U.S. patent application number 09/948011 was filed with the patent office on 2002-08-22 for novel n-(arylsulphonyl) amino acid derivatives, process for their preparation and pharmaceutical compositions containing them.
Invention is credited to Ferrari, Bernard, Gougat, Jean, Muneaux, Claude, Muneaux, Yvette, Perreaut, Pierre, Planchenault, Claudine.
Application Number | 20020115685 09/948011 |
Document ID | / |
Family ID | 27670805 |
Filed Date | 2002-08-22 |
United States Patent
Application |
20020115685 |
Kind Code |
A1 |
Ferrari, Bernard ; et
al. |
August 22, 2002 |
Novel N-(arylsulphonyl) amino acid derivatives, process for their
preparation and pharmaceutical compositions containing them
Abstract
The invention relates to compounds of formula 1 in which R.sub.1
to R.sub.9, R.sub.16 and R.sub.17 are as defined in claim 1. These
compounds are pharmacologically active.
Inventors: |
Ferrari, Bernard; (Les
Matelles, FR) ; Gougat, Jean; (Grabels, FR) ;
Muneaux, Claude; (Les Matelles, FR) ; Muneaux,
Yvette; (Les Matelles, FR) ; Perreaut, Pierre;
(St. Clement De Riviere, FR) ; Planchenault,
Claudine; (St. Georges D'Orques, FR) |
Correspondence
Address: |
SANOFI-SYNTHELABO INC.
9 GREAT VALLEY PARKWAY
P.O. BOX 3026
MALVERN
PA
19355
US
|
Family ID: |
27670805 |
Appl. No.: |
09/948011 |
Filed: |
September 6, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09948011 |
Sep 6, 2001 |
|
|
|
09593067 |
Jun 13, 2000 |
|
|
|
6313120 |
|
|
|
|
09593067 |
Jun 13, 2000 |
|
|
|
09434333 |
Nov 4, 1999 |
|
|
|
6100278 |
|
|
|
|
09434333 |
Nov 4, 1999 |
|
|
|
09101214 |
Jul 2, 1998 |
|
|
|
6015812 |
|
|
|
|
09101214 |
Jul 2, 1998 |
|
|
|
PCT/FR97/00026 |
Jan 7, 1997 |
|
|
|
Current U.S.
Class: |
514/309 ;
514/12.5; 514/16.4; 514/21.91; 514/312; 514/602; 546/141; 546/153;
564/84 |
Current CPC
Class: |
C07D 233/24 20130101;
C07D 239/06 20130101; C07D 295/185 20130101; C07D 233/26 20130101;
C07C 311/19 20130101; C07D 233/22 20130101; C07D 403/12
20130101 |
Class at
Publication: |
514/309 ;
514/312; 514/602; 514/19; 564/84; 546/141; 546/153 |
International
Class: |
A61K 038/05; A61K
031/47; C07D 215/36; C07D 217/24 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 11, 1996 |
FR |
9600269 |
Claims
1. A compound of formula: 152in which: R is a phenyl, a naphthyl, a
tetrahydronaphthyl, a quinolyl or an isoquinolyl, the said rings
being unsubstltuted or substituted one or more times with R.sub.2
is a phenyl which is unsubstituted or substituted one or more times
with R.sub.11, a phenyl(C.sub.1-C.sub.4)alkyl which is
unsubstituted or substituted one or more times on the phenyl with
R.sub.11, a naphthyl which is unsubstituted or substituted one or
more times with R.sub.11, a cyclohexyl which is unsubstituted or
substituted one or more times with R.sub.11; or R.sub.2 and R.sub.9
are linked together and constitute a (C.sub.3-C.sub.5)alkylen- e
which is unsubstituted or substituted with R.sub.12 or a
(C.sub.2-C.sub.4)alkylene which is interrupted with an oxygen atom
or a sulphur atom and is unsubstituted or substituted with
R.sub.12; or R.sub.2 and R.sub.9, together with the carbon atom and
the nitrogen atom to which they are attached, constitute
tetrahydroisoquinoline which is unsubstituted or substituted one or
more times with a halogen, a hydroxyl, a (C.sub.1-C.sub.4)alkyl, a
(C.sub.1-C.sub.4)alkoxy or a benzyloxy; R.sub.3 is hydrogen or a
hydroxyl; R.sub.4 and R.sub.5 are each independently hydrogen or a
(C.sub.1-C.sub.4) alkyl; or R.sub.4 and R.sub.5, together with the
nitrogen atom to which they are attached, constitute a heterocyclic
radical chosen from:1-pyrrolidinyl, 1-piperidyl,
perhydro-1-azepinyl, 4-morpholinyl, 4-oxo-1-piperidyl,
dihydro-1-pyrrolyl or dihydro-2-imidazolyl, the said heterocyclic
radicals being unsubstituted or substituted one or more times with
R.sub.13; R.sub.6 is hydrogen and R.sub.6 can also be R.sub.8 when
R.sub.7 is hydrogen; R.sub.7 is hydrogen or a
(C.sub.1-C.sub.4)alkyl; R.sub.8 is hydrogen; a benzyl which is
unsubstituted or substituted on the phenyl one or more times with
R.sub.13; or a group ZR.sub.14; or R.sub.7 and R.sub.8, together
with the nitrogen atom to which they are attached, constitute a
heterocyclic radical chosen from: 1-pyrrolidinyl, 1-piperidyl,
1-perhydro-1-azepinyl, 4-morpholinyl, tetrahydro-2-pyrimidinyl,
1-piperazinyl or 1-piperazinyl substituted in position 4 with a
(C.sub.1-C.sub.4)alkyl or a benzyl; or, when R.sub.7 is hydrogen,
R.sub.6 and R.sub.9 are linked together to form a
(C.sub.2-C.sub.4)alkylene which is unsubstituted or substituted one
or more times with a (C.sub.1-C.sub.4) alkyl; R.sub.9 is hydrogen,
a (C.sub.1-C.sub.4)alkyl or a phenyl(C.sub.1-C.sub.4)alkyl which is
unsubstituted or substituted on the phenyl one or more times with
R.sub.11; R.sub.10 is a halogen, a (C.sub.1-C.sub.4)alkyl, a
(C.sub.1-C.sub.4)alkoxy, a hydroxyl, an amino, a
(C.sub.1-C.sub.4)alkylam- ino or a di(C.sub.1-C.sub.4) alkylamino;
R.sub.11 is a halogen, a (C.sub.1-C.sub.4)alkyl, a trifluoromethyl,
a phenyl, a hydroxyl, a (C.sub.1-C.sub.4)alkoxy or a benzyloxy; or
R.sub.11 is in the ortho position to the phenyl representing
R.sub.2 and forms with R.sub.3 a methylene group or an ethylene
group; or R.sub.1, is in the ortho position to the phenyl
representing R.sub.2 and forms with R.sub.9 a methylene group or an
ethylene group; R.sub.12 is a halogen, a (C.sub.1-C.sub.4)alkyl, a
hydroxyl, a (C.sub.1-C.sub.4)alkoxy, a benzyloxy, an oxo, a phenyl,
an acetyloxy or a trifluoroacetyloxy; R.sub.13 is a
(C.sub.1-C.sub.4)alkyl, a halogen or a hydroxyl; R.sub.14 is a
methyl, an amino, a (C.sub.1-C.sub.4)alkylamino, a di
(C.sub.1-C.sub.4)alkylamino, a tri (C.sub.1-C.sub.4)alkylammronium,
an amidino, a (C.sub.1-C.sub.4)alkylamidino, a guanidino, a
(C.sub.1-C.sub.4)alkylguanidino, a hydroxyl, a
(C.sub.1-C.sub.4)alkoxy, a (C!-C.sub.4)alkoxycarbonyl, a group
--AlkN(R.sub.15)Alk'N(R'.sub.15).sub.- 2, or a heterocyclic radical
chosen from 1-pyrrolidinyl, 1-piperidyl, perhydro-1-azepinyl,
pyridyl, imidazolyl, dihydroimidazolyl, imidazolidinyl, pyrimidinyl
and indolyl; R.sub.15 and R'.sub.15 are, independently of each
other, hydrogen or a (C.sub.1-C.sub.4) alkyl; R.sub.16 is hydrogen
or a methyl, or R.sub.16 forms with R.sub.9 a methylene group;
R.sub.17 is hydrogen or a methyl; Alk and Alk' are, independently
of each other, a (C.sub.1-C.sub.4)alkylene; Z is a
(C.sub.2-C.sub.12)alkylene or a (C.sub.1-C.sub.6)alkylene which is
interrupted or substituted with a (C.sub.5-C.sub.7)cycloalkyl or
with a phenyl; C* is an asymmetric carbon atom; as well as the
salts thereof with inorganic or organic acids.
2. A compound of formula (I) according to claim 1, in which:
R.sub.1 is a phenyl, a naphthyl, a tetrahydronaphthyl, a quinolyl
or an isoquinolyl, the said rings being unsubstituted or
substituted one or more times with R.sub.10; R.sub.2 is a phenyl
which is unsubstituted or substituted one or more times with
R.sub.11, a phenyl(C.sub.1-C.sub.4)alkyl which is unsubstituted or
substituted one or more times on the phenyl with R.sub.11, or a
naphthyl which is unsubstituted or substituted one or more times
with R.sub.11; or R.sub.2 and R.sub.9 are linked together and
constitute a (C.sub.3-C.sub.5)alkylene which is unsubstituted or
substituted with R.sub.12 or a (C.sub.2-C.sub.4)alkylene which is
interrupted with an oxygen atom or a sulphur atom and is
unsubstituted or substituted with R.sub.12; or R.sub.2 and R.sub.9
together with the carbon atom and the nitrogen atom to which they
are attached, constitute tetrahydroisoquinoline which is
unsubstituted or substituted one or more times with a halogen, a
hydroxyl, a (C.sub.1-C.sub.4) alkyl, a (C.sub.1-C.sub.4)alkoxy or a
benzyloxy; R.sub.3 is hydrogen or a hydroxyl; R.sub.4 and R.sub.9
are each independently hydrogen or a (C.sub.1-C.sub.4) alkyl; or
R.sub.4 and R.sub.9, together with the nitrogen atom to which they
are attached, constitute a heterocyclic radical chosen
from:1-pyrrolidinyl, 1-piperidyl, perhydro-1-azepinyl,
4-morpholinyl or 4-oxo-1-piperidyl, the said heterocyclic radicals
being unsubstituted or substituted with R.sub.13; R.sub.6 is
hydrogen, R.sub.6 can also be R.sub.8 when R.sub.7 is hydrogen;
R.sub.7 is hydrogen or a (C.sub.1-C.sub.4)alkyl; R.sub.8 is
hydrogen; a benzyl which is unsubstituted or substituted on the
phenyl one or more times with R.sub.13; or a group ZR.sub.14; or
R.sub.7 and R.sub.8, together with the nitrogen atom to which they
are attached, constitute a heterocyclic radical chosen
from:1-pyrrolidinyl, 1-piperidyl, 1-perhydro-1-azepinyl,
4-morpholinyl, 1-piperazinyl or 1-piperazinyl substituted in
position 4 with a (C.sub.1-C.sub.4)alkyl or a benzyl; or, when
R.sub.7 is hydrogen, R.sub.6 and R.sub.8 are linked together to
form a (C.sub.2-C.sub.4)alkyle- ne which is unsubstituted or
substituted one or more times with a (C.sub.1-C.sub.4)alkyl;
R.sub.9 is hydrogen, a (C.sub.1-C.sub.4)alkyl or a phenyl
(C.sub.1-C.sub.4) alkyl which is unsubstituted or substituted on
the phenyl one or more times with R.sub.1,; R.sub.10 is a halogen,
a (C.sub.1-C.sub.4)alkyl, a (C.sub.1-C.sub.4)alkoxy, a hydroxyl, an
amino, a (C.sub.1-C.sub.4)alkylamino or a di(C.sub.1-C.sub.4)
alkylamino; R.sub.11 is a halogen, a (C.sub.1-C.sub.4)alkyl, a
hydroxyl, a (C.sub.1-C.sub.4)alkoxy or a benzyloxy; R.sub.12 is a
halogen, a (C.sub.1-C.sub.4)alkyl, a hydroxyl, a (C.sub.1-C.sub.4)
alkoxy, a benzyloxy, an oxo or a phenyl; R.sub.1.sub.3 is a
(C.sub.1-C.sub.4)alkyl, a halogen or a hydroxyl; R.sub.14 is a
methyl, an amino, a (C.sub.1-C.sub.4)alkylamino, a
di(C.sub.1-C.sub.4)alkylamino, a tri(C.sub.1-C.sub.4)alkylammonia,
an amidino, a (C.sub.1-C.sub.4)alkylami- dino, a guanidino, a
(C.sub.1-C.sub.4)alkylguanidino, a hydroxyl, a
(C.sub.1-C.sub.4)alkoxy, a (C.sub.1-C.sub.4)alkoxycarbonyl, a group
--Alk(R.sub.15)Alk'N(R.sub.15).sub.2, or a heterocyclic radical
chosen from:1-pyrrolidinyl, 1-piperidyl, perhydro-1-azepinyl,
pyridyl, 2imidazolyl, dihydroimidazolyl, imidazolidinyl,
pyrimidinyl and indolyl; R.sub.15 and R'.sub.15 are, independently
of each other, hydrogen or a (C.sub.1-C.sub.4)alkyl; R.sub.16 is
hydrogen; R.sub.17 is hydrogen; Alk and Alk' are, independently of
each other, a (C.sub.1-C.sub.4) alkylene; Z is a
(C.sub.2-C.sub.12)alkylene or a (C.sub.1-C.sub.6)alkylene which is
interrupted or substituted with a (C.sub.5-C.sub.7)cycloalkyl or
with a phenyl; as well as the salts thereof with inorganic or
organic acids.
3. A compound of formula (I) according to either of claims 1 and 2,
which satisfies at least one of the following conditions: a
--R.sub.1 is a naphthyl, a quinolyl or a trichlorophenyl; R.sub.2,
R.sub.3, R.sub.4, R.sub.9, R.sub.6, R.sub.7, R.sub.8, R.sub.9,
R.sub.16 and R.sub.17 being as defined in claim 1; b --R.sub.2 is a
phenyl which is unsubstituted or substituted with R.sub.11;
R.sub.1, R.sub.3, R.sub.4, R.sub.9, R.sub.6, R.sub.7, R.sub.8,
R.sub.9, R.sub.16 and R.sub.17 being as defined in claim 1; c
--NR.sub.4R.sub.5 is a 1-pyrrolidinyl group; R.sub.1, R.sub.2,
R.sub.3, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.16 and R.sub.17
being as defined in claim 1; d --C(NR.sub.6)NR.sub.7R.sub.8 is a
4,5-dihydro-2-imidazolyl; R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.9, R.sub.16 and R.sub.17 being as defined in claim
1; e --R.sub.3=R.sub.9=R.sub.16=R.sub.17=H; R.sub.1, R.sub.2,
R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 being as defined in
claim 1; and the salts thereof with inorganic or organic acids.
4. A compound according to any one of claims 1, 2 and 3, of
formula: 153in which: R.sub.2a is a phenyl which is unsubstituted
or substituted in a meta or para position with R.sub.11; a
1-naphthyl or a 2-naphthyl; R.sub.1, R.sub.6, R.sub.7, R.sub.8 and
R.sub.11 are as defined in claim 1 for (I); and the salts thereof
with inorganic or organic acids.
5. A compound according to any one of claims 1, 2, 3 and 4, of
formula: 154in which: R.sub.1a is a 1-naphthyl, a 2-naphthyl, a
2,4,6-trichloro-phenyl or a 2-quinolyl; R.sub.2a is as defined in
claim 4 for (Ia); and the salts thereof with inorganic or organic
acids.
6. A compound of formula (IIa) according to claim 5, in which
R.sub.2a is a phenyl which is unsubstituted or substituted in a
meta position or para position with R.sub.11.
7. A compound according to any one of claims 1, 2, 3, 4, 5 and:6,
having (R,R) isomerism on the C* labelled carbon atoms.
8. A process for the preparation of the compounds of formula (1)
according to claim 1, characterized in that: a1) a compound of
formula: 155in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.9, R.sub.16, R.sub.17 and C* have the definItions given in
claim I for (I), in the form of a pure enantiomer or a mixture of
isomers in any proportion, is treated with an alcohol of formula
R--OH in which R is a (C.sub.1-C.sub.4)alkyl, in acidic medium, in
order to form an intermediate imidate which is reacted with an
amine of formula HNR.sub.7R.sub.8 (III) or a diamine of formula
H.sub.2NR.sub.6R.sub.8NH.s- ub.2 (IV) in which R.sub.6, R.sub.7 and
R.sub.8 have the definitions given in claim 1 for (I); b1) the
compound of formula (I) thus obtained is isolated in base form or
salt form, c1) where appropriate, another salt of the compound of
formula (I) is prepared.
9. A process for the preparation of a compound of formula (I)
according to claim 1, characterized in that: a2) a compound of
formula: 156In which X is hydrogen or a Boc group and R.sub.4,
R.sub.5 and C* are as defined for (I) in claim 1, in the form of a
pure enantiomer or a mixture of isomers in any proportion, is
treated with an alcohol of formula R--OH in which R is a
(C.sub.1-C.sub.4)alkyl, in acidic medium, in order to form an
intermediate imidate which is reacted with an amine of formula
HNR.sub.7R.sub.8 (III) or a diamine of formula
H.sub.2NR.sub.6R.sub.8NH.s- ub.2 (IV) in which R.sub.6, R.sub.7 and
R.sub.8 have the definitions given for (I) in claim 1: b2) the
compound thus obtained, of formula: 157is coupled either with a
compound of formula: 158in which R.sub.2, R.sub.3 and R.sub.9 are
as defined for (I) in claim 1 and Pr is a protecting group, then,
after deprotection of the amine in acidIc mediuir, a suiphonyl
halide of formula R.sub.1SO.sub.2Hal in which R.sub.1 is as defined
for (I) in claim 1 and Hal is a halogen, for example chlorne, is
reacted; or with a compound of formula: 159in which R.sub.1,
R.sub.2, R.sub.3 and R.sub.9 are as defined for (7) in claim 1: c2)
the compound of formula (1) thus obtained is isolated in base form
or in salt form; d2) where appropriate, another salt of the
compound of formula (I) is prepared.
10. A compound of formula: 160in which R.sub.1, R.sub.2, R.sub.3,
R.sub.9 and C* are as defined for (7) in claim 1, it being
understood that: when R is phenyl or p-tolyl and R.sub.3 is
hydrogen, then R.sub.2 and R.sub.9, together with the carbon and
nitrogen atoms to which they are attached, are neither pyrrolidinyl
nor 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolyl, and when R.sub.1
is p-tolyl and R.sub.9 is hydrogen, then R.sub.2 is no: an
unsubstituted phenyl.
11. A compound of formula: 161in which R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.9, R.sub.16, R.sub.17 and C* have the
definitions given for (I), in claim 1.
12. Pharmaceutical composition comprising, as active principle, a
compound according to any one of claims 1 to 7.
Description
[0001] The present invention relates to novel
N-(arylsulphonyl)amino acid derivatives, to their preparation and
to pharmaceutical compositions containing them.
[0002] These compounds have affinity for bradyklnin (BK) receptors.
Bradykinin is a nonapeptide belonging, like the decapeptide
kallidin, to the class of kinins and which shows physiological
activity in the cardiovascular field and as a mediator in
inflammation and pain. Several bradykinin receptors are
distinguished: the B.sub.1 and B.sub.2 receptors (D. Regoli et al.,
Pharmacol. Rev., 1980, 32, 1-46). More precisely, the B.sub.2
receptors are the bradykinin and kallidin receptors: they are
predominant and are normally found in most tissues; the B.sub.1
receptors are the receptors specific for [des-Arg.sup.9] bradykinin
and for [des-Arg.sup.10] kallidin: they are induced during
inflammatory processes.
[0003] Bradykinin receptors have been cloned for different species,
in particular for the human species: B.sub.1 receptor : J. G. Menke
et al., J. Biol. Chem., 1994, 269 (34) 21583-21586; B.sub.2
receptor : J. F. Hess, Biochem. Biophys. Res. Commun., 1992,.184,
260-268.
[0004] The reviews: Drug News and Perspectives, 1994, 7 (10),
603-611 and Exp. Opin. Ther. Patents, 1995, 5 (4), 331-340, give an
account on bradykinin-receptor antagonists. Many antagonists
described have peptide structures. As bradykinin-receptor
antagonists, mention may be made in particular of HOE-140 (F. J.
Hock, Brit. J. Pharmacol. 1991, 102, 769-773) for the B2 receptor
and [des-Arg.sup.9, Leu.sup.8] bradykinin for the B.sub.1 receptor
(M. N. Perkins et al., Pain, 1993, 53, 191-197). Recently, a
B.sub.2 receptor antagonist of non-peptide structure, SR 173657,
has been described in Archiv. Pharmacol., 1996, Suppl. 1, 354 (4),
R6.
[0005] According to the present invention, a novel family of
compounds having affinity for the bradykinin receptors has now been
found; these compounds are N-(arylsulphonyl)amino acid
derivatives.
[0006] Among the N-(arylsulphonyl)amino acid derivatives, some are
known and have various pharmacological activities. Thus, compounds
with anti-thrombotic activity are described in the European, German
and international patents or patent applications EP 558,961, EP
236,163, BP 236,164, DD 155,954, DE 4,115,468 and WO 92/16549. In
this field of activity, NAPAP, derived from
N-(naphthalenesulphonyl)-glycine of formula: 2
[0007] is described in Pharmazie, 1987, 42 (5), 346. 3
[0008] Furthermore, N-tosyl-p-alanine derivatives of formula: in
which a and b, together with the nitrogen atom to which they are
attached, constitute a ring such as piperidine, pyrrolidine or
morpholine, are described in Pharmazie, 1984, 39 (5), 315-317.
[0009] Similarly, N-(arylsulphonyl)proline derivatives have been
cited as thrombin inhibitors in Pharmazie, 1986, 41 (4), 233-235
and Pharmazie, 1987, 42 (2), 114-116.
[0010] Moreover, patent application EP 614,911 describes compounds
of formula: 4
[0011] in which, in particular:
[0012] Ar.sub.I is a naphthyl, a phenyl, a quinolyl or an
isocuinolyl, which are optionally substituted;
[0013] Ar.sub.II, is a phenyl or a thienyl, which are optionally
substituted;
[0014] R.sub.I, R.sub.II and R'.sub.II are, independently of each
other, H or (C.sub.1-C.sub.4) alkyl;
[0015] or R.sub.I is nothing and N is linked to Ar.sub.II and
optionally R.sub.I, and R'.sub.II form a double bond;
[0016] or R.sub.I or R.sub.I, is linked to Ar.sub.II and is a
(C.sub.1-C.sub.3) alkylene;
[0017] R.sub.III and R.sub.IV, which may be identical or different,
are H, (C.sub.1-C.sub.4)alkyl or form, together with the nitrogen
atom to which they are attached, a (C.sub.5-C.sub.7)
heterocycle;
[0018] Z.sub.1 is a (C.sub.1-C.sub.12)alkylene;
[0019] Q.sub.1 is methyl, amino,
(C.sub.1-C.sub.4)alkoxycarbonylamino, (C.sub.1-C.sub.4) alkylamino,
di (C.sub.1-C.sub.4)alkylamino, pyrrolidinyl, piperidino,
morpholino, piperazinyl, (C.sub.1-C.sub.4)alkyl-4-piperazinyl,
amidino, (C.sub.1-C.sub.4)alkylamid- ino, guanidino,
(C.sub.1-C.sub.4) alkylguanidino, pyridyl, imidazolyl, pyrimidinyl,
indolyl, hydroxyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.2-C.sub.8)alkoxycarbonyl, amino(C.sub.1-C.sub.4)
alkyl-N-(C.sub.1-C.sub.4) alkyl-amino, carbamoyl or phenyl, which
is optionally substituted,
[0020] Q.sub.2 is H or (C.sub.1-C.sub.4)alkyl;
[0021] Q.sub.3 is H or (C.sub.1-C.sub.4)alkyl or Q.sub.1 and
Q.sub.3 are linked to form a heterocycle and together are
(C.sub.2-C.sub.3)alkylene when Z.sub.1 is nothing, in the form of
pure enantiomers or mixtures thereof in any proportion; as well as
the salts thereof with acids.
[0022] These compounds have affinity for the biological receptors
of the neuropeptide Y.
[0023] According to the present invention, noveL compounds have now
been found which have, unexpectedly, affinity for the bradykinin
receptors.
[0024] The subject of the present invention is the compounds of
formula: 5
[0025] in which:
[0026] R.sub.1 is a phenyl, a naphthyl, a tetrahydronaphthyl, a
quinolyl or an isoquinolyl, the said rings being unsubstituted or
substituted one or more times with R.sub.10;
[0027] R.sub.2 is a phenyl which is unsubstituted or substituted
one or more times with R.sub.11, a phenyl(C.sub.1-C.sub.4)alkyl
which is unsubstituted or substituted one or more times on the
phenyl with R.sub.11, a naphthyl which is unsubstituted or
substituted one or more times with R.sub.11, a cyclohexyl which is
unsubstituted or substituted one or more times with R.sub.II; or
R.sub.2 and R.sub.9 are linked together and constitute a
(C.sub.3-C.sub.5)alkylene which is unsubstituted or substituted
with R.sub.12 or a (C.sub.2-C.sub.4)alkylene which is interrupted
with an oxygen atom or a sulphur atom and is unsubstituted or
substituted with R.sub.12;
[0028] or R.sub.2 and R.sub.9, together with the carbon atom and
the nitrogen atom to which they are attached, constitute
tetrahydroisoquinoline which is unsubstituted or substituted one or
more times with a halogen, a hydroxyl, a (C.sub.1-C.sub.4)alkyl, a
(C.sub.1-C.sub.4) alkoxy or a benzyloxy;
[0029] R.sub.3 is hydrogen or a hydroxyl;
[0030] R.sub.4 and R.sub.5 are each independently hydrogen or a
(C.sub.1-C.sub.4)alkyl;
[0031] or R.sub.4 and R.sub.5, together with the nitrogen atom to
which they are attached, constitute a heterocyclic radical chosen
from 1-pyrrolidinyl, 1-piperidyl, perhydro-1-azepinyl,
4-morpholinyl, 4-oxo-1-piperldyl, dihydro-1-pyrrolyl or
dihydro-2-imidazolyl, the said heterocyclic radicals being
unsubstituted or substituted one or more tmes with R.sub.13;
[0032] R.sub.6 is hydrogen and R.sub.6 can also be R.sub.8 when
R.sub.7 is hydrogen;
[0033] R.sub.7 is hydrogen or a (C.sub.1-C.sub.4)alkyl;
[0034] R.sub.8 is hydrogen; a benzyl which is unsubstituted or
substituted on the phenyl one or more times with R.sub.13; or a
group ZR.sub.14;
[0035] or R.sub.7 and R.sub.8, together with the nitrogen atom to
which they are attached, constitute a heterocyclic radical chosen
from 1-pyrrolidinyl, 1-piperidyl, 1-perhydro-1-azepinyl,
4-morpholinyl, tetrahydro-2-pyrimidinyl, 1-piperazinyl or
1-piperazinyl substituted in position 4 with a
(C.sub.1-C.sub.4)alkyl or a benzyl;
[0036] or, when R.sub.7 is hydrogen, R.sub.6 and R.sub.8 are linked
together to form a (C.sub.2-C.sub.4)alkylene which is unsubstituted
or substituted one or more times with a (C.sub.1-C.sub.4)
alkyl;
[0037] R.sub.9 is hydrogen, a (C.sub.1-C.sub.4)alkyl or a
phenyl(C.sub.1-C.sub.4)alkyl which is unsubstituted or substituted
on the phenyl one or more times with R.sub.11;
[0038] R.sub.10 is a halogen, a (C.sub.1-C.sub.4)alkyl, a
(C.sub.1-C.sub.4)alkoxy, a hydroxyl, an amino, a
(C.sub.1-C.sub.4)alkylam- ino or a di(C.sub.1-C.sub.4)
alkylamino;
[0039] R.sub.11 is a halogen, a (C.sub.1-C.sub.4)alkyl, a
trifluoromethyl, a phenyl, a hydroxyl, a (C.sub.1-C.sub.4)alkoxy or
a benzyloxy; or R.sub.11 is in the ortho position to the phenyl
representing R.sub.2 and forms with R.sub.3 a methylene group or an
ethylene group;
[0040] or R.sub.11 is in the ortho position to the phenyl
representing R.sub.2 and forms with R.sub.9 a methylene group or an
ethylene group;
[0041] R.sub.12 is a halogen, a (C.sub.1-C.sub.4)alkyl, a hydroxyl,
a (C.sub.1.sub.1-C.sub.4) alkoxy, a benzyloxy, an oxo, a phenyl, an
acetyloxy or a trifluoroacetyloxy;
[0042] R.sub.13 is a (C.sub.1-C.sub.4)alkyl, a halogen or a
hydroxyl;
[0043] R.sub.14 is a methyl, an amino, a
(C.sub.1-C.sub.4)alkylamino, a di (C.sub.1-C.sub.4) alkylamino, a
tri (C.sub.1-C.sub.4) alkylamrronium, an amidino, a
(C.sub.1-C.sub.4)alkylamidino, a guanidino, a
(C.sub.1-C.sub.4)alkylguanidino, a hydroxyl, a
(C.sub.1-C.sub.4)alkoxy, a (C.sub.1-C.sub.4)alkoxycarbonyl, a group
--AlkN(R.sub.15)Alk'N(R.sub.15).- sub.2, or a heterocyclic radical
chosen from 1-pyrrol-idinyl, 1-piperidyl, perhydro-1-azepinyl,
pyridyl, imidazolyl, dihydroimidazolyl, imidazolidinyl, pyrimidinyl
and indolyl;
[0044] R.sub.15 and R'.sub.15 are, independently of each other,
hydrogen or a (C.sub.1-C.sub.4)alkyl;
[0045] R.sub.16 is hydrogen or a methyl, or R.sub.16 forms with
R.sub.9 a methylene group;
[0046] R.sub.17 is hydrogen or a methyl;
[0047] Alk and Alk' are, independently of each other, a
(C.sub.1-C.sub.4) alkylene;
[0048] Z is a (C.sub.2-C.sub.1..sub.2)alkylene or a
(C.sub.1-C.sub.6)alkylene which is interrupted or substituted with
a (C.sub.1-C.sub.7)cycloalkyl or with a phenyl;
[0049] C* is an asymmetric carbon atom; as well as the salts
thereof with inorganic or organic acids.
[0050] The salts are generally prepared with pharmaceutically
acceptable acids, but the salts of other acids which are useful for
the purification or isolation of the compounds of formula (I) also
form part of the invention. The pharmaceutically acceptable salts
of the compounds of formula (I) are, for example, the
hydrochloride, the hydrobromide, the sulphate, he
methanesulphonate, the benzenesulphonate, the
naphthalenesulphonate, the maleate, the fumarate, the citrate, the
acetate, the gluconate, the dobesilate or the sultosilate.
[0051] The compounds of formula (I) comprise 2 (or possibly more)
asymmetric carbon atoms and the 4 (or possibly more) pure
enantiomers, as well as the mixture thereof in any proportion, are
subjects of the invention.
[0052] The term halogen is understood to refer to chlorine,
fluorine, bromine or iodine, chlorine and fluorine being
preferred.
[0053] The terms, alkyl, alkylene and alkoxy are understood to
refer, respectively, to a linear or branched alkyl radical,
alkylene radical or alkoxy radical.
[0054] Those compounds of formula (I) are preferred in which:
[0055] R.sub.1 is a phenyl, a naphthyl, a tetrahydronaphthyl, a
quinolyl or an isoquinolyl, the said rings being unsubstituted or
substituted one or more times with R.sub.10;
[0056] R.sub.2 is a phenyl which is unsubstituted or substituted
one or more times with R.sub.11, a phenyl(C.sub.1-C.sub.4)alkyl
which is unsubstituted or substituted one or more times on the
phenyl with R.sub.11, or a naphthyl which is unsubstituted or
substituted one or more times with
[0057] or R.sub.2 and R.sub.8 are linked together and constitute a
(C.sub.3-Cs)alkylene which is unsubstituted or substituted with
R.sub.12 or a (C.sub.2-C.sub.4)alkylene which is interrupted with
an oxygen atom or a sulphur atom and is unsubstituted or
substituted with R.sub.12;
[0058] or R.sub.2 and R.sub.9 together with the carbon atom and the
nitrogen atom to which they are attached, constitute
tetrahydroisoquinoline which is unsubstituted or substituted one or
more times with a halogen, a hydroxyl, a (C.sub.1-C.sub.4)alkyl, a
(C.sub.1-C.sub.4)alkoxy or a benzyloxy;
[0059] R.sub.3 is hydrogen or a hydroxyl;
[0060] R.sub.4 and R.sub.5 are each independently hydrogen or a
(C.sub.1-C.sub.4) alkyl;
[0061] or R.sub.4 and R.sub.5, together with the nitrogen atom to
which they are attached, constitute a heterocyclic radical chosen
from 1-pyrrolidinyl, 1-piperidyl, perhydro-1-azepinyl,
4-morpholinyl or 4-oxo-1-piperidyl, the said heterocyclic radicals
being unsubstituted or substituted with R.sub.13;
[0062] R.sub.6 is hydrogen, R.sub.6 can also be Rs when R.sub.7 is
hydrogen;
[0063] R.sub.7 is hydrogen or a (C.sub.1-C.sub.4)alkyl;
[0064] R.sub.9 is hydrogen; a benzyl which is unsubstituted or
substituted on the phenyl one or more times with R.sub.13; or a
group ZR.sub.14;
[0065] or R.sub.7 and R.sub.8, together with the nitrogen atom to
which they are attached, constitute a heterocyclic radical chosen
from 1-pyrrolidinyl, 1-piperidyl, perhydro-1-azepinyl,
4-morpholinyl, 1-piperazinyl or 1-piperazinyl substituted in
position 4 with a (C.sub.1-C.sub.4)alkyl or a benzyl;
[0066] or, when R.sub.7 is hydrogen, R.sub.6 and R.sub.8 are linked
together to form a (C.sub.2-C.sub.4)alkylene which is unsubstituted
or substituted one or more times with a (C.sub.1-C.sub.4)
alkyl;
[0067] R.sub.9 is hydrogen, a (C.sub.1-C.sub.4)alkyl or a
phenyl(C.sub.1-C.sub.4)alkyl which is unsubstituted or substituted
on the phenyl one or more times with R.sub.11;
[0068] R.sub.10 is a halogen, a (C.sub.1-C.sub.4)alkyl, a
(C.sub.1-C.sub.4)alkoxy, a hydroxyl, an amino, a
(C.sub.1-C.sub.4)alkylam- ino or a di (C.sub.1-C.sub.4)
alkylamino;
[0069] R.sub.11 is a halogen, a (C.sub.1-C.sub.4)alkyl, a hydroxyl,
a (C.sub.1-C.sub.4)alkoxy or a benzyloxy;
[0070] R.sub.12 is a halogen, a (C.sub.1-C.sub.4) alkyl, a
hydroxyl, a (C.sub.1-C.sub.4) alkoxy, a benzyloxy, an oxo or a
phenyl;
[0071] R.sub.13 is a (C.sub.1-C.sub.4)alkyl, a halogen or a
hydroxyl;
[0072] R.sub.14 is a methyl, an amino, a
(C.sub.1-C.sub.4)alkylamino, a di(C.sub.1-C.sub.4)alkylamino, a
tri(C.sub.1-C.sub.4)alkylammonium, an amidino, a
(C.sub.1-C.sub.4)alkylamidino, a guanidino, a
(C.sub.1-C.sub.4)alkylguanidino, a hydroxyl, a
(C.sub.1-C.sub.4)alkoxy, a (C.sub.1-C.sub.4)alkoxycarbonyl, a group
--AlkN(R.sub.15)Alk'N(R.sub.15).- sub.2, or a heterocyclic radical
chosen from 1-pyrrolidinyl, 1-piperidyl, perhydro-1-azepinyl,
pyridyl, imidazolyl, dLhydroimidazolyl, imidazolidinyl, pyrimidinyl
and indolyl;
[0073] R.sub.15 and R.sub.15 are, independently of each other,
hydrogen or a (C.sub.1-C.sub.4)alkyl;
[0074] R.sub.16 is hydrogen;
[0075] R.sub.17 is hydrogen;
[0076] Alk and Alk' are, independently of each other, a
(C.sub.1-C.sub.4) alkylene;
[0077] Z is a (C.sub.2-C.sub.12)alkylene or a
(C.sub.1-C.sub.6)alkylene which is interrupted or substituted with
a (C.sub.5-C.sub.7)cycloalkyl or with a phenyl;
[0078] as well as the salts thereof with inorganic or organic
acids.
[0079] Certain values for the substituents are preferred. Thus, the
preferred compounds of formula (I) are those which satisfy at least
one of the following conditions:
[0080] a --R.sub.1 is a naphthyl, a quinolyl or a trichlorophenyl;
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8,
R.sub.9, R.sub.16 and R.sub.17 being as defined above for formula
I;
[0081] b --R.sub.2 is a phenyl which is unsubstituted or
substituted with R.sub.11; R.sub.1, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.16 and R.sub.17 being as
defined above for formula I;
[0082] --NR.sub.4R.sub.5 is a 1-pyrrolidinyl group; R.sub.1,
R.sub.2, R.sub.3, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.16 and
R.sub.17 being as defined above for formula I;
[0083] d --C(NRE)NR.sub.7R.sub.8 is a 4,5-dihydro-2-imidazolyl;
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.9, R.sub.16 and
R.sub.17 being as defined above for formula I;
[0084] e --R.sub.3=R.sub.9=R.sub.16=R.sub.17=H; R.sub.1, R.sub.2,
R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 being as defined
above for formula I; and the salts thereof with inorganic or
organic acids.
[0085] According to the invention, the preferred compounds are
those of formula: 6
[0086] in which:
[0087] R.sub.2a, is a phenyl whIch is unsubstituted or substituted
in a meta or para position with R.sub.11; a 1-naphthyl or a
2-naphthyl;
[0088] R.sub.1, R.sub.6, R.sub.7, R.sub.8 and R.sub.11 are as
defined above for (I); and the salts thereof with inorganic or
organic acids.
[0089] Most particularly, the preferred compounds are those of
formula: 7
[0090] in which:
[0091] R.sub.1a is a 1-naphthyl, a 2-naphthyl, a
2,4,6-trichloro-phenyl or a 2-quinolyl;
[0092] R.sub.2a is as defined above for (Ia); and the salts.
thereof with inorganic or organic acids.
[0093] More particularly, the preferred compounds are those of
formula (I'a) in which R.sub.2a is a phenyl which is unsubstituted
or substituted in a meta or para position with R.sub.11.
[0094] Most particularly, the preferred compounds are those of
formula (I), (Ia) or (I'a) having (R,R) isomerism on the
C*-labelled carbon atoms.
[0095] The following abbreviations are used in the description and
in the claims:
[0096] Me:methyl
[0097] Et:ethyl
[0098] iPr:isopropyl
[0099] nBuOH:n-butanol
[0100] iPrOH:isopropanol
[0101] EtOH:ethanol
[0102] MeCH:methanol
[0103] Et.sub.2O:ether:diethyl ether
[0104] DMF:dimethylformamide
[0105] DCM:dichloromethane
[0106] THF:tetrahydrofuran
[0107] AcOH: acetic acid
[0108] EtOAc:ethyl acetate
[0109] DIPEA:diisopropylethylamine
[0110] DMAP:4-dimethylaminopyridine
[0111] DCC:1,3-dicyclohexylcarbodiimide
[0112] DCU:dicyclohexylurea
[0113] NSuOH:N-hydroxysuccinimide
[0114] NSu:succinimido
[0115] NBS: N-bromosuccinimide
[0116] Fmoc:fluorenylmethoxycarbonyl
[0117] Boc:tert-butoxycarbonyl
[0118] (Boc).sub.2O: di-tert-butyl dicarbonate
[0119] Et.sub.3N:triethylamine
[0120] Bn:benzyl
[0121] Pd/C:palladium-on-charcoal
[0122] Sephadex.RTM. LH 20:sold by Pharmacia
[0123] Sephadex.RTM. 25:sold by Pharmacia
[0124] Alcalase.RTM.:Carlsberg subtilisin sold by Novo
(Denmark)
[0125] Penicillin amidase:penicillin amidohydrolase, sold by
Sigma
[0126] BOP:benzotriazol-1-yloxytris(dimethylamino)-phosphonium
hexafluorophosphate
[0127] K.sub.2CO.sub.3:potassium carbonate
[0128] K2SO.sub.4: potassium sulphate
[0129] KHSO.sub.4:potassium hydrogen sulphate
[0130] KHSO.sub.4/K.sub.2SO.sub.4 solution of 16.66 g of KHSO.sub.4
and
[0131] 32.32 g of K.sub.2SO.sub.4 in 11 of water
[0132] NaCl:sodium chloride
[0133] Na.sub.2SO.sub.4 sodium sulphate
[0134] MgSO4:magnesium sulphate
[0135] NaCH:sodium hydroxide
[0136] TH.sub.4OH:aqueous ammonia
[0137] HCl:hydrochloric acid
[0138] TFA:trifluoroacetic acid
[0139] hydrochloric ether:saturated solution of
[0140] hydrogen chloride gas in diethyl ether
[0141] mPa.s:milliPascal/second
[0142] m.p.:melting point
[0143] RT: room temperature
[0144] NMR:nuclear magnetic resonance
[0145] DMSO dimethyl sulphoxide
[0146] .delta.: chemical shift
[0147] s:singlet; bs:broad singlet; ds:doubled
[0148] singlet; d:doublet; dd:doubled doublet; t
[0149] triplet; bt:broad triplet; q:quartet; quint
[0150] quintet; mt:multiplet; m:unresolved multiplet
[0151] The subject of the present invention is also the process for
the preparation of the compounds of formula (I) and the salts
thereof. This process, referred to as process 1, is characterized
in that:
[0152] a1) a compound of formula: 8
[0153] in which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.9, R.sub.16, R.sub.17 and C* have the definitions given above
for (I), in the form of a pure enantiomer or a mixture of isomers
in any proportion, is treated with an alcohol of formula R--OH in
which R is a (C.sub.1-C.sub.4)alkyl, in acidic medium, in order to
form an intermediate imidate which is reacted with an amine of.
formula HN=7R.sub.8 (III) or a diamine of formula
H.sub.2NR.sub.6R.sub.8NH.sub.2 (IV) in which R.sub.6, R.sub.7 and
R.sub.8 have the definitions given above for (I);
[0154] b1) the compound of formula (7) thus obtained is isolated in
base form or salt form,
[0155] c1) where appropriate, another salt of the compound of
formula (I) is prepared.
[0156] Many processes for the synthesis of amidines are described
in the book "The chemistry of amidines and imidates", D. G.
Neilson, Ed. Saul Patai, Wiley and Sons, 1975, 389-394. The
preparation of certain amidines is described precisely in patent
application EP 614,911 A.
[0157] The formation of the imidate is preferably carried out in a
strong acid medium, whereas the imido ester in free base form or in
salt form is reacted with the amine (III) or the diamine (IV) in an
inert polar solvent, for example an alcohol, at a temperature of
between 0.degree. C. and the reflux temperature of the solvent.
[0158] The intermediate imidate is reacted with an amine whose
formula depends on that of the compound (I) which it is desired to
obtain. In order to prepare a compound of formula (I) in which
R.sub.6=H, an amine HNR.sub.7R.sub.8 is reacted; in order to
prepare a compound of formula (I) in which R.sub.6=R.sub.8 and
R.sub.7=H, two moles of an amine of formula H.sub.2NR.sub.8 are
reacted per mole of imidate; in order to prepare a compound of
formula (I) in which R.sub.7 is hydrogen and R.sub.6 and R.sub.8
are linked together to form a (C.sub.2-C.sub.4)alkyle- ne which is
unsubstituted or substituted one or more times with an alkyl, a
diamine of formula H.sub.2NR.sub.6R.sub.8NH.sub.2 is reacted.
[0159] Most of the amines (III) and of the diamines (IV) are known
and the novel products can be prepared by applying principles and
methods that are well known to those skilled in the art. For
example, for the derivatives in which R.sub.14 is an imidazolyl,
reference will be made to U.S. Pat. No. 3,881,016 and to the
publication Synth. Communic. 1987, 17 (21), 223-227.
[0160] The compounds of formula (I) in which R.sub.14 is NH.sub.2
or alkylamino can be prepared by hydrolysis of the compounds of
formula (I) in which R.sub.14 contains a t-butoxycarbonylamino
group, which is in turn obtained according to Synth. Commun. 1990,
20 (16), 2559-2564.
[0161] The compounds of formula (I) in which R.sub.14 is a
substituted or unsubstituted guanidino group can be prepared by the
action on the compound of formula (I), n which R.sub.14=NH.sub.2 of
a compound of formula: 9
[0162] in which T is H or (C.sub.1-C.sub.4)alkyl and Y is a
nucleofugal group, such as SO.sub.3H, for example,
aminoiminomethane-sulphonic acid (under the conditions described in
Tetrahedron Letters, 1988, 3183-3186) or
N-methyl-aminoiminomethanesulphonic acid (obtained according to the
process described in J. Org. Chem., 1986, 51(10), 1882).
[0163] The action of an amine (III) of formula H.sub.2NR.sub.8 in
excess on the imidate resulting from the reaction of ROH with a
compound of formula (II) leads to the formation of a mixture of two
compounds of formula (I): for one R.sub.6=R.sub.7=H and for the
other R.sub.6=R.sub.8 and R.sub.7=H.
[0164] The compounds of formula (I) in which R.sub.6 and R.sub.8
together form a (C.sub.2-C.sub.4)alkylene which is unsubstituted or
substituted one or more times with a (C.sub.1-C.sub.4)alkyl can be
prepared in a manner which is known per se, by the action of a
diamine H.sub.2N--R.sub.6R.sub.8--NH.sub.2 on the imido ester or
optionally by the action of the same diamine, one of the functions
of which is protected by a labile group (such as Boc or Fmoc for
example) which will be removed before cyclization.
[0165] The compounds of formula (I) in which R.sub.14 is a
dihydroimidazole can be prepared by the action of an alcohol in
acidic medium on a compound of formula: 10
[0166] in order to form an intermediate imidate, which is reacted
with an appropriate amine according to the usual methods.
[0167] The nitriles of formula (II) are pnrepared using the
standard methods of peptide chemistry, for example those described
in The Peptides Ed. E. Gross and J. Meienhofer, Academic Press,
1979, 1, 65-104. Known methods make it possible to carry out
peptide couplings without racemization of the carbon atoms of each
constituent amino acid; furthermore, the .beta.-substituted
.beta.-alanines for which the chiral carbon is not adjacent to the
carboxyl group are reputed as not suffering racemization (Ann. Rev.
Biochem., 1986, 55, 855-878). moreover, patent application EP
236,l63 describes processes which allow the chiralitv of each amino
acid to be conserved.
[0168] In general, the coupling reactions between the 2 amino acids
take place at temperatures of between 0.degree. C. and 400.degree.
C. in an inert solvent such as dichloromethane, acetonitrile,
tetrahydrofuran or dimethylformamide, in the presence of a coupling
agent and of at least one equivalent of a tertiary amine such as
triethylamine, N-ethylmorpholine or diisopropylethylamine.
[0169] Thus, the preparation of a nitrile of formula (II) can be
carried out according to one of the synthetic routes below. 11
12
[0170] In order to prepare a compound of formula (V), which is
useful in route 1, the radical R.sub.1SO.sub.2 is introduced in a
conventional manner by the action of a sulphonyl halide of formula:
R.sub.1SO.sub.2Hal in which R.sub.1 is as defined above for (I) and
Hal is a halogen, preferably chlorine, on a compound of formula:
13
[0171] in which R.sub.2, R.sub.3 and R.sub.9 have the meanings
given above for (I) and R' is hydrogen or a
(C.sub.1-C.sub.4)alkyl.
[0172] A compound of formula (V) in which R.sub.3 is hydrogen can
also be prepared in 2 steps: firstly, a compound of formula: 14
[0173] in which Y is R.sub.1SO.sub.2 or a protecting group such as
Boc or Fmoc, aftLer which the carbon chain is extended by one atom
using known methods, then, if necessary, the protecting group is
removed and a sulphonyl halide of formula R.sub.1SO.sub.2Hal is
reacted and, lastly, the group R' is removed, if it is other than
H.
[0174] This procedure is suitable, for example, when R.sub.2 and
R.sub.9 are linked together and constitute a
(C.sub.3-C.sub.5)-alkylene which is unsubstituted or substituted
with R.sub.12 or a (C.sub.2-C.sub.4)-alkylen- e which is
interrupted by an oxygen atom or a sulphur atom which is
unsubstituted or substituted one or more times with R.sub.12.
[0175] The sulphonyl halides are known or are prepared by known
methods.
[0176] The compounds of formula (VI) are prepared by the action of
an amine HNR.sub.4R.sub.5 on an amino acid of formula: 15
[0177] in which the amine is protected, for example by a Boc or
Fmoc group, followed by the removal of the protecting group.
[0178] In the reaction sequence of route 2, the amine is
deprotected in acidic medium (TFA) and the radical R.sub.1SO.sub.2
is introduced in a conventional manner by the action of a sulphonyl
halide of formula: R.sub.1SO.sub.2Haal in which R.sub.1 is as
defined above for (I) and Hal is a halogen, preferably
chlorine.
[0179] In route 1, as in route 2, the group R.sub.1SO.sub.2 is
introduced in the presence of a base, optionally in a two-phase
medium, in the presence of a phase-transfer catalyst.
[0180] A subszituent R.sub.9 can be introduced into a compound of
formula (II) in which R.sub.9=H by known methods, for example by
the action of a halide of formula R.sub.9Hal, in which Hal is a
halogen atom, for example chlorine.
[0181] The compounds of formula (II) in which R.sub.9 and R.sub.16
together form a methylene group are prepared by the action of
para-formaldehyde on compounds of formula (II) in which
R.sub.9=R.sub.16=H.
[0182] The compounds of formula (II) are novel and constitute a
further aspect of the present invention.
[0183] Certain compounds of formula (V), which are
toluenesulphonamide or phenylsulphonamide derivatives, have been
described in the following publications:
[0184] Tetrahedron, 1993, 49 (48), 11329-11340;
[0185] Centralblatt, 1929, II, 1398;
[0186] J. Org. Chem., 1978, 43(23), 4438-4441;
[0187] J. Org. Chem., 1966, 31(7), 2385-2386.
[0188] Thus, the compounds of formula: 16
[0189] in which R.sub.1, R.sub.2, R.sub.3, R.sub.9 and C* are as
defined for (I); it being understood that:
[0190] when R.sub.1 is phenyl or p-tolyl and R.sub.3 is hydrogen,
then R.sub.2 and R.sub.9, together with the carbon and nitrogen
atoms to which they are attached, are not pyrrolidinyl or
6,7-dimethoxy-1,2,3,4-tetrahyd- roisoquinolyl, and
[0191] when R.sub.1 is p-tolyl and R.sub.9 is hydrogen, then
R.sub.2 is not an unsubstituted phenyl; are novel and form part of
the invention.
[0192] In order to prepare a compound of formula (I) in which
R.sub.9 and R.sub.1, together form a methylene or ethylene group, a
beta-amino acid of formula (XIII) 17
[0193] in which R.sub.9 and R.sub.11 form a methylene or ethylene
group, is prepared using knownl methods, for example the one
described in J. Org. Chem., 1937, 52, 616-622.
[0194] In order to prepare a beta-amino acid of Formula (XIII) in
which R.sub.3 and R.sub.11 Together form a methylene or ethylene
group, known methods are used. Thus, methyl
1-aminoindane-2-carboxylate is prepared in 3 steps from 1-indanone:
according to J. Med. Chem., 1970, 650, the action of methyl
carbonate in the presence of sodium hydride makes it possible to
obtain methyl (1-oxo)indane-2-carboxylate, then, according to J.
Heterocycl. Chem., 1974, 11, 982, methyl
1-hydroxyiminoindan-2-carboxy- late is prepared and, lastly, the
hydroxylamine is reduced to amine in the presence of a
catalyst.
[0195] 1-Amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid can
be prepared according to the method described in J. Chromatogr., A
1994, 676, 297-302. Alternatively, according to another process,
when the amidine group C(=NR.sub.6)NR.sub.7R.sub.8 contains no
function liable to react in a subsequent step under the peptide
coupling conditions, an amino acid derivative containing the
amidine group can be prepared from the corresponding derivative
containing a cyano group, and the couplings required to obtain a
compound according to the invention can then be carried out.
[0196] Thus, according to a further aspect, the subject of the
present invention is another process foe the preparation of a
compound of formula (I), which is referred to as process 2,
characterized in that:
[0197] a2) a compound of formula: 18
[0198] in which X is hydrogen or a Boc group and R.sub.4, R.sub.5
and C* are as defined for (I), in the form of a pure enantiomer or
a mixture of isomers in any proportion, is treated with an alcohol
of formula R--OH in which R is a (C.sub.1-C.sub.4)alkyl, in acidic
medium, in order to form an intermediate imidate which is reacted
with an amine of formula HNR.sub.7R.sub.8 (III) or a diamine of
formula H.sub.2NR.sub.6R.sub.8NH.s- ub.2 (IV) in which R.sub.6,
R.sub.7 and Re have the definitions given above for (I):
[0199] b2) the compound thus obtained, of formula: 19
[0200] is coupled
[0201] either with a compound of formula: 20
[0202] in which R.sub.2, R.sub.3 and R.sub.9 are as defined for (I)
and Pr is a protecting group, for example Boc or Fmoc, then, after
deprotection of the amine in acidic medium, a sulphonyl halide of
formula R.sub.1SO.sub.2Hal in which R.sub.1 is as defined for (I)
and Hal is a halogen, for example chlorine, is reacted;
[0203] or with a compound of formula: 21
[0204] in which R.sub.1, R.sub.2, R.sub.3 and R.sub.9 are as
defined for (I):
[0205] c2) the compound of formula (I) thus obtained is isolated in
base form or in salt form;
[0206] d2) where appropriate, another salt of the compound of
formula (I) is prepared.
[0207] The compounds of formulae (VI) and (XI) in optically pure
form can be obtained from an ester, for example the racemic ethyl
ester of 4-cyanophenyl-alanine, according to the reaction scheme
described below: 22
[0208] The racemic ethyl ester of 4-cyanophenylalanine is described
in patent application EP 614,911A. The aamine function of this
compound is protected in a conventional manner, by the action of
(Boc).sub.2O in the presence of triethylamine. The action of an
enzyme, Alcalase.RTM., on the compound 4 thus obtained makes it
possible to selectively hydrolyse the ester function of the amino
acid of (L) configuration and thus to isolate each of the compounds
5 and 6 in optically pure form (Synthesis, 1983, 1041-1043).
[0209] The compound of (L) configuration is isolated in acid
form:(L) 6. The compound of (D) configuration is isolated in the
form of an ethyl ester:(D) 5; this compound is hydrolysed with
sodium hydroxide in order to obtain the acid form (D) 6. Each of
these 2 compounds of formula 6 is then treated with
N-hydroxy-succinimide in an inert solvent such as DMF or dioxane,
in the presence of a coupling agent such as DCC in order to obtain
a compound of formula 7. The action of an amine HNR.sub.4R.sub.5,
followed by the action of trifluoro-acetic acid, makes it possible
to prepare the compounds of formulae (L) (VI) and (D) (VI); the
conventional reactions described above are then carried out in
order to obtain the desired amidines of formulae (L) (XI) and (D)
(XI).
[0210] The beta-amino acids of formula XIII: 23
[0211] or the corresponding aliphatic esters are known or can be
prepared by various methods, for example according to J. Am. Chem.,
1936, 58, 299. One specific way of preparing the beca-amino acids
consists in carrying out a chain extension starting with an
alpha-amino acid, according to Tetrahedron, 1994, 50, 9457-9470 or
according to J. Chem. Soc., Perin Transact. II, 1977, 370.
[0212] More specifically, the preparation of certain beta-amino
acids of formula (XIV) H.sub.2N--CH(R.sub.2)--CH.sub.2--COOH is
described in the following publications or patents.
1 R.sub.2 Reference 24 (R, S):commercial (R):Ber. 1910, 43, 2020
(S) J.Org. Chem., 1991, 56, 5883 J.Chem. Soc. Chem. Commun., 1993,
1153 25 Heterocycles, 1989, 28, 1015 Bull. Soc. Chim. Fr., 1987,
1079 26 Heterocycles, 1978, 1277-1285 27 Tetrahedron, 1987, 43,
3509-3517 28 EP-355819 29 Tetrahedron Lett., 1988, 29, 6465 30
Heterocycles, 1989, 28, 1015 31 J. Agric. Food Chem. 1977, 25, 965
32 Terehedron, 1994, 50 (31), 9457-9470 Tetrahedron Lett., 1990,
31, 5153-5156
[0213] The compounds (I) in which R.sub.2 and R.sub.9 are linked
together and constitute a C.sub.3-C.sub.5 alkylene which is
unsubstituted or substituted with R.sub.12 are prepared from
compounds of formula (XIII) which are known or are prepared by
known methods.
[0214] In order to obtain optically pure compounds of formula
(XIII) or (XIV), it is possible, for example, to use a menthol
ester according to the technique described in Tetrahedron Lett.,
1988, 29, 6465-6466; a quinine or quinidine salt can also be used,
according to Chem. Ber., 1910, 43, 2020, or alternatively the
phenylacetamido derivative of the compound of formula (XIV) in
racemic form can be used for an enzymatic resolution with a
penicillin amylase (Syrlett, 1993, 339). Enantioselective syntheses
can also be carried out: Tetrahedron, 1994, 50, 9517; Aldrichimica,
Acta, 1994, 27(1), 3.
[0215] In order to prepare an alpha-hydroxy-beta-amino acid, the
method described in Bull. Soc. Chim., France, 1940, 7, 593-603 can
be used.
[0216] The affinity of the compounds-according to the invention for
the bradykinin B, receptors was measured on suspensions of
MRC.sub.5 cell membranes using a technique similar to that
described by K. H. Schneck et al., in Eur. J. Pharmacol., 1994,
266, 227-282. In this test, the affinity of [des-Arg.sup.9]
bradykinin is between 10.sup.-6M and 10-.sup.7M, that of
[des-Arg.sup.1]kallidin is 2.times.10.sup.-9M; and the compounds of
the invention have an affinity ranging down to 10.sup.-10 M.
[0217] The affinity of the compounds according to the invention for
the bradykinin B.sub.2 receptors was measured on suspensions of
MRC.sub.5 cell membranes according to a technique similar to that
described by D. G. Sawutz et al., in Eur. J. Pharmacol., 1992, 227,
309-315. In that test, the affinity of bradykinin is close to
10.sup.-9M and that of the compounds of the invention varies around
10.sup.-6M or 10.sup.-7M.
[0218] The toxicity of the compounds according to the invention is
compatible with their therapeutic use.
[0219] The compounds according to the invention may be useful for
the treatment or prevention of many pathologies, in particular
inflammation pathologies and persistent or chronic inflammatory
diseases (Drug News and Perspectives, 1994, 10(7), 603-611). By way
of example, mention may be made of:
[0220] neurogenic inflammation, pain (Brit. J. Pharmacol., 1993,
110, 193-198), septic shock, asthma, rheumatoid arthritis,
inflammatory diseases of the joints, burns (Pain, 1993, 53,
191-197), wounds, diseases of the respiratory tracts, for example
rhinitis of viral or allergic origin, systematic inflammatory
response syndrome, oedema (Brit. J. Pharmacol., 1995,- 114,
1005-1013), angiogenesis (Brit. J. Pharmacol., 1993, 109, 14-17),
type-I infectious diabetes (Abst. 14th Intern. Symp. on Kinins,
C49, Denver Colorado, Sep. 10-15, 1995), ventricular hypertrophy
associated with diabetes, pulmonary fibrosis and systemic
progressive sclerosis, enterocolitis, and more generally any
bradykinin-dependent pathology.
[0221] The compounds according to the invention are generally
administered in dosage units.
[0222] The invention also relates to pharmaceutical compositions
comprising, as active principle, one of the enantiomers of the
compounds of formula (I), a mixture thereof or salts thereof with a
pharmaceutically acceptable acid, as well as to arn excipient which
is suitable for oral, injectable, topical or transdermal
administration. The daily doses depend on the pathology to be
treated and on the patient.
[0223] The subject of the present invention is also pharmaceutical
compositions containing an effective dose of a compound according
to the invention or of a pharmaceutically acceptable salt and
suitable excipients.
[0224] The said excipients are chosen depending on the
pharmaceutical form and the desired mode of administration.
[0225] In the pharmaceutical compositions of the present invention
for oral, sublingual, subcutaneous, intramuscular, intravenous,
topical, intratracheal, intranasal, transdermal or rectal
administration, the active principles of formula (I) above, or the
possible salts thereof, can be administered in unit forms of
administration, as a mixture with standard pharmaceutical supports,
to animals and to human beings for the prophylaxis or treatment of
the above disorders or diseases. The appropriate unit forms of
administration comprise oral forms such as tablets, gelati.
capsules, powders, granules or oral solutions or suspensions,
sublingual, buccal, intratracheal or intranasal administration
forms, subcutaneous, intramuscular or intravenous administration
forms and rectal administration forms. For topical application, the
compounds according to the invention can be used in creams,
ointments, gels or lotions.
[0226] In order to obtain the desired prophylactic or therapeutic
effect, the dose of active principle can range between 0.01 and 50
mg per kg of body weight and per day.
[0227] Each unit dose can contain from 0.5 to 1000 mg, preferably
from 1 to 500 mg, of active ingredients in combination with a
pharmaceutical support. This unit dose can be administered 1 to 5
times a day so as to administer a daily dose of from 0.5 to 5000
mg, preferably from 1 to 2500 mg.
[0228] When a solid composition is prepared in the form of tablets,
the main active ingredient is mixed with a pharmaceutical vehicle
such as gelatin, starch, lactose, magnesium stearate, talc, gum
arabic or the like. The tablets can be coated with sucrose, with a
cellulose derivative or with other suitable materials or
alternatively they can be treated such that they have sustained or
delayed activity and such that they release a predetermined amount
of active principle continuously.
[0229] A preparation as gelatin capsules can be obtained by mixing
the active ingredient with a diluent such as a glycol or a glycol
ester and by pouring the mixture obtained into soft or hard gelatin
capsules.
[0230] A preparation in syrup or elixir form or for administration
in the form of drops can contain the active ingredient together
with a sweetener, preferably a calorie-free sweetener,
methylparaben and propyl-paraben as antiseptic, as well as a
flavouring agent and a suitable dye.
[0231] The water-dispersible powders or granules can contain the
active ingredient as a mixture with dispersing agents; wetting
agents or suspension agents, such as polyvinylpyrrolidone, as well
as with sweeteners or flavour enhancers.
[0232] For rectal administration, use is made of suppositories
which are prepared with binders which melt at the rectal
temperature, for example cocoa butteror polyethylene glycols.
[0233] Aqueous suspensions, isotonic saline solutions or sterile
and injectable solutions which contain pharmacologically compatible
dispersing agents and/or wetting agents, for example propylene
glycol or butylene glycol, are used for parenteral
administration.
[0234] Creams, ointments, lotions or gels, for example, can be used
for local administration.
[0235] Patches in multilaminar or reservoir form in which the
active principle may be dissolved can be used for transdermal
administration.
[0236] The active principle can also be formulated in the form of
microcapsules, optionally with one or more supports or
additives.
[0237] The compositions of the present invention can contain, along
with the products of formula (I) above or one of the
pharmaceutically acceptable salts, other active principles which
can be used in the treatment of the disorders or diseases mentioned
above.
[0238] The preparations and the examples below illustrate the
invention. Except where otherwise mentioned, the compounds are
obtained in the form of a mixture of diastereoisomers.
[0239] The nuclear magnetic resonance (NMR) spectra are recorded at
200 MHz in deuterated DMSO optionally containing TFA, using
tetramethylsilane as reference. The chemical shifts are indicated
in ppm.
[0240] The mass spectra indicate the value MH.sup.+.
PREPARATIONS
[0241] Preparation 1.1
[0242] 1-[2-Amino-3-(4-cyanophenyl)propionyl]pyrrolidine
trifluoroacetate.
[0243] 4.06 g of 2-[N-(Boc)amino]-3-(4-cyanophenyl)-propionic acid
are mixed with 1.15 ml of pyrrolidine and 7.5 g of BOP in 20 ml of
DMF; the mixture is left stirring for 2 hours at RT while
maintaining at pH=7 by addition of Et.sub.3N. After evaporating to
dryness, the residue is chromatographed on silica, eluting with a
chloroform/methanol mixture (9/0.5; v/v). After evaporating off the
solvents, the solid obtained Is treated with 20 ml of TFA in 20 ml
of DCM for 30 minutes at RT. The solvents are evaporated off and
the residue is taken up in ether and then dried in order to obtain
3.95 g of the expected product.
Preparation 1.2
[0244]
1-[2-Amino-3-(4-(3,4-dihydroimidazol-2-yl)phenyl))-propionyl]pyrrol-
idine dihydrochloride.
[0245] 18 g of
1-[2-((N-Boc)amino)-3-(4-cyanophenyl)-propionyl]pyrrolidine are
dissolved in 90 ml of DCM, 90 ml of TFA are added and the mixture
is left stirring for 40 minutes at RT. After evaporating to
dryness, the residue is taken up in DCM and then evaporated
(twice). The residue is then taken up in 300 ml of HCl-saturated
anhydrous ethanol at 0.degree. C. and the mixture is left for 18
hours at +4.degree. C. The medium is evaporated to dryness, taken
up in ethanol, evaporated again and then taken up again in DCM and
evaporated (twice). 23 g of intermediate imidate are obtained. The
product obtained is dissolved in 1 liter of anhydrous ethanol and
4.41 g of ethylenediamine in 50 ml of anhydrous ethanol are added
over 30 minutes. After stirring for 48 hours at RT, the medium is
concentrated and then acidified to pH =2 by addition of a saturated
solution of HCl in methanol. The mixture is drained, evaporated to
dryness and then taken up in ether, drained and dried to give 17.4
g of the expected product.
[0246] NNR (DMSO+TFA):50-1.80:m:4H; 2.50-3.60:m:6H; 4.00:s:4H;
4.35:bs:H; 7.50: d:2H; 8.15:d:2H; 8.60:bs:3H; 11.10:s:2H.
Preparation 1.3
[0247]
1-[2-Amino-3-(4(N.sup.1-[3-(dimethylam,ino)propyl]amidino)-phenyl)p-
ropionyl]pyrrolidine tris(trifluoroacetate). A)
1-[2-Amino-3-(44N.sup.1-[3-
-(dimethylamino)propyl]-amidino)phenyl)propionyl]pyrrolidine
trihydrochloride.
[0248] 809 mg of 1-[2-amino-3-(4-cyanophenyl)-propionyllpyrrolidine
trifluoroacetate are dissolved in 50 ml of hydrochloric
acid-saturated methanol at 0.degree. C. and the mixture is left
overnight in a refrigerator.
[0249] After evaporating to dryness, the imidate formed is taken up
in toluene, the mixture is then evaporated and the residue is dried
under vacuum over potassium hydroxide. The product obtained is
dissolved in 75 ml of anhydrous methanol and 570 .mu.l of
N-(dimethyl)-propane-1,3-diamin- e dissolved in 15 ml of anhydrous
methanol are added slowly. After stirring for 3 hours at RT, the
mixture is evaporated to dryness and the residue is then dissolved
in 30 ml of methanol, adding 5 ml of 4N HCl in dioxane, and is
evaporated to dryness.
[0250]
[0251] B)
1-[2-(N-Boc)amino-3-(4-(N.sup.1-[3-(dimethylamino)-propyl]amidin-
o)phenyl)propionyl]pyrrolidine dihydrochloride.
[0252] The crude product obtained in the above step is dissolved in
10 ml of dioxane and 10 ml of water. Triethylamine is added to
reach pH=8.3, followed by 600 mg of (Boc).sub.2O and the mixture is
left stirring at RT for 15 hours. The medium is diluted with water,
washed twice with ether, acidified to pH=1.5 by addition of 1N HCl
and then washed with DCM. This mixture is brought to pH=7 by
addition of IN sodium hydroxide and is evaporated to dryness. The
residue is taken up in DCM, the insoluble material is filtered off
and the filtrate is then purified by chromatography on silica,
eluting with a chloroform/methanol mixture (85/15 to 80/20; v/v).
560 mg of the expected product are obtained.
[0253] C)
1-(2-Amino-3-(4-(N.sup.1-[3-(dimethylamino)propyl]-amidino)pheny-
l)propionyl]pyrrolidine tris(trifluoro-acetate).
[0254] 550 mg of the compound of step B are mixed with 15 ml of DCM
and 15 ml of TFA and the mixture is left stirring for 45 minutes at
RT. After evaporating to dryness, the residue is dissolved in
isopropanol, evaporated to dryness again and taken up twice in
ether. The product is isolated by decanting and then dried under
vacuum in the presence of potassium hydroxide. 380 mg of the
expected compound are obtained.
Preparation 1.4
[0255]
1-[2-Amino-3-(4-cyanophenyl)propionyl]-2,5-dimethyl-2,5-dihydropyrr-
ole trifluoroacetate.
[0256] A)
1-[2-(N-Boc)amino-3-(4-cyanophenyl)propionyl]-2,5-dimethyl-2,5-d-
ihydropyrrole.
[0257] 2.1 g of 2-[(N-Boc)amino]-3-(4-cyanophenyl)-propionic acid
are mixed with 0.715 g of 2,5-dimethyl-2,5-dihydropyrrole in 10 ml
of DMF, 3.9 g of BOP are added and the pH is adjusted to 7 by
addition of Et.sub.3N. After stirring for 18 hours at RT, the
mixture is evaporated to dryness and is then taken up in EtOAc,
washed with NaHCO.sub.3 solution, with KHSO.sub.4/K.sub.2SO.sub.4
and with saturated NaCl solution. The resulting solution is dried
over Na.sub.2SO.sub.4 and then evaporated. The residue is taken up
in an ether/hexane mixture and then dried over Na.sub.2SO.sub.4.
1.4 g of the expected compound are obtained.
[0258] NMR:(DMSO +TFA) 1.15-1.25 m:6H; 1.30 s 9H; 2.9-3.1 m:2H;
4.3-4.6 m :H; 4.6-4.75 m 1H; 4.9-5.1 m 1H; 5.75-5.9:m:2H; 7.5:d 2H;
7.9:d:2H.
[0259] B)
I-[2-Amino-3-(4-cyanophenyl)propionyl]-2,5-dimethyl-2,5-dihydrop-
yrrole trifluoroacetate.
[0260] The compound of the above step is dissolved in 5 ml of DCM,
5 ml of TFA are added and the mixture is left stirring for 40
minutes at RT. It is evaporated to dryness and- the residue is
taken up in DCM and evaporated (3 times) and is then taken up in an
ether/ hexane mixture. The product is drained and then dried over
Na.sub.2SO.sub.4 in order to obtain 1.5 g of the expected
product.
[0261] Working as in Preparation 1.4, step A above, the compounds
described in the table below are prepared:
2TABLE 1 33 Preparation --NR.sub.4R.sub.5 NMR (DMSO + TFA) 1.5 34
1.20:s:9H; 2.75-2.95:mt:2H; 3.30-3.60:m:8H; 4.60:mt:1H; 7.40:d:2H;
7.70:d:2H 1.6 35 0.8-1.2:m:6H; 1.3:s:9H; 2.7-3:m:5H; 4-4.8:m:2H;
7.5:d:2H; 7.8:d:2H 1.7 36 0.8-1.1:m:6H; 1.15:s:9H; 1.5-2.1:m:4H;
2.7-2.9:m:2H; 3.6-4:m:2H; 4.1-4.4:m:2H; 7.4:d:2H; 7.7:d:2H
[0262] Preparation 1.8
[0263] 1-[2-N-Methylamino-3-(4-cyanophenyl)propionyl]-pyrrolidine
trifluoroacetate.
[0264] A) 2-(N-Boc-N-methyl)amino-3-(4-cyanophenyl)propionic
acid.
[0265] 1.16 g of 2-[N-Boc-amino]-3-(4-cyanophenyl)-propionic acid
are dissolved in 20 ml of THF and 2 ml of methyl iodide are added
at 0.degree. C., followed by portionwise addition of 360 mg of
sodium hydride at 80% in oil. The mixture is left stirring
overnight at RT. The reaction medium is diluted with EtOAc and then
water is added and the pH is brought to 2.5 with 1N HCl. The
organic phase is separated out after settling has taken place, then
washed with water, with saturated NaCl solution and then dried over
Na.sub.2SO.sub.4 and evaporated. The residue is taken up in an
Et.sub.2O/hexane mixture (1/1; v/v) . The powder formed is filtered
off and dried to give 1.11 g of the expected compound.
[0266] NMR (DMSO+TFA):1.20:ds: 9H; 2.55 ds: 3H; 2.90-3.25:m: 2H;
4.50-4.80:m:H; 7.30-7.70: m:4H.
[0267] B)
1-[2-(N-Boc-N-methyl)amino-3-(4-cyanophenyl)-propionyl]pyrrolidi-
ne.
[0268] 1.10 g of the compound of the above step, 0.35 ml of
pyrrolidine and 1.78 g of BOP are mixed with stirring in 15 ml of
DMF and the pH is adjusted to 6 by addition of DIPEA. After
stirring for 2 and a half hours, the mixture is extracted with
EtOAc and the organic phase is then washed with 0.25N NaOH, 0.25N
HCl, H.sub.2O and then with saturated NaCl solution. The thick wax
formed sets to a solid after a few days at +4.degree. C. 1.25 g of
the expected compound are obtained.
[0269] NMR (DMSO +TFA):1.10 ds 9H; 1.60-1.85 m:4H; 2.60:ds 3H;
2.75-3.40 m:6H; 4.80-5.10 m :H; 7.25-7.70 m:4H.
[0270] C)
1-[2-N-Methylamino-3-(4-cyanophenyl)propionyl]-pyrrolidine
trifluoroacetate.
[0271] 0.72 g of the compound of the above step is placed in 12 ml
of TFA and 12 ml of DCM. After stirring for 40 minutes at RT, the
reaction medium is concentrated under vacuum and then evaporated
with DCM. 0.75 g of the expected compound is obtained in the form
of a thick wax.
Preparation 1.9
[0272]
N,N-Diethyl-[2-amino-3-(4-(3,4-dihydroimidazo]-2-yl)-phenyl)]propio-
namide dihydrochloride.
[0273] N,N-Diethyl-[2-(N-Boc)amino-3-(4-cyanophenyl)]-propionamide
is prepared by working according to the procedure described in
Preparation 1.4, step A. The expected product is then obtained
according to the procedure described in Preparation 1.2.
Preparation 1.10
[0274] Ethyl ester of 2-(N-Boc)amino-3-(4-cyanophenyl)-propionic
acid.
[0275] 26 g of Boc.sub.2O dissolved in 100 ml of DCM are gradually
added to a solution of 25.5 g of the ethyl ester hydrochloride of
2-amino-3-(4-cyanophenyl)-propionic acid and 13.9 ml of Et3N in 400
ml of DCM. After stirring for 6 hours at RT, the reaction medium is
washed with KHSO.sub.4/K.sub.2SO.sub.4 solution, with saturated
NaHCO.sub.3 solution and with saturated NaCl solution. After drying
over Na.sub.2SO.sub.4 and evaporation of the DCM, the residue is
triturated from heptane to give 29 g of white powder.
Preparation 1.11
[0276] Ethyl ester of
(R)-2-(N-Boc)amino-3-(4-cyanophenyl)-propionic acid:compound B and
(S)-2-(N-Boc)amino-3-(4-cyanophenyl)propionic acid:compound A.
[0277] A mixture of 24 g of the product obtained above and 8.4 g of
NaHCO.sub.3 in 900 ml of EtOAc and 500 ml of H.sub.2O is treated
with 2 ml of AlcalaseO for 24 hours at RT. The 2 phases are
separated out after settling has taken place; the EtOAc phase is
rewashed with 100 ml of 10% NaHCO.sub.3 solution which is added to
the first aqueous phase and the aqueous phase is rewashed with 100
ml of EtOAc added to the first EtOAc phase. The EtOAc phase thus
obtained is dried over Na.sub.2SO.sub.4 and then evaporated to
dryness; 12.45 g of compound B are obtained.
[0278] .alpha..sub.D.sup.25=+8.8.degree. (c=1; MeOH)
[0279] The aqueous phase is taken up in EtOAc and brought to pH=2:5
with 6N HCl. EtOAc is separated out after settling has taken place
and rewashed with KHSO.sub.4/K.sub.2SO.sub.4 solution, with
saturated NaCl solution, dried over Na.sub.2SO.sub.4 and evaporated
to dryness, and 10.1 g of compound A are obtained.
[0280] .alpha..sub.D.sup.25=+8.8.degree. (c=1; MeOH)
Preparation 1.12
[0281] 1-[2-Amino-3-(4-cyanophenyl)propionyl]pyrrolidine
trifluoroacetate, (S) isomer.
[0282] A) 2,5-Dioxo-1-pyrrolidinyl ester of
2-(N-Boc)amino-3-(4-cyanopheny- l)propionic acid, (S) isomer.
[0283] 9.85 g of 2-(N-Boc)amino-3-(4-cyanophenyl)-propionic acid,
(S) isomer, and 4.14 g of NSuOH are dissolved in 100 ml of dioxane
and 8.5 g of DCC dissolved in 30 ml of dioxane are added slowly at
RT, after which the mixture is stirred for 8 hours at RT. The DCU
is filtered off and washed with acetone. After evaporating the
filtrate to dryness, the residue is dissolved in acetone and then
left overnight at RT. The remaining DCU which has precipitated is
removed and the filtrate is then evaporated to dryness, triturated
from Et.sub.2O and then drained, washed with Et.sub.2O and dried.
11.5 g of the expected compound are obtained,
[0284] .alpha..sub.D.sup.25=-29.7.degree. (c=1, MeOH)
[0285] B)
1-[2-(N-Boc)amino-3-(4-cyanophenyl)propionyl]-pyrrolidine, (S)
isomer.
[0286] 11 g of the compound of the above step are placed in 150 ml
of acetonitrile and 20 ml of DMF and 2.5 ml of pyrrolidine in 30 ml
of acetonitrile are added over 10 minutes. The mixture is left
stirring for 2 hours at RT and is then left overnight at RT. It is
evaporated to dryness, the residue is taken up in EtOAc and a
KHSO.sub.4/K.sub.2SO.sub.- 4 buffer is then added. This mixture is
extracted with EtOAc, then washed with saturated NaHCO.sub.3
solution and then with saturated NaCl solution; it is dried over
Na.sub.2SO.sub.4 and then evaporated to dryness. The residue is
triturated from Et.sub.2O, drained, washed with Et.sub.2O and
dried. 6.95 g of the expected compound are obtained.
[0287] .alpha..sub.D.sup.25=+260 (c=1, MeOH)
[0288] C) 1-(2-Amino-3-(4-cyanophenyl)propionyl]pyrrolidine
trifluoroacetate, (S) isomer.
[0289] 6.75 g of the compound of the above step are dissolved in 50
ml of DCM and the insoluble material is filtered off. 50 ml of TFA
are added and the mixture is left stirring for 45 minutes. It is
evaporated to dryness, the residue is redissolved in isopropanol,
this solution is again evaporated to dryness and the residue is
then triturated from Et.sub.2O, drained, washed with Et2O and dried
over Na.sub.2SO.sub.4. 6.13 g of the expected compound are
obtained, m.p.=193-196.degree. C. .alpha..sub.D.sup.25=+510 (c=1,
MeOH)
Preparation 1.13
[0290] 1-[2-Amino-3-(4-cyanophenyl)propionyl]pyrrolidine
trifluoroacetate, (R) isomer.
[0291] A) (R)-2-(N-Boc)amino-3-(4-cyanophenyl)propionic acid.
[0292] 43 ml of lN NaOH solution are added to 12.18 g of compound B
of Preparation 1.11 dissolved in 180 ml of MeOH and the mixture is
stirred for 1 hour at RT. 43 ml of lN HCl solution are then added
and 150 ml of methanol are evaporated off, after which the mixture
is taken up in EtOAc and is washed with water and then with
saturated NaCl solution. 11 g of the expected compound are obtained
after crystallization from an Et.sub.2O/heptane mixture.
[0293] .alpha..sub.D.sup.25=9.5=20 (c=1; MeOH)
[0294] B) Ester of 2,5-dioxo-1-pyrrolidinyl
(R)-2-(N-Boc)-amino-3-(4-cyano- phenyl)propionic acid.
[0295] 4.2 g of NSuOH are added to 10 g of the acid obtained above
dissolved in 10 ml of dioxane, followed by addition, over 20
minutes, of 8.62 g of DCC dissolved in 30. ml of dioxane. After
stirring overnight at RT, the DCU formed is filtered off and washed
with dioxane. The filtrate is evaporated to dryness and the residue
is triturated from ether to give a solid which is filtered off and
dried. 12.09 g of the expected compound are obtained.
[0296] .alpha..sub.D.sup.25=+27.1.degree. (c=1; MeOH)
[0297] C)
1-[2-(N-Boc)amino-3-(4-cyanophenyl)propionyl]-pyrrolidine, (R)
isomer.
[0298] 2.6 ml of pyrrolidine dissolved in 20 ml of acetonitrile are
added to 11.6 g of the compound obtained in the above step
dissolved in 150 ml of acetonitrile plus 20 ml of DMF. After
stirring overnight at PT, a small amount of insoluble material is
removed and the filtrate is concentrated under vacuum. The residue
is taken up in EtOAc and washed with KHSO.sub.4/K.sub.2SO.sub.4
solution, with saturated NaHCO.sub.3 solution and with saturated
NaCl solution; after drying over Na.sub.2SO.sub.4, the EtOAc is
evaporated under vacuum, the residue is triturated from ether and
9.3 g of the expected compound are obtained in the form of a white
solid.
[0299] .alpha..sub.D.sup.25=-29.2.degree. (c=1; MeOH)
[0300] D) 1-[.sup.2-Amino-3-(4-cyanophenyl)propionyl]pyrrolidine
trifluoroacetate, (R) isomer.
[0301] 8.7 g of the product obtained in the above step are stirred
for 35 minutes in a mixture of 50 ml of DCM and 50 ml of TFA. After
evaporating to dryness, the residue is taken up in isopropanol and
re-evaporated to dryness, and 8.67 g of the expected compound are
obtained in solid form.
[0302] .alpha..sub.D.sup.25=46.degree. (c=1; MeOH)
Preparation 1.14
[0303] 1-[2-mino-2-methyl-3-(4-cyanophenyl)propionyl]-pyrrolidine
trifluoroacetate.
[0304] A)
[0305] A mixture of 7 g of (D,L) alanine methyl ester, 14 ml of
Et.sub.3N, 4.2 g of MgSO.sub.4.multidot.3H.sub.2O and 5.1 ml of
benzaldehyde in 100 ml of dichloromethane is stirred for 18 hours
at RT. The insoluble material is filtered off, the filtrate is
concentrated under vacuum and the residue is taken up in an
ether/water mixture; the ether is separated out after settling of
the phases has taken place, rewashed with water and then with
saturated NaCl solution, dried over Na.sub.2SO.sub.4 and
evaporated. 8.3 g of the expected compound are obtained in the form
of an oil.
[0306] B)
[0307] 13.2 ml of lithium bis(trimethylsilyl)amide (1M in THF) are
added, at -70.degree. C. over 20 minutes, to 2.29 g of the product
of the above step dissolved in 60 ml of THF. After 30 minutes, 2.35
g of 4-bromomethylbenzo-nitrile dissolved in 15 ml of THF are added
over 15 minutes and the temperature is then allowed to rise slowly.
After 3 and a half hours, the reaction medium is taken up in EtOAc
and washed with water and with saturated NaCl solution. After
drying and evaporating the EtOAc, 3.6 g of the expected compound
are obtained in the form of an oil.
[0308] C)
[0309] The compound of the above step is taken up in 60 ml of ether
plus 60 ml of 1N HCl and is stirred for 18 hours at RT. The aqueous
phase is separated out after settling of the phases has taken
place, placed in contact with EtOAc and brought to pH=10 with lON
NaOH; the EtOAc is separated out after settling of the phases has
taken place, rewashed with H.sub.2O and with saturated NaCl
solution, dried and evaporated. 2.20 g of the expected compound are
obtained in the form of an oil.
[0310] D)
[0311] 2.42 g of Boc.sub.2O dissolved in 10 ml of dioxane are
added, at 10.degree. C. over 10 minutes, to 2.18 g of the compound
of the above step dissolved in 10 ml of dioxane; the mixture is
then stirred overnight at RT and then for 3 hours at 400.degree. C.
The reaction medium is taken up in EtOAc, washed with water and
then with saturated NaCl solution, dried and then evaporated to
give an oil which is used directly in the following step.
[0312] E)
[0313] The product of the above step is dissolved in 10 ml of
methanol; 2.4 ml of 8.36N KOH solution are added and the mixture is
stirred overnight; a further 2.4 ml of the KOH solution are added
and the mixture is refluxed for 1 hour. The reaction medium is
cooled and taken up in a water/ether mixture; the aqueous phase is
separated out after settling of the phases has taken place, taken
up in EtOAc and brought to pH=2 with 1N HCl. The EtOAc is separated
out after settling of the phases has taken place, rewashed with
H.sub.2O and with saturated NaCl solution, dried over
Na.sub.2SO.sub.4 and then evaporated. 0.99 g of the expected
compound is obtained after chromatography on silica, eluting with
chloroform/MeOH/AcOH (94/6/0.2; v/v/v)
[0314] F)
[0315] 0.30 ml of pyrrolidine, 1.55 g of BOP and DIPEA to obtain a
pH of 6-7 are added to 0.98 g of the compound of the above step in
10 ml of DMF. After stirring for 2 and a half hours, the reaction
medium is taken up in EtOAc and washed with H.sub.2O, 0.2N NaOH,
0.2N HCl, H.sub.2O and saturated NaCl solution. After drying and
evaporating, 1.13 g of the expected compound are obtained,
m.p.=84-87.degree. C.
[0316] NR (DMSO +TFA):1.20 s 3H; 1.45 s 9H; 1.60-1.90 m:4H;
3.00-3.50 m 6H; 7.30 d 2H; 7.80:d 2H.
[0317] G)
[0318] 1.12 g of the compound of the above step are stirred for 1
hour in a mixture of 10 ml of DCM and 12 ml of TFA. After
evaporating and drying, 1.15 g of the expected compound are
obtained in the form of a solid.
[0319] Preparation 2.1
[0320] 3-Amino-3-(2-naphthyl)propionic acid hydrochloride.
[0321] The method described in J. Am. Chem. Soc., 1936, 58, 299 is
used. 15.5 g of 2-formylnaphthalene, 10.4 g of malonic acid and
15.4 g of ammonium acetate in 150 ml of ethanol are mixed together
and refluxed for 6 hours. After cooling to RT, the producz is
drained, washed with EtOH and dried. The product obtained is
dissolved in a sufficient amount of 2N HCl and the insoluble
material is then filtered off. The acidic solution is concentrated
by evaporating under vacuum and the solid thus formed is
recrystallized from 20 ml of an AcOH/H.sub.2O mixture (1/1; v/v).
3.8 g of the expected product are obtained.
[0322] The compounds of Table 2 below are prepared according to the
procedure described above.
3TABLE 2 37 Preparations R.sub.2 2.2 38 2.3 39 2.4 40 2,5 41
[0323] Preparation 2.6
[0324] 3-(N-Boc)amino-3-(3,4-dichlorophenyl)propionic acid.
[0325] Starting with the compound of Preparation 2.5, the
N-protected beta-amino acid is prepared in the following way.
[0326] 10 g of 3-amino-3-(3,4-dichlorophenyl)propionic acid are
dissolved in 100 ml of water and 9 ml of triethylamine are added,
followed by gradual addition of 9.3 g of (Boc).sub.2O in 100 ml of
dioxane. After stirring overnight at RT, the medium is concentrated
andthe residue is then taken up in water, adjusting the pH to 9 by
addition of 1N sodium hydroxide. This mixture is washed twice with
ether, the aqueous phase is taken up and acidified to pH=3 by
addition of 1N HCl and is extracted with EtOAc and concentrated in
order to obtain 3.9 g of the expected compound, m.p.=128.degree.
C.
[0327] NMR (DMSO)
[0328] 1.25 ppm:s:9H; 2.50-2.65 ppm:mt:2H; 4.75 ppm q:1H; 7.25
ppm:d:1H; 7.20-7.40 ppm:m:3H
Preparation 2.7
[0329] 3-Amino-3-(3-isopropyloxyphenyl)propionic acid
hydrochloride
[0330] A) (3-Isopropyloxy)benzaldehyde.
[0331] 3.4 g of K.sub.2CO.sub.3 and 1.5 g of
benzyltriethyl-ammonium chloride are added to 12.2 g of
3-hydroxy-benzaidehyde in 100 ml of DMSO, followed by addition,
over 30 minutes, of 10 ml of isopropyl iodide dissolved in 20 ml of
DMSO, and the mixture is left stirring overnight at RT. The mixture
is poured onto 400 ml of water and is then extracted with EtOAc,
washed with saturated NaCl solution and then dried over
Na.sub.2SO.sub.4 and evaporated to dryness. The oil obtained (14.4
g) is used without further purification in the following step.
[0332] B) 3-Amino-3-(3-isopropyloxyphenyl)propionic acid
hydrochloride.
[0333] A mixture containing 14 g of the oil obtained in the above
step, 150 ml of methoxyethanol, 8.95 g of malonic acid and 13.2 g
of ammonium acetate is heated overnight at 80.degree. C. After
cooling, the mixture is evaporated to dryness and the oil formed is
then dissolved in ethanol and 50 ml of 2N HCl. Fractional
evaporation is carried out in order to obtain the expected
compound, which is drained and then washed with EtOAc. 4.56 g are
obtained.
[0334] NMR (DMSO):1.25 d 6H; 4.65:septet:1H; 7.20-7.55:mt:4H; 9.95
s 1H.
[0335] The compounds described in the table below are prepared
according to the procedure described in the above preparation.
4TABLE 3 42 Preparations R.sub.2 NMR 2.8 43 (DMSO) 2.85-3.15:mt:2H;
3.85:s:3H; 4.60:t:1H; 6.95-7.45:mt:4H 2.9 44 (DMSO + TFA)
2.50-3.00:mt:2H; 3.70:s:3H; 4.50:t:1H; 6.90:d:2H; 7.40:d: 2H 2.10
45 (DMSO + TFA) 2.80-3.10:mt:2H; 4.60:t:1H; 7.30-7.60:m:4H 2.11 46
(DMSO + TFA) 2.90-3.20:mt:2H; 4.75:t:1H; 7.00-8.05:mt:4H 2.12 47
(DMSO + TFA) 3.00-3.20:mt:2H; 5.40-5.60:mt: 1H; 7.50-8.30:m:7H 2.13
48 (DMSO + TFA) 2.75-3.10:mt:2H; 5.60:t:1H; 7.00-7.45:m:4H 2.14 49
(DMSO + TFA) 0.90-1.75:m:1H; 2.40-2.70:mt: 2H; 3.15-3.30:m:1H 2.15
50 (DMSO + TFA) 2.25:s:3H; 2.80-3.05:mt:2H; 4.55:t:1H;
7.10-7.30:m:4H
Preparation 2.16
[0336] 3-(N-Boc)amino-3-biphenyl-4-ylpropionic acid.
[0337] A) 3-Amino-3-biphenyl-4-ylpropionic acid hydrochloride.
[0338] 18.2 g of 4-phenylbenzaldehyde, 10.4 g of malonic acid and
15.4 g of ammonium acetate in 150 ml of methoxyethanol are mixed
together. After heating overnight at 80.degree. C., the mixture is
cooled and the product formed is then washed with ethanol, with
ether and then dried. After washing again with water, the product
is recrystallized from a methanol/water mixture with a small amount
of HCl. A mixture of the expected product and of the methyl ester
hydrochloride of 3-amino-3-biphenyl-4-ylpropionic acid is obtained,
which is used without further purification in the following
step.
[0339] B) 3-(N-Boc)Amino-3-biphenyl-4-ylpropionic acid.
[0340] The product of the above step is placed in 200 ml of
dioxane, 55 ml of 2N NaOH are added and the mixture is left
stirring at RT for 1 hour 40 minutes. 13 g of Boc.sub.2O are added
and stirring is continued overnight. The insoluble material is
filtered off, dilution is carried out with 200 ml of water, the
mixture is washed with Et.sub.2O and then acidified to pH=2.5 by
addition of 2N HCl in the presence of 100 ml of EtOAc. This mixture
is extracted with EtOAc, washed with KHSO.sub.4/K.sub.2SO.sub.4,
with saturated NaCl solution and then dried over Na.sub.2SO.sub.4
and evaporated to dryness in order to obtain 11.03 g of the
expected compound.
[0341] NMR (DMSO) 1.40:s: 9H; 2.60-2.85 mt: 2H; 5.00:dq:1H;
7.35-7.80 mt:10H; 12.30:bs: 1H.
Preparation 2.17
[0342] 2,5-Dioxo-1-pyrrolidinyl
3-(N-Boc)amino-3-biphenyl-4-ylpropionate.
[0343] 3.41 g of the acid described in the above preparation are
placed in 50 ml of dioxane and treated with 1.26 g of
hydroxysuccinimide in the presence of 2.5 g of DCC. The mixture is
left stirring overnight at RT and is then drained and washed with
acetone. The filtrate is evaporated to dryness and then taken up in
isopropanol. The solid is drained, washed with ether and dried to
give 3.46 g of the expected compound, m.p. =161.degree.C.
[0344] NMR (DMSO) 1.35 s:9H; 2.80 s:4H; 3.00-3.20:mt:2H; 5.00 dq
1H; 7.30-7.75 mt 10H.
Preparation 2.18
[0345] (1,2,3,4-Tetrahydro-1-isoquinolyl)acetic acid.
[0346] This compound is prepared according to J. Org, Chem., 1987,
52, 616-622.
[0347] A) 3,4-Dihydroisoquinoline.
[0348] 9.4 ml of 1,2,3,4-tetrahydroisoquinoline are dissolved in
200 ml of DCM and 14.7 g of NBS are gradually added. The mixture is
left stirring at RT, cooling slightly in order to maintain a
temperature of less than 400.degree. C. for 30 minutes, after which
50 ml of 10N NaOH are added and the mixture is left stirring for 1
hour at RT. The organic phase is separated out after settling of
the phases has taken place and is washed with 100 ml of water and
then twice with 100 ml of 4N HCl. The aqueous phases are washed
with DCM and then brought to pH=9 by addition of concentrated
NH.sub.4OH. This mixture is extracted with DCM, dried over
Na.sub.2SO.sub.4 and evaporated to dryness. The oil obtained is
distilled off. 7.16 g of the expected compound are obtained, b.p.
=50-540C at 0.05 mbar.
[0349] B) (1,2,3,4-Tetrahydro-1-isoquinolyl)acetic acid.
[0350] A mixture containing 6.62 g of 3,4-dihydro-isoquinoline and
5.13 g of malonic acid is triturated in an oil bath at 120.degree.
C. The mixture thickens and becomes entirely solid; it is worked
into a powder with a spatula. The total duration of heating is
about 40 minutes. The mixture is cooled to about 60.degree. C. and
treated with 120 ml of MeOH and 20 ml of water, which dissolves the
medium. A first crop is obtained under cold conditions and a second
crop is then obtained by evaporating the filtrate and crystallizing
the residue from acetone.
[0351] NMR (DMSO +TFA) 2.90-3.15 mt 4H; 3.30-3.60:mt:2H; 4.90:t:1H;
7.20-7.40 m 4H.
Preparation 2.19
[0352] 3-Amino-3-phenylprooionic acid trifluoroacetate, (R)
isomer.
[0353] A) (2-Isopropyl-5-methyl)cyclohexyl
3-(N-Boc)amino-3-phenylpropiona- te, (R) isomer.
[0354] This reaction is carried out according to Tetrahedron
Letters, 1988, 29, 6465-6466. A solution containing 11.1 g of
3-(N-Boc)amino-3-phenylpropionic acid, 7.5 g of L(-)-menthol and
2.1 g of DMAP in 400 ml of DCM is prepared; after stirring, 11.2 g
of DCC dissolved in 50 ml of DCM are gradually introduced. After
stirring overnight at RT, the mixture is filtered, the DCU is
washed with acetone and the filtrate is evaporated to dryness. The
residue is taken up in 150 ml of heptane at 80-90.degree. C.; the
insoluble material is filtered off and the solution is left at RT
for 4 hours. The solid is drained, washed with heptane and dried at
400.degree. C. until the menthol odour has disappeared. 4.25 g of
the expected compound are obtained.
[0355] .alpha..sub.D.sup.25=-16.50 (c=1; MeOH)
[0356] B) 3-(N-Boc)amino-3-phenylpropionic acid, (R) isomer.
[0357] A mixture containing 4.22 g of the compound of the above
step and 15.7 ml of 1N NaOH in 100 ml of methanol is refluxed for 4
hours. The reaction medium is cooled, treated with 15.7 ml of 1N
HCl and then evaporated to dryness and taken up in heptane. After
leaving for a few hours at RT, the product crystallizes, it is
drained, washed with heptane and then dried at 400.degree. C. until
the menthol odour has disappeared. 2.65 g of the expected compound
are obtained.
[0358] .alpha..sub.D.sup.25=+42.2 (c=1; MeOH)
[0359] C) 3-Amino-3-phenylpropionic acid trifluoroacetate, (R)
isomer.
[0360] 2.3 g of the compound obtained in the above step are
dissolved in 15 ml of DCM and 15 ml of TFA are added. After
stirring for 35 minutes at RT, the solution is evaporated to
dryness. The product is taken up in isopropanol, evaporated and
then crystallized from Et.sub.2O. The product is drained, washed
with Et.sub.2O and dried in order to obtain 2.16 g of the expected
compound.
Preparation 2.20
[0361] 3-Amino-4-phenylbutyric acid hydrochloride, (S) isomer.
[0362] A) Methyl 2-(N-Boc)amino-3-phenylpropionate, (S) isomer.
[0363] 10 g of methyl (L)-2-amino-3-phenylpropionate hydrochloride
in 150 ml of DCM are mixed with 7 ml of Et.sub.3N and 13 g of
(Boc).sub.2O in 50 ml of DCM are gradually-. added. After stirring
for 5 hours at RT, the reaction meaium is washed with
KHSO.sub.4/K.sub.2SO.sub.4 and then with saturated NaCl solution.
The resulting solution is dried in order to remove the excess
(Boc).sub.2O and is then dissolved in DCM and 1.5 ml of
N,N-dimezhylpropane-damine are added. After stirring for 4 hours,
the mixture is washed with KHSO.sub.4/K.sub.2SO.sub.4 and then with
saturated NaCl solution. This solution is dried over
Na.sub.2SO.sub.4 and then evaporated to dryness in order to obtain
11.9 g of the expected compound.
[0364] B) 2-(N-Boc)amino-3-phenylpropanol, (S) isomer.
[0365] This step and the following 2 are carried out according to
Tetrahedron, 1994, 50(31), 9457. 10 g of the compound of the above
step are dissolved in 120 ml of THF and the solution is cooled on
an ice bath; 3.17 g of lithium chloride are added, followed by 2.8
g of sodium borohydride and, gradually, 170 ml of EtOH. After
stirring overnight at RT, 70 ml of 1M KHSO.sub.4 are added slowly
and the mixture is concentrated almost to dryness. The concentrate
is diluted in chloroform and 1M KHSO.sub.4 and is then extracted
with chloroform. The extracts are washed with saturated NaCl
solution, dried over Na.sub.2SO.sub.4 and evaporated to dryness in
order to obtain 8.65 g of the expected compound.
[0366] C) 2-Amino-3-phenylpropyl methanesulphonate, (S) isomer.
[0367] 7.5 g of the compound of the above step are dissolved in 40
ml of pyridine and the mixture is cooled in an ice bath; 3.3 ml of
mesyl chloride are added over 15 min and the mixture is then left
stirring for 2 hours at RT. 15 ml of water are added over 5 minutes
and the medium is then diluted with ether and washed with 1M
KHSO.sub.4 (twice), with water and then with saturated NaCl
solution; the resulting solution is dried over Na.sub.2SO.sub.4 and
then evaporated to dryness in order to obtain 9.2 g of the expected
compound.
[0368] .alpha..sub.D.sup.25=-24.3.degree. (c=1; MeOH)
[0369] D) 3-(N-Boc)arnino-4-phenylbutyronitrile, (S) isomer.
[0370] A solution containing 9.05 g of the compound of the above
step with 7.3 g of 18-crown-6 crown ether and 120 ml of DMSO is
prepared and 9 g of potassium cyanide are added with stirring in an
ice bath. After heating at 50.degree. C. for 5 hours, the mixture
is cooled and 600 ml of Et.sub.2O are then added. This mixture is
washed with water (3 times) and then with saturated NaCl solution;
the resulting solution is dried over Na.sub.2SO.sub.4 and then
evaporated to dryness in order to obtain 6.58 g of the expected
compound.
[0371] E) 3-Amino-4-phenylbutyric acid hydrochloride, (S)
isomer.
[0372] This step is carried out according to Tetrahedron Letters,
1990, 31, 5153. 4.1 g of the compound of the above step are
suspended in 50 ml of 6N HCl and the mixture is refluxed for 5
hours. It is concentrated in order to obtain a first crop of the
pure expected compound. On evaporating to dryness, a second crop of
1.4 g of the expected compound contaminated with NH.sub.4Cl is
obtained. A sample is treated with (Boc).sub.2O and its optical
rotation is measured.
[0373] .alpha..sub.D.sup.25=17.degree. (c=1; NeOH) literature
[0374] .alpha..sub.D.sup.25=16.degree. (c=1; MeOH)
Preparation 2.21
[0375] 3-Amino-3-phenylpropionic acid trifluoroacetate, (S)
isomer.
[0376] The preparation is identical to the one described in 2.19,
but using D(+)-menthol.
Preparation 3.1
[0377] 3-Phenyl-3-(2,4,6-trichlorobenzenesulphonamido)-propionic
acid.
[0378] 1.15 g of 3-amino-3-phenylprooionic acid are dissolved in 25
ml of dioxane and 7 ml of 1N sodium hydroxide and 1.95 g of
2,4,6-trichlorobenzenesulphonyl chloride in 5 ml of dioxane are
gradually added, while. maintaining the pH at 10.5-11 by addition
of 1N sodium hydroxide. After stirring for 2 hours at RT, the
mixture is diluted with 100 ml of water, extracted twice with EtOAc
and acidified to pH=2 by addition of 6N HCl. The solid formed is
drained, washed with water and dried at 400.degree. C. 2.09 g of
the expected product are obtained, m.p.=218-219.degree. C.
[0379] NMR (DMSO+TFA):2.60-2,95 mt:2H; 4.75:q:1H; 7.10-7.30:m 5H;
7.60:s:2H; 8.85:d: 1H.
Preparation 3.2
[0380] 3-(Naphth-2-ylsulphonamido)-3-phenylpropionic acid.
[0381] 4.13 g of 3-amino-3-phenylpropionic acid are dissolved in
100 ml of dioxane and 25 ml of 1N sodium hydroxide and 5.6 g of
2-naphthalenesulphonyl chloride are added portionwise, while
maintaining the pH at 10.5-11 by addition of 1N sodium hydroxide.
After stirring for 2 hours at RT, the mixture is diluted with 400
ml of water and 2N HCl is added in order to obtain pH=2. This
mixture is extracted with EtOAc and the extracts are washed with a
KHSO.sub.4/K2SO.sub.4 buffer, dried over Na.sub.2SO.sub.4 and
evaporated to dryness. The residue is triturated from heptane and
the product is isolated by decanting and is then dried under
vacuum. 7.33 g of the expected product are obtained, m.D.
=126-129.degree. C.
[0382] NMR (DMSO+TFA):2.55-2.70:mt:2H; 4.70 t:1H;
6.85-8.15:m:12H.
Preparation 3.3
[0383] 2-Hydroxy-3-(naphth-2-ylsulphonamido)-3-phenylpropionic
acid.
[0384] This compound is prepared according to Bull. Soc. Chim.,
France, 1940, 593-603.
[0385] Working according to the procedures described in
Preparations 3.1 and 3.2, starting with the compounds obtained in
Preparation 2 and 2-naphthalene-sulphonyl chloride, the acids
described in Table 4 below are obtained.
5TABLE 4 51 Prep- arations R.sub.2 NMR m.p. .degree. C. 3.4 52
(DMSO) 2.80:d:2H; 4.90:q:2H; 7.15-8.20:m:14H; 8.60:d:1H 145-150 3.5
53 (DMSO + TFA) 2.00-2.20:mt:2H; 4.45:t:1H; 7.10-8.25:m:11H 223-228
3.6 54 (DMSO) 2.50-2.75:mt:2H 4.60-4.80:mt:3H 6.65-8.15:m:16H
8.40:bs:1H 253-255 3.7 55 RMN (DMSO) 2.40-2.65:mt:2H 4.65:s:2H;
4.75:dq:1H; 6.40-8.05:m:16H 8.40:bs:1H
[0386] The acids described above are converted by the action of
N-hydroxysuccinimide in the presence of DCC in DMF. The compounds
obtained are described in Table 5 below.
6TABLE 5 56 Prep- m.p. arations R.sub.2 NMR (DMSO) .degree. C. 3.8
57 2.75:s:4H; 3.20:mt:2H; 4.90:dq:1H; 7.20-8.10:m:14H; 8.70:d:1H
165 3.9 58 192 3.10 59 187 3.11 60 2.80:s:4H; 3.15:mt:2H;
4.65:s:2H; 4.75:dq:1H; 6.45-7.95:mt:4H; 7.25-8.20:mt:12H; 8.60:d:1H
110
Preparation 3.12
[0387] 3-(2-Hydroxyphenyl)-3-(naphth-2-ylsulphonamido)-propionic
acid.
[0388] 1.1 g of 3-amino-3-(2-hydroxyphenyl)propionic acid
hydrochloride, prepared according to J. Agric. Food Chem., 1977,
25, 965, are dissolved in 25 ml of dioxane and 10 ml of 1N NaOH are
added; 1.12 g of 2-naphthalenesulphonyl chloride are gradually
added while maintaining the pH at 11.5-12 by addition of 1N NaOH.
After stirring for 2 hours at RT, the reaction medium is diluted in
water, washed with EtOAc (twice) and then acidified to pH=1.5-2 by
addition of 6N HCl.
[0389] The white precipitate formed is drained, washed with water
and dried in order to obtain 0.82 g of the expected product,
m.p.=190-200.degree. C.
[0390] NMR (DMSO)
[0391] 2.50-3.20 mt:2H; 4.80 :mt H; 6.95-8.30:m 11H; 8.75:s:
1H.
Preparation 3.13
[0392] 3-Phenyl-3-(quuinol-2-ylsulphonamido)propionic acid.
[0393] A) 2-Quinolinesulphonyl chloride.
[0394] 3.2 g of 2-mercaptocuinoline are suspended in 40 ml of water
containing 0.156 g of iron trichloride. The mixture is cooled in an
ice bath and chlorine is then bubbled through for 1 hour at
4.degree. C. The mixture is evaporated and the residue is then
taken up in the minimum amount of water and the product is drained
and dried in order to obtain 2.30 g of the expected. compound in
dry form.
[0395] B) 3-Phenyl-3-(quinol-2-ylsulphonamido)propionic acid.
[0396] 1.65 g of the compound prepared in the above step are
dissolved in 40 ml of dioxane and 20 ml of 1N NaOH are added, along
with portionwise addition of 2.27 g of 3-amino-3-phenylpropionic
acid, while maintaining the pH at 10. The mixture is left stirring
for 18 hours at RT and is then evaporated to dryness. The residue
is taken up in a DCM/H.sub.2O mixture, the phases are separated
after settling has taken place and the organic phase is extracted
with water. Acidification to pH=1 is carried out by addition of HCl
and the product is then drained and dried over MgSO.sub.4 in order
to obtain 1.9 g of the expected compound.
[0397] NMR (DMSO+TFA):2.4-2.9:m:2H; 4.9:mt 1H; 6.9-7.1:mt:3H;
7.2:d:2H; 7.7-8.1:m:5H; 8.4:d:1H; 8.8 d:1H.
Preparation 3.14
[0398] 3-Phenyl-3-(quinol-8-ylsulphonamido)propionic acid.
[0399] This compound is prepared according to the procedure
described above, starting with 8-quinoline-sulphonyl chloride.
Preparation 3.15
[0400]
3-(3-Isopropyloxyphenyl)-3-(naphth-2-ylsulphonamrido)-propionic
acid.
[0401] 1.3 g of the compound of Preparation 2.7 are suspended in 20
ml of dioxane and treated with 2N NaOH and then with iN NaOH in
order to bring the mixture to pH=12. 1.13 g of
2-naphthalenesulphonyl chloride are added portionwise, while
maintaining the pH at 10.5-11.5 by addition of iN NaOH. The mixture
is left stirring for 2 hours at RT and is then diluted with water,
washed with EtOAc and then brought to pH=2 by addition of 2N HCl.
This mixture is extracted with EtOAc and then washed with a
KHSO.sub.4/K.sub.2SO.sub.4 buffer and with saturated NaCl solution.
The resulting solution is dried over Na.sub.2SO.sub.4 and
concentrated in order to obtain 900 mg of the expected compound,
m.p.=126.degree. C.
[0402] NMR (DMSO) 0.95 d 6H; 2.40-2.55:mt: 2H; 4.10:tq:1H;
4.60:da:1H; 6.20-8.05:mt: 11H; 8.30:d:1H; 12.20:bs:1H.
[0403] Following the procedure described in the above preparation,
and using the compounds of Preparations 2.8 to 2.15 as starting
materials, the compounds described in Table 6 below are
prepared.
7TABLE 6 61 Preparations R.sub.2 NMR m.p. .degree. C. 3.16 62
(DMSO) 2.35-2.55:mt:2H; 3.35:s:3H; 4.60:dq:1H; 6.20-6.85:mt:4H;
7.40-8.0:mt:7J; 8.30:d:1H; 12.20:bs:1H 154 3.17 63 (DMSO)
2.35-2.60:mt:2H; 3.35:s:3H; 4.55:dq:1H; 6.35:d:2H; 6.90:d:2H;
7.40-7.95:mt:7H; 8.25:d:1H; 12.20:bs:1H 139 3.18 64 (DMSO)
2.40-2.70:mt:2H; 4.60:mt:1H; 6.70-7.10:m:4H; 7.40-8.20:m:7H;;
8.45:bd:1H; 12.30:bs:1H 133 3.19 65 (DMSO) 2.40-2.70:mt:2H;
4.70:dq:1H; 7.00-8.00:m:11H; 8.45:d:1H; 12.20:bs:1H 164 3.20 66
(DMSO) 2.80:bd:2H; 5.60:mt:1H; 7.10-8.10:m:14H; 8.65:d:1H;
12.30:bs:1H 189 3.21 67 (DMSO) 2.45-2.65:mt:2H; 4.70:dq: 1H
6.60-7.05:m:4H; 7.50-8.15:m:7H; 8.50:d:1H; 12.30:bs:1H 167 3.22 68
(DMSO + TFA) 0.80-1.60:m:11H; 1.85-2.30:mt:2H; 3.40:dq:1H;
7.50-8.30:m:7H 198 3.23 69 (DMSO) 1.85:s:3H; 2.45-2.65:mt:2H;
4.65:dq:1H; 6.60-6.90:m:4H; 7.50-8.15:m:7H; 8.40:bd:1H; 12.20:bs:1H
102
[0404] The acids described above (Preparations 3.15 to 3.23) are
converted by the action of N-hydroxy-succinimide in the presence of
DCC in dioxane. The compounds obtained are described in Table 7
below.
8TABLE 7 70 Preparations R.sub.2 NMR m.p. .degree. C. 3.24 71 -- 97
3.25 72 -- 142 3.26 73 -- 135 3.27 74 -- 163 3.28 75 -- 142 3.29 76
(DMSO + TFA) 2.70:s:4H; 3.25:d:2H; 5.60:t:1H; 7.05-7.95:m:14H 192
3.30 77 (DMSO) 2.70:s:4H; 2.95-3.10:mt:2H; 4.75:dq:1H;
6.50-6.90:m:4H; 7.45-8.10:m:7H; 8.60:d:1H 174 3.31 78 (DMSO + TFA)
0.60-1.60:m:11H; 2.40-2.80:mt:2H; 2.70:s:4H; 3.35:mt:1H;
7.50-8.30:m:7H 135 3.32 79 -- 142
Preparation 3.33
[0405] 3-(3,4-Dichlorobenzenesulphonamido)-3-phenylpropionic
acid.
[0406] A) 3,4-Dichlorophenylbenzenesulphonyl chloride.
[0407] 5.4 g of (3,4-dichloro)thiophenol are suspended in 60 ml of
water; 0.234 g of FeCl.sub.3 is added and chlorine is bubbled
through for one hour at a temperature below 10.degree. C. The
mixture is evaporated, drained, washed with water and then dried by
azeotropic entrainment in order to obtain 6.7 g of the expected
compound.
[0408] B) 3-(3,4-Dichlorobenzenesulphonamido)-3-phenyl-propionic
acid.
[0409] The process is then carried out according to the procedure
of Preparation 3.1 in order to obtain the expected compound.
[0410] NMR (DMSO): 2.5-2.9:m:2H; 4.6-4.8:q: 1H; 7.1:s:5H;
7.5-7.7:mt: 3H; 8.7:d:1H; 12.4:s:1H.
Preparation 3.34
[0411]
3-(5,6,7,8-Tetrahydronaphth-2-ylsulphonamido)-3-phenylpropionic
acid.
[0412] A) Sodium 5,6,7,8-tetrahydronaphthalene-2-sulphonate.
[0413] 3.9 g of 1,2,3,4-tetrahydronaphthalene are dissolvedin 10 ml
of anhydrous CCl.sub.4 at 0.degree. C.; 4.3 g of dioxane in 10 ml
of CCl.sub.4 are added, followed by 6.1 ml of sulphuric anhydride.
The mixture is left stirring for 18 hours at RT and then for 3
hours at 80.degree. C. A water/ice mixture is added and the
resulting mixture is extracted with ether. The aqueous phase is
adjusted to pH=6.5 by addition of 5N NaOH. The product is drained
and dried over Na.sub.2SO.sub.4 and then by azeotropic entrainment.
10.6 g are obtained.
[0414] B) 5,6,7,8-Tetrahydronaphthalene-2-sulphonyl chloride.
[0415] 2 g of the sulphonate obtained in the above step are mixed
with 5 g of phosphorus pentachloride and the mixture is refluxed
for 6 hours. It is evaporated, poured onto a water/ice mixture and
then extracted with DCM, dried over Na.sub.2SO.sub.4 and evaporated
in order to obtain 1.5 g of the expected compound.
[0416] C)
3-(5,6,7,8-Tetrahydronaphth-2-ylsulphonamido)-3-phenylpropionic
acid.
[0417] The process is then performed according to the procedure of
Preparation 3.1 in order to obtain the expected product.
[0418] NMR (DMSO):1.6-1.8:m:4H; 2.5-2.8:m: 6H; 4.5-4.7:dd: 1H;
7-7.2:m:7H; 7.3:d:1H; 8.1:d:1H; 12.3 s:1H.
Preparation 3.35
[0419] 1-(Naphth-2-ylsulphonamido)indane-2-carboxylic acid.
[0420] A) Methyl (1-oxo)indan-2-carboxylate.
[0421] The reaction is carried out according to J. Med. Chem.,
1970, 650. A suspension of 6.75 g of sodium hydride at 80% in oil
and 45 g of methyl carbonate in 120 ml of benzene are mixed
together. 11.9 g of 1-indanone dissolved in 100 ml of benzene are
added, at 60.degree. C., over 1 and a half hours and the mixture is
then refluxed. After 1 hour, the benzene is distilled off. Xylene
is added and the mixture is again refluxed. After 1 hour, it is
cooled, 30 ml of AcOH are added and the resulting mixture is poured
onto 200 ml of a water/ice mixture containing 30 ml of 1N HCl. The
insoluble material is removed by filtration and the filtrate is
extracted with Et.sub.2O. The extracts are washed with water, with
saturated NaHCO.sub.3 solution, with water, with saturated NaCl
solution and then dried over Na.sub.2SO.sub.4. The product is
chromatographed on silica, eluting with EtOAc/hexane (1.3; v/v) in
order to obtain 3.05 g of the expected compound.
[0422] NMR (DMSO):3.25-3.50:mt:2H; 3.70:ds: 3H; 4.85-4.90:mt:1H;
7.40-7.80:m:4H. Multiple signals since the product is partly in
enolic form.
[0423] Comment: using THF as solvent instead of benzene and xylene,
a better yield is obtained: 67% instead of 30%.
[0424] B) Methyl 1-hydroxyiminoindan-2-carboxylate.
[0425] The reaction is carried out according to J. Heterocycl.
Chem., 1974, 11, 982. 3.04 g of the compound of the above step in 9
ml of MeOH are added over 10 minutes to a mixture of 2.21 g of
sodium acetate and 3.1 g of hydroxylamine hydrochloride in 3 ml of
water. The mixture is then refluxed for 1 hour 30 minutes, after
which it is cooled and extracted with EtOAc. The extracts are
washed with water, with 3/4 saturated NaHCO.sub.3 solution, with
water and with saturated NaCl solution. After evaporating off the
EtOAc, 3.28 g of the expected compound are obtained in solid
form.
[0426] C) Methyl 1-aminoindan-2-carboxylate hydrochloride.
[0427] 3.27 g of the compound of the above step are dissolved in 80
ml of EtOH, 1.2 g of 10% Pd/C are added, followed by 20 ml of 1M
hydrochloric ethanol and the mixture is left stirring under a
pressure of hydrogen (5 bar) at RT overnight. The catalyst is
filtered off, the filtrate is concentrated under vacuum and the
residue is then taken up in EtOAc and water. The water is separated
out after settling of the phases has taken place and is then
brought to pH=8.5 by addition of 2N NaOH. This phase is extracted
with EtOAc, washed with water, with saturated NaCl solution, dried
over Na.sub.2SO.sub.4 and evaporated. The residue is taken up in 20
ml of MeOH and 6 ml of 2.5N HCl. The mixture is concentrated under
vacuum and the residue is then triturated from Et.sub.2O. 2.71 g of
the expected compound are obtained in the form of a powder.
[0428] D) Methyl
1-(2-naphthalenesulphonamido)indan-2-carboxylate.
[0429] 0.91 g of the above compound is placed in 10 ml of
chloroform and 0.95 g of 2-naphthalenesulphonyl chloride is then
added portionwise, followed by portionwise addition of 0.68 ml of
DIPEA in order to maintain the mixture at pH=7-8. After 3 hours,
the reaction medium is extracted with EtOAc and then washed with
0.05N NaOH, 0.25N HCl, with water and with saturated NaCl solution.
0.99 g of she expected compound is obtained in the form of a
pink-white solid.
[0430] NMR (DMSO+TFA):2.80-3.30 mt 2H; 3.40: s:3H; 3.50:q:H; 5.10
d:H; 6.40-8.50:mt: 11H.
[0431] E) 1-(Naphth-2-ylsulphonamido)indan-2-carboxylic acid.
[0432] 0.98 g of the compound of the above step is placed in 10 ml
of MeOH, 1 ml of 8.36N KOH is added, the mixture is heated at
50.degree. C. for 3 hours and a further 0.25 ml of 8.36N KOH is
then added. After 2 hours, the medium is diluted by addition of
water and EtOAc and the pH is brought to 2.5 by addition of 1N HCl.
The organic phase is separated out after settling of the phases has
taken place, washed with H.sub.2O, with saturated NaCl solution and
then dried over Na.sub.2SO.sub.4 and evaporated. 0.80 g of the
expected compound is obtained in the form of a foam.
Preparation 3.36
[0433]
[2-(2-Naphthalenesulphonyl)-1,2,3,4-tetrahydro-1-isoquinolyl]acetic
acid.
[0434] 1.91 g of (1,2,3,4-tetrahydro-1-isoquinolyl)-acetic acid
(Preparation 2.18) are suspended in 25 ml of dioxane, 10 ml of 1N
NaOH are added, followed by porionwise addition of 2.3 g of
2-naphthalenesulphonyl chloride, and the mixture is maintained at
pH=10.5-12 by addition of --1N--NaOH. The mixture is kept stirring
at a constant pH for 2 hours at RT. The reaction medium is diluted
with 100 ml of water and is then washed twice with EtOAc and
brought to pH=1.2 by addition of 6N HCl in the presence of EtOAc.
This mixture is extracted with EtOAc, washed with saturated NaCl
solution, dried over Na.sub.2SO.sub.4 and evaporated to dryness.
The expected product crystallizes from heptane, and is drained,
washed with heptane and then dried to give 3.14 g, m.p.
=132.degree. C.
[0435] NMR (DMSO+TFA) 2.40-2.80:m: 4H; 3.40-3.90: m:2H; 5.45:t: 1H;
6.90-7.20:m: 4H; 7.50-8.40:m: 7H.
Preparation 3.37
[0436] The 2,5-dioxo-1-pyrrolidinyl ester of the above acid is
prepared by the action of NSuOH in the presence of DCC in
dioxane.
[0437] NMR (DMSO+TFA) 2.50-2.70:m 2H; 2.75 s:4H; 3.10-3.35 mt 2H;
3.50-3.80 mt 2H; 5.50:t:1H; 6.80-8.40 m:1H.
Preparation 3.38
[0438] 3-(2-Naphthalenesulphonamido)-3-phenylpropionic acid, (R)
isomer.
[0439] 2 g of the compound of step 2.19 are placed in 30 ml of
dioxane in the presence of 7.2 ml of 2N NaOH; 1.6 g of
2-naphthalenesulphonyl chloride are added portionwise while
maintaining the mixture at pH=10.5-11.5 by addition of 1N NaOH.
After stirring for 2 hours at RT, the mixture is diluted by
addition of 100 ml of water and is then washed with EtOAc (several
times). The aqueous phase is diluted with EtOAc and then treated
with 2N HCl until the pH=2.2. The resulting mixture is extracted
with EtOAc, washed with saturated NaCl solution, dried over
Na.sub.2SO.sub.4 and evaporated to dryness. The expected compound
crystallizes from heptane, and is drained, washed with heptane and
then dried. 2.2 g are obtained, m.p.=123-126.degree. C.
[0440] .alpha..sub.D.sup.25 =+67.9 (c=1; MeOH)
Preparation 3.39
[0441] 2,5-Dioxo-1-pyrrolidinyl
3-(2-naphthalenesulohonamido)-3-phenylprop- ionate, (R) isomer.
[0442] A solution of 2 g of the above compound and 657 mg of
N-hydroxysuccinimide in 35 ml of dioxane is prepared and 1.24 g of
DCCI in 10 ml of dioxane are gradually added. After stirring for 5
hours at RT, the DCU is drained and washed with acetone and the
filtrate is then evaporated to dryness. The residue is taken up in
isopropanol. The product which crystallizes is drained, washed with
Et.sub.2O and then dried. 2.18 g of the expected compound are
obtained.
Preparations 3.40 and 3.41
[0443] The process is performed as in the 2 preparations described
above, starting with the compound of Preparation 2.21 in order to
obtain 3-(2-naphthalenesulphonamido)-3-phenylpropionic acid, (S)
isomer and its 2,5-dioxo-1-pyrrolidinyl ester.
Preparation 3.42
[0444] 3-(4-Chlorophenyl)-3-(2-naphthalenesulphonamido)-propionic
acid, (R) isomer.
[0445] A) 3-(4-Chlorophenyl)-3-(phenylacetamido)propionic acid.
[0446] 9.6 g of 3-amino-3-(4-chlorophenyl)propionic acid are
dissolved in 200 ml of dioxane and about 50 ml of 1N NaOH in order
to reach pH=10.5-11.5. The medium is cooled to+50.degree. C. and
6.34 ml of phenylacetyl chloride are then gradually added, while
maintaining the mixture at pH=10.5-11.5 and at a temperature of
between +5.degree. C. and +10.degree. C. Stirring is continued for
1 and a half hours and the medium is then concentrated to one-half
before diluting with 500 ml of water. The resulting mixture is
washed twice with EtOAc and then acidified to pH=1-2 by addition of
6N HCl. The solid is drained, washed with water and dried to give
14 g of the expected compound.
[0447] B) 3-Amino-3-(4-chlorophenyl)propionic acid, (R) isomer.
[0448] This step is carried out according to Syn. Letters, 1993,
-339. 16.8 g of the compound of the above step are suspended in 300
ml of water and 1N NH.sub.4OH is added until a pH=7.5 is obtained.
0.6 ml of Sigma penicillamidase.RTM. is added and the mixture is
left stirring for 72 hours at 400.degree. C. The expected compound
precipitates. It is drained, washed with water and with acetone and
then dried at 400.degree. C. 2.85 g are obtained.
[0449] .alpha..sub.D.sup.25=5.degree. (c=1, 1N HCl)
[0450] C)
3-(4-Chlorophenyl)-3-(2-naphthalenesulphonamido)-propionic acid,
(R) isomer.
[0451] 1 g of the compound obtained in the above step is dissolved
in 15 ml of dioxane and 5 ml of 1N NaOH in order to reach
pH=10.5-11.5. 1.15 g of 2-naphthalene-sulphonyl chloride are
gradually added while keeping the pH constant. After stirring for 2
hours at RT, the medium is diluted by addition of an equal volume
of water and is then washed twice with EtOAc. The medium is
acidified to pH=1.3 by addition of 6N HCl. This mixture is
extracted with EtOAc and the extracts are washed with saturated
NaCl solution (several times). The resulting solution is dried over
Na.sub.2SO.sub.4 and evaporated to dryness, and the expected
product then crystallizes from heptane. 1.31 g are obtained.
[0452] .alpha..sub.D.sup.25=+92.degree. (c=1; MeOH)
Preparation 3.43
[0453] The 2,5-dioxo-1-pyrrolidinyl ester of the above acid is
prepared according to the usual technique.
Preparation 3.44
[0454] 4-Phenyl-3-(2-naphthalenesulphonamido)butanoic acid, (S)
isomer.
[0455] 1.08 g of the compound of Preparation 2.20 are dissolved in
30 ml of dioxane and 10 ml of water. 10N NaOH is added in order to
reach pH=14 and 1.13 g of 2-naphthalenesulphonyl chloride are then
added portion-wise, while maintaining the mixture at pH=10.5-11.5.
Stirring is continued for 2 hours and the mixture is then diluted
with water and washed with EtOAc. It is again diluted with EtOAc
and acidified to pH=2 by addition of 2N HCl and extracted with
EtOAc; the extracts are washed with saturated NaCl solution
(several times) and then dried and evaporated to dryness. On
addition of heptane, the expected product crystallizes. 1.25 g are
obtained.
[0456] .alpha..sub.D.sup.25 =-26.8 (c=1; MeOH)
Preparation 3.45
[0457] The 2,5-dioxo-1-pyrrolidinyl ester of the above acid is
prepared using the usual techniques.
Preparation 3.46
[0458] (2S,4R)
(4-(Benzyloxy)-1-(2-naphthalenesulphonyl)-2-pyrrolidinyl)ac- etic
acid.
[0459] A)
4-(Hydroxy)-1-(2-naphthalenesulphonyl)pyrrolidine-2-carboxylic
acid.
[0460] 2.62 g of (2S,4R)-4-hydroxyproline are dissolved in 15 ml of
water containing 5.9 g of Na.sub.2CO.sub.3 and 5.21 g of
2-naphthalenesulphonyl chloride are added. After vigorous stirring
for 18 hours at RT, the mixture is drained and the filtrate is then
acidified to pH=1. The resulting mixture is again drained, washed
with water and dried in order to obtain 4.1 g of the expected
compound.
[0461] B)
4-(Benzyloxy)-1-(2-naphthalenesulphonyl)2-pyrrolidinylacetic
acid.
[0462] 1 g of the compound of the above step is dissolved in 20 ml
of DyF at 0.degree. C. under nitrogen; 0.204 g of sodium hydride at
80% in oil is added and the mixture is then left stirring for 1
hour at 0.degree. C. and for 30 minutes at RT. The mixture is
cooled to 0.degree. C. and 10 mg of 16-crown-6 crown ether and
0.921 ml of benzyl bromide are then added. The mixture is left
stirring for 1 hour at 0.degree. C. and then for 18 hours at
50.degree. C. and 10 ml of 1N NaOH are added. After stirring for 18
hours at RT, the mixture is diluted with water and then extracted
with ether and acidified to pH 2 by addition of 1N HCl. The
resulting mixture is extracted with EtOAc and the extracts are
dried over Na.sub.2SO.sub.4 and evaporated in order to obtain 0.8 g
of the expected compound.
[0463] C)
(2S,4R)-4-Benzyloxy-2-hydroxymethyl-1-(2-naphthalenesulphonyl)py-
rrolidine.
[0464] 2.8 g of the compound of the above step are dissolved in 20
ml of THF. 1.12 ml of Et.sub.3N and 0.968 ml of ethyl chloroformate
are added over 30 minutes at RT, followed by addition of 0.762 g of
sodium borohydride in 5 ml of water. After stirring for 20 hours at
RT, the mixture is evaporated and the residue is taken up in 20 ml
of water and acidified to pH=3 by addition of 1N HCl. The product
is drained, washed with water, dried and then precipitated from an
EtOAc/hexane mixture in order to obtain 1.9 g of the expected
compound.
[0465] D)
(2S,4R)-4-Benzyloxy-2-mesyloxymethyl-1-(2-naphthalenesulphonyl)p-
yrrolidine.
[0466] 3 g of the compound of the above step are dissolved in 100
ml of DCM at 0.degree. C. and 1.28 ml of Et.sub.3N and then 0.72 ml
of mesyl chloride are added. After stirring for 30 minutes at
0.degree. C., a further 1.28 ml of Et.sub.3N and then 0.72 ml of
mesyl chloride are added, after which the mixture is left stirring
for 30 minutes at RT. It is washed, while cold, with
KHSO.sub.4/K.sub.2SO.sub.4 and the insoluble material is then
filtered off and the filtrate is dried and evaporated. The residue
is taken up in Et.sub.2O and used without further purification in
the following step.
[0467] E) (2S,4R)
4-Benzyloxy-2-cyanomethyl-2-(2-naphthalenesulphonyl)pyrr-
olidine.
[0468] The product of the above step is dissolved in 50 ml of DMSO,
2 g of 10-crown-6 crown ether are added and the mixture is cooled
on an ice bath. 5 g of potassium cyanide are then added and the
mixture is heated for 4 hours at 50.degree. C. The medium is
diluted with 250 ml of EtOAc and is then washed with water, dried
and evaporated. The residue is taken up in ether. The expected
compound crystallizes and 1.7 g are obtained,
[0469] F) Ethyl (2S,4R)
(4-(benzyloxy)-1-(2-naphthalene-sulphonyl)-2-pyrro-
lidinyl)acetate.
[0470] 1.6 g of the compound of the above step are dissolved in 50
ml of HCl-saturated ethanol at 0.degree. C. The mixture is left
stirring for 48 hours at+400 and is then evaporated. The residue is
taken up in EtOH and evaporated (twice) and then taken up in
Et.sub.2O and evaporated (twice). 20 ml of boiling water are added
and a few ml of dioxane/EtOH mixture are then added to homogenize
it. The solution is heated for 15 minutes at 100.degree. C. This
mixture is evaporated and the residue is taken up in dioxane and
then neutralized to pH=6 by addition of 1N NaOH. The solution is
used without further purification in the following step.
[0471] G) (2S,4R) (4-Benzyloxy)-1-(2-naphthalenesulphonyl)-,
2-pyrrolidinyl)acetic acid. 2.4 ml of 5N NaOH are added to the
solution of the above step and the mixture is heated at 50.degree.
C. for 30 minutes. The solvent is evaporated off and the residue is
then acidified to pH=3 by addition of concentrated HCl. The product
is drained, washed with water and dried in order to obtain 1.44 g
of the expected compound.
Preparation 4.1
[0472] A)
N-(2-(4-(3,4-Dihydroimidazol-2-yl)phenyl)-1-((1-pyrrolidinyl)car-
bonyl)ethyl)-3-(3,4-dichlorophenyl)-3-(N-Boc)aminopropionamide.
[0473] 1.09 g of
1-[2-amino-3-(4-(3,4-dihydroimidazol-2-yl)phenylpropionyl-
]pyrrolidine dihydrochloride are dissolved in 15 ml of DMF, 350
.mu.l of Et.sub.3N are added and the mixture is stirred for a few
minutes before adding 835 mg of
3-((N-Boc)amino)-3-(3,4-dichlorophenyl)-propionic acid (obtained in
Preparation 2.6) and 515 mg of DCC.
[0474] After stirring for 3 hours, the mixture is evaporated to
dryness and the residue is then taken up in methanol. The DCU is
drained and the filtrate is concentrated to one-half and diluted
with acetone. This mixture is filtered and then evaporated to
dryness. The residue is chromatographed, eluting with a
chloroform/methanol mixture (from 100/2.5 to 100/20; v/v).
[0475] B)
N-(2-(4-(3,4-Dihydroimidazol-2-yl)phenyl)-1-((1-pyrrolidinylcarb-
onyl)ethyl)-3-(3,4-dichlorophenyl)-3-aminopropionamide.
[0476] The crude product obtained in the above step is placed in 20
ml of a solution of 4N HCl in dioxane and a sufficient amount of
MeOH to allow complete dissolution. After 1 hour at RT, the mixture
is evaporated to dryness and the residue is triturated twice from
ether and then drained, washed with ether and dried under vacuum in
the presence of KOH. 225 mg of the expected compound are
obtained.
Preparation 4.2
[0477]
N-(2-(4-Cyanophenyl)-1-((1-pyrrolidinyl)carbonyl)-ethyl]-3-phenyl-3-
-aminopropionamide trifluoroacetate, (R,R) isomer.
[0478] A)
N-[2-(4-Cyanophenyl)-1-((1-pyrrolidinyl)carbonyl)-ethyl]-3-pheny-
l-3-(N-Boc)aminopropionamide, (R,R) isomer.
[0479] The 2,5-dioxo-1-pyrrolidinyl ester of the acid obtained in
Preparation 2.19, step B is prepared. 800 mg of this compound are
added to a mixture containing 790 mg of the compound of Preparation
1.13 in 15 ml of acetonitrile and 380 .mu.l of DIPEA. The mixture
is left stirring for a few hours and is then left overnight at RT.
The medium is evaporated to dryness and the residue is taken up in
KHSO.sub.4/K.sub.2SO.sub.4 and then extracted with EtOAc. The
organic phase is washed with saturated NaCl solution and then dried
over Na.sub.2SO.sub.4 and evaporated to dryness. 1.1 g of the
expected compound are obtained, this compound crystallizing from
heptane.
[0480] B)
N-[2-(4-Cyanophenyl)-1-((1-pyrrolidinyl)carbonyl)-ethyl]-3-pheny-
l-3-aminopropionamide trifluoroacetate, (R,R) isomer.
[0481] 1 g of the compound of the above step is dissolved in 6 ml
of DCM, 6 ml of TFA are then added and the mixture is left stirring
for 35 minutes at RT. The reaction medium is evaporated to dryness,
the residue is redissolved in isopropanol and then evaporated, the
residue is triturated from Et.sub.2O and the product is drained and
dried in order to obtain 0.88 g of the expected compound.
EXAMPLE 1
[0482] 80
[0483] 210 mg of the compound of Preparation 4.1 are dissolved in
10 ml of dioxane and 5 ml of water, and 1N sodium hydroxide is
added in order to reach pH=9.5. 84 mg of 2-naphthalenesulphonyl
chloride are added 3 times, while maintaining the mixture at
pH=9-9.5 by addition of 0.5N sodium hydroxide. After leaving
overnight at RT, the medium is diluted with water and acidified to
pH=2.5 by addition of 1N HCl. The solid formed is chromatographed
onSephadex.RTM. LH 20, eluting with methanol. The fraction
containing the expected product is concentrated, treated with a
solution of 4N HCl in dioxane and then evaporated to dryness; the
residue is taken up in ether, drained and dried. 41 mg of the
expected compound are obtained.
[0484] MH.sup.+:692:dichloro isotopic profile
[0485] NMR (DMSO+TFA) 1.40-1.70:m:4H; 2.50-3.40 m 8H; 4.00:ds 4H;
4.45-4.70:m:2H; 6.60-8.00:m 14H
EXAMPLE 2
[0486] 81
[0487] 715 mg of the compound of Preparation 1.1, 15 ml of
CH.sub.3CN, 250 .sup.1l of triethylamine, 710 mg of the compound of
Preparation 3.2 and 450 mg of DCC are mixed together and left
stirring for 5 hours at RT. The mixture is evaporated to dryness,
the residue is taken up in acetone, the DCU is drained and the
filtrate is then evaporated to dryness again. The residue is
triturated from ether and the product is then isolated by
decanting, several times. It is dried under vacuum in the presence
of P.sub.20.sub.5 in order to obtain 610 mg of the expected
compound, m.p.=195-200.degree. C.
[0488] NMR (DMSO+TFA)
[0489] 1.40-1.70:m 4H; 2.30-3.40:m 8H; 4.40-4.60 m and 4.60-4.70
m:2H; 6.75-8.15:m:16H
[0490] B)
[0491] 600 mg of the product obtained in the above step are
dissolved in 20 ml of a solution of ethanol saturated with
hydrochloric acid, at 0.degree. C. After leaving overnight in a
refrigerator, the mixture is evaporated to dryness and the residue
is then dried under vacuum in the presence of KOH. The product
obtained is diluted in 25 ml of anhydrous ethanol and 134 .mu.l of
ethylene-diamine in 2 ml of anhydrous EtOH are then added several
times. After leaving overnight at RT, the mixture is evaporated to
dryness and the residue is then chromatographed on silica, eluting
with a chloroform/methanol mixture (85/15; v/v). The fractions
containing the expected compound are combined, evaporated and then
taken up in dilute hydrochloric ether. After draining and drying
under vacuum in the presence of KOH, 180 mg of the expected product
are obtained.
[0492] MH.sup.+: 624
[0493] NMR (DMSO+TFA) 1.40-1.80 m:4H; 2.55-3.45 m:8H; 4.00 s:4H;
4.55:bt:and 4.70 bt 2H; 6.70-8.20 m 16H
EXAMPLE 3
[0494] 82
[0495] 800 mg of the compound obtained in Example 2, step A are
dissolved in 20 ml of a satuurated solution of HCl in anhydrous
EtOH. After leaving overnight in a refrigerator, the mixture is
evaporated to dryness and the residue is then dried under vacuum in
the presence of KOH. The residue is dissolved in 30 ml of anhydrous
EtOH and 175 .mu.l of Et.sub.3N are added, followed by 350 mg of
N-Boc-(4-aminomethyl)benzylamine. After 48 hours at RT, the mixture
is evaporated to dryness and the residue is then chromatographed on
Sephadex.RTM. LH 20, eluting with MeCH. 2 fractions containing two
different compounds are obtained. For one (fraction 1, 570 mg), the
amidine is monosubstituted with a group R.sub.8=-4((N-Boc)amino--
methyl)benzyl and R.sub.6 and R.sub.7=H; for the other (fraction 2,
150 mg), the amidine is disubstituted with
R.sub.6=R.sub.8=-4(N-(Bor)aminomet- hyl)benzyl and R.sub.7=H.
[0496] B)
[0497] 125 mg of the compound of fraction 2 obtained in the above
step are suspended in 1 ml of DCM, 1 ml of TFA is added and the
mixture is left stirring for 40 minutes at RT. After evaporating
the medium to dryness, the residue is dissolved in isopropanol and
is then evaporated to dryness again; the residue is triturated from
Et.sub.2O, drained, washed with Et.sub.2O and then dried. 110 mg of
the expected compound are obtained.
[0498] MH.sup.+836
[0499] NMR (DMSO+TFA)
[0500] 1.40-1.80:m: 4H; 2.40-3.30:m:8H; 3.90-4.80:m: 10H;
6.80-8.45:m:24H
EXAMPLE 4
[0501] 83
[0502] 535 mg of the compound of fraction 1 obtained in Example 3,
step A are suspended in 8 ml of DCM, 8 ml of TFA are added and the
mixture is left stirring for 40 minutes at RT. After evaporating
the medium to dryness, the residue is triturated from ether and
then dried under vacuum in the presence of potassium hydroxide. 520
mg of the expected compound are obtained.
[0503] MH.sup.+:717
[0504] NMR (DMSO+TFA); 1.30-1.70:m:4H; 2.20-3.30 m:8H; 3.90::s:2H;
4.40-4.70:m:4H; 6.30-3.00:m:20H
EXAMPLE 5
[0505] 84
[0506] 960 mg of the compound of Preparation 3.8 in 20 ml of DMF
are mixed with 852 mg of the compound of Preparation 1.2 and 280
.mu.l of Et.sub.3N and the mixture is adjusted to pH=7-7.5 by
addition of Et.sub.3N. After stirring overnight, the mixture is
evaporated to dryness and the residue is then taken up in methanol
and chromatographed on Sephadex.RTM. LH 20, eluting with methanol.
The fractions containing the product are combined, evaporated and
then taken up in 20 ml of butanol, 10 ml of 1N HCl and 10 ml of
water. After stirring and separation of the phases by settling,
the. organic phase is evaporated. The residue is chromatographed on
Sephadex.RTM. LH 20, eluting with methanol, and the fractions
collected are subjected to the same treatment as above. 180 mg of
the expected compound are obtained.
[0507] MH.sup.+:674
[0508] NMR (DMSO+TFA)
[0509] 1.00-1.70:m:4H; 2.30-3.20:m:8H; 4.05:ds 4H; 4.50:mt and 4.80
mt 2H; 7.05-8.10:m:18H
EXAMPLE 6
[0510] 85
[0511] This compound is obtained by working as in Example 5,
starting with the compounds of Preparations 3.9 and 1.2.
[0512] MH.sup.+:658:monochloro isotopic profile
[0513] NMR (DMSO+TFA) 1.40-1.70:m:4H; 2.40-3.30:m:8H; 3.90:ds: 4H;
4.40-4.65:m: 2H; 6.70-8.00:m:15H
EXAMPLE 7
[0514] 86
[0515] 880 mg of the compound of Preparation 1.2 are dissolved in
15 ml of DMF and 300 .mu.l of Et.sub.3N, 1.12 g of the compound of
Preparation 3.10 are added and the mixture is left stirring for 5
hours at RT. After evaporating the medium to dryness, the residue
is taken up in a mixture of 1N HCl and butanol, and the upper
nphase is then separated out after settling has taken place and
evaporated to dryness. The residue is chromatographed on
Sephadex.RTM. LH 20, eluting with MeOH. The product thus obtained
is taken up in a solution of 1N HCl in butanol and then evaporated
to dryness and the residue is triturated from ether, drained,
washed with ether and dried in order to obtain 330 mg of the
expected product.
[0516] MH.sup.+:730
[0517] NMR (DMSO+TFA); 1.45-2.25 m:4H; 2.30-3.30:m:8H; 3.85:s and
3.95::s:4H; 4.50-4.70:m:4H; 6.35-8.00:m:20H.
EXAMPLE 8
[0518] 87
[0519] The debenzylation reaction is carried out according to J.
Chem. Educ., 1987, 64, 1062.
[0520] 425 mg of the compound of Example 7 in 20 ml of methanol are
mixed with 120 mg of ammonium formate in the presence of 500 mg of
10% Pd/C containing 50% water. After refluxing for 24 hours, the
palladium is filtered off and washed with methanol and the filtrate
is evaporated -to dryness; the residue is dissolved in methanol and
then chromatographed on Sephadex.RTM. LH 20, eluting with methanol.
The product obtained is taken up in a mixture of a solution of 2N
HCl in water and butanol; after stirring, the aqueous fraction is
extracted with butanol and the combined organic fractions are
evaporated to dryrness. The residue is taken up in ether and the
product is filtered off, washed with ether and dried. 171 mg of the
expected product are obtained.
[0521] MH.sup.+:640
[0522] NMR (DMSO+TFA)
[0523] 1.50-1.85:m:4H; 2.40-3.30:m:8H; 4.05 ds :4H; 4.50-4.70:m:2H;
6.40-8.20 m:15H
[0524] The compounds described in Table 8 are prepared as in
Examples 7 and 8 above.
9TABLE 8 88 Example R.sub.2 89 MH.sup.+NMR (DMSO + TFA) 9 90 91
MH.sup.+:730 1.45-1.75:m:4H; 2.40-3.40:m:8H; 3.95:s: and 4.00:s:4H;
4.50-4.70:m:4H; 6.40-8.10:m:20H 10 92 93 MH.sup.+:640
1.45-1.80:m:4H 2.25-3.30:m:8H 3.95:s:4H 4.45-4.70:m:2H
6.30-8.20:m:15H 11 94 95 MH.sup.+:683 1.45-1.80:m:4H 1.95-2.10:m:2H
2.75:ds:6H 2.50-3.60:m:12H 4.55:m.t.: and 4.70:mt: 2H
6.80-8.10:m:16H
EXAMPLE 12
[0525] 96
[0526] 900 mg of the compound of Preparation 1.2 in 10 ml of DMF
and 550 .mu.l of Et.sub.3N are mixed with 1.04 g of the compound of
Preparation 3.1 and 1.3 g of BOP and a sufficient amount of
Et.sub.3N to reach pH=6-7 are added. After stirring for 5 hours,
while maintaining the medium at pH=6-7 by addition of Et.sub.3N,
the medium is diluted with ether and is then triturated and the
phases are allowed to separate by settling (twice). The oil is
chromatographed on Sephadex.RTM. LH 20, eluting with methanol, and
the product obtained is then chromatographed again on silica,
eluting with a chloroform/methanol mixture (90/10; v/v). The
product obtained is washed with EtOAc in water, with EtOAc and
dried. 313 mg of the expected product are obtained.
[0527] M.sup.+:676:trichloro isotopic profile
[0528] NMR (DMSO+TFA)
[0529] 1.50-1.85:m:4H; 2.70-3.20:m:8H; 3.95 bs 4H; 4.50-4.75:m:2H;
6.90-8.00:m :1H
[0530] Working as in Example 12, the compounds described in the
table below are prepared.
10TABLE 9 97 Exam ples R.sub.2 R.sub.3 98 MH.sup.+NMR (DMSO + TFA)
13 99 H 100 MH.sup.+:640 1.60-1.80:m:4H 2.60-3.50:m:8H 3.80:s:and
4.00:s:4H 4.60-4.90:m:2H 6.90-8.70:m:15H 14 101 OH 102 MH.sup.+:640
1.40-1.70:m:4H 2.50-3.20:m:8H 3.85:ds:4H 4.00:d.d.:1H
4.30-4.70:m:2H 6.55-8.10:m:16H
EXAMPLE 15
[0531] 103
[0532] This compound is prepared from the compound prepared in
Example 2, step A, and working as in Example 2, step B. using
2-methylpropane-1,2-diamine.
[0533] MH.sup.+: 652
[0534] NMR (DMSO+TFA)
[0535] 1.30 s:6H; 1.30-1.70:m: 4H; 2.25-3.20:m:8H;, 3.65 :s:2H;
4.40-4.70 m:2H; 6.70-8.05: m:16H
EXAMPLE 16
[0536] 104
[0537] 0.812 g of the compound of Preparation 3.13 and 0.810 g of
the compound of Preparation 1.2 are dissolved in 10 ml of IDYF and
1.22 g of BOP are added, and the mixture is then brought to pH=7 by
addition of Et.sub.3N. After stirring for 18 hours at RT, the
medium is evaporated to dryness. The residue is taken up in EtOAc
and saturated NaHCO.sub.3 solution, then the aqueous phase is
washed with EtOAc and the organic phases are washed with the
KHSO.sub.4/K.sub.2SO.sub.4 buffer and with saturated NaCl solution.
The resulting solution is dried over Na.sub.2SO.sub.4 and
evaporated. The residue is chromatographed on silica, eluting with
a CHCl.sub.3/MeOH/concentrated ammonia mixture (10/0.5/0.1; v/v/v).
0.390 g of the expected compound are obtained.
[0538] MH.sup.+: 625
[0539] NMR (DMSO) 1.5-1.8:mt:4H; 2.5-3.7:m: 8H; 4:s: 4H;
4.4-4.6:mt:1H; 4.7-4.9:mt:1H; 6.8-7:mt:3H; 7-7.1:mt:2H; 7.4:d:2H;
7.7-8.1:m:5H; 8.3-8.4:m:2H; 8.7:d: 1H; 10.7 s:1H.
EXAMPLE 17
[0540] 105
[0541] This compound is prepared according to the procedure of the
above example, starting with the compound of Preparation 3.14 and
that of Preparation 1.2.
[0542] MH.sup.+:625
[0543] NMR (DMSO):1.4-1.7:mt:4H; 2.4-3.3:m: 4H; 4 mt:4H; 4.5-4.7
mt:2H; 6.7-6.9:mt:2H; 7.2-8.4:m:16H; 9:mt:1H; 10.7:s: 1H.
EXAMPLE 18
[0544] 106
[0545] 740 mg of the compound of Preparation 1.2 are placed in 10
ml of DMF and:240 .mu.l of DIPEA are added, .followed by 740 mg of
the compound of Preparation 3.24. After stirring overnight at RT,
ether is added, the mixture is decanted and washed again with ether
and is then triturated and decanted. The organic phase is
chromatographed on Sephadex.RTM. LH 20, eluting with MeOH. The
fractions of interest are taken up in a mixture containing 5 ml of
butanol, 5 ml of 1N HCl and:5 ml of EtOAc. The organic phase is
washed with 5 ml of 1N HCl and evaporated to dryness. The residue
is dissolved in methanol and precipitated with ether. 470 mg of the
expected compound are obtained.
[0546] MH.sup.+:682
[0547] NMR (DMSO):1.00:d: 6H; 1.45-1.80:m: 4H; 2.30-3.20:m:8H;
3.95:ds:4H; 4.05-4.20:m:1H; 4.50-4.70:m:2H; 6.30-8.40:m:17H (1SH
aromatic+2H amides); 10.70:bs:1H.
[0548] Working according to the procedure described above, the
compounds according to the invention in the table below are
prepared from the compounds of Preparations 3.25 to 3.32.
11TABLE 10 107 Example R.sub.2 NMR MH.sup.+ 19 108 (DMSO + TFA)
1.50-1.80:m:4H; 2.25-3.25:m:8H;3.40:s:3H; 4.00:ds:4H;
4.45-4.75:m:2H; 6.35-6.90:mt:4H; 7,30-8.15:m: 11H 654 20 109 (DMSO
+ TFA) 1.50-1.80:m:4H; 2.30-3.25:m:8H; 3.40:s:3H; 4.00:ds:4H;
4.60:tq:1H; 6.40: d:2H; 6.90:d:2H; 7.25 8.05:m: 11H 654 21 110
(DMSO + TFA) 1.50-1.80:m:4H; 2.35-3.40:m:8H; 4.00:ds:4H;
4.50-4.70:m:2H; 6.75-7.00: 4H; 7.25-8.10:m:11H 658-660 22 111 (DMSO
+ TFA) 1.40-1.80:m:4H; 2.40-3.40:m:8H; 3.95:ds:4H; 4.50-4.65:mt:1H;
4.75:dq:1H; 6.90-8.00:m:15H 692 23 112 (DMSO + TFA) 1.20-1.60:m:4H;
2.40-3.20:m:8H; 3.95:bs:4H; 4.25-4.50:mt:1H; 5.45:t:1H;
7,00-7.90:m:18H 674 24 113 (DMSO + TFA) 1.50-1.75:m:4H;
2.60-3.40:m:8H; 4.00:bs:4H; 4.50-4.75:m:2H; 6.55-8.10:m: 15H 642 25
114 (DMSO + TFA) 0.60-1.70:m:15H; 1.80-2.20:m:2H; 2.60-3.40: m:7H;
3.90:s:4H; 4.30-4.60:m: 1H; 7.25-8.25:m:11H 630 26 115 (DMSO + TFA)
1.50-1.50:m:4H; 1.90:s:3H; 2.20-3.30:m:8H; 4.05:ds:4H;
4.55-4.75:m:2H; 6.60-8.10:m:15H 638
[0549] 116
EXAMPLE 27
[0550] A)
N-(2-(4-Cyanophenyl)-1-(1-pyrrolidinylcarbonyl)-ethyl)-3-(4-biph-
enylyl)-3-(N-Boc)aminopropionamide.
[0551] 1.19 g of the compound of Preparation 1.1 are placed in 30
ml of acetonitrile and:0.46 ml of Et.sub.3N and 1.46 g of the
compound of Preparation 2.17 are added. The mixture is left
overnight at RT and is then evaporated to dryness and the residue
is taken up in KHSO.sub.4/K.sub.2SO.sub.4 and extracted with EtOAc.
The extracts are washed with saturated NaCl solution, dried over
Na.sub.2SO.sub.4 and then evaporated to dryness. The expected
compound crystallizes from heptane and is filtered off, washed with
heptane and then dried in order to obtain 1.86 g.
[0552] B)
N-(2-(4-Cyanophenyl)-1-(1-pyrrolidinylcarbonyl)-ethyl)-3-(4-biph-
enylyl)-3-aminopropionamide trifluoro-acetate.
[0553] A mixture containing 1.82 g of the compound of the above
step in 15 ml of DCM and:15 ml of TFA is left stirring at RT for 35
minutes. The mixture is evaporated to dryness and the residue is
dissolved in isopropanol and evaporated to dryness again. The
expected product crystallizes from Et.sub.2O and is filtered off,
washed with Et.sub.2O and then dried to give 1.37 g. 117
[0554] 1.34 g of the compound of the above step are placed in 25 ml
of DCM and:850 .mu.l of DIPEA and:522 mg of 2-naphthalenesulphonyl
chloride in 5 ml of DCM are gradually added. After stirring for 2
hours at RT, the mixture is diluted with 60 ml of DCM and is then
washed with KHSO.sub.4/K.sub.2SO.sub.4 and with saturated NaCl
solution. The resulting solution is dried over Na.sub.2SO.sub.4 and
evaporated to dryness, and the residue is then chromatographed on
fine silica, eluting with chloroform containing 1% MeOH. 0.802 g of
the expected compound is obtained.
[0555] NMR (DMSO+TFA) 1.45-1.85:m:4H; 2.40-3.35: m:8H;
4.50-4.90:mt:2H; 7.05-8.20:m:20H.
[0556] D)
[0557] 0.778 g of the compound of the above step is placed in 50 ml
of anhydrous EtOH saturated with HCl, at 0.degree. C.; the mixture
is left stirring in a refrigerator until dissolved and is then left
in the refrigerator for 48 hours. It is evaporated to dryness and
dried in a desiccator under vacuum in the presence of potassium
hydroxide for 2 hours. This residue is dissolved in 80 ml of
anhydrous EtOH and:206 Al of DIPEA and:93 .mu.l of ethylenediamine
are added. After 24 hours at RT, the mixture is evaporated to
dryness and the residue is then chromatographed on Sephadex.RTM. LH
20, eluting with methanol. The fractions containing the product are
taken up in a mixture of 6 ml of butanol and:6 ml of 1N HCl. After
stirring and separation of the phases by settling, the organic
phase is washed with 3 ml of 1N HCl and evaporated under vacuum.
The residue is taken up in Et.sub.2O and the solid formed is
filtered off, washed with Et.sub.2O and dried to give 0.495 g of
the expected compound.
[0558] MH.sup.+: 700
[0559] NMR:1.40-1.80:m:4H; 2.40-3.30 m:8H; 3.80:s: 2H; 3.95:s:2H;
4.50-4.80:mt:2H; 7.00-8.05:m:20H.
EXAMPLE 28
[0560] 118
[0561] 0.790 g of the compound obtained in Example 2, step A is
dissolved in 10 ml of BtOH saturated with HCl, at 0.degree. C., and
the mixture is left stirring for 48 hours at 0.degree. C. It is
evaporated to dryness and the residue is then taken up in EtOH and
evaporated (twice). The residue is taken up in DCM and evaporated
(twice). The resulting residue is taken up in 20 ml of EtOH and
then neutralized by addition of Et.sub.3N. 0.109 ml of
diaminopropane is added and the mixture is left for 24 hours at RT.
It is evaporated to dryness and the residue is taken up in DCM and
washed with KHSO.sub.4/K.sub.2SO.sub.4. Chromatography on silica is
then carried out, eluting with a chloroform/methanol/concentrat- ed
ammonia mixture (10/1/1; v/v/v). 0.12 g of the expected compound is
obtained.
[0562] MH.sup.+: 638
EXAMPLE 29
[0563] 119
[0564] 0.888 g of the compound of Preparation 3.2 and 0.957 g of
the compound of Preparation 1.4 are dissolved in 5 ml of DMF; 1.22
g of BOP are added and the medium is then adjusted to pH=7 by
addition of Et.sub.3N. After stirring for 18 hours at RT, the
mixture is evaporated to dryness and the residue is then taken up
in EtOAc. The solution is washed with NaHCO.sub.3 solution, with
KHSO.sub.4/K.sub.2SO.sub.4 and with saturated NaCl solution and is
then dried over Na.sub.2SO.sub.4 and evaporated. The residue is
taken up in ether and a few drops of hexane and is hen filtered and
dried over Na.sub.2SO.sub.4 in order to obtain 1.1 g of the
expected compound.
[0565] B)
[0566] 1 g of the compound of the above step is dissolved in 20 ml
of EtOH saturated with HCl, at 0.degree. C. After 48 hours
at+4.degree. C., the solution is evaporated and the residue is
taken up in EtOH (3 times) and is then evaporated and taken up in
DCM (twice) The residue is taken up in 20 ml of EtCH, the pH is
then adjusted to 7 by addition of Et.sub.3N and:0.122 ml of
ethylenediamine is added. After stirring for 18 hours at RT, the
mixture is evaporated to dryness and is then taken up in DCM and
washed with 10 ml of KHSO.sub.4/K.sub.2SO.sub.4. This solution is
chromatographed on silica, eluting with a chloroform/
methanol/aqueous ammonia mixture (10/1/0.1; v/v/v) in order to
obtain 0.640 g of the expected compound.
[0567] MH.sup.+: 650
[0568] NMR (DMSO+TFA):0.8-1.2 m:4H; 2.3-3.1: m:4H; 4 :s:4H;
4.3-4.7:m:4H; 5.4-5.7:mt: 2H; 6.8-7.9:m:15H; 8.2:d:1H.
[0569] Working as in Example 12, the compounds described in Table
11 below are prepared.
12TABLE 11 120 Example R.sub.1 R.sub.2 MH.sup.+ 30 121 122 642-644
31 123 124 628
[0570] Working according to the procedure of Example 2, steps A and
B, the compounds according to the invention in the table below are
prepared.
13TABLE 12 125 Example --NR.sub.4R.sub.5 m.p. .degree. C./NMR (DMSO
+ TFA) MH.sup.+ 32 126 170.degree. C. 2.40-3.45:m:12H; 4.00:se:4H;
4.60-4.90:m:2H; 6.80-8.15:m:16H 640 33 127 0.6-0.9:mt:6H;
2.2-3:m:7H; 3.9:s:4H; 4.3-4.9:m:3H; 6.7-7.8:m:15H; 8.:d:1H 626 34
128 0.6-1.6:m:8H; 1.6-1.9:mt:2H; 2.4-3.1:m:4H; 3.2-4:m:6H;
4.2-4.8:m:2H; 6.8-7.9:m:15H; 8:s:1H 652
EXAMPLE 35
[0571] 129
[0572] 580 mg of the compound obtained in Example 2, step A are
mixed with 250 mg of paraformaldehyde and 60 mg of
para-toluenesulphonic acid monohydrate in 25 ml of benzene. The
mixture is refluxed in Dean-Stark apparatus for 1 hour. The
reaction medium is then washed with saturated NaHCO.sub.3 solution
and with saturated NaCl solution and then dried over
Na.sub.2SO.sub.4 and evaporated to dryness. The residue is
chromatographed on fine silica, eluting with chloroform, in order
to obtain 165 mg of the expected compound.
[0573] NMR (DMSO+TFA) 1.55-1.85:m:4H; 2.40-3.40:m:8H;
4.60-5.50:m:4H; 6.90-8.30 m:16H.
[0574] B)
[0575] The process is performed as in Example 2, step B in order to
obtain the expected compound, which is purified bv chromatography
on Sephadex.RTM. LH 20, eluting with MeOH.
[0576] MH.sup.+: 636
[0577] NMR (DMSO+TFA) 1.50-1.80 m:4H; 2.40-3.30:m:8H; 3.95:s: 4H;
4.90-5.45:m: 4H; 6.90-8.10:m:16H.
EXAMPLE 36
[0578] 130
[0579] 1.05 g of the compound of Example 2, step A are mixed with
0.262 g of potassium carbonate in 12 ml of DMF and:423 .mu.l of
methyl iodide are added. The following day, the mixture is
evaporated to dryness and the residue is taken up in water and
EtOAc. The organic phase is washed with water and with saturated
NaCl solution and is then dried over Na.sub.2SO.sub.4. 0.6 g of the
expected compound is obtained.
[0580] MH.sup.+: 595
[0581] NMR (DMSO+TFA) 1.50-1.80:m: 4H; 2.20-3.30:m: 8H; 2.55:bs 3H;
4.35-4.65 mt:1H; 5.45-5.60:mt:1H; 7.10-8.45:m:16H.
[0582] B)
[0583] The process is performed as in Example 2, step B, in order
to obtain the expected compound, which is purified by
chromatography on silica, eluting with DCM/MeOH (93/7; v/v) and
then by a second chromatography on Sephadex.RTM. LH 20, eluting
with methanol, m.p.=154.degree. C.
[0584] MH.sup.+: 638
[0585] NMR=(DMSO+TFA) 1.20-1.80:m:4H; 2.10-2.40: mt:2H; 2.50:bs:3H;
2.40-3.20:m: 6H; 4.00:s: 4H; 4.40-4.70:mt:1H; 5.35-5.55:mt: 1H;
7.05-8.40 m:16H.
EXAMPLE 37
[0586] 131
[0587] A mixture containing 0.79 g of the compound of Preparation
3.35, 0.79 g of the compound of Preparation 1.1 and:1.06 g of BOP
in 10 ml of DMF is prepared, DIPEA is added in order to obtain pH=7
and the mixture is left stirring for 2 hours at RT. The mixture is
extracted with EtOAc and the extracts are washed with H.sub.2O,
with 0.25N NaOH solution, with 0.25N HCl solution, with water and
then with saturated NaCl solution. The resulting solution is dried
over Na.sub.2SO.sub.4 and then evaporated and the residue is
chromatographed on silica, eluting with a chloroform/MeOH mixture
(95/5; v/v).
[0588] B)
[0589] The expected product is obtained by working as in Example 2,
step B. It is purified by chromatography on Sephadex.RTM. LH 20,
eluting with DCM/MeOH (3/2; v/v)
[0590] MH.sup.+:636
[0591] NMR (DMSO+TFA) 1.40-1.80:m:4H; 2.60-3.60:mt:9H; 3.95:S 4H;
4.60-5.20:m:2H; 6.20-8.50:m:15H.
EXAMPLE 38
[0592] 132
[0593] 533 g of the compound of Preparation 3.37 are placed in 10
ml of IDMF and:205 .mu.l of DIPEA, 573 mg of the compound of
Preparation 1.2 are added and the mixture is then left overnight at
RT. This mxture is diluted with 100 ml of Et.sub.2O and the gum
formed is then chromatographed on Sephadex.RTM. LH 20, eluting with
MeOH. The fractions of interest are combined and filtered and the
residue is taken up in 6 ml of butanol and:6 ml of HCl. The organic
phase is separated out after settling of the phases has taken place
and is then washed with 3 ml of 1N HCl and evaporated to dryness.
The product crystallizes from Et.sub.2O and is filtered off and
dried to give 430 mg of the expected compound.
[0594] MH.sup.+:650
[0595] NMR (D)MSO+TFA) 1.50-1.90:m:4H; 2.50-3.80:m:12H; 4.00:ds:4H;
4.45-4.80 m :1H; 5.40:dq: 1H; 6.75-8.35:m:15H.
EXAMPLE 39
[0596] 133
[0597] A reaction medium containing 710 mg of the compound of
Preparation 3.2, 750 mg of the compound of Preparation 1.8 and:0.98
g of BOP in 12 ml of DMF is stirred and DIPEA is added to bring the
mixture to pH 6. After stirring for 2 hours at RT, the mixture is
extracted with EtOAc. The crude product obtained is chromatographed
on silica, eluting with EtOAc/toluene (3/2; v/v). 0.52 g of the
expected compound is obtained in the form of a white solid.
[0598] B)
[0599] The expected compound is obtained by working as in Example
2, step B. It is purified on Sephadex.RTM. LH 20, eluting with
DCM/MeOH (3/2; v/v).
[0600] MH.sup.+: 638
[0601] NMR (DMSO+TFA) 1.40-1.75:m:4H; 2.30-3.20:m:1H; 4.00:s: 4H;
4.60-5.40:mt:2H; 6.80-7.15:m:16H.
EXAMPLE 40
[0602] 134
[0603] A)
[0604] 0.42 g of the compound of Example 2, step A is treated with
10 ml of saturated hydrochloric ethanol at -10.degree. C. After 72
hours at +4.degree. C., the mixture is evaporated to dryness and is
then dried under vacuum in the presence of potassium hydroxide.
0.51 g of unpurified product is obtained in the form of the
hydrochloride.
[0605] B)
[0606] 0.5 g of the ethyl imidate obtained in the above step is
cooled to 0.degree. C. and:10 ml of saturated ammoniacal ethanol
are added, at 0.degree. C. The mixture is allowed to return to RT.
The following day, the mixture is evaporated to dryness and the
residue is then chromatographed on silica, eluting with a DCM/MeOH
mixture (90/10; v/v), then another chromatography on Sephadex.RTM.
LH 20 is carried out, eluting with MeOH. 0.15 g of the expected
compound is obtained, m.p.=
[0607] MH.sup.+:598
[0608] NNR (DMSO) 1.40-1.70 m:4H; 2.25-3.10:m: 8H; 4.40-4.70:m:2H;
6.80-8.30:m:18H.
EXAMPLE 41
[0609] 135
[0610] A) 4-Aminobutyronitrile.
[0611] This compound is prepared according to J. Am. Soc., 1952,
74, 1836). 6.7 ml of 4-bromobutyronitrile and:35 ml of liquid
ammonia are placed in a bomb at -50.degree. C. After closing, the
bomb is left at RT for 48 hours. The residue is taken up in 50%
NaOH solution and is then extracted with ether; the organic phase
is dried over Na.sub.2SO.sub.4, evaporated to dryness and then
chromatographed on silica, eluting with DCM/MeOH/NMH.sub.4OH
(90/10/0.3; v/v/v). 1.07 g of the expected compound are
obtained.
[0612] B)
[0613] 0.62 g of the compound of Example 2, step A is treated with
10 ml of saturated hydrochloric ethanol at -10.degree. C. After 24
hours at +40.degree. C., the mixture is evaporated to dryness and
the residue is then dried under vacuum. 0.8 g of unpurified product
is obtained in the form of the hydrochloride.
[0614] C) 136
[0615] 0.8 g of the compound prepared in the above step is
dissolved in 10 ml of EtOH and:108 mg of 4-aminobutyronitrile
diluted in 10 ml of EtOH are added dropwise. The following day, the
mixture is evaporated to dryness and the residue is taken up in
LeOH and a few drops of hydrochloric ether are then added. After
evaporating to dryness, the residue is chromatographed on silica,
eluting with DCM/MeOH (90/10; v/v) in order to obtain 0.38 g of the
expected compound, m.z.=144.degree. C.
[0616] MH.sup.+:665
[0617] D)
[0618] 10 ml of saturated hydrochloric ethanol at -10.degree. C.
are added to 0.35 g of the compound obtained in the above step, at
0.degree. C. The mixture is left in a refrigerator overnight. The
following day, the mixture is evaporated to dryness and the residue
is dried under vacuum in the presence of KOH. The product obtained
(0.35 g) is dissolved in 80 ml of ethanol; 43 .mu.l of
ethylenediamine in 10 ml of ethanol are added dropwise. After
stirring overnight, the mixture is evaporated to dryness and the
residue is then chromatographed on silica, eluting with a DCM/MeOH
mixture (50/50; v/v), 0.075 g of the expected compound is obtained,
m.p.=195.degree. C.
[0619] MH.sup.+:708
[0620] NMR (DMSO+TFA):1.35-1.50:m:4H; 1.80-2.00:mt:2H;
2.40-3.20:m:10H; 3.40:mt:2H; 3.70:s:4H; 4.40-4.70:mt:2H;
6.70-8.05:m: 16H.
EXAMPLE 42
[0621] 137
[0622] This compound is prepared according to the process described
in Example 12, starting with the compounds of Preparations 1.9
and:3.2.
[0623] MH.sup.+: 626
EXAMPLE 43
[0624] 138
[0625] (R,R) isomer. 139
[0626] (R,R) isomer.
[0627] 1.44 g of the compound of Preparation 1.13 in 40 ml of
acetonitrile are mixed with 700 .mu.l of DIPEA and:1.81 g of the
compound of Preparation 3.39. The precipitate formed is dissolved
in DCM and is then washed with KHSO.sub.4/K.sub.2SO.sub.4, with
saturated NaHCO.sub.3 solution and with saturated NaCl solution.
The resulting solution is dried and evaporated to dryness, and the
product obtained (1.57 g) is used without further purification in
the following step.
[0628] NMR (DMSO):1.40-1.60:m:4H; 2.20-3.10:m:8H; 4.40:dq:1H;
4.60:dq:1H; 6.80-8.35:m 18H.
[0629] B)
[0630] 1 g of the product of the above step is suspended in 30 ml
of HCl-saturated anhydrous ethanol at 0.degree. C. and the mixture
is left stirring for 24 hours in a refrigerator. The mixture is
evaporated to dryness and dried in a desiccator in the presence of
potassium hydroxide. The product is placed in 100 ml of anhydrous
ethanol and:273 .mu.l of DIPEA and:136 .mu.l of ethylene-diamine
are added. After stirring for 24 hours at RT, he mixture is
evaporated to dryness and the residue is taken up in a
butanol/chloroform/lN HCl mixture (1/1/1; v/v/v). The phases are
separated out after settling has taken place and the organic phase
is then washed with lN HCl and evaporated to dryness. The residue
is chromatographed on Sephadex.RTM. LH 20, eluting with MeOH. The
product obtained is treated with a butanol/chloro-form/1N HCl
mixture (1/1/1; v/v/v) and then concentrated. After crystallization
from Et.sub.2O, the crystals are filtered off, washed with
Et.sub.2O and then dried. 198 mg of the expected compound are
obtained.
[0631] .alpha..sub.D.sup.25 =+38.1.degree. (c=1, DMF)
[0632] MH.sup.+:624
[0633] NMR (DMSO); 1.50-1.75 m:4H; 2.40-2.70: mt:2H; 2.75-3.25
m:6H; 4.05:s:4H; 4.55:dq: 1H; 4.775:dq:1H; 6.95-8.20:m:16H; 8.50:t
2H; 10.80:bs:2H.
[0634] Using the procedure described in Example 43 and in the
corresponding preparations, the various isomers described in the
table below are prepared.
14TABLE 13 140 .alpha..sub.D.sup.25 = (c = 1, DMF) Example Isomer
m.p. .degree. C. MH.sup.+ 44 (S,S) -41.9.degree. 624 45 (R.S)
+42.2.degree. 624 46 (S,R) m.p. = 195-201.degree. C. 624
[0635] NMR (DMSO) of Example 44:1.50-1.75:m:4H; 2.40-2.70 mt:2H;
2.75-3.25:m:6H; 4.05 :s:4H; 4.55 dq 1H; 4.75:dq:1H;
6.95-8.20:m:16H; 8.50:t:2H; 10.80:bs:2H.
[0636] NMR (DMSO) of Example 45:1.65-1.90:m:4H; 2.40-3.45:m:8H;
4.05::s:4H; 4.55-4.85:mt:2H; 6.95-8.25:m: 16H; 8.45 t 2H; 10.80 bs
2H.
[0637] NMR (DMSO+TFA) of Example 46 :1.50-1.80:m:4H;
2.25-2.95:m:4H; 3.00-3.40:m:4H; 4.00:s: 4H; 4.30-4.75:mt:2H;
6.80-8.15:m :16H.
EXAMPLE 47
[0638] 141
[0639] (R,R) isomer. 142
[0640] (R,R) isomer.
[0641] These 2 compounds are prepared in 2 successive steps
according to the procedure described in Example 27, steps C and D,
from the compound obtained in Preparation 4.2 and
(2,4,6-trichlorophenyl)sulphonyl chloride.
[0642] .alpha..sub.D.sup.25=-24.degree. (c=0.5; MeOH)
[0643] MH.sup.+: 676 with trichloroisotopic profile NMR
(DMSO):1.50-1.65 m:4H; 2.45-3.20: m:8H; 3.95 s:4H; 4.40-4.70:mt:2H;
7.05:s 5H; 7.45:d:2H; 7.50:s:,2H; 7.90 d:2H; 8.45: d:1H; 8.80:d:1H;
10.70:bs:1H.
[0644] II:NMR (DMSO) 1.50-1.60:m:4H; 2.45-3.15: m: 8H; 4.40-4.55
dq:1H; 4.60-4.75 dq:1H; 7.05:s 5H; 7.40 d:2H; 7.50:s:2H; 7.70:d 2H;
8.40 d:1H; 8.70:d:1H.
EXAMPLE 48
[0645] 143
[0646] (R,R) isomer 144
[0647] (R,R) isomer
[0648] This compound is prepared in 2 steps according to the
procedure described in Example 43, starting with the compounds of
Preparations 3.43 and:1.13.
[0649] I: .alpha..sub.D.sup.25=+57.degree. (c=1; DMF)
[0650] MH.sup.+:658 and:660
[0651] NMR (DMSO+TFA) 1.40-1.60:m:4H; 2.25-3.10:m:8H; 3.95 :s:4H;
4.45-4.65:mt:2H; 6.80-8.05 m:15H.
[0652] II:.alpha..sub.D.sup.25=+61.degree. (c=1; DMF)
[0653] NMR (DMSO) 1.40-1.60 m:4H; 2.25-3.10: m:8H; 4.35-4.50:mt:2H;
6.85-8.05:m:15H; 8.25:t:2H.
EXAMPLE 49
[0654] 145
[0655] (S),(R,S) isomer.
[0656] 800 mg of the compound of Preparation 1.2 in 20 ml of DMF
are mixed with 250 .mu.l of DIPEA and:933 mg of the compound of
Preparation 3.45. After stirring overnight at RT, the mixture is
diluted with ether and the product is then isolated by decanting.
The gum formed is triturated frorm ether and is then
chromatographed on Sephadex.RTM. LH 20, eluting with MeOH. The
fractions of interest are evaporated and the residue is taken up in
a butanol/EtOAc/1N HCl mixture (1/1/1; v/v/v). The organic phase is
separated out after settling has taken place and evaporated to
dryness, the residue is taken up in Et.sub.2O and the product is
filtered off and dried to give 770 mg of the expected compound.
[0657] MH.sup.+:638
[0658] NMR (DMSO+TFA): 1.55-1.85:m: 4H; 2.05-3.50:m :1H; 3.75:s:2H;
4.00:s: 2H; 4.45-4.95:mt: 1H; 6.70-8.20:m:16H.
EXAMPLE 50
[0659] 146
[0660] This compound is prepared from the compound of Preparation
3.46 and from the compound of Preparation 1.2 according to the
procedure of Example 5.
[0661] NMR (DMSO+TFA):1.5-1.8:mt:6H; 2.7-3.6: m:6H; 3.6:mt:3H;
3.6-3.9:mt:8H; 4.6-4.8: mt:2H; 6.5 d:2H; 6.8-7:m:4H; 7.4-8.1:m: 8H;
8.4:d:2H.
EXAMPLE 51
[0662] 147
[0663] 0.4 g of the compound obtained in the above example is
dissolved in 8 ml of TFA and:0.2 ml of thioanisole. After stirring
for 24 hours at RT, the mixture is evaporated, the residue is then
taken up in Et.sub.2O and the product is filtered off. It is washed
several times with ether and then dried over Na.sub.2SO.sub.4 in
order to obtain 0.385 g of the expected compound.
[0664] MH.sup.+:700
[0665] NMR (DMSO+TFA) 1.7-2.1 mt:6H; 2.5:d: 2H; 2.9-3.7:m:13H;
3.7-4:m:13H; 4.8:mt:1H; 5.3:mt:1H; 7.2-8.3:m :1H; 8.5:s:1H.
EXAMPLE 52
[0666] 148
[0667] The compound obtained in the above example is dissolved in
50 ml of MeOH containing 0.106 g of KOH. After stirring for 18
hours at RT, the medium is acidified to pH=2 by addition of a
saturated solution of HCl gas in dioxane. This mixture is
evaporated and the residue is taken up in 5 ml of water and
triturated. The product is filtered off, washed with water and then
dried in order to obtain 0.160 g of the expected compound.
[0668] MH.sup.+=604
EXAMPLE 53
[0669] 149
[0670] (R,R) isomer
[0671] This compound is prepared according to the procedure
described in Example 43, but using the 1-naphthalenesulphonyl
chloride in Preparation 3.38.
[0672] .alpha..sub.D.sup.25=18.degree. (c=1; DMF)
[0673] MH.sup.+:624
[0674] NMR (DMSO) 1.50-1.75:m:4H; 2.25-3.20: m:8H; 4.05:4H;
4.50-4.75:mt:2H; 6.85-8.70: m:18H (16H aromatic+2H).
EXAMPLE 54
[0675] 150
[0676] This product is prepared in 2 steps according to the
procedure described for Example 2, using the compounds obtained
from Preparations 3.2 and:1.14.
[0677] MH.sup.+:638
[0678] NMR (DMSO+TFA):0.95:ds: 3H; 1.30-1.60: m:4H; 2.40-3.40 m:8H;
4.00 ds:4H; 4.75:mt: 1H; 6.65-8.15:m:16H.
EXAMPLE 55
[0679] 151
[0680] (R,R) isomer
[0681] 1.30 g of the product obtained according to the procedure of
Example 43, step A are stirred for 18 hours at 4.degree. C. in 45
ml of methanol containing 22 g of HCl gas. The reaction medium is
concentrated under vacuum, re-evaporated twice with MeOH and the
residue is dried under vacuum in the presence of KOH. This product
is dissolved in 250 ml of methanol and:0.18 ml of ethylenediamine
diluted in 15 ml of methanol are added over 90 minutes, after which
the mixture is stirred for a further 18 hours. The reaction medium
is concentrated under vacuum to 10 ml, an Et.sub.2O/HCl solution is
added in order to bring the mixture to pH 3 and the resulting
mixture is concentrated to dryness. The residue is purified
by_partition chromatography on Sephadex.RTM. G 25, using the
nBuOH/iPrOH/H.sub.2O solvent system (4/0.2/5; v/v/v). The product
with the cyclized amidine (410 m g) as described in Example 43 is
first isolated, followed by the expected product with the open
amidine (410 mg).
[0682] .alpha..sub.D.sup.25=+37.6.degree. (c=0.5; DMF)
[0683] NMR (DMSO+TFA) 1.50-1.70:m:4H; 2.30-3.15:m:1OH; 3.70:t:2H;
4.55 t :H; 4.70: t:1H; 6.90-8.10:m:16H.
EXAMPLE 56
[0684] Gelatin capsule containing a 10 mg dose
15 Compound of Example 43 (weight expressed as 10.0 mg equivalent
in non-salified form) Lactose monohydrate 200 mesh qs
Methylhydroxypropylcellulose 6 mPa .multidot. s 3.0 mg Crosslinked
sodium carboxymethylcellulose 4.5 mg Magnesium stearate 1.5 mg
Purified water for wet granulation For a No. 3 size "opaque-white"
gelatin capsule filled to 150 mg.
EXAMPLE 57
[0685] Splittable uncoated tablet containing 50 mg dose
16 Compound of Example 43 (weight expressed as 50.0 mg equivalent
in non-salified form) Lactose monohydrate 200 mesh qs
Microcrystalline cellulose 50 .mu.m 27.0 mg
Methylhydroxypropylcellulose 6 mPa .multidot. s 3.6 mg Crosslinked
sodium carboxymethylcellulose 5.4 mg Magnesium stearate 1.8 mg
Purified water for wet granulation For a finished splittable
uncoated tablet containing 180 mg
EXAMPLE 58
[0686] Gelatin capsule containing a 1 mg dose
17 Compound of Example 43 (weight expressed as 1.0 mg equivalent in
non-salified form) Lactose monohydrate 200 mesh qs
Methylhydroxypropylcellulose 6 mPa .multidot. s 3.0 mg Crosslinked
sodium carboxymethylcellulose 4.5 mg Magnesium stearate 1.5 mg
Purified water for wet granulation For a No. 3 size "opaque-white"
gelatin capsule filled to 100 mg.
* * * * *