U.S. patent application number 12/005763 was filed with the patent office on 2008-08-07 for modulation of pathogenicity.
Invention is credited to Aldo Ammendola, Katharina Aulinger-Fuchs, Astrid Gotschlich, Bernd Kramer, Martin Lang, Wael Saeb, Udo Sinks, Andreas Wuzik.
Application Number | 20080188536 12/005763 |
Document ID | / |
Family ID | 39810287 |
Filed Date | 2008-08-07 |
United States Patent
Application |
20080188536 |
Kind Code |
A1 |
Ammendola; Aldo ; et
al. |
August 7, 2008 |
Modulation of pathogenicity
Abstract
The present invention relates to the use of compounds of the
general Formula (I): ##STR00001## wherein in Formula (I), R is H,
alkyl, cycloalkyl, aryl or heteroaryl; R.sup.1 is H, alkyl,
cycloalkyl, aryl or heteroaryl; R.sup.2 is H, alkyl, cycloalkyl,
aryl or heteroaryl; A.sup.1 and A.sup.2 each independently
represent an optionally substituted C.sub.1-C.sub.20-alkyl group
which may contain one or more group(s) Z, or a monocyclic or
polycyclic optionally substituted aromatic or non-aromatic ring
system which may contain one or more group(s) X, and in case of a
polycyclic ring system, said system contains at least one aromatic
ring; Z is selected from the group consisting of S, O, N, NR.sup.4,
CO, CO.sub.2, CS, SO or SO.sub.2 X is selected from the group
consisting of S, O, N, NR.sup.4, SO or SO.sub.2;
Inventors: |
Ammendola; Aldo; (Munchen,
DE) ; Aulinger-Fuchs; Katharina; (Neuried, DE)
; Gotschlich; Astrid; (Munchen, DE) ; Kramer;
Bernd; (Aachen, DE) ; Lang; Martin;
(Grafelfing, DE) ; Saeb; Wael;
(Planegg-Martinsried, DE) ; Sinks; Udo; (Munchen,
DE) ; Wuzik; Andreas; (Untermeitingen, DE) |
Correspondence
Address: |
Womble Carlyle Sandridge & Rice, PLLC;Attn: Patent Docketing 32nd Floor
P.O. Box 7037
Atlanta
GA
30357-0037
US
|
Family ID: |
39810287 |
Appl. No.: |
12/005763 |
Filed: |
December 28, 2007 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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10429875 |
May 6, 2003 |
7335779 |
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12005763 |
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10094301 |
Mar 8, 2002 |
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10429875 |
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Current U.S.
Class: |
514/407 ;
548/372.5 |
Current CPC
Class: |
C07D 409/04 20130101;
C07D 471/04 20130101; A61K 8/49 20130101; A61Q 17/005 20130101;
C07D 231/16 20130101; Y02A 50/30 20180101; A61K 8/4973 20130101;
A61K 31/175 20130101; A61Q 19/00 20130101; A61K 8/4986 20130101;
A61K 31/415 20130101; A01N 43/54 20130101; A61K 31/44 20130101;
C07D 231/40 20130101; A61K 31/445 20130101; C07D 333/70 20130101;
A61P 31/04 20180101; C07D 409/12 20130101; A61K 31/38 20130101;
A01N 43/56 20130101; A61K 31/42 20130101; Y02A 50/473 20180101;
C07D 307/68 20130101; C07D 403/12 20130101; A61K 31/435 20130101;
A61K 31/505 20130101; C07D 333/38 20130101 |
Class at
Publication: |
514/407 ;
548/372.5 |
International
Class: |
A61K 31/415 20060101
A61K031/415; C07D 231/40 20060101 C07D231/40; A01N 43/56 20060101
A01N043/56; A61P 31/04 20060101 A61P031/04; A01P 1/00 20060101
A01P001/00 |
Claims
1-26. (canceled)
27. A compound of Formula (XIII) ##STR00163## or a pharmaceutically
acceptable salt or physiologically functional derivative thereof,
wherein A.sup.6 is pyrazolyl, which may be optionally substituted
with one or more R.sup.3; m is 1; R.sup.12 is H, CH.sub.3,
CH.sub.2CH.sub.3, OCH.sub.3, OCH.sub.2CH.sub.3, OH, or SH; r is 1;
A.sup.7 is C(O) or C(S); A.sup.8 is C(R.sup.14).sub.2; each
R.sup.14 independently is H, alkyl, alkoxy, OH, or SH; A.sup.9 is
C(O) or C(S); q is 0 or 1; A.sup.5 is alkyl or heteroaryl, each of
which may be optionally substituted with one or more R.sup.3; each
R.sup.3 independently is OR.sup.4, SR.sup.4, hydroxyalkyl,
hydroxyalkylamino, cycloalkyl, halogen, haloalkyl, haloalkoxy,
NO.sub.2, CN, SO.sub.2NR.sup.4R.sup.5, CO.sub.2NR.sup.4R.sup.5,
COR.sup.4, CO.sub.2R.sup.4, SO.sub.2R.sup.4, SO.sub.3R.sup.4,
NR.sup.4R.sup.5, alkyl, aryl, aryl substituted with halogen, or
heteroaryl; each R.sup.4 independently is H, alkyl, cycloalkyl,
aryl, or heteroaryl; and each R.sup.5 independently is H, O-alkyl,
O-aryl, alkyl, heteroaryl, or aryl.
28. The compound of claim 27 wherein A.sup.5 is C.sub.6-C.sub.8
alkyl.
29. The compound of claim 27 wherein A.sup.9 is C(O).
30. The compound of claim 27 wherein A.sup.8 is CH.sub.2.
31. The compound of claim 27 wherein A.sup.7 is C(O).
32. The compound of claim 27 wherein R.sup.12 is H.
33. The compound of claim 27 wherein A.sup.6 is ##STR00164##
wherein a is 0, 1, or 2.
34. The compound of claim 27 wherein A.sup.1 is ##STR00165##
35. A compound selected from: ##STR00166## or a pharmaceutically
acceptable salt or physiologically acceptable derivative
thereof.
36. A method for inhibiting the production of a virulence factor
comprising contact with a compound of claim 27.
37. A method for inhibiting the production of a virulence factor
comprising contact with a compound of claim 35.
38. The method of claim 36 for the treatment or prevention of
bacterial damage or disease.
39. The method of claim 37 for the treatment or prevention of
bacterial damage or disease.
40. The method of claim 38 wherein the bacteria is Pseudomonas
aeruginosa or Burkholderia cepacia.
41. The method of claim 39 wherein the bacteria is Pseudomonas
aeruginosa or Burkholderia cepacia.
42. A composition for inhibiting biofilm formation comprising a
compound of claim 27.
43. A composition for inhibiting biofilm formation comprising a
compound of claim 35.
Description
STATEMENT OF RELATED APPLICATIONS
[0001] The present application is a divisional of co-pending
application Ser. No. 10/429,875, filed May 6, 2003, which is a
continuation-in-part of application Ser. No. 10/094,301, filed Mar.
8, 2002, now abandoned, the contents of each are herein
incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to the use of compounds such
as amide, carbazide and hydrazide derivatives as selective
inhibitors of bacterial pathogens. In particular the invention
refers to a family of compounds that block the quorum sensing
system of Gram-negative bacteria, a process for their manufacture,
pharmaceutical compositions containing them and to their use for
the treatment and prevention of microbial damages and diseases, in
particular for diseases where there is an advantage in inhibiting
quorum sensing regulated phenotypes of pathogens.
[0003] Many microorganisms, including bacteria, fungi, protozoa and
algae cause severe damages or diseases in different areas such as
industry, agriculture, environment and medicine. Especially
bacteria as human pathogens cause tremendous costs in public health
systems worldwide. The continuing emergence of
multiple-drug-resistant bacterial strains has necessitated finding
new compounds that can be used in antibacterial treatment. There
are two broad strategies for the control of bacterial infection:
either to kill the organism or to attenuate its virulence such that
it fails to adapt to the host environment. The latter approach has,
however, lacked specific targets for rational drug design. The
discovery that Gram-negative bacteria employ a signal transduction
pathway comprising a small molecule to globally regulate the
production of virulence determinants offers such a novel
target.
[0004] A wide variety of Gram-negative bacteria produce
N-acyl-L-homoserine lactone (AHL or HSL, FIG. 1) derivatives as
signal molecules in intercellular communication. These molecules,
also referred to as "pheromones" or "quoromones", comprise a
homoserine lactone moiety linked to an acyl side chain. Bacteria
use this signaling system to monitor their population cell density
in a process referred to as "quorum sensing". In each cell of a
population an HSL synthase from usually the LuxI family of proteins
produce a low basal level of diffusible HSLs. The HSL concentration
increases with bacterial population density until a threshold
concentration is reached which results in expression of various
HSL-dependent genes through an HSL-receptor protein belonging
generally to the LuxR family of transcriptional regulators. This
HSL-receptor protein complex serves not only as positive
transcription regulator of quorum sensing regulated genes but also
as positive regulator for the HSL synthesis itself. Therefore, the
entire system is amplified via a process of autoinduction.
[0005] This system was first discovered in the bioluminescent
marine bacteria Vibrio harveyi and V. fischeri where it is used to
control bioluminescence expression. In recent years it has become
apparent that many Gram-negative bacteria employ one or more quorum
sensing systems comprising HSL derivatives with different acyl side
chains to regulate in a cell-density dependent manner a wide
variety of physiological processes such as swarming motility,
biofilm formation, pathogenicity, conjugation, bioluminescence or
production of pigments and antibiotics (Table 1, for reviews and
further references see, e.g.: Fuqua et al, Ann. Rev. Microbiol.
50:727-51, 1996; Fuqua & Greenberg, Curr. Opinion Microbiol.
1:183-89, 1998; Eberl, Syst. Appl. Microbiol. 22:493-506, 1999; De
Kievit & Iglewski, Infect. Immun. 68:4839-49, 2000).
TABLE-US-00001 TABLE 1 Summary of HSL-based quorum sensing systems
Regulatory Bacterium proteins Major HSL HSL-regulated phenotype
Aeromonas hydrophila AhyR, AhyI C4-HSL Extracellular protease,
biofilm formation Aeromonas salmonicida AsaR, AsaI C4-HSL
Extracellular protease Agrobacterium tumefaciens TraR, TraI
3-oxo-C8-HSL Conjugal transfer Burkholderia cepacia CepR, CepI
C8-HSL Protease, lipase, ornibactin synthesis, biofilm formation,
swarming motility Chromobacterium violaceum CviR, CviI C6-HSL
Antibiotics, violacein, exoenzymes, cyanide Enterobacter
agglomerans EagR, EagI 3-oxo-C6-HSL Unknown Erwinia carotovora
CarR, (CarI) 3-oxo-C6-HSL Carbapenem antibiotics, ExpR, ExpI
exoenzyme production Erwinia chrysanthemi ExpR, ExpI 3-oxo-C6-HSL
Pectinase expression (EchR, EchI) Escherichia coli SdiA Unknown
Cell division, virulence factor production Nitrosomonas europaea
Unknown 3-oxo-C6-HSL Emergence from lag phase Obesumbacterium
proteus OprR, OprI 3-oxo-C6-HSL Unknown Pantoea stewartii EsaR,
EsaI 3-oxo-C6-HSL Exopolysaccharide production, virulence factor
production Pseudomonas aeruginosa LasR, LasI 3-oxo-C12-
Extracellular virulence HSL factors, Xcp, biofilm formation, RpoS,
RhlR Pseudomonas aeruginosa RhlR, RhlI C4-HSL Extracellular
virulence factors, cyanide, lectins, pyocyanin, rhamnolipid, type 4
pili, twitching motility Pseudomonas aureofaciens PhzR, PhzI C6-HSL
Phenazine antibiotics Pseudomonas fluorescens HdtS 3-hydroxy-7-
Unknown cis-C14-HSL Ralstonia solanacearum SolR, SolI C8-HSL
Unknown Rhizobium etli RaiR, RaiI 7 HSLs Root nodulation Rhizobium
leguminosarum RhiR 3-hydroxy-7- Nodulation, bacteriocin,
cis-C14-HSL stationary phase survival Rhizobium leguminosarum RhiR,
RhiI C6-HSL, rhizome interactions C8-HSL Rhodobacter sphaeroides
CerR, CerI 7-cis-CH-HSL Clumping factor Serratia liquefaciens SwrR,
SwrI C4-HSL Swarming motility, protease, serrawettin W2, lipase
Vibrio anguillarum VanR, VanI 3-oxo-C10- Unknown HSL Vibrio
anguillarum VanM, VanN C6-HSL, Unknown 3-hydroxy-C6- HSL Vibrio
fischeri LuxR, LuxI 3-oxo-C6-HSL Bioluminescence Vibrio harveyi
LuxM, LuxN 3-hydroxy-C4- Bioluminescence, PHB HSL synthesis
Xenorhabdus nematophilus Unknown 3-hydroxy-C4- Virulence HSL
Yersinia enterocolitica YenR, YenI C6-HSL, Unknown 3-oxo-C6-HSL
Yersinia pestis YpeR, YpeI Unknown Unknown Yersinia
pseudotuberculosis YpsR, YpsI 3-oxo-C6-HSL Motility, clumping
Yersinia pseudotuberculosis YtbR, YtbI C8-HSL Unknown Yersinia
ruckeri YukR, YukI Unknown Unknown
[0006] With regard to bacteria that utilize HSL-based quorum
sensing as part of their lifestyle, Pseudomonas aeruginosa is
perhaps the best understood in terms of the role quorum sensing
plays in pathogenicity. In this human opportunistic pathogen, which
causes nosocomial infections in immunocompromised patients and has
an extremely high potential to develop resistance mechanisms
against traditional antibiotic treatment, production of many
virulence factors including expression of alkaline protease,
endoproteinase, LasA protease, LasB elastase, anthranilate
synthase, hemolysins, lectin, cytochrome c oxidase, catalase, Mn-
and Fe-dependent superoxide dismutases, exotoxin A, exoenzyme S,
chitinase, chitin binding protein, phenazine, hydrogen cyanide,
pyocyanin, pyoverdine, phospholipase C, rhamnolipids, sigma factor
S, components of the protein secretion apparatus, efflux
transporters, production of alginate and adhesion, twitching
motility and pilin export is regulated by two interlinked quorum
sensing circuits, Moreover, it has been demonstrated that this
signaling system is involved in the ability of P. aeruginosa to
form biofilms (Davies et al, Science 280:295-8, 1998). Recently
Huber et al. (Microbiology 147:2517-28, 2001) demonstrated that
biofilm formation and swarming motility of Burkholderia cepacia,
like P. aeruginosa a human opportunistic pathogen, is also
dependent on an HSL-based quorum sensing system.
[0007] Biofilms are defined as an association of microorganisms
growing attached to a surface and producing a slime layer of
extracellular polymers in which the microbial consortia is embedded
in a protective environment (for a review see: Costerton et al.,
Ann. Rev. Microbiol. 49:711-45, 1995). Biofilms represent a severe
problem as bacteria integrated in such a polymer matrix develop
resistance to conventional antimicrobial agents. P. aeruginosa
cells, for example, growing in an alginate slime matrix have been
demonstrated to be resistant to antibiotics (e.g., aminoglycosides,
.beta.-lactam antibiotics, fluoroquinolones) and disinfectants
(Govan & Deretic, Microbiol. Rev. 60:539-74, 1996). Several
mechanisms for biofilm-mediated resistance development have been
proposed (Costerton et al., Science 284:1318-22, 1999).
[0008] In most natural, clinical and industrial settings bacteria
are predominantly found in biofilms. Drinking water pipes, ship
hulls, teeth or medical devices represent typical surfaces
colonized by bacteria. On the one hand biofilms decrease the life
time of materials through corrosive action in the industrial field,
a process also referred to as "biofouling". Furthermore, microbial
biofilms growing for example on ship hulls increase fuel
consumption through enhanced frictional resistance and
simultaneously reduce maneuverability. On the other hand two thirds
of all bacterial infections in humans are associated with biofilms
(Lewis, Antimicrob. Agents Chemother. 45:999-1007, 2001).
[0009] Pseudomonas aeruginosa, for example, forms infectious
biofilms on surfaces as diverse as cystic fibrosis lung tissue,
contact lenses, and Catheter tubes (Stickler et al., Appl.
Environm. Microbiol. 64:3486-90, 1998). Burkholderia cepacia also
forms biofilms in lungs of cystic fibrosis patients and is a major
industrial contaminant (Govan et al., J. Med. Microbiol.
45:395-407, 1996). Since biofilm formation of both organisms is
demonstrated to require an HSL signaling system, inhibition of
their quorum sensing systems would result in an impaired ability to
form biofilms and therefore in an increased susceptability to
antibacterial treatment.
[0010] Beside the role of HSL derivatives as signaling molecules of
bacterial cell-to-cell communication it has been demonstrated that
HSL interfere also with higher organisms. Since HSL derivatives
inhibit murine and human leucocyte proliferation and TNF-alpha
secretion by lipopolysaccharide (LPS) stimulated human leucocytes
(Chhabra et al., J. Med. Chem. 46:97-104, 2003), the suitability of
these compounds for immunological diseases, particularly autoimmune
diseases such as psoriasis, rheumatoid arthritis, multiple
sclerosis and type 1 (autoimmune) diabetes is indicated (WO
03/004017, WO 03/022828).
[0011] Furthermore, certain HSL molecules are capable of reducing
the heart beat without substancially reducing arterial blood
pressure. These compounds and analogs of them could, therefore, be
suitable for the treatment of cardiac tachyarrhythmias, ischaemic
heart disease, congestive heart failure (WO 01/26650).
Additionally, HSL compounds have been reported as possible
antiallergic drug (WO 95/01175) and for the treatment of a range of
diseases including cancer, breast cancer, obesity, lipid metabolism
disorders, immune disease, immune deficiency or immune disorders by
modulating STAT activity (WO 03/026641).
[0012] The discovery that a wide spectrum of bacterial organisms
use quorum sensing to control virulence factor production and other
phenotypes such as biofilm formation makes it an attractive target
for antimicrobial therapy. Pathogenic organisms using this
signaling system to control virulence could potentially be rendered
avirulent by blocking this cell-cell communication system. In
contrast to traditional antibiotics, the risk of resistance
development seems to be very low, since quorum sensing blocking
agents would not kill the organism but disturb signal transduction
pathways. There are several possibilities of interrupting the
quorum sensing circuit.
[0013] For example, plants expressing an HSL-lactonase enzyme
originally derived from Bacillus sp. have been demonstrated to
quench pathogen quorum sensing signaling and to significantly
enhance resistance to Erwinia carotovora infections (Dong et al.,
Nature 411:813-7, 2001). An alternative way to block cell signaling
could be to interrupt the HSL synthesis by using analogs of HSL
precursors.
[0014] However, the most promising possibility to block quorum
sensing is to take advantage of the unique specificity the HSLs and
HSL-receptor proteins show for one another. The ability of
homoserine lactone-based analogs to inhibit activation of
HSL-receptor proteins has already been demonstrated in a number of
bacteria including Vibrio fischeri (Schaefer et al, J. Bacteriol.
178:2897-901, 1996), Agrobacterium tumefaciens (Zhu et al., J.
Bacteriol. 180:5398-405, 1998), Chromobacterium violaceum (McLean
et al., Microbiology 143:3703-11, 1997), Aeromonas salmonicida
(Swift et al., J. Bacteriol. 179:5271-81, 1997) and Pseudomonas
aeruginosa (Pesci et al., J. Bacteriol. 179:3127-32, 1997).
However, none of these compounds have been developed as
antimicrobial agents, e.g. in medical therapy, so far.
[0015] The are only few non-HSL-based antimicrobials described
which are supposed to interfere specifically with HSL-regulated
processes, for example halogenated furanone derivatives which are
structurally similar to HSLs and have been isolated from red marine
algae Delisea pulchra (WO 96129392; Hentzer et al., Microbiology
148:87-102, 2002). Additionally, these substances have been
demonstrated to inhibit also Gram-positive bacteria (WO 99/53915).
However, the use of most of these furanone compounds is limited due
to their toxicity making them unsuitable for veterinary and medical
applications.
[0016] Furthermore, Smith et al. (Chem. Biol., 10:81-9, 2003)
recently published Pseudomonas aeruginosa HSL analogs with slight
structural variations targeted to the HSL moiety which act both as
quorum sensing agonists and antagonists. Additionally, WO 02/088298
reportedly provides certain nitrogen heterocyclic molecules for
controlling biofilms based on the interference with quorum
sensing.
[0017] Many target genes involved in biofilm formation, methods of
screening for compounds to control biofilm development and
HSL-based compositions to prevent biofilm formation have been
described (WO 99/55368, WO 98/57618, WO 99/27786, WO 98/58075), but
until now no promising antibacterial drug candidate has been
developed that is capable of inhibiting virulence gene expression
and biofilm formation in different areas, preferentially in the
medical field.
[0018] It is an object of the present invention to provide
compounds blocking specifically quorum sensing regulated processes
without inhibiting bacterial growth, Furthermore, these compounds
should not be structural derivatives of the homoserine lactone
family of regulatory compounds and should not exhibit any toxic
properties.
BRIEF SUMMARY OF THE INVENTION
[0019] Accordingly, we have been able to find compounds that can
significantly reduce virulence gene expression and biofilm
formation of several human pathogens. In contrast to the furanones
the compounds of this invention do not show any toxic effect and
are therefore suitable for applications in a wide area. Such
applications could be the use of the compounds for instance as new
antibiotic therapeutics, disinfectants, antifouling coatings or
coatings of medical devices. In contrast to traditional
antibacterial agents (like amide or 1,2-acylhydrazine derivatives
in WO 01/51456; for the synthesis of amide or 1,2-acylhydrazine
derivatives see also EP 638545 and EP 982292), the compounds of the
present invention do not kill the microorganisms, but render them
avirulent. The advantage of this alternative strategy is that the
emergence of bacterial resistance against such antimicrobials is
extremely improbable.
[0020] In general, the present invention provides compounds
selectively modulating bacterial cell-cell communication. Through
inhibition of this communication system the expression of many
HSL-dependent virulence genes and other phenotypes like swarming
motility and biofilm formation are significantly reduced or
completely abolished rendering a bacterial population more
susceptible to the host immune-response or to treatment with
traditional antibacterial agents.
[0021] Thus, in one aspect, the invention refers to a method for
inhibiting an HSL-regulated process in a microorganism by exposing
the microorganism to a new class of compounds with an inhibitory
effect on bacterial signaling.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] FIG. 1 illustrates a general N-acyl-L-homoserine lactone
structure where the depicted R is an acyl side chain;
[0023] FIG. 2 graphically illustrates the influence of
representative compounds of the present invention on the growth of
E. coli MT102 (pSB403);
[0024] FIG. 3 graphically illustrates the inhibitory effect of
representative compounds of the present invention on the protease
production of P. aeruginosa PAO-JP2;
[0025] FIG. 4 graphically illustrates the influence of
representative compounds of the present invention on the growth of
P. aeruginosa PAO-JP2;
[0026] FIG. 5A graphically illustrates the inhibitory effect of
representative compounds of the present invention (0.4 mM) on
biofilm formation of Burkholderia cepacia H111, with statistical
data of at least five (5) separate representative experiments;
[0027] FIG. 5B is an illustration of a microtitre dish;
[0028] FIG. 6 graphically illustrates the influence of
representative compounds of the present invention (0.4 mM) on the
growth of Burkholderia cepacia H111.
DETAILED DESCRIPTION OF THE INVENTION
[0029] The present invention therefore refers to compounds of the
general Formula (I)
##STR00002##
wherein [0030] R is H, alkyl, cycloalkyl, aryl or heteroaryl;
[0031] R.sup.1 is H, alkyl, cycloalkyl, aryl or heteroaryl; [0032]
R.sup.2 is H, alkyl, cycloalkyl, aryl or heteroaryl; [0033] A.sup.1
and A.sup.2 each independently represent an optionally substituted
C.sub.1-C.sub.20-alkyl group which may contain one or more group(s)
Z, or a monocyclic or polycyclic optionally substituted aromatic or
non-aromatic rind system which may contain one or more group(s) X,
and in case of a polycyclic ring system, said system contains at
least one aromatic ring; [0034] Z is selected from the group
consisting of S, O, N, NR.sup.4, CO, CO.sub.2, CS, SO or SO.sub.2
[0035] X is selected from the group consisting of S, O, N,
NR.sup.4, SO or SO.sub.2; [0036] said substituted ring system
carries a substituent R.sup.3 on one or more of the carbon atoms of
said ring system; [0037] said substituted C.sub.1-C.sub.20-alkyl
group carries a substituent R.sup.3 on one or more of the carbon
atoms of said alkyl group; [0038] R.sup.3 is independently H,
OR.sup.4, SR.sup.4, hydroxyalkyl, hydroxyalkylamino, cycloalkyl,
halogen, haloalkyl, haloalkyloxy, NO.sub.2, CN,
SO.sub.2NR.sup.4R.sup.5, CO.sub.2NR.sup.4R.sup.5, COR.sup.4,
CO.sub.2R.sup.4, SO.sub.2R.sup.4, SO.sub.3R.sup.4, NR.sup.4R.sup.5,
alkyl, aryl or heteroaryl; [0039] R.sup.3' is independently H,
OR.sup.4, SR.sup.4, hydroxyalkyl, hydroxyalkylamino, cycloalkyl,
halogen, haloalkyl, haloalkyloxy, NO.sub.2, CN,
SO.sub.2NR.sup.4R.sup.5, CO.sub.2R.sup.4R.sup.5, COR.sup.4,
CO.sub.2R.sup.4, SO.sub.2R.sup.4, SO.sub.3R.sup.4, NR.sup.4R.sup.5,
alkyl, aryl or heteroaryl; [0040] R.sup.3'' is independently H,
OR.sup.4, SR.sup.4, hydroxyalkyl, hydroxyalkylamino, cycloalkyl,
halogen, haloalkyl, haloalkyloxy, NO.sub.2, CN,
SO.sub.2NR.sup.4R.sup.5, CO.sub.2NR.sup.4R.sup.5, COR.sup.4,
CO.sub.2R.sup.4, SO.sub.2R.sup.4, SO.sub.3R.sup.4, NR.sup.4R.sup.5,
alkyl, aryl or heteroaryl; [0041] R.sup.4 is H, alkyl, cycloalkyl,
aryl or heteroaryl; [0042] R.sup.5 is H, O-alkyl, O-aryl, alkyl,
heteroaryl or aryl; [0043] Y.sup.1 and Y.sup.2 are independent from
each other C.dbd.O, C.dbd.S, SO.sub.2, or C.dbd.NR.sup.5; [0044] p
is 0, n is 0; [0045] or p is 0, n is 1; [0046] or p is 1, n is 0;
[0047] or p is 1, n is 1;
[0048] In Formula (I) the following definitions are used: [0049] an
alkyl group, if not stated otherwise, denotes a linear or branched
C.sub.1-C.sub.6-alkyl, preferably a linear or branched chain of one
to five carbon atoms, a linear or branched C.sub.1-C.sub.6-alkenyl
or a linear or branched C.sub.1-C.sub.6-alkinyl group, which can
optionally be substituted by one or more substituents R.sup.3,
preferably by halogen; [0050] the C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkenyl and C.sub.1-C.sub.6-alkinyl residue may be
selected from the group comprising --CH.sub.3, --C.sub.2H.sub.5,
--CH.dbd.CH.sub.2, --C.ident.CH, --C.sub.3H.sub.7, --CH(CH).sub.2,
--CH.sub.2--CH.dbd.CH.sub.2, --C(CH.sub.3).dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.3, --C.ident.C--CH.sub.3,
--CH.sub.2.dbd.C.ident.CH, --C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--C.sub.2H.sub.5,
--C(CH.sub.3).sub.3, --C.sub.5H.sub.11, --C.sub.6H.sub.13,
--C(R.sub.3).sup.3, --CR.sup.3(R.sup.3').sub.2,
--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.2(R.sup.3).sub.5,
--CH.sub.2--C(R.sup.3).sub.3, --CH.sub.2--CR.sup.3(R.sup.3').sub.2,
--CH.sub.2--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.3(R.sup.3).sub.7,
--C.sub.3(R.sup.3).sub.7, --C.sub.2H.sub.4--C(R.sup.3).sub.3,
--C.sub.2H.sub.4--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.2H.sub.5,
--CH.dbd.C(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.dbd.CH.sub.2, --C.sub.2H.sub.4--C.ident.CH,
--C.ident.C--C.sub.2H.sub.5, --CH.sub.2--C.ident.CH.sub.3,
--C.ident.C--CH.dbd.CH.sub.2, --CH.dbd.CH--C.ident.CH,
--C.ident.C--C.ident.CH, --C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.2--CH.sub.5,
--CH.sub.2--C(CH.sub.3).sub.3, --C.sub.3H.sub.6--CH.dbd.CH.sub.2,
--CH.dbd.CH--C.sub.3H.sub.7, --C.sub.2H.sub.4--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--CH.dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.dbd.C--CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2--CH.dbd.C(CH.sub.3).sub.2,
--C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.3H.sub.6--C.ident.CH,
--C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.ident.CH.sub.3,
--CH--C.ident.C--C.sub.2H.sub.5, --CH.sub.2--C.ident.C--CH.sub.2,
--CH.sub.2--CH.dbd.CH--C.ident.CH,
--CH.sub.2--C.ident.C--C.ident.CH,
--C.ident.C--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--C.ident.C--CH.sub.3,
--C.ident.C--C.ident.C--CH.sub.3,
--C.ident.C--CH.sub.2--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.2--C.ident.CH,
--C.ident.C--CH.sub.2--C.ident.CH,
--C(CH.sub.3).dbd.CH--CH--CH.dbd.CH.sub.2,
--CH.dbd.CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--C.ident.CH, --CH.dbd.C(CH.sub.3)--C.ident.CH,
--C.ident.C--C(CH.sub.3).dbd.CH.sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3, --C.sub.4H.sub.8H.dbd.CH.sub.2,
--CH.dbd.CH--C.sub.4H.sub.9, --C.sub.3H.sub.6--CH.dbd.CH--CH.sub.3,
--CH.sub.2--H.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--C(CH.sub.3).dbd.C(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH.dbd.C(CH.sub.3).sub.2,
--C.sub.4H.sub.8--C.ident.CH, --C.ident.C--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C.ident.C--C.sub.2H.sub.5; [0051] a cycloalkyl
group denotes a non-aromatic ring system containing three to eight
carbon atoms, preferably four to eight carbon atoms, wherein one or
more of the carbon atoms in the ring can be substituted by a group
X, X being as defined above; the C.sub.3-C.sub.8-cycloalkyl residue
may be selected from the group comprising -cyclo-C.sub.3H.sub.5,
-cyclo-C.sub.4H.sub.7, -cyclo-C.sub.5H.sub.9,
-cyclo-C.sub.6H.sub.11, -cyclo-C.sub.7H.sub.13,
-cyclo-C.sub.8H.sub.15; [0052] an alkoxy group denotes an O-alkyl
group, the alkyl group being as defined above; the alkoxy group is
preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy
group; [0053] an haloalkyl group denotes an alkyl group which is
substituted by one to five halogen atoms, the alkyl group being as
defined above; the haloalkyl group is preferably a
--C(R.sup.10).sub.3, --CR.sup.10(R.sup.10').sub.2,
--CR.sup.10(R.sup.10')R.sup.10'', --C.sub.2(R.sup.10).sub.5,
--CH.sub.2--C(R.sup.10).sub.3,
--CH.sub.2--CR.sup.10(R.sup.10').sub.2,
--CH.sub.2--CR.sup.10(R.sup.10')R.sup.10'',
--C.sub.3(R.sup.10).sub.7 or --C.sub.2H.sub.4--C(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10', R.sup.10'' represent F, Cl, Br or I,
preferably F; [0054] a hydroxyalkyl group denotes an HO-alkyl
group, the alkyl group being as defined above; [0055] an
haloalkyloxy group denotes an alkoxy group which is substituted by
one to five halogen atoms, the alkyl group being as defined above;
the haloalkyloxy group is preferably a --OC(R.sup.10).sub.3,
--OCR.sup.10(R.sup.10').sub.2, --OCR.sup.10(R.sup.10')R.sup.10'',
--OC.sub.2(R.sup.10'').sub.5, --OCH.sub.2--(R.sup.10).sub.3,
--OCH.sub.2--CR.sup.10(R.sup.10').sub.2,
--OCH.sub.2--CR.sup.10(R.sup.10')R.sup.10'',
--OC.sub.3(R.sup.10).sub.7 or --OC.sub.2H.sub.4--C(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10', R.sup.10'', represent F, Cl, Br or I,
preferably F; [0056] a hydroxyalkylamino group denotes an
(HO-alkyl).sub.2-N-group or HO-alkyl-NH-group, the alkyl group
being as defined above; [0057] a halogen group is chlorine,
bromine, fluorine or iodine; [0058] an aryl group preferably
denotes an aromatic group having five to fifteen carbon atoms,
which can optionally be substituted by one or more substituents
R.sup.3, where R.sup.3 is as defined above; the aryl group is
preferably a phenyl group, --CH.sub.2--C.sub.6H.sub.4,
--C.sub.2H.sub.4--C.sub.6H.sub.4, --CH.dbd.CH--C.sub.6H.sub.4,
--C.ident.C--C.sub.6H.sub.4, -o-C.sub.6H.sub.4--R.sup.3,
-m-C.sub.64--R.sup.3, -p-C.sub.6H.sub.4R.sup.3,
-o-CH.sub.2--C.sub.6H.sub.4--R.sup.3,
-m-CH.sub.2--C.sub.6H.sub.4--R.sup.3,
-p-CH.sub.2--C.sub.6H.sub.4--R.sup.3; [0059] a heteroaryl group
denotes a 5- or 6-membered heterocyclic group which contains at
least one heteroatom like O, N, S. This heterocyclic group can be
fused to another ring. For example, this group can be selected from
an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,
isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,
1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl,
2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl,
1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, indolyl, indolinyl,
benzo-[b]-furanyl, benzo[b]thiophenyl, benzimidazolyl,
benzothiazolyl, quinazolinyl, quinoxazolinyl, or preferably
isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, quinolinyl,
tetrahydro-quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl
group. This heterocyclic group can optionally be substituted by one
or more substituents R.sup.3, where R.sup.3 is as defined
above.
[0060] In Formula (I), A.sup.1 or A.sup.2 each independently
represent a C.sub.1-C.sub.20-alkyl group which is optionally
substituted by one or more substituents R.sup.3, or a monocyclic or
polycyclic aromatic or non-aromatic ring system which is optionally
substituted by one or more substituents R.sup.3 and in case of an
aromatic ring system contains at least one aromatic ring. The
optionally substituted monocyclic or polycyclic aromatic or
non-aromatic ring system may also contain one or more groups X
selected from S, O, N, NR.sup.4, SO or SO.sub.2. In preferred
embodiments, A.sup.1 and A.sup.2 each independently represent an
optionally substituted C.sub.1-C.sub.20-alkyl group or an
optionally substituted monocyclic or bicyclic aromatic ring system.
In case of substitutions of carbon atoms in the ring system,
preferably one, two or three carbon atoms am substituted by a group
X, wherein X is selected from the group consisting of S, O, N,
NR.sup.4, SO or SO.sub.2. In one preferred embodiment, one of the
carbon atoms is substituted by a group X.dbd.O, S, NH.
[0061] In Formula (I), A.sup.1 and/or A.sup.2 independently
represent an optionally substituted C.sub.1-C.sub.20-alkyl group
which is optionally substituted by one or more substituents
R.sup.3. Preferably A.sup.1 and/or A.sup.2 independently represent
an optionally substituted C.sub.1-C.sub.12-alkyl group, said alkyl
group may be a straight chain or branched chain alkyl group, and
examples include methyl, ethyl, propyl, isopropyl, butyl, t-butyl,
isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and
dodecyl groups. The term alkyl group also contains alkenyl and
alkinyl groups, that means that the alkyl group contains one or
more double or triple bounds.
[0062] In Formula (I), A.sup.1 and/or A.sup.2 represent an
optionally aromatic or non-aromatic ring system, which is
substituted by one or more substituents R.sup.3, said ring system
may be a phenyl, 1-naphthyl, 2-napthyl, 1-anthracenyl,
2-anthracenyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2-thiazolyl,
4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, in
particular 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl,
3-pyrazinyl, 1-imidazolyl, 2-imidazolyl, 2-thienyl, 3-thienyl,
2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, benzothiophene,
pyrazolo[3,4-b]-pyridyl, 2-pyrimidyl, 4-pyrimidyl and
9H-thioxanthene-10,10-dioxide ring, in which the ring system can be
fused to one or more other monocyclic aromatic or non-aromatic
rings.
[0063] Suitable substituents for A.sup.1 and/or A.sup.2 are
independently H, CO.sub.2R.sup.4, COR.sup.4, CONR.sup.4R.sup.5,
NR.sup.4R.sup.5, OR.sup.4, SR.sup.4, hydroxyalkylamino, NO.sub.2,
CN, hydroxylalkyl, halogen, haloalkyl, haloalkyloxy,
SO.sub.2NR.sup.4R.sup.5, CO.sub.2NR.sup.4R.sup.5, CO.sub.2R.sup.4,
SO.sub.2R.sup.4, SO.sub.3R.sup.4, NR.sup.4R.sup.5, alkyl,
cycloalkyl, arylalkyl, aryl or heteroaryl.
[0064] Furthermore the present invention is directed to novel
compounds of the general Formula (X) and pharmaceutically
acceptable salts thereof:
##STR00003##
wherein [0065] A.sup.3 is an optionally substituted
C.sub.3-C.sub.20-alkyl group or
[0065] ##STR00004## [0066] an C.sub.3-C.sub.20-alkyl group denotes
a linear or branched C.sub.3-C.sub.20-alkyl group, which is
optionally substituted by R.sup.3, R.sup.3 being as defined below;
the C.sub.3-C.sub.20-alkyl residue may be selected from the group
comprising --C.sub.3H.sub.7, --CH(CH.sub.3).sub.2,
--CH.sub.4H.sub.9, --CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.2H.sub.5, --CH.sub.2--CH(CH.sub.3)--CH.sub.3,
--C(CH.sub.3).sub.3, --C.sub.5H.sub.C3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.6H.sub.13, --C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2),
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3, --C.sub.7H.sub.15,
--C.sub.3H.sub.6--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH(CH.sub.3).sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.3H.sub.5,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH(CH.sub.3)--C.sub.5H.sub.11, --C(CH.sub.3).sub.2--CH.sub.3,
--C(CH.sub.3).sub.2--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH.sub.2--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH.sub.2--C(CH.sub.3).sub.3,
--CH.sub.2--CH(CH.sub.3)--C(CH.sub.3).sub.3, --C.sub.8H17,
--C.sub.4H.sub.8--C(CH.sub.3).sub.3,
--C.sub.5H.sub.10--CH(CH.sub.3).sub.2,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.5H.sub.11,
--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--CH(CH.sub.3)--C.sub.6H.sub.13, --C.sub.9H.sub.19,
--C.sub.5H.sub.10--C(CH.sub.3).sub.3,
--C.sub.6H.sub.12--CH(CH.sub.3).sub.2,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.4H.sub.8--C(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.49,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.5H.sub.11,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--CH.sub.2--CH(CH.sub.3)--C.sub.6H.sub.13,
--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--CH(CH.sub.3)--C.sub.7H.sub.15, --C.sub.10H.sub.21,
--C.sub.6H.sub.12--C(CH.sub.3).sub.3,
--C.sub.7H.sub.14--CH(CH.sub.3).sub.2,
--C.sub.6H.sub.12--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.5H.sub.10--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.5H.sub.11,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.6H.sub.13,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--CH.sub.2--CH(CH.sub.3)--C.sub.7H.sub.15,
--C(CH.sub.3).sub.2--C.sub.7H.sub.15,
--CH(CH.sub.3)--C.sub.8H.sub.17, --C.sub.11H.sub.23,
--C.sub.7H.sub.14--C(CH.sub.3).sub.3,
--C.sub.8H.sub.16--CH(CH.sub.3).sub.2,
--C.sub.7H.sub.14--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.6H.sub.12--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.6H.sub.12--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.5H.sub.10--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.5H.sub.11,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.5H11,
--C.sub.3H6--CH(CH.sub.3)--C.sub.6H.sub.13,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.7H.sub.15,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.7H.sub.15,
--CH.sub.2--CH(CH.sub.3)--C.sub.8H.sub.17,
--C(CH.sub.3).sub.2--C.sub.8H.sub.17,
--CH(CH.sub.3)--C.sub.9H.sub.19, --C.sub.12H.sub.25,
--C.sub.8H.sub.16--C(CH.sub.3).sub.3,
--C.sub.9H.sub.18--CH(CH.sub.3).sub.2,
--C.sub.8H.sub.16--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.7H.sub.14--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.7H.sub.14--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.6H.sub.12--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.6H.sub.12--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.5H.sub.10--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.5H.sub.11,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.6H.sub.13,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.7H.sub.15,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.7H.sub.15,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.8H.sub.17,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.8H.sub.17,
--CH.sub.2--CH(CH.sub.3)--C.sub.9H.sub.19,
--C(CH.sub.3).sub.2--C.sub.9H.sub.19,
--CH(CH.sub.3)--C.sub.10H.sub.21; [0067] R.sup.6 is independently
of each other --H, --F, --Cl, --Br, --I, --NO.sub.2,
--NR.sup.4R.sup.5, --CN, alkyl, cycloalkyl, --OH, alkoxy,
alkylthio, hydroxyalkylamino, haloalkyl, haloalkyloxy,
hydroxyalkyl, aryl or heteroaryl; [0068] R.sup.7 is independently
of each other --H, --F, --Cl, --Br, --I, --NO.sub.2,
--NR.sup.4R.sup.5, --CN, alkyl, cycloalkyl, --OH, alkoxy,
alkylthio, hydroxyalkylamino, haloalkyl, haloalkyloxy,
hydroxyalkyl, aryl or heteroaryl; [0069] R.sup.8 is independently
of each other --H, --F, --Cl, --Br, --I, --NO.sub.2,
--NR.sup.4R.sup.5, --CN, alkyl, cycloalkyl, --OH, alkoxy,
alkylthio, hydroxyalkylamino, haloalkyl, haloalkyloxy,
hydroxyalkyl, aryl or heteroaryl; [0070] X is selected from the
group consisting of S, O, N, NR.sup.4, SO or SO.sub.2; [0071]
R.sup.4 is H, alkyl, cycloalkyl, aryl or heteroaryl; [0072] R.sup.5
is H, O-alkyl, O-aryl, alkyl, heteroaryl or aryl; [0073] R.sup.3,
R.sup.3' or R.sup.3'' are independently H, OR.sup.4, SR.sup.4,
hydroxyalkyl, hydroxyalkylamino, cycloalkyl, halogen, haloalkyl,
haloalkyloxy, NO.sub.2, CN, SO.sub.2NR.sup.4R.sup.5,
CO.sub.2NR.sup.4R.sup.5, COR.sup.4, CO.sub.2R.sup.4,
SO.sub.2R.sup.4, SO.sub.3R.sup.4, NR.sup.4R.sup.5, alkyl aryl or
heteroaryl; with R.sup.4, R.sup.5 being as defined above; [0074] an
alkyl group, if not stated otherwise, denotes a linear or branched
C.sub.1-C.sub.6-alkyl, preferably a linear or branched chain of one
to five carbon atoms, a linear or branched C.sub.1-C.sub.6-alkenyl
or a linear or branched C.sub.1-C.sub.6-alkinyl group, which can
optionally be substituted by one or more substituents R.sup.3,
preferably by halogen; [0075] the C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkenyl and C.sub.1-C.sub.6-alkinyl residue may be
selected from the group comprising --CH.sub.3, --C.sub.2H.sub.5,
--CH.dbd.CH.sub.2, --C.ident.CH, --C.sub.3H.sub.7,
--CH(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3,
--C.ident.C--CH.sub.3, --CH.sub.2--C.ident.CH, --C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--C.sub.2H.sub.5,
--C(CH.sub.3).sub.3, --C.sub.5H.sub.11, --C.sub.6H.sub.13,
--C(R.sup.3).sub.3, --CR(R.sup.3').sub.2,
--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.2(R.sup.3).sub.5,
--CH.sub.2--C(R.sup.3).sub.3, --CH.sub.2--CR.sup.3(R.sup.3').sub.2,
--CH.sub.2--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.3(R.sup.3).sub.7,
--C.sub.2H.sub.4--C(R.sup.3).sub.3,
--C.sub.2H.sub.4--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.2H.sub.5,
--CH.dbd.C(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.dbd.CH.sub.2, --C.sub.2H.sub.4--C.ident.CH,
--C.ident.C-c.sub.2H.sub.5, --CH.sub.2--CH.ident.C--CH.sub.3,
--C.ident.C--CH.dbd.CH.sub.2, --CH.dbd.CH--C.ident.CH,
--C.ident.C--C.ident.CH, --C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.3H.sub.6--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--CH.dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2--CH.dbd.C(CH.sub.3).sub.2,
--C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.3H.sub.6--C.ident.CH,
--C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.2H.sub.5,
--CH.sub.2--C.ident.C--CH.dbd.CH.sub.2,
--CH.sub.2--CH.dbd.CH--C.ident.CH,
--CH.sub.2--C.ident.C--C.ident.CH,
--C.ident.C--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--C.ident.C--CH.sub.3,
--C.ident.C--C.ident.C--CH.sub.3,
--C.ident.C--CH.sub.2--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.2--C.ident.CH,
--C.ident.C--CH.sub.2--C.ident.CH,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--C.ident.CH, --CH.dbd.C(CH.sub.3)--C.ident.CH,
--C.ident.C--C(CH.sub.3).dbd.CH.sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--.sub.CH2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.2H.sub.7,
--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.4H.sub.9,
--C.sub.3H.sub.6--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--C(CH.sub.3).dbd.C(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH.dbd.C(CH.sub.3).sub.2,
--C.sub.4H.sub.8--C.ident.CH, --C.ident.C.sub.4H.sub.9,
--C.sub.3H.sub.6--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C.ident.C--C.sub.2H.sub.5; [0076] a cycloalkyl
group denotes a non-aromatic ring system containing three to eight
carbon atoms, preferably four to eight carbon atoms, wherein one or
more of the carbon atoms in the ring can be substituted by a group
X, X being as defined above; the C.sub.3-C.sub.8-cycloalkyl residue
may be selected from the group comprising -cyclo-C.sub.3H.sub.5,
-cyclo-C.sub.4H.sub.7, -cyclo-C.sub.5H.sub.9,
-cyclo-C.sub.6H.sub.11, -cyclo-C.sub.7H.sub.13,
-cyclo-C.sub.8H.sub.15; [0077] an alkoxy group denotes an O-alkyl
group, the alkyl group being as defined above; the alkoxy group is
preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy
group. [0078] an haloalkyl group denotes an alkyl group which is
substituted by one to five halogen atoms, the alkyl group being as
defined above; the haloalkyl group is preferably a
--C(R.sup.10).sub.3, --CR.sup.10(R.sup.10').sub.2,
--CR.sup.10(R.sup.10')R.sup.10'', --C.sub.2(R.sup.10).sub.5,
--CH.sub.2--C(R.sup.10).sub.3,
--CH.sub.2--CR.sup.10(R.sup.10').sub.2,
--CH.sub.2--CR.sup.10(R.sup.10')R.sup.10'',
--C.sub.3(R.sup.10).sub.7 or --C.sub.2H.sub.4--C(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10', R.sup.10'' represent F, Cl, Br or I,
preferably F; [0079] a hydroxyalkyl group denotes an HO-alkyl
group, the alkyl group being as defined above: [0080] an
haloalkyloxy group denotes an alkoxy group which is substituted by
one to five halogen atoms, the alkyl group being as defined above;
the haloalkyloxy group is preferably a --OC(R.sup.10).sub.3,
--OCR.sup.10(R.sup.10').sub.2, --OCR.sup.10(R.sup.10')R.sup.10'',
--OC.sub.2(R.sup.10).sub.5, --OCH.sub.2--C(R.sup.10).sub.3,
--OCH.sub.2--CR.sup.10(R.sup.10').sub.2,
--OCH.sub.2--CR.sup.10(R.sup.10')R.sup.10'',
--OC.sub.3(R.sup.10).sub.7 or --OC.sub.2H.sub.4--C(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10', R.sup.10'' represent F, Cl, Br or I,
preferably F; [0081] a hydroxyalkylamino group denotes an
(HO-alkyl).sub.2-N-group or HO-alkyl-NH-group, the alkyl group
being as defined above; [0082] a halogen group is chlorine,
bromine, fluorine or iodine; [0083] an aryl group preferably
denotes an aromatic group having five to fifteen carbon atoms,
which can optionally be substituted by one or more substituents
R.sup.3, where R.sup.3 is as defined above, the aryl group is
preferably a phenyl group, --CH.sub.2--C.sub.6H.sub.4,
--C.sub.2H.sub.4--C.sub.6H.sub.4, --CH.dbd.CH--C.sub.6H.sub.4,
--C.ident.C--C.sub.6H.sub.4, -o-C.sub.6H.sub.4--R.sup.3,
-m-C.sub.6H.sub.4--R.sup.3, -p-C.sub.6H.sub.4--R.sup.3,
-o-CH.sub.2--C.sub.6H.sub.4R.sup.3,
-m-CH.sub.2--C.sub.6H.sub.4--R.sup.3,
-p-CH.sub.2--C.sub.6H.sub.4--R.sup.3; [0084] a heteroaryl group
denotes a 5- or 6-membered heterocyclic group which contains at
least one heteroatom like O, N, S. This heterocyclic group can be
fused to another ring. For example, this group can be selected from
an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,
isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,
1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl,
2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl,
1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, indolyl, indolinyl,
benzo-[b]-furanyl, benzo[b]thiophenyl, benzimidazolyl,
benzothiazolyl, quinazolinyl, quinoxazolinyl, or preferably
isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, quinolinyl,
tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl group.
This heterocyclic group can optionally be substituted by one or
more substituents R.sup.3, where R.sup.3 is as defined above.
[0085] However, the following compounds are excluded from Formula
(X): [0086] 2-thiophenecarboxylic
acid-5-nitro-2-(2-thienylcarbonyl)hydrazide,
4butylthiophene-2-carboxylic
acid-N'-(4-butyl-thiophen-2-carbonyl)hydrazide,
2-thiophenecarboxylic acid-3-chloro-2-(2-thienylcarbonyl)hydrazide,
2-thiophene carboxylic acid-5-bromo-2-(2-thienylcarbonyl)hydrazide,
1H-pyrazole-5-carboxylic
acid-1-methyl-2-(2-thienylcarbonyl)hydrazide, 2-thiophenecarboxylic
acid-5-(4,5,6,7-tetrahydro-benzo[b]thien-2-yl)-2-[[5-(4,5,6,7-tertahydrob-
enzo[b]thien-2-yl)-2-thienyl]-carbonyl]-hydrazide,
1H-pyrrole-2-carboxylic acid-2-(2-thienylcarbonyl)hydrazide,
2-thiophenecarboxylic acid-2-(2-thienylcarbonyl)-hydrazide,
2-thiophenecarboxylic acid N'-(furan-2-carbonyl)hydrazide,
2-thiophenecarboxylic acid-N-(5-bromofuran-2-carbonyl)hydrazide,
1H-pyrazole-3-carboxylic
acid-4-bromo-1,5-dimethyl-2-(2-thienylcarbonyl)hydrazide,
thiophene-2-carboxylic acid
N'-(3-chloro-4-methylthiophene-2-carbonyl)hydrazide and
2-furancarboxylic
acid-5-[[[4-methyl-6-(trifluoromethyl)-2-pyrimidinyl]thio]methyl]-2-(2-th-
ienylcarbonyl)hydrazide. Furthermore the present invention is
directed to novel compounds of the general Formula (X) and
pharmaceutically acceptable salts thereof:
##STR00005##
[0086] wherein [0087] A.sup.3 is an optionally substituted
C.sub.3-C.sub.20-alkyl group or
[0087] ##STR00006## [0088] with the C.sub.3-C.sub.20-alkyl group
being as defined above for Formula (X) [0089] R.sup.3 is defined as
above in Formula (X) [0090] R.sup.4 is defined as above in Formula
(X) [0091] R.sup.5 is defined as above in Formula (X) [0092]
R.sup.6 is independently of each other --H, --F, --Cl, --Br, --I,
--NR.sup.4R.sup.5, C.sub.1-C.sub.3-alkyl, alkoxy, alkylthio,
hydroxyalkylamino, --CN, --NO.sub.2, --OH, haloalkyl, haloalkyloxy,
hydroxyalkyl, aryl or heteroaryl; [0093] said C.sub.1-C.sub.3-alkyl
of R.sup.6 denotes a linear or branched C.sub.1-C.sub.3-alkyl, a
linear or branched C.sub.1-C.sub.3-alkenyl or a linear or branched
C.sub.1-C.sub.3-alkinyl group, which can optionally be substituted
by one or more substituents R', preferably by halogen; the
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkenyl and
C.sub.1-C.sub.3-alkinyl residue may be selected from the group
comprising --CH.sub.3, --C.sub.2H.sub.5, --CH.dbd.CH.sub.2,
--.ident.CH, --C.sub.3H.sub.7, --CH(CH.sub.3).sub.2,
--C.ident.C--CH.sub.3, --CH.sub.2--C.ident.CH; [0094] R.sup.7 is
independently H, OR.sup.4, hydroxyalkyl, hydroxyalkylamino,
cycloalkyl, halogen, haloalkyl, haloalkyloxy, NO.sub.2, CN,
SO.sub.2NR.sup.4R.sup.5, CO.sub.2NR.sup.4R.sup.5, COR.sup.4,
CO.sub.2R.sup.4, SO.sub.2R.sup.4, SO.sub.3R.sup.4, NR.sup.4R.sup.5,
alkyl, aryl or heteroaryl; [0095] R.sup.7 is independently of each
other --H, --F, --Cl, --I, --NO.sub.2, --NR.sup.4R.sup.5, --CN,
C.sub.2-C.sub.6-alkyl, cycloalkyl, --OH, alkoxy, alkylthio,
hydroxyalkylamino, haloalkyl, haloalkyloxy, hydroxyalkyl, aryl or
heteroaryl; [0096] said C.sub.2-C.sub.6-alkyl of R.sup.7, denotes a
linear or branched C.sub.2-C.sub.6-alkyl, a linear or branched
C.sub.2-C.sub.6-alkenyl or a linear or branched
C.sub.1-C.sub.6-alkinyl group, which can optionally be substituted
by one or more substituents R.sup.3, preferably by halogen; the
C.sub.2-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl and
C.sub.2-C.sub.6-alkinyl residue may be selected from the group
comprising --C.sub.2H.sub.5, --CH.dbd.CH.sub.2, --C.ident.CH,
--C.sub.3H.sub.7, --CH(CH.sub.3).sub.2, --C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.CH, --CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3,
--C.sub.4H.sub.9, --CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.2H.sub.5, --C(CH.sub.3).sub.3,
--C.sub.5H.sub.11, --C.sub.6H.sub.13, --C(R.sup.3).sub.3,
--CR.sup.3(R.sup.3').sub.2, --CR.sup.3(R.sup.3')R.sup.3'',
--C.sub.2(R.sup.3).sub.5, --CH.sub.2--C(R.sup.3).sub.3,
--CH.sub.2--CR.sup.3(R.sup.3').sub.2,
--CH.sub.2--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.3(R.sup.3).sub.7,
--C.sub.2H.sub.4--C(R.sup.3).sub.3,
--C.sub.2H.sub.4--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.2H.sub.5,
--CH.dbd.C(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.dbd.CH.sub.2, --C.sub.2H.sub.4--C.ident.CH.sub.2,
--C.ident.C--C.sub.2H.sub.5, --CH.sub.2--C.ident.C--CH.sub.3,
--C.ident.C--CH.dbd.CH.sub.2, --CH.dbd.CH--C.ident.CH,
--C.ident.C--C.ident.CH, --C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.3H.sub.6--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--CH.dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2--CH.dbd.C(CH.sub.3).sub.2,
--C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.3H.sub.6--C.ident.CH,
--C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.2H.sub.5,
--CH.sub.2--C.ident.C--CH.dbd.CH.sub.2,
--CH.sub.2--CH.dbd.CH--C.ident.CH,
--CH.sub.2--C.ident.C--C.ident.CH,
--C.ident.C--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--C.ident.C--CH.sub.3,
--C.ident.C--C.ident.C--CH.sub.3,
--C.ident.C--CH.sub.2--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.2--C.ident.CH,
--C.ident.C--CH.sub.3--C.ident.CH,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--C.ident.CH, --CH.dbd.C(CH.sub.3)--C.ident.CH,
--C.ident.C--C(CH.sub.3).dbd.CH.sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.4H.sub.9,
--C.sub.3H.sub.6--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--C(CH.sub.3).dbd.C(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH.dbd.C(CH.sub.3).sub.2,
--C.sub.4H.sub.8--C.ident.CH, --C.ident.C--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C.ident.C--C.sub.2H.sub.5; [0097] R.sup.3,
R.sup.3' or R.sup.3' are defined as above in Formula (X) [0098]
R.sup.4, R.sup.5 are defined as above in Formula (X); [0099]
R.sup.8 is independently of each other --H, --'F, --I,
--NR.sup.4R.sup.5, --CN, C.sub.1-C.sub.3-alkyl, --OH, alkoxy,
alkylthio, hydroxyalkylamino, haloalkyl, haloalkyloxy,
hydroxyalkyl, aryl or heteroaryl; [0100] said C.sub.1-C.sub.3-alkyl
of R.sup.8, denotes a linear or branched C.sub.1-C.sub.3-alkyl, a
linear or branched C.sub.1-C.sub.3-alkenyl or a linear or branched
C.sub.1-C.sub.3-alkinyl group, which can optionally be substituted
by one or more substituents R', preferably by halogen; the
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkenyl and
C.sub.1-C.sub.3-alkinyl residue may be selected from the group
comprising --CH.sub.3, --C.sub.2H.sub.5, --CH.dbd.CH.sub.2,
C.ident.CH, --C.sub.3H.sub.7, --CH(CH.sub.3).sub.2,
--C.ident.C--CH.sub.3, --CH.sub.2--C.ident.CH; [0101] R' is defined
as above in Formula (X); [0102] R.sup.4, R.sup.5 are defined as
above in Formula (X); [0103] R.sup.8 is independently of each other
--F, --I, --NR.sup.4R.sup.5, --CN, C.sub.1-C.sub.3-alkyl, --OH,
alkoxy, alkylthio, hydroxyalkylamino, haloalkyl, haloalkyloxy,
hydroxyalkyl, aryl or heteroaryl; [0104] said C.sub.1-C.sub.3-alkyl
of R.sup.8', denotes a linear or branched C.sub.1-C.sub.3-alkyl, a
linear or branched C.sub.1-C.sub.3-alkenyl or a linear or branched
C.sub.1-C.sub.3-alkinyl group, which can optionally be substituted
by one or more substituents R', preferably by halogen; the
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkenyl and
C.sub.1-C.sub.3-alkinyl residue may be selected from the group
comprising --CH.sub.3, --C.sub.2H.sub.5, --CH.dbd.CH.sub.2,
--C.ident.CH, --C.sub.3H.sub.7, --CH(CH.sub.3).sub.2,
--C.ident.C--CH.sub.3, --CH.sub.2--C.ident.CH; [0105] R' is defined
as above in Formula (X); [0106] an alkyl group, referring to
R.sup.3, R.sup.3', R.sup.3'', R.sup.4 or R.sup.5 denotes a linear
or branched C.sub.1-C.sub.6-alkyl, preferably a linear or branched
chain of 1 to 5 carbon atoms, a linear or branched
C.sub.1-C.sub.6-alkenyl or a linear or branched
C.sub.1-C.sub.6-alkinyl group, which can optionally be substituted
by one or more substituents R.sup.3, preferably by halogen; [0107]
the C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkenyl and
C.sub.1-C.sub.6-alkinyl residue may be selected from the group
comprising --CH.sub.3, --C.sub.2H.sub.5, --CH.dbd.CH.sub.2,
--C.ident.CH, --C.sub.3H.sub.7, --CH(CH.sub.3).sub.2,
--CH.sub.2--CH.dbd.CH.sub.2, --C(CH.sub.3).dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.3, --C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.CH, --C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--C.sub.2H.sub.5,
--C(CH.sub.3).sub.3, --C.sub.5H.sub.11, --C.sub.6H.sub.13,
--C(R.sup.3).sub.3, --CR.sup.3(R.sup.3').sub.2,
--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.2(R.sup.3).sub.5,
--CH.sub.2--C(R.sup.3).sub.3, --CH.sub.2--CR.sup.3(R.sup.3').sub.2,
--CH.sub.2--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.3(R.sup.3).sub.7,
--C.sub.2H.sub.4--C(R.sup.3).sub.3,
--C.sub.2H.sub.4--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.2H.sub.5,
--CH.dbd.C(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.dbd.CH.sub.2, --C.sub.2H.sub.4--C.ident.CH,
--C.ident.C--C.sub.2H.sub.5, --CH.sub.2--C.ident.C--CH.sub.3,
--C.ident.C--CH.dbd.CH.sub.2, --CH.dbd.CH--C.ident.CH,
--C.ident.C--C.ident.CH, --C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.3H.sub.6--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--CH.dbd.CH--CH.dbd.CH.sub.2--,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2--CH.dbd.C(CH.sub.3).sub.2,
--C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.3H.sub.6--C.ident.CH,
--C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.2H.sub.5,
--CH.sub.2--C.ident.C--CH.dbd.CH.sub.2,
--CH.sub.2--CH.dbd.CH--C.ident.CH,
--CH.sub.2--C.ident.C--C.ident.CH,
--C.ident.C--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--C.ident.C--CH.sub.3,
--C.ident.C--C.ident.C--CH.sub.3,
--C.ident.C--CH.sub.2--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.2--C.ident.CH, --C.ident.C--CH.sub.2--C--CH,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--C.ident.CH, --CH.dbd.C(CH.sub.3)--C.ident.CH,
--C.ident.C--C(CH.sub.3).dbd.CH.sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.4H.sub.9,
--C.sub.3H.sub.6--CH.dbd.CH--CH.sub.3,
--CH.sub.2--H.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--C(CH.sub.3).dbd.C(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH.dbd.C(CH.sub.3).sub.2,
--C.sub.4H.sub.8--C.ident.CH, --C.ident.C--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C.ident.C--C.sub.2H.sub.5; [0108] R.sup.3,
R.sup.3' or R.sup.3'' are defined as above in Formula (X); [0109] a
cycloalkyl group is defined as above in Formula (X); [0110] an
alkoxy group is defined as above in Formula (X); [0111] an
haloalkyl is defined as above for in Formula (X); [0112] a
hydroxyalkyl group is defined as above in Formula (X); [0113] an
haloalkyloxy group is defined as above in Formula (X); [0114] a
hydroxyalkylamino group is defined as above in Formula (X); [0115]
a halogen group is defined as above in Formula (X); [0116] an aryl
group is defined as above in Formula (X); [0117] a heteroaryl group
is defined as above in Formula (X).
[0118] Furthermore the present invention is directed to novel
compounds of the general Formula (XI) and pharmaceutically
acceptable salts thereof:
##STR00007##
wherein [0119] A.sup.4 is an optionally substituted
C.sub.2-C.sub.20-alkyl or a 5-membered heteroaryl group, which
contains at least one heteroatom like O, N, S, NR.sup.4, SO,
SO.sub.2, Se; which can optionally be substituted by one or more
substituents R.sup.3; [0120] R.sup.3 is independently H, OR.sup.4,
SR.sup.4, hydroxyalkyl, hydroxyalkylamino, cycloalkyl, halogen,
haloalkyl, haloalkyloxy, NO.sub.2, CN, SO.sub.2NR.sup.4R.sup.5,
CO.sub.2NR.sup.4R.sup.5, COR.sup.4, CO.sub.2R.sup.4,
SO.sub.2R.sup.4, SO.sub.3R.sup.4, NR.sup.4R.sup.5, alkyl, aryl or
heteroaryl; [0121] R.sup.4 is H, alkyl, cycloalkyl, aryl or
heteroaryl; [0122] R.sup.5 is H, O-alkyl, O-aryl, alkyl, heteroaryl
or aryl; [0123] R.sup.17 is independently of each other --H, --F,
--Cl, --I, --NO.sub.2, --NR.sup.4R.sup.5, --CN, alkyl, cycloalkyl,
--OH, alkoxy, alkylthio, hydroxyalkylamino, haloalkyl,
haloalkyloxy, hydroxyalkyl, aryl or heteroaryl; [0124] said
C.sub.2-C.sub.10-alkyl residue may be selected from the group
comprising --C.sub.2H.sub.5, --C.sub.3H.sub.7,
--CH(CH.sub.3).sub.2, --C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--C.sub.2H.sub.5,
--C(CH.sub.3).sub.3, --C.sub.5H.sub.11,
--C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.6H.sub.13, --C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3, --C.sub.7H.sub.15,
--C.sub.3H.sub.6--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH(CH.sub.3).sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.2)--C.sub.4H.sub.9,
--CH(CH.sub.2)--C.sub.5H.sub.11, --C.sub.8H.sub.17,
--C.sub.4H.sub.8--C(CH.sub.3).sub.3,
--C.sub.5H.sub.10--CH(CH.sub.3).sub.2,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.2H.sub.3--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.5H.sub.11,
--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--CH(CH.sub.3)--C.sub.6H.sub.13, --C.sub.9H.sub.19,
--C.sub.5H.sub.10--C(CH.sub.3).sub.3,
--C.sub.6H.sub.12--CH(CH.sub.3).sub.2,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.3h.sub.7,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.5H.sub.11,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--CH.sub.2--CH(CH.sub.3)--C.sub.6H.sub.13,
--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--CH(CH.sub.3)--C.sub.7H.sub.15, --C.sub.10H.sub.21,
---C.sub.6H.sub.12--C(CH.sub.3).sub.3,
--C.sub.7H.sub.14--CH(CH.sub.3).sub.2,
--C.sub.6H.sub.12--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.5H.sub.10--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.5H.sub.11,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.6H.sub.13,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--CH.sub.2--CH(CH.sub.3)--C.sub.7H.sub.15,
--C(CH.sub.3).sub.2--C.sub.7H.sub.15,
--CH(CH.sub.3)--C.sub.8H.sub.17, --C.sub.11H.sub.23,
--C.sub.7H.sub.14--C(CH.sub.3).sub.3,
--C.sub.8H.sub.16--CH(CH.sub.3).sub.2,
--C.sub.7H.sub.14--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.6H.sub.12--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.6H.sub.12--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.5H.sub.10--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.5H.sub.11,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.6H.sub.13,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.7H.sub.15,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.7H.sub.15,
--CH.sub.2--CH(CH.sub.3)--C.sub.8H.sub.17,
--C(CH.sub.3).sub.2--C.sub.8H.sub.17,
--CH(CH.sub.3)--C.sub.9H.sub.19, --C.sub.12H.sub.21,
--C.sub.8H.sub.16--C(CH.sub.3).sub.3,
--C.sub.9H.sub.18--CH(CH.sub.3).sub.2,
C.sub.8H.sub.16--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.7H.sub.14--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.7H.sub.14--C(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.6H.sub.12--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.6H.sub.12--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.5H.sub.10--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.5H.sub.11,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.6H.sub.13,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.7H.sub.15,
C.sub.2H.sub.4'C(CH.sub.3).sub.2--C.sub.7H.sub.15,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.8H.sub.17,
CH.sub.2--C(CH.sub.3).sub.2--C.sub.8H.sub.17,
--CH.sub.2--CH(CH.sub.3)--C.sub.9H.sub.19,
--C(CH.sub.3).sub.2--C.sub.9H.sub.19,
--CH(CH.sub.3)--C.sub.10H.sub.21; [0125] an alkyl group, if not
stated otherwise, denotes a linear or branched
C.sub.1-C.sub.6-alkyl, preferably a linear or branched chain of one
to live carbon atoms, a linear or branched C.sub.1-C.sub.6-alkenyl
or a linear or branched C.sub.1-C.sub.6-alkinyl group, which can
optionally be substituted by one or more substituents R.sup.3,
preferably by halogen; [0126] the C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkenyl and C.sub.1-C.sub.6alkinyl residue may be
selected from the group comprising --CH.sub.3, --C.sub.2H.sub.5,
--CH.dbd.CH.sub.2, --C.ident.CH, --C.sub.3H.sub.7,
--CH(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3,
--C.ident.C--CH.sub.3, --CH.sub.2--C.ident.CH, --C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--C.sub.2H.sub.5,
--C(CH.sub.3).sub.3, --C.sub.5H.sub.11, --C.sub.6H.sub.13,
--C(R.sup.3).sub.3, --CR.sup.3(R.sup.3').sub.2,
--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.2(R.sup.3).sub.5,
--CH.sub.2--C(R.sup.3).sub.3, --CH.sub.2--CR.sup.3(R.sup.3').sub.2,
--CH.sub.2--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.3(R.sup.3).sub.7,
--C.sub.2H.sub.4--C(R.sup.3).sub.3,
--C.sub.2H.sub.4--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.2H.sub.5,
--CH.dbd.C(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH--CH.sub.2,
--CH.dbd.CH--CH.dbd.CH.sub.2, --C.sub.2H.sub.4--C.ident.CH,
--C.ident.C--C.sub.2H.sub.5, --CH.sub.2--C.ident.C--CH.sub.3,
--C.ident.C--CH.dbd.CH.sub.2, --CH.dbd.CH--C.ident.CH,
--C.ident.C--C.ident.CH, --C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.3H.sub.6--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--CH.dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3)CH.sub.2,
--CH.sub.2--CH.dbd.C(CH.sub.3).sub.2,
--C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.3H.sub.6--C.ident.CH,
--C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.2H.sub.5,
--CH.sub.2--C.ident.C--CH.dbd.CH.sub.2,
--CH.sub.2--CH.dbd.CH--C.ident.CH,
--CH.sub.2--C.ident.C--C.ident.CH,
--C.ident.C--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--C.ident.C--CH.sub.3,
--C.ident.C--C.ident.C--CH.sub.3, --C.ident.C--C.ident.CH.sub.3,
--C.ident.C--CH.sub.2--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.2--C.ident.CH,
--C.ident.C--CH.sub.2--C.ident.CH,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--C.ident.CH, --CH.dbd.C(CH.sub.3)--C.ident.CH,
--C.ident.C--C(CH.sub.3).dbd.CH.sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.4H.sub.9,
--C.sub.3H.sub.6--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--(CH.sub.3).dbd.C(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH.dbd.C(CH.sub.3).sub.2,
--C.sub.4H.sub.8--C.ident.CH, --C.ident.C--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C.ident.C--C.sub.2H.sub.5; [0127] a cycloalkyl
group denotes a non-aromatic ring system containing three to eight
carbon atoms, preferably four to eight carbon atoms, wherein one or
more of the carbon atoms in the ring can be substituted by a group
X, X being as defined above; the C.sub.3-C.sub.8-cycloalkyl residue
may be selected from the group comprising -cyclo-C.sub.3H.sub.5,
-cyclo-C.sub.4H.sub.7, -cyclo-C.sub.5H.sub.9,
-cyclo-C.sub.6H.sub.11, -cyclo-C.sub.7H.sub.13,
-cyclo-C.sub.8H.sub.15; [0128] an alkoxy group denotes an O-alkyl
group, the alkyl group being as defined above, the alkoxy group is
preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy
group. [0129] an haloalkyl group denotes an alkyl group which is
substituted by one to five halogen atoms, the alkyl group being as
defined above; the haloalkyl group is preferably a
--C(R.sup.10).sub.3, --CR.sup.10(R.sup.10').sub.2,
--CR.sup.10(R.sup.10')R.sup.10'', --C.sub.2(R.sup.10).sub.5,
--CH.sub.2--C(R.sup.10).sub.3,
--CH.sub.2--CR.sup.10(R.sup.10').sub.2,
--CH.sub.2--CR.sup.10(R.sup.10')R.sup.10'',
--C.sub.3(R.sup.10).sub.7 or --C.sub.2H.sub.4--C(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10', R.sup.10'' represent F, Cl, Br or I,
preferably F; [0130] a hydroxyalkyl group denotes an HO-alkyl
group, the alkyl group being as defined above; [0131] an
haloalkyloxy group denotes an alkoxy group which is substituted by
one to five halogen atoms, the alkyl group being as defined above;
the haloalkyloxy group is preferably a --OC(R.sup.10).sub.3,
--OCR.sup.10(R.sup.10').sub.2, --OCR.sup.10(R.sup.10')R.sup.10'',
--OC.sub.2(R.sup.10).sub.5, --OCH.sub.2--C(R.sup.10).sub.3,
--OCH.sub.2--CR.sup.10(R.sup.10').sub.2,
--OCH.sup.10(R.sup.10')R.sup.10'', --OC.sub.3(R.sup.10).sub.7 or
--OC.sub.2H.sub.4--C(R.sup.10).sub.3, wherein R.sup.10, R.sup.10',
R.sup.10'' represent F, Cl, Br or I, preferably F; [0132] a
hydroxyalkylamino group denotes an (HO-alkyl).sub.2-N-group or
HO-alkyl-NH-group, the alkyl group being as defined above; [0133] a
halogen group is chlorine, bromine, fluorine or iodine; [0134] an
aryl group preferably denotes an aromatic group having five to
fifteen carbon atoms, which can optionally be substituted by one or
more substituents R.sup.3, where R.sup.3 is as defined above; the
aryl group is preferably a phenyl group,
--CH.sub.2--C.sub.6H.sub.4, --C.sub.2H.sub.4--C.sub.6H.sub.4,
--CH.dbd.CH--C.sub.6H.sub.4, --C.ident.C--C.sub.6H.sub.4,
-o-C.sub.6H.sub.4--R.sup.3, -m-C.sub.6H.sub.4--R.sup.3,
-p-C.sub.6H.sub.4--R.sup.3, -o-CH.sub.2--C.sub.6H.sub.4--R.sup.3,
-m-CH.sub.2--C.sub.6H.sub.4--R.sup.3,
-p-CH.sub.2--C.sub.6H.sub.4--R.sup.3; [0135] a heteroaryl group
denotes a 5- or 6-membered heterocyclic group which contains at
least one heteroatom like O, N, S. This heterocyclic group can be
fused to another ring. For example, this group can be selected from
an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,
isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,
1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl,
2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl,
1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, indolyl, indolinyl,
benzo-[b]-furanyl, benzo[b]thiophenyl, benzimidazolyl,
benzothiazolyl, quinazolinyl, quinoxazolinyl, or preferably
isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, quinolinyl,
tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl group.
This heterocyclic group can optionally be substituted by one or
more substituents R.sup.3, where R.sup.3 is as defined above.
[0136] with the proviso that
N-(1-methyl-1H-pyrazole-5-yl)-1H-pyrazole-1-carboxamide, and
1-ethyl-3-methyl-N-(1-methyl-1H-pyrazole-5-yl)-4-nitro-1H-pyrazole-5-carb-
oxamide are excluded.
[0137] Furthermore the present invention is directed to novel
compounds of the general Formula (XI) and pharmaceutically
acceptable salts thereof,
##STR00008##
wherein [0138] A.sup.4 is an optionally substituted
C.sub.2-C.sub.20-alkyl or a 5-membered heteroaryl group, which
contains at least one heteroatom like O, N, S, NR.sup.4, SO,
SO.sub.2, Se; which can optionally be substituted by one or more
substituents R.sup.3; [0139] R.sup.3 is independently H, OR.sup.4,
SR.sup.4, hydroxyalkyl, hydroxyalkylamino, cycloalkyl, halogen,
haloalkyl, haloalkyloxy, NO.sub.2, CN, SO.sub.2NR.sup.4R.sup.5,
CO.sub.2NR.sup.4R.sup.5, COR.sup.4, CO.sub.2R.sup.4,
SO.sub.2R.sup.4, SO.sub.3R.sup.4, NR.sup.4R.sup.5, alkyl, aryl or
heteroaryl; [0140] R.sup.4 is H, alkyl, cycloalkyl, aryl or
heteroaryl; [0141] R.sup.5 is H, O-alkyl, O-aryl, alkyl, heteroaryl
or aryl; [0142] R.sup.17 is independently of each other --H, --F,
--Cl, --I, --NO.sub.2, --NR.sup.4R.sup.5, --CN, alkyl, cycloalkyl,
--OH, alkoxy, alkylthio, hydroxyalkylamino, haloalkyl,
haloalkyloxy, hydroxyalkyl, aryl or heteroaryl; [0143] said
C.sub.2-C.sub.20-alkyl residue may be selected from the group given
above for C.sub.2-C.sub.20-alkyl residue of Formula (XI). [0144] a
cycloalkyl group is defined as above in Formula (X); [0145] an
alkoxy group is defined as above in Formula (X); [0146] an
haloalkyl is defined as above for in Formula (X); [0147] a
hydroxyalkyl group is defined as above in Formula (X); [0148] an
haloalkyloxy group is defined as above in Formula (X); [0149] a
hydroxyalkylamino group is defined as above in Formula (X); [0150]
a halogen group is defined as above in Formula (X); [0151] an aryl
group is defined as above in Formula (X); [0152] a heteroaryl group
may be selected from the group comprising oxazole2-yl, oxazol-4-yl,
oxazole-5-yl, thiazole-2-yl, thiazole-4-yl, thiazole-5-yl,
isothiazole-3-yl, isothiazole-4-yl, isothiazole-5-yl,
1,2,4-oxadiazole-3-yl, 1,2,4oxadiazole-5-yl,
1,2,4-thiadiazole-3-yl, 1,2,4-thiadiazole-5-yl,
1,2,5-oxadiazole-3-yl, 1,2,5-oxadiazole-4-yl,
1,2,5-thiadiazole-3-yl, 1-imidazolyl, 2-imidazolyl,
1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl, 2-pyrrolyl,
3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 4-pyridyl,
4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl,
2-pyrazinyl, 3-pyrazolyl, 4-pyrazolyl, indolyl, indolinyl,
benzo[b]thiophenyl, benzimidazolyl, quinazolinyl, quinoxazolinyl,
preferably isoxazole-3-yl, isoxazole-4-yl, isoxazole-5-yl,
tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl group,
wherein said heteroaryl group can optionally be substituted by one
or more substituents R.sup.3, R.sup.3 being as defined above in
Formula (XI).
[0153] Furthermore the present invention is directed to novel
compounds of the general Formula (XII) and pharmaceutically
acceptable salts thereof:
##STR00009##
wherein [0154] R.sup.11 is an optionally substituted phenyl group
by one to five substituents R.sup.9 or an optionally substituted
C.sub.4-C.sub.20-alkyl group by one or more substituents R.sup.3;
[0155] R.sup.9 is independently of each other --H, --F, --Cl, --Br,
--I, --SO.sub.2NH.sup.4, --SO.sub.2N(R.sup.4).sub.2,
--NR.sup.4R.sup.5, --NR.sup.4--CO--(C.sub.1-C.sub.6)-haloalkyl,
--NO.sub.2, --NR.sup.4--SO.sub.2--(C.sub.1-C.sub.6)-haloalkyl,
--CN, alkyl, cycloalkyl, --OH, --SH, alkylthio, alkoxy,
hydroxyalkylamino, haloalkyloxy, haloalkyl, hydroxyalkyl, aryl or
heteroaryl; [0156] R.sup.10 is independently of each other --H,
--F, --Cl, --Br, --I, --NO.sub.2, NR.sup.4R.sup.5, --CN, alkyl,
--OH, cycloalkyl, --SH, alkylthio, hydroxyalkylamino, hydroxyalkyl,
aryl or heteroaryl; [0157] R.sup.3, R.sup.3', R.sup.3'' is
independently H, OR.sup.4, SR.sup.4, hydroxyalkyl,
hydroxyalkylamino, cycloalkyl, halogen, haloalkyl, haloalkyloxy,
NO.sub.2, CN, SO.sub.2NR.sup.4R.sup.5, CO.sub.2NR.sup.4R.sup.5,
COR.sup.4, CO.sub.2R.sup.4, SO.sub.2R.sup.4, SO.sub.3R.sup.4,
NR.sup.4R.sup.5, alkyl, aryl or heteroaryl, [0158] R.sup.4 is H,
alkyl, cycloalkyl, aryl or heteroaryl; [0159] R.sup.5 is H,
O-alkyl, O-aryl, alkyl, heteroaryl or aryl; [0160] X is selected
from the group consisting of S, O, N, NR.sup.4, SO or SO.sub.2;
[0161] said C.sub.4-C.sub.20-alkyl residue may be selected from the
group comprising --C.sub.4H.sub.9, --CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.2H.sub.5, --C(CH.sub.3).sub.3,
--C.sub.5H.sub.11, --C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.6H.sub.13, --C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3, --C.sub.7H.sub.15,
--C.sub.3H.sub.6--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH(CH.sub.3).sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH(CH.sub.3)--C.sub.5H.sub.11, --C.sub.8H.sub.17,
--C.sub.4H.sub.8--C(CH.sub.3).sub.3,
--C.sub.5H.sub.10--CH(CH.sub.3).sub.2,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.5C.sub.11,
--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--CH(CH.sub.3)--C.sub.6H.sub.13, --C.sub.9H.sub.19,
--C.sub.5H.sub.10--C(CH.sub.3).sub.3,
--C.sub.6H.sub.12--CH(CH.sub.3).sub.2,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.3H.sub.6CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.5H.sub.11,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--CH.sub.2--CH(CH.sub.3)--C.sub.6H.sub.13,
--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--CH(CH.sub.3)--C.sub.7H.sub.15, --C.sub.10H.sub.21,
--C.sub.6H.sub.12--C(CH.sub.3).sub.3,
--C.sub.7H.sub.14--CH(CH.sub.3).sub.2,
--C.sub.6H.sub.12--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.5H.sub.10--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.5H.sub.11,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.6H.sub.13,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--CH.sub.2--CH(CH.sub.3)--C.sub.7h.sub.15,
--C(CH.sub.3).sub.2--C.sub.7H.sub.15,
--CH(CH.sub.3)--C.sub.8H.sub.17, --C.sub.11H.sub.23,
--C.sub.7H.sub.14--C(CH.sub.3).sub.3,
--C.sub.8H.sub.16--CH(CH.sub.3).sub.2,
--C.sub.7H.sub.14--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.6H.sub.12--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.6H.sub.12--CH(CH.sub.3)--C.sub.31H.sub.7,
--C.sub.5H.sub.10--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.4H.sub.8--H(CH.sub.3)--C.sub.5H.sub.11,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--C.sub.3h.sub.6-CH(CH.sub.3)--C.sub.6H.sub.13,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.7H.sub.15,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.7H.sub.15,
--CH.sub.2--CH(CH.sub.3)--C.sub.17,
--C(CH.sub.3).sub.2--C.sub.8H.sub.17,
--CH(CH.sub.3)--C.sub.9H.sub.19, --C.sub.12H.sub.25,
--C.sub.8H.sub.16--C(CH.sub.3).sub.3,
--C.sub.9H.sub.18--CH(CH.sub.3).sub.2,
--C.sub.8H.sub.16--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.7H.sub.14--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.7H.sub.14--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.6H.sub.12--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.6H.sub.12--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.5H.sub.10--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.5H.sub.10--CH(CH.sub.3)1'C.sub.5H.sub.11,
--C.sub.4H.sub.8(CH.sub.3).sub.2--C.sub.5H.sub.11,
--C.sub.4--CH(CH.sub.3)--C.sub.6H.sub.13,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.7H.sub.15,
C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.7H.sub.15,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.8H.sub.17,
CH.sub.2--C(CH.sub.3).sub.2--C.sub.8H.sub.17,
--CH.sub.2--CH(CH.sub.3)--C.sub.9H.sub.19,
--C(CH.sub.3).sub.2--C.sub.9H.sub.19,
--CH(CH.sub.3)--C.sub.10H.sub.21; [0162] an alkyl group, if not
stated otherwise, denotes a linear or branched
C.sub.1-C.sub.6-alkyl, preferably a linear or branched chain of one
to five carbon atoms, a linear or branched C.sub.1-C.sub.6-alkenyl
or a linear or branched C.sub.2-C.sub.6-alkinyl group, which can
optionally be substituted by one or more substituents R.sup.3,
preferably by halogen; [0163] the C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkenyl and C.sub.1-C.sub.6-alkinyl residue may be
selected from the group comprising --CH.sub.3, --C.sub.2H.sub.5,
--CH.dbd.CH.sub.2, --C.ident.CH, --C.sub.3H.sub.7,
--CH(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3)--CH.sub.2, --CH.dbd.CH--CH.sub.3,
--C.ident.C--CH.sub.3, --CH.sub.2--C.ident.CH, --C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--C.sub.2H.sub.5,
--C(CH.sub.3).sub.3, --C.sub.5H.sub.11, --C.sub.6H.sub.13,
--C(R.sup.3).sub.3, --CR.sup.3(R.sup.3')R.sup.3'',
--C.sub.2(R.sup.3).sub.5, --CH(CH.sub.3)--C.sub.2H.sub.5,
--C(CH.sub.3).sub.3, --C.sub.5H.sub.11, --C.sub.6H.sub.13,
--C(R.sup.3).sub.3, --CR.sup.3(R.sup.3').sub.2,
--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.2(R.sup.3).sub.5,
--CH.sub.2--C(R.sup.3).sub.3, --CH.sub.2--CR.sup.3(R.sup.3').sub.2,
--CH.sub.2--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.3(R.sup.3).sub.7,
C.sub.2H.sub.4--C(R.sup.3).sub.3,
--C.sub.2H.sub.4--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.2H.sub.5,
--CH.dbd.C(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.dbd.CH.sub.2, --C.sub.2H.sub.4--C.dbd.CH,
--C.ident.C--C.sub.2h.sub.5, --CH.sub.2--C.ident.C--CH.sub.3,
--C.ident.C--CH--CH.dbd.CH.sub.2, --CH.dbd.CH--C.ident.CH,
--C.ident.C--C.ident.CH, --C.sub.2H.sub.4CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2C(CH.sub.3).sub.3,
--C.sub.3H.sub.6--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--CH.dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2--CH.dbd.C(CH.sub.3).sub.2,
--C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.3H.sub.6--C.ident.CH,
--C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.2H.sub.5,
--CH.sub.2--C.ident.C--CH.dbd.CH.sub.2,
--CH.sub.2--CH.dbd.CH--C.ident.CH,
--CH.sub.2--C.ident.C--C.ident.CH,
--C.ident.C--CH.alpha.CH--CH.sub.3,
--CH.dbd.CH--C--C.ident.C--CH.sub.3,
--C.ident.C--C.ident.C--CH.sub.3,
--C.ident.C--CH.sub.2--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.2C.ident.CH, --C.dbd.C--CH.sub.2--C.dbd.CH,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH'CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--C.ident.CH, --CH.dbd.C(CH.sub.3)--C.ident.CH,
--C.ident.C--C(CH.sub.3).dbd.CH.sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH.dbd.CH.sub.2, --CH.alpha.CH--C.sub.4H.sub.9,
--C.sub.3H.sub.6--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--C(CH.sub.3).dbd.C(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH.dbd.C(CH.sub.3).sub.2,
--C.sub.4H.sub.8--C.ident.CH, --C.ident.C--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C.ident.c-CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C.ident.C--C.sub.2H.sub.5; R.sup.3, R.sup.3' or
R.sup.3'' being as defined above; [0164] a cycloalkyl group denotes
a non-aromatic ring system containing three to eight carbon atoms,
preferably four to eight carbon atoms, wherein one or more of the
carbon atoms in the ring can be substituted by a group X, X being
as defined above; the C.sub.3-C.sub.8-cycloalkyl residue may be
selected from the group comprising -cyclo-C.sub.3H.sub.5,
-cyclo-C.sub.4H.sub.7, -cyclo-C.sub.5H.sub.9,
-cyclo-C.sub.6H.sub.11, -cyclo-C.sub.7H.sub.13,
-cyclo-C.sub.8H.sub.15; [0165] an alkoxy group denotes an O-alkyl
group, the alkyl group being as defined above; the alkoxy group is
preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy
group, [0166] an haloalkyl group denotes an alkyl group which is
substituted by one to five halogen atoms, the alkyl group being as
defined above; the haloalkyl group is preferably a
--C(R.sup.10).sub.3, --CR.sup.10(R.sup.10').sub.2,
--CR.sup.10(R.sup.10')R.sup.10'', --C.sub.2(R.sup.10).sub.5,
--CH.sub.2--C(R.sup.10).sub.3,
--CH.sub.2--CR.sup.10(R.sup.10').sub.2,
--CH.sub.2--CR.sup.10(R.sup.10')R.sup.10'',
--C.sub.3(R.sup.10).sub.7 or --C.sub.2H.sub.4--C(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10', R.sup.10'' represent F, Cl, Br or I,
preferably F; [0167] a hydroxyalkyl group denotes an HO-alkyl
group, the alkyl group being as defined above; [0168] an
haloalkyloxy group denotes an alkoxy group which is substituted by
one to five halogen atoms, the alkyl group being as defined above;
the haloalkyloxy group is preferably a --OC(R.sup.10).sub.3,
--OCR.sup.10(R.sup.10').sub.2, --OCR.sup.10(R.sup.10')R.sup.10'',
--OC.sub.2(R.sup.10).sub.5, --OCH.sub.2--C(R.sup.10).sub.3,
--OCH.sub.2--CR.sup.1(R.sup.10').sub.2,
--OCH.sub.2CR.sup.10(R.sup.10')R.sup.10'',
--OC.sub.3(R.sub.10).sub.7 or --OC.sub.2H.sub.4(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10', R.sup.10'' represent F, Cl, Br or I,
preferably F; [0169] a hydroxyalkylamino group denotes an
(HO-alkyl).sub.2-N-group or HO-alkyl-NH-group, the alkyl group
being as defined above; [0170] a halogen group is chlorine,
bromine, fluorine or iodine; [0171] an aryl group preferably
denotes an aromatic group having five to fifteen carbon atoms,
which can optionally be substituted by one or more substituents
R.sup.3, where R.sup.3 is as defined above; the aryl group is
preferably a phenyl group, --CH.sub.2--C.sub.6H.sub.4,
--C.sub.2H.sub.4--C.sub.6H.sub.4, --CH.dbd.CH--C.sub.6H.sub.4,
--C.ident.C--C.sub.6H.sub.4, -o-C.sub.6H.sub.4--R.sup.3,
-m-C.sub.6H.sub.4--R.sup.3, -p-C.sub.6H.sub.4--R.sup.3,
-o-CH.sub.2--C.sub.6H.sub.4--R.sup.3,
-m-CH.sub.2--C.sub.6H.sub.4--R.sup.3,
-p-CH.sub.2--C.sub.6H.sub.4--R.sup.3; [0172] a heteroaryl group
denotes a 5- or 6-membered heterocyclic group which contains at
least one heteroatom like O, N, S. This heterocyclic group can be
fused to another ring. For example, this group can be selected from
an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,
isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,
1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl,
2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl,
1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, indolyl, indolinyl,
benzo-[b]-furanyl, benzo[b]thiophenyl, benzimidazolyl,
benzothiazolyl, quinazolinyl, quinoxazolinyl, or preferably
isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, quinolinyl,
tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl group.
This heterocyclic group can optionally be substituted by one or
more substituents R.sup.3, where R.sup.3 is as defined above.
[0173] However, the following compounds are excluded from Formula
(XI): 2-thiophenecarboxylic
acid-5-bromo-2-[[(4-chlorophenyl)amino]carbonyl]hydrazide,
2-thiophenecarboxylic
acid-2-[[(4-ethoxyphenyl)amino]carbonyl]hydrazide,
2-thiophenecarboxylic
acid-3-methyl-2-[[(3,4-dichlorophenyl)amino]carbonyl]hydrazide,
2-thiophenecarboxylic
acid-2-[[(4-methylphenyl)amino]carbonyl]hydrazide,
2-thiophene-carboxylic
acid-2-[[(4-chlorophenyl)amino]carbonyl]hydrazide,
2-thiophenecarboxylic
acid-2-[[(3-chlorophenyl)amino]carbonyl]hydrazide and
2-thiophenecarboxylic acid-2-[(phenylamino)carbonyl]hydrazide.
[0174] Furthermore the present invention is directed to novel
compounds of the general Formula (XII) and pharmaceutically
acceptable salts thereof:
##STR00010##
wherein [0175] R.sup.11 is an optionally substituted phenyl group
by one to five substituents R.sup.9 or an optionally substituted
C.sub.4-C.sub.20-alkyl group by one or more substituents R.sup.3;
[0176] R.sup.9 is independently of each other --F, --I,
--SO.sub.2NHR.sup.4, --SO.sub.2N(R.sup.4).sub.2, --NR.sup.4R.sup.5,
--NR.sup.4--CO--(C.sub.1-C.sub.6)-haloalkyl, --NO.sub.2,
--NR.sub.4--SO.sub.2--(C.sub.1-C.sub.6)-haloalkyl, --CN,
C.sub.2-C.sub.5-alkyl, cycloalkyl, --OH, --SH, alkylthio methoxy,
propoxy, hydroxyalkylamino, haloalkyloxy, haloalkyl, hydroxyalkyl,
aryl or heteroaryl; [0177] R.sup.10 is independently of each other
--H, --F, --Cl, --I, --NO.sub.2, NR.sup.4R.sup.5, --CN,
C.sub.2-C.sub.5-alkyl, cycloalkyl, --OH, --SH, alkylthio,
hydroxyalkylamino, hydroxyalkyl, aryl or heteroaryl; [0178] wherein
said C.sub.2-C.sub.5-alkyl group of R.sup.9 and R.sup.10 denotes a
linear or branched C.sub.2-C.sub.5-alkyl, a linear or branched
C.sub.2-C.sub.5-alkenyl or a linear or branched
C.sub.2-C.sub.5-alkinyl group, which can optionally be substituted
by one or more substituents R.sup.3, preferably by halogen; the
C.sub.2-C.sub.5-alkyl, C.sub.2-C.sub.5-alkenyl and
C.sub.2-C.sub.5-alkinyl residue may be selected from the group
comprising --C.sub.2H.sub.5, --CH.dbd.CH.sub.2, --C.ident.CH,
--C.sub.3H.sub.7, --CH(CH.sub.3).sub.2, --C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.CH, --CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH.sub.2, --CH.dbd.CH--CH.sub.3,
--C.sub.4H.sub.9, --C.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.2H.sub.5, --C(CH.sub.3).sub.3,
--C.sub.5H.sub.11, --C(R.sup.3).sub.3, --CR.sup.3(R.sup.3').sub.2,
--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.2(R.sup.3).sub.5,
--CH.sub.2--C(R.sup.3).sub.3, --CH.sub.2--CR.sup.3(R.sup.3').sub.2,
--CH.sub.2--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.3(R.sup.3).sub.7,
--C.sub.2H.sub.4--C(R.sup.3).sub.3,
--C.sub.2H.sub.4--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.2H.sub.5,
--CH.dbd.C(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.dbd.CH.sub.2, --C.sub.2H.sub.4--C.ident.CH,
--C.ident.C--C.sub.2H.sub.5, --CH.sub.2--C.ident.C--CH.sub.3,
--C.ident.C--CH.dbd.CH.sub.2, --CH.dbd.CH--C.ident.CH,
--C.ident.C--C.ident.CH, --C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.3H.sub.6--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2h.sub.4-CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--CH.dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2--CH.dbd.C(CH.sub.3).sub.2,
--C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.3H.sub.6--C.ident.CH,
--C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.2H.sub.5,
--CH.sub.2--C.ident.CH--C.dbd.CH.sub.2,
--CH.sub.2--CH.dbd.CH--C.ident.CH,
--CH.sub.2--C.ident.C--C.ident.CH,
--C.ident.C--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--C.ident.C--CH.sub.3,
--C.ident.C--C.ident.C--CH.sub.3,
--C.ident.C--CH.sub.2--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.2--C.ident.CH,
--C.ident.C--CH.sub.2--C.ident.CH,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--C.ident.CH, --CH.dbd.C(CH.sub.3)--C.ident.CH,
--C.ident.C--C(CH.sub.3).dbd.CH.sub.2; [0179] R.sup.3, R.sup.3' or
R.sup.3'' are defined as above for Formula (XII); [0180] R.sup.4 is
defined as above for Formula (XII); [0181] R.sup.5 is defined as
above for Formula (XII); [0182] said C.sub.2-C.sub.20-alkyl residue
is defined as above for Formula (XII); [0183] an alkyl group,
referring to R.sup.3, R.sup.3', .sup.3'', R.sup.4 R.sup.5R.sup.9 or
R.sup.10 denotes a linear or branched C.sub.1-C.sub.6-alkyl,
preferably a linear or branched chain of one to five carbon atoms,
a linear or branched C.sub.1-C.sub.6-alkenyl or a linear or
branched C.sub.1-C.sub.6-alkinyl group, which can optionally be
substituted by one or more substituents R.sup.3, preferably by
halogen; the C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkenyl and
C.sub.1-C.sub.6alkinyl residue may be selected from the group
comprising --CH.sub.3, --C.sub.2H.sub.5, --CH.dbd.CH.sub.2,
--C.ident.CH, --C.sub.3H.sub.7, --CH(CH.sub.3).sub.2,
--CH.sub.2--CH.dbd.CH.sub.2, --C(CH.sub.3).dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.3, --C.ident.CH.sub.3, --CH.sub.2--C.ident.CH,
--C.sub.4H.sub.9, --CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.2H.sub.5, --C(CH.sub.3).sub.3,
--C.sub.5H.sub.11, --C.sub.6H.sub.13, --C(R.sup.3).sub.3,
--CR.sup.3(R.sup.3').sub.2, --CR.sup.3(R.sup.3')R.sup.3'',
--C.sub.2(R.sup.3).sub.5, --CH.sub.2--C(R.sup.3).sub.3,
--CH.sub.2--CR.sup.3(R.sup.3').sub.2,
--CH--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.3(R.sup.3).sub.7,
--C.sub.2H.sub.4--C(R.sup.3).sub.3,
--C.sub.2H.sub.4--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.2H.sub.5,
--H.dbd.C(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.dbd.CH.sub.2, --C.sub.2H.sub.4--C.ident.CH,
--C.ident.C--C.sub.2H.sub.5, --CH.sub.2--C.ident.C--CH.sub.3,
--C.ident.C--CH.dbd.CH.sub.2, --CH.dbd.CH--C.ident.CH,
--C.ident.C--C.ident.CH, --C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.3H.sub.6--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--CH.dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2--CH.dbd.C(CH.sub.3).sub.2,
--C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.3H.sub.6--C.ident.CH,
--C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.dbd.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.2H.sub.5,
--CH.sub.2--C.ident.CH.dbd.CH.sub.2,
--CH.sub.2--CH.dbd.CH--C.ident.CH,
--CH.sub.2--C.ident.C--C.ident.CH,
--C.ident.C--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--C.ident.C--CH.sub.3,
--C.ident.C--CH.sub.2--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.2--C.ident.CH,
--C.ident.C--CH.sub.2--C.ident.CH,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--C.ident.CH, --CH.dbd.C(CH.sub.3)--C.dbd.CH,
--C.ident.C--C(CH.sub.3).alpha.CH.sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2--CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.3H.sub.9,
--C.sub.3H.sub.6--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--C(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH.dbd.C(CH.sub.3).sub.2,
--C.sub.4H.sub.8--C.ident.CH, --C.ident.C--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C.ident.C--C.sub.2H.sub.5; R.sup.3, R.sup.3' or
R.sup.3'' being as defined above; [0184] an cycloalkyl group is
defined as above in Formula (XII); [0185] an alkoxy group is
defined as above in Formula (XII); [0186] an haloalkyl group is
defined as above in Formula (XII); [0187] a hydroxyalkyl group is
defined as above in Formula (XII); [0188] an haloalkyloxy group is
defined as above in Formula (XII); [0189] a hydroxyalkylamino group
is defined as above in Formula (XII); [0190] a halogen group is
chlorine, bromine, fluorine or iodine; [0191] an aryl group is
defined as above in Formula (XII); [0192] a heteroaryl group is
defined as above in Formula (XII);
[0193] Furthermore the present invention is directed to novel
compounds of the general Formula (XIII) and pharmaceutically
acceptable salts thereof:
##STR00011##
wherein [0194] A.sup.7 is independently C.dbd.O, C.dbd.S, SO.sub.2,
CH--OR.sup.13, C.dbd.NR.sup.12, or CH--CHOR.sup.13; [0195] A.sup.8
is independently C(R.sup.14).sub.2, O, S, or NR.sup.12; [0196]
A.sup.9 is independently C.dbd.O, C.dbd.S, SO.sub.2, CH--OR.sup.13,
C.dbd.NR.sup.12, or CH.sub.2--CHOR.sup.13; [0197] m is 0, or 1;
[0198] q is 0, or 1; [0199] r is 0, or 1; [0200] R.sup.12 is
independently H, CH.sub.3, CH.sub.2--CH.sub.3, OCH.sub.3,
OCH.sub.2--CH.sub.3, OH, or SH; [0201] R.sup.13 is independently H,
CH.sub.3, or CH.sub.2--CH.sub.3; [0202] R.sup.14 is independently
H, alkyl, alkoxy, OH, or SH; [0203] A.sup.5 is a optionally
substituted C.sub.3-C.sub.16-alkyl group by one or more
substituents R.sup.3 or an optionally substituted heteroaryl group,
which contains at least one heteroatom like O, N, S, NR.sup.4, SO,
SO.sub.2, Se, and which can optionally be substituted by one or
more substituents R.sup.8, R.sup.8', or R.sup.9; [0204] A.sup.6 is
an optionally substituted heteroaryl group, which contains at least
one heteroatom like O, N, S, NR.sup.4, SO, SO.sub.2, Se, and which
can optionally be substituted by one or more substituents R.sup.8,
R.sup.8', or R.sup.9, [0205] or a heterocyclic group, which
contains at least one double bond, and which may contain a
heteroatom like O, N, S, NR.sup.4, SO, SO.sub.2, Se, and which can
optionally be substituted by one or more substituents R.sup.8,
R.sup.8', or R.sup.9, [0206] or one of the groups below:
[0206] ##STR00012## ##STR00013## [0207] or one of the groups
mentioned below: wherein m=0,
[0207] ##STR00014## [0208] or one of the groups mentioned below:
wherein m and r=0,
[0208] ##STR00015## [0209] wherein X', X'', X''', X'''' is
independently H, S, O, N, NR.sup.4, SO, SO.sub.2, CH, or CH.sub.2;
[0210] R.sup.8, R.sup.8', R.sup.9 is independently H, methyl,
ethyl, t-butyl, CN, halogen, OH, alkoxy, NR.sup.4R.sup.5,
COOR.sup.4; [0211] R.sup.3 is independently H, OR.sup.4, SR.sup.4,
hydroxyalkyl, hydroxyalkylamino, cycloalkyl, halogen, haloalkyl,
haloalkyloxy, NO.sub.2, CN, SO.sub.2NR.sup.4R.sup.5,
CO.sub.2NR.sup.4R.sup.5, COR.sup.4, CO.sub.2R.sup.4,
SO.sub.2R.sup.4, SO.sub.3R.sup.4, NR.sup.4R.sup.5, alkyl, aryl or
heteroaryl; [0212] R.sup.4 is H, alkyl, cycloalkyl, aryl or
heteroaryl; [0213] R.sup.5 is H, O-alkyl, O-aryl, alkyl, heteroaryl
or aryl; [0214] said heteroaryl group of A.sup.5 or A.sup.6 may be
selected from the group comprising:
[0214] ##STR00016## ##STR00017## ##STR00018## [0215] said
C.sub.3-C.sub.16alkyl residue may be selected from the group
comprising --C.sub.3H.sub.7, --CH(CH.sub.3).sub.2,
--C.sub.4H.sub.9, --CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.2H.sub.5, --CH.sub.2--CH(CH.sub.3)--CH.sub.3,
--C(CH.sub.3).sub.3, --C.sub.5H.sub.11,
--C.sub.2H.sub.4CH(CH.sub.3).sub.2, --CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.6H.sub.13, --C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3, --C.sub.7H.sub.15,
--C.sub.3H.sub.6--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH(CH.sub.3).sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH(CH.sub.3)--C.sub.5H.sub.11, --C.sub.8H.sub.17,
--C.sub.4H.sub.8--C(CH.sub.3).sub.3,
--C.sub.5H.sub.10--CH(CH.sub.3).sub.2,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.2H.sub.6--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.5H.sub.11,
--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--CH(CH.sub.3)--C.sub.6H.sub.13, --C.sub.9H.sub.19,
--C.sub.5H.sub.10--C(CH.sub.3).sub.3,
--C.sub.6H.sub.12--CH(CH.sub.3).sub.2,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2C.sub.3H.sub.7,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.5H.sub.11,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--CH.sub.2--CH(CH.sub.3)--C.sub.6H.sub.13,
--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--CH(CH.sub.3)--C.sub.7H.sub.15, --C.sub.10H.sub.21,
--C.sub.6H.sub.12--C(CH.sub.3).sub.3,
--C.sub.7H.sub.14--CH(CH.sub.3).sub.2,
--C.sub.6H.sub.12--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.5H.sub.10--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.3H.sub.6CH(CH.sub.3)--C.sub.5H.sub.11, --C.sub.5H.sub.11,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.6H.sub.13,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--CH.sub.2--CH(CH.sub.3)--C.sub.7H.sub.15,
--C(CH.sub.3).sub.2--C.sub.7H.sub.15,
--CH(CH.sub.3)--C.sub.8H.sub.17, --C.sub.11H.sub.23,
--C.sub.7H.sub.14--C(CH.sub.3).sub.3,
--C.sub.8H.sub.16--CH(CH.sub.3).sub.2,
--C.sub.7H.sub.1413-CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.6H.sub.12--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.6H.sub.12--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.5H.sub.10--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.5H.sub.11,
--C.sub.3H.sub.6C(CH.sub.3).sub.2--C.sub.5H.sub.11,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.6H.sub.13,
--C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.7H.sub.15,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.7H.sub.15,
--CH.sub.2--CH(CH.sub.3)--C.sub.8H.sub.17,
--C(CH.sub.3).sub.2--C.sub.8H.sub.17,
--CH(CH.sub.3)--C.sub.9H.sub.19, --C.sub.12H.sub.25,
--C.sub.8H.sub.16--C(CH.sub.3).sub.3,
--C.sub.9H.sub.18--CH(CH.sub.3).sub.2,
--C.sub.8H.sub.16--CH(CH.sub.3)--C.sub.2H.sub.5,
--C.sub.7H.sub.14--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C.sub.7H.sub.14--CH(CH.sub.3)--C.sub.3H.sub.7,
--C.sub.6H.sub.12--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C.sub.6H.sub.12--CH(CH.sub.3)--C.sub.4H.sub.9,
--C.sub.5H.sub.10--C(CH.sub.3).sub.2--C.sub.4H.sub.9,
--C.sub.5H.sub.10--CH(CH.sub.3)--C.sub.5H.sub.11,
--C.sub.4H.sub.8--C(CH.sub.3).sub.2C.sub.5H.sub.11,
--C.sub.4H.sub.8--CH(CH.sub.3)--C.sub.6H.sub.13,
--C.sub.3H.sub.6--C(CH.sub.3).sub.2--C.sub.6H.sub.13,
--C.sub.3H.sub.6--CH(CH.sub.3)--C.sub.7H.sub.15,
C.sub.2H.sub.4--C(CH.sub.3).sub.2--C.sub.7H.sub.15,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.8H.sub.17,
CH.sub.2--C(CH.sub.3).sub.2--C.sub.8H.sub.17,
--CH.sub.2--CH(CH.sub.3)--C.sub.9H.sub.19,
--C(CH.sub.3).sub.2--C.sub.9H.sub.19,
--CH(CH.sub.3)--C.sub.10H.sub.21; [0216] an alkyl group, if not
stated otherwise, denotes a linear or branched
C.sub.1-C.sub.6-alkyl, preferably a linear or branched chain of one
to five carbon atoms, a linear or branched C.sub.1-C.sub.6-alkenyl
or a linear or branched C.sub.1-C.sub.6-alkinyl group, which can
optionally be substituted by one or more substituents R.sup.3,
preferably by halogen; [0217] the C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-alkenyl and C.sub.1-C.sub.6-alkinyl residue may be
selected from the group comprising --CH.sub.3, --C.sub.2H.sub.5,
--CH.dbd.CH.sub.2, --C.ident.CH, --C.sub.3H.sub.7,
--CH(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH, --CH.dbd.CH--CH.sub.3, --C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.CH, --C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3).sub.2, --CH(CH.sub.3)--C.sub.2H.sub.5,
--C(CH.sub.3).sub.3, --C.sub.5H.sub.11, --C.sub.6H.sub.13,
--C(R.sup.3).sub.3, --CR.sup.3(R.sup.3').sub.2,
--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.2(R.sup.3).sub.5,
--CH.sub.2--C(R.sup.3).sub.3, --CH.sub.2--CR.sup.3(R.sup.3').sub.2,
--CH.sub.2--CR.sup.3(R.sup.3')R.sup.3'', --C.sub.3(R.sup.3).sub.7,
--C.sub.2H.sub.4--C(R.sup.3).sub.3,
--C.sub.2H.sub.4--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.2H.sub.5,
--CH.dbd.C(CH.sub.3).sub.2, --CH.sub.2--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.dbd.CH.sub.2, --C.sub.2H.sub.4--C.ident.CH,
--C.ident.C--C.sub.2H.sub.5, --CH.sub.2--C.ident.C--CH.sub.3,
--C.ident.C--CH.dbd.CH.sub.2, --H.dbd.CH--C.ident.CH,
--C.ident.C--C.ident.CH, --C.sub.2H.sub.4--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH.sub.2--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--C.sub.2H.sub.5, --CH.sub.2--C(CH.sub.3).sub.3,
--C.sub.3H.sub.6--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--H.dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.dbd.CH--CH.sub.2--CH.dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--CH.sub.2--CH.dbd.C(CH.sub.3).sub.2,
--C(CH.sub.3).dbd.C(CH.sub.3).sub.2, --C.sub.3H.sub.6--C.ident.CH,
--C.ident.C--C.sub.3H.sub.7, --C.sub.2H.sub.4--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.2H.sub.5,
--CH.sub.2--C.ident.C--H.dbd.CH.sub.2,
--CH.sub.2--CH.dbd.CH--C.ident.CH,
--CH.sub.2--C.ident.C--C.ident.CH,
--C.ident.C--CH.dbd.CH--CH.sub.3, --CH.dbd.CH--C.ident.C--CH.sub.3,
--C.ident.C--C.ident.C--CH.sub.3,
--C.ident.C--CH.sub.2--CH.dbd.CH.sub.2,
--CH.dbd.CH--CH.sub.2--C.ident.CH, --C.ident.C--CH--C.ident.CH,
--C(CH.sub.3).dbd.CH--CH.dbd.CH.sub.2,
--CH.dbd.C(CH.sub.3)--CH.dbd.CH.sub.2,
--CH.dbd.CH--C(CH.sub.3).dbd.CH.sub.2,
--C(CH.sub.3).dbd.CH--C.ident.CH, --CH.dbd.C(CH.sub.3)--C.ident.CH,
--C.ident.C--C(CH.sub.3).dbd.CH.sub.2,
--C.sub.3H.sub.6--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH(CH.sub.3)--C.sub.4H.sub.9,
--CH.sub.2--CH(CH.sub.3)--C.sub.3H.sub.7,
--CH(CH.sub.3)--CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--CH(CH.sub.3)--CH(CH.sub.3).sub.2,
--CH.sub.2--C(CH.sub.3).sub.2--C.sub.2H.sub.5,
--C(CH.sub.3).sub.2--C.sub.3H.sub.7,
--C(CH.sub.3).sub.2--CH(CH.sub.3).sub.2,
--C.sub.2H.sub.4--C(CH.sub.3).sub.3,
--CH(CH.sub.3)--C(CH.sub.3).sub.3,
--C.sub.4H.sub.8--CH.dbd.CH.sub.2, --CH.dbd.CH--C.sub.4H.sub.9,
--C.sub.3H.sub.6--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.dbd.CH--C.sub.3H.sub.7,
--C.sub.2H.sub.4--CH.dbd.CH--C.sub.2H.sub.5,
--CH.sub.2--C(CH.sub.3).dbd.C(CH.sub.3).sub.2,
--C.sub.2H.sub.4--CH.dbd.C(CH.sub.3).sub.2,
--C.sub.4H.sub.8--C.ident.CH, --C.ident.C--C.sub.4H.sub.9,
--C.sub.3H.sub.6--C.ident.C--CH.sub.3,
--CH.sub.2--C.ident.C--C.sub.3H.sub.7,
--C.sub.2H.sub.4--C.ident.C.sub.2H.sub.5; R.sup.3, R.sup.3' or
R.sup.3'' being as defined above; [0218] a cycloalkyl group denotes
a non-aromatic ring system containing three to eight carbon atoms,
preferably four to eight carbon atoms, wherein one or more of the
carbon atoms in the ring can be substituted by a group X, X being
as defined above; the C.sub.3-C.sub.8-cycloalkyl residue may be
selected from the group comprising-cyclo-C.sub.3H.sub.5,
-cyclo-C.sub.4H.sub.7, -cyclo-C.sub.5H.sub.9,
-cyclo-C.sub.6H.sub.11, -cyclo-C.sub.7H.sub.13,
-cyclo-C.sub.8H.sub.15, [0219] an alkoxy group denotes an O-alkyl
group, the alkyl group being as defined above; the alkoxy group is
preferably a methoxy, ethoxy, isopropoxy, t-butoxy or pentoxy
group. [0220] an haloalkyl group denotes an alkyl group which is
substituted by one to five halogen atoms, the alkyl group being as
defined above; the haloalkyl group is preferably a
--C(R.sup.10).sub.3, --CR.sup.10(R.sup.10').sub.2,
--CR.sup.10(R.sup.10')R.sup.10'', --C.sub.2(R.sup.10).sub.5,
--CH.sub.2--C(R.sup.10).sub.3,
--CH.sub.2--CR.sup.10(R.sup.10').sub.2,
--CH.sub.2--CR.sup.10(R.sup.10')R.sup.10'',
--C.sub.3(R.sup.10).sub.7 or --C.sub.2H.sub.4--C(R.sup.10).sub.3
wherein R.sup.10, R.sup.10', R.sup.10'' represent F, Cl, Br or I,
preferably F; [0221] a hydroxyalkyl group denotes an HO-alkyl
group, the alkyl group being as defined above; [0222] an
haloalkyloxy group denotes an alkoxy group which is substituted by
one to five halogen atoms, the alkyl group being as defined above;
the haloalkyloxy group is preferably a --OC(R.sup.10).sub.3,
--OCR.sup.10(R.sup.10').sub.2, --OCR.sup.10(R.sup.10')R.sup.10'',
--OC.sub.2(R.sup.10).sub.5, --OCH.sub.2--C(R.sup.10).sub.3,
--OCH.sub.2--CR.sup.10(R.sup.10').sub.2,
--OCH.sub.2--CR.sup.10(R.sup.10')R.sup.10'',
--OC.sub.3(R.sup.10).sub.7 or --OC.sub.2H.sub.4--C(R.sup.10).sub.3,
wherein R.sup.10, R.sup.10', R.sup.10'' represent F, Cl, Br or I,
preferably F; [0223] a hydroxyalkylamino group denotes an
(HO-alkyl).sub.2-N-group or HO-alkyl-NH-group, the alkyl group
being as defined above; [0224] a halogen group is chlorine,
bromine, fluorine or iodine; [0225] an aryl group preferably
denotes an aromatic group having five to fifteen carbon atoms,
which can optionally be substituted by one or more substituents
R.sup.3, where R.sup.3 is as defined above; the aryl group is
preferably a phenyl group, --CH.sub.2--C.sub.6H.sub.4,
--C.sub.6H.sub.4--C.sub.6H.sub.4, --CH.dbd.CH--C.sub.6H.sub.4,
--C.ident.C--C.sub.6H.sub.4, -o-C.sub.6H.sub.4--R.sup.3,
-m-C.sub.6H.sub.4--R.sup.3, -p-C.sub.6H.sub.4--R.sup.3,
-o-CH.sub.2--C.sub.6H.sub.4--R.sup.3,
-m-CH.sub.2--C.sub.6H.sub.4--R.sup.3,
-p-CH.sub.2--C.sub.6H.sub.4--R.sup.3; [0226] a heteroaryl group
denotes a 5- or 6-membered heterocyclic group which contains at
least one heteroatom like O, N, S. This heterocyclic group can be
fused to another ring. For example, this group can be selected from
an oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl,
isothiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,
1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,5-oxadiazol-3-yl,
1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl, 1-imidazolyl,
2-imidazolyl, 1,2,5-thiadiazol-4-yl, 4-imidazolyl, 1-pyrrolyl,
2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl,
1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, indolyl, indolinyl,
benzo-[b]-furanyl, benzo[b]thiophenyl, benzimidazolyl,
benzothiazolyl, quinazolinyl, quinoxazolinyl, or preferably
isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, quinolinyl,
tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl group.
This heterocyclic group can optionally be substituted by one or
more substituents R.sup.3, where R.sup.3 is as defined above.
[0227] The invention also provides a pharmaceutical composition
comprising a compound of Formula (I), (XIII), (X), (XI) or (XII),
in free form or in the form of pharmaceutically acceptable salts
and physiologically functional derivatives, together with a
pharmaceutically acceptable diluent or carrier therefore.
[0228] The term "physiologically functional derivative" as used
herein refers to compounds which are not pharmaceutically active
themselves but which are transformed into their pharmaceutical
active form in vivo, i.e. in the subject to which the compound is
administered.
[0229] In another aspect, the present invention also provides a
method for the treatment or prophylaxis of a condition where there
is an advantage in inhibiting quorum sensing which comprises the
administration of an effective amount of a compound of Formula (I),
(XIII), (X), (XI) or (XII) and physiologically acceptable salts or
physiologically functional derivatives thereof. The term "quorum
sensing" is intended to describe cell-density dependent gene
regulation through a diffusible signal molecule (Fuqua et al., J.
Bacteriol. 176:269-75, 1994).
[0230] The invention is also directed to the use of compounds of
Formula (I), (XIII), (X), (XI) or (XII) and of their
pharmacologically tolerable salts or physiologically functional
derivatives for the production of a medicament or medical device
for the prevention and treatment of diseases, where quorum sensing
inhibition is beneficial. Furthermore, the invention is also
directed to the use of compounds of Formula (I), (XIII), (X), (XI)
or (XII) and of their pharmacologically tolerable salts or
physiologically functional derivatives for the production of an
antibacterial agent for the prevention and treatment of bacterial
biofilms in industrial and environmental settings.
[0231] In addition, the present invention provides methods for
preparing the desired compounds of Formula (I), (XIII), (X), (XI)
or (XII).
[0232] One possibility for the synthesis of compounds of Formula
(I) (m, p=0) or compounds of Formula (XI) comprises the step of
reacting an amine of Formula (II) with a compound of Formula (III).
Possibilities for preparing different amides are described by J.
Zabicky in "The Chemistry of Amides", in the serial of S. Patai
(ed.), "The Chemistry of Functional Groups", John Wiley & Sons,
1975, p. 74-131. Methods for preparing thioamides are described in
Houben-Weyl, J. Falbe (ed.), G. Thieme Verlag, vol. E5, p. 1219-59.
Methods for preparing sulfamides are described by Caldwell et al.,
J. Am. Chem. Soc. 1944, 66, 1479-82, or by Flynn et al, Med. Chem.
Res., 1998, 8, 219-43 and Dziadulewicz et al, Bioorg. Med. Chem.
Lett. 2001, 11, 5, 705-10.
##STR00019##
[0233] One method for preparing the compounds of Formula (I) (p=0,
n=1) or compounds of Formula (X) comprises the step of reacting a
compound of Formula (IV) with a compound of Formula (III). Other
methods for preparing different 1,2-diacylhydrazines are described
in Houben-Weyl, "Methoden der organischen Chemie", Vierte Auflage,
G. Thieme Verlag, J. Falbe (ed.), vol. E5, p. 1173-80 or P. A. S.
Smith, "Open-Chain Organic Nitrogen Compounds", W. A. Benjamin
Inc., New York, vol. 2, p. 173-201. Methods for preparing different
1,2-disulfonylhydrazines are described in Arch. Pharm. 1953, 286,
338-43 or in U.S. Pat. No. 6,291,504. Methods for preparing
1-acyl-2-sulfonylhydrazines are described in Russ. J. Gen. Chem.
2000, 70, 3, 459-60 or by Leadini et al., J. Chem. Soc. Perkin
Trans. 1 1998, 1833-8 and by M. Reinecke et al., J. Org. Chem.
1988, 53, 1, 208-10.
##STR00020##
[0234] One possibility for the synthesis of compounds of Formula
(I) (n,p=1) or compounds of Formula (XII) comprises the step of
reacting a compound of Formula (V) with a compound of the Formula
(VI). For example, one method for preparing carbamoylhydrazide is
described in Bull. Soc. Chim. Fr. 1975, 864.
##STR00021##
[0235] One possibility for preparing the compounds of Formula
(XIII) (A.sup.7, A.sup.9=CO, A.sup.8=CH.sub.2) comprises the step
of reacting a compound of Formula XIV with a compound of the
Formula XV. For example, this method is described in Synthesis
1992, 1213-1214.
##STR00022##
[0236] One method for preparation of compounds of Formula (XIV)
comprises the step of reacting a carboxylic acid chloride with
Meldrum's acid in presence of a base. For example, this reaction is
described in Org. Synth., Coll. Vol. 7, 359-360 (Org. Synth. 1984,
Ann. Vol. 63, 198-199), or J. Org. Chem. 1978, 43, 2087-2088, and
Bull. Chem. Soc. Jpn. 1982, 55, 2186-2189.
[0237] Another possibility for preparing compounds of Formula
(XIII) (A.sup.7, A.sup.9=CO, A.sup.8CH.sub.2) comprises the
reaction of a 3-oxo carboxylic acid chloride with a compound of
Formula (XV). For example, this procedure is described in Chem.
Pharm. Bull. 1980, 28, 2494-2502.
[0238] Another possibility for preparing compounds of Formula
(XIII) (A.sup.7, A.sup.9=CO, A.sup.8=CH.sub.2) comprises the
reaction of a 3-oxo carboxylic acid ester with a compound of
Formula (XV). For example, this procedure is described in Gazz.
Chim. Ital. 1936, 66, 723-731.
[0239] Another possibility for preparing the compounds of Formula
(XIII) (A.sup.7, A.sup.9=CO, A.sup.8=CH.sub.2) comprises the
reaction of a 3-oxo carboxylic acid with or without 3-oxo
protection with a compound of Formula (XV) using a peptide coupling
method. For example, this procedure is described in Tetrahedron
Lett. 1996, 37, 1883-1884, and Chem. Biol. 2003, 10, 81-89.
[0240] Another possibility for preparing compounds of Formula
(XIII) (A.sup.7, A.sup.9=CO, A.sup.8=CH.sub.2) comprises the
reaction of a deprotonated methyl ketone with an isocyanate. For
example, this method is described in J. Med. Chem. 1993, 36,
2943-2949, or J. Med. Chem. 1993, 36, 3386-3396.
[0241] Other methods for preparing compounds of Formula (XIII) are
described in Chem. Pharm. Bull. 1984, 32, 3848-3856, or Tetrahedron
Lett. 2001, 5195-5197, and J. Am. Chem. Soc. 1995, 117,
12360-12361.
##STR00023##
[0242] One possibility for preparing the compounds of Formula
(XIII) (A 7, A.sup.9=CO, A.sup.8=NR.sup.12) comprises the step of
reacting a compound of Formula (XVI) with a compound of Formula
(XVII). For example, this method described in Farmaco Ed. Sci.
1982, 37, 335-342, or in Monatsh. Chemie 1981, 112, 871-874, or in
Monatsh. Chemie 1982, 113, 101-110, or in J. Am. Chem. Soc. 2000,
122, 8155-8167, or in Synth. Commun. 1989, 19, 3543-3552.
[0243] A preferred compound of Formula (I) is a compound wherein p,
and n are 0, A.sup.1 represents a substituted monocyclic aromatic
ring system, and A.sup.2 represents an optionally substituted
monocyclic aromatic ring system.
[0244] A preferred compound of Formula (I) is a compound wherein p,
and n are 0, A.sup.1 represents a substituted monocyclic aromatic
ring system, and A.sup.2 represents an optionally substituted alkyl
group.
[0245] A more preferred compound of Formula (I) is a compound
wherein p is 0 and n is 1, one of A.sup.1 and A.sup.2 represent an
optionally substituted 5-membered aromatic ring system, and the
other one of A.sup.1 and A.sup.2 represent an optionally
substituted alkyl group or a substituted monocyclic aromatic ring
system.
[0246] A more preferred compound of Formula (I) is a compound
wherein p is 0 and n is 1, A.sup.1 and A.sup.2 represent an
optionally substituted 5-membered aromatic ring system.
[0247] A more preferred compound of Formula (I) is a compound
wherein p, and n are 1, one of A.sup.1 and A.sup.2 represent an
optionally substituted 5-membered aromatic ring system, and the
other one of A.sup.1 and A.sup.2 represent an optionally
substituted alkyl group or a substituted monocyclic aromatic ring
system.
[0248] A more preferred compound of Formula (I) is a compound
wherein p, n are 1, A.sup.1 and A.sup.2 represents an optionally
substituted 5-membered aromatic ring system.
[0249] A more preferred compound of Formula (I) is a compound
wherein p and n are 1, one of A.sup.1 and A.sup.2 represent an
optionally substituted 5-membered aromatic ring system, and the
other one of A.sup.1 and A.sup.2 represent an optionally
substituted alkyl group or a substituted monocyclic aromatic ring
system.
[0250] A more preferred compound of Formula (I) is a compound
wherein p and n are 1 A.sup.1 and A.sup.2 represent an optionally
substituted 5-membered aromatic ring system.
[0251] In the compounds of Formula (I), R is independently H,
alkyl, cycloalkyl, aryl or heteroaryl. Preferably, R is H.
[0252] In the compounds of Formula (I), R.sup.1 is independently H,
alkyl, cycloalkyl, aryl or heteroaryl. Preferably, R.sup.1 is
H.
[0253] In the compounds of Formula (I), R.sup.2 is independently H,
alkyl, cycloalkyl, aryl or heteroaryl. Preferably, R.sup.2 is
H.
[0254] Preferably, R.sup.3 in Formula (XIII), (I), (X), (XI) or
(XII) is independently H, halogen, CF.sub.3, OCF.sub.3, phenyl or
alkyl.
[0255] R.sup.4 in Formula (XIII), (I), (X) or (XII) is
independently H, alkyl, cycloalkyl, aryl or heteroaryl. Preferably
R.sup.4 is H.
[0256] R.sup.5 in Formula (XIII), (I), (X) or (XII) is
independently H, O-alkyl, O-aryl, alkyl, heteroaryl or aryl.
Preferably R.sup.5 is H.
[0257] In Formula (I) Y.sup.1 and Y.sup.2 are independently from
each other CO, CS, SO.sub.2, or CNR.sup.5, preferably both are
CO.
[0258] In Formula (I) Z is independently S, O, N, NR.sup.4, CO,
CO.sub.2, CS, SO or SO.sub.2. Preferably, Z is O, CO, CO.sub.2.
[0259] In Formula (I) or (X) X is independently S, O, N, NR.sup.4,
SO or SO.sub.2. Preferably, X is N, S, O, NR.sup.4.
[0260] In Formula (I), most preferably, n is 1 and p is 0.
[0261] In Formula (I), more preferably, n and p are 0.
[0262] In Formula (I), most preferably, n and p are 1.
[0263] In Formula (XII), most preferably q is 1 or 2.
[0264] A preferred compound of Formula (XIII) is a compound wherein
R.sup.14 is H or methyl more preferably H.
[0265] A preferred compound of Formula (XIII) is a compound wherein
R.sup.12 is H or methyl more preferably H.
[0266] A preferred compound of Formula (XIII) is a compound wherein
A.sup.8 is CH.sub.2.
[0267] A preferred compound of Formula (XIII) is a compound wherein
A.sup.7 and/or A) are CO.
[0268] A preferred compound of Formula (XIII) is a compound wherein
A.sup.5 is C.sub.6-C.sub.10-alkyl.
[0269] A preferred compound of Formula (XIII) is a compound wherein
A.sup.6 is selected from the following group:
##STR00024##
[0270] A preferred compound of Formula (XIII) is a compound wherein
A.sup.6 is 5-membered ring system wherein X' is N, and X'' is O or
S, and X''' is CH or CH.sub.2.
[0271] A preferred compound of Formula (XIII) is a compound wherein
A.sup.6 is 5-membered ring system wherein X' is N and X'' is N, and
X''' is CH or CH.sub.2.
[0272] A preferred compound of Formula (XIII) is a compound wherein
A.sup.6 is 6-membered ring system wherein X' is N, and X'' is O or
S, and X''' is CH or CH.sub.2, and X'''' is CH or CH.sub.2.
[0273] A preferred compound of Formula (XIII) is a compound wherein
A.sup.6 is 6-membered ring system wherein X' is N and X'' is N, and
X''' is CH or CH.sub.2, and X'''' is CH or CH.sub.2.
[0274] A preferred compound of Formula (XIII) is a compound wherein
m is 1 and q, r are 0.
[0275] A preferred compound of Formula (XIII) is a compound wherein
R.sup.13 is R.
[0276] A preferred compound of Formula (XIII) is a compound wherein
R.sup.6, R.sup.8' or R.sup.9 are H.
[0277] Most preferred is the use of one or more compounds of
Formula (I), (X), (XI) or (XII), including the compounds excluded
by any of the disclaimers, and/or pharmaceutically acceptable salts
thereof for regulation of the quorum sensing system of
microorganisms, in particular gram-negative bacteria. In one
embodiment of the invention also the use of the following compounds
is preferred: [0278]
2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid
(2-methyl-2H-pyrazol-3-yl)-amide
2,5-Dichloro-thio-phene-3-carboxylic acid pyridin-3-ylamide;
2-[(2-Chloro-4-trifluoro-methyl-pyrimidine-5-carbonyl)-amino]-thiophene-3-
-carboxylic acid methyl ester;
2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid
(3-trifluoromethyl-phenyl)-amide;
2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid
(4-trifluoromethoxy-phenyl)-amide;
2-Methyl-6-trifluoromethyl-nicotinic acid
N'-(thiophene-2-carbonyl)-hydrazide; 4-Trifluoromethyl-benzoic acid
N'-(4-methyl-thiophene-2-carbonyl)-hydrazide; 4-Chloro-benzoic acid
N'-(4-methoxy-thiophene-3-carbonyl)-hydrazide; 3-Chloro-benzoic
acid N'-(thiophene-2-carbonyl)-hydrazide;
N'-(3-Methyl-1,4-dioxy-quinoxaline-2-carbonyl)-thiophene-2-carboxylic
acid hydrazide; Furan-2-carboxylic acid
N'-(thiophene-2-carbonyl)-hydrazide; Furan-2-carboxylic acid
N'-(3-chloro-4-methyl-thiophene-2-carbonyl)-hydrazide;
Furan-2-carboxylic acid
N'-(3-ethoxy-thiophene-2-carbonyl)-hydrazide; Furan-2-carboxylic
acid N'-(3-chloro-benzo[b]thiophene-2-carbonyl)-hydrazide;
Thiophene-2-carboxylic acid
N'-(5-bromo-4-methoxy-thiophene-3-carbonyl)-hydrazide;
Thiophene-2-carboxylic acid
N'-(3-chloro-4-methyl-thiophene-2-carbonyl)-hydrazide;
Thiophene-2-carboxylic acid N'-(thiophene-2-carbonyl)-hydrazide;
3-Chloro-thiophene-2-carboxylic acid
N'-(thiophene-2-carbonyl)-hydrazide; Thiophene-2-carboxylic acid
N'-(5-bromo-thiophene-2-carbonyl)-hydrazide;
3-Chloro-benzo[b]thiophene-2-carboxylic acid
N'-(thiophene-2-carbonyl)-hydrazide; Thiophene-2-carboxylic acid
N'-(4-bromo-1,5-dimethyl-1H-pyrazole-3-carbonyl)-hydrazide;
Thiophene-2-carboxylic acid N'-butyryl-hydrazide.
[0279] Preferred compounds of the present invention and/or
pharmaceutically acceptable salts thereof are selected from the
group comprising; [0280] 3-Oxo-nonanoic acid
(2H-pyrazol-3-yl)-amide; 3-Oxo-nonanoic acid
(2-methyl-2H-pyrazol-3-yl)-amide; 3-Oxo-dodecanoic acid
(2-methyl-2H-pyrazol-3-yl)-amide; 3-Oxo-nonanoic acid
(2-ethyl-2H-pyrazol-3-yl)-amide; 3-Oxo-dodecanoic acid
(2-ethyl-2H-pyrazol-3-yl)-amide; 3-Oxo-nonanoic acid
(2,5-dimethyl-2H-pyrazol-3-yl)-amide; 3-Oxo-dodecanoic acid
(2,5-dimethyl-2H-pyrazol-3-yl)-amide; 3-Oxo-nonanoic acid
pyrazol-1-ylamide; 2-(3-Oxo-nonanoylamino)-thiophene-3-carboxylic
acid methyl ester; Z(3-Oxo-dodecanoylamino)-thiophene-3-carboxylic
acid methyl ester;
4-Methyl-2-(3-oxo-nonanoylamino)-thiophene-3-carboxylic acid ethyl
ester; 4-Methyl-2-(3-oxo-dodecanoylamino)-thiophene-3-carboxylic
acid ethyl ester; 3-Oxo-nonanoic acid
(3-methyl-isothiazol-5-yl)-amide; 3-Oxo-dodecanoic acid
(3-methyl-isothiazol-5-yl)-amide; 3-Oxo-nonanoic acid
thiazol-2-ylamide; 3-Oxo-dodecanoic acid thiazol-2-ylamide;
3-Oxo-nonanoic acid (5-acetyl-2-methylsulfanyl-thiazol-4-yl)-amide;
3-Oxo-nonanoic acid isoxazol-3-ylamide; 3-Oxo-dodecanoic acid
isoxazol-3-ylamide; 3-Oxo-nonanoic acid
(3-methyl-isoxazol-5-yl)-amide; 3-Oxo-dodecanoic acid
(3-methyl-isoxazol-5-yl)-amide; 3-Oxo-nonanoic acid
(4-methyl-oxazol-2-yl)-amide; 3-Oxo-nonanoic acid
(4cyano-2-methyl-oxazol-5-yl)-amide; 3-Oxo-nonanoic acid
(3-cyano-4,5-dimethyl-furan-2-yl)-amide; 3-Oxododecanoic acid
(3-cyano-4,5-dimethyl-furan-2-yl)-amide;
5-(3-Oxo-nonanoylamino)-furan-2-carboxylic acid methyl ester [0281]
3-Bromo-thiophene-2-carboxylic acid (6-methoxy-pyridin-3-yl)-amide;
4-Methyl-3-[(thio-phene-2-carbonyl)-amino]-thiophene-2-carboxylic
acid methyl ester;
N-(6-Methoxy-pyridin-3-yl)-2-methylsulfanyl-nicotinamide;
5-Bromo-N-(6-methoxy-pyridin-3-yl)-nicotinamide;
N-(5-Bromo-pyridin-2-yl)-2,6-dichloro-isonicotinamide;
2-Chloro-6-methyl-N-pyridin-3-yl-iso-nicotinamide;
4-Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid
(2-methyl-2H-pyrazol-3-yl)-amide;
2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid
(2-methyl-2H-pyrazol-3-yl)-amide; Thiophene-2-carboxylic acid
[5-(4-chloro-phenyl)-2-methyl-2H-pyrazol-3-yl]-amide;
3-Chloro-N-(2-methyl-5-thiophen-2-yl-2H-pyrazol-3-yl)-benzamide;
6-Bromo-hexanoic acid
[5-(4chloro-phenyl)-2-methyl-2H-pyrazol-3-yl]-amide; Heptanoic acid
(2-methyl-5-phenyl-2H-pyrazol-3-yl)-amide; 6-Bromo-hexanoic acid
(2-methyl-5-phenyl-2H-pyrazol-3-yl)-amide; Heptanoic acid
(2-methyl-5-thiophen-2-yl-2H-pyrazol-3-yl)-amide; 6-Bromo-hexanoic
acid (2-methyl-5-thiophen-2-yl-2H-pyrazol-3-yl)-amide; Heptanoic
acid (4-bromo-2-methyl-2H-pyrazol-3-yl-amide; 6-Bromo-hexanoic acid
(2-methyl-2H-pyrazole-3-yl)-amide; 6-Bromo-hexanoic acid
(4-bromo-2-methyl-2H-pyrazol-3-yl)-amide; Heptanoic acid
(2-methyl-2H-pyrazol-3-yl)-amide; Thiophene-2carboxylic acid
N'-(4-trifluoromethyl-pyrimidin-2-yl)-hydrazide;
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid
N'-(4-trifluoromethyl-pyrimidin-2-yl)-hydrazide;
4-Trifluoromethoxy-benzoic acid
N'-(thiophene-2-carbonyl)-hydrazide;
3-Chloro-thiophene-2-carboxylic acid
N'-(1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl)-hydrazide;
Thio-phene-2-carboxylic acid
N'-[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-hydrazi-
de; Furan-2-carboxylic acid
N'-(5-chloro-4-methoxy-thiophene-3-carbonyl)-hydrazide;
Furan-2-carboxylic acid
N'-(3-bromo-thiophene-2-carbonyl)-hydrazide; Furan-2-carboxylic
acid N'-(2,5-dichloro-thiophene-3-carbonyl)-hydrazide;
3-Chloro-thiophene-2-carboxylic acid
N'-(3-ethoxy-thiophene-2-carbonyl)-hydrazide;
Thiophene-2-carboxylic acid
N'-(3-ethoxy-thiophene-2-carbonyl)-hydrazide;
Thiophene-3-carboxylic acid N'-(thiophene-2-carbonyl)-hydrazide;
3-Bromo-thiophene-2-carboxylic acid
N'-(2-chloromethylsulfanyl-acetyl)-hydrazide;
3-Chloro-thiophene-2-carboxylic acid
N'-(3-chloro-thiophene-2-carbonyl)-hydrazide;
5-Chloro-4-methoxy-thiophene-3-carboxylic acid
N'-(thiophene-2-carbonyl)-hydrazide; Thiophene-2-carboxylic acid
N'-(5-chloro-thiophene-2-carbonyl)-hydrazide;
5-Bromo-4-methoxy-thiophene-3-carboxylic acid
N'-(5-methyl-thiophene-2-carbonyl)-hydrazide;
Thiophene-2-carboxylic acid
N'-(5-methyl-thiophene-2-carbonyl)-hydrazide;
Thiophene-2-carboxylic acid
N'-(3-bromo-thiophene-2-carbonyl)-hydrazide;
3-Bromo-thiophene-2-carboxylic acid
N'-(3-ethoxy-thiophene-2-carbonyl)-hydrazide;
3-Bromo-thiophene-2-carboxylic acid
N'-(5-methyl-thiophene-2-carbonyl)-hydrazide;
3-Chloro-thiophene-2-carboxylic acid
N'-(5-chloro-thiophene-2-carbonyl)-hydrazide;
3-Chloro-benzo[b]thiophene-2-carboxylic acid
N'-(3-bromo-thiophene-2-carbonyl)-hydrazide;
3-Chloro-benzo[b]thiophene-2-carboxylic acid
N'-(5-bromo-thiophene-2-carbonyl)-hydrazide;
4-Chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxylic acid
N'-(thiophene-2-carbonyl-hydrazide;
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid
N'-(3-chloro-benzo[b]thiophene-2-carbonyl)-hydrazide;
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid
N'-(thiophene-2-carbonyl)-hydrazide;
4-Bromo-2ethyl-5-methyl-2H-pyrazole-3-carboxylic acid
N'-(5-chloro-thiophene-2-carbonyl)-hydrazide;
Thiophene-2-carboxylic acid
N'-(2-tert-butyl-5-methyl-2H-pyrazole-3-carbonyl)-hydrazide;
5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid
N'-(5-chloro-thiophene-2-carbonyl)-hydrazide;
Thiophene-2-carboxylic acid
N'-(5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-hydrazide;
4Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid
N'-(5-bromo-thiophene-2-carbonyl)-hydrazide;
4-Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid
N'-(3-chloro-4-methylthiophene-2-carbonyl)-hydrazide;
4-Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid
N'-(5-chloro-thiophene-2-carbonyl)-hydrazide;
4-Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid
N'-(4,5-di-bromo-thiophene-2-carbonyl)-hydrazide;
5-Methyl-thiophene-2-carboxylic acid N'-butyryl-hydrazide;
5-Bromo-thiophene-2-carboxylic acid N'-butyryl-hydrazide;
Thiophene-2-carboxylic acid N'-(6-bromo-hexanoyl)-hydrazide;
Thiophene-2-carboxylic acid N'-heptanoyl-hydrazide;
3-Chloro-4-methyl-thiophene-2-carboxylic acid
N'-(6-bromo-hexanoyl)-hydrazide;
3-Chloro-4-methyl-thiophene-Z-carboxylic acid
N'-heptanoyl-hydrazide; 5-Methyl-thiophene-2-carboxylic acid
N'-(6-bromohexanoyl)-hydrazide; 5-Methyl-thiophene-2-carboxylic
acid N'-heptanoyl-hydrazide; 5-Bromo-thiophene-2-carboxylic acid
N'-heptanoyl-hydrazide; 3-Bromo-thiophene-2carboxylic acid
N'-octanoyl-hydrazide; Thiophene-2-carboxylic acid
N'-dodecanoyl-hydrazide; 5-Methyl-thiophene-2-carboxylic acid
N'-(3-cyclopentyl-propionyl)-hydrazide;
5-[N'-(5-Methyl-thiophene-2-carbonyl)-hydrazinol-5-oxo-pentanoic
acid methyl ester; Furan-2-carboxylic acid N'-heptanoyl-hydrazide;
Furan-2-carboxylic acid N'-(3-cyclopentyl-propionyl)-hydrazide;
3,5-Dimethyl-isoxazole-4carboxylic acid N'-octanoyl-hydrazide;
4-Bromo-2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid
N'-octanoyl-hydrazide; 2-Chloro-isonicotinic acid
N'-octanoyl-hydrazide; 2-Chloro-nicotinic acid
N'-octanoyl-hydrazide;
3-[N'-(3-Bromo-thiophene-2-carbonyl)-hydrazinol-3-oxo-propionic
acid ethyl ester;
3-[N'-(Benzo[b]thiophene-2-carbonyl)-hydrazino]-3-oxo-propionic
acid ethyl ester;
N'-(5-Chloro-thiophen-2-sulfonyl)-thiophene-2-carboxylic acid
hydrazide; Butyric acid
N'-(5-chloro-thiophen-2-sulfonyl)-hydrazide;
N'-(5-Chloro-thiophen-2-sulfonyl)-heptanoic acid hydrazide;
4-Butyl-1-(thiophene-2-carbonyl)-thiosemicarbazide;
1-(4,5-Dibromo-thiophene-2-carbonyl)-4-pentyl-semicarbazide;
1-(5-Bromo-thiophene-2-carbonyl)-4-(4-fluoro-2-trifluoromethyl-phenyl)-se-
micarbazide;
4-(4-Chloro-3-trifluoromethyl-phenyl)-1-(4,5-dibromo-thiophene-2-carbonyl-
)-semicarbazide;
1-(4,5-Dibromo-thiophene-2-carbonyl)-4-(3-trifluoromethyl-phenyl)-semi-ca-
rbazide;
1-(3-Chloro-4-methyl-thiophene-2-carbonyl)-4-(4-methylsulfanyl-ph-
enyl)-semicarbazide;
4-(4-Bromo-phenyl)-1-(3-chloro-4-methyl-thiophene-2-carbonyl)-semicarbazi-
de;
1-(5-Bromo-thiophene2-carbonyl)-4-(2-chloromethyl-phenyl)-semicarbazid-
e;
4(2-Chloro-methyl-phenyl)-1-(5-chloro-thiophene-2-carbonyl)-semicarbazi-
de;
1-(5-Bromo-thiophene-2-carbonyl)-4-(4-methoxy-phenyl)-semicarbazide;
1-(5-Bromo-thiophene-2-carbonyl)-4-(2,6-difluoro-phenyl)-semicarbazide;
1-(3-Chloro-benzo[b]thiophene-2-carbonyl)-4-(2,6-dichloro-pyridinyl)-semi-
carbazide;
1-(3-Chloro-benzo[b]thiophene-2-carbonyl)-4-o-tolyl-semi-carbaz-
ide
[0282] The compounds of the Formula (XIII), (I), (X), (XI) or (XII)
according to the invention can be also used in form of the
corresponding salts with inorganic or organic acids or bases.
Examples of such salts are, e.g., alkali metal salts, in particular
sodium and potassium salts, hydrochloride or ammonium salts.
[0283] In general, the compounds of the present invention can be
used to inhibit quorum sensing signaling of bacteria employing HSLs
as signal molecules for cell-cell communication. Preferably, the
compounds can be applied to the bacteria listed in Table 1, and
more preferably to the bacteria of Table 1 that are pathogens. In
the following it is explained that the compounds of the present
invention can be used as antibacterial agents in various
applications.
[0284] In a preferred form, the compounds of Formula (XIII), (I),
(X), (XI) or (XII) are useful for the treatment of a variety of
human, animal and plant diseases, where bacterial pathogens
regulate the expression of virulence genes and other phenotypes,
e.g. biofilm formation, through an HSL-based quorum sensing system.
Furthermore, as the list of organisms (see Table 1) employing
quorum sensing signaling for their virulence continues to increase,
the compounds of the invention can be used also for organisms which
will be added to the above listed in future.
[0285] In a first embodiment, the compounds are useful for the
treatment of mammalian in particular human diseases caused by
bacteria through the inhibition of the bacterial quorum sensing
cascade rendering the pathogen avirulent. Such diseases include
endocarditis, respiratory and pulmonary infections (preferably in
immunocompromised and cystic fibrosis patients), bacteremia,
central nervous system infections, ear infections including
external otitis, eye infections, bone and joint infections, urinary
tract infections, gastrointestinal infections and skin and soft
tissue infections including wound infections, pyoderma and
dermatitis which all can be triggered by Pseudomonas aeruginosa.
Furthermore, the compounds can be used for the treatment of
pulmonary infections caused by Burkholderia cepacia (preferably in
immunocompromised and cystic fibrosis patients), gastroenteritis
and wound infections caused by Aeromonas hydrophila, sepsis in
tropical and subtropical areas caused by Chromobacterium violaceum,
diarrhoea with blood and haemolytic uremic syndrome (HUS) caused by
Escherichia coli, yersiniosis triggered by Yersinia enterocolitica
and Y. pseudotuberculosis, and transfusion-related sepsis and
fistulous pyoderma caused by Serratia liquefaciens.
[0286] In a second embodiment the compounds can be used in the
treatment of immunological diseases, particularly autoimmune
diseases such as psoriasis, rheumatoid arthritis, multiple
sclerosis and type 1 (autoimmune) diabetes, of cardiovascular
diseases such as cardiac tachyarrhythmias, ischaemic heart disease,
congestive heart failure, of allergic diseases and of diseases
including cancer, breast cancer, obesity, lipid metabolism
disorders, immune disease, immune deficiency or immune
disorders.
[0287] In a third embodiment, the compounds can be used to prevent
and/or treat plant diseases, where inhibition of the HSL-mediated
signaling system reduces or abolishes virulence of bacterial plant
pathogens. Such diseases include crown gall tumors caused by
Agrobacterium tumefaciens, soft rot caused by Burkholderia cepacia,
Erwinia carotovora and Erwinia chrysanthemi, sweet corn and maize
infections caused by Pantoea stewartii and wilt disease caused by
Ralstonia solanacearum.
[0288] In a fourth embodiment, the compounds can be used for the
prevention and/or treatment of animal diseases, preferably fish
diseases such as septicemia caused by Aeromonas hydrophila and
Vibrio anguillarum, furunculosis in salmonids caused by Aeromonas
salmonicida, prawn infections caused by Vibrio harveyi and enteric
redmouth disease caused by Yersinia ruckeri, but also for the
prevention and/or treatment of insect diseases caused, for example,
by Xenorhabdus nematophilus.
[0289] In general, the present invention provides a method for
reducing the virulence of bacterial pathogens employing an
HSL-based signaling system. In a preferred form, a method is
provided to remove, diminish, detach or disperse a bacterial
biofilm from a living or nonliving surface by treating the surface
with a compound of Formula (XIII), (I), (X), (XI) or (XII). This
method is also useful to prevent biofilm formation on a living or
nonliving surface by treating the surface with a compound of
Formula (XIII), (I), (X), (XI) or (XII) before bacterial
colonization can initialize. The term "biofilm" refers to cell
aggregations comprising either a single type of organism or a
mixture of more than one organism, then also referred to as "mixed
biofilms". It is clear to persons skilled in the art, that the
compounds of the present invention can be applied in a wide variety
of different fields such as environmental, industrial and medical
applications in order to prevent and/or treat damages or diseases
caused by bacteria.
[0290] In one aspect, the compounds of Formula (XIII), (I), (X),
(XI) or (XII) can be used for all kinds of surfaces in private and
public areas, where it is beneficial to inhibit quorum sensing
systems of Gram-negative bacteria in order to prevent and/or treat
colonization and biofilm formation. The compounds here can be used
in form of a solution, powder or as a coating. The compound is
preferably applied to the surface as a solution of the compound,
alone or together with other materials such as conventional
surfactants, preferably sodium dodecyl sulfate, or detergents,
biocides, fungicides, antibiotics, pH regulators, perfumes, dyes or
colorants, In combination with a bacteriocidal agent, e.g., the
compounds of Formula (XIII), (I), (X), (XI) or (XII) inhibit
virulence or biofilm formation whilst the bacteriocidal agent kills
the pathogens.
[0291] In one embodiment, the compounds can be used as
antibacterial agent for topical use in cleaning and treatment
solutions such as disinfectants, detergents, household cleaner and
washing powder formulations in the form of a spray or a dispensable
liquid. In a preferred form, these solutions can be applied to
windows, floors, clothes, kitchen and bathroom surfaces and other
surfaces in the area of food preparation and personal hygiene. In
addition, the compounds of Formula (XIII), (I), (X), (XI) or (XII)
can be used as antibacterial ingredients in personal hygiene
articles, toiletries and cosmetics such as dentifrices,
mouthwashes, soaps, shampoos, shower gels, ointments, creams,
lotions, deodorants and disinfectants and storage solutions for
contact lenses. In the case of contact lenses the compounds of
Formula (XIII), (I), (X), (XI) or (XII) can also be applied as
coating or additive to the lens material.
[0292] In another embodiment, the compounds can be used to prevent
or treat bacterial biofilms in industrial settings such as ship
hulls, paper and metal manufacturing, oil recovery, food processing
and other applications where process disturbances are referred to
biofouling on surfaces. The compounds here can be used in form of a
solution, paint or coating, for example as an ingredient in cooling
lubricants. The compounds can also be applied to water processing
plants or drinking water distribution systems where the colonized
surface (preferably by Pseudomonas aeruginosa) is preferably the
inside of an aqueous liquid system such as water pipes, water
injection jets, heat exchangers and cooling towers. Until now
biocides are the preferred tools to encounter these problems, but
since biocides do not have a high specificity for bacteria, they
are often toxic to humans as well. This can be circumvented by the
application of the compounds of the present invention.
[0293] In a further embodiment, the present invention relates to a
method of inhibiting and/or preventing medical device-associated
bacterial infections. The invention provides articles coated and/or
impregnated with a compound of Formula (XIII), (I), (X), (XI) or
(XII) in order to inhibit and/or prevent biofilm formation thereon.
The articles are preferably surgical instruments, blood bag systems
or medical devices; more preferably either permanently implanted
devices such as artificial heart valve, prostethic joint, voice
prosthesis, stent, shunt or not permanently implanted devices such
as endotracheal or gastrointestinal tube, pacemaker, surgical pin
or indwelling catheter.
[0294] In a more preferred form, the indwelling catheters are
urinary catheters, vascular catheters, peritoneal dialysis
catheter, central venous catheters and needleless connectors. The
catheter materials can be polyvinylchloride, polyethylene, latex,
teflon or similar polymeric materials, but preferably polyurethane
and silicone or a mixture thereof. In order to reduce the risk of
catheter-related bacterial infections, several catheters coated
and/or impregnated with antiseptic or antimicrobial agents such as
chlorhexidine/silver-sulfadiazine and minocycline/rifampin,
respectively, have been developed. Furthermore, collection bags or
layers sandwiched between an external surface sheath and a luminal
silicone sheath have been constructed to overcome rapid loss of
antimicrobial activity. Nevertheless, the emerging risk of
bacterial resistance against traditional antibiotics limits the
routine use of antibiotic-coated catheters.
[0295] the compounds of the present invention, however, offer the
possibility to effectively reduce catheter-related bacterial
infections with a low risk of resistance development due to a novel
therapeutic strategy targeting highly sensitive signal transduction
mechanisms in bacteria. The preferred form of application is the
coating and/or impregnating of catheter materials on both the inner
and outer catheter surfaces. More preferably, the compounds of
Formula (XIII), (I) can be included in a mixture of antibacterial
agents released continuously from a catheter-associated depot into
the environment.
[0296] In a further embodiment, the compounds of the present
invention and their pharmacologically acceptable salts can be
administered directly to animals, preferably to mammals, and in
particular to humans as antibiotics per se, as mixtures with one
another or in the form of pharmaceutical preparations which allow
enteral or parenteral use and which as active constituent contain
an effective dose of at least one compound of the Formula (XIII),
(I), (X), (XI) or (XII) or a salt thereof, in addition to customary
pharmaceutical excipients and additives. The compounds of Formula
(XIII), (I), (X), (XI) or (XII) can also be administered in form of
their salts, which are obtainable by reacting the respective
compounds with physiologically acceptable acids and bases.
[0297] The therapeutics can be administered orally, e.g., in the
form of pills, tablets, coated tablets, sugar coated tablets,
lozenges, hard and soft gelatin capsules, solutions, syrups,
emulsions or suspensions or as aerosol mixtures. Administration,
however, can also be carried out rectally, e.g., in the form of
suppositories, or parenterally, e.g., in the form of injections or
infusions, or percutaneously, e.g., in the form of ointments,
creams or tinctures.
[0298] In addition to the active compounds of Formula (XIII), (I),
(X), (XI) or (XII), the pharmaceutical composition can contain
further customary, usually inert carrier materials or excipients.
Thus, the pharmaceutical preparations can also contain additives or
adjuvants commonly used in galenic formulations, such as, e.g.,
fillers, extenders, disintegrants, binders, glidants, wetting
agents, stabilizers, emulsifiers, preservatives, sweetening agents,
colorants, flavorings or aromatizers, buffer substances, and
furthermore solvents or solubilizers or agents for achieving a
depot effect, as well as salts for modifying the osmotic pressure,
coating agents or antioxidants. They can also contain two or more
compounds of the Formula (I) or (XIII) or their pharmacologically
acceptable salts and also other therapeutically active
substances.
[0299] Thus, the compounds of the present invention can be used
alone, in combination with other compounds of this invention or in
combination with other active compounds, for example with active
ingredients already known for the treatment of the afore mentioned
diseases, whereby in the latter case a favorable additive effect is
noticed. Suitable amounts to be administered to mammalian in
particular humans range from 5 to 1000 mg,
[0300] To prepare the pharmaceutical preparations, pharmaceutically
inert inorganic or organic excipients can be used. To prepare
pills, tablets, coated tablets and hard gelatin capsules, e.g.,
lactose, corn starch or derivatives thereof, talc, stearic acid or
its salts, etc. can be used. Excipients for soft gelatin capsules
and suppositories are, e.g., fats, waxes, semi-solid and liquid
polyols, natural or hardened oils etc. Suitable excipients for the
production of solutions and syrups are, e.g., water, alcohol,
sucrose, invert sugar, glucose, polyols etc. Suitable excipients
for the production of injection solutions are, e.g., water,
alcohol, glycerol, polyols or vegetable oils.
[0301] The dose can vary within wide limits and is to be suited to
the individual conditions in each individual case. For the above
uses the appropriate dosage will vary depending on the mode of
administration, the particular condition to be treated and the
effect desired. In general, however, satisfactory results are
achieved at dosage rates of about 0.1 to 100 mg/kg animal body
weight preferably 1 to 50 mg/kg. Suitable dosage fates for larger
mammals, e.g., humans, are of the order of from about 10 mg to 3
g/day, conveniently administered once, in divided doses 2 to 4
times a day, or in sustained release form.
[0302] In general, a daily dose of approximately 0.1 mg to 5000 mg,
preferably 10 to 500 mg, per mammalian in particular human
individual is appropriate in the case of the oral administration
which is the preferred form of administration according to the
invention. In the case of other administration forms too, the daily
dose is in similar ranges. The compounds of Formula (I) or (XIII)
can also be used in the form of a precursor (prodrug) or a suitably
modified form, that releases the active compound in vivo.
[0303] In a further embodiment, the compounds of the present
invention can be used as pharmacologically active components or
ingredients of medical devices, instruments and articles with an
effective dose of at least one compound of the Formula (XIII), (I),
(X), (XI) or (XII) or a salt thereof. The amount of the compounds
used to coat for example medical device surfaces varies to some
extent with the coating method and the application field. In
general, however, the concentration range from about 0.01 mg per
cm.sup.2 to about 100 mg per cm.sup.2. In a similar way the amount
of the compounds has to be adjusted to the application mode it the
compounds of the invention are used as components or ingredients in
cleaning or treatment solutions. In general, effective dosages
range from about 0.1 .mu.M to about 1000 mM.
[0304] The following section shows examples for the synthesis of
the compounds of the present invention and demonstrate their quorum
sensing inhibiting effect.
EXAMPLES
1. Synthesis of Compounds of Formula (XIII), (I), (X), or (XII)
[0305] Synthesis Method A (1,2-diacylhydrazine or
1-acyl-2sulfonylhydrazine Derivatives) A solution of (1.2 eq) acid
chloride or (1.2 eq) sulfonyl chloride in tetrahydrofuran was added
to a solution of (1 eq) hydrazide in tetrahydrofuran and molecular
sieve (0.4 nm) at 0.degree. C. The mixture was stirred at room
temperature. After 1 h the reaction mixture was concentrated in
vacuum, and the resulting solid was purified by preparative thin
layer chromatography (Merck, 20.times.20 cm, Silica gel 60
F.sub.254, 1 mm) (CH.sub.2Cl.sub.2:MeOH, 100:1).
Synthesis Method B
1,2-diacylhydrazine or 1-acyl-2-sulfonylhydrazine Derivatives
[0306] A solution of (1.2 eq) acid chloride or (1.2 eq) sulfonyl
chloride in dimethylformamide was added to a solution of (1 eq)
hydrazide in dimethylformamide and (1.2 eq) triethylamine at
0.degree. C. The mixture was stirred at room temperature. After 1 h
the reaction mixture was concentrated in vacuum, and the resulting
solid was purified by preparative thin layer chromatography (Merck,
20.times.20 cm, Silica gel 60 F.sub.254, 1 mm)
(CH.sub.2Cl.sub.2:MeOH, 100:1).
Synthesis Method C
1,2diacylhydrazine or 1-acyl-2-sulfonylhydrazine Derivatives
[0307] A solution of (1.2 eq) acid chloride or (1.2 eq) sulfonyl
chloride in dichloromethane was added to a solution of (1 eq)
hydrazide in dichloromethane and (1.2 eq) triethylamine at
0.degree. C. The mixture was stirred at room temperature. After 1 h
the reaction mixture was concentrated in vacuum, and the resulting
solid was purified by preparative thin layer chromatography (Merck,
20.times.20 cm, Silica gel 60 F.sub.254, 1 mm) (n-hexane:EtOAc,
9:1).
Synthesis Method D
Amide Derivatives
[0308] A solution of (1.2 eq) acid chloride in tetrahydrofuran was
added to a solution of (1 eq) amine in tetrahydrofuran and
molecular sieve (0.4 nm) at 0.degree. C. The mixture was stirred at
room temperature. After 1 h the reaction mixture was concentrated
in vacuum, and the resulting solid was purified by preparative thin
layer chromatography (Merck, 20.times.20 cm, Silica gel 60
F.sub.254, 1 mm) (CH.sub.7Cl.sub.2:MeOH, 100:1).
Synthesis Method E
Amide Derivatives
[0309] A solution of (1.2 eq) acid chloride in dichloromethane was
added to a solution of (1 eq) amine in dichloromethane and (1.2 eq)
triethylamine at 0.degree. C. The mixture was stirred at room
temperature. After 1 h the reaction mixture was concentrated in
vacuum, and the resulting solid was purified by preparative thin
layer chromatography (Merck, 20.times.20 cm, Silica gel 60
F.sub.254, 1 mm) (n-hexane:EtOAc, 9:1).
Synthesis Method F
Semicarbazide or Thiosemicarbazide Derivatives
[0310] A solution of (1.3 eq) isocyanate or (1.3 eq) isothiocyanate
in tetrahydrofuran was added to a solution of (1 eq) hydrazide in
tetrahydrofuran and molecular sieve (0.4 nm) at 0.degree. C. The
mixture was stirred at room temperature. After 1 h the reaction
mixture was concentrated in vacuum, and the resulting solid was
purified by preparative thin layer chromatography (Merck,
20.times.20 cm, Silica gel 60 F.sub.254, 1 mm)
(CH.sub.2Cl.sub.2:MeOH, 100:5).
Synthesis Method G
Hydrazide Derivatives
[0311] A solution of (1.2 eq) acid chloride in tetrahydrofuran was
added to a solution of (1 eq) hydrazine in tetrahydrofuran and
molecular sieve (0.4 nm) at 0.degree. C. The mixture was stirred at
room temperature. After 1 h the reaction mixture was concentrated
in vacuum, and the resulting solid was purified by preparative thin
layer chromatography (Merck, 20.times.20 cm, Silica gel 60
F.sub.254, 1 mm) (CH.sub.2Cl.sub.2:MeOH, 100:1).
Synthesis Method H
.beta.-Ketoamides
[0312] The acyl Meldrum's acid (1.2 eq) was dissolved in anhydrous
benzene (concentration approximately 0.4 mol/l), and the amine (1.0
eq) was added. In case of amine hydrochlorides, one equivalent of
triethylamine or N,N-diisopropylethylamine was added. The mixture
was refluxed until tic showed complete conversion (typically, 4 to
6 h). The benzene solutions were directly chromatographed on silica
gel in an appropriate solvent mixture (isohexane-ethyl acetate,
dichloromethane-methanol, or dichloromethane-acetonitrile
mixtures). Yields of the purified products typically were in the
range from 30 to 75%.
[0313] In the following Table 2, the synthesis method employed in
each case for the respective compound or whether the compound was
obtained is indicated. Furthermore, the mass found by LC/(+)-ESI
and LC/(-)-ESI mass spectrometry, the molecular mass, the NMR data
(300.13 MHz, residual solvent peaks were used as internal standards
(chloroform, .delta.7.26; methanol, .delta.3.31; dimethyl
sulfoxide, .delta.2.49; abbreviations: .psi.=pseudo, br.=broad,
s=singulet, d=doublet, t=triplet, q=quartet, quint.=quintet,
sext.=sextet, m.sub.c=multiplet centered, m=multiplet,
CH.sub.ar=aromatic H, J=.sup.1H-.sup.1H coupling constant) and the
IC.sub.50 range as a measure of anti-quorum sensing activity are
indicated. The NMR data of the small signals due to enol-tautomers
or possible rotamers of the 3-oxo-carboxylic acid amides are not
listed.
TABLE-US-00002 TABLE 2 Structure and biosensor assay results of the
tested compounds. Synthesis method/ HPLC/MS # Compound supplier
(ESI) .sup.1H-NMR (300 MHz) IC.sub.50* 1 ##STR00025## May-bridge --
-- +++ 2 ##STR00026## E 313[M + H].sup.+311[M - H].sup.-
.delta.(CDCl.sub.3) = 3.88 (s, 3H, OCH.sub.3), 6.72 (d,J = 8.9 Hz,
1H, H-3), 7.03 (d, J = 5.2Hz, 1H, H-4'), 7.46 (d, J = 5.3 Hz,1H,
H-5'), 7.95 (dd, J = 8.9, 2.7 Hz,1H, H-4), 8.24 (d, J = 2.7 Hz, 1H,
H-6), 8.65 (br.s, 1H, NH) +++ 3 ##STR00027## May-bridge -- -- +++ 4
##STR00028## May-bridge -- -- + 5 ##STR00029## D 282[M +
H].sup.+280[M - H].sup.- .delta.(CD.sub.3OD) = 2.23 (s, 3H,
CH.sub.3), 3.79 (s,3H, 3H, OCH.sub.3), 7.06-7.11 (m, 2H, H-4and
H-2'), 7.50 (dd, J = 4.9, 1.1 Hz,1H, H-3), 7.69 (dd, J = 3.8, 1.1
Hz,1H, H-5), 9.71 (s, 1H, NH) + 6 ##STR00030## May-bridge -- -- ++
7 ##STR00031## May-bridge -- -- +++ 8 ##STR00032## E 276[M +
H].sup.+274[M - H].sup.- .delta.(CDCl.sub.3) = 2.54 (s, 3H,
SCH.sub.3), 3.86 (s,3H, OCH.sub.3), 6.70 (d, J = 8.9 Hz, 1H, H-3),
7.01 (t, J = 4.8 Hz, 1H, H-5'),7.85 (d, J = 6.3 Hz, 1H, H-4'),
7.97(d, J = 8.7 Hz, 1H, H-4), 8.22-8.23(br.s, 2H, H-6 and NH), 8.46
(dd, J =4.8, 1.7 Hz, 1H, H-6') + 9 ##STR00033## E 308[M +
H].sup.+306[M - H].sup.- .delta.(CD.sub.3OD) = 3.85 (s, 3H,
OCH.sub.3), 6.87 (d,J = 8.8 Hz, 1H, H-3), 8.10 (dd, J =8.9, 2.6 Hz,
1H, H-4), 8.57 (d, J =2.5 Hz, 1H, H-6), 8.64 (d, J = 2.1 Hz,1H,
H-4'), 8.91 (d, J = 2.2 Hz, 1H, H-6'), 9.13 (d, J = 1.9 Hz, 1H,
H-2'),10.81 (s, 1H, NH) + 10 ##STR00034## E 346[M + H].sup.+344[M -
H].sup.- .delta.(CDCl.sub.3) = 7.63 (s, 2H, H-3' and H-5'),7.83
(dd, J = 8.8, 2.3 Hz, 1H, H-4),8.17 (d, J = 8.8 Hz, 1H, H-3),
8.28(d, J = 2.3 Hz, 1H, H-6), 8.63 (s, 1H,NH) + 11 ##STR00035## E
248[M + H].sup.+246[M - H].sup.- .delta.(CDCl.sub.3) = 2.53 (s, 3H,
CH.sub.3), 7.24 (dd,J = 8.2, 4.9 Hz, 1H, H-5), 7.82 (s,1H, H-3'),
7.87 (s, 1H, H-5'), 8.29(d, J = 4.4 Hz, 1H, H-4), 8.36 (d, J =8.4
Hz, 1H, H-6), 9.09 (s, 1H, H-2),10.30 (br.s, 1H, NH) +++ 12
##STR00036## D 312[M + H].sup.+310[M - H].sup.- .delta.(CD.sub.3OD)
= 1.40 (t, J = 7.2 Hz, 3H,NCH.sub.2CH.sub.3), 2.25 (s, 3H,
CH.sub.3), 3.82 (s,3H, NCH.sub.3), 4.33 (q, J = 7.2 Hz,
2H,NCH.sub.2CH.sub.3), 6.40 (br.s, 1H, CH.sub.ar), 7.44(d, J = 1.8
Hz, 1H, CH.sub.ar) +++ 13 ##STR00037## D 262[M + H].sup.+260[M -
H].sup.- .delta.(CD.sub.3OD) = 1.66 (s, 9H, N-tBu), 2.24(s, 3H,
CH.sub.3), 3.75 (s, 3H, NCH.sub.3), 6.30(br.s, 1H, CH.sub.ar), 6.50
(br.s, 1H, CH.sub.ar),7.43 (d, J = 2.1 Hz, 1H, CH.sub.ar) + 14
##STR00038## D 318[M + H].sup.+316[M - H].sup.-
.delta.(DMSO-d.sub.6) = 3.73 (s, 3H, NCH.sub.3), 6.72(s, 1H, H-4'),
7.25 (dd, J = 3.6, 5.1Hz, 1H, H-4), 7.43 (d, J = 8.3 Hz,
2H,CH.sub.ar), 7.80 (d, J = 8.7 Hz, 2H, CH.sub.ar),7.90 (dd, J =
1.2, 4.8 Hz, 1H, H-3),8.01 (dd, J = 0.9, 3.9 Hz, 1H, H-5),10.43 (s,
1H, NH) +++ 15 ##STR00039## D 218[M + H].sup.+216[M - H].sup.-
.delta.(CD.sub.3OD) = 3.65 (s, 3H, NCH.sub.3), 6.44 (s,1H, H-4'),
6.92 (dd, J = 3.6, 5.1 Hz,1H, H-4''), 7.19-7.23 (m, 2H,
CH.sub.ar),7.38 (t, J = 8.1 Hz, 1H, CH.sub.ar), 7.50(d, J = 8.1 Hz,
1H, CH.sub.ar), 7.78 (d, J =7.8 Hz, 1H, CH.sub.ar), 7.87 (d, J =
1.8 Hz,1H, CH.sub.ar) +++ 16 ##STR00040## D 384[M + H].sup.+382[M -
H].sup.- .delta.(DMSO-d.sub.6) = 1.34 (m.sub.c, 2H, CH.sub.2),
1.53(m.sub.c, 2H, CH.sub.2), 1.74 (m.sub.c, 2H, CH.sub.2), 2.28(t,
J = 7.2 Hz, 2H, CH.sub.2), 3.45 (t, J =6.6 Hz, 2H, CH.sub.2), 3.59
(s, 3H, NCH.sub.3),6.55 (s, 1H, H-4), 7.33 (d, J = 8.7Hz, 2H,
CH.sub.ar), 7.65 (d, J = 8.4 Hz, 2H,CH.sub.ar), 9.86 (s, 1H, NH)
+++ 17 ##STR00041## D 286[M + H].sup.+284[M - H].sup.-
.delta.(CD.sub.3OD) = 0.80 (t, J = 6.6 Hz, 3H,CH.sub.3), 1.21-1.34
(m, 6H, (CH.sub.2).sub.3), 1.59(quint., J = 7.8 Hz, 2H, CH.sub.2),
2.31 (t,J = 7.5 Hz, 2H, CH.sub.2), 3.64 (s, 3H,NCH.sub.3), 6.47 (s,
1H, H-4), 7.15-7.29 (m,3H, CH.sub.ar), 7.62 (d, J = 6.9 Hz,
2H,CH.sub.ar) +++ 18 ##STR00042## D 350[M + H].sup.+
.delta.(DMSO-d.sub.6) = 1.41 (m.sub.c, 2H, CH.sub.2), 1.55(m.sub.c,
2H, CH.sub.2), 1.82 (m.sub.c, 2H, CH.sub.2), 2.31(t, J = 6.9 Hz,
2H, CH.sub.2), 3.51 (t, J =6.6 Hz, 2H, CH.sub.2), 3.70 (s, 3H,
NCH.sub.3),6.62 (s, 1H, H-4), 7.28 (t, J = 7.5Hz, 1H, CH.sub.ar),
7.38 (t, J = 8.4 Hz, 2H,CH.sub.ar), 7.74 (t, J = 6.9 Hz, 2H,
CH.sub.ar),9.95 (s, 1H, NH) +++ 19 ##STR00043## D 292[M +
H].sup.+290[M - H].sup.- .delta.(CD.sub.3OD) = 0.81 (t, J = 6.6 Hz,
3H,CH.sub.3), 1.22-1.33 (m, 6H, (CH.sub.2).sub.3), 1.61(quint., J =
7.8 Hz, 2H, CH.sub.2), 2.33 (t,J = 7.5 Hz, 2H, CH.sub.2), 3.61 (s,
3H,NCH.sub.3), 6.38 (s, 1H, H-4), 6.93 (t, J =4.5 Hz, 1H, H-4'),
7.20 (d, J = 4.5Hz, 2H, H-3' and H-5') +++ 20 ##STR00044## D 356[M
+ H].sup.+354[M - H].sup.- .delta.(CD.sub.3OD) = 1.44 (m.sub.c, 2H,
CH.sub.2), 1.64 (m.sub.c,2H, CH.sub.2), 1.80 (m.sub.c, 2H,
CH.sub.2), 2.36 (t,J = 7.2 Hz, 2H, CH.sub.2), 3.37 (t, J = 6.6Hz,
2H, CH.sub.2), 3.62 (s, 3H, NCH.sub.3), 6.39(s, 1H, H-4), 6.93 (t,
J = 4.5 Hz, 1H,H-4'), 7.21 (d, J = 4.5 Hz, 2H, H-3'and H-5') +++ 21
##STR00045## D 288[M + H].sup.+286[M - H].sup.- .delta.(CD.sub.3OD)
= 0.92 (t, J = 7.2 Hz, 3H,CH.sub.3), 1.38 (m.sub.c, 6H,
(CH.sub.2).sub.3), 1.71(quint., J = 7.5 Hz, 2H, CH.sub.2), 2.43
(t,J = 7.5 Hz, 2H, CH.sub.2), 3.68 (s, 3H,NCH.sub.3), 7.45 (s, 1H,
H-3) +++ 22 ##STR00046## D 274[M + H].sup.+ .delta.(CD.sub.3OD) =
1.46 (m.sub.c, 2H, CH.sub.2), 1.63 (m.sub.c,2H, CH.sub.2), 1.80
(m.sub.c, 2H, CH.sub.2), 2.34 (t,J = 7.2 Hz, 2R, CH.sub.2), 3.37
(t, J = 6.6Hz, 2H, CH.sub.2), 3.61 (s, 3H, NCH.sub.3), 6.11(d, J =
2.1 Hz, 1H, H-4), 7.29 (d, J =2.1 Hz, 1H, H-3) +++ 23 ##STR00047##
D 352[M + H].sup.+ .delta.(CD.sub.3OD) = 1.50 (m.sub.c, 2H,
CH.sub.2), 1.66 (m.sub.c,2H, CH.sub.2), 1.79 (m.sub.c, 2H,
CH.sub.2), 2.37 (t,J = 7.2 Hz, 2H, CH.sub.2), 3.37 (t, J = 6.6Hz,
2H, CH.sub.2), 3.60 (s, 3H, NCH.sub.3), 7.36(s, 1H, H-3) +++ 24
##STR00048## D 210[M + H].sup.+208[M - H].sup.- .delta.(CD.sub.3OD)
= 0.92 (t, J = 6.6 Hz, 3H,CH.sub.3), 1.34-1.46 (m, 6H,
(CH.sub.2).sub.3), 1.72(quint., J = 7.8 Hz, 2H, CH.sub.2), 2.42
(t,J = 7.8 Hz, 2H, CH.sub.2), 3.72 s, 3H,NCH.sub.3), 6.22 (d, J =
2.1 Hz, 1H, H-4),7.39 (d, J = 2.1 Hz, 1H, H-3) +++ 25 ##STR00049##
G 289[M + H].sup.+287[M - H].sup.- .delta.(DMSO-d.sub.6) =
7.33-7.37 (m, 2H, CH.sub.ar),7.80 (dd, J = 3.6, 5.4 Hz, 2H,
CH.sub.ar),8.87 (d, J = 4.8 Hz, 1H, CH.sub.ar), 9.89(s, 1H, NH),
10.71 (s, 1H, NH) +++ 26 ##STR00050## G 301[M + H].sup.+299[M -
H].sup.- .delta.(DMSO-d.sub.6) = 2.19 (s, 3H, CH.sub.3), 3.95(s,
3H, NCH.sub.3), 6.73 (s, 1H, H-4), 7.23(d, J = 4.8 Hz, 1H,
CH.sub.ar), 8.74 (d, J =4.8 Hz, 1H, CH.sub.ar), 9.76 (s, 1H,
NH),10.46 (s, 1H, NH) +++ 27 ##STR00051## May-bridge -- -- +++ 28
##STR00052## May-bridge -- -- ++ 29 ##STR00053## A 331[M +
H].sup.+329[M - H].sup.- .delta.(DMSO-d.sub.6) = 7.21 (t, J = 4.5
Hz, 1H,H-4), 7.52 (d, J = 8.7 Hz, 2H, CH.sub.ar),7.85 (d, J = 4.8
Hz, 1H, H-3), 7.88(d, J = 3.6 Hz, 1H, H-5), 8.03 (d, J =8.7 Hz, 2H,
CH.sub.ar), 10.57 (s, 1H, NH),10.62 (s, 1H, NH) + 30 ##STR00054##
May-bridge -- -- + 31 ##STR00055## May-bridge -- -- ++ 32
##STR00056## May-bridge -- -- ++ 33 ##STR00057## B 415[M +
H].sup.+413[M - H].sup.- .delta.(CD.sub.3OD) = 7.15 (d, J = 5.3 Hz,
1H, H-4), 7.53-7.55 (m, 2H, CH.sub.ar), 7.61-7.63(m, 3H,
CH.sub.ar), 7.80 (d, J = 5.3 Hz, 1H,H-5), 8.19 (s, 1H, H-3') + 34
##STR00058## A 415[M + H].sup.+413[M - H].sup.- .delta.(CD.sub.3OD)
= 7.05 (t, J = 5.1 Hz, 1H, H-4), 7.38 (d, J = 9.0 Hz, 2H,
CH.sub.ar),7.47 (d, J = 9.0 Hz, 2H, CH.sub.ar), 7.62(dd, J = 5.1,
1.2 Hz, 1H, H-3), 7.70(dd, J = 4.2, 1.5 Hz, 1H, H-5), 8.05(s, 1H,
H-3') ++ 35 ##STR00059## TimTec 237[M + H].sup.+235[M - H].sup.-
.delta.(DMSO-d.sub.6) = 3.45 (dd, J = 1.8, 3.3 Hz,1H, CH.sub.ar),
7.23 (dd, J = 3.6, 4.8 Hz,1H, CH.sub.ar), 7.29 (d, J = 3.6 Hz,
1H,CH.sub.ar), 7.87-7.95 (m, 3H, CH.sub.ar), 10.44(s, 1H, NH),
10.52 (s, 1H, NH) ++ 36 ##STR00060## May-bridge -- -- ++ 37
##STR00061## May-bridge -- -- ++ 38 ##STR00062## A 301[M +
H].sup.+299[M - H].sup.- .delta.(DMSO-d.sub.6) = 3.89 (s, 3H,
OCH.sub.3), 6.67(dd, J = 1.5, 3.3 Hz, 1H, H-4), 7.26(d, J = 3.6 Hz,
1H, H-3), 7.24 (d, J =3.3 Hz, 1H, H-3), 7.91 (d, J = 1.5 Hz,1H,
H-5), 7.94 (s, 1H, H-3'), 10.12(br.s, 1H, NH), 10.36 (br.s, 1H, NH)
+++ 39 ##STR00063## A 315[M + H].sup.+313[M - H].sup.-
.delta.(DMSO-d.sub.6) = 6.66 (dd, J = 1.8, 3.3 Hz,1H, H-4), 7.22
(d, J = 5.1 Hz, 1H, H-4'), 7.24 (d, J = 3.3 Hz, 1H, H-3),7.58 (d, J
= 5.1 Hz, 1H, H-5'), 7.90(d, J = 1.8 Hz, 1H, H-5), 10.37 (br.s,2H,
NH) +++ 40 ##STR00064## A 305[M + H].sup.+303[M - H].sup.-
.delta.(DMSO-d.sub.6) = 6.59 (dd, J = 1.8, 3.3 Hz,1H, H-4), 7.17
(d, J = 3.6 Hz, 1H, H-3), 7.39 (s, 1H, H-4'), 7.83 (d, J =1.8 Hz,
1H, H-5), 10.25 (s, 1H, NH),10.38 (s, 1H, NH) +++ 41 ##STR00065##
TimTec 321[M + H].sup.+319[M - H].sup.- .delta.(DMSO-d.sub.6) =
6.52 (dd, J = 1.8, 3.6 Hz,1H, H-4), 7.13 (dd, J = 1.8, 3.6 Hz,1H,
H-3), 7.44-7.47 (m, 2H, CH.sub.ar),7.76-7.79 (m, 2H, CH.sub.ar),
7.99 (m.sub.c, 1H,H-5), 10.35 (s, 1H, NH), 10.42 (s, 1H,NH) +++ 42
##STR00066## May-bridge -- -- +++ 43 ##STR00067## May-bridge -- --
+++ 44 ##STR00068## B 331[M + H].sup.+329[M - H].sup.-
.delta.(CDCl.sub.3) = 1.51 (t, J = 7.0 Hz, 3H,OCH.sub.2CH.sub.3),
4.24 (q, J = 7.1 Hz, 2H,OCH.sub.2CH.sub.3), 6.80 (d, J = 5.4 Hz,
1H, H-4), 6.96 (d, J = 5.3 Hz, 1H, H-4'),7.41 (d, J = 5.4 Hz, 1H,
H-5), 7.46(d, J = 5.3 Hz, 1H, H-5'), 9.97 (d, J =7.3 Hz, 1H, NH),
10.15 (d, J = 7.3Hz, 1H, NH) + 45 ##STR00069## B 297[M +
H].sup.+295[M - H].sup.- .delta.(CDCl.sub.3) = 1.50 (t, J = 7.0 Hz,
3H,OCH.sub.2CH.sub.3), 4.25 (q, J = 7.0 Hz, 2H,OCH.sub.2CH.sub.3),
6.80 (d, J = 5.5 Hz, 1H, H-4), 7.01 (dd, J = 6.0, 3.8 Hz, 1H,
H-4'0), 7.40 (d, J = 5.4 Hz, 1H, H-5),7.43 (d, J = 3.9 Hz, 1H,
H-3'), 7.62(d, J = 3.9 Hz, 1H, H-5'), 9.50 (br.s,1H, NH), 9.90 (d,
J = 5.3 Hz, 1H, NH) +++ 46 ##STR00070## AsInEx -- -- ++ 47
##STR00071## A 253[M + H].sup.+251[M - H].sup.- .delta.(CD.sub.3OD)
= 7.06 (t, J = 3.9 Hz, 1H, H-4), 7.41-7.48 (m, 2H, H-4' and
H-5'),7.63 (d, J = 4.8 Hz, 1H, H-3), 7.72(d, J = 4.8 Hz, 1H, H-5),
8.08 (s, 1H,H-2') +++ 48 ##STR00072## A 365[M + H].sup.+363[M -
H].sup.- .delta.(CDCl.sub.3) = 6.87 (d, J = 4.1 Hz, 1H, H-2'), 7.03
(d, J = 5.2 Hz, 1H, H-1),7.47 (d, J = 5.2 Hz, 1H, H-2), 7.49(d, J =
4.1 Hz, 1H, H-1') ++ 49 ##STR00073## A 319[M + H].sup.+
.delta.(CD.sub.3OD) = 7.21 (d, J = 5.4 Hz, 2H, H-4and H-4'), 7.84
(d, J = 5.4 Hz, 2H, H-5 and H-5') ++ 50 ##STR00074## B 315[M +
H].sup.+ .delta.(CD.sub.3OD) = 4.05 (s, 3H, OCH.sub.3), 7.16(dd, J
= 5.1, 3.9 Hz, 1H, H-4'), 7.72(dd, J = 5.1, 1.2 Hz, 1H, H-3'),
7.81(dd, J = 3.9, 1.2 Hz, 1H, H-5'), 7.96(s, 1H, H-5) ++ 51
##STR00075## SPECSand Bio-SPECS -- -- ++ 52 ##STR00076## A 285[M -
H].sup.- .delta.(DMSO-d.sub.6) = 7.08 (d, J = 3.9 Hz, 1H,H-4'),
7.13 (d, J = 4.2 Hz, 1H, H-4),7.68 (d, J = 3.9 Hz, 1H, H-3),
7.74(d, J = 3.9 Hz, 1H, H-3'), 7.78 (d, J =3.2 Hz, 1H, H-5'), 10.55
(s, 2H, NH) ++ 53 ##STR00077## A 375[M + H].sup.+373[M - H].sup.-
.delta.(CD.sub.3OD) = 2.44 (s, 3H, CH.sub.3), 3.93 (s,3H,
OCH.sub.3), 6.75 (dd, J = 1.2, 3.9 Hz,1H, H-4), 7.52 (d, J = 3.6
Hz, 1H, H-3), 8.01 (s, 1H, H-5') +++ 54 ##STR00078## A 267[M +
H].sup.+265[M - H].sup.- .delta.(CD.sub.3OD) = 2.52 (s, 3H,
CH.sub.3), 6.84 (d,J = 3.3 Hz, 1H, H-4'), 7.16 (t, J =4.8 Hz, 1H,
H-4), 7.61 (d, J = 3.6 Hz,1H, H-3'), 7.72 (d, J = 4.8 Hz, 1H, H-3),
7.80 (d, J = 4.2 Hz, 1H, H-5) +++ 55 ##STR00079## A 331[M +
H].sup.+329[M - H].sup.- .delta.(CD.sub.3OD) = 7.04-7.08 (m, 2H,
H-4 and H-4'), 7.58-7.65 (m, 2H, H-5 and H3'),7.70 (d, J = 3.6 Hz,
1H, H-5') +++ 56 ##STR00080## B 375[M + H].sup.+373[M - H].sup.-
.delta.(CD.sub.3OD) = 1.41 (t, J = 6.9 Hz, 3H,CH.sub.3), 4.27 (q, J
= 6.9 Hz, 2H, OCH.sub.2),6.98 (d, J = 5.4 Hz, 1H, CH.sub.ar),
7.07(d, J = 5.4 Hz, 1H, CH.sub.ar), 7.59 (d, J =5.7 Hz, 1H,
CH.sub.ar), 7.63 (d, J = 5.4 Hz,1H, CH.sub.ar) +++ 57 ##STR00081##
A 345[M + H].sup.+343[M - H].sup.- .delta.(CD.sub.3OD) =
2.64 (s, 3H, CH.sub.3), 6.96 (dd,J = 0.9, 3.6 Hz, 1H, CH.sub.ar),
7.26 (d, J =5.1 Hz, 1H, CH.sub.ar), 7.72 (d, J = 3.6Hz, 1H,
CH.sub.ar), 7.82 (d, J = 5.1 Hz, 1H,CH.sub.ar) +++ 58 ##STR00082##
A 319[M + H].sup.+ .delta.(DMSO-d.sub.6) = 7.10 (d, J = 5.1 Hz,
1H,H-4), 7.13 (d, J = 4.2 Hz, 1H, H-4'),7.60 (d, J = 3.9 Hz, 1H,
H-3'), 7.80(d, J = 5.1 Hz, 1H, H-5) +++ 59 ##STR00083## TimTec --
-- +++ 60 ##STR00084## TimTec -- -- +++ 61 ##STR00085## B 415[M +
H].sup.+413[M - H].sup.- .delta.(CD.sub.3OD) = 7.01 (d, J = 5.4 Hz,
1H, H-4'), 7.39-7.43 (m, 2H, CH.sub.ar), 7.56 (d,J = 5.1 Hz, 1H,
H-5'), 7.78-7.82 (m,2H, CH.sub.ar) ++ 62 ##STR00086## B 413[M -
H].sup.- .delta.(CDCl.sub.3) = 7.03 (d, J = 3.7 Hz, 1H, H-4), 7.40
(d, J = 3.2 Hz, 1H, H-3),7.45-7.48 (m, 2H, CH.sub.ar), 7.77-7.87
(m,2H, CH.sub.ar), 9.14 (s, 1H, NH), 9.79 (s,1H, NH) ++ 63
##STR00087## B 350[M + H].sup.+348[M - H].sup.- .delta.(CD.sub.3OD)
= 2.73 (s, 3H, CH.sub.3), 4.05 (s,3H, NCH.sub.3), 7.18 (dd, J =
5.1, 3.6 Hz,1H, H-4'), 7.75 (dd, J = 5.1, 1.2 Hz,1H, H-3'), 7.83
(dd, J = 3.6, 1.2 Hz,1H, H-5'), 8.68 (s, 1H, H-6) + 64 ##STR00088##
B 347[M - H].sup.- .delta.(CD.sub.3OD) = 2.28 (s, 3H, CH.sub.3),
4.08 (s,3H, NCH.sub.3), 6.70 (s, 1H, H-4), 7.57-7.62(m, 2H,
CH.sub.ar), 7.96-8.01 (m, 2H, CH.sub.ar) + 65 ##STR00089##
May-bridge -- -- +++ 66 ##STR00090## B 265[M + H].sup.+263[M -
H].sup.- .delta.(CD.sub.3OD) = 2.25 (s, 3H, CH.sub.3), 4.04 (s,3H,
NCH.sub.3), 6.65 (s, 1H, H-4), 7.17 (dd,J = 5.1, 3.9 Hz, 1H, H-4'),
7.73 (dd,J = 5.1, 0.9 Hz, 1H, H-3'), 7.79 (d, J =3.9 Hz, 1H, H-5')
+ 67 ##STR00091## A 391[M + H].sup.+389[M - H].sup.-
.delta.(CDCl.sub.3) = 1.33 (t, J = 7.1 Hz, 3H,NCH.sub.2CH.sub.3),
1.83 (s, 3H, CH.sub.3), 4.42 (dd,J = 14.3, 7.2 Hz, 2H,
NCH.sub.2CH.sub.3), 6.85(d, J = 4.1 Hz, 1H, H-4), 7.44 (d, J =4.1
Hz, 1H, H-3) + 68 ##STR00092## A 305[M - H].sup.-
.delta.(CD.sub.3OD) = 1.68 (s, 9H, --C(CH.sub.3).sub.3 ), 2.86(s,
3H, CH.sub.3), 6.47 (s, 1H, H-4'), 7.17(t, J = 3.9 Hz, 1H, H-4),
7.74 (dd, J =4.2, 0.9 Hz, 1H, H-3), 7.82 (dd, J =3.6, 0.9 Hz, 1H,
H-5) + 69 ##STR00093## B 341[M + H].sup.+339[M - H].sup.-
.delta.(CDCl.sub.3) = 1.22 (s, 9H, tBu), 4.00 (s,3H, NCH.sub.3),
6.58 (s, 1H, H-4'), 6.81 (d,J = 3.9 Hz, 1H, H-4), 7.44 (d, J =
3.9Hz, 1H, H-3) +++ 70 ##STR00094## A 307[M + H].sup.+305[M -
H].sup.- .delta.(CD.sub.3OD) = 1.33 (s, 9H, --C(CH.sub.3).sub.3),
4.08(s, 3H, NCH.sub.3), 6.80 (s, 1H, H-4'), 7.18(t, J = 3.6 Hz, 1H,
H-4), 7.75 (dd, J =5.1, 1.2 Hz, 1H, H-3), 7.82 (d, J =3.6 Hz, 1H,
H-5) + 71 ##STR00095## A 435[M + H].sup.+433[M - H].sup.-
.delta.(CD.sub.3OD) = 1.31 (t, J = 7.5 Hz, 3H,NCH.sub.2CH.sub.3),
(s, 3H, CH.sub.3), (q, J =7.2 Hz, 2H, NCH.sub.2CH.sub.3), 7.10 (d,
J =4.2 Hz, 1H, H-4), 7.48 (d, J = 3.9 Hz,1H, H-3) +++ 72
##STR00096## A 405[M + H].sup.+403[M - H].sup.- .delta.(CD.sub.3OD)
= 1.29 (t, J = 6.9 Hz, 3H,NCH.sub.2CH.sub.3), 2.12 (s, 3H,
CH.sub.3), 2.13 (s,3H, CH.sub.3), 4.23 (q, J = 7.2 Hz,
2H,NCH.sub.2CH.sub.3), 7.36 (s, 1H, H-5) + 73 ##STR00097## A 391[M
+ H].sup.+389[M - H].sup.- .delta.(CD.sub.3OD) = 1.28 (t, J = 7.2
Hz, 3H,NCH.sub.2CH.sub.3), 2.10 (s, 3H, CH.sub.3), 4.20 (q, J =6.9
Hz, 2H, NCH.sub.2CH.sub.3), 6.94 (d, J =4.2 Hz, 1H, H-4), 7.50 (d,
J = 4.2 Hz,1H, H-3) +++ 74 ##STR00098## A 513[M + H].sup.+511[M -
H].sup.- .delta.(DMSOd6) = 1.37 (t, J = 7.2 Hz,
3H,NCH.sub.2CH.sub.3), 2.23 (s, 3H, CH.sub.3), 4.28 (q, J =7.2 Hz,
2H, NCH.sub.2CH.sub.3), 7.94 (s, 1H, H-3), 10.75 (s, 1H, NH), 11.09
(s, 1H,NH) + 75 ##STR00099## TimTec 213[M + H].sup.+211[M -
H].sup.- .delta.(CD.sub.3OD) = 0.90 (t, J = 7.5 Hz, 3H,CH.sub.3),
1.60 (sext., J = 7.5 Hz, 2H,CH.sub.2), 2.18 (t, J = 7.2 Hz, 2H,
CH.sub.2),7.04 (dd, J = 3.9, 5.1 Hz, 1H, H-4),7.60 (dd, J = 3.9,
5.1 Hz, 1H, H-3),7.65 (dd, J = 3.9, 5.1 Hz, 1H, H-5) +++ 76
##STR00100## A 227[M + H].sup.+225[M - H].sup.- .delta.(CD.sub.3OD)
= 1.01 (t, J = 7.5 Hz, 3H,CH.sub.3), 1.71 (sext., J = 7.5 Hz,
2H,CH.sub.2), 2.28 (t, J = 7.5 Hz, 2H, CH.sub.2),2.52 (s, 3H,
CH.sub.3), 6.82 (d, J = 3.9 Hz,1H, H-4), 7.57 (d, J = 3.6 Hz, 1H,
H-3) ++ 77 ##STR00101## A 291[M + H].sup.+289[M - H].sup.-
.delta.(CD.sub.3OD) = 0.90 (t, J = 7.5 Hz, 3H,CH.sub.3), 1.59
(sext., J = 7.8 Hz, 2H,CH.sub.2), 2.17 (t, J = 7.5 Hz, 2H,
CH.sub.2),7.05 (d, J = 3.9 Hz, 1H, H-4), 7.43(d, J = 4.2 Hz, 1H,
H-3) +++ 78 ##STR00102## A 319[M + H].sup.+ .delta.(DMSO-d.sub.6) =
1.41 (m.sub.c, 2H, H-3'), 1.56(m.sub.c, 2H, H-2'), 1.81 (m.sub.c,
2H, H-4'),2.17 (t, J = 7.2 Hz, 2H, H-1'), 3.52(t, J = 6.6 Hz, 2H,
H-5'), 7.16 (t, J =4.5 Hz, 1H, H-4), 7.81 (d, J = 4.2Hz, 2H, H-3
and H-5), 9.82 (s, 1H,NH), 10.28 (s, 1H, NH) +++ 79 ##STR00103## A
255[M + H].sup.+253[M - H].sup.- .delta.(DMSO-d.sub.6) = 0.86 (t, J
= 6.9 Hz, 2H,H-6'), 1.20-1.36 (m, 6H, H-3', H-4'and H-5'), 1.53
(m.sub.c, 2H, H-2'), 2.17(t, J = 7.2 Hz, 2H, H-1'), 7.16 (t, J =4.5
Hz, 1H, H-4), 7.80-7.84 (m, 2H,H-3 and H-5), 9.79 (s, 1H, NH),
10.27(s, 1H, NH) +++ 80 ##STR00104## C 367[M + H].sup.+365[M -
H].sup.- .delta.(CDCl.sub.3) = 1.45 (m.sub.c, 1H, H-3'),
1.68(m.sub.c, 1H, H-2'), 1.80 (m.sub.c, 1H, H-4'),2.17 (s, 3H,
CH.sub.3), 2.35 (t, J = 7.4Hz, 1H, H-1'), 3.33 (t, J = 6.7 Hz,1H,
H-5'), 7.19 (s, 1H, H-5), 9.66 (d,J = 6.4 Hz, 1H, NH), 9.82 (d, J =
6.3Hz, 1H, NH) +++ 81 ##STR00105## C 303[M + H].sup.+301[M -
H].sup.- .delta.(CDCl.sub.3) = 0.80 (t, J = 6.7 Hz, 1H, H-6'),
1.18-1.28 (m, 3H, H-3', H-4' andH-5'), 1.62 (m.sub.c, 1H, H-2'),
2.16 (s,3H, CH.sub.3), 2.31 (t, J = 7.4 Hz, 1H, H-1'), 7.19 (s, 1H,
H-5), 9.60 (d, J =6.5 Hz, 1H, NH), 9.84 (d, J = 6.4 Hz,1H, NH) +++
82 ##STR00106## A 333[M + H].sup.+ .delta.(DMSO-d.sub.6) = 1.41
(m.sub.c, 2H, CH.sub.2), 1.53(m.sub.c, 2H, CH.sub.2), 1.79 (quint.,
J = 7.2Hz, 2H, CH.sub.2), 2.16 (t, J = 7.2 Hz, 2H,CH.sub.2), 2.46
(s, 3H, CH.sub.3), 3.52 (t, J =6.9 Hz, 2H, CH.sub.2), 6.85 (dd, J =
0.9,4.8 Hz, 1H, H-4), 7.61 (d, J = 3.9 Hz,1H, H-3), 9.77 (s, 1H,
NH), 10.16 (s,1H, NH) +++ 83 ##STR00107## A 269[M + H].sup.+267[M -
H].sup.- .delta.(DMSO-d.sub.6) = 0.84 (t, J = 4.2 Hz, 3H,CH.sub.3),
1.24 (m.sub.c, 6H, (CH.sub.2).sub.3), 1.48(quint., J = 7.2 Hz, 2H,
CH.sub.2), 2.18 (t,J = 7.5 Hz, 2H, CH.sub.2), 2.46 (s,
3H,CH.sub.3), 6.85 (d, J = 3.9 Hz, 1H, H-4),7.60 (d, J = 3.3 Hz,
1H, H-3), 9.74(s, 1H, NH), 10.14 (s, 1H, NH) +++ 84 ##STR00108## A
333[M + H].sup.+331[M - H].sup.- .delta.(CD.sub.3OD) = 0.82 (t, J =
6.9 Hz, 3H,CH.sub.3), 1.19-1.34 (m, 6H, (CH.sub.2).sub.3),
1.56(quint., J = 7.2 Hz, 2H, CH.sub.2), 2.19 (t,J = 7.5 Hz, 2H,
CH.sub.2), 7.05 (d, J = 4.2Hz, 1H, H-4), 7.43 (d, J = 4.2 Hz,
1H,H-3) +++ 85 ##STR00109## A 347[M + H].sup.+345[M - H].sup.-
.delta.(DMSO-d.sub.6) = 0.89 (t, J = 6.9 Hz, 3H,CH.sub.3),
1.30-1.37 (m, 8H, (CH.sub.2).sub.4), 1.57(quint., J = 6.6 Hz, 2H,
CH.sub.2), 2.19 (t,J = 7.5 Hz, 2H, CH.sub.2), 7.24 (d, J = 5.1Hz,
1H, H-4), 7.87 (d, J = 5.1 Hz, 1H,H-5), 9.95-10.16 (br.s, 2H, NH)
+++ 86 ##STR00110## A 325[M + H].sup.+323[M - H].sup.-
.delta.(CD.sub.3OD) = 0.80 (t, J = 6.9 Hz, 3H,CH.sub.3), 1.14-1.32
(m, 16H, (CH.sub.2).sub.8), 1.57(quint., J = 7.5 Hz, 2H, CH.sub.2),
2.20 (t,J = 7.5 Hz, 2H, CH.sub.2), 7.04 (dd, J =3.9, 4.8 Hz, 1H,
H-4), 7.60 (dd, J =0.9, 4.8 Hz, 1H, H-3), 7.65 (dd, J =1.2, 4.2 Hz,
1H, H-5) +++ 87 ##STR00111## A 281[M + H].sup.+279[M - H].sup.-
.delta.(DMSO-d.sub.6) = 1.06 (m.sub.c, 2H, CH.sub.2), 1.50(m.sub.c,
6H, (CH.sub.2).sub.3), 1.72 (m.sub.c, 3H, CH andCH.sub.2), 2.16 (t,
J = 7.8 Hz, 2H, CH.sub.2),2.46 (s, 3H, CH.sub.3), 6.65 (dd, J =
0.9,3.9 Hz, 1H, H-4), 7.61 (d, J = 3.6 Hz,1H, H-3), 9.75 (s, 1H,
NH), 10.14 (s,1H, NH) +++ 88 ##STR00112## A 285[M + H].sup.+283[M -
H].sup.- .delta.(CD.sub.3OD) = 1.96 (t, J = 7.2 Hz, 2H,CH.sub.2),
2.36 (t, J = 7.5 Hz, 2H, CH.sub.2),2.44 (t, J = 7.5 Hz, 2H,
CH.sub.2), 2.51 (s,3H, CH.sub.3), 3.67 (s, 3H, OCH.sub.3), 6.82
(d,J = 3.9 Hz, 1H, H-4), 7.57 (d, J = 3.6Hz, 1H, H-3) + 89
##STR00113## A 239[M + H].sup.+237[M - H].sup.- .delta.(CD.sub.3OD)
= 1.11 (t, J = 6.6 Hz, 3H,CH.sub.3), 1.47-1.63 (m, 6H,
(CH.sub.2).sub.3), 1.86(quint., J = 7.2 Hz, 2H, CH.sub.2), 2.48
(t,J = 7.5 Hz, 2H, CH.sub.2), 6.79 (br.s, 1H,H-4), 7.39 (d, J = 3.6
Hz, 1H, H-3),7.88 (br.s, 1H, H-5) +++ 90 ##STR00114## A 251[M +
H].sup.+249[M - H].sup.- .delta.(DMSO-d.sub.6) = 1.14 (m.sub.c, 2H,
CH.sub.2), 1.60(m.sub.c, 6H, (CH.sub.2).sub.3), 1.80 (m.sub.c, 3H,
CH andCH.sub.2). 2.23 (t, J = 7.2 Hz, 2H, CH.sub.2),6.70 (dd, J =
1.8, 3.6 Hz, 1H, H-4),7.62 (d, J = 3.6 Hz, 1H, H-3), 7.94(d, J =
2.7 Hz, 1H, H-5), 9.82 (s, 1H,NH), 10.19 (s, 1H, NH) +++ 91
##STR00115## A 282[M + H].sup.+280[M - H].sup.-
.delta.(DMSO-d.sub.6) = 0.75 (t, J = 6.9 Hz, 3H,CH.sub.3),
1.15-1.23 (m, 8H, (CH.sub.2).sub.4), 1.43(quint., J = 6.9 Hz, 2H,
CH.sub.2), 2.05 (t,J = 7.8 Hz, 2H, CH.sub.2), 2.17 (s,
3H,CH.sub.3), 2.42 (s, 3H, CH.sub.3), 9.71 (s, 1H,NH), 9.76 (s, 1H,
NH) +++ 92 ##STR00116## A 373[M + H].sup.+371[M - H].sup.-
.delta.(DMSO-d.sub.6) = 0.65 (t, J = 6.6 Hz, 3H,CH.sub.3),
0.97-1.12 (m, 11H, NCH.sub.2CH.sub.3 and(CH.sub.2).sub.4), 1.33
(quint., J = 6.9 Hz, 2H,CH.sub.2), 1.92-1.97 (m, 5H, CH.sub.3-3 and
CH.sub.2),3.98 (q, J = 7.5 Hz, 2H, NCH.sub.2), 9.79(s, 1H, NH),
10.09 (s, 1H, NH) ++ 93 ##STR00117## A 298[M + H].sup.+296[M -
H].sup.- .delta.(DMSO-d.sub.6) = 0.81 (t, J = 7.2 Hz, 3H,CH.sub.3),
1.16-1.27 (m, 8H, (CH.sub.2).sub.4), 1.48(m.sub.c, 2H, CH.sub.2),
2.12 (t, J = 7.5 Hz, 2H,CH.sub.2), 7.71 (dd, J = 1.5, 5.1 Hz, 1H,
H-5), 7.80 (br.s, 1H, H-3), 8.54 (d, J =5.1 Hz, 1H, H-6), 9.94 (s,
1H, NH),10.62 (s, 1H, NH) +++ 94 ##STR00118## A 298[M +
H].sup.+296[M - H].sup.- .delta.(DMSO-d.sub.6) = 0.94 (t, J = 7.2
Hz, 3H,CH.sub.3), 1.34-1.39 (m, 8H, (CH.sub.2).sub.4), 1.62(quint.,
J = 6.9 Hz, 2H, CH.sub.2), 2.25 (t,J = 7.2 Hz, 2H, CH.sub.2), 7.61
(dd, J =5.1, 7.8 Hz, 1H, H-5), 7.98 (dd, J =1.8, 7.5 Hz, 1H, H-4),
8.59 (dd, J =1.8, 4.5 Hz, 1H, H-6), 10.12 (s, 1H,NH), 10.47 (s, 1H,
NH) +++ 95 ##STR00119## A 335[M + H].sup.+333[M - H].sup.-
.delta.(DMSO-d.sub.6) = 0.96 (t, J = 7.2 Hz, 3H,CH.sub.3), 3.09 (s,
2H, CH.sub.2), 3.86 (q, J =7.2 Hz, 2H, OCH.sub.2), 6.97 (d, J = 5.4
Hz,1H, H-4), 7.60 (d, J = 5.1 Hz, 1H, H-5), 10.05 (s, 2H, NH) +++
96 ##STR00120## A 307[M + H].sup.+305[M - H].sup.-
.delta.(DMSO-d.sub.6) = 1.33 (t, J = 7.2 Hz, 3H,CH.sub.3), 3.49 (s,
2H, CH.sub.2), 4.24 (q, J =7.2 Hz, 2H, OCH.sub.3), 7.55-7.64 (m,
2H,CH.sub.ar), 8.10 (d, J = 6.8 Hz, 1H, CH.sub.ar),8.17 (d, J = 6.9
Hz, 1H, CH.sub.ar), 8.30(s, 1H, H-3), 10.39 (s, 1H, NH), 10.92(s,
1H, NH) ++ 97 ##STR00121## A 323[M + H].sup.+321[M - H].sup.-
.delta.(CD.sub.3OD) = 6.92 (d, J = 4.2 Hz, 1H,CH.sub.ar), 7.03 (d,
J = 4.5 Hz, 1H, CH.sub.ar),7.37 (d, J = 3.9 Hz, 1H, CH.sub.ar),
7.60(d, J = 4.5 Hz, 2H, CH.sub.ar) +++ 98 ##STR00122## A 283[M +
H].sup.+281[M - H].sup.- .delta.(CD.sub.3OD) = 0.78 (t, J = 7.5 Hz,
3H,CH.sub.3), 1.44 (sext., J = 7.5 Hz, 2H,CH.sub.2), 1.98 (t, J =
7.5 Hz, 2H, CH.sub.2),6.96 (d, J = 3.9 Hz, 1H, H-4), 7.37(d, J =
4.2 Hz, 1H, H-3) ++ 99 ##STR00123## A 325[M + H].sup.+323[M -
H].sup.- .delta.(CD.sub.3OD) = 0.80 (t, J = 6.9 Hz, 3H,CH.sub.3),
1.12-1.25 (m, 6H, (CH.sub.2).sub.3), 1.40(quint., J = 7.2 Hz, 2H,
CH.sub.2), 2.02 (t,J = 7.5 Hz, 2H, CH.sub.2), 6.96 (d, J = 4.2Hz,
1H, H-4), 7.37 (d, J = 4.2 Hz, 1H,H-3) + 100 ##STR00124## F 258[M +
H].sup.+256[M - H].sup.- .delta.(CD.sub.3OD) = 0.82 (t, J = 7.5 Hz,
3H,CH.sub.3), 1.25 (sext, J = 7.5 Hz, 2H, CH.sub.2),1.48 (quint., J
= 7.5 Hz, 2H, CH.sub.2),3.45 (t, J = 7.2 Hz, 2H, CH.sub.2),
7.06(dd, J = 3.9, 3.9 Hz, 1H, H-4), 7.63(dd, J = 1.2, 4.8 Hz, 1H,
H-3), 7.69(d, J = 3.6 Hz, 1H, H-5) +++ 101 ##STR00125## F 412[M +
H].sup.+410[M - H].sup.- .delta.(DMSO-d.sub.6) = 1.04 (t, J = 7.2
Hz, 3H,CH.sub.3), 1.33-1.61 (m, 6H, CH.sub.2), 3.17 (q,J = 6.3 Hz,
2H, CH.sub.2), 6.71 (s, 1H, H-3), 7.97 (s, 1H, NH), 8.08 (s,
1H,NH), 10.44 (s, 1H, NH) + 102 ##STR00126## F 426[M +
H].sup.+424[M - H].sup.- .delta.(DMSO-d.sub.6) = 7.32 (d, J = 3.9
Hz, 1H,H-4), 7.49-7.59 (m, 2H, H-5' and H-6'), 7.66 (d, J = 4.2 Hz,
1H, H-3),8.21 (s, 1H, NH), 8.73 (s, 1H, NH),10.47 (s, 1H, NH) + 103
##STR00127## F 520[M + H].sup.+518[M - H].sup.-
.delta.(DMSO-d.sub.6) = 7.65 (d, J = 8.7 Hz, 1H,CH.sub.ar), 7.85
(d, J = 8.7 Hz, 1H, CH.sub.ar),7.89 (s, 1H, CH.sub.ar), 8.13 (s,
1H, H-3),8.71 (s, 1H, NH), 9.43 (s, 1H, NH),10.61 (s, 1H, NH) ++
104 ##STR00128## F 486[M + H].sup.+484[M - H].sup.-
.delta.(DMSO-d.sub.6) = 7.47 (d, J = 7.8 Hz, 1H,CH.sub.ar), 7.59
(t, J = 7.8 Hz, 1H, CH.sub.ar),7.82 (d, J = 7.8 Hz, 1H, CH.sub.ar),
7.85(s, 1H, NH), 7.98-8.00 (br.s, 2H, CH.sub.arand NH), 8.01 (s,
1H, H-3), 10.58 (s,1H, NH) +++ 105 ##STR00129## F 356[M +
H].sup.+354[M - H].sup.-
.delta.(DMSO-d.sub.6) = 2.28 (s, 3H, CH.sub.3), 2.52(s, 3H,
SCH.sub.3), 7.29 (d, J = 8.7 Hz, 2H,CH.sub.ar), 7.52 (d, J = 8.7
Hz, 2H, CH.sub.ar),7.69 (s, 1H, H-5), 8.37 (s, 1H, NH),8.94 (s, 1H,
NH), 9.96 (s, 1H, NH) +++ 106 ##STR00130## F 388[M + H].sup.+386[M
- H].sup.- .delta.(DMSO-d.sub.6) = 2.24 (s, 3H, CH.sub.3),
7.48-7.53 (m, 4H, CH.sub.ar), 7.62 (s, 1H, H-5),8.54 (s, 1H, NH),
9.19 (s, 1H, NH),9.97 (s, 1H, NH) +++ 107 ##STR00131## F 388[M +
H].sup.+386[M - H].sup.- .delta.(DMSO-d.sub.6) = 4.77 (s, 2H,
CH.sub.2), 7.08(t, J = 7.5 Hz, 1H, CH.sub.ar), 7.29 (d, J =7.5 Hz,
1H, CH.sub.ar), 7.33 (d, J = 3.9 Hz,1H, H-4), 7.42 (d, J = 7.5 Hz,
1H,CH.sub.ar), 7.65-7.70 (m, 2H, H-3 and CH.sub.ar),8.31 (s, 1H,
NH), 8.61 (s, 1H, NH),10.48 (s, 1H, NH) +++ 108 ##STR00132## F
344[M + H].sup.+342[M - H].sup.- .delta.(DMSO-d.sub.6) = 4.82 (s,
2H, CH.sub.2), 7.13(t, J = 6.9 Hz, 1H, CH.sub.ar), 7.28 (d, J =4.2
Hz, 1H, H-4), 7.36 (d, J = 7.5 Hz,1H, CH.sub.ar), 7.46 (d, J = 7.5
Hz, 1H,CH.sub.ar), 7.71 (d, J = 8.4 Hz, 1H, CH.sub.ar),7.79 (d, J =
3.9 Hz, 1H, H-3), 8.38(s, 1H, NH), 8.68 (s, 1H, NH), 10.55(s, 1H,
NH) +++ 109 ##STR00133## F 370[M + H].sup.+368[M - H].sup.-
.delta.(DMSO-d.sub.6) = 3.55 (s, 3H, OCH.sub.3), 6.69(d, J = 7.5
Hz, 2H, CH.sub.ar), 7.17-7.24(m, 3H, CH.sub.ar), 7.53 (br.s, 1H,
CH.sub.ar),7.97 (s, 1H, NH), 8.53 (s, 1H, NH),10.19 (s, 1H, NH) +
110 ##STR00134## F 376[M + H].sup.+374[M - H].sup.-
.delta.(DMSO-d.sub.6) = 7.15-7.20 (m, 2H, CH.sub.ar),7.33-7.41 (m,
2H, CH.sub.ar), 7.69 (br.s,1H, CH.sub.ar), 8.47 (s, 1H, NH), 8.59
(s,1H, NH), 10.52 (s, 1H, NH) + 111 ##STR00135## F 415[M +
H].sup.+413[M - H].sup.- .delta.(DMSO-d.sub.6) = 7.71-7.75 (m, 4H,
CH.sub.ar),8.02 (t, J = 4.2 Hz, 1H, CH.sub.ar), 8.24(t, J = 5.1 Hz,
1H, CH.sub.ar), 9.23 (br.s,1H, NH), 9.97 (br.s, 1H, NH),
10.46(br.s, 1H, NH) + 112 ##STR00136## F 360[M + H].sup.+358[M -
H].sup.- .delta.(DMSO-d.sub.6) = 2.19 (s, 3H, CH.sub.3), 6.88(t, J
= 8.7 Hz, 1H, CH.sub.ar), 7.05-7.13(m, 2H, CH.sub.ar), 7.49-7.54
(m, 2H, CH.sub.ar),7.72 (d, J = 6.3 Hz, 1H, CH.sub.ar), 7.82(d, J =
6.3 Hz, 1H, CH.sub.ar),8.03 (d, J =6.9 Hz, 1H, CH.sub.ar), 8.10 (s,
1H, NH),8.50 (s, 1H, NH), 10.26 (s, 1H, NH) + 113 ##STR00137## H
238[M + H].sup.+236[M - H].sup.- .delta.(CDCl.sub.3) = 0.86
(.psi.-t, J .apprxeq. 7 Hz, 1H, 9-H), 1.21-1.38 (m, 6H, 6-H, 7-H,
8-H),1.59 (.psi.-quint, J = 7.3 Hz, 2H, 5-H),2.63 (t, J = 7.4 Hz,
2H, 4-H), 3.60(s, 2H, 2H), 6.61 (s, br., 1H, ring-H), 7.46 (s, br.,
1H, ring-H), 10.61(s, br., 1H, NH). + 114 ##STR00138## H 252[M +
H].sup.+250[M - H].sup.- .delta.(CDCl.sub.3) = 0.89 (.psi.-t, J
.apprxeq. 7 Hz, 1H, 9-H), 1.23-1.37 (m, 6H, 6-H, 7-H, 8-H),1.63
(.psi.-quint, J = 7.3 Hz, 2H, 5-H),2.58 (t, J = 7.3 Hz, 2H, 4-H),
3.66(s, 2H, 2-H), 3.87 (s, 2H, NCH.sub.3), 6.44(d, J = 2.1 Hz, 1H,
ring-H), 7.47 (d,J = 2.1 Hz, 1H, ring-H), 9.85 (s, br.,1H, NH). +
115 ##STR00139## H 294[M + H].sup.+292[M - H].sup.-
.delta.(CDCl.sub.3) = 0.87 (.psi.-t, J .apprxeq. 7 Hz, 1H, 12-H),
1.19-1.37 (m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.61
(.psi.-quint, J =7.3 Hz, 2H, 5-H), 2.53 (t, J = 7.3 Hz,2H, 4-H),
3.57 (s, 2H, 2-H), 3.75 (s,2H, NCH.sub.3), 6.30 (d, J = 1.8 Hz,
1H,ring-H), 7.38 (d, J = 1.8 Hz, 1H,ring-H), 9.55 (s, br., 1H, NH).
+ 116 ##STR00140## H 266[M + H].sup.+264[M - H].sup.-
.delta.(CDCl.sub.3) = 0.89 (.psi.-t, J .apprxeq. 7 Hz, 1H, 9-H),
1.24-1.36 (m, 6H, 6-H, 7-H, 8-H),1.46 (t, J = 7.2 Hz, 3H,
NCH.sub.2CH.sub.3), 1.63(.psi.-quint, J = 7.3 Hz, 2H, 5H), 2.58(t,
J = 7.3 Hz, 2H, 4-H), 3.66 (s, 2H,2-H), 4.21 (q, J = 7.3 Hz,
2H,NCH.sub.2CH.sub.3), 6.46 (d, J = 2.1 Hz, 1H,ring-H), 7.49 (d, J
= 2.1 Hz, 1H,ring-H), 9.85 (s, br., 1H, NH). + 117 ##STR00141## H
308[M + H].sup.+306[M - H].sup.- .delta.(CDCl.sub.3) = 0.88
(.psi.-t, J .apprxeq. 7 Hz, 1H, 12-H), 1.22-1.37 (m, 12H, 6-H, 7-H,
8-H,9-H, 10-H, 11-H), 1.46 (t, J = 7.3 Hz,3H, NCH.sub.2CH.sub.3),
1.64 (.psi.-quint, J = 7.3Hz, 2H, 5-H), 2.58 (t, J = 7.3 Hz,
2H,4-H), 3.61 (s, 2H, 2-H), 4.10 (q, J =7.3 Hz, 2H,
NCH.sub.2CH.sub.3), 6.37 (d, J = 1.8Hz, 1H, ring-H), 7.43 (d, J =
1.8 Hz,1H, ring-H), 9.56 (s, br., 1H, NH). + 118 ##STR00142## H
266[M + H].sup.+264[M - H].sup.- .delta.(CDCl.sub.3) = 0.88
(.psi.-t, J .apprxeq. 7 Hz, 1H, 9-H), 1.23-1.36 (m, 6H, 6-H, 7-H,
8-H),1.61 (.psi.-quint, J = 7.3 Hz, 2H, 5-H),2.22 (s, 3H,
ring-CH.sub.3), 2.57 (t, J =7.3 Hz, 2H, 4-H), 3.60 (s, 2H,
2-H),3.72 (s, 3H, NCH.sub.3), 6.15 (s, 1H, ring-H), 9.58 (s,br.,
1H, NH). + 119 ##STR00143## H 308[M + H].sup.+306[M - H].sup.-
.delta.(CDCl.sub.3) = 0.88 (.psi.-t, J = 7 Hz, 1H, 12-H), 1.21-1.36
(m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.63 (.psi.-quint, J =7.3
Hz, 2H, 5-H), 2.22 (s, 3H, ring-CH.sub.3), 2.57 (t, J = 7.3 Hz, 2H,
4-H),3.60 (s, 2H, 2-H), 3.72 (s, 3H, NCH.sub.3),6.14 (s, 1H,
ring-H), 9.44 (s, br.,1H, NH). + 120 ##STR00144## H 238[M +
H].sup.+236[M - H].sup.- .delta.(CDCl.sub.3) = 0.88 (.psi.-t, J
.apprxeq. 7 Hz, 1H, 9-H), 1.17-1.34 (m, 6H, 6-H, 7-H, 8-H),1.59
(.psi.-quint, J = 7.3 Hz, 2H, 5-H),2.56 (t, J = 7.3 Hz, 2H, 4-H),
3.59(s, 2H, 2-H), 6.31 (.psi.-t, J = 2.3 Hz,1H, ring-H), 7.44 (dd,
J = 2.3 Hz, J =0.6 Hz, 1H, ring-H), 7.49 (d, J = 2Hz, 1H, ring-H),
10.64 (s, br., 1H,NH). + 121 ##STR00145## H 312[M + H].sup.+310[M -
H].sup.- .delta.(CDCl.sub.3) = 0.88 (.psi.-t, J .apprxeq. 7 Hz, 1H,
9-H), 1.21-1.36 (m, 6H, 6-H, 7-H, 8-H),1.65 (.psi.-quint, J = 7.3
Hz, 2H, 5-H),2.59 (t, J = 7.3 Hz, 2H, 4-H), 3.66(s, 2H, 2-H), 3.94
(s, 3H, CO.sub.2CH.sub.3),6.75 (dd, J = 5.8 Hz, J = 0.8 Hz,
1H,ring-H), 7.23 (d, J = 5.8 Hz, 1H,ring-H), 11.88 (s, br., 1H,
NH). + 122 ##STR00146## H 354[M + H].sup.+352[M - H].sup.-
.delta.(CDCl.sub.3) = 0.88 (.psi.-t, J .apprxeq. 7 Hz, 1H, 12-H),
1.21-1.36 (m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.65
(.psi.-quint, J =7.3 Hz, 2H, 5-H), 2.58 (t, J = 7.3 Hz,2H, 4-H),
3.66 (s, 2H, 2-H), 3.93 (s,3H, CO.sub.2CH.sub.3), 6.74 (dd, J = 5.8
Hz, J =0.8 Hz, 1H, ring-H), 7.22 (d, J = 5.8Hz, 1H, ring-H), 11.88
(s, br., 1H,NH). + 123 ##STR00147## H 340[M + H].sup.+338[M -
H].sup.- .delta.(CDCl.sub.3) = 0.88 (.psi.-t, J .apprxeq. 7 Hz, 1H,
9-H), 1.24-1.35 (m, 6H, 6-H, 7-H, 8-H),1.41 (t, J = 7.1 Hz, 3H,
CO.sub.2CH.sub.2CH.sub.3),1.63 (.psi.-quint, J = 7.4 Hz, 2H,
5H),2.38 (d, J = 1.1 Hz, 3H, ring-CH.sub.3),2.58 (t, J = 7.3 Hz,
2H, 4H), 3.63(s, 2H, 2H), 4.42 (q, J = 7.1 Hz,
2H,CO.sub.2CH.sub.2CH.sub.3), 6.39-6.41 (m, 1H, ring-H),11.97 (s,
br., 1H, NH). + 124 ##STR00148## H 382[M + H].sup.+380[M - H].sup.-
.delta.(CDCl.sub.3) = 0.88 (.psi.-t, J .apprxeq. 7 Hz, 1H, 12-H),
1.21-1.36 (m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.41 (t, J = 7.1
Hz,3H, CO.sub.2CH.sub.2CH.sub.3), 1.63 (.psi.-quint, J = 7.4Hz, 2H,
5-H), 2.38 (d, J = 1.1 Hz, 3H,ring-CH.sub.3), 2.58 (t, J = 7.3 Hz,
2H, 4-H), 3.63 (s, 2H, 2-H), 4.42 (q, J =7.1 Hz, 2H,
CO.sub.2CH.sub.2CH.sub.3), 6.39-6.41 (m,1H, ring-H), 11.97 (s, br.,
1H, NH). + 125 ##STR00149## H 269[M + H].sup.+267[M - H].sup.-
.delta.(CDCl.sub.3) = 0.88 (.psi.-t, J .apprxeq. 7 Hz, 1H, 9-H),
1.23-1.37 (m, 6H, 6-H, 7-H, 8-H),1.61 (.psi.-quint, J = 7.3 Hz, 2H,
5-H),2.55 (s, 3H, ring-CH.sub.3), 2.60 (t, J =7.3 Hz, 2H, 4-H),
3.84 (s, 2H, 2-H),6.91 (s, 1H, ring-H). + 126 ##STR00150## H 311[M
+ H].sup.+309[M - H].sup.- .delta.(CDCl.sub.3) = 0.88 (.psi.-t, J
.apprxeq. 7 Hz, 1H, 12-H), 1.22-1.37 (m, 12H, 6-H, 7-H, 8-H,9-H,
10-H, 11-H), 1.63 (.psi.-quint, J =7.3 Hz, 2H, 5-H), 2.42 (s, 3H,
ring-CH.sub.3), 2.58 (t, J = 7.3 Hz, 2H, 4-H),3.66 (s, 2H, 2-H),
6.66 (s, 1H, ring-H), 10.51 (s, br., 1H, NH). + 127 ##STR00151## H
255[M + H].sup.+253[M - H].sup.- .delta.(CDCl.sub.3) = 0.88
(.psi.-t, J .apprxeq. 7 Hz, 1H, 9-H), 1.24-1.37 (m, 6H, 6-H, 7-H,
8-H),1.62 (.psi.-quint, J = 7.3 Hz, 2H, 5-H),2.59 (t, J = 7.3 Hz,
2H, 4-H), 3.71(s, 2H, 2-H), 7.00 (d, J = 3.7 Hz, 1H,ring-H), 7.47
(d, J = 3.7 Hz, 1H,ring-H), [NH proton not visible]. + 128
##STR00152## H 297[M + H].sup.+295[M - H].sup.- .delta.(CDCl.sub.3)
= 0.88 (.psi.-t, J .apprxeq. 7 Hz, 1H, 12-H), 1.21-1.37 (m, 12H,
6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.62 (.psi.-quint, J =7.3 Hz, 2H,
5-H), 2.61 (t, J = 7.3 Hz,2H, 4-H), 3.66 (s, 2H, 2-H), 7.00 (d,J =
3.6 Hz, 1H, ring-H), 7.49 (d, J =3.6 Hz, 1H, ring-H), 11.54 (s,
br.,1H, NH). + 129 ##STR00153## H 343[M + H].sup.+341[M - H].sup.-
.delta.(CDCl.sub.3) = 0.85 (.psi.-t, J = 7 Hz, 1H, 9-H), 1.21-1.37
(m, 6H, 6-H, 7-H, 8-H),1.59 (.psi.-quint, J = 7.3 Hz, 2H, 5-H),2.38
(s, 3H, SCH.sub.3), 2.56 (t, J = 7.3Hz, 2H, 4-H), 2.68 (s, 3H,
COCH.sub.3.sup.+),3.87 (s, br., 2H, 2-H), 10.88 (s, br.,1H, NH). +
130 ##STR00154## H 239[M + H].sup.+237[M - H].sup.-
.delta.(CDCl.sub.3) = 0.89 (.psi.-t, J .apprxeq. 7 Hz, 1H, 9-H),
1.23-1.36 (m, 6H, 6-H, 7-H, 8-H),1.62 (.psi.-quint, J = 7.3 Hz, 2H,
5-H),2.57 (t, J = 7.3 Hz, 2H, 4-H), 3.60(s, 2H, 2-H), 7.01 (d, J =
1.7 Hz, 1H,ring-H), 8.28 (dd, J = 1.7 Hz, J = 0.5Hz, 1H, ring-H),
9.90 (s, br., 1H,NH). + 131 ##STR00155## H 281[M + H].sup.+279[M -
H].sup.- .delta.(CDCl.sub.3) = 0.88 (.psi.-t, J .apprxeq. 7 Hz, 1H,
12-H), 1.22-1.36 (m, 12H, 6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.62
(.psi.-quint, J =7.3 Hz, 2H, 5-H), 2.57 (t, J = 7.3 Hz,2H, 4-H),
3.60 (s, 2H, 2-H), 7.00 (d,J = 1.7 Hz, 1H, ring-H), 8.28 (dd, J
=1.7 Hz, J = 0.5 Hz, 1H, ring-H), 9.88(s, br., 1H, NH). + 132
##STR00156## H 253[M + H].sup.+251[M - H].sup.- .delta.(CDCl.sub.3)
= 0.89 (.psi.-t, J .apprxeq. 7 Hz, 1H, 9-H), 1.25-1.37 (m, 6H, 6-H,
7-H, 8-H),1.63 (.psi.-quint, J = 7.3 Hz, 2H, 5-H),2.27 (s, 3H,
ring-CH.sub.3), 2.56 (t, J =7.3 Hz, 2H, 4-H), 3.60 (s, 2H,
2-H),6.20 (s, 1H, ring-H), 10.17 (s, br.,1H, NH). + 133
##STR00157## H 295[M + H].sup.+293[M - H].sup.- .delta.(CDCl.sub.3)
= 0.88 (.psi.-t, J .apprxeq. 7 Hz, 1H, 12-H), 1.20-1.37 (m, 12H,
6-H, 7-H, 8-H,9-H, 10-H, 11-H), 1.63 (.psi.-quint, J =7.3 Hz, 2H,
5-H), 2.26 (s, 3H, ring-CH.sub.3), 2.56 (t, J = 7.3 Hz, 2H,
4H),3.60 (s, 2H, 2-H), 6.20 (s, 1H, ring-H), 10.15 (s, br., 1H,
NH). + 134 ##STR00158## H 253[M + H].sup.+251[M - H].sup.-
.delta.(CDCl.sub.3) = 0.88 (.psi.-t, J .apprxeq. 7 Hz, 1H, 9-H),
1.25-1.38 (m, 6H, 6-H, 7-H, 8-H),1.61 (.psi.-quint, J = 7.3 Hz, 2H,
5-H),2.12 (d, J = 1.3 Hz, 1H, ring-CH.sub.3),2.57 (t, J = 7.3 Hz,
2H, 4-H), 3.68(s, br., 2H, 2-H), 7.12 (q, J = 1.3Hz, 1H, ring-H),
[NH proton notvisible]. + 135 ##STR00159## H 278[M + H].sup.+276[M
- H].sup.- .delta.(CDCl.sub.3) = 0.87 (.psi.-t, J .apprxeq. 7 Hz,
1H, 9-H), 1.21-1.37 (m, 6H, 6-H, 7-H, 8-H),1.59 (.psi.-quint, J =
7.3 Hz, 2H, 5-H),2.41 (s, 3H, ring-CH.sub.3), 2.57 (t, J =7.3 Hz,
2H, 4-H), 3.65 (s, 2H, 2-H),10.10 (s, br., 1H, NH). ++ 136
##STR00160## H 291[M + H].sup.+289[M - H].sup.- .delta.(CDCl.sub.3)
= 0.85 (.psi.-t, J .apprxeq. 7 Hz, 1H, 9-H), 1.21-1.34 (m, 6H, 6-H,
7-H, 8-H),1.57 (.psi.-quint, J = 7.3 Hz, 2H, 5-H),1.97 (q, J = 0.8
Hz, 3H, ring-CH.sub.3),2.13 (q, J = 0.9 Hz, 3H, ring-CH.sub.3),2.55
(t, J = 7.4 Hz, 2H, 4-H), 3.60(s, 2H, 2-H), 9.81 (s, br., 1H, NH).
+ 137 ##STR00161## H 333[M + H].sup.+331[M - H].sup.- 0.88
(.psi.-t, J .apprxeq. 7 Hz, 1H, 12-H), 1.21-1.37 (m, 12H, 6-H, 7-H,
8-H, 9-H, 10-H, 11-H), 1.62 (.psi.-quint, J = 7.3 Hz,2H, 5-H), 2.01
(q, J = 0.9 Hz, 3H,ring-CH.sub.3), 2.17 (q, J = 0.9 Hz,
3H,ring-CH.sub.3), 2.57 (t, J = 7.4 Hz, 2H, 4-H), 3.60 (s, 2H,
2-H), 9.78 (s, br.,1H, NH). + 138 ##STR00162## H 296[M +
H].sup.+294[M - H].sup.- .delta.(CDCl.sub.3) = 0.84 (.psi.-t, J
.apprxeq. 7 Hz, 1H, 9-H), 1.17-1.35 (m, 6H, 6-H, 7-H, 8-H),1.57
(.psi.-quint, J = 7.3 Hz, 2H, 5-H),2.55 (t, J = 7.3 Hz, 2H, 4-H),
3.63(s, 2H, 2-H), 3.83 (s, 3H, CO.sub.2CH.sub.3),6.47 (d, J = 3.6
Hz, 1H, ring-H), 7.14(d, J = 3.6 Hz, 1H, ring-H), 10.15 (s,br., 1H,
NH). + *+++: 1-50 .mu.M; ++: 50-100 .mu.M; +: >100 .mu.M; -not
determined
2. Biosensor Assay
[0314] Quorum sensing inhibition of the compounds was investigated
with the aid of the bioluminescent sensor strain Escherichia coli
MT102 (pSB403) (Winson et al., FEMS Microbiol. Lett. 163:185-92,
1998). Plasmid pSB403 contains the Photobacterium fischeri luxR
gene together with the tuxI promoter region as a transcriptional
fusion to the bioluminescence genes luxCDABE of Photorhabdus
luminescence. Although E. coli pSB403 exhibits the highest
sensitivity for the Photobacterium fischeri quorum sensing signal
N-(3-oxohexanoyl)homoserine lactone (3-oxo-C6-HSL), a wide range of
other HSL molecules are detected by the sensor (Winson et al., FEMS
Microbiol. Lett. 163:185-92, 1998; Geisenberger et al, FEMS
Microbiol. Lett. 184:273-8, 2000).
[0315] Inhibitory studies were conducted in a microtitre dish assay
as follows: the E. coli sensor strain grown over night in LB medium
(Sambrook et al., Molecular Cloning: A Laboratory Maual. 2.sup.nd
Edn. Cold Spring Harbor Laboratory, New York, 1989) was diluted 1:4
and grown for another 1 hour at 30.degree. C. After addition of
3oxo-C6-HSL (final concentration 100 nM) 100 .mu.l of an
exponential culture suspension were filled in the wells of a
FluoroNunc Polysorp microtitre dish. The test compounds were added
to the culture in different concentrations and bioluminescence was
measured after 4 hours of incubation at 30.degree. C. with a Lamda
Fluoro 320 Plus reader (Bio-Tek Instruments). Inhibitor-mediated
reduction of light emission was correlated with the value obtained
without addition of the test compounds. IC.sub.50 values
(concentration of inhibitor required for 50% inhibition of the
signal compared to the signal without inhibitor) were determined by
using a fitting function after drawing a graph of the activities of
eight different inhibitor concentrations. The determined IC.sub.50
range of each compound is listed in Table 2.
[0316] To exclude the possibility that the inhibitory effect is
attributed to growth inhibition but not to a specific interaction
of the test compound with the sensors quorum sensing system growth
curves in the presence and absence of the test compounds were
compared. E. coli MT102 (pSB403) was grown in LB medium at
37.degree. C. in the presence of 0.4 mM test compound. Growth was
measured as optical density at 600 nm. None of the compounds listed
in Table 2 exhibit any growth inhibitory effects on the sensor
strain E. coli MT102 (pSB403). FIG. 2 shows the growth curves of
representative compounds indicating a specific inhibitory effect of
the compounds on the quorum sensing system.
3. Inhibition of Protease Production
[0317] The inhibitory effect of the compounds on quorum sensing
regulated virulence factors was demonstrated by investigating the
expression of extracellular proteases by Pseudomonas aeruginosa.
The P. aeruginosa mutant strain PAO-JP2 (Pearson et al., J.
Bacteriol. 179:5756-67, 1997) carrying mutations in the quorum
sensing genes lasI and rhlI is unable to produce extracellular
proteolytic enzymes. Protease expression can be completely restored
by external addition of 3-oxo-C12-HSL. The protease assay was
performed according to Riedel et at. (J. Bacteriol. 183:1805-9,
2001) with few modifications. PAO-JP2 was grown in LB medium at
30.degree. C. and shaking at 250 rpm to an OD600 nm of 0.5. The
test compounds were added at a final concentration of 0.4 mM and
the culture was incubated for further 30 min at 30.degree. C. and
shaking at 250 rpm. After addition of 3-oxo-C12-HSL at a final
concentration of 0.3 .mu.M the cultures were grown for an
additional 6 hours at 30.degree. C. and shaking at 250 rpm. The
proteolytic activity was measured as described by Ayora & Gotz
(Mol. Gen. Genet. 242:421-30, 1994). 50 .mu.l culture supernatant
were incubated with Azocasein (250 .mu.l 2%, Sigma, St. Louis, Mo.)
for 1 hour at 37.degree. C. After precipitation of undigested
substrate with trichloroacetic acid (1.2 ml 10%) for 20 minutes at
room temperature, followed by 5 minutes centrifugation at 13000
rpm, NaOH (0.75 ml 1M) was added to the supernatant. The relative
protease activity was measured as absorbance at 440 nm
(OD.sub.440nm) of the supernatant divided by the optical density of
the culture (OD.sub.600nm). FIG. 3 demonstrates the inhibitory
effect of several compounds on protease production of P. aeruginosa
PAO-JP2. The data presented are representative for at least three
separate experiments.
[0318] To demonstrate that inhibition of protease production is due
to a specific interference with the quorum sensing system growth
curves in the presence and absence of the test compounds were
compared. P. aeruginosa PAO-JP2 was grown in LB medium at
30.degree. C. in the presence of 0.4 mM test compound. Growth was
measured as optical density at 600 nm. None of the compounds listed
in Table 2 exhibit any growth inhibitory effects on P. aeruginosa
PAO-JP2. FIG. 4 shows the growth curves of representative compounds
indicating a specific inhibitory effect of the compounds on the
quorum sensing system.
4. Inhibition of Biofilm Formation
[0319] The bacterial biofilm formation assay was performed in
polystyrene microtitre dishes (FluoroNunc Polysorp) according to
the method described by O'Toole & Kolter (Mol. Microbiol.
28:449-61, 1998) and Pratt & Kolter (Mol. Microbiol. 4 30;
285-93, 1998) with few modifications (Huber et al., Microbiology,
147:2517-28, 2001). Cells were grown in the wells of the microtitre
dishes in 100 .mu.l AB medium (Clark & Maaloe, J. Mol. Biol.
23:99-112, 1967) supplemented with 10 mM sodium citrate (Sigma).
After addition of the test compound (0.4 mM) the cells were
incubated for 48 hours at 30.degree. C. The medium was then removed
and 100 .mu.l of a 1% (w/v) aqueous solution of crystal violet
(Merck) was added. Following staining at room temperature for 20
minutes, the dye was removed and the wells were washed thoroughly
with water. For quantification of attached cells, the crystal
violet was solubilized in a 80;20 (v/v) mixture of ethanol and
acetone and the absorbance was determined at 570 nm (Ultrospec Plus
spectrometer, Pharmacia). FIGS. 5A and 5B demonstrate the
inhibitory effect of several compounds on biofilm formation of
Burkholderia cepacia H11 (Romling et al., J. Infect. Dis.
170:1616-21, 1994; Gotschlich et al., Syst. Appl. Microbiol.
24:1-14, 2001). The data presented are representative for at least
five separate experiments.
[0320] To exclude the possibility that biofilm inhibition is
attributed to growth inhibition growth curves in the presence and
absence of the test compounds were compared. Burkholderia cepacia
H111 was grown in LB medium at 37.degree. C. in the presence of 0.4
mM test compound. Growth was measured as optical density at 600 nm.
None of the compounds listed in Table 2 exhibit any growth
inhibitory effects on the sensor strain Burkholderia cepacia H111.
FIG. 6 shows the growth curves of the tested compounds indicating a
specific inhibitory effect of the compounds on the quorum sensing
system.
* * * * *