U.S. patent application number 10/847166 was filed with the patent office on 2004-10-28 for aromatic dicarboxylic acid derivatives.
Invention is credited to Leser-Reiff, Ulrike, Sattelkau, Tim, Zimmermann, Gerd.
Application Number | 20040214862 10/847166 |
Document ID | / |
Family ID | 8177731 |
Filed Date | 2004-10-28 |
United States Patent
Application |
20040214862 |
Kind Code |
A1 |
Leser-Reiff, Ulrike ; et
al. |
October 28, 2004 |
Aromatic dicarboxylic acid derivatives
Abstract
Compounds of formula I 1 wherein A, R.sup.1 and R.sup.2 are
defined in the specification. These compounds are useful as HDAC
inhibitors. Also disclosed are methods of making and using said
compounds.
Inventors: |
Leser-Reiff, Ulrike;
(Penzberg, DE) ; Sattelkau, Tim; (Mannheim,
DE) ; Zimmermann, Gerd; (Linkenheim, DE) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
8177731 |
Appl. No.: |
10/847166 |
Filed: |
May 17, 2004 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10847166 |
May 17, 2004 |
|
|
|
10167677 |
Jun 11, 2002 |
|
|
|
6784173 |
|
|
|
|
Current U.S.
Class: |
514/317 ;
514/423; 514/575; 546/226; 548/537; 562/622 |
Current CPC
Class: |
C07C 2602/08 20170501;
C07D 211/16 20130101; C07D 317/58 20130101; C07D 213/40 20130101;
C07C 259/10 20130101; A61P 43/00 20180101; C07C 2602/10 20170501;
C07C 2601/14 20170501; A61P 35/00 20180101; C07D 333/38 20130101;
C07D 307/14 20130101; C07C 2601/02 20170501; C07D 207/09
20130101 |
Class at
Publication: |
514/317 ;
514/423; 514/575; 546/226; 548/537; 562/622 |
International
Class: |
A61K 031/445; C07D
211/06; A61K 031/401; C07C 259/04; A61K 031/19 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 15, 2001 |
EP |
01114496.1 |
Claims
1. A compound of formula I 9is a phenyl ring that may be
unsubstituted or substituted by 1, 2 or 3 substituents
independently selected from halogen, C.sub.1-4-alkyl-,
trifluoromethyl-, hydroxy-, C.sub.1-4-alkoxy-, nitro-, amino-,
C.sub.1-4-alkylamino-, di[C.sub.1-4-alkyl]-amino-,
C.sub.1-4-alkanoylamino, C.sub.1-3-alkylenedioxy or an acyl group;
and R1 and R2 are each independently selected from hydrogen, a
branched or unbranched C.sub.1-14-alkyl group that may be
unsubstituted or substituted with 1 or more substituents
independently selected from halogen, hydroxy-, nitro-, an amino
group, a carbocyclic group or a heterocyclic group, and wherein at
a chain length of longer than 2 carbon atoms, one or more non
adjacent atoms may be replaced by oxygen, nitrogen or sulfur atoms,
and wherein 2 atoms may be bound together by a double or triple
bond, a carbocyclic group, and a heterocyclic group, or
alternatively, the group --NR.sup.1R.sup.2 forms a 3-6 membered
ring that may contain additional heteroatoms independently selected
from nitrogen, oxygen and sulfur, said ring optionally being
annulated to a carbocyclic ring or a heterocyclic ring, and said
--NR.sup.1R.sup.2 ring being unsubstituted or optionally
substituted by 1, 2, or 3 substituents independently selected from
a halogen atom, an C.sub.1-4-alkyl-, trifluoromethyl-, hydroxy-,
C.sub.1-4-alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-,
aryloxy, C.sub.1-3-alkylenedioxy-, nitro-, amino-,
C.sub.1-4-alkylamino-, di[C.sub.1-4-alkyl]amino-,
C.sub.1-4-alkanoylamino- or an acyl-group; or the enantiomers,
diastereoisomers, racemates and physiologically acceptable salts
thereof.
2. The compound of claim 1 wherein R.sup.2 is benzyl or substituted
benzyl.
3. The compound of claim 1 wherein R.sup.2 is benzyl or substituted
benzyl.
4. A compound selected from the group consisting of
N-hydroxy-N'-naphthalen-1-ylmethyl-terephthalamide;
4-(4-benzhydryl-piperazine-1-carbonyl)-N-hydroxy-benzamide;
N-hydroxy-N'-pyridin-3-ylmethyl-terephthalamide;
N-benzyl-N'-hydroxy-tere- phthalamide;
N-cyclohexyl-N'-hydroxy-terephthalamide;
N-cyclopropyl-N'-hydroxy-terephthalamide;
N-hexyl-N'-hydroxy-terephthalam- ide;
N-hydroxy-N'-(3-methyl-butyl)-terephthalamide;
N-hydroxy-N'-phenethyl-terephthalamide; and
N-hydroxy-N'-[2-(4-methoxy-ph- enyl)-ethyl]-terephthalamide.
5. A compound selected from the group consisting of
N-(3-chloro-benzyl)-N'-hydroxy-terephthalamide;
N-hydroxy-N'-(2-methoxy-b- enzyl)-terephthalamide;
N-(4-fluoro-benzyl)-N'-hydroxy-terephthalamide;
N-hydroxy-N'-(1,2,3,4-tetrahydro-naphthalen-1-yl)-terephthalamide;
N-hydroxy-N'-(4-trifluoromethyl-benzyl)-terephthalamide;
N-(2,4-difluoro-benzyl)-N'-hydroxy-terephthalamide;
N-hydroxy-N'-indan-1-yl-terephthalamide; N-benzo
[1,3]dioxol-5-ylmethyl-N- '-hydroxy-terephthalamide;
N-hydroxy-4-(4-phenyl-piperazine-1-carbonyl)-be- nzamide; and
N-(3,5-dimethyl-benzyl)-N'-hydroxy-terephthalamide.
6. A compound selected from the group consisting of
N-hydroxy-N'-(3-isopropoxy-propyl)-terephthalamide;
4-(4-acetyl-piperazine-1-carbonyl)-N-hydroxy-benzamide;
N,N-dibutyl-N'-hydroxy-terephthalamide;
4-(4-benzyl-piperidine-1-carbonyl- )-N-hydroxy-benzamide;
N-hydroxy-N'-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-t-
erephthalamide; N-(2-ethoxy-benzyl)-N'-hydroxy-terephthalamide;
N-(2-cyclohex-1-enyl-ethyl)-N'-hydroxy-terephthalamide;
N-hydroxy-N'-(2-morpholin-4-yl-ethyl) terephthalamide;
N-hydroxy-N'-(2-methylsulfanyl-ethyl)-terephthalamide; and
N-hydroxy-N'-(tetrahydro-furan-2-ylmethyl)-terephthalamide.
7. A process of manufacturing a compound of formula I comprising
reacting a compound of formula III 10 with an amine of the formula
HNR.sub.1R.sub.2 in the presence of an activating agent, to give a
compound of formula II 11 reacting the compound of formula II with
hydroxylamine in the presence of a suitable base, wherein 12 is a
phenyl ring that may be unsubstituted or substituted by 1, 2 or 3
substituents independently selected from halogen, a
C.sub.1-4-alkyl-, trifluoromethyl-, hydroxy-, C.sub.1-4-alkoxy-,
nitro-, amino-, C.sub.1-4-alkylamino-, di[C.sub.1-4-alkyl]-amino-,
C.sub.1-4-alkanoylamino, a C.sub.1-3-alkylenedioxy-group or an acyl
group; R1 and R2 are each independently selected from hydrogen, a
branched or unbranched C.sub.1-14-alkyl group that may be
unsubstituted or substituted with 1 or more substituents
independently selected from halogen, hydroxy-, nitro-, an amino
group, a carbocyclic group or a heterocyclic group, and wherein at
a chain length of longer than 2 carbon atoms, one or more non
adjacent atoms may be replaced by oxygen, nitrogen or sulfur atoms,
and wherein 2 atoms may be bound together by a double or triple
bond, a carbocyclic group, and a heterocyclic group, or
alternatively, the group --NR.sup.1R.sup.2 forms a 3-6 membered
ring that may contain additional heteroatoms independently selected
from nitrogen, oxygen and sulfur, said ring optionally being
annulated to a carbocyclic ring or a heterocyclic ring, and said
--NR.sup.1R.sup.2 ring being unsubstituted or optionally
substituted by 1, 2, or 3 substituents independently selected from
a halogen atom, an C.sub.1-4-alkyl-, trifluoromethyl-, hydroxy-,
C.sub.1-4-alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-,
aryloxy, C.sub.1-3-alkylenedioxy-, nitro-, amino-,
C.sub.1-4-alkylamino-, di[C.sub.1-4-alkyl]amino-,
C.sub.1-4-alkanoylamino- or an acyl-group; and R3 is
C.sub.1-4-alkyl.
8. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 and a pharmaceutically
acceptable carrier or excipient.
9. A method of treating breast, lung, colon, rectal, stomach,
prostate, bladder, pancreas or ovarian cancer comprising
administering to a subject in need of such treatment a
therapeutically effective amount of a compound of claim 1.
10. A compound of formula 13is a phenyl ring that may be
unsubstituted or substituted by 1, 2 or 3 substituents
independently selected from halogen, a C.sub.1-4-alkyl-,
trifluoromethyl-, hydroxy-, C.sub.1-4-alkoxy-, nitro-, amino-,
C.sub.1-4-alkylamino-, di[C.sub.1-4-alkyl]-amino-,
C.sub.1-4-alkanoylamino, a C.sub.1-3-alkylenedioxy-group or an acyl
group; R1 and R2 are each independently selected from hydrogen, a
branched or unbranched C.sub.1-14-alkyl group that may be
unsubstituted or substituted with 1 or more substituents
independently selected from halogen, hydroxy-, nitro-, an amino
group, a carbocyclic group or a heterocyclic group, and wherein at
a chain length of longer than 2 carbon atoms, one or more non
adjacent atoms may be replaced by oxygen, nitrogen or sulfur atoms,
and wherein 2 atoms may be bound together by a double or triple
bond, a carbocyclic group, and a heterocyclic group, or
alternatively, the group --NR.sup.1R.sup.2, forms a 3-6 membered
ring that may contain additional heteroatoms independently selected
from nitrogen, oxygen and sulfur, said ring optionally being
annulated to a carbocyclic ring or a heterocyclic ring, and said
--NR1R.sup.2 ring being unsubstituted or optionally substituted by
1, 2, or 3 substituents independently selected from a halogen atom,
an C.sub.1-4-alkyl-, trifluoromethyl-, hydroxy-, C.sub.1-4-alkoxy-,
aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy,
C.sub.1-3-alkylenedioxy-, nitro-, amino-, C.sub.1-4-alkylamino-,
di[C.sub.1-4-alkyl]amino-, C.sub.1-4-alkanoylamino- or an
acyl-group; and Y is a protecting group.
Description
PRIORITY TO RELATED APPLICATIONS
[0001] This application is a Division of Ser. No. 10/167,677, filed
Jun. 11, 2002, which is now pending.
[0002] The invention relates to aromatic dicarboxylic acid
derivatives, or pharmaceutically-acceptable salts thereof, which
possess anti-cell-proliferation activity such as anti-tumor
activity and are accordingly useful in methods of treatment of
humans and other animals. The invention also relates to processes
for the manufacture of said dicarboxylic acid derivatives, to
pharmaceutical compositions containing the derivatives and to their
use in the treatment of cell-proliferation disorders.
BACKGROUND OF THE INVENTION
[0003] Transcriptional regulation is a major event in cell
differentiation, proliferation, and apoptosis. Transcriptional
activation of a set of genes determines cell destination and for
this reason transcription is tightly regulated by a variety of
factors. One of its regulatory mechanisms involved in the process
is an alteration in the tertiary structure of DNA, which affects
transcription by modulating the accessibility of transcription
factors to their target DNA segments. Nucleosomal integrity is
regulated by the acetylation status of the core histones. In a
hypoacetylated state, nucleosomes are tightly compacted and thus
are nonpermissive for transcription. On the other hand, nucleosomes
are relaxed by acetylation of the core histones, with the result
being permissiveness to transcription. The acetylation status of
the histones is governed by the balance of the activities of
histone acetyl transferase (HAT) and histone deacetylase (HDAC).
Recently, HDAC inhibitors have been found to arrest growth and
apoptosis in several types of cancer cells, including colon cancer,
T-cell lymphoma, and erythroleukemic cells. Given that apoptosis is
a crucial factor for cancer progression, HDAC inhibitors are
promising reagents for cancer therapy as effective inducers of
apoptosis (Koyama, Y., et al., Blood 96 (2000) 1490-1495). !
[0004] Several structural classes of HDAC inhibitors have been
identified and are reviewed in Marks, P. M., et al., J. Natl.
Cancer Inst. 92 (2000) 1210-1216. More specifically, WO 98/55449
and U.S. Pat. No. 5,369,108 report alkanoyl hydroxamates with HDAC
inhibitory activity.
[0005] It has now been found that certain aromatic dicarboxylic
acid derivatives are more potent inhibitors of cell-proliferation
than the compounds reported in the aforementioned references.
Furthermore, these compounds have HDAC inhibitiory activity.
DESCRIPTION OF THE INVENTION
[0006] The invention is directed to an aromatic dicarboxylic acid
derivative of the formula I 2
[0007] denotes a phenyl ring which may be unsubstituted or
substituted by 1, 2 or 3 substituents independently selected from a
halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-,
(1-4C)alkoxy-, nitro-, amino-, (1-4C)alkylamino-,
di[(1-4C)alkyl]-amino-, (1-4C)alkanoylamino, a
(1-3C)alkylenedioxy-group or an acyl group, or alternatively, 3
[0008] denotes a thiophene ring which may be unsubstituted or
substituted by 1 or 2 substituents independently selected from a
halogen atom, an (1-4C)alkyl-, trifluoromethyl-, hydroxy-,
(1-4C)alkoxy-, nitro-, amino-, (1-4C)alkylamino-,
di[(1-4C)alkyl]-amino- or a (1-4C)alkanoylamino, a
(1-3C)alkylenedioxy-group or an acyl group,
[0009] and
[0010] R1 and R2 are each independently selected from
[0011] a hydrogen atom;
[0012] a branched or unbranched (1-14C)alkyl group, which
[0013] may be unsubstituted or substituted with 1 or several
substituents independently selected from the group consisting of a
halogen-, hydroxy-, nitro-, amino-, carbocyclic- or a heterocyclic
group,
[0014] and wherein at a chain length of larger than 2 C-atoms one
or several non adjacent C-atoms may be replaced by a corresponding
number of heteroatoms such as oxygen, nitrogen or sulfur,
[0015] and wherein 2 C-atoms may be bound together by a double or
triple bond;
[0016] a carbocyclic group;
[0017] or a heterocyclic group;
[0018] or alternatively, R1 and R2 together with the nitrogen atom
to which they are attached form a 3-6 membered ring that may
contain additional heteroatoms independently selected from
nitrogen, oxygen and sulfur, said ring optionally being annulated
to a carbocyclic ring or a heterocyclic ring, said --NR1R.sup.2
ring being unsubstituted or optionally substituted by 1, 2, or 3
substituents independently selected from a halogen atom, an
(1-4C)alkyl-, trifluoro-methyl-, hydroxy-, (1-4C)alkoxy-, aryl-,
hetaryl-, arylalkyl, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-,
nitro-, amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-,
(1-4C)alkanoylamino- or an acyl-group.
[0019] An alkyl group may be e.g. pentyl, hexyl or
3-methyl-butyl.
[0020] A substituted alkyl group may be e.g. benzyl, phenethyl,
tetrahydro-furan-2-yl-methyl or 2-cyclohex-1-enyl-ethyl.
[0021] An alkyl group where one or several non adjacent atom groups
may be replaced by oxygen, nitrogen or sulfur atoms may be e.g.
3-isopropoxy-propyl or 2-methylsulfanyl-ethyl.
[0022] An alkyl group wherein 2 atoms may be bound together by a
double or triple bond may be e.g. 1-hexinyl or 2-heptenyl.
[0023] "Annulated" as used herein means the fusion of a new ring to
a molecule via two new bonds.
[0024] A carbocyclic group is a non-aromatic ring system having 3-7
carbon ring atoms, for example cyclopentane, cyclohexane,
cyclohexene or cyclopropane, said ring system being unsubstituted
or optionally substituted by 1, 2, or 3 substituents independently
selected from halogen, (1-4C)alkyl-, trifluoro-methyl-, hydroxy-,
(1-4C)alkoxy-, aryl-, hetaryl-, arylalkyl, arylalkyloxy-, aryloxy,
(1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-,
di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino- or an acyl-group. Said
ring atoms optionally may be annulated to an aryl or hetaryl group,
to form e.g. an indane or a tetraline. A carbocyclic group as
herein defined may be an aryl group.
[0025] An aryl group is a carbocyclic conjugated ring system, for
example phenyl, naphthyl, preferably phenyl, which may be
unsubstituted or substituted by 1, 2, or 3 substituents
independently selected from a halogen atom, an (1-4C)alkyl-,
trifluoromethyl-, hydroxy-, (1-4C)alkoxy-, arylalkyloxy-, aryloxy,
(1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-,
di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino-, carboxyl-,
carboxyalkyl- or an acyl-group.
[0026] A heterocyclic group is a non-aromatic ring system having
3-7 ring atoms, said ring atoms comprising carbon atoms and one or
two hetero atoms independently chosen from nitrogen, oxygen, and
sulfur. Examples of heterocyclic groups include piperidino,
morpholino, pyrrolidino and piperazino. Said ring system may be
unsubstituted or substituted by 1, 2, or 3 substituents
independently selected from halogen, (1-4C)alkyl-,
trifluoro-methyl-, hydroxy-, (1-4C)alkoxy-, aryl-, hetaryl-,
arylalkyl, arylalkyloxy-, aryloxy, (1-3C)alkylenedioxy-, nitro-,
amino-, (1-4C)alkylamino-, di[(1-4C)alkyl]amino-,
(1-4C)alkanoylamino, or an acyl-group. Moreover, said ring atoms
optionally may be annulated to an aryl or hetaryl group, to form
e.g. a tetrahydrochinoline, tetrahydroisochinoline or a
dihydroindole. A heterocyclic group as defined herein also may be a
hetaryl group.
[0027] A hetaryl group is either a 5 or 6 membered cyclic
conjugated ring system with one or two hetero atoms independently
chosen from nitrogen, oxygen, and sulfur, for example pyridinyl,
thiophenyl, furyl or pyrrolyl, or an annulated bicydic conjugated
ring system like indolyl-, quinolyl- or isoquinolyl-, which may be
unsubstituted or substituted by 1, 2, or 3 substituents
independently selected from a halogen atom, an (1-4C)alkyl-,
trifluoro-methyl-, hydroxy-, (1-4C)alkoxy-, arylalkyloxy-, aryloxy,
(1-3C)alkylenedioxy-, nitro-, amino-, (1-4C)alkylamino-,
di[(1-4C)alkyl]amino-, (1-4C)alkanoylamino, or an acyl group.
[0028] When R1 and R2 together with the nitrogen atom form a 3-6
membered ring which may contain additional heteroatoms
independently selected from nitrogen, oxygen and sulfur, it may be
e.g. piperidine, piperazine or morpholine.
[0029] A suitable value for a substituent when it is a halogen atom
is, for example, fluoro, chloro, bromo and iodo; when it is
(1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl; when it is (1-4C)alkoxy is, for
example, methoxy, ethoxy, propoxy, isopropoxy or butoxy; when it is
(1-4C)alkylamino is, for example, methylamino, ethylamino or
propylamino; when it is di-[(1-4C)alkyl]amino is, for example,
dimethylamino, N-ethyl-N-methylamino, diethylamino,
N-methyl-N-propylamino or dipropylamino; when it is
(1-4C)alkanoylamino is, for example, formylamido, acetamido,
propionamido or butyramido; when it is (1-3C)alkylenedioxy is, for
example, methylenedioxy, ethylenedioxy or propylenedioxy; and when
it is acyl is, for example, formyl, acetyl, propionyl, benzoyl, or
phenylacetyl.
[0030] In a preferred embodiment, R1 is hydrogen and R2 has one of
the above values. In a more preferred embodiment, R2 is a
(1-14C)alkyl group. Most preferrably, R2 is an arylalkyl-radical,
for example the benzyl-radical or substituted benzyl-radicals.
[0031] Preferred are compounds wherin A denotes a thiophene ring.
Even more preferred are compounds wherein the thiophene ring is
unsubstituted. Most preferred are compounds wherin two carboxylic
moieties are bonded at positions 2 and 5 of a further unsubstituted
thiophene ring. Enantiomers, diastereoisomers, racemates and
mixtures thereof and pharmaceutically acceptable salts of aromatic
dicarboxylic acid derivatives of the formula I are also part of the
invention.
[0032] The invention is also directed to a pharmaceutical
composition comprising a therapeutically effective amount of an
aromatic dicarboxylic acid derivative of the formula I, or a
pharmaceutically-acceptable salt thereof, as defined above, in
association with a pharmaceutically-accepta- ble diluent or
carrier. The pharmaceutical composition may be in a form suitable
for oral administration, for example as a tablet or capsule, for
parenteral injection (including intravenous, subcutaneous,
intramuscular, intravascular or infusion) as a sterile solution,
suspension or emulsion, for topical administration as an ointment
or cream or for rectal administration as a suppository. In general
the above compositions may be prepared in a manner using
conventional excipients. The aromatic dicarboxylic acid derivative
will normally be administered to a warm-blooded animal at a unit
dose within the range 5-5000 mg per square meter body area of the
animal, i.e. approximately 0.1-100 mg/kg, and this normally
provides a therapeutically-effective dose. A unit dose form such as
a tablet or capsule will usually contain, for example 1-250 mg of
active ingredient. Preferably a daily dose in the range of 1-100
mg/kg is employed. However the daily dose will necessarily be
varied depending upon the host treated, the particular route of
administration, and the severity of the illness being treated.
Accordingly the optimum dosage may be determined by the
practitioner who is treating any particular patient.
[0033] According to a further aspect of the present invention there
is provided an aromatic dicarboxylic acid derivative of the formula
I as defined hereinbefore for use in a method of treatment of the
human or animal body by therapy. It has now been found that the
compounds of the present invention possess anti-cell-proliferation
properties due to inhibition of histone deacetylase. Accordingly
the compounds of the present invention provide a method for
treating the proliferation of malignant cells. These compounds are
useful in the treatment of cancer by providing an
anti-proliferative effect, particularly in the treatment of cancers
of the breast, lung, colon, rectum, stomach, prostate, bladder,
pancreas and ovary. It is in addition expected that a derivative of
the present invention will possess activity against a range of
leukemias, lymphoid malignancies and solid tumors such as
carcinomas and sarcomas in tissues such as the liver, kidney,
prostate and pancreas.
[0034] Thus according to this aspect of the invention there is
provided the use of an aromatic dicarboxylic acid derivative of the
formula I, or a pharmaceutically-acceptable salt thereof, as
defined herein in the manufacture of a medicament for use in the
production of an anti-cell-proliferation effect in a warm-blooded
animal such as a human being.
[0035] According to a further feature of this aspect of the
invention there is provided a method for producing an
anti-cell-proliferation effect in a warm-blooded animal, such as
man, in need of such treatment which comprises administering to
said animal an effective amount of an aromatic dicarboxylic acid
derivative as defined hereinbefore.
[0036] The anti-cell-proliferation treatment defined hereinbefore
may be applied as a sole therapy or may involve, in addition to the
aromatic dicarboxylic acid derivative of the invention, one or more
other anti-tumor substances, for example those selected from, for
example, mitotic inhibitors, for example vinblastine; alkylating
agents, for example cis-platin, carboplatin and cydophosphamide;
inhibitors of microtubule assembly, like paclitaxel or other
taxanes; antimetabolites, for example 5-fluorouracil, capecitabine,
cytosine arabinoside and hydroxyurea, or, for example,
intercalating antibiotics, for example adriamycin and bleomycin;
immunostimulants, for example trastuzumab; DNA synthesis
inhibitors, e.g. gemcitabine; enzymes, for example asparaginase;
topoisomerase inhibitors, for example etoposide; biological
response modifiers, for example interferon; and anti-hormones, for
example antioestrogens such as tamoxifen or, for example
antiandrogens such as
(4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trif-
luoromethyl)-propionanilide, or other therapeutic agents and
principles as described in, for example, Cancer: Principles &
Practice of Oncology, Vincent T. DeVita, Jr., Samuel Hellmann,
Steven A. Rosenberg; 5th Ed., Lippincott-Raven Publishers 1997.
Such conjoint treatment may be achieved by way of the simultaneous,
sequential or separate dosing of individual components of the
treatment. According to this aspect of the invention there is
provided a pharmaceutical product comprising an aromatic
dicarboxylic acid derivative of the formula I as defined
hereinbefore and an additional anti-tumor substance as defined
hereinbefore for the conjoint treatment of cancer.
[0037] Another object of the present invention is a pharmaceutical
composition containing a therapeutically effective amount of one or
more compounds of the invention in admixture with pharmaceutically
acceptable excipients and/or diluents.
[0038] Examples for physiologically acceptable salts of compounds
of formula I are salts with physiologically acceptable bases. These
salts can be, among others, alkali, earth alkali, ammonium and
alkylammonium salts, for example sodium, potassium, calcium,
tetra-methyl-ammonium salts.
[0039] The compounds of formula I may exist in a racemic mixture.
The separation of racemic compounds into their enantiomers can be
performed by chromatography on an analytical, semipreparative or
preparative scale using suitable optically active stationary phases
with suitable eluents. Suitable optically active stationary phases
include, but are not limited to, silica (e.g. ChiraSper, Merck;
Chiralpak OT/OP, Baker), cellulose esters or carbamates (e.g.
Chiracel OB/OY, Baker) or others (e.g. Crownpak, Daicel or Chiracel
OJ-R, Baker). Other methods for the separation of enantiomers can
also be applied, like the formation of diastereomeric compounds
from compounds of the formula I together with other optically
active compounds, e.g. camphorsulfonic acid or brucin, and
separation of these diastereomeric compounds, followed by the
liberation from the optically active agent. Enantiomerically
enriched or pure compounds of formula I are also obtainable by the
usage of optically active starting materials.
[0040] Preparation of the Compounds of the Invention
[0041] An aromatic dicarboxylic acid derivative of the formula I,
or a pharmaceutically-acceptable salt thereof, may be prepared by
any process known to be applicable to the preparation of
chemically-related compounds. Such processes, when used to prepare
an aromatic dicarboxylic acid derivative of the formula I, or a
pharmaceutically-acceptable salt thereof, are provided as a further
feature of the invention and are illustrated by the following
representative examples in which, unless otherwise stated, A, R1
and R2 have any of the meanings defined above. Necessary starting
materials may be obtained by standard procedures of organic
chemistry. The preparation of such starting materials is described
within the accompanying non-limiting examples. Alternatively
necessary starting materials are obtainable by analogous procedures
to those illustrated which are within the ordinary skill of an
organic chemist.
[0042] (a) One preferred method for the production of compounds of
the formula I involves the reaction of compounds of the formula II
4
[0043] wherein A, R1 and R2 have the meaning defined above and R3
is a (1-4C)alkyl group, preferably a methyl or ethyl group, with
hydroxylamine in the presence of a suitable base. The reaction is
carried out in an inert solvent or diluent such as methanol or
ethanol at temperatures between 0.degree. C. and 100.degree. C.,
conveniently at or near ambient temperature, and at a pH between 10
and 12. A suitable base is, for example, an alcoholate, for
example, sodium methylate.
[0044] Compounds of formula II are prepared from compounds of the
formula III wherein A and R3 have the meaning defined hereinbefore
5
[0045] This reaction typically involves a two-step one-pot
procedure. In the first step, the carboxylate of the formula III
becomes activated. This reaction is carried out in an inert solvent
or diluent, for example, in dichloromethane, dioxane, or
tetrahydrofuran, in the presence of an activating agent. A suitable
reactive derivative of an acid is, for example, an acyl halide, for
example an acyl chloride formed by the reaction of the acid and an
inorganic acid chloride, for example thionyl chloride; a mixed
anhydride, for example an anhydride formed by the reaction of the
acid and a chloroformate such as isobutyl chloroformate; an active
ester, for example an ester formed by the reaction of the acid and
a phenol such as pentafluorophenol; an active ester formed by the
reaction of the acid and N-hydroxybenzotriazole; an acyl azide, for
example an azide formed by the reaction of the acid and an azide
such as diphenylphosphoryl azide; an acyl cyanide, for example a
cyanide formed by the reaction of an acid and a cyanide such as
diethylphosphoryl cyanide; or the product of the reaction of the
acid and a carbodiimide such as dicyclohexylcarbodiimide, or the
product of the reaction of the acid and
bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. The reaction is
carried out between -30.degree. C. and 60.degree. C., conveniently
at or below 0.degree. C. In the second step, an amine of the
formula HNR1R2 in which R1 and R2 have the meaning defined
hereinbefore is added to the solution, at the temperature used for
the activation, and the temperature is slowly adjusted to ambient
temperature. An appropriate scavenger base like e.g. triethylamine,
or diisopropyethlyamine may be added to the reaction mixture. These
methods are well known to those skilled in the art. In principle,
all methods for the synthesis of amides as used in peptide
chemistry as described in e.g. "Methoden der organischen Chemie
(Houben-Weyl)" Vol. XV/1 and XV/2 are also applicable.
[0046] There are quite a few compounds of formula III described in
the literature. For example, the prototypic terephthalic
monomethylester is described in e.g. Z. Phys. Chem.(Leipzig) 262
(3) (1981) 445-448. It is also commercially available.
Thiophene-2,5-dicarboxylic acid monomethyl ester is described in
e.g. U.S. Pat. No. 2,680,731. These monoesters are usually prepared
by selective saponification of the diester, but other method may be
useful as well and are well known to those skilled in the art.
[0047] (b) Another preferred method for the preparation of
compounds of the formula I is the deprotection of compounds of the
formula IV 6
[0048] wherein Y is a suitable protecting group and A, R1 and R2
have the meaning defined hereinbefore.
[0049] Compounds of the formula IV are new and included within the
scope of the present invention.
[0050] Suitable protecting groups may be the benzyl-,
p-methoxybenzyl-, tert.butyloxy-carbonyl-, trityl-, or silyl groups
such as the trimethylsilyl- or dimethyl-tert.butylsilyl-group. The
reactions carried out depend on the type of the protecting group.
When the protecting group is a benzyl- or p-methoxybenzyl group,
the reaction carried out is a hydrogenolysis in an inert solvent
such as an alcohol like methanol or ethanol, in the presence of a
noble metal catalyst such as palladium on a suitable carrier such
as carbon, barium sulfate, or barium carbonate, at ambient
temperature and pressure. When the protecting group is the
tert.butyloxycarbonyl-, trityl-, or a silyl group such as the
trimethylsilyl- or dimethyl-tert.butylsilyl-group, the reaction is
carried out in the presence of acids at a temperature between
-20.degree. C. and 60.degree. C., preferably between 0.degree. C.
and ambient temperature. The acid may be a solution of hydrochloric
acid in an inert solvent such as diethyl ether or dioxane, or
trifluoro acetic acid in dichloromethane. When the protecting group
is a silyl group such as the trimethylsilyl or
dimethyl-tert.butylsilyl group, the reaction can also be carried
out in the presence of a fluoride source such as sodium fluoride or
tetrabutyl ammonium fluoride in an inert solvent such as
dichloromethane. Not necessarily all protecting groups Y are
compatible with all groups R1 or R2. In cases where the features of
these groups do not allow the usage of a certain protecting group,
other protecting groups Y or other methods of preparation need to
be applied.
[0051] Compounds of formula IV are obtained from the reaction of
compounds of formula V 7
[0052] with a compound of the formula VI 8
[0053] wherein Y is a suitable protecting group as described above.
This reaction typically involves a two-step one-pot procedure. In
the first step, the carboxylate of the formula V becomes activated.
This reaction is carried out in an inert solvent or diluent, for
example, in dichloromethane, dioxane, or tetrahydrofuran, in the
presence of an activating agent. A suitable reactive derivative of
an acid is, for example, an acyl halide, for example an acyl
chloride formed by the reaction of the acid and an inorganic acid
chloride, for example thionyl chloride; a mixed anhydride, for
example an anhydride formed by the reaction of the acid and a
chloroformate such as isobutyl chloroformate; an active ester, for
example an ester formed by the reaction of the acid and a phenol
such as pentafluorophenol; an active ester formed by the reaction
of the acid and N-hydroxybenzotriazole; an acyl azide, for example
an azide formed by the reaction of the acid and an azide such as
diphenylphosphoryl azide; an acyl cyanide, for example a cyanide
formed by the reaction of an acid and a cyanide such as
diethylphosphoryl cyanide; or the product of the reaction of the
acid and a carbodiimide such as dicyclohexylcarbodiimide, or the
product of the reaction of the acid and
bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. The reaction is
carried out between -30.degree. C. and 60.degree. C., conveniently
at or below 0.degree. C. In the second step, compound VI is added
to the solution, at the temperature used for the activation, and
the temperature is slowly adjusted to ambient temperature. These
methods are well known to those skilled in the art. In principle,
all methods for the synthesis of amides as used in peptide
chemistry as described in e.g. "Methoden der organischen Chemie
(Houben-Weyl)" Vol. XV/1 and XV/2 are also applicable.
[0054] Compounds of the formula V are prepared from compounds of
the formula II by hydrolysis. The conditions under which the
hydrolysis is carried out depend on the nature of the group R3.
When R3 is a methyl or ethyl group, the reaction is carried out in
the presence of a base, for example, lithium hydroxide, sodium
hydroxide, or potassium hydroxide in an inert solvent or diluent,
for example, in methanol or ethanol. When R3 is the tert.butyl
group, the reaction is carried out in the presence of an acid, for
example, a solution of hydrochloric acid in an inert solvent such
as diethyl ether or dioxane, or trifluoroacetic acid in
dichloromethane. When R3 is the benzyl group, the reaction is
carried out by hydrogenolysis in the presence of a noble metal
catalyst such as palladium or platinum on a suitable carrier, such
as carbon. Not necessarily all methods of hydrolysis are compatible
with all groups R1 or R2. In cases where the features of these
groups do not allow the usage of a certain method of hydrolysis,
other methods of preparation need to be applied.
[0055] (c) Another preferred method for the preparation of
compounds of the formula I is the reaction of a compound of the
formula V with hydroxylamine. This reaction typically involves a
two-step one-pot procedure. In the first step, the carboxylate of
the formula V becomes activated. This reaction is carried out in an
inert solvent or diluent, for example, in dichloromethane, dioxane,
or tetrahydrofuran, in the presence of an activating agent. A
suitable reactive derivative of an acid is, for example, an acyl
halide, for example an acyl chloride formed by the reaction of the
acid and an inorganic acid chloride, for example thionyl chloride;
a mixed anhydride, for example an anhydride formed by the reaction
of the acid and a chloroformate such as isobutyl chloroformate; an
active ester, for example an ester formed by the reaction of the
acid and a phenol such as pentafluorophenol; an active ester formed
by the reaction of the acid and N-hydroxybenzotriazole; an acyl
azide, for example an azide formed by the reaction of the acid and
an azide such as diphenylphosphoryl azide; an acyl cyanide, for
example a cyanide formed by the reaction of an acid and a cyanide
such as diethylphosphoryl cyanide; or the product of the reaction
of the acid and a carbodiimide such as dicyclohexylcarbodiimide, or
the product of the reaction of the acid and
bis-(2-oxo-3-oxazolidinyl)-phosphorylchloride. The reaction is
carried out between -30.degree. C. and 60.degree. C., conveniently
at or below 0.degree. C. In the second step, hydroxylamine is added
to the solution, at the temperature used for the activation, and
the temperature is slowly adjusted to ambient temperature. These
methods are well known to those skilled in the art. In principle,
all methods for the synthesis of amides as used in peptide
chemistry as described in e.g. "Methoden der organischen Chemie
(Houben-Weyl)" Vol. XV/1 and XV/2 are also applicable.
[0056] (d) Compounds of formula I can also be prepared with methods
of solid phase supported synthesis. Terephthalic acid or
2,5-thiophenedicarboxylic acid is reacted with a hydroxylamine
moiety (--O--NH.sub.2) bound to a resin, e.g. a Wang resin
(Wang-O--NH.sub.2 resin was supplied by EMC microcollections,
Tubingen) to form a resin-bound hydroxamic acid. The second
carbonic acid moiety is reacted with an amine by standard methods
of amide formation as described in e.g. "Methoden der organischen
Chemie (Houben-Weyl)" Vol. XV/1 and XV/2. After this, the
hydroxamic acid is liberated from the solid support. This can be
done for example with TFA. The crude product can be purified by
LC-MS, if necessary.
[0057] The invention will now be illustrated in the following
non-limiting examples in which, unless otherwise stated:
[0058] (i) evaporations were carried out by rotary evaporation in
vacuo and work-up procedures were carried out after removal of
residual solids such as drying agents by filtration;
[0059] (ii) operations were carried out at ambient temperature,
that is in the range 18-25.degree. C. and under an atmosphere of an
inert gas such as argon or nitrogen;
[0060] (iii) column chromatography (by the flash procedure) and
high pressure liquid chromatography (HPLC) were performed on Merck
Kieselgel silica or Merck Lichroprep RP-18 reversed-phase silica
obtained from E. Merck, Darmstadt, Germany;
[0061] (iv) yields are given for illustration only and are not
necessarily the maximum attainable;
[0062] (v) melting points were determined using a Mettler SP62
automatic melting point apparatus, an oil-bath apparatus or a
Kofler hot plate apparatus.
[0063] (vi) the structures of the end-products of the formula I
were confirmed by nuclear (generally proton) magnetic resonance
(NMR) and mass spectral techniques (Micromass Platform II machine
using APCI or Micromass Platform ZMD using electrospray);
[0064] (vii) intermediates were not generally fully characterized
and purity was assessed by thin layer chromatography;
[0065] (viii) the examples were actually performed; and
[0066] (viv) the following abbreviations have been used:
[0067] DMF, N,N-dimethylformamide;
[0068] DMSO, dimethylsulphoxide;
[0069] THF, tetrahydrofuran;
[0070] MeOH, methanol;
[0071] HCl, hydrochloric acid;
[0072] NaH, sodium hydride
[0073] CH.sub.2Cl.sub.2, dichloromethane;
[0074] H.sub.2SO.sub.4, sulphuric acid
[0075] sat., saturated
[0076] sol., solution
[0077] rt, room temperature
[0078] eq, equivalent
EXAMPLE 1
Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(naphthalen-1-ylethyl)-a- mide] (1a)
[0079] 1.9 g Thiophene-2,5-dicarboxylic acid monomethyl ester and
1.2 mL N-methylmorpholine is dissolved in 20 mL of CH.sub.2Cl.sub.2
at -10.degree. C. To this solution is added 1.5 mL isobutyl
chloroformate. After 10 min of stirring, 1.7 mL
1-(aminomethyl)-naphthalene in 5 mL of CH.sub.2Cl.sub.2 is added.
The cooling bath is removed and the reaction mixture is allowed to
reach rt. After 90 min, 10 mL of water and 10 mL 2N HCl are added.
The phases are separated, and the organic phase is washed with
water. After evaporation of the solvent there is obtained 4.4 g
crude 5-[(naphtalen-1-ylmethyl)-carbamoyl]-thiophene-2-carboxylic
acid methyl ester (1b) which is purified by recrystalisation from
ethylacetate, petrol ether, yielding 58%, mp 125.degree. C.
[0080] To a solution of 550 mg hydroxylamine hydrochloride in 8 mL
MeOH is added 2/3 of a solution of 275 mg of sodium in 8 mL of
MeOH. To this, a solution of 1.30 g
5-[(naphtalen-1-ylmethyl)-carbamoyl]-thiophene-2-carbo- xylic acid
methyl ester (1b) in 30 mL MeOH is added, followed by the remaining
sodium methylate solution. After stirring for 4 h at rt the solvent
is evaporated. 20 mL of water are added, acidified with 4 mL 50%
acetic acid, and the precipitate is collected by filtration. After
trituration with THF there is obtained 0.76 g
thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(naphthalen-1-ylmethyl)-amide] (1a) as a white powder, mp
170.degree. C.
EXAMPLE 2
Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-(4-trifluoromethyl-benzyl- amide) (2a)
[0081] 2a is prepared from thiophene-2,5-dicarboxylic acid
monomethyl ester in an analogous manner to that described for the
preparation of 1a example 1. The last step yields 40% of
thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-(4-trifluoromethyl-benzylamide) (2a), mp. 172-174.degree. C.
EXAMPLE 3
N-hydroxy-N'-naphthalen-1-ylmethyl-terephthalamide (3a)
[0082] 1 eq of Wang-O--NH.sub.2 is shaken with 11 eq of
terephthalic acid, 5.5 eq N,N'-diisopropylcarbodiimide, 5.5 eq
1-hydroxybenzotriazole and 25 eq diisopropylethylamine in DMF for 4
h at 25.degree. C. After that, the resin is washed with DMF (5
times), MeOH (3 times), THF (3 times), CH.sub.2Cl.sub.2 (3 times)
and diethylether (3 times). The resin is then shaken with 5 eq
pentafluorophenyl trifluoroacetate and 10 eq pyridine. After that,
the resin is washed with DMF (2 times), followed by
CH.sub.2Cl.sub.2 (2 times), followed by diethylether (2 times). The
resin is then shaken with 5 eq of naphtalenemethylamine, 10 eq of
diisopropylethylamine and 1 eq of 1-hydroxybenzotriazole. It is
then shaken with 5 eq pentafluorophenyl trifluoroacetate and 10 eq
pyridine. After that, the resin is washed with DMF (2 times),
followed by CH.sub.2Cl.sub.2 (2 times). To liberate the product
from the solid support, the resin is shaken with 50% TFA in dry
CH.sub.2Cl.sub.2 with 5% triisopropylsilane added at rt for 1 h.
The liquid phase is filtered, the resin washed with
CH.sub.2Cl.sub.2 (3 times), and the combined filtrates are
evaporated. The crude product is dissolved in tert-butanol/H.sub.2O
(80:20) and freeze-dried. To neutralize any remaining TFA, 100
.mu.L of a 25% NH.sub.4OH-sol is added and freeze-dried, again. The
remaining solid is purified by preparative LC-MS to
N-hydroxy-N'-naphthalen-1-ylmethyl-te- rephthalamide, MS (APCI):
321.1 (M+1)
EXAMPLE 4
[0083] Thiophene-2,5-dicarboxylic acid
2-(3-chloro-benzylamide)5-hydroxyam- ide (4a)
[0084] 9.0 g Thiophene-2,5-dicarboxylic acid monomethyl ester is
refluxed in 30 mL of thionylchloride until gas evolution has
ceased. The mixture is evaporated and the residue is slowly added
to a solution of 10.3 g 3-chlorobenzylamine and 20 g triethylamine
in 180 mL CH.sub.2Cl.sub.2 at 0.degree. C. After 15 min the cooling
bath is removed and the reaction mixture is allowed to reach rt.
After 2 h it is quenched with water, the phases are separated, and
the aqueous phase is extracted with CH.sub.2Cl.sub.2. The combined
organic phases are dried with Na.sub.2SO.sub.4 and evaporated
yielding a crude product. This is purified by recrystallisation
from diethylether/heptane yielding 13.9 g (93%) crude
5-[(3-chlorobenzyl)-carbamoyl]-thiophene-2-carboxylic acid methyl
ester (4b), mp 91-93.degree. C. To a solution of 2.9 g
hydroxylamine hydrochloride in 45 mL MeOH is added 25 mL of a
solution of 1.4 g sodium in 40 mL of MeOH. To this, a solution of
6.4 g ester 4b in 30 mL MeOH is added, followed by the remaining 15
mL of the sodium methylate solution. After stirring for 3 h at rt
the solution is acidified with 1N HCl and some ethylacetate is
added. Thiophene-2,5-dicarboxylic acid 2-(3-chloro-benzylamide)
5-hydroxyamide (4a) precipitates as a white solid; 4.7 g, 73%, mp.
183.degree. C.
EXAMPLE 5
Thiophene-2,5-dicarboxylic acid
2-(3,5-dimethyl-benzylamide)5-hydroxyamide (5a)
[0085] 5a is prepared from thiophene-2,5-dicarboxylic acid
monomethyl ester in an analogous manner to that described for the
preparation of 4a example 4. MS (APCI): 305.3 (M+1)
EXAMPLE 6
Thiophene-2,5-dicarboxylic acid 2-hexylamide 5-hydroxyamide
(6a)
[0086] 6a is prepared from thiophene-2,5-dicarboxylic acid
monomethyl ester in an analogous manner to that described for the
preparation of 4a example 4, mp 171-173.degree. C.
EXAMPLE 7
Thiophene-2,4-dicarboxylic acid
2-(3,5-dimethyl-benzylamide)4-hydroxyamide (7a)
[0087] 0.5 g 2-carboxy-thiophen-4-carboxylic acid ethyl ester (M.
Janda, J. Srogl, M. Nemec, I. Stibor; Org. Prep. and Proced. Int. 3
(6) (1971)295.) and 0.67 g
N'-(3-dimethylaminopropyl)-N-ethylcarbodiimid.time- s.HCl are
stirred in 50 mL DCM for 15 min. Then, 0.338 g
3,5-dimethylbenzylamin are added and the mixture is stirred
overnight. The solution is extracted with 2N HCl and water, then
evaporated. The residue is titurated with isohexan, and the
resulting crystals are filtrated and air-dried, yielding 0.58 g
(73%) crude 5-(3,5-Dimethyl-benzylcarbamoyl)-thiophene-3-carboxylic
acid ethyl ester (7b). This ester in converted to title compound by
reaction with hydroxylamine hydrochloride in a manner similar to
that described for the conversion of 4b into 4a in example 4. After
chromatography (silica, ethylacetate), thiophene-2,4-dicarboxylic
acid 2-(3,5-dimethyl-benzylamid- e)4-hydroxyamide (7a) is obtained
as crystals; 44 mg, 9%, mp: 181.degree. C. (decomp.).
EXAMPLE 8
Thiophene-2,4-dicarboxylic acid
2-(3-chloro-benzylamide)4-hydroxyamide (8a)
[0088] 8a is prepared from 2-carboxy-thiophen-4-carboxylic acid
ethyl ester in an analogous manner to that described for the
preparation of 7a example 7; 163 mg, 34%, mp: 90.degree. C.
(decomp.).
EXAMPLE 9
Thiophene-2,4-dicarboxylic acid 4-hydroxyamide
2-(4-trifluoromethyl-benzyl- amide) (9a)
[0089] 9a is prepared from 2-carboxy-thiophen-4-carboxylic acid
ethyl ester in an analogous manner to that described for the
preparation of 7a example 7; 56 mg, 10%, mp: 174-177.degree. C.
EXAMPLE 10
Thiophene-2,4-dicarboxylic acid 2-[(benzo
[1,3]dioxol-5-ylmethyl)-amide]4-- hydroxyamide (10a)
[0090] 10a is prepared from 2-carboxy-thiophen-4-carboxylic acid
ethyl ester in an analogous manner to that described for the
preparation of 7a example 7; 16 mg, 3%, mp: 182.degree. C.
(decomp.).
EXAMPLE 11
Thiophene-2,4-dicarboxylic acid 2-hexylamide 4-hydroxyamide
(11a)
[0091] 11a is prepared from 2-carboxy-thiophen-4-carboxylic acid
ethyl ester in an analogous manner to that described for the
preparation of 7a example 7; 92 mg, 20%, mp: 150.degree. C.
(decomp.).
EXAMPLE 12
Thiophene-2,4-dicarboxylic acid
4-(3,5-dimethyl-benzylamide)2-hydroxyamide (12a)
[0092] 5.0 g 2-carboxy-thiophen-4-carboxylic acid ethyl ester (Org.
Prep. and Proced. Int. 3 (6) (1971) 295) is dissolved in 50 mL THF
and 4.5 g thionylchloride is added. After refluxing for 4 h, the
mixture is evaporated. The crude acid chloride is added to a
solution of 3.1 g O-benzylhydroxylamine and 3.06 g triethylamine in
80 mL DCM. After stirring for 4 h the solution is washed with 2N
HCl and water, dried and evaporated. After titurating the residue
with isohexan/diethylether, bright crystals of
5-benzyloxycarbamoyl-thiophene-3-carboxylic acid ethyl ester (12b)
are obtained, which are filtered and air-dried; 3.5 g, 46%. 0.46 g
NaOH are dissolved in 45 mL ethanol and 5 mL water. The ester 12b
is added and the solution refluxed for 2 h. After cooling, the
ethanol is evaporated and the aqueous phase extracted with
diethylether. The aqueous phase is acidified with 2N HCl and the
precipitate formed is collected by filtration, yielding 2.8 g (88%)
5-benzyloxycarbamoyl-thiophene-3-carboxy- lic acid (12c) as a
solid.
[0093] 0.4 g 5-benzyloxycarbamoyl-thiophene-3-carboxylic acid (12c)
is dissolved in 50 mL DCM, and 0.387 g
N'-(3-dimethylaminopropyl)-N-ethylcar- bodiimid.times.HCl are
added. After stirring for 15 min, 0.195 g 3,5-dimethylbenzylamine
is added, and the mixture is stirred overnight.
[0094] The solution is extracted with 2N HCl and water, then
evaporated. The residue is titurated with ether/isohexan, and the
resulting crystals are filtrated and air-dried, yielding 0.44 g
(77%) of thiophene-2,4-dicarboxylic acid
2-(benzyloxy-amide)4-(3,5-dimethyl-benzyl- amide) (12d). This is
hydrogenated in a 1:1 mixture of THF and MeOH using Pd/CaSO.sub.4/C
and purified by preparative HPLC/MS yielding 12a: MS (APCI): 303.1
(M-1).
EXAMPLE 13
[0095] In an analogous manner to that described in the example 12,
the following compounds are prepared:
[0096] 1. Thiophene-2,4-dicarboxylic acid
4-(3-chloro-benzylamide)2-hydrox- yamide
[0097] 2. Thiophene-2,4-dicarboxylic acid 4-hexylamide
2-hydroxyamide
EXAMPLE 14
4-{[(5-Hydroxycarbamoyl-thiophene-2-carbonyl)-amino]-methyl}-benzoic
acid methyl ester
[0098] In an analogous manner to that described in the example 12,
but using 2-carboxy-thiophen-5-carboxylic acid methyl ester and
methyl 4-(aminomethyl)-benzoate as starting material,
4-{[(5-Hydroxycarbamoyl-th-
iophene-2-carbonyl)-amino]-methyl}-benzoic acid methyl ester is
prepared, mp.: 156-166.degree. C.
EXAMPLE 15
[0099] In an analogous manner to that described in the example 1,
and using known methods as described in the literature (e.g. in
standard works such as Houben-Weyl, "Methoden der Organischen
Chemie, Georg Thieme Verlag", Stuttgart; Organic Reactions, John
Wiley & Sons, Inc., New York) the following compounds are
prepared and characterized with MS (APCI):
[0100] 1.
5-(4-benzhydryl-piperazine-1-carbonyl)-thiophene-2-carboxylic acid
hydroxyamide
[0101] 2. thiophene-2,5-dicarboxylic acid 2-benzylamide
5-hydroxyamide
[0102] 3. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(3-methyl-butyl)-amide]
[0103] 4. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-(phenethyl-amide)
[0104] 5. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-{[2-(4-methoxy-phenyl)-ethyl]-amide}
[0105] 6. thiophene-2,5-dicarboxylic acid
2-(4-fluoro-benzylamide)5-hydrox- yamide
[0106] 7. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(1,2,3,4-tetrahydro-naphthalen-1-yl)-amide]
[0107] 8. thiophene-2,5-dicarboxylic acid
2-(2-ethoxy-benzylamide)5-hydrox- yamide
[0108] 9. thiophene-2,5-dicarboxylic acid
2-(2,4-difluoro-benzylamide)5-hy- droxyamide
[0109] 10. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-indan-1-ylamide
[0110] 11. thiophene-2,5-dicarboxylic acid
2-[(benzo[1,3]dioxol-5-ylmethyl- )-amide]5-hydroxyamide
[0111] 12.
5-(4-phenyl-piperazine-1-carbonyl)-thiophene-2-carboxylic acid
hydroxyamide
[0112] 13. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(3-isopropoxy-propyl)-amide]
[0113] 14.
5-(4-acetyl-piperazine-1-carbonyl)-thiophene-2-carboxylic acid
hydroxyamide
[0114] 15. thiophene-2,5-dicarboxylic acid 2-dibutylamide
5-hydroxyamide
[0115] 16.
5-(4-benzyl-piperidine-1-carbonyl)-thiophene-2-carboxylic acid
hydroxyamide
[0116] 17. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(pyridin-3-ylmethyl)-amide]
[0117] 18. thiophene-2,5-dicarboxylic acid 2-cyclohexylamide
5-hydroxyamide
[0118] 19. thiophene-2,5-dicarboxylic acid 2-cyclopropylamide
5-hydroxyamide
[0119] 20. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-{[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide}
[0120] 21. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-(2-methoxy-benzylamide)
[0121] 22. thiophene-2,5-dicarboxylic acid
2-[(2-cyclohex-1-enyl-ethyl)-am- ide]5-hydroxyamide
[0122] 23. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(2-morpholin-4-yl-ethyl)-amide]
[0123] 24. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(2-methylsulfanyl-ethyl)-amide]
[0124] 25. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(tetrahydro-furan-2-ylmethyl)-amide]
[0125] 26. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-phenylamide
[0126] 27. 5-(morpholine-4-carbonyl)-thiophene-2-carboxylic acid
hydroxyamide
[0127] 28. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(4-methoxy-phenyl)-amide]
[0128] 29. 5-(pyrrolidine-1-carbonyl)-thiophene-2-carboxylic acid
hydroxyamide
[0129] 30. thiophene-2,5-dicarboxylic acid
2-[(4-benzyloxy-phenyl)-amide]5- -hydroxyamide
[0130] 31. thiophene-2,5-dicarboxylic acid
2-[(4-chloro-phenyl)-amide]5-hy- droxyamide
[0131] 32. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(4-iodo-phenyl)-amide]
[0132] 33. thiophene-2,5-dicarboxylic acid
2-[(3-ethyl-phenyl)-amide]5-hyd- roxyamide
[0133] 34. thiophene-2,5-dicarboxylic acid
2-[(4-ethyl-phenyl)-amide]5-hyd- roxyamide
[0134] 35. thiophene-2,5-dicarboxylic acid
2-[(3-chloro-phenyl)-amide]5-hy- droxyamide
[0135] 36. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(3-iodo-phenyl)-amide]
[0136] 37.
5-(1,4-dioxa-8-aza-spiro[4.5]decane-8-carbonyl)-thiophene-2-car-
boxylic acid hydroxyamide
[0137] 38. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(3-morpholin-4-yl-propyl)-amide]
[0138] 39. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-pentylamide
[0139] 40. thiophene-2,5-dicarboxylic acid
2-[(2-diethylamino-ethyl)-amide- ]5-hydroxyamide
[0140] 41. thiophene-2,5-dicarboxylic acid 2-heptylamide
5-hydroxyamide
[0141] 42. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-(isobutyl-amide)
[0142] 43. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-nonylamide
[0143] 44. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(1-phenyl-ethyl)-amide]
[0144] 45. thiophene-2,5-dicarboxylic acid
2-[2-(4-fluoro-phenyl)-ethyl]-a- mide 5-hydroxyamide
[0145] 46. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[2-(5-nitro-pyridin-2-ylamino)-ethyl]-amide
[0146] 47. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-(3-methyl-benzylamide)
[0147] 48. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(2-p-tolyl-ethyl)-amide]
[0148] 49. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide
[0149] 50. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(2-piperidin-1-yl-ethyl)-amide]
[0150] 51. thiophene-2,5-dicarboxylic acid 2-cyclobutylamide
5-hydroxyamide
[0151] 52. thiophene-2,5-dicarboxylic acid
2-(2-fluoro-benzylamide)5-hydro- xyamide
[0152] 53. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(2-phenyl-propyl)-amide]
[0153] 54. thiophene-2,5-dicarboxylic acid
2-(2,3-dimethoxy-benzylamide)5-- hydroxyamide
[0154] 55. thiophene-2,5-dicarboxylic acid
2-[(1-benzyl-piperidin-4-yl)-am- ide]5-hydroxyamide
[0155] 56.
4-[(5-hydroxycarbamoyl-thiophene-2-carbonyl)-amino]-piperidine--
1-carboxylic acid ethyl ester
[0156] 57. thiophene-2,5-dicarboxylic acid
2-[(3-dimethylamino-2,2-dimethy- l-propyl)-amide]5-hydroxyamide
[0157] 58. thiophene-2,5-dicarboxylic acid
2-[(3-ethoxy-propyl)-amide]5-hy- droxyamide
[0158] 59. thiophene-2,5-dicarboxylic acid
2-[(3-dimethylamino-propyl)-ami- de]5-58
[0159] 60. thiophene-2,5-dicarboxylic acid
2-[2-(2-chloro-phenyl)-ethyl]-a- mide 5-hydroxyamide
[0160] 61. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-(2-trifluoromethyl-benzylamide)
[0161] 62. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-(3-trifluoromethyl-benzylamide)
[0162] 63. thiophene-2,5-dicarboxylic acid
2-(2,5-difluoro-benzylamide)5-h- ydroxyamide
[0163] 64. thiophene-2,5-dicarboxylic acid
2-(2,6-difluoro-benzylamide)5-h- ydroxyamide
[0164] 65. thiophene-2,5-dicarboxylic acid
2-(3,4-difluoro-benzylamide)5-h- ydroxyamide
[0165] 66. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(3-imidazol-1-yl-propyl)-amide]
[0166] 67. thiophene-2,5-dicarboxylic acid
2-[(1-cyclohexyl-ethyl)-amide]5- -hydroxyamide
[0167] 68. thiophene-2,5-dicarboxylic acid
2-[2-(3-chloro-phenyl)-ethyl]-a- mide 5-hydroxyamide
[0168] 69. thiophene-2,5-dicarboxylic acid
2-[2-(3-fluoro-phenyl)-ethyl]-a- mide 5-hydroxyamide
[0169] 70. thiophene-2,5-dicarboxylic acid
2-[2-(2,4-dichloro-phenyl)-ethy- l]-amide 5-hydroxyamide
[0170] 71. thiophene-2,5-dicarboxylic acid
2-cyclopropylmethyl-amide 5-hydroxyamide
[0171] 72. thiophene-2,5-dicarboxylic acid
2-[2-(2-fluoro-phenyl)-ethyl]-a- mide 5-hydroxyamide
[0172] 73. thiophene-2,5-dicarboxylic acid
2-[(4-diethylamino-1-methyl-but- yl)-amide]5-hydroxyamide
[0173] 74. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(2-pyridin-2-yl-ethyl)-amide]
[0174] 75. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(2-pyrrolidin-1-yl-ethyl)-amide]
[0175] 76. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(1-methyl-hexyl)-amide]
[0176] 77. thiophene-2,5-dicarboxylic acid 2-cycloheptylamide
5-hydroxyamide
[0177] 78. thiophene-2,5-dicarboxylic acid 2-cyclopentylamide
5-hydroxyamide
[0178] 79. thiophene-2,5-dicarboxylic acid
2-(2,4-dichloro-benzylamide)5-h- ydroxyamide
[0179] 80. thiophene-2,5-dicarboxylic acid
2-[(3-diethylamino-propyl)-amid- e]5-hydroxyamide
[0180] 81. thiophene-2,5-dicarboxylic acid
2-[(1,5-dimethyl-hexyl)-amide]5- -hydroxyamide
[0181] 82. thiophene-2,5-dicarboxylic acid
2-[(2,2-diphenyl-ethyl)-amide]5- -hydroxyamide
[0182] 83.
3-[(5-hydroxycarbamoyl-thiophene-2-carbonyl)-amino]-butyric acid
ethyl ester
[0183] 84. thiophene-2,5-dicarboxylic acid
2-[(2-ethyl-hexyl)-amide]5-hydr- oxyamide
[0184] 85. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-(4-methoxy-benzylamide)
[0185] 86. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-(4-methyl-benzylamide)
[0186] 87. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(3-phenyl-propyl)-amide]
[0187] 88. thiophene-2,5-dicarboxylic acid
2-[(2-diisopropylamino-ethyl)-a- mide]5-hydroxyamide
[0188] 89. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[2-(4-nitro-phenyl)-ethyl]-amide
[0189] 90. thiophene-2,5-dicarboxylic acid
2-[(3,3-diphenyl-propyl)-amide]- 5-hydroxyamide
[0190] 91. thiophene-2,5-dicarboxylic acid
2-(2-amino-benzylamide)5-hydrox- yamide
[0191] 92. Thiophene-2,5-dicarboxylic acid
2-(4-bromo-benzylamide)5-hydrox- yamide
[0192] 93. Thiophene-2,5-dicarboxylic acid
2-(3,5-bis-trifluoromethyl-benz- ylamide) 5-hydroxyamide
[0193] 94. Thiophene-2,5-dicarboxylic acid
2-(3-bromo-benzylamide)5-hydrox- yamide
[0194] 95. Thiophene-2,5-dicarboxylic acid
2-(3-fluoro-benzylamide)5-hydro- xyamide
[0195] 96. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-(3-methoxy-benzylamide)
[0196] 97. Thiophene-2,5-dicarboxylic acid
2-(2-chloro-6-fluoro-benzylamid- e)5-hydroxyamide
[0197] 98. Thiophene-2,5-dicarboxylic acid
2-(4-tert-butyl-benzylamide)5-h- ydroxyamide
[0198] 99. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-{[2-(4-sulfamoyl-phenyl)-ethyl]-amide}
[0199] 100. Thiophene-2,5-dicarboxylic acid
2-[(2-benzylsulfanyl-ethyl)-am- ide]5-hydroxyamide
[0200] 101. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-{[2-(4-hydroxy-phenyl)-ethyl]-amide}
[0201] 102. Thiophene-2,5-dicarboxylic acid
2-{[2-(4-chloro-phenyl)-ethyl]- -amide}5-hydroxyamide
[0202] 103. Thiophene-2,5-dicarboxylic acid
2-{[2-(3,4-dimethoxy-phenyl)-e- thyl]-amide} 5-hydroxyamide
[0203] 104. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(2-phenoxy-ethyl)-amide]
[0204] 105. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(4-phenyl-butyl)-amide]
[0205] 106. Thiophene-2,5-dicarboxylic acid
2-[(3,4-dimethyl-phenyl)-amide- ]5-hydroxyamide
[0206] 107.
5-(4-Pyrimidin-2-yl-piperazine-1-carbonyl)-thiophene-2-carboxy- lic
acid hydroxyamide
[0207] 108. Thiophene-2,5-dicarboxylic acid
2-[(3,4-dimethoxy-phenyl)-amid- e]5-hydroxyamide
[0208] 109. Thiophene-2,5-dicarboxylic acid
2-[(4-tert-butyl-phenyl)-amide- ]5-hydroxyamide
[0209] 110. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(4-methoxy-2-methyl-phenyl)-amide]
[0210] 111. Thiophene-2,5-dicarboxylic acid
2-[(4-dimethylamino-phenyl)-am- ide]5-hydroxyamide
[0211] 112. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(4-phenoxy-phenyl)-amide]
[0212] 113. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-p-tolylamide
[0213] 114. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(4-piperidin-1-yl-phenyl)-amide]
[0214] 115.
1-(5-Hydroxycarbamoyl-thiophene-2-carbonyl)-piperidine-4-carbo-
xylic acid methyl ester
[0215] 116. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[methyl-(1-methyl-piperidin-4-yl)-amide]
[0216] 117. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-{methyl-[2-(4-nitro-phenyl)-ethyl]-amide}
[0217] 118. Thiophene-2,5-dicarboxylic acid
2-(butyl-methyl-amide)5-hydrox- yamide
[0218] 119. Thiophene-2,5-dicarboxylic acid 2-diethylamide
5-hydroxyamide
[0219] 120. Thiophene-2,5-dicarboxylic acid
2-[(4-cyclohexyl-phenyl)-amide- ]5-hydroxyamide
[0220] 121. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[methyl-(2-methylamino-ethyl)-amide]
[0221] 122. Thiophene-2,5-dicarboxylic acid
2-[ethyl-(3-ethylamino-propyl)- -amide]5-hydroxyamide
[0222] 123.
5-[4-(2-Morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-thi-
ophene-2-carboxylic acid hydroxyamide
[0223] 124.
5-(4-Dimethylcarbamoylmethyl-piperazine-1-carbonyl)-thiophene--
2-carboxylic acid hydroxyamide
[0224] 125.
5-[4-(2-Oxo-2-piperidin-1-yl-ethyl)-piperazine-1-carbonyl]-thi-
ophene-2-carboxylic acid hydroxyamide
[0225] 126. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-(3-trifluoromethoxy-benzylamide)
[0226] 127. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-(3-phenoxy-benzylamide)
[0227] 128. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(1-methyl-3-phenyl-propyl)-amide]
[0228] 129. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(3-methoxy-propyl)-amide]
[0229] 130. Thiophene-2,5-dicarboxylic acid
2-(4-chloro-benzylamide)5-hydr- oxyamide
[0230] 131. Thiophene-2,5-dicarboxylic acid
2-[(2-acetylamino-ethyl)-amide- ]5-hydroxyamide
[0231] 132. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(1-methyl-heptyl)-amide]
[0232] 133. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[(1-methyl-butyl)-amide]
[0233] 134. Thiophene-2,5-dicarboxylic acid 2-allylamide
5-hydroxyamide
[0234] 135. Thiophene-2,5-dicarboxylic acid
2-[(1,3-dimethyl-butyl)-amide]- 5-hydroxyamide
[0235] 136. Thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-propylamide
[0236] 137. Thiophene-2,5-dicarboxylic acid 2-sec-butylamide
5-hydroxyamide
[0237] 138. Thiophene-2,5-dicarboxylic acid 2-butylamide
5-hydroxyamide
[0238] 139. Thiophene-2,5-dicarboxylic acid
2-(3,4-dichloro-benzylamide)5-- hydroxyamide
[0239] 140. Thiophene-2,5-dicarboxylic acid
2-(2,3-dichloro-benzylamide)5-- hydroxyamide
[0240] 141. thiophene-2,5-dicarboxylic acid
2-(2,3-difluoro-benzylamide)5-- hydroxyamide
[0241] 142. thiophene-2,5-dicarboxylic acid
2-(2-chloro-benzylamide)5-hydr- oxyamide
[0242] 143. thiophene-2,5-dicarboxylic acid
2-(3,4-dimethoxy-benzylamide)5- -hydroxyamide
[0243] 144. thiophene-2,5-dicarboxylic acid
2-(3,5-difluoro-benzylamide)5-- hydroxyamide
[0244] 145. thiophene-2,5-dicarboxylic acid
2-[(2-amino-phenyl)-amide]5-hy- droxyamide
[0245] 146. thiophene-2,5-dicarboxylic acid
2-[4-(2-amino-phenylcarbamoyl)-
-benzylamide]5-(benzyloxy-amide)
[0246] 147. thiophene-2,5-dicarboxylic acid 2-hydroxyamide
5-[methyl-(4-trifluoromethyl-benzyl)-amide]
EXAMPLE 16
[0247] In an analogous manner to that described in the example 3,
and using known methods as described in the literature (e.g. in
standard works such as Houben-Weyl, "Methoden der Organischen
Chemie, Georg Thieme Verlag", Stuttgart; Organic Reactions, John
Wiley & Sons, Inc., New York) the following compounds are
prepared and characterized with MS (APCI):
[0248] 1.
4-(4-benzhydryl-piperazine-1-carbonyl)-N-hydroxy-benzamide
[0249] 2. N-hydroxy-N'-pyridin-3-ylmethyl-terephthalamide
[0250] 3. N-benzyl-N'-hydroxy-terephthalamide
[0251] 4. N-cyclohexyl-N'-hydroxy-terephthalamide
[0252] 5. N-cyclopropyl-N'-hydroxy-terephthalamide
[0253] 6. N-hexyl-N'-hydroxy-terephthalamide
[0254] 7. N-hydroxy-N'-(3-methyl-butyl)-terephthalamide
[0255] 8. N-hydroxy-N'-phenethyl-terephthalamide
[0256] 9.
N-hydroxy-N'-[2-(4-methoxy-phenyl)-ethyl]-terephthalamide
[0257] 10. N-(3-chloro-benzyl)-N'-hydroxy-terephthalamide
[0258] 11. N-hydroxy-N'-(2-methoxy-benzyl)-terephthalamide
[0259] 12. N-(4-fluoro-benzyl)-N'-hydroxy-terephthalamide
[0260] 13.
N-hydroxy-N'-(1,2,3,4-tetrahydro-naphthalen-1-yl)-terephthalami-
de
[0261] 14.
N-hydroxy-N'-(4-trifluoromethyl-benzyl)-terephthalamide
[0262] 15. N-(2,4-difluoro-benzyl)-N'-hydroxy-terephthalamide
[0263] 16. N-hydroxy-N'-indan-1-yl-terephthalamide
[0264] 17. N-benzo
[1,3]dioxol-5-ylmethyl-N'-hydroxy-terephthalamide
[0265] 18.
N-hydroxy-4-(4-phenyl-piperazine-1-carbonyl)-benzamide
[0266] 19. N-(3,5-dimethyl-benzyl)-N'-hydroxy-terephthalamide
[0267] 20. N-hydroxy-N'-(3-isopropoxy-propyl)-terephthalamide
[0268] 21.
4-(4-acetyl-piperazine-1-carbonyl)-N-hydroxy-benzamide
[0269] 22. N,N-dibutyl-N'-hydroxy-terephthalamide
[0270] 23.
4-(4-benzyl-piperidine-1-carbonyl)-N-hydroxy-benzamide
[0271] 24.
N-hydroxy-N'-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-terephthalami-
de
[0272] 25. N-(2-ethoxy-benzyl)-N'-hydroxy-terephthalamide
[0273] 26.
N-(2-cyclohex-1-enyl-ethyl)-N'-hydroxy-terephthalamide
[0274] 27.
N-hydroxy-N'-(2-morpholin-4-yl-ethyl)-terephthalamide
[0275] 28.
N-hydroxy-N'-(2-methylsulfanyl-ethyl)-terephthalamide
[0276] 29.
N-hydroxy-N'-(tetrahydro-furan-2-ylmethyl)-terephthalamide
EXAMPLE 17
Evaluation of Effects on a Human Colon Caminoma Cell Line of the
Compounds of the Invention
[0277] MTT (tetrazolium dye proliferation assay) is widely used for
the quantitative determination of cytotoxic effects or in vitro
chemosensitivity of tumor cells. The assay is based on the cleavage
of the yellow tetrazolium salt MTT to purple formazan crystals by
metabolic active cells. For details, see Rubinstein, L. V., et al.,
J. Natl. Cancer Inst. 82 (1990) 1113-1118.
[0278] The following procedure was performed: HT-29 cells (human
colon carcinoma cell line) were cultivated in RPMI 1640, 2.5% FCS,
2 mM Glutamine, 100 u/ml Penicillin, 100 ug/ml Streptomycin. For
the assay the cells were seeded in 384 well plates, 900 cells per
well, in the same medium The next day compounds (dissolved 10 mM in
DMSO) were added in various concentrations ranging from 30 uM to
1.5 nM. After 5 days the MTT assay was done mainly according to the
instructions of the manufacturer (Cell proliferation kit I, MTT,
fom Roche Molecular Biochemicals). In brief: MTT labeling reagent
was added to a final concentration of 0.5 mg/ml, added and
incubated for 4 hrs at 37 C, 5% CO.sub.2. During this incubation
time purple formazan crystals are formed. After addition of the
solubilization solution (20% SDS in 0.02 M HCl) the plates were
incubated overnight at 37 C, 5% CO.sub.2. After careful mixing
plates were measured in Victor 2 (scanning multiwell
spectrophotometer, Wallac) at 550 nm.
[0279] A decrease in number of living cells results in a decrease
in the total metabolic activity in the sample. The decrease
directly correlates to the amount of purple colour resulting from
the solubilization of the purple formazan crystals. Determination
of IC50 was done using XL-fit. The results of this experiment are
provided below in Table 1.
1 TABLE 1 Compounds according to this invention IC50 HT29 [.mu.M]
Example 15, No. 128 0.02 Example 15, No. 81 0.03 Example 15, No.
104 0.04 Example 5 0.05 Example 15, No. 93 0.05 Example 15, No. 94
0.07 Example 15, No. 98 0.07 Example 2 0.11 Example 4 0.14 Example
15, No. 90 0.14 Example 15, No. 139 0.17
EXAMPLE 18
[0280]
2 Tablet formulation Item Ingredients mg/Tablet 1 Compound 2a 25
100 2 Anhydrous Lactose 73 35 3 Croscarmellose 6 8 Sodium 4
Povidone K30 5 6 5 Magnesium Stearate 1 1 Total Weight 110 150
[0281] Compound 2a is described in Example 2.
[0282] Procedure:
[0283] 1. Mix Items 1, 2 and 3 in a suitable mixer for 15
minutes.
[0284] 2. Granulate the powder mix from Step 1 with 20% Povidone
K30 Solution (Item 4).
[0285] 3. Dry the granulation from Step 2 at 50.degree. C.
[0286] 4. Pass the granulation from Step 3 through a suitable
milling equipment.
[0287] 5. Add the Item 5 to the milled granulation Step 4 and mix
for 3 minutes.
[0288] 6. Compress the granulation from Step 5 on a suitable
press.
LIST OF REFERENCES
[0289] Cancer: Principles & Practice of Oncology, Vincent T.
DeVita, Jr., Samuel Hellmann, Steven A. Rosenberg; 5th Ed.,
Lippincott-Raven Publishers 1997
[0290] Houben-Weyl, "Methoden der Organischen Chemie, Georg Thieme
Verlag", Stuttgart; Organic Reactions, John Wiley & Sons, Inc.,
New York
[0291] Houben-Weyl, Methoden der organischen Chemie, Vol. XV/1 and
XV/2
[0292] Koyama, Y., et al., Blood 96 (2000) 1490-1495
[0293] Marks, P. M., et al., J. Natl. Cancer Inst. 92 (2000)
1210-1216
[0294] Org. Prep. and Proced. Int. 3 (6) (1971) 295
[0295] Rubinstein, L. V., et al., J. Natl. Cancer Inst. 82 (1990)
1113-1118
[0296] U.S. Pat. No. 2,680,731
[0297] U.S. Pat. No. 5,369,108
[0298] WO 98/55449
[0299] Z. Phys. Chem.(Leipzig) 262 (3) (1981) 445-448
* * * * *