U.S. patent application number 10/601356 was filed with the patent office on 2004-05-20 for novel heterocyclically substituted amides, their preparation and use.
Invention is credited to Knopp, Monika, Lubisch, Wilfried, Moller, Achim, Treiber, Hans-Jorg.
Application Number | 20040097508 10/601356 |
Document ID | / |
Family ID | 7865111 |
Filed Date | 2004-05-20 |
United States Patent
Application |
20040097508 |
Kind Code |
A1 |
Lubisch, Wilfried ; et
al. |
May 20, 2004 |
Novel heterocyclically substituted amides, their preparation and
use
Abstract
Amides of the general formula I 1 and their tautomeric and
isomeric forms, possible enantiomeric and diastereomeric forms, as
well as possible physiologically tolerable salts, in which the
variables have the meanings stated in the description, their
preparation and use as calpain inhibitors.
Inventors: |
Lubisch, Wilfried;
(Heidelberg, DE) ; Moller, Achim; (Grunstadt,
DE) ; Treiber, Hans-Jorg; (Bruhl, DE) ; Knopp,
Monika; (Ledwigshafen, DE) |
Correspondence
Address: |
WOOD, PHILLIPS, KATZ, CLARK & MORTIMER
500 W. MADISON STREET
SUITE 3800
CHICAGO
IL
60661
US
|
Family ID: |
7865111 |
Appl. No.: |
10/601356 |
Filed: |
June 23, 2003 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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10601356 |
Jun 23, 2003 |
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09673087 |
Oct 11, 2000 |
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6630493 |
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Current U.S.
Class: |
514/247 ;
514/249; 514/252.1; 514/256; 514/266.1; 514/310; 514/311; 514/357;
514/365; 514/400; 514/406; 514/419; 514/442; 514/469; 514/471;
514/563; 544/224; 544/283; 544/334; 544/336; 544/353; 546/176;
546/336; 548/203; 548/338.1; 548/375.1; 562/450 |
Current CPC
Class: |
C07D 401/04 20130101;
A61P 9/10 20180101; A61P 9/08 20180101; C07D 239/30 20130101; C07D
213/82 20130101; A61P 25/08 20180101; A61P 43/00 20180101; C07D
239/28 20130101; A61P 25/00 20180101; C07D 277/56 20130101; A61P
25/28 20180101; C07D 233/90 20130101; A61P 27/12 20180101; A61P
9/04 20180101; A61P 13/12 20180101; A61P 21/00 20180101 |
Class at
Publication: |
514/247 ;
514/252.1; 514/256; 514/266.1; 514/249; 514/357; 514/365; 514/310;
514/311; 514/400; 514/406; 514/419; 514/471; 514/442; 514/469;
514/563; 544/224; 544/334; 544/283; 544/336; 544/353; 546/176;
546/336; 548/203; 548/338.1; 548/375.1; 562/450 |
International
Class: |
A61K 031/50; A61K
031/495; A61K 031/505; A61K 031/517 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 20, 1998 |
DE |
19817459.4 |
Claims
We claim:
1. An amide of the general formula I 224and its tautomeric and
isomeric forms, possible enantiomeric and diastereomeric forms, as
well as possible physiologically tolerable salts, in which the
variables have the following meanings: R.sup.1 can be phenyl,
naphthyl, quinolyl, pyridyl, pyrimidyl, pyrazyl [sic], pyridazyl,
imidazolyl, thiazole, quinazyl, isoquinolyl, quinazyl [sic],
quinoxalyl, thienyl, benzothienyl, benzofuranyl, furanyl, and
indolyl, where the rings can be additionally substituted by up to 3
radicals R.sup.5, R.sup.2 is chlorine, bromine, fluorine,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkenyl,
C.sub.1-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkylphenyl,
C.sub.1-C.sub.6-alkenylphenyl, C.sub.1-C.sub.6-alkynylphenyl,
phenyl, NHCO--C.sub.1-C.sub.4-alkyl,
NHSO.sub.2--C.sub.1-C.sub.4-alkyl, --NHCOphenyl [sic],
--NHCO-naphthyl, NO.sub.2, --O--C.sub.1-C.sub.4-alkyl and NH.sub.2,
where the aromatic rings can additionally carry one or two radicals
R.sup.5 and two radicals R.sup.2 together can also be a chain
--CH.dbd.CH--CH.dbd.CH-- and thus form a fused benzo ring, which
for its part can be substituted by one R.sup.5 and R.sup.3 is
--C.sub.1-C.sub.6-alkyl, which is branched or unbranched, and which
can additionally carry an S--CH.sub.3 radical or a phenyl,
cyclohexyl, cycloheptyl, cyclopentyl, indolyl, pyridyl or naphthyl
ring which for its part is substituted by by [sic] at most two
radicals R.sup.5, where R.sup.5 is hydrogen, C.sub.1-C.sub.4-alkyl,
which is branched or unbranched, --O--C.sub.1-C.sub.4-alkyl, OH,
Cl, F, Br, I, CF.sub.3, NO.sub.2, NH.sub.2, CN, COOH,
COO--C.sub.1-C.sub.4-alkyl, --NHCO--C.sub.1-C.sub.4-alkyl,
--NHCO-phenyl, --NHSO.sub.2--C.sub.1-C.sub- .4-alkyl,
--NHSO.sub.2-phenyl, --SO.sub.2--C.sub.1-C.sub.4-alkyl,
--(CH.sub.2).sub.n--NR.sup.12R.sup.13 and --SO.sub.2-phenyl, X is a
bond, --(CH.sub.2).sub.m--,
--(CH.sub.2).sub.m--O--(CH.sub.2).sub.o--,
--(CH.sub.2).sub.o--S--(CH.sub.2).sub.m-- [sic],
--(CH.sub.2).sub.o--SO--- (CH.sub.2).sub.m--,
--(CH.sub.2).sub.o--SO.sub.2--(CH.sub.2).sub.m--, --CH.dbd.CH--,
--C.ident.C--, --CO--CH.dbd.CH--, --(CH.sub.2).sub.o--CO---
(CH.sub.2).sub.m--, --(CH.sub.2).sub.m--NHCO--(CH.sub.2).sub.o--,
--(CH.sub.2).sub.m--CONH--(CH.sub.2).sub.o--,
--(CH.sub.2).sub.m--NHSO.su- b.2--(CH.sub.2).sub.o--,
--NH--CO--CH.dbd.CH--, --(CH.sub.2).sub.m--SO.sub-
.2NH--(CH.sub.2).sub.o--, --CH.dbd.CH--CONH-- and 225and in the
case of CH.dbd.CH double bonds can be either the E or the Z form
and R.sup.1--X together are also 226and Y is an unsaturated
heterocyclic ring such as pyridine, pyrimidine, pyrazine, imidazole
and thiazole and R.sup.4 is hydrogen, COOR.sup.6 and CO-Z, in which
Z is NR.sup.7R.sup.8, and is 227 R.sup.6 is hydrogen,
C.sub.1-C.sub.6-alkyl, which is linear or branched, and which can
be substituted by a phenyl ring which itself can additionally be
substituted by one or two radicals R.sup.9, and R.sup.7 is
hydrogen, C.sub.1-C.sub.6-alkyl, which is branched and unbranched,
and R.sup.8 is hydrogen, C.sub.1-C.sub.6-alkyl, which is branched
or unbranched which can additionally be substituted by a phenyl
ring which can additionally carry a radical R.sup.9, and by 228and
R.sup.9 can be hydrogen, C.sub.1-C.sub.4-alkyl, which is branched
or unbranched, --O--C.sub.1-C.sub.4-alkyl, OH, Cl, F, Br, I,
CF.sub.3, NO.sub.2, NH.sub.2, CN, COOH, COO--C.sub.1-C.sub.4-alkyl,
--NHCO--C.sub.1-C.sub.4-a- lkyl, --NHCO-phenyl,
--NHSO.sub.2--C.sub.1-C.sub.4-alkyl, --NHSO.sub.2-phenyl,
--SO.sub.2--C.sub.1-C.sub.4-alkyl and --SO.sub.2-phenyl R.sup.10 is
hydrogen, C.sub.1-C.sub.6-alkyl, which is linear or branched, and
which can be substituted by a phenyl ring which itself can
additionally be substituted by one or two radicals R.sup.9, and
R.sup.11 is hydrogen, C.sub.1-C.sub.6-alkyl, which is linear or
branched, and which can be substituted by a phenyl ring which
itself can additionally be substituted by one or two radicals
R.sup.9, and n is a number 0, 1 or 2, and m,o independently of one
another is a numeral 0, 1, 2, 3 or 4.
2. An amide of the formula I as claimed in claim 1, where R.sup.3
is benzyl, CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2CH.sub.2CH.sub.- 2CH.sub.3 and Y is pyridine and
R.sup.4 is CO--NR.sup.7NR.sup.8 and R.sup.7 is hydrogen R.sup.8 is
CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2- ,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2 and R.sup.9 is hydrogen and n is 0
and 1 and all remaining variables have the same meanings as in
claim 1.
3. An amide of the formula I as claimed in claim 1, where R.sup.3
is benzyl, CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2CH.sub.2CH.sub.- 2CH.sub.3 and Y is pyridine and
R.sup.4 is hydrogen and R.sup.9 is hydrogen n is 0 and 1 and all
remaining variables have the same meanings as in claim 1.
4. An amide of the formula I as claimed in claim 1, where R.sup.3
is benzyl, CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2CH.sub.2CH.sub.- 2CH.sub.3 and Y is imidazole and
thiazole and R.sup.4 is CO--NR.sup.7NR.sup.8 and R.sup.7 is
hydrogen R.sup.8 is CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2 and R.sup.9 is hydrogen and n is 0
and 1 and all remaining variables have the same meanings as in
claim 1.
5. An amide of the formula I as claimed in claim 1, where R.sup.3
is benzyl, CH.sub.2-pyridine, CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3 and Y is imidazole and
thiazole and R.sup.4 is hydrogen and R.sup.9 is hydrogen and n is 0
and 1 and all remaining variables have the same meanings as in
claim 1.
6. The use of amides of the formula I as claimed in claim [sic] 1-5
for the treatment of diseases.
7. The use of amides of the formula I as claimed in claim [sic] 1-5
as inhibitors of cysteine proteases.
8. The use as claimed in claim 6 as inhibitors of cysteine
proteases such as calpains and cathepsins, in particular calpains I
and II and cathepsins B and L.
9. The use of amides of the formula I as claimed in claim [sic] 1-5
for the production as [sic] pharmaceuticals for the treatment of
diseases in which increased calpain activity occurs.
10. The use of amides of the formula I as claimed in claim [sic]
1-5 for the production of pharmaceuticals for the treatment of
neurodegenerative diseases and neuronal damage.
11. The use as claimed in claim 9 for the treatment of those
neurodegenerative diseases and that neuronal damage which is caused
by ischemia, trauma or mass hemorrhages.
12. The use as claimed in claim 10 for the treatment of cerebral
stroke and craniocerebral trauma.
13. The use as claimed in claim 10 for the treatment of Alzheimer's
disease and Huntington's disease.
14. The use as claimed in claim 10 for the treatment of
epilepsy.
15. The use of the compounds of the formula I as claimed in claim
[sic] 1-5 for the production of pharmaceuticals and treatment of
damage to the heart after cardiac ischemias, reperfusion damage
after vascular occlusion, damage to the kidneys after renal
ischemias, skeletal muscular damage, muscular dystrophies, damage
which results due to proliferation of the smooth muscle cells,
coronary vasospasm, cerebral vasospasm, cataracts of the eyes and
restenosis of the blood vessels after angioplasty.
16. The use of the amides of the formula I as claimed in claim
[sic] 1-5 for the production of pharmaceuticals for treating tumors
and metastasis thereof.
17. The use of the amides of the formula I as claimed in claim
[sic] 1-5 for the production of pharmaceuticals for treating
diseases in which increased interleukin-1 levels occur.
18. The use of the amides as claimed in claim [sic] 1-5 for
treating immunological diseases such as inflammations and rheumatic
disorders.
19. A pharmaceutical preparation for oral, parenteral and
intraperitoneal use, comprising per individual dose, in addition to
the customary pharmaceutical auxiliaries, at least of [sic] one
amide I as claimed in claim [sic] 1-5.
Description
[0001] The present invention relates to novel amides, which are
inhibitors of enzymes, in particular cysteine proteases, such as
calpain (=calcium-dependent cysteine proteases) and its isoenzymes,
and cathepsins, for example B and L.
[0002] Calpains are intracellular, proteolytic enzymes from the
so-called cysteine proteases group and are found in many cells.
Calpains are activated by an increased calcium concentration, a
differentiation being made between calpain I or .mu.-calpain, which
is activated by .mu.-molar concentrations of calcium ions, and
calpain II or m-calpain, which is activated by m-molar
concentrations of calcium ions (P. Johnson, Int. J. Biochem. 1990,
22(8), 811-22). Still further calpain isoenzymes are postulated
today (K. Suzuki et al., Biol. Chem. Hoppe-Seyler, 1995, 376(9),
523-9).
[0003] It is suspected that calpains play an important part in
various physiological processes. These include cleavage of
regulatory proteins such as protein kinase C, cytoskeletal proteins
such as MAP 2 and spectrin, muscle proteins, protein breakdown in
rheumatoid arthritis, proteins in the activation of platelets,
neuropeptide metabolism, proteins in mitosis and others which are
listed in M. J. Barrett et al., Life Sci. 1991, 48, 1659-69 and K.
K. Wang et al., Trends in Pharmacol. Sci., 1994, 15, 412-9.
[0004] Increased calpain levels have been measured in various
pathophysiological processes, for example: ischemias of the heart
(e.g. cardiac infarct), of the kidney or of the central nervous
system (e.g. "stroke"), inflammations, muscular dystrophy,
cataracts of the eyes, injuries to the central nervous system (e.g.
trauma), Alzheimer's disease etc. (see K. K. Wang, above). A
relationship of these diseases with increased and lasting
intracellular calcium levels is suspected. As a result,
calcium-dependent processes are overactivated and are no longer
subject to physiological regulation. Accordingly, overactivation of
calpains can also initiate pathophysiological processes.
[0005] It was therefore postulated that inhibitors of the capain
enzymes can be useful for the treatment of these diseases. Various
investigations confirm this. Thus Seung-Chyul Hong et al., Stroke
1994, 25(3), 663-9 and R. T. Bartus et al., Neurological Res. 1995,
17, 249-58 have shown a neuroprotective action of calpain
inhibitors in acute neurodegenerative disorders or ischemias, such
as occur after cerebral stroke. Likewise, after experimental brain
traumata, calpain inhibitors improved recovery from the memory
power deficits and neuromotor disorders which occurred (K. E.
Saatman et al. Proc. Natl. Acad. Sci. USA, 1996, 93,3428-3433). C.
L. Edelstein et al., Proc. Natl. Acad. Sci. USA, 1995, 92, 7662-6,
found a protective action of calpain inhibitors on kidneys damaged
by hypoxia. Yoshida, Ken Ischi et al., Jap. Circ. J. 1995, 59(1),
40-8, were able to show favorable effects of calpain inhibitors
after cardiac damage which was produced by ischemia or reperfusion.
Since calpain inhibitors inhibit the release of the .beta.-AP4
protein, potential use as a therapeutic for Alzheimer's disease was
proposed (J. Higaki et al., Neuron, 1995, 14, 651-59). The release
of interleukin-1.alpha. is also inhibited by calpain inhibitors (N.
Watanabe et al., Cytokine 1994, 6(6), 597-601). It was furthermore
found that calpain inhibitors show cytotoxic effects on tumor cells
(E. Shiba et al., 20th Meeting Int. Ass. Breast Cancer Res., Sendai
Jp, 1994, 25-28 Sept., Int. J. Oncol. 5(Suppl.), 1994, 381).
[0006] Further possible uses of calpain inhibitors are listed in K.
K. Wang, Trends in Pharmacol. Sci., 1994, 15, 412-8.
[0007] Calpain inhibitors have already been described in the
literature. These are mainly, however, either irreversible or
peptide inhibitors. As a rule, irreversible inhibitors are
alkylating substances and have the disadvantage that they react
nonselectively in the body or are unstable. Thus these inhibitors
often show undesirable side effects, such as toxicity, and are
accordingly restricted in their use or unutilizable. Among the
irreversible inhibitors can be included, for example, the epoxides
E 64 (E. B. McGowan et al., Biochem. Biophys. Res. Commun. 1989,
158, 432-5), .alpha.-haloketones (H. Angliker et al., J. Med. Chem.
1992, 35, 216-20) or disulfides (R. Matsueda et al., Chem. Lett.
1990, 191-194).
[0008] Many known reversible inhibitors of cysteine proteases, such
as calpain, are peptide aldehydes, in particular dipeptide and
tripeptide aldehydes such as, for example, Z-Val-Phe-H (MDL 28170)
(S. Mehdi, Tends [sic] in Biol. Sci. 1991, 16, 150-3). Under
physiological conditions, peptide aldehydes have the disadvantage
that they are often unstable on account of the great reactivity,
can be rapidly metabolized and are prone to nonspecific reactions
which can be the cause of toxic effects (J. A. Fehrentz and B.
Castro, Synthesis 1983, 676-78.
[0009] In JP 08183771 (CA 1996, 605307) and in EP 520336, aldehydes
which are derived from 4-piperidinoylamides and
1-carbonylpiperidino-4-ylamides have been described as calpain
inhibitors. In WO 97/21690, aldehydes derived from
N-sulfonylprolinamide were prepared. WO 96/06211 describes an
aldehyde derivative analogous to the general structure I, but where
Y is a xanthine derivative which does not carry any further
radicals such as R.sup.1--X. However, the aldehydes claimed here,
which are derived from heteroaromatically substituted amides of the
general structure I, have never previously been described.
[0010] Peptide ketone derivatives are also inhibitors of cysteine
proteases, in particular calpains. Thus, for example, in the case
of serine proteases ketone derivatives are known as inhibitors, the
keto group being activated by an electron-withdrawing group such as
CF.sub.3. In the case of cysteine proteases, derivatives with
ketones activated by CF.sub.3 or similar groups are not very active
or inactive (M. R. Angelastro et al., J. Med. Chem. 1990, 33,
11-13). Surprisingly, in the case of calpain hitherto only ketone
derivatives, in which, on the one hand, leaving groups in the
.alpha.-position cause an irreversible inhibition and, on the other
hand, a carboxylic acid derivative activates the keto group, were
found to be effective inhibitors (see M. R. Angelastro et al., see
above; WO 92/11850; WO 92,12140; WO 94/00095 and WO 95/00535).
However, of these ketoamides and ketoesters, hitherto only peptide
derivatives have been described as effective (Zhaozhao Li et al.,
J. Med. Chem. 1993, 36, 3472-80; S. L. Harbenson et al., J. Med.
Chem. 1994, 37, 2918-29 and see above M. R. Angelastro et al.).
[0011] Ketobenzamides are already known in the literature. Thus the
keto ester PhCO-Abu-COOCH.sub.2CH.sub.3 was described in WO
91/09801, WO 94/00095 and WO 92/11850. The analogous phenyl
derivative Ph-CONH--CH(CH.sub.2Ph)-CO--COCOOCH.sub.3 was found in
M. R. Angelastro et al., J. Med. Chem. 1990, 33, 11-13 to be,
however, only a weak calpain inhibitor. This derivative is also
described in J. P. Burkhardt, Tetrahedron Lett., 1988, 3433-36. The
significance of the substituted benzamides, however, has never been
investigated until now.
[0012] In the present invention, substituted nonpeptide aldehydes,
ketocarboxylic acid esters and ketoamide derivatives were [sic]
described. These compounds are new and surprisingly show the
possibility of obtaining potent nonpeptide inhibitors of cysteine
proteases, such as, for example, calpain, by incorporation of rigid
structural fragments.
[0013] The present invention relates to heterocyclically
substituted amides of the general formula I 2
[0014] and their tautomeric and isomeric forms, possible
enantiomeric and diastereomeric forms, as well as possible
physiologically tolerable salts, in which the variables have the
following meanings:
[0015] R.sup.1 can be phenyl, naphthyl, quinolyl, pyridyl,
pyrimidyl, pyrazyl [sic], pyridazyl, imidazolyl, thiazole,
quinazyl, isoquinolyl, quinazyl [sic], quinoxalyl, thienyl,
benzothienyl, benzofuranyl, furanyl, and indolyl, where the rings
can be additionally substituted by up to 3 radicals R.sup.5,
[0016] R.sup.2 is chlorine, bromine, fluorine,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkenyl,
C.sub.1-C.sub.6-alkynyl, C.sub.1-C.sub.6-alkylph- enyl,
C.sub.1-C.sub.6-alkenylphenyl, C.sub.1-C.sub.6-alkynylphenyl,
phenyl, NHCO--C.sub.1-C.sub.4-alkyl,
NHSO.sub.2--C.sub.1-C.sub.4-alkyl, --NHCOphenyl [sic],
--NHCO-naphthyl, NO.sub.2, --O--C.sub.1-C.sub.4-alkyl and NH.sub.2,
where the aromatic rings can additionally carry one or two radicals
R.sup.5 and two radicals R.sup.2 together can also be a chain
--CH.dbd.CH--CH.dbd.CH-- and thus form a fused benzo ring, which
for its part can be substituted by one R.sup.5 and
[0017] R.sup.3 is --C.sub.1-C.sub.6-alkyl, which is branched or
unbranched, and which can additionally carry an S--CH.sub.3 radical
or a phenyl, cyclohexyl, cycloheptyl, cyclopentyl, indolyl, pyridyl
or naphthyl ring which for its part can be substituted by by [sic]
at most two radicals R.sup.5, where R.sup.5 is hydrogen,
C.sub.1-C.sub.4-alkyl, which is branched or unbranched,
--O--C.sub.1-C.sub.4-alkyl, OH, Cl, F, Br, I, CF.sub.3, NO.sub.2,
NH.sub.2, CN, COOH, COO--C.sub.1-C.sub.4-alkyl- ,
--NHCO--C.sub.1-C.sub.4-alkyl, --NHCO-phenyl,
--NHSO.sub.2-C.sub.1-C.sub- .4-alkyl, --NHSO.sub.2-phenyl,
--SO.sub.2--C.sub.1-C.sub.4-alkyl,
--(CH.sub.2).sub.n--NR.sup.12R.sup.13 and --SO.sub.2-phenyl;
[0018] X is a bond, --(CH.sub.2).sub.m--,
--(CH.sub.2).sub.m--O--(CH.sub.2- ).sub.o--,
(CH.sub.2).sub.o--S--(CH2).sub.m- [sic],
--(CH.sub.2).sub.o--SO--(CH.sub.2).sub.m--,
--(CH.sub.2).sub.o--SO.sub.2-- -(CH.sub.2).sub.m--, --CH.dbd.CH--,
--C.ident.C--, --CO--CH.dbd.CH--,
--(CH.sub.2).sub.o--CO--(CH.sub.2).sub.m--,
--(CH.sub.2).sub.m--NHCO--(CH- .sub.2).sub.o--,
--(CH.sub.2).sub.m--CONH--(CH.sub.2).sub.o--,
--(CH.sub.2).sub.m--NHSO.sub.2--(CH.sub.2).sub.o--,
--NH--CO--CH.dbd.CH--,
--(CH.sub.2).sub.m--SO.sub.2NH--(CH.sub.2).sub.o--- ,
--CH.dbd.CH--CONH-- and 3
[0019] and in the case of CH.dbd.CH double bonds can be either the
E or the Z form and
[0020] R.sup.1--X together are also 4
[0021] Y is an unsaturated heterocyclic ring such as pyridine,
pyrimidine, pyrazine, imidazole and thiazole and
[0022] R.sup.4 is hydrogen, COOR.sup.6 and CO-Z, in which Z is
NR.sup.7R.sup.8, and is 5
[0023] R.sup.6 is hydrogen, C.sub.1-C.sub.6-alkyl, which is linear
or branched, and which can be substituted by a phenyl ring which
itself can additionally be substituted by one or two radicals
R.sup.9, and
[0024] R.sup.7 is hydrogen, C.sub.1-C.sub.6-alkyl, which is
branched and unbranched, and
[0025] R.sup.8 is hydrogen, C.sub.1-C.sub.6-alkyl, which is
branched or unbranched, which can additionally be substituted by a
phenyl ring which can additionally carry a radical R.sup.9, and by
6
[0026] and
[0027] R.sup.9 can be hydrogen, C.sub.1-C.sub.4-alkyl, which is
branched or unbranched, --O--C.sub.1-C.sub.4-alkyl, OH, Cl, F, Br,
I, CF.sub.3, NO.sub.2, NH.sub.2, CN, COOH,
COO--C.sub.1-C.sub.4-alkyl, --NHCO--C.sub.1-C.sub.4-alkyl,
--NHCO-phenyl, --NHSO.sub.2--C.sub.1-C.sub- .4-alkyl,
--NHSO.sub.2-phenyl, --SO.sub.2--C.sub.1-C.sub.4-alkyl and
--SO.sub.2-phenyl
[0028] R.sup.10 is hydrogen, C.sub.1-C.sub.6-alkyl, which is linear
or branched, and which can be substituted by a phenyl ring which
itself can additionally be substituted by one or two radicals
R.sup.9, and
[0029] R.sup.11 is hydrogen, C.sub.1-C.sub.6-alkyl, which is linear
or branched, and which can be substituted by a phenyl ring which
itself can additionally be substituted by one or two radicals
R.sup.9, and
[0030] n is a number 0, 1 or 2, and
[0031] m,o independently of one another is a numeral 0, 1, 2, 3 or
4.
[0032] The compounds of the formula I can be employed as racemates,
as enantiomerically pure compounds or as diastereomers. If
enantiomerically pure compounds are desired, these can be obtained,
for example, by carrying out a classical racemate resolution with
the compounds of the formula I or their intermediates using a
suitable optically active base or acid. On the other hand, the
enantiomeric compounds can also be prepared by use of commercially
obtainable compounds, for example optically active amino acids such
as phenylalanine, tryptophan and tyrosine.
[0033] The present invention also relates to compounds which are
mesomeric or tautomeric with compounds of the formula I, for
example those in which the aldehyde or keto group of the formula I
is present as an enol tautomer.
[0034] The present invention further relates to the physiologically
tolerable salts of the compounds I, which can be obtained by
reaction of compounds I with a suitable acid or base. Suitable
acids and bases are listed, for example, in Fortschritte der
Arzneimittelforschung, 1996, Birkhauser Verlag, Vol. 10, pp.
224-285. These include, for example, hydrochloric acid, citric
acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic
acid, acetic acid, formic acid, maleic acid, fumaric acid, malic
acid, succinic acid, malonic acid, sulfuric acid etc. or sodium
hydroxide, lithium hydroxide, potassium hydroxide,
.alpha.,.alpha.,.alpha.-tris(hydroxymethyl)methylamine,
triethylamine etc.
[0035] The amides I according to the invention can be prepared in
various ways, which have been outlined in the synthesis scheme.
7
[0036] Heterocyclic carboxylic acids II are linked to suitable
aminoalcohols III to give the corresponding amides IV. Use is made
here of customary peptide coupling methods, which are mentioned
either in C. R. Larock, Comprehensive Organic Transformations, VCH
Publisher, 1989, page 972f. or in Houben-Weyl, Methoden der
organischen Chemie [Methods of Organic Chemistry], 4th Edition, E5,
Chap. V. The reaction is preferably carried out using "activated"
acid derivatives of II, the acid group COOH being converted into a
group COL. L is a leaving group such as, for example, Cl, imidazole
and N-hydroxybenzotriazole. This activated acid is then converted
to the amides IV using amines. The reaction is carried out in
anhydrous, inert solvents such as methylene chloride,
tetrahydrofuran and dimethylformamide at temperatures from -20 to
+25.degree. C.
[0037] These alcohol derivatives IV can be oxidized to the aldehyde
derivatives I according to the invention. It is possible to use
various customary oxidation reactions for this (see C. R. Larock,
Comrenhensive [sic] Organic Transformations, VCH Publisher, 1989,
page 604 f.) such as, for example, Swern and Swern-analogous
oxidations (T. T. Tidwell, Synthesis 1990, 857-70), sodium
hypochloride [sic)/TEMPO (S. L. Harbenson et al., see above) or
Dess-Martin (J. Org. Chem. 1983, 48, 4155). Preferably, here the
reaction is carried out in inert aprotic solvents such as
dimethylformamide, tetrahydrofuran or methylene chloride using
oxidants such as DMSO/py.times.SO.sub.3 or DMSO/oxalyl chloride at
temperatures from -50 to +25.degree. C., depending on the method
(see above references).
[0038] Alternatively, the carboxylic acid II can be reacted with
aminohydroxamic acid derivatives VI to give benzamides VII. In this
case, use is made of the same reaction procedure as in the
preparation of IV. The hydroxamic [lacuna] derivatives VI are
obtainable from the protected amino acids V by reaction with a
hydroxylamine. In this process, use is also made here of an amide
preparation process which has already been described. The removal
of the protective group X, for example Boc, is carried out in the
customary manner, for example using trifluoroacetic acid. The
amidohydroxamic acids VII thus obtained can be converted into the
aldehydes I according to the invention by reduction. In this
process, use is made, for example, of lithium aluminum hydride as a
reductant at temperatures from -60 to 0.degree. C. in inert
solvents such as tetrahydrofuran or ether.
[0039] Analogously to the last process, carboxylic acids or acid
derivatives, such as esters IX (Y=COOR', COSR') can also be
prepared, which can likewise be converted into the aldehydes I
according to the invention by reduction. These processes are listed
in R. C. Larock, Comprehensive Organic Transformations, VCH
Publisher, 1989, page 619-26.
[0040] The preparation of the heterocyclically substituted amides I
according to the invention, [lacuna] carry a ketoamide or ketoester
group, can be carried out in various ways, which have been outlined
in synthesis schemes 2 and 3.
[0041] If appropriate, the carboxylic acid esters IIa are converted
into the acids II using acids or bases such as lithium hydroxide,
sodium hydroxide or potassium hydroxide in aqueous medium or in
mixtures of water and organic solvents such as alcohols or
tetrahydrofuran at room temperature or elevated temperatures, such
as 25-100.degree. C.
[0042] These acids II are linked to an .alpha.-amino acid
derivative, customary conditions being used, which are listed, for
example, in Houben-Weyl, Methoden der organischen Chemie [Methods
of Organic Chemistry], 4th Edition, E5, Chap. V, and C. R. Larock,
Comprehensive Organic Transformations, VCH Publisher, 1989, Ch.
9.
[0043] For example, the carboxylic acids II are converted into the
"activated" acid derivatives IIb=Y--COL, where L is a leaving group
such as Cl, imidazole and N-hydroxybenzotriazole, and are then
converted into the derivative XI by addition of an amino acid
derivative H.sub.2N--CH(R.sup.3)--COOR. This reaction is carried
out in anhydrous, inert solvents such as methylene chloride,
tetrahydrofuran and dimethylformamide at temperatures from -20 to
+25.degree. C. 8
[0044] The derivatives XI, which as a rule are esters, are
converted into the ketocarboxylic acids XII analogously to the
hydrolysis described above. The ketoesters I' are prepared in a
reaction analogous to that of Dakin-West, the reaction being
carried out according to a method of Zhaozhao Li et al., J. Med.
Chem., 1993, 36, 3472-80. In this process, carboxylic acids such as
XII are reacted with oxalic acid monoester chloride at elevated
temperature (50-100.degree. C.) in solvents, such as, for example,
tetrahydrofuran and the products thus obtained are then reacted
with bases such as sodium methoxide in ethanol at temperatures of
25-80.degree. C. to give the ketoesters I' according to the
invention. The ketoesters I' can be hydrolyzed as described above,
for example to ketocarboxylic acids according to the invention.
[0045] The reaction to give ketobenzamides I' is also carried out
analogously to the method of Zhaozhao Li et al. (see above). The
keto group in I' is protected by addition of 1,2-ethanedithiol
under Lewis acid catalysis, such as, for example, boron trifluoride
etherate, in inert solvents, such as methylene chloride, at room
temperature, a dithian being obtained. These derivatives are
reacted with amines R.sup.3--H in polar solvents, such as alcohols,
at temperatures of 0-80.degree. C., the ketoamides I (R.sup.4=Z or
NR.sup.7R.sup.8) being obtained. 9
[0046] An alternative method is shown in scheme 2. The
ketocarboxylic acids II are reacted with aminohydroxycarboxylic
acid derivatives XIII (for preparation of XIII see S. L. Harbenson
et al., J. Med. Chem. 1994, 37, 2918-29 or J. P. Burkhardt et al.
Tetrahedron Lett. 1988, 29, 3433-3436) under customary peptide
coupling methods (see above, Houben-Weyl), amides XIV being
obtained. These alcohol derivatives XIV can be oxidized to the
ketocarboxylic acid derivatives I according to the invention. Use
can be made for this of various customary oxidation reactions (see
C. R. Larock, Comprehensive Organic Transformations, VCH Publisher,
1989, page 604 f.) such as, for example, Swern and Swern-analogous
oxidations, preferably dimethyl sulfoxide/pyridine-sulfur trioxide
complex in solvents such as methylene chloride or tetrahydrofuran,
if appropriate with addition of dimethyl sulfoxide, at room
temperature or temperatures of -50 to 25.degree. C. (T. T. Tidwell,
Synthesis 1990, 857-70) or sodium hypochloride [sic]/TEMPO (S. L.
Harbenson et al., see above).
[0047] If XIV are .alpha.-hydroxy esters (X.dbd.O-alkyl), these can
be hydrolyzed to carboxylic acids XV, the reaction being carried
out analogously to the above methods, but preferably using lithium
hydroxide in water/tetrahydrofuran mixtures at room temperature.
The preparation of other esters or amides XVI is carried out by
reaction with alcohols or amines under coupling conditions which
have already been described. The alcohol derivative XVI can be
oxidized again to give ketocarboxylic acid derivatives I according
to the invention.
[0048] The preparation of the carboxylic acid esters II have [sic]
already been described in some cases or are [sic] carried out
according to customary chemical methods.
[0049] Compounds in which X is a bond are prepared by customary
aromatic coupling, for example the Suzuki coupling with boric acid
derivatives and halides with palladium catalysis or
copper-catalyzed coupling of aromatic halides. The alkyl-bridged
radicals (X.dbd.--(CH.sub.2).sub.m--) can be prepared by reduction
of the analogous ketones or by alkylation of the organolithium,
e.g. ortho-phenyloxazolidines, or other organometal compounds (cf.
I. M. Dordor et al., J. Chem. Soc. Perkin Trans. I, 1984,
1247-52).
[0050] Ether-bridged derivatives are prepared by alkylation of the
corresponding alcohols or phenols with halides.
[0051] The sulfoxides and sulfones are accessible by oxidation of
the corresponding thioethers.
[0052] Alkene- and alkyne-bridged compounds are prepared, for
example, by Heck reaction from aromatic halides and appropriate
alkenes and alkynes (cf. I. Sakamoto et al., Chem. Pharm. Bull.,
1986, 34, 2754-59).
[0053] The chalcones are formed by condensation of acetophenones
with aldehydes and can optionally be converted into the analogous
alkyl derivatives by hydrogenation.
[0054] Amides and sulfonamides are prepared from the amines and
acid derivatives analogously to the methods described above.
[0055] The heterocyclically substituted amides I contained in the
present invention are inhibitors of cysteine proteases, in
particular cysteine proteases such as the calpains I and II and
cathepsins B and L.
[0056] The inhibitory action of the heterocyclically substituted
amides I was determined using enzyme tests customary in the
literature, a concentration of the inhibitor at which 50% of the
enzyme activity is inhibited (.dbd.IC.sub.50) being determined as a
scale of action. The amides I were measured in this manner for
inhibitory action of calpain I, calpain II and cathepsin B.
Cathepsin B Test
[0057] The cathepsin B inhibition was determined analogously to a
method by S. Hasnain et al., J. Biol. Chem. 1993, 268, 235-40.
[0058] 2 .mu.L of an inhibitor solution, prepared from inhibitor
and DMSO (final concentrations: 100 .mu.M to 0.01 .mu.M), are
[lacuna] to 88 .mu.L of cathepsin B (cathepsin B from human liver
(Calbiochem), diluted to 5 units in 500 .mu.M buffer). This mixture
is preincubated at room temperature (25.degree. C.) for 60 minutes
and the reaction is then started by addition of 10 .mu.L of 10 mM
Z-Arg-Arg-pNA (in buffer with 10% DMSO). The reaction is monitored
at 405 nM in a microtiter plate reader for 30 minutes. The
IC.sub.50s are then determined from the maximum gradients.
Calpain I and II Test
[0059] The testing of the inhibitory properties of calpain
inhibitors is carried out in buffer using 50 mM tris HCl, pH 7.5;
0.1 M NaCl; 1 mM dithiotreithol [sic]; 0.11 mM CaCl.sub.2, the
fluorogenic calpain substrate Suc-Leu-Tyr-AMC (25 mM dissolved in
DMSO, Bachem/Switzerland) being used. Human .mu.-calpain is
isolated from erythrocytes and, after several chromatographic steps
(DEAE-Sepharose, phenyl-Sepharose, Superdex 200 and Blue
Sepharose), enzyme having a purity of >95%, assessed according
to SDS-PAGE, Western blot analysis and N-terminal sequencing, is
obtained. The fluorescence of the cleavage product
7-amino-4-methylcoumarin (AMC) is monitored in a Spex-Fluorolog
fluorimeter at .lambda.ex=380 nm and .lambda.em=460 nm. In a
measuring range of 60 min, the cleavage of the substrate is linear
and the autocatalytic activity of calpain is low if the experiments
are carried out at temperatures of 12.degree. C. The inhibitors and
the calpain substrate are added to the experimental batch as DMSO
solutions, where DMSO should not exceed 2% in the final
concentration.
[0060] In an experimental batch, 10 .mu.l of substrate (250 .mu.M
final) and then 10 .mu.l of .mu.-calpain (2 .mu.g/ml final, i.e. 18
nM) are added to a 1 ml cuvette which contains buffer. The
calpain-mediated cleavage of the substrate is measured for 15-20
min. 10 .mu.l of inhibitor (50-100 .mu.M solution in DMSO) are then
added and the inhibition of the cleavage is measured for a further
40 min.
[0061] K.sub.i values are determined according to the classical
equation for reversible inhibition:
Ki=I/(v0/vi)-1;
[0062] where I=inhibitor concentration, v0=initial velocity before
addition of the inhibitor; vi=reaction velocity in equilibrium.
[0063] The velocity is calculated from v=release of AMC/time i.e.
height/time.
[0064] Calpain is an intracellular cysteine protease. Calpain
inhibitors must pass through the cell membrane in order to prevent
the breakdown of intracellular proteins by calpain. Some known
calpain inhibitors, such as, for example, E 64 and leupeptin, only
cross the cell membranes with difficulty and accordingly show,
although they are good calpain inhibitors, only a poor action in
cells. The aim is to find compounds having better membrane
accessibility. As a demonstration of the membrane accessibility of
calpain inhibitors, we use human platelets.
Calpain-Mediated Breakdown of Tyrosine Kinase pp60src in
Platelets
[0065] After the activation of platelets, the tyrosine kinase
pp60src is cleaved by calpain. This was investigated in detail by
Oda et al. in J. Biol. Chem., 1993, Vol 268, 12603-12608. It was
shown in this context that the cleavage of pp60src can be prevented
by calpeptin, an inhibitor of calpain. The cellular effectiveness
of our substances was tested following this publication. Fresh
human blood treated with citrate was centrifuged at 200 g for 15
min. The platelet-rich plasma was pooled and diluted 1:1 with
platelet buffer (platelet buffer: 68 mM NaCl, 2.7 mM KCl, 0.5 mM
MgCl.sub.2.times.6 H.sub.2O, 0.24 mM NaH.sub.2PO.sub.4.times.-
H.sub.2O, 12 mM NaHCO.sub.3, 5.6 mM glucose, 1 mM EDTA, pH 7.4).
After a centrifugation and washing step with platelet buffer, the
platelets were adjusted to 10.sup.7 cells/ml. The isolation of the
human platelets was carried out at RT.
[0066] In the test batch, isolated platelets (2 H 10.sup.6) were
preincubated at 37.degree. C. with different concentrations of
inhibitors (dissolved in DMSO) for 5 min. The platelets were then
activated with 1 .mu.M ionophore A23187 and 5 mM CaCl.sub.2. After
incubation for 5 min, the platelets were briefly centrifuged at
13000 rpm and the pellet was taken up in SDS sample buffer (SDS
sample buffer: 20 mM tris HCl, 5 mM EDTA, 5 mM EGTA, 1 mM DTT, 0.5
mM PMSF, 5 .mu.g/ml leupeptin, 10 .mu.g/ml pepstatin, 10% glycerol
and 1% SDS). The proteins were separated in a 12% strength gel and
pp60src and its 52 kDa and 47 kDa cleavage products were identified
by Western blotting. The polyclonal rabbit antibody anti-Cys-src
(pp60.sup.c-src) used was purchased from the company Biomol
Feinchemikalien (Hamburg). This primary antibody was detected using
an HRP-coupled second antibody from goats (Boehringer Mannheim,
FRG). The Western blotting was carried out according to known
methods.
[0067] The quantification of the cleavage of pp60src was carried
out by densitometry, the controls used being nonactivated platelets
(control 1: no cleavage) and platelets treated with ionophore and
calcium (control 2: corresponds to 100% cleavage). The ED.sub.50
value corresponds to the concentration of inhibitor at which the
intensity of the color reaction is reduced by 50%.
Glutamate-Induced Cell Death in Cortical Neurones
[0068] The test was carried out as in Choi D. W., Maulucci-Gedde M.
A. and Kriegstein A. R., "Glutamate neurotoxicity in cortical cell
culture". J. Neurosci. 1989, 7, 357-368.
[0069] The halves of the cortex of 15 day-old mouse embryos were
dissected and the individual cells were obtained enzymatically
(trypsin). These cells (glia and cortical neurons) are inoculated
into 24-well plates. After three days (laminin-coated plates) or
seven days (ornithine-coated plates), the mitosis treatment is
carried out using FDU (5-fluoro-2-deoxyuridines [sic]). 15 days
after the cell preparation, cell death is induced by addition of
glutamate (15 minutes). After the removal of glutamate, the calpain
inhibitors are added. 24 hours later, the cell damage is determined
by means of the determination of lactate dehydrogenase (LDH) in the
cell culture supernatant.
[0070] It is postulated that calpain also plays a part in apoptotic
cell death (M. K. T. Squier et al. J. Cell. Physiol. 1994, 159,
229-237; T. Patel et al. Faseb Journal 1996, 590, 587-597).
Therefore, in a further model, cell death was inducted with calcium
in the presence of a calcium ionophore in a human cell line.
Calpain inhibitors must pass into the cell and inhibit calpain
there in order to prevent the induced cell death.
Calcium-Mediated Cell Death in NT2 Cells
[0071] Cell death can be induced in the human cell line NT2
(precursor cells, Strategene GmbH) by means of calcium in the
presence of the ionophore A 23187. 10.sup.5 cells/well were plated
out into microtiter plates 20 hours before the experiment. After
this period, the cells were incubated with various concentrations
of inhibitors in the presence of 2.5 .mu.M ionophore and 5 mM
calcium. 0.05 ml of XTT (cell proliferation kit II, Boehringer
Mannheim) was added to the reaction batch after 5 hours. The
optical density is determined approximately 17 hours later,
according to the instructions of the manufacturer, in the Easy
Reader EAR 400 from the company SLT. The optical density at which
half of the cells have died is calculated from the two controls
with cells without inhibitors, which were incubated in the absence
and presence of ionophore.
[0072] In a number of neurological diseases or psychological
disorders, increased glutamate activity, which leads to states of
overstimulation or toxic effects in the central nervous system
(CNS), occurs. Glutamate mediates its effects by means of various
receptors. Two of these receptors are classified by the specific
agonists NMDA receptor and AMPA receptor. Substances which weaken
these glutamate-induced effects can thus be employed for the
treatment of these diseases, in particular for therapeutic
administration against neurodegenerative diseases such as
Huntington's chorea and Parkinson's disease, neurotoxic disorders
after hypoxia, anoxia, ischemia and after lesions, such as occur
after stroke and trauma, or alternatively as antiepileptics (cf.
Arzneim. Forschung 1990, 40, 511-514; TIPS, 1990, 11, 334-338;
Drugs of the Future 1989, 14, 1059-1071).
Protection Against Cerebral Overstimulation by Excitatory Amino
Acids (NMDA or AMPA Antagonism in Mice)
[0073] As a result of intracerebral administration of excitatory
amino acids (EAA), such a massive overstimulation is induced that
in a short time this leads to spasms and to the death of the
animals (mice). These symptoms can be inhibited by systemic, e.g.
intraperitoneal, administration of centrally active compounds (EAA
antagonists). Since the excessive activation of EAA receptors of
the central nervous system plays an important part in the
pathogenesis of various neurological disorders, a conclusion can be
drawn from the demonstrated EAA antagonism in vivo regarding a
possible therapeutic utility of the substances against CNS
disorders of this type. As a measure of the efficacy of the
substances, an ED.sub.50 value was determined at which 50% of the
animals become symptom-free as a result of a fixed dose of either
NMDA or AMPA as a result of the prior i.p. administration of the
standard substance.
[0074] It has already been shown that calpain inhibitors, too, have
protective activity in cell cultures against cell death caused by
EAA (H. Cauer et al., Brain Research 1993, 607, 354-356; Yu Cheg
and A. Y. Sun, Neurochem. Res. 1994, 19, 1557-1564). Surprisingly,
the calpain inhibitors included in this application are active even
against spasms elicited in vivo (mouse) by EAA (for example NMDA or
AMPA), thus pointing to a possible therapeutic use for the
abovementioned CNS disorders.
[0075] The heterocyclically substituted amides I are inhibitors of
cysteine derivatives such as calpain I or II and cathepsin B or L
and can thus be used for the control of diseases which are
associated with an increased enzyme activity of the calpain enzymes
or cathepsin enzymes. The present amides I can accordingly be used
for the treatment of neurodegenerative diseases which occur after
ischemia, trauma, subarachnoid hemorrhages and stroke, and of
neurodegenerative diseases such as multiple infarct dementia,
Alzheimer's disease, Huntington's disease and of epilepsies and
furthermore for the treatment of damage to the heart after cardiac
ischemia, reperfusion damage after vascular occlusion, damage to
the kidneys after renal ischemia, skeletal muscle damage, muscular
dystrophy, damage which occurs due to proliferation of the smooth
muscle cells, coronary vasospasms, cerebral vasospasms, cataracts
of the eyes, restenosis of the blood vessels after angioplasty.
Moreover, the amides I can be useful in the chemotherapy of tumors
and metastasis thereof and for the treatment of diseases in which
an increased interleukin-1 level occurs, such as in inflammations
and rheumatic disorders.
[0076] In addition to the customary pharmaceutical auxiliaries, the
pharmaceutical preparations according to the invention contain a
therapeutically efficacious amount of the compounds I.
[0077] For local external application, for example in powders,
ointments or sprays, the active compounds can be contained in the
customary concentrations. As a rule, the active compounds are
contained in an amount from 0.001 to 1% by weight, preferably 0.001
to 0.1% by weight.
[0078] In the case of internal administration, the preparations are
administered in individual doses. 0.1 to 100 mg are provided in an
individual dose per kg of body weight. The preparation can be
administered daily in one or more doses depending on the nature and
severity of the disorders.
[0079] According to the desired type of administration, the
pharmaceutical preparations according to the invention contain the
customary excipients and diluents in addition to the active
compound. For local external application, pharmaceutical
auxiliaries such as ethanol, isopropanol, ethoxylated castor oil,
ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene
glycol, polyethylene glyco [sic] stearate, ethoxylated fatty
alcohols, paraffin oil, petroleum jelly and wool fat can be used.
For internal administration, for example, lactose, propylene
glycol, ethanol, starch, talc and polyvinylpyrrolidone are
suitable.
[0080] Antioxidants such as tocopherol and butylated hydroxyanisole
as well as butylated hydroxytoluene, flavor-enhancing additives,
stabilizers, emulsifiers and lubricants can additionally be
contained.
[0081] The substances contained in the preparation in addition to
the active compound and the substances used in the production of
the pharmaceutical preparations are toxicologically acceptable and
compatible with the respective active compound. The pharmaceutical
preparations are prepared in a customary manner, for example by
mixing the active compound with other customary excipients and
diluents.
[0082] The pharmaceutical preparations can be administered in
various administration procedures, for example, orally,
parenterally such as intravenously by infusion, subcutaneously,
intraperitoneally and topically. Thus preparation forms such as
tablets, emulsions, infusion and injection solutions, pastes,
ointments, gels, creams, lotions, powders and sprays are
possible.
EXAMPLES
Example 1
[0083] 10
(S)-4(N-(1-Naphthylmethyl)carbamoyl)-N-(3-phenylpropan-1-al-2-yl)pyridine--
2-carboxamide
a) Ethyl
4-(N-(1-naphthylmethyl)carbamoyl)pyridine-2-carboxylate
[0084] 4.9 g (25 mmol) of 2-ethoxycarbonylpyridine-3-carboxylic
acid (N. Finch et al., J. Med. Chem. 1980, 23, 1405) were dissolved
in 110 ml of tetrahydrofuran/dimethylformamide (10/1) and treated
with 4.5 g (27.5 mmol) of 1,1'-carbonyldiimidazole. After the
mixture had been stirred at room temperature for 30 min, 3.9 g (25
mmol) of 1-aminomethylnaphthalene were additionally added and the
mixture was stirred at room temperature for a further 72 h. The
tetrahydrofuran was then removed in vacuo and the residue was
partitioned between 200 ml of ethyl acetate and 200 ml of aqueous
sodium hydrogencarbonate solution. The organic phase was
additionally washed with water, dried and concentrated in vacuo.
7.9 g (95%) of the product were obtained.
[0085] 1H-NMR: [lacuna]
b) 4-(N-(1-Naphthylmethyl)carbamoyl)pyridine-2-carboxylic acid
[0086] 6.9 g (20 mmol) of the intermediate 1a were dissolved in 100
ml of ethanol and treated with 3.3 g (82 mmol) of sodium hydroxide,
dissolved in 50 ml of water. The entire mixture was stirred at room
temperature for 16 h. The reaction solution was then neutralized
with 1M hydrochloric acid and the ethanol was removed in vacuo. The
precipitate obtained was filtered off with suction and dried. 5.6 g
(89%) of the product were obtained.
c)
(S)-4-(N-(1-Naphthylmethyl)carbamoyl)-N-(3-phenylpropan-1-ol-2-yl)pyrid-
ine-2-carboxamide
[0087] 2.7 g (9 mmol) of the intermediate 1b and 1.4 g (9 mmol) of
(S)-phenylalaninol were added to 60 ml of methylene chloride and
treated with 2.3 g (22.5 mmol) of triethylamine, 50 ml of
dimethylformamide and 0.4 g (3 mmol) of 1-hydroxybenzotriazole. 1.7
g (9 mmol) of 1-ethyl-3-(dimethylaminopropyl)carbodiimide
hydrochloride was [sic] then added at 0.degree. C. and the entire
mixture was first stirred at 0.degree. C. for 16 h, then at room
temperature. The reaction mixture was washed successively with 100
ml of 5% strength citric acid and 100 ml of sodium
hydrogencarbonate solution and, after drying, concentrated in
vacuo. 2.4 g (62%) of the product were obtained.
d)
(S)-4-(N-(l-Naphthylmethyl)carbamoyl)-N-(3-phenylpropan-1-al-2-yl)pyrid-
ine-2-carboxamide
[0088] 1.9 g (4.4 mmol) of the intermediate compound 1c were
dissolved in 50 ml of dry dimethyl sulfoxide and treated with a
solution of 1.8 g (17.4 mmol) of triethylamine and 2.8 g (17.4
mmol) of pyridine-sulfur trioxide complex in 50 ml of dry dimethyl
sulfoxide. The entire mixture was stirred at room temperature for
16 h. The reaction mixture was then added to water and the
precipitate was filtered off with suction. 1.5 g (80%) of the
product were obtained.
[0089] 1H-NMR (D.sub.6-DMSO): .delta.=3.1 (1H), 3.5(1H), 4.7(1H),
5.1 (1H), 7.1-7.3(6H), 7.4-7.7(5H), 7.9(1H), 7.95(1H), 8.15 (1H),
8.2(1H), 8.4(1H), 9.1(1H), 9.2(1H), 9.4(1H) and 9.8(1H) ppm.
Example 2
[0090] 11
(S)-2-(2-Naphthalenesulfonamido)-N-(3-phenylpropan-1-al-2-yl)pyridine-3-ca-
rboxamide
a) Methyl 2-(2-naphthalenesulfonamido)pyridine-3-carboxylate
[0091] 5.9 g (26 mmol) of naphthalene-2-sulfonyl chloride were
added in portions at room temperature to 4.7 g (25 mmol) of methyl
6-aminonicotinate hydrochloride in 100 ml of dry pyridine. The
entire mixture was then stirred at room temperature for 16 h. The
reaction solution was then poured onto 500 ml of water and the
precipitate obtained was filtered off with suction. 6.4 g (75%) of
the product were obtained.
b) 2-(2-Naphthalenesulfonamido)pyridine-3-carboxylic acid
[0092] 6 g (17 mmol) of the intermediate compound 2a, dissolved in
100 ml of methanol, were stirred at room temperature for 16 h with
4.2 g (104 mmol) of sodium hydroxide, dissolved in 100 ml of water.
The organic solvent was then removed in vacuo and the aqueous
solution obtained was neutralized with 1M hydrochloric acid. The
resulting precipitate was filtered off with suction. 5.1 g (90%) of
the product were obtained.
c)
(S)-2-(2-Naphthalenesulfonamido)-N-(3-phenylpropan-1-ol-2-yl)-pyridine--
3-carboxamide
[0093] 2.5 g (7.5 mmol) of the intermediate compound 2b was [sic]
reacted with (S)-phenylalaninol analogously to procedure 1c. 0.7 g
(21%) of the product was obtained.
d)
(S)-2-(2-Naphthalenesulfonamido)-N-(3-phenylpropan-1-al-2-yl)-pyridine--
3-carboxamide
[0094] 0.5 g (1.2 mmol) of the intermediate compound 2c were
oxidized analogously to the procedure 1d, 0.4 g (78%) of the
product being obtained.
[0095] 1H-NMR (D.sub.6-DMSO): .delta.=2.8(1H), 3.3(1H), 4.5(1H),
7.0-7.4 (5H), 7.7(2H), 7.9(1H), 8.1(3H), 8.25(1H), 8.5(1H), 8.7
(1H), 8.9(1H), 9.6(1H) and about 12.5(broad, 1H) ppm.
Example 3
[0096] 12
(S)-2-(2-Naphthalenamido)-N-(3-phenylpropan-1-al-2-yl)-pyridine-5-carboxam-
ide
a) 6-Aminonicotinic acid hydrochloride
[0097] 20 g (0.145 mol) of 6-aminonicotinic acid were refluxed for
approximately 5 h in a mixture of 200 ml of methanol [lacuna] 250
ml of 2.5 M hydrochloric acid. The entire mixture was then
concentrated in vacuo and 26.6 g (97%) of the product were
obtained.
b) Methyl 6-(2-naphthalenamido)nicotinate
[0098] 4.7 g (25 mmol) of the intermediate compound 3a were
dissolved in 100 ml of pyridine and treated in portions at room
temperature with 5 g (25 mol [sic]) of 2-naphthoyl chloride. The
entire mixture was stirred at room temperature for 16 h. The
reaction mixture was then poured onto water and the precipitate
obtained was filtered off with suction. 5.4 g (70%) of the product
were obtained.
c) 6-(2-Naphthalenamido)nicotinic acid
[0099] 4.7 g (15 mmol) of the intermediate compound 3b were
dissolved in 75 ml of ethanol and treated with 2.5 g of sodium
hydroxide, dissolved in 50 ml of water. The entire mixture was
stirred at room temperature for 16 h. The ethanol was then removed
in vacuo and the aqueous residue was neutralized with 1M
hydrochloric acid. The precipitate obtained was filtered off with
suction. 3.1 g (69%) of the product were obtained.
d)
(S)-2-(2-Naphthalenamido)-N-(3-phenylpropan-1-ol-2-yl)-pyridine-5-carbo-
xamide
[0100] 2.7 g (9.2 mmol) of the intermediate compound 3c were
reacted with (S)-phenylalaninol analogously to the procedure 1c.
2.1 g (54%) of the product were obtained.
e)
(S)-2-(2-Naphthalenamido)-N-(3-phenylpropan-1-al-2-yl)pyridine-5-carbox-
amide
[0101] 1.7 g (4 mmol) of the intermediate compound 3d were oxidized
analogously to the procedure 1d. 1.3 g (79%) of the product were
obtained.
[0102] MS: m/e=423 (M.sup.+).
Example 4
[0103] 13
(S)-5-Chloro-2-(2-naphthalenesulfonamido)-N-(3-phenylpropan-1-al-2-yl)pyri-
midine-6-carboxamide
a) Ethyl
5-(chloro-2-(2-naphthalenesulfonamido)pyrimidine-6-carboxylate
[0104] 6 g (26 mmol) of 2-naphthalenesulfonyl chloride were added
at room temperature to 5 g (25 mmol) of ethyl
2-amino-5-chloropyrimidine-6-carbox- ylate in 100 ml of dry
pyridine. The entire mixture was additionally stirred for 16 h. The
batch was then poured onto water and the precipitate obtained was
filtered off with suction. 9.8 g (59%) of the product were
obtained.
b) 5-Chloro-2-(2-naphthalenesulfonamido)pyrimidine-6-carboxylic
acid
[0105] 5.6 g (14 mmol) of the intermediate compound 4a were
dissolved in 100 ml of methanol/tetrahydrofuran (1/1) and
hydrolyzed at room temperature with 2.8 g of sodium hydroxide,
dissolved in 10 ml of water. After 16 h, the organic solvent was
removed in vacuo and the aqueous phase was adjusted to pH=6 using
2M hydrochloric acid. The precipitate formed was filtered off with
suction. 2.8 g (55%) of the product were obtained.
c)
(S)-5-Chloro-2-(2-naphthalenesulfonamido)-N-(3-phenylpropan-1-ol-2-yl)p-
yrimidine-6-carboxamide
[0106] 1.9 g (5.2 mmol) of the intermediate compound 4b were
reacted with (S)-phenylalaninol analogously to procedure 1c. 1.4 g
(55%) of the product were obtained.
d)
(S)-5-Chloro-2-(2-naphthalenesulfonamido)-N-(3-phenylpropan-1-al-2-yl)p-
yrimidine-6-carboxamide
[0107] 1.73 [lacuna] (2.5 mmol) of the intermediate compound 4c
were oxidized analogously to procedure 1d. 1.1 g (85%) of the
product were obtained.
[0108] 1H-NMR (D.sub.6-DMSO): .delta.=2.95(1H), 3.4(1H), 4.6(1H),
7.2-8.2 (12H) 8.45(1H), 9.2(1H) and 9.7(1H) ppm
Example 5
[0109] 14
(S)-5-Chloro-2-(2-naphthalenesulfonamido)-N-(1-carbamoyl-1-oxo-3-phenylpro-
pan-2-yl)pyrimidine-6-carboxamide
a)
(S)-5-Chloro-2-(2-naphthalenesulfonamido)-N-(1-carbamoyl-1-hydroxy-3-ph-
enylpropan-2-yl)pyrimidine-6-carboxamide
[0110] 0.77 g (2.1 mmol) of the intermediate compound 4b and
(2S),(3R,S)-3-amino-2-hydroxy-3-phenylbutyramide was reacted
analogously to procedure 1c. 0.24 g (23%) of the product was
obtained.
b)
(S)-5-Chloro-2-(2-naphthalenesulfonamido)-N-(1-carbamoyl-1-oxo-3-phenyl-
propan-2-yl)pyrimidine-6-carboxamide
[0111] 0.19 g (0.35 mmol) of the intermediate compound 5a was
oxidized analogously to procedure 1d. 0.024 g of the product was
obtained.
[0112] 1H-NMR (D.sub.6-DMSO): .delta.=3.0(1H), 3.25(1H), 5.4(1H),
7.2-8.0 (11H), 8.1(1H), 8.4(1H), 9.0(1H).
Example 6
(S)-2-(2-Naphthalenamido)-N-(3-phenylpropan-1-al-2-yl)-thiazole-4-carboxam-
ide
[0113] 15
a) Ethyl 2-(2-naphthalenamido)thiazole-4-carboxylate
[0114] 4.7 g (24.9 mmol) of 2-naphthoyl chloride, dissolved in 50
ml of anhydrous tetrahydrofuran, were added dropwise at 0.degree.
C. [sic] to 4 g (23.3 mmol) of ethyl 2-aminothiazole-4-carboxylate
and 6.4 ml (46.5 mmol) of triethylamine in 150 ml of anhydrous
tetrahydrofuran. The entire mixture was then stirred for 16 h. The
reaction solution was then poured into plenty of water and
extracted with ethyl acetate. The organic phase was then washed
with aqueous sodium hydrogencarbonate solution, dried and
concentrated in vacuo. The residue was purified by chromatography
(eluent:methylene chloride), 5.6 g (82%) of the product being
obtained.
b) 2-(2-Naphthalenamido)thiazole-4-carboxylic acid
[0115] 5.4 g (16.6 mmol) of the intermediate compound 6a were
dissolved in 50 ml of tetrahydrofuran and treated with 100 ml of 2M
sodium hydroxide solution. The entire mixture was stirred at room
temperature for 16 h. The batch was then diluted with water and
neutralized with concentrated acetic acid. The precipitate formed
was filtered off with suction. 4.7 g (95%) of the product were
obtained.
c)
(S)-2-(2-Naphthalenamido)-N-(3-phenylpropan-1-ol-2-yl)-thiazole-4-carbo-
xamide
[0116] 1 g (3.4 mmol) of the intermediate compound 6b and and [sic]
(2S),(3R,S)-3-amino-2-hydroxy-3-phenylbutyramide were reacted
analogously to procedure 1c. 1.2 g (93%) of the product were
obtained.
d)
(S)-2-(2-Naphthalenamido)-N-(3-phenylpropan-1-al-2-yl)-thiazole-4-carbo-
xamide
[0117] 1 g (2.3 mmol) of the intermediate compound 6c were [sic]
oxidized analogously to procedure 1d. 0.73 g (74%) of the product
was obtained.
[0118] MS: m/e=429 (M.sup.+).
Example 7
(S)-2-(2-Naphthalenamido)-N-(1-carbamoyl-1-oxo-3-phenyl-propan-2-yl)thiazo-
le-4-carboxamide
[0119] 16
a)
(S)-2-(2-Naphthalenamido)-N-(1-carbamoyl-1-hydroxy-3-phenyl-propan-2-yl-
)thiazole-4-carboxamide
[0120] 1.35 g (4.5 mmol) of the intermediate compound 6b and 1.4 g
of (2S)(3R,S)-3-amino-2-hydroxy-3-phenylbutyramide trifluoroacetate
were reacted analogously to procedure 1c. 1.4 g (66%) of the
product were obtained.
b)
(S)-2-(2-Naphthalenamido)-N-(1-carbamoyl-1-oxo-3-phenylpropan-2-yl)thia-
zole-4-carboxamide
[0121] 1.2 g (2.5 mmol) of the intermediate compound 7a were
oxidized analogously to procedure 1d. 1.05 g (88%) of the product
were obtained.
[0122] MS: m/e=472 (M.sup.+).
Example 8
(S)-N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-4-methyl-1-(2-naphthalenemet-
hyl)imidazole-5-carboxamide
[0123] 17
a) Ethyl
4-methyl-1-(2-naphthalenemethyl)imidazole-5-carboxylate
[0124] 4.2 g (27.2 mmol) of etheyl [sic]
4-methylimidazole-5-carboxylate, 3.8 g (27.2 mmol) of potassium
carbonate and 6.0 [lacuna] (27.2 mmol) of 2-bromomethylnaphthalene
were heated at 100.degree. C. for 1 h in 100 ml of
dimethylformamide. The entire mixture was then poured onto water
and extracted with ethyl acetate. The organic phase was dried and
concentrated in vacuo. The residue was then purified by
chromatography on silica gel (eluent: ethyl acetate). 4.8 g (60%)
of the product were obtained.
b) 4-Methyl-1-(2-naphthalenemethyl)imidazole-5-carboxylic acid
[0125] 4.6 g (15.6 mmol) of the intermediate compound 8a were
dissolved in 50 ml of tetrahydrofuran, treated with 100 ml of 1M
sodium hydroxide solution and the entire mixture was then refluxed
for 6 h. The organic solvent was then removed in vacuo and the
aqueous residue was neutralized with acetic acid. The precipitate
formed was filtered off with suction. 3.5 g (85%) of the product
were obtained.
c)
(S)--N-(1-Carbamoyl-1-hydroxy-3-phenylpropan-2-yl)-4-methyl-1-(2-naphth-
alenemethyl)imidazole-5-carboxamide
[0126] 1 g (3.8 mmol) of the intermediate compound 8b and and [sic]
1.2 g (3.8 mmol) of
(2S),(3R,S)-3-amino-2-hydroxy-3-phenylbutyramide trifluoroacetate
were reacted analogously to procedure 1c. 0.7 g (42%) of the
product was obtained.
d)
(S)--N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-4-methyl-1-(2-naphthalen-
emethyl)-imidazole-5-carboxamide
[0127] 0.6 g (1.4 mmol) of the intermediate compound 8c was
oxidized 10, analogously to procedure 1d. 0.33 g (56%) of the
product was obtained.
[0128] MS: m/e=440 (M.sup.+).
Example 9
(S)--N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-methyl-1-(2-naphthylmethy-
l)imidazole-5-carboxamide
[0129] 18
a) Ethyl 2-methyl-1-(2-naphthyl)methylimidazole-4-carboxylate
[0130] 4.6 g (29.8 mmol) of ethyl 2-methylimidazole-4-carboxylate
and 6.6 g (29.8 mmol) of 2-bromomethylnaphthalene were reacted
analogously to procedure 8a. 5.7 g (65%) of the product were
obtained.
b) 2-Methyl-1-(2-naphthyl)methylimidazole-4-carboxylic acid
[0131] 5.5 g (18.7 mmol) of the intermediate compound 9a were
hydrolyzed analogously to procedure 8b. 3.2 g (65%) of the product
were obtained.
c)
(S)--N-(1-Carbamoyl-1-hydroxy-3-phenylpropan-2-yl)-2-methyl-1-(2-naphth-
ylmethyl)imidazole-5-carboxamide
[0132] 1 g (3.8 mmol) of the intermediate compound 9b and and [sic]
1.2 g (3.8 mmol) of
(2S),(3R,S)-3-amino-2-hydroxy-3-phenylbutyramide trifluoroacetate
were reacted analogously to procedure 1c. 0.65 g (39%) of the
product was obtained.
d)
(S)--N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-methyl-1-(2-naphthylme-
thyl)imidazole-5-carboxamide
[0133] 0.6 g (1.4 mmol) of the intermediate product 9c was oxidized
analogously to procedure 1d. 0.42 g (71%) of the product was
obtained.
[0134] MS: m/e=440 (M.sup.+).
Example 10
(S)--N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-1-(2-naphthyl-methyl)imidaz-
ole-2-carboxamide
[0135] 19
a) Butyl 1-(2-naphthyl)methylimidazole-2-carboxylate
[0136] 5.0 g (29.7 mmol) of butyl imidazole-2-carboxylate and 6.6 g
(29.7 mmol) of 2-bromomethylnaphthalene were reacted analogously to
procedure 8a. 6.4 g (71%) of the product were obtained.
b) 1-(2-Naphthyl)methylimidazole-2-carboxylic acid
[0137] 6.2 g (20.1 mmol) of the intermediate compound 10a were
hydrolyzed analogously to procedure 8b. 4.2 g (83%) of the product
were obtained.
c)
(S)--N-(1-Carbamoyl-1-hydroxy-3-phenylpropan-2-yl)-1-(2-naphthylmethyl)-
imidazole-2-carboxamide
[0138] 1.1 g (4.4 mmol) of the intermediate compound 10b and and
[sic] 1.3 g (4.4 mmol) of
(2S),(3R,S)-3-amino-2-hydroxy-3-phenylbutyramide trifluoroacetate
were reacted analogously to procedure 1c. 1.3 g (70%) of the
product were obtained.
d)
(S)--N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-1-(2-naphthylmethyl)imid-
azole-2-carboxamide
[0139] 1.0 g (2.3 mmol) of the intermediate compound 10c were
oxidized analogously to procedure 1d. 0.73 g (74%) of the product
was obtained.
[0140] MS: m/e=426 (M.sup.+).
Example 11
(S)-1-Benzyl-N-(1-carbamoyl-1-oxo-3-phenylpropan-2-yl)-imidazole-2-carboxa-
mide
[0141] 20
a) Butyl 1-benzylimidazole-2-carboxylate
[0142] 5.4 g (32.1 mmol) of butyl imidazole-2-carboxylate were
reacted with 4.1 g (32.1 mmol) of benzyl chloride analogously to
procedure 8a. 7.3 g (78%) of the product were obtained.
b) 1-Benzylimidazole-2-carboxylic acid
[0143] 7 g (27.1 mmol) of the intermediate compound 11a were
hydrolyzed using sodium hydroxide solution analogously to procedure
8b. 3.7 g (68%) of the product were obtained.
c)
(S)-1-Benzyl-(1-carbamoyl-1-hydroxy-3-phenylpropan-2-yl)-imidazole-2-ca-
rboxamide
[0144] 1.0 g (5.1 mmol) of the intermediate compound 11b and and
[sic] 1.6 g (5.1 mmol) of
(2S),(3R,S)-3-amino-2-hydroxy-3-phenylbutyramide trifluoroacetate
were reacted analogously to procedure 1c. 1.1 g (58%) of the
product were obtained.
d)
(S)-1-Benzyl-N-(1-carbamoyl-1-oxo-3-phenylpropan-2-yl)-imidazole-2-carb-
oxamide
[0145] 1.0 g (2.3 mmol) of the intermediate compound 11c were [sic]
oxidized analogously to procedure 1d. 0.79 g (80%) of the product
was obtained.
[0146] MS: m/e=376 (M.sup.+).
Example 12
(S)--N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-1-(2-naphthylmethyl)imidazo-
le-5-carboxamide
[0147] 21
a) Ethyl 1-(2-naphthylmethyl)imidazole-5-carboxylate
[0148] 2.4 g (17.1 mmol) of butyl imidazole-5-carboxylate were
reacted with 4.1 g (32.1 mmol) of benzyl chloride analogously to
procedure 8a. 7.3 g (78%) of the product were obtained.
b) -1(2-Naphthylmethyl)imidazole-5-carboxylic [sic] acid
[0149] 3 g (10.7 mmol) of the intermediate compound 12a were
hydrolyzed using sodium hydroxide solution analogously to procedure
8b. 1.9 g (73%) of the product were obtained.
c)
(S)--N-(1-Carbamoyl-1-hydroxy-3-phenylpropan-2-yl)-1-(2-naphthylmethyl)-
imidazole-5-carboxamide
[0150] 1.0 g (4.0 mmol) of the intermediate compound 12b and 1.2 g
(4.0 mmol) of (2S),(3R,S)-3-amino-2-hydroxy-3-phenylbutyramide
trifluoroacetate were reacted analogously to procedure 1c. 0.85 g
(51%) of the product was obtained.
d)
(S)--N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-1-(2-naphthyl-methyl)imi-
dazole-5-carboxamide
[0151] 0.8 g (1.9 mmol) of the intermediate compound 12c was
oxidized analogously to procedure 1d. 0.41 g (52%) of the product
was obtained.
[0152] MS: m/e=426 (M.sup.+).
Example 13
[0153] 22
(S)-2-(2-Naphthyl)ethen-1-yl)-N-(3-phenylpropan-1-al-2-yl)pyridine-3-carbo-
xamide
a) Ethyl 2-(2-naphthylethen-1-yl)pyridine-3-carboxylate
hydrochloride
[0154] 10 g (43.5 mmol) of ethyl 2-bromopyridine-3-carboxylate, 8.7
g (56.5 mmol) of 2-vinylnaphthalene, 15 ml (0.11 mol) of
triethylamine, 0.36 g of palladium(II) acetate and 0.96 g of
tri-o-tolylphosphine were dissolved in 150 ml of dimethylformamide.
A further 1 ml of water was then added and the entire mixture was
refluxed for 3 h. The entire mixture was then extracted with ether.
The organic phase was additionally washed with water, dried and
concentrated in vacuo. The residue was dissolved in acetone and
treated with hydrogen chloride, dissolved in dioxane. The product
was then precipitated by addition of ether. 8.7 g (67%) of the
product were obtained.
b) 2-(2-Naphthylethen-1-yl)pyridine-3-carboxylic acid
[0155] 8.5 g (28 mmol) of the intermediate product 13a were
dissolved in 70 ml of tetrahydrofuran and treated with 140 ml of 2M
sodium hydroxide solution. The entire mixture was refluxed for 8 h.
The batch was then poured onto ice water and neutralized with
acetic acid. The slowly crystallizing product was filtered off with
suction and dried. 5.6 g (73%) of the product were obtained.
c)
(S)-2-(2-Naphthyl)ethen-1-yl-N-(3-phenylpropan-1-ol-2-yl)pyridine-3-car-
boxamide
[0156] 2 g (7.3 mmol) of the intermediate 13b and 1.1 g (7.3 mmol)
of (2S),(3R,S)-3-amino-2-hydroxy-3-phenylbutyramide
trifluoroacetate were reacted analogously to procedure 1c. 2.1 g
(71%) of the product were obtained.
d)
(S)-2-(2-Naphthyl)ethen-1-yl)-N-(3-phenylpropan-1-al-2-yl)pyridine-3-ca-
rboxamide
[0157] 1.9 g (4.7 mmol) of the intermediate compound 13c were
oxidized analogously to procedure 1d. 0.56 g (30%) of the product
was obtained.
[0158] MS: m/e=406 (M.sup.+).
Example 14
[0159] 23
(S)--N-(3-Phenylpropan-1-al-2-yl)-2-(4-pyridyl)ethen-1-yl)pyridine-3-carbo-
xamide [sic]
a) Ethyl 2-(4-pyridine)ethen-1-ylpyridine-3-carboxylate [sic]
[0160] 11.5 g (49.9 mmol) of ethyl 2-bromopyridine-3-carboxylate
and 6.8 g (64.9 mmol) of 4-vinylpyridine were reacted analogously
to procedure 13a. 7.0 g (49%) of the product were obtained.
b) 2-(4-Pyridyl)ethen-1-ylpyridine-3-carboxylic acid
[0161] 7.0 g (27.5 mmol) of the intermediate 14a were dissolved in
50 ml of tetrahydrofuran and treated with 100 ml of 2M sodium
hydroxide solution. The entire mixture was refluxed for 2 h. The
organic solvent was then removed in vacuo and the aqueous phase
obtained was acidified with acetic acid. The aqueous phase was
concentrated and the residue was purified by chromatography
(eluent: ethyl acetate/methanol/acetic acid=50/50/1)d [sic]. 5.5 g
(89%) of the product were obtained.
c)
(S)--N-(3-Phenylpropan-1-ol-2-yl)-2-(4-pyridyl)ethen-1-ylpyridine-3-car-
boxamide
[0162] 1.5 g (6.6 mmol) of the intermediate 14b and 1.0 g (6.6
mmol) of (S)-2-amino-3-phenylpropanol were reacted analogously to
procedure 1c. 1.7 g (72%) of the product were obtained.
d)
(S)--N-(3-Phenylpropan-1-al-2-yl)-2-(4-pyridyl)ethen-1-ylpyridine-3-car-
boxamide
[0163] 1.5 g (4.2 mmol) of the intermediate compound 14c were
oxidized analogously to procedure 1d. 0.71 g (48%) of the product
was obtained.
[0164] MS: m/e=357 (M.sup.+).
[0165] The following examples were prepared analogously to the
above examples and procedures:
Example 15
(S)--N-(3-Phenylpropan-1-al-2-yl)-2-(4-pyridyl)quinoline-4-carboxamide
[0166] .sup.1H-NMR (d.sub.6-DMSO): .delta.=3.0(1H), 3.4(1H),
4.8(1H), 7.25 (1H), 7.7(2H), 7.9(2H), 8.1(1H9 [sic], 8.25(1H),
8.7(1H), 9.0 (1H9 [sic], 9.5(1H) and 9.8(1H) ppm.
Example 16
(S)--N-(3-Phenylpropan-1-al-2-yl)-2-(2-pyridyl)quinoline-4-carboxamide
[0167] .sup.1H-NMR (D.sub.6-DMSO): .delta.=2.9(1H), 3.3(1H9 [sic],
4.8(1H), 7.2-(0.2(11H) [sic], 8.5(1H), 8.6(1H), 8.8(1H), 9.4(1H)
and 9.0(1H) ppm.
Example 17
N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(2-pyridyl)quinoline-4-carboxa-
mide
[0168] MS: m/e=424 (M.sup.+).
Example 18
N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(E-2-(4-pyridyl)-ethen-1-yl)py-
ridine-3-carboxamide
[0169] .sup.1H-NMR (CF.sub.3COOD): .delta.=3.1(1H), 3.7(1H),
6.1(1H), 7.1-7.6 (5H), 8.0(1H), 8.1-8.5(4H9 [sic], 8.6(1H), 9.0(2H)
and 9.1(1H) ppm.
Example 19
N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(2-pyridyl)-quinoline-4-carbox-
amide
[0170] MS: m/e=424 (M.sup.+).
Example 20
N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(1,2,3,4-tetrahydroixo-quinoli-
n-2-yl)pyridine-3-carboxamide [sic]
[0171] .sup.1H-NMR (D.sub.6-DMSO): .delta.=2.8(2H), 2.9(1H),
3.2(2H), 3.3(1H), 4.3(1H), 5.3(1H), 6.8(1H), 7.0-7.5 (9H), 7.5(1H),
7.9-8.1 (2H) and 9.0(1H) ppm.
Example 21
N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinolin-2-yl)pyridine-3-carboxamide
[0172] .sup.1H-NMR (D.sub.6-DMSO): .delta.=2.7(2H), 2.8(1H),
3.2(2H), 3.4(1H), 3.7(6H), 4.2(1H), 5.3(1H9 [sic], 6.7(1H),
6.95(1H), 7.1-7.5 (6&H) [sic], 7.9(1H), 8.1(1H), 8.4(1H),
9.0(1H) ppm.
Example 22
N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(3-phenylpyrrolidin-1-yl)pyrid-
ine-3-carboxamide
[0173] .sup.1H-NMR (CF.sub.3COOD): .delta.=2.0-2.7(2H), 2.95(1H),
3.3-4.0(6H), 5.9(1H), 6.9(1H), 7.0-7.5(10H) and 7.9(1H) ppm.
1 24 Example R.sup.1 X Y R.sup.3 R.sup.4 15 25 26 27 CH.sub.2Ph
CONH.sub.2 16 28 29 30 CH.sub.2Ph 31 17 32 33 34 CH.sub.2Ph 35 18
36 37 38 CH.sub.2Ph 39 19 40 41 42 (CH.sub.2).sub.3--CH.sub.3
CONH.sub.2 20 43 44 45 (CH.sub.2).sub.3--CH.sub.3 H 21 46 47 48
CH.sub.2Ph H 22 49 50 51 CH.sub.2Ph CONH.sub.2 23 52 53 54
(CH.sub.2).sub.3--CH.sub.3 CONH.sub.2 24 55 56 57
(CH.sub.2).sub.3--CH.sub.3 H 25 58 59 CH.sub.2Ph H 26 60 61
CH.sub.2Ph CONH.sub.2 27 62 63 CH.sub.2Ph CONH.sub.2 28 64 65
CH.sub.2Ph H 29 66 67 CH.sub.2Ph H 30 68 69 CH.sub.2Ph CONH.sub.2
31 70 71 72 CH.sub.2Ph H 32 73 74 75 CH.sub.2Ph CONH.sub.2 33 76 77
78 (CH.sub.2).sub.3CH.sub.- 3 H 34 79 80 81
(CH.sub.2).sub.3CH.sub.3 CONH.sub.2 35 82 83 84 CH.sub.2Ph 85 36 86
87 88 89 37 90 91 92 CH.sub.2Ph 38 93 94 95 CH.sub.2Ph 96 39 97 98
99 CH.sub.2Ph 100 40 101 102 103 CH.sub.2Ph 104 41 105 106 107
CH.sub.2Ph H 42 108 109 110 CH.sub.2Ph CONH.sub.2 43 111
--SO.sub.2NH-- 112 CH.sub.2Ph H 44 113 --SO.sub.2NH-- 114
CH.sub.2Ph CONH.sub.2 45 115 --SO.sub.2NH-- 116 CH.sub.2Ph H 46 117
--SO.sub.2NH-- 118 CH.sub.2Ph CONH.sub.2 47 119 --CONH-- 120
CH.sub.2Ph H 48 121 --CONH-- 122 CH.sub.2Ph CONH.sub.2 49 123
.ident. 124 CH.sub.2Ph H 50 125 .ident. 126 CH.sub.2Ph CONH.sub.2
51 127 --SO.sub.2NH-- 128 CH.sub.2Ph H 52 129 --SO.sub.2NH-- 130
CH.sub.2Ph CONH.sub.2 53 131 --SO.sub.2NH-- 132 CH.sub.2Ph
CONH.sub.2 54 133 --NHCO-- 134 CH.sub.2Ph H 55 135 --NHCO-- 136
CH.sub.2Ph CONH.sub.2 56 137 --NHCO-- 138 CH.sub.2Ph CONH.sub.2 57
139 140 141 CH.sub.2Ph H 58 142 143 144 CH.sub.2Ph CONH.sub.2 59
145 146 147 CH.sub.2Ph CONH.sub.2 60 148 149 150 CH.sub.2Ph
CONH.sub.2 61 151 152 153 CH.sub.2Ph 154 62 155 156 157 CH.sub.2Ph
158 63 159 160 161 CH.sub.2Ph 162 64 163 --SO.sub.2NH-- 164
CH.sub.2Ph CONH.sub.2 65 165 --SO.sub.2NH-- 166 CH.sub.2Ph H 66 167
--CH.sub.2O-- 168 CH.sub.2Ph H 67 169 --CH.sub.2O-- 170 CH.sub.2Ph
CONH.sub.2 68 171 --SO.sub.2NH-- 172 CH.sub.2Ph CONH.sub.2 69 173
--NHCO-- 174 CH.sub.2Ph H 70 175 --CH.sub.2NHCO-- 176 CH.sub.2Ph
CONH.sub.2 71 177 --SO.sub.2NH-- 178 CH.sub.2Ph 72 179
--SO.sub.2NH-- 180 CH.sub.2Ph 181 73 182 --SO.sub.2NH-- 183
CH.sub.2Ph 184 74 185 186 187 CH.sub.2Ph CONH.sub.2 75 188 189 190
CH.sub.2Ph 191 76 192 193 194 CH.sub.2Ph 195 77 196 --SO.sub.2NH--
197 CH.sub.2Ph CONH.sub.2 78 198 --CH.sub.2CH.sub.2 199 CH.sub.2Ph
CONH.sub.2 79 200 --CH.sub.2CH.sub.2 201 CH.sub.2Ph H 80 202 203
204 205 206 81 207 208 209 210 211 82 212 213 214 CH.sub.2Ph H 83
215 216 217 CH.sub.2Ph CONH.sub.2 84 218 219 220 CH.sub.2Ph
CONH.sub.2 85 221 222 223 CH.sub.2Ph H
Example 86
2-(4,6-Dimethoxypyrimidin-1-yl)oxy-N-(3-phenylpropan-1-al-2-yl)-quinoline--
4-carboxamide
[0174] MS: m/e=458 (M.sup.+)
Example 87
N-(3-Phenylpropan-1-al-2-yl)-2-(2-pyridyl)oxy-8-trifluoromethy-quinoline-4-
-carboxamide [sic]
[0175] .sup.1H-NMR (D.sub.6-DMSO): .delta.=3.0(1H), 3.4(1H),
4.9(1H), 7.3-8.9 (13H), 9.5(1H) and 9.9(1H) ppm.
Example 88
N-(3-Phenylpropan-1-al-2-yl)-2-(naphtho[c]pyrimidion-3-yl)-5-nicotinamide
[0176] .sup.1H-NMR (CF.sub.3COOD): .delta.=3.1-3.4(2H), 4.8(1H),
6.7(1H), 7.1-8.3(12 H), 8.7(1H) and 8.9(1H) ppm.
Example 89
N-(3-Chlorophenyl)carbamoyl-6-methyl-N-(3-phenylpropan-1-al-2-yl)-pyridine-
-3-carboxamide
[0177] .sup.1H-NMR (CF.sub.3COOD): .delta.=2.0-2.7(2H), 2.95(1H),
3.3-4.0(6H), 5.9(1H), 6.9(1H), 7.0-7.5(10H) and 7.9(1H) ppm.
* * * * *