U.S. patent application number 11/838180 was filed with the patent office on 2008-02-21 for omega-aminoalkylamides of r-2-aryl-propionic acids as inhibitors of the chemotaxis of polymorphonucleate and mononucleate cells.
This patent application is currently assigned to Dompe pha.r.ma S.p.A.. Invention is credited to Marcello ALLEGRETTI, Valerio Berdini, Riccardo Bertini, Cinzia Bizzarri, Gianfranco Caselli, Maria Candida Cesta, Francesco Colotta, Vito Di Cioccio, Arrigo Aldo Gandolfi, Carmelo Gandolfi, Giulio Agostino Gandolfi, Janete Peloia Barroso Gandolfi, Maria Carla Gandolfi.
Application Number | 20080045522 11/838180 |
Document ID | / |
Family ID | 11447032 |
Filed Date | 2008-02-21 |
United States Patent
Application |
20080045522 |
Kind Code |
A1 |
ALLEGRETTI; Marcello ; et
al. |
February 21, 2008 |
OMEGA-AMINOALKYLAMIDES OF R-2-ARYL-PROPIONIC ACIDS AS INHIBITORS OF
THE CHEMOTAXIS OF POLYMORPHONUCLEATE AND MONONUCLEATE CELLS
Abstract
(R)-2-Arylpropionamide compounds of formula (I) are described.
##STR1## The process for their preparation and pharmaceutical
preparations thereof are also described. The 2-Arylpropionamides of
the invention are useful in the prevention and treatment of tissue
damage due to the exacerbate recruitment of polymorphonuclear
leukocytes (leukocytes PMN) and of monocytes at the inflammatory
sites. In particular, the invention relates to the R enantiomers of
omega-aminoalkylamides of 2-aryl propionic acids, of formula (I),
for use in the inhibition of the chemotaxis of neutrophils and
monocytes induced by the C5a fraction of the complement and by
other chemotactic proteins whose biological activity is associated
with activation of a 7-TD receptor. Selected compounds of formula
(I) are dual inhibitors of both the C5a-induced chemotaxis of
neutrophils and monocytes and the IL-8-induced chemotaxis of PMN
leukocytes. The compounds of the invention are used in the
treatment of psoriasis, ulcerative cholitis, glomerular nephritis,
acute respiratory insufficiency, idiopathic fibrosis, rheumatoid
arthritis and in the prevention and the treatment of injury caused
by ischemia and reperfusion.
Inventors: |
ALLEGRETTI; Marcello;
(L'Aquila, IT) ; Bertini; Riccardo; (L'Aquila,
IT) ; Berdini; Valerio; (L'Aquila, IT) ;
Bizzarri; Cinzia; (L'Aquila, IT) ; Cesta; Maria
Candida; (L'Aquila, IT) ; Di Cioccio; Vito;
(L'Aquila, IT) ; Caselli; Gianfranco; (L'Aquila,
IT) ; Colotta; Francesco; (L'Aquila, IT) ;
Gandolfi; Carmelo; (L'Aquila, IT) ; Gandolfi; Janete
Peloia Barroso; (Milan, IT) ; Gandolfi; Giulio
Agostino; (Milan, IT) ; Gandolfi; Maria Carla;
(Milan, IT) ; Gandolfi; Arrigo Aldo; (Saronno,
IT) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
Dompe pha.r.ma S.p.A.
L'Aquila
IT
|
Family ID: |
11447032 |
Appl. No.: |
11/838180 |
Filed: |
August 13, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10469094 |
Jun 16, 2004 |
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PCT/EP02/01974 |
Feb 25, 2002 |
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11838180 |
Aug 13, 2007 |
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Current U.S.
Class: |
514/231.2 ;
514/299; 514/329; 514/331; 514/563; 514/616; 514/617 |
Current CPC
Class: |
C07D 233/46 20130101;
A61P 19/02 20180101; C07C 231/02 20130101; A61K 31/4453 20130101;
A61P 9/00 20180101; A61P 43/00 20180101; C07B 2200/07 20130101;
A61P 19/04 20180101; A61P 29/00 20180101; C07C 235/78 20130101;
A61P 11/00 20180101; A61K 31/165 20130101; A61P 13/12 20180101;
C07C 235/70 20130101; C07C 233/44 20130101; C07C 237/20 20130101;
C07D 233/24 20130101; C07C 281/16 20130101; C07C 233/40 20130101;
A61P 17/06 20180101; C07D 295/13 20130101; A61K 31/5375 20130101;
C07C 279/12 20130101; A61P 37/06 20180101; C07D 211/58 20130101;
C07C 235/34 20130101; A61P 9/10 20180101; A61P 17/02 20180101; A61K
31/445 20130101; C07D 211/04 20130101; A61P 37/00 20180101; A61P
1/04 20180101; A61K 31/198 20130101; A61P 1/00 20180101; C07C
233/51 20130101; C07C 231/16 20130101; C07D 451/04 20130101; C07C
237/22 20130101 |
Class at
Publication: |
514/231.2 ;
514/299; 514/329; 514/331; 514/563; 514/616; 514/617 |
International
Class: |
A61K 31/165 20060101
A61K031/165; A61K 31/192 20060101 A61K031/192; A61K 31/435 20060101
A61K031/435; A61K 31/445 20060101 A61K031/445; A61K 31/4468
20060101 A61K031/4468; A61K 31/5375 20060101 A61K031/5375; A61P
17/06 20060101 A61P017/06; A61P 9/00 20060101 A61P009/00; A61P 9/10
20060101 A61P009/10 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 27, 2001 |
IT |
MI2001A000395 |
Claims
1. A method for treating psoriasis, pemphigus and pemphigoid,
rheumatoid arthritis, intestinal chronic inflammatory pathologies
including ulcerative colitis, acute respiratory distress syndrome,
idiopathic fibrosis, cystic fibrosis, chronic obstructive pulmonary
disease or glomerulonephritis, comprising administering to a
patient in need thereof an effective amount of a
(R)-2-Aryl-propionamide compound of formula (I): ##STR36## or a
pharmaceutically acceptable salt thereof, wherein Ar represents a
substituted or non-substituted aryl group; R represents hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4
alkynyl, optionally substituted by a CO.sub.2R.sub.3 group, wherein
R.sub.3 represents hydrogen or a linear or branched C.sub.1-C.sub.6
alkyl group or a linear or branched C.sub.2-C.sub.6 alkenyl group;
X represents a linear or branched C.sub.1-C.sub.6 alkylene,
C.sub.4-C.sub.6 alkenylene, C.sub.4-C.sub.6 alkynylene, optionally
substituted by a CO.sub.2R.sub.3 group or by a CONHR.sub.4 group
wherein R.sub.4 represents hydrogen, linear or branched
C.sub.2-C.sub.6 alkyl or an OR.sub.3 group, R.sub.3 being defined
as above; a (CH.sub.2).sub.m--B--(CH.sub.2).sub.n, group,
optionally substituted by a CO.sub.2R.sub.3 or CONHR.sub.4 group,
as defined above, wherein B is an oxygen or sulfur atom, m is zero
or an integer from 2 to 3 and n is an integer from 2 to 3; or B is
a CO, SO or CONH group, m is an integer from 1 to 3 and n is an
integer from 2 to 3; or X together with the nitrogen atom of the
omega-amino group to which it is bound and with the R.sub.1 group
forms a non-aromatic nitrogen containing 3-7 membered heterocyclic,
monocyclic or polycyclic ring wherein the nitrogen atom has a
substituent Rc, where Rc represents hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 hydroxylalkyl, C.sub.1-C.sub.4 acyl,
substituted or non-substituted phenyl, diphenylmethyl; R.sub.1 and
R.sub.2 are independently hydrogen, linear or branched
C.sub.1-C.sub.6 alkyl, optionally interrupted by an O or S atom, a
C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.6 alkenyl,
C.sub.3-C.sub.6-alkynyl, aryl-C.sub.1-C.sub.3-alkyl,
hydroxy-C.sub.2-C.sub.3-alkyl group; or R.sub.1 and R.sub.2
together with the N atom to which they are bound, form a nitrogen
containing 3-7 membered heterocyclic ring of formula (II) ##STR37##
wherein Y represents a single bond, CH.sub.2, O, S, or a N-Rc group
as defined above and p represents an integer from 0 to 3; or,
R.sub.1 being as defined above, R.sub.2 represents a group of
formula (III): ##STR38## wherein R.sub.a is hydrogen and R.sub.b is
hydrogen, hydroxy, C.sub.1-C.sub.4-alkyl or an NR.sub.dR.sub.e
group wherein R.sub.d and R.sub.e are independently hydrogen,
C.sub.1-C.sub.4-alkyl or phenyl; or R.sub.a and R.sub.b, together
with the nitrogen atoms to which they are bound, form a 5-7
membered heterocyclic ring, monocyclic or fused with a benzene,
pyridine or pyrimidine ring; with the proviso that when Ar is
4-diphenyl and X is (CH.sub.2).sub.2 or (CH.sub.2).sub.3, R.sub.1
and R.sub.2 are not ethyl; with the further proviso that, when Ar
is a 4-(2-fluoro)diphenyl residue, and X is butylene substituted by
a CO.sub.2H group, R.sub.a and R.sub.b are not hydrogen; and with
the further proviso that, when Ar is phenyl and X is butylene,
R.sub.1 and R.sub.2 together are not a N-(2-methoxy
phenyl)piperazine.
2. The method of claim 1 in which in the compound of the formula
(I): Ar represents a substituted or non-substituted aryl group; R
represents hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4
alkenyl, C.sub.2-C.sub.4 alkynyl, optionally substituted by a
CO.sub.2R.sub.3 group, wherein R.sub.3 represents hydrogen or a
linear or branched C.sub.1-C.sub.6 alkyl group or a linear or
branched C.sub.2-C.sub.6 alkenyl group; X represents: a linear or
branched C.sub.1-C.sub.6 alkylene, C.sub.4-C.sub.6 alkenylene,
C.sub.4-C.sub.6 alkynylene, optionally substituted by a
CO.sub.2R.sub.3 group or by a CONHR.sub.4 group wherein R.sub.4
represents hydrogen, linear or branched C.sub.2-C.sub.6 alkyl or an
OR.sub.3 group, R.sub.3 being defined as in claim 1; a
(CH.sub.2).sub.m--B--(CH.sub.2).sub.n, group, optionally
substituted by a CO.sub.2R.sub.3 or CONHR.sub.4 group, as defined
above, wherein B is an oxygen or sulfur atom, m is zero or an
integer from 2 to 3 and n is an integer from 2 to 3; or B is a CO,
SO or CONH group, m is an integer from 1 to 3 and n is an integer
from 2 to 3; or X together with the nitrogen atom of the
omega-amino group to which it is bound and with the R.sub.1 group
forms a non-aromatic nitrogen containing 3-7 membered heterocyclic,
monocyclic or polycyclic ring wherein the nitrogen atom has a
substituent Rc, where Rc represents hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 hydroxylalkyl, C.sub.1-C.sub.4 acyl,
substituted or non-substituted phenyl, diphenylmethyl; R.sub.1 and
R.sub.2 are independently hydrogen, linear or branched
C.sub.1-C.sub.6 alkyl, optionally interrupted by an O or S atom, a
C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.6 alkenyl,
C.sub.3-C.sub.6-alkynyl, aryl-C.sub.1-C.sub.3-alkyl or
hydroxy-C.sub.2-C.sub.3-alkyl group; or R.sub.1 and R.sub.2
together with the N atom to which they are bound, form a 3-7
membered nitrogen heterocyclic ring of formula (II) ##STR39##
wherein Y represents a single bond, CH.sub.2, O, S, or a N-Rc group
as defined above and p represents an integer from 0 to 3; or,
R.sub.1 being as defined above, R.sub.2 represents a group of
formula (III): ##STR40## wherein R.sub.a is hydrogen and R.sub.b is
hydrogen, hydroxy, C.sub.1-C.sub.4-alkyl or an NR.sub.dR.sub.e
group wherein R.sub.d and R.sub.e, are each independently,
hydrogen, C.sub.1-C.sub.4-alkyl or phenyl; or R.sub.a and R.sub.b,
together with the nitrogen atoms to which they are bound, form a
5-7 membered heterocyclic ring, monocyclic or fused with a benzene,
pyridine or pyrimidine ring; said compound of the formula (I)
having activity of inhibiting C5a-induced chemotaxis of
polymorphonucleate leukocytes and monocytes.
3. The method of claim 1, in which in the formula (I), Ar is
selected from the group consisting of: a) an Ara mono- or
poly-substituted aryl group of (.+-.)2-aryl-propionic acids
selected from alminoprofen, benoxaprofen, carprofen, fenbufen,
fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen,
loxoprofen, R-naproxen, pirprofen, dehydropirprofen,
dihydropirprofen, pranoprofen, surprofen, tiaprofenic acid and
zaltoprofen; b) an aryl-hydroxymethyl-aryl group of formula (IVa),
both as diastereoisomeric mixture and as single S' and/or R'
diastereoisomers ##STR41## wherein, when Ar.sub.2 is phenyl
Ar.sub.1 is selected from the group consisting of phenyl and
thien-2-yl while when Ar.sub.1 is phenyl, Ar.sub.2 is selected from
the group consisting of phenyl, 4-thienyl and pyridyl; c) an aryl
group of formula (IVb): .PHI.-Ar.sub.b (IV b) wherein Ar.sub.b is
phenyl that is mono- and poly-substituted by hydroxy, mercapto,
C.sub.1-C.sub.3-alcoxy, C.sub.1-C.sub.3-alkylthio, chlorine,
fluorine, trifluoromethyl, nitro, amino, C.sub.1-C.sub.7-acylamino
optionally substituted; and .PHI. is hydrogen or a linear or
branched C.sub.1-C.sub.5 alkyl, C.sub.2-C.sub.5-- alkenyl or
C.sub.2-C.sub.5-- alkynyl residue optionally substituted by
C.sub.1-C.sub.3-alkoxycarbonyl, substituted or non-substituted
phenyl, 2-, 3- or 4-pyridyl, quinolin-2-yl; a
C.sub.3-C.sub.6-cycloalkyl; 2-furyl; 3-tetrahydrofuryl;
2-thiophenyl; 2-tetrahydrothiophenyl or a residue of formula (IVc)
.PHI.--(CH.sub.2).sub.q- (IVc) wherein A is a
C.sub.1-C.sub.5-dialkylamino group, a C.sub.1-C.sub.8-(alkanoyl,
cycloalkanoyl, arylalkanoyl)-C.sub.1-C.sub.5-alkylamino group; a
nitrogen containing 5-7 membered monocyclic ring optionally
containing one or two double bonds and optionally another
heteroatom separated by at least 2 carbon atoms from the N atom, so
as to form; or a residue of formula (IVd) ##STR42## wherein Rg is
hydrogen, C.sub.1-C.sub.3-alkyl or the residue of a
C.sub.1-C.sub.3-alkanoic acid; q is zero or the integer 1, d)
2-(phenylamino)-phenyl of formula (IV e): ##STR43## wherein the
substituents P.sub.1 and P.sub.2 indicate that the two phenyl
groups bear, each independently, mono- or poly-substitutions with
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.3-alkoxy groups, chlorine,
fluorine and/or trifluoromethyl.
4. The method according to claim 1, wherein in the compound of
formula (I), Ar is selected from the group consisting of:
4-isobutylphenyl, 4-(2-methyl)allyl-phenyl, 3-phenoxyphenyl,
3-benzoyl-phenyl, 3-acetyl-phenyl, the single diastereoisomers
(R),(S) and the diastereoisomeric mixture (R,S) of
3-C.sub.6H.sub.5--CH(OH)-phenyl, 3-CH.sub.3--CH(OH)-phenyl,
5-C.sub.6H.sub.5--CH(OH)-thienyl, 4-thienyl-CH(OH)-phenyl,
3-(pyrid-3-yl)-CH(OH)-phenyl, 5-benzoyl-thien-2-yl, 4
thienoyl-phenyl, 3-nicotinoyl-phenyl, 2-fluoro-4-phenyl,
6-methoxy-2-naphthyl, 5-benzoyl-2-acetoxy-phenyl and
5-benzoyl-2-hydroxy-phenyl.
5. The method according to claim 1, wherein in the compound of
formula (I), wherein Ar is phenyl 3-substituted by a group selected
form: isoprop-1-en-1-yl, isopropyl, pent-2-en-3-yl, pent-3-yl,
1-phenylethylen-1-yl and .alpha.-methylbenzyl.
6. The method according to claim 1, wherein in the compound of
formula (I), the Ar group of formula IVc is selected from the group
consisting of: 4-(pyrrolidin-1-yl)-methyl-phenyl,
3-chloro-4-(pyrrolidin-1-yl)-methyl-phenyl,
3-chloro-4-(2,5-dihydro-1-H-pyrrol-1-yl)-methyl-phenyl, 3
chloro-4-(thiomorpholin-4-yl)phenyl,
3-chloro-4-(piperidin-1-yl)-phenyl,
4-((N-ethyl-N-quinolin-2-yl-methylamino)-methyl)phenyl and
3-chloro-4-(morpholin-4-yl)-phenyl.
7. The method according to claim 1, wherein in the compound of
formula (I), the Ar group of formula IVe is selected from:
2-(2,6-dichloro-phenyl-amino)-phenyl,
2-(2,6-dichloro-phenyl-amino)-5-chloro-phenyl,
2-(2,6-dichloro-3-methyl-phenyl-amino)-phenyl and
2-(3-trifluoromethyl-phenyl-amino)-phenyl.
8. The method according to claim 1, wherein in the compound of
formula (I), R is hydrogen, X is: a linear alkylene optionally
substituted at C.sub.1 by a --CO.sub.2R.sub.3 group as defined
above; a linear alkylene optionally substituted at C.sub.1 by a
--CONHR.sub.4 group wherein R.sub.4 is OH; 2-butynylene,
cis-2-butenylene, trans-2-butenylene; 3-oxa-pentylene,
3-thio-pentylene, 3-oxa-hexylene, 3-thio-hexylene;
(CH.sub.2).sub.m--CO--NH--(CH.sub.2).sub.n-- wherein m and n are
each independently an integer from 2 to 3;
(CHR')--CONH--(CH.sub.2).sub.n wherein n is an integer from 2 to 3
and R'' is a methyl, in absolute configuration R or S; or X,
together with the N atom of the omega-amino group, forms a nitrogen
containing cycloaliphatic ring selected from
1-methyl-piperidin-4-yl and 1,5-tropan-3-yl.
9. The method according to claim 1, wherein in the compound of
formula (I), NR.sub.1R.sub.2 represents an NH.sub.2 group,
dimethylamino, diethylamino, diisopropylamino, 1-piperidinyl,
4-morpholyl, 4-thiomorpholyl or, R.sub.1 and R.sub.2 together form
a residue of guanidine, aminoguanidine, hydroxyguanidine,
2-amino-3,4,5,6-tetrahydropyrimidyl or
2-amino-3,5-dihydro-imidazolyl.
10. The method according to claim 1, wherein the compound of
formula (I) is one selected from the group consisting of
(R)-2-[(4-isobutyl)phenyl]-N-(3-dimethylaminopropyl)propionamide;
(R)-2-[(4-isobutyl)phenyl]-N-(4-dimethylaminobutyl)-propionamide
hydrochloride;
(R)-2-[(4-isobutyl)phenyl]-N-(3-N-morpholinylpropyl)propionamide;
(R)-2-[(4-isobutyl)phenyl]-N-(2-dimethylaminoethyl)propionamide;
(R)-2-[(4-isobutyl)phenyl)-propionyl]-N-[2-(4-methyl-piperazin-1-yl)ethyl-
]propionamide;
(R)--N-(exo-8-methyl-8-aza-bicyclo[3,2,1]oct-3-yl)-2-[(4-isobutylphenyl)--
propionamide;
(R)-2-[(4-isobutyl)phenyl]-N-(3-N-thiomorpholinylpropyl)propionamide;
(R)-2-[(4-isobutyl)phenyl]-N-[4-(N'-methyl)piperidinyl]propionamide
hydrochloride;
(R),(S')-2-[(4-isobutyl)phenyl]-N-(1-carboxy-2-dimethylaminoethyl)-propio-
namide;
(R),(S')-2-[(4-isobutyl)phenyl]-N-[(1-carboxy-4-piperidin-1-yl)bu-
tyl]propionamide;
(R),(S')-2-[(4-isobutyl)phenyl]-N-(1-carboxy-4-aminobutyl)propionamide;
(R)-2-(4-isobutyl)phenyl-N-[2-(dimethylaminoethyl)aminocarbonylmethyl)]pr-
opionamide hydrochloride;
2-(2,6-dichlorophenylamino)-phenyl-N-(3-dimethylaminopropyl)propionamide;
(R),(R',S')-3-[3-.alpha.-methyl)benzyl]phenyl-N-(3-dimethylaminopropyl)--
propionamide;
(R)-2-[(3-isopropyl)phenyl]-N-(3-dimethylaminopropyl)propionamide;
(R)-2-[3-(pent-3-yl)phenyl]-N-(3-dimethylaminopropyl)propionamide;
(R)-2-[(4-isobutyl)phenyl]-N-(3-guanidylpropyl)propionamide;
(R)-2-[(4-isobutyl)phenyl]-N-[(3-hydroxy-guanidyl)propyl]propionamide;
(R)-2-[(4-isobutyl)phenyl]-N-[(3-amino-guanidyl)propyl]propionamide;
(R)-2-[(4-isobutyl)phenyl]-N-[3-(2-amino-2-imidazoline)
propyl]propionamide;
(R)-2-[(4-isobutyl)phenyl]-N--[N-methyl-N-(2-hydroxyethyl)aminoethoxy]pro-
pionamide and
(R),(S')-2-[(4-isobutyl)phenyl]-N-[1-carboxy-5-aminopentyl]propionamide.
11. The method according to claim 1, wherein the compound of
formula (I) is
(R)-2-(4-isobutylphenyl)-N-(3-dimethylaminopropyl)propionamide
hydrochloride.
12. The method according to claim 1, wherein the compound of
formula (I), is
(R)-2-(4-isobutylphenyl)-N-3-(1-piperidinylpropyl)propionamide
hydrochloride.
13. The method according to claim 1, wherein in the compound of
formula (I), R.sub.1 and R.sub.2 are groups different from
hydrogen.
14. The method according to claim 13, wherein in the compound of
formula (I), X is linear C.sub.2-C.sub.4 alkylene.
15. A method for preventing or treating of injury caused by
ischemia and reperfusion comprising administering a compound
administering to a patient in need thereof an effective amount of a
(R)-2-Aryl-propionamide compound of formula (I): ##STR44## or a
pharmaceutically acceptable salt thereof, wherein Ar represents a
substituted or non-substituted aryl group; R represents hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4
alkynyl, optionally substituted by a CO.sub.2R.sub.3 group, wherein
R.sub.3 represents hydrogen or a linear or branched C.sub.1-C.sub.6
alkyl group or a linear or branched C.sub.2-C.sub.6 alkenyl group;
X represents: a linear or branched C.sub.1-C.sub.6 alkylene,
C.sub.4-C.sub.6 alkenylene, C.sub.4-C.sub.6 alkynylene, optionally
substituted by a CO.sub.2R.sub.3 group or by a CONHR.sub.4 group
wherein R.sub.4 represents hydrogen, linear or branched
C.sub.2-C.sub.6 alkyl or an OR.sub.3 group, R.sub.3 being defined
as in claim 1; a (CH.sub.2).sub.m--B--(CH.sub.2).sub.n, group,
optionally substituted by a CO.sub.2R.sub.3 or CONHR.sub.4 group,
as defined above, wherein B is an oxygen or sulfur atom, m is zero
or an integer from 2 to 3 and n is an integer from 2 to 3; or B is
a CO, SO or CONH group, m is an integer from 1 to 3 and n is an
integer from 2 to 3; or X together with the nitrogen atom of the
omega-amino group to which it is bound and with the R.sub.1 group
forms a non-aromatic nitrogen containing 3-7 membered heterocyclic,
monocyclic or polycyclic ring wherein the nitrogen atom has a
substituent Rc, where Rc represents hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 hydroxylalkyl, C.sub.1-C.sub.4 acyl,
substituted or non-substituted phenyl, diphenylmethyl; R.sub.1 and
R.sub.2 are independently hydrogen, linear or branched
C.sub.1-C.sub.6 alkyl, optionally interrupted by an O or S atom, a
C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.6 alkenyl,
C.sub.3-C.sub.6-alkynyl, aryl-C.sub.1-C.sub.3-alkyl or
hydroxy-C.sub.2-C.sub.3-alkyl group; or R.sub.1 and R.sub.2
together with the N atom to which they are bound, form a 3-7
membered nitrogen heterocyclic ring of formula (II) ##STR45##
wherein Y represents a single bond, CH.sub.2, O, S, or a N-Rc group
as defined above and p represents an integer from 0 to 3; or,
R.sub.1 being as defined above, R.sub.2 represents a group of
formula (III): ##STR46## wherein R.sub.a is hydrogen and R.sub.b is
hydrogen, hydroxy, C.sub.1-C.sub.4-alkyl or an NR.sub.dR.sub.e
group wherein R.sub.d and R.sub.e, are each independently,
hydrogen, C.sub.1-C.sub.4-alkyl or phenyl; or R.sub.a and R.sub.b,
together with the nitrogen atoms to which they are bound, form a
5-7 membered heterocyclic ring, monocyclic or fused with a benzene,
pyridine or pyrimidine ring; said compound of the formula (I)
having activity of inhibiting C5a-induced chemotaxis of
polymorphonucleate leukocytes and monocytes.
16. The method according to claim 15, wherein in the compound of
formula (I), R.sub.1 and R.sub.2 are groups different from
hydrogen.
17. A method for inhibiting both the Cfa-induced chemotaxis of
polymorphonucleate leukocytes and monocytes, and the interleukin
8-induced chemotaxis of polymorphonucleate leukocytes, comprising
administering comprising administering to a patient in need thereof
an effective amount of a (R)-2-Aryl-propionamide compound of
formula (I): ##STR47## or a pharmaceutically acceptable salt
thereof, wherein Ar represents a substituted or non-substituted
aryl group; R represents hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl, optionally
substituted by a CO.sub.2R.sub.3 group, wherein R.sub.3 represents
hydrogen or a linear or branched C.sub.1-C.sub.6 alkyl group or a
linear or branched C.sub.2-C.sub.6 alkenyl group; X represents a
linear or branched C.sub.1-C.sub.6 alkylene, C.sub.4-C.sub.6
alkenylene, C.sub.4-C.sub.6 alkynylene, optionally substituted by a
CO.sub.2R.sub.3 group or by a CONHR.sub.4 group wherein R.sub.4
represents hydrogen, linear or branched C.sub.2-C.sub.6 alkyl or an
OR.sub.3 group, R.sub.3 being defined as above; a
(CH.sub.2).sub.m--B--(CH.sub.2).sub.n, group, optionally
substituted by a CO.sub.2R.sub.3 or CONHR.sub.4 group, as defined
above, wherein B is an oxygen or sulfur atom, m is zero or an
integer from 2 to 3 and n is an integer from 2 to 3; or B is a CO,
SO or CONH group, m is an integer from 1 to 3 and n is an integer
from 2 to 3; or X together with the nitrogen atom of the
omega-amino group to which it is bound and with the R.sub.1 group
forms a non-aromatic nitrogen containing 3-7 membered heterocyclic,
monocyclic or polycyclic ring wherein the nitrogen atom has a
substituent Rc, where Rc represents hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 hydroxylalkyl, C.sub.1-C.sub.4 acyl,
substituted or non-substituted phenyl, diphenylmethyl; R.sub.1 and
R.sub.2 are independently linear or branched C.sub.1-C.sub.6 alkyl,
optionally interrupted by an O or S atom, a C.sub.3-C.sub.7
cycloalkyl, C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6-alkynyl,
aryl-C.sub.1-C.sub.3-alkyl, hydroxy-C.sub.2-C.sub.3-alkyl group; or
R.sub.1 and R.sub.2 together with the N atom to which they are
bound, form a nitrogen containing 3-7 membered heterocyclic ring of
formula (II) ##STR48## wherein Y represents a single bond,
CH.sub.2, O, S, or a N-Rc group as defined above and p represents
an integer from 0 to 3; or, R.sub.1 being as defined above, R.sub.2
represents a group of formula (III): ##STR49## wherein R.sub.a is
hydrogen and R.sub.b is hydrogen, hydroxy, C.sub.1-C.sub.4-alkyl or
an NR.sub.dR.sub.e group wherein R.sub.d and R.sub.e are
independently hydrogen, C.sub.1-C.sub.4-alkyl or phenyl; or R.sub.a
and R.sub.b, together with the nitrogen atoms to which they are
bound, form a 5-7 membered heterocyclic ring, monocyclic or fused
with a benzene, pyridine or pyrimidine ring; with the proviso that
when Ar is 4-diphenyl and X is (CH.sub.2).sub.2 or
(CH.sub.2).sub.3, R.sub.1 and R.sub.2 are not ethyl; with the
further proviso that, when Ar is a 4-(2-fluoro)diphenyl residue,
and X is butylene substituted by a CO.sub.2H group, R.sub.a and
R.sub.b are not hydrogen; and with the further proviso that, when
Ar is phenyl and X is butylene, R.sub.1 and R.sub.2 together are
not a N-(2-methoxy phenyl)piperazine.
18. The method of claim 17, in which in the compound of the formula
(I), X is a linear C.sub.2-C.sub.4 alkylene.
19. The method of claim 1, in which in the compound of the formula
(I), Ar.sub.b has the formula IV(c) in which A is selected from the
group consisting of dimethylamino, diethylamino,
methyl-N-ethyl-amino, acetyl-N-methyl-amino and
pivaloyl-N-ethyl-amino.
20. The method of claim 1, in which in the compound of the formula
(I), Ar.sub.b has the formula IV(c) in which A is selected from the
group consisting of a 1-pyrrolidino, 2,5-dihydro-pyrrol-1-yl,
1-pyrrol, 1-piperidino, 1-piperazino-4-non-substituted or
4-substituted (methyl, ethyl, 2-hydroxyethyl, benzyl, benzyhydril
or phenyl), 4-morpholino, 4-3,5-dimethyl-morpholino,
4-thiomorpholino group.
Description
[0001] This application is a Rule 53(b) Divisional of co-pending
application Ser. No. 10/469,094, filed on Jun. 16, 2004, which is
the U.S. National Stage application of PCT Application No.
PCT/EP02/01974, filed Feb. 25, 2002, which claims priority to
Italian Application No. M12001A000395, filed on Feb. 27, 2001, the
entire contents of which are hereby incorporated by reference and
for which priority is claimed under 35 U.S.C. .sctn. 120.
[0002] The present invention relates to omega-aminoalkylamides of
(R)2-aryl-propionic acids as inhibitors of the chemotaxis of
polymorphonucleate and mononucleate cells. In particular, the
invention relates to inhibitors of the C5a--induced chemotaxis of
polymorphonucleate leukocytes and monocytes, which are used in the
treatment of pathologies including psoriasis, rheumatoid arthritis
and injury caused by ischemia and reperfusion.
INTRODUCTION AND BACKGROUND OF THE INVENTION
[0003] Animal studies show that some aminoalkylester and amide
prodrugs of racemic ibuprofen and naproxen, in particular some
N-(3-diethylaminopropyl)amides, exhibit analgesic and
antiinflammatory activity significantly better than the parent
compounds, even though "in vitro" they have been found to be poor
inhibitors of the synthesis of prostaglandins. All these prodrugs,
except a glycine amide, have also been found to be significantly
less irritating to the gastric mucosa than their precursor free
acids. (Shanbhag V R et al., J. Pharm. Sci., 81, 149, 1992 and
references 8-19) therein cited.
[0004]
Piketoprofen[(.+-.)2-(3-benzoylphenyl)-N-(4-methyl-2-pyridinyl)pro-
pionamide] and Amtolmetin Guacil (also named guaiacol ester of
tolmetinglycinamide, Eufans) are further examples of non steroidal
antiinflammatory (NSAI) prodrugs in current therapeutic use.
Moderate antiinflammatory activity, minor side effects and good
gastro-intestinal tolerance are reported for a series of
N-[2-(1-piperidinyl)propyl]amides of some NSAI drugs such as
racemic ibuprofen, indomethacin, p-chlorobenzoic acid,
acetylsalicyclic acid, diacetylgentisic acid and
adamantane-1-carboxylic acid (Nawladonski F. and Reewuski, Pol. J.
Chem., 52, 1805, 1978). Other amides of racemic 2-arylpropionic
acids have been disclosed by 1. Biniecki et al., [PL 114050 (31,
Jan. 1981)], H. Akguen et al., [Arzneim-Forsch., 46, 891, 1986] and
by G. L. Levitt et al., [Russ. J. Org. Chem., 34, 346, 1998].
[0005] Anti-inflammatory and analgesic potencies "in vivo",
comparable and sometimes greater than those of the precursor free
acids, along with decreased number of gastric lesions, have been
reported for some N-3-[(1-piperidinyl)propyl]amides of racemic
ketoprofen and flurbiprofen and for certain Mannich bases obtained
reacting their amides with formaldehyde and secondary amines such
as morpholine, piperidine, dicyclohexylamine, dimethylamine,
diethylamine, dibenzylamine and dibutylamine (N. Kawathekar et al.,
Indian J. Pharm. Sci., 60, 346, 1998).
[0006] International patent application, WO 00/40088, has recently
reported that the mere conversion to an amide derivative of a
2-arylacetic and/or 2-arylpropionic acid is enough to change a
selective COX-1 inhibitor into a COX-2 selective inhibitor which
explains the decreased gastrolesivity of said amides, for a long
time believed to be only NSAI prodrugs.
[0007] In the past, inhibition of the cyclooxygenase enzymes was
known to be proper of the S enantiomer of 2-arylpropionic acids
alone, joined together with the portion of R CoA-thioester
suffering bioconversion "in vivo". Therefore, the poor correlation
between enzymatic inhibition "in vitro" and analgesic effects "in
vivo" found for certain R,S 2-arylpropionic acids (Brune K. et al.,
Experientia, 47, 257, 1991) has induced to presume that alternative
mechanisms, such as inhibition of transcription of the kB-nuclear
transcription factor (NF-kB) and/or inhibition of neutrophil
chemotaxis induced by interleukin 8 (IL-8), can be operating.
[0008] R enantiomers of flurbiprofen, ketoprofen, naproxen,
thiaprofen and phenoprofen are, in fact, disclosed in WO 00/40088
as inhibitors of the NF-kB transcription factor activation and
claimed to be useful in the treatment of NF-kB dependent diseases
(asthma, tumor, shock, Crohn's disease and ulcerative colitis,
arteriosclerosis, etc). IL-8 is an important mediator of
inflammation and has been shown to be a potent chemotactic/cell
activator for polymorphonucleate neutrophils and basophils (PMNs),
and T lymphocytes. Cellular sources of IL-8 include monocytes,
PMNs, endotelial cells, epithelial cells, and keratinocytes when
stimulated by factors such as lipopolysaccaride, IL-1 and
TNF-.alpha.. On the other hand, the complement fragment C5a, in
addition to being a direct mediator of inflammation, has been found
to induce both IL-8 synthesis and high level of IL-8 release from
monocytes. The quantity of IL-8 recovered from C5a activated
monocytes in peripheral blood mononuclear cells is up to 1,000 fold
greater than that released from comparable numbers of PMNs under
similar conditions. Therefore IL-8 released from C5a-activated
monocytes may play a significant role in expanding and prolonging
cellular infiltration and activation at the sites of infection,
inflammation, or tissue injury (Ember J. A. et al., Am. J. Pathol.,
144, 393, 1994).
[0009] In response to immunologic and infective events, activation
of the complement system mediates amplification of inflammatory
response both via direct membrane action and via release of a
series of peptide fragments, generally known as anaphylatoxins,
generated by enzymatic cleavage of the C3, C4 and C5 complement
fractions. These peptides include C3a, C4a, both made of 77
aminoacids; in turn, C5 convertase cleaves the C5 complement
fraction to give the glycoprotein C5a of 74 aminoacids.
Anaphilatoxins contribute to the spreading of the inflammatory
process by interaction with individual cell components; their
common properties are cellular release of vasoactive amines and
lysosomal enzymes, contraction of smooth muscle and increased
vascular permeability. Moreover, C5a causes chemotaxis and
aggregation of neutrophils, stimulates the release of leukotrienes
and of oxidized oxygen species, induces the transcription of IL-1
in macrophages and the production of antibodies.
[0010] The C5a peptide fragment of the complement has been defined
as the "complete" pro-inflammatory mediator. On the contrary, other
inflammatory mediators such as selected cytokines (IL-8, MCP-1 and
RANTES, for example) are highly selective towards self-attracted
cells, while histamine and bradykinin are only weak chemotactic
agents. Convincing evidences support the involvement of C5a, "in
vivo", in several pathological conditions including
ischemia/reperfusion, autoimmune dermatitis, membrane-proliferative
idiopathic glomerulonephritis, airway iperresponsiveness and
chronic inflammatory diseases, ARDS and COPD, Alzheimer's disease,
juvenile rheumatoid arthritis (N. P. Gerard, Ann. Rev. Immunol.,
12, 755, 1994).
[0011] In view of the neuro-inflammatory potential of
C5a/C5a-desArg generated by both local complement production and
amyloid activation joined with astrocyte and microglia chemotaxis
and activation directly induced by C5a, complement inhibitors have
been proposed for the treatment of neurological diseases such as
Alzheimer's disease (McGeer & McGeer P. L., Drugs, 55, 738,
1998).
[0012] Therefore, the control of the local synthesis of complement
fractions is considered of high therapeutic potential in the
treatment of shock and in the prevention of rejection (multiple
organ failure and hyperacute graft rejection) (Issekutz A. C. et
al., Int. J. Immunopharmacol, 12, 1, 1990; Inagi R. et at.,
Immunol. Lett., 27, 49, 1991). More recently, inhibition of
complement fractions has been reported to be involved in the
prevention of native and transplanted kidney injuries taking
account of complement involvement in the pathogenesis of both
chronic interstitial and acute glomerular renal injuries. (Sheerin
N. S. & Sacks S. H., Curr. Opinion Nephrol. Hypert., 7, 395,
1998).
[0013] Genetic engineering and molecular biology studies led to the
cloning of complement receptors (CRs) and to the production of CRs
agonists and antagonists. The recombinant soluble receptor CR1
(sCR1), that blocks enzymes activating C3 and C5, has been
identified as a potential agent for the suppression of C activation
on ischemia/reperfusion injury (Weisman H. F. et al., Science, 239,
146, 1990; Pemberton M. et al., J. Immunol., 150, 5104, 1993). The
cyclic peptide F--[OPdChWR], is reported to antagonize the C5a
binding to its CD38 receptor on PMNs and to inhibit C5a-dependent
chemotaxis and cytokine production by macrophages and rat
neutropenia induced by C5a and LPS stimulation (Short A. et al.,
Br. J. Pharmacol., 126, 551, 1999; Haynes D. R. et al., Biochem.
Pharmacol., 60, 729, 2000). Both C5aR antagonist CGS 27913 and its
dimer CGS 32359 are reported to inhibit, "in vitro", C5a binding to
neutrophil membranes, intracellular Ca.sup.2+ mobilization,
lysozyme release, neutrophil chemotaxis and dermal edema in rabbits
(Pellas T. C. et al., J. Immunol., 160, 5616, 1998).
[0014] Finally, selection from phage libraries with the "phage
display" technique has led to the isolation of a specific C5aR
antagonist able to decrease inflammatory responses in diseases
mediated by immuno-complexes and in ischemia and reperfusion
injuries (Heller T. et al., J. Immunol., 163, 985, 1999). Despite
their therapeutic potential, only two of the above discussed C5a
antagonists have demonstrated activity "in vivo"; furthermore,
their use is therapeutically limited by their peptidic nature.
(Pellas T. C., Wennogle P., Curr. Pharm. Des., 10, 737, 1999).
[0015] Characteristic neutrophil accumulation can be observed in
some pathologic conditions, for example in the highly inflamed and
therapeutically recalcitrant areas of psoriatic lesions.
Neutrophils are chemotactically attracted and activated by the
sinergistic action of chemokines, IL-8 and Gro-a released by the
stimulated keratinocytes, and of the C5a/C5a-desArg fraction
produced via the alternative complement pathway activation (T.
Terui et al., Exp. Dermatol., 9, 1, 2000). In many circumstances it
is, therefore, highly desirable to combine inhibition of the
chemotaxis induced by C5a and inhibition of the chemotaxis induced
by IL-8 in one single agent.
[0016] Non-peptidic antagonists of complement fractions have also
been prepared, for example substituted-4,6-diamino-quinolines. In
particular, [N,N''-bis-(4-amino-2-methyl-6-quinolyl)]urea and
[6-N-2-chlorocynnamoyl)-4,6-diamino-2-methylquinoline] have been
found selective C5R antagonists, their IC.sub.50 ranging between
3.3 and 12 .mu.g/mL (Lanza T. J. et al., J. Med. Chem., 35, 252,
1992).
[0017] Some serine-protease inhibitors [nafamostat mesilate (FUT
175) and certain analogs] have been recently reported to be
inhibitors of both complement activation and C3a/C5a production
(Ueda N. et al., Inflammation Res. 49, 42, 2000).
[0018] U.S. Pat. No. 6,069,172 reports the use of pharmaceutical
formulations of R(-) ketoprofen ammonium salts for the inhibition
of neutrophil chemotaxis induced by IL-8.
[0019] WO 00/24710 discloses N-acylsulfonamides of
R(-)2-aryl-propionic acids as inhibitors of IL-8 dependent
polymorphonucleate leukocytes chemotaxis.
[0020] Two recent patent applications [WO 01/58852 and WO 01/79189]
disclose certain R-2-aryl-propionamides and
R-2-(aminophenyl)propionamides useful for preventing leukocyte
activation induced by IL-8.
[0021] We have recently observed that the mere formal reduction of
the hetero-aromatic ring of certain
R2-aryl-N-(pyridinyl)propionamides causes marked loss of potency (1
or 2 logarithmic order) in the capacity to inhibit PMN neutrophil
chemotaxis induced by IL-8. Unexpectedly, the related
R2-aryl-N-(piperidinyl)propionamides have been found to be potent
inhibitors of chemotaxis of human PMN leukocytes and monocytes
induced by the C5a fraction of the complement.
[0022] These unexpected findings have originated a novel family of
omega-aminoalkylamides of R-2-aryl-propionic acids which are able
to inhibit the chemotactic activity induced by C5a and other
chemotactic proteins whose biological activity is associated with
activation of a 7-membered-domain receptor (7-TD) homologous to the
receptor of C5a (for example, the C3a receptor and the CXCR2
receptor; Neote K. et al., Cell, 72, 415, 1993; Tornetta M. A., J.
Immunol., 158, 5277, 1997).
BRIEF DESCRIPTION OF THE INVENTION
[0023] It is the object of the present invention a novel class of
omega-aminoalkylamides of R-2-aryl-propionic acids and
pharmaceutical compositions containing them. The position "omega"
in the alkyl chain refers to the furthest carbon atom starting from
the N atom of the amide group to which said alkyl is linked. Such
amides are useful in the inhibition of the chemotactic activation
induced by C5a and by other chemotactic proteins whose biological
activity is associated with the activation of 7-transmembrane
domains (7-TD) receptors homologous to the C5a receptor. In
particular such amides are useful in the inhibition of the
chemotactic activation of polymorphonucleate leukocytes, monocytes
and lymphocytes T induced by the fraction C5a of the complement and
in the treatment of pathologies related to said activation.
DETAILED DESCRIPTION OF THE INVENTION
[0024] The following paragraphs provide definitions of outstanding
chemical moieties that make up the compounds according to the
invention and are intended to apply uniformly throughout the
specification and claims unless an otherwise expressly set out
definition provides a broader definition.
[0025] The term "alkyl" refers to monovalent alkyl groups having
preferably 1 to 6 carbon atoms. These terms are exemplified by
groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, tert-butyl, and the like.
"Aryl" refers to an unsaturated aromatic carbocyclic group of from
6 to 14 carbon atoms having a single ring (e.g. phenyl) or multiple
condensed rings (e.g. naphthyl). Preferred aryl include phenyl,
biphenyl, naphthyl, phenantrenyl and the like.
"Alkenyl" refers to alkenyl groups preferably having from 2 to 5
carbon atoms and having one or more sites of alkenyl unsaturation.
Preferred alkenyl groups include ethenyl (--CH.dbd.CH.sub.2),
n-2-propenyl(allyl, --CH.sub.2CH.dbd.CH.sub.2) and the like.
"Alkylene", "Alkenylene", Alkynylene" refer to groups disubstituted
at both ends. Preferred groups include methylene, ethylene,
propylene, and like.
[0026] "Substituted or non-substituted": unless otherwise
constrained by the definition of the individual substituent, the
above set out groups, like "alkyl", "alkenyl", "aryl" groups etc.
can optionally be substituted with from 1 to 5 substituents
selected from the group consisting of "C.sub.1-C.sub.6-alkyl",
"C.sub.1-C.sub.6-alkyl aryl", "C.sub.1-C.sub.6-alkyl heteroaryl",
"C.sub.2-C.sub.6-alkenyl", primary, secondary or tertiary amino
groups or quaternary ammonium moieties, "acyl", "acyloxy",
"acylamino", "aminocarbonyl", "alkoxycarbonyl", "aryl",
"heteroaryl", carboxyl, cyano, halogen, hydroxy, mercapto, nitro,
sulfoxy, sulfonyl, alkoxy, thioalkoxy, trihalomethyl and the like.
Within the framework of this invention, said "substitution" is
meant to also comprise situations where neighbouring substituents
undergo ring closure, in particular when vicinal functional
substituents are involved, thus forming e.g. lactams, lactons,
cyclic anhydrides or cycloalkanes, but also acetals, thioacetals,
animals formed by ring closure for instance in an effort to obtain
a protective group.
[0027] "Pharmaceutically acceptable salts" refers to salts or
complexes of the below-identified compounds of formula I that
retain the desired biological activity. Examples of such salts
include, but are not restricted to, acid addition salts formed with
inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric
acid, phosphoric acid, nitric acid, and the like), and salts formed
with organic acids such as acetic acid, oxalic acid, tartaric acid,
succinic acid, malic acid, fumaric acid, maleic acid, ascorbic
acid, benzoic acid, tannic acid, pamoic acid, alginic acid,
polyglutamic acid, naphthalene sulfonic acid, naphthalene
disulfonic acid, and poly-galacturonic acid.
[0028] Examples of salts also include acid addition salts formed
with inorganic bases such as sodium hydroxyde and with organic
bases such as tromethamine, L-lysine, L-arginine and the like.
[0029] The present invention provides (R)-2-aryl-propionamide
compounds of formula (I), ##STR2## wherein Ar represents a
substituted or non-substituted aryl group; R represents hydrogen,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4
alkynyl, optionally substituted by a CO.sub.2R.sub.3 group, wherein
R.sub.3 represents hydrogen or a linear or branched C.sub.1-C.sub.6
alkyl group or a linear or branched C.sub.2-C.sub.6 alkenyl group;
X represents: linear or branched C.sub.1-C.sub.6 alkylene,
C.sub.4-C.sub.6 alkenylene, C.sub.4-C.sub.6 alkynylene, optionally
substituted by a CO.sub.2R.sub.3 group or by a CONHR.sub.4 group
wherein R.sub.4 represents hydrogen, linear or branched
C.sub.2-C.sub.6 alkyl or an OR.sub.3 group, R.sub.3 being defined
as above; a (CH.sub.2).sub.m--B--(CH.sub.2).sub.n, group,
optionally substituted by a CO.sub.2R.sub.3 or CONHR.sub.4 group,
as defined above, wherein B is an oxygen or sulfur atom, m is zero
or an integer from 2 to 3 and n is an integer from 2 to 3; or B is
a CO, SO or CONH group, m is an integer from 1 to 3 and n is an
integer from 2 to 3;
[0030] or X together with the nitrogen atom of the omega-amino
group to which it is bound and with the R.sub.1 group forms a
non-aromatic nitrogen containing 3-7 membered heterocyclic,
monocyclic or polycyclic ring wherein the nitrogen atom has a
substituent Rc, where Rc represents hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 hydroxylalkyl, C.sub.1-C.sub.4 acyl,
substituted or non-substituted phenyl, diphenylmethyl;
[0031] R.sub.1 and R.sub.2 are independently hydrogen, linear or
branched C.sub.1-C.sub.6 alkyl, optionally interrupted by an O or S
atom, a C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.6 alkenyl,
C.sub.3-C.sub.6-alkynyl, aryl-C.sub.1-C.sub.3-alkyl,
hydroxy-C.sub.2-C.sub.3-alkyl group; or R.sub.1 and R.sub.2
together with the N atom to which they are bound, form a nitrogen
containing 3-7 membered heterocyclic ring of formula (II) ##STR3##
wherein Y represents a single bond, CH.sub.2, O, S, or a N-Rc group
as defined above and p represents an integer from 0 to 3; or,
R.sub.1 being as defined above, R.sub.2 represents a group of
formula (III): ##STR4## wherein R.sub.a is hydrogen and R.sub.b is
hydrogen, hydroxy, C.sub.1-C.sub.4-alkyl or an NR.sub.dR.sub.e
group wherein R.sub.d and R.sub.e, are each independently,
hydrogen, C.sub.1-C.sub.4-alkyl or phenyl; or R.sub.a and R.sub.b,
together with the nitrogen atoms to which they are bound, form a
5-7 membered heterocyclic ring, monocyclic or fused with a benzene,
pyridine or pyrimidine ring; with the proviso that when Ar is a
4-diphenyl residue and X is an ethylene or propylene residue,
R.sub.1 and R.sub.2 are not ethyl; with the further proviso that,
when Ar is a 4-(2-fluoro)diphenyl residue, and X is butylene
substituted by a CO.sub.2H group, R.sub.a and R.sub.b are not
hydrogen; and with the further proviso that, when Ar is phenyl and
X is butylene, R1 and R2 together are not a N-(2-methoxy
phenyl)piperazine.
[0032] In addition, the present invention further provides
(R)-2-aryl-propionamide compounds of formula (I) ##STR5## wherein
Ar represents a substituted or non-substituted aryl group; R
represents hydrogen, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4
alkenyl, C.sub.2-C.sub.4 alkynyl, optionally substituted by a
CO.sub.2R.sub.3 group, wherein R.sub.3 represents hydrogen or a
linear or branched C.sub.1-C.sub.6 alkyl group or a linear or
branched C.sub.2-C.sub.6 alkenyl group; X represents: linear or
branched C.sub.1-C.sub.6 alkylene, C.sub.4-C.sub.6 alkenylene,
C.sub.4-C.sub.6 alkynylene, optionally substituted by a
CO.sub.2R.sub.3 group or by a CONHR.sub.4 group wherein R.sub.4
represents hydrogen, linear or branched C.sub.2-C.sub.6 alkyl or an
OR.sub.3 group, R.sub.3 being defined as above; a
(CH.sub.2).sub.m--B--(CH.sub.2).sub.n, group, optionally
substituted by a CO.sub.2R.sub.3 or CONHR.sub.4 group, as defined
above, wherein B is an oxygen or sulfur atom, m is zero or an
integer from 2 to 3 and n is an integer from 2 to 3; or B is a CO,
SO or CONH group, m is an integer from 1 to 3 and n is an integer
from 2 to 3; or X together with the nitrogen atom of the
omega-amino group to which it is bound and with the R.sub.1 group
forms a non-aromatic nitrogen containing 3-7 membered heterocyclic,
monocyclic or polycyclic ring wherein the nitrogen atom has a
substituent Rc, where Rc represents hydrogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 hydroxylalkyl, C.sub.1-C.sub.4 acyl,
substituted or non-substituted phenyl, diphenylmethyl; R.sub.1 and
R.sub.2 are independently hydrogen, linear or branched
C.sub.1-C.sub.6 alkyl, optionally interrupted by an O or S atom, a
C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.6 alkenyl,
C.sub.3-C.sub.6-alkynyl, aryl-C.sub.1-C.sub.3-alkyl,
hydroxy-C.sub.2-C.sub.3-alkyl group; or R.sub.1 and R.sub.2
together with the N atom to which they are bound, form a 3-7
membered nitrogen heterocyclic ring of formula (II) ##STR6##
wherein Y represents a single bond, CH.sub.2, O, S, or a N-Rc group
as defined above and p represents an integer from 0 to 3; or,
R.sub.1 being as defined above, R.sub.2 represents a group of
formula (III): ##STR7## wherein R.sub.a is hydrogen and R.sub.b is
hydrogen, hydroxy, C.sub.1-C.sub.4-alkyl or an NR.sub.dR.sub.e
group wherein R.sub.d and R.sub.e, are each independently,
hydrogen, C.sub.1-C.sub.4-alkyl or phenyl; or R.sub.a and R.sub.b,
together with the nitrogen atoms to which they are bound, form a
5-7 membered heterocyclic ring, monocyclic or fused with a benzene,
pyridine or pyrimidine ring; for use as inhibitors of the
C5a-induced chemotaxis of polymorphonucleate leukocytes and
monocytes.
[0033] Pharmaceutically acceptable salts of the compounds of
formula (I) are also within the scope of the present invention.
[0034] Examples of aryl groups preferably comprise: [0035] a) an
Ara mono- or poly-substituted aryl group, or the most common
heterocyclic rings found 2-aryl-propionic acids in current
therapeutic use: alminoprofen, benoxaprofen, carprofen, fenbufen,
fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen,
loxoprofen, naproxen, pirprofen and its dehydro and dihydro
derivatives, pranoprofen, surprofen, tiaprofenic acid, zaltoprofen;
[0036] b) an aryl-hydroxymethyl-aryl group of formula (IVa)
deriving from the reduction of the phenone carbonyl of
2-aryl-propionic acids: ketoprofen, surprofen, thiaprofenic acid,
both as single (S',R) and/or (R',R) diastereoisomer and as
diastereoisomeric mixture, ##STR8## wherein, when Ar.sub.2 is
phenyl, Ar.sub.1 is selected from the group consisting of phenyl
and thien-2-yl and, when Ar.sub.1 is phenyl, Ar.sub.2 is selected
from the group consisting of phenyl, 4-thienyl, pyridyl, [0037] c)
an aryl of formula (IVb): .phi.-Ar.sub.b (IV b) wherein Ar.sub.b is
a phenyl mono- and poly-substituted by optionally substituted
hydroxy, mercapto, C.sub.1-C.sub.3-alcoxy,
C.sub.1-C.sub.3-alkylthio, chlorine, fluorine, trifluoromethyl,
nitro, amino, C.sub.1-C.sub.7-acylamino optionally substituted; and
.phi. is hydrogen; a linear or branched C.sub.1-C.sub.5 alkyl,
C.sub.2-C.sub.5-- alkenyl or C.sub.2-C.sub.5-- alkynyl residue by
C.sub.1-C.sub.3-alkoxycarbonyl, substituted or non-substituted
phenyl, 2-, 3- or 4-pyridyl, quinolin-2-yl; a
C.sub.3-C.sub.6-cycloalkyl group; 2-furyl; 3-tetrahydrofuryl;
2-thiophenyl; 2-tetrahydrothiophenyl or a residue of formula (IVc)
A--(CH.sub.2).sub.q- (IVc) wherein A is a
C.sub.1-C.sub.5-dialkylamino group, a C.sub.1-C.sub.8-(alcanoyl,
cycloalcanoyl, arylalcanoyl)-C.sub.1-C.sub.5-alkylamino group, for
example dimethyamino, diethylamino, methyl-N-ethyl-amino,
acetyl-N-methyl-amino, pivaloyl-N-ethyl-amino; a nitrogen
containing 5-7 membered monocyclic ring optionally containing one
or two double bonds and optionally an additional heteroatom
separated by at least 2 carbon atoms from the atom of N, so as to
form, for example, a 1-pyrrolidino, 2,5-dihydro-pyrrol-1-yl,
1-pyrrol, 1-piperidino, 1-piperazino-4-non-substituted or
4-substituted (methyl, ethyl, 2-hydroxyethyl, benzyl, benzhydril or
phenyl), 4-morpholino, 4-3,5-dimethyl-morpholino, 4-thiomorpholino
group; or alternatively, a residue of formula (IVd) ##STR9##
wherein Rg is hydrogen, C.sub.1-C.sub.3-alkyl or the residue of a
C.sub.1-C.sub.3-alcanoic acid; [0038] q is zero or the integer 1,
[0039] d) a 2-(phenylamino)-phenyl of formula (IV e): ##STR10##
wherein P.sub.1 and P.sub.2 indicate that the two phenyl groups may
be substituted independently, with one or more
C.sub.1-C.sub.4-alkyl groups, C.sub.1-C.sub.3-alkoxy groups,
chlorine, fluorine and/or trifluoromethyl.
[0040] Preferred compounds of the invention are compounds
wherein:
R is hydrogen,
X is:
a linear alkylene optionally substituted at C.sub.1 by a
--CO.sub.2R.sub.3 group as defined above;
a linear alkylene optionally substituted at C.sub.1 by a
--CONHR.sub.4 group wherein R.sub.4 is OH;
2-butynylene, cis-2-butenylene, trans-2-butenylene;
3-oxa-pentylene, 3-thio-pentylene, 3-oxa-hexylene,
3-thio-hexylene;
(CH.sub.2).sub.m--CO--NH--(CH.sub.2).sub.n-- wherein m and n are
each independently an integer from 2 to 3;
(CHR')--CONH--(CH.sub.2).sub.n wherein n is an integer from 2 to 3
and R' is a methyl, in absolute configuration R or S;
or X, together with the N atom of the omega-amino group, forms a
nitrogen containing cycloaliphatic ring, preferably
1-methyl-piperidin-4-yl or 1,5-tropan-3-yl.
[0041] Preferred compounds are also those wherein NR.sub.1R.sub.2
represents an NH.sub.2 group, dimethylamino, diethylamino,
diisopropylamino, 1-piperidinyl, 4-morpholyl, 4-thiomorpholyl or
R.sub.1 and R.sub.2 together form a residue of guanidine,
aminoguanidine, hydroxyguanidine,
2-amino-3,4,5,6-tetrahydropyrimidyl,
2-amino-3,5-dihydro-imidazolyl.
[0042] Examples of particularly preferred aryl groups comprise:
[0043] 4-isobutylphenyl, 4-cyclohexylmethylphenyl,
4-(2-methyl)allyl-phenyl, 3-phenoxyphenyl, 3-benzoyl-phenyl,
3-acetyl-phenyl, the single diastereoisomers (R)(S) and the
diastereoisomeric mixture (R,S) of 3-C.sub.6H.sub.5--CH(OH)-phenyl,
3-CH.sub.3--CH(OH)-phenyl, 5-C.sub.6H.sub.5--CH(OH)-thienyl,
4-thienyl-CH(OH)-phenyl, 3-(pyrid-3-yl)-CH(OH)-phenyl,
5-benzoyl-thien-2-yl, 4 thienoyl-phenyl, 3-nicotinoyl-phenyl,
2-fluoro-4-phenyl, 6-metoxy-2-naphthyl, 5-benzoyl-2-acetoxy-phenyl
and 5-benzoyl-2-hydroxy-phenyl.
[0044] Particularly preferred aryl groups of formula (IV b) are
phenyl groups 3-substituted by: isoprop-1-en-1-yl, isopropyl,
pent-2-en-3-yl; pent-3-yl; 1-phenylethylen-1-yl;
.alpha.-methylbenzyl.
[0045] Particularly preferred aryls of formula (IV c) are
4-(pyrrolidin-1-yl)-methyl-phenyl,
3-chloro-4-(pyrrolidin-1-yl)-methyl-phenyl,
3-chloro-4-(2,5-dihydro-1-H-pyrrol-1-yl)-methyl-phenyl, 3
chloro-4-(thiomorpholin-4-yl)phenyl;
3-chloro-4-(piperidin-1-yl)-phenyl,
4-((N-ethyl-N-quinolin-2-yl-methylamino)-methyl)phenyl,
3-chloro-4-(morpholin-4-yl)-phenyl.
[0046] Particularly preferred aryls of formula (IVe) are
2-(2,6-dichloro-phenyl-amino)-phenyl;
2-(2,6-dichloro-phenyl-amino)-5-chloro-phenyl;
2-(2,6-dichloro-3-methyl-phenyl-amino)-phenyl;
2-(3-trifluoromethyl-phenyl-amino)-phenyl.
[0047] Particularly preferred compounds of the invention are:
[0048]
(R)-2-[(4-isobutyl)phenyl]-N-(3-dimethylaminopropyl)propionamide;
[0049]
(R)-2-[(4-isobutyl)phenyl]-N-(4-dimethylaminobutyl)-propionamide
hydrochloride; [0050]
(R)-2-[(4-isobutyl)phenyl]-N-(3-N-morpholinylpropyl)propionamide;
[0051]
(R)-2-[(4-isobutyl)phenyl]-N-(2-dimethylaminoethyl)propionamide;
[0052]
(R)-2-[(4-isobutyl)phenyl)-propionyl]-N-[2-(4-methyl-piperazin-1-yl)ethy-
l]propionamide; [0053]
(R)--N-(exo-8-methyl-8-aza-bicyclo[3,2,1]oct-3-yl)-2-[(4-isobutylphenyl)--
propionamide; [0054]
(R)-2-[(4-isobutyl)phenyl]-N-(3-N-thiomorpholinylpropyl)propionamide;
[0055]
(R)-2-[(4-isobutyl)phenyl]-N-[4-(N'-methyl)piperidinyl]propionami-
de hydrochloride; [0056]
(R),(S')-2-[(4-isobutyl)phenyl]-N-(1-carboxy-2-dimethylaminoethyl)-propio-
namide; [0057]
(R),(S')-2-[(4-isobutyl)phenyl]-N-[(1-carboxy-4-piperidin-1-yl)butyl]prop-
ionamide; [0058]
(R),(S')-2-[(4-isobutyl)phenyl]-N-(1-carboxy-4-aminobutyl)propionamide;
[0059]
(R)-2-(4-isobutyl)phenyl-N-[2-(dimethylaminoethyl)aminocarbonylme-
thyl]propionamide hydrochloride; [0060]
2-(2,6-dichlorophenylamino)-phenyl-N-(3-dimethylaminopropyl)propionamide;
[0061]
(R),(R',S')-3-[3-(.alpha.-methyl)benzyl]phenyl-N-(3-dimethylamin-
opropyl)-propionamide; [0062]
(R)-2-[(3-isopropyl)phenyl]-N-(3-dimethylaminopropyl)propionamide;
[0063]
(R)-2-[3-(pent-3-yl)phenyl]-N-(3-dimethylaminopropyl)propionamide-
; [0064]
(R)-2-[(4-isobutyl)phenyl]-N-(3-guanidylpropyl)propionamide; [0065]
(R)-2-[(4-isobutyl)phenyl]-N-[(3-hydroxy-guanidyl)propyl]propiona-
mide; [0066]
(R)-2-[(4-isobutyl)phenyl]-N-[(3-amino-guanidyl)propyl]propionamide;
[0067] (R)-2-[(4-isobutyl)phenyl]-N-[3-(2-amino-2-imidazoline)
propyl]propionamide; [0068]
(R)-2-[(4-isobutyl)phenyl]-N--[N-methyl-N-(2-hydroxyethyl)aminoethoxy]pro-
pionamide; [0069]
(R),(S')-2-[(4-isobutyl)phenyl]-N-[1-carboxy-5-aminopentyl]propionamide.
[0070] The preparation of the compounds of formula (I) has been
carried out using known methods such as the reaction of an
activated form of an R-2-arylpropionic acid of formula (V) with an
amine of formula (VI) in non-racemizing conditions, preferably in
the presence of a molar excess of a base: ##STR11## wherein: AT is
the residue activating the carboxy group. Examples of activated
forms of 2-arylpropionic acids of formula (V, AT=OH) are chlorides
(AT=Cl), imidazolides (AT=1-imidazole), phenol esters such as
p-nitrophenol (AT=p-NO2-C6H4O--) or activated forms obtained by
reaction in the presence of 1-hydroxybenzotriazole (HOBZ) or of a
carbodiimide, for example dicyclohexylcarbodiimide. Ar, R, X,
R.sub.1 and R.sub.2 are as defined above, optionally protected,
where necessary.
[0071] The reaction of the activated form of a 2-aryl-propionic
acid of formula (V) with a protected amine of formula (VI), is
usually carried out at room temperature, using conventional protic
or aprotic solvents and/or their mixtures, preferably anhydrous
solvents, for example esters such as methyl acetate, ethyl acetate,
ethyl formate, nitriles such as acetonitrile, linear or cyclic
ethers such as ethyl ether, sulfolane, dioxane, tetrahydrofuran,
amides such as dimethylformamide, formamide, halogenated solvents
such as dichloromethane, aromatic hydrocarbons such as toluene,
chlorobenzene or hetero-aromatic hydrocarbons such as pyridine and
picoline. The reactions may be carried out in the presence of a
base; preferred inorganic bases are alkaline and alkaline-earth
carbonates and bicarbonates, such as for instance finely ground
potassium carbonate, potassium bicarbonate, and magnesium and/or
calcium carbonate.
[0072] The obtained protected amides may be converted into amides
of formula (I) by cleaving the protective groups and any ester
groups that might be present. A particularly preferred ester of
this kind is the allyl ester, which is removable in highly
selective conditions, for example through the transfer of the allyl
group to a morpholine molecule, which, in the presence of Pd(0) as
catalyst, acts as transferor of H and as nucleophile acceptor
according to the procedure disclosed in J. Org. Chem., 54, 751
1989.
[0073] Amides of formula (I) wherein R.sub.2 is a group of formula
(III) can be prepared by reaction of primary and secondary amines
of formula (I) with an isothioureide or the corresponding
isothio-uronium salts of formula (IIIa) ##STR12## wherein Alk is a
C.sub.1-C.sub.3-alkyl and R.sub.a and R.sub.b are as defined
above.
[0074] The preparation of hydroxy-isothioureas of formula (IIIa),
wherein Ra is OH and Rb is H, is described in Bernd Clement, Arch.
Pharm. (Wheineim) 319, 968 (1986); other compounds of formula IIIa
are known compounds or can be prepared by the conventional methods
for alkylation in basic medium of the corresponding linear and/or
cyclic thioureas and of thiosemicarbazides. The compounds of
formula IIIa are isolated as isothio-uronium salts and may be
reacted with the amines of formula Ie according to the method
disclosed by Bodansky M. et al., J. Am. Chem. Soc., 86, 4452, 1964.
Alternatively, an excess of a solvent such as ethyl acetate (AcOEt)
is added to an aqueous solution or suspension of the
isothio-uronium salt of formula IIIa and under vigorous stirring
the salt is neutralized by adding the equivalent base solution
(NaOH N, potassium carbonate N), to yield the corresponding
isothioureide. ##STR13## wherein Ar.sub.1, Ar.sub.2, X, R, R.sub.1
and R.sub.2 have the meanings disclosed above, can undergo
reduction of the phenone carbonyl group to give a diastereoisomeric
pair of R', S' alcohols optionally separated by fractioned
crystallization and/or preparative chromatography to provide the
individual diastereoisomers of formula (Ib): ##STR14##
[0075] The convention has been adopted of indicating the absolute
configuration S' to the most polar diastereoisomer.
[0076] Compounds of formula (I) may be converted into
pharmaceutically acceptable salts through salification of the basic
or acid groups which are present in their structure, using
respectively pharmaceutically acceptable acids or bases. Examples
of salts with pharmaceutically acceptable bases are those with
alkaline or alkaline-earth metals, preferably lithium, sodium and
magnesium, or with organic bases, such as tromethamine,
D-glucosamine, lysine, arginine.
[0077] The compounds of formula (I) are generally isolated in the
form of their addition salts with both organic and inorganic
pharmaceutically acceptable acids. Examples of these acids are:
hydrochloric, nitric, sulfuric, phosphoric, formic, acetic,
trifluoroacetic, propionic, maleic and succinic, malonic and
methansulfonic, D and L-tartaric acids. The R enantiomers of the
2-arylpropionic acids of formula (Va): ##STR15## wherein Ar is as
defined above, are weak inhibitors of cycloxygenases and are
usually known compounds.
[0078] The acids of formula (Vb): ##STR16## wherein .phi. and
Ar.sub.b are as defined above, are obtained by alkylation with
stannanes of a polysubstitute 2-phenyl-propionic acid bearing, in
ortho or meta or para, a perfluorobutanesulfonate group, as
described herein below.
[0079] The compounds of formula (Vb) are disclosed in International
patent application WO 01/58852. In particular,
2-[3'-isopropyl)phenyl]-propionic,
2-[3'-(.alpha.-methyl)benzyl)phenyl]-propionic and
2-[3'-(3-isopentyl)phenyl]-propionic acids, are among the preferred
precursors of the amides of formula (I).
[0080] Each 2-arylpropionic acid can be prepared by total and
stereospecific synthesis or by conversion of the racemate into one
of the individual enantiomers after conversion into
2-aryl-2-propyl-ketenes, as disclosed by Larse R. D. et al., J. Am.
Chem. Soc., 111, 7650, 1989, and by Myers A. G., ibidem, 119, 6496,
1997. Stereoselective syntheses of 2-arylpropionic acids are
usually directed to the S enantiomers, but may be easily modified
in order to obtain R enantiomers via a convenient choice of the
chiral auxiliary agent. The use of arylalkylketones as reactants in
the synthesis of .alpha.-arylalcanoic acids, is described for
example in B. M. Trost and J. H. Rigby, J. Org. Chem., 14, 2926,
1978; the arylation of Meldrum acids, is described in J. T. Piney
and R. A. Rowe, Tetrah. Lett., 21, 965, 1980; the use of tartaric
acid as chiral auxiliary agent, in G. Castaldi et al., J. Org.
Chem., 52, 3019, 1987; the use of .alpha.-hydroxyesters as chiral
reactants is reported in R. D. Larsen et al., J. Am. Chem. Soc.,
111, 7650, 1989 and U.S. Pat. No. 4,940,813 and the references
cited therein.
[0081] A process for the preparation of 2-(2-OH-phenyl)-propionic
acids and their esters is disclosed in Italian patent No.
1,283,649. A tested and efficient method for the preparation of the
R enantiomer of the (R,S)-2-(5-benzoyl-2-acetoxy)-propionic acid
and of the acids of formula (Vb) disclosed above consists in the
conversion of the chlorides of said prop-1-ketene acids by reaction
with a tertiary amine, such as dimethyl-ethyl-amine, followed by
the reaction of the ketene with R(-)-pantolactone, which yields the
esters of R-enantiomers of said acids with
R-dihydro-3-hydroxy-4,4-dimethyl-2(3H)-furan-2-one. The subsequent
saponification of the ester with LiOH yields the corresponding free
acid. A general procedure for the preparation of
R(-)-2-arylpropionic acids of formula (Vb) includes the reaction of
hydroxyarylketones of formula (Vc) mono or polysubstituted with a
perfluorobutanesulfonylfluoride to yield perfluorobutanesulfonic
esters of formula (Vd) where n is an integer from 1 to 9. ##STR17##
The compounds of formula (Vd) are subjected to Willgerodt
re-arrangement to obtain, after esterification and methylation on
the alpha carbon, arylpropionic derivates of formula (Ve) where n
is an integer from 1 to 9 and R.sub.3 represents a C.sub.1-C.sub.4
alkyl or a C.sub.2-C.sub.4 alkenyl. ##STR18## The compounds of
formula (Ve) are reacted with the appropriate tributylstannane of
formula Bu.sub.3SnR.sub.5 where R.sub.5 is a linear or branched
C.sub.1-C.sub.6 alkyl, a linear or branched C.sub.2-C.sub.6 alkenyl
or a linear or branched C.sub.2-C.sub.6 alkynyl, non-substituted or
substituted with an aryl group, to obtain the corresponding
(R,S)-2-arylpropionates of formula (Vf). ##STR19##
[0082] The alkenyl or alkynyl groups can be hydrogenated in
catalytic hydrogenation conditions to obtain the corresponding
saturated alkyl groups. The compounds of formula (Vf) are submitted
to the de-racemization process as disclosed above of conversion of
the corresponding acid chlorides into ketenes which, by reaction
with R(-)-pantonolactone and subsequent hydrolysis, are converted
into pure R enantiomers.
[0083] The amines of formula (VI) are known products, mostly
commercially available or can be prepared by known methods. The
synthesis of 4-dialkylamino-2-butynyl-amine and, from this, of cis-
and trans-4-dialkylamino-2-butenylamine is reported in R. Dalhome
et al., J. Med. Chem., 9, 843, 1966 and T. Singh et al. ibidem, 12,
368, 1969, respectively.
[0084] .alpha.-Amino acids with an amino group of formula
--NR.sub.1'R.sub.2' bound to the terminal carbon atom are prepared
by known methods starting from m-hydroxy-.alpha.-amino acids, the
carboxy and amino groups of which have been conveniently protected.
The alcoholic group is transformed into a bromide through reaction
with triphenylphosphine and CBr.sub.4 (R G Weiss et al., J. Org.
Chem. 36, 403, 1971 and M. Kang., ibidem, 64, 5528, 1966) followed
by reaction of the halide thus obtained with at least 2M excess of
the desired amine (i.e. dimethylamine, piperidine). Commercially
available substrates for this purpose are serine and homoserine:
superior homologs are obtained starting from commercially available
dicarboxylic .alpha.-amino-acids protected at C.sub.1 and at the
amino group, the free carboxy group of which is selectively reduced
to alcohol by reduction in THF at room temperature with an excess
of diborane.
The present invention provides compounds of formula (I), which are
R enantiomers of 2-arylpropionamides, for use as medicaments.
[0085] The compounds of the invention of formula (I) were evaluated
"in vitro" for their ability to inhibit chemotaxis of
polymorphonucleate leukocytes (hereinafter referred to as PMNs) and
monocytes, induced by the fractions of the complement C5a and
C5a-desArg. For this purpose, to isolate the PMNs from heparinized
human blood, taken from healthy adult volunteers, mononucleates
were removed by means of sedimentation on dextrane (according to
the procedure disclosed by W. J. Ming et al., J. Immunol., 138,
1469, 1987) and red blood cells by a hypotonic solution. The cell
vitality was calculated by exclusion with Trypan blue, whilst the
ratio of PMNs was estimated on the cytocentrifugate after staining
with Diff Quick.
[0086] The fractions hr-C5a and hrC5a-desArg (Sigma) were used as
stimulating agents in chemotaxis experiments, obtaining practically
identical results. Lyophilized C5a was dissolved in a volume of
HBSS containing 0.2% BSA so as to obtain a stock solution having a
concentration of 10.sup.-5 M, to be diluted in HBSS to a
concentration of 10.sup.-9 M, for the chemotaxis assays.
[0087] In the chemotaxis experiments, the PMNs were incubated with
the compounds of the invention of formula (I) for 15' at 37.degree.
C. in an atmosphere containing 5% CO.sub.2. The chemotactic
activity of the C5a was evaluated on human circulating
polymorphonucleates (PMNs) resuspended in HBSS at a concentration
of 1.5.times.10.sup.6 PMNs per ml.
[0088] During the chemotaxis assay (according to W. Falket et al.,
J. Immunol. Methods, 33, 239, 1980) PVP-free filters with a
porosity of 5 mcm and microchambers suitable for carrying out the
test were used.
[0089] The compounds of the invention in formula (I) were evaluated
at a concentration ranging between 10.sup.-6 and 10.sup.-10 M; for
this purpose they were added, at the same concentration, both to
the lower pores and the upper pores of the microchamber. The wells
in the lower part contain the solution of C5a or the simple
carrier, those in the upper part contain the suspension in
PMNs.
[0090] Inhibition of C5a-induced chemotactic activity by the
individual compounds of the invention of formula (I) was evaluated
by incubating the microchamber for the chemotaxis for 60 min at
37.degree. C. in an atmosphere containing 5% CO.sub.2. Evaluation
of the ability of the compounds of the invention of formula (I) to
inhibit C5a-induced chemotaxis of human monocytes was carried out
according to the method reported above (Van Damme J. et al., Eur.
J. Immunol., 19, 2367, 1989). Inhibition of C5a-induced chemotactic
activity by the individual compounds of the invention of formula
(I) towards human monocytes was evaluated at a concentration
ranging between 10.sup.-6 and 10.sup.-10 M by incubating the
microchamber for the chemotaxis for 120 min. at 37.degree. C. in an
atmosphere containing 5% CO2.
[0091] The compounds of the invention were also evaluated in their
ability to inhibit IL-8-induced chemotaxis of human PMNs. For this
purpose, recombinant human interleukin-8 (rhIL-8, Pepro Tech) was
used: the lyophilized protein was dissolved in HBSS (Hank's
balanced salts solution) at the concentration of 100 mcg/mL and
then diluted down to a concentration of 10 ng/mL in the chemotaxis
experiments. R(-)-2-[(4'-isobutyl)phenyl]-propionyl
methansulfonamide (ED.sub.50=10.sup.-9 M) described in WO 00/24710,
was used as reference standard.
[0092] Results on inhibition of the chemotaxis induced by C5a and
by IL-8 are listed in Table I. Results show that different
structures of the amide group can lead to different selectivity in
the compounds of the present invention.
[0093] A selected number of compounds are dual inhibitors,
inhibiting chemotaxis induced both by C5a and by IL-8, others are
selective inhibitors of the chemotaxis induced by C5a. For example,
N-(1-methyl-pyrid-4-yl)amides, .beta.-tropylamides,
N--(H2N-alkyl)-amides of formula (I) are all selective inhibitors
of C5a-induced chemotaxis of PMN and of monocytes in the
concentration range between 10.sup.-6 and 10.sup.-8 M. All these
compounds have shown poor activity as inhibitors of
interleukin-8-induced chemotaxis in the same concentration
range.
[0094] A selected number of compounds of the invention are able of
inhibiting also interleukin 8-induced chemotaxis of PMN leukocytes
and lymphocytes T, in addition to the C5a-induced chemotaxis of PMN
leukocytes and monocytes in the concentration range between
10.sup.-6 and 10.sup.-8 M. More particularly, the compounds of
formula (I) wherein R1 and R2 are different from hydrogen, exert
both activities of inhibition of C5a-induced chemotaxis and
IL-8-induced chemotaxis. Both activities are present in compounds
wherein the distance between the terminal basic N and the amide N
is between 2 and 4 C atoms, with an optimum for n=3. In this
structural framework, it can be stated that the compounds of the
invention exert the dual role of inhibitors of C5a-induced
chemotaxis and IL-8-induced chemotaxis.
[0095] The compounds of formula (I), evaluated ex vivo in blood in
toto according to the procedure disclosed by Patrignani et al., in
J. Pharmacol. Exper. Ther., 271, 1705, 1994, were found to be
totally ineffective as inhibitors of COX enzymes. In almost all
cases, the compounds of formula (I) do not interfere with the
production of PGE.sub.2 induced in murine macrophages by
lipopolysaccharides stimulation (LPS, 1 .mu.g/mL) at a
concentration ranging between 10.sup.-5 and 10.sup.-7 M. Inhibition
of the production of PGE.sub.2 which may be recorded, is mostly at
the limit of statistical significance, and more often is below
15-20% of the basal value.
[0096] In consideration of the experimental evidence discussed
above and of the role of complement activation, through its
fraction C5a, in pathologies such as psoriasis (R. J. Nicholoff et
al., Am. J. Pathol., 138, 129, 1991), pemphigus and pemphigoid,
rheumatoid arthritis (M. Selz et al., J. Clin. Invest., 87, 463,
1981), intestinal chronic inflammatory pathologies such as
ulcerative colitis (Y. R. Mahida et al., Clin. Sci., 82, 273,
1992), acute respiratory distress syndrome, cystic fibrosis and
idiopathic fibrosis (E. J. Miller, previously cited, and P. C.
Carre et al., J. Clin. Invest., 88, 1882, 1991), Chronic
Obstructive Pulmonary Disease (COPD), glomerulonephritis (T. Wada
et al., J. Exp. Med., 180, 1135, 1994) as well as in the prevention
and treatment of injury caused by ischemia and reperfusion, the
compounds of the present invention are particularly useful to
attain these therapeutic purposes.
[0097] The present invention thus provides the compounds of formula
(I) for use in the treatment of psoriasis, pemphigus and
pemphigoid, rheumatoid arthritis, intestinal chronic inflammatory
pathologies including ulcerative colitis, acute respiratory
distress syndrome, systemic and pulmonary idiopathic fibrosis,
cystic fibrosis, chronic obstructive pulmonary disease,
glomerulonephritis and in the prevention and in the treatment of
injury caused by ischemia and reperfusion.
[0098] The invention further provides the use of the compounds of
formula (I) in the manufacture of medicaments for the treatment and
prevention of said pathologies.
[0099] The compounds of the invention, together with a
conventionally employed adjuvant, carrier, diluent or excipient may
be placed into the form of pharmaceutical compositions and unit
dosages thereof, and in such form may be employed as solids, such
as tablets or filled capsules, or liquids such as solutions,
suspensions, emulsions, elixirs, or capsules filled with the same,
all for oral use, or in the form of sterile injectable solutions
for parenteral (including subcutaneous) use. Such pharmaceutical
compositions and unit dosage forms thereof may comprise ingredients
in conventional proportions, with or without additional active
compounds or principles, and such unit dosage forms may contain any
suitable effective amount of the active ingredient commensurate
with the intended daily dosage range to be employed.
[0100] When employed as pharmaceuticals, the amides of this
invention are typically administered in the form of a
pharmaceutical composition. Such compositions can be prepared in a
manner well known in the pharmaceutical art and comprise at least
one active compound. Generally, the compounds of this invention are
administered in a pharmaceutically effective amount. The amount of
the compound actually administered will typically be determined by
a physician, in the light of the relevant circumstances, including
the condition to be treated, the chosen route of administration,
the actual compound administered, the age, weight, and response of
the individual patient, the severity of the patient's symptoms, and
the like.
[0101] The pharmaceutical compositions of the invention can be
administered by a variety of routes including oral, rectal,
transdermal, subcutaneous, intravenous, intramuscular, and
intranasal. Depending on the intended route of delivery, the
compounds are preferably formulated as either injectable or oral
compositions. The compositions for oral administration can take the
form of bulk liquid solutions or suspensions, or bulk powders. More
commonly, however, the compositions are presented in unit dosage
forms to facilitate accurate dosing. The term "unit dosage forms"
refers to physically discrete units suitable as unitary dosages for
human subjects and other mammals, each unit containing a
predetermined quantity of active material calculated to produce the
desired therapeutic effect, in association with a suitable
pharmaceutical excipient. Typical unit dosage forms include
prefilled, premeasured ampoules or syringes of the liquid
compositions or pills, tablets, capsules or the like in the case of
solid compositions. In such compositions, the amide compound is
usually a minor component (from about 0.1 to about 50% by weight or
preferably from about 1 to about 40% by weight) with the remainder
being various vehicles or carriers and processing aids helpful for
forming the desired dosing form. Liquid forms suitable for oral
administration may include a suitable aqueous or nonaqueous vehicle
with buffers, suspending and dispensing agents, colorants, flavors
and the like. Liquid forms, including the injectable compositions
described herebelow, are always stored in the absence of light, so
as to avoid any catalytic effect of light, such as hydroperoxide or
peroxide formation. Solid forms may include, for example, any of
the following ingredients, or compounds of a similar nature: a
binder such as microcrystalline cellulose, gum tragacanth or
gelatine; an excipient such as starch or lactose, a disintegrating
agent such as alginic acid, Primogel, or corn starch; a lubricant
such as magnesium stearate; a glidant such as colloidal silicon
dioxide; a sweetening agent such as sucrose or saccharin; or a
flavoring agent such as peppermint, methyl salicylate, or orange
flavoring.
[0102] Injectable compositions are typically based upon injectable
sterile saline or phosphate-buffered saline or other injectable
carriers known in the art. As above mentioned, the amide derivative
of formula I in such compositions is typically a minor component,
frequently ranging between 0.05 to 10% by weight with the remainder
being the injectable carrier and the like. The mean daily dosage
will depend upon various factors, such as the seriousness of the
disease and the conditions of the patient (age, sex and weight).
The dose will generally vary from 1 mg or a few mg up to 1500 mg of
the compounds of formula (I) per day, optionally divided into
multiple administrations. Higher dosages may be administered also
thanks to the low toxicity of the compounds of the invention over
long periods of time.
[0103] The above described components for orally administered or
injectable compositions are merely representative. Further
materials as well as processing techniques and the like are set out
in Part 8 of "Remington's Pharmaceutical Sciences Handbook",
18.sup.th Edition, 1990, Mack Publishing Company, Easton, Pa.,
which is incorporated herein by reference.
[0104] The compounds of this invention can also be administered in
sustained release forms or from sustained release drug delivery
systems. A description of representative sustained release
materials can also be found in the incorporated materials in the
Remington's Handbook as above.
[0105] The present invention shall be illustrated by means of the
following examples which are not construed to be viewed as limiting
the scope of the invention.
[0106] In the description of the compounds of the invention of
formula (I), the convention has been adopted of indicating the
absolute configurations of any additional chiral substituents,
optionally present in the structure of said compounds, with prime
signs (e.g., R', S', S'', etc.).
[0107] Examples of abbreviations are: AcOH for acetic acid, AcOEt
for ethyl acetate, BOC for N-tert-butoxycarbonyl-, DCC for
dicyclohexylcarbodiimide, DCU for dicylohexylurea, DMF for
dimethylformamide, EtOH for ethanol, Et2O for diethyl ether, HOBZ
for 1-hydroxybenzothiazole, hr for hour, hrs for hours, MeOH for
methanol, r.t. for room temperature, THF for tetrahydrofuran, Z for
N-benzyloxycarbonyl.
Preparations:
[0108] Intermediate compounds, which are used in the Examples
herebelow, have been prepared according to the following
procedures.
1-amino, 4-dimethylamino-butane
[0109] Dimethylamine hydrochloride (1.2 g; 12.5 mmol) and, 1 hr
later, 4-bromobutylphtalimide (3.5 g; 12.4 mmol) are added to a
suspension of K.sub.2CO.sub.3 (4.3 g; 31 mmol), in acetone (5 mL)
at 25.degree. C.; the suspension is then refluxed overnight. After
cooling at r. t., the mixture is filtered and evaporated to
dryness; silica gel flash chromatography of the residue oil (eluent
CHCl.sub.3/CH.sub.3OH 8:2) yields
N-(4-dimethylamino-butyl)-phtalimide as a white solid (2.2 g; 8.94
mmol).
[0110] A solution of said compound in EtOH, treated with a 35%
aqueous hydrazine (0.45 mL), is heated at reflux temperature until
all the reagents are disappeared (.about.2 hrs), filtered and
evaporated to dryness. Final crystallization from
CH.sub.2Cl.sub.2/CH.sub.3OH (98:2) yields 0.85 g (7.32 mmol; 82%
yield) of 1-amino, 4-dimethylamino-butane as a white solid.
[0111] .sup.1H-NMR (CDCl.sub.3): .delta. 7.75 (m, 2H); 7.65 (m,
2H); 2.72 (m, 2H); 2.35 (t, 2H, J=7 Hz); 2.23 (s, 6H); 1.75 (m,
2H); 1.56 (bs, 2H, NH.sub.2); 1.48 (m, 2H).
1-amino,4-methylamino-butane
[0112] A lot of 1-amino, 4-methylamino-butane is obtained using
methylamine instead of dimethylamine in the previous procedure.
1-(3-aminopropyl)-thiamorpholine
[0113] A solution of 3-BOC-aminopropyl bromide (3.07 g; 12.9 mmol)
and thiamorpholine (2.6 mL; 25.8 mmol) in CH.sub.2Cl.sub.2 (25 mL)
is heated at the reflux temperature for 24 h. The mixture is cooled
at r. t., filtered, washed with water (2.times.50 mL), dried over
Na.sub.2SO.sub.4 and evaporated to dryness in vacuum. Purification
by flash chromatography on silica gel (eluent CHCl.sub.3/CH.sub.3OH
9:1) yields 1-(3-BOC-aminopropyl)-thiamorpholine (3.1 g; 11.96
mmol), as a transparent oil.
[0114] Cleavage of the protective group is performed dissolving 1.4
g (5.4 mmol) of said compound in 3N aqueous HCl (6 mL) at r t.; 18
hrs later, the solution, made alkaline by addition of aqueous 2N
NaOH until to reach pH=8, is extracted with CH.sub.2Cl.sub.2
(2.times.10 mL). The combined extracts, dried over
Na.sub.2SO.sub.4, are evaporated to dryness to give
1-(3-aminopropyl)-thiamorpholine as a transparent oil (0.63 g; 3.96
mmol).
[0115] .sup.1H-NMR (CDCl.sub.3): .delta. 7.75 (m, 2H); 7.65 (m,
2H); 2.72 (m, 2H); 2.35 (t, 2H, J=7 Hz); 2.23 (s, 6H); 1.75 (m,
2H); 1.56 (bs, 2H, NH.sub.2); 1.48 (m, 2H).
1-(3-aminopropyl),4-methyl-piperazine (isolated as the
hydrochloride salt)
[0116] .sup.1H-NMR (D.sub.2O): .delta. 3.75 (m, 7H); 3.45 (m, 3H);
3.15 (m, 2H); 3.05 (m, 4H); 2.20 (m, 2H) is obtained using
4-methyl-piperazine instead of thiamorpholine in the same
procedure.
1-(3-aminopropyl)-piperidine
[0117] .sup.1H-NMR (CDCl.sub.3): .delta. 2.85 (t, 2H, J=8 Hz); 2.45
(m, 6H); 1.90 (bs, 2H, NH.sub.2); 1.8-1.62 (m, 6H); 1.55 (m, 2H) is
obtained using piperidine instead of thiamorpholine in the same
procedure.
1-BOC-propane-1,3-diamine
[0118] An aqueous solution (5 mL) of NaN3 (1.4 g; 21.5 mmol) and
2-3 drops of Aliquat 336 are added to a stirred solution of
3-BOC-amino-propyl bromide (5 g; 21.5 mmol) in toluene (10 mL); the
mixture is heated at the reflux temperature for 4 hrs. After
cooling at r. t., the organic phase is separated, dried over
Na.sub.2SO.sub.4, and evaporated to dryness in vacuum to give
3-BOC-amino-propyl azide (3.75 g; 18.3 mmol) as a transparent oil
(yield 85%).
[0119] A triphenylphosphine (4.8 g; 18.3 mmol) solution in THF (15
mL) is added dropwise to a stirred solution of the above azide in
THF (30 mL)/H2O (0.3 mL; 18.3 mmol); the stirring is continued for
24 hrs at r. t. After removal of the solvents to dryness in vacuum,
the residue is taken up with a few of EtOH to separate a white
precipitate of triphenylphosphine oxide by stirring for 6 hrs at r.
t. The final EtOH removal to dryness, at low pressure, gives 3.22 g
(18 mmol) of 1-BOC-propane-1,3-diamine as a pale yellow oil.
[0120] .sup.1H-NMR (CDCl.sub.3): .delta. 4.90 (bs, 1H, CONH); 3.25
(m, 2H), 2.85 (t, 2H, J=7 Hz); 1.75 (t, 2H, J=7 Hz); 1.60 (bs, 2H,
NH.sub.2); 1.55 (s, 9H).
3-(BOC-methylamino)-propylamine
[0121] It is obtained by use of 3-(BOC-methylamino)-propyl bromide
in the previous procedure.
Methyl(S)-2-amino-3-dimethylamino-propionate
[0122] A 2M solution of dimethylamine in THF (2.5 mL) is added
dropwise to a stirred solution of
methyl(S)2-BOC-amino-3-bromo-propionate (0.45 g; 1.42 mmol) (Weiss
R. G. et al., J. Org. Chem., 36, 403, 1971; Kang M. et al., ibidem,
61, 5528, 1996) in anhydrous THF (10 mL) at 25.degree. C. The
mixture is stirred overnight at r. t. and evaporated to dryness in
vacuum. The residue is partitioned between Et2O (30 mL) and aqueous
0.5 N NaOH (2.times.5 mL); the ethereal extracts are combined,
washed with brine, dried over Na.sub.2SO.sub.4 and evaporated to
dryness to obtain 0.34 g (1.22 mmol) of
methyl(S)-2-amino-3-dimethylamino-propionate as a pale yellow
oil.
[0123] .sup.1H-NMR (CDCl.sub.3): .delta. 7.45 (m, 5H); 5.73 (bs,
1H, CONH); 5.15 (s, 2H), 4.32 (m, 1H); 3.82 (s, 3H); 2.75 (m, 2H);
2.22 (s, 6H).
[0124] A stirred solution of said methyl ester (0.34 g; 1.22 mmol)
in acetonitrile (12 mL) is treated with trimethylsilyl iodide (0.21
mL; 1.46 mmol) at r. t.; 3 hrs later, the mixture is quenched with
MeOH (0.24 mL; 5.9 mmol) and evaporated in vacuum to dryness. The
residue is taken up with Et2O (2.times.10 mL); the ethereal
extracts are re-extracted with a 30% aqueous AcOH (2.times.5 mL),
collected, made basic up to pH=8 and extracted with
CH.sub.2Cl.sub.2 (2.times.10 mL). The dichloromethane extracts are
combined, dried over Na.sub.2SO.sub.4, evaporated to dryness to
yield 0.16 g (1.1 mmol) of
methyl(S)2-amino-3-dimethylamino-propionate.
[0125] .sup.1H-NMR (CDCl.sub.3): .delta. 4.32 (m, 1H); 3.82 (s,
3H); 3.24 (bs, 2H, NH.sub.2); 2.75 (m, 2H), 2.22 (s, 6H).
Methyl(S)-2-amino-5-(piperidin-1-yl)-pentanoate
[0126] Under stirring and with external cooling to maintain the
reaction temperature between 20-25.degree. C., 0.03 molar
equivalents of 1 N B2H6 (diborane) solution in THF are added to a
0.01 M solution of (S)2-BOC-amino-1,5-pentadioic acid 1-hemi-methyl
ester in THF (15 mL); 2 hrs later, the diborane excess is destroyed
by cautious addition of water. After concentration to a small
volume under vacuum, the solution is diluted with AcOEt (25 mL).
The organic phase is washed with 5% aqueous NaHCO.sub.3, brine and
water to neutrality, dried over Na.sub.2SO.sub.4 and evaporated to
dryness. The crude residue of
methyl(S)2-BOC-amino-5-hydroxy-pentanoate is treated with
triphenylphosphine and CBr.sub.4 to obtain a crude sample of
methyl(S)2-BOC-amino-5-bromo-pentanoate.
[0127] Reaction of the latter compound with piperidine in THF
provides methyl(S)2-BOC-amino-5-(piperidin-1-yl)-pentanoate that by
treatment with a trifluoroacetic acid in dichloromethane, affords
methyl(S)-2-amino-5-(piperidin-1-yl)-pentanoate
bis-trifluoroacetate salt.
[0128] .sup.1H-NMR (CDCl.sub.3): .delta. 4.32 (m, 1H); 3.82 (s,
3H); 3.54 (m, 1H); 2.85 (t, 2H, J=7 Hz); 2.45 (m, 6H), .delta. 1.85
(bs, 2H, NH2); .delta. 1.75-1.6 (m, 6H), .delta. 1.5 (m, 2H).
5-BOC-ornithine-methyl ester hydrochloride
[0129] Maintaining the reaction temperature around 0-5.degree. C.
by external cooling, solid 2-Z,5-BOC-ornithine (1 g 2.7 mmol;
commercial reagent) and, 15 min. later, methyl iodide (0.34 mL, 5.4
mmol) are added to a stirred suspension of finely powdered
K.sub.2CO.sub.3 (0.38 g; 2.7 mmol) in dry DMF (20 mL). The mixture
is stirred for an additional hr at 0-5.degree. C. and at r. t. for
1 hr, then diluted with EtOAc (40 ml) and filtered. The clear
solution is washed with water (40 ml) and brine (3.times.30 ml);
dried over Na.sub.2SO.sub.4 and evaporated to dryness. Following
purification by silica gel flash chromatography (eluent
CHCl.sub.3/CH.sub.3OH 8:2) yields 2-Z,5-BOC-ornithine methyl ester
(0.8 g; 2.1 mmol). Hydrolytic cleavage of the Z protecting group
(carried out according to the procedure of Meienhofer J. et. al,
Tetrahedron. Lett., 3259, 1974) yields 5-BOC-ornithine methyl ester
hydrochloride (0.73 g; 2.0 mmol) as a white solid.
[0130] .sup.1H-NMR (CDCl.sub.3): .delta. 9.25 (bs, 3H,
NH.sub.3.sup.4); 5.40 (bs, 1H CONH); 4.40 (m, 1H); 3.8 (s, 3H); 3.0
(m, 2H); 1.8 (m, 4H); 1.4 (s, 9H).
Exo-8-methyl-8-aza-bicyclo[3,2,1]octan-3-amine(.beta.-1H,5H-tropanamine)
[0131] A sample is prepared starting from tropinone according to
the procedure of Burks J. E. et al., Org. Proc. Res. Dev., 1, 198,
1997.
4-(N,N-dimethylamino)aniline
[0132] 4-nitroaniline (1.83 g; 13.24 mmol) is added portionwise to
cooled (T=+4.degree. C.) formic acid (3 mL; 66.2 mmol).
Formaldehyde (37 wt. % solution in water; 2.72 mL; 29.13 mmol) is
added and the resulting mixture refluxed for 24 h. After cooling at
room temperature 6NHCl is added (2.2 mL) and the formed precipitate
is filtered off. The filtrate is diluted with 1N NaOH (5 mL) and
extracted with CH.sub.2Cl.sub.2 (3.times.20 mL); the organic
collected extracts are dried over Na.sub.2SO.sub.4 and evaporated
under vacuum to give a solid residue which, after treatment with a
mixture of diisopropyl ether/acetone 1:1 and filtration, gives
4-nitro-N,N-dimethylaniline as a yellow powder (1.65 g; 9.93 mmol).
Iron powder (2.145 g; 38.3 mmol) and 37% HCl (28 .mu.l) are
suspended in 96% ethyl alcohol (35 mL) and the mixture refluxed for
30'; at the end 4-nitro-N,N-dimethylaniline (0.64 g; 3.84 mmol) is
added and the mixture left under reflux and stirring for 2 h. The
hot mixture is filter over a Celite pad and, after cooling at room
temperature, the filtrate is evaporated under vacuum. The oily
residue is diluted with CH.sub.2Cl.sub.2 (25 mL) and washed with 1N
NaOH (3.times.25 mL), dried over Na.sub.2SO.sub.4 and evaporated
under vacuum to give 4-(N,N-dimethylamino)aniline as pale yellow
oil (0.44 g; 3.26 mmol).
[0133] .sup.1H-NMR (CDCl.sub.3): .delta. 7.10 (d, 2H, J=8 Hz); 6.60
(d, 2H, J=8 Hz); 3.55 (bs, 2H, NH.sub.2); 2.25 (s, 6H).
[0134] According the same procedure
4-(N,N-dimethylaminomethyl)aniline is prepared as pale yellow
oil.
[0135] .sup.1H-NMR (CDCl.sub.3): .delta. 7.12 (d, 2H, J=8 Hz); 6.64
(d, 2H, J=8 Hz); 3.50 (bs, 2H, NH.sub.2); 3.28 (s, 2H); 2.25 (s,
6H).
N,N-dimethylbutin-2-yl diamine
[0136] Propargyl bromide (1.3 mL, 17.4 mmol) is dissolved in DMF
(30 mL) and potassium phtalimide (3.4 g; 18.4 mmol) is added. The
mixture is refluxed for 5 h. After cooling at room temperature the
mixture is diluted with diethyl ether, washed with water
(3.times.50 mL), dried over Na.sub.2SO.sub.4 and evaporated under
vacuum to give N-propargyl phtalimide as white solid (3.15 g; 17
mmol).
[0137] N-propargyl phtalimide (0.64 g; 3.4 mmol) is dissolved in
1,4-dioxane (20 mL), then dimethylamine (8.5 mL; 17 mmol),
copper(I)chloride (0.35 g) and paraformaldehyde (1 g) are added.
The solution is refluxed for 3 h. After cooling at room temperature
the formed precipitate is filtered off and the filtrate is
evaporated under vacuum to give a green oily residue that, after
dissolution in CH.sub.2Cl.sub.2, is washed with sat. sol.
NaHCO.sub.3 (2.times.30 mL) and water (2.times.30 mL). The organic
phase is dried over Na.sub.2SO.sub.4 and evaporated under vacuum.
The crude product is purified by treatment with diethyl ether to
give N-phtalimido-N',N'-dimethylbutin-2-yl-1,4-diamine as pale
yellow solid (0.5 g; 2.05 mmol). A suspension of
N-phtalimido-N',N'-dimethylbutin-2-yl-1,4-diamine (0.5 g; 2.05
mmol) in ethyl alcohol (10 mL) is treated with hydrazine hydrate
(98 .mu.L; 2 mmol)) and the mixture is refluxed overnight. After
cooling at room temperature the precipitate is filtered off and the
filtrate is evaporated under vacuum; the crude residue is treated
with acetone at room temperature to give, after removal of the
formed precipitate, the pure product
N,N-dimethylbutin-2-yl-1,4-diamine as red oil (0.2 g; 1.78
mmol).
[0138] .sup.1H-NMR (CDCl.sub.3): .delta. 3.52 (m, 2H); 3.27 (m,
2H); 2.35 (s, 6H); 1.90-1.65 (bs, 2H, NH.sub.2).
2-(amineoxy)-N-methyl-N-(2-hydroxyethyl)]ethylamine
a) (Z-amineoxy)-acetic acid
[0139] Maintaining the reaction temperature around 0-5.degree. C.
by external cooling, benzylchloroformate (1.41 mL, 10 mmol) and
aqueous 4N NaOH (2.23 mL) are, dropwise and alternately, added to a
solution in aqueous 2N NaOH (5 mL) of 2.18 g (10 mmol) of
carboxymethoxylamine hemihydrochloride [(commercial reagent) also
named (amineoxy)acetic acidhydrochloride]. Stirring is continued
for 15 min before removal of any organic impurities with Et.sub.2O
(2.times.15 mL); then addition of crushed ice and acidification
until pH=2 with 37% HCl yields a solid that is filtered, washed
with cold water and dried under vacuum at T=40.degree. C. to give
2.62 g (8.2 mmol) of (Z-amineoxy)-acetic acid.
b) 2-(Z-amineoxy)-N-methyl-N-(2-hydroxyethyl)acetamide
[0140] Thionyl chloride (0.78 mL, 9 mmol) is added to a stirred
solution of (Z-amineoxy)-acetic acid (2.62 g, 8.2 mmol) in MeOH (10
mL). The mixture is maintained overnight at room temperature to
give a crude sample of (Z-amineoxy)-acetyl chloride after the usual
solvent evaporation under high-vacuum conditions. Without any
further purification, a solution of said compound in
CH.sub.2Cl.sub.2 (10 mL) is dropwise added at r. t. into a stirred
solution of 2-methylaminoethanol (1.44 mL, 18 mmol) in
CH.sub.2Cl.sub.2 (5 mL); 18 hrs later, the reaction mixture is
diluted with aqueous 1NHCl (15 mL). The organic phase is separated;
washed with water (2.times.15 mL), dried over Na.sub.2SO.sub.4 and
evaporated to yield
2-(Z-amineoxy)-N-methyl-N-(2-hydroxyethyl)acetamide (2.64 g, 7
mmol) as a transparent oil.
c) 2-(Z-amineoxy)-N-methyl-N-(2-hydroxyethyl)ethylamine
[0141] The selective reduction with diborane of the
2-(Z-amineoxy)-N-methyl-N-(2-hydroxyethyl)acetamide, carried out
according to the Brown procedure (J. Am. Chem. Soc. 86, 3566, 1964
and J. Org. Chem., 38, 912, 1973) yields 2.1 g (5.8 mmol) of
2-(Z-amineoxy)-N-methyl-N-(2-hydroxyethyl)ethylamine, as an
oil.
d) 2-(amineoxy)-N-methyl-N-(2-hydroxyethyl)ethylamine
[0142] Benzyloxycarbonyl hydrogenolytic cleavage, carried out in
the presence of ammonium formate according to Makowski procedure
(Liebigs Ann. Chem., 1457, 1985) gives
2-(amineoxy)-N-methyl-N-(2-hydroxyethyl)ethylamine (1.06 g, 4.64
mmol) as a transparent oil.
[0143] .sup.1H-NMR (CDCl.sub.3): .delta. 5.28 (bs, 2H, ONH.sub.2);
4.67 (t, 2H, J=7 Hz); 3.40 (m, 2H); 2.75 (t, 2H, J=7 Hz); 2.42 (t,
2H, J=7 Hz); 2.21 (s, 3H); 1.8 (bs, 1H, OH).
2-aryl-propionyl chlorides of formula V (General Procedure)
[0144] A solution of 72.8 mmol of a 2-arylpropionic acid of formula
V [for example, (R)-2-(4-isobutylphenyl)propionic acid,
(R)(-).ibuprofen, 72.8 mmol] in thionyl chloride (37.5 mL) is
refluxed for 3 hrs. The mixture is cooled at r. t.; the excess
reagent is evaporated to dryness in vacuum; then, twice in
succession, small amounts of anhydrous dioxane are added and
evaporated to dryness under high vacuum conditions to fully
eliminate any residual thionyl chloride. The final oily residue is
used in the following reactions.
[0145] IR (film) cm.sup.-1: 1800 (CIC.dbd.O)
(S)2-(4-isobutylphenyl)]-N-(3-dimethylaminopropyl)-propionamide
hydrochloride
[0146] Using the previous procedure, (S)(+)ibuprofen (Fluka
reagent) is converted into its propionyl chloride, whose treatment
with 3-dimethylaminopropylamine, in the procedure of the example 1,
allows to obtain a sample of
(S)2-(4-isobutylphenyl)]-N-(3-dimethylaminopropyl)-propionamide
hydrochloride m.p. 97-98.degree. C., [.alpha.].sub.D=+27 (c=1;
CH.sub.3OH).
[0147] .sup.1H-NMR (D.sub.2O): .delta. 7.45-7.21 (m, 4H); 3.75 (q,
1H, J.sub.1=7 Hz, J.sub.2=7 Hz); 3.45-3.15 (m, 2H); 2.95 (t, 2H,
J=8 Hz); 2.85 (s, 6H); 2.52 (d, 2H, J=7 Hz); 1.98 (m, 1H); 1.47 (d,
3H, J=7 Hz); 0.90 (d, 6H, J=7 Hz).
EXAMPLE 1
(R)2-(4-isobutylphenyl)-N-(3-dimethylaminopropyl)propionamide
hydrochloride
[0148] With external cooling, keeping the reaction temperature
below 40.degree. C., a solution of
(R)2-(4-isobutylphenyl)-propionyl chloride (16.35 g; 72.8 mmol) in
CH.sub.2Cl.sub.2 (10 mL) is slowly added to a stirred solution of
3-dimethylaminopropylamine (19 mL; 152 mmol). After a night at
r.t., the reaction mixture is diluted with water (100 mL), the
organic phase is separated, washed with water (50 mL) and dried
over Na.sub.2SO.sub.4. After solvent removal at low pressure, 20 g
(68.8 mmol) of crude
(R)2-(4-isobutylphenyl)-N-(3-dimethylaminopropyl)propionamide are
obtained as a pale yellow oil.
[0149] A stirred solution of a portion of said amide (58 mmol) in
isopropyl alcohol (200 mL) is treated with aqueous 37% HCl (6 mL),
slowly added at r.t.; after 2 hrs, the reaction mixture is
evaporated to dryness, at low pressure. The residual water is
eliminated by azeotropic removal through the addition of small
amounts of anhydrous isopropyl alcohol, in vacuum. Final
crystallization from AcOEt (300 mL) separates a white powder that
is filtered, washed with dry AcOEt and dried for 24 h under vacuum
conditions at T=40.degree. C. to obtain 18 g (55 mmol) of
(R)2-(4-isobutylphenyl)-N-(3-dimethylaminopropyl)propionamide
hydrochloride.
[0150] m.p. 95-98.degree. C.,
[0151] [.alpha.].sub.D=-26 (c=1.6; CH.sub.3OH).
[0152] .sup.1H-NMR (D.sub.2O): .delta. 7.5-7.2 (m, 4H); 3.75 (q,
1H, J.sub.1=7 Hz, J.sub.2=7 Hz); 3.45-3.15 (m, 2H); 3.05 (t, 2H,
J=8 Hz); 2.80 (d, 6H, J=4.5 Hz); 2.55 (d, 2H, J=7 Hz); 1.95 (m,
1H); 1.45 (d, 3H, J=7 Hz); 0.93 (d, 6H, J=7 Hz).
EXAMPLE 2
[0153] Using 2-dimethylaminoethylamine and
4-dimethylaminobutylamine instead of 3-dimethylpropylamine in the
procedure of the example 1, the following compounds are
obtained:
(R)-2-(4-isobutylphenyl)-N-(2-dimethylaminoethyl)propionamide.HCl
[0154] m.p. 90-93.degree. C.; [.alpha.].sub.D=-16 (c=1;
CH.sub.3OH).
[0155] .sup.1H-NMR (CDCl.sub.3): .delta. 12.25 (bs, 1H, NH.sup.+);
7.82 (bs, 1H, CONH); 7.45 (d, 2H, J=8 Hz); 7.05 (d, 2H, J=8 Hz);
3.85 (m, 2H); 3.70 (m, 1H); 3.10 (m, 2H); 2.80 (s, 3H); 2.75 (s,
3H); 2.55 (d, 2H, J=7 Hz); 1.97 (m, 1H); 1.65 (d, 3H, J=7 Hz); 0.98
(d, 6H, J=7 Hz).
(R)2-(4-isobutylphenyl)-N-(4-dimethylaminobutyl)propionamide.
HCl
[0156] m.p. 95-97.degree. C.; [.alpha.].sub.D=-16 (c=0.52;
CH.sub.3OH).
[0157] .sup.1H-NMR (CDCl.sub.3): .delta. 7.25 (d, 2H, J=8 Hz); 7.10
(d, 2H, J=8 Hz); 6.18 (bs, 1H, CONH); 3.60 (q, 1H, J.sub.1=7 Hz,
J.sub.2=7 Hz); 3.25-3.15 (m, 2H); 2.95 (m, 2H); 2.75 (s, 6H); 2.45
(d, 2H, J=7 Hz); 1.85 (m, 1H); 1.65 (m, 4H); 1.48 (d, 3H, J=7 Hz);
0.93 (d, 6H, J=7 Hz).
EXAMPLE 3
(R)2-(4-isobutylphenyl)-N-2-(N-morpholinyl
ethyl)propionamide.HCl
[0158] Using 1-aminoethyl-morpholine in the procedure of the
example 1, crude
(R)2-(4-isobutylphenyl)-N-[2-(1-morpholinyl)ethyl]propionamide is
obtained.
[0159] A solution of 4.2N acetyl chloride in absolute EtOH (3 mL)
is added dropwise to a stirred solution of said amide (0,416 g, 1.3
mmol) in absolute EtOH (5 mL). The mixture is stirred for
additional 2 hrs at r. t. before removal of solvents at low
pressure. The residue is taken up with ethyl ether to separate 0.39
g (1.1 mmol) of
(R)2-(4-isobutylphenyl)-N-[2-(1-morpholinyl)ethyl]propionamide
hydrochloride as a white solid, that is filtered and washed with
the same solvent.
[0160] m.p. 123-125.degree. C.; [.alpha.].sub.D=-36.3 (c=0.5;
CH.sub.3OH).
[0161] .sup.1H-NMR (CDCl.sub.3): .delta. 12.55 (bs, 1H, NH.sup.+);
7.80 (bs, 1H, CONH); 7.45 (d, 2H, J=8 Hz); 7.05 (d, 2H, J=8 Hz);
4.25 (m, 2H); 3.95 (m, 1H); 3.70 (m, 4H); 3.41 (m, 1H); 3.05 (m,
3H); 2.75 (m, 2H); 2.45 (d, 2H, J=7 Hz); 1.97 (m, 1H); 1.65 (d, 3H,
J=7 Hz); 0.95 (d, 6H, J=7 Hz
EXAMPLE 4
[0162] The use in the procedure of the Example 3 of the following
amines: 1-(3-aminopropyl)morpholine,
1-(3-aminopropyl)-4-thiomorpholine,
1-(2-aminoethyl)-piperazine-4-methyl,
1-(3-aminopropyl)-piperazine-4-methyl.,
1-(3-aminopropyl)piperidine, and
exo-8-methyl-8-aza-bicyclo[3,2,1]octan-3-amine instead of
1-(3-aminopropyl)morpholine gives:
(R)2-(4-isobutylphenyl)-N-3-(N-morpholinyl
propyl)propionamide.HCl
[0163] m.p. 90-93.degree. C.
[0164] [.alpha.].sub.D=-22.6 (c=0.5; CH.sub.3OH).
[0165] .sup.1H-NMR (CDCl.sub.3): .delta. 12.55 (bs, 1H, NH.sup.+);
7.80 (bs, 1H, CONH); 7.45 (d, 2H, J=8 Hz); 7.05 (d, 2H, J=8 Hz);
4.25 (m, 2H); 3.95 (m, 1H); 3.70 (m, 4H); 3.41 (m, 1H); 3.05 (m,
3H); 2.75 (m, 2H); 2.45 (d, 2H, J=7 Hz); 2.15 (m, 2H); 1.97 (m,
1H); 1.65 (d, 3H, J=7 Hz); 0.95 (d, 6H, J=7 Hz).
(R)2(4-isobutylphenyl)-N-3-(N-thiomorpholinyl propyl)propionamide
HCl
[0166] m.p. 70-73.degree. C.; [.alpha.].sub.D=-23 (c=0.5;
CH.sub.3OH).
[0167] .sup.1H-NMR (D.sub.2O): .delta. 8.15 (bs, 1H, CONH); 7.40
(m, 4H); 3.82 (q, 1H, J=7 Hz); 3.65 (m, 2H); 3.41 (m, 1H); 3.25 (m,
1H); 3.15-2.80 (m, 8H); 2.45 (d, 2H, J=7 Hz); 1.95 (m, 3H); 1.55
(d, 3H, J=7 Hz); 0.95 (d, 6H, J=7 Hz).
(R)2-(4-isobutylphenyl)-N-[2-(4-methyl-piperazin-1-yl)ethyl]propionamide
hydrochloride;
[0168] m.p. above 240.degree. C.; [.alpha.].sub.D=-33.7 (c=0.5;
CH.sub.3OH).
[0169] .sup.1H-NMR (DMSO-d.sub.6): .delta. 7.15 (m, 4H); 4.45 (M,
1H); 4.13 (m, 2H); 3.02 (m, 3H); 2.75 (m, 4H); 2.38 (d, 2H, J=7
Hz); 1.85 (m, 1H); 1.30 (d, 3H, J=7 Hz); 0.81 (d, 6H, J=7 Hz).
(R)2-(4-isobutylphenyl)-N-[3-(4-methyl-piperazin-1-yl)propyl]propionamid-
e bis-hydrochloride
[0170] m.p. 216-220.degree. C.; [.alpha.].sub.D=-20.5 (c=0.5;
CH.sub.3OH).
[0171] .sup.1H-NMR (D.sub.2O): .delta. 7.25 (m, 4H); 3.75 (m, 1H);
3.55 (m, 8H); 3.25 (m, 2H); 3.15 (m, 1H); 3.00 (s, 3H); 2.48 (d,
2H, J=7 Hz); 1.95 (m, 3H); 1.45 (d, 3H, J=7 Hz); 0.90 (d, 6H, J=7
Hz).
(R)2-(4-isobutylphenyl)-N-[3-(1-piperidinyl)propyl]propionamide
hydrochloride
[0172] m.p. 76-80.degree. C.;
[0173] [.alpha.].sub.D=-29 (c=0.5; CH.sub.3OH).
[0174] .sup.1H-NMR (CDCl.sub.3): .delta. 11.4 (bs, 1H, NH.sup.+);
7.45 (d, 2H, J=8 Hz); 7.35 (bs, 1H, CONH); 7.05 (d, 2H, J=8 Hz);
3.85 (q, 1H, J=7 Hz); 3.45 (m, 4H); 2.75 (m, 2H); 2.52 (m, 4H);
2.25 (m, 2H); 2.05 (m, 2H); 1.97 (m, 3H); 1.60 (d, 3H, J=7 Hz);
0.97 (d, 6H, J=7 Hz).
(R)2-(4-isobutylphenyl)-N-(exo-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)pro-
pionamide hydrochloride
[0175] m.p. 72-75.degree. C.; [.alpha.].sub.D=-3.3 (c=0.5;
CH.sub.3OH).
[0176] .sup.1H-NMR (CDCl.sub.3): .delta. 7.15 (d, 2H, J=8 Hz); 7.05
(d, 2H, J=8 Hz); 6.15 (bs, 1H, CONH); 4.34 (m, 1H); 3.75 (m, 2H);
3.47 (q, 1H, J=7 Hz); 2.72 (s, 3H); 2.60-2.38 (m, 4H); 2.30-1.98
(m, 6H); 1.92 (m, 2H); 1.45 (d, 3H, J=7 Hz); 0.9 (d, 6H, J=7
Hz).
EXAMPLE 5
(R)2-(4-isobutylphenyl)-N-(3-aminopropyl)propionamide
hydrochloride
[0177] A solution of 3-BOC-aminopropylamine (3.22 g; 18 mmol) in
CH.sub.2Cl.sub.2 (10 mL) is added dropwise to a stirred suspension
of (R)(-)ibuprofen (3 g; 17.5 mmol), DCC (3.8 g; 18 mmol) and HOBZ
(2.8 g; 18 mmol) in CH.sub.2Cl.sub.2 (50 mL) at 25.degree. C. The
stirring is continued for 18 hrs at r. t.; after DCU removal by
filtration, the reaction mixture is evaporated to dryness in
vacuum. The residue oil is more times taken up with acetonitrile;
finally the collected extracts are filtered, evaporated to dryness
to give a crude sample of
(R)2-(4-isobutylphenyl)-N-3-(BOC-aminopropyl)propionamide that is
crystallized from hot MeOH (50 mL) to obtain 3.4 g (9.25 mmol, 53%
yield) of pure
(R)2-(4-isobutylphenyl)-N-3-(BOC-aminopropyl)propionamide by
cooling at T=+4.degree. C. for 18 hrs
[0178] A suspension of said compound in 10 mL of aqueous 3NHCl is
stirred at r.t. for 48 hrs to give
(R)2-(4-isobutylphenyl)-N-3-(aminopropyl)propionamide hydrochloride
(1.9 g; 6.3 mmol);
[0179] m.p. 160-163.degree. C.;
[0180] [.alpha.].sub.D=-31 (c=0.5; CH.sub.3OH).
[0181] .sup.1H-NMR (CDCl.sub.3): .delta. 8.2 (bs, 1H,
NH.sub.3.sup.+); 7.18 (d, 2H, J=8 Hz); 7.05 (d, 2H, J=8 Hz); 6.83
(bs, 1H, CONH); 3.65 (q, 1H, J=7 Hz); 3.30 (m, 2H); 3.00 (m, 2H);
2.40 (d, 2H, J=7 Hz); 1.95-1.74 (m, 3H); 1.45 (d, 3H, J=7 Hz); 0.92
(d, 6H, J=7 Hz).
EXAMPLE 6
(R)2-(4-isobutylphenyl)-N-(1-methyl-piperidin-4-yl)propionamide
hydrochloride
[0182] Ammonium formate (15.4 g; 240 mmol) and 10% Pd/C (3.14 g; 29
mmol) are added to a solution of 1-methyl-4-piperidone (3.26 mL;
26.5 mmol) in aqueous methanol (80 mL, CH.sub.3OH/H.sub.2O 9:1);
the mixture is stirred for 24 h. at r.t.; catalyst removal by
filtration over Celite and solvent evaporation to dryness at low
pressure give a pale yellow residue of 1-methyl-4-aminopiperidine.
Dropwise addition of 37% HCl (4.6 mL) to a stirred solution of said
amine in EtOH (50 mL) separates a white precipitate of
1-methyl-4-aminopiperidine hydrochloride that is filtered 18 hrs
later, after cooling for 18 hrs at T=+4.degree. C. Finally, an
aqueous solution of the hydrochloride treated with an excess of 0.1
N NaOH (.apprxeq.10 mL) is extracted with CH.sub.2Cl.sub.2
(3.times.10 mL). After the usual work-up, solvent evaporation to
dryness yields pure 1-methyl-4-aminopiperidine (1.4 g; 12.4
mmol).
[0183] .sup.1H-NMR (CDCl.sub.3): .delta. 2.85 (m, 2H); 2.58 (m,
1H); 2.25 (s, 3H); 2.01 (m, 2H); 1.85 (m, 2H); 1.63 (bs, 2H,
NH.sub.2); 1.47 (m, 2H).
[0184] At room temperature, a solution of
(R)2-(4-isobutylphenyl)-propionyl chloride (1.12 g; 5 mmol) in
CH.sub.2Cl.sub.2 (20 mL) is slowly added dropwise to a solution of
1-methyl-4-aminopiperidine (1.1 g; 10 mmol) in CH.sub.2Cl.sub.2 (10
mL). After 3 hrs., the reaction mixture is diluted again with
CH.sub.2Cl.sub.2 (10 mL), washed with 1 NHCl (25 mL) and with
brine, dried over Na.sub.2SO.sub.4 to give after solvent removal to
dryness
(R)2-(4-isobutylphenyl)-N-(1-methyl-piperidin-4-yl)propionamide
hydrochloride as a glass solid (1.2 g; 3.5 mmol).
[0185] [.alpha.].sub.D=-11 (c=0.5; CH.sub.3OH).
[0186] .sup.1H-NMR (D.sub.2O): .delta. 7.28 (m, 5H); 3.95 (m, 1H);
3.75 (q, 1H, J=7 Hz); 3.54 (m, 2H); 3.15 (m, 2H); 2.90 (s, 3H);
2.53 (d, 2H, J=7 Hz); 2.28-2.05 (m, 2H); 1.95-1.65 (m, 4H); 1.45
(d, 3H, J=7 Hz); 0.95 (d, 6H, J=7 Hz).
EXAMPLE 7
(R),(S)2-(4-isobutylphenyl)-N-(1-carboxy-2-dimethylamino-ethyl)propionam-
ide sodium salt
[0187] A solution of (S) methyl 3-dimethylamino-2-amino-propanoate
(0.16 g; 1.1 mmol) in CH.sub.2Cl.sub.2 (2 mL) is added dropwise to
a stirred suspension of (R)(-)ibuprofen (0.23 g; 1.1 mmol), DCC
(0.23 g; 1.1 mmol) and HOBZ (0.17 g; 1.1 mmol) in CH.sub.2Cl.sub.2
(5 mL) at room temperature. The stirring is continued for 18 hrs at
r. t.; after DCU removal by filtration, the reaction mixture is
evaporated to dryness in vacuum. The residue is more times taken up
with acetonitrile; then, the collected extracts are filtered and
evaporated to dryness in vacuum. Following purification by flash
chromatography on silica gel (eluent CH.sub.2Cl.sub.2/CH.sub.3OH
95:5) yields 0.3 g (0.88 mmol) of
methyl(S),(R)3-dimethylamino-2-[2-(4-isobutylphenyl)propionyl]amino-propa-
noate (80% yield) as a transparent oil.
[0188] A stirred solution of said ester (0.3 g; 0.88 mmol) in
dioxane (2 mL) is treated with a stechiometrical amount of aqueous
N NaOH (0.88 mL) and maintained for 18 hrs. at r. t., before
dilution with cooled water (20 mL). The frozen solution is
lyophilized to yield 0.307 g (0.88 mmol) of
(R),(S)2-(4-isobutylphenyl)-N-(1-carboxy-2-dimethylamino-ethyl)propion-
amide sodium salt, as a white solid
[0189] m.p. above 240.degree. C.;
[0190] [.alpha.].sub.D=-25 (c=0.5; CH.sub.3OH)
[0191] .sup.1H-NMR (CDCl.sub.3): .delta. 7.35 (m, 4H); 6.25 (bs,
1H, CONH); 4.72 (m, 1H); 3.60 (m, 1H); 2.51 (d, 2H, J=7 Hz); 2.30
(d, 2H, J=7 Hz); 2.22 (m, 6H); 1.55 (d, 3H, J=7 Hz); 0.95 (d, 6H,
J=7 Hz).
EXAMPLE 8
[0192]
(R),(S)2-(4-isobutylphenyl)-N-(1-carboxy-2-piperidin-1-yl-butyl)pr-
opionamide sodium salt; and
(R),(S)2-(4-isobutylphenyl)-N-(1-ethoxycarbonyl-2-piperidin-1-yl-butyl)pr-
opionamide are obtained using (S)
methyl-5-(piperidin-1-yl)-2-amino-pentanoate in the procedure of
the example 7 instead of (S) methyl
3-dimethylamino-2-amino-propanoate.
EXAMPLE 9
R-2-[(4'-isobutylphenyl]-N-[2-(dimethylaminoethyl)aminocarbonylmethyl]-p-
ropionamide hydrochloride
[0193] HOBZ (0.607 g; 4.49 mmol) is added to a stirred solution of
(R)(-)ibuprofen (1.01 g; 4.9 mmol) in DMF (4 mL) at T=0.degree. C.
and left under stirring for 30 min. Then a mixture of
N-(3-dimethylaminopropyl)glycinamide hydrochloride (0.64 g; 4.47
mmol) in DMF (8 mL) and triethylamine (0.6 mL; 4.45 mmol) is added
and N,N-dicyclohexylcarbodiimide (1 g; 4.85 mmol), in small
portions, is also added. The mixture is stirred for 2 hrs at
T=0.degree. C. and then for 18 hrs at r.t. After DCU filtration
most of DMF is then removed by distillation at low pressure. The
residue is taken up with water and extracted with Et.sub.2O
(3.times.25 mL); the organic extracts are combined, dried over
Na.sub.2SO.sub.4, and evaporated a low pressure to yield a
transparent oil (1 g; 3.43 mmol). Then a solution of this compound
in dioxane (3.5 mL) is treated with 1N NaOH (3.5 mL), stirred for
24 hrs at r t., diluted with water (10 mL) and then acidified with
2NHCl, and extracted with CH.sub.2Cl.sub.2 (3.times.10 mL). Then,
the organic extracts are combined, dried over Na.sub.2SO.sub.4,
evaporated at low pressure to yield
R-2-[(4'-isobutyl)phenyl]-N-[2-(dimethylaminoethyl)aminocarbonylmethyl]-p-
ropionamide hydrochloride (0.68 g; 2.04 mmol), as a pale yellow
oil.
[0194] [.alpha.].sub.D=-25 (c=0.5; CH.sub.3OH).
[0195] .sup.1H-NMR (CDCl.sub.3): .delta. 7.24 (m, 2H); 7.10 (m,
2H); 6.10 (bs, 1H, CONH); 3.55 (m, 1H); 3.30 (m, 2H); 2.45 (d, 2H,
J=7 Hz); 2.35 (m, 2H); 2.18 (s, 6H); 1.85 (m, 1H); 1.52 (d, 3H, J=7
Hz); 0.90 (d, 6H, J=7 Hz).
EXAMPLE 10
(R)-2-[2-(2,6-dichlorophenylamino)-phenyl]-N-3-(dimethylaminopropyl)
propionamide
[0196] A suspension of
(R)2-[2-(2,6-dichlorophenylamino)-phenyl]propionic acid (0.15 g;
0.48 mmol), DCC (0.173 g; 0.84 mmol) and HOBZ (0.075 g; 0.56 mmol)
in CH.sub.2Cl.sub.2(6 m L) is stirred for 4 hrs at r.t.; then, a
solution of 3-(dimethylamino)propylamine (0.06 ml; 0.48 mmol) in
CH.sub.2Cl.sub.2 (5 mL) is added dropwise. The stirring is
continued for 18 hrs at r. t., then the separated DCU is filtered
and the solvent removed at low pressure. The residue is taken up
with acetonitrile twice, the extracts are combined, filtered to
totally eliminate DCU, and evaporated at low pressure. Purification
by flash chromatography (eluent CH.sub.2Cl.sub.2/CH.sub.3OH 95:5)
yields
(R)2-[2-(2,6-dichlorophenylamino)-phenyl]-N-3-(dimethylaminopropyl)propio-
namide (0.141 g; 0.36 mmol; 75% yield), as a transparent oil.
[0197] [.alpha.].sub.D=-30 (c=1; CH.sub.3OH).
[0198] .sup.1H-NMR (D.sub.2O): .delta. 7.38 (m, 4H); 7.15 (m, 1H);
7.05 (m, 1H); 6.60 (m, 1H+CONH); 4.25 (dd, 2H, J.sub.1=7 Hz,
J.sub.2=3 Hz); 3.30 (m, 2H); 2.35 (m, 2H); 2.10 (s, 6H); 1.65 (m,
2H); 1.65 (d, 3H, J=7 Hz).
EXAMPLE 11
[0199] The following amides are obtained using
(R),(R',S')-2-[3-(.alpha.-hydroxybenzyl)phenyl]propionic acid,
2-[3'-(.alpha.-hydroxyethyl)phenyl]propionic acid and
(R),(R',S')2-[3'-(.alpha.-hydroxy,.alpha.-methylbenzyl)phenyl]propionic
acid as starting material instead of
(R)2-[2-(2,6-dichlorophenylamino)]phenyl]propionic acid in the
procedure of example 10.
[0200]
(R),(R',S')2-[3-(.alpha.-hydroxybenzyl)phenyl]-N-3-(dimethylaminop-
ropyl)propionamide as a colourless oil, [.alpha.].sub.D=-24 (c=1;
CH.sub.3OH).
[0201] .sup.1H-NMR (CDCl.sub.3): .delta. 7.41-7.3 (m, 3H);
7.31-7.14 (m, 6H); 5.75 (s, 1H); 4.02 (bs, 1H, OH) 3.31 (m, 2H);
2.38 (t, 2H, J=8 Hz); 2.15 (s, 6H); 1.75 (m, 2H); 3.68 (q, 1H, J=7
Hz); 1.4 (d, 3H, J=7 Hz).
[0202]
(R),(R',S')2-[3'-(.alpha.-hydroxy,.alpha.-methylbenzyl)phenyl]-N-3-
-(dimethylaminopropyl propionamide as a colourless oil.
[0203] [.alpha.].sub.D=-28 (c=1; CH.sub.3OH).
[0204] .sup.1H-NMR (CDCl.sub.3): .delta. 7.41-7.3 (m, 3H);
7.31-7.14 (m, 6H); 4.02 (bs, 1H, OH) 3.31 (m, 2H); 2.38 (t, 2H, J=8
Hz); 2.15 (s, 6H); 1.75 (m, 2H); 3.68 (q, 1H, J=7 Hz); 1.4 (d, 3H,
J=7 Hz).
(R),(R',S')2-[3-(.alpha.-hydroxyethyl)phenyl]-(3-dimethylaminopropyl)pro-
pionamide
[0205] .sup.1H-NMR (DMSO-d.sub.6): .delta. 8.12 (bs, 1H, CONH);
7.31 (s, 1H); 7.25-7.10 (m, 3H); 5.1 (bs, 1H, OH); 4.7 (m, 1H);
3.62 (m, 1H); 3.10 (m, 2H); 2.91 (m, 2H); 3.65 (s, 6H); 1.73 (m,
2H); 1.30 (m, 6H)
EXAMPLE 12
(R),(R',S')2-[3'-(.pi.-methylbenzyl)phenyl]-N-3-(dimethylaminopropyl)pro-
pionamide as a pale yellow oil (1.2 g; 3.52 mmol).
[0206] [.alpha.].sub.D=-30 (c=1; CH.sub.3OH).
[0207] .sup.1H-NMR (CDCl.sub.3): .delta. 7.38-7.13 (m, 9H); 6.60
(bs, 1H, CONH) 4.20 (m, 1H); 3.78 (m, 1H); 3.27 (m, 2H); 2.30 (m,
2H); 2.12 (s, 6H); 1.72 (d, 3H, J=7 Hz); 1.65 (m, 2H); 1.55 (d, 3H,
J=7 Hz) is prepared using the
(R),(R',S')2-[3-(.alpha.-methylbenzyl)phenyl]propionyl chloride in
the procedure of the example 1 instead of the
(R)2-(4-isobutylphenyl)-propionyl chloride.
[0208] The alternative use of (R)2-(3-isopropylphenyl)propionyl
chloride, (R)2-(3-isobutylphenyl),
(R)2-[3-(styren-1-yl)phenyl]propionyl chloride,
(R)2-[3'-(pent-3-yl)phenyl]propionyl chloride in the procedure of
the example 1 gives:
(R)2-(3-isopropylphenyl)-N-3-(dimethylaminopropyl)propionamide
[0209] .sup.1H-NMR (CDCl.sub.3): .delta. 7.21-7.13 (m, 4H); 6.95
(bs, 1H, CONH) 3.53 (m, 1H); 3.30 (m, 2H); 2.90 (m, 1H); 2.37 (m,
2H); 2.15 (s, 6H); 1.65 (d, 3H, J=7 Hz); 1.23 (d, 3H, J=7 Hz).
(R)2-(3-isobutylphenyl)-N-3-(dimethylaminopropyl)propionamide
[0210] [.alpha.].sub.D=-30 (c=1; CH.sub.3OH).
[0211] .sup.1H-NMR (CDCl.sub.3): .delta. 7.21-7.13 (m, 4H); 6.85
(bs, 1H, CONH) 3.53 (m, 1H); 3.25 (m, 2H); 2.48 (d, 2H, J=7 Hz);
2.30 (t, 2H, J=7 Hz); 209 (s, 6H); 1.9 (m, 1H); 1.55 (m, 2H); 1.45
(d, 3H, J=7 Hz); 0.95 (d, 3H, J=7 Hz).
(R)2-[3-(styren-1-yl)phenyl]-N-3-(dimethylaminopropyl)propionamide
[0212] [.alpha.].sub.D=-31 (c=1; CH.sub.3OH).
[0213] .sup.1H-NMR (CDCl.sub.3): .delta. 7.8-7.13 (m, 9H); 6.95
(bs, 1H, CONH) 5.0 (s, 2H); 3.53 (m, 1H); 3.30 (m, 2H); 2.37 (m,
2H); 2.15 (s, 6H).
(R)2-[3'-(pent-3-yl)phenyl]-N-3-(dimethylaminopropyl)propionamide
[0214] [.alpha.].sub.D=-28 (c=1; CH.sub.3OH).
[0215] .sup.1H-NMR (CDCl.sub.3): .delta. 7.25 (m, 3H); 7.12 (m,
1H); 7.08 (bs, 1H, CONH) 3.65 (m, 1H); 3.5-3.13 (m, 2H); 2.75 (m,
2H); 2.55 (s, 6H); 2.35 (m, 1H); 1.95 (m, 2H); 1.70 (m, 2H); 1.58
(m, 2H); 1.50 (d, 3H, J=7 Hz); 0.76 (t, 6H, J=7 Hz).
(R)-2-[(3-benzoyl)phenyl]-N-(3-diethylaminopropyl)propionamide
[0216] [.alpha.].sub.D=-11.5 (c=3; CH.sub.3OH)
[0217] .sup.1H-NMR (CDCl.sub.3): .delta. 7.8 (m, 3H); 7.70-7.55 (m,
3H); 7.50-7.28 (m, 3H); 7.25 (bs, 1H, CONH); 3.75 (m, 1H);
3.50-3.20 (m, 2H); 3.3.15-2.80 (m, 6H); 2.05 (m, 2H); 1.65 (d, 3H,
J=7 Hz); 1.70-1.53 (m, 3H); 1.50-1.45 (m, 3H).
(R)-2-[(3-benzoyl)phenyl]-N-(3-dimethylaminopropyl)propionamide
[0218] [.alpha.].sub.D=-20 (c=1; CH.sub.3OH)
[0219] .sup.1H-NMR (CDCl.sub.3): .delta. 7.88-7.78 (m, 3H);
7.75-7.58 (m, 3H); 7.55-7.46 (m, 3H); 7.25 (bs, 1H, CONH); 3.62 (m,
1H); 3.28 (m, 2H); 2.35 (m, 2H); 2.12 (s, 6H); 1.68-1.53 (m,
5H).
EXAMPLE 13
(R)2-(4-isobutylphenyl)-N-3(guanidinylpropyl)propionamide
hydrochloride
[0220] (R)2-(4-isobutylphenyl)-N-3-(aminopropyl)propionamide
hydrochloride of example 5 is converted into the free amine and
treated with isothiouronium chloride according to the procedure of
Bodanszky M. et al., (J. Am. Chem. Soc., 86, 4452, 1964) to obtain
(R)2-(4-isobutylphenyl)-N-3(guanidinylpropyl)propionamide
hydrochloride
[0221] m.p. 142-146.degree. C.; [.alpha.].sub.D=-24 (c=1;
CH.sub.3OH).
[0222] .sup.1H-NMR (D.sub.2O): .delta. 7.2 (d, 2H, J=8 Hz); 7.1 (d,
2H, J=8 Hz); 6.8 (bs, 1H, CONH); 3.6 (q, 1H, J=7 Hz); 3.55 (m, 2H);
2.95 (m, 2H); 2.4 (d, 2H, J=7 Hz); 2.0-1.8 (m, 3H); 1.5 (d, 3H, J=7
Hz); 0.9 (d, 6H, J=7 Hz).
Alternative use in the same procedure of the
N-hydroxy-carbamidothioic acid methylester hydrochloride salt and
of the N-amino-carbamidothioic acid methylester gives:
(R)2-(4-isobutylphenyl)-N-[3-(hydroxyguanidinyl)propyl]propionamide.HCl
(R)2-(4-isobutylphenyl)-N-[3-(aminoguanidinyl)propyl]propionamide.HCl
EXAMPLE 14
(R)2-(4-isobutylphenyl)-N-[3-(imidazolin-2-yl)aminopropyl]propionamide
[0223] The (R)2-[(4-isobutylphenyl)-N-3-(aminopropyl)propionamide
hydrochloride (see example 5) is converted in the free amine and
treated with 2-methylthio-2-imidazoline iodohydrate (commercial
reactant) according to the above cited Bodanszky procedure (J. Am.
Chem. Soc., 86, 4452, 1964) to give
(R)2-(4'-isobutylphenyl)-N-[3-(imidazolin-2-yl)aminopropyl]propionamide
[0224] m.p. 155-168.degree. C.; [.alpha.].sub.D=-15 (c=1;
CH.sub.3OH).
[0225] .sup.1H-NMR (D.sub.2O): .delta. 7.2 (d, 2H, J=8 Hz); 7.1 (d,
2H, J=8 Hz); 6.8 (bs, 1H, CONH); 3.6 (q, 1H, J=7 Hz); 3.55 (m, 2H);
3.40 (s, 4H); 2.90 (m, 2H); 2.35 (d, 2H, J=7 Hz); 2.0-1.8 (m, 3H);
1.55 (d, 3H, J=7 Hz); 1.0 (d, 6H, J=7 Hz).
[0226] The use of 2-methylthio-tetrahydropyrimidine in the above
procedure yields:
(R)2-(4-isobutylphenyl)-N-[3-(tetrahydropyrimidin-2-yl)aminopropyl]propio-
namide.
[0227] .sup.1H-NMR (D.sub.2O): .delta. 7.2 (d, 2H, J=8 Hz); 7.1 (d,
2H, J=8 Hz); 6.8 (bs, 1H, CONH); 3.6 (q, 1H, J=7 Hz); 3.55 (m, 2H);
3.40 (s, 4H); 2.90 (m, 2H); 2.35 (d, 2H, J=7 Hz); 2.0-1.8 (m, 5H);
1.55 (d, 3H, J=7 Hz); 1.0 (d, 6H, J=7 Hz).
EXAMPLE 15
(R),(S')2-(4-isobutylphenyl)-N-[(1-carboxy-4-amino)butyl]propionamide
[0228] A solution of (R)2-(4-isobutylphenyl)propionyl chloride
(0.54 g; 2.42 mmol) in CH.sub.2Cl.sub.2 (10 mL) is slowly added
dropwise to a suspension of 5-BOC-ornithine methyl ester
hydrochloride (0.69 g; 2.42 mmol) and triethylamine (0.68 mL; 4.84
mmol) in CH.sub.2Cl.sub.2 at 25.degree. C. The mixture is kept
under stirring overnight at r. t., then diluted with water (10 mL).
The organic phase is separated and washed with a saturated solution
of NaHCO.sub.3 (10 mL), dried over Na.sub.2SO.sub.4, and evaporated
to obtain a crude product, which is purified by flash
chromatography (eluent CHCl.sub.3/CH.sub.3OH 9:1) to yield
(R),(S)2-(4-isobutylphenyl)propionyl-(5-BOC)ornithine methyl ester
as a transparent oil (0.6 g; 1.4 mmol). Treatment of said compound
with HCl 3N (8 mL) for 18 h at r. t. followed by solvent
evaporation yields
(R),(S')2-(4-isobutylphenyl)-N-[(1-methoxycarbonyl-4-amino)butyl]propiona-
mide hydrochloride (0.41 g, 1.25 mmol).
[0229] To a solution of said hydrochloride in dioxane 4N NaOH
(0.625 mL; 2.5 mmol) is added at r. t. the mixture is stirred
overnight and evaporated to dryness at low pressure. The residue is
taken up with EtOAc (15 mL); the organic phase is washed with a
saturated NaCl solution (2.times.15 mL) and dried over
Na.sub.2SO.sub.4. AcOEt evaporation yields
(R),(S')2-(4-isobutylphenyl)-N-[(1-carboxy-4-amino)butyl]propionamide
as a white solid,
[0230] m.p. above 240.degree. C.;
[0231] [.alpha.].sub.D=-29 (c=0.5; CH.sub.3OH).
[0232] .sup.1H-NMR (DMSO-d.sub.6): .delta. 7.3 (d, 2H); .delta. 7.1
(d, 2H); 6.25 (bs, 1H, CONH); 4.20 (m, 1H); 3.70 (m, 1H); 3.50 (m,
2H); 2.5 (d, 2H); 1.9 (m, 1H); 1.8 (m, 4H); 1.6 (d, 3H); 0.95 (d,
6H, J=7 Hz).
(R),(S')2-(4'-isobutylphenyl)-N-(1-carboxy-5-aminopentyl)propionamide
hydro-chloride
[0233] Prepared using the corresponding (L)-lysine derivative
instead of the ornithine derivative.
[0234] [.alpha.].sub.D=-28.3 (c=1; CH.sub.3OH)
[0235] .sup.1H-NMR (DMSO-d.sub.6): .delta. 12.62 (bs, 1H, COOH);
8.25 (d, 1H, CONH, J=8 Hz); 7.75 (bs, 3H, NH.sub.3.sup.+); 7.25 (d,
2H, J=8 Hz); 7.06 (d, 2H, J=8 Hz); 4.15 (m, 1H); 3.70 (m, 1H); 2.63
(m, 2H); 2.38 (d, 2H, J=7 Hz); 1.92-2.78 (m, 1H); 1.70-1.38 (m,
4H); 1.35 (d, 3H, J=7 Hz); 1.20 (m, 2H); 0.92 (d, 6H, J=7 Hz).
EXAMPLE 16
(R)2-(4-isobutylphenyl)-N--[(N'-methyl,N'2-hydroxyethyl)-aminoethoxy]pro-
pionamide
[0236] A solution of (R)2-(4-isobutylphenyl)propionyl chloride
(0.42 g; 1.875 mmol) in CH.sub.2Cl.sub.2 (10 mL) is slowly added
dropwise to a solution of 0.85 g (3.75 mmol) of
2-(amineoxy)-N-methyl-N-(2-hydroxyethyl)ethylamine in
CH.sub.2Cl.sub.2 (10 mL) at 25.degree. C. The mixture is kept under
stirring at room temperature for 3 h, and then diluted with
H.sub.2O (10 mL). The two phases are then shaken and the organic
phase is separated, washed with water (5 mL), dried over
Na.sub.2SO.sub.4 and evaporated to yield 0.59 g (1.43 mmol). of
(R)2-(4-isobutylphenyl)-N-2-[(N'-methyl,N'2-hydroxyethyl)-aminoethoxy]pro-
pionamide as an oil.
[0237] [.alpha.].sub.D=-35 (c=1; CH.sub.3OH).
[0238] .sup.1H-NMR (CDCl.sub.3): .delta. 7.25 (m, 4H); 6.15 (bs,
1H, CONH); 4.67 (t, 2H, J=7 Hz; 3.40 (m, 2H); 2.75 (t, 2H, J=7 Hz);
2.55 (d, 2H, J=7 Hz); 2.35 (bs, 1H, OH); 2.42 (t, 2H, J=7 Hz); 2.21
(s, 3H); 1.95 (m, 1H); 1.53 (d, 3H, J=7 Hz); 1.00 (d, 6H, J=7
Hz).
EXAMPLE 17
R-2-[(4-isobutyl)phenyl]-N-[4-(dimethylamino)-2-butinyl]propionamide
[0239] R(-)-ibuprofen (0.34 g; 1.65 mmol) is dissolved in dry
CH.sub.2Cl.sub.2; DCC (0.37 g; 1.8 mmol) and HOBZ (0.24 g; 1.78
mmol) are added and the solution is left at r. t under stirring.
for 3 hrs. N,N-dimethylbutin-2-yl-1,4-diamine (0.2 g; 1.78 mmol)
dissolved in dry CH.sub.2Cl.sub.2 (2 mL) is added to the solution
and the resulting mixture is stirred overnight. After 18 hrs, DCU
is filtered off and the filtrate is diluted with CH.sub.2Cl.sub.2,
washed with sat. sol. NaHCO.sub.3 (2.times.10 mL), water
(2.times.10 mL) and brine, dried over Na.sub.2SO.sub.4 and
evaporated under vacuum to give a red oily crude residue. The
following purification by flash chromatography gives
R(-)-2-[(4'-isobutyl)phenyl]-N-[4-(dimethylamino)-2-butinyl]propionamide
as a yellow oil (0.347; 1.155 mmol).
[0240] [.alpha.].sub.D=+4.4 (c=0.5; CH.sub.3OH)
[0241] .sup.1H-NMR (CDCl.sub.3): .delta. 7.15-7.10 (m, 2H);
7.09-7.05 (m, 2H); 5.45 (bs, 1H, CONH); 4.05 (m, 2H); 3.55 (m, 1H);
3.15 (s, 2H); 2.47 (d, 2H, J=7 Hz); 2.22 (s, 6H); 1.85 (m, 1H);
1.48 (d, 3H, J=7 Hz); 0.91 (d, 6H, J=7 Hz).
EXAMPLE 18
R-Z-2-[(4-isobutyl)phenyl]-N-[4-(dimethylamino)-2-butenyl]propionamide
[0242]
R-2-[(4'-isobutyl)phenyl]-N-[4-dimethylamino-2-butinyl]propionamid-
e of example 17 (0.08 g; 0.27 mmol) is dissolved in abs. EtOH (5
mL) and 5% Palladium on calcium carbonate (Lindlar catalyst; 0.08
g) is added. The mixture is hydrogenated under atmospheric pressure
at r. t. for 2 hrs, then is filtered over a Celite pad. The filter
cake is deeply washed with EtOH, the filtrate is evaporated under
vacuum to give pure
R-Z-2-[(4-isobutyl)phenyl]-N-[4-(dimethylamino)-2-butenyl]propionamide
as pale yellow oil (0.07 g; 0.23 mmol)
[0243] [.alpha.].sub.D=-26.5 (c=1.1; CH.sub.3OH)
[0244] .sup.1H-NMR (CDCl.sub.3): .delta. 7.20-7.12 (d, 2H, J=8 Hz);
7.10-7.05 (d, 2H, J=8 Hz); 5.95 (bs, 1H, CONH); 5.67-5.55 (m, 2H);
3.93-3.85 (m, 2H); 5.02 (m, 1H); 3.05 (d, 2H J=8 Hz); 2.47 (d, 2H,
J=7 Hz); 2.25 (s, 6H); 1.93 (m, 1H); 1.55 (d, 3H, J=7 Hz); 0.95 (d,
6H, J=7 Hz).
EXAMPLE 19
R-2-[(4-isobutyl)phenyl]-N-[4-(dimethylaminomethyl)phenyl]propionamide
[0245] R(-)Ibuprofen (0.31 g; 1.5 mmol) is dissolved in thionyl
chloride (5 mL) and the solution is refluxed for 90'. The complete
disappearance of starting carboxylic acid is monitored by IR; after
cooling at room temperature and solvent stripping by 1.4-dioxane
additions, the oily residue is diluted with dry DMF (5 mL) and
added dropwise to a stirred solution of
4-(N,N-dimethylaminomethyl)aniline (0.27 g; 1.8 mmol) in dry DMF (3
mL) at room temperature. The solution is left under stirring
overnight; the solvent evaporated under vacuum and the residue
purified by flash chromatography to give
R2-[(4-isobutyl)phenyl]-N-[4-(dimethylaminomethyl)phenyl]propionamide
as a pale yellow oil (0.406 g; 1.2 mmol).
[0246] [.alpha.].sub.D=-98 (c=1; CH.sub.3OH)
[0247] .sup.1H-NMR (CDCl.sub.3): .delta. 7.40-7.18 (m, 9H); 3.75
(m, 1H); 3.47 (s, 2H); 2.50 (d, 2H, J=7 Hz); 2.17 (s, 6H); 1.95 (m,
1H); 1.56 (d, 3H, J=7 Hz); 0.94 (d, 6H, J=7 Hz). Following the same
procedure
R-2-[(4-isobutyl)phenyl]-N-[4-(dimethylamino)phenyl]propionamide
has been prepared.
[0248] [.alpha.].sub.D=-131 (c=0.25; CH.sub.3OH)
[0249] .sup.1H-NMR (CDCl.sub.3): .delta. 7.28-7.25 (m, 4H);
7.22-7.15 (m, 2H); 6.83-6.79 (bs, 1H, CONH); 6.73-6.65 (m, 2H);
3.72 (m, 1H); 2.80 (s, 6H); 2.48 (d, 2H, J=7 Hz); 1.85 (m, 1H);
1.52 (d, 3H, J=7 Hz); 0.97 (d, 6H, J=7 Hz). TABLE-US-00001 TABLE I
% Inhibition % Inhibition of C5a of induced IL-8 induced (1 ng/mL)
(10 ng/mL) PMNs PMNs Chemo- Example Structure Chemotaxis taxis
(R),(S')-2-(4'-isobutylphenyl)-N-(1-carboxy-5-
aminopentyl)propionamide hydrochloride ##STR20## 10.sup.-8 M 5 .+-.
8 10.sup.-5 M 49 .+-. 3
(S'),(R)-2-(4-isobutylphenyl)-N-[1-carboxy-4-(1-
piperidinyl)butyl]propionamide sodium salt ##STR21## 56 .+-. 9 33
.+-. 15 (R)-2-(4-isobutylphenyl)-N-(2-dimethylamino- ethyl)
propionamide hydrochloride ##STR22## 56 .+-. 13 62 .+-. 12
(R)-2-(4-isobutylphenyl)-N-(3-dimethylamino- propyl) propionamide
hydrochloride ##STR23## 51 .+-. 15 65 .+-. 14
(R)-2-(4-isobutylphenyl)-N-(3-aminopropyl) propionamide
hydrochloride ##STR24## 2 .+-. 7 84 .+-. 8
(R)-2-(4-isobutylphenyl)-N-(4-dimethylamino- butyl) propionamide
hydrochloride ##STR25## 34 .+-. 6 55 .+-. 8
(R)-2-(4-isobutylphenyl)-N-(1-methyl-piperidin- 4-yl)propionamide
hydrochloride ##STR26## 4 .+-. 9 48 .+-. 8
(R)-2-(4-isobutylphenyl)-N-(exo-8-methyl-8-aza-
bicyclo[3.2.1]oct-3-yl)propionamide hydrochloride ##STR27## 3 .+-.
8 57 .+-. 6 (R)-2-(4-isobutylphenyl)-N-3-(N-morpholinyl
propyl)propionamide hydrochloride ##STR28## 55 .+-. 12 24 .+-. 11
(R)-2-(4-isobutylphenyl)-N-3-(1-piperidinylpropyl) propionamide
hydrochloride ##STR29## 46 .+-. 8 76 .+-. 6
(R)-2-(4-isobutyl)phenyl-N-[2-(dimethylaminoethyl)
aminocarbonylmethyl]propionamide hydrochloride ##STR30## 31 .+-. 6
68 .+-. 4 (R)-2-(3-isopropylphenyl)-N-3- (dimethylaminopropyl)
propionamide ##STR31## 48 .+-. 2 (c = 10.sup.-6 M) 42 .+-. 18
(R)-2-(3-isopropylphenyl)-N-3- (dimethylaminopropyl) propionamide
##STR32## 5 .+-. 6 42 .+-. 18
(R)-2-(3-benzoylphenyl)-N-3-(dimethylamino propyl) propionamide
##STR33## 53 .+-. 8 56 .+-. 2
(R)-2-[2-(2,6-dichlorophenylamino)phenyl]-N-3-
(dimethylaminopropyl)propionamide ##STR34## 58 .+-. 5 (c =
10.sup.-6 M) 41 .+-. 2
(R)-2-[2-(2,6-dichlorophenylamino)-phenyl]-N-3-
(dimethylaminopropyl)propionamide ##STR35## 1 .+-. 13 41 .+-. 2
* * * * *