U.S. patent application number 10/870274 was filed with the patent office on 2004-11-25 for azetidine derivatives, their preparation and medicaments containing them.
This patent application is currently assigned to Aventis Pharma S.A.. Invention is credited to Achard, Daniel, Bouchard, Herve, Bouquerel, Jean, Capet, Marc, Grisoni, Serg, Hittinger, Augustin, Malleron, Jean-Luc, Mignani, Serg.
Application Number | 20040235816 10/870274 |
Document ID | / |
Family ID | 26234537 |
Filed Date | 2004-11-25 |
United States Patent
Application |
20040235816 |
Kind Code |
A1 |
Achard, Daniel ; et
al. |
November 25, 2004 |
Azetidine derivatives, their preparation and medicaments containing
them
Abstract
Disclosed are azetidine derivatives of formula: 1 their optical
isomers, their salts, their preparation and medicaments containing
them.
Inventors: |
Achard, Daniel; (Thiais,
FR) ; Bouchard, Herve; (Thiais, FR) ;
Bouquerel, Jean; (Drancy, FR) ; Capet, Marc;
(Vitry-Chatillon, FR) ; Grisoni, Serg; (Choisy Le
Roi, FR) ; Malleron, Jean-Luc; (Marcoussis, FR)
; Mignani, Serg; (Chatenay-Malabry, FR) ;
Hittinger, Augustin; (Igny, FR) |
Correspondence
Address: |
ROSS J. OEHLER
AVENTIS PHARMACEUTICALS INC.
ROUTE 202-206
MAIL CODE: D303A
BRIDGEWATER
NJ
08807
US
|
Assignee: |
Aventis Pharma S.A.
Antony Cedex
FR
|
Family ID: |
26234537 |
Appl. No.: |
10/870274 |
Filed: |
June 17, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10870274 |
Jun 17, 2004 |
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10320344 |
Dec 16, 2002 |
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10320344 |
Dec 16, 2002 |
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09803723 |
Mar 9, 2001 |
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6518264 |
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09803723 |
Mar 9, 2001 |
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PCT/FR99/02147 |
Sep 9, 1999 |
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60119929 |
Feb 12, 1999 |
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Current U.S.
Class: |
514/210.2 ;
514/210.21 |
Current CPC
Class: |
C07D 409/06 20130101;
A61P 1/08 20180101; A61P 9/02 20180101; A61P 25/04 20180101; A61P
25/30 20180101; A61P 27/06 20180101; C07D 205/06 20130101; A61P
21/00 20180101; A61P 25/14 20180101; A61P 25/24 20180101; A61P
11/06 20180101; A61P 37/00 20180101; A61P 3/04 20180101; A61P 9/00
20180101; A61P 25/16 20180101; C07D 401/06 20130101; C07D 417/06
20130101; A61P 25/00 20180101; A61P 33/00 20180101; A61P 25/28
20180101; A61P 25/06 20180101; A61P 1/00 20180101; A61P 37/02
20180101; C07D 409/14 20130101; A61P 25/08 20180101; A61P 25/18
20180101; A61P 31/00 20180101; A61P 31/12 20180101; A61P 31/04
20180101; A61P 35/00 20180101; A61P 5/00 20180101 |
Class at
Publication: |
514/210.2 ;
514/210.21 |
International
Class: |
A61K 031/4709; A61K
031/427 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 11, 1998 |
FR |
98/11342 |
Claims
1. A method of treating a condition selected from the group
consisting of schizophrenia, Parkinson's disease, and Alzeimer's
disease, this method comprising administering to a patient in need
of such treatment an effective amount to treat said condition of a
compound of formula: 13in which R represents 14R.sub.1 represents a
methyl or ethyl radical; R.sub.2 represents either an aromatic
radical selected from phenyl, naphthyl and indenyl, these aromatic
radicals being nonsubstituted or substituted with one or more
substituents selected from halogen, alkyl, alkoxy, --CO-alk,
hydroxyl, --COOR.sub.5, formyl, trifluoromethyl,
trifluoromethylsulfanyl, trifluoromethoxy, nitro,
--NR.sub.6R.sub.7, --CO--NH--NR.sub.6R.sub.7, --N(alk)COOR.sub.8,
cyano, --CONHR.sub.9, --CO--NR.sub.16R.sub.1 .sub.7, alkylsulfanyl,
hydroxyalkyl, --O-alk-NR.sub.12R.sub.13 and alkylthioalkyl or a
heteroaromatic radical selected from benzofuryl, benzothiazolyl,
benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl,
2,3-dihydrobenzothienyl, indolinyl, indolyl, isochromanyl,
isoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl,
1,2,3,4-tetrahydroquinolyl, thiazolyl, and thienyl, these
heteroaromatic radicals being nonsubstituted or substituted with a
substituent selected from halogen, alkyl, alkoxy, --COOR.sub.5,
trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro,
--NR.sub.6R.sub.7, --CO--NH--NR.sub.6R.sub.7, cyano, --CONHR.sub.9,
alkylsulfanyl, hydroxyalkyl and alkylthioalkyl; R.sub.3 and
R.sub.4, which are identical or different, each represent either an
aromatic radical selected from phenyl, naphthyl and indenyl, these
aromatic radicals being nonsubstituted or substituted with one or
more substituents selected from halogen, alkyl, alkoxy, formyl,
hydroxyl, trifluoromethyl, trifluoromethoxy, --CO-alk, cyano,
--COOR.sub.5, --CONR.sub.10R.sub.11, --CO--NH--NR.sub.6R.sub.7,
alkylsulfanyl, hydroxyalkyl, -alk-NR.sub.6R.sub.7 and
alkylthioalkyl; or a heteroaromatic radical selected from
benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,
2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl,
isochromanyl, isoquinolyl, pyrrolyl, quinolyl,
1,2,3,4-tetrahydroisoquinolyl, thiazolyl and thienyl, these
heteroaromatics being nonsubstituted or substituted with a
substituent selected from halogen, alkyl, alkoxy, hydroxyl,
trifluoromethyl, trifluoromethoxy, cyano, --COOR.sub.5,
--CO--NH--NR.sub.6R.sub.7, --CONR.sub.10R.sub.11,
-alk-NR.sub.6R.sub.7, alkylsulfanyl, hydroxyalkyl and
alkylthioalkyl; R.sub.5 is an alkyl or phenyl radical which is
optionally substituted with one or more halogens; R.sub.6 and
R.sub.7, which are identical or different, represent a hydrogen,
alkyl, --COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or
hydroxyalkyl radical or, alternatively, R.sub.6 and R.sub.7
together with the nitrogen atom to which they are attached, form a
3- to 10-membered saturated or unsaturated mono- or bicyclic
heterocycle optionally containing another heteroatom selected from
oxygen, sulfur and nitrogen and being optionally substituted with
one or more alkyl, --COalk, --COOalk, --CO--NHalk, --CS--NHalk,
--CO-alk-NR.sub.14R.sub.15, oxo, hydroxyalkyl, -alk-O-alk or
--CO--NH.sub.2 radicals; R.sub.8 represents an alkyl radical;
R.sub.9 represents a hydrogen or unsubstituted alkyl radical or an
alkyl radical that is substituted with a dialkylamino, phenyl,
cycloalkyl (optionally substituted with --COalk) or a 3- to
10-membered saturated or unsaturated mono- or bicyclic heterocycle
containing one or more heteroatoms selected from oxygen, sulfur and
nitrogen and being optionally substituted with one or more alkyl
radicals; R.sub.10 and R, .sub.1, which are identical or different,
each represent a hydrogen atom or an alkyl radical or,
alternatively, R.sub.10 and R.sub.11, together with the nitrogen
atom to which they are attached, form a 3- to 10-membered saturated
mono- or bicyclic heterocycle optionally containing another
heteroatom selected from oxygen, sulfur and nitrogen and are
optionally substituted with an alkyl radical; R.sub.12 and
R.sub.13, which are identical or different, represent a hydrogen,
alkyl or cycloalkyl radical or, alternatively, R.sub.12 and
R.sub.13, together with the nitrogen atom to which they are
attached, form a 3- to 10-membered saturated mono- or bicyclic
heterocycle optionally containing another heteroatom selected from
oxygen, sulfur and nitrogen and being optionally substituted with
an alkyl, --COalk, --COOalk, --CO--NHalk, --CS--NHalk or
--CO-alk-NR.sub.14R.sub.15 radical, or a 3- to 10-membered
saturated mono- or bicyclic heterocycle containing a heteroatom
selected from oxygen, sulfur and nitrogen; R.sub.14 and R.sub.15,
which are identical or different, represent a hydrogen, alkyl or
--COOalk radical; R.sub.16 and R.sub.17, together with the nitrogen
atom to which they are attached, form a 3-to 10-membered saturated
mono- or bicyclic heterocycle optionally containing another
heteroatom selected from oxygen, sulfur and nitrogen; R' represents
a hydrogen or --CO-alk radical; alk represents an alkyl or alkylene
radical, it being understood that the alkyl and alkylene radicals
and portions and the alkoxy radicals and portions are in the form
of a straight or branched chain and contain 1 to 6 carbon atoms, or
an optical isomer thereof or a salt thereof with an inorganic or
organic acid.
2. The method of claim 1 wherein, in the compound of formula (I)
according to claim 1, when R.sub.6 and R.sub.7, together with the
nitrogen atom to which they are attached, form a 3- to 10-membered
saturated or unsaturated mono- or bicyclic heterocycle, the latter
is an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl,
morpholinyl, imidazolyl, thiomorpholinyl or furyl ring, these rings
being optionally substituted with an alkyl, hydroxyalkyl,
-alk-O-alk, --CONH.sub.2, --COalk, --COOalk, oxo, --CSNHalk,
--CONHalk or --CO-alk-NR.sub.14R.sub.15 in which alk, R.sub.14 and
R.sub.15 have the same meanings as in claim 1, or an optical isomer
thereof or a salt thereof with an inorganic or organic acid.
3. The method of claim 1 wherein, in the compound of formula (I)
according to claim 1, when R.sub.10 and R.sub.11, together with the
nitrogen atom to which they are attached, form a 3- to 10-membered
saturated mono- or bicyclic heterocycle, said heterocycle is an
azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or
thiomorpholinyl ring, these rings being optionally substituted with
an alkyl.
4. The method of claim 1 wherein, in the compound of formula (I)
according to claim 1, when R.sub.12 and R.sub.13, together with the
nitrogen atom to which they are attached, form a 3- to 10-membered
saturated mono- or bicyclic heterocycle, said heterocycle is
selected from azetidinyl, pyrrolidinyl, piperazinyl, piperidyl,
morpholinyl and thiomorpholinyl rings, these rings being optionally
substituted with an alkyl, --COalk, --COOalk, --CO--NHalk,
--CS--NHalk or --CO-alk-NR.sub.14R.sub.15 radical or a 3- to
10-membered saturated mono- or bicyclic heterocycle containing a
heteroatom selected from oxygen, sulfur and nitrogen, alk, R.sub.14
and R.sub.1 .sub.5 having the same meanings as in claim 1, an
optical isomer thereof, or a salt thereof with an inorganic or
organic acid.
5. The method of claim 4 wherein said heterocycle is a
thiomorpholinyl radical.
6. The method of claim 1 wherein, in the compound of formula (I)
according to claim 1, when R.sub.16 and R.sub.17, together with the
nitrogen atom to which they are attached, form a 3- to 10-membered
saturated mono- or bicyclic heterocycle, said heterocycle is a
piperidyl ring, or an optical isomer thereof or a salt thereof with
an inorganic or organic acid.
7. The method of claim 1 wherein, in the compound of formula (I)
according to claim 1, R.sub.9 is an alkyl radical substituted with
a 3- to 10-membered saturated or unsaturated mono- or bicyclic
heterocycle selected from pyrrolidinyl, tetrahydrofuryl,
morpholinyl and pyrrolyl rings, these rings being optionally
substituted with one or more alkyl radicals, an optical isomer
thereof or a salt thereof with an inorganic or organic acid.
8. The method of claim 1 wherein, in the compound of formula (I)
according to claim 1, R represents structure (A) or (B); R'
represents a hydrogen atom or a --COalk radical; R.sub.1 represents
a methyl or ethyl radical; R.sub.2 represents either an aromatic
radical selected from phenyl and naphthyl, these aromatic radicals
being nonsubstituted or substituted with one or more substituents
selected from halogen, alkyl, alkoxy, hydroxyl, --COOR.sub.5,
trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy,
--NR.sub.6R.sub.7, --CO--NH--NR.sub.6R.sub.7, cyano, --CONHR.sub.9,
alkylsulfanyl, hydroxyalkyl, nitro, --CO--NR.sub.16R.sub.17,
--O-alkNR.sub.12R.sub.13 and alkylthioalkyl, or a heteroaromatic
radical selected from isoquinolyl, pyridyl, quinolyl,
1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl and
thienyl, these heteroaromatic radicals being unsubstituted or
substituted with a halogen, alkyl, alkoxy, --COOR.sub.5,
trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy,
--NR.sub.6R.sub.7, --CO--NH--NR.sub.6R.sub.7, cyano, --CONHR.sub.9,
alkylsulfanyl, hydroxyalkyl, nitro or alkylthioalkyl substituent;
R.sub.3 and R.sub.4, which may be identical or different, represent
either an aromatic radical selected from phenyl and naphthyl, these
aromatic radicals being nonsubstituted or substituted with one or
more substituents selected from halogen, alkyl, alkoxy,
trifluoromethyl, trifluoromethoxy, --CONR.sub.10R.sub.11,
-alk-NR.sub.6R.sub.7, hydroxyalkyl, formyl and --COOR.sub.5, or a
heteroaromatic radical selected from thiazolyl and thienyl rings,
these heteroaromatic rings being nonsubstituted or substituted by a
halogen, alkyl, alkoxy, --CONR.sub.10R.sub.11,
-alk-NR.sub.6R.sub.7, hydroxyalkyl or --COOR.sub.5; R.sub.5 is
alkyl or phenyl which is optionally substituted with one or more
halogens; R.sub.6 and R.sub.7, which may be identical or different,
represent a hydrogen, alkyl, --COOalk, cycloalkyl, alkylcycloalkyl,
alk-O-alk or hydroxyalkyl radical or, alternatively, R.sub.6 and
R.sub.7, together with the nitrogen atom to which they are
attached, form a 3- to 10-membered saturated or unsaturated mono-
or bicyclic heterocycle optionally containing another heteroatom
selected from oxygen, sulfur and nitrogen and being optionally
substituted with one or more alkyl, --COalk, --COOalk, --CO--NHalk,
--CS--NHalk, --CO-alk-NR.sub.14R.sub.15, oxo, hydroxyalkyl,
alk-O-alk or --CO--NH.sub.2 radicals; R.sub.9 represents a hydrogen
or unsubstituted alkyl radical or an alkyl radical substituted with
dialkylamino, phenyl, cycloalkyl (optionally substituted with
--COOalk) or a 3- to 10-membered saturated or unsaturated mono- or
bicyclic heterocycle containing one or more heteroatoms selected
from oxygen, sulfur and nitrogen and being optionally substituted
with one or more alkyl radicals; R.sub.10 and R.sub.11, which may
be identical or different, represent a hydrogen or alkyl radical
or, alternatively, R.sub.10 and R.sub.11, together with the
nitrogen atom to which they are attached, form a 3- to 10-membered
saturated mono- or bicyclic heterocycle optionally containing
another heteroatom selected from oxygen, sulfur and nitrogen and
being optionally substituted with an alkyl radical; R.sub.12 and
R.sub.13, which may be identical or different, represent a
hydrogen, alkyl or cycloalkyl radical or, alternatively, R.sub.12
and R.sub.13, together with the nitrogen atom to which they are
attached, form a 3- to 10-membered saturated mono- or bicyclic
heterocycle optionally containing another heteroatom selected from
oxygen, sulfur and nitrogen and being optionally substituted with
an alkyl, --COalk, --COOalk, --CO--NHalk, --CS--NHalk or
--CO-alk-NR.sub.14R.sub.15 radical, or a 3- to 10-membered
saturated mono- or bicyclic heterocycle containing a heteroatom
selected from oxygen, sulfur and nitrogen; R.sub.14 and R.sub.15,
which may be identical or different, represent a hydrogen, alkyl or
--COOalk radical; R.sub.16 and R.sub.17, together with the nitrogen
atom to which they are attached, form a 3-to 10-membered saturated
mono- or bicyclic heterocycle optionally containing another
heteroatom selected from oxygen, sulfur and nitrogen; alk
represents an alkyl or alkylene radical, it being understood that
the alkyl and alkylene radicals and portions and the alkoxy
radicals and portions are in the form of a straight or branched
chain and contain 1 to 6 carbon atoms, an optical isomer thereof or
a salt thereof with an inorganic or organic acid.
9. The method of claim 1 wherein said compound is selected from:
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)meth-
ylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(met-
hylsulfonyl)methyl-(RS)]azetidin-3-ol,
3-acetoxy-1-[bis-(4-chlorophenyl)me-
thyl]-3-[(3,5-difluorophenyl)(methylulfonyl)methyl)methylsulfonylmethyl-(R-
S)]azetidine, their optical isomers and their salts with an
inorganic or organic acid.
10. The method of claim 1 wherein, in the compound of formula (I)
according to claim 1, R represents structure (A) or (B); R'
representing a hydrogen or --COalk radical; R.sub.1 represents a
methyl or ethyl radical; R.sub.2 represents either (I) an aromatic
selected from naphthyl, phenyl, phenyl substituted with one or more
halogen, alkyl, alkoxy, hydroxyl, --COOR.sub.5 (in which R.sub.5
represents an alkyl or phenyl radical optionally substituted with
several halogens) trifluoromethyl, trifluoromethylsulfanyl,
trifluoromethoxy, --NR.sub.6R.sub.7 (in which R.sub.6 and R.sub.7,
which may be identical or different, represent a hydrogen, alkyl or
--COOalk radical or, alternatively, R.sub.6 and R.sub.7, together
with the nitrogen atom to which they are attached, form a
heterocycle selected from pyrrolidinyl, piperidyl, piperazinyl and
piperazinyl substituted with one or more alkyl, --COalk, --COOalk,
--CO--NHalk, --CS--NHalk or --CO-alk-NR.sub.14R.sub.15 radicals (in
which R.sub.14 and R.sub.15, which may be identical or different,
represent a hydrogen or alkyl radical), --CO--NH--NR.sub.6R.sub.7
(in which R.sub.6 and R.sub.7, which may be identical or different,
represent a hydrogen or alkyl radical or, alternatively, R.sub.6
and R.sub.7, together with the nitrogen atom to which they are
attached, form a heterocycle selected from piperidyl, pyrrolyl,
piperazinyl and piperazyl substituted with one or more alkyl
radicals), cyano, --CONHR.sub.9 (in which R.sub.9 represents a
hydrogen or unsubstituted alkyl radical or an alkyl radical
substituted with dialkylamino, phenyl or cycloalkyl (optionally
substituted with --COOalk)) or (II) a heterocycle selected from
pyrrolidinyl (optionally substituted with alkyl), tetrahydrofuryl
or morpholinyl), alkylsulfanyl, hydroxyalkyl, nitro,
--CO--NR.sub.16R.sub.17, (in which R.sub.16 and R.sub.17, together
with the nitrogen atom to which they are attached, form a piperidyl
ring), --O-alkNR.sub.12R.sub.13 (in which R.sub.12 and R.sub.13,
together with the nitrogen atom to which they are attached, form a
morpholino ring) and alkylthioalkyl, or (III) a heteroaromatic
selected from isoquinolyl, pyridyl, quinolyl,
1,2,3,4-tetrahydroisoquinol- yl,
1,2,3,4-tetrahydroquinolyl,thienyl, and thienyl substituted with a
--COOR.sub.5 (in which R.sub.5 represents an alkyl radical) or
--CONHR.sub.9, (in which R.sub.9 represents an alkyl radical);
R.sub.3 and R.sub.4, which may be identical or different, represent
either (IV) an aromatic selected from phenyl and phenyl substituted
with one or more substituents selected from halogen, alkyl, alkoxy,
trifluoromethyl, trifluoromethoxy, hydroxyalkyl, formyl,
--COOR.sub.5 (in which R.sub.5 is an alkyl radical),
--CONR.sub.10R.sub.11 (in which R.sub.10 and R.sub.11, which may be
identical or different, represent a hydrogen or alkyl radical),
-alk-NR.sub.6R.sub.7 (in which R.sub.6 and R.sub.7, which may be
identical or different, represent a hydrogen, alkyl, cycloalkyl,
-alk-O-alk or hydroxyalkyl radical or, alternatively, R.sub.6 and
R.sub.7, together with the nitrogen atom to which they are
attached, form a heterocycle selected from piperidyl (optionally
substituted with alkyl or oxo), pyrrolidinyl (optionally
substituted with alkyl, hydroxyalkyl, -alk-O-alk or
--CO--NH.sub.2), thiomorpholinyl, morpholinyl, pyrrolyl,
piperazinyl optionally substituted with oxo, alkyl, hydroxyalkyl,
and --COOR.sub.5 (in which R.sub.5 is an alkyl radical), or (V) a
heteroaromatic selected from thiazolyl and thienyl; alk represents
an alkyl or alkylene radical, it being understood that the alkyl
and alkylene radicals and portions and the alkoxy radicals and
portions are in the form of a straight or branched chain and
contain 1 to 6 carbon atoms, an optical isomer thereof or a salt
thereof with an inorganic or organic acid.
11. The method of claim 1 wherein said compound is selected from:
1-benzhydryl-3-[(methylsulfonyl)(phenyl)methylene]azetidine,
1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]
azetidine,
1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methylene]
azetidine,
1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methylene]azetidine,
1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methylene]azeti-
dine,
1-benzhydryl-3-[(3-methylsulfonyl)(3-trifluoromethylphenyl)methylene-
]azetidine,
1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfony-
l)-methylene} azetidine,
1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulfony- l)methylene]
azetidine, 1-benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsu-
lfonyl)methylene] azetidine,
1-benzhydryl-3-[(3-cyanophenyl)(methylsulfony- l)methylene]
azetidine, 1-benzhydryl-3-[(3-carbamoylphenyl)(methylsulfonyl-
)methylene]azetidine,
1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)(methyl-
sulfonyl)-methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-diflu-
orophenyl)-(methylsulfonyl)methylene]azetidine,
1-[bis(4-methoxyphenyl)met-
hyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,
1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)met-
hylene] azetidine,
(RS)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]--
1-[(4-methoxyphenyl)(phenyl)methyl]azetidine,
(R)-3-[(3,5-difluorophenyl)(-
methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]
azetidine,
(S)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl-
)(phenyl)methyl] azetidine,
1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,-
5-difluorophenyl)(methylsulfonyl)methylene]azetidine, and
1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulf-
onyl)methylene]azetidine.
12. The method of claims 1, wherein said compound is selected from:
1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl)-phenyl]methyls-
ulfonylmethylene} azetidine,
(RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)m-
ethyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl-
)(methylsulfonyl)methylene]azetidine,
(S)-1-[(4-chlorophenyl)(2,4-dichloro-
phenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]
azetidine,
(RS)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3-
,5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
(R)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorop-
henyl)(methylsulfonyl)methylene]azetidine,
(S)-1-{(4-chlorophenyl)[4-(hydr-
oxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]
azetidine,
(RS)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluo-
rophenyl)(methylsulfonyl)methylene] azetidine,
(S)-1-{(4-chlorophenyl)[4-(-
pyrrolidylmethyl)phenyl]methyl}-3-[(3,5difluorophenyl)(methylsulfonyl)meth-
ylene] azetidine,
1-{(RS)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-m-
ethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]
azetidine,
1-{(R)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)p-
henyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methy-
l}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3-
,5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
1-{(R)-(4-chlorophenyl)
[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3-
,5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
1-{(S)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,-
5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
1-{(RS)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl-
}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R.sub.15)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]-
methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]
azetidine,
1-{(S)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-
-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, and
1-{{(RS)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)-methyl]phenyl}-
methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
their optical isomers and their salts with an inorganic or organic
acid.
13. The method of claim 1, wherein said compound is selected from:
1-{{(R)-(4-chlorophenyl)
{4-[(4-ethoxycarbonylpiperazinyl)-methyl]phenyl}-
methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(S)-(4-chlorophenyl)
{4-[(4-ethoxycarbonylpiperazinyl)-methyl]phenyl}-
methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)
[4-(N-cyclopropyl-N-propylaminomethyl)phenyl]met-
hyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene] azetidine,
1-{(R)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propylaminomethyl)phenyl]methy-
l}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]meth-
yl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-
-difluorophenyl)(methylsulfonyl)methylene] azetidine,
1-{(R)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5--
difluorophenyl)(methylsulfonyl)methylene] azetidine,
1-{(S)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5--
difluorophenyl)(methylsulfonyl)methylene] azetidine,
1-{{(RS)-(4-chlorophenyl)
{4-[bis-(2-methoxyethyl)aminomethyl]-phenyl}met-
hyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(R)-(4-chlorophenyl)
{4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methy-
l}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{{(S)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl-
}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-
-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5--
difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)
[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-
-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-d-
ifluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)
[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsul-
fonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl-
)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine-
, and
1-{(RS)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]met-
hyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
their optical isomers and their salts with an inorganic or organic
acid.
14. The method of claim 1, wherein said compound is selected from:
1-{(R)-(4-chlorophenyl)
[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}--
3-[(3,5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
1-{(S)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5--
difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)
[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5--
difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-d-
ifluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(RS)-(4-chlorophenyl-
)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfo-
nyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)[4-(diethylaminomethyl)phe-
nyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]
azetidine,
1-{(S)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-difl-
uorophenyl)(methylsulfonyl)methylene] azetidine,
1-{(RS)-(4-chlorophenyl)[-
4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[3,5-difluorophenyl)(methyl-
sulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)[4-(piperazin-2-on-4--
yl-methyl)phenyl]methyl}-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]a-
zetidine, 1-{(S)-(4-chlorophenyl)
[4-(piperazin-2-on-4-yl-methyl)phenyl]me-
thyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
1-{(RS)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-d-
ifluorophenyl)(methylsulfonyl)methylene]azetidine,
1-{(R)-(4-chlorophenyl)-
[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulf-
onyl)methylene]azetidine,
1-{(S)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)-
phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(RS)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5--
difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-d-
ifluorophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-{(4-chlorophenyl)-
[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsul-
fonyl)methylene] azetidine,
(RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)p-
henyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluo-
rophenyl)(methylsulfonyl)methylene]azetidine,
(S)-1-{(4-chlorophenyl)[4-(N-
-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)meth-
ylene]azetidine,
(RS)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,-
5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
(R)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-
(methylsulfonyl)methylene]azetidine, and
(S)-1-[(4-carbamoylphenyl)(4-chlo-
rophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidin-
e, their optical isomers and their salts with an inorganic or
organic acid.
15. The method of claim 1, wherein said compound is selected from:
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)-(methylsulfonyl)met-
hylene]azetidine,
1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)-
methylene]azetidine,
1-benzhydryl-3-[(3-methylsulfanylmethyl)phenyl)]-(met-
hylsulfonyl)methylene] azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3-cyan-
ophenyl)-(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl-
]-3-[(3-carbamoylphenyl)-(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)-(methylsulfonyl)methyl-
ene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxyphenyl)-(methyls-
ulfonyl)methylene] azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulf-
onyl)-(3-pyrrolidinylphenyl)methylene]azetidine,
1-[bis(4-chlorophenyl)met-
hyl]-3-[(3-hydroxymethyl-phenyl)(methylsulfonyl)-methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)-
phenyl]methylene} azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfo-
nyl)-(3-trifluoromethylsulfanylphenyl)(methylsulfonyl)-methylene]azetidine-
,
1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)me-
thylene]azetidine,
1-[bis(2-fluorophenyl)methyl]-3-[3,5-difluorophenyl)-(m-
ethylsulfonyl)methylene] azetidine,
1-[bis(3-fluorophenyl)methyl]-3-[(3,5--
difluorophenyl)-(methylsulfonyl)methylene] azetidine,
(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)-
methylene] azetidine,
(R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(met-
hylsulfonyl)(phenyl)methylene]azetidine,
(S)-1-[(4-chlorophenyl)(thiazol-2-
-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,
(RS)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methy-
lsulfonyl)methylene]azetidine,
(R)-1-[(4-chlorophenyl)(thien-2-yl)methyl]--
3-[(3,5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
(S)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methyl-
sulfonyl)methylene] azetidine,
1-benzhydryl-3-[(ethylsulfonyl)(phenyl)meth- ylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-{{3-[N-(4-methylpiperazin-
yl)carbamoyl]phenyl} (methylsulfonyl)methylene} azetidine,
1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2-dimethylcarbohydrazido)-phenyl](-
methylsulfonyl)methylene} azetidine,
1-[bis(thien-2-yl)methyl]-3-[3,5-difl-
uorophenyl)(methylsulfonyl)-methylene]azetidine,
1-[bis(p-tolyl)methyl]-3-- [(methylsulfonyl)(phenyl)methylene]
azetidine, 1-[(4-chlorophenyl)(4-hydro-
xymethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]az-
etidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenyl)-(methylsul-
fonyl)methylene]azetidine,
(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
(R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(meth-
ylsulfonyl)methylene]azetidine,
(S)-1-[(4-chlorophenyl)(thiazol-2-yl)methy-
l]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien--
5-yl)methylene]azetidine, and
(RS)-1-[bis(4-chlorophenyl)methyl]-3-hydroxy-
-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methyl]azetidine,
their optical isomers and their salts with an inorganic or organic
acid.
16. The method of claim 1, wherein said compound is selected from:
1-[bis(4-chlorophenyl)methyl]-3-[(2-isobutylaminocarbonylthien-5-yl)(meth-
ylsulfonyl)methylene]azetidine,
1-[bis(4-chlorophenyl)methyl]-3-[(3-methox-
ycarbonylphenyl)(methylsulfonyl)methyl-(RS)azetidin-3-ol,
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-4-yl)methyl-(RS-
)azetidin-3-ol,
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin--
3-yl)methyl-(RS)azetidin-3-ol,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-
-ylidene}-methanesulfonylmethyl)-N-(3-morpholin-4-yl-propyl)benzamide,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethy-
l)-N-(3-dimethylaminopropyl)benzamide,
3-({1-[bis(4-chlorophenyl)methyl]az-
etidin-3-ylidene}-methanesulfonylmethyl)-N-(2-pyrrolidin-1-ylethyl)benzami-
de,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylme-
thyl)-N-(2-dimethylamino-1-methylethyl)benzamide,
3-({1-[bis(4-chloropheny-
l)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-piperidin-1-ylbenzam-
ide,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylm-
ethyl)-N-isobutylbenzamide,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl-
idene}-methanesulfonylmethyl)-N-(3-imidazol-1-ylpropyl)benzamide,
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethy-
l)-N-(2-dimethylaminoethyl)benzamide,
3-({1-[bis-(4-chlorophenyl)methyl]az- etidin-3-ylidene}
methanesulfonylmethyl)benzoic acid N'-methylhydrazide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmeth-
yl)-N-(2-morpholin-4-ylethyl)benzamide,
3-({1-[bis-(4-chlorophenyl)methyl]-
azetidin-3-ylidene}-methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl-
)benzamide, 3-({1-[bis-(4-chlorophenyl)methyl]
azetidin-3-ylidene}-methane-
sulfonylmethyl)-N-(2,2-dimethylpropyl)benzamide,
3-({1-[bis-(4-chloropheny-
l)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-cyclohexylmethylbenz-
amide, and
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesu-
lfonylmethyl)-N-cyclopropylmethylbenzamide, their optical isomers
and their salts with an inorganic or organic acid.
17. The method of claim 1, wherein said compound is selected from:
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmeth-
yl)-N-(2-methylbutyl)benzamide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-
-3-ylidene}-methanesulfonylmethyl)-N-(2-phenylpropyl)benzamide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmeth-
yl)-N-(tetrahydrofuran-2-ylmethyl)benzamide,
3-({1-[bis-(4-chlorophenyl)me-
thyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2,2-diphenylethyl)benza-
mide,
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfony-
lmethyl)-N-(2-ethylbutyl)benzamide,
4-{[3-({1-[bis(4-chlorophenyl)methyl]a-
zetidin-3-ylidene}methanesulfonylmethyl)benzoylamino]methyl}cyclohexanecar-
boxylic acid methyl ester,
2-amino-1-{4-[3-({1-[bis-(4-chlorophenyl)methyl-
]-azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}ethanone,
(2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamic
acid tert-butyl ester,
1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylide- ne}
methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-methylaminoethanone,
(2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamic
acid tert-butyl ester,
4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yli-
dene}methanesulfonylmethyl)phenyl]piperazine-1-carbothioic acid
N-methylamide,
4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}met-
hanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid
N-methylamide,
4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid methyl
ester,
1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmet-
hyl)phenyl]-4-isobutylpiperazine,
1-[3-({1-[bis(4-chlorophenyl)methyl]azet- idin-3-ylidene}
methanesulfonylmethyl)phenyl]-4-ethylpiperazine, 4-acetyl
1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazine,
1-{4-[3-({1-[bis(4-chlorophenyl)-
methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-d-
imethylaminoethanone,
1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylide-
ne}methanesulfonylmethyl)phenyl]piperazine,
4-[3-({1-[bis(4-chlorophenyl)m-
ethyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxy-
lic acid tert-butyl ester,
1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5--
difluorophenyl)(methylsulfonyl)methylene]azetidine,
3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(-
methylsulfonyl)methyl-(RS)azetidine, (RS)-4-[4-((4-chlorophenyl)
{3-[(3,5-difluorophenyl)-methanesulfonylmethylene]azetidin-1-yl}methyl)be-
nzyl]morpholine, and
4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfo-
nylmethyl]phenoxy} butyl)morpholine,
4-(4-{3-[(1-benzhydrylazetidin-3-ylid-
ene)methanesulfonylmethyl]phenoxy}propyl)morpholine, their optical
isomers and their salts with an inorganic or organic acid.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/320,344, filed Dec. 16, 2002, which is a continuation of
U.S. application Ser. No. 09/803,723, filed Mar. 9, 2001, now U.S.
Pat. No. 6,518,264 which is a continuation of International
Application No. PCT/FR99/02147, filed Sep. 9, 1999, which, in turn,
claims the benefit of U.S. Provisional Application No, 60/119,929,
filed on Feb. 12, 1999, and of French Patent Application
FR98/11342, filed on Sep. 11, 1998.
SUMMARY OF THE INVENTION
[0002] The present invention relates to azetidine derivatives of
formula: 2
[0003] their optical isomers, their salts, their preparation and
medicaments containing them, as well as to methods of using these
derivatives to treat a variety of medical conditions and
disorders.
DETAILED DESCRIPTION
[0004] In formula (I),
[0005] R represents a chain 3
[0006] R.sub.1 represents a methyl or ethyl radical,
[0007] R.sub.2 represents either an aromatic chosen from phenyl,
naphthyl or indenyl, these aromatics being nonsubstituted or
substituted with one or more halogens, alkyl, alkoxy, --CO-alk,
hydroxyl, --COOR.sub.5, formyl, trifluoromethyl,
trifluoromethylsulfanyl, trifluoromethoxy, nitro,
--NR.sub.6R.sub.7, --CO--NH--NR.sub.6R.sub.7, --N(alk)COOR.sub.8,
cyano, --CONHR.sub.9, --CO--NR.sub.16R.sub.17, alkylsulfanyl,
hydroxyalkyl, --O-alk-NR.sub.12R.sub.13 or alkylthioalkyl or a
heteroaromatic chosen from the benzofuryl, benzothiazolyl,
benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl,
2,3-dihydrobenzothienyl, indolinyl, isochromanyl, isoquinolyl,
pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl,
1,2,3,4-tetrahydroquinolyl, thiazolyl, or thienyl rings, it being
possible for these heteroaromatics to be nonsubstituted or
substituted with a halogen, alkyl, alkoxy, --COOR.sub.5,
trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro,
--NR.sub.6R.sub.7, --CO--NH--NR.sub.6R.sub.7, cyano, --CONHR.sub.9,
alkylsulfanyl, hydroxyalkyl or alkylthioalkyl,
[0008] R.sub.3 and R.sub.4, which are identical or different,
represent either an aromatic chosen from phenyl, naphthyl or
indenyl, these aromatics being nonsubstituted or substituted with
one or more halogens, alkyl, alkoxy, formyl, hydroxyl,
trifluoromethyl, trifluoromethoxy, --CO-alk, cyano, --COOR.sub.5,
--CONR.sub.10R.sub.11, --CO--NH--NR.sub.6R.sub.7, alkylsulfanyl,
hydroxyalkyl, -alk-NR.sub.6R.sub.7 or alkylthioalkyl; or a
heteroaromatic chosen from benzofuryl, benzothiazolyl,
benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl,
2,3-dihydrobenzothienyl, furyl, isochromanyl, isoquinolyl,
pyrrolyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl or
thienyl rings, it being possible for these heteroaromatics to be
nonsubstituted or substituted with a halogen, alkyl, alkoxy,
hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, --COOR.sub.5,
--CO--NH--NR.sub.6R.sub.7, --CONR.sub.10R.sub.11,
-alk-NR.sub.6R.sub.7, alkylsulfanyl, hydroxyalkyl or
alkylthioalkyl;
[0009] R.sub.5 is an alkyl or phenyl radical which is optionally
substituted with one or more halogen atoms,
[0010] R.sub.6 and R.sub.7, which are identical or different,
represent a hydrogen atom or an alkyl, --COOalk, cycloalkyl,
alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or
alternatively R.sub.6 and R.sub.7 together form with the nitrogen
atom to which they are attached a 3- to 10-membered saturated or
unsaturated mono- or bicyclic heterocycle optionally containing
another heteroatom chosen from oxygen, sulfur and nitrogen and
being optionally substituted with one or more alkyl, --COalk,
--COOalk, --CO--NHalk, --CS--NHalk, --CO-alk-NR.sub.14R.sub.15,
oxo, hydroxyalkyl, -alk-O-alk or --CO--NH.sub.2 radicals,
[0011] R.sub.8 represents an alkyl radical,
[0012] R.sub.9 represents a hydrogen atom or an alkyl radical or an
alkyl radical substituted with a dialkylamino, phenyl, cycloalkyl
(optionally substituted with --COOalk) or a 3- to 10-membered
saturated or unsaturated mono- or bicyclic heterocycle optionally
containing one or more heteroatoms chosen from oxygen, sulfur and
nitrogen and being optionally substituted with one or more alkyl
radicals,
[0013] R.sub.10 and R.sub.11, which are identical or different,
represent a hydrogen atom or an alkyl radical or alternatively
R.sub.10 and R.sub.11 together form with the nitrogen atom to which
they are attached a 3- to 10-membered saturated mono- or bicyclic
heterocycle optionally containing another heteroatom chosen from
oxygen, sulfur and nitrogen and being optionally substituted with
an alkyl radical,
[0014] R.sub.12 and R.sub.13, which are identical or different,
represent a hydrogen atom or an alkyl or cycloalkyl radical or
alternatively R.sub.12 and R.sub.13 together form with the nitrogen
atom to which they are attached a 3- to 10-membered saturated mono-
or bicyclic heterocycle optionally containing another heteroatom
chosen from oxygen, sulfur and nitrogen and being optionally
substituted with an alkyl, --COalk, --COOalk, --CO--NHalk,
--CS--NHalk or --CO-alk-NR.sub.14R.sub.15 radical or a 3- to
10-membered saturated mono- or bicyclic heterocycle containing a
heteroatom chosen from oxygen, sulfur and nitrogen,
[0015] R.sub.14 and R.sub.15, which are identical or different,
represent a hydrogen atom or an alkyl or --COOalk radical,
[0016] R.sub.16 and R.sub.17 together form with the nitrogen atom
to which they are attached a 3- to 10-membered saturated mono- or
bicyclic heterocycle optionally containing another heteroatom
chosen from oxygen, sulfur and nitrogen,
[0017] R' represents a hydrogen atom or a --CO-alk radical, alk
represents an alkyl or alkylene radical.
[0018] In the preceding definitions and in those which follow,
unless otherwise stated, the alkyl and alkylene radicals and
portions and the alkoxy radicals and portions are in the form of a
straight or branched chain and contain 1 to 6 carbon atoms.
[0019] Among the alkyl radicals, there may be mentioned methyl,
ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, pentyl and hexyl radicals. Among the alkoxy radicals,
there may be mentioned methoxy, ethoxy, n-propoxy, iso-propoxy,
n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and pentyloxy
radicals.
[0020] The term halogen comprises chlorine, fluorine, bromine and
iodine.
[0021] When R.sub.2 and/or R.sub.3 and/or R.sub.4 represent
independently a substituted phenyl, the latter is preferably mono-,
di- or trisubstituted.
[0022] When R.sub.6 and R.sub.7 together form with the nitrogen
atom to which they are attached a 3- to 10-membered saturated or
unsaturated mono- or bicyclic heterocycle, the latter is preferably
an azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl,
imidazolyl, thiomorpholinyl or furyl ring, these rings being
optionally substituted with an alkyl, hydroxyalkyl, -alk-O-alk,
--CONH.sub.2, --COalk, --COOalk, oxo, --CSNHalk, --CONHalk or
--CO-alk-NR.sub.14R.sub.15 radical and, in particular, with a
methyl, ethyl, propyl, isobutyl, acetyl,
N,N-dimethylaminomethylcarbonyl, methyloxycarbonyl,
methylcarbamoyl, methylthiocarbamoyl, N-methylaminomethylcarbonyl,
N-methyl-N-tertbutoxyca- rbonylaminomethylcarbonyl, oxo,
--CSNHCH.sub.3 or --CONHCH.sub.3 radical.
[0023] When R.sub.10 and R.sub.11, together form with the nitrogen
atom to which they are attached a 3- to 10-membered saturated mono-
or bicyclic heterocycle, the latter is preferably an azetidinyl,
pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or
thiomorpholinyl ring, these rings being optionally substituted with
an alkyl.
[0024] When R.sub.12 and R.sub.13 form together with the nitrogen
atom to which they are attached a 3- to 10-membered saturated mono-
or bicyclic heterocycle, the latter is preferably an azetidinyl,
pyrrolidinyl, piperazinyl, piperidyl, morpholinyl or
thiomorpholinyl ring, these rings being optionally substituted with
an alkyl, --COalk, --COOalk, --CO--NHalk, --CS--NHalk or
--CO-alk-NR.sub.14R.sub.15 radical or a 3- to 10-membered saturated
mono- or bicyclic heterocycle containing a heteroatom chosen from
oxygen, sulfur and nitrogen, and, in particular, with a
thiomorpholinyl radical.
[0025] When R.sub.16 and R.sub.17 together form with the nitrogen
atom to which they are attached a 3- to 10-membered saturated mono-
or bicyclic heterocycle, the latter is preferably a piperidyl
ring.
[0026] When R.sub.9 represents an alkyl radical substituted with a
3- to 10-membered saturated or unsaturated mono- or bicyclic
heterocycle optionally containing one or more heteroatoms chosen
from oxygen, sulfur and nitrogen, the latter is preferably a
pyrrolidinyl, tetrahydrofuryl, morpholinyl or pyrrolyl ring, these
rings being optionally substituted with one or more alkyl
radicals.
[0027] The compounds of formula (I) may be provided in the form of
enantiomers and diastereoisomers. These optical isomers and
mixtures thereof form part of the invention.
[0028] The compounds of formula (I) for which R represents a chain
of formula (A) may be prepared by dehydration of a corresponding
compound of formula (Ia) 4
[0029] in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4 have the same
meanings as in formula (I) and R" represents a hydroxyl,
methanesulfonyloxy or acetyloxy radical.
[0030] This dehydration is carried out by any method known to
persons skilled in the art which makes it possible to dehydrate an
alcohol or one of its derivatives in order to obtain the
corresponding alkene. Preferably, derivatives are used for which R"
is a methanesulfonyloxy or acetyloxy radical obtained from the
corresponding derivative for which R" is a hydroxyl radical by the
action of methanesulfonyl chloride or acetyl chloride, in an inert
solvent such as pyridine, tetrahydrofuran, dioxane, a chlorinated
solvent (dichloromethane or chloroform for example), at a
temperature of between 5.degree. C. and 20.degree. C. and then the
medium is treated with a base such as an alkali metal hydroxide
(sodium hydroxide for example), an alkali metal carbonate (sodium
or potassium carbonate for example), an amine such as a
trialkylamine (triethylamine for example), 4-dimethylaminopyridine,
diaza-1,8-bicyclo[5.4.0]undec-7-en- e, at a temperature of between
0.degree. C. and the boiling temperature of the reaction mixture.
The methanesulfonyloxy and the acetyloxy may be isolated or
otherwise.
[0031] The compounds of formula (I) for which R represents a chain
(B) in which R' is a hydrogen atom may be prepared by reacting the
derivative R.sub.1SO.sub.2CH.sub.2R.sub.2 (II) for which R.sub.1
and R.sub.2 have the same meanings as in formula (I) with an
azetidinone of formula: 5
[0032] in which R.sub.3 and R.sub.4 have the same meanings as in
formula (I).
[0033] The procedure is generally carried out in an inert solvent
such as an ether (tetrahydrofuran for example), in the presence of
a strong base such as lithium diisopropylamide, potassium
tert-butoxide or n-butyllithium, at a temperature of between
-70.degree. C. and -15.degree. C.
[0034] The derivatives of formula (II) may be obtained by
application or adaptation of the methods described in the examples.
In particular, the procedure is carried out according to the
following reaction schemes: 6
[0035] In these formulae Hal represents a halogen atom and,
preferably, chlorine, bromine or iodine, R.sub.1 and R.sub.2 have
the same meanings as in formula (I).
[0036] The reaction (a) is generally carried out in an inert
solvent such as dimethylformamide or a 1-4C aliphatic alcohol, at a
temperature of between 20 and 30.degree. C.
[0037] The reaction (b) is carried out by any known method which
makes it possible to oxidize a sulfur-containing derivative without
affecting the rest of the molecule such as the methods described by
M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186,
252-263 (1990). For example, the procedure is carried out by the
action of an organic peroxy acid or a salt of such a peroxy acid
(peroxycarboxylic or peroxysulfonic acids, especially peroxybenzoic
acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid,
peroxyacetic acid, trifluoroperoxyacetic acid, peroxyformic acid or
monoperoxyphthalic acid) or in organic peracids or a salt of such
an acid (for example periodic or persulfuric acid), in an inert
solvent such as a chlorinated solvent (chloroform or
dichloromethane for example), at a temperature of between 0 and
25.degree. C. It is also possible to use hydrogen peroxide or a
periodate (sodium periodate for example), in an inert solvent such
as 1-4C aliphatic alcohol (methanol or ethanol for example), water
or a mixture of these solvents, at a temperature of between 0 and
20.degree. C. It is also possible to carry out the procedure using
tert-butyl hydroperoxide in the presence of titanium
tetraisopropoxide in a 1-4C aliphatic alcohol (methanol or ethanol
for example) or a water-alcohol mixture, at a temperature close to
25.degree. C. or using oxone.sup.R (potassium peroxymonosulfate),
in a 1-4C aliphatic alcohol (methanol or ethanol for example), in
the presence of water, acetic acid or sulfuric acid, at a
temperature close to 20.degree. C.
[0038] The reaction (c) is preferably carried out in an inert
solvent such as a 1-4C aliphatic alcohol (methanol or ethanol for
example), at a temperature of between 20.degree. C. and the boiling
temperature of the reaction medium.
[0039] The derivatives of formula (IV) are commercially available
or may be obtained by application or adaptation of the methods
described in the examples. In particular, the methylated derivative
or the corresponding alcohol is halogenated using a halogenating
agent such as hydrobromic acid, in acetic acid, at a temperature
close to 20.degree. C. or N-bromo- or chlorosuccinimide in the
presence of benzoyl peroxide, in an inert solvent such as
tetrachloromethane, at the boiling temperature of the reaction
medium. The methylated derivatives or the corresponding alcohols
are commercially available or may be obtained according to the
methods described by BRINE G. A. et al., J. Heterocycl. Chem., 26,
677 (1989) and NAGARATHNAM D., Synthesis, 8, 743 (1992) and in the
examples.
[0040] The azetidinones of formula (III) may be obtained by
application or adaptation of the methods described by KATRITZKY A.
R. et al., J. Heterocycl. Chem., 271 (1994) or DAVE P. R., J. Org.
Chem., 61, 5453 (1996) and in the examples. The procedure is
generally carried out according to the following reaction scheme:
7
[0041] In these formulae, R.sub.3 and R.sub.4 have the same
meanings as in formula (I) and X represents a chlorine or bromine
atom.
[0042] In step A, the procedure is preferably carried out in an
inert solvent such as a 1-4C aliphatic alcohol (ethanol or methanol
for example), optionally in the presence of an alkali metal
hydroxide, at the boiling temperature of the reaction medium.
[0043] In step B, the reduction is generally carried out using
lithium aluminum hydride, in tetrahydrofuran at the boiling
temperature of the reaction medium.
[0044] In step C, the procedure is preferably carried out in an
inert solvent such as a 1-4C aliphatic alcohol (ethanol or methanol
for example) in the presence of sodium hydrogen carbonate, at a
temperature of between 20.degree. C. and the boiling temperature of
the reaction medium.
[0045] In step D, the oxidation is preferably carried out in DMSO,
using the sulfurtrioxide-pyridine complex, at a temperature close
to 20.degree. C. or using dimethyl sulfoxide, in the presence of
oxalyl chloride and triethylamine, at a temperature of between -70
and -50.degree. C.
[0046] In step E, the procedure is carried out according to the
method described by GRISAR M. et al., in J. Med. Chem., 885 (1973).
The magnesium compound of the brominated derivative is formed and
then the nitrile is reacted, in an ether such as ethyl ether, at a
temperature of between 0.degree. C. and the boiling temperature of
the reaction medium. After hydrolysis with an alcohol, the
intermediate imine is reduced in situ with sodium borohydride at a
temperature of between 0.degree. C. and the boiling temperature of
the reaction medium.
[0047] The R.sub.3--CO--R.sub.4 derivatives are commercially
available or may be obtained by application or adaptation of the
methods described by KUNDER N. G. et al. J. Chem. Soc. Perkin Trans
1, 2815 (1997); MORENO-MARRAS M., Eur. J. Med. Chem., 23 (5) 477
(1988); SKINNER et al., J. Med. Chem., 1A (6) 546 (1971); HURN N.
K., Tet. Lett., M (52) 9453 (1995); MEDICI A. et al., Tet. Lett.,
24 (28) 2901 (1983); RIECKE R. D. et al., J. Org. Chem., 62 (20)
6921 (1997); KNABE J. et al., Arch. Pharm., 306 (9) 648 (1973);
CONSONNI R. et al., J. Chem. Soc. Perkin Trans 1, 1809 (1996);
FR-96-2481 and JP-94-261393.
[0048] The R.sub.3Br derivatives are commercially available or may
be obtained by application or adaptation of the methods described
by BRANDSMA L. et al., Synth. Comm., 20 (11) 1697 and 3153 (1990);
LEMAIRE M. et al., Synth. Comm., 24 (1) 95 (1994); GODA H. et al.,
Synthesis, 9 849 (1992); BAEUERLE P. et al., J. Chem. Soc. Perkin
Trans 2, 489 (1993).
[0049] The R.sub.4CN derivatives are commercially available or may
be obtained by application or adaptation of the methods described
by BOUYSSOU P. et al., J. Het. Chem., 29 (4) 895 (1992); SUZUKI N.
et al., J. Chem. Soc. Chem. Comm., 1523 (1984); MARBURG S. et al.,
J. Het. Chem., 17 1333 (1980); PERCEC V. et al., J. Org. Chem. 60
(21) 6895 (1995).
[0050] The compounds of formula (I) for which R represents a chain
(B) in which R' is a hydrogen atom may also be prepared by action
of a derivative R.sub.3CH(Br)R.sub.4 (VI) for which R.sub.3 and
R.sub.4 have the same meanings as in formula (I) with a derivative
of formula: 8
[0051] in which R.sub.1 and R.sub.2 have the same meanings as in
formula (I).
[0052] This reaction is generally carried out in the presence of a
base such as an alkali metal carbonate (potassium carbonate for
example), in an inert solvent such as acetonitrile, at the boiling
temperature of the reaction medium.
[0053] The derivatives of formula (VI) are commercially available
or may be obtained by application or adaptation of the method
described by BACHMANN W. E., J. Am. Chem. Soc., 2135 (1933).
Generally, the corresponding alcohol R.sub.3CHOHR.sub.4 is
brominated using hydrobromic acid, in acetic acid, at a temperature
of between 0.degree. C. and the boiling temperature of the reaction
medium.
[0054] The corresponding R.sub.3CHOHR.sub.4 alcohols are
commercially available or may be obtained by application or
adaptation of the methods described by PLASZ A. C. et al., J. Chem.
Soc. Chem. Comm., 527 (1972).
[0055] The derivatives of formula (VII) may be obtained by
hydrolysis of a derivative of formula: 9
[0056] in which R.sub.1 and R.sub.2 have the same meanings as in
formula (I).
[0057] This reaction is generally carried out using hydrochloric
acid, in an inert solvent such as an ether (dioxane for example),
at a temperature close to 20.degree. C.
[0058] The derivatives of formula (VIII) are obtained by reacting
vinyl chloroformate with a corresponding compound of formula (1)
for [lacuna] R represents a chain of formula (B), R' represents a
hydroxyl radical, R.sub.3 and R.sub.4 are phenyl radicals, in an
inert solvent such as a chlorinated solvent (dichloromethane or
chloroform for example), at a temperature of between 0.degree. C.
and the boiling temperature of the reaction mixture.
[0059] The compounds of formula (I) for which R is a chain (B) in
which R' is a --CO-alk radical may be prepared by reacting a halide
Hal-CO-alk in which Hal represents a halogen atom and, preferably,
a chlorine atom and alk represents an alkyl radical with a
corresponding compound of formula (I) for which R is a chain (B) in
which R' is a hydrogen atom.
[0060] This reaction is generally carried out in an inert solvent
such as tetrahydrofuran, dioxane, a chlorinated solvent
(dichloromethane or chloroform for example), at a temperature of
between -50.degree. C. and 20.degree. C., in the presence of
n-butyllithium.
[0061] The compounds of formula (I) for which R.sub.2 represents an
aromatic or a heteroaromatic substituted with --NR.sub.6R.sub.7 in
which R.sub.6 and R.sub.7 each represent a hydrogen atom may also
be prepared by reducing a corresponding compound of formula (I) for
which R.sub.2 represents an aromatic or a heteroaromatic
substituted with nitro.
[0062] This reaction is carried out by any known method which makes
it possible to reduce a nitro to an amino without affecting the
rest of the molecule. Preferably, iron is used in the presence of
hydrochloric acid in a 1-4C aliphatic alcohol such as ethanol, at
the boiling temperature of the reaction medium.
[0063] The compounds of formula (I) for which R.sub.2 represents an
aromatic or heteroaromatic substituted with --COHNR.sub.9 and/or
R.sub.3 and/or R.sub.4 represent an aromatic or a heteroaromatic
substituted with --CONR.sub.10R.sub.11 may also be prepared by
reacting a corresponding compound of formula (I) for which R.sub.2
and/or R.sub.3 and/or R.sub.4 represent an aromatic or a
heteroaromatic substituted with --COOR.sub.5 for which R.sub.5 is
alkyl or phenyl optionally substituted with halogens with
respectively an amine H.sub.2NR.sub.9 or HNR.sub.10R.sub.11 for
which R.sub.9, R.sub.10 and R.sub.11 have the same meanings as in
formula (I).
[0064] This reaction is generally carried out in an inert solvent
such as a chlorinated solvent (dichloromethane or chloroform for
example) or a 1-4C aliphatic alcohol (methanol or ethanol for
example), at a temperature of between 0.degree. C. and the boiling
temperature of the reaction mixture.
[0065] The compounds of formula (I) for which R.sub.2 represents an
aromatic substituted with hydroxyl and/or R.sub.3 and/or R.sub.4
represent an aromatic or a heteroaromatic substituted with hydroxyl
may also be prepared by hydrolysis of a corresponding compound of
formula (1) for which R.sub.2 represents an aromatic substituted
with alkoxy and/or R.sub.3 and/or R.sub.4 represent an aromatic or
a heteroaromatic substituted with alkoxy.
[0066] This reaction is carried out by any method of hydrolyzing an
alkoxy to a hydroxyl without affecting the rest of the molecule.
Preferably, the hydrolysis is carried out using boron tribromide,
in a chlorinated solvent such as dichloromethane, at a temperature
close to 20.degree. C.
[0067] The compounds of formula (I) for which R.sub.2 represents an
aromatic substituted with --NR.sub.6R.sub.7 for which R.sub.6
represents an alkyl radical and R.sub.7 represents a hydrogen atom
may also be prepared by deprotecting a corresponding compound of
formula (I) for which R.sub.2 represents an aromatic substituted
with an --N(alk)COOR.sub.8 in which R.sub.8 represents a tert-butyl
radical.
[0068] This reaction is generally carried out using hydrochloric
acid, in a solvent such as dioxane at a temperature close to
20.degree. C.
[0069] The compounds of formula (I) for which R.sub.2 and/or
R.sub.3 and/or R.sub.4 represent an aromatic substituted with
--COOR.sub.5 may also be prepared by esterification of a derivative
of formula: 10
[0070] for which R represents a chain
C.dbd.C(SO.sub.2R.sub.1)R'.sub.2 or
C(OR')CH(SO.sub.2R.sub.1)R'.sub.2, R.sub.1, R'.sub.2, R'.sub.3 and
R'.sub.4 have the same meanings as the substituents R.sub.1,
R.sub.2, R.sub.3 and R.sub.4 of formula (I) with the proviso that
at least one of the substituents R'.sub.2, R'.sub.3 and R'.sub.4
represents an aromatic or a heteroaromatic substituted with
carboxyl, using a derivative of formula R.sub.5OH for which R.sub.5
is alkyl or phenyl optionally substituted with one or more
halogens.
[0071] When R.sub.5 is alkyl, this reaction is generally carried
out in the presence of an inorganic acid (sulfuric acid for
example), at a temperature of between 20.degree. C. and the boiling
temperature of the reaction medium. When R.sub.5 is optionally
substituted phenyl, this reaction is preferably carried out in the
presence of a carbodiimide
(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or
N,N'-dicyclohexylcarbod- iimide for example), in an inert solvent
such as an imide (dimethylformamide) or a chlorinated solvent
(methylene chloride, 1,2-dichloroethane or chloroform for example),
at a temperature of between 0.degree. C. and the boiling
temperature of the reaction mixture.
[0072] The derivatives of formula (IX) for which R represents a
chain C.dbd.C(SO.sub.2R.sub.1)R'.sub.2 or
C(OR')CH(SO.sub.2R.sub.1)R'.sub.2, R', R.sub.1, R'.sub.2, R'.sub.3
and R'.sub.4 have the same meanings as the substituents R',
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 of the formula (I) with the
proviso that at least one of the substituents R'.sub.2, R'.sub.3
and R'.sub.4 represents an aromatic or a heteroaromatic substituted
with carboxyl may be obtained according to the methods described
above for the preparation of the compounds of formula (I) from the
corresponding intermediates and in particular according to the
method described in Example 29.
[0073] The compounds of formula (I) for which R.sub.2 and/or
R.sub.3 and/or R.sub.4 represent an aromatic or a heteroaromatic
substituted with alkylthioalkyl may also be prepared by reaction of
a derivative of formula (IX) for which R represents a chain
C.dbd.C(SO.sub.2R.sub.1)R'.su- b.2 or
C(OR')CH(SO.sub.2R.sub.1)R'.sub.2, R', R.sub.1, R'.sub.2, R'.sub.3
and R'.sub.4 have the same meanings as the substituents R',
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 of the formula (I) with the
proviso that at least one of the substituents R'.sub.2, R'.sub.3
and R'.sub.4 represents an aromatic or a heteroaromatic substituted
with haloalkyl with sodium alkylthiolate.
[0074] This reaction is generally carried out in an inert solvent
such as an amide (dimethylformamide for example), at a temperature
close to 20.degree. C.
[0075] The derivatives of formula (IX) for which R represents a
chain C.dbd.C(SO.sub.2R.sub.1)R'.sub.2 or
C(OR')CH(SO.sub.2R.sub.1)R'.sub.2, R', R.sub.1, R'.sub.2, R'.sub.3
and R'.sub.4 have the same meanings as the substituents R',
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 of the formula (I) with the
proviso that at least one of the substituents R'.sub.2, R'.sub.3
and R'.sub.4 represents an aromatic or a heteroaromatic substituted
with haloalkyl may be obtained by reacting a phosphorus trihalide
(preferably phosphorus tribromide) with a corresponding compound of
formula (I) for which R.sub.2 and/or R.sub.3 and/or R.sub.4
represent an aromatic or a heteroaromatic substituted with
hydroxyalkyl, in an inert solvent such as a chlorinated solvent
(carbon tetrachloride or chloroform for example), at a temperature
close to 20.degree. C.
[0076] The compounds of formula (I) for which R.sub.2 and/or
R.sub.3 and/or R.sub.4 represent an aromatic substituted with
hydroxyalkyl in which the alkyl contains one carbon atom may also
be prepared by reducing a compound of formula (I) for which at
least one of the substituents R.sub.2, R.sub.3 and R.sub.4
represents an aromatic substituted with formyl.
[0077] This reaction is generally carried out using sodium
borohydride, in a 1-4C aliphatic alcohol (methanol or ethanol for
example), at a temperature close to 0.degree. C.
[0078] The compounds of formula (I) for which R.sub.3 and/or
R.sub.4 represents an aromatic substituted with
-alk-NR.sub.6R.sub.7 for which alk is an alkyl containing one
carbon atom may also be prepared by reacting a compound of formula
(I) for which at least one of the substituents R.sub.3 and R.sub.4
represents an aromatic substituted with formyl with an amine
HNR.sub.6R.sub.7 in which R.sub.6 and R.sub.7 have the same
meanings as in formula (I).
[0079] This reaction is generally carried out in an inert solvent
such as a chlorinated solvent (dichloroethane for example), at a
temperature close to 20.degree. C. in the presence of sodium
triacetoxyborohydride or sodium cyanoborohydride.
[0080] The compounds of formula (I) for which R.sub.2 represents an
aromatic or a heteroaromatic substituted with --CONHR.sub.9 and/or
R.sub.3 and/or R.sub.4 represents an aromatic or heteroaromatic
substituted with --CO--NR.sub.10R.sub.11 may also be prepared by
reacting a derivative of formula (IX) for which R represents a
chain C.dbd.C(SO.sub.2R.sub.1)R'.sub.2 or
C(OR')CH(SO.sub.2R.sub.1)R'.sub.2, R', R.sub.1, R'.sub.2, R'.sub.3
and R'.sub.4 have the same meanings as the substituents R',
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 of the formula (I) with the
proviso that at least one of the substituents R'.sub.2, R'.sub.3
and R'.sub.4 represents an aromatic or a heteroaromatic substituted
with carboxyl with respectively an amine H.sub.2NR.sub.9 or
HNR.sub.10R.sub.11 in which R.sub.9, R.sub.10 and R.sub.11 have the
same meanings as in formula (I).
[0081] This reaction is preferably carried out in the presence of a
condensing agent which is used in peptide chemistry such as a
carbodiimide (for example
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or
N,N'-dicyclohexylcarbodiimide) or N,N'-carbonyldiimidazole, in an
inert solvent such as an ether (tetrahydrofuran or dioxane for
example), an amide (dimethylformamide) or a chlorinated solvent
(methylene chloride, 1,2-dichloroethane or chloroform for example)
at a temperature of between 0.degree. C. and the boiling
temperature of the reaction mixture, or after prior binding of the
acid to a resin of the TFP type of formula: 11
[0082] in which S represents an aminopolystyrene resin, in an inert
solvent such as dimethylformamide, in the presence of
4-dimethylaminopyridine, at a temperature close to 20.degree. C.
The binding to the resin is generally carried out in
dimethylformamide, in the presence of 4-dimethylaminopyridine and
1,3-diisopropylcarbodiimide, at a temperature close to 20.degree.
C.
[0083] The compounds of formula (I) for which R.sub.2 and/or
R.sub.3 and/or R.sub.4 represent an aromatic or a heteroaromatic
substituted with --CO--NH--NR.sub.6R.sub.7 may also be prepared by
reacting a corresponding compound of formula (I) for which R.sub.2
and/or R.sub.3 and/or R.sub.4 represent an aromatic or a
heteroaromatic substituted with --COOR.sub.5 and R.sub.5 represents
an alkyl or phenyl radical optionally substituted with halogens,
with a hydrazine H.sub.2N--NR.sub.6R.sub.7 for which R.sub.6 and
R.sub.7 have the same meanings as in formula (I).
[0084] This reaction is generally carried out in an inert solvent
such as dimethylformamide, at a temperature close to 20.degree.
C.
[0085] The compounds of formula (I) for which R.sub.2 represents an
aromatic or a heteroaromatic substituted with --CO--NHR.sub.9 in
which R.sub.9 represents a hydrogen atom and/or R.sub.3 and/or
R.sub.4 represent an aromatic or a heteroaromatic substituted with
--CO--NR.sub.10R.sub.11 in which R.sub.10 and R.sub.11 are hydrogen
atoms may also be prepared by hydrolysis of a corresponding
compound of formula (I) for which R.sub.2 and/or R.sub.3 and/or
R.sub.4 represent an aromatic or a heteroaromatic substituted with
cyano.
[0086] This reaction is carried out by any known method which makes
it possible to pass from a nitrile to the corresponding carbamoyl
without affecting the rest of the molecule. Preferably, the
procedure is carried out using hydrochloric acid, in acetic acid,
at a temperature close to 20.degree. C.
[0087] The compounds of formula (I) for which R.sub.2 represents an
aromatic substituted with --O-alk-NR.sub.12R.sub.13 may also be
prepared by reacting a derivative of formula (IX) for which R
represents a chain C.dbd.C(SO.sub.2R.sub.1)-R'.sub.2 or
C(OR')CH(SO.sub.2R.sub.1)R'.sub.2, R', R.sub.1, R.sub.2', R.sub.3'
and R.sub.4' have the same meanings as the substituents R',
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 of the formula (I) with the
proviso that at least one of the substituents R.sub.2', R.sub.3' or
R.sub.4' represents an aromatic substituted with -O-alk-Hal in
which alk represents an alkyl radical and Hal represents a halogen
atom and, preferably, a chlorine or bromine atom, with an amine
HNR.sub.12R.sub.13 in which R.sub.12R.sub.13 have the same meanings
as in formula (I).
[0088] This reaction is generally carried out in an inert solvent
such as acetonitrile, in the presence of an alkali metal carbonate
(potassium carbonate for example), at a temperature close to
20.degree. C.
[0089] The derivatives of formula (IX) for which R represents a
chain C.dbd.C(SO.sub.2R.sub.1)R'.sub.2 or
C(OR')CH(SO.sub.2R.sub.1)R'.sub.2, R', R.sub.1, R.sub.2', R.sub.3'
and R.sub.4' have the same meanings as the substituents R',
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 of the formula (I) with the
proviso that at least one of the substituents R.sub.2', R.sub.3' or
R.sub.4' represents an aromatic substituted with --O-alk-Hal in
which alk represents an alkyl radical and Hal represents a halogen
atom may be obtained by reacting a corresponding compound of
formula (I) for which R.sub.2 represents an aromatic substituted
with hydroxide with a Hal-alk-Hal derivative in which Hal
represents a halogen.
[0090] This reaction is generally carried out in an inert solvent
such as a ketone (methyl ethyl ketone for example), in the presence
of a base such as an alkali metal carbonate (potassium carbonate
for example), at the boiling temperature of the reaction
medium.
[0091] The compounds of formula (I) for which R.sub.3 and/or
R.sub.4 represents an aromatic substituted with
-alk-NR.sub.6R.sub.7 may also be prepared by reacting a derivative
of formula (IX) for which R represents a chain
C.dbd.C(SO.sub.2R.sub.1)R'.sub.2 or C(OR')CH(SO.sub.2R.sub.1)R'.s-
ub.2, R', R.sub.1, R.sub.2', R.sub.3' and R.sub.4' have the same
meanings as the substituents R', R.sub.1, R.sub.2, R.sub.3 and
R.sub.4 of the formula (I) with the proviso that at least one of
the substituents R.sub.3' or R.sub.4' represents a substituted
aromatic -alk-Cl in which alk represents an alkyl radical with an
amine HNR.sub.6R.sub.7 in which R.sub.6R.sub.7 have the same
meanings as in formula (I).
[0092] This reaction is generally carried out in an inert solvent
such as a chlorinated solvent (dichloromethane for example),
optionally in the presence of a nitrogen base such as
dimethylaminopyridine, diisopropylethylamine, at a temperature of
between 5 and 25.degree. C.
[0093] The derivatives of formula (IX) in which R represents a
chain C.dbd.C(SO.sub.2R.sub.1)R'.sub.2 or
C(OR')CH(SO.sub.2R.sub.1)R.sub.2, R', R.sub.1, R.sub.2', R.sub.3'
and R.sub.4' have the same meanings as the substituents R',
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 of the formula (I) with the
proviso that at least one of the substituents R.sub.3' or R.sub.4'
represents an aromatic substituted with -alk-Cl may be obtained by
reacting thionyl chloride with a corresponding compound of formula
(I) for which at least one of the substituents R.sub.3 or R.sub.4
represents an aromatic substituted with one or more hydroxyalkyl
radicals.
[0094] This reaction is generally carried out in an inert solvent
such as a chlorinated solvent (dichloromethane for example), at a
temperature of between 10 and 30.degree. C.
[0095] The compounds of formula (I) for which R represents a chain
B, R' represents a hydrogen atom and R.sub.3 and/or R.sub.4
represents an aromatic substituted with hydroxyalkyl in which the
alkyl residue contains one carbon atom may also be prepared by
reacting diisobutylaluminum hydride with a corresponding compound
of formula (I) for which R represents a chain B, R' represents a
hydrogen atom and R.sub.3 and/or R.sub.4 represents an aromatic
substituted with one or more --COOR.sub.5 radicals, in which
R.sub.5 is an alkyl radical.
[0096] This reaction is generally carried out in toluene, at a
temperature of between -30.degree. C. and 0.degree. C.
[0097] The compounds of formula (I) for which R.sub.2 represents a
phenyl radical substituted with --NR.sub.6R.sub.7 representing a
1-piperazinyl ring substituted at the 4 position with an alkyl
radical may also be prepared by reacting a corresponding compound
of formula (I) for which R.sub.2 represents a phenyl radical
substituted with a radical --NR.sub.6R.sub.7 representing a
1-piperazinyl ring with an alk-CHO derivative in which alk
represents a straight- or branched-chain alkyl radical containing 1
to 5 carbon atoms.
[0098] This reaction is generally carried out in an inert solvent
such as a chlorinated solvent (dichloroethane or chloroform for
example), in the presence of NaBH(OCOCH.sub.3).sub.3, at a
temperature close to 20.degree. C.
[0099] The compounds of formula (1) for which R.sub.2 represents a
phenyl radical substituted with --NR.sub.6R.sub.7 representing a
1-piperazinyl ring substituted at the 4 position with a radical
--COOalk may also be prepared by reacting a corresponding compound
of formula (I) for which R.sub.2 represents a phenyl radical
substituted with a radical --NR.sub.6R.sub.7 representing a
1-piperazinyl ring with a derivative of formula Hal-COOalk in which
alk represents an alkyl radical and Hal represents a halogen atom
and, preferably, a chlorine atom.
[0100] This reaction is generally carried out in pyridine, at a
temperature close to 20.degree. C.
[0101] The compounds of formula (I) for which R.sub.2 represents a
phenyl radical substituted with --NR.sub.6R.sub.7 representing a
1-piperazinyl ring substituted at the 4 position with a radical
--CO--NHalk or --CS--NHalk may also be prepared by reacting a
corresponding compound of formula (I) for which R.sub.2 represents
a phenyl radical substituted with --NR.sub.6R.sub.7 representing a
1-piperazinyl ring with a derivative of formula Y.dbd.C.dbd.Nalk in
which alk represents a straight- or branched-chain alkyl radical
containing 1 to 6 carbon atoms and Y represents a sulfur or oxygen
atom.
[0102] This reaction is generally carried out in an inert solvent
such as a chlorinated solvent (dichloromethane for example), at a
temperature close to 20.degree. C.
[0103] The compounds of formula (I) for which R.sub.2 represents a
phenyl radical substituted with a radical --NR.sub.6R.sub.7
representing a 1-piperazinyl ring substituted at the 4 position
with a radical --CO-alk-NR.sub.14R.sub.15 may also be prepared by
reacting a corresponding compound of formula (I) for which R.sub.2
represents a phenyl radical substituted with a radical
--NR.sub.6R.sub.7 representing a 1-piperazinyl ring with an acid of
formula R.sub.15R.sub.14N-alk-COOH in which alk represents an alkyl
radical and R.sub.14 and R.sub.15 have the same meanings as in
formula (I), optionally followed by deprotection of the product for
which R.sub.14 is a tert-butoxycarbonyl radical in order to obtain
the compounds for which R.sub.14 is a hydrogen atom.
[0104] This reaction is generally carried out in an inert solvent
such as a chlorinated solvent (dichloroethane for example), at a
temperature close to 20.degree. C. The deprotection is carried out
using formic acid at a temperature close to 20.degree. C.
[0105] The compounds of formula (I) for which R.sub.2 represents a
phenyl radical substituted with a radical --NR.sub.6R.sub.7
representing a 1-piperazinyl ring substituted at the 4 position
with a radical --CO-alk in which alk represents a methyl radical
may also be prepared by reacting a corresponding compound of
formula (I) for which R.sub.2 represents a phenyl radical
substituted with a radical --NR.sub.6R.sub.7 representing a
1-piperazinyl ring with acetic anhydride.
[0106] This reaction is generally carried out in the presence of
pyridine, at a temperature close to 20.degree. C.
[0107] It is understood for persons skilled in the art that, to
carry out the processes according to the invention which are
described above, it may be necessary to introduce groups protecting
amino, hydroxyl and carboxyl functions in order to avoid side
reactions. These groups are those which allow removal without
affecting the rest of the molecule. As examples of groups
protecting the amino function, there may be mentioned tert-butyl or
methylcarbamates which may be regenerated using iodotrimethylsilane
or allyl using palladium catalysts. As examples of groups
protecting the hydroxyl function, there may be mentioned
triethylsilyl and tert-butyldimethylsilyl which may be regenerated
using tetrabutylammonium fluoride or alternatively asymmetric
acetals (methoxymethyl or tetrahydropyranyl for example) with
regeneration using hydrochloric acid. As groups protecting carboxyl
functions, there may be mentioned esters (allyl or benzyl for
example), oxazoles and 2-alkyl-1,3-oxazolines. Other protecting
groups which can be used are described by GREENE T. W. et al.,
Protecting Groups in Organic Synthesis, second edition, 1991, John
Wiley & Sons.
[0108] The compounds of formula (I) may be purified by the
customary known methods, for example by crystallization,
chromatography or extraction.
[0109] The enantiomers of the compounds of formula (I) may be
obtained by resolution of the racemates for example by
chromatography on a chiral column according to PIRCKLE W. H. et
al., Asymmetric synthesis, Vol. 1, Academic Press (1983) or by
formation of salts or by synthesis from chiral precursors. The
diastereoisomers may be prepared according to known conventional
methods (crystallization, chromatography or from chiral
precursors).
[0110] The compounds of formula (I) may be optionally converted to
addition salts with an inorganic or organic acid by the action of
such an acid in an organic solvent such as an alcohol, a ketone, an
ether or a chlorinated solvent. These salts also form part of the
invention.
[0111] As examples of pharmaceutically acceptable salts, the
following salts may be mentioned: benzenesulfonate, hydrobromide,
hydrochloride, citrate, ethanesulfonate, fumarate, gluconate,
iodate, isethionate, maleate, methane sulfonate,
methylene-bis-.beta.-oxynaphtoate, nitrate, oxalate, pamoate,
phosphate, salicylate, succinate, sulfate, tartrate,
theophyllineacetate and p-toluenesulfonate.
[0112] The compounds of formula (I) exhibit advantageous
pharmacological properties. These compounds possess a high affinity
for the cannabinoid receptors and particularly those of the CB1
type. They are CBI receptor antagonists and are therefore useful in
the treatment and prevention of disorders affecting the central
nervous system, the immune system, the cardiovascular or endocrine
system, the respiratory system, the gastrointestinal apparatus and
reproductive disorders (Hollister, Pharm. Rev.; 38, 1986, 1-20,
Reny and Sinha, Prog. Drug Res., 36, 71-114 (1991), Consroe and
Sandyk, in Marijuana/Cannabinoids, Neurobiology and
Neurophysiology, 459, Murphy L. and Barthe A. Eds, CRC Press, 1992)
of bacterial, viral and parasitic infections.
[0113] Accordingly, these compounds may be used for the treatment
or prevention of psychoses including schizophrenia, anxiety
disorders, depression, epilepsy, neurodegeneration, cerebellar and
spinocerebellar disorders, cognitive disorders, cranial trauma,
panic attacks, peripheral neuropathies, glaucomas, migraine,
Parkinson's disease, Alzeimer's disease, Huntington's chorea,
Raynaud's syndrome, tremor, obsessive-compulsive disorder, senile
dementia, thymic disorders, Tourette's syndrome, tardive
dyskinesia, bipolar disorders, cancers, movement disorders induced
by medicaments, dystonia, endotoxemic shocks, hemorrhagic shocks,
hypotension, insomnia, immunological diseases, multiple sclerosis,
vomiting, asthma, appetite disorders (bulimia, anorexia), obesity,
memory disorders, in weaning from chronic treatments and alcohol or
drug abuse (opiods, barbiturates, cannabis, cocaine, amphetamine,
phencyclide, hallucinogens, benzodiazepines for example), as
analgesics or potentiators of the analgesic activity of the
narcotic and normarcotic drugs. They may also be used for the
treatment or prevention of intestinal transit disorders, as
antibacterial, antiviral and antiparasitic agents.
[0114] The affinity of the compounds of formula (I) for the
cannabis receptors has been determined according to the method
described by KUSTER J. E., STEVENSON J. I., WARD S. J., D'AMBRA T.
E., HAYCOCK D. A. in J. Pharmacol. Exp. Ther., 264 1352-1363
(1993).
[0115] In this test, the IC.sub.50 of the compounds of formula (I)
is less than or equal to 100 nM.
[0116] Their antagonist activity has been shown by means of the
model of hypothermia induced by an agonist of the cannabis
receptors (CP-55940) in mice, according to the method described by
Pertwee R. G. in Marijuana, Harvey D. J. eds, 84 Oxford IRL Press,
263-277 (1985).
[0117] In this text the ED50 of the compounds of formula (I) is
less than or equal to 50 mg/kg.
[0118] The compounds of formula (I) exhibit low toxicity. Their
LD.sub.50 is greater than 40 mg/kg by the subcutaneous route in
mice.
[0119] The preferred compounds of formula (I) are those for
which
[0120] R represents a chain (A) or (B) and R' represents a hydrogen
atom or a --COalk radical,
[0121] R.sub.1 represents a methyl or ethyl radical,
[0122] R.sub.2 represents either an aromatic chosen from phenyl and
naphthyl, these aromatics being nonsubstituted or substituted with
one or more halogens, alkyl, alkoxy, hydroxyl, --COOR.sub.5,
trifluoromethyl, trifluoromethyl-sulfanyl, trifluoromethoxy,
--NR.sub.6R.sub.7, --CO--NH--NR.sub.6R.sub.7, cyano, --CONHR.sub.9,
alkylsulfanyl, hydroxyalkyl, nitro, --CO--NR.sub.16R.sub.17,
--O-alkNR.sub.12R.sub.13 or alkylthioalkyl or a heteroaromatic
chosen from isoquinolyl, pyridyl, quinolyl,
1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl and
thienyl, these heteroaromatics being unsubstituted or substituted
with a halogen, alkyl, alkoxy, --COOR.sub.5, trifluoromethyl,
trifluoromethylsulfanyl, trifluoromethoxy, --NR.sub.6R.sub.7,
--CO--NH--NR.sub.6R.sub.7, cyano, --CONHR.sub.9, alkylsulfanyl,
hydroxyalkyl, nitro or alkylthioalkyl,
[0123] R.sub.3 and R.sub.4, which are identical or different,
represent either an aromatic chosen from phenyl or naphthyl, these
aromatics being nonsubstituted or substituted with one or more
halogens, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy,
--CONR.sub.10R.sub.11, -alk-NR.sub.6R.sub.7, hydroxyalkyl, formyl
or --COOR.sub.5, or a heteroaromatic chosen from thiazolyl or
thienyl rings, these heteroaromatics being unsubstituted or
substituted with a halogen, alkyl, alkoxy, --CONR.sub.10R.sub.11,
-alk-NR.sub.6R.sub.7, hydroxyalkyl or --COOR.sub.5.
[0124] R.sub.5 is alkyl or phenyl which is optionally substituted
with one or more halogens,
[0125] R.sub.6 and R.sub.7, which are identical or different,
represent a hydrogen atom or an alkyl, --COOalk, cycloalkyl,
alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or
alternatively R.sub.6 and R.sub.7 together form with the nitrogen
atom to which they are attached a 3- to 10-membered saturated or
unsaturated mono- or bicyclic heterocycle optionally containing
another heteroatom chosen from oxygen, sulfur and nitrogen and
being optionally substituted with one or more alkyl, --COalk,
--COOalk, --CO--NHalk, --CS--NHalk, --CO-alk-NR.sub.14R.sub.15,
oxo, hydroxyalkyl, alk-O-alk or --CO--NH.sub.2 radicals,
[0126] R.sub.9 represents a hydrogen atom or an alkyl radical or an
alkyl radical substituted with dialkylamino, phenyl, cycloalkyl
(optionally substituted with --COOalk) or a 3-to 10-membered
saturated or unsaturated mono- or bicyclic heterocycle optionally
containing one or more heteroatoms chosen from oxygen, sulfur and
nitrogen and being optionally substituted with one or more alkyl
radicals,
[0127] R.sub.10 and R.sub.11, which are identical or different,
represent a hydrogen atom or an alkyl radical or alternatively
R.sub.10 and R.sub.11 together form with the nitrogen atom to which
they are attached a 3- to 10-membered saturated mono- or bicyclic
heterocycle optionally containing another heteroatom chosen from
oxygen, sulfur and nitrogen and being optionally substituted with
an alkyl radical,
[0128] R.sub.12 and R.sub.13, which are identical or different,
represent a hydrogen atom or an alkyl or cycloalkyl radical or
alternatively R.sub.12 and R.sub.13 together form with the nitrogen
atom to which they are attached a 3- to 10-membered saturated mono-
or bicyclic heterocycle optionally containing another heteroatom
chosen from oxygen, sulfur and nitrogen and being optionally
substituted with an alkyl, --COalk, --COOalk, --CO--NHalk,
--CS--NHalk or --CO-alk-NR.sub.14R.sub.15 radical or a 3- to
10-membered saturated mono- or bicyclic heterocycle containing a
heteroatom chosen from oxygen, sulfur and nitrogen,
[0129] R.sub.14 and R.sub.15, which are identical or different,
represent a hydrogen atom or an alkyl or --COOalk radical,
[0130] R.sub.16 and R.sub.17 together form with the nitrogen atom
to which they are attached a 3- to 10-membered saturated mono- or
bicyclic heterocycle optionally containing
[0131] another heteroatom chosen from oxygen, sulfur and
nitrogen,
[0132] alk represents an alkyl or alkylene radical,
[0133] their optical isomers and their salts with an inorganic or
organic acid.
[0134] The compounds of formula (I) which are particularly
preferred are those for which
[0135] R represents a chain (A) or (B),
[0136] R' representing a hydrogen atom or a radical --COalk,
[0137] R.sub.1 represents a methyl or ethyl radical,
[0138] R.sub.2 represents either an aromatic chosen from
[0139] naphthyl,
[0140] phenyl,
[0141] phenyl substituted with one or more halogen, alkyl, alkoxy,
hydroxyl, --COOR.sub.5 (in which R.sub.5 represents an alkyl or
phenyl radical optionally substituted with several halogens)
trifluoromethyl, trifluoromethyl-sulfanyl, trifluoromethoxy,
--NR.sub.6R.sub.7 (in which R.sub.6 and R.sub.7, which are
identical or different, represent a hydrogen atom or an alkyl or
--COOalk radical or alternatively R.sub.6 and R.sub.7 together form
with the nitrogen atom to which they are attached a heterocycle
chosen from pyrrolidinyl, piperidyl, piperazinyl or piperazinyl
substituted with one or more alkyl, --COalk, --COOalk, --CO--NHalk,
--CS--NHalk or --CO-alk-NR.sub.14R.sub.15 radicals, in which
R.sub.14 and R.sub.15, which are identical or different, represent
a hydrogen atom or an alkyl radical), --CO--NH--NR.sub.6R.sub.7
(R.sub.6 and R.sub.7, which are identical or different, represent a
hydrogen atom or an alkyl radical or alternatively R.sub.6 and
R.sub.7 together form with the nitrogen atom to which they are
attached a heterocycle chosen from piperidyl, piperazinyl or
piperazyl substituted with one or more alkyl radicals), cyano,
--CONHR.sub.9 (in which R.sub.9 represents a hydrogen atom or an
alkyl radical or an alkyl radical substituted with dialkylamino,
phenyl, cycloalkyl (optionally substituted with --COOalk) or a
heterocycle chosen from pyrrolidinyl (optionally substituted with
alkyl), tetrahydrofuryl, or morpholinyl), alkylsulfanyl,
hydroxyalkyl, nitro, --CO--NR.sub.16R.sub.17, (in which R.sub.16
and R.sub.17 together form with the nitrogen atom to which they are
attached a piperidyl ring), --O-alkNR.sub.12R.sub.13 (in which
R.sub.12 and R.sub.13 together form with the nitrogen atom to which
they are attached a morpholino ring) or alkylthioalkyl, or a
heteroaromatic chosen from
[0142] isoquinolyl,
[0143] pyridyl,
[0144] quinolyl,
[0145] 1,2,3,4-tetrahydroisoquinolyl,
[0146] 1,2,3,4-tetrahydroquinolyl,
[0147] thienyl, or
[0148] thienyl substituted with a --COOR.sub.5 (in which R.sub.5
represents an alkyl radical) or --CONHR.sub.9, (in which R.sub.9
represents an alkyl radical),
[0149] R.sub.3 and R.sub.4, which are identical or different,
represent either an aromatic chosen from
[0150] phenyl or
[0151] phenyl substituted with one or more halogen, alkyl, alkoxy,
trifluoromethyl, trifluoromethoxy, hydroxyalkyl, formyl,
--COOR.sub.5 (in which R.sub.5 is an alkyl radical),
--CONR.sub.10R.sub.11 (in which R.sub.10 and R.sub.11, which are
identical or different, represent a hydrogen atom or an alkyl
radical), -alk-NR.sub.6R.sub.7 (in which R.sub.6 and R.sub.7, which
are identical or different, represent a hydrogen atom or an alkyl,
cycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively
R.sub.6 and R.sub.7 together form with the nitrogen atom to which
they are attached a heterocycle chosen from piperidyl (optionally
substituted with alkyl or oxo), pyrrolidinyl (optionally
substituted with alkyl, hydroxyalkyl, -alk-O-alk or
--CO--NH.sub.2), thiomorpholinyl, morpholinyl, pyrrolyl,
piperazinyl optionally substituted with oxo, alkyl, hydroxyalkyl,
--COOR.sub.5 (in which R.sub.5 is an alkyl radical),
[0152] or a heteroaromatic chosen from
[0153] thiazolyl or
[0154] thienyl,
[0155] alk represents an alkyl or alkylene radical,
[0156] their optical isomers and their salts with an inorganic or
organic acid.
[0157] Preferably, R.sub.2 is a substituted phenyl radical, the
latter is monosubstituted and, in particular, at the 3-position or
alternatively disubstituted and, in particular at the 3,5, 2,5 or
2,3-positions.
[0158] Preferably, when R.sub.3 is a substituted phenyl radical,
the latter is monosubstituted and, in particular, at the 4-position
or disubstituted and, in particular, at the 2,4-positions.
[0159] Preferably, when R.sub.4 is a substituted phenyl radical,
the latter is monosubstituted and, in particular, at the 4-position
or disubstituted and, in particular, at the 2,4-positions.
[0160] The following compounds may be mentioned among the preferred
compounds:
[0161]
1-benzhydryl-3-[(methylsulfonyl)(phenyl)methylene]azetidine,
[0162]
1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methylene]azetidine-
,
[0163]
1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methylene]azetidine-
,
[0164]
1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azeti-
dine,
[0165]
1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methylene]azeti-
dine,
[0166]
1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methylene]azeti-
dine,
[0167]
1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methylene]azetidine-
,
[0168]
1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azeti-
dine,
[0169]
1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methylene]azetidine,
[0170]
1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methylene]azetidine,
[0171]
1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methylene-
]azetidine,
[0172]
1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methylene]-
azetidine,
[0173]
1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)-me-
thylene} azetidine,
[0174]
1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulfonyl)methylene]
azetidine,
[0175]
1-benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methylene]-
azetidine,
[0176] 1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]
azetidine,
[0177]
1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,
[0178]
1-benzhydryl-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]
azetidine,
[0179]
1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)(methylsulfonyl)-methy-
lene] azetidine,
[0180]
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfon-
yl)methylene]azetidine,
[0181]
1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfo-
nyl)methylene] azetidine,
[0182]
1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfon-
yl)methylene]azetidine,
[0183]
(RS)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methox-
yphenyl)(phenyl)methyl)] azetidine,
[0184]
(R)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxy-
phenyl)(phenyl)methyl)] azetidine,
[0185]
(S)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxy-
phenyl)(phenyl)methyl)]azetidine,
[0186]
1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl(meth-
ylsulfonyl)methylene]azetidine,
[0187]
1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl(methy-
lsulfonyl)methylene]azetidine,
[0188]
1-[bis(4-chlorophenyl)methyl]-3-{[(3,5-bis(trifluoromethyl)-phenyl]-
methylsulfonylmethylene} azetidine,
[0189]
(RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluor-
ophenyl)(methylsulfonyl)methylene] azetidine,
[0190]
(R)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluoro-
phenyl)(methylsulfonyl)methylene]azetidine,
[0191]
(S)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluoro-
phenyl)(methylsulfonyl)methylene] azetidine,
[0192]
(RS)-1-{(4-chlorophenyl)[4-hydroxymethyl)phenyl]methyl}-3-[(3,5-dif-
luorophenyl)(methylsulfonyl)methylene]azetidine,
[0193]
(R)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-dif-
luorophenyl)(methylsulfonyl)methylene] azetidine,
[0194]
(S)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-dif-
luorophenyl)(methylsulfonyl)methylene]azetidine,
[0195]
(RS)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-
-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0196]
(R)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5--
difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0197]
(S)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5--
difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0198]
1-{(RS)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)pheny-
l]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0199] 1-{(R*)-(4-chlorophenyl)
[4-(3,3-dimethylpiperidin-1-yl-methyl)phen-
yl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]
azetidine,
[0200] 1-{(S)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1
yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene-
] azetidine,
[0201]
1-{(RS)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-
-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0202] 1-{(R*)-(4-chlorophenyl)
[4-(thiomorpholin-4-ylmethyl)phenyl]methyl-
}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0203]
1-{(S)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}--
3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0204]
1-{(RS)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]-
methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0205]
1-{(R*)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]-
methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0206]
1-{(S)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]m-
ethyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0207] 1-{{(RS)-(4-chlorophenyl)
{4-[(4-ethoxycarbonylpiperazinyl)-methyl]-
phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]
azetidine,
[0208] 1-{{(R*)-(4-chlorophenyl)
{4-[(4-ethoxycarbonylpiperazinyl)-methyl]-
phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine-
,
[0209] 1-{{(S)-(4-chlorophenyl)
{4-[(4-ethoxycarbonylpiperazinyl)-methyl]p-
henyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]
azetidine,
[0210] 1-{(RS)-(4-chlorophenyl)
[4-(N-cyclopropyl-N-propyl-aminomethyl)phe-
nyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,
[0211] 1-{(R*)-(4-chlorophenyl)
[4-(N-cyclopropyl-N-propyl-aminomethyl)phe-
nyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]
azetidine,
[0212]
1-{(S)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)pheny-
l]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0213]
1-{(RS)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0214]
1-{(R*)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0215]
1-{(S)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3--
(3,5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
[0216] 1-{{(RS)-(4-chlorophenyl)
{4-[bis-(2-methoxyethyl)aminomethyl]-phen-
yl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0217] 1-{{(R*)-(4-chlorophenyl)
{4-[bis-(2-methoxyethyl)aminomethyl]pheny-
l}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0218]
1-{{(S)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}-
methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0219]
1-{(RS)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0220]
1-{(R*)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0221]
1-{(S)-(4-chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0222]
1-{(RS)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[-
(3,5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
[0223]
1-{(R*)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[-
(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0224]
1-{(S)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]methyl}-3-[(-
3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0225]
1-{(RS)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]me-
thyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0226]
1-{(R*)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]me-
thyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0227]
1-{(S)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]met-
hyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0228]
1-{(RS)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0229]
1-{(R*)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0230]
1-{(S)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[-
(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0231]
1-{(RS)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3-
,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0232] 1-{(R*)-(4-chlorophenyl)
[4-(diethylaminomethyl)phenyl]methyl}-3-[(-
3,5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
[0233]
1-{(S)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,-
5-difluorophenyl)(methylsulfonyl)methylene] azetidine,
[0234]
1-{(RS)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methy-
l}-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0235]
1-{(R*)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methy-
l}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0236]
1-{(S)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl-
}-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0237]
1-{(RS)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[-
(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0238]
1-{(R*)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[-
(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0239]
1-{(S)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(-
3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0240]
(RS)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0241]
(R)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[-
(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0242]
(S)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[-
(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0243]
(RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-
-difluorophenyl)(methylsulfonyl)methylene] azetidine,
[0244]
(R)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5--
difluorophenyl)(methylsulfonyl)methylene] azetidine,
[0245]
(S)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5--
difluorophenyl)(methylsulfonyl)methylene]azetidine,
[0246]
(RS)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluoro-
phenyl)(methylsulfonyl)methylene]azetidine,
[0247]
(R)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorop-
henyl)(methylsulfonyl)methylene]azetidine,
[0248]
(S)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorop-
henyl)(methylsulfonyl)methylene]azetidine,
[0249]
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)-(methylsulfon-
yl)methylene] azetidine,
[0250]
1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methylene]a-
zetidine,
[0251]
1-benzhydryl-3-[(3-methylsulfanylmethyl)phenyl)]-(methylsulfonyl)me-
thylene] azetidine,
[0252]
1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)-(methylsulfonyl)me-
thylene]azetidine,
[0253]
1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenyl)-(methylsulfony-
l)methylene]azetidine,
[0254]
1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)-(methylsulfonyl)-
methylene]azetidine,
[0255]
1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxyphenyl)-(methylsulfonyl)-
methylene] azetidine,
[0256]
1-[bis(4-chlorophenyl)methyl]-3-[(3-methylsulfonyl)-(3-pyrrolidinyl-
phenyl)methylene]azetidine,
[0257]
1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethyl-phenyl)(methylsul-
fonyl)-methylene]azetidine,
[0258]
1-[bis(4-chlorophenyl)methyl]3-{(methylsulfonyl)[3-(N-piperidylcarb-
amoyl)phenyl]methylene} azetidine,
[0259]
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)-(3-trifluoromethy-
lsulfanylphenyl)(methylsulfonyl)-methylene]azetidine,
[0260]
1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfon-
yl)methylene]azetidine,
[0261]
1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfon-
yl)methylene] azetidine,
[0262]
1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfon-
yl)methylene]azetidine,
[0263]
(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(p-
henyl)methylene]azetidine,
[0264]
(R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(ph-
enyl)methylene]azetidine,
[0265]
(S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(ph-
enyl)methylene]azetidine,
[0266]
(RS)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)-
(methylsulfonyl)methylene] azetidine,
[0267]
(R)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(-
methylsulfonyl)methylene] azetidine,
[0268]
(S)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(-
methylsulfonyl)methylene] azetidine,
[0269] 1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methylene]
azetidine,
[0270]
1-[bis(4-chlorophenyl)methyl]-3-{{3-[N-(4-methylpiperazinyl)carbamo-
yl]phenyl}(methylsulfonyl)methylene]azetidine,
[0271]
1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2-dimethylcarbohydrazido)-ph-
enyl] (methylsulfonyl)methylene} azetidine,
[0272]
1-[bis(thien-2-yl)methyl]-3-[3,5-difluorophenyl)(methylsulfonyl)-me-
thylene]azetidine,
[0273]
1-[bis(p-tolyl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidi-
ne,
[0274]
1-[4-chlorophenyl)(4-hydroxymethylphenyl)methyl]-3-[(3,5-difluoroph-
enyl)(methylsulfonyl)methylene]azetidine,
[0275]
1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenyl)-(methylsulfo-
nyl)methylene] azetidine,
[0276]
(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluoropheny-
l)(methylsulfonyl)methylene]azetidine,
[0277]
(R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl-
)(methylsulfonyl)methylene] azetidine,
[0278]
(S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl-
)(methylsulfonyl)methylene] azetidine,
[0279]
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonyl-
thien-5-yl)methylene]azetidine,
[0280]
-1-[bis(4-chlorophenyl)methyl]-3-hydroxy-3-[(methylsulfonyl)(2-meth-
oxycarbonylthien-5-yl)methyl]azetidine (RS),
[0281]
1-[bis(4-chlorophenyl)methyl]-3-[(2-isobutylaminocarbonylthien-5-yl-
)(methylsulfonyl)methylene]azetidine,
[0282]
1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxycarbonyl-phenyl)(methyls-
ulfonyl)methyl-(RS)azetidin-3-ol,
[0283]
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-4-yl)meth-
yl-(RS)azetidin-3-ol,
[0284]
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-3-yl)meth-
yl-(RS)azetidin-3-ol,
[0285]
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfony-
lmethyl)-N-(3-morpholin-4-yl-propyl)benzamide,
[0286]
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfony-
lmethyl)-N-(3-dimethylaminopropyl)benzamide,
[0287]
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfony-
lmethyl)-N-(2-pyrrolidin-1-ylethyl)benzamide,
[0288]
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfony-
lmethyl)-N-(2-dimethylamino-1-methylethyl)benzamide,
[0289]
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfony-
lmethyl)-N-piperidin-1-ylbenzamide,
[0290]
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfony-
lmethyl)-N-isobutylbenzamide,
[0291] 3-({1-[bis(4-chlorophenyl)methyl]
azetidin-3-ylidene}-methanesulfon-
ylmethyl)-N-(3-imidazol-1-ylpropyl)benzamide,
[0292]
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfony-
lmethyl)-N-(2-dimethylaminoethyl)benzamide,
[0293] 3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)benzoic acid N'-methylhydrazide,
[0294]
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfon-
ylmethyl)-N-(2-morpholin-4-ylethyl)benzamide,
[0295]
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfon-
ylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide,
[0296]
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfon-
ylmethyl)-N-(2,2-dimethylpropyl)benzamide,
[0297]
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfon-
ylmethyl)-N-cyclohexylmethylbenzamide,
[0298]
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfon-
ylmethyl)-N-cyclopropylmethylbenzamide,
[0299]
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfon-
ylmethyl)-N-(2-methylbutyl)benzamide,
[0300]
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfon-
ylmethyl)-N-(2-phenylpropyl)benzamide,
[0301]
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfon-
ylmethyl)-N-(tetrahydrofuran-2-ylmethyl)benzamide,
[0302]
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfon-
ylmethyl)-N-(2,2-diphenylethyl)benzamide,
[0303]
3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfon-
ylmethyl)-N-(2-ethylbutyl)benzamide,
[0304] 4-{[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)benzoylamino]methyl} cyclohexanecarboxylic
acid methyl ester,
[0305]
2-amino-1-{4-[3-({1-[bis-(4-chlorophenyl]methyl]-azetidin-3-ylidene-
}methanesulfonylmethyl)phenyl]piperazin-1-yl}ethanone,
[0306] (2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamic
acid tert-butyl ester,
[0307] 1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-methylaminoethanone,
[0308] (2-{4-[3-({1-[bis(4-chlorophenyl)methyl] azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamic
acid tert-butyl ester,
[0309]
4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfo-
nylmethyl)phenyl]piperazine-1-carbothioic acid N-methylamide,
[0310] 4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid
N-methylamide,
[0311] 4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid methyl
ester,
[0312] 1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]-4-isobutylpiperazine,
[0313]
1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfo-
nylmethyl)phenyl]-4-ethylpiperazine,
[0314] 4-acetyl
1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}met-
hanesulfonylmethyl)phenyl]piperazine,
[0315] 1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-dimethylaminoethanone,
[0316]
1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfo-
nylmethyl)phenyl]piperazine,
[0317]
4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfo-
nylmethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester,
[0318]
1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(meth-
ylsulfonyl)methylene]azetidine,
[0319]
3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluoroph-
enyl)(methylsulfonyl)methyl-(RS)azetidine,
[0320]
(RS)-4-[4-((4-chlorophenyl){3-[(3,5-difluorophenyl)-methanesulfonyl-
methylene]azetidin-1-yl}methyl)benzyl]morpholine,
[0321]
4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phen-
oxy}butyl)morpholine,
[0322]
4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phen-
oxy}propyl)morpholine,
[0323] their optical isomers and their esters.
[0324] Among these compounds, the following compounds are
particularly preferred;
[0325]
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfony-
l)methylene]azetidine,
[0326]
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfony-
l)methylene(RS)]azetidin-3-ol,
[0327]
3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(met-
hylsulfonyl)methyl)methyl-sulfonylmethyl(RS)]azetidine their
optical isomers and their salts with an inorganic or organic
acid.
[0328] The following examples illustrate the invention without
limiting it.
Example 1
[0329] 0.3 cm.sup.3 of methanesulfonyl chloride is added to a
solution of 1 g of
1-benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol
in 10 cm.sup.3 of pyridine, cooled to 5.degree. C. The mixture is
stirred for 2 hours at 5.degree. C. and then 1 g of
4-dimethylaminopyridine is added in 10 cm.sup.3 of dichloromethane
at 5.degree. C. The solution is stirred for 15 hours at room
temperature and then concentrated to a dryness under reduced
pressure (2.7 kPa). The residue obtained is chomatographed on a
silica gel column (particle size 0.04-0.06 mm, diameter 3 cm,
height 25 cm), eluting at a nitrogen pressure of 0.5 bar with
dichloromethane and collecting 80 cm.sup.3 fractions. Fractions 17
to 20 are combined and then concentrated to dryness under reduced
pressure (2.7 kPa). The residue is crystallized from 10 cm.sup.3 of
ethyl ether. 0.14 g of
1-benzhydryl-3-[(methylsulfonyl)(phenyl)methylene]azetid- ine is
obtained melting at 210.degree. C. [NMR spectrum in DMSO-d.sub.6,
T=300K, .quadrature. in ppm (300 MHz): 2.95 (3H, s, SCH.sub.3),
3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75 (1H, s,
NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz, 4CH
arom.), between 7.40 and 7.60 (9H, m, 9 CH arom.)].
[0330]
1-Benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol
may be obtained in the following manner: 6.25 cm.sup.3 of 1.6 N
n-butyllithium in solution in hexane are added to a solution of 1.4
cm.sup.3 of diisopropylamine in 10 cm.sup.3 of tetrahydrofuran,
under an argon atmosphere, cooled to 0.degree. C., and then the
mixture is cooled to -70.degree. C. A mixture of 1.7 g of benzyl
methyl sulfone in 30 cm.sup.3 of tetrahydrofuran are then added and
the stirring is maintained for 45 minutes at -70.degree. C. 2.4 g
of 1-benzhydrylazetidin-3-one are added and then the mixture is
stirred for 20 minutes while allowing the mixture to return to room
temperature. The reaction mixture is filtered and then concentrated
to dryness under reduced pressure (2.7 kPa). The residue is taken
up in 50 cm.sup.3 of ethyl acetate, 30 cm.sup.3 of water and 20
cm.sup.3 of normal hydrochloric acid. The precipitate is filtered,
washed with 30 cm.sup.3 of distilled water, drained and dried. 2 g
of
1-benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol
are obtained melting at 260.degree. C.
[0331] 1-Benzhydrylazetidin-3-one may be prepared according to the
procedure described by KATRITZKY A. R. et al. in J. Heterocycl.
Chem., 271 (1994).
Example 2
[0332] On carrying out the operation according to the procedure of
Example 1 starting with 1.9 g of
1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)-
methyl-(RS)]azetidin-3-ol, 0.52 cm.sup.3 of methanesulfonyl
chloride and 1.7 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 17 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane and then a dichloromethane and
ethanol mixture (98.5/1.5 by volume) as eluents and collecting 100
cm.sup.3 fractions. Fractions 5 and 6 are combined and concentrated
to dryness under reduced pressure (2.7 kPa). The solid obtained is
crystallized from 2 cm.sup.3 of dichloromethane and 20 cm.sup.3 of
diisopropyl ether. 0.9 g of
1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)-methylene]azetidine
is obtained melting at 180.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.35 (3H, s,
PhCH.sub.3), 2.95 (3H, s, SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20
(2H, s, NCH.sub.2), 4.75 (1H, s, NCH), 7.20 (5H, m, 5CH arom.),
7.30 (5H, t, J=7 Hz, 5CH arom.), 7.50 (4H, d, J=7 Hz, 4 CH
arom.)].
[0333]
1-Benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidi-
n-3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 2.8
g of methyl(3-methylbenzyl)sulfone and 3.6 g of
1-benzhydrylazetidin-3-one, 2.6 g of a solid are obtained after
purification on a silica gel column (particle size 0.04-0.06 mm,
diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar with
a dichloromethane and ethanol mixture (98.5/1.5 by volume) as
eluent. The solid is taken up in 25 cm.sup.3 of diisopropyl ether.
After filtration, draining and drying, 1.9 g of
1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol
are obtained melting at 170.degree. C.
[0334] Methyl(3-methylbenzyl)sulfone may be prepared in the
following manner: 10.5 g of oxone.sup.R and then 2.6 g of
methyl(3-methylbenzyl)sul- fide and 30 cm.sup.3 of ethanol are
added, at room temperature, to a solution of 30 cm.sup.3 of water,
30 cm.sup.3 of acetic acid and 15 cm.sup.3 of 36 N sulfuric acid.
The mixture is stirred for 48 hours at room temperature and then
taken up in 100 cm.sup.3 of water and 100 cm.sup.3 of ethyl
acetate. The organic phase is washed with a saturated aqueous
sodium bicarbonate solution, decanted off, dried over magnesium
sulfate and concentrated to dryness under reduced pressure (2.7
kPa). 2.8 g of methyl(3-methylbenzyl)sulfone are obtained in the
form of a gum.
[0335] Methyl(3-methylbenzyl)sulfide may be prepared in the
following manner: 1.7 g of sodium methylthiolate are added, while
the temperature is kept below 30.degree. C., to a solution of 3.7 g
of 3-methylbenzyl bromide in 25 cm.sup.3 of dimethylformamide. The
mixture is stirred for 2 hours at a temperature close to 20.degree.
C. and then taken up in 50 cm.sup.3 of ethyl acetate. The organic
phase is washed with 3 times 100 cm.sup.3 of water, dried over
magnesium sulfate and concentrated to dryness under reduced
pressure (2.7 kPa). 2.6 g of methyl(3-methyl-benzyl)sulfide are
obtained in the form of an oil.
Example 3
[0336] 0.3 cm.sup.3 of methanesulfonyl chloride is added to a
solution of 3.3 g of
1-benzhydryl-3-[(4-methylphenyl)(methylsulfonyl)methyl-(RS)]azet-
idin-3-ol in 10 cm.sup.3 of pyridine, cooled to 5.degree. C. The
mixture is stirred for 2 hours at 5.degree. C. and then 1 g of
4-dimethylaminopyridine is added in 10 cm.sup.3 of dichloromethane
at 5.degree. C. The solution is stirred for 15 hours at room
temperature and then concentrated to dryness under reduced pressure
(2.7 kPa). The residue obtained is chromatographed on a silica gel
column (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm),
eluting at a nitrogen pressure of 0.5 bar with dichloromethane and
collecting 80 cm.sup.3 fractions. Fractions 17 to 20 are combined
and then concentrated to dryness under reduced pressure (2.7 kPa).
The solid obtained is crystallized from 30 cm.sup.3 of
acetonitrile. 0.14 g of
1-benzhydryl-3-[(4-methylphenyl)(methylsulfonyl)methylene]azetidine
is obtained melting at 210.degree. C. [NMR spectrum in DMSO-d6,
T=300K, .quadrature. in ppm (300 MHz): 2.30 (3H, s, PhCH.sub.3),
2.95 (3H, s, SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s,
NCH.sub.2), 4.75 (1H, s, NCH), 7.20 (4H, m, 4CH arom.), 7.30 (6H,
t, J=7 Hz, 6CH arom.), 7.45 (4H, d, J=7 Hz, 4 CH arom.)].
[0337]
1-Benzhydryl-3-[(4-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidi-
n-3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 4 g
of methyl(4-methylbenzyl)sulfone and 5.1 g of
1-benzhydrylazetidin-3-one, 3 g of
1-benzhydryl-3-[(4-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-
-3-ol are obtained melting at 226.degree. C.
[0338] Methyl(4-methylbenzyl)sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 3.5 g of
methyl(4-methylbenzyl)sulfide and 12.3 g of oxone.sup.R, 3.5 g of
methyl(4-methylbenzyl)sulfone are obtained in the form of a
solid.
[0339] Methyl(4-methylbenzyl)sulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 5.6 g of 4-methylbenzyl
bromide and 2.3 g of sodium methylthiolate, 4.7 g of
methyl(4-methylbenzyl)sulfide are obtained in the form of a
solid.
Example 4
[0340] 0.7 cm.sup.3 of methanesulfonyl chloride and then 3.8 g of
4-dimethylaminopyridine are added to a solution of 3.3 g of
1-benzhydryl-3-[(2-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol
in 50 cm.sup.3 of dichloromethane, at room temperature. The
solution is stirred for 3 hours under reflux and then taken up in
twice 50 cm.sup.3 of water. The organic phase is decanted off,
dried and concentrated to dryness under reduced pressure (2.7 kPa).
The residue obtained is chromatographed on a silica gel column
(particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm), eluting
at a nitrogen pressure of 0.5 bar with dichloromethane and then
with a dichloromethane and ethanol mixture (99/1 by volume mixture)
and collecting 100 cm.sup.3 fractions. Fractions 6 to 17 are
combined and then concentrated to dryness under reduced pressure
(2.7 kPa). The solid obtained is crystallized from 50 cm.sup.3 of
ethyl ether. 2.6 g of
1-benzhydryl-3-[(2-methylphenyl)(methylsulfonyl)-
methylene]azetidine are obtained in the form of a foam [NMR
spectrum in DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz):
2.30 (3H, s, PhCH.sub.3), 2.95 (3H, s, SCH.sub.3), 3.50 (2H, s,
NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.70 (1H, s, NCH) between 7.10
and 7.35 (10H, m, 10CH arom.), 7.45 (4H, m, 4CH arom.)].
[0341]
1-Benzhydryl-3-[(2-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidi-
n-3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 3.4
g of methyl(2-methylbenzyl)sulfone and 4.3 g of
1-benzhydrylazetidin-3-one, 3.4 g of
1-benzhydryl-3-[(2-methylphenyl)(methylsulfonyl)methyl-(RS)]azet-
idin-3-ol are obtained melting at 218.degree. C.
[0342] Methyl(2-methylbenzyl)sulfone may be prepared in the
following manner: by carrying out the operation according to the
procedure of Example 2 starting with 4.5 g of
methyl(2-methylbenzyl)sulfide and 16.2 g of oxone.sup.R, 3.4 g of
methyl(2-methylbenzyl)sulfone are obtained in the form of a
solid.
[0343] Methyl(2-methylbenzyl)sulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 but starting with 5.6 g of 2-methylbenzyl
bromide and 2.1 g of sodium methylthiolate, 4.5 g of
methyl(2-methylbenzyl)sulfide are obtained in the form of a
solid.
Example 5
[0344] On carrying out the operation according to the procedure of
Example 4 but starting with 2.1 g of
1-benzhydryl-3-[(2-chlorophenyl)(methylsulfo-
nyl)methyl-(RS)]azetidin-3-ol, 0.55 cm.sup.3 of methanesulfonyl
chloride and 2.3 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent and collecting 100
cm.sup.3 fractions. Fractions 12 to 18 are combined and
concentrated to dryness under reduced pressure (2.7 kPa). The solid
obtained is crystallized from a mixture of 3 cm.sup.3 of
dichloromethane and 40 cm.sup.3 of ethyl ether. 1.1 g of
1-benzhydryl-3-[(2-chlorophenyl)(methylsulfonyl)-methylene]azetidine
are obtained melting at 204.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.95 (3H, s,
SCH.sub.3), 3.60 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.70
(1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,
4CH arom.), 7.45 (7H, m, 7CH arom.), 7.55 (1H, d, J=7 Hz, CH
arom.)].
[0345]
1-Benzhydryl-3-[(2-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidi-
n-3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 4 g
of (2-chlorobenzyl)methylsulfone and 4.6 g of
1-benzhydrylazetidin-3-one, the residue obtained is taken up in 50
cm.sup.3 of ethyl acetate, filtered and dried. 2.4 g of
1-benzhydryl-3-[(2-chlorophenyl)(methylsulfo-
nyl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white
solid.
[0346] (2-Chlorobenzyl)methylsulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 3.4 g of
(2-chlorobenzyl)methylsulfide and 12 g of oxone.sup.R, 4 g of
(2-chlorobenzyl)methylsulfone are obtained in the form of an oil
which crystallizes.
[0347] (2-Chlorobenzyl)methylsulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 but starting with 4 g of 2-chlorobenzyl
bromide and 1.5 g of sodium methylthiolate, 3.4 g of
(2-chlorobenzyl)methylsulfide are obtained in the form of an
oil.
Example 6
[0348] On carrying out the operation according to the procedure of
Example 4 starting with 3 g of
1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)me-
thyl-(RS)]azetidin-3-ol, 0.79 cm.sup.3 of methanesulfonyl chloride
and 3.3 g of 4-dimethylaminopyridine, the residue obtained is
purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent and collecting 100
cm.sup.3 fractions. Fractions 2 to 5 are combined and concentrated
to dryness under reduced pressure (2.7 kPa). The solid obtained is
crystallized from 40 cm.sup.3 of ethyl ether. 1.7 g of
1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)-
methylene]azetidine are obtained melting at 205.degree. C. [NMR
spectrum in DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz):
2.95 (3H, s, SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s,
NCH.sub.2), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.),
7.30 (4H, t, J=7 Hz, 4CH arom.), 7.45 (8H, m, 8CH arom.)].
[0349]
1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidi-
n-3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 3.1
g of (3-chlorobenzyl)methylsulfone and 3.4 g of
1-benzhydrylazetidin-3-one, 3.4 g of
1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methyl-(RS)]azet-
idin-3-ol are obtained in the form of a white solid.
[0350] (3-Chlorobenzyl)methylsulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 3.2 g of
(3-chlorobenzyl)methylsulfide and 12 g of oxone.sup.R, 3.2 g of
(3-chlorobenzyl)methylsulfone are obtained in the form of a white
solid.
[0351] (3-Chlorobenzyl)methylsulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 4 g of 3-chlorobenzyl bromide
and 1.5 g of sodium methylthiolate, 3.2 g of
3-chlorobenzylmethylsulfide are obtained in the form of an oil.
Example 7
[0352] On carrying out the operation according to the procedure of
Example 4 starting with 3.3 g of
1-benzhydryl-3-[(4-chlorophenyl)(methylsulfonyl)-
methyl-(RS)]azetidin-3-ol, 0.87 cm.sup.3 of methanesulfonyl
chloride and 3.6 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent and collecting 100
cm.sup.3 fractions. Fractions 8 to 12 are combined and concentrated
to dryness under reduced pressure (2.7 kPa). The solid obtained is
crystallized from a mixture of 3 cm.sup.3 and 30 cm.sup.3 of ethyl
ether. 0.5 g of
1-benzhydryl-3-[(4-chlorophenyl)(methylsulfonyl)methylene]azetidine
is obtained melting at 192.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.95 (3H, s,
SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.70
(1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,
4CH arom.), between 7.40 and 7.55 (8H, m, 8CH arom.)].
[0353]
1-Benzhydryl-3-[(4-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidi-
n-3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 2.8
g of (4-chlorobenzyl)methylsulfone and 3.24 g of
1-benzhydrylazetidin-3-one, 3.4 g of
1-benzhydryl-3-[(4-chlorophenyl)(methylsulfonyl)methyl-(RS)]azet-
idin-3-ol are obtained in the form of a white solid after
crystallization from 80 cm.sup.3.
[0354] (4-Chlorobenzyl)methylsulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 3.5 g of
(4-chlorobenzyl)methylsulfide and 12.3 g of oxone.sup.R, 3.5 g of
(4-chlorobenzyl)methylsulfone are obtained in the form of a
solid.
Example 8
[0355] On carrying out the operation according to the procedure of
Example 4 starting with 3.1 g of
1-benzhydryl-3-[(3,5-dichlorophenyl)-(methylsulf-
onyl)methyl-(RS)]azetidin-3-ol, 0.75 cm.sup.3 of methanesulfonyl
chloride and 3.1 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent and collecting 100
cm.sup.3 fractions. Fractions 6 to 10 are combined and concentrated
to dryness under reduced pressure (2.7 kPa). The solid obtained is
crystallized from a mixture of 2 cm.sup.3 of dichloromethane and 30
cm.sup.3 of ethyl ether. 0.8 g of
1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine
is obtained melting at 204.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.95 (3H, s,
SCH.sub.3), 3.85 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,
4CH arom.), 7.45 (6H, m, 6CH arom.), 7.70 (1H, s, CH arom.)].
[0356]
1-Benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]aze-
tidin-3-ol may be obtained in the following manner: on carrying out
the operation according to the procedure of Example 1 starting with
4 g of (3,5-dichlorobenzyl)methylsulfone and 4 g of
1-benzhydrylazetidin-3-one, 3.2 g of
1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]-
azetidin-3-ol are obtained in the form of a white solid.
[0357] (3,5-Dichlorobenzyl)methylsulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 5.3 g of
(3,5-dichlorobenzyl)methylsulfide and 17 g of oxone.sup.R.sub., 5 g
of (3,5-dichlorobenzyl)methylsulfone are obtained in the form of a
white solid.
[0358] (3,5-Dichlorobenzyl)methylsulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 5 g of 3,5-dichlorobenzyl
chloride and 2 g of sodium methylthiolate, 5.3 g of
(3,5-dichlorobenzyl)methylsulfide are obtained in the form of an
oil.
Example 9
[0359] On carrying out the operation according to the procedure of
Example 4 starting with 5 g of
1-benzhydryl-3-[(3,4-dichlorophenyl)-(methylsulfon-
yl)methyl-(RS)]azetidin-3-ol, 1.2 cm.sup.3 of methanesulfonyl
chloride and 3.8 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 4 cm, height 35 cm) at a nitrogen pressure
of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30
by volume) as eluent and collecting 35 cm.sup.3 fractions.
Fractions 30 to 55 are combined and concentrated to dryness under
reduced pressure (2.7 kPa). The solid obtained is crystallized from
50 cm.sup.3 of ethyl ether. 1.5 g of
1-benzhydryl-3-[(3,4-dichlorophenyl)(methylsulfonyl)methylene]azetidine
are obtained melting at 170.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.95 (3H, s,
SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.70
(1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,
4CH arom.), between 7.35 and 7.50 (5H, m, 5CH arom.), 7.65 (2H, m,
2CH arom.)].
[0360]
1-Benzhydryl-3-[(3,4-dichlorophenyl)(methylsulfonyl)methyl-(RS)]aze-
tidin-3-ol may be obtained in the following manner: on carrying out
the operation according to the procedure of Example 1 starting with
4.5 g of (3,4-dichlorobenzyl)methylsulfone and 4.3 g of
1-benzhydrylazetidin-3-one- , 5 g of
1-benzhydryl-3-[(3,4-dichlorophenyl)(methylsulfonyl)methyl-(RS)]a-
zetidin-3-ol are obtained in the form of a white solid.
[0361] (3,4-Dichlorobenzyl)methylsulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 4.3 g of
(3,4-dichlorobenzyl)methylsulfide and 13 g of oxone.sup.R.sub., 4.7
g of (3,4-dichlorobenzyl)methylsulfone are obtained in the form of
a white solid.
[0362] (3,4-Dichlorobenzyl)methylsulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 2.8 cm.sup.3 of
3,4-dichlorobenzyl chloride and 1.5 g of sodium methylthiolate, 4.3
g of (3,4-dichlorobenzyl)methylsulfid- e are obtained in the form
of an oil.
Example 10
[0363] On carrying out the operation according to the procedure of
Example 4 starting with 1.8 g of
1-benzhydryl-3-[(2,5-dichlorophenyl)-(methylsulf-
onyl)methyl-(RS)]azetidin-3-ol, 0.4 cm.sup.3 of methanesulfonyl
chloride and 1.8 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent and collecting 100
cm.sup.3 fractions. Fractions 8 to 14 are combined and concentrated
to dryness under reduced pressure (2.7 kPa). The solid obtained is
crystallized from a mixture of 2 cm.sup.3 of dichloromethane and 30
cm.sup.3 of ethyl ether. 1.2 g of
1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine
are obtained melting at 202.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (250 MHz): 3.00 (3H, s,
SCH.sub.3), 3.70 (2H, m, NCH.sub.2), 4.25 (2H, m, NCH.sub.2), 4.70
(1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,
4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), between 7.55 and 7.70
(3H, m, 3CH arom.)].
[0364]
1-Benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]aze-
tidin-3-ol may be obtained in the following manner: on carrying out
the operation according to the procedure of Example 1 starting with
1.2 g of (2,5-dichlorobenzyl)methylsulfone and 1.2 g of
1-benzhydrylazetidin-3-one- , 1.8 g of
1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)-
]azetidin-3-ol are obtained in the form of a white solid.
[0365] (2,5-Dichlorobenzyl)methylsulfone may be prepared in the
following manner: 1.9 g of sodium methanesulfinate are added, at
room temperature, to a solution of 2.7 g of 2,5-dichlorobenzyl
chloride in 30 cm.sup.3 of ethanol. The mixture is heated under
reflux for 5 hours, cooled to room temperature and then taken up in
50 cm.sup.3 of water and 50 cm.sup.3 of ethyl acetate. The organic
phase is decanted off, washed with 20 cm of a saturated aqueous
sodium chloride solution, dried over magnesium sulfate and
concentrated to dryness under reduced pressure (2.7 kPa). 1.2 g of
(2,5-dichlorobenzyl)methylsulfone are obtained in the form of a
white solid.
Example 11
[0366] On carrying out the operation according to the procedure of
Example 4 starting with 9.1 g of
1-benzhydryl-3-[(2,4-dichlorophenyl)-(methylsulf-
onyl)methyl-(RS)]azetidin-3-ol, 2.2 cm.sup.3 of methanesulfonyl
chloride and 7 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 5.5 cm, height 30 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent and collecting 40
cm.sup.3 fractions. Fractions 27 to 39 are combined and
concentrated to dryness under reduced pressure (2.7 kPa). The solid
obtained is crystallized from 20 cm.sup.3 of ethyl ether. 1.5 g of
1-benzhydryl-3-[(2,4-dichlorophenyl)-(methylsulfonyl)meth-
ylene]azetidine are obtained melting at 165.degree. C. [NMR
spectrum in DMSO-d.sub.6, T=300K, .quadrature. in ppm (250 MHz):
3.00 (3H, s, SCH.sub.3), 3.65 (2H, m, NCH.sub.2), 4.25 (2H, m,
NCH.sub.2), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.),
7.30 (4H, t, J=7 Hz, 4CH arom.), 7.45 (6H, m, 6CH arom.), 7.80 (1H,
s, CH arom.)].
[0367]
1-Benzhydryl-3-[(2,4-dichlorophenyl)(methylsulfonyl)methyl-(RS)]aze-
tidin-3-ol may be obtained in the following manner: on carrying out
the operation according to the procedure of Example 1 starting with
4.8 g of (2,4-dichlorobenzyl)methylsulfone and 4.7 g of
1-benzhydrylazetidin-3-one- , 9.1 g of
1-benzhydryl-3-[(2,4-dichlorophenyl)(methylsulfonyl)methyl-(RS)-
]azetidin-3-ol are obtained in the form of a brown foam.
[0368] (2,4-Dichlorobenzyl)methylsulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 4 g of
(2,4-dichlorobenzyl)methylsulfide and 13 g of oxone.sup.R, 4.8 g of
(2,4-dichlorobenzyl)methylsulfone are obtained in the form of a
white solid melting at 111.degree. C.
[0369] (2,4-Dichlorobenzyl)methylsulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 2.8 cm.sup.3 of
2,4-dichlorobenzyl chloride and 1.5 g of sodium methylthiolate, 4 g
of (2,4-dichlorobenzyl)methylsulfide are obtained in the form of an
oil.
Example 12
[0370] On carrying out the operation according to the procedure of
Example 4 starting with 3 g of
1-benzhydryl-3-[(2,3-dichlorophenyl)-(methylsulfon-
yl)methyl-(RS)]azetidin-3-ol, 1.1 g of methanesulfonyl chloride and
3 g of 4-dimethylaminopyridine, the residue obtained is purified by
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with
a mixture of dichloromethane and ethanol (98/2 by volume) as eluent
and collecting 100 cm.sup.3 fractions. Fractions 10 to 20 are
combined and concentrated to dryness under reduced pressure (2.7
kPa). The solid obtained is crystallized from 40 cm.sup.3 of ethyl
ether. 1.6 g of
1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methylene]azetidine
are obtained melting at 201.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 3.00 (3H, s,
SCH.sub.3), 3.60 (2H, m, NCH.sub.2), 4.20 (2H, m, NCH.sub.2), 4.70
(1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,
4CH arom.), 7.45 (6H, m, 6CH arom.), 7.70 (1H, dd, J=8 and 2 Hz, CH
arom.)].
[0371]
1-Benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methyl-(RS)]aze-
tidin-3-ol may be obtained in the following manner: on carrying out
the operation according to the procedure of Example 1 starting with
3.6 g of (2,3-dichlorobenzyl)methylsulfone and 3.6 g of
1-benzhydrylazetidin-3-one- , 5.4 g of
1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methyl-(RS)- ]
azetidin-3-ol are obtained in the form of a white solid.
[0372] (2,3-Dichlorobenzyl)methylsulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 10 starting with 3 g of 2,3-dichlorobenzyl
chloride and 2.4 g of sodium methanesulfinate, 3.6 g of
(2,3-dichlorobenzyl)methylsulfonate are obtained in the form of a
white solid.
Example 13
[0373] On carrying out the operation according to the procedure of
Example 4 starting with 2.5 g of
1-benzhydryl-3-[(3-fluorophenyl)-(methylsulfonyl-
)methyl-(RS)]azetidin-3-ol, 0.72 cm.sup.3 of methanesulfonyl
chloride and 2.9 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent, collecting 100 cm.sup.3
fractions. Fractions 2 to 6 are combined and concentrated to
dryness under reduced pressure (2.7 kPa). The solid obtained is
crystallized from 40 cm.sup.3 of ethyl ether. 1.5 g of
1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)-methylene]azeti-
dine are obtained melting at 210.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.95 (3H, s,
SCH.sub.3), 3.80 (2H, m, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.70
(1H, s, NCH), between 7.10 and 7.30 (9H, m, 9CH arom.), 7.45 (5H,
m, 5CH arom.)].
[0374]
1-Benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidi-
n-3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 2.6
g of 3-fluorobenzyl methyl sulfone and 3.3 g of
1-benzhydrylazetidin-3-one, 2.9 g of
1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methyl-(RS)]azet-
idin-3-ol are obtained in the form of a white solid melting at
200.degree. C.
[0375] (3-Fluorobenzyl) methyl sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 3.1 g of 3-fluorobenzyl methyl
sulfide and 13 g of oxone.sup.R, 2.7 g of 3-fluorobenzyl methyl
sulfone are obtained in the form of a white solid.
[0376] (3-Fluorobenzyl) methyl sulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 2.6 cm.sup.3 of 3-fluorobenzyl
bromide and 1.6 g of sodium methylthiolate, 3.1 g of 3-fluorobenzyl
methyl sulfide are obtained in the form of an oil.
Example 14
[0377] On carrying out the operation according to the procedure of
Example 4 starting with 4.3 g of
1-benzhydryl-3-[(2-fluorophenyl)-(methylsulfonyl-
)methyl-(RS)]azetidin-3-ol, 1.2 cm.sup.3 of methanesulfonyl
chloride and 3.7 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 4.5 cm, height 30 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent and collecting 30
cm.sup.3 fractions. Fractions 28 to 58 are combined and
concentrated to dryness under reduced pressure (2.7 kPa). The solid
obtained is crystallized from 100 cm.sup.3 of ethyl ether. 2.3 g of
1-benzhydryl-3-[(2-fluorophenyl)(methylsulfonyl)-methylen-
e]azetidine are obtained melting at 188.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 3.00 (3H, s,
SCH.sub.3), 3.65 (2H, m, NCH.sub.2), 4.20 (2H, m, NCH.sub.2), 4.75
(1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (6H, m, 6CH
arom.), 7.50 (6H, m, 6CH arom.)].
[0378]
1-Benzhydryl-3-[(2-fluorophenyl)(methylsulfonyl)methyl-(RS)]-azetid-
in-3-ol may be obtained in the following manner: on carrying out
the operation according to the procedure of Example 1 starting with
3.4 g of 2-fluorobenzyl methyl sulfone and 4.2 g of
1-benzhydrylazetidin-3-one, 4.3 g of
1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methyl-(RS)]azet-
idin-3-ol are obtained in the form of a white solid.
[0379] (2-Fluorobenzyl) methyl sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 R starting with 3 g of 2-fluorobenzyl methyl
sulfide and 13 g of oxone.sup.R, 3.6 g of 3-fluorobenzyl methyl
sulfone are obtained in the form of a white solid.
[0380] (2-Fluorobenzyl) methyl sulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 2.4 cm.sup.3 of 2-fluorobenzyl
bromide and 1.5 g of sodium methylthiolate, 3 g of 2-fluorobenzyl
methyl sulfide are obtained in the form of an oil.
Example 15
[0381] On carrying out the operation according to the procedure of
Example 4 starting with 1 g of
1-benzhydryl-3-[(4-fluorophenyl)(methylsulfonyl)-m-
ethyl-(RS)]azetidin-3-ol, 0.3 cm.sup.3 of methanesulfonyl chloride
and 0.9 g of 4-dimethylaminopyridine, the residue obtained is
purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent and collecting 30
cm.sup.3 fractions. Fractions 20 to 35 are combined and
concentrated to dryness under reduced pressure (2.7 kPa). The solid
obtained is crystallized from 50 cm.sup.3 of ethyl ether. 0.4 g of
1-benzhydryl-3-[(4-fluorophenyl)(methylsulfonyl)methylene-
]-azetidine are obtained melting at 186.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.95 (3H, s,
SCH.sub.3), 3.80 (2H, m, NCH.sub.2), 4.20 (2H, m, NCH.sub.2), 4.75
(1H, s, NCH), between 7.15 and 7.35 (8H, m, 8CH arom.), 7.45 (6H,
m, 6CH arom.)].
[0382]
1-Benzhydryl-3-[(4-fluorophenyl)(methylsulfonyl)methyl-(RS)]-azetid-
in-3-ol may be obtained in the following manner: on carrying out
the operation according to the procedure of Example 1 starting with
2.8 g of 4-fluorobenzyl methyl sulfone and 3.6 g of
1-benzhydrylazetidin-3-one, 1 g of
1-benzhydryl-3-[(4-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-
-3-ol is obtained in the form of a white solid.
[0383] (4-Fluorobenzyl) methyl sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 3 g of 4-fluorobenzyl methyl
sulfide and 13 g of oxone.sup.R, 3 g of 4-fluorobenzyl methyl
sulfone are obtained in the form of a white solid melting at
110.degree. C.
[0384] (4-Fluorobenzyl) methyl sulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 2.5 cm.sup.3 of 4-fluorobenzyl
chloride and 1.5 g of sodium methylthiolate, 3 g of 4-fluorobenzyl
methyl sulfide are obtained in the form of an oil.
Example 16
[0385] On carrying out the operation according to the procedure of
Example 4 starting with 3.8 g of
1-benzhydryl-3-[(3,5-difluorophenyl)-(methylsulf-
onyl)methyl-(RS)]azetidin-3-ol, 1 cm.sup.3 of methanesulfonyl
chloride and 4.2 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent, collecting 100 cm.sup.3
fractions. Fractions 5 to 10 are combined and concentrated to
dryness under reduced pressure (2.7 kPa). The solid obtained is
crystallized from 30 cm.sup.3 of ethyl ether. 0.8 g of
1-benzhydryl-3-[(3,5-difluorophenyl)-(methylsulfonyl)meth-
ylene]azetidine are obtained melting at 172.degree. C. [NMR
spectrum in DMSO-d.sub.6, T=300K, .quadrature. in ppm (250 MHz):
3.00 (3H, s, SCH.sub.3), 3.85 (2H, m, NCH.sub.2), 4.20 (2H, m,
NCH.sub.2), 4.75 (1H, s, NCH), between 7.10 and 7.40 (9H, m, 9CH
arom.), 7.50 (4H, d, J=7 Hz, 4CH arom.)].
[0386]
1-Benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-az-
etidin-3-ol may be obtained in the following manner: on carrying
out the operation according to the procedure of Example 1 starting
with 3.2 g of 3,5-difluorobenzyl methyl sulfone and 3.7 g of
1-benzhydrylazetidin-3-one- , 3.9 g of
1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)-
]azetidin-3-ol are obtained in the form of a white solid.
[0387] (3,5-Difluorobenzyl) methyl sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 4.2 g of 3,5-difluorobenzyl
methyl sulfide and 16 g of oxone.sup.R, 3.3 g of 3,5-difluorobenzyl
methyl sulfone are obtained in the form of a white solid.
[0388] (3,5-Difluorobenzyl) methyl sulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 5 g of 3,5-difluorobenzyl
bromide and 2 g of sodium methylthiolate, 4.9 g of
3,5-difluorobenzyl methyl sulfide are obtained in the form of an
oil.
Example 17
[0389] On carrying out the operation according to the procedure of
Example 4 starting with 5.2 g of
1-benzhydryl-3-[(2,3-difluorophenyl)-(methylsulf-
onyl)methyl-(RS)]azetidin-3-ol, 2.3 cm.sup.3 of methanesulfonyl
chloride and 7.3 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 6 cm, height 40 cm) at a nitrogen pressure
of 0.5 bar with a mixture of dichloromethane and methanol (98/2 by
volume) as eluent and collecting 50 cm.sup.3 fractions. Fractions
65 to 87 are combined and concentrated to dryness under reduced
pressure (2.7 kPa). The solid obtained is crystallized from 75
cm.sup.3 of ethyl ether. 2.5 g of
1-benzhydryl-3-[(2,3-difluorophenyl)(methylsulfonyl)methylene]azetidine
are obtained melting at 208.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (400 MHz): 3.05 (3H, s,
SCH.sub.3), 3.70 (2H, s, NCH.sub.2), 4.25 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), between 7.15 and 7.55 (13H, m, 13CH arom.)].
[0390]
1-Benzhydryl-3-[(2,3-difluorophenyl)(methylsulfonyl)methyl-(RS)]-az-
etidin-3-ol may be obtained in the following manner: on carrying
out the operation according to the procedure of Example 1 starting
with 4 g of (2,3-difluorobenzyl) methyl sulfone and 4.8 g of
1-benzhydrylazetidin-3-o- ne, 5.5 g of
1-benzhydryl-3-[(2,3-difluorophenyl)(methyl-sulfonyl)methyl-(-
RS)]azetidin-3-ol are obtained in the form of a beige solid.
[0391] (2,3-Difluorobenzyl) methyl sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 10 starting with 4.1 g of 2,3-difluorobenzyl
bromide and 4.1 g of sodium methanesulfinate, 4 g of
(2,3-difluorobenzyl) methyl sulfone are obtained in the form of a
white solid.
Example 18
[0392] On carrying out the operation according to the procedure of
Example 4 starting with 5.2 g of
1-benzhydryl-3-[(2,5-difluorophenyl)-(methylsulf-
onyl)methyl-(RS)]azetidin-3-ol, 2.3 cm.sup.3 of methanesulfonyl
chloride and 7.3 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 6 cm, height 40 cm) at a nitrogen pressure
of 0.5 bar with a mixture of dichloromethane and methanol (98/2 by
volume) as eluent and collecting 50 cm.sup.3 fractions. Fractions
73 to 90 are combined and concentrated to dryness under reduced
pressure (2.7 kPa). The solid obtained is crystallized from 75
cm.sup.3 of ethyl ether. 2.6 g of
1-benzhydryl-3-[(2,5-difluorophenyl)(methylsulfonyl)methylene]azetidine
are obtained melting at 176.degree. C.
[0393]
1-Benzhydryl-3-[(2,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-az-
etidin-3-ol may be obtained in the following manner: on carrying
out the operation according to the procedure of Example 1 starting
with 4 g of (2,5-difluorobenzyl) methyl sulfone and 4.8 g of
1-benzhydrylazetidin-3-o- ne, 5.9 g of
1-benzhydryl-3-[(2,5-difluorophenyl)(methylsulfonyl)methyl-(R-
S)]azetidin-3-ol are obtained in the form of a cream-colored
solid.
[0394] (2,5-Difluorobenzyl) methyl sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 10 starting with 4.1 g of 2,5-difluorobenzyl
bromide and 4.1 g of sodium methanesulfinate, 4.8 g of
(2,5-difluorobenzyl) methyl sulfone are obtained in the form of a
white solid melting at 95.degree. C.
Example 19
[0395] On carrying out the operation according to the procedure of
Example 4 starting with 7.7 g of
1-benzhydryl-3-[(3-bromophenyl)-(methylsulfonyl)-
methyl-(RS)]azetidin-3-ol, 1.8 cm.sup.3 of methanesulfonyl chloride
and 5.8 g of 4-dimethylaminopyridine, the residue obtained is
purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane and then a dichloromethane and
ethanol mixture (99.5/0.5 by volume) as eluents and collecting 100
cm.sup.3 fractions. Fractions 17 to 28 are combined and
concentrated to dryness under reduced pressure (2.7 kPa). The solid
obtained is crystallized from a mixture of 5 cm.sup.3 of
dichloromethane and 50 cm.sup.3 of ethyl ether. 3.5 g of
1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methylene]azetidine
are obtained melting at 200.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.95 (3H, s,
SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,
4CH arom.), between 7.35 and 7.55 (6H, m, 6CH arom.), 7.65 (2H, m,
2CH arom.)].
[0396]
1-Benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methyl-(RS)]-azetidi-
n-3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 8 g
of 3-bromobenzyl methyl sulfone and 7.6 g of
1-benzhydrylazetidin-3-one, 8 g of
1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3--
ol are obtained in the form of a white solid.
[0397] 3-Bromobenzyl methyl sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 9 g of 3-bromobenzyl methyl
sulfide and 27 g of oxone.sup.R, 8.2 g of 3-bromobenzyl methyl
sulfone are obtained in the form of a white solid.
[0398] 3-Bromobenzyl methyl sulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 10 g of 3-bromobenzyl bromide
and 3.1 g of sodium methylthiolate, 9 g of 3-bromobenzyl methyl
sulfide are obtained in the form of an oil.
Example 20
[0399] On carrying out the operation according to the procedure of
Example 4 starting with 1.5 g of
1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)-m-
ethyl-(RS)]azetidin-3-ol, 0.3 cm.sup.3 of methanesulfonyl chloride
and 1.4 g of 4-dimethylaminopyridine, the residue obtained is
purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane and then a mixture of
dichloromethane and ethanol (99.7/0.3 by volume) as eluents and
collecting 100 cm.sup.3 fractions. Fractions 16 to 24 are combined
and concentrated to dryness under reduced pressure (2.7 kPa). The
solid obtained is crystallized from a mixture of 1.5 cm.sup.3 of
dichloromethane and 25 cm.sup.3 of ethyl ether. 0.5 g of
1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methylene]azetidine
is obtained melting at 198.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.95 (3H, s,
SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), between 7.10 and 7.30 (7H, m, 7CH arom.), 7.45 (5H,
m, 5CH arom.), 7.80 (2H, m, 2CH arom.)].
[0400]
1-Benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methyl-(RS)]-azetidin-
-3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 3.7
g of 3-iodobenzyl methyl sulfone and 3 g of
1-benzhydrylazetidin-3-one, 1.5 g of
1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-o-
l are obtained in the form of a white solid.
[0401] 3-Iodobenzyl methyl sulfone may be prepared in the following
manner: on carrying out the operation according to the procedure of
Example 2 starting with 3.6 g of 3-iodobenzyl methyl sulfide and
10.3 g of oxone.sup.R, 3.7 g of 3-iodobenzyl methyl sulfone are
obtained in the form of a white solid.
[0402] 3-Iodobenzyl methyl sulfide may be prepared in the following
manner: on carrying out the operation according to the procedure of
Example 2 starting with 5 g of 3-iodobenzyl bromide and 1.3 g of
sodium methylthiolate, 4 g of 3-iodobenzyl methyl sulfide are
obtained in the form of an oil.
Example 21
[0403] On carrying out the operation according to the procedure of
Example 4 starting with 2.4 g of
1-benzhydryl-3-[(methylsulfonyl)(3-trifluorometh-
oxyphenyl)methyl-(RS)]azetidin-3-ol, 0.6 cm.sup.3 of
methanesulfonyl chloride and 2.3 g of 4-dimethylaminopyridine, the
residue obtained is purified by chromatography on a silica gel
column (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm) at
a nitrogen pressure of 0.5 bar with dichloromethane and then a
mixture of dichloromethane and ethanol (99.7/0.3 by volume) as
eluents and collecting 100 cm.sup.3 fractions. Fractions 12 to 25
are combined and concentrated to dryness under reduced pressure
(2.7 kPa). The solid obtained is crystallized from a mixture of 2
cm.sup.3 of dichloromethane and 30 cm.sup.3 of ethyl ether. 0.7 g
of 1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl-
)methylene]azetidine is obtained melting at 162.degree. C. [NMR
spectrum in DMSO-d.sub.6, T=300K, .quadrature. in ppm (250 MHz):
3.00 (3H, s, SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s,
NCH.sub.2), 4.75 (1H, s, NCH), between 7.15 and 7.40 (6H, m, 6CH
arom.), between 7.45 and 7.55 (7H, m, 7CH arom.), 7.60 (1H, t, J=7
Hz, CH arom.)].
[0404]
1-Benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)-methyl-(-
RS)]azetidin-3-ol may be obtained in the following manner: on
carrying out the operation according to the procedure of Example 1
starting with 2.4 g of methyl(3-trifluoromethoxybenzyl)sulfone and
2.2 g of 1-benzhydrylazetidin-3-one, 2.4 g of
1-benzhydryl-3-[(methylsulfonyl)(3-t-
rifluoromethoxyphenyl)methyl-(RS)]-azetidin-3-ol are obtained in
the form of a white solid.
[0405] Methyl(3-fluoromethoxybenzyl)sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 2.6 g of
methyl(3-trifluoromethoxybe- nzyl)sulfide and 7.2 g of oxone.sup.R,
2.4 g of methyl(3-trifluoromethoxyb- enzyl)sulfone are obtained in
the form of a white solid.
[0406] Methyl(3-trifluoromethoxybenzyl)sulfide may be prepared in
the following manner: on carrying out the operation according to
the procedure of Example 2 starting with 3 g of
3-trifluoromethoxybenzyl bromide and 1 g of sodium methylthiolate,
3.3 g of methyl(3-trifluoromethoxybenzyl)sulfide are obtained in
the form of an oil.
Example 22
[0407] On carrying out the operation according to the procedure of
Example 4 starting with 4.1 g of
1-benzhydryl-3-[(methylsulfonyl)(3-trifluorometh-
ylphenyl)methyl-(RS)]azetidin-3-ol, 1 cm.sup.3 of methanesulfonyl
chloride and 4.2 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent, collecting 100 cm.sup.3
fractions. Fractions 10 to 14 are combined and concentrated to
dryness under reduced pressure (2.7 kPa). The solid obtained is
crystallized from a mixture of 2 cm.sup.3 of dichloromethane and 30
cm.sup.3 of ethyl ether. 1.2 g of
1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methylene]azetid-
ine are obtained melting at 178.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 3.00 (3H, s,
SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.15 (2H, s, NCH.sub.2), 4.70
(1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,
4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), between 7.60 and 7.80
(4H, m, 4CH arom.)].
[0408]
1-Benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methyl-(RS-
)]azetidin-3-ol may be obtained in the following manner: on
carrying out the operation according to the procedure of Example 1
starting with 3.4 g of methyl(3-trifluoromethylbenzyl)sulfone and
3.4 g of 1-benzhydrylazetidin-3-one, 4.2 g of
1-benzhydryl-3-[(methylsulfonyl)(3-t-
rifluoromethylphenyl)methyl-(RS)]-azetidin-3-ol are obtained in the
form of a white solid.
[0409] Methyl(3-trifluoromethylbenzyl)sulfone may be prepared in
the following manner: on carrying out the operation according to
the procedure of Example 2 starting with 3.3 g of
methyl(3-trifluoromethylben- zyl)sulfide and 10 g of oxone.sup.R,
3.4 g of methyl(3-trifluoromethylbenz- yl)sulfone are obtained in
the form of a white solid.
[0410] Methyl(3-trifluoromethylbenzyl)sulfide may be prepared in
the following manner: on carrying out the operation according to
the procedure of Example 2 starting with 3.9 g of
3-trifluoromethylbenzyl bromide and 1.4 g of sodium methylthiolate,
3.3 g of methyl(3-trifluoromethylbenzyl)sulfide are obtained in the
form of an oil.
Example 23
[0411] On carrying out the operation according to the procedure of
Example 4 starting with 2.7 g of
1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl]-
-(methylsulfonyl)methyl-(RS)}azetidin-3-ol, 0.6 cm.sup.3 of
methanesulfonyl chloride and 2.4 g of 4-dimethylaminopyridine, the
residue obtained is purified by chromatography on a silica gel
column (particle size 0.04-0.06 mm, diameter 6 cm, height 40 cm) at
a nitrogen pressure of 0.5 bar with dichloromethane as eluent,
collecting 100 cm.sup.3 fractions. Fractions 7 to 12 are combined
and concentrated to dryness under reduced pressure (2.7 kPa). The
solid obtained is crystallized from 10 cm.sup.3 of ethyl ether. 1 g
of
1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl]-(methylsulfonyl)methylen-
e}azetidine is obtained melting at 192.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 3.00 (3H, s,
SCH.sub.3), 3.85 (2H, s, NCH.sub.2), 4.15 (2H, s, NCH.sub.2), 4.70
(1H, s, NCH), 7.15 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,
4CH arom.), 7.40 (4H, d, J=7 Hz, 4CH arom.), 8.05 (2H, s, 2CH
arom.), 8.15 (1H, s, CH arom.)].
[0412]
1-Benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)-me-
thylene}azetidin-3-ol may be obtained in the following manner: on
carrying out the operation according to the procedure of Example 1
starting with 3.1 g of
methyl[3,5-bis(trifluoromethyl)benzyl]sulfone and 2.4 g of
1-benzhydrylazetidin-3-one, 2.8 g of
1-benzhydryl-3-{[(3,5-bis(trifluorom-
ethyl)phenyl](methylsulfonyl)-methylene}azetidin-3-ol are obtained
in the form of a white solid.
[0413] Methyl[3,5-bis(trifluoromethyl)benzylsulfone may be prepared
in the following manner: on carrying out the operation according to
the procedure of Example 10 starting with 3 g of
3,5-bis(trifluoromethyl)benz- yl chloride and 2 g of sodium
methanesulfinate, 3.1 g of
methyl[3,5-bis(trifluoromethyl)benzyl]sulfone are obtained in the
form of a white solid melting at 132.degree. C.
Example 24
[0414] On carrying out the operation according to the procedure of
Example 4 starting with 10.7 g of
1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulfo-
nyl)methyl-(RS)]azetidin-3-ol, 2.2 cm.sup.3 of methanesulfonyl
chloride and 7 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 5.5 cm, height 30 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent and collecting 35
cm.sup.3 fractions. Fractions 40 to 58 are combined and
concentrated to dryness under reduced pressure (2.7 kPa). The solid
obtained is crystallized from 50 cm.sup.3 of ethyl ether. 1.5 g of
1-benzhydryl-3-[3,5-dibromophenyl)(methylsulfonyl)methyle-
ne]azetidine are obtained melting at 209.degree. C. [NMR spectrum
in DMSO-d.sub.6, T=300K, .quadrature. in ppm (250 MHz): 3.00 (3H,
s, SCH.sub.3), 3.88 (2H, s, NCH.sub.2), 4.22 (2H, s, NCH.sub.2),
4.75 (1H, s, NCH), 7.22 (2H, t, J=7 Hz, 2CH arom.), 7.33 (4H, t,
J=7 Hz, 4CH arom.), 7.48 (4H, d, J=7 Hz, 4CH arom.), 7.68 (2H, s,
2CH arom.), 7.95 (1H, s, CH arom.)].
[0415]
1-Benzhydryl-3-[(3,5-dibromophenyl)(methylsulfonyl)methyl-(RS)]azet-
idin-3-ol may be obtained in the following manner: on carrying out
the operation according to the procedure of Example 1 starting with
6.2 g of (3,5-dibromobenzyl)methylsulfone and 4.5 g of
1-benzhydrylazetidin-3-one, 10.7 g of
1-benzhydryl-3-[3,5-dibromophenyl)(methylsulfonyl)methyl-(RS)]a-
zetidin-3-ol are obtained in the form of a foam.
[0416] (3,5-Dibromobenzyl)methylsulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 5.8 g of
(3,5-dibromobenzyl)methylsulfide and 13 g of oxone.sup.R, 6.2 g of
(3,5-dibromobenzyl)methylsulfone are obtained in the form of a
white solid.
[0417] (3,5-Dibromobenzyl)methylsulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 6.6 g of 3,5-dibromobenzyl
bromide and 1.5 g of sodium methylthiolate, 5.8 g of
(3,5-dibromobenzyl)methylsulfide are obtained in the form of an
oil.
Example 25
[0418] On carrying out the operation according to the procedure of
Example 4 starting with 4.2 g of
1-benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)--
methyl-(RS)]azetidin-3-ol, 1.1 cm.sup.3 of methanesulfonyl chloride
and 2.5 g of 4-dimethylaminopyridine, the residue obtained is
purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 4 cm, height 35 cm) at a nitrogen pressure
of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50/50
by volume) as eluents, collecting 400 cm.sup.3 fractions. Fractions
17 to 33 are combined and concentrated to dryness under reduced
pressure (2.7 kPa). The solid obtained is recrystallized from 15
cm.sup.3 of ethyl acetate. 0.6 g of
1-benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methylene]azetidine
is obtained melting at 184.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 3.00 (3H, s,
SCH.sub.3), 3.85 (2H, s, NCH.sub.2), 4.25 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,
4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.75 (1H, t, J=7 Hz,
CH arom.), 7.85 (1H, d, J=7 Hz, CH arom.), 8.25 (2H, m, 2CH
arom.)].
[0419]
1-Benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methyl-(RS)]azetidin-
-3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 3.9
g of methyl(3-nitrobenzyl)sulfone and 4.2 g of
1-benzhydrylazetidin-3-one, 4.2 g of
1-benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methyl-(RS)]azetidin--
3-ol are obtained in the form of a foam.
[0420] Methyl(3-nitrobenzyl)sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 but starting with 18.1 g of
methyl(3-nitrobenzyl)sulfide and 68 g of oxone.sup.R, 13.9 g of
methyl(3-nitrobenzyl)sulfone are obtained in the form of a
foam.
[0421] Methyl(3-nitrobenzyl)sulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 17.2 g of 3-nitrobenzyl
chloride and 7.7 g of sodium methylthiolate, 18.2 g of
methyl(3-nitrobenzyl)sulfide are obtained in the form of an
oil.
Example 26
[0422] A mixture of 0.34 g of
1-benzhydryl-3-[(methylsulfonyl)-(3-nitrophe-
nyl)methylene]azetidine, 16 cm.sup.3 of 1 N hydrochloric acid in 8
cm.sup.3 of ethanol and 16 cm.sup.3 of tetrahydrofuran is heated
under reflux. 0.17 g of iron powder is added and the reflux is
maintained for 3 hours. The mixture is then cooled to room
temperature and the insoluble matter is filtered off. The solution
is taken up in 10 cm.sup.3 of 1 N sodium hydroxide and 50 cm.sup.3
of a saturated aqueous sodium chloride solution. The aqueous phase
is extracted with 3 times 40 cm.sup.3 of dichloromethane, the
extracts are combined, dried over sodium sulfate and concentrated
to dryness under reduced pressure (2.7 kPa). The residue is
purified on a silica gel column (particle size 0.04-0.06 mm,
diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with
a mixture of cyclohexane and ethyl acetate (50/50 by volume) as
eluent, collecting 20 cm.sup.3 fractions. Fractions 13 to 31 are
combined and concentrated to dryness under reduced pressure (2.7
kPa). The solid obtained is crystallized from 15 cm.sup.3 of ethyl
ether. 0.17 g of
3-[(3-aminophenyl)-(methylsulfonyl)methylene]-1-benzhydrylazetidine
is obtained melting at 197.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (250 MHz): 2.95 (3H, s,
SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), 5.25 (2H, s, NH.sub.2), 6.55 (3H, m, 3CH arom.), 7.05
(1H, t, J=7 Hz, CH arom.), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30
(4H, t, J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.)].
Example 27
[0423] On carrying out the operation according to the procedure of
Example 4 starting with 1.2 g of
1-benzhydryl-3-[(3-methoxycarbonylphenyl)-(methy-
lsulfonyl)methyl-(RS)]azetidin-3-ol, 0.3 cm.sup.3 of
methanesulfonyl chloride and 1.3 g of 4-dimethylaminopyridine, the
residue obtained is purified by chromatography on a silica gel
column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) at
a nitrogen pressure of 0.5 bar with dichloromethane and then a
mixture of dichloromethane and ethyl acetate (99.5/0.5 by volume)
as eluents and collecting 100 cm.sup.3 fractions. Fraction 18 is
concentrated to dryness under reduced pressure (2.7 kPa). The solid
obtained is precipitated in 5 cm.sup.3 of ethyl ether. 0.13 g of
1-benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl-
)-methylene]azetidine is obtained in the form of a foamy solid [NMR
spectrum in DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz):
2.95 (3H, s, SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s,
NCH.sub.2), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.),
7.30 (4H, t, J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.),
7.60 (1H, t, J=7 Hz, CH arom.), 7.70 (1H, d, J=7 Hz, CH arom.),
8.00 (2H, m, 2CH arom.)].
[0424]
1-Benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)-methyl-(R-
S)]azetidin-3-ol may be obtained in the following manner: on
carrying out the operation according to the procedure of Example 1
starting with 3 g of (3-methoxycarbonylbenzyl)methylsulfone and 3.6
g of 1-benzhydrylazetidin-3-one, 1.2 g of
1-benzhydryl-3-[(3-methoxycarbonylph-
enyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the
form of a foam after purification by chromatography on a silica gel
column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) at
a nitrogen pressure of 0.5 bar with dichloromethane and then a
dichloromethane and ethanol mixture (99/1 by volume) as
eluents.
[0425] (3-Methoxycarbonylbenzyl)methylsulfone may be prepared in
the following manner: on carrying out the operation according to
the procedure of Example 2 starting with 4.3 g of
(3-methoxycarbonylbenzyl)me- thylsulfide and 13.4 g of oxone.sup.R,
3.4 g of (3-methoxycarbonylbenzyl)m- ethylsulfone are obtained in
the form of a white solid.
[0426] (3-Methoxycarbonylbenzyl)methylsulfide may be prepared in
the following manner: on carrying out the operation according to
the procedure of Example 2 starting with 5 g of
3-methoxycarbonylbenzyl bromide and 1.7 g of sodium methylthiolate,
4.3 g of (3-methoxycarbonylbenzyl)methylsulfide are obtained in the
form of an oil.
Example 28
[0427] On carrying out the operation according to the procedure of
Example 4 starting with 6.2 g of
1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)m-
ethyl-(RS)]azetidin-3-ol, 1.6 cm.sup.3 of methanesulfonyl chloride
and 6.8 g of 4-dimethylaminopyridine, the residue obtained is
purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane and then a dichloromethane and
ethyl acetate mixture (99.5/0.5 by volume) as eluents and
collecting 250 cm.sup.3 fractions. Fractions 10 to 15 are combined
and concentrated to dryness under reduced pressure (2.7 kPa). The
solid obtained is crystallized from a mixture of 5 cm.sup.3 of
dichloromethane and 70 cm.sup.3 of ethyl ether. 2.9 g of
1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]-azetidine
are obtained melting at 152.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 3.00 (3H, s,
SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,
4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.65 (1H, t, J=7 Hz,
CH arom.), 7.75 (1H, d, J=7 Hz, CH arom.), 7.90 (2H, m, 2CH
arom.)].
[0428]
1-Benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]-azetidi-
n-3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 3.9
g of (3-cyanobenzyl)methylsulfone and 4.7 g of
1-benzhydrylazetidin-3-one, 6.2 g of
1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin--
3-ol are obtained in the form of a white solid.
[0429] (3-Cyanobenzyl)methylsulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 6.7 g of
(3-cyanobenzyl)methylsulfide and 27.6 g of oxone.sup.R, 3.9 g of
(3-cyanobenzyl)methylsulfone are obtained in the form of a white
solid.
[0430] (3-Cyanobenzyl)methylsulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 8 g of 3-cyanobenzyl bromide
and 3.1 g of sodium methylthiolate, 6.8 g of
(3-cyanobenzyl)methylsulfide are obtained in the form of an
oil.
Example 29
[0431] A mixture of 3 g of
1-benzhydryl-3-[(3-carboxyphenyl)(methylsulfony-
l)methylene]azetidine hydrochloride, 1.3 g of pentafluorophenol,
1.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 30
cm.sup.3 of dimethylformamide is stirred at room temperature for 15
hours. The mixture is taken up in 100 cm.sup.3 of water and 100
cm.sup.3 of a saturated aqueous sodium chloride solution and 50
cm.sup.3 of ethyl acetate. The organic phase is decanted off, dried
over magnesium sulfate and concentrated to dryness under reduced
pressure (2.7 kPa). The residue is purified by chromatography on a
silica gel column (particle size 0.04-0.06 mm, diameter 3 cm,
height 35 cm) at a nitrogen pressure of 0.5 bar with
dichloromethane and then a dichloromethane and methanol mixture
(99.4/0.6 by volume) as eluents and collecting 100 cm.sup.3
fractions. Fractions 13 to 16 are combined and concentrated to
dryness under reduced pressure (2.7 kPa). The solid obtained is
crystallized from 10 cm.sup.3 of ethyl ether. 0.6 g of
1-benzhydryl-3-[(methylsulfonyl)(3-pentafluoroph-
enoxy-carbonylphenyl)methylene]azetidine is obtained melting at
182.degree. C. [NMR spectrum in DMSO-d.sub.6, T=300K, .quadrature.
in ppm (400 MHz): 3.00 (3H, s, SCH.sub.3), 3.85 (2H, s, NCH.sub.2),
4.25 (2H, s, NCH.sub.2), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz,
2CH arom.), 7.30 (4H, t, J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz,
4CH arom.), 7.70 (1H, t, J=7 Hz, CH arom.), 8.20 (2H, m, 2CH
arom.)].
[0432]
1-Benzhydryl-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]-azetidi-
ne hydrochloride may be prepared in the following manner: a mixture
of 10 g of
1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine
in 40 cm.sup.3 of acetic acid and 40 cm.sup.3 of concentrated
hydrochloric acid (d=1.18) is heated at 45.degree. C. for 7 days.
The reaction medium is cooled on an ice-cold water bath and the
precipitate formed is filtered on sintered glass. The solid is
washed with 20 cm.sup.3 of a mixture of acetic acid and
concentrated hydrochloric acid (50-50 by volume) and then with 3
times 20 cm.sup.3 of water and finally with 20 cm.sup.3 of ethanol.
The white solid obtained is under reduced pressure (2.7 kPa) at
45.degree. C. and 2.5 g of 1-benzhydryl-3-[(3-carbo-
xyphenyl)(methylsulfonyl)methylene] azetidine hydrochloride are
obtained in the form of a white solid.
Example 30
[0433] A solution of 0.65 g of
1-benzhydryl-3-[(methylsulfonyl)(3-pentaflu-
orophenoxycarbonylphenyl)methylene]azetidine in 25 cm.sup.3 of 6.2
N ammoniacal ethanol is stirred for 4 hours at room temperature.
The mixture is concentrated to dryness under reduced pressure (2.7
kPa) and then the residue is purified by chromatography on a silica
gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30
cm) at a nitrogen pressure of 0.5 bar with a dichloromethane and
ethanol mixture (99/1 by volume) and then a dichloromethane and
ethanol mixture (98/2 by volume) as eluents and collecting 60
cm.sup.3 fractions. Fractions 18 to 30 are combined and
concentrated to dryness under reduced pressure (2.7 kPa). 0.2 g of
1-benzhydryl-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]aze-
tidine is obtained melting at 140.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 3.00 (3H, s,
SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.25 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), 7.25 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,
4CH arom.), between 7.45 and 7.65 (7H, m, 6CH arom. and 2
CONH.sub.2), 7.95 (2H, m, 2CH arom.), 8.10 (1H, s, 2
CONH.sub.2).
Example 31
[0434] On carrying out the operation according to the procedure of
Example 4 starting with 4.6 g of
1-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl-
)methyl-(RS)]azetidin-3-ol, 1.2 cm.sup.3 of methanesulfonyl
chloride and 3.8 g of 4-dimethylaminopyridine, 2.6 g of
1-benzhydryl-3-[(3-methoxyphen-
yl)(methylsulfonyl)methylene]azetidine are obtained, after
recrystallization from 150 cm.sup.3 of acetonitrile, melting at
179.degree. C. [NMR spectrum in DMSO-d.sub.6, T=300K, .quadrature.
in ppm (250 MHz): 2.95 (3H, s, SCH.sub.3), 3.75 (3H, s, OCH.sub.3),
3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75 (1H, s,
NCH), 7.00 (3H, m, 3 CH arom.), between 7.20 and 7.12 (11H, m, 10OH
phenyls and 1CH arom.)].
[0435]
1-Benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetid-
in-3-ol may be obtained in the following manner: on carrying out
the operation according to the procedure of Example 1 starting with
3.4 g of (3-methoxybenzyl)methylsulfone and 4 g of
1-benzhydrylazetidin-3-one, 4.6 g of
1-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidi-
n-3-ol are obtained in the form of a white solid.
[0436] (3-Methoxybenzyl)methylsulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 3.4 g of
(3-methoxybenzyl)methylsulfide and 13 g of oxone.sup.R, 4 g of
(3-methoxybenzyl)methylsulfone are obtained in the form of a white
solid melting at 71.degree. C.
[0437] (3-Methoxybenzyl)methylsulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 3.1 g of 3-methoxybenzyl
bromide and 1.5 g of sodium methylthiolate, 3.4 g of
(3-methoxybenzyl)methylsulfide are obtained in the form of an
oil.
Example 32
[0438] 10 cm.sup.3 of a 1 M solution of boron tetrabromide in
dichloromethane are added, with stirring, to a solution of 1.3 g of
1-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine
in 100 cm.sup.3 of dichloromethane. The stirring is maintained for
16 hours at room temperature. The reaction medium is taken up in
100 cm.sup.3 of ice-cold water. The organic phase is washed with 3
times 50 cm.sup.3 of water, dried over magnesium sulfate and
concentrated to dryness under reduced pressure (2.7 kPa). The
residue is precipitated in 150 cm.sup.3 of isopropyl ether and then
dissolved in 50 cm.sup.3 of dichloromethane. The organic phase is
washed with 3 times 30 cm.sup.3 of a saturated aqueous solution of
sodium bicarbonate, decanted off, dried over magnesium sulfate and
concentrated to dryness under reduced pressure (2.7 kPa). The
residue is precipitated in 80 cm.sup.3 of ethyl ether. 0.36 g of
1-benzhydryl-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine
is obtained from a solid melting at 248.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.95 (3H, s,
SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), 6.85 (3H, m, 3 CH arom.), 7.25 (3H, m, 3 CH arom.),
7.35 (4H, t, J=7 Hz, 4CH arom.), 7.50 (4H, d, J=7 Hz, 4CH arom.),
9.50 (1H, s, OH)].
Example 33
[0439] On carrying out the operation according to the procedure of
Example 32 starting with 1.4 g of
1-benzhydryl-3-[(4-methoxyphenyl)(methylsulfony-
l)methylene]azetidine, 10 cm.sup.3 of a 1 M boron tribromide
solution and 100 cm.sup.3 of dichloromethane, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 3.5 cm, height 24 cm) at a nitrogen pressure
of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50/50
by volume) as eluents and collecting 25 cm.sup.3 fractions.
Fractions 21 to 37 are combined and concentrated to dryness under
reduced pressure (2.7 kPa). The solid obtained is crystallized from
a mixture of 30 cm.sup.3 of ethyl ether. 0.6 g of
1-benzhydryl-3-[(4-hydroxyphenyl)(methylsulfonyl)-methylene]azet-
idine is obtained melting at 211.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.90 (3H, s,
SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), 6.80 (2H, d, J=7 Hz, 2CH arom.), between 7.10 and
7.35 (8H, m, 8CH arom.), 7.48 (4H, d, J=7 Hz, 4CH arom.), 9.80 (1H,
s, OH)].
[0440]
1-Benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methylene]-azetidi-
ne may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 4 starting with 3.5
g of
1-benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-o-
l, 0.9 cm.sup.3 of methanesulfonyl chloride and 2.9 g of
4-dimethylaminopyridine, the residue obtained is purified by
recrystallization from 100 cm.sup.3 of acetonitrile. 1 g of
1-benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methylene]azetidine
is obtained melting at 181.degree. C.
[0441]
1-Benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methyl-(RS)]-azeti-
din-3-ol may be obtained in the following manner: on carrying out
the operation according to the procedure of Example 1 starting with
3.5 g of (4-methoxybenzyl)methylsulfone and 4 g of
1-benzhydrylazetidin-3-one, 3.6 g of
1-benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidi-
n-3-ol are obtained in the form of a white solid.
[0442] (4-Methoxybenzyl)methylsulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 3.4 g of
(4-methoxybenzyl)methylsulfide and 13 g of oxone.sup.R, 3.5 g of
(3-methoxybenzyl)methylsulfone are obtained in the form of a white
solid melting at 113.degree. C.
[0443] (4-Methoxybenzyl)methylsulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 3.1 g of 4-methoxybenzyl
chloride and 1.5 g of sodium methylthiolate, 3.4 g of
(4-methoxybenzyl)methylsulfide are obtained in the form of an
oil.
Example 34
[0444] On carrying out the operation according to the procedure of
Example 32 starting with 1.4 g of
1-benzhydryl-3-[(2-methoxyphenyl)(methylsulfony-
l)methylene]azetidine, 10 cm.sup.3 of a 1 M solution of boron
tribromide and 100 cm.sup.3 of dichloromethane, the residue
obtained is purified by chromatography on a silica gel column
(particle size 0.04-0.06 mm, diameter 4 cm, height 30 cm) at a
nitrogen pressure of 0.5 bar with dichloromethane as eluent and
collecting 40 cm.sup.3 fractions. Fractions 15 to 34 are combined
and concentrated to dryness under reduced pressure (2.7 kPa). The
solid obtained is crystallized from 40 cm.sup.3 of ethyl ether. 0.7
g of 1-benzhydryl-3-[(2-hydroxyphenyl)(methylsulfonyl)-methyle-
ne]azetidine is obtained melting at 196.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 3.00 (3H, s,
SCH.sub.3), 3.60 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), 6.85 (1H, t, J=7 Hz, CH arom.), 6.90 (1H, d, J=7 Hz,
CH arom.), 7.20 (4H, m, 4CH arom.), 7.30 (4H, t, J=7 Hz, 4CH
arom.), 7.48 (4H, d, J=7 Hz, 4CH arom.), 9.90 (1H, s, OH)].
[0445]
1-Benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)-methylene]azetidi-
ne may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 4 starting with 4.2
g of
1-benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-o-
l, 1.1 cm.sup.3 of methanesulfonyl chloride and 3.5 g of
4-dimethylaminopyridine, the residue obtained is purified by
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 4 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with
a mixture of dichloromethane and ethyl acetate (50/50 by volume) as
eluents and collecting 40 cm.sup.3 fractions. Fractions 23 to 54
are combined and concentrated to dryness under reduced pressure
(2.7 kPa). The solid obtained is crystallized from 40 cm.sup.3 of
ethyl ether. 1.9 g of
1-benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methylene]azetidine
are obtained melting at 204.degree. C.
[0446]
1-Benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methyl-(RS)]-azeti-
din-3-ol may be obtained in the following manner: on carrying out
the operation according to the procedure of Example 1 starting with
4 g of (2-methoxybenzyl)methylsulfone and 4.5 g of
1-benzhydrylazetidin-3-one, 4.3 g of
1-benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methyl-(RS)]aze-
tidin-3-ol are obtained in the form of a brown foam.
[0447] (2-Methoxybenzyl)methylsulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 10 starting with 3.1 g of (2-methoxybenzyl)
chloride and 4.1 g of sodium methanesulfinate, 4 g of
(2-methoxybenzyl)methylsulfone are obtained in the form of a white
solid.
Example 35
[0448] On carrying out the operation according to the procedure of
Example 4 starting with 2.1 g of
1-benzhydryl-3-[(methylsulfonyl)(naphth-2-yl)met-
hyl-(RS)]azetidin-3-ol, 0.5 cm.sup.3 of methanesulfonyl chloride
and 2.2 g of 4-dimethylaminopyridine, the residue obtained is
purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 4 cm, height 30 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent and collecting 100
cm.sup.3 fractions. Fractions 6 to 10 are combined and concentrated
to dryness under reduced pressure (2.7 kPa). The solid obtained is
crystallized from 20 cm.sup.3 of ethyl ether. 0.6 g of
1-benzhydryl-3-[(methylsulfonyl)(naphth-2-yl)met- hylene]azetidine
is obtained melting at 178.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 3.00 (3H, s,
SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), 7.20 (4H, m, 4CH arom.), 7.30 (4H, t, J=7 Hz, 4CH
arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.52 (3H, m, 3CH arom.),
7.90 (4H, m, 4CH arom.)].
[0449]
1-Benzhydryl-3-[(methylsulfonyl)(naphth-2-yl)methyl-(RS)]-azetidin--
3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 3.5
g of methyl(naphth-2-ylmethyl)sulfone and 3.8 g of
1-benzhydrylazetidin-3-one, 2.2 g of
1-benzhydryl-3-[(methylsulfonyl)(naphth-2-yl)methyl-(RS)]azetidi-
n-3-ol are obtained in the form of a white solid melting at
196.degree. C.
[0450] Methyl(naphth-2-ylmethyl)sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 4.2 g of
methyl(naphth-2-ylmethyl)sulfide and 13.7 g of oxone.sup.R, 3.6 g
of methyl(naphth-2-ylmethyl)sulfone are obtained in the form of a
cream-colored solid.
[0451] Methyl(naphth-2-ylmethyl)sulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 5 g of
(2-bromomethyl)naphthalene and 1.8 g of sodium methylthiolate, 4.2
g of methyl(naphth-2-ylmethyl)sulfide are obtained in the form of
an oil.
Example 36
[0452] On carrying out the operation according to the procedure of
Example 4 starting with 4.3 g of
1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)met-
hyl-(RS)]azetidin-3-ol, 1.1 cm.sup.3 of methanesulfonyl chloride
and 4.6 g of 4-dimethylaminopyridine, the residue obtained is
purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 4 cm, height 30 cm) at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent and collecting 100
cm.sup.3 fractions. Fractions 6 to 14 are combined and concentrated
to dryness under reduced pressure (2.7 kPa). The solid obtained is
crystallized from 30 cm.sup.3 of ethyl ether. 2.5 g of
1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)met- hylene] azetidine
are obtained melting at 196.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 3.00 (3H, s,
SCH.sub.3), 3.35 and 3.50 (1H each, dd, J=16 and 3 Hz, NCH.sub.2),
4.35 (2H, m, NCH.sub.2), 4.75 (1H, s, NCH), between 7.10 and 7.70
(14H, m, 14CH arom.), 8.00 (3H, m, 3CH arom.)].
[0453]
1-Benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)methyl-(RS)]-azetidin--
3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 4.1
g of methyl(naphth-1-ylmethyl)sulfone and 4.4 g of
1-benzhydrylazetidin-3-one, 4.3 g of
1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)methyl-(RS)]azetidi-
n-3-ol are obtained in the form of a solid.
[0454] Methyl(naphth-1-ylmethyl)sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 R starting with 4.3 g of
methyl(naphth-1-ylmethyl)sulfide and 13.9 g of oxone.sup.R, 4.1 g
of methyl(naphth-1-ylmethyl)sulfone are obtained in the form of a
white solid.
[0455] Methyl(naphth-1-ylmethyl)sulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 4 g of
1-chloromethylnaphthalene chloride and 1.8 g of sodium
methylthiolate, 4.5 g of methyl(naphth-1-ylmethyl)sulfide are
obtained in the form of an oil.
Example 37
[0456] On carrying out the operation according to the procedure of
Example 4 starting with 0.6 g of
1-benzhydryl-3-[(methylsulfonyl)(3-pyrrolidinoph-
enyl)methyl-(RS)]azetidin-3-ol, 0.15 cm.sup.3 of methanesulfonyl
chloride and 0.6 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 2 cm, height 30 cm) at a nitrogen pressure
of 0.5 bar with a dichloromethane and methanol mixture (98/2 by
volume) as eluents and collecting 20 cm.sup.3 fractions. Fractions
8 to 13 are combined and concentrated to dryness under reduced
pressure (2.7 kPa). The solid obtained is crystallized from 8
cm.sup.3 of ethyl ether. 0.36 g of
1-benzhydryl-3-[(methylsulfonyl)-(3-pyrrolidinophenyl)methylene]azetidine
is obtained melting at 153.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (250 MHz): 1.95 (4H, m, 2
CH.sub.2), 2.95 (3H, s, SCH.sub.3), 3.20 (4H, m, 2 NCH.sub.2), 3.80
(2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75 (1H, s, NCH),
6.60 (3H, m, 3CH arom.), 7.20 (3H, m, 3CH arom.), 7.30 (4H, t, J=7
Hz, 4CH arom.), 7.48 (4H, d, J=7 Hz, 4CH arom.)].
[0457]
1-Benzhydryl-3-[(methylsulfonyl)(3-pyrrolidinophenyl)methyl-(RS)]az-
etidin-3-ol may be obtained in the following manner: on carrying
out the operation according to the procedure of Example 1 starting
with 0.77 g of 3-pyrrolidinobenzyl methyl sulfone and 0.76 g of
1-benzhydrylazetidin-3-o- ne, 0.6 g of
1-benzhydryl-3-[(methylsulfonyl)(3-pyrrolidinophenyl)methyl-(-
RS)]azetidin-3-ol is obtained in the form of a solid.
[0458] Methyl(3-pyrrolidinobenzyl)sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 1 g of
methyl(3-pyrrolidinobenzyl)sulfide and 3.3 g of oxone.sup.R, 0.8 g
of methyl(3-pyrrolidinobenzyl)sulfone is obtained in the form of a
solid.
[0459] Methyl(3-pyrrolidinobenzyl)sulfide may be prepared in the
following manner: a mixture of 2 g of (3-iodobenzyl)methylsulfide,
1.3 cm.sup.3 of pyrrolidine, 1.1 g of sodium tert-butoxide, 0.28 g
of 1,1'-bis(diphenylphosphino)-ferrocenyl palladium chloride, 0.63
g of 1,1'-bis(diphenylphosphino)ferrocene and 60 cm.sup.3 of
tetrahydrofuran is heated under reflux, under a nitrogen stream,
for 3 hours. The reaction medium is cooled to room temperature and
filtered on sintered glass. The precipitate is washed with 20
cm.sup.3 of tetrahydrofuran and 10 cm.sup.3 of dichloromethane and
then the filtrate is concentrated to dryness under reduced pressure
(2.7 kPa). The residue is taken up with 30 cm.sup.3 of ethyl
acetate and 30 cm.sup.3 of 3 N hydrochloric acid. The aqueous phase
is decanted off, neutralized (pH=7-8) with 35 cm.sup.3 of 3 N
sodium hydroxide and taken up in 50 cm.sup.3 of ethyl acetate. The
organic phase is extracted; 4 g of silica are added and then the
mixture is concentrated to dryness under reduced pressure (2.5
kPa). The powder obtained is eluted on sintered glass containing 20
g of silica with a mixture of cyclohexane and ethyl acetate (90/10
by volume). The filtrate is concentrated to dryness under reduced
pressure (2.7 kPa). 1.2 g of methyl(3-pyrrolidinobenzyl)sulfide are
obtained in the form of an oil.
[0460] 1,1'-Bis(diphenylphosphino)ferrocenyl palladium chloride may
be prepared according to Hayashi T. et al., J. Am. Chem. Soc., 106,
158 (1984).
Example 38
[0461] Method 1
[0462] 0.65 cm.sup.3 of methanesulfonyl chloride is added to a
solution of 2.94 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsul-
fonyl)methyl-(RS)]azetidin-3-ol in 250 cm.sup.3 of dichloromethane
at 22.degree. C., followed, in small portions over 15 minutes, by
2.42 g of 4-dimethylaminopyridine; the orange-colored solution is
stirred for 2 hours at room temperature. The reaction mixture is
washed 3 times with 150 cm.sup.3 of distilled water and once with
150 cm.sup.3 of a saturated sodium chloride solution and then dried
with magnesium sulfate, filtered and concentrated to dryness under
reduced pressure (2.7 kPa). The residue obtained is chromatographed
on a silica gel column (particle size 0.04-0.06 mm, diameter 5.5
cm, height 15 cm), at an argon pressure of 0.5 bar with a mixture
of ethyl acetate and cyclohexane (1/9 by volume) as eluents and
collecting 70 cm.sup.3 fractions. Fractions 15 to 36 are combined
and then concentrated to dryness under reduced pressure (2.7 kPa).
1.86 g of white foam are obtained, which foam is crystallized from
isopropyl ether in order to obtain a solid melting at 190.degree.
C. A recrystallization from 145 cm.sup.3 of ethanol gives 1.08 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)meth-
ylene]azetidine melting at 206.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 3.00 (3H,s,
SCH.sub.3), 3.87 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), 7.15 (2H, d, J=8 Hz, 2CH arom.), 7.30 (5H, m, 5CH
arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.)].
[0463] Method 2
[0464] 0.80 g of ground sodium hydroxide is added to a solution of
2.2 g of
3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methyl-
sulfonyl)-methyl-(RS)]azetidine in 25 cm.sup.3 of dioxane at room
temperature. After 16 hours at room temperature, 50 cm.sup.3 of
water and 100 cm.sup.3 of ethyl acetate are added. The mixture is
separated after settling out, the organic phase rewashed with 100
cm.sup.3 of water, dried over magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (2.7 kPa). A white
foam is obtained which is crystallized from isopropyl ether in
order to obtain 0.85 g of a solid melting at 190.degree. C.
Recrystallization from 20 cm.sup.3 of ethanol gives 0.70 g of
1-[bis(4-chlorophenyl)-methyl]-3-[(3,5-difluorophenyl)(me-
thylsulfonyl)methylene]azetidine melting at 205.degree. C.
Example 39
[0465] 6.75 g of
3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-azeti- din-3-ol
hydrochloride and then 2.97 g of potassium carbonate are added to a
solution of 6.8 g of bis(4-chlorophenyl)bromomethane in 300
cm.sup.3 of acetonitrile. The reaction mixture is heated for 1 hour
under reflux, cooled to room temperature, filtered and concentrated
to dryness under reduced pressure (2.7 kPa). The residue obtained
is chromatographed on a silica gel column (particle size 0.04-0.06
mm, diameter 8.5 cm, height 22 cm), at an argon pressure of 0.5 bar
with a mixture of ethyl acetate and cyclohexane (25/75 by volume)
as eluents and collecting 250 cm.sup.3 fractions. Fractions 11 to
48 are combined and then concentrated to dryness under reduced
pressure (2.7 kPa). 5.3 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)
methyl-(RS)]azetidin-3-ol are obtained. [.sup.1H NMR spectrum
[0466] (300 MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 2.00
(s, 3H), 2.94 (s, 3H), 3.25 (mt, 2H), 3.48 (d, J=9 Hz, 1H), 3.80
(d, J=9 Hz, 1H), 4.54 (s, 1H), 5.34 (s, 1H), 7.15 (d, J=8.5 Hz,
2H), from 7.20 to 7.40 (mt, 8H), 7.50 (broad t, J=9 Hz, 1H)].
[0467] Bis(4-chlorophenyl)bromomethane may be prepared according to
the procedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135
(1933).
[0468]
3-[(3,5-Difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol
hydrochloride may be obtained in the following manner: 160 cm.sup.3
of a 6.2 N hydrochloric acid solution in dioxane are added to a
solution of 37 g of
3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbo-
nyl)azetidin-3-ol in 160 cm.sup.3 of dioxane. After 16 hours at
room temperature, the reaction mixture is concentrated to dryness
under reduced pressure (2.7 kPa). The residue obtained is taken up
in 320 cm.sup.3 of ethanol, heated for 1 hour under reflux and
cooled in an ice-cold water bath. The solid which appears is
filtered, washed with ethyl ether and dried at 40.degree. C. under
reduced pressure (2.7 kPa). 29.85 g of white crystals are obtained
whose melting point is greater than 260.degree. C.
[0469]
3-[(3,5-Difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarb-
onyl)azetidin-3-ol may be obtained in the following manner: a
solution of 14.0 cm.sup.3 of vinyl chloroformate in 35 cm.sup.3 of
dichloromethane is added at 5.degree. C. to a solution of 60.18 g
of 1-benzhydryl-3-[(3,5-di-
fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol in 1000
cm.sup.3 of dichloromethane. After 20 hours at room temperature,
the reaction mixture is concentrated to dryness under reduced
pressure (2.7 kPa). The residue obtained is chromatographed on a
silica gel column (particle size 0.04-0.06 mm, diameter 11 cm,
height 32 cm), at an argon pressure of 0.5 bar with a mixture of
ethyl acetate and cyclohexane (3/7 by volume) as eluents and
collecting 1000 cm.sup.3 fractions. Fractions 8 to 18 are combined
and then concentrated to dryness under reduced pressure (2.7 kPa).
37 g of
3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-(viny-
loxycarbonyl)azetidin-3-ol are obtained in the form of white
crystals melting at 195.degree. C.
Example 40
[0470] 14 cm.sup.3 of a 1.6 N n-butyllithium solution in hexane are
added at -70.degree. C. to a solution of 4.77 g of
(3,5-difluorobenzyl)methylsu- lfone in 70 cm.sup.3 of
tetrahydrofuran under an argon atmosphere. After 1 hour at
-70.degree. C., a solution of 6.8 g of 1-[bis(4-chlorophenyl)meth-
yl]azetidin-3-one in 30 cm.sup.3 of tetrahydrofuran is added and
then, 1 hour later, a solution of 2.34 cm.sup.3 of acetyl chloride
in 20 cm.sup.3 of tetrahydrofuran and the temperature of the
reaction mixture is raised to 20.degree. C. for 1 hour. 50 cm.sup.3
of water and 200 cm.sup.3 of ethyl acetate are added. The mixture
is separated after settling out, the organic phase washed with 100
cm.sup.3 of water, 100 cm.sup.3 of a saturated sodium chloride
solution, dried over magnesium sulfate, filtered and concentrated
to dryness under reduced pressure (2.7 kPa). 14.4 g of
3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-
(methylsulfonyl)methyl)methylsulfonylmethyl-(RS)]azetidine are
obtained in the form of a yellow oil [.sup.1H NMR spectrum (400
MHz, CDCl.sub.3, .quadrature. in ppm): 2.79 (s, 3H), 3.04 (AB, J=9
Hz, 2H), 3.27 (d, J=9 Hz, 1H), 3.45 (s, 1H), 3.81 (d, J=9 Hz, 1H),
4.32 (s, 1H), 4.49 (s, 1H), 6.88 (tt, J=9 and 2.5 Hz, 1H), from
7.20 to 7.35 (mt, 10H)].
[0471] 1-[Bis(4-chlorophenyl)methyl]azetidin-3-one may be prepared
according to the following procedure: a solution of 8.1 cm.sup.3 of
dimethyl sulfoxide in 17.6 cm.sup.3 of dichloromethane is added to
a solution of 5.0 cm.sup.3 of oxalyl chloride in 73 cm.sup.3 of
dichloromethane cooled to -78.degree. C. After 0.5 hour at
-78.degree. C., a solution of 16.0 g of
1-[bis(4-chlorophenyl)methyl]azetidin-3-ol dissolved in 50 cm.sup.3
of dichloromethane is poured in. After 5 hours at -78.degree. C.,
26.6 cm.sup.3 of triethylamine are added dropwise and the reaction
mixture is allowed to return to room temperature. After 16 hours,
the reaction mixture is washed with 4 times 200 cm.sup.3 of water
and then with 200 cm.sup.3 of a saturated sodium chloride solution,
dried over magnesium sulfate, filtered and concentrated to dryness
under reduced pressure (2.7 kPa). The residue obtained is
chromatographed on a silica gel column (particle size 0.04-0.06 mm,
diameter 9.2 cm, height 21 cm) at an argon pressure of 0.5 bar with
a mixture of ethyl acetate and cyclohexane (40/60 by volume) as
eluents and collecting 200 cm.sup.3 fractions. Fractions 15 to 25
are combined and then concentrated to dryness under reduced
pressure (2.7 kPa). 8.9 g of
1-[bis(4-chlorophenyl)methyl]azetidin-3-one are obtained in the
form of pale yellow crystals melting at 111.degree. C.
[0472] 1-[Bis(4-chlorophenyl)methyl]azetidin-3-ol may be prepared
according to the procedure described by KATRITZKY A. R. et al., J.
Heterocycl. Chem., (1994), 271 starting with 35.5 g of
[bis(4-chlorophenyl)-methyl]amine hydrochloride and 11.0 cm.sup.3
of epichlorohydrin. 9.0 g of
1-[bis(4-chlorophenyl)-methyl]azetidin-3-ol are isolated.
[0473] [Bis(4-chlorophenyl)methyl]amine hydrochloride may be
prepared according to the method described by GRISAR M. et al., J.
Med. Chem., 885 (1973).
Example 41
[0474] On carrying out the operation according to the procedure of
Example 38 (Method 1), starting with 0.72 g of
1-[bis(4-methoxyphenyl)methyl]-3-[-
(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol and
after chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 4.0 cm, height 16.5 cm) at an argon pressure
of 0.5 bar with a mixture of ethyl acetate and cyclohexane (2/8 by
volume) as eluent and collecting 40 cm.sup.3 fractions, 0.10 g of a
white foam is obtained. After crystallization from a mixture of
ethyl acetate and cyclohexane, 60 mg of
1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfon-
yl)methylene]azetidine are obtained in the form of a solid melting
at 180.degree. C. [NMR spectrum in DMSO-d.sub.6, T=300K,
.quadrature. in ppm (250 MHz): 3.00 (3H, s, SCH.sub.3), 3.70 (6H,
s, 2 OCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.15 (2H, s, NCH.sub.2),
4.58 (1H, s, NCH), 6.85 (4H, d, J=7 Hz, 4CH arom.), 7.15 (2H, d,
J=8 Hz, 2CH arom.), 7.30 (5H, m, 5CH arom.)].
[0475]
1-[Bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfo-
nyl)methyl-(RS)]azetidin-3-ol may be obtained in the following
manner: on carrying out the operation according to Example 39
starting with 1.2 g of bis(4-methoxyphenyl)bromomethane and 1.2 g
of 3-[(3,5-difluorophenyl)-(me-
thylsulfonyl)methyl-(RS)]azetidin-3-ol hydrochloride and after
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 4.8 cm, height 18 cm), at an argon pressure of 0.5 bar
with a mixture of ethyl acetate and cyclohexane (25/75 by volume)
as eluent and collecting 50 cm.sup.3 fractions, fractions 9 to 18
are combined and then concentrated to dryness under reduced
pressure (2.7 kPa). 0.55 g of
1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)-me-
thyl-(RS)]azetidin-3-ol is obtained.
[0476] Bis(4-methoxyphenyl)bromomethane may be prepared according
to the procedure described by BACHMANN W. E., J. Am. Chem. Soc.,
2135 (1933).
Example 42
[0477] On carrying out the operation according to Example 38
(Method 1), starting with 0.47 g of
1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophe-
nyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-ol and after
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 3.2 cm, height 18.5 cm), at an argon pressure of 0.5 bar
with a mixture of ethyl acetate and cyclohexane (1/9 by volume) as
eluent and collecting 35 cm.sup.3 fractions, 0.30 g of a white
solid is obtained. After crystallization from diisopropyl ether,
0.20 g of 1-[bis(4-methylphenyl)methyl]-3-[(3,5-d-
ifluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in
the form of white needles melting at 200.degree. C.
[0478]
1-[Bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfon-
yl)methyl-(RS)]azetidin-3-ol may be obtained in the following
manner: on carrying out the operation as in Example 39 starting
with 0.7 g of bis(4-methylphenyl)bromomethane and 0.8 g of
3-[(3,5-difluorophenyl)-(met- hylsulfonyl)methyl-(RS)]azetidin-3-ol
hydrochloride and after chromatography on a silica gel column
(particle size 0.04-0.06 mm, diameter 4.0 cm, height 19 cm), at an
argon pressure of 0.5 bar with a mixture of ethyl acetate and
cyclohexane (2/8 by volume) as eluent and collecting 40 cm.sup.3
fractions, fractions 35 to 40 are combined and then concentrated to
dryness under reduced pressure (2.7 kPa). 0.47 g of
1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)-met-
hyl-(RS)]azetidin-3-ol is obtained.
[0479] Bis(4-methylphenyl)bromomethane may be prepared according to
the procedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135
(1933).
Example 43
[0480] On carrying out the operation according to Example 38
(Method 1), starting with 1.42 g of
3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS-
)]-1-[(4-methoxyphenyl)(phenyl)methyl-(RS)]azetidin-3-ol, a mixture
of the two diastereoisomers, and after chromatography on a silica
gel column (particle size 0.04-0.06 mm, diameter 4.0 cm, height 21
m), at an argon pressure of 0.5 bar with a mixture of ethyl acetate
and cyclohexane (2/8 by volume) as eluent and collecting 40
cm.sup.3 fractions, 0.10 g of a white solid is obtained. After
crystallization from diisopropyl ether, 50 mg of
(RS)-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]-1-(4-methox-
yphenyl)(phenyl)methyl]azetidine are obtained in the form of a
white solid [NMR spectrum in DMSO-d.sub.6, T=300K, .quadrature. in
ppm (300 MHz): 2.23 (6H,s, 2 PhCH.sub.3), 3.00 (3H,s, SCH.sub.3),
3.80 (2H, s, NCH.sub.2), 4.12 (2H, s, NCH.sub.2), 4.58 (1H, s,
NCH), 7.08 (4H, d, J=7 Hz, 4CH arom.), 7.15 (2H, d, J=8 Hz, 2CH
arom.), 7.25 (5H, m, 5CH arom.)]
[0481] The mixture of diastereoisomers
3-[(3,5-difluorophenyl)-(methylsulf-
onyl)methyl-(RS)]-1-[(4-methoxyphenyl)(phenyl)methyl-(RS)]azetidin-3-ol
may be obtained in the following manner: on carrying out the
operation according to Example 39 starting with 2.52 g
(RS)-bromo(4-methoxyphenyl)(- phenyl)methane and 2.85 g of
3-[(3,5-difluorophenyl)-(methylsulfonyl)methy- l-(RS)]azetidin-3-ol
hydrochloride and after chromatography on a silica gel column
(particle size 0.04-0.06 mm, diameter 5.6 cm, height 19 cm), at an
argon pressure of 0.5 bar with a mixture of ethyl acetate and
cyclohexane (25/75 by volume) as eluent and collecting 100 cm.sup.3
fractions, fractions 11 to 18 are combined and then concentrated to
dryness under reduced pressure (2.7 kPa). 1.16 g of the mixture of
diastereoisomers
3-[(3,5-difluorophenyl)(methylsulfonyl)-methyl-(RS)]-1-[-
(4-methoxyphenyl)(phenyl)methyl-(RS)]azetidin-3-ol are
obtained.
[0482] (RS)-bromo(4-methoxyphenyl)(phenyl)methane may be prepared
according to the procedure described by BACHMANN W. E., J. Am.
Chem. Soc., 2135 (1933).
Example 44
[0483] On carrying out the operation as in Example 38 (Method 1),
starting with 0.47 g of
1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluoroph-
enyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-ol, and after
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 4.2 cm, height 14 cm), at an argon pressure of 0.5 bar
with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as
eluent and collecting 25 cm.sup.3 fractions, 0.28 g of
1-[bis-(4-trifluoromethoxyphenyl)methyl]-3--
[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine is
obtained in the form of a solid [NMR spectrum in DMSO-d6, T=300K,
.quadrature. in ppm (300 MHz): 3.05 (3H, s, SCH.sub.3), 3.95 (2H,
s, NCH.sub.2), 4.25 (2H, s, NCH.sub.2), 4.90 (1H, s, NCH), 7.20
(2H, d, J=8 Hz, 2CH arom.), 7.32 (5H, m, 5CH arom.), 7.60 (4H, d,
J=7 Hz, 4CH arom.)].
[0484]
1-[Bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl)-(me-
thylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the
following manner: on carrying out the operation as in Example 39
starting with 1.59 g of bis(4-trifluoromethoxyphenyl)bromomethane
and 1.2 g of
3-[(3,5-difluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-ol
hydrochloride and after chromatography on a silica gel column
(particle size 0.04-0.06 mm, diameter 4.8 cm, height 17 cm), at an
argon pressure of 0.5 bar with a mixture of ethyl acetate and
cyclohexane (25/75 by volume) as eluent and collecting 50 cm.sup.3
fractions, fractions 15 to 23 are combined and then concentrated to
dryness under reduced pressure (2.7 kPa). 0.49 g of
1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difl-
uorophenyl)-(methylsulfonyl)methyl]azetidin-3-ol is obtained.
[0485] Bis(4-trifluoromethoxyphenyl)bromomethane may be prepared
according to the procedure described by BACHMANN W. E., J. Am.
Chem. Soc., 2135 (1933), starting with 1.39 g of
bis(4-trifluoromethoxyphenyl)methanol, 3 cm.sup.3 of 33%
hydrobromic acid in acetic acid and 0.6 cm.sup.3 of acetyl bromide.
1.59 g of bis(4-trifluoromethoxyphenyl)bromomethane are obtained in
the form of a brown oil.
[0486] Bis(4-trifluoromethoxyphenyl)methanol is prepared according
to PAVIA M. R. et al., J. Med. Chem., 4238 (1992).
Example 45
[0487] On carrying out the operation as in Example 38 (Method 1),
starting with 0.25 g of
1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophe-
nyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-ol, and after
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 2.4 cm, height 14 cm), at an argon pressure of 0.5 bar
with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as
eluent and collecting 20 cm.sup.3 fractions, 0.12 g of
1-[bis-(4-trifluoromethylphenyl)methyl]-3-[-
(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine is
obtained in the form of a white solid [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 3.05 (3H, s,
SCH.sub.3), 3.95 (2H, s, NCH.sub.2), 4.25 (2H, s, NCH.sub.2), 4.90
(1H, s, NCH), 7.20 (2H, d, J=8 Hz, 2CH arom.), 7.32 (5H, m, 5CH
arom.), 7.60 (4H, d, J=7 Hz, 4CH arom.)].
[0488]
1-[Bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl)-(met-
hylsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the
following manner: on carrying out the operation as in Example 39
starting with 1.46 g of bis(4-trifluoromethylphenyl)bromomethane
and 1.2 g of
3-[(3,5-difluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-ol
hydrochloride and after chromatography on a silica gel column
(particle size 0.04-0.06 mm, diameter 4.8 cm, height 17 cm), at an
argon pressure of 0.5 bar with a mixture of ethyl acetate and
cyclohexane (30/70 by volume) as eluent and collecting 50 cm.sup.3
fractions, fractions 9 to 14 are combined and then concentrated to
dryness under reduced pressure (2.7 kPa). 0.25 g of
1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluoroph-
enyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-ol is obtained.
[0489] Bis(4-trifluoromethylphenyl)bromomethane may be prepared
according to the procedure described by BACHMANN W. E., J. Am.
Chem. Soc., 2135 (1933), starting with 2.5 g of
bis(4-trifluoromethylphenyl)methanol, 6 cm.sup.3 of 33% hydrobromic
acid in acetic acid and 1.2 cm.sup.3 of acetyl bromide. 2.9 g of
bis(4-trifluoromethylphenyl)bromomethane are obtained in the form
of a brown oil.
[0490] Bis(4-trifluoromethylphenyl)methanol is prepared according
to PAVIA M. R. et al., J. Med. Chem., 4238 (1992).
Example 46
[0491] On carrying out the operation according to Example 38
(Method 2), starting with 3.16 g of
3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-{[3,5-b-
is(trifluoromethyl)phenyl](methylsulfonyl)methyl-(RS)} azetidine
and 0.96 g of ground sodium hydroxide, a yellow foam is obtained,
after 16 hours at room temperature, which is chromatographed on a
silica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm,
height 14 cm), at an argon pressure of 0.5 bar with a mixture of
ethyl acetate and cyclohexane (15/85 by volume) as eluent and
collecting 40 cm.sup.3 fractions. 1.49 g of
1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis-(trifluoromethyl)phenyl](met-
hylsulfonyl)methylene} azetidine are thus obtained in the form of a
white foam [NMR spectrum in DMSO-d.sub.6, T=300K, .quadrature. in
ppm (300 MHz): 3.05 (3H,s, SCH.sub.3), 3.90 (2H, s, NCH.sub.2),
4.30 (2H, s, NCH.sub.2), 4.80 (1H, s, NCH), 7.40 (2H, d, J=7 Hz,
2CH arom.), 7.50 (2H, d, J=7 Hz, 2CH arom.), 8.10 (2H, s, 2CH
arom.), 8.20 (1H, s, CH arom.)].
[0492]
3-Acetoxy-1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl-
)phenyl](methylsulfonyl)methyl-(RS)} azetidine may be obtained in
the following manner: on carrying out the operation as in Example
40 starting with 2.0 g of
[3,5-bis(trifluoromethyl)benzyl]methylsulfone, 4.1 cm of a 1.6 N
solution of n-butyllithium in hexane, 2.0 g of
1-[bis(4-chlorophenyl)-methyl]azetidin-3-one and 0.77 cm.sup.3 of
acetyl chloride in 20 cm.sup.3 of anhydrous diisopropyl ether, 3.56
g of
3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl)pheny-
l](methylsulfonyl)methyl-(RS)}azetidine are obtained in the form of
a white foam after chromatography on a silica gel column (particle
size 0.04-0.06 mm, diameter 5.6 cm, height 16 cm), at an argon
pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane
(1/9 by volume) as eluent and collecting 100 cm.sup.3
fractions.
[0493] [3,5-Bis(trifluoromethyl)benzyl]methylsulfone is prepared in
the following manner: on carrying out the operation according to
Example 10 starting with 1.8 g of 3,5-bis(trifluoromethyl)benzyl
chloride and 1.22 g of sodium methanesulfinate, 1.86 g of
[3,5-bis(trifluoromethyl)benzyl]met- hylsulfone are obtained in the
form of a white solid.
Example 47
[0494] On carrying out the operation as in Example 38 (Method 1),
starting with 0.27 g of the mixture of the two diastereoisomers
1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl-(RS)]-3-[(3,5-difluoropheny-
l)(methylsulfonyl)methyl-(RS)]azetidin-3-ol and after
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 2.4 cm, height 7.5 cm), at an argon pressure of 0.5 bar
with a mixture of ethyl acetate and cyclohexane (15/85 by volume)
as eluent and collecting 20 cm.sup.3 fractions, 0.10 g of
(RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]--
3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine is
obtained in the form of a white solid [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (250 MHz): 3.02 (3H, s,
SCH.sub.3), 3.82 (1H, dd, J=3 and 16 Hz, NCHH), 4.04 (1H, dd, J=3
and 16 Hz, NCHH), 4.10 (1H, dd, J=3 and 16 Hz, NCHH), 4.35 (1H, dd,
J=3 and 16 Hz, NCHH), 5.12 (1H, s, NCH), 7.18 (2H, d, J=8 Hz, 2CH
arom.), 7.32 (1H, t, J=8 Hz, CH arom.), 7.38 (2H, d, J=7 Hz, 2CH
arom.), 7.45 (2H, d, J=7 Hz, 2CH arom.), 7.48 (1H, dd, J=2 and 7
Hz, CH arom.), 7.58 (1H, d, J=2 Hz, CH arom.), 7.80 (1H, d, J=7 Hz,
CH arom.)].
[0495] The mixture of the two diastereoisomers
1-[(4-chlorophenyl)(2,4-dic-
hlorophenyl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS-
)]azetidin-3-ol may be obtained in the following manner: on
carrying out the operation according to Example 39 starting with
0.56 g of (RS)-bromo(4-chlorophenyl)(2,4-dichlorophenyl)methane and
0.50 g of
3-[(3,5-difluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-ol
hydrochloride and after chromatography on a silica gel column
(particle size 0.04-0.06 mm, diameter 4.0 cm, height 13 cm), at an
argon pressure of 0.5 bar with a mixture of ethyl acetate and
cyclohexane (20/80 by volume) as eluent and collecting 40 cm.sup.3
fractions, fractions 9 to 14 are combined and then concentrated to
dryness under reduced pressure (2.7 kPa). 0.27 g of the mixture of
the two diastereoisomers
1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl-(RS)]-3-[(3,5-difluoro-phen-
yl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol is obtained.
[0496] (RS)-bromo(4-chlorophenyl)(2,4-dichlorophenyl)methane may be
prepared according to the procedure described by BACHMANN W. E., J.
Am. Chem. Soc., 2135 (1933) starting with 4.05 g of
(RS)-(4-chlorophenyl)(2,4- -dichlorophenyl)methanol, 10 cm.sup.3 of
33% hydrobromic acid in acetic acid and 2.1 cm.sup.3 of acetyl
bromide. 4.6 g of (RS)-bromo(4-chlorophen-
yl)(2,4-dichlorophenyl)methane are obtained in the form of a
greenish oil.
[0497] (RS)-(4-chlorophenyl)(2,4-dichlorophenyl)methanol is
prepared according to PAVIA M. R. et al., J. Med. Chem., 4238
(1992).
Example 48
[0498] 75.6 cm.sup.3 of 5 N hydrochloric acid are added to a
solution of 18.9 g of
1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine in 80
cm.sup.3 of tetrahydrofuran. After 3 hours at room temperature, the
mixture is taken up in dichloromethane and distilled water and then
adjusted to pH 14 by addition of 30% sodium hydroxide and separated
after settling out. The organic phase is washed twice with 100
cm.sup.3 of water and then 100 cm.sup.3 of a saturated aqueous
sodium chloride solution, dried over magnesium sulfate, filtered
and concentrated to dryness under reduced pressure (2.7 kPa). 16 g
of (RS)-1-[(4-chlorophenyl)(4-formylphenyl)methy-
l]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine are
obtained in the form of a white foam [Spectrum in DMSO-d.sub.6,
T=300K, .quadrature. in ppm (300 MHz): 3.06 (3H, s, SCH.sub.3),
3.95 (2H, m, NCH.sub.2), 4.26 (2H, m, NCH.sub.2), 4.91 (1H, s,
NCH), 7.20 (2H, d, J=8 Hz, 2CH arom.), 7.36 (1H, t, J=8 Hz, 1CH
arom.), 7.40 and 7.52 (4H, 2d, J=7.5 Hz, 4CH arom.), 7.70 and 7.88
(4H, 2d, J=7.5 Hz, 4CH arom.), 9.97 (1H, s, CH aldehydic)].
[0499]
1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,-
5-difluorophenyl)(methylsulfonyl)methylene]azetidine may be
prepared according to the following method: 13.0 cm.sup.3 of
1,8-diazabicyclo[5.4.0]undec-7-ene are added dropwise to a solution
of 34.45 g of the mixture of the two diastereoisomers
3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-azetidine in 400
cm.sup.3 of tetrahydrofuran under argon at 0.degree. C., and after
customary treatment, 16.6 g of
1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)p-
henyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetid-
ine are obtained in the form of a white solid after chromatography
on a silica gel column (particle size 0.04-0.06 mm, diameter 10.2
cm, height 23 cm), at an argon pressure of 0.5 bar with a mixture
of ethyl acetate and cyclohexane (2/8 by volume) as eluent and
collecting 250 cm.sup.3 fractions.
[0500] The mixture of the two diastereoisomers
3-acetoxy-1-{(4-chloropheny-
l)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)-(methy-
lsulfonyl)methyl-(RS)]azetidine may be obtained in the following
manner: on carrying out the operation according to Example 40,
starting with 11.6 g of (3,5-difluorobenzyl)methylsulfone, 35.1
cm.sup.3 of a 1.6 N solution of n-butyllithium in hexane, 19.3 g of
1-{(4-chlorophenyl)[4-(1,3-dioxola-
n-2-yl)phenyl]methyl-(RS)}azetidin-3-one and 8.8 cm.sup.3 of acetyl
chloride in 500 cm.sup.3 of tetrahydrofuran, 37.8 g of the mixture
of the two diastereoisomers
3-acetoxy-1-{(4-chlorophenyl)-[4-(1,3-dioxolan-2-yl)-
phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]aze-
tidine are obtained in the form of a white foam.
[0501]
1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}azetidi-
n-3-one may be prepared in the following manner: 46 cm.sup.3 of
triethylamine are added at room temperature to a solution of 28.32
g of 1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}
azetidin-3-ol in 200 cm.sup.3 of dimethyl sulfoxide, and then a
solution of 34 g of sulfur trioxide-pyridine complex in 100
cm.sup.3 of dimethyl sulfoxide are added dropwise. After 0.25 hour
at room temperature, the reaction mixture is poured over ice,
extracted with ethyl acetate, washed with 3 times 400 cm.sup.3 of
water and then with 400 cm.sup.3 of a saturated sodium chloride
solution, dried over magnesium sulfate, filtered and concentrated
to dryness under reduced pressure (2.7 kPa). The residue obtained
is chromatographed on a silica gel column (particle size 0.04-0.06
mm, diameter 9.2 cm, height 21 cm), at an argon pressure of 0.5 bar
with a mixture of ethyl acetate and cyclohexane (20/80 by volume)
as eluent and collecting 250 cm.sup.3 fractions. Fractions 9 to 18
are combined and then concentrated to dryness under reduced
pressure (2.7 kPa). 20.4 g of
1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]-met-
hyl-(RS)}azetidin-3-one are obtained in the form of a yellow
oil.
[0502]
1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}azetidi-
n-3-ol may be prepared according to the procedure described by
KATRITZKY A. R. et al., J. Heterocycl. Chem., 271 (1994) starting
with 35.0 g of
{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl} amine, 8.3 g
of epibromohydrin, 5.1 g of sodium hydrogen carbonate and 400
cm.sup.3 of ethanol. 30.3 g of
1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-
-(RS)}azetidin-3-ol are isolated.
[0503]
{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}amine
hydrochloride may be prepared according to the method described by
GRISAR M. et al., J. Med. Chem., 885 (1973) starting with 67.2 g of
4-(1,3-dioxolan-2-yl)benzonitrile, 88.2 g of
1-bromo-4-chlorobenzene, 11 g of magnesium and 600 cm.sup.3 of
ethyl ether. 42.3 g of
{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]-methyl-(RS)}amine
are obtained in the form of a yellow oil.
Example 49
[0504] 0.020 g of sodium borohydride is added to a solution of 0.50
g of
(RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)-(-
methylsulfonyl)methylene]azetidine in 15 cm.sup.3 of methanol at
0.degree. C. After 1 hour at 0.degree. C., 40 cm.sup.3 of water are
added and the product extracted with 100 cm.sup.3 of
dichloromethane. The organic phase is washed twice with 40 cm.sup.3
of water and then 40 cm.sup.3 of a saturated sodium chloride
solution, dried over magnesium sulfate, filtered and concentrated
to dryness under reduced pressure (2.7 kPa). The residue obtained
is chromatographed on a silica gel column (particle size 0.04-0.06
mm, diameter 3.2 cm, height 14 cm), at an argon pressure of 0.5 bar
with a mixture of ethyl acetate and cyclohexane (30/70 by volume)
and collecting 20 cm.sup.3 fractions. Fractions 20 to 25 are
combined and then concentrated to dryness under reduced pressure
(2.7 kPa). 0.29 g of
(RS)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]-methyl}-
-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is
obtained in the form of a white foam [NMR spectrum in DMSO-d.sub.6,
T=300K, .quadrature. in ppm (250 MHz): 3.02 (3H, s, SCH.sub.3),
3.90 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.42 (2H, d, J=5
Hz, OCH.sub.2), 4.75 (1H, s, NCH), 5.10 (1H, t, J=5 Hz, OH),
between 7.10 and 7.50 (1H, m, 11CH arom.)].
Example 50
[0505] 0.75 g of
(RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-d-
ifluorophenyl)(methylsulfonyl)methylene]azetidine and then 0.68 g
of sodium triacetoxyborohydride are added to a solution of 0.10 g
of pyrrolidine in 20 cm.sup.3 of 1,2-dichloroethane. After 20 hours
at room temperature, 2 cm.sup.3 of 1 N sodium hydroxide are added,
the product is extracted with 100 cm.sup.3 of dichloromethane, the
organic phase is washed twice with 50 cm of water and then 50
cm.sup.3 of a saturated sodium chloride solution, dried over
magnesium sulfate, filtered and concentrated to dryness under
reduced pressure (2.7 kPa). The residue obtained is chromatographed
on a silica gel column (particle size 0.04-0.06 mm, diameter 4.1
cm, height 13 cm), at an argon pressure of 0.5 bar with acetate as
eluent and collecting 20 cm.sup.3 fractions. Fractions 10 to 18 are
combined and then concentrated to dryness under reduced pressure
(2.7 kPa). 0.39 g of (RS)-1-{(4-chlorophenyl)[4-(pyrroli-
dylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-
azetidine is obtained in the form of a white foam [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 1.65 (4H, m,
2CH.sub.2), 2.40 (4H,m, 2NCH.sub.2), 3.02 (3H,s, SCH.sub.3), 3.50
(2H, s, NCH.sub.2Ph), 3.85 (2H, s, NCH.sub.2), 4.20 (2H, s,
NCH.sub.2), 4.75 (1H, s, NCH), between 7.15 and 7.40 (9H, m, 9CH
arom.), 7.48 (2H, d, J=7 Hz, 2CH arom.)].
Example 51
[0506] On carrying out the operation as in Example 50 starting with
0.93 cm.sup.3 of a 2 M solution of dimethylamine in methanol, 30
cm.sup.3 of 1,2-dichloroethane, 0.75 g of
(RS)-1-{(4-chlorophenyl)(4-formylphenyl)met-
hyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine and
then 0.9 g of sodium triacetoxyborohydride, there is obtained after
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 4 cm, height 17.5 cm), at an argon pressure of 0.5 bar
with a mixture of ethyl acetate and cyclohexane (30/70 by volume)
as eluent and collecting 40 cm.sup.3 fractions, 0.46 g of
(RS)-1-[(4-chlorophenyl)(4-di-
methylaminomethyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylen-
e]azetidine in the form of a white solid [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.12 (6H, s,
N(CH.sub.3).sub.2), 3.02 (3H,s, SCH.sub.3), 3.32 (2H, s,
NCH.sub.2Ph), 3.90 (2H,s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75
(1H, s, NCH), 7.18 (2H, d, J=8 Hz, 2CH arom.), 7.22 (2H, d, J=8 Hz,
2CH arom.), 7.35 (1H, t, J=8 Hz, CH arom.), 7.39 (4H, m, 4CH
arom.), 7.48 (4H, d, J=7 Hz, 4CH arom.)].
Example 52
[0507] A solution of 0.5 g of
(RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)-me-
thyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine in
10 cm.sup.3 of dichloromethane at 0.degree. C. is stirred with 0.5
cm.sup.3 of a solution (2 M) of dimethylamine in ethanol. 13 mg of
hydroxybenzotriazole, 0.2 g of
1,3-dimethylaminopropyl-3-ethylcarbodiimid- e hydrochloride and
0.18 cm.sup.3 of diisopropylethylamine are then added. After 20
hours at room temperature, the reaction mixture is diluted with
dichloromethane, washed twice with 80 cm.sup.3 of water and then 80
cm.sup.3 of a saturated sodium chloride solution, dried over
magnesium sulfate, filtered and concentrated to dryness under
reduced pressure (2.7 kPa). The residue obtained is chromatographed
on a silica gel column (particle size 0.04-0.06 mm, diameter 4.1
cm, height 13 cm), at an argon pressure of 0.5 bar with a
dichloromethane/acetonitrile/methanol (98/1/1 by volume) mixture as
eluent and collecting 15 cm.sup.3 fractions. Fractions 13 to 15 are
combined and then concentrated to dryness under reduced pressure
(2.7 kPa). 0.16 g of a cream-colored solid is obtained which, after
taking up in isopropyl ether and drying, gives 0.11 g of
(RS)-1-{(4-chlorophenyl)
[4-N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5--
difluorophenyl)(methylsulfonyl)methylene]azetidine in the form of a
solid [NMR spectrum in DMSO-d.sub.6, T=300K, .quadrature. in ppm
(300 MHz): 2.85 (3H, broad s, NCH.sub.3), 2.95 (3H,broad s,
NCH.sub.3), 3.00 (3H, s, SCH.sub.3), 3.90 (2H, s, NCH.sub.2), 4.20
(2H, s, NCH.sub.2), 4.80 (1H, s, NCH), 7.15 (2H, d, J=8 Hz, 2CH
arom.), 7.30 (1H, t, J=8 Hz, CH arom.), 7.35 (4H, m, 4CH arom.),
7.50 (4H, d, J=7 Hz, 4CH arom.)].
[0508]
(RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluoroph-
enyl)(methylsulfonyl)methylene]azetidine may be prepared in the
following manner: 1.0 cm.sup.3 of Jones reagent is added to a
solution of 0.50 g of
(RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)-(-
methylsulfonyl)methylene]azetidine in 10 cm.sup.3 acetone at
0.degree. C. After 5 hours, the reaction mixture is poured into
distilled water, the product is extracted with 50 cm.sup.3 of ethyl
acetate, the organic phase is washed twice with 50 cm.sup.3 of
water and then 50 cm.sup.3 of a saturated sodium chloride solution,
dried over magnesium sulfate, filtered and concentrated to dryness
under reduced pressure (2.7 kPa). The solid obtained is
crystallized from an ethyl acetate-cyclohexane mixture, filtered
and dried. 0.50 g of (RS)-1-{(4-carboxyphenyl)(4-chloro-
phenyl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azeti-
dine is obtained in the form of a white solid.
Example 53
[0509] The operation is carried out as in Example 52, starting with
1 g of
(RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)--
(methylsulfonyl)methylene]azetidine, 0.38 g of
1,3-dimethylaminopropyl-3-e- thylcarbodiimide hydrochloride, 22 mg
of hydroxybenzotriazole hydrate, 30 cm.sup.3 of dichloromethane and
0.83 cm.sup.3 of a 2 M ethylamine solution in THF, chromatographing
on a silica gel column (particle size 0.04-0.06 mm, diameter 4.1
cm, height 15 cm), at an argon pressure of 0.5 bar with a mixture
of ethyl acetate and cyclohexane (45/55 by volume) as eluent and
collecting 30 cm.sup.3 fractions. Fractions 22 to 32 are combined
and then concentrated to dryness under reduced pressure (2.7 kPa).
0.29 g of
(RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)-phenyl]meth-
yl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is
obtained in the form of a white solid [NMR spectrum in DMSO-d6
T=300K, .quadrature. in ppm (300 MHz): 1.07 (3H, t, J=6 Hz,
CH.sub.3), 3.00 (3H, s, SCH.sub.3), 3.35 (2H, m, NCH.sub.2), 3.90
(2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.80 (1H, s, NCH),
7.15 (2H, d, J=8 Hz, 2CH arom.), 7.30 (1H, t, J=8 Hz, CH arom.),
7.35 (2H, d, J=7 Hz, 2CH arom.), 7.48 (4H, m, 4CH arom.), 7.74 (2H,
d, J=7 Hz, 2CH arom.), 8.37 (1H, t, CONH)].
Example 54
[0510] The operation is carried out as in Example 52, starting with
1 g of
(RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)--
(methylsulfonyl)methylene]azetidine, 0.38 g of
1,3-dimethylaminopropyl-3-e- thylcarbodiimide hydrochloride, 22 mg
of hydroxybenzotriazole hydrate, 40 cm.sup.3 of dichloromethane and
0.24 cm.sup.3 of a 7 N solution of ammonium hydroxide in methanol
and chromatographing on a silica gel column (particle size
0.04-0.06 mm, diameter 4.1 cm, height 15 cm), at an argon pressure
of 0.5 bar with a mixture of ethyl acetate and cyclohexane (60/40
by volume) as eluent and collecting 35 cm.sup.3 fractions.
Fractions 38 to 48 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 0.29 g of a solid is obtained
which, after taking up in isopropyl ether and drying, gives 0.22 g
of
(RS)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl-(RS)]-3-[(3,5-difluorop-
henyl)(methylsulfonyl)-methylene]azetidine in the form of a white
solid [NMR spectrum in DMSO-d.sub.6, T=300K, .quadrature. in ppm
(300 MHz): 3.00 (3H, s, SCH.sub.3, 3.90 (2H, s, NCH.sub.2), 4.20
(2H, s, NCH.sub.2), 4.82 (1H, s, NCH), 7.17 (2H, d, J=8 Hz, 2CH
arom.), 7.30 (1H, t, J=8 Hz, CH arom.), 7.38 (2H, d, J=7 Hz, 2CH
arom.), 7.50 (5H, m, 4CH arom. and 2 CONH.sub.2), 7.80 (2H, d, J=7
Hz, 2CH arom.), 7.90 (1H, s, 2 CONH.sub.2)].
Example 55
[0511] The operation is carried out according to the procedure of
Example 4 starting with 1.7 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluoroph-
enyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.35 cm.sup.3 of
methanesulfonyl chloride and 1.5 g of 4-dimethylaminopyridine. The
residue obtained is purified by chromatography on a silica gel
column (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm),
at a nitrogen pressure of 0.5 bar with a mixture of dichloromethane
and ethanol (99.5/0.5 by volume) as eluent and collecting 100
cm.sup.3 fractions. Fractions 7 to 10 are combined and then
concentrated to dryness under reduced pressure (2.7 kPa). The solid
is crystallized from 15 cm.sup.3 of ethyl ether. 0.2 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluoropheny-
l)(methylsulfonyl)methylene]-azetidine is obtained melting at
200.degree. C. [NMR spectrum in DMSO-d.sub.6, T=300K, .quadrature.
in ppm (300 MHz): 3.00 (3H, s, SCH.sub.3), 3.80 (2H, s, NCH.sub.2),
4.20 (2H, s, NCH.sub.2), 4.75 (1H, s, NCH), 7.35 (4H, d, J=7 Hz,
4CH arom.), 7.45 (6H, m, 6CH arom.), 7.67 (1H, s, CH arom.)].
[0512]
1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)-(methylsulfon-
yl)methyl-(RS)]azetidin-3-ol may be obtained in the following
manner: on carrying out the operation according to the procedure of
Example 39 starting with 4 g of bis(4-chlorophenyl)bromomethane and
3 g of
3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol
hydrochloride, the residue obtained is purified by chromatography
on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm,
height 40 cm), at a nitrogen pressure of 0.5 bar with
dichloromethane and then a mixture of dichloromethane and ethanol
(99/1 by volume) as eluent and collecting 100 cm.sup.3 fractions.
Fractions 15 to 19 are combined and concentrated to dryness under
reduced pressure (2.7 kPa). 1.7 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulfonyl)meth-
yl-(RS)]azetidin-3-ol are obtained in the form of a foam.
[0513] Bis(4-chlorophenyl)bromomethane may be prepared according to
the procedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135
(1933).
[0514]
3-[(3,5-Dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol
hydrochloride may be obtained in the following manner: on carrying
out the operation according to the procedure of Example 39 starting
with 5.6 g of
3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbo-
nyl)azetidin-3-ol and 56 cm.sup.3 of a 6.2 N solution of
hydrochloric dioxane in 56 cm.sup.3 of dioxane, 5.1 g of
3-[(3,5-dichlorophenyl)(methy- lsulfonyl)methyl-(RS)]azetidin-3-ol
hydrochloride are obtained in the form of a foam.
[0515]
3-[(3,5-Dichlorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarb-
onyl)azetidin-3-ol may be prepared in the following manner: on
carrying out the operation according to the procedure of Example 39
starting with 7.4 g of
1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]-
-azetidin-3-ol and 1.6 cm.sup.3 of vinyl chloroformate in 75
cm.sup.3 of dichloromethane, the residue obtained is purified by
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 3 cm, height 40 cm), at a nitrogen pressure of 0.5 bar
with a mixture of ethyl acetate and cyclohexane (30/70 by volume)
as eluent and collecting 100 cm.sup.3 fractions. Fractions 4 to 10
are combined and concentrated to dryness under reduced pressure
(2.7 kPa). 5.6 g of 3-[(3,5-dichlorophenyl)-(methy-
lsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol are
obtained in the form of a foam.
Example 56
[0516] On carrying out the operation according to the procedure of
Example 4 starting with 0.5 g of
1-benzhydryl-3-[(3-dimethylaminophenyl)-(methyls-
ulfonyl)methyl-(RS)]azetidin-3-ol, 0.1 cm.sup.3 of methanesulfonyl
chloride and 0.5 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 2 cm, height 30 cm), at a nitrogen pressure
of 0.5 bar with a mixture of dichloromethane and ethanol (98/2 by
volume) as eluent and collecting 20 cm.sup.3 fractions. Fractions 8
to 13 are combined and concentrated to dryness under reduced
pressure (2.7 kPa). The solid obtained is crystallized from 8
cm.sup.3 of ethyl ether. 0.3 g of
1-benzhydryl-3-[(3-dimethylaminophenyl)(methylsulfonyl)methylene]azeti-
dine is obtained melting at 176.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (250 MHz): 2.90 (6H, s,
N(CH.sub.3).sub.2), 2.95 (3H, s, SCH.sub.3), 3.80 (2H, s,
NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75 (1H, s, NCH), 6.70 (3H,
m, 3CH arom.), 7.20 (3H, m, 3CH arom.), 7.30 (4H, t, J=7 Hz, 4CH
arom.), 7.48 (4H, d, J=7 Hz, 4CH arom.)].
[0517]
1-Benzhydryl-3-[(3-dimethylaminophenyl)(methylsulfonyl)methyl-(RS)]-
azetidin-3-ol may be obtained in the following manner: on carrying
out the operation according to the procedure of Example 1 starting
with 0.4 g of (3-dimethylaminobenzyl)methylsulfone, 0.4 g of
1-benzhydrylazetidin-3-one and 1.2 cm.sup.3 of a 1.6 M solution of
n-butyllithium in hexane, 0.5 g of
1-benzhydryl-3-[(3-dimethylaminophenyl)(methylsulfonyl)methyl-(RS)]aze-
tidin-3-ol is obtained in the form of a solid melting at
185.degree. C.
[0518] (3-Dimethylaminobenzyl)methylsulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 2 starting with 1.4 g of
(3-dimethylaminobenzyl)meth- ylsulfide and 5.1 g of oxone.sup.R,
1.1 g of (3-dimethylaminobenzyl)methyl- sulfone are obtained in the
form of a white solid melting at 195.degree. C.
[0519] (3-Dimethylaminobenzyl)methylsulfide may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 37 starting with 4 g of
(3-iodobenzyl)methylsulfide, 1.4 g of dimethylamine in solution in
5 cm.sup.3 of tetrahydrofuran, 2.9 g of sodium tert-butoxide, 0.56
g of 1,1-bis(diphenylphosphino)ferrocenyl- palladium chloride and
1.3 g of 1,1'-bis(diphenylphosphino)ferrocene in 35 cm.sup.3 of
tetrahydrofuran, 0.9 g of (3-dimethylaminobenzyl)methylsulfid- e is
obtained in the form of an oil.
Example 57
[0520] On carrying out the operation according to the procedure of
Example 4 starting with 1.3 g of
1-benzhydryl-3-[(3-methylsulfanylphenyl)-(methyl-
sulfonyl)methyl-(RS)]azetidin-3-ol, 0.3 cm.sup.3 of methanesulfonyl
chloride and 1.4 g of 4-dimethylaminopyridine, the residue obtained
is purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 2 cm, height 30 cm), at a nitrogen pressure
of 0.5 bar with a mixture of dichloromethane and ethanol (98/2 by
volume) as eluent and collecting 20 cm.sup.3 fractions. Fractions
11 to 13 are combined and concentrated to dryness under reduced
pressure (2.7 kPa). The solid obtained is crystallized from 15
cm.sup.3 of ethyl ether. 0.6 g of
1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methylene]azet-
idine is obtained melting at 146.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.45 (3H, s,
PhSCH.sub.3), 2.95 (3H, s, SCH.sub.3), 3.80 (2H, s, NCH.sub.2),
4.20 (2H, s, NCH.sub.2), 4.75 (1H, s, NCH), between 7.10 and 7.50
(14H, m, 14CH arom.)].
[0521]
1-Benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methyl-(RS)-
]azetidin-3-ol may be obtained in the following manner: on carrying
out the operation according to the procedure of Example 1 starting
with 1.1 g of methyl(3-methylsulfanylbenzyl)sulfone, 1.2 g of
1-benzhydrylazetidin-3-one, 1.3 g of
1-benzhydryl-3-[(3-methylsulfanylphe-
nyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the
form of a solid.
[0522] Methyl(3-methylsulfanylbenzyl)sulfone may be prepared in the
following manner: a mixture of 5 g of (3-iodobenzyl)methylsulfone
and 1 g of tetrakistriphenylphosphinepalladium in 250 cm.sup.3 of
dimethyl sulfoxide is heated at a temperature close to 100.degree.
C., under a nitrogen stream, for 1 hour. 2.5 g of sodium
methylthiolate are added and then the heating at 100.degree. C. is
maintained for 18 hours. The reaction medium is cooled to room
temperature and taken up in 700 cm.sup.3 of ethyl acetate and 500
cm.sup.3 of water. The organic phase is decanted off, washed with
10 times 500 cm.sup.3 of water, 500 cm.sup.3 of a saturated aqueous
sodium chloride solution, filtered on sintered glass and
concentrated to dryness under reduced pressure (2.7 kPa). The
residue obtained is purified by chromatography on a silica gel
column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm),
at a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and
ethyl acetate (70/30 and then 60/40 and then 50/50 by volume) as
eluent and collecting 30 cm.sup.3 fractions. Fractions 26 to 30 are
combined and concentrated to dryness under reduced pressure (2.7
kPa). 1.2 g of methyl(3-methylsulfanyl-benzyl- )methylsulfone are
obtained in the form of an oil.
Example 58
[0523] 4 cm.sup.3 of a 1 M solution of tetrabutylammonium fluoride
in tetrahydrofuran are added to a solution, cooled to 5.degree. C.,
of 1.1 g 1-benzhydryl-3-{[3-(tert-butyldimethylsiloxymethyl)phenyl]
(methylsulfonyl)methylene} azetidine in 10 cm.sup.3 of
tetrahydrofuran. The mixture is stirred for 3 hours at a
temperature close to 20.degree. C. and then taken up in 100
cm.sup.3 of ethyl acetate and twice 50 cm.sup.3 of water. The
organic phase is decanted off, extracted, dried over anhydrous
magnesium sulfate and concentrated to dryness under reduced
pressure (2.7 kPa). The residue obtained is purified by
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar
with a mixture of dichloromethane and ethanol (95/5 by volume) as
eluent and collecting 60 cm 3fractions. Fractions 4 to 6 are
combined and concentrated to dryness under reduced pressure (2.7
kPa). 0.5 g of
1-benzhydryl-3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]azetidin-
e is obtained in the form of a white solid melting at 152.degree.
C. [NMR spectrum in DMSO-d.sub.6, T=300K, .quadrature. in ppm (300
MHz): 2.95 (3H, s, SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H,
s, NCH.sub.2), 4.50 (2H, d, J=5 Hz, OCH.sub.2), 4.75 (1H, s, NCH),
5.25 (1H, t, J=5 Hz, OH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30
(8H, m. 8CH arom.), 7.45 (4H, d, J=7 Hz, 4 CH arom.)].
[0524]
1-Benzhydryl-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl]-(methy-
lsulfonyl)methylene}azetidine may be prepared in the following
manner: on carrying out the operation according to the procedure of
Example 4 starting with 1.6 g of
1-benzhydryl-3-{[3-(tert-butyldimethylsiloxymethyl-
)phenyl](methyl-sulfonyl)methyl-(RS)]azetidin-3-ol, 0.3 cm.sup.3 of
methanesulfonyl chloride and 1.4 g of 4-dimethylaminopyridine, the
residue obtained is purified by chromatography on a silica gel
column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm),
at a nitrogen pressure of 0.5 bar with dichloromethane as eluent
and collecting 60 cm.sup.3 fractions. Fractions 15 to 30 are
combined and concentrated to dryness under reduced pressure (2.7
kPa). 1.1 g of
1-benzhydryl-3-{[3-(tert-butyldimethylsiloxymethyl)phenyl](methylsulfonyl-
)methylene}azetidine are obtained in the form of a white solid
melting at 148.degree. C.
[0525]
1-Benzhydryl-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl]-(methy-
lsulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the
following manner: on carrying out the operation according to the
procedure of Example 1 starting with 2 g of
[3-(tert-butyldimethylsilyloxymethyl)benzy- l]methylsulfone and 1.5
g of 1-benzhydrylazetidin-3-one, 1.6 g of
1-benzhydryl-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfon-
yl)methyl-(RS)]azetidin-3-ol are obtained in the form of a white
solid melting at 175.degree. C.
[0526] [(3-(Tert-butyldimethylsilyloxy-methyl)benzyl]methylsulfone
may be prepared in the following manner: a mixture of 13.4 g of
(3-hydroxymethylbenzyl)methylsulfone, 11 g of imidazole and 12 g of
tert-butyldimethylsilane chloride is stirred for 18 hours at a
temperature close to 20.degree. C. The solution is concentrated to
dryness under reduced pressure (2.7 kPa). The residue obtained is
purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 5 cm, height 50 cm), at a nitrogen pressure
of 0.5 bar with dichloromethane as eluent and collecting 100
cm.sup.3 fractions. Fractions 7 to 14 are combined and concentrated
to dryness under reduced pressure (2.7 kPa). 5.7 g of
[3-(tert-butyldimethylsilyloxymethyl)benzyl]- methylsulfone are
obtained in the form of a white solid melting at 80.degree. C.
[0527] (3-Hydroxymethylbenzyl)methylsulfone may be prepared in the
following manner: a mixture of 26 g of
3-(methylsulfonylmethyl)benzoic acid and 4.6 g of lithium aluminium
hydride in 600 cm.sup.3 of tetrahydrofuran is stirred for 18 hours
at a temperature close to 20.degree. C. The solution is cooled to
0.degree. C. and then 15 cm.sup.3 of ethyl acetate, 5 cm.sup.3 of
water, 5 cm.sup.3 of a 15% aqueous solution of sodium hydroxide and
finally 30 cm.sup.3 of water are added successively. The mixture is
filtered on celite, the filtrate taken up in 600 cm.sup.3 of ethyl
acetate. The organic phase is taken up in 500 cm.sup.3 of water and
then 200 cm of a saturated aqueous sodium chloride solution,
decanted off, dried over anhydrous magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (2.7 kPa). 10.4 g of
(3-hydroxymethylbenzyl)methylsulfone are obtained in the form of a
gum.
[0528] 3-(Methylsulfonylmethyl)benzoic acid may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 10 starting with 23.3 g of
3-chloromethylbenzoic acid and 23.3 g of sodium methanesulfinate,
26 g of 3-(methylsulfonylmethyl)benzoic acid are obtained in the
form of a white solid melting at 210.degree. C.
Example 59
[0529] 0.13 g of sodium methylthiolate is added, while the
temperature is maintained below 30.degree. C., to a solution of 0.8
g of
1-benzhydryl-3-[(3-bromomethyl-phenyl)(methylsulfonyl)methylene]azetidine
in 8 cm.sup.3 of dimethylformamide. The mixture is stirred for 18
hours at a temperature close to 20.degree. C. and then taken up in
30 cm.sup.3 of ethyl acetate and 50 cm.sup.3 of water. The organic
phase is decanted off, extracted and washed with 3 times 50
cm.sup.3 of water, dried over magnesium sulfate and concentrated to
dryness under reduced pressure (2.7 kPa). The residue obtained is
purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 2 cm, height 28 cm) at a nitrogen pressure
of 0.5 bar with a mixture of cyclohexane and ethyl acetate (90/10
by volume) as eluent and collecting 50 cm.sup.3 fractions.
Fractions 8 to 14 are combined and concentrated to dryness under
reduced pressure (2.7 kPa). 0.3 g of
1-benzhydryl-3-{[3-(methylsulfanylmethyl)phe-
nyl](methylsulfonyl)methylene])} azetidine is obtained in the form
of a white solid melting at 150.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .delta. in ppm (300 MHz): 1.95 (3H, s,
SCH.sub.3), 2.95 (3H, s, SCH.sub.3), 3.75 (2H, s, SCH.sub.2), 3.80
(2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75 (1H, s, NCH),
7.20 (2H, t, J=7 Hz, CH arom.), 7.30 (8H, d, J=7 Hz, 8CH arom.),
7.45 (4H, d, J=7 Hz, 4 CH arom.)].
[0530]
1-Benzhydryl-3-[(3-bromomethylphenyl)(methylsulfonyl)-methylene]aze-
tidine may be prepared in the following manner: 0.23 cm.sup.3 of
phosphorus tribromide and then a drop of pyridine are added, at a
temperature close to 20.degree. C., to a mixture of 1 g of
1-benzhydryl-3-[(3-hydroxymethylphenyl)-(methylsulfonyl)methylene]azetidi-
ne in 10 cm.sup.3 of dichloromethane. The stirring is maintained
for 18 hours at the same temperature. The reaction medium is taken
up in 20 cm.sup.3 of water and 10 cm.sup.3 of a saturated aqueous
sodium chloride solution. The organic phase is decanted off,
extracted, dried over anhydrous magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (2.7 kPa). 1 g of
1-benzhydryl-3-[(3-bromomethylphenyl)(-
methylsulfonyl)methylene]azetidine is obtained in the form of a
foam used in the crude state in subsequent syntheses.
Example 60
[0531] On carrying out the operation according to the procedure of
Example 4 starting with 6.6 g of
1-benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)-me-
thyl-(RS)]azetidin-3-ol, 1.7 cm.sup.3 of methanesulfonyl chloride
and 5.2 g of 4-dimethylaminopyridine, the residue obtained is
purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 6.5 cm, height 35 cm), at a nitrogen
pressure of 0.5 bar with a dichloromethane and methanol mixture
(95/5 by volume) as eluent and collecting 40 cm.sup.3 fractions.
Fractions 7 to 15 are combined and concentrated to dryness under
reduced pressure (2.7 kPa). The solid obtained is crystallized from
100 cm.sup.3 of ethyl ether. 4.4 g of
1-benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)methylene]azetidine
are obtained melting at 212.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (250 MHz): 3.15 (3H, s,
SCH.sub.3), 3.55 (2H, broad s, NCH.sub.2), 4.30 (2H, s, NCH.sub.2),
4.70 (1H, s, NCH), 7.18 (2H, t, J=7 Hz, 2CH arom.), 7.25 (4H, t,
J=7 Hz, 4CH arom.), 7.43 (4H, d, J=7 Hz, 4 CH arom.), 7.62 (2H, m,
2CH quinoline), 7.75 (1H, dd, J=2 and 7 Hz, CH quinoline), 8.05
(1H, dd, J=2 and 7 Hz, CH quinoline), 8.43 (1H, dd, J=2 and 8 Hz,
CH quinoline), 9.00 (1H, dd, J=2 and 5 Hz, CH quinoline)].
[0532]
1-Benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)methyl-(RS)]-azetidin--
3-ol may be obtained in the following manner: on carrying out the
operation according to the procedure of Example 1 starting with 5.5
g of methyl(quinol-8-ylmethyl)sulfone, 5.9 g of
1-benzhydrylazetidin-3-one and 18.8 cm.sup.3 of a 1.6 M solution of
n-butyllithium in hexane, 6.6 g of
1-benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)methyl-(RS)]azetidin-3-ol
are obtained in the form of a beige solid.
[0533] Methyl(quinol-8-ylmethyl)sulfone may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 10 starting with 4.5 g of
8-chloromethylquinoline and 4.4 g of sodium methanesulfinate, 5.7 g
of methyl(quinol-8-ylmethyl)sulfone are obtained in the form of a
beige solid.
[0534] 8-Chloromethyl quinoline may be prepared in the following
manner: 6.7 g of N-chlorosuccinimide and then 250 mg of benzoyl
peroxide are added, at a temperature close to 20.degree. C., to a
mixture of 7.1 g of 8-methylquinoline in 250 cm.sup.3 of carbon
tetrachloride. The reaction medium is heated at the reflux
temperature of the solvent for 36 hours and then cooled to
20.degree. C. The mixture is filtered on sintered glass and the
filtrate is concentrated to dryness under reduced pressure (2.7
kPa). The residue obtained is purified by chromatography on a
silica gel column (particle size 0.04-0.06 mm, diameter 5.5 cm,
height 32 cm), at a nitrogen pressure of 0.5 bar with
dichloromethane as eluent and collecting 40 cm.sup.3 fractions.
Fractions 21 to 40 are combined and concentrated to dryness under
reduced pressure (2.7 kPa). 4.5 g of 8-chloromethyl-quinoline are
obtained in the form of a brown oil which is used in the crude
state in subsequent syntheses.
Example 61
[0535] On carrying out the operation according to the procedure of
Example 4 starting with 6.2 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)-
(methylsulfonyl)methyl-(RS)]azetidin-3-ol, 1.4 cm.sup.3 of
methanesulfonyl chloride and 6.1 g of 4-dimethylaminopyridine, the
residue obtained is purified by chromatography on a silica gel
column (particle size 0.04-0.06 mm, diameter 4 cm, height 60 cm),
at a nitrogen pressure of 0.5 bar with dichloromethane as eluent
and collecting 100 cm.sup.3 fractions. Fractions 4 to 7 are
combined and concentrated to dryness under reduced pressure (2.7
kPa). The solid obtained is crystallized from 25 cm.sup.3 of ethyl
ether. 0.7 g of 1-[bis(4-chlorophenyl)-methyl]-3-[(3-cyanophenyl-
)(methylsulfonyl)methylene]azetidine is obtained in the form of a
solid melting at 178.degree. C. [NMR spectrum in DMSO-d.sub.6,
T=300K, .quadrature. in ppm (300 MHz): 3.00 (3H, s, SCH.sub.3),
3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75 (1H, s,
NCH), 7.30 (4H, d, J=7 Hz, 4CH arom.), 7.40 (4H, d, J=7 Hz, 4CH
arom.), 7.60 (1H, t, J=7 Hz, CH arom.), 7.70 (1H, d, J=7 Hz, CH
arom.), 7.85 (2H, m, 2CH arom.)].
[0536]
1-[Bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)-me-
thyl-(RS)]azetidin-3-ol may be obtained in the following manner: on
carrying out the operation according to the procedure of Example 1
starting with 5.5 g of (3-cyanophenyl)-methylsulfone, 6.1 g of
1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 13.8 cm.sup.3 of a
1.6 M solution of n-butyllithium in hexane, 6.3 g of
1-[bis-(4-chlorophenyl)met-
hyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol
are obtained in the form of a foam.
Example-62
[0537] A mixture of 4.5 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophen-
yl)(methylsulfonyl)methylene]azetidine in 50 cm.sup.3 of acetic
acid and 50 cm.sup.3 of concentrated hydrochloric acid (d=1.18) is
heated at 50.degree. C. for 20 hours. The reaction medium is cooled
to room temperature and concentrated to dryness under reduced
pressure (2.7 kPa). The oil obtained is taken up in 100 cm.sup.3 of
ethanol and then the solution is concentrated to dryness under
reduced pressure (2.7 kPa). The residue is precipitated in 60
cm.sup.3 of ethyl ether. The solid obtained is purified by
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 25 cm, height 40 cm) at a nitrogen pressure of 0.5 bar
with dichloromethane and then a dichloromethane and ethanol mixture
(99.5/0.5 by volume) as eluent and collecting 30 cm.sup.3
fractions. Fractions 35 to 46 are combined and concentrated to
dryness under reduced pressure (2.7 kPa). The solid obtained is
crystallized from 15 cm.sup.3 of ethyl ether. 0.2 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphe-
nyl)(methylsulfonyl)methylene]azetidine is obtained in the form of
a solid melting at 192.degree. C. [NMR spectrum in DMSO-d.sub.6,
T=300K, .quadrature. in ppm (300 MHz): 2.95 (3H, s, SCH.sub.3),
3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.80 (1H, s,
NCH), 7.35 (4H, d, J=7 Hz, 4CH arom.), 7.45 (5H, d, J=7 Hz, 4CH
arom. and 2 CONH.sub.2), 7.50 (2H, m, 2CH arom.), 7.85 (2H, m, 2CH
arom.)].
Example 63
[0538] On carrying out the operation according to the procedure of
Example 1 starting with 0.8 g of
1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-me-
thylamino)phenyl](methylsulfonyl)methyl-(RS)} azetidin-3-ol, 0.2
cm.sup.3 of methanesulfonyl chloride and 0.7 g of
4-dimethylaminopyridine, the residue obtained is purified by
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar
with a dichloromethane and ethanol mixture (98/2 by volume) as
eluent, collecting 20 cm.sup.3 fractions. Fractions 4 to 8 are
combined and concentrated to dryness under reduced pressure (2.7
kPa). The solid obtained is recrystallized from 10 cm.sup.3 of
ethyl acetate. 0.5 g of
1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl-
](methylsulfonyl)methylene}-azetidine is obtained in the form of a
solid melting at 161.degree. C. [NMR spectrum in DMSO-d.sub.6,
T=300K, .quadrature. in ppm (300 MHz): 1.30 (9H, s,
(CH.sub.3).sub.3), 2.95 (3H, s, SCH.sub.3), 3.15 (3H, s,
NCH.sub.3), 3.75 (2H, s, SCH.sub.2), 3.80 (2H, s, NCH.sub.2), 4.20
(2H, s, NCH.sub.2), 4.75 (1H, s, NCH), between 7.15 and 7.50 (14H,
m, 14CH arom.)].
[0539]
1-Benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](m-
ethylsulfonyl)methyl-(RS)}azetidin-3-ol may be obtained in the
following manner: on carrying out the operation according to the
procedure of Example 1 starting with 1.6 g of
[3-(N-tert-butyloxycarbonyl-N-methylamin- o)benzyl]methylsulfone,
1.3 g of 1-benzhydrylazetidin-3-one and 3.8 cm.sup.3 of a 1.6 M
solution of n-butyllithium in hexane, 0.8 g of
1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methyls-
ulfonyl)methyl-(RS)}azetidin-3-ol is obtained in the form of a
white solid.
[0540]
[3-(N-tert-butyloxycarbonyl-N-methylamino)benzyl]methylsulfone may
be prepared in the following manner: 2.5 g of di-tert-butyl
dicarbonate in 40 cm.sup.3 of dioxane are added to a solution,
cooled to 0.degree. C. of methyl(3-methylaminobenzyl)sulfone in 30
cm.sup.3 of dioxane. The stirring is maintained for 18 hours at
room temperature. The reaction medium is taken up in 75 cm.sup.3 of
dichloromethane; the organic phase is washed with 75 cm.sup.3 of
water and then with 75 cm.sup.3 of a saturated aqueous sodium
chloride solution. The organic phase is decanted off, extracted,
dried over anhydrous sodium sulfate, filtered and concentrated to
dryness under reduced pressure (2.7 kPa). The residue obtained is
purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 2 cm, height 35 cm) at a nitrogen pressure
of 0.5 bar with a cyclohexane and ethyl acetate mixture (50/50 by
volume) as eluent, collecting 20 cm.sup.3 fractions. Fractions 5 to
10 are combined and concentrated to dryness under reduced pressure
(2.7 kPa). 1.8 g of
[3-(N-tert-butyloxycarbonyl-N-methylamino)benzyl]methylsulfone are
obtained in the form of a colorless oil.
[0541] Methyl(3-methylaminobenzyl)sulfone may be prepared in the
following manner: a mixture of 9.7 cm.sup.3 of formic acid (d=1.22)
and 19.6 cm.sup.3 of acetic anhydride (d=1.08) is heated for 3
hours at 50.degree. C. and then the solution is allowed to return
to room temperature. 40 cm.sup.3 of tetrahydrofuran are added and
the mixture is cooled to -20.degree. C. 14.8 g of
(3-aminobenzyl)methylsulfone and 200 cm.sup.3 of tetrahydrofuran
are then added. The stirring is maintained for 2 hours at
-20.degree. C. and then 48 hours at room temperature. The mixture
is filtered on sintered glass, the precipitate is washed with 3
times 50 cm.sup.3 of diisopropyl ether and then dried. The filtrate
is concentrated to half its volume (2.7 kPa), the precipitate
obtained is filtered on sintered glass and washed with 3 times 30
cm.sup.3 of diisopropyl ether and then dried. The two precipitates
are combined and dissolved in 375 cm.sup.3 of tetrahydrofuran. The
solution is cooled to 0.degree. C.; 100 cm.sup.3 of a 2 M solution
of borane dimethyl sulfide in tetrahydrofuran added and then heated
under reflux for 3 hours. The mixture is cooled to 5.degree. C. and
then 60 cm.sup.3 of methanol are added over 20 minutes. The
stirring is maintained for 1 hour at room temperature. A stream of
hydrogen chloride is bubbled in the solution for 5 minutes. The
reaction medium is then heated under reflux for 1 hour, cooled to
room temperature and taken up in 300 cm.sup.3 of water. The
solution is alkalinized with 3N sodium hydroxide and then with a
saturated aqueous sodium bicarbonate solution. The organic phase is
extracted with twice 250 cm.sup.3 of ethyl acetate, washed with 300
cm.sup.3 of a saturated aqueous sodium bicarbonate solution and
twice 300 cm.sup.3. It is concentrated to dryness under reduced
pressure (2.7 kPa). The oil obtained is taken up in 100 cm.sup.3 of
4 N hydrochloric acid and then with 100 cm.sup.3 of ethyl acetate.
The aqueous phase is alkalinized with 120 cm.sup.3 of 3 N sodium
hydroxide, and then with an aqueous sodium bicarbonate solution.
The organic phase is extracted with twice 75 cm.sup.3 of ethyl
acetate, dried over anhydrous magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (2.7 kPa). 9 g of
methyl(3-methylaminobenzyl)sulfone are obtained in the form of a
pink solid.
[0542] (3-Aminobenzyl)methylsulfone may be prepared in the
following manner: a mixture of 23.7 g of
methyl(3-nitrobenzyl)sulfone, 65 cm.sup.3 of hydrochloric acid
(d=1.18) and 150 cm.sup.3 of methanol is heated under reflux for 15
minutes. 18.5 g of iron are added over 10 minutes and the reflux is
maintained for 4 hours and then 18 hours at room temperature. The
reaction medium is alkalinized with an aqueous solution of ammonium
hydroxide and then with an aqueous sodium bicarbonate solution. The
organic phase is extracted with 3 times 250 cm.sup.3 of ethyl
acetate, dried over magnesium sulfate, filtered on sintered glass
and concentrated to dryness under reduced pressure (2.7 kPa). 14.9
g of (3-aminobenzyl)methylsulfone are obtained in the form of a
beige solid which is used in the crude state in subsequent
syntheses.
Example 64
[0543] A mixture of 0.3 g of
1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-
-methylamino)phenyl](methylsulfonyl)methylene}azetidine, 4 cm.sup.3
of a 4.7 N solution of hydrochloric dioxane and 4 cm.sup.3 of
dioxane is stirred for 18 hours at room temperature. The reaction
medium is concentrated to dryness under reduced pressure (2.7 kPa).
The residue is taken up in 100 cm.sup.3 of water and 20 cm.sup.3 of
diethyl ether. The aqueous phase is alkalinized with 30 cm.sup.3 of
an aqueous sodium bicarbonate solution. The organic phase is
extracted with twice 40 cm.sup.3 of ethyl acetate, washed with
twice 30 cm.sup.3 of water, decanted off, dried over anhydrous
magnesium sulfate, filtered and concentrated to dryness under
reduced pressure (2.7 kPa). The residue is crystallized from 20
cm.sup.3 of diethyl ether. 0.16 g of
1-benzhydryl-3-[(3-methylaminophenyl)(methylsulfonyl)methylene]azetidine
is obtained in the form of a solid melting at 161.degree. C. [NMR
spectrum in DMSO-d.sub.6, T=300K, .quadrature. in ppm (250 MHz):
2.65 (3H, d, J=5 Hz, NCH.sub.3), 2.95 (3H, s, SCH.sub.3), 3.80 (2H,
s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75 (1H, s, NCH), 5.80
(1H, q, J=5 Hz, NH), 6.60 (3H, m, 3CH arom.), 7.15 (1H, t, J=7 Hz,
CH arom.), 7.22 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,
4CH arom.), 7.48 (4H, d, J=7 Hz, 4 CH arom.)].
Example 65
[0544] On carrying out the operation according to the procedure of
Example 4 starting with 11.3 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphen-
yl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol, 2.6 cm.sup.3 of
methanesulfonyl chloride and 10.9 g of 4-dimethylaminopyridine, 5 g
of
1-[bis-(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-
ene]-azetidine are obtained after recrystallization from 20
cm.sup.3 of diethyl ether, melting at 181.degree. C. [NMR spectrum
in DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.95 (3H,
s, SCH.sub.3), 3.77 (3H, s, OCH.sub.3), 3.80 (2H, s, NCH.sub.2),
4.20 (2H, s, NCH.sub.2), 4.80 (1H, s, NCH), 6.95 (3H, m, 3CH
arom.), 7.35 (5H, m, 5CH arom.), 7.45 (4H, d, J=7 Hz, 4CH
arom.)].
[0545]
1-[Bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)m-
ethyl-(RS)]azetidin-3-ol may be obtained in the following manner:
on carrying out the operation according to the procedure of Example
1 starting with 6.6 g of (3-methoxybenzyl)methylsulfone, 10 g of
1-[bis-(4-chlorophenyl)methyl]azetidin-3-one and 23 cm.sup.3 of a
1.6 N solution of n-butyllithium in hexane, 11.4 g of
1-[bis(4-chlorophenyl)met-
hyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol
are obtained in the form of a white solid melting at 130.degree.
C.
Example 66
[0546] On carrying out the operation according to the procedure of
Example 32 starting with 4.8 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphen-
yl)(methylsulfonyl)methylene]azetidine, 32 cm.sup.3 of a 1 M
solution of boron tribromide in dichloromethane, the residue
obtained is purified by chromatography on a silica gel column
(particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), at a
nitrogen pressure of 0.5 bar with a mixture of dichloromethane and
ethanol (98/2 by volume) as eluent and collecting 20 cm.sup.3
fractions. Fractions 16 to 17 are concentrated to dryness under
reduced pressure (2.7 kPa). 0.1 g 1-[bis(4-chlorophenyl)met-
hyl]-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine is
obtained, after recrystallization from 5 cm.sup.3 of diethyl ether,
in the form of a solid melting at 114.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (250 MHz): 2.92 (3H, s,
SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.80
(1H, s, NCH), 6.80 (3H, m, 3CH arom.), 7.20 (1H, t, J=7 Hz, CH
arom.), 7.37 (4H, t, J=7 Hz, 4CH arom.), 7.47 (4H, d, J=7 Hz, 4 CH
arom.)].
Example 67
[0547] On carrying out the operation according to the procedure of
Example 4 starting with 0.6 g of
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl-
)(3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3-ol, 0.1 cm.sup.3 of
methanesulfonyl chloride and 0.5 g of 4-dimethylaminopyridine, the
residue obtained is purified by chromatography on a silica gel
column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm) at
a nitrogen pressure of 0.5 bar with a dichloromethane and ethanol
mixture as eluent (98.5/1.5 by volume) and collecting 10 cm.sup.3
fractions. Fraction 4 is concentrated to dryness under reduced
pressure (2.7 kPa). 0.5 g
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)me-
thylene]azetidine is obtained, after recrystallization from 5
cm.sup.3 of diethyl ether, in the form of a solid melting at
133.degree. C. [NMR spectrum in DMSO-d6, T=300K, .quadrature. in
ppm (400 MHz): 2.00 (4H, m, 2 CH.sub.2), 2.95 (3H, s, SCH.sub.3),
3.20 (4H, m, 2 NCH.sub.2), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s,
NCH.sub.2), 4.80 (1H, s, NCH), 6.50 (1H, s, CH arom.), 6.60 (1H, d,
J=7 Hz, CH arom.), 6.65 (1H, d, J=7 Hz, CH arom), 7.20 (1H, t, J=7
Hz, CH arom.), 7.40 (4H, d, J=7 Hz, 4 CH arom.), 7.50 (4H, d, J=7
Hz, 4 CH arom.)].
[0548]
1-[Bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphe-
nyl)methyl-(RS)]azetidin-3-ol may be obtained in the following
manner: on carrying out the operation according to the procedure of
Example 1 starting with 0.5 g of
methyl(3-pyrrolidinylbenzyl)sulfone, 0.6 g of
1-[bis(4-chlorophenyl)-methyl]azetidin-3-one and 1.4 cm.sup.3 of a
1.6 N solution of n-butyllithium in hexane, 0.6 g of
1-[bis(4-chlorophenyl)meth-
yl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)-methyl-(RS)]azetidin-3-ol
is obtained in the form of a cream-colored solid.
Example 68
[0549] On carrying out the operation according to the procedure of
Example 58 starting with 5.1 g of
1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyl-
dimethylsilyloxymethyl)phenyl](methylsulfonyl)methylene}azetidine
and 17 cm.sup.3 of a 1 M solution of tetrabutylammonium fluoride in
tetrahydrofuran, the residue obtained is purified by chromatography
on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm,
height 30 cm), at a nitrogen pressure of 0.5 bar with a
dichloromethane and ethanol mixture (97/3 by volume) as eluent and
collecting 100 cm.sup.3 fractions. Fractions 10 to 14 are combined,
concentrated to dryness under reduced pressure (2.7 kPa). The
yellow solid obtained is taken up in 2 cm.sup.3 of dichloromethane
and 10 cm.sup.3 of ethyl acetate and then filtered on sintered
glass and washed with 2 cm.sup.3 of ethyl acetate. 1.6 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylphenyl)(methylsulfonyl)m-
ethylene]azetidine are obtained in the form of a white solid
melting at 214.degree. C. [NMR spectrum in DMSO-d.sub.6, T=300K,
.quadrature. in ppm (400 MHz): 2.95 (3H, s, SCH.sub.3), 3.80 (2H,
s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.50 (2H, d, J=5 Hz,
OCH.sub.2), 4.80 (1H, s, NCH), 5.25 (1H, t, J=5 Hz, OH), 7.30 (1H,
d, J=7 Hz, CH arom.), between 7.35 and 7.45 (7H, m, 7CH arom.),
7.50 (4H, d, J=7 Hz, 4CH arom.)].
[0550]
1-[Bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymeth-
yl)phenyl](methylsulfonyl)methylene} azetidine may be prepared in
the following manner: on carrying out the operation according to
the procedure of Example 4 starting with 10.8 g of
1-[bis(4-chlorophenyl)meth-
yl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methyl--
(RS)}azetidin-3-ol, 2 cm.sup.3 of methanesulfonyl chloride and 8.5
g of 4-dimethylaminopyridine, the residue obtained is purified by
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 4 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with
dichloromethane as eluent and collecting 100 cm.sup.3 fractions.
Fractions 12 to 29 are combined, concentrated to dryness under
reduced pressure (2.7 kPa). 5.2 g of
1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-bu-
tyldimethylsilyloxymethyl)phenyl] (methyl sulfonyl)methylene}
azetidine are obtained in the form of a gum.
[0551]
1-[Bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymeth-
yl)phenyl](methylsulfonyl)methyl-(RS)} azetidin-3-ol may be
obtained in the following manner: on carrying out the operation
according to the procedure of Example 1 starting with 5.8 g of
[3-(tert-butylsilyloxymethy- l)-benzyl]methylsulfone and 5.6 g of
1-[bis(4-chlorophenyl)methyl]azetidin- -3-one, 10.8 g of
1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethyls-
ilyloxymethyl)-phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-ol are
obtained in the form of a gum.
Example 69
[0552] A mixture of 0.45 g of
1-[bis(4-chlorophenyl)methyl]-3-{(methylsulf-
onyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidine,
0.07 cm.sup.3 of 1-aminopiperidine in 4 cm of dimethylformamide is
stirred for 18 hours at room temperature. The mixture is taken up
in 30 cm.sup.3 of ethyl acetate. The organic phase is washed with 3
times 50 cm.sup.3 of water, dried over magnesium sulfate, filtered
and concentrated to dryness under reduced pressure (2.7 kPa). 0.2 g
of 1-[bis(4-chlorophenyl)methyl]--
3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}--azetidine
is obtained melting at 175.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (400 MHz): 1.40 (2H, m,
CH.sub.2), 1.60 (4H, m, 2CH.sub.2), 2.85 (4H, m, 2NCH.sub.2), 3.00
(3H, s, SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s,
NCH.sub.2), 4.80 (1H, s, NCH), between 7.45 and 7.60 (10H, m, 10CH
arom.), 7.75 (2H, m, 2CH arom.), 9.45 (1H, s, NH)].
[0553]
1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophe-
noxycarbonyl)phenyl]methylene} azetidine may be prepared in the
following manner: on carrying out the operation according to the
procedure of Example 29 starting with 2.6 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3-car-
boxyphenyl)(methylsulfonyl)methylene]azetidine hydrochloride, 0.9 g
of pentafluorophenol, 0.9 g of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 25
cm.sup.3 of dimethylformamide, the residue obtained is purified by
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar
with a mixture of dichloromethane and ethanol (99/1 by volume) as
eluent and collecting 30 cm.sup.3 fractions. Fractions 7 to 12 are
combined and concentrated to dryness under reduced pressure (2.7
kPa). 0.9 g of
1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluoro-
phenoxycarbonyl)phenyl]methylene}azetidine is obtained in the form
of a foam.
[0554]
1-[Bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)m-
ethylene]azetidine may be prepared in the following manner: 2
cm.sup.3 of Jones reagent are added to a mixture of 0.5 g of
1-[bis-(4-chlorophenyl)m-
ethyl]-3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]-azetidine
in 9 cm.sup.3 of acetone, cooled to 5.degree. C. This stirring is
maintained for 2 hours at this temperature and then 50 cm.sup.3 of
a mixture of water and ice and 50 cm.sup.3 of ethyl acetate are
added. The organic phase is decanted off, washed with 50 cm.sup.3
of a saturated aqueous sodium chloride solution, dried over
magnesium sulfate, filtered and concentrated to dryness under
reduced pressure (2.7 kPa). The residue obtained is purified by
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 3 cm, height 25 cm), at a nitrogen pressure of 0.5 bar
with a mixture of dichloromethane and ethanol as eluent and
collecting 60 cm.sup.3 fractions. Fractions 12 to 14 are combined,
concentrated to dryness under reduced pressure (2.7 kPa). The solid
obtained is crystallized from 10 cm.sup.3 of ethyl ether. 32 mg of
1-[bis-(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methyl-
ene]-azetidine are obtained in the form of a solid melting at
205.degree. C. [NMR spectrum in DMSO-d.sub.6, T=300K, .quadrature.
in ppm (400 MHz): 2.90 (3H, s, SCH.sub.3), 3.80 (2H, s, NCH.sub.2),
4.20 (2H, s, NCH.sub.2), 4.80 (1H, s, NCH), 7.33 (4H, d, J=7 Hz,
4CH arom.), 7.39 (1H, d, J=7 Hz, CH arom.), 7.42 (4H, d, J=7 Hz,
4CH arom.), 7.49 (1H, t, J=7 Hz, CH arom.), 7.57 (1H, d, J=7 Hz, CH
arom.), 7.90 (2H, s, CH arom. and NH.sup.+)].
Example 70
[0555] On carrying out the operation according to the procedure for
Example 4 starting with 0.8 g of
1-[bis(4-chlorophenyl)methyl]-3-[(methyl-
sulfonyl)(3-trifluoromethylsulfanylphenyl)methyl(RS)]azetidin-3-ol,
0.24 g of methanesulfonyl chloride and 0.7 g of
4-dimethylaminopyridine, the residue obtained is purified by
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 2 cm, height 18 cm) at a nitrogen pressure of 0.5 bar with
dichloromethane as eluent and collecting 50 cm.sup.3 fractions.
Fractions 12 to 17 are combined, concentrated to dryness under
reduced pressure (2.7 kPa). The residue obtained is again purified
by chromatography on a silica gel column (particle size 0.04-0.06
mm, diameter 2 cm, height 20 cm), at a nitrogen pressure of 0.5 bar
with dichloromethane as eluent and collecting 30 cm.sup.3
fractions. Fractions 15 to 28 are combined, concentrated to dryness
under reduced pressure (2.7 kPa). 0.25 g of
1-[bis(4-chlorophenyl)methyl]-3-[(methylsul-
fonyl)(3-trifluoromethylsulfanylphenyl)methylene]azetidine is
obtained melting at 70.degree. C. [NMR spectrum in
DMSO-d6+CD.sub.3CO.sub.2D, T=300K, .quadrature. in ppm (300 MHz):
3.00 (3H, s, SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20 (2H, s,
NCH.sub.2), 4.80 (1H, s, NCH), 7.35 (4H, d, J=7 Hz, 4CH arom.),
7.45 (4H, d, J=7 Hz, 4 CH arom.), 7.60 (2H, m, 2CH arom), 7.75 (2H,
m, 2CH arom.)].
[0556]
1-[Bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-trifluoromethyl-
sulfanylphenyl)methyl-(RS)]azetidin-3-ol may be obtained in the
following manner: on carrying out the operation according to the
procedure of Example 1 starting with 2 g of
methyl(3-trifluoromethylsulfanylbenzyl)sul- fone, 2.3 g of
1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 5.5 cm.sup.3 of a
1.6 M solution of n-butyllithium in hexane, 0.9 g of
1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)methyl-(-
RS)]azetidin-3-ol is obtained in the form of a white solid.
[0557] Methyl(3-trifluoromethylsulfanylbenzyl)sulfone may be
prepared in the following manner: on carrying out the operation
according to the procedure of Example 10 starting with 5 g of
3-trifluoromethylsulfanylben- zyl chloride and 3.2 g of sodium
methanesulfinate, 5.2 g of
methyl(3-trifluoromethylsulfanylbenzyl)sulfone are obtained in the
form of a white solid melting at 125.degree. C.
Example 71
[0558] On carrying out the operation as in Example 38 (Method 1),
starting with 0.72 g of
1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(meth-
ylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.18 cm.sup.3 of
methanesulfonyl chloride and 0.66 g of 4-dimethylaminopyridine,
0.42 g of
1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)meth-
ylene]azetidine is obtained, after chromatography on a silica gel
column (particle size 0.04-0.06 mm, diameter 2.5 cm, height 15 cm),
at an argon pressure of 1 bar with a mixture of ethyl acetate and
cyclohexane (15/85 by volume) as eluent and collecting 25 cm.sup.3
fractions, in the form of a white foam [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (250 MHz): 3.05 (3H, s,
SCH.sub.3), 3.90 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.80
(1H, s, NCH), 7.15 (6H, m, 6CH arom.), 7.35 (1H, t, J=8 Hz, CH
arom.), 7.50 (4H, dd, J=6 and 8 Hz, 4CH arom.)].
[0559]
1-[Bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfony-
l)methyl-(RS)]azetidin-3-ol may be obtained in the following
manner: the operation is carried out as in Example 39 starting with
2.25 g of bis(4-fluorophenyl)bromomethane, 1.1 g of potassium
carbonate and 2.5 g of
3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol
hydrochloride. After chromatography on a silica gel column
(particle size 0.04-0.06 mm, diameter 4.4 cm, height 25 cm), at an
argon pressure of 0.9 bar with a mixture of ethyl acetate and
cyclohexane (2/8 by volume) as eluent and collecting 60 cm.sup.3
fractions, fractions 23 to 39 are combined and then concentrated to
dryness under reduced pressure (2.7 kPa). 0.72 g of
1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(met-
hylsulfonyl)methyl-(RS)]azetidin-3-ol is obtained in the form of a
white solid.
[0560] Bis(4-fluorophenyl)bromomethane may be prepared according to
the procedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135
(1933) starting with 4 g of 4,4'-difluorobenzydrol, 2.70 cm.sup.3
of acetal bromide and 14 cm.sup.3 of a 33% hydrobromic acid
solution in acetic acid.
Example 72
[0561] On carrying out the operation as in Example 38 (Method 1),
starting with 1.22 g of
1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(meth-
ylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.29 cm.sup.3 of
methanesulfonyl chloride and 1.1 g of 4-dimethylaminopyridine,
0.177 g of
1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)meth-
ylene]azetidine is obtained, after chromatography on a silica gel
column (particle size 0.04-0.06 mm, diameter 3 cm, height 23 cm),
at an argon pressure of 1 bar with a mixture of ethyl acetate and
cyclohexane (15/85 by volume) as eluent and collecting 60 cm.sup.3
fractions, in the form of a white foam [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 3.05 (3H, s,
SCH.sub.3), 3.95 (2H, s, NCH.sub.2), 4.25 (2H, s, NCH.sub.2), 5.35
(1H, s, NCH), 7.20 (6H, m, 6CH arom.), 7.35 (3H, m, 3CH arom.),
7.55 (2H, m, 2CH arom.)].
[0562]
1-[Bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfony-
l)methyl-(RS)]azetidin-3-ol may be obtained in the following
manner: the operation is carried out as in Example 39 starting with
2 g of bis(2-fluorophenyl)bromomethane, 1.0 g of potassium
carbonate and 2.22 g of
3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol
hydrochloride. After chromatography on a silica gel column
(particle size 0.04-0.06 mm, diameter 3 cm, height 17 cm), at an
argon pressure of 1 bar with a mixture of ethyl acetate and
cyclohexane (2/8 by volume) as eluent and collecting 60 cm.sup.3
fractions, fractions 6 to 10 are combined and then concentrated to
dryness under reduced pressure (2.7 kPa). 1.22 g of
1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)meth-
yl-(RS)]azetidin-3-ol are obtained in the form of a whitish
solid.
[0563] Bis(2-fluorophenyl)bromomethane may be prepared according to
the procedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135
(1933), starting with 1.80 g of 2,2'-difluorobenzydrol, 1.22
cm.sup.3 of acetyl bromide and 6.5 cm.sup.3 of a 33% solution of
hydrobromic acid in acetic acid.
[0564] 2,2'-difluorobenzydrol may be prepared according to the
following method: 32 cm.sup.3 of a 1.6 M solution of n-butyllithium
in hexane are poured dropwise into a solution, cooled to
-70.degree. C. under argon, of 8.8 g of 2-bromofluorobenzene in 100
cm.sup.3 of tetrahydrofuran. After stirring for 10 minutes at
-70.degree. C., 2.1 cm.sup.3 of ethyl formate are added slowly and
then the mixture is stirred at -70.degree. C. for 30 minutes. The
reaction medium is then brought to 0.degree. C. and then
supplemented with 50 cm.sup.3 of ethyl acetate and 100 cm.sup.3 of
saturated ammonium chloride solution. After stirring, the organic
phase is separated, dried over magnesium sulfate, concentrated to
dryness at 55.degree. C., under reduced pressure (2.7 Kpa). 3.63 g
of 2,2'-difluorobenzydrol are obtained in the form of a yellow
oil.
Example 73
[0565] On carrying out the operation as in Example 38 (Method 1),
starting with 1.15 g of
1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(meth-
ylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.264 cm.sup.3 of
methanesulfonyl chloride, and 0.98 g of 4-dimethylaminopyridine,
0.55 g of
1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)meth-
ylene]azetidine is obtained, after chromatography on a silica gel
column (particle size 0.06-0.200 mm, diameter 2.8 cm, height 25
cm), at an argon pressure of 1 bar with a mixture of ethyl acetate
and cyclohexane (15/85 by volume) as eluent and collecting 60
cm.sup.3 fractions, in the form of a white solid melting at
178.degree. C. [NMR spectrum in DMSO-d.sub.6, T=300K, .quadrature.
in ppm (250 MHz): 3.05 (3H, s, SCH.sub.3), 3.95 (2H, s, NCH.sub.2),
4.25 (2H, s, NCH.sub.2), 4.80 (1H, s, NCH), 7.10 (2H, m, 2CH
arom.), 7.20 (2H, m, 2CH arom.), between 7.30 and 7.50 (7H, m, 7CH
arom.)].
[0566]
1-[Bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfony-
l)methyl-(RS)]azetidin-3-ol may be prepared in the following
manner: on carrying out the operation according to Example 1
starting with 1.2 g of (3,5-difluorobenzyl)methylsulfone and 1.5 g
of 1-[bis(3-fluorophenyl)meth- yl]azetidin-3-one, 1.95 g of
1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluor-
ophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained,
after purification on a silica gel column (particle size 0.06-0.200
mm, diameter 3.2 cm, height 30 cm), at an argon pressure of 1 bar
with a mixture of ethyl acetate and cyclohexane (2/8 by volume) as
eluent and collecting 60 cm.sup.3 fractions, in the form of a white
solid melting at 170.degree. C. (decomposition).
[0567] 1-[Bis(3-fluorophenyl)methyl]azetidin-3-one may be prepared
by carrying out the operation in a manner identical to the
procedure described by KATRITZKY A. R. et al., J. Heterocycl.
Chem., 271 (1994), starting with 4.9 g of
[bis(3-fluorophenyl)methyl]amine and 1.78 cm.sup.3 of
epichlorohydrin.
[0568] [Bis(3-fluorophenyl)methyl]amine may be prepared in the
following manner: a solution of 5.17 g of 3,3'-difluorobenzophenone
oxime in 30 cm.sup.3 of tetrahydrofuran is poured, under an argon
atmosphere over 30 minutes, into a suspension of 1.27 g of lithium
aluminum hydride in 80 cm.sup.3 of tetrahydrofuran. After stirring
for 5 hours under reflux, 1.3 cm.sup.3 of water, 1.3 cm.sup.3 of 4
N sodium hydroxide, 2.6 cm.sup.3 of water and then 50 cm.sup.3 of
ethyl acetate are added successively. After drying over magnesium
sulfate and concentrating to dryness under reduced pressure (2.7
kPa), 4.9 g of [bis(3-fluorophenyl)methyl]amine are obtained in the
form of a yellow oil.
[0569] 3-3'-Difluorobenzophenone oxime may be prepared according to
the following procedure: a solution of 1.6 g of hydroxylamine
hydrochloride in 8 cm.sup.3 of water is poured dropwise into a
solution of 5.0 g of 3,3'-difluorobenzophenone in 10 cm.sup.3 of
ethanol, and then 1.2 g of sodium hydroxide pellets are added in
small fractions. The reaction mixture, heated under reflux for 10
minutes, is cooled to 20.degree. C. and then acidified with 7.5
cm.sup.3 of 4 N hydrochloric acid. Once triturated, the oily
precipitate obtained becomes a white solid which is filtered,
washed with water and then dried at 35.degree. C. under reduced
pressure (2.7 kPa). 5.17g of 3,3'-difluorobenzophenone oxime are
obtained in the form of a white solid.
Example 74
[0570] On carrying out the operation as in Example 1, starting with
1.30 g of a mixture of two diastereoisomers
1-[(4-chlorophenyl)(thiazol-2-yl)met-
hyl-(RS)]-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol,
0.35 cm.sup.3 of methanesulfonyl chloride and 1.22 g of
4-dimethylaminopyridine, 0.7 g of
(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)m-
ethyl]-3-[(methylsulfonyl)(phenyl)-methylene]azetidine is obtained,
after chromatography on a silica gel column (particle size
0.06-0.200 mm, diameter 2.4 cm, height 25 cm), at an argon pressure
of 1 bar with a mixture of ethyl acetate and cyclohexane (1/1 by
volume) as eluent and collecting 30 cm.sup.3 fractions, in the form
of a pinkish solid [NMR spectrum in DMSO-d.sub.6, T=300K,
.quadrature. in ppm (300 MHz): 2.95 (3H, s, SCH.sub.3), 3.95 (2H,
m, NCH.sub.2), 4.35 (2H, m, NCH.sub.2), 5.25 (1H, s, NCH), 7.45
(9H, m, 9CH arom.), 7.65 (1H, d, J=2 Hz, CH thiazole), 7.70 (1H, d,
J=2 Hz, CH thiazole)].
[0571] The mixture of the two diastereoisomers
1-[(4-chlorophenyl)-(thiazo-
l-2-yl)methyl-(RS)]-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol
may be obtained in the following manner: on carrying out the
operation as in Example 39 starting with 4.47 g of
(RS)-bromo(4-chlorophenyl)(thiazol-- 2-yl)-methane and 4.31 g of
3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidi- n-3-ol
hydrochloride and after chromatography on a silica gel column
(particle size 0.06-0.200 mm, diameter 5.6 cm, height 40 cm), at an
argon pressure of 0.5 bar with a mixture of ethyl acetate and
cyclohexane (25/75 by volume) up to fraction 35 and then with pure
ethyl acetate as eluent and collecting 60 cm.sup.3 fractions,
fractions 38 to 40 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 1.3 g of the mixture of the two
diastereoisomers
1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[(methylsulfonyl)(phenyl)-
methyl-(RS)]azetidin-3-ol are obtained in the form of a whitish
solid.
[0572] (RS)-bromo(4-chlorophenyl)(thiazol-2-yl)methane may be
prepared according to the procedure described by BACHMANN W. E., J.
Am. Chem. Soc., 2135 (1933), starting with 3.5 g of
(RS)-(4-chlorophenyl)(2-thiazol- yl)methanol, 3.81 g of acetyl
bromide and 12.0 cm.sup.3 of a 33% solution of hydrobromic acid in
acetic acid.
[0573] (RS)-(4-chlorophenyl)(thiazol-2-yl)methanol may be prepared
according to the procedure described by G. EVAN BOSWELL et al., J.
Heterocyclic Chem., 32, 1801 (1995), starting with 4.22 g of
4-chlorobenzaldehyde and 4.92 g of 2-bromothiazole.
Example 75
[0574] On carrying out the operation as in Example 1, starting with
0.52 g of a mixture of the two diastereoisomers
1-[(4-chlorophenyl)(thien-2-yl)m-
ethyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3--
ol, 0.14 cm.sup.3 of methanesulfonyl chloride and 0.49 g of
4-dimethylaminopyridine, 0.32 g of
(RS)-1-[(4-chlorophenyl)(thien-2-yl)me-
thyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine is
obtained, after chromatography on a silica gel column (particle
size 0.06-0.200 mm, diameter 2.4 cm, height 20 cm), at an argon
pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane
(20/80 by volume) as eluent and collecting 30 cm.sup.3 fractions,
in the form of a white solid melting at 176.degree. C. [NMR
spectrum in DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz):
2.98 (3H, s, SCH.sub.3), 3.90 (2H, m, NCH.sub.2), 4.20 (2H, s,
NCH.sub.2), 5.03 (1H, s, NCH), 6.85 (1H, dd, J=3 and 5 Hz, CH
thiophene), 7.08 (3H, m, 2CH arom. and 1CH thiophene), 7.22 (1H, t,
J=8 Hz, CH arom.),7.32 (3H, m, 2CH arom. and 1CH thiophene), 7.40
(2H, d, J=7 Hz, 2CH arom.)].
[0575] The mixture of the two diastereoisomers
1-[(4-chlorophenyl)(thien-2-
-yl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetid-
in-3-ol may be prepared in the following manner: on carrying out
the operation as in Example 1 starting with 1.60 cm.sup.3 of 1.6 N
n-butyllithium in solution in hexane, 0.83 g of
(3,5-difluorobenzyl)methy- lsulfone and 1.06 g of
1-[(4-chlorophenyl)-(thien-2-yl)methyl-(RS)]azetidi- n-3-one, 0.55
g of the mixture of diastereoisomers 1-[4-chlorophenyl)(thie-
n-2-yl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]aze-
tidin-3-ol is obtained, after purification on a silica gel column
(particle size 0.06-0.200 mm, diameter 2.8 cm, height 30 cm), at an
argon pressure of 0.5 bar with a mixture of ethyl acetate and
cyclohexane (25/75 by volume) as eluent and collecting 40 cm.sup.3
fractions, in the form of an off-white solid.
[0576] 1-[(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]-azetidin-3-one
may be prepared by carrying out the operation in the following
manner: 3.04 cm.sup.3 of dimethyl sulfoxide are poured over 10
minutes into a solution, cooled to -70.degree. C., of 1.83 cm.sup.3
of oxalyl chloride in 20 cm.sup.3 of dichloromethane under argon.
After stirring for 30 minutes at -60.degree. C., a solution of 5.2
g of 1-[(4-chlorophenyl)(thi- en-2-yl)methyl-(RS)]azetidin-3-ol in
80 cm.sup.3 of dichloromethane is poured in over 20 minutes, the
mixture is stirred for 3 hours at a temperature of between
-60.degree. and -70.degree. C. and then 9.12 cm.sup.3 of
triethylamine are added. The mixture is then allowed to return to
room temperature and then diluted with water. The organic phase is
separated, dried over magnesium sulfate and then concentrated to
dryness under reduced pressure. The residue is chromatographed on a
silica gel column (particle size 0.06-0.200 mm, diameter 4 cm,
height 36 cm), at an argon pressure of 0.5 bar with a mixture of
ethyl acetate and cyclohexane (1/9 by volume) as eluent and
collecting 60 cm.sup.3 fractions. 3.3 g of
1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-zetidin-3- -one are
obtained in the form of a yellow oil which crystallizes at room
temperature.
[0577] 1-[(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin-3-ol may
be prepared in the following manner: 4.12 g of sodium bicarbonate
are added to a solution of 11.0 g of
[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-amin- e in 80 cm.sup.3 of
ethanol. The mixture is heated at 65.degree. C. and supplemented
with 4.03 cm.sup.3 of epibromohydrin. After stirring for 20 hours
at 65.degree. C., the cooled mixture is filtered and the filtrate
concentrated to dryness under reduced pressure (2.7 Kpa). The
residue is chromatographed on a silica gel column (particle size
0.06-0.200 mm, diameter 3.6 cm, height 32 cm), at an argon pressure
of 0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75
by volume) as eluent and collecting 60 cm.sup.3 fractions. 6.3 g of
1-[(4-chlorophenyl)(thien-2-yl- )methyl-(RS)]azetidin-3-ol are
obtained in the form of a pale yellow oil.
[0578] [(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]-amine may be
prepared in the following manner: a solution of 10.92 g of
2-thiophenecarbonitrile in 80 cm.sup.3 of ethyl ether is poured
slowly into a suspension, cooled to 10.degree. C., of
4-chlorophenylmagnesium bromide (prepared from 19.15 g of
4-bromochlorobenzene and 2.43 g of magnesium) in 120 cm.sup.3 of
anhydrous ethyl ether. After refluxing for one hour, the mixture is
cooled to 10.degree. C., supplemented slowly with 40 cm.sup.3 of
methanol and then filtered on supercel. 4.54 g of sodium
borohydride are added under argon and in small fractions over 15
minutes and then the reaction medium is stirred for 20 hours at
20.degree. C. The mixture obtained is diluted with ethyl acetate
and then washed with water. The organic phase is dried over
magnesium sulfate, concentrated to dryness at 50.degree. C. under
reduced pressure (2.7 kPa). The residue is chromatographed on a
silica gel column (particle size 0.06-0.200 mm, diameter 5 cm,
height 42 cm), at an argon pressure of 0.5 bar with a mixture of
ethyl acetate and cyclohexane (4/6 by volume) as eluent and
collecting 100 cm.sup.3 fractions. Fractions 6 to 12, concentrated
to dryness, correspond to 13 g of imine in the form of a yellow oil
which is taken up in 100 cm.sup.3 of methanol. The solution
obtained is supplemented with 2.4 g of sodium borohydride and
stirred for one hour at 5.degree. C. The mixture obtained is
diluted with ethyl acetate and then washed with water. The organic
phase is dried over magnesium sulfate, concentrated to dryness at
50.degree. C. under reduced pressure (2.7 Kpa). The residue is
chromatographed on a silica gel column (particle size 0.06-0.200
mm, diameter 3.2 cm, height 40 cm), at an argon pressure of 0.5 bar
with a mixture of ethyl acetate and cyclohexane (4/6 by volume) as
eluent and collecting 60 cm.sup.3 fractions. 11.0 g of
[(4-chlorophenyl)(thien-2-yl)- methyl-(RS)]amine are obtained in
the form of a yellow oil.
Example 76
[0579] On carrying out the operation as described in Example 75,
starting with 1.66 g of the mixture of the two chiral
diastereoisomers
1-[(4-chlorophenyl)-(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(meth-
ylsulfonyl)methyl-(R*)]-azetidin-3-ol and
1-[(4-chlorophenyl)(thien-2-yl)m-
ethyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidin-3--
ol, 50 cm.sup.3 of dichloromethane, 0.45 cm.sup.3 of
methanesulfonyl chloride, and 1.64 g of 4-dimethylaminopyridine,
0.6 g of
(+)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methyl-
sulfonyl)methylene]azetidine is obtained in the form of white
crystals melting at 136.degree. C.,
[a].sup.20.sub.D=+3.2.degree.(c=0.5% in dichloromethane).
[0580] The mixture of the two chiral diastereoisomers
1-[(4-chlorophenyl)-(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(meth-
ylsulfonyl)methyl-(R*)]-azetidin-3-ol and
1-[(4-chlorophenyl)(thien-2-yl)m-
ethyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidin-3--
ol may be prepared as described in Example 75, starting with 1.06 g
of (+)-1-[(4-chlorophenyl)(thien-2-yl)-methyl]azetidin-3-one, 0.82
g of (3,5-difluorobenzyl)methylsulfone, 2.5 cm.sup.3 of 1.6 N
solution of n-butyllithium in hexane, and 25 cm.sup.3 of
tetrahydrofuran. 1.7 g of the mixture of the two chiral
diastereoisomers 1-[(4-chlorophenyl)(thien--
2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]azeti-
din-3-ol and
1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorop-
henyl)(methylsulfonyl)methyl-(S*)]azetidin-3-ol are obtained, after
purification by chromatography, in the form of a white solid.
[0581] (+)-1-[(4-Chlorophenyl)(thien-2-yl)methyl]azetidin-3-one may
be prepared as described in Example 75, starting with 12.4 g of
(+)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-ol, 220
cm.sup.3 of dichloromethane, 7.1 cm.sup.3 of dimethyl sulfoxide,
4.4 cm.sup.3 of oxalyl chloride and 21.5 cm.sup.3 of triethylamine.
9.2 g of (+)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-one
are obtained in the form of a pale yellow oil crystallizing at
20.degree. C.
[0582] (+)-1-[(4-Chlorophenyl)(thien-2-yl)methyl]-azetidin-3-ol may
be prepared as described in Example 75, starting with 16.1 g of
(+)-[(4-chlorophenyl)-(thien-2-yl)methyl]amine, 130 cm.sup.3 of
ethanol, 5.9 cm.sup.3 of epibromohydrin and 6.05 g of sodium
bicarbonate. 11.5 g of
(+)-1-[(4-chlorophenyl)(thien-2-yl)-methyl]azetidin-3-ol are
obtained, after purification by chromatography, in the form of a
cream-colored oil.
[0583] (+)-4-[(Chlorophenyl)(thien-2-yl)methyl]amine may be
prepared in the following manner: 73 g of D-(-)-tartaric acid are
added to a solution of 109 g of
[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]amine in 500 cm.sup.3 of
methanol. The mixture is concentrated to dryness under reduced
pressure (2.7 kPa). The foam obtained is taken up in 2.05 liters of
an ethanol-water 90/10 by volume mixture. After stirring slowly for
20 hours at 20.degree. C., the crystalline suspension obtained is
filtered, the crystals washed with a minimum amount of the same
mixture of solvents, and then dried. Another recrystallization is
carried out under the same conditions with 1.5 liters of the same
mixture of solvents. 44.9 g of crystals of the acid tartrate of the
amine are obtained. [a].sup.20.sub.D=+10.3.degree.(c=0.5% in
dimethylformamide). This compound is recrystallized from 600
cm.sup.3 of an ethanol-water 80/20 by volume mixture (the crystals
are filtered and washed with twice 30 cm.sup.3 of the same mixture
of solvents and then drained) and then recrystallized under the
same conditions with 400 cm.sup.3 of an ethanol-water 78/22
mixture. 28.2 g of acid D-(-)-tartrate of
(+)-[(4-chlorophenyl)thien-2-yl)methyl]amine are obtained in the
form of white crystals [a].sup.20.sub.D=+10.8.degree.(c=0.5% in
dimethylformamide).
[0584] This salt is taken up in 400 cm.sup.3 of a 1 N aqueous
solution of sodium hydroxide and with 100 cm.sup.3 of ethyl
acetate. The organic phase is separated, washed with 100 cm.sup.3
of water, dried over magnesium sulfate and then concentrated to
dryness under reduced pressure (2.7 kPa). 16.1 g of
(+)-[(4-chlorophenyl)-(thien-2-yl)methyl]amine are obtained in the
form of an oil which crystallizes at 20.degree. C.
[a].sup.20.sub.D=+32.7.degree.(c=0.5% in dichloromethane).
Example 77
[0585] On carrying out the operation as described in Example 75,
starting with 1.30 g of the mixture of the two chiral
diastereoisomers
1-[(4-chlorophenyl)-(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(meth-
ylsulfonyl)methyl-(R*)]-azetidin-3-ol and
1-[(4-chlorophenyl)(thien-2-yl)m-
ethyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidin-3--
ol, 40 cm.sup.3 of dichloromethane, 0.35 cm.sup.3 of
methanesulfonyl chloride and 1.28 g of 4-dimethylaminopyridine,
0.97 g of
(-)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methyl-
sulfonyl)methylene]zetidine is obtained in the form of white
crystals melting at 135.degree. C., [a].sup.20.sub.D=-3.4.degree.
(c=0.5% in dichloromethane).
[0586] The mixture of the two chiral diastereoisomers
1-[(4-chlorophenyl)-(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(meth-
ylsulfonyl)methyl-(R*)]-azetidin-3-ol and
1-[(4-chlorophenyl)(thien-2-yl)m-
ethyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidin-3--
ol may be prepared as described in Example 75, starting with 1.06 g
of (-)-1-[(4-chlorophenyl)(thien-2-yl)-methyl]azetidin-3-one, 0.82
g of (3,5-difluorobenzyl)methylsulfone, 2.5 cm.sup.3 of 1.6 N
solution of n-butyllithium in hexane, and 25 cm.sup.3 of
tetrahydrofuran. 1.3 g of the mixture of the two chiral
diastereoisomers 1-[(4-chlorophenyl)(thien--
2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]azeti-
din-3-ol and
1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorop-
henyl)(methylsulfonyl)methyl-(S*)]azetidin-3-ol are obtained after
purification by chromatography in the form of a white solid.
[0587] (-)-1-[(4-Chlorophenyl)(thien-2-yl)methyl]azetidin-3-one may
be prepared as described in Example 75, starting with 11.4 g of
(-)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-ol, 200
cm.sup.3 of dichloromethane, 4.0 cm.sup.3 of dimethyl sulfoxide,
4.0 cm.sup.3 of oxalyl chloride and 19.5 cm.sup.3 of triethylamine.
8.3 g of (-)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-one
are obtained in the form of a pale yellow oil crystallizing at
20.degree. C.
[0588] (-)-1-[(4-Chlorophenyl)(thien-2-yl)methyl]azetidin-3-ol may
be prepared as described in Example 75, starting with 15.4 g of
(-)-[(4-chlorophenyl)-(thien-2-yl)methyl]amine, 120 cm.sup.3 of
ethanol, 5.8 cm.sup.3 of epibromohydrin and 5.8 g of sodium
bicarbonate. 10.7 g of
(-)-1-[(4-chlorophenyl)(thien-2-yl)-methyl]azetidin-3-ol are
obtained, after purification by chromatography, in the form of a
cream-colored oil.
[0589] (-)-[(4-Chlorophenyl)(thien-2-yl)methyl]amine may be
prepared in the following manner: 29 g of L-(+)-tartaric acid are
added to a solution of 43 g of
[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]amine in 200 cm.sup.3 of
methanol. The mixture obtained crystallizes in 2 hours at room
temperature. The crystals are filtered, washed with twice 10
cm.sup.3 of methanol. Recrystallization is carried out with 500
cm.sup.3 of an ethanol-water 80/20 by volume mixture, the crystals
are filtered, washed with twice 30 cm.sup.3 of the same mixture of
solvents and then dried under vacuum at 45.degree. C. A final
recrystallization is carried out with 350 cm.sup.3 of an
ethanol-water 78/22 by volume mixture, allowing the mixture to be
stirred for 20 hours at 20.degree. C. The crystals obtained are
drained, dried under reduced pressure (2.7 kPa). 26 g of acid
L-(+)-tartrate of (-)-[(4-chlorophenyl)(thien-2-yl)methyl]amine are
obtained. [a].sup.20.sub.D=-10.7.degree.(c=0.5% in
dimethylformamide).
[0590] This salt is taken up in 400 cm.sup.3 of a 1 N aqueous
sodium hydroxide solution and with 100 cm.sup.3 of ethyl acetate.
The organic phase is separated, washed with 100 cm.sup.3 of water,
dried over magnesium sulfate and then concentrated to dryness under
reduced pressure (2.7 kPa). 15.4 g of
(-)-[(4-chlorophenyl)(thien-2-yl)methyl]amine are obtained in the
form of an oil which crystallizes at 20.degree. C.
[a].sup.20.sub.D=-31.7.degree. (c=0.5% in dichloromethane).
Example 78
[0591] On carrying out the operation according to the procedure of
Example 1 starting with 3.4 g of
1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methyl-(R- S)]azetidin-3-ol,
0.72 cm.sup.3 of methanesulfonyl chloride and 3.8 g of
4-dimethylaminopyridine, 1.9 g of
1-benzhydryl-3-[(ethylsulfonyl)(phenyl)- -methylene]azetidine are
obtained, after recrystallization from 40 cm.sup.3 of acetonitrile,
in the form of crystals melting at 210.degree. C. [[NMR spectrum in
DMSO-d6, T=300K, .quadrature. in ppm (300 MHz): 1.15 (3H, t, J=6
Hz, CH.sub.3), 2.92 (2H, q, J=6 Hz, CH.sub.2), 3.83 (2H, s,
NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.75 (1H, s, NCH), between
7.20 and 7.50 (15H, m, 3 phenyls)].
[0592]
1-Benzhydryl-3-[(ethylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol
may be obtained by carrying out the operation according to the
procedure described in Example 1 starting with 2.4 g of
benzylethylsulfone, 2.2 cm.sup.3 of diisopropylamine, 10 cm.sup.3
of 1.6 N n-butyllithium in solution in hexane, 65 cm.sup.3 of
tetrahydrofuran and 3.1 g of 1-benzhydrylazetidin-3-one. 3.6 g of
1-benzhydryl-3-[(ethylsulfonyl)(phen- yl)methyl-(RS)]azetidin-3-ol
are obtained, after recrystallization from 30 cm.sup.3 of
acetonitrile, in the form of white crystals melting at 222.degree.
C.
[0593] Benzylethylsulfone may be prepared by carrying out the
operation according to the procedure of Example 2 starting with 6.3
g of benzylethylsulfide, 50 cm.sup.3 of acetic acid, 50 cm.sup.3 of
water, 25 cm.sup.3 of 36 N sulfuric acid and 24.8 g of oxone.sup.R.
3.2 g of benzylethylsulfone are obtained, by recrystallization from
20 cm of ethyl ether, in the form of a solid melting at 86.degree.
C.
[0594] Benzylethylsulfide may be prepared in the following manner:
1.2 g of sodium hydride are added in small portions to a solution
of 5 g of benzylmercaptan in 50 cm.sup.3 of dimethylformamide under
argon, and then 3.36 cm.sup.3 of ethyl iodide are poured in, while
the temperature is maintained below 45.degree. C. The mixture is
stirred for 2 hours and then taken up in 200 cm.sup.3 of ethyl
ether. The organic phase is washed with 200 cm.sup.3 of water and
then with 3 times 100 cm.sup.3 of water, dried over magnesium
sulfate and concentrated to dryness under reduced pressure (2.7
kPa). 6.3 g of benzylethylsulfide are obtained in the form of a
pale yellow liquid.
Example 79
[0595] 0.083 g of 1-amino-4-methylpiperazine is added to a solution
of 0.45 g of
1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluor-
ophenoxycarbonyl)phenyl]methylene]azetidine in 5 cm.sup.3 of
dimethylformamide. The mixture is stirred for 20 hours at room
temperature and then 40 cm.sup.3 of ethyl acetate are added. The
organic phase is washed with 4 times 20 cm.sup.3 of water, dried
over magnesium sulfate and concentrated to dryness under reduced
pressure (2.7 kPa). The residue is triturated with 10 cm.sup.3 of
ethyl ether, filtered and then dried. 0.2 g of
1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[(N-4-me-
thylpiperazinylcarbamoyl)phenyl]methylene}azetidine is obtained in
the form of a yellow solid melting at 162.degree. C. [NMR spectrum
in DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.20 (3H,
s, NCH.sub.3), 2.40 (4H, m, 2 NCH.sub.2), 2.90 (4H, m, 2
NCH.sub.2), 2.95 (3H, s, SCH.sub.3), 3.80 (2H, s, NCH.sub.2), 4.20
(2H, s, NCH.sub.2), 4.80 (1H, s, NCH), 7.40 (4H, d, J=7 Hz, 4CH
arom.), 7.50 (4H, d, J=7 Hz, 4CH arom.), 7.55 (2H, m, 2CH arom.),
7.80 (2H, m, 2CH arom.), 9.50 (1H, s, CONH)].
[0596]
1-[Bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophe-
noxycarbonyl)phenyl]methylene]azetidine may be prepared in the
following manner: 0.94 g of
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and
0.89 g of pentafluorophenol are added to a solution of 2.9 g of
1-[bis-(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfon-
yl)methylene]-azetidine in 25 cm.sup.3 of dimethylformamide. The
mixture is stirred for 20 hours at room temperature and then taken
up in 50 cm.sup.3 of ethyl acetate. The organic phase is washed
with 100 cm.sup.3 of water, 200 cm.sup.3 of a saturated aqueous
sodium bicarbonate solution and then with twice 50 cm.sup.3 of
distilled water, dried over magnesium sulfate and concentrated to
dryness under reduced pressure (2.7 kpa). The residue is
chromatographed on a silica column (particle size 0.04-0.006 mm,
diameter 2 cm), eluting with a mixture of dichloromethane and
ethanol (99/1 by volume). 0.92 g of
1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfo-
nyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene]azetidine is
obtained in the form of a white foam.
[0597]
1-[Bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)m-
ethylene]azetidine may be prepared in the following manner: a 36%
solution of hydrochloric acid at a temperature of 50.degree. C. is
added to a solution of 3.8 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(met-
hylsulfonyl)methylene]azetidine in 5 cm.sup.3 of acetic acid. The
heating is continued for 48 hours and then the mixture is
evaporated to dryness under reduced pressure (2.7 Kpa). The residue
is taken up in 30 cm.sup.3 of ethanol and again evaporated to
dryness. The residue is triturated in 35 cm.sup.3 of ethyl ether.
3.8 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3--
carboxyphenyl)(methylsulfonyl)-methylene)]azetidine are obtained in
the form of a beige solid.
[0598]
1-[Bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)-me-
thylene]azetidine may be prepared according to the procedure of
Example 4, starting with 11 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(me-
thylsulfonyl)methyl-(RS)]azetidin-3-ol, 150 cm.sup.3 of
dichloromethane, 2.54 cm.sup.3 of methanesulfonyl chloride and 10.7
g of 4-dimethylaminopyridine, at room temperature for 3 hours. The
residue obtained is purified by chromatography on a silica gel
column (particle size 0.04-0.06 mm, diameter 4.5 cm) and eluted
with dichloromethane and then with a mixture of dichloromethane and
ethanol (99.6/0.4 by volume). The fractions are evaporated to
dryness under reduced pressure (2.7 Kpa). 3.8 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)-
methylene]azetidine are obtained in the form of a white foam.
[0599]
1-[Bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)-me-
thyl-(RS)]azetidin-3-ol may be prepared in the following manner: a
solution of 5 g of 3-cyanobenzyl methyl sulfone in 500 cm of
tetrahydrofuran is added over 15 minutes to a solution of 17.6
cm.sup.3 of 1.6 M n-butyllithium in hexane, in 30 cm.sup.3 of
tetrahydrofuran under argon, and cooled to -70.degree. C. The
mixture is stirred for 1 hour 30 minutes. Next, a solution of 7.8 g
of 1-[bis(4-chlorophenyl)methy- l]-azetidin-3-one in 80 cm.sup.3 of
tetrahydrofuran is poured in over 10 minutes. After stirring for 1
hour 30 minutes, 60 cm.sup.3 of a saturated aqueous ammonium
chloride solution are poured in and then the mixture is allowed to
return to room temperature. The mixture is taken up in 300 cm.sup.3
of ethyl acetate, the organic phase washed with 200 cm.sup.3 of a
saturated aqueous sodium chloride solution, dried over magnesium
sulfate and evaporated under reduced pressure (2.7 Kpa). 11 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(R-
S)]-azetidin-3-ol are obtained in the form of a foam.
[0600] (3-Cyanobenzyl)methylsulfone may be prepared in the
following manner: starting with a solution of 20.2 g of
3-chloromethylbenzonitrile in 200 cm.sup.3 of ethanol, 17.4 g of
85% sodium methanesulfinate are added. The mixture is stirred for
20 hours under reflux and then taken up in 500 cm.sup.3 of ethyl
acetate and 500 cm.sup.3 of water. The insoluble matter is filtered
off, the organic phase in the filtrate is dried over magnesium
sulfate and evaporated to dryness under reduced pressure (2.7 Kpa).
The solid obtained is triturated with 100 cm.sup.3 of ethyl ether.
After filtration and drying of the solid, 21 g of
(3-cyanobenzyl)methylsu- lfone are obtained in the form of white
crystals melting at 165.degree. C.
[0601] 3-Chloromethylbenzonitrile may be prepared in the following
manner: 32 g of 3-chloromethylbenzoamide in 200 cm.sup.3 of
phosphorus oxychloride are heated at 95.degree. C. for 3 hours, and
then 1 liter of ice is loaded, the mixture stirred for 1 hour and
extracted with 500 cm.sup.3 of dichloromethane. The organic phase
is washed with 200 cm.sup.3 of water, dried over magnesium sulfate
and evaporated to dryness under reduced pressure (2.7 Kpa). 20.2 g
of 3-chloromethylbenzonitrile are obtained in the form of a white
solid.
[0602] 3-Chloromethylbenzoamide may be prepared in the following
manner: 150 cm.sup.3 of a solution of ammonium hydroxide (d=0.90)
are poured into a solution of 50 g of 3-chloromethylbenzoyl
chloride in 150 cm.sup.3 of ethyl ether, the mixture is cooled,
stirred for 1 hour, filtered and washed with twice 200 cm.sup.3 of
ethyl ether. 32 g of 3-chloromethylbenzoamide are obtained in the
form of white crystals.
Example 80
[0603] On carrying out the operation according to the procedure of
Example 79 starting with 0.5 g of
1-[bis(4-chlorophenyl)methyl]-0.3-{(methylsulfo-
nyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidine, 0.06
cm.sup.3, 1,1-dimethylhydrazine and 5 cm.sup.3 of
dimethylformamide, 0.125 g of
1-[bis-(4-chlorophenyl)methyl]-3-{(3-(2,2-dimethylcarbohydrazi-
do)phenyl] (methylsulfonyl)methylene}azetidine is obtained in the
form of a white solid melting at 134.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.60 (6H, s,
N(CH.sub.3).sub.2), 2.95 (3H, s, SCH.sub.3), 3.80 (2H, s,
NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.80 (1H, s, NCH), 7.35 (4H,
d, J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.50 (2H,
m, 2CH arom.), 7.80 (2H, m, 2CH arom.), 9.50 (1H, s, CONH)].
Example 81
[0604] On carrying out the operation according to the procedure
described in Example 1 starting with 2.2 g of
1-[bis(thien-2-yl)methyl]-3-[(3,5-dif-
luorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol, 0.64
cm.sup.3 of methanesulfonyl chloride, 2.3 g of
4-dimethylaminopyridine and 75 cm.sup.3 of dichloromethane, 1.3 g
of 1-[bis(thien-2-yl)methyl]-3-[(3,5-d-
ifluorophenyl)(methylsulfonyl)methylene]-azetidine are obtained,
after purification by chromatography and crystallization from
diisopropyl ether, in the form of white crystals melting at
165.degree. C. [NMR spectrum in DMSO-d.sub.6, T=300K, .quadrature.
in ppm (300 MHz): 3.00 (3H, s, SCH.sub.3), 3.92 (2H, s, NCH.sub.2),
4.28 (2H, s, NCH.sub.2), 5.40 (1H, s, NCH), 6.95 (2H, dd, J=5 and 2
Hz, 2CH thio.), 7.15 (2H, d, J=2 Hz, 2CH thio.), 7.20 (2H, m, 2CH
arom.), 7.35 (1H, t, J=8 Hz, CH arom.), 7.50 (2H, d, J=5 Hz, 2CH
thio.)].
[0605]
1-[Bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)-m-
ethyl-(RS)]azetidin-3-ol may be obtained according to the procedure
described in Example 1, starting with 1.5 g of
1-[bis(thien-2-yl)methyl]a- zetidin-3-one, 4 cm.sup.3 of 1.6 N
n-butyllithium in hexane, 1.3 g of
(3,5-dichlorobenzyl)methylsulfone and 40 cm.sup.3 of
tetrahydrofuran. 2.2 g of
1-[bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)met-
hyl-(RS)]azetidin-3-ol are obtained, after purification by
chromatography, in the form of white crystals melting at
145.degree. C.
[0606] 1-[Bis-thien-2-yl)methyl]azetidin-3-one may be prepared by
carrying out the operation as described in Example 73, starting
with 4 g of 1-[bis(thien-2-yl)methyl]azetidin-3-ol, 2.6 cm.sup.3 of
dimethyl sulfoxide, 7.7 cm.sup.3 of triethylamine, 7.7 cm.sup.3 of
oxalyl chloride, and 100 cm.sup.3 of dichloromethane. The residue
obtained is purified by chromatography on a silica gel column
(particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) with, as
eluent, a mixture of cyclohexane/ethyl acetate (1/1 by volume). The
fractions obtained are evaporated to dryness under reduced pressure
(2.7 Kpa). 3.2 g of 1-[bis(thien-2-yl)methyl]azetidin-3-one are
obtained in the form of cream-colored crystals melting at
70.degree. C.
[0607] 1-[Bis(thien-2-yl)methyl]azetidin-3-ol may be prepared by
carrying out the operation as described in Example 73, starting
with 6 g of 1-[bis(thien-2-yl)methyl]amine, 2.5 cm.sup.3 of
epibromohydrin, 2.6 g of sodium bicarbonate and 50 cm.sup.3 of
ethanol. 4 g of 1-[bis(thien-2-yl)methyl]azetidin-3-ol are obtained
in the form of beige crystals melting at 115.degree. C.
[0608] 1-[Bis(thien-2-yl)methyl]amine may be prepared in the
following manner: a solution of 5 cm.sup.3 of
thien-2-ylcarbonitrile in 50 cm.sup.3 of diethyl ether is poured
dropwise into a suspension, cooled under argon to 10.degree. C., of
thien-2-ylmagnesium bromide (prepared from 1.29 g of magnesium and
3.22 cm.sup.3 2-bromothiophene in 75 cm.sup.3 of diethyl ether).
After refluxing for 1 hour and 30 minutes, the reaction medium is
cooled to 5.degree. C. and then 20 cm of methanol are poured in
dropwise, the suspension filtered and the solid washed with
methanol. The filtrate obtained a brown solution. 2.45 g of sodium
borohydride are added to this solution, under argon, in several
portions. The mixture is stirred at room temperature for 16 hours
and then diluted with ethyl acetate and supplemented with water
slowly. The organic phase is extracted, washed with water, dried
over magnesium sulfate and evaporated to dryness under reduced
pressure (2.7 kpa) at 55.degree. C. A brown oil is obtained which
is chromatographed on a silica gel column (particle size 0.2-0.063
mm, diameter 8 cm, height 25 cm) and eluted with a mixture of
cyclohexane/ethyl acetate (90/10 and then 85/15 by volume).
Fractions 21 to 30 are combined and evaporated to dryness under
reduced pressure (2.7 kpa). 11 g of 1-[bis(thien-2-yl)methyl]amine
are obtained in the form of a crystallized solid.
Example 82
[0609] On carrying out the operation according to the procedure
described in Example 1 starting with 0.47 g of
4-dimethylaminopyridine, 0.13 cm.sup.3 of methanesulfonyl chloride,
25 cm.sup.3 of dichloromethane and 0.48 g of
1-(bis-p-tolylmethyl)-3-[(methylsulfonyl)(phenyl)methyl-(RS)]az-
etidin-3-ol, 0.25 g of
1-(bis-p-tolylmethyl)-3-[(methylsulfonyl)(phenyl)me-
thylene]azetidine is obtained, after purification by chromatography
and crystallization from diisopropyl ether, in the form of a white
solid [NMR spectrum in DMSO-d.sub.6, T=300K, .quadrature. in ppm
(250 MHz): 2.23 (6H, s, 2 PhCH.sub.3), 2.98 (3H, s, SCH.sub.3),
3.76 (2H, s, NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 5.55 (1H, s,
NCH), 7.10 (4H, d, J=7 Hz, 4 CH arom.), 7.32 (4H, d, J=7 Hz, 4 CH
arom.), 7.43 (5H, s, phenyl)].
[0610]
1-(Bis-p-tolylmethyl)-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetid-
in-3-ol may be prepared according to the procedure described in
Example 39, starting with 0.59 g of bromo(bis-p-tolyl)methane, 20
cm.sup.3 of acetonitrile, 0.3 g of potassium carbonate and 0.6 g of
3-[(methylsulfonyl)-(phenyl)methyl-(RS)]azetidin-3-ol
hydrochloride. The residue obtained is chromatographed on a silica
gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 16
cm) with, as eluent, a cyclohexane/ethyl acetate (7/3 by volume)
mixture. The fractions are concentrated to dryness under reduced
pressure (2.7 Kpa). 0.48 g of
1-(bis-p-tolylmethyl)-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-o-
l is obtained in the form of a white solid.
[0611] Bromo(di-p-tolyl)methane may be prepared according to the
procedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135
(1933).
[0612] 3-[(Methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol
hydrochloride may be prepared according to the procedure described
in Example 39 starting with 7 g of
3-[(methylsulfonyl)(phenyl)methyl-(RS)]-1-(vinyloxyc-
arbonyl)azetidin-3-ol, 35 cm.sup.3 of dioxane, 35 cm.sup.3 of a 6.2
N solution of hydrochloric acid in dioxane. 5 g of
3-[(methylsulfonyl)(phen- yl)methyl-(RS)]azetidin-3-ol
hydrochloride are obtained in the form of a white solid.
[0613]
3-[(Methylsulfonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidi-
n-3-ol may be prepared according to the procedure described in
Example 38 (Method 1), starting with 10 g of
1-benzhydryl-3-[(methylsulfonyl)(phenyl-
)methyl-(RS)]azetidin-3-ol, 600 cm.sup.3 of dichloromethane and
2.52 cm.sup.3 of vinyl chloroformate. The residue is
chromatographed on a silica gel column (particle size 0.06-0.2 mm,
diameter 5.2 cm, height 36 cm with, as eluent, a cyclohexane/ethyl
acetate (7/3 by volume) mixture. The fractions are evaporated to
dryness under reduced pressure (2.7 Kpa). 7 g of
3-[(methylsulfonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetid-
in-3-ol are obtained in the form of a white solid.
Example 83
[0614] A solution of 30 mg of sodium borohydride in 2 cm.sup.3 of
methanol is poured into a solution of 0.77 g of
(-)-1-[(4-chlorophenyl)(4-formylph-
enyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine
in 20 cm.sup.3 of methanol at 0.degree. C. under argon. After
stirring for 4 hours at 0.degree. C., water is added and the
mixture is then extracted with dichloromethane. The organic phase
is washed with a saturated aqueous sodium chloride solution, dried
over magnesium sulfate and then evaporated to dryness under reduced
pressure (2.7 kpa). The white foam obtained is purified on a silica
gel column (particle size 0.04-0.06 mm, diameter 3.2 cm, height 17
cm) with, as eluent, a cyclohexane/ethyl acetate (60/40 by volume)
mixture. 0.1 g of (+)-1-[(4-chlorophenyl)(4-hyd-
roxymethylphenyl)-methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene-
]azetidine is obtained, after crystallization from 1.5 cm.sup.3 of
absolute ethanol, in the form of white crystals melting at
190.degree. C., [a].sup.20.sub.D=+4.2.degree.(c=0.5% in methanol)
[NMR spectrum in DMSO-d.sub.6, T=300K, .quadrature. in ppm (300
MHz): 3.05 (3H, s, SCH.sub.3), 3.95 (2H, s, NCH.sub.2), 4.22 (2H,
s, NCH.sub.2), 4.48 (2H, d, J=6 Hz, CH.sub.2O), 4.75 (1H, s, NCH),
5.15 (1H, t, J=6 Hz, OH), 7.20 (2H, m, 2CH arom.), 7.28 (2H, d, J=7
Hz, 2CH arom.), 7.40(5H, m, 5 CH arom.), 7.50 (2H, d, J=7 Hz, 2CH
arom.)].
[0615]
(-)-1-[(4-Chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5-difluorophen-
yl)methylsulfonylmethylene]azetidine may be prepared in the
following manner: 3.32 cm.sup.3 of a 5 N solution of hydrochloric
acid are poured into a solution of 0.83 g of
(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl-
)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine
in 5 cm.sup.3 of tetrahydrofuran and then the mixture is kept
stirring for 20 hours. Dichloromethane and water are added to the
reaction medium followed by a 30% aqueous solution of sodium
hydroxide until a pH=14 is obtained. The aqueous phase is extracted
with dichloromethane, the organic phase is washed successively with
water, with a saturated aqueous solution of sodium chloride, dried
over magnesium sulfate, filtered and evaporated to dryness under
reduced pressure (2.7 kpa). 0.8 g of
(-)-1-[(4-chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5-difluorophenyl)(me-
thylsulfonyl)methylene]azetidine is obtained in the form of a white
foam.
[0616] (+)-1-{(4-Chlorophenyl)
[4-(1,3-dioxolan-2-yl)phenyl]methyl}-3-[(3,-
5-difluorophenyl)(methylsulfonyl)methylene]azetidine may be
obtained in the following manner: 0.93 g of
1,8-Diazabicyclo[5-4-O]undec-7-ene is poured dropwise into a
solution of 2.42 g of the mixture of the two diastereoisomers
3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)pheny-
l]methyl-(R*)}-3-[(3,5-difluoro-phenyl)(methylsulfonyl)methyl-(R*)]azetidi-
ne and 3-acetoxy-1-{(4-chlorophenyl)
[4-(1,3-dioxolan-2-yl)phenyl]methyl-(-
R*)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidine
in 25 cm.sup.3 of tetrahydrofuran under argon at 0.degree. C. After
stirring for 1 hour and 30 minutes at 0.degree. C., the reaction
medium is diluted with ethyl acetate, washed with water and with a
saturated aqueous sodium chloride solution. The organic phase is
dried over magnesium sulfate, filtered and evaporated to dryness
under reduced pressure. The crude product is purified on a silica
gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, height
17.5 cm) with, as eluent, a cyclohexane/ethyl acetate (80/20 by
volume) mixture. 1.21 g of (+)-1-{(4-chlorophenyl)[4-(1-
,3-dioxolan-2-yl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)met-
hylene]azetidine are obtained in the form of a yellow foam.
[0617] The mixture of the two diastereoisomers
3-acetoxy-1-{(4-chloropheny-
l)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluorophenyl)-(methy-
lsulfonyl)methyl-(R*)]azetidine and
3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-d-
ioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluorophenyl)(methylsulfonyl)me-
thyl-(S*)]azetidine may be prepared in the following manner: 3.27
cm.sup.3 of n-butyllithium are poured dropwise into a solution of
1.08 g of 3-5-difluorobenzyl methyl sulfone under argon, cooled to
-70.degree. C., and then the mixture is kept stirring for 1 hour at
-70.degree. C. and then a solution of 1.80 g of
(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl-
)phenyl]methyl}azetidin-3-one in 10 cm.sup.3 of tetrahydrofuran is
poured in dropwise. After stirring for 3 hours at -70.degree. C.
and for 1 hour at -20.degree. C., a solution of 0.74 cm.sup.3 of
acetyl chloride in 10 cm.sup.3 of anhydrous diethyl ether at
-20.degree. C. is poured in and the mixture is stirred for 2 hours
at -20.degree. C. The reaction medium is thrown over water, the
mixture is extracted with ethyl acetate, the organic phase washed
with water and with a saturated aqueous sodium chloride solution,
dried over magnesium sulfate and concentrated to dryness under
reduced pressure (2.7 kpa). 2.42 g of the mixture of the two
diastereoisomers
3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)p-
henyl]methyl-(R*)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]azet-
idine and
3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-
-(R*)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidine
are obtained in the form of a yellow oil.
[0618]
(+)-1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-
-3-one may be prepared in the following manner: 2.24 cm.sup.3 of
triethylamine are poured into a solution of 1.38g of
(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-ol
in 20 cm.sup.3 of anhydrous dimethyl sulfoxide under argon,
followed dropwise by 1.65 g of a solution of sulfur trioxide
pyridine complex in 20 cm.sup.3 of anhydrous dimethyl sulfoxide.
After stirring for 1 hour and 15 minutes at room temperature, the
reaction medium is thrown over ice, extracted with ethyl acetate,
the organic phase washed with water, with a saturated aqueous
sodium chloride solution, dried over magnesium sulfate, filtered
and concentrated to dryness under reduced pressure (2.7 kpa). The
oily residue obtained (1.31 g), combined with another batch of the
same crude compound (1.21 g), are purified together on a silica gel
column (particle size 0.04-0.06 mm, diameter 4.8 cm, height 18 cm),
with, as eluent, a cyclohexane/ethyl acetate (80/20 by volume)
mixture. 1.87 g of
(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3--
one are obtained in the form of a yellow oil. [a].sup.20365
nm=+5.9.degree. (c=0.5; methanol).
[0619] (+)-1-{(4-Chlorophenyl)
[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidi- n-3-ol may be
described according to the procedure described in Example 73,
starting with 4.43 g of
(+)-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)ph- enyl]methyl}amine,
40 cm.sup.3 of absolute ethanol, 1.25 cm.sup.3 of epibromohydrin
and 1.28 g of sodium bicarbonate. 1.66 g of
(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-ol
are obtained in the form of a yellow oil.
[0620] Chiral (+)-{(4-chlorophenyl)
[4-(1,3-dioxolan-2-yl)phenyl]methyl}am- ine may be obtained in the
following manner: 3.95 cm.sup.3 of ethylene glycol are poured into
a suspension of 18.16 g of chiral
(R*)-[(4-chlorophenyl)(4-formylphenyl)methyl]amine hydrochloride,
in 1000 cm.sup.3 of toluene, and 0.82 g of para-toluenesulfonic
acid monohydrate is added. After stirring for 20 hours at the
reflux temperature, the reaction medium is cooled, washed with a
saturated aqueous sodium bicarbonate solution, with water and with
a saturated aqueous sodium chloride solution. The organic phase is
dried over magnesium sulfate, filtered and concentrated to dryness
under reduced pressure. The residue obtained is purified on a
silica gel column (particle size 0.04-0.06 mm, diameter 8.4 cm,
height 21.5 cm) with, as eluent, a cyclohexane/ethyl acetate (30/70
by volume) mixture, collecting 250 cm.sup.3 fractions. Fractions 23
to 30 are concentrated to dryness under reduced pressure (2.7 kpa).
1.39 g of chiral (+)-{(4-chlorophenyl)-[4-(1,3-dioxolan-2-yl)p-
henyl]methyl}amine are obtained in the form of a yellow oil.
[0621] Chiral (R*)-[(4-chlorophenyl)(4-formylphenyl)methyl]amine
hydrochloride may be prepared in the following manner: 330 cm of
methanol are poured into a solution of 51.4 g of the
diastereoisomer
N-{(4-chlorophenyl)[4-(diethoxymethyl)phenyl]methyl-(R*)}-(R)-2-phenylgly-
cinol in 660 cm.sup.3 of anhydrous dichloromethane, the mixture
cooled with an ice bath, 60.96 g of lead tetraacetate added, the
mixture stirred for 5 minutes and then 1 liter of a phosphate
buffer solution pH 7 poured in. After stirring for 30 minutes at
room temperature, the mixture is filtered and the aqueous phase is
extracted with dichloromethane. The organic phase is concentrated
to dryness under reduced pressure (2.7 kpa). The residue is taken
up in 1 liter of diethyl ether and supplemented with 1 liter of a 3
N aqueous solution of hydrochloric acid, the mixture is stirred for
15 minutes at room temperature, the aqueous phase is separated,
washed with ethyl acetate and then concentrated to dryness under
reduced pressure (2.7 kpa). 18.16 g of chiral
(R*)-[(4-chlorophenyl)(4-formylphenyl)methyl]amine hydrochloride
are obtained in the form of a white solid.
[0622]
N-{(4-chlorophenyl)[4-(diethoxymethyl)phenyl]methyl-(R*)}-(R)-2-phe-
nylglycinol may be prepared in the following manner: 286 cm.sup.3
of 1.6 M n-butyllithium in hexane are poured dropwise into a
solution, cooled to -70.degree. C., under argon, of 87.7 g of
4-bromochlorobenzene and the mixture is stirred for 15 minutes at
-70.degree. C. This solution obtained is then added dropwise to the
following solution cooled to 0.degree. C.: 30 g of
(R)-N-[4-(diethoxymethyl)benzylidene]-2-phenylglyci- nol in 300
cm.sup.3 of diethyl ether. The mixture is stirred for 2 hours at
0.degree. C. and then thrown over water. The organic phase is
washed with water and then with a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered and concentrated
to dryness under reduced pressure (2.7 kpa). 71.5 g of a reddish
oil are obtained, which oil is purified on a silica gel column
(particle size 0.04-0.06 mm, diameter 11 cm, height 45 cm), with,
as eluent, a cyclohexane/ethyl acetate (85/15 by volume, then 80/20
and 75/25) mixture, collecting 1 liter fractions. Fractions 11 to
17 are concentrated to dryness under reduced pressure (2.7 kpa).
39.85 g of the sole diastereoisomer
N-{(4-chlorophenyl)-[4-(diethoxymethyl)phenyl]methyl-(R*)}--(R)-2-phenylg-
lycinol are obtained in the form of an orange red oil.
[0623] (R)-N-[4-(diethoxymethyl)benzylidene]-2-phenylglycinol may
be prepared in the following manner: 35.9 cm.sup.3 of
4-(diethoxymethyl)benzaldehyde are poured into a white suspension
of 24.7 g of (R)-(-)-2-phenylglycinol in 500 cm.sup.3 of toluene.
The cloudy yellow solution is heated under reflux for 6 hours 30
minutes, and is then stirred at room temperature for 20 hours.
After concentrating the reaction medium to dryness under reduced
pressure (2.7 kpa), 61.6 g of
(R)-N-[4-(diethoxymethyl)benzylidene]-2-phenylglycinol are obtained
in the form of a yellow oil.
Example 84
[0624] On carrying out the operation according to the procedure of
Example 1, but starting with 5.6 g of
1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tert-
butyloxycarbonyl-N-methylamino)phenyl]
(methylsulfonyl)methyl-(RS)}azetidi- n-3-ol, 100 cm.sup.3 of
dichloromethane, 1.59 g of methanesulfonyl chloride and 4.5 g of
4-dimethylaminopyridine. The mixture is kept stirring for 3 hours
at room temperature. The crude product obtained is purified by
chromatography on a silica gel column (particle size 0.04-0.06 mm,
diameter 4 cm and weight of silica 250 g), eluting at a nitrogen
pressure of 0.5 bar with an ethyl acetate/cyclohexane (30/70 by
volume) mixture and collecting 100 cm.sup.3 fractions. Fractions 12
to 18 are combined, concentrated to dryness under reduced pressure
(2.7 kpa). 3.2 g of
1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxy-carbonyl-N-m-
ethylamino)phenyl](methylsulfonyl)-methylene]azetidine are obtained
in the form of a white foam [NMR spectrum in DMSO-d.sub.6, T=300K,
.quadrature. in ppm (300 MHz): 1.30 (9H, s, OC(CH.sub.3).sub.3),
2.65 (3H, s, J=6 Hz, NCH.sub.3), 2.85 (3H, s, SCH.sub.3), 3.50 (2H,
s, NCH.sub.2), 3.90 (2H, s, NCH.sub.2), 4.45 (1H, s, NCH) between
6.85 and 7.05 (8H, m, 8 CH arom.), 7.10 (4H, d, J=7 Hz, 4 CH
arom.)].
[0625]
1-[Bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxycarbonyl-N-methy-
lamino)phenyl] (methylsulfonyl)methyl-(RS)} azetidin-3-ol may be
prepared according to the procedure described in Example 1 starting
with 3.8 g of
[3-(N-tertbutyloxycarbonyl-N-methylamino)benzyl]methylsulfone, 50
cm.sup.3 of tetrahydrofuran, 9.5 cm.sup.3 of a 1.6 N solution of
n-butyllithium in hexane, 3.82 g of
1-[bis(4-chlorophenyl)methyl]azetidin- -3-one. The crude product is
purified by chromatography on a silica gel column (particle size
0.04-0.06 mm, diameter 4 cm, weight of silica 250 g), eluting at a
nitrogen pressure of 0.5 bar with dichloromethane and then with a
dichloromethane and ethanol mixture (99/1 by volume) and collecting
500 cm.sup.3 fractions. Fractions 10 to 16 are combined,
concentrated to dryness under reduced pressure (2.7 kPa). 5.6 g of
1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxycarbonyl-N-methylamino-
)phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-ol, are obtained in
the form of a foam.
Example 85
[0626] 2.7 g of
1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxycarbony-
l-N-methylamino)phenyl] (methylsulfonyl)-methylene}azetidine in 30
cm.sup.3 of dioxane and 30 cm.sup.3 of a 4.7 N solution of
hydrochloric dioxane are stirred for 20 hours. The reaction medium
is evaporated to dryness under reduced pressure (2.7 kpa), taken up
in 50 cm.sup.3 of water and 50 cm of ethyl acetate, stirred and
neutralized carefully with a saturated aqueous sodium bicarbonate
solution. The organic phase is separated, dried over magnesium
sulfate, treated with animal charcoal and then concentrated under
reduced pressure (2.7 kpa) to a volume of about 25 cm.sup.3, then
filtered, concentrated to dryness under reduced pressure. 1.3 g of
1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenyl)-
(methylsulfonyl)methylene]azetidine are obtained in the form of
white crystals melting at 228.degree. C. [NMR spectrum in
DMSO-d.sub.6, T=300K, .quadrature. in ppm (300 MHz): 2.65 (3H, s,
J=6 Hz, NCH.sub.3), 2.95 (3H, s, SCH.sub.3), 3.80 (2H, s,
NCH.sub.2), 4.20 (2H, s, NCH.sub.2), 4.80 (1H, s, NCH), 5.85 (1H,
q, J=6 Hz, NH), 6.55 (3H, m, 3 CH arom.), 7.15 (1H, t, J=7 Hz, CH
arom.), 7.40 (4H, d, J=7 Hz, 4CH arom.), 7.50 (4H, m, 4CH
arom.)].
Example 86
[0627] On carrying out the operation as in Example 1, starting with
0.40 g of a mixture of two diastereoisomers
1-[(4-chlorophenyl)(thiazol-2-yl)met-
hyl-(RS)]-3-[3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,
0.10 cm.sup.3 of methanesulfonyl chloride and 0.37 g of
4-dimethylaminopyridine, 0.13 g of
(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)-
methyl]-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine
is obtained, after chromatography on a silica gel column (particle
size 0.06-0.200 mm, diameter 1.2 cm, height 20 cm), at an argon
pressure of 1 bar with a mixture of ethyl acetate and cyclohexane
(40/60 by volume) as eluent and collecting 20 cm.sup.3 fractions,
in the form of a pinkish solid [NMR spectrum in DMSO-d.sub.6,
T=300K, .quadrature. in ppm (300 MHz): 3.05 (3H, s, SCH.sub.3),
4.05 (2H, s, NCH.sub.2), 4.35 (2H, m, NCH.sub.2), 5.25 (1H, s,
NCH), 7.20 (2H, d, J=8 Hz, 2CH arom.), 7.35 (1H, t, J=8 Hz, CH
arom.), 7.45 (2H, d, J=7 Hz, 2CH arom.), 7.50 (2H, d, J=7 Hz, 2CH
arom.), 7.70 (1H, d, J=2 Hz, CH thiazole), 7.75 (1H, d, J=2 Hz, CH
thiazole)].
[0628] The mixture of the two diastereoisomers
1-[(4-chlorophenyl)(thiazol-
-2-yl)methyl-(RS)]-3-[3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azeti-
din-3-ol may be obtained in the following manner: on carrying out
the operation as in Example 72, starting with 1.01 g of
(RS)-bromo(4-chlorophenyl)thiazol-2-ylmethane and 0.55 g of
(RS)-3-[3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-ol
hydrochloride and after chromatography on a silica gel column
(particle size 0.06-0.200 mm, diameter 4.4 cm, height 38 cm), at an
argon pressure of 0.5 bar and eluting with a mixture of ethyl
acetate and cyclohexane (30/70 by volume and then 40/60 from
fraction 16) and collecting 60 cm.sup.3 fractions, fractions 21 to
35 are combined and concentrated to dryness under reduced pressure
(2.7 kPa). 0.40 g of the mixture of the two diastereoisomers
1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[3,5-
-difluorophenyl)(methyl-sulfonyl)methyl-(RS)]azetidin-3-ol which is
obtained in the form of a whitish solid.
Example 87
[0629] 50 mm.sup.3 of pyrrolidine are added to a solution of 0.32 g
of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorop-
henyl)(methylsulfonyl)methylene]azetidine, form A isomer, and 5 mg
of sodium iodide in 10 cm.sup.3 of dichloromethane. After stirring
for 20 hours at 20.degree. C., 50 mm.sup.3 of pyrrolidine are added
to the mixture, stirred for 8 hours and then 50 mm.sup.3 of
pyrrolidine are again added and the mixture is stirred for 20 hours
at 20.degree. C. The reaction mixture is washed with water and then
the organic phase is dried over magnesium sulfate and concentrated
to dryness under vacuum (2.7 kPa). The residue obtained is
chromatographed on a silica gel column (particle size 0.06-0.200
mm, diameter 1.2 cm, height 30 cm), at an argon pressure of 0.1
bar, eluting with dichloromethane and then with a dichloromethane
and methanol mixture (97.5/2.5 by volume) and collecting 3 cm.sup.3
fractions. Fractions 12 to 40 are combined and then concentrated to
dryness under reduced pressure (2.7 kPa). 0.18 g of
1-{(R*)-(4-chlorophenyl)[4-pyrrolidinylmethyl)phenyl]-methyl}-3-[(3,5-dif-
luorophenyl)(methylsulfonyl)methyl-ene]azetidine, form A isomer, is
obtained in the form of a white foam [a]2365 nm=-22.5.degree.+/-0.7
(c=0.5%; dichloromethane) [.sup.1H NMR spectrum (300 MHz,
CDCl.sub.3, .quadrature. in ppm): 1.78 (mt, 4H), 2.51 (mt, 4H),
2.81 (s, 3H), 3.58 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s,
1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to
7.40 (mt, 8H)].
[0630] 1-{(R*)-[(4-chloromethyl)phenyl]
(4-chlorophenyl)methyl}-3-[(3,5-di-
fluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer,
may be prepared by carrying out the operation in the following
manner:. 12.4 cm.sup.3 of methanesulfonyl chloride are added to a
solution of 28.0 g of the mixture of the 2 diastereoisomers (forms
A) 1-{(R*)-[(4-chloromethyl)-
phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)-
methyl]azetidin-3-ol and
1-{(R*)-[(4-chloromethyl)phenyl](4-chlorophenyl)m-
ethyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-ol
and 32 g of 4-dimethylaminopyridine, in 500 cm.sup.3 of
dichloromethane. After stirring for 1 hour at 10.degree. C. and
then 1 hour at 20.degree. C., the reaction mixture is washed with
500 cm.sup.3 of water, the organic phase is dried over magnesium
sulfate and concentrated to dryness under reduced pressure (2.7
kPa). The residue is chromatographed on a silica gel column
(particle size 0.06-0.200 mm, diameter 6 cm, height 30 cm), at an
argon pressure of 0.2 bar, eluting with dichloromethane and
collecting 250 cm.sup.3 fractions. Fractions 9 to 25 are combined
and then concentrated to dryness under reduced pressure (2.7 kPa).
6.3 g of
1-[((R*)-[4-(chloromethyl)-phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluor-
ophenyl)-(methylsulfonyl)methylene]azetidine, form A isomer, are
obtained in the form of a white foam.
[0631] The mixture of the 2 diastereoisomers (forms A)
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-diflu-
orophenyl)-(methylsulfonyl)methyl)]azetidin-3-ol, and
1-(R*)-[(4-chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(S)-(3,5-difluo-
rophenyl)(methylsulfonyl)methyl)]-azetidin-3-ol, may be prepared by
carrying out the operation in the following manner: 60 mm.sup.3 of
thionyl chloride are added to a solution of 0.20 g of the mixture
of the 2 diastereoisomers (forms A)
1-{(R*)-[4-(chlorophenyl)[4-(hydroxymethyl)p-
henyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin--
3-ol, and
1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-(S)-(-
3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-ol, in 10
cm.sup.3 of dichloromethane. After-stirring for 20 hours at
20.degree. C., 5 cm.sup.3 of a saturated aqueous sodium hydrogen
carbonate solution are added to the reaction mixture and then the
mixture is stirred for 15 minutes. The mixture is separated after
settling out, the organic phase is washed with water, dried over
magnesium sulfate and then concentrated to dryness under reduced
pressure (2.7 kPa). The residue is chromatographed on a silica gel
column (particle size 0.04-0.06 mm, diameter 1.0 cm, height 20 cm),
at an argon pressure of 0.2 bar, eluting with a cyclohexane and
ethyl acetate mixture (75/25 by volume) and collecting 20 cm.sup.3
fractions. Fractions 4 to 7 are combined and then concentrated to
dryness under reduced pressure (2.7 kPa). 0.17 g of the mixture of
the 2 diastereoisomers (forms A)
1-{(R*)-[4-(chloromethyl)phenyl]-[4-chlorophen-
yl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-o-
l, and
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(S)(3,5--
difluorophenyl)(methylsulfonyl)methyl)]-azetidin-3-ol is obtained
in the form of a white foam.
[0632] The mixture of the 2 diastereoisomers (forms A)
1-{(R*)-4-(chlorophenyl)phenyl][4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3-
,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol, and
1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(S)-(3,5-difl-
uorophenyl)(methylsulfonyl)methyl]azetidin-3-ol, may be prepared by
carrying out the operation in the following manner: 1.6 cm.sup.3 of
a 1.5 M solution of diisobutylaluminum hydride in toluene are added
to a solution, maintained under argon and cooled to -30.degree. C.,
of 0.58 g of the mixture of the 2 diastereoisomers (forms A)
3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(-
R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidine and
3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(-
S)-(3,5-difluorophenyl)(methylsulfonyl)methyl]-azetidine, in 10
cm.sup.3 of anhydrous toluene. After stirring for 15 minutes at
-30.degree. C., 1.0 cm.sup.3 of this same hydride solution is again
added and then the mixture is allowed to return to 0.degree. C.
After stirring for 30 minutes, the stirred mixture is supplemented
with 3 cm.sup.3 of water and 6 cm.sup.3 of 1 N sodium hydroxide and
then extracted with 25 cm.sup.3 of dichloromethane. The organic
phase is washed with 5 cm.sup.3 of water, 5 cm.sup.3 of brine, and
then dried over magnesium sulfate and concentrated to dryness under
reduced pressure (2.7 kPa). The residue is chromatographed on a
silica gel column (particle size 0.06-0.200 mm, diameter 1.2 cm,
height 30 cm), at an argon pressure of 0.1 bar, eluting with a
cyclohexane and ethyl acetate mixture (50/50 by volume) and
collecting 30 cm.sup.3 fractions. Fractions 4 to 12 are combined
and then concentrated to dryness under reduced pressure (2.7 kPa).
0.42 g of the mixture of the 2 diastereoisomers (forms A)
1-{(R*)-(4-chlorophenyl)[4-(h-
ydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)met-
hyl)]azetidin-3-ol, and
1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]m-
ethyl}-3-[(S)(3,5-difluorophenyl)(methylsulfonyl)-methyl)]azetidin-3-ol
is obtained in the form of a white lacquer.
[0633] The mixture of the 2 diastereomers (forms A)
3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(-
R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)}azetidine and
3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(-
S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)} azetidine may be
prepared by carrying out the operation as described in Example 40,
starting with 1.0 g of (3,5-difluorobenzyl)methylsulfone, 30
cm.sup.3 of tetrahydrofuran, 3 cm.sup.3 of a 1.6 N solution of
n-butyllithium in hexane, 1.45 g of
1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)-phenyl]met-
hyl}azetidin-3-one, form A isomer, and
[0634] 0.43 cm.sup.3 of acetyl chloride. 1.28 g of the mixture of
the 2 diastereoisomers (forms A)
3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-methoxyca-
rbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]a-
zetidine and
3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-methoxycarbonyl)phenyl]m-
ethyl}-3-[(S)-(3,5-difluorophenyl)-(methylsulfonyl)methyl)]azetidine
are obtained in the form of a beige foam.
[0635]
1-{(R*)-[(4-chlorophenyl)[4-(methoxycarbonyl)-phenyl]methyl}azetidi-
n-3-one, form A isomer, may be prepared by carrying out the
operation as described in Example 40, starting with 0.55 cm.sup.3
of oxalyl chloride, 25 cm.sup.3 of dichloromethane, 0.90 cm.sup.3
of dimethyl sulfoxide, 1.75 g of
1-{(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol,
and 2.70 cm.sup.3 of triethylamine. 1.45 g of
1-{(R*)-(4-chlorophenyl)[4--
(methoxycarbonyl)phenyl]-methyl}azetidin-3-one, form A isomer, are
obtained in the form of a yellow foam.
[0636]
1-{(R*)(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]-methyl}azetidin--
3-ol, form A isomer, may be prepared by carrying out the operation
according to the procedure described by KATRITZKY A. R. et al., in
J. Heterocycl. Chem., (1994), 271 from 2.0 g of methyl
(+)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate,
[0637] 30 cm.sup.3 of ethanol, 0.60 g of sodium hydrogen carbonate
and 0.60 cm.sup.3 of epibromhydrin. 1.76 g of
1-(R)-(4-chlorophenyl)[4-(metho-
xycarbonyl)phenyl]-methyl}azetidin-3-ol, form A isomer, are
obtained in the form of a pasty solid.
[0638] Methyl (+)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate may
be prepared by carrying out the operation in the following manner:
2.51 g of D-(-)-tartaric acid are added to a solution of 9.2 g of
methyl (4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate in 10
cm.sup.3 of methanol. The solution is concentrated to dryness under
reduced pressure (2.7 kPa). The cream-colored foam obtained is
dissolved in 50 cm.sup.3 of ethanol containing 5% water and the
resulting solution is allowed to crystallize for 20 hours at
20.degree. C. The crystals are filtered, washed with ethanol
containing 5% water, drained and then dried under reduced pressure
(2.7 kPa). 3.4 g of white crystals are obtained which are called "A
crystals" [and which are stored for the subsequent preparation of
the second enantiomer, methyl (-)-4-[(R*)-amino-(4-chlorop-
henyl)methyl]benzoate]. The mother liquors are concentrated to
dryness and a white foam (8.1 g) is obtained which is dissolved in
100 cm.sup.3 of ethyl acetate. The solution obtained is
supplemented with 50 cm.sup.3 of 1 N sodium hydroxide, stirred and
separated after settling out. The organic phase is washed with 50
cm.sup.3 of water and then dried over magnesium sulfate and
concentrated to dryness under reduced pressure (2.7 kPa). A yellow
solid is obtained which is dissolved in 100 cm.sup.3 of methanol.
The solution obtained is supplemented with 1.85 g of L-(+)-tartaric
acid and the resulting solution is concentrated to dryness under
reduced pressure (2.7 kPa). A cream-colored foam is obtained which,
once dissolved in 27 cm.sup.3 of ethanol containing 4% water, is
allowed to crystallize for 20 hours at 20.degree. C. The crystals
are filtered, washed with ethanol containing 4% water, drained and
then dried under reduced pressure (2.7 kPa). 3.4 g of methyl
(+)-4-[(R*)-amino-(4-chloroph- enyl)methyl]benzoate L-(+)-tartrate
crystals are obtained which are recrystallized from 60 cm.sup.3 of
ethanol containing 5% water. After draining and then drying, 2.78 g
of white crystals are obtained which are dissolved in 50 cm.sup.3
of ethyl acetate. The solution obtained is supplemented with 100
cm.sup.3 of 1 N sodium hydroxide, stirred and separated after
settling out. The organic phase is washed with 50 cm.sup.3 of water
and then dried over magnesium sulfate and concentrated to dryness
under reduced pressure (2.7 kPa). 2.1 g of methyl
(+)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate are obtained in
the form of a white solid.
[0639] Methyl 4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate may be
prepared by carrying out the operation in the following manner: 3.9
cm.sup.3 of hydrazine hydrate are added to a suspension of 16.3 g
of methyl 4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate in
200 cm.sup.3 of methanol. After stirring for 5 hours at the reflux
temperature and then for 20 hours at 20.degree. C., the reaction
mixture is filtered and the filtrate is concentrated to dryness
under reduced pressure
[0640] (2.7 kPa). The residue obtained is taken up in a mixture of
200 cm.sup.3 of water and 200 cm.sup.3 of ethyl acetate. After
stirring for 15 minutes, the resulting suspension is filtered, the
filtrate separated after settling out in a separating funnel, and
the organic phase is washed with 50 cm.sup.3 of water, dried over
magnesium sulfate and concentrated to dryness under reduced
pressure (2.7 kPa). 8.4 g of methyl
4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate are obtained in the
form of a pale yellow 25 oil.
[0641] Methyl 4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate
may be prepared by carrying out the operation in the following
manner: 12.6 g of potassium phthalimide are added to a solution of
11.6 g of methyl 4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate in
70 cm.sup.3 of dimethylformamide. After stirring for 3 hours at the
reflux temperature, the reaction mixture is cooled to 20.degree. C.
and then supplemented with 300 cm.sup.3 of ethyl acetate and 300
cm.sup.3 of water. After stirring, the mixture is separated after
settling out, the aqueous phase reextracted with twice 100 cm.sup.3
of ethyl acetate, the combined organic phases are washed with twice
400 cm.sup.3 of water and then dried over magnesium sulfate and
concentrated to dryness under reduced pressure
[0642] (2.7 kPa). 16.3 g of methyl
4-[(RS)-phthalimido-(4-chlorophenyl)met- hyl]benzoate are obtained
in the form of a pasty yellow solid.
[0643] Methyl 4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate may be
prepared by carrying out the operation in the following manner:
10.18 g of N,N'-carbonyldiimidazole and 54.3 cm.sup.3 of allyl
bromide are added to a solution of 17.4 g of methyl
4-[(RS)-(4-chlorophenyl)(hydroxy)methyl- ]benzoate in 200 cm.sup.3
of acetonitrile. After stirring for 30 minutes at 20.degree. C.,
the reaction mixture is heated under reflux for 2 hours, stirred
for 20 hours at 20.degree. C. and concentrated to dryness under
reduced pressure (2.7 kPa). The mixture, taken up in
dichloromethane, is chromatographed on a silica gel column
(particle size 0.06-0.200 mm, diameter 7 cm, height 30 cm), at an
argon pressure of 0.5 bar, eluting with dichloromethane and
collecting 500 cm.sup.3 fractoins. Fractions 3 to 6 are combined
and then concentrated to dryness under reduced pressure (2.7 kPa).
11.6 g of methyl 4-[(RS)-bromo-(4-chloropheny- l)methyl]benzoate
are obtained in the form of an oil which will be used as it is in
the next step.
[0644] Methyl 4-[(RS)-(4-chlorophenyl)(hydroxy)methyl]benzoate may
be prepared by carrying out the operation in the following manner:
1.21 g of sodium borohydride are slowly added in small fractions to
a suspension of 2.75 g of methyl 4-(4-chlorobenzoyl)benzoate in 200
cm.sup.3 of methanol at 20.degree. C. (heating of the medium up to
50.degree. C. occurs). After stirring for 20 hours at 20.degree.
C., the reaction mixture is concentrated to a reduced volume and
then supplemented with 150 cm.sup.3 of dichloromethane and, while
stirring, with 100 cm.sup.3 of 0.5 N hydrochloric acid. After
separating after settling out, the organic phase is dried over
magnesium sulfate and concentrated to dryness under reduced
pressure (2.7 kPa). 2.5 g of methyl
4-[(RS)-(4-chlorophenyl)-(hydroxy)met- hyl]benzoate are obtained in
the form of a colorless oil which slowly crystallizes at 20.degree.
C., and which will be used as it is in the next step.
[0645] Methyl 4-(4-chlorobenzoyl)benzoate may be prepared by
carrying out the operation in the following manner: 27.4 cm.sup.3
of tri-n-butylphosphine are added, under argon, to a solution,
cooled to -22.degree. C., of 19.3 g of terephthalic acid chloride
monomethyl ester in 200 cm.sup.3 of tetrahydrofuran. After stirring
for 20 minutes at -22.degree. C., a solution of
4-chlorophenylmagnesium bromide (prepared from 19.15 g of
4-bromochlorobenzene, 2.43 g of magnesium and an iodine crystal in
100 cm.sup.3 of diethyl ether under reflux) is poured in while this
temperature is maintained. After stirring for 30 minutes at
-22.degree. C., 150 cm.sup.3 of 1 N hydrochloric acid are slowly
added, the mixture is allowed to return to 20.degree. C. and then
the medium is diluted with 200 cm.sup.3 of diethyl ether. The white
suspension obtained is filtered, the solid is washed with twice 50
cm.sup.3 of water and then with twice 50 cm.sup.3 of diethyl ether.
16.2 g of methyl 4-(4-chlorobenzoyl)benzoate are obtained, after
draining and then drying under reduced pressure (2.7 kPa), in the
form of a white solid melting at 170.degree. C.
Example 88
[0646] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane and 0.025 g of
3,3-dimethylpiperidine. The crude product is chromatographed on a
silica gel column (particle size 0.06-0.200 mm, diameter 8 mm,
height 8 cm), eluting with 80 cm of dichloromethane and then
eluting with a dichloromethane and methanol mixture (95/5 by
volume), collecting 2.5 cm.sup.3 fractions immediately after using
this eluent mixture. Fractions 3 to 8 are combined and then
concentrated to dryness under reduced pressure (2.7 kPa). 0.040 g
of
1-{(R*)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-ylmethyl)phenyl]methy-
l}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form
A isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm): 0.94 (s, 6H),
1.21 (mt, 2H), from 1.50 to 1.65 (mt, 2H), 1.99 (broad s, 2H), 2.27
(unresolved complex, 2H), 2.81 (s, 3H), 3.36 (s, 2H), 3.85 (mt,
2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H),
6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Example 89
[0647] The operation is carried out as described in Example 87,
starting with 0.05 g of methylsulfonyl methyl
1-{(R*)-[4-(chloromethyl)phenyl](4-c-
hlorophenyl)methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azet-
idine, form A isomer, 1.0 cm.sup.3 of dichloromethane and 0.025 g
of thiomorpholine. The crude product is chromatographed on a silica
gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8
cm), eluting with 80 cm of dichloromethane and then with a
dichloromethane and methanol mixture (95/5 by volume), collecting
2.5 cm.sup.3 fractions immediately after using this eluent mixture.
Fractions 3 to 8 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 0.038 g of
1-{(R*)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phe-
nyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
form A isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm): from 2.60 to
2.75 (mt, 8H), 2.80 (s, 3H), 3.44 (s, 2H), 3.84 (mt, 2H), 4.33 (mt,
2H), 4.50 (s, 1H), 6.83 (tt, J=8.5 and 2.5 Hz, 1H), 6.97 (mt, 2H),
from 7.20 to 7.40 (mt, 8H)].
Example 90
[0648] The operation is carried out as described in Example 87,
starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]
(4-(chlorophenyl)methyl}--
3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane and 0.025 g of
N-cyclohexyl-N-ethylamine. The crude product is chromatographed on
a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm,
height 8 cm), eluting with 80 cm of dichloromethane and then with a
dichloromethane and ethanol mixture (95/5) by volume), collecting
2.5 cm.sup.3 fractions immediately after using this eluent mixture.
0.022 g of 1-{(R*)-(4-chlorophenyl)[4-(N-ethyl-
-N-cyclohexylaminomethyl)phenyl]-methyl}}-3-[(3,5-difluorophenyl)(methylsu-
lfonyl)-methylene]azetidine, form A isomer, is obtained in the form
of a white foam [.sup.1H NMR spectrum (300 MHz, CDCl.sub.3 with
addition of a few drops of CD.sub.3COOD-d4, .quadrature. in ppm):
from 1.15 to 1.25 (mt, 2H), 1.29 (t, J=7.5 Hz, 3H), from 1.45 to
1.65 (mt, 4H), 1.88 (mt, 2H), 2.17 (mt, 2H), 2.81 (s, 3H), 3.05 (q,
J=7.5 Hz, 2H), 3.27 (mt, 1H), 3.95 (mt, 2H), 4.18 (s, 2H), 4.40
(mt, 2H), 4.66 (s, 1H), 6.82 (tt, J=8.5 and 2.5 Hz, 1H), 7.00 (mt,
2H), from 7.20 to 7.40 (mt, 4H), 7.41 (d, J=8 Hz, 2H), 7.53 (d, J=8
Hz, 2H)].
Example 91
[0649] The procedure is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane and 0.032 g of
4-(ethoxycarbonyl)piperazi- ne. The crude product is
chromatographed on a silica gel column (particle size 0.06-0.200
mm, diameter 8 mm, height 8 cm), eluting with 80 cm.sup.3 of
dichloromethane and then with a dichloromethane and methanol
mixture (95/5 by volume), collecting 2.5 cm.sup.3 fractions
immediately after using this eluent mixture. Fractions 2 to 8 are
combined and then concentrated to dryness under reduced pressure
(2.7 kPa). 0.021 g of 1-{{(R*)-(4-chlorophenyl)
{4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}-
methyl}}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,
form A isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (400 MHz, CDCl.sub.3, .quadrature. in ppm): 1.25 (t, J=7
Hz, 3H), 2.36 (mt, 4H), 2.80 (s, 3H), 3.44 (s, 2H), 3.46 (mt, 4H),
3.85 (mt, 2H), 4.13 (q, J=7 Hz, 2H), 4.34 (mt, 2H), 4.50 (s, 1H),
6.83 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40
(mt, 8H)].
Example 92
[0650] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane and 0.023 g of
N-cyclopropyl-N-propylamin- e. The crude product is chromatographed
on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm,
height 8 cm), eluting with 80 cm.sup.3 of dichloromethane and then
with a dichloromethane and methanol mixture (95/5 by volume),
collecting 2.5 cm.sup.3 fractions immediately after using this
eluent mixture. Fractions 3 to 9 are combined and then concentrated
to dryness under reduced pressure (2.7 kPa). 0.026 g of
1-{(R*)-(4-chlorophenyl)[(4-N-cyclopropyl-N-propylaminomethyl)phenyl]meth-
yl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
form A isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (400 MHz, CDCl.sub.3 with addition of a few drops of
CD.sub.3COOD-d4, .quadrature. in ppm): 0.34 (mt, 2H), 0.70 (mt,
2H), 0.91 (t, J=7 Hz, 3H), 1.08 (mt, 1H), 1.76 (mt, 2H), 2.82 (s,
3H), 2.92 (d, J=7 Hz, 2H), 3.00 (mt, 2H), 3.90 (mt, 2H), 4.25 (s,
2H), 4.37 (mt, 2H), 4.59 (s, 1H), 6.83 (tt, J=9 and 2.5 Hz, 1H),
7.00 (mt, 2H), from 7.20 to 7.45 (mt, 8H)].
Example 93
[0651] The operation is carried out as described in Example 87, but
by stirring the reaction mixture for 6 days at 20.degree. C.,
starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]
(4-(chlorophenyl)methyl}-3-[(3-
,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane, 5 mg of sodium iodide and
0.020 g of diisopropylamine. The crude product is chromatographed
on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm,
height
[0652] 8 cm), eluting with 80 cm.sup.3 of dichloromethane and then
with a dichloromethane and methanol mixture (95/5 by volume),
collecting 2.5 cm.sup.3 fractions immediately after using this
eluent mixture. Fractions 2 to 8 are combined and then concentrated
to dryness under reduced pressure (2.7 kPa). 0.028 g of
1-{(R*)-(4-chlorophenyl)[4-(diisopropylami-
nomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]a-
zetidine, form A isomer, is obtained in the form of a white foam
[.sup.1H NMR spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm):
1.00 (unresolved complex, 12H), 2.80 (s, 3H), from 2.90 to 3.10
(unresolved complex, 2H), 3.58 (mt, 2H), 3.84 (mt, 2H), 4.33 (mt,
2H), 4.48 (s, 1H), 6.82 (tt, J=8.5 and 2.5 Hz, 1H), 6.97 (mt, 2H),
from 7.20 to 7.40 (mt, 8H)].
Example 94
[0653] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane, and 0.027 g of
bis(2-methoxyethyl)amine. The crude product is chromatographed on a
silica gel column (particle size 0.06-0.200 mm, diameter 8 mm,
height 8 cm), eluting with 80 cm of dichloromethane and then with a
dichloromethane and methanol mixture (95/5 by volume), collecting
2.5 cm.sup.3 fractions immediately after using this eluent mixture.
Fractions 3 to 10 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 0.014 g of
1-{{(R*)-(4-chlorophenyl){4-[bis(2-methoxyethyl)aminomethyl]phenyl}methyl-
}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form
A isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm): 2.70 (broad t,
J=5.5 Hz, 4H), 2.81 (s, 3H), 3.29 (s, 6H), 3.46 (broad t, J=5.5 Hz,
4H) 3.65 (broad s, 2H), 3.85 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H),
6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40
(mt, 8H)].
Example 95
[0654] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane, and 0.020 g of
di-n-propylamine. The crude product is chromatographed on a silica
gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8
cm), eluting with 80 cm.sup.3 of dichloromethane and then with a
dichloromethane and methanol mixture (95/5 by volume), collecting
2.5 cm.sup.3 fractions immediately after using this eluent mixture.
Fractions 3 to 8 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 0.025 g of
1-{(R*)-(4-(chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,-
5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (400 MHz, CDCl.sub.3, .quadrature. in ppm): 0.85 (t, J=7
Hz, 6H) 1.45 (mt, 4H), 2.34 (t, J=7.5 Hz, 4H), 2.80 (s, 3H), 3.48
(s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=9
and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Example 96
[0655] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane, and 0.017 g of piperidine.
The crude product is chromatographed on a silica gel column
(particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting
with 80 cm.sup.3 of dichloromethane and then with a dichloromethane
and methanol mixture (95/5 by volume), collecting 2.5 cm.sup.3
fractions immediately after using this eluent mixture. Fractions 5
to 10 are combined and then concentrated to dryness under reduced
pressure (2.7 kPa). 0.035 g of
1-{(R*)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]-methyl}-3-[(3,5--
difluorophenyl)-(methylsulfonyl)methyl-ene]azetidine, form A
isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm): from 1.35 to
1.65 (mt, 6H), 2.35 (unresolved complex, 4H), 2.80 (s, 3H), 3.41
(broad s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84
(tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt,
8H)].
Example 97
[0656] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane, and 0.020 g of
N-methylpiperazine. The crude product is chromatographed on a
silica gel column (particle size 0.06-0.200 mm, diameter 8 mm,
height 8 cm), eluting with 80 cm.sup.3 of dichloromethane and then
with a dichloromethane and methanol mixture (95/5 by volume),
collecting 2.5 cm.sup.3 fractions immediately after using this
eluent mixture. Fractions 3 to 9 are combined and then concentrated
to dryness under reduced pressure (2.7 kPa). 0.025 g of
1-{(R*)-(4-chlorophenyl)[4-(4-methylpiperazin-1-ylmethyl)phenyl]methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm): 2.28 (s, 3H),
from 2.30 to 2.60 (unresolved complex, 8H), 2.80 (s, 3H), 3.45 (s,
2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5
and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Example 98
[0657] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane, and 0.018 g of morpholine.
The crude product is chromatographed on a silica gel column
(particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting
with 80 cm of dichloromethane and then with a dichloromethane and
methanol mixture (95/5 by volume), collecting 2.5 cm.sup.3
fractions immediately after using this eluent mixture. Fractions 3
to 8 are combined and then concentrated to dryness under reduced
pressure (2.7 kPa). 0.022 g of
1-{(R*)-(4-chlorophenyl)[4-(morpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-d-
ifluorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer,
is obtained in the form of a white foam [.sup.1H NMR spectrum (300
MHz, CDCl.sub.3, .quadrature. in ppm): 2.41 (t, J=5 Hz, 4H), 2.80
(s, 3H), 3.43 (s, 2H), 3.69 (t, J=5 Hz, 4H), 3.85 (mt, 2H), 4.33
(mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt,
2H), from 7.20 to 7.40 (mt, 8H)].
Example 99
[0658] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane, and 0.020 cm.sup.3 of
D-prolinol. The crude product is chromatographed on a silica gel
column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm),
eluting with 80 cm of dichloromethane and then with a
dichloromethane and methanol mixture (95/5 by volume), collecting
2.5 cm.sup.3 fractions immediately after using this eluent mixture.
Fractions 3 to 8 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 0.025 g of
1-{(R*)-(4-chlorophenyl)[4-((2R)-hydroxymethylpyrrolidin-1-ylmethyl)pheny-
l]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
form A isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (300 MHz, (CD.sub.3).sub.2SO-d6 with addition of a few
drops of CD.sub.3COOD-d4, .quadrature. in ppm): from 1.60 to 2.15
(mt, 4H), from 2.90 to 3.05 (mt, 1H), 2.98 (s, 3H), 3.13 (mt, 1H),
3.38 (mt, 1H), from 3.50 to 3.60 (mt, 1H), 3.56 (d, J=5 Hz, 2H),
3.90 (mt, 2H), 4.04 (d, J=13.5 Hz, 2H), 4.21 (mt, 2H), 4.40 (d,
J=13.5 Hz, 2H), 4.78 (s, 1H), 7.14 (mt, 2H), 7.27 (tt, J=9 and 2.5
Hz, 1H), from 7.30 to 7.55 (mt, 8H)].
Example 100
[0659] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane, and 0.015 g of
diethylamine. The crude product is chromatographed on a silica gel
column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm),
eluting with 80 cm of dichloromethane and then with a
dichloromethane and methanol mixture (95/5 by volume), collecting
2.5 cm.sup.3 fractions immediately after using this eluent mixture.
Fractions 4 to 9 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 0.025 g of
1-{(R*)-(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]methyl}-3-[(3,5-dif-
luorophenyl)(methylsulfonyl)methylene]azetidine, form A isomer, is
obtained in the form of a white foam [.sup.1H NMR spectrum (400
MHz, CDCl.sub.3, .quadrature. in ppm): 1.03 (t, J=7 Hz, 6H), 2.50
(q, J=7 Hz, 4H), 2.81 (s, 3H), 3.50 (s, 2H), 3.85 (mt, 2H), 4.34
(mt, 2H), 4.49 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.99 (mt,
2H), from 7.20 to 7.40 (mt, 8H)].
Example 101
[0660] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane, and 0.026 g of
N-(hydroxyethyl)piperazin- e. The crude product is chromatographed
on a silica gel column (particle size 0.06-0.200 mm, diameter 8 mm,
height 8 cm), eluting with 80 cm.sup.3 of dichloromethane and then
with a dichloromethane and methanol mixture (95/5 by volume),
collecting 2.5 cm.sup.3 fractions immediately after using this
eluent mixture. Fractions 3 to 10 are combined and then
concentrated to dryness under reduced pressure (2.7 kPa). 0.032 g
of
1-{{(R*)-(4-chlorophenyl).sub.4-[4-(hydroxyethyl)piperazin-1-ylmethyl]phe-
nyl}-methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
form A isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm): from 2.40 to
2.60 (mt, 8H), 2.54 (t, J=5.5 Hz, 2H), 2.80 (s, 3H), 3.44 (s, 2H),
3.60 (t, J=5.5 Hz, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H),
6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40
(mt, 8H)].
Example 102
[0661] The operation is carried out as described in Example 87 but
by stirring the reaction mixture for 4 days at 20.degree. C.,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-
-difluorophenyl)-(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane, and 0.023 g of
2(RS),6(RS)-dimethylpiperidin- e. The crude product is
chromatographed on a silica gel column (particle size 0.06-0.200
mm, diameter 8 mm, height 8 cm), eluting with 80 cm.sup.3 of
dichloromethane and then with a dichloromethane and methanol
mixture (95/5 by volume), collecting 2.5 cm.sup.3 fractions
immediately after using this eluent mixture. Fractions 2 to 9 are
combined and then concentrated to dryness under reduced pressure
(2.7 kPa). 0.024 g of 1-{(R*)-(4-chlorophenyl)[4-(2(RS),
6(RS)dimethyl(piperidin-1-ylmethyl)phe-
nyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
form A isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (400 MHz, CDCl.sub.3 with addition of a few drops of
CD.sub.3COOD-d4, at a temperature of 353K, .quadrature. in ppm):
from 1.20 to 1.45 (mt, 2H), 1.60(d,J=7 Hz, 6H), from 1.80 to 2.10
(mt, 4H), 2.80 (s, 3H), 3.17 (mt, 2H), 3.90 (mt,2H), 4.34 (broad d,
J=16 Hz, 1H), 4.40 (mt, 2H), 4.43 (broad d, J=16 Hz, 1H), 4.62
(s,1H), 6.82 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to
7.50 (mt,8H)].
Example 103
[0662] The operation is carried out as described in Example 87, but
by stirring the reaction mixture for 4 days at 20.degree. C.,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-
-difluorophenyl)-(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane, and 0.024 g of
piperazin-2-one. The crude product is chromato-graphed on a silica
gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8
cm), eluting with 80 cm.sup.3 of dichloromethane and then with a
dichloromethane and methanol mixture (95/5 by volume), collecting
2.5 cm.sup.3 fractions immediately after using this eluent mixture.
Fractions 3 to 8 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 0.022 g of
1-{(R*)-(4-chlorophenyl)[4-(piperazin-2-on-4-ylmethyl)phenyl]methyl}-3-[(-
3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine, form A
isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (400 MHz, CDCl.sub.3, .quadrature. in ppm): 2.62 (t, J=5.5
Hz, 2H), 2.80 (s, 3H), 3.11 (s, 2H), 3.34 (mt, 2H), 3.51 (s, 2H),
3.85 (mt, 2H), 4.34 (mt, 2H), 4.51 (s, 1H), 5.76 (unresolved
complex, 1H), 6.84 (broad t, J.sub.HF=9 Hz, 1H), 6.98 (mt, 2H) from
7.20 to 7.40 (mt, 8H)].
Example 104
[0663] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl(4-(chlorophenyl)methyl}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane and 0.020 g of L-prolinol.
The crude product is chromatographed on a silica gel column
(particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting
with 80 cm.sup.3 of dichloromethane and then with a dichloromethane
and 3 methanol mixture (95/5 by volume), collecting 2.5 cm
fractions immediately after using this eluent mixture. Fractions 3
to 8 are combined and then concentrated to dryness under reduced
pressure (2.7 kPa). 0.028 g of
1-{{(R*)-(4-chlorophenyl){4-[(2S)-(hydroxymethyl)pyrrolidin-1-ylmethyl]ph-
enyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
form A isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm): from 1.50 to
2.00 (mt, 4H), 2.24 (mt, 1H), 2.71 (mt, 1H), 2.80 (s, 3H), 2.93
(mt, 1H), 3.28 (d, J=13.5 Hz, 1H), 3.45 (mt, 1H), 3.65 (d, J=11 and
4 Hz, 1H), 3.84 (mt, 2H), 3.91 (d, J=13.5 Hz, 1H), 4.33 (mt, 2H),
4.50 (s, 1H), 6.83 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from
7.20 to 7.40 (mt, 8H)].
Example 105
[0664] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3--
[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane and 0.023 g of
(2S)-(methoxymethyl)pyrrol- idine. The crude product is
chromatographed on a silica gel column (particle size 0.06-0.200
mm, diameter 8 mm, height 8 cm), eluting with 80 cm.sup.3 of
dichloromethane and then with a dichloromethane and methanol
mixture (95/5 by volume), collecting 2.5 cm.sup.3 fractions
immediately after using this eluent mixture. Fractions 2 to 6 are
combined and then concentrated to dryness under reduced pressure
(2.7 kPa). 0.037 g of 1-{{(R*)-(4-chlorophenyl)
4-[(2S)-(methoxymethyl)pyrroli-
din-1-ylmethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)-met-
hylene]azetidine, form A isomer, is obtained in the form of a white
foam [.sup.1H NMR spectrum (300 MHz, CDCl.sub.3, .quadrature. in
ppm): 1.66 (mt, 2H), 1.90 (mt, 1H), 2.16 (mt, 1H), 2.68 (mt, 1H),
2.80 (s, 3H), 2.89 (mt, 1H), from 3.25 to 3.45 (mt, 4H), 3.31 (s,
3H), 3.84 (mt, 2H), 4.04 (d, J=13.5 Hz, 1H), 4.33 (mt, 2H), 4.50
(s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H) from 7.20
to 7.40 (mt, 8H)].
Example 106
[0665] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane and 0.020 g of
2(RS),5(RS)-dimethylpyrrol- idine. The crude product is
chromatographed on a silica gel column (particle size 0.06-0.200
mm, diameter 8 mm, height 8 cm), eluting with 80 cm.sup.3 of
dichloromethane and then with a dichloromethane and methanol
mixture (95/5 by volume), collecting 2.5 cm.sup.3 fractions
immediately after using this eluent mixture. Fractions 3 to 6 are
combined and then concentrated to dryness under reduced pressure
(2.7 kPa). 0.024 g of
1-{(R*)-(4-chlorophenyl)[4-(2(RS),5(RS)-dimethylpyrrolid-
in-1-ylmethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methy-
lene]azetidine, mixture of isomers, form A, is obtained in the form
of a white foam [.sup.1H NMR spectrum (400 MHz, CDCl.sub.3 with
addition of a few drops of CD.sub.3COOD-d4, .quadrature. in ppm):
1.68 (d, J=7 Hz, 6H), from 2.00 to 2.15 (mt, 4H), 2.82 (s, 3H),
3.22 (mt, 2H), 3.92 (mt, 2H), 4.30 (s, 2H), 4.33 (mt, 1H), 4.45 (d,
J=16.5 and 3 Hz, 1H), 4.63 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz,
1H), 7.00 (mt, 2H), from 7.20 to 7.55 (mt, 8H)].
Example 107
[0666] The operation is carried out as described in Example 87,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl]-4-(chlorophenyl)methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane and 0.023 g of
L-prolinamide. The crude product is chromatographed on a silica gel
column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm),
eluting with 80 cm.sup.3 of dichloromethane and then with a
dichloromethane and methanol mixture (95/5 by volume), collecting
2.5 cm.sup.3 fractions immediately after using this eluent mixture.
Fractions 2 to 5 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 0.028 g of
1-{(R*)-(4-chlorophenyl)[4-((2S)-carbamoylpyrrolidin-1-ylmethyl)phenyl]me-
thyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,
form A isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (400 MHz, CDCl.sub.3, .quadrature. in ppm): from 1.65 to
1.85 (mt, 2H), 1.92 (mt, 1H), from 2.15 to 2.35 (mt, 2H), 2.80 (s,
3H), 3.00 (mt, 1H), 3.16 (dd, J=10 and 5.5 Hz, 1H), 3.41 (d, J=13.5
Hz, 1H), 3.86 (mt, 2H), 3.89 (d, J=13.5 Hz, 1H), 4.33 (mt, 2H),
4.51 (s, 1H), 5.23 (unresolved complex, 1H), 6.84 (tt, J=9 and 2.5
Hz, 1H), 6.98 (mt, 2H), 7.17 (unresolved complex, 1H), from 7.20 to
7.40 (mt, 8H)].
Example 108
[0667] The operation is carried out as described in Example 87, but
by stirring the reaction mixture for 4 days at 20.degree. C.,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,-
5-difluorophenyl)-(methylsulfonyl)methylene]azetidine, form A
isomer, 1.0 cm.sup.3 of dichloromethane and 0.021 g of
diethanolamine. The crude product is chromatographed on a silica
gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8
cm), eluting with 80 cm.sup.3 of dichloromethane and then with a
dichloromethane and methanol mixture (95/5 by volume), collecting
2.5 cm.sup.3 fractions immediately after using this eluent mixture.
Fractions 2 to 9 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 0.004 g of
1-{(R*)-(4-chlorophenyl)[4-(dihydroxyethylaminomethyl)phenyl]methyl}-3-[(-
3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine, form A
isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm): 2.69 (t, J=5.5
Hz, 4H), 2.80 (s, 3H), 3.61 (t, J=5.5 Hz, 4H), 3.65 (s, 2H), 3.84
(mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=9 and 2.5 Hz,
1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
Example 109
[0668] 0.055 g of imidazole is added to solution of 0.24 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorop-
henyl)-(methylsulfonyl)methylene]azetidine, form A isomer,
[0669] in 5 cm.sup.3 of dichloromethane. After heating for 3 hours
under reflux, the mixture is supplemented with 5 mg of sodium
iodide. After stirring for 20 hours under reflux, the reaction
mixture is cooled to 20.degree. C. and then chromatographed on a
silica gel column (particle size 0.06-0.200 mm, diameter 1.0 cm,
height 20 cm), eluting with 120 cm of dichloromethane without
fractionating, and then with a
[0670] dichloromethane and methanol mixture (98/2 and then 96/4 by
volume), collecting 4 cm.sup.3 fractions. Fractions 12 to 14 are
combined and then concentrated to dryness under reduced pressure
(2.7 kPa). 0.039 g of
1-{(R*)-(4-chlorophenyl)[4-(imidazol-1-ylmethyl)phenyl]methyl}-3-[(3-
,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine, form A
isomer, is obtained in the form of a white foam.
Example 110
[0671] The operation is carried out as described in Example 87,
starting with 0.50 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form B
isomer, 5 mg of sodium iodide, 15 cm.sup.3 of dichloromethane and
0.0190 g of pyrrolidine. The crude product is chromatographed on a
silica gel column (particle size 0.06-0.200 mm, diameter 1.5 cm,
height 20 cm), at an argon pressure of 0.1 bar, eluting with
dichloromethane and then with a dichloromethane and methanol
mixture (95/5 by volume) and collecting 25 cm.sup.3 fractions.
Fractions 20 to 40 are combined and then concentrated to dryness
under reduced pressure
[0672] (2.7 kPa). 0.028 g of
1-{(R*)-(4-chlorophenyl)[4-(pyrrolidin-1-ylme-
thyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azet-
idine, form B isomer, is obtained in the form of a white foam.
[a].sup.20365 nm=+26.8.degree.+/-0.8 (c=0.5%, dichloromethane)
[.sup.1H NMR spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm):
1.78 (mt, 4H), 2.50 (mt, 4H), 2.80 (s, 3H), 3.57 (s, 2H), 3.84 (mt,
2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H),
6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].
[0673]
1-{(R*)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-di-
fluorophenyl)(methylsulfonyl)methylene]azetidine, form B isomer,
may be prepared by carrying out the operation as described in
Example 87, starting with 7.3 g of the mixture of the 2
diastereoisomers (B forms)
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-diflu-
orophenyl)-(methylsulfonyl)methylene]azetidin-3-ol and
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)-methyl}-3-[(S)-(3,5-difl-
uorophenyl)(methylsulfonyl)-methyl]-azetidin-3-ol, 8.2 g of
4-dimethylaminopyridine, 150 cm.sup.3 of dichloromethane and 3.2
cm.sup.3 of methanesulfonyl chloride. The crude product is
chromatographed on a silica gel column (particle size 0.04-0.06 mm,
diameter 3 cm, height 30 cm), at an argon pressure of 0.2 bar,
eluting with dichloromethane and collecting 100 cm.sup.3 fractions.
Fractions 15 to 30 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 2.50 g of
1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-{(3,5-difluoro-
phenyl)(methylsulfonyl)methylene]azetidine, form B isomer, are
obtained in the form of a white foam.
[0674] The mixture of the 2 diastereoisomers
1-{(R*)-[4-(chloromethyl)phen-
yl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)-(methylsulfonyl)met-
hyl)]azetidin-3-ol and
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)-me-
thyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)-methyl)]-azetidin-3-ol,
may be prepared by carrying out the operation as described in
Example 87, starting with 11.0 g of a mixture of the 2
diastereoisomers
1-{(R*)-[4-chlorophenyl)[4-(hydroxymethyl)phenyl)methyl}-3-[(R)-(3,5-difl-
uorophenyl)-(methylsulfonyl)methyl)]azetidin-3-ol and
1-{(R*)-[4-(chlorophenyl](4-(hydroxymethyl)phenyl)methyl}-3-[(S)-(3,5-dif-
luorophenyl)-(methylsulfonyl)methyl)]azetidin-3-ol, 250 cm.sup.3 of
dichloromethane and 3.1 cm.sup.3 of thionyl chloride. The crude
product is chromatographed on a silica gel column (particle size
0.04-0.06 mm, diameter 3 cm, height 30 cm), at an argon pressure of
0.2 bar, eluting with a cyclohexane and ethyl acetate mixture
(70/30 by volume) and collecting 50 cm.sup.3 fractions. Fractions 9
to 25 are combined and then concentrated to dryness under reduced
pressure (2.7 kPa). 7.3 g of the mixture of the 2 diastereoisomers
(B forms) 1-{(R*)-[4-(chloromethyl)phen-
yl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)meth-
yl)]azetidin-3-ol and
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)meth-
yl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol
are obtained in the form of a white foam.
[0675] The mixture of the 2 diastereoisomers (B forms)
1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difl-
uorophenyl)-(methylsulfonyl)methyl)]azetidin-3-ol and
1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difl-
uorophenyl)-(methylsulfonyl)methyl)]azetidin-3-ol may be prepared
by carrying out the operation as described in Example 87, starting
with 18.0 g of the mixture of the 2 diastereoisomers (B form)
3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(-
R)-(3,5-difluorophenyl)-(methylsulfonyl)methyl]azetidine and
3-acetoxy-1-(R*)-(4-chlorophenyl)[4-(methyloxycarbonyl)phenyl]methyl}-3-[-
(S)-(3,5-difluorophenyl)-(methylsulfonyl)methyl)]azetidine, 150
cm.sup.3 of anhydrous toluene and 100 cm.sup.3 of a 20% solution of
diisobutylaluminum hydride in toluene. The crude product is
chromatographed on a silica gel column (particle size 0.06-0.200
mm, diameter 3 cm, height 30 cm), at an argon pressure of 0.1 bar,
eluting with a cyclohexane and 3 ethyl acetate mixture (50/50 by
volume) and collecting 50 cm.sup.3 fractions. Fractions 15 to 30
are combined and then concentrated to dryness under reduced
pressure (2.7 kPa). 11.0 g of the mixture of the 2 diastereoisomers
(B forms) 1-{(R*)-(4-chlorophenyl)[-
4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)-(methylsulfony-
l)methyl]azetidin-3-ol and
1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)pheny-
l]methyl}-3-[(S)-(3,5-difluorophenyl)-(methylsulfonyl)methyl]azetidin-3-ol
are obtained in the form of white foam.
[0676] The mixture of the 2 diastereoisomers (B forms)
3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(-
R)-(3,5-difluorophenyl)-(methylsulfonyl)methyl)]azetidine and
3-acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(-
R)-(3,5-difluorophenyl)-(methylsulfonyl)methyl)]azetidine may be
prepared by carrying out the operation as described in Example 40,
starting with 11.2 g of (3,5-difluorobenzyl)-methylsulfone, 350
cm.sup.3 of tetrahydrofuran, 34 cm.sup.3 of a 1.6 N solution of
n-butyllithium in hexane, 11.2 g of
1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)-phenyl]met-
hyl}azetidin-3-one, form B isomer, and 5.5 cm.sup.3 of acetyl
chloride. The crude product is chromatographed on a silica gel
column (particle size 0.06-0.200 mm, diameter 4 cm, height 40 cm),
eluting with a cyclohexane and ethyl acetate mixture (70/30 by
volume) and collecting 100 cm.sup.3 fractions. Fractions 10 to 30
are combined and then concentrated to dryness under reduced
pressure (2.7 kPa). 21 g of a still impure cream-colored foam are
obtained, which foam is chromatographed on a silica gel column
(particle size 0.06-0.200 mm, diameter 4 cm, height 40 cm), eluting
with dichloromethane and collecting 100 cm.sup.3 fractions.
Fractions 11 to 30 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 20.0 g of the mixture of the 2
diastereoisomers (B forms) 3-acetoxy-1
(R*)-(4-chlorophenyl)[4-(methoxyca-
rbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)-(methylsulfonyl)methyl)]-
azetidine and
3-acetoxy-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]m-
ethyl}-3-[(S)-(3,5-difluorophenyl)-(methylsulfonyl)methyl)]azetidine
are obtained in the form of a white foam.
[0677]
1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)-phenyl]methyl}azetidin-
-3-one, form B isomer, may be prepared by carrying out the
operation as described in Example 40, starting with 8.7 cm.sup.3 of
oxalyl chloride, 350 cm.sup.3 of dichloromethane, 14.2 cm.sup.3 of
dimethyl sulfoxide, 29.0 g of
1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}
azetidin-3-ole, form B isomer, and 43 cm.sup.3 of triethylamine.
The crude product is chromatographed on a silica gel column
(particle size 0.06-0.200 mm, diameter 4 cm, height 40 cm), eluting
with dichloromethane and collecting 250 cm.sup.3 fractions.
Fractions 7 to 25 are combined and then concentrated to dryness
under reduced pressure
[0678] (2.7 kPa). 15.5 g of
1-{(R*)-(4-[chlorophenyl)[4-(methoxycarbonyl)-- phenyl]methyl}
azetidin-3-one, form B isomer, are obtained in the form of an
orange-colored oil.
[0679] 1-{(R*)-(4-chlorophenyl)
[4-(methoxycarbonyl)-phenyl]methyl}azetidi- n-3-ol, form B isomer,
may be prepared according to the procedure described by KATRITZKY
A. R. et al., in J. Heterocycl. Chem., (1994), 271, starting with
25.5 g of methyl (-)-4-[1-(R*)-amino-1-(4-chlorophenyl-
)methyl]benzoate, 250 cm.sup.3 of ethanol, 7.9 g of sodium hydrogen
carbonate, and 7.7 cm.sup.3 of epibromohydrin. 29 g of
1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol,
form B isomer, are obtained in the form of a yellow oil.
[0680] Methyl (-)-4-[(R)amino(4-chlorophenyl)methyl]benzoate, may
be prepared by carrying out two successive recrystallizations of
the white crystals (3.4 g) called "A crystals" of Example 87, from
68 cm.sup.3 of ethanol containing 5% water under reflux. The
crystals obtained are filtered, drained and then dried under
reduced pressure (2.7 kPa). 2.2 g of methyl
[0681] (-)-4-[(R*)amino(4-chlorophenyl)methyl]benzoate
D-(-)-tartrate are obtained in the form of white crystals which are
dissolved in 50 cm.sup.3 of ethyl acetate. The solution obtained is
supplemented with 50 cm.sup.3 of 1 N sodium hydroxide, stirred and
then separated after settling out. The organic phase is washed with
50 cm.sup.3 of water and then dried over magnesium sulfate and
concentrated to dryness under reduced pressure
[0682] (2.7 kPa). 1.9 g of methyl
(-)-4-[(R*)amino(4-chlorophenyl)methyl]b- enzoate are obtained in
the form of a white solid [a]20.degree. C., 365
nm=-58.1.degree.+/-1 (c=0.5%)
Example 111
[0683] The operation is carried out as described in Example 110,
but by stirring the reaction mixture for 48 hours at 20.degree. C.,
starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]
(4-chlorophenyl)methyl}-3-
-[(3,5-difluorophenyl)-(methylsulfonyl)methylene)]azetidine, form B
isomer, 1.0 cm.sup.3 of dichloromethane and 0.030 cm.sup.3 of
N-methylpiperazine. The crude product is chromatographed on a
silica gel column (particle size 0.06-0.200 mm, diameter 8 mm,
height 5 cm), eluting with 50 cm.sup.3 of dichloromethane and then
with a dichloromethane and methanol mixture (95/5 by volume),
collecting 3 cm fractions immediately after using this eluent
mixture. Fractions 4 to 10 are combined and then concentrated to
dryness under reduced pressure
[0684] (2.7 kPa). 0.025 g of
1-{(R*)-(4-chlorophenyl)[4-(4-methylpiperazin-
-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylen-
e)]-azetidine, form B isomer, is obtained in the form of a
cream-colored foam [.sup.1H NMR spectrum (300 MHz, CDCl.sub.3,
.quadrature. in ppm): 2.28 (s, 3H), 2.44 (unresolved complex, 8H),
2.80 (s, 3H), 3.45 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.50 (s,
1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.99 (mt, 2H), from 7.20 to
7.40 (mt, 8H)].
Example 112
[0685] The operation is carried out as described in Example 110,
but by stirring the reaction mixture for 48 hours at 20.degree. C.,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3--
[(3,5-difluorophenyl)-(methylsulfonyl)methylene)]azetidine, form B
isomer, 1.0 cm.sup.3 of dichloromethane and 0.030 cm.sup.3 of
L-Prolinol. The crude product is chromatographed on a silica gel
column (particle size 0.06-0.200 mm, diameter 8 mm, height 5 cm),
eluting with 50 cm.sup.3 of dichloromethane and then with a
dichloromethane and methanol mixture (95/5 by volume), collecting 3
cm.sup.3 fractions immediately after using this eluent mixture.
Fractions 2 to 8 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 0.025 g of
1-{{(R*)-(4-chlorophenyl){4-[(2S)-(hydroxymethyl)-pyrrolidin-1-ylmethyl]p-
henyl}methyl}}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine-
, form B isomer, is obtained in the form of a cream-colored foam
[.sup.1H NMR spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm):
from 1.80 to 2.00 (mt, 4H), 2.24 (mt, 1H), 2.72 (mt, 1H), 2.80 (s,
3H), 2.94 (mt, 1H), 3.28 (d, J=13.5 Hz, 1H), 3.45 (mt, 1H), 3.65
(d, J=10.5 and 3.5 Hz, 1H), 3.85 (mt, 2H), 3.92 (d, J=13.5 Hz, 1H),
4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98
(mt, 2H), from 7.15 to 7.40 (mt, 8H)].
Example 113
[0686] The operation is carried out as described in Example 110,
but by stirring the reaction mixture for 48 hours at 20.degree. C.,
starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]
(4-chlorophenyl)methyl}-3-
-[(3,5-difluorophenyl)-(methylsulfonyl)methylene)]azetidine, form B
isomer, 1.0 cm.sup.3 of dichloromethane and 0.030 cm.sup.3 of
D-Prolinol. The crude product is chromatographed on a silica gel
column (particle size 0.06-0.200 mm, diameter 8 mm, height 5 cm),
eluting with 50 cm.sup.3 of dichloromethane and then with a
dichloromethane and methanol mixture (95/5 by volume), collecting 3
cm.sup.3 fractions immediately after using this eluent mixture.
Fractions 2 to 9 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 0.029 g of
1-{{(R*)-(4-chlorophenyl){4-(2R)-(hydroxymethyl)pyrrolidin-1-ylmethyl]phe-
nyl}methyl}}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,
form B isomer, is obtained in the form of a cream-colored foam
[.sup.1H NMR spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm):
from 1.50 to 2.00 (mt, 4H), 2.24 (mt, 1H), 2.71 (mt, 1H), 2.81 (s,
3H), 2.93 (mt, 1H), 3.28 (d, J=13.5 Hz, 1H), 3.44 (split t, J=10.5
and 2.5 Hz, 1H), 3.66 (dd, J=10.5 and 3.5 Hz, 1H), 3.85 (mt, 2H),
3.92 (d, J=13.5 Hz, 1H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9
and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.15 to 7.40 (mt, 8H)].
Example 114
[0687] The operation is carried out as described in Example 110,
but by stirring the reaction mixture for 48 hours at 20.degree. C.,
starting with 0.05 g of 1-{(R*)-[4-(chloromethyl)phenyl]
(4-chlorophenyl)methyl}-3-
-[(3,5-difluorophenyl)-(methylsulfonyl)methylene)]azetidine, form B
isomer, 1.0 cm.sup.3 of dichloromethane and 0.030 cm.sup.3 of
morpholine. The crude product is chromatographed on a silica gel
column (particle size 0.06-0.200 mm, diameter 8 mm, height 5 cm),
eluting with 50 cm.sup.3 of dichloromethane and then with a
dichloromethane and methanol mixture (95/5 by volume), collecting 3
cm.sup.3 fractions immediately after using this eluent mixture.
Fractions 2 to 9 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 0.047 g of
1-{(R*)-(4-chlorophenyl)[4-(morpholin-1-ylmethyl)phenyl]methyl}-3-[(3,5-d-
ifluorophenyl)(methylsulfonyl)methylene]-azetidine, form B isomer,
is obtained in the form of a white foam [.sup.1H NMR spectrum (300
MHz, CDCl.sub.3, .quadrature. in ppm): 2.40 (mt, 4H), 2.81 (s, 3H),
3.43 (s, 2H), 3.69 (mt, 4H), 3.84 (mt, 2H), 4.34 (mt, 2H), 4.50 (s,
1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.99 (mt, 2H), from 7.20 to
7.40 (mt, 8H)].
Example 115
[0688] The operation is carried out as described in Example 110,
but by stirring the reaction mixture for 48 hours at 20.degree. C.,
starting with 0.05 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3--
[(3,5-difluorophenyl)-(methylsulfonyl)methylene)]azetidine, form B
isomer, 1.0 cm.sup.3 of dichloromethane and 0.030 cm.sup.3 of
thiomorpholine. The crude product is chromatographed on a silica
gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 5
cm), eluting with 50 cm.sup.3 of dichloromethane and then with a
dichloromethane and methanol mixture (95/5 by volume), collecting 3
cm.sup.3 fractions immediately after using this eluent mixture.
Fractions 2 to 9 are combined and then concentrated to dryness
under reduced pressure (2.7 kPa). 0.047 g of
1-{(R*)-(4-(chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(-
3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, form B
isomer, is obtained in the form of a white foam [.sup.1H NMR
spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm): from 2.60 to
2.75 (mt, 8H), 2.81 (s, 3H), 3.44 (s, 2H), 3.85 (mt, 2H), 4.34 (mt,
2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H),
from 7.15 to 7.40 (mt, 8H)].
Example 116
[0689] The operation is carried out as described in Example 110,
but by stirring the reaction mixture for 48 hours at 20.degree. C.,
starting with 0.200 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-
-[(3,5-difluorophenyl)-(methylsulfonyl)methylene)]azetidine, form B
isomer, 5.0 cm.sup.3 of dichloromethane and 0.120 cm.sup.3 of
piperazin-2-one. The crude product is chromatographed on a silica
gel column (particle size 0.06-0.200 mm, diameter 1.0 cm, height 10
cm), eluting with 50 cm.sup.3 of dichloromethane and then with a
dichloromethane and methanol mixture (95/5 by volume), collecting 5
cm.sup.3 fractions immediately after using this eluent mixture.
Fractions 3 to 13 are combined and then concentrated to dryness
under reduced pressure
[0690] (2.7 kPa). 0.090 g of
1-{(R*)-(4-(chlorophenyl)[4-(piperazin-2-on-4-
-ylmethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene-
]azetidine, form B isomer, is obtained in the form of a white
powder.
Example 117
[0691] The operation is carried out as described in Example 110
starting with 0.200 g of 1-{(R*)-[4-(chloromethyl)phenyl]
(4-chlorophenyl)methyl}--
3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine, form B
isomer, 5.0 cm.sup.3 of dichloromethane and 0.120 of
3,3-dimethylpiperidine. The crude product is chromatographed on a
silica gel column (particle size 0.06-0.200 mm, diameter 1.0 cm,
height 10 cm), eluting with 50 cm.sup.3 of dichloromethane and then
with a dichloromethane and methanol mixture (95/5 by volume),
collecting 5 cm.sup.3 fractions immediately after using this eluent
mixture. Fractions 4 to 11 are combined and then concentrated to
dryness under reduced pressure (2.7 kPa). 0.120 g of
1-{(R*)-(4-chlorophenyl)[4-(3,3-dimethylpi-
peridinylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)meth-
ylene]azetidine, form B isomer, is obtained in the form of a white
powder.
Example 118
[0692] The operation is carried out as described in Example 110, by
stirring for 72 hours at 20.degree. C., starting with 0.200 g of
1-{(R*)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorop-
henyl)(methylsulfonyl)methylene)]-azetidine, form B isomer, 5.0
cm.sup.3 of dichloromethane and 0.080 of imidazole. The reaction
mixture is directly chromatographed on a silica gel column
(particle size 0.06-0.200 mm, diameter 1.0 cm, height 10 cm),
eluting with 100 cm.sup.3 of dichloromethane without fractionating,
and then with a dichloromethane and methanol mixture (98/2 and then
96/4 by volume), collecting 5 cm.sup.3 fractions.
[0693] Fractions 5 to 12 are combined and then concentrated to
dryness under reduced pressure (2.7 kPa). 0.35 g of
1-{(R*)-(4-chlorophenyl)[4-(i-
midazol-1-ylmethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-
methylene]} azetidine, form B isomer, is obtained in the form of a
white powder. [a].sup.2D=-6.7.degree. (c=0.5% dichloromethane)
Example 119
[0694] 2.47 g of potassium tert-butoxide are added to a suspension
of 6.12 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 5.15 g
of methyl 5-(methylsulfonylmethyl)thiophene-2-carboxylate in 200
cm.sup.3 of tetrahydrofuran, under an argon atomosphere, cooled to
-70.degree. C. The mixture is stirred for 1 hour 30 min at a
temperature close to -70.degree. C., and then 1.7 cm.sup.3 of
methanesulfonyl chloride in solution in 8 cm.sup.3 of ethyl ether
is added. After stirring for 1 hour at a temperature close to
-70.degree. C., the mixture is allowed to return to room
temperature and then 80 cm of distilled water are added. The
mixture is concentrated in a rotary evaporator to one third of its
initial volume, and is then extracted with 500 cm.sup.3 of
dichloromethane. The organic phase is washed with three times 80
cm.sup.3 of distilled water, dried over magnesium sulfate and
concentrated to dryness under reduced pressure
[0695] (2.7 kPa). The residue obtained is chromatographed on a
silica gel column (particle size 0.02-0.04 mm, diameter 7.5 cm,
height 35 cm), eluting at a nitrogen pressure of 0.5 bar with a
cyclohexane and ethyl acetate mixture (70/30 by volume) and
collecting 40 cm.sup.3 fractions. Fractions 19 to 29 are combined
and then concentrated to dryness under reduced pressure (2.7 kPa).
1.6 g of 1-[bis(4-chlorophenyl)methyl]-3-[(me-
thylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidine are
obtained in the form of a cream-colored foam [.sup.1H NMR spectrum
(400 MHz, CDCl.sub.3, .quadrature. in ppm): 2.91 (s, 3H), 3.88 (s,
3H), 4.08 (mt, 2H), 4.37 (mt, 2H), 4.53 (s, 1H), from 7.25 to 7.45
(mt, 9H), 7.71 (d, J=3.5 Hz, 1H)].
[0696] Fractions 34 to 48 are combined and then concentrated to
dryness under reduced pressure (2.7 kPa). 2.6 g of
(RS)-1-[bis(4-chlorophenyl)met-
hyl]-3-hydroxy-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methyl]azet-
idine are obtained in the form of cream-colored powder [.sup.1H NMR
spectrum (400 MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm):
2.87 (s, 3H), 2.89 (d, J=8 Hz, 1H), 2.96 (d, J=8 Hz, 1H), 3.21 (d,
J=8 Hz, 1H), 3.76 (d, J=8 Hz, 1H), 3.82 (s, 3H), 4.55 (s, 1H), 4.86
(s, 1H), 6.86 (s, 1H), from 7.35 to 7.45 (mt, 9H), 7.73 (d, J=4 Hz,
1H)].
[0697] Methyl 5-(methylsulfonylmethyl)thiophene-2-carboxylate may
be prepared in the following manner: 6.94 g of sodium
methanesulfinate are added, at room temperature, to a solution of
16 g of methyl 5-bromomethylthiophene-2-carboxylate in 150 cm.sup.3
of tetrahydrofuran. The suspension is stirred for 2 hours 30 min
under reflux, and then after addition of 50 cm.sup.3 of ethanol is
again stirred for 3 hours under reflux. The mixture is concentrated
to dryness under reduced pressure (2.7 kPa) and the residue
obtained is supplemented with 150 cm.sup.3 of distilled water and
is then extracted with twice 300 cm.sup.3 of ethyl acetate. The
organic phase is successively washed with 100 cm.sup.3 of distilled
water and twice 50 cm.sup.3 of saturated aqueous sodium chloride
solution and then dried over magnesium sulfate and concentrated to
dryness under reduced pressure (2.7 kPa). 14 g of methyl
5-(methylsulfonylmethyl)thiophene-2-carboxylate are thus obtained
in the form of a yellow solid melting around 133.degree. C.
[.sup.1H NMR spectrum (400 MHz, (CD.sub.3).sub.2SO-d6, at a
temperature of 373 K, .quadrature. in ppm): 3.05 (s, 3H), 4.22 (mt,
2H), 4.40 (mt, 2H), 4.98 (broad s, 1H), 7.30 (d, J=3.5 Hz, 1H),
7.39 (d, J=8 Hz, 4H), 7.50 (d, J=8 Hz, 4H), 7.66 (d, J=3.5 Hz,
1H)].
[0698] Methyl 5-bromomethylthiophene-2-carboxylate may be prepared
according to Curtin M. L., Davidsen S. K., Heyman H. R., Garland R.
B., Sheppard G. S., J. Med. Chem., 1998, 41 (1), 74-95.
Example 120
[0699] 47 .mu.l of N,N'-diisopropylcarbodiimide, 3.66 mg of
4-dimethylaminopyridine and 60 .mu.l of isobutylamine are added to
a solution of 163.5 mg of
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)-
(2-hydroxycarbonylthien-5-yl)methylene]azetidine hydrochloride in 3
cm.sup.3 of dichloromethane, at room temperature. The mixture is
stirred for 18 hours at room temperature and then chromatographed
on a silica gel column (particle size 0.04-0.06 mm), eluting with a
dichloromethane and ethyl acetate mixture (90/10 by volume). 60 mg
of 1-[bis(4-chlorophenyl)m-
ethyl]-3-[2-isobutylaminocarbonylthien-5-yl)(methylsulfonyl)methylene]azet-
idine are thus obtained in the form of a colorless lacquer [.sup.1H
NMR spectrum (400 MHz, CDCl.sub.3, .quadrature. in ppm): 0.97 (d,
J=7 Hz, 6H), 1.88 (mt, 1H), 2.90 (s, 3H), 3.25 (t, J=7 Hz, 2H),
4.08 (mt, 2H), 4.36 (mt, 2H), 4.52 (s, 1H), 4.56 (broad t, J=7 Hz,
1H), from 7.20 to 7.40 (mt, 10H)].
[0700]
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-hydroxycarbonyl-
thien-5-yl)methylene]azetidine hydrochloride may be prepared in the
following manner: 250 cm.sup.3 of concentrated hydrochloric acid
are added to a solution of 14 g of
1-[bis(4-chlorophenyl)methyl]-3-[(methylsu-
lfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidine in 250 cm
of acetic acid, at room temperature. The mixture is stirred for 38
hours at a temperature of 50.degree. C. and is then concentrated to
dryness under reduced pressure (2.7 kPa). Three times, the residue
is supplemented with 250 cm.sup.3 of toluene and concentrated to
dryness under reduced pressure (2.7 kPa). After trituration of the
residue in 400 cm.sup.3 of ethyl ether, 14.2 g of
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(-
2-hydroxycarbonylthien-5-yl)methylene]azetidine hydrochloride are
obtained in the form of a beige powder.
Example 121
[0701] 0.37 g of potassium tert-butoxide is added to a solution of
0.92 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 0.75 g of
[(3-methoxycarbonylphenyl)methyl]methylsulfone in 30 cm of
tetrahydrofuran, under an argon atmosphere, cooled to -70.degree.
C., and the mixture is stirred for 2 hours at -70.degree. C. 10
cm.sup.3 of a 0.1 N solution of hydrochloric acid are then added
and the mixture is allowed to return to room temperature. After
addition of 50 cm.sup.3 of ethyl acetate, the reaction mixture is
separated after settling out, dried over magnesium sulfate,
filtered and then concentrated to dryness under reduced
pressure
[0702] (2.7 pKa). The residue is chromatographed on a silica gel
column (particle size 0.20-0.06 mm, diameter 3 cm, height 50 cm),
eluting at a nitrogen pressure of 0.8 bar with a cyclohexane and
ethyl acetate mixture (70/30 by volume) and collecting 120 cm.sup.3
fractions. Fractions 11 to 18 are combined and then concentrated to
dryness under reduced pressure (2.7 kPA). The residue is
crystallized from 10 cm.sup.3 of isopropyl ether and 30 cm.sup.3 of
pentane. 0.30 g of 1-[bis(4-chlorophenyl)methyl]-
-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methyl(RS)]azetidin-3-ol
is thus obtained in the form of a white solid [.sup.1H NMR spectrum
(400 MHz, CDCl.sub.3, .quadrature. in ppm): 2.73 (s, 3H), 3.05 (AB,
J=9 Hz, 2H), 3.27 (d, J=9 Hz, 1H), 3.63 (s, 1H), 3.79 (d, J=9 Hz,
1H), 3.95 (s, 3H), 4.32 (s, 1H), 4.59 (s, 1H), from 7.15 to 7.35
(mt, 8H), 7.51 (t, J=8 Hz, 1H), 7.94 (broad d, J=8 Hz, 1H), 8.10
(broad d, J=8 Hz, 1H), 8.32 (broad s, 1H))].
Example 122
[0703] By carrying out the operation according to the procedure of
Example 1, starting with 0.66 g of
methyl(pyridin-4-ylmethyl)sulfone and 1.18 g of
1-[bis(4-chlorophenyl)methyl]azetidin-3-one, 0.20 g of a white
solid is obtained after purification on a silica gel column
(particle size 0.20-0.06 mm, diameter 3 cm, height 50 cm), at a
nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate
mixture (70/30 by volume) as eluent and collecting 120 cm.sup.3
fractions. The solid is taken up in 20 cm.sup.3 of diisopropyl
ether. After filtration, draining and drying, 0.16 g of
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-4-yl)-
methyl-(RS)]-azetidin-3-ol is obtained [.sup.1H NMR spectrum (400
MHz, CDCl.sub.3, .quadrature. in ppm): 2.76 (s, 3H), 3.03 (AB, J=9
Hz, 2H), 3.27 (d, J=9 Hz, 1H), 3.53 (s, 1H), 3.83 (d, J=9 Hz, 1H),
4.32 (s, 1H), 4.51 (s, 1H), from 7.20 to 7.30 (mt, 8H), 7.63 (d,
J=6 Hz, 2H), 8.68 (d, J=6 Hz, 2H)].
[0704] Methyl(pyridin-4-ylmethyl)sulfone may be prepared according
to the reference JP43002711.
Example 123
[0705] By carrying out the operation according to the procedure of
Example 1, starting with 0.47 g of
methyl(pyridin-3-ylmethyl)sulfone and 0.83 g of
1-[bis(4-chlorophenyl)methyl]azetidin-3-one, 0.50 g of a white
solid is obtained after purification on a silica gel column
(particle size 0.20-0.06 mm, diameter 3 cm, height 50 cm), at a
nitrogen pressure of 0.5 bar with a cyclohexane and ethyl 25
acetate mixture (70/30 by volume) as eluent and collecting 120
cm.sup.3 fractions. The solid is taken up in 30 cm.sup.3 of
diisopropyl ether. After filtration, draining and drying, 0.40 g of
1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-3yl)m-
ethyl-(RS)]-azetidin-3-ol is obtained [.sup.1H NMR spectrum (300
MHz, CDCl.sub.3, .quadrature. in ppm): 2.77 (s, 3H), 3.03 (AB, J=9
Hz, 2H), 3.28 (d, J=9 Hz, 1H), 3.66 (s, 1H), 3.83 (d, J=9 Hz, 1H),
4.33 (s, 1H), 4.55 (s, 1H), from 7.20 to 7.30 (mt, 8H), 7.37 (dd,
J=8 and 5 Hz, 1H), 8.16 (dt, J=8 and 2 Hz, 1H), 8.68 (dd, J=5 and
1.5 Hz, 1H), .delta. 8.83 (d, J=2 Hz, 1H)].
[0706] Methyl(pyridin-3-ylmethyl)sulfone may be prepared according
to the reference JP43002711.
Example 124
[0707] 0.0388 cm.sup.3 of N-(3-aminopropyl)morpholine is added, at
the same temperature, to a suspension of 150 mg of
3-({1-[bis(4-chlorophenyl)-
methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid
activated on TFP resin (165 .mu.M) in 3 cm.sup.3 of
dichloromethane, pre-stirred for 90 minutes at a temperature close
to 20.degree. C. The suspension is stirred at a temperature close
to 20.degree. C. for 22 hours and then filtered on sintered glass.
The solid residue is rewashed with twice 1.5 cm.sup.3 of
dichloromethane. The filtrates are combined and concentrated to
dryness under reduced pressure (2.7 kPa) at a temperature close to
40.degree. C. 60 mg of
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yliden- e}
methanesulfonylmethyl)-N-(3-morpholin-4-ylpropyl)benzamide are thus
obtained in the form of a pale yellow foam.
[0708]
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonyl-
methyl)-N-(3-morpholin-4-ylpropyl)benzamide may also be prepared in
the following manner: 0.083 cm.sup.3 of
N-(3-aminopropyl)morpholine, 110 mg of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 5 mg of
4-dimethylaminopyridine are successively added to a solution of 300
mg of 3-({1-[bis(4-chlorophenyl)methyl]
azetidin-3-ylidene}methanesulfonylmethy- l)benzoic acid in 10
cm.sup.3 of anhydrous dichloromethane (over calcium chloride) and 5
cm.sup.3 of dimethylformamide, under an inert atmosphere of
nitrogen, at a temperature close to 20.degree. C. The solution
obtained is stirred at a temperature close to 20.degree. C. for
about 22 hours and then concentrated to dryness under reduced
pressure (0.27 kPa) at a temperature close to 40.degree. C. The
solid residue is taken up in 25 cm.sup.3 of dichloromethane and
washed with twice 20 cm.sup.3 of a saturated aqueous sodium
bicarbonate solution. After separation after settling out, the
organic phase is dried over magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (2.7 kPa) at a
temperature close to 40.degree. C. 400 mg of a yellow oil are thus
obtained, which oil is purified by chromatography under nitrogen
pressure (0.8 bar) on 60 cm.sup.3 of silica (0.040-0.063 mm)
contained in a column 2.2 cm in diameter, eluting with a
methanol/dichloromethane mixture (2-98 by volume). The fractions
containing only the desired product are combined and concentrated
to dryness under reduced pressure (0.27 kPa) at 40.degree. C. for 2
hours. 130 mg of 3-({1-[bis(4-chlorophenyl)methyl]-az-
etidin-3-ylidene}
methanesulfonylmethyl)-N-(3-morpholin-4-ylpropyl)benzami- de are
thus obtained in the form of a white crystalline powder [.sup.1H
NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm):
1.68 (mt, 2H), from 2.25 to 2.40 (mt, 6H), 2.97 (s, 3H), from 3.20
to 3.35 (mt, 2H), 3.57 (t, J=4.5 Hz, 4H), 3.81 (mt, 2H), 4.22 (mt,
2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H),
from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8
Hz, 1H), 8.53 (t, J=5.5 Hz, 1H)].
Example 125
[0709] The operation is carried out under the conditions described
in Example 124 starting with 150 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (165 .mu.M) and 0.033 cm.sup.3 of
N,N-dimethyl-1,3-propanediamine. 52 mg of
3-({1-[bis(4-chlorophenyl)-methyl] azetidin-3-ylidene}
methanesulfonylmethyl)-N-(3-dimethylaminopropyl)benzamide are thus
obtained in the form of a white powder [.sup.1H NMR spectrum (400
MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 1.65 (mt, 2H),
2.18 (s, 6H), from 2.20 to 2.35 (mt, 2H), 2.98 (s, 3H), from 3.25
to 3.45 (mt, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.80 (s, 1H), 7.36
(d, J=8.5 Hz, 4H),7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt,
2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.57 (t, J=5.5
Hz, 1H)].
Example 126
[0710] The operation is carried out under the conditions described
in Example 124 starting with 150 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (165 .mu.M) and 0.0333 cm.sup.3 of 1-(aminoethyl)pyrrolidine.
39 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)-N-(2-pyrrolidin-1-ylethyl)benzamide are thus
obtained in the form of a pale yelow powder [.sup.1H NMR spectrum
(300 MHz, (CD.sub.3).sub.2SO-d6 with addition of a few drops of
CD.sub.3COOD-d4, .quadrature. in ppm): from 1.80 to 2.00 (mt, 4H),
2.97 (s, 3H), 3.20 (mt, 6H), 3.57 (t, J=6.5 Hz, 2H), 3.80 (mt, 2H),
4.23 (mt, 2H), 4.77 (s, 1H), 7.35 (d, J=8.5 Hz, 4H), 7.45 (d, J=8.5
Hz, 4H), from 7.50 to 7.65 (mt, 2H), 7.87 (broad s, 1H), 7.90
(broad d, J=7.5 Hz, 1H)].
Example 127
[0711] The operation is carried out under the conditions described
in Example 124 starting with 150 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (165 .mu.M) and 0.0333 cm.sup.3 of
1-(dimethylamino)-2-propylamine. 49 mg of
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmet-
hyl)-N-(2-dimethylamino-1-methylethyl)benzamide are thus obtained
in the form of a white powder [.sup.1H NMR spectrum (400 MHz,
(CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 1.13 (d, J=6.5 Hz,
3H), from 2.10 to 2.25 (mt, 1H), 2.15 (s, 6H), 2.38 (dd, J=13 and 8
Hz, 1H), 2.98 (s, 3H), 3.80 (mt, 2H), 4.14 (mt, 1H), 4.23 (mt, 2H),
4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), from 7.45 to 7.60 (mt, 2H),
7.46 (d, J=8 Hz, 4H), 7.83 (broad s, 1H), 7.87 (broad d, J=8 Hz,
1H), 8.16 (broad d, J=8 Hz, 1H)].
Example 128
[0712] The operation is carried out under the conditions described
in Example 124 starting with 150 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (165 .mu.M) and 0.026 cm.sup.3 of piperidine. 56 mg of
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)-N-piperidin-1-ylbenzamide are thus obtained
in the form of a white powder [.sup.1H NMR spectrum (400 MHz,
(CD.sub.3).sub.2SO-d6, .quadrature. in ppm): from 1.45 to 1.70 (mt,
6H), from 2.90 to 3.05 (mt, 2H), 2.98 (s, 3H), 3.19 (unresolved
complex, 1H), 3.57 (unresolved complex, 1H), 3.85 (mt, 2H), 4.23
(mt, 2H), 4.80 (s, 1H), from 7.30 to 7.55 (mt, 12H)].
Example 129
[0713] The operation is carried out under the conditions described
in Example 124 starting with 150 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (165 .mu.M) and 0.0265 cm.sup.3 of isobutylamine. 46 mg of
3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethy-
l)-N-isobutylbenzamide are thus obtained in the form of a white
powder [.sup.1H NMR spectrum (400 MHz, (CD.sub.3).sub.2SO-d6,
.quadrature. in ppm): 0.89 (d, J=7 Hz, 6H), 1.85 (mt, 1H), 2.98 (s,
3H), 3.09 (t, J=6.5 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s,
1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to
7.60 (mt, 2H), 7.84 (broad s, 1H), 7.88 (broad d, J=8 Hz, 1H), 8.51
(t, J=6 Hz, 1H)].
Example 130
[0714] The operation is carried out under the conditions described
in Example 124 starting with 150 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (165 .mu.M) and 0.0316 cm.sup.3 of
N-(3-aminopropyl)imidazole. 54 mg of
3-({1-[bis(4-chlorophenyl)methyl] azetidin-3-ylidene}
methanesulfonylmethyl)-N-(3-imidazol-1-ylpropyl)benzamide are thus
obtained in the form of a yellow foam [.sup.1H NMR spectrum (400
MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 1.97 (mt, 2H),
2.98 (s, 3H), 3.25 (mt, 2H), 3.81 (mt, 2H), 4.02 (t, J=7 Hz, 2H),
4.23 (mt, 2H), 4.79 (s, 1H), from 6.85 to 6.95 (mt, 2H), 7.36 (d,
J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H),
7.84 (broad s, 1H), 7.88 (broad d, J=8 Hz, 1H), 8.56 (t, J=5.5 Hz,
1H)].
Example 131
[0715] The operation is carried out under the conditions described
in Example 124 starting with 150 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (165 .mu.M) and 0.030 cm.sup.3 of
N,N-(dimethyl)ethylenediamine. 53 mg of
3-({1-[bis(4-chlorophenyl)methyl] azetidin-3-ylidene}
methanesulfonylmethyl)-N-(2-dimethylaminoethyl)benzamide are thus
obtained in the form of an ochre-colored foam [.sup.1H NMR spectrum
(400 MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 2.18 (2s,
6H), from 2.35 to 2.45 (mt, 2H), 2.98 (s, 3H), from 3.25 to 3.50
(mt, 2H), 3.81 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8
Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45 to 7.60 (mt, 2H) 7.83
(broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.43 (t, J=6.5 Hz,
1H)].
Example 132
[0716] The operation is carried out under the conditions described
in Example 124 starting with 150 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (165 .mu.M) and 0.0141 cm.sup.3 of methylhydrazine. 42 mg of
3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethy-
l)benzoic acid N'methylhydrazide are thus obtained in the form of a
pale yellow foam [.sup.1H NMR spectrum (400 MHz,
(CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 2.96 (s, 3H), 3.18
(broad s, 3H), 3.83 (mt, 2H), 4.22 (mt, 2H), 4.80 (broad s, 2H),
from 7.35 to 7.65 (mt, 12H)].
Example 133
[0717] The operation is carried out under the conditions described
in Example 124 starting with 150 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (165 .mu.M) and 0.0345 cm.sup.3 of
N-(2-aminoethyl)morpholine. 62 mg of
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl-
)-N-(2-morpholin-4-ylethyl)benzamide are thus obtained in the form
of an ochre-colored foam [.sup.1H NMR spectrum (400 MHz,
(CD.sub.3).sub.2SO-d6, .quadrature. in ppm): from 2.30 to 2.45 (mt,
4H), 2.46 (t, J=7.5 Hz, 2H), 2.98 (s, 3H), 3.38 (mt, 2H), from 3.50
to 3.65 (mt, 4H), 3.82 (mt, 2H), 4.24 (mt, 2H), 4.79 (s, 1H), 7.36
(d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt,
2H), 7.83 (broad s, 1H), 7.85 (dd, J=8 and 2 Hz, 1H), 8.45 (t,
J=6.5 Hz, 1H)].
Example 134
[0718] The operation is carried out under the conditions described
in Example 124 starting with 150 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (165 .mu.M) and 0.0396 cm.sup.3 of
2-(aminomethyl)-N-ethylpyrrolidine. 58 mg of
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonyl-
methyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide are thus obtained
in the form of an ochre-colored foam.
[0719]
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonyl-
methyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide may also be
prepared under the conditions described in Example 126 starting
with 700 mg of activated
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulf-
onylmethyl)benzoic acid on TFP resin (770 .mu.M), 0.324 cm.sup.3 of
triethylamine and 0.25 cm.sup.3 of
2-(aminomethyl)-N-ethylpyrrolidine. 370 mg of a solid are thus
obtained, which solid is purified by chromatography under nitrogen
pressure (0.7 bar) on 100 cm.sup.3 of silica (0.040-0.063 mm)
contained in a column 2.5 cm in diameter, eluting with a
methanol-dichloromethane mixture (15-85 by volume). The fractions
containing only the desired product are combined and concentrated
to dryness under reduced pressure (0.27 kPa) at 40.degree. C. for 2
hours. 160 mg of
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulf-
onylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide are thus
obtained in the form of a pale yellow powder [.sup.1H NMR spectrum
(400 MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 1.04 (t, J=7
Hz, 3H), from 1.50 to 1.70 (mt, 3H), 1.78 (mt, 1H), 2.14 (mt, 1H),
2.28 (mt, 1H), 2.59 (mt, 1H), 2.83 (mt, 1H), 2.98 (s, 3H), from
3.00 to 3.15 (mt, 2H), from 3.30 to 3.45 (mt, 1H), 3.82 (mt, 2H),
4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5
Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.86 (broad s, 1H), 7.85
(broad d, J=8 Hz, 1H), 8.41 (t, J=6 Hz, 1H)].
Example 135
[0720] The operation is carried out under the conditions described
in Example 124 starting with 110 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (121 .mu.M) and 0.023 cm.sup.3 of neopentylamine. 69 mg of
3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}
methanesulfonylmethyl)-N-(2,2-dimethylpropyl)benzamide are thus
obtained in the form of a pale yellow powder [.sup.1H NMR spectrum
(400 MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 0.90 (s,
9H), 2.98 (s, 3H), 3.11 (d, J=6.5 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt,
2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from
7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz,
1H), 8.37 (t, J=6.5 Hz, 1H)].
Example 136
[0721] The operation is carried out under the conditions described
in Example 124 starting with 110 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (121 .mu.M) and 0.025 cm.sup.3 of aminomethylcyclohexane. 44
mg of
3-({1-[bis(4-chlorophenyl)-methyl]azetidin-3-ylidene}methanesulfonylmethy-
l)-N-cyclohexylmethylbenzamide are thus obtained in the form of a
pale yellow powder whose characteristics are the following [.sup.1H
NMR spectrum (400 MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm):
0.92 (mt, 2H), 1.17 (mt, 4H), from 1.45 to 1.80 (mt, 5H), 2.97 (s,
3H), 3.10 (d, J=6 Hz, 2H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.79 (s,
1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45 to 7.60
(mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.47 (t,
J=6 Hz, 1H)].
Example 137
[0722] The operation is carried out under the conditions described
in Example 124 starting with 110 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (121 .mu.M), 0.026 cm.sup.3 of triethylamine and 21 mg of
aminomethylcyclopropane hydrochloride. 68 mg of
3-({1-[bis(4-chlorophenyl-
)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-cyclopropylmethylbenza-
mide are thus obtained in the form of a yellow foam [.sup.1H NMR
spectrum (400 MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm):
0.24 (mt, 2H), 0.44 (mt, 2H), 1.03 (mt, 1H), 2.98 (s, 3H), 3.15 (t,
J=6 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d,
J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H),
7.86 (broad s, 1H), 7.89 (broad d, J=8 Hz, 1H), 8.64 (t, J=6 Hz,
1H)].
Example 138
[0723] The operation is carried out under the conditions described
in Example 124 starting with 110 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (121 .mu.M) and 0.023 cm.sup.3 of 2-methylbutylamine. 49 mg
of 3-({1-[bis(4-chlorophenyl)-methyl] azetidin-3-ylidene}
methanesulfonylmethyl)-N-(2-methylbutyl)benzamide are thus obtained
[.sup.1H NMR spectrum (400 MHz, (CD.sub.3).sub.2SO-d6, .quadrature.
in ppm): from 0.80 to 0.95 (mt, 6H), from 1.05 to 120 (mt, 1H),
1.41 (mt, 1H), 1.64 (mt, 1H), 2.98 (s, 3H), 3.06 (mt, 1H), 3.19
(mt, 1H), 3.81 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8
Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.35 to 7.60 (mt, 2H), 7.84
(broad s, 1H), 7.87 (broad d, J=8 Hz, 1H), 8.49 (t, J=5.5 Hz,
1H)].
Example 139
[0724] The operation is carried out under the conditions described
in Example 124 starting with 110 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (121 .mu.M) and 0.028 cm.sup.3 of 2-methylphenethylamine. 42
mg of
3-({1-[bis(4-chlorophenyl)-methyl]azetidin-3-ylidene}methanesulfonylmethy-
l)-N-(2-phenylpropyl)benzamide are thus obtained in the form of a
yellow paste [.sup.1H NMR spectrum (400 MHz, (CD.sub.3).sub.2SO-d6,
.quadrature. in ppm): 1.24 (d, J=7 Hz, 3H), 2.97 (s, 3H), 3.07 (mt,
1H), from 3.20 to 3.50 (mt, 2H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.80
(s, 1H), from 7.10 to 7.40 (mt, 5H), 7.38 (d, J=8 Hz, 4H), 7.47 (d,
J=8 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.77 (broad s, 1H), 7.79
(broad d, J=8 Hz, 1H), 8.55 (t, J=6 Hz, 1H)].
Example 140
[0725] The operation is carried out under the conditions described
in Example 124 starting with 110 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (121 .mu.M) and 0.020 cm.sup.3 of
tetrahydrofurfurylmethylamine. 42 mg of
3-({1-[bis(4-chlorophenyl)methyl] azetidin-3-ylidene}
methanesulfonylmethyl)-N-(tetrahydrofuran-2-ylmethyl)benzamide are
thus obtained in the form of a yellow paste [.sup.1H NMR spectrum
(400 MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 1.58 (mt,
1H), from 1.75 to 2.00 (mt, 3H), 2.98 (s, 3H), from 3.20 to 3.40
(mt, 2H), 3.63 (mt, 1H), 3.77 (mt, 1H), 3.82 (mt, 2H), 3.98 (mt,
1H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d,
J=8 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.88
(broad d, J=8 Hz, 1H), 8.60 (t, J=6 Hz, 1H)].
Example 141
[0726] The operation is carried out under the conditions described
in Example 124 starting with 110 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (121 .mu.M) and 39 mg of 2,2-diphenylethylamine. 39 mg of
3-({1-[bis(4-chlorophenyl)-methyl]azetidin-3-ylidene}methanesulfonylmethy-
l)-N-(2;2-diphenylethyl)benzamide are thus obtained in the form of
a yellow paste [.sup.1H NMR spectrum (400 MHz,
(CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 2.95 (s, 3H), 3.77
(mt, 2H), 3.90 (dd, J=8 and 6.5 Hz, 2H), 4.22 (mt, 2H), 4.42 (t,
J=8 Hz, 1H), 4.79 (s, 1H), from 7.10 to 7.40 (mt, 10H), 7.38 (d,
J=8.5 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.48 (d, J=8.5 Hz, 4H),
7.70 (mt, 2H), 8.56 (t, J=6.5 Hz, 1H)].
Example 142
[0727] The operation is carried out under the conditions described
in Example 124 starting with 110 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (121 .mu.M) and 19 mg of 2-ethylbutylamine. 47 mg of
3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethy-
l)-N-(2-ethylbutyl)benzamide are thus obtained in the form of a
pale yellow powder [.sup.1H NMR spectrum (400 MHz,
(CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 0.86 (t, J=7 Hz, 6H),
from 1.20 to 1.40 (mt, 4H), 1.50 (mt, 1H), 2.98 (s, 3H), 3.19 (t,
J=6 Hz, 2H), 3.82 (mt, 2H), 4.24 (mt, 2H), 4.79 (s, 1H), 7.36 (d,
J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.45 to 7.60 (mt, 2H),
7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.42 (t, J=6 Hz,
1H)].
Example 143
[0728] The operation is carried out under the conditions described
in Example 124 starting with 110 mg of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin (121 .mu.M), 0.026 cm.sup.3 of triethylamine and 39 mg of
4-aminomethylcyclohexanecarboxylic acid methyl ester hydrochloride.
47 mg of
4-{[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfon-
ylmethyl)benzoylamino]methyl}cyclohexanecarboxylic acid methyl
ester are thus obtained in the form of a pale yellow paste [.sup.1H
NMR spectrum (400 MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm):
from 0.90 to 1.05 (mt, 2H), from 1.20 to 1.40 (mt, 2H), 1.52 (mt,
1H), from 1.70 to 2.00 (mt, 4H), 2.27 (mt, 1H), 2.98 (s, 3H), 3.12
(t, J=6.5 Hz, 2H), 3.60 (s, 3H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.79
(s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45 to
7.60 (mt, 2H), 7.83 (broad s, 1H), 7.87 (broad d, J=8 Hz, 1H), 8.50
(t, J=6 Hz, 1H)].
[0729] Activated
3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}metha-
nesulfonylmethyl)benzoic acid on TFP resin may be prepared under
the following conditions: 1.18 g of
3-({1-[bis(4-chlorophenyl)methyl]azetidin-
-3-ylidene}methanesulfonylmethyl)benzoic acid is added, at the same
temperature, to a suspension of 1.07 g of TFP resin (free phenol
function, 1.1 mmol/g, that is to say 1.17 mM) in 15 cm.sup.3 of
anhydrous dimethylformamide, prestirred for 10 minutes at a
temperature close to 20.degree. C. After stirring for 10 minutes at
a temperature close to 20.degree. C., 14 mg of
4-dimethylaminopyridine are added and then after stirring for 10
minutes at the same temperature, 0.185 cm.sup.3 of
1,3-diisopropylcarbodiimide. After stirring for 23 hours at a
temperature close to 20.degree. C., the suspension is filtered and
the resin is washed with 45 cm.sup.3 of dimethylformamide, 45
cm.sup.3 of tetrahydrofuran, 45 cm.sup.3 of dichloromethane, and
then dried under vacuum to constant weight. 1.5 g of activated
3-({1-[bis(4-chlorophenyl)m-
ethyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoic acid on TFP
resin are thus obtained in the form of a pale yellow resin.
[0730] The TFP resin (structure below) may be prepared in the
following manner: 12
[0731] 492 mg of diisopropylcarbodiimide, 819.3 mg of
2,3,5,6-tetrafluoro-4-hydroxybenzoic acid and 50 mg of
4-dimethylaminopyridine are successively added to a suspension of 2
g of commercially available aminomethyl polystyrene resin (0.39
mmol/g; 0.78 mmol) in 15 cm.sup.3 of dimethylformamide, prestirred
for 5 minutes at a temperature close to 20.degree. C. After
stirring for about 20 hours at a temperature close to 20.degree.
C., the suspension is filtered and the resin is rinsed with three
times 20 cm.sup.3 of dimethylformamide, three times 20 cm.sup.3 of
tetrahydrofuran and three times 20 cm.sup.3 of dichloromethane. The
resin obtained is dried under reduced pressure at a temperature
close to 40.degree. C. The resin obtained is then stirred, at a
temperature close to 20.degree. C., for about 20 hours, in
suspension in a piperidine/dimethylformamide mixture (10/90 by
volume). The suspension is filtered and the resin is rinsed with
three times 20 cm.sup.3 of dimethylformamide, three times 20
cm.sup.3 of tetrahydrofuran and three times 20 cm.sup.3 of
dichloromethane. The resin obtained is dried under reduced pressure
at a temperature close to 40.degree. C. and is used as it is.
Example 144
[0732] A solution of 76 mg of
(2-{4-[3-({1-[bis-(4-chlorophenyl)methyl] azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoeth- yl)carbamic
acid tert-butyl ester in 2.5 cm.sup.3 of formic acid is stirred for
1 hour at a temperature close to 45.degree. C. The reaction medium
is concentrated to dryness under reduced pressure (5 kPa) at a
temperature close to 30.degree. C., taken up in 10 cm.sup.3 of
ethyl acetate and alkalinized with 10 cm.sup.3 of a saturated
aqueous sodium bicarbonate solution. After separating after
settling out, the organic phase is washed with 10 cm.sup.3 of
water, dried over magnesium sulfate, filtered and concentrated to
dryness under reduced pressure (1 kPa) at a temperature close to
40.degree. C. 51 mg of 2-amino-1-{4-[3-({1-[bis-(4-c-
hlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperaz-
in-1-yl}ethanone are thus obtained in the form of a beige lacquer
[.sup.1H NMR spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm):
from 1.95 to 2.25 (broad unresolved complex, 2H), 2.77 (s, 3H),
from 3.10 to 3.30 (mt, 4H), from 3.50 to 3.60 (mt, 2H), 3.56 (broad
s, 2H), from 3.75 to 3.90 (mt, 4H), 4.34 (mt, 2H), 4.50 (s, 1H),
6.84 (broad d, J=8 Hz, 1H), 6.91 (dd, J=8 and 2 Hz, 1H), 7.01 (mt,
1H), from 7.20 to 7.40 (mt, 9H)].
Example 145
[0733] 1.02 g of supported EDCI (5 mM), 44 mg of N-Boc-glycine and
then 10 cm.sup.3 of dichloromethane are successively added, at a
temperature close to 20.degree. C., to 108.5 mg of
1-[3-({1-[bis-(4-chlorophenyl)meth-
yl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.
After stirring for 20 hours at a temperature close to 20.degree.
C., the reaction mixture is filtered on sintered glass. The resin
is rinsed with three times 5 cm.sup.3 of dichloromethane. The
combined filtrates are washed with 20 cm of water, dried over
magnesium sulfate, filtered on sintered glass and concentrated to
dryness under reduced pressure (1 kPa) at a temperature close to
40.degree. C. 143 mg of (2-{4-[3-({1-[bis-(4-ch-
lorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazi-
n-1-yl}-2-oxoethyl)carbamic acid tert-butyl ester are thus obtained
in the form of a cream-colored lacquer [.sup.1H NMR spectrum (400
MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 1.40 (s, 9H),
2.93 (s, 3H), from 3.05 to (mt, 4H), 3.57 (mt, 4H), 3.80 (mt, 2H),
3.84 (d, J=6 Hz, 2H), 4.19 (mt, 2H), 4.78 (s, 1H), 6.79 (t, J=6 Hz,
1H), 6.82 (d, J=8 Hz, 1H), 6.93 (broad s, 1H), 6.99 (dd, J=8 and
2.5 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d,
J=8 Hz, 4H)].
[0734] The supported EDCI reagent is commercially available and may
also be prepared according to the following reference: M. Desai, L.
Stramiello, Tetrahedron Letters, 34, 48, 7685-7688 (1993).
Example 146
[0735] A solution of 81 mg of
(2-{4-[3-({1-[bis-(4-chlorophenyl)-methyl]az- etidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-
-N-methylcarbamic acid tert-butyl ester in 2.5 cm.sup.3 of formic
acid is stirred for 1 hour at a temperature close to 45.degree. C.
The reaction mixture is concentrated to dryness under reduced
pressure (5 kPa) at a temperature close to 30.degree. C., taken up
in 10 cm.sup.3 of ethyl acetate and alkalinized with 10 cm.sup.3 of
a saturated aqueous sodium bicarbonate solution. After separating
after settling out, the organic phase is washed with 10 cm.sup.3 of
water, dried over magnesium sulfate, filtered and concentrated to
dryness under reduced pressure (1 kPa) at a temperature close to
40.degree. C. 58 mg of 1-{4-[3-({1-[bis-(4-chlorophe- nyl)methyl]
azetidin-3-ylidene} methanesulfonylmethyl)phenyl]piperazin-1-y-
l}-2-methylaminoethanone are thus obtained in the form of a beige
lacquer [.sup.1H NMR spectrum (300 MHz, CDCl.sub.3), .quadrature.
in ppm): from 1.95 to 2.15 (broad unresolved complex, 1H), 2.51
(broad s, 3H), 2.77 (s, 3H), from 3.10 to 3.30 (mt, 4H), 3.49
(broad s, 2H), 3.58 (mt, 2H), from 3.75 to 3.90 (mt, 4H), 4.33 (mt,
2H), 4.49 (s, 1H), 6.83 (broad d, J=8 Hz, 1H), 6.90 (dd, J=8 and 2
Hz, 1H), 7.00 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].
Example 147
[0736] 1.02 g of supported EDCI (5 mM), 47.3 mg of N-Boc-sarcosine
and 3 then 10 cm of dichloromethane are successively added, at a
temperature close to 20.degree. C., to 108.5 mg of
1-[3-({1-[bis-(4-chlorophenyl)meth-
yl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.
After stirring for 20 hours at a temperature close to 20.degree.
C., the reaction mixture is filtered on sintered glass. The resin
is rinsed with three times 5 cm.sup.3 of dichloromethane. The
combined filtrates are washed with 20 cm of water, dried over
magnesium sulfate, filtered on sintered glass and concentrated to
dryness under reduced pressure (1 kPa) at a temperature close to
40.degree. C. 143 mg of (2-{4-[3-({1-[bis-(4-ch- lorophenyl)methyl]
azetidin-3-ylidene} methanesulfonylmethyl)phenyl]pipera-
zin-1-yl}-2-oxoethyl)-N-methylcarbamic acid tert-butyl ester are
thus obtained in the form of a cream-colored lacquer [.sup.1H NMR
spectrum (400 MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm). A
mixture of rotamers is observed at room temperature; 1.31 and 1.41
(2s, 9H in total), 2.78 and 2.81 (2s, 3H in total), 2.93 (2s, 3H),
from 3.10 to 3.25 (unresolved complex, 4H), from 3.45 to 3.65 (mt,
4H), 3.80 (mt, 2H), 4.06 and 4.09 (2s, 2H in total), 4.19 (mt, 2H),
4.78 (s, 1H), 6.83 (broad d, J=8 Hz, 1H), 6.93 (broad s, 1H), 7.00
(dd, J=8 and 2.5 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz,
4H), 7.46 (d, J=8 Hz, 4H)].
Example 148
[0737] 2 cm.sup.3 of dichloromethane and then 11 mg of methyl
isothiocyanate are successively added, at a temperature close to
20.degree. C., to 54.25 mg of
1-[3-({1-[bis-(4-chlorophenyl)methyl]azetid-
in-3-ylidene}methanesulfonylmethyl)-phenyl]piperazine. After
stirring for 6 hours at a temperature close to 20.degree. C., 0.05
cm.sup.3 of water is added to the reaction mixture. After stirring
for 15 minutes at the same temperature, the reaction medium is
dried over magnesium sulfate, filtered and concentrated to dryness
under reduced pressure (1 kPa) at a temperature close to 40.degree.
C. 61 mg of 4-[3-({1-[bis-(4-chlorophenyl-
)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carbo-
thioic acid N-methylamide are thus obtained in the form of a beige
lacquer [.sup.1H NMR spectrum (400 MHz, CDCl.sub.3), .quadrature.
in ppm): 2.77 (s, 3H), 3.20 (d, J=5 Hz, 3H), 3.32 (t, J=5.5 Hz,
4H), 3.81 (mt, 2H), 4.00 (t, J=5.5 Hz, 4H), 4.33 (mt, 2H), 4.49 (s,
1H), 5.63 (broad q, J=5 Hz, 1H), 6.80 (d, J=8 Hz, 1H), 6.85 (dd,
J=8 and 2.5 Hz, 1H), 6.94 (broad s, 1H), from 7.20 to 7.30 (mt,
5H), 7.32 (d, J=8 Hz, 4H)].
Example 149
[0738] 2 cm.sup.3 of dichloromethane and then 11.5 mg of methyl
isocyanate are successively added, at a temperature close to
20.degree. C., to 54.25 mg of
1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulf-
onylmethyl)-phenyl]piperazine. After stirring for 4 hours at a
temperature close to 20.degree. C., 0.05 cm.sup.3 of water is added
to the mixture. After stirring for 15 minutes at the same
temperature, the reaction medium is dried over magnesium sulfate,
filtered on paper and concentrated to dryness under reduced
pressure (1 kPa) at a temperature close to 40.degree. C. 66 mg of
4-[3-({1-[bis-(4-chlorophenyl)methyl]azet-
idin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylic
acid N-methylamide are thus obtained in the form of a beige lacquer
[.sup.1H NMR spectrum (400 MHz, CDCl.sub.3), .quadrature. in ppm):
2.75 (s, 3H), 2.85 (d, J=5 Hz, 3H), 3.19 (broad t, J=5.5 Hz, 4H),
3.52 (broad t, J=5.5 Hz, 4H), 3.80 (mt, 2H), 4.33 (mt, 2H), 4.45
(broad q, J=5 Hz, 1H), 4.49 (s, 1H), 6.81 (d, J=8 Hz, 1H), 6.89
(dd, J=8 and 2.5 Hz, 1H), 6.98 (broad s, 1H), from 7.20 to 7.30
(mt, 5H), 7.32 (d, J=8 Hz, 4H)].
Example 150
[0739] 2 cm.sup.3 of pyridine and then 10.4 mg of methyl
chloroformate are successively added, at a temperature close to
20.degree. C., to 54.25 mg of
1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfony-
lmethyl)-phenyl]piperazine. After stirring for 6 hours at a
temperature close to 20.degree. C., the reaction medium is
concentrated to dryness under reduced pressure (5 kPa) at a
temperature close to 30.degree. C. The residue obtained is taken up
in 5 cm.sup.3 of ethyl acetate and 5 cm.sup.3 of water. After
separating after settling out, the organic phase is washed with 2
cm.sup.3 of water, dried over magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (1 kPa) at a
temperature close to 40.degree. C. 62 mg of
4-[3-({1-[bis-(4-chlorophenyl-
)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carbo-
xylic acid methyl ester are thus obtained in the form of a beige
lacquer [.sup.1H NM spectrum (400 MHz, CDCl.sub.3), .quadrature. in
ppm): 2.75 (s, 3H), 3.15 (broad t, J=5.5 Hz, 4H), 3.62 (mt, 4H),
3.74 (s, 3H), 3.80 (mt, 2H), 4.32 (mt, 2H), 4.49 (s, 1H), 6.81 (d,
J=8 Hz, 1H), 6.90 (dd, J=8 and 2.5 Hz, 1H), 6.99 (broad s, 1H),
from 7.20 to 7.40 (mt, 9H)].
Example 151
[0740] 32 mg of sodium acetoxyborohydride and then 22 mg of
isobutyraldehyde are successively added, at a temperature close to
20.degree. C., to a solution of 54.25 mg of
1-[3-({1-[bis-(4-chlorophenyl- )methyl]azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazine in 2 cm.sup.3 of
1,2-dichloroethane. After stirring for 4 hours at a temperature
close to 20.degree. C., 3 cm.sup.3 of dichloromethane and 2
cm.sup.3 of a saturated aqueous sodium bicarbonate solution are
added to the reaction medium. After separating after settling out,
the organic [lacuna] is dried over magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (1 kPa) at a
temperature close to 40.degree. C. 63 mg of
1-[3-({1-[bis-(4-chlorophenyl)methyl]
azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-isobutylpiperazine
are thus obtained in the form of a beige lacquer [.sup.1H NMR
spectrum (400 MHz, CDCl.sub.3), .quadrature. in ppm): 0.92 (d, J=7
Hz, 6H), 1.82 (mt, 1H), 2.14 (d, J=8 Hz, 2H), 2.54 (t, J=5.5 Hz,
4H), 2.75 (s, 3H), 3.18 (t, J=5.5 Hz, 4H), 3.81 (mt, 2H), 4.32 (mt,
2H), 4.49 (s, 1H), 6.78 (d, J=8 Hz, 1H), 6.89 (dd, J=8 and 2.5 Hz,
1H), 6.97 (broad s, 1H), from 7.15 to 7.30 (mt, 5H), 7.32 (d, J=8
Hz, 4H)].
Example 152
[0741] 32 mg of sodium acetoxyborohydride and then 13 mg of
acetaldehyde are successively added, at a temperature close to
20.degree. C., to a solution of 54 mg of
1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylid-
ene}methanesulfonylmethyl)phenyl]piperazine in 2 cm.sup.3 of
1,2-dichloroethane. After stirring for 21 hours at a temperature
close to 20.degree. C., 2 cm.sup.3 of a saturated aqueous sodium
bicarbonate solution are added to the reaction medium. After
separating after settling out, the aqueous phase is reextracted
with 2 cm.sup.3 of dichloromethane. The pooled organic phases are
dried over magnesium sulfate, filtered and concentrated to dryness
under reduced pressure (1 kPa) at a temperature close to 20.degree.
C. 60 mg of a solid residue are thus obtained, which residue is
taken up in 2 cm.sup.3 of methanol and 0.5 cm.sup.3 of
dichloromethane. The solution obtained is deposited on a silica
catridge (500 mg of SCX phase). The cartridge is washed with 5
cm.sup.3 of methanol and then the expected product is eluted with 5
cm.sup.3 of ammoniacal methanol (2 N) and then with an additional 5
cm.sup.3 of methanol. The filtrate is concentrated to dryness under
reduced pressure (1 kPa) at a temperature close to 30.degree. C. 42
mg of
1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylme-
thyl)-phenyl]-4-ethylpiperazine are thus obtained in the form of a
colorless lacquer [.sup.1H NMR spectrum (300 MHz, CDCl.sub.3),
.quadrature. in ppm): 1.14 (t, J=7.5 Hz, 3H), 2.48 (q, J=7.5 Hz,
2H), 2.60 (broad t, J=5 Hz, 4H), 2.77 (s, 3H), 3.22 (broad t, J=5
Hz, 4H), 3.82 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.79 (broad d,
J=8 Hz, 1H), 6.91 (dd, J=8 and 2 Hz, 1H), 6.98 (mt, 1H), from 7.20
to 7.40 (mt, 9H)].
Example 153
[0742] 2 cm.sup.3 of pyridine and then 11.5 mg of acetic anhydride
are successively added, at a temperature close to 20.degree. C., to
54 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)-phenyl]piperazine. After stirring for 23
hours at a temperature close to 20.degree. C., the reaction medium
is concentrated to dryness under reduced pressure (1 kPa) at a
temperature close to 30.degree. C. The residue obtained is taken up
in 5 cm.sup.3 of ethyl acetate and 2 cm.sup.3 of water. After
separating after settling out, the organic phase is washed with 2
cm.sup.3 of water, dried over magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (1 kPa) at a
temperature close to 40.degree. C. 52 mg of 4-acetyl
1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylme-
thyl)phenyl]piperazine are thus obtained in the form of a beige
foam [.sup.1H NMR spectrum (300 MHz, CDCl.sub.3), .quadrature. in
ppm): 2.16 (s, 3H), 2.77 (s, 3H), from 3.10 to 3.25 (mt, 4H), 3.63
(broad t, J=5.5 Hz, 2H), 3.78 (broad t, J=5.5 Hz, 2H), 3.82 (mt,
2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (broad d, J=8 Hz, 1H), 6.92
(dd, J=8 and 2 Hz, 1H), 7.02 (mt, 1H), from 7.20 to 7.40 (mt,
9H)].
Example 154
[0743] 511 mg of supported EDCI (2.5 mM), 11.5 mg of
N,N-dimethylglycine and then 5 cm.sup.3 of dichloromethane are
successively added, at a temperature close to 20.degree. C., to 54
mg of 1-[3-({1-[bis-(4-chloroph-
enyl)-methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.
After stirring for 24 hours at a temperature close to 20.degree.
C., 35 mg of N,N-dimethylglycine are added. After stirring for 96
hours at a temperature close to 20.degree. C., the reaction mixture
is filtered on sintered glass. The resin is rinsed with three times
2.5 cm.sup.3 of dichloromethane. The combined filtrates are washed
with 10 cm.sup.3 of water, dried over magnesium sulfate, filtered
and concentrated to dryness under reduced pressure (5 kPa) at a
temperature close to 20.degree. C. 53 mg of
1-{4-[3-({1-[bis-(4-chlorophenyl)methyl] azetidin-3-ylidene}
methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-dimethylaminoethanone
are thus obtained in the form of a beige foam [H NMR spectrum (400
MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 2.20 (s, 6H),
2.94 (s, 3H), 3.12 (s, 2H), 3.16 (mt, 4H), 3.58 (mt, 2H), 3.68 (mt,
2H), 3.80 (mt, 2H), 4.19 (mt, 2H), 4.78 (s, 1H), 6.81 (broad d, J=8
Hz, 1H), 6.93 (broad s, 1H), 6.99 (dd, J=8 and 2.5 Hz, 1H), 7.26
(t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H)].
Example 155
[0744] A solution of 320 mg of
4-[3-({1-[bis-(4-chlorophenyl)-methyl]azeti- din-3-ylidene}
methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid
tert-butyl ester in 5 cm.sup.3 of formic acid is stirred for 5
hours at a temperature close to 20.degree. C., and then for 1 hour
at a temperature close to 45.degree. C. The reaction medium is
concentrated to dryness under reduced pressure (5 kPa) at a
temperature close to 30.degree. C., taken up in 20 cm.sup.3 of
ethyl acetate and alkalinized with 10 cm.sup.3 of a saturated
aqueous sodium bicarbonate solution. After separating after
settling out, the organic phase is washed with three times 10
cm.sup.3 of water, dried over magnesium sulfate, filtered and
concentrated to dryness under reduced pressure (1 kPa) at a
temperature close to 40.degree. C. The residue obtained is purified
by depositing, in solution in a minimum of dichloromethane, on
silica gel deposited on a plate [(gel 0.5 mm thick, 5 plates of 20
.quadrature. 20 cm, eluent: dichloromethane-methanol (80-20 by
volume)]. The zone corresponding to the adsorbed desired product,
located with UV rays, is scraped and the silica recovered is washed
on sintered glass with a dichloromethane-methanol mixture (75-25 by
volume). The filtrates are combined and concentrated to dryness
under reduced pressure (1 kPa) at a temperature close to 30.degree.
C. 180 mg of 1-[3-({1-[bis-(4-chloropheny-
l)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine
are thus obtained in the form of a white powder [.sup.1H NMR
spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm): 2.77 (s, 3H),
3.05 (mt, 4H), 3.16 (mt, 4H), 3.81 (mt, 2H), 4.33 (mt, 2H), 4.49
(s, 1H), 6.79 (broad d, J=8 Hz, 1H), 6.90 (dd, J=8 and 2.5 Hz, 1H),
6.98 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].
[0745]
4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulf-
onylmethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester may
be prepared in the following manner: on carrying out the operation
according to the procedure of Example 4 starting with 1.32 g of
4-[3-({1-[bis-(4-chlorophenyl)-methyl]-3-hydroxyazetidin-3-yl}methanesulf-
onylmethyl)phenyl]piperazine 1-1-carboxylic acid tert-butyl ester,
0.232 cm.sup.3 of methanesulfonyl chloride and 0.733 g of
4-dimethylaminopyridine, the residue obtained is purified by
chromatography on a silica gel column (particle size 0.063-0.200
mm, diameter 2 cm, height 25 cm) at atmospheric pressure with a
dichloromethane-methanol mixture (99.5-0.5 by volume) as eluent and
collecting 15 cm.sup.3 fractions. The fractions containing the
desired product are combined and concentrated to dryness under
reduced pressure (5 kPa) at a temperature close to 30.degree. C.
0.86 g of 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}
methanesulfonylmethyl)-phenyl]piperazine-1-carboxylic acid
tert-butyl ester is thus obtained in the form of a white foam
[.sup.1H NMR spectrum (400 MHz, CDCl.sub.3, .quadrature. in ppm):
1.50 (s, 9H), 2.77 (s, 3H), 3.14 (t, J=5 Hz, 4H), 3.57 (t, J=5 Hz,
4H), 3.81 (mt, 2H), 4.34 (mt, 2H) 4.49 (s, 1H), 6.81 (d, J=8 Hz,
1H), 6.90 (dd, J=8 and 2.5 Hz, 1H), 6.99 (broad s, 1H), from 7.20
to 7.30 (mt, 5H), 7.32 (d, J=8 Hz, 4H)].
4-[3-({1-[bis-(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methanesulfo-
nylmethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester may
be prepared in the following manner: on carrying out the operation
according to the procedure of Example 1 starting with 0.886 g of
4-(3-methanesulfonylmethylphenyl)piperazine-1-carboxylic acid
tert-butyl ester, 0.765 g of
1-[bis-(4-chlorophenyl)methyl]azetidin-3-one and 1.72 cm.sup.3 of a
1.6 M solution of n-butyllithium in hexane, 1.37 g of
4-[3-({1-[bis-(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}
methanesulfonylmethyl)phenyl]piperazine-1-carboxylic acid
tert-butyl ester are obtained in the form of a beige powder.
[0746] 4-(3-Methanesulfonylmethylphenyl)piperazine-1-carboxylic
acid tert-butyl ester may be prepared in the following manner: on
carrying out the operation according to the procedure of Example 10
starting with 1.55 g of
4-(3--chloromethylphenyl)piperazine-1-carboxylic acid tert-butyl
ester and 0.766 g of sodium methanesulfinate, 0.9 g of
4-(3-methanesulfonylmethylphenyl)piperazine-1-carboxylic acid
tert-butyl ester is obtained in the form of a beige powder.
[0747] 4-(3-Chloromethylphenyl)piperazine-1-carboxylic acid
tert-butyl ester may be prepared in the following manner: by
reacting 16.4 g of 4-(3-hydroxymethylphenyl)piperazine-1-carboxylic
acid tert-butyl ester in 150 cm.sup.3 of dichloromethane, at a
temperature close to 20.degree. C., with 29 cm.sup.3 of
diisopropylethylamine and 8.7 cm.sup.3 of methanesulfonyl chloride,
15 g of 4-(3-chloromethylphenyl)piperazine-1-ca- rboxylic acid
tert-butyl ester are obtained in the form of a beige powder after
purification on a chromatographic column (silica 0.063-0.200 mm,
diameter 6 cm, height 45 cm, 100 cm.sup.3 fractions), eluting with
dichloromethane.
[0748] 4-(3-Hydroxymethylphenyl)piperazine-1-carboxylic acid
tert-butyl ester may be prepared in the following manner: by
reacting 15.8 g of tert-butyl esters of
4-(3-butoxycarbonylphenyl)piperazine-1-carboxylic and
4-(3-n-butyloxycarbonylphenyl)piperazine-1-carboxylic acids in
solution in 500 cm.sup.3 of anhydrous THF, at a temperature close
to -10C, with 102 cm.sup.3 of diisobutylaluminum hydride in
solution in toluene (20% by weight), 12.8 g of
4-(3-hydroxymethylphenyl)piperazine-1-- carboxylic acid tert-butyl
ester are obtained in the form of a beige oil.
[0749] The mixture of tert-butyl esters of
4-(3-ethoxycarbonylphenyl)piper- azine-1-carboxylic and
4-(3-n-butyloxycarbonylphenyl)piperazine-1-carboxyl- ic acids may
be prepared according to the method described in patent WO
9726250.
Example 156
[0750] On carrying out the operation according to Example 38
(method 2) starting with 0.3 g of
3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-
-[(3,5-difluorophenyl)(methylsulfonyl)methyl(RS)]azetidine and 105
mg of lithium hydroxide monohydrate in 10 cm.sup.3 of acetonitrile,
at a temperature close to 70.degree. C., 0.24 g of
1-[bis(4-methoxycarbonylphe-
nyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine
is obtained in the form of an orange-colored foam [.sup.1H NMR
spectrum (300 MHz, CDCl.sub.3, .quadrature. in ppm): 2.81 (s, 3H),
from 3.85 to 3.95 (mt, 2H), 3.89 (s, 6H), 4.37 (mt, 2H), 4.67 (s,
1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.99 (mt, 2H), 7.50 (d, J=8 Hz,
4H), 7.97 (d, J=8 Hz, 4H)].
Example 157
[0751] On carrying out the operation according to the procedure of
Example 40 starting with 4.45 g of
(3,5-difluorobenzyl)methylsulfone, 6.36 g of
1-[bis(4-methoxycarbonylphenyl)methyl]azetidin-3-one, 2.18
cm.sup.3
[0752] of acetyl chloride and 17 cm.sup.3 of a 1.6 M solution of
n-butyllithium in hexane, 10.8 g of
3-acetoxy-1-[bis(4-methoxycarbonylphe-
nyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methyl(RS)]azetidine
are obtained in the form of a pale yellow foam [.sup.1H NMR
spectrum
[0753] (400 MHz, (CD.sub.3).sub.2SO-d6, .quadrature. in ppm): 2.03
(s, 3H), 2.96 (s, 3H), from 3.25 to 3.40 (mt, 2H), 3.52 (broad d,
J=8 Hz, 1H), from 3.75 to 3.90 (mt, 1H), 3.82 (s, 3H), 3.83 (s,
3H), 4.72 (s, 1H), 5.36 (s, 1H), 7.27 (d, J=8 Hz, 2H), from 7.35 to
7.45 (mt, 2H), 7.43 (d, J=8 Hz, 2H), 7.54 (tt, J=9.5 and 2.5 Hz,
1H), 7.81 (d, J=8 Hz, 2H), 7.88 (d, J=8 Hz, 2H)].
[0754] 1-[bis(4-methoxycarbonylphenyl)methyl]azetidin-3-one may be
prepared in the same manner as
1-{(R*)-(4-chlorophenyl)[4-(methoxycarbony-
l)phenyl]methyl}azetidin-3-one (Example 110) from
1-[bis(4-methoxycarbonyl- phenyl)methyl] azetidin-3-ol.
[0755] 1-[bis(4-methoxycarbonylphenyl)methyl]azetidin-3-ol, may be
prepared in the same manner as
1-{(R*)-(4-chlorophenyl)[4-(methoxycarbony-
l)phenyl]methyl}azetidin-3-ol (Example 110) from
bis(4-methoxycarbonylphen- yl)methylamine.
[0756] Bis(4-methoxycarbonylphenyl)methylamine may be prepared in
the same manner as methyl
4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate (Example 87) from
4,4'-dimethoxycarbonylbenzophenone.
Example 158
[0757] On carrying out the operation according to the procedure of
Example 110 starting with 40 mg of
(RS)-1-{[4-(chloromethyl)phenyl](4-chloropheny-
l)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methyl)methylsulfonylmet-
hylene]azetidine, 0.25 cm.sup.3 of dichloromethane and 0.0196
cm.sup.3 of morpholine, 35.8 mg of
(RS)-4-[4-((4-chlorophenyl){3-[(3,5-difluorophenyl-
)methanesulfonylmethylene]azetidin-1-yl}methyl)benzyl]morpholine
are obtained in the form of a white foam [.sup.1H NMR spectrum (400
MHz, CDCl.sub.3, .quadrature. in ppm): 2.41 (mt, 4H), 2.80 (s, 3H),
3.42 (s, 2H), 3.69 (t, J=4.5 Hz, 4H), 3.84 (mt, 2H), 4.33 (mt, 2H),
4.50 (s, 1H), 6.83 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from
7.20 to 7.40 (mt, 8H)].
[0758]
(RS)-1-{[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-dif-
luorophenyl)(methylsulfonyl)methyl)methylsulfonylmethylene]azetidine
may be prepared in the following manner: on carrying out the
operation according to Example 87 starting with 415 mg of
(RS)-1-{(4-(chlorophenyl)-
[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)me-
thylene]azetidine, 5 cm.sup.3 of dichloromethane, 0.19 cm.sup.3 of
methanesulfonyl chloride and 0.53 cm.sup.3 of
diisopropylethylamine, 421.2 mg of (RS)-1-{[4-(chloromethyl)phenyl]
(4-chlorophenyl)methyl}-3-[(-
3,5-difluorophenyl)(methylsulfonyl)methyl)methylsulfonylmethylene]azetidin-
e are obtained in the form of a cream-colored foam.
Example 159
[0759] 25 mg of potassium carbonate and then 0.016 cm.sup.3 of
morpholine are successively added, at a temperature close to
20.degree. C., under an inert atmosphere of argon, to a solution of
33 mg of
1-benzhydryl-3-{[3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}azetidi-
ne in 2 cm.sup.3 of anhydrous acetonitrile. After stirring for 17
hours at a temperature close to 20.degree. C., the reaction medium
is diluted with 10 cm.sup.3 of ethyl acetate and 4 cm.sup.3 of
water. The separated organic phase is washed with 4 cm.sup.3 of a
saturated aqueous sodium chloride solution, dried over magnesium
sulfate, filtered on sintered glass and then concentrated to
dryness under reduced pressure (1 kPa) at a temperature close to
40.degree. C. The residue obtained is purified by depositing, in
solution in a minimum of dichloromethane, on chromatography on
silica gel deposited on a plate [(gel 0.5 mm thick, 2 plates of 20
.quadrature. 20 cm, eluent: dichloromethane-methanol (92.5-7.5 by
volume)]. The zone corresponding to the desired product adsorbed,
located with UV rays, is scraped and the silica recovered is washed
on sintered glass with a dichloromethane-methanol mixture (80-20 by
volume). The filtrates are combined and concentrated to dryness
under reduced pressure (1 kPa) at a temperature close to 40.degree.
C. 25.2 mg of
4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy-
}butyl)morpholine are obtained in the form of a pale yellow foam
[.sup.1H NMR spectrum (400 MHz, CDCl.sub.3, .quadrature. in ppm):
1.66 (mt, 2H), 1.81 (mt, 2H), 2.40 (t, J=7.5 Hz, 2H), 2.46 (mt,
4H), 2.77 (s, 3H), 3.72 (t, J=5 Hz, 4H), 3.84 (mt, 2H), 3.96 (t,
J=6.5 Hz, 2H), 4.36 (mt, 2H), 4.53 (s, 1H), 6.87 (dd, J=8 and 2 Hz,
1H), 6.93 (d, J=8 Hz, 1H), 6.96 (d, J=2 Hz, 1H), from 7.10 to 7.35
(mt, 7H), 7.42 (d, J=8 Hz, 4H)].
[0760]
1-Benzhydryl-3-{[3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}a-
zetidine may be prepared in the following manner: 0.586 cm.sup.3 of
1,4-dibromobutane and 255 mg of potassium carbonate are
successively added at a temperature close to 20.degree. C., under
an inert atmosphere of argon, to a solution of 500 mg of
1-benzhydryl-3-[(3-hydroxyphenyl)(me-
thylsulfonyl)methylene]azetidine in 10 cm.sup.3 of methylethyl
ketone. The reaction mixture is heated at the reflux temperature of
the solvent, under an inert atomosphere of argon, for 7 hours and
then left at a temperature close to 20.degree. C. for about 4 days.
The reaction mixtue is filtered on sintered glass covered with
celite. The solid residue is rinsed with ethyl acetate and then the
filtrate is concentrated to dryness under reduced pressure (10 kPa)
at a temperature close to 40.degree. C. The brown oil obtained is
purified by chromatography at atmospheric pressure on 40 g of
silica (0.063-0.200 mm) contained in a column 3 cm in diameter,
eluting with a methanol-dichloromethane mixture (0.5-99.5 by
volume). The fractions (10 cm.sup.3) containing only the desired
product are combined and concentrated to dryness under reduced
pressure (0.27 kPa) at 40.degree. C. for 2 hours, 408.4 mg of
1-benzhydryl-3-{[3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}azetidi-
ne are thus obtained in the form of a brown foam.
Example 160
[0761] 0.110 cm.sup.3 of morpholine and then 35 mg of potassium
carbonate are successively added, at a temperature close to
20.degree. C., to a solution of 45 mg of
1-benzhydryl-3-{[3-(4-bromopropyloxy)phenyl]methanes-
ulfonylmethylene}azetidine in 3.5 cm.sup.3 of anhydrous
acetonitrile. After stirring for 20 hours at a temperature close to
20.degree. C., the reaction medium is diluted with 40 cm.sup.3 of
ethyl acetate and 10 cm.sup.3 of water. The separated organic phase
is washed with 10 cm.sup.3 of water, and then twice 10 cm.sup.3 of
a saturated aqueous sodium chloride solution, dried over magnesium
sulfate, filtered on sintered glass and then concentrated to
dryness under reduced pressure (9 kPa) at a temperature close to
40.degree. C. The yellow lacquer obtained is purified by
depositing, in solution in a minimum of dichloromethane, on
chromatography on silica gel deposited on a plate [(gel 0.5 mm
thick, 2 plates of 20 .quadrature. 20 cm, eluent:
dichloromethanemethanol (97.5-2.5 by volume)]. The zone
corresponding to the desired product adsorbed, located with UV
rays, is scraped and the silica recovered is washed on sintered
glass with a dichloromethane-methanol mixture (85-15 by volume).
The filtrates are combined and concentrated to dryness under
reduced pressure (1 kPa) at a temperature close to 40.degree. C. 33
mg of
4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}pr-
opyl)morpholine are thus obtained in the form of a white foam
[.sup.1H NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d6, .quadrature.
in ppm): 1.87 (mt, 2H), 2.37 (mt, 4H), 2.42 (t, J=7.5 Hz, 2H), 2.94
(s, 3H), 3.58 (mt, 4H), 3.80 (mt, 2H), 4.02 (t, J=7 Hz, 2H), 4.20
(mt, 2H), 4.74 (s, 1H), 6.97 (mt, 3H), 7.22 (t, J=7.5 Hz, 2H), from
7.25 to 7.40 (mt, 1H), 7.32 (t, J=7.5 Hz, 4H), 7.48 (d, J=7.5 Hz,
4H)].
[0762]
1-Benzhydryl-3-{[3-(4-bromopropyloxy)phenyl]methanesulfonylmethylen-
e}azetidine may be prepared in the following manner: 0.5 cm of
1,3-dibromopropane and 255 mg of potassium carbonate are
successively added at a temperature close to 20.degree. C., under
an inert atmosphere of argon, to a solution of 500 mg of
1-benzhydryl-3-[(3-hydroxyphenyl)(me-
thylsulfonyl)methylene]azetidine in 10 cm.sup.3 of methyl ethyl
ketone. The reaction mixture is heated at the reflux temperature of
the solvent, under an inert atmosphere of argon, for 7 hours, and
then left at a temperature close to 20.degree. C. for about 4 days.
The reaction mixture is filtered on sintered glass covered with
celite. The solid residue is rinsed with ethyl acetate and then the
filtrate is concentrated to dryness under reduced pressure (10 kPa)
at a temperature close to 40.degree. C. The brown oil obtained is
purified by chromatography at atmospheric pressure on 40 g of
silica (0.063-0.200 mm) contained in a column 3 cm in diameter,
eluting with a methanol-dichloromethane mixture (0.5-99.5 by
volume). The fractions (10 cm.sup.3) containing only the desired
product are combined and concentrated to dryness under reduced
pressure (0.27 kPa) at 40.degree. C. for 2 hours. 511.1 mg of
benzhydryl-3-{[3-(4-bromopropyloxy)-phenyl]methanesulfonylmethylene}azeti-
dine are thus obtained in the form of a brown foam.
[0763] The medicaments according to the invention consists of a
compound of formula (I) or an isomer or a salt of such a compound,
in the pure state or in the form of a composition in which it is
combined with any other pharmaceutically compatible product which
may be inert or physiologically active. The medicaments according
to the invention may be used orally, parenterally, rectally or
topically.
[0764] As solid compositions for oral administration, tablets,
pills, powders (gelatine capsules, sachets) or granules may be
used. In these compositions, the active ingredient according to the
invention is mixed with one or more inert diluents, such as starch,
cellulose, sucrose, lactose or silica, under an argon stream. These
compositions may also comprise substances other than diluents, for
example one or more lubricants such as magnesium stearate or talc,
a coloring, a coating (sugar-coated tablet) or a glaze.
[0765] As liquid compositions for oral administration, there may be
used pharmaceutically acceptable solutions, suspensions, emulsions,
syrups and elixirs containing inert diluents such as water,
ethanol, glycerol, vegetable oils or paraffin oil. These
compositions may comprise substances other than diluents, for
example wetting, sweetening, thickening, flavoring or stabilizing
products.
[0766] Sterile compositions for parenteral administration may be
preferably solutions which are aqueous or nonaqueous, suspensions
or emulsions. As solvent or vehicle, there may be used water,
propylene glycol, polyethylene glycol, vegetable oils, in
particular olive oil, injectable organic esters, for example ethyl
oleate or other suitable organic solvents. These compositions may
also contain adjuvants, in particular wetting, isotonizing,
emulsifying, dispersing and stabilizing agents. Sterilization may
be carried out in several ways, for example by aseptisizing
filtration, by incorporating sterilizing agents into the
composition, by irradiation or by heating. They may also be
prepared in the form of sterile solid compositions which may be
dissolved at the time of use in sterile water or any other
injectable sterile medium.
[0767] Compositions for rectal administration are suppositories or
rectal capsules which contain, in addition to the active product,
excipients such as cocoa butter, semisynthetic glycerides or
polyethylene glycols.
[0768] Compositions for topical administration may be, for example,
creams, lotions, collyria, collutoria, nasal drops or aerosols.
[0769] In human therapy, the compounds according to the invention
are particularly useful for the treatment and/or prevention of
psychoses including schizophrenia, anxiety disorders, depression,
epilepsy, neurodegeneration, cerebellar and spinocerebellar
disorders, cognitive disorders, cranial trauma, panic attacks,
peripheral neuropathies, glaucomas, migraine, Parkinson's disease,
Alzheimer's disease, Huntington's chorea, Raynaud's syndrome,
tremor, obsessive-compulsive disorder, senile dementia, thymic
disorders, Tourette's syndrome, tardive dyskinesia, bipolar
disorders, cancers, movement disorders induced by medicaments,
dystonia, endotoxemic shocks, hemorrhagic shocks, hypotension,
insomnia, immunological diseases, multiple sclerosis, vomiting,
asthma, appetite disorders (bulimia, anorexia), obesity, memory
disorders, intestinal transit disorders, in weaning from chronic
treatments and alcohol or drug abuse (opiods, barbiturates,
cannabis, cocaine, amphetamine, phencyclide, hallucinogens,
benzodiazepines for example), as analgesics or potentiators of the
analgesic activity of the narcotic and nonnarcotic drugs as
antibacterial, antiviral and antiparasitic agents.
[0770] The doses depend on the desired effect, the duration of the
treatment and the route of administration used; they are generally
between 5 mg and 1000 mg per day orally for an adult with unit
doses ranging from 1 mg to 250 mg of active substance.
[0771] In general, the doctor will determine the appropriate dosage
depending on the age, weight and any other factors specific to the
subject to be treated.
[0772] The following examples illustrate the compositions according
to the invention:
EXAMPLE A
[0773] Gelatin capsules containing a dose of 50 mg of active
product and having the following composition are prepared according
to the usual technique:
1 Compound of formula (I) 50 mg Cellulose 18 mg Lactose 55 mg
Colloidal silica 1 mg Sodium carboxymethylstarch 10 mg Talc 10 mg
Magnesium stearate 1 mg
EXAMPLE B
[0774] Tablets containing a dose of 50 mg of active product and
having the following composition are prepared according to the
usual technique:
2 Compound of formula (I) 50 mg Lactose 104 mg Cellulose 40 mg
Polyvidone 10 mg Sodium carboxymethylstarch 22 mg Talc 10 mg
Magnesium stearate 2 mg Colloidal silica 2 mg Mixture of
hydroxymethylcellulose, glycerin, titanium oxide (72-3.5-24.5) qs 1
finished film-coated tablet containing 245 mg
EXAMPLE C
[0775] An injectable solution containing 10 mg of active product
and having the following composition is prepared:
3 Compound of formula (I) 10 mg Benzoic acid 80 mg Benzyl alcohol
0.06 ml Sodium benzoate 80 mg Ethanol, 95% 0.4 ml Sodium hydroxide
24 mg Propylene glycol 1.6 ml Water qs 4 ml
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