U.S. patent application number 11/189540 was filed with the patent office on 2006-03-16 for combinations for the treatment of diseases involving cell proliferation.
This patent application is currently assigned to Boehringer Ingelheim International GmbH. Invention is credited to Anke Baum, Gerd Munzert, Martin Steegmaier.
Application Number | 20060058311 11/189540 |
Document ID | / |
Family ID | 35241347 |
Filed Date | 2006-03-16 |
United States Patent
Application |
20060058311 |
Kind Code |
A1 |
Munzert; Gerd ; et
al. |
March 16, 2006 |
Combinations for the treatment of diseases involving cell
proliferation
Abstract
Disclosed are pharmaceutical compositions for the treatment of
diseases which involve cell proliferation. Also disclosed are
methods for the treatment of said diseases, comprising
co-administration of a compound 1 of Formula (I) ##STR1## wherein
the groups L, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have
the meanings given herein and of an effective amount of an active
compound 2 and/or co-treatment with radiation therapy, in a ratio
which provides an additive and synergistic effect, and to the
combined use of a compound 1 of Formula (I) and of an effective
amount of an active compound 2 and/or radiotherapy for the
manufacture of corresponding pharmaceutical combination
preparations.
Inventors: |
Munzert; Gerd; (Ulm, DE)
; Steegmaier; Martin; (Wien, AT) ; Baum; Anke;
(Vienna, AT) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
Boehringer Ingelheim International
GmbH
Ingelheim
DE
|
Family ID: |
35241347 |
Appl. No.: |
11/189540 |
Filed: |
July 26, 2005 |
Current U.S.
Class: |
514/251 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 31/4985 20130101; A61P 17/00 20180101; A61P 37/06 20180101;
A61P 29/00 20180101; A61K 31/435 20130101; A61P 1/00 20180101; A61P
25/00 20180101; A61P 9/00 20180101; A61P 19/02 20180101; A61P 37/02
20180101; A61P 17/06 20180101; A61K 31/4409 20130101; A61K 31/519
20130101; A61P 35/04 20180101; A61P 3/10 20180101; A61P 27/02
20180101; A61P 35/00 20180101 |
Class at
Publication: |
514/251 |
International
Class: |
A61K 31/525 20060101
A61K031/525 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 14, 2004 |
EP |
04 019 361 |
Aug 17, 2004 |
EP |
04 019 448 |
Claims
1. A pharmaceutical composition comprising therapeutically
effective amounts of: (i) A compound 1 of Formula (I) ##STR1026##
wherein R.sup.1, R.sup.2 which may be identical or different,
denote hydrogen or optionally substituted C.sub.1-C.sub.6-alkyl, or
R.sup.1 and R.sup.2 together denote a 2- to 5-membered alkyl bridge
which may contain 1 to 2 heteroatoms, R.sup.3 denotes hydrogen or a
group selected from among optionally substituted
C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.12-alkenyl,
C.sub.2-C.sub.12-alkynyl and C.sub.6-C.sub.14-aryl, or a group
selected from among optionally substituted and/or bridged
C.sub.3-C.sub.12-cycloalkyl, C.sub.3-C.sub.12-cycloalkenyl,
C.sub.7-C.sub.12-polycycloalkyl, C.sub.7-C.sub.12-polycycloalkenyl,
C.sub.5-C.sub.12-spirocycloalkyl, C.sub.3-C.sub.12-heterocycloalkyl
which contains 1 to 2 heteroatoms, and
C.sub.3-C.sub.12-heterocycloalkenyl which contains 1 to 2
heteroatoms, or R.sup.1 and R.sup.3or R.sup.2 and R.sup.3 together
denote a saturated or unsaturated C.sub.3-C.sub.4-alkyl bridge
which may contain 1 heteroatom, R.sup.4 denotes a group selected
from among hydrogen, --CN, hydroxy, --NR.sub.6R.sub.7 and halogen,
or a group selected from among optionally substituted
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.5-alkyloxy,
C.sub.2-C.sub.5-alkenyloxy, C.sub.2-C.sub.5-alkynyloxy,
C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulphoxo and
C.sub.1-C.sub.6-alkylsulphonyl, L denotes a linker selected from
among optionally substituted C.sub.2-C.sub.10-alkyl,
C.sub.2-C.sub.10-alkenyl, C.sub.6-C.sub.14-aryl,
--C.sub.2-C.sub.4-alkyl-C.sub.6-C.sub.14-aryl,
--C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, optionally bridged
C.sub.3-C.sub.12-cycloalkyl and heteroaryl which contains 1 or 2
nitrogen atoms, n denotes 0 or 1 m denotes 1 or 2 R.sup.5 denotes a
group selected from among optionally substituted morpholinyl,
piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl,
tropenyl, R.sup.8-diketomethylpiperazinyl, sulphoxomorpholinyl,
sulphonylmorpholinyl, thiomorpholinyl, --NR.sup.8R.sup.9 and
azacycloheptyl, R.sup.6, R.sup.7 which may be identical or
different, denote hydrogen or C.sub.1-C.sub.4-alkyl, and R.sup.8,
R.sup.9 denote unsubstituted nitrogen substituents at R.sup.5,
which may be identical or different, denote either hydrogen or a
group selected from among Cl-C.sub.6-alkyl,
--C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.6-C.sub.14-aryl,
--C.sub.1-C.sub.4-alkyl-C.sub.6-C.sub.14-aryl, pyranyl, pyridinyl,
pyrimidinyl, C.sub.1-C.sub.4-alkyloxycarbonyl,
C.sub.6-C.sub.14-arylcarbonyl, C.sub.1-C.sub.4-alkylcarbonyl,
C.sub.6-C.sub.14-arylmethyloxycarbonyl,
C.sub.6-C.sub.14-arylsulphonyl, C.sub.1-C.sub.4-alkylsulphonyl- and
C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkylsulphonyl-, optionally
in form of its tautomers, racemates, enantiomers, diastereomers and
the mixtures thereof and optionally in form of the
pharmacologically acceptable acid addition salts, solvates,
hydrates, polymorphs, physiologically fimctional derivatives or
prodrugs thereof; and (ii) at least one further chemotherapeutic or
naturally occurring, semi-synthetic or synthetic therapeutic agent
2; optionally in combination with one or more pharmaceutically
acceptable excipients, and optionally adapted for a co-treatment
with radiotherapy or radio-immunotherapy, in the form of a combined
preparation for simultaneous, separate or sequential use in the
treatment of diseases involving cell proliferation, migration or
apoptosis of cancer cells, is or angiogenesis.
2. The pharmaceutical composition according to claim 1, wherein the
compound 1 is selected from the group consisting of the compounds
of formula shown in the following Table TABLE-US-00006 ##STR1027##
Config. Example R.sup.1 R.sup.2 R.sup.1 or R.sup.2 R.sup.3 R.sup.4
L.sub.n-R.sup.5.sub.m 27 H ##STR1028## R ##STR1029## ##STR1030##
##STR1031## 44 H ##STR1032## R ##STR1033## H ##STR1034## 55 H
##STR1035## R ##STR1036## ##STR1037## ##STR1038## 58 H ##STR1039##
R ##STR1040## ##STR1041## ##STR1042## 102 H ##STR1043## R
##STR1044## ##STR1045## ##STR1046## 103 H ##STR1047## R ##STR1048##
##STR1049## ##STR1050## 105 H ##STR1051## R ##STR1052## ##STR1053##
##STR1054## 110 H ##STR1055## R ##STR1056## ##STR1057## ##STR1058##
115 H ##STR1059## R ##STR1060## ##STR1061## ##STR1062## 133 H
##STR1063## R ##STR1064## ##STR1065## ##STR1066## 134 H ##STR1067##
R ##STR1068## ##STR1069## ##STR1070## 234 H ##STR1071## R
##STR1072## ##STR1073## ##STR1074## 240 H ##STR1075## R ##STR1076##
##STR1077## ##STR1078##
wherein the abbreviations X.sub.1, X.sub.2, X.sub.3, X.sub.4 and
X.sub.5 used in the Table in each case denote a link to a position
in the general Formula shown in the Table instead of the
corresponding groups R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
L-R.sup.5.
3. The pharmaceutical composition according to claim 2, wherein the
further chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2 is selected from the group consisting
of synthetic small molecule VEGF receptor antagonists, small
molecule growth factor receptor antagonists, inhibitors of the EGF
receptor and/or VEGF receptor and/or integrin receptors or any
other protein tyrosine kinase receptors which are not classified
under the synthetic small-molecules, inhibitors directed to EGF
receptor and/or VEGF receptor and/or integrin receptors or any
other protein tyrosine kinase receptors, which are fusion proteins,
compounds which interact with nucleic acids and which are
classified as alkylating agents or platinum compounds, compounds
which interact with nucleic acids and which are classified as
anthracyclines, as DNA intercalators or as DNA cross-linking
agents, including DNA minor-groove binding compounds,
anti-metabolites, naturally occurring, semi-synthetic or synthetic
bleomycin type antibiotics, inhibitors of DNA transcribing enzymes,
and especially the topoisomerase I or topoisomerase II inhibitors,
chromatin modifying agents, mitosis inhibitors, anti-mitotic
agents, cell-cycle inhibitors, proteasome inhibitors, enzymes,
hormones, hormone antagonists, hormone inhibitors, inhibitors of
steroid biosynthesis, steroids, cytokines, hypoxia-selective
cytotoxins, inhibitors of cytokines, lymphokines, antibodies
directed against cytokines, oral and parenteral tolerance induction
agents, supportive agents, chemical radiation sensitizers and
protectors, photo-chemically activated drugs, synthetic poly- or
oligonucleotides, optionally modified or conjugated, non-steroidal
anti-inflammatory drugs, cytotoxic antibiotics, antibodies
targeting growth factors or their receptors, antibodies targeting
the surface molecules of cancer cells, inhibitors of
metalloproteinases, metals, inhibitors of oncogenes, inhibitors of
gene transcription or of RNA translation or protein expression,
complexes of rare earth elements, compounds which reduces the
transport of hyaluronan mediated by one or more ABC transporters,
and photo-chemotherapeutic agents.
4. The pharmaceutical combination according to claim 2, wherein the
further chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2 is selected from the group consisting
of a small molecule VEGF receptor antagonist such as vatalanib
(PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474,
AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or GW-786034, a
dual EGFR/HER2 antagonist such as gefitinib, erlotinib, CI-1033 or
GW-2016, an EGFR antagonist such as iressa (ZD-1839), tarceva
(OSI-774), PKI-166, EKB-569, HKI-272 or herceptin, an antagonist of
the mitogen-activated protein kinase such as BAY-43-9006 or
BAY-57-9006, a quinazoline derivative such as
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, or a
pharmaceutically acceptable salt thereof, a protein kinase receptor
antagonist which is not classified under the synthetic small
molecules such as atrasentan, rituximab, cetuximab, Avastin.TM.
(bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000,
vitaxin, imatinib, a protein tyrosine kinase inhibitor which is a
fusion protein such as VEGFtrap, an alkylating agent or a platinum
compound such as melphalan, cyclophosphamide, an oxazaphosphorine,
cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin,
iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine
(CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil,
a nitrogen mustard such as mechlorethamine, an ethyleneimine
compound, an alkylsulphonate, daunorubicin, doxorubicin
(adriamycin), liposomal doxorubicin (doxil), epirubicin,
idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a
derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a
duocarmycin, mithramycin, chromomycin, olivomycin, a phtalanilide
such as propamidine or stilbamidine, an anthramycin, an aziridine,
a nitrosourea or a derivative thereof, a pyrimidine or purine
analogue or antagonist or an inhibitor of the nucleoside
diphosphate reductase such as cytarabine, 5-fluorouracile (5-FU),
pemetrexed, tegafur/uracil, uracil mustard, fludarabine,
gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine,
methotrexate, pentostatin, hydroxyurea, or folic acid, a
phleomycin, a bleomycin or a derivative or salt thereof, CHPP,
BZPP, MTPP, BAPP, liblomycin, an acridine or a derivative thereof,
a rifamycin, an actinomycin, adramycin, a camptothecin such as
irinotecan or topotecan, an amsacrine or analogue thereof, a
tricyclic carboxamide, an histonedeacetylase inhibitor such as
SAHA, MD-275, trichostatin A, CBHA, LAQ824, or valproic acid, an
anti-cancer drug from plants such as paclitaxel (taxol), docetaxel
or taxotere, a vinca alkaloid such as navelbine, vinblastin,
vincristin, vindesine or vinorelbine, a tropolone alkaloid such as
colchicine or a derivative thereof, a macrolide such as maytansine,
an ansamitocin or rhizoxin, an antimitotic peptide such as
phomopsin or dolastatin, an epipodophyllotoxin or a derivative of
podophyllotoxin such as etoposide or teniposide, a steganacin, an
antimitotic carbamate derivative such as combretastatin or
amphetinile, procarbazine, a proteasome inhibitor such as
bortezomib, an enzyme such as asparaginase, pegylated asparaginase
(pegaspargase) or a thymidine-phosphorylase inhibitor, a gestagen
or an estrogen such as estramustine (T-66) or megestrol, an
anti-androgen such as flutamide, casodex, anandron or cyproterone
acetate, an aromatase inhibitor such as aminogluthetimide,
anastrozole, formestan or letrozole, a GNrH analogue such as
leuprorelin, buserelin, goserelin or triptorelin, an anti-estrogen
such as tamoxifen or its citrate salt, droloxifene, trioxifene,
raloxifene or zindoxifene, a derivative of 17.beta.-estradiol such
as ICI 164,384 or ICI 182,780, aminoglutethimide, formestane,
fadrozole, finasteride, ketoconazole, a LH-RH antagonist such as
leuprolide, a steroid such as prednisone, prednisolone,
methylprednisolone, dexamethasone, budenoside, fluocortolone or
triamcinolone, an interferon such as interferon .beta., an
interleukin such as IL-10 or IL-12, an anti-TNF.alpha. antibody
such as etanercept, an immunomodulatory drug such as thalidomide,
its R- and S-enantiomers and its derivatives, or revimid (CC-5013),
a leukotrien antagonist, mitomycin C, an aziridoquinone such as
BMY-42355, AZQ or EO-9, a 2-nitroimidazole such as misonidazole,
NLP-1 or NLA-1, a nitroacridine, a nitroquinoline, a
nitropyrazoloacridine, a "dual-function" nitro aromatic such as
RSU-1069 or RB-6145, CB-1954, a N-oxide of nitrogen mustard such as
nitromin, a metal complex of a nitrogen mustard, an anti-CD3 or
anti-CD25 antibody, a tolerance induction agent, a biphosphonate or
derivative thereof such as minodronic acid or its derivatives
(YM-529, Ono-5920, YH-529), zoledronic acid monohydrate,
ibandronate sodium hydrate or clodronate disodium, a nitroimidazole
such as metronidazole, misonidazole, benznidazole or nimorazole, a
nitroaryl compound such as RSU-1069, a nitroxyl or N-oxide such as
SR-4233, an halogenated pyrimidine analogue such as
bromodeoxyuridine, iododeoxyuridine, a thiophosphate such as WR-272
1, a photo-chemically activated drug such as porfimer, photofrin, a
benzoporphyrin derivative, a pheophorbide derivative, merocyanin
540 (MC-540) or tin etioporpurin, an ant-template or an anti-sense
RNA or DNA such as oblimersen, a non-steroidal inflammatory drug
such as acetylsalicyclic acid, mesalazin, ibuprofen, naproxen,
flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen,
pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,
tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen,
indomethacin, sulindac, tolmetin, zomepirac, nabumetone,
diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac,
aceclofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac,
mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic
acid, tolfenamic acid, diflunisal, flufenisal, piroxicam,
tenoxicam, lomoxicam, nimesulide, meloxicam, celecoxib, rofecoxib,
or a pharmaceutically acceptable salt of a non-steroidal
inflammatory drug, a cytotoxic antibiotic, an antibody targeting
the surface molecules of cancer cells such as apolizumab or 1D09C3,
an inhibitor of metalloproteinases such as TIMP-1 or TIMP-2, Zinc,
an inhibitor of oncogenes such as P53 and Rb, a complex of rare
earth elements such as the heterocyclic complexes of lanthanides, a
photo-chemotherapeutic agent such as PUVA, an inhibitor of the
transcription factor complex ESX/DRIP130/Sur-2, an inhibitor of
HER-2 expression, such as the heat shock protein HSP90 modulator
geldanamycin and its derivative 17-allylaminogeldanamycin or
17-AAG, a compound which reduces the transport of hyaluronan
mediated by one or more ABC transporters selected from a
P-glycoprotein (P-gp) inhibitor molecule or inhibitor peptide, an
MRP1 inhibitor, an antibody directed against and capable of
blocking the ABC transporter, an antisense oligomer, iRNA, siRNA or
aptamer directed against one or more ABC transporters, or a
therapeutic agent selected from IM-842, tetrathiomolybdate,
squalamine, combrestatin A4, TNP-470, marimastat, neovastat,
bicalutamide, abarelix, oregovomab, mitumomab, TLK-286,
alemtuzumab, ibritumomab, temozolomide, denileukin diftitox,
aldesleukin, dacarbazine, floxuridine, plicamycin, mitotane,
pipobroman, plicamycin, tamloxifen and testolactone.
5. The pharmaceutical composition according to claim 2, wherein the
further chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2 is selected from the group consisting
of an anti-cancer drug from plants such as paclitaxel (taxol),
docetaxel or taxotere, a vinca alkaloid such as navelbine,
vinblastin, vincristin, vindesine or vinorelbine, a vinca alkaloid
such as navelbine, vinblastin, vincristin, vindesine or
vinorelbine, an alkylating agent or a platinum compound such as
melphalan, cyclophosphamide, an oxazaphosphorine, cisplatin,
carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin,
mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU),
busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, a
nitrogen mustard such as mechlorethamine, an immunomodulatory drug
such as thalidomide, its R- and S-enantiomers and its derivatives,
or revimid (CC-5013)), an ethyleneimine compound, an
alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal
doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone,
amsacrine, dactinomycin, distamycin or a derivative thereof,
netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin,
mithramycin, chromomycin, olivomycin, a phtalanilide such as
propamidine or stilbamidine, an anthramycin, an aziridine, a
nitrosourea or a derivative thereof, a pyrimidine or purine
analogue or antagonist or an inhibitor of the nucleoside
diphosphate reductase such as cytarabine, 5-fluorouracile (5-FU),
pemetrexed, tegafur/uracil, uracil mustard, fludarabine,
gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine,
methotrexate, pentostatin, hydroxyurea, or folic acid, an acridine
or a derivative thereof, a rifamycin, an actinomycin, adramycin, a
camptothecin such as irinotecan or topotecan, an amsacrine or
analogue thereof, a tricyclic carboxamide, an histonedeacetylase
inhibitor such as SAHA, MD-275, trichostatin A, CBHA, LAQ824, or
valproic acid, a proteasome inhibitor such as bortezomib, a small
molecule VEGF receptor antagonist such as vatalanib
(PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474,
AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or GW-786034, an
antagonist of the mitogen-activated protein kinase such as
BAY-43-9006 or BAY-57-9006, a dual EGFR/HER2 antagonist such as
gefitinib, erlotinib, CI-1033 or GW-2016, an EGFR antagonist such
as iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272
or herceptin, a quinazoline derivative such as
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, or a
pharmaceutically acceptable salt thereof, an inhibitor of the
transcription factor complex ESX/DRIP130/Sur-2, an inhibitor of
HER-2 expression, such as the heat shock protein HSP90 modulator
geldanamycin and its derivative 17-allylaminogeldanamycin or
17-AAG, a protein kinase receptor antagonist which is not
classified under the synthetic small molecules such as atrasentan,
rituximab, cetuximab, Avastin.TM. (bevacizumab), IMC-1C11, erbitux
(C-225), DC-1 01, EMD-72000, vitaxin, imatinib, a P-glycoprotein
(P-gp) inhibitor molecule such as zosuquidar (LY 335973), its salts
(especially the trichloride salt) and its polymorphs, cyclosporin
A, verapamil or its R-isomer, tamoxifen, quinidine, d-alpha
tocopheryl polyethylene glycol 1000 succinate, VX-710, PSC833,
phenothiazine, GF120918 (II), SDZ PSC 833, TMBY, MS-073, S-9788,
SDZ 280-446, XR(9051) and functional derivatives, analogues and
isomers of these, or an antibody targeting the surface molecules of
cancer cells such as apolizumab or ID09C3.
6. The pharmaceutical composition according to claim 1, wherein the
further chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2 is the quinazoline derivative
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or a
pharmaceutically acceptable salt thereof.
7. The pharmaceutical combination according to claim 1, wherein the
further chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2 is the di-maleic acid salt of the
compound
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, or 4-
[(3
-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, or the
tautomers, stereoisomers or a pharmaceutically acceptable salt
thereof.
8. The pharmaceutical combination according to claim 1, wherein the
further chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2 is
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, or
the tautomers, stereoisomers or a pharmaceutically acceptable salt
thereof.
9. The pharmaceutical combination according to claim 1, wherein the
further chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2 is 3-Z-[ 1
-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino-
)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, or a
polymorph, metabolite or pharmaceutically acceptable salt
thereof.
10. The pharmaceutical combination according to claim 1, wherein
the further chemotherapeutic or naturally occurring, semi-synthetic
or synthetic therapeutic agent 2 is the monoethanesulfonate salt of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone.
11. The pharmaceutical combination according to claim 1, wherein
the further chemotherapeutic or naturally occurring, semi-synthetic
or synthetic therapeutic agent 2 is
3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methyle-
ne]-6-fluoro-2-indolinone, or a polymorph, metabolite or
pharmaceutically acceptable salt thereof.
12. The pharmaceutical composition according to claim 1, wherein
the further chemotherapeutic or naturally occurring, semi-synthetic
or synthetic therapeutic agent 2 is selected from the group
consisting of irinotecan, topotecan, oxaliplatin, docetaxel,
paclitaxel, gemcitabine, pemetrexed, cisplatin, carboplatin,
bevacizumab, cetuximab, gefitinib or erlotinib.
13. A method of treating an oncological disease, comprising
administering to a patient a therapeutically effective amount of a
pharmaceutical composition according to claim 1.
14. The method according to claim 13, wherein the oncological
disease is selected from the group consisting of solid tumours.
15. The method according to claim 13 wherein the oncological
disease is selected from the group consisting of urogenital
cancers, lung cancers, gastrointestinal cancers, head and neck
cancer, malignant mesotheliomas, breast cancer, malignant melanoma,
childhood cancers and bone or soft tissue sarcomas.
16. The method according to claim 13 wherein the oncological
disease is selected from the group consisting of refractory or
relapsed multiple myeloma, acute or chronic myelogenous leukaemia,
myelodysplastic syndrome, myeloproliferativesyndromes, acute
lymphoblastic leukaemia, Hodgkin's and non-Hodgkin's lymphoma.
17. A method of treating a disease or condition selected from the
group consisting of autoimmune disorders, diabetic retinopathy and
rheumatoid arthritis comprising administering to a patient a
therapeutically effective amount of a pharmaceutical composition
according to claim 1.
18. A pharmaceutical combination preparation kit for the treatment
of diseases involving cell proliferation, migration or apoptosis of
cancer cells, or angiogenesis, comprising a therapeutically
effective amount of: (i) a compound 1 of Formula (I) as defined in
claim 1; and (ii) at least a further chemotherapeutic or naturally
occurring, semi-synthetic or synthetic therapeutic agent 2; and
optionally adapted for a co-treatment with radiotherapy or
radio-immunotherapy; wherein the compound 1 of Formula (I) is
comprised within a first compartment and the further
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2 is comprised within a second
compartment, such that the administration to a patient in need
thereof can be simultaneous, separate or sequential.
19. The pharmaceutical combination preparation kit in accordance
with claim 18, wherein the formulation of the compound 1 of Formula
(I) is for oral administration or injection.
20. A method of treating diseases involving cell proliferation,
migration or apoptosis of cancer cells, or angiogenesis, in a human
or non-human mammalian body comprising administering to a patient a
therapeutically effective amount of a pharmaceutical composition
according to claim 1 or a pharmaceutical combination preparation
kit according to claim 18, optionally adapted for a co-treatment
with radiotherapy or radio-immunotherapy.
21. A method of treating diseases involving cell proliferation,
migration or apoptosis of cancer cells, or angiogenesis, in a human
or non-human mammalian body comprising administering
simultaneously, separately or sequentially to a patient a
therapeutically effective amount of a pharmaceutical composition
according to claim 1 in combination with at least a further
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2, optionally adapted for a
co-treatment with radiotherapy or radio-immunotherapy.
22. A method for the treatment of diseases involving cell
proliferation, migration or apoptosis of cancer cells, or
angiogenesis, which method comprises simultaneous, separate or
sequential co-administration to a patient, therapeutically
effective amounts of: (iii) a compound 1 of Formula (I) as defined
in claim 1; and (iv) at least a further chemotherapeutic or
naturally occurring, semi-synthetic or synthetic therapeutic agent
2; in the form of a combined preparation optionally adapted for a
co-treatment with radiotherapy or radio-immunotherapy.
23. The method according to any one of claims 13 to 17, or 21,
wherein the compound 1 of Formula (I), or its polymorph, hydrate,
metabolite or pharmaceutically acceptable salt, is administered
intermittent or in a daily dosage such that the plasma level of the
active substance lies between 10 and 5000 nM for at least 12 hours
of the dosing interval.
24. The method according to claim 20, wherein the compound 1 of
Formula (I), or its polymorph, hydrate, metabolite or
pharmaceutically acceptable salt, is administered intermittent or
in a daily dosage such that the plasma level of the active
substance lies between 10 and 5000 nM for at least 12 hours of the
dosing interval.
Description
APPLICATION DATA
[0001] This application claims benefit to European Patent
application nos. EP 04 019 361.7 filed Aug. 14, 2004 and EP 04 019
448.2 filed Aug. 17, 2004.
FIELD OF INVENTION
[0002] The invention relates to new pharmaceutical compositions for
the treatment of diseases involving cell proliferation, migration
or apoptosis of cancer cells, or angiogenesis and the preparation
thereof. The invention further relates to a method for the
treatment of diseases involving cell proliferation, migration or
apoptosis of cancer cells, or angiogenesis, which method comprises
co-administration to a person in need of such treatment and/or
co-treatment of a person in need of such treatment with effective
amounts of: [0003] (i) A compound 1 of Formula (I) ##STR2## [0004]
wherein the groups L, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
R.sup.5 have the meanings given in the claims and specification,
optionally in form of its tautomers, racemates, enantiomers,
diastereomers and the mixtures thereof and optionally in form of
the pharmacologically acceptable acid addition salts, solvates,
hydrates, polymorphs, physiologically functional derivatives or
prodrugs thereof; and [0005] (ii) At least a further
chemotherapeutic, immunotherapeutic or immunomodulatory,
antiangiogenic, homional or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2; and/or [0006] (iii) Radiotherapy or
radio-immunotherapy.
BACKGROUND OF THE INVENTION
[0007] Polo-like kinases (PLKs) are serine/threonine kinases that
play important roles in regulating processes in the cell cycle.
There are four PLKs disclosed in the state of the art, i.e. PLK-1,
PLK-2, PLK-3.and PLK-4. PLKs play a role in the entry into and the
exit from mitosis in mammalian cells. Especially for PLK-1 a
central role with respect to the regulation of mitosis was shown
(Glover et al. 1998, Genes Dev. 12:3777-87; Qian et al. 2001, Mol
Biol Cell. 12:1791-9). Overexpression of PLK-1 seems to be strongly
associated with neoplastic cells including cancers (WO
2004/014899). Overexpression of PLK1 has been documented for
various tumor types such as non-small cell lung cancer, squamous
cell carcinomas, breast, ovary or papillary carcinomas as well as
colorectal cancers (Wolf et al. 1997, Oncogene 14, pages 543-549;
Knecht et al. 1999, Cancer Res. 59, pages 2794-2797; Wolf et al.
2000, Pathol Res Pract. 196, pages 753-759; Weichert et al. 2004,
Br. J Cancer 90, pages 815-821; Ito et al. 2004, Br. J. Cancer 90,
pages 414-418; Takahashi et al. 2003, Cancer Sci. 94, pages
148-152).
[0008] For the treatment of diseases of oncological nature, a large
number of chemotherapeutic, immunotherapeutic or immunomodulatory,
antiangiogenic or hormonal agents have already been suggested,
which can be used as monotherapy (treatment with one agent) or as
combination therapy (simultaneous, separate or sequential treatment
with more than one agent) and/or which may be combined with
radiotherapy or radio-immunotherapy. In this respect,
chemotherapeutic agent means a naturally occurring, semi-synthetic
or synthetic chemical compound which, alone or via further
activation, for example with radiations in the case of
radio-immunotherapy, inhibits or kills growing cells, and which can
be used or is approved for use in the treatment of diseases of
oncological nature, which are commonly also denominated as cancers.
In the literature, these agents are generally classified according
to their mechanism of action. In this matter, reference can be
made, for example, to the classification made in "Cancer
Chemotherapeutic Agents", American Chemical Society, 1995, W. O.
Foye Ed.
[0009] The efficacy of chemotherapeutic agents can be improved by
using combination therapies with other chemotherapeutic,
immunotherapeutic, immunomodulatory, antiangiogenic or hormonal
compounds. Combination therapies constitute the gold standard in
many settings of cancer therapy.
[0010] Even if the concept of combining several therapeutic agents
or therapies already has been suggested, and although various
combination therapies are under investigation and in clinical
trials, there is still a need for new and efficient therapeutic
compositions for the treatment of cancer diseases, which show
advantages over standard therapies.
[0011] It is the purpose of the present invention to provide a
combination therapy with the PLK Inhibitors of Formula (I) for the
treatment of various cancer diseases.
DESCRIPTION OF THE INVENTION
[0012] Thus, within the meaning of the present invention, the
following classes of chemotherapeutic agents are especially of
interest, although not representing a limitation: [0013] Synthetic
small molecule VEGF receptor antagonists [0014] Small molecule
growth factor (GF) receptor antagonists [0015] Inhibitors of the
EGF receptor and/or VEGF receptor and/or integrin receptors or any
other protein tyrosine kinase receptors, which are not classified
under the synthetic small-molecules [0016] Small molecule
inhibitors of the Ras/Raf/MAPK or PI3K/AKT pathways or any other
serine/threonine kinases. [0017] Inhibitors of the Ras/Ra MAPK or
PI3K/AKT pathways or any other serine/threonine kinases, which are
not classified under the synthetic small-molecules [0018]
Inhibitors directed to EGF receptor and/or VEGF receptor and/or
integrin receptors or any other protein tyrosine kinase receptors,
which are synthetically manufactured antibodies, antibody fragments
or fusion proteins [0019] Compounds which interact with nucleic
acids and which are classified as alkylating agents or platinum
compounds [0020] Compounds which interact with nucleic acids and
which are classified as anthracyclines, as DNA intercalators or as
DNA cross-linking agents [0021] Anti-metabolites [0022] Naturally
occurring, semi-synthetic or synthetic bleomycin type antibiotics
(BLM-group antibiotics) [0023] Inhibitors of DNA transcribing
enzymes, especially topoisomerase I or topoisomerase II inhibitors
[0024] Chromatin modifying agents [0025] Mitosis inhibitors,
anti-mitotic agents, or cell-cycle inhibitors [0026] Compounds
interacting with or binding tubulin [0027] Compounds inhibiting
mitotic kinesins or other motor proteins including but not limited
to Eg5, CENP-E, MCAK, Kid, MKLP-1 [0028] Proteasome inhibitors
[0029] Heat shock protein inhibitors [0030] Compounds targeting the
anti-apoptotic function of Bcl-2, Bcl-x.sub.1 and like molecules
[0031] Enzymes Hormones, hormone antagonists or hormone inhibitors,
or inhibitors of steroid biosynthesis [0032] Steroids [0033]
Cytokines, hypoxia-selective cytotoxins, inhibitors of cytokines,
lymphokines, antibodies directed against cytokines or oral and
parenteral tolerance induction strategies [0034] Supportive agents
[0035] Antiinflammatory compounds such as but not limited to COX-2
inhibitors [0036] Chemical radiation sensitizers and protectors
[0037] Photochemically activated drugs [0038] Synthetic poly- or
oligonucleotides [0039] Other chemotherapeutic or naturally
occurring, semi-synthetic or synthetic therapeutic agents, such as
cytotoxic antibiotics, antibodies targeting surface molecules of
cancer cells, antibodies targeting growth factors or their
receptors, inhibitors of metalloproteinases, inhibitors of
oncogenes, inhibitors of gene transcription or of RNA translation
or protein expression, or complexes of rare earth elements.
[0040] The beneficial effects of the invention are mainly based on
the additive and synergistic effects of the combined treatment, or
to an improved tolerability of the treatment by the patient due,
for example, to the administration of lower doses of the
therapeutic agents involved.
[0041] Within the meaning of the present invention, the compound I
has the structure of the following general Formula (I): ##STR3##
wherein R.sup.1, R.sup.2 which may be identical or different,
denote hydrogen or optionally substituted C.sub.1-C.sub.6-alkyl, or
R.sup.1 and R.sup.2 together denote a 2- to 5-membered alkyl bridge
which may contain 1 to 2 heteroatoms, R.sup.3 denotes hydrogen or a
group selected from among optionally substituted
C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.12-alkenyl,
C.sub.2-C.sub.12-alkynyl and C.sub.6-C.sub.14-aryl, or a group
selected from among optionally substituted and/or bridged
C.sub.3-C.sub.12-cycloalkyl, C.sub.3-C.sub.12-cycloalkenyl,
C.sub.7-C.sub.12-polycycloalkyl, C.sub.7-C.sub.12-polycycloalkenyl,
C.sub.5-C.sub.12-spirocycloalkyl, C.sub.3-C.sub.12-heterocycloalkyl
which contains 1 to 2 heteroatoms, and
C.sub.3-C.sub.12-heterocycloalkenyl which contains 1 to 2
heteroatoms, or R.sup.1 and R.sup.3 or R.sup.2 and R.sup.3 together
denote a saturated or unsaturated C.sub.3-C.sub.4-alkyl bridge
which may contain 1 heteroatom, R.sup.4 denotes a group selected
from among hydrogen, --CN, hydroxy, --NR.sub.6R.sub.7 and halogen,
or a group selected from among optionally substituted
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, C.sub.1-C.sub.5-alkyloxy,
C.sub.2-C.sub.5-alkenyloxy, C.sub.2-C.sub.5-alkynyloxy,
C.sub.1-C.sub.6-alkylthio, C.sub.1-C.sub.6-alkylsulphoxo and
C.sub.1-C.sub.6-alkylsulphonyl, L denotes a linker selected from
among optionally substituted C.sub.2-C.sub.10-alkyl,
C.sub.2-C.sub.10-alkenyl, C.sub.6-C.sub.14-ayl,
--C.sub.2-C.sub.4-alkyl-C.sub.6-C.sub.14-aryl,
-C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, optionally bridged
C.sub.3-C.sub.12-cycloalkyl and heteroaryl which contains 1 or 2
nitrogen atoms, n denotes 0 or 1 m denotes 1 or 2 R.sup.5 denotes a
group selected from among optionally substituted morpholinyl,
piperidinyl, piperazinyl, piperazinylcarbonyl, pyrrolidinyl,
tropenyl, R.sup.8-diketomethylpiperazinyl, sulphoxomorpholinyl,
sulphonylmorpholinyl, thiomorpholinyl, --NR.sup.8R.sup.9 and
azacycloheptyl, R.sup.6, R.sup.7 which may be identical or
different, denote hydrogen or C.sub.1-C.sub.4-alkyl, and R.sup.8,
R.sup.9 denote unsubstituted nitrogen substituents at R.sup.5,
which may be identical or different, denote either hydrogen or a
group selected from among C.sub.1-C.sub.6-alkyl,
--C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.6-C.sub.14-aryl,
--C.sub.1-C.sub.4-alkyl-C.sub.6-C.sub.14-aryl, pyranyl, pyridinyl,
pyrimidinyl, C.sub.1-C.sub.4-alkyloxycarbonyl,
C.sub.6-C.sub.14-arylcarbonyl, C.sub.1-C.sub.4-alkylcarbonyl,
C.sub.6-C.sub.14-arylmethyloxycarbonyl,
C.sub.6-C.sub.14-arylsulphonyl, C.sub.1-C.sub.4-alkylsulphonyl- and
C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkylsulphonyl-, optionally
in form of its tautomers, racemates, enantiomers, diastereomers and
the mixtures thereof and optionally in form of the
pharmacologically acceptable acid addition salts, solvates,
hydrates, polymorphs, physiologically functional derivatives or
prodrugs thereof.
[0042] Preferred compounds of Formula (I) are those wherein
R.sup.1 to R.sup.4, R.sup.6 and R.sup.7 are as hereinbefore
defined, and
L denotes a linker selected from among optionally substituted
C.sub.2-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl,
C.sub.6-C.sub.14-aryl,
--C.sub.2-C.sub.4-alkyl-C.sub.6-C.sub.14-aryl,
--C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, optionally bridged
C.sub.3-C.sub.12-cycloalkyl and heteroaryl which contains 1 or 2
nitrogen atoms
n denotes 1
m denotes 1 or 2
[0043] R.sup.5 denotes a group which is bound to L via a nitrogen
atom, selected from among optionally substituted morpholinyl,
piperidinyl, R.sup.8-piperazinyl, pyrrolidinyl, tropenyl,
R.sup.8-diketomethylpiperazinyl, sulphoxomorpholinyl,
sulphonylmorpholinyl, thiomorpholinyl, --NR.sup.8R.sup.9 and
azacycloheptyl,
[0044] R.sup.8, R.sup.9 denote unsubstituted nitrogen substituents
at R.sup.5, which may be identical or different, hydrogen or a
group selected from among C.sub.1-C.sub.6-alkyl,
--C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.6-C.sub.14-aryl,
--C.sub.1-C.sub.4-alkyl-C.sub.6-C.sub.14-aryl, pyranyl, pyridinyl,
pyrimidinyl, C.sub.1-C.sub.4-alkyloxycarbonyl,
C.sub.6-C.sub.14-arylcarbonyl, C.sub.1-C.sub.4-alkylcarbonyl,
C.sub.6-C.sub.14-arylmethyloxycarbonyl,
C.sub.6-C.sub.14-arylsulphonyl, C.sub.1-C.sub.4-alkylsulphonyl and
C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkylsulphonyl.
[0045] Also preferred are compounds of Formula (I), wherein
R.sup.1 to R.sup.4, R.sup.6 and R.sup.7 are as hereinbefore
defined,
L denotes a linker selected from among optionally substituted
C.sub.2-C.sub.10-alkyl, C.sub.2-C.sub.10-alkenyl,
C.sub.6-C.sub.14-aryl,
--C.sub.2-C.sub.4-alkyl-C.sub.6-C.sub.14-aryl,
-C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkyl, optionally bridged
C.sub.3-C.sub.12-cycloalkyl and heteroaryl which contains 1 or 2
nitrogen atoms
n denotes 0 or 1
m denotes 1 or 2
R.sup.5 denotes a group which is bound to L via a carbon atom,
selected from among R.sup.8-piperidinyl,
R.sup.8R.sup.9-piperazinyl, R.sup.8-pyrrolidinyl,
R.sup.8-piperazinylcarbonyl, R.sup.8-tropenyl, R.sup.8-morpholinyl
and R.sup.8-azacycloheptyl, and
[0046] R.sup.8, R.sup.9 denote unsubstituted nitrogen substituents
at R.sup.5, which may be identical or different, hydrogen or a
group selected from among C.sub.1-C.sub.6-alkyl,
--C.sub.1-C.sub.4-alkyl-C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.6-C.sub.14-aryl,
--C.sub.1-C.sub.4-alkyl-C.sub.6-C.sub.14-aryl, pyranyl, pyridinyl,
pyrimidinyl, C.sub.1-C.sub.4-alkyloxycarbonyl,
C.sub.6-C.sub.14-arylcarbonyl, Cl-C.sub.4-alkylcarbonyl,
C.sub.6-C.sub.14-arylmethyloxycarbonyl,
C.sub.6-C.sub.14-arylsulphonyl, C.sub.1-C.sub.4-alkylsulphonyl and
C.sub.6-C.sub.14-aryl-C.sub.1-C.sub.4-alkylsulphonyl, optionally in
the form of the tautomers, the racemates, the enantiomers, the
diastereomers and the mixtures thereof, and optionally the
pharmacologically acceptable acid addition salts thereof.
[0047] Particularly preferred are compounds of Formula I
wherein
L, m, n and R.sup.3 to R.sup.9 are as hereinbefore defined, and
R.sup.1, R.sup.2 which may be identical or different, denote a
group selected from among hydrogen, Me, Et, Pr, or
R.sup.1 and R.sup.2 together form a C.sub.2-C.sub.4-alkyl
bridge,
optionally in the form of the tautomers, the racemates, the
enantiomers, the diastereomers and the mixtures thereof, and
optionally the pharmacologically acceptable acid addition salts
thereof.
[0048] Especially preferred are compounds of Formula I wherein
R.sup.1, R.sup.2, m, n and R.sup.5 to R.sup.8 are as hereinbefore
defined, and
R.sup.3 denotes a group selected from among optionally substituted
C.sup.1-C.sub.10-alkyl, C.sub.3-C.sub.7-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl and C.sub.6-C.sub.14-aryl or
R.sup.1 and R.sup.3 or R.sup.2 and R.sup.3 together denote a
saturated or unsaturated C.sub.3-C.sub.4-alkyl bridge which may
contain 1 to 2 heteroatoms,
R.sup.4 denotes a group selected from among hydrogen, OMe, OH, Me,
Et, Pr, OEt, NHMe, NH.sub.2, F, CL, Br, O-propargyl, O-butynyl, CN,
SMe, NMe.sub.2, CONH.sub.2, ethynyl, propynyl, butynyl and allyl,
and
L denotes a linker selected from among optionally substituted
phenyl, phenylmethyl, cyclohexyl and branched
C.sub.1-C.sub.6-alkyl,
optionally in the form of the tautomers, the racemates, the
enantiomers, the diastereomers and the mixtures thereof, and
optionally the pharmacologically acceptable acid addition salts
thereof.
[0049] In a further embodiment, the compound 1 in accordance with
the present invention is selected from the group consisting of the
compounds of Formula (I) shown in the following Table
TABLE-US-00001 ##STR4## Config. Ex. R.sup.1 R.sup.2 R.sup.1 or
R.sup.2 R.sup.3 R.sup.4 L.sub.n--R.sup.5.sub.m 27 H ##STR5## R
##STR6## ##STR7## ##STR8## 44 H ##STR9## R ##STR10## H ##STR11## 55
H ##STR12## R ##STR13## ##STR14## ##STR15## 58 H ##STR16## R
##STR17## ##STR18## ##STR19## 102 H ##STR20## R ##STR21## ##STR22##
##STR23## 103 H ##STR24## R ##STR25## ##STR26## ##STR27## 105 H
##STR28## R ##STR29## ##STR30## ##STR31## 110 H ##STR32## R
##STR33## ##STR34## ##STR35## 115 H ##STR36## R ##STR37## ##STR38##
##STR39## 133 H ##STR40## R ##STR41## ##STR42## ##STR43## 134 H
##STR44## R ##STR45## ##STR46## ##STR47## 234 H ##STR48## R
##STR49## ##STR50## ##STR51## 240 H ##STR52## R ##STR53## ##STR54##
##STR55##
wherein the abbreviations X.sub.1, X.sub.2, X.sub.3, X.sub.4 and
X.sub.5 used in the Table in each case denote a link to a position
in the general Formula shown in the Table instead of the
corresponding groups R.sup.1, R.sup.2, R.sup.3, R.sup.4 and
L-R.sup.5.
[0050] This invention thus relates to a pharmaceutical composition
comprising effective amounts of: [0051] (i) A compound 1 of Formula
(I) or optionally a polymorph, metabolite, hydrate, preferably the
mono hydrate, solvate, individual optical isomers, mixtures of the
individual enantiomers or racemates thereof, or a pharmaceutically
acceptable salt thereof; and [0052] (ii) At least one further
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2; optionally in combination with one
or more pharmaceutically acceptable excipients, and optionally
adapted for a co-treatment with radiotherapy or
radio-immunotherapy, in the form of a combined preparation for
simultaneous, separate or sequential use in the treatment of
diseases involving cell proliferation, migration or apoptosis of
cancer cells, or angiogenesis, preferably involving cell
proliferation or apoptosis of cancer cells.
[0053] In a preferred embodiment the instant invention is directed
to a pharmaceutical composition, wherein the further
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2 is selected from the group consisting
of compounds interacting with or binding tubulin, synthetic small
molecule VEGF receptor antagonists, small molecule growth factor
receptor antagonists, inhibitors of the EGF receptor and/or VEGF
receptor and/or integrin receptors or any other protein tyrosine
kinase receptors which are not classified under the synthetic
small-molecules, inhibitors directed to EGF receptor and/or VEGF
receptor and/or integrin receptors or any other protein tyrosine
kinase receptors, which are fusion proteins, compounds which
interact with nucleic acids and which are classified as alkylating
agents or platinum compounds, compounds which interact with nucleic
acids and which are classified as anthracyclines, as DNA
intercalators or as DNA cross-linking agents, including DNA
minor-groove binding compounds, anti-metabolites, naturally
occurring, semi-synthetic or synthetic bleomycin type antibiotics,
inhibitors of DNA transcribing enzymes, and especially the
topoisomerase I or topoisomerase II inhibitors, chromatin modifying
agents, mitosis inhibitors, anti-mitotic agents, cell-cycle
inhibitors, proteasome inhibitors, enzymes, hormones, hormone
antagonists, hormone inhibitors, inhibitors of steroid
biosynthesis, steroids, cytokines, hypoxia-selective cytotoxins,
inhibitors of cytokines, lymphokines, antibodies directed against
cytokines, oral and parenteral tolerance induction agents,
supportive agents, chemical radiation sensitizers and protectors,
photo-chemically activated drugs, synthetic poly- or
oligonucleotides, optionally modified or conjugated, non-steroidal
anti-inflammatory drugs, cytotoxic antibiotics, antibodies
targeting the surface molecules of cancer cells, antibodies
targeting growth factors or their receptors, inhibitors of
metalloproteinases, metals, inhibitors of oncogenes, inhibitors of
gene transcription or of RNA translation or protein expression,
complexes of rare earth elements, and photo-chemotherapeutic
agents.
[0054] Preferred compounds include small molecule tyrosin kinase or
serine/threonine kinase inhibitors, compounds interacting with
nucleic acids classified as alkylating agents or anthracyclines,
anti-metabolites, inhibitors of DNA transcribing enzymes such as
topoisomerase I or II, tubulin binding drugs, anti-mitotic agents,
antibodies targeting growth factors or their receptors and
antibodies binding to surface molecules of cancer cells or ligands
of these surface molecules in form of the hydrates and/or solvates
and optionally in the form of the individual optical isomers,
mixtures of the individual enantiomers or racemates thereof.
[0055] In another preferred embodiment the instant invention is
directed to a pharmaceutical combination, wherein the further
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2 is selected from the group consisting
of a small molecule VEGF receptor antagonist such as vatalanib
(PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474,
AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or GW-786034, a
dual EGFR/HER2 antagonist such as gefitinib, erlotinib, CI-1033 or
GW-2016, an EGFR antagonist such as iressa (ZD-1839), tarceva
(OSI-774), PKI-166, EKB-569, HKI-272 or herceptin, an antagonist of
the mitogen-activated protein kinase such as BAY-43-9006 or
BAY-57-9006, a quinazoline derivative such as
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, or a
pharmaceutically acceptable salt thereof, a protein kinase receptor
antagonist which is not classified under the synthetic small
molecules such as atrasentan, rituximab, cetuximab, Avastin.TM.
(bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000,
vitaxin, imatinib, a protein tyrosine kinase inhibitor which is a
fusion protein such as VEGFtrap, an alkylating agent or a platinum
compound such as melphalan, cyclophosphamide, an oxazaphosphorine,
cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin,
iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine
(CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil,
a nitrogen mustard such as mechlorethamine, an ethyleneimine
compound, an alkylsulphonate, daunorubicin, doxorubicin
(adriamycin), liposomal doxorubicin (doxil), epirubicin,
idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a
derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a
duocarmycin, mithramycin, chromomycin, olivomycin, a phtalanilide
such as propamidine or stilbamidine, an anthramycin, an aziridine,
a nitrosourea or a derivative thereof, a pyrimidine or purine
analogue or antagonist or an inhibitor of the nucleoside
diphosphate reductase such as cytarabine, 5-fluorouracile (5-FU),
pemetrexed, tegafur/uracil, uracil mustard, fludarabine,
gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine,
methotrexate, pentostatin, hydroxyurea, or folic acid, a
phleomycin, a bleomycin or a derivative or salt thereof, CHPP,
BZPP, MTPP, BAPP, liblomycin, an acridine or a derivative thereof,
a rifamycin, an actinomycin, adramycin, a camptothecin such as
irinotecan (camptosar) or topotecan, an amsacrine or analogue
thereof, a tricyclic carboxamide, an histonedeacetylase inhibitor
such as SAHA, MD-275, trichostatin A, CBHA, LAQ824, or valproic
acid, an anti-cancer drug from plants such as paclitaxel (taxol),
docetaxel or taxotere, a vinca alkaloid such as navelbine,
vinblastin, vincristin, vindesine or vinorelbine, a tropolone
alkaloid such as colchicine or a derivative thereof, a macrolide
such as maytansine, an ansamitocin or rhizoxin, an antimitotic
peptide such as phomopsin or dolastatin, an epipodophyllotoxin or a
derivative of podophyllotoxin such as etoposide or teniposide, a
steganacin, an antimitotic carbamate derivative such as
combretastatin or amphetinile, procarbazine, a proteasome inhibitor
such as bortezomib, an enzyme such as asparaginase, pegylated
asparaginase (pegaspargase) or a thymidine-phosphorylase inhibitor,
a gestagen or an estrogen such as estramustine (T-66) or megestrol,
an anti-androgen such as flutamide, casodex, anandron or
cyproterone acetate, an aromatase inhibitor such as
aminogluthetimide, anastrozole, formestan or letrozole, a GNrH
analogue such as leuprorelin, buserelin, goserelin or triptorelin,
an anti-estrogen such as tamoxifen or its citrate salt,
droloxifene, trioxifene, raloxifene or zindoxifene, a derivative of
17.beta.-estradiol such as ICI 164,384 or ICI 182,780,
aminoglutethimide, formestane, fadrozole, finasteride,
ketoconazole, a LH-RH antagonist such as leuprolide, a steroid such
as prednisone, prednisolone, methylprednisolone, dexamethasone,
budenoside, fluocortolone or triamcinolone, an interferon such as
interferon .beta., an interleukin such as IL-10 or IL-12, an
anti-TNF.alpha. antibody such as etanercept, an immunomodulatory
drug such as thalidomide, its R- and S-enantiomers and its
derivatives, or revimid (CC-5013), a leukotrien antagonist,
mitomycin C, an aziridoquinone such as BMY-42355, AZQ or EO-9, a
2-nitroimidazole such as misonidazole, NLP-1 or NLA-1, a
nitroacridine, a nitroquinoline, a nitropyrazoloacridine, a
"dual-function" nitro aromatic such as RSU-1069 or RB-6145,
CB-1954, a N-oxide of nitrogen mustard such as nitromin, a metal
complex of a nitrogen mustard, an anti-CD3 or anti-CD25 antibody, a
tolerance induction agent, a biphosphonate or derivative thereof
such as minodronic acid or its derivatives (YM-529, Ono-5920,
YH-529), zoledronic acid monohydrate, ibandronate sodium hydrate or
clodronate disodium, a nitroimidazole such as metronidazole,
misonidazole, benznidazole or nimorazole, a nitroaryl compound such
as RSU-1069, a nitroxyl or N-oxide such as SR-4233, an halogenated
pyrimidine analogue such as bromodeoxyuridine, iododeoxyuridine, a
thiophosphate such as WR-272 1, a photo-chemically activated drug
such as porfimer, photofrin, a benzoporphyrin derivative, a
pheophorbide derivative, merocyanin 540 (MC-540) or tin
etioporpurin, an ant-template or an anti-sense RNA or DNA such as
oblimersen, a non-steroidal inflammatory drug such as
acetylsalicyclic acid, mesalazin, ibuprofen, naproxen,
flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen,
pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,
tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen,
indomethacin, sulindac, tolmetin, zomepirac, nabumetone,
diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac,
aceclofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac,
mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic
acid, tolfenamic acid, diflunisal, flufenisal, piroxicam,
tenoxicam, lomoxicam, nimesulide, meloxicam, celecoxib, rofecoxib,
or a pharmaceutically acceptable salt of a non-steroidal
inflammatory drug, a cytotoxic antibiotic, an antibody targeting
the surface molecules of cancer cells such as apolizumab or 1D09C3,
an inhibitor of metalloproteinases such as TIMP-1 or TIMP-2, Zinc,
an inhibitor of oncogenes such as P53 and Rb, a complex of rare
earth elements such as the heterocyclic complexes of lanthanides, a
photo-chemotherapeutic agent such as PUVA, an inhibitor of the
transcription factor complex ESX/DRIP130/Sur-2, an inhibitor of
HER-2 expression, such as the heat shock protein HSP90 modulator
geldanamycin and its derivative 17-allylaminogeldanamycin or
17-AAG, or a therapeutic agent selected from IM-842,
tetrathiomolybdate, squalamine, combrestatin A4, TNP-470,
marimastat, neovastat, bicalutamide, abarelix, oregovomab,
mitumomab, TLK-286, alemtuzumab, ibritumomab, temozolomide,
denileukin diftitox, aldesleukin, dacarbazine, floxuridine,
plicamycin, mitotane, pipobroman, plicamycin, tamoxifen and
testolactone. Preferred compounds include small molecule VEGF
receptor antagonist such as vatalanib (PTK-787/ZK222584), SU-5416,
SU-6668, SU-11248, SU-14813, AZD-6474, EGFR/HER2 antagonists such
as CI-1033 or GW-2016, an EGFR antagonist such as iressa
(gefitinib, ZD-1839), tarceva (erlotinib, OSI-774), PKI-166,
EKB-569, HKI-272 or herceptin, an antagonist of the
mitogen-activated protein kinase such as BAY-43-9006 or
BAY-57-9006, atrasentan, rituximab, cetuximab, Avastin.TM.
(bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000,
vitaxin, imatinib, an alkylating agent or a platinum compound such
as melphalan, cyclophosphamide, cisplatin, carboplatin,
oxaliplatin, satraplatin, daunorubicin, doxorubicin (adriamycin),
liposomal doxorubicin (doxil), epirubicin, idarubicin, a pyrimidine
or purine analogue or antagonist or an inhibitor of the nucleoside
diphosphate reductase such as cytarabine, 5-fluorouracile (5-FU),
pemetrexed, tegafur/uracil, gemcitabine, capecitabine,
mercaptopurine, methotrexate, an anti-cancer drug such as
paclitaxel (taxol) or docetaxel, a vinca alkaloid such as
navelbine, vinblastin, vincristin, vindesine or vinorelbine, an
antimitotic peptide such as dolastatin, an epipodophyllotoxin or a
derivative of podophyllotoxin such as etoposide or teniposide, a
non-steroidal inflammatory drug such as meloxicam, celecoxib,
rofecoxib, an antibody targeting the surface molecules of cancer
cells such as apolizumab or ID09C3 or the heat shock protein HSP90
modulator geldanamycin and its derivative 17-allylaminogeldanamycin
or 17-AAG.
[0056] In another preferred embodiment the instant invention is
directed to a pharmaceutical composition, wherein the further
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2 is selected from the group consisting
of an anti-cancer drug from plants such as paclitaxel (taxol),
docetaxel, a vinca alkaloid such as navelbine, vinblastin,
vincristin, vindesine or vinorelbine, an alkylating agent or a
platinum compound such as melphalan, cyclophosphamide, an
oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin,
tetraplatin, iproplatin, mitomycin, streptozocin, carmustine
(BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin,
thiotepa, chlorambucil, a nitrogen mustard such as mechlorethamine,
an immunomodulatory drug such as thalidomide, its R- and
S-enantiomers and its derivatives, or revimid (CC-5013)), an
ethyleneimine compound, an alkylsulphonate, daunorubicin,
doxorubicin (adriamycin), liposomal doxorubicin (doxil),
epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin,
distamycin or a derivative thereof, netropsin, pibenzimol,
mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin,
olivomycin, a phtalanilide such as propamidine or stilbamidine, an
anthramycin, an aziridine, a nitrosourea or a derivative thereof, a
pyrimidine or purine analogue or antagonist or an inhibitor of the
nucleoside diphosphate reductase such as cytarabine,
5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine,
capecitabine, mercaptopurine, cladribine, thioguanine,
methotrexate, pentostatin, hydroxyurea, or folic acid, an acridine
or a derivative thereof, a rifamycin, an actinomycin, adramycin, a
camptothecin such as irinotecan (camptosar) or topotecan, an
amsacrine or analogue thereof, a tricyclic carboxamide, an
histonedeacetylase inhibitor such as SAHA, MD-275, trichostatin A,
CBHA, LAQ824, or valproic acid, a proteasome inhibitor such as
bortezomib, a small molecule VEGF receptor antagonist such as
vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813,
AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or
GW-786034, an antagonist of the mitogen-activated protein kinase
such as BAY-43-9006 or BAY-57-9006, a dual EGFR/HER2 antagonist
such as gefitinib, erlotinib, CI-1033 or GW-2016, an EGFR
antagonist such as iressa (ZD-1839), tarceva (OSI-774), PKI-166,
EKB-569, HKI-272 or herceptin, a quinazoline derivative such as
4-[(3-chloro-4-fluorophenyl)amino]-6-{[-4-(N,N-dimethylamino)-1-oxo-2-but-
en-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, or a
pharmaceutically acceptable salt thereof, an inhibitor of the
transcription factor complex ESX/DRIP130/Sur-2, an inhibitor of
HER-2 expression, such as the heat shock protein HSP90 modulator
geldanamycin and its derivative 17-allylaminogeldanamycin or
17-AAG, a protein kinase receptor antagonist which is not
classified under the synthetic small molecules such as atrasentan,
rituximab, cetuximab, Avastin.TM. (bevacizumab), IMC-1C11, erbitux
(C-225), DC-101, EMD-72000, vitaxin, imatinib, and an antibody
targeting the surface molecules of cancer cells such as apolizumab
or 1D09C3.
[0057] Preferred compounds include small molecule receptor
antagonists such aus vatalanib, SU 11248 or AZD-6474, EGFR or HER2
antagonists such as gefitinib, erlotinib, CI-1033 or Herceptin,
antibodies such as bevacizumab, cetuximab, rituximab, DNA
alkylating drugs such as cisplatin, oxaliplatin or carboplatin,
anthracyclines such as doxorubicin or epirubicin, an antimetabolite
such as 5-FU, pemetrexed, gemcitabine or capecitabine, a
camptothecin such as irinotecan or topotecan, an anti-cancer drug
such as paclitaxel or docetaxel, an epipodophyllotoxin such as
etoposide or teniposide, a proteasome inhibitor such as bortezomib
or antiinflammatory drugs such as celecoxib or rofecoxib,
optionally in form of the pharmaceutically acceptable salts, in
form of the hydrates and/or solvates and optionally in the form of
the individual optical isomers, mixtures of the individual
enantiomers or racemates thereof.
[0058] In another preferred embodiment the instant invention is
directed to a pharmaceutical composition as defined hereinbefore,
wherein the further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent 2 is the quinazoline
derivative
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or a
pharmaceutically acceptable salt thereof.
[0059] In another preferred embodiment the instant invention is
directed to a pharmaceutical composition as defined hereinbefore,
wherein the further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent 2 is the di-maleic
acid salt of the compound
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, or
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, or
the tautomers, stereoisomers or a pharmaceutically acceptable salt
thereof.
[0060] In another preferred embodiment the instant invention is
directed to a pharmaceutical composition as defined hereinbefore,
wherein the further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent 2 is the
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, or a
pharmaceutically acceptable salt thereof.
[0061] In another preferred embodiment the instant invention is
directed to a pharmaceutical composition as defined hereinbefore,
wherein the further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent 2 is the
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, or a
polymorph, metabolite or pharmaceutically acceptable salt
thereof.
[0062] In another preferred embodiment the instant invention is
directed to a pharmaceutical composition as defined hereinbefore,
wherein the further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent 2 is the
monoethanesulfonate salt of 3-Z- [1 -(4-(N-((4-methyl-piperazin- 1
-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-metho-
xycarbonyl-2-indolinone.
[0063] In another preferred embodiment the instant invention is
directed to a pharmaceutical composition as defined hereinbefore,
wherein the further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent 2 is the
3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methyle-
ne]-6-fluoro-2-indolinone, or a polymorph, metabolite or
pharmaceutically acceptable salt thereof.
[0064] In another preferred embodiment the instant invention is
directed to a pharmaceutical composition, wherein the further
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2 is irinotecan, topotecan,
oxaliplatin, docetaxel, paclitaxel, gemcitabine, pemetrexed,
cisplatin, carboplatin, bevacizumab, cetuximab, gefitinib or
erlotinib, particularly preferred irinotecan, docetaxel,
gemcitabine, topotecan or paclitaxel.
[0065] In another preferred embodiment the instant invention is
directed to a pharmaceutical composition as defined hereinbefore,
wherein the further naturally occurring, semi-synthetic or
synthetic therapeutic agent 2 is a compound which reduces the
transport of hyaluronan mediated by one or more ABC transporters,
or drug transport inhibitor, such as a P-glycoprotein (P-gp)
inhibitor molecule or inhibitor peptide, an MRP1 inhibitor, an
antibody directed against and capable of blocking the ABC
transporter, an antisense oligomer, iRNA, siRNA or aptamer directed
against one or more ABC transporters. Examples of P-glycoprotein
(P-gp) inhibitor molecules in accordance with the present invention
are zosuquidar (LY 335973), its salts (especially the trichloride
salt) and its polymorphs, cyclosporin A (also known as
cyclosporine), verapamil or its R-isomer, tamoxifen, quinidine,
d-alpha tocopheryl polyethylene glycol 1000 succinate, VX-710,
PSC833, phenothiazine, GF120918 (II), SDZ PSC 833, TMBY, MS-073,
S-9788, SDZ 280-446, XR(9051) and functional derivatives, analogues
and isomers of these.
[0066] Furthermore, where the compounds 2 carries an acidic moiety,
suitable pharmaceutically acceptable salts thereof may include
alkali metal salts (e.g. sodium or potassium salts), alkaline earth
metal salts (e. g. calcium or magnesium salts) and salts formed
with suitable organic ligands (e.g. quaternary ammonium salts).
[0067] The compounds 2 may have chiral centers and may occur as
racemates, racemic mixtures and as individual diastereomers, or
enantiomers with all isomeric forms being included in the present
invention. Hence, where a compound is chiral, the separate
enantiomers, substantially free of the others, are included within
the scope of the invention. Further included are all mixtures of
the two enantiomers. Also included within the scope of the
invention are polymorphs and hydrates of the compounds of the
instant invention.
[0068] The present invention includes within its scope prodrugs of
a compound 1 of Formula (I) and of the further active ingredient 2.
In general, such prodrugs will be functional derivatives of the
compounds or active ingredients of this invention which are readily
convertible in vivo into the required compound.
[0069] In a further embodiment the invention relates to a
composition as defined hereinbefore, which inhibits the
proliferation of various human tumour cell lines including but not
limited to Saos-2, H4, MDA-MB-435S, MDA-MB453, MCF7, HeLa S3,
HCT116, Colo 205, HT29, FaDu, HL-60, K-562, THP-1, HepG2, A549,
NCI-H460, GRANTA-519, Raji, Ramos, BRO, SKOV-3, BxPC-3, Mia CaPa-2,
DU145, PC-3, NCI-N87, MES-SA, SK-UT-1B and A431.
[0070] Another embodiment of the invention relates to the use of a
pharmaceutical composition as defined hereinbefore for the
preparation of a medicament for the treatment of oncological
diseases, such as malignant human neoplasias.
[0071] In a preferred embodiment the instant invention relates to
the use of a pharmaceutical composition as defined hereinbefore,
wherein the oncological disease is selected from the group
consisting of solid tumours.
[0072] In a further preferred embodiment the invention relates to
the use of a pharmaceutical composition as defined hereinbefore,
wherein the oncological disease is selected from the group
consisting of urogenital cancers (such as prostate cancer, renal
cell cancers, bladder cancers), gynecological cancers (such as
ovarian cancers, cervical cancers, endometrial cancers), lung
cancer, gastrointestinal cancers (such as colorectal cancers,
pancreatic cancer, gastric cancer, oesophageal cancers,
hepatocellular cancers, cholangiocellular cancers), head and neck
cancer, malignant mesothelioma, breast cancer, malignant melanoma
or bone and soft tissue sarcomas.
[0073] In a further preferred embodiment the invention relates to
the use of a pharmaceutical composition as defined hereinbefore
wherein the oncological disease is selected from the group
consisting of refractory or relapsed multiple myeloma, acute or
chronic myelogenous leukaemia, myelodysplastic syndrome, acute
lymphoblastic leukaemia, Hodgkin's or non-Hodgkin's lymphoma.
[0074] In a further preferred embodiment, the disease is hormone
sensitive or hormone refractory prostate cancer, ovarian carcinoma,
or small cell lung cancer.
[0075] In a further preferred embodiment the invention relates to
the use of a composition as defined hereinbefore, wherein the
oncological disease is characterized by inappropriate cellular
proliferation, migration, apoptosis or angiogenesis, preferably by
inappropriate cellular proliferation. Inappropriate cell
proliferation means cellular proliferation resulting from
inappropriate cell growth, from excessive cell division, from cell
division at an accelerated rate and/or from inappropriate cell
survival.
[0076] In a further preferred embodiment the invention relates to
the use according to the invention, wherein the disease is cancer
selected from the group consisting of carcinomas, sarcomas,
melanomas, myelomas, hematological neoplasias, lymphomas and
childhood cancers.
[0077] Examples of carcinomas within the scope of the invention
include but are not limited to adenocarcinoma (AC), squamous cell
carcinoma (SCC) and mixed or undifferentiated carcinomas.
Carcinomas within the scope of the invention include but are not
limited to the following histologies: [0078] Head and neck tumours:
SCC, AC, transitional cell cancers, mucoepidermoid cancers,
undifferentiated carcinomas; [0079] Central nervous system tumours:
Astrocytoma, glioblastoma, meningeoma, neurinoma, schwannoma,
ependymoma, hypophysoma, oligodendroglioma, medulloblastoma; [0080]
Bronchial and Mediastinal Tumours: [0081] Bronchial Tumours: [0082]
Small cell lung cancers (SCLC): oat-cell lung cancer, intermediate
cell cancer, combined oat-cell lung cancer; [0083] Non-small cell
lung cancers (NSCLC): SCC, spindle cell carcinoma, AC,
bronchioalveolar carcinoma, large cell NSCLC, clear cell NSCLC;
[0084] Mesothelioma; [0085] Thymoma; [0086] Thyroid carcinomas:
papillary, follicular, anaplastic, medullary; [0087] Tumours of the
Gastrointestinal Tract: [0088] Oesophageal cancers: SCC, AC,
anaplastic, carcinoid, sarcoma; [0089] Gastric cancers: AC,
adenosquamous, anaplastic; [0090] Colorectal cancers: AC, including
hereditary forms of AC, carcinoid, sarcoma; [0091] Anal cancers:
SCC, transitional epithelial cancer, AC, basal cell carcinoma;
[0092] Pancreatic cancers: AC, including ductal and acinary
cancers, papillary, adenosquamous, undifferentiated, tumours of the
endocrine pancreas; [0093] Hepatocellular carcinoma,
cholangiocarcinoma, angiosarcoma, hepatoblastoma; [0094] Biliary
carcinomas: AC, SCC, small cell, undifferentiated; [0095]
Gastrointestinal stroma tumours (GIST); [0096] Gynaecological
Cancers: [0097] Breast cancers: AC, including invasive ductal,
lobular and medullary cancers, tubular, mucinous cancers,
Paget-carcinoma, inflammatory carcinoma, ductal and lobular
carcinoma in situ; [0098] Ovarian cancers: Epithelial tumours,
stroma tumours, germ cell tumours, undifferentiated tumours; [0099]
Cervical cancers: SCC, AC, mixed and undifferentiated tumours;
[0100] Endometrial cancers: AC, SCC, mixed, undifferentiated
tumours; [0101] Vulvar cancers: SCC, AC; [0102] Vaginal cancers:
SCC, AC; [0103] Urinary Tract and Testicular Cancers: [0104]
Testicular cancers: seminoma; [0105] Non-seminomatous germ cell
tumours: teratoma, embryonal cell carcinoma, choriocarcinoma, yolk
sac tumour, mixed, Sertoli and Leydig-cell tumours; [0106]
Extragonadal germ cell tumours; [0107] Prostate cancers: AC, small
cell, SCC; [0108] Renal cell cancers: AC, including clear cell,
papillary and chromophobous carcinomas, hereditary forms (e.g.
von-Hippel-Lindau syndrome), nephroblastoma; [0109] Urinary bladder
cancers: transitional cell (urothelial) cancers, SCC, AC; [0110]
Urethral cancers: SCC, transitional cell cancers, AC; [0111] Penile
cancers: SCC; [0112] Tumours of Endocrine Tissue: [0113] Thyroid
cancers: papillary, follicular, anaplastic, medullary carcinomas,
including MEN syndrome; [0114] Tumours of the endocrine pancreas;
[0115] Carcinoids; [0116] Adrenal tumours, e.g.
Pheochromocytoma.
[0117] Examples of sarcomas within the scope of the invention
include but are not limited to Ewing-sarcoma, osteosarcoma or
osteogenic sarcoma, chondrosarcoma, synovial sarcoma,
leiomyosarcoma, rhabdomyosarcoma, mesothelial sarcoma or
mesothelioma, fibrosarcoma, angiosarcoma or hemangioendothelioma,
liposarcoma, glioma or astrocytoma, myxosarcoma, malignant fibrous
histiocytoma, mesenchymous or mixed mesodermal tumour,
neuroblastoma and clear cell sarcoma.
[0118] Examples of skin tumors within the scope of the invention
include but are not limited to basal cell carcinoma, Merkel cell
carcinoma, sebaceous carcinoma, fibroxanthoma, malignant fibrous
histiocytoma, and skin sarcoma.
[0119] Examples of melanomas within the scope of the invention
include but are not limited to superficial spreading melanoma,
nodular and lentigo-maligna melanoma.
[0120] Examples of myelomas within the scope of the invention
include but are not limited to immunocytoma, plasmocytoma and
multiple myeloma.
[0121] Examples of childhood cancers within the scope of the
invention include but are not limited to Wilms' tumor,
neuroblastoma, retinoblastoma, rhabdomyosarcoma, Ewing's sarcoma
and peripheral primitive neuroectodermal tumors, germ cell tumors
and childhood lymphoma and leukemias.
[0122] In another preferred embodiment the invention relates to the
use of a composition as defined hereinbefore, wherein the
hematologic cancer is leukemia.
[0123] Further examples of hematologic neoplasias within the scope
of the invention include but are not limited to acute or chronic
leukemias of myeloid, erythroid or lymphatic origin,
myelodysplastic syndromes (MDS) and myeloproliferative syndromes
(MPS, such as chronic myelogeneous leukemia, osteomyelofibrosis,
polycythemia vera or essential thrombocythemia).
[0124] Examples of lymphomas within the scope of the invention
include but are not limited to: [0125] Hodgkin-Lymphoma; [0126]
Non-Hodgkin-lymphomas: T- and B-cell lymphomas [0127] B-Cell
Lymphomas: [0128] Low and intermediate grade: Chronic lymphocytic
leukemia (CLL), prolymphocytic leukemia (PLL), small lymphocytic
lymphoma, hairy cell leukemia, plasmacytoid lymphoma, mantle cell
lymphoma, follicular lymphoma, marginal zone lymphoma including
MALT-lymphoma; [0129] High grade: diffuse large B-cell lymphoma
(DLBCL including immunoblastic and centroblastic variants),
lymphoblastic, Burkitt's lymphoma; [0130] T-Cell Lymphomas: [0131]
Low grade: T-CLL, T-PLL, Mycosis fungoides, Sezary-syndrome; [0132]
High grade: Anaplastic large cell, T-immunoblastic and
lymphoblastic.
[0133] In another preferred embodiment the invention relates to the
use according to the invention, wherein the disease is cancer
selected from the group consisting of mixed tumours,
undifferentiated tumours and metastases thereof.
[0134] Examples of mixed tumours within the scope of the invention
include but are not limited to adenosquamous carcinomas, mixed
mesodermal tumours, carcinosarcomas and teratocarcinomas.
[0135] Examples of undifferentiated, other tumours or metastases
thereof within the scope of the invention include but are not
limited to undifferentiated tumours, carcinomas of unknown primary
(CUP), metastases of unknown primary (MUP) and pheochromocytoma,
carcinoids.
[0136] In a further embodiment the invention relates to the use of
a composition as defined hereinbefore, for the preparation of a
medicament for the treatment of autoimmune disorders selected from
the group consisting of amyloidosis, systemic lupus erythematosus,
rheumatoid arthritis, Crohn's disease, multiple sclerosis, systemic
sclerosis (scleroderma), mixed connective tissue disease, Sjogren's
syndrome, ankylosing spondylitis, autoimmune vasculitis, Behcet's
syndrome, psoriasis, autoimmune arthritis, sarcoidosis and diabetes
mellitus.
[0137] In a further embodiment the invention relates to the use of
a pharmaceutical composition as defined hereinbefore for the
preparation of a medicament for the treatment of further
non-oncological diseases, such as diabetic retinopathy and
rheumatoid arthritis.
[0138] In a further embodiment the invention relates to the use of
a composition as defined hereinbefore wherein the composition
according to the invention is administered orally, enterically,
transdermally, intravenously, peritoneally or by injection,
preferably intravenously.
[0139] In a further embodiment the invention relates to a
pharmaceutical combination preparation kit for the treatment of
diseases involving cell proliferation, migration or apoptosis of
myeloma cells, or angiogenesis, comprising a therapeutically
effective amount of a compound 1 of Formula (I) in accordance with
the present invention, or a polymorph, hydrate, metabolite or
pharmaceutically acceptable salt thereof, and at least a further
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent 2, and optionally adapted for a
co-treatment with radiotherapy or radio-immunotherapy,
characterised in that the compound 1 of Formula (I) is comprised
within a first compartment and the further chemotherapeutic or
naturally occurring, semi-synthetic or synthetic therapeutic agent
2 is comprised within a second compartment, such that the
administration to a patient in need thereof can be simultaneous,
separate or sequential.
[0140] In a preferred embodiment the invention relates to a
pharmaceutical combination preparation kit, wherein the formulation
of the compound 1 of Formula (I) in accordance with the present
invention is for oral administration or injection.
[0141] In a further embodiment the invention relates to the use of
a pharmaceutical combination or a pharmaceutical combination
preparation kit, for the manufacture of a medicament, optionally
adapted for a co-treatment with radiotherapy or
radio-immunotherapy, to treat diseases involving cell
proliferation, migration or apoptosis of cancer cells, or
angiogenesis, in a human or non-human mammalian body.
[0142] In a further embodiment the invention relates to the use of
an effective amount of a compound 1 of Formula (I) or a polymorph,
hydrate, metabolite or pharmaceutically acceptable salt thereof, in
combination with at least a further chemotherapeutic or naturally
occurring, semi-synthetic or synthetic therapeutic agent 2, for the
manufacture of a pharmaceutical combination preparation, optionally
adapted for a co-treatment with radiotherapy or
radio-immunotherapy, for simultaneous, separate or sequential use
in the treatment of diseases involving cell proliferation,
migration or apoptosis of cancer cells, or angiogenesis, in a human
or non-human mammalian body.
[0143] In a further embodiment the invention relates to a method
for the treatment of diseases involving cell proliferation,
migration or apoptosis of cancer cells, or angiogenesis, which
method comprises simultaneous, separate or sequential
co-administration of effective amounts of: [0144] (i) a compound 1
of Formula (I) or a polymorph, metabolite, hydrate, solvate, an
individual optical isomer, mixtures of the individual enantiomers
or racemates thereof, or a pharmaceutically acceptable salt
thereof; and [0145] (ii) at least a further chemotherapeutic or
naturally occurring, semi-synthetic or synthetic therapeutic agent
2; in the form of a combined preparation optionally adapted for a
co-treatment with radiotherapy or radio-immunotherapy, to a person
in need of such treatment.
[0146] In a further embodiment the invention relates to the uses
described above, characterised in that a compound 1 of Formula (I),
or its polymorph, metabolite, hydrate, solvate, an individual
optical isomer, mixtures of the individual enantiomers or racemates
thereof, or a pharmaceutically acceptable salt thereof, is
administered intermittent or in a daily dosage such that the plasma
level of the active substance lies between 10 and 5000 nM for at
least 12 hours of the dosing interval.
[0147] The term "therapeutically effective amount" shall mean that
amount of a drug or pharmaceutical agent that will elicit the
biological or medical response of a tissue, system, animal or human
that is being sought by a researcher or clinician.
[0148] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from a combination of the specified ingredients in
the specified amounts.
[0149] As already mentioned before, within the meaning of the
present invention, the components 1 and 2 of the composition for a
combination therapy may be administered separately (which implies
that they are formulated separately) or together (which implies
that they are formulated together). Hence, the administration of
one element of the combination of the present invention may be
prior to, concurrent to, or subsequent to the administration of the
other element of the combination.
[0150] In accordance with the present invention, the elements of
the combination of 1 and 2 may be administered by oral (including
buccal or sublingual), enterical, parenteral (e.g., intramuscular,
intraperitoneal, intravenous, transdermal or subcutaneous
injection, or implant), nasal, vaginal, rectal, or topical (e.g.
ocular eyedrops) routes of administration and may be formulated,
alone or together, in suitable dosage unit formulations containing
conventional non-toxic pharmaceutically acceptable carriers,
adjuvants and vehicles appropriate for each route of
administration.
[0151] In a preferred embodiment the element 1 of the combination
in accordance with the invention is administered orally,
enterically, transdermally, intravenously, peritoneally or by
injection, preferably intravenously.
[0152] The pharmaceutical compositions for the administration of
the components 1 and 2 of this invention may conveniently be
presented in dosage unit form and may be prepared by any of the
methods well known in the art of pharmacy. All methods include the
step of bringing the active ingredient into association with the
carrier which is constituted of one or more accessory ingredients.
In general, the pharmaceutical compositions are prepared by
uniformly and intimately bringing the active ingredients into
association with a liquid carrier or a finely divided solid carrier
or both, and then, if necessary, shaping the product into the
desired dosage form. In the pharmaceutical compositions the active
compounds are included in an amount sufficient to produce the
desired pharmacologic effect.
[0153] The pharmaceutical compositions containing the active
ingredients 1 and 2, separately or together, that are suitable for
oral administration may be in the form of discrete units such as
hard or soft capsules, tablets, troches or lozenges, each
containing a predetermined amount of the active ingredients, or in
the form of a dispersible powder or granules, or in the form of a
solution or a suspension in an aqueous liquid or non-aqueous
liquid, or in the form of syrups or elixirs, or in the form of an
oil-in-water emulsion or a water-in-oil emulsion.
[0154] Dosage forms intended for oral use may be prepared according
to any method known to the art for the manufacture of
pharmaceutical formulations and such compositions.
[0155] The excipients used may be, for example: (a) inert diluents
such as mannitol, sorbitol, calcium carbonate, pregelatinized
starch, lactose, calcium phosphate or sodium phosphate; (b)
granulating and disintegrating agents, such as povidone,
copovidone, hydroxypropylmethylcellulose, corn starch, alginic
acid, crospovidone, sodiumstarchglycolate, croscarmellose, or
polacrilin potassium; (c) binding agents such as microcrystalline
cellulose or acacia; and (d) lubricating agents such as magnesium
stearate, stearic acid, fumaric acid or talc.
[0156] In some cases, formulations for oral use may be in the form
of hard gelatin or HPMC (hydroxypropylmethylcellulose) capsules
wherein the active ingredients 1 or 2, separately or together, is
mixed with an inert solid diluent, for example pregelatinized
starch, calcium carbonate, calcium phosphate or kaolin, or
dispensed via a pellet formulation. They may also be in the form of
soft gelatin capsules wherein the active ingredient is mixed with
water or an oil medium, for example peanut oil, liquid paraffin,
medium chain triglycerides or olive oil.
[0157] The tablets, capsules or pellets may be uncoated or they may
be coated by known techniques to delay disintegration and
absorption in the gastrointestinal tract and thereby provide a
delayed action or sustained action over a longer period. For
example, a time delay material such as celluloseacetate phtalate or
hydroxypropylcellulose acetate succinate or sustained release
material such as ethylcellulose or ammoniomethacrylate copolymer
(type B) may be employed.
[0158] Liquid dosage forms for oral administration in accordance
with the present invention include pharmaceutically acceptable
emulsions, solutions, suspensions, syrups, and elixirs containing
inert diluents commonly used in the art, such as water. Besides
such inert diluents, compositions can also include adjuvants, such
as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring, perfuming and preserving agents.
[0159] Aqueous suspensions in accordance with the present invention
normally contain the active materials 1 and 2, separately or
together, in admixture with excipients suitable for the manufacture
of aqueous suspensions. Such excipients may be (a) suspending
agents such as hydroxy ethylcellulose, sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; (b) dispersing
or wetting agents which may be (b.1) a naturally-occurring
phosphatide such as lecithin, (b.2) a condensation product of an
alkylene oxide with a fatty acid, for example, polyoxyethylene
stearate, (b.3) a condensation product of ethylene oxide with a
long chain aliphatic alcohol, for example
heptadecaethyleneoxycetanol, (b.4) a condensation product of
ethylene oxide with a partial ester derived from a fatty acid and a
hexitol such as polyoxyethylene sorbitol monooleate, or (b.5) a
condensation product of ethylene oxide with a partial ester derived
from a fatty acid and a hexitol anhydride, for example
polyoxyethylene sorbitan monooleate.
[0160] The aqueous suspensions may also contain: one or more
preservatives, for example, ethyl or n-propyl p-hydroxybenzoate;
one or more coloring agents; one or more flavoring agents; and one
or more sweetening agents, such as sucrose or saccharin.
[0161] Oily suspensions in accordance with the present invention
may be formulated by suspending the active ingredients 1 and 2,
separately or together, in a vegetable oil, for example arachis
(peanut) oil, olive oil, sesame oil or coconut oil, or in a mineral
oil such as liquid paraffin. The oily suspensions may contain a
thickening agent, for example beeswax, hard paraffin or cetyl
alcohol. Sweetening agents and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
prepared by the addition of an antioxidant such as ascorbic
acid.
[0162] Dispersible powders and granules are suitable formulations
for the preparation of an aqueous suspension in accordance with the
present invention. In these formulations the active ingredients 1
and 2 are present, separately or together, in admixture with a
dispersing or wetting agent, a suspending agent and one or more
preservatives. Suitable examples of dispersing or wetting agents,
suspending agents and preservatives are those already mentioned
hereinbefore. Additional excipients such as, for example,
sweetening, flavouring and colouring agents may also be present.
Suitable examples of excipients are those already mentioned
hereinbefore.
[0163] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil such as olive oil or arachis (peanut) oil, or a
mineral oil such as liquid paraffin or a mixture thereof.
[0164] Suitable emulsifying agents may be (a) naturally-occurring
gums such as gum acacia and gum tragacanth, (b) naturally-occurring
phosphatides such as soybean and lecithin, (c) esters or partial
esters derived from fatty acids and hexitol anhydrides, for example
sorbitan monooleate, (d) condensation products of said partial
esters with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and
flavouring agents.
[0165] Syrups and elixirs in accordance with the present invention
may be formulated with sweetening agents, for example glycerol,
propylene glycol, sorbitol or sucrose. Such formulations may also
contain a preservative and flavoring and coloring agents.
[0166] The pharmaceutical compositions containing 1 and 2,
separately or together, may be in the form of a sterile injectable
aqueous or oleagenous suspension or solution. The suspension may be
formulated according to known methods using those suitable
dispersing or wetting agents and suspending agents which have been
mentioned hereinbefore. A suitable sterile injectable preparation
may also be a sterile injectable solution or suspension in a non
toxic parenterally-acceptable diluent or solvent, for example a
solution in 1,3-butane-diol. Examples of suitable acceptable
vehicles and solvents that may be employed are water, Ringer's
solution and an isotonic sodium chloride solution. In addition,
sterile, fixed oils may conventionally be employed as a solvent or
suspending medium. For this purpose any bland fixed oil may be
employed, including synthetic mono-or diglycerides. In addition,
fatty acids such as oleic acid find use in the preparation of
injectables in accordance with the present invention.
[0167] Preparations for parenteral administration according to the
present invention containing 1 and 2, separately or together,
include sterile aqueous or non-aqueous solutions, suspension, or
emulsions.
[0168] Examples of suitables non-aqueous solvents or vehicles for
the preparations in accordance with the present invention are
propylene glycol, polyethylene glycol, vegetable oils, such as
olive oil and corn oil, gelatin, and injectable organic esters such
as ethyl oleate. Such dosage forms may also contain adjuvants such
as preserving, wetting, emulsifying, and dispersing agents. They
may be sterilized by, for example, by filtration through a
bacteria-retaining filter, by incorporating sterilizing agents into
the compositions, by irradiating the compositions, or by heating
the compositions. They may also be manufactured in the form of
sterile solid compositions which can be reconstituted in sterile
water, or some other sterile injectable medium immediately before
use.
[0169] The elements 1 and 2 of the combination of this invention
may also be administered in the form of suppositories for rectal
administration. Such compositions can be prepared by mixing the
active ingredient with a suitable non-irritating excipient which is
solid at ordinary temperatures but liquid at the rectal temperature
and will therefore melt in the rectum to release the active
ingredient. Such materials are cocoa butter, hard fat, and
polyethylene glycols.
[0170] Compositions for buccal, nasal or sublingual administration
in accordance with the present invention may be prepared with
standard excipients well known in the art.
[0171] For topical administration, the elements 1 and 2 of the
combination of this invention may be formulated, separately or
together, in liquid or semi-liquid preparations. Examples of
suitable preparations are: liniments, lotions, applications;
oil-in-water or water-in-oil emulsions such as creams, ointments,
jellies or pastes, including tooth-pastes; solutions or suspensions
such as drops.
[0172] The dosage of the active ingredients in the compositions in
accordance with the present invention may be varied, although the
amount of the active ingredients 1 and 2 shall be such that a
suitable dosage form is obtained. Hence, the selected dosage and
the selected dosage form shall depend on the desired therapeutic
effect, the route of administration and the duration of the
treatment. Suitable dosage ranges for the combination are from the
maximal tolerated dose for the single agent to lower doses, e.g. to
one tenth of the maximal tolerated dose.
[0173] In the following, the present invention is illustrated via
examples of pharmaceutical compositions comprising a compound 1 of
chemical structure (I) in combination with one of the
aforementioned combination partners 2, and by in vivo combination
studies showing the potency of the combination to inhibit the
proliferationn and/or to induce the apoptosis of tumour cells. In
these examples, the compound 1 of chemical structure (I) is
4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pterid-
inyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide, which
is a compound of Formula (I) according to the invention
(Exemplified compound Nr. 46 in Table 1).
Combination of Exemplified Compound Nr. 46 of Table 1 and
Irinotecan
(HCT 116 colon cancer model combination study)
Objective of the Study
[0174] Exemplified compound Nr. 46 of Table 1 is a potent and
selective inhibitor of the serine/threonine kinase PLK-1.
irinotecan (sold under the Trade name Campto.RTM.) is a standard
chemotherapeutic agent for treatment of colorectal carcinomas.
Previous studies have shown that exemplified compound Nr. 46 of
Table 1 and irinotecan are active on HCT 116 derived tumors in nude
mice. The goal of the present study was to assess the anti-cancer
efficacy of suboptimal doses of exemplified compound Nr. 46 of
Table 1, irinotecan and the combination of exemplified compound Nr.
46 of Table 1 and irinotecan, in the human colon carcinoma model
HCT 116 grown as xenograft in nude mice. Suboptimal doses of both
compounds were used to facilitate the detection of additive,
synergistic or antagonistic effects.
Design of the Study
[0175] Model: Human colon carcinoma model HCT 116 grown as
subcutaneous xenografts in nude mice. TABLE-US-00002 Treatment
groups (10 animals per group): Controls Vehicle, i.v., once weekly
for 6 weeks ((q7d) .times. 6) Exemplified compound Nr. 46 of Table
1 30 mg/kg, i.v., once weekly for 10 weeks ((q7d) .times. 10)
Irinotecan 12.5 mg/kg, i.p., once weekly for 10 weeks ((q7d)
.times. 10) Combination 30 mg/kg exemplified compound Nr. 46 of
Table 1, i.v., once weekly for 10 weeks ((q7d) .times. 10) and 12.5
mg/kg irinotecan, i.p., once weekly (.about.1 h after exemplified
compound Nr. 46 of Table 1) for 10 weeks ((q7d) .times. 10)
[0176] Tumor volumes and animal weights were recorded 3 times per
week. Evaluation of therapy results was based on the absolute
volumes of individual tumors.
[0177] Material and Methods:
[0178] Mice were female BomTac:NMRI-nu/nu. Exemplified compound Nr.
46 of Table 1 was dissolved in hydrochloric acid (0.1 N) diluted
with 0.9% NaCl and injected intravenously into the tail vein.
irinotecan infusion concentrate was diluted with 0.9% NaCl and
injected intraperitoneally. The administration volume was 10 ml per
kg body weight for both compounds. HCT 116 tumors were established
from cultured HCT 116 cells. Tumor volumes were determined three
times a week using a caliper. The weight of mice was determined as
an indicator of tolerability on the same days. Plasma samples were
taken on the last treatment day.
Main results (see FIGS. 1.1-1.3)
BRIEF DESCRIPTION OF THE FIGURES
[0179] FIG. 1.1 HCT 116 tumor responses to treatment with 30 mg/kg
exemplified compound Nr. 46 of Table 1, 12.5 mg/kg irinotecan or
both. HCT 116 tumor-bearing mice were treated intravenously with 30
mg/kg exemplified compound Nr. 46 of Table 1 once weekly
((q7d).times.10), with 12.5 mg/kg irinotecan once weekly
((q7d).times.10), with both in parallel ((q7d).times.10) or once
weekly with the vehicle only, and median tumor volumes were plotted
over time. Day 1 was the first day, day 64 the last day of
treatment and day 121 the final day of the study. The triangles
indicate the treatment days.
[0180] FIG. 1.2 Days until HCT 116 tumors reach 1000 mm3 in volume.
HCT 116 tumor-bearing mice were treated with 30 mg/kg exemplified
compound Nr. 46 of Table 1 i.v. once weekly ((q7d).times.10), with
12.5 mg/kg irinotecan i.p. once weekly ((q7d).times.10), or a
combination of both compounds ((q7d).times.10) at respective doses.
Vehicle treated mice (once weekly) were used as controls.
Individual days until HCT 116 tumors reach 1000 mm.sup.3 in volume
were plotted. Each symbol represents one individual tumor. The
horizontal lines represent the mean days.
[0181] FIG. 1.3 Change of body weight in response to treatment with
30 mg/kg exemplified compound Nr. 46 of Table 1, 12.5 mg/kg
irinotecan or both. HCT 116 tumor-bearing mice were treated
intravenously with 30 mg/kg exemplified compound Nr. 46 of Table 1
once weekly ((q7d).times.10), with 12.5 mg/kg irinotecan once
weekly ((q7d).times.10), with both in parallel ((q7d).times.10) or
once weekly with the vehicle only and average changes of body
weight were plotted over time. Day 1 was the first day, day 64 the
last day of treatment and day 121 the final day of the study. The
triangles indicate the treatment days. The triangles indicate the
treatment days.
Results on Day 39 (End of the Controls):
[0182] 30 mg/kg exemplified compound Nr. 46 of Table 1 i.v.
significantly delays HCT 116 tumor growth (T/C=20%, p<0.001)
12.5 mg/kg irinotecan i.p. significantly delays tumor growth
(T/C=25 %, p<0.001)
[0183] Combined administration of 30 mg/kg exemplified compound Nr.
46 of Table 1 and of 12.5 mg/kg irinotecan significantly delays
tumor growth (T/C=8%, p<0.001).
[0184] 30 mg/kg exemplified compound Nr. 46 of Table 1, 12.5 mg/kg
irinotecan and their combination are well tolerated. Control mice
gained 10.3% body weight. Mice treated with 30 mg/kg exemplified
compound Nr. 46 of Table 1 showed 8.6% body weight increase, mice
treated with 12.5 mg/kg irinotecan gained 5.9% body weight in
average, and mice treated with the combination gained 5.5.% body
weight.
Results on Day 121 (End of the Study):
[0185] Weekly treatment (until day 64) with exemplified compound
Nr. 46 of Table 1, irinotecan or a combination thereof delays the
average time to reach 1000 mm in tumor volume for 33.7 days, 35.1
days or 56.0 days, respectively.
Conclusions
[0186] A treatment with suboptimal doses of exemplified compound
Nr. 46 of Table 1 or irinotecan significantly delays tumor growth
and is well tolerated.
[0187] Treatment with the combination of suboptimal doses of
exemplified compound Nr. 46 of Table 1 and irinotecan shows a
significant growth delay and a higher efficacy than either of the
compounds alone, without a decrease in tolerability.
[0188] The comparison of the growth delay (time until 1000 mM3 in
tumor size) shows an additive/synergistic effect.
Combination of Exemplified Compound Nr. 46 of Table 1 and
Docetaxel
(NCI-H460 Lung Model)
Objective of the Study
[0189] Exemplified compound Nr. 46 of Table 1 is a potent and
selective inhibitor of the PLK1 serine/threonine kinase. Docetaxel
(sold under the Trade Name Taxotere.RTM.) is a standard
chemotherapeutic agent for treatment of lung cancer. Previous
studies have shown that exemplified compound Nr. 46 of Table 1 is
active on nude mice xenografts derived from the human lung cancer
cell line NCI-H460. The goal of the present study was to assess the
anti-cancer effects of suboptimal doses of exemplified compound Nr.
46 of Table 1 and docetaxel on NCI-H460 tumor growth when
administered alone or in combination. Suboptimal doses of both
compounds were used to facilitate the detection of additive,
synergistic or antagonistic effects.
Design of the Study
[0190] Model: Human non-small cell lung carcinoma model NCI-H460
grown as subcutaneous xenografts in nude mice. TABLE-US-00003
Treatment groups (intravenous administration, 10 animals per
group): Controls Vehicle, once weekly for 4 weeks ((q7 d) .times.
4) Exemplified compound Nr. 46 of Table 1 50 mg/kg, once weekly for
4 weeks ((q7 d) .times. 4) Docetaxel 15 mg/kg, once weekly for 4
weeks ((q7 d) .times. 4) Combination 50 mg/kg exemplified compound
Nr. 46 of Table 1, once weekly for 4 weeks ((q7 d) .times. 4) and
15 mg/kg Docetaxel, once weekly (3 days after exemplified compound
Nr. 46 of Table 1) for 4 weeks ((q7 d) .times. 4)
[0191] Tumor volumes and animal weights were recorded 3 times per
week. Evaluation of therapy results was based on the absolute
volumes of individual tumors.
[0192] Material and Methods:
[0193] Mice were female BomTac:NMRI-nu/nu. Exemplified compound Nr.
46 of Table 1 was dissolved in hydrochloric acid (0.1 N) diluted
with 0.9% NaCl and injected intravenously into the tail vein.
Docetaxel infusion concentrate was diluted with 0.9% NaCl and
injected intravenously. The administration volume was 10 ml per kg
body weight. NCI-H460 tumors were established from cultured
NCI-H460 cells. Tumor volumes were determined three times a week
using a caliper. The weight of mice was determined as an indicator
of tolerability on the same days. Plasma samples were taken on the
last treatment day.
Main Results (see FIGS. 2.1-2.3)
BRIEF DESCRIPTION OF THE FIGURES
[0194] FIG. 2.1 NCI-H460 tumor responses to treatment with 50 mg/kg
exemplified compound Nr. 46 of Table 1, 15 mg/kg Docetaxel or both.
NCI-H460 tumor-bearing mice were treated intravenously with 50
mg/kg exemplified compound Nr. 46 of Table 1 once weekly
((q7d).times.4), with 15 mg/kg Docetaxel once weekly
((q7d).times.4), with both in parallel or once weekly with the
vehicle only, and median tumor volumes were plotted over time. Day
1 was the first day, day 25 the last day of treatment and day 43
the last day of the calculation of the median tumor volume. The
triangles indicate the treatment days.
[0195] FIG. 2.2 Days until NCI-H460 tumors reach 1000 mm.sup.3 in
volume. NCI-H460 tumor-bearing mice were treated with 50 mg/kg
exemplified compound Nr. 46 of Table 1 i.v. once weekly
((q7d).times.4), with 15 mg/kg Docetaxel i.v. once weekly
((q7d).times.4), or a combination of both compounds at the same
doses. Vehicle treated mice (once weekly) were used as controls.
Individual days until NCI-H460 tumors reach 1000 mm.sup.3 in volume
were plotted. Each symbol represents one individual tumor. The
horizontal lines represent the median days.
[0196] FIG. 2.3
[0197] Change of body weight in response to treatment with 50 mg/kg
exemplified compound Nr. 46 of Table 1, 15 mg/kg Docetaxel or both.
NCI-H460 tumor-bearing mice were treated intravenously with 50
mg/kg exemplified compound Nr. 46 of Table 1 once weekly
((q7d).times.4), with 15 mg/kg Docetaxel once weekly
((q7d).times.4), with both in parallel or once weekly with the
vehicle only and average changes of body weight were plotted over
time. Day 1 was the first day, day 25 the last day of treatment and
day 43 the last day of the calculation of the median body weights.
The triangles indicate the treatment days.
Results on Day 17 (End of the Controls)
[0198] 50 mg/kg exemplified compound Nr. 46 of Table 1 i.v. once
weekly does not significantly delay NCI-H460 tumor growth (T/C=65%,
p>0.05).
[0199] 15 mg/kg Docetaxel i.v. once weekly significantly delays
tumor growth (T/C=42%, p<0.05).
[0200] Combined administration of 50 mg/kg exemplified compound Nr.
46 of Table 1 and of 15 mg/kg Docetaxel significantly delays tumor
growth (T/C=26%, p<0.001).
[0201] 50 mg/kg exemplified compound Nr. 46 of Table 1 is well
tolerated.
[0202] 15 mg/kg Docetaxel administered alone or in combination is
not well tolerated. Mice treated with 15 mg/kg Docetaxel on average
lost 4.8% body weight until day 17. The combination of exemplified
compound Nr. 46 of Table 1 and Docetaxel induced a body weight loss
of 8.3.%.
Results until Day 71 (End of the Study)
[0203] Weekly treatment (until day 25) with exemplified compound
Nr. 46 of Table 1, Docetaxel or a combination thereof delays the
average time to reach 1000 mm.sup.3 in tumor volume for 4.0 days,
10.5 days or 28.0 days compared to the controls, respectively.
[0204] Mice treated with 15 mg/kg Docetaxel further lost body
weight (up to 9.4% on day 24) and one mouse had to be euthanized
due to severe loss of body weight. Mice treated simultaneously with
exemplified compound Nr. 46 of Table 1 and Docetaxel further lost
body weight (up to 10.4% on day 24) and two mice had to be
euthanized due to severe loss of body weight.
Conclusions
[0205] A treatment with suboptimal doses of exemplified compound
Nr. 46 of Table 1 does not significantly delay tumor growth
(T/C=65%, p>0.05).
[0206] Docetaxel significantly delays tumor growth (T/C=42%,
p<0.05).
[0207] A combination of exemplified compound Nr. 46 of Table 1 and
Docetaxel shows a significant growth delay compared to the controls
(T/C=26%, p<0.001). The difference to the single treatment with
exemplified compound Nr. 46 of Table 1 is also significant
(p<0.01), indicating that the two agents might act at least
additively.
Combination of Exemplified Compound Nr. 46 of Table 1 and
Gemcitabine
(BxPC-3 Pancreas Model)
Objective of the Study
[0208] Exemplified compound Nr. 46 of Table 1 is a potent and
selective inhibitor of the serine/threonine kinase PLK1.
Gemcitabine (sold under the Trade Name Gemzar.RTM.) is a standard
chemotherapeutic agent for treatment of pancreatic adenocarcinomas
. The goal of the present study was to assess the anti-cancer
efficacy of suboptimal doses of exemplified compound Nr. 46 of
Table 1, gemcitabine and their combination in the human pancreas
adenocarcinoma model BxPC-3 grown as xenograft in nude mice.
Suboptimal doses of both compounds were used to facilitate the
detection of additive, synergistic or antagonistic effects.
Design of the Study
[0209] Model: Human adenocarcinoma model BxPC-3 grown as
subcutaneous xenografts in nude mice. TABLE-US-00004 Treatment
groups (10 animals per group): Controls Vehicle, i.v., once weekly
for 4 weeks ((q7 d) .times. 4) Exemplified compound Nr. 46 of Table
1 50 mg/kg, i.v., once weekly for 6 weeks ((q7 d) .times. 6)
Gemcitabine 100 mg/kg, i.p., once weekly for 6 weeks ((q7 d)
.times. 6) Combination 50 mg/kg exemplified compound Nr. 46 of
Table 1, i.v., once weekly for 6 weeks ((q7 d) .times. 6) and 100
mg/kg gemcitabine, i.p., once weekly (.about.1 h after exemplified
compound Nr. 46 of Table 1) for 6 weeks ((q7 d) .times. 6)
[0210] Tumor volumes and animal weights were recorded 3 times per
week. Evaluation of therapy results was based on the absolute
volumes of individual tumors.
[0211] Material and Methods:
[0212] Mice were female BomTac:NMRI-nu/nu. Exemplified compound Nr.
46 of Table 1 was dissolved in hydrochloric acid (0.1 N) diluted
with 0.9% NaCl and injected intravenously into the tail vein.
Gemcitabin infusion concentrate was diluted with 0.9% NaCl and
injected intraperitoneally. The administration volume was 10 ml per
kg body weight for both compounds. BxPC-3 tumours were established
from cultured BxPC-3. Tumour volumes were determined three times a
week using a calliper. The weight of mice was determined as an
indicator of tolerability on the same days. Plasma samples were
taken on the last treatment day.
Main Results (see FIGS. 3.1-3.2)
BRIEF DESCRIPTION OF THE FIGURES
[0213] FIG. 3.1 BxPC-3 tumor responses to treatment with 50 mg/kg
exemplified compound Nr. 46 of Table 1, 100 mg/kg gemcitabine or
both. BxBC-3 tumor-bearing mice were treated intravenously with 50
mg/kg exemplified compound Nr. 46 of Table 1 once weekly
((q7d).times.6), with 100 mg/kg gemcitabine once weekly
((q7d).times.6), with both in parallel or once weekly with the
vehicle only, and median tumour volumes were plotted over time. Day
1 was the first day, day 36 the last day of treatment and day 26
the last day of the calculation of the median tumour volume.
[0214] FIG. 3.2 Change of body weight in response to treatment with
50 mg/kg exemplified compound Nr. 46 of Table 1, 100 mg/kg
gemcitabine or both. BxPC-3 tumour-bearing mice were treated
intravenously with 50 mg/kg exemplified compound Nr. 46 of Table 1
once weekly ((q7d).times.6), with 100 mg/kg gemcitabine once weekly
((q7d).times.6), with both in parallel or once weekly with the
vehicle only and average changes of body weight were plotted over
time. Day 1 was the first day, day 36 the last day of treatment and
day 43 the last day of the calculation of the median body weights.
The triangles indicate the treatment days.
Results on Day 26 (End of the Controls):
[0215] 50 mg/kg exemplified compound Nr. 46 of Table 1 i.v.
significantly delays HCT 116 tumour growth (T/C=28%).
[0216] 100 mg/kg gemcitabine i.p. only marginally delays tumour
growth (T/C=65%) Higher doses of gemcitabine were not
tolerated.
[0217] A combined administration of 50 mg/kg exemplified compound
Nr. 46 of Table 1 and of 100 mg/kg gemcitabine delays tumour growth
to the same extend as exemplified compound Nr. 46 of Table 1 alone
(T/C=24%).
[0218] 50 mg/kg exemplified compound Nr. 46 of Table 1, 100 mg/kg
gemcitabine and their combination were well tolerated. Control mice
gained 6.2% body weight. Mice treated with 50 mg/kg exemplified
compound Nr. 46 of Table 1 showed 8.2% body weight increase, mice
treated with 100 mg/kg gemcitabine gained 8.8% in average and mice
treated with the combination gained 8.5.% body weight.
[0219] Results on day 43 (end of the study): [0220] Weekly
treatment (until day 36) with exemplified compound Nr. 46 of Table
1 or a combination of exemplified compound Nr. 46 of Table 1 and
gemcitabine delays the average time to reach 1000 mm.sup.3 in
tumour volume to the same extend. There is no significant
difference between the two treatment groups. Conclusions
[0221] Treatment with suboptimal doses of exemplified compound Nr.
46 of Table 1 significantly delays tumour growth and is tolerated
well. In contrast, the maximal tolerated dose of gemcitabine does
not result in significant anti-tumour activity.
[0222] Treatment with the combination of suboptimal doses of
exemplified compound Nr. 46 of Table 1 and gemcitabine shows a
comparable growth delay as exemplified compound Nr. 46 of Table 1
alone, indicating that the two agents do not act antagonistically
in this model.
[0223] A process for the manufacture of exemplified compound Nr. 46
of Table 1, i.e. the compound
4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pterid-
inyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide, is
described in WO 03/20722 as well as in WO 04/76454, which are
incorporated herein by reference.
[0224] However, for the sake of completeness, a process for the
manufacture of the compound
4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pterid-
inyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide is
described as well hereinafter. This method is to be understood as
an illustration of the invention without restricting it to the
subject matter thereof.
Synthesis of
4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pterid-
inyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide
[0225] For the synthesis, first of all an intermediate compound Z3
is prepared as described below. ##STR56##
[0226] 54.0 g (0.52 mol) D-2-aminobutyric acid are suspended in 540
mL methanol and slowly combined with 132 g (1.1 mol) thionyl
chloride while cooling with ice. The mixture is refluxed for 1.5 h
and then evaporated down. The oil remaining is combined with 540 mL
tert-butylmethylether and the colourless crystals formed are
suction filtered. Yield: 78.8 g of a compound Z3a (colourless
crystals)
[0227] 74.2 g of the compound Z3a and 43.5 mL (0.49 mol)
cyclopentanone are dissolved in 800 mL dichloromethane. After the
addition of 40.0 g (0.49 mol) sodium acetate and 150.0 g (0.71 mol)
sodium triacetoxyborohydride at 0C the mixture is stirred for 12 h
at ambient temperature and then 500 mL of 20% sodium hydrogen
carbonate solution are added. The aqueous phase is extracted with
dichloromethane. The combined organic phases are washed with water,
dried over MgSO.sub.4 and evaporated down. Yield: 85.8 g of a
compound Z3b (light yellow oil)
[0228] 40.0 g of the compound Z3b and 30.0 g (0.22 mol) potassium
carbonate are suspended in 600 mL acetone and combined with 45.0 g
(0.23 mol) 2,4-dichloro-5-nitropyrimidin in 200 mL acetone while
cooling with ice. After 12 h a further 5.0 g
2,4-dichloro-5-nitropyrimidin are added and stirred for 3 h. The
reaction mixture is evaporated down, taken up in 800 mL ethyl
acetate and 600 mL water and the aqueous phase is extracted with
ethyl acetate. The combined organic phases are washed with water,
dried over MgSO.sub.4 and evaporated down. Yield: 75.0 g of a
compound Z3c (brown oil)
[0229] 100 g of the compound Z3c are dissolved in 650 mL glacial
acetic acid and at 70.degree. C. 20 g of iron powder are added
batchwise. The mixture is stirred for 1 h at 70.degree. C., then
for 1.5 h at 100.degree. C. and then filtered hot through diatomite
(kieselguhr). The reaction mixture is evaporated down, taken up in
methanol/dichloromethane, applied to silica gel and purified with
ethyl acetate by Soxhlet extraction. The solvent is removed and the
residue stirred with methanol. Yield: 30.0 g of a compound Z3d
(light brown crystals)
[0230] 25.0 g of the compound Z3d and 6.5 mL (0.1 mol) methyl
iodide are placed in 250 mL dimethylacetamide and at -10.degree. C.
3.8 g (0.95 mol) sodium hydride as a 60% dispersion in mineral oil
is added. It is stirred for 20 min at 0.degree. C., then for 30 min
at ambient temperature and finally ice is added. The reaction
mixture is evaporated down and combined with 300 mL water. The
precipitate formed is suction filtered and washed with petroleum
ether. Yield: 23.0 g of a compound Z3e (colourless solid)
[0231] 6.0 g of the compound Z3e and 5.1 g (31 mmol)
4-amino-3-methoxybenzoic acid are suspended in 90 mL ethanol and
350 mL water, combined with 3.5 mL concentrated hydrochloric acid
and refluxed for 48 h. The reaction mixture is evaporated down, the
residue stirred with methanol/diethyl ether and the precipitate
formed is suction filtered. Yield: 6.3 g of a compound Z3 (light
beige crystals)
[0232]
4-[[(7R)-8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-
-pteridinyl]amino]-3-methoxy-N-(1-methyl-4-piperidinyl)-benzamide
is obtained as described below.
[0233] 0.15 g of the compound Z3, 0.12 g TBTU, 0.12 mL DIPEA are
dissolved in 5 mL dichloromethane and stirred for 30 minutes at
25.degree. C. Then 50 mg 1-methyl-4-aminopiperidin are added and
the mixture is stirred for a further 2.5 hours at 25.degree. C. The
solution is then extracted with water and then evaporated down. The
residue is dissolved in warm ethyl acetate and crystallised from
ether and petroleum ether. Yield: 0.025 g of white crystals. M.p.:
203.degree. C. as the base.
[0234] All compounds of Formula (I) according to the invention may
be prepared by the synthesis methods A described hereinafter, while
the substituents of general Formula (A1) to (A9) have the meanings
given hereinbefore. This method is to be understood as an
illustration of the invention without restricting it to the subject
matter thereof.
Method A
Step 1A
[0235] A compound of Formula (A1) is reacted with a compound of
Formula (A2) to obtain a compound of Formula (A3) (Diagram 1A).
This reaction may be carried out according to WO 00/43369 or WO
00/43372. Compound (A1) is commercially obtainable, for example,
from City Chemical LLC, 139 Allings Crossing Road, West Haven,
Conn., 06516, USA. Compound (A2) may be prepared by procedures
known from the literature: (a) F. Effenberger, U. Burkhart, J.
Willfahrt Liebigs Ann. Chem. 1986, 314-333; (b) T. Fukuyama, C.-K.
Jow, M. Cheung, Tetrahedron Lett. 1995, 36, 6373-6374; (c) R. K.
Olsen, J. Org. Chem. 1970, 35, 1912-1915; (d) F. E. Dutton, B. H.
Byung Tetrahedron Lett. 1998, 30, 5313-5316; (e) J. M. Ranajuhi, M.
M. Joullie Synth. Commun. 1996, 26, 1379-1384). ##STR57##
[0236] In Step 1A, 1 equivalent of the compound (A1) and 1 to 1.5
equivalents, preferably 1.1 equivalents of a base, preferably
potassium carbonate, potassium hydrogen carbonate, sodium carbonate
or sodium hydrogen carbonate, calcium carbonate, most preferably
potassium carbonate, are stirred in a diluent optionally mixed with
water, for example acetone, tetrahydrofuran, diethylether,
cyclohexane, petroleum ether or dioxane, preferably cyclohexane or
diethylether.
[0237] At a temperature of 0 to 15.degree. C., preferably 5 to
10.degree. C., 1 equivalent of an amino acid of Formula (A2),
dissolved in an organic solvent, for example acetone,
tetrahydrofurane, diethylether, cyclohexane or dioxane, is added
dropwise. The reaction mixture is heated to a temperature of
18.degree. C. to 30.degree. C., preferably about 22.degree. C.,
with stirring and then stirred for a further 10 to 24 hours,
preferably about 12 hours. Then the diluent is distilled off, the
residue is combined with water and the mixture is extracted two to
three times with an organic solvent, such as diethylether or ethyl
acetate, preferably ethyl acetate. The combined organic extracts
are dried and the solvent is distilled off. The residue (compound
A3) may be used in Step 2 without any prior purification.
Step 2A
[0238] The compound obtained in Step 1A (A3) is reduced at the
nitro group and cyclised to form the compound of Formula (A4)
(Diagram 2A). ##STR58##
[0239] In Step 2A, 1 equivalent of the nitro compound (A3) is
dissolved in an acid, preferably glacial acetic acid, formic acid
or hydrochloric acid, preferably glacial acetic acid, and heated to
50 to 70.degree. C., preferably about 60.degree. C. Then a reducing
agent, for example zinc, tin or iron, preferably iron filings, is
added to complete the exothermic reaction and the mixture is
stirred for 0.2 to 2 hours, preferably 0.5 hours, at 100 to
125.degree. C., preferably at about 117.degree. C. After cooling to
ambient temperature the iron salt is filtered off and the solvent
is distilled off. The residue is taken up in a solvent or mixture
of solvents, for example ethyl acetate or dichloromethane/methanol
9/1 and semisaturated NaCl solution, and filtered through
kieselgur, for example. The organic phase is dried and evaporated
down. The residue (compound (A4)) may be purified by chromatography
or by crystallisation or used as the crude product in Step 3A of
the synthesis.
Step 3A
[0240] The compound obtained in Step 2A (A4) may be reacted by
electrophilic substitution as shown in Diagram 3A to obtain the
compound of Formula (A5). ##STR59##
[0241] In Step 3A 1 equivalent of the amide of Formula (A4) is
dissolved in an organic solvent, for example dimethylformamide or
dimethylacetamide, preferably dimethylacetamide, and cooled to
about -5 to 5.degree. C., preferably 0.degree. C.
[0242] Then 0.9 to 1.3 equivalents of sodium hydride and 0.9 to 1.3
equivalents of a methylating reagent, e.g. methyl iodide, are
added. The reaction mixture is stirred for 0.1-3 hours, preferably
about 1 hour, at about 0 to 10.degree. C., preferably at about
5.degree. C., and may optionally be left to stand for a further 12
hours at this temperature. The reaction mixture is poured onto ice
water and the precipitate is isolated. The residue (compound (A5))
may be purified by chromatography, preferably over silica gel, or
by crystallisation, or used as the crude product in step 4A of the
synthesis.
Step 4A
[0243] The amination of the compound (A5) obtained in Step 3A to
yield the compound of Formula (A9) (Diagram 4A) may be carried out
using the methods known from the literature, for variants 4.1 A
from e.g. (a) M. P. V. Boariand, J. F. W. McOmie J. Chem. Soc.
1951, 1218-1221 or (b) F. H. S. Curd, F. C. Rose J. Chem. Soc.
1946, 343-348, for variants 4.2 A from e.g. (a) Banks J. Am. Chem.
Soc. 1944, 66, 1131, (b) Ghosh and Dolly J. Indian Chem. Soc. 1981,
58, 512-513 or (c) N. P. Reddy and M. Tanaka Tetrahedron Lett.
1997, 38, 4807-4810. ##STR60##
[0244] For example, in variant 4.1 A, 1 equivalent of the compound
(A5) and 1 to 3 equivalents, preferably about 2 equivalents of the
compound (A6) are heated without a solvent or in an organic solvent
such as for example sulpholane, dimethylformamide,
dimethylacetamide, toluene, N-methylpyrrolidone, dimethylsulphoxide
or dioxane, preferably sulpholane, for 0.1 to 4 hours, preferably 1
hour, at 100 to 220.degree. C., preferably at about 160.degree. C.
After cooling, the product (A9) is crystallised by the addition of
organic solvents or mixtures of solvents, e.g.
diethylether/methanol, ethyl acetate, methylene chloride, or
diethylether, preferably diethylether/methanol 9/1, or purified by
chromatography.
[0245] For example, in variant 4.2 A, 1 equivalent of the compound
(A5) and 1 to 3 equivalents of the compound (A6) are stirred with
acid, for example 1-10 equivalents of 10-38% hydrochloric acid
and/or an alcohol, for example ethanol, propanol, butanol,
preferably ethanol, at reflux temperature for 1 to 48 hours,
preferably about 5 hours. The product precipitated (A9) is filtered
off and optionally washed with water, dried and crystallised from a
suitable organic solvent.
[0246] For example, in variant 4.3 A, 1 equivalent of the compound
(A5) and 1 to 3 equivalents of the compound (A7) are dissolved in a
solvent, for example toluene or dioxane and combined with a
phosphine ligand, for example
2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl and a palladium
catalyst, for example tris(dibenzylidene-acetone)-dipalladium(0)
and a base, for example caesium carbonate, and refluxed for 1-24 h,
preferably 17 h. The reaction mixture is purified for example over
silica gel and the product (A8) is isolated from the solution or
obtained by suitable crystallisation. The product (A8) is dissolved
in a suitable solvent, for example dioxane and mixed with acid, for
example semiconcentrated hydrochloric acid, for example in the
ratio of solvent to acid of 3:1. Then the mixture is refluxed for
1-48 h, for example 12 h, and the precipitate formed is isolated.
If desired the product (A9) is purified by crystallisation. Step 5A
##STR61##
[0247] For example, 1 equivalent of the compound (A9) is dissolved
with 1 equivalent of an activating reagent, e.g.
O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) and a base, for example 1.5 equivalents of
diisopropylethylamine (DIPEA) in an organic diluent, for example
dichloromethane, tetrahydrofuran, dimethylformamide,
N-methylpyrrolidone, dimethylacetamide, preferably dichloromethane
or dimethylformamide. After the addition of 1 equivalent of the
amine (A10) the reaction mixture is stirred for 0.1 to 24 hours,
preferably about 2 hours at 20.degree. C. to 100.degree. C. The
product of Formula (A11) is obtained for example by crystallisation
or chromatographic purification.
[0248] The compounds of general Formula (I) may be synthesised
analogously to the following examples of synthesis. The numbering
of the Examples corresponds to the numbering used in Table 1. These
Examples are, however, intended only as examples of procedures to
illustrate the invention further, without restricting the invention
to their subject matter.
[0249] The preparation of some intermediate compounds used to
synthesise the compounds is also described hereinafter.
Preparation of the Acids
[0250] To synthesise the compounds of Examples 94 and 95 of Table
1, first an intermediate compound Z1 ##STR62## is prepared as
described hereinafter.
[0251] 50.0 g (0.48 mol) of D-alanine methyl ester.times.HCl and
49.1 g (0.50 mol) cyclohexanone are placed in 300 mL
dichloromethane and then combined with 41.0 g (0.50 mol) sodium
acetate and 159.0 g (0.75 mol) sodium triacetoxyborohydride. The
mixture is stirred overnight and then 300 mL of 10% sodium hydrogen
carbonate solution are added. The aqueous phase is extracted with
dichloromethane. The combined organic phases are washed with 10%
sodium hydrogen carbonate solution, dried over Na.sub.2SO.sub.4 and
evaporated down. Yield: 72.5 g of a compound Z1a (clear liquid)
[0252] 72.5 g of the compound Z1a are placed in 500 mL water and
76.6 g (0.39 mol) of 2,4-dichloro-5-nitropyrimidine in 500 mL
diethyl ether are added. At a temperature of -5.degree. C. 100 mL
10% potassium hydrogen carbonate solution are added dropwise. The
mixture is stirred for 3 h at -5.degree. C. and for a further 12 h
at ambient temperature. The organic phase is separated off and
dried over Na.sub.2SO.sub.4. On evaporation, the product
crystallizes out. Yield: 48.0 g of a compound Z1b (yellow
crystals)
[0253] 48.0 g of the compound Z1b are dissolved in 350 mL glacial
acetic acid and heated to 60.degree. C. 47.5 g of iron powder are
added, while the temperature rises to 105.degree. C. The reaction
mixture is stirred for three hours at 80.degree. C., then filtered
hot through cellulose and evaporated down. The residue is stirred
in water and ethyl acetate, suction filtered and the light-grey
precipitate is washed with ethyl acetate. The filtrate is washed
with dilute ammonia and water, the organic phase is dried over
Na.sub.2SO.sub.4, filtered through activated charcoal and
evaporated down. Some more light-grey solids are obtained. Yield:
29.5 g of a compound Z1c (light-grey crystals)
[0254] 32.1 g of the compound Z1c are placed in 300 mL
dimethylacetamide and combined with 13 mL (0.2 mol) methyl iodide.
At -5.degree. C. 6.4 g (0.16 mol) sodium hydride as a 60%
dispersion in mineral oil is added batchwise. After 2 h the
reaction mixture is poured onto 800 mL ice water. The precipitate
formed is suction filtered and washed with petroleum ether. Yield:
33.0 g of a compound Z1d (beige crystals)
[0255] 4.0 g of the compound Z1d and 2.3 g (15 mmol)
4-amino-3-methylbenzoic acid are suspended in 50 mL ethanol and 120
mL water, combined with 2 mL concentrated hydrochloric acid and
refluxed for 48 h. The precipitate formed on cooling is suction
filtered and washed with water, ethanol and diethyl ether. Yield:
2.9 g of a compound ZI (colourless crystals)
[0256] To synthesise the compounds Example 188 and Example 203 of
Table 1, first of all an intermediate compound Z2 ##STR63## is
prepared as described below.
[0257] A solution of 128.2 g (0.83 mol) D-alanine ethyl
ester.times.HCl and 71.5 g (0.85 mol) cyclopentanone in 1500 mL
dichloromethane is combined with 70.1 (0.85 mol) sodium acetate and
265.6 g (1.25 mol) sodium triacetoxyborohydride. The reaction
mixture is stirred for 12 h and then poured into 1.5 L of a 10%
sodium hydrogen carbonate solution. The aqueous phase is extracted
with dichloromethane. The combined organic phases are dried over
Na.sub.2SO.sub.4 and evaporated down. Yield: 143.4 g of a compound
Z2a (colourless oil)
[0258] 66.0 g of the compound Z2a are placed in 500 mL water and
combined with 85.0 g (0.44 mol) 2,4-dichloro-5-nitropyrimidine in
500 mL diethyl ether. At -5.degree. C. 100 mL 10% potassium
hydrogen carbonate solution are added dropwise and the reaction
mixture is stirred for 48 h at ambient temperature. The aqueous
phase is extracted with diethyl ether, the combined organic phases
are dried over Na.sub.2SO.sub.4 and evaporated down. The dark red
solid is stirred with petroleum ether and suction filtered. Yield:
88.0 g of a compound Z2b (yellow crystals)
[0259] 88.0 g of the compound Z2b are dissolved in 1000 mL glacial
acetic acid and at 60.degree. C. combined batchwise with 85 g iron
powder, while the temperature rises to 110.degree. C. It is stirred
for 1 h at 60.degree. C., then suction filtered hot through
cellulose and evaporated down. The brown solid is stirred with 700
mL water and suction filtered. Yield: 53.3 g of a compound Z2c
(light brown crystals)
[0260] 53.3 g of the compound Z2c are dissolved in 300 mL
dimethylacetamide and combined with 13 mL (0.21 mol) methyl iodide.
At -5.degree. C. 5.0 g (0.21 mol) sodium hydride as a 60%
dispersion in mineral oil are added batchwise. After 12 h the
reaction mixture is poured onto 1000 mL ice water and the
precipitate formed is suction filtered. Yield: 40.0 g of a compound
Z2d (colourless crystals)
[0261] 4.0 g of the compound Z2d and 2.8 g (16 mmol)
4-amino-3-chlorbenzoic acid are suspended in 25 mL ethanol and 60
mL water, combined with 3 mL concentrated hydrochloric acid and
refluxed for 43 h. The precipitate formed on cooling is suction
filtered and washed with water, ethanol and diethyl ether. Yield:
0.9 g of a compound Z2 (colourless crystals)
[0262] To synthesise the compounds of Examples 19, 21, 22, 23, 45,
46, 55, 58, 116, 128, 131, 133, 134, 136, 138, 177, 217, 231, 239,
46, 184, 166 and 187 of Table 1, first of all an intermediate
compound Z3 ##STR64## is prepared as described below.
[0263] 54.0 g (0.52 mol) D-2-aminobutyric acid are suspended in 540
mL methanol and slowly combined with 132 g (1.1 mol) thionyl
chloride while cooling with ice. The mixture is refluxed for 1.5 h
and then evaporated down. The oil remaining is combined with 540 mL
tert-butylmethylether and the colourless crystals formed are
suction filtered. Yield: 78.8 g of a compound Z3a (colourless
crystals)
[0264] 74.2 g of the compound Z3a and 43.5 mL (0.49 mol)
cyclopentanone are dissolved in 800 mL dichloromethane. After the
addition of 40.0 g (0.49 mol) sodium acetate and 150.0 g (0.71 mol)
sodium triacetoxyborohydride at 0.degree. C. the mixture is stirred
for 12 h at ambient temperature and then 500 mL of 20% sodium
hydrogen carbonate solution are added. The aqueous phase is
extracted with dichloromethane. The combined organic phases are
washed with water, dried over MgSO.sub.4 and evaporated down.
Yield: 85.8 g of a compound Z3b (light yellow oil)
[0265] 40.0 g of the compound Z3b and 30.0 g (0.22 mol) potassium
carbonate are suspended in 600 mL acetone and combined with 45.0 g
(0.23 mol) 2,4-dichloro-5-nitropyrimidin in 200 mL acetone while
cooling with ice. After 12 h a further 5.0 g
2,4-dichloro-5-nitropyrimidin are added and stirred for 3 h. The
reaction mixture is evaporated down, taken up in 800 mL ethyl
acetate and 600 mL water and the aqueous phase is extracted with
ethyl acetate. The combined organic phases are washed with water,
dried over MgSO.sub.4 and evaporated down. Yield: 75.0 g of a
compound Z3c (brown oil)
[0266] 100 g of the compound Z3c are dissolved in 650 mL glacial
acetic acid and at 70.degree. C. 20 g of iron powder are added
batchwise. The mixture is stirred for 1 h at 70.degree. C., then
for 1.5 h at 100.degree. C. and then filtered hot through
kieselgur. The reaction mixture is evaporated down, taken up in
methanol/dichloromethane, applied to silica gel and purified with
ethyl acetate by Soxhlet extraction. The solvent is removed and the
residue stirred with methanol. Yield: 30.0 g of a compound Z3d
(light brown crystals)
[0267] 25.0 g of the compound Z3d and 6.5 mL (0.1 mol) methyl
iodide are placed in 250 mL dimethylacetamide and at -10.degree. C.
3.8 g (0.95 mol) sodium hydride as a 60% dispersion in mineral oil
is added. It is stirred for 20 min at 0.degree. C., then for 30 min
at ambient temperature and finally ice is added. The reaction
mixture is evaporated down and combined with 300 mL water. The
precipitate formed is suction filtered and washed with petroleum
ether. Yield: 23.0 g of a compound Z3e (colourless solid)
[0268] 6.0 g of the compound Z3e and 5.1 g (31 mmol)
4-amino-3-methoxybenzoic acid are suspended in 90 mL ethanol and
350 mL water, combined with 3.5 mL concentrated hydrochloric acid
and refluxed for 48 h. The reaction mixture is evaporated down, the
residue stirred with methanol/diethyl ether and the precipitate
formed is suction filtered. Yield: 6.3 g of a compound Z3 (light
beige crystals)
[0269] To synthesise the compound of Examples 81, 82, 93 and 137 of
Table 1, first of all an intermediate compound Z4 ##STR65## is
prepared as described below.
[0270] 25.0 g (0.19 mol) of ethyl
1-aminocyclopropane-1-carboxylate.times.HCl and 16.8 g (0.20 mol)
of cyclopentanone are dissolved in 300 mL of dichloromethane and
combined with 16.4 g (0.20 mol) of sodium acetate and 61.7 g (0.29
mol) of sodium triacetoxyborohydride. It is stirred overnight and
the reaction mixture is then poured onto 400 mL of 10% sodium
hydrogen carbonate solution. The aqueous phase is extracted with
dichloromethane. The combined organic phases are dried over
Na.sub.2SO.sub.4 and evaporated down. Yield: 34.5 g of a compound
Z4a (colourless oil)
[0271] 42.5 g (0.22 mol) of 2,4-dichloro-5-nitropyrimidine in 350
mL of diethyl ether are added to a mixture of 34.5 g of the
compound Z4a in 350 mL water. At -5.degree. C. the mixture is
combined with 80 mL 10% potassium hydrogen carbonate solution and
stirred overnight at ambient temperature. The aqueous phase is
extracted with diethyl ether. The combined organic phases are dried
over Na.sub.2SO.sub.4 and evaporated down. Yield: 53.8 g of a
compound Z4b (brown oil)
[0272] 20.1 g of the compound Z4b are dissolved in 200 mL glacial
acetic acid and combined batchwise at 60.degree. C. with 19.1 g
iron powder, during which time the temperature rose to 100.degree.
C. The mixture is stirred for 3 h at 60.degree. C., then suction
filtered through cellulose and evaporated down. The residue is
stirred in water and ethyl acetate and the yellow precipitate is
suction filtered. The filtrate is washed with dilute ammonia and
water, the organic phase dried over Na.sub.2SO.sub.4 and evaporated
down. After the addition of diethyl ether additional product
crystallised out. Yield: 4.0 g of a compound Z4c (yellow
crystals)
[0273] 7.8 g of the compound Z4c and 2.6 mL (0.04 mol) methyl
iodide are dissolved in 100 mL dimethylacetamide and at -5.degree.
C. 1.5 g (0.04 mol) sodium hydride are added batchwise as a 60%
dispersion in mineral oil. After 2 h the reaction mixture is poured
onto ice water and the precipitate formed is suction filtered.
Yield: 7.5 g of a compound Z4d (light brown crystals)
[0274] 3.0 g of the compound Z4d and 1.9 g (11 mmol)
4-amino-3-methoxybenzoic acid are suspended in 40 mL ethanol and 80
mL water, combined with 2 mL concentrated hydrochloric acid and
refluxed for 20 h. A further 0.5 g of 4-amino-3-methoxybenzoic acid
are added and refluxed for48 h. The precipitate formed on cooling
is suction filtered and washed with water, ethanol and diethyl
ether. Yield: 2.1 g of a compound Z4 (colourless crystals) m.p.:
222-223.degree. C.
[0275] To synthesise the compounds of Examples 162, 43, 53, 161,
202, 211, 215 and 212 of Table 1, first of all an intermediate
compound Z5 ##STR66## is prepared as described below.
[0276] A mixture of 73.4 mL (0.5 mol) ethyl 2-bromoisobutyrate,
87.1 mL (0.75 mol) of 3-methyl-1-butylamine, 82.5 g (0.6 mol)
sodium iodide and 76.0 g (0.6 mol) of potassium carbonate in 1000
mL ethyl acetate is refluxed for3 days. Any salts present are
filtered off and the filtrate evaporated down. Yield: 97.0 g of a
compound Z5a (red oil)
[0277] 49.0 g (0.25 mol) of 2,4-dichloro-5-nitropyrimidine and 38.3
g (0.28 mol) of potassium carbonate are suspended in 500 mL acetone
and at 0.degree. C. combined with 93.0 g of the compound Z5a in 375
mL acetone. The reaction mixture is stirred overnight at ambient
temperature, filtered and evaporated down. The residue dissolved in
ethyl acetate is washed with water and the organic phase dried over
MgSO.sub.4 and evaporated down. Yield: 102.7 g of a compound Z5b
(brown oil)
[0278] 22.7 g of the compound Z5b are dissolved in 350 mL glacial
acetic acid and at 60.degree. C. combined batchwise with 17.4 g
iron powder. After the addition ends the mixture is refluxed for
0.5 h, filtered hot and evaporated down. The residue is taken up in
200 mL dichloromethane/methanol (9:1) and washed with sodium
chloride solution. The organic phase is suction filtered through
kieselguhr, dried over MgSO.sub.4, evaporated down and purified by
column chromatography (eluant: ethyl acetate/cyclohexane 1: 1).
Yield: 1.9 g of a compound Z5c (colourless crystals)
[0279] 1.9 g of the compound Z5c are dissolved in 32 mL
dimethylacetamide and while cooling with ice combined with 0.3 g (7
mmol) sodium hydride as a 60% dispersion in mineral oil. After 10
min 0.5 mL (7 mmol) methyl iodide are added and stirred for 3 h at
ambient temperature. The reaction mixture is evaporated down and
combined with water. The precipitate formed is suction filtered and
washed with petroleum ether. Yield: 1.6 g of a compound Z5d
(colourless crystals)
[0280] 14.0 g of the compound Z5d and 10.0 g (0.06 mol)
4-amino-3-methoxybenzoic acid are suspended in 200 mL dioxane and
80 mL water, combined with 10 mL concentrated hydrochloric acid and
refluxed for 40 h. The precipitate formed on cooling is suction
filtered and washed with water, dioxane and diethyl ether. Yield:
13.9 g of a compound Z5 (colourless crystals)
[0281] To synthesise the compounds of Examples 88, 194, 229 and 89
of Table 1, first of all an intermediate compound Z6 ##STR67## is
prepared as described below.
[0282] 6.0 g (0.06 mol) L-2-aminobutyric acid is placed in 80 mL
0.5 M sulphuric acid and at 0.degree. C. combined with 5.5 g (0.08
mol) sodium nitrite in 15 mL water. The reaction mixture is stirred
for 22 h at 0.degree. C., combined with ammonium sulphate and
filtered. The filtrate is extracted with diethyl ether and the
combined organic dried over MgSO.sub.4 and evaporated down. Yield:
6.0 g of a compound Z6a (yellow oil)
[0283] 200 mL methanol are combined successively with 65.0 mL (0.89
mol) thionyl chloride and 76.0 g of the compound Z6a in 50 mL
methanol while cooling with ice. The resulting mixture is stirred
for 1 h at 0.degree. C. and 2 h at ambient temperature and then the
methanol and remaining thionyl chloride are eliminated in vacuo at
0C. Yield: 40.0 g of a compound Z6b (yellow oil)
[0284] 30.0 mL (0.17 mol) of trifluoromethanesulphonic acid
anhydride are placed in 150 mL dichloromethane and while cooling
with ice a solution of 20.0 g of the compound Z6b and 14.0 mL (0.17
mol) pyridine in 50 mL dichloromethane is added within one hour.
The mixture is stirred for 2 h at ambient temperature, any salts
formed are suction filtered and then washed with 100 mL water. The
organic phase is dried over MgSO.sub.4 and evaporated down. Yield:
42.0 g of a compound Z6c (light yellow oil)
[0285] 42.0 g of the compound Z6c in 200 mL dichloromethane is
added dropwise within one hour to a solution of 15.5 mL (0.17 mol)
of aniline and 24.0 mL (0.17 mol) of triethylamine in 400 mL
dichloromethane while cooling with ice. The mixture is stirred for
1 h at ambient temperature and a further 2 h at 35.degree. C. The
reaction mixture is washed with water, dried over MgSO.sub.4 and
evaporated down. The residue remaining is purified by distillation
(95-100.degree. C., 1*10.sup.-3 mbar). Yield: 14.0 of a compound
Z6d (colourless oil)
[0286] 14.0 g of the compound Z6d and 16.0 g (0.1 mol) potassium
carbonate are suspended in 100 mL acetone and at 10.degree. C.
combined with 16.0 g (0.08 mol) of 2,4-dichloro-5-nitropyrimidine.
The mixture is stirred for 4 h at 40.degree. C., any salts formed
are suction filtered and the filtrate evaporated down. The residue
is taken up in 300 mL ethyl acetate and washed with water. The
organic phase is dried over MgSO.sub.4 and evaporated down. Yield:
31.0 g of a compound Z6e (brown oil)
[0287] 31.0 g of the compound Z6e are dissolved in 200 mL glacial
acetic acid and at 60.degree. C. combined batchwise with 10 g iron
powder, during which time the temperature rose to 85.degree. C. The
mixture is stirred for a further hour at 60.degree. C., filtered
through kieselguhr and evaporated down. The residue is stirred with
methanol. Yield: 4.5 g of a compound Z6f (brown crystals)
[0288] At -20.degree. C. 0.6 g (16 mmol) of sodium hydride as a 60%
dispersion in mineral oil are added batchwise to a mixture of 4.5 g
of the compound Z6f and 1.0 mL (16 mmol) methyl iodide in 100 mL
dimethylacetamide. After 1 h the reaction mixture is combined with
50 mL water and evaporated down. The residue is stirred with 200 mL
water, the precipitate is suction filtered and washed with
petroleum ether. Yield: 4.5 g of a compound Z6g (colourless
crystals)
[0289] A suspension of 1.5 g of the compound Z6g and 1.4 g (8 mmol)
of methyl 4-amino-3-methoxybenzoate in 30 mL toluene is combined
with 0.4 g (0.6 mmol) of
2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl, 0.23 g (0.3 mmol) of
tris(dibenzylideneacetone)-dipalladium(0) and 7.0 g (21 mmol) of
caesium carbonate and refluxed for 17 h. The reaction mixture is
applied to silica gel and purified by column chromatography
(eluant: dichloromethane/methanol 9:1). Yield: 1.7 g of a compound
Z6h (yellow crystals)
[0290] 1.7 g of the compound Z6h are dissolved in 50 mL dioxane,
combined with 15 mL of semiconcentrated hydrochloric acid and
refluxed for 12 h. After cooling the precipitate formed is suction
filtered. Yield: 1.1 g of a compound Z6 (colourless solid)
[0291] To synthesise the compounds of Examples 26, 20,32, 56, 101,
112 and 209 of Table 1, first of all an intermediate compound Z7
##STR68## is prepared as described below.
[0292] 50.0 g (0.36 mol) D-alanine methyl ester.times.HCl is
suspended in 500 mL of dichloromethane and 35 mL of acetone and
combined with 30.0 g (0.37 mol) of sodium acetate and 80.0 g (0.38
mol) of sodium triacetoxyborohydride. The mixture is stirred for 12
h and then poured onto 400 mL of 10% sodium hydrogen carbonate
solution. The organic phase is dried over Na.sub.2SO.sub.4 and
evaporated down. Yield: 51.0 g of a compound Z7a (yellow oil)
[0293] A suspension of 51.0 g of the compound Z7a in 450 mL water
is combined with 80.0 g (0.41 mol) of 2,4-dichloro-5-nitropyridine
in 450 mL of diethyl ether. At -5.degree. C. 100 mL of 10%
potassium hydrogen carbonate solution are added dropwise. The
reaction mixture is stirred for 3 h, the organic phase dried over
Na.sub.2SO.sub.4 and evaporated down. Yield: 74 g of a compound Z7b
(yellow oil)
[0294] 18.6 g of the compound Z7b are dissolved in 200 mL glacial
acetic acid and at 60.degree. C. combined batchwise with 20.0 g
iron powder. The mixture is stirred for 2 h at 60.degree. C. and
then suction filtered through cellulose. The residue is dissolved
in ethyl acetate and washed with water and concentrated ammonia.
The organic phase is dried over Na.sub.2SO.sub.4 and evaporated
down. The residue is crystallised from diethyl ether. Yield: 9.8 g
of a compound Z7c (colourless crystals)
[0295] 17.0 g of the compound Z7c and 7 mL (0.1 mol) methyl iodide
are dissolved in 200 mL dimethylacetamide and at -5.degree. C.
combined with 4.0 g (0.1 mol) of sodium hydride as a 60% dispersion
in mineral oil. The reaction mixture is stirred for 30 min and then
poured onto 300 mL ice water. The precipitate formed is suction
filtered and stirred with petroleum ether. Yield: 14.8 g of a
compound Z7d (beige crystals)
[0296] 0.9 g of the compound Z7d and 1.5 g (9 mmol)
4-amino-3-methoxybenzoic acid are heated to 210.degree. C. for 30
min. After cooling the residue is stirred with ethyl acetate and
the precipitate obtained is suction filtered. Yield: 1.2 g of a
compound Z7 (grey crystals)
[0297] The following acids can, for example, be prepared
analogously to the methods of synthesis hereinbefore described.
##STR69## Synthesis of the Amino Components L-R5
[0298] The following amines,
[0299] 1,1-dimethyl-2-dimethylamino-1-yl-ethylamine and 1,1
-dimethyl-2-piperidin-1-yl-ethylamine, ##STR70## may be obtained as
follows.
[0300] The compounds may be prepared according to the following
references: (a) S. Schuetz et al. Arzneimittel-Forschung 1971, 21,
739-763, (b) V. M. Belikov et al. Tetrahedron 1970, 26, 1199-1216
and (c) E. B. Butler and McMillan J. Amer. Chem. Soc. 1950, 72,
2978. Z8
[0301] Other amines can be prepared as follows, in a modified
manner compared with the literature described above.
[0302] 1,1-dimethyl-2-morpholin-1-yl-ethylamine ##STR71##
[0303] 8.7 mL morpholine and 9.3 mL 2-nitropropane are prepared
while cooling the reaction with ice, 7.5 mL formaldehyde (37%) and
4 mL of a 0.5 mol/L NaOH solution are slowly added dropwise
(<10.degree. C.). Then the mixture is stirred for 1h at
25.degree. C. and 1h at 50.degree. C. The solution is treated with
water and ether and the aqueous phase is extracted 3.times. with
ether. The combined organic phase is dried over NaSO4 and combined
with HCl in dioxane (4mol/l), the precipitate formed is suction
filtered. Yield: 21.7 of white powder 5 g of the white powder are
dissolved in 80 mL methanol and with the addition of 2 g RaNi
treated with hydrogen at 35.degree. C. and 50 psi for 40 minutes.
This yields 3.6 g of 1,1-dimethyl-2-morpholin-1-yl-ethylamine.
[0304] The following amines can be prepared analogously.
[0305] 1,1-dimethyl-N-methylpiperazin-1-yl-ethylamine ##STR72##
[0306] 1,1-dimethyl-2-pyrrolidin-1-yl-ethylamine ##STR73##
[0307] 1,3-DIMORPHOLIN-2-AMINO-PROPANE ##STR74##
[0308] 5 g of 1,3 Dimorpholine-2-nitropropane obtained from Messrs.
Aldrich is dissolved in 80 mL methanol and treated with hydrogen
for 5.5 h at 30.degree. C. and 50 psi with the addition of 2 g
RaNi. This yields 4.2 g of 1,3 dimorpholin-2-amino-propane.
[0309] 4-Aminobenzylmorpholine ##STR75##
[0310] The preparation of this amine is described in the following
reference: S. Mitsuru et al. J. Med. Chem. 2000, 43, 2049-2063.
[0311] 4-amino-1-tetrahydro-4H-pyran-4-yl-piperidine ##STR76##
[0312] 20 g (100 mmol) of 4-tert-butyloxycarbony-aminopiperidine
are dissolved in 250 mL CH.sub.2Cl.sub.2 and stirred for 12 h at RT
with 10 g (100 mmol) tetrahydro-4H-pyran-4-one and 42 g (200 mmol)
NaBH(OAc).sub.3. Then water and potassium carbonate are added, the
organic phase is separated off, dried and the solvent is eliminated
in vacuo. The residue is dissolved in 200 mL CH.sub.2Cl.sub.2 and
stirred for 12 h at RT with 100 mL trifluoroacetic acid. The
solvent is eliminated in vacuo, the residue taken up with
CHCl.sub.3 and evaporated down again, then taken up in acetone and
the hydrochloride is precipitated with ethereal HCl. Yield: 14.3 g
(56%).
[0313] Cis- and trans-4-morpholino-cyclohexylamine ##STR77##
[0314] 3.9 g (30 mmol) of 4-dibenzylcyclohexanone are dissolved in
100 mL of CH.sub.2Cl.sub.2 and stirred for 12 h at RT with 3.9 g
(45 mmol) of morpholine and 9.5 g (45 mmol) NaBH(OAc).sub.3. Then
water and potassium carbonate are added, the organic phase is
separated off, dried and the solvent is eliminated in vacuo. The
residue is purified through a silica gel column (about 20 mL silica
gel; about 500 mL of ethyl acetate 90/ methanol 10+1% concentrated
ammonia). The appropriate fractions are evaporated down in vacuo.
Yield: 6.6 g (60%) of cis-isomer and 2 g (18%) of trans-isomer.
[0315] Alternatively, the
trans-dibenzyl-4-morpholino-cyclohexylamine may be prepared by the
following method:
[0316] 33 g (112 mmol) of 4-dibenzylcyclohexanone are dissolved in
300 mL MeOH, combined with 17.4 g (250 mmol) of hydroxylamine
hydrochloride and stirred for 4 h at 60.degree. C. The solvent is
evaporated down in vacuo, combined with 500 mL water and 50 g
potassium carbonate and extracted twice with 300 mL of
dichloromethane. The organic phase is dried, evaporated down in
vacuo, the residue is crystallised from petroleum ether, dissolved
in 1.5 L of EtOH and heated to 70.degree. C. 166 g of sodium are
added batchwise and the mixture is refluxed until the sodium
dissolves. The solvent is eliminated in vacuo, the residue combined
with 100 mL water and extracted twice with 400 mL of ether. The
organic phase is washed with water, dried, evaporated down in vacuo
and the trans isomer is isolated using a column (about 1.5 L silica
gel; about 2 L of ethyl acetate 80/methanol 20+2% concentrated
ammonia). Yield: 12.6 g (41.2%).
[0317] 6.8 g (23 mmol) of trans-1-amino-4-dibenzylaminocyclohexane
is dissolved in 90 mL of DMF and stirred for 8 h at 100.degree. C.
with 5 mL (42 mmol) of 2,2'-dichloroethyl ether and 5 g of
potassium carbonate. After cooling 30 mL of water is added, the
precipitated crystals are suction filtered and purified through a
short column (about 20 mL silica gel, about 100 mL ethyl acetate).
The residue is crystallised from methanol and concentrated HCl as
the dihydrochloride. Yield: 7.3 g (72.4%).
[0318] Trans-4-morpholino-cyclohexylamine
[0319] 7.2 g (16.4 mmol) of
trans-dibenzyl-4-morpholino-cyclohexylamine are dissolved in 100 mL
of MeOH and hydrogenated on 1.4 g of Pd/C (10%) at 30-50.degree. C.
The solvent is eliminated in vacuo and the residue is crystallised
from ethanol and concentrated HCl. Yield: 3.9 g (93%).
[0320] The cis isomer may be prepared analogously.
[0321] Cis- and trans-4-piperidino-cyclohexylamine ##STR78##
[0322] Trans-dibenzyl-4-piperidino-cyclohexylamine
[0323] 2.0 g (6.8 mmol) of trans-1amino-4-dibenzylaminocyclohexane
(see Example 2) is dissolved in 50 mL DMF and stirred for 48 h at
RT with 1.6 g (7 mmol) of 1,5-dibromopentane and 2 g of potassium
carbonate. The mixture is cooled, combined with water, extracted
twice with 100 mL of dichloromethane, dried and the solvent is
eliminated in vacuo. The residue is purified over a column ( about
100 mL silica gel, about 500 mL ethyl acetate 80/methanol 20+1%
concentrated ammonia). The desired fractions are evaporated down in
vacuo and crystallised from petroleum ether. Yield: 1.2 g
(49%).
[0324] Trans-4-piperidino-cyclohexylamine
[0325] 1.7 g (4.8 mmol) of
trans-dibenzyl-4-piperidino-cyclohexylamine are dissolved in 35 mL
MeOH and hydrogenated on 350 mg of Pd/C (10%) at 20.degree. C. The
solvent is eliminated in vacuo and the residue crystallised from
ethanol and concentrated HCl. Yield: 1.1 g (78%).
[0326] The cis isomer may be prepared analogously.
[0327] Cis- and trans-4-(4-phenyl-piperazin-1-yl)-cyclohexylamine
##STR79##
[0328] 4.1 g (25.3 mmol) of 4-dibenzylcyclohexanone is dissolved in
50 mL of dichloromethane and stirred for 12 h at RT with 7.4 g
(25.3 mmol) of N-phenylpyperazine and 7.4 g (35 mmol) of
NaBH(OAc).sub.3. Then water and potassium carbonate are added, the
organic phase is separated off, dried and the solvent is eliminated
in vacuo. The residue is purified over a silica gel column (ethyl
acetate 80/ methanol 20+0.5% concentrated ammonia). Yield: 1.7 g
(15.8%) of cis-isomer and 0.27 (2.5%) of trans-isomer.
[0329] Trans-4-(4-phenyl-piperazin-1-yl)-cyclohexylamine
[0330] 270 mg (0,61 mmol) of
trans-dibenzyl-[4-(4-phenyl-piperazin-1-yl)-cyclohexyl]-amine are
dissolved in 5 mL MeOH and hydrogenated on 40 mg of Pd/C (10%) at
20-30 .degree. C. The solvent is eliminated in vacuo and the
residue crystallised from ethanol and concentrated HCl. Yield: 110
mg (69%).
[0331] The cis isomer may be prepared analogously.
[0332] Cis- and
trans-4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexylamine
##STR80##
[0333] 9.8 g (33.4 mmol) of 4-dibenzylcyclohexanone is dissolved in
100 mL dichloromethane and stirred for 12 h at RT with 5.6 g (40
mmol) of N-cyclopropylmethylpiperazine and 8.5 g (40 mmol) of
NaBH(OAc).sub.3. Then water and potassium carbonate are added, the
organic phase is separated off, dried and the solvent is eliminated
in vacuo. The residue is purified over a silica gel column (about
50 mL silica gel, about 3 L ethyl acetate 95/ methanol 5+0.25%
concentrated ammonia. The appropriate fractions are evaporated down
in vacuo. The faster eluting cis compound crystallised from ethyl
acetate. The trans-compound is crystallised from
ethanol+concentrated HCl. Yield: 8.5 g (61%) cis-isomer and 2.2
(13%) trans-isomer.
[0334]
cis-4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexylamine
[0335] 8.5 g (20 mmol) of
cis-dibenzyl-[4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexyl]-amine
are dissolved in 170 mL MeOH and hydrogenated on 1.7 g Pd/C (10%)
at 30-50.degree. C. The solvent is eliminated in vacuo and the
residue is crystallised from ethanol and concentrated HCl. Yield:
4.4 g (91%).
[0336] The trans-isomer may be prepared analogously.
SYNTHESIS OF THE EXAMPLES
Example 152
[0337] 0.15 g of the compound Z10, 0.14 g TBTU, 0.13 mL DIPEA are
dissolved in dichloromethane and stirred for 20 minutes at
25.degree. C. Then 90 .mu.L 1-(3-aminopropyl)-4-methylpiperazine is
added and stirred for a further 2 hours at 25.degree. C. The
solution is then diluted with dichloromethane and extracted with
water. The product is precipitated by the addition of petroleum
ether, ether and ethyl acetate to the organic phase. Yield: 0.16 g
of beige solid.
Example 164
[0338] 0.10 g of the compound Z10, 0.1 g TBTU, 0.08 mL DIPEA are
dissolved in 4 mL dichloromethane and stirred for 20 minutes at
25.degree. C. Then 44 .mu.L dimethylaminopropylamine are added and
stirred for a further 2 hours at 25.degree. C. The solution is then
diluted with dichloromethane and extracted with water. The product
is precipitated by the addition of petroleum ether, ether and
acetone to the organic phase. Yield: 0.08 g yellow solid.
Example 242
[0339] 0.15 g of the compound Z10, 0.14 g TBTU, 0.13 mL DIPEA are
dissolved in 5 mL dichloromethane and stirred for 20 minutes at
25.degree. C. Then 75 .mu.L 1-(2-aminoethyl) piperidine are added
and stirred for a further 2 hours at 25.degree. C. The solution is
then diluted with dichloromethane and extracted with water. The
product is precipitated by the addition of petroleum ether, ether
and ethyl acetate to the organic phase. Yield: 0.14 g yellow
solid.
Example 188
[0340] 0.1 g of the compound Z2, 0.09 g TBTU, 0.05 mL DIPEA are
dissolved in 15 mL dichloromethane and stirred for 20 minutes at
25.degree. C. Then 33 mg 1-methyl-4-aminopiperidin are added and
the mixture is stirred for a further 3 hours at 25.degree. C. The
solution is extracted with 20 mL water, then evaporated down in
vacuo. The product is crystallised using ether. Yield: 0.047 g of
white crystals.
Example 203
[0341] 0.1 g of the compound Z2, 0.09 g TBTU, 0.5 mL DIPEA are
dissolved in 15 mL dichloromethane and stirred for 30 minutes at
25.degree. C. Then 50 mg 4-amino-1-benzylpiperidin are added and
the mixture is stirred for a further 3 hours at 25.degree. C. The
solution is extracted with 20 mL water, then evaporated down in
vacuo. Then the residue is chromatographed over silica gel and the
isolated product is crystallised with ether. Yield: 0.015 g of
white crystals.
Example 94
[0342] 0.17 g of the compound Z1, 0.19 g TBTU, 0.11 mL DIPEA are
dissolved in 50 mL dichloromethane and stirred for 30 minutes at
25.degree. C. Then 63 mg of 1-methyl-4-aminopiperidine are added
and the mixture is stirred for a further 17 hours at 25.degree. C.
50 mL of water and 1 g of potassium carbonate are added to the
solution and the organic phase is separated off using a phase
separation cartridge, then evaporated down in vacuo. Then the
product is purified by silica gel chromatography and the purified
product is crystallised with ether. Yield: 0.1 g of white
crystals.
Example 95
[0343] 0.17 g of the compound Z1, 0.19 g TBTU, 0.11 mL DIPEA are
dissolved in 50 mL dichloromethane and stirred for 30 minutes at
25.degree. C. Then 77 mg of exo-3-(3-amino-tropane are added and
the mixture is stirred for a further 17 hours at 25.degree. C. 50
mL of water and 1 g of potassium carbonate are added to the
solution and the organic phase is separated off using a phase
separation cartridge, then evaporated down in vacuo. Then the
product is purified by silica gel chromatography and the purified
product is crystallised with ether. Yield: 0.03 g of white
crystals.
Example 46
[0344] 0.15 g of the compound Z3, 0.12 g TBTU, 0.12 mL DIPEA are
dissolved in 5 mL dichloromethane and stirred for 30 minutes at
25.degree. C. Then 50 mg 1-methyl-4-aminopiperidin are added and
the mixture is stirred for a further 2.5 hours at 25.degree. C. The
solution is then extracted with water and then evaporated down. The
residue is dissolved in warm ethyl acetate and crystallised from
ether and petroleum ether. Yield: 0.025 g of white crystals.
Example 80
[0345] 0.2 g of the compound Z8, 0.2 g of TBTU, 0.1 mL of DIPEA are
dissolved in 10 mL dichloromethane and stirred for 30 minutes at
25.degree. C. Then 100 mg of 1-methyl-4-aminopiperidine are added
and the mixture is stirred for a further 17 hours at 25.degree. C.
The solution is then extracted with a dilute potassium carbonate
solution and evaporated down. The residue is crystallised using
ether. Yield: 0.12 g of white crystals.
Example 190
[0346] 0.2 g of compound Z8, 0.2 g of TBTU, 0.3 mL of DIPEA are
dissolved in 5 mL dichloromethane and stirred for 1h at 25.degree.
C. Then 0.13 g of 4-amino-1-benzylpiperidine are added and the
mixture is stirred for a further hour at 25.degree. C. The solution
is then diluted with 10 mL methylene chloride and extracted with 20
mL water. Then the product is purified over silica gel and
crystallised from ethyl acetate and ether. Yield: 0.23 g of the
compound Z8.
[0347] 0.23 g of the benzylamine Z8 are dissolved in 10 mL
methanol, combined with 50 mg of Pd/C and hydrogenated under 3 bar
for 3h at 25.degree. C. By adding petroleum ether and ethyl acetate
white crystals are produced. These are chromatographed over silica
gel and crystallised from ethyl acetate and ether. Yield: 0.075 g
of white crystals.
Example 196
[0348] 0.1 g of compound Z10, 0.09 g of TBTU, 0.3 mL of DIPEA are
dissolved in 4 mL of dichloromethane and stirred for 20 minutes at
25.degree. C. Then 67 mg xx amine is added and stirred for a
further 2 hours at 25.degree. C. The solution is then diluted with
dichloromethane and extracted with water. It is then
chromatographed over silica gel and the residue is dissolved in
acetone, combined with ethereal HCl and the precipitate formed is
isolated. Yield: 0.09 g light yellow solid.
Example 166
[0349] 0.1 g of the compound Z10, 0.11 g of TBTU, 0.14 mL of DIPEA
are dissolved in 2 mL dimethylformamide and stirred for 3h at
50.degree. C. Then 55 mg of 4-morpholinomethylphenylamine is added.
The reaction mixture is then cooled to ambient temperature within
17 h. Then the dimethylformamide is eliminated in vacuo, the
residue is taken up in dichloromethane and extracted with water. It
is then chromatographed over silica gel and the product
crystallised from ethyl acetate and ether. Yield: 0.06 g yellowish
crystals.
Example 81
[0350] 0.2 g of the compound Z4, 0.2 g of TBTU, 0.1 mL of DIPEA are
dissolved in 10 mL dichloromethane and stirred for 30 minutes at
25.degree. C. Then 0.1 g of 1-methyl-4-aminopiperidine are added
and the mixture is stirred for a further 17 hours at 25.degree. C.
The solution is then extracted with aqueous potassium carbonate
solution and then evaporated down. The product is crystallised
using ether. Yield: 0.16 g of white crystals.
Example 162
[0351] 0.1 g of the compound Z5, 0.07 g of TBTU, 0.15 mL of DIPEA
are dissolved in 5 mL dichloromethane and stirred for 20 minutes at
25.degree. C. Then 0.04 g 1 -methyl-4-aminopiperidine are added and
the mixture is stirred for a further 2 hours at 25.degree. C. The
solution is then diluted with 15 mL dichloromethane and extracted
with 20 mL water. The residue is dissolved in MeOH and acetone,
combined with 1 mL ethereal HCl and evaporated down. A crystalline
product is produced using ether, ethyl acetate and a little MeOH.
Yield: 0.1 g of white crystals.
Example 88
[0352] 0.1 g of the compound Z6, 0.12 g of TBTU, 0.12 mL of DIPEA
are in 10 mL dichloromethane dissolved and stirred for 30 minutes
at 25.degree. C. Then 0.04 g of 1-methyl-4-aminopiperidine are
added and the mixture is stirred for a further 2 hours at
25.degree. C. The solution is then diluted with 10 mL
dichloromethane and extracted with 10 mL water. A crystalline
product is produced using ether, ethyl acetate and petroleum ether.
Yield: 0.6 g of white crystals.
Example 89
[0353] 0.1 g of the compound Z6, 0.08 g of TBTU, 0.08 mL of DIPEA
are dissolved in 10 mL dichloromethane and stirred for 30 minutes
at 25.degree. C. Then 37 .mu.L g N,N-dimethylneopentanediamine are
added and the mixture is stirred for a further 2 hours at
25.degree. C. The solution is then diluted with 10 mL
dichloromethane and extracted with 10 mL water. The product is then
chromatographed over silica gel and crystallised from ethyl
acetate, ether and petroleum ether. Yield: 0.005 g of white
crystals.
Example 26
[0354] 0.15 g of the compound Z7, 0.16 g of TBTU, 1 mL of DIPEA are
dissolved in 5 mL dichloromethane and stirred for 30 minutes at
25.degree. C. Then 0.1 g 4-morpholinocyclohexylamine are added and
the mixture is stirred for a further 17 hours at 25.degree. C. The
residue is then combined with 10 mL of 10% potassium carbonate
solution, the precipitate is isolated and washed with water. It is
then dissolved in dichloromethane and evaporated down again. The
product is crystallised from ethyl acetate. Yield: 0.1 g of white
crystals.
Example 9
[0355] 150 mg of the compound Z9 and 93 mg of amine are dissolved
in 5 mL dichloromethane and stirred with 160 mg of TBTU and 1 mL of
DIPEA for 12 h at RT. The solvent is eliminated in vacuo, the
residue is combined with 10 mL of 10% potassium carbonate solution.
The precipitate is suction filtered, washed with water, taken up in
dichloromethane, dried and the solvent eliminated in vacuo. The
residue is crystallised from ethyl acetate. Yield: 82.0 mg.
Example 16
[0356] 150 mg of the compound Z8 and 73 mg of
trans-4-piperidino-cyclohexylamine are dissolved in 5 mL
dichloromethane and stirred with 160 mg (0.50 mmol) of TBTU and 1
mL of DIPEA for 12 h at RT. The solvent is eliminated in vacuo, the
residue is combined with 10 mL of 10% potassium carbonate solution.
The precipitate is suction filtered, washed with water, taken up in
dichloromethane, dried and the solvent eliminated in vacuo. The
residue is crystallised from ethyl acetate. Yield: 87.0 mg.
[0357] 100 mg of the compound Z9 and 42 mg of
3-amino-1-ethyl-pyrolidine are dissolved in 10 mL dichloromethane
and stirred with 90 mg of TBTU and 0.5 mL of DIPEA for 12 h at RT.
The solvent is eliminated in vacuo, the residue is combined with 10
mL of 10% potassium carbonate solution. The precipitate is suction
filtered, washed with water, taken up in dichloromethane, dried and
the solvent is eliminated in vacuo. The residue is crystallised
from ethyl acetate/petroleum ether. Yield: 24.0 mg.
Example 120
[0358] 100 mg of the compound Z1 1 and 73 mg of
4-amino-ltetrahydro-4H-pyran-4-yl-piperidine are dissolved in 10 mL
dichloromethane and stirred with 90 mg of TBTU and 0.5 mL of DIPEA
for 1 h at RT. The solvent is eliminated in vacuo, the residue is
combined with 10 mL of 10% potassium carbonate solution. The
precipitate is suction filtered, washed with water, taken up in
dichloromethane, dried and the solvent is eliminated in vacuo. The
residue is crystallised from ethyl acetate/petroleum ether. Yield:
89 mg.
Example 212
[0359] 150 mg of the compound Z5 and 150 mg of
trans-4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexylamine (as
the hydrochloride) are dissolved in 5 mL of dichloromethane and
stirred with 160 mg of TBTU and 2 mL of DIPEA for 2 h at RT. The
solvent is eliminated in vacuo, the residue is combined with 10 mL
of 10% potassium carbonate solution. The precipitate is suction
filtered, washed with water, taken up in dichloromethane, dried and
the solvent eliminated in vacuo. The residue is purified over a
column (20 mL silica gel, 300 mL ethyl acetate 90/ methanol 10+2%
concentrated ammonia). The appropriate fractions are evaporated
down in vacuo and crystallised from ethyl acetate. Yield: 140
mg.
Example 232
[0360] 390 mg of the compound Z11 and 240 mg of
trans-4-(4-tbutyloxycarbonyl-piperazin-1-yl)-cyclohexylamine are
dissolved in 2.5 mL of NMP and stirred with 482 mg of TBTU and 1 mL
triethylamine for 2 h at RT. Then 100 mL of water and 200 mg of
potassium carbonate are added, the precipitate is suction filtered,
washed with water and purified through a silica gel column. The
appropriate fractions are evaporated down in vacuo, dissolved in 2
mL dichloromethane, combined with 2 mL of trifluoroacetic acid and
stirred for 2 h at RT, combined with another 100 ml of water and
200 mg potassium carbonate and the precipitate is suction filtered
and washed with water. Then the precipitate is purified through a
silica gel column. The appropriate fractions are evaporated down in
vacuo and the residue is crystallised from ethanol and concentrated
hydrochloric acid. Yield: 95 mg.
Example 213
[0361] 60 mg of the compound of Example 232 is dissolved in 10 mL
ethyl acetate and stirred with 1 mL of acetic anhydride and 1 mL of
triethylamine for 30 min. at RT. The solvent is eliminated in
vacuo, the residue combined with water and ammonia, the crystals
precipitated are suction filtered and washed with water and a
little cold acetone. Yield: 40 mg.
Example 218
[0362] 1.2 g of the compound Z9 and 0.5g of
1,4-dioxaspiro[4.5]dec-8-ylamine were dissolved in 20 mL
dichloromethane and stirred with 1.28 g of TBTU and 4 mL of
triethylamine for 12 h at RT. Then 50 mL of water and 0.5 g of
potassium carbonate are added, the organic phase is separated off,
dried and evaporated down in vacuo. The residue is crystallised
from ethyl acetate, combined with 25 mL of 1 N hydrochloric acid
and 20 mL of methanol and stirred for 30 min at 50.degree. C. The
methanol is eliminated in vacuo, the precipitate is suction
filtered, washed with water and dried. The residue is taken up in
20 mL dichloromethane, stirred with 0.5 g of thiomorpholine and 0.5
g of NaBH(OAc).sub.3 for 12 h at RT . Then water and potassium
carbonate are added, the organic phase is separated off, dried and
the solvent is eliminated in vacuo. The residue is purified over a
silica gel column. The appropriate fractions are evaporated down in
vacuo and the hydrochloride is precipitated with ethereal HCl.
Yield: 86 mg of trans-isomer; amorphous powder.
Example 187
[0363] 200 mg of the compound Z3 in 5 mL dichloromethane is
combined with 0.1 mL of diisopropylethylamine and 180 mg of TBTU
and stirred for 30 min. Then 191 mg of
4-(4-methyl-piperazin-1-yl)-phenylamine are added and the mixture
is stirred overnight. The reaction mixture is combined with water
and the aqueous phase extracted with dichloromethane. The combined
organic phases are dried over Na.sub.2SO.sub.4 and evaporated down.
The residue is purified by column chromatography (eluant:
dichloromethane/methanol 100:7). Yield: 128 mg (light yellow
crystals).
[0364] The compounds of Formula (1) listed in Table 1, inter alia,
are obtained analogously to the procedure described hereinbefore.
The abbreviations X.sub.1, X.sub.2, X.sub.3, X4 and X.sub.5 used in
Table 1 in each case denote a link to a position in the general
Formula shown under Table 1 instead of the corresponding groups
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and L-R.sup.5. TABLE-US-00005
TABLE 1 ##STR81## Config. Example R.sup.1 R.sup.2 R.sup.1 or
R.sup.2 R.sup.3 R.sup.4 L.sub.n--R.sup.5.sub.m 1 H ##STR82## R
##STR83## ##STR84## ##STR85## 2 H ##STR86## R ##STR87## ##STR88##
##STR89## 3 H ##STR90## R ##STR91## H ##STR92## 4 H ##STR93## R
##STR94## H ##STR95## 5 H ##STR96## R ##STR97## ##STR98## ##STR99##
6 H ##STR100## R ##STR101## ##STR102## ##STR103## 7 H ##STR104## R
##STR105## ##STR106## ##STR107## 8 H ##STR108## R ##STR109## H
##STR110## 9 H ##STR111## R ##STR112## ##STR113## ##STR114## 10 H
##STR115## R ##STR116## H ##STR117## 11 H ##STR118## R ##STR119## H
##STR120## 12 H ##STR121## R ##STR122## H ##STR123## 13 H
##STR124## R ##STR125## ##STR126## ##STR127## 14 H ##STR128## R
##STR129## H ##STR130## 15 H ##STR131## R ##STR132## ##STR133##
##STR134## 16 H ##STR135## R ##STR136## ##STR137## ##STR138## 17 H
##STR139## R ##STR140## ##STR141## ##STR142## 18 H ##STR143## R
##STR144## H ##STR145## 19 H ##STR146## R ##STR147## ##STR148##
##STR149## 20 H ##STR150## R ##STR151## ##STR152## ##STR153## 21 H
##STR154## R ##STR155## ##STR156## ##STR157## 22 H ##STR158## R
##STR159## ##STR160## ##STR161## 23 H ##STR162## R ##STR163##
##STR164## ##STR165## 24 H ##STR166## R ##STR167## ##STR168##
##STR169## 25 H ##STR170## R ##STR171## ##STR172## ##STR173## 26 H
##STR174## R ##STR175## ##STR176## ##STR177## 27 H ##STR178## R
##STR179## ##STR180## ##STR181## 28 H ##STR182## R ##STR183##
##STR184## ##STR185## 29 H ##STR186## R ##STR187## ##STR188##
##STR189## 30 H ##STR190## R ##STR191## ##STR192## ##STR193## 31 H
##STR194## R ##STR195## H ##STR196## 32 H ##STR197## R ##STR198##
##STR199## ##STR200## 33 H ##STR201## R ##STR202## H ##STR203## 34
H ##STR204## R ##STR205## ##STR206## ##STR207## 35 H ##STR208## R
##STR209## ##STR210## ##STR211## 36 H ##STR212## R ##STR213##
##STR214## ##STR215## 37 H ##STR216## R ##STR217## ##STR218##
##STR219## 38 H ##STR220## R ##STR221## ##STR222## ##STR223## 39 H
##STR224## R ##STR225## H ##STR226## 40 H ##STR227## R ##STR228##
##STR229## ##STR230## 41 H ##STR231## R ##STR232## ##STR233##
##STR234## 42 H ##STR235## R ##STR236## ##STR237## ##STR238## 43
X.sub.1--CH.sub.3 ##STR239## ##STR240## ##STR241## ##STR242## 44 H
##STR243## R ##STR244## H ##STR245## 45 H ##STR246## R ##STR247##
##STR248## ##STR249## 46 H ##STR250## R ##STR251## ##STR252##
##STR253## 47 H ##STR254## R ##STR255## H ##STR256## 48 H
##STR257## R ##STR258## H ##STR259## 49 H ##STR260## R ##STR261##
##STR262## ##STR263## 50 H ##STR264## R ##STR265## ##STR266##
##STR267## 51 H ##STR268## R ##STR269## ##STR270## ##STR271## 52 H
##STR272## R ##STR273## ##STR274## ##STR275## 53 ##STR276##
##STR277## ##STR278## ##STR279## ##STR280## 54 H ##STR281## R
##STR282## ##STR283## ##STR284## 55 H ##STR285## R ##STR286##
##STR287## ##STR288## 56 H ##STR289## R ##STR290## ##STR291##
##STR292## 57 H ##STR293## R ##STR294## ##STR295## ##STR296## 58 H
##STR297## R ##STR298## ##STR299## ##STR300## 59 H ##STR301## R
##STR302## ##STR303## ##STR304## 60 H ##STR305## R ##STR306##
##STR307## ##STR308## 61 ##STR309## ##STR310## ##STR311##
##STR312## ##STR313## 62 H ##STR314## R ##STR315## ##STR316##
##STR317## 63 H ##STR318## R ##STR319## ##STR320## ##STR321## 64 H
##STR322## R ##STR323## ##STR324## ##STR325## 65 H ##STR326## R
##STR327## ##STR328## ##STR329## 66 H ##STR330## R ##STR331##
##STR332## ##STR333## 67 H ##STR334## R ##STR335## ##STR336##
##STR337## 68 H ##STR338## R ##STR339## H ##STR340## 69 H
##STR341## R ##STR342## H ##STR343## 70 H ##STR344## R ##STR345## H
##STR346## 71 H ##STR347## R ##STR348## ##STR349## ##STR350## 72 H
##STR351## R ##STR352## ##STR353## ##STR354## 73 H ##STR355## R
##STR356## H ##STR357## 74 H ##STR358## R ##STR359## ##STR360##
##STR361## 75 H ##STR362## R ##STR363## ##STR364## ##STR365## 76 H
##STR366## R ##STR367## ##STR368## ##STR369## 77 H ##STR370## R
##STR371## H ##STR372## 78 H ##STR373## R ##STR374## H ##STR375##
79 H ##STR376## R ##STR377## H ##STR378## 80 H ##STR379## R
##STR380## ##STR381## ##STR382## 81 H ##STR383## R ##STR384##
##STR385## ##STR386## 82 H ##STR387## R ##STR388## ##STR389##
##STR390## 83 H ##STR391## R ##STR392## ##STR393## ##STR394## 84 H
##STR395## R ##STR396## ##STR397## ##STR398## 85 H ##STR399## R
##STR400## H ##STR401## 86 H ##STR402## R ##STR403## ##STR404##
##STR405## 87 H ##STR406## R ##STR407## ##STR408## ##STR409## 88 H
##STR410## R ##STR411## ##STR412## ##STR413## 89 H ##STR414## R
##STR415## ##STR416## ##STR417## 90 H ##STR418## R ##STR419##
##STR420## ##STR421## 91 H ##STR422## R ##STR423## ##STR424##
##STR425## 92 H ##STR426## R ##STR427## H ##STR428## 93 H
##STR429## R ##STR430## H ##STR431## 94 H ##STR432## R ##STR433##
##STR434## ##STR435## 95 H ##STR436## R ##STR437## ##STR438##
##STR439## 96 H ##STR440## R ##STR441## ##STR442## ##STR443## 97 H
##STR444## R ##STR445## ##STR446## ##STR447## 98 H ##STR448## R
##STR449## ##STR450## ##STR451## 99 H ##STR452## R ##STR453##
##STR454## ##STR455## 100 H ##STR456## R ##STR457## ##STR458##
##STR459## 101 H ##STR460## R ##STR461## ##STR462## ##STR463## 102
H ##STR464## R ##STR465## ##STR466## ##STR467## 103 H ##STR468## R
##STR469## ##STR470## ##STR471## 104 H ##STR472## R ##STR473##
##STR474## ##STR475## 105 H ##STR476## R ##STR477## ##STR478##
##STR479## 106 H ##STR480## R ##STR481## ##STR482## ##STR483## 107
H ##STR484## R ##STR485## ##STR486## ##STR487## 108 H ##STR488## R
##STR489## ##STR490## ##STR491## 109 H ##STR492## R ##STR493##
##STR494## ##STR495## 110 H ##STR496## R ##STR497## ##STR498##
##STR499## 111 H ##STR500## R ##STR501## ##STR502## ##STR503## 112
H ##STR504## R ##STR505## ##STR506## ##STR507## 113 H ##STR508## R
##STR509## ##STR510## ##STR511## 114 H ##STR512## R ##STR513##
##STR514## ##STR515## 115 H ##STR516## R ##STR517## ##STR518##
##STR519## 116 H ##STR520## R ##STR521## ##STR522## ##STR523## 117
H ##STR524## R ##STR525## ##STR526## ##STR527##
118 H ##STR528## R ##STR529## ##STR530## ##STR531## 119 H
##STR532## R ##STR533## ##STR534## ##STR535## 120 H ##STR536## R
##STR537## ##STR538## ##STR539## 121 H ##STR540## R ##STR541##
##STR542## ##STR543## 122 H ##STR544## R ##STR545## ##STR546##
##STR547## 123 H ##STR548## R ##STR549## ##STR550## ##STR551## 124
H ##STR552## R ##STR553## ##STR554## ##STR555## 125 H ##STR556## R
##STR557## ##STR558## ##STR559## 126 H ##STR560## R ##STR561##
##STR562## ##STR563## 127 H ##STR564## R ##STR565## ##STR566##
##STR567## 128 H ##STR568## R ##STR569## ##STR570## ##STR571## 129
H ##STR572## R ##STR573## ##STR574## ##STR575## 130 H ##STR576## R
##STR577## ##STR578## ##STR579## 131 H ##STR580## R ##STR581##
##STR582## ##STR583## 132 H ##STR584## R ##STR585## ##STR586##
##STR587## 133 H ##STR588## R ##STR589## ##STR590## ##STR591## 134
H ##STR592## R ##STR593## ##STR594## ##STR595## 135 H ##STR596## R
##STR597## ##STR598## ##STR599## 136 H ##STR600## R ##STR601##
##STR602## ##STR603## 137 H ##STR604## R ##STR605## ##STR606##
##STR607## 138 H ##STR608## R ##STR609## ##STR610## ##STR611## 139
H ##STR612## R ##STR613## ##STR614## ##STR615## 140 H ##STR616## R
##STR617## ##STR618## ##STR619## 141 H ##STR620## R ##STR621##
##STR622## ##STR623## 142 H ##STR624## R ##STR625## ##STR626##
##STR627## 143 H ##STR628## R ##STR629## H ##STR630## 144 H
##STR631## R ##STR632## H ##STR633## 145 H ##STR634## R ##STR635##
##STR636## ##STR637## 146 H ##STR638## R ##STR639## ##STR640##
##STR641## 147 H ##STR642## R ##STR643## H ##STR644## 148 H
##STR645## R ##STR646## ##STR647## ##STR648## 149 H ##STR649## R
##STR650## ##STR651## ##STR652## 150 H ##STR653## R ##STR654## H
##STR655## 151 H ##STR656## R ##STR657## ##STR658## ##STR659## 152
H ##STR660## R ##STR661## ##STR662## ##STR663## 153 H ##STR664## R
##STR665## ##STR666## ##STR667## 154 H ##STR668## R ##STR669## H
##STR670## 155 H ##STR671## R ##STR672## H ##STR673## 156 H
##STR674## R ##STR675## ##STR676## ##STR677## 157 H ##STR678## R
##STR679## ##STR680## ##STR681## 158 H ##STR682## R ##STR683##
##STR684## ##STR685## 159 H ##STR686## R ##STR687## ##STR688##
##STR689## 160 H ##STR690## R ##STR691## ##STR692## ##STR693## 161
X.sub.1--CH.sub.3 ##STR694## ##STR695## ##STR696## ##STR697## 162
X.sub.1--CH.sub.3 ##STR698## ##STR699## ##STR700## ##STR701## 163 H
##STR702## R ##STR703## ##STR704## ##STR705## 164 H ##STR706## R
##STR707## ##STR708## ##STR709## 165 H ##STR710## R ##STR711##
##STR712## ##STR713## 166 H ##STR714## R ##STR715## ##STR716##
##STR717## 167 H ##STR718## R ##STR719## ##STR720## ##STR721## 168
H ##STR722## R ##STR723## ##STR724## ##STR725## 169 H ##STR726## R
##STR727## ##STR728## ##STR729## 170 H ##STR730## R ##STR731##
##STR732## ##STR733## 171 H ##STR734## R ##STR735## ##STR736##
##STR737## 172 H ##STR738## R ##STR739## ##STR740## ##STR741## 173
H ##STR742## R ##STR743## ##STR744## ##STR745## 174 H ##STR746## R
##STR747## ##STR748## ##STR749## 175 H ##STR750## R ##STR751##
##STR752## ##STR753## 176 H ##STR754## R ##STR755## ##STR756##
##STR757## 177 H ##STR758## R ##STR759## ##STR760## ##STR761## 178
H ##STR762## R ##STR763## ##STR764## ##STR765## 179 H ##STR766## R
##STR767## ##STR768## ##STR769## 180 H ##STR770## R ##STR771##
##STR772## ##STR773## 181 H ##STR774## R ##STR775## ##STR776##
##STR777## 182 H ##STR778## R ##STR779## ##STR780## ##STR781## 183
H ##STR782## R ##STR783## ##STR784## ##STR785## 184 H ##STR786## R
##STR787## ##STR788## ##STR789## 185 H ##STR790## R ##STR791##
##STR792## ##STR793## 186 H ##STR794## R ##STR795## ##STR796##
##STR797## 187 H ##STR798## R ##STR799## ##STR800## ##STR801## 188
H ##STR802## R ##STR803## ##STR804## ##STR805## 189 H ##STR806## R
##STR807## ##STR808## ##STR809## 190 H ##STR810## R ##STR811##
##STR812## ##STR813## 191 H ##STR814## R ##STR815## ##STR816##
##STR817## 192 H ##STR818## R ##STR819## ##STR820## ##STR821## 193
H ##STR822## R ##STR823## ##STR824## ##STR825## 194 H ##STR826## R
##STR827## ##STR828## ##STR829## 195 H ##STR830## R ##STR831##
##STR832## ##STR833## 196 H ##STR834## R ##STR835## ##STR836##
##STR837## 197 H ##STR838## ##STR839## ##STR840## ##STR841## 198 H
##STR842## R ##STR843## ##STR844## 199 H ##STR845## R ##STR846##
##STR847## 200 H ##STR848## R ##STR849## ##STR850## 201 H
##STR851## R ##STR852## ##STR853## 202 ##STR854## ##STR855##
##STR856## ##STR857## ##STR858## 203 H ##STR859## R ##STR860##
##STR861## ##STR862## 204 H ##STR863## R ##STR864## ##STR865##
##STR866## 205 H ##STR867## R ##STR868## ##STR869## ##STR870## 206
H ##STR871## R ##STR872## ##STR873## ##STR874## 207 H ##STR875## R
##STR876## ##STR877## ##STR878## 208 H ##STR879## R ##STR880##
##STR881## ##STR882## 209 H ##STR883## R ##STR884## ##STR885##
##STR886## 210 H ##STR887## R ##STR888## ##STR889## ##STR890## 211
X.sub.1--CH.sub.3 ##STR891## ##STR892## ##STR893## ##STR894## 212
X.sub.1--CH.sub.3 ##STR895## ##STR896## ##STR897## ##STR898## 213 H
##STR899## R ##STR900## ##STR901## ##STR902## 214 H ##STR903## R
##STR904## ##STR905## ##STR906## 215 X.sub.1--CH.sub.3 ##STR907##
##STR908## ##STR909## ##STR910## 216 H ##STR911## R ##STR912##
##STR913## ##STR914## 217 H ##STR915## R ##STR916## ##STR917##
##STR918## 218 H ##STR919## R ##STR920## ##STR921## ##STR922## 219
H ##STR923## R ##STR924## ##STR925## ##STR926## 220 H ##STR927## R
##STR928## ##STR929## ##STR930## 221 H ##STR931## R ##STR932##
##STR933## ##STR934## 222 H ##STR935## R ##STR936## ##STR937##
##STR938## 223 H ##STR939## R ##STR940## ##STR941## ##STR942## 224
H ##STR943## R ##STR944## ##STR945## ##STR946## 225 H ##STR947## R
##STR948## H ##STR949## 226 H ##STR950## R ##STR951## ##STR952##
##STR953## 227 H ##STR954## R ##STR955## ##STR956## ##STR957## 228
H ##STR958## R ##STR959## ##STR960## ##STR961## 229 H ##STR962## R
##STR963## ##STR964## ##STR965## 230 H ##STR966## R ##STR967##
##STR968## ##STR969## 231 H ##STR970## R ##STR971## ##STR972##
##STR973## 232 H ##STR974## R ##STR975## ##STR976## ##STR977## 233
H ##STR978## R ##STR979## ##STR980## ##STR981## 234 H ##STR982## R
##STR983## ##STR984## ##STR985## 235 H ##STR986## R ##STR987##
##STR988## ##STR989## 236 H ##STR990## R ##STR991## ##STR992##
##STR993## 237 H ##STR994## R ##STR995## ##STR996## ##STR997## 238
H ##STR998## R ##STR999## ##STR1000## ##STR1001## 239 H ##STR1002##
R ##STR1003## ##STR1004## ##STR1005## 240 H ##STR1006## R
##STR1007## ##STR1008## ##STR1009##
241 H ##STR1010## R ##STR1011## ##STR1012## ##STR1013## 242 H
##STR1014## R ##STR1015## ##STR1016## ##STR1017## 243 H ##STR1018##
R ##STR1019## ##STR1020## ##STR1021## 244 H ##STR1022## R
##STR1023## ##STR1024## ##STR1025##
* * * * *