FI106551B - Process for preparing α- [(heterocyclylalkoxy)phenyl]-ω-arylalkane compounds or α-[(heterocyclyloxy)phenyl]-ω-arylalkane compounds which can be used as drugs - Google Patents

Description

106551

A process for the preparation of an alpha-[(heterocyclylalkoxy) phenyl] -M-alkylalkane or o - [(heterocyclyloxy) phenyl] - ω-arylalkane compound for use as a medicament. arylalkan- eller

O - [(heterocyclyloxi) phenyl] - ω-arylalkanenfureningar 10

The present invention relates to a series of novel α, ω-diarylalkane derivatives which are antagonists of the serotonin-2 receptor and are therefore useful in the treatment and prevention of circulatory diseases (cardiovascular) and psychoses. The invention also provides methods and compositions using these new compounds as well as methods for preparing them.

Traditionally, serotonin has been grouped with autosoids. One known neurotransmitter, serotin, has many physiological effects in vivo which are mediated through various receptors. Several subtypes of serotin receptors are known. In the circulatory system, receptors classified as serotonin-2 receptors divide into vascular endothelial cells and platelets, and these receptors strongly influence blood vessels and particle agglutination [e.g. SJ. Peroutka et al., Fed. Proc., 42, 213 (1983)]. Antagonists of these receptors are useful in preventing vasoconstriction and in preventing the agglutination of blood particles.

25, Recent reports have suggested the use of MCI-9042, which is {2 - [(- aminoalkoxy) phenyl] ethyl} benzene, to prevent agglutination of blood particles based on its 4 serotonin 2 receptor antagonist activity [e.g. J. Med. Chem., 1992, 35, 189].

Although these compounds have no antagonistic effect on adrenaline α1, their antagonistic effect on serotonin-2 receptors and / or their anti-agglutinating activity on platelet particles is also insufficiently potent. Therefore, in order to achieve results at the clinical level, there was a need to develop a drug that has both potent and selective antagonism at the serotonin-2 receptors.

5 Compounds having a general οί, ω-diarylalkane structure have been proposed for the treatment of circulatory diseases due to their agglutination effects on blood particles. Examples of such compounds are disclosed in European Patent Nos. 1,759, 72,942 and 398,326, as well as in J. Med. Chem., 33, 1818 (1990) and J. Med. Chem., 35, 1S9 (1992).

10

We have surprisingly found that many of these types of compounds, apart from having a surprisingly better serotonin-2 receptor antagonist effect leading to their use in the treatment and prevention of circulatory diseases, also have a surprising dopamine-2 receptor antagonist effect leading to their use. for the treatment of conditions and for the prevention of en-15 paralysis, especially of psychoses.

EP-398326 describes {2- [pho- (aminoalkoxy) phenyl] ethyl! Bem-gene derivatives that inhibit platelet adhesion due to their serotonin-1-nin-2 receptor antagonist activity. Of the compounds disclosed in this prior art publication, the compound MCI-9042 is closest in structure to the compounds disclosed in the present application and has the strongest effect on platelet aggre-. ligations.

As shown in Table 4 of the current application, the effect of MCI-9042 is weak (IC-25 was 72.0 nM). Accordingly, the compounds of the present invention disclosed in the present application have a significant and surprisingly superior vasoconstrictor activity compared with the EP 1759, EP 72942, EP 398326 and J. Med. Chem ..

33, 1818 (1990).

WO-92/22527, WO-92/02501 and WO-92/02502 (the first of which was published only after the first priority date of the present application) disclose diaryl-3 106551 cyano derivatives in which one of the aryl rings may be substituted by 1-alkyl-3-pyrrolidinylalkoxy , a 1-alkyl-3-piperidinylalkoxy group or a 1-alkyl-4-piperidinylalkoxy group, respectively. These compounds are shown to have potency as calcium antagonists. Again, these publications do not claim that their compounds act as serotonin-2 receptor antagonists.

Thus, the compounds of the present application may be used in the treatment of a variety of circulatory disorders for which the calcium antagonists of the prior art publications mentioned above would be unsuitable. Further, none of these prior art publications disclose any facts that would lead one of ordinary skill in the art to believe that the compounds of the present invention would also have an effect in the treatment and prevention of psychosis. Therefore, the compounds of the present invention are clearly inventive over the compounds disclosed in the prior art.

15

Thus, it is an object of the present invention to provide a plurality of novel θί, ω-diarylialcanan derivatives.

Furthermore, it is a particular object of the present invention to provide compounds that are serotonin-2 receptor antagonists.

Other objects and advantages of the present invention will become apparent as the specification proceeds.

The present invention relates to a process for the preparation of a 25 ° - [(heterocyclyloxyalkoxy) phenyl] - N -arylalkane or α - [(heterocyclyloxy) phenyl] - N- (arylalkane) compound having the general formula (I): * 7 Λ

R-D-Q

Wherein R 1 is an unsubstituted naphthyl group or a phenyl group unsubstituted or substituted with at least one substituent selected from alkyl groups having from 1 to 6 carbon atoms, hydroxy groups, alkoxy groups having from 1 to 6 carbon atoms, halogen atoms, cyano groups, carbamoyl groups and difluoromethoxy groups; D is a single carbon-oxygen bond or an alkylene group having 1-4 carbon atoms; R 7 is a pyrrolidine ring, a morpholine ring or a piperidine ring linked through a carbon atom in the heterocyclic ring to D, said group R 7 being optionally substituted on a carbon atom by a substituent selected from the group consisting of 15 alkyl groups, alkoxycarbonyloxy groups. having from 2 to 7 carbon atoms, alkanoyloxy groups having from 1 to 20 carbon atoms and substituted alkanoyloxy groups having from 2 to 5 carbon atoms, substituted with a carboxy group and / or optionally substituted with a nitrogen atom having from 1 to 6 carbon atoms; and A is an alkylene group having from 2 to 8 carbon atoms; and pharmaceutically acceptable acid addition salts and esters thereof; PROVIDED THAT: R7 is other than:: a 1-alkyl-3-piperidinyl, 1-alkyl-4-piperidinyl or 1-alkyl-3-pyrrolidinyl group; And the process is characterized in that the process provides a compound of formula (II) 30 (5 106551% - 3) - 5 where A is as defined above and R 11 is any group according to R 'except that the hydroxy groups (if any) are protected; With a compound of formula (VII): Z-D-R7a (VII) wherein D is as defined above; R7a is any group according to R7 except that any hydroxy group is protected and any heterocyclic nitrogen atom is protected; and Z is a hydroxy group or a group or atom capable of being removed as a nucleophilic residue; and, if necessary, removing protecting groups; 25 v and, if necessary, any or more of the following steps (i) to (iv); (5551 (ii) where R7 is an N-unsubstituted heterocyclic group, alkylating said compound to give a compound wherein R7 is an N-alkyl substituted heterocyclic group; (iii) converting the alkoxycarbonyl group to a methyl group; and (iv) forming a salt of the product; an ester to provide a pharmaceutically acceptable acid addition salt or ester of a compound of formula (I).

The invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, in admixture with a pharmaceutically acceptable carrier or diluent.

The invention further provides a method of treating or preventing circulatory disorders in a mammal by administering to said mammal an effective amount of an active compound, the active compound being at least one compound of formula (I), or a pharmaceutically acceptable salt or ester thereof.

The invention further provides a method of treating or preventing psychosis in a mammal by administering to said mammal an effective amount of an active compound, wherein the active compound is at least one compound of formula (I), or a pharmaceutically acceptable salt or ester thereof.

•

The invention also provides methods for preparing the compounds of the present invention, which methods will be described in more detail below.

25

In the compounds of the present invention, R1 is an unsubstituted naphthyl group or a phenyl group which is unsubstituted or substituted with at least one substituent. In the case of a • t-substituted phenyl group, the number of substituents is not particularly limited except possibly by etheric barriers. Generally, however, 1, 2 or 3 such substituents are preferred, with 1 30 or 2 being more preferred. Examples of groups and atoms that may belong to the substituents include: 7 106551 alkyl groups having 1-6 carbon atoms, which may be straight or branched chains such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl -, sec-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2- methylpentyl, 1-methylpentyl, 3.3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl, of which alkyl groups having from 1 to 4 carbon atoms are preferred, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups and methyl and ethyl groups are more preferred. even more affordable; the methyl group is the most preferred such alkyl group; . hydroxy groups; alkoxy groups having from 1 to 6 carbon atoms, which may be straight or branched groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy. 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy -20 and 2-ethylbutoxy groups, of which alkoxy groups having 1 to 4 carbon atoms are preferred, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and t-butoxy groups are more preferred and methoxy and ethoxy groups are even more preferred; a methoxy group is most preferred, such as an alkoxy group; A difluoromethoxy group; . halogen atoms such as fluorine, chlorine, bromine and iodine atoms, preferably fluorine, chlorine or bromine; 30 cyano groups; 8 106551 carbamoyl groups.

Of these substituents, alkyl groups having from 1 to 4 carbon atoms, hydroxy groups, alkoxy groups having from 1 to 4 carbon atoms, halogen atoms, cyano groups and carbamoyl-5-yl groups, methyl, ethyl, hydroxy, methoxy, ethoxy, are preferred. difluoromethoxy and cyano groups, with fluorine, chlorine and bromine atoms being more preferred.

Specific examples of preferred substituted and unsubstituted aryl groups which R 1 may represent are phenyl, N-naphthyl, β-naphthyl, 2-methoxyphenyl, ΒΙΟ methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl. -, 4-ethoxyphenyl. 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 4-difluoromethoxyphenyl. 2- (2-fluoroethoxy) phenyl, 3- (2-fluoroethoxy) phenyl, 4- (2-fluoroethoxy) phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3- ethylphenyl, 4-ethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-15 chlorophenyl, 2-bromophenyl, 3-bromophenyl, , 4-bromophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-carbamoylphenyl, 3-carbamoylphenyl, 4- carbamoylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 3,4-dimethoxyphenyl.

3,5-dimethoxyphenyl, biphenylyl, 3,5-dimethylphenyl, 3-ethoxy-5-methoxyphenyl. 3-20 hydroxy-5-methoxyphenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl.

3.4.5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 3,4,5-trichlorophenyl and 2.4.6-trichlorophenyl.

The group D of the formula -D-R7 has a single carbon-oxygen bond or an alkylene group having 1-4 carbon atoms and R7 represents a pyrrolidine, morpholine or piperidine ring attached to D via a carbon atom in the heterocyclic group;

When D is an alkylene group, there may be 1-4, preferably 1 or 2, carbon atoms and may be a straight or branched chain. In the present invention, it is preferable that the two "free" valences 30 are attached to different carbon atoms, and more preferably those compounds wherein the stupid is a straight chain wherein two "free" valences are attached to non-carbon atoms. Preferred alkylene groups represented by Group D are methylene, ethylene, trimethylene and tetramethylene groups, of which methylene and ethylene groups are preferred.

The heterocyclic group R7 is attached to the single bond or alkyl-5 moiety of brand D on the carbon atom of the heterocyclic group.

Specific examples of preferred substituted and unsubstituted heterocyclic groups which may be represented by R 7 include: pyrrolidinyl, methylpyrrolidinyl, ethyl p-T-rolidinyl, propylpyrrolidinyl, isopropylpyrrolidinyl, butylpyrrolidinyl.

10 hydroksipyrrolidinyyli-, metoksikarbonyylioksipyrrolidinyyli-, etoksikarbonvylioksipyrroli- dinyyli-, propoksikarbonyylioksipyrrolidinyyli-, isopropoksikarbonyylioksip \ Trolidinyyli-, butoksikarbonyylioksipyrrolidinyyli-, t-butoksikarbonyylioksipyrrolidinyyli-, formyloxy-pyixolidinyyli-, asetoksipyrrolidinyyli-, propionyylioksipyrrolidinyyli-, butyiyy-lioksipyrrolidinyyli-, pivaloyylioksipyrrolidinyyli-, valeryylioksipyrrolidinyyli-. Lauro γ-15 oxy-pyrrolidinyl, myristoyloxy-pyrrolidinyl, tridecanoyl-oxy-pyrrolidinyl.

pentadecanoyloxy-pyrrolidinyl, palmitoyloxy-pyrrolidinyl, heptadecanoyloxy-pyrrolidinyl, stearoyloxy-pyrrolidinyl, nonadecanoyloxy-pyrrolidinyl, icosanoyloxy-pyrrolidinyl, (succinoyloxy) pyrrolidinyl, (glutenoyloxy) pyrrolidinyl, (glutenoyloxy) pyrrolidinyl, (glutenoyloxy) pyrrolidinyl, (glutoyloxy) 1-methylhydroxypyrrolidinyl, 1-methylmethoxycarbonyloxypyrrolidinyl.

20 1-methylethoxycarbonyloxy-pyrrolidinyl, 1-methyl-propoxycarbonyloxy-pyrididinyl, 1-methyl-isopropoxycarbonyloxy-pyrrolidinyl, 1-methyl-butoxycarbonyl-yloxy-pyrrolidinyl, 1-methyl-t-butoxycarbonyloxy-1-methyl-1 , 1-methyl-lipivaloyloxypyrrolidinyl, 1-methyl-lauroyl-pyrrolidinyl, 1-methyl-myristoyl-25-yloxypyrrolidinyl, 1-methyl-tridecanoyloxypyrrolidinyl, 1-methyl-pentadec-4-canoyloxy-pyrrolidinyl, 1-methyl-1 tadecanoyloxy-pyrrolidinyl, 1-methyl-stearoyloxy-pyrrolidinyl, 1-methyl: - »nonadecanoyloxy-pyrrolidinyl, 1-methyl-icosanoyloxypyrrolidine, 1-methyl (succinoyloxy) pyrrolidinyl, 1-methyl (glutaroyl) 3 0 ethylhydroxypyrrolidinyl, 1-ethylmethoxycarbonyloxypyrrolidinyl, 1-ethylethoxycarbonyloxypyrrolidinyl, 1-ethylpropoxy ikarbonyylioksip \ Trolidiny> di-.

10 106551 1-Ethyl-isopropoxycarbonyloxy-pyrrolidinyl, 1-ethyl-butoxycarbonyloxy-pyrrolidinyl, 1-ethyl-t-butoxycarbonyloxy-pyrrolidinyl, 1-ethyl-acetoxy-pyrrolidinyl, 1-ethyl-pivaloyloxy-pyrrolidinyl, -ethyltridecanoyloxypyrrolidinyl, 1- 5 -ethylpentadecanoyloxy-pyrrolidinyl, 1-ethyl-palmitoyloxypyrrolidinyl, 1-ethyl-heptadecanoyloxy-pyrrolidinyl, 1-ethyl-styro-yloxy-pyrrolidinyl, 1-ethyl-butyl-oxyloxy-pyrrolidinyl, , methylpiperidyl, ethylpiperidyl, propylpiperidyl, isopropylpiperidyl, butylpiperidyl, hydroxypiperidyl, methoxycarbonyloxypiperidyl, ethoxycarbonyloxypiperidyl, propoxycarbonyloxypiperidyl, isopropoxycarbonyl overoxypiperidyl, acetoxypiperidyl, propionyloxypiperidyl, pivaloyloxypiperidyl, lauroyloxypiperidyl, myristoyl overoxypiperidyl, tridecanoyloxypiperidyl, pentadecanoylpiperidyl. pal-15 mitoyloxypiperidyl, heptadecanoyloxypiperidyl, stearoyloxypiperidyl. nonadecanoyloxypiperidyl, icosanoyloxypiperidyl, succinoyloxypiperidyl, glutaroyloxypiperidyl, 1-methylhydroxypiperidyl, 1-methylmethoxycarbonyl-oxypiperidyl, 1-methylethoxycarbonyloxypiperidyl, 1-methylethoxycarbonyloxypiperidyl, over-.

20 1-methylbutoxycarbonyloxypiperidyl, 1-methyl-t-butoxycarbonyloxypiperidine, 1-methylacetoxypiperidyl, 1-methylpropionyloxypiperidyl, 1-methyl-pivaloyloxypiperidyl, 1-methyl-lauroyloxypiperidyl, 1-methyl-lauroyl-oxy methyltridecanoyloxypiperidyl, 1-methylpentadeo-canoyloxypiperidyl, 1-methylphthalmitoyloxypiperidyl, 1-methylheptanoyloxypiperidyl, 1-methylstearoyloxypiperidyl, 1-methylnonadanoyloxypiperidyl, 1-methylnonadanoyloxypiperidyl, ) piperidyl, 1-etyl. dihydroxypiperidyl, 1-ethylmethoxycarbonyloxypiperidyl, 1-ethyl-ethoxycarbonyloxypiperidyl, 1-ethyl-propoxycarbonyloxypiperidyl, 1-ethyl-isopropoxycarbonyloxypiperidyl, 1-ethyl-butoxycarbonyloxy-piperidyl, etyyliasetoksipiperidyyli-, 1-etyylipiva- loyylioksipiperidyyli-, 1-etyylimyristoyylioksipiperidyyli-, l-etyylitridekano \ yliok- 106 551 sipiperidyyli-, 1 -etyylipentadekanoyylioksipiperidyyli-, -etyylipalmitoyylioksipiperidyyli- 1, 1-etyyliheptadekanoyylioksipiperidyyli-, 1-etyylistearoyylioksipiperidyyli-, 1 - etyylinonadekanoyylioksipiperidyyli-, 1-Ethyl-icosananoyloxypiperidyl, 1-ethylcyclo-quinoyloxypiperidyl, morpholinyl, 4-methylmorpholinyl, 4-ethylmorpholinyl, 4-5 propylmorpholinyl, 4-isopropylmorpholinyl, 4-butylmorpholinyl, 1 -methylpyrrolidinyl, 1-ethylpyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-ethoxy arbonyloxy-2-pyrrolidinyl, 4-isopropoxycarbonyloxy-2-pyrrolidinyl, 4-t-butoxycarbonyloxy-2-pyrrolidinyl, 4-formyloxy-2-pyrrolidinyl, 4-acetoxy-2-pyrrolidinyl, 4-pivaloyloxy-2 pyrrolidinyl, 10-valeryloxy-2-pyrrolidinyl, 4-myristoyloxy-2-pyrrolidinyl, 4-tridecanoyloxy-2-pyrrolidinyl, 4-pentadecanoyloxy-2-pyrrolidinyl, 4-palmitoyloxy-2-pyrrolidinyl, 4-heptadecanoyloxy-2-pyrrolidinyl, 4-stearoyloxy-2-pyrrolidinyl, 4-nonadecanoyloxy-2-pyrrolidinyl, 4-icanosanoyloxy-2-pyrrolidinyl, 4- (succinoyloxy) -2-pyrrolidinyl, 4- ( glutaryloxy) -2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-ethoxycarbonyloxy-2-pyrrolidinyl, 1-methyl-4-isopropoxycarbonyloxy-2-pyrrolidinyl, 1- methyl 4-t-butoxycarbonyloxy-2-pyrrolidinyl, 1-methyl-4-acetoxy-2-pyrrolidinyl, 1-methyl-4-myristoyloxy-2-pyrrolidinyl, 1-methyl-4-tridecanoyloxy-2-pyrrolidinyl i-, 1-mem-4-pentadecanoyloxy-2-pyrrolidinyl, 1-methyl-4-palmitoyloxy-2-pyrrolidinyl. 1 -20 methyl-4-heptadecanoyloxy-2-pyrrolidinyl, 1-ethyl-4-palmitoyloxy-2-pyrrolidinyl, 1-methyl-4-stealoyloxy-2-pyrrolidinyl, 1-methyl-4-nonadecanoyl * ' oxy-2-pyrrolidinyl, 1-methyl-4-icosanoyloxy-2-pyrrolidinyl, 1-methyl-4-succinoyloxy-2-pyrrolidinyl, 1-methyl-4-glutaroyloxy-2-pyrrolidinyl, 1- ethyl 4-hydroxy-2-pyrrolidinyl, 1-ethyl-4-ethoxycarbonyloxy-2-pyrrolidinyl, 1-ethyl-4'-isopropoxycarbonyloxy-2-pyrrolidinyl, 1-ethyl-4-t -butoxycarbonyloxy-2-pyrrolidinyl, 1-ethyl-4-acetoxy-2-pyrrolidinyl, 1-ethyl-4-myristoyloxy-2-. pyrrolidinyl, 1-ethyl-4-tridecanoyloxy-2-pyrrolidinyl, 1-ethyl-4-pentadecanoyloxy-2-pyrrolidinyl, 1-ethyl-4-palmitoyloxy-2-pyrrolidinyl, 1-ethyl-4- heptadecanoyloxy-2-pyrrolidinyl, 1-ethyl-4-stealoyloxy-2-pyrrolidinyl, 1-ethyl-4-nonadecanoyloxy-2-pyrrolidinyl, 1-ethyl-4-icosanoyloxy-2-pyrrolidinyl, 1-ethyl -4-Succinoyloxy-2-pyrrolidinyl, piperidyl, 1-methylpiperidyl, 1-ethyl-106551 piperidyl, hydroxypiperidyl, ethoxycarbonyloxypiperidyl, isopropoxycarbonyloxypiperidyl, t-butoxycarbonyloxypiperidyl, acetoxy , tridecanoyloxypiperidyl, pentadecanoyloxypiperidyl, palmitoyloxypiperidyl, heptadecanoyloxypiperidyl, stearoyloxypiperidyl, nonadecanoyloxypiperidyl, icosanoyloxypiperidyl, succinoyloxy -peridyl, 1-methyl-isopropoxycarbonyloxypiperidyl, 1-methyl-t-butoxycarbonyl-oxypiperidyl, 1-methyl-acetoxypiperidyl, 1-methyl-myristoyloxypiperidyl, 1-methyl-tridecanoyloxypiperidyl, 1-methyl-pyridyl, , 1-methylheptade-canoyloxypiperidyl, 1-methyl-stearoyloxypiperidyl, 1-methyl-nonadecanoyloxypiperidyl, 1-methyl-icanosanoyloxypiperidyl, 1-methyl (succinoyloxy) piperidyl, 1-ethylhydroxypiperidyl, 1-ethylhydroxy ethyl-isopropoxycarbonyloxypiperidyl, 1-ethyl-t-butoxycarbonyloxypiperidyl, 1-ethyl-acetoxypiperidyl, 1-ethyl-myristoyloxypiperidyl, 1-ethyl-tri-decanoyloxy-piperidyl, 1-ethyl-tri-decanoyloxy oxypiperidyl, 1-ethylnonadecanoyloxypiperidyl, 1-ethyl i-icosananoyloxypiperidyl, 1-ethylsuccinoyloxypiperidyl, morpholinyl, 4-methyl-20-morpholinyl, 4-ethylmorpholinyl, 4-propylmorpholinyl, 4-isopropylmorpholinyl, 4-butylmorpholinyl. Most preferred of these are pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-ethoxycarbonyloxy-2-pyrrolidinyl, 4-isopropoxycarbonyloxy-2-pyrrolidinyl, 4-t- butoxycarbonyloxy-2-pyrrolidinyl, 4-acetoxy-2-pyrrolidinyl, 4-myristoyloxy-2-pyrrolidinyl, 4-palmitoyloxy-2-pyrrolidinyl, 4-stearoyloxy-2-pyrrolidinyl, 4-icanosanoyloxy -2-pyrrolidinyl, 4- (succinoyloxy) -2-pyrrolidinyl, 4- (glutaroyloxy) -2-pyrrolidinyl, 1-methyl-4-. hydroxy-2-pyrrolidinyl, 1-methyl-4-ethoxycarbonyloxy-2-pyrrolidinyl, 1-methyl-4-t-butoxycarbonyloxy-2-pyrrolidinyl, 1-methyl-4-acetoxy-2-pyrrolidinyl, 1- methyl 4-myristoyloxy-2-pyrrolidinyl, 1-methyl-4-palmitoyloxy-2-pyrrolidinyl, 1-methyl-4-stealoyloxy-2-pyrrolidinyl, 1-methyl-4-icosanoyloxy-2-pyrimidinyl- , 1-Methyl-4-succinoyloxy-pyrrolidinyl, 1-methyl-4-glutaroyloxy-2-pyrrolidinyl, - (1-ethyl-4-hydroxy-2-pyrrolidinyl, 1-ethyl-4-ethoxycarbonyloxy-2-pyrrolidinyl) -, 1-ethyl-4-isopropoxycarbonyloxy-2-pyrrolidinyl, 1-ethyl-4-t-butoxycarbonyloxy-2-pyrrolidinyl, 1-ethyl-4-acetoxy-2-pyrrolidinyl, 1-ethyl-4- myristoyloxy-2-pyrrolidinyl, 1-ethyl-4-palmitoyloxy-2-pyrrolidinyl, 1-ethyl-4-stealoyloxy-2-pyrrolidinyl, 1-ethyl-4-icosanoyloxy-2-pyrrolidinyl, 1-ethyl -4-succinoyloxy-2-pyrrolidinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-methyl-2-piperidyl, 2-morpholinyl, 4-methyl-2-morpholinyl, 4-ethyl-2-morpholinyl. Even more preferred groups are 2-pyrrolidinyl, 3-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-ethoxycarbonyloxy-2-pyrrolidinyl, 4-isopropyl-10-oxycarbonyloxy-2- pyrrolidinyl, 4-t-butoxycarbonyloxy-2-pyrrolidinyl, 4-acetoxy-2-pyrrolidinyl, 4-myristoyloxy-2-pyrrolidinyl, 4-palmitoyloxy-2-pyrrolidinyl, 4-stearoyloxy-2-pyrrolidinyl, 4- (Succinoyloxy) -2-pyrrolidinyl, 1-methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl-4-ethoxycarbonyloxy-2-pyrrolidinyl, 1-methyl-4-t-butoxycarbonyloxy-2-pyrrolidinyl -, 1-methyl-4-acetoxy-2-pyrrolidinyl, 1-methyl-4-myristoyloxy-2-pyrrolidinyl, 1-methyl-4-palmitoyloxy-2-pyrrolidinyl, 1-methyl-4-stearoyloxy- 2-pyrrolidinyl, 1-methyl-4-succinoyloxy-2-pyrrolidinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-methyl-2-piperidyl, 2-morpholinyl, and 4-pyrrolidinyl; methyl-2-morpholinyl. Most preferred groups are 2-pyrrolidinyl, 1-methyl-2-pyrrolidinyl, 4-hydroxy-2-pyrrolidinyl, 4-acetoxy-2-20 pyrrolidinyl, 4- (succinoyloxy) -2-pyrrolidinyl, 1-methyl -4-hydroxy-2-pyrrolidinyl, 1-methyl-4-succinoyloxy-2-pyrrolidinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-methyl-2-piperidyl, 2- morpholinyl and 4-methyl-2-morpholinyl groups.

A is an alkylene group having from 2 to 8 carbon atoms, preferably from 2 to 7 carbon atoms, most preferably from 2 to 5 carbon atoms. In the case of compounds intended for the treatment of circulatory diseases. or for prevention, A is more preferably an alkylene group having 2-4, more preferably 2 or 4, and most preferably 2, carbon atoms. In the case of compounds for the prophylaxis or treatment of psychosis, A is more preferably an alkylene group having 4 to 30 or 5 carbon atoms. Examples of such alkylene groups which may be represented by Group A include ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene and octamethylene, with ethylene, trimethylene, tetramethylene, tetramethylene and tetramethylene being preferred. , pentamethylene, hexamethylene and heptamethylene groups, with ethylene and tetramethylene groups being most preferred for the prophylaxis or treatment of circulatory diseases and tetramethylene and pentamethylene groups being most preferred for the prophylaxis or treatment of psychosis.

The compounds of the present invention may form salts. There is no limitation on the quality of such salts, provided that when the compounds are used for therapeutic purposes, the salts are pharmaceutically acceptable, i.e., they are not less active or too much less active or toxic or too toxic than the free acid. When the compounds are used for non-therapeutic purposes, e.g. as media for the preparation of other compounds, this limitation does not apply either. When a compound contains a carboxy group as a substituent on an alkanoyloxy group, examples of such salts include: salts with an alkali metal such as sodium, potassium or lithium; salts with an alkaline earth metal such as batium or calcium; salts with another metal such as magnesium or aluminum; ammonium salts; organic base salts such as triethylamine, diisopropylamine, cyclohexylamine or dicyclohexylamine; and salts with a basic amino acid such as lysine or arginine. Also, when the compound of the present invention contains a basic group in its molecule, it can form acid addition salts. Preliminary examples of such acid addition salts include: salts with mineral acids, in particular, hydrohalic acids (such as hydrobromic acid, hydroiodic acid or hydrochloric acid), nitric, perchloric, carbonic, sulfuric or phosphoric acids; salts with lower alkyl sulfonic acids, such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; salts with arylsulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid; hydrochloric acids with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid, or citric acid; and salts with amino acids such as glutamic acid or aspartic acid.

When the compounds of the present invention contain a carboxy group, they may also form esters as is well known in the art. Also, the quality of such esters is not particularly limited, although they are preferably pharmaceutically acceptable and examples of esters are well known in the art. Exemplary preferred esters are: alkyl esters having from 1 to 6, preferably from 1 to 4, carbon atoms in the alkyl group and may be present. as defined and exemplified above in connection with alkyl groups, or aralkyl esters having preferably from 1 to 4, more preferably 1 or 2, carbon atoms in the alkyl moiety. Preferred examples of esters include: methyl, ethyl, propyl, isopropyl, butyl, t-butyl, benzyl, phenethyl, and benzhydryl esters.

The compounds of the present invention may contain one or more asymmetric carbon atoms of 10 min in their molecules and may thus form optical isomers. Although all of these are represented herein by a single molecular formula, the present invention includes both individual isolated isomers and mixtures including their racemates. Using stereo-specific synthesis techniques or optically active compounds as starting materials, the individual isomers can be prepared directly; on the other hand, if a mixture of isomers is made, the individual isomers 15 can be obtained by conventional separation techniques.

A preferred group of compounds of the present invention are those compounds of formula (I) wherein: D is a single carbon-oxygen bond or an alkylene group having 1 to 3 carbon atoms; 'R' is a pyrrolidine ring, a morpholine ring or a piperidine ring bonded to D through a carbon atom of the heterocyclic ring, said group R7 being optionally substituted on the carbon atom by a substituent selected from the group consisting of: , alkoxycarbonyloxy groups having 2 to 5 carbon atoms, alkanoyloxy groups having 2 to 20 carbon atoms and carboxy-substituted alkanoyloxy groups having 3 or 4 carbon atoms in the alkanoyl moiety and / or optionally substituted with 4 nitrogen atoms, wherein —4 carbon atoms.

A preferred group of compounds of the present invention are those compounds of formula (I) wherein A is an alkylene group having from 2 to 7 carbon atoms.

4, 106551

A preferred group of compounds of the present invention are those compounds of formula (I) wherein: R 1 is an unsubstituted naphthyl group or a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of 1-4 alkyl groups. 4 carbon atoms, hydroxy groups, alkoxy groups having 1 to 4 carbon atoms, halogen atoms, cyano groups, carbamoyl groups and difluoromethoxy groups; D is a single carbon-oxygen bond or an alkylene group having 1 to 3 carbon atoms; R 7 is a pyrrolidine ring, a morpholine ring or a piperidine ring bonded to D via a carbon atom in the heterocyclic ring, said group R 7 being optionally substituted on a carbon atom by a substituent selected from the group consisting of: , alkoxycarbonyloxy groups having 2 to 5 carbon atoms, alkanoyloxy groups having 2 to 20 carbon atoms and carboxy-substituted alkanoyloxy groups having 3 or 4 carbon atoms in the alkanoyl moiety and / or optionally substituted on the nitrogen atom with 1 to 4 carbon atoms; and 20A is an alkylene group having from 2 to 7 carbon atoms.

* A preferred group of compounds of the present invention are those compounds of formula (I) wherein: R 1 is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl, ethyl, difluoromethoxy, hydroxy, methoxy groups, ethoxy groups, fluorine atoms, chlorine atoms, bromine atoms, and cyano groups; r 30 D simple is a carbon-oxygen bond or an alkylene group having 1 or 2 carbon atoms; R 10 is a pyrrolidine ring, a morpholine ring or a piperidine ring bonded to D via a carbon atom of the heterocyclic ring, said group R 7 being optionally substituted on a carbon atom by a substituent selected from the group consisting of: alkoxycarbonyloxy groups having 2 to 5 carbon atoms, alkanoyloxy groups having 2 or 3 carbon atoms, alkanoyloxy groups having 12 to 20 carbon atoms and carboxy-substituted alkanoyloxy groups having 3 or 4 carbon atoms in the alkanoyl moiety and having 1 to 4 carbon atoms; and 10A is an alkylene ring having 2 to 5 carbon atoms.

A preferred group of compounds of the present invention are those compounds of formula (I) wherein: R1 is a phenyl group unsubstituted or substituted with at least one substituent selected from the group consisting of methyl groups, ethyl groups, difluoromethoxy groups, hydroxy groups, methoxy groups, , ethoxy groups, fluorine atoms, chlorine atoms, bromine atoms and cyano groups; D is a single carbon-oxygen bond or an alkylene yl group having 1 or 2 carbon atoms; R 7 is a pyrrolidine ring, a morpholine ring or a piperidine ring bonded to D via a carbon atom of the heterocyclic ring, said group R 7 being optionally substituted on a carbon atom with a substituent selected from methyl, hydroxy, ethyl, hydroxy, ethyl, , t-butoxycarbonyloxy groups, alkanoyloxy groups having 2 or 3 carbon atoms, lauroyloxy groups, 14-20 carbon atoms, and carboxy-substituted alkanoyloxy groups having 3 or 4 carbon atoms or methyloxy-substituted or unsubstituted or substituted alkanoyl groups; through; and 30 A is an alkylene alkyl having 2-4 carbon atoms.

18 106551

A preferred group of compounds of the present invention are those compounds of formula (I) wherein: R1 is a phenyl group unsubstituted or substituted with at least one substituent selected from the group consisting of methyl groups, hydroxy groups, methoxy groups, ethoxy groups, difluoromethoxy groups, , chlorine atoms, bromine atoms, and cyano groups; D is a single carbon-oxygen bond or an alkylene group having 1 or 2 carbon atoms; R 7 is a heterocyclic group bonded to D via a carbon atom in the heterocyclic group, said heterocyclic group being selected from the group consisting of pyrrolidinyl groups, 1-methylpyrrolidinyl groups, 4-hydroxy-1-methyl-pyrrolidinylcarboxy-4-hydroxy-1 , 4-isopropoxycarbonyloxy-1-methylpyrrolidinyl groups, 4-t-butoxycarbonyloxy-1-methylpyrrolidinyl groups, 4-lauroyloxy-1-methylpyrrolidinyl groups. 4-palmitoyloxy-1-methylpyrrolidinyl groups, piperidyl groups, 1-methylpiperidyl groups, and morpholinyl groups; and 20A is an ethylene group or a tetramethylene group.

• c

A preferred group of compounds of the present invention are those compounds of formula (I) wherein: R1 is a phenyl group, which is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl, ethyl, and hydroxy groups, methoxy groups, ethoxy groups, difluoromethoxy groups, fluorine atoms, chlorine atoms, bromine atoms and cyano groups; D is a single carbon-oxygen bond or an alkylene group having 1 or 2 carbon atoms; ♦ 30 19 106551 R7 is a pyrrolidine ring, a morpholine ring or a piperidine ring bonded to D via a carbon atom in the heterocyclic ring, said group R7 being optionally substituted on a carbon atom by a substituent selected from the group consisting of alkyl 5 —4 carbon atoms, hydroxy groups, alkoxycarbonyloxy groups having 2 to 5 carbon atoms, alkanoyloxy groups having 2 or 3 carbon atoms, alkanoyloxy groups having 12 to 20 carbon atoms and carboxy-substituted alkanoyloxy groups or alkanoyloxy groups substituted with 3 or 4 carbon atoms, or having 1 to 4 carbon atoms; and 10A is an alkylene group having from 2 to 7 carbon atoms.

A preferred group of compounds of the present invention are those compounds of formula (I) wherein: R 1 is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl groups, ethyl groups, hydroxy groups, methoxy groups, ethoxy groups, difluoromethoxy groups, fluorine atoms, chlorine atoms, bromine atoms, and cyano groups; D is a single carbon-oxygen bond or an alkylene group having 1 or 2 carbon atoms; R 7 is a pyrrolidine ring, a morpholine ring or a piperidine ring bonded to D via a carbon atom in the heterocyclic ring, said group R 7 being optionally substituted on carbon by a substituent selected from the group consisting of methyl, hydroxy, ethyl and hydroxy; isopropoxycarbonyloxy groups, t-butoxycarbonyloxy groups, alkanoyloxy groups having 2 or 3 carbon atoms, lauroyloxy groups, alkanoyloxy groups having 14-20 carbon atoms, carboxy-substituted alkanoyloxy or 4-alkanoyloxy groups, or with an ethyl group; and • 106551 20 A is an alkylene group having 2 to 5 carbon atoms.

A preferred group of compounds of the present invention are those compounds of formula (I) wherein: R 1 is a phenyl group unsubstituted or substituted with at least one substituent selected from the group consisting of methyl groups, ethyl groups, hydroxy groups, methoxy groups, ethoxy groups, , fluorine atoms, chlorine atoms, bromine atoms, and cyano groups; D is a single carbon-oxygen bond or an alkylene group having 1 or 2 carbon atoms; R 7 is a heterocyclic group bonded to D via the carbon atom of the heterocyclic group, said heterocyclic group being selected from the group consisting of pyrrolidin-15-yl groups, 1-methylpyrrolidinyl groups, 4-hydroxy-1-methylpyrroprinyl groups. piperidyl groups, 1-methylpiperidyl groups, morpholinyl groups and 4-methylmorpholinyl groups; and A is an alkylene group having from 2 to 5 carbon atoms.

20

A preferred group of compounds of the present invention are those compounds of formula (I) wherein: R 1 is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl groups, hydroxy groups . methoxy groups, ethoxy groups, difluoromethoxy groups, fluorine atoms, chlorine atoms, bromine atoms and: cyano groups; D is a single carbon-oxygen bond or an alkylene group having 1 or 2 carbon atoms; R 21 is a heterocyclic group bonded to D via the carbon atom of the heterocyclic group, said heterocyclic group being selected from the group consisting of pyrrolidinyl groups, 1-methylpyrrolidinyl groups, 4-hydroxy-1-methylpyrrolidinyl groups, methylpiperidyl groups, morpholinyl groups and 4-5 methylmorpholinyl groups; and A is a tetramethylene group or a pentamethylene group; and the pharmaceutically acceptable salts and esters thereof.

10

A more preferred set of compounds of the present invention for the treatment of circulatory disorders comprises those compounds of formula (I) wherein R 1 is a phenyl group which is unsubstituted or substituted with at least one substituent group selected from the group consisting of methyl groups, ethyl groups, fluoromethoxy groups. , difluoromethoxy groups, 2-fluoroethoxy groups, hydroxy groups, methoxy groups, ethoxy groups, fluorine atoms, chlorine atoms, bromine atoms and cyano groups; in the group -D-R7 the group D has a single carbon-oxygen bond or an alkylene group having 1 or 2 carbon atoms and R7 is a heterocyclic group having 5 or 6 ring atoms bonded to D via a carbon atom in the heterocyclic group, said heterocyclic group being selected from the group consisting of pyrrolidinyl groups, piperidyl groups and morpholinyl groups which are unsubstituted or substituted on a carbon atom and / or a nitrogen atom by at least one substituent selected from the group consisting of 25 carbon atoms substituents, alkyl atoms - , hydroxy groups, alkoxycarbonyloxy groups having 2 to 5 carbon atoms, alkanoyloxy groups having 2 or 3 carbon atoms, alkanoyloxy groups having 12 to 20 carbon atoms, carboxy-substituted alkanoyloxy groups having 3 or 4 carbon atoms.

A is an alkylene group having from 2 to 5 carbon atoms; 30 22 106551; and pharmaceutically acceptable salts and esters thereof.

An even more preferred group of compounds of this invention for the treatment of circulatory disorders comprises those compounds of formula (I) wherein: R 1 is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl groups, ethyl groups, difluoromethoxy groups, hydroxy groups, methoxy groups, ethoxy groups, fluorine atoms, chlorine atoms, bromine atoms and cyano groups; the group D of the formula -DR 'has a single carbon-oxygen bond or an alkylene group having 1 or 2 carbon atoms and the heterocyclic ring R 7 is unsubstituted or substituted on the carbon atom and / or nitrogen atom with at least one substituent selected from the group consisting of : for substituents on carbon, methyl groups, ethyl groups, hydroxy groups, ethoxycarbonyloxy groups, isopropoxycarbonyloxy groups, t-butoxycarbonyloxy groups, alkanoyloxy groups having 2 or 3 carbon atoms, where has 3 or 4 carbon atoms in the alkanoyl moiety; • A is an alkylene group having 2 to 4 carbon atoms; And pharmaceutically acceptable salts and esters thereof.

An even more preferred class of compounds of this invention for the treatment of circulatory disorders are those compounds of formula (I) wherein: R1 is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl groups, hydroxy groups, methoxy groups, ethoxy groups, difluoromethoxy groups, fluorine atoms, chlorine atoms, bromine atoms and svanory groups; in the group -D-R7 the group D has a single carbon-oxygen bond or an alkylene group having 1 or 2 carbon atoms and R7 is a heterocyclic group bonded to D via a carbon atom in the heterocyclic group, said heterocyclic group being selected from the group consisting of pyrrolidinyl groups, 1-methylpyrrolidinyl groups, 4-hydroxy-1-methylpyrrolidinyl groups, 4-ethoxycarbonyloxy-1-methylpyrrolidinyl groups, 4-isopropoxycarbonyloxy-1-methylpyrrolidin-1-ylmethoxy-1 . 4-stealoyloxy-1-methylpyrrolidinyl groups, piperidyl groups, 1-methylpiperidyl groups and morpholinyl groups; A is an ethylene group or a tetramethylene group; And pharmaceutically acceptable salts and esters thereof.

The most preferred class of compounds of this invention for the treatment of circulatory disorders are those compounds of formula (I) wherein: R 1 is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl groups, hydroxy groups, methoxy groups , ethoxy groups, difluoromethoxy groups, fluorine atoms, chlorine atoms, bromine atoms, and cyano groups; The group D of the formula -D-R7 has a single carbon-oxygen bond or an alkylene group. having 1 or 2 carbon atoms and R 7 is a heterocyclic group bonded to D via a carbon atom in the «heterocyclic group, said heterocyclic group being selected from the group consisting of pyrrolidinyl groups, 1-methylpyrrolidinyl groups, 4-hydroxy-1-methylpyrrolidine-yl group. , piperidyl groups, 1-methylpiperidyl groups and morpholinyl groups; 106551 A is an ethylene group; and pharmaceutically acceptable salts and esters thereof.

A more preferred class of compounds of this invention for the treatment of psychoses are those compounds of formula (I) wherein: R 1 is a phenyl group, which is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl groups, ethyl groups, hydroxy groups, methoxy groups, ethoxy groups, difluoromethoxy groups, fluorine atoms, chlorine atoms, bromine atoms and cyano groups; the group D of the formula -D-R7 has a single carbon-oxygen bond or an alkylene group. having 1 or 2 carbon atoms and R 'being a heterocyclic group bonded to D via a carbon atom in a 15 heterocyclic group, said heterocyclic group being selected from the group consisting of pyrrolidinyl groups, piperidyl groups and morpholinyl groups which are unsubstituted or substituted with nitrogen atom with at least one substituent. selected from the group consisting of 1 * * for substituents on carbon, alkyl groups of 1 to 4 carbon atoms, hydroxy groups, alkoxycarbonyloxy groups of 2 to 5 carbon atoms, allcanoyloxy groups, of 2 or 3 carbon atoms, alkanoyl having from 12 to 20 carbon atoms, carboxy-substituted alkanoyloxy groups having 3 or 4 carbon atoms in the alkanoyl moiety.

A is an alkylene group having from 2 to 7 carbon atoms; and pharmaceutically acceptable salts and esters thereof.

An even more preferred class of compounds of this invention for the treatment of psychoses are those compounds of formula (I) wherein: R 10 is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl groups, ethyl groups, hydroxy groups, methoxy groups, ethoxy groups, difluoromethoxy groups, fluorine atoms, chlorine atoms, bromine atoms and cyano groups; 5 in the group -D-R7 of formula D has a single carbon-oxygen bond or an alkylene group having 1 or 2 carbon atoms and R 7 is a heterocyclic group bonded to D via a carbon atom in the heterocyclic group, said heterocyclic group being selected from the group consisting of pyrrolidinyl groups, piperidyl groups and morpholinyl groups which are unsubstituted or substituted on a carbon atom and / or a nitrogen atom with at least one substituent selected from the group consisting of carbon substituents, methyl groups, ethylhydroxy groups, hydroxy groups, hydroxy groups, hydroxy groups, carbonyloxy groups, alkanoyloxy groups having 2 or 3 carbon atoms, alkanoyloxy groups having 14-20 carbon atoms, carboxy substituted alkanoyloxy groups having 3 or 4 carbon atoms in the alkanoyl moiety.

A is an alkylene group having from 2 to 5 carbon atoms; And pharmaceutically acceptable salts and esters thereof.

An even more preferred class of compounds of this invention for the treatment of psychoses are those compounds of formula (I) wherein: 25, R1 is a phenyl group which is unsubstituted or substituted with at least one substituent selected from the group consisting of methyl groups, ethyl groups. , hydroxy groups, methoxy groups, ethoxy groups, difluoromethoxy groups, fluorine atoms, chlorine atoms, bromine atoms and cyano groups; In the group -D-R7 of formula D-R7, D has a single carbon-oxygen bond or an alkylene group having 1 or 2 carbon atoms and R7 is a heterocyclic group bonded to D via a carbon atom in the heterocyclic group, said heterocyclic group being selected from the group consisting of pyrrolidinyl groups, 4-hydroxy-1-methylpyrrolidinyl groups, piperidyl groups, morpho-5-linyl groups and 4-methylmorpholinyl groups; A is an alkylene group having from 2 to 5 carbon atoms; and pharmaceutically acceptable salts and esters thereof.

10

The most preferred class of compounds of this invention for the treatment of psychoses are those compounds of formula (I) wherein: R 1 is a phenyl group which is unsubstituted or substituted with at least one substituent-group selected from the group consisting of methyl groups, hydroxy groups, methoxy groups. ethoxy groups, difluoromethoxy groups, fluorine atoms, chlorine atoms, bromine atoms, and cyano groups; in the group -D-R7, the group D has a single carbon-oxygen bond or an alkylene group having 1 or 2 carbon atoms and R 7 is a heterocyclic group bonded to D via a carbon atom in the heterocyclic group, said heterocyclic group being selected from . include pyrrolidinyl groups, 1-methylpyrrolidinyl groups, 4-hydroxy-1-methylpyrrolidinyl groups, piperidyl groups, 1-methylpiperidyl groups, morpholinyl groups and 4-methylmorpholinyl groups; A is a tetramethylene group or a pentamethylene group; and pharmaceutically acceptable salts and esters thereof.

The most preferred compounds for treating circulatory diseases are compounds # 27 106551 1-18. 1-Methyl-2- {2- [2- (4-phenylbutyl) phenoxy] ethyl} pyrrolidine; 1-38. l-Methyl-2- (2- {2- [4- (3-methoxyphenyl) butyl] phenoxy} ethyl) pyrrolidine; 5 3-1. 1-Methyl-2- {2- [2- (2-phenylethyl) phenoxy] ethyl} pyrrolidine; 3-38. 4-Hydroxy-l-methyl-2- {2- [2- (2-phenylethyl) phenoxy] ethyl} pyrrolidine; 3-50. 1-Methyl-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine; 10 3-70. 2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) -l-methylpyrrolidine; 3-95. 2- (2- {2- [2- (3-Fluorophenyl) ethyl] phenoxy} ethyl) -l-methylpyrrolidine; 15 3-137. 2- (2- {2- [2- (3-Bromophenyl) ethyl] phenoxy} ethyl) -l-methylpyrrolidine; 3-248. 4-Hydroxy-1-methyl-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine; 20 3-334. 2- (2- {2- [2- (3-Fluorophenyl) ethyl] phenoxy} ethyl) -4-hydroxy-1-methylpyrrolidine; 3-405. 2- (2- {2- [2- (3-difluoromethoxyphenyl) ethyl] phenoxy} ethyl) -l-methyl-pyrrolidine; 25 3-408. 2- (2- {2- [2- (3-Difluoromethoxyphenyl) ethyl] phenoxy} ethyl) -4-hydroxy; 1-methylpyrrolidine; 3-549. 2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) -4-hydroxy-1-30 methylpyrrolidine; 106551 28 3-568. 1-Methyl-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) -4-succinyl-oxypyrrolidine; 3-570. 2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) -4-succinyloxy-5'-methylpyrrolidine; 3-630. 2- (2- {2- [2- (3-Bromophenyl) ethyl] phenoxy} ethyl) -4-hydroxy-1-methylpyrrolidine; and 3-687. 2- (2- {2- [2- (2-Difluoromethoxyphenyl) ethyl] phenoxy} ethyl) -4-succinyloxy-1-methylpyrrolidine; and pharmaceutically acceptable salts and esters thereof.

The most preferred compounds for treating psychiatric conditions are Compounds Nos. 1-18. 1-Methyl-2- {2- [2- (4-phenylbutyl) phenoxy] ethyl} pyrrolidine; 1-81. 1-Methyl-2- (2- {2- [4- (2-methoxyphenyl) butyl] phenoxy} ethylpyrrolidine; 20-1117. 2- (2- {2- [4- (3,5-Dimethoxyphenyl) butyl) ] phenoxy} ethyl) -1-methylpyrrolidine; 2- 17. 1-Methyl-2- {2- [2- (5-phenylpentyl) phenoxy] ethyl} pyrrolidine; and pharmaceutically acceptable salts thereof.

The compounds of the present invention may be prepared by a variety of well known processes for the preparation of this type of compound. For example, in general, they can be prepared by administering a compound of formula (II): 30 106551 29 —Or ”5 (Π) (wherein:

R 11a is any of the groups represented by R 1, except that the hydroxy groups (if any) are protected with a compound of formula (VII): ZD-R 7a (VII) (where: 20 D is as defined above; R 7a is which only the groups represented by R7 except that the hydroxy group is protected and any heterocyclic nitrogen atom is protected Z is a hydroxy group or a group or atom capable of removing as a nucleophilic residue; and, if necessary, removing one or more of the following steps (i) ) - (iv) carrying out: (i) converting a cyano group to a carbamoyl group, (ii) alkylating a group of the formula R 7 of substituent R (5) (iii) converting the alkoxycarbonyl group to a methyl group, (iv) salting or esterifying the product.

Examples of preferred groups and atoms, Z, which are capable of leaving as a nucleophilic residue are: halogen atoms such as chlorine, bromine and iodine atoms; Aliphatic acyloxy groups including: alkylcarbonyloxy groups such as acetoxy and propionyloxy groups; halogenated alkylcarbonyloxy groups such as chloroacetoxy, dichloroacetoxy, tri-chloroacetoxy and trifluoroacetoxy; Lower alkoxyalkylcarbonyloxy groups such as methoxyacetoxy groups; and alkenylcarbonyloxy groups such as the (E) -2-methyl-2-butenoyloxy group; Aromatic acyloxy groups including: • arylcarbonyloxy groups such as benzoyloxy group; Halogenated arylcarbonyloxy groups such as the 4-chlorobenzoyloxy group; 106551 lower alkylated arylcarbonyloxy groups such as 2,4,6-trimethylbenzoyloxy and 4-toluoyloxy groups; lower alkoxylated arylcarbonyloxy groups such as the 4-anisoyloxy group; and 5 nitrated arylcarbonyloxy groups such as 4-nitrobenzoyloxy and 2-nitrobenzoyloxiryl; trihalomethoxy groups such as the trichloromethoxy group; Lower alkanesulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy and butanesulfonyloxy; halogenated lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethane sulfonyloxy groups; and arylsulfonyloxy groups such as benzenesulfonyloxy, o-, m- or p-toluenesulfonyloxy, o-, m- or p-methoxybenzenesulfonyloxy, o-, m- or p-chlorobenzenesulfonyloxy, o-, m- or p-fluorobenzenesulfonyloxy, o, m or p-20 nitrobenzenesulfonyloxy and naphthalenesulfonyloxy groups.

. Of these, halogen atoms, lower alkanesulfonyloxy groups, halogenated lower alkanesulfonyloxy groups and arylsulfonyloxy groups, of which chlorine, bromine and iodine atoms and methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p- are preferred; Toluenesulfonyloxy and p-nitrobenzenesulfonyloxy groups are more preferred.

* The protecting group used to protect the hydroxy groups in these reactions is not particularly limited in these reactions, and any group most commonly used for this purpose may equally be used herein. In particular, it is possible to use protecting groups capable of chemical cleavage such as hydrogenolysis, hydrolysis, electrolysis 106551 or photolysis, and protecting groups capable of biological cleavage such as hydrolysis in vivo.

Examples of a hydroxy protecting group capable of chemical removal include: 5 aliphatic acyl groups, preferably: alkanoyl groups having from 1 to 25 carbon atoms, more preferably from 1 to 20 carbon atoms, more preferably from 1 to 6 carbon atoms, and most preferably from 1 to 4 carbon atoms, (such as formyl). , acetyl, pro-10 pionyl, butyryl, isobutyryl, pivaloyl, valeryl, iso-valeryl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, lauroyl, myristoyl, tridecanoic, yl, palmitoyl, stearoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, tridecanoyl, pentadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, -, 13,13-dimethyl-15 tetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, icosanoyl and henicosanoyl groups, of which the acetyl group is the most preferred; yl, glutaiyl and adipoyl moieties; Halogenated alkanoyl groups having from 2 to 6 carbon atoms, especially halogenated acetyl groups (such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl); Lower alkoxyalkanoyl groups having from 1 to 5, preferably 1 to 3, carbon atoms in the alkoxy moiety and from 2 to 6 carbon atoms in the alkanoyl moiety and preferably having an acetyl group (such as methoxyacetyl: *); and * unsaturated analogs of groups, in particular alkenoyl or alkynoyl groups having from 3 to 6 carbon atoms [such as acryloyl, methacryloyl, propioloyl, crotonoyl, isocrotonoyl and (E) -2-methyl-2-butenoyl groups]; * t 33 106551 aromatic acyl groups, preferably arylcarbonyl groups, wherein the aryl moiety has 6-14 carbon atoms, more preferably 6-10, more preferably 6 or 10, and most preferably 6, ring carbon atoms and is a unsubstituted or 1-5 carbocyclic group , preferably 5 1 to 3 substituents selected from the group consisting of substituents a as defined above and examples are given below, preferably unsubstituted groups (such as benzoyl, α-naphthoyl and β-naphthoyl groups); Halogenated arylcarbonyl groups (such as 2-bromobenzoyl and 4-chlorobenzoyl); lower alkyl-substituted arylcarbonyl groups having from one to five, preferably from one to four, carbon atoms in each alkyl substituent (such as 2,4,6-trimethylbenzoyl and 15 4-toloyl groups); lower alkoxy-substituted arylcarbonyl groups wherein each alkoxy substituent preferably has from 1 to 5, preferably from 1 to 4, carbon atoms (such as a 4-anisoyl group); Carboxy-substituted arylcarbonyl groups such as 2-carboxybenzoyl, 3-carboxybenzoyl and 4-carboxybenzoyl; > «Nitro-substituted arylcarbonyl groups (such as 4-nitrobenzoyl and 2-nitrobenzoyl); Lower alkoxycarbonyl-substituted arylcarbonyl groups wherein each alkoxy-carbonyl substituent preferably has from 2 to 6 carbon atoms [such as 2- (methoxycarbonyl-benzoyl group); except that when substituted with an additional aryl group, this aryl group itself is not substituted with an aryl group (such as a 4-phenylbenzoyl group); 5 heterocyclic groups having 5 or 6 ring atoms, 1 or 2 of which are heteroatoms selected from the group consisting of oxygen; , sulfur and nitrogen atoms, preferably oxygen or sulfur atoms, which groups may be unsubstituted or may have at least one substituent selected from the group consisting of substituents a as defined and exemplified above and oxygen atoms; are: 10 tetrahydropyranyl groups already t can be substituted or unsubstituted such as tetrahydropyran-2-yl and 4-methoxytetrahydropyran-4-yl; tetrahydrothiopyranyl groups which may be substituted or unsubstituted such as tetrahydrothiopyran-2-yl and 4-methoxytetrahydrothiopyran-4-yl groups; tetrahydrofuranyl groups which may be substituted or unsubstituted, such as the tetrahydrofuran-2-yl group; and tetrahydrothienyl groups which may be substituted or unsubstituted, such as a tetrahydrothien-2-yl group; tri-substituted silyl groups wherein all three or two or one of the substituents are alkyl groups having 1 to 5, preferably 1 to 4, carbon atoms and none, one or two of the substituents are aryl groups as defined above but preferably phenyl or substituted phenyl groups, preferably: «« tri (lower alkylsilyl groups (such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldis) and tri-isopropylsilyl groups) and 35 106551 tri (lower alkyl) silyl groups in which one or two alkyl groups are replaced by aryl groups (such as diphenylmethylsilyl, diphenylbutylsopropyl) diphenyl-t-butylsilyl, diphenyl) , 5 alkoxyalkyl groups in which the alkoxy and alkyl moieties each have from 1 to 5, preferably from 1 to 4, carbon atoms, in particular alkoxymethyl and groups having at least one substituent, preferably 1-5, more preferably 1-3 and most preferably 1, lower alkoxymethyl groups and other alkoxyalkyl groups (such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl). -, propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl groups); lower alkoxy-substituted lower alkoxymethyl groups (such as methoxymethoxy-methyl and 2-methoxyethoxymethyl); Halogenated lower alkoxymethyl groups [such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl groups]; and lower alkoxy-substituted ethyl groups (such as 1-ethoxyethyl, 1-methyl-1-20 methoxyethyl and 1-isopropoxyethyl groups); •. other substituted ethyl groups, preferably: halogenated ethyl groups (such as 2,2,2-trichloroethyl group); and · 25 arylselenyl substituted ethyl groups wherein the aryl moiety is as defined above [such as: 4 2- (phenylselenyl) ethyl group]; 4 aralkyl groups, preferably alkyl groups having 1-4, preferably 1-3 and most preferably 30 1 or 2, carbon atoms substituted with 1-3 aryl groups as defined and provided above, which may be unsubstituted (such as benzyl). , • 36 106551 1-phenylethyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl and 9-anthrylmethyl) or substituted on the aryl moiety with a lower alkyl group, a lower alkoxy group, a lower alkoxy group, a lower alkoxy group, or an alkylenedioxy group having 1 to 3 carbon atoms, preferably a methylene dioxy group, [such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxyphenyldiphenylmethyl- , 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzoyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl and piperoyl groups); Alkoxycarbonyl groups, especially those having 2 to 7, more preferably 2 to 5, carbon atoms, which may be unsubstituted (such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl) or substituted with a halogen atom, e.g. a tri- (lower alkylsilyl) group (such as 2,2,2-tri-chloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl groups); alkenyloxycarbonyl groups having from 2 to 6, preferably from 2 to 4, carbon atoms in the alkenyl moiety (such as vinyloxycarbonyl and allyloxycarbonyl groups); and 20 aralkyloxycarbonyl groups wherein the aralkyl moiety is as defined and exemplified above and wherein the aryl ring, if substituted, preferably has one or two lower alkoxy or nitro substituents (such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl, -bromobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxy-carbonyl groups).

Examples of protecting groups which are capable of biological cleavage, such as in vivo hydrolysis, include: for example the above -carbonyloxyalkyl groups; the above aliphatic acyl groups; aromatic acyl groups as defined above; a salt residue of a carboxylated lower alkylcarbonyl group, such as a salt residue of succinic acid monoester; phosphate salt residue; an amino acid ester residue; a carbamoyl group; substituted carbamoyl group • 1CCE51 which is a carbamoyl group substituted by one or two alkyl groups each having 1-6 carbon atoms such as methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, butylcarbamoyl, butylcarbamoyl, butylcarbamoyl, - or hexylcarbamoyl groups; and a carbonyloxyalkyloxy-5 carbonyl group such as a pivaloyloxymethyloxycarbonyl group. It is easy to determine whether the protecting group is capable of biological degradation, such as in vivo hydrolysis, by administering the protected compound or a pharmaceutically acceptable salt thereof by intravenous injection into a test animal such as rat or mouse and then determining the quality of the active compound recovered from the body fluids.

10

Examples of preferred protecting groups for a protected hydroxy group include: tetrahydrofuranyl, tetrahydropyranyl and tetrahydrothiopyranyl; silyl; alkoksimet \ yliryhmät; metoksimetoksimetyyliryhmät; aralkyl groups; and aralkyloxycarbonyl groups: more preferably tetrahydropyranyl, methoxymethyl, benzyl, p-methoxybenzyl, p-bromobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and p-bromobenzyloxycarbonyl.

R 7a is any one of the groups represented by R 7 wherein the ring nitrogen atom or atoms are substituted with an amino protecting group or lower alkyl group and one or more ring carbon atoms or atoms may optionally be substituted with any substituent -1 defined and exemplified above except that any hydroxy group is protected.

There is no particular limitation on the nature of the amino protecting group used, and any group conventionally used for this purpose can equally be used herein. Examples of preferred amino protecting groups are: aliphatic acyl groups, aromatic acyl groups, alkoxycarbonyl groups, alkenyl pycarbonyl groups, aralkyloxycarbonyl groups, silyl groups and aralkyl groups, as defined above, as defined above. Of these, t-butoxycarbonyl, benzyl, p-methoxybenzyl, p-bromobenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and p-bromobenzyloxycarbonyl groups are preferred.

«38 1GCGG1

In more detail, the compounds of the present invention may be prepared as described in Scheme C below.

5 Reaction Scheme C:

In Scheme C, a compound of formula (Ie) is prepared.

Ria a— + z— ° —R? A ci ^ \ - / (VII) "(II), -v .0-D-R7a / Z 'Step C2 R'3-A- {f - (Ie' ) ^ - ^^ 0-DR? Dc) «39 106551

Step Cl:

In step C1, a compound of formula (I'c) is prepared by reacting a compound of formula (II) with a compound of formula (VII).

5

Step Cl:

Step C2 is optional and may consist of one or more of the following reactions: Reaction (a): elimination of a hydroxy protecting group in R a and R 7a;

Reaction (c): elimination of the nitrogen protecting group in R7a;

Reaction (d): Conversion of an alkoxycarbonyl group in R7a to a methyl group; 15

Reaction (e): alkylation of the = NH group produced in Reaction (c);

Reaction (g): Conversion of a cyano group to a carbamoyl group.

These reactions can be carried out in any order.

. ·, Reaction (a):

In reaction (a), the hydroxy protecting group is eliminated. By selecting the type of protecting group and the conditions used for elimination, the protection in R7a alone can be eliminated.

«

Reaction (c): 40-106551

In reaction (c), the elimination of the nitrogen protecting group in R7a is carried out. The nature of the Elimination reaction depends on the protecting group, but the reaction can be carried out by methods well known in the art of organic synthesis chemistry.

For example, when the nitrogen protecting group is an aralkyl or aralkyloxycarbonyl group, the elimination may be carried out in the same manner as that described in Step B3 in Reaction (a) wherein the hydroxy protecting group is an aralkyl group.

10

When the nitrogen protecting group is a t-butoxycarbonyl group, the elimination is carried out in the same manner as that described in Reaction A3 of Reaction A3, in which the hydroxy protecting group is an alkoxyalkyl group.

When the nitrogen protecting group is an alkoxycarbonyl residue, the corresponding protecting group can be eliminated by subjecting the protected compound to hydrolysis using a base, preferably an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; or an alkali metal carbonate such as sodium carbonate or potassium carbonate. The reaction is carried out normally and preferably in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that it has no adverse effect on the reaction or reagents contained therein and that it is capable of dissolving the reagents, at least to some extent. Examples of suitable solvents include: alcohols such as methanol or ethanol; ethers such as tetrahydrofuran or dioxane; water; and a mixture of one or more of these organic solvents with water.

25

The reaction can take place over a wide range of temperatures and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of 0-100 ° C, more preferably about room temperature -60 ° C. The time required for the reaction may also vary widely depending on many factors, including the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out under the preferred conditions described above, 1 to 24 hours, more preferably 1 to 16 hours, will usually suffice.

41 1C6551

Upon completion of the reaction, the reaction product may be recovered from the reaction mixture in a manner similar to that described in Method A, Step A1.

Reaction (s):

In reaction (d), the alkoxycarbonyl group in R7a is converted to a methyl group using a reducing agent, preferably an alkali metal aluminum hydride such as lithium aluminum hydride. The reaction is carried out normally and preferably in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that it has no adverse effect on the reaction or reagents contained therein and that it is capable of dissolving the reagents, at least to some extent. Examples of suitable solvents are: ethers such as diethyl ether, tetrahydrofuran or dioxane.

The reaction can take place over a wide range of temperatures and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of 0 to 100 ° C, more preferably about room temperature to 80 ° C. The time required for the reaction may also vary widely depending on many factors, including the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out under the preferred conditions of Figure 20, 30 minutes to 24 hours, more preferably 1 to 16 hours, usually sufficient.

•

After completion of the reaction, the desired compound can be recovered from the reaction mixture by conventional means. For example, one suitable recovery method is that the insoluble materials, if any, are filtered off and then the solvent is distilled off from the filtrate under reduced pressure to give the desired compound. Alternatively, the solvent is distilled off under reduced pressure: the residue is diluted with water and extracted with a water-immiscible organic solvent such as ethyl acetate, the extract is dried with a desiccant, for example anhydrous magnesium sulfate, and finally the solvent is distilled off. The resulting residue may, if necessary, be further purified by conventional means, for example, by recrystallization or by various chromatography techniques, including column chromatography.

Reaction (e): 42 106551

Alkylation of the = NH group produced in Reaction (e) in Reaction (c) is carried out using a C 1 -C 6-5 alkyl halide such as methyl iodide, ethyl iodide, propyl iodide, butyl iodide, pentyl iodide or hexyl iodide, in the presence of a alkali metal or sodium carbonate or an alkali metal hydride such as sodium hydride.

Reaction (g):

In reaction (g), conversion of the cyano group to a carbamoyl group is carried out. This reaction is substantially the same as that described above in Reaction (c) of Step A2 of Method A and may be carried out using the same reagents and reaction conditions.

15

The compounds of formula (I) may be converted into pharmaceutically acceptable salts by treatment with an acid in a conventional manner. For example, salts may be prepared by reacting the base with the corresponding acid. The reaction is carried out normally and preferably in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that it has no adverse effect on the reaction or reagents contained therein and that it is capable of dissolving the reagents, at least to some extent. Examples of suitable solvents are: ethers such as diethyl ether, tetrahydrofuran or dioxane; alcohols such as methanol or ethanol; and halogenated hydrocarbons, preferably halogenated aliphatic hydrocarbons such as methylene chloride or chloroform. The reaction can take place over a wide range of temperatures and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of about room temperature. The time required for the reaction may also vary widely depending on many factors, including the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out under the preferred conditions described above, 5 minutes to 1 hour will usually suffice. The solvent can then be removed by distillation under reduced pressure. Alternatively, the compound of formula (1), or an acid addition salt thereof, is absorbed onto a column packed with an acidic resin (e.g., CM Sephadex C-25 Commercial Mark) and the adsorbate is eluted with dilute hydrochloric acid to afford the hydrochloride.

The starting compounds used in Method C are known and can be prepared by known methods (for example, as in Japanese Patent Application Kokai No. Sho 55-20740, No. Hei 2-304022 and the like). Some of the compounds of formula (II) may also be prepared by a process summarized in the following reaction schemes D and E:

Reaction Scheme D: OR12

Rla r9 R8 -Q + —- Ks Step Dl

R 10 ') - P (R 13) 3 (VIII) /; RU (IX)

Rla r9

RU

/ 0R12

RioV

\ f) i Step D2 '__J i --- ► (X) (· cave (Ha)

Reaction Scheme E: 44 106551 R11 / R9 ^ R9 rm0 ^ ^ ~ oh (XI) (XII)

Rla R9

Step E2 V X Step E3 "" / 0R12 R8 CHO / (XIII) Lvv ^ / = P (R3) 3 R11 (IX) 'R9 R11 | ORl2

Rla / I Step E4 (ΙΓο) R9 Rll

j OH

Rla .. I / r8 ivV ^ _ ^ (He) 106551

In the above formulas:

R 11a is as defined above; 5A "is a tetramethylene group which is unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms; R 8, R 9, R 10 and R 11 are the same or different and each is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; a protecting group; R13 is a C6-C10-aryl group; and R14 is an alkyl group having from 1 to 6 carbon atoms.

Reaction Scheme D:

In Scheme D, a compound of formula (HA) is prepared, which is a compound of formula (II) wherein A 'is a group of formula A "wherein A" is as defined above.

Step Dl:

In step D1, a compound of formula (X) is prepared by reacting a compound of formula (VIII) with a compound of formula (IX). The reaction can take place over a wide range of temperatures and the precise reaction temperature is not critical to the invention. Usually pi-. we suitably carry out the reaction at a temperature of 0 to 200 ° C, more preferably 20 to 150 ° C. The time required for the reaction may also vary widely depending on many factors, including the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out under the preferred conditions described above, 30 minutes to 24 hours, more preferably 1 to 10 hours, is usually sufficient. The reaction is carried out normally and preferably in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that it has no adverse effect on the reaction or reagents contained therein and that it is capable of dissolving the reagents, at least to some extent. Examples of suitable solvents include: nitriles such as acetnitrile; aromatic hydrocarbons such as benzene, toluene or xylene; amides such as dimethylacetamide, N-methyl-2-pyrrolidinone or hexamethylphosphoritriamide; and ethers such as diethyl ether, tetrahydrofuran or dioxane. The compound of formula (IX) is readily synthesized via the ylide, which is well known in the art of organic chemistry. For example, it may be synthesized by administration of a compound of formula (IX1):

> -P (R! 3) 3 X

R 11 (IX ·) 20 (wherein R 12, R 12 and R 13 are as defined above and X is a halogen atom) is reacted with a base such as an amine such as 1,8-diazabicyclo [5.4,0] undec-7-ene or 1,5-diazabicyclo [4,3,0] non-5-ene; an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; an alkali metal hydride such as lithium hydride, sodium hydride or potassium hydride; an alkali metal amide such as sodium amide or potassium amide; or an alkali metal alkoxide such as sodium methoxide, sodium ethoxide or potassium t-butoxide. The reaction can take place over a wide range of temperatures and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of 0-100 ° C, more preferably 10-60 ° C. The time required for the reaction may also vary widely depending on many factors, including the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction 30 is carried out under the preferred conditions described above, 10 minutes to 10 hours, more preferably 30 minutes to 5 hours, is usually sufficient. The reaction is carried out nonnally and preferably in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that it has no adverse effect on the reaction or reagents contained therein and that it is capable of dissolving the reagents, at least to some extent. Examples of suitable solvents include: nitriles such as acetnitrile; hydrocarbons such as hexane, benzene or toluene; Amides such as dimethylacetamide, N-methyl-2-pyrrolidinone or hexamethylphosphoric triamide; ethers such as diethyl ether, tetrahydrofuran or dioxane; alcohols such as methanol, ethanol, propanol or isopropanol; halogenated hydrocarbons, preferably halogenated aliphatic hydrocarbons such as methylene chloride, chloroform or dichloroethane; water; or a mixture of one or more organic solvents with water.

10

Step D2:

In step D2, a compound of formula (Ha) is prepared from a compound of formula (X) by reduction of the double bond and then elimination of the hydroxy protecting group R 1 '. This reaction is substantially the same as that described above in Process A, Step A2, and may be carried out using the same reagents and reaction conditions.

Reaction Scheme E: In Scheme E, a compound of formula (IIb) is prepared wherein A 'is a group of formula: CH (R8) CH (R9) CH = C (R ") 25 (wherein R8, R9 and R" are as defined above) or a compound of formula (Ile) which is a compound of formula (II) wherein A 'is a group of the formula: CH (R 8) CH (R 9) CH 2 CH (R 11) (wherein R 8, R 9 and R 11 are as defined above).

48 106551

Step El:

In Step E1, a compound of formula (XII) is prepared from a compound of formula (XI) by reduction of a double bond and an alkoxycarbonyl group.

5

Step E2:

In step E2, a compound of formula (XIII) is prepared by reacting a compound of formula (XII) with an oxidizing agent (e.g., oxalyl chloride-dimethylsulfoxide-triethylamine, sulfur trioxide-pyridine complex, pyridine chloroformate, pyridine dichromate or activated manganese dioxide). The reaction can take place over a wide range of temperatures and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of + -100 ° C, preferably 10-60 ° C. The time required for the reaction may also vary widely depending on many factors, including the reaction temperature and the nature of the reagents and solvent used. However, provided that the reaction is carried out under the preferred conditions described above, 10 minutes to 10 hours, more preferably 20 minutes to 3 hours, is usually sufficient. The reaction is carried out normally and preferably in the presence of a solvent. There is no particular limitation on the nature of the solvent used, provided that it has no adverse effect on the reaction or reagents contained therein and that it is capable of dissolving the reagents, at least to some extent. Examples of suitable solvents include: halogenated hydrocarbons, preferably halogenated aliphatic hydrocarbons such as methylene chloride or chloroform; ethers such as diethyl ether, tetrahydrofuran or dioxane; and esters such as ethyl acetate.

Step E3: In Step E3, a compound of formula (Hb) is prepared by reacting a compound of formula (XIII) with a compound of formula (IX). This reaction is substantially the same as that described above in step D1 of Method D and can be carried out using the same reagents and reaction conditions.

Step E4: 5

In Step E4, the compound of formula (Ile) is prepared by reducing the compound of formula (Hb) and then eliminating the hydroxy protecting group R

10 BIOLOGICAL EFFECT

Test Example 1

Verisuonten Fuel Test 15

Curvature of rat tail veins was examined by the method described by Van Neuten et al. (J. Oharmacol. Exp. Ther., 218, 217, 230, 1981).

Male Sprague-Dawley rats, each weighing about 500 g, were rapidly killed by squeezing 20 blood. The tail arteries were dissected free from the surrounding tissue and cut into spiral strips (2 x 20 mm). The resulting preparations were mounted in organ baths, each. containing 10 ml of Tyrodi solution maintained at 37 ° C and then gasified with a mixture of 95% v / v and 5% CO 2. The formulations were allowed to equilibrate for 1 hour before being used in the experiment.

25

The preparations were subjected to an optimum initial rest tension of 0.5 g and the isometric contractions were recorded by forced-beam transducers. The relaxing effects of the test compounds were determined with preparations pre-reduced with 5-HT (5-hydroxytryptamine) (3 x 10 6 M), which is * 50 106551 5-HT 2 receptor agonist or phenylephrine (10 6 6 M). an agonist of adrenaline α1 receptors. After reaching a steady state contraction response to 5-HT or Phenylephine, the test compound was accumulatively added to the bath medium. At the end of the experiments, papaverine (10 µM) was added to produce the maximum relaxation effect.

5

The relaxation achieved with each test compound was calculated as a percentage of the maximal relaxation produced by 10 µM papaverine. Concentrations causing half-maximal relaxation (IC50) were calculated using a smaller square method. The results are shown in Table 4.

10 51 106551

Table 4

Compound of Experiment # IC 50 (nM) 5 5-HT 2 adrenaline-C 1, 48 3.7 2500 58 5.0 4900 97 6.5 860 10 98 5.4 2200 99 6.1 1300 101 3.7 3700 108 2.2 1700 113 2.2 1200 15 114 5.7 1100 115 3.3 2300 116 2.2 117 1.8 5900 118 2.6 5400 20 120 4.2 123 5.7 - MCI-9042 72.0 50000 25 52 106551 Case Study 2

Receptor Binding Experiment Brain membrane fractions were prepared by the method described by Leyson et al. (Mol. Pharmacol. 21, 301-314, 1982). Male Wistar rats, each weighing 280-320 g, were used as experimental animals.

The rats were sacrificed by dissection of the neck and then the brain was immediately removed from the skulls, the shell and the striatum were dissected, frozen and then stored at -80 ° C until needed.

Frozen brain tissues were placed in 50 mM Tris-HCl buffer solution (pH 7.7) and homogenized using Polytron PT-20; they were then centrifuged at 49,000 g for 10 minutes. [Tris is tris (hydroxymethyl) aminomethane]. The resulting pellet was resuspended in the same Tris buffer solution and centrifugation was repeated. Finally, the resulting pellet was resuspended in the same Tris buffer solution by adjusting the protein content to 0.57 mg protein per ml and the suspension was stored at -80 ° C.

Receptor binding assay was initiated by adding 440 μΐ of membrane suspension to a tube containing 50 μΐ of 3H ligand and 10 μΐ of test compound (dissolved in dimethylsulfoxide). The mixture was incubated at 30 ° C for one hour and then quenched by vacuum filtration through Whatman GF / B glass. The filter was rinsed twice each time with 4 ice-cold Tris buffer solution and then ACS-II was added and radioactivity on the filter was measured using a liquid heart rate counter.

: Non-specific binding was analyzed in the presence of an additional amount of 20 μΜ atropine.

Binding inhibition of the test compound was analyzed to estimate the IC50 (the concentration of test compound that causes 50% inhibition of binding) using the smallest square method. The results are shown in Table 5.

> · 53 106551

Table 5 5 _

Experiment # IC50 (ng / ml) Compound Serotonin-2 Dopamine-2 11.5 10.5 10 78 0.5 17 79 8.7 16 80 2.3 22 81 3.0 22 82 1.7 17 15 85 5.4 8.8 »- t I · 54 106551

As clearly illustrated in the results of Table 4, the compounds of the present invention bind strongly and selectively to the serotonin-2 receptor.

It can be concluded from this that the compounds of the present invention potently and selectively inhibit the serotonin-2 receptor present in vascular endothelial cells and particles. As a result, they are extremely useful in inhibiting vasoconstriction and agglutination of blood particles via serotonin-2 receptors. Therefore, these compounds are useful in treating and preventing recurrence of circulatory diseases, for example, anemia such as cardiac arrhythmia, angina pecto-10 ris and myocardial infarction, cerebrovascular diseases such as vasoconstriction after hypertension and peripheral haemorrhage, and peripheral haemorrhage.

As clearly illustrated in the results of Table 5, the compounds of the present invention bind strongly to serotonin-2 receptors and dopamine-2 receptors.

15

In conclusion, the compounds of the present invention are potent inhibitors of serotin-2 receptors and dopamine-2 receptors and are thus extremely useful in the prevention and treatment of psychiatric disorders such as psychosis without the presence of pyramidal syndrome.

For these purposes, the compounds of the present invention may be administered orally or in any suitable form, for example, in the form of tablets, capsules, granules, powders or syrups, or by parenteral injection, suppositories or the like. These pharmaceutical preparations may be prepared by admixing the compound of the present invention with one or more excipients such as excipients (e.g., organic excipients which include sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch). , potato starch, α-starch, dextrin or carboxymethyl starch; cellulose derivatives, such as crystalline cellulose, lower 1 555 655 hydroxypropyl-substituted cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose; and Pullulan; inorganic fillers which include silicates such as lactic anhydride (colloidal silica), synthetic aluminosilicate or magnesium methacetic acid aluminate; phosphates such as calcium phosphate; carbonates such as calcium carbonates; and sulfates such as calcium sulfate); lubricants (e.g., metal stearates such as stearic acid, calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bees or whale oil; boric acid; adipic acid; sulfates such as sodium sulfate; glycolate; fumaric acid) , such as sodium lauryl sulphate or magnesium lauryl sulphate; silicates such as silicic anhydride or silicic acid hydrate; and the above starch derivatives); binders [e.g. polyvinylpyrrolidone, Macrogol (polymer of glycols); and compounds of the same type as the excipients described above]; disintegrants (eg, compounds similar to the above excipients; and chemically modified starch celluloses such as cross-linked carmellose sodium (cross-linked sodium carboxymethyl cellulose), sodium carboxymethyl starch or cross-linked polyvinyl); stabilizers (e.g., p-hydroxybenzoates such as methyl paraben or propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal, dehydroacetic acid); a moth (e.g. sweeteners, vinegar or perfumes commonly used); diluents and the like.

•

The dosage will vary depending upon the condition and age of the patient and the route of administration, but, for example, the compounds of the present invention may be administered in a daily dose of 1 to 1000 mg '25 (preferably 10 to 500 mg) for oral administration or 0.1 to 500 daily doses. mg (preferably 1 to 300 mg) in the case of an intravenous syringe for an adult human patient, which can be administered in a single dose or in divided doses.

• · 56 106551

The invention is further illustrated by the following non-limiting Examples which illustrate the preparation of the compounds of the present invention and the following Preparation Examples which illustrate the preparation of the starting materials used in these Examples.

EXAMPLE 1 3-Dimethylamino-1- [2- (4-phenylbutyl) phenoxy] -2-propanol hydrochloride (not included in the invention) 10 1 (a) 2- [2- (4-Phenylbutyl) phenoxymethyl] oxirane 7, 84 g of potassium t-butoxide was added at room temperature to a solution of 15.81 g of 2- (4-phenylbutyl) phenol (prepared as described in Preparation Example 3) in 350 ml of dime-15-style acetamide and the resulting mixture was stirred at the same temperature for 20 minutes. 11.46 ml of epibromohydrin was added thereto. The mixture was then stirred at room temperature overnight, after which the reaction mixture was partitioned between water and ethyl acetate. The organic layer was then washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography over silica gel using a 7: 1 by volume mixture of hexane and ethyl acetate as eluent to afford 19.68 g (yield * 99.8%) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CD3 0, 270 MHz), δ ppm: 1.5-1.8 (4H, multiplet); 2.6-2.9 (6H, multiplet); 3.2-3.4 (1H, multiplet); ? 3.97 (1H, doublet of doublets, J = 5 & 11 Hz); 57 106551 4.19 (1H, doublet of doublets, J = 3 & 11 Hz); 6.8 - 6.9 (2H, multiplet); 7.1 - 7.35 (7H, multiplet).

5 1 (b) 3-Dimethylamino-1- [2- (4-phenylbutyl) phenoxy] -2-propanol 30 mL of 50% aqueous dimethylamine was added to a solution of 19.68 g of 2- [2- (4-phenylbutyl) phenoxymethyl] oxirane [prepared as described in step (a) above] in 300 ml tetrahydrofuran and the resulting mixture was stirred at room temperature overnight. The solvent was then removed by distillation under reduced pressure and the pale yellow oily residue was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluent to afford 20.6 g (yield 90.4%) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDC03.270 MHz), δ ppm: 1.5 - 1.8 (4H, multiplet); 2.34 (6H, singlet); 2.3 - 2.8 (6H, multiplet); 3.9 - 4.2 (3H, multiplet); 6.8-7.3 (9H, multiplet).

1 (c) 3-Dimethylamino-1- [2- (4-phenylbutyl) phenoxy] -2-propanol hydrochloride 23.5 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 20.5 g of 3-dimethylamino- 1- [2- (4-phenylbutyl) phenoxy] -2-propanol [prepared as described in step (b) above] in 200 mL of dioxane and the resulting mixture was stirred at room temperature for 10 minutes. It was then concentrated by evaporation under reduced pressure. The oily residue thus obtained was dissolved in 50 ml of ethyl acetate and the solution was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried to give 22.1 g (97% yield) of the title compound as colorless needles having a melting point of 120-122 ° C.

Nuclear Magnetic Resonance Spectrum (CDC (3 + D 2 O, 270 MHz), δ ppm: 1.5 - 1.8 (4H, multiplet); 2.5 - 2.7 (4H, multiplet); 2.89 (6H, singlet); 3.1 - 3.4 (2H, multiplet); 3.8-4.2 (2H, multiplet); 4.4 - 4.6 (1H, multiplet); 6.83 (1H, doublet, J = 8.3 Hz); 6.91 (1H, triplet, J = 7.3 Hz); 7.1 - 7.3 (7H, multiplet).

15

Infrared Absorption Spectrum (CHCC3), νmax cm -1: 1600, 1585, 1493, 1474, 1450, 1225.

EXAMPLE 5 1-Methyl-2- {2- [2- (4-phenylbutyl) phenoxy] ethyl} pyrrolidine hydrochloride 5 (a) 1-Methyl-2- {2- [2- (4-phenylbutyl) phenoxy] ethyl } Pyrrolidine 25 522 mg of diethyl azodicarboxylate was added under ice-cooling and stirring to a solution of 226 mg of 2- (4-phenylbutyl) phenol (prepared as described in Preparation Example 3), 390 mg of 2- (2-hydroxyethyl) -1-methylpyrrolidine and 790 mg of triphenyl-phosphine in 40 ml of methylene chloride and the resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was then concentrated by evaporation under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated by evaporation under reduced pressure. The resulting yellow oily concentrate was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to give 130 mg (yield 38%) of the title compound as an oil.

Nuclear Magnetic Resonance Spectrum (CDC (3.270 MHz), δ ppm: δ 1.6 - 2.6 (12H, multiplet); 2.44 (3H, singlet); 2.6 - 2.75 (4H, multiplet); 3.2 - 3.3 (1H, multiplet); 3.95 - 4.15 (2H, multiplet); 6.85 (1H, doublet, J = 8.6 Hz); 6.89 (1H, triplet, J = 7.3 Hz); 7.1-7.4 (7H, multiplet).

5 (b) 1-Methyl-2- {2- [2- (4-phenylbutyl) phenoxy] ethyl} pyrrolidine hydrochloride * 0.2 mL of a 4N solution of hydrogen chloride in dioxane was added to a solution containing 130 mg of 1-methyl-2 - {2- [2- (4-phenylbutyl) phenoxy] ethyl} pyrrolidine [prepared as described in step (a) above] in 5 ml of ethyl acetate and the resulting mixture was worked up in a similar manner to that described in Example 1 (c). The solvent was removed by distillation under reduced pressure and the residue was dried in vacuo to give 144 mg of the title compound as a colorless oil.

60 106551

Nuclear Magnetic Resonance Spectrum (CDCl3, 270 MHz), δ ppm: 1.55-1.8 (4H, multiplet); 1.9 - 2.15 (2H, multiplet); 2.15 - 2.35 (2H, multiplet); Δ 2.35-2.85 (7H, multiplet); 2.75 (3H, singlet); 3.2 - 3.4 (1H, multiplet); 3.8 - 4.3 (3H, multiplet); 6.82 (1H, doublet, J = 8.3 Hz); 6.91 (1H, triplet, J = 7.3 Hz); 7.1-7.3 (7H, multiplet).

Infrared Absorption Spectrum (CHQ> 3), ν max cm -1: 1602, 1588, 1497, 1475, 1452, 1235.

15 EXAMPLE 7 2- [2- (4-Phenylbutyl) phenoxymethyl] morpholine hydrochloride 20 7 (a) 4-t-Butoxycarbonyl-2- [2- (4-phenylbutyl) phenoxymethyl] morpholine * 218 mg sodium hydride (55% w / w). (dispersion in mineral oil) was added while cooling with ice and stirring to a solution of 1.13 g of 2- (4-phenylbutyl) phenol (prepared as described in Preparation Example 3) in 20 ml of dimethylacetamide and the resulting mixture was stirred at room temperature for 30 minutes. . Thereafter, 2.04 g of 4-t-butoxycarbonyl-2- (E-toluenesulfonyloxymethyl) morpholine was added and the reaction mixture was stirred at 60 ° C for 6 hours. The mixture was then partitioned between ethyl acetate and water.

Λ 61 106551

The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The oily residue thus obtained was purified by column chromatography over silica gel using a 20: 1 by volume mixture of benzene and acetnitrile as eluant to give 671 mg of the title compound as an oil.

Nuclear Magnetic Resonance Spectrum (CDC (3.270 MHz), δ ppm: 1.47 (9H, singlet); 1.6 - 1.8 (4H, multiplet); ? 2.6 - 2.75 (4H, multiplet); 2.75-3.1 (2H, multiplet); 3.5-4.2 (7H, multiplet); 6.81 (1H, doublet, J = 7.9 Hz); 6.89 (1H, triplet, J = 7.3 Hz); 7.1-7.3 (7H, multiplet).

7 (b) 2- [2- (4-Phenylbutyl) phenoxymethyl] morpholine hydrochloride 671 mg of 4-t-butoxycarbonyl-2- [2- (4-phenylbutyl) phenoxymethyl] morpholine [prepared as described in step (a) above]. was dissolved in 10 ml of a 4N solution of hydrogen chloride in dioxane with ice-cooling and the resulting solution was allowed to stand at room temperature for 30 minutes. The solvent was then removed by distillation under reduced pressure, and the resulting oily residue was dissolved in 20 mL of ethyl acetate. The solution thus obtained was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 494 mg (86% yield) of the title compound as colorless crystals having a melting point of 131-132 ° C.

62 106551

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.55-1.8 (4H, multiplet); 2.6 - 2.8 (4H, multiplet); 3.0 - 3.2 (2H, multiplet); Δ 3.33 (1H, doublet, J = 12.5 Hz); 3.46 (1H, doublet, J = 12.5 Hz); 3.95 - 4.2 (4H, multiplet); 4.25 - 4.4 (1H, multiplet); 6.78 (1H, doublet, J = 7.9 Hz); 6.91 (1H, triplet, J = 7.3 Hz); 7.1 - 7.4 (7H, multiplet).

Infrared Absorption Spectrum (KBr), ν ™ χ cm -1: 1602, 1589, 1497, 1483, 1455, 1248.

EXAMPLE 8 4-Methyl-2- (2- (4-phenyl-butyl) -phenoxymethyl] -morpholine hydrochloride 20 -8 (a) 4-Methyl-2- [2- (4-phenyl-butyl) -phenoxymethyl] -morpholine 115 mg of potassium carbonate and 118 mg methyl iodide was added to a solution of 300 mg of 2- [2- (4-phenylbutyl) phenoxymethyl] morpholine hydrochloride (prepared as in Example 7) in 6 ml of dimethylacetamide and the resulting mixture was allowed to react at room temperature for 3 hours. The organic layer was washed with a saturated aqueous solution of sodium chloride and concentrated by evaporation under reduced pressure.

30 63 106551

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.6 - 1.8 (4H, multiplet); 2.0 - 2.25 (2H, multiplet); 2.32 (3H, singlet); Δ 2.6 - 2.75 (5H, multiplet); 2.92 (1H, doublet, J = 11.9 Hz); 3.65 - 3.8 (1H, multiplet); 3.85 - 4.1 (4H, multiplet); 6.81 (1H, doublet, J = 7.9 Hz); Δ 6.87 (1H, doublet, J = 7.3 Hz); 7.1 - 7.3 (7H, multiplet).

8 (b) 4-Methyl-2- [2- (4-phenylbutyl) phenoxymethyl] morpholine hydrochloride 15.26 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 183 mg of 4-methyl-2- [2- (4) -phenylbutyl) phenoxymethyl] morpholine [prepared as described in step (a) above] in 5 ml of ethyl acetate and the resulting mixture was allowed to stand at room temperature. The crystals that precipitated were collected by filtration and dried in yacuo to give 175 mg (86% yield) of the title compound as colorless crystals, m.p. 135-136 ° C.

Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 1.55-1.8 (4H, multiplet); 2.6-2.75 (4H, multiplet); 2.76 (3H, singlet); 2.8-3.0 (2H, multiplet); 3.3-3.55 (2H, multiplet); 3.95-4.2 (3H, multiplet); 4.36 (1H, triplet, J = 12 , 2 Hz); 30 4.55 (1H, doublet, J = 8.6 Hz); 6.81 (1H, doublet, J = 8.6 Hz); 64 106551 6.93 (1H, triplet, J = 7, 3 Hz); 7.1-7.35 (7H, multiplet).

Infrared Absorption Spectrum (KBr), νπ1Μ cm-1: δ 1601, 1586, 1493, 1453, 1242.

EXAMPLE 31 2- {2- [2- (4-Phenylbutyl) phenoxy] ethyl} piperidine hydrochloride 10 31 (a) 1-t-Butoxycarbonyl-2- {2- [2- (4-phenylbutyl) phenoxy] ethyl} piperidine

By following a procedure similar to that described in Example 5 (a), 1.69 g of 2- (4-phenylbutyl) phenol (prepared as described in Preparation Example 3), 1.72 g of 15-butoxycarbonyl-2- (2-hydroxyethyl). piperidine, 5.9 g of triphenylphosphine and 3.92 g of diethyl azodicarboxylic acid were reacted in 75 ml of methylene chloride. The oily crude product, which was extracted as described in Example 5 (a), was purified by column chromatography over silica gel using a 5: 1 by volume mixture of hexane and ethyl acetate as eluant to afford 1.13 g (34% yield) of the title compound as an oil.

20

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.39 (9H, singlet); 1.3 - 1.75 (10H, multiplet); 1.8 - 2.0 (1H, multiplet); 2.1 - 2.3 (1H, multiplet); 2.6-2.7 (4H, triplet, J = 7.3 Hz); 2.82 (1H, triplet, J = 13.1 Hz); 3.85 - 4.1 (3H, multiplet); * 65 106551 4.4 - 4.55 (1H, multiplet); 6.77 (1H, doublet, J = 7.9 Hz); 6.84 (1H, triplet, J = 6.6 Hz); 7.05 - 7.3 (7H, multiplet).

5 31 (b) 2- {2- [2- (4-Phenylbutyl) phenoxy] ethyl} piperidine hydrochloride 10 mL of a 4N solution of hydrogen chloride in dioxane was added to a solution of 1.13 g of 1-butoxycarbonyl-2- {2 - [2- (4-phenylbutyl) phenoxy] ethyl} piperidine [prepared as described in step (b) above] in 10 mL of dioxane and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was then freed from the solvent by distillation under reduced pressure. The resulting residue was washed with hexane and dried in vacuo to give 0.94 g (97% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCf3, 2701 MHz), δ ppm: 1.2 - 2.3 (11H, multiplet); 2.4 - 2.7 (5H, multiplet); 2.75 - 2.9 (1H, multiplet); 3.15-3.3 (1H, multiplet); 3.45 (1H, doublet, J = 12.5 Hz); 4.0 - 4.2 (2H, multiplet); * 6.8 - 6.95 (2H, multiplet); 7.05 - 7.3 (7H, multiplet).

Infrared Absorption Spectrum (CHC (? 3), vn,? X cm -1: 1600, 1585, 1495, 1475, 1450, 1235.

66 106551 EXAMPLE 32 1-Methyl-2- {2- [2- (4-phenylbutyl) phenoxy] ethyl} piperidine 5 32 (a) 1-Methyl-2- {2- [2- (4-phenylbutyl) phenoxy] ethyl} piperidine

A solution of 820 mg of tert-butoxycarbonyl-2- {2- [2- (4-phenylbutyl) phenoxy] ethyl] piperidine [prepared as described in Example 31 (a)] in 4 ml of tetrahydrofuran was added dropwise to the dispersion, containing 140 mg of lithium aluminum hydride in 10 4 ml of tetrahydrofuran while cooling with ice. After the addition was complete, the reaction mixture was refluxed for 2 hours and then cooled. Sodium sulfate tide decahydrate was carefully added to the mixture to decompose any excess hydride. The insolubles were then filtered off and the filtrate was concentrated by evaporation under reduced pressure. The resulting oily residue was purified by column chromatography over silica gel using a 20: 1 by volume mixture of methylene chloride and methanol as eluant to afford 455 mg (69% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 1.15 - 1.5 (2H, multiplet); 1.6 - 1.95 (9H, multiplet); 2.1 - 2.3 (3H, multiplet); 2.35 (3H, singlet); 2.64 (4H, triplet, J = 6.9 Hz); 2.85-3.0 (1H, multiplet); 3.95 - 4.1 (2H, multiplet); 6.8 - 6.95 (2H, multiplet); 7.1 - 7.3 (7H, multiplet).

67 106551 32 (b) 1-Methyl-2- {2- [3- (4-phenylbutyl) phenoxy] ethyl} piperidine hydrochloride

By following a procedure similar to that described in Example 1 (c), 450 mg of 1-methyl-2- {2- [2- (4-phenylbutyl) phenoxy] ethyl} piperidine [prepared as described in step 5 (a) above] dissolved To 5 ml of ethyl acetate was converted to the hydrochloride by treatment with 0.4 ml of a 4N solution of hydrogen chloride in dioxane. The reaction mixture was then concentrated by evaporation under reduced pressure and dried in vacuo to give 496 mg of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDC < 3 + D20,270 MHz), δ ppm: 1.2-1.5 (1H, multiplet); 1.55 - 2.45 (11H, multiplet); 2.45 - 2.9 (5H, multiplet); 2.76 (3H, singlet); 2.9 - 3.7 (2H, multiplet); 3.95 - 4.2 (2H, multiplet); 6.81 (1H, doublet, J = 8.6 Hz); 6.91 (1H, triplet, J = 6.9 Hz); 7.1-7.3 (7H, multiplet).

20

Infrared Absorption Spectrum (CHCC3), ν max cm -1: 1600, 1585, 1495, 1470, 1450, 1230.

68 106551 EXAMPLE 34 (4R) -4-Hydroxy-2- [2- (4-phenylbutyl) phenoxymethyl] pyrrolidine hydrochloride 5 34 (a) (4R) -4-Benzyloxy-1-butoxycarbonyl-2- [2- ( 4-Phenylbutyl) phenoxymethyl] pyrrolidine 441 mg of 2- (4-phenylbutyl) phenol (prepared as described in Preparation Example 3) and 241 mg of potassium t-butoxide were dissolved in ice-cooling and stirring in 20 ml of dimethyl-10-acetamide. 900 mg of (4R) -4-benzyloxy-t-butoxycarbonyl-2- (p-toluene-sulfonyloxymethyl) -pyrrolidine was then added to the solution thus obtained, and the resulting mixture was stirred at 40 ° C for 5 hours, after which the reaction mixture was cooled and partitioned between ethyl acetate and aqueous. The layer was dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure.The residue was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluent to give 242 mg (yield 24%) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDC ^ 270, 270 MHz), δ ppm: δ 1.45 (9H, singlet); 1.5-1.75 (4H, multiplet); * 2.1 - 2.3 (2H, multiplet); 2.5 - 2.7 (4H, multiplet); 3.4 - 4.6 (8H, multiplet); 6.7 - 6.95 (2H, multiplet); 7.05 - 7.4 (12H, multiplet).

<· - 69 106551 34 (b) (4R) -1-Butoxycarbonyl-4-hydroxy-2- [2- (4-phenylbutyl) phenoxymethyl] pyrrolidine

A solution of 238 mg of (4R) -4-benzyloxy-t-butoxycarbonyl-2- [2- (4-5 phenylbutyl) phenoxymethyl] pyrrolidine [prepared as described in step (a) above] in 10 ml of ethanol was stirred at 55 ° C for six hours under a hydrogen atmosphere at atmospheric pressure and 20 mg 5% w / w palladium on charcoal. The mixture was cooled and then the catalyst was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The residue was purified by column chromatography over silica gel using a 1: 1 by volume mixture of hexane and ethyl acetate as eluent to give 177 mg (90% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCd3.270 MHz), δ ppm: 1.46 (9H, singlet); 1.5 - 1.8 (4H, multiplet); 2.0 - 2.3 (2H, multiplet); 2.5 - 2.7 (4H, multiplet); 3.4-4.6 (6H, multiplet); 6.75 - 6.95 (2H, multiplet); 7.05 - 7.35 (7H, multiplet).

34 (c) (4R) -4-Hydroxy-2- [2- (4-phenylbutyl) phenoxymethyl] pyrrolidine hydrochloride 3 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 173 mg of (4R) -lt-butoxycarbonyl-4 -hydroxy-2- [2- (4-phenylbutyl) phenoxymethyl] pyrrolidine prepared as described in step (b) above] in 3 ml of dioxane and the resulting mixture was allowed to stand at room temperature for two hours. The reaction mixture was then concentrated by evaporation under reduced pressure and the residue was dissolved in methylene chloride. Ethyl acetate was added to the solution and the mixture was allowed to stand. The crystals which precipitated were collected at <70 ° (5551 by filtration) to give 109 mg (yield 74%) of the title compound as colorless crystals, m.p. 135-137 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl3, 2770 MHz), δ ppm: δ 1.6-1.85 (4H, multiplet); 1.9 - 2.05 (1H, multiplet); 2.14 (1H, doublet of doublets, J = 6.6 & 13.2 Hz); 2.5 - 2.7 (4H, multiplet); 3.25 (1H, doublet of doublets, J = 3.3 & 12.5 Hz); Δ 3.56 (1H, doublet, J = 12.5 Hz); 4.05 (1H, doublet of doublets, J = 4.6 & 10.6 Hz); 4.23 (1H, doublet of doublets, J = 4.0 & 10.6 Hz); 4.2 - 4.4 (1H, multiplet); 4.4 - 4.55 (1H, multiplet); 6.82 (1H, doublet, J = 7.9 Hz); 6.88 (1H, triplet, J = 7.6 Hz); 7.05 - 7.3 (7H, multiplet).

Infrared Absorption Spectrum (KBr), ν max cm -1: 20 1602, 1588, 1495, 1465, 1451, 1237.

EXAMPLE 35 2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl] -1-methylpyrrolidine hydrochloride 35 (a) 2- (2- {2- [2- (3-Methoxyphenyl)) ethyl] phenoxy} ethyl 1-methylpyrrolidine 9.83 g of potassium t-butoxide was added with ice-cooling and stirring to a solution of 20.0 g of 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described Preparation (71 1G6551 in Example 20) in 50 ml of dimethylacetamide and the resulting mixture was stirred at the same temperature for 30 minutes to give potassium 2- [2- (3-methoxyphenyl) ethyl] phenolate.

Meanwhile, 9.83 g of potassium t-butoxide was added to a solution of 16.1 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride in 80 ml of dimethylacetamide while cooling with ice to give the free amine compound, which was then added at room temperature. and stirring with a solution of potassium 2- [2- (3-methoxyphenyl) ethyl] phenolate, prepared as described above. The resulting mixture was then stirred at 70 ° C for 20 hours, after which it was cooled and diluted with 500 mL of ethyl acetate. The diluted solution was washed with water and a saturated aqueous solution of sodium chloride, in the aforementioned setting, and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure and the resulting residue was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to afford 14.6 g (49% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDQ? 3, 270 MHz), δ ppm: 1.55 - 2.6 (8H, multiplet); 2.42 (3H, singlet); 2.8 - 3.0 (4H, multiplet); 3.1-3.3 (1H, multiplet); 3.78 (3H, singlet); 3.9 - 4.15 (2H, multiplet); 6.7 - 6.95 (5H, multiplet); 7.1-7.3 (3H, multiplet).

35 (b) 2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl] -1-methylpyrrolidine hydrochloride 30 ml of a 4N solution of hydrogen chloride in ethyl acetate was added under ice-cooling to a solution of 14.5 g of 2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine (106551) [prepared as described in step (a) above] in 100 ml of ethyl acetate and the resulting mixture was The crystals which precipitated were collected by filtration and dried in vacuo to give 1.30 g (81% yield) of the title compound as colorless crystals having a melting point of 109-110 ° C.

5

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: I, 9-2.15 (2H, multiplet); 2.15 - 2.4 (2H, multiplet); 2.4 - 2.65 (2H, multiplet); 10 2.77 (3H, singlet); 2.7 - 3.0 (5H, multiplet); 3.2 - 3.4 (1H, multiplet); 3.78 (3H, singlet); 3.8 - 4.1 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.7 - 7.0 (5H, multiplet); 7.15 - 7.3 (3H, multiplet).

EXAMPLE 36 2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl] -1-methylpyrrolidine hydrochloride 36 (a) 2- (2- {2- [2- (3-Methoxyphenyl)) ethyl] phenoxy} ethyl) -1-methylpyrrolidine 25 g of diethyl azodicarboxylate were added dropwise with ice-cooling while stirring to a solution of 10.6 g of 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 20), 8.4 g of 1-methyl-2-pyrrolidylethanol and 17 g of triphenylphosphine in 200 ml of methylene chloride and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was then concentrated by evaporation under reduced pressure and the resulting residue was partitioned between ethyl acetate. The organic »73 106551 layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography over silica gel using methylene chloride. 10: 1 v / v methanol as eluant to give 5.70 mg (36% yield) of the title compound as a colorless oil.

The nuclear magnetic resonance spectrum of this product was identical to that of the compound prepared as described in Example 35 (a).

36 (b) 2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl] -1-methylpyrrolidine hydro-10 chloride

Following a procedure similar to that described in Example 35 (a), 5.70 g of 2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in Step ( a) above] was converted to the hydrochloride to give 4.89 g (36% yield) of the title compound as colorless crystals.

The melting point and the nuclear magnetic resonance spectrum of this product were identical to the compounds prepared as described in Example 35 (b).

EXAMPLE 37 *: 4- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} piperidine hydrochloride 37 (a) t-Butoxycarbonyl-4- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} piperidine 25

By following a procedure similar to that described in Example 36 (a), 456 g of 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 20), 600 mg of 1-butoxycarbonyl-4-hydroxypiperidine and 865 mg of triphenylphosphine was reacted with 575 mg of diethyl azodicarboxylate in 30 ml of methylene chloride. The reaction mixture 30 was worked up as described in Example 36 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluent to give 379 mg (yield 46%) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCd 3,270 MHz), δ ppm: δ 1.47 (9H, singlet); 1.7 - 2.0 (4H, multiplet); 2.8-3.0 (4H, multiplet); 3.35 - 3.55 (2H, multiplet); 3.6 - 3.75 (2H, multiplet); Δ 3.78 (3H, singlet); 4.55 - 4.6 (1H, multiplet); 6.7 - 6.9 (5H, multiplet); 7.1 - 7.3 (3H, multiplet).

37 (b) 4- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} piperidine hydrochloride 379 mg of t-butoxycarbonyl-4- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} piperidine [prepared as described in step (a) above] was dissolved in 5 ml of a 4N solution of hydrogen chloride in dioxane and allowed to stand at room temperature for one hour. The reaction mixture was then concentrated by distillation under reduced pressure, and the resulting oily residue was dissolved in 10 ml of ethyl acetate and then allowed to stand at room temperature. *: The crystals which precipitated were collected by filtration and dried in vacuo to give 290 mg (90% yield) of the title compound as colorless crystals having a melting point of 121-122: C.

Nuclear Magnetic Resonance Spectrum (CDQ?, 270 MHz), δ ppm: 2.05 - 2.2 (2H, multiplet); 2.25 - 2.4 (2H, multiplet); 2.8-3.0 (4H, multiplet); 3.2 - 3.4 (4H, multiplet); 30 3.76 (3H, singlet); 4.55 - 4.6 (1H, multiplet); 75 1C6551 6.6-6.8 (4H, multiplet); 6.92 (1H, triplet, J = 7.3 Hz); 7.1-7.3 (3H, multiplet).

EXAMPLE 38 4- {2-] 2- (3-Methoxyphenyl) ethyl] phenoxy} -1-methylpiperidine hydrochloride (not included in the invention) 10 38 (a) 4- {2- [2- (3-Methoxyphenyl) ) ethyl] phenoxy} -l-methylpiperidine

A solution of 482 g of tert-butoxycarbonyl-4- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} piperidine (prepared in a manner similar to that described in Example 37) in 5 ml of tetra-15 hydrofuran was added dropwise dispersion containing 44.5 g of lithium aluminum hydride in 5 ml of tetrahydrofuran with stirring. After the addition was complete, the reaction mixture was refluxed for one hour and then cooled. A sufficient amount of sodium sulfate decahydrate was then added to the reaction mixture to decompose any excess hydride, followed by stirring for about 30 minutes. The insoluble materials were filtered off and then the filtrate was freed from the solvent by distillation under reduced pressure. The resulting oily residue was purified by column chromatography over silica gel; Passing through a 10: 1 by volume mixture of methylene chloride and hexane as the eluent gave 220 mg (57% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCP3, 270 MHz), δ ppm: 1.85 - 2.15 (4H, multiplet); 2.3 - 2.5 (2H, multiplet); 2.33 (3H, singlet); 2.6 - 2.75 (2H, multiplet); 2.8 - 3.0 (4H, multiplet); 3.79 (3H, singlet); ? 76 106551 4.35-4.5 (1H, multiplet); 6.7 - 6.9 (5H, multiplet); 7.1 - 7.3 (3H, multiplet).

38 (b) 4- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} -1-methylpiperidine hydrochloride 0.2 mL of a 4N solution of hydrogen chloride in dioxane was added dropwise to a solution of 220 mg of 4- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} -1-methylpiperidine [prepared as described in step (a) above] in 20 ml of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 170 mg (69% yield) of the title compound as colorless crystals, m.p. 147-148 ° C.

Nuclear Magnetic Resonance Spectrum (CD? 3, 270 MHz),? Ppm:? 2.0 - 2.25 (2H, multiplet); 2.5 - 2.8 (2H, multiplet); 2.73 (3H, singlet); 2.8 - 3.1 (6H, multiplet); 3.2 - 3.4 (2H, multiplet); 3.76 (3H, singlet); 3.6 - 3.8 (1H, multiplet); * 6.65-6.85 (4H, multiplet); 6.95 (1H, triplet, J = 7.3 Hz); 7.15 - 7.3 (3H, multiplet).

2- (2- (2- [2- (3-Hydroxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 77 EXAMPLE 39 106551 5 39 (a) 2- (2- {2- [2- (3-Hydroxyphenyl) ethyl] phenoxy} ethyl) -l-methylpyrrolidine

By following a procedure similar to that described in Example 35 (a), 2.37 g of 2- [2- (3-methoxymethoxyphenyl) ethyl] phenol (prepared as described in Preparation 10 in Example 21), 1.03 g of potassium t- butoxide and 1.69 g of 2- (2-chloroethyl) -1-merpyrrolidine hydrochloride were reacted with 50 ml of dimethylacetamide. The reaction mixture was then worked up as described in Example 35 (a) and the crude product was purified by column chromatography over silica gel using a 20: 1 by volume mixture of methylene chloride and methanol as eluant to afford 1.87 g (62% yield) of the title compound as a colorless oil.

15

Nuclear Magnetic Resonance Spectrum (CDC (J 270 MHz), δ ppm: 1.5 - 2.4 (8H, multiplet); 2.39 (3H, singlet); 2.8 - 3.0 (4H, multiplet); - 3.2 (1H, multiplet); 3.48 (3H, singlet); *: 3.95-4.15 (2H, multiplet); 5.15 (2H, singlet); 6.8-6.95 (5H) , multiplet); 7.1-7.3 (3H, multiplet).

39 (b) 2- (2- {2- [2- (3-Hydroxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 106551 1.80 g of 2- (2- {2- [2- (3-Methoxymethoxyphenyl) ethyl] phenoxy} ethyl] -1-methylpyrrolidine 5 [prepared as described in step (a) above] was dissolved in 20 ml of a 4N solution of hydrogen chloride in dioxane and allowed to stand at room temperature for 30 minutes. under reduced pressure, and the resulting oily residue was dissolved in 20 mL of methylene chloride Ethyl acetate was slowly added to the solution until it just began to show signs of turbidity, then allowed to stand overnight at room temperature The crystals which precipitated were collected by filtration and dried in vacuo to give 1.25 g (71% yield) of the title compound as colorless crystals, m.p. 68-70: C.

Nuclear Magnetic Resonance Spectrum (CDC (3 3.270 MHz), δ ppm: 1.9 - 2.6 (6H, multiplet); 2.65-3.1 (5H, multiplet); 2.83 (3H, singlet); 3.15 - 3.45 (1H, multiplet); 3.6 - 4.1 (3H, multiplet); 6.57 (1H, doublet, J = 7.3 Hz); 6.7-6.8 (2H, multiplet); 6.92 (1H, triplet, J = 7.3 Hz); *: 7.00 (1H, singlet); 7.05 (1H, triplet, J = 7.9 Hz); 7.1 - 7.25 (2H, multiplet).

25 ♦ (S) -2- {2- [2- (3-Hydroxyphenyl) ethyl] phenoxymethyl} pyrrolidine hydrochloride 79 EXAMPLE 40 106551 5 40 (a) (S) -lt-Butoxycarbonyl-2- {2- [2- (3-Methoxymethoxyphenyl) ethyl] phenoxymethyl] pyrrolidine 0.721 g of potassium t-butoxide was added under ice-cooling to a solution of 1.66 g of 2- [2- (3-methoxymethoxyphenyl) ethyl] phenol (prepared as described in Preparation 1). 10 in Example 21) in 5 ml of dimethylacetamide and the resulting mixture was stirred for 15 minutes. Thereafter, 2.28 g of (S) -lt-butoxycarbonyl-2- (p-toluenesulfonyl-oxymethyl) -pyrrolidine were added to the mixture and the mixture was stirred at 50 ° C for 2 hours, then cooled and partitioned between ethyl acetate and and dried over anhydrous magnesium sulfate, The solvent was removed by distillation under reduced pressure and the resulting residue was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as the eluent to afford 1.70 g (60% yield) of the title compound.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.47 (9H, singlet); 1.75 - 2.2 (4H, multiplet); 2.8-3.0 (4H, multiplet); 3.25 - 3.55 (2H, multiplet); 3.48 (3H, singlet); 3.75 - 4.3 (3H, multiplet); 5.15 (2H, singlet); 6.8 - 7.0 (5H, multiplet); 7.05 - 7.3 (3H, multiplet).

30 <80 106551 40 (b) (S) -2- {2- [2- (3-Hydroxyphenyl) ethyl] phenoxymethyl} pyrrolidine hydrochloride 630 mg of (S) -lt-butoxycarbonyl-2- {2- [2- ( 3-Methoxymethoxyphenyl) ethyl] phenoxymethyl} -pyrrolidine [prepared as described in step (a) above] was dissolved in 10 ml of a 4N solution of chlorine-5 dyn in dioxane with ice-cooling and allowed to stand at room temperature for 3 hours. The mixture was then concentrated by distillation under reduced pressure, and the resulting oily residue was dissolved in a small amount of isopropyl alcohol; the solution was then allowed to stand while cooling with ice. The crystals which precipitated were collected by filtration and dried in vacuo to give 318 mg (66% yield) of the title compound as colorless crystals having a melting point of 127-129 ° C.

[α] 25 D + 10.5 ° (c = 1.0, methanol).

D

Nuclear Magnetic Resonance Spectrum (Hexadeuterated Dimethylsulfoxide + D 2 O, 270 MHz), δ ppm: 1.8 - 2.0 (1H, multiplet); 2.05 - 2.2 (2H, multiplet); 2.2 - 2.35 (1H, multiplet); 2.7 - 3.1 (4H, multiplet); 3.2 - 3.35 (1H, multiplet); 3.4 - 3.55 (1H, multiplet); 4.05 - 4.25 (3H, multiplet); 6.61 (1H, doublet, J = 7.9 Hz); 6.66 (1H, doublet of doublets, J = 1.2 & 7.9 Hz); 6.84 (1H, doublet, J = 7.9 Hz); 6.94 (1H, triplet, J = 7.3 Hz); 7.0 - 7.25 (4H, multiplet).

(2- {2- [2- (3-Hydroxyphenyl) ethyl] phenoxymethyl} -1-methylpyrrolidine hydrochloride 81 EXAMPLE 41 106551 5 41 (a) 2- {2- [2- (3-Methoxymethoxyphenyl) ethyl] phenoxymethyl} - l-methyl-pyrrolidine

By following a procedure similar to that described in Example 38, 1.00 g of 10 1-t-butoxycarbonyl-2- {2- [2- (3-methoxymethoxyphenyl) ethyl] phenoxymethyl} pyrrolidine [prepared in a similar manner to described in Example 40 (a)] was reacted with a dispersion of 88.1 mg of lithium aluminum hydride in 10 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38 and the crude product thus obtained was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to give 668 mg (yield 83%) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDC (3.270 MHz), δ ppm: 1.7 - 2.0 (3H, multiplet); 2.0-2.2 (1H, multiplet); 2.3 - 2.45 (1H, multiplet); ; ··· 2.53 (3H, singlet); 2.7 - 3.0 (5H, multiplet); 3.1 - 3.2 (1H, multiplet); 3.48 (3H, singlet); 3.85 (1H, doublet of doublets, J = 6.6 & 9.2 Hz); 4.08 (1H, doublet of doublets, J = 5.3 & 9.2 Hz); ? 5.15 (2H, singlet); 6.8 - 6.9 (5H, multiplet); 7.1-7.3 (3H, multiplet).

«41 (b) 2- {2- [2- (3-Hydroxyphenyl) ethyl] phenoxymethyl} -1-methylpyrrolidine hydrochloride 82 106551 660 mg 2- {2- [2- (3-methoxymethoxyphenyl) ethyl] phenoxymethyl} -1-methylpyrrolidine 5 [prepared as described in step (a) above] was dissolved in 5 ml of a 4N solution of hydrogen chloride in dioxane and allowed to stand at room temperature for 30 minutes. The solvent was then removed by distillation under reduced pressure, and the resulting solid residue was recrystallized from isopropyl alcohol to give 529 mg (82% yield) of the title compound as colorless needles, m.p. 232-233 ° C (with decomposition).

10

Nuclear Magnetic Resonance Spectrum (Hexadeuterated Dimethylsulfoxide + D, 0, 270 MHz), δ ppm: 1.8 - 2.2 (3H, multiplet); 2.2 - 2.4 (1H, multiplet); 2.7 - 2.95 (4H, multiplet); 2.97 (3H, singlet); 3.05-3.25 (1H, multiplet); 3.5 - 3.7 (1H, multiplet); 3.8 - 3.95 (1H, multiplet); 4.28 (1H, doublet of doublets, J = 4.0 & 10.6 Hz); 4.40 (1H, doublet of doublets, J = 7.9 & 10.6 Hz); ; ··· 6.55-6.7 (3H, multiplet); 6.75 - 7.1 (3H, multiplet); 7.15 - 7.3 (2H, multiplet).

25 1 · EXAMPLE 42 (R) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} morpholine hydrochloride 83 106551 5 42 (a) (R) -4-t-Butoxycarbonyl-2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} morpholine

By following a procedure similar to that described in Example 40 (a), 1.14 g of 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 20), 0.560 g of potassium t-butoxide and 1. 86 g of (R) -4-t-butoxycarbonyl-2- (g-toluenesulfonyloxymethyl) morpholine were reacted in 20 mL of dimethylacetamide. The mixture was then worked up as described in Example 40 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluant to give 1.68 g (79% yield) of the title compound as an oil.

15

Nuclear Magnetic Resonance Spectrum (CDC (3.270 MHz), δ ppm: 1.44 (9H, singlet); 2.8 - 3.1 (6H, multiplet); 3.5 - 3.7 (1H, multiplet); 3.7-4.2 (6H, multiplet); 3.77 (3H, singlet); ; 6.7-6.95 (5H, multiplet); 7.1-7.3 (3H, multiplet).

42 (b) (R) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} morpholine hydrochloride 10 mL of a 4N solution of hydrogen chloride in dioxane was added to a solution of 1.68 g of (R) -4- t-Butoxycarbonyl-2- {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl} morpholine was prepared as described in step (a) above] in 10 ml of dioxane and the resulting mixture was allowed to stand at room temperature for 30 minutes. Thereafter, the solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in a small amount of methylene chloride. Ethyl acetate was added to the mixture which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 1.24 g (86% yield) of the title compound as colorless crystals having a melting point of 112-113 ° C.

[Α] 25: -7.4 ° (c = 1.0, water).

D

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: δ 2.75 - 2.95 (4H, multiplet); 3.0-3.2 (2H, multiplet); 3.35 (1H, doublet, J = 13.2 Hz); 3.46 (1H, doublet, J = 11.2 Hz); 3.75 (3H, singlet); 3.95-4.2 (4H, multiplet); 4.3 - 4.4 (1H, multiplet); 6.65 - 6.95 (5H, multiplet); 7.05 - 7.3 (3H, multiplet).

EXAMPLE 43 (R) -2- {2- [2- (3-Methoxy-phenyl) -ethyl] -phenoxymethyl} -4-methyl-morpholine> · · · hydrochloride 25 (a) (R) -2- {2- [2- ( 3-Methoxyphenyl) ethyl] phenoxymethyl} -4-methylmorpholine 152 mg of potassium carbonate was added to a solution of 404 mg of (R) -2- {2- [2- (3- .. methoxyphenyl) ethyl] phenoxymethyl} morpholine hydrochloride (prepared as described in Example 42) in 10 mL of dimethylacetamide and the resulting mixture was stirred at room temperature for 1 hour. Subsequently, 157 mg of methyl iodide was added and the mixture was stirred at room temperature for 14 hours. The reaction mixture was then diluted with ethyl acetate. The diluted solution was washed with water and a saturated aqueous sodium chloride solution, in the order of? 85 106551, then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure and the resulting oily residue was purified by column chromatography over silica gel using a 20: 1 by volume mixture of methylene chloride and methanol as eluent to afford 310 mg (yield 82%) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 2.0 - 2.25 (2H, multiplet); 2.32 (3H, singlet); 10.65 - 2.75 (1H, multiplet); 2.8 - 3.05 (5H, multiplet); 3.7 - 3.85 (1H, multiplet); 3.78 (3H, singlet); 3.9 - 4.1 (4H, multiplet); 6.7 - 6.95 (5H, multiplet); 7.1 - 7.3 (3H, multiplet).

43 (b) (R) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} -4-methylmorpholine hydrochloride 20 mL of a 4N solution of hydrogen chloride in dioxane was added to a solution of 310 mg ( R) -2- ··· {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl} -4-methylmorpholine [prepared as described in step (a) above] with a small amount of ethyl acetate and the resulting mixture was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 323 mg (94% yield) of the title compound as colorless needles with a melting point of 184-185 ° C.

[α] 25: + 10.5 ° (c = 1.0, methanol).

D 1686 106551 Nuclear Magnetic Resonance Spectrum (CDC03, 270 MHz), δ ppm: 2.75 (3H, singlet); 2.75-3.05 (6H, multiplet); 3.38 (2H, triplet, J = 13.2 Hz); Δ 3.78 (3H, singlet); 4.0 - 4.2 (3H, multiplet); 4.3 - 4.45 (1H, multiplet); 4.5 - 4.6 (1H, multiplet); 6.7 - 6.9 (4H, multiplet); 6.94 (1H, triplet, J = 7.3 Hz); 7.1 - 7.3 (3H, multiplet).

EXAMPLE 44 2- (2- {2- [2- (3,4-Dimethoxyphenyl) ethyl] phenoxy}] ethyl] -1-pyrrolidine hydrochloride 44 (a) 2- (2- {2- [2- (3) , 4-Dimethoxyphenyl) ethyl] phenoxy} ethyl] -1-methylpyrrolidine By following a procedure similar to that described in Example 35 (a), 1.30 g of 2- [2- (3,4-dimethoxyphenyl) ethyl] phenol ( prepared as described in Preparation Example 27), 1.69 g of potassium t-butoxide and 1.39 g of 2- (2-chloroethyl) -1-methylpyrrolidine were reacted in 30 ml of dimethylacetamide. as described in Example 35 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to give 1.50 g (80% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.55 - 2.5 (8H, multiplet); 2.41 (3H, singlet); 2.8-3.0 (4H, multiplet); 87 106551 3.15-3.25 (1H, multiplet); 3.82 (3H, singlet); 3.86 (3H, singlet); 3.9 - 4.15 (2H, multiplet); Δ 6.6-6.9 (5H, multiplet); 7.05 - 7.25 (2H, multiplet).

44 (b) 2- (2- {2- [2- (3,4-Dimethoxyphenyl) ethyl] phenoxy} ethyl] -1-methylpyrrolidine hydrochloride 10 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 1, 50 g of 2- (2- {2- [2- (3,4-dimethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] in 20 ml of methylene chloride and the mixture was concentrated by distillation under reduced pressure. The resulting residue was dissolved in ethyl acetate and allowed to stand at room temperature for 15 hours, The crystals which precipitated were collected by filtration and dried in vacuo to give 1.10 g (yield (67%)) of the title compound as colorless crystals having a melting point of 147-148 ° C. C.

Nuclear Magnetic Resonance Spectrum (CDCl3, 270 MHz), δ ppm: 1.95 - 2.15 (2H, multiplet); 2.2 - 2.4 (2H, multiplet); f * 2.4 - 2.6 (2H, multiplet); 2.76 & 2.78 (3G together, each singlet); 2.75 - 3.0 (5H, multiplet); 3.15 - 3.55 (1H, multiplet); 3.80 (3H, singlet); 3.86 (3H, singlet);

• I

3.8 - 4.1 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.6-7.0 (5Ή, multiplet); 7.1-7.3 (2H, multiplet).

EXAMPLE 45 88 106551 2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} morpholine hydrochloride 5 45 (a) 4-t-Butoxycarbonyl-2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy-methyl} morpholine

By following a procedure similar to that described in Example 40, 1.00 g of 2- [2- (3-10 methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 20), 1.63 g of 4-t-butoxycarbonyl-2- ( E-toluenesulfonyloxymethyl) morpholine and 0.490 g of potassium t-butoxide were reacted in 20 ml of dimethylacetamide. The mixture was then worked up as described in Example 40 and the crude product thus obtained was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluant to afford 1.87 g (94.5% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CD? 3.270 MHz),? Ppm: 1.45 (9H, singlet); 2.8 - 3.1 (6H, multiplet); 3.55 - 3.7 (1H, multiplet); 3.7 - 4.2 (6H, multiplet); ; ··· 3.77 (3H, singlet); 6.7 - 6.95 (5H, multiplet); 7.1-7.3 (3H, multiplet).

45 (b) 2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} morpholine hydrochloride ♦ <2 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 0.99 g of 4-t-butoxycarbonyl-2 {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl] morpholine [prepared as described in step (a) above] in 2 ml of dioxane and allowed to stand at room temperature for 16 hours, after which it was concentrated by distillation under reduced pressure. .

89 106551

The resulting residue was dissolved in ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.42 g (52% yield) of the title compound as colorless crystals having a melting point of 110-112 ° C.

5

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 2.8 - 3.0 (4H, multiplet); 3.0 - 3.2 (2H, multiplet); 3.36 (1H, doublet, J = 12.5 Hz); 3.48 (1H, doublet, J = 13.2 Hz); 3.76 (3H, singlet); 4.0 - 4.2 (4H, multiplet); 4.25 - 4.4 (1H, multiplet); 6.7 - 7.0 (5H, multiplet); 7.1-7.3 (3H, multiplet).

EXAMPLE 46 2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} -4-methylmorpholine hydrochloride 46 (a) 2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} -4- methylmorpholine i · ·

By following a procedure similar to that described in Example 38, 870 mg of 4-t-butoxycarbonyl-2- {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl} morpholine [prepared as described in Example 45 (a)]. was reacted with a dispersion of 113 mg of lithium aluminum hydride in 15 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38 and the crude product thus obtained was purified by column chromatography on silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to give 620 mg (94% yield) of the title compound as a colorless oil.

30 90 106551

Nuclear Magnetic Resonance Spectrum (CDC |3, 270 MHz), δ ppm: 2.0 - 2.3 (2H, multiplet); 2.33 (3H, singlet); 2.65 - 2.75 (1H, multiplet); 2.8 - 3.0 (5H, multiplet); 3.7 - 3.85 (1H, multiplet); 3.78 (3H, singlet); 3.9 - 4.1 (4H, multiplet); 6.7 - 6.95 (5H, multiplet); 7.1-7.3 (3H, multiplet).

46 (b) 2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} -4-methylmorpholine hydrochloride 15 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 620 mg of 2- {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl} -1-methylmorpholine [prepared as described in step (a) above] to the appropriate amount of ethyl acetate and the resulting mixture was concentrated by distillation under reduced pressure. The resulting solid residue was recrystallized from ethyl acetate to give 476 mg (69% yield) of the title compound as colorless crystals having a melting point of 174-176 ° C.

; ·· Nuclear Magnetic Resonance Spectrum (CDCC3, 270 MHz), δ ppm: 2.77 (3H, singlet); 2.7 - 3.1 (6H, multiplet); 3.40 (2H, triplet, J = 11.9 Hz); 3.79 (3H, multiplet); 4.3 - 4.5 (1H, multiplet); ? 4.5-4.65 (1H, multiplet); 6.7 - 6.9 (4H, multiplet); 6.95 (1H, triplet, J = 7.6 Hz); 7.1 - 7.3 (3H, multiplet).

91 106551 EXAMPLE 47 2- (2- {2- [2- (3-Methoxy-phenyl) -ethyl] -phenoxy} -ethyl) -piperidine hydrochloride 47 47 (a) t-Butoxycarbonyl-2- (2- {2- [2- (3) methoxyphenyl) ethyl] phenoxy} ethyl) piperidine

By following a procedure similar to that described in Example 36 (a), 1.00 g of 10 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 20), 1.51 g of 1-butoxycarbonyl-2 (2-Hydroxyethyl) piperidine, 1.72 g of triphenylphosphine and 1.14 g of diethyl azodicarboxylate were reacted in 20 ml of methylene chloride. The mixture was then worked up as described in Example 36 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluent to give 0.630 mg (32% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCfj, 270 MHz), δ ppm: 1.46 (9H, singlet); 1.4 - 2.0 (7H, multiplet); 2.15 - 2.35 (1H, multiplet); ; 2.65-3.0 (5H, multiplet); 3.78 (3H, singlet); 3.9-4.2 (3H, singlet); 4.35 - 4.45 (1H, multiplet); 6.7 - 6.9 (5H, multiplet); 7.05 - 7.3 (3H, multiplet).

(B) 2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) piperidine hydrochloride 1 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 0.63 g of 5 t-Butoxycarbonyl-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) piperidine [prepared as described in step (a) above] in 1 ml of dioxane and the resulting solution was allowed to stand at room temperature for 2 hours. After 5 hours, it was concentrated by distillation under reduced pressure, the resulting residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, the ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated by distillation under reduced pressure. packed with CM Sephadex C-25 (type H "). The column was washed with ethanol and eluted with a 0.1N solution of hydrogen chloride in ethanol. The eluate was concentrated by evaporation of the under vacuum and dried in vacuo to give 0.22 g (40% yield) of the title compound as a colorless oil.

15

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.3 - 2.1 (6H, multiplet); 2.1 - 2.3 (1H, multiplet); 2.5 - 2.7 (1H, multiplet); 2.7 - 3.0 (5H, multiplet); 3.15 - 3.35 (1H, multiplet); 3.4-3.55 (1H, doublet, J = 13.2 Hz); 3.77 (3H, singlet); 4.0 - 4.25 (2H, multiplet); 6.7 - 6.95 (5H, multiplet); 7.05 - 7.3 (3H, multiplet).

Infrared Absorption Spectrum (liquid film), δmax: 1601, 1585, 1495, 1455, 1436, 1241.

EXAMPLE 48 93 106551 2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpiperidine hydrochloride 5 48 (a) 2- (2- {2- [2- (3) methoxyphenyl) ethyl] phenoxy} ethyl) -l-methylpiperidine

By following a procedure similar to that described in Example 38, 1.70 g of 1-butoxycarbonyl-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) piperidine [prepared as described in Example 47 (a)] was reacted with a dispersion of 0.294 g of lithium-10 aluminum hydride in 30 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38 and the crude product thus obtained was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to give 0.730 mg (yield 53%) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 1.2 - 2.0 (7H, multiplet); 2.05 - 2.35 (3H, multiplet); 2.34 (3H, singlet); 2.8 - 3.0 (5H, multiplet); 3.78 (3H, singlet); 4.04 (2H, triplet, J = 7.3 Hz); : 6.7-6.9 (5H, multiplet); 7.1 - 7.25 (3H, multiplet).

48 (b) 2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpiperidine hydrochloride 1 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 0.730 mg of 2- (2- (2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpiperidine [prepared as described in step (a) above] in an appropriate amount of ethyl acetate and the resulting mixture was concentrated by distillation under reduced pressure. The residue was dissolved in 15 ml of 94 106551 ethyl acetate and allowed to stand at room temperature The precipitated wefts were collected by filtration and dried in vacuo to give 0.561 g (69% yield) of the title compound as colorless crystals, m.p. 115-117 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.3 - 2.2 (5H, multiplet); 2.2 - 2.45 (2H, multiplet); 2.45 - 2.7 (2H, multiplet); 2.75 (3H, singlet); 2.8 - 3.2 (5H, multiplet); 3.4 - 3.55 (1H, multiplet); 3.78 (3H, singlet); 3.95 - 4.2 (2H, multiplet); 6.65 - 6.8 (3H, multiplet); 6.84 (1H, doublet, J = 7.9 Hz); 6.93 (1H, triplet, J = 7.3 Hz); 7.1-7.3 (3H, multiplet).

EXAMPLE 49 3- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} piperidine hydrochloride • <49 (a) 1-Butoxycarbonyl-3- {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl} - piperidine 25

By following a procedure similar to that described in Example 40, 0.790 g of 2- [2- (3- (methoxyphenyl) ethyl] phenol [prepared as described in Preparation Example 20], 0.388 g of potassium t-butoxide and 1.28 g of lt- butoxycarbonyl-3- (p-toluenesulfonyloxymethyl) -piperidine was reacted with 15 mL of dimethylacetamide. The mixture was then worked up as described in Example 40 and the crude product thus obtained was purified by column chromatography over silica gel 95 106551 using a 4: 1 by volume mixture of hexane and ethyl acetate as eluant to afford 1.09 g (74% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDG> 3.270 MHz), δ ppm: δ 1.1-1.8 (3H, multiplet); 1.43 (9H, multiplet); 1.85 - 2.15 (2H, multiplet); 2.7-3.0 (6H, multiplet); 3.79 (3H, singlet); Δ 3.85 (2H, doublet, J = 5.9 Hz); 3.9 - 4.25 (2H, multiplet); 6.7 - 6.95 (5H, multiplet); 7.1-7.3 (3H, multiplet).

15 49 (b) 3- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} piperidine hydrochloride 240 mg 1-butoxycarbonyl-3- {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl} piperidine [prepared as described in step (a) above] was dissolved in 4 ml of a 4N solution of hydrogen chloride in dioxane. The solution was allowed to stand at room temperature for three hours, after which it was concentrated by evaporation under reduced pressure. The resulting residue was dissolved in ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration to give 183 mg (76% yield) of the title compound as colorless crystals, m.p. 155-157 ° C. 1 2 3 4 5 6

Nuclear Magnetic Resonance Spectrum (CDCf3, 2701 MHz), δ ppm: 2 1.4 - 2.2 (4H, multiplet); 3, 2.45 - 2.6 (1H, multiplet); 4 2.7 - 3.0 (6H, multiplet); 3.4-3.6 (2H, multiplet); Δ 3.76 (3H, singlet); 3.86 (2H, doublet, J = 4.6 Hz); 96 106551 6.65-6.85 (4H, multiplet); 6.89 (1H, triplet, J = 7.3 Hz); 7.1-7.3 (3H, multiplet).

EXAMPLE 51 3- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} piperidine hydrochloride 51 (a) 1-t-Butoxycarbonyl-3- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} piperidine

By following a procedure similar to that described in Example 36 (a), 1.50 g of 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 20), 2.64 g of t-butoxycarbonyl-3-hydroxypiperidine , 3.44 g of triphenylphosphine and 2.29 g of diethyl azodicarboxylate were reacted. The mixture was then worked up as described in Example 15 (36) (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 7: 1 by volume mixture of hexane and ethyl acetate as eluant to afford 1.68 g (62% yield) of the title compound.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 20 1.37 (9H, singlet); 1.4 - 2.2 (4H, multiplet); :; 2.75 - 2.95 (4H, multiplet); 3.0-3.8 (4H, multiplet); 3.79 (3H, singlet); : 4.2 - 4.4 (1H, multiplet); 6.7 - 6.95 (5H, multiplet); *. 7.05 - 7.25 (3H, multiplet).

»97 106551 51 (b) 3- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} piperidine hydrochloride 800 mg of t-butoxycarbonyl-3- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} piperidine [prepared as described in step (a) above] was dissolved in 8 ml of a 4N solution of hydrogen chloride in dioxane and allowed to stand at room temperature for two hours. The solution was then concentrated by evaporation under reduced pressure, the resulting residue was dissolved in ethyl acetate and the resulting solution was allowed to stand at room temperature. The crystals which precipitated were collected by filtration to give 300 mg (44% yield) of the title compound as colorless crystals having a melting point of 130-132 ° C.

10

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.6 - 1.8 (1H, multiplet); 1.9 - 2.3 (3H, multiplet); 2.8 - 3.1 (6H, multiplet); 3.25 - 3.4 (1H, multiplet); 3.55 (1H, doublet of doublets, J = 3.3 & 12.6 Hz); 3.77 (3H, singlet); 4.7 - 4.85 (1H, multiplet); 6.7 - 6.8 (3H, multiplet); 6.85-7.0 (2H, multiplet); 7.1-7.3 (3H, multiplet).

EXAMPLE 53 4- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) piperidine hydrochloride. 53 (a) 1-t-Butoxycarbonyl-4- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) piperidine 1

By following a procedure similar to that described in Example 40 (a), 1.20 g of 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 20), 98 106551, 2.00 g of lt-butoxycarbonyl-4 - [2- (p-Toluenesulfonyloxy) ethyl] piperidine and 0.590 g of potassium t-butoxide were reacted in 20 ml of dimethylacetamide. The mixture was then worked up as described in Example 40 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluent to give 2.00 g (86% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.1-1.3 (2H, multiplet); Δ 1.45 (9H, singlet); 1.6 - 1.85 (5H, multiplet); 2.68 (2H, triplet, J = 12.5 Hz); 2.8-3.0 (4H, multiplet); 3.78 (3H, singlet); 4.0-4.2 (2H, multiplet); 4.18 (2H, triplet, J = 5.9 Hz); 6.7 - 6.9 (5H, multiplet); 7.1 - 7.3 (3H, multiplet).

53 (b) 4- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) piperidine hydrochloride:. 2.00 g of t-butoxycarbonyl-4- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl] piperidine [prepared as described in step (a) above] were dissolved in 10 ml of a 4N solution of hydrogen chloride dioxane and the solution was allowed to stand at room temperature for 4 hours, then the solvent was removed by distillation under reduced pressure, and the resulting solid residue was dissolved in a small amount of methylene chloride, followed by ethyl acetate.

"The crystals which precipitated were collected by filtration to give 1.59 g (93% yield) of the title compound as colorless crystals having a melting point of 119-121 ° C. 1

Nuclear Magnetic Resonance Spectrum (CDC ?3, 270 MHz), δ ppm: 1.6 - 2.05 (7H, multiplet); 99 1C6551 2.7-2.95 (6H, multiplet); 3.47 (2H, doublet, J = 12.5 Hz); 3.79 (3H, singlet); 4.00 (2H, triplet, J = 5.9 Hz); Δ 6.7-7.0 (5H, multiplet); 7.1 - 7.3 (3H, multiplet).

EXAMPLE 55 10 4- (2- {2- [2- (3-Hydroxyphenyl) ethyl] phenoxy} ethyl] piperidine hydrochloride 55 (a) lt -Butoxycarbonyl-4- (2- {2- [2- (3-methoxymethoxyphenyl) ) ethyl] -phenoxy} ethyl) piperidine By following a procedure similar to that described in Example 40 (a), 1.58 g of 2- [2- (3-methoxymethoxyphenyl) ethyl] phenol, 2.34 g of t-butoxycarbonyl- 4- [2- (p-Toluenesulfonyloxy) ethyl] piperidine and 0.686 g of potassium t-butoxide were reacted with 10% dimethylacetamide.The mixture was then worked up as described in Example 40 (a) and the crude product thus obtained was purified by column chromatography over silica gel. and ethyl acetate 4: 1 by volume as eluent to give 1.96 g (68% yield) of the title compound as a colorless oil.

•

Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 1.1 - 1.3 (2H, multiplet); 1.25 (9H, singlet); 1.65 - 1.85 (5H, multiplet); ·. 2.68 (2H, triplet, J = 12.5 Hz); 2.8-3.0 (4H, multiplet); 3.48 (3H, singlet); 4.0-4.2 (2H, multiplet); 4.02 (2H, triplet, J = 5.9 Hz); ? 100 106551 5.15 (2H, singlet); 6.8 - 6.95 (5H, multiplet); 7.1 - 7.3 (3H, multiplet).

55 (b) 4- (2- {2- [2- (3-Hydroxyphenyl) ethyl] phenoxy} ethyl) piperidine hydrochloride 8 mL of a 4N solution of hydrogen chloride in dioxane was added to a solution of 890 mg of 1-butoxycarbonyl-4- ( 2- {2- [2- (3-Methoxymethoxyphenyl) ethyl] phenoxy} ethyl) piperidine 10 [prepared as described in step (a) above] in 8 mL of dioxane and the resulting mixture was allowed to stand at room temperature. The crystals which precipitated were collected by filtration, washed with ethyl acetate and dried in vacuo to give 651 mg (95% yield) of the title compound as colorless needles melting at 156-158 ° C.

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide, 270 MHz), δ ppm: 1.3 - 1.5 (2H, multiplet); 1.65 - 1.95 (5H, multiplet); 2.65 - 2.9 (6H, multiplet); 3.24 (2H, doublet, J = 12.5 Hz); 4.02 (2H, triplet, J = 5.9 Hz); : 6.55 - 6.7 (3H, multiplet); 6.84 (1H, triplet, J = 7.3 Hz); 6.95 (1H, doublet, J = 7.9 Hz); 7.06 (1H, triplet, J = 7.3 Hz); 7.1 - 7.3 (2H, multiplet).

«101 106551 EXAMPLE 57 (S) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} pyrrolidine hydrochloride 57 (a) (S) -lt-Butoxycarbonyl-2- {2- [2- ( 3-methoxyphenyl) ethyl] phenoxymethyl} pyrrolidine

By following a procedure similar to that described in Example 40 (a), 2.00 g of 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 20), 3.74 g of (S) -lt- butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) pyrrolidine and 0.983 g of potassium t-butoxide were reacted with 20 ml of dimethylacetamide. The mixture was then worked up as described in Example 40 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluant to give 1.65 g (45% yield) of the title compound as a colorless oil. as.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.47 (9H, singlet); 1.8 - 2.2 (4H, multiplet); 2.8 - 3.0 (4H, multiplet); 3.3 - 3.5 (2H, multiplet); 1.7 - 4.3 (3H, multiplet); 3.78 (3H, singlet); 6.7 - 7.0 (5H, multiplet); 7.05 - 7.3 (3H, multiplet).

57 (b) (S) -2- {2- [2- (3-Methoxyphenyl) ethyl] -1'-enoxymethyl} pyrrolidine? 5 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 1.65 g of (S). -lt-butoxycarbonyl-2- {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl} pynolidine [prepared as described in step (a) above] in 5 mL of dioxane and the resulting 102 106551 mixture was allowed to stand at room temperature 2, 5 hours. The reaction mixture was then concentrated by evaporation under reduced pressure and the resulting oily residue was purified by column chromatography over silica gel using a 20: 1 by volume mixture of methylene chloride and methanol as eluant to give 910 mg (yield 73%) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.7 - 2.05 (4H, multiplet); 2.8-3.0 (4H, multiplet); 3.05 - 3.25 (2H, multiplet); 3.65 - 3.8 (1H, multiplet); 3.76 (3H, singlet); 3.95 - 4.1 (2H, multiplet); 6.7 - 6.8 (3H, multiplet); 6.85 - 6.95 (2H, multiplet); 7.1 - 7.25 (3H, multiplet).

57 (c) (S) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} pyrrolidine hydrochloride 20 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 410 mg of (S) -2-- j2-: Y [2- (3-methoxyphenyl) ethyl] phenoxymethyl} pyrrolidine [prepared as described in step (b) above] with an appropriate amount of ethyl acetate and the resulting mixture was freed from the solvent by distillation under reduced pressure. 458 mg (quantitative) of the title compound 25 were obtained as a colorless oil.

*. [α] 25: + 6 ° (c = 1.0, ethanol).

- *. D 1

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.8 - 2.2 (4H, multiplet); 2.8 - 3.1 (4H, multiplet); 103 106551 3.29 (2H, triplet, J = 6.6 Hz); 4.75 (3H, singlet); 3.9 - 4.0 (1H, multiplet); 4.11 (1H, doublet of doublets, J = 5.3 & 9.9 Hz); Δ 4.22 (1H, doublet of doublets, J = 5.3 & 9.9 Hz); 6.65 - 6.75 (3H, multiplet); 6.85 - 6.95 (2H, multiplet); 7.05 - 7.2 (3H, multiplet).

EXAMPLE 58 (S) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} -1-methylpyrrolidine Hydrochloride 58 (a) (S) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} -1-methylpyrrolidine 130 mg of potassium carbonate was added to a solution of 500 mg of (S) -2- {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl} pyrrolidine [prepared as described in Example 57 (b). ] In 5 ml of dimethylacetamide and the resulting mixture was stirred at room temperature for 5 minutes, after which 288 mg of methyl iodide was added. The reaction mixture was then stirred at room temperature for 20 minutes, after which it was diluted with ethyl acetate. The diluted solution was then washed with water and a saturated aqueous sodium chloride solution, respectively: and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure and the resulting residue was purified by column chromatography over silica gel using a 20: 1 by volume mixture of methylene chloride and methanol as eluent to give 320 mg (yield 61%) of the title compound as a colorless oil.

δ Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.6 - 2.0 (3H, multiplet); 2.0 - 2.2 (1H, multiplet); 2.34 (1H, quartet, J = 8.6 Hz); 2.52 (3H, singlet); t 104 1C6551 2.65-2.8 (1H, multiplet); 2.8-3.0 (4H, multiplet); 3.05-3.2 (1H, multiplet); 3.79 (3H, singlet); Δ 3.85 (1H, doublet of doublets, J = 6.6 & 9.2 Hz); 4.07 (1H, doublet of doublets, J = 5.3 & 9.2 Hz); 6.7 - 6.95 (5H, multiplet); 7.1-7.3 (3H, multiplet).

58 (b) (S) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} -1-methylpyrrolidine hydrochloride 0.37 mL of a 4N solution of hydrogen chloride in dioxane was added to a solution containing (S) -2- {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl} -1-methylpyrrolidine [prepared as described in step (a) above] in 10 ml of ethyl acetate and the resulting mixture was allowed to stand at room temperature. The crystals which precipitated were collected by filtration to give 101 mg (28% yield) of the title compound as colorless needles having a melting point of 124-126 ° C.

[α] 25: + 3.8 ° (c = 1.0, ethanol).

20 D

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethylsulfoxide, * 270 MHz), δ ppm: 1.75 - 2.2 (3H, multiplet); 2.2 - 2.4 (1H, multiplet); 3.75-3.0 (4H, multiplet); 3.95 (3H, singlet); 3.0-3.2 (1H, multiplet); 3.5 - 3.7 (1H, multiplet); 30 3.72 (1H, singlet); 3.75 - 3.95 (1H, multiplet); 4.2-4.45 (2H, multiplet); 4 105 106551 6.7 - 6.85 (3H, multiplet); 6.91 (1H, triplet, J = 7.3 Hz); 7.00 (1H, doublet, J = 7.9 Hz); 7.15 - 7.3 (3H, multiplet).

EXAMPLE 59 1-Methyl-2- {2- [2- (3-phenylethyl) phenoxy] ethyl} pyrrolidine hydrochloride 59 (a) 1-Methyl-2- {2- [2- (3-phenylethyl) phenoxy] ethyl} -pyrrolidine

By following a procedure similar to that described in Example 35 (a), 900 mg of 2- (phenylethyl) phenol (prepared as described in Preparation Example 19), 1.02 g of potassium t-butoxide and 836 mg of 2- (2-chloroethyl) - The 1-methylpyrrolidine hydrochloride was reacted with 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to give 480 mg of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDC (3.270 MHz), δ ppm: 1.55-2.15 (5H, multiplet); 2.2 - 2.4 (2H, multiplet); 2.4-3.0 (1H, multiplet); 2.42 (3H, singlet); 2.8 - 3.0 (4H, multiplet); 3.1 - 3.25 (1H, multiplet); 3.9-4.2 (2H, multiplet); ? 6.8 - 6.95 (2H, multiplet); 7.1 - 7.35 (7H, multiplet).

30 106 106551 59 (b) 1-Methyl-2- {2- [2- (3-phenylethyl) phenoxy] ethyl} pyrrolidine hydrochloride

A solution of 480 mg of 1-methyl-2- {2- [2- (2-phenylethyl) phenoxy] ethyl} pyrrolidine [prepared as described in step (a) above] was reacted with 0.5 mL of 4 A solution of N in dioxane and the resulting mixture was then concentrated by distillation under reduced pressure. The resulting oily residue was dissolved in 10 ml of ethyl acetate and the resulting solution was allowed to stand at room temperature. The crystals which precipitated were collected by filtration to give 130 mg (24% yield) of the title compound as colorless needles with a melting point of 154-156 ° C.

10

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.9 - 2.15 (2H, multiplet); 2.15 - 2.4 (2H, multiplet); 2.4 - 2.6 (2H, multiplet); 2.7 - 3.0 (5H, multiplet); 2.75 (3H, singlet); 3.2 - 3.4 (1H, multiplet); 3.8 - 4.05 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.85 (1H, doublet, J = 7.9 Hz); 6.93 (1H, trip pig, J = 7.6 Hz); 7.1 - 7.35 (7H, multiplet).

• - 107 106551 EXAMPLE 60 1-Methyl-2- (2- {2- [2- (3-methyl-phenyl) -ethyl] -phenoxy} -ethyl} -pyrrolidine hydrochloride 60 (a) 1-Methyl-2- (2- {2 - [2- (3-methylphenyl) ethyl] phenoxy} ethyl) pyrrolidine

By following a procedure similar to that described in Example 35 (a), 1.00 g of 2- [2- (3-methylphenyl) ethyl] phenol (prepared as described in Preparation Example 25), 1.05 g of potassium t-butoxide and 0.870 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride was reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to give 150 mg (11% yield) of the title compound as an oil.

15

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.6 - 2.0 (4H, multiplet); 2.0 - 2.15 (1H, multiplet); 2.2 - 2.55 (3H, multiplet); 2.33 (3H, singlet); 2.42 (3H, singlet); 2.8-3.0 (4H, multiplet); 3.15-3.25 (1H, multiplet); 3.95 - 4.2 (2H, multiplet); 6.8 - 6.95 (2H, multiplet); 7.0 - 7.1 (3H, multiplet); 7.1 - 7.25 (3H, multiplet).

108 106551 60 (b) 1,4Methyl 2- (2- {2- [2- (3-methylphenyl) ethyl] phenoxy} ethyl] pyrrolidine hydrochloride 0.2 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of contained 150 mg of 5 1-methyl-2- (2- {2- [2- (3-methylphenyl) ethyl] phenoxy} ethyl) pyrrolidine [prepared as described in step (a) above] in an appropriate amount of ethyl acetate for its conversion to the hydrochloride, which was recrystallized from ethyl acetate to give 87 mg (52% yield) of the title compound as colorless crystals having a melting point of 128-130 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ? 3.270 MHz), δ ppm: 1.9 - 2.15 (2H, multiplet); 2.15 - 2.4 (2H, multiplet); 2.33 (3H, singlet); 2.4 - 2.65 (2H, multiplet); 2.7 - 3.0 (5H, multiplet); 2.75 (3H, singlet); 3.2 - 3.4 (1H, multiplet); 3.8 - 4.1 (2H, multiplet); 4.2 - 4.3 (1H, multiplet); 6.8 - 7.1 (5H, multiplet); 7.1-7.3 (3H, multiplet).

EXAMPLE 61 2- {2- [2- (3-Phenylethyl) phenoxy] ethyl} piperidine hydrochloride, 61 (a) -t-Butoxycarbonyl-2- {2- [2- (3-phenylethyl) phenoxy] ethyl} piperidine

By following a procedure similar to that described in Example 40 (a), 0.930 mg of 2- (2-phenylethyl) phenol (prepared as described in Preparation Example 19), 0.527 g of potassium t-butoxide and 1.66 g of t-butoxycarbonyl -2- [2- (p-Toluenesulfonyloxy) ethyl] - (<109 106551 piperidine was reacted with 20 ml of dimethylacetamide. The mixture was then worked up as described in Example 40 (a) and the crude product thus obtained was purified by column chromatography on silica gel using hexane and ethyl acetate. 4: 1 v / v as eluent to give 1.34 g (75% yield) of the title compound as a colorless oil.

5

Nuclear Magnetic Resonance Spectrum (CDC δ 3.270 MHz), δ ppm: 1.3 - 1.8 (6H, multiplet); 1.38 (9H, singlet); 1.8 - 2.0 (1H, multiplet); 2.15 - 2.35 (1H, multiplet); 2.7 - 3.0 (5H, multiplet); 3.9 - 4.15 (3H, multiplet); 4.4 - 4.6 (1H, multiplet); 6.75 - 6.9 (2H, multiplet); 7.05 - 7.35 (7H, multiplet).

61 (b) 2- {2- [2- (3-Phenylethyl) phenoxy] ethyl} piperidine hydrochloride 5 mL of a 4N solution of hydrogen chloride in dioxane was added to a solution of 440 mg of 20-butoxycarbonyl-2- {2- [2- (2-phenylethyl) phenoxy] ethyl} piperidine [prepared as described in step (a) above] in 5 mL of dioxane and the resulting mixture was allowed to stand at room temperature for two hours. The solvent was then removed by distillation under reduced pressure and the resulting solid residue was dissolved in a small amount of methylene chloride; 20 ml of ethyl acetate were then added to the solution thus obtained, after which it was allowed to stand at room temperature. The crystals which precipitated were collected by filtration to give 214 mg (53% yield) of the title compound as colorless crystals having a melting point of 95-97 ° C.

Nuclear Magnetic Resonance Spectrum (CDG> 3.270 MHz), δ ppm: 1.3 1.3 - 1.5 (1H, multiplet); 1.7 - 2.1 (5H, multiplet); 110 106551 2.15-2.3 (1H, multiplet); 2.5 - 2.7 (1H, multiplet); 2.7 - 3.0 (5H, multiplet); 3.2 - 3.35 (1H, multiplet); Δ 3.45 (1H, doublet, J = 12.5 Hz); 4.0 - 4.2 (2H, multiplet); 6.8 - 6.9 (2H, multiplet); 7.05 - 7.35 (7H, multiplet).

EXAMPLE 62 1-Methyl-2- {2- [2- (2-phenylethyl) phenoxy] ethyl} piperidone hydrochloride 62 (a) 1-Methyl-2- {2- [2- (2-phenylethyl) phenoxy] ethyl } piperidine 15

By following a procedure similar to that described in Example 38, 1.34 g of 1-t-butoxycarbonyl-2- {2- [2- (2-phenylethyl) phenoxy] ethyl} piperidine [prepared as described in Example 61 (a)] were administered. reacted with 0.269 g of lithium aluminum hydride dispersed in 30 ml of tetrahydrofuran. The mixture was then worked up as described in Example 20 and the crude product thus obtained was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to give 1.12 g (96% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDC ';' 270 MHz), δ ppm: δ 1.2 - 2.4 (1 OH, multiplet); 2.35 (3H, singlet); 2.8-3.0 (5H, multiplet); 4.0 - 4.1 (2H, multiplet); 6.8 - 6.95 (2H, multiplet); 7.1 - 7.35 (7H, multiplet).

106551 62 (b) 1-Methyl-2- {2- [2- (2-phenylethyl) phenoxy] ethyl} piperidine hydrochloride 0.6 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 670 mg of 1-methyl2- {2 - [2- (2-Phenylethyl) phenoxy] ethyl} piperidine [prepared as described in Step 5 (a) above] in an appropriate amount of ethyl acetate and the resulting mixture was concentrated by distillation under reduced pressure. The resulting crude residue was recrystallized from ethyl acetate to give 350 mg (47% yield) of the title compound as colorless crystals, mp 128-130 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.2 - 2.4 (7H, multiplet); 2.4 - 2.65 (2H, multiplet); 2.74 (3H, singlet); 2.8 - 3.2 (5H, multiplet); 3.2-3.6 (1H, multiplet); 3.95 - 4.2 (2H, multiplet); 6.84 (1H, doublet, J = 7.9 Hz); 6.92 (1H, triplet, J = 7.3 Hz); 7.1 - 7.35 (7H, multiplet).

EXAMPLE 63 2- (2- {2- [2- (2-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 25 63 (a) 2- (2- {2- [2- (2-Methoxyphenyl) ) ethyl] phenoxy} ethyl) -1-methylpyrrolidine • -

By following a procedure similar to that described in Example 35 (a), 1.00 g of 2- [2- (2-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 23). 1.47 g of potassium t-butoxide and 1.61 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride were reacted with 10 ml of dimethylacetamide. The mixture was then worked up as described in pre-112 106551 in Example 35 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol to afford 300 mg (20% yield) of the title compound as an oil.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.5 - 1.95 (4H, multiplet); 2.0 - 2.15 (1H, multiplet); 2.2 - 2.55 (3H, multiplet); 2.38 (3H, singlet); ? 2.89 (4H, singlet); 3.1 - 3.2 (1H, multiplet); 3.82 (3H, singlet); 3.9 - 4.15 (2H, multiplet); 6.8 - 6.9 (4H, multiplet); 7.1-7.25 (4H, multiplet).

63 (b) 2- (2- {2- [2- (2-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 0.3 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 300 mg. 2- (2- (2- [2- (2-methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] in an appropriate amount of ethyl acetate and the resulting mixture was concentrated by distillation under reduced pressure. The resulting solid residue was recrystallized from ethyl acetate to give 186 mg (yield 56%) of the title compound as colorless needles having a melting point of 143-145 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.7 - 2.65 (6H, multiplet); 2.65 - 2.95 (5H, multiplet); 30 2.74 (3H, singlet); 3.25 - 3.4 (1H, multiplet); 113 106551 3.75-3.9 (1H, multiplet); 3.80 (3H, singlet); 3.9 - 4.05 (1H, multiplet); 4.15 - 4.3 (1H, multiplet); Δ 6.8-7.0 (4H, multiplet); 7.05 - 7.3 (4H, multiplet).

EXAMPLE 64 1-Methyl-2- (2- {2- [2- (2-methylphenyl) ethyl] phenoxy} ethyl) pyrrolidine hydrochloride 64 (a) 1-Methyl-2- (2- {2- [2- (2-Methylphenyl) ethyl] phenoxy} ethyl) pyrrolidine By following a procedure similar to that described in Example 35 (a). 1.00 g of 2- [2- (2-methylphenyl) ethyl] phenol (prepared as described in Preparation Example 24), 1.59 g of potassium t-butoxide and 1.73 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride was reacted with 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to afford 350 mg (23% yield) of the title compound as a solid.

• «

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.5 - 1.9 (4H, multiplet); 1.95 - 2.5 (4H, multiplet); 2.34 (3H, singlet); · 2.37 (3H, singlet); 2.86 (4H, singlet); 3.1 - 3.2 (1H, multiplet); 3.9-4.2 (2H, multiplet); ? 114 106551 6.8-6.95 (2H, multiplet); 7.1 - 7.25 (6H, multiplet).

64 (b) 1-Methyl-2- (2- {2- [2- (2-methylphenyl) ethyl] phenoxy} ethyl) pyrrolidine hydro-5 chloride 0.3 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 350 ml. mg of 1-methyl-2- (2- (2- [2- (2-methylphenyl) ethyl] phenoxy) ethylpyrrolidine [prepared as described in step (a) above] in an appropriate amount of ethyl acetate and the resulting mixture was concentrated by distillation under reduced pressure. The resulting oily residue was dissolved in 7 mL of ethyl acetate then allowed to stand at room temperature The crystals which precipitated were collected by filtration to give 212 mg (yield 54%) of the title compound as colorless crystals, m.p. 163-165 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.85 - 2.6 (6H, multiplet); 2.29 (3H, singlet); 2.6 - 2.95 (5H, multiplet); 2.73 (3H, singlet); 3.2 - 3.4 (1H, multiplet); 3.8 - 4.1 (2H, multiplet); '. 4.2-4.3 (1H, multiplet); 6.86 (1H, doublet, J = 7.9 Hz); 6.93 (1H, trip pig, J = 7.6 Hz); 7.1-7.3 (6H, multiplet).

• l •.

115 106551 EXAMPLE 65 (4R) -4-Hydroxy-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine hydrochloride 5 65 (a) (4R) -4-Benzyloxy-1-butoxycarbonyl-2- [2- (2) -phenylethyl) phenoxymethyl] pyrrolidine

By following a procedure similar to that described in Example 40 (a), 200 mg of 2- (2-phenylethyl) phenol (prepared as described in Preparation Example 19), 124 mg of ka-10 lithium t-butoxide and 500 mg of (4R) -4 -Benzyloxy-1-butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) pyrrolidine was reacted with 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 40 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluant to give 400 mg (81% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.45 (9H, singlet); 2.15 - 2.35 (2H, multiplet); 2.75 - 3.0 (4H, multiplet); 3.4 - 4.6 (8H, multiplet); ·. 6.8 - 6.95 (2H, multiplet); 7.05 - 7.4 (12H, multiplet).

65 (b) (4R) -lt-Butoxycarbonyl-4-hydroxy-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine 1 3 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 200 mg (4R). -lt-butoxycarbonyl-4-hydroxy-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine [prepared as described in step (b) above] in 3 ml of dioxane and the resulting solution was stirred at room temperature for 2 hours. Thereafter, the solution was concentrated by distillation under reduced pressure, the resulting residue was dissolved in a small amount of methylene chloride and ethyl acetate was added to the solution. The resulting mixture was allowed to stand at room temperature. The crystals which precipitated were collected by filtration to give 133 mg (79% yield) of the title compound as colorless crystals having a melting point of 143-145 ° C.

5

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.8 - 2.0 (1H, multiplet); 2.13 (1H, doublet of doublets, J = 7.3 & 13.9 Hz); 2.85-3.0 (4H, multiplet); 3.21 (1H, doublet of doublets, J = 3.3 & 11.9 Hz); 3.51 (1H, doublet, J = 11.9 Hz); 4.01 (1H, doublet of doublets, J = 5.3 & 10.6 Hz); 4.10 (1H, doublet of doublets, J = 4.0 & 10.6 Hz); 4.2 - 4.35 (1H, multiplet); 4.4-4.5 (1H, multiplet); 6.75 - 6.95 (2H, multiplet); 7.0 - 7.3 (7H, multiplet).

EXAMPLE 66 20 (4R) -4-Hydroxy-1-methyl-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine hydrochloride 66 (a) (4R) -4-Hydroxy-1-methyl-2- [ 2- (2-phenylethyl) phenoxymethyl] pyrrolidine 25

By following a procedure similar to that described in Example 38, 300 mg of (4R) -1-t-butoxycarbonyl-4-hydroxy-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine [prepared as described in Example 65 (b). )] was reacted with 85.9 mg of lithium aluminum hydride. which had been dispersed in 30 ml of tetrahydrofuran. The mixture was then worked up as described in Example 30 in Example 38 and the crude product thus obtained was purified by column chromatography over silica gel 117 106551 using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to afford 150 mg (yield 63%) of the title compound.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: δ 1.95-2.1 (2H, multiplet); 2.38 (1H, doublet of doublets, J = 5.3 & 9.9 Hz); 2.51 (3H, singlet); 2.8-3.0 (4H, multiplet); 3.0 - 3.15 (1H, multiplet); Δ 3.42 (1H, doublet of doublets, J = 5.9 & 10.6 Hz); 3.85 (1H, doublet of doublets, J = 5.9 & 9.2 Hz); 4.02 (1H, doublet of doublets, J = 5.3 & 9.2 Hz); 4.35 - 4.5 (1H, multiplet); 6.8 - 6.95 (2H, multiplet); 7.05 - 7.35 (7H, multiplet).

66 (b) (4R) -4-Hydroxy-1-methyl-2- [2- (2-phenylethyl) phenoxymethyl] -pyrrolidine hydrochloride 0.36 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution containing 150 mg ( 4R) -4-Hydroxy-1-methyl-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine [prepared as described in (a) above] in an appropriate amount of dioxane and the resulting mixture was concentrated by distillation under reduced pressure. The resulting solid residue was recrystallized from ethyl acetate to give 91.6 mg (55% yield) of the title compound as colorless crystals, m.p. 97-99 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 2.1 - 2.4 (2H, multiplet); 2.7 - 3.3 (5H, multiplet); 30 2.89 (3H, singlet); 3.8 - 4.3 (3H, multiplet); 118 106551 4.5 - 4.8 (2H, multiplet); 6.8 - 7.0 (2H, multiplet); 7.05 - 7.35 (7H, multiplet).

EXAMPLE 67 (4R) -4-Hydroxy-2- {2- [2- (3-methylphenyl) ethyl] phenoxymethyl} pyrrolidine hydrochloride 10 67 (a) (4R) -4-Benzyloxy-1-butoxycarbonyl-2 - {2- [2- (3-methylphenyl) ethyl] phenoxymethyl} pyrrolidine

By following a procedure similar to that described in Example 40 (a), 400 mg of 2- [2- (3-methylphenyl) ethyl] phenol (prepared as described in Preparation Example 25). 232 mg of potassium t-butoxide and 870 mg of (4R) -4-benzyloxy-1-t-butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) pyrrolidine were reacted with 25 ml of dimethylacetamide. The mixture was then worked up as described in Example 40 (a) and the crude product thus obtained was purified by column chromatography on silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluant to give 560 mg (59% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.45 (9H, singlet); 2.15 - 2.4 (2H, multiplet); 2.31 (3H, singlet); 2.75 - 3.0 (4H, multiplet); f 3.4-4.6 (8H, multiplet); 6.8 - 7.55 (13H, multiplet).

(B) (4R) -1-t-Butoxycarbonyl-4-hydroxy-2- {2- [2- (3-methylphenyl) ethyl] phenoxymethyl} pyrrolidine

By following a procedure similar to that described in Example 65 (b), 550 mg of 5 (4R) -4-benzyloxy-1-butoxycarbonyl-2- {2- [2- (3-methylphenyl) ethyl] phenoxymethyl} pyrrolidine [ prepared as described in step (a) above] was dissolved in 20 ml of ethanol and hydrogenated under a hydrogen atmosphere at atmospheric pressure and 120 mg of 5% w / w palladium on charcoal as catalyst. The mixture was then worked up as described in Example 65 (b) and the crude product thus obtained was purified by column chromatography over silica gel using a 1: 1 by volume mixture of hexane and ethyl acetate as eluent to give 370 mg (82% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.46 (9H, singlet); 2.0 - 2.4 (2H, multiplet); 2.34 (3H, singlet); 2.75 - 3.0 (4H, multiplet); 3.4-4.6 (6H, multiplet); 6.8 - 7.3 (8H, multiplet).

67 (c) (4R) -4-Hydroxy-2- {2- [2- (3-methylphenyl) ethyl] phenoxymethyl} -: Pyrrolidine hydrochloride 3 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 348 mg ( 4R) -lt-: butoxycarbonyl-4-hydroxy-2- {2- [2- (3-methylphenyl) ethyl] phenoxymethyl} pynolidine [prepared as described in step (b) above] in 3 mL of dioxane and the resulting *. the mixture was allowed to stand at room temperature for three hours. The solvent was then removed by distillation under reduced pressure, the resulting solid residue was dissolved in methylene chloride and ethyl acetate was added to the solution, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 208 mg (70% yield) of the title compound as colorless crystals, m.p. 141-143 ° C.

120 106551

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.85 - 2.05 (1H, multiplet); 2.15 (1H, doublet of doublets, J = 6.6 & 13.2 Hz); Δ 2.27 (3H, singlet); 2.7 - 2.95 (4H, multiplet); 3.18 (1H, doublet of doublets, J = 4.0 & 12.5 Hz); 3.49 (1H, doublet, J = 12.5 Hz); 4.01 (1H, doublet of doublets, J = 4.6 & 10.6 Hz); Δ 4.12 (1H, doublet of doublets, J = 4.6 & 10.6 Hz); 4.2 - 4.35 (1H, multiplet); 4.4 - 4.5 (1H, multiplet); 6.75 - 7.2 (8H, multiplet).

EXAMPLE 68 2- (2- {2- (2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 68 (a) 2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine; By following a procedure similar to that described in Example 35 (a), 1.00 g of 2- [2- (3,5-dimethoxyphenyl) ethyl); ] phenol (prepared as described in Preparation Example 27), 1.30 g of potassium t-butoxide and 1.06 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride were reacted with 10 ml of dimethylacetamide. described in Example 35 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to give 1.15 g (80% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.5 - 2.5 (8H, multiplet); «121 106551 2.39 (3H, singlet); 2.75 - 3.0 (4H, multiplet); 3.1 - 3.2 (1H, multiplet); 3.76 (6H, singlet); Δ 3.95-4.15 (2H, multiplet); 6.3 - 6.4 (3H, multiplet); 6.8 - 6.95 (2H, multiplet); 7.1 - 7.25 (2H, multiplet).

68 (b) 2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride Using 0.9 ml of a 4N solution of hydrogen chloride in dioxane 1.15 g 2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was converted to the hydrochloride which was recrystallized from ethyl acetate to give 0.657 g. (yield 52%) of the title compound as colorless crystals having a melting point of 99-101 ° C.

Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 1.9 - 2.6 (6H, multiplet); 2.7 - 3.0 (5H, multiplet); :: 2.78 (3H, singlet); 3.3 - 3.45 (1H, multiplet); 3.76 (6H, singlet); 3.8-4.05 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); ·. 6.25 - 6.35 (3H, multiplet); 6.8 - 7.0 (2H, multiplet); 7.15 - 7.25 (2H, multiplet).

EXAMPLE 69 122 1U6551 2- (2- {2- [2- (4-Ethylphenyl) ethyl] phenoxy} ethyl) piperidine hydrochloride 69 (a) t-Butoxycarbonyl-2- (2- {2- [2- (4) -ethylphenyl) ethyl] phenoxy} ethyl) - piperidine

By following a procedure similar to that described in Example 40 (a), 1.00 g of 2- [2- (4-ethylphenyl) ethyl] phenol (prepared as described in Preparation Example 26), 0.496 g of potassium t-butoxide and 70 g of t-butoxycarbonyl-2- [2- (E-toluenesulfonyloxy) ethyl] piperidine were reacted in 20 ml of dimethylacetamide. The mixture was then worked up as described in Example 40 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluant to give 1.92 g (99% yield) of the title compound as a colorless oil. as.

Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 1.2 (3H, triplet, J = 7.3 Hz); 1.2 - 1.8 (6H, multiplet); 1.38 (9H, singlet); 1.8 - 2.0 (1H, multiplet); . . 2.15 - 2.35 (1H, multiplet); 2.63 (2H, quartet, J = 7.3 Hz); 2.75-3.0 (5H, multiplet); 3.9 - 4.15 (3H, multiplet); 4.4 - 4.6 (1H, multiplet); 6.75 - 6.9 (2H, multiplet); 7.1 - 7.25 (6H, multiplet).

123 106551 69 (b) 2- (2- {2- [2- (4-Ethylphenyl) ethyl] phenoxy} ethyl) piperldinim hydrochloride 5 mL of a 4N solution of hydrogen chloride in dioxane was added to a solution of 0.91 g of t-butoxycarbonyl- 2- (2- {2- [2- (4-ethylphenyl) ethyl] phenoxy} ethyl) piperidine [prepared as described in step (a) above] in 5 mL of dioxane and the resulting solution was allowed to stand at room temperature for one hour. . The mixture was then concentrated by distillation under reduced pressure and the resulting oily residue was dissolved in a small amount of ethyl acetate. Diethyl ether was added to the solution, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 687 mg (88% yield) of the title compound as colorless crystals, m.p. 74-76 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.21 (3H, triplet, J = 7.6 Hz); 1.3 - 1.5 (1H, multiplet); 1.7 - 2.1 (6H, multiplet); 2.15-2.3 (1H, multiplet); 2.61 (2H, quartet, J = 7.6 Hz); 2.6-3.0 (5H, multiplet); 3.2 - 3.35 (1H, multiplet); 3.4 - 3.55 (1H, multiplet); : 4.0-4.2 (2H, multiplet); 6.8 - 6.95 (2H, multiplet); 7.05 - 7.2 (6H, multiplet).

EXAMPLE 70> 24 106551 2- (2- {2- [2- (4-Ethylphenyl) ethyl] phenoxy} ethyl) -1-methylpiperidine 5 70 (a) 2- (2- {2- [2- (4) -EtyylifenyyIi) ethyl] phenoxy} ethyl) -l-methylpiperidine

By following a procedure similar to that described in Example 38 (a), 1.00 g of 1-t-butoxycarbonyl-2- (2- {2- [2- (4-ethylphenyl) ethyl] phenoxy} ethyl) piperidine [prepared as described in Example 69 (a)] was reacted with 0.173 g of lithium aluminum hydride 10 dispersed in 20 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to afford 0.650 g (81% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCC3, 270 MHz), δ ppm: 1.23 (3H, triplet, J = 7.6 Hz); 1.2 - 2.35 (10H, multiplet); 2.38 (3H, singlet); 2.63 (2H, quartet, J = 7.6 Hz); 2.8 - 3.0 (5H, multiplet); 4.0 - 4.15 (2H, multiplet); : 6.8 - 7.0 (2H, multiplet); 7.1 - 7.25 (6H, multiplet).

70 (b) 2- (2- {2- [2- (4-Ethylphenyl) ethyl] phenoxy} ethyl) -1-methylpiperidine hydrochloride 0.6 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution containing 0.650 g. 2- (2- (2- [2- (4-ethylphenyl) ethyl] phenoxy} ethyl) -1-methylpiperidine [prepared as described in step (a) above] in an appropriate amount of ethyl acetate and the resulting solution was concentrated by distillation under reduced pressure. the resulting oily residue was dissolved in a small amount of ethyl acetate, and a small amount of diethyl ether was added to the solution which was then allowed to stand at room temperature The crystals which precipitated were collected by filtration and dried in vacuo to give 0.590 mg (82% yield) of the title compound. having a melting point of 101-103 ° C 5

Nuclear Magnetic Resonance Spectrum (CDCl 3, 3.270 MHz), δ ppm: 1.23 (3H, triplet, J = 7.6 Hz); 1.25 - 1.55 (1H, multiplet); 1.6 - 2.7 (8H, multiplet); 10.63 (2H, quartet, J = 7.6 Hz); 2.74 (3H, singlet); 2.8 - 3.2 (5H, multiplet); 3.3 - 3.55 (1H, multiplet); 3.95 - 4.2 (2H, multiplet); 6.8 - 7.0 (2H, multiplet); 7.05 - 7.25 (6H, multiplet).

EXAMPLE 71 20 (S) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} morpholine hydrochloride; : 71 (a) (S) -4-t-Butoxycarbonyl-2- {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl} morpholine 1 2 3 4 5 6

By following a procedure similar to that described in Example 40 (a), 1.14 g of 2 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 20), 3 ·. 0.560 g of potassium t-butoxide and 1.86 g of (S) -4-t-butoxycarbonyl-2- (p-toluenesulfonyl-4-oxymethyl) morpholine were reacted in 25 ml of dimethylacetamide. The mixture was then worked up as described in Example 40 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 5: 1 by volume mixture of hexane and ethyl acetate as eluant to give 1.97 g (92% yield) of the title compound as a colorless oil.

«126 106551

Nuclear Magnetic Resonance Spectrum (CDC ?3, 270 MHz), δ ppm: 1.44 (9H, singlet); 2.8-3.1 (6H, multiplet); 3.5-3.7 (1H, multiplet); 3.7 - 4.2 (6H, multiplet); 3.77 (3H, singlet); 6.7 - 6.95 (5H, multiplet); 7.1-7.3 (3H, multiplet).

10 71 (b) (S) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} morpholine hydrochloride 5 mL of a 4N solution of hydrogen chloride in dioxane was added to a solution of 420 mg of (S) -4-t- Butoxycarbonyl-2- {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl} morpholine [prepared as described in step (a) above] to 5 ml of dioxane and the resulting solution was allowed to stand at room temperature for one hour. The solution was then concentrated by evaporation under reduced pressure, the resulting oily residue was dissolved in 20 mL of ethyl acetate and the resulting solution was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 279 mg (78% yield) of the title compound as colorless needles having a melting point of 105-106 ° C.

&Lt; + &gt; [α] 20 D: + 7.3 ° (c = 1.0, water).

D

25

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 2.75 - 2.95 (4H, multiplet); 3.0-3.2 (2H, multiplet); 3.35 (1H, doublet, J = 12.5 Hz); 3.46 (1H, doublet, J = 12.5 Hz); 3.76 (3H, singlet); 3.95 - 4.2 (4H, multiplet); 127 106551 4.3-4.4 (1H, multiplet); 6.65 - 6.95 (5H, multiplet); 7.05 - 7.3 (3H, multiplet).

EXAMPLE 72 (S) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} -4-methylmorpholine hydrochloride 10 72 (a) (S) -2- {2- [2- (3-Methoxyphenyl) ) ethyl] phenoxymethyl} -4-metyylimorfoIiini

By performing a procedure similar to that described in Example 38 (a). 1.50 g of (S) -4-t-butoxycarbonyl-2- {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl} morpholine [prepared as described in Example 71 (a)] were reacted with 167 mg of lithium aluminum hydride 15 dispersed in 20 ml tetrahydrofuran. The mixture was then worked up as described in Example 38 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 20: 1 by volume mixture of methylene chloride and methanol as eluant to afford 1.04 g (87% yield) of the title compound as a colorless oil. 1 2 3 4 5 6 • 30

Nuclear Magnetic Resonance Spectrum (CDCl3.270 MHz), δ ppm: 2 2.0 - 2.25 (2H, multiplet); 3 ti 2.31 (3H, singlet); Δ 2.65-2.75 (1H, multiplet); 2.8 - 3.0 (5H, multiplet); Δ 3.7-3.85 (1H, multiplet); 3.77 (3H, singlet); 3.9-4.1 (4H, multiplet); ? 6.7-6.95 (5H, multiplet); 7.1 - 7.3 (3H, multiplet).

72 (b) (S) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} -4-methylmorpholymer hydrochloride 128 106551 1 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution containing 1.04 g (S) -2- {2- [2-5 (3-methoxyphenyl) ethyl] phenoxymethyl} -4-methylmorpholine [prepared as described in step (a) above] in 20 ml of ethyl acetate and the resulting mixture was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried under vacuum to give 1.05 g (91% yield) of the title compound as colorless crystals, m.p. 186-187 ° C.

[.Alpha.] D @ 20: + 5.7 DEG (c = 1.0, ethanol).

D

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: δ 2.77 (3H, singlet); 2.7 - 3.1 (6H, multiplet); 3.41 (2H, triplet, J = 10.2 Hz); 3.78 (3H, singlet); 4.0 - 4.2 (3H, multiplet); 4.3 - 4.45 (1H, multiplet); 4.5 - 4.6 (1H, multiplet); 6.7 - 6.9 (4H, multiplet); 6.94 (1H, triplet, J = 7.4 Hz); 7.1 - 7.3 (3H, multiplet).

25 <1-Methyl-2- (2- {2- [2- (3,4,5-trimethoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine hydrochloride 129 EXAMPLE 73 106551 5 73 (a) 1-Methyl-2 - (2- {2- [2- (3,4,5-trimetoksifenyyii) ethyl] phenoxy} ethyl) -pyrrolidine

By following a procedure similar to that described in Example 35 (a), 1.00 g of 10 2- [2- (3,4,5-trimethoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 28), 1.18 g of potassium t-Butoxide and 0.958 g of 2- (2-chloroethyl) -1-methyl-pyxolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to give 0.900 g (65% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDÖ > 3, 270 MHz), δ ppm: 1.6 - 2.6 (8H, multiplet); 2.46 (3H, singlet); 2.75 - 3.0 (4H, multiplet); 3.25 - 3.35 (1H, multiplet); . 3.81 (6H, singlet); 3.82 (3H, singlet); 3.9 - 4.2 (2H, multiplet); 6.35 (2H, singlet); 6.8 - 6.95 (2H, multiplet); 7.05 - 7.25 (2H, multiplet).

130 106551 73 (b) 1-Methyl-2- (2- {2- [2- (3,4,5-trimethoxyphenyl) ethyl] phenoxy} ethyl) -pyrrolidine hydrochloride 0.84 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution. containing 0.900 g of 5-methyl-2- (2- {2- [2- (3,4,5-trimethoxyphenyl) ethyl] phenoxy} ethylpyrrolidine [prepared as described in step (a) above] in an appropriate amount of dioxane and resulting The resulting solution was freed from the solvent by distillation under reduced pressure, and the resulting solid was then dissolved in a small amount of methylene chloride and ethyl acetate was added to the solution which was then allowed to stand at room temperature The crystals precipitated were collected by filtration and dried in vacuo to give 0.755 mg. ) as colorless crystals having a melting point of 130-131 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.9 - 2.1 (2H, multiplet); 2.1 - 2.35 (2H, multiplet); 2.70 (3H, singlet); 2.75 - 2.95 (5H, multiplet); 3.0-3.1 (1H, multiplet); 3.7 - 4.0 (2H, multiplet); 3.77 (6H, multiplet); 3.81 (3H, singlet); 4.1 - 4.2 (1H, multiplet); 6.27 (2H, singlet); 6.83 (1H, doublet, J = 8.6 Hz); 6.94 (1H, triplet, J = 7.9 Hz); 7.1 - 7.25 (2H, multiplet).

* I

•.

EXAMPLE 74 (R) -2- [2- (2-Phenylethyl) phenoxymethyl] pyrrolidine hydrochloride 131 106551 5 74 (a) (R) -1-t-Butoxycarbonyl-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine

By following a procedure similar to that described in Example 40 (a), 1.00 g of 2- (2-phenylethyl) phenol (prepared as described in Preparation Example 19), 2.89 g of 1-butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) pyrrolidine and 0.906 g of potassium t-10 butoxide was reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 40 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluant to give 1.77 g (92% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDC (3.270 MHz), δ ppm: 1.47 (9H, singlet); 1.8 - 2.2 (4H, multiplet); 2.8-3.0 (4H, multiplet); 3.3 - 3.5 (2H, multiplet); 3.8-4.3 (3H, multiplet); 6.8 - 7.0 (2H, multiplet); 7.05 - 7.35 (7H, multiplet).

74 (b) (R) -2- [2- (2-Phenylethyl) phenoxymethyl] pyrrolidine hydrochloride 5 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 630 mg of '(R) -lt-butoxycarbonyl-2- [ 2- (2-phenylethyl) phenoxymethyl] pyrrolidine [prepared •.

'' As described in step (a) above] in 5 ml of dioxane and the resulting mixture was allowed to stand at room temperature for one hour. The solvent was then removed by distillation under reduced pressure and the resulting oily residue was cooled, resulting in its solidification. The solid was triturated with pentane and the resulting powder was collected by filtration 106551132 to give 360 mg (68% yield) of the title compound as a colorless solid, m.p. 73-88 ° C.

[α] 25: -7.5 ° (c = 3.76, ethanol).

5

Nuclear Magnetic Resonance Spectrum (Hexadeuterated Dimethylsulfoxide + D 2 O, 270 MHz), δ ppm: 1.75 - 2.1 (3H, multiplet); 2.1-2.25 (1H, multiplet); 2.8-3.0 (4H, multiplet); 3.15-3.3 (2H, multiplet); 3.9 - 4.05 (1H, multiplet); 4.1 - 4.3 (2H, multiplet); 6.89 (1H, triplet, J = 6.9 Hz); 6.97 (1H, doublet, J = 7.3 Hz); 7.1 - 7.35 (7H, multiplet).

EXAMPLE 75 20 (R) -1-Methyl-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine hydrochloride ** 75 (a) (R) -1-Methyl-2- [2- (2-phenylethyl) phenoxymethyl ] Pyrrolidine By following a procedure similar to that described in Example 38 (a), 1.14 g of (R) -lt-butoxycarbonyl-2- [2 - (- phenylethyl) phenoxymethyl] pyrrolidine [prepared as described in Example 74 (a) ] was reacted with 0.227 g of lithium aluminum hydride dispersed in 10 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluant to give 0.670 g (76% yield) of the title compound as a colorless oil.

133 106551

Nuclear Magnetic Resonance Spectrum (CDCd 3, 270 MHz), δ ppm: 1.6 - 1.95 (3H, multiplet); 2.0 - 2.2 (1H, multiplet); 2.25-2.4 (1H, multiplet); Δ 2.52 (3H, singlet); 2.65 - 2.8 (1H, multiplet); 2.8-3.0 (4H, multiplet); 3.05-3.2 (1H, multiplet); 3.84 (1H, doublet of doublets, J = 6.6 & 9.2 Hz); 10 4.06 (1H, doublet of doublets, J = 5.3 & 9.2 Hz); 6.8 - 6.9 (2H, multiplet); 7.1 - 7.35 (7H, multiplet).

75 (b) (R) -1-Methyl-2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine hydrochloride 0.63 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution of 670 mg of (R) -1-methyl -2- [2- (2-phenylethyl) phenoxymethyl] pyrrolidine [prepared as described in step (a) above] with a small amount of dioxane and the resulting mixture was freed from solvent-20 by evaporation under reduced pressure. The resulting residue was then dissolved in a small amount of methanol, ethyl acetate was added to the solution, and the resulting mixture was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 596 mg (85% yield) of the title compound as colorless crystals having a melting point of 211-212 ° C.

[Α] 25: -5.6 ° (c = 3.42, methanol).

D

«

Nuclear Magnetic Resonance Spectrum (Hexadeuterated Dimethylsulfoxide + D, 30.270 MHz), δ ppm: 1.8 - 2.2 (3H, multiplet); 2.2 - 2.4 (1H, multiplet); 134 106551 2.8-3.0 (4H, multiplet); 2.94 (3H, singlet); 3.0-3.3 (1H, multiplet); 3.5 - 3.7 (1H, multiplet); Δ 3.75-3.95 (1H, multiplet); 4.2 - 4.45 (2H, multiplet); 6.91 (1H, triplet, J = 6.9 Hz); 6.99 (1H, doublet, J = 7.9 Hz); 7.15 - 7.35 (7H, multiplet).

EXAMPLE 76 (R) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} pyrrolidine hydrochloride 15 76 (a) (R) -lt-Butoxycarbonyl-2- {2- [2- (3- methoxyphenyl) ethyl] phenoxymethyl} pyrrolidine

By following a procedure similar to that described in Example 40 (a), 1.00 g of 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 20), 0.740 g of potassium t-butoxide and 2, 33 g of (N-tert-butoxycarbonyl-2- (p-toluenesulfonyloxymethyl) pyrrolidine were reacted in 10 ml of dimethylacetamide, then worked up as described in Example 40 (a) and the crude product thus obtained was purified by column chromatography over silica gel. using a 4: 1 by volume mixture of hexane and ethyl acetate as eluent to give 1.54 g (85% yield) of the title compound as a colorless oil.

. * Nuclear Magnetic Resonance Spectrum (CDQ> 3, 270 MHz), δ ppm: 1.47 (9H, singlet); 1.8 - 2.2 (4H, multiplet); 2.8 - 3.0 (4H, multiplet); 3.3 - 3.5 (2H, multiplet);

135 10655 V

3.7 - 4.3 (3H, multiplet); 3.78 (3H, singlet); 6.7 - 7.0 (5H, multiplet); 7.05 - 7.3 (3H, multiplet).

76 (b) (R) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} pyrrolidine hydrochloride 5 mL of a 4N solution of hydrogen chloride in dioxane was added to a solution of 540 mg of (R) -lt-10 butoxycarbonyl -2- {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl} pyrrolidine [prepared as described in step (a) above] in 5 ml of dioxane and the resulting solution was allowed to stand at room temperature for one hour. The solvent was then removed by distillation under reduced pressure and the resulting residue was dried in vacuo to give 456 mg (quantitative yield) of the title compound as a colorless oil.

[Α] 25 D = -5.5 ° (c = 2.04, ethanol).

D

Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 1.75 - 2.2 (4H, multiplet); 2.8 - 3.1 (4H, multiplet); 3.30 (2H, triplet, J = 6.6 Hz); 3.75 (3H, singlet); 3.85 - 4.0 (1H, multiplet); Δ 4.11 (1H, doublet of doublets, J = 4.6 & 9.9 Hz); 4.23 (1H, doublet of doublets, J = 5.3 & 9.9 Hz); 6.65 - 6.75 (3H, multiplet); Δ v 6.85-6.95 (2H, multiplet); 7.05 - 7.3 (3H, multiplet).

30 136 EXAMPLE 77 106551 (R) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} -1-methylpyrrolidine hydrochloride 5 77 (a) (R) -2- {2- [2- (3-methoxyphenyl) ethyl] fenoksimetyyIi} -l-methylpyrrolidine

By following a procedure similar to that described in Example 38 (a), 1.00 g of (R) -lt-butoxycarbonyl-2- {2- [2- (3-methoxyphenyl) ethyl] phenoxymethyl] pyrrolidine 10 [prepared as described in Example 76 (a)] was reacted with 0.184 g of lithium aluminum hydride dispersed in 10 ml of tetrahydrofuran. The mixture was then worked up as described in Example 38 (a) and the crude product thus obtained was purified by column chromatography over silica gel using a 20: 1 by volume mixture of methylene chloride and methanol as eluant to give 0.750 g (95% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCC 3.270 MHz), δ ppm: 1.6 - 1.95 (3H, multiplet); 2.0 - 2.2 (1H, multiplet); 2.25 - 2.4 (1H, multiplet); 2.52 (3H, singlet); . ? 2.65-2.8 (1H, multiplet); 2.8-3.0 (4H, multiplet); 3.05-3.2 (1H, multiplet); 3.79 (3H, singlet); 3.84 (1H, doublet of doublets, J = 6.6 & 9.2 Hz); 4.06 (1H, doublet of doublets, J = 5.9 & 9.2 Hz); 6.7 - 6.95 (5H, multiplet); 7.1 - 7.3 (3H, multiplet).

106551 137 77 (b) (R) -2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} -1-methylpyrrolidine hydrochloride 0.7 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution containing 750 mg ( R) -2- {-2-5 [2- (3-methoxyphenyl) ethyl] phenoxymethyl} -1-methylpyrroldine [prepared as described in step (a) above] in an appropriate amount of dioxane and the resulting mixture was concentrated by evaporation under reduced pressure. The resulting oily residue was dissolved in 10 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 686 mg (82% yield) of the title compound as a colorless powder, m.p. 124-125 ° C.

[α] 25: -4.2 ° (c = 3.45, ethanol).

D

Nuclear Magnetic Resonance Spectrum (Hexadeuterated Dimethylsulfoxide + D 2 O, 270 MHz), δ ppm: 1.75 - 2.2 (3H, multiplet); 2.2 - 2.4 (1H, multiplet); 2.75-3.0 (4H, multiplet); 2.94 (3H, singlet); 3.0-3.2 (1H, multiplet); 3.5 - 3.7 (1H, multiplet); 3.72 (3H, singlet); 3.75 - 3.95 (1H, multiplet); 4.2-4.45 (2H, multiplet); 6.7 - 6.85 (3H, multiplet); 6.92 (1H, triplet, J = 7.3 Hz); C 7.00 (1H, doublet, J = 7.9 Hz); 7.15 - 7.3 (3H, multiplet).

EXAMPLE 78 106551 138 2- (2- (2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 5 78 (a) 2- (2- {2- [2- (3) -Methoxyphenyl) butyl] phenoxy} ethyl) -1-methylpyrrolidine 1.48 g of potassium t-butoxide was added to a solution of 1.35 g of 2- [4- (3-methoxyphenyl) butyl] phenol (prepared as described In Preparation 7), 20 ml of dimethyl-10-acetylacetamide were cooled with ice and stirring 1.45 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride were then added to the solution and the mixture was stirred at 55 ° C for 2 hours. of ethyl acetate and 100 ml of water were added to the mixture and the mixture was shaken The ethyl acetate layer was separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. by chromatography on silica gel using a 10: 1 by volume mixture of methylene chloride and methanol as eluent to give 0.92 g (48% yield) of the title compound as an oil.

Nuclear Magnetic Resonance Spectrum (CDQ> 3, 270 MHz), δ ppm: 1.55 - 2.5 (12H, multiplet); . 2.38 (3H, singlet); 2.55 - 2.7 (1H, multiplet); 3.79 (3H, singlet); 3.9 - 4.15 (2H, multiplet); 6.65 - 6.9 (5H, multiplet); * 7.1 - 7.25 (3H, multiplet).

139 106551 78 (b) 2- (2- {2- [4- (3-Methoxyphenyl) butyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 900 mg 2- (2- {2- [4- (3-methoxyphenyl) ) butyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in a small amount of dioxane and 0.8 ml of a 4N solution of hydrogen chloride in dioxane was added to the resulting solution. The solution was then shaken, after which it was concentrated by distillation under reduced pressure. The concentrate was dissolved in 15 ml of ethyl acetate and the resulting solution was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 343 mg (yield 35%) of the title compound as colorless crystals, m.p. 65-66 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.5 - 1.8 (4H, multiplet); 1.85 - 2.15 (2H, multiplet); 2.15 - 2.35 (2H, multiplet); 2.35 - 2.9 (7H, multiplet); 2.74 (3H, singlet); 3.2 - 3.35 (1H, multiplet); 3.7 - 4.1 (2H, multiplet); 3.79 (3H, singlet); 4.1-4.3 (1H, multiplet); 6.65 - 6.8 (3H, multiplet); 6.82 (1H, doublet, J = 8.6 Hz); 6.91 (1H, triplet, J = 7.6 Hz); 7.1-7.3 (3H, multiplet).

EXAMPLE 79 140 106551 2- (2- (2- [4- (2-Methoxyphenyl) butyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 5 79 (a) 2- (2- {2- [4- (2) methoxyphenyl) butyl] phenoxy} ethyl) -l-methylpyrrolidine

Following a procedure similar to that described in Example 78 (a), 900 mg (36% yield) of the title compound was obtained as a colorless oil using 1.74 g of 2- [4- (2-methoxyphenyl) butyl] phenol (prepared as described in Preparation Example 4). , 1.9 g of potassium t-butoxide, 1.87 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.5 - 1.9 (8H, multiplet); 1.95 - 2.1 (1H, multiplet); 2.15 - 2.5 (3H, multiplet); 2.38 (3H, singlet); 2.55 - 2.7 (4H, multiplet); 3.1 - 3.2 (1H, multiplet); 3.79 (3H, singlet); 3.9 - 4.1 (2H, multiplet); ,. 6.75 - 7.2 (4H, multiplet); 7.1 - 7.2 (4H, multiplet). 1 2 3 4 5 6 79 (b) 2- (2- {2- [4- (2-Methoxyphenyl) butyl] phenoxy} ethyl) -1-methylpyrrolidine 2 hydrochloride 3 • c 4 • <5

Following a procedure similar to that described in Example 78 (a), and after further recrystallization from ethyl acetate, 530 mg (54% yield) of the title compound 6 were obtained as a colorless solid, m.p. 111-112 ° C using 900 mg 141 106551 2- (2- {2- [4- (2-methoxyphenyl) butyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] and 0.8 ml of a 4N solution of hydrogen chloride in dioxane.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 3.270 MHz), δ ppm: δ 1.5-1.8 (4H, multiplet); 1.9 - 2.15 (2H, multiplet); 2.15 - 2.4 (2H, multiplet); 2.4-2.9 (7H, multiplet); 2.75 (3H, singlet); Δ 3.25-3.5 (1H, multiplet); 3.7 - 4.05 (2H, multiplet); 3.80 (3H, singlet); 4.15 - 4.3 (1H, multiplet); 6.8 - 7.0 (4H, multiplet); 7.05 - 7.25 (4H, multiplet).

EXAMPLE 80 2- (2- {2- [4- (4-Methoxyphenyl) butyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 80 (a) 2- (2- {2- [4- (4-Methoxyphenyl)) butyl] phenoxy} ethyl) -l-methylpyrrolidine

Following a procedure similar to that described in Example 78 (a), 0.830 g (39% yield) of the title compound were obtained as an oil using 1.50 g of 2- [4- (4-methoxy-phenyl) butyl] phenol (prepared as described in Preparation Example 12), 1.64 g of potassium t-butoxide, 1.62 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 30 ml of dimethylacetamide.

9 9

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.5 1.5 - 1.95 (8H, multiplet); 1.95 - 2.15 (1H, multiplet); 142 106551 2.15-2.5 (3H, multiplet); 2.40 (3H, singlet); 2.5 - 2.7 (4H, multiplet); 3.1 - 3.25 (1H, multiplet); Δ 3.78 (3H, singlet); 3.9 - 4.1 (2H, multiplet); 6.75 - 6.9 (4H, multiplet); 7.05 - 7.2 (4H, multiplet).

80 (b) 2- (2- (2- [4- (4-Methoxyphenyl) butylphenoxy} ethyl) -1-methylpyrrolidone hydrochloride

Following a procedure similar to that described in Example 78 (b), after further recrystallization from ethyl acetate, 0.275 g (30% yield) of the title compound 15 were obtained as a colorless solid, m.p. 91-92 ° C using 0.830 g of 2 (2- {2- [4- (4-methoxyphenyl) butyl] phenoxy} ethyl) -1-methylpyrrolidine and 0.75 mL of a 4N solution of hydrogen chloride in dioxane.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: δ 1.5-1.75 (4H, multiplet); 1.9 - -2.15 (2H, multiplet); . 2.15 - 2.4 (2H, multiplet); 2.4 - 2.7 (6H, multiplet); 2.7 - 2.9 (1H, multiplet); 2.73 & 2.75 (together 3H, each singlet); 3.2 - 3.35 (1H, multiplet); , · 3.78 (3H, singlet); 3.8 - 4.3 (1H, multiplet); 6.75 - 6.9 (3H, multiplet); 6.91 (1H, triplet, J = 7.6 Hz); 7.0 - 7.2 (4H, multiplet).

EXAMPLE 81 143 106551 2- (2- (2- [4- (3,5-Dimethoxyphenyl) butyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 81 (a) 2- (2- {2- [4- (3,5-Dimethoxyphenyl) butyl] phenoxy} ethyl) -1-methylpyrrolidine Using a procedure similar to that described in Example 78 (a), 1.00 g (40% yield) of the title compound were obtained as an oil. 1.80 g of 2- [4- (3,5-dimethoxyphenyl) butyl] phenol (prepared as described in Preparation Example 9), 1.76 g of potassium t-butoxide, 1.76 g of 2- (2-chloroethyl) -1- methylpyrrolidine hydrochloride and 35 ml dimethylacetamide.

15

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.5 - 2.5 (12H, multiplet); 2.38 (3H, singlet); 2.5 - 2.7 (4H, multiplet); 3.1 - 3.2 (1H, multiplet); 3.77 (6H, singlet); 3.9 - 4.1 (2H, multiplet); 6.25-6.4 (3H, multiplet); 6.75 - 6.9 (2H, multiplet); 7.1-7.2 (2H, multiplet).

* 81 (b) 2- (2- {2- [4- (3,5-Dimethoxyphenyl) butyl] phenoxy} ethyl) -1-methyl-pyrrolidine hydrochloride 1a 1.00 g of 2- (2- { 2- [4- (3,5-Dimethoxyphenyl) butyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in 10 ml of dioxane and 0.8 ml of chlorine. A solution of N in dioxane was added to the resulting solution. The mixture was stirred and then concentrated by evaporation under reduced pressure. A suitable amount of pentane was added to the concentrate and the mixture was stirred. The upper pentane layer was removed and the resulting oil dried in vacuo to give 1.09 g (quantitative yield) of the title compound as an oil.

5

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm 1.55-1.7 (4H, multiplet); 1.85 - 2.9 (11H, multiplet); 2.75 & 2.77 (together 3H, each singlet); 3.2 - 3.4 (1H, multiplet); 3.76 (6H, singlet); 3.8 - 4.1 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.30 (3H, singlet); 6.82 (1H, doublet, J = 8.6 Hz); 6.91 (1H, triplet, J = 7.9 Hz); 7.1-7.25 (2H, multiplet).

Infrared Absorption Spectrum (Liquid Film), νmax cm -1: 20 1596,1456,1239,1205,1151.

EXAMPLE 82 3- {2- [4- (3-Methoxyphenyl) butyl] phenoxymethyl} piperidine hydrochloride 82 82 (a) t-Butoxycarbonyl-3- {2- [4- (3-methoxyphenyl) butyl] phenoxymethyl} piperidine 0.965 g of potassium t-butoxide was added to a solution of 1.70 g of 2- [4- (3-methoxy-30-phenyl) butyl] phenol (prepared as described in Preparation Example 7) in 30 ml of dimethylacetamide while cooling with ice and the mixture was stirred at the same temperature «145 106551 for 15 minutes. A solution of 3.18 g of 1-t-butoxycarbonyl-3- (p-toluenesulfonyloxymethyl) piperidine in 30 ml of dimethylacetamide was then added dropwise to the solution at the same temperature and the mixture was stirred at 55 ° C for 1.5 hours. The reaction mixture was then cooled and 200 ml of ethyl acetate and 100 ml of water were added to the mixture which was then shaken. The ethyl acetate layer was separated, washed twice with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The ethyl acetate layer was then concentrated by distillation under reduced pressure and the concentrate was purified by column chromatography over silica gel using a 3: 1 by volume mixture of hexane and ethyl acetate as eluent to give 4.54 g (95% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.3 - 2.1 (9H, multiplet); 1.45 (9H, singlet); 2.55 - 2.9 (6H, multiplet); 3.7 - 4.2 (4H, multiplet); 3.78 (3H, singlet); 6.7 - 6.9 (5H, multiplet); 7.1 - 7.25 (3H, multiplet).

82 (b) 3- {2- [4- (3-Methoxyphenyl) butyl] phenoxymethyl} piperidine hydrochloride * · 1.79 g of t-butoxycarbonyl-3- {2- [4- (3-methoxyphenyl) butyl] phenoxymethyl} piperidine [prepared as described in step (a) above] was dissolved in 5 mL of dioxane and 5 mL of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was allowed to stand at room temperature for two hours, after which time the solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in 20 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 1.31 g (85% yield) of the title compound as needles having a melting point of 136-137 ° C.

146 106551

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.3 - 2.2 (9H, multiplet); 2.4 - 2.95 (6H, multiplet); 3.4 - 3.6 (2H, multiplet); Δ 3.75-3.6 (2H, multiplet); 3.78 (3H, singlet); 6.65 - 6.85 (4H, multiplet); 6.89 (1H, doublet, J = 7.3 Hz); 7.1 - 7.25 (3H, multiplet).

EXAMPLE 84 2- (2- {2- [4- (3-Methoxyphenyl) butyl] phenoxy} ethyl) piperidine hydrochloride 84 (a) 1-Butoxycarbonyl-2- (2- {2- [4- (3- methoxyphenyl) butyl] phenoxy} ethyl) piperidime

Following a procedure similar to that described in Example 82 (a), except that a 5: 1 by volume mixture of hexane and ethyl acetate was used as eluent, 1.99 g of the title compound were obtained (yield: 87%) as an oil using 1.20 g of 2- [4- (3-methoxyphenyl) butyl] phenol (prepared as described in Preparation Example 7), 0.68 g of potassium t-butoxide, 2.34 g of t-butoxycarbonyl-2- [2- (p-toluenesulfonyloxy) ethyl] piperidine and 20 ml dimethylacetamide. 1 2 3 4 5 6

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 2 1.3 - 1.8 (10H, multiplet); 3 1.39 (9H, singlet); Δ 1.8 - 2.0 (1H, multiplet); 2.1-2.3 (1H, multiplet); Δ 2.5 - 2.7 (4H, multiplet); 2.7 - 2.95 (1H, multiplet); 147 106551 3.79 (3H, singlet); 3.8 - 4.1 (3H, multiplet); 4.35 - 4.55 (1H, multiplet); 6.7 - 6.9 (5H, multiplet); Δ 7.05 - 7.25 (3H, multiplet).

84 (b) 2- (2- {2- [4- (3-Methoxyphenyl) butyl] phenoxy} ethyl) piperidine hydrochloride 104 mg of t-butoxycarbonyl-2- (2- {2- [4- (3- methoxyphenyl) butyl] phenoxy} ethyl) piperidine [prepared as described in step (a) above] was dissolved in 2 mL of dioxane and 2 mL of a 4N solution of hydrogen chloride in dioxane was added to the solution which was then allowed to stand at room temperature for 30 minutes. The solution was then concentrated by distillation under reduced pressure and the resulting oil was dissolved in diethyl ether and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 276 mg (80% yield) of the title compound as a colorless solid, m.p. 76-79 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: δ 1.2 - 2.1 (9H, multiplet); 2.1-3.0 (7H, multiplet); 3.1 - 3.3 (1H, multiplet); 3.35 - 3.6 (1H, multiplet); 3.77 (3H, singlet); 3.8-4.2 (3H, multiplet); 6.55 - 6.9 (5H, multiplet); '· 7.05 - 7.3 (3H, multiplet).

EXAMPLE 85 148 106551 2- (2- {2- [4- (3-Methoxyphenyl) butyl] phenoxy} ethyl) -1-methylpiperidine Citrate 5 85 (a) 2 - (- {2- [4- (3-Methoxyphenyl) ) butyl] phenoxy} ethyl) -l-methylpiperidine

Following a procedure similar to that described in Example 83 (a), 1.10 g (89% yield) of the title compound were obtained as an oil using 1.50 g of 1-butoxycarbonyl-2- (2- {2- [4- (3-methoxyphenyl) ) butyl] phenoxy} ethyl) piperidine [prepared as described in Example 10 84 (a)], 0.245 g of lithium aluminum hydride and 30 ml of tetrahydrofuran.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.2 - 2.3 (14H, multiplet); 2.35 (3H, singlet); 2.55 - 2.7 (4H, multiplet); 2.85-3.0 (1H, multiplet); 3.79 (3H, singlet); 3.9 - 6.9 (5H, multiplet); 7.05 - 7.25 (3H, multiplet).

85 (b) 2- (2- {2- [4- (3-Methoxyphenyl) butyl] ethyl) -1-methylpiperidine hydrochloride 1.05 g of 2- (2- {2- [4- (3- methoxyphenyl) butyl] phenoxy} ethyl) -1-methylpiperidine [prepared as described in step (a) above] and 0.58 g of citric acid monohydrate was dissolved in 10 ml of ethanol and the resulting solution was concentrated by evaporation under reduced pressure.

*; The resulting oil was dissolved in 20 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 1.20 g (76% yield) of the title compound as a colorless solid, m.p. 77-79 ° C.

149 106551

Nuclear Magnetic Resonance Spectrum (Hexadeuterated Dimethylsulfoxide + D 2 O, 270 MHz), δ ppm: 1.2 - 2.3 (12H, multiplet); 2.5-3.7 (11H, multiplet); Δ 2.69 (3H, singlet); 3.71 (3H, singlet); 3.9 - 4.1 (2H, multiplet); 6.7 - 6.8 (3H, multiplet); 6.86 (1H, triplet, J = 7.3 Hz); Δ 6.92 (1H, doublet, J = 7.9 Hz); 7.1-7.3 (3H, multiplet).

EXAMPLE 91 15-1-Methyl-2- {2- [2- (5-phenylpentyl) phenoxy] ethyl} pyrrolidine hydrochloride 91 (a) 1-Methyl-2- {2- [2- (5-phenylpentyl) phenoxy] ethyl } pyrrolidine

Following a procedure similar to that described in Example 5 (a), except that a 20: 1 by volume mixture of methylene chloride and methanol was used as eluent, 130 mg (19% yield) of the title compound were obtained as a yellow oil using 480 mg of 2- (5- phenylpentyl) phenol (prepared as described in Preparation Example 31), 387 mg of 2- (2-hydroxypentyl) -1-methylpyrrolidine, 786 mg of triphenylphosphine, 10 ml of methylene chloride and 520 mg of diethyl azodicarboxylate.

25

Nuclear Magnetic Resonance Spectrum (CDC (3.270 MHz), δ ppm: 1.35-1.5 (2H, multiplet); 1.55 - 2.0 (8H, multiplet); 2.0 - 2.5 (4H, multiplet); 2.42 (3H, singlet); 2.64 (4H, triplet, J = 7.6 Hz); ? 150 106551 3.1-3.3 (1H, multiplet); 3.9 - 4.2 (2H, multiplet); 6.8 - 6.95 (2H, multiplet); 7.1 - 7.4 (7H, multiplet).

5 91 (b) 1-Methyl-2- {2- [2- (5-phenylpentyl) phenoxy] ethyl} pyrrolidine hydrochloride 125 mg 1-methyl-2- {2- [2- (5-phenylpentyl) phenoxy] ethyl } pyrrolidine [prepared as described in step (a) above] was dissolved in 3 mL of dioxane and 0.13 mL of a 4N solution of hydrogen chloride in dioxane was added to the solution. The resulting mixture was then shaken and concentrated by distillation under reduced pressure. Pentane was added to the resulting concentrate and the mixture was agitated and then concentrated by distillation under reduced pressure. This operation was repeated twice and then the resulting oil was dried in vacuo to give 0.138 g (quantitative yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.3 - 1.5 (2H, multiplet); 1.5 - 1.75 (4H, multiplet); 1.8 - 2.15 (2H, multiplet); 2.15 - 2.4 (2H, multiplet); ? 2.4-2.7 (7H, multiplet); 2.71 (3H, singlet); 3.2 - 3.5 (1H, multiplet); 3.8 - 4.1 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.82 (1H, doublet, J = 8.3 Hz); •.

6.91 (1H, triplet, J = 7.3 Hz); 7.1-7.4 (7H, multiplet).

• 1 '30 151

Infrared Absorption Spectrum (CHC? 3),? Max cm -1: 106551 1600,1585,1495, 1450, 1230.

EXAMPLE 92 2- (2- {2- [2- (3-Chlorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine 92 (a) 2- (2- {2- [2- (3-Chlorophenyl) ethyl) ] phenoxy} ethyl) -1-methylpyrrolidine 1.06 g of potassium t-butoxide was added to a solution of 1.00 g of 2- [2- (3-chlorophenyl) ethyl] phenol (prepared as described in Preparation Example 44) in 20 ml: dimethylacetamide while cooling with ice and sodium chloride and stirring. 0.949 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride was then added to the solution. The reaction mixture was then cooled and 100 ml of ethyl acetate and 50 ml of water were added to the mixture which was then shaken. The ethyl acetate layer was separated, washed twice with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The ethyl acetate layer was then concentrated by distillation under reduced pressure and the concentrate was purified by column chromatography over silica gel using a 20: 1 by volume mixture of methylene chloride and methanol as eluant to give 0.770 g (52% yield) of the title compound as a colorless oil.

: Nuclear Magnetic Resonance Spectrum (CDC! 3.270 MHz), δ ppm: 1.55 - 1.95 (4H, multiplet); 1.95 - 2.15 (1H, multiplet); 2.2 - 2.5 (3H, multiplet); 2.42 (3H, singlet); *. 2.75 - 3.0 (4H, multiplet); 3.1 - 3.25 (1H, multiplet); 3.9 - 4.15 (2H, multiplet); 6.8 - 6.95 (2H, multiplet); 7.0 - 7.3 (6H, multiplet).

«152 106551 92 (b) 2- (2- {2- [2- (3-Chlorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 0.752 g of 2- (2- {2- [2- (3-Chlorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in 15 ml of ethyl acetate and 0.6 ml of a 4N solution of hydrogen chloride in dioxane was added to the resulting solution. The mixture was then concentrated by distillation under reduced pressure. The concentrate was dissolved in 20 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.530 g (64% yield) of the title compound as colorless crystals having a melting point of 119-121 ° C.

Nuclear Magnetic Resonance Spectrum (CDCf3, 2701 MHz), δ ppm: 1.95 - 2.2 (2H, multiplet); 2.2 - 2.4 (2H, multiplet); 2.4 - 2.6 (2H, multiplet); 2.7-3.0 (5H, multiplet); 2.79 (3H, singlet); 3.15 - 3.4 (1H, multiplet); 3.8-4.1 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); V 6.84 (1H, doublet, J = 7.9 Hz); 6.93 (1H, triplet, J = 7.9 Hz); 6.95 - 7.05 (1H, multiplet); 7.1-7.3 (5H, multiplet).

«153 EXAMPLE 93 106551 2- (2- {2- [2- (2-Chlorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 5 93 (a) 2- (2- {2- [2- (2) chlorophenyl) ethyl] phenoxy} ethyl) -l-methylpyrrolidine

Following a procedure similar to that described in Example 92 (a), 0.410 g (29% yield) of the title compound was obtained as a colorless solid using 0.950 g of 10 2- [2- (2-chlorophenyl) ethyl] phenol (prepared as described in Preparative Example 45). , 1.15 g of potassium t-butoxide, 1.13 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDCf3, 2701 MHz), δ ppm: 1.6 - 2.0 (4H, multiplet); 2.0 - 2.15 (1H, multiplet); 2.2 - 2.4 (2H, multiplet); 2.4 - 2.6 (1H, multiplet); 2.44 (3H, singlet); 2.85 - 3.05 (4H, multiplet); 3.15-3.3 (1H, multiplet); V 3.9-4.1 (2H, multiplet); 6.8 - 6.95 (2H, multiplet); 7.1 - 7.2 (5H, multiplet); 7.3-7.4 (1H, multiplet).

; 93 (b) 2- (2- {2- [2- (2-Chlorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 1 → 0.410 g 2- (2- {2- [2- ( 2-Chlorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in 5 ml of methylene chloride and 0.35 ml of a 4N solution of chlorine in dioxane was added to the solution. The resulting mixture was concentrated by distillation under reduced pressure. The resulting solid was dissolved in a small amount of methylene chloride and 10 mL of ethyl acetate was added to the solution, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.408 g (90% yield) of the title compound as colorless crystals having a melting point of 187-188 ° C.

Nuclear Magnetic Resonance Spectrum (CDCl3, 2770 MHz), δ ppm: 1.9 - 2.15 (2H, multiplet); Δ 2.15-2.4 (2H, multiplet); 2.4 - 2.6 (2H, multiplet); 2.7-3.1 (5H, multiplet); 2.78 (3H, singlet); 1.3 - 3.5 (1H, multiplet); 3.8-4.0 (2H, multiplet); 4.1-4.2 (1H, multiplet); 6.82 (1H, doublet, J = 7.9 Hz); 6.94 (1H, triplet, J = 7.6 Hz); 7.05 - 7.25 (5H, multiplet); 7.3-7.4 (1H, multiplet).

:: EXAMPLE 94 2- (2- {2- [2- (4-Chlorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride *. 94 (a) 2- (2- {2- [2- (2-Chlorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine →

Following a procedure similar to that described in Example 92 (a), 0.450 g (30% yield) of the title compound were obtained as a colorless oil using 1.00 g of 2- [2- (4-chlorophenyl) ethyl] phenol (prepared as described in Preparation Example 46), 155 106551 1.21 g of potassium t-butoxide, 1.19 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 2770 MHz), δ ppm: δ 1.6 - 2.7 (8H, multiplet); 2.47 (3H, singlet); 2.86 (4H, singlet); 3.2 - 3.35 (1H, multiplet); 3.9 - 4.15 (2H, multiplet); Δ 6.8-6.95 (2H, multiplet); 7.0 - 7.3 (6H, multiplet).

94 (b) 2- (2- {2- [2- (4-Chloro-phenyl) -ethyl] -phenoxy} -ethyl) -1-methyl-pyrrolidine qudro-chloride 0.450 g of 2- (2- {2- [2- (4- chlorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in a small amount of dioxane and 0.36 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then concentrated by distillation under reduced pressure. The concentrate was dissolved in 15 mL of ethyl acetate and allowed to stand at room temperature. The wefts that precipitated were collected by filtration and dried in vacuo to give 0.350 g (70% yield) of the title compound as colorless crystals, m.p.: 145-146 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.9 - 2.15 (2H, multiplet); 2.2 - 2.4 (2H, multiplet); *. 2.4 - 2.65 (2H, multiplet); 2.7-3.0 (1H, multiplet); 2.77 (3H, singlet); 30 2.86 (4H, singlet); 3.15-3.3 (1H, multiplet); 156 3.8 - 4.1 (2H, multiplet); 106551 6.82 (1H, doublet, J = 8.6 Hz); 6.92 (1H, triplet, J = 7.6 Hz); 7.0 - 7.15 (3H, multiplet); Δ 7.15-7.3 (3H, multiplet).

EXAMPLE 95 2- (2- {2- [2- (3-Fluorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 95 (a) 2- (2- {2- [2- (3) fluorophenyl) ethyl] phenoxy} ethyl) -l-methylpyrrolidine

Following a procedure similar to that described in Example 92 (a), 0.940 g (62% yield) of the title compound was obtained as a colorless oil using 1.00 g of 2- [2- (3-fluorophenyl) ethyl] phenol (prepared as described in Preparation Example 48), 1.14 g of potassium t-butoxide, 1.02 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDC? 3.270 MHz), δ ppm: 1.6 - 2.0 (4H, multiplet); 2.0 - 2.1 (1H, multiplet); 2.2 - 2.4 (2H, multiplet); 2.4 - 2.6 (1H, multiplet); 2.44 (3H, singlet); 2.8-3.0 (4H, multiplet); * · 3.15 - 3.3 (1H, multiplet); 3.9 - 4.2 (2H, multiplet); 6.8 - 7.0 (5H, multiplet); 7.05 - 7.3 (3H, multiplet).

157 106551 95 (b) 2- (2- {2- [2- (3-Fluorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 0.923 g of 2- (2- {2- [2- (3-) fluorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in 15 ml of ethyl acetate and 0.8 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then concentrated by distillation under reduced pressure. The concentrate was dissolved in 25 ml of ethyl acetate and the solution was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.585 g (56% yield) of the title compound as colorless crystals, m.p. 135-136 ° C.

Nuclear Magnetic Resonance Spectrum (CDCC 3.270 MHz), δ ppm: 1.9 - 2.2 (2H, multiplet); 2.2 - 2.4 (2H, multiplet); 2.4 - 2.65 (2H, multiplet); 2.7-3.0 (1H, multiplet); 2.78 (3H, singlet); 2.88 (4H, singlet); 3.2 - 3.4 (1H, multiplet); 3.8-4.1 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.8 - 7.0 (5H, multiplet); 7.1-7.3 (3H, multiplet).

158 EXAMPLE 96 106551 2- (2- {2- [2- (4-Fluorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 5 96 (a) 2- (2- {2- [2- (4- fluorophenyl) ethyl] phenoxy} ethyl) -l-methylpyrrolidine

Following a procedure similar to that described in Example 92 (a), 0.560 g (37% yield) of the title compound was obtained as a colorless oil using 1.00 g of 2- [2- (4-10 fluorophenyl) ethyl] phenol (prepared as described in Preparative Example 49). ), 1.30 g of potassium t-butoxide, 1.27 g of 2- (2-chlorophenyl) -1-methylpyrrolidine hydrochloride and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.55 - 1.95 (4H, multiplet); 1.95 - 2.15 (1H, multiplet); 2.15 - 2.5 (3H, multiplet); 2.40 (3H, singlet); 2.75 - 2.95 (4H, multiplet); 3.1 - 3.2 (1H, multiplet); 3.9 - 4.15 (2H, multiplet); : 6.8-7.0 (4H, multiplet); 7.05 - 7.25 (4H, multiplet). 1 2 3 4 5 6 «96 (b) 2- (2- {2- [2- (4-Fluorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine 2 hydrochloride 3,460 0.560 g 2- (2- { 2- [2- (4-Fluorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [Prepared 5 as described in step (a) above] was dissolved in 10 mL of ethyl acetate and 0.5 mL of a 4N solution of hydrochloric 6 in dioxane was added to the solution. . The resulting mixture was then concentrated by distillation under reduced pressure and the concentrate was dissolved in 15 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.484 g (78% yield) of the title compound as colorless crystals, m.p. 114-115 ° C.

Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 1.9 - 2.2 (2H, multiplet); 2.2 - 2.4 (2H, multiplet); 2.4-2m65 (2H, multiplet); 2.7-3.0 (1H, multiplet); 10 2.78 (3H, singlet); 2.86 (4H, singlet); 3.15 - 3.35 (1H, multiplet); 3.8 - 4.1 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.8-7.0 (4H, multiplet); 7.0 - 7.2 (4H, multiplet).

EXAMPLE 97 2- (2- {2- [2- (2-Fluoro-phenyl) -ethyl] -phenoxy} -ethyl) -1-methyl-pyrrolidine Hydrochloride · · · · 97 (a) 2- (2- {2- [2- (2-Fluorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine Following a procedure similar to that described in Example 92 (a), 0.316 g (21% yield) of the title compound was obtained as a colorless oil using 1.00 g of 2- [2 - (2-fluorophenyl) ethyl] phenol (prepared as described in Preparation Example 47), 1.30 g of potassium t-butoxide, 1.26 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 20 ml dimethylacetamide.

30 160 106551

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.6 - 2.6 (7H, multiplet); 2.54 (3H, singlet); 2.6 - 2.9 (1H, multiplet); Δ 2.90 (4H, singlet); 3.3 - 3.45 (1H, multiplet); 3.9 - 4.2 (2H, multiplet); 6.8 - 6.95 (2H, multiplet); 6.95 - 7.1 (2H, multiplet); 7.1-7.25 (4H, multiplet).

97 (b) 2- (2- {2- [2- (2-Fluorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 0.311 g of 2- (2- {2- [2- (2-fluorophenyl)) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in 10 ml of ethyl acetate and 0.36 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then allowed to stand at room temperature and the crystals which precipitated were collected by filtration and dried in vacuo to give 0.290 g (84% yield) of the title compound as colorless crystals having a melting point of 20 178-180 ° C.

Nuclear Magnetic Resonance Spectrum (CDC ^,, 270 MHz), δ ppm: 1.9 - 2.2 (2H, multiplet); 2.2 - 2.7 (4H, multiplet); 2.7 - 3.0 (1H, multiplet); 2.84 (3H, singlet); v 2.87 (4H, singlet); 3.4 - 3.65 (1H, multiplet); 3.8 - 4.1 (2H, multiplet); 4.2-4.3 (1H, multiplet); 6.8 - 7.3 (8H, multiplet).

161 EXAMPLE 98 106551 2- (2- {2- [2- (3-Bromophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 98 (a) 2- (2- {2- [2- (3-) bromophenyl) ethyl] phenoxy} ethyl) -L-metyylipyrrolidilni

Following a procedure similar to that described in Example 92 (a), 0.450 g (32% yield) of the title compound was obtained as a colorless oil using 1.00 g of 2- [2- (3-bromophenyl) ethyl] phenol (prepared as described in Preparation Example 50), 1.01 g of potassium t-butoxide, 0.996 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.6 - 2.0 (4H, multiplet); 2.0 - 2.6 (4H, multiplet); 2.44 (3H, singlet); 2.8 - 2.95 (4H, multiplet); 3.15-3.3 (1H, multiplet); 3.9 - 4.15 (2H, multiplet); . 6.8 - 6.95 (2H, multiplet); 7.1 - 7.4 (6H, multiplet). 1 2 3 4 5 6 98 (b) 2- (2- {2- [2- (3-Bromophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydro 2 chloride 3 x 4. 0.450 g of 2- (2- {2- [2- (3-bromophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in a small amount of dioxane and 0.4 ml of chlorine A solution of 6 hydrogen in 4N in dioxane was added to the solution. The mixture was then concentrated by distillation under reduced pressure. The concentrate was dissolved in 15 mL of ethyl acetate and allowed to stand at room temperature 162-106551. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.394 g (80% yield) of the title compound as colorless crystals having a melting point of 127-129 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.9 - 2.2 (2H, multiplet); 2.2 - 2.4 (2H, multiplet); 2.4-2.7 (2H, multiplet); 2.75-3.1 (5H, multiplet); 10.79 (3H, singlet); 3.2 - 3.4 (1H, multiplet); 3.8 - 4.3 (1H, multiplet); 6.85 (1H, doublet, J = 7.9 Hz); 6.93 (1H, triplet, J = 7.3 Hz); 7.05 (1H, triplet, J = 7.3 Hz); 7.1-7.4 (5H, multiplet).

EXAMPLE 99 2- (2- {2- [2- (3-Ethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride c 99 (a) 2- (2- {2- [2- (3) -Ethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine Following a procedure similar to that described in Example 92 (a), 0.900 g (35% yield) of the title compound was obtained as a colorless oil using 1.78 g of 2- [2- ( 3-ethoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 33), 2.06 g of potassium t-butoxide, 2.03 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 40 ml of dimethylacetamide.

30,163 106551

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.40 (3H, triplet, J = 7.3 Hz); 1.6 - 2.0 (4H, multiplet); 2.0 - 2.15 (1H, multiplet); Δ 2.2 - 2.4 (2H, multiplet); 2.4 - 2.6 (1H, multiplet); 2.45 (3H, singlet); 2.75 - 3.0 (4H, multiplet); 3.15-3.3 (1H, multiplet); Δ 3.9-4.2 (2H, multiplet); 4.00 (2H, quartet, J = 7.3 Hz); 6.7 - 7.0 (5H, multiplet); 7.05 - 7.25 (3H, multiplet).

99 (b) 2- (2- {2- [2- (3-Ethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 0.891 g 2 '(2- {2- [2- (3- ethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in a small amount of ethyl acetate and 0.76 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then concentrated by distillation under reduced pressure and the concentrate was dissolved in 25 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.518 g (53% yield) of the title compound as colorless crystals having a melting point of 120-121 ° C. : 25

Nuclear Magnetic Resonance Spectrum (CDCC 3, 270 MHz), δ ppm: δ 1.39 (3H, triplet, J = 7.3 Hz); 1.9 - 2.15 (2H, multiplet); 2.15 - 2.4 (2H, multiplet); 2.4 - 2.65 (2H, multiplet); 2.7 - 3.0 (5H, multiplet); 164 106551 2.78 (3H, singlet); 3.2 - 3.4 (1H, multiplet); 3.8 - 4.1 (2H, multiplet); 4.00 (2H, quartet, J = 7.3 Hz); 4.1 - 4.2 (1H, multiplet); 6.65 - 6.8 (3H, multiplet); 6.84 (1H, doublet, J = 7.9 Hz); 6.93 (1H, triplet, J = 7.9 Hz); 7.1 - 7.25 (3H, multiplet).

EXAMPLE 100 2- (2- {2- [2- (2-Ethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 15 100 (a) 2- (2- {2- [2- (2-Ethoxyphenyl) ) ethyl] phenoxy} ethyl) -L-metyylipyrroIidiini

Following a procedure similar to that described in Example 92 (a), 0.636 g (40% yield) of the title compound was obtained as a colorless oil using 1.10 g of 2- [2- (2-20 ethoxyphenyl) ethyl] phenol (prepared as described in Preparation 34). ), 1.27 g of potassium t-butoxide, 1.26 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 15 ml. dimethylacetamide.

• ·

Nuclear Magnetic Resonance Spectrum (CDCd 3, 270 MHz), δ ppm: δ 1.42 (3H, triplet, J = 7.2); 1.5 δ - 2.0 (4H, multiplet); * v 2.0 - 2.15 (1H, multiplet); 2.2 - 2.55 (3H, multiplet); 2.40 (3H, singlet); 30 2.90 (4H, singlet); 3.1-3.25 (1H, multiplet); 165 3.9-4.15 (2H, multiplet); 106551 4.02 (2H, quartet, J = 7.2 Hz); 6.8 - 6.95 (4H, multiplet); 7.1 - 7.25 (4H, multiplet).

100 (b) 2- (2- {2- [2- (2-Ethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 0.600 g 2- (2- {2- [2- (2-) ethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in a small amount of ethyl acetate and 0.41 mL of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then concentrated by distillation under reduced pressure. The resulting solid was dissolved in a small amount of methanol and 30 mL of ethyl acetate was added to the solution, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.420 g (63% yield) of the title compound as colorless crystals having a melting point of 148-150 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.40 (3H, triplet, J = 7.3 Hz); 1.9 - 2.4 (2H, multiplet); 2.4 - 2.65 (2H, multiplet); 2.65-3.0 (5H, multiplet); 2.71 (3H, singlet); 3.2 - 3.4 (1H, multiplet); 3.8 - 4.1 (2H, multiplet); 4.02 (2H, quartet, J = 7.3 Hz); 4.15-4.3 (1H, multiplet); Δ 6.8-7.0 (4H, multiplet); 7.05 - 7.25 (4H, multiplet).

EXAMPLE 101 166 106551 2- (2- {2- [2- (4-Ethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 5 101 (a) 2- (2- {2- [2- (4- Ethoxyphenyl) ethyl] phenoxy} ethyl) -l-methylpyrrolidine

Following a procedure similar to that described in Example 92 (a), 1.00 g (69% yield) of the title compound was obtained as a colorless oil using 1.00 g of 2- [2- (4-ethoxyphenyl) -10-ethyl] phenol (prepared as described in Preparation Example 35), 1.16 g of potassium t-butoxide, 1.14 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 15 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.40 (3H, triplet, J = 7.2 Hz); 1.55 - 1.95 (4H, multiplet); 1.95 - 2.15 (1H, multiplet); 2.15 - 2.5 (3H, multiplet); 2.40 (3H, singlet); 2.75 - 2.95 (4H, multiplet); 3.1 - 3.25 (1H, multiplet); . 3.9 - 4.15 (2H, multiplet); 4.00 (2H, quartet, J = 7.2 Hz); 6.75 - 6.9 (4H, multiplet); 7.05 - 7.2 (4H, multiplet).

J. 101 (b) 2- (2- (2- [2- (4-Ethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 1.00 g of 2- (2- {2- [2- (4- ethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in 10 ml of ethyl acetate and 0.6 ml of a 4N solution of chlorine 167 106551 in dioxane was added to the solution. The resulting solid was dissolved in a small amount of methanol and 30 mL of ethyl acetate was added to the solution, which was then allowed to stand at room temperature The crystals which precipitated were collected by filtration and dried in vacuo to give 0.810 g (53.7% yield) having a melting point of 131-132 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.40 (3H, triplet, J = 7.2 Hz); 1.9 - 2.15 (2H, multiplet); Δ 2.15 - 2.4 (2H, multiplet); 2.4 - 2.65 (2H, multiplet); 2.7-3.0 (5H, multiplet); 2.76 (3H, singlet); 3.2 - 3.4 (1H, multiplet); 3.8 - 4.1 (2H, multiplet); 4.01 (2H, quartet, J = 7.2 Hz); 4.15 - 4.3 (1H, multiplet); 6.75 - 6.9 (3H, multiplet); 6.92 (1H, triplet, J = 7.3 Hz); 7.04 (2H, doublet, J = 8.6 Hz); 7.1 - 7.25 (2H, multiplet).

EXAMPLE 102 25 (R) -2- [2- (2-Phenylethyl) phenoxymethyl] morpholine hydrochloride · 102 (a) (R) -4-t-Butoxycarbonyl-2- [2- (2-phenylethyl) phenoxymethyl ] morpholine

Following a procedure similar to that described in Example 40 (a), except that a 5: 1 by volume mixture of hexane and ethyl acetate was used as eluent, 1.96 g (98% yield) of the title compound were obtained as a colorless oil using 1.00 g of 2- (2) -phenyl-168 106551 ethyl) phenol (prepared as described in Preparation Example 19), 2.33 g of (R) -4-t-butoxycarbonyl-2- (2-toluenesulfonyloxymethyl) morpholine, 743 g of potassium t-butoxide and 20 ml. dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.45 (9H, singlet); 2.8 - 3.1 (6H, multiplet); 3.5 - 3.7 (1H, multiplet); 3.75-4.2 (6H, multiplet); Δ 6.8-6.95 (2H, multiplet); 7.1-7.3 (7H, multiplet).

102 (b) (R) - [2- (2-Phenylethyl) phenoxymethyl] morpholine hydrochloride 0.930 g of (R) -4-t-butoxycarbonyl-2- [2- (2-phenylethyl) phenoxymethyl] morpholine [prepared as described in step (a) above] was dissolved in 5 mL of dioxane and 5 mL of a 4N solution of hydrogen chloride in dioxane was added to the solution which was then allowed to stand at room temperature for one hour. Subsequently, the mixture was concentrated by distillation under reduced pressure and the resulting oil was dissolved in 25 ml of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.692 g (89% yield) of the title compound as colorless crystals having a melting point of 150-151 ° C.

[?] D = -7.94 ° (c = 1.0, H2O).

D

25

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 2.8 - 3.0 (4H, multiplet); 3.0-3.2 (2H, multiplet); 3.33 (1H, doublet, J = 12.5 Hz); 3.45 (1H, doublet, J = 12.5 Hz); 3.9 - 4.2 (4H, multiplet); 4.25 - 4.4 (1H, multiplet); 169 106551 6.78 (1H, doublet, j = 7.9 Hz); 6.91 (1H, triplet, J = 7.9 Hz); 7.1 - 7.4 (7H, multiplet).

EXAMPLE 103 (R) -4-Methyl-2- [2- (2-phenylethyl) -phenoxymethyl] -morpholine hydrochloride 103 (a) (R) -4-Methyl-2- [2- (2-phenylethyl) -phenoxymethyl] -morpholine 10

Following a procedure similar to that described in Example 38 (a), 0.800 g (99% yield) of the title compound was obtained as a colorless oil using 1.03 g of (R) -4-t-butoxycarbonyl-2- [2- (2-phenylethyl) phenoxymethyl] morpholine [prepared as described in Example 102 (a)], 0.196 g of lithium aluminum hydride and 20 ml of tetrahydrofuran.

15

Nuclear Magnetic Resonance Spectrum (CDQ>, 270 MHz), δ ppm: 2.2 - 2.4 (2H, multiplet); 2.44 (3H, singlet); 2.8-3.0 (5H, multiplet); 3.08 (1H, doublet, J = 11.2 Hz); 3.8 - 4.2 (5H, multiplet); . 6.8 - 6.95 (2H, multiplet); 7.1 - 7.35 (7H, multiplet). 1 2 3 4 5 6 103 (b) (R) -4-Methyl-2- [2- (2-phenylethyl) phenoxymethyl] morpholine 2 hydrochloride 3 x 4 0.800 g of (R) -4-methyl-2- [ 2- (2-Phenylethyl) phenoxymethyl] morpholine [prepared as described in step (a) above] was dissolved in 10 ml of dioxane and 0.8 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then concentrated by distillation under reduced pressure. The resulting oil was dissolved in 15 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.541 g (61% yield) of the title compound as colorless crystals having a melting point of 123-125 ° C.

[Α] 25: -5.08 ° (c = 1.3, ethanol).

D

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 2.7 - 3.0 (6H, multiplet); 10 2.73 (3H, singlet); 3.40 (2H, triplet, J = 11.9 Hz); 4.0 - 4.2 (3H, multiplet); 4.37 (1H, triplet, J = 11.9 Hz); 4.5 - 4.6 (1H, multiplet); 6.83 (1H, doublet, J = 7.9 Hz); 6.94 (1H, triplet, J = 7.9 Hz); 7.1 - 7.3 (7H, multiplet).

EXAMPLE 104 20 (S) -2- [2- (2-Phenylethyl) phenoxymethyl] morpholine hydrochloride *: 104 (a) (S) -4-t-Butoxycarbonyl-2- [2- (2-phenylethyl) phenoxymethyl] morpholine Following a procedure similar to that described in Example 40 (a) except that a 5: 1 by volume mixture of hexane and ethyl acetate was used as eluent, 1.23 g (99% yield) of the title compound as a colorless oil were obtained using 0.620 gm of 2- (2-phenylethyl). ) phenol (prepared as described in Preparation Example 19), 1.51 g of (S) -4-t-butoxycarbonyl-2- (E-toluenesulfonyloxymethyl) morpholine, 460 g of potassium t-butoxy-30-dia and 16 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 171-106551 1.45 (9H, singlet); 2.8-3.1 (6H, multiplet); 3.5-3.7 (1H, multiplet); 3.75 4.2 (6H, multiplet); 6.8-6.95 (2H, multiplet); 7.1-7.3 (7H, multiplet).

104 (b) (S) -2- [2- (2-Phenylethyl) phenoxymethyl] morpholine hydrochloride 10,500 g of (S) -4-t-butoxycarbonyl-2- [2- (2-phenylethyl) phenoxymethyl] morpholine [val] solubilized as described in step (a) above] was dissolved in 2 ml of dioxane and 4 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution which was then allowed to stand at room temperature for one hour. The mixture was then concentrated by distillation under reduced pressure. The resulting oil was dissolved in 15 volumes of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.345 g (82% yield) of the title compound as colorless crystals, m.p. 143-145 ° C.

[α] D = -7.25 ° (c = 1.49, H 2 O).

20 D

Nuclear Magnetic Resonance Spectrum (CDCd3.270 MHz), δ ppm: •; 2.8-3.0 (4H, multiplet); 3.0 - 3.2 (2H, multiplet); 3.33 (1H, doublet, J = 12.5 Hz); 3.45 (1H, doublet, J = 12.5 Hz); 3.9 - 4.2 (4H, multiplet); 4.25 - 4.4 (1H, multiplet); 6.79 (1H, triplet, J = 7.9 Hz); 6.91 (1H, triplet, J = 7.9 Hz); 7.1 - 7.4 (7H, multiplet).

EXAMPLE 105 172 106551 (S) -4-Methyl-2- [2- (2-phenylethyl) phenoxymethyl] morpholine hydrochloride 105 (a) (S) -4-Methyl-2- [2- (2-phenylethyl) phenoxymethyl ] morpholine

Following a procedure similar to that described in Example 38 (a), 0.560 g (99% yield) of the title compound was obtained as a colorless oil using 0.720 g of (S) -4-t-butoxycarbonyl-2- [2- (2-phenylethyl) phenoxymethyl]. morpholine [prepared as described in Example 104 (a)], 0.142 g of lithium aluminum anhydride and 15 ml of tetrahydrofuran.

Nuclear Magnetic Resonance Spectrum (CDCl3, 2770 MHz), δ ppm: 2.2 - 2.4 (2H, multiplet); 2.44 (3H, singlet); 2.8 - 3.0 (5H, multiplet); 3.08 (1H, doublet, J = 11.2 Hz); 3.8 - 4.2 (5H, multiplet); 6.8 - 6.95 (2H, multiplet); 7.1 - 7.35 (7H, multiplet).

105 (b) (S) -4-Methyl-2- [2- (2-phenylethyl) phenoxymethyl] morpholine hydrochloride 0.560 g of (S) -4-methyl-2- [2- (2-phenylethyl) phenoxymethyl] morpholine [prepared as described in step (a) above] was dissolved in 5 mL of dioxane and 0.56 mL of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then concentrated by distillation under reduced pressure and the resulting oil was dissolved in 10 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.448 g (72% yield) of the title compound as colorless crystals having a melting point of 125-127 ° C.

173 106551 [α] 25: + 5.29 ° (c = 1.36, ethanol).

D

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: δ 2.7-3.0 (6H, multiplet); 2.73 (3H, singlet); 3.40 (2H, triplet, J = 11.9 Hz); 4.0 - 4.2 (3H, multiplet); 4.38 (1H, triplet, J = 11.9 Hz); 4.5-4.6 (1H, multiplet); 6.83 (1H, doublet, J = 7.9 Hz); 6.94 (1H, triplet, J = 7.9 Hz); 7.1 - 7.3 (7H, multiplet).

EXAMPLE 106 2- (2- {2- [2- (4-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine Hydrochloride 106 (a) 2- (2- {2- [2- (4-Methoxyphenyl) ) ethyl] phenoxy} ethyl) -L-metyyIipyrrolidiini

Performing a procedure similar to that described in Example 92 (a) gave »··· 0.602 g (40% yield) of the title compound as a colorless oil using 1.00 g of 2- [2- (4-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 36), 1.23 g of potassium t-butoxide, 1.51 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDCC3, 270 MHz), δ ppm: 1.5 - 2.7 (8H, multiplet); 30 2.65 (3H, singlet); 2.75 - 3.0 (4H, multiplet); 3.5 - 3.7 (1H, multiplet); 174 106551 3.82 (3H, singlet); 3.95 - 4.1 (1H, multiplet); 4.15 - 4.25 (1H, multiplet); 6.8 - 7.0 (4H, multiplet); Δ 7.1-7.3 (4H, multiplet).

106 (b) 2- (2- {2- [2- (4-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidinyl hydrochloride 10 0.602 g of 2- (2- {2- [2- (4-methoxyphenyl)) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in a small amount of dioxane and 0.66 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then concentrated by distillation under reduced pressure and the resulting oil was dissolved in 15 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.331 g (50% yield) of the title compound as colorless crystals having a melting point of 136-138 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.9 - 2.15 (2H, multiplet); 2.15 - 2.4 (2H, multiplet); 2.4 - 2.6 (2H, multiplet); 2.7 - 2.95 (5H, multiplet); 2.78 (3H, singlet); 3.2 - 3.35 (1H, multiplet); 3.79 (3H, singlet); 3.8 - 4.1 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.8 - 6.9 (3H, multiplet); 6.92 (1H, triplet, J = 7.6 Hz); 7.0 - 7.25 (4H, multiplet).

175 Example 107 106551 2- (2- {2- [2- (4-Methylphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 107 107 (a) 2- (2- {2- [2- (4) -MetyylifenyyIi) ethyl] phenoxy} ethyl) -l-methylpyrrolidine

Following a procedure similar to that described in Example 92 (a), 0.813 g (53% yield) of the title compound was obtained as a colorless oil using 1.00 g of 2- [2- (4-10 methylphenyl) ethyl] phenol (prepared as described in Preparative Example 37). ), 1.32 g of potassium t-butoxide, 1.30 g of 2- (2-chloroethyl) -1-methylpynOlidine hydrochloride and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDCf3, 2701 MHz), δ ppm: 1.6 - 2.0 (4H, multiplet); 2.0 - 2.2 (1H, multiplet); 2.2 - 2.4 (2H, multiplet); 2.32 (3H, singlet); 2.45 - 2.65 (1H, multiplet); 2.46 (3H, singlet); 2.75 - 2.95 (4H, multiplet); : 3.2 - 3.35 (1H, multiplet); 3.9 - 4.3 (2H, multiplet); 6.8 - 6.95 (2H, multiplet); 7.05 - 7.25 (6H, multiplet).

176 106551 107 (b) 2- (2- {2- [2- (4-Methylphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 0.813 g of 2- (2- {2- [2- (4-methylphenyl) ) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in 5 mL of dioxane and 0.95 mL of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then concentrated by distillation under reduced pressure and the resulting oil was dissolved in 15 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.740 mg (82% yield) of the title compound as colorless crystals having a melting point of 137-138 ° C.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.94.34 2.15 (2H, multiplet); 2.15 - 2.4 (2H, multiplet); Δ 2.33 (3H, singlet); 2.4 - 2.65 (2H, multiplet); 2.7-3.0 (5H, multiplet); 2.75 (3H, singlet); 3.2 - 3.4 (1H, multiplet); 3.8-4.1 (2H, multiplet) ·; 4.2 - 4.3 (1H, multiplet); 6.85 (1H, doublet, J = 7.9 Hz); 6.93 (1H, trip); 7.0 - 7.3 (6H, multiplet).

EXAMPLE 108 177 106551 2- (2- {2- [2- (2-Cyanophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 108 (a) 2- (2- {2- [2- (2-cyanophenyl) ethyl] phenoxy} ethyl) -L-metyyIipyrroIidiini

Following a procedure similar to that described in Example 92 (a), 0.201 g (13% yield) of the title compound was obtained as a colorless oil using 1.00 g of 2- [2- (2-10 cyano-phenyl) -ethyl] -phenol (prepared as described in Preparation 40). ), 1.26 g of potassium t-butoxide, 1.24 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.55 - 1.95 (4H, multiplet); 1.95 - 2.2 (1H, multiplet); 2.2 - 2.35 (2H, multiplet); 2.35 - 2.55 (1H, multiplet); 2.43 (3H, singlet); 2.9 - 3.3 (5H, multiplet); 3.95 - 4.15 (2H, multiplet); Δ ** 6.8-6.9 (2H, multiplet); 7.05 - 7.35 (4H, multiplet); 7.47 (1H, triplet, J = 7.6 Hz); 7.60 (1H, doublet, J = 8.6 Hz).

108 (b) 2- (2- {2- [2- (2-Cyanophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 0.201 g of 2- (2- {2- [2- (2-) cyanophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in a small amount of dioxane and 0.25 mL of a 4N solution of chlorine 106551 178 hydrogen in dioxane was added to the solution. The mixture was then concentrated by distillation under reduced pressure and the resulting oil was dissolved in 10 ml of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.170 g (76% yield) of the title compound as colorless crystals, m.p. 172-173 ° C.

Nuclear Magnetic Resonance Spectrum (CDC >3, 270 MHz), δ ppm: 1.95 - 2.2 (2H, multiplet); 2.2 - 2.7 (4H, multiplet); 10.75 - 3.2 (5H, multiplet); 2.88 (3H, singlet); 3.55 - 3.8 (1H, multiplet); 3.8 - 4.1 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.85 (1H, doublet, J = 7.9 Hz); 6.92 (1H, triplet, J = 7.6 Hz); 7.1-7.4 (4H, multiplet); 7.52 (1H, triplet, J = 7.6 Hz); 7.61 (1H, doublet, J = 7.9 Hz).

20 EXAMPLE 109 • · 2- (2- {2- [2- (3-Cyanophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 109 109 (a) 2- (2- {2- [2- (3) -Syanofenyyli) ethyl] phenoxy} ethyl) -l-methylpyrrolidine

By performing a procedure similar to that described in Example 92 (a). 0.510 g (34% yield) of the title compound were obtained as a colorless oil using 1.00 g of 2- [2- (2-30 cyanophenyl) ethyl] phenol (prepared as described in Preparation Example 41), 1.26 g of • 179 106551 potassium t-butoxide , 1.24 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDC? 3.270 MHz), δ ppm: δ 1.55-1.95 (4H, multiplet); 1.95 - 2.15 (1H, multiplet); 2.15 - 2.5 (3H, multiplet); 2.40 (3H, singlet); 2.91 (4H, singlet); 3.1 - 3.2 (1H, multiplet); 3.95 - 4.15 (2H, multiplet); 6.8 - 6.9 (2H, multiplet); 7.04 (1H, doublet, J = 5.9 Hz); 7.19 (1H, triplet, J = 7.2 Hz); 7.25 - 7.55 (4H, multiplet).

109 (b) 2- (2- {2- [2- (3-Cyanophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 0.50 g of 2- (2- {2- [2- ( 3-Cyanophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in a small amount of dioxane and 0.56 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then concentrated by distillation under reduced pressure and the resulting oil was dissolved in 20 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.406 g (72% yield) of the title compound as colorless crystals having a melting point of 101-102 ° C.

• I

«

Nuclear Magnetic Resonance Spectrum (CDCt> 3.270 MHz), δ ppm: 1.95 - 2.2 (2H, multiplet); Δ 2.2 - 2.45 (2H, multiplet); 2.45 - 2.65 (2H, multiplet); 106551 180 2.8-2.65 (2H, multiplet); 2.83 (3H, singlet); 2.90 (4H, singlet); 3.2 - 3.4 (1H, multiplet); Δ 3.85-4.1 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.85 (1H, doublet, J = 7.9 Hz); 6.91 (1H, triplet, J = 7.3 Hz); 7.06 (1H, doublet, J = 7.3 Hz); 7.21 (1H, triplet, J = 7.9 Hz); 7.3 - 7.45 (3H, multiplet); 7.50 (1H, doublet, J = 6.9 Hz).

EXAMPLE 110 2- (2- {2- [2- (4-Cyanophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 110 (a) 2- (2- {2- [2- (4-Cyanophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine 20

Performing a procedure similar to that described in Example 92 (a) gave: 0.310 g (21% yield) of the title compound as a colorless oil using 1.00 g of 2- [2- (4-cyanophenyl) ethyl] phenol (prepared as described in Preparation Example). 42), 1.26 g of potassium t-butoxide, 1.24 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 20 ml of '25 dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: ♦ · 1.55 - 1.95 (4H, multiplet); 1.95 - 2.15 (1H, multiplet); Δ 2.2 - 2.5 (3H, multiplet); 2.42 (3H, singlet); 181 106551 2.8 - 3.05 (4H, multiplet); 3.15-3.3 (1H, multiplet); 3.9 - 4.15 (2H, multiplet); 6.8 - 6.9 (2H, multiplet); Δ 7.03 (1H, triplet, J = 5.9 Hz); 7.19 (1H, doublet, J = 7.9 Hz); 7.25 (2H, doublet, J = 7.9 Hz); 7.55 (2H, doublet, J = 7.9 Hz).

10 110 (b) 2- (2- {2- [2- (4-Cyanophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 0.300 g 2- (2- {2- [2- (4-cyanophenyl)) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (a) above] was dissolved in a small amount of dioxane and 0.25 ml of a 4N solution of chlorine-15 hydrogen in dioxane was added to the solution. The mixture was then concentrated by distillation under reduced pressure and the resulting oil was dissolved in 10 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.170 g (49% yield) of the title compound as colorless crystals having a melting point of 137.5-139 ° C.

20

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm:; 1.95 - 2.2 (2H, multiplet); 2.2 - 2.45 (2H, multiplet); 2.45 - 2.65 (2H, multiplet); 2.75 - 3.1 (5H, multiplet); 2.81 (3H, singlet); 3.15 - 3.35 (1H, multiplet); ? 3.8-4.1 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.8-7.0 (2H, multiplet); 7.02 (1H, triplet, J = 7.3 Hz); 182 106551 7.15-7.3 (3H, multiplet); 7.56 (2H, doublet, J = 7.9 Hz).

EXAMPLE 111 2- (2- {2- [2- (2-Hydroxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 111 (a) 2- (2- {2- [2- (2-Methoxymethyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine 10

Following a procedure similar to that described in Example 92 (a), 0.660 g (46% yield) of the title compound was obtained as a colorless oil using 1.00 g of 2- [2- (2-methoxymethoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 38). 1.09 g of potassium t-butoxide, 1.07 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 15 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.6 - 2.0 (4H, multiplet); 2.0 - 2.2 (1H, multiplet); 2.2 - 2.4 (2H, multiplet); 2.46 (3H, singlet); : * 2.45 - 2.65 (1H, multiplet); 2.91 (4H, singlet); 3.2 - 3.3 (1H, multiplet); 3.48 (3H, singlet); 3.9 - 4.2 (2H, multiplet); 5.12 (2H, singlet); 6.8 - 7.0 (3H, multiplet); 7.05 - 7.2 (5H, multiplet).

30 • 111 (b) 2- (2- {2- [2- (2-Hydroxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 183 106551 0.660 g 2- (2- {2- [2- (2) -methoxymethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine 5 [prepared as described in step (a) above] was dissolved in 5 ml of dioxane and 5 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then allowed to stand at room temperature for 30 minutes, after which it was concentrated by distillation under reduced pressure. The resulting colorless solid was dissolved in a small amount of a mixture of methylene chloride and methanol, and about 30 mL of ethyl acetate was added to the solution, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.555 g (86% yield) of the title compound as colorless crystals, m.p. 168.5-171 ° C.

Nuclear Magnetic Resonance Spectrum (Hexadeuterated Dimethylsulfoxide + D 2 O, 15 270 MHz), δ ppm: 1.7 - 2.5 (6H, multiplet); 2.65 - 2.9 (4H, multiplet); 2.79 (3H, singlet); 2.9 - 3.15 (1H, multiplet); 3.3-3.15 (1H, multiplet); 3.3 - 3.65 (2H, multiplet); 3.9 - 4.2 (2H, multiplet); 6.69 (1H, triplet, J = 7.3 Hz); 6.8 - 7.2 (7H, multiplet).

25 184 106551 EXAMPLE 112 2- (2- {2- [2- (4-Hydroxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 112 (a) 2- (2- {2- [2- (4-Methoxymethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine

Following a procedure similar to that described in Example 92 (a), 0.411 g (26% yield) of the title compound was obtained as a colorless oil using 1.10 g of 2- [2- (4-methoxymethoxyphenyl) ethyl] phenol (prepared as described in Preparative Example 39). ), 1.20 g of potassium t-butoxide, 1.18 g of 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.7 - 2.2 (5H, multiplet); 2.25 - 2.5 (2H, multiplet); 2.54 (3H, singlet); 2.6 - 2.95 (5H, multiplet); 3.35-3.5 (1H, multiplet); 3.48 (3H, singlet); 3.95-4.05 (1H, multiplet); 4.05 - 4.2 (1H, multiplet); 5.15 (2H, singlet); 6.8-7.0 (4H, multiplet); 7.05 - 7.25 (4H, multiplet).

«112 (b) 2- (2- {2- [2- (4-Hydroxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 185 106551 0.400 g of 2- (2 - {- 2 [2- (4) -methoxymethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine 5 [prepared as described in step (a) above] was dissolved in 5 ml of dioxane and 5 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution. The mixture was then allowed to stand at room temperature for 30 minutes, after which it was concentrated by distillation under reduced pressure. The resulting crude material was dissolved in a small amount of methanol and about 50 mL of ethyl acetate was added to the solution, which was then allowed to stand at room temperature. The crystals purchased from sa-10 were collected by filtration and dried in vacuo to give 0.219 g (56% yield) of the title compound as colorless crystals having a melting point of 132-133.5 ° C.

Nuclear Magnetic Resonance Spectrum (Hexadeuterated Dimethylsulfoxide + D 2 O, 270 MHz), δ ppm: 1.7 - 2.5 (6H, multiplet); 2.6-2.9 (4H, multiplet); 2.80 (3H, singlet); 2.95 - 3.15 (1H, multiplet); 3.25 - 3.45 (1H, multiplet); 3.45 - 3.65 (1H, multiplet); 3.95 - 4.15 (2H, multiplet); 6.67 (2H, doublet, J = 8.6 Hz); 6.86 (1H, triplet, J = 6.9 Hz); 6.9 - 7.05 (3H, multiplet); 7.1-7.25 (2H, multiplet). 1 - «« 186 106551 EXAMPLE 113 (S) -2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 5 113 (a) (S) -l-ethoxycarbonyl-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine

Following a procedure similar to that described in Example 40 (a), 1.08 g (89% yield) of the title compound was obtained as a colorless oil using 0.700 g of 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 20), 1.15 g of (S) -1-ethoxycarbonyl-2- [2- (E-toluenesulfonyloxy) ethyl] pyrrolidine, 0.378 g of potassium t-butoxide and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDCC3.270 MHz), δ ppm: 1.1 - 1.35 (3H, multiplet); 1.75 - 2.1 (5H, multiplet); 2.1 - 2.45 (1H, multiplet); 2.8-3.0 (4H, multiplet); 3.3 - 3.55 (2H, multiplet); 3.88 (3H, singlet); , 3.95-4.2 (5H, multiplet); 6.7 - 6.95 (5H, multiplet); 7.05 - 7.25 (3H, multiplet).

113 (b) (S) -2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methyl- 1 pyrrolidine

Following a procedure similar to that described in Example 38 (a), 0.852 g (94% yield) of the title compound was obtained as a colorless oil using 1.06 g of (S) -1-ethoxycarbonyl-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine [prepared as described in step (a) above], 0.303 g of lithium aluminum hydride and 40 ml of tetrahydrofuran.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: δ 1.5 δ - 2.0 (4H, multiplet); 2.0 - 2.15 (1H, multiplet); 2.2 - 2.4 (2H, multiplet); 2.4 - 2.6 (1H, multiplet); 2.43 (3H, singlet); 2.8 - 3.0 (4H, multiplet); 3.15-3.3 (1H, multiplet); 3.78 (3H, singlet); 3.9 - 4.15 (2H, multiplet); 6.7 - 6.95 (5H, multiplet); 7.1-7.3 (3H, multiplet).

113 (c) (S) -2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 0.829 g of (S) -2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine was dissolved in 10 mL of dioxane and 1.83 mL of a 4N solution of hydrogen chloride in dioxane was added to the solution, which was then concentrated by distillation under reduced pressure. The resulting oil was dissolved in 15 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.741 g (81% yield) of the title compound as colorless crystals having a melting point of 133-135 ° C.

[α] 25: -18.4 ° (c = 1.29, methanol).

* D

30 Nuclear Magnetic Resonance Spectrum (CDCd3.270 MHz), δ ppm: 1.9 - 2.15 (2H, multiplet); 2.15 - 2.4 (2H, multiplet); 188 106551 2.4-2.6 (2H, multiplet); 2.7 - 3.0 (5H, multiplet); 2.76 (3H, singlet); 3.2 - 3.4 (1H, multiplet); Δ 3.78 (3H, singlet); 3.8 - 4.05 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.65 - 6.8 (3H, multiplet); 6.84 (1H, doublet, J = 7.9 Hz); 6.93 (1H, triplet, J = 7.9 Hz); 7.1 - 7.3 (3H, multiplet).

EXAMPLE 114 (R) -2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 114 (a) (R) -1-Ethoxycarbonyl-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine

Performing a procedure similar to that described in Example 40 gave 0.475 g. (yield 86%) of the title compound as a colorless oil using 0.320 g of 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 20), 0.526 g of (R) -1-ethoxycarbonyl-2- [2- (p- toluenesulfonyloxy) ethyl] pynOlidine, 0.173 g of potassium t-25 butoxide and 15 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.1 - 1.35 (3H, multiplet); 1.75 - 2.1 (5H, multiplet); 2.1 - 2.45 (1H, multiplet); 2.8-3.0 (4H, multiplet); ? 189 106551 3.3? 3.55 (2H, multiplet); 3.78 (3H, singlet); 3.95 - 4.2 (5H, multiplet); 6.7 - 6.95 (5H, multiplet); Δ 7.05 - 7.25 (3H, multiplet).

114 (b) (R) -2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine Following a procedure similar to that described in Example 38 (a). , afforded 0.392 g (99% yield) of the title compound as a colorless oil using (R) -1-ethoxycarbonyl-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine [prepared as described in step (a) above], 0.192 g of lithium aluminum hydride and 20 ml of tetrahydrofuran.

15

Nuclear Magnetic Resonance Spectrum (CDQ? 3, 270 MHz), δ ppm: 1.55 - 2.0 (4H, multiplet); 2.0 - 2.15 (1H, multiplet); 2.2 - 2.4 (2H, multiplet); Δ 2.4-2.6 (1H, multiplet); 2.42 (3H, singlet); 2.8-3.0 (4H, multiplet); 3.15-3.3 (1H, multiplet); 3.78 (3H, singlet); 3.9 - 4.15 (2H, multiplet); 6.7 - 6.95 (5H, multiplet); 7.1 - 7.3 (3H, multiplet).

«114 (c) (R) -2- (2- {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 190 106551 0.392 g of (R) -2- (2 - {2- [2- (3-Methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine was dissolved in 7 mL of dioxane and 0.87 mL of a 4N solution of hydrogen chloride in dioxane was added to the solution, which was then concentrated by distillation under reduced pressure. . The resulting oil was dissolved in 10 volumes of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.272 g (67% yield) of the title compound as colorless crystals having a melting point of 133-136 °.

[Α] 25: + 18.8 ° (c = 1.8, methanol).

D

Nuclear Magnetic Resonance Spectrum (CDC ^ 270, 270 MHz), δ ppm: 1.9 - 2.15 (2H, multiplet); 2.15 - 2.4 (2H, multiplet); 2.4 - 2.6 (2H, multiplet); 2.7 - 3.0 (5H, multiplet); 2.77 (3H, singlet); 3.2 - 3.4 (1H, multiplet); 3.77 (3H, singlet); 3.8 - 4.05 (2H, multiplet); * '- 4.15-4.3 (1H, multiplet); 6.65 - 6.8 (3H, multiplet); 6.84 (1H, doublet, J = 7.9 Hz); 6.93 (1H, triplet, J = 7.3 Hz); 7.1-7.3 (3H, multiplet).

(S) -2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine Hydrochloride 191 106551 EXAMPLE 115 5 115 (a) (S) -1- ethoxycarbonyl-2- (2- {2- [2- (3,5-dimethoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine

Following a procedure similar to that described in Example 40 (a) except that a 5: 1 by volume mixture of hexane and ethyl acetate was used as eluent, 0.723 g (93% yield) of the title compound were obtained using 0.450 g of 2- [2- (3,5- dimethoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 27), 0.773 g of (S) -1-ethoxycarbonyl-2- [2- (E-toluenesulfonyloxy) ethyl] pyrrolidine, 0.254 g of potassium t-butoxide and 20 ml of dimethylacetamide .

15

Nuclear Magnetic Resonance Spectrum (CDCf3, 2701 MHz), δ ppm: 1.1 - 1.35 (3H, multiplet); 1.75 - 2.1 (5H, multiplet); 2.1 - 2.45 (1H, multiplet); 2.75 - 3.0 (4H, multiplet); 3.3 - 3.55 (2H, multiplet); 3.76 (6H, singlet); 3.95 - 4.2 (5H, multiplet); 6.3 - 6.4 (3H, multiplet); 6.8 - 6.9 (2H, multiplet); 7.05 - 7.25 (2H, multiplet).

«115 (b) (S) -2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine 192 106551

Following a procedure similar to that described in Example 38 (a), 0.56 g of 5 (yield 93%) of the title compound was obtained as a colorless oil using 0.704 g of (S) -1-ethoxycarbonyl-2- (2- {2- [ 2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine [prepared as described in step (a) above], 0.187 g of lithium aluminum hydride and 35 ml of tetrahydrofuran.

Nuclear Magnetic Resonance Spectrum (CDC (3.270 MHz), δ ppm: 1.6 - 2.0 (4H, multiplet); 2.0 - 2.2 (1H, multiplet); 2.2 - 2.4 (2H, multiplet); 2.4 - 2.65 (1H, multiplet); 2.46 (3H, singlet); 2.75 - 2.95 (4H, multiplet); 3.2 - 3.35 (1H, multiplet); 3.76 (6H) , singlet); 3.9-4.2 (2H, multiplet); 6.3-6.4 (3H, multiplet); 6.8-6.95 (2H, multiplet); 7.05-7.25 ( 2H, multiplet).

115 (c) (S) -2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) -1-methyl-pyrrolidine hydrochloride · * 0.545 g of (S) -2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (b) above] was dissolved in 8 mL of dioxane and 1.11 mL of a 4N solution of hydrogen chloride in dioxane was added to the solution, which was then concentrated by distillation under reduced pressure. The resulting oil was dissolved in 10 mL of ethyl acetate and allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.361 g (60% yield) of the title compound as colorless crystals having a melting point of 125-126 ° C.

[α] D -19.0 ° (c = 1.15, methanol).

5

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: 1.9 - 2.15 (2H, multiplet); 2.15 - 2.4 (2H, multiplet); Δ 2.4 - 2.65 (2H, multiplet); 2.7-3.0 (5H, multiplet); 2.78 (3H, singlet); 3.2 - 3.4 (1H, multiplet); 3.76 (6H, singlet); 3.8-4.05 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.25 - 6.35 (3H, multiplet); 6.84 (1H, doublet, J = 8.6 Hz); 6.94 (1H, triplet, J = 7.3 Hz); Δ 7.15-7.25 (2H, multiplet).

EXAMPLE 116 (e) (S) -2- (2- {2- [2- (3-Difluoromethoxyphenyl) ethyl] phenoxy} ethyl) -1-methyl-pyrrolidine hydrochloride 116 (a) (S) -1-Ethoxycarbonyl- 2- (2- {2- [2- (3-Difluoromethoxyphenyl) ethyl] -9' * phenoxy} ethyl) pyrrolidine Using a procedure similar to that described in Example 40 (a), 0.865 g (yield) was obtained. 99%) of the title compound as a colorless oil using 0.529 g of 2- [2- (3-difluoromethoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 43), 194 106551 0.683 g of (S) -1-ethoxycarbonyl-2- [2- (2- toluenesulfonyloxy) ethyl] pyrrolidine, 0.225 g of potassium t-butoxide and 10 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDCf3, 2701 MHz), δ ppm: δ 1.1-1.35 (3H, multiplet); 1.75 - 2.1 (5H, multiplet); 2.1 - 2.45 (1H, multiplet); 2.90 (4H, singlet); 3.3 - 3.55 (2H, multiplet); Δ 3.9-4.2 (5H, multiplet); 6.47 (1H, triplet, J = 74.6 Hz); 6.8 - 7.0 (4H, multiplet); 7.0 - 7.1 (2H, multiplet); 7.1 - 7.3 (2H, multiplet).

116 116 (b) (S) -2- (2- {2- [2- (3-Difluoromethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine

Following a procedure similar to that described in Example 38 (a), 0.690 g (94% yield) of the title compound was obtained as a colorless oil using 0.850 g of (S) -1-ethoxycarbonyl-2- (2- {2- [2- (3-Difluoromethoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine [prepared as described in step (a) above], 0.175 g of lithium aluminum hydride and 10 ml of tetrahydrofuran.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.55 - 1.95 (4H, multiplet); 1.95 - 2.15 (1H, multiplet); ? 2.15-2.45 (2H, multiplet); 2.40 (3H, singlet); 2.5 - 2.75 (1H, multiplet); 2.8-3.0 (4H, multiplet); ? 195 3.1-3.3 (1H, multiplet); 106551 3.9-4.15 (2H, multiplet); 6.45 (1H, triplet, J = 74.2 Hz); 6.8 - 7.0 (4H, multiplet); Δ 7.0-7.1 (2H, multiplet); 7.15 - 7.3 (2H, multiplet).

116 (c) (S) -2- (2- {2- [2- (3-Difluoromethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 10.

0.690 g of (S) -2- (2- {2- [2- (3-difluoromethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (b) above] was dissolved in 5 ml of dioxane and 0.55 ml of a 4N solution of hydrogen chloride in dioxane was added to the solution, which was then concentrated by distillation under reduced pressure. The resulting oil was dissolved in 15 mL of ethyl acetate and the solution was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.375 g (50% yield) of the title compound as colorless crystals having a melting point of 119-120 ° C.

[α] D = -16.4 ° (c = 2.38, methanol).

20 D

Nuclear Magnetic Resonance Spectrum (CDCd 3,270 MHz), δ ppm: * * 1.95-2.15 (2H, multiplet); 2.15 - 2.4 (2H, multiplet); 2.4 - 2.65 (2H, multiplet); 2.75 - 3.0 (5H, multiplet); 2.79 (3H, singlet); 3.2-3.4 (1H, multiplet); 3.8 - 4.1 (2H, multiplet); 4.15 - 4.3 (1H, multiplet); 6.49 (1H, triplet, J = 73.9 Hz); *.

196 106551 6.75-7.05 (5H, multiplet); 7.1 - 7.35 (3H, multiplet).

EXAMPLE 117 5 (2R, 4R) -4-Hydroxy-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 117 (a) (2R, 4R) ) -4-Benzyloxy-1-ethoxycarbonyl-2- (2- {2- [2- (3-methoxy-10-phenyl) -ethyl] -phenoxy} -ethyl) -pyrrolidine

Following a procedure similar to that described in Example 40 (a), 0.880 g (80% yield) of the title compound was obtained as a colorless oil using 0.500 g of 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 20). , 19 g of 15 (2R, 4R) -4-benzyloxy-1-ethoxycarbonyl-2- [2- (p-toluenesulfonyloxy) ethyl] pyrrolidine, 0.270 g of potassium t-butoxide and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 1.1 - 1.35 (3H, multiplet); 1.75 - 2.1 (2H, multiplet); 2.2 - 2.6 (2H, multiplet); "2.8-3.0 (4H, multiplet); 3.43 (1H, doublet of doublets, J = 4.6 & 11.9 Hz); 3.55-4.3 (7H, multiplet); , 75 (3H, singlet); 4.45 (2H, singlet); 6.65-6.9 (5H, multiplet); ≤7.05-7.4 (8H, multiplet).

197 * 106551 117 (b) (2R, 4R) -1-Ethoxycarbonyl-4-hydroxy-2- (2- {2 - [- (3-methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine

A mixture of 0.853 g of (2R, 4R) -4-benzyloxy-1-ethoxycarbonyl-2- (2- {2- [2- (3-5 methoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine [prepared as described in step ( a) above] and 85 mg of 5% w / w palladium on charcoal in 6 ml of ethanol were stirred under a hydrogen atmosphere at 60 ° C for 7 hours. The mixture was then cooled and the catalyst removed by filtration. The filtrate was concentrated by distillation under reduced pressure and the resulting oil was purified by column chromatography over silica gel using a 1: 1 by volume mixture of hexane and ethyl acetate as eluent to give 0.650 g (93% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCl3, 2770 MHz), δ ppm: 1.1 - 1.35 (3H, multiplet); 1.7 - 2.3 (3H, multiplet); 2.3 - 2.6 (1H, multiplet); 2.8-3.0 (4H, multiplet); 3.46 (1H, doublet of doublets, J = 4.6 & 11.9 Hz); 3.5-3.8 (1H, multiplet); 3.78 (3H, singlet); 3.95 - 4.3 (5H, multiplet); : 4.35 - 4.5 (1H, multiplet); 6.7 - 6.95 (5H, multiplet); 7.1 - 7.3 (3H, multiplet).

25 117 (c) (2R, 4R) -4-Hydroxy-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine

Following a procedure similar to that described in Example 38 (a), 0.553 g (95% yield) of the title compound was obtained as a colorless oil using 0.640 g of (2R, 4R) -1-ethoxycarbonyl-4-hydroxy-2- (2- {2) - [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine 198 106551 [prepared as described in step (b) above], 0.176 g of lithium aluminum hydride and 30 ml of tetrahydrofuran.

Nuclear Magnetic Resonance Spectrum (CDC (,2 3.270 MHz), δ ppm: δ 1.7-2.5 (5H, multiplet); 2.48 (3H, singlet); 2.8-3.0 (5H, multiplet); 3 , 59 (1H, doublet of doublets, J = 5.9 & 10.6 Hz); 3.78 (3H, singlet); δ 3.9-4.2 (2H, multiplet); 4.4-4.5 (1H, multiplet); 6.7-7.0 (5H, multiplet); 7.1-7.3 (3H, multiplet).

117 (d) (2R, 4R) -4-Hydroxy-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine hydrochloride 0.520 g (2R, 4R) - 4-hydroxy-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine [prepared as described in step (c) above] was dissolved in 5 mL of dioxane 20 and 1, 1 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution which was then concentrated by distillation under reduced pressure. The resulting oil was dissolved in 2 mL of methylene chloride and "40 mL of ethyl acetate was added to the solution, which was then allowed to stand at room temperature.

The crystals which precipitated were collected by filtration and dried in vacuo to give 0.420 g (73% yield) of the title compound as colorless crystals having a melting point of 100-102 ° C.

[Α] D: -12.2 ° (c = 1.06, methanol).

D

♦

Nuclear Magnetic Resonance Spectrum (CDQ3 + D220,420 MHz), δ ppm: δ 2.0 - 2.2 (1H, multiplet); 2.3 - 2.65 (3H, multiplet); 2.75-3.1 (5H, multiplet); δ »106551 2.88 (3H, singlet); 3.77 (3H, singlet); 3.8 - 4.3 (4H, multiplet); 4.5534 4.7 (1H, multiplet); Δ 6.7-6.8 (3H, multiplet); 6.83 (1H, doublet, J = 8.1 Hz); 6.92 (1H, triplet, J = 7.3 Hz); 7.1 - 7.3 (3H, multiplet).

EXAMPLE 118 (2R, 4R) -2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) -4-hydroxy-1-methylpyrrolidine hydrochloride 15 118 (a) (2R, 4R) -4-Benzyloxy-1-ethoxycarbonyl-2- (2- {2- [2- (3,5-dimethoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine

Following a procedure similar to that described in Example 40 (a), 0.980 g (78% yield) of the title compound was obtained as a colorless oil using 0.605 g of 2- [2- (3,5-20 dimethoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 27). ), 1.15 g of (2R, 4R) -4-benzyloxy-1-ethoxycarbonyl-2- [2- (p-toluenesulfonyloxy) -ethyl] -pyrrolidine, 0.289 g of potassium t-butoxide and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: δ 1.1 (3H, multiplet); 1.75 - 2.1 (2H, multiplet); 2.2 - 2.55 (2H, multiplet); 2.75-3.0 (4H, multiplet); 3.43 (1H, doublet of doublets, J = 4.6 & 11.9 Hz); 3.55 - 4.3 (7H, multiplet); 3.74 (6H, singlet); * 200 106551 4.45 (2H, singlet); 1. 6.25 - 6.4 (3H, multiplet); 6.75 - 6.95 (2H, multiplet); 7.05 - 7.4 (7H, multiplet).

5,118 (b) (2R, 4R) -1-Ethoxycarbonyl-4-hydroxy-2- (2- {2- [2- (3,5-dimethoxy-phenyl) -ethyl] -phenoxy} -ethyl) -pyrrolidine

A solution of 0.951 g of (2R, 4R) -4-benzyloxy-1-ethoxycarbonyl-2- (2- (2- [2- (3,5-10 dimethoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine and 95 mg of of palladium on charcoal in 6 ml of ethanol was stirred under a hydrogen atmosphere at 60 ° C for 9 hours, then the mixture was cooled and the catalyst was removed by filtration, then the filtrate was concentrated by distillation under reduced pressure, and the resulting oil was purified by column chromatography on 1: 2 by volume mixture of eluent to give 0.717 g (91% yield) of (2R, 4R) -1-ethoxycarbonyl-4-hydroxy-2- (2- {2- [2- (3,5-dimethoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.1 - 1.3 (3H, multiplet); 1.75 - 2.3 (3H, multiplet); 2.3 - 2.65 (1H, multiplet); “2.75-3.0 (4H, multiplet); 3.46 (1H, doublet of doublets, J = 4.6 & 11.9 Hz); 3.5 - 3.8 (1H, multiplet); 3.77 (6H, singlet); 3.95 - 4.3 (3H, multiplet); 4.12 (2H, quartet, J = 7.3 Hz); 4.35 - 4.5 (1H, multiplet); 6.25 - 6.4 (3H, multiplet); 6.83 (1H, doublet, J = 8.6 Hz); 201 106551 6.89 (1H, (tablet, J = 6.6 Hz); 7.1-7.25 (2H, multiplet).

118 (b) (2R, 4R) -4-Hydroxy-2- (2- {2- [2- (3,5-dimethoxyphenyl) ethyl] phenoxy} -5 ethyl) -1-methylpyrrolidine

Following a procedure similar to that described in Example 38 (a), 0.547 g (91% yield) of the title compound was obtained as a colorless oil using 0.693 g of (2R, 4R) -1-ethoxycarbonyl-4-hydroxy-2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) pyrrole-10-dine [prepared as described in step (b) above], 0.178 g of lithium aluminum hydride and 30 ml of tetrahydrofuran.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.1 - 1.3 (3H, multiplet); 1.75 - 2.3 (3H, multiplet); 2.3 - 2.65 (1H, multiplet); 2.75 - 3.0 (4H, multiplet); 3.46 (1H, doublet of doublets, J = 4.6 & 11.9 Hz); 3.5-3.8 (1H, multiplet); 3.77 (6H, singlet); 3.95 - 4.3 (3H, multiplet); : * 4.12 (2H, quartet, J = 7.3 Hz); 4.35 - 4.5 (1H, multiplet); 6.25-6.4 (3H, multiplet); 6.83 (1H, doublet, j = 8.6 Hz); 6.89 (1H, doublet, J = 6.6 Hz); 7.1 - 7.25 (2H, multiplet).

202 106551 118 (c) (2R, 4R) -4-Hydroxy-2- (2- {2- [2- (3,5-dimethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine

Following a procedure similar to that described in Example 38 (a), 0.547 g (91% yield) of the title compound was obtained as a colorless oil using 0.693 g of (2R, 4R) -1-ethoxycarbonyl-4-hydroxy-2- (2- {2) - [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine [prepared as described in step (b) above], 0.178 g of lithium aluminum hydride and 30 ml of tetrahydrofuran.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.75 - 2.5 (5H, multiplet); 2.51 (3H, singlet); 2.75-3.1 (5H, multiplet); 3.62 (1H, doublet of doublets, J = 5.9 & 10.6 Hz); Δ 3.77 (6H, singlet); 3.9 - 4.2 (2H, multiplet); 4.4 - 4.55 (1H, multiplet); 6.3-6.4 (3H, multiplet); 6.84 (1H, doublet, J = 7.9 Hz); 6.91 (1H, doublet, J = 7.3 Hz); 7.1 - 7.25 (2H, multiplet).

· · · 118 (d) (2R, 4R) -2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} ethyl) -4-hydroxy-1-methylpyrrolidine hydrochloride 0.535 g ( 2R, 4R) -4-Hydroxy-2- (2- {2- [2- (3,5-dimethoxyphenyl) ethyl] phenoxy) ethyl) -1-methylpyrrolidine [prepared as described in step (c) above] * dioxane and 1.04 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution which was then concentrated by distillation under reduced pressure. The resulting oil was dissolved in 2 of any methylene chloride and 40 mL of ethyl acetate was added to the solution, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give m 203 106551 0.501 g (84% yield) of the title compound as colorless crystals having a melting point of 134-136 ° C.

<[α]: -12.1 ° (c = 1.15, methanol).

5

Nuclear Magnetic Resonance Spectrum (Hexadeuterated Dimethylsulfoxide + D 2 O, 400 MHz), δ ppm: 2.0 - 2.2 (1H, multiplet); Δ 2.3 - 2.65 (3H, multiplet); 2.7 - 3.1 (5H, multiplet); 2.89 (3H, singlet); 3.76 (6H, singlet); 3.8 - 4.3 (4H, multiplet); 4.55 - 4.65 (1H, multiplet); 6.25-6.4 (3H, multiplet); 6.83 (1H, doublet, J = 8.0 Hz); 6.92 (1H, triplet, J = 7.3 Hz); 7.1 - 7.3 (2H, multiplet).

EXAMPLE 119 (S) -2- (3- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} propyl] -1-methylpyrrolidine hydrochloride 259 (a) (S) -1-Ethoxycarbonyl-2 - (3- {2- [2- (3,5-dimetoksifenvyli) ethyl] phenoxy} propyl) pyrrolidine

Following a procedure similar to that described in Example 40 (a), 1.68 g (yield 98%) of the title compound was obtained as a colorless oil using 1.00 g of 2- [2- (3,5-dimethoxyphenyl) ethyl] phenol. (prepared as described in Preparation Example 27), 1.51 g of 106551204 (S) -1-ethoxycarbonyl-2- [2- (g-toluenesulfonyloxy) propyl] pyrrolidine, 0.478 g of potassium t-butoxide and 17 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: δ 1.15-1.3 (3H, multiplet); 1.5 - 2.1 (8H, multiplet); 2.75 - 3.0 (4H, multiplet); 3.25 - 3.6 (2H, multiplet); 3.76 (6H, singlet); 3.8-4.2 (5H, multiplet); 6.25 - 6.4 (3H, multiplet); 6.8 - 6.95 (2H, multiplet); 7.05 - 7.25 (2H, multiplet).

15 119 (b) (S) -2- (3- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} propyl) -1-methylpyrrolidine

Following a procedure similar to that described in Example 38 (a), 1.22 g (86% yield) of the title compound was obtained as a colorless oil using 1.63 g of (S) -1-ethoxycarbonyl-2- (2- {2- [ 2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} propyl) pyrrolidine [prepared as described in (a) above], 0.419 g of lithium aluminum hydride and 35 ml of tetrahydrofuran.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.4 - 2.3 (8H, multiplet); 2.35 (3H, singlet); 2.4 - 2.65 (2H, multiplet); . 2.75 - 3.0 (4H, multiplet); t 3.1 - 3.25 (1H, multiplet); 3.76 (6H, singlet); 3.9-4.1 (2H, multiplet); 6.25 - 6.4 (3H, multiplet); 205 106551 6.8 - 6.95 (2H, multiplet); 7.05 - 7.25 (2H, multiplet).

119 (c) (S) -2- (2- {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} propyl) -1-methylpyrrolidine hydrochloride 1.19 g of (S) -2- (3 - {2- [2- (3,5-Dimethoxyphenyl) ethyl] phenoxy} propyl) -1-methylpyrrolidine [prepared as described in step (b) above] was dissolved in 8 mL of dioxane and 2.33 mL of a 4N solution of hydrogen chloride in dioxane was added to the solution, which was then concentrated by distillation under reduced pressure. The resulting oil was dissolved in 20 volumes of ethyl acetate and about 4 ml of diethyl ether was added to the solution, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give 0.536 g (41% yield) of the title compound as colorless crystals having a melting point of 101-102 ° C.

[Α] D -19.7 ° (c = 0.94, methanol).

D

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.75 - 2.4 (8H, multiplet); 2.7 - 3.0 (5H, multiplet); 2.72 (3H, singlet); 3.0-3.2 (1H, multiplet); φ 3.77 (6H, singlet); 3.8 - 4.15 (3H, multiplet); 6.25 - 6.4 (3H, multiplet); 6.82 (1H, doublet, J = 7.9 Hz); 6.91 (1H, triplet, J = 7.3 Hz); · ". 7.1 - 7.25 (2H, multiplet).

206 106551 EXAMPLE 120 (S) -3- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} piperidine hydrochloride 120 (a) (S) -lt-Butoxycarbonyl-3- {2- [2- (3) -methoxyphenyl) ethyl] phenoxymethyl} piperidine 0.295 g of a 50% w / w dispersion of sodium hydride in mineral oil was added to a solution of 1.55 g of 2- [2- (3-methoxyphenyl) ethyl] phenol (prepared as described in Preparative Example 21). 60 ml of dimethylacetamide while cooling with ice and stirring, and the mixture was stirred at the same temperature for 15 minutes. 2.50 g of (S) -lt-butoxycarbonyl-3- (p-toluenesulfonyloxymethyl) piperidine were then added to the mixture under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes and then at room temperature for 6 hours, followed by 250 ml of ethyl acetate and 150 ml of water. The aqueous layer was extracted with 50 mL of ethyl acetate once and the ethyl acetate layer and extract were combined, washed twice with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated by distillation under reduced pressure with ethyl acetate. eluent to give 2.78 g (96% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.4 - 1.8 (3H, multiplet); 1.42 (9H, singlet); 1.85 - 2.15 (2H, multiplet); 2.75 - 3.0 (6H, multiplet); 3.78 (3H, singlet); 3.8 - 4.25 (4H, multiplet); 6.7 - 6.9 (5H, multiplet); 7.1 - 7.25 (3H, multiplet).

207 106551 120 (b) (S) -3- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} piperidine hydrochloride 1.00 g of (S) -lt-butoxycarbonyl-3- {2- [2- (3-Methoxyphenyl) ethyl] phenoxymethyl} piper-5-dine [prepared as described in step (a) above] was dissolved in 10 ml of dioxane and 10 ml of a 4N solution of hydrogen chloride in dioxane was added to a solution which was allowed to stand at room temperature for 1 hour and then concentrated. by distillation under reduced pressure. The resulting solid was dissolved in a small amount of methylene chloride and 50 mL of ethyl acetate was added to the solution, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo to give the title compound as colorless crystals having a melting point of 150-152 ° C.

[α] D = -7.46 ° (c = 2.44, methanol).

D

15

Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 1.4 - 1.7 (1H, multiplet); 1.85 - 2.15 (3H, multiplet); 2.45 - 2.65 (1H, multiplet); 2.7 - 3.0 (6H, multiplet); 3.4 - 3.6 (2H, multiplet); 3.76 (3H, singlet); 3.8 - 3.95 (2H, multiplet); 6.65 - 6.85 (4H, multiplet); 6.89 (1H, doublet, J = 7.3 Hz); 7.05 - 7.3 (3H, multiplet).

EXAMPLE 123 3- {2- [2- (3-Difluoromethoxyphenyl) ethyl] phenoxymethyl} piperidine hydrochloride 123 123 (a) t-Butoxycarbonyl-3- {2- [2- (3-difluoromethoxyphenyl) ethyl] ] phenoxymethyl] piperidine

Following a procedure similar to that described in Example 40 (a), 1.55 g (84% yield) of the title compound was obtained as a colorless oil using 1.05 g of 2- [2- (3-difluoro-10-methoxyphenyl) ethyl] phenol (prepared as described in Preparation Example 43), 1.47 g of t-butoxycarbonyl-3- (p-toluenesulfonyloxymethyl) piperidine, 0.45 g of potassium t-butoxide and 20 ml of dimethylacetamide.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: δ 1.35-1.8 (3H, multiplet); 1.42 (9H, singlet); 1.85 - 2.15 (2H, multiplet); 2.7-3.0 (6H, multiplet); 3.75-4.3 (4H, multiplet); 6.46 (1H, triplet, J = 74.6 Hz); 6.8 - 7.0 (4H, multiplet); * 7.0 - 7.1 (2H, multiplet); 7.1-7.3 (2H, multiplet).

123 123 (b) 3- {2- [2- (3-Difluoromethoxyphenyl) ethyl] phenoxymethyl} piperidine hydrochloride • <0.858 g of t-butoxycarbonyl-3- {2- [2- (3-difluoromethoxyphenyl) ethyl] piperidine [ prepared as described in step (a) above] was dissolved in 8 ml of dioxane. 8 ml of a 4N solution of hydrogen chloride in dioxane was then added to the solution while cooling with ice and the solution was allowed to stand at room temperature for one hour. It was then concentrated by distillation under reduced pressure and the resulting oil was dissolved in 50 ml of ethyl acetate. The solution was allowed to stand at room temperature and the crystals which precipitated were collected by filtration and dried in vacuo to give 0.680 g (92% yield) of the title compound as colorless crystals, m.p. 153-154 ° C.

5

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 1.4 - 1.65 (1H, multiplet); 1.85 - 2.2 (3H, multiplet); 2.45 - 2.65 (1H, multiplet); Δ 2.7 - 3.0 (6H, multiplet); 2.87 (4H, singlet); 3.4 - 3.6 (2H, multiplet); 3.8 - 3.95 (2H, multiplet); 6.49 (1H, triplet, J = 73.9 Hz); 6.75 - 7.35 (8H, multiplet).

PREPARATIVE EXAMPLE 1 2-Benzyloxybenzyltriphenylphosphonic chloride 20 g of potassium t-butoxide was added under ice-cooling and stirring to a solution of 152 g of salicyl alcohol in 600 ml of dimethylformamide and the resulting mixture was stirred at room temperature for 30 minutes; 160 ml of benzyl bromide was then added dropwise to the mixture. The reaction mixture was then stirred at 30-40 ° C for 2 hours, after which it was partitioned between ethyl acetate and water. The organic layer was washed twice, each with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The oily residue thus obtained was subjected to column chromatography over silica gel using a 5: 1 by volume mixture of hexane and ethyl acetate as eluent to give 228.5 g (87% yield) of 30-benzyloxybenzyl alcohol as a colorless oil.

210 106551

All this 2-benzyloxybenzyl alcohol thus obtained was dissolved in 500 ml of tetrahydrofuran and 85 ml of thionyl chloride was added dropwise with ice-cooling to the resulting solution. The reaction mixture was then allowed to stand overnight at room temperature, after which it was concentrated by evaporation under reduced pressure to give a dark brown oil. This product was dissolved in toluene and the solution was decolorized by treatment with silica gel for chromatography followed by filtration. The filtrate was concentrated by evaporation under reduced pressure to give 2-benzyloxybenzyl chloride as a yellow oil which was used in the next reaction without further purification.

All this yellow oil was dissolved in 500 mL of toluene and 420 g of triphenylphosphine was added to the resulting solution. The mixture was then heated at reflux for three hours. During heating, white insoluble materials gradually appeared in the reaction mixture. After cooling, the precipitates were collected by filtration and dried in vacuo to give 539.9 g (96% yield) of the title compound as a colorless solid.

15

Nuclear Magnetic Resonance Spectrum (CDC (3, 60 MHz), δ ppm: 4.46 (2H, singlet); 5.28 (2H, doublet, J = 14.0 Hz); 6.5-8.0 (24H, multiplet) .

PREPARATIVE EXAMPLE 2 2-Methoxymethoxybenzyltriphenyl phosphonic chloride 25 2 (a) 2-Methoxymethoxybenzyl chloride 16.4 ml of carbon tetrachloride followed by 44.5 g of triphenylphosphine were added under ice-cooling to a solution of 23.8 g of 2-methoxydimeth the resulting mixture was refluxed for 5 hours. The mixture was then cooled, the insolubles were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography over 106551 silica gel using a 9: 1 by volume mixture of hexane and ethyl acetate as eluent to afford 15.5 g (57% yield) of the title compound as a colorless liquid.

Nuclear Magnetic Resonance Spectrum (CDC δ 3.270 MHz), δ ppm: δ 3.51 (3H, singlet); 4.68 (2H, singlet); 5.26 (2H, singlet); 6.9 - 7.4 (4H, multiplet). ' 2 2 (b) 2-Methoxymethoxybenzyl-triphenyl-phosphonic chloride 32 g of triphenylphosphine were added to a solution of 15.0 g of 2-methoxymethoxybenzyl chloride [prepared as described in step (a) above] in 150 ml of toluene and the resulting mixture was heated under reflux for 14 hours. The reaction mixture was then cooled and the resulting precipitate was collected by filtration, washed with toluene and dried in vacuo to give 21.3 g (59% yield) of the title compound as a colorless solid.

Nuclear Magnetic Resonance Spectrum (Hexadeuterated Dimethylsulfoxide + D 2 O, 270 MHz), δ ppm: δ 3.12 (3H, singlet); 4.65 (2H, singlet); 4.98 (2H, doublet, J = 15.2 Hz); 6.84 (1H, triplet, J = 7.3 Hz); 6.9 - 7.1 (2H, multiplet); 7.2-7.35 (1H, multiplet); 7.7-8.0 (15H, multiplet).

.> · I

212 106551 PREPARATIVE EXAMPLE 3 2- (4-Phenylbutyl) phenol 5 5.28 g of cinnamaldehyde and 19.8 g of 2-benzyloxybenzyltriphenyl phosphonic chloride (prepared as described in Preparation Example 1) were dissolved by heating in 200 ml of acetonitrile, then 4.0] undec-7-ene was added dropwise to the solution. The resulting mixture was then heated at reflux for three hours. The solvent was then removed by distillation under reduced pressure and the resulting residue was partitioned between ethyl acetate-10 and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The oily residue thus obtained was redissolved in 200 ml of ethyl acetate with heating and 50 ml of hexane was added to the solution, after which the precipitated insolubles were filtered off. The filtrate was concentrated by evaporation under reduced pressure and the resulting residue was purified by column chromatography over silica gel using a 9: 1 by volume mixture of hexane and ethyl acetate as eluent. yielding 12.2 g (97.7% yield) of 1- (2-benzyloxyphenyl) -4-phenylbutadiene as a colorless oil.

All of this 1- (2-benzyloxyphenyl) -4-phenylbutadiene was mixed with 300 ml of ethanol and the mixture was stirred at 60 ° C for 5 hours under a hydrogen atmosphere in the presence of 1 g of 5% w / w palladium on charcoal. Thereafter, the catalyst was removed by filtration and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography over silica gel using an 8: 1 by volume mixture of hexane and ethyl acetate as eluent to give 8.34 g (94.4% yield) of the title compound as a colorless solid.

.. Nuclear Magnetic Resonance Spectrum (CDC? 3.60 MHz), δ ppm: 1, -1.9 (4H, multiplet); 2.4 - 2.9 (4H, multiplet); 30 4.64 (1H, singlet); 6.5 - 7.5 (9H, multiplet).

213 106551 PREPARATIVE EXAMPLE 4 2- [4- (2-Methoxyphenyl) butyl] phenol 5

A solution of 980 mg of 2-methoxysimamate in 15 ml of tetrahydrofuran was added to a dispersion of 290 mg of lithium aluminum hydride and 10 ml of tetrahydrofuran while cooling with ice. After the addition was complete, the reaction mixture was stirred at room temperature for 1.5 hours and then sufficient sodium sulfate decahydrate was added slowly while cooling with ice to decompose any excess hydride. Insolubles were filtered off and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography over silica gel using a 3: 1 by volume mixture of hexane and ethyl acetate as eluent to give 640 mg of 3- (2-methoxyphenyl) propanol as a colorless oil.

15

Meanwhile, a solution of 760 mg of dimethyl sulfoxide in 2 mL of methylene chloride was added dropwise to a solution of 740 mg of oxalyl chloride in 12 mL of methylene chloride with stirring at -60 ° C and the mixture was stirred at the same temperature for 10 minutes. Subsequently, a solution of 640 mg of 3- (2-methoxyphenyl) propanol (prepared as described above) in 3 ml of methylene chloride was added dropwise to the mixture and the mixture was stirred for an additional 10 minutes. 1.96 g of triethylamine were then slowly added dropwise to the mixture at the same temperature. The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 minutes and then stirred with water. The methylene chloride was separated, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The oily residue thus obtained was purified by column chromatography over silica gel using a 5: 1 by volume mixture of hexane and ethyl acetate as eluent to give 540 mg of 3- (2-methoxyphenyl) propanal as a colorless oil.

214 106551

Nuclear Magnetic Resonance Spectrum (CDC 3, 270 MHz), δ ppm: 2.72 (2H, triplet, J = 7.3 Hz); 2.95 (2H, triplet, J = 7.3 Hz); 3.82 (3H, singlet); Δ 6.8-6.95 (2H, multiplet); 7.1-7.3 (2H, multiplet); 9.80 (1H, singlet).

By following a procedure similar to that described in Preparation Example 3, first part, all of 3- (2-methoxyphenyl) propanol was prepared as described above, 1.65 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation Example 1) and 1, 01 g of 8-diazabicyclo [5.4.0] undec-7-ene was reacted in 30 ml of acetnitrile. The crude product, which was extracted as described in Preparation Example 3, was purified by column chromatography over silica gel using a 9: 1 by volume mixture of hexane and ethyl acetate as eluent to give 0.98 g of benzyl 2- [4- (2-methoxyphenyl) -1-butenyl] phenyl ether as colorless as an oil.

By following a procedure similar to that described in the last part of Preparation Example 3, the entire benzyl 2- [4- (2-methoxyphenyl) -1-butenyl] phenyl ether, prepared as described above, was dissolved in 50 ml of ethanol and hydrogenated at 50 ° C. atmosphere at atmospheric pressure and 100 mg of 5% w / w palladium on charcoal. sa 6 hours. The crude product thus obtained was purified by column chromatography over silica gel using a 10: 1 by volume mixture of hexane and ethyl acetate as eluent to give 0.44 g of the title compound as a colorless oil.

25

Nuclear Magnetic Resonance Spectrum (CDCl3, 270 MHz), δ ppm: .delta. 1.6-1.75 (4H, multiplet); 2.55 - 2.7 (4H, multiplet); 3.80 (3H, singlet); 30 4.75 (1H, singlet); 6.7 - 7.3 (8H, multiplet).

215 106551 PREPARATIVE EXAMPLE 2- 2- [4- (3-Methoxymethoxyphenyl) butyl] phenol 511.2 g of potassium t-butoxide was added under ice-cooling and stirring to a solution of 12.0 g of 3-hydroxybenzaldehyde in 100 ml of dimethylacetamide and about ten minutes. later, 8.05 g of methoxymethyl chloride was added dropwise to the resulting mixture. The reaction mixture was then stirred at room temperature for 1 hour, then partitioned between ethyl acetate and water. The organic layer was concentrated by distillation under reduced pressure and the residue was purified by column chromatography over silica gel using a 5: 1 by volume mixture of hexane and ethyl acetate as eluent to give 11.1 g (68% yield) of 3-methoxymethoxybenzaldehyde as a colorless oil. 10 g of this colorless oil were dissolved in 100 ml of acetonitrile and 18.3 g (triphenylphosphoranylidene) acetal-15-dehyde was added to the solution. The resulting mixture was then heated at reflux for 5 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue was mixed with a mixture of ethyl acetate and hexane in a ratio of about 2: 1 by volume. The mixture was stirred and the resulting precipitate was filtered off. The filtrate was concentrated by distillation under reduced pressure and the residue was purified by column chromatography over silica gel using a 3: 1 by volume mixture of hexane and ethyl acetate as eluent to give 7.16 g (62% yield) of 3- (3-methoxymethoxyphenyl) -2-propenal as a color.

•

Following a procedure similar to that described in the first part of Preparation Example 3, 7.00 g of 3- (3-methoxymethoxyphenyl) -2-propenal and 18 g of 2-benzyloxybenzyltriphenyl phosphonic chloride (prepared as described in Preparation Example 1) were dissolved in 200 ml of acetonitrile and 5.54 g of 1,8-diazabicyclo [5.4.0] undec-7-ene were added to the mixture and allowed to react. The crude product extracted as described in Preparation Example 3 was purified as described in Preparation Example 3 to give 12.0 g of 1- (2-benzyloxyphenyl) 4- (3-methoxymethoxyphenyl) butadiene as a colorless oil.

216 106551

All this colorless oil was dissolved in 250 mL of ethanol and the resulting solution was stirred for 5 hours at 50 ° C under a hydrogen atmosphere at atmospheric pressure and 500 mg of 5% w / w palladium on charcoal. The catalyst was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography over silica gel using a 3: 1 by volume mixture of hexane and ethyl acetate as eluent to afford 8.46 g (91% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCö3.270 MHz), δ ppm: 1.6 - 1.75 (4H, multiplet); 2.55 - 2.7 (4H, multiplet); 3.49 (3H, singlet); 4.73 (1H, singlet); 5.17 (2H, singlet); 6.74 (1H, doublet, J = 7.9 Hz); 6.8 - 6.95 (4H, multiplet); 7.05 - 7.25 (3H, multiplet).

PREPARATIVE EXAMPLES 6-12 The following phenol derivatives were synthesized in a manner similar to that described in Preparative Examples 3 and 4.

PREPARATIVE EXAMPLE 6 2- [4- (4-Methylphenyl) butyl] phenol; * Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.6 - 1.8 (4H, multiplet); 2.31 (3H, singlet); 2.55 - 2.7 (4H, multiplet); 4.64 (1H, singlet); 217 106551 6.74 (1H, doublet, J = 7.3 Hz); 6.85 (1H, triplet, J = 7.6 Hz); 7.05 - 7.11 (6H, multiplet).

PREPARATIVE EXAMPLE 7 2- [4- (3-Methoxyphenyl) butyl] phenol

Nuclear Magnetic Resonance Spectrum (CDC >3, 270 MHz), δ ppm: δ 1.6-1.8 (4H, multiplet); 2.63 (4H, triplet, J = 6.9 Hz); 3.79 (3H, singlet); 4.72 (1H, singlet); 6.65 - 6.8 (4H, multiplet); 6.85 (1H, triplet, J = 7.9 Hz); 7.0 - 7.25 (3H, multiplet).

PREPARATIVE EXAMPLE 8 2- [4- (3-Isopropylphenyl) butyl] phenol. Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 1.4 (6H, doublet, J = 7.3 Hz); 1.65 - 1.8 (4H, multiplet); 2.55 - 2.7 (4H, multiplet); 2.8-3.0 (1H, multiplet); . * 4.65 (1H, singlet); 6.74 (1H, doublet, J = 7.9 Hz); 6.85 (1H, triplet, J = 7.6 Hz); 7.0-7.2 (6H, multiplet).

218 106551 PREPARATIVE EXAMPLE 9 2- [4- (3-Dimethoxyphenyl) butyl] phenol Nuclear Magnetic Resonance Spectrum (CDQ3, 60 MHz), δ ppm: 1.6 - 1.9 (4H, multiplet); 2.4 - 2.8 (4H, multiplet); 3.77 (6H, singlet); 4.70 (1H, singlet); Δ 6.33 (3H, singlet); 6.6 - 7.3 (4H, multiplet).

PREPARATIVE EXAMPLE 10 2- [4- (3-Methylphenyl) butyl] phenol

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.6 - 1.8 (4H, multiplet); 2.32 (3H, singlet); 2.5 - 2.7 (4H, multiplet); 4.60 (1H, singlet); 6.74 (1H, doublet, J = 6.6 Hz); 6.86 (1H, triplet, J = 7.3 Hz); 6.9 - 7.4 (6H, multiplet).

25 «219 106551 PREPARATIVE EXAMPLE 11 2- [4- (3-Cyanophenyl) butyl] phenol Nuclear Magnetic Resonance Spectrum (CDQ3.60 MHz), δ ppm: 1.5 - 2.0 (4H, multiplet); 2.4 - 3.0 (4H, multiplet); 5.20 (1H, broad singlet); 6.5 - 7.7 (8H, multiplet).

10 PREPARATIVE EXAMPLE 12 2- [4- (4-Methoxyphenyl) butyl] phenol Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.55 - 1.75 (4H, multiplet); 2.5 - 2.7 (4H, multiplet); 3.78 (3H, singlet); 4.73 (1H, singlet); 6.7-6.9 (4H, multiplet); 7.0 - 7.2 (4H, multiplet).

• PREPARATIVE EXAMPLE 13 2- (3-Methyl-4-phenyl-butyl) -phenol

By following a procedure similar to that described in the first part of Preparation Example 3, 1.32 g of α-methylcinnamaldehyde, 4.47 g of 2-benzyloxybenzyltriphenyl phosphonic chloride (prepared as described in Preparation Example 1) and 1.37 g of 30 L, 8 -diazabicyclo [5.4.0] -undec-7-ene was reacted in acetnitrile. The crude product thus obtained was purified by column chromatography as described in the first part of Preparation Example 3, 22026565, to give 2.66 g (90% yield) of 1- (2-benzyloxyphenyl) -3-methyl-4-phenylbutadiene as a colorless oil.

This was then followed by a procedure similar to that described in the last part of Preparation Example 3, all of this 1- (2-benzyloxyphenyl) -3-methyl-4-phenylbutadiene was hydrogenated to give 1.87 g (95% yield) of the title compound. as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDQ3.270 MHz), δ ppm: 0.94 (3H, doublet, J = 6.6 Hz); 1.4 - 1.9 (3H, multiplet); 2.43 (1H, doublet of doublets, J = 7.9 & 13.2 Hz); 2.5 - 2.8 (3H, multiplet); 4.57 (1H, singlet); 6.74 (1H, doublet, J = 7.9 Hz); 6.86 (1H, triplet, J = 7.9 Hz); 7.05 - 7.35 (7H, multiplet).

PREPARATIVE EXAMPLE 14 2- [4- (2-Benzyloxyphenyl) -1-butene-1-yl] phenol. By following a procedure similar to that described in the first part of Preparation Example 3, 2.51 g of 3- (2-benzyloxyphenyl) propanal, 5.6 g of methoxymethoxybenzylphosphonium chloride (prepared as described in Preparation Example 2) and 1.91.25 g of 8 -diazabicyclo [5.4.0] -undec-7-ene was reacted in 50 ml of acetnitrile. The crude product, extracted as described in the first part of Preparation Example 3, was purified by co-column chromatography over silica gel using 10: 1 v / v hexane / ethyl acetate as eluent to give 2.52 g (64% yield) of 1- (2-methoxymethoxyphenyl) 4- (2-Benzyloxyphenyl) -1-butene as a colorless oil.

30 221 106551

All this colorless oil was dissolved in 20 ml of methylene chloride. 5 ml of a 4N solution of hydrogen chloride in dioxane was then added to the solution and the resulting solution was allowed to stand at room temperature for 30 minutes, after which it was concentrated by distillation under reduced pressure. The oily residue thus obtained was purified by column chromatography over silica gel using a 5: 1 by volume mixture of hexane and ethyl acetate as eluent to give 1.60 g (72% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDC63.270 MHz; cis-trans mixture), δ ppm: 2.5 - 2.9 (4H, multiplet); Δ 4.82 & 4.91 (together 1H, each singlet); 5.00 & 5.10 (together 2H, each singlet); 5.9 - 7.5 (15H, multiplet).

PREPARATIVE EXAMPLE 15 2- [4- (2-Naphthyl) butyl] phenol

A solution of 3.00 g of 2-naphtaldehyde and 6.69 g of ethoxycarbonylmethylene triphenylphosphorane in 100 ml of acetnitrile was heated at reflux for 1 hour, after which the reaction mixture was concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography over silica gel using hexane and ethyl acetate. acetate: 4: 1 v / v as eluent to give 4.32 g (99% yield) of ethyl 3- (2-naphthyl) -2-propenoate as a colorless solid.

Ϊ́ 25.29 g of this ethyl 3- (2-naphthyl) -2-propenoate were dissolved in 60 ml of ethanol. The solution was stirred at room temperature for 3 hours under hydrogen atmosphere at atmospheric pressure and 500 mg / 5% w / w palladium on charcoal. Thereafter, the catalyst was removed by filtration and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography over silica gel using a 5: 1 by volume mixture of hexane and ethyl acetate as eluant to afford 4.04 g (93% yield) of the title compound 3- (2-naphthyl) propionate as a colorless oil.

222 106551

Following a procedure similar to that described in the first part of Preparation Example 4, all this ethyl 3- (2-naphthyl) propionate was reacted with 668 mg of lithium aluminum hydride in tetrahydrofuran at room temperature for 1.5 hours. The reaction mixture was then worked up and purified as described in the first part of Preparation Example 4 to give 3.29 g of 3- (2-naphthyl) propanol as a colorless oil.

Then, following a procedure similar to that described in the second part of Preparation Example 4, all of this 3- (2-naphthyl) propanol was reacted with 2.06 g of dimethyl-10 sulfoxide, 3.35 g of oxalyl chloride and 7.34 ml of triethylamine. In 45 ml of methylene chloride. The reaction mixture was worked up and purified as described in the second part of Preparation Example 4 to give 1.74 g (53% yield) of 3- (2-naphthyl) propanal as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDC3 3, 270 MHz), δ ppm: 2.86 (2H, triplet, J = 7.9 Hz); 3.12 (2H, triplet, J = 7.9 Hz); 7.2-7.9 (7H, multiplet); 9.85 (1H, singlet).

By following a procedure similar to that described in the first part of Preparation Example 3, 1.73 g of 3- (2-naphthyl) propanal, prepared as described above, 4.65 g of 2-. benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation Example 1) and 2.15 g of 1,8-diazabicyclo [5.4.0] undec-7-ene were reacted in 200 mL of acetnitrile. The reaction mixture was worked up and purified as described in the first part of Preparation Example 3 to give 2.83 g (82% yield) of 4- (2-naphthyl) -1- (2-benzyloxyphenyl) -1-butene as a colorless oil.

♦ «»

All of this 4- (2-naphthyl) -1- (2-benzyloxyphenyl) -1-butene was catalytically reduced in a manner similar to that described in the second part of this Preparation Example to give 2.60 g of 4- (2-naphthyl) -. 1- (2-benzyloxyphenyl) butane as a colorless oil.

223 106551

All of this 4- (2-naphthyl) -1- (2-benzyloxyphenyl) butane was dissolved in 20 ml of methylene chloride and 9.5 ml of a 1M solution of boron tribromide in methylene chloride was added while cooling with ice and stirring. The resulting mixture was then stirred at the same temperature for one hour. The reaction mixture was then diluted with methylene chloride, washed with water, dried over anhydrous sodium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluent to give 1.56 g (78% yield) of the title compound as a colorless solid.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.6 - 1.9 (4H, multiplet); 2.65 (2H, triplet, J = 7.6 Hz); 2.81 (2H, triplet, J = 6.9 Hz); 4.64 (1H, singlet); 6.73 (1H, doublet, J = 7.9 Hz); 6.85 (1H, triplet, J = 7.9 Hz); 7.0 - 7.9 (9H, multiplet).

PREPARATIVE EXAMPLE 16 2- [4- (1-Naphthyl) butyl] phenol was •

Following a procedure similar to that described in Preparation Example 15, but using 3.0 g of 1-naphtaldehyde and 6.69 g of carboethoxymethylene triphenylphosphorane, 0.88 g of the title compound was obtained as a colorless solid.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.7 - 1.9 (4H, multiplet); 2.68 (2H, triplet, J = 7.3 Hz); 3.12 (2H, triplet, J = 7.3 Hz); 4.73 (1H, singlet); 224 106551 6.76 (1H, doublet, J = 6.6 Hz); 6.87 (1H, triplet, J = 7.3 Hz); 7.04 - 7.6 (6H, multiplet); 7.71 (1H, doublet, J = 7.9 Hz); Δ 7.8-7.95 (1H, multiplet); 8.0 - 8.1 (1H, multiplet).

PREPARATIVE EXAMPLE 17 2- [4- (3-Chlorophenyl) butyl] phenol

A solution of 3.00 g of 3-chlorobenzaldehyde and 6.49 g (triphenylphosphoranylidene) acetaldehyde in 100 ml of acetnitrile was heated at reflux for 5 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting ice-residue was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and enyl acetate as eluent to afford 2.11 g (59% yield) of 3- (3-chlorophenyl). propenal as a solid.

Following a procedure similar to that described in the first to 20 parts of Preparation Example 3, all of this 3- (3-chlorophenyl) -2-propenal was reacted with 6.9 g of 2-benzyloxybenzyltriphenyl phosphonic chloride (prepared as described in Preparation Example 1). and 2.89 g of 1,8-diazabicyclo [5.4.0] undec-7-ene in 100 ml of acetyl ril. The crude product extracted as described in the first part of Preparation Example 3 was purified as described in the first part of Preparation Example 3 to give 4.13 g (25% yield) of 1- (2-benzyloxyphenyl) -4- (3-chlorophenyl) butadiene as an oil.

. 3.50 g of this 1- (2-benzyloxyphenyl) -4- (3-chlorophenyl) butadiene were dissolved in 125 ml of a 4: 1 by volume mixture of tetrahydrofuran and ethanol. The resulting solution was stirred for four hours under a hydrogen atmosphere at atmospheric pressure and 100 mg of 5% w / w palladium on charcoal while cooling with ice. Thereafter, the catalyst was removed by filtration and the filtrate was concentrated by evaporation under reduced pressure. The resulting 225-106551 residue was then purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as the eluent to give 3.06 g (86% yield) of 1- (2-benzyloxyphenyl) -4- (3-chlorophenyl) butane as a colorless oil. .

Following a procedure similar to that described in the last part of Preparation Example 15, a solution of 3.04 g of this 1- (2-benzyloxyphenyl) -4- (3-chlorophenyl) butane in 18 ml of methylene chloride was treated with 8.67 ml. 1M solution of boron tribromide in methylene chloride to eliminate the benzyl group The resulting crude product was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluent to afford 1.82 g (80% yield) of the title compound.

Nuclear Magnetic Resonance Spectrum (CDC (3.270 MHz), δ ppm: 1.55 - 1.8 (4H, multiplet); 2.55 - 2.75 (4H, multiplet); 4.64 (1H, singlet); 6.74 (1H, doublet, J = 7.9 Hz); 6.86 (1H, triplet, J = 7.6 Hz); 7.0 - 7.3 (6H, multiplet).

20 PREPARATION EXAMPLES18 ·

2- [4- (2-Chlorophenyl) butyl] fenoH

Following a procedure similar to that described in the first part of Preparation Example 17, 3.00 g of 2-chlorobenzaldehyde and 7.5 g of (triphenylphosphoranyl, · diene) acetaldehyde were reacted in 100 ml of acetonitrile. The crude product thus obtained was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluent to give 2.44 g (68% yield) of 3- (2-chlorophenyl) 2-O propenal as a solid.

«226 106551

Then, following a procedure similar to that described in the first part of Preparation Example 3, all of this 3- (2-chlorophenyl) -2-propenal was reacted with 7.97 g of 2-benzyloxybenzyltriphenylphosphonic chloride (prepared as described in Preparation Example 1) and 3. , 35 g of 1,8-diazabicyclo [5,40] undec-7-ene. The resulting crude product was purified as described in the first part of Preparation Example 3 to give 4.57 g (90% yield) of 1- (2-benzyloxyphenyl) -4- (2-chlorophenyl) butadiene as an oil.

Following a procedure similar to that described in the last 10 parts of Preparation Example 3, 4.53 g of this 1- (2-benzyloxyphenyl) -4- (2-chlorophenyl) butadiene were dissolved in a 4: 1 by volume mixture of tetrahydrofuran and ethanol and hydrogenated with cooling. on the ice. The reaction mixture was then worked up as described in the latter part of Preparation Example 3 to give 2.86 g (62% yield) of 1- (2-benzyloxyphenyl) -4- (2-chlorophenyl) butane.

15

Finally, following a procedure similar to that described in the last part of Preparation Example 15, all of this 1- (2-benzyloxyphenyl) -4- (2-chlorophenyl) butane was dissolved in 18 mL of methylene chloride and debenzylated with 8.15 mL of a 1M solution of boron tribromide in methylene chloride. The crude product thus obtained was purified by column chromatography over silica gel using a 4: 1 by volume mixture of hexane and ethyl acetate as eluent to give 2.0 g (94% yield) of the title compound as a colorless solid.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 1.55-1.8 (4H, multiplet); 2.5-2.9 (4H, multiplet); 4.66 (1H, singlet); · 6.75 (1H, singlet); 6.75 (1H, doublet, J = 8.6 Hz); 6.86 (1H, triplet, J = 7.3 Hz); 7.0-7.4 (6H, multiplet).

PREPARATIVE EXAMPLE 19 2- (2-Phenylethyl) phenol 227 106551 5.09 g of benzaldehyde and 26.1 g of 2-benzyloxybenzyltriphenyl phosphonic chloride (prepared as described in Preparation Example 1) were dissolved in 100 ml of acetonitrile with heating.

8.04 g of 1,8-diazabicyclo [5.4.0] undec-7-ene was then added dropwise to the solution at 80 ° C with stirring, and the resulting mixture was stirred at the same temperature for 40 minutes. The solvent was then removed by distillation under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. The organic layer was concentrated by distillation under reduced pressure and 100 ml of a 2: 1 by volume mixture of hexane and ethyl acetate was added to the resulting residue and the mixture was agitated. Insolubles were filtered off and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography over silica gel using a 10: 1 by volume mixture of hexane and ethyl acetate as eluent to give 10.4 g (76% yield) of 2-benzyloxystilbene.

All of this 2-benzyloxystilbene was dissolved in 300 ml of ethanol and the resulting solution was stirred at 60 ° C for 3.5 hours in the presence of 1.00 g of 5% w / w palladium on charcoal. The catalyst was removed by filtration and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was then purified by column chromatography on silica gel. Passing through a 4: 1 by volume mixture of hexane and ethyl acetate as the eluent gave 6.41 g (89% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDCC3, 270 MHz), δ ppm: 2.92 (4H, singlet); , 1. 4.64 (1H, singlet); 6.74 (1H, doublet, J = 7.9 Hz); 6.86 (1H, triplet, J = 7.3 Hz); 7.0-7.4 (7H, multiplet).

228 106551 PREPARATION EXAMPLES 20-28

Following a procedure similar to that described in Example 19, the following phenolic derivatives were synthesized using the corresponding aldehyde and 2-benzyloxy-5-benzyltriphenylphosphonium chloride (prepared as described in Preparation Example 1).

PREPARATIVE EXAMPLE 20 2- [2- (3-Methoxyphenyl) ethyl] phenol 10

Nuclear Magnetic Resonance Spectrum (CDC £3, 270 MHz), δ ppm: 2.91 (4H, singlet); 3.79 (3H, singlet); 4.65 (1H, singlet); 6.7 - 6.95 (5H, multiplet); 7.05 - 7.3 (3H, multiplet).

PREPARATIVE EXAMPLE 21 2- [2- (3-Methoxymethoxyphenyl) ethyl] phenol · Nuclear Magnetic Resonance Spectrum (CDCt3,270 MHz), δ ppm: 2.90 (4H, singlet); 3.47 (3H, singlet); 4.78 (1H, singlet); 5.15 (2H, singlet); 6.73 (1H, doublet, J = 7.9 Hz); Δ 6.8-6.95 (4H, multiplet); 7.0 - 7.3 (3H, multiplet).

30 1 229 106551 PREPARATIVE EXAMPLE 22 2- [2- (3,4-Dimethoxyphenyl) ethyl] phenol δ NMR magnetic resonance spectrum (CDC £3, 270 MHz), δ ppm: 2.8 - 3.0 (4H, multiplet); 3.81 (3H, singlet); 3.86 (3H, singlet); 4.71 (1H, singlet); Δ 6.6-6.9 (5H, multiplet); 7.05 - 7.15 (2H, multiplet).

PREPARATIVE EXAMPLE 23 2- [2- (2-Methoxyphenyl) ethyl] phenol

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 2.7 - 2.9 (4H, multiplet); 3.94 (3H, singlet); 6.25 (1H, singlet); 6.7 - 7.0 (4H, multiplet); : * 7.05 - 7.3 (4H, multiplet).

PREPARATIVE EXAMPLE 24 2- [2- (2-Methoxyphenyl) ethyl] phenol

Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 2.31 (3H, singlet); 2.8 - 3.0 (4H, multiplet); 4.70 (1H, singlet); φ ♦ 230 106551 6.74 (1H, doublet, J = 7.9 Hz); 6.87 (1H, triplet, J = 7.6 Hz); 7.0-7.2 (6H, multiplet).

PREPARATIVE EXAMPLE 25 2- [2- (3-Methylphenyl) ethyl] phenol

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: δ 2.33 (3H, singlet); 2.89 (4H, singlet); 4.63 (1H, singlet); 6.75 (1H, doublet, J = 7.9 Hz); 6.87 (1H, triplet, J = 7.9 Hz); 7.0 - 7.25 (6H, multiplet).

PREPARATIVE EXAMPLE 26 2- [2- (4-Ethylphenyl) ethyl] phenol 20

Nuclear Magnetic Resonance Spectrum (CDC ?3, 270 MHz), δ ppm: 1.23 (3H, triplet, J = 7.6 Hz); 2.63 (2H, quartet, J = 7.6 Hz); 2.89 (4H, singlet); ; 4.64 (1H, singlet); 6.75 (1H, doublet, J = 7.9 Hz); 6.87 (1H, triplet, J = 7.6 Hz); 7.05 - 7.2 (6H, multiplet).

PREPARATIVE EXAMPLE 27 2- [2- (3,5-Dimethoxyphenyl) ethyl] phenol 231 106551 5 Nuclear Magnetic Resonance Spectrum (CDC (3.270 MHz), δ ppm: 2.8 - 3.0 (4H, multiplet); 3.75 (6H, singlet); 4.78 (1H, singlet); 6.3-6.4 (3H, multiplet); Δ 6.74 (1H, doublet, J = 8.6 Hz); 6.86 (1H, triplet, J = 8.6 Hz); 7.05 - 7.2 (2H, multiplet).

PREPARATIVE EXAMPLE 28 2- [2- (3,4,5-T-Methoxyphenyl) ethyl] phenol

Nuclear Magnetic Resonance Spectrum (CD3 0, 270 MHz), δ ppm: 2.8 - 3.0 (4H, multiplet); 3.81 (6H, singlet); 3.83 (3H, singlet); : 1. 4.76 (1H, singlet); 6.38 (2H, singlet); 6.75 (1H, doublet, J = 9.9 Hz); 6.86 (1H, triplet, J = 6.9 Hz); 7.05 - 7.15 (2H, multiplet).

PREPARATIVE EXAMPLE 29 2- (3-Phenylpropyl) -phenol 232 106551 By following a procedure similar to that described in the first part of Preparation Example 3 except that an 8: 1 by volume mixture of hexane and ethyl acetate was used, 0.390 g of benzyl 2- (3-phenyl) was obtained. -1-propenyl) phenyl ether using 0.480 g of phenylacetaldehyde, 1.98 g of 2-benzyloxybenzyltriphenylphosphonic chloride, 20 ml of acetnitrile and 0.609 g of 8-diazabicyclo [5.4.0] undec-7-ene.

10

All of this benzyl 2- (3-phenyl-1-propenyl) phenyl ether was treated with hydrogen in the presence of 100 mg of 5% w / w palladium on charcoal in 40 ml of ethanol at room temperature for 3 hours. The insolubles were then removed by filtration and the filtrate concentrated by distillation under reduced pressure to give 0.230 g (83% yield) of the title compound as a colorless oil.

Nuclear Magnetic Resonance Spectrum (CDQ> 3.60 MHz), δ ppm: 1.6 - 2.2 (2H, multiplet); 2.4-3.0 (4H, multiplet); 4.3-5.2 (1H, broad); 6.6-7.4 (9H, multiplet) -: PREPARATIVE EXAMPLE 30 2- (7-Phenylheptyl) phenol

Following a procedure similar to that described in the first part of Preparation Example 3, 1.92 g of 1-benzyloxy-6-phenyl-3,5-hexadiene was obtained as a colorless oil using 1.32 g of cinnamaldehyde, 4.91 g of benzyloxypropyltriphenylphosphonium bromide. 25 ml of acetnitrile and 1.6 g of 8-diazabicyclo [5.4.0] undec-7-ene.

All of this 1-benzyloxy-6-phenyl-3,5-hexadiene was then treated with hydrogen in the presence of 250 mg of 5% w / w palladium on charcoal in 40 mL of ethanol at room temperature • V · 233 106551 for 15 hours, the catalyst removed by filtration and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography over silica gel using a 2: 1 by volume mixture of hexane and ethyl acetate as the eluent to give 1.14 g (88% yield) of 6-phenyl-dexanol as an oil.

5

Following a procedure similar to that described in the second step of Preparation Example 4 except that a 5: 1 by volume mixture of hexane and ethyl acetate was used as eluent, 1.08 g of 6-phenylhexanal as an oil was obtained from 1.15 g of 6-phenylhexanol (prepared as described above), 0.895 g of oxalyl chloride, 1.10 g of dimethylsulfoxide, 3.24 g of triethylamine and 18 ml of methylene chloride.

Following a procedure similar to that described in the first step of Preparation Example 3, 2.00 g of benzyl 2- (7-phenyl-1-heptenyl) phenyl was obtained using 1.08 g of 6-phenylhexanal (prepared as described above), 3.34 g of 2-benzyloxy-15-benzyltriphenylphosphonic chloride (prepared as described in Preparation Example 1), 30 ml of acetnitrile, and 1.03 g of 8-diazabicyclo [5.4.0] undec-7-ene.

All of this benzyl 2- (7-phenyl-1-heptenyl) phenyl ether was then treated with hydrogen in the presence of 200 mg of 5% w / w palladium on charcoal in 250 ml of ethanol at 50 ° C for 20 hours at atmospheric pressure. The insolubles were then removed by filtration and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel using a 5: 1 by volume mixture of hexane and ethyl acetate as eluent to afford 1.03 g (69% yield) of the title compound as a colorless oil. : 25

Nuclear Magnetic Resonance Spectrum (CDC (3.60 MHz), δ ppm: 1.2 - 2.0 (10H, multiplet); 2.3 - 2.9 (4H, multiplet); 4.56 (1H, singlet); 6.5-7.4 (9H, multiplet).

1- (PREPARATIVE EXAMPLE 31) 2- (5-Phenyl-pentyl) -phenol 234 106551 5 By following a procedure similar to that described in the second step of Preparation Example 4, 4-phenylbutanal was prepared in 62% yield from 4-phenylbutanol.

A procedure similar to that described in the first step of Preparation Example 3 was then repeated, except that all of this 4-phenylbutanal was treated to give Bent-10 silyl 2- (5-phenyl-1-pentenyl) phenyl ether in a 67% yield and hydrogenated , as described in the final step of Preparation Example 31 to afford the title compound in 70% yield.

Nuclear Magnetic Resonance Spectrum (CDC £3, 270 MHz), δ ppm: δ 1.35-1.5 (2H, multiplet); 1.5-1.75 (4H, multiplet); 2.55 - 2.7 (4H, multiplet); 4.73 (1H, singlet); 6.75 (1H, doublet, J = 7.9 Hz); 6.86 (1H, triplet, J = 6.9 Hz); 7.05 - 7.35 (7H, multiplet).

• «* · PREPARATIVE EXAMPLE 32 2- (6-Phenylhexyl) phenol

By following a procedure similar to that described in the second step of Preparation Example 4, 5-phenylpentanal was prepared in 77% yield from 5-phenylpentanol.

A procedure similar to that described in the first step of Preparation Example 3 was repeated except that 5-phenylpentanal was treated to give benzyl 2- (6- 235 106551 phenyl-1-hexenyl) phenyl ether in a 67% yield and then hydrogenated as was described in the last step of Preparation Example 31 to afford the title compound in 80% yield.

Nuclear Magnetic Resonance Spectrum (CDC? 3.270 MHz), δ ppm: 1.3 - 1.5 (4H, multiplet); 1.5 - 1.7 (4H, multiplet); 2.5 - 2.7 (4H, multiplet); 4.66 (1H, singlet); Δ 6.74 (1H, doublet, J = 7.9 Hz); 6.86 (1H, triplet, J = 6.9 Hz); 6.05 - 7.4 (7H, multiplet).

PREPARATIVE EXAMPLES 33-43 15

Following a procedure similar to that described in Preparative Example 19, the following phenols were prepared from the corresponding aldehyde and 2-benzyloxybenzyltriphenylphosphonium chloride.

PREPARATIVE EXAMPLE 33 2- '2- [2- (3-Ethoxyphenyl) ethyl] phenol

Nuclear Magnetic Resonance Spectrum (CDQ> 3.270 MHz), δ ppm: δ 1.39 (3H, triplet, J = 7.3 Hz); 2.89 (4H, singlet); 4.00 (2H, quartet, J = 7.3 Hz); 4.65 (1H, singlet); 6.7 - 6.9 (5H, multiplet); 7.05 - 7.25 (3H, multiplet).

PREPARATIVE EXAMPLE 34 2- [2- (2-Ethoxyphenyl) ethyl] phen was 236 106551 δ Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.52 (3H, triplet, J = 6.9 Hz); 2.82 (4H, singlet); 4.18 (2H, quartet, J = 6.9 Hz); 5.90 (1H, singlet); Δ 6.8-7.0 (4H, multiplet); 7.1-7.3 (4H, multiplet).

PREPARATIVE EXAMPLE 35 2- [2- (4-Ethoxyphenyl) ethyl] phenol

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 1.40 (3H, triplet, J = 7.2 Hz); 2.87 (4H, singlet); Δ 4.01 (2H, quartet, J = 7.2 Hz); 4.57 (1H, singlet); · 6.7-6.9 (4H, multiplet); 7.05 - 7.15 (4H, multiplet).

PREPARATIVE EXAMPLE 36 2- [2- (4-Methoxyphenyl) ethyl] phenol

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 2.87 (4H, singlet); 3.79 (3H, singlet); 237 106551 4.58 (1H, singlet); 6.75 (1H, doublet, J = 7.9 Hz); 6.8 - 6.9 (3H, multiplet); 7.05 - 7.15 (4H, multiplet).

PREPARATIVE EXAMPLE37 2- [2- (4-Methylphenyl) ethyl] phenol Nuclear Magnetic Resonance Spectrum (CDC03, 270 MHz), δ ppm: 2.32 (3H, singlet); 2.88 (4H, singlet); 4.57 (1H, singlet); 6.75 (1H, doublet, J = 7.9 Hz); 6.86 (1H, triplet, J = 6.9 Hz); 7.0 - 7.2 (6H, multiplet).

PREPARATIVE EXAMPLE 38 2- [2- (2-Methoxymethoxyphenyl) ethyl] phenol '·' Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 2.75 - 2.95 (4H, multiplet); 3.53 (3H, singlet); Δ 5.30 (2H, singlet); 5.95 (1H, singlet); 6.8 - 7.05 (3H, multiplet); »7.1-7.3 (4H, multiplet).

238 106551 PREPARATIVE EXAMPLE 39 2- [2- (4-Methoxymethoxyphenyl) ethyl] phenol 5 Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 2.87 (4H, singlet); 3.48 (3H, multiplet); 4.68 (1H, singlet); 5.15 (2H, singlet); Δ 6.74 (1H, doublet, J = 7.9 Hz); 6.85 (1H, triplet, J = 6.9 Hz); 6.9 - 7.0 (2H, multiplet); 7.05 - 7.15 (4H, multiplet).

PREPARATIVE EXAMPLE 40 2- [2- (2-Cyanophenyl) ethyl] phenol

Nuclear Magnetic Resonance Spectrum (CDQ3, 270 MHz), δ ppm: 2.9-3.2 (4H, multiplet); 4.99 (1H, singlet); : 6.76 (1H, doublet, J = 7.9 Hz); 6.83 (1H, triplet, J = 7.3 Hz); 7.04 (1H, doublet, J = 7.3 Hz); Δ 7.10 (1H, triplet, J = 7.9 Hz); 7.2 - 7.35 (2H, multiplet); 7.49 (1H, triplet, J = 7.3 Hz); 7.61 (1H, doublet, J = 7.9 Hz).

PREPARATIVE EXAMPLE41 2- [2- (3-Cyanophenyl) ethyl] phenol 239 106551 δ Nuclear Magnetic Resonance Spectrum (CDC? 3.270 MHz), δ ppm: 2.75-3.1 (4H, multiplet); 4.87 (1H, singlet); 6.74 (1H, doublet, J = 7.9 Hz); 6.84 (1H, triplet, J = 7.3 Hz); Δ 7.01 (1H, doublet, J = 7.3 Hz); 7.09 (1H, triplet, J = 7.9 Hz); 7.3 - 7.55 (4H, multiplet).

PREPARATIVE EXAMPLE 42 2- [2- (4-Cyanophenyl) ethyl] phenol

Nuclear Magnetic Resonance Spectrum (CDC (δ, 270 MHz), δ ppm: 2.85-3.1 (4H, multiplet); Δ 4.81 (1H, singlet); 6.74 (1H, doublet, J = 7.9 Hz); 6.84 (1H, triplet, J = 7.3 Hz); 7.01 (1H, doublet, J = 7.3 Hz); 7.09 (1H, triplet, J = 7.9 Hz); 7.27 (2H, doublet, J = 8.6 Hz); 7.55 (2H, doublet, J = 8.6 Hz).

240 106551 PREPARATIVE EXAMPLE43 2- [2- (3-Difluoromethoxyphenyl) ethyl] phenol 5 Nuclear Magnetic Resonance Spectrum (CDC (3.270 MHz), δ ppm: 2.91 (4H, singlet); 4.90 (1H, singlet); 6.44 (1H, triplet, J = 74.6 Hz); 6.7 - 7.2 (6H, multiplet); Δ 7.25 (1H, triplet, J = 7.6 Hz).

PREPARATIVE EXAMPLE 44 2- [2- (3-Chlorophenyl) ethyl] phenol

Following a procedure similar to that described in Example 19, except that a 9: 1 by volume mixture of hexane and ethyl acetate was used as eluent, 28.8 g (90% yield) of 2-benzyloxy-3'-chloro-stilbene were obtained using chlorobenzaldehyde, 59.4 g of 2-benzyloxybenzyltriphenylphosphonic chloride, 300 ml of acetnitrile and 18.0 g of 1,8-diazabicyclo-20 [5.4.0] undec-7-ene.

5.4 g of this 2-benzyloxy-3'-chlorostilbene were treated with hydrogen in the presence of 300 mg of tris (triphenylphosphine) rhodium (I) chloride in a mixture of 60 ml of benzene and 40 ml of ethanol at room temperature for one day. Subsequently, an aqueous sodium hydrogensulphite containing a small amount of sodium metabisulphite was added to the reaction mixture and allowed to react. Insolubles were removed by filtration. Ethyl acetate was added to the filtrate and the mixture was washed once with water and twice with a saturated aqueous solution of sodium chloride. It was then dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography over silica gel using a 20: 1 by volume mixture of hexane and ethyl acetate as eluent to give 5.35 g (98% yield) of benzyl 2- [2- (3-chlorophenyl) ethyl] phenyl ether.

«241 106551

All of this benzyl 2- [2- (3-chlorophenyl) ethyl] phenyl ether was dissolved in 50 mL of methylene chloride and 17 mL of a 1M solution of boron tribromide in methylene chloride was added to the solution while cooling with ice. The mixture was then allowed to stand at room temperature for two hours. The solvent was then removed by distillation under reduced pressure and the resulting residue was purified by column chromatography over silica gel using a 10: 1 by volume mixture of hexane and ethyl acetate as eluent to afford 3.80 g (99% yield) of the title compound as a solid.

Nuclear Magnetic Resonance Spectrum (CDC (3.270 MHz), δ ppm: 2.89 (4H, singlet); 4.5-4.9 (1H, broad); 6.74 (1H, doublet, J = 7.9 Hz); 6.86 (1H, triplet, J = 7.9 Hz); 7.0-7.3 (6H, multiplet).

PREPARATIVE EXAMPLES 45-50

Following a procedure similar to that described in Preparative Example 44, the following phenols were prepared from the corresponding aldehyde and 2-benzyloxybenzyltriphenylphosphonium chloride.

PREPARATIVE EXAMPLE 45 2- [2- (2-Chlorophenyl) ethyl] phenol. Nuclear Magnetic Resonance Spectrum (CDCl 3, 3.270 MHz), δ ppm: 2.85-3.1 (4H, multiplet); 4.77 (1H, singlet); 6.78 (1H, doublet, J = 7.9 Hz); 6.87 (1H, triplet, J = 7.6 Hz); 242 106551 7.1-7.3 (5H, multiplet); 7.3-7.4 (1H, multiplet).

PREPARATIVE EXAMPLE46 2- [2- (4-Chlorophenyl) ethyl] phenol

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: 2.89 (4H, singlet); Δ 4.61 (1H, singlet); 6.74 (1H, doublet, J = 7.9 Hz); 6.85 (1H, triplet, J = 7.3 Hz); 7.0 - 7.15 (4H, multiplet); 7.2 - 7.3 (2H, multiplet).

PREPARATIVE EXAMPLE 47 2- [2- (2-Fluorophenyl) ethyl] phenol 20 Nuclear Magnetic Resonance Spectrum (CDG> 3, 270 MHz), δ ppm: 2.85-3.05 (4H, multiplet); * 4.72 (1H, singlet); 6.77 (1H, doublet, J = 7.9 Hz); 6.86 (1H, triplet, J = 7.3 Hz); 7.0 - 7.25 (6H, multiplet).

t «243 106551 PREPARATIVE EXAMPLE48 2- [2- (3-Fluorophenyl) ethyl] phenol 5 Nuclear Magnetic Resonance Spectrum (CDC (3,270 MHz), δ ppm: 2.91 (4H, singlet); 4.65 (1H, singlet); 6.7 - 7.3 (8H, multiplet).

10 PREPARATIVE EXAMPLE 49 2- [2- (4-Fluorophenyl) ethyl] phenol

Nuclear Magnetic Resonance Spectrum (CDC >3, 270 MHz), δ ppm: 2.89 (4H, singlet); 4.61 (1H, singlet); 6.74 (1H, doublet, J = 8.6 Hz); 6.8 - 7.3 (7H, multiplet).

PREPARATIVE EXAMPLE. 2- [2- (2-Bromophenyl) ethyl] phenol

Nuclear Magnetic Resonance Spectrum (CDCl 3, 270 MHz), δ ppm: δ 2.89 (4H, singlet); 4.67 (1H, singlet); 6.74 (1H, doublet, J = 7.9 Hz); •.

6.86 (1H, triplet, J = 7.3 Hz); 7.0 - 7.2 (4H, multiplet); 7.3-7.4 (2H, multiplet).

244 106551

Toxicity test A 0.5 wt.% Mixture of the compound of Example 117 and tragacanth gum containing 250 mg of compound was administered orally to each of five F344 male rats (7 weeks old and weighed 5,145-155 g) daily for four days and no mortality was observed.

1>

Claims (30)

A process for the preparation of a drug useful as a "- [(heterocyclyl alkoxy) phenyl] -" - arylalkane or ou [(heterocyclyloxy) phenyl] -w-arylalkane compound of general formula (I): V. wherein R 1 represents an unsubstituted naphthyl group or phenyl group which is unsubstituted or substituted by at least one substituent selected from alkyl groups of 1-6 carbon atoms, hydroxy groups, alkoxy groups of 1-6 carbon atoms, halogen atoms, cyano groups, carbamoyl groups and difluoromethoxy groups; D is a simple carbon-acid bond or an alkylene group having 1-4 carbon atoms; R7 is a pyrrolidine ring, morpholine ring or piperidine ring connected to D via a carbon atom of a heterocyclic group, said group R7 being optionally substituted to the carbon atom by a substituent selected from the following groups: alkyl groups of 1-6 carbon atoms, hydroxy groups, alkoxycarbonyloxy groups of 2-7 carbon atoms, alkanoyloxy groups of 1-20 carbon atoms and substituted 2-5 carbon atoms of alkanoyloxy and substituted with a carboxy group and / or optionally substituted to a nitrogen atom with an alkyl group of 1-6 carbon atoms; and 258 106551 A refers to an alkylene group of 2-8 carbon atoms; and for the preparation of pharmaceutically acceptable acid addition salts and esters thereof; WITH THE CONDITION THAT: R7 is other than: 1-alkyl-3-piperidinyl, 1-alkyl-4-piperidinyl or 1-alkyl-3-pyrrolidinyl group; Characterized in that in the process, a compound of formula (II) is HO R ~ A ~ X * 3) (Π) X-7 where A is defined as above, and R1a refers to which is the heist group of R1, without the hydroxy groups (if any) being protected; React with a compound of formula (VII): Z-D-R7a (VII) wherein D is as defined above; R7a refers to which heist group according to R7, except that which heist hydroxy group is protected and which heist heterocyclic nitrogen atom is protected; and Z represents a hydroxy group or group or atom capable of emitting as a nucleophile residue; ; and, if necessary, protecting groups are removed; And if necessary, which is carried out by one or more of the following steps (i) - (iv); (i) when the product is a compound of formula (I) wherein R 1 is a phenyl group substituted by a cyano group, said product is reacted with a base to give a compound of formula (I) wherein R 1 refers to phenyl group which is substituted by a carbamoyl group; (ii) where the substituent R7 is an N-unsubstituted heterocyclic group, said compound is alkylated to give a compound wherein R7 is an N-alkyl substituted heterocyclic group; (iii) alkoxycarbonyl group is converted to a methyl group; and (iv) a salt or ester is formed to obtain a pharmaceutically acceptable salt or ester of a compound of formula (I). A process according to claim 1, characterized in that reagents and reaction conditions are selected, such that the compound of formula (I) is produced, wherein: 25. refers to a single carbon-oxygen bond or an alkylene group, having 1-3 carbon atoms ; and> R7 represents a pyrrolidine ring, a morpholine ring or a piperidine ring connected to D via a carbon atom of the heterocyclic ring, said group R7 being optionally substituted to a carbon atom by a substituent selected from alkyl groups of 1-4 carbon atoms, hydroxy -30 groups, alkoxycarbonyloxy groups of 2-5 carbon atoms, alkanoyloxy groups of 2-20 carbon atoms and carboxy-substituted alkanoyloxy groups of 3 or 4 carbon atoms in an alkanoyl moiety and / or optionally substituted to the nitrogen atom by an alkyl group of 1-4 carbon atoms. . A process according to claim 1 or 2, characterized in that reagents and reaction conditions are selected such that a compound of formula (I) is produced, wherein A represents an alkylene group of 2-7 carbon atoms. 4. A process according to claim 1, characterized in that reagents and reaction conditions are selected to produce a compound of formula (I), wherein: R 1 is an unsubstituted naphthyl group or phenyl group which is unsubstituted or substituted by at least one substituent selected from: alkyl groups of 1-4 carbon atoms, hydroxy groups, alkoxy groups of 1-4 carbon atoms, halogen atoms, cyano groups, carbamoyl groups and difluoromethoxy groups; D is a simple carbon-acid bond or an alkylene group having 1-3 carbon atoms; R7 is a pyrrolidine ring, a morpholine ring, or a piperidine ring connected to D via a carbon atom in the heterocyclic ring, said group R7 being optionally substituted to a carbon atom with a substituent selected from alkyl groups of 1-4 carbon atoms, hydroxy groups, alkoxycarbonyloxy groups having 2-5 carbon atoms, alkanoyloxy groups having ·; 2-20 carbon atoms and carboxy-substituted alkanoyloxy groups having 3 or 4 carbon atoms in the alkanoyl moiety and / or which are optionally substituted for the nitrogen atom by an alkyl group of 1-4 carbon atoms; and 25A refers to an alkylene group of 2-7 carbon atoms. 5. A process according to claim 1 or 4, characterized in that reagents and reaction conditions are selected so as to produce a compound of formula (I), wherein: a refers to a phenyl group which is unsubstituted or substituted with at least a substituent selected from: methyl groups, ethyl groups, difluoromethoxy groups, hydroxy groups, methoxy groups, ethoxy groups, fluorine atoms, chlorine atoms, bromine atoms and cyano groups; 5. refers to a single carbon-acid bond or an alkylene group having 1 or 2 carbon atoms; R7 represents a pyrrolidine ring, a morpholine ring or a piperidine ring connected to D via a carbon atom in the heterocyclic ring, said group R7 being optionally substituted to a carbon atom with a substituent selected from alkyl groups of 1-4 carbon atoms, hydroxy groups, alkoxycarbonyloxy groups of 2-5 carbon atoms, alkanoyloxy groups of 2 or 3 carbon atoms, alkanoyloxy groups of 12-20 carbon atoms and carboxy-substituted alkanoyloxy groups of 3 or 4 carbon atoms in the alkanoyloxy moiety and / or which are optionally substituted by a nitrogen atom 4 carbon atoms; and 15. refers to an alkylene ring having 2-5 carbon atoms. A process according to any one of claims 1, 4 or 5, characterized in that reagents and reaction conditions are selected so as to produce a compound of formula (I), wherein: R1 represents a phenyl group which is unsubstituted or substituted by at least one substituent selected from: methyl groups, ethyl groups, difluoromethoxy groups, hydroxy groups, methoxy groups, ethoxy groups, fluorine atoms, chlorine atoms, bromine atoms and cyano groups; 25. refers to a single carbon-acid bond or an alkylene group having 1 or 2 carbon atoms; R7 is a pyrrolidine ring, a morpholine ring or a piperidine ring attached to • I; ! D via a carbon atom in the heterocyclic ring, said group R7 is optionally substituted for a carbon atom with a substituent selected from the following groups: methyl groups, ethyl groups, hydroxy groups, ethoxycarbonyloxy groups, isopropoxycarbonyloxy groups, t-butoxycarbonyloxy groups, t-butoxycarbonyloxy groups 3 carbon atoms, lauroyloxy groups, alkanoyloxy groups having 14-20 carbon atoms, and carboxy-substituted alkanoyl groups, hydroxy groups, methoxy groups, ethoxy groups, difluoromethoxy groups, fluorine atoms, chloromers, bromine atoms, D is a simple carbon-acid bond or an alkylene group having 1 or 2 carbon atoms; R7 represents a pyrrolidine ring, a morpholine ring or a piperidine ring connected to D via a carbon atom of the heterocyclic ring, said group R7 being optionally substituted to a carbon atom by a substituent selected from: methyl groups, ethyl groups, hydroxy groups, ethoxycarbonyloxy groups, isopropoxy carbonyloxy groups, t-butoxy carbonyloxy groups, 2-3 carbon atoms alkanoyloxy groups, lauroyloxy groups, 14-20 carbon atoms alkanoyloxy groups, carboxy substituted alkanoyloxy substituents having 3 or 4 carbon atoms or one or more carbon atoms in the alkanoyland moiety a methyl or ethyl group; and 15. refers to an alkylene group having 2-5 carbon atoms. A process according to any one of claims 1, 8 or 9, characterized in that reagents and reaction conditions are selected such that a compound of formula (I) is prepared, wherein: R1 represents a phenyl group which is unsubstituted or substituted with at least one substituent selected from: methyl groups, ethyl groups, hydroxy groups, methoxy groups, ethoxy groups, difluoromethoxy groups, fluorine atoms, chlorine atoms, bromine atoms and cyano groups; D is a simple carbon-acid bond or an alkylene group having 1 or 2 carbon atoms; R7 represents a heterocyclic group attached to D via a carbon atom of the heterocyclic group, said heterocyclic group is optionally selected from: pyrrolidinyl groups, 1-methylpyrrolidinyl groups, 265-hydroxy-1-methylpyrrolidinyl groups, piperidinyl groups, piperidinyl groups morpholinyl groups and 4-methylmorpholinyl groups; and A is an alkylene group having 2-5 carbon atoms. 11. A process according to any one of claims 1, 8, 9 or 10, characterized in that reagents and reaction conditions are selected to produce a compound of formula (I), wherein: R1 represents a phenyl group which is unsubstituted or substituted with at least one substituent selected from: methyl groups, hydroxy groups, methoxy groups, ethoxy groups, difluoromethoxy groups, fluorine atoms, chlorine atoms, bromine atoms and cyano groups; D is a simple carbon-acid bond or an alkylene group having 1 or 2 carbon atoms; R7 represents a heterocyclic group attached to D via a carbon atom of the heterocyclic group, said heterocyclic group is selected from: pyrrolidinyl groups, *: - - 1-methylpyrrolidinyl groups, 4-hydroxy-1-methylpyrrolidinyl groups, piperidyl groups,; 1-methylpiperidyl groups, "morpholinyl groups and 4-methyl morpholinyl groups; and A is a tetramethylene group or a pentamethylene group! 30 266 106551 12. A process according to claim 1 for the preparation of a drug useful o- [2- (heterocyclylalkoxy) phenyl] - arylalkane compound, characterized in that the compound is prepared to react with a compound of formula (II) with a compound of formula (VII) to give a compound of formula (I), which compound is 1-methyl-2- {2- [2- (4-phenylbutyl) phenoxy] ethyl} pyrrolidine or a pharmaceutically acceptable acid addition salt thereof . 13. A process according to claim 1 for the preparation of a drug useful o- [2- (heterocyclylalkoxy) phenyl] - arylalkane compound, characterized in that the compound is prepared so that a compound of formula (II) is reacted with a a compound of formula (VII), yielding a compound of formula (I) which is 1-methyl-2- (2- {2- [4- (3-methoxyphenyl) butyl] phenoxy} ethyl) pyrrolidine or a pharmaceutically acceptable acid addition salt thereof. A process according to claim 1 for the preparation of the drug useful Q 1- [2- (heterocyclylalkoxy) phenyl] -w-arylalkane compound, characterized in that the compound is prepared so as to react a compound of formula (II) with a compound of formula (VII) to give a compound of formula (I) which is 1-methyl-2- {2- [2- (2-phenylethyl) phenoxy] ethyl} pyrrolidine or a pharmaceutically acceptable acid addition salt of this. A process according to claim 1 for the preparation of a drug useful as [2- (heterocyclylalkoxy) phenyl] - arylalkane compound, characterized in that the compound is prepared so as to react a compound of formula (II) with a compound Of formula (VII) to give a compound of formula (I) which is 4-hydroxy-1-methyl-2- {2- [2- (2-phenylethyl) phenoxy] ethyl} pyrrolidine or a pharmaceutically acceptable acid addition salt thereof. 16. A process according to claim 1 for the preparation of a medicament useful as a [2- (heterocyclylalkoxy) phenyl] -w-arylalkane compound, characterized in that the compound is prepared so that a compound of formula (II) is reacted with a Compound 106551 267 to give a compound of formula (I) which is 1-methyl-2- (2- {2- [2- (3-methoxyphenyl) ethyl] phenoxy} ethyl) pyrrolidine or a pharmaceutically acceptable acid addition salt thereof. A process according to claim 1 for the preparation of a drug useful o- [2- (heterocyclylalkoxy) phenyl] - arylalkane compound, characterized in that the compound is prepared so that a compound of formula (II) is reacted with a compound of formula (VII) to give a compound of formula (I) which is 2- (2- {2- [2- (3,5-dimethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine or a pharmaceutically acceptable acid addition salt thereof. 18. A process according to claim 1 for the preparation of a drug useful as a- [2- (heterocyclylalkoxy) phenyl] -w-arylalkane compound, characterized in that the compound is prepared so as to react a compound of formula (II) with a compound Compound of formula (VII) to give a compound of formula (I), which compound is 2- (2- {2- [2- (3-fluorophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine or a pharmaceutically acceptable acid addition salt of this. 1 of A process according to claim 1 for the preparation of a drug useful as α- [2- (heterocyclylalkoxy) phenyl] - arylalkane compound, characterized in that the compound is prepared so that a compound of formula (II) is reacted with a a compound of formula (VII), yielding a compound of formula (I), which compound is 2- (2- {2- [2- (3-bromophenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine or a pharmaceutically acceptable acid addition salt thereof. A process according to claim 1 for the preparation of a drug useful as a- [2- (heterocyclylalkoxy) phenyl] -w-arylalkane compound, characterized in that the compound is prepared to react a compound of formula (II) with a compound of formula (VII) to give a compound of formula (I), which compound is 4-hydroxy-1-methyl-2- (2- {2- [2- (3-methoxyphenyl) ethyl]) phenoxy} ethyl) pyrrolidine or a pharmaceutically acceptable acid addition salt thereof. 268 106551 21. A process according to claim 1 for the preparation of a drug useful as a [2- (heterocycloalkylalkoxy) phenyl] - <α> -alkylalkane compound, characterized in that the compound is prepared so as to allow a compound of formula (II) to react with a compound of formula (VII), obtaining a compound of formula (I), which compound is 2- (2- {2- [2- (3-difluoromethoxyphenyl) ethyl] phenoxy} ethyl) -1-methylpyrrolidine or a pharmaceutically acceptable acid addition salt thereof. 22. A process according to claim 1 for the preparation of a drug useful o- [2- (heterocyclylalkoxy) phenyl] - "- arylalkane compound, characterized in that the compound is prepared so that a compound of formula (II) is reacted with a compound of formula (VII) to give a compound of formula (I) which is 2- (2- {2- [2- (3,5-dimethoxyphenyl) ethyl] phenoxy} ethyl) -4-hydroxy 1-methylpyrrolidine or a pharmaceutically acceptable acid addition salt thereof. A process according to claim 1 for the preparation of a drug useful o- [2- (heterocyclylalkoxy) phenyl] -w-arylalkane compound, characterized in that the compound is prepared so that a compound of formula (II) is reacted with a compound of formula (VII) to give a compound of formula (I) which is 1-methyl-2- (2- {2- [4- (2-methoxyphenyl) butyl] phenoxy} ethyl) pyrrolidine or a pharmaceutically acceptable acid addition salt thereof. A process according to claim 1 for the preparation of a drug useful O- [2- (heterocyclylalkoxy) phenyl] - "- arylalkane compound, characterized in that the compound is prepared so that a compound of formula (II) is reacted with a compound of formula (VII) to give a compound of formula (I), which compound is 2- (2- {2- [4- (3,5-dimethoxyphenyl) butyl] phenoxy} ethyl) -1- methyl pyrrolidine or a pharmaceutically acceptable acid addition salt thereof. 25, A process according to claim 1 for the preparation of a medicament useful as a "- [2- (heterocyclylalkoxy) phenyl] -" - arylalkane compound, characterized in that the compound is prepared so that a compound of formula (II) is reacted with a compound 269 106551 to give a compound of formula (I) which is 1-methyl-2- {2- [2- (5-phenylpentyl) phenoxy] ethyl} p) tolidolidine or a pharmaceutical acceptable acid addition salt thereof. 5 »FI I06552B Batch: N0105822 Date: 28/02/2001 Number of pages: 66 Previous document: FI 106551B Next document: FI 106553B