U.S. patent application number 13/140591 was filed with the patent office on 2012-03-01 for cyclic pyrimidin-4-carboxamides as ccr2 receptor antagonists for treatment of inflammation, asthma and copd.
This patent application is currently assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH. Invention is credited to Frank Buettner, Heiner Ebel, Sara Frattini, Riccardo Giovannini, Silke Hobbie, Christoph Hoenke, Stefan Scheuerer, Patrick Tielmann, Thomas Trieselmann.
Application Number | 20120053164 13/140591 |
Document ID | / |
Family ID | 42049604 |
Filed Date | 2012-03-01 |
United States Patent
Application |
20120053164 |
Kind Code |
A1 |
Ebel; Heiner ; et
al. |
March 1, 2012 |
CYCLIC PYRIMIDIN-4-CARBOXAMIDES AS CCR2 RECEPTOR ANTAGONISTS FOR
TREATMENT OF INFLAMMATION, ASTHMA AND COPD
Abstract
The present invention relates to novel antagonists for CCR2 (CC
chemokine receptor 2) and their use for providing medicaments for
treating conditions and diseases, especially pulmonary diseases
like asthma and COPD. Formula (I), wherein A is selected from among
a single bond, .dbd.CH--, --CH.sub.2--, --O--, --S--, and --NH--;
wherein n is 1, 2 or 3; wherein Z is C or N, the other variables
are as defined in the claims, as well as in form of their acid
addition salts with pharmacologically acceptable acids.
##STR00001##
Inventors: |
Ebel; Heiner; (Biberach,
DE) ; Frattini; Sara; (Castelleone, IT) ;
Giovannini; Riccardo; (Verona, IT) ; Hoenke;
Christoph; (Ingelheim am Rhein, DE) ; Trieselmann;
Thomas; (Warthausen, DE) ; Tielmann; Patrick;
(Offenbach, DE) ; Scheuerer; Stefan; (Warthausen,
DE) ; Hobbie; Silke; (Biberach, DE) ;
Buettner; Frank; (Attenweiler, DE) |
Assignee: |
BOEHRINGER INGELHEIM INTERNATIONAL
GMBH
Ingelheim am Rhein
DE
|
Family ID: |
42049604 |
Appl. No.: |
13/140591 |
Filed: |
December 17, 2009 |
PCT Filed: |
December 17, 2009 |
PCT NO: |
PCT/EP2009/067378 |
371 Date: |
August 10, 2011 |
Current U.S.
Class: |
514/210.18 ;
514/210.2; 514/211.15; 514/217.06; 514/218; 514/233.5; 514/235.8;
514/252.18; 514/256; 514/269; 540/544; 540/575; 540/601; 544/122;
544/230; 544/295; 544/319; 544/327; 544/328; 544/329 |
Current CPC
Class: |
C07D 498/10 20130101;
C07D 417/14 20130101; C07D 403/06 20130101; Y02A 50/411 20180101;
A61P 11/08 20180101; A61K 31/5377 20130101; A61K 31/551 20130101;
A61P 13/00 20180101; A61P 21/00 20180101; C07D 401/14 20130101;
C07D 413/14 20130101; A61P 43/00 20180101; Y02A 50/30 20180101;
C07D 403/14 20130101; A61K 31/506 20130101; A61P 25/00 20180101;
A61P 19/08 20180101; A61K 31/55 20130101; A61P 37/02 20180101; C07D
405/14 20130101; A61P 11/00 20180101; A61P 25/02 20180101; A61P
29/00 20180101; A61P 37/00 20180101; Y02A 50/385 20180101; C07D
451/02 20130101; C07D 471/04 20130101; A61P 3/10 20180101; A61P
9/00 20180101; C07D 471/10 20130101; A61P 9/10 20180101; A61P 25/04
20180101; C07D 401/06 20130101; Y02A 50/409 20180101; A61K 31/553
20130101; C07D 491/052 20130101; C07D 407/14 20130101; A61P 13/12
20180101; A61P 11/06 20180101 |
Class at
Publication: |
514/210.18 ;
544/327; 514/256; 544/329; 544/328; 544/122; 514/235.8; 514/233.5;
540/601; 514/217.06; 544/230; 514/210.2; 540/544; 514/211.15;
544/295; 514/252.18; 540/575; 514/218; 544/319; 514/269 |
International
Class: |
A61K 31/506 20060101
A61K031/506; C07D 405/14 20060101 C07D405/14; C07D 413/14 20060101
C07D413/14; A61K 31/5377 20060101 A61K031/5377; C07D 403/14
20060101 C07D403/14; A61K 31/55 20060101 A61K031/55; C07D 401/06
20060101 C07D401/06; C07D 471/10 20060101 C07D471/10; C07D 417/14
20060101 C07D417/14; C07D 471/04 20060101 C07D471/04; C07D 498/10
20060101 C07D498/10; C07D 451/02 20060101 C07D451/02; A61K 31/553
20060101 A61K031/553; C07D 403/06 20060101 C07D403/06; A61K 31/551
20060101 A61K031/551; A61P 29/00 20060101 A61P029/00; A61P 11/00
20060101 A61P011/00; A61P 11/06 20060101 A61P011/06; A61P 25/00
20060101 A61P025/00; A61P 37/00 20060101 A61P037/00; A61P 9/00
20060101 A61P009/00; A61P 13/12 20060101 A61P013/12; A61P 3/10
20060101 A61P003/10; A61P 9/10 20060101 A61P009/10; A61P 25/04
20060101 A61P025/04; C07D 401/14 20060101 C07D401/14 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 19, 2008 |
EP |
08172336.3 |
May 15, 2009 |
EP |
09160416.5 |
Claims
1. A compound according to formula (I), ##STR00722## wherein
R.sub.1 is -L.sub.1-R.sub.7, wherein L.sub.1 is a linker selected
from a bond or a group selected from among
--C.sub.1-C.sub.2-alkylene, and --C.sub.1-C.sub.2-alkenylene which
optionally comprises one or more groups selected from --O--,
--C(O)--, and --NH-- in the chain and which is optionally
substituted by a group selected from among --OH, --NH.sub.2,
--C.sub.1-C.sub.3-alkyl, O--C.sub.1-C.sub.6-alkyl, and --CN,
wherein R.sub.7 is a ring selected from among
--C.sub.3-C.sub.8-cycloalkyl, --C.sub.3-C.sub.8-heterocyclyl,
--C.sub.5-C.sub.10-aryl, and --C.sub.5-C.sub.10-heteroaryl, wherein
the ring R.sub.7 is optionally substituted with one or more groups
selected from among --CF.sub.3, --O--CF.sub.3, --CN, and -halogen,
or wherein the ring R.sub.7 is optionally substituted with one or
more groups selected from among --C.sub.1-C.sub.6-alkyl,
--O--C.sub.1-C.sub.6-alkyl, --C.sub.5-C.sub.10-aryl,
--C.sub.5-C.sub.10-heteroaryl, --C.sub.3-C.sub.8-cycloalkyl,
--C.sub.3-C.sub.8-heterocyclyl, --C.sub.1-C.sub.6-alkenyl, and
--C.sub.1-C.sub.6-alkynyl, optionally being substituted by one or
more groups selected from among --OH, --NH.sub.2,
--C.sub.1-C.sub.3-alkyl, --O--C.sub.1-C.sub.6-alkyl, --CN,
--CF.sub.3, --OCF.sub.3, halogen, and .dbd.O, or wherein the ring
R.sub.7 is optionally further bi-valently substituted on two
neighbouring ring atoms, such that an annellated ring is formed by
one or more groups selected from among --C.sub.1-C.sub.6-alkylene,
--C.sub.2-C.sub.6-alkenylene and --C.sub.4-C.sub.6-alkynylene, in
which one or two carbon centers may optionally by replaced by 1 or
2 hetero atoms selected from N, O and S, the bivalent group being
optionally substituted by one or more groups selected from --OH,
--NH.sub.2, --C.sub.1-C.sub.3-alkyl, --O--C.sub.1-C.sub.6-alkyl,
--CN, --CF.sub.3, --OCF.sub.3, halogen, and .dbd.O; wherein R.sub.2
is selected from among --H, -halogen, --CN,
--O--C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-alkyl,
--CH.dbd.CH.sub.2, --C.ident.CH, --CF.sub.3, --OCF.sub.3,
--OCF.sub.2H, and --OCFH.sub.2; wherein R.sub.3 is selected from
among --H, -methyl, -ethyl, -propyl, -1-propyl, -cyclopropyl,
--OCH.sub.3, and --CN; wherein R.sub.4 and R.sub.5 are
independently selected from among an electron pair, --H, and a
group selected from among --C.sub.1-C.sub.6-alkyl, --NH.sub.2,
--C.sub.3-C.sub.8-cycloalkyl, --C.sub.3-C.sub.8-heterocyclyl,
--C.sub.5-C.sub.10-aryl, --C.sub.5-C.sub.10-heteroaryl, and
--C(O)--N(R.sub.8,R.sub.8'), with R.sub.8 and R.sub.8'
independently being selected from among --H, and
--C.sub.1-C.sub.6-alkyl, and wherein R.sub.4 and R.sub.5 if
different from an electron pair or --H are optionally independently
substituted with one or more groups selected from among -halogen,
--OH, --CF.sub.3, --CN, --C.sub.1-C.sub.6-alkyl,
--O--C.sub.1-C.sub.6-alkyl, --O--C.sub.3-C.sub.8-cycloalkyl,
--O--C.sub.3-C.sub.8-heterocyclyl, --O--C.sub.5-C.sub.10-aryl,
--O--C.sub.5-C.sub.10-heteroaryl, --C.sub.0-C.sub.6-alkylene-CN,
--C.sub.0-C.sub.4-alkylene-O--C.sub.1-C.sub.4-alkyl,
--C.sub.0-C.sub.4-alkylene-O--C.sub.3-C.sub.8-cycloalkyl,
--C.sub.0-C.sub.4-alkylene-O--C.sub.3-C.sub.8-heterocyclyl,
--C.sub.0-C.sub.4-alkylene-O--C.sub.5-C.sub.10-aryl,
--C.sub.0-C.sub.4-alkylene-O--C.sub.5-C.sub.10-heteroaryl,
--C.sub.0-C.sub.4-alkylene-Q-C.sub.0-C.sub.4-alkyl-N(R.sub.9,R.sub.9'),
--C.sub.0-C.sub.4-alkylene-N(R.sub.10)-Q-C.sub.1-C.sub.4-alkyl,
--C.sub.0-C.sub.4-alkylene-N(R.sub.10)-Q-C.sub.3-C.sub.8-cycloalkyl,
--C.sub.0-C.sub.4-alkylene-N(R.sub.10)-Q-C.sub.3-C.sub.8-heterocyclyl,
--C.sub.0-C.sub.4-alkylene-N(R.sub.10)-Q--C.sub.5-C.sub.10-aryl,
--C.sub.0-C.sub.4-alkylene-N(R.sub.10)-Q-C.sub.5-C.sub.10-heteroaryl,
--C.sub.0-C.sub.4-alkylene-Q-N(R.sub.11,R.sub.11'),
--C.sub.0-C.sub.4-alkylen-N(R.sub.12)-Q-N(R.sub.13,R.sub.13'),
--C.sub.0-C.sub.4-alkylen-R.sub.14,
--C.sub.0-C.sub.4-alkylene-Q-C.sub.1-C.sub.6-alkyl,
--C.sub.0-C.sub.4-alkylene-Q-C.sub.3-C.sub.8-cycloalkyl,
--C.sub.0-C.sub.4-alkylene-Q-C.sub.3-C.sub.8-heterocyclyl,
--C.sub.0-C.sub.4-alkylene-Q-C.sub.5-C.sub.10-aryl,
--C.sub.0-C.sub.4-alkylene-Q-C.sub.5-C.sub.10-heteroaryl,
--C.sub.0-C.sub.4-alkylene-O-Q-N(R.sub.15,R.sub.15'), and
--C.sub.0-C.sub.4-alkylene-N(R.sub.16)-Q-O--(R.sub.17), wherein Q
is selected from among --C(O)--, and --SO.sub.2--, wherein
R.sub.12, R.sub.16, are independently selected from among --H,
--C.sub.1-C.sub.6-alkyl, and --C.sub.3-C.sub.6-cycloalkyl, wherein
R.sub.9, R.sub.9', R.sub.10, R.sub.11, R.sub.11', R.sub.13,
R.sub.13', R.sub.15, R.sub.15', are independently selected from
among --H, --C.sub.1-C.sub.6-alkyl, and
--C.sub.3-C.sub.6-cycloalkyl, or wherein R.sub.9 and R.sub.9',
R.sub.11 and R.sub.11', R.sub.13 and R.sub.13', R.sub.15 and
R.sub.15' together form a --C.sub.2-C.sub.6-alkylene group, wherein
R.sub.14 and R.sub.17 are independently selected from among --H,
--C.sub.1-C.sub.6-alkyl, --C.sub.5-C.sub.10-aryl,
--C.sub.5-C.sub.10-heteroaryl, --C.sub.3-C.sub.8-cycloalkyl, and
--C.sub.3-C.sub.8-heterocyclyl, wherein said
--C.sub.3-C.sub.8-heterocyclyl optionally comprises nitrogen and/or
--SO.sub.2-- in the ring, and wherein R.sub.14 and R.sub.17 are
optionally substituted with one or more groups selected from among
--OH, --OCH.sub.3, --CF.sub.3, --OCF.sub.3, --CN, -halogen,
--C.sub.1-C.sub.4-alkyl, .dbd.O, and
--SO.sub.2--C.sub.1-C.sub.4-alkyl, or wherein R.sub.4 and/or
R.sub.5 are independently a group of the structure
-L.sub.2-R.sub.18, wherein L.sub.2 is selected from among --NH--
and --N(C.sub.1-C.sub.4-alkyl)-, wherein R.sub.18 is selected from
among --C.sub.5-C.sub.10-aryl, --C.sub.5-C.sub.10-heteroaryl,
--C.sub.3-C.sub.8-cycloalkyl, and --C.sub.3-C.sub.8-heterocyclyl,
wherein R.sub.18 is optionally substituted by one or more groups
selected from among halogen, --CF.sub.3, --OCF.sub.3, --CN, --OH,
--O--C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.6-alkyl,
--NH--C(O)--C.sub.1-C.sub.6-alkyl,
--N(C.sub.1-C.sub.4-alkyl)-C(O)--C.sub.1-C.sub.6-alkyl,
--C(O)--C.sub.1-C.sub.6-alkyl, --S(O).sub.2--C.sub.1-C.sub.6-alkyl,
--NH--S(O).sub.2--C.sub.1-C.sub.6-alkyl,
--N(C.sub.1-C.sub.4-alkyl)-S(O).sub.2--C.sub.1-C.sub.6-alkyl, and
--C(O)--O--C.sub.1-C.sub.6-alkyl, and wherein R.sub.4, R.sub.5 and
R.sub.18 are optionally further substituted by
spiro-C.sub.3-C.sub.8-cycloalkyl or
spiro-C.sub.3-C.sub.8-heterocyclyl such that together with R.sub.4,
R.sub.5 and/or R.sub.18 a spirocycle is formed, wherein said
spiro-C.sub.3-C.sub.8-heterocyclyl optionally comprises one or more
groups selected from among nitrogen, --C(O)--, --SO.sub.2--, and
--N(SO.sub.2--C.sub.1-C.sub.4-alkyl)- in the ring, or wherein
R.sub.4, R.sub.5 and R.sub.18 are optionally further bi-valently
substituted by one or more spirocyclic or annellated ring forming
groups selected from among --C.sub.1-C.sub.6-alkylene,
--C.sub.2-C.sub.6-alkenylene, and --C.sub.4-C.sub.6-alkynylene, in
which one or two carbon centers may optionally be replaced by one
or two hetero atoms selected from among N, O and S and which may
optionally be substituted by one or more groups on one ring atom or
on two neighbouring ring atoms selected from among --OH,
--NH.sub.2, --C.sub.1-C.sub.3-alkyl, O--C.sub.1-C.sub.6-alkyl,
--CN, --CF.sub.3, --OCF.sub.3, and halogen; wherein R.sub.6 is
selected from among --H, --C.sub.1-C.sub.4-alkyl, --OH,
--O--C.sub.1-C.sub.4-alkyl, -halogen, --CN, --CF.sub.3, and
--OCF.sub.3; wherein A is selected from among a single bond,
.dbd.CH--, --CH.sub.2--, --O--, --S--, and --NH--; wherein n is 1,
2 or 3; wherein Z is C or N, as well as in form of their acid
addition salts with pharmacologically acceptable acids.
2. The compound of claim 1, wherein R.sub.1 is -L.sub.1-R.sub.7,
and wherein L.sub.1 is a bond or a group selected from among
methylene, ethylene, methenylene, and ethenylene, and wherein
R.sub.7 is a ring selected from among cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl,
azepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, phenyl,
pyridyl, and furanyl, wherein L.sub.1 if different from a bond is
optionally substituted with one or more groups selected from among
methyl, and ethyl, wherein L.sub.1 if different from a bond
optionally comprises one or more --O-- atoms, wherein the ring
R.sub.7 is optionally substituted with one or more groups selected
from among --F, --Cl, -methyl, -ethyl, -propyl, -1-propyl,
-cyclopropyl, -t-butyl, --CF.sub.3, --O--CF.sub.3, --CN,
--O-methyl, furanyl and phenyl, wherein said furanyl and said
phenyl are optionally independently substituted by one or more
groups selected from among --C.sub.1-C.sub.3-alkyl, halogen,
--OCH.sub.3, --CF.sub.3, and --OCF.sub.3, or wherein the ring
R.sub.7 is bi-valently substituted by one or more groups selected
from among ##STR00723## on two neighbouring ring atoms, such that
an annellated ring is formed.
3. The compound of claim 1, wherein R.sub.1 is selected from among
##STR00724## ##STR00725## ##STR00726## ##STR00727## ##STR00728##
##STR00729## ##STR00730##
4. The compound of claim 1, wherein R.sub.2 is selected from among
--H, -methyl, -ethyl, -propyl, -1-propyl, -cyclopropyl, -butyl,
-i-butyl, -t-butyl, --F, --Cl, --Br, --I, --CN, --CH.dbd.CH.sub.2,
--C.ident.CH, and --OCH.sub.3.
5. The compound of claim 1, wherein R.sub.2 is selected from among
--H, -Methyl, -Ethyl, --Br, and --OCH.sub.3.
6. The compound of claim 1, wherein R.sub.3 is selected from among
--H, and -methyl.
7. The compound of claim 1, wherein R.sub.4 and R.sub.5 are
independently selected from among an electron pair, --H, and a
group selected from among-1-propyl, -amino, -pyrrolidinyl,
-piperidinyl, -morpholinyl, -azepanyl, -oxazepanyl, -piperazinyl,
-azetidinyl, -tetrahydropyranyl, -cyclopentyl, -cyclohexyl, and
--C(O)--N(R.sub.8,R.sub.8'), with R.sub.8 and R.sub.8'
independently being selected from among --H and
--C.sub.1-C.sub.6-alkyl, wherein R.sub.4 and R.sub.5 if different
from an electron pair, and --H are optionally independently
substituted with one or more groups selected from among -fluoro,
-methyl, -ethyl, propyl, -1-propyl, -butyl, -1-butyl, -t-butyl,
-hydroxy, --CF.sub.3, --OCF.sub.3, --CN, --O--CH.sub.3,
--O--C.sub.2H.sub.5, --O--C.sub.3H.sub.7, --CH.sub.2--CN,
--CH.sub.2--O--CH.sub.3, --(CH.sub.2).sub.2--O--CH.sub.3,
--C(O)--CH.sub.3, --C(O)--C.sub.2H.sub.5, --C(O)--C.sub.3H.sub.7,
--COOH, --C(O)--NH.sub.2, --C(O)--NH--CH.sub.3,
--C(O)--N(CH.sub.3).sub.2, --NH--C(O)--CH.sub.3,
--N(CH.sub.3)C(O)--CH.sub.3, --NH--C(O)--C.sub.2H.sub.5,
--N(CH.sub.3)--C(O)--C.sub.2H.sub.5, --NH--C(O)--C.sub.3H.sub.7,
--N(CH.sub.3)--C(O)--C.sub.3H.sub.7, --NH--SO.sub.2--CH.sub.3,
--N(CH.sub.3)--SO.sub.2--CH.sub.3,
--N(C.sub.2H.sub.5)--SO.sub.2--CH.sub.3,
--N(C.sub.3H.sub.7)--SO.sub.2--CH.sub.3, --NH--SO.sub.2.sup.-
C.sub.2H.sub.5, --N(CH.sub.3)--SO.sub.2--C.sub.2H.sub.5,
--N(C.sub.2H.sub.5)--SO.sub.2--C.sub.2H.sub.5,
--N(C.sub.3H.sub.7)--SO.sub.2--C.sub.2H.sub.5,
--H--SO.sub.2--C.sub.3H.sub.7,
--N(CH.sub.3)--SO.sub.2--C.sub.3H.sub.7,
--N(C.sub.2H.sub.5)--SO.sub.2--C.sub.3H.sub.7,
--N(C.sub.3H.sub.7)--SO.sub.2--C.sub.3H.sub.7,
--NH--SO.sub.2--C.sub.3H.sub.5, --N(CH.sub.3)
SO.sub.2--C.sub.3H.sub.5,
--N(C.sub.2H.sub.5)--SO.sub.2--C.sub.3H.sub.5,
--N(C.sub.3H.sub.7)--SO.sub.2--C.sub.2H.sub.5,
--CH.sub.2--NH--SO.sub.2--CH.sub.3, --CH.sub.2--N(CH.sub.3)
SO.sub.2--CH.sub.3, --CH.sub.2--NH--SO.sub.2--C.sub.2H.sub.5,
--CH.sub.2--N(CH.sub.3)--SO.sub.2--C.sub.2H.sub.5,
--CH.sub.2--NH--SO.sub.2--C.sub.3H.sub.7,
--CH.sub.2--N(CH.sub.3)--SO.sub.2--C.sub.3H.sub.7,
--CH.sub.2--NH--SO.sub.2--C.sub.3H.sub.5,
--CH.sub.2--N(CH.sub.3)--SO.sub.2--C.sub.3H.sub.5,
--NH--C(O)--NH.sub.2, --N(CH.sub.3)--C(O)--NH.sub.2,
--NH--C(O)--NH--CH.sub.3, --N(CH.sub.3)--C(O)--NH--CH.sub.3,
--NH--C(O)--N(CH.sub.3).sub.2,
--N(CH.sub.3)--C(O)--N(CH.sub.3).sub.2, --SO.sub.2--NH.sub.2,
--SO.sub.2--NH(CH.sub.3), --SO.sub.2--N(CH.sub.3).sub.2,
--C(O)--NH--C.sub.2H.sub.5, --C(O)--N(CH.sub.3)--C.sub.2H.sub.5,
--C(O)--N(CH.sub.3)--C.sub.3H.sub.7,
--C(O)--N(CH.sub.3)--C.sub.4H.sub.9,
--C(O)--NH--CH(CH.sub.3)--C.sub.2H.sub.5,
--C(O)--N(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--C(O)--NH.sub.2, --CH.sub.2--C(O)--NH--CH.sub.3,
--CH.sub.2--C(O)--N(CH.sub.3).sub.2,
--N(CH.sub.3)--SO.sub.2--N(CH.sub.3).sub.2, -phenyl, -pyridin-4-yl,
--CH.sub.2-3-methyl-oxetan-3-yl, --O-1,2-difluoro-phen-5-yl,
--O-pyridin-2-yl, -pyrrolidine-2-one-1-yl,
-3,5-dimethyl-[1,2,4]triazol-4-yl, 3-methyl-[1,2,4]oxadiazol-5-yl,
##STR00731## or wherein R.sub.4 and R.sub.5 are independently a
group of the structure -L.sub.2-R.sub.18, wherein L.sub.2 is
selected from among --NH--, --N(CH.sub.3)--, and
--N(C.sub.2H.sub.5)--, and wherein R.sub.18 is selected from among
-tetrahydropyranyl, -cyclopropyl, -cyclobutyl, -cyclopentyl,
-cyclohexyl, -cycloheptyl, -cyclooctyl, -pyrrolidinyl,
-piperidinyl, -piperazinyl, -morpholinyl, -chromanyl,
-octahydro-pyrano-pyrrolyl, -octahydro-pyrano-pyridinyl,
-octahydro-pyrano-oxazinyl, -oxaspirodecanyl, and
-tetrahydro-naphthyridinyl, wherein R.sub.18 is optionally
substituted by one or more groups selected from among --F,
--CF.sub.3, --OCF.sub.3, --CN, --OH, --O--CH.sub.3, --CH.sub.3,
--NH--C(O)--CH.sub.3, --N(CH.sub.3)--C(O)--CH.sub.3,
--C(O)--CH.sub.3, --S(O).sub.2--CH.sub.3,
--NH--S(O).sub.2--CH.sub.3, --N(CH.sub.3)--S(O).sub.2--CH.sub.3,
and --C(O)--O--C.sub.2H.sub.5, and wherein R.sub.4, R.sub.5 and
R.sub.18 are optionally further bi-valently substituted by one or
more groups selected from among ##STR00732## on one ring atom or on
two neighboring ring atoms, such that spirocyclic or annellated
rings are formed.
8. The compound of claim 1, wherein R.sub.4 is selected from among
##STR00733## ##STR00734## ##STR00735## ##STR00736## ##STR00737##
##STR00738## ##STR00739## ##STR00740##
9. The compound of claim 1, wherein R.sub.5 is selected from among
an electron pair, --H, and --C(O)--NH.sub.2.
10. The compound of claim 1, wherein R.sub.6 is selected from among
--H, --CH.sub.3, --C.sub.2H.sub.5, --O--CH.sub.3,
--O--C.sub.2H.sub.5, --F, --CF.sub.3, and --OCF.sub.3.
11. The compound of claim 1, wherein R.sub.6 is H or
--O--CH.sub.3.
12. The compound of claim 1, wherein A is selected from a single
bond, .dbd.CH--, --CH.sub.2, --O-- or --NH--.
13. The compound of claim 1, wherein A is selected from among --O--
and --NH--.
14. The compound of claim 1, wherein A is --NH--.
15. The compound of claim 1, wherein Z is C or N.
16. (canceled)
17. A method for the treatment of inflammatory diseases comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound according to claim 1 or a
pharmacologically acceptable salt thereof.
18. The method according to claim 17, wherein the inflammatory
diseases are selected from inflammatory diseases of the respiratory
tract.
19. The method according to claim 18, wherein the diseases are
selected from chronic obstructive pulmonary disease, asthma, and
cystic fibrosis.
20. A method for the treatment of neurologic diseases comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound according to claim 1 or a
pharmacologically acceptable salt thereof.
21. A method for the treatment of immune related diseases
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound according to claim 1
or a pharmacologically acceptable salt thereof.
22. A method for the treatment of cardiovascular diseases,
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound according to claim 1
or a pharmacologically acceptable salt thereof.
23. A method for the treatment of diabetic nephropathy comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound according to claim 1 or a
pharmacologically acceptable salt thereof.
24. The method according to claim 20 wherein the neurologic disease
is neuropathic pain.
25. The method according to claim 21 wherein the immune related
disease is diabetes mellitus.
26. The method according to claim 22 wherein the cardiovascular
disease is atherosclerosis.
Description
FIELD OF INVENTION
[0001] The present invention relates to novel antagonists for CCR2
(CC chemokine receptor 2) and their use for providing medicaments
for treating conditions and diseases where activation of CCR2 plays
a causative role, especially pulmonary diseases like asthma and
COPD, neurologic disease, especially of pain diseases, immune
related diseases, especially diabetes mellitus including diabetes
nephropathy, and cardiovascular diseases, especially
atherosclerotic disease.
BACKGROUND OF THE INVENTION
[0002] The chemokines are a family of small, proinflammatory
cytokines, with potent chemotactic activities. Chemokines are
chemotactic cytokines that are released by a wide variety of cells
to attract various cells, such as monocytes, macrophages, T cells,
eosinophils, basophils and neutrophils to sites of
inflammation.
[0003] Chemokine receptors, such as CCR2 or CCR5 have been
implicated as being important mediators of inflammatory and
immunoregulatory disorders and diseases as well as autoimmune
pathologies such as rheumatoid arthritis and atherosclerosis.
Accordingly, agents which modulate chemokine receptors such as the
CCR2 and CCR5 receptor would be useful in such disorders and
diseases.
[0004] In particular it is widely accepted that numerous conditions
and diseases involve inflammatory processes. Such inflammations are
critically triggered and/or promoted by the activity of
macrophages, which are formed by differentiation out of monocytes.
It has further been found that monocytes are characterized by,
e.g., a high expression of membrane-resident CCR2, whereas the CCR2
expression in macrophages is lower. CCR2 is a critical regulator of
monocytes trafficking, which can be described as the movement of
the monocytes towards an inflammation along a gradient of monocyte
chemoattractant proteins (MCP-1, MCP-2, MCP-3, MCP-4).
[0005] Therefore, in order to reduce macrophage-induced
inflammation, it would be desirable to block the monocyte CCR2 by
an antagonist, so that the monocytes can be less triggered to move
towards an inflammation area for conversion into macrophages.
[0006] Based on the aforesaid there is a need for providing
effective antagonists for CCR2, which are pharmacologically
acceptable.
DESCRIPTION OF THE INVENTION
[0007] It has now been found that such effective CCR2 inhibitors
can be provided by compounds according to general formula (I),
##STR00002##
wherein R.sub.1 is -L.sub.1-R.sub.7, wherein L.sub.1 is a linker
selected from a bond or a group selected from
--C.sub.1-C.sub.2-alkylene, and --C.sub.1-C.sub.2-alkenylene which
optionally comprises one or more groups selected from --O--,
--C(O)--, and --NH-- in the chain and which is optionally
substituted by a group selected from among --OH, --NH.sub.2,
--C.sub.1-C.sub.3-alkyl, O--C.sub.1-C.sub.6-alkyl, and --CN,
wherein R.sub.7 is a ring selected from among
--C.sub.3-C.sub.8-cycloalkyl, --C.sub.3-C.sub.8-heterocyclyl,
--C.sub.5-C.sub.10-aryl, and --C.sub.5-C.sub.10-heteroaryl, wherein
the ring R.sub.7 is optionally substituted with one or more groups
selected from among --CF.sub.3, --O--CF.sub.3, --CN, and -halogen,
or wherein the ring R.sub.7 is optionally substituted with one or
more groups selected from among --C.sub.1-C.sub.6-alkyl,
--O--C.sub.1-C.sub.6-alkyl, --C.sub.5-C.sub.10-aryl,
--C.sub.5-C.sub.10-heteroaryl, --C.sub.3-C.sub.8-cycloalkyl,
--C.sub.3-C.sub.8-heterocyclyl, --C.sub.1-C.sub.6-alkenyl, and
--C.sub.1-C.sub.6-alkynyl, optionally being further substituted by
one or more groups selected from --OH, --NH.sub.2,
--C.sub.1-C.sub.3-alkyl, --O--C.sub.1-C.sub.6-alkyl, --CN,
--CF.sub.3, --OCF.sub.3, halogen, and .dbd.O, or wherein the ring
R.sub.7 is optionally further bi-valently substituted on two
neighbouring ring atoms, such that an annellated ring is formed by
one or more groups selected from among --C.sub.1-C.sub.6-alkylene,
--C.sub.2-C.sub.6-alkenylene and --C.sub.4-C.sub.6-alkynylene, in
which one or two carbon centers may optionally by replaced by 1 or
2 hetero atoms selected from N, O and S, the bivalent group being
optionally substituted by one or more groups selected from --OH,
--NH.sub.2, --C.sub.1-C.sub.3-alkyl, --O--C.sub.1-C.sub.6-alkyl,
--CN, --CF.sub.3, --OCF.sub.3, halogen, and .dbd.O; R.sub.2 is
selected from among --H, -halogen, --CN,
--O--C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-alkyl,
--CH.dbd.CH.sub.2, --C.ident.CH, --CF.sub.3, --OCF.sub.3,
--OCF.sub.2H, and --OCFH.sub.2; R.sub.3 is selected from among --H,
-methyl, -ethyl, -propyl, -1-propyl, -cyclopropyl, --OCH.sub.3, and
--CN; R.sub.4 and R.sub.5 are independently selected from among an
electron pair, --H, --C.sub.1-C.sub.6-alkyl, --NH.sub.2,
--C.sub.3-C.sub.8-cycloalkyl, --C.sub.3-C.sub.8-heterocyclyl,
--C.sub.5-C.sub.10-aryl, --C.sub.5-C.sub.10-hetero aryl, and
--C(O)--N(R.sub.8,R.sub.8'), with R.sub.8 and R.sub.8'
independently being selected from among --H and
--C.sub.1-C.sub.6-alkyl, wherein R.sub.4 and R.sub.5 if different
from an electron pair or --H are optionally independently
substituted with one or more groups selected from among -halogen,
--OH, --CF.sub.3, --CN, --C.sub.1-C.sub.6-alkyl,
--O--C.sub.1-C.sub.6-alkyl, --O--C.sub.3-C.sub.8-cycloalkyl,
--O--C.sub.3-C.sub.8-heterocyclyl, --O--C.sub.5-C.sub.10-aryl,
--O--C.sub.5-C.sub.10-heteroaryl, --C.sub.0-C.sub.6-alkylene-CN,
--C.sub.0-C.sub.4-alkylene-O--C.sub.1-C.sub.4-alkyl,
--C.sub.0-C.sub.4-alkylene-O--C.sub.3-C.sub.8-cycloalkyl,
--C.sub.0-C.sub.4-alkylene-O--C.sub.3-C.sub.8-heterocyclyl,
--C.sub.0-C.sub.4-alkylene-O--C.sub.5-C.sub.10-aryl,
--C.sub.0-C.sub.4-alkylene-O--C.sub.5-C.sub.10-heteroaryl,
--C.sub.0-C.sub.4-alkylene-Q-C.sub.0-C.sub.4-alkyl-N(R.sub.9,R.sub.9'),
--C.sub.0-C.sub.4-alkylene-N(R.sub.10)-Q-C.sub.1-C.sub.4-alkyl,
--C.sub.0-C.sub.4-alkylene-N(R.sub.10)--O--C.sub.3-C.sub.8-cycloalkyl,
--C.sub.0-C.sub.4-alkylene-N(R.sub.10)-Q-C.sub.3-C.sub.8-heterocyclyl,
--C.sub.0-C.sub.4-alkylene-N(R.sub.10)--O--C.sub.5-C.sub.10-aryl,
--C.sub.0-C.sub.4-alkylene-N(R.sub.10)-Q-C.sub.5-C.sub.10-heteroaryl,
--C.sub.0-C.sub.4-alkylene-Q-N(R.sub.11,R.sub.11'),
--C.sub.0-C.sub.4-alkylen-N(R.sub.12)--O--N(R.sub.13,R.sub.13'),
--C.sub.0-C.sub.4-alkylen-R.sub.14,
--C.sub.0-C.sub.4-alkylene-Q-C.sub.1-C.sub.6-alkyl,
--C.sub.0-C.sub.4-alkylene-Q-C.sub.3-C.sub.8-cycloalkyl,
--C.sub.0-C.sub.4-alkylene-Q-C.sub.3-C.sub.8-heterocyclyl,
--C.sub.0-C.sub.4-alkylene-Q-C.sub.5-C.sub.10-aryl,
--C.sub.0-C.sub.4-alkylene-Q-C.sub.5-C.sub.10-heteroaryl,
--C.sub.0-C.sub.4-alkylene-O-Q-N(R.sub.15,R.sub.15'), and
--C.sub.0-C.sub.4-alkylene-N(R.sub.16)-Q-O--(R.sub.17) wherein Q is
selected from among --C(O)-- and --SO.sub.2-- wherein R.sub.12,
R.sub.16, are independently selected from among --H,
--C.sub.1-C.sub.6-alkyl, and --C.sub.3-C.sub.6-cycloalkyl, wherein
R.sub.9, R.sub.9', R.sub.10, R.sub.11, R.sub.11', R.sub.13,
R.sub.13', R.sub.15, R.sub.15' are independently selected from
among --H and --C.sub.1-C.sub.6-alkyl, and
--C.sub.3-C.sub.6-cycloalkyl, or wherein R.sub.9 and R.sub.9',
R.sub.11 and R.sub.11', R.sub.13 and R.sub.13', R.sub.15 and
R.sub.15', together form a --C.sub.2-C.sub.6-alkylene group,
preferably a --C.sub.5-C.sub.6-alkylene group, wherein R.sub.14 and
R.sub.17 are independently selected from among --H,
--C.sub.1-C.sub.6-alkyl, --C.sub.5-C.sub.10-aryl,
--C.sub.5-C.sub.10-heteroaryl, --C.sub.3-C.sub.8-cycloalkyl, and
--C.sub.3-C.sub.8-heterocyclyl, wherein said
--C.sub.3-C.sub.8-heterocyclyl optionally comprises nitrogen and/or
--SO.sub.2-- in the ring, and wherein R.sub.14 and R.sub.17 are
optionally substituted with one or more groups selected from among
--OH, --OCH.sub.3, --CF.sub.3, --OCF.sub.3, --CN, -halogen,
--C.sub.1-C.sub.4-alkyl, .dbd.O, and
--SO.sub.2--C.sub.1-C.sub.4-alkyl, or wherein R.sub.4 and/or
R.sub.5 are independently a group of the structure
-L.sub.2-R.sub.18, wherein L.sub.2 is selected from among --NH--,
and --N(C.sub.1-C.sub.4-alkyl)-, wherein R.sub.18 is selected from
among --C.sub.5-C.sub.10-aryl, --C.sub.5-C.sub.10-heteroaryl,
--C.sub.3-C.sub.8-cycloalkyl, and --C.sub.3-C.sub.8-heterocyclyl,
wherein R.sub.18 is optionally substituted by one or more groups
selected from among halogen, --CF.sub.3, --OCF.sub.3, --CN, --OH,
--O--C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.6-alkyl,
--NH--C(O)--C.sub.1-C.sub.6-alkyl,
--N(C.sub.1-C.sub.4-alkyl)-C(O)--C.sub.1-C.sub.6-alkyl,
--C(O)--C.sub.1-C.sub.6-alkyl, --S(O).sub.2--C.sub.1-C.sub.6-alkyl,
--NH--S(O).sub.2--C.sub.1-C.sub.6-alkyl,
--N(C.sub.1-C.sub.4-alkyl)-S(O).sub.2--C.sub.1-C.sub.6-alkyl, and
--C(O)--O--C.sub.1-C.sub.6-alkyl, and wherein R.sub.4, R.sub.5 and
R.sub.18 are optionally further substituted by
spiro-C.sub.3-C.sub.8-cycloalkyl or
spiro-C.sub.3-C.sub.8-heterocyclyl such that together with R.sub.4,
R.sub.5 and/or R.sub.18 a spirocycle is formed, wherein said
spiro-C.sub.3-C.sub.8-heterocyclyl optionally comprises one or more
groups selected from among nitrogen, --C(O)--, --SO.sub.2--, and
--N(SO.sub.2--C.sub.1-C.sub.4-alkyl)- in the ring, or wherein
R.sub.4, R.sub.5 and R.sub.18 are optionally further bi-valently
substituted by one or more spirocyclic or annellated ring forming
groups selected from among --C.sub.1-C.sub.6-alkylene,
--C.sub.2-C.sub.6-alkenylene, and --C.sub.4-C.sub.6-alkynylene, in
which one or two carbon centers may optionally be replaced by one
or two hetero atoms selected from among N, O and S and which may
optionally be substituted by one or more groups on one ring atom or
on two neighbouring ring atoms selected from among --OH,
--NH.sub.2, --C.sub.1-C.sub.3-alkyl, O--C.sub.1-C.sub.6-alkyl,
--CN, --CF.sub.3, --OCF.sub.3, and halogen; R.sub.6 is selected
from among --H, --C.sub.1-C.sub.4-alkyl, --OH,
--O--C.sub.1-C.sub.4-alkyl, -halogen, --CN, --CF.sub.3, and
--OCF.sub.3; A is selected from among a single bond, .dbd.CH--,
--CH.sub.2--, --O--, --S--, and --NH--; n is 1, 2 or 3;
Z is C or N,
[0008] as well as in form of their acid addition salts with
pharmacologically acceptable acids, as well as in form of their
solvates and/or hydrates.
[0009] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.8, R.sub.8', R.sub.9, R.sub.9', R.sub.10, R.sub.11,
R.sub.11' R.sub.12, R.sub.13, R.sub.13', R.sub.14, R.sub.15,
R.sub.15'R.sub.16, R.sub.17, R.sub.18, A, L.sub.2, Z, Q, and n as
herein before or below defined, wherein R.sub.1 is
-L.sub.1-R.sub.7,
with L.sub.1 being a linker selected from a bond or a group
selected from among --C.sub.1-C.sub.2-alkylene, and
--C.sub.1-C.sub.2-alkenylene optionally comprising one or more
groups selected from among --O--, --C(O)--, and, --NH-- in the
chain and optionally being substituted by a group selected from
among --OH, --NH.sub.2, --C.sub.1-C.sub.3-alkyl,
O--C.sub.1-C.sub.6-alkyl, and --CN, wherein R.sub.7 is a ring
selected from among --C.sub.3-C.sub.8-cycloalkyl,
--C.sub.5-C.sub.10-aryl, --C.sub.3-C.sub.8-heterocyclyl comprising
1 or 2 hetero atoms selected from among N, and O, and
--C.sub.5-C.sub.10-heteroaryl comprising 1 or 2 hetero atoms
selected from among N, and O, wherein the ring R.sub.7 is
optionally substituted with one or more groups selected from among
--CF.sub.3, --O--CF.sub.3, --CN, and -halogen, or wherein the ring
R.sub.7 is optionally substituted with one or more groups selected
from among --C.sub.1-C.sub.6-alkyl, --O--C.sub.1-C.sub.6-alkyl,
--C.sub.5-C.sub.10-aryl, --C.sub.3-C.sub.8-cycloalkyl,
--C.sub.3-C.sub.8-heterocyclyl, --C.sub.1-C.sub.6-alkenyl, and
--C.sub.1-C.sub.6-alkynyl, optionally being substituted by one or
more groups selected from --OH, --NH.sub.2,
--C.sub.1-C.sub.3-alkyl, --O--C.sub.1-C.sub.6-alkyl, --CN,
--CF.sub.3, --OCF.sub.3, halogen, and .dbd.O, or wherein the ring
R.sub.7 is optionally further bi-valently substituted by one or
more annellated ring forming groups selected from among
--C.sub.1-C.sub.6-alkylene, --C.sub.2-C.sub.6-alkenylene and
--C.sub.4-C.sub.6-alkynylene, in which one or two carbon centers
may optionally by replaced by 1 or 2 hetero atoms selected from N,
and O, wherein the bivalent group is optionally substituted by one
or more groups selected from --OH, --NH.sub.2,
--C.sub.1-C.sub.3-alkyl, --O--C.sub.1-C.sub.6-alkyl, --CN,
--CF.sub.3, --OCF.sub.3, halogen, and .dbd.O;
[0010] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.8, R.sub.8', R.sub.9, R.sub.9', R.sub.10, R.sub.11,
R.sub.11'R.sub.12, R.sub.13, R.sub.13', R.sub.14, R.sub.15,
R.sub.15' R.sub.16, R.sub.17, R.sub.18, A, L.sub.2, Z, Q, and n as
herein before or below defined, wherein R.sub.1 is
-L.sub.1-R.sub.7,
wherein L.sub.1 is a linker selected from among a bond, methylene,
ethylene, methenylene, and ethenylene, wherein L.sub.1, if
different from a bond, is optionally substituted with one or more
groups selected from among methyl, and ethyl, wherein R.sub.7 is a
ring selected from among cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, azepanyl,
tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, phenyl, pyridyl,
and furanyl, wherein the ring R.sub.7 is optionally substituted
with one or more groups selected from among --F, --Cl, -methyl,
-ethyl, -propyl, -1-propyl, -cyclopropyl, -t-butyl, --CF.sub.3,
--O--CF.sub.3, --CN, --O-methyl, -furanyl and -phenyl, wherein said
furanyl and said phenyl are optionally independently substituted by
one or more groups selected from among --C.sub.1-C.sub.6-alkyl, or
halogen, --OCH.sub.3, --CF.sub.3, and --OCF.sub.3. or wherein
R.sub.7 is bi-valently substituted by one or more groups selected
from among
##STR00003##
on two neighbouring ring atoms, such that an annellated ring is
formed.
[0011] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.8, R.sub.8', R.sub.9, R.sub.9', R.sub.10,
R.sub.11, R.sub.11' R.sub.12, R.sub.13, R.sub.13', R.sub.14,
R.sub.15, R.sub.15' R.sub.16, R.sub.17, R.sub.18, A, L.sub.2, Z, Q,
and n as herein before or below defined, wherein R.sub.1 is
-L.sub.1-R.sub.7,
and wherein L.sub.1 is a linker selected from among a bond,
methylene, ethylene, methenylene, and ethenylene and wherein
L.sub.1 is optionally substituted with one or more of methyl or
ethyl and wherein L.sub.1 optionally comprises one or more --O--
atoms.
[0012] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.8, R.sub.8', R.sub.9, R.sub.9', R.sub.10,
R.sub.11, R.sub.11'R.sub.12, R.sub.13, R.sub.13', R.sub.14,
R.sub.15, R.sub.15'R.sub.16, R.sub.17, R.sub.18, A, L.sub.2, Z, Q
and n as herein before or below defined, wherein R.sub.1 is
selected from among
##STR00004## ##STR00005## ##STR00006## ##STR00007## ##STR00008##
##STR00009## ##STR00010##
[0013] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.1, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.8, R.sub.8', R.sub.9, R.sub.9', R.sub.10,
R.sub.11, R.sub.11', R.sub.12, R.sub.13, R.sub.13', R.sub.14,
R.sub.15, R.sub.15', R.sub.16, R.sub.17, R.sub.18, A, L.sub.1,
L.sub.2, Z, Q, and n as herein before or below defined, wherein
R.sub.2 is selected from among --H, -methyl, -ethyl, -propyl,
-1-propyl, -cyclopropyl, -butyl, -1-butyl, -t-butyl, --F, --Cl,
--Br, --I, --CN, --CH.dbd.CH.sub.2, --C.ident.CH, and --OCH.sub.3,
more preferred from among H, -methyl, -ethyl, -propyl, -1-propyl,
-cyclopropyl, and --OCH.sub.3.
[0014] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.1, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.8, R.sub.8', R.sub.9, R.sub.9', R.sub.10,
R.sub.11, R.sub.11', R.sub.12, R.sub.13, R.sub.13'', R.sub.14,
R.sub.15, R.sub.15', R.sub.16, R.sub.17, R.sub.18, A, L.sub.1,
L.sub.2, Z, Q, and n as herein before or below defined, wherein
R.sub.2 is selected from among --H, -Methyl, -Ethyl, --Br, and
--OCH.sub.3.
[0015] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.1, R.sub.2, R.sub.4, R.sub.5,
R.sub.6, R.sub.7, R.sub.8, R.sub.8', R.sub.9, R.sub.9', R.sub.10,
R.sub.11, R.sub.11', R.sub.12, R.sub.13, R.sub.13', R.sub.14,
R.sub.15, R.sub.15', R.sub.16, R.sub.17, R.sub.18, A, L.sub.1,
L.sub.2, Z, Q, and n as herein before or below defined, wherein
R.sub.3 is selected from among --H, and -methyl.
[0016] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.1, R.sub.2, R.sub.3, R.sub.6,
R.sub.7, R.sub.9, R.sub.9', R.sub.10, R.sub.11, R.sub.11',
R.sub.12, R.sub.13, R.sub.13', R.sub.14, R.sub.15, R.sub.15',
R.sub.16, R.sub.17, R.sub.18, A, L.sub.1, L.sub.2, Z, Q, and n as
herein before or below defined, wherein R.sub.4 and R.sub.5 are
independently selected from among an electron pair, --H, -1-propyl,
-amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl,
-oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl,
-cyclopentyl, -cyclohexyl, and --C(O)--N(R.sub.8,R.sub.8'), with
R.sub.8 and R.sub.8' independently being selected from among --H
and --C.sub.1-C.sub.6-alkyl,
wherein R.sub.4 and R.sub.5 are optionally independently
substituted with one or more groups selected from among -fluoro,
-methyl, -ethyl, propyl, -1-propyl, -butyl, -1-butyl, -t-butyl,
-hydroxy, --CF.sub.3, --OCF.sub.3, --CN, --O--CH.sub.3,
--O--C.sub.2H.sub.5, --O--C.sub.3H.sub.7, --CH.sub.2--CN,
--CH.sub.2--O--CH.sub.3, --(CH.sub.2).sub.2--O--CH.sub.3,
--C(O)--CH.sub.3, --C(O)--C.sub.2H.sub.5, --C(O)--C.sub.3H.sub.7,
--COOH, --C(O)--NH.sub.2, --C(O)--NH--CH.sub.3,
--C(O)--N(CH.sub.3).sub.2, --NH--C(O)--CH.sub.3,
--N(CH.sub.3)C(O)--CH.sub.3, --NH--C(O)--C.sub.2H.sub.5,
--N(CH.sub.3)--C(O)--C.sub.2H.sub.5, --NH--C(O)--C.sub.3H.sub.7,
--N(CH.sub.3)--C(O)--C.sub.3H.sub.7, --NH--SO.sub.2--CH.sub.3,
--N(CH.sub.3)--SO.sub.2--CH.sub.3,
--N(C.sub.2H.sub.5)--SO.sub.2--CH.sub.3,
--N(C.sub.3H.sub.7)--SO.sub.2--CH.sub.3,
--NH--SO.sub.2--C.sub.2H.sub.5,
--N(CH.sub.3)--SO.sub.2--C.sub.2H.sub.5,
--N(C.sub.2H.sub.5)--SO.sub.2--C.sub.2H.sub.5,
--N(C.sub.3H.sub.7)--SO.sub.2--C.sub.2H.sub.5,
--NH--SO.sub.2--C.sub.3H.sub.7,
--N(CH.sub.3)--SO.sub.2--C.sub.3H.sub.7,
--N(C.sub.2H.sub.5)--SO.sub.2--C.sub.3H.sub.7,
--N(C.sub.3H.sub.7)--SO.sub.2--C.sub.3H.sub.7,
--NH--SO.sub.2--C.sub.3H.sub.5,
--N(CH.sub.3)--SO.sub.2--C.sub.3H.sub.5,
--N(C.sub.2H.sub.5)--SO.sub.2--C.sub.3H.sub.5,
--N(C.sub.3H.sub.7)--SO.sub.2--C.sub.2H.sub.5,
--CH.sub.2--NH--SO.sub.2--CH.sub.3,
--CH.sub.2--N(CH.sub.3)--SO.sub.2--CH.sub.3,
--CH.sub.2--NH--SO.sub.2--C.sub.2H.sub.5,
--CH.sub.2--N(CH.sub.3)--SO.sub.2--C.sub.2H.sub.5,
--CH.sub.2--NH--SO.sub.2--C.sub.3H.sub.7,
--CH.sub.2--N(CH.sub.3)--SO.sub.2--C.sub.3H.sub.7,
--CH.sub.2--NH--SO.sub.2--C.sub.3H.sub.5,
--CH.sub.2--N(CH.sub.3)--SO.sub.2--C.sub.3H.sub.5,
--NH--C(O)--NH.sub.2, --N(CH.sub.3)--C(O)--NH.sub.2,
--NH--C(O)--NH--CH.sub.3, --N(CH.sub.3)--C(O)--NH--CH.sub.3,
--NH--C(O)--N(CH.sub.3).sub.2,
--N(CH.sub.3)--C(O)--N(CH.sub.3).sub.2, --SO.sub.2--NH.sub.2,
--SO.sub.2--NH(CH.sub.3), --SO.sub.2--N(CH.sub.3).sub.2,
--C(O)--NH--C.sub.2H.sub.5, --C(O)--N(CH.sub.3)--C.sub.2H.sub.5,
--C(O)--N(CH.sub.3)--C.sub.3H.sub.7,
--C(O)--N(CH.sub.3)--C.sub.4H.sub.9,
--C(O)--NH--CH(CH.sub.3)--C.sub.2H.sub.5,
--C(O)--N(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--C(O)--NH.sub.2, --CH.sub.2--C(O)--NH--CH.sub.3,
--CH.sub.2--C(O)--N(CH.sub.3).sub.2,
--N(CH.sub.3)--SO.sub.2--N(CH.sub.3).sub.2, -phenyl, -pyridin-4-yl,
--CH.sub.2-3-methyl-oxetan-3-yl, --O-1,2-difluoro-phen-5-yl,
--O-pyridin-2-yl, -pyrrolidine-2-one-1-yl,
-3,5-dimethyl-[1,2,4]triazol-4-yl,
-3-methyl-[1,2,4]oxadiazol-5-yl,
##STR00011##
Preferred compounds of formula (I) according to the invention are
compounds with R.sub.1, R.sub.2, R.sub.3, R.sub.6, R.sub.7,
R.sub.8, R.sub.8', R.sub.9, R.sub.9', R.sub.10, R.sub.11,
R.sub.11', R.sub.12, R.sub.13, R.sub.13', R.sub.14, R.sub.15,
R.sub.15', R.sub.16, R.sub.17, R.sub.18, A, L.sub.1, L.sub.2, Z, Q,
and n as herein before or below defined, wherein R.sub.4 and
R.sub.5 are independently selected from among an electron pair,
--H, -amino, -piperidinyl, -tetrahydropyranyl, and -pyrrolidinyl,
wherein R.sub.4 and R.sub.5 are optionally independently
substituted with one or more groups selected from among -fluoro,
--CF.sub.3, -hydroxy, --O--CH.sub.3, --OCF.sub.3, --CN,
--NH--SO.sub.2--CH.sub.3, --N(CH.sub.3)--SO.sub.2--CH.sub.3,
--N(C.sub.2H.sub.5)--SO.sub.2--CH.sub.3,
--N(C.sub.3H.sub.7)--SO.sub.2--CH.sub.3,
--NH--SO.sub.2--C.sub.2H.sub.5,
--N(CH.sub.3)--SO.sub.2--C.sub.2H.sub.5,
--N(C.sub.2H.sub.5)--SO.sub.2--C.sub.2H.sub.5,
--N(C.sub.3H.sub.7)--SO.sub.2--C.sub.2H.sub.5,
--NH--SO.sub.2--C.sub.3H.sub.7,
--N(CH.sub.3)--SO.sub.2--C.sub.3H.sub.7,
--N(C.sub.2H.sub.5)--SO.sub.2--C.sub.3H.sub.7,
--N(C.sub.3H.sub.7)--SO.sub.2--C.sub.3H.sub.7,
--NH--SO.sub.2--C.sub.3H.sub.5,
--N(CH.sub.3)--SO.sub.2--C.sub.3H.sub.5,
--N(C.sub.2H.sub.5)--SO.sub.2--C.sub.3H.sub.5,
--N(C.sub.3H.sub.7)--SO.sub.2--C.sub.2H.sub.5,
--CH.sub.2--NH--SO.sub.2--CH.sub.3,
--CH.sub.2--N(CH.sub.3)--SO.sub.2--CH.sub.3,
--CH.sub.2--NH--SO.sub.2--C.sub.2H.sub.5,
--CH.sub.2--N(CH.sub.3)--SO.sub.2--C.sub.2H.sub.5,
--CH.sub.2--NH--SO.sub.2--C.sub.3H.sub.7,
--CH.sub.2--N(CH.sub.3)--SO.sub.2--C.sub.3H.sub.7,
--CH.sub.2--NH--SO.sub.2--C.sub.3H.sub.5,
--CH.sub.2--N(CH.sub.3)--SO.sub.2--C.sub.3H.sub.5,
--NH--C(O)--NH.sub.2, --N(CH.sub.3)--C(O)--NH.sub.2,
--NH--C(O)--NH--CH.sub.3, --N(CH.sub.3)--C(O)--NH--CH.sub.3,
--NH--C(O)--N(CH.sub.3).sub.2,
--N(CH.sub.3)--C(O)--N(CH.sub.3).sub.2, --SO.sub.2--NH.sub.2,
--SO.sub.2--NH(CH.sub.3), --SO.sub.2--N(CH.sub.3).sub.2,
--C(O)--NH--C.sub.2H.sub.5, --C(O)--N(CH.sub.3)--C.sub.2H.sub.5,
--C(O)--N(CH.sub.3)--C.sub.3H.sub.7,
--C(O)--N(CH.sub.3)--C.sub.4H.sub.9,
--C(O)--NH--CH(CH.sub.3)--C.sub.2H.sub.5,
--C(O)--N(CH.sub.3)--CH(CH.sub.3)--C.sub.2H.sub.5,
--CH.sub.2--C(O)--NH.sub.2, --CH.sub.2--C(O)--NH--CH.sub.3,
--CH.sub.2--C(O)--N(CH.sub.3).sub.2,
--N(CH.sub.3)--SO.sub.2--N(CH.sub.3).sub.2, -pyridin-4-yl,
--CH.sub.2-3-methyl-oxetan-3-yl, --O-1,2-difluoro-phen-5-yl,
--O-pyridin-2-yl, -pyrrolidine-2-one-1-yl,
-3,5-dimethyl-[1,2,4]triazol-4-yl,
-3-methyl-[1,2,4]oxadiazol-5-yl,
##STR00012##
[0017] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.1, R.sub.2, R.sub.3, R.sub.6,
R.sub.7, R.sub.8, R.sub.8', R.sub.9, R.sub.9', R.sub.10, R.sub.11,
R.sub.11', R.sub.12, R.sub.13, R.sub.13', R.sub.14, R.sub.15,
R.sub.15', R.sub.16, R.sub.17, A, L.sub.1, Z, Q, and n as herein
before or below defined, wherein R.sub.4 and R.sub.5 are
independently a group of the structure -L.sub.2-R.sub.18, wherein
L.sub.2 is selected from among --NH--, --N(CH.sub.3)-- and
--N(C.sub.2H.sub.5)--, wherein R.sub.18 is selected from among
-tetrahydropyranyl, -cyclopropyl, -cyclobutyl, -cyclopentyl,
-cyclohexyl, -cycloheptyl, -cyclooctyl, -pyrrolidinyl,
-piperidinyl, -piperazinyl, -morpholinyl, -chromanyl,
-octahydro-pyrano-pyrrolyl, -octahydro-pyrano-pyridinyl,
-octahydro-pyrano-oxazinyl, -oxaspirodecanyl, and
-tetrahydro-naphthyridinyl,
wherein R.sub.18 is optionally substituted by one or more groups
selected from among --F, --CF.sub.3, --OCF.sub.3, --CN, --OH,
--O--CH.sub.3, --CH.sub.3, --NH--C(O)--CH.sub.3,
--N(CH.sub.3)--C(O)--CH.sub.3, --C(O)--CH.sub.3,
--S(O).sub.2--CH.sub.3, --NH--S(O).sub.2--CH.sub.3,
--N(CH.sub.3)--S(O).sub.2--CH.sub.3, and
--C(O)--O--C.sub.2H.sub.5.
[0018] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.8', R.sub.9, R.sub.9',
R.sub.10, R.sub.11, R.sub.11', R.sub.12, R.sub.13, R.sub.13',
R.sub.14, R.sub.15, R.sub.15', R.sub.16, R.sub.17, R.sub.18, A,
L.sub.1, L.sub.2, Z, Q, and n as herein before or below defined,
wherein R.sub.4, R.sub.5 and R.sub.18 are optionally further
bi-valently substituted by one or more groups selected from
among
##STR00013##
on one ring atom or on two neighboring ring atoms, such that
spirocyclic or annellated rings are formed.
[0019] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.1, R.sub.2, R.sub.3, R.sub.5,
R.sub.6, R.sub.7, R.sub.8, R.sub.8', R.sub.9, R.sub.9', R.sub.10,
R.sub.11, R.sub.11', R.sub.12, R.sub.13, R.sub.13', R.sub.14,
R.sub.15, R.sub.15', R.sub.16, R.sub.17, R.sub.18, A, L.sub.1,
L.sub.2, Z, Q, and n as herein before or below defined, wherein
R.sub.4 is selected from among
##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018##
##STR00019## ##STR00020## ##STR00021##
[0020] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.6, R.sub.7, R.sub.8, R.sub.8', R.sub.9, R.sub.9', R.sub.10,
R.sub.11, R.sub.11', R.sub.12, R.sub.13, R.sub.13', R.sub.14,
R.sub.15, R.sub.15', R.sub.16, R.sub.17, R.sub.18, A, L.sub.1,
L.sub.2, Z, Q, and n as herein before or below defined, wherein
R.sub.5 is selected from among an electron pair, --H, and
--C(O)--NH.sub.2.
[0021] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.7, R.sub.8, R.sub.8', R.sub.9, R.sub.9', R.sub.10,
R.sub.11, R.sub.11', R.sub.12, R.sub.13, R.sub.13', R.sub.14,
R.sub.15, R.sub.15', R.sub.16, R.sub.17, R.sub.18, A, L.sub.1,
L.sub.2, Z, Q, and n as herein before or below defined, wherein
R.sub.6 is selected from among --H, --CH.sub.3, --C.sub.2H.sub.5,
--O--CH.sub.3, --O--C.sub.2H.sub.5, --F, --CF.sub.3, and
--OCF.sub.3, and more preferred wherein R.sub.6 is selected from
among H, and --O--CH.sub.3, and most preferred wherein R.sub.6 is
--H.
[0022] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.8', R.sub.9, R.sub.9',
R.sub.10, R.sub.11, R.sub.11', R.sub.12, R.sub.13, R.sub.13',
R.sub.14, R.sub.15, R.sub.15', R.sub.16, R.sub.17, R.sub.18,
L.sub.1, L.sub.2, Z, Q, and n as herein before or below defined,
wherein A is selected from among a single bond, .dbd.CH--,
--CH.sub.2, --O--, and --NH--, and more preferred wherein A is
selected from among --O-- and --NH--, and most preferred wherein A
is --NH--.
[0023] Preferred compounds of formula (I) according to the
invention are compounds with R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.8', R.sub.9, R.sub.9',
R.sub.10, R.sub.11, R.sub.11', R.sub.12, R.sub.13, R.sub.13',
R.sub.14, R.sub.15, R.sub.15', R.sub.16, R.sub.17, R.sub.18, A,
L.sub.1, L.sub.2, Q, and n as herein before or below defined,
wherein Z is selected from among C, and N, and more preferred
wherein Z is C.
[0024] All of the above embodiments under formula (I) have to be
understood to optionally be present in form of their individual
optical isomers, mixtures of their individual optical isomers, or
racemates, as well as in form of their acid addition salts with
pharmacologically acceptable acids, as well as in form of their
solvates and/or hydrates.
DEFINITIONS
[0025] Unless otherwise stated, all the substituents are
independent of one another. If for example there might be a
plurality of C.sub.1-C.sub.6-alkyl groups as substituents in one
group, in the case of three substituents C.sub.1-C.sub.6-alkyl, one
may represent methyl, one n-propyl and one tert-butyl.
[0026] Within the scope of this application, in the definition of
possible substituents, these may also be represented in the form of
a structural formula. An asterisk (*) in the structural formula of
the substituent is to be understood as being the linking point to
the rest of the molecule. Moreover, the atom of the substituent
which follows the linking point is referred to as the atom in
position number 1. Thus, for example, the groups N-piperidinyl
(Piperidin-A), 4-piperidinyl (Piperidin-B), 2-tolyl (Tolyl-C),
3-tolyl (Tolyl-D), and 4-tolyl (Tolyl-E) are shown as follows:
##STR00022##
[0027] If there is no asterisk (*) in the structural formula of the
substituent, each hydrogen atom may be removed from the substituent
and the valency thus freed may act as a binding site to the rest of
a molecule. Thus, for example, (Tolyl-F) may represent 2-tolyl,
3-tolyl, 4-tolyl, and benzyl
##STR00023##
[0028] By the term "branched or unbranched, saturated or
unsaturated C.sub.1-C.sub.6-carbon chain" it is meant a chain of
carbon atoms, which is constituted by six carbon atoms arranged in
a row and which can optionally further comprise branches or one or
more hetero atoms selected from N, O or S. Said carbon chain can be
saturated or unsaturated by comprising double or triple bonds.
[0029] By the term "C.sub.1-C.sub.6-alkyl" (including those which
are part of other groups) are meant branched and unbranched alkyl
groups with 1 to 6 carbon atoms and by the term
"C.sub.1-C.sub.4-alkyl" are meant branched and unbranched alkyl
groups with 1 to 4 carbon atoms. Alkyl groups with 1 to 4 carbon
atoms are preferred. Examples for alkyl groups with 1-6 carbon
atoms include: methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl
or hexyl. Optionally the abbreviations Me, Et, n-Pr, i-Pr, n-Bu,
i-Bu, t-Bu, etc. may also be used for the above-mentioned groups.
Unless stated otherwise, the definitions propyl, butyl, pentyl and
hexyl include all the possible isomeric forms of the groups in
question. Thus, for example, propyl includes n-propyl and
iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl
etc.
[0030] By the term "C.sub.1-C.sub.8-alkylene" (including those
which are part of other groups) are meant branched and unbranched
alkylene groups with 1 to 8 carbon atoms. By the term
"C.sub.2-C.sub.8-alkylene" are meant branched and unbranched
alkylene groups with 2 to 8 carbon atoms. By the term
"C.sub.2-C.sub.6-alkylene" are meant branched and unbranched
alkylene groups with 2 to 6 carbon atoms. By the term
"C.sub.1-C.sub.4-alkylene" are meant branched and unbranched
alkylene groups with 1 to 4 carbon atoms. By the term
"C.sub.1-C.sub.2-alkylene" are meant branched and unbranched
alkylene groups with 1 to 2 carbon atoms. By the term
"C.sub.0-C.sub.4-alkylene" are meant branched and unbranched
alkylene groups with 0 to 4 carbon atoms, thus also a single bond
is encompassed. By the term "C.sub.1-C.sub.3-alkylene" are meant
branched and unbranched alkylene groups with 1 to 3 carbon atoms.
Examples for C.sub.1-C.sub.8-alkylene include: methylene, ethylene,
propylene, 1-methylethylene, butylene, 1-methylpropylene,
1,1-dimethylethylene, 1,2-dimethylethylene, pentylene,
1,1-dimethylpropylene, 2,2-dimethylpropylene,
1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene, heptylene
or octylene. Unless stated otherwise, the definitions propylene,
butylene, pentylene, hexylene, heptylene and octylene include all
the possible isomeric forms of the groups in question with the same
number of carbons. Thus, for example, propyl also includes
1-methylethylene and butylene includes 1-methylpropylene,
1,1-dimethylethylene, 1,2-dimethylethylene.
[0031] If the carbon chain is to be substituted by a group which
together with one or two carbon atoms of the alkylene chain forms a
carbocyclic ring with 3, 5 or 6 carbon atoms, this includes the
following examples of the rings:
##STR00024##
[0032] By the term "C.sub.2-C.sub.6-alkenyl" (including those which
are part of other groups) are meant branched and unbranched alkenyl
groups with 2 to 6 carbon atoms and by the term
"C.sub.2-C.sub.4-alkenyl" are meant branched and unbranched alkenyl
groups with 2 to 4 carbon atoms, provided that they have at least
one double bond. Alkenyl groups with 2 to 4 carbon atoms are
preferred. Examples for C.sub.2-C.sub.6-alkenyls include: ethenyl
or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless stated
otherwise, the definitions propenyl, butenyl, pentenyl and hexenyl
include all the possible isomeric forms of the groups in question.
Thus, for example, propenyl includes 1-propenyl and 2-propenyl,
butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl,
1-methyl-2-propenyl etc.
[0033] By the term "methenylene" is meant a group with 1 carbon
atom, provided that it is linked by a single bond as well as on the
other side by a double bond:
##STR00025##
[0034] By the term "C.sub.2-C.sub.8-alkenylene" (including those
which are part of other groups) are meant branched and unbranched
alkenylene groups with 2 to 8 carbon atoms and by the term
"C.sub.2-C.sub.6-alkenylene" are meant branched and unbranched
alkylene groups with 2 to 6 carbon atoms. By the term
"C.sub.1-C.sub.2-alkenylene" are meant alkenylene groups with 1 to
2 carbon atoms, provided that they have at least one double bond,
whereas by the term "C.sub.1-alkenylene" is meant "methenylene".
Examples for C.sub.2-C.sub.8-alkenylenes include: ethenylene,
propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene,
1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene,
1,1-dimethylpropenylene, 2,2-dimethylpropenylene,
1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene,
heptenylene or octenylene. Unless stated otherwise, the definitions
propenylene, butenylene, pentenylene and hexenylene include all the
possible isomeric forms of the groups in question with the same
number of carbons. Thus, for example, propenyl also includes
1-methylethenylene and butenylene includes 1-methylpropenylene,
1,1-dimethylethenylene, 1,2-dimethylethenylene.
[0035] By the term "C.sub.2-C.sub.6-alkynyl" (including those which
are part of other groups) are meant branched and unbranched alkynyl
groups with 2 to 6 carbon atoms and by the term
"C.sub.2-C.sub.4-alkynyl" are meant branched and unbranched alkynyl
groups with 2 to 4 carbon atoms, provided that they have at least
one triple bond. Examples for C.sub.2-C.sub.6-alkynyls include:
ethynyl, propynyl, butynyl, pentynyl or hexynyl. Unless stated
otherwise, the definitions propynyl, butynyl, pentynyl and hexynyl
include all the possible isomeric forms of the groups in question.
Thus for example propynyl includes 1-propynyl and 2-propynyl,
butynyl includes 1-, 2-, and 3-butynyl, 1-methyl-1-propynyl,
1-methyl-2-propynyl etc.
[0036] By the term "C.sub.2-C.sub.8-alkynylene" (including those
which are part of other groups) are meant branched and unbranched
alkynylene groups with 2 to 8 carbon atoms and by the term
"C.sub.2-C.sub.6-alkynylene" are meant branched and unbranched
alkylene groups with 2 to 6 carbon atoms. Examples of
C.sub.2-C.sub.8-alkynylenes include: ethynylene, propynylene,
1-methylethynylene, butynylene, 1-methylpropynylene,
1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene,
1,1-dimethylpropynylene, 2,2-dimethylpropynylene,
1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene,
heptynylene or octynylene. Unless stated otherwise, the definitions
propynylene, butynylene, pentynylene and hexynylene include all the
possible isomeric forms of the groups in question with the same
number of carbons. Thus for example propynyl also includes
1-methylethynylene and butynylene includes 1-methylpropynylene,
1,1-dimethylethynylene, 1,2-dimethylethynylene.
[0037] By the term "ring" are meant carbocycles, which can be
saturated, unsaturated or aromatic and which optionally can
comprise one or more hetero atoms selected from N, O or S.
[0038] By the term "--C.sub.3-C.sub.8-heterocyclyl" are meant
three-, four-, five-, six-, or seven-membered, saturated or
unsaturated heterocyclic rings which may contain one, two, or three
heteroatoms, selected from among oxygen, sulfur, and nitrogen,
while the ring may be linked to the molecule through a carbon atom
or through a nitrogen atom, if there is one. By the term
"--C.sub.5-C.sub.8-heterocyclyl" are meant five-, six-, or
seven-membered, saturated or unsaturated heterocyclic rings which
may contain one, two, or three heteroatoms, selected from among
oxygen, sulfur, and nitrogen, while the ring may be linked to the
molecule through a carbon atom or through a nitrogen atom, if there
is one. Examples include:
##STR00026##
[0039] Unless otherwise mentioned, a heterocyclic ring (or
"heterocycle") may be provided with a keto group. Examples
include:
##STR00027##
[0040] By the term "C.sub.3-C.sub.8-cycloalkyl" (including those
which are part of other groups) are meant cyclic alkyl groups with
3 to 8 carbon atoms. Likewise, by the term
"C.sub.3-C.sub.6-cycloalkyl" are meant cyclic alkyl groups with 3
to 6 carbon atoms. Examples of C.sub.3-C.sub.8-cycloalkyls include:
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or
cyclooctyl. Unless otherwise stated, the cyclic alkyl groups may be
substituted by one or more groups selected from among methyl,
ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine,
and iodine.
[0041] By the term "aryl" (including those which are part of other
groups) are meant aromatic ring systems. By the term
"C.sub.5-C.sub.10-aryl" (including those which are part of other
groups) are meant aromatic ring systems with 5 to 10 carbon atoms.
Preferred are "C.sub.6-C.sub.10-aryl" groups whereas aromatic rings
are meant with 6 to 10 carbon atoms. Examples include: phenyl or
naphthyl. Also preferred are "C.sub.5-C.sub.6-aryl" groups whereas
aromatic rings are meant with 5 to 6 carbon atoms Unless otherwise
stated, the aromatic ring systems may be substituted by one or more
groups selected from among methyl, ethyl, iso-propyl, tert-butyl,
hydroxy, fluorine, chlorine, bromine and iodine.
[0042] By the term "C.sub.5-C.sub.10-heteroaryl" (including those
which are part of other groups) are meant five- or six-membered
heterocyclic aromatic groups or 5-10-membered, bicyclic heteroaryl
rings which may contain one, two, or three heteroatoms selected
from among oxygen, sulfur, and nitrogen, and contain so many
conjugated double bonds that an aromatic system is formed. The
following are examples of five- or six- or nine-membered
heterocyclic aromatic groups:
##STR00028##
[0043] Preferred are "C.sub.5-C.sub.6-heteroaryl" groups whereas
aromatic rings are meant five- or six-membered heterocyclic
aromatic groups. Unless otherwise stated, these heteroaryls may be
substituted by one or more groups selected from among methyl,
ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine,
and iodine.
[0044] When a generic combined groups are used, for example
--X--C.sub.1-C.sub.4-alkyl- with X being a functional group such as
--CO--, --NH--, --C(OH)-- and the like, the functional group X can
be located at either of the ends of the --C.sub.1-C.sub.4-alkyl
chain.
[0045] By the term "spiro-C.sub.3-C.sub.8-cycloalkyl" (spiro) are
meant 3-8 membered, spirocyclic rings while the ring is linked to
the molecule through a carbon atom. By the term
"spiro-C.sub.3-C.sub.8-heterocyclyl" (spiro) are meant 3-8
membered, spirocyclic rings which may contain one, two, or three
heteroatoms selected from among oxygen, sulfur, and nitrogen, while
the ring may be linked to the molecule through a carbon atom or
through a nitrogen atom, if there is one.
[0046] Unless otherwise mentioned, a spirocyclic ring may be
provided with an oxo, methyl, or ethyl group. Examples include:
##STR00029##
[0047] "Halogen" within the scope of the present invention denotes
fluorine, chlorine, bromine or iodine. Unless stated to the
contrary, fluorine, chlorine and bromine are regarded as preferred
halogens.
[0048] "Linker" within the scope of the present invention
denominates a bivalent group or a bond.
[0049] The above listed groups and residues can be combined to form
more complex structures composed from carbon chains and rings or
the like.
[0050] Compounds of general formula (I) may have acid groups,
chiefly carboxyl groups, and/or basic groups such as e.g. amino
functions. Compounds of general formula (I) may therefore occur as
internal salts, as salts with pharmaceutically useable inorganic
acids such as hydrochloric acid, sulphuric acid, phosphoric acid,
sulphonic acid or organic acids (such as for example maleic acid,
fumaric acid, citric acid, tartaric acid or acetic acid) or as
salts with pharmaceutically useable bases such as alkali or
alklaline earth metal hydroxides or carbonates, zinc or ammonium
hydroxides or organic amines such as e.g. diethylamine,
triethylamine, triethanolamine inter alia.
[0051] As mentioned hereinbefore, the compounds of formula (I) may
be converted into the salts thereof, particularly for
pharmaceutical use, into the physiologically and pharmacologically
acceptable salts thereof. These salts may on the one hand be in the
form of the physiologically and pharmacologically acceptable acid
addition salts of the compounds of formula (I) with inorganic or
organic acids. On the other hand, if R is hydrogen, the compound of
formula (I) may also be converted by reaction with inorganic bases
into physiologically and pharmacologically acceptable salts with
alkali or alkaline earth metal cations as counter ion. The acid
addition salts may be prepared for example using hydrochloric acid,
hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic
acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric
acid, tartaric acid or maleic acid. It is also possible to use
mixtures of the above-mentioned acids. The alkali and alkaline
earth metal salts of the compound of formula (I) are preferably
prepared using the alkali and alkaline earth metal hydroxides and
hydrides thereof, of which the hydroxides and hydrides of the
alkaline earth metals, particularly of sodium and potassium, are
preferred and sodium and potassium hydroxide are particularly
preferred.
[0052] If desired, the compounds of general formula (I) may be
converted into the salts thereof, particularly, for pharmaceutical
use, into the pharmacologically acceptable acid addition salts with
an inorganic or organic acid. Suitable acids include for example
succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic
acid, methanesulphonic acid, lactic acid, phosphoric acid,
hydrochloric acid, sulphuric acid, tartaric acid or citric acid. It
is also possible to use mixtures of the above-mentioned acids.
[0053] The invention relates to the compounds in question,
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates, in the form of the
tautomers as well as in the form of the free bases or the
corresponding acid addition salts with pharmacologically acceptable
acids--such as for example acid addition salts with hydrohalic
acids--for example hydrochloric or hydrobromic acid or organic
acids--such as for example oxalic, fumaric, diglycolic or
methanesulphonic acid.
[0054] The compounds according to the invention may optionally
occur as racemates, but they may also be obtained as pure
enantiomers/diastereomers.
[0055] The invention relates to the compounds in question,
optionally in the form of the individual optical isomers, mixtures
of the individual enantiomers or racemates, in the form of the
tautomers as well as in the form of the free bases or the
corresponding acid addition salts with pharmacologically acceptable
acids--such as for example acid addition salts with hydrohalic
acids--for example hydrochloric or hydrobromic acid or organic
acids--such as for example oxalic, fumaric, diglycolic or
methanesulphonic acid.
[0056] The compounds according to formula (I) according to the
invention have the meanings hereinbefore whereas in particular the
preferred embodiments defined by R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.9',
R.sub.10, R.sub.11, R.sub.11' R.sub.12, R.sub.13, R.sub.13',
R.sub.14, R.sub.15, R.sub.15' R.sub.16, R.sub.17, R.sub.18, A,
L.sub.1, L.sub.2, Z, Q, and n in each case are independently
selected of one another.
Therapeutic Applications
[0057] The above exemplary substances have been tested for binding
to CCR2 using a binding assay as outlined herein below:
Cell Culture:
[0058] THP-1 cells (human acute monocytic leukaemia cells) were
cultured under standardized conditions at 37.degree. C. and 5% CO2
in a humidified incubator. THP-1 cells were cultivated in RPMI 1640
medium (Gibco 21875) containing 1% MEM-NEAA (Gibso 11140) 2 mM
L-glutamine, 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10 mM
HEPES and 1.0 mM sodium pyruvate, 90%; 10% fetal calf serum (FCS
Gibco 10500-064). Membranes were prepared from THP-1 cells. THP-1
cells were centrifuged at 300.times.g at 4.degree. C. for 10 min.
The cell pellet was resuspendet in Phosphate Buffer Saline (PBS ,
including 10 .mu.M Pefabloc and a protease inhibitor mix
`complete`, Boehringer Mannheim (1 tablet/50 ml)), to a
concentration of 80 cells/ml. The membrane preparation was
performed by disrupting the cells by nitrogen decomposition (at 50
bar, for 1 h) in a "Nitrogen Bombe" (Parr Instrument). Cell debris
was removed by centrifugation (800.times.g at 4.degree. C., 1 min).
The supernatant was centrifuged at 80000.times.g , 4.degree. C. for
30 min to sediment the cell membranes . Usually 50 mg of protein
(Bradford assay) were yielded from 1.times.10E9 cells. The
membranes were resuspendet in 25 mM HEPES, 25 mM MgCl2, 1 mM CaCl2,
10% Glycerine for storage in aliquots at -80.degree. C. in 25 mM
HEPES, 25 mM MgCl2, 1 mM CaCl2, 10% Glycerine and stored at
-80.degree. C.
Receptor Membrane Binding Assay:
[0059] Perkin Elmer NEX 332 Jod 125 MCP-1, Stock: 2200 Ci/mmol
solved in 2000 .mu.l assay buffer, stored at -20.degree. C. THP-1
membrane were adjusted with 25 mM HEPES, pH 7.2; 5 mM MgCl.sub.2;
0.5 mM CaCl.sub.2; 0.2% BSA assay buffer to a concentration of 2.5
.mu.g/15 .mu.l. Amersham Biosciences PVT-WGA Beads (RPNQ0001) were
adjusted with assay buffer to a concentration of 0.24 mg/30 .mu.l.
For preparation of the membrane-bead-suspension membranes and beads
were incubated for 30 min at RT under rotation (60 rpm) with a
ratio of 1:2. Test compounds dissolved in 100% DMSO to a
concentration of 10 mM and are further diluted with 100% DMSO to 1
mM. All additional compound dilutions were obtained with assay
buffer, final 1% DMSO. Compounds, membrane-bead-suspension and
[125I]MCP-1 (ca. 25000 cpm/10 .mu.l) were incubated. Bound
radioactivity was determined by scintillation counter after 8 h.
Determination of affinity of test compounds (dissociation constant
hKi) is calculated by iterative fitting of experimental data using
the "easy sys" program, which is based on law of mass action
(Schittkowski K. (1994), Numerische Mathematik, Vol. 68,
129-142).
[0060] All of the above-referenced examples have been found to have
an activity in this assay of 10 .mu.M or less.
TABLE-US-00001 CCR2 % ctrl CCR2 % ctrl Example hKi @ 10 .mu.M
Example hKi @ 10 .mu.M 1 32 1 15 200 14 2 222 13 16 1904 40 3 204
14 17 302 18 4 1593 43 18 3505 52 5 616 26 19 269 40 6 1928 41 20
303 24 7 306 16 21 2660 51 8 1023 36 22 466 24 9 974 32 23 169 7 10
650 27 24 4029 58 11 1710 38 25 2406 47 12 664 29 26 914 30 13 1332
42 27 620 25 14 387 22 28 4176 58 29 2097 40 59 55 5 30 446 18 60
44 5 31 790 28 61 46 2 32 37 2 62 38 3 33 22 0 63 54 7 34 62 4 64
65 8 35 24 5 65 176 8 36 10 1 66 138 8 37 11 4 67 1423 27 38 69 13
68 98 7 39 36 2 69 63 7 40 174 9 70 80 6 41 11 6 71 117 12 42 433
16 72 81 7 43 566 17 73 38 2 44 1639 27 74 71 2 45 501 17 75 67 7
46 225 12 76 132 12 47 222 14 77 650 27 48 1778 26 78 740 28 49 97
7 79 89 10 50 928 22 80 53 7 51 290 13 81 52 8 52 175 12 82 43 4 53
18 4 83 43 3 54 356 13 84 69 4 55 200 17 85 55 13 56 127 8 86 39 3
57 93 10 87 78 9 58 336 12 88 58 6 89 770 29 119 1033 37 90 127 10
120 499 30 91 236 23 121 147 15 92 175 14 122 415 23 93 123 6 123
542 26 94 211 8 124 361 20 95 170 2 125 446 25 96 939 21 126 399 23
97 665 17 127 665 35 98 214 2 128 445 26 99 1826 32 129 336 21 100
395 18 130 4266 50 101 986 35 131 55 6 102 224 15 132 672 31 103
1605 30 133 205 15 104 617 31 134 399 23 105 687 31 135 888 19 106
405 13 136 773 14 107 232 12 137 634 14 108 627 20 138 145 6 109
213 11 139 443 9 110 527 28 140 692 16 111 464 27 141 422 7 112 378
21 142 529 8 113 3306 46 143 422 8 114 62 8 144 91 7 115 847 33 145
181 17 116 198 16 146 3 7 117 285 19 147 40 8 118 2162 41 148 119 4
149 41 10 179 1637 42 150 12 3 189 4812 60 151 14 7 181 3607 58 152
44 7 182 2991 53 153 27 1 183 426 45 154 123 15 184 908 30 155 76 8
185 4209 53 156 18 8 186 78 8 157 1147 23 187 256 15 158 6 0 188
3934 53 159 25 4 189 170 13 160 43 3 190 783 27 161 1996 30 191 519
20 162 3798 43 192 1446 37 163 1560 32 193 1536 35 164 353 15 194
491 25 165 222 15 195 141 14 166 227 16 196 666 19 167 246 16 197
33 4 168 51 9 198 58 1 169 2287 54 199 534 9 170 705 31 200 108 5
171 356 16 201 101 6 172 736 28 202 292 7 173 89 6 203 641 11 174
2718 53 204 123 6 175 434 14 205 135 11 176 648 31 206 44 3 177
1252 43 207 1180 35 178 27 0 208 99 7 209 177 7 239 2319 33 210 83
0 240 104 7 211 140 5 241 522 21 212 731 24 242 516 21 213 430 14
243 1615 40 214 711 20 244 366 24 215 2146 42 245 555 15 216 4283
59 246 306 2 217 4326 54 247 149 6 218 281 8 248 576 17 219 476 22
249 3249 36 220 979 27 250 1263 32 221 172 12 251 439 75 222 1306
31 252 38 6 223 244 14 253 350 17 224 1230 35 254 101 11 225 21 0
255 33 5 226 1170 36 256 438 25 227 333 22 257 186 14 228 331 16
258 64 4 229 1133 39 259 277 16 230 1845 45 260 493 20 231 215 15
261 120 8 232 924 34 262 224 13 233 194 8 263 1968 27 234 401 19
264 41 3 235 460 26 265 462 23 236 175 14 266 149 237 133 9 267 487
20 238 239 14 268 119 5 228a 1564 9 228e 3720 40 228b 2 4 228f 15 1
228c 29 0 228g 169 6 228d 91 1 228h 5 0 269 2340 36 285 1306 35 270
179 9 286 965 19 271 1608 15 287 2547 33 272 155 8 288 738 13 273
1435 27 289 1667 34 274 4421 48 290 1601 28 275 593 19 291 3123 32
276 1842 23 292 136 15 277 1376 34 293 717 27 278 1078 32 294 230
16 279 192 9 295 140 0 280 1435 32 296 69 3 281 1012 24 297 164 10
282 1527 39 298 599 17 283 4421 48 299 70 6 284 1514 42 300 136 8
275a 29 0 275c 2932 38 275b 26 3 275d 318 10 Example hKi Example
hKi 228go 54 159e 28 228gp 1354 159f 14 228ga 23 159g 15 228gb 3828
159h 39 228gc 561 159i 24 228gd 1094 159k 22 228ge 37 159l 22 228gf
145 159m 9 228gg 1026 159n 233 228gh 4066 159o 12 228gi 1101 159p 7
228gj 55 159q 10 228gk 44 159r 2578 228gl 537 159s 1314 228gm 28
159t 1202 228gn 333 159u 29 275da 4 159w 9 275db 33 159y 169 275dc
11 159x 147 275dd 40 159z 11 275de 16 159aa 18 275df 15 159ba 11
275dg 12 159ca 3 275dh 3 159da 5 275di 1 159ea 7 275dj 4 159fa 35
159a 10 159ga 28 159b 7 159ha 27 159c 13 159ia 17 159d 15 159ja 18
159ka 19 159pb 10 159la 19 159qb 69 159ma 20 159rb 54 159na 21
159sb 21 159oa 29 159tb 13 159pa 32 159ub 18 159qa 19 159wb 16
159ra 22 159yb 15 159sa 22 159xb 6 159ta 27 159zb 15 159ua 23 159ac
5936 159wa 33 159bc 3492 159ya 18 159cc 10 159xa 21 159dc 38 159za
6 159ec 961 159ab 27 159fc 13 159bb 48 159gc 26 159cb 39 228ha 32
159db 16 301 22 159eb 72 302 32 159fb 199 275dk 17 159gb 39 275dl
372 159hb 20 159ib 15 159jb 39 159kb 24 159lb 12 159mb 14 159nb 88
159ob 118
[0061] Based on the ability of the substances described by formula
(I) to effectively bind to CCR2a range of therapeutic applications
can be envisaged. The present invention provides a method for
modulating or treating at least one MCP-1 related disease, in a
cell, tissue, organ, animal, or patient, as known in the art or as
described herein, using at least one CCR2 antagonist of the present
invention. The present invention also provides a method for
modulating or treating at least one MCP-1 related disease, in a
cell, tissue, organ, animal, or patient including, but not limited
to, at least one of malignant disease, metabolic disease, an immune
or inflammatory related disease, a cardiovascular disease, an
infectious disease, or a neurologic disease. Such conditions are
selected from, but not limited to, diseases or conditions mediated
by cell adhesion and/or angiogenesis. Such diseases or conditions
include an immune disorder or disease, a cardiovascular disorder or
disease, an infectious, malignant, and/or neurologic disorder or
disease, or other known or specified MCP-1 related conditions. In
particular, the CCR2 antagonists are useful for the treatment of
diseases that involve inflammation such as COPD, angiogenesis such
as disease of the eye and neoplastic disease, tissue remodeling
such as restenosis, and proliferation of certain cells types
particularly epithelial and squamous cell carcinomas. Particular
indications include use in the treatment of atherosclerosis,
restenosis, cancer metastasis, rheumatoid arthritis, diabetic
retinopathy and macular degeneration. The antagonists may also be
useful in the treatment of various fibrotic diseases such as
idiopathic pulmonary fibrosis, diabetic nephropathy, hepatitis, and
cirrhosis. Thus, the present invention provides a method for
modulating or treating at least one CCR2 related disease, in a
cell, tissue, organ, animal, or patient, as known in the art or as
described herein, using at least one CCR2 antagonist of the present
invention. Particular indications are discussed below:
Pulmonary Diseases
[0062] The present invention also provides a method for modulating
or treating at least one malignant disease in a cell, tissue,
organ, animal or patient, including, but not limited to, at least
one of: pneumonia; lung abscess; occupational lung diseases caused
be agents in the form or dusts, gases, or mists; asthma,
bronchiolitis fibrosa obliterans, respiratory failure,
hypersensitivity diseases of the lungs iricludeing hypersensitivity
pneumonitis (extrinsic allergic alveolitis), allergic
bronchopulmonary aspergillosis, and drug reactions; adult
respiratory distress syndrome (ARDS), Goodpasture's Syndrome,
chronic obstructive airway disorders (COPD), idiopathic
interstitial lung diseases such as idiopathic pulmonary fibrosis
and sarcoidosis, desquamative interstitial pneumonia, acute
interstitial pneumonia, respiratory bronchiolitis-associated
interstitial lung disease, idiopathic bronchiolitis obliterans with
organizing pneumonia, lymphocytic interstitial pneumonitis,
Langerhans' cell granulomatosis, idiopathic pulmonary
hemosiderosis; acute bronchitis, pulmonary alveolar, proteinosis,
bronchiectasis, pleural disorders, atelectasis, cystic fibrosis,
and tumors of the lung, and pulmonary embolism.
Malignant Diseases
[0063] The present invention also provides a method for modulating
or treating at least one malignant disease in a cell, tissue,
organ, animal or patient, including, but not limited to, at least
one of: leukemia, acute leukemia, acute lymphoblastic leukemia
(ALL), B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML),
chromic myelocytic leukemia (CML), chronic lymphocytic leukemia
(CLL), hairy cell leukemia, myelodyplastic syndrome (MDS), a
lymphoma, Hodgkin's disease, a malignant lymphoma, non-hodgkin's
lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi's sarcoma,
colorectal carcinoma, pancreatic carcinoma, renal cell carcinoma,
breast cancer, nasopharyngeal carcinoma, malignant histiocytosis,
paraneoplastic syndrome/hypercalcemia of malignancy, solid tumors,
adenocarcinomas, squamous cell carcinomas, sarcomas, malignant
melanoma, particularly metastatic melanoma, hemangioma, metastatic
disease, cancer related bone resorption, cancer related bone pain,
and the like.
Immune Related Diseases
[0064] The present invention also provides a method for modulating
or treating at least one immune related disease, in a cell, tissue,
organ, animal, or patient including, but not limited to, at least
one of rheumatoid arthritis, juvenile rheumatoid arthritis,
systemic onset juvenile rheumatoid arthritis, psoriatic arthritis,
ankylosing spondilitis, gastric ulcer, seronegative arthropathies,
osteoarthritis, inflammatory bowel disease, ulcerative colitis,
systemic lupus erythematosis, antiphospholipid syndrome,
iridocyclitisluveitisloptic neuritis, idiopathic pulmonary
fibrosis, systemic vasculitis/wegener's granulomatosis,
sarcoidosis, orchitislvasectomy reversal procedures,
allergiclatopic diseases, asthma, allergic rhinitis, eczema,
allergic contact dermatitis, allergic conjunctivitis,
hypersensitivity pneumonitis, transplants, organ transplant
rejection, graft-versus-host disease, systemic inflammatory
response syndrome, sepsis syndrome, gram positive sepsis, gram
negative sepsis, culture negative sepsis, fungal sepsis,
neutropenic fever, urosepsis, meningococcemia,
traumalhemo.about..about.hage, burns, ionizing radiation exposure,
acute pancreatitis, adult respiratory distress syndrome, rheumatoid
arthritis, alcohol-induced hepatitis, chronic inflammatory
pathologies, sarcoidosis, Crohn's pathology, sickle cell anemia,
diabetes, nephrosis, atopic diseases, hypersensitity reactions,
allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis,
endometriosis, asthma, urticaria, systemic anaphalaxis, dermatitis,
pernicious anemia, hemolytic diseases, thrombocytopenia, graft
rejection of any organ or tissue, kidney transplant rejection,
heart transplant rejection, liver transplant rejection, pancreas
transplant rejection, lung transplant rejection, bone marrow
transplant (BMT) rejection, skin allograft rejection, cartilage
transplant rejection, bone graft rejection, small bowel transplant
rejection, fetal thymus implant rejection, parathyroid transplant
rejection, xenograft rejection of any organ or tissue, allograft
rejection, anti-receptor hypersensitivity reactions, Graves
disease, Raynoud's disease, type B insulin-resistant diabetes,
asthma, myasthenia gravis, antibody-meditated cytotoxicity, type IU
hypersensitivity reactions, systemic lupus erythematosus, POEMS
syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal
gammopathy, and skin changes syndrome), polyneuropathy,
organomegaly, endocrinopathy, monoclonal garnrnopathy, skin changes
syndrome, antiphospholipid syndrome, pemphigus, scleroderma, mixed
connective tissue disease, idiopathic Addison's disease, diabetes
mellitus, chronic active hepatitis, primary billiary cirrhosis,
vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV
hypersensitivity , contact dermatitis, hypersensitivity
pneumonitis, allograft rejection, granulomas due to intracellular
organisms, drug sensitivity, metabolic/idiopathic, Wilson's
disease, hemachromatosis, alpha-1-antitrypsin deficiency, diabetic
retinopathy, hashimoto's thyroiditis, osteoporosis,
hypothalamic-pituitary-adrenal axis evaluation, primary biliary
cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic
fibrosis, neonatal chronic lung disease, chronic obstructive
pulmonary disease (COPD), familial hematophagocytic
lymphohistiocytosis, dermatologic conditions, psoriasis, alopecia,
nephrotic syndrome, nephritis, glomerular nephritis, acute renal
failure, hemodialysis, uremia, toxicity, preeclampsia, OKT3
therapy, anti-CD3 therapy, cytokine therapy, chemotherapy,
radiation therapy (e.g., including but not limited toasthenia,
anemia, cachexia, and the like), chronic salicylate intoxication,
and the like.
Cardiovascular Diseases
[0065] The present invention also provides a method for modulating
or treating at least one cardiovascular disease in a cell, tissue,
organ, animal, or patient, including, but not limited to, at least
one of cardiac 25 stun syndrome, myocardial infarction, congestive
heart failure, stroke, ischemic stroke, hemorrhage,
arteriosclerosis, atherosclerosis, restenosis, diabetic
ateriosclerotic disease, hypertension, arterial hypertension,
renovascular hypertension, syncope, shock, syphilis of the
cardiovascular system, heart failure, cor pulmonale, primary
pulmonary hypertension, cardiac arrhythmias, atrial ectopic beats,
atrial flutter, atrial fibrillation (sustained or paroxysmal), post
perfusion syndrome, cardiopulmonary bypass inflammation response,
chaotic or multifocal atrial tachycardia, regular narrow QRS
tachycardia, specific arrythmias, ventricular fibrillation, His
bundle arrythmias, atrioventricular block, bundle branch block,
myocardial ischemic disorders, coronary artery disease, angina
pectoris, myocardial infarction, cardiomyopathy, dilated congestive
cardiomyopathy, restrictive cardiomyopathy, valvular heart
diseases, endocarditis, pericardial disease, cardiac tumors, aordic
and peripheral aneuryisms, aortic dissection, inflammation of the
aorta, occulsion of the abdominal aorta and its branches,
peripheral vascular disorders, occulsive arterial disorders,
peripheral atherlosclerotic disease, thromboangitis obliterans,
functional peripheral arterial disorders, Raynaud's phenomenon and
disease, acrocyanosis, erythromelalgia, venous diseases, venous
thrombosis, varicose veins, arteriovenous fistula, lymphederma,
lipedema, unstable angina, reperfusion injury, post pump syndrome,
ischemia-reperfusion injury, and the like. Such a method can
optionally comprise administering an effective amount of a
composition or pharmaceutical composition comprising at least one
CCR2 antagonist to a cell, tissue, organ, animal or patient in need
of such modulation, treatment or therapy.
Neurologic Diseases
[0066] The present invention also provides a method for modulating
or treating at least one neurologic disease in a cell, tissue,
organ, animal or patient, including, but not limited to, at least
one of: Neuropathic pain such as low back pain, hip pain, leg pain,
non-herpetic neuralgia, post herpetic neuralgia, diabetic
neuropathy, nerve injury-induced pain, acquired immune deficiency
syndrome (AIDS) related neuropathic pain, head trauma, toxin and
chemotherapy caused nerve injuries, phantom limb pain, multiple
sclerosis, root avulsions, painful traumatic mononeuropathy,
painful polyneuropathy, thalamic pain syndrome, post-stroke pain,
central nervous system injury, post surgical pain, carpal tunnel
syndrome, trigeminal neuralgia, post mastectomy syndrome,
postthoracotomy syndrome, stump pain, repetitive motion pain,
neuropathic pain associated hyperalgesia and allodynia, alcoholism
and other drug-induced pain; neurodegenerative diseases, multiple
sclerosis, migraine headache, AIDS dementia complex, demyelinating
diseases, such as multiple sclerosis and acute transverse myelitis;
extrapyramidal and cerebellar disorders' such as lesions of the
corticospinal system; disorders of the basal ganglia or cerebellar
disorders; hyperkinetic movement disorders such as Huntington's
Chorea and senile chorea; drug-induced movement disorders, such as
those induced by drugs which block CNS dopamine receptors;
hypokinetic movement disorders, such as Parkinson's disease;
Progressive supra-nucleo Palsy; structural lesions of the
cerebellum; spinocerebellar degenerations, such as spinal ataxia,
Friedreich's ataxia, cerebellar cortical degenerations, multiple
systems degenerations (Mencel, Dej erine-Thomas, Shi-Drager, and
Machado-Joseph); systemic disorders (Refsum's disease,
abetalipoprotemia, ataxia, telangiectasia, and mitochondrial multi
system disorder); demyelinating core disorders, such as multiple
sclerosis, acute transverse myelitis; and disorders of the motor
unit' such as neurogenic muscular atrophies (anterior horn cell
degeneration, such as amyotrophic lateral sclerosis, infantile
spinal muscular atrophy and juvenile spinal muscular atrophy);
Alzheimer's disease; Down's Syndrome in middle age; Diffuse Lewy
body disease; Senile Dementia of Lewy body type; Wernicke-Korsakoff
syndrome; chronic alcoholism; Creutzfeldt-Jakob disease; Subacute
sclerosing panencephalitis, Hallerrorden-Spatz disease; and
Dementia pugilistica, and the like.
Fibrotic Conditions
[0067] In addition to the above described conditions and diseases,
the present invention also provides a method for modulating or
treating fibrotic conditions of various etiologies such as liver
fibrosis (including but not limited to alcohol-induced cirrhosis,
viral-induced cirrhosis, autoirnrnune-induced hepatitis); lung
fibrosis (including but not limited to scleroderma, idiopathic
pulmonary fibrosis); kidney fibrosis (including but not limited to
scleroderma, diabetic nephritis, glomerular pehpritis, lupus
nephritis); dermal fibrosis (including but not limited to
scleroderma, hypertrophic and keloid scarring, burns);
myelofibrosis; Neurofibromatosis; fibroma; intestinal fibrosis; and
fibrotic adhesions resulting from surgical procedures.
[0068] The present invention also provides a method for modulating
or treating at least one wound, trauma or tissue injury or chronic
condition resulting from or related thereto, in a cell, tissue,
organ, animal or patient, including, but not limited to, at least
one of: bodily injury or a trauma associated with surgery including
thoracic, abdominal, cranial, or oral surgery; or wherein the wound
is selected from the group consisting of aseptic wounds, contused
wounds, incised wounds, lacerated wounds, non-penetrating wounds,
open wounds, penetrating wounds, perforating wounds, puncture
wounds, septic wounds, infarctions and subcutaneous wounds; or
wherein the wound is selected from the group consisting of ischemic
ulcers, pressure sores, fistulae, severe bites, thermal burns and
donor site wounds; or wherein the wound is anaphthous wound, a
traumatic wound or a herpes associated wound. Donor site wounds are
wounds which e.g. occur in connection with removal of hard tissue
from one part of the body to another part of the body e.g. in
connection with transplantation. The wounds resulting from such
operations are very painful and an improved healing is therefore
most valuable. Wound fibrosis is also amenable to CCR2 antagonist
therapy as the first cells to invade the wound area are neutrophils
followed by monocytes which are activated by macrophages.
Macrophages are believed to be essential for efficient wound
healing in that they also are responsible for phagocytosis of
pathogenic organisms and a clearing up of tissue debris.
Furthermore, they release numerous factors involved in subsequent
events of the healing process. The macrophages attract fibroblasts
which start the production of collagen. Almost all tissue repair
processes include the early connective tissue formation, a
stimulation of this and the subsequent processes improve tissue
healing, however, overproduction of connective tissue and collegen
can lead to a fibrotic tissue characterized as inelastic and
hypoxic. The CCR2 antagonist of the invention can be used in
methods for modulating, treating or preventing such sequelae of
wound healing.
Other Therapeutic Uses of CCR2 Antagonists
[0069] The present invention also provides a method for modulating
or treating at least one infectious disease in a cell, tissue,
organ, animal or patient, including, but not limited to, at least
one of: acute or chronic bacterial infection, acute and chronic
parasitic or infectious processes, including bacterial, viral and
fungal infections, HIV infection, HIV neuropathy, meningitis,
hepatitis (A, B or C, or the like), septic arthritis, peritonitis,
pneumonia, epiglottitis, e. coli 0157:h7, hemolytic uremic
syndrome/thrombolytic thrombocytopenic purpura, malaria, dengue
hemorrhagic fever, leishmaniasis, leprosy, toxic shock syndrome,
streptococcal myositis, gas gangrene, mycobacterium tuberculosis,
mycobacterium avium intracellulare, pneumocystis carinii pneumonia,
pelvic inflammatory disease, orchitislepidydimitis, legionella,
lyme disease, influenza a, epstein-barr virus, vital-associated
hemaphagocytic syndrome, vital encephalitisiaseptic meningitis, and
the like.
[0070] Any method of the present invention can comprise
administering an effective amount of a composition or
pharmaceutical composition comprising at least one CCR2 antagonist
to a cell, tissue, organ, animal or patient in need of such
modulation, treatment or therapy.
[0071] Besides being useful for human treatment, these compounds
are also useful for veterinary treatment of companion animals,
exotic animals and farm animals, including mammals, rodents, and
the like.
Combinations
[0072] The compounds of formula I may be used on their own or in
conjunction with other active substances of formula I according to
the invention. If desired the compounds of formula I may also be
used in combination with other pharmacologically active substances.
It is preferable to use for this purpose active substances selected
for example from among betamimetics, anticholinergics,
corticosteroids, other PDE4-inhibitors, LTD4-antagonists,
EGFR-inhibitors, MRP4-inhibitors, dopamine agonists,
H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors or
double or triple combinations thereof, such as for example
combinations of compounds of formula I with one or two compounds
selected from among [0073] betamimetics, corticosteroids,
PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists, [0074]
anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors,
EGFR-inhibitors and LTD4-antagonists, [0075] PDE4-inhibitors,
corticosteroids, EGFR-inhibitors and LTD4-antagonists [0076]
EGFR-inhibitors, PDE4-inhibitors and LTD4-antagonists [0077]
EGFR-inhibitors and LTD4-antagonists [0078] --CCR3-inhibitors,
iNOS-inhibitors (inducible nitric oxide synthase-inhibitors),
(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (hereinafter referred to
as "BH4") and the derivatives thereof as mentioned in WO
2006/120176 and SYK-inhibitors (spleen tyrosine kinase-inhibitors)
[0079] anticholinergics, betamimetics, corticosteroids,
PDE4-inhibitors and MRP4-inhibitors.
[0080] The invention also encompasses combinations of three active
substances, each selected from one of the above-mentioned
categories of compounds.
[0081] The betamimetics used are preferably compounds selected from
among albuterol, bambuterol, bitolterol, broxaterol, carbuterol,
clenbuterol, fenoterol, formoterol, arformoterol, zinterol,
hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol,
mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol,
procaterol, reproterol, rimiterol, ritodrine, salmeterol,
salmefamol, soterenol, sulphonterol, tiaramide, terbutaline,
tolubuterol, CHF-1035, HOKU-81, KUL-1248,
3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-
oxy}-butyl)-benzyl-sulphonamide,
5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-
-2-one,
4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-ami-
no}ethyl]-2(3H)-benzothiazolone,
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamin-
o]ethanol,
1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimida-
zolyl)-2-methyl-2-butylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminoph-
enyl)-2-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-me-
thyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1-
,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,
5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on-
e,
1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol-
,
6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]--
ethyl}-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetate
ethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic
acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,
8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-
-ethyl}-4H-benzo[1,4]oxazin-3-one,
8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydr-
oxy-4H-benzo[1,4]oxazin-3-one,
8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one,
4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-y-
l)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid,
8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one and
1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)eth-
anol, optionally in the form of the racemates, enantiomers,
diastereomers thereof and optionally in the form of the
pharmacologically acceptable acid addition salts, solvates or
hydrates thereof.
[0082] Preferably the beta mimetics are selected from among
bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol,
formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol,
reproterol, salmeterol, sulphonterol, terbutaline, tolubuterol,
3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-
oxy}-butyl)-benzenesulphonamide,
5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-
-2-one ,
4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-am-
ino}ethyl]-2(3H)-benzothiazolone,
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamin-
o]ethanol,
1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimida-
zolyl)-2-methyl-2-butylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminoph-
enyl)-2-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-me-
thyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1-
,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,
5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on-
e,
1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol-
,
6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]--
ethyl}-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetate
ethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic
acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,
8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1-dimethyl-ethylamino]-
-ethyl}-4H-benzo[1,4]oxazin-3-one,
8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydr-
oxy-4H-benzo[1,4]oxazin-3-one,
8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one,
4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-y-
l)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid,
8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one and
1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)etha-
nol, optionally in the form of the racemates, enantiomers,
diastereomers thereof and optionally in the form of the
pharmacologically acceptable acid addition salts, solvates or
hydrates thereof.
[0083] Particularly preferred betamimetics are selected from among
fenoterol, formoterol, salmeterol,
3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-
oxy}-butyl)-benzenesulphonamide,
5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-
-2-one,
1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazol-
yl)-2-methyl-2-butylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminoph-
enyl)-2-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-me-
thyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
-methyl-2-propylamino]ethanol,
6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetate
ethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic
acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,
8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-
-ethyl}-4H-benzo[1,4]oxazin-3-one,
8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydr-
oxy-4H-benzo[1,4]oxazin-3-one,
8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one,
4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-y-
l)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid,
8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one and
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1-
,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, optionally in the
form of the racemates, enantiomers, diastereomers thereof and
optionally in the form of the pharmacologically acceptable acid
addition salts, solvates or hydrates thereof.
[0084] Of these betamimetics those which are particularly preferred
according to the invention are formoterol, salmeterol,
3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyl-
oxy}-butyl)-benzenesulphonamide,
6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(ethyl
4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3--
one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic
acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,
8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-
-6-hydroxy-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-e-
thyl}-4H-benzo[1,4]oxazin-3-one,
6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-
-ethyl}-4H-benzo[1,4]oxazin-3-one,
8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydr-
oxy-4H-benzo[1,4]oxazin-3-one,
8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hyd-
roxy-4H-benzo[1,4]oxazin-3-one,
4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-y-
l)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid,
8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-
-hydroxy-4H-benzo[1,4]oxazin-3-one and
5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-
-2-one, optionally in the form of the racemates, enantiomers,
diastereomers thereof and optionally in the form of the
pharmacologically acceptable acid addition salts, solvates or
hydrates thereof.
[0085] According to the invention the acid addition salts of the
betamimetics are preferably selected from among hydrochloride,
hydrobromide, hydriodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate,
hydroxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonat, preferably hydrochloride, hydrobromide,
hydrosulphate, hydrophosphate, hydrofumarate and
hydromethanesulphonate. Of the above-mentioned acid addition salts
the salts of hydrochloric acid, methanesulphonic acid, benzoic acid
and acetic acid are particularly preferred according to the
invention.
[0086] The anticholinergics used are preferably compounds selected
from among the tiotropium salts, oxitropium salts, flutropium
salts, ipratropium salts, glycopyrronium salts, trospium salts,
tropenol 2,2-diphenylpropionate methobromide, scopine
2,2-diphenylpropionate methobromide, scopine
2-fluoro-2,2-diphenylacetate methobromide, tropenol
2-fluoro-2,2-diphenylacetate methobromide, tropenol
3,3',4,4'-tetrafluorobenzilate methobromide, scopine
3,3',4,4'-tetrafluorobenzilate methobromide, tropenol
4,4'-difluorobenzilate methobromide, scopine 4,4'-difluorobenzilate
methobromide, tropenol 3,3'-difluorobenzilate methobromide,
-scopine 3,3'-difluorobenzilate methobromide, tropenol
9-hydroxy-fluorene-9-carboxylate -methobromide, tropenol
9-fluoro-fluorene-9-carboxylate -methobromide, scopine
9-hydroxy-fluoren-9-carboxylate methobromide, scopine
9-fluoro-fluorene-9-carboxylate methobromide, tropenol
9-methyl-fluorene-9-carboxylate methobromide, scopine
9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropine
benzilate methobromide, cyclopropyltropine 2,2-diphenylpropionate
methobromide, cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate
methobromide, cyclopropyltropine 9-methyl-fluorene-9-carboxylate
methobromide, cyclopropyltropine 9-methyl-xanthene-9-carboxylate
methobromide, cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate
methobromide, methyl -cyclopropyltropine 4,4'-difluorobenzilate
methobromide, tropenol 9-hydroxy-xanthene-9-carboxylate
-methobromide, scopine 9-hydroxy-xanthene-9-carboxylate
methobromide, tropenol 9-methyl-xanthene-9-carboxylate
methobromide, scopine 9-methyl-xanthene-9-carboxylate methobromide,
tropenol 9-ethyl-xanthene-9-carboxylate methobromide, tropenol
9-difluoromethyl-xanthene-9-carboxylate methobromide, scopine
9-hydroxymethyl-xanthene-9-carboxylate methobromide, optionally in
the form of the solvates or hydrates thereof.
[0087] In the above-mentioned salts the cations tiotropium,
oxitropium, flutropium, ipratropium, glycopyrronium and trospium
are the pharmacologically active ingredients. As anions, the
above-mentioned salts may preferably contain chloride, bromide,
iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate,
acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate
or p-toluenesulphonate, while chloride, bromide, iodide, sulphate,
methanesulphonate or p-toluenesulphonate are preferred as
counter-ions. Of all the salts, the chlorides, bromides, iodides
and methanesulphonate are particularly preferred.
[0088] Of particular importance is tiotropium bromide. In the case
of tiotropium bromide the pharmaceutical combinations according to
the invention preferably contain it in the form of the crystalline
tiotropium bromide monohydrate, which is known from WO 02/30928. If
the tiotropium bromide is used in anhydrous form in the
pharmaceutical combinations according to the invention, it is
preferable to use anhydrous crystalline tiotropium bromide, which
is known from WO 03/000265.
[0089] Corticosteroids used here are preferably compounds selected
from among prednisolone, prednisone, butixocortpropionate,
flunisolide, beclomethasone, triamcinolone, budesonide,
fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone,
betamethasone, deflazacort, RPR-106541, NS-126, (S)-fluoromethyl
6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-andro-
sta-1,4-diene-17-carbothionate and (S)-(2-oxo-tetrahydro-furan-3S
-yl)
6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-
e-17-carbothionate, optionally in the form of the racemates,
enantiomers or diastereomers thereof and optionally in the form of
the salts and derivatives, solvates and/or hydrates thereof.
[0090] Particularly preferred is the steroid selected from among
flunisolide, beclomethasone, triamcinolone, budesonide,
fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone,
NS-126, (S)-fluoromethyl
6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-andro-
sta-1,4-diene-17-carbothionate and
(S)-(2-oxo-tetrahydro-furan-3S-yl)
6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-
e-17-carbothionate, optionally in the form of the racemates,
enantiomers or diastereomers thereof and optionally in the form of
the salts and derivatives, solvates and/or hydrates thereof.
[0091] Particularly preferred is the steroid selected from among
budesonide, fluticasone, mometasone, ciclesonide and
(S)-fluoromethyl
6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-andro-
sta-1,4-diene-17-carbothionate, optionally in the form of the
racemates, enantiomers or diastereomers thereof and optionally in
the form of the salts and derivatives, solvates and/or hydrates
thereof.
[0092] Any reference to steroids includes a reference to any salts
or derivatives, hydrates or solvates thereof which may exist.
Examples of possible salts and derivatives of the steroids may be:
alkali metal salts, such as for example sodium or potassium salts,
sulphobenzoates, phosphates, isonicotinates, acetates, propionates,
dihydrogen phosphates, palmitates, pivalates or furoates
thereof.
[0093] Other PDE4 inhibitors which may be used are preferably
compounds selected from among enprofyllin, theophyllin,
roflumilast, ariflo (cilomilast), tofimilast, pumafentrin,
lirimilast, arofyllin, atizoram, D-4396 (Sch-351591), AWD-12-281
(GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585,
V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370,
N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethox-
ybenzamide,
(-)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbe-
nzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrol-
idone,
3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'-[N-2-cyano-S-methyl-isot-
hioureido]benzyl)-2-pyrrolidone,
cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic
acid],
2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyph-
enyl)cyclohexane-1-one,
cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1--
ol],
(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden-
e]acetate,
(S)-(-)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2--
ylidene]acetate,
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4--
triazolo[4,3-a]pyridine and
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-
-triazolo[4,3-a]pyridine, optionally in the form of the racemates,
enantiomers or diastereomers and optionally in the form of the
pharmacologically acceptable acid addition salts, solvates and/or
hydrates thereof.
[0094] Particularly preferably the PDE4-inhibitor is selected from
among enprofyllin, roflumilast, ariflo (cilomilast), arofyllin,
atizoram, AWD-12-281 (GW-842470), T-440, T-2585, PD-168787,
V-11294A, Cl-1018, CDC-801, D-22888, YM-58997, Z-15370,
N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethox-
ybenzamide,
cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic
acid],
2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyph-
enyl)cyclohexan-1-one,
cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1--
ol],
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,-
2,4-triazolo[4,3-a]pyridine and
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-
-triazolo[4,3-a]pyridine, optionally in the form of the racemates,
enantiomers or diastereomers and optionally in the form of the
pharmacologically acceptable acid addition salts, solvates and/or
hydrates thereof.
[0095] By acid addition salts with pharmacologically acceptable
acids which the above-mentioned PDE4-inhibitors might be in a
position to form are meant, for example, salts selected from among
the hydrochloride, hydrobromide, hydroiodide, hydrosulphate,
hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,
hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,
hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,
hydrosulphate, hydrophosphate, hydrofumarate and
hydromethanesulphonate.
[0096] LTD4-antagonists which may be used are preferably compounds
selected from among montelukast, pranlukast, zafirlukast, MCC-847
(ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707,
L-733321,
1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy--
2-propyl)phenyl)thio)methylcyclopropane-acetic acid,
1-(((1(R)-3(3-(2-(2.3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phen-
yl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-a-
cetic acid and
[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic
acid, optionally in the form of the racemates, enantiomers or
diastereomers, optionally in the form of the pharmacologically
acceptable acid addition salts and optionally in the form of the
salts and derivatives, solvates and/or hydrates thereof.
[0097] Preferably the LTD4-antagonist is selected from among
montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001,
MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 and L-733321, optionally
in the form of the racemates, enantiomers or diastereomers,
optionally in the form of the pharmacologically acceptable acid
addition salts and optionally in the form of the salts and
derivatives, solvates and/or hydrates thereof.
[0098] Particularly preferably the LTD4-antagonist is selected from
among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523),
MN-001 and MEN-91507 (LM-1507), optionally in the form of the
racemates, enantiomers or diastereomers, optionally in the form of
the pharmacologically acceptable acid addition salts and optionally
in the form of the salts and derivatives, solvates and/or hydrates
thereof.
[0099] By acid addition salts with pharmacologically acceptable
acids which the LTD4-antagonists may be capable of forming are
meant, for example, salts selected from among the hydrochloride,
hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate,
hydrooxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,
hydrosulphate, hydrophosphate, hydrofumarate and
hydromethanesulphonate. By salts or derivatives which the
LTD4-antagonists may be capable of forming are meant, for example:
alkali metal salts, such as, for example, sodium or potassium
salts, alkaline earth metal salts, sulphobenzoates, phosphates,
isonicotinates, acetates, propionates, dihydrogen phosphates,
palmitates, pivalates or furoates.
[0100] The EGFR-inhibitors used are preferably compounds selected
from among
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-b-
uten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]a-
mino}-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-
-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-
-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoli-
ne,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-m-
orpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4--
yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopentyloxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-o-
xo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-
-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]--
1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,
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,
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-
-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(v-
inylcarbonyl)amino]-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrim-
idin,
3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-
-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,
4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulpho-
nyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-
-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino-
]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-o-
xo-2-buten-1-yl]amino}-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperi-
din-1-yl]-ethoxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperid-
in-4-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)--
7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cycl-
ohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-
-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-meth-
oxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperi-
din-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quina-
zoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-pip-
eridin-4-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy--
quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hyd-
roxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
oxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonyla-
mino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonyla-
mino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonyl-
amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acet-
ylamino-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
anesulphonylamino-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4--
yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)ca-
rbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl-
]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphony-
l]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclo-
hexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-ethoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-(2-methoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-y-
loxy]-7-(2-methoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-ylo-
xy)-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-ylo-
xy]-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazo-
line,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)car-
bonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl-
)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylami-
no]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]--
piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quin-
azoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-meth-
oxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-me-
thoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-me-
thoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-
-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-ylo-
xy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-meth-
yl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7--
methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-y-
loxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2.6-dimethyl-morpholin-4-y-
l)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbon-
yl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,-
1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amin-
o)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-metho-
xy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbony-
l]-piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-
-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cy-
clohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-y-
loxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-meth-
yl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-
-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbon-
yl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-metho-
xy-quinazoline, Cetuximab, Trastuzumab, ABX-EGF and Mab ICR-62,
optionally in the form of the racemates, enantiomers or
diastereomers thereof, optionally in the form of the
pharmacologically acceptable acid addition salts, the solvates
and/or hydrates thereof.
[0101] Preferred EGFR inhibitors are selected from among
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-
-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]a-
mino}-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(((R)-6-methyl-2-oxo-morpholin--
4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-
-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoli-
ne,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-m-
orpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4--
yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-cyclopentyloxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-o-
xo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-
-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]--
1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,
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,
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-
-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(v-
inylcarbonyl)amino]-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrim-
idine,
3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino-
)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,
4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulpho-
nyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-
-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino-
]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-o-
xo-2-buten-1-yl]amino}-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperi-
din-1-yl]-ethoxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperid-
in-4-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)--
7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cycl-
ohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-
-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-meth-
oxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperi-
din-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quina-
zoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-pip-
eridin-4-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy--
quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hyd-
roxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
oxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonyla-
mino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonyla-
mino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonyl-
amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acet-
ylamino-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-meth-
anesulphonylamino-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4--
yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)ca-
rbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl-
]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphony-
l]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclo-
hexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-ethoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-(2-methoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-y-
loxy]-7-(2-methoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-ylo-
xy)-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-ylo-
xy]-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazo-
line,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)car-
bonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl-
)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylami-
no]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]--
piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quin-
azoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-meth-
oxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-me-
thoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-me-
thoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-
-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-ylo-
xy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-meth-
yl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7--
methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-y-
loxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2.6-dimethyl-morpholin-4-y-
l)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbon-
yl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,-
1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amin-
o)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-metho-
xy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbony-
l]-piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-
-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cy-
clohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-y-
loxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-meth-
yl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-
-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbon-
yl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-metho-
xy-quinazoline, and Cetuximab, optionally in the form of the
racemates, enantiomers or diastereomers thereof, optionally in the
form of the pharmacologically acceptable acid addition salts, the
solvates and/or hydrates thereof.
[0102] It is particularly preferable within the scope of the
present invention to use those EGFR-inhibitors which are selected
from among
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]a-
mino}-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-
-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoli-
ne,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-
-4-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrim-
idine,
3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino-
)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-
-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-o-
xo-2-buten-1-yl]amino}-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperi-
din-1-yl]-ethoxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)--
7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cycl-
ohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-
-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quina-
zoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-pip-
eridin-4-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy--
quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonyla-
mino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl-
]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclo-
hexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-(2-methoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-y-
loxy]-7-(2-methoxy-ethoxy)-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazo-
line,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)car-
bonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylami-
no]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]--
piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quin-
azoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-meth-
oxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-me-
thoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-me-
thoxy-ethoxy)-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-y-
loxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amin-
o)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-metho-
xy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-
-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cy-
clohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-y-
loxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-meth-
yl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-
-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbon-
yl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-metho-
xy-quinazoline, and
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline, optionally in the form of the
racemates, enantiomers or diastereomers thereof, optionally in the
form of the pharmacologically acceptable acid addition salts, the
solvates and/or hydrates thereof.
[0103] Particularly preferred EGFR-inhibitors according to the
invention are the compounds selected from among
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-
-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoli-
ne,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-
-4-yl)-ethoxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-
-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-o-
xo-2-buten-1-yl]amino}-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cycl-
ohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-
-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]--
piperidin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quin-
azoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-meth-
oxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-me-
thoxy-quinazoline,
4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-y-
loxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piper-
idin-4-yloxy}-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-
-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cy-
clohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-y-
loxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-meth-
yl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-
-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbon-
yl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4--
yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-ylo-
xy)-7-methoxy-quinazoline and
4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-metho-
xy-quinazoline optionally in the form of the racemates, enantiomers
or diastereomers thereof, optionally in the form of the
pharmacologically acceptable acid addition salts, the solvates
and/or hydrates thereof.
[0104] By acid addition salts with pharmacologically acceptable
acids which the EGFR-inhibitors may be capable of forming are
meant, for example, salts selected from among the hydrochloride,
hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,
hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,
hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate,
hydrooxalate, hydrosuccinate, hydrobenzoate and
hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,
hydrosulphate, hydrophosphate, hydrofumarate and
hydromethanesulphonate.
[0105] Examples of dopamine agonists which may be used preferably
include compounds selected from among bromocriptine, cabergoline,
alpha-dihydroergocryptine, lisuride, pergolide, pramipexol,
roxindol, ropinirol, talipexol, terguride and viozan. Any reference
to the above-mentioned dopamine agonists within the scope of the
present invention includes a reference to any pharmacologically
acceptable acid addition salts and optionally hydrates thereof
which may exist. By the physiologically acceptable acid addition
salts which may be formed by the above-mentioned dopamine agonists
are meant, for example, pharmaceutically acceptable salts which are
selected from the salts of hydrochloric acid, hydrobromic acid,
sulphuric acid, phosphoric acid, methanesulphonic acid, acetic
acid, fumaric acid, succinic acid, lactic acid, citric acid,
tartaric acid and maleic acid.
[0106] Examples of H1-antihistamines preferably include compounds
selected from among epinastine, cetirizine, azelastine,
fexofenadine, levocabastine, loratadine, mizolastine, ketotifen,
emedastine, dimetinden, clemastine, bamipin, cexchlorpheniramine,
pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate,
diphenhydramine, promethazine, ebastine, desloratidine and
meclozine. Any reference to the above-mentioned H1-antihistamines
within the scope of the present invention includes a reference to
any pharmacologically acceptable acid addition salts which may
exist.
[0107] Examples of PAF-antagonists preferably include compounds
selected from among
4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thien-
o-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines,
6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-
-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines.
[0108] MRP4-inhibitors used are preferably compounds selected from
among N-acetyl-dinitrophenyl-cysteine, cGMP, cholate, diclofenac,
dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone
3-sulphate, dilazep, dinitrophenyl-s-glutathione, estradiol
17-.beta.-glucuronide, estradiol 3,17-disulphate, estradiol
3-glucuronide, estradiol 3-sulphate, estrone 3-sulphate,
flurbiprofen, folate, N5-formyl-tetrahydrofolate, glycocholate,
clycolithocholic acid sulphate, ibuprofen, indomethacin,
indoprofen, ketoprofen, lithocholic acid sulphate, methotrexate,
MK571
((E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)--
3-oxopropyl]thio]methyl]thio]-propanoic acid),
.alpha.-naphthyl-.beta.-D-glucuronide, nitrobenzyl mercaptopurine
riboside, probenecid, PSC833, sildenafil, sulfinpyrazone,
taurochenodeoxycholate, taurocholate, taurodeoxycholate,
taurolithocholate, taurolithocholic acid sulphate, topotecan,
trequinsin and zaprinast, dipyridamole, optionally in the form of
the racemates, enantiomers, diastereomers and the pharmacologically
acceptable acid addition salts and hydrates thereof.
[0109] Preferably the invention relates to the use of
MRP4-inhibitors for preparing a pharmaceutical composition for the
treatment of respiratory complaints, containing the
PDE4B-inhibitors and MRP4-inhibitors, the MRP4-inhibitors
preferably being selected from among
N-acetyl-dinitrophenyl-cysteine, dehydroepiandrosterone 3-sulphate,
dilazep, dinitrophenyl-S-glutathione, estradiol 3,17-disulphate,
flurbiprofen, glycocholate, glycolithocholic acid sulphate,
ibuprofen, indomethacin, indoprofen, lithocholic acid sulphate,
MK571, PSC833, sildenafil, taurochenodeoxycholate, taurocholate,
taurolithocholate, taurolithocholic acid sulphate, trequinsin and
zaprinast, dipyridamole, optionally in the form of the racemates,
enantiomers, diastereomers and the pharmacologically acceptable
acid addition salts and hydrates thereof.
[0110] The invention relates more preferably to the use of
MRP4-inhibitors for preparing a pharmaceutical composition for
treating respiratory complaints, containing the PDE4B-inhibitors
and MRP4-inhibitors according to the invention, the MRP4-inhibitors
preferably being selected from among dehydroepiandrosterone
3-sulphate, estradiol 3,17-disulphate, flurbiprofen, indomethacin,
indoprofen, MK571, taurocholate, optionally in the form of the
racemates, enantiomers, diastereomers and the pharmacologically
acceptable acid addition salts and hydrates thereof. The separation
of enantiomers from the racemates can be carried out using methods
known from the art (e.g. chromatography on chiral phases,
etc.).
[0111] By acid addition salts with pharmacologically acceptable
acids are meant, for example, salts selected from among the
hydrochlorides, hydrobromides, hydroiodides, hydrosulphates,
hydrophosphates, hydromethanesulphonates, hydronitrates,
hydromaleates, hydroacetates, hydrobenzoates, hydrocitrates,
hydrofumarates, hydrotartrates, hydrooxalates, hydrosuccinates,
hydrobenzoates and hydro-p-toluenesulphonates, preferably the
hydrochlorides, hydrobromides, hydrosulphates, hydrophosphates,
hydrofumarates and hydromethanesulphonates.
[0112] The invention further relates to pharmaceutical preparations
which contain a triple combination of the PDE4B-inhibitors,
MRP4-inhibitors and another active substance according to the
invention, such as, for example, an anticholinergic, a steroid, an
LTD4-antagonist or a betamimetic, and the preparation thereof and
the use thereof for treating respiratory complaints.
[0113] The iNOS-inhibitors used are preferably compounds selected
from among: S-(2-aminoethyl)isothiourea, aminoguanidine,
2-aminomethylpyridine, AMT, L-canavanine, 2-iminopiperidine,
S-isopropylisothiourea, S-methylisothiourea, S-ethylisothiourea,
S-methyltiocitrulline, S-ethylthiocitrulline, L-NA
(N.sup..omega.-nitro-L-arginine), L-NAME
(N.sup..omega.-nitro-L-arginine methylester), L-NMMA
(N.sup.G-monomethyl-L-arginine), L-NIO
(N.sup..omega.-iminoethyl-L-ornithine), L-NIL
(N.sup..omega.-iminoethyl-lysine),
(S)-6-acetimidoylamino-2-amino-hexanoic acid
(1H-tetrazol-5-yl)-amide (SC-51) (J. Med. Chem. 2002, 45,
1686-1689), 1400W,
(S)-4-(2-acetimidoylamino-ethylsulphanyl)-2-amino-butyric acid
(GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600),
2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine
(BYK191023) (Mol. Pharmacol. 2006, 69, 328-337),
2-((R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile (WO
01/62704),
2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-6-trifluorome-
thyl-nicotinonitrile (WO 2004/041794),
2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-4-chloro-benz-
onitrile (WO 2004/041794),
2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-benz-
onitrile (WO 2004/041794),
(2S,4R)-2-amino-4-(2-chloro-5-trifluoromethyl-phenylsulphanyl)-4-thiazol--
5-yl-butan-1-ol (WO 2004/041794),
2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-nico-
tinonitrile (WO 2004/041794),
4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulphanyl)-6-methoxy-nicotinonitri-
le (WO 02/090332), substituted
3-phenyl-3,4-dihydro-1-isoquinolinamines such as e.g. AR-C102222
(J. Med. Chem. 2003, 46, 913-916),
(1S,5S,6R)-7-chloro-5-methyl-2-aza-bicyclo[4.1.0]hept-2-en-3-ylamine
(ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667),
(4R,5R)-5-ethyl-4-methyl-thiazolidin-2-ylideneamine (Bioorg. Med.
Chem. 2004, 12, 4101),
(4R,5R)-5-ethyl-4-methyl-selenazolidin-2-ylideneamine (Bioorg. Med.
Chem. Lett. 2005, 15, 1361), 4-aminotetrahydrobiopterine (Curr.
Drug Metabol. 2002, 3, 119-121),
(E)-3-(4-chloro-phenyl)-N-(1-{2-oxo-2-[4-(6-trifluoromethyl-pyrimidin-4-y-
loxy)-piperidin-1-yl]-ethylcarbamoyl}-2-pyridin-2-yl-ethyl)-acrylamide
(FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76),
3-(2,4-difluoro-phenyl)-6-[2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy]-2-ph-
enyl-pyridine (PPA250) (J. Pharmacol. Exp. Ther. 2002, 303, 52-57),
methyl
3-{[(benzo[1.3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazol-1-yl-p-
yrimidin-4-yl)-piperazin-1-carboxylate (BBS-1) (Drugs Future 2004,
29, 45-52),
(R)-1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-2-car-
boxylic acid (2-benzo[1.3]dioxol-5-yl-ethyl)-amide (BBS-2) (Drugs
Future 2004, 29, 45-52) and the pharmaceutical salts, prodrugs or
solvates thereof.
[0114] Other iNOS-inhibitors which may be used within the scope of
the present invention are antisense oligonucleotides, particularly
antisense oligonucleotides that bind iNOS-coding nucleic acids. For
example, WO 01/52902 describes antisense oligonucleotides,
particularly antisense-oligonucleotides, which bind iNOS-coding
nucleic acids, for modulating the expression of iNOS. Those
iNOS-antisense-oligonucleotides as described particularly in WO
01/52902 may therefore also be combined with the PDE4-inhibitors of
the present invention on the basis of their similar activity to the
iNOS inhibitors.
[0115] Compounds which may be used as SYK-inhibitors are preferably
compounds selected from among: R343 or R788.
Pharmaceutical Formulations
[0116] Suitable forms for administration are for example tablets,
capsules, solutions, syrups, emulsions or inhalable powders or
aerosols. The content of the pharmaceutically effective compound(s)
in each case should be in the range from 0.1 to 90 wt. %,
preferably 0.5 to 50 wt. % of the total composition, i.e. in
amounts which are sufficient to achieve the dosage range specified
hereinafter.
[0117] The preparations may be administered orally in the form of a
tablet, as a powder, as a powder in a capsule (e.g. a hard gelatine
capsule), as a solution or suspension. When administered by
inhalation the active substance combination may be given as a
powder, as an aqueous or aqueous-ethanolic solution or using a
propellant gas formulation.
[0118] Preferably, therefore, pharmaceutical formulations are
characterised in that they contain one or more compounds of formula
I according to the preferred embodiments above.
[0119] It is particularly preferable if the compounds of formula I
are administered orally, and it is also particularly preferable if
they are administered once or twice a day. Suitable tablets may be
obtained, for example, by mixing the active substance(s) with known
excipients, for example inert diluents such as calcium carbonate,
calcium phosphate or lactose, disintegrants such as corn starch or
alginic acid, binders such as starch or gelatine, lubricants such
as magnesium stearate or talc and/or agents for delaying release,
such as carboxymethyl cellulose, cellulose acetate phthalate, or
polyvinyl acetate. The tablets may also comprise several
layers.
[0120] Coated tablets may be prepared accordingly by coating cores
produced analogously to the tablets with substances normally used
for tablet coatings, for example collidone or shellac, gum arabic,
talc, titanium dioxide or sugar. To achieve delayed release or
prevent incompatibilities the core may also consist of a number of
layers. Similarly the tablet coating may consist of a number of
layers to achieve delayed release, possibly using the excipients
mentioned above for the tablets.
[0121] Syrups containing the active substances or combinations
thereof according to the invention may additionally contain a
sweetener such as saccharine, cyclamate, glycerol or sugar and a
flavour enhancer, e.g. a flavouring such as vanillin or orange
extract. They may also contain suspension adjuvants or thickeners
such as sodium carboxymethyl cellulose, wetting agents such as, for
example, condensation products of fatty alcohols with ethylene
oxide, or preservatives such as p-hydroxybenzoates.
[0122] Capsules containing one or more active substances or
combinations of active substances may for example be prepared by
mixing the active substances with inert carriers such as lactose or
sorbitol and packing them into gelatine capsules.
[0123] Suitable suppositories may be made for example by mixing
with carriers provided for this purpose, such as neutral fats or
polyethyleneglycol or the derivatives thereof.
[0124] Excipients which may be used include, for example, water,
pharmaceutically acceptable organic solvents such as paraffins
(e.g. petroleum fractions), vegetable oils (e.g. groundnut or
sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or
glycerol), carriers such as e.g. natural mineral powders (e.g.
kaolins, clays, talc, chalk), synthetic mineral powders (e.g.
highly dispersed silicic acid and silicates), sugars (e.g. cane
sugar, lactose and glucose), emulsifiers (e.g. lignin, spent
sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone)
and lubricants (e.g. magnesium stearate, talc, stearic acid and
sodium lauryl sulphate).
[0125] For oral administration the tablets may, of course, contain,
apart from the abovementioned carriers, additives such as sodium
citrate, calcium carbonate and dicalcium phosphate together with
various additives such as starch, preferably potato starch,
gelatine and the like. Moreover, lubricants such as magnesium
stearate, sodium lauryl sulphate and talc may be used at the same
time for the tabletting process. In the case of aqueous suspensions
the active substances may be combined with various flavour
enhancers or colourings in addition to the excipients mentioned
above.
[0126] It is also preferred if the compounds of formula I are
administered by inhalation, particularly preferably if they are
administered once or twice a day. For this purpose, the compounds
of formula I have to be made available in forms suitable for
inhalation. Inhalable preparations include inhalable powders,
propellant-containing metered-dose aerosols or propellant-free
inhalable solutions, which are optionally present in admixture with
conventional physiologically acceptable excipients.
[0127] Within the scope of the present invention, the term
propellant-free inhalable solutions also includes concentrates or
sterile ready-to-use inhalable solutions. The preparations which
may be used according to the invention are described in more detail
in the next part of the specification.
Inhalable Powders
[0128] If the active substances of formula I are present in
admixture with physiologically acceptable excipients, the following
physiologically acceptable excipients may be used to prepare the
inhalable powders according to the invention: monosaccharides (e.g.
glucose or arabinose), disaccharides (e.g. lactose, saccharose,
maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols
(e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride,
calcium carbonate) or mixtures of these excipients with one
another. Preferably, mono- or disaccharides are used, while the use
of lactose or glucose is preferred, particularly, but not
exclusively, in the form of their hydrates. For the purposes of the
invention, lactose is the particularly preferred excipient, while
lactose monohydrate is most particularly preferred. Methods of
preparing the inhalable powders according to the invention by
grinding and micronising and by finally mixing the components
together are known from the prior art.
Propellant-Containing Inhalable Aerosols
[0129] The propellant-containing inhalable aerosols which may be
used according to the invention may contain 1 dissolved in the
propellant gas or in dispersed form. The propellant gases which may
be used to prepare the inhalation aerosols according to the
invention are known from the prior art. Suitable propellant gases
are selected from among hydrocarbons such as n-propane, n-butane or
isobutane and halohydrocarbons such as preferably fluorinated
derivatives of methane, ethane, propane, butane, cyclopropane or
cyclobutane. The propellant gases mentioned above may be used on
their own or in mixtures thereof. Particularly preferred propellant
gases are fluorinated alkane derivatives selected from TG134a
(1,1,1,2-tetrafluoroethane), TG227
(1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. The
propellant-driven inhalation aerosols used within the scope of the
use according to the invention may also contain other ingredients
such as co-solvents, stabilisers, surfactants, antioxidants,
lubricants and pH adjusters. All these ingredients are known in the
art.
Propellant-Free Inhalable Solutions
[0130] The compounds of formula I according to the invention are
preferably used to prepare propellant-free inhalable solutions and
inhalable suspensions. Solvents used for this purpose include
aqueous or alcoholic, preferably ethanolic solutions. The solvent
may be water on its own or a mixture of water and ethanol. The
solutions or suspensions are adjusted to a pH of 2 to 7, preferably
2 to 5, using suitable acids. The pH may be adjusted using acids
selected from inorganic or organic acids. Examples of particularly
suitable inorganic acids include hydrochloric acid, hydrobromic
acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples
of particularly suitable organic acids include ascorbic acid,
citric acid, malic acid, tartaric acid, maleic acid, succinic acid,
fumaric acid, acetic acid, formic acid and/or propionic acid etc.
Preferred inorganic acids are hydrochloric and sulphuric acids. It
is also possible to use the acids which have already formed an acid
addition salt with one of the active substances. Of the organic
acids, ascorbic acid, fumaric acid and citric acid are preferred.
If desired, mixtures of the above acids may also be used,
particularly in the case of acids which have other properties in
addition to their acidifying qualities, e.g. as flavourings,
antioxidants or complexing agents, such as citric acid or ascorbic
acid, for example. According to the invention, it is particularly
preferred to use hydrochloric acid to adjust the pH. Co-solvents
and/or other excipients may be added to the propellant-free
inhalable solutions used for the purpose according to the
invention. Preferred co-solvents are those which contain hydroxyl
groups or other polar groups, e.g. alcohols--particularly isopropyl
alcohol, glycols--particularly propyleneglycol, polyethyleneglycol,
polypropyleneglycol, glycolether, glycerol, polyoxyethylene
alcohols and polyoxyethylene fatty acid esters. The terms
excipients and additives in this context denote any
pharmacologically acceptable substance which is not an active
substance but which can be formulated with the active substance or
substances in the pharmacologically suitable solvent in order to
improve the qualitative properties of the active substance
formulation. Preferably, these substances have no pharmacological
effect or, in connection with the desired therapy, no appreciable
or at least no undesirable pharmacological effect. The excipients
and additives include, for example, surfactants such as soya
lecithin, oleic acid, sorbitan esters, such as polysorbates,
polyvinylpyrrolidone, other stabilisers, complexing agents,
antioxidants and/or preservatives which guarantee or prolong the
shelf life of the finished pharmaceutical formulation, flavourings,
vitamins and/or other additives known in the art. The additives
also include pharmacologically acceptable salts such as sodium
chloride as isotonic agents. The preferred excipients include
antioxidants such as ascorbic acid, for example, provided that it
has not already been used to adjust the pH, vitamin A, vitamin E,
tocopherols and similar vitamins or provitamins occurring in the
human body. Preservatives may be used to protect the formulation
from contamination with pathogens. Suitable preservatives are those
which are known in the art, particularly cetyl pyridinium chloride,
benzalkonium chloride or benzoic acid or benzoates such as sodium
benzoate in the concentration known from the prior art. For the
treatment forms described above, ready-to-use packs of a medicament
for the treatment of respiratory complaints are provided,
containing an enclosed description including for example the words
respiratory disease, COPD or asthma, a pteridine and one or more
combination partners selected from those described above.
EXPERIMENTAL PROCEDURES AND SYNTHETIC EXAMPLES
List Of Abbreviations
[0131] ACN acetonitrile [0132] APCI atmospheric pressure chemical
ionization (in MS) [0133] Ctrl control [0134] DAD diode array
detector [0135] DMA N,N-dimethylacetamide' [0136] DMF
N,N-dimethylformamide [0137] DMSO dimethyl sulfoxide [0138] EI
electron impact (in MS) [0139] ESI electrospray ionization (in MS)
[0140] ex example [0141] GC/MS gas chromatography with mass
spectrometric detection [0142] h hour(s) [0143] HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluoro-phosphate [0144] HPLC high performance liquid
chromatography [0145] HPLC/MS coupled high performance liquid
chromatography-mass spectrometry [0146] min minutes [0147] MS mass
spectrometry [0148] NMR nuclear magnetic resonance [0149] R.sub.t
retention time (in HPLC) [0150] sec secondary [0151] TBTU
O-(1H-benzo-1,2,3-triazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate [0152] tert tertiary [0153] TFA trifluoroacetic
acid [0154] TLC thin-layer chromatography [0155] UV ultraviolet
absorption
Analytical Methods
HPLC Methods
[0156] Methods:
[0157] 1A [0158] Column: Sunfire MS-C8, 5 .mu.m, 4.6.times.100 mm
[0159] Mobile phase: A=(10 nM aqueous solution of NH.sub.4COOH)+10%
ACN; [0160] B=ACN+10% (10 nM aqueous solution of NH.sub.4COOH).
[0161] Flow rate: 1500 .mu.L/min [0162] Gradient: A/B (95/5%) for 1
min then to A/B (5/95%) in 10 min for 2 min.
[0163] 1E [0164] Column: Symmetry C8, 5 .mu.m, 3.times.150 mm
[0165] Mobile phase: A=(10 nM aqueous solution of NH.sub.4COOH)+10%
ACN; [0166] B=ACN+10% (10 nM aqueous solution of NH.sub.4COOH).
[0167] Flow rate: 1200 .mu.L/min [0168] Gradient: A (100%) for 1.5
min then to B (100%) in 10 min for 3 min
[0169] 1E (Fusion) [0170] Column: Synergy Fusion RP80A, 4 .mu.m,
4.6.times.100 mm [0171] Mobile phase: A=(10 nM aqueous solution of
NH.sub.4COOH)+10% ACN; [0172] B=ACN+10% (10 nM aqueous solution of
NH.sub.4COOH). [0173] Flow rate: 1200 .mu.L/min [0174] Gradient: A
(100%) for 1.5 min then to B (100%) in 10 min for 3 min
[0175] 1E (Hydro) [0176] Column: Synergy Hydro RP80A, 4 .mu.m,
4.6.times.100 mm [0177] Mobile phase: A=(10 nM aqueous solution of
NH.sub.4COOH)+10% ACN; [0178] B=ACN+10% (10 nM aqueous solution of
NH.sub.4COOH). [0179] Flow rate: 1200 .mu.L/min [0180] Gradient: A
(100%) for 1.5 min then to B (100%) in 10 min for 3 min
[0181] Equipment: [0182] Instrument: HPLC/MS ThermoFinnigan HPLC
Surveyor DAD, [0183] Detection: UV @ 254 nm [0184] Detection:
Finnigan MSQ, quadrupole [0185] Ion source: APCI
Method:
[0186] 1F [0187] Column: Xterra MS-C8, 3.5 .mu.m, 4.6.times.50 mm
[0188] Mobile phase: A=(H.sub.2O+0.1% TFA)+10% ACN; B=ACN [0189]
Flow rate: 1300 .mu.L/min [0190] Gradient: A (100%) then to A/B
(10/90%) in 3.25 min for 0.75 min
[0191] 1Fa [0192] Column: Xterra MS-C18, 5 .mu.m, 4.6.times.50 mm
[0193] Mobile phase: A=(H.sub.2O+0.1% NH.sub.4COOH)+10% ACN; B=ACN
[0194] Flow rate: 1300 .mu.L/min [0195] Gradient: A (100%) then to
A/B (10/90%) in 3.25 min for 0.75 min
[0196] Equipment: [0197] Instrument: HPLC/MS Waters. Hplc Alliance
2695 DAD, ZQ Quadrupole [0198] Detection: UV @ 254 nm [0199]
Detection: Waters ZQ, Quadrupole; [0200] Ion source: ESI
Methods:
[0201] 2A [0202] Column: X-Terra MS C18 4.6.times.50 mm, 3.5 .mu.m;
[0203] Column Temperature: 40.0.degree. C. [0204] Mobile phase:
A=H.sub.2O+0.1% TFA; B=ACN+0.1% TFA [0205] Flow rate: 1500
.mu.L/min
TABLE-US-00002 [0205] Time A % B % Gradient: 0.00 95.00 5.00 2.00
0.00 100.00 2.49 0.00 100.00 2.50 95.00 5.00
[0206] 2B [0207] Column: X-Terra MS C18 4.6.times.50 mm, 3.5 .mu.m;
[0208] Column Temperature: 40.0.degree. C. [0209] Mobile phase:
A=H.sub.2O+0.1% TFA; B=ACN+0.1% TFA [0210] Flow rate: 1000
.mu.L/min
TABLE-US-00003 [0210] Time A % B % Gradient: 0.00 95.00 5.00 0.40
95.00 5.00 4.00 2.00 98.00 4.35 2.00 98.00 4.50 95.00 5.00
[0211] 2C [0212] Column: Sunfire C18 4.6.times.50 mm, 3.5 .mu.m;
[0213] Column Temperature: 40.0.degree. C. [0214] Mobile phase:
A=H.sub.2O+0.1% TFA; B=ACN+0.1% TFA [0215] Flow rate: 1500
.mu.L/min
TABLE-US-00004 [0215] Time: A % B % Gradient: 0.00 95.00 5.00 2.00
0.00 100.00 2.49 0.00 100.00 2.50 95.00 5.00
[0216] Equipment [0217] Instrument: Waters ZQ2000 mass spectrometer
[0218] Detection: HP1100 HPLC+DAD (Wavelength range: 210 to 500
nM)+Gilson 215 Autosampler [0219] Ion source: ESI+
Method:
[0220] 2Ca [0221] Column: MERCK; Chromolith Flash; RP18e;
25.times.4.6 mm [0222] Mobile phase: A=water+0.1% HCOOH; B=ACN+0.1%
HCOOH [0223] Flow rate: 1.6 ml/min
TABLE-US-00005 [0223] A % B % Time [min] Gradient: 90 10 0.00 10 90
2.70 10 90 3.00 90 10 3.30
[0224] 2Cb [0225] Column: MERCK; Chromolith Flash; RP18e;
25.times.4.6 mm [0226] Mobile: A=water+0.1% HCOOH; B=MeOH [0227]
Flow rate: 1.6 ml/min
TABLE-US-00006 [0227] A % B % Time [min] Gradient: 90 10 0.00 0 100
2.50 0 100 3.50
[0228] Equipment [0229] Instrument: Agilent Technology; HP 1200
Series , DAD SL [0230] Detection: UV 240-254 nm
[0231] Detection: Waters ZQ Single Quad
[0232] Ion source: ESI+
Method:
[0233] 2F [0234] Column: Symmetry Shield RP8, 5 .mu.m,
4.6.times.150 mm [0235] Mobile phase: A=(H.sub.2O+HCOOH 0.1%)+10%
ACN [0236] B=ACN+10% (H.sub.2O+0.1% HCOOH) [0237] Flow rate: 1000
.mu.L/min [0238] Gradient: A/B (95/5%) for 1.5 min then to A/B
(5/95%) in 10 min for 1.5 min
[0239] 2M [0240] Column: Symmetry Shield RP8, 5 .mu.m,
4.6.times.150 mm [0241] Mobile phase: A=(H.sub.2O+HCOOH 0.1%)+10%
ACN [0242] B=ACN+10% (H.sub.2O+0.1% HCOOH) [0243] Flow rate: 1200
.mu.L/min [0244] Gradient: A/B (90/10%) for 1.5 min then to A/B
(5/95%) in 10 min for 2 min
[0245] Equipment: [0246] nstrument: HPLC/MS ThermoFinnigan HPLC
Surveyor DAD, LCQDuo Ion Trap [0247] Detection: UV .lamda. 254 nm
[0248] Detection: Finnigan LCQDuo Ion Trap [0249] Ion source:
ESI
Method:
[0250] 2G [0251] Eluent: A=H2O+0.05% TFA; B=ACN [0252] Column:
Waters SunFire C18 30.times.100 mm 5 .mu.m
TABLE-US-00007 [0252] Gradient: slope 5%/min Initial: Flow = 40
mL/min % A = 80 % B = 20 8 min Flow = 40 mL/min % A = 40 % B = 60 9
min Flow = 40 mL/min % A = 40 % B = 60 10 min Flow = 40 mL/min % A
= 5 % B = 95 11 min Flow = 40 mL/min % A = 5 % B = 95 11.5 min Flow
= 40 mL/min % A = 80 % B = 20 Stop run after 12 min Pre-run method:
Initial condition for 3 min
Equipment:
TABLE-US-00008 [0253] Detector MS Waters ZQ: Detector DAD Waters
996: File: APrep_ESI.ipr Start Wavelength: 210 nm Polarity: ESI+
End Wavelength: 600 nm Mass range: 130 to 900 amu Resolution: 1.2
nm Sampling rate: 1 spectra/sec Sample Manager mod Waters 2767:
Make up pump mod Waters 515: Injection type: partial loop Flow =
1000 .mu.L/min Injection Volume: set to Open Solvent = ACN/Water/
Access Login mask Formic acid (90/10/0.1) Syringe size: 5000 uL
Splitter: 1:1000 Trigger: mixed Total scan UV plus MS A Loop
Volume: 5000 uL
Method:
[0254] 2G a [0255] Column: BEH C18, 1.8 um, 2.1.times.100 mm [0256]
Mobile phase: A=(H.sub.2O+NH4COOH 0.1%) [0257] B=ACN+10% H.sub.2O
[0258] Flow rate: 450 .mu.L/min [0259] Gradient: 100% A for 1.5 min
then to 100% B in 2.2 min
[0260] 2 Gb [0261] Column: BEH C18, 1.7 um, 2.1.times.50 mm [0262]
Mobile phase: A=H.sub.2O 90%+0.1% TFA+10% ACN [0263] B=ACN+10%
H.sub.2O [0264] Flow rate: 480 .mu.L/min [0265] Gradient: A/B
(90:10), then to A/B (10:90) in 1.2 minutes for 0.46 minute
[0266] Equipment: [0267] Instrument: HPLC/MS AcquityWaters [0268]
Detection: UV .lamda. 254 nm [0269] Detection: Waters SQD,
Quadrupole [0270] Ion source: ESI
Method:
[0271] 2H (Isocratic) [0272] Column: DAICEL (IC) 5 .mu.m,
4.6.times.250 mm [0273] Mobile phase: A=(hexane+0.2% diethylamine);
B=(MeOH/EtOH 50/50%). [0274] A/B=50/50% [0275] Flow rate: 1
ml/min
[0276] 2I (Isocratic) [0277] Column: DAICEL AS-H 5 .mu.m,
4.6.times.250 mm [0278] Mobile phase: A=Hexane ; B=EtOH (con AS-H),
IPA (con AD-H) [0279] A/B=98/2% [0280] Flow rate: 1 ml/min
[0281] Equipment [0282] Instrument: LC Agilent Technologies. HPLC
1100 Serie, DAD Version A. [0283] Detection: UV 220-300 nm
GC-MS Methods:
Method:
[0284] 3A [0285] Column: Agilent DB-5MS, 25 m.times.0.25
mm.times.0.25 .mu.m [0286] Carrier gas: Helium, 1 ml/min constant
flow [0287] Oven Program: 50.degree. C. (hold 1 min.), to
100.degree. C. in 10.degree. C./min, to 200.degree. C. in
20.degree. C./min, to 300.degree. C. in 30.degree. C. /min
[0288] Equipment [0289] Instrument: GC/MS Finnigan TRACE GC, TRACE
MS quadrupole [0290] Detection: TRACE MS quadrupole [0291] Ion
source: EI
Microwave Heating:
[0291] [0292] Discover.RTM. CEM instruments, equipped with 10 and
35 mL vessels.
Synthesis of Intermediates
##STR00030##
[0294] Potassium hydroxide (37.9 g, 0.67 mol) was suspended in 200
ml of dry ethanol, formamidine acetate (28.1 g, 0.27 mol) and
diethyl oxalpropionate (50 ml, 0.27 mol) were added and the
reaction mixture was stirred under reflux overnight. The reaction
mixture was cooled to room temperature and the precipitate formed
was filtered, washed with ethanol and diethyl ether, dissolved in
200 ml of water and the solution obtained acidified by a 37%
aqueous solution of hydrochloric acid until pH=2. The acidic
aqueous solution was concentrated under vacuum and the residue
obtained was suspended and stirred in 100 ml of methanol. The
insoluble inorganic salts were filtered off. The solution was
concentrated. 15 g (97.4 mmol) of the desired compound were
obtained.
##STR00031##
was synthesized in analogy to Intermediate 1a, starting from
acetamidine hydrochloride.
##STR00032##
[0295] Potassium-tert-butylate (185.4 g, 1.65 mol) was dissolved in
650 ml of dry ethanol and added slowly at -10.degree. C. to a
suspension of 2-ethyl-3-oxo-succinic-acid diethyl ester (274.3 g,
1.27 mol) and formamidine acetate (171.4 g, 1.65 mol). The reaction
mixture was stirred at room temperature overnight, concentrated in
vacuum and ice water was added. The mixture was acidified by a 37%
aqueous solution of hydrochloric acid until pH=5 and extracted with
chloroform. After drying the organic layer, evaporation of the
solvent in vacuum and crystallization from ethyl acetate/hexane
(2:3) gave 38 g (0.19 mol) of the desired compound.
##STR00033##
[0296] A suspension of sodium tert-butoxide (3.9 g, 40.5 mmol) in
25 ml dry ethanol was added to a solution of diethyl oxalpropionate
(3.0 ml, 16.2 mmol) and O-methylisourea hydrochloride (2.15 g, 19.5
mmol) in 25 ml dry ethanol and the reaction mixture was refluxed
for 18 h. The reaction mixture was allowed to cool to room
temperature and the precipitate removed by filtration. The filtrate
was concentrated in vacuum, and the residue was purified by
reversed phase HPLC to give the desired product (752 mg, 3.5
mmol).
##STR00034##
[0297] Intermediate 1d (550 mg, 2.6 mmol) was dissolved in a 4 M
aqueous solution of sodium hydroxide (3.0 ml, 12.0 mmol) and
stirred for 3 h at room temperature. The reaction mixture was
acidified with concentrated hydrochloric acid to yield the desired
product as precipitate (443 mg, 2.4 mmol).
##STR00035##
[0298] Intermediate 1a (7.0 g, 45.4 mmol) was suspended in 35 ml of
thionyl chloride (0.45 mol), 0.10 ml of DMF was added and the
reaction mixture was refluxed for 1 h. The reaction mixture was
concentrated in vacuum. 8.6 g (45 mmol) of the desired product were
obtained and used in the next steps without further
purification.
##STR00036##
was synthesized in analogy to Intermediate 2a, starting from
Intermediate 1b.
##STR00037##
was synthesized in analogy to Intermediate 2a, starting from
Intermediate 1e.
##STR00038##
[0299] Potassium carbonate (43.34 g, 0.31 mol) was suspended in 350
ml of dry ethanol. A solution of Intermediate 2a (20 g, 0.10 mol)
in 10 ml of dichloromethane was added slowly at 0.degree. C. The
reaction mixture was allowed to reach room temperature and stirred
for 1 h. Potassium carbonate was filtered off and the solvent was
removed under vacuum. The crude product was purified by flash
chromathography (BIOTAGE SP1; silica gel cartridge: 65i; eluent:
dichloromethane/ethyl acetate=95/5%). 5.3 g (26 mmol) of the
desired compound were obtained.
##STR00039##
was synthesized in analogy to Intermediate 3a, starting from
Intermediate 2b.
##STR00040##
[0300] Intermediate 1c (38 g, 0.19 mol) was added to a mixture of
phosphorpentachloride (40.3 g, 0.19 mol) in 240 ml of
phosphoroxychloride. The reaction mixture was refluxed until a
clear solution was observed. The reaction mixture was concentrated
in vacuum. The crude product obtained was purified by destillation
in vacuum. 12 g (94.5 mmol) of the desired compound were obtained
and used in the next steps without further purification.
##STR00041##
[0301] 5-Bromo-6-hydroxy-pyrimidine-4-carboxylic acid ethyl ester
(63 g, 0.26 mol) was suspended in 140 ml of phosphoroxychloride.
Phosphorpentachloride (54 g, 0.26 mmol) was added and the reaction
mixture was refluxed 72 h. The reaction mixture was concentrated in
vacuum and the crude product was suspended and stirred in warmed-up
hexane (50.degree. C.); a precipitate was formed and filtered off.
The filtrate was concentrated under vacuum to obtain 64 g (243
mmol) of the desired product which was used in the next steps
without further purification.
##STR00042##
[0302] 3-Phenylcyclohexanone (500 mg, 2.87 mmol) and
1-isocyanomethanesulfonyl-4-methyl-benzene (750 mg, 3.84 mmol) in
10 ml of 1,2-dimethoxyethane were stirred at 0.degree. C. A
solution of potassium tert-butoxide (650 mg, 5.79 mmol) in 10 ml of
1,2-dimethoxyethane and 20 ml of tert-butanol was added dropwise
and the reaction mixture was allowed to reach room temperature and
stirred overnight. The reaction mixture was diluted with diethyl
ether and washed with ice water. The organic phase was separated,
washed with brine, dried over sodium sulfate and concentrated under
vacuum. 439 mg (2.3 mmol) of the desired product were obtained.
##STR00043##
was synthesized in analogy to Intermediate 4a, starting from
(R)-3-Phenylcyclohexanone.
[0303] GC/MS (method 3A) R.sub.t=11.52 min and 11.68 min
(diastereoisomeric mixture)
[0304] [M].sup.+=185
##STR00044##
was synthesized in analogy to Intermediate 4a, starting from
(S)-3-Phenylcyclohexanone.
[0305] GC/MS (method 3A) R.sub.t=11.50 min and 11.65 min
(diastereoisomeric mixture)
[0306] [M].sup.+=185
[0307] The following intermediates were synthesized in analogy to
Intermediates 4a.
TABLE-US-00009 Starting Inter- ketone mediate STRUCTURE
3-(4-Chloro- phenyl)- cyclohexanone 4d ##STR00045## 3-(4-Fluoro-
phenyl)- cyclohexanone 4e ##STR00046## 3-(4-Methoxy- phenyl)-
cyclohexanone 4f ##STR00047## 3-(4-Methyl- phenyl)- cyclohexanone
4g ##STR00048## 3-(3-Fluoro- phenyl)- cyclohexanone 4h ##STR00049##
3-isopropyl- cyclohexanone 4i ##STR00050## 3-(5-Methyl-
furan-2-yl)- cyclohexanone 4j ##STR00051## 3- Phenylcyclo-
pentanone 4k ##STR00052## 3-(4-Chloro- phenyl)- cyclopentanone 4l
##STR00053## 3-(4-Fluoro- phenyl)- cyclopentanone 4m
##STR00054##
##STR00055##
[0308] Intermediate 4j (400 mg, 2.11 mmol) was purified by flash
chromatography (Biotage SP1 cartridge 25 g; eluent:
cyclohexane/ethyl acetate=99/1%). 60 mg (0.22 mmol) of
diastereoisomerically pure cis-intermediate was eluted as second
fraction (relative stereochemistry assigned by NMR).
[0309] GC/MS (method 3A) R.sub.t=9.62 min
[0310] [M].sup.+=189
##STR00056##
[0311] Intermediate 4n (120 mg, 4.22 mmol) was separated by chiral
semipreparative HPLC. 20 mg of enantiomerically pure intermediate
4o were obtained (absolute stereochemistry unknown).
[0312] Chiral HPLC (method 2I (isocratic)) R.sub.t=6.94 min
##STR00057##
[0313] Further elution of the column gave 20 mg of enantiomerically
pure intermediate 4p (absolute stereochemistry unknown).
[0314] Chiral HPLC (method 2I (isocratic)) R.sub.t=7.27
##STR00058##
[0315] Intermediate 4b (2.1 g, 11.28 mmol) was stirred under reflux
in 20 ml of 96% sulfuric acid and 20 ml of water overnight. The
reaction mixture was cooled, treated with a 30% aqueous solution of
sodium hydroxide and ice and washed with dichloromethane. The basic
water phase was treated with 37% aqueous solution of hydrochloric
acid. The acidic aqueous solution was extracted with
dichloromethane. The organic phase was washed with brine, dried
over sodium sulfate and concentrated under vacuum. 1.85 g (9.1
mmol) of the desired compound were obtained as a diastereoisomeric
mixture and used in the next steps without further
purification.
##STR00059##
[0316] Intermediate 5 (1.85 g, 9.06 mmol, mixture of 2
diastereomers) and triethylamine (2.02 ml, 14 mmol) were stirred at
0.degree. C. in 10 ml of tetrahydrofuran. A solution of
ethylchloroformate (1.29 ml, 13.58 mmol) in 5 ml of tetrahydrofuran
was added dropwise and the reaction mixture was stirred at
0.degree. C. for 1 h. Then, 10 ml of a 30% aqueous solution of
ammonium hydroxide were added dropwise and the reaction mixture was
allowed to reach room temperature and stirred overnight. The
reaction mixture was concentrated under vacuum, dissolved with
dichloromethane, washed with a 1M aqueous solution of sodium
hydroxide, washed with brine, dried over sodium sulfate and
concentrated under vacuum. The crude product was purified by flash
chromatography (Isolute silica cartridge 70 g; eluent:
dichloromethane/methanol=99/1%). 145 mg (0.71 mmol) of
diastereoisomerically pure (1R,3R)-3-phenyl-cyclohexanecarboxylic
acid amide (relative stereochemistry assigned by NMR) were
obtained.
[0317] GC/MS (method 3A) R.sub.t=12.88 min
[0318] [M].sup.+=203
##STR00060##
[0319] Further elution of the column gave 230 mg (1.13 mmol) of the
diastereoisomerically pure (1S,3R)-3-phenyl-cyclohexanecarboxylic
acid amide (relative stereochemistry assigned by NMR).
[0320] GC/MS (method 3A) R.sub.t=13.03 min
[0321] [M].sup.+=203
##STR00061##
[0322] Intermediate 4c (300 mg, 1.61 mmol) was stirred under reflux
in 2 ml of 96% sulfuric acid and 2 ml of water for 3 h. The
reaction mixture was cooled, treated with a 30% aqueous solution of
sodium hydroxide and ice and washed with ethyl acetate. The organic
phase was washed with brine, dried over sodium sulfate and
concentrated under vacuum. The crude product was purified by flash
chromatography (Isolute silica cartridge 20 g; eluent:
dichloromethane/methanol=99/1%). 37 mg (0.18 mmol) of the
diastereomerically pure (1S,3S)-3-phenyl-cyclohexanecarboxylic acid
amide were obtained (relative stereochemistry assigned by NMR).
[0323] GC/MS (method 3A) R.sub.t=12.88 min
[0324] [M].sup.+=203
##STR00062##
[0325] Further elution of the column gave 40 mg of the
diastereomerically pure (1R,3S)-3-phenyl-cyclohexanecarboxylic acid
amide (0.2 mmol) (relative stereochemistry assigned by NMR).
[0326] GC/MS (method 3A) R.sub.t=13.03 min
[0327] [M].sup.+=203
##STR00063##
[0328] 5-Bromo-3-furan carboxylic acid (1.0 g, 5.23 mmol),
phenylboronic acid (0.77 g, 6.28 mmol),
tetrakis(triphenylphosphine)palladium(0) (1.21 g, 1.04 mmol) and a
2M solution of sodium carbonate (6.28 ml, 12.57 mmol) were
dissolved in 12 ml of 1,2-dimethoxy-ethane and the reaction mixture
was stirred under nitrogen atmosphere at 80.degree. C. for 18 h.
The reaction mixture was cooled to room temperature, diluted with
dichloromethane and treated with a 1M aqueous solution of
hydrochloric acid until pH 1. The organic phase was separated,
dried over sodium sulphate and concentrated under vacuum. The
carboxylic acid was obtained and used without further purification
for the synthesis of intermediate 6e in analogy to intermediate
6a.
##STR00064##
[0329] Intermediate 6f was synthesized in analogy to intermediate
6a, starting from trans 3-(4-chlorophenyl)-cyclobutan carboxylic
acid (prepared as described in literature for the preparation of
trans 3-phenyl-cyclobutan-carboxylic acid: Wiberg, K. B.; Dailey,
W. P.; Walker, F. H.; Waddell, S. T.; Crocker, L. S.; Newton, M.
Journal of the American Chemical Society; 1985, 107,
7247-7257).
##STR00065##
[0330] Intermediate 6g was synthesized in analogy to Intermediate
6a, starting from cis 3-(4-chlorophenyl)-cyclobutan carboxylic acid
(prepared as described in literature for the preparation of cis
3-phenyl-cyclobutan-carboxylic acid: Wiberg, K. B.; Dailey, W. P.;
Walker, F. H.; Waddell, S. T.; Crocker, L. S.; Newton, M. Journal
of the American Chemical Society; 1985, 107, 7247-7257).
##STR00066##
[0331] Intermediate 4a (390 mg, 2.10 mmol) and Raney-Nickel (10 mg)
in 10 ml of 1M solution of ammonia in ethanol was stirred under a
hydrogen atmosphere (4 bar) overnight. The reaction mixture was
filtered on a celite pad and concentrated under vacuum. The crude
product was purified by flash chromatography
(dichloromethane/methanol/NH.sub.3(30% aqueous solution)=95/5/0.1%)
to obtain 217 mg (1.15 mmol) of the desired product.
##STR00067##
[0332] 2.85 ml of a 1M solution of lithium aluminium hydride (2.85
mmol) in tetrahydrofuran was dissolved in 10 ml of tetrahydrofuran
and stirred at 0.degree. C. under nitrogen atmosphere. Intermediate
6a (145 mg, 0.71 mmol) in 10 ml of tetrahydrofuran was added
dropwise. The reaction mixture was stirred at 0.degree. C. for 2 h
and then quenched with water and ice. The reaction mixture was
extracted with dichlorometane. The organic phase was washed with a
1M aqueous solution of sodium hydroxide, brine, dried over sodium
sulfate and concentrated under vacuum. 100 mg (0.55 mmol) of the
desired product were obtained.
[0333] GC/MS (method 3A) R.sub.t=11.53 min
[0334] [M].sup.+=189
##STR00068##
was synthesized in analogy to Intermediate 7b, starting from
Intermediate 6b.
[0335] GC/MS (method 3A) R.sub.t=11.47 min
[0336] [M].sup.+=189
##STR00069##
was synthesized in analogy to Intermediate 7b, starting from
Intermediate 6c.
[0337] GC/MS (method 3A) R.sub.t=11.53 min
[0338] [M].sup.+=189
##STR00070##
was synthesized in analogy to Intermediate 7b, starting from
Intermediate 6d.
[0339] GC/MS (method 3A) R.sub.t=13.03 min
[0340] [M].sup.+=189
[0341] The following intermediates were synthesised in atalogy to
Intermediate 7a.
TABLE-US-00010 Starting Inter- Inter- mediate mediate STRUCTURE 4d
7f ##STR00071## 4e 7g ##STR00072## 4f 7h ##STR00073## 4g 7i
##STR00074## 4h 7j ##STR00075## 4i 7k ##STR00076## 4k 7l
##STR00077## 4l 7m ##STR00078## 4m 7n ##STR00079## 4n 7o
##STR00080## 4o 7p ##STR00081## 4p 7q ##STR00082##
##STR00083##
was synthesized in analogy to intermediate 7b, starting from
intermediate 6e.
##STR00084##
was synthesized in analogy to intermediate 7b, starting from
intermediate 6f.
##STR00085##
was obtained and isolated as side product in the preparation of
Intermediate 7s
##STR00086##
was synthesized in analogy to Intermediate 7b, starting from
Intermediate 6g.
##STR00087##
was obtained and isolated as side product in the preparation of
Intermediate 7u.
##STR00088##
[0342] Tris(dibenzylideneacetone)dipalladium (1.71 g, 1.87 mmol)
and 2,2'-bis(diphenylphosphino)-1,1'-binaphtyl (2.32 g, 3.72 mmol)
were stirred in 30 ml of toluene for 10 min under argon
athmosphere.
[0343] Piperidine-3-yl-methyl-carbamic acid tert-butyl ester (2 g,
9.33 mmol), bromobenzene (1.27 ml, 0.01 mol) and sodium
tert-butoxide (1.43 g, 14.93 mmol) were added and the reaction
mixture was stirred under reflux overnight. The reaction mixture
was concentrated under vacuum, the crude product was dissolved in
dichlorometane and the organic phase was filtered on a celite pad.
The organic phase was washed with an aqueous saturated sodium
carbonate solution, with brine, dried over sodium sulfate,
concentrated under vacuum. The crude product obtained was dissolved
in methanol and loaded onto a SCX cartridge (25 g). After washing
with methanol the product was eluted with a 2M solution of ammonia
in methanol. 1.17 g (4.03 mmol) of the desired product were
obtained and used in next steps without any other purification.
##STR00089##
[0344] To a solution of Intermediate 8a (1.1 g, 3.79 mmol) in 10 ml
of 1,4-dioxane, a 4M solution of hydrochloric acid in 1,4-dioxane
(15 ml, 60 mmol) was added dropwise; the reaction mixture was
stirred at room temperature overnight before being concentrated
under vacuum. The crude product was purified by flash
chromatography (Isolute silica gel cartride: 50 g; eluent:
dichloromethane/methanol=95/5%). 250 mg (1.31 mmol) of the desired
compound were obtained.
[0345] The following intermediates were synthesized in analogy to
Intermediates 8a and 9a.
TABLE-US-00011 Starting Starting Inter- Inter- amine bromide
mediate STRUCTURE mediate STRUCTURE (S)-1- Pyrrolidin-3- ylmethyl-
carbamic acid tert- butyl ester bromo- benzene 8b ##STR00090## 9b
##STR00091## (R)-1- Pyrrolidin-3- ylmethyl- carbamic acid tert-
butyl ester bromo- benzene 8c ##STR00092## 9c ##STR00093##
Piperidine-3- yl-methyl- carbamic acid tert- butyl ester 1-bromo-
4-trifluoro methyl- benzene 8d ##STR00094## 9d ##STR00095##
##STR00096##
[0346] Piperidine-3-yl-methyl-carbamic acid tert-butyl ester (100
mg, 0.47 mmol), 2-chloro-4-fluoro-benzonitrile (72.5 mg, 0.47 mmol)
and N,N-diisopropylethylamine (0.160 ml, 1.23 mmol) were dissolved
in 10 ml of DMF and the reaction mixture was stirred at 125.degree.
C. overnight. The reaction mixture was concentrated under vacuum
and the crude product was purified by flash chromatography (Isolute
silica gel cartride: 5 g; eluent: ethyl acetate). 125 mg (0.36
mmol) of the desired compound were obtained.
##STR00097##
[0347] To a solution of Intermediate 10 (125 mg, 0.36 mmol) in 5 ml
of 1,4-dioxane, a 4M solution of hydrochloric acid in 1,4-dioxane
(0.12 ml, 480 mmol) was added dropwise; the reaction mixture was
stirred at room temperature overnight before being concentrated
under vacuum. 102 mg (0.36 mmol) of the desired compound were
obtained.
##STR00098##
[0348] A solution of 4-methanesulfonylamino-piperidine-1-carboxylic
acid tert-butyl ester (500 mg; 1.79 mmol) in 5 ml of acetonitrile
was cooled to -5.degree. C., iodoethane (308 mg, 1.79 mmol) and
sodium hydride (96 mg, 3.59 mmol) were added; the reaction mixture
was allowed to warm to room temperature and stirred for 72 h.
[0349] The reaction mixture was concentrated under vacuum; the
residue was dissolved in ethyl acetate and washed with an aqueous
saturated sodium bicarbonate solution and then with water.
[0350] The organic phase was dried over sodium sulfate, filtered
and concentrated under vacuum. The crude product was purified by
flash chromatography (Isolute silica gel cartridge: 10 g, eluent:
dichloromethane) to obtain 332 mg (1.1 mmol) of the desired
compound.
##STR00099##
[0351] To a solution of intermediate 12 (330 mg, 1.1 mmol) in 20 ml
of 1,4-dioxane, a 4M solution of hydrochloric acid in 1,4-dioxane
(4.06 ml, 16 mmol) was added dropwise; the reaction mixture was
stirred at room temperature overnight. The reaction mixture was
concentrated under vacuum to obtain 262 mg (1.1 mmol) of the
desired compound.
##STR00100##
[0352] trans-4-Azido-3-methoxy-piperidine-1-carboxylic acid
tert-butyl ester (1.6 g, 6.24 mmol), Pd/C 10% (200 mg) and acetic
acid (1.6 ml) were dissolved in 25 ml of methanol and the reaction
mixture was stirred under hydrogen atmosphere (4 bar) for 3 h. The
reaction mixture was filtered on a celite pad and concentrated
under vacuum. The crude product was purified by flash
chromatography (Biotage SP1 cartridge 65i, eluent:
dichloromethane/methanol=95/5%). 900 mg (3.91 mol) of the desired
compound were obtained.
##STR00101##
[0353] Intermediate 14 (900 mg, 3.91 mmol) and
N,N-diisopropylethylamine (0.86 ml, 5 mmol) were dissolved in 25 ml
of dichloromethane. The reaction mixture was cooled to 0.degree. C.
and methanesulfonylchloride (0.33 ml, 4.30 mmol) was added. The
reaction mixture was stirred at 0.degree. C. for 20 min, then,
water was added. The organic phase was separated, washed with an
aqueous saturated sodium bicarbonate solution, dried over sodium
sulfate and concentrated under vacuum. The crude product was
purified by flash chromatography (Isolute silica cartridge: 10 g,
eluent: hexane/ethyl acetate=50/50%). 170 mg (0.55 mol) of the
desired compound were obtained.
##STR00102##
[0354] Intermediate 15a (350 mg, 1.13 mmol) and potassium carbonate
(157 mg, 1.13 mmol) were dissolved and stirred in 15 ml of
acetonitrile. A solution of iodomethane (0.071 ml, 1.13 mmol) in 5
ml of acetonitrile was added dropwise and the reaction mixture was
warmed to 60.degree. C. overnight. The reaction mixture was
concentrated under vacuum and the crude product was dissolved in
ethyl acetate. The organic phase was washed with an aqueous
saturated sodium bicarbonate solution, separated, dried over sodium
sulfate and concentrated under vacuum. 300 mg (0.93 mmol) of the
desired compound were obtained and used in the next steps without
further purification.
##STR00103##
[0355] Intermediate 15a (170 mg, 0.55 mmol) in 2 ml of 1,4-dioxane
was stirred at 10.degree. C. A 4M solution of hydrochloric acid in
1,4-dioxane (8 ml, 32 mmol) was added dropwise and the reaction
mixture was stirred at room temperature for 5 h. The reaction
mixture was concentrated under vacuum to obtain 115 mg (0.55 mmol)
of the desired compound.
##STR00104##
was synthesized in analogy to Intermediate 16a, starting from
Intermediate 15b.
##STR00105##
was synthesized in analogy to Intermediate 15a, starting from
(3S,4R)-4-amino-3-methoxy-piperidine-1-carboxylic acid tert-butyl
ester.
##STR00106##
[0356] Intermediate 17 (660 mg, 2.14 mmol) in 10 ml of 1,4-dioxane
was stirred at 10.degree. C. Trifluoroacetic acid (2 ml, 26 mmol)
was added dropwise and the reaction mixture was stirred at room
temperature 18 h. The reaction mixture was concentrated under
vacuum to obtain 600 mg (1.86 mmol) of the desired compound, used
in the next step without further purification.
##STR00107##
[0357] N-methyl-N-piperidin-4-yl-methanesulfonamide hydrochloride
(11 g, 47.91 mmol) was suspended in 200 ml of 1,2-dichloroethane,
N,N-diisopropylethylamine (17.12 ml, 96.17 mmol) and
1-(tert-butoxycarbonyl)-piperidin-4-one (9.58 g, 48.08 mmol) were
added and the reaction mixture was stirred at room temperature for
30 min. Sodium triacetoxyborohydride (12.23 g, 57.50 mmol) was
added and the reaction mixture was stirred at room temperature for
72 h. The reaction mixture was diluted with dichloromethane and
washed with an aqueous saturated sodium bicarbonate solution.
[0358] The organic phase was dried over sodium sulfate and
concentrated under vacuum. The crude product was purified by flash
chromatography (Biotage SP1; silica gel cartridge: 65i; eluent:
ethyl acetate/methanol=50/50%) to obtain 7.2 g (19.2 mmol) of the
desired compound.
##STR00108##
[0359] Intermediate 19a (7.2 g, 19.2 mmol) was suspended in 20 ml
of 1,4-dioxane, a 4M solution of hydrochloric acid (48 ml, 192
mmol) in 1,4-dioxane was added dropwise. The reaction mixture was
stirred at room temperature overnight. The reaction mixture was
concentrated under vacuum. 6.3 g (18 mmol) of the desired compound
were obtained.
[0360] The following intermediates were synthesized in analogy to
Intermediates 19a and 20a.
TABLE-US-00012 Carba- mate Diamino Starting Starting Inter- Inter-
ketone amine mediate STRUCTURE mediate STRUCTURE 1-(tert- butoxy-
carbonyl)- 4-oxo- piperidine Ethane- sulfonic acid methyl- piperi-
din-4-yl- amide 19b ##STR00109## 20b ##STR00110## 1-(tert- butoxy-
carbonyl)- 4-oxo- piperidine (R)-N- Pyrrol- idin-3- yl- methane
sulfona- mide 19c ##STR00111## 20c ##STR00112## 1-(tert- butoxy-
carbonyl)- 4-oxo- piperidine (S)-N- Pyrrol- idin-3- yl- methane
sulfona- mide 19d ##STR00113## 20d ##STR00114## 1-(tert- butoxy-
carbonyl)- 4-oxo- piperidine Ethane- sulfonic acid piperi-
din-4-yl- amide 19e ##STR00115## 20e ##STR00116## 1-(tert- butoxy-
carbonyl)- 4-oxo- piperidine Piperi- dine-4- carbox- ylic acid
methyl amide 19f ##STR00117## 20f ##STR00118## 1-(tert- butoxy-
carbonyl)- 4-oxo- piperidine Piperi- dine-4- sulfo-nic acid methyl
amide 19g ##STR00119## 20g ##STR00120## 1-(tert- butoxy- carbonyl)-
4-oxo- piperidine (R)- Pyrrol- idine-3- carbox- ilic acid methyl-
amide 19h ##STR00121## 20h ##STR00122## 1-(tert- butoxy- carbonyl)-
4-oxo- piperidine (S)- Pyrrol- idine-3- carbox- ilic acid methyl-
amide 19i ##STR00123## 20i ##STR00124## 1-(tert- butoxy- carbonyl)-
4-oxo- piperidine (S)- Pyrrol- idine-3- carbox- ilic acid amide 19j
##STR00125## 20j ##STR00126## 1-(tert- butoxy- carbonyl)- 4-oxo-
piperidine 16a 19k ##STR00127## 20k ##STR00128## 1-(tert- butoxy-
carbonyl)- 4-oxo- piperidine (R)- Pyrrol- idine-3- carbox- ilic
acid amide 19l ##STR00129## 20l ##STR00130## 1-(tert- butoxy-
carbonyl)- 4-oxo- piperidine 47b 19lf ##STR00131## 20lf
##STR00132## 1-(tert- butoxy- carbonyl)- 4-oxo- piperidine 47c 19lg
##STR00133## 20lg ##STR00134##
##STR00135##
[0361] 4-Methylamino-piperidine-1-carboxylic acid tert-butyl ester
(500 mg, 1.87 mmol) was suspended in 10 ml of 1,2-dichloroethane.
Tetrahydro-pyran-4-one (0.17 ml, 1.87 mmol) was added and the
reaction mixture was stirred at room temperature for 30 min. Sodium
triacetoxyborohydride (593 mg, 2.80 mol) was added and the reaction
mixture was stirred for 18 h. The reaction mixture was diluted with
dichloromethane and washed with an aqueous saturated sodium
bicarbonate solution.
[0362] The organic phase was dried over sodium sulfate and
concentrated under vacuum. The crude product was purified by flash
chromatography (Isolute silica gel cartridge 10 g; eluent:
dichloromethane/methanol=94/6%). 240 mg (0.80 mmol) of the desired
compound were obtained.
##STR00136##
[0363] Intermediate 191a (240 mg, 0.80 mmol) was suspended in 10 ml
of 1,4-dioxane, a 4M solution of hydrochloric acid (2.0 ml, 8.0
mmol) in 1,4-dioxane was added dropwise. The reaction mixture was
stirred at room temperature for 18 h. The reaction mixture was
concentrated under vacuum. 200 mg (0.74 mmol) of the desired
compound were obtained.
[0364] The following intermediates were synthesized in analogy to
Intermediates 191a and 201a
TABLE-US-00013 Carba- mate Amino Starting Starting Inter- Inter-
amine ketone mediate STRUCTURE mediate STRUCTURE 4- Methyl- amino-
piperi- dine-1- carb- oxylic acid tert- butyl ester 3- Methoxy-
tetrahy- dro-pyran- 4-one 19lb ##STR00137## 20lb ##STR00138## 4-
Methyl- amino- piperi- dine-1- carb- oxylic acid tert- butyl ester
2,6- dimethyl- tetra- hydro- pyran-4- one 19lc ##STR00139## 20lc
##STR00140## 4- Methyl- amino- piperi- dine-1- carb- oxylic acid
tert- butyl ester 4,4- difluoro- cyclo- hexa- none 19ld
##STR00141## 20ld ##STR00142## 4- amino- piperi- dine-1- carb-
oxylic acid tert- butyl ester 3- Methoxy- tetrahy- dro-pyran- 4-one
19le ##STR00143## 20le ##STR00144##
##STR00145##
[0365] N-methyl-N-piperidin-4-yl-methanesulfonamide hydrochloride
(1.13 g, 4.95 mmol) was suspended in 10 ml of 1,2-dichloroethane,
N,N-diisopropylethylamine (2.6 ml, 14.9 mmol) and
N-carbethoxy-3-methoxy-piperidin-4-one (1 g, 4.95 mmol) were added
and the reaction mixture was stirred at room temperature for 30
min. Sodium triacetoxyborohydride (3.16 g, 14.85 mol) was added and
the reaction mixture was stirred at room temperature for 72 h. The
reaction mixture was diluted with dichloromethane and washed with
an aqueous saturated sodium bicarbonate solution.
[0366] The organic phase was dried over sodium sulfate and
concentrated under vacuum. 1.5 g (3.97 mmol) of the desired
compound were obtained and used without further purification.
##STR00146##
[0367] Intermediate 19m (1.5 g, 3.97 mmol) and potassion hydroxide
(4.46 g, 7.94 mmol) were suspended in 25 ml of ethanol and the
reaction mixture was stirred under reflux overnight.
[0368] The reaction mixture was concentrated under vacuum and the
crude product was loaded on a SCX cartridge (25 g) and eluted with
a 2M solution of ammonia in methanol. 1.2 g (3.97 mmol) of the
desired compound were obtained.
##STR00147##
[0369] Piperidin-4-yl-carbamic acid tert-butyl ester (6 g, 30 mmol)
and 1-(benzyloxycarbonyl)-4-oxopiperidine (9.6 g, 48 mmol) were
dissolved in 50 ml of dichloromethane and the reaction mixture was
stirred at room temperature for 30 min; sodium
triacetoxyborohydride (12.23 g, 57.5 mmol) was added and the
reaction mixture was stirred at room temperature overnight.
[0370] The reaction mixture was diluted with dichloromethane and
washed with an aqueous saturated sodium bicarbonate solution. The
organic phase was dried over sodium sulfate and concentrated under
vacuum. The crude product was treated with acetone/isopropyl ether
and the precipitate obtained was filtered off 8.4 g (20 mmol) of
the desired product were obtained.
##STR00148##
[0371] To a solution of intermediate 21 (8.4 g, 20 mmol) in 150 ml
of 1,4-dioxane previously cooled to 0.degree. C., 12.6 ml (50 mmol)
of a 4M solution of hydrochloric acid in 1,4-dioxane were added
dropwise; the reaction mixture was allowed to warm to room
temperature and was stirred at that temperature overnight. The
solid precipitated from the reaction mixture was filtered off and
dried at 50.degree. C. under vacuum to obtain 6 g (15 mmol) of the
desired compound.
##STR00149##
[0372] Intermediate 22 (6.0 g, 15 mmol) was suspended in 55 ml of
dichloromethane; triethylamine (6.43 ml, 46 mmol) was added and the
reaction mixture was cooled to 0.degree. C. and stirred at that
temperature for 30 min. Methanesulfonyl chloride (1.43 ml, 18 mmol)
in 5 ml of dichloromethane was added dropwise. The reaction mixture
was stirred at 0.degree. C. for 1 h; then water was added and the
reaction mixture was extracted with dichloromethane. The organic
phase was washed with an aqueous saturated sodium bicarbonate
solution, with brine, dried over sodium sulfate and concentrated
under vacuum. The crude product was treated with diisopropyl ether,
the precipitate was filtered off and dried. 5 g (13 mmol) of the
desired product were obtained.
##STR00150##
[0373] Intermediate 23 (5 g, 13 mmol) was dissolved in 50 ml of
methanol; acetic acid (1.5 ml, 25.3 mmol) and Pd/C 10% (500 mg)
were added in sequence and the reaction mixture was stirred under a
hydrogen atmosphere (3 bar) at room temperature for 5 days. The
reaction mixture was filtered on a celite pad and the organic phase
was loaded on a SCX cartridge (10 g). After washing with methanol,
the desired compound was eluted with a 2M solution of ammonia in
methanol. 3.7 g (4.6 mmol) of the title compound were obtained.
##STR00151##
[0374] Intermediate 24 (1.1 g, 4.21 mmol) was suspended in 20 ml of
dry dichloromethane, N,N-diisopropylethylamine (1.47 ml, 8.42 mmol)
and DMF (137 .mu.l, 1.67 mmol) were added and the reaction mixture
was stirred under nitrogen atmosphere and cooled to 0.degree. C.
Intermediate 2a (812 mg, 4.21 mmol) in 5 ml of dichloromethane was
added dropwise and the reaction mixture was allowed to warm up to
room temperature and stirred for 1.5 h; the reaction mixture was
diluted with dichloromethane and washed with an aqueous saturated
sodium bicarbonate solution. The organic phase was separated, dried
over sodium sulfate and concentrated under vacuum. The crude
product was purified by flash chromatography (isolute silica gel
cartridge: 10 g; eluent: dichloromethane/methanol=95/5%). 1.0 g
(2.41 mmol) of the title compound were obtained.
[0375] The following intermediates were synthesized in analogy to
Intermediate 25a.
TABLE-US-00014 Chloro- Piper- pyrim- Core idine idine Inter- Inter-
Inter- mediate mediate mediate STRUCTURE 2a 20a 25b ##STR00152## 2a
20b 25c ##STR00153## 2a 20f 25d ##STR00154## 2a 20h 25e
##STR00155## 2a [1,4']-Bi- piperidinyl- 4-ol 25f ##STR00156## 2a
4-Methoxy- [1,4']bi- piperidinyl 25g ##STR00157## 2a 4-Piperidin-
4-yl-morpho- line 25h ##STR00158## 2a [1,4']Bi- piperidinyl 25i
##STR00159## 2a [1,4']-Bi- piperidinyl- 3-ol 25j ##STR00160## 2b 24
25k ##STR00161## 2b 20a 25l ##STR00162## 2b [1,4']-Bi- piperidinyl-
4-ol 25m ##STR00163## 2c 20a 25n ##STR00164## 2a 20le 25o
##STR00165##
##STR00166##
[0376] Intermediate 3a (10 g, 49.35 mmol) and
N,N-diisopropylethylamine (17 ml, 99 mmol) were dissolved in 20 ml
of dry DMF; 2-(3,4-dichloro-phenyl)-ethylamine (9.57 g, 49.35 mmol)
in 10 ml of dry DMF was added and the reaction mixture was stirred
at 90.degree. C. for 2 h. The reaction mixture was cooled to room
temperature, water was added and the reaction mixture was extracted
with dichloromethane; the organic phase was concentrated under
vacuum, the crude product was suspended and stirred in diethyl
ether and the precipitate was filtered off and dried. 10.2 g (28.8
mmol) of the desired compound were obtained.
##STR00167##
[0377] Intermediate 26a (10.0 g, 28.25 mmol) was dissolved in 70 ml
of ethanol and a solution of LiOH (3.52 g, 83.88 mmol) in 70 ml of
water was added. The reaction mixture was stirred at 70.degree. C.
for 1 hour, concentrated under vacuum and the remaining aqueous
solution was acidified by 20 ml of 4M solution of hydrochloric acid
in 1,4-dioxane; the precipitate formed was filtered off and dried.
8.6 g (26.37 mmol) of the desired product were obtained.
[0378] The following intermediates were synthesized in analogy to
Intermediates 26a and 27a.
TABLE-US-00015 Ester Acid Core- Inter- Inter- Inter- medi- medi-
mediate Amine ate STRUCTURE ate STRUCTURE 3a 3,4- Dichloro- benzyl-
amine 26b ##STR00168## 27b ##STR00169## 3a 4-tert-butyl- benzyl-
amine 26c ##STR00170## 27c ##STR00171## 3a biphenyl-3- ylmethan-
amine 26d ##STR00172## 27d ##STR00173## 3b 4-tert-butyl- benzyl-
amine 26e ##STR00174## 27e ##STR00175## 3c 2-(3,4- dichloro-
phenyl)- ethylamine 26f ##STR00176## 27f ##STR00177## 3c
biphenyl-3- yl-methan- amine 26g ##STR00178## 27g ##STR00179## 3d
biphenyl-3- yl-methan- amine 26h ##STR00180## 27h ##STR00181## 3a
Inter- mediate 7c 26ha ##STR00182## 27ha ##STR00183## 3d Inter-
mediate 7c 26hb ##STR00184## 27hb ##STR00185## 3a Inter- mediate 7p
26hc ##STR00186## 27hc ##STR00187## 3a Inter- mediate 7q 26hd
##STR00188## 27hd ##STR00189## 3a Inter- mediate 7t 26he
##STR00190## 27he ##STR00191## 3a Inter- mediate 7v 26hf
##STR00192## 27hf ##STR00193## 3b Inter- mediate 7t 26hr
##STR00194## 27hr ##STR00195## 3b Inter- mediate 7v 26hs
##STR00196## 27hs ##STR00197##
##STR00198##
[0379] Intermediate 3d (2 g, 7.53 mmol) and
N,N-diisopropylethylamine (1.97 ml, 11.3 mmol) were dissolved in 15
ml of dry DMF; 4-tertbutyl-benzylamine (1.6 ml, 9.04 mmol) was
added and the reaction mixture was stirred at 60.degree. C. for 18
h. The reaction mixture was cooled to room temperature, water was
added and the reaction mixture was extracted with dichloromethane;
the organic phase was concentrated under vacuum and the crude
product was purified by flash chromatography (BIOTAGE SP1; silica
gel cartridge: 65i; eluent: hexane/ethyl acetate=70/30%). 1.5 g
(3.82 mmol) of the desired compound were obtained.
##STR00199##
[0380] Intermediate 26hb (75 mg, 179 .mu.mol), tributyl(vinyl)tin
(200 .mu.A, 685 .mu.mol) and bis(triphenylphosphine)palladium
chloride (13 mg, 18 .mu.mol) were added to 3 ml 1,2-dichloroethane.
The reaction mixture was heated in the microwave for 4 h at
120.degree. C. Then, the solvent was removed in vacuum and the
residue was purified by reversed phase HPLC to give the desired
product (56 mg, 117 mmol).
##STR00200##
was synthesized in analogy to intermediate 26ib, starting from
intermediate 26hb and tributyl(ethynyl)tin.
##STR00201##
[0381] Intermediate 26i (500 mg, 1.27 mmol) and CuCN (114 mg, 1.27
mmol) were dissolved in 5 ml of DMA and the reaction mixture was
stirred at 100.degree. C. overnight. The reaction mixture was
cooled, diluted with dichloromethane and the organic phase was
washed with water, dried over sodium sulfate and concentrated under
vacuum. 30 mg (0.1 mmol) of the crude product were obtained and
used in the next step without purification.
##STR00202##
was synthesized in analogy to 27a starting from intermediate
26ib.
##STR00203##
was synthesized in analogy to 27a starting from intermediate
26ic.
##STR00204##
[0382] Intermediate 27a (4 g, 12.14 mmol), TBTU (3.9 g, 12.14 mmol)
and N,N-diisopropylethylamine (5.34 ml, 30.35 mmol) were dissolved
in 25 ml of DMF. The reaction mixture was stirred under nitrogen
atmosphere at room temperature for 30 min; then piperidin-4-one
hydrochloride (1.66 g, 12.14 mmol) was added and the reaction
mixture was stirred at room temperature overnight. The reaction
mixture was concentrated under vacuum and the crude product was
dissolved in dichloromethane. The organic phase was washed with a
saturated aqueous solution of sodium bicarbonate, with a 1M aqueous
solution of sodium hydroxide, with brine, then dried over sodium
sulfate, filtered and concentrated under vacuum. The crude product
was purified by flash chromatography (BIOTAGE SP1; silica gel
cartridge: 65i; eluent: dichloromethane/methanol=95/5%). 2.2 g (5.4
mmol) of the desired compound were obtained.
[0383] The following intermediates were synthesized in analogy to
intermediate 28a.
TABLE-US-00016 Acid Inter- Inter- mediate Amine mediate STRUCTURE
27b Piperidin-4-one 28b ##STR00205## 27c Piperidin-4-one 28c
##STR00206## 27d Piperidin-4-one 28d ##STR00207## 27g
Piperidin-4-one 28e ##STR00208## 27c Azepan-4-one 28f ##STR00209##
27e Piperidin-4-one 28g ##STR00210##
##STR00211##
[0384] Intermediate 28a (500 mg, 1.22 mmol),
piperazine-1-carboxylic acid tert-butyl ester (228 mg, 1.23 mmol)
and 2-picoline borane complex (131.3 mg, 1.22 mmol) in 15 ml of
methanol were stirred at room temperature for 72 h; the reaction
mixture was concentrated under vacuum and the crude product was
dissolved in dichloromethane. The organic phase was washed with
water, dried over sodium sulfate, filtered and concentrated under
vacuum. The crude product was purified by flash chromatography
(Isolute silica gel cartridge: 20 g; eluent:
dichloromethane/methanol=98/2%). 280 mg (0.48 mmol) of the desired
compound were obtained.
##STR00212##
[0385] Intermediate 29 (280 mg, 0.48 mmol) was dissolved in 6 ml of
1,4-dioxane; 4 ml (16 mmol) of a 4M solution of hydrochloric acid
in 1,4-dioxane were added dropwise and the reaction mixture was
stirred at room temperature overnight. The solvent was concentrated
under vacuum. 240 mg (0.46 mmol) of the desired compound were
obtained.
##STR00213##
[0386] Intermediate 27c (500 mg, 1.67 mmol), TBTU (643 mg, 2 mmol)
and N,N-diisopropylethylamine (0.29 ml, 1.67 mmol) were dissolved
in 5 ml of DMF. The reaction mixture was stirred under nitrogen
atmosphere at room temperature for 10 min;
then[1,4]diazepan-1-carboxylic acid tert-butyl ester (334 mg, 1.67
mmol) was added and the reaction mixture was stirred at room
temperature overnight. The reaction mixture was diluted with
dichloromethane and washed with an aqueous saturated solution of
sodium bicarbonate. The organic phase was separated, dried over
sodium sulfate and concentrated under vacuum. The crude product was
suspended in diisopropyl ether and stirred, the solid obtained was
filtered and dried. 700 mg (1.45 mmol) of the desired compound were
obtained.
##STR00214##
[0387] Intermediate 31 (600 mg; 1.24 mmol) was suspended in 5 ml of
diethyl ether, 5 ml of a 1M solution of hydrochloric acid in
diethyl ether was added dropwise and the reaction mixture was
stirred at room temperature overnight. The solvent was concentrated
under vacuum and the crude product was loaded on a SCX cartridge
(10 g) and eluted with a 2M solution of ammonia in methanol. 470 mg
(1.23 mmol) of the title compound were obtained.
##STR00215##
[0388] Intermediate 3a (1.5 g, 7.47 mmol) and
tetrakis(triphenylphosphine)palladium (143.9 mg, 0.12 mmol) were
suspended in 40 ml of toluene under nitrogen atmosphere;
4-tert-butyl-benzylzinc bromide (29.9 ml, 15 mmol) was added
dropwise and then the reaction mixture was stirred at 20.degree. C.
for 8 h. 5 ml of methanol, 40 ml of water and 100 ml of
dichloromethane were added. The organic phase was separated, dried
over sodium sulfate and concentrated under vacuum. The crude
product obtained was purified by flash chromatography (Biotage
column 40M+; eluent: dichloromethane/ethyl acetate=95/5%). 230 mg
(0.74 mmol) of the desired compound were obtained.
##STR00216##
[0389] To a solution of 4-tert-butylphenylacetylene (5 ml, 28 mmol)
in 20 ml of dry tetrahydrofuran under nitrogen atmosphere, a
solution of catecholborane (3.41 ml, 31 mmol) in 20 ml of dry
tetrahydrofuran was added dropwise. The reaction mixture was
refluxed for 2 h and then concentrated under vacuum; the crude
product obtained was dissolved in ethyl acetate and the organic
phase was washed with a 2 M aqueous solution of hydrochloric acid.
The organic phase was separated, washed with brine, dried over
sodium sulfate and concentrated under vacuum. The crude product
obtained was purified by flash chromatography (Biotage column 40M+;
eluent: dichloromethane/ethyl acetate=95/5%). 230 mg (0.82 mmol) of
the desired compound were obtained.
##STR00217##
[0390] Intermediate 3a (600 mg, 3 mmol), intermediate 34 and
tetrakis(triphenylphosphine)palladium (347 mg, 0.3 mmol) were
dissolved in 3.6 ml of a 2 M aqueous solution of sodium carbonate
and 40 ml of 1,2 dimethoxyethane. The reaction mixture was stirred
at 80.degree. C. overnight. Water was added and the reaction
mixture was extracted with dichloromethane. The organic phase was
separated, dried over sodium sulfate and concentrated under vacuum.
The crude product obtained was purified by flash chromatography
(Biotage column 40M+; eluent: dichloromethane/ethyl acetate=95/5%).
550 mg (1.60 mmol) of the desired compound were obtained.
##STR00218##
[0391] Intermediate 35 (250 mg, 0.77 mmol) was dissolved in 5 ml of
ethanol and 5 ml of tetrahydrofuran. Pd/C (35 mg) was added and the
reaction mixture was stirred under hydrogen atmosphere (1 atm) at
room temperature overnight. The reaction mixture was filtered on a
celite pad and concentrated under vacuum. 170 mg (0.52 mmol) of the
desired compound were obtained.
##STR00219##
[0392] Palladium acetate (170 mg, 0.75 mmol) and
2,2'-bis(diphenylphosphino)-1,1'-binaphtyl (936 mg, 1.5 mmol) were
dissolved in 25 ml of 1,4-dioxane and stirred at 40.degree. C. for
30 minutes. 2-chloro-3-methylpyridine-4-carboxylic acid ethyl ester
(500 mg, 2.5 mmol), 3,4-dichlorobenzylamine (680 mg, 5 mmol) and
cesium carbonate (715.5 mg, 3.76 mmol) were added and the reaction
mixture was refluxed for 48 h. The solvent was concentrated under
vacuum and the crude product was loaded on a SCX cartridge (10 g)
and eluted with a 2M solution of ammonia in methanol. The solvent
was concentrated under vacuum and the crude product obtained was
purified by flash chromatography (Biotage column 25M+; eluent:
ethyl acetate). 250 mg (0.73 mmol) of the desired compound were
obtained.
##STR00220##
[0393] 3-(Bromomethyl)biphenyl (150 mg, 0.58 mmol), sodium
carbonate (188 mg, 1.75 mmol) and 3-amino-2-methyl-benzoic acid
ethyl ester (0.1 ml, 0.58 mmol) were mixed in 2 ml of DMF and
stirred at 100.degree. C. for 2 hours. The solvent was then
concentrated under vacuum and the crude product was purified by
reverse phase preparative HPLC. 131 mg (0.37 mmol) of the desired
compound were obtained.
##STR00221##
[0394] Intermediate 35 (300 mg, 0.92 mmol) was dissolved in 4 ml of
ethanol and 4 ml of water. Lithium hydroxide (194 mg, 4.7 mmol) was
added and the reaction mixture was stirred at 70.degree. C. for 2
h, concentrated under vacuum and the remaining aqueous solution was
acidified by 10 ml of a 4M solution of hydrochloric acid in
1,4-dioxane and extracted with dichloromethane; the organic phase
was separated, washed with brine, dried over sodium sulfate and
concentrated under vacuum. 250 mg (0.84 mmol) of the desired
product were obtained.
[0395] The following intermediates were synthesized in analogy to
intermediate 39a
TABLE-US-00017 Ester Acid Inter- Inter- medi- medi- ate ate
STRUCTURE 33 39b ##STR00222## 36 39c ##STR00223## 37 39d
##STR00224## 38 39e ##STR00225##
##STR00226##
[0396] Intermediate 27c (660 mg, 2.20 mmol), TBTU (849 mg, 2.65
mmol) and N,N-diisopropylethylamine (0.57 ml, 3.31 mmol) were
dissolved in 25 ml DMF. The reaction mixture was stirred under
nitrogen atmosphere at room temperature for 10 min; then piperidin
4-yl carbamic acid tert-butyl ester (441 mg, 2.20 mmol) was added
and the reaction mixture was stirred at room temperature for 18 h.
The reaction mixture was diluted with dichloromethane and washed
with an aqueous saturated solution of sodium bicarbonate. The
organic phase was separated, dried over sodium sulfate and
concentrated under vacuum. The crude product was purified by flash
chromatography (Biotage SNAP column 50 g; eluent:
dichloromethane/methanol=90/10%). 990 mg (2.05 mmol) of the desired
compound were obtained.
##STR00227##
[0397] Intermediate 40a (990 mg, 2.05 mmol) was suspended in 50 ml
of 1,4-dioxane, a 4M solution of hydrochloric acid (8.5 ml, 34
mmol) in 1,4-dioxane was added dropwise. The reaction mixture was
stirred at room temperature for 18 h. The reaction mixture was
concentrated under vacuum. 780 mg (18 mmol) of the desired compound
were obtained.
[0398] The following intermediates were synthesized in analogy to
Intermediates 40a and 41a.
TABLE-US-00018 Carba- mate Amine Starting Starting Inter- Inter-
acid amine mediate STRUCTURE mediate STRUCTURE Inter- mediate 27ha
piperidin 4-yl carbamic acid tert- butyl ester 40b ##STR00228## 41b
##STR00229##
##STR00230##
[0399] 4,4-Difluorocyclohexanone (500 mg, 3.73 mmol) and potassium
hydroxide (502 mg, 8.95 mmol) were disoolved in 10 ml of methanol.
The reaction mixture was cooled to 0.degree. C. and a solution of
iodine (1.04 g, 4.10 mmol) in 20 ml of methanol was added dropwise
within 1 h. The reaction mixture was stirred at room temperature
for 18 h, and then concentrated under vacuum. The crude product was
stirred in 10 ml of dichlorometane and the precipitate was filtered
off. The filtrate was concentrated under vacuum and 480 mg of the
desired product (2.45 mmol) were obtained as an oil.
##STR00231##
[0400] Sodium hydride (196 mg, 4.89 mmol) was suspended in 10 ml of
tetrahydrofurane. The reaction mixture was cooled to 0.degree. C.
and a solution of Intermediate 42 (480 mg, 4.45 mmol) in 5 ml of
tetrahydrofurane was added dropwise. The reaction mixture was
stirred at 0.degree. C. for 1 h, then iodomethane (0.305 ml, 4.89
mmol) was added. The reaction mixture was stirred at room
temperature for 4 h. 0.1 ml of a 37% aqueous solution of
hydrochloric acid and 0.1 ml of water were added, then additional
0.3 ml of a 37% aqueous solution of hydrochloric acid were added.
The reaction mixture was stirred at room temperature for 18 h. The
reaction mixture was concentrated under vacuum and 400 mg (2.44
mmol) of the desired product were obtained as an oil.
##STR00232##
[0401] Iodomethane (3.48 ml, 55.88 mmol) was dissolved in 250 ml of
tetrahydrofurane, the reaction mixture was stirred at 0.degree. C.
under nitrogen atmosphere and sodium hydride (60% on mineral oil,
2.23 mg, 5.88 mmol) was added. After 15 minutes, trans
4-azido-tetrahydropyran-3-ol (4.0 g, 27.94 mmol) was added and the
reaction mixture was allowed to reach room temperature and stirred
for 18 h. 50 ml of water were added, the organic phase was
separated, dried over sodium sulphate and concentrated under
vacuum. The crude oil obtained was purified by flash chromatography
(Biotage SNAP column 100 g; eluent: dichloromethane/ethyl
acetate=80/20%). 200 mg (1.27 mmol) of the desired regioisomer were
obtained as trans racemate (relative configuration assigned by
NMR).
##STR00233##
[0402] Intermediate 44 (200 mg, 1.27 mmol) was dissolved in 250 ml
of methanol, Pd/C (50 mg) was added and the reaction mixture was
stirred under hydrogen atmosphere (4 bar) for 18 h. The reaction
mixture was filtered on a celite pad and the organic phase was
concentrated under vacuum. 110 mg (0.84 mmol) of the desired
product were obtained as trans racemate.
##STR00234##
[0403] 3-Methoxy-tetrahydro-pyran-4-one (500 mg, 3.84 mmol),
benzylamine (0.42 ml, 3.84 mmol) and Raney-Nickel (100 mg) were
suspended in 20 ml of dry ethanol and the reaction mixture was
stirred under hydrogen atmosphere (4.5 bar) for 3 days. The
reaction mixture was filtered on a celite pad and the organic phase
was concentrated under vacuum. The crude product obtained was
dissolved in 10 ml of methanol, loaded on a SCX cartridge (10 g)
and eluted with a 2M solution of ammonia in methanol. The solvent
was concentrated under vacuum and the crude product obtained was
purified by flash chromatography (Isolute cartridge 10 g; eluent:
dichloromethane/methanol=96/4%). 163 mg (0.73 mmol) of the desired
product were obtained as cis racemate (relative configuration
assigned by NMR).
##STR00235##
[0404] 3-Methoxy-tetrahydro-pyran-4-one (1 g, 7.68 mmol),
(R)-(+)-1-phenylethylamine (0.99 ml, 7.68 mmol) and Raney-Nickel
(200 mg) in 10 ml dry ethanol were stirred under a hydrogen
atmosphere (5 bar) for 15 days. The reaction mixture was diluted
with 20 ml of methanol and 20 ml of tetrahydrofurane, stirred for
15 minutes, filtered on a celite pad and concentrated under vacuum.
The crude product was loaded on a SCX cartridge (50 g). The
cartridge was washed with methanol and the desired product was
eluted with a 7 M solution of ammonia in methanol. The basic
organic phase was concentrated under vacuum and the crude product
obtained was purified by flash chromatography
(dichloromethane/methanol=98/2%) to obtain 710 mg (3.02 mmol) of
the desired product as single stereoisomer (diastereoisomeric
purity confirmed and relative cis stereochemistry assigned by
NMR).
##STR00236##
was synthesised in analogy to Intermediate 46b, starting from
3-Methoxy-tetrahydro-pyran-4-one and (S)-(-)-1-phenylethylamine
(diastereoisomeric purity confirmed and relative cis
stereochemistry assigned by NMR).
##STR00237##
[0405] Intermediate 46a (163 mg, 0.73 mmol) was dissolved in 10 ml
of methanol, Pd/C (50 mg) was added and the reaction mixture was
stirred under hydrogen atmosphere (4.5 bar) for 18 h. The reaction
mixture was filtered on a celite pad and the organic phase was
concentrated under vacuum. 80 mg (0.61 mmol) of the desired product
were obtained as cis racemate.
##STR00238##
[0406] Intermediate 46b (1.18 g, 5.01 mmol), Pd/C 10% (200 mg) and
acetic acid (0.3 ml, 5.01 mmol) in 20 ml of methanol were stirred
under a hydrogen atmosphere (5 bar) for 18 h. The reaction mixture
was diluted with 20 ml of methanol, stirred for 15 minutes,
filtered on a celite pad and concentrated under vacuum. The crude
product was loaded on a SCX cartridge (50 g). The cartridge was
washed with methanol and the desired product was eluted with a 7 M
solution of ammonia in methanol. The basic organic phase was
concentrated under vacuum and 513 mg (3.91 mmol) of the desired
product were obtained as single stereoisomer.
##STR00239##
was synthesised in analogy to Intermediate 47b, starting from
Intermediate 46c
##STR00240##
[0407] Intermediate 47b was stirred in diethyl ether and a 2M
solution of hydrochloric acid in diethyl ether was added drop-wise
until a white solid was formed. The reaction mixture was
concentrated under vacuum, the crude product was suspended in
methanol and the reaction mixture was concentrated under vacuum to
give the desired hydrochloride.
##STR00241##
was synthesised in analogy to Intermediate 48b, starting from
Intermediate 47c.
##STR00242##
[0408] 3-(trifluoromethyl)benzaldheyde (6.46 ml, 48.24 mmol) was
dissolved in 80 ml of dry tetrahydrofurane, the reaction mixture
was cooled to -78.degree. C. and a 0.5M solution of
3-butenylmagnesiumbromide in tetrahydrofurane (106.13 ml, 53.06
mmol) was added dropwise over 30 minutes. The reaction mixture was
stirred at -78.degree. C. for 30 minutes. Then, the reaction
mixture was allowed to reach room temperature and stirred 18 h.
Then, 100 ml of a saturated aqueous solution of ammonium chloride
and 200 ml of ethyl acetate were added. the organic layer was
separated, dried over sodium sulfate and concentrated under vacuum.
7.75 g (33.69 mmol) of the desired product were obtained.
##STR00243##
[0409] Intermediate 49a was dissolved in 70 ml of dry
dichloromethane, the reaction mixture was stirred under nitrogen
atmosphere at 0.degree. C. and N-bromosuccinimmide was added. The
reaction mixture was allowed to reach room temperature and stirred
for 48 h. The reaction mixture was concentrated under vacuum. The
crude product was purified by flash chromatography (Isolera
cartridge eluent: hexane/ethyl acetate=90/10%) to obtain the
desired product as diastereoisomeric mixture.
##STR00244##
[0410] Intermediate 50a was purified by flash chromatography
(Isolera cartridge; eluent: hexane/ethyl acetate=98/2%). 2.3 g
(7.44 mmol) of the trans diastereoisomer were obtained as racemic
mixture (relative stereochemistry assigned by NMR).
##STR00245##
[0411] Further elution of the column gave 1.05 g (3.39 mmol) of the
cis diastereoisomer as racemic mixture (relative stereochemistry
assigned by NMR).
[0412] The following intermediates were synthesized in analogy to
Intermediates 49a, 50a, 51a and 52a
TABLE-US-00019 Starting Inter- Inter- Inter- Inter- aldehyde
mediate STRUCTURE mediate STRUCTURE mediate STRUCTURE mediate
STRUCTURE 3-Methyl- benzaldheyde 49b ##STR00246## 50b ##STR00247##
51b ##STR00248## 52b ##STR00249## 4-Methyl- benzaldheyde 49c
##STR00250## 50c ##STR00251## 51c ##STR00252## 52c ##STR00253##
4-Fluoro-3- methyl- benzaldheyde 49d ##STR00254## 50d ##STR00255##
51d ##STR00256## 52d ##STR00257## 3-Fluoro-4- methyl- benzaldheyde
49e ##STR00258## 50e ##STR00259## 51e ##STR00260## 52e ##STR00261##
4-Chloro- benzaldheyde 49f ##STR00262## 50f ##STR00263## 51f
##STR00264## 52f ##STR00265## 4- Trifluoro- methyl- benzaldheyde
49g ##STR00266## 50g ##STR00267## 51g ##STR00268## 52g
##STR00269##
##STR00270##
[0413] Intermediate 50a (1.7 g, 5.49 mmol) was dissolved in 5 ml of
DMSO and the reaction mixture was stirred under nitrogen atmosphere
at room temperature. Phtalimide potassium salt (2.54 g, 13.75 mmol)
and sodium iodide (240 mg, 1.60 mmol) were added and the reaction
mixture was stirred at 70.degree. C. for 18 h. The reaction mixture
was cooled to room temperature and diluted with 40 ml of a
saturated aqueous sodium bicarbonate solution and with 100 ml of
ethyl acetate. The organic layer was separated, dried on sodium
sulfate and concentrated under vacuum. The crude product was
purified by flash chromatography (Isolera cartridge; eluent:
hexane/ethyl acetate=85/15%) to yield 1.2 g (3.2 mmol) of the
phtalimido intermediate. The phtalimido intermediate (1.2 g, 3.2
mmol) was dissolved in 15 ml of methanol. Hydrazine hydrate (1.24
ml, 25.60 mmol) was added and the reaction mixture was stirred at
room temperature for 48 h. The reaction mixture was concentrated
under vacuum. The crude product was dissolved in 10 ml of
dichlorometane, the organic layer was washed with water, separated,
dried on sodium sulfate and concentrate under vacuum. 474 mg (1.93
mmol) of the desired product were obtained.
##STR00271##
was synthesized in analogy to Intermediate 53a starting from
intermediate 51a
##STR00272##
was synthesized in analogy to Intermediates 53a starting from
intermediate 52a.
[0414] The following intermediates were synthesized in analogy to
Intermediates 53a, 54a and 55a.
TABLE-US-00020 Starting Inter- Inter- mediate mediate STRUCTURE 50b
53b ##STR00273## 50c 53c ##STR00274## 50d 53d ##STR00275## 50e 53e
##STR00276## 50f 53f ##STR00277## 50g 53g ##STR00278## 2-
bromomethyl- 4-phenyl- tetrahydro- furan 53h ##STR00279## 51b 54b
##STR00280## 51c 54c ##STR00281## 51d 54d ##STR00282## 51e 54e
##STR00283## 51f 54f ##STR00284## 51g 54g ##STR00285## 52e 55e
##STR00286## 52b 55b ##STR00287## 52c 55c ##STR00288## 52d 55d
##STR00289## 52f 55f ##STR00290## 52g 55g ##STR00291##
##STR00292##
[0415] 2,3-Dihydro-pyrano[3,2-b]pyridine-4-one (250 mg, 1.7 mmol)
and Raney-Nickel (25 mg) were added to a solution of ammonia in
ethanol (10 ml) and the reaction mixture was stirred under hydrogen
atmosphere (3 bar) for 18 h at room temperature. Then, the catalyst
was removed by filtration on a celite pad and the mixture was
concentrated under vacuum. The residue was purified by reversed
phase HPLC to give the desired product (129 mg, 600 .mu.mol).
Synthesis of Examples
[0416] E and G within the scope of this invention denotes C or N,
preferred nitrogen.
[0417] The examples of this invention are synthesized according to
the following general synthetic procedures:
Synthetic Procedure A:
##STR00293##
[0418] Examples: 1-159gc; 289-302
Synthetic Procedure B:
##STR00294##
[0419] Examples: 160-247; 228a; 228ga-228gn; 229-247
##STR00295##
Examples: 286-288
##STR00296##
[0420] Examples: 228b-228g; 228go; 228gp
Synthetic Procedure C:
##STR00297##
[0421] Examples: 248-283; 275a-275dj
Example 1
##STR00298##
[0423] Intermediate 25b (70 mg, 0.16 mmol),
4-tert-butyl-benzylamine (32 mg, 0.19 mmol) and
N,N-diisopropyl-ethyl amine (0.042 ml, 0.24 mmol) in 2 ml of dry
1,4-dioxane were stirred at 70.degree. C. overnight. The reaction
mixture was concentrated under vacuum and the crude product was
dissolved in dichloromethane. The organic phase was washed with a
saturated aqueous sodium bicarbonate solution, dried over sodium
sulfate and concentrated under vacuum. The crude product was
purified by flash chromatography (Silica Isolute cartridge 5 g;
eluent: ethyl acetate/methanol=90/10%). 16 mg (0.027 mmol) of the
desired product were obtained. HPLC (Method 2F): R.sub.t.
(min)=7.59
[0424] [M+H].sup.+=557
[0425] The following examples were synthesized in analogy to the
preparation of Example 1.
TABLE-US-00021 HPLC Inter- [M + R.sub.t.cndot. Meth- Ex # STRUCTURE
mediate Amine H].sup.+ (min) od 2 ##STR00299## 25i 2-(3,4-
dichloro- phenyl)- ethyl- amine 476 7.98 1E 3 ##STR00300## 25f
2-(3,4- dichloro- phenyl)- ethyl- amine 492 2.91 B 4 ##STR00301##
25f 3- trifluoro methyl- benzyl- amine 478 6.77 1E 5 ##STR00302##
25f 4- trifluoro- methoxy- benzyl- amine 494 6.78 1E 6 ##STR00303##
25f 3-fluoro- 5- trifluoro methyl- benzyl- amine 496 6.73 1E 7
##STR00304## 25f 4-tert- butyl- benzyl- amine 466 7.45 1E 8
##STR00305## 25f 3- trifluoro methoxy- benzyl- amine 494 7.08 1E 9
##STR00306## 25f 4- trifluoro methyl- benzyl- amine 478 6.63 1E 10
##STR00307## 25f 3-fluoro- 4- trifluoro methyl- benzyl- amine 496
6.85 1E 11 ##STR00308## 25f 2-(3- trifluoro methyl- phenyl)- ethyl-
amine 492 7.23 1E 12 ##STR00309## 25f 2-(4- trifluoro methyl-
phenyl)- ethyl- amine 492 7.37 1E 13 ##STR00310## 25f (4-
(trifluoro- methyl)- cyclo- hexyl)- methan- amine 484 6.82 1E 14
##STR00311## 25f 2-(4- trifluoro- methoxy- phenyl)- ethyl- amine
508 7.37 1E (Fusion) 15 ##STR00312## 25f 4-phenyl- butyl- amine 452
7.15 1E 16 ##STR00313## 25f 2- phenoxy- ethyl- amine 440 7.10 1E
(Fusion) 17 ##STR00314## 25f 3-phenyl- propyl- amine 438 7.83 1E
(Fusion) 18 ##STR00315## 25f 2-benzyl- oxy- ethyl- amine 454 5.83
1E (Hydro) 19 ##STR00316## 25f chroman- 3-yl- methan- amine 466
7.85 1E (Fusion) 20 ##STR00317## 25f (1- phenyl- pyrrol- idin-3-
yl)- methan- amine 479 7.05 1E (Hydro) 21 ##STR00318## 25f
2-fluoro- 4- trifluoro methyl- benzyl- amine 496 8.38 1E (Fusion)
22 ##STR00319## 25f 4-phenyl- cyclo- hexyl- amine 478 9.38 1E
(Fusion) 23 ##STR00320## 25f indan-2- yl- methan- amine 450 6.55 1E
(Hydro) 24 ##STR00321## 25f chroman- 3- ylamine 452 6.18 1E (Hydro)
25 ##STR00322## 25f (R)- (1,2,3,4- tetra- hydro- naphtal- en-2-
yl)amine 450 7.08 1E (Hydro) 26 ##STR00323## 25f (1,2- dihydro-
cyclo- buta- benzen- 1-yl)- methan- amine 436 6.93 1E (Hydro) 27
##STR00324## 25f (2,3- dihyro- benzofu- ran-2- yl)- methan- amine
452 6.47 1E (Hydro) 28 ##STR00325## 25f Cyclo- hexyl- amine 402
4.90 1E 29 ##STR00326## 25f benzofu- ran-5- ylmethan amine 450 6.73
1E (Hydro) 30 ##STR00327## 25f 3-chloro- 4- methyl- benzyl- amine
458 7.75 1E (Hydro) 31 ##STR00328## 25f 3,4- dime- thyl- benzyl-
amine 438 7.37 1E (Hydro) 32 ##STR00329## 25c 3-chloro- 4- methyl-
benzyl- amine 563 6.98 2F 33 ##STR00330## 25c 3-chloro- 4-
trifluoro methyl- benzyl- amine 617 9.47 1E (Hydro) 34 ##STR00331##
25c 4- isopro- pyl- benzyl- amine 557 7.03 2F 35 ##STR00332## 25c
3,4- dichloro- benzyl- amine 583 8.65 1E (Hydro) 36 ##STR00333##
25c 2-(3,4- dichloro- phenyl)- ethyl- amine 597 9.72 1E (Hydro) 37
##STR00334## 25c 4-tert- butyl- benzyl- amine 571 9.28 1E (Hydro)
38 ##STR00335## 25c 9a 598 1.45 2F 39 ##STR00336## 25c 4-chloro-
3-fluoro- benzyl- amine 567 8.82 1E (Hydro) 40 ##STR00337## 25c (1-
phenyl- piper- idin- 4yl)- methan- amine 598 8.98 1E (Hydro) 41
##STR00338## 25c 9b 584 8.92 1E (Hydro) 42 ##STR00339## 25h 9a 479
8.67 1E (Hydro) 43 ##STR00340## 25h 3-chloro- 4- methyl- benzyl-
amine 444 8.63 1E (Hydro) 44 ##STR00341## 25h 3-fluoro- 4- methyl-
benzyl- amine 428 7.58 1E (Hydro) 45 ##STR00342## 25h 4-chloro-
3-fluoro- bemzyl- amine 448 7.88 1E (Hydro) 46 ##STR00343## 25h
indan- 2yl- methan- amine 436 8.27 1E (Hydro) 47 ##STR00344## 25h
3-chloro- 4- trifluoro methyl- benzyl- amine 498 7.30 2F 48
##STR00345## 25h 3,4- difluoro- benzyl- amine 432 4.20 2G 49
##STR00346## 25b 4-chloro- benzyl- amine 535 7.38 2F 50
##STR00347## 25h chroman- 3- ylmethan amine 452 7.85 1E (Hydro) 51
##STR00348## 25h (1- phenyl- pyrrol- idin-3- yl)- methan- amine 465
8.93 1E (Hydro) 52 ##STR00349## 25h 4-tert- butyl- benzyl- amine
452 7.18 2F 53 ##STR00350## 25b 2-(3,4- dichloro- phenyl)- ethyl-
amine 583 7.97 1E (Hydro) 54 ##STR00351## 25b (6-tert- butyl-
pyridin- 3-yl)- methan- amine 558 7.73 1E (Hydro) 55 ##STR00352##
25b 4-fluoro- 3- methyl- benzyl- amine 533 8.05 1E (Hydro) 56
##STR00353## 25b 4-ethyl- benzyl- amine 529 8.35 1E (Hydro) 57
##STR00354## 25b chroman- 3- ylmethan amine 557 7.62 1E (Hydro) 58
##STR00355## 25b (1- phenyl- piperi- din-4yl)- methan- amine 584
8.05 1E (Hydro) 59 ##STR00356## 25b 3-chloro- 4- methyl- benzyl-
amine 549 8.22 1E (Hydro) 60 ##STR00357## 25b (1- phenyl- pyrrol-
idin-3- yl)- methan- amine 570 8.07- 8.47 1E (Hydro) 61
##STR00358## 25b indan- 2yl- methan- amine 541 8.03 1E (Hydro) 62
##STR00359## 25b 3-chloro- 4- trifluoro methyl- benzyl- amine 603
8.68 1E (Hydro) 63 ##STR00360## 25b 4-chloro- 3-fluoro- benzyl-
amine 553 7.55 1E (Hydro) 64 ##STR00361## 25b 4- isopro- pyl-
benzyl- amine 543 6.82 2F 65 ##STR00362## 25b 3-fluoro- 4- methyl-
benzyl- amine 533 8.57 1E (Hydro) 66 ##STR00363## 25b 3-chloro-
benzyl- amine 535 6.72 2F 67 ##STR00364## 25b 4- methoxy- benzyl-
amine 531 2.39 2F 68 ##STR00365## 25b 3-chloro- 4-fluoro- benzyl-
amine 553 7.57 2F 69 ##STR00366## 25a 4-tert- butyl- benzyl- amine
543 7.97 1E (Hydro) 70 ##STR00367## 25a 4- trifluoro meth- oxy-
benzyl- amine 585 7.63 1E (Hydro) 71 ##STR00368## 25a chroman- 3-
ylmethan amine 543 6.75 1E (Hydro) 72 ##STR00369## 25a 3,4-
dichloro- benzyl- amine 555 7.30 1E (Hydro) 73 ##STR00370## 25a
indan- 2yl- methan- amine 527 7.35 1E (Hydro) 74 ##STR00371## 25a
(1- phenyl- pyrrol- idin-3- yl)- methan- amine 555 7.43- 7.80 1E
(Hydro) 75 ##STR00372## 25a 3-chloro- 4- trifluoro methyl- benzyl-
amine 589 7.48 2F 76 ##STR00373## 25a 4-chloro- 3-fluoro- benzyl-
amine 539 2.07 1F 77 ##STR00374## 25e 3-chloro- 4- trifluoro
methyl- benzyl- amine 539 8.23 1E (Hydro) 78 ##STR00375## 25e
4-chloro- 3-fluoro- benzyl- amine 489 7.33 1E (Hydro) 79
##STR00376## 25l chroman- 3- ylmethan amine 571 8.13 1E (Hydro) 80
##STR00377## 25l 4-chloro- 3-fluoro- benzyl- amine 567 8.36 1E
(Hydro) 81 ##STR00378## 25l 3-chloro- 4- trifluoro methyl- benzyl-
amine 617 9.12 1E (Hydro) 82 ##STR00379## 25l 3,4- dichloro-
benzyl- amine 583 8.83 1E (Hydro) 83 ##STR00380## 25l 4-tert-
butyl- benzyl- amine 571 9.73 1E (Hydro) 84 ##STR00381## 25l (1-
phenyl- pyrrol- idin-3- yl)- methan- amine 584 8.70- 9.02 1E
(Hydro) 85 ##STR00382## 25l 9c 584 9.1 1E (Hydro) 86 ##STR00383##
25l indan- 2yl- methan- amine 555 8.80 1E (Hydro) 87 ##STR00384##
25l 9a 598 8.97 1E (Hydro) 88 ##STR00385## 25k 3,4- dichloro-
benzyl- amine 569 7.78 1E (Hydro) 89 ##STR00386## 25k 3-phenyl-
cyclo- hexyl- amine 569 8.45 1E (Hydro) 90 ##STR00387## 25k
chroman- 3- ylmethan amine 557 7.20 1E (Hydro) 91 ##STR00388## 25m
2-(3,4- dichloro- phenyl)- ethyl- amine 506 7.87 1E 92 ##STR00389##
25m 3,4- dichloro- benzyl- amine 492 7.62 1E 93 ##STR00390## 25d
(1- phenyl- pyrrol- idin-3- yl)- methan- amine 520 7.70 1E (Hydro)
94 ##STR00391## 25g 4- isopro- pyl- benzyl- amine 466 6.71 2F 95
##STR00392## 25g 4-chloro- 3-fluoro- benzyl- amine 476 9.18 1E
(Hydro) 96 ##STR00393## 25g (1- phenyl- piper- idin- 4-yl)- methan-
amine 507 9.55 1E (Hydro) 97 ##STR00394## 25g 9a 507 1.22 2F 98
##STR00395## 25g 3-chloro- 4- methyl- benzyl- amine 472 9.62 1E
(Hydro)
Example 99
##STR00396##
[0427] Intermediate 2a (200 mg, 1.047 mmol) was dissolved in 30 ml
of dichlorometane. [1,4]Bipiperidinyl-4-ol (192 mg, 1.047 mmol) was
added and the reaction mixture was stirred at room temperature for
2 h. The reaction mixture was concentrated under vacuum and the
crude product was dissolved in 1 ml of DMSO. Phenethylamine (0.6
ml, 4.73 mmol) and N,N-diisopropyl-ethyl amine (0.013 ml, 0.075
mmol) were added and the reaction mixture was stirred at 80.degree.
C. overnight. The reaction mixture was concentrated under vacuum.
The crude product was purified by reverse phase preparative HPLC.
331 mg (0.616 mmol) of the desired product were obtained.
[0428] HPLC (Method C): R.sub.t. (min)=1.34
[0429] [M+H].sup.+=424
[0430] The following examples were synthesized in analogy to the
preparation of Example 99.
TABLE-US-00022 HPLC Ex Inter- Inter- R.sub.t.cndot. Meth- #
STRUCTURE mediate mediate Amine [M + H].sup.+ (min) od 100
##STR00397## 2a [1,4']- Bipiperi- dinyl- 3-ol Bi- phenyl- 3-yl-
methan- amine 486 1.53 2C 101 ##STR00398## 2a [1,4'] Bipiperi-
dinyl- 4-ol Bi- phenyl- 4-yl- methan- amine 486 1.51 2C 102
##STR00399## 2a [1,4'] Bipiperi- dinyl- 4-ol Bi- phenyl- 3-yl-
methan- amine 486 1.52 2C 103 ##STR00400## 6- chloro- pyri- midine-
4- carbonyl chloride [1,4']- Bipiperi- dinyl- 3-ol Bi- phenyl-
4-yl- methan- amine 472 1.59 2C
Example 104
##STR00401##
[0432] Intermediate 25i (17 mg, 0.05 mmol),
3-fluoro-4-methyl-benzylamine (10 mg, 0.075 mmol) and
diisopropyl-ethyl amine (0.013 ml, 0.075 mmol) in 1 ml of dry DMSO
were stirred at 80.degree. C. overnight. The reaction mixture was
concentrated under vacuum. The crude product was purified by
reverse phase preparative HPLC. 20 mg (0.047 mmol) of the desired
product were obtained.
[0433] HPLC (Method C): R.sub.t. (min)=1.45
[0434] [M+H].sup.+=426
[0435] The following examples were synthesized in analogy to the
preparation of Example 104.
TABLE-US-00023 HPLC Ex Inter- R.sub.t.cndot. # STRUCTURE mediate
Amine [M + H].sup.+ (min) Method 105 ##STR00402## 25f 2-(3-
chloro-4- methoxy- phenyl)- ethyl- amine 488 1.43 2C 106
##STR00403## 25f 2-(4- isopropyl- phenyl)- ethylamine 466 2.88 2B
107 ##STR00404## 25h 3,4- dichloro- benzyl- amine 464 5.6 1A 108
##STR00405## 25f Cyclohexyl- methan- amine 416 2.67 2B 109
##STR00406## 25f 3,4- dichloro- benzyl- amine 478 2.81 2B 110
##STR00407## 25f 4-chloro- benzyl- amine 444 1.6 2A 111
##STR00408## 25f 3-chloro-4- fluoro- benzyl- amine 462 1.63 2A 112
##STR00409## 25f 2-(4-tert- butyl- phenyl)- ethylamine 480 1.8 2A
113 ##STR00410## 25f (1-phenyl- piperidin- 4- yl)methan- amine 493
1.32 2A 114 ##STR00411## 25f 7a 492 7.42 2F 115 ##STR00412## 25f
2-(3,4- difluoro- phenyl)- ethylamine 460 1.61 2A 116 ##STR00413##
25f 3-chloro-4- trifluoro- methyl- benzyl- amine 512 1.74 2A 117
##STR00414## 25f 4-chloro-3- fluoro- benzyl- amine 462 1.64 2A 118
##STR00415## 25f 4-fluoro-3- methyl- benzyl- amine 442 1.61 2A 119
##STR00416## 25f 2-(3- chloro-4- methoxy- phenyl)- ethyl- amine 488
1.63 2A 120 ##STR00417## 25f 3-fluoro-4- methyl- benzyl- amine 442
1.61 2A 121 ##STR00418## 25f (4- phenylcyclo- hexyl)- methan- amine
492 1.78 2A 122 ##STR00419## 25f 2-(3-chloro- phenyl)- ethylamine
458 1.63 2A 123 ##STR00420## 25f 3-chloro- benzyl- amine 444 1.6 2A
124 ##STR00421## 25f 2-(4-chloro- phenyl)- ethylamine 458 1.65 2A
125 ##STR00422## 25f 4-chloro-3- trifluoro- methyl- benzyl- amine
512 1.74 2A 126 ##STR00423## 25f 2-(3,4- dimethyl- phenyl)-
ethylamine 452 1.68 2A 127 ##STR00424## 25i 4-chloro- benzyl- amine
428 1.65 2A 128 ##STR00425## 25i 3-chloro-4- fluoro- benzyl- amine
446 1.67 2A 129 ##STR00426## 25i 2-(4-tert- butyl- phenyl)-
ethylamine 464 1.84 2A 130 ##STR00427## 25i (1-phenyl- piperidin-
4-yl)- methan- amine 477 1.37 2A 131 ##STR00428## 25i 7a 476 1.84
2A 132 ##STR00429## 25i 2-(3,4- difluoro- phenyl)- ethylamine 444
1.66 2A 133 ##STR00430## 25i 3-chloro-4- trifluoro- methyl- benzyl-
amine 496 1.79 2A 134 ##STR00431## 25i 4-chloro-3- fluoro- benzyl-
amine 446 1.67 2A 135 ##STR00432## 25i 4-fluoro-3- methyl- benzyl-
amine 426 1.65 2A 136 ##STR00433## 25i 2-(3- chloro-4- methoxy-
phenyl)- ethylamine 472 1.66 2A 137 ##STR00434## 25i 3-fluoro-4-
methyl- benzyl- amine 426 1.65 2A 138 ##STR00435## 25i (4-
phenylcyclo- hexyl)- methan- amine 476 1.84 2A 139 ##STR00436## 25i
2-(3- chloro- phenyl)- ethylamine 442 1.68 2A 140 ##STR00437## 25i
3-chloro- benzyl- amine 428 1.64 2A 141 ##STR00438## 25i 2-(4-
chloro- phenyl)- ethylamine 442 1.69 2A 142 ##STR00439## 25i
4-chloro-3- trifluoro- methyl- benzyl- amine 496 1.79 2A 143
##STR00440## 25i 2-(3,4- dimethyl- phenyl)- ethylamine 436 1.72 2A
144 ##STR00441## 25f 7a 492 7.7 2H (iso- cratic) 145 ##STR00442##
25f 7a 492 10.2 2H (iso- cratic)
Example 146
##STR00443##
[0437] Intermediate 25b (80 mg, 0.18 mmol), Intermediate 7c (40 mg,
0.21 mmol) and N,N-diisopropyl-ethyl amine (0.046 ml, 0.26 mmol) in
0.2 ml of dry 1,4-dioxane were mixed in a microwave vial and
reacted in the following conditions: Power 100, Ramp 5 min, Hold 2
h, Temperature 150.degree. C., Pression 150.degree. C., Stirring.
The reaction mixture was concentrated under vacuum and diluted with
dichloromethane. The organic phase was washed with an aqueous
saturated sodium bicarbonate solution, dried over sodium sulfate
and concentrated under vacuum. The crude product was purified by
reverse phase preparative HPLC. 36 mg (0.06 mmol) of the desired
product were obtained.
[0438] HPLC (Method 1E Hydro): R.sub.t. (min)=9.52
[0439] [M+H].sup.+=583
[0440] The following examples were synthesized in analogy to the
preparation of Example 146
TABLE-US-00024 In- ter- me- HPLC Ex di- [M + R.sub.t.cndot. Meth- #
STRUCTURE ate Amine H].sup.+ (min) od 147 ##STR00444## 25c (trans-
2- phenyl- cyclo- propyl) methan- amine 555 8.48 1E (Hy- dro) 148
##STR00445## 25b (1,2, 3,4- tetra- hydro- naph- thalen- 1-yl)-
methan- amine 555 8.62 1E (Hy- dro) 149 ##STR00446## 25b 9c 570 8.7
1E (Hy- dro) 150 ##STR00447## 25b 7d 583 9.12 1E (Hy- dro) 151
##STR00448## 25b 7e 583 9.22 1E (Hy- dro) 152 ##STR00449## 25b
(trans- 2- phenyl- cyclo- propyl) methan- amine 541 8.03 1E (Hy-
dro) 153 ##STR00450## 25b 2-(4- tert- butyl- phenyl)- ethyl- amine
571 9.42 1E (Hy- dro) 154 ##STR00451## 25b 1l 643 8.65 1E (Hy- dro)
155 ##STR00452## 25b 9a 584 8.52 1E (Hy- dro) 156 ##STR00453## 25b
9b 570 8.48 1E (Hy- dro) 157 ##STR00454## 25b Quin- olin- 3- yl-
methan- amine 552 1.28 2F 158 ##STR00455## 25b 7b 583 9.48 1E (Hy-
dro) 159 ##STR00456## 25l 9b 584 8.85 1E (Hy- dro) 159a
##STR00457## 25n 7a 613 2.21 2Ca 159b ##STR00458## 25n 4-tert-
butyl- benzyl- amine 587 1.89 2Ca 159c ##STR00459## 25b 7m 603 9.88
1E (Hy- dro) 159d ##STR00460## 25b 7l 569 9.62 1E (Hy- dro) 159e
##STR00461## 25b C- Cyclo- hexyl- methyl- amine 507 8.37 1E (Hy-
dro) 159f ##STR00462## 25b C-(4- iso- propyl- cyclo- hexyl)-
methyl- amine 549 10.12 1E (Hy- dro) 159g ##STR00463## 25b C-(3-
methyl- cyclo- hexyl)- methyl- amine 521 9.25 1E (Hy- dro) 159h
##STR00464## 25b C- (3,3- di- methyl- cyclo- hexyl)- methyl- amine
535 9.68 1E (Hy- dro) 159i ##STR00465## 25d 7a 533 9.53 1E (Hy-
dro) 159k ##STR00466## 25b C-(4- ethyl- cyclo- hexyl)- methyl-
amine 535 9.98 1E (Hy- dro) 159l ##STR00467## 25b C-(4- methyl-
cyclo- hexyl)- methyl- amine 521 9.28 1E (Hy- dro) 159m
##STR00468## 25a 7a 569 9.33 1E (Hy- dro) 159n ##STR00469## 25b
C-(3- pyri- din- 2yl- cyclo- hexyl)- methyl- amine 584 7.90 8.05 1E
(Hy- dro) 159o ##STR00470## 25b C-(4- tert- butyl- cyclo- hexyl)-
methyl- amine 563 10.87 1E (Hy- dro) 159p ##STR00471## 25d 7c 533
9.53 1E (Hy- dro) 159q ##STR00472## 25b 7n 587 9.37 1E (Hy- dro)
159r ##STR00473## 25b C-[4- (1H- Benzo- imida- zol- 2-yl)- cyclo-
hexyl]- methyl- amine 623 7.17 1E (Hy- dro) 159s ##STR00474## 25b
C-[(4- phenyl- mor- pho- lin- 2-yl)- methyl- amine 586 7.73 1E (Hy-
dro) 159t ##STR00475## 25b C-(1- pheny- cyclo- hexyl)- methyl-
amine 583 9.5 1E (Hy- dro) 159u ##STR00476## 25b C-(5- pheny-
furan- 2yl)- methyl- amine 567 8.93 1E (Hy- dro) 159w ##STR00477##
25b 9d 652 9.57 1E (Hy- dro) 159y ##STR00478## 25b 2-(1- methyl-
1H- indol- 3yl)- ethyl- amine 568 8.2 1E (Hy- dro) 159x
##STR00479## 25b C- Indan- 1-yl- methyl- amine 541 8.27 1E (Hy-
dro) 159z ##STR00480## 25b 7g 601 9.8 1E (Hy- dro) 159 aa
##STR00481## 25d 7g 551 9.47 1E (Hy- dro) 159 ba ##STR00482## 25a
7g 587 9.32 1E (Hy- dro) 159 ca ##STR00483## 25a 7f 603 9.95 1E
(Hy- dro) 159 da ##STR00484## 25b 7f 617 10.5 1E (Hy- dro) 159 ea
##STR00485## 25d 7f 567 7.4 2F 159 fa ##STR00486## 25b C- cyclo-
heptyl- methyl- amine 521 8.88 1E (Hy- dro) 159 ga ##STR00487## 25l
54a 653 5.38 2M 159 ha ##STR00488## 25b 54a 639 5.94 2M 159 ia
##STR00489## 25b 54b 585 5.42 2M 159 ja ##STR00490## 25l 54b 599
4.76 2M 159 ka ##STR00491## 25l 55g 653 9.37 1E (Hy- dro) 159 la
##STR00492## 25b 55g 639 9.02 1E (Hy- dro) 159 ma ##STR00493## 25b
54g 639 9.07 1E (Hy- dro) 159 na ##STR00494## 25b 53e 603 8.6 1E
(Hy- dro) 159 oa ##STR00495## 25l 53c 599 9.01 1E (Hy- dro) 159 pa
##STR00496## 25b 53a 639 8.38 1E (Hy- dro) 159 qa ##STR00497## 25l
53a 653 8.85 1E (Hy- dro) 159 ra ##STR00498## 25b 53b 585 7.86 1E
(Hy- dro) 159 sa ##STR00499## 25l 53b 599 8.36 1E (Hy- dro) 159 ta
##STR00500## 25l 53e 617 9.03 1E (Hy- dro) 159 ua ##STR00501## 25l
54f 619 8.63 1E (Hy- dro) 159 wa ##STR00502## 25b 54f 605 8.10 1E
(Hy- dro) 159 ya ##STR00503## 25l 54d 617 5.08 2M 159 xa
##STR00504## 25b 7h 613 9.95 1E (Hy- dro) 159 za ##STR00505## 25b
7i 597 10.52 1E (Hy- dro) 159 ab ##STR00506## 25b 53f 605 9.0 1E
(Hy- dro) 159 bb ##STR00507## 25b C-(3- methyl- cyclo- pentyl)-
methyl- amine 507 8.53 1E (Hy- dro) 159 cb ##STR00508## 25b 53c 585
8.77 1E (Hy- dro) 159 db ##STR00509## 25b 7j 601 10 1E (Hy- dro)
159 eb ##STR00510## 25b 53h 571 7.93 1E (Hy- dro) 159 fb
##STR00511## 25b C-(5- phenyl- tetra- hydro furan- 3yl)- methyl-
amine 571 7.83 1E (Hy- dro) 159 gb ##STR00512## 25b 54c 585 8.36 1E
(Hy- dro) 159 hb ##STR00513## 25b 53g 639 8.94 1E (Hy- dro) 159 ib
##STR00514## 25l 53g 653 9.27 1E (Hy- dro) 159 jb ##STR00515## 25b
55c 585 8.38 1E (Hy- dro) 159 kb ##STR00516## 25g 7g 524 2.87 1Fa
159 lb ##STR00517## 25g 7f 540 3.02 1Fa 159 mb ##STR00518## 25b 7r
567 8.85 1E (Hy- dro) 159 nb ##STR00519## 25b C- Bicyclo [4.2.0]
octa- 1(6), 2,4- trien- 7-yl- methyl- amine 527 7.53 1E (Hy- dro)
159 ob ##STR00520## 25b C- Chro- man- 2yl- methyl- amine 557 7.9 1E
(Hy- dro) 159 pb ##STR00521## 25b C- (1,2, 3,4- Tetra- hydro- naph-
thalen- 2-yl-)- methyl- amine 555 8.47 1E (Hy- dro) 159 qb
##STR00522## 25b C- (2,3- Di- hydro- benzo- furan- 2yl)- methyl-
amine 543 7.4 1E (Hy- dro) 159 rb ##STR00523## 25b C-(5- Chloro-
2,3- Di- hydro- benzo- furan- 2yl)- methyl- amine 557 6.5 2F 159 sb
##STR00524## 25b C-(6- Chloro- cro- man- 3-yl)- methyl- amine 591
8.09 1E (Hy- dro) 159 tb ##STR00525## 25b 7s 589 9.8 1E (Hy- dro)
159 ub ##STR00526## 25b 7t 555 9.07 1E (Hy- dro) 159 wb
##STR00527## 25b 7u 589 9.7 1E (Hy- dro) 159 yb ##STR00528## 25b 7v
555 9.02 1E (Hy- dro) 159 xb ##STR00529## 25b 7o 587 9.55 1E (Hy-
dro) 159 zb ##STR00530## 25b 7k 549 10.37 1E (Hy- dro) 159 ac
##STR00531## 25b C- (tetra- hydro- pyran- 4- yl)- methyl- amine 509
5.92 1E (Hy- dro) 159 bc ##STR00532## 25b C- (tetra- hydro- pyran-
3- yl)- methyl- amine 509 6.15 1E (Hy- dro) 159 cc ##STR00533## 25l
7o 601 5.40 2M 159 dc ##STR00534## 25o C- cyclo- hexyl- methyl-
amine 446 1.23 2Gb 159 ec ##STR00535## 25o Indan- 2-yl- amine 466
1.24 2Gb 159 fc ##STR00536## 25o C- Indan- 2-yl- methyl- amine 480
2.97 2Ga 159 gc ##STR00537## 25b C- (1,2, 3,4- Tetra- hydro- quino-
lin- 2-yl)- methyl- amine 556 1.35 2Ca
Example 160
##STR00538##
[0442] Intermediate 28b (80 mg, 0.20 mmol), Intermediate 13 (74 mg,
0.30 mmol) and N,N-diisopropyl-ethylamine (0.087 ml, 0.51 mmol) in
2 ml of dichloromethane were stirred at room temperature for 10
min. Sodium triacetoxyborohydride (129 mg, 0.61 mmol) was added and
the reaction mixture was stirred at room temperature overnight. The
organic phase was washed with an aqueous saturated sodium
bicarbonate solution, dried over sodium sulfate and concentrated
under vacuum. The crude product was purified by reverse phase
preparative HPLC. 39 mg (0.06 mmol) of the desired product were
obtained.
[0443] HPLC (Method 2F): R.sub.t. (min)=7.25
[0444] [M+H].sup.+=583
[0445] The following examples were synthesized in analogy to the
preparation of Example 160.
TABLE-US-00025 Ex # STRUCTURE 161 ##STR00539## 162 ##STR00540## 163
##STR00541## 164 ##STR00542## 165 ##STR00543## 166 ##STR00544## 167
##STR00545## 168 ##STR00546## 169 ##STR00547## 170 ##STR00548## 171
##STR00549## 172 ##STR00550## 173 ##STR00551## 174 ##STR00552## 175
##STR00553## 176 ##STR00554## 177 ##STR00555## 178 ##STR00556## 179
##STR00557## 180 ##STR00558## 181 ##STR00559## 182 ##STR00560## 183
##STR00561## 184 ##STR00562## 185 ##STR00563## 186 ##STR00564## 187
##STR00565## 188 ##STR00566## 189 ##STR00567## 190 ##STR00568## 191
##STR00569## 192 ##STR00570## 193 ##STR00571## 194 ##STR00572## 195
##STR00573## 196 ##STR00574## 197 ##STR00575## 198 ##STR00576## 199
##STR00577## 200 ##STR00578## 201 ##STR00579## 202 ##STR00580## 203
##STR00581## 204 ##STR00582## 205 ##STR00583## 206 ##STR00584## 207
##STR00585## 208 ##STR00586## 209 ##STR00587## 210 ##STR00588## 211
##STR00589## 212 ##STR00590## 213 ##STR00591## 214 ##STR00592## 215
##STR00593## 216 ##STR00594## 217 ##STR00595## 218 ##STR00596## 219
##STR00597## 220 ##STR00598## 221 ##STR00599## 222 ##STR00600## 223
##STR00601## 224 ##STR00602## 225 ##STR00603## 226 ##STR00604## 227
##STR00605## 228 ##STR00606## 228a ##STR00607## 228b ##STR00608##
228c ##STR00609## 228d ##STR00610## 228e ##STR00611## 228f
##STR00612## 228g ##STR00613## 228ga ##STR00614## 228gb
##STR00615## 228gc ##STR00616## 228gd ##STR00617## 228ge
##STR00618## 228gf ##STR00619## 228gg ##STR00620## 228gh
##STR00621## 228gi ##STR00622## 228gj ##STR00623## 228gk
##STR00624## 228gl ##STR00625## 228gm ##STR00626## 228gn
##STR00627## 228go ##STR00628## 228gp ##STR00629## HPLC Ex Inter-
Amine or R.sub.t.cndot. # mediate Ketone [M + H].sup.+ (min) Method
161 28f N-Methyl- N- piperidin- 4-yl- methane- sulfon- amide 571
7.17 2F 162 28f Morpholine 466 9.97- 10.27 1E 163 28f Pyrrolidine
450 7.06 2F 164 28a 4,4- difluoro- piperidine 512 8.17 1E 165 28a
(R)- pyrrolidin- 3-ol 478 7.62 1E 166 28a (S)- pyrrolidin- 3-ol 478
7.57 1E 167 28a 4- fluoro- piperidine 494 7.37 2F 168 28a N-
piperidin- 4yl- methan- sulfon- amide 569 7.28 1E (Fusion) 169 28a
(S)-N- piperidin- 3yl- methan- sulfon- amide 569 8.50 1E 170 28a
N-piperidin- 4yl- isobutyr- amide 561 7.58 1E 171 28a N- piperidin-
4yl- acetamide 533 7.07 2F 172 28a Piperidin- 4- carboxylic acid
amide 519 7.07 1E (Fusion) 173 28a Piperidin- 4- carboxylic acid
methyl- amide 533 7.73 1E (Fusion) 174 28a (R)-N- piperidin- 3yl-
methan- sulfon- amide 569 8.48 1E (Fusion) 175 28a (S)- piperidine-
3- carboxylic acid amide 519 8.70 1E (Fusion) 176 28a (S)-
piperidine- 3- carboxylic acid methyl amide 533 7.03 2F 177 28a
(S)- piperidine- 3- carboxylic acid dimethyl amide 547 7.15 2F 178
28a N-Ethyl- N- piperidin- 4-yl- methane- sulfon- amide 597 9.62 1E
(Hydro) 179 28a (S)- piperidine- 3- carboxylic acid 520 6.60 1E
(Fusion) 180 28b Methyl- (3-methyl- oxetan- 3yl- methyl)- amine 492
8.05 1E (Hydro) 181 28b 2- (methoxy- ethyl)- methyl- amine 466 7.72
1E (Hydro) 182 28b Methyl- amino- acetonitrile 447 8.00 1E (Hydro)
183 28b 2,3- dihydro- 1H- isoindole 496 9.52 1E (Hydro) 184 28b 4-
trifluoro- methyl- piperidine 530 9.60 1E (Hydro) 185 28b 18 585
7.33 1E (Hydro) 186 28b Piperidin- 4- carboxylic acid methyl- amide
519 7.42 1E (Hydro) 187 28b Piperidin- 4yl-urea 520 7.05 2F 188 28b
2- methan- sulfonyl- 2,8- diazaspiro [4.5]- decane 595 8.32 1E
(Hydro) 189 28b 4- (1,1- dioxo- isothiazolidin- 2-yl)- piperidine
581 8.23 1E (Hydro) 190 28b 2,8- diazaspiro [4.5] decan- 1-one 531
7.58 1E (Hydro) 191 28b 16a 585 7.65 1E (Hydro) 192 28b 1-
piperidin- 4-yl- pyrrolidin- 2-one 545 8.08 1E (Hydro) 193 28b
Azetidin- 3- carboxylic acid methyl- amide 491 7.55 1E (Hydro) 194
28b N- methyl- N- piperidin- 4yl- acetamide 533 7.87 1E (Hydro) 195
28b Ethan- sulfonic acid- piperidin- 4-yl- amide 569 8.15 1E
(Hydro) 196 28c Piperidine- 4- sulfonic acid dimethyl- amide 557
9.11 1E (Hydro) 197 28b Propan- 2- sulfonic acid- piperidin- 4-yl-
amide 583 8.37 1E (Hydro) 198 28c 4- ethoxy- piperidine 494 10.75
1E (Hydro) 199 28c N- piperidin- 4- methyl- methan- sulfonamide 557
9.45 1E (Hydro) 200 28c 4-tert- butyl- piperidine 506 7.86 2F 201
28c 4- (piperidin- 4-yl)- pyridine 527 10.88 1E (Hydro) 202 28c
Piperidine- 4- carbonitrile 475 9.77 1E (Hydro) 203 28c 4- (3,4-
difluoro- phenoxy)- piperidine 578 11.05 1E (Hydro) 204 28c 2-
(piperidin- 4- yloxy)- pyridine 543 10.38 1E (Hydro) 205 28c
Propan-2- sulfonic- acid- piperidin- 4-yl-amide 571 9.12 1E (Hydro)
206 28c N-Ethyl- N- piperidin- 4-yl- methane- sulfon- amide 571
10.18 1E (Hydro) 207 28g Piperidine- 4- sulfonic acid dimethyl-
amide 571 9.67 1E (Hydro) 208 28c 4- methoxy- piperidine 480 2.21
2G 209 28c 2- methyl- morpholine 466 3.46 2F 210 28c 3- Phenyl-
pyrrolidine 512 9.68 2F 211 28c Piperidin- 4- carboxylic acid sec-
butyl amide 549 9.53 1E (Hydro) 212 28c 4-(3,5- dimethyl- [1,2,4]-
triazol- 4-yl)- piperidine 545 8.93 1E
(Hydro) 213 28c 4-(3- methyl- [1,2,4]- oxadriazol- 5-yl)-
piperidine 532 8.21 2F 214 28c N-methyl- 2-(R)- (pyrrolidin- 2-yl)
acetamide 507 9.35 1E (Hydro) 215 28c N-methyl- 2(S)- (pyrrolidin-
2-yl) acetamide 507 9.24 1E (Hydro) 216 28c N,N- dimethyl- 2-(R)-
(pyrrolidin- 2-yl) acetamide 521 9.71 1E (Hydro) 217 28c N,N-
dimethyl- 2-(S)- (pyrrolidin- 2-yl) acetamide 521 9.72 1E (Hydro)
218 28c 2,6- dimethyl- morpholine 480 8.92 2F 219 28c (R)-3-
methoxy- pyrrolidine 466 7.23 2F 220 28c (S)-3- methoxy-
pyrrolidine 466 7.23 2F 221 28c Piperidine- 4-sulfonic acid
methylamide 543 8.50 1E (Hydro) 222 28c N- azetidin-3- yl-N-
methyl- methane- sulfonamide 529 8.65 1E (Hydro) 223 28c N-
azetidin- 3-yl- methane- sulfonamide 515 8.02 1E (Hydro) 224 28c
4-methyl- piperidine- 4- carboxylic acid methyl- amide 521 9.00 1E
(Hydro) 225 28c 4-phenyl- piperidine 526 10.83 1E (Hydro) 226 28b
N-methyl- N-(S)- (pyrrolidin- 3yl)- methane- sulfonamide 555 8.04
1E (Hydro) 227 28b 16b 599 8.13 1E (Hydro) 228 28b Piperidine-
4-sulfonic acid amide 541 7.12 1E (Hydro) 228a 28c Methyl-
(tetrahydro- pyran- 3-yl)- amine 480 10.05 1E (Hydro) 228b 41b 3-
methoxy- tetrahydro- pyran- 4-one 522 9.25 1E (Hydro) 228c 41a 3-
methoxy- tetrahydro- pyran- 4-one 496 8.87 1E (Hydro) 228d 41a
3-fluoro- tetrahydro- pyran- 4-one 484 1E (Hydro) 228e 41a N-carb-
ethoxy-3- methoxy- 4- piperidone 567 7.42 2F 228f 41a 4- chromanone
514 10.31 1E (Hydro) 228g 41a 43 530 9.76 1E (Hydro) 228ga 28c 47a
496 5.77 2M 228gb 28c 1-(2- Methoxy- ethyl)- 3a,4,5,6,7, 7a-
hexahydro- 1H- pyrazolo- [3,4-c] pyridine 546 9.55 1E (Hydro) 228gc
28c 1-((R)-3- Amino- piperidin- 1-yl)- ethanone 507 8.85 1E (Hydro)
228gd 28c (R)-1- Methane- sulfonyl- piperidin- 3- yllamine 543 9.11
1E (Hydro) 228ge 28c 3- Phenoxy- methyl- pyrrolidine 542 10.92 1E
(Hydro) 228gf 28c 3- Pyrrolidin- 3-yl- pyridine 527 10.00 1E
(Hydro) 228gg 28c 3- Trifluoro methyl- 5,6,7,8- tetrahydro- [1,6]
naphthyridine 567 7.69 2F 228gh 28c C- (Tetrahydro- pyran- 2-yl)
methyl- amine 480 2.09 2Cb 228gi 28c 56 515 2.18 2Cb 228gj 28c
1-Oxa- 3,8- diazaspiro [4,5] decan- 2-one 521 8.30 1E (Hydro) 228gk
28c 4- Piperidin- 4-yl- benzonitrile 551 10.35 1E (Hydro) 228gl 28c
4-(3,4- Difluoro- benzyl)- piperidine 576 11.42 1E (Hydro) 228gm
28c 8-Aza- bicyclo [3.2.1] octan- 3-ol 492 9.30 1E (Hydro) 228gn
28c 45 496 5.96 2M 228go 41a 3- Methoxy- tetrahydro- pyran- 4-one
508 5.77 2M 228gp 41a 3- Tetrazol- 2-yl- tetrahydro- pyran- 4-one
534 7.09 2F
Example 228h
##STR00630##
[0447] Example 228b (22 mg, 0.032 mmol), formaldehyde (0.003 ml,
0.096 mmol), N,N-diisopropyl-ethylamine (0.008 ml, 0.048 mmol) and
trifluoroacetic acid (0.005 ml) in 1.5 ml of methanol were stirred
at room temperature for 5 min. Sodium cyanoborohydride (10 mg,
0.160 mmol) was added and the reaction mixture was stirred at room
temperature overnight. The organic phase was concentrated under
vacuum. The crude product was purified by flash chromatography
(Isolute silica gel cartridge 5 g, eluent: ethyl
acetate/methanol=7:3%). 8.4 mg (0.016 mmol) of the desired product
were obtained.
[0448] The following examples were synthesized in analogy to the
preparation of Example 228h.
TABLE-US-00026 Starting HPLC Ex # STRUCTURE example [M + H].sup.+
R.sub.t. (min) Method 228ha ##STR00631## 228ga 510 5.72 2M
Example 229
##STR00632##
[0450] Intermediate 28a (100 mg, 0.25 mmol),
(S)-3-hydroxypiperidine (67 mg, 0.49 mmol) and
trimethylorthoformate (1.07 ml, 9.82 mmol) in 5 ml of methanol were
stirred at 60.degree. C. for 1 h. 2-picoline borane complex (26 mg,
0.25 mmol) was added and the reaction mixture was stirred at
60.degree. C. overnight. The reaction mixture was concentrated
under vacuum. The crude product was purified by reverse phase
preparative HPLC. 64 mg (0.13 mmol) of the desired product were
obtained.
[0451] HPLC (Method 1E): R.sub.t. (min)=7.18
[0452] [M+H].sup.+=492
[0453] The following examples were synthesized in analogy to the
preparation of Example 229.
TABLE-US-00027 Inter- HPLC Ex # STRUCTURE mediate Amine [M +
H].sup.+ R.sub.t. (min) Method 230 ##STR00633## 28a 1- piperazin-
l-yl- ethanone 519 7.13 2F 231 ##STR00634## 28a (R)- piperidin-
3-ol 492 7.35 1E (Fusion) 232 ##STR00635## 28a (R)- pyrrolidin- 3-
carboxylic acid amide 505 7.83 1E (Fusion) 233 ##STR00636## 28b
3-fluoro- piperidine 480 8.32 1E (Hydro)
Example 234
##STR00637##
[0455] Intermediate 28d (20 mg, 0.05 mmol), 2-methyl-morpholine
(0.012 ml, 0.10 mmol), sodium triacetoxyborohydride (43 mg, 0.20
mmol), acetic acid (0.05 ml) and trimethylorthoformate (0.05 ml) in
0.9 ml of DMA were stirred at room temperature for 3 h. The
reaction mixture was concentrated under vacuum. The crude product
was purified by reverse phase preparative HPLC. 3 mg (0.006 mmol)
of the desired product were obtained.
[0456] HPLC (Method A): R.sub.t. (min)=1.74
[0457] [M+H].sup.+=486
[0458] The following examples were synthesized in analogy to the
preparation of Example 234.
TABLE-US-00028 Inter- HPLC Ex # STRUCTURE mediate Amine [M +
H].sup.+ R.sub.t. (min) Method 235 ##STR00638## 28b Azepane 476
1.72 2A 236 ##STR00639## 28d Dimethyl- piperidin- 4yl-amine 513
1.64 2A 237 ##STR00640## 28a 2-methyl- morpho- line 492 1.72 2A 238
##STR00641## 28b Pyrrolidin- 3-ol 464 1.65 2A 239 ##STR00642## 28d
Pyrrolidin- 3-ol 472 1.71 2A 240 ##STR00643## 28a 2-phenyl- morpho-
line 554 1.84 2A 241 ##STR00644## 28a Pyrrolidin- 3-ol 478 1.68 2A
242 ##STR00645## . 28b [1,4]-oxa- zepane 478 1.66 2A 243
##STR00646## 28d [1,4]-oxa- zepane 486 1.72 2A 244 ##STR00647## 28b
4,4- difluoro- piperidine 498 1.72 2A 245 ##STR00648## 28b Azepan-
4-ol 492 1.65 2A 246 ##STR00649## 28a (3S,4R)- piperidine- 3,4-diol
508 1.66 2A 247 ##STR00650## 28a Azepan- 4-ol 506 1.68 2A
Example 248
##STR00651##
[0460] Intermediate 27e (105 mg, 0.33 mmol), TBTU (215 mg, 0.67
mmol) and N,N-diisopropyl-ethylamine (0.12 ml, 0.67 mmol) in 2 ml
DMF were stirred at room temperature for 5 min.
[0461] Intermediate 20f (100 mg, 0.33 mmol) was added and the
reaction mixture was stirred at room temperature overnight. The
reaction mixture was concentrated under vacuum and the crude
product was dissolved in dichloromethane. The organic phase was
washed with an aqueous saturated sodium bicarbonate solution, dried
over sodium sulfate and concentrated under vacuum. The crude
product was purified by flash chromatography (Si Isolute cartridge
(5 g); eluent: ethyl acetate/methanol=90/10%). 30 mg (0.057 mmol)
of the desired product were obtained.
[0462] HPLC (Method 1E Hydro): R.sub.t. (min)=9.2
[0463] [M+H].sup.+=521
[0464] The following examples were synthesized in analogy to the
preparation of Example 248.
TABLE-US-00029 Inter- HPLC Ex # STRUCTURE mediate Amine [M +
H].sup.+ R.sub.t. (min) Method 249 ##STR00652## 27i 20a 568 10.07
1E (Hydro) 250 ##STR00653## 27c 1- pyrrolidin- 3-yl- piperidine 436
1.5 1E (Hydro) 251 ##STR00654## 27c [1,3']- Bipyrro- lidinyl 422
10.35 1E (Hydro) 252 ##STR00655## 27a [1,4']- Bipiper- idinyl-4'
carboxylic acid amide 519 8.60 1E (Fusion) 253 ##STR00656## 27a 4-
pyrrolidin- 1yl- piperidine 462 7.07 2F 254 ##STR00657## 27b 20g
555 7.50 1E (Hydro) 255 ##STR00658## 27b 20a 569 8.15 1E (Hydro)
256 ##STR00659## 27b 20j 491 7.03 1E (Hydro) 257 ##STR00660## 27b
20i 505 7.43 1E (Hydro) 258 ##STR00661## 27b 20d 541 7.50 1E
(Hydro) 259 ##STR00662## 27b 20c 541 7.48 1E (Hydro) 260
##STR00663## 27b 20h 505 7.85 1E (Hydro) 261 ##STR00664## 27c 20f
507 8.70 1E (Hydro) 262 ##STR00665## 27e 20g 557 9.11 1E (Hydro)
263 ##STR00666## 27c 20m 587 8.79 2F 264 ##STR00667## 27c 20e 557
8.85 1E (Hydro) 265 ##STR00668## 27c 201 479 8.37 1E (Hydro) 266
##STR00669## 27e 20f 521 9.2 1E (Hydro) 267 ##STR00670## 27e 201
493 8.93 1E (Hydro) 268 ##STR00671## 39b 20a 542 3.54 2F 269
##STR00672## 39b 4- piperidin- 4-yl- morpho- line 436 7.46 2F 270
##STR00673## 39a 20a 553 8.28 2F 271 ##STR00674## 39a 4- piperidin-
4-yl- morpho- line 449 7.60 2F 272 ##STR00675## 39c 20a 556 7.98 2F
273 ##STR00676## 39c 4- piperidin- 4-yl- morpho- line 450 7.29 2F
274 ##STR00677## 39d 24 554 8.28 1E (Hydro) 275 ##STR00678## 39d
[1,4']- bipiperidin yl-4-ol 477 7.77 1E (Hydro) 275a ##STR00679##
27c 201a 480 10.03 1E (Hydro) 275b ##STR00680## 27c 201b 510 9.48
1E (Hydro) 275c ##STR00681## 27c 201c 508 10.27 1E (Hydro) 275d
##STR00682## 27c 201d 514 10.13 1E (Hydro) 275da ##STR00683## 27hc
201g 526 9.16 1E (Hydro) 275db ##STR00684## 27hd 201g 526 9.18 1E
(Hydro) 275dc ##STR00685## 27hs 201g 508 7.25 1F 275dd ##STR00686##
27hf 201f 494 6.53 2F 275de ##STR00687## 27hr 201g 508 8.55 1E
(Hydro) 275df ##STR00688## 27he 201g 494 8.07 1E (Hydro) 275dg
##STR00689## 27hf 201g 494 8.10 1E (Hydro) 275dh ##STR00690## 27ha
201f 522 9.03 1E (Hydro) 275di ##STR00691## 27ha 201g 522 9.00 1E
(Hydro) 275dj ##STR00692## 27ha 201a 536 9.76 1E (Hydro) 275dk
##STR00693## 27ib 20a 595 2.16 2Cb 275dl ##STR00694## 27ic 20a 593
2.20 2Cb
Example 276
##STR00695##
[0466] Intermediate 27g (50 mg, 0.14 mmol), HATU (55 mg, 0.14 mmol)
and N,N-diisopropyl-ethylamine (0.05 ml, 0.28 mmol) in 2 ml DMF
were stirred at room temperature for 5 min.
4-piperidin-4-yl-morpholine (24 mg, 0.14 mmol) was added and the
reaction mixture was stirred at room temperature 3 h. The reaction
mixture was concentrated under vacuum and the crude product was
dissolved in dichloromethane. The organic phase was washed with an
aqueous saturated sodium bicarbonate solution, dried over sodium
sulfate and concentrated under vacuum. The crude product was
purified by reverse phase preparative HPLC. 80 mg (0.13 mmol) of
the desired product were obtained.
[0467] HPLC (Method C): R.sub.t. (min)=1.57
[0468] [M+H].sup.+=486
[0469] The following examples were synthesized in analogy to the
preparation of Example 276.
TABLE-US-00030 Inter- HPLC Ex # STRUCTURE mediate Amine [M +
H].sup.+ R.sub.t. (min) Method 277 ##STR00696## 27h 4-piperidin-
4-yl- morpholine 536 1.69 2C 278 ##STR00697## 27h [1,4']-
Bipiperidin- yl-4-ol 550 1.65 2C 279 ##STR00698## 27a 4-piperidin-
4-yl- morpholine 478 1.52 2C 280 ##STR00699## 27f [1,4']-
Bipiperidin- yl-4-ol 506 1.52 2C 281 ##STR00700## 27f 4-piperidin-
4-yl- morpholine 492 1.53 2C 282 ##STR00701## 27g [1,4']-
Bipiperidin- yl-4-ol 500 1.55 2C 283 ##STR00702## 39e [1,4']-
Bipiperidin- yl-4-ol 484 1.66 2C
##STR00703##
Example 284
[0470] Intermediate 30 (45 mg, 0.088 mmol) and
N,N-diisopropylethylamine (0.05 ml, 0.27 mmol) were dissolved in 5
ml of dichloromethane. The reaction mixture was stirred at
0.degree. C. and isobutyrylchloride (0.01 ml, 0.09 mmol) was added.
The reaction mixture was stirred at 0.degree. C. for 20 min, then
it was washed with an aqueous saturated sodium bicarbonate
solution, dried over sodium sulfate and concentrated under vacuum.
The crude product was suspended and stirred in diisopropyl ether,
the solid filtered off to obtain 30 mg (0.05 mmol) of the desired
compound.
[0471] HPLC (Method 1E): R.sub.t. (min)=7.02
[0472] [M+H].sup.+=547
[0473] The following examples were synthesized in analogy to the
preparation of Example 284.
TABLE-US-00031 HPLC Ex # STRUCTURE Intermediate Chloride [M +
H].sup.+ R.sub.t. (min) Method 285 ##STR00704## 30 Methane-
sulfonyl chloride 555 6.91 2F
Example 286
##STR00705##
[0475] Intermediate 32 (100 mg, 0.26 mmol) and cyclopentanone (0.02
ml, 0.26 mmol) in 2 ml of dichloromethane were stirred at room
temperature for 10 min. Sodium triacetoxyborohydride (132 mg, 0.62
mmol) was added and the reaction mixture was stirred at room
temperature overnight. The reaction mixture was washed with an
aqueous saturated sodium bicarbonate solution, dried over sodium
sulfate and concentrated under vacuum. The crude product was
purified by reverse phase preparative HPLC. 31 mg (0.07 mmol) of
the desired product were obtained.
[0476] HPLC (Method 2F): R.sub.t. (min)=7.52
[0477] [M+H].sup.+=450
[0478] The following examples were synthesized in analogy to the
preparation of Example 286.
TABLE-US-00032 Inter- HPLC Ex # STRUCTURE mediate Ketone [M +
H].sup.+ R.sub.t. (min) Method 287 ##STR00706## 32 Acetone 424 7.24
2F 288 ##STR00707## 32 Tetrahydro- pyran-4-one 466 7.18 2F
Example 289
##STR00708##
[0480] Intermediate 25b (200 mg, 0.46 mmol)
4-tert-butylphenylboronic acid (99 mg, 0.56 mmol),
tetrakis(triphenylphosphine)palladium (53 mg, 0.05 mmol) and 0.56
ml of a 2M aqueous solution of sodium carbonate in 2 ml of
1,2-dimethoxyethane were stirred at 80.degree. C. overnight. After
cooling to room temperature, water was added and the reaction
mixture was extracted with dichloromethane. The organic phase was
washed with an aqueous saturated sodium bicarbonate solution, dried
over sodium sulfate and concentrated under vacuum. The crude
product was purified by flash chromatography (Si Isolute cartridge
(5 g); eluent: ethyl acetate/methanol=95/5%). 41 mg (0.08 mmol) of
the desired product were obtained.
[0481] HPLC (Method 1E Hydro): R.sub.t. (min)=9.93
[0482] [M+H].sup.+=528
Example 290
##STR00709##
[0484] Intermediate 25b (60 mg, 0.14 mmol) and 4-chlorophenol
(0.014 ml, 0.14 mmol) were dissolved in 2 ml of DMF. Cesium
carbonate (45 mg, 0.14 mmol) was added and the reaction mixture was
stirred at room temperature overnight. The solvent was concentrated
under vacuum, the crude product was dissolved in dichloromethane
and the organic phase was washed with water, dried over sodium
sulfate and concentrated under vacuum. The crude product was
purified by flash chromatography (Si Isolute cartridge (5 g);
eluent: dichlorometane/ethyl acetate=90/1%). 50 mg (0.09 mmol) of
the desired product were obtained.
[0485] HPLC (Method 1E Hydro): R.sub.t. (min)=8.9
[0486] [M+H].sup.+=522
[0487] The following example was synthesized in analogy to the
preparation of Example 290.
TABLE-US-00033 Inter- HPLC Ex # STRUCTURE mediate Phenol [M +
H].sup.+ R.sub.t. (min) Method 291 ##STR00710## 25b 4-tertbutyl-
phenol 544 7.64 2F
##STR00711##
Example 292
[0488] Sodium hydride (19 mg, 0.46 mmol) and
4-chloro-3-methylbenzylalcohol (44 mg, 0.28 mmol) were suspended in
5 ml of dry tetrahydrofuran. The reaction mixture was stirred at
room temperature for 10 min, then Intermediate 25b (100 mg, 0.23
mmol) was added. The reaction mixture was stirred at 50.degree. C.
overnight. The solvent was concentrated under vacuum, the crude
product was dissolved in dichloromethane and the organic phase was
washed with water, dried over sodium sulfate and concentrated under
vacuum. The crude product was purified by flash chromatography (Si
Isolute cartridge (5 g); eluent: dichlorometane/methanol=95/5%). 40
mg (0.07 mmol) of the desired product were obtained.
[0489] HPLC (Method 1E Hydro): R.sub.t. (min)=9.95
[0490] [M+H].sup.+=550
[0491] The following examples were synthesized in analogy to the
preparation of Example 292.
TABLE-US-00034 Inter- HPLC Ex # STRUCTURE mediate Phenol [M +
H].sup.+ R.sub.t. (min) Method 293 ##STR00712## 25b 4-hydroxy-
methyl- benzonitrile 527 8.17 1E (Hydro) 294 ##STR00713## 25b
(3-fluoro-4- methyl- phenyl)- methanol 534 9.12 1E (Hydro) 295
##STR00714## 25b (1-phenyl- pyrrolydin- 3-yl)- methanol 571 10.2 1E
(Hydro) 296 ##STR00715## 25b (4-tert- butyl- phenyl)- methanol 558
2.71 1F 297 ##STR00716## 25f (4-tert- butyl- phenyl)- methanol 466
9.50 1E (Hydro) 298 ##STR00717## 25h (4-tert- butyl- phenyl)-
methanol 453 8.01 2F 299 ##STR00718## 25a (4-tert- butyl- phenyl)-
methanol 544 9.68 1E (Hydro) 300 ##STR00719## 25d (4-tert- butyl-
phenyl)- methanol 508 10.25 lE (Hydro) 301 ##STR00720## 25n
(4-tert- butyl- phenyl)- methanol 588 2.20 2Ca 302 ##STR00721## 25n
(3-Phenyl- cyclohexyl)- methanol 614 2.18 2Ca
* * * * *