IH) , 7.15 (d, IH) , 7.6 (d, IH) , 8.1 (dd, IH) , 35 8.45 (d, IH)

IIla-17 f£j-5-{2-[2-(2,3-Epoxypropoxy)-phenyl]-l-methyl- ethenyl}-3-(methoxymethyl)-isoxazole

40 The reaction was carried out analogous to the synthesis of

IIIa-l.The obtained E/Z-mixture was separated by chromatography.

"C-NMR [(CDC1 ₃ ; δ (ppm)]: 20.4, 44.6, 50.1, 58.5, 65.9, 69.0, 101.8, 112.9, 115.2, 121.4, 128.2, 129.2, 133.7, 144.5, 155.5, 45 161.4, 169.1

Cz -5-{2-[2- (2,3-Epoxypropoxy)-phenyl]-1-methyl-ethe- nyl}-3-(methoxymethyl)-isoxazole

"C-NMR [(CDC1 ₃ ; δ (ppm)]: 26.0, 44.5, 50.1, 58.2, 65.7, 65.9, 99.7, 112.5, 114.1, 121.8, 128.1, 129.4, 130.2, 144.2, 154.6, 160.8, 168.9

IIla-18 (Z/Fj-5-{2-[2-(2,3-Epoxypropoxy)-phenyl]-ethenyl}- 2-(methoxymethyl)-1,3,4-thiadiazole

The compound was prepared following the same procedutre as des¬ cribed for the synthesis of intermediate Illa-l. The obtained E/ Z-mixture (ratio 5:1) was separated by cristallisation from diethylether.

Precursor of type Ill-b

IIIb-1 2-(2,3-Epoxypropoxy)-4, 5-dimethoxy-benzaldehyde

8g of 4,5-dimethoxy-2-hydroxy-benzaldehyde and 9.1g of potassium carbonate were dissolved in 150ml dimethylformamide, and then 7.2g of epibromohydrine were slowly added thereto. The mixture was heated with stirring at 50°C. During addition of water at room temperature a yellow precipitate occured, which was filtered off, washed with water and dried in order to obtain 8.8g of the pure compound.

Mp.: 121-123°C iH-NMR [CDC1 ₃ ; δ (ppm)]: 2.8 (dd, IH) , 2.95 (dd, IH) , 3.35 (m IH) , 3.9 (s, 3H) , 4.0 (s, 3H) , 4.05 (dd, IH) , 4.45 (dd, IH) , 6.55 (s, IH) , 7.30 (s, IH) , 10.4 (s, IH)

The following compounds were prepared in an analogous manner:

IIIb-2 5-N,N-Diethylamino-2- (2,3-epoxypropoxy)-benzaldehyde

ⁱ H-NMR [CDC1 ₃ ; δ (ppm)]: 1.2 (t, 6H) , 2.8 (dd, IH) , 3.0 (dd, IH) , 3.4 (m, 5H) , 4.1 (dd, IH) , 4.35 (dd, IH) , 6.1 (d, IH) , 6.35 (dd, IH), 7.75 (d, IH) , 10.2 (s, IH)

IIIb-3 2- (2 , 3-Epoxypropoxy ) -3-f luoro-benzaldehyde

ⁱ H-NMR [CDC1 ₃ ; δ (ppm)]: 2.75 (dd, IH) , 2.95 (dd, IH) , 3.38 (m, IH) , 4.18 (dd, IH), 4.55 (dd, IH) , 7.08-7.40 (m, 2H) , 7.65 (m IH) , 10.45 (s, IH)

IIIb-4 2-(2,3-Epoxypropoxy)-4-nitro-benzaldehyde

In 150ml dimethylformamide were dissolved 15g of 2-hydroxy- 5-nitro-benzaldehyde, and 9.87g of potassium tert.butylate were added. With stirring, 13.2g of epibromohydrin were added drop¬ wise, and then the mixture was stirred at 50°C. After the reaction was completed the solvent was evaporated and the obtained residue chromatographed on silica gel , which afforded 5g of pure product.

iH-NMR [CDC1 ₃ ; δ (ppm)]: 2.85 (dd, 2H) , 3.05 (dd,2H), 3.5 (m, IH) , 4.15 (dd, 2H), 4.6 (dd, 2H) , 7.2 (d, IH) , 8.45 (dd, IH) , 8.7 (d, IH), 10.5 (s, IH)

Phosphonates IIIc

Preparation of diethyl (3-methoxy-isoxazol-5-yl)-methyl phosphonate (IIIc-2)

3.8g 5-chloromethyl-3-methoxy-isoxazole and 6.0g of triethyl¬ phosphite were stirred at 150°C until complete conversion of the chloromethyl isoxazole (2 -8 h) . Kugelrohr destination gave 3.6g of diethyl (3-methoxy-isoxazol-5-yl)-methane phosphonate.

Bp. 160 -165°C/0.3 mm Hg.

iH-NMR CDC1 ₃ ; δ(ppm)]: 1.3 (t, 6 H) , 3.2 (d, 2 H) , 3.9 (s, 3 H) , 4.2 (dq, 4 H) , 5.9 (d, 1 H)

The following compounds were prepared using the same procedure:

IIIc-1 Diethyl (3-trifluoromethyl-isoxazol-5-yl)-methy1- phosphonate

iH-NMR [CDC1 ₃ ; δ(ppm)]: 1.3 (t, 6 H) , 3.4 (d, 2 H) , 4.1 (dq, 4 H) , 6.5 (d, 1 H)

IIIc-3 Diethyl (5-methoxymethyl-isoxazol-3-yl)-methyl phosphonate

Bp = 145°C/0.4 mm Hg

IIIc-4 Diethyl (2-methoxymethyl-l,3-thiazol-4-yl)-methyl- phosphonate

Bp _. 150°C/0.1 mm Hg

IIIc-5 Diethyl [5- (4 -methyl -phenyl) -1 , 3 , 4-oxadiazol-2-yl] -methyl phosphonate

ⁱ H-NMR [CDC1 ₃ ; δ(ppm)]: 1.3 (t, 6 H) , 2.4 (s, 3 H) , 3.5 (d, 2 H) , 4.1 (dq, 4 H) , 7.3 (d, 2 H) , 7.9 (d, 2 H)

IIIc-6 Diethyl 2- (4-methoxy-phenyl)-l, 3-oxazol-4-yl] -methyl phosphonate

ⁱ H-NMR [CDCI3; δ(ppm)]: 1.3 (t, 6 H) . 3.1 (d, 2 H) , 3.8 (s, 3 H) , 4.0-4.2 ( , 4 H) , 6.9-7.0 (m, 2 H) , 7.6 (d, 2 H) , 7.9-8.0 (m, 2 H)

IIIc-7 Diethyl (2-methoxymethyl-l,3 ,4-thiadiazol-5-yl)-methyl- phosphonate

iH-NMR (CDC1 _3; δ (ppm)]: 1.35 (t, 6H) , 3.5 (s, 3H) , 3.7 (d, 2H) , 4.15 (q, 4H) , 4.85 (s, 2H) .

IIIc' 3-(Methoxymethyl-isoxazol-5-yl)-methyl-triphenyl- phosphonium-bromide

In 150ml toluene/acetone 2:1 were dissolved 30g of 5-bromome- thyl-3-(methoxymethyl)-isoxazole and 30.5g of triphenylphosphine. The mixture was refluxed and, after the reaction was completed, the precipitate was filtered off, dried and recristallized from acetone/diethylether affording 48.8g of the title compound.

Mp: >200°C.

iH-NMR [CDC1 ₃ ; δ (ppm)]: 2.3 (s, 3H) , 4.4 (s, 2H) , 5.95 (d, 2H) , 6.8 (d, IH), 7.6-7.9 (m, 15H) .

Precursor of f.vne V

Va-1 5-{ [2-(2,3-Epoxypropoxy)-phenoxy]-methoxymethyl}-3-(meth¬ oxymethyl)-isoxazole

0.73g of sodium hydride (60% in mineral oil) were washed with pentane to remove the mineral oil and 30ml of dry dimethylforma¬ mide added. 3.8g of 3- (methoxymethyl)-5-{2-[2-(hydroxy)-phen- oxy}-methoymethyl)-isoxazole -dissolved in 30ml of dimethylforma¬ mide- were added slowly and, after gas evolution had ceased, the mixture was stirred for another 15min. at 40°C.

At room temperature 2.0ml of epibromohydrine were added dropwise, maintaining a temperature of about 40°C, afterwards the mixture was stirred at 40°C. After the reaction was finished the mixture was diluted with ice water, extracted with ethylacetate, the 5 organic phase washed with sodium chloride solution and dried with magnesium sulfate. Evaporation of the solvent and purification by chromatography on silica gel afforded 3.1g of the pure compound as oil.

10 iH-NMR [CDC1 ₃ ; δ (ppm)]: 2.65 (dd, IH) , 2.83 (dd, IH) , 3.20 (m,

IH), 3.38 (s, 3H) , 3.50 (dd, IH) , 3.80 (dd, IH) , 4.53 (s, 2H) ,

4.65 (d, IH) , 5.18 (s, 2H) , 6.40 (s, IH) , 6.92 (d, IH) , 7.05 (m,

IH) , 7.28 (m, IH) , 7.43 (m, IH) .

15 Vb-1 3-(Methoxymethyl)-5-{2-[2-(hydroxy)-methoxymethyl] }- isoxazole

a) 2.9g of sodium hydride (60% in mineral oil) were washed with pentane to remove the mineral oil and 100ml of dry dimethy1forma-

20 mide added. 15g of 2-(tert.-butyldimethylsilyloxy)-benzylalcohol -dissolved in 40ml of dimethylformamide- were added slowly through a dropping funnel and after gas evolution had ceased the mixture was stirred for another 15min. at 40°C. After cooling to 10°C 5-(chloromethyl)-3-(methoxymethyl)-isoxazole -dissolved in

25 40ml dimethylformamide- was added dropwise, maintaining a reaction temperature of about 10°C, then the mixture was stirred at room temperature. After the reaction was completed the mixture was diluted with cold water and extracted with ethylacetate. The organic phase was washed with saturated sodium chloride solution

30 and then dried over magnesium sulfate. After evaporation of the solvent the crude product was purified by chromatography on silica gel, which afforded 10.6g of the pure compound.

b) In 90ml tetrahydrofuran were dissolved 10.6g of the above men- 35 tioned silylether, and 58.3ml tetrabutyla moniumfluoride (lm so¬ lution in tetrahydrofuran) were added slowly at 4°C. The mixture was stirred for 15min. at 4°C and then allowed to warm up to room temperature. After lh the mixture was diluted with cold water and extracted with methy1-tert.butylether. Then the organic phase was

40 washed with sature sodium chloride solution and dried with magnesium sulfate. After evaporation of the solvent the obtained oily residue was purified by chromatography on silica gel, which afforded 4.5g of the title compound as a yellow oil.

45

iH-NMR [CDC1 ₃ ; δ (ppm)]: 2.30 (s, IH) , 3.38 (s, 3H) , 4.53 (s, 2H) , 4.72 (s, 2H) , 5.24 (s, 2H) , 6.42 (s, IH) , 6.93 (d, IH) , 7.03 (m, IH), 7.25-7.40 (m, 2H)

Precursor of type VI

VIb-1 [2-(2-tert.Butyldimethylsiloxy-phenyl)-ethyl]- 4,5-dimethyl-oxazole (VIb)

To a solution of 5g freshly destilled diisopropylamine in 90ml tetrahydrofuran was added 33ml of a 1.5m solution of n-butylli- thium in hexane at 0°C. After stirring for 30min the solution was cooled to -78°C. 5g of 2,4,5-trimethyloxazole, dissolved in tetra¬ hydrofuran, were added to the lithiumdiisopropylamide solution, after 20min. 15.06g of 2-bromomethyl-pheny1-tert.butyldimethylsi- lyl ether were added. The reaction mixture was allowed to warm up to room temperature and was then poured into a saturated ammonium chloride solution. After extraction with diethyl ether, drying of the ether layer over sodium sulfate and evaporation of the sol- vent the residue was purified by chromatography on silica gel with heptane/ethyl acetate (5:1) to give 4.6g product.

iH-NMR [CDC1 ₃ ; δ(ppm)]: 0.3 (s, 6 H) , 1.0 (s, 9 H) , 2.1 (s, 3 H) , 2.2 (s, 3 H),.2.9-3.1 (m, 2 H) , 6.7-6.9 (m, 2 H) , 7.0-7.2 (m, 2 H)

Precursor of type VIII

VIIIa-1 5-[{2-(2,3-Epoxypropoxy)-phenyl)-carbonyl]-3-(methoxy- methyl)-isoxazole

The reaction was carried out according to the preparation of of epoxy compounds type Ilia using

5-{ [2-hydroxy)-phenyl]-carbonyl}-3-(methoxymethyl)-isoxazole (precursor VIIIb-1) .

iH-NMR (CDC1 _3; δ (ppm)]: 2.6 (m, IH) , 2.8 (m IH) , 3.05 (m, 2H) , 3.25 (s, 3H) , 4.05 (dd, IH) , 4.25 (dd, IH) , 4.6 (s, 2H) , 6.95 (s, IH), 7.0-7.2 (m, 2H) , 7.5-7.6 (m, 2H) .

VIIIb-1 5-[{2-(Hydroxy)-phenyl)-carbonyl]-3-(methoxymethyl)- isoxazole

a) 5-[2-(Methoxymethyl)-phenoxy)-carbonyl]-3-(methoxy- methyl)-isoxazole

22.8g of methoxymethyl-phenol and 23ml of N,N,N' ,N'-tetraethyle- nediamine were dissolved in 150ml of tetrahydrofuran. At -78°C 100ml of n-butyllithium (15% solution in n-hexane) were added slowly, then the reaction was stirred for 30min. at the same temperature. Afterwards this mixture was added to a precooled (-78°C) solution of 27.4g 3-(methoxymethyl)-5-(carboxymethyl)- isoxazole in a mixture of 100ml of tetrahydrofuran and 75ml of 1,3-dimethyl-tetrahydro-2 [lH]-pyrimidinon. The mixture was stir¬ red for another 3h at this temperature, then allowed to warm up to -20°C and diluted with an acidic buffer solution (citric acid/ sodium hydroxide; pH 5-6) . After extraction with dichloromethane the organic phase was washed with saturated sodium chloride-solu¬ tion, dried over magnesium sulfate and the solvent was evapora¬ ted. Purification by chromatography on silica gel afforded 5.6g of the product as an oil.

b) 5-[{2-(Hydroxy)-phenyl)-carbonyl]-3-(methoxymethyl)-isoxazol e

To a solution of 5.3g of 5-[2-(methoxymethyl)-phenoxy}-carbonyl]- 3-(methoxymethyl)-isoxazole in 40ml of tetrahydrofuran 16ml of a 2m hydrochloric acid-solution were added at room temperature, the reaction mixture was then refluxed for 3h. After the reaction was completed the liquid was extracted with ethylacetate, washed with saturated sodium chloride-solution and dried over magnesium sul- fate. Evaporation of the solvent afforded 4.8g of the pure com¬ pound.

iH-NMR (CDC1 _3; δ (ppm)]: 3.45 (s, 3H) , 4.6 (s, 2H) , 6.9 (s, IH) , 7.15 (m, IH) , 7.25 (m, IH) , 7.5 (m, 2H) .

VIIIa-2 2-[ (2,3-Epoxypropoxy)-4,5-dimethoxy]-3-phenyl-propanone

8.4g of sodium hydride (60% in mineral oil) were washed with pentane to remove the mineral oil, then 50g of l-(2-hydroxy- 4,5-dimethoxy)-3-phenyl-propanone - dissolved in 400ml of dry di¬ methylformamide - were added dropwise and after gas evolution had ceased the mixture was stirred for another 15min. Then 35.8g of epibromohydrine were added slowly and the mixture was stirred at 50°C. After the reaction was completed the mixture was diluted with ice water and extracted with ethylacetate. The organic phase was washed with saturated sodium chloride-solution and then dried with magnesium sulfate. Evaporation of the solvent and treatment of the residue with diethylether afforded 48.8g of the pure product.

Mp.: 120-121°C

ⁱ H-NMR [CDC1 ₃ ; δ (ppm)]: 2.75 (dd, IH) , 2.9 (dd, IH) , 3.1 (t, IH) , 3.3-3.4 (m, 3H), 3.9 (s, 3H) , 3.95 (s, 3H) , 4.0 (m, IH) , 4.4 (dd, IH), 6.55 (S, IH) , 7.15-7.35 (m, 5H) , 7.4 (s, IH)

VlIIb-2 1-(2-Hydroxy-4,5-dimethoxy)-3-phenyl-propanone

a) [1- (3, 4-Dimethoxy)-phenyl]-3-phenyl-propionat

To 48g of 3,4-dimethoxy-phenol in 700ml of tetrahydrofuran were added 44ml of triethylamine and a spatula of 4,4-dimethylaminopy- ridine. At 0°C 52.5g of 3-phenyl-propionylchloride -dissolved in 100ml of tetrahydrofuran- were added dropwise, then the mixture was stirred at room temperature. After the reaction was completed the precipitate was filtered off, the filtrate diluted with water and extracted several times with ethylacetate. The combined organic phases were washed with saturated sodium bicarbonate and sodium chloride solution and dried over magnesium sulfate. After evaporation of the solvent 87.6g of the pure ester were obtained.

ⁱ H-NMR [CDC1 ₃ ; δ (ppm)]: 2.9 (t, 2H) , 3.1 (t, 2H) , , 3.8 (s, 3H) , 3.85 (s, 3Η) , 6.5-6.6 (m, 2H) , 6.8 (d, IH) , 7.15-7.4 (m, 5H)

b) 1- (2-Hydroxy-4,5-dimethoxy)-3-phenyl-propanone

At 0°C 56.3g of titanium tetrachloride were added slowly to a so¬ lution of 85g of [1- (3,4-dimethoxy)-phenyl]-3-phenyl-propionat in 500ml of dry nitromethane, the reaction mixture was then stirred for about 5h at room temperature. Afterwards the liquid was dilu¬ ted with ice water, extracted several times with ethylacetate and the combined organic phases were washed with saturated sodium chloride solution and then dried over magnesium sulfate. After evaporation of the solvent the crude product obtained was puri¬ fied by chromatography on silica gel. Crystallization from iso- propanole afforded 83.4g of the pure product.

Mp. 81-82°C

iH-NMR [CDC1 ₃ ; δ (ppm)]: 3.1 (m, IH) , 3.2 (m IH) , 3.85 (s, 3H) , 3.9 (s, 3H) , 6.4 (s, IH) , 7.0 (s, IH) , 7.1-7.2 (m, 5H) , 12.85 (s, IH) .

Precursor of type IX

IXa-1 N-(5-Methyl-isoxazol-3-yl)-2- (2 ,3-epoxy-propoxy)- benzamide

The reaction was carried out according to the preparation of epoxy compounds type Ilia using N-(5-methyl-isoxazol-3-yl)- 2-hydroxy-benzamide (precursor IXb-1) and sodium hydride as base.

iH-NMR [CDC1 ₃ ; δ(pρm)]: 2.4 (s, 3 H) , 2.9 (dd, 1 H) , 3.0 (dd, 1

H) , 3.5-3.6 (m, 1 H) , 4.2 (dd, 1 H) , 4.5 (dd, 1 H) , 6.8 (s, 1 H) ,

7.0(d, 1 H), 7.1 (dd, 1 H), 7.5 (dd, 1 H) , 8.2 (d, 1 H) , 10.3 (s, 1 H)

IXb-1 N-(5-Methyl-isoxazol-3-yl)-2-hydroxy-benzamide

To a solution of lg 2-acetoxy-N- (5-methyl-isoxazol-3-yl)-benza¬ mide, in 20ml of methanol was added 0.58g potassium carbonate. After stirring overnight the mixture was poured into saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. Evaporation of the solvent gave 0.63g amide.

iH-NMR [CDCI ₃ ; δ(ppm)]: 2.5 (s, 3 H) , 6.9 (s, 1 H) , 7.0 (d, 1 H) , 7.0 (dd, 1 H), 7.5 (dd, 1 H) , 7.8 (d, 1 H) , 10.2 (s, 1 H) , 11.5 (br s, 1 H)

lXc-1 N-(5-Methyl-isoxazol-3-yl)-2-acetoxy-benzamide

To a solution 4.57g 3-amino-5-methyl-isoxazole and 4.7g triethy¬ lamine in tetrahydrofuran lOg 2-acetoxy-benzoyl chloride were ad¬ ded dropwise at 0°C and the reaction mixture was stirred at room temperature for 3h. The mixture was given on saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate. After concentration the residue was purified by flash chromatography on silica gel with heptane/ethyl acetate giving 7.12g amide.

iH-NMR [CDC1 ₃ ; δ(ppm)]: 2.3 (s, 3 H) , 2.4 (s, 3 H) , 6.8 (s, 1 H) , 7.2 (d, 1 H) , 7.3 (dd, 1 H) , 7.5 (dd, 1 H) , 7.9 (d, 1 H) , 9.7 (s, 1 H)

IXa-2 5-{2-N-[2-{2,3-Epoxypropoxy)-phenyl]-aminocarbony1}-3- (methoxymethyl)-isoxazole

The reaction was carried out according to the preparation of epoxy compounds type Ilia using 5-{2-N-[2-(hydroxy)-phenyl]- aminocarbonyl}-3-(methoxymethyl)-isoxazole (precursor IXb-2) and sodium hydride as base.

ⁱ H-NMR [{CDCI3; δ (ppm)]: 2.85 (dd, IH) , 2.95 (dd, IH) , 3.47 (s, 4H), 4.14 (dd, IH), 4.40 (dd, IH) , 4.63 (s, 2H) , 6.95-7.18 (m, 4H), 8.45 (dd, IH), 8.95 (s, IH) .

IXb-2 5-{2-N- [2- (Hydroxy) -phenyl] -aminocarbonyl}-3- (methoxy¬ methyl) -isoxazole

The reaction was carried out according to the preparation of pre¬ cursor IXb-1 using 2-amino-phenol and (3-methoxymethyl)-isoxazol- 5-yl-carbonylchloride.

"C-NMR [(CDCI ₃ ; δ (ppm)]: 58.7, 65.5, 106.8, 115.9, 120.1, 121.0, 125.4, 125.7, 147.0, 162.6, 163.8

IXa-3 5-.2-N-[2-(2,3,-Epoxypropoxy)-phenyl]-2-N-methy1-amino- carbonyl)-3-methoxymethyl)-isoxazole

The reaction was carried out according to the preparation of epoxy compounds type Ilia using 5-{2-N-[2-hydroxy)-phenyl]-2-N- methyl-aminocarbonyl)-3-(methoxymethyl)-isoxazole (precursor IXb-3) and sodium hydride as base.

IXb-3 5-{2-N-[2-Hydroxy)-phenyl]-2-N-methyl-aminocarbonyl}- 3-(methoxymethyl)-isoxazole

The reaction was carried out according to the synthesis of pre¬ cursor IXc-1 using 2-(N-methyl)-aminophenol and (3-methoxy- methyl)-isoxazol-5-yl-carbonylchloride.

iH-NMR (CDC1 _3; δ (ppm)]: 3.25 (s, 3H) , 3.4 (s, 3H) , 4.35 (s, 2H) , 5.85 (s, IH) , 6.9 (m, IH) , 7.05 (m, IH) , 7.1 (m, IH) , 7.25 (m, IH), 7.7-7.9 (broad, IH)

Various types of precursors;

ZH

Amino compounds of type ZH are either commercially available (e.g.: 1-diphenyl-methyl-piperazine) or can be easily prepared according to known procedures by those skilled in art (e.g.: mono-N-acyl-piperazines by debenzylation of l-acyl-4-benzyl-pipe- razines as described in Th. Greene "Protective Groups in Organic Synthesis" Wiley & Sons, 1981, page 272; mono-alkyl-piperazines according to Organc Synthesis Coll. Vol.5, 1973, page 88).

Compounds of the formula H-_5___3. can be prepared from amines of the formula:

10 by subjecting them photochemically to a 2+2-cycloaddition. This reaction can be performed in a solvent such as aacetone at a temperature between 20°C and 80°C. A mercury high pressure lamp is particularly suitable as light source. It may be advantageous to 15 carry out the photo cycloaddition under nitrogen in a quartz ap¬ paratus, possibly with the addition of about 1 mole of hydrochlo¬ ric acid per mole of amine (see DE 42 19 975) .

IIId-1 Diethyl 2- (2,3-epoxypropoxy)-benzyl phosphonate

20

To a solution of 0.2mol sodium hydride in 100ml absolute dime¬ thylformamide under inert gas a solution of 0.2mol of diethyl 2-hydroxy-benzyl phosphonate in 200ml absolute dimethylformamide was added dropwise at room temperature. The mixture was warmed to

25 50°C for 30min, then cooled to room temperature. At this temperature 0.35 mole of epibromohydrine were added dropwise. The reaction mixture was stirred at 50°C for 30min. The reaction was quenched by dropwise addition of 200ml water to the reaction mix¬ ture under permanent cooling with ice. The reaction mixture was

30 then poured into 31 water and extracted five times with dichloro¬ methane. The organic phase was washed with water, dried over so¬ dium sulfate, filtered and the solvent evaporated under reduced pressure. The remaining residue was chromatographed over silica gel. The product was isolated as viscous oil (28.Og).

35 iH-NMR [CDC1 ₃ ; δ (ppm)] : 1.25 (t,6H), 2.8 (t,lH), 2.9 (t,lH), 3.2 (d,2H), 3.4 (m,lH), 4.0 (dxd,lH), 4.1 (q,4H), 4.3 (dxd,lH), 6.8-7.2 (4H)

40 IIIh-1 Diethyl 2-{3-[4-(cyclohexyl-phenyl-methyl]-piperazin- 1-yl]-2-hydroxy-propoxy}-benzyl phosphonate

A mixture of 30mmol diethyl 2-(oxiran-2-yl methoxy)-benzyl phosphonate and 30mmol 1-cyclohexyl-phenyl-methyl-piperazin in 45 150ml ethanol was heated under reflux for 5h. The solvent was evaporated under reduced pressure. The remaining residue was

chromatographed over silica gel. The product was isolated as an viscous oil (14.3g).

"C-NMR [DMSO ; δ (ppm)] (citrate) : 15.1, 16.1, 25.5, 25.6, 26.3 29.6, 30.4, 36.3, 43.6, 52.8, 58.9, 61.3, 64.4, 70.1, 71.6, 73.3,

111.5, 120.1, 120.4, 126.9, 127.7, 128.1, 129.0 131.1, 136.2, 155.9, 171.2,176.0

Precursors for nhoat-honatea IIIc

Precursor for diethyl (3-trifluoromethyl-isoxazol-5-yl)-methyl- phosphonate (lllc-1)

5-Chloromethyl-3-trifluoromethyl-isoxazole

To a solution of 36.2g of l-bromo-2-trifluoro-ethanal oxime in dimethylformamide were added 140ml of a 70% solution of propargyl chloride in toluene. 59.8g sodium carbonate was added in small portions over a period of 6h. The suspension was stirred over- night and then filtrated. The filtrate was poured into water. Af¬ ter extraction with dichloromethane the combined organic phases were dried over sodium sulfate. Evaporation of the solvent gave 18.7g of an oily residue which contained 69% product and 31% to¬ luene due to gas chromatography analysis.

iH-NMR [CDC1 ₃ ; δ (ppm) ] : 4.7 ( s , 2 H) , 6.5 (s , 1 H)

Precursor for diethyl (3-methoxy-isoxazol-5-yl) -methy lphosphonate (IIIc-2 )

a) 5-Chloromethyl-3-methoxy-isoxazole

A mixture of l.Og 5-hydroxymethyl-3-methoxy-isoxazole and lOg thionyl chloride was stirred at room temperature for 2Oh. The ex- cess thionylchloride was removed in vacuo, dissolved in toluene and the solvent evaporated. l.Og of an oil was obtained.

iH-NMR [CDCI ₃ ; δ(ppm)]: 4.0 (s,31 H) , 4.5 (s, 2 H) , 6.0 (s, 1 H)

b) 5-Hydroxymethyl-3-methoxy-isoxazole

To a solution of 7.0g 3-methoxy-5-carbethoxy-isoxazole in 80ml tetrahydrofuran a 2m solution of lithiumborohydride in tetra¬ hydrofuran was added at 15 -20°C. The reaction mixture was stirred for 2h at room temperature, then poured into saturated ammoni- umchloride solution and extracted with dichloromethane. The

organic phase was dried over magnesium sulfate and evaporated to- give 4.87g alcohol.

iH-NMR [250 MHz; CDC1 ₃ ; δ(ppm) ] : 4.0 (s,3 H) , 4.6 (s, 2 H) , 5.9 (s, 1 H)

Precursor for diethyl (5-methoxymethyl-isoxazol-3-yl)-methyl- phosphonate (IIIc-3)

a) 3-Chloromethyl-5-methoxymethyl-isoxazole

8.2g of 3-hydroxymethyl-5-methoxymethyl-isoxazole were added to 34g thionyl chloride at 0°C. The resulting mixture was stirred overnight. Excess thionylchloride was removed in vacuo. The resi- due was dissolved in toluene and then the solution was evaporated again. This procedure was repeated three times to give 8.2g of crude chloromethylisoxazole.

iH-NMR [CDC1 ₃ ; δ(ppm) ] : 3.4 (S, 3 H) , 4.5 (s, 2 H) , 4.5 (s, 2 H) , 6.4 (s, 1 H)

b) 3-Hydroxymethyl-5-methoxymethyl-isoxazole

To a solution of 6.55g of 3-carbonylethoxy-5-methoxymethyl-isoxa- zole in 70ml dry tetrahydrofuran were added 77.6ml of a 1 N solu¬ tion of L-selectridew ⁾ at 0°C. The solution was stirred overnight at room temperature. After cooling to 0°C 13ml of water and 33ml of ethanol were added, then simultaneously 33ml of a 6 N solution of sodium hydroxide and 49ml hydrogen peroxide were added with caution. After stirring for half an hour the supernatant was de¬ canted, the residue washed several times with methylene chloride. The aqueous phase was extracted with dichloromethane in an ex¬ traction apparatus for one day. The organic phase was dried over sodium sulfate and the solvent evaporated to give 4.1g product.

iH-NMR [CDC1 ₃ ; δ(ppm) ] : 3 .3 ( s , 1 H) , 3 .4 ( s , 3 H) , 4 . 6 ( s , 2 H) , 4 . 8 ( s , 2 H) , 6 .3 ( s , IH)

c ) 3-Carbonylethoxy-5-methoxymethyl-isoxazole

A solution of 10.lg of dry triethylamine in 180ml diethyl ether was given dropwise to a stirred solution of 15.15g of ethyl chlo- rooximinoacetate and 17.52g propargyl methyl ether in 360ml ether over a period of 5 h at room temperature. After stirring over- night the suspension was diluted with 500ml diethyl ether and

then filtered. The filtrate was washed twice with water, dried over sodium sulfate and concentrated to give 14.8g product.

iH-NMR [CDC1 ₃ ; δtøpm)]. 1.4 (t, 3H), 3.5 (s, 3 H) , 4.5 (q, 2 H) , 5 4.6 (s, 2 H) , 6.7 (s, IH)

Precursor for diethyl (2-methoxymethyl-l,3-thiazol-4-yl)-methyl- phosphonate (IIIc-4)

0 a) 4-Chloromethyl-2-methoxymethyl-l,3-thiazole

A solution of 9g of 2-methoxy-thioacetamide and 10.87g 1,3-dich- loroacetone in 90ml ethanol was refluxed for 2h. The solvent was evaporated and the residue neutralized with saturated sodium bi- 5 carbonate solution. After extraction with ether the organic phase was washed twice with water and dried over sodium sulfate. Evaporation of the solvent left 13.Og crude product.

iH-NMR [CDC1 ₃ ; δ(ppm)]: 3.5 (s, 3H) , 4.7 (s, 2 H) , 4.8 (S, 2 H) , 0 7.3 (s, 1 H)

b) 2-Methoxy-thioacetamide

18g of hydrogen sulfide was bubbled into a solution of 30g of 5 2-methoxy-acetonitrile and 34.lg of triethylamine in 200ml dry dimethylformamide during 30min at a temperature betwen 55 and 60°C. After stirring overnight nitrogen was passed through the dark mixture. The solvent was removed in vacuo, the residue dilu¬ ted with ether and the organic phase was washed three times with 0 water. After drying over sodium sulfate and evaporation of the organic solvent the residue was destilled to give 17.9g product.

Bp = 90-94°C/0.2 mm Hg

35 Precursor for diethyl [2-(4-methoxyphenyl)-l,3-oxazol-4-yl]- methyl phosphonate (IIIc-5)

a) N-Chloroacetyl-N'-(4-methyIbenzoyD-hydrazide

40 56.5g of Chloroacetylchloride were added to a solution of 75.Og of 4-toluic hydrazide and 50.5g of triethylamine in 11 dimethyl¬ formamide at 0°C. After stirring for 1.5h at room temperature the mixture was given into ice water. The precipitate was filtered and washed with water and ethyl acetate. After drying at 30°C

45 71.3g of solid hydrazide were obtained.

Mp = 174-178°C.

b) 4-Chloromethyl-2- (4-methoxyphenyl)-1,3-oxazole

70g of N-chloroacetyl-N'-(4-methylbenzoyl)-hydrazide and 100ml of were stirred for lOh under reflux. Afterwards the excess of phosphoroxychloride was evaporated in vacuo, the obtained residue diluted with water and extracted with methyltert.butylether. The organic phase was dried with sodium sulfate, evaporation of the solvent left 36g of 4-chloromethyl-2-(4-methoxyphenyl)-l,3-oxa- . zole.

Mp = 114-116 °C.

Precursor for diethyl [2-(4-methoxyphenyl)-l,3-oxazol-4-yl]- methylphosphonate (IIIc-6)

4-Chloromethyl-2-(4-methoxy-phenyl)-oxazole

25g of 4-methoxy-benzamide and 21g of 1,3-dichloroacetone were heated to 140°C under nitrogen for 3h. After cooling dichlorome- thane was added and the suspension was filtered. Chromatography on silica gel with heptane/ ethyl acetate (1:2) gave 22.5g oxa¬ zole.

iH-NMR [CDC1 ₃ ;. δ(ppm) ] : 3.9 (s, 3 H) , 4.6 (s, 2 H) , 6.9-7.0 (m, 2 H) , 7.6 (s, 2 H) , 7.9-8.0 (m, 2 H) .

Precursor for diethyl (2-methoxymethyl-l,3,4-thiadiazol-5-yl)- methyl phosphonate (IIIc-7)

a) N-(2-Chloroacetyl)-N'-(2-methoxyacetyl)-hydrazide

104g of N-(2-methoxyacetyl)-hydrazide and lOlg of triethylamine were dissolved in 1200ml of dichloromethane. At 15°C 113g of 2-chloroacetylchloride were added dropwise. After the reaction was completed the precipitate was filtered off, the filtrate di¬ luted with water and and then extracted continuously with ethyla¬ cetate using a perforator. Cristallization of the obtained crude product from ethylacetate afforded 12lg of the product as a white solid.

Mp.: 97-100°C

b) 5-Chloromethy1-2-methoxymethyl-l,3,4-thiadiazole

lOOg of N-(2-chloroacetyl)-N'-(2-methoxyacetyl)-hydrazide were dissolved in 1200ml of 1,4-dioxane, 61.5g of phosphoropentasul- fide and 60g of potassium bicarbonate were added subsequently and

this mixture was refluxed until the reaction was completed. After evaporation of the solvent the obtained brown-red residue was dissolved in ethylacetate, washed with saturated sodium bicarbo¬ nate- and sodium chloride-solution and dried with magnesium sul- 5 fate. After evaporation of the solvent the residue was destilled in vacuo to yield 23g of the product as yellow oil.

Bp.: 155-160°C/0.8mm Hg

0 ⁱ H-NMR (CDC1 ₃ ; δ (ppm)]: 3.5 (s, 3H) , 4.9 (s, 2H) , 4.95 (s, 2H)

VIIc

a) 2-(3-Methyl-isoxazol-5-yl)-l-(2-tert.butyldimethylsiloxy- 5 phenyl)-ethanone

52ml of IN solution of n-butyllithium in hexane were added to a solution of 6g of 3, 5-dimethylisoxazol in 200ml of tetrahydro¬ furan at -78°C. After stirring for lh 15g of methyl 2-tert.butyl- 0 dimethylsiloxybenzoate in 50ml of tetrahydrofuran were added at the same temperature. The reaction mixture was slowly warmed up to -20°C. A saturated aqueous solution of ammo _* nium chloride was added, the mixture was extracted several times with ethylacetate. The organic phase was separated, washed with water and dried over 5 magnesium sulfate. Chromatography on silica gel with heptane/ ethylacetate gave 9.4g of the product.

iH-NMR (CDC1 _3; δ (ppm)]: 0.3 (s, 9H) , 1.0 (s, 3H) , 2.3 (S, 3H) , 4.4 (s, 2H), 6.1 (s, IH) , 6.9 (d, IH) , 7.0 (dd, IH) , 7.4 (dd, 30 IH) , 7.6 (d, IH) .

b) 2-(3-Methyl-isoxazol-5-yl-ethinyl)-pheny1-tert.butyldimethy1 - silyl-ether

35 14.6g of triethylamine were added to a suspension of 6g of 2-(3-methyl-isoxazol-5-yl)-l-(2-tert.butyldimethylsiloxy- phenyl)-ethanone and 5.8g 2-chloro-3-ethylbenzoxazolium tetra- fluoroborate in 150ml of dichloromethane at 0°C. After stirring at room temperature overnight the reaction mixture was poured into

40 water and extracted with ethylacetate. The organic phase was se¬ parated and dried over magnesium sulfate. After filtration and evaporation the residue was chromatographed on silica gel to af¬ ford 1.2g of the 2-(3-methyl-isoxazol-5-yl-ethinyl)-pheny1- tert.butyldimethylsily1-ether.

45

iH-NMR (CDCI ₃ ,. δ (ppm)] : 0.3 (s, 9H) , 1.0 (s, 6H) , 2.3 (s, 3H) , 6.3 (s, IH) , 6.9 (d, IH) , 7.0 (dd, IH) , 7.3 (dd, IH) , 7.5 (d, IH) .

The compounds of the present invention may be used to treat tu¬ mors by administration of the compound to the mammal in combina¬ tion with usual chemotherapy.

Usual chemotherapy means treatment with chemotherapeutic agents such as:

a) antibiotics such as actinomycine D, doxorubicine (adriamy- cine) , daunorubicine, mithramycine, bleo ycine or other interca¬ lating agents,

b) alkaloids such as vincristine, vinblastine, vindevinblastine, vindesine, etoposide and tenoposide,

c) alkylating agents such as cyclophosphamide, nitrosoureas, cis- platin

d) antimetabolites such as methotrexate, 5-fluorouracile and ana¬ logues, 6-mercaptopurine, 6-thioguanine and cytarabine,

and combinations of thereof.

Description of biological models

In vivo Tumor Models

• Murine Tumor model

The tumor line M109H2 is a subline of the murine Madison lung carcinoma M109 selected for resistance to Adriamycin (ADR) . M109 is of spontaneous origin in BALB/c mice. The M109H2 subline grows as a monolayer in 90% RPMI-1640 and 10% fetal bovine serum.

On day 0, mice are inoculated subcutaneously with lxlO ⁶ cells. The mice used are 4-6 weeks old athymic female nude mice obtained from Taconic or Charles River Laboratories. On day 7, the tumor bearing mice are randomized into groups of 5.

In the M109H2 model, for each experiment there is a negative con¬ trol group (receiving ADR only) and a positive control group (re- ceiving a known modulator and ADR) .

The new compounds (modulators) are given i.p. or p.o. twice daily for three consecutive days starting on day 7 of tumor growth. ADR is administered i.v. 1/2 hour after the first injection on the second day of treatment tumor measurements, using vernier cali- pers, begin on day seven and continue 2 or 3 times per week for two weeks. On day 20-22 after initial injection the mice are sa¬ crificed.

• Human Tumor Xenograph

The tumor line MIP-4 is a human colon carcinoma which is intrisi- cally resistant to Adriamycin. The cell line grows as a monolayer in 90% RPMI-1640 and 10% fetal bovine serum.

On day 0, mice are inoculated intramuscularly with 1.5x10s cells. The mice used are 4-6 weeks old athymic female nude mice obtained from Taconic or Charles River Laboratories. On day 7, the tumor bearing mice are randomized into groups of 5.

In the MIP-4 model, for each experiment there is a tumor growth control group (receiving vehicle only) , a negative control group (receiving Vinblastine [VBL] only) and a positive control group (receiving a known modulator and VBL) . The remaining groups are used for testing modulators and VBL.

The modulators are given i.p. or p.o. once per day on days 6, 13, and 20 of tumor growth. VBL is administered i.v. 1 hour after mo¬ dulator injection on all days of treatment. Tumor measurements are made on days 7 and 13, then, and continue 2 or 3 times per week. 30-35 days after initial injection the mice are sacrificed and the tumor bearing legs removed and weighted.

The efficacy of the modulators is determined by comparing the tu¬ mor growth of treated mice versus ADR only control mice. Tumor volumes are calculated from the tumor diameters using the formula for a ellipsoid volume (μl of tumor volume = L x WV2) . Results are expressed as a percentage relative to the mean tumor volume for the ADR only control group.

mean tumor volume of treated

% tumor growth = x 100 mean tumor volume of ADR only

In Vitro Tumor Model β

ME180R cells were plated in lOOμl of DMEM media at a concentra¬ tion of 5x10 ^s cells/ml and incubated overnight. Spent media was removed by blotting on day 2 and replaced with 100 μl of fresh media containig Ixl0- ⁷ M [ ³ H] Vinblastine sulphate (8.3 Ci/mmol) and varying concentrations of modulator compounds ranging from Ixl0-5M to lxl0- ⁷ M. Plates were incubated for 4-5 hours at 37°C, 5% C0 ₂ . Plates were washed 5x with 100 μl PBS to remove free Vinblastine. Cells were trypsinized and harvested into 3 mis of scintillation fluid. Enhancement of drug accumulation in the presence of modu¬ lator was monitored via LSC.

The compounds of the present invention show good activity in the models described.

The compounds of the formula 1 can be administered together with or seperately from the cancerostatics. However, seperate prior administration, and seperate prior administration with subsequent simultaneous administration of a new compound plus cancerostatic is preferred. Administration may be any of the means which are conventional for pharmaceutical, preferably oncological agents, including oral and parenteral means such as subcutaneously, in- traveneously, intramuscularly and intraperitoneally. The compounds may be administered alone or in the form of pharmaceu¬ tical compositions containing a compound of formula 1 together with a pharmaceutically accepted carrier appropriate for the de¬ sired route of administration. Such pharmaceutical compositions may be combination products, i.e., may also contain other thera- peutically active ingredients.

The dosage to be administered to the mammal will contain an ef¬ fective resistance-modulating amount of active ingredient which will depend upon conventional factors including the biological activity of the particular compound employed; the means of admi¬ nistration; the age, health and body weight of the recipient; the nature and extent of the symptoms; the frequency of treatment; the administration of other therapies; and the effect desired. A typical daily dose will be about 5 to 1000 milligrams per kilo- gramm of body weight on oral administration and about 1 to 100 mg milligrams per kilogramm of body weight on parenteral administra- tion.

The novel compounds can be administered alone or together with the cancerostatics in conventional solid or liquid pharmaceutical administration forms, eg. incoated or film-coated tablets, capsu- Ies, powders, granules, suppositories or solutions. These are produced in a conventional manner. The active substances can for this purpose be processed with conventional pharmaceutical aids

such as tablet binders, fillers, preservatives, tablet disinte- grants, flow regulators, plasticizers, wetting agents, disper- sants, emulsifiers, solvents, sustained release compositions, an- tioxidants, and/or propellant gases (cf. H.Sucker et al in "Phar- mazeutische Technologie", Thieme Verlag, Stuttgart, 1978). The administration forms obtained in this way normally contain up to 90% by weight of the active substances.