U.S. patent application number 12/273040 was filed with the patent office on 2009-06-25 for glycinamide derivatives as raf-kinase inhbitors.
Invention is credited to Christiane Amendt, Hans-Peter Buchstaller, Matthias Grell, Oliver Schadt, Christian Sirrenberg, Matthias Wiesner, Frank Zenke.
Application Number | 20090163556 12/273040 |
Document ID | / |
Family ID | 31970263 |
Filed Date | 2009-06-25 |
United States Patent
Application |
20090163556 |
Kind Code |
A1 |
Buchstaller; Hans-Peter ; et
al. |
June 25, 2009 |
GLYCINAMIDE DERIVATIVES AS RAF-KINASE INHBITORS
Abstract
The present invention relates to glycinamide derivatives of
formula I, A-D-B (I), wherein A, D, and B are as herein defined, as
well as the use of the compounds of formula I as inhibitors of
raf-kinase, the use of the compounds of formula I for the
manufacture of a pharmaceutical composition, and a method of
treatment comprising administering said pharmaceutical composition
to a patient.
Inventors: |
Buchstaller; Hans-Peter;
(Weiterstadt, DE) ; Wiesner; Matthias;
(Seeheim-Jugenheim, DE) ; Schadt; Oliver;
(Rodenbach, DE) ; Amendt; Christiane; (Darmstadt,
DE) ; Zenke; Frank; (Darmstadt, DE) ;
Sirrenberg; Christian; (Darmstadt, DE) ; Grell;
Matthias; (Darmstadt, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD., SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
31970263 |
Appl. No.: |
12/273040 |
Filed: |
November 18, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10526043 |
Feb 28, 2005 |
7476683 |
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PCT/EP03/08474 |
Jul 31, 2003 |
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12273040 |
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Current U.S.
Class: |
514/345 ;
546/290 |
Current CPC
Class: |
A61P 37/06 20180101;
C07D 213/68 20130101; A61P 31/00 20180101; A61P 35/00 20180101;
A61P 17/06 20180101; A61P 17/02 20180101; A61P 13/12 20180101; C07D
213/65 20130101; A61P 13/08 20180101; A61P 15/00 20180101; A61P
9/10 20180101; A61P 35/02 20180101; A61P 29/00 20180101; A61P 19/02
20180101; A61P 43/00 20180101; A61P 7/02 20180101; A61P 3/00
20180101; C07D 413/12 20130101; A61P 37/00 20180101; A61P 25/28
20180101 |
Class at
Publication: |
514/345 ;
546/290 |
International
Class: |
A61K 31/4406 20060101
A61K031/4406; A61K 31/4402 20060101 A61K031/4402; C07D 213/63
20060101 C07D213/63; A61P 35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 27, 2002 |
EP |
02019023.7 |
Claims
1. A method for the treatment and/or prophylaxis of disorders in a
patient caused, mediated and/or propagated by kinases, said method
comprising administering to said patient one or more compounds
according to formula I A-D-B (I) wherein D is a bivalent glycine
amide moiety, or a derivative thereof, A is an unsubstituted or
substituted moiety of up to 40 carbon atoms of the formula:
-L-(M-L').sub..alpha.; L is a 5, 6 or 7 membered cyclic structure
containing 0-4 members selected from nitrogen, oxygen and sulfur
bound directly to D; L' comprises an optionally substituted cyclic
moiety having at least 5 members and containing 0-4 members
selected from nitrogen, oxygen and sulfur, wherein L' is optionally
substituted by at least one substituent selected from
--SO.sub..beta.R.sub.x and --C(NR.sub.y)R.sub.z; M is a bond or a
bridging group having at least one atom; .alpha. is an integer of
from 1-4; B is a substituted or unsubstituted, up to tricyclic aryl
or heteroaryl moiety of up to 30 carbon atoms, comprising at least
one 5-, 6-, or 7-membered cyclic structure, bound directly to D and
containing 0-4 members selected from nitrogen, oxygen and sulfur;
where when B is substituted, L is substituted or L' is additionally
substituted, the substituents are selected from halogen, up to
per-halo, and W.gamma.; R.sub.y is hydrogen or a carbon based
moiety of up to 24 carbon atoms optionally containing heteroatoms
selected from N, S and O and optionally halosubstituted, up to per
halo; R.sub.z is hydrogen or a carbon based moiety of up to 30
carbon atoms optionally containing heteroatoms selected from N, S
and O and optionally substituted by halogen, hydroxy and carbon
based substituents of up to 24 carbon atoms, which optionally
contain heteroatoms selected from N, S and O and are optionally
substituted by halogen; R.sub.x is R.sub.z or NR.sub.aR.sub.b;
R.sub.a and R.sub.b are a) independently hydrogen, a carbon based
moiety of up to 30 carbon atoms optionally containing heteroatoms
selected from N, S and O and optionally substituted by halogen,
hydroxy and carbon based substituents of up to 24 carbon atoms,
which optionally contain heteroatoms selected from N, S and O and
are optionally substituted by halogen, or --OSi(R.sub.f).sub.3
where R.sub.f is hydrogen or a carbon based moiety of up to 24
carbon atoms optionally containing heteroatoms selected from N, S
and O and optionally substituted by halogen, hydroxy and carbon
based substituents of up to 24 carbon atoms, which optionally
contain heteroatoms selected from N, S and O and are optionally
substituted by halogen; or b) R.sub.a and R.sub.b together form a
5-7 member heterocyclic structure of 1-3 heteroatoms selected from
N, S and O, or a substituted 5-7 member heterocyclic structure of
1-3 heteroatoms selected from N, S and O substituted by halogen,
hydroxy or carbon based substituents of up to 24 carbon atoms,
which optionally contain heteroatoms selected from N, S and O and
are optionally substituted by halogen; or c) one of R.sub.a or
R.sub.b is --C(O)--, a C.sub.1-C.sub.5 divalent alkylene group or a
substituted C.sub.1-C.sub.5 divalent alkylene group bound to the
moiety L to form a cyclic structure with at least 5 members,
wherein the substituents of the substituted C.sub.1-C.sub.5
divalent alkylene group are selected from the group consisting of
halogen, hydroxy, and carbon based substituents of up to 24 carbon
atoms, which optionally contain heteroatoms selected from N, S and
O and are optionally substituted by halogen; .gamma. is 0-3; W is,
in each case, independently selected from --CN, --CO.sub.2R,
--C(O)NR.sup.5R.sup.5, --C(O)--R.sup.5, --NO.sub.2, --OR.sup.5,
--SR.sup.5, --SO.sub.2R.sup.5, --SO.sub.3H, --NR.sup.5R.sup.5,
--NR.sup.5C(O)OR.sup.5, --NR.sup.5C(O)R.sup.5, -Q-Ar, and carbon
based moieties of up to 24 carbon atoms, optionally containing
heteroatoms selected from N, S and O and optionally substituted by
one or more substituents independently selected from the groups
consisting of --CN, --CO.sub.2R, --C(O)NR.sup.5R.sup.5,
--C(O)--R.sup.5, --NO.sub.2, --OR.sup.5, --SR.sup.5,
--SO.sub.2R.sup.5, --SO.sub.3H, --NR.sup.5R.sup.5,
--NR.sup.5C(O)OR.sup.5, --NR.sup.5C(O)R.sup.5 and halogen up to
per-halo; R.sup.5 is, in each case, independently H or a carbon
based moiety of up to 24 carbon atoms, optionally containing
heteroatoms selected from N, S and O and optionally substituted by
halogen; Q is --O--, --S--, --N(R.sup.5)--,
--(CH.sub.2).sub..beta., --C(O)--, --CH(OH)--,
--(CH.sub.2).sub..beta.O--, --(CH.sub.2).sub..beta.S--,
--(CH.sub.2).sub..beta.N(R.sup.5)--, --O(CH.sub.2).sub..beta.,
--CHHal-, --CHal.sub.2-, --S--(CH.sub.2)-- or
--N(R.sup.5)(CH.sub.2).sub..beta.--; .beta. is 1-3; Hal is halogen;
Ar is 5- or 6-member aromatic structure containing 0-2 members
selected from nitrogen, oxygen and sulfur, which is optionally
substituted by halogen, up to per-halo, and optionally substituted
by Z.sub..delta.1; .delta.1 is 0 to 3; and Z is, in each case,
independently selected from --CN, --CO.sub.2R.sup.5,
--C(O)NR.sup.5R.sup.5, --C(O)--R.sup.5, --NO.sub.2, --OR.sup.5,
--SR.sup.5, --SO.sub.2R.sup.5, --SO.sub.3H, --NR.sup.5R.sup.5,
--NR.sup.5C(O)OR.sup.5, --NR.sup.5C(O)R.sup.5, and a carbon based
moiety of up to 24 carbon atoms, optionally containing heteroatoms
selected from N, S and O and optionally substituted by one or more
substituents selected from --CN, --CO.sub.2R.sup.5,
--C(O)NR.sup.5R.sup.5, --C(O)--R.sup.5, --NO.sub.2, --OR.sup.5,
--SR.sup.5, --SO.sub.2R.sup.5, --SO.sub.3H, --NR.sup.5R.sup.5,
--NR.sup.5C(O)OR.sup.5, and --NR.sup.5C(O)R.sup.5; or a
physiologically acceptable derivative, salts or solvate
thereof.
2. A method according to claim 1, wherein each M, independently
from one another, represents a bond or is a bridging group selected
from (CR.sup.5R.sup.5).sub.h, and
(CHR.sup.5).sub.h-Q-(CHR.sup.5).sub.i, Q is O, S, N--R.sup.5,
(CHal.sub.2).sub.j, (O--CHR.sup.5).sub.j, (CHR.sup.5--O).sub.j,
CR.sup.5.dbd.CR.sup.5, (O--CHR.sup.5CHR.sup.5).sub.j,
(CHR.sup.5CHR.sup.5--O).sub.j, C.dbd.O, C.dbd.S, C.dbd.NR.sup.5,
CH(OR.sup.5), C(OR.sup.5)(OR.sup.5), C(.dbd.O)O, OC(.dbd.O),
OC(.dbd.O)O, (C.dbd.O)N(R.sup.5)C(.dbd.O), OC(.dbd.O)N(R.sup.5),
N(R.sup.5)C(.dbd.O)O, CH.dbd.N--NR.sup.5, S.dbd.O, SO.sub.2,
SO.sub.2NR.sup.5, or NR.sup.5SO.sub.2, h, i are independently from
each other 0, 1, 2, 3, 4, 5, or 6, and j is 1, 2, 3, 4, 5 or 6.
3. A method according to claim 1, selected from the compounds of
formula II, ##STR00517## wherein Ar.sup.1, Ar.sup.2 are each,
independently from one another, selected from aromatic hydrocarbons
containing 6 to 14 carbon atoms and ethylenical unsaturated or
aromatic heterocyclic residues containing 3 to 10 carbon atoms and
one or two hetero atoms, independently selected from N, O and S,
R.sup.8, R.sup.9 and R.sup.10 are independently selected from H, A,
cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH.sub.2Hal,
CH(Hal).sub.2, C(Hal).sub.3, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nOR.sup.11,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOOR.sup.12, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11COR.sup.13,
(CH.sub.2).sub.nNR.sup.11CONR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11SO.sub.2A,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12,
(CH.sub.2).sub.nS(O).sub.uR.sup.13, (CH.sub.2).sub.nOC(O)R.sup.13,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nSR.sup.11,
CH.dbd.N--OA, CH.sub.2CH.dbd.N--OA, (CH.sub.2).sub.nNHOA,
(CH.sub.2).sub.nCH.dbd.N--R.sup.11,
(CH.sub.2).sub.nOC(O)NR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11COOR.sup.12,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2OR.sup.13,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2OCF.sub.3,
(CH.sub.2).sub.nN(R.sup.11)C(R.sup.13)HCOOR.sup.12,
C(R.sup.13)HCOR.sup.12,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2N(R.sup.12)CH.sub.2COOR.sup.12-
, (CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2NR.sup.11R.sup.12,
CH.dbd.CHCOOR.sup.11, CH.dbd.CHCH.sub.2NR.sup.11R.sup.12,
CH.dbd.CHCH.sub.2NR.sup.11R.sup.12, CH.dbd.CHCH.sub.2OR.sup.13,
(CH.sub.2).sub.nN(COOR.sup.11)COOR.sup.12,
(CH.sub.2).sub.nN(CONH.sub.2)COOR.sup.11,
(CH.sub.2).sub.nN(CONH.sub.2)CONH.sub.2,
(CH.sub.2).sub.nN(CH.sub.2COOR.sup.11)COOR.sup.12,
(CH.sub.2).sub.nN(CH.sub.2CONH.sub.2)COOR.sup.11,
(CH.sub.2).sub.nN(CH.sub.2CONH.sub.2)CONH.sub.2,
(CH.sub.2).sub.nCHR.sup.13COR.sup.11,
(CH.sub.2).sub.nCHR.sup.13COOR.sup.11,
(CH.sub.2).sub.nCHR.sup.13CH.sub.2OR.sup.14, (CH.sub.2).sub.nOCN
and (CH.sub.2).sub.nNCO, R.sup.11, R.sup.12 are independently
selected from H, A, (CH.sub.2).sub.mAr.sup.3 and
(CH.sub.2).sub.mHet, or, in NR.sup.11R.sup.12, R.sup.11 and
R.sup.12 form, together with the N-Atom they are bound to, a 5-, 6-
or 7-membered heterocycle which optionally contains 1 or 2
additional hetero atoms, selected from N, O an S, R.sup.13,
R.sup.14 are independently selected from H, Hal, A,
(CH.sub.2).sub.mAr.sup.4 and (CH.sub.2).sub.mHet, A is selected
from alkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, alkoxy and
alkoxyalkyl, Ar.sup.3, Ar.sup.4 are independently from one another
aromatic hydrocarbon residues comprising 5 to 12 which are
optionally substituted by one or more substituents, selected from
A, Hal, NO.sub.2, CN, OR.sup.15, NR.sup.15R.sup.16, COOR.sup.15,
CONR.sup.15R.sup.16, NR.sup.15COR.sup.16,
NR.sup.15CONR.sup.15R.sup.16, NR.sup.16SO.sub.2A, COR.sup.15,
SO.sub.2R.sup.15R.sup.16, S(O).sub.uA and OOCR.sup.15, Het is a
saturated, unsaturated or aromatic heterocyclic residue which is
optionally substituted by one or more substituents, selected from
A, Hal, NO.sub.2, CN, OR.sup.15, NR.sup.15R.sup.16, COOR.sup.15,
CONR.sup.15R.sup.16, NR.sup.15COR.sup.16,
NR.sup.15CONR.sup.15R.sup.16, NR.sup.16SO.sub.2A, COR.sup.15,
SO.sub.2R.sup.15R.sup.16, S(O).sub.uA and OOCR.sup.15, R.sup.15,
R.sup.16 are independently selected from H, A, and
(CH.sub.2).sub.mAr.sup.5, Ar.sup.5 is a 5- or 6-membered aromatic
hydrocarbon which is optionally substituted by one or more
substituents selected from methyl, ethyl, propyl, 2-propyl,
tert.-butyl, Hal, CN, OH, NH.sub.2 and CF.sub.3, k, n, m are
independently of one another 0, 1, 2, 3, 4, or 5; X represents a
bond or is (CR.sup.11R.sup.12).sub.h, or
(CHR.sup.11).sub.h-Q-(CHR.sup.12).sub.i, Q is selected from O, S,
N--R.sup.15, (CHal.sub.2).sub.j, (O--CHR.sup.18).sub.j,
(CHR.sup.18--O).sub.j, CR.sup.18.dbd.CR.sup.19,
(O--CHR.sup.18CHR.sup.19).sub.j, CHR.sup.18CHR.sup.19--O).sub.j,
C.dbd.O, C.dbd.S, C.dbd.NR.sup.15, CH(OR.sup.15),
C(OR.sup.17)(OR.sup.20), C(.dbd.O)O, OC(.dbd.O), OC(.dbd.O)O,
C(.dbd.)N(R.sup.15), N(R.sup.15)C(.dbd.O), OC(.dbd.O)N(R.sup.15),
N(R.sup.15)C(.dbd.O)O, CH.dbd.N--O, CH.dbd.N--NR.sup.15,
OC(O)NR.sup.15, NR.sup.15C(O)O, S.dbd.O, SO.sub.2,
SO.sub.2NR.sup.15 and NR.sup.15SO.sub.2, h, i are independently
from each other 0, 1, 2, 3, 4, 5 or 6, j is 1, 2, 3, 4, 5 or 6, Y
is selected from O, S, NR.sup.21, C(R.sup.22)--NO.sub.2,
C(R.sup.22)--CN and C(CN).sub.2, R.sup.21 is H, Hal, A,
(CH.sub.2).sub.mAr.sup.4 and (CH.sub.2).sub.mHet, R.sup.22 is H, A,
(CH.sub.2).sub.mAr.sup.3 and (CH.sub.2).sub.mHet, p, r are
independently from one another 0, 1, 2, 3, 4 or 5, q is 0, 1, 2, 3
or 4, u is 0, 1, 2 or 3, and Hal is independently selected from F,
Cl, Br and I; and the salts and solvates thereof.
4. A method according to claim 1, wherein said compound is selected
from the compounds of formulas IIa, IIb, IIc, IId, IIe, IIf, IIg
and IIh, ##STR00518## ##STR00519## wherein R.sup.8, R.sup.9 and
R.sup.10 are independently selected from H, A, cycloalkyl
comprising 3 to 7 carbon atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2,
C(Hal).sub.3, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nOR.sup.11,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOOR.sup.12, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.2NR.sup.11COR.sup.13,
(CH.sub.2).sub.nNR.sup.11CONR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11SO.sub.2A,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12,
(CH.sub.2).sub.nS(O).sub.uR.sup.13, (CH.sub.2).sub.nOC(O)R.sup.13,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nSR.sup.11,
CH.dbd.N--OA, CH.sub.2CH.dbd.N--OA, (CH.sub.2).sub.nNHOA,
(CH.sub.2).sub.nCH.dbd.N--R.sup.11,
(CH.sub.2).sub.nOC(O)NR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11COOR.sup.12,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2OR.sup.13,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2OCF.sub.3,
(CH.sub.2).sub.nN(R.sup.11)C(R.sup.13)HCOOR.sup.12,
C(R.sup.13)HCOR.sup.12,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2N(R.sup.12)CH.sub.2COOR.sup.12-
, (CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2NR.sup.11R.sup.12,
CH.dbd.CHCOOR.sup.11, CH.dbd.CHCH.sub.2NR.sup.11R.sup.12,
CH.dbd.CHCH.sub.2NR.sup.11R.sup.12, CH.dbd.CHCH.sub.2OR.sup.13,
(CH.sub.2).sub.nN(COOR.sup.11)COOR.sup.12,
(CH.sub.2).sub.nN(CONH.sub.2)COOR.sup.11,
(CH.sub.2).sub.nN(CONH.sub.2)CONH.sub.2,
(CH.sub.2).sub.nN(CH.sub.2COOR.sup.11)COOR.sup.12,
(CH.sub.2).sub.nN(CH.sub.2CONH.sub.2)COOR.sup.11,
(CH.sub.2).sub.nN(CH.sub.2CONH.sub.2)CONH.sub.2,
(CH.sub.2).sub.nCHR.sup.13COR.sup.11,
(CH.sub.2).sub.nCHR.sup.13COOR.sup.11,
(CH.sub.2).sub.nCHR.sup.13CH.sub.2OR.sup.14, (CH.sub.2).sub.nOCN
and (CH.sub.2).sub.nNCO, R.sup.11, R.sup.12 are independently
selected from H, A, (CH.sub.2).sub.mAr.sup.3 and
(CH.sub.2).sub.mHet, or, in NR.sup.11R.sup.12, R.sup.11 and
R.sup.12 form, together with the N-Atom they are bound to, a 5-, 6-
or 7-membered heterocycle which optionally contains 1 or 2
additional hetero atoms, selected from N, O an S, R.sup.13,
R.sup.14 are independently selected from H, Hal, A,
(CH.sub.2).sub.mAr.sup.4 and (CH.sub.2).sub.mHet, A is selected
from alkyl, alkenyl, cycloalkyl, alkylenecycloalkyl alkoxy and
alkoxyalkyl, Ar.sup.3, Ar.sup.4 are independently from one another
aromatic hydrocarbon residues comprising 5 to 12 carbon atoms which
are optionally substituted by one or more substituents, selected
from A, Hal, NO.sub.2, CN, OR.sup.15, NR.sup.15R.sup.16,
COOR.sup.15, CONR.sup.15R.sup.16, NR.sup.15COR.sup.16,
NR.sup.15CONR.sup.15R.sup.16, NR.sup.16SO.sub.2A, COR.sup.15,
SO.sub.2R.sup.15R.sup.16, S(O).sub.uA and OOCR.sup.15, Het is a
saturated, unsaturated or aromatic heterocyclic residue which is
optionally substituted by one or more substituents, selected from
A, Hal, NO.sub.2, CN, OR.sup.15, NR.sup.15R.sup.16, COOR.sup.15,
CONR.sup.15R.sup.16, NR.sup.15COR.sup.16, NR.sup.15CONR.sup.16,
NR.sup.6SO.sub.2A, COR.sup.15, SO.sub.2R.sup.15R.sup.16,
S(O).sub.uA and OOCR.sup.15, R.sup.15, R.sup.16 are independently
selected from H, A, and (CH.sub.2).sub.mAr.sup.5, Ar.sup.5 is a 5-
or 6-membered aromatic hydrocarbon which is optionally substituted
by one or more substituents selected from methyl, ethyl, propyl,
2-propyl, tert.-butyl, Hal, CN, OH, NH.sub.2 and CF.sub.3, n, m are
independently of one another 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3,
4 or 5, q is 0, 1, 2, 3 or 4, u is 0, 1, 2 or 3, Y is selected from
O, S, NR.sup.21, C(R.sup.22)--NO.sub.2, C(R.sup.22)--CN and
C(CN).sub.2, R.sup.21 is H, Hal, A, (CH.sub.2).sub.mAr.sup.4 and
(CH.sub.2).sub.mHet R.sup.22 is H, A, (CH.sub.2).sub.mAr.sup.3 and
(CH.sub.2).sub.mHet, and the salts and solvates thereof.
5. A method according to claim 1, wherein said compound is selected
from ##STR00520## ##STR00521##
6. (canceled)
7. (canceled)
8. A method according to claim 1, wherein said kinases are
raf-kinases.
9. (canceled)
10. (canceled)
11. (canceled)
12. (canceled)
13. (canceled)
14. (canceled)
15. (canceled)
16. A method according to claim 1, wherein said disorders are
selected from hyperproliferative and nonhyperproliferative
disorders.
17. A method according to claim 1, wherein said disorder is
cancer.
18. A method according to claim 1, wherein said disorder is
noncancerous.
19. A method according to claim 1 wherein said noncancerous
disorder is selected from infection, psoriasis, arthritis,
inflammation, endometriosis, scarring, benign prostatic
hyperplasia, immunological diseases, autoimmune diseases and
immunodeficiency diseases.
20. A method according to claim 1, wherein said disorders are
selected from brain cancer, lung cancer, squamous cell cancer,
bladder cancer, gastric cancer, pancreatic cancer, hepatic cancer,
renal cancer, colorectal cancer, breast cancer, head cancer, neck
cancer, oesophageal cancer, gynaecological cancer, thyroid cancer,
lymphoma, chronic leukemia and acute leukemia.
21. A method according to claim 1, wherein said disorders are
selected from arthritis, restenosis, fibrotic disorders, mesangial
cell proliferative disorders, diabetic nephropathy, malignant
nephrosclerosis, thrombotic microangiopathy syndromes, organ
transplant rejection, glomerulopathies, metabolic disorders,
inflammation and neurodegenerative diseases.
22. (canceled)
23. A method according to claim 8, wherein said raf-kinase is
selected from A-Raf, B-Raf and c-Raf-11.
24. (canceled)
25. (canceled)
26. (canceled)
27. A method according to claim 1, wherein said disorder is
cancerous cell growth mediated by raf-kinase.
28. (canceled)
29. A compound of formula III, ##STR00522## wherein L.sup.1 is Cl,
Br, I, OH, a reactive esterified OH-group or a diazonium moiety,
R.sup.8 is selected from H, A, cycloalkyl comprising 3 to 7 carbon
atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2, C(Hal).sub.3, NO.sub.2,
(CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nOR.sup.11,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOOR.sup.12, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11COR.sup.13,
(CH.sub.2).sub.nNR.sup.11CONR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11SO.sub.2A,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12,
(CH.sub.2).sub.nS(O).sub.nR.sup.13, (CH.sub.2).sub.nOC(O)R.sup.13,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nSR.sup.11,
CH.dbd.N--OA, CH.sub.2CH.dbd.N--OA, (CH.sub.2).sub.nNHOA,
(CH.sub.2).sub.nCH.dbd.N--R.sup.11,
(CH.sub.2).sub.nOC(O)NR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11COOR.sup.12,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2OR.sup.13,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2OCF.sub.3,
(CH.sub.2).sub.nN(R.sup.11)C(R.sup.13)HCOOR.sup.12,
C(R.sup.13)HCOR.sup.12,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2N(R.sup.12)CH.sub.2COOR.sup.12-
, (CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2NR.sup.11R.sup.12,
CH.dbd.CHCOOR.sup.11, CH.dbd.CHCH.sub.2NR.sup.11R.sup.12,
CH.dbd.CHCH.sub.2NR.sup.11R.sup.12, CH.dbd.CHCH.sub.2OR.sup.13,
(CH.sub.2).sub.nN(COOR.sup.11)COOR.sup.12,
(CH.sub.2).sub.nN(CONH.sub.2)COOR.sup.11,
(CH.sub.2).sub.nN(CONH.sub.2)CONH.sub.2,
(CH.sub.2).sub.nN(CH.sub.2COOR.sup.11)COOR.sup.12,
(CH.sub.2).sub.nN(CH.sub.2CONH.sub.2)COOR.sup.11,
(CH.sub.2).sub.nN(CH.sub.2CONH.sub.2)CONH.sub.2,
(CH.sub.2).sub.nCHR.sup.13COR.sup.11,
(CH.sub.2).sub.nCHR.sup.13COOR.sup.11,
(CH.sub.2).sub.nCHR.sup.13CH.sub.2OR.sup.14, (CH.sub.2).sub.nOCN
and (CH.sub.2).sub.nNCO, p is 0, 1, 2, 3, 4 or 5, Ar.sup.1 is
selected from aromatic hydrocarbons containing 6 to 14 carbon atoms
and ethylenical unsaturated or aromatic heterocyclic residues
containing 3 to 10 carbon atoms and one or two hetero atoms,
independently selected from N, O and S, Y is selected from O, S,
NR.sup.21, C(R.sup.22)--NO.sub.2, C(R.sup.22)--CN and C(CN).sub.2,
R.sup.11, R.sup.12 are independently selected from H, A,
(CH.sub.2).sub.mAr.sup.3 and (CH.sub.2).sub.mHet, or, in
NR.sup.11R.sup.12, R.sup.11 and R.sup.12 form, together with the
N-Atom they are bound to, a 5-, 6- or 7-membered heterocycle which
optionally contains 1 or 2 additional hetero atoms, selected from
N, O an S, n, m are independently of one another 0, 1, 2, 3, 4, or
5, A is selected from alkyl, alkenyl, cycloalkyl,
alkylenecycloalkyl, alkoxy and alkoxyalkyl, R.sup.13, R.sup.14 are
independently selected from H, Hal, A, (CH.sub.2).sub.mAr.sup.4 and
(CH.sub.2).sub.mHet, Ar.sup.3, Ar.sup.4 are independently from one
another aromatic hydrocarbon residues comprising 5 to 12 carbon
atoms which are optionally substituted by one or more substituents,
selected from A, Hal, NO.sub.2, CN, OR.sup.15,
NR.sup.15R.sup.16COOR.sup.15, CONR.sup.15R.sup.16,
NR.sup.15COR.sup.16, NR.sup.15CONR.sup.15R.sup.16,
NR.sup.16SO.sub.2A, COR.sup.15, SO.sub.2R.sup.15R.sup.16,
S(O).sub.uA and OOCR.sup.15, Het is a saturated, unsaturated or
aromatic heterocyclic residue which is optionally substituted by
one or more substituents, selected from A, Hal, NO.sub.2, CN,
OR.sup.15, NR.sup.15R.sup.16, COOR.sup.15, CONR.sup.15R.sup.16,
NR.sup.15COR.sup.16, NR.sup.15CONR.sup.15R.sup.16,
NR.sup.16SO.sub.2A, COR.sup.15, SO.sub.2R.sup.15R.sup.16,
S(O).sub.uA and OOCR.sup.15, R.sup.15, R.sup.16 are independently
selected from H, A, and (CH.sub.2).sub.mAR.sup.5, Ar.sup.5 is a 5-
or 6-membered aromatic hydrocarbon which is optionally substituted
by one or more substituents selected from methyl, ethyl, propyl,
2-propyl, tert.-butyl, Hal, CN, OH, NH.sub.2 and CF.sub.3. u is 0,
1, 2 or 3, R.sup.21 is H, Hal, A, (CH.sub.2).sub.mAr.sup.4 and
(CH.sub.2).sub.mHet, R.sup.22 is H, A, (CH.sub.2).sub.mAr.sup.3 and
(CH.sub.2).sub.mHet.
30. A compound of formula IV, ##STR00523## wherein L.sup.2, L.sup.3
are independently from one another H or a metal ion, R.sup.9 and
R.sup.10 are independent from one another selected from H, A,
cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH.sub.2Hal,
CH(Hal).sub.2, C(Hal).sub.3, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nOR.sup.11,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOOR.sup.12, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11COR.sup.13,
(CH.sub.2).sub.nNR.sup.11CONR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11SO.sub.2A,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12,
(CH.sub.2).sub.nS(O).sub.uR.sup.13, (CH.sub.2).sub.nOC(O)R.sup.13,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nSR.sup.11,
CH.dbd.N--OA, CH.sub.2CH.dbd.N--OA, (CH.sub.1).sub.nNHOA,
(CH.sub.2).sub.nCH.dbd.N--R.sup.11,
(CH.sub.2).sub.nOC(O)NR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11COOR.sup.12,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2OR.sup.13,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2OCF.sub.3,
(CH.sub.2).sub.nN(R.sup.11)C(R.sup.13)HCOOR.sup.12,
C(R.sup.13)HCOR.sup.12,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2N(R.sup.12)CH.sub.2COOR.sup.12-
, (CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2NR.sup.11R.sup.12,
CH.dbd.CHCOOR.sup.11, CH.dbd.CHCH.sub.2NR.sup.11R.sup.12,
CH.dbd.CHCH.sub.2NR.sup.11R.sup.12, CH.dbd.CHCH.sub.2OR.sup.13,
(CH.sub.2).sub.nN(COOR.sup.11)COOR.sup.12,
(CH.sub.2).sub.nN(CONH.sub.2)COOR.sup.11,
(CH.sub.2).sub.nN(CONH.sub.2)CONH.sub.2,
(CH.sub.2).sub.nN(CH.sub.2COOR.sup.11)COOR.sup.12,
(CH.sub.2).sub.nN(CH.sub.2CONH.sub.2)COOR.sup.11,
(CH.sub.2).sub.nN(CH.sub.2CONH.sub.2)CONH.sub.2,
(CH.sub.2).sub.nCHR.sup.13COR.sup.11,
(CH.sub.2).sub.nCHR.sup.13COOR.sup.11,
(CH.sub.2).sub.nCHR.sup.13CH.sub.2OR.sup.14, (CH.sub.2).sub.nOCN
and (CH.sub.2).sub.nNCO, A is selected from alkyl, alkenyl,
cycloalkyl, alkylenecycloalkyl, alkoxy and alkoxyalkyl, R.sup.11,
R.sup.12 are independently selected from H, A,
(CH.sub.2).sub.mAr.sup.3 and (CH.sub.2).sub.mHet, or, in
NR.sup.11R.sup.12, R.sup.11 and R.sup.12 form, together with the
N-Atom they are bound to, a 5-, 6- or 7-membered heterocycle which
optionally contains 1 or 2 additional hetero atoms, selected from
N, O an S, k, n, m are independently of one another 0, 1, 2, 3, 4,
or 5, R.sup.13, R.sup.14 are independently selected from H, Hal, A,
(CH.sub.2).sub.mAr.sup.4 and (CH.sub.2).sub.mHet, Ar.sup.3,
Ar.sup.4 are independently from one another aromatic hydrocarbon
residues comprising 5 to 12 carbon atoms which are optionally
substituted by one or more substituents, selected from A, Hal,
NO.sub.2, CN, OR.sup.15, NR.sup.15R.sup.16, COOR.sup.15,
CONR.sup.15R.sup.16, NR.sup.15COR.sup.16,
NR.sup.15CONR.sup.15R.sup.16, NR.sup.16SO.sub.2A, COR.sup.15,
SO.sub.2R.sup.15R.sup.16, S(O).sub.uA and OOCR.sup.15, q is 0, 1,
2, 3, or 4, X represents a bond or is (CR.sup.11R.sup.12).sub.h, or
(CHR.sup.11).sub.h-Q-(CHR.sup.12).sub.i, Ar.sup.2 is selected from
aromatic hydrocarbons containing 6 to 14 carbon atoms and
ethylenical unsaturated or aromatic heterocyclic residues
containing 3 to 10 carbon atoms and one or two hetero atoms,
independently selected from N, O and S, Het is a saturated,
unsaturated or aromatic heterocyclic residue which is optionally
substituted by one or more substituents, selected from A, Hal,
NO.sub.2--CN, OR.sup.15, NR.sup.15R.sup.16, COOR.sup.15,
CONR.sup.15R.sup.16, NR.sup.15COR.sup.16,
NR.sup.15CONR.sup.15R.sup.16, NR.sup.16SO.sub.2A, COR.sup.15,
SO.sub.2R.sup.15R.sup.16, S(O).sub.uA and OOCR.sup.15, R.sup.15,
R.sup.16 are independently selected from H, A, and
(CH.sub.2).sub.mAr.sup.5, Ar.sup.5 is a 5- or 6-membered aromatic
hydrocarbon which is optionally substituted by one or more
substituents selected from methyl, ethyl, propyl, 2-propyl,
tert.-butyl, Hal, CN, OH, NH.sub.2 and CF.sub.3, u is 0, 1, 2 or 3,
h, i are independently from each other 0, 1, 2, 3, 4, 5 or 6, and r
is 0, 1, 2, 3, 4 or 5.
31. A method according to claim 3, wherein Ar.sup.1 is phenyl,
pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl, p is 1, 2
or 3, R.sup.8 is selected from the group consisting of alkyl
comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon
atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl comprising 1
to 4 carbon atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nCOR.sup.13,
(CH.sub.2).sub.nCOOR.sup.11, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13 wherein n is 0 or 1, u is 0 or
2, q is 0 or 1, and X is O, S, NR.sup.15, CHOR.sup.11, CH.sub.2,
CH.sub.2CH.sub.2, OCH.sub.2, CH.sub.2O, OCH.sub.2CH.sub.2, or
CH.sub.2CH.sub.2O.
32. A method according to claim 31, wherein A.sup.2 is phenyl or
pyridinyl.
33. A method according to claim 31, wherein X is O or S.
34. A method according to claim 31, wherein Y is O or S.
35. A method according to claim 31, wherein A.sup.1 is phenyl or
oxazolyl.
36. A method according to claim 31, wherein A.sup.2 is
pyridinyl.
37. A method according to claim 31, wherein X is O.
38. A method according to claim 31, wherein Y is O.
39. A method according to claim 31, wherein Ar.sup.1 is phenyl,
pyridinyl or isoxazolyl.
40. A method according to claim 39, wherein A.sup.1 is phenyl.
41. A method according to claim 3, wherein A is alkyl having 1 to
10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl,
sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having
3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon
atoms, alkoxy having 1 to 10 carbon atoms, or
C.sub.uH.sub.2u+1--O--(CH.sub.2).sub.v wherein u is 1 to 6 and v is
1 to 6.
42. A method according to claim 4, wherein A is alkyl having 1 to
10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl,
sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having
3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon
atoms, alkoxy having 1 to 10 carbon atoms, or
C.sub.uH.sub.2u+1--O--(CH.sub.2).sub.v wherein u is 1 to 6 and v is
1 to 6.
43. A method according to claim 39, wherein A is alkyl having 1 to
10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl,
sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having
3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon
atoms, alkoxy having 1 to 10 carbon atoms, or
C.sub.uH.sub.2u+1--O--(CH.sub.2).sub.v wherein u is 1 to 6 and v is
1 to 6.
44. A compound according to claim 35, wherein A is alkyl having 1
to 10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl,
sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having
3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon
atoms, alkoxy having 1 to 10 carbon atoms, or
C.sub.uH.sub.2u+1--O--(CH.sub.2).sub.v wherein u is 1 to 6 and v is
1 to 6.
45. A compound according to claim 40, wherein A is alkyl having 1
to 10 carbon atoms, allyl, 2-butenyl, 3-butenyl, isobutenyl,
sec-butenyl, 4-pentenyl, isopentenyl, 5-hexenyl, cycloalkyl having
3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon
atoms, alkoxy having 1 to 10 carbon atoms, or
C.sub.uH.sub.2u+1--O--(CH.sub.2).sub.v wherein u is 1 to 6 and v is
1 to 6.
46. A compound according to claim 39, wherein A.sup.2 is pyridinyl
and X is O.
47. A compound according to claim 35, wherein A.sup.2 is pyridinyl
and X is O.
48. A compound according to claim 40, wherein A.sup.2 is pyridinyl
and X is O.
49. A compound according to claim 43, wherein A.sup.2 is pyridinyl
and X is O.
50. A compound according to claim 44, wherein A.sup.2 is pyridinyl
and X is O.
51. A compound according to claim 45, wherein A.sup.2 is pyridinyl
and X is O.
Description
[0001] The present invention relates to glycine amide derivatives,
glycine amide derivatives as medicaments, glycine amide derivatives
as inhibitors of raf-kinase, the use of glycine amide derivatives
for the manufacture of a pharmaceutical, a method for producing a
pharmaceutical composition containing said glycine amide
derivatives, the pharmaceutical composition obtainable by said
method and a method of treatment, comprising administering said
pharmaceutical composition.
[0002] Protein phosphorylation is a fundamental process for the
regulation of cellular functions. The coordinated action of both
protein kinases and phosphatases controls the levels of
phosphorylation and, hence, the activity of specific target
proteins. One of the predominant roles of protein phosphorylation
is in signal transduction, where extracellular signals are
amplified and propagated by a cascade of protein phosphorylation
and dephosphorylation events, e.g. in the p21.sup.ras/raf
pathway.
[0003] The p21.sup.ras gene was discovered as an oncogene of the
Harvey (rash) and Kirsten (rasK) rat sarcoma viruses. In humans,
characteristic mutations in the cellular ras gene (c-ras) have been
associated with many different types of cancers. These mutant
alleles, which render Ras constitutively active, have been shown to
transform cells, such as the murine cell line NIH 3T3, in
culture.
[0004] The p21.sup.ras oncogene is a major contributor to the
development and progression of human solid cancers and is mutated
in 30% of all human cancers (Bolton et al. (1994) Ann. Rep. Med.
Chem., 29, 165-74; Bos. (1989) Cancer Res., 49, 4682-9). In its
normal, unmutated form, the ras protein is a key element of the
signal transduction cascade directed by growth factor receptors in
almost ltittissues (Avruch et al. (1994) Trends Biochem. Sci., 19,
279-83).
[0005] Biochemically, ras is a guanine nucleotide binding protein,
and cycling between a GTP-bound activated and a GDP-bound resting
form is strictly controlled by ras endogenous GTPase activity and
other regulatory proteins. The ras gene product binds to guanine
triphosphate (GTP) and guanine diphosphate (GDP) and hydrolyzes GTP
to GDP. It is the GTP-bound state of Ras that is active. In the ras
mutants in cancer cells, the endogenous GTPase activity is
alleviated and, therefore, the protein delivers constitutive growth
signals to downstream effectors such as the enzyme raf kinase. This
leads to the cancerous growth of the cells which carry these
mutants (Magnuson et al. (1994) Semin. Cancer Biol., 5, 247-53).
The ras proto-oncogene requires a functionally intact c-rat1
proto-oncogene in order to transduce growth and differentiation
signals initiated by receptor and non-receptor tyrosine kinases in
higher eukaryotes.
[0006] Activated Ras is necessary for the activation of the c-raf1
proto-oncogene, but the biochemical steps through which Ras
activates the Rat-1 protein (Ser/Thr) kinase are now well
characterized. It has been shown that inhibiting the effect of
active ras by inhibiting the rat kinase signaling pathway by
administration of deactivating antibodies to rat kinase or by
co-expression of dominant negative rat kinase or dominant negative
MEK (MAPKK), the substrate of rat kinase, leads to the reversion of
transformed cells to the normal growth phenotype see. Daum et al.
(1994) Trends Biochem. Sci., 19, 474-80; Fridman et al. (1994) J.
Biol. Chem., 269, 30105-8. Kolch et al. (1991) Nature, 349, 426-28)
and for review Weinstein-Oppenheimer et al. Pharm. & Therap.
(2000), 88, 229-279.
[0007] Similarly, inhibition of rat kinase (by antisense
oligodeoxynucleotides) has been correlated in vitro and in vivo
with inhibition of the growth of a variety of human tumor types
(Monia et al., Nat. Med. 1996, 2, 668-75).
[0008] Raf serine- and threonine-specific protein kinases are
cytosolic enzymes that stimulate cell growth in a variety of cell
systems (Rapp, U. R., et al. (1988) in The oncogene handbook; T.
Curran, E. P. Reddy, and A. Skalka (ed.) Elsevier Science
Publishers; The Netherlands, pp. 213-258; Rapp, U. R., et al.
(1988) Cold Spring Harbor Sym. Quant. Biol. 53:173-184; Rapp, U.
R., et al. (1990) Inv Curr. Top. Microbiol. Amunol. Potter and
Melchers (eds), Berlin, Springer-Verlag 166:129-139).
[0009] Three isozymes have been characterized:
[0010] c-Rat (Raf-1) (Bonner, T. I., et al. (1986) Nucleic Acids
Res. 14:1009-1015). A-Raf (Beck, T. W., et al. (1987) Nucleic Acids
Res. 15:595-609), and B-Raf (Qkawa, S., et al. (1998) Mol. Cell.
Biol. 8:2651-2654; Sithanandam, G. et al. (1990) Oncogene: 1775).
These enzymes differ in their expression in various tissues. Raf-1
is expressed in all organs and in all cell lines that have been
examined, and A- and B-Raf are expressed in urogenital and brain
tissues, respectively (Storm, S. M. (1990) Oncogene 5:345-351).
[0011] Rat genes are proto-oncogenes: they can initiate malignant
transformation of cells when expressed in specifically altered
forms. Genetic changes that lead to oncogenic activation generate a
constitutively active protein kinase by removal or interference
with an N-terminal negative regulatory domain of the protein
(Heidecker, G., et al. (1990) Mol. Cell. Biol. 10:2503-2512; Rapp,
U. R., et al. (1987) in Oncogenes and cancer S. A. Aaronson, J.
Bishop, T. Sugimura, M. Terada, K. Toyoshima, and P. K. Vogt (ed).
Japan Scientific Press, Tokyo). Microinjection into NIH 3T3 cells
of oncogenically activated but not wild-type versions of the
Raf-protein prepared with Escherichia coli expression vectors
results in morphological transformation and stimulates DNA
synthesis (Rapp, U. R., et al. (1987) in Oncogenes and cancer; S.
A. Aaronson, J. Bishop, T. Sugimura, M. Terada, K. Toyoshima, and
P. K. Vogt (ed.) Japan Scientific Press, Tokyo; Smith, M. R., et al
(1990) Mol. Cell. Biol. 10:3828-3833). Activating mutants of B-Rat
have been identified in a wide range of human cancers e.g. colon,
ovarien, melanomas and sarcomas (Davies, H., et al. (2002), Nature
417 949-945. Published online Jun. 9, 2002, 10.1038/nature00766).
The preponderant mutation is a single phosphomimetic substitution
in the kinase activation domain (V599E), leading to constitutive
kinase activity and transformation of NIH3T3 cells.
[0012] Thus, activated Raf-1 is an intracellular activator of cell
growth. Raf-1 protein serine kinase in a candidate downstream
effector of mitogen signal transduction, since Raf oncogenes
overcome growth arrest resulting from a block of cellular ras
activity due either to a cellular mutaton (ras revertant cells) or
microinjection of anti-ras antibodies (Rapp, U. R., et al. (1988)
in The Oncogene Handbook, T. Curran, E. P. Reddy, and A. Skalka
(ed.), Elsevier Science Publishers; The Netherlands, pp. 213-253;
Smith, M. R., et al. (1986) Nature (London) 320:540-543).
[0013] c-Raf function is required for transformation by a variety
of membrane-bound oncogenes and for growth stimulation by mitogens
contained in serums (Smith, M. R., et al. (1986) Nature (London)
320:540-543). Raf-1 protein serine kinase activity is regulated by
mitogens via phosphorylation (Morrison, D. K., et al. (1989) Cell
58:648-657), which also effects sub cellular distribution (Olah,
Z., et al. (1991) Exp. Brain Res, 84:403; Rapp, U. R., et al.
(1988) Cold Spring Harbor Sym. Quant. Biol. 53:173-184. Rat-1
activating growth factors include platelet-derived growth factor
(PDGF) (Morrison, D. K., et al. (1988) Proc. Natl. Acad. Sci. USA
85:8855-8859), colony-stimulating factor (Baccarini, M., et al.
(1990) EMBO J. 9:3649-3657), insulin (Blackshear, P. J., et al.
(1990) J. Biol. Chem. 265:12115-12118), epidermal growth factor
(EGF) (Morrison, R. K., et al. (1988) Proc. Natl. Acad. Sci. USA
85:8855-8859), interleukin 2 (Turner, B. C., et al (1991) Proc.
Natl. Acad. Sci. USA 88:1227), and interleukin 3 and
granulocytemacrophage colony-stimulating factor (Carroll, M. P., et
al (1990) J. Biol. Chem. 265:19812-19817).
[0014] Upon mitogen treatment of cells, the transiently activated
Raf-1 protein serine kinase translocates to the perinuclear area
and the nucleus (Olah, Z., et al. (1991) Exp. Brain Res. 84:403;
Rapp, U. R., et al. (1988) Cold Spring Habor Sym, Quant. Biol.
53:173-184). Cells containing activated Raf are altered in their
pattern of gene expression (Heidecker, G., et al. (1989) in Genes
and signal transduction in multistage carcinogenesis, N. Colburn
(ed.), Marcel Dekker, Inc., New York, pp. 339-374), and Rat
oncogenes activate transcription from Ap-I/PEA3-dependent promoters
In transient transfection assays (Jamal, S., et al (1990) Science
344:463-466; Kaibuchi, K., et al (1989) J. Biol. Chem.
264:20855-20858; Wasylyk, C., et al. (1989) Mol. Cell. Biol.
9:2247-2250).
[0015] There are at least two independent pathways for Raf-1
activation by extracellular mitogens: one involving protein kinase
C (KC) and a second initiated by protein tyrosine kinases
(Blackshear, P. J., et al. (1990) J. Biol. Chem. 265:12131-12134;
Kovacina, K. S., et al (1990) J. Biol. Chem. 265:12115-12118;
Morrison, D. K., et al. (1988) Proc. Natl. Acad. Sci. USA
85:8856-8859; Siegel, J. N., et al (1990) J. Biol. Chem.
265:18472-18480; Turner, B. C., et al (1991) Proc. Natl. Acad. Sol.
USA 88:1227). In either case, activation involves Raf-1 protein
phosphorylation. Raf-1 phosphorylation may be a consequence of a
kinase cascade amplified by autophosphorylation or may be caused
entirely by autophosphorylation initiated by binding of a putative
activating ligand to the Raf-1 regulatory domain, analogous to PKC
activation by diacylglycerol (Nishizuka, Y. (1986) Science
233:305-312).
[0016] The process of angiogenesis is the development of new blood
vessels, generally capillaries, from pre-existing vasculature.
Angiogenesis is defined as involving (i) activation of endothelial
cells; (ii) increased vascular permeability; (iii) subsequent
dissolution of the basement membrane and extravisation of plasma
components leading to formation of a provisional fibrin gel
extracellular matrix; (iv) proliferation and mobilization of
endothelial cells; (v) reorganization of mobilized endothelial
cells to form functional capillaries; (vi) capillary loop
formation; and (vii) deposition of basement membrane and
recruitment of perivascular cells to newly formed vessels.
[0017] Normal angiogenesis is activated during tissue growth, from
embryonic development through maturity, and then enters a period of
relative quiescence during adulthood.
[0018] Normal angiogensesis is also activated during wound healing,
and at certain stages of the female reproductive cycle.
Inappropriate or pathological angiogenesis has been associated with
several disease states including various retinopathies; ischemic
disease; atherosclerosis; chronic inflammatory disorders;
rheumatoid arthritis, and cancer. The role of angiogenesis in
disease states is discussed, for instance, in Fan et al, Trends in
Pharmacol Sci. 16:54 66; Shawver et al, DOT Vol. 2, No. 2 Feb.
1997; Folkmann, 1995, Nature Medicine 1:27-31.
[0019] In cancer the growth of solid tumors has been shown to be
angiogenesis dependent. (See Folkmann, J., J. Nat'l. Cancer Inst.,
1990, 82, 4-6.) Consequently, the targeting of pro-angiogenic
pathways is a strategy being widely pursued in order to provide new
therapeutics in these areas of great, unmet medical need.
[0020] Raf is involved in angiogenic processes. Endothelial growth
factors (e.g. vascular endothelial growth factor VEGF) activates
receptor tyrosine kinases (e.g. VEGFR-2) and signal through the
Ras/Raf/Mek/Erk kinase cascade. Activation of VEGFR-2 by VEGF is a
critical step in the signal transduction pathway that initiates
tumor angiogenesis. VEGF expression may be constitutive to tumor
cells and can also be upregulated in response to certain stimuli.
One such stimuli is hypoxia, where VEGF expression is upregulated
in both tumor and associated host tissues. The VEGF ligand
activates VEGFR-2 by binding with its extracellular VEGF binding
site. This leads to receptor dimerization of VEGFRs and
autophosphorylation of tyrosine residues at the intracellular
kinase domain of VEGFR-2. The kinase domain operates to transfer a
phosphate from ATP to the tyrosine residues, thus providing binding
sites for signaling proteins downstream of VEGFR-2 leading
ultimately to initiation of angiogenesis (McMahon, G., The
Oncologist, Vol. 5, No. 90001, 3-10, Apr. 2000).
[0021] Mice with a targeted disruption in the Braf gene die of
vascular defects during development (Wojnowski, L. et al. 1997,
Nature genetics 16, page 293-296). These mice show defects in the
formation of the vascular system and in angiogenesis e.g. enlarged
blood vessels and increased apoptotic death of differentiated
endothelial cells.
[0022] For the identification of a signal transduction pathway and
the detection of cross talks with other signaling pathways suitable
models or model systems have been generated by various scientists,
for example cell culture models (e.g. Khwaja et al., EMBO, 1997,
16, 2783-93) and transgenic animal models (e.g. White et al.,
Oncogene, 2001, 20, 7064-7072). For the examination of particular
steps in the signal transduction cascade, interfering compounds can
be used for signal modulation (e.g. Stephens et al., Biochemical
J., 2000, 351, 95-105). The compounds according to the invention
may also be useful as reagents for the examination of kinase
dependent signal transduction pathways in animal and/or cell
culture models or any of the clinical disorders listed throughout
this application.
[0023] The measurement of kinase activity is a well known technique
feasible for each person skilled in the art. Generic test systems
for kinase activity detection with substrates, for example histone
(e.g. Alessi et al., FEBS Lett. 1996, 399, 3, page 333-8) or myelin
basic protein are well described in the literature (e.g.
Campos-Gonzalez, R. and Glenney, Jr., J. R. 1992 J. Biol. Chem.
267, Page 14535).
[0024] For the identification of kinase inhibitors various assay
systems are available (see for example Walters et al., Nature Drug
Discovery 2003, 2; page 259-266). For example, in scintillation
proximity assays (e.g. Sorg et al., J. of. Biomolecular Screening,
2002, 7, 11-19) or flashplate assays the radioactive
phosphorylation of a protein or peptide as substrate with
.gamma.ATP can be measured. In the presence of an inhibitory
compound no signal or a decreased radioactive signal is detectable.
Furthermore homogeneous time-resolved fluorescence resonance energy
transfer (HTR-FRET), and fluorescence polarization (FP)
technologies are useful for assay methods (for example Sills et
al., J. of Biomolecular Screening, 2002, 191-214).
[0025] Other non-radioactive ELISA based assay methods use specific
phospho-antibodies (AB). The phospho-AB binds only the
phosphorylated substrate. This binding is detectable with a
secondary peroxidase conjugated antibody, measured for example by
chemiluminescence (for example Ross et al., Biochem. J., 2002, 366,
977-981).
[0026] The present invention provides compounds generally described
as glycine amide derivatives, including both aryl and/or heteroaryl
derivatives, which are preferably inhibitors of the enzyme raf
kinase. Since the enzyme is a downstream effector of p21.sup.ras,
the inhibitors are useful in pharmaceutical compositions for human
or veterinary use where inhibition of the raf kinase pathway is
indicated, e.g., in the treatment of tumors and/or cancerous cell
growth mediated by raf kinase. In particular, the compounds are
useful in the treatment of human or animal solid cancers, e.g.
murine cancer, since the progression of these cancers is dependent
upon the ras protein signal transduction cascade and therefore
susceptible to treatment by interruption of the cascade, i.e., by
inhibiting raf kinase. Accordingly, the compound of Formula I or a
pharmaceutically acceptable salt thereof is administered for the
treatment of diseases mediated by the raf kinase pathway especially
cancers, including solid cancers, such as, for example, carcinomas
(e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid
disorders (e.g., myeloid leukemia) or adenomas (e.g., villous colon
adenoma), pathological angiogenesis and metastatic cell migration.
Furthermore the compounds are useful in the treatment of complement
activation dependent chronic inflammation (Niculescu et al. (2002)
Immunol. Res., 24:191-199) and HIV-1 (human immunodeficiency virus
type1) induced immunodeficiency (Popik et al. (1998) J Virol, 72:
6406-6413).
[0027] Therefore, subject of the present invention are glycinamide
derivatives of formula I
A-D-B (I)
wherein [0028] D is a bivalent glycinamide moiety which is bonded
to A and B, preferably to one bonding partner via the N-nitrogen
atom and to the other bonding partner via the N'-nitrogen atom,
wherein the N-nitrogen atom and/or the N'-nitrogen atom is
unsubstituted or substituted with one or more substituents, wherein
said substituents are preferably selected from the group consisting
of alkyl, alkylene, haloalkyl, C.sub.3-C.sub.7-cycloalkyl,
C.sub.3-C.sub.7-cycloalkylene, heterocyclyl, aryl, aralkyl,
heteroaryl, hydroxy, alkoxy, haloalkoxy, aralkoxy, aryloxy,
mercapto, alkylsulfanyl, haloalkylsulfanyl, arylsulfanyl,
heteroarylsulfanyl, alkylsulfenyl, haloalkylsulfenyl, arylsulfenyl,
heteroarylsulfenyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, carboxy, cyano, cyanoalkyl, aminosulfonyl,
acyl, acyloxy, carbamoyl, aroyl, heteroaryl, heteroaroyloxy,
unsubstituted amino groups and substituted amino groups, and
wherein the carbonyl group of said glycine amide moiety can be
derivatized, preferably to a C.dbd.S, C.dbd.NR.sup.5,
C.dbd.C(R.sup.5)--NO.sub.2, C.dbd.C(R.sup.5)--CN or
C.dbd.C(CN).sub.2 group, [0029] A is a substituted moiety of up to
40 carbon atoms of the formula: -L-(M-L').sub..alpha., where L is a
5, 6 or 7 membered cyclic structure, preferably selected from the
group consisting of aryl, heteroaryl, arylene and heteroarylene,
bound directly to D, L' comprises an optionally substituted cyclic
moiety having at least 5 members, preferably selected from the
group consisting of aryl, heteroaryl, aralkyl, cycloalkyl and
heterocyclyl, M is a bond or a bridging group having at least one
atom, .alpha. is an integer of from 1-4; and each cyclic structure
of L and L' contains 0-4 members of the group consisting of
nitrogen, oxygen and sulfur, wherein L.alpha. is preferably
substituted by at least one substituent which is preferably
selected from the group consisting of --SO.sub..beta.R.sub.x,
--C(O)R.sub.x and --C(NR.sub.y)R.sub.z, [0030] B is a substituted
or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up
to 30 carbon atoms, preferably of up to 20 carbon atoms, comprising
at least one 5-, 6-, or 7-membered cyclic structure, preferably a
5- or 6-membered cyclic structure, bound directly to D containing
0-4 members of the group consisting of nitrogen, oxygen and sulfur,
wherein said cyclic structure directly bound to D is preferably
selected from the group consisting of aryl; heteroaryl and
heterocyclyl, [0031] R.sub.y is hydrogen or a carbon based moiety
of up to 24 carbon atoms optionally containing heteroatoms selected
from N, S and O and optionally halosubstituted, up to per halo,
[0032] R.sub.z is hydrogen or a carbon based moiety of up to 30
carbon atoms optionally containing heteroatoms selected from N, S
and O and optionally substituted by halogen, hydroxy and carbon
based substituents of up to 24 carbon atoms, which optionally
contain heteroatoms selected from N, S and O and are optionally
substituted by halogen; [0033] R.sub.x is R.sub.z or
NR.sub.aR.sub.b, where R.sub.a and R.sub.b are [0034] a)
independently hydrogen, a carbon based moiety of up to 30 carbon
atoms optionally containing heteroatoms selected from N, S and O
and optionally substituted by halogen, hydroxy and carbon based
substituents of up to 24 carbon atoms, which optionally contain
heteroatoms, selected from N, S and O, and are optionally
substituted by halogen, or --OSi(R.sub.f).sub.3 where R.sub.f is
hydrogen or a carbon based moiety of up to 24 carbon atoms
optionally containing heteroatoms selected from N, S and O and
optionally substituted by halogen, hydroxy and carbon based
substituents of up to 24 carbon atoms, which optionally contain
heteroatoms selected from N, S and O, and are optionally
substituted by halogen; or [0035] b) R.sub.a and R.sub.b together
from a 5-7 member heterocyclic structure of 1-3 heteroatoms
selected from N, S and O, or a substituted 5-7 member heterocyclic
structure of 1-3 heteroatoms selected from N, S and O substituted
by halogen, hydroxy or carbon based substituents of up to 24 carbon
atoms, which optionally contain heteroatoms selected from N, S and
O and are optionally substituted by halogen; or one of R.sub.a or
R.sub.b is --C(O)--, a C.sub.1-C.sub.5 divalent alkylene group or a
substituted C.sub.1-C.sub.5 divalent alkylene group bound to the
moiety L to form a cyclic structure with at least 5 members,
wherein the substituents of the substituted C.sub.1-C.sub.5
divalent alkylene group are selected from the group consisting of
halogen, hydroxy, and carbon based substituents of up to 24 carbon
atoms, which optionally contain heteroatoms selected from N, S and
O and are optionally substituted by halogen; where B is
substituted, L is substituted or L' is additionally substituted,
the substituents are selected from the group consisting of halogen,
up to per-halo and W.gamma., where .gamma. is 0-3; wherein each W
is independently selected from the group consisting of --CN,
--CO.sub.2R, --C(O)NR.sup.5R.sup.5, --C(O)--R.sup.5, --NO.sub.2,
--OR.sup.5, --SR.sup.5, --SO.sub.2R.sup.5, --SO.sub.3H,
--NR.sup.5R.sup.5--NR.sup.5C(O)OR.sup.5, --NR.sup.5C(O)R.sup.5,
-Q-Ar, and carbon based moieties of up to 24 carbon atoms,
optionally containing heteroatoms selected from N, S and O and
optionally substituted by one or more substituents independently
selected from the group consisting of --CN, --CO.sub.2R,
--C(O)NR.sup.5R.sup.5, --C(O)--R.sup.5, --NO.sub.2, --OR.sup.5,
--SR.sup.5, --SO.sub.2R.sup.5, --SO.sub.3H, --NR.sup.5R.sup.5,
--NR.sup.5C(O)OR.sup.5, --NR.sup.5C(O)R.sup.5 and halogen up to
per-halo; with each R.sup.5 independently selected from H or a
carbon based moiety of up to 24 carbon atoms, optionally containing
heteroatoms selected from N, S and O and optionally substituted by
halogen; wherein Q is --O--, --S--, --N(R.sup.5)--,
--(CH.sub.2).sub..beta., --C(O)--, --CH(OH)--,
--(CH.sub.2).sub..beta.--O--, --(CH.sub.2).sub..beta.--S--,
--(CH.sub.2).sub..beta.N(R.sup.5)--,
--O(CH.sub.2).sub..beta.--CHHal-, --CHal.sub.2-, --S--(CH.sub.2)--
and --N(R.sup.5)(CH.sub.2).sub..beta.-- where .beta.=1-3, and Hal
is halogen; and Ar is a 5- or 6-member aromatic structure
containing 0-2 members selected from the group consisting of
nitrogen, oxygen and sulfur, which is optionally substituted by
halogen, up to per-halo, and optionally substituted by
Z.sub..delta.1 wherein .delta.1 is 0 to 3 and each Z is
independently selected from the group consisting --CN,
--CO.sub.2R.sup.5, --C(O)NR.sup.5R.sup.5, --C(O)--R.sup.5,
--NO.sub.2, --OR.sup.5, --SR.sup.5, --NR.sup.5R.sup.5,
--NR.sup.5C(O)OR.sup.5, --NR.sup.5C(O)R.sup.5, and a carbon based
moiety of up to 24 carbon atoms, optionally containing heteroatoms
selected from N, S and O and optionally substituted by one or more
substituents selected from the group consisting of --CN,
--CO.sub.2R.sup.5, --C(O)NR.sup.5R.sup.5, C(O)--R.sup.5,
--NO.sub.2; --OR.sup.5, --SR.sup.5, --SO.sub.2R.sup.5, --SO.sub.3H,
--NR.sup.5R.sup.5, --NR.sup.5C(O)OR.sup.5--NR.sup.5C(O)R.sup.5, and
with R.sup.5 as defined above.
[0036] More preferred, in the compound of formula I, [0037] R.sub.y
is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkoxy, C.sub.2-10
alkenyl, C.sub.1-10 alkenoyl, C.sub.6-12 aryl, C.sub.3-12 hetaryl
having 1-3 heteroatoms selected from N, S and O, C.sub.7-24
aralkyl, C.sub.7-24 alkaryl, substituted C.sub.1-10 alkyl,
substituted C.sub.1-10 alkoxy, substituted C.sub.3-10 cycloalkyl
having 0-3 heteroatoms selected from N, S and O, substituted
C.sub.6-C.sub.14 aryl, substituted C.sub.3-12 hetaryl having 1-3
heteroatoms selected from N, S and O, substituted C.sub.7-24
alkaryl or substituted C.sub.7-24 aralkyl, where Ry is a
substituted group, it is substituted by halogen up to per halo,
[0038] R.sub.z is hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkoxy,
C.sub.3-10 cycloalkyl having 0-3 heteroatoms, C.sub.2-10 alkenyl,
C.sub.1-10 alkenoyl, C.sub.6-12 aryl, C.sub.3-C.sub.12 hetaryl
having 1-3 heteroatoms selected form S, N and O, C.sub.7-24
alkaryl, C.sub.7-24 aralkyl, substituted C.sub.3-C.sub.10
cycloalkyl having 0-3 heteroatoms selected from S, N and O,
substituted C.sub.3-12 hetaryl having 1-3 heteroatoms selected from
S, N and O, substituted C.sub.7-24 alkaryl or substituted
C.sub.7-C.sub.24 aralkyl where R.sub.z is a substituted group, it
is substituted by halogen up to per halo, hydroxy, C.sub.1-10
alkyl, C.sub.3-12 cycloalkyl having 0-3 heteroatoms selected from
N, S and O, substituted C.sub.3-C.sub.12 hetaryl having 1-3
heteroatoms selected from N, S and O, C.sub.1-10 alkoxy, C.sub.6-12
aryl, C.sub.1-6 halo substituted alkyl up to per halo alkyl,
C.sub.6-C.sub.12 halo substituted aryl up to per halo aryl,
C.sub.3-C.sub.12 halo substituted cycloalkyl up to per halo
cycloalkyl having 0-3 heteroatoms selected from N, S and O, halo
substituted C.sub.3-C.sub.12 hetaryl up to per halo, hetaryl having
1-3 heteroatoms selected from O, N and S, halo substituted
C.sub.7-C.sub.24 aralkyl up to per halo aralkyl, halo substituted
C.sub.7-C.sub.24 alkaryl up to per halo alkaryl, and --C(O)R.sub.g,
[0039] R.sub.a and R.sub.b are: [0040] a) independently hydrogen, a
carbon based moiety selected from the group consisting of
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-10
cycloalkyl, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, C.sub.6-12
aryl, C.sub.3-12 hetaryl having 1-3 heteroatoms selected from O, N
and S, C.sub.3-12 cycloalkyl having 0-3 heteroatoms selected from
N, S and O, C.sub.7-24 aralkyl, C.sub.7-C.sub.24 alkaryl,
substituted C.sub.1-10 alkyl, substituted C.sub.1-10 alkoxy,
substituted C.sub.3-10 cycloalkyl, having 0-3 heteroatoms selected
from N, S and O, substituted C.sub.6-12 aryl, substituted
C.sub.3-12 hetaryl having 1-3 heteroatoms selected from N, S and O,
substituted C.sub.7-24 aralkyl, substituted C.sub.7-24 alkaryl;
where R.sub.a and R.sub.b are a substituted group, they are
substituted by halogen up to per halo, hydroxy, C.sub.1-10 alkyl,
C.sub.3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and
N, C.sub.3-12 hetaryl having 1-3 heteroatoms selected from N, S and
O, C.sub.1-10 alkoxy C.sub.6-12 aryl, C.sub.1-6 halo substituted
alkyl up to per halo alkyl, C.sub.6-12 halo substituted aryl up to
per halo aryl, C.sub.3-C.sub.12 halo substituted cycloalkyl having
0-3 heteroatoms selected from N, S and O, up to per halo
cycloalkyl, halo substituted C.sub.3-C.sub.12 hetaryl up to per
halo heteraryl, halo substituted C.sub.7-C.sub.24 aralkyl up to per
halo aralkyl, halo substituted C.sub.7-C.sub.24 alkaryl up to per
halo alkaryl, and --C(O)R.sub.g; or --OSi(R.sub.f).sub.3 where
R.sub.f is hydrogen, C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10
alkoxy, C.sub.3-10 cycloalkyl, C.sub.2-10 alkenyl, C.sub.1-10
alkenoyl; C.sub.6-12 aryl, C.sub.3-12 hetaryl having 1-3
heteroatoms selected from O, N and S, C.sub.3-12 cycloalkyl having
0-3 heteroatoms selected from N, S and O, C.sub.7-24 aralkyl,
C.sub.7-C.sub.24 alkaryl, substituted C.sub.1-10 alkyl, substituted
C.sub.1-10 alkoxy, substituted C.sub.3-10 cycloalkyl, having 0-3
heteroatoms selected from N, S and O, substituted C.sub.6-12 aryl,
substituted C.sub.3-12 hetaryl having 1-3 heteroatoms selected from
N, S and O, substituted C.sub.7-24 aralkyl, substituted C.sub.7-24
alkaryl, or [0041] b) R.sub.a and R.sub.b together form a 5-7
member heterocyclic structure of 1-3 heteroatoms selected from N, S
and O, or a substituted 5-7 member heterocyclic structure of 1-3
heteroatoms selected from N, S and O with substituents selected
from the group consisting of halogen up to per halo, hydroxy,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy, C.sub.3-10
cycloalkyl, C.sub.2-10 alkenyl, C.sub.1-10 alkenoyl, C.sub.6-12
aryl, C.sub.3-12 hetaryl having 1-3 heteroatoms selected from O, N
and S, C.sub.3-12 cycloalkyl having 0-3 heteroatoms selected from
N, S and O, C.sub.7-24 aralkyl, C.sub.7-C.sub.24 alkaryl,
substituted C.sub.1-10 alkyl, substituted C.sub.1-10 alkoxy,
substituted C.sub.3-10 cycloalkyl, having 0-3 heteroatoms selected
from N, S and O, substituted C.sub.6-12 aryl, substituted
C.sub.3-12 hetaryl having 1-3 heteroatoms selected from N, S and O,
substituted C.sub.7-24 aralkyl, substituted C.sub.7-24 alkaryl,
where R.sub.a and R.sub.b are a substituted group, they are
substituted by halogen up to per halo, hydroxy, C.sub.1-10 alkyl,
C.sub.3-12 cycloalkyl having 0-3 heteroatoms selected from O, S and
N, C.sub.3-12 hetaryl having 1-3 heteroatoms selected from N, S and
O, C.sub.1-10 alkoxy, C.sub.6-12 aryl, C.sub.1-6 halo substituted
alkyl up to per halo alkyl, C.sub.5-C.sub.12 halo substituted aryl
up to per halo aryl, C.sub.3-C.sub.12 halo substituted cycloalkyl
having 0-3 heteroatoms selected from N, S and O, up to per halo
cycloalkyl, halo substituted C.sub.3-C.sub.12 hetaryl up to per
halo heteraryl, halo substituted C.sub.7-C.sub.24 aralkyl up to per
halo aralkyl, halo substituted C.sub.7-C.sub.24 alkaryl up to per
halo alkaryl, and --C(O)R.sub.g, or [0042] c) one of R.sub.a or
R.sub.b is --C(O)--, a C.sub.1-C.sub.5 divalent alkylene group or a
substituted C.sub.1-C.sub.5 divalent alkylene group bound to the
moiety L to form a cyclic structure with at least 5 members,
wherein the substituents of the substituted C.sub.1-C.sub.5
divalent alkylene group are selected from the group consisting of
halogen, hydroxy C.sub.1-10 alkyl, C.sub.3-12 cycloalkyl having 0-3
heteroatoms selected from, S, O and N, C.sub.3-12 hetaryl having
1-3 heteroatoms selected from N, S and O, C.sub.1-10 alkoxy,
C.sub.6-12 aryl, C.sub.7-C.sub.24 alkaryl, C.sub.7-C.sub.24
aralkyl, C.sub.1-6 halo substituted alkyl up to per halo alkyl,
C.sub.6-C.sub.12 halo substituted aryl up to per halo aryl,
C.sub.3-C.sub.12 halo substituted cycloalkyl having 0-3 heteroatoms
selected from N, S and O, up to per halo cycloalkyl, halo
substituted C.sub.3-C.sub.12 hetaryl up to per halo heteraryl, halo
substituted C.sub.7-C.sub.24 aralkyl up to per halo aralkyl, halo
substituted C.sub.7-C.sub.24 alkaryl up to per halo alkaryl, and
C(O)R.sub.g, where R.sub.g is C.sub.1-10 ally; --CN,
--CO.sub.2R.sub.d, --OR.sub.d, --SR.sub.d, --SO.sub.2R.sub.d,
--SO.sub.3H, --NO.sub.2, --C(O)R.sub.e, --NR.sub.dR.sub.e,
--NR.sub.dC(O)OR.sub.e and --NR.sub.d(CO)R.sub.e, and R.sub.d and
R.sub.e are independently selected from the group consisting of
hydrogen, C.sub.1-10 alkyl, C.sub.1-10 alkoxy, C.sub.3-10
cycloalkyl having 0-3 heteroatoms selected from O, N and S,
C.sub.6-12 aryl, C.sub.3-C.sub.12 hetaryl with 1-3 heteroatoms
selected from O, N and S, C.sub.7-C.sub.24 aralkyl,
C.sub.7-C.sub.24 alkaryl, up to per halo substituted
C.sub.1-C.sub.10 alkyl, up to per halo substituted C.sub.3-C.sub.10
cycloalkyl having 0-3 heteroatoms selected from O, N and S, up to
per halo substituted C.sub.6-C.sub.14 aryl, up to per halo
substituted C.sub.3-C.sub.12 hetaryl having 1-3 heteroatoms
selected from O, N and S, halo substituted C.sub.1-C.sub.24 alkaryl
up to per halo alkaryl, and up to per halo substituted
C.sub.7-C.sub.24-aralkyl, [0043] W is independently selected from
the group consisting --CN, --CO.sub.2R.sup.5,
--C(O)NR.sup.5R.sup.5, --C(O)--R.sup.5, --NO.sub.2, --OR.sup.5,
--SR.sup.5, --SO.sub.2R.sup.5, --SO.sub.3H, --NR.sup.5R.sup.5,
--NR.sup.5C(O)OR.sup.5, --NR.sup.5C(O)R.sup.5, C.sub.1-C.sub.10
alkyl, C.sub.1-C.sub.10 alkoxy C.sub.2-C.sub.10 alkenyl,
C.sub.1-C.sub.10 alkenoyl, C.sub.3-C.sub.10 cycloalkyl having 0-3
heteroatoms selected from O, S and N, C.sub.6-C.sub.14 aryl,
C.sub.7-C.sub.24 alkaryl, C.sub.7-C.sub.24 aralkyl,
C.sub.3-C.sub.12 heteroaryl having 1-3 heteroatoms selected form O,
N and S, C.sub.4-C.sub.23 alkheteroaryl having 1-3 heteroatoms
selected from O, N and S, substituted C.sub.1-C.sub.10 alkyl,
substituted C.sub.1-C.sub.10 alkoxy, substituted C.sub.2-C.sub.10
alkenyl, substituted C.sub.1-C.sub.10 alkenoyl, substituted
C.sub.3-C.sub.10 cycloalkyl having 0-3 heteroatoms selected from O,
N and S, substituted C.sub.6-C.sub.12 aryl, substituted
C.sub.3-C.sub.12 hetaryl having 1-3 heteroatoms selected from O, N
and S, substituted C.sub.7-C.sub.24 aralkyl, substituted
C.sub.7-C.sub.24 alkaryl, substituted C.sub.4-C.sub.23
alkheteroaryl having 1-3 heteroatoms selected from O, N and S, and
-Q-Ar; [0044] R.sup.5 is independently selected from H,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy C.sub.2-C.sub.10
alkenyl, C.sub.1-C.sub.10 alkenoyl, C.sub.3-C.sub.10 cycloalkyl
having 0-3 heteroatoms selected from O, S and N, C.sub.6-C.sub.14
aryl, C.sub.3-C.sub.13 hetaryl having 1-3 heteroatoms selected from
O, N and S, C.sub.7-C.sub.14 alkaryl, C.sub.7-C.sub.24 aralkyl,
C.sub.4-C.sub.23 alkheteroaryl having 1-3 heteroatoms selected from
O, N and S, up to per-halosubstituted C.sub.1-C.sub.10 alkyl, up to
per-halosubstituted C.sub.3-C.sub.10 cycloalkyl having 0-3
heteroatoms selected from O, N and S, up to per-halosubstituted
C.sub.6-C.sub.14 aryl, up to per-halosubstituted C.sub.3-C.sub.13
hetaryl having 1-3 heteroatoms selected from O, N and S, up to
per-halosubstituted C.sub.7-C.sub.24 aralkyl, up to
per-halosubstituted C.sub.7-C.sub.24 alkaryl, and up to
per-halosubstituted C.sub.4-C.sub.23 alkheteroaryl; and each Z is
independently selected from the group consisting --CN,
--CO.sub.2R.sup.5, --C(O)NR.sup.5R.sup.5, --C(O)--R.sup.5,
--NO.sub.2, --OR.sup.5, --SR.sup.5, --SO.sub.2R.sup.5, --SO.sub.3H,
--NR.sup.5R.sup.5, --NR.sup.5C(O)OR.sup.5, --NR.sup.5C(O)R.sup.5,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy, C.sub.2-C.sub.10
alkenyl, C.sub.1-C.sub.10 alkenoyl, C.sub.3-C.sub.10 cycloalkyl
having 0-3 heteroatoms selected from O, S and N, C.sub.6-C.sub.14
aryl, C.sub.7-C.sub.24 alkaryl, C.sub.7-C.sub.24 aralkyl,
C.sub.3-C.sub.12 heteroaryl having 1-3 heteroatoms selected from O,
N and S, C.sub.4-C.sub.23 alkheteroaryl having 1-3 heteroatoms
selected from O, N and S, substituted C.sub.1-C.sub.10 alkyl,
substituted C.sub.1-C.sub.10 alkoxy, substituted C.sub.2-C.sub.10
alkenyl, substituted C.sub.1-C.sub.10 alkenoyl, substituted
C.sub.3-C.sub.10 cycloalkyl having 0-3 heteroatoms selected from O,
N and S, substituted C.sub.6-C.sub.12 aryl, substituted
C.sub.3-C.sub.12 hetaryl having 1-3 heteroatoms selected from O, N
and S; wherein if Z is a substituted group, the one or more
substituents are selected from the group consisting of --CN,
--CO.sub.2R.sup.5, --C(O)NR.sup.5R.sup.5, --C(O)--R.sup.5,
--NO.sub.2, --OR.sup.5, --SR.sup.5, --SO.sub.2R.sup.5, --SO.sub.3H,
--NR.sup.5R.sup.5, --NR.sup.5C(O)OR.sup.5,
--NR.sup.5C(O)R.sup.5.
[0045] According to the invention, each M independently from one
another represents a bond OR is a bridging group, selected from the
group consisting of (CR.sup.5R.sup.5).sub.h, or
(CHR.sup.5).sub.h-Q-(CHR.sup.5).sub.i, wherein [0046] Q is selected
from a group consisting of O, S, N--R.sup.5, (CHal.sub.2).sub.j,
(O--CHR.sup.5).sub.j, (CHR.sup.5--O).sub.j, CR.sup.5.dbd.CR.sup.5,
(O--CHR.sup.5CHR.sup.5).sub.j, (CHR.sup.5CHR.sup.5--O).sub.j,
C.dbd.O, C.dbd.S, C.dbd.NR.sup.5, CH(OR.sup.5),
C(OR.sup.5)(OR.sup.5), C(.dbd.O)O, OC(.dbd.O), OC(.dbd.O)O,
C(.dbd.O)N(R.sup.5), N(R.sup.5)C(.dbd.O), OC(.dbd.O)N(R.sup.5),
N(R.sup.5C(.dbd.O)O, CH.dbd.N--O, CH.dbd.N--NR.sup.5,
OC(O)NR.sup.5, NR.sup.5C(O)O, S.dbd.O, SO.sub.2, O.sub.2NR.sup.5
and NR.sup.5SO.sub.2, wherein [0047] R.sup.5 is in each case
independently selected from the meanings given above, preferably
from hydrogen, halogen, alkyl, aryl, aralkyl, [0048] h, i are
independently from each other 0, 1, 2, 3, 4, 5 or 6, preferably 0,
1, 2, or 3, and [0049] j is 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2
or 3.
[0050] More preferred, each M independently from one another
represents a bond or is a bridging group, selected from the group
consisting of --O--, --S--, --N(R.sup.5)--,
--(CH.sub.2).sub..beta.--, --C(O)--, --CH(OH)--,
--(CH.sub.2).sub..beta.O--, --(CH.sub.2).sub..beta.S--,
--(CH.sub.2).sub..beta.N(R.sup.5)--, --O(CH.sub.2).sub..beta.,
--CHHal-, --CHal.sub.2-, --S--(CH.sub.2).sub..beta.-- and
--N(R.sup.5)(CH.sub.2).sub..beta., where .beta. is 1 to 6 and
especially preferred 1 to 3, Hal is halogen and R.sup.5 is as
defined above. More preferred, the group B of Formula I is a
substituted or unsubstituted six member aryl moiety or six member
hetaryl moiety, said hetaryl moiety having 1 to 4 members selected
from the group of hetaryl atoms consisting of nitrogen, oxygen and
sulfur with the balance of the hetaryl moiety being carbon.
[0051] Even more preferred, the group B of Formula I is [0052] a)
an unsubstituted phenyl group, an unsubstituted pyridyl group, an
unsubstituted pyrimidinyl, a phenyl group substituted by a
substituent selected from the group consisting of halogen and
W.gamma. wherein W and .gamma. are as defined in claim 1, a
pyrimidinyl group substituted by a substituent selected from the
group constituting of halogen and W.gamma., whereas W and .gamma.
are as defined above, or a substituted pyridyl group, substituted
by a substituent selected from the group consisting of halogen and
W.gamma. wherein W and .gamma. are as defined above; or a
substituted phenyl group, a substituted pyrimidinyl group, or
substituted pyridyl group substituted 1 to 3 times by 1 or more
substituents selected from the group consisting of --CN, halogen,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkyl alkoxy, --OH, up to
per halo substituted C.sub.1-C.sub.10 alkyl, up to per halo
substituted C.sub.1-C.sub.10 alkoxy or phenyl substituted by
halogen up to per halo; or [0053] b) a substituted phenyl group, a
substituted pyrimidinyl group, or substituted pyridyl group
substituted 1 to 3 times by 1 or more substituents selected from
the group consisting of CN, halogen, alkyl, especially
C.sub.1-C.sub.4 alkyl, alkoxy, especially C.sub.1-C.sub.4 alkoxy,
OH, up to per halo substituted alkyl, especially up to per halo
substituted C.sub.1-C.sub.4 alkyl, up to per halo substituted
alkoxy, especially up to per halo substituted C.sub.1-C.sub.4
alkoxy or phenyl substituted by halogen up to per halo.
[0054] In the formula I, the group L which is directly bound to D
is preferably a substituted or unsubstituted 6 member aryl moiety
or a substituted or unsubstituted 6 member hetaryl moiety, wherein
said hetaryl moiety has 1 to 4 members selected from the group of
heteroatoms consisting of nitrogen, oxygen and sulfur with the
balance of said hetaryl moiety being carbon, wherein the one or
more substituents are selected from the group consisting of halogen
and W.gamma. wherein W and .gamma. are as defined above.
[0055] More preferred, the group L is a substituted phenyl,
unsubstituted phenyl, substituted pyrimidinyl, unsubstituted
pyrimidinyl, substituted pyridyl or unsubstituted pyridyl
group.
[0056] In the formula I, the group L' preferably comprises a 5 to 6
membered aryl moiety or hetaryl moiety, wherein said heteraryl
moiety comprises 1 to 4 members selected from the group of
heteroatoms consisting of nitrogen, oxygen and sulfur.
[0057] More preferred, the group L' is phenyl, pyridinyl or
pyrimdinyl.
[0058] According to the invention, a bivalent glycinamide moiety is
preferably a bivalent radical derived from substituted or
unsubstituted, preferably unsubstituted amide of the amino acid
glycine, or a derivative thereof. If the amide of the amino acid
glycine is substituted, it is preferably mono substituted on the
nitrogen atom of the amide group and/or mono substituted on the
nitrogen atom of the amino group. Preferably, the substituted or
unsubstituted amide of the amino acid glycine is bonded to A and B
via its nitrogen atoms of the amide group and the amino group,
respectively. This kind of linkage is usually referred to as an
N,N'-linkage. The hydrogen atoms of one or both nitrogen atoms of
the glycine amide moiety can be substituted by suitable
substituents, preferably selected from the group consisting of
alkyl, alkylene, haloalkyl, C.sub.3-C.sub.7-cycloalkyl,
C.sub.3-C.sub.7-cycloalkylene, heterocyclyl, aryl, aralkyl,
heteroaryl, carboxy, cyanoalkyl, acyl and heteroaryl. Preferably,
both nitrogen atoms of the glycine amide moiety are unsubstituted.
Therefore, D is more preferred an unsubstituted amide of the amino
acid glycine, which is bonded to the radicals A and B via its
N,N'-atoms, or a derivative thereof. In this respect, one or both
of the nitrogen atoms of D can, independently from one another,
optionally be deprotonated, protonated and/or quarternized. The
resulting ions or salts are also subject of the present invention.
Derivatives of the glycine amide moiety according to the invention
are preferably derivatives, wherein the carbonyl group of said
glycine amide moiety is derivatized to a C.dbd.S, C.dbd.NR.sup.5,
C.dbd.C(R.sup.5)--NO.sub.2, C.dbd.C(R.sup.5)--CN or
C.dbd.C(CN).sub.2 group.
[0059] Accordingly, preferred compounds of formula I are of formula
Ia and/or Ib
##STR00001##
wherein A and B are as defined above/below, Y is selected from O,
S, NR.sup.5, C(R.sup.5)--NO.sub.2, C(R.sup.5)--CN and
C.dbd.C(CN).sub.2, and wherein R.sup.6 and R.sup.7 are
independently selected from the group consisting of H, alkyl,
alkylene, haloalkyl, C.sub.3-C.sub.7-cycloalkyl,
C.sub.3-C.sub.7-cycloalkylene, heterocyclyl, aryl, aralkyl,
heteroaryl, carboxy, cyanoalkyl, acyl and heteroaryl, and the salts
or solvates thereof. More preferred are compounds of formula Ia
and/or Ib, wherein Y is O and/or wherein one or both of the
residues R.sup.6 and R.sup.7 are H, and the salts or solvates
thereof.
[0060] Accordingly, one aspect of the instant invention relates to
compounds of formula Ic and/or Id,
##STR00002##
wherein A and B are as defined above/below, and the salts or
solvates thereof.
[0061] As used herein, the term "effective amount" means that
amount of a drug or pharmaceutical agent that will elicit the
biological or medical response of a tissue, system, animal or human
that is being sought, for instance, by a researcher or clinician.
Furthermore, the term "therapeutically effective amount" means any
amount which, as compared to a corresponding subject who has not
received such amount, results in improved treatment, heating,
prevention, or amelioration of a disease, disorder, or side effect,
or a decrease in the rate of advancement of a disease or disorder.
The term also includes within its scope amounts effective to
enhance normal physiological function.
[0062] As used herein, the term "alkyl" preferably refers to a
straight or branched chain hydrocarbon having from one to twelve
carbon atoms, optionally substituted with substituents selected
from the group consisting of C.sub.1-C.sub.10 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylsulfanyl,
C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6 alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen, or C.sub.1-C.sub.6
perfluoroalkyl, multiple degrees of substitution being allowed.
Examples of "alkyl" as used herein include, but are not limited to,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,
n-pentyl, isopentyl, and the like.
[0063] As used herein, the term "C.sub.1-C.sub.6 alkyl" preferably
refers to an alkyl group as defined above containing at least 1,
and at most 6, carbon atoms. Examples of branched or straight
chained "C.sub.1-C.sub.6 alkyl" groups useful in the present
invention include, but are not limited to, methyl, ethyl, n-propyl,
isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl and isopentyl.
[0064] As used herein, the term "alkylene" preferably refers to a
straight or branched chain divalent hydrocarbon radical having from
one to ten carbon atoms, optionally substituted with substituents
selected from the group which includes lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl,
optionally substituted by alkyl, nitro, cyano, halogen and lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Examples of "alkylene" as used herein include, but are not limited
to, methylene, ethylene, n-propylene, n-butylene and the like.
[0065] As used herein, the term "C.sub.1-C.sub.6 alkylene"
preferably refers to an alkylene group, as defined above, which
contains at least 1, and at most 6, carbon atoms respectively.
Examples of "C.sub.1-C.sub.6 alkylene" groups useful in the present
invention include, but are not limited to, methylene, ethylene and
n-propylene.
[0066] As used herein, the term "halogen" or "hal" preferably
refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine
(I).
[0067] As used herein, the term "C.sub.1-C.sub.6 haloalkyl"
preferably refers to an alkyl group as defined above containing at
least 1, and at most 6, carbon atoms substituted with at least one
halogen, halogen being as defined herein. Examples of branched or
straight chained "C.sub.1-C.sub.6 haloalkyl" groups useful in the
present invention include, but are not limited to, methyl, ethyl,
propyl, isopropyl, isobutyl and n-butyl substituted independently
with one or more halogens, e.g., fluoro, chloro, bromo and
Iodo.
[0068] As used herein, the term "C.sub.3-C.sub.7 cycloalkyl"
preferably refers to a non-aromatic cyclic hydrocarbon ring having
from three to seven carbon atoms and which optionally includes a
C.sub.1-C.sub.6 alkyl linker through which it may be attached. The
C.sub.1-C.sub.6 alkyl group is as defined above. Exemplary
"C.sub.3-C.sub.7 cycloalkyl" groups include, but are not limited
to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl.
[0069] As used herein, the term "C.sub.3-C.sub.7 cycloalkylene"
preferably refers to a non-aromatic alicyclic divalent hydrocarbon
radical having from three to seven carbon atoms, optionally
substituted with substituents selected from the group which
includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, nitro, cyano, halogen, lower perfluoroalkyl, multiple
degrees of substitution being allowed. Examples of "cycloalkylene"
as used herein include, but are not limited to,
cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl,
cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or
cyclooctyl-1,5-diyl, and the like.
[0070] As used herein, the term "heterocyclic" or the term
"heterocyclyl" preferably refers to a three to twelve-membered
heterocyclic ring having one or more degrees of unsaturation
containing one or more heteroatomic substitutions selected from S,
SO, SO.sub.2, O or N, optionally substituted with substituents
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylsulfanyl, C.sub.1-C.sub.6 haloalkylsulfanyl, C.sub.1-C.sub.6
alkylsulfenyl, C.sub.1-C.sub.6 alkylsulfonyl, oxo, hydroxy,
mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl
optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen, or C.sub.1-C.sub.6
perfluoroalkyl, multiple degrees of substitution being allowed.
Such a ring may be optionally fused to one or more other
"heterocyclic" ring(s) or cycloalkyl ring(s). Examples of
"heterocyclic" moieties include, but are not limited to,
tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, pyrrolidine,
piperidine, morpholine, tetrahydrothiopyran, tetrahydrothiophene,
and the like.
[0071] As used herein, the term "heterocyclylene" preferably refers
to a three to twelve-membered heterocyclic ring diradical having
one or more degrees of unsaturation containing one or more
heteroatoms selected from S, SO, SO.sub.2, O or N, optionally
substituted with substituents selected from the group which
includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, nitro, cyano, halogen, lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such a ring may be
optionally fused to one or more benzene rings or to one or more of
another "heterocyclic" rings or cycloalkyl rings. Examples of
"heterocyclylene" include, but are not limited to,
tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl,
1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl,
piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl, and
the like.
[0072] As used herein, the term "aryl" preferably refers to an
optionally substituted benzene ring or to an optionally substituted
benzene ring system fused to one or more optionally substituted
benzene rings to form, for example, anthracene, phenanthrene, or
napthalene ring systems. Exemplary optional substituents include
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6
alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted
by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by
alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl,
nitro, cyano, halogen, C.sub.1-C.sub.6 perfluoroalkyl, heteroaryl,
or aryl, multiple degrees of substitution being allowed. Examples
of "aryl" groups include, but are not limited to Phenyl,
2-naphthyl, 1-naphthyl, biphenyl, as well as substituted
derivatives thereof.
[0073] As used herein, the term "arylene" preferably refers to a
benzene ring diradical or to a benzene ring system diradical fused
to one or more optionally substituted benzene rings, optionally
substituted with substituents selected from the group which
includes lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl
optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,
heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lower
perfluoroalkyl, heteroaryl and aryl, multiple degrees of
substitution being allowed. Examples of "arylene" include, but are
not limited to benzene-1,4-diyl, naphthalene-1,8-diyl,
anthracene-1,4-diyl, and the like.
[0074] As used herein, the term "aralkyl" preferably refers to an
aryl or heteroaryl group, as defined herein, attached through a
C.sub.1-C.sub.6 alkyl linker, wherein C.sub.1-C.sub.6 alkyl is as
defined herein. Examples of "aralkyl" include, but are not limited
to, benzyl, phenylpropyl, 2-pyridylmethyl, 3-isoxazolylmethyl,
5-methyl-3-isoxazolylmethyl and 2-imidazolylethyl.
[0075] As used herein, the term "heteroaryl" preferably refers to a
monocyclic five to seven-membered aromatic ring, or to a fused
bicyclic aromatic ring system comprising two of such monocyclic
five to seven-membered aromatic rings. These hetroaryl rings
contain one or more nitrogen, sulfur and/or oxygen heteroatoms,
where N-Oxides and sulfur Oxides and dioxides are permissible
heteroatom substitutions and may be optionally substituted with up
to three members selected from a group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 alkylsulfanyl, C.sub.1-C.sub.6
haloalkylsulfanyl, C.sub.1-C.sub.6 alkylsulfenyl, C.sub.1-C.sub.6
alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted
by alkyl, carboxy, tetrazolyl, carbamoyl optionally substituted by
alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl,
nitro, cyano, halogen, C.sub.1-C.sub.6 perfluoroalkyl, heteroaryl
or aryl, multiple degrees of substitution being allowed. Examples
of "heteroaryl" groups used herein include furanyl, thiophenyl,
pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl,
oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl, thiadiazolyl,
isothiazolyl, pyridyl, pyridazyl, pyrazinyl, pyrimidyl, quinolinyl,
isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl,
and substituted versions thereof. As used herein, the term
"heteroarylene" preferably refers to a five- to seven-membered
aromatic ring diradical, or to a polycyclic heterocyclic aromatic
ring diradical, containing one or more nitrogen, oxygen, or sulfur
heteroatoms, where N-Oxides and sulfur monoxides and sulfur
dioxides are permissible heteroaromatic substitutions, optionally
substituted with substituents selected from the group consisting of
lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl
optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,
heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lower
perfluoroalkyl, heteroaryl, or aryl, multiple degrees of
substitution being allowed. For polycyclic aromatic ring system
diradicals, one or more of the rings may contain one or more
heteroatoms. Examples of "heteroarylene" used herein are
furan-2,5-diyl, thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,
1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,5-diyl,
pyridine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,5-diyl,
pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the like.
[0076] As used herein, the term "alkoxy" preferably refers to the
group R.sub.aO--, where R.sub.a is alkyl as defined above and the
term "C.sub.1-C.sub.6 alkoxy" preferably refers to an alkoxy group
as defined herein wherein the alkyl moiety contains at least 1 and
at most 6 carbon atoms. Exemplary C.sub.1-C.sub.6 alkoxy groups
useful in the present invention include, but are not limited to
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and t-butoxy.
[0077] As used herein, the term "haloalkoxy" preferably refers to
the group R.sub.aO--, where R.sub.a is haloalkyl as defined above
and the term "C.sub.1-C.sub.6 haloalkoxy" preferably refers to an
haloalkoxy group as defined herein wherein the haloalkyl moiety
contains at least 1 and at most 6 carbon atoms. Exemplary
C.sub.1-C.sub.6 haloalkoxy groups useful in the present invention
include, but are not limited to, methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy and t-butoxy substituted with one or more halo
groups, for instance trifluoromethoxy.
[0078] As used herein the term "aralkoxy" preferably refers to the
group R.sub.CR.sub.BO--, where R.sub.B is alkyl and R.sub.C is aryl
as defined above.
[0079] As used herein the term "aryloxy" preferably refers to the
group R.sub.CO--, where R.sup.C is aryl as defined above.
[0080] As used herein, the term "alkylsulfanyl" preferably refers
to the group R.sub.AS--, where R.sub.A is alkyl as defined above
and the term "C.sub.1-C.sub.6 alkylsulfanyl" preferably refers to
an alkylsulfanyl group as defined herein wherein the alkyl moiety
contains at least 1 and at most 6 carbon atoms.
[0081] As used herein, the term "haloalkylsulfanyl" preferably
refers to the group R.sub.DS--, where R.sub.D is haloalkyl as
defined above and the term "C.sub.1-C.sub.6 haloalkylsulfanyl"
preferably refers to a haloalkylsulfanyl group as defined herein
wherein the alkyl moiety contains at least 2 and at most 6 carbon
atoms.
[0082] As used herein, the term "alkylsulfenyl" preferably refers
to the group R.sub.AS(O)--, where R.sub.A is alkyl as defined above
and the term "C.sub.1-C.sub.6 alkylsulfenyl" preferably refers to
an alkylsulfenyl group as defined herein wherein the alkyl moiety
contains at least 1 and at most 6 carbon atoms.
[0083] As used herein, the term "alkylsulfonyl" preferably refers
to the group R.sub.ASO.sub.2--, where R.sub.A is alkyl as defined
above and the term "C.sub.1-C.sub.6 alkylsulfonyl" preferably
refers to an alkylsulfonyl group as defined herein wherein the
alkyl moiety contains at least 1 and at most 6 carbon atoms.
[0084] As used herein, the term "oxo" preferably refers to the
group .dbd.O.
[0085] As used herein, the term "mercapto" preferably refers to the
group --SH.
[0086] As used herein, the term "carboxy" preferably refers to the
group --COOH.
[0087] As used herein, the term "cyano" preferably refers to the
group --CN.
[0088] As used herein, the term "cyanoalkyl" preferably refers to
the group --R.sub.BCN, wherein R.sub.B is alkylen as defined above.
Exemplary "cyanoalkyl" groups useful in the present invention
include, but are not limited to, cyanomethyl, cyanoethyl and
cyanoisopropyl.
[0089] As used herein, the term "aminosulfonyl" preferably refers
to the group --SO.sub.2NH.sub.2.
[0090] As used herein, the term "carbamoyl" preferably refers to
the group --C(O)NH.sub.2.
[0091] As used herein, the term, "sulfanyl" shall refer to the
group --S--.
[0092] As used herein, the term "sulfenyl" shall refer to the group
--S(O)--.
[0093] As used herein, the term "sulfonyl" shall refer to the group
--S(O).sub.2-- or --SO.sub.2--.
[0094] As used herein, the term "acyly" preferably refers to the
group R.sub.FC(O)--, where R.sub.F is alkyl, cycloalkyl or
heterocyclyl as defined herein.
[0095] As used herein, the term "aryl" preferably refers to the
group R.sub.CC(O)--, where R.sub.C is aryl as defined herein.
[0096] As used herein, the term "heteroaroyl" preferably refers to
the group R.sub.EC(O)--, where R.sub.E is heteroaryl as defined
herein.
[0097] As used herein, the term "alkoxycarbonyl" preferably refers
to the group R.sub.AOC(O)--, where R.sub.A is alkyl as defined
herein.
[0098] As used herein, the term "acyloxy" preferably refers to the
group R.sub.FC(O)O--, where R.sub.F is alkyl, cycloalkyl, or
heterocyclyl as defined herein.
[0099] As used herein, the term "aryloxy" preferably refers to the
group R.sub.CC(O)O--, where R.sub.C is aryl as defined herein.
[0100] As used herein, the term "heteroaroyloxy" preferably refers
to the group R.sub.EC(O)O--, where R.sub.E is heteroaryl as defined
herein.
[0101] As used herein, the term "carbonyl" or "carbonyl moiety"
preferably refers to the group C.dbd.O.
[0102] As used herein, the term "thiocarbonyl" or "thiocarbonyl
moiety" preferably refers to the group C.dbd.S.
[0103] As used herein, the term "amino", "amino group" or "amino
moiety" preferably refers to the group NR.sub.GR.sub.G', wherein
R.sub.G and R.sub.G', are preferably selected, independently from
one another, from the group consisting of hydrogen, alkyl,
haloalkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, cyanoalkyl,
aryl, aralkyl, heteroaryl, acyl and aroyl. If both R.sub.G and
R.sub.G' are hydrogen, NR.sub.GR.sub.G' is also referred to as
"unsubstituted amino moiety" or "unsubstituted amino group". If
R.sub.G and/or R.sub.G' are other than hydrogen, NR.sub.GR.sub.G'
is also referred to as "substituted amino moiety" or "substituted
amino group".
[0104] As used herein, the term "imino" or "imino moiety"
preferably refers to the group C.dbd.NR.sub.G, wherein R.sub.G is
preferably selected from the group consisting of hydrogen, alkyl,
haloalkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, cyanoalkyl,
aryl, aralkyl, heteroaryl, acyl and aroyl. If R.sub.G is hydrogen
C.dbd.NR.sub.G is also referred to as "unsubstituted imino moiety".
If R.sub.G is a residue other than hydrogen, C.dbd.NR.sub.G is also
referred to as "substituted imino moiety".
[0105] As used herein, the term "ethene-1,1-diyl moiety" preferably
refers to the group C.dbd.CR.sub.KR.sub.L, wherein R.sub.K and
R.sub.L are preferably selected, independently from one another,
from the group consisting of hydrogen, halogen, alkyl, haloalkyl,
alkenyl, cycloalkyl, nitro, alkylenecycloalkyl, cyanoalkyl, aryl,
aralkyl, heteroaryl, acyl and aroyl. If both hydrogen R.sub.K and
R.sub.L are hydrogen, C.dbd.CR.sub.KR.sub.L is also referred to as
"unsubstituted ethene-1,1-diyl moiety". If one of R.sub.K and
R.sub.L or both are a residue other than hydrogen,
C.dbd.CR.sub.KR.sub.L is also referred to as "substituted
ethene-1,1-diyl moiety".
[0106] As used herein, the terms "group", "residue" and "radical"
or "groups", "residues" and "radicals" are usually used as
synonyms, respectively, as it is common practice in the art.
[0107] As used herein, the term "optionally" means that the
subsequently described event(s) may or may not occur, and includes
both event(s), which occur, and events that do not occur.
[0108] As used herein, the term "physiologically functional
derivative" preferably refers to any pharmaceutically acceptable
derivative of a compound of the present invention, for example, an
ester or an amide, which upon administration to a mammal is capable
of providing (directly or indirectly) a compound of the present
invention or an active metabolite thereof. Such derivatives are
clear to those skilled in the art, without undue experimentation,
and with reference to the teaching of Burger's Medicinal Chemistry
And Drug Discovery, 5th Edition, Vol 1: Principles and Practice,
which is incorporated herein by reference to the extent that it
teaches physiologically functional derivatives.
[0109] As used herein, the term "solvate" preferably refers to a
complex of variable stoichiometry formed by a solute (in this
invention, a compound of formula I or formula II or a salt or
physiologically functional derivative thereof) and a solvent. Such
solvents for the purpose of the invention may not interfere with
the biological activity of the solute. Examples of suitable
solvents include, but are not limited to, water, methanol, ethanol
and acetic acid. Preferably the solvent used is a pharmaceutically
acceptable solvent. Examples of suitable pharmaceutically
acceptable solvents include, without limitation, water, ethanol and
acetic acid. Most preferably the solvent used is water.
[0110] As used herein, the term "substituted" preferably refers to
substitution with the named substituent or substituents, multiple
degrees of substitution being allowed unless otherwise stated.
[0111] Certain of the compounds described herein may contain one or
more chiral atoms, or may otherwise be capable of existing as two
or more stereoisomers, which are usually enantiomers and/or
diastereomers. Accordingly, the compounds of this invention include
mixtures of stereoisomers, especially mixtures of enantiomers, as
well as purified stereoisomers, especially purified enantiomers, or
stereoisomerically enriched mixtures, especially enantiomerically
enriched mixtures. Also included within the scope of the invention
are the individual isomers of the compounds represented by formulae
I and II above as well as any wholly or partially equilibrated
mixtures thereof. The present invention also covers the individual
isomers of the compounds represented by the formulas above as
mixtures with isomers thereof in which one or more chiral Centers
are inverted. Also, it is understood that all tautomers and
mixtures of tautomers of the compounds of formulae (I) or (II) are
included within the scope of the compounds of formulae (I) and (II)
and preferably the formulae and subformulae corresponding
thereto.
[0112] Racemates obtained can be resolved into the isomers
mechanically or chemically by methods known per se. Diastereomers
are preferably formed from the racemic mixture by reaction with an
optically active resolving agent. Examples of suitable resolving
agents are optically active acids, such as the D and L forms of
tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,
mandelic acid, malic acid, lactic acid or the various optically
active camphorsulfonic acids, such as .beta.-camphorsulfonic acid.
Also advantageous is enantiomer resolution with the aid of a column
filled with an optically active resolving agent (for example
dinitrobenzoylphenylglycine); an example of a suitable eluent is a
hexane/isopropanol/acetonitrile mixture.
[0113] The diastereomer resolution can also be carried out by
standard purification processes, such as, for example,
chromatography or fractional crystallization.
[0114] It is of course also possible to obtain optically active
compounds of the formula I or II by the methods described above by
using starting materials which are already optically active.
[0115] Unless indicated otherwise, it is to be understood that
reference to compounds of formula I preferably includes the
reference to the compounds formulae Ia to Id and/or of formula II.
Unless indicated otherwise, it is to be understood that reference
to the compounds of formula II preferably includes the reference to
the sub formulae corresponding thereto, for example the sub
formulae II.1 to II.20 and preferably formulae IIa to IIh. It is
also understood that the following embodiments, including uses and
compositions, although recited with respect to formula I are
preferably also applicable to formulae II, sub formulae II.1 to
II.20 and preferably formulae IIa to IIh.
[0116] Especially preferred compounds according to the invention
are compounds of formula II
##STR00003##
wherein [0117] Ar.sup.1, Ar.sup.2 are selected independently from
one another from aromatic hydrocarbons containing 6 to 14 carbon
atoms and ethylenical unsaturated or aromatic heterocyclic residues
containing 3 to 10 carbon atoms and one or two heteroatoms,
independently selected from N, O and S, [0118] R.sup.8, R.sup.9 and
R.sup.10 are independently selected from a group consisting of H,
A, cycloalkyl comprising 3 to 7 carbon atoms, Hal, CH.sub.2Hal,
CH(Hal).sub.2, C(Hal).sub.3, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nOR.sup.11,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOOR.sup.12, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11COR.sup.13,
(CH.sub.2).sub.nNR.sup.11CONR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11SO.sub.2A,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12,
(CH.sub.2).sub.nS(O).sub.uR.sup.13, (CH).sub.nOC(O)R.sup.13,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nSR.sup.11,
CH.dbd.N--OA, CH.sub.2CH.dbd.N--OA, (CH.sub.2).sub.nNHOA,
(CH.sub.2).sub.nCH.dbd.N--R.sup.11,
(CH.sub.2).sub.nOC(O)NR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11COOR.sup.12,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2OR.sup.13,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2OCF.sub.3,
(CH.sub.2).sub.nN(R.sup.11)C(R.sup.13)HCOOR.sup.12,
C(R.sup.13)HCOR.sup.14,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2N(R.sup.12)CH.sub.2COOR.sup.12-
, (CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2NR.sup.11R.sup.12,
CH.dbd.CHCOOR.sup.11, CH.dbd.CHCH.sub.2NR.sup.11R.sup.12,
CH.dbd.CHCH.sub.2NR.sup.11R.sup.12, CH.dbd.CHCH.sub.2OR.sup.13,
(CH.sub.2).sub.n(COOR.sup.11)COOR.sup.12,
(CH.sub.2).sub.nN(CONH.sub.2)COOR.sup.11,
(CH.sub.2).sub.nN(CONH.sub.2)CONH.sub.2,
(CH.sub.2).sub.nN(CH.sub.2COOR.sup.11)COOR.sup.12,
(CH.sub.2).sub.nN(CH.sub.2CONH.sub.2)COOR.sup.11,
(CH.sub.2).sub.nN(CH.sub.2CONH.sub.2)CONH.sub.2,
(CH.sub.2).sub.nCHR.sup.13COR.sup.14,
(CH.sub.2).sub.nCHR.sup.13COOR.sup.11,
(CH.sub.2).sub.nCHR.sup.13CH.sub.2OR.sup.11, (CH.sub.2).sub.nOCN
and (CH.sub.2).sub.nNCO, wherein [0119] R.sup.11, R.sup.12 are
independently selected from a group consisting of H, A,
(CH.sub.2).sub.mAr.sup.3 and (CH.sub.2).sub.mHet, or in
NR.sup.11R.sup.12, [0120] R.sup.11 and R.sup.12 form, together with
the N-Atom they are bound to, a S--, 6- or 7-membered heterocyclus
which additionally contains 1 or 2 hetero atoms, selected from N, O
an S, [0121] R.sup.13, R.sup.14 are independently selected from a
group consisting of H, Hal, A, (CH.sub.2).sub.mAr.sup.4 and
(CH.sub.2).sub.mHet, [0122] A is selected from the group consisting
of alkyl, alkenyl, cycloalkyl, alkylenecycloalkyl, alkoxy and
alkoxyalkyl, [0123] Ar.sup.3, Ar.sup.4 are independently from one
another aromatic hydrocarbon residues comprising 5 to 12 and
preferably 5 to 10 carbon atoms which are optionally substituted by
one or more substituents, selected from a group consisting of A,
Hal, NO.sub.2, CN, OR.sup.15, NR.sup.15R.sup.16, COOR.sup.15,
CONR.sup.15R.sup.16, NR.sup.15COR.sup.16,
NR.sup.15CONR.sup.15R.sup.16, NR.sup.16SO.sub.2A, COR.sup.15,
SO.sub.2R.sup.15R.sup.16, S(O).sub.uA and OOCR.sup.15, [0124] Het
is a saturated, unsaturated or aromatic heterocyclic residue which
is optionally substituted by one or more substituents, selected
from a group consisting of A, Hal, NR.sup.15COR.sup.16,
NR.sup.15CONR.sup.15R.sup.16, NR.sup.16SO.sub.2A, COR.sup.15,
SO.sub.2R.sup.15R.sup.16, S(O).sub.uA and OOCR.sup.15, [0125]
R.sup.15, R.sup.16 are independently selected from a group
consisting of H, A, and (CH.sub.2).sub.mAr.sup.6, wherein [0126]
Ar.sup.6 is a 5- or 6-membered aromatic hydrocarbon which is
optionally substituted by one or more substituents selected from a
group consisting of methyl, ethyl, propyl, 2-propyl, tert.-butyl,
Hal, CN, OH, NH.sub.2 and CF.sub.3, [0127] k, m and n are
independently of one another 0, 1, 2, 3, 4, or 5, [0128] X
represents a bond or is (CR.sup.11R.sup.12).sub.h, or
(CHR.sup.11).sub.h-Q-(CHR.sup.12).sub.i, wherein [0129] Q is
selected from a group consisting of O, S, N--R.sup.15,
(CHal.sub.2).sub.j, (O--CHR.sup.18).sub.j, (CHR.sup.8--O).sub.j,
CR.sup.18.dbd.CR.sup.19, (O--CHR.sup.18CHR.sup.19).sub.j,
(CHR.sup.18CHR.sup.19--O).sub.j, C.dbd.O, C.dbd.S, C.dbd.NR.sup.15,
CH(OR.sup.15), C(OR.sup.15)(OR.sup.20), C(.dbd.O)O, OC(--O),
OC(.dbd.O)O, C(.dbd.O)N(R.sup.15), N(R.sup.15)C(.dbd.O),
OC(--O)N(R.sup.15), N(R.sup.15)C(.dbd.O)O, CH.dbd.N--O,
CH.dbd.N--NR.sup.15, S.dbd.O, SO.sub.2, SO.sub.2NR.sup.15 and
NR.sup.15SO.sub.2, wherein [0130] R.sup.18, R.sup.19, R.sup.20 are
independently selected from the meanings given for R.sup.8, R.sup.9
and R.sup.10, preferably independently selected from the group
consisting of H, A, Hal, CH.sub.2Hal, CH(Hal).sub.2, C(Hal).sub.3,
NO.sub.2, (CH.sub.2).sub.nCN, (CH.sub.2).sub.nOR.sup.11,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOOR.sup.11, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11COR.sup.13,
(CH.sub.2).sub.nNR.sup.11CONR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11SO.sub.2A,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12,
(CH.sub.2).sub.nS(O).sub.uR.sup.13, (CH.sub.2).sub.nCOR.sup.13,
(CH.sub.2).sub.nSR.sup.11, (CH.sub.2).sub.nNHOA and
(CH.sub.2).sub.nNR.sup.11COOR.sup.12, [0131] h, i are independently
from each other 0, 1, 2, 3, 4, 5, or 6, and [0132] j is 1, 2, 3, 4,
5, or 6, [0133] Y is selected from O, S, NR.sup.21,
C(R.sup.22)--NO.sub.2, C(R.sup.22)--CN and C(CN).sub.2, wherein
[0134] R.sup.21 is independently selected from the meanings given
for R.sup.13, R.sup.14 and [0135] R.sup.22 is independently
selected from the meanings given for R.sup.11, R.sup.12, [0136] p,
r are independently from one another 0, 1, 2, 3, 4 or 5, [0137] q
is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, [0138] u is 0, 1, 2 or 3,
preferably Q, 1 or 2, and [0139] Hal is independently selected from
a group consisting of F, Cl, Br and I; and the salts and solvates
thereof, preferably the physiologically acceptable salts and
solvates thereof.
[0140] Even more preferred are compounds of formula II
wherein [0141] Ar.sup.1, Ar.sup.2 are selected independently from
one another from aromatic hydrocarbons containing 6 to 10 and
especially 6 carbon atoms and ethylenical unsaturated or aromatic
heterocyclic residues containing 3 to 8 and especially 4 to 6
carbon atoms and one or two heteroatoms, independently selected
from N, O and S and especially selected from N and O, [0142]
R.sup.8, R.sup.9 and R.sup.10 are independently selected from a
group consisting of H, A, cycloalkyl 3 to 7 carbon atoms, Hal,
CH.sub.2Hal, CH(Hal).sub.2, C(Hal).sub.3, NO.sub.2,
(CH.sub.2).sub.nCN, (CH.sub.2).sub.nOR.sup.11,
(CH.sub.2).sub.nNR.sup.11R.sup.12
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.11, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11COR.sup.13,
(CH.sub.2).sub.nNR.sup.11CONR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11SO.sub.2A,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12,
(CH.sub.2).sub.nS(O).sub.uR.sup.13, (CH.sub.2).sub.nOC(O)R.sup.13,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nSR.sup.11,
(CH.sub.2).sub.nNHOA, (CH.sub.2).sub.nNR.sup.11COOR.sup.12,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2OR.sup.13,
(CH.sub.2).sub.nN(R.sup.11)CH.sub.2CH.sub.2OCF.sub.3,
(CH.sub.2).sub.nN(R.sup.11)C(R.sup.13)HCOOR.sup.12,
(CH.sub.2).sub.nN(R.sup.11)C(R.sup.13)HCOR.sup.13,
(CH.sub.2).sub.nN(COOR.sup.13)COOR.sup.14,
(CH.sub.2).sub.nN(CONH.sub.2)COOR.sup.11,
(CH.sub.2).sub.nN(CONH.sub.2)CONH.sub.2,
(CH.sub.2).sub.nN(CH.sub.2COOR.sup.11)COOR.sup.12,
(CH.sub.2).sub.nN(CH.sub.2CONH.sub.2)COOR.sup.11,
(CH.sub.2).sub.nN(CH.sub.2CONH.sub.2)CONH.sub.2,
(CH.sub.2).sub.nCOHR.sup.13COR.sup.14,
(CH.sub.2).sub.nCHR.sup.13COOR.sup.12 and
(CH.sub.2).sub.nCHR.sup.13CH.sub.2OR.sup.14, [0143] X represents a
bond or is (CR.sup.11R.sup.12).sub.h, or
(CHR.sup.11).sub.h-Q-(CHR.sup.12).sub.i, wherein [0144] Q is
selected from a group consisting of O, S, N--R.sup.15,
(CHal.sub.2).sub.j, (O--CHR.sup.18).sub.j, (CHR.sup.18--O).sub.j,
CR.sup.18.dbd.CR.sup.19, (O--CHR.sup.18CHR.sup.19).sub.j,
(CHR.sup.18CHR.sup.19--O).sub.j, C.dbd.O, C.dbd.NR.sup.15,
CH(OR.sup.15), C(OR.sup.15)(OR.sup.20), C(.dbd.O)N(R.sup.15),
N(R.sup.15)C(.dbd.O), CH.dbd.N--NR.sup.15, S.dbd.O, SO.sub.2,
SO.sub.2NR.sup.15 and NR.sup.15SO.sub.2, wherein [0145] h, i are
independently from each other 0, 1, 2, 3, 4, 5 or 6, preferably 0,
1, 2 or 3 and [0146] j is 1, 2, 3, 4, 5 or 6, preferably 1, 2, 3 or
4, [0147] p is 1, 2, 3 or 4, preferably 1, 2 or 3, and [0148] r is
0, 1, 2, or 3, preferably 0, 1 or 2; and the salts and solvates
thereof, preferably the physiologically acceptable salts and
solvates thereof.
[0149] Subject of the present invention are especially compounds of
formula I and II, in which one or more substituents or groups,
preferably the major part of the substituents or groups has a
meaning which is indicated as preferred, more preferred, even more
preferred or especially preferred.
[0150] In compounds of formula II, the term alkyl preferably refers
to an unbranched or branched alkyl residue, preferably an
unbranched alkyl residue comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or
10, preferably 1, 2, 3, 4, 5 or 6, more preferred 1, 2, 3 or 4 and
especially i or 2 carbon atoms, or a branched alkyl residue
comprising 3, 4, 5, 6, 7, 8, 9 or 10, preferably 3, 4, 5 or 6 more
preferred 3 or 4 carbon atoms. The alkyl residues can be optionally
substituted, especially by one or more halogen atoms, for example
up to perhaloalkyl, by one or more hydroxy groups or by one or more
amino groups, all of which can optionally be substituted by alkyl.
If an alkyl residue is substituted by halogen, it usually comprises
1, 2, 3, 4 or 5 halogen atoms, depending on the number of carbon
atoms of the alkyl residue. For example, a methyl group can
comprise, 1, 2 or 3 halogen atoms, an ethyl group (an alkyl residue
comprising 2 carbon atoms) can comprise 1, 2, 3, 4 or 5 halogen
atoms. If an alkyl residue is substituted by hydroxy groups, it
usually comprises one or two, preferably one hydroxy groups. If the
hydroxy group is substituted by alkyl, the alkyl substituent
comprises preferably 1 to 4 carbon atoms and is preferably
unsubstituted or substituted by halogen and more preferred
unsubstituted. If an alkyl residue is substituted by amino groups,
it usually comprises one or two, preferably one amino groups. If
the amino group is substituted by alkyl, the alkyl substituent
comprises preferably 1 to 4 carbon atoms and is preferably
unsubstituted or substituted by halogen and more preferred
unsubstituted. According to compounds of formula II, alkyl is
preferably selected from the group consisting of methyl, ethyl,
trifluoro methyl, pentafluoro ethyl, isopropyl, tert.-butyl,
2-amino ethyl, N-methyl-2-amino ethyl, N,N-dimethyl-2-amino ethyl,
N-ethyl-2-amino ethyl, N,N-diethyl-2-amino ethyl, 2-hydroxy ethyl,
2-methoxy ethyl and 2-ethoxy ethyl, further preferred of the group
consisting of 2-butyl, n-pentyl, neo-nentyl, isopentyl, hexyl and
n-decyl, more preferred of methyl, ethyl, trifluoro methyl,
isoproply and tert.-butyl.
[0151] In compounds of formula II, alkenyl is preferably selected
from the group consisting of allyl, 2- or 3-butenyl, isobutenyl,
sec-butenyl, furthermore preferably 4-pentenyl, isopentenyl and
5-hexenyl.
[0152] In compounds of formula II, alkylene is preferably
unbranched and is more preferably methylene or ethylene,
furthermore preferably propylene or butylene.
[0153] In compounds of formula II, alkylenecycloalkyl preferably
has 5 to 10 carbon atoms and is preferably methylenecyclopropyl,
methylenencyclobutyl, furthermore preferably methylenecyclopentyl,
methylenecyclohexyl or methylenecycloheptyl, furthermore
alternatively ethylenecyclopropyl, ethylenecyclobutyl,
ethylenecyclopentyl, ethylenecyclohexyl or ethylenencycloheptyl,
propylenecyclopentyl, propylenecyclohexyl, butylenecyclopentyl or
butylenecyclohexyl.
[0154] In compounds of formula II, the term "alkoxy" preferably
comprises groups of formula O-alkyl, where alkyl is an alkyl group
as defined above. More preferred, alkoxy is selected from group
consisting of methoxy, ethoxy, n-propoxy, isopropoxy, 2-butoxy,
tert.-butoxy and halogenated, especially perhalogenated,
derivatives thereof. Preferred perhalogenated derivatives are
selected from the group consisting of O--CCl.sub.3, O--CF.sub.3,
O--C.sub.2Cl.sub.5, O--C.sub.2F.sub.5, O--C(CCl.sub.3).sub.3 and
O--C(CF.sub.3).sub.3.
[0155] In compounds of formula II, the term "alkoxyalkyl"
preferably comprises branched and unbranched residues, more
preferred unbranched residues, of formula
C.sub.uH.sub.2u+1--O--(CH.sub.2).sub.v, wherein u and v are
independently from each other 1 to 6. Especially preferred is u=1
and v=1 to 4.
[0156] In compounds of formula II the term "alkoxyalkyl" includes
alkoxyalkyl groups as defined above, wherein one or more of the
hydrogen atoms are substituted by halogen, for example up to
perhalo alkoxyalkyl.
[0157] In compounds of formula II, cycloalkyl preferably has 3-7
carbon atoms and is preferably cyclopropyl or cyclobutyl,
furthermore preferably cyclopentyl or cyclohexyl, furthermore also
cycloheptyl, particularly preferably cyclopentyl.
[0158] In compounds of formula II, Ar.sup.3 to Ar.sup.6 are
preferably selected independently from one another from phenyl,
naphthyl and biphenyl which is optionally substituted by one or
more substituents, selected from the group consisting of A, Hal,
NO.sub.2, CN, OR.sup.15, NR.sup.15R.sup.16, COOR.sup.15,
CONR.sup.15R.sup.16, NR.sup.15COR.sup.16,
NR.sup.15CONR.sup.15R.sup.16, NR.sup.16SO.sub.2A, COR.sup.15,
SO.sub.2R.sup.15R.sup.16, S(O).sub.uA and OOR.sup.15.
[0159] In compounds of formula II, het is preferably an optionally
substituted aromatic heterocyclic residue and even more preferred
and optionally substituted saturated heterocyclic residue, wherein
the substituents are preferably selected from A, CN and Hal. Even
more preferred, het is selected from the group consisting of
1-piperidyl, 1-piperazyl, 1-(4-methyl)-piperazyl,
4-methylpiperazin-1-yl amine, 4-morpholinyl, 1-4pyrrolidinyl,
1-pyrazolidinyl 1-(2-methyl)-pyrazolidinyl, 1-imidazolidinyl or
1-(3-methyl)-imidazolidinyl, thiophen-2-yl, thiophen-3-yl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-oxazolyl, 4-oxazolyl,
5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, chinolinyl,
isochinolinyl, 2-pyridazyl, 4-pyridazyl, 2-pyrimidyl, 4-pyrimidyl,
5-pyrimidyl, 2-pyrazinyl and 3-pyrazinyl.
[0160] Preferably, the sum of h and l exceeds 0.
[0161] A preferred aspect of the instant invention relates to
compounds of formula II, wherein n is 0 or 1 and especially 0.
[0162] Another preferred aspect of the instant invention relates to
compounds of formula II, wherein n is 0 in the residues R.sup.8,
R.sup.9 and/or R.sup.10 and especially in R.sup.10.
[0163] Another preferred aspect of the instant invention relates to
compounds of formula II, wherein X represents a bridging group,
selected from (CR.sup.11R.sup.12).sub.h or
(CHR.sup.11).sub.h-Q-(CHR.sup.12).sub.i.
[0164] The invention relates in particular to compounds of the
formula II in which at least one of said radicals has one of the
preferred meanings given above.
[0165] Some mere preferred groups of compounds may be expressed by
the following sub-formulae II.1) to II.20), which correspond to the
formula II and in which radicals not denoted in greater detail are
as defined in the formula II, but in which [0166] II.1) Ar.sup.1 is
phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl,
preferably phenyl, pyridinyl or isoxazolyl and especially phenyl or
oxazolyl; [0167] II.2) Ar.sup.1 is phenyl, pyridinyl, oxazolyl,
isoxazolyl, pyrazolyl or imidazolyl, preferably phenyl, pyridinyl
or isoxazolyl and especially phenyl or oxazolyl, and p is 1, 3 or
3; [0168] II.3) Ar.sup.1 is phenyl, pyridinyl, oxazolyl,
isoxazolyl, pyrazolyl or imidazolyl, preferably phenyl, pyridinyl
or isoxazolyl and especially phenyl or oxazolyl, p is 1, 2 or 3,
and R.sup.8 is selected from the group consisting of alkyl
comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon
atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl comprising 1
to 4 carbon atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nCOR.sup.13,
(CH.sub.2).sub.nCOOR.sup.11, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.12).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13; [0169] II.4) Ar.sup.1 is
phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl,
preferably phenyl, pyridinyl or isoxazolyl and especially phenyl or
oxazolyl, p is 1, 2 or 3, R.sup.8 is selected from the group
consisting of alkyl comprising 1 to 4 carbon atoms, alkoxy
comprising 1 to 4 carbon atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2,
perhaloalkyl comprising 1 to 4 carbon atoms, NO.sub.2,
(CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13; [0170] II.5) Ar.sup.1 is
phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl,
preferably phenyl, pyridinyl or isoxazolyl and especially phenyl or
oxazolyl, p is 1, 2 or 3, R.sup.8 is selected from the group
consisting of alkyl comprising 1 to 4 carbon atoms, alkoxy
comprising 1 to 4 carbon atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2,
perhaloalkyl comprising 1 to 4 carbon atoms, NO.sub.2,
(CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.rCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, wherein n is 0 or 1; [0171]
II.6) Ar.sup.1 is phenyl, pyridinyl, oxazolyl, isoxazolyl,
pyrazolyl or imidazolyl, preferably phenyl, pyridinyl or isoxazolyl
and especially phenyl or oxazolyl, p is 1, 2 or 3, R.sup.8 is
selected from the group consisting of alkyl comprising 1 to 4
carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,
CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl comprising 1 to 4 carbon
atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nCOR.sup.13,
(CH.sub.2).sub.rCOOR.sup.11, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, wherein n is 0 or 1, and E, is
0; [0172] II.7) Ar.sup.1 is phenyl, pyridinyl, oxazolyl,
isoxazolyl, pyrazolyl or imidazolyl, preferably phenyl, pyridinyl
or isoxazolyl and especially phenyl or oxazolyl, p is 1, 2 or 3,
R.sup.8 is selected from the group consisting of alkyl comprising 1
to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,
CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl comprising 1 to 4 carbon
atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nCOR.sup.13,
(CH.sub.2).sub.nCOOR.sup.11, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, wherein n is 0 or 1, u is 0 or
2, preferably 0, and q is 0 or 1, and X is selected from the group
consisting of O, S, NR.sup.15, CHOR.sup.11, CH.sub.2,
CH.sub.2OH.sub.2, OCH.sub.2, CH.sub.2O, OCH.sub.2OH.sub.2,
CH.sub.2CH.sub.2O, preferably O, S and CH.sub.2 and especially O
and S; [0173] II.8) Ar.sup.1 is phenyl, pyridinyl, oxazolyl,
isoxazolyl, pyrazolyl or imidazolyl, preferably phenyl, pyridinyl
or isoxazolyl and especially phenyl or oxazolyl, p is 1, 2 or 3,
R.sup.8 is selected from the group consisting of alkyl comprising 1
to 4 carbon atoms, alkoxy comprising 1 to 4 carbon atoms, Hal,
CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl comprising 1 to 4 carbon
atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nCOR.sup.13,
(CH.sub.2).sub.nCOOR.sup.11, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, wherein n is 0 or 1, u is 0 or
2, preferably 0, and q is 0 or 1, and X is selected from the group
consisting of O, S, NR.sup.15, CHOR.sup.11, CH.sub.2
CH.sub.2CH.sub.2, OCH.sub.2, CH.sub.2O, OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2O, preferably O, S and CH.sub.2 and especially O
and S, Ar.sup.2 is phenyl, pyridinyl or pyrimidyl, and especially
is phenyl or pyridinyl; [0174] II.9) Ar.sup.1 is phenyl, pyridinyl,
oxazolyl, isoxazolyl, pyrazolyl or imidazolyl, preferably phenyl,
pyridinyl or isoxazolyl and especially phenyl or oxazolyl, p is 1,
2 or 3, R.sup.8 is selected from the group consisting of alkyl
comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon
atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl comprising 1
to 4 carbon atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nCOR.sup.13,
(CH.sub.2).sub.nCOOR.sup.11, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, wherein n is 0 or 1, u is 0 or
2, preferably 0, and q is 0 or 1, and X is selected from the group
consisting of O, S, NR.sup.15, CHOR.sup.11, CH.sub.2,
CH.sub.2CH.sub.2, OCH.sub.2, CH.sub.2O, OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2O, preferably O, S and CH.sub.2 and especially O
and S, Ar.sup.2 is phenyl, pyridinyl or pyrimidyl, and especially
is phenyl or pyridinyl, and R.sup.10 is selected from the group
consisting of H, alkyl comprising 1 to 4 carbon atoms, alkoxy
comprising 1 to 4 carbon atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2,
perhaloalkyl comprising 1 to 4 carbon atoms, NO.sub.2,
(CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.t--O--(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, preferably selected from the
group consisting of alkyl comprising 1 to 4 carbon atoms,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.13,
(CH.sub.2).sub.nCONR.sup.11R.sup.12 and especially
(CH.sub.2).sub.nCONR.sup.11R.sup.12; [0175] II.10) Ar.sup.1 is
phenyl, pyridinyl, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl,
preferably phenyl, pyridinyl or isoxazolyl and especially phenyl or
oxazolyl, p is 1, 2 or 3, R.sup.8 is selected from the group
consisting of alkyl comprising 1 to 4 carbon atoms, alkoxy
comprising 1 to 4 carbon atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2,
perhaloalkyl comprising 1 to 4 carbon atoms, NO.sub.2,
(CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, wherein n is 0 or 1, u is 0 or
2, preferably O, and q is 0 or 1 and X is selected from the group
consisting of O, S, NR.sup.15, CHOR.sup.11, CH.sub.2,
CH.sub.2CH.sub.2OCH.sub.2, CH.sub.2, OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2O, preferably O, S and CH.sub.2 and especially O
and S, Ar.sup.2 is phenyl, pyridinyl or pyrimidyl, and especially
is phenyl or pyridinyl, and R.sup.10 is selected from the group
consisting of H, alkyl comprising 1 to 4 carbon atoms, alkoxy
comprising 1 to 4 carbon atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2,
perhaloalkyl comprising 1 to 4 carbon atoms, NO.sub.2,
(CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, preferably selected from the
group consisting of alkyl comprising 1 to 4 carbon atoms,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.13,
(CH.sub.2).sub.nCONR.sup.11R.sup.12 and especially
(CH.sub.2).sub.nCONR.sup.11R.sup.12, wherein n is 0, 1 or 2,
preferably 0 or 1; [0176] II.11) Ar.sup.1 is phenyl, pyridinyl,
oxazolyl, isoxazolyl, pyrazolyl or imidazolyl, preferably phenyl,
pyridinyl or isoxazolyl and especially phenyl or oxazolyl, p is 1,
2 or 3, R.sup.8 is selected from the group consisting of alkyl
comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon
atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl comprising 1
to 4 carbon atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nCOR.sup.13,
(CH.sub.2).sub.nCOOR.sup.11, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, wherein n is 0 or 1, u is 0 or
2, preferably 0, and q is 0 or 1, and X is selected from the group
consisting of O, S, NR.sup.15, CHOR.sup.11, CH.sub.2,
CH.sub.2CH.sub.2, OCH.sub.2, CH.sub.2O, OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2O, preferably O, S and CH.sub.2 and especially O
and S, Ar.sup.2 is phenyl, pyridinyl or pyrimidyl, and especially
is phenyl or pyridinyl, and R.sup.10 is selected from the group
consisting of H, alkyl comprising 1 to 4 carbon atoms, alkoxy
comprising 1 to 4 carbon atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2,
perhaloalkyl comprising 1 to 4 carbon atoms, NO.sub.2,
(CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, preferably selected from the
group consisting of alkyl comprising 1 to 4 carbon atoms,
(CH.sub.2).sub.nNP.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.13,
(CH.sub.2).sub.nCONR.sup.11R.sup.12 and especially
(CH.sub.2).sub.nCONR.sup.11R.sup.12, wherein n is 0, 1 or 2,
preferably 0 or 1 and r is 0, 1 or 2, preferably 0 or 1; [0177]
II.12) p is 1, 2 or 3, R.sup.8 is selected from the group
consisting of alkyl comprising 1 to 4 carbon atoms, alkoxy
comprising 1 to 4 carbon atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2,
perhaloalkyl comprising 1 to 4 carbon atoms, NO.sub.2,
(CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, wherein n is 0 or 1, u is 0 or
2, preferably 0, and q is 0 or 1, and X is selected from the group
consisting of O, S, NR.sup.15, CHOR.sup.11, CH.sub.2,
CH.sub.2CH.sub.2, OCH.sub.2, CH.sub.2O, OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2O, preferably O, S and CH.sub.2 and especially O
and S, Ar.sup.2 is phenyl, pyridinyl or pyrimidyl, and especially
is phenyl or pyridinyl, and R.sup.10 is selected from the group
consisting of H, alkyl comprising 1 to 4 carbon atoms, alkoxy
comprising 1 to 4 carbon atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2,
perhaloalkyl Comprising 1 to 4 carbon atoms, NO.sub.2,
(CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, preferably selected from the
group consisting of alkyl comprising 1 to 4 carbon atoms,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.13,
(CH.sub.2).sub.nCONR.sup.11R.sup.12 and especially
(CH.sub.2).sub.nCONR.sup.11R.sup.12, wherein n is 0, 1 or 2,
preferably 0 or 1 and r is 0, 1 or 2, preferably 0 or 1; [0178]
II.13) R.sup.8 is selected from the group consisting of alkyl
comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon
atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl comprising 1
to 4 carbon atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nCOR.sup.13,
(CH.sub.2).sub.nCOOR.sup.11, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, wherein n is 0 or 1, u is 0 or
2, preferably 0, and q is 0 or 1, and X is selected from the group
consisting of O, S, NR.sup.15, CHOR.sup.11, CH.sub.2,
CH.sub.2CH.sub.2, OCH.sub.2, CH.sub.2O, OCH.sub.2CH.sub.2,
CH.sub.2CH.sub.2O, preferably O, S and CH.sub.2 and especially O
and S, Ar.sup.2 is phenyl, pyridinyl or pyrimidyl, and especially
is phenyl or pyridinyl, and R.sup.10 is selected from the group
consisting of H, alkyl comprising 1 to 4 carbon atoms, alkoxy
comprising 1 to 4 carbon atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2,
perhaloalkyl comprising 1 to 4 carbon atoms, NO.sub.2,
(CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, preferably selected from the
group consisting of alkyl comprising 1 to 4 carbon atoms,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.13,
(CH.sub.2).sub.nCONR.sup.11R.sup.12 and especially
(CH.sub.2).sub.nCONR.sup.11R.sup.12, wherein n is 0, 1 or 2,
preferably 0 or 1 and r is 0, 1 or 2, preferably 0 or 1; [0179]
II.14) R.sup.8 is selected from the group consisting of alkyl
comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon
atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl comprising 1
to 4 carbon atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nCOR.sup.13,
(CH.sub.2).sub.nCOOR.sup.11, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, wherein u is 0 or 2, preferably
0, and q is 0 or 1, and X is selected from the group consisting of
O, S, NR.sup.15, CHOR.sup.11, CH.sub.2, CH.sub.2CH.sub.2,
OCH.sub.2, CH.sub.2O, OCH.sub.2CH.sub.2, CH.sub.2CH.sub.2O,
preferably O, S and CH.sub.2 and especially O and S, Ar.sup.2 is
phenyl, pyridinyl or pyrimidyl, and especially is phenyl or
pyridinyl, and
R.sup.10 is selected from the group consisting of H, alkyl
comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon
atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl comprising 1
to 4 carbon atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2)CONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, preferably selected from the
group consisting of alkyl comprising 1 to 4 carbon atoms,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.13,
(CH.sub.2).sub.nCONR.sup.11R.sup.12 and especially
(CH.sub.2).sub.nCONR.sup.11R.sup.12, wherein n is 0, 1 or 2,
preferably 0 or 1 and r is 0, 1 or 2, preferably 0 or 1; [0180]
II.15) R.sup.8 is selected from the group consisting of alkyl
comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon
atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl comprising 1
to 4 carbon atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12, (CH.sub.2).sub.nCOR.sup.13,
(CH.sub.2).sub.nCOOR.sup.13, (CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, wherein q is 0 or 1, and X is
selected from the group consisting of O, S, NR.sup.15; CHOR.sup.11,
CH.sub.2, CH.sub.2CH.sub.2, OCH.sub.2, CH.sub.2O,
OCH.sub.2CH.sub.2, CH.sub.2CH.sub.2O, preferably O, S and CH.sub.2
and especially O and S, Ar.sup.2 is phenyl, pyridinyl or pyrimidyl,
and especially is phenyl or pyridinyl, and R.sup.10 is selected
from the group consisting of H, alkyl comprising 1 to 4 carbon
atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH.sub.2Hal,
CH(Hal).sub.2, perhaloalkyl comprising 1 to 4 carbon atoms,
NO.sub.2, (CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, preferably selected from the
group consisting of alkyl comprising 1 to 4 carbon atoms,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.13,
(CH.sub.2).sub.nCONR.sup.11R.sup.12 and especially
(CH.sub.2).sub.nCONR.sup.11R.sup.12, wherein n is 0, 1 or 2,
preferably 0 or 1 and r is 0, 1 or 2, preferably 0 or 1; [0181]
II.16) q is 0 or 1, and X is selected from the group consisting of
O, S, NR.sup.15, CHOR.sup.11, CH.sub.2, CH.sub.2CH.sub.2,
OCH.sub.2, CH.sub.2O, OCH.sub.2CH.sub.2, CH.sub.2CH.sub.2O,
preferably O, S and CH.sub.2 and especially O and S, Ar.sup.2 is
phenyl, pyridinyl or pyrimidyl, and especially is phenyl or
pyridinyl, and R.sup.10 is selected from the group consisting of H,
alkyl comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4
carbon atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl
comprising 1 to 4 carbon atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, preferably selected from the
group consisting of alkyl comprising 1 to 4 carbon atoms,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.13,
(CH.sub.2).sub.nCONR.sup.11R.sup.12 and especially
(CH.sub.2).sub.nCONR.sup.11R.sup.12, wherein n is 0, 1 or 2,
preferably 0 or 1 and r is 0, 1 or 2, preferably 0 or 1; [0182]
II.17) X is selected from the group consisting of O, S, NR.sup.15,
CHOR.sup.11, CH.sub.2, CH.sub.2CH.sub.2, OCH.sub.2, CH.sub.2O,
OCH.sub.2CH.sub.2, CH.sub.2CH.sub.2O, preferably O, S and CH.sub.2
and especially O and S, Ar.sup.2 is phenyl, pyridinyl or pyrimidyl,
and especially is phenyl or pyridinyl, and R.sup.10 is selected
from the group consisting of H, alkyl comprising 1 to 4 carbon
atoms, alkoxy comprising 1 to 4 carbon atoms, Hal, CH.sub.2Hal,
CH(Hal).sub.2, perhaloalkyl comprising 1 to 4 carbon atoms,
NO.sub.2, (CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, preferably selected from the
group consisting of alkyl comprising 1 to 4 carbon atoms,
(CH.sub.2).sub.nNR.sup.11R.sup.12
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.13,
(CH.sub.2).sub.nCONR.sup.11R.sup.12 and especially
(CH.sub.2).sub.nCONR.sup.11R.sup.12, wherein n is 0, 1 or 2,
preferably 0 or 1 and r is 0, 1 or 2, preferably 0 or 1; [0183]
II.18) Ar.sup.2 is phenyl, pyridinyl or pyrimidyl, and especially
is phenyl or pyridinyl, and R.sup.10 is selected from the group
consisting of H, ally comprising 1 to 4 carbon atoms, alkoxy
comprising 1 to 4 carbon atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2,
perhaloalkyl comprising 1 to 4 carbon atoms, NO.sub.2,
(CH.sub.2).sub.nCN, (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, preferably selected from the
group consisting of alkyl comprising 1 to 4 carbon atoms,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.13,
(CH.sub.2).sub.nCONR.sup.11R.sup.12 and especially
(CH.sub.2).sub.nCONR.sup.11R.sup.12, wherein n is 0, 1 or 2,
preferably 0 or 1 and r is 0, 1 or 2, preferably 0 or 1; [0184]
II.19) R.sup.10 is selected from the group consisting of H, alkyl
comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon
atoms, Hal, CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl comprising 1
to 4 carbon atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, preferably selected from the
group consisting of alkyl comprising 1 to 4 carbon atoms,
(CH.sub.2)NR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12 and especially
(CH.sub.2).sub.nCONR.sup.11R.sup.12, wherein n is 0, 1 or 2,
preferably 0 or 1 and r is 0, 1 or 2, preferably 0 or 1; [0185]
II.20) R.sup.10 is selected from the group consisting of H, alkyl
comprising 1 to 4 carbon atoms, alkoxy comprising 1 to 4 carbon
atoms; Hal, CH.sub.2Hal, CH(Hal).sub.2, perhaloalkyl comprising 1
to 4 carbon atoms, NO.sub.2, (CH.sub.2).sub.nCN,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.11,
(CH.sub.2).sub.nCONR.sup.11R.sup.12,
(CH.sub.2).sub.nSO.sub.2NR.sup.11R.sup.12 and
(CH.sub.2).sub.nS(O).sub.uR.sup.13, preferably selected from the
group consisting of alkyl comprising 1 to 4 carbon atoms,
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nCOR.sup.13, (CH.sub.2).sub.nCOOR.sup.13,
(CH.sub.2).sub.nCONR.sup.11R.sup.12 and especially
(CH.sub.2).sub.nCONR.sup.11R.sup.12, and r is 0, 1 or 2, preferably
0 or 1.
[0186] One preferred embodiment of the instant invention relates to
compounds of formula II and preferably one or more of sub formulae
II.1) to II.20), wherein p is 1, 2 or 3 and R.sup.8 is
independently selected from the group consisting of methyl, ethyl,
isopropyl, tert.-butyl, F, Cl, Br, CF.sub.3, C(CF.sub.3).sub.3,
methoxy, ethoxy, tert.-butoxy, perfluoro tert.-butoxy
(OC(CF.sub.3).sub.3), methyl sulfanyl (SCH.sub.3), ethyl sulfanyl
(SCH.sub.2CH.sub.3), acetyl (COCH.sub.3), propionyl
(COCH.sub.2CH.sub.3), butyryl (COCH.sub.2CH.sub.2CH.sub.3). If p is
2 or 3, all substituents can, be the same or different.
[0187] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein X is selected from the group
consisting of S, N--R.sup.21, CH.sub.2, CH.sub.2CH.sub.2, OCH.sub.2
and CH.sub.2O.
[0188] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein X is selected from the group
consisting of S, CH.sub.2.
[0189] Another even more preferred embodiment of the instant
invention relates to compounds of formula II and preferably one or
more of sub formulae II.1) to II.20), wherein X is O.
[0190] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein Y is selected from the group
consisting of C(R.sup.22)--NO.sub.2, C(R.sup.22)--CN and
C(CN).sub.2.
[0191] Another more preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein Y is selected from the group
consisting of O, S and NR.sup.21.
[0192] Another even more preferred embodiment of the instant
invention relates to compounds of formula II and preferably one or
more of sub formulae II.1) to II.20), wherein Y is selected from
the group consisting of O and S.
[0193] Another even more preferred embodiment of the instant
invention relates to compounds of formula II and preferably one or
more of sub formulae II.1) to II.20), wherein Y is O.
[0194] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein Ar.sup.2 is pyridinyl.
[0195] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein r is either 0 or 1. If r is
1, R.sup.10 is preferably (CH.sub.2).sub.nCONR.sup.11R.sup.12 and
especially (CH.sub.2).sub.nCONR.sup.11R.sup.12, wherein n in 0. In
this embodiment, R.sup.11 is preferably selected from the group
consisting of H and A and more preferred from H and alkyl, and
R.sup.12 is preferably selected from the group consisting of H and
A and more preferred from H and alkyl. Especially preferred as
residue R.sup.10 are carbamoyl, more preferred alkyl carbamoyl or
diaalkyl carbamoyl, even more preferred methyl carbamoyl or
dimethyl carbamoyl, ethyl carbamoyl or diethyl carbamoyl and
especially preferred methyl carbamoyl (--CONHCH.sub.3). This
embodiment is especially preferred when Ar.sup.2 is pyridinyl. When
Ar.sup.2 is pyridinyl, R.sup.10 is preferably bonded in a vicinal
position to the nitrogen atom of the pyrindiyl residue, i.e. in 2-
and/or 6-position of the pyridinyl residue.
[0196] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein r is either 0 or 1. If r is
1, R.sup.10 is preferably (CH.sub.2).sub.nCONR.sup.11R.sup.12 and
especially (CH.sub.2).sub.nCONR.sup.11R.sup.12, wherein n is 0. In
this embodiment, R.sup.11 is preferably selected from the group
consisting of H and A, more preferred from H and alkyl and
especially is H, and R.sup.12 is preferably selected from the group
consisting of H and A and more preferred from H, unsubstituted
alkyl and substituted alkyl, preferably comprising 1 to 6 and
especially 1 or 2 carbon atoms. Suitable for substituents include
amino groups, such as NH.sub.2, NHCH.sub.3, NHCH.sub.2CH.sub.3,
N(CH.sub.3).sub.2 and NH(CH.sub.2CH.sub.3), and carboxyl groups and
derivatives thereof, such as COOH, COOCH.sub.3, CONH.sub.2, and
CONHCH.sub.3. Especially preferred as residue R.sup.10 are
CONHCH.sub.3, CONHCH.sub.2CH.sub.2NH.sub.2,
CONHCH.sub.2CH.sub.2NHCH.sub.3,
CONHCH.sub.2CH.sub.2N(CH.sub.3).sub.2, CONHCH.sub.2COOH and
CONHCH.sub.2CH.sub.2COOH. This embodiment is especially preferred
when Ar.sup.2 is pyridinyl. When Ar.sup.2 is pyridinyl, R.sup.10 is
preferably bonded in a vicinal position to the nitrogen atom of the
pyrindiyl residue, i.e. in 2- and/or 6-position of the pyridinyl
residue.
[0197] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein Ar.sup.1 comprises two or
more substituents R.sup.8, wherein one or more, preferably one
substituent R.sup.8 is selected from the group consisting of
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11(CH.sub.2).sub.kOR.sup.12,
(CH.sub.2).sub.nNPR.sup.11(CH.sub.2).sub.kNR.sup.12R.sup.12,
(CH.sub.2).sub.nCOOR.sup.11 and (CH.sub.2).sub.nS(O).sub.uR.sup.13
wherein R.sup.11, R.sup.12 and R.sup.13 are defined as above and n
is as defined above, preferably n is 0, 1 or 2 and especially is 0,
k is 1 to 4 and preferably 1 or 2, and u is preferably 2. In this
embodiment R.sup.11, R.sup.12 and R.sup.13 are more preferably
selected independently from each other from the group consisting of
H, methyl and ethyl. In this embodiment, one or two substituents
R.sup.8 and preferably one substituent R.sub.8 is especially
preferably selected from the group consisting of NH.sub.2,
N(CH.sub.3).sub.2, N(C.sub.2H.sub.5).sub.2,
NHCH.sub.2CH.sub.2NH.sub.2, N(CH.sub.3)CH.sub.2CH.sub.2NH.sub.2,
N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
N(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, SCH.sub.3, SC.sub.2H.sub.5,
SO.sub.2CH.sub.3, COOCH.sub.3 and COOH. Accordingly, in this
embodiment Ar.sup.1 especially preferably comprises at least one
substituent R.sup.8 other than (CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11(CH.sub.2).sub.kOR.sup.12,
(CH.sub.2).sub.nNR.sup.11(CH.sub.2).sub.kNR.sup.12R.sup.12,
(CH.sub.2).sub.nCOOR.sup.13 and (CH.sub.2).sub.nS(O).sub.uR.sup.13
as defined in this paragraph and especially other than NH.sub.2,
N(CH.sub.3).sub.2, N(C.sub.2H.sub.5).sub.2,
NHCH.sub.2CH.sub.2NH.sub.2, N(CH.sub.3)CH.sub.2CH.sub.2NH.sub.2,
N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
N(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, SCH.sub.3, SC.sub.2H.sub.5,
SO.sub.2CH.sub.3, COOCH.sub.3 and COOH.
[0198] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein q is 1, i.e. the phenylen
moiety bound to the glycine amide group and the radical X is
substituted once, preferably by a substituent selected from the
group consisting of alkyl and halogen and more preferred from
methyl, ethyl, F, Cl and Br.
[0199] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1). to II.20), wherein q is 0, i.e. the phenylen
moiety bound to the glycine amide group and the radical X is
unsubstituted.
[0200] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
formulae II.1) to II.20), wherein (R.sup.8).sub.p--Ar.sup.1 is
selected from the group consisting of 3-acetyl-phenyl,
4-acetyl-phenyl, 2-bromo-phenyl, 3-bromo-phenyl, 4-bromo-phenyl,
4-bromo-2-chloro-phenyl, 4-bromo-3-methyl-phenyl,
4-bromo-3-trifluoromethyl-phenyl, 2-chloro-phenyl,
2-chloro-4-trifluoromethyl-phenyl,
2-chloro-5-trifluoromethyl-phenyl, 3-chloro-phenyl,
3-chloro-4-methyl-phenyl, 3-chloro-4-methoxy-phenyl,
3-chloro-4-methoxy-phenyl, 4-chloro-phenyl,
4-chloro-2-trifluoromethyl-phenyl,
4-chloro-3-trifluoromethyl-phenyl, 4-chloro-2-methyl-phenyl,
5-chloro-2-methyl-phenyl, 5-chloro-2-methoxy-phenyl,
4-chloro-2-methoxy-5-methyl-phenyl,
4-chloro-2-methoxy-5-trifluoromethyl-phenyl, 2,3-dichloro-phenyl,
2,4-dichloro-phenyl, 2,5-dichloro-phenyl, 3,4-dichloro-phenyl,
3,5-dichloro-phenyl, 2,4,5-trichloro-phenyl, 4-fluoro-phenyl,
4-fluoro-3-trifluoromethyl-phenyl, 4-ethoxy-phenyl,
2-methoxy-phenyl, 2-methoxy-5-trifluoromethylphenyl,
4-methoxy-phenyl, 2,5-dimethoxy-phenyl, 2-trifluoromethyl-phenyl,
3-trifluoromethyl-phenyl, 3-trifluoromethoxy-phenyl,
4-trifluoromethyl-phenyl, 4-trifluoromethoxy-phenyl,
3,5-bis-trifluoromethyl-phenyl, 3-methoxy-phenyl,
3-methylsulfanyl-phenyl, 4-methylsulfanyl-phenyl, o-tolyl
(2-methyl-phenyl), m-tolyl (3-methyl-phenyl), p-tolyl
(4-methyl-phenyl), 2,3-dimethyl-phenyl, 2,3-di-methyl-phenyl,
2,5-dimethyl-phenyl, 3,4-dimethyl-phenyl, 3,5-dimethyl-phenyl,
2-ethyl-phenyl, 3-ethyl-phenyl, 4-ethyl-phenyl, 4-isopropyl-phenyl,
4-tert-butyl-phenyl and 5-tert-butyl-isoxazol-3-yl.
[0201] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein (R.sup.8).sub.p--Ar.sup.1 is
as defined above, but comprises one or more additional residues,
preferably one additional residue. The additional residues are
preferably selected from the meanings given for R.sup.8 and more
preferably selected from the group consisting of
(CH.sub.2).sub.nNR.sup.11R.sup.12,
(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
(CH.sub.2).sub.nNR.sup.11(CH.sub.2).sub.kOR.sup.12,
(CH.sub.2).sub.nNR.sup.11(CH.sub.2).sub.kNR.sup.12R.sup.12,
(CH.sub.2).sub.nCOOR.sup.13 and (CH.sub.2).sub.nS(O).sub.uR.sup.13
wherein R.sup.11, R.sup.12 and R.sup.13 are defined as above and n
is as defined above, preferably n is 0, 1 or 2 and especially is 0,
k is 1 to 4 and preferably 1 or 2, and u is preferably 2. In this
embodiment R.sup.11, R.sup.12 and R.sup.13 are more preferably
selected independently from each other from the group consisting of
H, methyl and ethyl. Even more preferred, the additional residue(s)
is/are selected from the group consisting of NH.sub.2,
N(CH.sub.3).sub.2, N(C.sub.2H.sub.5).sub.2,
NHCH.sub.2CH.sub.2NH.sub.2, N(CH.sub.3)CH.sub.2CH.sub.2NH.sub.2,
N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
N(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
OCH.sub.2CH.sub.2N(CH.sub.3).sub.2, SCH.sub.3, SC.sub.2H.sub.5,
SO.sub.2CH.sub.3, COOCH.sub.3 and COOH.
[0202] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein X is bonded in the para- (p-)
or metha- (m-) position to the phenyl residue that is bonded
directly to the glycine amide moiety.
[0203] Another preferred embodiment of the instant invention
relates to compounds of formula 31 and preferably one or more of
sub formulae II.1) to II.20), wherein Ar.sup.2 is a pyridinyl
residue and wherein said pyridinyl residue is bonded to X in the 3-
or 4-position, preferably the 4-position, relative to the nitrogen
atom of the pyridinyl residue.
[0204] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein Ar.sup.2 comprises one or
more substituents R.sup.10 and wherein one or two, preferably one
substituent R.sup.10 is selected from unsubstituted or substituted
carbamoyl moieties. Substituted carbamoyl moieties are preferably
selected from CONHR.sup.23 or CONR.sup.23R.sup.24, preferably
CONHR.sup.23, wherein R.sup.23 and R.sup.24 are independently
selected from the definitions given for R.sup.8, more preferably
selected from alkyl, preferably methyl, ethyl, propyl and butyl,
(CH.sub.2).sub.nNR.sup.11R.sup.12 and (CH.sub.2).sub.nOR.sup.12,
wherein R.sup.11, R.sup.12 and n are as defined above. In this
embodiment, n is preferably not 0 and more preferred 1 to 3 and
especially 1 or 2. Preferred examples for R.sup.23 are selected
from the group consisting of methyl, ethyl,
CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2N(C.sub.3).sub.2,
CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2OCH.sub.3 and
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3.
[0205] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein Ar.sup.2 comprises one or
more substituents R.sup.10 and wherein one or two, preferably one
substituent R.sup.10 is selected from substituted carbamoyl
moieties. Substituted carbamoyl moieties are preferably selected
from CONHR.sup.23, wherein R.sup.23 is preferably unsubstituted
C.sub.1-C.sub.4 alkyl and especially methyl.
[0206] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein Ar.sup.2 comprises one or
more substituents R.sup.10 and wherein one or two, preferably one
substituent R.sup.10 is selected from substituted carbamoyl
moieties. Substituted carbamoyl moieties are preferably selected
from CONHR.sup.23 wherein R.sup.23 selected from
(CH.sub.2).sub.nNR.sup.11R.sup.12 and (CH.sub.2).sub.nOR.sup.12,
wherein R.sup.11, R.sup.12 and n are as defined above. In this
embodiment, n is preferably not 0 and more preferred 1 to 3 and
especially 1 or 2. Preferred examples for R.sup.23 are selected
from the group consisting of CH.sub.2CH.sub.2NH.sub.2,
CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2OCH.sub.3 and
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3.
[0207] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein Ar.sup.1 comprises one or
more substituents R.sup.8 and wherein one or two, preferably one
substituent R.sup.8 is selected from the group consisting of
NH.sub.2, N(CH.sub.3).sub.2, NHCH.sub.3, N(C.sub.2H.sub.5).sub.2,
HNCH.sub.2CH.sub.2NH.sub.2, OCH.sub.2CH.sub.2NH.sub.2,
HOCH.sub.2CH.sub.2NH, OCH.sub.2CH.sub.2NHCH.sub.3,
N(CH.sub.3)CH.sub.2CH.sub.2NH.sub.2,
HN(CH.sub.3)CH.sub.2CH.sub.2NH,
N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
N(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
OCH.sub.2CH.sub.2N(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2, SCH.sub.3,
SC.sub.2H.sub.5, and compounds of the formulae
##STR00004##
and/or Ar.sup.2 comprises one or more substituents R.sup.10 and
wherein one or two, preferably one substituent R.sup.10 is
independently selected from the meanings given for R.sup.8 in this
paragraph.
[0208] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20), wherein --Ar.sup.2--(R.sup.10).sub.r
is selected from the formulae
##STR00005##
wherein R.sup.10, R.sup.23 and R.sup.24 are as defined above and
below.
[0209] Another especially preferred embodiment of the instant
invention relates to compounds of formula II and preferably one or
more of sub formulae II.1) to II.20), wherein one or more features
of the above and below mentioned embodiments are combined in one
compound.
[0210] Subject of the present invention are therefore especially
preferred compounds of formula II according to one or more of the
formulae IIa, IIb, IIc, IId, IIe IIf, IIg and IIh,
##STR00006## ##STR00007##
Wherein R.sup.8, p, Y, R.sup.9 and q are as defined above and
below, R.sup.10 is H or as defined above/below, and preferably as
defined in sub formulae II.1) to II.20) and/or the embodiments
related thereto.
[0211] Another preferred embodiment of the instant invention
relates to compounds of formula II and preferably one or more of
sub formulae II.1) to II.20) and IIa to IIh, wherein R.sup.10 is H
or a substituted carbamoyl moiety CONHR.sup.23 or
CONR.sup.23R.sup.24, preferably CONHR.sup.23, wherein R.sup.23 and
R.sup.24 are independently selected from the definitions given for
R.sup.8, more preferably selected from
(CH.sub.2).sub.nNR.sup.11R.sup.12 and (CH.sub.2).sub.nOR.sup.12,
wherein R.sup.11, R.sup.12 and n are as defined above. In this
embodiment, n is preferably not 0 and more preferred 1 to 3 and
especially 1 or 2. Preferred examples for R.sup.23 are selected
from the group consisting of CH.sub.2CH.sub.2NH.sub.2,
CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2, CH.sub.2CH.sub.2OH,
CH.sub.2CH.sub.2OCH.sub.3 and
CH.sub.2CH.sub.2OCH.sub.2CH.sub.3.
[0212] It is understood that when a residue, for example R.sup.8,
R.sup.9, R.sup.10 or R.sup.14 or R.sup.23, is comprised twice or
more times in one or more of the formulae I, II and the sub
formulae corresponding thereto, it is in each case independently
from one another selected from the meanings given for the
respective residue. For example, R.sup.11 and R.sup.12 are defined
to be independently selected from a group consisting of H, A,
(CH.sub.2).sub.mAr.sup.3 and (CH.sub.2).sub.mHet. Then
(CH.sub.29.sub.nNR.sup.11(CH.sub.2).sub.mNR.sup.12R.sup.12 can be
(CH.sub.2).sub.nNA(CH.sub.2).sub.mNA.sub.2 (if R.sup.11=A,
R.sup.12=A and R.sup.12=H) as well as
(CH.sub.2).sub.nNA(CH.sub.2).sub.mNHA (if R.sup.11=A, R.sup.12=H
and R.sup.12=A or (CH.sub.2).sub.nNA(CH.sub.2).sub.mNH(CH.sub.2mHet
(if R.sup.11=A, R.sup.12=H and R.sup.12=(CH.sub.2).sub.mHet).
Accordingly, if a compound of formula II comprises one residue R8H,
R9H and R.sup.10, then for example R.sup.8, R.sup.9 and R.sup.10
can all be (CH.sub.2).sub.nCOOR.sup.13.sup.4, wherein all residues
R.sup.13 are the same (for example CH.sub.2Hal, wherein Hal is Cl;
then all residues R.sup.8, R.sup.9 and R.sup.10 are the same) or
different (for example CH.sub.2Hal, wherein in R.sup.8 Hal is cl;
in R.sup.9 Hal is F; and in R.sup.10 Hal is Br; then all residues
R.sup.8, R.sup.9 and R.sup.10 are different); or for example
R.sup.8 is (CH.sub.2).sub.nCOOR.sup.13, R.sup.9 is NO.sub.2 and
R.sup.10 is (CH.sub.2).sub.nSR.sup.11, wherein R.sup.11 and
R.sup.13 can be the same (for example both can be H or both can be
A which is methyl) of different (for example R.sup.11 can be H and
R.sup.13 can be A which is methyl).
[0213] If not stated otherwise, reference to compounds of formula I
and formula II also includes the sub formulae related thereto,
especially sub formulae II.1) to II.20) and IIa to IIh.
[0214] Subject of the instant invention are especially those
compounds of formula I and/or formula II, in which at least one of
the residues mentioned in said formulae has one of the preferred or
especially preferred meanings given above and below.
[0215] The present invention further relates to compounds (1) to
(8) as given below:
##STR00008##
(1):
N-(4-Chloro-3-trifluoromethyl-phenyl)-2-[4-(pyridin-4-yloxy)-phenyla-
mino]-acetamide
##STR00009##
[0216] (2):
N-(4-Chloro-5-trifluoromethyl-phenyl)-2-[3-(pyridin-4-yloxy)-phenylamino]-
-acetamide
##STR00010##
[0217] (3):
N-(4-Chloro-3-trifluoromethyl-phenyl)-2-[4-(pyridin-3-yloxy)-phenylamino]-
-acetamide
##STR00011##
[0218] (4):
N-(4-Chloro-3-trifluoromethyl-phenyl)-2-[3-(pyridin-3-yloxy)-phenylamino]-
-acetamide
##STR00012##
[0219] (5):
N-(3-tert.-Butyl-isoxazol-5-yl)-2-[3-(pyridin-4-yloxy)-phenylamino]-aceta-
mide
##STR00013##
[0220] (6):
N-(3-tert.-Butyl-isoxazol-5-yl)-2-[4-(pyridin-4-yloxy)-phenylamino]-aceta-
mide
##STR00014##
[0221] (7):
N-(5-tert.Butyl-isoxazol-3-yl)-2-[3-(pyridin-4-yloxy)-phenylamino]-acetam-
ide
##STR00015##
[0222] (8):
N-(5-tert.-Butyl-isoxazol-3-yl)-2-[4-(pyridin-4-yloxy)-phenylamino]-aceta-
mide
[0223] The present invention also relates to compounds (9) to (235)
of formula A-NH--CO--CH.sub.2--NH--B, wherein A and B are as given
in the table below:
TABLE-US-00001 [0223] A B (9) ##STR00016## ##STR00017## (10)
##STR00018## ##STR00019## (11) ##STR00020## ##STR00021## (12)
##STR00022## ##STR00023## (13) ##STR00024## ##STR00025## (14)
##STR00026## ##STR00027## (15) ##STR00028## ##STR00029## (16)
##STR00030## ##STR00031## (17) ##STR00032## ##STR00033## (18)
##STR00034## ##STR00035## (19) ##STR00036## ##STR00037## (20)
##STR00038## ##STR00039## (21) ##STR00040## ##STR00041## (22)
##STR00042## ##STR00043## (23) ##STR00044## ##STR00045## (24)
##STR00046## ##STR00047## (25) ##STR00048## ##STR00049## (26)
##STR00050## ##STR00051## (27) ##STR00052## ##STR00053## (28)
##STR00054## ##STR00055## (29) ##STR00056## ##STR00057## (30)
##STR00058## ##STR00059## (31) ##STR00060## ##STR00061## (32)
##STR00062## ##STR00063## (33) ##STR00064## ##STR00065## (34)
##STR00066## ##STR00067## (35) ##STR00068## ##STR00069## (36)
##STR00070## ##STR00071## (37) ##STR00072## ##STR00073## (38)
##STR00074## ##STR00075## (39) ##STR00076## ##STR00077## (40)
##STR00078## ##STR00079## (41) ##STR00080## ##STR00081## (42)
##STR00082## ##STR00083## (43) ##STR00084## ##STR00085## (44)
##STR00086## ##STR00087## (45) ##STR00088## ##STR00089## (46)
##STR00090## ##STR00091## (47) ##STR00092## ##STR00093## (48)
##STR00094## ##STR00095## (49) ##STR00096## ##STR00097## (50)
##STR00098## ##STR00099## (51) ##STR00100## ##STR00101## (52)
##STR00102## ##STR00103## (53) ##STR00104## ##STR00105## (54)
##STR00106## ##STR00107## (55) ##STR00108## ##STR00109## (56)
##STR00110## ##STR00111## (57) ##STR00112## ##STR00113## (58)
##STR00114## ##STR00115## (59) ##STR00116## ##STR00117## (60)
##STR00118## ##STR00119## (61) ##STR00120## ##STR00121## (62)
##STR00122## ##STR00123## (63) ##STR00124## ##STR00125## (64)
##STR00126## ##STR00127## (65) ##STR00128## ##STR00129## (66)
##STR00130## ##STR00131## (67) ##STR00132## ##STR00133## (68)
##STR00134## ##STR00135## (69) ##STR00136## ##STR00137## (70)
##STR00138## ##STR00139## (71) ##STR00140## ##STR00141## (72)
##STR00142## ##STR00143## (73) ##STR00144## ##STR00145## (74)
##STR00146## ##STR00147## (75) ##STR00148## ##STR00149## (76)
##STR00150## ##STR00151## (77) ##STR00152## ##STR00153## (78)
##STR00154## ##STR00155## (79) ##STR00156## ##STR00157## (80)
##STR00158## ##STR00159## (81) ##STR00160## ##STR00161## (82)
##STR00162## ##STR00163## (83) ##STR00164## ##STR00165## (84)
##STR00166## ##STR00167## (85) ##STR00168## ##STR00169## (86)
##STR00170## ##STR00171## (87) ##STR00172## ##STR00173## (88)
##STR00174## ##STR00175## (89) ##STR00176## ##STR00177## (90)
##STR00178## ##STR00179## (91) ##STR00180## ##STR00181## (92)
##STR00182## ##STR00183## (93) ##STR00184## ##STR00185## (94)
##STR00186## ##STR00187## (95) ##STR00188## ##STR00189## (96)
##STR00190## ##STR00191## (97) ##STR00192## ##STR00193## (98)
##STR00194## ##STR00195## (99) ##STR00196## ##STR00197## (100)
##STR00198## ##STR00199## (101) ##STR00200## ##STR00201## (102)
##STR00202## ##STR00203## (103) ##STR00204## ##STR00205## (104)
##STR00206## ##STR00207## (105) ##STR00208## ##STR00209## (106)
##STR00210## ##STR00211## (107) ##STR00212## ##STR00213## (108)
##STR00214## ##STR00215## (109) ##STR00216## ##STR00217## (110)
##STR00218## ##STR00219## (111) ##STR00220## ##STR00221## (112)
##STR00222## ##STR00223## (113) ##STR00224## ##STR00225## (114)
##STR00226## ##STR00227## (115) ##STR00228## ##STR00229## (116)
##STR00230## ##STR00231## (117) ##STR00232## ##STR00233## (118)
##STR00234## ##STR00235## (119) ##STR00236## ##STR00237## (120)
##STR00238## ##STR00239## (121) ##STR00240## ##STR00241## (122)
##STR00242## ##STR00243## (123) ##STR00244## ##STR00245## (124)
##STR00246## ##STR00247## (125) ##STR00248## ##STR00249## (126)
##STR00250## ##STR00251## (127) ##STR00252## ##STR00253## (128)
##STR00254## ##STR00255## (129) ##STR00256## ##STR00257## (130)
##STR00258## ##STR00259## (131) ##STR00260## ##STR00261##
(132) ##STR00262## ##STR00263## (133) ##STR00264## ##STR00265##
(134) ##STR00266## ##STR00267## (135) ##STR00268## ##STR00269##
(136) ##STR00270## ##STR00271## (137) ##STR00272## ##STR00273##
(138) ##STR00274## ##STR00275## (139) ##STR00276## ##STR00277##
(140) ##STR00278## ##STR00279## (141) ##STR00280## ##STR00281##
(142) ##STR00282## ##STR00283## (143) ##STR00284## ##STR00285##
(144) ##STR00286## ##STR00287## (145) ##STR00288## ##STR00289##
(146) ##STR00290## ##STR00291## (147) ##STR00292## ##STR00293##
(148) ##STR00294## ##STR00295## (149) ##STR00296## ##STR00297##
(150) ##STR00298## ##STR00299## (151) ##STR00300## ##STR00301##
(152) ##STR00302## ##STR00303## (153) ##STR00304## ##STR00305##
(154) ##STR00306## ##STR00307## (155) ##STR00308## ##STR00309##
(156) ##STR00310## ##STR00311## (157) ##STR00312## ##STR00313##
(158) ##STR00314## ##STR00315## (159) ##STR00316## ##STR00317##
(160) ##STR00318## ##STR00319## (161) ##STR00320## ##STR00321##
(162) ##STR00322## ##STR00323## (163) ##STR00324## ##STR00325##
(164) ##STR00326## ##STR00327## (165) ##STR00328## ##STR00329##
(166) ##STR00330## ##STR00331## (167) ##STR00332## ##STR00333##
(168) ##STR00334## ##STR00335## (169) ##STR00336## ##STR00337##
(170) ##STR00338## ##STR00339## (171) ##STR00340## ##STR00341##
(172) ##STR00342## ##STR00343## (173) ##STR00344## ##STR00345##
(174) ##STR00346## ##STR00347## (175) ##STR00348## ##STR00349##
(176) ##STR00350## ##STR00351## (177) ##STR00352## ##STR00353##
(178) ##STR00354## ##STR00355## (179) ##STR00356## ##STR00357##
(180) ##STR00358## ##STR00359## (181) ##STR00360## ##STR00361##
(182) ##STR00362## ##STR00363## (183) ##STR00364## ##STR00365##
(184) ##STR00366## ##STR00367## (185) ##STR00368## ##STR00369##
(186) ##STR00370## ##STR00371## (187) ##STR00372## ##STR00373##
(188) ##STR00374## ##STR00375## (189) ##STR00376## ##STR00377##
(190) ##STR00378## ##STR00379## (191) ##STR00380## ##STR00381##
(192) ##STR00382## ##STR00383## (193) ##STR00384## ##STR00385##
(194) ##STR00386## ##STR00387## (195) ##STR00388## ##STR00389##
(196) ##STR00390## ##STR00391## (197) ##STR00392## ##STR00393##
(198) ##STR00394## ##STR00395## (199) ##STR00396## ##STR00397##
(200) ##STR00398## ##STR00399## (201) ##STR00400## ##STR00401##
(202) ##STR00402## ##STR00403## (203) ##STR00404## ##STR00405##
(204) ##STR00406## ##STR00407## (205) ##STR00408## ##STR00409##
(206) ##STR00410## ##STR00411## (207) ##STR00412## ##STR00413##
(208) ##STR00414## ##STR00415## (209) ##STR00416## ##STR00417##
(210) ##STR00418## ##STR00419## (211) ##STR00420## ##STR00421##
(212) ##STR00422## ##STR00423## (213) ##STR00424## ##STR00425##
(214) ##STR00426## ##STR00427## (215) ##STR00428## ##STR00429##
(216) ##STR00430## ##STR00431## (217) ##STR00432## ##STR00433##
(218) ##STR00434## ##STR00435## (219) ##STR00436## ##STR00437##
(220) ##STR00438## ##STR00439## (221) ##STR00440## ##STR00441##
(222) ##STR00442## ##STR00443## (223) ##STR00444## ##STR00445##
(224) ##STR00446## ##STR00447## (225) ##STR00448## ##STR00449##
(226) ##STR00450## ##STR00451## (227) ##STR00452## ##STR00453##
(228) ##STR00454## ##STR00455## (229) ##STR00456## ##STR00457##
(230) ##STR00458## ##STR00459## (231) ##STR00460## ##STR00461##
(232) ##STR00462## ##STR00463## (233) ##STR00464## ##STR00465##
(234) ##STR00466## ##STR00467## (235) ##STR00468## ##STR00469##
[0224] In a special embodiment, the glycinamide derivatives
according to sub formulae IIa, IIb, IIc, IId, IIe, IIg, IIh and/or
compounds (1) to (235) additionally comprise one or two
substituents selected from the group consisting of
O(CH.sub.2).sub.nNR.sup.11R.sup.12,
NR.sup.11(CH.sub.2).sub.nNR.sup.11R.sup.12,
O(CH.sub.2).sub.nOR.sup.12 and
NR.sup.11(CH.sub.2).sub.nOR.sup.12,
wherein [0225] R.sup.11, R.sup.12 are independently selected from a
group consisting of H, A, (CH.sub.2).sub.mAr.sup.3 and
(CH.sub.2).sub.mHet, or in NR.sup.11R.sup.12, [0226] R.sup.11 and
R.sup.12 form, together with the N-Atom they are bound to, a 5-, 6-
or 7-membered heterocyclus which optionally contains 1 or 2
additional hetero atoms, selected from N, O an S, and [0227] n is
1, 2, 3, 4, 5 or 6, preferably 2, 3 or 4.
[0228] In this embodiment, the substituents are preferably selected
from the group consisting of HNCH.sub.2CH.sub.2NH.sub.2,
OCH.sub.2CH.sub.2NH.sub.2, NHCH.sub.2CH.sub.2OH,
OCH.sub.2CH.sub.2NHCH.sub.3, N(CH.sub.3)CH.sub.2CH.sub.2NH.sub.2,
HN(CH.sub.3)CH.sub.2CH.sub.2NH,
N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
N(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
OCH.sub.2CH.sub.2N(CH.sub.3).sub.2,
OCH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2 and compounds of the
formulae
##STR00470##
[0229] In this embodiment, the additional substituents are
preferably bound to one of the aromatic residues directly bound to
the glycinamide moiety and/or the pyridinyl residue. Preferably,
one additional substituent is bound to the aromatic residue
directly bound to the amide-nitrogen atom of the glycinamide moiety
and/or one additional substituent is bound to the pyridinyl
residue.
[0230] The nomenclature as used herein for defining compounds,
especially the compounds according to the invention, is in general
based on the rules of the IUPAC-organisation for chemical compounds
and especially organic compounds.
[0231] Another aspect of the invention relates to a method for
producing compounds of formula II, characterised in that [0232] a)
A compound of formula III
[0232] ##STR00471## wherein [0233] L.sup.1 is Cl, Br, I, OH, a
reactive esterified OH-group or a diazonium moiety, and R.sup.8, p,
Ar.sup.1, Y are as defined above and below, is reacted [0234] b)
with a compound of formula IV,
[0234] ##STR00472## wherein [0235] L.sup.2, L.sup.3 are
independently from one another H or a metal ion, and R.sup.9, q, X,
Ar.sup.2, R.sup.10 and r are as defined above and below, and
optionally [0236] c) isolating and/or treating the compound of
formula II obtained by said reaction with an acid, to obtain the
salt thereof.
[0237] The compounds of the formula I and preferably the compounds
of the formula II and also the starting materials for their
preparation are, in addition, prepared by methods known per se, as
described in the literature (for example in the standard works,
such as Houben-Weyl, Methoden der organischen Chemie [Methods of
Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise
under reaction conditions which are known and suitable for the said
reactions. Use can also be made here of variants which are known
per se, but are not mentioned here in greater detail.
[0238] If desired, the starting materials can also be formed in
situ by not isolating them from the reaction mixture, but instead
immediately converting them further into the compounds of the
formula I or II, respectively. On the other hand, it is possible to
carry out the reaction stepwise.
[0239] The compounds of the formula I and especially the compounds
of formula II can preferably be obtained by reacting compounds of
the formula III with compounds of the formula IV.
[0240] In detail, the reaction of the compounds of the formula III
with the compounds of the formula IV is carried out in the presence
or absence of a preferably inert solvent at temperatures between
about -20.degree. and about 200.degree., preferably between
0.degree. and 150.degree. and especially between room temperature
(25.degree.) and 120.degree.. In many cases, it is advantageous to
combine one compound of formula III with one compound of formula IV
at the lower end of the given temperature range, preferably between
-20.degree. and 75.degree., more preferred between 0.degree. and
60.degree. and especially between 10.degree. and 40.degree., for
example at about room temperature, and heat the mixture up to a
temperature at the upper end of the given temperature range,
preferably between 80.degree. and 180.degree., more preferred
between 90.degree. and 150.degree. and especially between
95.degree. and 120.degree., for example at about 100.degree. or at
about 110.degree..
[0241] In general, the compounds of formula III and/or formula IV
are new. In any case, they can be prepared according to methods
known in the art or analogous to those procedures.
[0242] In the compounds of formula III, L.sup.1 is preferably Cl,
Br, I, OH, a reactive derivatized OH-moiety, especially a reactive
esterified OH-moiety, for example an alkylsulfonyloxy-moiety
comprising 1 to 6 carbon atoms (preferably methylsulfonyloxy) or
and arylsulfonyloxy-moiety comprising 6 to 10 carbon atoms
(preferably phenyl- or p-tolylsulfonyloxy), or diazonium moiety,
more preferred Cl, Br or I and even more preferred Cl.
[0243] In the compounds of formula IV, L.sup.2 and/or L.sup.3 is
preferably H or a moiety which activates the amino group it is
bonded to, for example a metal ion. Suitable metal ions are
preferably selected from the group consisting of alkaline metal
ions, alkaline-earth metal ions and aluminium ions. Especially
preferred metal ions are alkaline metal ions, of which Li, Na and K
are especially preferred. In case of multi-valent metal ions, the
metal ions and the compounds of formula IV form a complex
containing one or more compounds of formula IV and one or more
metal ions wherein the ratio between compounds of formula IV and
metal ions is depending on the valency of the metal ion(s)
according to the rules of stoichiometry and/or
electroneutrality.
[0244] The reaction between the compounds of formula III and
compounds of formula IV is preferably carried out in the presence
of an acid binding means, for example one or more bases. Suitable
acid binding means are known in the art. Preferred as acid binding
means are inorganic bases and especially organic bases. Examples
for inorganic bases are alkaline or alkaline-earth hydroxides,
alkaline or alkaline-earth carbonates and alkaline or
alkaline-earth bicarbonates or other salts of a weak acid and
alkaline or alkaline-earth metals, preferably of potassium, sodium,
calcium or cesium. Examples for organic bases are triethyl amine,
diisopropyl ethyl amine (DIPEA), dimethyl aniline, pyridine or
chinoline. If an organic base is used, it is advantageous in
general to use a base with a boiling point that is higher than the
highest reaction temperature employed during the reaction.
Especially preferred as organic base is diisopropyl ethyl amine.
Reaction times are generally in the range between some minutes and
several days, depending on the reactivity of the respective
compounds and the respective reaction conditions. Suitable reaction
times are readily determinable by methods known in the art, for
example reaction monitoring. Based on the reaction temperatures
given above, suitable reaction times generally lie in the range 10
min and 24 hrs, preferably 30 min and 12 hrs and especially between
45 min and 8 hrs, for example about 1 h, about 2 hrs, about 4 hrs
or about 6 hrs.
[0245] Preferably, the reaction of the compounds of the formula III
with the compounds of the formula IV is carried out in the presence
of a suitable solvent, that is preferably inert under the
respective reaction conditions. Examples of suitable solvents are
hydrocarbons, such as hexane, petroleum ether, benzene, toluene or
xylene; chlorinated hydrocarbons, such as trichlorethylene,
1,2-dichloroethane, tetrachloromethane, chloroform or
dichloromethane; alcohols, such as methanol, ethanol, isopropanol,
n-propanol, n-butanol or tert-butanol; ethers, such as diethyl
ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol
ethers, such as ethylene glycol monomethyl or monoethyl ether or
ethylene glycol dimethyl ether (diglyme); ketones, such as acetone
or butanone; amides, such as acetamide, dimethylacetamide or
dimethylformamide (DMF); nitriles, such as acetonitrile;
sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds,
such as nitromethane or nitrobenzene; esters, such as ethyl
acetate, or mixtures of the said solvents. Polar solvents are in
general preferred. Examples for suitable polar solvents are
chlorinated hydrocarbons, alcohols, glycol ethers, nitrites, amides
and sulfoxides or mixtures thereof. More preferred are amides,
especially dimethylformamide (DMF).
[0246] The compounds of formula III can be obtained according to
methods known in the art. In an advantageous manner, they can be
readily obtained by reacting a compound of formula V
##STR00473##
wherein R.sup.8, p, and Ar.sup.1 are as defined above/below and
L.sup.4 and L.sup.5 are selected independently from each other from
the meanings given for L.sup.2 and L.sup.3 and more preferred are
hydrogen, with a compound of formula VI
##STR00474##
wherein Y is as defined above/below and L.sup.6 and L.sup.7 are
selected independently from each other from the meanings given for
L.sup.1. Preferably, L.sup.6 and/or L.sup.7 are halogen. More
preferred, both L.sup.6 and L.sup.7 are independently selected from
the group consisting of Cl, Br and I. Especially preferred, both
L.sup.6 and L.sup.7 are Cl.
[0247] Some of the starting materials of the formula V and/or the
formula VI are known and preferably commercially available. If they
are not known, they can be prepared by methods known per se.
[0248] Suitable reaction conditions for carrying out reaction of
compounds of formula V with compounds of formula VI are known in
the art. In detail, the reaction of the compounds of the formula V
with the compounds of the formula VI is carried out in the presence
or absence of a preferably inert solvent at temperatures between
about -40.degree. and about 180.degree., preferably between
-20.degree. C. and 100.degree. and especially between -10.degree.
and 50.degree., for example at about 0.degree. and/or about room
temperature (25.degree.). In many cases, it is advantageous to
combine one compound of formula V with one compound of formula VI
at the lower end of the given temperature range, preferably between
-20.degree. and 40.degree., more preferred between -10.degree. and
20.degree. and especially between -5.degree. and 10.degree., for
example at about 0.degree., and heat the mixture up to a
temperature at the upper end of the given temperature range,
preferably between 20.degree. and 150.degree., more preferred
between 20.degree. and 100.degree. and especially between
20.degree. and 50.degree., for example at about room
temperature.
[0249] The reaction between compounds of formula V and compounds of
formula VI is preferably carried out in the presence of an acid
binding means, for example one or more bases. Suitable acid binding
means are known in the art. Preferred as acid binding means are
inorganic bases and especially organic bases. Examples for
inorganic bases are alkaline or alkaline-earth hydroxides, alkaline
or alkaline-earth carbonates and alkaline or alkaline-earth
bicarbonates or other salts of a weak acid and alkaline or
alkaline-earth metals, preferably of potassium, sodium, calcium or
cesium. Examples for organic bases are triethyl amine, diisopropyl
ethyl amine (DIPEA), dimethyl aniline, pyridine or chinoline. If an
organic base is used, it is advantageous in general to use a base
with a boiling point that is higher than the highest reaction
temperature employed during the reaction. Especially preferred as
organic base is pyridine.
[0250] The reaction between compounds of formula V and compounds of
formula VI can be carried out in the presence of a suitable
solvent, that is preferably inert at the chosen reaction
conditions. Suitable solvents are known in the art. Examples of
suitable solvents include hydrocarbons, such as hexane, petroleum
ether, benzene, toluene or xylene; chlorinated hydrocarbons, such
as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,
chloroform or dichloromethane; ethers, such as diethyl ether,
diisopropyl ether, tetrahydrofuran (THF) or dioxane; nitriles, such
as acetonitrile; esters, such as ethyl acetate, or mixtures of the
aid solvents. Non-protic solvents are in general preferred.
[0251] If the reaction between a compound of formula V and a
compound of formula VI is carried out in presence of an organic
base that is liquid at the chosen reaction conditions, preferably
no additional solvent is used.
[0252] The compounds of formula IV can be obtained according to
methods known in the art.
[0253] If the compound of formula IV is a compound according to
formula IVa,
##STR00475##
it can be readily obtained in an advantageous manner by reacting a
compound of formula VIIa,
##STR00476##
wherein R.sup.9 and q are as defined above/below, with a compound
of formula VIII,
L.sup.8-X-Ar.sup.2(R.sup.10).sub.r VIII
wherein L.sup.8 is H or a metal ion, preferably a metal ion
selected from the group consisting of alkaline metal ions,
alkaline-earth metal ions and aluminum ions, especially preferred
alkaline metal ions, of which Li, Na and K are especially
preferred, and even more preferred is H; and Ar.sup.2, R.sup.10, r
and X are as defined above/below, and especially wherein X is
(CHR.sup.11).sub.h-Q-(CHR.sup.12).sub.i, wherein R.sup.11, h and
R.sup.12 are defined above/below, j is 0 and Q is selected from a
group consisting of O, S, N--R.sup.15, (CHR.sup.18--O).sub.j,
(CHR.sup.18CHR.sup.19--O).sub.j, CH.dbd.N--O, CH.dbd.N--NR.sup.15,
SO.sub.2NR.sup.15, wherein R.sup.15, R.sup.18 and R.sup.19 are as
defined above/below; optionally isolating the reaction product, and
transferring the obtained reaction product of formula IX
##STR00477##
into a compound of formula IVa, preferably by hydrogenating the
NO.sub.2-moiety of the compound of formula IX into a
NH.sub.2-moiety. Methods and reaction conditions for hydrogenating
said NO.sub.2-moiety into a NH.sub.2-moiety are known in the art.
In general, it is advantageous to carry out the hydrogenation
reaction in a hydrogen atmosphere in the presence of a suitable
catalyst, preferably a Palladium catalyst, for example Pd/C. In
general, such hydrogenation reactions are carried out in a suitable
solvent. Suitable solvents for hydrogenation reactions are known in
the art. Suitable solvents, for example, are alcohols, especially
methanol and ethanol and ethers, especially THF, and mixtures
thereof. In general, the hydrogenation reactions are carried out at
about normal pressure or slightly elevated pressure, for example
between normal pressure and 3 bar pressure (about 300 kPa). The
hydrogenation reaction is usually carried out in the temperature
range between -20.degree. and 150.degree., preferably 0.degree. and
50.degree..
[0254] Ar.sup.2 is preferably pyridinyl. Accordingly, the compound
of formula VIII is preferably selected from the group consisting of
formulae VIIIa and VIIIb,
##STR00478##
wherein L.sup.8, X, R.sup.10 and r are as defined above, and
especially preferred from the group consisting of formulae VIIIc
and VIIId,
##STR00479##
wherein R.sup.10 and r are as defined above, or the alkaline metal
salts and especially the sodium or potassium salts thereof.
[0255] Accordingly, in formulae IVa, VIIII, VIIIa, VIIIb and IX,
the bridging group X is preferably O, S, OCH.sub.2 and
OCH.sub.2CH.sub.2 and especially is O.
[0256] In the formulae VIII, VIIIa and VIIIb, L.sup.8 is preferably
H or selected from the group consisting of Na, K and Cs and
especially preferred is H.
[0257] In general, this reaction is advantageous to produce
compounds of formula IVaa,
##STR00480##
wherein R.sup.9, q, X, Ar.sup.2, R.sup.10 and r are as defined
above/below.
[0258] To obtain compounds of formula IVaa, it is reasonable to
employ a compound of formula VII that is selected from the
compounds of formula VIIa,
##STR00481##
and proceed the reaction as described above/below.
[0259] Accordingly, by starting from a compound of formula VIIIa
and a compound of formula VIIIa, the reaction preferably leads to
compounds of formula IVaaa,
##STR00482##
wherein R.sup.9, q, X, R.sup.10 and r are as defined
above/below.
[0260] Accordingly, by starting from a compound of formula VIIIa
and a compound of formula VIIIb, the reaction preferably leads to
compounds of formula IVaab,
##STR00483##
wherein R.sup.9, q, X, R.sup.10 and r are as defined
above/below.
[0261] Accordingly, by starting from a compound of formula VIIIa
and a compound of formula VIIIc, the reaction preferably leads to
compounds of formula IVaac,
##STR00484##
wherein R.sup.9, q, R.sup.10 and r are as defined above/below.
[0262] Accordingly, by starting from a compound of formula VIIa and
a compound of formula VIIId, the reaction preferably leads to
compounds of formula
##STR00485##
wherein R.sup.9, q, R.sup.10 and r are as defined above/below.
[0263] Some of the starting materials of the formula VIII and/or
the formula VIII are known and preferably commercially available.
If they are not known, they can be prepared by methods known per
se.
[0264] The reaction between the compound of formula VII and VIII is
preferably carried out in the temperature range between 0.degree.
and 250.degree., more preferred room temperature and 200.degree.,
for example at about 120.degree., at about 150.degree. or at about
180.degree.. Reaction times depend on the respective reactants and
the respective reaction temperature, but generally lie in the range
between 30 min and 36 hrs, preferably 3 hrs and 24 hrs, more
preferably 8 hrs and 20 hrs for example about 10 hrs, about 16 hrs
or about 18 hrs.
[0265] The reaction can be carried out in the absence of solvent or
preferably in the presence of an solvent, preferable a solvent that
is inert under the respective reaction conditions. Suitable inert
solvents for carrying out the reaction are known in the art.
Examples for suitable solvents are high boiling aliphatic
hydrocarbons, high boiling aromatic carbons, for example toluene,
xylenes, high boiling chlorinated hydrocarbons, such as
trichloroethylene, tetrachloroethanes, pentachlo roethanes and
hexachloroethanes; high boiling ethers, such as ethylene glycol and
propylene glycols; glycol ethers, such as ethylene glycol
monomethyl or monoethyl ether or ethylene glycol dimethyl ether
(diglyme); amides, such as acetamide, dimethylacetamide,
dimethylformamide (DMF) or N-methyl pyrrolidinone (NMP);
sulfoxides, such as dimethyl sulfoxide (DMSO); or mixtures of the
said solvents. Preferred are amides, especially dimethylformamide
(DMF).
[0266] Preferably, the reaction is carried out in the presence of a
base. Suitable bases are known in the art. Preferred bases are
organic bases and especially inorganic bases. Examples for
inorganic bases are alkaline or alkaline-earth hydroxides, alkaline
or alkaline-earth carbonates and alkaline or alkaline-earth
bicarbonates or other salts of a weak acid and alkaline or
alkaline-earth metals, preferably of potassium, sodium, calcium or
cesium. Preferred inorganic bases are K.sub.2CO.sub.3,
Na.sub.2CO.sub.3, MgCO.sub.3, CaCO.sub.3, NaOH and KOH, especially
preferred is K.sub.2CO.sub.3. Examples for organic bases are
triethyl amine, diisopropyl ethyl amine (DIPEA), dimethyl aniline,
pyridine or chinoline. If an organic base is used, it is
advantageous in general to use a base with a boiling point that is
higher than the highest reaction temperature employed during the
reaction.
[0267] Alternatively, if the compound of formula IV is a compound
according to formula IVb,
##STR00486##
it can be readily obtained in an advantageous manner by reacting a
compound of formula VIIIb,
##STR00487##
wherein R.sup.9 and q are as defined above/below and wherein
L.sup.9 is selected independently from the meanings given for
L.sup.1. Preferably, L.sup.9 is halogen. More preferred, L.sup.9 is
selected from the group consisting of Cl, Br and I. Especially
preferred, L.sup.9 is Cl. with a compound of formula VIIIb,
L.sup.10-X--Ar.sup.2(R.sup.10).sub.r VIIIb
wherein L.sup.10 is H or a metal ion, preferably a metal ion, more
preferred a metal ion selected from the group consisting of
alkaline metal ions, alkaline-earth metal ions and aluminium ions,
especially preferred alkaline metal ions, of which Li, Na and K are
especially preferred; and Ar.sup.2, R.sup.10, r and X are as
defined above/below, and especially wherein X is
(CHR.sup.11).sub.h-Q-(CHR.sup.12).sub.i, CH.dbd.N--O,
CH.dbd.N--NR.sup.15, SO.sub.2NR.sup.15, wherein R.sup.15, R.sup.18
and R.sup.19 are as defined above/below; optionally isolating the
reaction product, and transferring the obtained reaction product of
formula IXb
##STR00488##
into a compound of formula Iva, preferably by hydrogenating the
NO.sub.2'' -moiety of the compound of formula IX into a
NH.sub.2-moiety. Methods and reaction conditions for hydrogenating
said NO.sub.2-moiety into a NH.sub.2-moiety are known in the art.
In general, it is advantageous to carry out the hydrogenation
reaction in a hydrogen atmosphere in the presence of a suitable
catalyst, preferably a Palladium catalyst, for example Pd/C. in
general, such hydrogenation reactions are carried out in a suitable
solvent. Suitable solvents for hydrogenation reactions are carried
out in a suitable solvent. Suitable solvents for hydrogenation
reactions are known in the art. Suitable solvents, for example, are
alcohols, especially methanol and ethanol, ethers, especially THF,
and mixtures thereof. In general, the hydrogenation reactions are
carried out at about normal pressure or slightly elevated pressure,
for example between normal pressure or slightly elevated pressure,
for example between normal pressure and 3 bar pressure (about 300
kPa). The hydrogenation reaction is usually carried out in the
temperature range between -20.degree. and 150.degree., preferably
0.degree. and 50.degree..
[0268] Ar.sup.2 is preferably pyridinyl. Accordingly, the compound
of formula VIIIb is preferably selected from the group consisting
of formulae VIIIe and VIIIf,
##STR00489##
wherein L.sup.10, X, R.sup.10 and r are as defined above, and
especially preferred from the group consisting of formulae VIIIg
and VIIIh,
##STR00490##
wherein R.sup.10 and r are as defined above, and wherein M is an
alkaline metal ion and especially sodium or potassium, or the
corresponding alcohols thereof.
[0269] Accordingly, in formulae IVb, VIIIb, VIIIe, VIIIf and IXb,
the bridging group X is preferably O, S, OCH.sub.2 and
OCH.sub.2CH.sub.2 and especially is O.
[0270] In general, this alternative reaction is advantageous to
produce compounds of formula IVbb,
##STR00491##
wherein R.sup.9, q, X, Ar.sup.2, R.sup.10 and r are as defined
above/below.
[0271] To obtain compounds of formula IVbb, it is reasonable to
employ a compound of formula VIIb that is selected from the
compounds of formula VIIbb,
##STR00492##
wherein hal is as defined above/below and especially is Cl, and
proceed the alternative reaction as described above/below.
[0272] Accordingly, by starting from a compound a formula VIIbb and
a compound of formula VIIe, the reaction preferably leads to
compounds of formula IVbbe,
##STR00493##
wherein R.sup.9, q, X, R.sup.10 and r are as defined
above/below.
[0273] Accordingly, by starting from a compound of formula VIIbb
and a compound of formula VIIIf, the reaction preferably leads to
compounds of formula IVbbf,
##STR00494##
wherein R.sup.9, q, X, R.sup.10 and rare as defined
above/below.
[0274] Accordingly, by starting from a compound of formula VIIbb
and a compound of formula VIIIg, the reaction preferably leads to
compounds of formula IVbbg,
##STR00495##
wherein R.sup.9, q, R.sup.10 and r are as defined above/below.
[0275] Accordingly, by starting from a compound of formula VIIb and
a compound of formula VIIIh, the reaction preferably leads to
compounds of formula IVbbh,
##STR00496##
wherein R.sup.9, q, R.sup.10 and r are as defined above/below.
[0276] Some of the starting materials of the formula VIIIb and/or
the formula VIIIb are known and preferably commercially available.
If they are not known, they can be prepared by methods known per
se.
[0277] The reaction between the compound of formula VIIIb and VIIIb
is preferably carried out in the temperature range between
0.degree. and 25.degree., more preferred 50.degree. and
220.degree., for example at about 90.degree., at about 120.degree.,
at about 160.degree., at about 180.degree. or at about 200.degree..
Reaction times depend on the respective reactants and the
respective reaction temperature, but generally lie in the range
between 10 min and 24 hrs, preferably 30 min and 12 hrs, more
preferably 1 h and 6 hrs for example about 1.5 hrs, about 3 hrs,
about 4 hrs or about 5 hrs.
[0278] The reaction can be carried out in the absence or the
presence of a solvent, preferable a solvent that is inert under the
respective reaction conditions. Suitable inert solvents for
carrying out the reaction are known in the art. Examples for
suitable solvents are high aliphatic hydrocarbons, aromatic
carbons, for example toluene and xylenes, high boiling chlorinated
hydrocarbons, such as dichloromethane, trichloromethane
trichloroethylene, tetrachloroethanes, pentachloroethanes and
hexachloroethanes; ethers, such as diethylether, tert.-butyl methyl
ether, ethylene glycol and propylene glycols; glycol ethers, such
as ethylene glycol monomethyl or monoethyl ether or ethylene glycol
dimethyl, ether (diglyme); nitriles, such as acetonitrile, amides
such as acetamide, diemthyacetamide, dimethyltormamide (DMF) or
N-methylpyrrolidinone (NMP); sulfoxides, such as dimethyl sulfoxide
(DMSO); or mixtures of the said solvents.
[0279] Preferably, the reaction is carried out in the presence of a
catalyst. Suitable catalysts are known in the art. Preferred
catalytic active metals and especially copper.
[0280] Preferably, the reaction is carried out by heating up a
reaction mixture comprising one compound of formula VIIIb and one
compound of formula VIIIb to a suitable reaction temperature, which
preferably lies at the upper end of the given temperature ranges
and more preferred is in the range between 150.degree. and
200.degree., for example at about 180.degree., preferably in the
presence of the suitable catalyst and especially in the presence of
copper. Reaction times at this temperature are preferably as given
above and especially in the range between 1 h and 5 hrs, for
example about 3 hrs. Preferably, the reaction mixture is then
allowed to cool down to a temperature in the lower range of the
given temperature, more preferred to a temperature in the range
between 50.degree. and 150.degree., for example to about
90.degree.. Preferably, a suitable solvent, especially tert.-butyl
methyl ether, is then added and the reaction mixture is preferably
kept at about the same temperature for some more time, preferably
for 30 min to 2 hrs and more preferred for about one hour.
[0281] If the compound IV is a compound according to formula
IVc,
##STR00497##
it can be readily obtained in an advantageous manner by reacting a
compound of formula XI
##STR00498##
wherein L.sup.9 is H or a metal ion, preferably a metal ion
selected from the group consisting of alkaline metal ions,
alkaline-earth metal ions and aluminium ions, especially preferred
alkaline metal ions, of which Li, Na and K are especially
preferred, and even more preferred is H; and R.sup.9, q and X are
as defined above/below, and especially wherein X is
(CHR.sup.11).sub.h-Q-(CHR.sup.12).sub.l, wherein R.sup.11, h and
R.sup.12 are defined above/below, j is 0 and Q is selected from a
group consisting of O, S, N--R.sup.15, (CHR.sup.18--O).sub.j,
(CHR.sup.18CHR.sup.19--O).sub.j, CH.dbd.N--O, CH.dbd.N--NR.sup.15,
SO.sub.2NR.sup.15, wherein R.sup.15, R.sup.18 and R.sup.19 are as
defined above/below; with a compound of formula XII,
##STR00499##
wherein hal is independently select selected from the group
consisting of Cl, Br and I, the residue R.sup.10 are the same or
different and have the meanings given above/below and preferably
have both the same meaning, and the indices r are the same or
different and have the meanings given above/below and preferably
are the same, optionally isolating the reaction product, and
transferring the obtained reaction product of formula XIII
##STR00500##
into a compound of formula IVc, preferably by hydrogenating the
NO.sub.2-moiety of the compound of formula XIII into a
NH.sub.2-moiety, for example as described above for the compound of
formula IX.
[0282] In the compounds IVc, XII and XIII, r is preferably in each
case identical and even more preferred in each case 0.
[0283] In formulae IVc, XI and XIII, the bridging group X is
preferably O, S, OCH.sub.2 and OCH.sub.2CH.sub.2 and especially is
O.
[0284] In the formula XI, L.sup.9 is preferably H or selected from
the group consisting of Na and K and especially preferred is H.
[0285] The reaction between the compound of formula XI and XII is
preferably carried out in the temperature range between 0.degree.
and 250.degree., more preferred room temperature and 200.degree.,
for example at about 120.degree., at about 150.degree. or at about
180.degree.. Reaction times depend on the respective reactants and
the respective reaction temperature, but generally lie in the range
between 30 min and 24 hrs, preferably one hour and 12 hrs, for
example about 2 hrs, about 3 hrs or about 6 hrs. The reaction can
be carried out in the absence of solvent or in the presence of an
solvent, preferable a solvent that is inert under the respective
reaction conditions. Suitable inert solvents for carrying out the
reaction are known in the art.
[0286] Some of the starting materials of the formula XI and/or the
formula XII are known and preferably commercially available. If
they are not known, they can be prepared by methods known per
se.
[0287] Independently of the chosen reaction route, it is in many
cases possible or even feasible to introduce residues R.sup.8,
R.sup.9 and/or R.sup.10 into one or more of the compounds described
above, or, if the compound already comprises one or more residues
R.sup.8, R.sup.9 and/or R.sup.10, to introduce additional residues
R.sup.8, R.sup.9 and/or R.sup.10 into said compound. The
introduction of additional residues can be readily performed by
methods known in the art and especially by aromatic substitution,
for example nucleophilic aromatic substitution or electrophilic
aromatic substitution. For example, in compounds comprising
Ar.sup.1, wherein Ar.sup.1 comprises one or more halogen and
preferably fluorine substituents, one or more of the
halogen/fluorine substituents can be easily substituted by hydroxy,
thio and/or amino substituted hydrocarbons, preferably selected
from the group consisting of HO(CH.sub.2).sub.nNRR.sup.11R.sup.12,
HO(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
HO(CH.sub.2).sub.nNR.sup.11(CH.sub.2).sub.kOR.sup.12,
HO(CH.sub.2).sub.nNR.sup.11(CH.sub.2).sub.kNR.sup.11R.sup.12,
HO(CG.sub.2).sub.nCOOR.sup.13,
HO(CH.sub.2).sub.nS(O).sub.uR.sup.13HNR.sup.11(CH.sub.2).sub.nNR.sup.11R.-
sup.12,
HNR.sup.11(CH.sub.2).sub.nO(CH.sub.2).sub.kNR.sup.11R.sup.12,
HNR.sup.11(CH.sub.2).sub.nNR.sup.11(CH.sub.2).sub.kOR.sup.12,
HNR.sup.11(CH.sub.2).sub.nNR.sup.11(CH.sub.2).sub.kNR.sup.11R.sup.12,
HNR.sup.11(CH.sub.2).sub.nCOOR.sup.12 and
HNR.sup.11(CH.sub.2).sub.nS(O).sub.uR.sup.13 wherein R.sup.11,
R.sup.12 and R.sup.13 are defined as above and n is as defined
above, preferably n is 0, 1 or 2 and especially is 0, k is 1 to 4
and preferably 1 or 2, and u is preferably 2. In this embodiment
R.sup.11, R.sup.12 and R.sup.13 are more preferably selected
independently from each other from the group consisting of H,
methyl and ethyl. Even more preferred, the hydroxy, thio and/or
amino substituted hydrocarbons are selected from the group
consisting of NH.sub.3, HN(CH.sub.3).sub.2, NH.sub.2CH.sub.3,
HN(C.sub.2H.sub.5).sub.2, H.sub.2NCH.sub.2CH.sub.2NH.sub.2,
HOCH.sub.2CH.sub.2NH.sub.2, HOCH.sub.2CH.sub.2NHCH.sub.3,
HN(CH.sub.3)CH.sub.2CH.sub.2NH.sub.2,
HN(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
HN(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
HN(CH.sub.3)CH.sub.2CH.sub.2OCH.sub.3,
HOCH.sub.2CH.sub.2N(CH.sub.3).sub.2,
HOCH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2, HSCH.sub.3,
HSC.sub.2H.sub.5, and compounds of the formulae
##STR00501##
or salts and especially metal salts thereof.
[0288] On the other hand, it is in many cases possible or even
feasible to modify or derivatize one or more of the residue is
R.sup.8, R.sup.9 and R.sup.10 into residues R.sup.8, R.sup.9 and/or
R.sup.10 other than the ones originally present. For example,
CH.sub.3-- groups can be oxidized into aldehyde groups or carbonic
acid groups, thio atom containing groups, for example S-alkyl or
S-aryl groups, can be oxidized into SO.sub.2-alkyl or
SO.sub.2-aryl-groups, respectively, carboxylic acid groups can be
derivatized to carboxylic acid ester groups or carboxylic acid
amide groups and carboxylic acid ester groups or carboxylic acid
amide groups can be hydrolysed into the corresponding carboxylic
acid groups. Methods for performing such modifications or
derivatizations are known in the art, for example from Houben-Weyl,
Methods of Organic Chemistry.
[0289] Every reaction step described herein can optionally be
followed by one or more working up procedures and/or isolating
procedures. Suitable such procedures are known in the art, for
example from standard works, such as Houben-Weyl, Methoden der
organischen Chemie [Methods of Organic Chemistry],
Georg-Thieme-Verlag, Stuttgart) Examples for such procedures
include, but are not limited to evaporating a solvent, distilling,
crystallization, fractionised crystallization, extraction
procedures, washing procedures, digesting, filtration procedures
chromatography and chromatography by HPLC.
[0290] A base of the formula I or the formula II can be converted
into the associated acid-addition salt using an acid, for example
by reaction of equivalent amounts of the base and the acid in a
preferably inert solvent, such as ethanol, followed by evaporation.
Suitable acids for this reaction are, in particular, those which
give physiologically acceptable salts. Thus, it is possible to use
inorganic acids, for example sulfuric acid, sulfurous acid,
dithionic acid, nitric acid, hydrohalic acids, such as hydrochloric
acid or hydrobromic acid, phosphoric acids, such as, for example,
orthophosphoric acid, sulfamic acid, furthermore organic acids, in
particular aliphatic, alicyclic, araliphatic, aromatic or
heterocyclic monobasic or polybasic carboxylic, sulfonic or
sulfuric acids, for example formic acid, acetic acid, propionic
acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic
acid, octadecanoic acid, pivalic acid, diethylacetic acid, malonic
acid, succinic acid, pimelic acid, fumaric acid, maleic acid,
lactic acid, tartaric acid, malic acid, citric acid, gluconic acid,
ascorbic acid, nicotinic acid, isonicotinic acid, methane- or
ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic
acid, benzenesulfonic acid, trimethoxybenzoic acid,
adamantanecarboxylic acid, p-toluene-sulfonic acid, glycolic acid,
embonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic
acid, proline, glyoxylic acid, palmitic acid,
parachlorophenoxyisobutyric acid, cyclohexanecarboxylic acid,
glucose 1-phosphate, naphthalenemono- and -disulfonic acids or
laurylsulfuric acid. Salts with physiologically unacceptable acids,
for example picrates, can be used to isolate and/or purify the
compounds of the formula I. On the other hand, compounds of the
formula I can be converted into the corresponding metal salts, in
particular alkali metal salts or alkaline earth metal salts, or
into the corresponding ammonium salts, using bases (for example
sodium hydroxide, potassium hydroxide, sodium carbonate or
potassium carbonate). Suitable salts are furthermore substituted
ammonium salts, for example the dimethyl-, diethyl- and
diisopropyl-ammonium salts, monoethanol-, diethanol- and
diisopropanolammonium salts, cyclohexyl- and dicyclohexylammonium
salts, dibenzylethylenediammonium salts, furthermore, for example,
salts with arginine or lysine.
[0291] On the other hand, if desired, the free bases of the formula
I or the formula II can be liberated from their salts using bases
(for example sodium hydroxide, potassium hydroxide, sodium
carbonate or potassium carbonate).
[0292] The invention relates to compounds of the formula I and of
the formula II and physiologically acceptable salts and solvates
thereof as medicaments.
[0293] The invention also relates to the compounds for the formula
I and of the formula II and physiologically acceptable salts and
solvates thereof as kinase inhibitors.
[0294] The invention furthermore relates to the use of the
compounds of the formula I and/or physiologically acceptable salts
and/or solvates thereof for the preparation of pharmaceutical
compositions and/or pharmaceutical preparations, in particular by
non-chemical methods. The invention furthermore relates to the use
of the compounds of the formula II and/or physiologically
acceptable salts and/or solvates thereof for the preparation of
pharmaceutical compositions and/or pharmaceutical preparations, in
particular by non-chemical methods. In this cases, one or more
compounds according to the invention can be converted into a
suitable dosage form together with at least one solid, liquid
and/or semi-liquid excipient or adjuvant and, if desired, in
combination with one or more further active ingredients.
[0295] The invention further relates to the use of one or more of
the compounds according to the invention, selected from the group
consisting of compounds of the formula I as free bases, solvates of
compounds of the formula I, salts of compounds of formula I, of
compounds of the formula II as free bases, solvates of compounds of
the formula II and salts of compounds of formula II, for the
production of pharmaceutical compositions and/or pharmaceutical
preparations, in particular by a non-chemical route. In general,
non-chemical routes for the production of pharmaceutical
compositions and/or pharmaceutical preparations comprise processing
steps on suitable mechanical means known in the art that transfer
one or more compounds according to the invention into a dosage form
suitable for administration to a patient in need of such a
treatment. Usually, the transfer of one or more compounds according
to the invention into such a dosage form comprises the addition of
one or more compounds, selected from the group consisting of
carriers, excipients, auxiliaries and pharmaceutical active
ingredients other than the compounds according to the invention.
Suitable processing steps include, but are not limited to
combining, milling, mixing, granulating, dissolving, dispersing,
homogenizing, casting and/or compressing the respective active and
non-active ingredients. In this respect, active ingredients are
preferably at least one compound according to this invention and
one or more additional compounds other than the compounds according
to the invention, which show valuable pharmaceutical properties,
preferably those pharmaceutical active agents other than the
compounds according to invention which are disclosed herein.
[0296] The process for preparing pharmaceutical compositions and/or
pharmaceutical preparations preferably comprises one or more
processing steps, selected from the group consisting of combining,
milling, mixing, granulating, dissolving, dispersing, homogenizing
and compressing. The one or more processing steps are preferably
performed on one or more of the ingredients which are to form the
pharmaceutical composition and/or pharmaceutical preparation
preferably according to invention. Even more preferred, said
processing steps are performed on two or more of the ingredients
which are to form the pharmaceutical composition and/or
pharmaceutical preparation, said ingredients comprising one or more
compounds according to the invention and, additionally, one or more
compounds, preferably selected from the group consisting of active
ingredients other than the compounds according to the invention,
excipients, auxiliaries, adjuvants and carriers. Mechanical means
for performing said processing steps are known in the art, for
example from Ullmann's Encyclopedia of Industrial Chemistry, 5th
Edition.
[0297] Preferably, one or more compounds according to the invention
are converted into a suitable dosage form together with at least
one compound selected from the group consisting of excipients,
auxiliaries, adjuvants and carriers, especially solid, liquid
and/or semi-liquid excipients, auxiliaries, adjuvants and carriers,
and, if desired, in combination with one or more further active
ingredients.
[0298] Suitable dosage forms include, but are not limited to
tablets, capsules, semi-solids, suppositories, aerosols, which can
be produced according to methods known in the art, for example as
described below: [0299] tablets mixing of active ingredient/s and
auxiliaries, compression of said mixture into tablets (direct
compression), optionally granulation of part of mixture before
compression [0300] capsules mixing of active ingredient/s and
auxiliaries to obtain a flowable powder, optionally granulating
powder, filling powders/granulate into opened capsules, capping of
capsules [0301] semi-solids (ointments, gels, creams)
dissolving/dispersing active ingredient/s in an aqueous or fatty
carrier; subsequent mixing of aqueous/fatty phase with
complementary fatty resp. aqueous phase, homogenisation (creams
only) [0302] suppositories (rectal and vaginal)
dissolving/dispersing active ingredient/s in carrier material
liquified by heat (rectal: carrier material normally a wax;
vaginal: carrier normally a heated solution of a gelling agent),
casting said mixture into suppository forms, annealing and
withdrawal suppositories from the forms [0303] aerosols:
dispersing/dissolving active agent/s in a propellant, bottling said
mixture into an atomizer
[0304] The invention thus relates to pharmaceutical compositions
and/or pharmaceutical preparations comprising at least one compound
of the formula I and/or one of its physiologically acceptable salts
and/or solvates and especially to pharmaceutical compositions
and/or pharmaceutical preparations comprising at least one compound
of the formula II and/or one of its physiologically acceptable
salts and/or solvates.
[0305] Preferably, the pharmaceutical compositions and/or
pharmaceutical preparations according to the invention contain a
therapeutic effective amount of one or more compounds according to
the invention. Said therapeutic effective amount of one or more of
the compounds according to the invention is known to the skilled
artisan or can be easily determined by standard methods known in
the art. For example, the compounds according to the invention can
be administered to a patient in an analogous manner to other
compounds that are effective as raf-kinase inhibitors. Usually,
suitable doses that are therapeutically effective lie in the range
between 0.0005 mg and 1000 mg, preferably between 0.005 mg and 500
mg and especially between 0.5 and 100 mg per dose unit. The daily
dose comprises preferably more than 0.001 mg, more preferred more
than 0.01 milligram, even more preferred more than 0.1 mg and
especially more than 1.0 mg, for example more than 2.0 mg, more
than 5 mg, more than 10 mg, more than 20 mg, more than 50 mg or
more than 100 mg, and preferably less than 1500 mg, more preferred
less than 750 my, even more preferred less than 500 my, for example
less than 400 mg, less than 250 mg, less than 150 mg, less than 100
mg, less than 50 mg or less than 10 mg.
[0306] The specific dose for the individual patient depends,
however, on the multitude of factors, for example on the efficacy
of the specific compounds employed, on the age, body weight,
general state of health, the sex, the kind of diet, on the time and
route of administration, on the excretion rate, the kind of
administration and the dosage form to be administered, the
pharmaceutical combination and severity of the particular disorder
to which the therapy relates. The specific therapeutic effective
dose for the individual patient can readily be determined by
routine experimentation, for example by the doctor or physician
which advises or attends the therapeutic treatment.
[0307] However, the specific dose for each patient depends on a
wide variety of factors, for example on the efficacy of the
specific compound employed, on the age, body weight, general state
of health, sex, on the diet, on the time and method of
administration, on the rate of excretion, medicament combination
and severity of the particular illness to which the therapy
applies. Parenteral administration is preferred. Oral
administration is especially preferred.
[0308] These compositions and/or preparations can be used as
medicaments in human or veterinary medicine. Suitable excipients
are organic or inorganic substances which are suitable for enteral
(for example oral), parenteral or topical administration and do not
react with the novel compounds, for example water, vegetable oils,
benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol
triacetate, gelatine, carbohydrates, such as lactose or starch,
magnesium stearate, talc or vaseline. Examples for suitable dosage
forms, which are especially suitable for oral administration are,
in particular, tablets, pills, coated tablets, capsules, powders,
granules, syrups, juices or drops. Further examples for suitable
dosage forms, which are especially suitable for rectal
administration are suppositories, further examples for suitable
dosage forms, which are especially suitable for parenteral
administration are solutions, preferably oil-based or aqueous
solutions, furthermore suspensions, emulsions or implants, and
suitable for topical application are ointments, creams or powders.
The novel compounds may also be lyophilised and the resultant
lyophilisates used, for example, for the preparation of injection
preparations. The compositions and/or preparations indicated may be
sterilized and/or comprise assistants, such as lubricants,
preservatives, stabilizers and/or wetting agents, emulsifiers,
salts for modifying the osmotic pressure, buffer substances, dyes
and flavors and/or one or more further active ingredients, for
example one or more vitamins.
[0309] For administration as an inhalation spray, it is possible to
use sprays in which the active ingredient is either dissolved or
suspended in a propellant gas or propellant gas mixture (for
example CO.sub.2 or chlorofluorocarbons), The active ingredient is
advantageously used here in micronized form, in which case one or
more additional physiologically acceptable solvents may be present,
for example ethanol. Inhalation solutions can be administered with
the aid of conventional inhalers.
[0310] The compounds of the formula I and their physiologically
acceptable salts and solvates and especially the compounds of
formula II and their physiologically acceptable salts and solvates
can be employed for combating one or more diseases, for example
allergic diseases, psoriasis and other skin diseases, especially
melanoma, autoimmune diseases, such as, for example, rheumatoid
arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus
or ulcerative colitis.
[0311] In general, the substances according to the invention are
preferably administered in doses corresponding to the compound
rolipram of between 1 and 500 mg, in particular between 5 and 100
mg per dosage unit. The daily dose is preferably between about 0.02
and 10 mg/kg of body weight. However, the specific dose for each
patient depends on a wide variety of factors, for example on the
efficacy of the specific compound employed, on the age, body
weight, general state of health, sex, on the diet, on the time and
method of administration, on the excretion rate, medicament
combination and severity of the particular illness to which the
therapy applies.
[0312] The compounds of the formula I according to claim 1 and/or
their physiologically acceptable salts are also used in
pathological processes which are maintained or propagated by
angiogenesis, in particular in tumours, restenoses, diabetic
retinopathy, macular degenerative disease or rheumatoid
arthritis.
[0313] Those of skill will readily appreciate that dose levels can
vary as a function of the specific compound, the severity of the
symptoms and the susceptibility of the subject to side effects.
Some of the specific compounds are more potent than others.
Preferred dosages for a given compound are readily determinable by
those of skill in the art by a variety of means. A preferred means
is to measure the physiological potency of a given compound.
[0314] For use in the subject methods, the subject compounds may be
formulated with pharmaceutically active agents other than the
compounds according to the invention, particularly other
anti-metastatic, antitumor or anti-angiogenic agents. Angiostatic
compounds of interest include angiostatin, enclostatin, carboxy
terminal peptides of collagen alpha (XV), etc. Cytotoxic and
cytostatic agents of interest include adriamycin, aleran, Ara-C,
BICNU, busulfan, CNNU, cisplatinum, cytoxan, daunorubicin, DTIC,
5-FU, hydrea, ifosfamicle, methotrexate, mithramycin, mitomycin,
mitoxantrone, nitrogen mustard, velban, vincristine, vinblastine,
VP-16, carboplatinum, fludarabine, gemcitabine, idarubicin,
irinotecan, leustatin, navelbine, taxol, taxotere, topotecan,
etc.
[0315] The compounds of the invention preferably show
antiproliferative effects, for example in an in vivo xenograft
tumor model. The subject compounds can be administered to a subject
having a hyperproliferative disorders, e.g., to inhibit tumor
growth, to decrease inflammation associated with a
lymphoproliferative disorder, to inhibit graft rejection, or
neurological damage due to tissue repair, etc. The present
compounds can be useful for prophylactic or therapeutic purposes.
As used herein, the term "treating" is used to refer to both
prevention of disease, and treatment of pre-existing conditions.
The prevention of proliferation is accomplished by administration
of the subject compounds prior to development of overt disease,
e.g., to prevent the regrowth of tumors, prevent metastatic growth,
diminish restenosis associated with cardiovascular surgery, etc.
Alternatively the compounds are used to treat ongoing disease, by
stabilizing or improving the clinical symptoms of the patient.
[0316] Furthermore, the compounds according the invention
preferably can be utilized in the treatment of infectious diseases
of diverse genesis.
[0317] Infections according the invention include, but are not
limited to infections caused by pathogenic microorganisms, such as
bacteria, fungi, viruses and protozoans, for example influenza
(Pleschka, S. et al. Nature, Cell Biol. 2001, 3, page 301-305),
retroviruses, for example HIV infection (Yang, X. et al. J. Biol.
Chem. 1999, 274, page 27981-27988; Popik, W et al Mol Cel Biol.
1996, 16, page 6532-6541), Hepatitis B (Benn, J et al., Proc. Natl.
Acad. Sci. 1995, 92, page 11215-11219), Hepatitis C (Aoki et al. J.
Virol. 2000, 74, page 1736-1741), papillomavirus, parainfluenza,
rhinoviruses, adenoviruses, Heliobacter pylori, and viral and
bacterial infections of the skin (e.g. cold sores, warts,
chickenpox, molluscum. contagiosum, herpes zoster, boils,
cellulitis, erysipelas, impetigo, tinea, Athlete's foot and
ringworm).
[0318] Furthermore, the compounds according the invention
preferably show anti-angiogenic properties.
[0319] Thus, compounds of the present invention can be
advantageously employed in the treatment of one or more diseases
afflicting mammals which are characterized by cellular
proliferation in the area of disorders associated with
neo-vascularization and/or vascular permeability including blood
vessel proliferative disorders including arthritis and restenosis;
fibrotic disorders including hepatic cirrhosis and atherosclerosis;
mesangial cell proliferative disorders include glomerulonephritis,
diabetic nephropathy, malignant nephrosclerosis, thrombotic
microangiopathy syndromes, organ transplant rejection and
glomerulopathies; and metabolic disorders include psoriasis,
diabetes mellitus, chronic wound healing, inflammation and
neurodegenerative diseases.
[0320] The host, or patient may be from any mammalian species,
e.g., primate sp., particularly human; rodents, including mice,
rats and hamsters; rabbits; equines, bovines, canines, felines;
etc. Animal models are of interest for experimental investigations,
providing a model for treatment of human disease.
[0321] The susceptibility of a particular cell to treatment with
the subject compounds may be determined by in vitro testing. Such
in vitro testing methods are known in the art. For example, they
can be performed as described herein or in the literature cited
herein, or in an analogous manner thereof. Typically a culture of
the cell is combined with a subject compound at varying
concentrations for a period of time sufficient to allow the active
agents to induce cell death or inhibit migration, usually between
about one hour and one week. For in vitro testing, cultured cells
from a biopsy sample may be used. The viable cells left after
treatment are then counted.
[0322] The dose will vary depending on the specific compound
utilized, specific disorder, patient status, etc. Typically a
therapeutic dose will be sufficient to substantially decrease the
undesirable cell population in the targeted tissue, while
maintaining patient viability, Treatment will generally be
continued until there is a substantial reduction, e.g., at least
about 50% decrease in the cell burden, and may be continued until
there are essentially none of the undesirable cells detected in the
body.
[0323] The compounds according to the invention are preferably
administered to human or nonhuman animals, more preferred to
mammalian animals and especially to humans.
[0324] The compounds also find use in the specific inhibition of a
signaling pathway mediated by protein kinases. Protein kinases are
involved in signaling pathways for such important cellular
activities as responses to extracellular signals and cell cycle
checkpoints. Inhibition of specific protein kinases provided a
means of intervening in these signaling pathways, for example to
block the effect of an extracellular signal, to release a cell from
cell cycle checkpoint, etc. Defects in the activity of protein
kinases are associated with a variety of pathological or clinical
conditions, where there is a defect in the signaling mediated by
protein kinases. Such conditions include those associated with
defects in cell cycle regulation or in response to extracellular
signals, e.g., immunological disorders, autoimmune and
immunodeficiency diseases; hyperproliferative disorders, which may
include infection, psoriasis, arthritis, inflammation,
endometriosis, scarring, cancer, etc. The compounds of the present
invention are active in inhibiting purified kinase proteins
preferably raf kinases, e.g., there is a decrease in the
phosphorylation of a specific substrate in the presence of the
compound. The compounds of the invention may also be useful as
reagents for studying signal transduction or any of the clinical
disorders listed throughout this application.
[0325] There are many disorders associated with a dysregulation of
cellular proliferation. The conditions of interest include, but are
not limited to, the following conditions. The subject compounds are
useful in the treatment of a variety of conditions where there is
proliferation and/or migration of smooth muscle cells, and/or
inflammatory cells into the intimal layer of a vessel, resulting in
restricted blood flow through that vessel, e.g., neointimal
occlusive lesions. Occlusive vascular conditions of interest
include atherosclerosis, graft coronary vascular disease after
transplantation, vein graft stenosis, peri-anastomatic prothetic
graft stenosis, restenosis after angioplasty or stent placement,
and the like.
[0326] Diseases where there is hyperproliferation and tissue
remodelling or repair or reproductive tissue, e.g., uterine,
testicular and ovarian carcinomas, endometriosis, squamous and
glandular epithelial carcinomas of the cervix, etc. are reduced in
cell number by administration of the subject compounds. The growth
and proliferation of neural cells is also of interest.
[0327] Tumor cells are characterized by uncontrolled growth,
invasion to surrounding tissues, and metastatic spread to distant
sites. Growth and expansion requires an ability not only to
proliferate, but also to down-modulate cell death (apoptosis) and
activate angiogenesis to produce a tumor neovasculature.
[0328] Tumors of interest for treatment include carcinomas, e.g.,
colon, duodenal, prostate, breast, melanoma, ductal, hepatic,
pancreatic, renal, endometrial, stomach, dysplastic oral mucosa,
polyposis, invasive oral cancer, non-small cell lung carcinoma,
transitional and squamous cell urinary carcinoma etc.; neurological
malignancies; e.g. neuroplastoma, gliomas, etc.; hematological
malignancies, e.g., childhood acute leukaemia, non-Hodgkin's
lymphomas, chronic lymphocytic leukaemia, malignant cutaneous
T-cells, mycosis fungoides, non-MF cutaneous T-cell-lymphoma,
lymphomatoid papulosis, T-cell rich cutaneous lymphoid hyperplasia,
bullous pemphigoid, discoid lupus erythematosus, lichen planus,
etc.; and the like.
[0329] Tumors of neural tissue are of particular interest, e.g.,
gliomas, neuromas, etc. Some cancers of particular interest include
breast cancers, which are primarily adenocarcinoma subtypes. Ductal
carcinoma in situ is the most common type of noninvasive breast
cancer. In DCIS, the malignant cells have not metastasized through
the walls of the ducts into the fatty tissue of the breast.
Infiltration (or invasive) ductal carcinoma (IDC) has metastasized
through the wall of the duct and invaded the fatty tissue of the
breast. Infiltrating (or invasive) lobular carcinoma (ILC) is
similar to IDC, in that it has the potential to metastasize
elsewhere in the body. About 10% to 15% of invasive breast cancers
are invasive lobular carcinomas.
[0330] Also of interest is non-small cell lung carcinoma. Non-small
cell lung cancer (NSCLC) is made up of three general subtypes of
lung cancer. Epidermoid carcinoma (also called squamos cell
carcinoma) usually starts in one of the larger bronchial tubes and
grows relatively slowly. The size of these tumors can range from
very small to quite large. Adenocarcinoma starts growing near the
outside surface of the lung and may vary in both size and growth
rate. Some slowly growing adenocarcinomas are described as alveolar
cell cancer. Large cell carcinoma starts near the surface of the
lung, grows rapidly, and the growth is usually fairly large when
diagnosed. Other less common forms of lung cancer are carcinoid,
cylindroma, mucoepidermoid, and malignant mesothelioma.
[0331] Melanoma is a malignant tumor of melanocytes. Although most
melanomas arise in the skin, they also may arise from mucosal
surfaces or at other sites to which neural crest cells migrate.
Melanoma occurs predominantly in adults, and more than half of the
cases arise in apparently normal areas of the skin. Prognosis is
affected by clinical and histological factors and by anatomic
location of the lesion. Thickness and/or level of invasion of the
melanoma, mitotic index, tumor infiltrating lymphocytes, and
ulceration or bleeding at the primary site affect the prognosis.
Clinical staging is based on whether the tumor has spread to
regional lymph nodes or distant sites. For disease clinically
confined to the primary site, the greater the thickness and depth
of local invasion of the melanoma, the higher the chance of lymph
node metastases and the worse the prognosis. Melanoma can spread by
local extension (through lymphatics) and/or by hematogenous routes
to distant sites. Any organ may be involved by metastases, but
lungs and liver are common sites.
[0332] Other hyperproliferative diseases of interest relate to
epidermal hyperproliferation, tissue, remodeling and repair. For
example, the chronic skin inflammation of psoriasis is associated
with hyperplastic epidermal keratinocyctes as well as infiltrating
mononuclear cells, including CD4+ memory T cells, neutrophils and
macrophages.
[0333] The proliferation of immune cells is associated with a
number of autoimmune and lymphoproliferative disorders. Diseases of
interest include multiple sclerosis, rheumatoid arthritis and
insulin dependent diabetes mellitus. Evidence suggests that
abnormalities in apoptosis play a pan in the pathogenesis of
systemic lupus erythematosus (SLE). Other lymphoproliferative
conditions the inherited disorder of lymphocyte apoptosis, which is
an autoimmune lymphoproliferative syndrome, as well as a number of
leukemia's and lymphomas. Symptoms of allergies to environmental
and food agents, as well as inflammatory bowel disease, may also be
alleviated by the compounds of the invention.
[0334] Surprisingly, it has been found that glycine amide
derivatives according to invention are able to interact with
signaling pathways, especially the signaling pathways described
herein and preferably the raf-kinase signaling pathway. Glycine
amide derivatives according to the invention preferably show
advantageous biological activity which can easily be demonstrated
according to methods known in the art, for example by enzyme based
assays. Suitable assays are known in the art, for example from the
literature cited herein and the references cited in the literature,
or can be developed and/or performed in an analogous manner
thereof. In such enzyme based assays, glycine amide derivatives
according to invention show an effect, preferably a modulating and
especially an inhibiting effect which is usually documented by
IC.sub.50 values in a suitable range, preferably in the micromolar
range and more preferred in the nanomolar range.
[0335] In general, compounds according to the invention are to be
regarded as suitable kinase-modulators and especially suitable
kinase-inhibitors according to the invention if they show an effect
or an activity to one or more kinases, preferably to one or more
raf-kinases that preferably lies, determined as IC.sub.50-value, in
the range of 100 .mu.mol or below, preferably 10 .mu.mol or below,
more preferably in the range of 3 .mu.mol or below, even more
preferably in the range of 1 .mu.mol or below and most preferably
in the nanomolar range. Especially preferred for use according to
the invention are kinase-inhibitors as defined above/below, that
show an activity, determined as IC.sub.50-value; to one or more
raf-kinases, preferably including A-raft, B-rat and c-raf1 or
consisting of A-raf, B-raf and c-raf1 and more preferred including
c-raft or consisting of c-raf1, in the range of 0.5 .mu.mol or
below and especially in the range of 0.1 .mu.mol or below. In many
cases an IC.sub.50-value at the lower end of the given ranges is
advantageous and in some cases it is highly desirable that the
IC.sub.50-value is as small as possible or the he IC.sub.50-values
are as small as possible, but in general IC.sub.50-values that lie
between the above given upper limits and a lower limit in the range
of 0.0001 .mu.mol, 0.001 .mu.mol, 0.01 .mu.mol or even above 0.1
.mu.mol are sufficient to indicate the desired pharmaceutical
activity. However, the activities measured can vary depending on
the respective testing system or assay chosen.
[0336] As discussed herein, these signaling pathways are relevant
for various disorders. Accordingly, by interacting with one or more
of said signaling pathways, glycine amide derivatives are useful in
the prevention and/or the treatment of disorders that are dependent
from said signaling pathways.
[0337] Subject of the present invention are therefore glycine amide
derivatives according to the invention as promoters or inhibitors,
preferably as inhibitors, of the signaling pathways described
herein. Preferred subject of the invention are therefore glycine
amide derivatives according to the invention as promoters or
inhibitors, preferably as inhibitors of the raf-kinase pathway.
More preferred subject of the invention are therefore glycine amide
derivatives according to the invention as promoters or inhibitors,
preferably as inhibitors of the raf-kinase. Even more preferred
subject of the invention are glycine amide derivatives according to
invention as promoters or inhibitors, preferably as inhibitors, of
one or more raf-kinases, selected from the group consisting of
A-raft, B-raf and c-raf1. Especially preferred subject of the
invention are glycine amide derivatives according to the invention
as promoters or inhibitors, preferably as inhibitors of c-raf1.
[0338] Thus, subject of the present invention are glycine amide
derivatives according to the invention as medicaments. Subject of
the present invention are glycine amide derivatives according to
the invention as medicament active ingredients. Further subject of
the present invention is the use of one or more glycine amide
derivatives according to the invention as a pharmaceutical. Further
subject of the present invention is the use of one or more glycine
amide derivatives according to the invention in the treatment
and/or the prophylaxis of disorders, preferably the disorders
described herein, more preferred disorders that are caused,
mediated and/or propagated by signalling pathways discussed herein,
even more preferred disorders that are caused, mediated and/or
propagated by raf-kinases and especially disorders that are caused,
mediated and/or propagated by raf-kinases, selected from the group
consisting of A-raf, B-raf and c-raf1. Usually, the disorders
discussed herein are divided into two groups, hyperproliferative
and non hyperproliferative disorders. In this context, infection,
psoriasis, arthritis, inflammation, endometriosis, scarring, begnin
prostatic hyperplasia, immunological diseases, autoimmune diseases
and immunodeficiency diseases are to be regarded as noncancerous
disorders, of which infections, arthritis, inflammation,
immunological diseases, autoimmune diseases and immunodeficiency
diseases are usually regarded as non hyperproliferative disorders.
In this context, brain cancer, lung cancer, squamous cell cancer,
bladder cancer, gastric cancer, pancreatic cancer, hepatic cancer,
renal cancer, colorectal cancer, breast cancer, head cancer, neck
cancer, oesophageal cancer, gynaecological cancer, thyroid cancer,
lymphoma, chronic leukaemia and acute leukaemia are to be regarded
as cancerous disorders, all of which are usually regarded as
hyperproliferative disorders. Especially cancerous cell growth and
especially cancerous cell growth mediated by raf-kinase is a
disorder which is a target of the present invention. Subject of the
present invention therefore are glycine amide derivatives according
to the invention as medicaments and/or medicament active
ingredients in the treatment and/or the prophylaxis of said
disorders and the use of glycine amide derivatives according to the
invention for the manufacture of a pharmaceutical for the treatment
and/or the prophylaxis of said disorders as well as a method of
treatment of said disorders, comprising administering one or more
glycine amide derivatives according to the invention to a patient
in need of such an administration.
[0339] Accordingly, subject of the present invention are
pharmaceutical compositions that contain one or more glycine amide
derivatives according to the invention. Subject of the present
invention are especially pharmaceutical compositions that contain
one or more glycine amide derivatives according to the invention
and one or more additional compounds (other than the compounds of
the instant invention), preferably selected from the group
consisting of physiologically acceptable excipients, auxiliaries,
adjuvants, carriers and pharmaceutically active ingredients other
than the compounds according to the invention.
[0340] Accordingly, subject of the present invention is a process
for the manufacture of a pharmaceutical composition, wherein one or
more glycine amide derivatives according to the invention and one
or more compounds (other than the compounds of the instant
invention), preferably selected from the group consisting of
carriers, excipients, auxiliaries, adjuvants and pharmaceutically
active ingredients other than the compounds according to the
invention.
[0341] Accordingly, the use of the compounds according to the
invention in the treatment of hyperproliferative disorders is a
subject of the instant invention.
[0342] Accordingly, the use of the compounds according to the
invention for producing a medicament for the treatment of
hyperproliferative disorders is a subject of the instant
invention.
[0343] Above and below, all temperatures are given in .degree. C.
In the examples below, "conventional workup" means that the organic
phase is washed with saturated NaHCO.sub.3 solution, if desired
with water and saturated NaCl solution, the phases are separated,
the organic phase is dried over sodium sulfate and evaporated, and
the product is purified by chromatography on silica gel, by
preparative HPLC and/or by crystallization.
[0344] The present invention relates to glycinamide derivatives of
formula I, the use of the compounds of formula I as inhibitors of
raf-kinase, the use of the compounds of formula I for the
manufacture of a pharmaceutical composition and a method of
treatment, comprising administering said pharmaceutical composition
to a patient.
EXAMPLES
4-(4-Pyridinyloxy)-phenylamine (2)
[0345] ##STR00502## [0346] a) In a reaction apparatus equipped with
a stirring means and a cooler, 195 g (1.4 mol) 4-nitrophenol and
445.2 g (1.4 mol) bipyridin are slowly heated up to a temperature
of 150.degree. C. under agitation. After three hours of stirring at
150.degree. C., the hot reaction mixture is poured into ice-cool
water, acidified with hydrochloric acid and washed with methyl
tert.-butyl ether (2.times.3 l). The organic phase is turned basic
(pH about 12) by addition of concentrated caustic soda solution and
extracted with methyl tert.-butyl ether (2.times.3 l). The
combined, organic phases are washed with water (4.times.1 l), dried
over Na.sub.2SO.sub.4, filtered and evaporated. The residue is
dissolved in 100 ml ether, cooled in an ice bath and caused to
crystallize by addition of petroleum ether (200 ml). The
crystalline residue is collected by suction and dried in vacuum to
yield 75 g (25%) brownish crystals of 1. [0347] b) Compound 1 is
hydrogenated with Pd/C in methanol. The reaction mixture is
filtered over kieselguhr, the residue washed with methanol and the
filtrate evaporated. The residue is digested with a diethyl
ether/petroleum ether-mixture (2:1), filtered by suction, washed
with petrol ether and dried in vaccuo at 40.degree. C. overnight to
yield 50.94 g (76%) brownish crystals of 2.
3-(4-Pyridinyloxy)-phenylamine (4)
[0348] ##STR00503## [0349] a) In a reaction apparatus equipped with
a stirring means and a cooler, 200 g (1.44 mol/l) 3-nitrophenol and
457.93 g (1.44 mol) bipyridin are slowly heated up to a temperature
of 150.degree. C. under agitation. After three hours of stirring at
150.degree. C., the hot reaction mixture is poured into ice-cool
water, acidified with hydrochloric acid and washed with methyl
tert.-butyl ether (2.times.3 l). The organic phase is turned basic
(pH about 12) by addition of concentrated caustic soda solution and
extracted with methyl tert.-butyl ether (2.times.3 l). The combined
organic phases are washed with water (4.times.1 l), dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue is dissolved
in 200 ml diethyl ether, treated with charcoal (20 g) for 1 h under
stirring and filtered. The filtrate is evaporated to about 200 ml,
cooled in a ice bath and caused to crystallize by addition of
petroleum ether (500 ml). The crystalline residue is collected by
suction and dried in vacuum to yield 131 g (42%) light brownish
crystals of 3. [0350] b) Compound 3 is hydrogenated with Pd/C in
methanol. The reaction mixture is filtered over kieselguhr, the
residue washed with methanol and the filtrate evaporated. The
residue is digested with diethyl ether, filtered by suction, washed
with diethyl ether and dried in vacuum at 40.degree. C. overnight
to yield 98.08 g (87%) light brownish crystals of 4.
4-(3-Pyridinyloxy)-phenylamine
[0351] ##STR00504## [0352] a) In a reaction apparatus equipped with
a stirring means and a cooler, 125 g (0.94 mol) 3-hydroxypyridine,
potassium salt, 300 g 1-chloronitrobenzene and 15 g copper are
heated up to a temperature of 180.degree. C. under agitation for
homogenization. After three hours of stirring at 180.degree. C.,
the reaction mixture is cooled to 90.degree. C. and
methyl-tert.-butyl ether is added quickly. The resulting suspension
is further stirred for 1 h, filtered by suction and the filtrate is
extracted with 10% aqueous hydrochloric acid (3.times.1 l). The
resulting aqueous phase is made alkaline with ammonium hydroxide
solution and extracted with ethyl acetate. The obtained organic
phase is dried over Na.sub.2SO.sub.4, filtered and evaporated in
vacuum. The residue is purified by column chromatography on silica
gel (1 kg) with dichloromethan as eluent, dissolved in 10% aqueous
hydrochloric acid and extracted with ethyl acetate. The aqueous
phase is made alkaline with ammonium hydroxide solution and the
resulting crystalline precipitate is collected by suction, washed
with little cold water and dried on air for 4 days to yield 44.7 g
(22%) brownish crystals of 5. [0353] b) Compound 5 is hydrogenated
with Pd/C in methanol/tetrahydrofurane at room temperature. The
reaction mixture is filtered over kieselguhr, the residue washed
with methanol and the filtrate evaporated. The residue is digested
with diethyl ether, filtered by suction, washed with diethyl ether
and dried in vacuum at 40.degree. C. overnight to yield 37.14 g
(95%) light brownish crystals of 6.
3-(Pyridinyloxy)-phenylamine (8)
[0354] ##STR00505## [0355] a) In a reaction apparatus equipped with
a stirring means and a cooler, 50 g (0.53 mol) 3-hydroxypyridine,
178.8 g (1.05 mol) 1,3-dinitrobenzene and 159.9 g (1.16 mol)
K.sub.2CO.sub.3 are suspended in 1.4 l dimethyl formamide (DMF) and
heated to 150.degree. C., After 16 hours stirring at 150.degree.
C., the reaction mixture is cooled to room temperature and
evaporated. The residue is treated with ethyl acetate (1.5 l) under
stirring for 30 minutes, filtered and the filtrate is extracted
with 10% aqueous hydrochloric acid. The aqueous phase is made
alkaline with ammonium hydroxide solution and extracted with ethyl
acetate. The combined organic phases our dried over
Na.sub.2SO.sub.4, filtered and evaporated. The residue is purified
by column chromatography on silica gel (1 kg) with dichloromethane
as eluent, dissolved in 10% aqueous hydrochloric acid and extracted
with ethyl acetate. The aqueous phase is made alkaline with
ammonium hydroxide solution and extracted with ethyl acetate. The
combined organic phases are dried over Na.sub.2SO.sub.4, filtered
and evaporated to yield 98 g (86%) brownish oil of 7. [0356] b)
Compound 7 is hydrogenated with Pd/C in methanol/tetrahydrofurane
at room temperature. The reaction mixture is filtered over
kieselguhr, the residue washed with methanol and the filtrate
evaporated. The residue is digested with a diethyl ether/petroleum
ether-mixture (2:1), filtered by suction, washed with petrol ether
and the resulting crystals are collected. The mother liquor is
evaporated to dryness and allowed to stand in the refrigerator
overnight. The resulting crystals where digested with a petroleum
ether/diethyl ether-mixture (9:1) and filtered by suction. The
combined crystalline residues are dried in vacuum at 40.degree. C.
overnight to yield 77.7 g (91%) light brownish crystals of 8.
2-Chloro-N-(4-chloro-3-trifluoro methyl phenyl)-acetamide (9)
##STR00506##
[0358] Chloroacetic acid chloride (0:69 ml; 8.44 mmol) is dropped
slowly into a stirred solution of 4-chloro-3-trifluoro methyl
aniline (1.5 g; 7.67 mmol) in pyridine (0.81 ml; 9.97 mmol) and
dichloromethane (15 ml), cooled to 0.degree. C. Stirring is
continued for 2 h at room temperature. The reaction mixture is
diluted with dichloromethane, washed twice with 1N aqueous
hydrochloric acid and with water. The reaction mixture is then
dried over Na.sub.2SO.sub.4, filtered and evaporated to yield 2.05
g (98%) brownish solid of 9.
N-(4-Chloro-3-trifluoro methyl phenyl)-2-[4-(4-pyridinyloxy)phenyl
amino]-acetamide
##STR00507##
[0360] A solution of 146.1 mg (0.54 mmol) of compound 9 in
dimethylformamide (DMF) is given to a solution of 100 mg (0.54
mmol) of compound 2 and 0.1 ml (0.59 mmol) N-Ethyl-diisopropylamine
in DMF. The reaction mixture is heated to 100.degree. C. for 6 h,
then evaporated and the residue is purified by preparative HPLC to
yield 10.7 mg (5%) colourless solid.
N-(4-Chloro-3-trifluoro methyl phenyl)-2[3-(4-pyridinyloxy)phenyl
amino]-acetamide
##STR00508##
[0362] A solution of 146.1 mg (0.54 mmol) of compound 9 in
dimethylformamide (DMF) is given to a solution of 100 mg (0.54
mmol) of compound 4 and 0.1 ml (0.59 mmol) N-Ethyl-diisopropylamine
in DMF. The reaction mixture is heated to 100.degree. C. for 6 h,
then evaporated and the residue is purified by preparative HPLC to
yield 110 mg (48%) colourless solid.
N-(4-Chloro-3-trifluoro methyl phenyl)-2-[4-(3-pyridinyloxy)phenyl
amino]-acetamide
##STR00509##
[0364] A solution of 146.1 mg (0.54 mmol) of compound 9 in
dimethylformamide (DMF) is given to a solution of 100 mg (0.54
mmol) of compound 6 and 0.1 ml (0.59 mmol) N-Ethyl-diisopropylamine
in DMF. The reaction mixture is heated to 100.degree. C. for 4 h,
then evaporated and the residue is purified by preparative HPLC to
yield 20 mg (9%) colourless solid.
N-(4-Chloro-3-trifluoro methyl
phenyl)-2-[3-(3-pyridinyloxy)phenylamine]-acetamide
##STR00510##
[0366] A solution of 146.1 mg (0.54 mmol) of compound 9 in
dimethylformamide (DMF) is given to a solution of 100 mg (0.54
mmol) of compound 8 and 0.1 ml (0.59 mmol) N-Ethyl-diisopropylamine
in DMF. The reaction mixture is heated to 100.degree. C. for 4 h,
then evaporated and the residue is purified by preparative HPLC to
yield 24 mg (11%) colourless solid.
N-(5-t-Butyl-3-isoxazolyl)-2-chloro-acetamide
##STR00511##
[0368] Chloroacetic acid chloride (0.93 ml; 11.42 mmol) is dropped
slowly into a stirred solution of 5-t-Butyl-3-amino isoxazole (1.5
g; 7.67 mmol) in pyridine (1.09 ml; 13.49 mmol) and dichloromethane
(20 ml), cooled to 0.degree. C. Stirring is continued for 2 h at
room temperature. The reaction mixture is diluted with
dichloromethane, washed twice with 1N aqueous hydrochloric acid,
twice with an aqueous solution of NaHCO.sub.3 and with water. The
reaction mixture is then dried over Na.sub.2SO.sub.4, filtered and
evaporated to yield 2.2 g (98%) brownish solid of 10.
N-(5-t-Butyl-3-isoxazolyl)-2-[4-(4-pyridinyloxy)phenyl
amino]-acetamide
##STR00512##
[0370] A solution of 58.2 mg (0.27 mmol) of compound 10 in
dimethylformamide (DMF) is given to a solution of 50 mg (0.27 mmol)
of compound 2 and 0.05 ml (0.3 mmol) N-Ethyl-diisopropylamine in
DMF. The reaction mixture is heated to 100.degree. C. for 4 h, then
evaporated and the residue is purified by preparative HPLC to yield
28 mg (29%) colourless solid.
N-(5-t-Butyl-3-isoxazolyl)-2-[3-(4-pyridinyloxy)phenyl
amino]-acetamide
##STR00513##
[0372] A solution of 58.2 mg (0.27 mmol) of compound 10 in
dimethylformamide (DMF) is given to a solution of 50 mg (0.27 mmol)
of compound 4 and 0.05 ml (0.3 mmol) N-Ethyl-diisopropylamine in
DMF. The reaction mixture is heated to 100.degree. C. for 4 h, then
evaporated and the residue is purified by preparative HPLC to yield
47 mg (48%) colourless solid.
N-(3-t-Butyl-5-isoxazolyl)-2-chloro-acetamide
##STR00514##
[0374] Chloroacetic acid chloride (0.25 ml; 3.14 mmol) is dropped
slowly into a stirred solution of 3-t-Butyl-5-amino isoxazole (400
my; 2.85 mmol) in pyridine (0.3 ml; 3.71 mmol) and dichloromethane
(2 ml) cooled to 0.degree. C. Stirring is continued for 2 h at room
temperature. The reaction mixture is diluted with dichloromethane,
washed twice with 1N aqueous hydrochloric acid, twice with an
aqueous solution of NaHCO.sub.3 and with water. The reaction
mixture is then dried over Na.sub.2SO.sub.4, filtered and
evaporated to yield 600 mg (97%) brownish solid of 11.
N-(3-t-Butyl-5-isoxazolyl)-2-[4-(4-pyridinyloxy)phenyl
amino]-acetamide
##STR00515##
[0376] A solution of 58.2 mg (0.27 mmol) of compound 11 in
dimethylformamide (DMF) is given to a solution of so mg (0.27 mmol)
of compound 2 and 0.05 ml (0.3 mmol)N-Ethyl-diisopropylamine in
DMF. The reaction mixture is heated to 100.degree. C. for 2 h, then
evaporated and the residue is purified by preparative HPLC to yield
5.5 my (6%) colourless solid.
N-(3-t-Butyl-5-isoxazolyl)-2-[3-(4-pyridinyloxy)phenyl
amino]-acetamide
##STR00516##
[0378] A solution of 58.2 mg (0.27 mmol) of compound 11 in
dimethylformamide (DMF) is given to a solution of 50 mg (0.27 mmol)
of compound 4 and 0.05 ml (0.3 mmol) N-Ethyl-diisopropylamine in
DMF. The reaction mixture is heated to 100.degree. C. for 2 h, then
evaporated and the residue is purified by preparative HPLC to yield
20 mg (20%) colourless solid.
[0379] The compounds (1) to (235) as described above can preferably
be produced according to the procedures described herein or in an
analogous manner thereof.
Example A
Injection Vials
[0380] A solution of 100 g of an active compound of the formula I
and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 l
of double-distilled water using 2N hydrochloric acid,
sterile-filtered, dispensed into injection vials, lyophilized under
sterile conditions and aseptically sealed. Each injection vial
contains 5 mg of active compound.
Example B
Suppositories
[0381] A mixture of 20 g of an active compound of the formula I is
fused with 100 g of soya lecithin and 1400 g of cocoa butter,
poured into moulds and allowed to cool. Each suppository contains
20 mg of active compound.
Example C
Solution
[0382] A solution of 1 g of an active compound of the formula I,
9.38 g of NaH.sub.2PO.sub.4.2H.sub.2O, 28.48 g of
Na.sub.2HPO.sub.4.12H.sub.2O and 0.1 g of benzalkonium chloride in
940 ml of double-distilled water is prepared. It is adjusted to pH
6.8, made up to 1 l and sterilized by irradiation. This solution
can be used in the form of eye drops.
Example D
Ointment
[0383] 500 mg of an active compound of the formula I is mixed with
99.5 g of petroleum jelly under aseptic conditions.
Example E
Tablets
[0384] A mixture of 1 kg of active compound of the formula 1, 4 kg
of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of
magnesium stearate is compressed to give tablets in a customary
manner such that each tablet contains 10 mg of active compound.
Example F
Coated Tablets
[0385] Analogously to Example E, tablets are pressed and are then
coated in a customary manner using a coating of sucrose, potato
starch, talc, tragacanth and colourant.
Example G
Capsules
[0386] 2 kg of active compound of the formula I are dispensed into
hard gelatin capsules in a customary manner such that each capsule
contains 20 mg of the active compound.
Example H
Ampoules
[0387] A solution of 1 kg of active compound of the formula I in 60
l of double-distilled water is sterile-filtered, dispensed into
ampoules, lyophilized under sterile conditions and aseptically
sealed. Each ampoule contains 10 mg of active compound.
* * * * *