U.S. patent application number 15/173173 was filed with the patent office on 2016-09-29 for novel benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics.
The applicant listed for this patent is GALDERMA RESEARCH & DEVELOPMENT. Invention is credited to Sandrine CHAMBON, Laurent CHANTALAT, Laurence CLARY, Jean-Claude PASCAL, Carine ROSIGNOLI, Olivier ROYE, Marlene SCHUPPLI-NOLLET.
Application Number | 20160280650 15/173173 |
Document ID | / |
Family ID | 41600633 |
Filed Date | 2016-09-29 |
United States Patent
Application |
20160280650 |
Kind Code |
A1 |
CLARY; Laurence ; et
al. |
September 29, 2016 |
NOVEL BENZENESULFONAMIDE COMPOUNDS, METHOD FOR SYNTHESIZING SAME,
AND USE THEREOF IN MEDICINE AS WELL AS IN COSMETICS
Abstract
Benzenesulfonamide compounds having a structure of formula (I)
are described. Also described, are methods for synthesizing the
compounds and to the use thereof in pharmaceutical compositions for
human or veterinary medicine and in cosmetic compositions.
Inventors: |
CLARY; Laurence; (La Colle
sur Loup, FR) ; CHAMBON; Sandrine; (Le Cannet,
FR) ; CHANTALAT; Laurent; (Grasse, FR) ;
ROSIGNOLI; Carine; (Mougins le Haut, FR) ; ROYE;
Olivier; (Fayence, FR) ; PASCAL; Jean-Claude;
(Nice, FR) ; SCHUPPLI-NOLLET; Marlene; (Le Rouret,
FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GALDERMA RESEARCH & DEVELOPMENT |
|
|
|
|
|
Family ID: |
41600633 |
Appl. No.: |
15/173173 |
Filed: |
June 3, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14626302 |
Feb 19, 2015 |
9365529 |
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15173173 |
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14103470 |
Dec 11, 2013 |
8980897 |
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14626302 |
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|
13774023 |
Feb 22, 2013 |
8633196 |
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14103470 |
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13381234 |
Aug 27, 2012 |
8420632 |
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PCT/FR2010/051331 |
Jun 28, 2010 |
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13774023 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 17/00 20180101;
C07D 261/20 20130101; Y02A 50/411 20180101; A61P 9/00 20180101;
A61P 25/08 20180101; A61P 43/00 20180101; C07D 215/14 20130101;
A61P 25/00 20180101; A61K 31/551 20130101; A61P 19/02 20180101;
A61P 21/00 20180101; A61P 25/28 20180101; A61P 19/08 20180101; C07D
209/10 20130101; A61P 11/06 20180101; A61P 27/02 20180101; A61P
37/06 20180101; A61P 9/10 20180101; A61P 25/14 20180101; A61P 35/00
20180101; A61P 37/08 20180101; C07D 209/12 20130101; A61K 31/4965
20130101; A61P 25/02 20180101; A61P 17/06 20180101; A61P 25/04
20180101; C07D 213/56 20130101; A61P 29/00 20180101; C07D 213/30
20130101; A61P 7/00 20180101; A61P 19/00 20180101; A61P 33/06
20180101; A61K 31/497 20130101; A61P 25/16 20180101; A61P 11/00
20180101; A61P 21/02 20180101; C07D 213/55 20130101; C07D 295/15
20130101; C07D 209/20 20130101; Y02A 50/30 20180101; A61P 3/04
20180101; C07D 471/04 20130101; A61P 31/06 20180101; C07D 295/26
20130101; A61P 1/04 20180101; A61P 25/06 20180101; A61P 3/10
20180101; A61P 31/04 20180101; C07D 209/26 20130101; C07D 209/24
20130101; C07D 213/68 20130101; A61P 31/18 20180101 |
International
Class: |
C07D 215/14 20060101
C07D215/14; C07D 471/04 20060101 C07D471/04; C07D 209/12 20060101
C07D209/12; C07D 261/20 20060101 C07D261/20; C07D 295/26 20060101
C07D295/26; C07D 213/30 20060101 C07D213/30 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 30, 2009 |
FR |
09/54460 |
Claims
1. A compound of formula (I), a salt thereof, or an enantiomer
thereof, ##STR00007## in which: R.sub.1 represents a hydrogen, an
alkyl radical, a substituted alkyl radical, an alkenyl radical, a
substituted alkenyl radical, an alkynyl radical, a substituted
alkynyl radical, an aralkyl radical, a substituted aralkyl radical,
a heteroaralkyl radical, a substituted heteroaralkyl radical, a
--C(O)--R.sub.4 radical, a --SO.sub.2--R.sub.4 radical, or a
C(O)OR.sub.4 radical, with R.sub.4 having the meanings given
hereinafter; R.sub.2 is a hydrogen atom or a lower alkyl radical;
R.sub.3 is an alkyl radical, a substituted alkyl radical, an
alkenyl radical, a substituted alkenyl radical, an alkynyl radical,
a substituted alkynyl radical, an aryl radical, a substituted aryl
radical, an aralkyl radical, a substituted aralkyl radical, a
heterocyclic radical, a substituted heterocyclic radical, a
cycloalkyl radical, a substituted cycloalkyl radical, a heteroaryl
radical, a substituted heteroaryl radical, a heteroaralkyl radical,
or a substituted heteroaralkyl radical; R.sub.4 is an alkyl
radical, a substituted alkyl radical, an alkenyl radical, a
substituted alkenyl radical, an alkynyl radical, a substituted
alkynyl radical, an aryl radical, a substituted aryl radical, an
aralkyl radical, or a substituted aralkyl radical; and, n is 1.
Description
PRIOR APPLICATIONS
[0001] This application is a Continuation of U.S. patent
application Ser. No. 14/626,302, filed Feb. 19, 2015, now allowed,
which is a Divisional of U.S. patent application Ser. No.
14/103,470, filed Dec. 11, 2013, now U.S. Pat. No. 8,980,897, which
is a Continuation of U.S. patent application Ser. No. 13/774,023,
filed Feb. 22, 2013, now U.S. Pat. No. 8,633,196, which is a
Continuation of U.S. patent application Ser. No. 13/381,234, filed
Aug. 27, 2012, now U.S. Pat. No. 8,420,632 B2, which is the United
States national phase of PCT/FR2010/051331, filed Jun. 28, 2010,
which claims foreign priority under 35 U.S.C. .sctn.119 of FR
09/54460, filed Jun. 30, 2009, each hereby expressly incorporated
by reference in its entirety.
TECHNICAL FIELD
[0002] The present invention relates to novel benzenesulfonamide
compounds corresponding to general formula (I) below:
##STR00001##
and also to the process for synthesizing same and to the use
thereof in pharmaceutical compositions intended for use in human or
veterinary medicine.
[0003] The compounds of the present invention act as inhibitors of
TNF.alpha.--converting enzyme, also known as TACE. They are
consequently of use in the treatment of diseases for which reducing
TNF.alpha. production is of great interest.
[0004] The present invention also relates to the use of the
compounds corresponding to general formula (I) in cosmetic
compositions.
PRIOR ART
[0005] Adamalysins ("ADAM" or A Disintegrin and Metalloproteinase)
are a subfamily of zinc metalloendopeptidase enzymes. Their
ectodomain comprises a protease domain, the activation of which is
zinc-dependent, a disintegrin domain and a cysteine-rich domain. To
date, at least 30 different ADAMs have been identified, of which
the first characterized was ADAM17, also known as TACE
(TNF.alpha.-converting enzyme) [Gueydan C et al. Med. Sci 1997, 13,
83-88; Black R. A et al. Nature 1997, 385:729-733; Moss et al.
Nature 1997, 385:733-736]. The TACE mRNA is present in many tissues
and more particularly in monocytes, macrophages and T lymphocytes,
but also in keratinocytes for example. TACE is responsible for the
cleavage of pro-TNF.alpha., a 26 kDa membrane protein, so as to
result in the release of biologically active soluble TNF.alpha., a
17kDa protein [Schlondorff et al. Biochem. . 2000, 347, 131-138].
The soluble TNF.alpha. released by the cell is capable of acting on
sites very remote from the site of synthesis.
[0006] TNF.alpha. is involved in a large number of pro-inflammatory
biological processes [Aggarwal et al, Eur. Cytokine Netw., 1996, 7:
93-124]. Several pharmacological and clinical studies have shown in
an obvious manner that blocking the effects of TNF.alpha. with
specific anti-TNF.alpha. antibodies or anti-TNF.alpha. biologicals
(Etanercept, Adalimumab, Infliximab) is beneficial in the treatment
of autoimmune diseases such as rheumatoid arthritis [Feldman et al.
Lancet, 1994, 344, 1105], non-insulin-dependent diabetes mellitus
[Lohmander L.S et al. Arthritis Rheum, 1993, 36, 1214-1222], or
Crohn's disease [MacDonald et al. Clin. Exp. Immunol. 1990, 81,
301].
[0007] TNF.alpha. also plays a fundamental role during the
inflammantory phenomenon triggered in psoriasis lesions. Serum
TNF.alpha. levels are elevated in psoriatic patients [Mussi A et
al. J. Biol. Regul. Homeost Agents, 1997, 11, 115-118]; TNF.alpha.
levels are also elevated in the actual psoriasis plaques [Bonifati
C. et al. Clin. Exp. Dermatol., 1994, 19, 383-387]. The key cells
in the physiopathology of psoriasis are keratinocytes, dendritic
cells and certain T lymphocytes. The interaction between these
families of cells results in an inflammatory cascade that leads to
the characteristic psoriasis lesions with release of TNF.alpha.
[Kupper TS, N. Engl. J. Med, 2003, 349, 1987-1990]. Clinical
studies for the treatment of moderate to severe plaque psoriasis
with anti-TNF.alpha. biologicals (Etanercept, Adalimumab,
Infliximab) have demonstrated their efficacy both on psoriasis
lesions and on the quality of life of the patients [Ortonne JP,
Annales de dermatologie et de venereologie {Annals of dermatology
and venereology], 2005, 132 (8-9 pt2), 4S6-9 and 2005, 132,
9S01-9S70]. Thus, compounds which inhibit TNF.alpha. production are
of great interest for the treatment of inflammatory diseases and
diseases involving TNF.alpha. release.
SUMMARY OF THE INVENTION
[0008] Our invention therefore describes novel molecules which
inhibit the TACE enzyme (TNF.alpha.-converting enzyme) and, as a
result, inhibit the secretion of soluble TNF.alpha. (active form of
TNF.alpha.) by cells. These novel molecules are therefore potential
active ingredients for the treatment of pathological conditions
which involves a decrease or an inhibition of TNF.alpha.
production.
[0009] By way of illustration, and in a nonlimiting manner, these
pathological conditions are, for example, septic shock, hemodynamic
shock, malaria, inflammatory bowel diseaases (IBDs) such as Crohn's
disease and ulcerative colitis, inflammatory bone diseases,
mycobacterial infections, meningitis, fibrotic diseases, cardiac
diseases, ischemic attack, transplant rejection, cancer,
atherosclerosis, obesity, diseases involving angiogenesis
phenomena, autoimmune diseases, osteoarthritis, rheumatoid
arthritis, ankylosing spondylitis, juvenile chronic arthritis,
multiple sclerosis, HIV, non-insulin-dependent diabetes mellitus,
allergic diseases, asthma, chronic obstructive pulmonary disease
(COPD), occular inflammation, inflammatory skin diseases,
psoriasis, atopic dermatitis and psoriatic arthritis.
[0010] These molecules are also potential active ingredients for
the treatment of neurological pathological conditions that are
inflammatory in nature, for which reducing TNF.alpha. production
would be of great interest. These pathological conditions listed
hereinafter in a nonlimiting manner are, for example, Alzheimer's
disease, Parkinson's disease, parkinsonian disorders, amyotrophic
lateral sclerosis, autoimmune diseases of the nervous system,
autonomic diseases of the nervous system, dorsal pain, cerebral
edema, cerebrovascular disorders, dementia, nervous system nerve
fiber demyelinating autoimmune diseases, diabetic neuropathies,
encephalitis, encephalomyelitis, epilepsy, chronic fatigue
syndrome, giant cell arteritis, Guillain-Barre syndrome, headaches,
multiple sclerosis, neuralgia, peripheral nervous system diseases,
polyneuropathies, polyradiculoneuropathy, radiculopathy,
respiratory paralysis, spinal cord diseases, Tourette's syndrome,
central nervous system vasculitis, Huntington's disease and stroke.
A large variety of TACE inhibitors is already known as indicated
below. However, a large number of these inhibitors do not act
selectively on the TACE enzyme compared with other enzymes of the
family of ADAMs and/or of matrix metalloproteinases (MMPs). As it
happens, the nonselective inhibition of these enzyme families
induces adverse side effects observed in vivo. For example, the
inhibition of MMP-1 (collagenase-1) has been associated with
musculoskeletal toxicity problems.
[0011] As a nonselective inhibitor, mention may also be made of
Apratastat, a known inhibitor tested clinically in phase 2 for the
treatment of rheumatoid arthritis (Curr Opin Investig Drugs. 2006
Nov; 7(11),1014-1019). This inhibitor is not selective for the TACE
enzyme compared with certain MMPs (WO 00/44709; page 251, table 10,
example 61). Other TACE inhibitors which are also known and are
part of the same family as Apratastat, namely that of cyclic
benzenesulfonamide derivatives, have been described in WO 00/44709
and WO 97/18194. Other patents (WO 96/00214, WO 97/22587) claim MMP
and/or TACE inhibitors for which the benzenesulfonamide part is
separated from the hydroxamic acid function by a single carbon
atom. Publications describing MMP inhibitors of this type more
broadly are also the publication by MacPherson et al. J. Med. Chem.
1997, 40, 2525 and the publication by Tamura et al. J. Med. Chem.
1998, 41, 640. Other examples of MMP/TACE inhibitors for which the
sulfonamide function is separated from the hydroxamic acid by a
series of two carbon atoms forming a ring are described in patents
WO 98/16503, WO 98/16506, WO 98/16514 and WO 98/16520. Other
examples of MMP inhibitors for which the sulfonamide function is
separated from the hydroxamic acid by a series of two carbon atoms
are also described in WO 2008/045671. As it happens, the applicant
has now discovered, unexpectedly and surprisingly, that novel
compounds of general formula (I) exhibit a very good
TACE-inhibiting activity, and in particular inhibit the TACE enzyme
selectively compared with other ADAMs and MMPs. Thus, the present
invention relates to compounds of general formula (I) below:
##STR00002##
in which:
[0012] R.sub.1 represents a hydrogen, an alkyl radical, a
substituted alkyl radical, an alkenyl radical, a substituted
alkenyl radical, an alkynyl radical, a substituted alkynyl radical,
an aralkyl radical, a substituted aralkyl radical, a heteroaralkyl
radical, a substituted heteroaralkyl radical, a --C(O)--R.sub.4
radical, an --SO.sub.2--R.sub.4 radical, or a C(O)OR.sub.4 radical,
R.sub.4 having the meanings given hereinafter;
[0013] R.sub.2 is a hydrogen atom or a lower alkyl radical;
[0014] R.sub.3 is an alkyl radical, a substituted alkyl radical, an
alkenyl radical, a substituted alkenyl radical, an alkynyl radical,
a substituted alkynyl radical, an aryl radical, a substituted aryl
radical, an aralkyl radical, a substituted aralkyl radical, a
heterocyclic radical, a substituted heterocyclic radical, a
cycloalkyl radical, a substituted cycloalkyl radical, a heteroaryl
radical, a substituted heteroaryl radical, a heteroaralkyl radical
or a substituted heteroaralkyl radical;
[0015] R.sub.4 is an alkyl radical, a substituted alkyl radical, an
alkenyl radical, a substituted alkenyl radical, an alkynyl radical,
a substituted alkynyl radical, an aryl radical, a substituted aryl
radical, an aralkyl radical or a substituted aralkyl radical;
[0016] n can take the values of 0, 1, 2 or 3;
[0017] and also the addition salts of the compounds of general
formula (I) with a pharmaceutically acceptable acid, the addition
salts of the compounds of general formula (I) with a
pharmaceutically acceptable base, and the enantiomers of the
compounds of general formula (I).
[0018] Among the addition salts of the compounds of general formula
(I) with a pharmaceutically acceptable acid, mention may preferably
be made of the salts with an organic acid or with an inorganic
acid.
[0019] The suitable inorganic acids are, for exaple, hydrohalic
acids such as hydrochloric acid or hydrobromic acid, sulfuric acid,
nitric acid and phosphoric acid.
[0020] The suitable organic acids are, for example, acetic acid,
trifluoroacetic acid, trichloroacetic acid, propionic acid,
glycolic acid, pyruvic acid, succinic acid, benzoic acid, cinnamic
acid, mandelic acid, methanesulfonic acid, para-toluenesulfonic
acid, salicylic acid, picric acid, citric acid, oxalic acid,
tartaric acid, malonic acid, maleic acid, camphorsulfonic acid and
fumaric acid.
[0021] Among the addition salts of the compounds of general formula
(I) with a pharmaceutically acceptable base, mention may preferably
be made of the salts with an organic base or with an inorganic
base.
[0022] The inorganic bases are, for example, potassium hydroxide,
sodium hydroxide, lithium hydroxide or calcium hydroxide.
[0023] The suitable organic bases comprise amines and amino acids.
Among the amines, mention may, for example, be made of aliphatic or
aromatic, primary, secondary or tertiary amines, such as
methylamine, ethylamine, ethanolamine, propylamine, isopropylamine,
the 4 isomers of butylamine, dimethylamine, diethylamine,
diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine,
pyrrolidine, piperidine, morpholine, diethanolphenylamine,
trimethylamine, triethylamine, tripropylamine, quinuclidine,
pyridine, quinoline or isoquinoline.
[0024] Among the amino acids, mention may, for example, be made of
lysine, arginine and ornithine.
[0025] According to the present invention, the term "lower alkyl
radical" denotes a linear or branched, saturated hydrocarbon-based
chain containing from 1 to 4 carbon atoms.
[0026] According to the present invention, the term "alkyl radical"
denotes a linear or branched, saturated hydrocarbon-based chain
containing from 1 to 10 carbon atoms.
[0027] According to the present invention, the term "alkenyl
radical" denotes a linear or branched, unsaturated
hydrocarbon-based chain containing from 2 to 10 carbon atoms and
comprising one or more double bonds.
[0028] According to the present invention, the term "alkynyl
radical" denotes a linear or branched, unsaturated
hydrocarbon-based chain containing from 2 to 10 carbon atoms and
comprising one or more triple bonds.
[0029] According to the present invention, the term "substituted
alkyl radical" denotes a linear or branched, saturated
hydrocarbon-based chain containing from 1 to 10 carbon atoms and
substituted with one or more radicals chosen from a halogen atom,
an alkoxy radical and a hydroxyl radical.
[0030] According to the present invention, the term "substituted
alkenyl radical" denotes a linear or branched, unsaturated
hydrocarbon-based chain containing from 2 to 10 carbon atoms,
comprising one or more double bonds and substituted with one or
more radicals chosen from a halogen atom, an alkoxy radical and a
hydroxyl radical.
[0031] According to the present invention, the term "substituted
alkynyl radical" denotes a linear or branched, unsaturated
hydrocarbon-based chain containing from 2 to 10 carbon atoms,
comprising one or more triple bonds and substituted with one or
more radicals chosen from a halogen atom, an alkoxy radical and a
hydroxyl radical.
[0032] According to the present invention, the term "cycloalkyl"
denotes a cyclic saturated hydrocarbon-based chain containing from
3 to 7 carbon atoms.
[0033] According to the present invention, the term "substituted
cycloalkyl" denotes a cyclic saturated hydrocarbon-based chain
containing from 3 to 7 carbon atoms and substituted with one or
more radicals chosen from a halogen atom, an alkoxy radical and a
hydroxyl radical.
[0034] According to the present invention, the term "aryl radical"
denotes an aromatic hydrocarbon-based ring or two fused aromatic
hydrocarbon-based rings.
[0035] The preferred aryl radicals are chosen from phenyl and
naphthyl radicals.
[0036] According to the present invention, the term "substituted
aryl radical" denotes an aromatic hydrocarbon-based ring or two
fused aromatic hydrocarbon-based rings which is (are) substituted
with one or more groups of atoms chosen from an alkyl, an alkoxy,
an aryl, a halogen, a hydroxyl, a cyano, a trifluoromethyl and a
nitro.
[0037] According to the present invention, the term "aralkyl
radical" denotes an alkyl substituted with an aryl.
[0038] According to the present invention, the term "substituted
aralkyl radical" denotes an alkyl substituted with a substituted
aryl.
[0039] According to the present invention, the term "heterocyclic
radical" denotes a saturated or unsaturated, cyclic or polycyclic
hydrocarbon-based chain comprising one or more heteroatoms chosen
from O, S and N.
[0040] According to the present invention, the term "substituted
heterocyclic radical" denotes a heterocyclic radical substituted
with one or more groups of atoms chosen from an alkyl, an alkoxy, a
halogen, a hydroxyl, a cyano, a trifluoromethyl and a nitro.
[0041] According to the present invention, the term "heteroaryl
radical" denotes an aromatic heterocyclic radical, i.e. a cyclic or
polycyclic aromatic hydrocarbon-based chain, comprising one or more
heteroatoms chosen from O, S and N.
[0042] According to the present invention, the term "substituted
heteroaryl radical" denotes a heteroaryl radical substituted with
one or more groups of atoms chosen, for example, from an alkyl, an
alkoxy, an aryl, a substituted aryl, a halogen, a hydroxyl, a
cyano, a trifluoromethyl and a nitro.
[0043] According to the present invention, the term "heteroaralkyl
radical" denotes an alkyl radical substituted with a heteroaryl
radical.
[0044] According to the present invention, the term "substituted
heteroaralkyl radical" denotes a heteroaralkyl radical substituted
with one or more groups of atoms chosen from an alkyl, an alkoxy, a
halogen, a hydroxyl, a cyano, a trifluoromethyl and a nitro.
[0045] According to the present invention, the term "alkoxy
radical" denotes an oxygen atom substituted with an alkyl
radical.
[0046] According to the present invention, the term "halogen atom"
denotes a fluorine, chlorine, bromine or iodine atom.
[0047] Among the compounds of general formula (I) which fall within
the context of the present invention, mention may in particular be
made of the following compounds:
[0048] 1)
3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-m-
ethanesulfonylpiperazin-1-yl)propionamide
[0049] 2)
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-metha-
nesulfonylpiperazin-1-yl)propionamide
[0050] 3)
(S)-3-(4-benzyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesu-
lfonylpiperazin-1-yl)propionamide
[0051] 4)
(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-m-
ethanesulfonylpiperazin-1-yl)propionamide
[0052] 5)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methyl-
quinolin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0053] 6)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthal-
en-1-ylmethoxy)benzenesulfonylamino]propionamide
[0054] 7)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybe-
nzenesulfonylamino)propionamide 8)
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesu-
lfonylpiperazin-1-yl)propionamide
[0055] 9)
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4--
methanesulfonylpiperazin-1-yl)propionamide
[0056] 10) benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfo-
nylamino]ethyl)piperazine-1-carboxylate
[0057] 11)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-pheny-
lpyridin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0058] 12)
(R)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methy-
lquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0059] 13)
(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfony-
lamino]-2-piperazin-1-yl-propionamide
[0060] 14)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methy-
lquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide
hydrochloride
[0061] 15) tert-butyl
3-{4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulfonylpiperazin-1-yl)ethylsulf-
amoyl]phenoxymethyl}-2-methylindole-1-carboxylate
di(trifluoroacetate)
[0062] 16)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinoli-
n-4-ylmethoxy)benzenesulfonylamino]propionamide
[0063] 17)
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide
[0064] 18)
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-meth-
ylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0065] 19)
(S)-2-(4-ethylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin--
4-ylmethoxy)benzenesulfonylamino]propionamide
[0066] 20)
(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfony-
lamino]-2-[4-(4-trifluoromethyl-benzyl)piperazin-1-yl]propionamide
[0067] 21)
(S)-N-hydroxy-2-[4-(4-methylbenzyl)piperazin-1-yl]-3-[4-(2-meth-
ylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0068] 22)
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-N-hyd-
roxy-2-(4-methanesulfonylpiperazin-1-yl)propionamide
[0069] 23)
(S)-N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquin-
olin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0070] 24)
(S)-N-hydroxy-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]--
3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0071] 25)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifl-
uoromethylpyrazolo[1,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]pr-
opionamide
[0072] 26)
(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfony-
lamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide
[0073] 27) (S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy
-3-[4-(2-trifluoromethylpyrazolo[1,5-.alpha.]pyridin-3-ylmethoxy)benzenes-
ulfonylamino]propionamide
[0074] 28)
(S)-2-(4-acetylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide
[0075] 29)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-{propyl-[4--
(quinolin-4-ylmethoxy)benzenesulfonyl]amino}propionamide
[0076] 30)
(S)-2-(4-benzenesulfonylpiperazin-1-yl)-N-hydroxy-3-[4-(pyrazol-
o[1,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide
[0077] 31)
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(1-methylpiperidi-
n-4-ylmethoxy)benzenesulfonylamino]propionamide
[0078] 32)
(S)-2-[4-(4-fluorobenzoyl)piperazin-1-yl]-N-hydroxy-3-[4-(3-m-t-
olyl-propoxy)benzenesulfonylamino]propionamide
[0079] 33)
(S)-N-hydroxy-3-[4-(2-methylnaphthalen-1-ylmethoxy)benzenesulfo-
nylamino]-2-(4-propionylpiperazin-1-yl)propionamide
[0080] 34)
(S)-N-hydroxy-3-[4-(4-methylpentyloxy)benzenesulfonylamino]-2-(-
4-phenylacetylpiperazin-1-yl)propionamide
[0081] 35)
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methy-
lpyridin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0082] 36)
(S)-2-(3-acetylimidazolidin-1-yl)-N-hydroxy-3-[4-(2-methylquino-
lin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0083] 37)
(S)-3-[4-(3,5-dimethylbenzyloxy)benzenesulfonylamino]-N-hydroxy-
-2-imidazolidin-1-yl-propionamide
[0084] 38)
(S)-N-hydroxy-2-(4-methanesulfonyl-[1,4]diazepan-1-yl)-3-[4-(2--
methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0085] 39)
(S)-2-(4-benzyl-[1,4]diazepan-1-yl)-N-hydroxy-3-[4-(2-methylqui-
nolin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0086] 40)
(S)-2-[1,4]diazocan-1-yl-N-hydroxy-3-[4-(2-methylquinolin-4-ylm-
ethoxy)benzenesulfonylamino]propionamide.
[0087] 41)
(S)-N-hydroxy-3-[4-(2-methylbenzofuran-3-ylmethoxy)benzenesulfo-
nylamino]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide
[0088] 42)
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-isopropyl-1H-i-
ndol-3-ylmethoxy)benzenesulfonylamino]propionamide
[0089] The compounds of general formula (I) are prepared according
to the reaction scheme (Scheme 1) presented below.
##STR00003##
[0090] According to Scheme 1, the compounds (3) are obtained by
reaction between the amino acid (1) H-DAP(Boc)-OMe.HCl or
H-(D)-DAP(Boc)-OMe.HCl and the compound (2) (commercial or prepared
beforehand) in the presence of an organic tertiary base such as
diisopropylethylamine or triethylamine at a temperature of between
60.degree. C. and 120.degree. C. The compounds (4) are obtained by
deprotection of the amine function of compounds (3) according to
conventional methods such as, for example, the use of a solution of
hydrochloric acid in isopropanol.
[0091] A reaction between the compound (4) and
4-hydroxybenzenesulfonyl chloride O-protected with a benzyl group
for example (P.dbd.CH.sub.2--Ph) (5) in the presence of a tertiary
amine such as, for example, triethylamine in dichloromethane,
produces the compound (6). An N-alkylation of the sulfonamide
function can then be carried out by reaction with an alkyl halide
in the presence of a base such as, for example, potassium carbonate
in a solvent such as DMF, so as to give the derivative (7). The
compound (8) is obtained by deprotection according to methods known
by those skilled in the art for deprotecting a phenol function. The
compound (9) is obtained by alkylation of the phenol function of
the compound (8) by reaction with an alkyl halide in the presence
of a base such as, for example, cesium carbonate in acetone, or via
a Mitsunobu reaction with a primary alcohol derivative in the
presence of triphenylphosphine and of diisopropyl azodicarboxylate
for example. The compound (10) is obtained via a saponification
reaction in the presence of a base such as lithium hydroxide in the
presence of water and of tetrahydrofuran for example. In a final
step, the compound (11) is obtained by coupling between
O-(tert-butyldimethylsilyl)hydroxylamine for example and the
derivative (10) under conventional peptide coupling conditions,
using, for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride, hydroxybenzotriazole or TBTU as coupling agents, and
triethylamine or diisopropylethylamine as base, in a solvent such
as dichloromethane or dimethylformamide. The deprotection of the
silylated hydroxamic acid intermediately formed is carried out in
situ or by washing with a slightly acidic aqueous solution, so as
to give the compound (11).
[0092] Another alternative for obtaining the compound (11) is
presented in Scheme 2 below.
##STR00004##
[0093] According to the synthesis scheme of Scheme 2, the
derivative (3) can optionally be alkylated in the presence of a
base such as sodium hydride and of an alkyl halide in
dimethylformamide, for example, so as to give the compound (12),
from which the compound (13) is obtained according to conventional
methods for deprotecting amines, for instance the use of a solution
of hydrochloric acid in isopropanol. The compound (14) is prepared
beforehand from the commercially available 4-hydroxybenzenesulfonic
acid sodium salt by alkylation with an alkyl halide in the presence
of a base such as sodium hydroxide, for example, in a mixture of
solvents such as isopropanol and water, for example. The compound
(15) is then obtained by reacting the derivative (14) with oxalyl
chloride in the presence of dimethylformamide in dichloromethane,
for example. _o The derivative (9) is obtained by reaction between
the compounds (13) and (15) in the presence of a base such as
triethylamine in dichloromethane, for example.
[0094] An alternative synthesis pathway for obtaining the compound
(11) is also presented in Scheme 3 below.
##STR00005##
[0095] According to Scheme 3, the compound (17) is obtained by
reaction between the amino acid (1) H-DAP(Boc)-OMe.HCl or
H-(D)-DAP(Boc)-OMe.HCl and the compound (16) (prepared beforehand
by reacting bis(2-chloroethyl)amine for example and benzyl bromide
in the presence of potassium carbonate in acetonitrile) in the
presence of an organic tertiary base such as diisopropylethylamine
at a temperature of approximately 120.degree. C. After deprotection
of the amine function, the compound (18) is condensed with sulfonyl
chloride (15) so as to give the derivative (19). An N-alkylation of
the sulfonamide function can then be carried out by reaction with
an alkyl halide in the presence of a base such as, for example,
potassium carbonate in a solvent such as DMF, so as to give the
derivative (20). The compound (21) is obtained according to the
conventional conditions for hydrogenation of the compound (20) in
the presence of palladium-on-carbon in a solvent such as ethanol
for example. The compound (9) is obtained according to the
conventional synthesis methods, for example, by reaction of the
compound (21) with an acyl chloride, or a sulfonyl chloride in the
presence of triethylamine, or by reaction with an alkyl halide in
the presence of a base such as sodium hydride, for example. The
compound (10) is obtained via a saponification reaction in the
presence of a base such as lithium hydroxide in the presence of
water and of tetrahydrofuran, for example. In a final step, the
compound (11) is obtained by coupling between
O-(tert-butyldimethylsilyl)hydroxylamine, for example, and the
derivative (10) under conventional peptide coupling conditions,
using, for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride, hydroxybenzotriazole or TBTU as coupling agents, and
triethylamine or diisopropylethylamine as base, in a solvent such
as dichloromethane or dimethylformamide. The deprotection of the
silylated hydroxamic acid intermediately formed is carried out in
situ or by washing with an acidic aqueous solution, so as to give
the compound (11).
[0096] An alternative synthesis pathway for the compounds with R1
representing a --(CO)--R.sub.4 radical is described in Scheme
4.
##STR00006##
[0097] After deprotection of the amine function of the compound
(17) according to conventional conditions for hydrogenation in the
presence of palladium-on-carbon in a solvent such as ethanol for
example, the compound (22) is obtained. The compound (23) is
obtained by reaction with an acyl chloride, R.sub.4COCI, in the
presence of a base such as triethylamine. When R.sub.2 represents a
lower alkyl radical, an N-alkylation of the carbamate is then
carried out by reaction with an alkyl halide in the presence of a
base such as, for example, potassium carbonate in a solvent such as
DMF, so as to give the derivative (24). The compound (25) is
prepared via a saponification reaction in the presence of a base
such as lithium hydroxide in the presence of water and of
tetrahydrofuran, for example. Coupling between 0-allylhydroxylamine
hydrochloride, for example, and the derivative (25) makes it
possible to obtain the compound (26) under conventional peptide
coupling conditions. For this, use is made, for example, of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,
hydroxybenzotriazole or TBTU as coupling agents, and triethylamine
or diisopropylethylamine as base. The reaction is carried out in a
solvent such as dichloromethane or dimethylformamide. After
deprotection of the amine function of the compound (26) according
to conventional methods, the compound (27) is obtained. It is
condensed with sulfonyl chloride (15) so as to give the compound
(28). In a final step, the compound (29) is obtained by
deprotection of the hydroxylamine function of the compound (28)
according to conventional methods such as, for example, treatment
with tetrakis(triphenylphosphine)palladium(O) and potassium
carbonate in methanol. According to the present invention, the
preferred compounds of general formula (I) are those for which:
[0098] R.sub.1 represents a hydrogen, an alkyl radical, a
substituted alkyl radical, an alkenyl radical, a substituted
alkenyl radical, an alkynyl radical, a substituted alkynyl radical,
an aralkyl radical, a substituted aralkyl radical, a heteroaralkyl
radical, a substituted heteroaralkyl radical, a --C(O)--R.sub.4
radical, an --SO.sub.2--R.sub.4 radical or a C(O)OR.sub.4 radical,
R.sub.4 having the meanings given hereinafter;
[0099] R.sub.2 is a hydrogen atom or a a lower alkyl radical;
[0100] R.sub.3 is an aryl radical, a substituted aryl radical, an
aralkyl radical, a substituted aralkyl radical, a heterocyclic
radical, a substituted heterocyclic radical, a heteroaryl radical,
a substituted heteroaryl radical, a heteroaralkyl radical or a
substituted heteroaralkyl radical;
[0101] R.sub.4 is an alkyl radical, a substituted alkyl radical, an
alkenyl radical, a substituted alkenyl radical, an alkynyl radical,
a substituted alkynyl radical, an aryl radical, a substituted aryl
radical, an aralkyl radical or a substituted aralkyl radical;
[0102] n can take the values of 0, 1 or 2;
[0103] and also their addition salts with a pharmaceutically
acceptable acid, their addition salts with a pharmaceutically
acceptable base, and the enantiomers of said compounds.
[0104] According to the present invention, the particularly
preferred compounds of general formula (I) are those for which:
[0105] R.sub.1 represents a hydrogen, an alkyl radical, a
substituted alkyl radical, an alkenyl radical, a substituted
alkenyl radical, an alkynyl radical, a substituted alkynyl radical,
an aralkyl radical, a substituted aralkyl radical, a
--C(O)--R.sub.4 radical or an --SO.sub.2--R.sub.4 radical, R.sub.4
having the meanings given hereinafter;
[0106] R.sub.2 is a hydrogen atom or a lower alkyl radical;
[0107] R.sub.3 is an aryl radical, a substituted aryl radical, an
aralkyl radical, a substituted aralkyl radical, a heterocyclic
radical, a substituted heterocyclic radical, a heteroaryl radical,
a substituted heteroaryl radical, a heteroaralkyl radical or a
substituted heteroaralkyl radical;
[0108] R.sub.4 is an alkyl radical, a substituted alkyl radical, an
aryl radical, a substituted aryl radical, an aralkyl radical or a
substituted aralkyl radical;
[0109] n can take the values of 1 or 2;
[0110] and also their addition salts with a pharmaceutically
acceptable acid, their addition salts with a pharmaceutically
acceptable base, and the enantiomers of said compounds.
[0111] According to the present invention, the more particularly
preferred compounds of general formula (I) are those for which:
[0112] R.sub.1 represents an alkyl radical, a substituted alkyl
radical, an aralkyl radical, a substituted aralkyl radical, a
--C(O)--R.sub.4 radical or an --SO.sub.2--R.sub.4 radical, R.sub.4
having the meanings given hereinafter;
[0113] R.sub.2 is a hydrogen atom;
[0114] R.sub.3 is an aryl radical, a substituted aryl radical, an
aralkyl radical, a substituted aralkyl radical, a heterocyclic
radical, a substituted heterocyclic radical, a heteroaryl radical,
a substituted heteroaryl radical, a heteroaralkyl radical or a
substituted heteroaralkyl radical;
[0115] R.sub.4 is an alkyl radical, a substituted alkyl radical, an
aryl radical, a substituted aryl radical, an aralkyl radical or a
substituted aralkyl radical;
[0116] n takes the value of 1;
[0117] and also their addition salts with a pharmaceutically
acceptable acid, their addition salts with a pharmaceutically
acceptable base, and the enantiomers of said compounds.
[0118] According to the present invention, the even more
particularly preferred compounds of general formula (I) are those
for which:
[0119] R.sub.1 represents an alkyl radical, a substituted alkyl
radical, an aralkyl radical, a substituted aralkyl radical, a
--C(O)--R.sub.4 radical or an --SO.sub.2--R.sub.4 radical, R.sub.4
having the meanings given hereinafter;
[0120] R.sub.2 is a hydrogen atom;
[0121] R.sub.3 is a heterocyclic radical, a substituted
heterocyclic radical, a heteroaryl radical, a substituted
heteroaryl radical, a heteroaralkyl radical or a substituted
heteroaralkyl radical;
[0122] R.sub.4 is an alkyl radical, a substituted alkyl radical, an
aryl radical, a substituted aryl radical, an aralkyl radical or a
substituted aralkyl radical;
[0123] n takes the value of 1;
[0124] and also their addition salts with a pharmaceutically
acceptable acid, their addition salts with a pharmaceutically
acceptable base, and the enantiomers of said compounds.
[0125] According to the present invention, the most particularly
preferred compounds of general formula (I) are those for which:
[0126] R.sub.1 represents an alkyl radical, a substituted alkyl
radical, an aralkyl radical, a substituted aralkyl radical, a
--C(O)--R.sub.4 radical or an --SO.sub.2--R.sub.4 radical, R.sub.4
having the meanings given hereinafter;
[0127] R.sub.2 is a hydrogen atom;
[0128] R.sub.3 is a heteroaryl radical or a substituted heteroaryl
radical;
[0129] R.sub.4 is an alkyl radical, a substituted alkyl radical, an
aryl radical, a substituted aryl radical, an aralkyl radical or a
substituted aralkyl radical;
[0130] n takes the value of 1;
[0131] and also their addition salts with a pharmaceutically
acceptable acid, their addition salts with a pharmaceutically
acceptable base, and the enantiomers of said compounds.
[0132] The compounds according to the invention exhibit a very good
TACE-inhibiting activity and, in particular, they inhibit the TACE
enzyme selectively compared with other ADAMs and MMPs. This TACE
enzyme-inhibiting activity is measured in an enzymatic assay and
quantified via the measurement of an IC.sub.50 (inhibitory
concentration necessary to obtain 50% inhibition of the TACE
enzyme), as described in example 28. The compounds of the present
invention have an IC.sub.50 for TACE less than or equal to 10 .mu.M
and more particularly less than or equal to 1 .mu.M.
Advantageously, the compounds of the present invention have an
IC.sub.50 for TACE less than or equal to 0.5 .mu.M.
[0133] Advantageously, these compounds are also very selective for
TACE compared with the other ADAMs and MMPs (assay described in
example 29): ther inhibitory activity is at least 10 times greater
for TACE than for other ADAMs and MMPs (i.e. the IC.sub.50 value
for TACE is at least 10 times smaller than that for other ADAMs and
MMPs), and more advantageously at least 100 times greater.
[0134] TACE (TNF.alpha.-converting enzyme) catalyses the formation
of soluble TNF-alpha from the precursor protein (transmembrane
TNF.alpha.) bound to the membranes of certain cells. TNF.alpha. is
a pro-inflammatory cytokine which is known to play a role in many
pathological conditions with an inflammatory nature.
[0135] The invention is therefore directed toward the use of at
least one compound of general formula (I) as defined above, for the
treatment of pathological conditions and disorders linked to
TNF.alpha. release. A TACE enzyme inhibitor of general formula (I)
decreases TNF.alpha. production. As a result, it is of use for the
treatment of pathological conditions linked to TNF.alpha.
release.
[0136] The invention is also directed toward the use of at least
one compound of general formula (I) as defined above, for preparing
a pharmaceutical or cosmetic composition in which said compound has
TACE enzyme-inhibiting activity.
[0137] It is therefore directed toward the use of at least one
compound of general formula (I) as defined above, for the treatment
of pathological conditions or disorders which are improved by
inhibiting the TACE enzyme.
[0138] The invention also relates to a method of therapeutic (human
or animal) or cosmetic treatment, which consists of the
administration or the application of a pharmaceutical or cosmetic
composition comprising a compound of general formula (I) as a TACE
inhibitor and, consequently, as an inhibitor of soluble TNF.alpha.
production.
[0139] Thus, the invention relates to the use of at least one
compound of general formula (I) as defined above, for the treatment
of pathological conditions or disorders linked to TNF.alpha.
production.
[0140] The invention also relates to the use of a compound of
general formula (I) as defined above, for preparing a medicament
intended for the treatment of pathological conditions for which
reducing TNF.alpha. production would be of great interest.
[0141] Indeed, the compounds used according to the invention are
particularly suitable for the treatment and prevention of
disorders/diseaes such as the inflammatory diseases listed
hereinafter, but are not limited thereto, such as septic shock,
hemodynamic shock, malaria, inflammatory bowel diseases (IBDs) such
as Crohn's disease and ulcerative colitis, inflammatory bone
diseases, mycobacterial infections, meningitis, fibrotic diseases,
cardiac diseases, atherosclerosis, obesity, ischemic attack,
transplant rejection, cancer, diseases involving angiogenesis
phenomena, autoimmune diseases, osteoarthritis, rheumatoid
arthritis, ankylosing spondylitis, juvenile chronic arthritis,
multiple sclerosis, HIV, non-insulin-dependent diabetes mellitus,
allergic diseases, asthma, chronic obstructive pulmonary disease
(COPD), inflammatory skin diseases, psoriasis, atopic dermatitis
and psoriatic arthritis.
[0142] These molecules are also potential active ingredients for
the treatment of neurological pathological conditions with an
inflammatory nature, for which reducing TNF.alpha. production would
be of great interest. These pathological conditions listed
hereinafter in a nonlimiting manner are, for example, Alzheimer's
disease, Parkinson's disease, parkinsonian disorders, amyotrophic
lateral sclerosis, autoimmune diseases of the nervous system,
autonomic diseases of the nervous system, dorsal pain, cerebral
edema, cerebrovascular disorders, dementia, nervous system nerve
fiber demyelinating autoimmune diseases, diabetic neuropathies,
encephalitis, encephalomyelitis, epilepsy, chronic fatigue
syndrome, giant cell arteritis, Guillain-Barre syndrome, headaches,
multiple sclerosis, neuralgia, peripheral nervous system diseases,
polyneuropathies, polyradiculoneuropathy, radiculopathy,
respiratory paralysis, spinal cord diseases, Tourette's syndrome,
central nervous system vasculitis, Huntington's disease and
stroke.
[0143] The invention relates to the use of a compound of general
formula (I) as defined above, for preparing a medicament intended
for the treatment of pathological conditions with an inflammatory
nature, in which TNF.alpha. is involved.
[0144] The invention relates to the use of a compound of general
formula (I) as defined above, for preparing a medicament intended
for the treatment of inflammatory skin diseases, of psoriasis, of
atopic dermatitis or of psoriatic arthritis.
[0145] A subject of the present invention is also a pharmaceutical
composition intended in particular for the treatment of the
abovementioned conditions, and which is characterized in that it
comprises, in a carrier which is pharmaceutically acceptable and
compatible with the method of administration selected for this
composition, at least one compound of general formula (I). This
compound of general formula (I) can also be in one of its
enantiomeric forms or in the form of one of its pharmaceutically
acceptable salts. Several examples of preparation of active
compounds of formula (I) according to the invention, and also of
the results of biological activity of such compounds, will now be
given by way of illustration and without being in any way limiting
in nature.
Exemplary Embodiments
[0146] The compounds of general formula (I) are characterized by
proton NMR analysis on a Bruker Avance 400MHz instrument.
EXAMPLE 1
3-[(4-but-2-ynyloxybenzenesulfonyl)methylamimo]-N-hydroxy-2-(4-methanesulf-
onylpiperazin-1-yl)propionamide
1-1: Dimethyl 2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate
[0147] 19.5 g (141 mmol) of potassium carbonate and then 19.5 ml
(134 mmol) of dimethyl bromomalonate are added to a solution of 25
g (134 mmol) of tert-butyl piperazine-1-carboxylate in 300 ml of
acetonitrile. The reaction medium is stirred at ambient temperature
for 24 h and then filtered in order to remove the insoluble salts,
and concentrated under vacuum. The crude residue obtained is
purified by chromatography on silica gel, elution being carried out
with a 70/30 heptane/ethyl acetate mixture. 41 g (97%) of dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate are obtained in the
form of a light oil.
1-2: Dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindol--
2-ylmethyl)malonate
[0148] 3.5 g (87 mmol) of sodium hydride are added portionwise to a
solution of 25 g (87 mmol) of dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate in 250 ml of
tetrahydrofuran cooled to 2.degree. C. The reaction medium is
stirred at ambient temperature for 30 minutes and then brought back
to 2.degree. C., before adding, dropwise, 21 g (87 mmol) of
2-bromomethylisoindole-1,3-dione in 200 ml of tetrahydrofuran. The
reaction medium is stirred at ambient temperature for 20 h, treated
by adding 500 ml of water and then extracted with ethyl acetate.
The organic phase is dried over magnesium sulfate, filtered, and
concentrated under vacuum.
[0149] The crude product obtained is purified by chromatography on
silica gel, elution being carried out with a 70/30 heptane/ethyl
acetate mixture. 27.5 g (73%) of dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindo1--
2-ylmethyl)malonate are obtained in the form of a white solid.
[0150] 1-3: Dimethyl
2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate A
solution of 2.9 ml (64 mmol) of hydrazine hydrate in 8 ml of
methanol is added to a solution of 27.5 g (58 mmol) of dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(1,3-dioxo-1,3-dihydroisoindol--
2-ylmethyl)malonate in 300 ml of methanol cooled beforehand to
-5.degree. C. The reaction medium is stirred at from -5.degree. C.
to ambient temperature over the course of 3 h. After evaporation
and addition of 300 ml of water, the reaction medium is extracted
with ethyl acetate. The organic phases are washed with a saturated
aqueous solution of sodium hydrogen carbonate, dried over magnesium
sulfate, filtered and evaporated. The residue obtained is purified
by chromatography on silica gel, elution being carried out with an
8/2 heptane/ethyl acetate mixture and then an increase in polarity
up to a 90/10 ethyl acetate/methanol mixture. 10 g (50%) of
dimethyl
2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate are
thus obtained in the form of a light oil.
1-4: Dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenzenesulfony-
lamino)methyl]malonate
[0151] 1.1 ml (8 mmol) of triethylamine and then 1.8 ml (7 mmol) of
4-but-2-ynyloxybenzenesulfonyl chloride are added to a solution of
2.5 g (7 mmol) of dimethyl
2-aminomethyl-2-(4-tert-butoxycarbonylpiperazin-1-yl)malonate in 30
ml of dichloromethane. The reaction medium is stirred at ambient
temperature for 2 hours and then concentrated under vacuum. The
crude product obtained is purified by chromatography on silica gel,
elution being carried out with a 70/30 heptane/ethyl acetate
mixture. 2.1 g (51%) of dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenze-
nesulfonylamino)methyl]malonate are obtained in the form of a white
solid.
1-5: Dimethyl
2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-ylmalonate
[0152] 2.8 ml of trifluoroacetic acid are added to a solution of
2.1 g (4 mmol) of dimethyl
2-(4-tert-butoxycarbonylpiperazin-1-yl)-2-[(4-but-2-ynyloxybenzenesulfony-
lamino)methyl]malonate diluted in 30 ml of dichloromethane. After
stirring at ambient temperature for 24 h, a saturated aqueous
solution of sodium hydrogen carbonate is added to pH=8 and the
reaction medium is extracted with dichloromethane. The organic
phases are combined, washed with water, dried over magnesium
sulfate, and then filtered and evaporated. 1.7 g (98%) of dimethyl
2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-ylmalonate
are obtained in the form of a white solid.
1-6: Dimethyl
2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-(4-methanesulfonylpiper-
azin-1-yl)malonate
[0153] 0.6 ml (4 mmol) of triethylamine and then 0.3 ml (4 mmol) of
methanesulfonyl chloride are added to a solution of 1.6 g (4 mmol)
of dimethyl
2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-piperazin-1-yl-
malonate diluted in 30 ml of dichloromethane. The reaction medium
is then stirred at ambient temperature for 3 h and then evaporated
to dryness. The crude residue is purified by chromatography on
silica gel, elution being carried out with a 99/1
dichloromethane/methanol mixture. 1.1 g (58%) of dimethyl
2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-(4-methanesulfonylpiper-
azin-1-yl)malonate are obtained in the form of a white solid.
1-7: Dimethyl
2-{(4-but-2-ynyloxybenzenesulfonyl)methylamino]methyl}-2-(4-methanesulfon-
ylpiperazin-1-yl)malonate
[0154] 120 mg (0.9 mmol) of potassium carbonate and then 56 .mu.l
(0.9 mmol) of methyl iodide are added to a solution of 400 mg (0.8
mmol) of dimethyl
2-[(4-but-2-ynyloxybenzenesulfonylamino)methyl]-2-(4-methanesulf-
onylpiperazin-1-yl)malonate in 10 ml of dimethylformamide. The
reaction medium is then stirred at ambient temperature for 18 h and
then hydrolyzed by adding water and extracted with ethyl acetate.
The organic phases are washed with water and then dried over
magnesium sulfate, filtered and concentrated under vacuum. The
crude product obtained is purified by chromatography on silica gel,
elution being carried out with a 50/50 heptane/ethyl acetate
mixture. 410 mg (100%) of dimethyl
2-{[(4-but-2-ynyloxybenzenesulfonyl)methylamino]methyl]-2-(4-methanesulfo-
nylpiperazin-1-yl)malonate are obtained in the form of a white
solid.
1-8:
3-[(4-But-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylp-
iperazin-1-yl)propanoic acid /
[0155] 1.7 ml (1.7 mmol) of an aqueous solution of sodium hydroxide
having a concentration of 1M are added to a solution of 270 mg (0.5
mmol) of dimethyl
2-{[(4-but-2-ynyloxybenzenesulfonyl)methylamino]methyl}-2-(4-met-
hanesulfonylpiperazin-1-yl)malonate in 7 ml of tetrahydrofuran and
2 ml of methanol. The reaction medium is stirred at 40.degree. C.
for 15 h and then brought back to pH=6 by adding an aqueous
solution of hydrochloric acid having a concentration of 1 M. After
evaporation of the solvents under vacuum, the product precipitates.
The residue obtained is taken up in 5 ml of water and stirred for
30 min until precipitation occurs. The product is filtered off,
rinsed with water and then dried under vacuum. 200 mg (87%) of
3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiper-
azin-1-yl)propanoic acid are obtained in the form of a white
solid.
1-9:
3-[(4-But-2-ynyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methan-
esulfonylpiperazin-1-yl)propionamide
[0156] 63 mg (0.5 mmol) of 1-hydroxybenzotriazole and then 88 mg
(0.5 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride are added to a solution of 200 mg (0.4 mmol) of
3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiper-
azin-1-yl)propanoic acid in 6 ml of dimethylformamide. The reaction
medium is stirred for 10 min at ambient temperature and then 68 mg
(0.5 mmol) of O-tert-butyldimethysilylhydroxylamine are added. The
reaction medium is then stirred at ambient temperature for 24 h,
hydrolyzed by adding 2 ml of a 5% aqueous citric acid solution, and
stirred for a further 30 minutes. After extraction with ethyl
acetate, the organic phase is washed with water, dried over
magnesium sulfate, filtered and concentrated. The crude residue is
purified by chromatography on silica gel, elution being carried out
with a 95/5 dichloromethane/methanol mixture. 100 mg (50%) of
3-[(4-but-2-ynyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesul-
fonylpiperazin-1-yl)propionamide are obtained in the form of a
white solid with a melting point of 86.degree. C.
[0157] .sup.1H NMR (.delta., DMSO): 1.91 (s, 3H); 2.63-2.68 (m,
2H); 2.72 (s, 3H); 2.72-2.75 (m, 2H); 2.92 (s, 3H); 3.05-3.15 (m,
5H); 3.30-3.38 (m, 2H); 4.93 (s, 2H); 7.24 (d, J=6.8 Hz, 2H); 7.79
(d, J=6.8 Hz, 2H); 9.06 (s, 1H); 10.77 (s, 1H).
EXAMPLE 2
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonyl-
piperazin-1-yl)propionamide
2.1: Sodium salt of 4-but-2-ynyloxybenzenesulfonic acid
[0158] 50 g (370 mmol) of 1-bromo-2-butyne are added to a solution
of 43 g (185 mmol) of commercial sodium salt of
4-hydroxybenzenesulfonic acid and of 185 ml (185 mmol) of an
aqueous solution of sodium hydroxide having a concentration of 1M,
in 800 ml of isopropanol. The reaction medium is heated at
70.degree. C. for 18 h. After evaporation of the isopropanol, the
product obtained is filtered, rinsed with isopropanol and with
diethyl ether and then dried under vacuum. 46 g (100%) of the
sodium salt of 4-but-2-ynyloxybenzenesulfonic acid are obtained in
the form of a white solid.
2.2: 4-But-2-ynyloxybenzenesulfonyl chloride
[0159] 30 g (107 mmol) of the sodium salt of
4-but-2-ynyloxybenzenesulfonic acid in 120 ml of dimethylformamide
are added dropwise to a solution of 28 ml (321 mmol) of oxalyl
chloride in 120 ml of dichloromethane, cooled beforehand to
-10.degree. C., and then the reaction medium is stirred at ambient
temperature for 18 h. 800 ml of ice are added and the medium is
extracted with ethyl acetate. The organic phases are combined,
washed with water, dried over magnesium sulfate, filtered and
concentrated under vacuum. 22 g (84%) of
4-but-2-ynyloxybenzenesulfonyl chloride are obtained in the form of
a beige solid.
2.3: N,N-bis(2-Chloroethyl)methanesulfonamide
[0160] 8.6 ml (62 mmol) of triethylamine are added to a solution of
5 g (28 mmol) of bis(2-chloroethyl)amine hydrochloride in 60 ml of
dichloromethane. The triethylammonium chloride salts precipitate
and are filtered off. 2.4 ml (31 mmol) of methylsulfonyl chloride
are then added to the filtrate obtained, and the reaction medium is
stirred at ambient temperature for 3 h. After the addition of
water, the product is extracted with dichloromethane. The organic
phase is washed with water, dried over magnesium sulfate, filtered
and concentrated. 5.8 g (94%) of
N,N-bis(2-chloroethyl)methanesulfonamide are obtained in the form
of a beige solid.
2.4: Methyl
(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate
[0161] In a Schlenk tube, a solution of 5 g (20 mmol) of methyl
(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and
4.3 g (20 mmol) of N,N-bis(2-chloroethyl)methanesulfonamide in 65
ml of N,N-diisopropylethylamine is heated at 127.degree. C. with
vigorous stirring for 18 h. After the addition of water, the
product is extracted with ethyl acetate. The organic phases are
combined, washed with water, dried over magnesium sulfate, filtered
and concentrated under vacuum. The crude product obtained is
purified by chromatography on silica gel, elution being carried out
with a 50/50 heptane/ethyl acetate mixture. 3.3 g (46%) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate are obtained in the form of a white solid.
2.5: Methyl
(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
hydrochloride
[0162] 15 ml of a solution of hydrochloric acid in isopropanol,
having a concentration of 5-6N are added dropwise to a solution of
2.7 g (7.4 mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate in 30 ml of methanol. The reaction medium is stirred at
40.degree. C. for 2 h, concentrated under vacuum, and then taken up
in 20 ml of methanol and 150 ml of diethyl ether. The product
precipitates, and is filtered off under vacuum, rinsed with diethyl
ether and then dried under vacuum. 2.3 g (100%) of methyl
(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
hydrochloride are obtained in the form of a white solid.
2.6: Methyl
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-
-1-yl)propanoate
[0163] 0.3 ml (2 mmol) of triethylamine and 270 mg (1 mmol) of
4-but-2-ynyloxybenzenesulfonyl chloride (prepared as described in
2.2) are added to a solution of 300 mg (1 mmol) of methyl
(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
hydrochloride (prrepared as described in 2.5) in 8 ml of
dichloromethane. After stirring at ambient temperature for 18 h,
water is added and the reaction medium is extracted with
dichloromethane. The organic phases are washed with water, dried
over magnesium sulfate, filtered and concentrated.
[0164] The crude product obtained is purified by chromatography on
silica gel, elution being carried out with a 50/50 heptane/ethyl
acetate mixture. 400 mg (85%) of methyl
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-
-1-yl)propanoate are obtained in the form of a white solid.
2.7:
(S)-3-(4-But-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiper-
azin-1-yl)propanoic acid
[0165] 1.3 ml (1.3 mmol) of an aqueous solution of lithium
hydroxide having a concentration of 1M are added to a solution of
400 mg (0.8 mmol) of methyl
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfony-
lpiperazin-1-yl)propanoate diluted in 10 ml of tetrahydrofuran
cooled beforehand to 0.degree. C. The reaction medium is stirred at
ambient temperature for 20 h. After evaporation to dryness, 1.5 ml
of an aqueous solution of acetic acid having a concentration of 1M
are added so as to obtain a pH=6. The product precipitates, and is
filtered off, rinsed with water and then with diethyl ether and
dried under vacuum. 340 mg (89%) of
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-
-1-yl)propanoic acid are obtained in the form of a white solid.
2.8:
(S)-3-(4-But-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesul-
fonylpiperazin-1-yl)propionamide
[0166] 120 mg (0.9 mmol) of 1-hydroxybenzotriazole and 170 mg (0.9
mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride are added to a solution of 340 mg (0.7 mmol) of
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-
-1-yl)propanoic acid in 8 ml of dimethylformamide. The reaction
medium is stirred for 30 min, and then 120 mg (0.8 mmol) of
0-tert-butyldimethysilylhydroxylamine in 3 ml of dimethylformamide
are added. The reaction medium is then stirred at ambient
temperature for 20 h, and then hydrolyzed with 2 ml of water and 2
ml of a 5% aqueous solution of citric acid. After stirring for 30
min, a saturated aqueous solution of sodium hydrogen carbonate is
added to pH=8, and then the reaction medium is extracted with ethyl
acetate. The organic phase is dried over magnesium sulfate,
filtered and concentrated. The residue is taken up in
dichloromethane, filtered, and then dried under vacuum. 80 mg (23%)
of
(S)-3-(4-but-2-ynyloxybenzenesulfonylamino)-N-hydroxy-2-(4-metha-
nesulfonylpiperazin-1-yl)propionamide are obtained in the form of a
white solid with a melting point of 150.degree. C.
[0167] .sup.1H NMR (.delta., DMSO): 1.86 (s, 3H); 2.55 (m, 4H);
2.83 (s, 3H); 2.85-2.88 (m, 1H); 2.97-3.00 (m, 3H); 3.00-3.06 (m,
2H); 3.10-3.12 (t, J=4.8 Hz, 1H); 4.86 (s, 2H); 7.15 (d, J=9.2 Hz,
2H); 7.51 (s, 1H); 7.75 (d, J=9.2 Hz, 2H); 8.94 (s, 1H); 10.6 (s,
1H).
EXAMPLE 3
(S)-3-(4-benzyloxy-benzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylpip-
erazin-1-yl)propionamide
3.1: N,N-bis-(2-Chloroethyl)methanesulfonamide
[0168] 14.3 ml (185 mmol) of methanesulfonyl chloride are added
slowly to a solution of 15 g (84 mmol) of commercial
bis(2-chloroethylamine) hydrochloride and 26 ml (185 mmol) of
triethylamine in 200 ml of dichloromethane and 70 ml of
tetrahydrofuran previously stirred for 15 min and then filtered in
order to remove the triethylammonium chloride. The reaction medium
is then stirred at ambient temperature for 18 h, extracted with
dichloromethane, and washed with water. The organic phase is dried
over magnesium sulfate, filtered and evaporated. The residue
obtained is washed with diisopropyl ether, filtered and then dried
under vacuum. 15.3 g (82%) of
N,N-bis-(2-chloroethyl)methanesulfonamide are obtained in the form
of a solid.
3.2: Methyl
(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate
[0169] A solution of 9.6 g (44 mmol) of
N,N-bis-(2-chloroethyl)methanesulfonamide and 11.1 g (44 mmol) of
methyl 2-amino-3-tert-butoxypropanoate hydrochloride in 90 ml of
diisopropylethylamine is heated at 127.degree. C. for 18 h. The
reaction medium is evaporated to dryness. 31 g of crude residue are
obtained and purified by chromatography on silica gel, elution
being carried out with a 9/1 heptane/ethyl acetate mixture and then
an increase in polarity up to 4/6. 5.5 g (35%) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate are obtained.
3.3: Methyl
(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
dihydrochloride
[0170] A solution of 4 g (11 mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate (prepared as described in example 2.4) in 40 ml of methanol and
20 ml of a solution of hydrochloric acid in isopropanol, having a
concentration of 5 or 6M, is stirred at 40.degree. C. for 18 h and
then concentrated under vacuum. The residue obtained is taken up in
200 ml of diethyl ether, filtered, and then dried under vacuum. 3.5
g (94%) of methyl
(S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
dihydrochloride are obtained in the form of a beige solid.
3.4: Sodium salt of 4-benzyloxybenzenesulfonic acid
[0171] 64 ml (539 mmol) of benzyl bromide are added to a solution
of 50 g (215 mmol) of the sodium salt of 4-hydroxybenzenesulfonic
acid dihydrate in 700 ml of isopropanol and 250 ml (250 mmol) of an
aqueous solution of sodium hydroxide having a concentration of 1M.
The reaction medium is heated at 70.degree. C. for 20 h. After
concentration of the isopropanol under vacuum, the product
precipitates and is filtered off. 61 g (100%) of the sodium salt of
4-benzyloxybenzenesulfonic acid are obtained in the form of a white
solid.
3.5: 4-Benzyloxybenzenesulfonyl chloride
[0172] A solution of 55 ml (639 mmol) of oxalyl chloride in 250 ml
of dichloromethane is added dropwise to a solution of 61 g (213
mmol) of the sodium salt of 4-benzyloxybenzenesulfonic acid in 200
ml of dimethylformamide, while maintaining the temperature between
-20.degree. C. and -10.degree. C. After addition, the reaction
medium is slowly brought back to ambient temperature and then
stirred for 18 h, poured onto ice and extracted with ethyl acetate.
The organic phase is washed with water and with a saturated aqueous
solution of sodium chloride and concentrated under vacuum. 54 g
(89%) of 4-benzyloxybenzenesulfonyl chloride are obtained in the
form of a white solid.
3.6: Methyl
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoate
[0173] 1.1 ml (7.8 mmol) of triethylamine and then 730 mg (2.6
mmol) of 4-benzyloxybenzenesulfonyl chloride in 8 ml of
dichloromethane are added to a solution of 800 mg (2.4 mmol) of
methyl (S)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
dihydrochloride in 20 ml of dichloromethane and the reaction medium
is stirred at ambient temperature for 3 h. After the addition of
water, the product is extracted with dichloromethane. The organic
phase is washed with water, dried over magnesium sulfate, filtered
and concentrated.
[0174] The residue obtained is purified by chromatography on silica
gel, elution being carried out with an 8/2 heptane/ethyl acetate
mixture. 0.9 g (75%) of methyl
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoate are obtained in the form of a white solid.
3.7:
(S)-3-(4-Benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-
-1-yl)propanoic acid
[0175] 2.6 ml (2.6 mmol) of an aqueous solution of lithium
hydroxide having a concentration of 1M are added to a solution of
900 mg (1.8 mmol) of methyl
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpip-
erazin-1-yl)propanoate in 20 ml of tetrahydrofuran and 0.5 ml of
water. The reaction medium is stirred at ambient temperature for 18
h and then the THF is evaporated off under vacuum. 2.8 ml of an
aqueous solution of acetic acid having of concentration of 1M and
then 30 ml of water are added and the product precipitates. The
suspension is stirred for 30 min at 100.degree. C. and then brought
back to ambient temperature, filtered and dried under vacuum. 750
mg (86%) of
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoic acid are obtained in the form of a white solid.
3.8:
(S)-3-(4-Benzyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfony-
l-piperazin-1-yl)propionamide
[0176] 224 mg (1.7 mmol) of 1-hydroxybenzotriazole and 318 mg (1.7
mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride are added successively to 750 mg (1.5 mmol) of
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoic acid in 20 ml of dimethylformamide. After stirring at
ambient temperature for 20 min, a solution of 244 mg (1.7 mmol) of
0-tert-butyldimethylsilylhydroxylamine in 3 ml of dimethylformamide
is added. The reaction medium is then stirred at ambient
temperature for 18 h and then 2 ml of a saturated aqueous solution
of sodium hydrogen carbonate and finally 2 ml of water are added.
After extraction with ethyl acetate, the organic phase is washed
with a saturated aqueous solution of sodium hydrogen carbonate,
dried over magnesium sulfate, filtered and concentrated. The crude
residue obtained is taken up in 15 ml of ethyl acetate, heated to
70.degree. C. and then brought back to ambient temperature,
filtered and dried under vacuum.
[0177] 300 mg (34%) of
(S)-3-(4-benzyloxybenzenesulfonylamino)-N-hydroxy-2-(4-methanesulfonylpip-
erazin-1-yl)propionamide are obtained in the form of a white solid
having a melting point of 165.degree. C.
[0178] .sup.1H NMR (.delta., DMSO): 2.40-2.50 (m, 2H); 2.50-2.60
(m, 2H); 2.84 (s, 3H), 3.00-3.05 (m, 4H); 3.06-3.09 (m, 2H); 3.34
(s, 1H); 5.19 (s, 2H); 7.19 (d, J=8,4 Hz, 2H); 7.30-7.34 (m, 1H);
7.35-7.47 (m, 5H); 7.73 (d, J=8.4 Hz, 2H); 8.93 (s, 1H); 10.65 (s,
1H).
EXAMPLE 4
(S)-3-[(4-Benzyloxybenzenesulfonyl)methylamino]N-hydroxy-2-(4-methanesulfo-
nylpiperazin-1-yl)propionamide
[0179] 4.1: Methyl
(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiper-
azin-1-yl)propanoate
[0180] 300 mg (1.9 mmol) of potassium carbonate and then 0.2 ml
(3.1 mmol) of methyl iodide are added to a solution of 800 mg (1.6
mmol) of methyl
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoate (prepared as described in 3.6) in 15 ml of
dimethylformamide. The reaction medium is then stirred at ambient
temperature for 20 h, hydrolyzed, and then diluted with ethyl
acetate. The product is extracted with ethyl acetate. The organic
phases are washed with water, dried over magnesium sulfate and
filtered.
[0181] The filtrate is concentrated under vacuum, to give 820 mg
(100%) of methyl
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpipera-
zin-1-yl)propanoate in the form of a white solid.
4.2:
(S)-3-[(4-Benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylp-
iperazin-1-yl)propanoic acid
[0182] In a manner analogous to example 3.7, using 820 mg (1,6
mmol) of methyl
(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfon-
ylpiperazin-1-yl)propanoate, 720 mg (90%) of
(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiper-
azin-1-yl)propanoic acid are obtained in the form of a white
solid.
4.3:
(S)-3-[(4-Benzyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methan-
esulfonylpiperazin-1-yl)propionamide
[0183] In a manner analogous to example 3.8, using 720 mg (1.4
mmol) of
(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-2-(4-methanesulfonylpiper-
azin-1-yl)propanoic acid, 360 mg (49%) of
(S)-3-[(4-benzyloxybenzenesulfonyl)methylamino]-N-hydroxy-2-(4-methanesul-
fonylpiperazin-1-yl)propionamide are obtained in the form of a
white solid with a melting point of 110.degree. C.
[0184] .sup.1H NMR (.delta., DMSO): 2.58-2.63 (m, 2H); 2.65 (s,
3H); 2.67-2.73 (m, 2H); 2.86 (s, 3H); 2.98-3.05 (m, 4H); 3.05-3.09
(m, 1H); 3.24-3.25 (m, 1H); 3.28-3.31 (m, 1H); 5.21 (s, 2H); 7.24
(d, J=8.9 Hz, 2H); 7.34-7.44 (m, 3H); 7.48 (d, J=7.2 Hz, 2H); 7.72
(d, J=8.9 Hz, 2H); 8.99 (s, 1H); 10.69 (s, 1H).
EXAMPLE 5
(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-
-ylmethoxy)benzenesulfonylamino]propionamide
5.1: Methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate
[0185] A solution of 2.0 g (3.9 mmol) of methyl
(S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoate (prepared as described in example 3.6) in 60 ml of
ethanol, 30 ml of dioxane and 0.5 ml of glacial acetic acid is
degassed under a nitrogen stream and then 200 mg (10% by weight) of
palladium-on-carbon at 10% in suspension in 3 ml of dioxane are
added. The reaction medium is placed under a hydrogen atmosphere
and stirred at ambient temperature for 18 h. After filtration
through celite, the filtrate is hydrolyzed and then the product is
extracted with ethyl acetate. The organic phase is washed with
water and then with a saturated aqueous solution of sodium
chloride, dried over magnesium sulfate, filtered and concentrated
under vacuum. 1.65 g (100%) of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate are obtained in the form of a white solid.
5.2: Methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propanoate
[0186] 280 mg (0.85 mmol) of cesium carbonate followed by 160 mg
(0.85 mmol) of 4-chloromethyl-2-methylquinoline and by 15 mg of
potassium iodide are added to a solution of 300 mg (0.71 mmol) of
methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate in 10 ml of acetone. The reaction medium is stirred at
ambient temperature for 18 h, filtered and concentrated under
vacuum. The crude product is purified by chromatography on silica
gel, elution being carried out with a 40/60 heptane/ethyl acetate
mixture. 130 mg (32%) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-y-
lmethoxy)benzenesulfonylamino]propanoate are obtained in the form
of a white solid.
5.3:
(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylme-
thoxy)benzenesulfonylamino]propanoic acid
[0187] In a manner analogous to example 3.7, using 130 mg (0.2
mmol) of methyl
(S)-2-(4-methanesulfonyl-piperidin-1-yl)-3-[4-(2-methylquinolin-4--
ylmethoxy)benzenesufonylamino]propanoate, 120 mg (99%) of
(S)-2-(4-methanesulfonylpiperidin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]-propanoic acid are obtained in the form of
a white solid.
5.4:
(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquino-
lin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0188] In a manner analogous to example 3.8, using 123 mg (0.2
mmol) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propanoic acid, 90 mg (69%) of
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin--
4-ylmethoxy)benzenesulfonyl-amino]propionamide are obtained in the
form of a solid with a melting point of 185.degree. C.
[0189] .sup.1H NMR (.delta., DMSO): 2.54-2.60 (m, 4H); 2.72 (s,
3H); 2.88 (s, 3H), 2.88-2.93 (m, 1H); 3.01-3.05 (m, 1H); 3.06-3.12
(m, 4H); 3.13-3.16 (t, J=7 Hz, 1H); 5.76 (s, 2H); 7.38 (d, J=8 Hz,
2H); 7.57 (s, 1H); 7.61-7.66 (m, 2H); 7.78-7.85 (m, 3H); 8.02 (d,
J=8.2 Hz, 1H); 8.15 (d, J=8.2 Hz, 1H); 8.98 (s, 1H); 10.71 (s,
1H).
EXAMPLE 6
(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmet-
hoxy)benzenesulfonylamino]propionamide
6.1: Methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propanoate
[0190] In a manner analogous to example 5.2, using 160 mg (0.9
mmol) of 4-chloromethyl-2-methylquinoline and 300 mg (0.7 mmol) of
methyl
(S)-3-(4-hydroxy-benzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl-
)propanoate (prepared as described in 5.1), 130 mg (32%) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propanoate are obtained in the form of a
white solid.
6.2:
(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)-
benzenesulfonylamino]propanoic acid
[0191] In a manner analogous to example 3.7, using 240 mg (0.6
mmol) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmetho-
xy)benzenesulfonylamino]propanoate, 210 mg (91%) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)benz-
enesulfonylamino]-propanoic acid are obtained in the form of a
white solid.
6.3:
(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1--
ylmethoxy)benzenesulfonylamino]propionamide
[0192] In a manner analogous to example 3.8, using 210 mg (0.4
mmol) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylmethoxy)benz-
enesulfonylamino]propanoic acid, 70 mg (33%) of
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(naphthalen-1-ylme-
thoxy)benzene-sulfonylamino]propionamide are obtained in the form
of a beige solid with a melting point of 148.degree. C.
[0193] .sup.1H NMR (.delta., DMSO): 2.45 (m, 2H); 2.60 (m, 2H);
2.85 (s, 3H); 2.90-3.05 (m, 4H); 3.06-3.15 (m, 2H); 3.35 (s, 1H);
5.66 (s, 2H); 7.30 (d, J=8.4 Hz, 2H); 7.50-7.60 (m, 4H); 7.70 (d,
J=6.2 Hz, 1H); 7.77 (d, J=8.2 Hz, 2H); 7.95-8.05 (m, 2H); 8.10 (d,
J=6.4 Hz, 1H); 8.94 (s, 1H); 10.70 (s, 1H).
EXAMPLE 7
(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfo-
nylamino)propionamide
7.1: Methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)-
propanoate
[0194] In a manner analogous to example 5.2, using 0.1 ml (1.3
mmol) of 1-bromopropane and 400 mg (0.95 mmol) of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate (prepared as described in 5.1), 220 mg (50%) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)-
propanoate are obtained in the form of a colorless oil.
7.2:
(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylam-
ino)propanoic acid
[0195] In a manner analogous to example 3.7, using 220 mg (0.5
mmol) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfony-
lamino)propanoate, 190 mg (90%) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)-
propanoic acid are obtained in the form of a white solid.
7.3:
(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzene-
sulfonylamino)propionamide
[0196] In a manner analogous to example 3.8, using 190 mg (0.4
mmol) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulfonylamino)-
propanoic acid, 30 mg (16%) of
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-(4-propoxybenzenesulf-
onylamino)propionamide are obtained in the form of a white solid
with a melting point of 137.degree. C.
[0197] .sup.1H NMR (.delta., DMSO): 0.91 (t, J=7.3 Hz, 3H);
1.63-1.73 (m, 2H); 2.45 (m, 2H); 2.55 (m, 2H); 2.77 (s, 3H); 2.82
(m, 1H); 2.83-2.95 (m, 4H); 2.95-3.05 (m, 2H); 3.94 (t, J=6.4 Hz,
2H); 7.03 (d, J=8.7 Hz, 2H); 7.38 (m, 1H); 7.65 (d, J=8.7 Hz, 2H);
8.85 (s, 1H); 10.58 (s, 1H).
EXAMPLE 8
(S)-3-[4-(3-Cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesul-
fonylpiperazin-1-yl)propionamide
[0198] 8.1: Methyl
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoate
[0199] In a manner analogous to example 5.2, using 205 mg (1 mmol)
of 3-(bromomethyl)benzonitrile and 400 mg (0.95 mmol) of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate (prepared as described in example 5.1), 295 mg (58%) of
methyl
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoate are obtained in the form of a white
solid.
8.2:
(S)-3-[4-(3-Cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonyl-
piperazin-1-yl)propanoic acid
[0200] In a manner analogous to example 3.7, using 295 mg (0.5
mmol) of methyl
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfo-
nylpiperazin-1-yl)propanoate, 270 mg (94%) of
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoic acid are obtained in the form of a white
solid.
8.3:
(S)-3-[4-(4-Cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-metha-
nesulfonylpiperazin-1-yl)propionamide
[0201] In a manner analogous to example 3.8, using 264 mg (0.5
mmol) of
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoic acid, 107 mg (40%) of
(S)-3-[4-(3-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesu-
lfonylpiperazin-1-yl)propionamide are obtained in the form of a
beige powder with a melting point of 108.degree. C.
[0202] .sup.1H NMR (.delta., DMSO): 2.55 (m, 4H); 2.84 (s, 3H);
2.95-3.05 (m, 4H); 3.10 (t, J=6.4 Hz, 1H); 3.34 (m; 2H); 5.26 (s,
2H); 7.22 (d, J=8.6 Hz, 2H); 7.50 (s, 1H); 7.64 (t, J=7.6 Hz, 1H);
7.76 (d, J=8.6 Hz, 2H); 7.83 (t, J=8 Hz, 2H); 7.96 (s, 1H); 8.93
(s, 1H); 10.66 (s, 1H).
EXAMPLE 9
(S)-3-[4-(4-Cyanobenzyloxy)benzenesulfonylamino]N-hydroxy-2-(4-methanesulf-
onylpiperazin-1-yl)propionamide
9.1: Methyl
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoate
[0203] In a manner analogous to example 5.2, using 400 mg (1 mmol)
of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazi-
n-1-yl)propanoate (prepared as described in 5.1) and 205 mg (1.1
mmol) of 4-(bromomethyl)benzonitrile, 229 mg (45%) of methyl
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoate are obtained in the form of a white
solid.
9.2:
(S)-3-[4-(4-Cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonyl-
piperazin-1-yl)propanoic acid
[0204] In a manner analogous to example 3.7, using 229 mg (0.4
mmol) of methyl
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfo-
nylpiperazin-1-yl)propanoate,
[0205] 202 mg (91%)
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)propanoic acid are obtained in the form of a white
solid.
9.3:
(S)-3-[4-(4-Cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-metha-
nesulfonylpiperazin-1-yl)propionamide
[0206] In a manner analogous to example 3.8, using 197 mg (0.4
mmol) of
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-2-(4-methanesulfonylpipe-
razin-1-yl)-propanoic acid, 81 mg (40%) of
(S)-3-[4-(4-cyanobenzyloxy)benzenesulfonylamino]-N-hydroxy-2-(4-methanesu-
lfonylpiperazin-1-yl)propionamide are obtained in the form of a
beige powder with a melting point of 109.degree. C.
[0207] .sup.1H NMR (.delta., DMSO): 2.50-2.60 (m, 4H); 2.84 (s,
3H); 2.96 -3.01 (m, 4H); 3.09 (t, J=7 Hz, 1H); 3.34 (s, 2H); 5.32
(s, 2H); 7.22 (d, J=8.8 Hz, 2H); 7.50 (m, 1H); 7.66 (d, J=8.1 Hz,
2H); 7.75 (d, J=8.8 Hz, 2H); 7.89 (d, J=8.1 Hz, 2H); 8.93 (s, 1H);
10.66 (s, 1H).
EXAMPLE 10
Benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzen-
esulfonylamino]ethyl}piperazine-1-carboxylate
10.1: Benzyl bis(2-chloroethyl)carbamate
[0208] 13.2 ml (92 mmol) of benzyl chloroformate are added slowly
to a solution, cooled to 0.degree. C., of 15 g (84 mmol) of
bis(2-chloroethylamine) hydrochloride, 26 ml (185 mmol) of
triethylamine in 200 ml of dichloromethane and 70 ml of
tetrahydrofuran, stirred beforehand for 15 min and then filtered in
order to remove the triethylammonium chloride. The reaction medium
is stirred at ambient temperature for 18 h. After the addition of
water, the reaction medium is extracted with ethyl acetate. The
organic phase is dried over magnesium sulfate, filtered and
evaporated. 20 g of crude residue are obtained and purified by
chromatography on silica gel, elution being carried out with an 8/2
heptane/ethyl acetate mixture. 6 g (26%) of benzyl
bis(2-chloroethyl)carbamate are thus obtained.
10.2: Benzyl
4-((S)-2-tert-butoxycarbonylamino-1-methoxycarbonylethyl)piperazine-1-car-
boxylate
[0209] A solution of 5.5 g (20 mmol) of benzyl
bis(2-chloroethyl)carbamate and 5.1 g (20 mmol) of methyl
2-amino-3-tert-butoxypropanoate hydrochloride in 40 ml of
diisopropylethylamine is heated at 127.degree. C. for 18 h. After
cooling, the reaction medium is evaporated to dryness. 17 g of
crude residue are obtained and purified by chromatography on silica
gel, elution being carried out with a 9/1 up to 4/6 heptane/ethyl
acetate mixture. 1.6 g (19%) of benzyl
4-((S)-2-tert-butoxycarbonylamino-1-methoxycarbonylethyl)piperazine-1-car-
boxylate.
10.3: Benzyl
4-(2-amino-1-methoxycarbonylethyl)piperazine-1-carboxylate
dihydrochloride
[0210] A solution of 1.45 g (3.4 mmol) of benzyl
4-((S)-2-tert-butoxycarbonylamino-1-methoxycarbonylethyl)piperazine-1-car-
boxylate in 3.5 ml of a solution of hydrochloric acid in
isopropanol, having a concentration 5-6N, and 10 ml of methanol is
heated at 40.degree. C. for 3 h and then evaporated. The residue is
taken up in diethyl ether and filtered. 1.2 g (90%) of benzyl
4-(2-amino-1-methoxycarbonylethyl)piperazine-1-carboxylate
dihydrochloride are obtained in the form of a solid.
10.4: Benzyl
4-[(S)-2-(4-hydroxybenzenesulfonylamino)-1-methoxycarbonylethyl]piperazin-
e-1-carboxylate
[0211] 2.1 ml (15 mmol) of triethylamine and then 920 mg (5 mmol)
of 4-hydroxybenzenesulfonyl chloride in 20 ml of dichloromethane
are added dropwise to a solution of 1.1 g (3 mmol) of benzyl
4-(2-amino-1-methoxycarbonylethyl)piperazine-1-carboxylate
dihydrochloride in 30 ml of dichloromethane, cooled beforehand to
0.degree. C. The reaction medium is then stirred at ambient
temperature for 18 h. After the addition of water, the reaction
medium is extracted with dichloromethane. The organic phase is with
water and then dried over magnesium sulfate, filtered and
concentrated under vacuum. The crude residue obtained is purified
by chromatography on silica gel, elution being carried out with a
50/50 heptane/ethyl acetate mixture. 60 mg (46%) of benzyl
442-(4-hydroxybenzenesulfonylamino)-1-methoxycarbonylethyl]pipe-
razine-1-carboxylate are obtained in the form of a white solid.
10.5: Benzyl
4-{(S)-1-methoxycarbonyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzensulfony-
lamino]ethyl}piperazine-1-carboxylate
[0212] In a manner analogous to example 5.2, using 260 mg (1.4
mmol) of 4-chloromethyl-2-methylquinoline and 600 mg (1.3 mmol) of
benzyl
4-[(S)-2-(4-hydroxybenzensulfonylamino)-1-methoxycarbonylethyl]piperazine-
-1-carboxylate, 320 mg (40%) of benzyl
4-{(S)-1-methoxycarbonyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfon-
ylamino]ethyl}piperazine-1-carboxylate are obtained in the form of
a white solid.
10.6: Benzyl
4-{(S)-1-carboxy-2-[4-(2-methylquinolin-4-ylmethoxybenzenesulfonylamino]e-
thyl}piperazine-1-carboxylate
[0213] In a manner analogous to example 3.7, using 160 mg (0.25
mmol) of benzyl
4-{(S)-1-methoxycarbonyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzen-
esulfonylamino]ethyl}piperazine-1-carboxylate, 135 mg (87%) of
benzyl
4-{(S)-1-carboxy-2-[4-(2-methylquinolin-4-ylmethoxy-benzenesulfonylamino]-
ethyl}piperazine-1-carboxylate are obtained in the form of a beige
solid.
10.7: Benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfo-
nylamino]ethyl}piperazine-1-carboxylate
[0214] In a manner analogous to example 3.8, using 135 mg (0.2
mmol) of benzyl
4-{(S)-1-carboxy-2-[4-(2-methylquinolin-4-ylmethoxybenzenesulfonyl-
amino]ethyl}piperazine-1-carboxylate, 115 mg (82%) of benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfo-
nylamino]ethyl}piperazine-1-carboxylate are obtained in the form of
a white solid with a melting point of 162.degree. C.
[0215] .sup.1H NMR (.delta., DMSO): 2.35-2.45 (m, 4H); 2.70 (s,
3H); 2.80-2.90 (m, 1H); 2.95-3.05 (m, 1H); 3.05-3.10 (m, 1H);
3.25-3.40 (m, 4H); 5.05 (s, 2H); 5.74 (s, 2H); 7.29-7.40 (m, 7H);
7.55 (m, 1H); 7.60-7.70 (m, 2H); 7.79 (d, J=8.8 Hz, 3H); 8.01 (d,
J=8 Hz, 1H); 8.14 (d, J=8 Hz, 1H); 8.91 (s, 1H); 10.67 (s, 1H).
EXAMPLE 11
(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4--
ylmethoxy)benzenesulfonylamino]propionamide
11.1: Methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy-
)benzenesulfonylamino]propanoate
[0216] 0.23 ml (1.4 mmol) of diethyl azodicarboxylate is added
slowly to a solution of 400 mg (0.9 mmol) of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate (prepared as described in example 5.1), 193 mg (1.0
mmol) of (2-phenylpyridin-4-yl)methanol and 373 mg (1.4 mmol) of
triphenylphosphine in 4 ml of tetrahydrofuran. The reaction mixture
is stirred for one hour at ambient temperature and then evaporated
to dryness. The residue obtained is purified by chromatography on
silica gel, elution being carried out with a 60/40 heptane/ethyl
acetate mixture. 318 mg (57%) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy-
)-benzenesulfonylamino]propanoate are obtained in the form of a
white powder.
11.2:
(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylme-
thoxy)benzenesulfonylamino]propanoic acid
[0217] In a manner analogous to example 3.7, using 317 mg (0.5
mmol) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-yl-
methoxy)benzenesulfonylamino]propanoate, 298 mg (96%) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethoxy-
)benzene-sulfonylamino]propanoic acid are obtained in the form of a
white solid.
11.3:
(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4)-(2-(2-phenyl-
pyridin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0218] In a manner analogous to example 3.8, using 293 mg (0.5
mmol) of
(S)-2-(4-methane-sulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-ylmethox-
y)benzenesulfonylamino]propanoic acid, 64 mg (21%) of
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-phenylpyridin-4-
-ylmethoxy)benzenesulfonylamino]propionamide are obtained in the
form of a white powder with a melting point of 100.degree. C.
[0219] .sup.1H NMR (.delta., DMSO): 2.52-2.59 (m, 4H); 2.84 (s,
3H); 2.85-2.90 (m, 1H); 2.90-3.00 (m, 1H); 3.00-3.08 (m, 4H); 3.10
(t, J=7.0 Hz, 1H); 5.35 (s, 2H); 7.26 (d, J=8.9 Hz, 2H); 7.42 (m,
1H); 7.45-7.55 (m, 4H); 7.78 (d, J=8.8 Hz, 2H); 8.03 (s, 1H); 8.10
(d, J=7.0 Hz, 2H); 8.69 (d, J=5.0 Hz, 1H); 8.93 (s, 1H); 10.66 (s,
1H).
EXAMPLE 12
(R)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-
-ylmethoxy)benzenesulfonylamino]propionamide
12.1: Methyl
(R)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate
[0220] In a manner analogous to example 3.2, using 3.8 g (17 mmol)
of N,N-bis(2-chloroethyl)-methanesulfonamide (prepared as described
in 3.1) and 4 g (16 mmol) of commercial methyl
(R)-2-amino-3-tert-butoxypropanoate hydrochloride, 2.6 g (46%) of
methyl
(R)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)propano-
ate are obtained in the form of a light yellow solid.
12.2: Methyl
(R)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
dihydrochloride
[0221] In a manner analogous to example 3.3, using 2.5 g (7 mmol)
of methyl
(R)-3-tert-butoxycarbonylamino-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate, 2.3 g (100%) of methyl
(R)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate are
obtained.
12.3: Methyl
(R)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoate
[0222] In a manner analogous to example 3.6, using 2.4 g (8.4 mmol)
of 4-benzyloxybenzenesulfonyl chloride (prepared as described in
example 3.5) and 2.3 g (7.6 mmol) of methyl
(R)-3-amino-2-(4-methanesulfonylpiperazin-1-yl)propanoate
dihydrochloride, 3 g (77%) of methyl
(R)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-y-
l)propanoate are obtained in the form of a solid.
12.4: Methyl
(R)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate
[0223] In a manner analogous to example 5.1, using 3 g (5.9 mmol)
of methyl
(R)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpipera-
zin-1-yl)propanoate, 2 g (80%) of methyl
(R)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate are obtained in the form of a white solid.
12.5: Methyl
(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmeth-o-
xy)benzenesulfonylamino]propanoate
[0224] In a manner analogous to example 5.2, using 1 g (2.4 mmol)
of methyl
(R)-3-(4-hydroxy-benzenesulfonylamino)-2-(4-methanesulfonylpiperaz-
in-1-yl)propanoate and 500 mg (2.6 mmol) of
4-chloromethyl-2-methylquinoline, 740 mg (53%) of methyl
(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propanoate are obtained in the form of a
solid.
12.6:
(R)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylm-
ethoxy)benzenesulfonylamino]propanoic acid
[0225] In a manner analogous to example 3.7, using 740 mg (1.3
mmol) of methyl
(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-y-
lmethoxy)benzenesulfonylamino]propanoate, 622 mg (86%) of
(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)-benzenesulfonylamino]propanoic acid are obtained.
12.7:
(R)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquin-
olin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0226] In a manner analogous to example 3.8, using 620 mg (1.1
mmol) of
(R)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propanoic acid, 465 mg (73%) of
(R)-N-hydroxy-2-(4-methansulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-
-ylmethoxy)benzenesulfonylamino]propionamide are obtained in the
form of a white solid.
[0227] .sup.1H NMR (.delta., DMSO): 2.53 (m, 4H); 2.68 (s, 3H);
2.84 (s, 3H); 2.85 (m, 2H); 2.95-3.05 (m, 4H); 3.10 (m, 1H); 5.72
(s, 2H); 7.35 (d, J=8.8 Hz, 2H); 7.52 (m, 1H); 7.57-7.62 (m, 2H);
7.75-7.82 (m, 3H); 7.98 (d, J=8.4 Hz, 1H); 8.11 (d, J=8.16 Hz, 1H);
8.93 (s, 1H); 10.70 (s, 1H).
EXAMPLE 13
(S)-N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-p-
iperazin-1-ylpropionamide
13.1: Benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfo-
nylamino]ethyl}piperazine-1-carboxylate
[0228] In a manner analogous to example 3.8, using 135 mg (0.2
mmol) of benzyl
4-{(S)-1-carboxy-2-[4-(2-methylquinolin-4-ylmethoxybenzenesulfonyl-
amino]ethyl}piperazine-1-carboxylate (prepared as described in
10.6), 115mg (82%) of benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfo-
nylamino]ethyl}piperazine-1-carboxylate are obtained in the form of
a white solid with a melting point of 162.degree. C.
13.2:
(S)-N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamin-
o]-2-piperazin-1-ylpropionamide
[0229] 90 mg (0.15 mmol) of benzyl
4-{(S)-1-hydroxycarbamoyl-2-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfo-
nylamino]ethyl}piperazine-1-carboxylate are placed in solution
in
[0230] 5 ml of dichloromethane and 5 ml of trifluoroacetic acid.
The reaction medium is then stirred at ambient temperature for 96
h. After evaporation of the trifluoroacetic acid, the residue is
taken up with 5 ml of saturated aqueous solution of sodium hydrogen
carbonate and extracted with n-butanol. The organic phase is washed
with water and then with a saturated aqueous solution of sodium
chloride, dried over magnesium sulfate, filtered and concentrated
under vacuum. The crude product obtained is taken up in a 50/50
heptane/ethyl acetate mixture, stirred for 1 h and then filtered
and dried under vacuum. 50 mg (70%) of
(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2--
piperazin-1-ylpropionamide are obtained in the form of a beige
solid with a melting point of 225.degree. C.
[0231] .sup.1H NMR (.delta., DMSO): 2.35-2.45 (m, 4H); 2.67 (s,
3H); 2.70 (m, 4H); 2.80-3.00 (m, 2H); 3.15 (s, 1H); 5.72 (s, 2H);
7.35 (d, J=8.6 Hz, 2H); 7.70-7.80 (m, 3H); 7.98 (d, J=8.4 Hz, 1H);
8.12 (d, J=8.2 Hz, 1H).
EXAMPLE 14
(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-
-ylmethoxy)benzenesulfonylamino]propionamide hydrochloride
[0232] 0.2 ml (1.3 mmol) of a solution of hydrochloric acid in
isopropanol having a concentration of 5-6N is added to a solution
of 301 mg (0.5 mmol) of
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methyl-
quinolin-4-ylmethoxy)benzenesulfonylamino]propionamide (prepared as
described in example 14) in 10 ml of isopropanol. After stirring at
ambient temperature for 1 h, the product precipitates. Through
filtration, 927 mg of
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin--
4-ylmethoxy)benzenesulfonylamino]propionamide hydrochloride are
obtained in the form of a white powder. This solid is
recrystallized from a 30 ml/5 ml isopropanol/water mixture. 176 mg
(52%) of
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin--
4-ylmethoxy)benzenesulfonylamino]propionamide are obtained in the
form of a white powder with a melting point of 209.degree. C.
[0233] .sup.1H NMR (.delta., DMSO): 2.67 (m, 4H); 2.87 (s, 3H);
2.93 (s, 3H); 3.00-3.15 (m, 4H); 3.22 (m, 1H); 3.35-3.90 (m, 2H);
5.94 (s, 2H); 7.42 (d, J=8.7 Hz, 2H); 7.64 (m, 1H); 7.83-7.90 (m,
3H); 7.98 (m, 1H); 8.05 (m, 1H); 8.30 (d, J=7.6 Hz; 1H); 8.38 (d,
J=8.5 Hz, 1H); 9.00 (m, 1H); 10.75 (m, 1H).
EXAMPLE 15
tert-Butyl
3-{4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulfonylpiperazin-1-yl-
)ethylsulfamoyl]phenoxymethyl}-2-methylindole-1-carboxylate
di(trifluoroacetate).
15.1: tert-Butyl
3-{4-[(S)-2-(4-methanesulfonylpiperazin-1-yl)-2-methoxycarbonylethylsulfa-
moyl]-phenoxymethyl}-2-methylindole-1-carboxylate
[0234] In a manner analogous to example 11.1, using 400 mg (0.95
mmol) of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazi-
n-1-yl)propanoate (prepared as described in example 5.1) and 248 mg
(0.95 mmol) of commercial tert-butyl
3-hydroxymethyl-2-methylindole-1-carboxylate, 326 mg (52%) of
tert-butyl
3-{4-[(S)-2-(4-methanesulfonylpiperazin-1-yl)-2-methoxycarbonylethylsulfa-
moyl]phenoxymethyl}-2-methylindole-1-carboxylate are obtained in
the form of a beige powder.
15.2: tert-Butyl
3-{4-[(S)-2-carboxy-2-(4-methanesulfonylpiperazin-1-yl)-ethylsulfamoyl]ph-
enoxymethyl}-2-methylindole-1-carboxylate
[0235] In a manner analogous to example 3.7, using 325 mg (0.5
mmol) of tert-butyl
3-{4-[(S)-2-(4-methanesulfonylpiperazin-1-yl)-2-methoxycarbonylethylsulfa-
moyl]phenoxymethyl}-2-methylindole-1-carboxylate, 179 mg (100%) of
tert-butyl
3-{4-[(S)-2-carboxy-2-(4-methanesulfonylpiperazin-1-Aethylsulfamoyl]pheno-
xymethyl}-2-methylindole-1-carboxylate are obtained in the form of
a yellow powder.
15.3: tert-Butyl
3-{4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulfonylpiperazin-1-yl)ethylsulf-
amoyl]phenoxymethyl}-2-methylindole-1-carboxylate
di(trifluoroacetate)
[0236] 45 mg (0.3 mmol) of O-tert-butyldimethylsilylhydroxylamine
in solution in 1 ml of dimethylformamide are added to a solution of
179 mg (0.3 mmol) of tert-butyl
3-{4-[(S)-2-carboxy-2-(4-methanesulfonylpiperazin-1-yl)ethylsulfamoyl]phe-
noxymethyl}-2-methyl-indole-1-carboxylate, 41 mg (0.3 mmol) of
1-hydroxybenzotriazole and 58 mg (0.3 mmol) of
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in 3 ml
of dimethylformamide. The reaction mixture is stirred at ambient
temperature for 18 h. After the addition of water and then
extraction with ethyl acetate, the organic phases are combined,
washed with a saturated solution of sodium hydrogen carbonate and
then dried over sodium sulfate, filtered and evaporated. The
residue is purified by preparative HPLC (Gemini C6 phenyl column,
150.times.3 mm, 3 .mu.m; UV detector: 190-420 nm; flow rate: 0.3
ml/mn; solvent A: CH.sub.3CN+0.02% trifluoroacetic acid; solvent B:
water+0.02% trifluoroacetic acid).
[0237] Gradient :
TABLE-US-00001 Time Composition 0.0 min A = 5% B = 95% 20.0 min A =
98% B = 2% 30.0 min A = 98% B = 2% Retention time: 14.6 min, M + 1
= 666.1.
[0238] After concentration of the various fractions, 21 mg (10%) of
tert-butyl
3-{4-[(S)-2-hydroxycarbamoyl-2-(4-methanesulfonylpiperazin-1-yl)ethylsulf-
amoyl]phenoxymethyl}-2-methylindole-1-carboxylate
di(trifluoroacetate) are obtained.
EXAMPLE 16
(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmetho-
xy)benzenesulfonylamino]propionamide.
16.1: Methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzen-
esulfonylamino]propanoate
[0239] In a manner analogous to example 5.2, using 440 mg (2.5
mmol) of 4-chloromethylquinoline and 950 mg (2.2 mmol) of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)-
propanoate (prepared as described in 5.1), 550 mg (43%) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzen-
esulfonylamino]propanoate are obtained in the form of a colorless
oil.
16.2:
(S)-2-(4-Methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)b-
enzenesulfonylamino]propanoic acid
[0240] In a manner analogous to example 3.7, using 550 mg (1.0
mmol) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy-
)benzenesulfonylamino]propanoate, 450 mg (83%)
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzen-
esulfonylamino]-propanoic acid are obtained in the form of a white
solid.
16.3:
(S)-N-Hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-y-
lmethoxy)benzenesulfonylamino]propionamide
[0241] In a manner analogous to example 3.8, using 450 mg (0.8
mmol) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmethoxy)benzen-
esulfonylamino]propanoic acid, 260 mg (56%) of
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(quinolin-4-ylmeth-
oxy)benzenesulfonylamino]propionamide are obtained in the form of a
white solid with a melting point of 180.degree. C.
[0242] .sup.1H NMR (.delta., DMSO): 2.52-2.54 (m, 4H); 2.84 (s,
3H); 2.87 (m, 1H); 2.97 (m, 1H); 2.98-3.05 (m, 4H), 3.11 (t, J=7
Hz, 1H); 5.78 (s, 2H); 7.34 (d, J=8.8 Hz, 2H); 7.52 (m, 1H);
7.66-7.72 (m, 2H); 7.78-7.84 (m, 3H); 8.10 (d, J=8.3 Hz, 1H); 8.19
(d, J=8.2 Hz, 1H); 8.93 (s, 1H); 8.94 (s, 1H); 10.67 (s, 1H).
EXAMPLE 17
(S)-2-(4-Benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propionamide
[0243] 17.1: Sodium salt of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonic acid 100 g (438
mmol) of 4-chloromethyl-2-methylquinoline hydrochloride are added
to a solution of 77 g (395 mmol) of the sodium salt of
4-hydroxybenzenesulfonic acid and of 84 ml (84 mmol) of an aqueous
solution of sodium hydroxide, having a concentration of 1M, in 800
ml of isopropanol. The reaction medium is heated at 70.degree. C.
for 5 h and then at 40.degree. C. for 18 h.
[0244] After evaporation of the isopropanol, the product obtained
is filtered, rinsed with isopropanol and with diethyl ether and
then dried under vacuum. 114 g (75%) of the sodium salt of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonic acid are obtained
in the form of a white solid.
17.2: 4-(2-Methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
[0245] 76 g (216 mmol) of the sodium salt of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonic acid in 500 ml of
dimethylformamide are added dropwise to a solution of 55 ml (649
mmol) of oxalyl chloride in 100 ml of dichloromethane, cooled
beforehand to -10.degree. C. After the addition, the reaction
medium is stirred at ambient temperature for 18 h. The reaction
medium is then poured into 1 I of ice and then extracted with ethyl
acetate. The organic phases are combined, washed with water and
then with a saturated aqueous solution of sodium chloride, dried
over magnesium sulfate, filtered and concentrated under vacuum. 77
g (92%) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride are obtained in the form of a beige solid.
17.3: Benzylbis(2-chloroethyl)amine
[0246] 21 g (152 mmol) of potassium carbonate and then 8 ml (67
mmol) of benzyl bromide are added to a solution of 10 g (56 mmol)
of bis(2-chloroethyl)amine hydrochloride in 130 ml of acetonitrile,
and then the reaction medium is heated at 60.degree. C. for 24 h.
After filtration, the filtrate is concentrated under vacuum. The
crude residue is purified by chromatography on silica gel, elution
being carried out with a 90/10 heptane/ethyl acetate mixture, to
give 8.5 g (65%) of benzylbis(2-chloroethyl)amine.
17.4: Methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate
[0247] A solution of 5.9 g (23 mmol) of commercial methyl
(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and
of 9.6 g (23 mmol) of benzylbis(2-chloroethyl)amine in 50 ml of
N,N-diisopropylethylamine is heated at 127.degree. C. for 3h 30.
After evaporation of the N,N-diisopropylethylamine, the reaction
medium is hydrolyzed and then extracted with ethyl acetate. The
organic phase is washed with an aqueous solution of sodium
hydroxide having a concentration of 1N, and with water, and then
dried over magnesium sulfate, filtered and concentrated under
vacuum. The crude product obtained is purified by chromatography on
silica gel, elution being carried out with a 50/50 heptane/ethyl
acetate mixture. 8.9 g (64%) of methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoat-
e are obtained in the form of a yellow oil.
17.5: Methyl (S)-3-amino-2-(4-benzylpiperazin-1-yl)propanoate
trihydrochloride
[0248] 8.9 g (23.5 mmol) of methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate
are placed in solution in 60 ml of methanol and in 20 ml of
isopropanolic hydrochloric acid having a concentration of 5-6N. The
reaction medium is stirred at 40.degree. C. for 18 h and then
concentrated under vacuum. 9.0 g (100%) of methyl
(S)-3-amino-2-(4-benzylpiperazin-1-yl)propanoate trihydrochloride
are obtained in the form of a beige solid.
17.6: Methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzene-
sulfonylamino]propanoate
[0249] In a manner analogous to example 3.6, using 1.0 g (2.6 mmol)
of methyl (S)-3-amino-2-(4-benzylpiperazin-1-yl)propanoate
trihydrochloride and 1.1 g (2.8 mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride in
hydrochloride form, 750 mg (50%) of methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzene-
sulfonylamino]propanoate are obtained in the form a beige
solid.
17.7:
(S)-2-(4-Benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)be-
nzenesulfonylamino]propanoic acid
[0250] In a manner analogous to example 3.7, using 750 mg (1.3
mmol) of methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)-
benzenesulfonylamino]propanoate, 680 mg (93%) of
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzene-
sulfonylamino]propanoic acid are obtained in the form of a white
solid.
17.8:
(S)-2-(4-Benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-yl-
methoxy)benzenesulfonylamino]propionamide
[0251] In a manner analogous to example 3.8, using 680 mg (1.2
mmol) of
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzene-
sulfonylamino]propanoic acid, 250 mg (36%) of
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propionamide are obtained in the form of a
white solid with a melting point of 188.degree. C.
[0252] .sup.1H NMR (.delta., DMSO): 2.33 (m, 4H); 2.49 (m, 4H);
2.73 (s, 3H); 2.80-2.90 (m, 1H); 3.00-3.10 (m, 2H); 2.46 (m, 2H);
5.77 (s, 2H); 7.25-7.40 (m, 7H); 7.50(m, 1H); 7.61-7.67 (m, 2H);
7.78-7.85 (m, 3H); 8.04 (d, J=8 Hz, 1H); 8.17 (d, J=8.2 Hz, 1H);
8.95 (s, 1H); 10.65 (s, 1H).
EXAMPLE 18
(S)-2-[4-(4-Fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-methylquinolin--
4-ylmethoxy)benzenesulfonylamino]propionamide
18.1: Bis(2-chloroethyl)(4-fluorobenzyl)amine
[0253] In a manner analogous to example 17.3, using 5 g (28 mmol)
of bis(2-chloroethyl)amine hydrochloride and 3.8 ml (31 mmol) of
1-bromomethyl-4-fluorobenzene, 6.9 g (98%) of
bis(2-chloroethyl)(4-fluorobenzyl)amine are obtained.
18.2: Methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propan-
oate
[0254] In a manner analogous to example 17.4, using 7.1 g (28 mmol)
of methyl (S)-2-amino-3-tert-butoxycarbonylaminopropanoate
hydrochloride and 6.9 g (28 mmol) of bis(2-chloroethyl)
(4-fluorobenzyl)amine, 5.3 g (48%) of methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-fluorobenzyl)piperazin-1-
-yl]propanoate are obtained in the form of an oil.
18.3: Methyl
(S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate
trihydrochloride
[0255] In a manner analogous to example 17.5, using 5.3 g (13.4
mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-fluorobenzyl)piperazin-1-yl-
]propanoate, 5.4 g (100%) of methyl
(S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate
trihydrochloride are obtained in the form of a beige solid.
18.4: Methyl
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propanoate
[0256] In a manner analogous to example 3.6, using 1.5 g (3.7 mmol)
of methyl
(S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate
trihydrochloride and 1.6 g (4.1mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride (prepared as described in 17.2), 1.0 g (46%) of
methyl
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propanoate is obtained in the form of a
white solid.
18.5:
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-yl-
methoxy)benzenesulfonylamino]propanoic acid
[0257] In a manner analogous to example 3.7, using 1.1 g (1.7 mmol)
of methyl
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4--
ylmethoxy)benzenesulfonylamino]propanoate, 1.0 g (100%) of
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzene-sulfonylamino]propanoic acid are obtained in the form of
a white solid.
18.6:
(S)-2-[4-(4-Fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-methylqui-
nolin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0258] In a manner analogous to example 3.8, using 990 mg (1.7
mmol) of
(S)-2-[4-(4-fluorobenzyl)-piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmeth-
oxy)benzenesulfonylamino]propanoic acid, 330 mg (33%) of
(S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-N-hydroxy-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzene-sulfonylamino]propionamide are obtained in the
form of a white solid with a melting point of 180.degree. C.
[0259] .sup.1H NMR (.delta., DMSO): 2.20-2.30 (m, 4H); 2.35-2.45
(m, 4H); 2.66 (s, 3H); 2.72-2.80 (m, 1H); 2.87-3.00 (m, 2H); 3.38
(s, 2H); 5.70 (s, 2H); 7.10 (t, J=8.8 Hz, 2H); 7.26-7.33 (m, 4H);
7.56-7.60(m, 2H); 7.73-7.78 (m, 3H); 7.97 (d, J=8.4 Hz, 1H); 8.10
(d, J=8,2 Hz, 1H).
EXAMPLE 19
(S)-2-(4-ethyl-piperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-yl-metho-
xy)benzenesulfonylamino]propionamide
19.1: bis(2-Chloroethyl)ethylamine
[0260] 24 ml (330 mmol) of thionyl chloride are added dropwise to a
solution of 20 g (150 mmol) of
2-[ethyl(2-hydroxyethyl)amino]ethanol in 200 ml of dichloromethane
cooled beforehand to 0.degree. C., and then the reaction medium is
stirred at ambient temperature for 20 h. After the addition of a
saturated aqueous solution of sodium hydrogen carbonate, the
product is extracted with dichloromethane. The organic phase
obtained is then washed with water, dried over magnesium sulfate,
filtered and concentrated under vacuum. 19.5 g (76%) of
bis(2-chloroethyl)ethylamine are obtained in the form of an
oil.
19.2: Methyl
(S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate
[0261] A solution of 5.0 g (19.6 mmol) of commercial methyl
(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and
3.3 g (19.6 mmol) of bis(2-chloroethyl)ethylamine in 50 ml of
N,N-diisopropylethylamine is heated at 127.degree. C. for 5 h.
[0262] After evaporation of a maximum amount of
diisopropylethylamine, the reaction medium is diluted with ethyl
acetate and washed with an aqueous solution of sodium hydroxide
having a concentration of 1 N. The organic phase obtained is then
washed with water, dried over magnesium sulfate, filtered and
concentrated under vacuum. The crude product obtained is purified
by chromatography on silica gel, elution being carried out with a
30/70 heptane/ethyl acetate mixture. 2.5 g (40%) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate
are obtained in the form of an oil.
19.3: Methyl (S)-3-amino-2-(4-ethylpiperazin-1-yl)propanoate
trihydrochloride
[0263] 2.5 g (7.9 mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-ethylpiperazin-1-yl)propanoate
are placed in 20 ml of methanol and 10 ml of isopropanolic
hydrochloric acid having a concentration of 5-6N. The reaction
medium is heated at 40.degree. C. for 3 h and then evaporated to
dryness. The residue is taken up in 50 ml of ethanol, stirred for 1
h at ambient temperature and then filtered. 1.4 g (54%) of methyl
(S)-3-amino-2-(4-ethylpiperazin-1-yl)propanoate trihydrochloride
are obtained in the form of a beige solid.
19.4: Methyl
(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenes-
ulfonylamino]propanoate
[0264] In a manner analogous to example 3.6, using 700 mg (2.1
mmol) of methyl (S)-3-amino-2-(4-ethylpiperazin-1-yl)propanoate
trihydrochloride and 900 mg (2.3 mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride (prepared as described in 17.2), 740 mg (67%) of
methyl
(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)b-
enzenesulfonylamino]propanoate are obtained in the form of a white
solid.
19.5:
(S)-2-(4-Ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)ben-
zenesulfonylamino]propanoic acid
[0265] In a manner analogous to example 3.7, using 740 mg (1.4
mmol) of methyl
(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)b-
enzenesulfonylamino]propanoate, 630 mg (87%) of
(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenes-
ulfonylamino]propanoic acid are obtained in the form of a white
solid.
19.6:
(S)-2-(4-Ethylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylm-
ethoxy)benzenesulfonylamino]propionamide
[0266] In a manner analogous to example 3.8, using 630 mg (1.2
mmol) of
(S)-2-(4-ethylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenes-
ulfonylamino]propanoic acid, 60 mg (8%) of
(S)-2-(4-ethylpiperazin-1-yl)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethox-
y)benzenesulfonylamino]propionamide are obtained in the form of a
white solid with a melting point of 150.degree. C.
[0267] .sup.1H NMR (.delta., DMSO): 2.49 (s, 3H); 2.55-2.65 (m,
2H); 2.69 (s, 3H); 2.70-2.90 (m, 6H); 2.90-3.00 (m, 2H); 3.13 (t,
J=7.3 Hz, 1H); 3.20-3.35 (m, 2H); 3.36 (s, 2H); 5.72 (s, 2H); 7.35
(d, J=8.9 Hz, 2H); 7.58-7.62 (m, 3H); 7.74-7.81 (m, 3H); 7.98 (d,
J=7.9 Hz, 1H); 8.12 (d, J=8.3 Hz, 1H); 9.03 (s, 1H), 10.82 (s,
1H).
EXAMPLE 20
(S)-N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[-
4-(4-trifluoromethylbenzyl)piperazin-1-yl]propionamide
20.1: bis-(2-Chloroethyl)(4-trifluoromethylbenzyl)amine
[0268] In a manner analogous to example 32.3, using 5.0 g (28 mmol)
of bis(2-chloroethyl)amine hydrochloride and 7.4 g (31 mmol) of
1-bromomethyl-4-trifluoromethylbenzene, 5 g (59%) of a
bis(2-chloroethyl)(4-trifluoromethylbenzyl)amine mixture are
obtained in the form of a colorless oil.
20.2: Methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-trifluoromethylbenzyl)piperazin-1--
yl]propanoate
[0269] A solution of 4.2 g (16.5 mmol) of methyl
(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and
4.95 g (16.5 mmol) of
bis(2-chloroethyl)(4-trifluoromethylbenzyl)amine in 25 ml of
N,N-diisopropylethylamine is heated at 127.degree. C. for 6 h.
After evaporation of a maximum amount of diisopropylethylamine, the
reaction medium is diluted with ethyl acetate and washed with an
aqueous solution of sodium hydroxide having a concentration of 1N.
The organic phase obtained is washed with water, dried over
magnesium sulfate, filtered and concentrated under vacuum. The
crude residue is purified by chromatography on silica gel, elution
being carried out with a 60/40 heptane/ethyl acetate mixture. 4.0 g
(55%) of methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-trifluoromethylbenzyl)piperazin-1--
yl]propanoate are obtained in the form of an oil.
20.3: Methyl
(S)-3-amino-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoate
trihydrochloride
[0270] In a manner analogous to example 17.5, using 4 g (9.1 mmol)
of methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-trifluoromethylbenzyl)piper-
azin-1-yl]propanoate, 3.8 g (93%) of methyl
(S)-3-amino-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoate
are obtained in the form of a beige solid.
20.4: Methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trif-
luoromethylbenzyl)piperazin-1-yl]propanoate
[0271] In a manner analogous to example 3.6, using 1.0 g (2.2 mmol)
of methyl
(S)-3-amino-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propanoat-
e trihydrochloride and 1.2 g (3.1 mmol) of 4-(2-methylquinolin-4-yl
methoxy)benzenesulfonyl chloride hydrochloride (prepared as
described in example 17.2), 910 mg (65%) of methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trif-
luoromethylbenzyl)piperazin-1-yl]propanoate are obtained in the
form of a white solid.
20.5:
(S)-3-[4-(2-Methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-
-trifluoromethylbenzyl)piperazin-1-yl]propanoic acid
[0272] In a manner analogous to example 3.7, using 910 mg (1.4
mmol) of methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4--
(4-trifluoromethylbenzyl)piperazin-1-yl]-propanoate, 790 mg (88%)
of
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trif-
luoromethylbenzyl)-piperazin-1-yl]propanoic acid are obtained in
the form of a white solid.
20.6:
S)-N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino-
]-2-[4-(4-trifluoromethylbenzyl)piperazin-1-yl]propionamide
[0273] In a manner analogous to example 3.8, using 790 mg (1.2
mmol) of
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-trif-
luoromethylbenzyl)piperazin-1-yl]propanoic acid, 550 mg (68%) of
(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2--
[4-(4-trifluoro-methylbenzyl)piperazin-1-yl]propionamide are
obtained in the form of a white solid with a melting point of
148.degree. C.
[0274] .sup.1H NMR (.delta., DMSO): 2.21 (m, 4H); 2.38 (m, 4H);
2.58 (s, 3H); 2.69-2.75 (m, 1H); 2.85-2.93 (m, 1H); 2.93-2.98 (m,
1H); 3.42 (s, 2H); 5.63 (s, 2H); 7.25 (d, J=9 Hz, 2H); 7.40 (d, J=8
Hz, 3H); 7.47-7.53 (m, 2H); 7.57 (d, J=8.1 Hz, 2H); 7.65-7.72 (m,
3H); 7.90 (d, J=7.9 Hz, 1H); 8.03 (d, J=7.8 Hz, 1H); 8.83 (s, 1H),
10.56 (s, 1H).
EXAMPLE 21
(S)-N-hydroxy-2-[44-(4-methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide
21.1: bis(2-Chloroethyl)(4-methylbenzyl)amine
[0275] In a manner analogous to example 17.3, using 5.0 g (28 mmol)
of bis(2-chloroethyl)amine hydrochloride and 5.7 g (31 mmol) of
1-bromomethyl-4-methylbenzene, 4.9 g (71%) of
bis(2-chloroethyl)(4-methylbenzyl)amine are obtained.
21.2: Methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-methylbenzyl)piperazin-1-yl]propan-
oate
[0276] In a manner analogous to example 17.4, using 5.1 g (20 mmol)
of commercial methyl
(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride and
4.9 g (20 mmol) of bis(2-chloroethyl)(4-methylbenzyl)amine, 4.1 g
(53%) of methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-methylbenzyl)piperazin-1-yl]propan-
oate are obtained in the form of an oil.
21.3: Methyl
(S)-3-amino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoate
trihydrochloride
[0277] In a manner analogous to example 19.3, using 4.1 g (10,5
mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(4-methylbenzyl)piperazin-1-yl-
]propanoate, 3.95 g (94%) of methyl
(S)-3-amino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoate
trihydrochloride are obtained in the form of a cream solid.
21.4: Methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-meth-
ylbenzyl)piperazin-1-yl]propanoate
[0278] In a manner analogous to example 3.6, using 1.0 g (2.5 mmol)
of methyl
(S)-3-amino-2-[4-(4-methylbenzyl)piperazin-1-yl]propanoate
trihydrochloride and 1.3 g (3.5 mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride (prepared as described in example 17.2), 950 mg (63%)
of methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-meth-
ylbenzyl)piperazin-1-yl]propanoate are obtained in the form of a
white solid.
21.5:
(S)-2-[4-(4-Methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-yl-
methoxy)benzenesulfonylamino]propanoic acid
[0279] In a manner analogous to example 3.7, using 950 mg (1.6
mmol) of methyl
(S)-2-[4-(4-methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4--
ylmethoxy)benzenesulfonylamino]propanoate, 880 mg (95%) of
(S)-2-[4-(4-methylbenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmetho-
xy)benzenesulfonylamino]propanoic acid are obtained in the form of
a cream solid.
21.6:
(S)-N-Hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamin-
o]-2-[4-(4-methylbenzyl)piperazin-1-yl]propionamide
[0280] In a manner analogous to example 3.8, using 880 mg (1,5
mmol) of
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(4-meth-
ylbenzyl)piperazin-1-yl]propanoic acid, 150 mg (17%) of
(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2--
[4-(4-methylbenzyl)piperazin-1-yl]propionamide are obtained in the
form of a white solid with a melting point of 170.degree. C.
[0281] .sup.1H NMR (.delta., DMSO): 2.25 (m, 4H); 2.25 (s, 3H);
2.43 (m, 4H); 2.67 (s, 3H); 2.80 (m, 1H); 2.95-3.05 (m, 2H); 3.37
(m, 2H); 5.71 (s, 2H); 7.10 (q, J=8 Hz, 4H); 7.33 (d, J=8.9 Hz,
2H); 7.43 (m, 1H); 7.56-7.61 (m, 2H); 7.73-7.79 (m, 3H); 7.98 (d,
J=8.3 Hz, 1H); 8.11 (d, J=8.2 Hz, 1H); 8.89 (s, 1H); 10.59 (s,
1H).
EXAMPLE 22
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-N-hydroxy-2-(4-m-
ethanesulfonylpiperazin-1-yl)propionamide
22.1: Benzoisoxazol-3-ylmethanol
[0282] 589 mg (3.0 mmol) of ethyl 1.2-benzoisoxazole-3-carboxylate
in solution in 10 ml of tetrahydrofuran are added to a suspension
of 129 mg (3.5 mmol) of lithium aluminum hydride in 5 ml of
tetrahydrofuran. The reaction mixture is stirred for one hour at
60.degree. C. and then treated by adding 2 ml of methanol dropwise,
filtered through celite and rinsed with ethyl acetate. The organic
phases are combined, dried over sodium sulfate and evaporated. The
residue obtained is purified by chromatography on silica gel,
elution being carried out with a 60/40 heptane/ethyl acetate
mixture. 180 mg (39%) of benzoisoxazol-3-ylmethanol are obtained in
the form of a white solid.
22.2: Methyl
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-methanesul-
fonylpiperazin-1-yl)propanoate
[0283] In a manner analogous to example 11.1, using 494 mg (1.2
mmol) of methyl
(S)-3-(4-hydroxy-benzenesulfonylamino)-2-(4-methanesulfonylpiperaz-
in-1-yl)propanoate (prepared as described in 5.1) and 175 mg (1.2
mmol) of benzoisoxazol-3-ylmethanol, 459 mg (71%) of methyl
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-methanesul-
fonylpiperazin-1-yl)propanoate are obtained in the form of an
oil.
22.3:
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-metha-
nesulfonylpiperazin-1-yl)propanoic acid
[0284] In a manner analogous to example 3.7, using 458 mg (0.8
mmol) of methyl
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-met-
hanesulfonylpiperazin-1-yl)propanoate, 283 mg (63%) of
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-methanesul-
fonylpiperazin-1-yl)propanoic acid are obtained in the form of a
white solid.
22.4:
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-N-hydroxy--
2-(4-methanesulfonylpiperazin-1-yl)propionamide
[0285] In a manner analogous to example 3.8, using 283 mg (0.5
mmol) of
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-2-(4-ethanesulf-
onylpiperazin-1-yl)propanoic acid, 231 mg (80%) of
(S)-3-[4-(benzoisoxazol-3-ylmethoxy)benzenesulfonylamino]-N-hydroxy-2-(4--
methanesulfonylpiperazin-1-yl)propionamide are obtained in the form
of a beige solid with a melting point of 107.degree. C.
[0286] .sup.1H NMR (.delta., DMSO): 2.53-2.55 (m, 4H); 2.88 (s,
3H); 2.90-2.93 (m, 2H); 3.00-3.10 (m, 4H); 3.13 (t, J=6.9 Hz,1H);
5.77 (s, 2H); 7.35 (d, J=8.8 Hz, 2H); 7.49 (t, J=7.5 Hz, 1H); 7.57
(m, 1H); 7.75 (t, J=7.4 Hz, 1H); 7.78-7.87 (m, 3H); 8.01 (d, J=8
Hz, 1H); 8.96 (m, 1H); 10.67 (m, 1H).
EXAMPLE 23
(S)-N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylme-
thoxy)-benzenesulfonylamino]propionamide.
23.1: Methyl
(S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate
[0287] 2 g (25% by weight) of palladium-on-carbon at 10% are added
to a solution of 8 g (21 mmol) of
methyl(S)-2-(4-benzylpiperazin-1-yl)-3-tert-butoxycarbonylaminopropanoate
(prepared as described in example 17.4) in 120 ml of ethanol,
degassed beforehand under a nitrogen stream. The reaction medium is
then placed under a hydrogen atmospheric pressure for 24 h and then
filtered through celite and thoroughly rinsed with dichloromethane.
After concentration under vacuum, 6.1 g (100%) of methyl
(S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate are
obtained.
23.2: Methyl
(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoate
[0288] 1.2 ml (8.3 mmol) of triethylamine and then 0.8 ml (7.6
mmol) of isobutyryl chloride are added to a solution of 2.0 g (6.9
mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate in 20 ml
of dichloromethane, cooled beforehand to 0.degree. C. After
stirring at ambient temperature for 1 h 30, water is added. The
reaction medium is extracted with dichloromethane. The organic
phase is washed with water, dried over magnesium sulfate, filtered
and concentrated under vacuum. The crude residue obtained is
purified by chromatography on silica gel, elution being carried out
with a 50/50 heptane/ethyl acetate mixture. 2.0g (81%) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoate
are obtained in the form of a colorless oil.
23.3:
(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propano-
ic acid
[0289] 10 ml (10 mmol) of an aqueous solution of lithium hydroxide
having a concentration of 1N are added to a solution of 2.0 g (5.6
mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propa-
noate in 40 ml of tetrahydrofuran and 8 ml of water, and then the
reaction medium is stirred at ambient temperature for 20 h. After
the addition of an aqueous solution of acetic acid having a
concentration of 1N, the product is extracted with n-butanol. The
organic phase is dried over magnesium sulfate, filtered and
concentrated under vacuum, 1.5 g (78%) of
(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoic
acid are obtained in the form of a white solid.
23.4: tert-Butyl
[(S)-2-allyloxycarbamoyl-2-(4-isobutyrylpiperazin-1-yl)ethyl]carbamate
[0290] 1.4 g (4.4 mmol) of O-(benzotriazol-1
-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate and then 2.3 ml
(13.1 mmol) of diisopropylethylamine are added to a solution of 1.5
g (4.4 mmol) of
(S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)pro-
panoic acid in 20 ml of dimethylformamide. After stirring at
ambient temperature for 15 min, a solution of 500 mg (4.6 mmol) of
0-allylhydroxylamine hydrochloride and of 0.8 ml (4.6 mmol) of
diisopropylethylamine in 10 ml of dimethylformamide is added. The
reaction medium is stirred at ambient temperature for 20 h,
hydrolyzed with a saturated aqueous solution of sodium hydrogen
carbonate, and then diluted with ethyl acetate. The organic phase
is washed with a saturated aqueous solution of sodium chloride,
dried over magnesium sulfate, filtered and concentrated under
vacuum, 1.45 g (83%) of tert-butyl
[(S)-2-allyloxycarbamoyl-2-(4-isobutyrylpiperazin-1-yl)ethyl]carbamate
are obtained in the form of a colorless oil.
23.5:
(S)-N-allyloxy-3-amino-2-(4-isobutyrylpiperazin-1-yl)propionamide
dihydrochloride
[0291] In a manner analogous to example 19.3, using 1.45 g (3.6
mmol) of tert-butyl
[(S)-2-allyloxycarbamoyl-2-(4-isobutyrylpiperazin-1-yl)ethyl]carbamate,
1.4 g (100%) of
(S)-N-allyloxy-3-amino-2-(4-isobutyrylpiperazin-1-yl)propionamide
dihydrochloride are obtained in the form of a white solid.
23.6:
(S)-N-allyloxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-
-4-ylmethoxy)benzenesulfonylamino]propionamide
[0292] 1.9 g (5.1 mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride (prepared as described in 32.2) are added to a
solution of 1.3 g (3.6 mmol) of
(S)-N-allyloxy-3-amino-2-(4-isobutyrylpiperazin-1-yl)propionamide
dihydrochloride, 2.0 ml (14.5 mmol) of triethylamine in 15 ml of
dichloromethane and 15 ml of dimethylformamide, cooled beforehand
to 0.degree. C. The reaction medium is then stirred at from
0.degree. C. to ambient temperature over the course of 3 h. After
the addition of water, the reaction medium is extracted with
dichloromethane. The organic phase is washed with a saturated
aqueous solution of sodium hydrogen carbonate and with water, dried
over magnesium sulfate, filtered and concentrated.
[0293] The crude residue obtained is purified by silica column
chromatography, elution being carried out with a 97/3
dichloromethane/methanol mixture. 900 mg (41%) of
(S)-N-allyloxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-yl-
methoxy)benzenesulfonylamino]propionamide are obtained in the form
of a white solid.
23.7:
(S)-N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin--
4-ylmethoxy)-benzenesulfonylamino]propionamide
[0294] 33 mg (0.06 mmol) of tetrakis(triphenylphosphine)palladium
and then 920 mg (6.6 mmol) of potassium carbamate are added to a
solution of 670 mg (1.1 mmol) of
(S)-N-allyloxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-yl-
methoxy)benzenesulfonylamino]propionamide in 15 ml of methanol and
then the reaction medium is refluxed for 8 h. After the addition of
ethyl acetate, the reaction medium is washed with a saturated
aqueous solution of sodium hydrogen carbonate. The organic phase is
then washed with water, dried over magnesium sulfate. filtered and
concentrated. The crude product is taken up in 6 ml of ethanol and
12 ml of water and then heated at 80.degree. C. until
solubilization occurs. After cooling, crystallization is initiated
by evaporation of a minimum amount of ethanol. 120 mg of product
are obtained by filtration and are purified by preparative thin
layer chromatography on silica, elution being carried out with a
97/3 dichloromethane/methanol mixture.
[0295] 20 mg (3%) of
(S)-N-hydroxy-2-(4-isobutyrylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-yl--
methoxy)benzenesulfonylamino]propionamide are finally obtained in
the form of a beige solid.
[0296] .sup.1H NMR (.delta., DMSO): 0.84 (s, 3H); 0.85 (s, 3H);
2.30-2.44 (m, 2H); 2.52 (m, 2H); 2.67 (s, 3H); 2.77 (m, 1H); 2.85
(m, 2H); 2.95 (m, 1H); 3.35 (m, 4H); 5.71 (s, 2H); 7.33 (d, J=8.9
Hz, 2H); 7.43 (m, 1H); 7.55-7.62 (m, 2H); 7.72-7.82 (m, 3H); 7.98
(d, J=8.4 Hz, 1H); 8.11 (d, J=8.2 Hz, 1H); 8.96 (m, 1H); 10.67 (m,
1H).
EXAMPLE 24
(S)-N-hydroxy-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-met-
hylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide
24.1: Methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-
-1-yl]propanoate
[0297] 479 mg (3.0 mmol) of 2-methylpropane-1-sulfonyl chloride are
added to a solution of 800 mg (2.8 mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate (prepared
as described in example 23.1) and 775 pl (5.5 mmol) of
triethylamine in 8 ml of dichloromethane, cooled beforehand to
0.degree. C. The reaction medium is stirred at ambient temperature
for 18 h and then water is added and the medium is extracted with
dichloromethane. The organic phase is washed with water, dried over
magnesium sulfate, filtered and concentrated. The residue obtained
is purified by chromatography on silica gel, elution being carried
out with a 5/5 heptane/ethyl acetate mixture. 785 mg (71%) of
methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(2-methylpropane-1-sulfonyl-
)piperazin-1-yl]propanoate are obtained in the form of a colorless
oil.
24.2: Methyl
(S)-3-amino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoate
dihydrochloride
[0298] In a manner analogous to example 3.3, using 785 mg (1.9
mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(2-methylpropane-1-sulfonyl)pi-
perazin-1-yl]propanoate, 621 mg (85%) of methyl
(S)-3-amino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propanoate
dihydrochloride are obtained in the form of a solid.
24.3: Methyl
(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinol-
in-4-ylmethoxy)benzenesulfonylamino]propanoate
[0299] In a manner analogous to example 3.6, using 621 mg (1.6
mmol) of methyl
(S)-3-amino-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]propan-
oate dihydrochloride and 876 mg (2.3 mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride (prepared as described in example 17.2), 643 mg (64%)
of methyl
(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinol-
in-4-ylmethoxy)benzenesulfonylamino]propanoate are obtained in the
form of an oil.
24.4:
(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylq-
uinolin-4-ylmethoxy)benzenesulfonylamino]propanoic acid
[0300] In a manner analogous to example 3.7, using 643 mg (1.0
mmol) of methyl
(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methy-
lquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate, 395 mg (63%)
of
(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinol-
in-4-ylmethoxy)benzenesulfonylamino]propanoic acid are obtained in
the form of a white solid.
24.5:
(S)-N-hydroxy-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4--
(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide
[0301] In a manner analogous to example 3.8, using 390 mg (0.6
mmol) of
(S)-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-methylquinol-
in-4-ylmethoxy)benzenesulfonylamino]propanoic acid, 12 mg (3%) of
(S)-N-hydroxy-2-[4-(2-methylpropane-1-sulfonyl)piperazin-1-yl]-3-[4-(2-me-
thylquinolin-4-ylmethoxy)benzenesulfonylamino]propionamide are
obtained in the form of a white solid.
[0302] .sup.1H NMR (.delta., DMSO): 1.01 (d, J=6.7 Hz, 6H); 2.05
(m, 1H); 2.49 (m, 4H); 2.67 (s, 3H); 2.86 (d, J=6.6 Hz, 2H);
3.00-3.10 (m, 6H); 3.31 (m, 1H); 5.71 (s, 2H); 7.34 (d, J=8.9 Hz,
2H); 7.52 (m, 1H); 7.57 (m, 2H); 7.76-7.80 (m, 3H); 7.98 (d, J=8.2
Hz, 1H); 8.10 (m, 1H); 8.93 (s, 1H); 10.66 (s, 1H).
EXAMPLE 25
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethyl--
pyrazolo[1,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide
25.1: Ethyl
2-trifluoromethylpyrazolo[1,5-.alpha.]pyridine-3-carboxylate
[0303] A solution of 2.1 g (38 mmol) of KOH in 20 ml of water and
then 6.7 g (30 mmol) of 1-aminopyridinium iodide are added to a
solution of 2.5 g (15 mmol) of ethyl 4,4,4-trifluorobut-2-ynoate in
25 ml of dichloromethane. After stirring at ambient temperature for
5 h, water is added and the reaction medium is extracted with
dichloromethane. The organic phase is washed with water, dried over
magnesium sulfate. filtered and concentrated. The residue obtained
is purified by chromatography on silica gel, elution being carried
out with an 8/2 heptane/ethyl acetate mixture. 2.8 g (73%) of ethyl
2-trifluoromethylpyrazolo[1,5-.alpha.]pyridine-3-carboxylate are
obtained in the form of a yellow solid.
25.2:
(2-trifluoromethylpyrazolo[1,5-.alpha.]pyridin-3-yl)methanol
[0304] A solution of 2.8 g (11 mmol) of ethyl
2-trifluoromethylpyrazolo[1,5-.alpha.]pyridine-3-carboxylate in 50
ml of tetrahydrofuran is added dropwise to a suspension of 0.5 g
(12 mmol) of lithium aluminum hydride in 45 ml of tetrahydrofuran.
The reaction medium is then stirred at 70.degree. C. for 3 h. After
dropwise addition of 2.5 ml of methanol and then of 1.8 ml of an
aqueous solution of sodium hydroxide having a concentration of 2N,
the reaction medium is stirred for 20 min at ambient temperature
and then filtered. The filtrate is dried over magnesium sulfate,
filtered and concentrated under vacuum. 2.3 g (100%) of
(2-trifluoromethylpyrazolo[1,5-.alpha.]pyridin-3-yl)methanol are
obtained in the form of a solid.
25.3: Methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1-
,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoate
[0305] In a manner analogous to example 11.1, using 800 mg (1.9
mmol) of methyl
(S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazi-
n-1-yl)propanoate (prepared as described in 5.1) and 540 mg (2.5
mmol) of
(2-trifluoromethylpyrazolo[1,5-.alpha.]pyridin-3-yl)methanol, 380
mg (32%) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1-
,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoate are
obtained in the form of a white solid.
25.4:
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyraz-
olo[1,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoic
acid
[0306] In a manner analogous to example 3.7, using 380 mg (0.6
mmol) of methyl
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyr-
azolo[1,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoate,
237 mg (64%) of
(S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1-
,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoic acid
are obtained in the form of a white solid.
25.5:
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluorom-
ethylpyrazolo[1,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propion-
amide
[0307] In a manner analogous to example 3.8, using 230 mg (0.4
mmol) of
(S)-2-(4-methanesulfonyl-piperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[-
1,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoic
acid, 9 mg (4%) of
(S)-N-hydroxy-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-trifluo-
romethylpyrazolo[1,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]prop-
ionamide are obtained in the form of a white solid.
[0308] .sup.1H NMR (a, DMSO): 2.51-2.54 (m, 4H); 2.84 (s, 3H); 2.95
(m, 1H); 2.97-3.04 (m, 4H); 3.10 (m, 1H); 3.32 (m, 1H); 5.45 (s,
2H); 7.20-7.25 (m, 3H); 7.49-7.51 (m, 2H); 7.76 (d, J=8.8 Hz, 2H);
8.04 (m, 1H); 8.87 (d, J=7 Hz, 2H); 8.90 (m, 1H).
EXAMPLE 26
(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[-
4-(propane-2-sulfonyl)piperazin-1-yl]propionamide
26.1: Methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]pr-
opanoate
[0309] In a manner analogous to example 20.2, using 800 mg (2.8
mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-piperazin-1-ylpropanoate (prepared
as described in example 23.1) and 342 pl (3.1 mmol) of
propane-2-sulfonyl chloride, 700 mg (64%) of methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]pr-
opanoate are obtained in the form of an oil.
26.2: Methyl
(S)-3-amino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoate
dihydrochloride
[0310] In a manner analogous to example 3.3, using 700 mg (1.8
mmol) of methyl
(S)-3-tert-butoxycarbonylamino-2-[4-(propane-2-sulfonyl)piperazin--
1-yl]propanoate, 620 mg (86%) of methyl
(S)-3-amino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoate
dihydrochloride are obtained in the form of an oil.
26.3: Methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propan-
e-2-sulfonyl)piperazin-1-yl]propanoate
[0311] In a manner analogous to example 17.6, using 620 mg (1.5
mmol) of methyl
(S)-3-amino-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propanoate
dihydrochloride and 830 mg (2.1 mmol) of
4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride
hydrochloride (prepared as described in the example 17.2), 505 mg
(54%) of methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propan-
e-2-sulfonyl)piperazin-1-yl]propanoate are obtained in the form of
a white solid.
26.4:
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(p-
ropane-2-sulfonyl)piperazin-1-yl]propanoic acid
[0312] In a manner analogous to example 3.7, using 505 mg (0.8
mmol) of methyl
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4--
(propane-2-sulfonyl)piperazin-1-yl]propanoate, 135 mg (27%) of
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propan-
e-2-sulfonyl)piperazin-1-yl]propanoic acid are obtained in the form
of a white solid.
26.5:
(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamin-
o]-2-[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide
[0313] In a manner analogous to example 3.8, using 135 mg (0.2
mmol) of
(S)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2-[4-(propan-
e-2-sulfonyl)piperazin-1-yl]propanoic acid, 24 mg (17%) of
(S)-N-hydroxy-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]-2--
[4-(propane-2-sulfonyl)piperazin-1-yl]propionamide are obtained in
the form of a white solid.
[0314] .sup.1H NMR (.delta., DMSO): 1.19 (d, J=6.8 Hz, 6H); 2.45
(m, 4H); 2.68 (s, 3H); 2.80-2.90 (m, 1H); 2.95-3.15 (m, 6H); 3.29
(m, 1H); 5.72 (s, 2H); 7.34 (d, J=8.9 Hz, 2H); 7.52 (m, 1H); 7.57
(m, 2H); 7.76-7.80 (m, 3H); 7.98 (d, J=8.2 Hz, 1H); 8.10 (d, J=8.1
Hz, 1H); 8.93 (s, 1H); 10.66 (s, 1H).
EXAMPLE 27
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-trifluoromethylpyrazolo[1-
,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide
27.1: 4-Hydroxybenzenesulfonyl chloride
[0315] A solution of 7 g (30 mmol) of the sodium salt of
4-hydroxybenzenesulfonic acid dihydrate in 40 ml of
dimethylformamide is added dropwise to a solution of 15.5 ml (181
mmol) of oxalyl chloride in 120 ml of dichloromethane cooled to
-30.degree. C. The reaction medium is slowly brought back to
ambient temperature and then stirred at ambient temperature for 18
h. After the addition of 200 ml of ice, the reaction medium is
extracted with ethyl acetate. The organic phase is washed with
water and with a saturated aqueous solution of sodium chloride,
dried over magnesium sulfate, filtered and concentrated. 6.2 g
(100%) of 4-hydroxybenzenesulfonyl chloride are obtained in the
form of a colorless oil.
27.2: Methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-(4-hydroxybenzenesulfonylamino)propanoat-
e
[0316] In a manner analogous to example 3.6, using 5.8 g (30 mmol)
of 4-hydroxybenzenesulfonyl chloride and 7.7 g (20 mmol) of methyl
(S)-3-amino-2-(4-benzylpiperazin-1-yl)propanoate trihydrochloride
(prepared as described in example 17.5), 2.25 g (27%) of methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-(4-hydroxybenzenesulfonylamino)propanoat-
e are obtained in the form of a white solid.
27.3: Methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-.alpha-
.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoate
[0317] In a manner analogous to example 11.1, using 500 mg (1.1
mmol) of methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-(4-hydroxybenzenesulfonylamino)pr-
opanoate and 370 mg (1.7 mmol) of
(2-trifluoromethylpyrazolo[1,5-.alpha.]pyridin-3-yl)methanol
(prepared as described in example 25.2), 350 mg (50%) of methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-.alpha-
.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoate are obtained
in the form of a colorless oil.
27.4:
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-.-
alpha.]pyridin-3-ylmeth-oxy)benzenesulfonylamino]propanoic acid
[0318] In a manner analogous to example 3.7, using 350 mg (0.5
mmol) of methyl
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-
-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoate, 165
mg (48%) of
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-.al-
pha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoic acid are
obtained in the form of a white solid.
27.5:
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-trifluoromethylpyra-
zolo[1,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide
[0319] In a manner analogous to example 3.8, using 165 mg (0.3
mmol) of
(S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-.alpha-
.]pyridin-3-ylmethoxy)benzenesulfonylamino]propanoic acid, 50 mg
(29%) of
(S)-2-(4-benzylpiperazin-1-yl)-N-hydroxy-3-[4-(2-trifluoromethylpyrazolo[-
1,5-.alpha.]pyridin-3-ylmethoxy)benzenesulfonylamino]propionamide
are obtained in the form of a white solid with a melting point of
138.degree. C.
[0320] .sup.1H NMR (.delta., DMSO): 2.20 (m, 4H); 2.38 (m, 4H);
2.65-2.75 (m, 1H); 2.86-2.98 (m, 2H); 3.35 (m, 2H); 5.37 (s, 2H);
7.10-7.25 (m, 8H); 7.35-7.44 (m, 2H); 7.68 (d, J=8.9 Hz, 2H); 7.98
(d, J=9 Hz, 1H); 8.81 (m, 2H); 10.52 (s, 1H).
EXAMPLE 28
Enzymatic assay for TACE Inhibition
[0321] Description of the Assay
[0322] The products are solubilized in DMSO at a concentration of
10 mM. A serial 3-fold dilution over 10 points is carried out so as
to have a concentration range of from 10 .mu.M to 0.5 nM final
concentration.
[0323] The TACE enzyme is an internal production (carried out
according to the publication "protein Eng Des Sel 2006,
19,155-161") and is added so as to have a signal equivalent to 6
times the background noise in 2 h at 37.degree. C. The reaction is
carried out in 50 mM Tris buffered medium containing 4% glycerol,
pH 7.4. The fluorescent substrate is
MCA-Pro-Leu-Ala-Val-(Dpa)-Arg-Ser-Ser-Arg-NH.sub.2 (R&D
systems, reference: ES003). The substrate is cleaved by the enzyme
between the alanine and the valine, thus releasing a fluorescent
peptide (excitation: 320 nm, emission: 420 nm). The substrate is
used at 40 .mu.M. The reaction is carried out in a final volume of
10 .mu.l (4 .mu.l inhibitor, 4 .mu.l substrate, 2 .mu.l enzyme) in
a low volume 384-well plate (Corning reference: 3676). The plate is
incubated at ambient temperature for 2 h, and then read by
fluorescence on a Pherastar reader (BMG labtech). The 10.sub.50 is
determined using mathematical processing software (XLfit).
[0324] Product Assay
TABLE-US-00002 Example % TACE inhibition at IC50 - No. 10 .mu.M
TACE (nM) ex1 100 87 ex2 100 32 ex4 95 497 ex5 99 21 ex6 99 52 ex8
100 127 ex9 100 147 ex10 93 47 ex11 93 24 ex13 96 108 ex14 98 64
ex16 96 168 ex17 91 62 ex18 90 67 ex19 92 41 ex21 97 63 ex23 97 53
ex24 98 86 ex26 98 33
[0325] On the basis of the results obtained in the TACE enzymatic
assay described above, the compounds claimed in the present
invention are TNF-alpha converting enzyme (TACE) inhibitors and
consequently may be potential active ingredients for the treatment
of pathological conditions for which reducing TNF-alpha production
would be of great interest.
Example 29
Selectivity Assay
[0326] Principle of the Assay:
[0327] The molecules are dose-response tested on the following
enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same
protocol as that described for the TACE enzyme in example 28, but
with different substrates (MMP R&D systems, reference:
P126-990, and ADAM R&D systems, reference: ES003).
[0328] The enzymes are purchased from Calbiochem.
[0329] Product Assay:
TABLE-US-00003 IC50 (nM) Example MMP1 MMP3 MMP9 ADAM9 ADAM10 TACE 5
5100 3200 >10000 >10000 >10000 21 18 670 849 >10000
9254 >10000 67 19 2303 1770 >10000 3054 >10000 41 20 3935
4775 >10000 >10000 >10000 140 21 1166 887 >10000
>10000 >10000 63 23 2221 1065 >10000 >10000 >10000
53 24 2059 1878 >10000 >10000 >10000 86 26 969 574
>10000 >10000 >10000 16 Apratastat 145 10 82 85 71 5
[0330] On the basis of the results obtained in the selectivity
assay described above, these compounds are also very selective for
TACE compared with the other ADAMs and MMPs, i.e. they have
IC.sub.50 values for other ADAMs or MMPs that are at least 10 times
higher than that obtained for TACE, and more advantageously at
least 100 times higher. As it happens, insofar as it is known that
the nonselective inhibition of these families of enzymes induces
adverse side effects observed in vivo, the selective inhibition of
TACE compared with these other enzymes should make it possible to
reduce adverse side effects when these molecules are administered
for the treatment of pathological conditions for which reducing
TNF-alpha production would be of great interest.
* * * * *