U.S. patent application number 10/159842 was filed with the patent office on 2002-12-12 for use of 2-aminothiazoline derivatives as inhibitors of inducible no-synthase.
Invention is credited to Bacque, Eric, Bigot, Antony, Carry, Jean-Christophe, Damour, Dominique, Guyon, Claude, Mignani, Serge, Tabart, Michel.
Application Number | 20020187987 10/159842 |
Document ID | / |
Family ID | 26212457 |
Filed Date | 2002-12-12 |
United States Patent
Application |
20020187987 |
Kind Code |
A1 |
Carry, Jean-Christophe ; et
al. |
December 12, 2002 |
Use of 2-aminothiazoline derivatives as inhibitors of inducible
NO-synthase
Abstract
The present invention relates to the use of 2-aminothiazoline
derivatives of formula I: 1 in which either R.sub.1 is a hydrogen
atom or an alkyl radical and R.sub.2 is an alkyl, -alk-NH.sub.2,
--CH.sub.2--R.sub.3, --CH.sub.2--S--R.sub.4 or phenyl radical
substituted with a nitro or --NH--C(.dbd.NH)CH.sub.3 radical, or
R.sub.1 is an alkyl radical and R.sub.2 is a hydrogen atom, R.sub.3
is a (3-6C) cycloalkyl, pyridyl, pyridyl N-oxide, thienyl,
thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or a
phenyl radical substituted with a nitro, hydroxy or carboxyl
radical, R.sub.4 represents a pyridyl or pyridyl N-oxide radical,
alk represents an alkylene radical, or pharmaceutically acceptable
salts thereof, as inhibitors of inducible NO-synthase.
Inventors: |
Carry, Jean-Christophe;
(Saint Maur Des Fosses, FR) ; Damour, Dominique;
(Orly, FR) ; Guyon, Claude; (Saint Maur Des
Fosses, FR) ; Mignani, Serge; (Chatenay-Malabry,
FR) ; Bigot, Antony; (Massy, FR) ; Bacque,
Eric; (Morsang Sur Orge, FR) ; Tabart, Michel;
(La Norville, FR) |
Correspondence
Address: |
AVENTIS PHARMACEUTICALS, INC.
PATENTS DEPARTMENT
ROUTE 202-206, P.O. BOX 6800
BRIDGEWATER
NJ
08807-0800
US
|
Family ID: |
26212457 |
Appl. No.: |
10/159842 |
Filed: |
May 31, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10159842 |
May 31, 2002 |
|
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09878814 |
Jun 8, 2001 |
|
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60232038 |
Sep 12, 2000 |
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Current U.S.
Class: |
514/255.05 ;
514/342; 514/370 |
Current CPC
Class: |
C07D 277/18 20130101;
A61K 31/4439 20130101; A61K 31/426 20130101; C07D 417/06
20130101 |
Class at
Publication: |
514/255.05 ;
514/342; 514/370 |
International
Class: |
A61K 031/497; A61K
031/4439 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 9, 2000 |
FR |
0007397 |
Claims
What is claimed is:
1. A method of treating disease conditions associated with an
abnormal production of nitric oxide (NO) by induction of inducible
NO-synthase (NOS-2) comprising administering to a patient in need
of said treatment a therapeutically effective amount of a compound
of formula (I): 10wherein R.sub.1 is hydrogen or C.sub.1-6alkyl;
and R.sub.2 is C.sub.1-6alkyl, -alk-NH.sub.2, --CH.sub.2--R.sub.3,
--CH.sub.2--S--R.sub.4 or phenyl substituted with nitro or
--NH--C(.dbd.NH)CH.sub.3; and wherein R.sub.3 is
C.sub.3-6cycloalkyl, pyridyl, pyridyl N-oxide, thienyl, thiazolyl,
imidazolyl, pyrazinyl, triazolyl or phenyl or phenyl substituted
with nitro, hydroxy or carboxyl; R.sub.4 is pyridyl or pyridyl
N-oxide; and alk is C.sub.1-6alkylene; or a racemic mixture, an
enantiomer, a diastereomer or a mixture thereof, or a tautomer
thereof or a pharmaceutically acceptable salt thereof, optionally
in combination with a pharmaceutically acceptable carrier.
2. The method according to claim 1, wherein, in formula (I):
R.sub.1 is hydrogen or C.sub.1-6alkyl; and R.sub.2 is -alk-NH.sub.2
or phenyl substituted with an --NH--C(.dbd.NH)CH.sub.3,
--CH.sub.2--R.sub.3 or --CH.sub.2--S--R.sub.4; and wherein R.sub.3
is pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or
phenyl or phenyl substituted with nitro, carboxyl; and R.sub.4 is
pyridyl.
3. The method according to claim 2, wherein R.sub.2 is
--CH.sub.2--R.sub.3; and wherein R.sub.3 is 3- or 4-pyridyl, 2- or
3-thienyl, 4- or 5-thiazolyl, 1-imidazolyl, 1-triazolyl,
2-pyrazinyl or phenyl or phenyl substituted in position -3 with a
nitro or carboxyl.
4. The method according to claim 1, wherein, in formula (I),
R.sub.2 is --CH.sub.2--R.sub.3 or --CH.sub.2--S--R.sub.4; wherein
R.sub.3 is 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-thiazolyl,
1-imidazolyl, 1-triazolyl, 2-pyrazinyl or phenyl or phenyl
substituted in position -3 with a nitro or carboxyl; and R.sub.4 is
4-pyridyl.
5. The method according to claim 1, wherein the compound of formula
(I) is chosen from the following compounds:
4-(3-pyridylmethyl)-4,5-dihydro-1,3-- thiazol-2-ylamine,
4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl]-(1-iminoethyl)amine,
4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(3-carboxybenzyl)-4,5-dihyd- ro-1,3-thiazol-2-ylamine,
4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylami- ne,
4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine,
4-cyclohexylmethyl-4,5-dihy- dro-1,3-thiazol-2-ylamine,
4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-yla- mine,
4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-hydroxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(3-aminopropyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine N-oxide, or a
racemic mixture, an enantiomer, a diastereoisomer or a tautomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof.
6. The method according to claim 1, wherein the compound of formula
(I) is chosen from the following compounds:
(+)-(4R)-4-(3-pyridylmethyl)-4,5-dih- ydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thi- azol-2-ylamine,
(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-yl- amine,
(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(-) -(4R) -4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine,
(+)-(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4R)-4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R,5R)-5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamin-
e,
(+)-(4R,5R)-5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylami-
ne, (+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(3-aminopropyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-hydroxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine N-oxide,
(+)-4-(1-triazolylmethyl)-4,5-dihiydro-1,3-thiazol-2-ylamine, or a
tautomer thereof, or a pharmaceutically acceptable salt
thereof.
7. The method according to claim 2, wherein the compound of formula
(I) is chosen from the following compounds:
4-(3-pyridylmethyl)-4,5-dihydro-1,3-- thiazol-2-ylamine,
4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl]-(1-iminoethyl)amine,
4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(3-carboxybenzyl)-4,5-dihyd- ro-1,3-thiazol-2-ylamine,
4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylami- ne,
4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, or
a racemic mixture, an enantiomer, a diastereoisomer or a tautomer
thereof, or a pharmaceutically acceptable salt thereof.
8. The method according to claim 2, wherein the compound of formula
(I) is chosen from the following compounds:
(+)-(4R)-4-(3-pyridylmethyl)-4,5-dih- ydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thi- azol-2-ylamine,
(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-yl- amine,
(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl]-(1-iminoethyl)amine,
(+)-(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4S,5R)-4-benzyl-5-methyl-4,5--dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R,5R)-5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamin-
e,
(+)-(4R,5R)-5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylami-
ne, (+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, or a
tautomer thereof, or a pharmaceutically acceptable salts
thereof.
9. The method according to claim 1 wherein said disease condition
is caused by degenerative pathologies of the nervous system.
10. The method according to claim 1 wherein said disease condition
may be any one of the following: multiple sclerosis, cerebral,
focal or global ischemia, cerebral or spinal trauma, Parkinson's
disease, Huntington's disease, Alzheimer's disease, amyotrophic
lateral sclerosis, migraine, depression, schizophrenia, anxiety and
epilepsy.
11. The method according to claim 1 wherein said disease condition
may be any one of the following: diabetes, atherosclerosis,
myocarditis, arthritis, arthrosis, asthma, irritable bowel
syndrome, Crohn's disease, peritonitis, gastro-esophageal reflux,
uveitis, Guillain-Barr syndrome, glomerulonephritis, lupus
erythematosus and psoriasis.
12. The method according to claim 1 wherein said disease condition
is a growth of tumor selected from the group consisting of
epitheliomas, adenocarcinoma and sarcoma.
13. A method of treating disease conditions of the central nervous
system in a patient comprising administering to a patient in need
of said treatment a therapeutically effective amount of a compound
of formula (I): 11wherein R.sub.1 is hydrogen or C.sub.1-6alkyl;
and R.sub.2 is C.sub.1-6alkyl, -alk-NH.sub.2, --CH.sub.2--R.sub.3,
--CH.sub.2--S--R.sub.4 or phenyl substituted with nitro or
--NH--C(.dbd.NH)CH.sub.3; and wherein R.sub.3 is
C.sub.3-6cycloalkyl, pyridyl, pyridyl N-oxide, thienyl, thiazolyl,
imidazolyl, pyrazinyl, triazolyl or phenyl or phenyl substituted
with nitro, hydroxy or carboxyl; R.sub.4 is pyridyl or pyridyl
N-oxide; and alk is C.sub.1-6alkylene; or a racemic mixture, an
enantiomer, a diastereomer or a mixture thereof, or a tautomer
thereof or a pharmaceutically acceptable salt thereof, optionally
in combination with a pharmaceutically acceptable carrier.
14. The method according to claim 13, wherein, in formula (I):
R.sub.1 is hydrogen or C.sub.1-6alkyl; and R.sub.2 is -alk-NH.sub.2
or phenyl substituted with an --NH--C(.dbd.NH)CH.sub.3,
--CH.sub.2--R.sub.3 or --CH.sub.2--S--R.sub.4; and wherein R.sub.3
is pyridyl, thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or
phenyl or phenyl substituted with nitro, carboxyl; and R.sub.4 is
pyridyl.
15. The method according to claim 14, wherein R.sub.2 is
--CH.sub.2--R.sub.3; and wherein R.sub.3 is 3- or 4-pyridyl, 2- or
3-thienyl, 4- or 5-thiazolyl, 1-imidazolyl, 1-triazolyl,
2-pyrazinyl or phenyl or phenyl substituted in position -3 with a
nitro or carboxyl.
16. The method according to claim 13, wherein, in formula (I),
R.sub.2 is --CH.sub.2--R.sub.3 or --CH.sub.2--S--R.sub.4; wherein
R.sub.3 is 3- or 4-pyridyl, 2- or 3-thienyl, 4- or 5-thiazolyl,
1-imidazolyl, 1-triazolyl, 2-pyrazinyl or phenyl or phenyl
substituted in position -3 with a nitro or carboxyl; and R.sub.4 is
4-pyridyl.
17. The method according to claim 13, wherein the compound of
formula (I) is chosen from the following compounds:
4-(3-pyridylmethyl)-4,5-dihydro-1- ,3-thiazol-2-ylamine,
4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl]-(1-iminoethyl)amine,
4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(3-carboxybenzyl)-4,5-dihyd- ro-1,3-thiazol-2-ylamine,
4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylami- ne,
4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine,
4-cyclohexylmethyl-4,5-dihy- dro-1,3-thiazol-2-ylamine,
4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-yla- mine,
4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-hydroxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(3-aminopropyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine N-oxide, or a
racemic mixture, an enantiomer, a diastereoisomer or a tautomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof.
18. The method according to claim 13, wherein the compound of
formula (I) is chosen from the following compounds:
(+)-(4R)-4-(3-pyridylmethyl)-4,5-- dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-- thiazol-2-ylamine,
(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2- -ylamine,
(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine,
(+)-(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4R)-4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R,5R)-5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamin-
e,
(+)-(4R,5R)-5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylami-
ne, (+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(3-aminopropyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-hydroxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine N-oxide,
(+)-4-(1-triazolylmethyl)-4,5-dihiydro-1,3-thiazol-2-ylamine, or a
tautomer thereof, or a pharmaceutically acceptable salt
thereof.
19. The method according to claim 14, wherein the compound of
formula (I) is chosen from the following compounds:
4-(3-pyridylmethyl)-4,5-dihydro-1- ,3-thiazol-2-ylamine,
4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl]-(1-iminoethyl)amine,
4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(3-carboxybenzyl)-4,5-dihyd- ro-1,3-thiazol-2-ylamine,
4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylami- ne,
4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, or
a racemic mixture, an enantiomer, a diastereoisomer or a tautomer
thereof, or a pharmaceutically acceptable salt thereof.
20. The method according to claim 14, wherein the compound of
formula (I) is chosen from the following compounds:
(+)-(4R)-4-(3-pyridylmethyl)-4,5-- dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-- thiazol-2-ylamine,
(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2- -ylamine,
(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl]-(1-iminoethyl)amine,
(+)-(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R,5R)-5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamin-
e,
(+)-(4R,5R)-5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylami-
ne, (+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(+)-4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, or a
tautomer thereof, or a pharmaceutically acceptable salts
thereof.
21. The method according to claim 13 wherein said disease condition
may be any one of the following: multiple sclerosis, cerebral,
focal or global ischemia, cerebral or spinal trauma, Parkinson's
disease, Huntington's disease, Alzheimer's disease, amyotrophic
lateral sclerosis, migraine, depression, schizophrenia, anxiety and
epilepsy.
22. A method of treating disease conditions associated with an
abnormal production of nitric oxide (NO) by induction of inducible
NO-synthase (NOS-2) comprising administering to a patient in need
of said treatment a therapeutically effective amount of a compound
of formula (I): 12wherein R.sub.1 is C.sub.1-6alkyl and R.sub.2 is
hydrogen.
23. The method according to claim 22, wherein said compound is
5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine or a racemic mixture, an
enantiomer, a diastereoisomer or a tautomer thereof, or a
pharmaceutically acceptable salt thereof.
24. The method according to claim 22, wherein said compound is
(+)-(5S)-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine or a tautomer
thereof, or a pharmaceutically acceptable salt thereof.
25. The method according to claim 22 wherein said disease condition
may be any one of the following: multiple sclerosis, cerebral,
focal or global ischemia, cerebral or spinal trauma, Parkinson's
disease, Huntington's disease, Alzheimer's disease, amyotrophic
lateral sclerosis, migraine, depression, schizophrenia, anxiety and
epilepsy.
Description
[0001] This application is a division of U.S. application Ser. No.
09/878,814, filed Jun. 8, 2001, now allowed, which claims the
benefit of U.S. Provisional Application No. 60/232,038, filed Sep.
12, 2000, which claims the benefit of priority of French Patent
Application No. 00/07,397, filed Jun. 9, 2000.
[0002] The present invention relates to the use of
2-aminothiazoline derivatives of formula (I): 2
[0003] or pharmaceutically acceptable salts thereof, as inhibitors
of inducible NO-synthase.
[0004] The subject of the invention is the use of 2-aminothiazoline
derivatives of formula (I) and pharmaceutically acceptable salts
thereof, for the preparation of pharmaceutical compositions
intended for preventing and treating diseases in which an abnormal
production of nitric oxide (NO) by induction of inducible
NO-synthase (NOS-2 or iNOS) is involved, the pharmaceutical
compositions containing the novel 2-aminothiazoline derivatives and
the pharmaceutically acceptable salts thereof, and the novel
2-aminothiazoline derivatives and the pharmaceutically acceptable
salts thereof.
[0005] Nitric oxide (NO) is a diffusable radical involved in many
physiological and pathological processes. It is synthesized by
oxidation of L-arginine, this reaction being catalyzed by a family
of enzymes known as nitric oxide synthases or NO-synthases (NOSs),
which is referenced in the international enzyme nomenclature system
under the number E.C. 1.14.13.39.
[0006] Three NOS isoforms, two of which are constitutive and one
inducible, are known:
[0007] a neuronal NOS (NOS-1 or nNOS) was originally isolated and
cloned from nerve tissue in which it is a constitutive enzyme.
NOS-1 produces NO in response to various physiological stimuli such
as the activation of membrane receptors according to a mechanism
dependent on calcium and on calmodulin;
[0008] an inducible NOS (NOS-2 or iNOS) can be induced in response
to immunological stimuli such as, for example, cytokines or
bacterial antigens in various cells such as, for example,
macrophages, endothelial cells, hepatocytes, glial cells, as well
as many other types of cell. The activity of this isoform is not
regulated by calcium. Consequently, once induced, it produces large
amounts of NO over prolonged periods.
[0009] an endothelial NOS (NOS-3 or eNOS) is constitutive and
calcium/calmodulin-dependent. It was originally identified in
vascular endothelial cells, in which it generates NO in response to
physiological stimuli such as the activation of membrane
receptors.
[0010] The NO produced by the neuronal and endothelial constitutive
isoforms (NOS-1 and NOS-3) is generally involved in intercellular
signalling functions. For example, the endothelial cells which line
the inner wall of the blood vessels induce the relaxation of the
underlying smooth muscle cells via the production of NO. It thus
contributes towards regulating the arterial pressure.
[0011] The NO produced in large amount by the inducible isoform
NOS-2 is, inter alia, involved in pathological phenomena associated
with acute and chronic inflammatory processes in a large variety of
tissues and organs.
[0012] An excessive production of NO by induction of NOS-2 thus
plays a part in degenerative pathologies of the nervous system such
as, for example, multiple sclerosis, cerebral, focal or global
ischemia, cerebral or spinal trauma, Parkinson's disease,
Huntington's disease, Alzheimer's disease, amiotrophic lateral
sclerosis, migraine, depression, schizophrenia, anxiety and
epilepsy. Similarly, aside from the central nervous system, the
induction of NOS-2 is involved in numerous pathologies with
inflammatory components, such as, for example, diabetes,
atherosclerosis, myocarditis, arthritis, arthrosis, asthma,
irritable bowel syndrome, Crohn's disease, peritonitis,
gastro-esophageal reflux, uveitis, Guillain-Barr syndrome,
glomerulonephritis, lupus erythematosus and psoriasis. NOS-2 has
also been implicated in the growth of certain forms of tumors such
as, for example, epitheliomas, adenocarcinoma or sarcoma, and in
infections with Gram-positive or Gram-negative intracellular or
extracellular bacteria.
[0013] In all the situations in which an overproduction of NO is
deleterious, it thus appears to be desirable to reduce the
production of NO by administering substances capable of inhibiting
NOS-2. However, given the important physiological roles played by
the constitutive isoform NOS-3, in particular in regulating
arterial pressure, it is of fundamental importance that the
inhibition of the isoform NOS-2 should have the least possible
effect on the isoform NOS-3. The reason for this is that it is
known that the administration of unselective inhibitors of the NOS
isoforms leads to vasoconstriction and an increase in arterial
pressure (Moncada, S., Palmer, R. M. J. and Higgs, E. A.,
Biosynthesis of nitric oxide from L-arginine: a pathway for the
regulation of cell function and communication, Biochem. Pharmacol.,
1989, 38: 1709-1715). These effects on the cardiovascular system
are deleterious since they reduce the supply of nutrients to the
tissues. Consequently, the present invention relates to compounds
whose inhibitory activity with respect to NOS-2 is significantly
higher than their inhibitory activity with respect to NOS-3.
[0014] Thiazoline-based NOS inhibitors are described in particular
in patent applications WO 94/12165, WO 95/11231 and WO
96/14842.
[0015] The present invention relates to the use of
2-aminothiazoline derivatives of formula (I) in which:
[0016] either R.sub.1 is a hydrogen atom or an alkyl radical and
R.sub.2 is an alkyl, -alk-NH.sub.2, --CH.sub.2--R.sub.3,
--CH.sub.2--S--R.sub.4 or phenyl radical substituted with a nitro
or --NH--C(.dbd.NH)CH.sub.3 radical,
[0017] or R.sub.1 is an alkyl radical and R.sub.2 is a hydrogen
atom, R.sub.3 is a (3-6C) cycloalkyl, pyridyl, pyridyl N-oxide,
thienyl, thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl
radical or a phenyl radical substituted with a nitro or carboxyl
radical,
[0018] R.sub.4 represents a pyridyl or pyridyl N-oxide radical, alk
represents an alkylene radical
[0019] for the preparation of medicinal products that are useful
for preventing or treating diseases in which an abnormal production
of nitric oxide (NO) by induction of inducible NO-synthase (NOS-2
or iNOS) is involved.
[0020] In the above definitions and in those which follow, the
alkyl and alkylene radicals contain 1 to 6 carbon atoms in a
straight or branched chain.
[0021] The compounds of formula (I) contain one or more asymmetric
carbons and can thus be in racemic form or in the form of
enantiomers and diastereoisomers; these also form part of the
invention, along with mixtures thereof.
[0022] Moreover, the compounds of formula (I) can be in the
tautomeric form (Ia): 3
[0023] These tautomers also form part of the invention.
[0024] Among the compounds of formula (I) that are useful according
to the invention, mention may be made of the following
compounds:
[0025] 4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0026] 4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0027] 4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0028] 4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0029] 4-(2-thienylmethyl)-4,5-dihyro-1,3-thiazol-2-ylamine
[0030]
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine
[0031] 4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0032] 4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0033] 4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0034] 4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0035] 5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0036] 4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0037] 4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0038] 4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0039]
5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0040]
5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0041] 4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0042] 4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0043] 4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0044] 4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0045] 4-(4-hydroxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0046]
4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0047] 4-(3-aminopropyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0048] 4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0049] 4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
N-oxide
[0050] the racemic mixtures, enantiomers, diastereoisomers and
tautomers thereof, as well as the pharmaceutically acceptable salts
thereof, and most particularly the following compounds:
[0051]
(+)-(4R)-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0052]
(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0053]
(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0054]
(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0055]
(-)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0056]
(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0057]
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine
[0058] (+)-(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0059]
(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0060]
(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0061]
(-)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0062]
(-)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0063]
(-)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0064]
(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0065] (-)-(4R)-4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0066] (+)-(5S)-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0067]
(-)-(4S)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0068]
(+)-(4R)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0069] 4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0070]
(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0071]
(+)-(4R,5R)-5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2--
ylamine
[0072]
(+)-(4R,5R)-5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-y-
lamine
[0073]
(+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0074]
(-)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0075]
(+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0076]
(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0077]
(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0078]
(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0079]
(+)-(4R)-4-(3-aminopropyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0080]
(+)-(4R)-4-(4-hydroxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0081]
(+)-(4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
N-oxide
[0082]
(+)-4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0083] the tautomers thereof, as well as the pharmaceutically
acceptable salts thereof.
[0084] The compounds which are particularly preferred are the
useful compounds of formula (I) according to the invention for
which R.sub.1 is a hydrogen atom or an alkyl radical and R.sub.2 is
an -alk-NH.sub.2 radical or a phenyl radical substituted with an
--NH--C(.dbd.NH)CH.sub.3, --CH.sub.2--R.sub.3 or
--CH.sub.2--S--R.sub.4 radical and R.sub.3 is a pyridyl, thienyl,
thiazolyl, imidazolyl, pyrazinyl, triazolyl or phenyl radical or
phenyl radical substituted with a nitro or carboxyl radical,
R.sub.4 is a pyridyl radical.
[0085] In particular, when R.sub.2 is a --CH.sub.2--R.sub.3 or
--CH.sub.2--S--R.sub.4 chain, R.sub.3 is a 3- or 4-pyridyl, 2- or
3-thienyl, 4- or 5-thiazolyl, 1-imidazolyl, 1-triazolyl,
2-pyrazinyl or phenyl radical or a phenyl radical substituted in
position-3 with a nitro or carboxyl radical and R.sub.4 is a
4-pyridyl radical.
[0086] Among the compounds which are useful according to the
invention and particularly preferred, mention may be made of the
following compounds:
[0087] 4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0088] 4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0089] 4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0090] 4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0091] 4-(2-thienylmethyl)-4,5-dihyro-1,3-thiazol-2-ylamine
[0092]
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine
[0093] 4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0094] 4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0095] 4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0096] 4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0097]
5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0098]
5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0099] 4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0100] 4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0101] 4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0102] 4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0103]
4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0104] 4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0105] the racemic mixtures, enantiomers, diastereoisomers and
tautomers thereof, as well as the pharmaceutically acceptable salts
thereof, and in particular the following compounds:
[0106]
(+)-(4R)-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0107]
(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0108]
(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0109]
(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0110]
(-)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0111]
(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0112]
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine
[0113] (+)-(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0114]
(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0115]
(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0116]
(-)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0117]
(-)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0118]
(-)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0119]
(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0120]
(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0121]
(+)-(4R,5R)-5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2--
ylamine
[0122]
(+)-(4R,5R)-5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-y-
lamine
[0123]
(+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0124]
(-)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0125]
(+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0126]
(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0127]
(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0128]
(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0129]
(+)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0130]
(+)-4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0131] the tautomers thereof, as well as the pharmaceutically
acceptable salts thereof.
[0132] The compounds of formula (I) for which R.sub.1 is methyl or
hexyl and R.sub.2 is hydrogen or else R.sub.1 and R.sub.2 are
methyl are known as chemical products (J. Org. Chem., 27, 1049
(1962); J. Org. Chem., 37, 4401 (1972); Beilstein Registry Numbers
6114855, 6114856, 6117694, 6117695).
[0133] Moreover, certain compounds of formula (I) are known as
radioprotective agents. These are the racemic compounds for
which
[0134] R.sub.1 is a methyl radical and R.sub.2 is a hydrogen atom
(Chem. Abst., 1980, 92, 209060 and 209061),
[0135] R.sub.1 is hydrogen and R.sub.2 is methyl (Chem. Abst.,
1997, 87, 193910),
[0136] R.sub.1 is hydrogen and R.sub.2 is ethyl (Khim. Geterotsikl.
Soedin, 1987, 11, 1572),
[0137] R.sub.1 is hydrogen and R.sub.2 is n-propyl (Radiobiologiya,
1979, 19 (5), 671).
[0138] The other compounds of formula (I) are novel and, as such,
they form part of the invention, as do the racemic mixtures,
enantiomers, diastereoisomers and tautomers thereof and the
pharmaceutically acceptable salts thereof.
[0139] These are the compounds for which either R.sub.1 is a
hydrogen atom or an alkyl radical and R.sub.2 is an alkyl,
-alk-NH.sub.2, --CH.sub.2--R.sub.3 or --CH.sub.2--S--R.sub.4
radical or a phenyl radical substituted with a nitro or
--NH--C(.dbd.NH)CH.sub.3 radical,
[0140] or R.sub.1 is an alkyl radical and R.sub.2 is a hydrogen
atom, R.sub.3 is a cycloalkyl (3-6C), pyridyl, thienyl, thiazolyl,
imidazolyl, pyrazinyl, triazolyl or phenyl radical or a phenyl
radical substituted with a nitro, hydroxyl or carboxyl radical,
[0141] R.sub.4 represents a pyridyl radical,
[0142] alk represents an alkylene radical,
[0143] the racemic mixtures, enantiomers and diastereoisomers
thereof and mixtures thereof, the tautomers thereof and the
pharmaceutically acceptable salts thereof, with the exception of
the compounds for which R.sub.1 is hexyl or methyl and R.sub.2 is
hydrogen or else R.sub.1 and R.sub.2 are methyl, and the racemic
mixtures of the compounds for which R.sub.1 is hydrogen and R.sub.2
is methyl, ethyl or n-propyl.
[0144] The compounds of formula (I) that are particularly preferred
are those for which R.sub.1 is a hydrogen atom or an alkyl radical
and R.sub.2 is an -alk-NH.sub.2 radical, a phenyl radical
substituted with an --NH--C(.dbd.NH)CH.sub.3 radical, a radical
--CH.sub.2--R.sub.3 for which R.sub.3 is a pyridyl, thienyl,
thiazolyl, imidazolyl, triazolyl, pyrazinyl or phenyl radical or a
phenyl radical substituted with a nitro or carboxyl radical, or a
radical --CH.sub.2--S--R.sub.4 for which R.sub.4 is a pyridyl
radical, the racemic mixtures, enantiomers and diastereoisomers
thereof and mixtures thereof, the tautomers thereof and the
pharmaceutically acceptable salts thereof.
[0145] In particular, R.sub.3 is a 3- or 4-pyridyl, 2- or
3-thienyl, 4- or 5-thiazolyl, 1-imidazolyl, 1-triazolyl,
2-pyrazinyl or phenyl radical or a phenyl radical substituted in
position-3 with a nitro or carboxyl radical and R.sub.4 is a
4-pyridyl radical.
[0146] Among the novel compounds of formula (I) which may be
mentioned are the following compounds:
[0147] 4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0148] 4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0149] 4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0150] 4-(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0151] 4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0152] 4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0153]
5-methyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0154]
5-ethyl-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0155] 4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0156] 4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0157] 4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0158] 4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0159] 4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0160]
4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0161] the racemic mixtures, enantiomers, diastereoisomers and
tautomers thereof and the pharmaceutically acceptable salts
thereof, and in particular the following compounds:
[0162]
(+)-(4R)-4-(3-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0163]
(+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0164]
(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0165]
(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0166]
(-)-(4R)-4--(3-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0167]
(4R)-4-(2-thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0168]
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl](1-iminoethyl)amine
[0169] (+)-(4R)-4-benzyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0170]
(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0171]
(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0172]
(-)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0173]
(-)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0174]
(-)-(4S)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0175]
(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0176]
(+)-(4R)-4-(4-pyridylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0177]
(+)-(4R,5R)-5-methyl-4-(4-pyridylmethyl-4,5-dihydro-1,3-thiazol-2-y-
lamine
[0178]
(+)-(4R,5R)-5-ethyl-4-(4-pyridylmethyl-4,5-dihydro-1,3-thiazol-2-yl-
amine
[0179]
(4S,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0180]
(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0181]
(+)-(4R,5R))-5-methyl)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol--
2-ylamine
[0182]
(+)-(4R,5R))-5-ethyl)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-
-ylamine
[0183]
(+)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0184]
(-)-4-(5-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0185]
(+)-(4R)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0186]
(4R)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0187]
(4S)-4-(1-imidazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0188]
(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0189]
(+)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0190]
(+)-4-(1-triazolylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0191] the tautomers thereof and the pharmaceutically acceptable
salts thereof.
[0192] The invention also relates to pharmaceutical compositions
containing, as active principle, a derivative of formula (I) for
which
[0193] either R.sub.1 is a hydrogen atom or an alkyl radical and
R.sub.2 is an alkyl, -alk-NH.sub.2, --CH.sub.2--R.sub.3 or
--CH.sub.2--S--R.sub.4 radical or a phenyl radical substituted with
a nitro or --NH--C(.dbd.NH)CH.sub.3 radical,
[0194] or R.sub.1 is an alkyl radical and R.sub.2 is a hydrogen
atom, R.sub.3 is a cycloalkyl (3-6C), pyridyl, thienyl, thiazolyl,
imidazolyl, pyrazinyl, triazolyl or phenyl radical or a phenyl
radical substituted with a nitro, hydroxyl or carboxyl radical,
[0195] R.sub.4 represents a pyridyl radical and alk represents an
alkylene radical,
[0196] as well as the racemic mixtures, enantiomers and
diastereoisomers thereof and mixtures thereof, the tautomer thereof
and the pharmaceutically acceptable salts thereof,
[0197] with the exception of the racemic compounds for which
R.sub.1 is a methyl radical and R.sub.2 is a hydrogen atom or else
R.sub.1 is hydrogen and R.sub.2 is methyl, ethyl or n-propyl.
[0198] The compounds of formula (I) can be prepared by cyclization
of a derivative of formula: 4
[0199] in which R.sub.1 and R.sub.2 have the same meanings as in
formula (I).
[0200] This cyclization is generally carried out using an acid such
as hydrochloric acid, in aqueous medium, at a temperature of
100.degree. C. 6N hydrochloric acid is preferably used.
[0201] The derivatives of formula (II) can be obtained according to
the following reaction schemes:
[0202] Scheme 1 for the compounds for which R.sub.1 is hydrogen
5
[0203] in these formulae R.sub.2 has the same meanings as in
formula (I), Ra is a hydrogen atom or a protecting group for the
amine function, such as those described by T. W. Greene, Protective
groups in organic synthesis, J. Wiley-Interscience Publication
(1991) and Rb is a (1-4C) alkyl or alkoxycarbonyl radical,
preferably methyl, ethyl or isobutyloxycarbonyl. The protecting
group for the amine function is preferably an acetyl or
tert-butoxycarbonyl radical.
[0204] Reaction a is generally carried out in the presence of a
sodium (1-4C) alkoxide (preferably sodium ethoxide), in the
corresponding alcohol, at a temperature of between 10.degree. C.
and the boiling point of the reaction medium.
[0205] Reaction b is generally carried out in an inert solvent such
as dimethylformamide in the presence of lithium iodide, at a
temperature of between 100.degree. C. and the boiling point of the
reaction medium, or in a (1-4C) aliphatic alcohol, in the presence
of sodium hydroxide, at a temperature from 10.degree. C. to
30.degree. C., followed by neutralizing with 6N HCl then heating in
a solvent such as dioxane at a temperature in the region of
100.degree. C.
[0206] Reaction b' is preferably carried out using hydrochloric
acid, at a temperature of 100.degree. C.
[0207] Reaction b" for the derivatives for which Rb is an alkyl
radical is generally carried out by the action of a (1-4C)
aliphatic alcohol (preferably methanol or ethanol), in the presence
of an inorganic acid such as sulfuric acid, at a temperature of
between 50.degree. C. and the boiling point of the reaction medium.
For the derivatives for which Rb is an isobutyloxycarbonyl radical,
this reaction is generally carried out by the action of isobutyl
chloroformate in the presence of a base such as triethylamine, in
an inert solvent such as tetrahydrofuran, at a temperature of
between -20.degree. C. and 0.degree. C.
[0208] The reduction reactions c, g and i are preferably carried
out using a hydride such as sodium borohydride or lithium aluminum
hydride, in a (1-4C) aliphatic alcohol or tetrahydrofuran, at a
temperature of between 10.degree. C. and 30.degree. C., or
alternatively using a borane derivative such as the BH.sub.3-THF
complex, in a solvent such as tetrahydrofuran, at a temperature of
between 0.degree. C. and 30.degree. C.
[0209] The deprotection reaction d for the compounds for which Ra
is a protecting group for the amine function is carried out by any
deprotection method known to those skilled in the art, and in
particular those described by T. W. Greene, Protective groups in
organic synthesis, J. Wiley-Interscience Publication (1991).
Preferably, when the protecting group is an acetyl radical, this
reaction is carried out using aqueous hydrochloric acid, at a
temperature of 100.degree. C. When the protecting group is a
tert-butoxycarbonyl radical, this reaction is carried out using
hydrochloric acid in dioxane, at a temperature in the region of
20.degree. C.
[0210] Reactions e and h are carried out by the action of
tert-butyl isothiocyanate, in an inert solvent such as a (1-4C)
aliphatic alcohol (preferably methanol or ethanol), optionally in
the presence of a tertiary amine such as triethylamine, at a
temperature of between 20.degree. C. and the boiling point of the
reaction medium.
[0211] Reaction f is carried out by the action of a (1-4C)
aliphatic alcohol (preferably methanol or ethanol), in the presence
of an inorganic acid such as hydrochloric acid, at a temperature of
between 20.degree. C. and the boiling point of the reaction medium,
or alternatively by the action of thionyl chloride, in a (1-4C)
aliphatic alcohol (preferably methanol or ethanol), at a
temperature of between -25.degree. C. and 30.degree. C. Scheme 2
for the compounds for which R.sub.1 is alkyl 6
[0212] in these formulae R.sub.1 and R.sub.2 have the same meanings
as in formula (I), Ra is a hydrogen atom or a protecting group for
the amine function, such as those described by T. W. Greene,
Protective groups in organic synthesis, J. Wiley-Interscience
Publication (1991) and preferably an acetyl or tert-butoxycarbonyl
radical, and Rb is an alkyl or alkoxycarbonyl radical, and
preferably methyl, ethyl or isobutyloxycarbonyl.
[0213] Reaction a is preferably carried out in an inert solvent
such as a chlorinated solvent (for example chloroform or
dichloromethane), optionally in the presence of a base such as
N-methylmorpholine or triethylamine, at a temperature of between
-15.degree. C. and 30.degree. C.
[0214] Reaction b is carried out by the action of an alkylmagnesium
halide such as an alkylmagnesium bromide, in an ether such as
tetrahydrofuran or ethyl ether, at a temperature of between
0.degree. C. and 30.degree. C.
[0215] The reduction reaction c is preferably carried out using a
hydride such as sodium borohydride or lithium aluminum hydride, in
a (1-4C) aliphatic alcohol or tetrahydrofuran, at a temperature of
between 10.degree. C. and 30.degree. C., or using a borane
derivative such as the BH.sub.3-THF complex, in a solvent such as
tetrahydrofuran, at a temperature of between 0.degree. C. and
30.degree. C.
[0216] The deprotection reaction d is carried out by any method
known to those skilled in the art for deprotecting an amine
function, and in particular those described by T. W. Greene,
Protective groups in organic synthesis, J. Wiley-Interscience
Publication (1991). Preferably, when the protecting group is an
acetyl radical, this reaction is carried out using aqueous
hydrochloric acid, at a temperature of 100.degree. C. When the
protecting group is a tert-butoxycarbonyl radical, this reaction is
carried out using hydrochloric acid in dioxane, at a temperature in
the region of 20.degree. C.
[0217] Reaction e is carried out by the action of tert-butyl
isothiocyanate, in an inert solvent such as a (1-4C) aliphatic
alcohol (preferably methanol or ethanol), in the presence of a
tertiary amine such as triethylamine, at a temperature of between
20.degree. C. and the boiling point of the reaction medium.
[0218] The compounds of formula (I) for which R.sub.2 is a phenyl
radical substituted with an --NH--C(.dbd.NH)CH.sub.3 radical can
also be prepared from the corresponding amine derivatives which are
themselves obtained by reducing the nitro derivatives of formula
(I) according to the following scheme: 7
[0219] The reduction reaction a is carried out by any reduction
method known to those skilled in the art for proceeding from a
nitro to an amino without affecting the rest of the molecule. The
process is preferably performed using zinc, in acetic acid, at a
temperature in the region of 20.degree. C.
[0220] Reaction b is carried out by reaction of benzyl
ethanimidothioate hydrochloride, in an inert solvent such as a
(1-4C) aliphatic alcohol and preferably methanol or ethanol, at a
temperature of between 0.degree. C. and 45.degree. C.
[0221] The intermediates of formula (III) are novel and form part
of the invention.
[0222] The compounds of formula (I) for which R.sub.2 is a radical
--CH.sub.2--R.sub.3 in which R.sub.3 is a 1-imidazolyl or
1-(1,2,4-triazolyl) radical may also be prepared by the action of
imidazolyl or of 1,2,4-triazole on a derivative of formula: 8
[0223] in which R.sub.1 has the same meanings as in formula (I), X
is a halogen atom, and in particular an iodine atom, or a tosyl
radical, Ra and Rb are hydrogen atoms or protecting groups for the
amine function such as those described by T. W. Greene, Protective
Groups in Organic Synthesis, J. Wiley-Interscience Publication
(1991), preferably alkoxycarbonyl or acetyl and more particularly
tert-butoxycarbonyl, optionally followed by a deprotection.
[0224] This reaction is generally carried out in the presence of a
base such as an alkali metal hydride, preferably sodium hydride, in
a solvent such as dimethyl sulfoxide, at a temperature of between
20.degree. C. and the boiling point of the reaction medium.
[0225] The deprotection reaction for the compounds for which Ra or
Rb is a protecting group for the amine function is carried out by
any deprotection method known to those skilled in the art and in
particular those described by T. W. Greene, Protective Groups in
Organic Synthesis, J. Wiley-Interscience Publication (1991).
Preferably, when the protecting group is an acetyl radical, this
reaction is carried out using aqueous hydrochloric acid, at a
temperature of 100.degree. C. When the protecting group is a
tert-butoxycarbonyl radical, this reaction is carried out using
hydrochloric acid in dioxane, at a temperature in the region of
20.degree. C.
[0226] The compounds of formula (IV) may themselves be obtained
according to the following reaction scheme: 9
[0227] In these formulae, R.sub.1 has the same meaning as in
formula (I), Ts is a tosylate radical, Ra and Rb are a hydrogen
atom or a protecting group for the amine function such as those
described by T. W. Greene, Protective Groups in Organic Synthesis,
J. Wiley-Interscience Publication (1991), preferably alkoxycarbonyl
or acetyl and more particularly tert-butoxycarbonyl.
[0228] Reaction a is generally carried out by the action of
tert-butyl isothiocyanate, in an inert solvent such as an aliphatic
alcohol (1-4C) (preferably methanol or ethanol), optionally in the
presence of a tertiary amine such as triethylamine, at a
temperature of between 20.degree. C. and the boiling point of the
reaction medium.
[0229] Cyclization reaction b is generally carried out using an
acid such as hydrochloric acid, in aqueous medium, at a temperature
in the region of 100.degree. C. 6N hydrochloric acid is preferably
used.
[0230] When Ra or Rb is a tert-butoxycarbonyl group, reactions c
and g are carried out by any protection method known to those
skilled in the art and in particular those described by T. W.
Greene, Protective Groups in Organic Synthesis, J.
Wiley-Interscience Publication (1991). This reaction is preferably
carried out using di-tert-butyl dicarbonate, in the presence of a
base such as triethylamine and optionally in the presence of
4-(dimethylamino)pyridine, in a solvent such as dichloromethane and
at a temperature in the region of 20.degree. C., or alternatively
in the presence of a base such as potassium carbonate, in a solvent
such as water and at a temperature in the region of 20.degree.
C.
[0231] Reaction d is generally carried out by the action of
p-toluenesulfonyl chloride, in the presence of a tertiary amine
such as triethylamine, in an inert solvent such as dichloromethane,
at a temperature of between 20.degree. C. and the boiling point of
the reaction medium.
[0232] Reaction e is generally carried out by the action of sodium
iodide, in an inert solvent such as acetone, at a temperature of
between 20.degree. C. and the boiling point of the reaction
medium.
[0233] Reaction f is generally carried out by the action of an
allyl halide, for example allyl chloride, in an aliphatic alcohol
(1-4C), preferably ethanol, at a temperature of between 20.degree.
C. and the boiling point of the reaction medium.
[0234] Reaction h is generally carried out by the action of iodine,
in the presence of base such as sodium bicarbonate, in a solvent
such as dichloromethane, at a temperature of between 20.degree. C.
and the boiling point of the reaction medium.
[0235] The compounds of formula (I) for which R.sub.2 is a radical
--CH.sub.2--S--R.sub.4 may be prepared by the action of a
corresponding compound of formula (IVa) or (IVb) with a derivative
of formula HS--R.sub.4 in which R.sub.4 has the same meaning as in
formula (I) and Ra and Rb are hydrogen atoms or protecting groups
for the amine function such as those described by T. W. Greene,
Protective Groups in Organic Synthesis, J. Wiley-Interscience
Publication (1991), preferably alkoxycarbonyl or acetyl and more
particularly tert-butoxycarbonyl, optionally followed by a
deprotection of the amine function.
[0236] This reaction is generally carried out in the presence of a
base such as potassium carbonate, in a solvent such as acetonitrile
or dimethylformamide (preferably acetonitrile), at a temperature of
between 20.degree. C. and the boiling point of the reaction
medium.
[0237] The deprotection reaction for the compounds for which Ra or
Rb is a protecting group for the amine function is carried out by
any deprotection method known to those skilled in the art and in
particular those described by T. W. Greene, Protective Groups in
Organic Synthesis, J. Wiley-Interscience Publication (1991).
Preferably, when the protecting group is an acetyl radical, this
reaction is carried out using aqueous hydrochloric acid, at a
temperature of 100.degree. C. When the protecting group is a
tert-butoxycarbonyl radical, this reaction is carried out using
hydrochloric acid in dioxane, at a temperature in the region of
20.degree. C. The compounds of formula (I) are isolated and may be
purified by the usual known methods, for example by
crystallization, chromatography or extraction.
[0238] The enantiomers of the compounds of formula (I) can be
obtained by resolving the racemic mixtures, 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 can be prepared according to the known
conventional methods (crystallization or chromatography or from
chiral precursors).
[0239] The compounds of formula (I) can optionally be converted
into 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.
[0240] Examples of pharmaceutically acceptable salts which may be
mentioned are the following salts: benzenesulfonate, hydrobromide,
hydrochloride, citrate, ethanesulfonate, fumarate, gluconate,
iodate, isethionate, maleate, methanesulfonate,
methylenebis-.beta.-oxynaphthoate- , nitrate, oxalate, pamoate,
phosphate, salicylate, succinate, sulfate, tartrate,
theophyllineacetate and p-toluenesulfonate.
[0241] The compounds of formula (I) are inhibitors of inducible
NO-synthase or type-2 NO-synthase (NOS-2) and are thus useful for
preventing and treating disorders associated with excessive NO
production, such as multiple sclerosis, cerebral, focal or global
ischemia, cerebral or spinal trauma, Parkinson's disease,
Huntington's disease, Alzheimer's disease, amiotrophic lateral
sclerosis, migraine, depression, schizophrenia, anxiety and
epilepsy, diabetes, atherosclerosis, myocarditis, arthritis,
arthrosis, asthma, irritable bowel syndrome, Crohn's disease,
peritonitis, gastro-esophageal reflux, uveitis, Guillain-Barr
syndrome, glomerulonephritis, lupus erythematosus, psoriasis, the
growth of certain forms of tumors such as, for example,
epitheliomas, adenocarcinomas or sarcomas, and infections with
Gram-positive or Gram-negative intracellular or extracellular
bacteria.
[0242] Their activities as NOS-2 and NOS-3 inhibitors were
determined by measuring the conversion of [.sup.3H]-L-arginine into
[.sup.3H]-L-citrulline with, respectively, an NOS-2 enzymatic
fraction extracted from the lungs of rats or mice pretreated with
lipopolysaccharides (10 mg/kg i.p. 6 hours before collecting the
tissue) and with a commercial preparation of recombinant bovine
NOS-3. The compounds were incubated for 20 to 30 minutes at
37.degree. C. in the presence of 5 .mu.M (for NOS-2 activity) or 10
.mu.M (for NOS-3 activity) of [.sup.3H]-L-arginine, 1 mM of NADPH,
15 .mu.M of tetrabiopterine, 1 .mu.M of FAD, 0.1 mM of DTT in a
HEPES buffer (50 mM, pH 6.7) containing 10 .mu.g/ml of calmodulin
and 1.25 mM of CaCl.sub.2 when the NOS-3 activity was measured. The
incubation was stopped by adding cold HEPES buffer (100 mM, pH 5.5)
containing 10 mM of EGTA and 500 mg of a cationic ion-exchange
resin (AG50W-X8, counterion: Na.sup.+) to separate the
[.sup.3H]-L-arginine from the [.sup.3H]-L-citrulline. After
separation of the phases by settling for 5 min, the radioactivity
remaining in the liquid phase was measured in a scintillation
counter in the presence of a suitable scintillation liquid. The
yield for the recovery of the [.sup.3H] -L-citrulline formed was
able to be estimated using [.sup.14C-ureido]-L-citrulline as
external standard.
[0243] The NOS-2 or NOS-3 activity was expressed in picomole(s) of
[.sup.3H]-L-citrulline formed per minute and per milligram of
protein contained in the reaction medium.
[0244] In this test on the enzyme NOS-2, the IC.sub.50 value for
the compounds of formula (I) is less than or equal to 10 .mu.M.
[0245] The selectivity is measured by the NOS-3 IC.sub.50/NOS-2
IC.sub.50 ratio. This selectivity is greater than 20.
[0246] The compounds of formula (I) are of low toxicity. Their
LD.sub.50 value is greater than 40 mg/kg via the cutaneous route in
mice.
[0247] The examples which follow illustrate the invention.
EXAMPLE 1
(+)-(4R)-4-(3-Pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
dihydrochloride
[0248] A suspension of 3.35 g of
N-(tert-butyl)-N'-[(1R)-2-hydroxy-1-(3-py-
ridylmethyl)ethyl]thiourea in 32 cm.sup.3 of 6N hydrochloric acid
is heated at a temperature in the region of 100.degree. C. for 5
hours and the heating is then stopped. The solution is then
evaporated under reduced pressure (2 kPa) at a temperature in the
region of 50.degree. C. 4.42 g of a yellow oil which becomes pasty
are obtained. This paste is taken up in acetone and then
re-evaporated under reduced pressure (2 kPa) at a temperature in
the region of 40.degree. C. The residue is taken up in diethyl
ether. Light beige-colored crystals are obtained, and are filtered
off on a sinter funnel and then washed with diethyl ether and dried
in an oven under reduced pressure (0.1 kPa) at a temperature in the
region of 50.degree. C. 3.28 g of
(+)-(4R)-4-(3-pyridylmethyl)-4,5-dihydr- o-1,3-thiazol-2-ylamine
dihydrochloride are obtained in the form of a light beige-colored
sandy solid melting at 124.degree. C. [.sup.1H NMR spectrum (300
MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 3.20 (mt: 2H);
3.40 (dd, J=11 and 5 Hz: 1H); 3.70 (dd, J=11 and 8 Hz: 1H); 4.67
(mt: 1H); 7.97 (dd, J=8 and 5.5 Hz: 1H); 8.46 (broad d, J=8 Hz:
1H); 8.83 (broad d, J=5.5 Hz: 1H); 8.90 (d, J=2 Hz: 1H); 9.28
(unres. mult.: 1H); 9.75 (unres. mult.: 1H); 10.30 (unres. mult.:
1H); (.alpha..sub.D.sup.20=+18.3.+-.0.7 at a concentration of 0.5%
in methanol)].
[0249]
N-(tert-Butyl)-N'-[(1R)-2-hydroxy-1-(3-pyridylmethyl)ethyl]thiourea-
: 22.7 cm.sup.3 of triethylamine and then 14 cm.sup.3 of tert-butyl
isothiocyanate are added dropwise to a suspension, under an inert
atmosphere, of 16.51 g of (2R)-2-amino-3-(3-pyridyl)-1-propanol
dihydrochloride in 200 cm.sup.3 of ethanol. The mixture is then
heated at a temperature in the region of 60.degree. C. for 1 hour
30 min. After cooling to a temperature in the region of 200.degree.
C., the insoluble material is filtered off on a sinter funnel and
the filtrate is then evaporated under reduced pressure (2 kPa) at a
temperature in the region of 40.degree. C. A yellow paste is
obtained, and is taken up in 200 cm.sup.3 of ethyl acetate and 100
cm.sup.3 of water. The aqueous phase is extracted and then washed
with twice 200 cm.sup.3 of ethyl acetate. The organic phases are
combined, washed with 3 times 50 cm.sup.3 of saturated sodium
chloride solution and dried over magnesium sulfate. After
filtration and then evaporation under reduced pressure (2 kPa) at a
temperature in the region of 40.degree. C., a yellow oil is
obtained, which is taken up in dichloromethane and re-evaporated to
give 3.25 g of
N-(tert-butyl)-N'-[(1R)-2-hydroxy-1-(3-pyridylmethyl)-ethyl]thiourea
in the form of a pale yellow foam: [.sup.1H NMR spectrum (400 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 1.41 (s: 9H); 2.84
(mt: 2H); 3.37 (mt: 2H); 4.43 (unres. mult.: 1H); 4.96 (t, J=5 Hz:
1H); 7.24 (d, J=8 Hz: 1H); 7.27 (broad s: 1H); 7.33 (dd, J=8 and 5
Hz 1H); 7.67 (dt, J=8 and 2 Hz: 1H); 8.42 (dd, J=5 and 2 Hz: 1H);
8.46 (d, J=2 Hz: 1H)].
[0250] (2R)-2-Amino-3-(3-pyridyl)-1-propanol dihydrochloride: A
suspension of 13.55 g of
N-[(1R)-2-hydroxy-1-(3-pyridylmethyl)ethyl]acetamide in 110
cm.sup.3 of aqueous 6N hydrochloric acid is heated at a temperature
in the region of 100.degree. C. for 3 hours. The water is
evaporated off under reduced pressure (3 kPa) at a temperature in
the region of 50.degree. C. 16.51 g of
(2R)-2-amino-3-(3-pyridyl)-1-propanol dihydrochloride are obtained
in the form of an off-white solid. [.sup.1H NMR spectrum (400 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 3.13 (d, J=7.5 Hz:
2H); 3.50 (mt: 2H); 3.62 (mt: 1H); 7.94 (dd, J=8 and 5.5 Hz: 1H);
8.27 (unres. mult.: 3H); 8.43 (broad d, J=8 Hz: 1H); 8.79 (broad d,
J=5.5 Hz 1H); 8.86 (broad s: 1H)].
[0251] N-[(1R)-2-Hydroxy-1-(3-pyridylmethyl)ethyl]-acetamide: A
solution, under an inert atmosphere, of 20.77 g of ethyl
(2R)-2-(acetylamino)-3-(3-- pyridyl)propanoate in 208 cm.sup.3 of
anhydrous ethanol is cooled to a temperature in the region of
10.degree. C., followed by portionwise addition of 8.31 g of sodium
borohydride. The reaction mixture is stirred for 16 hours at room
temperature. The ethanol is evaporated off under reduced pressure
(2 kPa) at a temperature in the region of 40.degree. C., to give
43.56 g of a pale yellow paste which is taken up and stirred in 50
cm.sup.3 of water. The solution, which has a pH in the region of
12, is cooled to a temperature in the region of 0.degree. C. and
then neutralized by dropwise addition of concentrated hydrochloric
acid. The resulting mixture is stirred for 1 hour at this
temperature and the white precipitate formed is then filtered off
on a sinter funnel, then dried in an oven under vacuum (0.1 kPa) at
a temperature in the region of 55.degree. C. 11.15 g of
N-[(1R)-2-hydroxy-1-(3-pyridylmethyl)ethyl]aceta- mide are obtained
in the form of a white solid melting at a temperature above
260.degree. C. The filtrate is extracted with 3 times 100 cm.sup.3
of ethyl acetate and the organic phases are then combined, dried
over magnesium sulfate, filtered and evaporated under reduced
pressure (2 kPa) at a temperature in the region of 40.degree. C.
2.4 g of N-[(1R)-2-hydroxyl-1-(3-pyridylmethyl)ethyl]acetamide
partially complexed with boron are obtained in the form of a white
paste. [.sup.1H NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6,
.delta. in ppm): 1.75 (s: 3H); 2.61 (dd, J=14 and 9 Hz: 1H); 2.88
(dd, J=14 and 5.5 Hz: 1H); from 3.20 to 3.45 (mt: 2H); 3.91 (mt:
1H); 4.82 (broad t, J=5 Hz: 1H); 7.30 (dd, J=7.5 and 5 Hz: 1H);
7.62 (dt, J=7.5 and 2 Hz: 1H); 7.72 (d, J=9 Hz: 1H); from 8.35 to
8.45 (mt: 2H)].
[0252] Ethyl (2R)-2-(acetylamino)-3-(3-pyridyl)propanoate: A
suspension of 54.7 g of ethyl
2-(acetylamino)-3-(3-pyridyl)propanoate in 420 .degree. cm.sup.3 of
water, to which has been added 18.5 g of potassium chloride, is
dissolved by adding 100 cm.sup.3 of acetonitrile. An orange-colored
solution of neutral pH is obtained, 0.168 g of .alpha.-chymotrypsin
is then added and the pH falls. Aqueous 2N potassium hydroxide
solution is added dropwise, with stirring, to remain at a constant
pH of 7.2. After 1 hour 30 min, with the pH showing little change,
the mixture is stirred for 48 hours at room temperature. The pH of
the solution is then approximately 5.6 and, on adding aqueous 2N
potassium hydroxide solution, it is thereby adjusted to about 7.
0.084 g of .alpha.-chymotrypsin is introduced and the pH is
adjusted to 7.2 by a further addition of aqueous 2N potassium
hydroxide solution, and the mixture is left stirring for 1 hour 30
min. The pH of the reaction medium does not change. 400 cm.sup.3 of
ethyl acetate are added and the mixture is stirred for 30 min and
then filtered through Celite. The filtrate is separated out after
settling has taken place and the aqueous phase is extracted with 3
times 400 cm.sup.3 of ethyl acetate. The organic phases are
combined, washed with 400 cm.sup.3 of saturated sodium chloride
solution and dried over magnesium sulfate. After filtration and
concentration under reduced pressure (2 kPa) at a temperature in
the region of 40.degree. C., 20.77 g of ethyl
(2R)-2-(acetylamino)-3-(3-pyridyl)propanoate are obtained in the
form of a beige-colored solid melting at 80.degree. C. [.sup.1H NMR
spectrum (400 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm):
1.13 (t, J=7 Hz: 3H); 1.81 (s: 3H); 2.92 (dd, J=14 and 9.5 Hz: 1H);
3.05 (dd, J=14 and 5.5 Hz: 1H); 4.07 (q, J=7 Hz: 2H); 4.48 (mt:
1H); 7.33 (dd, J=8 and 5 Hz: 1H); 7.66 (dt, J=8 and 2 Hz: 1H); 8.36
(d, J=8 Hz: 1H); 8.44 (mt: 2H)].
[0253] Ethyl 2-(acetylamino)-3-(3-pyridyl)propanoate: 44.45
cm.sup.3 of aqueous 6N sodium hydroxide are added dropwise to a
solution of 51.4 g of diethyl
2-(acetylamino)-2-(3-pyridylmethyl)malonate in 857 cm.sup.3 of
ethanol. The mixture is stirred for 1 hour 30 minutes at a
temperature in the region of 20.degree. C. and then cooled to a
temperature in the region of 0.degree. C. 22.2 cm.sup.3 of 12N
hydrochloric acid are added dropwise; a precipitate forms. The
reaction medium is warmed to room temperature and, after stirring
for 2 hours, its pH is 5-6. It is concentrated under reduced
pressure (4 kPa) at a temperature in the region of 50.degree. C.,
to give a sticky dark-beige solid which is dried for 16 hours in an
oven under vacuum (0.1 kPa) at a temperature in the region of
50.degree. C. This residue is taken up in 1000 cm.sup.3 of dioxane
and then heated to a temperature in the region of 100.degree. C.
for 1 hour. The dioxane is evaporated off under reduced pressure (2
kPa) at a temperature in the region of 40.degree. C., and the
residue is dissolved in 250 cm.sup.3 of water. This solution is
neutralized by addition of 4 cm.sup.3 of aqueous 10N sodium
hydroxide, followed by addition of 750 cm.sup.3 of ethyl acetate.
After separation of the phases by settling, the organic phase is
extracted and the aqueous phase is washed with twice 300 cm.sup.3
of ethyl acetate. The organic phases are combined, dried over
magnesium sulfate, filtered and concentrated under reduced pressure
(2 kPa) at a temperature in the region of 40.degree. C. The solid
residue obtained is taken up in 70 cm.sup.3 of ethyl acetate and 20
cm.sup.3 of heptane and then filtered on a sinter funnel. 27.76 g
of ethyl 2-(acetylamino)-3-(3-pyridyl)propanoate are obtained in
the form of a beige-colored solid melting at 118.degree. C.
[.sup.1H NMR spectrum (400 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta.
in ppm): 1.13 (t, J=7 Hz: 3H) 1.81 (s: 3H); 2.92 (dd, J=14 and 9
Hz: 1H); 3.04 (dd, J=14 and 5.5 Hz: 1H); 4.07 (q, J=7 Hz: 2H); 4.48
(mt: 1H); 7.33 (dd, J=8 and 5 Hz: 1H); 7.66 (dt, J=8 and 2 Hz: 1H);
8.38 (d, J=8 Hz: 1H); 8.45 (mt: 2H)]. By re-extracting the aqueous
phase with twice 500 cm.sup.3 of ethyl acetate and after drying and
concentration of the combined organic phases under reduced
pressure, 4 g of ethyl 2-(acetylamino)-3-(3-pyridyl)propano- ate
are recovered in the form of a beige-yellow solid melting at
121.degree. C.
[0254] In the same way, starting with 50.2 g of diethyl
2-(acetylamino)-2-(3-pyridylmethyl)malonate, 26.94 g of ethyl
2-(acetylamino)-3-(3-pyridyl)propanoate are obtained.
[0255] Diethyl 2-(acetylamino)-2-(3-pyridylmethyl)-malonate: 17.2 g
of sodium prewashed twice with pentane are added portionwise, with
stirring under an inert atmosphere, to 600 cm.sup.3 of ethanol.
After total consumption of the sodium, 73.5 g of diethyl
acetamidomalonate are added rapidly and the mixture is left
stirring for 30 min at a temperature in the region of 40.degree. C.
A suspension of 56 g of 3-picolyl chloride hydrochloride in 300
cm.sup.3 of ethanol is then added rapidly and the resulting pinkish
suspension is stirred for 44 hours at a temperature in the region
of 20.degree. C. 28.1 g of potassium iodide are added and stirring
is continued at room temperature for 4 hours, and the reaction
mixture is finally heated at a temperature in the region of
50.degree. C. for 44 hours. The mixture is cooled to a temperature
in the region of 0.degree. C. and then filtered through a sinter
funnel to remove the salts, which are washed with ethanol. The
filtrate is concentrated under reduced pressure (2 kPa) at a
temperature in the region of 40.degree. C. A brown-colored paste is
obtained, and is dissolved in 100 cm.sup.3 of water and treated
with 7 cm.sup.3 of aqueous 3N hydrochloric acid until a pH in the
region of 6 is obtained. The mixture is placed in a refrigerator
for 48 hours. The crystalline precipitate obtained is filtered off
on a sinter funnel, washed with 50 cm.sup.3 of ice-cold water,
spin-filtered and then dried in a desiccator under reduced pressure
(5 kPa) for 16 hours. After drying in an oven under reduced
pressure (0.1 kPa) at a temperature in the region of 40.degree. C.
for 4 hours, 50.2 g of diethyl
2-(acetylamino)-2-(3-pyridylmethyl)malonate are obtained in the
form of a dark beige-colored solid melting at 96.degree. C.
[.sup.1H NMR spectrum (400 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta.
in ppm): 1.19 (t, J=7 Hz: 6H); 1.97 (s: 3H); 3.47 (s: 2H); 4.17 (q,
J=7 Hz: 4H); 7.33 (dd, J=8 and 5 Hz: 1H); 7.41 (dt, J=8 and 2 Hz:
1H); 8.21 (d, J=2 Hz: 1H); 8.24 (s: 1H); 8.24 (s: 1H); 8.47 (dd,
J=5 and 2 Hz: 1H)].
EXAMPLE 2
(+)-(4R)-4-(3-Nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
hydrochloride
[0256] 1.1 g of
N-(tert-butyl)-N'-[(1R)-2-hydroxy-1-(3-nitrobenzyl)ethyl]t- hiourea
in 12 cm.sup.3 of 6N hydrochloric acid are heated for 5 hours at a
temperature in the region of 100.degree. C. The reaction medium is
then cooled to a temperature in the region of 0.degree. C.; a white
precipitate forms, which is filtered off on a sinter funnel and
then washed with 3 times 20 cm.sup.3 of diethyl ether. The filter
cake is then dried in a desiccator under vacuum. 0.68 g of
(+)-(4R)-4-(3-nitrobenzyl)-- 4,5-dihydro-1,3-thiazol-2-ylamine
hydrochloride is obtained in the form of beige-colored crystals
melting at 232.degree. C. [.sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 3.15 (limiting AB:
2H); from 3.25 to 3.45 (mt: 1H); 3.63 (dd, J=13 and 8 Hz 1H); 4.62
(mt: 1H); 7.68 (t, J=8 Hz: 1H); 7.81 (broad d, J=8 Hz: 1H); 8.18
(broad d, J=8 Hz 1H); 8.24 (broad s: 1H); from 9.00 to 10.40
(unres. mult.: 3H); (.alpha..sub.D.sup.20=+18.8.+-.0.6 at a
concentration of 0.5in methanol)].
[0257]
N-(tert-Butyl)-N'-[(1R)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea:
A suspension of 0.92 g of (2R)-2-amino-3-(3-nitrophenyl)-1-propanol
hydrochloride and 0.6 cm.sup.3 of tert-butyl isothiocyanate in 10
cm.sup.3 of ethanol is cooled to a temperature in the region of
0.degree. C. and 0.56 cm.sup.3 of triethylamine is then added. The
mixture is stirred for 18 hours at room temperature and is then
heated at a temperature in the region of 60.degree. C. for 2 hours;
the suspension thus dissolves. 0.6 cm.sup.3 of tert-butyl
isothiocyanate is added and heating is continued for 3 hours, after
which the reaction medium is concentrated under reduced pressure (2
kPa) at a temperature in the region of 50.degree. C. The yellow oil
obtained is dissolved in 50 cm.sup.3 of ethyl acetate, after which
the organic solution is washed with twice 50 cm.sup.3 of sodium
chloride solution, dried over sodium sulfate, filtered and
concentrated under reduced pressure (2 kPa) at a temperature in the
region of 40.degree. C. 1.2 g of
N-(tert-butyl)-N'-[(1R)-2-hydroxy-1-(3-nitrobenzyl)-ethyl]thiourea
are obtained in the form of a yellow oil. .sup.1H NMR spectrum (300
MHz, (CD.sub.3).sub.2SO-d.sub.6 with addition of a few drops of
CD.sub.3COOD-d.sub.4, .delta. in ppm): 1.39 (s: 9H); 2.98 (limiting
AB: 2H); 3.38 (limiting AB: 2H); 4.48 (mt: 1H); 7.60 (t, J=8 Hz:
1H); 7.74 (broad d, J=8 Hz: 1H); 8.09 (broad d, J=8 Hz: 1H); 8.16
(broad s: 1H).
[0258] (2R)-2-Amino-3-(3-nitrophenyl)-1-propanol hydrochloride: A
suspension of 0.98 g of
N-[(1R)-2-hydroxy-1-(3-nitrobenzyl)ethyl]acetamid- e in 10 cm.sup.3
of 6N hydrochloric acid is heated at a temperature in the region of
100.degree. C. for 10 hours (dissolution). The reaction medium is
concentrated under reduced pressure (2 kPa) at a temperature in the
region of 40.degree. C. The residue is taken up in 20 cm.sup.3 of
diethyl ether and re-evaporated under the same conditions to give
beige-colored crystals, which are washed with 3 times 20 cm.sup.3
of diethyl ether and then filtered off on a sinter funnel and
finally dried in a fume cupboard. 0.92 g of
(2R)-2-amino-3-(3-nitrophenyl)-1-propanol hydrochloride is obtained
in the form of beige-colored crystals melting at 192.degree. C.
[.sup.1H NMR spectrum (250 MHz, (CD.sub.3).sub.2SO-d.su- b.6,
.delta. in ppm): 3.06 (limiting AB: 2H); from 3.25 to 3.65 (mt:
3H); 5.45 (t, J=4.5 Hz: 1H); 7.65 (t, J=7 Hz: 1H); 7.79 (broad d,
J=7 Hz: 1H); from 8.05 to 8.40 (mt: 5H)].
[0259] N-[(1R)-2-Hydroxy-1-(3-nitrobenzyl)ethyl]-acetamide: A light
suspension, under an inert atmosphere, of 1.4 g of ethyl
(2R)-2-(acetylamino)-3-(3-nitrophenyl)propanoate in 13 cm.sup.3 of
ethanol is cooled to a temperature of 20.degree. C. and 0.29 g of
sodium borohydride is then added thereto. The yellow solution
obtained is stirred at room temperature for 18 hours. The reaction
medium is then concentrated under reduced pressure (2 kPa) at a
temperature in the region of 50.degree. C., after which 10 cm.sup.3
of water are added and the mixture is extracted with twice 50
cm.sup.3 of ethyl acetate. The combined organic phases are dried
over sodium sulfate, filtered and then concentrated under reduced
pressure (2 kPa) at a temperature in the region of 40.degree. C. 1
g of N-[(1R)-2-hydroxy-1-(3-nitrobenzyl)ethyl]-- acetamide is
obtained in the form of pale yellow crystals melting at 135.degree.
C. .sup.1H NMR spectrum (250 MHz, (CD.sub.3).sub.2SO-d.sub.6,
.delta. in ppm): 1.75 (s: 3H); 2.74 (dd, J=14 and 9 Hz: 1H); 3.02
(dd, J=14 and 5 Hz: 1H); from 3.25 to 3.45 (mt: 2H); 3.96 (mt: 1H);
4.90 (broad s: 1H); 7.59 (t, J=8 Hz: 1H); 7.70 (broad d, J=8 Hz:
1H); 7.82 (d, J=8.5 Hz: 1H); from 8.05 to 8.15 (mt: 2H).
[0260] Ethyl (2R)-2-(acetylamino)-3-(3-nitrophenyl)-propanoate: A
mixture of 2.8 g of ethyl
2-(acetylamino)-3-(3-nitrophenyl)propanoate in 17 cm.sup.3 of
acetonitrile [lacuna] to which is added 3.95 g of ammonium hydrogen
carbonate and 35 cm.sup.3 of water at a pH in the region of 8.
0.017 g of type-II .alpha.-chymotrypsin is then introduced and the
mixture is left stirring at room temperature for 1 hour 15 min,
while measuring the pH regularly. After this reaction time, the pH
is less than 8, a further 0.017 g of type-II .alpha.-chymotrypsin
is added and stirring of the reaction medium is continued for 2
hours 45 min. The aqueous phase is extracted with 3 times 50
cm.sup.3 of ethyl acetate; the combined organic phases are then
dried over sodium sulfate, filtered and evaporated under reduced
pressure (2 kPa) at a temperature in the region of 40.degree. C.
1.4 g of ethyl (2R)-2-(acetylamino)-3-(3-nitrophenyl)pro- panoate
are obtained in the form of white crystals melting at 110.degree.
C.
[0261] Ethyl 2-(acetylamino)-3-(3-nitrophenyl)-propanoate: 9.52
cm.sup.3 of acetic anhydride are added dropwise to 12 g of ethyl
2-amino-3-(3-nitrophenyl)propanoate at a temperature in the region
of 0.degree. C. After stirring at 0.degree. C. for 1 hour, the
mixture sets to a solid. 10 cm.sup.3 of acetic anhydride are then
added and stirring is continued at 0.degree. C. for a further 1
hour. The precipitate is filtered off on a sinter funnel, washed
with 3 times 25 cm.sup.3 of water and dried in a fume cupboard and
then in an oven under vacuum (10 Pa) at a temperature in the region
of 50.degree. C. 12 g of ethyl
2-(acetylamino)-3-(3-nitrophenyl)propanoate are obtained in the
form of white crystals melting at 91.degree. C. .sup.1H NMR
spectrum (250 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm):
1.14 (t, J=7 Hz: 3H); 1.80 (s: 3H); 3.04 (dd, J=14 and 9 Hz: 1H);
3.18 (t, J=14 and 4 Hz: 1H); 4.08 (q, J=7 Hz: 2H); 4.52 (mt: 1H);
7.61 (broad t, J=8 Hz: 1H); 7.72 (broad d, J=8 Hz: 1H); 8.12 (mt:
2H); 8.42 (d, J=8.5 Hz: 1H).
[0262] Ethyl 2-amino-3-(3-nitrophenyl)propanoate: Gaseous hydrogen
chloride is bubbled, to the saturation point, into a mixture of
23.4 g of 3-nitrophenylalanine hydrochloride in 300 cm.sup.3 of
ethanol cooled to a temperature in the region of 0.degree. C. The
suspension obtained is heated at a temperature in the region of
78.degree. C. for 18 hours: this suspension dissolves when hot. The
heating is stopped and gaseous hydrogen chloride is bubbled into
the solution for 15 min, with re-heating at a temperature in the
region of 78.degree. C. for 70 hours. The reaction medium is
concentrated under reduced pressure (2 kPa) at a temperature in the
region of 50.degree. C. and the residue is then basified to a pH of
about 10 with sodium carbonate solution. This aqueous phase is
extracted with 3 times 100 cm.sup.3 of dichloromethane and the
combined organic phases are then dried over sodium sulfate,
filtered and evaporated under reduced pressure (2 kPa) at a
temperature in the region of 40.degree. C. to give 12.2 g of ethyl
2-amino-3-(3-nitrophenyl)propano- ate in the form of an
orange-colored oil. .sup.1H NMR spectrum (250 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 1.14 (t, J=7 Hz: 3H)
1.88 (unres. mult.: 2H); 2.92 (dd, J=13 and 7 Hz: 1H); 3.02 (dd,
J=13 and 6 Hz: 1H); 3.62 (dd, J=7 and 6 Hz: 1H); 4.05 (q, J=7 Hz:
2H); 7.59 (resolved t, J=8.5 and 1.5 Hz: 1H); 7.71 (broad d, J=8
Hz: 1H); from 8.05 to 8.20 (mt: 2H).
[0263] 3-Nitrophenylalanine hydrochloride: A suspension of 34 g of
diethyl 2-(acetylamino)-2-(3-nitrobenzyl)malonate in 510 cm.sup.3
of concentrated hydrochloric acid is heated at a temperature in the
region of 100.degree. C. for 18 hours: a vigorous evolution of gas
takes place and the suspension dissolves when hot. The reaction
mixture is then cooled to a temperature in the region of 0.degree.
C., after which it is stirred for 1 hour at 0.degree. C. and
finally filtered through a sinter funnel. The filter cake is washed
with twice 50 cm.sup.3 of filtrate and dried in a fume cupboard and
then in an oven under vacuum (10 Pa) at a temperature in the region
of 60.degree. C. 23.4 g of 3-nitrophenylalanine hydrochloride are
obtained in the form of white crystals melting at 222.degree.
C.
[0264] Diethyl 2-(acetylamino)-2-(3-nitrobenzyl)-malonate: 3.1 g of
sodium are added, while stirring under an inert atmosphere, to 300
cm.sup.3 of ethanol. After total consumption of the sodium, 29.1 g
of diethyl acetamidomalonate are added and the mixture is then
heated at a temperature in the region of 78.degree. C. for 20
minutes. A solution of 23 g of 3-nitrobenzyl chloride in 100
cm.sup.3 of ethanol is then added and heating is continued at this
same temperature for 18 hours. The reaction mixture is cooled to a
temperature in the region of 0.degree. C. After stirring under
these cold conditions for 1 hour, the precipitate formed is
filtered off on a sinter funnel and the filter cake is washed with
twice 50 cm.sup.3 of filtrate and then twice 50 cm.sup.3 of water.
After drying under a fume cupboard and then in an oven under vacuum
(10 Pa) at a temperature in the region of 50.degree. C., 34 g of
diethyl 2-(acetylamino)-2-(3-nitrobenzyl)malonate are obtained in
the form of white crystals melting at 156.degree. C.
EXAMPLE 3
(+)-(4R,5S)-4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0265] A suspension of 1.8 g of
N-[(1R,2S)-1-benzyl-2-hydroxypropyl]-N'-te- rt-butylthiourea
(diastereoisomer A) in 21 cm.sup.3 of 6N hydrochloric acid is
heated at a temperature in the region of 100.degree. C. for 6
hours. A further 10 cm.sup.3 of 6N hydrochloric acid are added and
heating is continued for 6 hours. The reaction medium is filtered
while hot through a sinter funnel and the insoluble material-is
washed with twice 5 cm.sup.3 of hot 6N hydrochloric acid. The
filtrate is cooled to a temperature in the region of 0.degree. C.,
after which 20 cm.sup.3 of water are added and this mixture is
finally basified with 30 cm.sup.3 of 30% sodium hydroxide. The
resulting mixture is extracted with 3 times 50 cm.sup.3 of
dichloromethane. The combined organic phases are dried over sodium
sulfate, filtered and concentrated under reduced pressure (2 kPa)
at a temperature in the region of 40.degree. C. 1 g of a pink oil
is obtained, and is purified by chromatography under a pressure of
argon (50 kPa) on a column of silica gel (particle size 40-63
.mu.m; diameter 3 cm; height 35 cm), eluting with a mixture of 90%
dichloromethane/10% methanol. The fractions containing the expected
product are combined and concentrated under reduced pressure (2
kPa) at a temperature in the region of 40.degree. C. 0.31 g of
(+)-(4R,5S)-4-benzyl-5-methyl-4,5-dihyd- ro-1,3-thiazol-2-ylamine
is obtained in the form of white crystals melting at 90.degree. C.
[.sup.1H NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub- .6 with
addition of a few drops of CD.sub.3COOD-d.sub.4, .delta. in ppm):
1.31 (d, J=7 Hz: 3H); 2.89 (dd, J=14 and 7.5 Hz: 1H); 3.01 (dd,
J=14 and 7.5 Hz: 1H); 3.91 (mt: 1H); 4.41 (mt: 1H); from 7.15 to
7.40 (mt: 5H). The relative stereochemistry at positions 4 and 5
was validated by NOE. A strong response of the methylene of the
benzyl is noted after irradiating the methyl:
(.alpha..sub.D.sup.20=+29.6.+-.0.8 at a concentration of 0.5% in
methanol)].
[0266] N-[(1R,2S)-1-benzyl-2-hydroxypropyl]-N'-tert-butylthiourea:
A solution of 12.9 g of a 75%/25% mixture of the 2 diastereoisomers
of (3R)-3-amino-4-phenyl-2-butanol in 160 cm.sup.3 of ethanol, to
which 9.50 cm.sup.3 of tert-butyl isothiocyanate have been added,
is stirred at room temperature for 36 hours and then heated for 2
hours at a temperature in the region of 60.degree. C. The reaction
medium is concentrated under reduced pressure (2 kPa) at a
temperature in the region of 40.degree. C. to give 20.8 g of a
yellow oil. This oil is purified by chromatography under a pressure
of argon (50 kPa) on a column of silica gel (particle size 40-63
.mu.m; diameter 5 cm; height 50 cm), eluting with a mixture of 95%
dichloromethane/5% ethyl acetate. The fractions containing
diastereoisomer A are evaporated under reduced pressure (2 kPa) at
a temperature in the region of 40.degree. C. 1.95 g of
N-[(1R,2S)-1-benzyl-2-hydroxy-propyl]-N'-tert-butylthiourea are
obtained in the form of pale yellow crystals melting at 128.degree.
C. .sup.1H NMR spectrum (250 MHz, (CD.sub.3).sub.2SO-d.sub.6,
.delta. in ppm): 0.96 (d, J=7 Hz: 3H); 1.42 (s: 9H); 2.78 (limiting
AB: 2H); 3.64 (mt: 1H); 4.33 (mt: 1H); 5.02 (d, J=4 Hz: 1H); from
7.10 to 7.40 (mt, 6H); 7.44 (broad s, 1H). By concentrating the
fractions corresponding to diastereoisomer B under the same
conditions, 6.5 g of N-[(1R,2R)-1-benzyl-2-hydroxypropyl]--
N'-tert-butylthiourea are obtained in the form of white crystals
melting at 155.degree. C. .sup.1H NMR spectrum (250 MHz,
(CD.sub.3).sub.2SO-d.sub- .6, .delta. in ppm): 1.08 (d, J=7 Hz:
3H); 1.39 (s: 9H); 2.80 (limiting AB: 2H); 3.68 (mt: 1H); 4.42
(unres. mult.: 1H); 4.78 (unres. mult.: 1H); 7.08 (d, J=8.5 Hz:
1H); from 7.10 to 7.40 (mt: 6H).
[0267] (3R)-3-Amino-4-phenyl-2-butanol: A solution of 19.3 g of
tert-butyl (1R)-1-benzyl-2-hydroxypropylcarbamate in 160 cm.sup.3
of dioxane and 67 cm.sup.3 of 6.5N hydrochloric dioxane is stirred
at room temperature for 5 hours and is then concentrated under
reduced pressure (2 kPa) at a temperature in the region of
40.degree. C. A yellow oil is obtained, and is taken up in 50
cm.sup.3 of water and basified to a pH in the region of 10 with
potassium carbonate. This mixture is extracted with 3 times 100
cm.sup.3 of ethyl acetate and the combined organic phases are then
dried over sodium sulfate, filtered and evaporated under reduced
pressure (2 kPa) at a temperature in the region of 40.degree. C.
12.9 g of a 75%/25% mixture of the two diastereoisomers A and B of
(3R)-3-amino-4-phenyl-2-bu- tanol are obtained in the form of an
orange-colored oil. .sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm). A mixture of
diastereoisomers is observed: from 0.70 to 1.50 (broad unres.
mult.: 2H); 1.08 (d, J=6 Hz: 3H); from 2.25 to 2.45 (mt: 1H); from
2.70 to 2.85 (mt: 2H); 3.44 (mt: 1H); from 4.25 to 4.75 (unres.
mult.: 1H); from 7.10 to 7.35 (mt: 5H).
[0268] tert-Butyl (1R)-1-benzyl-2-hydroxypropylcarbamate: A
solution of 21 g of tert-butyl (1R)-1-benzyl-2-oxopropylcarbamate
in 200 cm.sup.3 of ethanol under an inert atmosphere is cooled to a
temperature in the region of 10.degree. C., followed by portionwise
addition of 4.55 g of sodium borohydride. The temperature of the
reaction medium is allowed to rise to room temperature with
stirring, and the stirring is then continued for 18 hours. The
reaction medium is concentrated under reduced pressure (2 kPa) at a
temperature in the region of 40.degree. C., to give white crystals
which are taken up in 150 cm.sup.3 of water. This mixture is
stirred for 2 hours at room temperature and then filtered through a
sinter funnel. The filter cake is washed with twice 150 cm.sup.3 of
water. After drying overnight in a fume cupboard, 19.37 g of
tert-butyl (1R)-1-benzyl-2-hydroxypropylcarbamate are obtained in
the form of white crystals melting at 127.degree. C. .sup.1H NMR
spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6 with addition of a
few drops of CD.sub.3COOD-d.sub.4, .delta. in ppm). A mixture of
two diastereoisomers in 70/30 proportions is observed: 1.04 and
1.10 (2d, J=6 Hz: 3H); 1.29 and 1.32 (2s: 9H); from 2.40 to 3.10
(mt: 2H); from 3.35 to 3.70 (mt: 2H); 6.40 and 6.54 (2d, J=9 Hz:
1H); from 7.10 to 7.35 (mt: 5H).
[0269] tert-Butyl (1R)-1-benzyl-2-oxopropylcarbamate: A mixture of
26.7 g of tert-butyl
(1R)-1-benzyl-2-[methoxy(methyl)amino]-2-oxoethylcarbamate in 534
cm.sup.3 of tetrahydrofuran dried over 4 .ANG. sieves is cooled,
under an inert atmosphere, to a temperature in the region of
0.degree. C. 87 cm.sup.3 of a 3 M solution of methylmagnesium
bromide in diethyl ether are then added over 45 minutes and the
resulting mixture is then stirred for 1 hour at 0.degree. C. and
for 18 hours at room temperature. The reaction medium is re-cooled
to a temperature in the region of 0.degree. C., 55 cm.sup.3 of 1N
hydrochloric acid are then added dropwise and the mixture is
stirred for 30 minutes at this temperature. After filtration
through Celite, 200 cm.sup.3 of water are added to the filtrate,
which is then extracted with twice 200 cm.sup.3 of ethyl acetate.
The combined organic phases are dried over sodium sulfate, filtered
and then concentrated under reduced pressure (2 kPa) at a
temperature in the region of 40.degree. C. 21.2 g of tert-butyl
(1R)-1-benzyl-2-oxopropylcar- bamate are obtained in the form of
yellow crystals melting at 59.degree. C. .sup.1H NMR spectrum (300
MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 1.34 (s: 9H);
2.13 (s: 3H); 2.71 (dd, J=14 and 10 Hz: 1H); 3.01 (dd, J=14 and 5
Hz: 1H); 4.13 (mt: 1H); from 7.10 to 7.35 (mt: 6H).
[0270] tert-Butyl
(1R)-1-benzyl-2-[methoxy(methyl)-amino]-2-oxoethylcarbam- ate: A
solution of 26.5 g of D-N-Boc-phenylalanine and 22 cm.sup.3 of
N-methylmorpholine in 300 cm.sup.3 of dichloromethane is cooled,
under an inert atmosphere, to a temperature in the region of
-15.degree. C. 13 cm.sup.3 of isobutyl chloroformate are then added
and the mixture is stirred for 15 min at this temperature. After
addition of 10.14 g of N,O-dimethylhydroxylamine hydrochloride,
stirring is continued for 1 hour at a temperature in the region of
-15.degree. C. and then for 3 hours at room temperature. 300
cm.sup.3 of water are added to the reaction medium, followed by
extraction with twice 200 cm.sup.3 of dichloromethane. The combined
organic phases are dried over sodium sulfate, filtered and
concentrated under reduced pressure (2 kPa) at a temperature in the
region of 50.degree. C. 32.2 g of an orange-colored oil are
obtained, and are purified on a column of silica gel (particle size
40-63 .mu.m; height 32 cm), eluting with a mixture of 97%
dichloromethane/3% methanol. After concentration of the fractions
containing the expected product under reduced pressure (2 kPa) at a
temperature in the region of 40.degree. C., 26.7 g of tert-butyl
(1R)-1-benzyl-2-[methoxy(methyl)amino]-2-oxoethylcar- bamate are
obtained in the form of a yellow oil. .sup.1H NMR spectrum (250
MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 1.32 (s: 9H);
2.72 (dd, J=13.5 and 10 Hz: 1H); 2.86 (dd, J=13.5 and 5 Hz: 1H);
3.12 (s: 3H); 3.74 (broad s: 3H); 4.55 (mt: 1H); from 7.10 to 7.35
(mt: 6H).
EXAMPLE 4
(+)-(4R,5R)-4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0271] A suspension of 6.5 g of
N-[(1R,2R)-1-benzyl-2-hydroxypropyl]-N'-te- rt-butylthiourea
(diastereoisomer B) in 77 cm.sup.3 of 6N hydrochloric acid is
heated at a temperature in the region of 100.degree. C. for 10
hours. The reaction medium is then concentrated under reduced
pressure (2 kPa) at a temperature in the region of 40.degree. C. to
give a yellow oil which is taken up in 100 cm.sup.3 of water. This
aqueous phase is washed with twice 50 cm.sup.3 of dichloromethane
and is then basified to a pH in the region of 10 by addition of 5
cm.sup.3 of concentrated sodium hydroxide. The resulting mixture is
then extracted with 3 times 50 cm.sup.3 of dichloromethane. The
combined organic phases are dried over sodium sulfate, filtered and
then concentrated under reduced pressure (2 kPa) at a temperature
in the region of 40.degree. C. 4.09 g of
(+)-(4R,5R)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine are
obtained in the form of white crystals melting at 89.degree. C.
[.sup.1H NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta.
in ppm): 1.22 (d, J=7 Hz: 3H); 2.66 (dd, J=13 and 7 Hz: 1H); 2.76
(dd, J=13 and 7 Hz: 1H); 3.54 (mt: 1H); 3.95 (mt: 1H); from 5.60 to
6.45 (unres. mult.: 2H); from 7.10 to 7,40 (mt: 5H). The relative
stereochemistry in positions 4 and 5 was validated by NOE. A strong
response of the proton H4 is noted after irradiating the methyl;
(.alpha..sub.D.sup.20=+83.9+.+-.1.3 at a concentration of 0.5% in
methanol)].
EXAMPLE 5
(-)-(4R)-4-(3-Thienylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
hydrochloride
[0272] A mixture of 0.94 g of
N-(tert-butyl)-N'-[(1R)-2-hydroxy-1-(3-thien-
ylmethyl)ethyl]thiourea in 9.2 cm.sup.3 of 6N hydrochloric acid is
heated at a temperature in the region of 100.degree. C. with
stirring for 3 hours and is then concentrated under reduced
pressure (2 kPa) at a temperature in the region of 40.degree. C. A
greenish oil is obtained, which is taken up in 10 cm.sup.3 of
acetone to give a sticky gum. 1.5 cm.sup.3 of ethanol are then
added, followed by dropwise addition, with stirring, of 6 cm.sup.3
of diethyl ether. The crystals obtained are filtered off on a
sinter funnel, washed with diethyl ether and then dried in an oven
under vacuum (10 Pa) at a temperature in the region of 50.degree.
C. 0.5 g of (-)-(4R)-4-(3-thienylmethyl)-4,5-dihydro-1,3-thiaz-
ol-2-ylamine hydrochloride is obtained in the form of gray crystals
melting at 152.degree. C. .sup.1H NMR spectrum (400 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 2.99 (mt: 2H); 3.26
(dd, J=11 and 5.5 Hz: 1H); 3.59 (dd, J=11 and 8 Hz: 1H); 4.54 (mt:
1H); 7.10 (dd, J=5.5 and 1 Hz: 1H); 7.38 (mt: 1H); 7.54 (dd, J=5
and 3 Hz: 1H); from 9.15 to 10.55 (broad unres. mult.: 3H).
(.alpha..sub.D.sup.20=-4.3.+- -.0.5 at a concentration of 0.5% in
methanol).
[0273]
N-(tert-butyl)-N'-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]thiourea-
: 0.9 cm.sup.3 of tert-butyl isothiocyanate and then 0.82 cm.sup.3
of triethylamine are added to a suspension of 0.9 g of
(2R)-2-amino-3-(3-thienyl)-1-propanol hydrochloride in 9 cm.sup.3
of absolute ethanol stirred and under an inert atmosphere. After
stirring for 66 hours at room temperature, the reaction medium is
evaporated under reduced pressure (2 kPa) at a temperature in the
region of 40.degree. C. The thick brown oil obtained is taken up in
6 cm.sup.3 of water and then extracted with twice 12 cm.sup.3 of
ethyl acetate. The organic phase is filtered through Celite and
washed with twice 4 cm.sup.3 of saturated aqueous sodium chloride
solution, dried over magnesium sulfate and evaporated under reduced
pressure (2 kPa) at a temperature in the region of 40.degree. C. A
brown oil is obtained, which crystallizes rapidly under cold
conditions and which is dried in an oven under vacuum (10 Pa) at a
temperature in the region of 48.degree. C. to give 0.97 g of
N-(tert-butyl)-N'-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]thiourea
in the form of a beige-colored solid melting at 109.degree. C.
.sup.1H NMR spectrum (400 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta.
in ppm): 1.43 (s: 9H); 2.84 (mt: 2H); 3.38 (mt: 2H); 4.42 (unres.
mult.: 1H); 4.86 (broad t, J=4.5 Hz: 1H); 7.04 (broad d, J=5 Hz:
1H); from 7.10 to 7.20 (mt: 2H); 7.25 (broad s: 1H); 7.46 (dd, J=5
and 3 Hz: 1H).
[0274] (2R)-2-Amino-3-(3-thienyl)-1-propanol hydrochloride: A
solution of 1.4 g of
N-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]acetamide in 17.6
cm.sup.3 of aqueous 6N hydrochloric acid is heated with stirring at
a temperature in the region of 100.degree. C. for 2 hours. The
reaction mixture is then concentrated under reduced pressure (2
kPa) at a temperature in the region of 40.degree. C. to give a
greenish oil, which crystallizes from 60 cm.sup.3 of acetone. The
crystals are filtered off on a sinter funnel, washed with acetone
and then dried in an oven under vacuum (10 Pa) at a temperature in
the region of 50.degree. C. 0.92 g of
(2R)-2-amino-3-(3-thienyl)-1-propanol hydrochloride is obtained in
the form of an off-white solid. .sup.1H NMR spectrum (400 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm) 2.93 (mt: 2H); from
3.25 to 3.50 (mt: 2H); 3.53 (broad d, J=11 Hz: 1H); 5.37 (unres.
mult.: 1H); 7.07 (broad d, J=5 Hz: 1H); 7.35 (mt: 1H); 7.53 (dd,
J=5 and 3 Hz: 1H); 8.18 (unres. mult.: 3H)
[0275] N-[(1R)-2-Hydroxy-1-(3-thienylmethyl)-ethyl]acetamide: A
solution of 2.15 g of ethyl
(2R)-2-(acetylamino)-3-(3-thienyl)propanoate in 24 cm.sup.3 of
ethanol, stirred under an inert atmosphere, is brought to a
temperature of 20.degree. C. 0.5 g of sodium borohydride is added
and the reaction medium, which is slightly brown, is stirred for 24
hours at room temperature. A further 0.2 g of sodium borohydride is
added and stirring is continued for 24 hours. After evaporation of
the reaction mixture under reduced pressure (2 kPa) at a
temperature in the region of 40.degree. C., a solid residue is
obtained, which is taken up in 30 cm.sup.3 of water. This mixture
is extracted with twice 100 cm.sup.3 of ethyl acetate and the
organic phase is then dried over magnesium sulfate and evaporated
under reduced pressure (2 kPa) at a temperature in the region of
40.degree. C. to give an off-white solid which is dried in an oven
under vacuum (10 Pa) at a temperature in the region of 48.degree.
C. 1.4 g of N-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]acetamide
are obtained in the form of an off-white solid melting at about
105.degree. C. to become pasty. .sup.1H NMR spectrum (400 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 1.78 (s: 3H); 2.64
(dd, J=14 and 8 Hz: 1H); 2.87 (dd, J=14 and 5.5 Hz: 1H); from 3.20
to 3.40 (mt: 2H); 3.90 (mt: 1H); 4.76 (t, J=5.5 Hz: 1H); 6.99 (dd,
J=5 and 1 Hz: 1H); 7.16 (dd, J=3 and 1 Hz: 1H); 7.43 (dd, J=5 and 3
Hz: 1H); 7.70 (d, J=8.5 Hz: 1H).
[0276] Ethyl (2R)-2-(acetylamino)-3-(3-thienyl)propanoate: 3.95 g
of ammonium hydrogen carbonate and 35 cm.sup.3 of deionized water
are added to a stirred solution, under an inert atmosphere, of 2.41
g of ethyl 2-(acetylamino)-3-(3-thienyl)propanoate in 17 cm.sup.3
of acetonitrile. 0.017 g of type-II .alpha.-chymotrypsin is added
and the pH of the reaction medium is then in the region of 8. This
mixture is stirred for 1 hour at room temperature and, after
checking that the pH is still at 8, a further 0.017 g of type-II
.alpha.-chymotrypsin is added. After stirring for 1 hour, with the
pH remaining constant, a further 0.017 g of type-II
.alpha.-chymotrypsin is introduced and stirring of the reaction
mixture is continued for 19 hours at room temperature. The
acetonitrile is evaporated off under reduced pressure (2 kPa) at a
temperature in the region of 33.degree. C. and 25 cm.sup.3 of ethyl
acetate are then added to the residual aqueous phase. The emulsion
obtained is filtered through Celite and the aqueous phase is then
extracted with twice 25 cm.sup.3 of ethyl acetate. The organic
phases are combined, washed with twice 15 cm.sup.3 of sodium
carbonate solution and then evaporated under reduced pressure (2
kPa) at a temperature in the region of 40.degree. C. The solid
residue is then dried in an oven under vacuum (10 Pa) at room
temperature. 1.1 g of ethyl
(2R)-2-(acetylamino)-3-(3-thienyl)propanoate are obtained in the
form of a beige-colored solid melting at about 75.degree. C.
[0277] Ethyl 2-(acetylamino)-3-(3-thienyl)-propanoate: 9.83 g of
lithium iodide are added in a single portion to a stirred pale
yellow solution, under an inert atmosphere, of 7.7 g of diethyl
2-(acetylamino)-2-(3-thien- ylmethyl)malonate in 62 cm.sup.3 of
dimethylformamide, and the resulting mixture is heated in an oil
bath at a temperature in the region of 128.degree. C. for 19 hours.
6.6 g of lithium iodide are added and heating is continued for 5
hours. The reaction medium is then evaporated under reduced
pressure (2.4 kPa) at a temperature in the region of 55.degree. C.
The residual brown oil is taken up in 180 cm.sup.3 of water and is
extracted with 4 times 60 cm.sup.3 of ethyl acetate. The organic
phases are combined, washed with 30 cm.sup.3 of saturated aqueous
sodium chloride solution, dried over magnesium sulfate and then
evaporated under reduced pressure (2 kPa) at a temperature in the
region of 62.degree. C., to give 5.34 g of a brown oil which
crystallizes under cold conditions. The crystals are taken up in 40
cm.sup.3 of petroleum ether, ground in a mortar and then filtered
off on a sinter funnel and dried in an oven under vacuum (10 Pa) at
room temperature. 4.9 g of ethyl
2-(acetylamino)-3-(3-thienyl)propanoate are obtained in the form of
an off-white solid melting at about 60.degree. C. .sup.1H NMR
spectrum (400 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm):
1.14 (t, J=7 Hz: 3H) 1.84 (s: 3H); 2.93 (dd, J=14 and 9 Hz: 1H);
3.03 (dd, J=14 and 5.5 Hz: 1H); 4.06 (mt: 2H); 4.44 (mt: 1H); 7.02
(dd, J=5 and 1 Hz: 1H); 7.24 (mt: 1H); 7.45 (dd, J=5 and 3 Hz: 1H);
8.31 (d, J=8 Hz: 1H).
[0278] Diethyl 2-(acetylamino)-2-(3-thienylmethyl)malonate: 1.54 g
of sodium are added, with stirring under an inert atmosphere, to
115 cm.sup.3 of absolute ethanol. After total consumption of the
sodium, 14.55 g of diethyl acetamidomalonate are added, followed by
heating at a temperature in the region of 78.degree. C. for 20
minutes. A solution of 16.5 g of freshly prepared
3-(bromomethyl)thiophene in 50 cm.sup.3 of ethanol is then added
and heating is continued at this same temperature for 19 hours. The
reaction medium, which contains an insoluble white material, is
cooled to a temperature in the region of 0.degree. C. and is then
filtered through a sinter funnel. The filtrate is concentrated
under reduced pressure (2 kPa) at a temperature in the region of
40.degree. C. and is then filtered through a sinter funnel. The
crystals are taken up in 100 cm.sup.3 of water, filtered again,
washed with petroleum ether and dried in a fume cupboard at room
temperature. 1.45 g of diethyl
2-(acetylamino)-2-(3-thienylmethyl)malonate are obtained in the
form of a white solid melting at about 92.degree. C. After
evaporation of the filtration solvent in ambient air, the residue
is taken up in 150 cm.sup.3 of water and is then filtered on a
sinter funnel. The yellowish solid obtained is washed with 50
cm.sup.3 of water and is then dissolved in 25 cm.sup.3 of absolute
ethanol, followed by crystallization by addition of 25 cm.sup.3 of
water. After filtration, washing with 3 times 30 cm.sup.3 of
petroleum ether and then drying in a fume cupboard at room
temperature, 6.57 g of diethyl
2-(acetylamino)-2-(3-thienylmethyl)malonat- e are obtained in the
form of a white solid melting at about 92.degree. C. .sup.1H NMR
spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm):
1.18 (t, J=7 Hz: 6H); 1.98 (s: 3H); 3.50 (s: 2H); 4.16 (q, J=7 Hz:
4H); 6.80 (broad d, J=5 Hz: 1H); 7.14 (broad s: 1H); 7.46 (dd, J=5
and 3 Hz: 1H); 8.20 (broad s: 1H).
[0279] 3-(Bromomethyl)thiophene can be prepared according to J.
Gourier and P. Cannone; Bull. Soc. Chim. Fr. 1971, 3299-3306.
EXAMPLE 6
[3-(2-Amino-4,5-dihydrothiazol-4-yl)phenyl]-(1-iminoethyl)amine
[0280] 0.15 g of benzyl ethanimidothioate hydrochloride and then 5
cm.sup.3 of ethanol are added, under an inert atmosphere and at a
temperature in the region of 0.degree. C., to a stirred solution of
0.14 g of 4-(3-aminophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine in 15
cm.sup.3 of ethanol. The mixture is stirred for 1 hour at about
0.degree. C. and then for 2 hours at a temperature in the region of
20.degree. C. A further 0.030 g of benzyl ethanimidothioate is
added to complete the reaction, after which the mixture is
maintained at a temperature in the region of 45.degree. C. for 24
hours. The reaction medium is evaporated under reduced pressure (5
kPa) at a temperature in the region of 40.degree. C. The residue
obtained is taken up in 30 cm.sup.3 of water and the solution is
washed with 30 cm.sup.3 of dichloromethane. The aqueous solution is
concentrated under the above conditions and the solid obtained is
then triturated from diethyl-ether, filtered, air-dried and
purified by chromatography at atmospheric pressure on a column of
silica gel (particle size 40-63 .mu.; mass 63 g), eluting with a
dichloromethane/methanol/aqueous ammonia mixture (12/3/0.5 by
volume). The fractions containing the expected product are
collected. These fractions are combined and then evaporated under
reduced pressure (5 kPa) at a temperature in the region of
40.degree. C. 0.100 g of
[3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl]-(1-iminoethyl)amine is
obtained in the form of a white solid melting at 180.degree. C.
.sup.1H NMR spectrum (250 MHz, (CD.sub.3).sub.2SO-d.sub.6, with
addition of a few drops of CD.sub.3COOD-d.sub.4, .delta. in ppm):
2.28 (unres. mult.: 3H); 3.18 (dd, J=12.5 and 8.5 Hz: 1H); 3.80
(dd, J=12.5 and 8.5 Hz: 1H); 5.30 (t, J=8.5 Hz: 1H); 7.21 (broad d,
J=8.5 Hz: 1H); 7.27 (broad s: 1H); 7.36 (broad d, J=8.5 Hz: 1H);
7.49 (broad t, J=8.5: Hz: 1H).
[0281] Benzyl ethanimidothioate hydrochloride can be obtained by
applying the method described in patent WO 96/19440.
[0282] 4-(3-Aminophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine: 3 g of
zinc powder are added, with stirring at a temperature in the region
of 20.degree. C., to a suspension of 2.4 g of
4-(3-nitrophenyl)-4,5-dihydro-- 1,3-thiazol-2-ylamine hydrochloride
in 50 cm.sup.3 of 85% by volume of acetic acid. After stirring for
20 minutes at room temperature, the reaction medium is filtered;
the filter cake is washed with 10 cm.sup.3 of water and the
filtrate is then concentrated under reduced pressure (5 kPa) at a
temperature in the region of 50.degree. C. The residue obtained is
taken up in methanol and then in diethyl ether, and concentrated
under the same conditions as above. This operation is repeated a
second time. The product obtained is taken up in 100 cm.sup.3 of
acetonitrile and filtered. The filtrate is concentrated as above
and taken up in 60 cm.sup.3 of water. The insoluble material is
filtered off, while the filtrate is made alkaline by addition of 7
cm.sup.3 of aqueous 1N sodium hydroxide solution. The insoluble
material is separated out by filtration and the filtrate is again
concentrated as above, and taken up in 40 cm.sup.3 of a
dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by
volume). The insoluble material is filtered off and the filtrate is
concentrated as above. 4.2 g of a yellow oil are obtained, and are
purified by chromatography at atmospheric pressure on a column of
silica gel (particle size 40-63.mu.; 100 g of silica), eluting with
a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by
volume). The fractions containing the product are combined and then
concentrated (5 kPa) at a temperature in the region of 40.degree.
C. 0.73 g of 4-(3-aminophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine is
obtained in the form of a yellow solid melting at 152.degree.
C.
[0283] 4-(3-Nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
hydrochloride: The process is performed as in Example 2, starting
with 4.77 g of
N-(tert-butyl)-N'-[2-hydroxy-1-(3-nitrophenyl)ethyl]thiourea and 44
cm.sup.3 of aqueous 6N hydrochloric acid, and this mixture is
maintained at a temperature in the region of 100.degree. C. for 2 h
30 min. After an identical work-up, 3.1 g of
4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-y- lamine hydrochloride
are obtained in the form of a cream-colored solid melting at
232.degree. C.
[0284]
N-(tert-Butyl)-N'-[2-hydroxy-1-(3-nitrophenyl)ethyl]thiourea: The
process is performed as in Example 2, starting with 5.1 g of
2-amino-2-(3-nitrophenyl)-1-ethanol in 170 cm.sup.3 of ethanol
containing 85 cm.sup.3 of dichloromethane and 4.6 cm.sup.3 of
tert-butyl isothiocyanate, at a temperature in the region of
20.degree. C. for 3 days and then at a temperature in the region of
60.degree. C. for 7 hours. After addition of a further 0.35
cm.sup.3 of tert-butyl isothiocyanate and 16 hours at a temperature
in the region of 60.degree. C., an identical work-up gives 5.7 g of
N-(tert-butyl)-N'-[2-hydroxy-1-(3- -nitrophenyl)ethyl]thiourea in
the form of an ocher-colored solid melting at 162.degree. C.
[0285] 2-Amino-2-(3-nitrophenyl)-1-ethanol: The process is
performed as in Example 2, starting with 1 g of ethyl
3-nitrophenylglycinate in 20 cm.sup.3 of ethanol with 0.255 g of
sodium borohydride and 20 hours at a temperature in the region of
20.degree. C. After an identical work-up, 0.200 g of
2-amino-2-(3-nitrophenyl)-1-ethanol is obtained in the form of an
ocher-yellow paste.(R.sub.f=0.18 in a 90/10 by volume mixture of
dichloromethane/methanol, on a Merck 60F.sub..sub.254.sub.R silica
plate).
[0286] Ethyl 3-nitrophenylglycinate: 2 g of 3-nitrophenylglycine
are heated for 20 hours with stirring at a temperature in the
region of 100.degree. C. in 100 cm.sup.3 of absolute ethanol
containing 20 cm.sup.3 of 6.5N hydrochloric ethanol. The suspension
is filtered at a temperature in the region of 50.degree. C.; the
filtrate is concentrated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. The residue obtained is
taken up in water and then extracted with about 100 cm.sup.3 of
ethyl acetate. The aqueous phase is made alkaline by addition of
sodium carbonate until a pH in the region of 10 is obtained. The
medium is extracted with ethyl acetate; the combined extracts are
washed with aqueous sodium chloride solution, dried over magnesium
sulfate and then concentrated under reduced pressure (5 kPa) at
40.degree. C. 1 g of ethyl 3-nitrophenylglycinate is obtained in
the form of a yellow oil.(R.sub.f=0.38 in a 95/5 by volume mixture
of dichloromethane/methanol, on a Merck 60F.sub..sub.254.sub.R
silica plate).
[0287] 3-Nitrophenylglycine: 1.01 g of potassium nitrate are added
slowly, at a temperature in the region of 0.degree. C. with
stirring, to a mixture of 1.51 g of D-(-)-.alpha.-phenylglycine in
6 cm.sup.3 of 95% sulfuric acid and the temperature is then allowed
to return to about 20.degree. C. The solution obtained is poured
into 30 cm.sup.3 of ice-cold water and then brought to pH 7 by
addition of 18.5 cm.sup.3 of 10N sodium hydroxide, at a temperature
below 5.degree. C. The mixture is stirred for 2 hours and then
filtered. The filter cake obtained is washed with twice 50 cm.sup.3
of water and then dried. 0.60 g of 3-nitrophenyl-glycine is
obtained in the form of a cream-colored solid melting at
230.degree. C.
EXAMPLE 7
(+)-(4R)-4-Benzyl-4,5-dihydro-1,3-thiazol-2-ylamine
hydrochloride
[0288] The process is performed as in Example 2, starting with 2 g
of N-(tert-butyl)-N'-[(1R)-2-hydroxy-1-(phenylmethyl)ethyl]thiourea
and 20 cm.sup.3 of aqueous 6N hydrochloric acid. The reaction lasts
1h 30 min. After cooling the reaction mass to a temperature in the
region of 0.degree. C., the solution is concentrated under reduced
pressure (5 kPa) at a temperature in the region of 40.degree. C.
Crystallization of the oil obtained is initiated by addition of
diethyl ether. The resulting precipitate is spin-filtered, washed
with twice 10 cm.sup.3 of diethyl ether and then dried under
reduced pressure (10 Pa) at a temperature in the region of
60.degree. C. The product is purified by taking it up in 100
cm.sup.3 of dichloromethane with stirring for 30 minutes. After
filtration of the suspension, the filter cake is washed with twice
10 cm.sup.3 of dichloromethane and is then dried under the same
conditions as above. 1.1 g of
(+)-(4R)-4-phenylmethyl-4,5-dihydro-1,3-thiazol-2-ylam- ine
hydrochloride are obtained in the form of a white solid melting at
168.degree. C. (.alpha..sub.D.sup.20=+8.7.+-.0.3 at a concentration
of 1% in methanol).
[0289] N-(tert-Butyl)-N'-[(1R)-2-hydroxy-1-(benzyl)ethyl]thiourea:
The process is performed as in Example 2, starting with 5 g of
(R)-(+)2-amino-3-phenyl-1-propanol in 50 cm.sup.3 of ethanol and
5.7 g of tert-butyl isothiocyanate at a temperature in the region
of 20.degree. C. for 16 hours. After an identical work-up, 8.7 g of
N-(tert-butyl)-N'-[(1R)-2-hydroxy-1-(phenylmethyl)ethyl]thiourea
are obtained in the form of a white solid melting at 107.degree.
C.
EXAMPLE 8
(+)-(4R)-4-(3-Carboxybenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
hydrochloride
[0290] The process is performed as in Example 2, starting with 2.31
g of
N-(tert-butyl)-N'-[(1R-)-2-hydroxy-1-(3-carboxybenzyl)ethyl]thiourea
in 25 cm.sup.3 of 6N hydrochloric acid for 18 hours. After
concentration of the reaction mixture under reduced pressure (5
kPa) at a temperature in the region of 55.degree. C., the residue
is taken up in 20 cm.sup.3 of acetone and is then concentrated
again under the above conditions. The residue obtained is purified
by chromatography under a pressure of 50 kPa of argon, on a column
of silica gel (particle size 40-63.mu.; mass of silica: 100 g),
eluting with a chloroform/methanol/20% aqueous ammonia mixture
(12/6/1 by volume) and collecting 30 cm.sup.3 fractions. Fractions
16 to 38 are combined and then concentrated under reduced pressure
(5 kPa) at a temperature in the region of 40.degree. C. The solid
obtained is dissolved in 10 cm.sup.3 of aqueous 6N hydrochloric
acid and is then concentrated as previously. After taking up the
residue obtained in 10 cm.sup.3 of acetone, the resulting insoluble
material is filtered off; the filtrate is concentrated as above. A
solid is obtained, which is dried for 5 hours in an oven at
40.degree. C., under reduced pressure (8 Pa). 0.650 g of
(+)-(4R)-4-(3-carboxybenzyl)-4,5-dihydro-1,3-- thiazol-2-ylamine
hydrochloride is obtained in the form of a beige-colored solid
melting at 151.degree. C. (.alpha..sub.D.sup.20=+13.4.+-.0.6 at a
concentration of 0.5% in methanol).
[0291]
N-(tert-Butyl)-N'-[(1R)-2-hydroxy-1-(3-carboxybenzyl)ethyl]thiourea-
: The process is performed as in Example 2, starting with 1.82 g of
(2R)-2-amino-3-(3-carboxyphenyl)-1-propanol hydrochloride in 20
cm.sup.3 of ethanol, 4.2 cm.sup.3 of triethylamine and 1.7 cm.sup.3
of tert-butyl isothiocyanate. After heating for 21 hours at a
temperature in the region of 60.degree. C. and an identical
work-up, 2.31 g of
N-(tert-butyl)-N'-[(1R)-2-hydroxy-1-(3-carboxybenzyl)ethyl]thiourea
are obtained in the form of a light brown foam. (R.sub.f=0.33 in a
12/6/1 by volume mixture of chloroform/methanol/aqueous ammonia, on
a Merck 60F.sub..sub.254.sub.R silica plate).
[0292] (2R)-2-Amino-3-(3-carboxyphenyl)-1-propanol hydrochloride:
The process is performed as in Example 2, starting with 1.96 g of
N-[(1R)-2-hydroxy-1-(3-carboxybenzyl)ethyl]acetamide in 14 cm.sup.3
of aqueous 6N hydrochloric acid heated at a temperature in the
region of 100.degree. C. for 17 hours. After an identical work-up,
2.16 g of (2R)-2-amino-3-(3-carboxyphenyl)-1-propanol hydrochloride
are obtained in the form of a white solid melting at 194.degree.
C.
[0293] N-[(1R)-2-Hydroxy-1-(3-cyanobenzyl)ethyl]-acetamide: The
process is performed as in Example 2, starting with 3.3 g of ethyl
(2R)-2-acetylamino-3-(3-cyanophenyl)propanoate and 1.23 g of sodium
borohydride in 50 cm.sup.3 of ethanol and working at a temperature
in the region of -30.degree. C. After stirring for 16 hours at a
temperature in the region of, 20.degree. C., the reaction medium is
evaporated under reduced pressure (5 kPa) at a temperature in the
region of 45.degree. C. and the residue obtained is then stirred in
a mixture of 100 cm.sup.3 of water and 100 cm.sup.3 of ethyl
acetate. The organic phase is separated out after settling has
taken place and the aqueous phase is extracted with twice 100
cm.sup.3 of ethyl acetate. The organic extracts are combined and
then washed with twice 50 cm.sup.3 of water, dried over magnesium
sulfate, filtered and evaporated under reduced pressure (5 kPa) at
a temperature in the region of 45.degree. C. 2.13 g of
N-[(1R)-2-hydroxy-1-(3-cyanobenzyl)ethyl]acetamide are obtained in
the form of a white solid. (.alpha..sub.D.sup.20=+7.5.+-.0.6 at a
concentration of 0.5% in methanol).
[0294] Ethyl (2R)-2-acetylamino-3-(3-cyanophenyl)-propanoate: The
process is performed as in Example 2, starting with 11.39 g of
ethyl (2RS)-2-acetylamino-3-(3-cyanophenyl)propanoate, 17.39 g of
ammonium hydrogen carbonate and 0.1 g of .alpha.-chymotrypsin in
200 cm.sup.3 of water and 70 cm.sup.3 of acetonitrile. After
stirring for 24 hours at a temperature in the region of 20.degree.
C. and an identical work-up, 5.40 g of ethyl
(2R)-2-acetylamino-3-(3-cyanophenyl)propanoate are obtained in the
form of a beige-colored solid.(R.sub.f=0.76 in a 40/10/20 by volume
mixture of n-butanol/acetic acid/water, on a Merck
60F.sub..sub.254.sub.R silica plate)
[0295] Ethyl (2RS)-2-acetylamino-3-(3-cyanophenyl)-propanoate: The
process is performed as in Example 5, starting with 14.9 g of ethyl
2-acetylamino-2-(3-cyanobenzyl)malonate, 30 g of anhydrous lithium
iodide and 150 cm.sup.3 of dry dimethylformamide. After stirring
for 5 hours at a temperature in the region of 150.degree. C., the
reaction mass is cooled to room temperature. 1500 cm.sup.3 of water
are added and the mixture is extracted with 3 times 300 cm.sup.3 of
ethyl acetate. The extracts are combined, dried over magnesium
sulfate, filtered and concentrated under reduced pressure (5 kPa)
at a temperature in the region of 45.degree. C. After drying in an
oven at a temperature in the region of 40.degree. C. under reduced
pressure (10 Pa), 11.39 g of ethyl
(2RS)-2-acetylamino-3-(3-cyanophenyl)propanoate are obtained in the
form of a beige-colored paste. (R.sub.f=0.51 in a 90/10 by volume
mixture of ethyl acetate/cyclohexane, on a Merck
60F.sub..sub.254.sub.R silica plate).
[0296] Ethyl 2-acetylamino-2-(3-cyanobenzyl)-malonate: The process
is performed as in Example 5, starting with 27.7 g of diethyl
acetamidomalonate, 25 g of 3-cyanobenzyl bromide and 3.2 g of
sodium in 400 cm.sup.3 of absolute ethanol. After an identical
work-up, the cooled reaction mass is filtered and the filter cake
is washed with twice 50 cm.sup.3 of ethanol and then with twice 50
cm.sup.3 of water. After drying in an oven under reduced pressure
(10 Pa) at a temperature in the region of 40.degree. C., 21.98 g of
a white powder are obtained. The filtrate is evaporated under
reduced pressure (5 kPa) at a temperature in the region of
50.degree. C.; a foam is obtained, which is taken up in 100
cm.sup.3 of water and extracted with 100 cm.sup.3 of ethyl acetate
and then twice 50 cm.sup.3 of the same solvent. The extracts are
combined, washed with twice 50 cm.sup.3 of water, dried over
magnesium sulfate, filtered and evaporated under reduced pressure
(5 kPa) at a temperature in the region of 45.degree. C. The residue
obtained is taken up in 20 cm.sup.3 of ethanol. The crystals
obtained are spin-filtered, washed with ethanol and dried in an
oven under reduced pressure (10 Pa) at a temperature in the region
of 40.degree. C. The two crops are combined to give 31.94 g of
ethyl 2-acetylamino-2-(3-cyanobenzyl)-malonate in the form of a
white powder melting at 138.degree. C.
EXAMPLE 9
(+)-(4R)-4-(4-Aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
dihydrochloride
[0297] The process is performed as in Example 1, starting with 5.9
g of benzyl
(5R)-5-{[(tert-butylamino)carbothioyl]amino}-6-hydroxyhexylcarbama-
te in 40 cm.sup.3 of aqueous 6N hydrochloric acid at a temperature
in the region of 100.degree. C. for 3 hours. After concentration of
the reaction-medium under reduced pressure (5 kPa) at a temperature
in the region of 50.degree. C., the residue obtained is taken up in
ethanol and then concentrated again under the above conditions. The
paste obtained is crystallized by trituration from an
ethanol/methanol mixture (8/2 by volume). The crystals are filtered
off, washed with acetonitrile and air-dried. 1.3 g of
(+)-(4R)-4-(4-aminobutyl)-4,5-dihydro-1,3-thiazol-2-y- lamine
dihydrochloride are obtained in the form of a white solid melting
at 188.degree. C. (.alpha..sub.D.sup.20=+16.2.+-.0.7 at a
concentration of 0.5% in methanol).
[0298] Benzyl
(5R)-5-{[(tert-butylamino)-carbothioyl]amino}-6-hydroxyhexyl-
carbamate: 1.78 g of lithium chloride and then 1.6 g of sodium
borohydride are added, under an inert atmosphere, to a stirred
solution of 12.7 g of ethyl
(2R)-6-{[(benzyloxy)-carbonyl]amino}-2-{[(tert-butylamino)carbothio-
yl]-amino}hexanoate in 130 cm.sup.3 of ethanol and 65 cm.sup.3 of
tetrahydrofuran, cooled to between 0.degree. C. and 5.degree. C.
After stirring for 16 hours at a temperature in the region of
20.degree. C., a further 0.4 g of borohydride is added and the
mixture is maintained at about 80.degree. C. for 4 hours. The
reaction medium is filtered and the filter cake is washed with
ethanol. The filtrate is concentrated under reduced pressure (5
kPa) at a temperature in the region of 40.degree. C. and the
residue obtained is taken up in a dichloromethane/ethyl acetate
mixture (85/15 by volume) and left under cold conditions at about
5.degree. C. The crystalline product is spin-filtered and purified
by chromatography at atmospheric pressure on a column of silica gel
(particle size 40-63.mu.; mass of silica: 600 g), eluting with a
dichloromethane/ethyl acetate mixture (85/15 by volume). The
fractions containing the expected product are collected. These
fractions are combined and then concentrated under reduced pressure
(5 kPa) at a temperature in the region of 40.degree. C. 6.9 g of
benzyl
(5R)-5-{[(tert-butylamino)carbothioyl]amino}-6-hydroxyhexylcarbamate
are obtained in the form of a colorless oil.
(.alpha..sub.D.sup.20=+24.0.+-.0- .8 at a concentration of 0.5% in
methanol).
[0299] Ethyl
(2R)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butylamino)carb-
othioyl]amino}hexanoate: The process is performed as in Example 2,
starting with 7.4 g of ethyl
(2R)-2-amino-6-{[(benzyloxy)carbonyl]-amino}- hexanoate with 5
cm.sup.3 of tert-butyl isothiocyanate in 200 cm.sup.3 of anhydrous
ethanol at a temperature in the region of 20.degree. C. for 20
hours. The reaction is completed by addition of a further 1
cm.sup.3 of isothiocyanate and heating for 2 hours at a temperature
in the region of 80.degree. C. The reaction medium is concentrated
under reduced pressure (5 kPa) at a temperature in the region of
40.degree. C. The residue obtained is taken up in ether and
concentrated again under the above conditions. 13 g of ethyl
(2R)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-b-
utylamino)carbothioyl]amino}hexanoate are obtained in the form of a
colorless oil. (.alpha..sub.D.sup.20=-12.5.+-.0.5 at a
concentration of 0.5% in methanol).
[0300] Ethyl (2R)-2-amino-6-{[(benzyloxy)carbonyl]-amino}hexanoate:
3.9 cm.sup.3 of thionyl chloride are added to a stirred suspension
of 7.9 g of (2R)-2-amino-6-{[(benzyloxy)carbonyl]amino}hexanoic
acid (N.epsilon.-CBZ-D-lysine) in 120 cm.sup.3 of anhydrous ethanol
cooled to a temperature in the region of -25.degree. C. The mixture
is stirred for 3 hours at this temperature and is then allowed to
warm to about 20.degree. C. After leaving for 3 days, the reaction
mass is concentrated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. The residue obtained is
taken up in 200 cm.sup.3 of ethyl acetate and the resulting
solution is washed with aqueous sodium carbonate solution and then
with aqueous sodium chloride solution. The organic solution is
dried over magnesium sulfate, filtered and concentrated under
reduced pressure (5 kPa) at a temperature in the region of
40.degree. C. 7.4 g of ethyl (2R)-2-amino-6-{[(benzyloxy)-carbo-
nyl]amino}hexanoate are obtained in the form of a pale yellow oil.
(.alpha..sub.D.sup.20=-11.7.+-.0.6 at a concentration of 0.5% in
methanol).
EXAMPLE 10
(-)-(4S)-4-(3-Nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
hydrochloride
[0301] The process is performed as in Example 2, starting with
N-(tert-butyl)-N'-[(1S)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea
in 80 cm.sup.3 of aqueous 6N hydrochloric acid. The heating time is
7 hours. The product is isolated in an identical manner and then
purified by chromatography under an argon pressure of 80 kPa, on a
column of silica gel (particle size 40-63.mu.; diameter 3.5 cm;
height 30 cm), eluting with a dichloromethane/methanol mixture
(95/5 by volume). The fractions corresponding to the expected
product are collected. These fractions are combined and then
concentrated under reduced pressure (5 kPa) at a temperature in the
region of 40.degree. C. 3.90 g of
(-)-(4S)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine
hydrochloride are obtained in the form of a white solid melting at
220.degree. C. (.alpha..sub.D.sup.20=-18.4.+-.0.05 at a
concentration of 0.5% in methanol).
[0302]
N-(tert-Butyl)-N'-[(1S)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea:
The process is performed as in Example 2, starting with 5.65 g of
(2S)-2-amino-3-(3-nitrophenyl)-1-propanol hydrochloride, 3.7
cm.sup.3 of tert-butyl isothiocyanate and 3.41 cm.sup.3 of
triethylamine in 60 cm.sup.3 of ethanol. After stirring for 3 days
at a temperature in the region of 20.degree. C. and then heating
for 30 minutes at a temperature in the region of 60.degree. C., 3.7
cm.sup.3 of tert-butyl isothiocyanate are added to the reaction
medium and heating is then continued for a further 3 hours at the
same temperature. After an identical work-up, 6.45 g of
N-(tert-butyl)-N'-[(1S)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea
are obtained in the form of a yellow foam.(R.sub.f=0.61 in a
40/5/0.5 by volume mixture of dichloromethane/methanol/aqueous
ammonia, on a Merck 60F.sub..sub.254.sub.R silica plate).
[0303] (2S)-2-Amino-3-(3-nitrophenyl)-1-propanol hydrochloride: The
process is performed as in Example 2, starting with 5.8 g of
N-[(1S)-2-hydroxy-1-(3-nitrobenzyl)ethyl]acetamide in 60 cm.sup.3
of aqueous 6N hydrochloric acid, for 10 hours at a temperature in
the region of 100.degree. C. After cooling the medium, the
precipitate is filtered off and then washed with 30 cm.sup.3 of
acetone and 3 times 50 cm.sup.3 of ether, and dried in an oven
under reduced pressure (10 Pa) at a temperature in the region of
60.degree. C. The filtrate is concentrated under reduced pressure
(5 kPa) at about 50.degree. C. The residue obtained is taken up in
30 cm.sup.3 of diethyl ether and the crystals are filtered off,
washed with twice 30 cm.sup.3 of ether and dried in an oven under
the same conditions as above. The 2 crops crystallized are
combined. 5.65 g of (2S)-2-amino-3-(3-nitrophenyl)-1-propanol
hydrochloride are obtained in the form of a-beige-colored-solid
melting at 188.degree. C.
[0304] N-[(1S)-2-Hydroxy-1-(3-nitrobenzyl)ethyl]-acetamide: The
process is performed as in Example 2, starting with 7.15 g of ethyl
(2S)-2-(acetylamino)-3-(3-nitrophenyl)propanoate and 1.46 g of
sodium borohydride in 70 cm.sup.3 of ethanol. After an identical
work-up, 5.8 g of
N-[(1S)-2-hydroxy-1-(3-nitrobenzyl)-ethyl]acetamide are obtained in
the form of a white solid melting at 131.degree. C.
[0305] Ethyl (2S)-2-(acetylamino)-3-(3-nitrophenyl)-propanoate can
be prepared according to Rivier et al., J. Med. Chem. (1995),
2658.
EXAMPLE 11
(-)-(4S,5S)-4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0306] The process is performed as in Example 3, starting with 3.9
g of diastereoisomer A of the
N-(tert-butyl)-N'-(1S)-1-benzyl-2-hydroxypropyl)- thiourea in 46
cm.sup.3 of aqueous 6N hydrochloric acid. After heating for 5 hours
at a temperature in the region of 100.degree. C., the reaction mass
is concentrated under reduced pressure (5 kPa) at a temperature in
the region of 50.degree. C. The oil obtained is dissolved in 50
cm.sup.3 of water; the solution is washed with twice 50 cm.sup.3 of
dichloromethane. The aqueous-phase is made alkaline by addition of
3 cm.sup.3 of 30% caustic soda and then extracted with 3 times 50
cm.sup.3 of dichloromethane. The organic extracts are combined and
dried over sodium sulfate. After filtration and concentration under
reduced pressure (5 kPa) at a temperature in the region of
40.degree. C., 2.5 g of
(-)-(4S,5S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine are
obtained in the form of a white solid melting at 89.degree. C.
(trans isomer). (.alpha..sub.D.sup.20=-87.3.+-.1.3 at a
concentration of 0.5% in methanol).
[0307] N-(tert-Butyl)-N'-(1S)-1-benzyl-2-hydroxypropyl)thiourea:
The process is performed as in Example 3, starting with 9.5 g of
(3S)-3-amino-4-phenyl-2-butanol in 80 cm.sup.3 of ethanol and in
the presence of 7.86 cm.sup.3 of tert-butyl isothiocyanate. After
stirring the mixture for 3 days at a temperature in the region of
20.degree. C. and an identical work-up, 15.9 g of an oil are
obtained, and are purified by chromatography under a pressure of
argon (50 kPa), on a column of silica gel (particle size 40-63.mu.;
diameter 5 cm; height of silica 38 cm), eluting with a
dichloromethane/ethyl acetate mixture (95/5 by volume). The
fractions containing diastereoisomer A are combined and evaporated
under reduced pressure (5 kPa) at a temperature in the region of
40.degree. C. 3.98 g of diastereoisomer A of
N-(tert-butyl)-N'-(1S)-1-- benzyl-2-hydroxypropyl)thiourea are
obtained in the form of a white solid melting at 156.degree. C. By
concentrating the fractions corresponding to diastereoisomer B
under the same conditions, 0.72 g of diastereoisomer B of
N-(tert-butyl)-N'-(1S)-1-benzyl-2-hydroxypropyl)thiourea is
obtained in the form of a yellow solid melting at 116.degree.
C.
[0308] (3S)-3-Amino-4-phenyl-2-butanol: The process is performed as
in Example 3, starting with 17.6 g of tert-butyl
(1S)-1-benzyl-2-hydroxyprop- ylcarbamate in 145 cm.sup.3 of dioxane
and 61 cm.sup.3 of 6.5N hydrochloric dioxane, stirring for 16 hours
at a temperature in the region of 20.degree. C. After an identical
work-up, 9.56 g of (3S)-3-amino-4-phenyl-2-butanol are obtained in
the form of an orange-colored oil as a mixture of the two
diastereoisomers (80/20). (R.sub.f=0.25 in a 40/5/0.5 by volume
mixture of dichloromethane/methanol- /aqueous ammonia, on a Merck
60F.sub..sub.254.sub.R silica plate).
[0309] tert-Butyl (1S)-1-benzyl-2-hydroxypropyl-carbamate: The
process is performed as in Example 3, starting with 2.66 g of
tert-butyl (1S)-1-benzyl-2-oxopropylcarbamate in 25 cm.sup.3 of
ethanol, with 0.58 g of sodium borohydride. After 4 h 30 min at a
temperature in the region of 20.degree. C., the reaction mixture is
worked up in an identical manner. 2.7 g of tert-butyl
(1S)-1-benzyl-2-hydroxypropylcarbamate are obtained in the form of
a white solid melting at 125.degree. C., as admixture of the two
diastereoisomers (70/30).
[0310] tert-Butyl (1S)-1-benzyl-2-oxopropyl-carbamate: The process
is performed as in Example 3, starting with 5 g of tert-butyl
(1S)-1-benzyl-2-[methoxy(methyl)amino]-2-oxoethylcarbamate, 16
cm.sup.3 of a 1M solution of methylmagnesium bromide in ether, and
100 cm.sup.3 of anhydrous tetrahydrofuran. Once the reaction is
complete, the reaction medium is stirred for 18 hours at a
temperature in the region of 20.degree. C. After an identical
work-up, 3.91 g of an orange-colored oil are obtained, and are
purified by chromatography at atmospheric pressure on a column of
silica gel (particle size 63-200.mu.; diameter 3.5 cm; height 20
cm), eluting with dichloromethane. The fractions corresponding to
the expected product are collected. These fractions are combined
and then concentrated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. 2.82 g of tert-butyl
(1S)-1-benzyl-2-oxopropylcar- bamate are obtained in the form of a
white solid melting at 62.degree. C.
[0311] tert-Butyl
(1S)-1-benzyl-2-[methoxy(methyl)-amino]-2-oxoethylcarbam- ate: The
process is performed as in Example 3, starting with 26.5 g of
L-N-Boc-phenylalanine, 22 cm.sup.3 of N-methylmorpholine, 13
cm.sup.3 of isobutyl chloroformate and 10.14 g of
N,O-dimethyl-hydroxylamine hydrochloride in 300 cm.sup.3 of
dichloromethane. The product is worked up in an identical manner
and then purified by chromatography at atmospheric pressure on a
column of silica gel (particle size 63-200.mu.; diameter 6 cm;
height 25 cm), eluting with a dichloromethane/methanol mixture
(97/3 by volume). The fractions containing the expected product are
collected. These fractions are combined and then concentrated under
reduced pressure (5 kPa) at a temperature in the region of
40.degree. C. 17.1 g of tert-butyl
(1S)-1-benzyl-2-[methoxy(methyl)amino]-2-oxoethylcar- bamate are
obtained in the form of a colorless oil.(R.sub.f=0.65 in a 97/3 by
volume mixture of dichloromethane/methanol, on a Merck
60F.sub..sub.254.sub.R silica plate).
EXAMPLE 12
(-)-(4S)-4-(4-Aminobutyl)-4,5-dihydro-1,3-thiazol-2-ylamine
dihydrochloride
[0312] The process is performed as in Example 9, starting with 0.59
g of ethyl
(2S)-6-{[(benzyloxy)-carbonyl]amino}-2-{[(tert-butylamino)carbothio-
yl]-amino}hexanoate in 6 cm.sup.3 of 6N hydrochloric acid. After
concentration of the reaction medium under the same conditions, the
foam obtained is taken up 3 times in diethyl ether and the phases
are separated each time after settling has taken place, and the
remaining insoluble material is then taken up in 10 cm.sup.3 of
acetonitrile. The resulting crystalline product is spin-filtered,
washed with hot acetonitrile and then dried under reduced pressure
(5 kPa) at a temperature in the region of 20.degree. C. 0.34 g of
(-)-(4S)-4-(4-amino-butyl)-4,5-dihydro-1,3-thiazol-2-ylamine
dihydrochloride in the form of cream-colored crystals melting at
170.degree. C.
[0313] (.alpha..sub.D.sup.20=-15.5.+-.0.6 at a concentration of
0.5% in methanol).
[0314] Ethyl
(2S)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butylamino)carb-
othioyl]amino}hexanoate: The process is performed as in Example 9,
starting with 0.42 g of benzyl (5S)-5-amino-6-hydroxyhexylcarbamate
and 0.24 cm.sup.3 of tert-butyl isothiocyanate in 30 cm.sup.3 of
ethanol at a temperature in the region of 20.degree. C. for 3 days.
The reaction is completed by addition of a further 0.48 cm.sup.3 of
isothiocyanate followed by heating for 1 hour at a temperature in
the region of 80.degree. C. After an identical work-up, 0.6 g of
ethyl
(2S)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butylamino)-carbothioyl]ami-
no}hexanoate is obtained in the form of a beige-colored oil with a
tendency to crystallize. (R.sub.f=0.62 in a 90/10 by volume mixture
of dichloromethane/methanol, on a Merck 60F.sub..sub.254.sub.R
silica plate).
[0315] Benzyl (5S)-5-amino-6-hydroxyhexylcarbamate: A mixture of 4
g of benzyl
(5S)-5-{[(tert-butyloxy)carbonyl]amino}-6-hydroxyhexylcarbamate, 30
cm.sup.3 of trifluoroacetic acid and 20 cm.sup.3 of ethanol is
stirred at a temperature in the region of 20.degree. C. for 2
hours. After concentration of the reaction medium under reduced
pressure (5 kPa) at a temperature in the region of 40.degree. C.,
the residue obtained is taken up in 50 cm.sup.3 of water and washed
with twice 100 cm.sup.3 of diethyl ether. The aqueous phase is
separated out after settling has taken place, basified with sodium
carbonate to pH 9-10 and then extracted with 3 times 100 cm.sup.3
of dichloromethane. The combined extracts are washed with aqueous
sodium chloride solution and then dried on magnesium sulfate,
filtered and concentrated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. 2.0 g of benzyl
(5S)-5-amino-6-hydroxyhexy- lcarbamate are obtained in the form of
a white solid melting at 82.degree. C.
[0316] Benzyl
(5S)-5-{[(tert-butyloxy)carbonyl]amino}-6-hydroxyhexylcarbam- ate:
The process is performed as in Example 9, starting with 7 g of
methyl
(2S)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butyloxy)carbonyl]amino}hex-
anoate in 70 cm.sup.3 of ethanol, 35 cm.sup.3 of tetrahydrofuran, 1
g of lithium chloride and 0.81 g of sodium borohydride. After 16
hours at a temperature in the region of 20.degree. C., the reaction
mass is filtered and the filter cake is washed with ethanol. The
resulting filtrate is concentrated under reduced pressure (5 kPa)
at a temperature in-the region of 40.degree. C. After dissolving
the residue obtained in 150 cm.sup.3 of dichloromethane, washing
with twice 100 cm.sup.3 of aqueous sodium chloride solution and
twice 100 cm.sup.3 of water, drying over magnesium sulfate and
finally concentrating under the same conditions as above, 5.2 g of
benzyl (5S)-5-{[(tert-butyloxy)carbonyl]amino}-6-hydroxyh-
exylcarbamate are obtained in the form of a white solid melting at
67.degree. C.
[0317] Methyl
(2S)-6-{[benzyloxy)carbonyl]amino}-2-{[(tert-butyloxy)carbon-
yl]amino}hexanoate: 4.8 g of di-tert-butyl dicarbonate are added,
under an inert atmosphere, to a stirred solution of 6.6 g of
N.epsilon.-CBZ-L-lysine methyl ester hydrochloride in 66 cm.sup.3
of methanol and 66 cm.sup.3 of tetrahydrofuran, cooled to a
temperature in the region of 0.degree. C., followed by addition of
5.7 cm.sup.3 of triethylamine and 10 cm.sup.3 of methanol. After
stirring the mixture at a temperature in the region of 5.degree. C.
for 2 hours and then at about 20.degree. C. for 2 hours, the
reaction medium is concentrated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. The residue obtained is
taken up in dichloromethane and the solution is washed with 100
cm.sup.3 of water, dried over magnesium sulfate, filtered and
concentrated under the same conditions as above. 7 g of methyl
(2S)-6-{[(benzyloxy)carbonyl]amino}-2-{[(tert-butyloxy)-carbonyl]amino}he-
xanoate are obtained in the form of a cream-colored oil.
(R.sub.f=0.90 in a 90/10 by volume mixture of
dichloromethane/methanol, on a Merck 60F.sub.254R silica
plate).
EXAMPLE 13
[0318]
(4S,5R)-4-Benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0319] The process is performed as in Example 3, starting with 0.7
g of diastereoisomer B of
N-(tert-butyl)-N'-(1S)-1-benzyl-2-hydroxypropyl)thio- urea which is
heated to a temperature in the region of 100.degree. C. for 5 hours
in 8.3 cm.sup.3 of aqueous 6N hydrochloric acid. After
concentration of the reaction medium under reduced pressure (5 kPa)
at a temperature in the region of 50.degree. C., 50 cm.sup.3 of
water are added to the residue obtained and the solution is then
extracted with 3 times 25 cm.sup.3 of dichloromethane. The aqueous
phase is made alkaline by addition of 0.5 cm.sup.3 of 30% caustic
soda and extracted with 3 times 50 cm.sup.3 of dichloromethane. The
extracts are combined, dried over sodium sulfate, filtered and then
concentrated under reduced pressure (5 kPa) at a temperature in the
region of 50.degree. C. An oil is obtained, which is purified by
chromatography under an argon pressure of 50 kPa, on a column of
silica gel (particle size 40-63.mu.; diameter 2 cm; height 28 cm),
eluting with a dichloromethane/methanol mixture (95/5 by volume).
The fractions containing the expected-product are collected. These
fractions are combined and then concentrated under reduced pressure
(5 kPa) at a temperature in the region of 40.degree. C. 0.10 g of
(4S)-4-benzyl-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine is
obtained in the form of a pale pink solid melting at 90.degree. C.
to become pasty (mixture of diastereoisomers: 82% of cis
[(4S,5R)-4-benzyl-5-methyl-4,5-d- ihydro-1,3-thiazol-2-ylamine] 18%
of trans [(4S,5S)-4-benzyl-5-methyl-4,5--
dihydro-1,3-thiazol-2-ylamine]). (R.sub.f=0.15 in a 95/5 by volume
mixture of dichloromethane/methanol, on a Merck
60F.sub..sub.254.sub.R silica plate).
EXAMPLE 14
(-)-(4R)-4-Butyl-4,5-dihydro-1,3-thiazol-2-ylamine oxalate
[0320] The process is performed as in Example 1, starting with 2.3
g of N-(tert-butyl)-N'-[(1R)-1-butyl-2-hydroxyethyl]thiourea in 32
cm.sup.3 of aqueous 6N hydrochloric acid. After concentration under
reduced pressure (5 kPa) at a temperature in the region of
50.degree. C., the residue obtained is taken up in 10 cm.sup.3 of
water and then made alkaline by addition of 2 cm.sup.3 of 30%
caustic soda. After extraction with 3 times 50 cm.sup.3 of
dichloromethane, the organic extracts are combined and dried over
sodium sulfate and concentrated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. 1.37 g of a yellow oil
are obtained, the oxalate of which is prepared in the following
way: starting with 0.3 g of the above oil in 1 cm.sup.3 of acetone,
0.24 g of oxalic acid dissolved in 1 cm.sup.3 of acetone is added.
After precipitation of the salt, the medium is diluted with 5
cm.sup.3 of acetone and filtered. The crystals are washed with
twice 4 cm.sup.3 of acetone and then dried in an oven under reduced
pressure (10 Pa) at a temperature in the region of 40.degree. C.
0.26 g of (-)-(4R)-4-butyl-4,5-dihydro-1,3-thiazol-2-ylamine
oxalate is obtained in the form of a white solid melting at
91.degree. C. (.alpha..sub.D.sup.20=-7 under a 589 nm Na lamp and
.alpha..sub.D.sup.20=-70.1.+-.1.2 under a 365 nm Hg lamp, at a
concentration of 0.5% in methanol).
[0321] N-(tert-Butyl)-N'-[(1R)-1-butyl-2-hydroxyethyl]thiourea: The
process is performed as in Example 2, starting with 1.14 g of
(2R)-2-amino-2-butyl-1-ethanol and 1.36 cm.sup.3 of tert-butyl
isothiocyanate in 15 cm.sup.3 of ethanol, with stirring for 18
hours at a temperature in the region of 20.degree. C. and then for
3 hours in the region of 60.degree. C. After concentration of the
reaction medium under reduced pressure (5 kPa) at a temperature in
the region of 40.degree. C. 2.38 g of
N-(tert-butyl)-N'-[(1R)-1-butyl-2-hydroxyethyl]thiourea are
obtained in the form of a yellow oil. Infrared spectrum
(CH.sub.2Cl.sub.2):3620; 4430; 4410; 2960; 1560; 1500; 1395; 1375
and 1205 cm.sup.-1.
[0322] (2R)-2-Aminohexanol: 3.7 g of L-norleucine methyl ester
hydrochloride are dissolved in 20 cm.sup.3 of water. The required
amount of aqueous sodium carbonate solution to obtain a pH of 10 is
added to this stirred solution at a temperature in the region of
20.degree. C. The medium is extracted with 3 times 50 cm.sup.3 of
ethyl acetate. The extracts are combined, dried over sodium
sulfate, filtered and concentrated under reduced pressure (5 kPa)
at a temperature in the region of 50.degree. C. 2.95 g of methyl
(2R)-2-amino-2-butylacetate are obtained in the form of a yellow
oil. The process is then performed as in Example 2, starting with
2.9 g of methyl (2R)-2-amino-2-butylacetate and 1.14 g of sodium
borohydride in 50 cm.sup.3 of ethanol. The reaction is carried out
at a temperature in the region of -15.degree. C. and the reaction
medium is then stirred for 18 hours at a temperature in the region
of 20.degree. C., and finally for 1 h 30 min at a temperature in
the region of 80.degree. C. After concentration of the reaction
mass under reduced pressure (5 kPa) at a temperature in the region
of 50.degree. C., the residue obtained is purified by
chromatography under a pressure of argon (50 kPa) on a column of
silica gel (particle size 40-63.mu.; diameter 2 cm; height 20 cm),
eluting with a mixture of ethyl acetate/methanol (80/20 by volume).
The fractions containing the expected product are combined and then
concentrated under reduced pressure (5 kPa) at a temperature in the
region of 40.degree. C. 1.2 g of (2R)-2-aminohexanol are obtained
in the form of an oil which has a tendency to crystallize.
(.alpha..sub.D.sup.20=+2.6.+-.0.4 at a concentration of 0.5% in
methanol).
EXAMPLE 15
(+)-(5S)-5-Methyl-4,5-dihydro-1,3-thiazol-2-ylamine
hydrochloride
[0323] The process is performed as in Example 1, starting with
11.86 g of N-[(2S)-2-hydroxypropyl]-N'-tert-butylthiourea in 168
cm.sup.3 of aqueous 6N hydrochloric acid. After heating for 3 hours
at a temperature in the region of 100.degree. C. and an identical
work-up, 2.30 g of
(+)-(5S)-5-methyl-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride
are obtained in the form of a white solid melting at 173.degree. C.
(.alpha..sub.D.sup.20=+73.8.+-.1.4 at a concentration of 0.5% in
methanol).
[0324] N-[(2S)-2-Hydroxypropyl]-N'-tert-butylthiourea: The process
is performed as in Example 1, starting with 5 g of
(+)-(S)-1-amino-2-propano- l and 8.43 g of tert-butyl
isothiocyanate in 60 cm.sup.3 of ethanol. After stirring the
reaction medium for 5 hours at a temperature in the region of
20.degree. C. and then concentration under reduced pressure (5 kPa)
at a temperature in the region of 50.degree. C., the white solid
obtained is taken up in diethyl ether. The suspension is again
concentrated under the same conditions as above. 11.86 g of
N-[(2S)-2-hydroxypropyl]-N'-tert-but- ylthiourea are obtained in
the form of a white solid melting at 106.degree. C.
EXAMPLE 16
(-)-(4S)-4-Cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine
[0325] The process is performed as in Example 1, starting with 11.1
g of
N-(tert-butyl)-N'-[(1S)-1-cyclohexylmethyl-2-hydroxyethyl]thiourea
in 110 cm.sup.3 of aqueous 6N hydrochloric acid maintained at a
temperature in the region of 100.degree. C. for 2 hours. By means
of an identical work-up, 3.6 g of
(-)-(4S)-4-cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-y- lamine are
obtained in the form of a white solid melting at 169.degree. C.
(.alpha..sub.D.sup.20=-33.9.+-.0.8 at a concentration of 0.5% in
methanol).
[0326]
N-(tert-Butyl)-N'-[(1S)-1-cyclohexylmethyl-2-hydroxyethyl]thiourea:
The process is performed as in Example 3, starting with 8.1 g of
(+)-(2S)-2-amino-3-cyclohexyl-1-propanol and 9.8 cm.sup.3 of
tert-butyl isothiocyanate in 79 cm.sup.3 of ethanol. The reaction
medium is stirred for 72 hours at a temperature in the region of
20.degree. C. After concentration of the reaction mass under
reduced pressure (5 kPa) at a temperature in the region of
50.degree. C., the oil obtained is taken up in 110 cm.sup.3 of cold
petroleum ether. The crystals are filtered off and dried under
reduced pressure (10 Pa) at a temperature in the region of
60.degree. C. 11.1 g of
N-(tert-butyl)-N'-[(1S)-1-cyclohexylmethyl-2-h-
ydroxyethyl]thiourea are obtained in the form of a white solid
melting at 97.degree. C.
EXAMPLE 17
(+)-(4R)-4-Cyclohexylmethyl-4,5-dihydro-1,3-thiazol-2-ylamine
hydrochloride
[0327] The process is performed as in Example 1, starting with 2.9
g of
N-(tert-butyl)-N'-[(1R)-1-cyclohexylmethyl-2-hydroxyethyl]thiourea
in 28 cm.sup.3 of aqueous 6N hydrochloric acid by heating at a
temperature in the region of 100.degree. C. for 2 h 15 min. By
means of an identical work-up, a solid is obtained which is
purified by dissolution in 15 cm.sup.3 of water and extraction with
10 cm.sup.3 of dichloromethane. The aqueous phase is made alkaline
by addition of 10 cm.sup.3 of 1N sodium hydroxide and is extracted
with twice 15 cm.sup.3 of ethyl acetate. The combined organic
extracts are concentrated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. The resulting paste is
taken up in twice 20 cm.sup.3 of diethyl ether. The solid is
filtered off and dried in an oven under reduced pressure (10 Pa) at
a temperature in the region of 60.degree. C. 0.4 g of
(+)-(4R)-4-cyclohexylmethyl-4,5-dihy- dro-1,3-thiazol-2-ylamine
hydrochloride is obtained in the form of a white solid melting at
169.degree. C. (.alpha..sub.D.sup.20=+31.8.+-.0.9 at a
concentration of 0.5% in methanol).
[0328]
N-(tert-Butyl)-N'-[(1R)-1-cyclohexylmethyl-2-hydroxyethyl]thiourea:
The process is performed as in Example 3, starting with 4.89 g of
(2R)-2-amino-3-cyclohexyl-1-propanol and 5.9 cm.sup.3 of tert-butyl
isothiocyanate in 48 cm.sup.3 of absolute ethanol. After stirring
for 5 days at a temperature in the region of 20.degree. C., the
reaction medium is concentrated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. The solid obtained is
taken up in 200 cm.sup.3 of petroleum ether and the insoluble
material is then filtered off and air-dried. 2.96 g of
N-(tert-butyl)-N'-[(1R)]-1-cyclohexylmethyl-2-hydrox-
yethyl]thiourea are obtained in the form of a white solid.
(R.sub.f=0.29 in an ethyl acetate/cyclohexane mixture, on a Merck
60F.sub.254.sub..sup.R silica plate).
[0329] (2R)-2-Amino-3-cyclohexyl-1-propanol: The process is
performed as in Example 1, starting with 6.2 g of ethyl
(2R)-2-amino-3-cyclohexylpropi- onate and 1.93 g of sodium
borohydride in 120 cm.sup.3 of absolute ethanol at about 5.degree.
C. for 10 minutes. The medium is warmed to room temperature and
stirred for a further 3 h 30 minutes. After cooling again to about
5.degree. C. and addition of a further 40.94 g of borohydride,
followed by stirring at a temperature in the region of 20.degree.
C. for 65 hours, the reaction medium is concentrated under reduced
pressure (5 kPa) at a temperature in the region of 40.degree. C. A
solid is obtained, which is purified by chromatography under a
pressure of argon (100 kPa) on a column of silica gel (particle
size 40-63.mu.; 320 g), eluting with pure methanol. The fractions
containing the expected product are collected. These fractions are
combined and then concentrated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. 5.16 g of
(2R)-2-amino-3-cyclohexyl-1-propanol are obtained in the form of a
sticky white solid. (R.sub.f=0.25 in methanol on a Merck
60F.sub.254.sub..sup.R silica plate).
[0330] Ethyl (2R)-2-amino-3-cyclohexylpropionate: The process is
performed as in Example 2, starting with 10 g of
.beta.-cyclohexyl-(D)-alanine hydrochloride in 96 cm.sup.3 of
absolute ethanol, by treating it with a stream of dry hydrogen
chloride at a temperature in the region of 0.degree. C. for 20
minutes. After heating to about 80.degree. C. for 4 days, followed
by cooling to 0.degree. C., the mixture is again treated with a
stream of hydrogen chloride for 20 minutes, followed by heating to
a temperature in the region of 80.degree. C. for 20 hours.
The-reaction medium is concentrated under reduced pressure (5 kPa)
at a temperature in the region of 40.degree. C., and the residue
obtained is dissolved in 200 cm.sup.3 of water, made alkaline by
addition of 19 g of solid potassium carbonate. After evaporation,
the resulting solid is taken up in 200 cm.sup.3 of ethanol at a
temperature in the region of 80.degree. C. The insoluble material
is filtered off and the filtrate is evaporated under reduced
pressure (5 kPa) at a temperature in the region of 40.degree. C.
The residue obtained is taken up in 130 cm.sup.3 of ethanol at room
temperature. The insoluble material is filtered off and the
filtrate is again evaporated under the same conditions as above.
4.8 g of ethyl (2R)-2-amino-3-cyclohexylpropionate are obtained in
the form of a whitish paste. (R.sub.f=0.80 in a 90/10 by volume
mixture of ethanol/aqueous ammonia, on a Merck
60F.sub.254.sub..sup.R silica plate)
EXAMPLE 18
4-(3-Nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
[0331] The process is performed as in Example 2, starting with 1.49
g of N-(tert-butyl)-N'-[2-hydroxy-1-(3-nitrophenyl)ethyl]thiourea
in 14 cm.sup.3 of aqueous 6 N hydrochloric acid by heating to a
temperature in the region of 100.degree. C. for 2 h 30 min. By
means of an identical work-up, 1.01 g of
4-(3-nitrophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine are obtained in
the form of a cream-colored solid melting at 232.degree. C.
EXAMPLE 19
(+)-(4R)-4-(4-Pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
dihydrochloride
[0332] The process is performed under the conditions of Example 1
starting with 0.46 g of
N-(tert-butyl)-N'-[(1R)-2-hydroxy-1-(4-pyridylmethyl)ethyl-
]thiourea which is heated in 5 cm.sup.3 of aqueous 5 N hydrochloric
acid for 16 hours at a temperature in the region of 100.degree. C.
After concentration of the reaction mass under reduced pressure (5
kPa) at a temperature in the region of 40.degree. C., an oil is
obtained which is taken up in 3 cm.sup.3 of 2-propanol. The
resulting crystalline precipitate is spin-filtered, washed with
2-propanol and air-dried. 0.1 g of
(+)-(4R)-4-(4-pyridylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine
dihydrochloride is obtained in the form of an orange-colored solid
melting at 150.degree. C. (.alpha..sub.D.sup.20=+38.3.+-.0.9 at a
concentration of 0.5% in MeOH).
[0333]
N-(tert-Butyl)-N'-[(1R)-2-hydroxy-1-(4-pyridylmethyl)ethyl]thiourea-
: A solution of 0.1 g of tert-butyl
(1R)-1-(4-pyridylmethyl)-2-hydroxyethy- l-carbamate in 3 cm.sup.3
of 4 N hydrochloric dioxane is stirred for 16 hours at a
temperature in the region of 20.degree. C. The reaction mass is
concentrated under reduced pressure (5 kPa) at a temperature in the
region of 40.degree. C. 0.075 g of a white product is obtained, and
is dissolved in 4 cm.sup.3 of ethanol. After addition of 0.08
cm.sup.3 of triethylamine and then 0.09 cm.sup.3 of tert-butyl
isothiocyanate, the mixture is stirred for 16 hours at a
temperature in the region of 20.degree. C. and then for 6 hours at
a temperature in the region of 50.degree. C. The mixture is
evaporated under reduced pressure (5 kPa) at a temperature in the
region of 40.degree. C. and the residue obtained is then triturated
from 20 cm.sup.3 of water. The water is separated out after
settling has taken place, ethanol is added to the resulting oil and
the solution is then concentrated under the above conditions. 0.10
g of
N-(tert-butyl)-N'-[(1R)-2-hydroxy-1-(4-pyridylmethyl)ethyl]thiourea
is obtained in the form of an orange-colored oil. (R.sub.f=0.50 in
a 4/1/1 by volume mixture of ethyl acetate/acetic acid/water, on a
Merck 60F.sub.254.sub..sup.R silica plate)
[0334] Tert-Butyl (1R)-1-(4-pyridylmethyl)-2-hydroxyethylcarbamate:
0.52 cm.sup.3 of triethylamine is added to a stirred mixture of 1 g
of Boc-D-4-pyridylalanine in 10 cm.sup.3 of tetrahydrofuran, under
an inert atmosphere, and the mixture is then cooled to a
temperature in the region of -18.degree. C. After addition of 0.47
cm.sup.3 of isobutyl chloroformate, stirring is continued for 30
minutes at a temperature of between -18.degree. C. and -10.degree.
C. The mixture is rapidly filtered, followed by addition to the
filtrate of 0.28 g of sodium borohydride predissolved in 2 cm.sup.3
of water. The mixture is stirred for 1 hour at a temperature in the
region of 0.degree. C. and then for 16 hours at a temperature in
the region of 20.degree. C. The mixture is made alkaline by
addition of aqueous potassium carbonate solution and then stirred
in the presence of ethyl acetate. The organic phase is separated
out after settling has taken place and then washed with water,
dried over magnesium sulfate, filtered and concentrated under
reduced pressure (5 kPa) at a temperature in the region of
40.degree. C. The residue obtained is purified by chromatography
under an argon pressure of 50 kPa on a column of silica gel
(particle size 40-63.mu.: diameter 2.2 cm; height of silica 30 cm),
eluting first with ethyl acetate alone and collecting 30-cm.sup.3
fractions. Fractions 1 to 18 are discarded and the column is then
eluted with a mixture of ethyl acetate/methanol (90/10 by volume).
Fractions 23 to 26 are collected and then combined. After
concentration under reduced pressure (5 kPa) at a temperature in
the region of 40.degree. C., 0.10 g of tert-butyl
(1R)-1-(4-pyridylmethyl)-2-hydroxy-et- hylcarbamate is obtained in
the form of an oil. Infrared spectrum (CH.sub.2Cl.sub.2): 3618;
3434; 2981; 1708; 1501; 1367; 1168 and 1057 cm.sup.-1.
EXAMPLE 20
(+)-(4R,5R)-5-Methyl-(4R,5R)-4-(4-pyridylmethyl)-4,5-dihydrothiazol-2-ylam-
ine dihydrochloride
[0335] A suspension of 1.96 g of
N-tert-butyl-N'-[1R,2RS)-1-(4-pyridylmeth-
yl)-2-hydroxypropyl]-thiourea in 25 cm.sup.3 of 5N hydrochloric
acid is heated at a temperature in the region of 100.degree. C. for
18 hours. The reaction medium is concentrated under reduced
pressure (2 kPa) at a temperature in the region of 40.degree. C.
The residue obtained is purified by chromatography on a Chiralcel
OD 20.mu. column in a heptane/isopropanol/-triethylamine mixture
(90/10/0.1 by volume). The fractions containing the expected
product are concentrated under reduced pressure (1 kPa) at a
temperature in the region of 40.degree. C. The residue obtained is
purified by chromatography at atmospheric pressure on a column of
silica gel (particle size 40-60 .mu.m; diameter 1.2 cm; height 30
cm), eluting with a mixture of ethyl acetate/acetic acid/water
(2/1/1 by volume). The fractions containing the expected product
are combined and concentrated under reduced pressure (2 kPa) at a
temperature in the region of 40.degree. C. The residue obtained is
taken up in 5 cm.sup.3 of 5N hydrochloric acid and ethanol and is
then concentrated under reduced pressure (2 kPa) at a temperature
in the region of 40.degree. C. After drying in a desiccator under
reduced pressure (0.1 kPa) at a temperature in the region of
40.degree. C., 0.4 g of
(+)-(4R,5R)-4-(4-pyridylmethyl)-5-methyl-4,5-dihydrothiazol-2-ylamine
dihydrochloride is obtained in the form of a highly hygroscopic
foam [.sup.1H NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6,
.delta. in ppm): 1.44 (d, J=7 Hz: 3H); 3.22 (dd, J=13.5 and 7.5 Hz:
1H); 3.32 (dd, J=13.5 and 5 Hz: 1H); 3.90 (mt: 1H); 4.37 (mt: 1H);
8.01 (broad d, J=6 Hz: 2H); 8.88 (broad d, J=6 Hz: 2H); 9.34 (broad
s: 1H); 9.85 (broad s: 1H); 10.31 (unresolved complex: 1H);
(a.sub.D.sup.20=+75.3 +/-1.3 in 0.5% methanol).
[0336]
N'-tert-Butyl-N'[(1R,2RS)-1(4-pyridylmethyl)-2-hydroxypropyl]thiour-
ea: a solution of 1.41 g of
(3R,2RS)-3-amino-4-(4-pyridinyl)-2-butanol in 30 cm.sup.3 of
ethanol, to which are added 1.08 cm.sup.3 of tert-butyl
isothiocyanate and then 2.16 cm.sup.3 of triethylamine, is heated
for 16 hours with stirring at a temperature in the region of
50.degree. C. The reaction medium is concentrated under reduced
pressure (2 kPa) at a temperature in the region of 40.degree. C.,
taken up in 10 cm.sup.3 of water, washed with twice 30 cm.sup.3 of
dichloromethane, dried over magnesium sulfate, filtered, evaporated
under the above conditions and then dried in a desiccator under
reduced pressure (0.1 kPa) at a temperature in the region of
40.degree. C. 2 g of N'-tert-butyl-N'-[(1R,2-
RS)-1-(4-pyridyl-methyl)-2-hydroxypropyl]thiourea are obtained in
the form of an orange-colored oil [.sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm) . We observe a mixture
of two diastereoisomers A and B in respective proportions of 70/30,
.delta.=0.99 (d, J=6.5 Hz: 0.9H); 1.09 (d, J=6.5 Hz: 2.1H); 1.37
(s: 6.3H); 1.41 (s: 2.7H); 2.74 (dd, J=14.5 and 9 Hz: 0.7H); from
2.75 to 2.90 (mt: 0.6H); 2.93 (dd, J=14.5 and 5 Hz: 0.7H); from
3.55 to 3.80 (mt: 1H); from 4.35 to 4.60 (unresolved complex: 1H;
4.65 (unresolved complex: 0.3H); 4.88 (unresolved complex: 0.7H);
from 7.10 to 7.25 (mt: 1H); 7.17 (broad s: 0.7H); 7.27 (broad d,
J=6 Hz: 1.4H); 7.31 (broad d, J=6 Hz: 0.6H); 7.44 (broad s: 0.3H);
from 8.35 to 8.50 (mt: 2H)
[0337] (3R,2RS)-3-Amino-4-(4-pyridyl)-2-butanol dihydrochloride: a
solution of 20 cm.sup.3 of 4N hydrochloric acid in dioxane is added
with stirring, at a temperature in the region of 20.degree. C., to
a solution of 1.85 g of tert-butyl
N-[(1R,2RS)-1-(4-pyridylmethyl)-2-hydroxypropyl[h-
ydroxypropyl]carbamate. The mixture is stirred at a temperature in
the region of 20.degree. C. for 5 hours and is then concentrated
under reduced pressure (2 kPa) at a temperature in the region of
40.degree. C. 1.8 g of (3R,2RS)-3-amino-4-(4-pyridyl)-2-butanol
dihydrochloride are obtained in the form of a yellow solid [.sup.1H
NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6 with addition of
a few drops of CD.sub.3COOD-d.sub.4, .delta. in ppm). We observe a
mixture of two diastereoisomers A and B in respective proportions
of 70/30; .delta.=1.18 and 1.20 (2 d, J=6.5 Hz: 3H in total); 3.13
(dd, J=10.5 and 6 Hz: 0.7H); from 3.20 to 3.35 (mt: 1.3H); from
3.45 to 3.65 (mt: 0.6H); 3.72 (mt: 0.7H); 3.96 (mt: 0.7H) ; from
8.05 to 8.15 (mt: 2H); 8.88 (broad d, J=6 Hz: 2H)].
[0338] Tert-Butyl
N-[(1R,2RS)-1-(4-pyridylmethyl)-2-hydroxy-propyl]carbama- te: 0.43
g of sodium borohydride is added, with stirring and at a
temperature in the region of 10.degree. C., to a solution of 2 g of
tert-butyl N-[(1R)-1-(4-pyridylmethyl-2-oxopropyl]carbamate and the
mixture is then stirred at a temperature in the region of
20.degree. C. for 18 hours. The reaction medium is concentrated
under reduced pressure (1 kPa) at a temperature in the region of
40.degree. C., taken up in 50 cm.sup.3 of water, extracted with 100
cm.sup.3 of ethyl acetate, dried over magnesium sulfate, filtered
and concentrated under reduced pressure (1 kPa) at a temperature in
the region of 40.degree. C. 1.83 g of tert-butyl
N-[(1R,2RS)-1-(4-pyridylmethyl)-2-hydroxy-propyl]carbamate are
obtained in the form of a yellow solid [.sup.1H NMR spectrum (300
MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm). We observe a
mixture of two diastereoisomers A and B in respective proportions
of 70/30; .delta.=1.03 (d, J=6.5 Hz: 0.9H); 1.09 (d, J=6.5 Hz:
2.1H); 1.28 (s:2.7H); 1.30 (s, 6.3H); from 2.45 to 2.55 (mt: 0.7H);
2.61 (dd, J=13.5 and 10.5 Hz: 0.3H); 2.81 (dd, J=13.5 and 4 Hz
0.3H); 3.01 (dd, J=13.5 and 2 Hz: 0.7H); from 3.40 to 3.70 (mt:
2H); 4.70 (d, J=5.5 Hz: 0.3H); 4.78 (d, J=5.5 Hz: 0.7H); 6.53 (d,
J=9 Hz: 0.3H); 6.67 (d, J=9 Hz: 0.7H); 7.20 (broad d, J=6 Hz:
1.4H); 7.25 (broad, J=6 Hz: 0.6H); from 8.40 to 8.50 (mt: 2H)].
[0339] Tert-Butyl
N-[(1R)-1-(4-pyridylmethyl)-2-oxopropyl]carbamate: a mixture, under
an inert atmosphere, of 5.3 g of N-{2-[N-methoxy-N-(methyl-
)-amino]-2-oxo-(1R)-1-(4-pyridylmethyl)ethyl}carbamate in 120
cm.sup.3 of tetrahydrofuran is cooled to a temperature in the
region on 0.degree. C. 17 cm.sup.3 of a 3M solution of
methylmagnesium bromide in diethyl ether are then added over 1 hour
and the mixture is stirred for 1 hour at 0.degree. C. and for 18
hours at a temperature in the region of 20.degree. C. The reaction
medium is cooled again to a temperature in the region of 0.degree.
C., followed by dropwise addition of 30 cm.sup.3 of 1N hydrochloric
acid and 100 cm.sup.3 of water, the resulting mixture is extracted
with ethyl acetate and the extracts are washed with twice 100
cm.sup.3 of water. The combined organic phases are dried over
sodium sulfate, filtered and then concentrated under reduced
pressure (2 kPa) at a temperature in the region of 40.degree. C.
The residue obtained is purified by chromatography at atmospheric
pressure on a column of silica gel (particle size 60-200 .mu.m;
diameter 4 cm; height 35 cm), eluting with ethyl acetate. The
fractions containing the expected product are combined and
concentrated under reduced pressure (2 kPa) at a temperature in the
region of 40.degree. C. 0.2 g of tert-butyl
N-[(1R,2RS)-1-(4-pyridylmethyl)-2-oxopropyl]carbamate is obtained
[.sup.1H NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta.
in ppm): 1.34 (s: 9H) ; 2.16 (s: 3H) ; 2.71 (dd, J=14 and 10,5 Hz:
1H); 3.08 (dd, J=14 and 4.5 Hz); 4.21 (mt: 1H); 7.27 (broad d,
J=5.5 Hz: 2H); 7.34 (d, J=8 Hz: 1H) ; 8.47 (broad d, J=5.5 Hz:
2H)].
[0340] Tert-Butyl
N-{2-[N-methoxy-N-(methyl)amino]-2-oxo-(1R)-1-(4-pyridyl-
methyl)ethyl}carbamate: a solution, under an inert atmosphere, of
20 g of D-N-Boc-pyridylalanine and 16.5 cm.sup.3 of
N-methyl-morpholine in 500 cm.sup.3 of dichloromethane is cooled to
a temperature in the region of -15.degree. C. 9.75 cm.sup.3 of
isobutyl chloroformate are then added and the mixture is stirred
for 15 minutes at this temperature. After addition of 7.61 g of
N,O-dimethylhydroxylamine hydrochloride, stirring is continued for
1 hour at a temperature in the region of -15.degree. C. and then
for 18 hours at room temperature. 250 cm.sup.3 of water are added
to the reaction medium, followed by extraction with 100 cm.sup.3 of
dichloromethane. The organic phase is dried over sodium sulfate,
filtered and concentrated under reduced pressure (2 kPa) at a
temperature in the region of 50.degree. C. The residue is purified
on a column of silica gel (particle size 60-200 .mu.m; height 35
cm), eluting with ethyl acetate. The fractions containing the
expected product are combined and concentrated under reduced
pressure (2 kPa) at a temperature in the region of 40.degree. C.
6.5 g of tert-butyl N-{2-[N-methoxy-N-(methyl)-am-
ino]-2-oxo-(1R)-1-(4-pyridylmethyl)ethyl}carbamate are obtained in
the form of a thick yellow oil [.sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 1.33 (s: 9H) 2.78 (dd,
J=13.5 and 10 Hz: 1H); 2.89 (dd, J=13.5 and 4.5 Hz: 1H); 3.14
(broad s: 3H); 3.76 (broad s: 3H); 4.63 (mt: 1H); 7.24 (mt: 1H);
7.27 (broad d, J=5.5 Hz: 2H); 8.48 (broad d, J=5.5 Hz: 2H)].
EXAMPLES 21 and 22
(+)-4-(5-Thiazolylmethyl)4,5-dihydrothiazol-2-ylamine
dihydrochloride and
(-)-4-(5-thiazolylmethyl)4,5-dihydrothiazol-2-ylamine
dihydrochloride
[0341] A racemic mixture of 0.38 g of
(4RS)-4-(5-thiazolylmethyl)-4,5-dihy- drothiazol-2-ylamine
dihydrochloride is separated on a Chiralcel OD 10.mu. column in a
mixture of heptane/2-isopropanol/triethyl-amine (80/20/0.1 by
volume). The fractions containing the expected product are
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 40.degree. C. to give 0.053 g of (+)-4-(5
thiazolylmethyl)4,5-dihydrothia- zol-2-ylamine dihydrochloride and
0.057 g of (-)-4-(5 thiazolylmethyl)4,5-dihydrothiazol-2-ylamine
dihydrochloride.
[0342] (+)-4-(5-Thiazolylmethyl)4,5-dihydro-thiazol-2-ylamine
dihydrochloride: .sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.- 6, .delta. in ppm): from 3.20 to 3.40
(mt: 3H) ; 3.70 (dd, J=11.5 and 8 Hz: 1H); 4.58 (mt: 1H); 7.85 (s:
1H); 9.10 (s: 1H); 9.26 (unresolved complex: 1H); 9.67 (unresolved
complex: 1H); 10.13 (broad s: 1H).
[0343] (-)-4-(5-Thiazolylmethyl)4,5-dihydro-thiazol-2-ylamine
dihydrochloride: .sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.- 6, .delta. in ppm): from 3.20 to 3.40
(mt: 3H) ; 3.70 (dd, J=12 and 8 Hz: 1H); 4.58 (mt: 1H); 7.85 (s:
1H); 9.10 (s: 1H); 9.26 (unresolved complex: 1H); 9.67 (unresolved
complex: 1H); 10.14 (broad s, 1H); .alpha..sub.D.sup.20=-4.2+/-0.6
at a concentration of 0.5% in methanol).
[0344] (4RS)-4-(5-Thiazolylmethyl)-4,5-dihydro-thiazol-2-ylamine
dihydrochloride: a solution of 0.56 g of
N-(tert-butyl)-N'-[(1RS)-1-hydro-
xymethyl-2-(5-thiazolyl)ethyl]thiourea in 5.5 cm.sup.3 of 6N
hydrochloric acid is heated at a temperature in the region of
110.degree. C. for 3 hours. The reaction medium is concentrated
under reduced pressure (1 kPa) at a temperature in the region of
60.degree. C., taken up in 4 cm.sup.3 of ethanol and 6 cm.sup.3 of
diethyl ether and evaporated under the same conditions as above.
The residue is taken up in 6 cm.sup.3 of ethanol and filtered, and
the solid is dried in a desiccator under reduced pressure (0.1 kPa)
at a temperature in the region of 40.degree. C. and then dissolved
in 5.5 cm.sup.3 of 6N hydrochloric acid solution and refluxed at a
temperature in the region of 110.degree. C. for 9 hours. The
reaction medium is concentrated under reduced pressure (1 kPa) at a
temperature in the region of 40.degree. C. and dried in a
desiccator under reduced pressure (0.1 kPa) at a temperature in the
region of 40.degree. C., to give 0.54 g of
(4RS)-4-(5-thiazolylmethyl)-4,5-dihydro-- thiazol-2-ylamine
dihydrochloride in the form of a pasty solid [.sup.1HNMR spectrum
(300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): from 3.20 to
3.40 (mt: 3H); from 3.60 to 3.80 (mt: 1H); 4.57 (mt: 1H); 7.85 (s,
1H); 9.10 (s: 1H); 9.26 (unresolved complex: 1H); 9.66 (unresolved
complex: 1H); 10.13 (broad s: 1H].
[0345]
N-(tert-Butyl)-N'-[(1RS)-1-hydroxymethyl-2-(5-thiazolyl)ethyl]thiou-
rea: 0.52 cm.sup.3 of triethylamine is added to a solution of 0.56
g of (2RS)-2-amino-3-(5-thiazolyl)-1-propanol hydrochloride in 8
cm.sup.3 of ethanol, followed by addition of 0.55 cm.sup.3 of
tert-butyl isothiocyanate. The mixture is stirred at a temperature
in the region of 20.degree. C. for 18 hours and is then heated at a
temperature in the region of 60.degree. C. for 1 hour 30 minutes.
After cooling, the reaction medium is concentrated under reduced
pressure (1 kPa) at a temperature in the region of 40.degree. C.,
taken up in 6 cm.sup.3 of water and washed with 3 times 20 cm.sup.3
of dichloromethane, dried over magnesium sulfate, filtered,
evaporated under the above conditions and then dried in a
desiccator under reduced pressure (0.1 kPa) at a temperature in the
region of 40.degree. C. 0.56 g of
N'-(tert-butyl-N[prime]-[(1RS)-1-hydroxymethyl-2-(5-thiazolyl)ethyl]-thio-
urea is obtained in the form of a viscous yellow oil [.sup.1H NMR
spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm):
1.43 (s: 9H) ; 3.03 (dd, J=15 and 7 Hz: 1H); 3.19 (dd, J=15 and
7Hz: 1H); from 3.30 to 3.50 (mt: 2H); 4.41 (mt: 1H); 4.97 (t, J=5
Hz: 1H); 7.23 (d, J=8 Hz: 1H); 7.30 (broad s: 1H); 7,67 (s: 1H);
8.94 (s: 1H)].
[0346] (2RS)-2-Amino-3-(5-thiazolyl)-1-propanol hydrochloride: a
solution of 0.63 g of
N-[(1RS)-1-hydroxymethyl-2-(5-thiazolyl)ethyl]acetamide in 7.86
cm.sup.3 of 6N hydrochloric acid is heated to a temperature in the
region of 110.degree. C. for 3 hours. The reaction mixture is
filtered, concentrated under reduced pressure (1 kPa) at a
temperature in the region of 40.degree. C., taken up in isopropyl
ether, concentrated under the above conditions, taken up in 10
cm.sup.3 of isopropyl ether, filtered and dried in a desiccator
under reduced pressure (0.1 kPa) at a temperature in the region of
40.degree. C. 0.56 g of (2RS)-2-amino-3-(5-thiazolyl)-1-propanol
hydrochloride is obtained in the form of a beige-colored solid
melting at 192.degree. C. [.sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 3.21 (d, J=7 Hz: 2H);
3.35 (mt: 1H); 3.48 (dd, J=11.5 and 5.5 Hz: 1H); 3.61 (dd, J=11.5
and 4 Hz: 1H); 7.83 (broad s: 1H); 8.19 (unresolved complex: 3H);
9.10 (broad s: 1H)].
[0347] N-[(1RS)-1-Hydroxymethyl-2-(5-thiazolyl)-ethyl]acetamide:
0.4 g of sodium borohydride is added to a solution of 1.2 g of
ethyl (2RS)-2-acetylamino-3-(5-thiazolyl)propanoate in 20 cm.sup.3
of ethanol, followed by stirring under an inert atmosphere at a
temperature in the region of 20.degree. C. After 18 hours, a
further 0.1 g of sodium borohydride is added and the mixture is
then stirred for 24 hours at a temperature in the region of
20.degree. C. The reaction medium is concentrated under reduced
pressure (1 kPa) at a temperature in the region of 40.degree. C.
The residue is taken up in 10 cm.sup.3 of water and extracted with
3 times 30 cm.sup.3 of ethyl acetate. The organic phase is dried
over magnesium sulfate, filtered and concentrated under reduced
pressure (1 kPa) at a temperature in the region of 40.degree. C.
The residue is chromatographed under an argon pressure of 60 kPa on
a column of silica gel (particle size 40-63.mu.; diameter 3.5 cm;
height 31 cm), eluting with 100 cm.sup.3 of dichloromethane, 600
cm.sup.3 of a dichloromethane/methanol mixture (98/2 by volume),
500 cm.sup.3 of a dichloromethane/-methanol mixture (96/4 by
volume) and 1 dm.sup.3 of a dichloromethane/methanol mixture (90/10
by volume). The fractions containing the expected product are
combined and then concentrated under the above conditions. 0.63 g
of N-[(1RS)-1-hydroxymethyl-2-(5-thiazolyl)-- ethyl]acetamide is
obtained in the form of a yellow oil [.sup.1H NMR spectrum (300
MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 1.80 (s: 3H);
2.85 (dd, J=15 and 9 Hz: 1H); 3.16 (dd, J=15 and 5 Hz: 1H); from
3.25 to 3.45 (mt: 2H); 3.87 (mt: 1H); 4.85 (mt: 1H); 7.65 (s: 1H);
7.79 (d, J=8.5 Hz: 1H); 8.91 (s: 1H)].
[0348] Ethyl (2RS)-2-acetylamino-3-(5-thiazolyl)-propanoate: 2.7
cm.sup.3 of 6N sodium hydroxide are added dropwise to a solution of
3.3 g of diethyl 2-acetyl-amino-2-(5-thiazolylmethyl)malonate in 70
cm.sup.3 of ethanol. The mixture is stirred for 5 hours, followed
by dropwise addition of 1.5 cm.sup.3 of 12N hydrochloric acid; a
precipitate forms. The product is concentrated under reduced
pressure (1 kPa) at a temperature in the region of 40.degree. C. to
give a brown solid which is dried for 12 hours in a desiccator
under reduced pressure (0.1 kPa) at a temperature in the region of
40.degree. C. This residue is taken up in 50 cm.sup.3 of dioxane
and then heated at a temperature in the region of 100.degree. C.
for 3 hours 30 minutes. The reaction medium is evaporated under
reduced pressure (1 kPa) at a temperature in the region of
40.degree. C. The residue is chromatographed under an argon
pressure of 60 kPa on a column of silica gel (particle size
40-63.mu.; diameter 3.5 cm; height 31 cm), eluting with 675
cm.sup.3 of dichloromethane, 500 cm.sup.3 of a
dichloromethane/methanol mixture (99/1 by volume), 500 cm.sup.3 of
a dichloromethane/methanol mixture (98/02 by volume), 500 cm.sup.3
of a dichloromethane/methanol mixture (97/3 by volume), 500
cm.sup.3 of a dichloromethane/methanol mixture (95/5 by volume),
500 cm.sup.3 of a dichloromethane/-methanol/aqueous ammonia mixture
(12/1.5/0.5 by volume) and 500 cm.sup.3 of a
dichloromethane/methanol/aqu- eous ammonia mixture (12/3/0.5 by
volume). The fractions containing the expected product are combined
and then concentrated under the above conditions. 0.8 g of ethyl
(2RS)-2-acetylamino-3-(5-thiazolyl)propanoate is obtained in the
form of brown oil [Mass spectrum: DCI m/z=243 MH.sup.+].
[0349] Diethyl 2-acetylamino-2-(5-thiazolylmethyl)-malonate: after
dissolving 1.24 g of sodium in 20 cm.sup.3 of ethanol, 10.86
cm.sup.3 of diethyl acetamidomalonate are added, followed by
heating at a temperature in the region of 75.degree. C. After 15
minutes, a solution of 5-chloromethylthiazole in 20 cm.sup.3 of
ethanol is added, followed by heating for 2 hours at a temperature
in the region of 75.degree. C. The reaction medium is evaporated
under reduced pressure (1 kPa) at a temperature in the region of
40.degree. C. The residue is chromatographed under an argon
pressure of 60 kPa on a column of silica gel (particle size
60-200.mu.; diameter 6.5 cm; height 40 cm), eluting with a
dichloromethane/methanol mixture (99/1 by volume), a
dichloromethane/methanol mixture (98/02 by volume) and then a
dichloromethane/methanol mixture (95/5 by volume). The fractions
containing the expected product are combined and then concentrated
under the above conditions. 3.3 g of diethyl
2-acetylamino-2-(5-thiazolylmethyl- )malonate are obtained in the
form of an orange-colored solid [.sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 1.18 (t, J=7.5 Hz: 6H)
; 2.00 (s: 3H); 3.75 (s: 2H); 4.17 (q, J=7.5 Hz: 4H); 7.61 (s: 1H);
8.37 (broad s: 1H); 9.00 (s: 1H)].
[0350] 5-Chloromethylthiazole: 11 g of N-chloro-succinimide are
added to a solution of 8.2 g of 5-methylthiazole in 250 cm.sup.3 of
carbon tetrachloride, followed by addition of 0.1 g of benzoyl
peroxide. The mixture is heated for 20 hours at a temperature in
the region of 80.degree. C. and is then exposed to UV for 5 hours.
The reaction mixture is cooled, filtered and concentrated under
reduced pressure (1 kPa) at a temperature in the region of
20.degree. C. 6.4 g of 5-chloro-methylthiazole are obtained [Mass
spectrum: DCI m/z=134 MH.sup.+].
EXAMPLE 23
(+)-(4R)-4-(2-Pyrazinylmethyl)-4,5-dihydro-2-thiazolylamine
dihydrochloride
[0351] A racemic mixture of 2.9 g of
(4RS)-4-(2-pyrazinylmethyl)-4,5-dihyd- ro-2-thiazolylamine
dihydrochloride is separated on a Chiralcel OD10.mu. column in a
heptane/ethanol/triethylamine mixture (80/20/0.1 by volume). The
fractions containing the expected product are concentrated under
reduced pressure (1 kPa) at a temperature in the region of
40.degree. C. The residue obtained is dissolved in 5 cm.sup.3 of
ethanol, followed by addition of 6 cm.sup.3 of hydrochloric acid
dissolved in diethyl ether and 15 cm.sup.3 of diethyl ether. After
filtration, washing with 15 cm.sup.3 of diethyl ether and drying,
0.371 g of (+)-(4R)-4-(2-pyrazinyl--
methyl)-4,5-dihydro-2-thiazolylamine dihydrochloride is obtained in
the form of a beige-colored solid melting at 154.degree. C.
[.sup.1H NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta.
in ppm): 3.22 (d, J=6.5 Hz: 2H); 3.45 (dd, J=11.5 and 5.5 Hz: 1H);
3.75 (dd, J=11.5 and 8 Hz: 1H); 4.73 (mt: 1H); 8.60 (broad d, J=2.5
Hz: 1H); 8.63 (dd, J=2.5 and 1.5 Hz: 1H); 8.66 (broad s; 1H); 9.09
(unresolved complex: 1H); 9.58 (unresolved complex: 1H) ; 9.95
(broad s: 1H); (.alpha..sub.D.sup.20=+46.- 3+/-1.1 at a
concentration of 0.5% in methanol)].
[0352] (4RS)-4-(2-Pyrazinylmethyl)-4,5-dihydro-2-thiazolylamine
dihydrochloride: A solution of 7.2 g of
N-(tert-butyl)-N'-[(1RS)-1-hydrox-
ymethyl-2-(2-pyrazinyl)ethyl]thiourea in 20 cm.sup.3 of 5N
hydrochloric acid is heated at a temperature in the region of
110.degree. C. for 20 hours. The reaction medium is concentrated
under reduced pressure (1 kPa) at a temperature in the region of
55.degree. C. and then taken up in ethanol and concentrated under
the same conditions as above. The residue is chromatographed at
atmospheric pressure on a column of silica gel (particle size
40-60.mu.; diameter 4 cm; height 30 cm), eluting with an acetic
acid/water/ethyl acetate mixture (1/1/4 by volume). The fractions
containing the expected product are combined and then concentrated
under the above conditions. The oil obtained is taken up in ethanol
and the precipitate obtained is filtered off and then dried in a
desiccator under reduced pressure (0.1 kPa) at a temperature in the
region of 40.degree. C. to give 2.9 g of
(4RS)-4-(2-pyrazinylmethyl)-4,5-dihydro-1,3-thiazol-2- -ylamine
dihydrochloride in the form of a brown solid melting at 190.degree.
C. [.sup.1H NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6- ,
.delta. in ppm) 3.23 (d, J=6 Hz: 2H); 3.43 (dd, J=11.5 and 5.5 Hz:
1H); 3.72 (dd, J=11.5 and 7.5 Hz: 1H); 4.74 (mt: 1H); 8.59 (broad
s: 1H); 8.64 (broad s: 1H); 8.67 (broad s: 1H); 9.29 (unresolved
complex: 1H); 9.77 (unresolved complex: 1H); 10.16 (broad s:
1H)].
[0353]
N-(tert-Butyl)-N'-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)ethyl]thiou-
rea: 11.2 cm.sup.3 of triethylamine are added with stirring to a
solution of 7.91 g of (2RS)-2-amino-3-(2-pyrazinyl)-1-propanol
dihydrochloride in 80 cm.sup.3 of ethanol, followed by addition of
7.2 cm.sup.3 of tert-butyl isothiocyanate. The mixture is heated at
a temperature in the region of 50.degree. C. for 18 hours. After
cooling, the reaction medium is concentrated under reduced pressure
(1 kPa) at a temperature in the region of 40.degree. C., taken up
in 100 cm.sup.3 of water and extracted with dichloromethane. The
organic phases are combined, washed with 50 cm.sup.3 of water,
dried over magnesium sulfate, filtered and then concentrated under
reduced pressure (1 kPa) at a temperature in the region of
40.degree. C. 7.2 g of N-(tert-butyl)-N'-[(1RS)-1-hydroxymethyl-
-2-(2-pyrazinyl)-ethyl]thiourea are obtained in the form of a
colorless paste [mass spectrum: DCI m/z=269 MH.sup.+].
[0354] (2RS)-2-Amino-3-(2-pyrazinyl)-1-propanol dihydrochloride: A
solution of 11 g of
N-[(1RS)-1-hydroxymethyl-2-(2-pyrazinyl)ethyl]acetami- de in 30
cm.sup.3 of 5N hydrochloric acid is heated at a temperature in the
region of 115.degree. C. for 18 hours. The reaction mixture is
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 40.degree. C. 7.9 g of
(2RS)-2-amino-3-(2-pyrazinyl)-1-propanol dihydrochloride are
obtained in the form of a black paste [mass spectrum: DCI m/z=154
MH.sup.+].
[0355] N-[(1RS)-1-Hydroxymethyl-2-(2-pyrazinyl)-ethyl]acetamide:
2.8 g of sodium borohydride are added to a solution of 8.5 g of
ethyl (2RS)-2-acetylamino-3-(2-pyrazinyl)propanoate in 100 cm.sup.3
of ethanol and the mixture is then stirred at a temperature in the
region of 20.degree. C. After 18 hours, the reaction medium is
taken up in 50 cm.sup.3 of water and 100 cm.sup.3 of
dichloromethane and the aqueous phase is concentrated under reduced
pressure (1 kPa) at a temperature in the region of 40.degree. C. 11
g of N-[(1RS)-1-hydroxymethyl-2-(2-pyrazin- yl)-ethyl]acetamide are
obtained in the form of a brown paste [.sup.1H NMR spectrum (300
MHz, (CD.sub.3).sub.2SO-d.sub.6 with addition of a few drops of
CD.sub.3COOD-d.sub.4 .delta. in ppm): 1.71 (s: 3H); 2.81 (dd,
J=14.5 and 9 Hz: 1H); 3.03 (dd, J=14.5 and 5 Hz: 1H); 3.35 (dd,
J=11 and 6 Hz); 3.42 (dd, J=11 and 5 Hz: 1H); 4.11 (mt: 1H); 7.75
(residual d, J=8.5 Hz: 0.5H); 8.45 (d, J=2.5 Hz: 1H); 8.50 (broad
s: 1H); 8.53 (mt: 1H)]).
[0356] Ethyl (2RS)-2-acetylamino-3-(2-pyrazinyl)-propanoate: 12
cm.sup.3 of 6N sodium hydroxide are added dropwise to a solution of
14 g of diethyl 2-acetylamino-2-(2-pyrazinylmethyl)malonate in 240
cm.sup.3 of ethanol and the mixture is then stirred at a
temperature in the region of 20.degree. C. After 1 hour, the
reaction medium is neutralized with 6 cm.sup.3 of 12N hydrochloric
acid. After stirring for 2 hours at a temperature in the region of
20.degree. C., the reaction medium is filtered and the filtrates
are then concentrated under reduced pressure (1 kPa) at a
temperature in the region of 40.degree. C. The residue is taken up
in 200 cm.sup.3 of dioxane, refluxed for 2 hours and concentrated
as above. 8.5 g of ethyl (2RS)-2-acetylamino-3-(2-pyrazinyl)-
propanoate are obtained in the form of a cream-colored solid
[.sup.1H NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6 .delta.
in ppm): 1.13 (t, J=7 Hz: 3H) ; 1.80 (s: 3H) ; 3.12 (dd, J=14 and
8.5 Hz: 1H); 3.22 (dd, J=14 and 6 Hz: 1H); 4.07 (q, J=7 Hz: 2H);
4.71 (mt: 1H); 8.36 (d, J=8 Hz: 1H); 8.52 (d, J=2.5 Hz: 1H); from
8.55 to 8.65 (mt: 2H]).
[0357] Diethyl 2-acetylamino-2-(2-pyrazinylmethyl)-malonate may be
prepared according to C. Petermann and J. L. Fauchere;
Helv.Chim.Acta (1983), 66(5), 1513-1518.
EXAMPLES 24 and 25
4-(1-Imidazolylmethyl)-4,5-dihydro-2-thiazolylamine, enantiomer A,
and 4-(1-imidazolyl-methyl)-4,5-dihydro-2-thiazolylamine,
enantiomer B
[0358] A racemic mixture of 0.75 g of
(4RS)-4-(1-imidazolylmethyl)-4,5-dih- ydroxy-2-thiazolylamine is
separated on a Chiralcel OD10.mu. column in a
heptane/2-isopropanol/triethylamine mixture (80/20/0.1 by volume).
The fractions containing the expected product are combined and then
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 40.degree. C. to give 0.215 g of
4-(1-imidazolyl-methyl)-4,5-di- hydro-2-thiazolylamine, enantiomer
A and 0.21 g of 4-(1-imidazolylmethyl)--
4,5-dihydro-2-thiazolylamine, enantiomer B.
[0359] 4-(1-Imidazolylmethyl)-4,5-dihydro-2-thiazolylamine,
enantiomer A: .sup.1H NMR spectrum (300 MHz,
CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 2.93 (dd, J=11 and 7
Hz: 1H); 3.25 (dd, J=11 and 7 Hz: 1H); 4.03 (d, J=6 Hz: 2H); 4.38
(mt: 1H); 6.49 (unresolved complex: 2H); 6.88 (broad s: 1H); 7.20
(broad s: 1H); 7.64 (broad s: 1H).
[0360] 4-(1-Imidazolylmethyl)-4,5-dihydro-2-thiazolylamine,
enantiomer B: .sup.1H NMR spectrum (300 MHz,
CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 2.96 (dd, J=11 and 7.5
Hz: 1H); from 3.20 to 3.40 (mt: 1H); 4.05 (d, J=6 Hz: 2H); 4.41
(mt: 1H); 6.88 (broad s: 1H); 7.20 (broad s: 1H); 7.64 (broad s:
1H).
[0361] (4RS)-4-(1-Imidazolylmethyl)-4,5-dihydro-2-thiazolylamine: 5
cm.sup.3 of 4N hydrochloric acid in dioxane are added to a solution
of 1.39 g of tert-butyl
N-[(4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazo- lyl]carbamate
in 5 cm.sup.3 of dioxane, followed by addition of methanol to
dissolve the reaction medium. After stirring at a temperature in
the region of 20.degree. C. for 48 hours, the reaction medium is
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 40.degree. C. and washed with isopropyl ether, with ethyl
acetate and then with methanol. The suspension obtained is filtered
and the filtrate is evaporated as above and then chromatographed on
a column of silica gel, eluting with a mixture of
dichloromethane/methanol/28% aqueous ammonia (50/5/1 by volume).
The fractions containing the expected product are combined and then
concentrated under the above conditions to give 0.33 g of
(4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolylamine in the
form of a viscous yellow oil [.sup.1H NMR spectrum (300 MHz,
CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 2.93 (mt: 1H) 3.26 (mt:
1H); 4.03 (d, J=6 Hz: 2H); 4.39 (mt: 1H); 6.49 (unresolved complex:
2H); 6.87 (mt: 1H); 7.20 (mt: 1H); 7.63 (broad s: 1H)].
[0362] Tert-Butyl
N-[(4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolyl]-
carbamate: 0.21 g of imidazole predissolved in 10 cm.sup.3 of
dimethylformamide is added to a solution of 0.085 g of sodium
hydride in 20 cm.sup.3 of dimethylformamide. After the sodium
hydride has disappeared, a solution of 1 g of tert-butyl
N-[(4RS)-4-(p-toluenesulfony-
loxymethyl)-4,5-dihydro-2-thiazolyl]carbamate in 10 cm.sup.3 of
dimethylformamide is added and the mixture is then stirred at a
temperature in the region of 70.degree. C. for 3 hours. The
reaction medium is diluted with ethyl acetate, washed with water,
dried over magnesium sulfate and then concentrated under reduced
pressure (1 kPa) at a temperature in the region of 40.degree. C.
The residue obtained is chromatographed on a column of alumina,
eluting with ethyl acetate and a mixture of ethyl acetate/methanol
(80/20 by volume). The fractions containing the expected product
are combined and then concentrated under the above conditions to
give 0.25 g of tert-butyl N-[(4RS)-4-(1-imidazoly-
lmethyl)-4,5-dihydro-2-thiazolyl]carbamate in the form of a sticky
yellow mass [mass spectrum: DCI m/z=283 MH.sup.+ m/z=183
(M--C.sub.5H.sub.7O.sub- .2).sup.+].
[0363] Tert-Butyl
N-[(4RS)-4-(p-toluenesulfonyloxy-methyl)-4,5-dihydro-2-t-
hiazolyl]carbamate: A solution of 0.8 g of tert-butyl
N-[(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolyl]carbamate, 0.76 g
of p-toluenesulfonyl chloride and 0.56 cm.sup.3 of triethylamine in
25 cm.sup.3 of dichloromethane is stirred for 16 hours at a
temperature in the region of 20.degree. C. The solution obtained is
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 40.degree. C. The evaporation residue obtained is
purified by chromatography at atmospheric pressure on a column of
silica gel (particle size 60-200.mu.; diameter 2 cm; height 25 cm),
eluting with a mixture of cyclohexane/ethyl acetate (70/30 by
volume) and collecting 30 cm.sup.3 fractions. The fractions
containing the expected product are combined and then concentrated
under the above conditions. 0.8 g of tert-butyl
N-[(4RS)-4-(p-toluenesulfonyloxymethyl)-4,5-dihydro-2-thiazolyl]carbamate
is obtained in the form of a white solid [.sup.1H NMR spectrum (300
MHz, CD.sub.3l.sub.2, .delta. in ppm): 1.48 (s: 9H); 2.46 (s: 3H);
3.10 (dd, J=11.5 and 5.5 Hz: 1H); 3.33 (dd, J=11.5 and 8.5 Hz: 1H);
3.97 (dd, J=9.5 and 8 Hz: 1H); 4.06 (dd, J=9.5 and 4.5 Hz: 1H);
4.43 (mt: 1H); 7.36 (d, J=8 Hz: 2H); 7.80 (d, J=8 Hz: 2H); from
8.50 to 9.40 (very broad unresolved complex: 1H)].
[0364] Tert-Butyl
N-[(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolyl]carbama- te: 10
cm.sup.3 of aqueous 1N sodium hydroxide are added to a solution of
2 g of tert-butyl
2-[(tert-butoxycarbonyl)imino]-(4RS)-4-[(tert-butoxycar-
bonyl)oxy]methyl-1,3-thiazolidine-3-carboxylate in 20 cm.sup.3 of
methanol and the mixture is then stirred at a temperature in the
region of 20.degree. C. for 4 hours. The reaction mixture is
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 50.degree. C. The residue obtained is taken up in 30
cm.sup.3 of water, filtered and washed with ethyl acetate and then
with water. 0.37 g of tert-butyl
N-[(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolyl]-carbamate is
obtained in the form of a white solid [mass spectrum: DCI m/z=233
MH.sup.+ m/z=177 (M--C.sub.4H.sub.7).sup.+].
[0365] Tert-Butyl
2-[(tert-butoxycarbonyl)imino]-(4RS)-4-[(tert-butoxycarb-
onyl)oxy]methyl-1,3-thiazolidine-3-carboxylate: 10.91 g of
di-tert-butyl dicarbonate and 2.81 cm.sup.3 of triethylamine are
added to a solution of 1.98 g of
(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolylamine in 20 cm.sup.3
of dichloromethane, and the mixture is then stirred at a
temperature in the region of 20.degree. C. After 4 hours, a further
3 cm.sup.3 of triethylamine are added and the mixture is then
stirred for 16 hours at a temperature in the region of 20.degree.
C. 50 cm.sup.3 of water are added to the reaction mixture and the
phases are separated after settling has taken place. The organic
phase is dried over magnesium sulfate, filtered and concentrated
under reduced pressure (1 kPa) at a temperature in the region of
40.degree. C. 7 g of tert-butyl
2-[(tert-butoxy-carbonyl)imino]-(4RS)-4-[(tert-butoxycarbonyl)oxy]-methyl-
-1,3-thiazolidine-3-carboxylate are obtained in the form of a white
solid [mass-spectrum: DCI m/z=433 MH.sup.+ m/z=333
(M--C.sub.5H.sub.7O.sub.2).s- up.+].
[0366] (4RS)-4-Hydroxymethyl-4,5-dihydro-2-thiazolylamine: A
solution of 90 g of
1-tert-butyl-3-(2-hydroxy-1-hydroxymethylethyl)thiourea in 500
cm.sup.3 of 6N hydrochloric acid is stirred at a temperature in the
region of 100.degree. C. After 3 hours, the reaction mixture is
cooled to a temperature in the region of 20.degree. C. and is then
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 50.degree. C. The residue obtained is taken up in 100
cm.sup.3 of water, basified with 100 cm.sup.3 of 5N sodium
hydroxide and then concentrated as above. The oil obtained is
stirred for 20 hours at a temperature in the region of 20.degree.
C. in 300 cm.sup.3 of ethanol, filtered and washed with 5 times 50
cm.sup.3 of ethanol and 3 times 100 cm.sup.3 of methanol. The
various filtrates are combined, evaporated under reduced pressure
(1 kPa) at a temperature in the region of 40.degree. C. and then
crystallized from 400 cm.sup.3 of ethanol to give 31 g of
(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolylamine in the form of a
white solid melting at 122.degree. C. [infrared spectrum (KBr):
3311; 3164; 1648; 1601; 1349; 1051 and 982 cm.sup.-1].
[0367] 1-tert-Butyl-3-(2-hydroxy-1-hydroxymethyl-ethyl)thiourea:
30.4 cm.sup.3 of tert-butyl isothiocyanate are added to a solution
of 14.6 g of 2-amino-1,3-propanediol in 245 cm.sup.3 of ethanol,
and the mixture is then stirred at a temperature in the region of
20.degree. C. for 94 hours. The reaction medium is concentrated
under reduced pressure (5 kPa) at a temperature in the region of
40.degree. C. and the residue is slurried in a mixture of 160
cm.sup.3 of petroleum ether and 26 cm.sup.3 of ethanol, and the
product is filtered off and then dried in a desiccator under
reduced pressure (0.1 kPa) at a temperature in the region of
60.degree. C. 30 g of 1-tert-butyl-3-(2-hydroxy-1-hydroxymethyl-
ethyl)thiourea are obtained in the form of a white solid [.sup.1H
NMR spectrum (250 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm):
1.42 (s: 9H); 3.38 (mt: 2H); 3.54 (mt: 2H); 4.17 (unresolved
complex: 1H); 4.70 (t, J=5 Hz: 2H); 7.08 (d, J=8 Hz: 1H); 7.38 (s:
1H]).
EXAMPLE 26
(+)-(4R)-4-(4-Thiazolylmethyl)-4,5-dihydro-2-thiazolyl-amine
dihydrochloride
[0368] A solution of 1.75 g of
N-(tert-butyl)-N'-[(1R)-1-hydroxymethyl-2-(-
4-thiazolyl)ethyl]thiourea in 20 cm.sup.3 of 6N hydrochloric acid
is heated at a temperature in the region of 110.degree. C. for 20
hours. The reaction medium is concentrated under reduced pressure
(1 kPa) at a temperature in the region of 60.degree. C., taken up
in 5 cm.sup.3 of ethanol and then concentrated under the same
conditions as above. The residue is taken up in 5 cm.sup.3 of
ethanol and the product is then filtered off and dried in a
desiccator under reduced pressure (0.1 kPa) at a temperature in the
region of 40.degree. C. 0.54 g of
(+)-(4R)-4-(4-thiazolylmethyl)-4,5-dihydro-2-thiazolylamine
dihydrochloride is obtained in the form of a cream-colored solid
melting at 195.degree. C. [.sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.su- b.6, .delta. in ppm): 3.67 (mt: 2H) ; 3.41
(dd, J=11.5 and 5.5 Hz: 1H); 3.68 (dd, J=11.5 and 8 Hz: 1H); 4.63
(mt: 1H); 7.59 (d, J=2 Hz: 1H); 9.14 (d, J=2 Hz: 1H); 9.18
(unresolved complex: 1H); 9.66 (unresolved complex: 1H); 10.04
(broad s: 1H); (.alpha..sub.D.sup.20=+24.2+/-0.8 at a concentration
of 0.5% in methanol)].
[0369]
N-(tert-Butyl)-N'-[(1R)-1-hydroxymethyl-2-(4-thiazolyl)ethyl]thiour-
ea: A solution of 2.5 g of tert-butyl
N-[(1R)-1-hydroxymethyl-2-(4-thiazol- yl)-ethyl]carbamate in 20
cm.sup.3 of 6N hydrochloric acid and 20 cm.sup.3 of dioxane is
stirred at a temperature in the region of 20.degree. C. for 18
hours. The reaction mixture is concentrated under reduced pressure
(1 kPa) at a temperature in the region of 40.degree. C. 1.9 g of a
white solid are obtained. The solid obtained is taken up in 6
cm.sup.3 of absolute ethanol and 2 cm.sup.3 of triethylamine are
added, followed by addition of 2.1 cm.sup.3 of tert-butyl
isothiocyanate. The mixture is stirred at a temperature in the
region of 50.degree. C. for 20 hours. The reaction medium is
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 40.degree. C. The residue is taken up in water and the
aqueous phase is extracted with dichloromethane. The organic phase
is dried over magnesium sulfate, filtered and concentrated under
the above conditions. The residue is dried in a desiccator under
reduced pressure (0.1 kPa) at a temperature in the region of
40.degree. C. 1.75 g of
N-(tert-butyl)-N'-[(1R)-1-hydroxymethyl-2-(4-thiazolyl)ethyl-
]thiourea are obtained in the form of a yellow solid [.sup.1H NMR
spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm):
1.41 (s: 9H) 2.96 (dd, J=15 and 7 Hz: 1H); 3.05 (dd, J=15 and 7 Hz:
1H); 3.41 (mt: 2H); 4.62 (unresolved complex: 1H); 4.85 (t, J=5 Hz:
1H); 7.21 (d, J=8.5 Hz: 1H); 7.23 (broad s: 1H); 7.37 (d, J=2 Hz:
1H); 9.04 (d, J=2 Hz: 1H)].
[0370] Tert-Butyl
N-[(1R)-1-hydroxymethyl-2-(4-thiazolyl)ethyl]carbamate: 1.59
cm.sup.3 of triethylamine are added with stirring to a solution of
3 g of BOC-D-(4-thiazolyl)alanine in 50 cm.sup.3 of
tetrahydrofuran. The reaction medium is cooled to a temperature in
the region of -18.degree. C., followed by addition, with stirring
and under an inert atmosphere, of 1.16 cm.sup.3 of isobutyl
chloroformate. After stirring for 40 minutes at a temperature in
the region of -15.degree. C., the reaction medium is rapidly
filtered under cold conditions and a solution of 0.85 g of sodium
borohydride predissolved in 6 cm.sup.3 of water is then added to
the filtrates, at a temperature in the region of -15.degree. C. and
with stirring. After stirring for 18 hours au a temperature in the
region of 20.degree. C., the reaction medium is diluted with 100
cm.sup.3 of water and extracted with ethyl acetate. The organic
phase is washed with water, dried over magnesium sulfate, filtered
and concentrated under reduced pressure (1 kPa) at a temperature in
the region of 50.degree. C. 2.5 g of tert-butyl
N-[(1R)-1-hydroxymethyl-2-(4-thiazolyl)ethyl]carbamate are obtained
in the form of a colorless oil [infrared spectrum (CCl.sub.4):
3442, 3368, 2980, 2932, 2874, 1710, 1501, 1392, 1367, 1243, 1171,
1048 and 875 cm.sup.-1].
EXAMPLE 27
(+)-(4R)-4-(3-Aminopropyl)-4,5-diydro-2-thiazolylamine
dihydrochloride
[0371] A solution of 9.6 g of benzyl
N-[(4R)-4-(3-tert-butylthioureido)-5-- hydroxypentyl]-carbamate in
50 cm.sup.3 of 6N hydrochloric acid is heated at a temperature in
the region of 110.degree. C. for 18 hours. The reaction medium is
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 40.degree. C., taken up successively in 30 cm.sup.3 of
ethanol and 20 cm.sup.3 of isopropanol, concentrating under the
same conditions as above between each washing. The solid obtained
is taken up in ethanol and diethyl ether, filtered off and dried in
a desiccator under reduced pressure (0.1 kPa) at a temperature in
the region of 40.degree. C. to give 2.8 g of
(+)-(4R)-4-(3-aminopropyl)-4,5-d- iydro-2-thiazolylamine
dihydrochloride in the form of a white solid melting at 166.degree.
C. [.sup.1H NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6,
.delta. in ppm): from 1.55 to 1.85 (mt: 4H); 2.81 (mt: 2H); 3.25
(dd, J=11 and 6 Hz: 1H); 3.69 (dd, J=11 and 8 Hz: 1H); 4.27 (mt:
1H); 8.16 (unresolved complex: 3H); 9.50 (broad unresolved complex:
2H); from 9.50 to 10.60 (very broad unresolved complex: 1H);
(.alpha..sub.D.sup.20=+7.5+/-0.4 at a concentration of 0.5% in
methanol)].
[0372] Benzyl
N-[(4R)-4-(3-tert-butylthioureido)-5-hydroxypentyl]carbamate- :
2.24 g of lithium chloride are added with stirring to a solution of
16 g of ethyl
(2R)-5-{[(benzyloxy)carbonyl]amino}-2-(3-tert-butyl-thioureido)p-
entanoate in 200 cm.sup.3 of ethanol and 100 cm.sup.3 of
tetrahydrofuran. After stirring for 15 minutes at a temperature in
the region of 0.degree. C., 2.24 g of sodium borohydride are added.
After stirring for 20 hours at a temperature in the region of
20.degree. C., a further 0.5 g of sodium borohydride is added. The
reaction medium is filtered and the filtrates are concentrated
under reduced pressure (1 kPa) at a temperature in the region of
40.degree. C. The residue is chromatographed at atmospheric
pressure on a column of silica gel (particle size 60-200.mu.;
diameter 5.6 cm; height 40 cm), eluting with a mixture of
dichloromethane/ethyl acetate (8/2 by volume) and a mixture of
dichloromethane/ethyl acetate (6/4 by volume). The fractions
containing the expected product are combined and then concentrated
under the above conditions. 9.6 g of benzyl
N-[(4R)-4-(3-tert-butylthioureido)-5-hydroxyp- entyl]carbamate are
obtained in the form of a yellow oil [.sup.1H NMR spectrum (300
MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): from 1.30 to 1.60
(mt: 4H) ; 1.42 (s: 9H); 3.00 (mt: 2H); from 3.25 to 3.40 (mt: 1H);
3.45 (mt: 1H); 4.21 (unresolved complex: 1H); 4.76 (unresolved
complex: 1H); 5.02 (s: 2H); 7.09 (d, J=8.5 Hz: 1H); 7.17 (broad s:
1H); 7.27 (t, J=5.5 Hz: 1H); from 7.30 to 7.45 (mt: 5H)].
[0373] Ethyl
(2R)-5-{[(Benzyloxy)carbonyl]amino}-2-(3-tert-butylthioureido-
)pentanoate: 7.5 cm.sup.3 of tert-butyl isothiocyanate are added to
a solution of 13 g of ethyl
(2R)-2-amino-5-[(benzyloxy)carbonyl]amino-penta- noate
hydrochloride in 200 cm.sup.3 of ethanol, and the mixture is then
stirred at a temperature in the region of 20.degree. C. After 48
hours, the reaction medium is concentrated under reduced pressure
(1 kPa) at a temperature in the region of 40.degree. C. to give 16
g of ethyl
(2R)-5-{[(benzyloxy)carbonyl]amino}-2-(3-tert-butyl-thioureido)pentanoate
in the form of a colorless oil [mass spectrum: EI m/z=409 M.sup.+
m/z=232 (C.sub.13H.sub.14NO.sub.3).sup.+ m/z=142 (232-PhCH).sup.+
m/z=91 (C.sub.7H.sub.7).sup.+].
[0374] Ethyl (2R)-2-amino-5-[(benzoyloxy)carbonyl]-aminopentanoate
hydrochloride: A solution of 12.5 g of
(2R)-2-amino-5-[(benzyloxy)carbony- l]aminopentanoic acid
hydrochloride in 200 cm.sup.3 of ethanol is cooled to a temperature
in the region of -20.degree. C. 6.5 cm.sup.3 of thionyl chloride
are added dropwise and the mixture is then stirred at a temperature
in the region of 20.degree. C. for 18 hours. The reaction medium is
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 40.degree. C. to give 13 g of ethyl
(2R)-2-amino-5-[(benzoy- loxy)carbonyl]aminopentanoate
hydrochloride [mass spectrum: DCI m/z=295 MH.sup.+].
[0375] (2R)-2-Amino-5-[(benzyloxy)carbonyl]amino-pentanoic acid
hydrochloride: 30 g of basic copper II carbonate are added to a
solution of 15.5 g of D-ornithine hydrochloride in 1 dm.sup.3 of
water. The mixture is heated at a temperature in the region of
100.degree. C. for 2 hours, filtered while hot and washed with
water. The filtrates are cooled to a temperature in the region of
20.degree. C., followed by addition of 14.5 g of magnesium oxide
with stirring. The reaction medium is cooled to a temperature in
the region of 0.degree. C., followed by addition of 4 times 15.5
cm.sup.3 of benzyl chloroformate. After 18 hours at a temperature
in the region of 20.degree. C., the mixture is filtered. The solid
is washed successively with 3 times 30 cm.sup.3 of water and 3
times 30 cm.sup.3 of diethyl ether and is then suspended in 500
cm.sup.3 of 1N hydrochloric acid with a gentle stream-of hydrogen
sulfide for 2 hours. The suspension is filtered and the solid is
washed with 0.5N hydrochloric acid. The filtrates are brought to pH
4-5 with dilute aqueous ammonia to give a white precipitate. After
filtration and drying in a desiccator, 12.5 g of
(2R)-2-amino-5-[(benzyloxy)carbonyl]aminopenta- noic acid
hydrochloride are obtained in the form of a white solid [.sup.1H
NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm):
from 1.40 to 1.80 (mt: 4H); 2.99 (mt: 2H); 3.11 (mt: 1H); 5.02
(broad s: 2H); from 7.25 to 7.45 (mt: 6H)].
EXAMPLE 28
(+)-(4R)-4-(4-Hydroxybenzyl)-4,5-dihydro-2-thiazolyl-amine
hydrochloride
[0376] A solution of 0.2 g of
N-(tert-butyl)-N'-[(1R)-1-hydroxymethyl-2-(4-
-hydroxyphenyl)ethyl]-thiourea in 2.6 cm.sup.3 of 6N hydrochloric
acid is heated at a temperature in the region of 110.degree. C. for
18 hours. The reaction medium is concentrated under reduced
pressure (1 kPa) at a temperature in the region of 55.degree. C.
and is then taken up successively in 10 cm.sup.3 of isopropyl
ether, 10 cm.sup.3 of diethyl ether, 10 cm.sup.3 of pentane, 10
cm.sup.3 of petroleum ether and 10 cm.sup.3 of isopropyl ether,
concentrating under the same conditions as above between each wash.
The solid obtained is dried in a desiccator under reduced pressure
(0.1 kPa) at a temperature in the region of 40.degree. C. to give
0.098 g of (+)-(4R)-4-(4-hydroxybenzyl)-4,5-dihydro-
-2-thiazolyl-amine hydrochloride in the form of an orange-colored
solid [.sup.1H NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6,
.delta. in ppm) 2.78 (dd, J=13.5 and 7.5 Hz: 1H); 2.88 (dd, J=13.5
and 5.5 Hz: 1H); 3.26 (dd, J=11.5 and 6 Hz: 1H); 3.55 (dd, J=11.5
and 7.5 Hz: 1H); 4.45 (mt: 1H); 6.74 (d, J=8.5 Hz: 2H); 7.07 (d,
J=8.5 Hz: 2H); 9.09 (unresolved complex: 1H); 9.41 (s: 1H); 9.56
(unresolved complex: 1H); 9.97 (broad s: 1H);
(.alpha..sub.D.sup.20=+9.5+/-0.5 at a concentration of 0.5% in
methanol)].
[0377]
N-(tert-Butyl)-N'-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]th-
iourea: 0.15 cm.sup.3 of triethylamine is added to a solution of
0.2 g of 4-[(2R)-2-amino-3-hydroxypropyl]phenol in 10 cm.sup.3 of
absolute ethanol, followed by addition of 0.18 cm.sup.3 of
tert-butyl isothiocyanate. The mixture is stirred at a temperature
in the region of 20.degree. C. for 18 hours and is then heated at a
temperature in the region of 60.degree. C. for 4 hours. After
cooling, the reaction medium is evaporated under reduced pressure
(1 kPa) at a temperature in the region of 40.degree. C. and then
chromatographed under an argon pressure of 60 kPa on a column of
silica gel (particle size 40-63.mu.; diameter 2.5 cm; height 29
cm), eluting with a mixture of dichloromethane/methanol (98/2 by
volume). The fractions containing the expected product are combined
and then concentrated under the above conditions. 0.2 g of
N-(tert-butyl)-N'-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]thiourea
is obtained in the form of a colorless viscous oil [.sup.1H NMR
spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm):
1.42 (s: 9H) ; 2.63 (dd, J=13.5 and 8 Hz: 1H); 2.72 (dd, J=13.5 and
5.5 Hz: 1H); from 3.25 to 3.40 (mt: 2H); 4.29 (unresolved complex:
1H); 4.83 (t, J=4.5 Hz: 1H); 6.67 (d, J=8 Hz: 2H); 7.05 (d, J=8 Hz:
2H); 7.15 (d, J=8 Hz: 1H); 7.26 (broad s: 1H); 9.16 (s: 1H)].
[0378] 4-[(2R)-2-Amino-3-hydroxypropyl)]phenol: A solution of 2.2 g
of tert-butyl
N-[(1R)-1-hydroxy-methyl-2-(4-hydroxyphenyl)ethyl]carbamate in 24
cm.sup.3 of dichloromethane and 4 cm.sup.3 of dioxane is added,
with stirring and under an inert atmosphere, at a temperature in
the region of 20.degree. C., to a solution of 20.5 cm.sup.3 of 4N
hydrochloric acid in dioxane. The mixture is heated at a
temperature in the region of 60.degree. C. for 18 hours and is then
cooled and concentrated under reduced pressure (1 kPa) at a
temperature in the region of 60.degree. C. The residue is taken up
in 50 cm.sup.3 of dichloromethane, filtered, slurried in 20
cm.sup.3 of diethyl ether, filtered again, washed with twice 5
cm.sup.3 of diethyl ether and then dried in a desiccator under
reduced pressure (0.1 kPa) at a temperature in the region of
40.degree. C. 1.4 g of 4-[(2R)-2-amino-3-hydroxy-propyl)]phenol are
obtained in the form of a beige-colored solid melting at
156.degree. C. [.sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 2.69 (dd, J=13 and 9
Hz: 1H); 2.79 (dd, J=13 and 5.5 Hz: 1H); 3.23 (mt: 1H); from 3.30
to 3.45 (mt: 1H); 3.51 (ddd, J=11.5-5 and 4.5 Hz: 1H); 5.32 (t, J=5
Hz: 1H); 6.73 (d, J=8.5 Hz: 2H); 7.06 (d, J=8.5 Hz: 2H); 7.95
(unresolved complex: 3H); 9.37 (s: 1H)].
[0379] Tert-Butyl
N-[(1R)-1-hydroxymethyl-2-(4-hydroxyphenyl)ethyl]carbama- te: A
solution of 29.6 cm.sup.3 of lithium aluminum hydride at 1M in
tetrahydrofuran is added, with stirring and under an inert
atmosphere, at a temperature in the region of 20.degree. C., to a
solution of 4.38 g of methyl BOC-D-tyrosinate in 25 cm.sup.3 of
tetrahydrofuran. After addition of 60 cm.sup.3 of tetrahydrofuran,
the reaction mixture is heated at a temperature in the region of
70.degree. C. for 3 hours. The reaction mixture is cooled and then
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 60.degree. C. The evaporation residue is dried in a
desiccator under reduced pressure (0.1 kPa) at a temperature in the
region of 40.degree. C. and is then chromatographed under an argon
pressure of 60 kPa on a column of silica gel (particle size
40-63.mu.; diameter 7 cm; height 24 cm), eluting with 10 dm.sup.3
of a dichloromethane/methanol mixture (98/2 by volume), 2 dm.sup.3
of a dichloromethane/methanol mixture (95/5 by volume) and 2
dm.sup.3 of a dichloromethane/methanol mixture (90/10 by volume).
The fractions containing the expected product are combined and then
concentrated under the above conditions. 2.2 g of tert-butyl
N-[(1R)-1-hydroxymethyl-2-(4-hy- droxyphenyl)ethyl]-carbamate are
obtained in the form of a white foam [.sup.1H NMR spectrum (400
MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 1.35 (s: 9H);
2.46 (dd, J=14 and 8 Hz: 1H); 2.68 (dd, J=14 and 6 Hz: 1H); from
3.15 to 3.40 (mt: 2H); 3.50 (mt: 1H); 4.61 (mt: 1H); 6.48 (d, J=8.5
Hz: 1H); 6.65 (d, J=8 Hz: 2H); 6.97 (d, J=8 Hz: 2H); 9.11 (broad s:
1H)].
EXAMPLE 29
(+)-4-(4-Pyridylsulphanylmethyl)-4,5-dihydro-2-thiazolylamine
[0380] A racemic mixture of 1.75 g of
(4RS)-4-(4-pyridylsulphanylmethyl)-4- ,5-dihydro-2-thiazolylamine
dihydrochloride is separated on a Chiralcel OD .sup.10.mu. column
in a heptane/2-isopropanol/triethylamine mixture (80/20/0.1 by
volume) to give 0.43 g of (+)-4-(4-pyridylsulphanylmethyl)--
4,5-dihydro-2-thiazolylamine [.sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 3.12 (dd, J=11 and 6.5
Hz: 1H); 3.20 (d, J=6.5 Hz: 2H); 3.44 (dd, J=11 and 7.5 Hz: 1H);
4.32 (mt: 1H); 6.49 (unresolved complex: 2H); 7.30 (dd, J=5 and 1.5
Hz: 2H); 8.37 (dd, J=5 and 1.5 Hz: 2H), (.alpha..sub.D.sup.20=+13.3
+/-0.6 at a concentration of 0.5% in methanol)].
[0381]
(4RS)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-2-thiazolylamine
dihydrochloride: 5 cm.sup.3 of 4N hydrochloric acid in dioxane are
added to a solution of 0.356 g of tert-butyl
N-(4RS)-4-(4-pyridylsulphanyl-meth-
yl)-4,5-dihydro-2-thiazolyl]carbamate in 5 cm.sup.3 of methanol and
20 cm.sup.3 of dioxane, and the mixture is then stirred at a
temperature in the region of 20.degree. C. for 18 hours. The
reaction medium is concentrated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C., taken up in diisopropyl
ether and then filtered to give 0.287 g of
(4RS)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-2-thiaz- olylamine
dihydrochloride in the form of a cream-colored solid [.sup.1H NMR
spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm):
3.45 (dd, J=11 and 4.5 Hz: 1H); 3.61 (dd, J=14 and 7 Hz: 1H); 3.69
(dd, J=14 and 5.5 Hz: 1H); 3.80 (dd, J=12 and 8 Hz: 1H); 4.59 (mt:
1H); 8.00 (broad d, J=6.5 Hz: 2H); 8.66 (broad d, J=6.5 Hz: 2H);
9.60 (unresolved complex: 1H); 9.81 (unresolved complex: 1H); from
10.00 to 10.50 (broad unresolved complex: 1H).
[0382] tert-Butyl
N-[(4RS)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-2-thia-
zolyl]carbamate: a suspension of 1.5 g of tert-butyl
N-[(4RS)-4-(p-toluenesulfonyloxymethyl)-4,5-dihydro-2-thiazolyl]carbamate
in 50 cm.sup.3 of acetonitrile is heated until the reagent has
dissolved and 0.604 g of 4-mercaptopyridine is then added with
stirring. After cooling to a temperature in the region of
20.degree. C., 1.07 g of potassium carbonate are added. After
stirring for 48 hours at a temperature in the region of 20.degree.
C., the reaction mixture is filtered. The filtrate is concentrated
under reduced pressure (1 kPa) at a temperature in the region of
50.degree. C. The residue obtained is taken up in ethyl acetate and
water and the phases are separated after settling has taken place.
The organic phase is washed with sodium chloride solution, dried
over magnesium sulfate and chromatographed on a column of alumina,
eluting with successive mixtures of ethyl acetate/cyclohexane
(50/50 by volume). The fractions containing the expected product
are purified by chromatography on a column of silica gel, eluting
with ethyl acetate. The fractions containing the expected product
are combined and then concentrated under the above conditions.
0.356 g of tert-butyl
N-[(4RS)-4-(4-pyridylsulphanylmethyl)-4,5-dihydro-2-
-thiazolyl]carbamate is obtained in the form of a yellow oil
[.sup.1H NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta.
in ppm): 1.42 (s: 9H); 3.09 (dd, J=11.5 and 6 Hz: 1H); 3.29 (mt:
2H); 3.40 (dd, J=11.5 and 8 Hz: 1H); 4.25 (mt: 1H); 7.35 (dd, J=5
and 1.5 Hz: 2H); 8.40 (dd, J=5 and 1.5 Hz: 2H); from 9.70 to 10.00
(broad unresolved complex: 1H)]
EXAMPLE 30
(4R)-4-(1-Oxy-4-pyridylmethyl)-4,5-dihydro-2-thiazolylamine
hydrochloride
[0383] A solution of 0.6 g of
N-(tert-butyl)-N'-[(1R)-1-hydroxymethyl-2-(1-
-oxy-4-pyridyl)ethyl]thiourea in 6 cm.sup.3 of 6N hydrochloric acid
is heated at a temperature in the region of 110.degree. C. for 18
hours. The reaction medium is concentrated under reduced pressure
(1 kPa) at a temperature in the region of 55.degree. C., taken up
in twice 20 cm.sup.3 of ethanol, concentrated under the same
conditions as above, taken up in 10 cm.sup.3 of ethanol, filtered
and dried in a desiccator under reduced pressure (0.1 kPa) at a
temperature in the region of 40.degree. C. to give 0.296 g of
(4R)-4-(1-oxy-4-pyridylmethyl)-4,5-dihydro-2-thiazolylami- ne
hydrochloride in the form of cream-colored crystals [.sup.1H NMR
spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm):
3.04 (limiting AB: 2H); 3.34 (dd, J=12 and 5.5 Hz: 1H); 3.68 (dd,
J=12 and 8 Hz: 1H); 4.63 (mt: 1H); 7.75 (d, J=7 Hz: 2H); 8.65 (d,
J=7 Hz: 2H); 9.30 (unresolved complex: 1H); 9.79 (unresolved
complex: 1H); 10.30 (broad s: 1H)].
[0384]
N-(tert-Butyl)-N'-[(1R)-1-hydroxymethyl-2-(1-oxy-4-pyridyl)ethyl]th-
iourea: 2.6 cm.sup.3 of triethylamine are added to a solution of
1.5 g of (2R)-2-amino-3-(1-oxy-4-pyridyl)-1-propanol hydrochloride
in 30 cm.sup.3 of absolute ethanol, followed by addition of 1.53
cm.sup.3 of tert-butyl isothiocyanate. After adding 20 cm.sup.3 of
methanol, the mixture is stirred at a temperature in the region of
20.degree. C. for 18 hours and is then concentrated under reduced
pressure (1 kPa) at a temperature in the region of 40.degree. C. 1
cm.sup.3 of triethylamine is added to the evaporation residue taken
up in 10 cm.sup.3 of methanol, followed by addition of 1.5 cm.sup.3
of tert-butyl isothiocyanate. The mixture is stirred at a
temperature in the region of 20.degree. C. for 48 hours. The
reaction medium is concentrated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. and the product is taken
up in 25 cm.sup.3 of ethyl acetate, filtered off and washed with 10
cm.sup.3 of ethyl acetate and 20 cm.sup.3 of isopropyl ether. The
triethylamine hydrochloride is removed by passage through a column
of alumina. 0.6 g of
N-(tert-butyl)-N'-[(1R)-1-hydroxymethyl-2-(1-oxy-4-pyridyl)ethyl]thiourea
is obtained in the form of white crystals [R.sup.f=0.36 in a
dichloromethane/methanol mixture (90/10 by volume) on a Merck 60
F.sub.254 alumina plate (type E)].
[0385] (2R)-2-Amino-3-(1-oxy-4-pyridyl)-1-propanol hydrochloride: a
solution of 20 cm.sup.3 of 4N hydrochloric acid in dioxane is added
with stirring, at a temperature in the region of 20.degree. C., to
a solution of 2 g of tert-butyl
N-[(1R)-1-hydroxymethyl-2-(1-oxy-4-pyridyl)ethyl]car- bamate in 20
cm.sup.3 of dioxane. The mixture is stirred at a temperature in the
region of 20.degree. C. for 18 hours and is then taken up in 40
cm.sup.3 of dioxane, stirred for 30 minutes and filtered. The
precipitate is washed with 10 cm.sup.3 of dioxane and then with 25
cm.sup.3 of isopropyl ether and dried in a desiccator under reduced
pressure (0.1 kPa) at a temperature in the region of 40.degree. C.
1.54 g of (2R)-2-amino-3-(1-oxy-4-pyridyl)-1-propanol hydrochloride
are obtained in the form of a pale yellow solid [.sup.1H NMR
spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm):
3.08 (d, J=6 Hz: 2H); from 3.40 to 3.55 (mt: 2H); from 3.55 to 3.70
(mt: 1H); 7.78 (d, J=6.5 Hz: 2H); 8.26 (broad s: 3H); 8.71 (d,
J=6.5 Hz: 2H)].
[0386] Tert-Butyl
N-[(1R)-1-hydroxymethyl-2-(1-oxy-4-pyridyl)ethyl]carbama- te: 1 g
of tert-butyl (1R)-1-(4-pyridylmethyl)-2-hydroxyethylcarbamate in 5
cm.sup.3 of dichloromethane is added to a solution of 1.01 g of 77%
m-chloroperbenzoic acid in 10 cm.sup.3 of dichloromethane, and the
mixture is then heated to a temperature in the region of 60.degree.
C. After 45 minutes, a further 0.65 g of m-chloroperbenzoic acid is
added and the mixture is heated for 1 hour at a temperature in the
region of 60.degree. C., and the above operation is then repeated.
After heating for 2 hours at a temperature in the region of
60.degree. C., the reaction medium is cooled and then taken up in
50 cm.sup.3 of dichloromethane and 50 cm.sup.3 of 1N sodium
hydroxide. The aqueous phase is concentrated under reduced pressure
(1 kPa) at a temperature in the region of 40.degree. C., taken up
in 50 cm.sup.3 of dichloromethane, dried over magnesium sulfate,
filtered and concentrated under reduced pressure (1 kPa) at a
temperature in the region of 40.degree. C. 0.15 g of tert-butyl
N-[(1R)-1-hydroxymethyl-2-(1-oxy-4-pyridyl)ethyl]carbamate is
obtained [.sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 1.32 (s: 9H) from 2.45
to 2.60 (mt: 1H); 2.86 (very broad d, J=13.5 Hz: 1H); from 3.20 to
3.45 (mt: 2H); 3.63 (mt: 1H); 4.80 (mt: 1H); 6.67 (broad d, J=9 Hz:
1H); 7.23 (broad d, J=5.5 Hz: 2H); 8.14 (broad d, J=5.5 Hz:
2H)].
EXAMPLE 31
(+)-4-(1,2,4-Triazol-1-ylmethyl)-4,5-dihydro-2-thiazolylamine
dihydrochloride
[0387] A racemic mixture of 0.35 g of
(4RS)-4-(1,2,4-triazol-1-ylmethyl-4,- 5-dihydro-2-thiazolylamine
dihydrochloride is separated on a Chiralpak AS 20.mu. column in a
heptane/ethanol/triethylamine mixture (80/20/0.1 by volume). The
fractions containing the expected product are combined and then
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 40.degree. C. to give 0.08 g of
(+)-4-(1,2,4-triazol-1-ylmethyl- )-4,5-dihydro-2-thiazolylamine
dihydrochloride in the form of a yellow solid [.sup.1H NMR spectrum
(300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 3.46 (dd,
J=11.5 and 4.5 Hz: 1H); 3.76 (dd, J=11.5 and 8.5 Hz: 1H); 4.51 (d,
J=5 Hz: 2H); 4.69 (mt: 1H); 8.13 (broad s: 1H); 8.68 (broad s: 1H);
9.30 (unresolved complex: 1H); 9.73 (unresolved complex: 1H); 10.10
(broad s: 1H), (.alpha..sub.D.sup.20=+13.2 +/-0.7 at a
concentration of 0.5% in methanol)].
[0388]
(4RS)-4-(1,2,4-Triazol-1-ylmethyl)-4,5-dihydro-2-thiazolylamine
dihydrochloride: a solution of 0.3 g of tert-butyl
N-[(4RS)-4-(1,2,4-triazol-1-ylmethyl)-4,5-dihydro-2-thiazolyl]carbamate
in 10 cm.sup.3 of 4N hydrochloric acid in dioxane is stirred at a
temperature in the region of 20.degree. C. for 34 hours. The
reaction medium is filtered and then washed with 3 times 5 cm.sup.3
of diethyl ether and dried in a desiccator. 0.14 g of
(4RS)-4-(1,2,4-triazol-1-ylmet- hyl)-4,5-dihydro-2-thiazolylamine
dihydrochloride is obtained in the form of a white foam [mass
spectrum: EI m/z=184 MH.sup.+ m/z=183 M.sup.+. m/z=114
C.sub.4H.sub.6N.sub.2.sup.+. M/z=101 C.sub.3H.sub.5N.sub.2S.sup.+
base peak m/z=36 HCl DCI m/z=184 MH.sup.+].
[0389] Tert-Butyl
N-[(4RS)-4-(1,2,4-triazol-1-ylmethyl)-4,5-dihydro-2-thia-
zolyl]carbamate: 0.6 g of 1,2,4-triazole is added, at a temperature
in the region of 20.degree. C. and under an inert atmosphere, to a
solution of 0.35 g of sodium hydride in 7 cm.sup.3 of dimethyl
sulfoxide. The mixture is stirred at a temperature in the region of
20.degree. C. for 45 minutes, followed by addition of 1 g of
tert-butyl
N-[(4RS)-4-(iodomethyl)-4,5-dihydro-2-thiazolyl]carbamate. After
stirring for 3 hours at a temperature in the region of 60.degree.
C., 30 cm.sup.3 of saturated ammonium chloride solution are added
to the reaction medium and the resulting mixture is extracted with
4 times 10 cm.sup.3 of ethyl acetate. The organic phases are washed
with 10 cm.sup.3 of saturated sodium chloride solution, dried over
magnesium sulfate, filtered and then concentrated under reduced
pressure (1 kPa) at a temperature in the region of 40.degree. C.
The residue is chromatographed under an argon pressure of 70 kPa on
a column of silica gel (particle size 40-63.mu.; diameter 4 cm;
height 18 cm), eluting with a dichloromethane/methanol mixture (5/1
by volume). The fractions containing the expected product are
combined and then concentrated under the above conditions. 0.34 g
of tert-butyl
N-[(4RS)-4-(1,2,4-triazol-1-ylmethyl)-4,5-dihydro-2-thiazolyl]-
carbamate is obtained in the form of a white foam [mass spectrum:
EI m/z=283 M.sup.+. m/z=201 C.sub.8H.sub.13N.sub.2O.sub.2S.sup.+
m/z=145 C.sub.4H.sub.5N.sub.2O.sub.2S.sup.+ m/z=101
C.sub.3H.sub.5N.sub.2S.sup.+ m/z=C.sub.3H.sub.4N.sub.3.sup.+ m/z=57
C.sub.4H.sub.9.sup.+].
[0390] Tert-Butyl
N-[(4RS)-4-(iodomethyl)-4,5-dihydro-2-thiazolyl]carbamat- e: 17 g
of sodium bicarbonate are added, at a temperature in the region of
20.degree. C., to a suspension of 25.4 g of tert-butyl
allylsulfanyl-[(tert-butoxycarbonyl)amino]methylidenecarbamate in
650 cm.sup.3 of dichloromethane, followed by addition of a solution
of 24.4 g of iodine predissolved in 850 cm.sup.3 of
dichloromethane. After 72 hours at a temperature in the region of
20.degree. C., 500 cm.sup.3 of water and 500 cm.sup.3 of saturated
sodium bicarbonate solution are added to the reaction medium and
the resulting mixture is then extracted with twice 1 dm.sup.3 of
ethyl acetate. The organic phases are washed with saturated sodium
sulfite solution and then with saturated sodium chloride solution,
dried over magnesium sulfate, filtered and then concentrated under
reduced pressure (1 kPa) at a temperature in the region of
50.degree. C. The residue obtained is crystallized from ethyl
acetate. 20.5 9 of tert-butyl
N-[(4RS)-4-(iodomethyl)-4,5-dihydro-2-thiazolyl]carb- amate are
obtained in the form of a yellow solid [.sup.1H NMR spectrum (300
MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 1.41 (s: 9H);
2.97 (dd, J=11.5 and 7 Hz: 1H); from 3.30 to 3.50 (mt: 3H); 4.12
(mt: 1H); 9.89 (unresolved complex: 1H)].
[0391] Tert-Butyl
allylsulfanyl-[(tert-butoxycarbonyl)amino]methylidenecar- bamate: a
catalytic amount of 4-(dimethylamino)pyridine and 4.7 cm.sup.3 of
triethylamine are added to a solution of 5 g of 2-allylisothiourea
hydrochloride in 50 cm.sup.3 of dichloromethane, followed by
dropwise addition of a solution of 7.1 g of di-tert-butyl
dicarbonate predissolved in 30 cm.sup.3 of dichloromethane. After
48 hours, the reaction medium is concentrated under reduced
pressure (1 kPa) at a temperature in the region of 40.degree. C.
The residue is chromatographed under an argon pressure of 70 kPa,
on a column of silica gel (particle size 40-63.mu.; diameter 4 cm;
height about 30 cm), eluting with an ethyl acetate/cyclohexane
mixture (90/10 by volume). The fractions containing the expected
product are combined and then concentrated under the above
conditions. 0.2 g of tert-butyl
allylsulfanyl-[(tert-butoxycarbonyl)amino- ]methylidenecarbamate is
obtained [mass spectrum: DCI m/z=317 MH.sup.+ m/z=261
C.sub.10H.sub.17O.sub.4N.sub.2S.sup.+ m/z=217
C.sub.9H.sub.17O.sub.2N.sub.2S.sup.+ m/z=161
C.sub.5H.sub.9O.sub.2N.sub.2- S.sup.+].
[0392] 2-Allylisothiorurea hydrochloride: 16 cm.sup.3 of allyl
chloride are added, at a temperature in the region of 20.degree.
C., to a suspension of 15 g of thiourea in 120 cm.sup.3 of ethanol.
After 15 hours at a temperature in the region of 80.degree. C., the
reaction medium is concentrated under reduced pressure (1 kPa) at a
temperature in the region of 50.degree. C. The solid obtained is
taken up in 3 times 100 cm.sup.3 of diethyl ether and then
filtered. 29 g of 2-allylisothiourea hydrochloride are obtained in
the form of a white solid [mass spectrum: DCI m/z=117
MH.sup.+].
EXAMPLE 32
(+)-(4R,5R)-5-(Ethyl-4-(4-pyridylmethyl)-4,5-dihydro-2-thiazolylamine
[0393] A suspension of 4.2 g of
N-tert-butyl-N'-[(1R,2S)-1-(4-pyridylmethy-
l)-2-hydroxybutyl]thiourea in 40 cm.sup.3 of 6N hydrochloric acid
is heated at a temperature in the region of 100.degree. C. for 20
hours. After cooling to room temperature, the reaction mixture is
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 50.degree. C. The residue is chromatographed at
atmospheric pressure on a column of silica gel (particle size
40-63.mu.; diameter 3.6 cm; height 24 cm), eluting with a
dichloromethane/methanol mixture (98/2 by volume) and then with a
dichloromethane/methanol mixture (97/3 by volume). The fractions
containing the expected product are combined and then concentrated
under the above conditions, taken up in 30 cm.sup.3 of
dichloromethane and basified with 1N sodium hydroxide. The organic
phase is dried over magnesium sulfate, filtered and dried in a
desiccator under reduced pressure (0.1 kPa) at a temperature in the
region of 40.degree. C. 1.4 g of
(+)-(4R,5R)-5-(ethyl-4-(4-pyridylmethyl)-4,5-dihydro-2-thiazo-
lylamine are obtained in the form of a white solid melting at
124.degree. C. [.sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 0.83 (t, J=7.5 Hz:
3H); 1.43 (mt: 1H); 1.61 (mt: 1H); 2.70 (limiting AB: 2H); 3.40
(mt: 1H); 4.08 (mt: 1H); 6.28 (unresolved complex: 2H); 7.29 (broad
d, J=5.5 Hz: 2H); 8.45 (broad d, J=5.5 Hz: 2H),
(.alpha..sub.D.sup.20=+166.9+/-2.4 at a concentration of 0.5% in
methanol)].
[0394]
N-tert-Butyl-N'-[(1R,2S)-1-(4-pyridylmethyl)-2-hydroxybutyl]thioure-
a: 4.3 cm.sup.3 of triethylamine are added to a solution of 3.6 g
of (2R,3S)-2-amino-1-(4-pyridyl)-3-pentanol dihydrochloride in 60
cm.sup.3 of ethanol, followed by addition of 2.6 cm.sup.3 of
tert-butyl isothiocyanate. The mixture is heated at a temperature
in the region of 50.degree. C. for 18 hours. After cooling, the
reaction medium is concentrated under reduced pressure (1 kPa) at a
temperature in the region of 40.degree. C. and the residue is taken
up in 50 cm.sup.3 of water and 100 cm.sup.3 of dichloromethane. The
organic phase is washed with 30 cm.sup.3 of water, dried over
sodium sulfate, filtered and concentrated under the above
conditions. 4.3 g of N-tert-butyl-N'-[(1R,2S-
)-1-(4-pyridylmethyl)-2-hydroxybutyl]thiourea are obtained in the
form of a thick colorless oil [.sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 0.80 (t, J=7.5 Hz:
3H); from 1.25 to 1.55 (mt: 2H); 1.37 (s: 9H); 2.72 (dd, J=14 and 9
Hz: 1H); 2.93 (dd, J=14 and 4.5 Hz: 1H); 3.37 (mt: 1H); 4.60 (mt:
1H); 4.88 (unresolved complex: 1H); 7.11 (s: 1H); 7.16 (d, J=8.5
Hz: 1H); 7.26 (broad d, J=5.5 Hz: 2H); 8.43 (broad d, J=5.5 Hz:
2H)].
[0395] (2R,3S)-2-Amino-1-(4-pyridyl)-3-pentanol dihydrochloride: a
solution of 50 cm.sup.3 of 4N hydrochloric acid in dioxane is
added, with stirring and at a temperature in the region of
20.degree. C., to a solution of 4 g of tert-butyl
N-[(1R,2S)-2-hydroxy-1-(4-pyridylmethyl)-bu- tyl]carbamate in 50
cm.sup.3 of dioxane. The mixture is stirred at a temperature in the
region of 20.degree. C. for 18 hours and is then concentrated under
reduced pressure (1 kPa) at a temperature in the region of
60.degree. C. 3.6 g of (2R,3S)-2-amino-1-(4-pyridyl)-3-pentanol
dihydrochloride are obtained in the form of a white solid [.sup.1H
NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm):
0.92 (t, J=7.5 Hz: 3H); from 1.30 to 1.65 (mt: 2H); 3.13 (dd, J=14
and 9 Hz: 1H); 3.28 (dd, J=14 and 5 Hz: 1H); 3.52 (mt: 1H); 3.68
(mt: 1H); 8.11 (broad d, J=6.5 Hz: 2H); 8.25 (unresolved complex:
3H); 8.90 (broad d, J=6.5 Hz: 2H)].
[0396] Tert-Butyl
N-[(1R,2S)-2-hydroxy-1-(4-pyridylmethyl)butyl]carbamate: 9.5 g of
an 85%/15% mixture of the two diastereoisomers of tert-butyl
N-[(2RS)-2-hydroxy-(1R)-1-(4-pyridylmethyl)butyl]-carbamate is
separated on a Kromasil.RTM. 10.mu. C8 column in an
acetonitrile/methanol/tetrahydr- ofuran/water mixture (15/15/5/65
by volume). The fractions containing the expected product are
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 40.degree. C. to give 4 g of tert-butyl
N-[(1R,2S)-2-hydroxy-1-(4-pyridylmethyl)butyl]carbamate
dihydrochloride in the form of a white solid [.sup.1H.NMR spectrum
(300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 0.91 (t,
J=7.5 Hz: 3H); 1.26 (s: 9H); 1.30 (mt: 1H); 1.52 (mt: 1H); from
2.45 to 2.60 (mt: 1H); 3.02 (dd, J=14 and 3.5 Hz: 1H); 3.28 (mt:
1H); 3.53 (mt: 1H); 4.71 (d, J=6 Hz: 1H); 6.62 (d, J=9.5 Hz: 1H);
7.20 (broad d, J=5.5 Hz: 2H); 8.42 (broad d, J=5.5 Hz: 2H)].
[0397] Tert-Butyl
N-[(2RS)-2-hydroxy-(1R)-1-(4-pyridylmethyl)butyl]carbama- te: 2.1 g
of sodium borohydride are added, with stirring and at a temperature
in the region of 10.degree. C., to a solution of 10.5 g of
tert-butyl N-[(1R)-2-oxobutyl-1-(4-pyridylmethyl)]carbamate in 150
cm.sup.3 of ethanol, and the mixture is then stirred at a
temperature in the region of 20.degree. C. for 18 hours. The
reaction medium is concentrated under reduced pressure (1 kPa) at a
temperature in the region of 40.degree. C., taken up in 100
cm.sup.3 of water and extracted with 200 cm.sup.3 of ethyl acetate.
The organic phase is dried over magnesium sulfate, filtered and
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 40.degree. C. 9.5 g of an 85%/15% mixture of the two
diastereoisomers of tert-butyl N-[(2RS)-2-hydroxy-(1R)-
-1-(4-pyridylmethyl)butyl]carbamate are obtained in the form of a
yellow gum [.sup.1H NMR spectrum (300 MHz,
(CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm). We observe a mixture
of two diastereoisomers in proportions of 85/15; .delta.=from 0.85
to 0.95 (mt: 3H); from 1.25 to 1.60 (mt: 2H); 1.26 and 1.29 (2s: 9H
in total); from 2.45 to 2.60 (mt: 0.85H); 2.67 (dd, J=14 and 1 Hz:
0.15H); 2.80 (dd, J=14 and 4.5 Hz: 0.15H); 3.02 (dd, J=14 and 4.5
Hz: 0.85H); from 3.20 to 3.35 (mt: 1H); 3.52 (mt: 0.85H); 3.69 (mt:
0.15H); 4.61 (d, J=6 Hz: 0.15H); 4.71 (d, J=6 Hz: 0.85H); 6.41 (d,
J=9.5 Hz: 0.15H); 6.62 (d, J=9.5 Hz: 0.85H); 7.20 (d, J=6 Hz:
1.7H); 7.23 (d, J=6 Hz: 0.3H); from 8.35 to 8.50 (mt: 2H in
total)].
[0398] Tert-Butyl N-[(1R)-2-oxo-(4-pyridylmethyl)-butyl]carbamate:
50 cm.sup.3 of a 3N solution of ethyl magnesium bromide dissolved
in diethyl ether are added over 1 hour to a mixture, under an inert
atmosphere, of 14 g of tert-butyl
N-{2-[N-methoxy-N-(methyl)amino]-2-oxo-(1R)-1-(4-pyrid-
ylmethyl)ethyl}carbamate in 350 cm.sup.3 of tetrahydrofuran, cooled
to a temperature in the region of 0.degree. C. After stirring for
48 hours at 0.degree. C., water is added to the reaction medium,
the resulting mixture is extracted with dichloromethane and the
extracts are washed with water. The organic phase is dried over
sodium sulfate, filtered and then concentrated under reduced
pressure (2 kPa) at a temperature in the region of 40.degree. C.
10.5 g of tert-butyl N-[(1R)-2-oxo-1-(4-pyridylme-
thyl)butyl]carbamate are obtained in the form of a yellow oil
[.sup.1H NMR spectrum (300 MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta.
in ppm): 0.94 (t, J=7 Hz: 3H); 1.32 (s: 9H); from 2.40 to 2.65 (mt:
2H); 2.70 (dd, J=14 and 10.5 Hz: 1H); 3.06 (dd, J=14 and 4.5 Hz:
1H); 4.22 (mt: 1H); 7.26 (broad d, J=5.5 Hz: 2H); 7.44 (broad d,
J=8 Hz: 1H); 8.45 (broad d, J=5.5 Hz: 2H)].
EXAMPLE 33
(4R)-4-(2-Thienylmethyl)-4,5-dihydro-2-thiazolylamine
hydrochloride
[0399] 0.9 cm.sup.3 (9.4 mmol) of ethyl chloroformate is added
dropwise to a solution of 2.5 g (9.23 mmol) of
Boc-D-2-thienylalanine and 1.3 cm.sup.3 (9.4 mmol) of triethylamine
in 100 cm.sup.3 of anhydrous tetrahydrofuran at -20.degree. C. The
resultant suspension is stirred at -20.degree. C. for 1 hour and
then filtered. The filtrate is cooled to -20.degree. C. and a
solution of 0.71 g (20.9 mmol) of sodium borohydride in 5 cm.sup.3
of water is then added. The reaction mixture is stirred at a
temperature in the region of 20.degree. C. for 64 hours and is then
concentrated under vacuum to give a residue which is used directly
without purification. A suspension of the product obtained in 20
cm.sup.3 of dioxane is treated with 6 cm.sup.3 of a 4M solution of
hydrochloric acid in dioxane and is then stirred at a temperature
in the region of 20.degree. C. for 16 hours. After concentrating
the reaction medium under vacuum, 7.5 g of a white solid are
obtained and are used directly without purification.
[0400] A suspension of the above product (1.0 g), triethylamine (4
cm.sup.3, 28.7 mmol) and tert-butyl isothiocyanate (0.50 g, 4.3
mmol) in 10 cm.sup.3 of ethanol is heated at a temperature in the
region of 50.degree. C. for 4 hours with stirring. After
concentrating under vacuum, the residue is taken up twice in 50
cm.sup.3 of ethyl acetate and is then purified by chromatography on
a column of silica gel (ethyl acetate/cyclohexane 1/1 by volume).
The fractions containing the expected product are concentrated
under reduced pressure to give 255 mg of a white solid which is
used directly.
[0401] A suspension of the product obtained above (240 mg, 0.88
mmol) is refluxed in 6 cm.sup.3 of 6N hydrochloric acid solution
for 8 hours. The reaction mixture is concentrated to dryness under
vacuum and the brown residue is slurried in a mixture of ethanol (5
cm.sup.3) and ethyl acetate (3 cm.sup.3) and then filtered. This
slurrying operation is repeated 3 times, until a clear yellow
solution is obtained. After partial concentration, the product
crystallizes and is filtered off and then dried under vacuum to
give 64 mg of (4R)-4-(2-thienylmethyl)-4,5-dih-
ydro-2-thiazolylamine hydrochloride in the form of pale yellow
crystals melting at 125-127.degree. C. [.sup.1H NMR spectrum (300
MHz, (CD.sub.3).sub.2SO-d.sub.6, .delta. in ppm): 10.1 (bs, 1H),
9.7 (bs, 1H), 9.3 (bs, 1H), 7.4 (m, 1H), 7.0 (m, 2H), 4.5 (m, 1H),
3.6 (m, 1H), 3.3 (m, 1H), 3.2 (m, 2H)].
[0402] The pharmaceutical compositions according to the invention
consist of a compound of formula (I) or an isomer or tautomer or
salt of such a compound, in pure form 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 medicinal products according to the invention may be used
orally, parenterally, rectally or topically.
[0403] Solid compositions for oral administration which can be used
include tablets, pills, powders (gelatin capsules, cachets) or
granules. In these compositions, the active principle according to
the invention is mixed with one or more inert diluents, such as
starch, cellulose, sucrose, lactose or silica, under a stream of
argon. These compositions can also comprise substances other than
diluents, for example one or more lubricants such as magnesium
stearate or talc, a dye, a coating (drage) or a varnish.
[0404] Liquid compositions for oral administration which can be
used include pharmaceutically acceptable solutions, suspensions,
emulsions, syrups and elixirs containing inert diluents such as
water, ethanol, glycerol, plant oils or liquid paraffin. These
compositions can comprise substances other than diluents, for
example wetting products, sweeteners, thickeners, flavorings or
stabilizers.
[0405] The sterile compositions for parenteral administration can
preferably be aqueous or non-aqueous solutions, suspensions or
emulsions. Solvents or vehicles which may be used include water,
propylene glycol, a polyethylene glycol, plant oils, in particular
olive oil, injectable organic esters, for example ethyl oleate, or
other suitable organic solvents. These compositions can also
contain adjuvants, in particular wetting agents, isotonic agents,
emulsifiers, dispersants and stabilizers. The sterilization can be
carried out in several ways, for example by aseptic filtration, by
incorporating sterilizing agents into the composition, by
irradiation or by heating. They can also be prepared in the form of
sterile solid compositions which can be dissolved at the time of
use in sterile water or any other injectable sterile medium.
[0406] The compositions for rectal administration are suppositories
or rectal capsules which contain, besides the active product,
excipients such as cocoa butter, semisynthetic glycerides or
polyethylene glycols.
[0407] Compositions for topical administration can be, for example,
creams, lotions, eye drops, mouth washes, nasal drops or
aerosols.
[0408] In human therapy, the compounds according to the invention
are particularly useful for treating and/or preventing multiple
sclerosis, cerebral, focal or global ischemia, cerebral or spinal
trauma, Parkinson's disease, Huntington's diseases, Alzheimer's
disease, amyotrophic lateral sclerosis, migraine, depression,
schizophrenia, anxiety, epilepsy, diabetes, atherosclerosis,
myocarditis, arthritis, arthrosis, asthma, irritable bowel
syndrome, Crohn's disease, peritonitis, gastro-esophageal reflux,
uveitis, Guillain-Barr syndrome, glomerulonephritis, lupus
erythematosus, psoriasis, the growth of certain forms of tumors
such as, for example, epithelioma, adenocarcinoma or sarcoma, and
in infections with Gram-positive or Gram-negative intracellular or
extracellular bacteria.
[0409] The doses depend on the desired effect, the duration of the
treatment and the route of administration used; they are generally
between 1 mg and 100 mg per day via the oral route for an adult,
with unit doses ranging from 0.5 mg to 50 mg of active
substance.
[0410] In general, the doctor will determine the appropriate dosage
as a function of the age, weight and all the other personal factors
of the individual to be treated.
[0411] The examples which follow illustrate compositions according
to the invention:
EXAMPLE A
[0412] Gel capsules containing a 50 mg dose of active product and
having the composition below 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
[0413] Tablets containing a 50 mg dose of active product and having
the composition below 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
[0414] Mixture of hydroxymethylcellulose, glycerol and titanium
oxide (72/3.5/24.5) qs 1 finished film-coated tablet weighing 245
mg
EXAMPLE C
[0415] An injectable solution containing 10 mg of active product
and having the composition below is prepared:
3 Compound of formula (I) 10 mg Benzoic acid 80 mg Benzyl alcohol
0.06 ml Sodium benzoate 80 mg 95% ethanol 0.4 ml Sodium hydroxide
24 mg Propylene glycol 1.6 ml Water qs 4 ml
[0416] The present invention also relates to the method for
preventing and treating diseases in which an abnormal production of
nitric oxide (NO) by induction of inducible NO-synthase (NOS-2 or
iNOS) is involved by administration of a compound of formula (I),
racemic mixtures, enantiomers and diastereoisomers thereof and
mixtures thereof, the tautomer thereof or pharmaceutically
acceptable salts thereof.
* * * * *