U.S. patent application number 11/993426 was filed with the patent office on 2010-08-26 for substituted glycinamides, process for their manufacture and use thereof as medicaments.
Invention is credited to Georg Dahmann, Kai Gerlach, Sandra Handschuh, Herbert Nar, Roland Pfau, Henning Priepke, Annette Schuler-Metz, Wolfgang Wienen.
Application Number | 20100216769 11/993426 |
Document ID | / |
Family ID | 35907001 |
Filed Date | 2010-08-26 |
United States Patent
Application |
20100216769 |
Kind Code |
A1 |
Priepke; Henning ; et
al. |
August 26, 2010 |
SUBSTITUTED GLYCINAMIDES, PROCESS FOR THEIR MANUFACTURE AND USE
THEREOF AS MEDICAMENTS
Abstract
The present invention relates to new substituted glycinamides of
general formula (I) ##STR00001## wherein D, M, R.sup.3, R.sup.4 and
R.sup.5 are defined as in the specification, the tautomers,
enantiomers, diastereomers, mixtures and salts thereof,
particularly the physiologically acceptable salts thereof with
inorganic or organic acids or bases, which have valuable
properties.
Inventors: |
Priepke; Henning;
(Warthausen, DE) ; Dahmann; Georg; (Attenweiler,
DE) ; Gerlach; Kai; (Biberach, DE) ; Pfau;
Roland; (Biberach, DE) ; Wienen; Wolfgang;
(Biberach, DE) ; Schuler-Metz; Annette; (Ulm,
DE) ; Handschuh; Sandra; (Biberach, DE) ; Nar;
Herbert; (Ochsenhausen, DE) |
Correspondence
Address: |
MICHAEL P. MORRIS;BOEHRINGER INGELHEIM USA CORPORATION
900 RIDGEBURY ROAD, P. O. BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Family ID: |
35907001 |
Appl. No.: |
11/993426 |
Filed: |
June 28, 2006 |
PCT Filed: |
June 28, 2006 |
PCT NO: |
PCT/EP06/63611 |
371 Date: |
April 9, 2010 |
Current U.S.
Class: |
514/211.1 ;
514/211.09; 514/211.11; 540/578; 540/580; 540/594 |
Current CPC
Class: |
C07D 409/14 20130101;
A61P 17/02 20180101; A61P 29/00 20180101; C07D 409/12 20130101;
C07D 413/14 20130101; C07D 471/04 20130101; A61P 7/02 20180101;
C07D 487/04 20130101; A61P 19/02 20180101; C07D 417/14 20130101;
A61P 25/28 20180101; A61P 25/16 20180101; C07D 471/08 20130101;
A61P 35/00 20180101; A61P 43/00 20180101; A61P 35/04 20180101; A61P
9/00 20180101; A61P 9/10 20180101; A61P 1/04 20180101; A61P 31/04
20180101 |
Class at
Publication: |
514/211.1 ;
540/594; 540/578; 540/580; 514/211.09; 514/211.11 |
International
Class: |
A61K 31/553 20060101
A61K031/553; C07D 405/12 20060101 C07D405/12; C07D 409/14 20060101
C07D409/14; C07D 409/12 20060101 C07D409/12; C07D 487/04 20060101
C07D487/04; C07D 413/14 20060101 C07D413/14; C07D 471/04 20060101
C07D471/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 30, 2005 |
EP |
05014270.2 |
Claims
1. Compounds of general formula (I) ##STR00209## wherein D denotes
a substituted bicyclic ring system of formula (II), ##STR00210##
wherein K.sup.1 and K.sup.4 each independently of one another
denote a --CH.sub.2, --CHR.sup.7a, --CR.sup.7bR.sup.7c or a --C(O)
group, and R.sup.7a/R.sup.7b/R.sup.7c each independently of one
another denote a fluorine atom, a hydroxy, C.sub.1-5-alkyloxy,
tetrahydrofuranyl, oxetanyl, amino, C.sub.1-5-alkylamino,
di-(C.sub.1-5-alkyl)-amino, C.sub.3-5-cycloalkyleneimino or
C.sub.1-5-alkylcarbonylamino group, a C.sub.1-5-alkyl group which
may be substituted by 1-3 fluorine atoms, a
hydroxy-C.sub.1-5-alkyl, C.sub.1-5-alkyloxy-C.sub.1-5-alkyl,
amino-C.sub.1-5-alkyl, C.sub.1-5-alkylamino-C.sub.1-5-alkyl,
di-(C.sub.1-5-alkyl)-amino-C.sub.1-5-alkyl,
C.sub.4-7-cycloalkyleneimino-C.sub.1-5-alkyl,
carboxy-C.sub.0-5-alkyl,
C.sub.1-5-alkyloxycarbonyl-C.sub.0-5-alkyl,
aminocarbonyl-C.sub.0-5-alkyl,
C.sub.1-5-alkylaminocarbonyl-C.sub.0-5-alkyl,
di-(C.sub.1-5-alkyl)-aminocarbonyl-C.sub.0-5-alkyl,
C.sub.4-7-cycloalkyleneiminocarbonyl-C.sub.0-5-alkyl-group, a
phenyl group or a 5- or 6-membered heteroaryl group which may be
substituted by 1-2 substituents selected from among a nitro, amino,
hydroxy, methoxy, cyano, C.sub.1-5-alkyl group or a fluorine,
chlorine or bromine atom, wherein the two groups R.sup.7b/R.sup.7c
cannot both simultaneously be bound to the cyclic carbon atom via a
heteroatom, except if --C(R.sup.7bR.sup.7c)-- corresponds to a
--CF.sub.2 group, or two groups R.sup.7b/R.sup.7c together with the
cyclic carbon atom may form a 3, 4, 5-, 6- or 7-membered saturated
carbocyclic group or a cyclopentene, cyclohexene, oxetane,
azetidine, thietane, tetrahydrofuran, pyrrolidine,
tetrahydrothiophene, tetrahydropyran, piperidine, pentamethylene
sulphide, hexamethyleneimine, 1,3-dioxolane, 1,4-dioxane,
hexahydropyridazine, piperazine, thiomorpholine, morpholine,
2-imidazolidinone, 2-oxazolidinone, tetrahydro-2(1H)-pyrimidinone,
[1,3]oxazinan-2-one ring, wherein the methylene groups thereof may
be substituted by 1-2 C.sub.1-3-alkyl or CF.sub.3-- groups, and/or
the methylene groups thereof, if they are not bound to a
heteroatom, may be substituted by 1-2 fluorine atoms, and/or
wherein a --CH.sub.2 group adjacent to an N atom may be replaced by
a --CO group, and/or the imino groups of which may be substituted
in each case by a C.sub.1-3-alkyl or C.sub.1-3-alkylcarbonyl group,
and/or wherein the sulphur atom may be oxidised to form a
sulphoxide or sulphone group, K.sup.2 and K.sup.3 each
independently of one another denote a --CH.sub.2, --CHR.sup.8a,
--CR.sup.8bR.sup.8c or a --C(O)-- group, and
R.sup.8a/R.sup.8b/R.sup.8c each independently of one another denote
a C.sub.1-5-alkyl group which may be substituted by 1-3 fluorine
atoms, a hydroxy-C.sub.1-5-alkyl,
C.sub.1-5-alkyloxy-C.sub.1-5-alkyl, amino-C.sub.1-5-alkyl,
C.sub.1-5-alkylamino-C.sub.1-5-alkyl,
di-(C.sub.1-5-alkyl)-amino-C.sub.1-5-alkyl,
C.sub.4-7-cycloalkyleneimino-C.sub.1-5-alkyl,
carboxy-C.sub.0-5-alkyl,
C.sub.1-5-alkyloxycarbonyl-C.sub.0-5-alkyl,
aminocarbonyl-C.sub.0-5-alkyl,
C.sub.1-5-alkylaminocarbonyl-C.sub.0-5-alkyl,
di-(C.sub.1-5-alkyl)-aminocarbonyl-C.sub.0-5-alkyl,
C.sub.4-7-cycloalkyleneiminocarbonyl-C.sub.0-5-alkyl group, or two
groups R.sup.8b/R.sup.8c together with the cyclic carbon atom may
form a 3, 4, 5-, 6- or 7-membered saturated carbocyclic group or a
cyclopentene, cyclohexene, oxetane, azetidine, thietane,
tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran,
piperidine, pentamethylene sulphide, hexamethyleneimine,
hexahydropyridazine, tetrahydro-2(1H)-pyrimidinone,
[1,3]oxazinan-2-one ring, wherein the methylene groups thereof may
be substituted by 1-2 C.sub.1-3-alkyl or CF.sub.3-- groups, and/or
the methylene groups thereof, if they are not bound to a
heteroatom, may be substituted by 1-2 fluorine atoms, and/or
wherein a --CH.sub.2 group next to a nitrogen atom may be replaced
by a --CO group, and/or the imino groups of which may be
substituted in each case by a C.sub.1-3-alkyl or
C.sub.1-3-alkylcarbonyl group, and/or wherein the sulphur atom may
be oxidised to form a sulphoxide or sulphone group, with the
proviso that a heteroatom introduced by R.sup.8b or R.sup.8c may
not be separated from X in formula (I) by only one carbon atom, and
in all there should be no more than four groups selected from among
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.8a, R.sup.8b and R.sup.8c in
formula (II), and X denotes an oxygen or sulphur atom, a sulphene,
sulphone or an NR.sup.1 group, wherein R.sup.1 denotes a hydrogen
atom or a hydroxy, C.sub.1-3-alkyloxy, amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino, a C.sub.1-5-alkyl,
C.sub.2-5-alkenyl-CH.sub.2, C.sub.2-5-alkynyl-CH.sub.2,
C.sub.3-6-cycloalkyl, C.sub.4-6-cycloalkenyl, oxetan-3-yl,
tetrahydrofuran-3-yl, benzyl, C.sub.1-5-alkyl-carbonyl,
trifluoromethylcarbonyl, C.sub.3-6-cycloalkyl-carbonyl,
C.sub.1-5-alkyl-sulphonyl, C.sub.3-6-cycloalkyl-sulphonyl,
aminocarbonyl, C.sub.1-5-alkylaminocarbonyl,
di-(C.sub.1-5-alkyl)-aminocarbonyl, C.sub.1-5-alkyloxycarbonyl,
C.sub.4-7-cycloalkyleneiminocarbonyl group, wherein the methylene
and methyl groups present in the above-mentioned groups may
additionally be substituted by a C.sub.1-3-alkyl, carboxy,
C.sub.1-5-alkoxycarbonyl group or by a hydroxy, C.sub.1-5-alkyloxy,
amino, C.sub.1-5-alkylamino, C.sub.1-5-dialkylamino or
C.sub.4-7-cycloalkyleneimino group, provided that the methylene or
methyl groups are not directly bound to a heteroatom selected from
among O, N or S, and/or one to three hydrogen atoms may be replaced
by fluorine atoms, provided that the methylene or methyl groups are
not directly bound to a heteroatom selected from among O, N or S,
and wherein A.sup.1 denotes either N or Ce, A.sup.2 denotes either
N or CR.sup.11, A.sup.3 denotes either N or CR.sup.12, wherein
R.sup.10, R.sup.11, and R.sup.12 each independently of one another
represent a hydrogen, fluorine, chlorine, bromine or iodine atom,
or a C.sub.1-5-alkyl, CF.sub.3, C.sub.2-5-alkenyl,
C.sub.2-5-alkynyl, a cyano, carboxy, C.sub.1-5-alkyloxycarbonyl,
hydroxy, C.sub.1-3-alkyloxy, CF.sub.3O, CHF.sub.2O, CH.sub.2FO,
amino, C.sub.1-5-alkylamino, di-(C.sub.1-5-alkyl)-amino or
C.sub.4-7-cycloalkyleneimino group, or D denotes one of the four
groups (II-1), (II-2), (II-3) or (II-4) ##STR00211## wherein the
groups A1, A2, A3, K1, K2, K3, K4 are as hereinbefore defined, and
Anion in (II-4) denotes a fluoride, chloride, bromide, iodide,
sulphate, hydrogen sulphate, phosphate, hydrogen phosphate,
benzoate, salicylate, succinate, citrate or tartrate, R.sup.3
denotes a hydrogen atom or a C.sub.1-3-alkyl group, and R.sup.4 and
R.sup.5 each independently of one another represent a hydrogen
atom, a straight-chain or branched C.sub.1-6-alkyl,
C.sub.2-6-alkenyl or C.sub.2-6-alkynyl group, wherein the hydrogen
atoms of the methylene and/or methyl fragments of the
straight-chain or branched C.sub.1-6-alkyl, C.sub.2-6-alkenyl or
C.sub.2-6-alkynyl group may optionally be wholly or partly replaced
by fluorine atoms, and/or one or two hydrogen atoms of the
straight-chain or branched C.sub.1-6-alkyl, C.sub.2-6-alkenyl or
C.sub.2-6-alkynyl group in their methylene and/or methyl fragments
may optionally each be replaced independently of one another by a
C.sub.3-7-cycloalkyl group, a nitrile, hydroxy or
C.sub.1-5-alkyloxy group, wherein the hydrogen atoms of the
C.sub.1-5-alkyloxy group may optionally be wholly or partly
replaced by fluorine atoms, an allyloxy, propargyloxy,
phenylmethyloxy, phenethyloxy, C.sub.1-5-alkylcarbonyloxy,
C.sub.1-5-alkyloxycarbonyloxy, carboxy-C.sub.1-5-alkyloxy,
C.sub.1-5-alkyloxycarbonyl-C.sub.1-5-alkyloxy,
C.sub.1-5-alkyloxy-C.sub.2-5-alkyloxy, mercapto,
C.sub.1-5-alkylsulphanyl, C.sub.1-5-alkylsulphinyl,
C.sub.1-5-alkylsulphonyl, carboxy, C.sub.1-5-alkyloxycarbonyl,
aminocarbonyl, C.sub.1-5-alkylaminocarbonyl,
di-(C.sub.1-5-alkyl)-aminocarbonyl,
C.sub.1-5-alkyl-aminocarbonyloxy,
di-(C.sub.1-5-alkyl)-aminocarbonyloxy,
C.sub.4-7-cycloalkyleneiminocarbonyl, aminosulphonyl,
C.sub.1-5-alkylaminosulphonyl, di-(C.sub.1-5-alkyl)-aminosulphonyl,
C.sub.4-7-cycloalkyleneiminosulphonyl,
di-(C.sub.1-5-alkyl)-phosphoryl, amino, C.sub.1-5-alkylamino,
di-(C.sub.1-5-alkyl)-amino, C.sub.1-5-alkylcarbonylamino,
trifluoracetylamino,
C.sub.1-5-alkyloxy-C.sub.1-5-alkylcarbonylamino,
phenylcarbonylamino, C.sub.1-5-alkylaminocarbonylamino,
di-(C.sub.1-5-alkyl)-aminocarbonylamino,
C.sub.1-5-alkyloxy-carbonylamino, phenylmethyloxy-carbonylamino,
C.sub.1-5-alkyloxy-C.sub.2-5-alkyloxy-C.sub.1-2-alkylcarbonylamino,
C.sub.1-5-alkylsulphonylamino,
N--(C.sub.1-5-alkylsulphonyl)-C.sub.1-5-alkylamino,
C.sub.3-6-cycloalkylcarbonylamino group, 4-morpholinocarbonylamino,
or a morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl,
piperazinyl, tetrahydrofuranyl, tetrahydropyranyl group, wherein
the above-mentioned carbo- and heterocycles in the ring may each be
substituted by 1 to 4 C.sub.1-3-alkyl or C.sub.1-3-alkylcarbonyl
groups or may each be substituted by 1 or 2 oxo groups, and/or the
above-mentioned phenyl and heteroaryl groups may be replaced by 1
or 2 substituents selected from among fluorine, chlorine, bromine,
methyl, methoxy, amino or trifluoromethyl or two adjacent carbon
atoms of a phenyl ring may be substituted by a
--CH.sub.2--O--CH.sub.2 group, and/or the above-mentioned alkyl
groups may be substituted by a cyano-C.sub.1-5-alkyloxycarbonyl or
carboxy group, wherein the above-mentioned carboxylic acid or
sulphonic acid amide may optionally be additionally substituted at
the nitrogen by a C.sub.1-5-alkyl group, and/or the hydrogen atoms
of the sp.sup.2-hybridised carbon atoms of the straight-chain or
branched C.sub.2-6-alkenyl group may optionally be wholly or partly
replaced by fluorine atoms, a carboxy, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, C.sub.3-6-cycloalkylaminocarbonyl,
di-(C.sub.1-5-alkyl)-aminocarbonyl, C.sub.1-5-alkyloxycarbonyl,
C.sub.4-7-cycloalkyleneiminocarbonyl group, a phenyl, mono- or
bicyclic heteroaryl, phenyl-C.sub.1-5-alkyl or mono- or bicyclic
heteroaryl-C.sub.1-5-alkyl group, which may optionally be mono- to
trisubstituted in the phenyl or heteroaryl moiety by identical or
different substituents selected from among fluorine, chlorine,
bromine and iodine atoms, and C.sub.1-5-alkyl, trifluoromethyl,
benzyl, amino, nitro, C.sub.1-5-alkyl-amino,
di-(C.sub.1-5-alkyl)-amino, hydroxy, C.sub.1-5-alkyloxy, mono-, di-
or trifluoromethoxy, carboxy- and C.sub.1-5-alkyloxycarbonyl group,
or two adjacent carbon atoms of a phenyl ring may be substituted by
a --CH.sub.2--O--CH.sub.2 group, or a C.sub.3-7cycloalkyl,
morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl,
piperazinyl, tetrahydrofuranyl, tetrahydropyranyl group, which may
optionally be substituted by one to two groups selected
independently of one another from among C.sub.1-3-alkyl, acetyl,
C.sub.1-5-alkyloxycarbonyl, and hydroxycarbonyl, or R.sup.4 and
R.sup.5 together with the carbon atom to which they are bound, form
a C.sub.3-7-cycloalkyl or C.sub.5-7-cycloalkenyl group, wherein one
of the methylene groups of a C.sub.4-7-cycloalkyl group may be
replaced by an oxygen or sulphur atom or an --NH,
--N(C.sub.1-5-alkyl), --N(C.sub.1-4-alkylcarbonyl),
--N(C.sub.1-4-alkyloxycarbonyl)- or a carbonyl, sulphinyl or
sulphonyl group, and/or two directly adjacent methylene groups of a
C.sub.4-7-cycloalkyl group may together be replaced by a --C(O)NH,
--C(O)N(C.sub.1-5-alkyl), --S(O).sub.2NH, or
--S(O).sub.2N(C.sub.1-5-alkyl) group, and/or 1 to 3 carbon atoms of
a C.sub.3-7-cycloalkyl group may each optionally be substituted
independently of one another by one or two fluorine atoms or one or
two C.sub.1-5-alkyl groups or a hydroxy, C.sub.1-5-alkyloxy,
formyloxy, C.sub.1-5-alkylcarbonyloxy, C.sub.1-5-alkylsulphanyl,
C.sub.1-5-alkylsulphonyl, aminosulphonyl,
C.sub.1-5-alkylaminosulphonyl, di-(C.sub.1-5-alkyl)-aminosulphonyl,
C.sub.4-7-cycloalkyleneiminosulphonyl, amino, C.sub.1-5-alkylamino,
di-(C.sub.1-5-alkyl)-amino, C.sub.1-5-alkylcarbonylamino,
C.sub.1-5-alkylsulphonylamino,
N--(C.sub.1-5-alkylsulphonyl)-C.sub.1-5-alkylamino,
C.sub.3-6-cycloalkylcarbonylamino, Nitril, carboxy-C.sub.1-5-alkyl,
C.sub.1-5-alkyloxycarbonyl-C.sub.1-5-alkyl, carboxy,
C.sub.1-5-alkyloxycarbonyl, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, di-(C.sub.1-5-alkyl)-aminocarbonyl or
C.sub.4-7-cycloalkyleneiminocarbonyl group, and/or 1 to 2 carbon
atoms of a C.sub.5-7-cycloalkenyl group may optionally be
substituted independently of one another by in each case a
C.sub.1-5-alkyl, nitrile, carboxy-C.sub.1-5-alkyl,
C.sub.1-5-alkyloxycarbonyl-C.sub.1-5-alkyl, carboxy,
C.sub.1-5-alkyloxycarbonyl, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, di-(C.sub.1-5-alkyl)-aminocarbonyl,
C.sub.3-6-cycloalkyleneiminocarbonyl, aminosulphonyl,
C.sub.1-5-alkylaminosulphonyl, di-(C.sub.1-5-alkyl)-aminosulphonyl,
C.sub.3-6-cycloalkyleneiminosulphonyl groups or 1-2 fluorine atoms,
and/or 1 to 2 carbon atoms of a C.sub.4-7-cycloalkenyl group which
are not bound to another carbon atom by a double bond, may
optionally be substituted independently of one another by a
hydroxy, C.sub.1-5-alkyloxy, C.sub.1-5-alkylcarbonyloxy,
C.sub.1-5-alkylsulphanyl, C.sub.1-5-alkylsulphonyl, amino,
C.sub.1-5-alkylamino, di-(C.sub.1-5-alkyl)-amino,
C.sub.1-5-alkylcarbonylamino, C.sub.1-5-alkylsulphonylamino,
N--(C.sub.1-5-alkylsulphonyl)-C.sub.1-5-alkylamino or
C.sub.3-6-cycloalkylcarbonylamino groups, with the proviso that a
C.sub.3-7-cycloalkyl or C.sub.5-7-cycloalkenyl group of this kind
formed from R.sup.4 and R.sup.5 together, wherein two heteroatoms
in the cyclic group selected from among oxygen and nitrogen are
separated from one another by precisely one optionally substituted
--CH.sub.2 group, and/or wherein one or both methylene groups of
the cyclic group which are joined directly to the carbon atom to
which the groups R.sup.4 and R.sup.5 are linked, are replaced by a
heteroatom selected from among oxygen, nitrogen and sulphur, and/or
wherein a substituent bound to the cyclic group, which is
characterised in that a heteroatom selected from among oxygen,
nitrogen, sulphur and fluorine is bound directly to the cyclic
group, is separated from one other heteroatom selected from among
oxygen, nitrogen and sulphur, with the exception of the sulphone
group, by precisely one, optionally substituted, methylene group,
and/or wherein two atoms in the ring form an --O--O or --S--O--
bond, is excluded, M denotes a thiophene ring according to formula
(III), ##STR00212## which is bound to the carbonyl group in formula
(I) via the 2-position and which is substituted the in 5-position
by R.sup.2 and optionally additionally by R.sup.6, wherein R.sup.2
denotes a hydrogen, fluorine, chlorine, bromine or iodine atom or a
methoxy, C.sub.1-2-alkyl, formyl, NH.sub.2CO or ethynyl group,
R.sup.6 denotes a hydrogen, fluorine, chlorine, bromine or iodine
atom or a C.sub.1-2-alkyl or amino group,
wherein, unless otherwise stated, the term "heteroaryl group"
mentioned hereinbefore in the definitions denotes a monocyclic 5-
or 6-membered heteroaryl group, wherein the 6-membered heteroaryl
group contains one, two or three nitrogen atoms, and the 5-membered
heteroaryl group contains an imino group optionally substituted by
a C.sub.1-3-alkyl group, or an oxygen or sulphur atom, or an imino
group optionally substituted by a C.sub.1-3-alkyl group or an
oxygen or sulphur atom and additionally one or two nitrogen atoms,
or an imino group optionally substituted by a C.sub.1-3-alkyl group
and three nitrogen atoms, and moreover a phenyl ring optionally
substituted by a fluorine, chlorine or bromine atom, a
C.sub.1-3-alkyl, hydroxy, C.sub.1-3-alkyloxy group, amino,
C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)-amino or
C.sub.3-6-cycloalkyleneimino group phenyl ring may be fused to the
above-mentioned monocyclic heteroaryl groups via two adjacent
carbon atoms, and the bond is effected via a nitrogen atom or a
carbon atom of the heterocyclic moiety or a fused-on phenyl ring,
and wherein, unless otherwise stated, by the term "halogen atom"
mentioned hereinbefore in the definitions is meant an atom selected
from among fluorine, chlorine, bromine and iodine, and wherein the
alkyl, alkenyl, alkynyl and alkyloxy groups contained in the
previously mentioned definitions which have more than two carbon
atoms may, unless otherwise stated, be straight-chain or branched
and the alkyl groups in the previously mentioned dialkylated
groups, for example the dialkylamino groups, may be identical or
different, and the hydrogen atoms of the methyl or ethyl groups
contained in the foregoing definitions, unless otherwise stated,
may be wholly or partly replaced by fluorine atoms, the tautomers,
enantiomers, diastereomers, mixtures and salts thereof.
2. Compounds of general formula (I) according to claim 1, wherein D
denotes a substituted bicyclic ring system of formula (II),
##STR00213## wherein K.sup.1 and K.sup.4 each independently of one
another denote a --CH.sub.2, --CHR.sup.7a, --CR.sup.7bR.sup.7c or a
--C(O) group, wherein R.sup.7a/R.sup.7b/R.sup.7c each independently
of one another denote a fluorine atom, a hydroxy,
C.sub.1-5-alkyloxy group, a C.sub.1-5-alkyl group which may be
substituted by 1-3 fluorine atoms, a hydroxy-C.sub.1-5-alkyl,
C.sub.1-5-alkyloxy-C.sub.1-5-alkyl group, or a phenyl group which
may be substituted by 1-2 substituents selected from among a nitro,
amino, hydroxy-methoxy, cyano, C.sub.1-5-alkyl group or a fluorine,
chlorine or bromine atom, or a 5- or 6-membered heteroaryl group,
wherein the two groups R.sup.7b/R.sup.7c cannot both simultaneously
be bound to the cyclic carbon atom via a heteroatom, except if
--C(R.sup.7bR.sup.7c)-- corresponds to a --CF.sub.2 group, or two
groups R.sup.7b/R.sup.7c may form, together with the cyclic carbon
atom, a 3-, 4-, 5-, 6- or 7-membered saturated carbocyclic group or
a cyclopentene, cyclohexene, oxetane, tetrahydrofuran or
tetrahydropyran ring, wherein the methylene groups thereof may be
substituted by 1-2 C.sub.1-3-alkyl or CF.sub.3-- groups, and/or the
methylene groups thereof, if they are not bound to a heteroatom,
may be substituted by 1-2 fluorine atoms, and K.sup.2 and K.sup.3
each independently of one another represent a --CH.sub.2,
--CHR.sup.8a, --CR.sup.8bR.sup.8c or a --C(O)-- group, and
R.sup.8a/R.sup.8b/R.sup.8c each independently of one another denote
a C.sub.1-5-alkyl group which may be substituted by 1-3 fluorine
atoms, a hydroxy-C.sub.1-5-alkyl,
C.sub.1-5-alkyloxy-C.sub.1-5-alkyl group, or two groups
R.sup.8b/R.sup.8c may form, together with the cyclic carbon atom, a
3-, 4-, 5-, 6- or 7-membered carbocyclic group or a cyclopentene,
cyclohexene, oxetane, tetrahydrofuran, tetrahydropyran ring,
wherein the methylene groups thereof may be substituted by 1-2
C.sub.1-3-alkyl or CF.sub.3-- groups, and/or the methylene groups
thereof, if they are not bound to a heteroatom, may be substituted
by 1-2 fluorine atoms, with the proviso that a heteroatom
introduced by R.sup.8b or R.sup.8c must not be separated from X in
formula (I) by only one carbon atom, and in all in formula (II)
there should be no more than four groups selected from among
R.sup.7a, R.sup.7b, R.sup.7c, R.sup.8a, R.sup.8b and R.sup.8c, and
X denotes an oxygen or sulphur atom, a sulphene, sulphone or an
NR.sup.1 group, wherein R.sup.1 denotes a hydrogen atom or a
C.sub.1-5-alkyl, C.sub.2-5-alkenyl-CH.sub.2,
C.sub.2-5-alkynyl-CH.sub.2, C.sub.3-6-cycloalkyl,
C.sub.4-6-cycloalkenyl, oxetan-3-yl, tetrahydrofuran-3-yl, benzyl,
C.sub.1-5-alkyl-carbonyl, trifluoromethylcarbonyl,
C.sub.3-6-cycloalkyl-carbonyl, C.sub.1-5-alkyl-sulphonyl,
C.sub.3-6-cycloalkyl-sulphonyl, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, di-(C.sub.1-5-alkyl)-aminocarbonyl,
C.sub.1-5-alkyloxycarbonyl, C.sub.4-7-cycloalkyleneiminocarbonyl
group, wherein the methylene and methyl groups present in the
above-mentioned groups may additionally be substituted by a
C.sub.1-3-alkyl, carboxy, C.sub.1-5-alkoxycarbonyl group or by a
hydroxy, C.sub.1-5-alkyloxy, amino, C.sub.1-5-alkylamino,
C.sub.1-5-dialkylamino or C.sub.4-7-cycloalkyleneimino group,
provided that the methylene or methyl groups are not directly bound
to a heteroatom selected from among O, N or S, and/or one to three
hydrogen atoms may be replaced by fluorine atoms, provided that the
methylene or methyl groups are not directly bound to a heteroatom
selected from among O, N or S, and wherein A.sup.1, A.sup.2, and
A.sup.3 are each defined as described in the 1st embodiment, or D
denotes one of the four groups (II-1a), (II-2a), (II-3) or (II-4)
##STR00214## wherein the groups A1, A2, A3, K1, K2, K3, K4 are as
hereinbefore defined, and Anion in (II-4) denotes a fluoride,
chloride, bromide, iodide, sulphate, hydrogen sulphate, phosphate,
hydrogen phosphate, benzoate, salicylate, succinate, citrate or
tartrate, and R.sup.3 denotes a hydrogen atom, and R.sup.4, R.sup.5
and M are each defined as described in the 1st embodiment, the
tautomers, enantiomers, diastereomers, mixtures and salts
thereof.
3. Compounds of general formula (I) according to claim 1, wherein D
denotes a substituted bicyclic ring system of formula (II),
##STR00215## wherein K1, K2, K3 and K4 are defined as in claim 1,
and X denotes an NR.sup.1 group, wherein R.sup.1 denotes a hydrogen
atom or a C.sub.1-5-alkyl, C.sub.2-5-alkenyl-CH.sub.2,
C.sub.2-5-alkynyl-CH.sub.2, C.sub.3-6-cycloalkyl,
C.sub.4-6-cycloalkenyl group, wherein the methylene and methyl
groups present in the above-mentioned groups may additionally be
substituted by a C.sub.1-3-alkyl, carboxy, C.sub.1-5-alkoxycarbonyl
group or by a hydroxy, C.sub.1-5-alkyloxy, amino,
C.sub.1-5-alkylamino, C.sub.1-5-dialkylamino or
C.sub.4-7-cycloalkyleneimino group, provided that the methylene or
methyl groups are not directly bound to a heteroatom selected from
among O, N or S, and/or one to three hydrogen atoms may be replaced
by fluorine atoms, so long as the methylene or methyl groups are
not directly bound to the nitrogen atom, and wherein A.sup.1
denotes either N or CR.sup.10, A.sup.2 denotes either N or
CR.sup.11, A.sup.3 denotes either N or CR.sup.12, wherein R.sup.10,
R.sup.11 and R.sup.12 each independently of one another represent a
hydrogen, fluorine, chlorine, bromine atom or a C.sub.1-5-alkyl,
CF.sub.3, a cyano, carboxy, C.sub.1-5-alkyloxycarbonyl, hydroxy,
C.sub.1-3-alkyloxy, CF.sub.3O, CHF.sub.2O, CH.sub.2FO-- group, or D
denotes one of the four groups (II-1a), (II-2a), (II-3) or (II-4)
##STR00216## wherein the groups A1, A2, A3, K1, K2, K3, K4 are as
hereinbefore defined, and Anion in (II-4) may be selected from
among fluoride, chloride, bromide, iodide, sulphate, phosphate,
benzoate, salicylate, succinate, citrate and tartrate, and R.sup.3,
R.sup.4, R.sup.5 and M are each defined as in 1, wherein R.sup.6
denotes a hydrogen atom, the tautomers, enantiomers, diastereomers,
mixtures and salts thereof.
4. Compounds of general formula (I) according to claim 1, wherein
D, R.sup.3 and M are each defined as in claim 1, and R.sup.4
denotes a straight-chain or branched C.sub.3-6-alkenyl or
C.sub.3-6-alkynyl group, a straight-chain or branched
C.sub.1-6-alkyl group, wherein the hydrogen atoms of the
straight-chain or branched C.sub.1-6-alkyl group may optionally be
wholly or partly replaced by fluorine atoms, and wherein optionally
one to two hydrogen atoms may be replaced independently of one
another by a C.sub.3-7-cycloalkyl, hydroxy, C.sub.1-5-alkyloxy,
phenylmethyloxy, phenethyloxy, carboxy-C.sub.1-5-alkyloxy,
C.sub.1-5-alkyloxycarbonyl-C.sub.1-5-alkyloxy,
C.sub.1-5-alkyloxy-C.sub.2-5-alkyloxy, C.sub.1-5-alkylsulphanyl,
C.sub.1-5-alkylsulphinyl, C.sub.1-5-alkylsulphonyl, carboxy,
C.sub.1-5-alkyloxycarbonyl, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, di-(C.sub.1-5-alkyl)-aminocarbonyl,
C.sub.1-5-alkyl-aminocarbonyloxy,
di-(C.sub.1-5-alkyl)-aminocarbonyloxy,
C.sub.4-7-cycloalkyleneiminocarbonyl, amino, C.sub.1-5-alkylamino
or di-(C.sub.1-5-alkyl)-amino group C.sub.1-5-alkylcarbonylamino,
trifluoracetylamino,
C.sub.1-5-alkyloxy-C.sub.1-5-alkylcarbonylamino,
phenylcarbonylamino, C.sub.1-5-alkylaminocarbonylamino,
di-(C.sub.1-5-alkyl)-aminocarbonylamino,
C.sub.1-5-alkyloxy-carbonylamino, phenylmethyloxy-carbonylamino,
C.sub.1-5-alkyloxy-C.sub.2-5-alkyloxy-C.sub.1-2-alkylcarbonylamino,
C.sub.1-5-alkylsulphonylamino, C.sub.3-6-cycloalkylcarbonylamino
group, 4-morpholinocarbonylamino-group, wherein the above-mentioned
carbo- and heterocycles in the ring may each be substituted by 1 to
4 C.sub.1-3-alkyl or C.sub.1-3-alkylcarbonyl groups or may each be
substituted by 1 or 2 oxo groups, and/or the above-mentioned phenyl
and heteroaryl groups may be replaced by 1 to 2 substituents
selected from among fluorine, chlorine, bromine, methyl, methoxy,
or trifluoromethyl, or two adjacent carbon atoms of a phenyl ring
may be substituted by a --CH.sub.2--O--CH.sub.2 group, and/or the
above-mentioned alkyl groups may be substituted by a
cyano-C.sub.1-5-alkyloxycarbonyl or carboxy group, wherein the
above-mentioned carboxylic acid or sulphonic acid amide may
optionally additionally be substituted at the nitrogen by a
C.sub.1-5-alkyl group, a phenyl, phenyl-C.sub.1-2-alkyl,
heteroaryl-C.sub.1-2-alkyl or C-linked heteroaryl group, wherein
the heteroaryl group is selected from among imidazolyl, furanyl,
thiophenyl, thiazolyl, pyrazolyl, tetrazolyl, benzimidazolyl,
indolyl, pyrimidinyl, pyrazinyl-oxazolyl, 1,2,4-triazolyl and
pyridinyl, and which may optionally be mono- to disubstituted in
the phenyl or heteroaryl moiety by identical or different
substituents selected from among chlorine or fluorine atoms or
C.sub.1-3-alkyl, benzyl, hydroxy, amino, CF.sub.3, CH.sub.3O-- or
CHF.sub.2O-- groups, R.sup.5 denotes a hydrogen atom, a
straight-chain or branched C.sub.1-4-alkyl group, wherein the
hydrogen atoms of the straight-chain or branched C.sub.1-4-alkyl
groups may optionally be wholly or partly replaced by fluorine
atoms, or a propargyl or C.sub.1-3alkyloxy-C.sub.1-3-alkyl group,
or R.sup.4 and R.sup.5 together with the carbon atom to which they
are bound, form a C.sub.5-6-cycloalkenyl or C.sub.3-7-cycloalkyl
group, wherein one of the methylene groups of a
C.sub.4-7-cycloalkyl group may be replaced by an oxygen or sulphur
atom or an --NH--, --N(C.sub.1-5-alkyl),
--N(C.sub.1-4-alkylcarbonyl), carbonyl, sulphinyl or a sulphonyl
group, or two immediately adjacent methylene groups of a
C.sub.4-7-cycloalkyl group may together be replaced by a --C(O)NH,
--C(O)N(C.sub.1-5-alkyl), --S(O).sub.2NH-- or
--S(O).sub.2N(C.sub.1-5-alkyl) group, and/or 1 to 2 carbon atoms of
a C.sub.3-7-cycloalkyl group may optionally be substituted
independently of one another by in each case one or two fluorine
atoms or one or two C.sub.1-5-alkyl groups or a hydroxy,
C.sub.1-5-alkyloxy, formyloxy, amino, C.sub.1-5-alkylamino,
di-(C.sub.1-5-alkyl)-amino, C.sub.1-5-alkylcarbonylamino,
C.sub.3-6-cycloalkylcarbonylamino, nitrile, carboxy,
C.sub.1-5-alkyloxycarbonyl, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, di-(C.sub.1-5-alkyl)-aminocarbonyl or
C.sub.4-7-cycloalkyleneiminocarbonyl group, with the proviso that a
C.sub.3-7-cycloalkyl group of this kind, formed from R.sup.4 and
R.sup.5 together, wherein two heteroatoms in the cyclic group
selected from among oxygen and nitrogen are separated from one
another by precisely one optionally substituted --CH.sub.2 group,
and/or wherein one or both methylene groups of the cyclic group
which are joined directly to the carbon atom to which the groups
R.sup.4 and R.sup.5 are bound, are replaced by a heteroatom
selected from among oxygen, nitrogen and sulphur, and/or wherein a
substituent bound to the cyclic group, which is characterised in
that a heteroatom selected from among oxygen, nitrogen, sulphur and
fluorine atom is bound directly to the cyclic group, is separated
from another heteroatom selected from among oxygen, nitrogen and
sulphur by precisely one optionally substituted methylene group,
and/or wherein two atoms in the ring form a --O--O or --S--O--
bond, is excluded, the tautomers, enantiomers, diastereomers,
mixtures and salts thereof.
5. Compounds of general formula (I) according to claim 1, wherein D
denotes a substituted bicyclic ring system of formula (II),
##STR00217## wherein K.sup.1 and K.sup.4 each independently of one
another represent a --CH.sub.2, --CHR.sup.7a or a
--CR.sup.7bR.sup.7c-group, wherein R.sup.7a/R.sup.7b/R.sup.7c each
independently of one another denote a C.sub.1-2-alkyl group or a
phenyl group which may be substituted by 1 or 2 substituents
selected from among a nitro, amino, hydroxyl, methoxy, cyano,
C.sub.1-5-alkyl group or a fluorine, chlorine or bromine atom,
K.sup.2 and K.sup.3 each denote a --CH.sub.2 group X denotes an
NR.sup.1 group, wherein R.sup.1 denotes a hydrogen atom or a
C.sub.1-5-alkyl, C.sub.2-4-alkenyl-CH.sub.2,
C.sub.2-4-alkynyl-CH.sub.2 or C.sub.3-6-cycloalkyl group, wherein
the methylene and methyl groups present in the previously mentioned
C.sub.2-5-alkyl groups may be substituted by one to three fluorine
atoms, as long as the methylene or methyl groups are not directly
bound to the nitrogen atom, and wherein A.sup.1 denotes either N or
CR.sup.10, A.sup.2 denotes either N or CR.sup.11, A.sup.3 denotes
either N or CR.sup.12, wherein R.sup.10, R.sup.11 and R.sup.12 each
independently of one another represent a hydrogen, fluorine or
chlorine atom, or a C.sub.1-3-alkyl, CF.sub.3, hydroxy or
CH.sub.3O-- group, or D denotes one of the groups (II-3) or (II-4)
##STR00218## wherein the groups A1, A2, A3, K1, K2, K3, K4 are as
hereinbefore defined, and the anion in (II-4) may be selected from
among fluoride, chloride, bromide, iodide, sulphate, phosphate,
benzoate, salicylate, succinate, citrate or tartrate, and R.sup.3
denotes a hydrogen atom, R.sup.4 denotes a straight-chain or
branched C.sub.3-6-alkenyl or C.sub.3-6-alkynyl group, a
straight-chain or branched C.sub.1-4-alkyl group, wherein the
hydrogen atoms of the straight-chain or branched C.sub.1-4-alkyl
group may optionally be partially replaced by up to four fluorine
atoms, and wherein optionally one to two hydrogen atoms may be
replaced independently of one another by a C.sub.3-7-cycloalkyl,
hydroxy, C.sub.1-5-alkyloxy, phenylmethyloxy,
C.sub.1-5-alkylsulphanyl, C.sub.1-5-alkylsulphinyl,
C.sub.1-5-alkylsulphonyl, carboxy, C.sub.1-5-alkyloxycarbonyl,
aminocarbonyl, C.sub.1-5-alkylaminocarbonyl,
di-(C.sub.1-5-alkyl)-aminocarbonyl,
C.sub.4-7-cycloalkyleneiminocarbonyl, amino, C.sub.1-5-alkylamino
or di-(C.sub.1-5-alkyl)-amino, C.sub.1-5-alkylcarbonylamino,
carboxy-C.sub.1-5-alkylcarbonylamino or a
C.sub.1-5-alkyloxycarbonyl-C.sub.1-5-alkylcarbonylamino group,
wherein the above-mentioned phenyl groups may be replaced by 1 or 2
substituents selected from fluorine, chlorine, bromine, methyl,
methoxy, or trifluoromethyl, or wherein the above-mentioned
carboxylic acid amide may optionally be additionally substituted at
the nitrogen by a C.sub.1-5-alkyl group, a phenyl,
phenyl-C.sub.1-2-alkyl, heteroaryl-C.sub.1-2-alkyl or C-linked
heteroaryl group, wherein the heteroaryl group is selected from
among imidazolyl, furanyl, thiophenyl, thiazolyl, pyrazolyl,
tetrazolyl, benzimidazolyl, indolyl, pyrimidinyl, pyrazinyl,
oxazolyl, and pyridinyl, and which may optionally be mono- to
disubstituted in the phenyl or heteroaryl moiety by identical or
different substituents selected from among chlorine or fluorine
atoms or C.sub.1-3-alkyl, CF.sub.3, HO, CH.sub.3O or CHF.sub.2O--
groups, R.sup.5 denotes a hydrogen atom, a straight-chain or
branched C.sub.1-4-alkyl group, a propargyl or
C.sub.1-3-alkyloxy-C.sub.1-3-alkyl group, or R.sup.4 and R.sup.5
together with the carbon atom to which they are bound form a
C.sub.5-6-cycloalkenyl or C.sub.3-7-cycloalkyl group, wherein one
of the methylene groups of a C.sub.4-7-cycloalkyl group may be
replaced by an oxygen or sulphur atom or a sulphonyl group, or 1 to
2 carbon atoms of a C.sub.3-7-cycloalkyl group may optionally be
substituted independently of one another by in each case one or two
fluorine atoms, or one or two C.sub.1-5-alkyl groups, or a hydroxy,
C.sub.1-5-alkyloxy, formyloxy, nitrile, carboxy,
C.sub.1-5-alkyloxycarbonyl, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, di-(C.sub.1-5-alkyl)-aminocarbonyl or
C.sub.4-7-cycloalkyleneiminocarbonyl group, with the proviso that a
C.sub.3-7-cycloalkyl group of this kind formed from R.sup.4 and
R.sup.5 together, wherein one of the methylene groups of the cyclic
group which is linked directly to the carbon atom to which the
groups R.sup.4 and R.sup.5 are bound, is replaced by an oxygen or
sulphur atom, is excluded, and M denotes a thiophene ring according
to formula (III), ##STR00219## which is bound to the carbonyl group
in formula (I) via the 2-position and is substituted by R.sup.2 in
the 5-position, where R.sup.2 denotes a chlorine or bromine atom or
an ethynyl group, and R.sup.6 denotes a hydrogen atom, wherein the
alkyl, alkenyl, alkynyl and alkyloxy groups contained in the
previously mentioned definitions which have more than two carbon
atoms may, unless otherwise stated, be straight-chain or branched
and the alkyl groups in the previously mentioned dialkylated
groups, for example the dialkylamino groups, may be identical or
different, the tautomers, enantiomers, diastereomers, mixtures and
salts thereof.
6. Compounds of general formula (I) according to claim 1, wherein
the group D denotes a substituted bicyclic ring system of formula
(II), ##STR00220## wherein K.sup.1 and K.sup.4 each independently
of one another represent a --CH.sub.2, --CHR.sup.7a or a
--CR.sup.7bR.sup.7c-group, where R.sup.7a/R.sup.7b/R.sup.7c each
independently of one another denote a C.sub.1-2-alkyl group,
K.sup.2 and K.sup.3 each denote a --CH.sub.2 group, X denotes an
NR.sup.1 group, wherein R.sup.1 denotes a hydrogen atom or a
C.sub.1-5-alkyl or C.sub.3-6-cycloalkyl group, wherein in the
methylene and methyl groups present in the above-mentioned groups
one to three hydrogen atoms may be replaced by fluorine atoms,
provided that the methylene or methyl groups are not directly bound
to the nitrogen atom, and wherein A.sup.1 denotes CR.sup.10,
A.sup.2 denotes CR.sup.11, A.sup.3 denotes CR.sup.12, where
R.sup.10, R.sup.11 and R.sup.12 each independently of one another
represent a hydrogen, fluorine or chlorine atom, or a
C.sub.1-3-alkyl, CF.sub.3, HO, CH.sub.3O-- group, or D denotes the
group (II-4) ##STR00221## wherein the groups A1, A2, A3, K1, K2,
K3, K4 are as hereinbefore defined, and the anion in (II-4) may be
selected from among fluoride, chloride, bromide, iodide, sulphate,
phosphate, benzoate, salicylate, succinate, citrate or tartrate,
the tautomers, enantiomers, diastereomers, mixtures and salts
thereof.
7. Compounds of general formula (I) according to claim 1, wherein
neither R.sup.4 nor R.sup.5 may represent a hydrogen atom, the
tautomers, enantiomers, diastereomers, mixtures and salts
thereof.
8. Compounds of general formula (I) according to claim 1, wherein
R.sup.4 and R.sup.5 together with the carbon atom to which they are
bound, form a C.sub.5-6-cycloalkenyl or C.sub.3-7-cycloalkyl group,
wherein one of the methylene groups of a C.sub.4-7-cycloalkyl group
may be replaced by an oxygen or sulphur atom, with the proviso that
a C.sub.3-7-cycloalkyl group of this kind formed from R.sup.4 and
R.sup.5 together, wherein one of the methylene groups of the cyclic
group, which is linked directly to the carbon atom, to which the
groups R.sup.4 and R.sup.5 are bound, is replaced by an oxygen or
sulphur atom, is excluded, the tautomers, enantiomers,
diastereomers, mixtures and salts thereof.
9. Physiologically acceptable salts of the compounds according to
claim 1.
10. Pharmaceutical compositions comprising a compound according to
claim 1 or a physiologically acceptable salt thereof optionally
together with one or more inert carriers and/or diluents.
11. Use of a compound according to claim 1 or a physiologically
acceptable salt thereof for preparing a pharmaceutical composition
with an inhibitory effect on factor Xa and/or an inhibitory effect
on related serine proteases.
12. Process for preparing a pharmaceutical composition according to
claim 10, wherein a compound according to claim 1 or a
physiologically acceptable salt thereof is incorporated in one or
more inert carriers and/or diluents by a non-chemical method.
Description
[0001] The present invention relates to new substituted
glycinamides of general formula (I)
##STR00002##
the tautomers, enantiomers, diastereomers, mixtures and salts
thereof, particularly the physiologically acceptable salts thereof
with inorganic or organic acids or bases, which have valuable
properties.
[0002] The compounds of the above general formula (I) as well as
the tautomers, enantiomers, diastereomers, mixtures and salts
thereof, particularly the physiologically acceptable salts thereof
with inorganic or organic acids or bases, and the stereoisomers
thereof, have valuable pharmacological properties, particularly an
antithrombotic activity and a factor Xa-inhibiting activity.
[0003] The present application relates to new compounds of the
above general formula (I), the preparation thereof, the
pharmaceutical compositions containing the pharmacologically
effective compounds, the preparation and use thereof.
[0004] A 1st embodiment of the present invention includes those
compounds of general formula (I) wherein
D denotes a substituted bicyclic ring system of formula (II),
##STR00003## [0005] wherein [0006] K.sup.1 and K.sup.4 [0007] each
independently of one another denote a --CH.sub.2, --CHR.sup.7a,
--CR.sup.7bR.sup.7c or a --C(O) group, and [0008]
R.sup.7a/R.sup.7b/R.sup.7c [0009] each independently of one another
denote a fluorine atom, a hydroxy, C.sub.1-5-alkyloxy,
tetrahydrofuranyl, oxetanyl, amino, C.sub.1-5-alkylamino,
di-(C.sub.1-5-alkyl)-amino, C.sub.3-5-cycloalkyleneimino or
C.sub.1-5-alkylcarbonylamino group, [0010] a C.sub.1-5-alkyl group
which may be substituted by 1-3 fluorine atoms, a
hydroxy-C.sub.1-5-alkyl, C.sub.1-5-alkyloxy-C.sub.1-5-alkyl,
amino-C.sub.1-5-alkyl, C.sub.1-5-alkylamino-C.sub.1-5-alkyl,
di-(C.sub.1-5-alkyl)-amino-C.sub.1-5-alkyl,
C.sub.4-7-cycloalkyleneimino-C.sub.1-5-alkyl,
carboxy-C.sub.1-5-alkyl,
C.sub.1-5-alkyloxycarbonyl-C.sub.1-5-alkyl,
aminocarbonyl-C.sub.1-5-alkyl,
C.sub.1-5-alkylaminocarbonyl-C.sub.1-5-alkyl,
di-(C.sub.1-5-alkyl)-aminocarbonyl-C.sub.0-5-alkyl,
C.sub.4-7-cycloalkyleneiminocarbonyl-C.sub.0-5-alkyl-group, a
phenyl group or a 5- or 6-membered heteroaryl group which may be
substituted by 1-2 substituents selected from among a nitro, amino,
hydroxy, methoxy, cyano, C.sub.1-5-alkyl group or a fluorine,
chlorine or bromine atom, [0011] wherein the two groups
R.sup.7b/R.sup.7c cannot both simultaneously be bound to the cyclic
carbon atom via a heteroatom, except if --C(R.sup.7bR.sup.7c)--
corresponds to a --CF.sub.2 group, [0012] or [0013] two groups
R.sup.7b/R.sup.7c together with the cyclic carbon atom may form a
3, 4, 5-, 6- or 7-membered saturated carbocyclic group or a
cyclopentene, cyclohexene, oxetane, azetidine, thietane,
tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran,
piperidine, pentamethylene sulphide, hexamethyleneimine,
1,3-dioxolane, 1,4-dioxane, hexahydropyridazine, piperazine,
thiomorpholine, morpholine, 2-imidazolidinone, 2-oxazolidinone,
tetrahydro-2(1H)-pyrimidinone, [1,3]oxazinan-2-one ring, [0014]
wherein the methylene groups thereof may be substituted by 1-2
C.sub.1-3-alkyl or CF.sub.3-- groups, and/or [0015] the methylene
groups thereof, if they are not bound to a heteroatom, may be
substituted by 1-2 fluorine atoms, and/or [0016] wherein a
--CH.sub.2 group adjacent to an N atom may be replaced by a --CO
group, and/or [0017] the imino groups of which may be substituted
in each case by a C.sub.1-3-alkyl or C.sub.1-3-alkylcarbonyl group,
and/or wherein the sulphur atom may be oxidised to form a
sulphoxide or sulphone group, [0018] K.sup.2 and K.sup.3 [0019]
each independently of one another denote a --CH.sub.2,
--CHR.sup.8a, --CR.sup.8bR.sup.8c or a --C(O)-- group, and [0020]
R.sup.8a/R.sup.8b/R.sup.8c [0021] each independently of one another
denote a C.sub.1-5-alkyl group which may be substituted by 1-3
fluorine atoms, a hydroxy-C.sub.1-5-alkyl,
C.sub.1-5-alkyloxy-C.sub.1-5-alkyl, amino-C.sub.1-5-alkyl,
C.sub.1-5-alkylamino-C.sub.1-5-alkyl,
di-(C.sub.1-5-alkyl)-amino-C.sub.1-5-alkyl,
C.sub.4-7-cycloalkyleneimino-C.sub.1-5-alkyl,
carboxy-C.sub.0-5-alkyl,
C.sub.1-5-alkyloxycarbonyl-C.sub.0-5-alkyl,
aminocarbonyl-C.sub.0-5-alkyl,
C.sub.1-5-alkylaminocarbonyl-C.sub.0-5-alkyl,
di-(C.sub.1-5-alkyl)aminocarbonyl-C.sub.0-5-alkyl,
C.sub.4-7-cycloalkyleneiminocarbonyl-C.sub.0-5-alkyl group, [0022]
or two groups R.sup.8b/R.sup.8c together with the cyclic carbon
atom may form a 3, 4, 5-, 6- or 7-membered saturated carbocyclic
group or a cyclopentene, cyclohexene, oxetane, azetidine, thietane,
tetrahydrofuran, pyrrolidine, tetrahydrothiophene, tetrahydropyran,
piperidine, pentamethylene sulphide, hexamethyleneimine,
hexahydropyridazine, tetrahydro-2(1H)-pyrimidinone,
[1,3]oxazinan-2-one ring, [0023] wherein the methylene groups
thereof may be substituted by 1-2 C.sub.1-3-alkyl or CF.sub.3--
groups, and/or the methylene groups thereof, if they are not bound
to a heteroatom, may be substituted by 1-2 fluorine atoms, and/or
[0024] wherein a --CH.sub.2 group next to a nitrogen atom may be
replaced by a --CO group, and/or the imino groups of which may be
substituted in each case by a C.sub.1-3-alkyl or
C.sub.1-3-alkylcarbonyl group, and/or wherein the sulphur atom may
be oxidised to form a sulphoxide or sulphone group, [0025] with the
proviso that a heteroatom introduced by R.sup.8b or R.sup.8c may
not be separated from X in formula (I) by only one carbon atom, and
[0026] in all there should be no more than four groups selected
from among R.sup.7a, R.sup.7b, R.sup.7c, R.sup.8a, R.sup.8b and
R.sup.8c in formula (II), and [0027] X denotes an oxygen or sulphur
atom, a sulphene, sulphone or an NR.sup.1 group, wherein [0028]
R.sup.1 denotes a hydrogen atom or a hydroxy, C.sub.1-3-alkyloxy,
amino, C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)-amino, a
C.sub.1-5-alkyl, C.sub.2-5-alkenyl-CH.sub.2,
C.sub.2-5-alkynyl-CH.sub.2, C.sub.3-6-cycloalkyl,
C.sub.4-6-cycloalkenyl, oxetan-3-yl, tetrahydrofuran-3-yl, benzyl,
alkyl-carbonyl, trifluoromethylcarbonyl,
C.sub.3-6-cycloalkyl-carbonyl, C.sub.1-5-alkyl-sulphonyl,
C.sub.3-6-cycloalkyl-sulphonyl, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, di-(C.sub.1-5-alkyl)-aminocarbonyl,
C.sub.1-5-alkyloxycarbonyl, C.sub.4-7-cycloalkyleneiminocarbonyl
group, [0029] wherein the methylene and methyl groups present in
the above-mentioned groups may additionally be substituted by a
C.sub.1-3-alkyl, carboxy, C.sub.1-5-alkoxycarbonyl group or by a
hydroxy, C.sub.1-5-alkyloxy, amino, C.sub.1-5-alkylamino,
C.sub.1-5-dialkylamino or C.sub.4-7-cycloalkyleneimino group,
provided that the methylene or methyl groups are not directly bound
to a heteroatom selected from among O, N or S, and/or [0030] one to
three hydrogen atoms may be replaced by fluorine atoms, provided
that the methylene or methyl groups are not directly bound to a
heteroatom selected from among O, N or S, [0031] and wherein [0032]
A.sup.1 denotes either N or CR.sup.10, [0033] A.sup.2 denotes
either N or CR.sup.11, [0034] A.sup.3 denotes either N or
CR.sup.12, [0035] wherein R.sup.10, R.sup.11 and R.sup.12 each
independently of one another represent [0036] a hydrogen, fluorine,
chlorine, bromine or iodine atom, or a C.sub.1-5-alkyl, CF.sub.3,
C.sub.2-5-alkenyl, C.sub.2-5-alkynyl, a cyano, carboxy,
C.sub.1-5-alkyloxycarbonyl, hydroxy, C.sub.1-3-alkyloxy, CF.sub.3O,
CHF.sub.2O, CH.sub.2FO, amino, C.sub.1-5-alkylamino,
di-(C.sub.1-5-alkyl)-amino or C.sub.4-7-cycloalkyleneimino group,
or D denotes one of the four groups (II-1), (II-2), (II-3) or
(II-4)
[0036] ##STR00004## [0037] wherein the groups A1, A2, A3, K1, K2,
K3, K4 are as hereinbefore defined, and [0038] Anion in (II-4)
denotes a fluoride, chloride, bromide, iodide, sulphate, hydrogen
sulphate, phosphate, hydrogen phosphate, benzoate, salicylate,
succinate, citrate or tartrate, R.sup.3 denotes a hydrogen atom or
a C.sub.1-3-alkyl group, and R.sup.4 and R.sup.5 each independently
of one another represent [0039] a hydrogen atom, [0040] a
straight-chain or branched C.sub.1-6-alkyl, C.sub.2-6-alkenyl or
C.sub.2-6-alkynyl group, [0041] wherein the hydrogen atoms of the
methylene and/or methyl fragments of the straight-chain or branched
C.sub.1-6-alkyl, C.sub.2-6-alkenyl or C.sub.2-6-alkynyl group may
optionally be wholly or partly replaced by fluorine atoms, and/or
[0042] one or two hydrogen atoms of the straight-chain or branched
C.sub.1-6-alkyl, C.sub.2-6-alkenyl or C.sub.2-6-alkynyl group in
their methylene independently of one another by a
C.sub.3-7-cycloalkyl group, a nitrile, hydroxy or
C.sub.1-5-alkyloxy group, [0043] wherein the hydrogen atoms of the
C.sub.1-5-alkyloxy group may [0044] optionally be wholly or partly
replaced by fluorine atoms, an allyloxy, propargyloxy,
phenylmethyloxy, phenethyloxy, C.sub.1-5-alkylcarbonyloxy,
C.sub.1-5-alkyloxycarbonyloxy, carboxy-C.sub.1-5-alkyloxy,
C.sub.1-5-alkyloxycarbonyl-C.sub.1-5-alkyloxy,
C.sub.1-5-alkyloxy-C.sub.2-5-alkyloxy, mercapto,
C.sub.1-5-alkylsulphanyl, C.sub.1-5-alkylsulphinyl,
C.sub.1-5-alkylsulphonyl, carboxy, C.sub.1-5-alkyloxycarbonyl,
aminocarbonyl, C.sub.1-5-alkylaminocarbonyl,
di-(C.sub.1-5-alkyl)-aminocarbonyl,
C.sub.1-5-alkyl-aminocarbonyloxy,
di-(C.sub.1-5-alkyl)-aminocarbonyloxy,
C.sub.4-7-cycloalkyleneiminocarbonyl, aminosulphonyl,
C.sub.1-5-alkylaminosulphonyl, di-(C.sub.1-5-alkyl)-aminosulphonyl,
C.sub.4-7-cycloalkyleneiminosulphonyl,
di-(C.sub.1-5-alkyl)-phosphoryl, amino, C.sub.1-5-alkylamino,
di-(C.sub.1-5-alkyl)-amino, C.sub.1-5-alkylcarbonylamino,
trifluoracetylamino,
C.sub.1-5-alkyloxy-C.sub.1-5-alkylcarbonylamino,
phenylcarbonylamino, C.sub.1-5-alkylaminocarbonylamino,
di-(C.sub.1-5-alkyl)-aminocarbonylamino,
C.sub.1-5-alkyloxy-carbonylamino, phenylmethyloxy-carbonylamino,
C.sub.1-5-alkyloxy-C.sub.2-5-alkyloxy-C.sub.1-2-alkylcarbonylamino,
C.sub.1-5-alkylsulphonylamino,
N--(C.sub.1-5-alkylsulphonyl)-C.sub.1-5-alkylamino,
C.sub.3-6-cycloalkylcarbonyl-amino group,
4-morpholinocarbonylamino, or a morpholinyl, thiomorpholinyl,
pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl,
tetrahydropyranyl group, [0045] wherein the above-mentioned carbo-
and heterocycles in the ring may each be substituted by 1 to 4
C.sub.1-3-alkyl or C.sub.1-3-alkylcarbonyl groups or may each be
substituted by 1 or 2 oxo groups, and/or [0046] the above-mentioned
phenyl and heteroaryl groups may be replaced by 1 or 2 substituents
selected from among fluorine, chlorine, bromine, methyl, methoxy,
amino or trifluoromethyl or two adjacent carbon atoms of a phenyl
ring may be substituted by a --CH.sub.2--O--CH.sub.2 group, and/or
the above-mentioned alkyl groups may be substituted by a
cyano-C.sub.1-5-alkyloxycarbonyl or carboxy group, [0047] wherein
the above-mentioned carboxylic acid or sulphonic acid amide may
optionally be additionally substituted at the nitrogen by a
C.sub.1-5-alkyl group, [0048] and/or the hydrogen atoms of the
sp.sup.2-hybridised carbon atoms of the straight-chain or branched
C.sub.2-6-alkenyl group may optionally be wholly or partly replaced
by fluorine atoms, [0049] a carboxy, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, C.sub.3-6-cycloalkylamino-carbonyl,
di-(C.sub.1-5-alkyl)-aminocarbonyl, C.sub.1-5-alkyloxycarbonyl,
C.sub.4-7-cycloalkyleneiminocarbonyl group, [0050] a phenyl, mono-
or bicyclic heteroaryl, phenyl-C.sub.1-5-alkyl or mono- or bicyclic
heteroaryl-C.sub.1-5-alkyl group, [0051] which may optionally be
mono- to trisubstituted in the phenyl or heteroaryl moiety by
identical or different substituents selected from among fluorine,
chlorine, bromine and iodine atoms, and C.sub.1-5-alkyl,
trifluoromethyl, benzyl, amino, nitro, C.sub.1-5-alkyl-amino,
di-(C.sub.1-5-alkyl)-amino, hydroxy, C.sub.1-5-alkyloxy, mono-, di-
or trifluoromethoxy, carboxy- and C.sub.1-5-alkyloxycarbonyl group,
or two adjacent carbon atoms of a phenyl ring may be substituted by
a --CH.sub.2--O--CH.sub.2 group, [0052] or [0053] a
C.sub.3-7cycloalkyl, morpholinyl, thiomorpholinyl, pyrrolidinyl,
piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl
group, [0054] which may optionally be substituted by one to two
groups selected independently of one another from among
C.sub.1-3-alkyl, acetyl, C.sub.1-5-alkyloxycarbonyl, and
hydroxycarbonyl, or R.sup.4 and R.sup.5 together with the carbon
atom to which they are bound, [0055] form a C.sub.3-7-cycloalkyl or
C.sub.5-7-cycloalkenyl group, [0056] wherein one of the methylene
groups of a C.sub.4-7-cycloalkyl group may be replaced by an oxygen
or sulphur atom or an --NH, --N(C.sub.1-5-alkyl),
--N(C.sub.1-4-alkylcarbonyl), --N(C.sub.1-4-alkyloxycarbonyl)- or a
carbonyl, sulphinyl or sulphonyl group, and/or [0057] two directly
adjacent methylene groups of a C.sub.4-7-cycloalkyl group may
together be replaced by a --C(O)NH, --C(O)N(C.sub.1-5-alkyl),
--S(O).sub.2NH, or --S(O).sub.2N(C.sub.1-5-alkyl) group, and/or
[0058] 1 to 3 carbon atoms of a C.sub.3-7-cycloalkyl group may each
optionally be substituted independently of one another by one or
two fluorine atoms or one or two C.sub.1-5-alkyl groups or a
hydroxy, C.sub.1-5-alkyloxy, formyloxy, C.sub.1-5-alkylcarbonyloxy,
C.sub.1-5-alkylsulphanyl, C.sub.1-5-alkylsulphonyl, aminosulphonyl,
C.sub.1-5-alkylaminosulphonyl, di-(C.sub.1-5-alkyl)-aminosulphonyl,
C.sub.4-7-cycloalkyleneiminosulphonyl, amino, C.sub.1-5-alkylamino,
di-(C.sub.1-5-alkyl)-amino, C.sub.1-5-alkylcarbonylamino,
C.sub.1-5-alkylsulphonylamino,
N--(C.sub.1-5-alkylsulphonyl)-C.sub.1-5-alkylamino,
C.sub.3-6-cycloalkylcarbonyl-amino, Nitril,
carboxy-C.sub.1-5-alkyl,
C.sub.1-5-alkyloxycarbonyl-C.sub.1-5-alkyl, carboxy,
C.sub.1-5-alkyloxycarbonyl, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, di-(C.sub.1-5-alkyl)-aminocarbonyl or
C.sub.4-7-cycloalkyleneiminocarbonyl group, and/or [0059] 1 to 2
carbon atoms of a C.sub.5-7-cycloalkenyl group may optionally be
substituted independently of one another by in each case a
C.sub.1-5-alkyl, nitrile, carboxy-C.sub.1-5-alkyl,
C.sub.1-5-alkyloxycarbonyl-C.sub.1-5-alkyl, carboxy,
C.sub.1-5-alkyloxycarbonyl, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, di-(C.sub.1-5-alkyl)-aminocarbonyl,
C.sub.3-6-cycloalkyleneiminocarbonyl, aminosulphonyl,
C.sub.1-5-alkylaminosulphonyl, di-(C.sub.1-5-alkyl)-aminosulphonyl,
C.sub.3-6-cycloalkyleneiminosulphonyl groups or 1-2 fluorine atoms,
and/or 1 to 2 carbon atoms of a C.sub.4-7-cycloalkenyl group which
are not bound to another carbon atom by a double bond, may
optionally be substituted independently of one another by a
hydroxy, C.sub.1-5-alkyloxy, C.sub.1-5-alkylcarbonyloxy,
C.sub.1-5-alkylsulphanyl, C.sub.1-5-alkylsulphonyl, amino,
C.sub.1-5-alkylamino, di-(C.sub.1-5-alkyl)-amino,
C.sub.1-5-alkylcarbonylamino, C.sub.1-5-alkylsulphonylamino,
N--(C.sub.1-5-alkylsulphonyl)-C.sub.1-5-alkylamino or
C.sub.3-6-cycloalkylcarbonyl-amino groups, [0060] with the proviso
that a C.sub.3-7-cycloalkyl or C.sub.5-7-cycloalkenyl group of this
kind formed from R.sup.4 and R.sup.5 together, [0061] wherein two
heteroatoms in the cyclic group selected from among oxygen and
nitrogen are separated from one another by precisely one optionally
substituted --CH.sub.2 group, and/or [0062] wherein one or both
methylene groups of the cyclic group which are joined directly to
the carbon atom to which the groups R.sup.4 and R.sup.5 are linked,
are replaced by a heteroatom selected from among oxygen, nitrogen
and sulphur, and/or [0063] wherein a substituent bound to the
cyclic group, which is characterised in that a heteroatom selected
from among oxygen, nitrogen, sulphur and fluorine is bound directly
to the cyclic group, is separated from one other heteroatom
selected from among oxygen, nitrogen and sulphur, with the
exception of the sulphone group, by precisely one, optionally
substituted, methylene group, and/or [0064] wherein two atoms in
the ring form an --O--O or --S--O-- bond, [0065] is excluded, M
denotes a thiophene ring according to formula (III),
[0065] ##STR00005## [0066] which is bound to the carbonyl group in
formula (I) via the 2-position and which is substituted the in
5-position by R.sup.2 and optionally additionally by R.sup.6,
wherein [0067] R.sup.2 denotes a hydrogen, fluorine, chlorine,
bromine or iodine atom or a methoxy, C.sub.1-2-alkyl, formyl,
NH.sub.2CO or ethynyl group, [0068] R.sup.6 denotes a hydrogen,
fluorine, chlorine, bromine or iodine atom or a C.sub.1-2-alkyl or
amino group, wherein, unless otherwise stated, the term "heteroaryl
group" mentioned hereinbefore in the definitions denotes a
monocyclic 5- or 6-membered heteroaryl group, wherein [0069] the
6-membered heteroaryl group contains one, two or three nitrogen
atoms, and [0070] the 5-membered heteroaryl group contains an imino
group optionally substituted by a C.sub.1-3-alkyl group, or an
oxygen or sulphur atom, or [0071] an imino group optionally
substituted by a C.sub.1-3-alkyl group or an oxygen or sulphur atom
and additionally one or two nitrogen atoms, or [0072] an imino
group optionally substituted by a C.sub.1-3-alkyl group and three
nitrogen atoms, [0073] and moreover a phenyl ring optionally
substituted by a fluorine, chlorine or bromine atom, a
C.sub.1-3-alkyl, hydroxy, C.sub.1-3-alkyloxy group, amino,
C.sub.1-3-alkylamino, di-(C.sub.1-3-alkyl)-amino or
C.sub.3-6-cycloalkyleneimino group phenyl ring may be fused to the
above-mentioned monocyclic heteroaryl groups via two adjacent
carbon atoms, [0074] and the bond is effected via a nitrogen atom
or a carbon atom of the heterocyclic moiety or a fused-on phenyl
ring, and wherein, unless otherwise stated, by the term "halogen
atom" mentioned hereinbefore in the definitions is meant an atom
selected from among fluorine, chlorine, bromine and iodine, and
wherein the alkyl, alkenyl, alkynyl and alkyloxy groups contained
in the previously mentioned definitions which have more than two
carbon atoms may, unless otherwise stated, be straight-chain or
branched and the alkyl groups in the previously mentioned
dialkylated groups, for example the dialkylamino groups, may be
identical or different, and the hydrogen atoms of the methyl or
ethyl groups contained in the foregoing definitions, unless
otherwise stated, may be wholly or partly replaced by fluorine
atoms, the tautomers, enantiomers, diastereomers, mixtures and
salts thereof.
[0075] Examples of monocyclic heteroaryl groups are the pyridyl,
N-oxy-pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl,
[1,2,3]triazinyl, [1,3,5]triazinyl, [1,2,4]triazinyl, pyrrolyl,
imidazolyl, [1,2,4]triazolyl, [1,2,3]triazolyl, tetrazolyl,
furanyl, isoxazolyl, oxazolyl, [1,2,3]oxadiazolyl,
[1,2,4]oxadiazolyl, furazanyl, thiophenyl, thiazolyl, isothiazolyl,
[1,2,3]thiadiazolyl, [1,2,4]thiadiazolyl or [1,2,5]thiadiazolyl
group.
[0076] Examples of bicyclic heteroaryl groups are the
benzimidazolyl, benzofuranyl, benzo[c]furanyl, benzothiophenyl,
benzo[c]thiophenyl, benzothiazolyl, benzo[c]-isothiazolyl,
benzo[d]isothiazolyl, benzooxazolyl, benzo[c]isoxazolyl,
benzo[d]-isoxazolyl, benzo[1,2,5]oxadiazolyl,
benzo[1,2,5]thiadiazolyl, benzo[1,2,3]thia-diazolyl,
benzo[d][1,2,3]triazinyl, benzo[1,2,4]triazinyl, benzotriazolyl,
cinnolinyl, quinolinyl, N-oxy-quinolinyl, isoquinolinyl,
quinazolinyl, N-oxy-quinazolinyl, quinoxalinyl, phthalazinyl,
indolyl, isoindolyl or 1-oxa-2,3-diaza-indenyl group.
[0077] Examples of the C.sub.1-6-alkyl groups mentioned
hereinbefore in the definitions are the methyl, ethyl, 1-propyl,
2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl,
3-pentyl, neo-pentyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl,
3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl,
2-methyl-3-pentyl, 2,2-dimethyl-3-butyl or 2,3-dimethyl-2-butyl
group.
[0078] Examples of the C.sub.1-6-alkyloxy groups mentioned
hereinbefore in the definitions are the methyloxy, ethyloxy,
1-propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy, tert-butyloxy,
1-pentyloxy, 2-pentyloxy, 3-pentyloxy or neo-pentyloxy group.
[0079] Examples of the C.sub.2-5-alkenyl groups mentioned
hereinbefore in the definitions are the ethenyl, 1-propen-1-yl,
2-propen-1-yl, 1-buten-1-yl, 2-buten-1-yl, 3-buten-1-yl,
1-penten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl,
1-hexen-1-yl, 2-hexen-1-yl, 3-hexen-1-yl, 4-hexen-1-yl,
5-hexen-1-yl, but-1-en-2-yl, but-2-en-2-yl, but-1-en-3-yl,
2-methyl-prop-2-en-1-yl, pent-1-en-2-yl, pent-2-en-2-yl,
pent-3-en-2-yl, pent-4-en-2-yl, pent-1-en-3-yl, pent-2-en-3-yl,
2-methyl-but-1-en-1-yl, 2-methyl-but-2-en-1-yl,
2-methyl-but-3-en-1-yl or 2-ethyl-prop-2-en-1-yl group.
[0080] Examples of the C.sub.2-5-alkynyl groups mentioned
hereinbefore in the definitions are the ethynyl, 1-propynyl,
2-propynyl, 1-butyn-1-yl, 1-butyn-3-yl, 2-butyn-1-yl, 3-butyn-1-yl,
1-pentyn-1-yl, 1-pentyn-3-yl, 1-pentyn-4-yl, 2-pentyn-1-yl,
2-pentyn-3-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 2-methyl-1-butyn-4-yl,
3-methyl-1-butyn-1-yl or 3-methyl-1-butyn-3-yl group.
[0081] A 2nd embodiment of the present invention includes those
compounds of general formula (I), wherein
D denotes a substituted bicyclic ring system of formula (II),
##STR00006## [0082] wherein [0083] K.sup.1 and K.sup.4 [0084] each
independently of one another denote a --CH.sub.2, --CHR.sup.7a,
--CR.sup.7bR.sup.7c or a --C(O) group, wherein [0085]
R.sup.7a/R.sup.7b/R.sup.7c [0086] each independently of one another
denote a fluorine atom, a hydroxy, C.sub.1-5-alkyloxy group, a
C.sub.1-5-alkyl group which may be substituted by 1-3 fluorine
atoms, a hydroxy-C.sub.1-5-alkyl,
C.sub.1-5-alkyloxy-C.sub.1-5-alkyl group, or a phenyl group which
may be substituted by 1-2 substituents selected from among a nitro,
amino, hydroxy-methoxy, cyano, C.sub.1-5-alkyl group or a fluorine,
chlorine or bromine atom, or a 5- or 6-membered heteroaryl group,
[0087] wherein the two groups R.sup.7b/R.sup.7c cannot both
simultaneously be bound to the cyclic carbon atom via a heteroatom,
except if --C(R.sup.7bR.sup.7c)-- corresponds to a --CF.sub.2
group, or [0088] two groups R.sup.7b/R.sup.7c may form, together
with the cyclic carbon atom, a 3-, 4-, 5-, 6- or 7-membered
saturated carbocyclic group or a cyclopentene, cyclohexene,
oxetane, tetrahydrofuran or [0089] wherein the methylene groups
thereof may be substituted by 1-2 C.sub.1-3-alkyl or CF.sub.3--
groups, and/or the methylene groups thereof, if they are not bound
to a heteroatom, may be substituted by 1-2 fluorine atoms, and
[0090] K.sup.2 and K.sup.3 [0091] each independently of one another
represent a --CH.sub.2, --CHR.sup.8a, --CR.sup.8bR.sup.8c or a
--C(O)-- group, and [0092] R.sup.8a/R.sup.8b/R.sup.8c [0093] each
independently of one another denote a C.sub.1-5-alkyl group which
may be substituted by 1-3 fluorine atoms, a
hydroxy-C.sub.1-5-alkyl, C.sub.1-5-alkyloxy-C.sub.1-5-alkyl group,
[0094] or two groups R.sup.8b/R.sup.8c may form, together with the
cyclic carbon atom, a 3-, 4-, 5-, 6- or 7-membered carbocyclic
group or a cyclopentene, cyclohexene, oxetane, tetrahydrofuran,
tetrahydropyran ring, [0095] wherein the methylene groups thereof
may be substituted by 1-2 C.sub.1-3-alkyl or CF.sub.3-- groups,
and/or [0096] the methylene groups thereof, if they are not bound
to a heteroatom, may be substituted by 1-2 fluorine atoms, with the
proviso that a heteroatom introduced by R.sup.8b or R.sup.8c must
not be separated from X in formula (I) by only one carbon atom, and
[0097] in all in formula (II) there should be no more than four
groups selected from among R.sup.7a, R.sup.7b, R.sup.7c, R.sup.8a,
R.sup.8b and R.sup.8c, and [0098] X denotes an oxygen or sulphur
atom, a sulphene, sulphone or an NR.sup.1 group, wherein [0099]
R.sup.1 denotes a hydrogen atom or [0100] a C.sub.1-5-alkyl,
C.sub.2-5-alkenyl-CH.sub.2, C.sub.2-5-alkynyl-CH.sub.2,
C.sub.3-6-cycloalkyl, C.sub.4-6-cycloalkenyl, oxetan-3-yl,
tetrahydrofuran-3-yl, benzyl, C.sub.1-5-alkyl-carbonyl,
trifluoromethylcarbonyl, C.sub.3-6-cycloalkyl-carbonyl,
C.sub.1-5-alkyl-sulphonyl, C.sub.3-6-cycloalkyl-sulphonyl,
aminocarbonyl, C.sub.1-5-alkylaminocarbonyl,
di-(C.sub.1-5-alkyl)-aminocarbonyl, C.sub.1-5-alkyloxycarbonyl,
C.sub.4-7-cycloalkyleneiminocarbonyl group, [0101] wherein the
methylene and methyl groups present in the above-mentioned groups
may additionally be substituted by a C.sub.1-3-alkyl, carboxy,
C.sub.1-5-alkoxycarbonyl group or by a hydroxy, C.sub.1-5-alkyloxy,
amino, C.sub.1-5-alkylamino, C.sub.1-5-dialkylamino or
C.sub.4-7-cycloalkyleneimino group, provided that the methylene or
methyl groups are not directly bound to a heteroatom selected from
among O, N or S, and/or [0102] one to three hydrogen atoms may be
replaced by fluorine atoms, provided that the methylene or methyl
groups are not directly bound to a heteroatom selected from among
O, N or S, [0103] and wherein [0104] A.sup.1, A.sup.2, and A.sup.3
are each defined as described in the 1st embodiment, or D denotes
one of the four groups (II-1a), (II-2a), (II-3) or (II-4)
[0104] ##STR00007## [0105] wherein the groups A1, A2, A3, K1, K2,
K3, K4 are as hereinbefore defined, and [0106] Anion in (II-4)
denotes a fluoride, chloride, bromide, iodide, sulphate, hydrogen
sulphate, phosphate, hydrogen phosphate, benzoate, salicylate,
succinate, citrate or tartrate, [0107] and R.sup.3 denotes a
hydrogen atom, and R.sup.4, R.sup.5 and M are each defined as
described in the 1st embodiment, the tautomers, enantiomers,
diastereomers, mixtures and salts thereof.
[0108] A 3rd embodiment of the present invention includes those
compounds of general formula (I), wherein
D denotes a substituted bicyclic ring system of formula (II),
##STR00008## [0109] wherein [0110] K1, K2, K3 and K4 are defined as
described in the 1st or 2nd embodiment, and [0111] X denotes an
NR.sup.1 group, wherein [0112] R.sup.1 denotes a hydrogen atom or
[0113] a C.sub.1-5-alkyl, C.sub.2-5-alkenyl-CH.sub.2,
C.sub.2-5-alkynyl-CH.sub.2, C.sub.3-6-cycloalkyl,
C.sub.4-6-cycloalkenyl group, [0114] wherein the methylene and
methyl groups present in the above-mentioned groups may
additionally be substituted by a C.sub.1-3-alkyl, carboxy,
C.sub.1-5-alkoxycarbonyl group or by a hydroxy, C.sub.1-5-alkyloxy,
amino, C.sub.1-5-alkylamino, C.sub.1-5-dialkylamino or
C.sub.4-7-cycloalkyleneimino group, provided that the methylene or
methyl groups are not directly bound to a heteroatom selected from
among O, N or S, and/or [0115] one to three hydrogen atoms may be
replaced by fluorine atoms, so long as the methylene or methyl
groups are not directly bound to the nitrogen atom, [0116] and
wherein [0117] A.sup.1 denotes either N or CR.sup.10, [0118]
A.sup.2 denotes either N or CR.sup.11, [0119] A.sup.3 denotes
either N or CR.sup.12, [0120] wherein R.sup.10, R.sup.11 and
R.sup.12 each independently of one another represent [0121] a
hydrogen, fluorine, chlorine, bromine atom or a C.sub.1-5-alkyl,
CF.sub.3, a cyano, carboxy, C.sub.1-5-alkyloxycarbonyl, hydroxy,
C.sub.1-3-alkyloxy, CF.sub.3O, CHF.sub.2O, CH.sub.2FO-- group, or D
denotes one of the four groups (II-1a), (II-2a), (II-3) or
(II-4)
[0121] ##STR00009## [0122] wherein the groups A1, A2, A3, K1, K2,
K3, K4 are as hereinbefore defined, and Anion in (II-4) may be
selected from among fluoride, chloride, bromide, iodide, sulphate,
phosphate, benzoate, salicylate, succinate, citrate and tartrate,
and R.sup.3, R.sup.4, R.sup.5 and M are each defined as in the 1st
or 2nd embodiment, wherein R.sup.6 denotes a hydrogen atom, the
tautomers, enantiomers, diastereomers, mixtures and salts
thereof.
[0123] A 4th embodiment of the present invention includes those
compounds of general formula (I), wherein [0124] D, R.sup.3 and M
are each defined as in the 1st, 2nd or 3rd embodiment, and [0125]
R.sup.4 denotes a straight-chain or branched C.sub.3-6-alkenyl or
C.sub.3-6-alkynyl group, [0126] a straight-chain or branched
C.sub.1-6-alkyl group, [0127] wherein the hydrogen atoms of the
straight-chain or branched C.sub.1-6-alkyl group may optionally be
wholly or partly replaced by fluorine atoms, [0128] and wherein
optionally one to two hydrogen atoms may be replaced independently
of one another by a C.sub.3-7-cycloalkyl, hydroxy,
C.sub.1-5-alkyloxy, phenylmethyloxy, phenethyloxy,
carboxy-C.sub.1-5-alkyloxy,
C.sub.1-5-alkyloxycarbonyl-C.sub.1-5-alkyloxy,
C.sub.1-5-alkyloxy-C.sub.2-5-alkyloxy, C.sub.1-5-alkylsulphanyl,
C.sub.1-5-alkylsulphinyl, C.sub.1-5-alkylsulphonyl, carboxy,
C.sub.1-5-alkyloxycarbonyl, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, di-(C.sub.1-5-alkyl)-aminocarbonyl,
C.sub.1-5-alkyl-aminocarbonyloxy,
di-(C.sub.1-5-alkyl)-aminocarbonyloxy,
C.sub.4-7-cycloalkyleneiminocarbonyl, amino, C.sub.1-5-alkylamino
or di-(C.sub.1-5-alkyl)-amino group C.sub.1-5-alkylcarbonylamino,
trifluoracetylamino,
C.sub.1-5-alkyloxy-C.sub.1-5-alkylcarbonylamino,
phenylcarbonylamino, C.sub.1-5-alkylaminocarbonylamino,
di-(C.sub.1-5-alkyl)-aminocarbonylamino,
C.sub.1-5-alkyloxy-carbonylamino, phenylmethyloxy-carbonylamino,
C.sub.1-5-alkyloxy-C.sub.2-5-alkyloxy-C.sub.1-2-alkylcarbonylamino,
C.sub.1-5-alkylsulphonylamino, C.sub.3-6-cycloalkylcarbonylamino
group, 4-morpholinocarbonylamino-group, [0129] wherein the
above-mentioned carbo- and heterocycles in the ring may each be
substituted by 1 to 4 C.sub.1-3-alkyl or C.sub.1-3-alkylcarbonyl
groups or may each be substituted by 1 or 2 oxo groups, and/or
[0130] the above-mentioned phenyl and heteroaryl groups may be
replaced by 1 to 2 substituents selected from among fluorine,
chlorine, bromine, methyl, methoxy, or trifluoromethyl, or two
adjacent carbon atoms of a phenyl ring may be substituted by a
--CH.sub.2--O--CH.sub.2 group, and/or the above-mentioned alkyl
groups may be substituted by a cyano-C.sub.1-5-alkyloxycarbonyl or
carboxy group, [0131] wherein the above-mentioned carboxylic acid
or sulphonic acid amide may optionally additionally be substituted
at the nitrogen by a C.sub.1-5-alkyl group, [0132] a phenyl,
phenyl-C.sub.1-2-alkyl, heteroaryl-C.sub.1-2-alkyl or C-linked
heteroaryl group, wherein the heteroaryl group is selected from
among imidazolyl, furanyl, thiophenyl, thiazolyl, pyrazolyl,
tetrazolyl, benzimidazolyl, indolyl, pyrimidinyl,
pyrazinyl-oxazolyl, 1,2,4-triazolyland pyridinyl, and which may
optionally be mono- to disubstituted in the phenyl or heteroaryl
moiety by identical or different substituents selected from among
chlorine or fluorine atoms or C.sub.1-3-alkyl, benzyl, hydroxy,
amino, CF.sub.3, CH.sub.3O-- or CHF.sub.2O-- groups, [0133] R.sup.5
denotes a hydrogen atom, a straight-chain or branched
C.sub.1-4-alkyl group, wherein the hydrogen atoms of the
straight-chain or branched C.sub.1-4-alkyl groups may optionally be
wholly or partly replaced by fluorine atoms, or a propargyl or
C.sub.1-3alkyloxy-C.sub.1-3-alkyl group, or [0134] R.sup.4 and
R.sup.5 together with the carbon atom to which they are bound,
[0135] form a C.sub.5-6-cycloalkenyl or C.sub.3-7-cycloalkyl group,
[0136] wherein one of the methylene groups of a
C.sub.4-7-cycloalkyl group may be replaced by an oxygen or sulphur
atom or an --NH--, --N(C.sub.1-5-alkyl),
--N(C.sub.1-4-alkylcarbonyl), carbonyl, sulphinyl or a sulphonyl
group, or two immediately adjacent methylene groups of a
C.sub.4-7-cycloalkyl group may together be replaced by a --C(O)NH,
--C(O)N(C.sub.1-5-alkyl), --S(O).sub.2NH-- or
--S(O).sub.2N(C.sub.1-5-alkyl) group, [0137] and/or 1 to 2 carbon
atoms of a C.sub.3-7-cycloalkyl group may optionally be substituted
independently of one another by in each case one or two fluorine
atoms or one or two C.sub.1-5-alkyl groups or a hydroxy,
C.sub.1-5-alkyloxy, formyloxy, amino, C.sub.1-5-alkylamino,
di-(C.sub.1-5-alkyl)-amino, C.sub.1-5-alkylcarbonylamino,
C.sub.3-6-cycloalkylcarbonylamino, nitrile, carboxy,
C.sub.1-5-alkyloxycarbonyl, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, di-(C.sub.1-5-alkyl)-aminocarbonyl or
C.sub.4-7-cycloalkyleneiminocarbonyl group, [0138] with the proviso
that a C.sub.3-7-cycloalkyl group of this kind, formed from R.sup.4
and R.sup.5 together, [0139] wherein two heteroatoms in the cyclic
group selected from among oxygen and nitrogen are separated from
one another by precisely one optionally substituted --CH.sub.2
group, and/or [0140] wherein one or both methylene groups of the
cyclic group which are joined directly to the carbon atom to which
the groups R.sup.4 and R.sup.5 are bound, are replaced by a
heteroatom selected from among oxygen, nitrogen and sulphur, and/or
[0141] wherein a substituent bound to the cyclic group, which is
characterised in that a heteroatom selected from among oxygen,
nitrogen, sulphur and fluorine atom is bound directly to the cyclic
group, is separated from another heteroatom selected from among
oxygen, nitrogen and sulphur by precisely one optionally
substituted methylene group, and/or [0142] wherein two atoms in the
ring form a --O--O or --S--O-- bond, [0143] is excluded, the
tautomers, enantiomers, diastereomers, mixtures and salts
thereof.
[0144] A 5th embodiment of the present invention includes those
compounds of general formula (I), wherein
D denotes a substituted bicyclic ring system of formula (II),
##STR00010## [0145] wherein [0146] K.sup.1 and K.sup.4 [0147] each
independently of one another represent a --CH.sub.2, --CHR.sup.7a
or a --CR.sup.7bR.sup.7c-- group, wherein [0148]
R.sup.7a/R.sup.7b/R.sup.7c [0149] each independently of one another
denote a C.sub.1-2-alkyl group or a phenyl group which may be
substituted by 1 or 2 substituents selected from among a nitro,
amino, hydroxyl, methoxy, cyano, C.sub.1-5-alkyl group or a
fluorine, chlorine or bromine atom, [0150] K.sup.2 and K.sup.3
[0151] each denote a --CH.sub.2 group [0152] X denotes an NR.sup.1
group, wherein [0153] R.sup.1 denotes a hydrogen atom or [0154] a
C.sub.1-5-alkyl, C.sub.2-4-alkenyl-CH.sub.2,
C.sub.2-4-alkynyl-CH.sub.2 or C.sub.3-6-cycloalkyl group, [0155]
wherein the methylene and methyl groups present in the previously
mentioned C.sub.2-5-alkyl groups may be substituted by one to three
fluorine atoms, as long as the methylene or methyl groups are not
directly bound to the nitrogen atom, [0156] and wherein [0157]
A.sup.1 denotes either N or CR.sup.10, [0158] A.sup.2 denotes
either N or CR.sup.11, [0159] A.sup.3 denotes either N or
CR.sup.12, [0160] wherein R.sup.10, R.sup.11 and R.sup.12 each
independently of one another represent [0161] a hydrogen, fluorine
or chlorine atom, or a C.sub.1-3-alkyl, CF.sub.3, hydroxy or
CH.sub.3O-- group, [0162] or D denotes one of the groups (II-3) or
(II-4)
[0162] ##STR00011## [0163] wherein the groups A1, A2, A3, K1, K2,
K3, K4 are as hereinbefore defined, and the anion in (II-4) may be
selected from among fluoride, chloride, bromide, iodide, sulphate,
phosphate, benzoate, salicylate, succinate, citrate or tartrate,
and [0164] R.sup.3 denotes a hydrogen atom, [0165] R.sup.4 denotes
a straight-chain or branched C.sub.3-6-alkenyl or C.sub.3-6-alkynyl
group, [0166] a straight-chain or branched C.sub.1-4-alkyl group,
[0167] wherein the hydrogen atoms of the straight-chain or branched
C.sub.1-4-alkyl group may optionally be partially replaced by up to
four fluorine atoms, [0168] and wherein optionally one to two
hydrogen atoms may be replaced independently of one another by a
C.sub.3-7-cycloalkyl, hydroxy, C.sub.1-5-alkyloxy, phenylmethyloxy,
C.sub.1-5-alkylsulphanyl, C.sub.1-5-alkylsulphinyl,
C.sub.1-5-alkylsulphonyl, carboxy, C.sub.1-5-alkyloxycarbonyl,
aminocarbonyl, C.sub.1-5-alkylaminocarbonyl,
di-(C.sub.1-5-alkyl)-aminocarbonyl,
C.sub.4-7-cycloalkyleneiminocarbonyl, amino, C.sub.1-5-alkylamino
or di-(C.sub.1-5-alkyl)-amino, C.sub.1-5-alkylcarbonylamino,
carboxy-C.sub.1-5-alkylcarbonylamino or a
C.sub.1-5-alkyloxycarbonyl-C.sub.1-5-alkylcarbonylamino group,
[0169] wherein the above-mentioned phenyl groups may be replaced by
1 or 2 substituents selected from fluorine, chlorine, bromine,
methyl, methoxy, or trifluoromethyl, or wherein the above-mentioned
carboxylic acid amide may optionally be additionally substituted at
the nitrogen by a C.sub.1-5-alkyl group, [0170] a phenyl,
phenyl-C.sub.1-2-alkyl, heteroaryl-C.sub.1-2-alkyl or C-linked
heteroaryl group, wherein the heteroaryl group is selected from
among imidazolyl, furanyl, thiophenyl, thiazolyl, pyrazolyl,
tetrazolyl, benzimidazolyl, indolyl, pyrimidinyl, pyrazinyl,
oxazolyl, and pyridinyl, and which may optionally be mono- to
disubstituted in the phenyl or heteroaryl moiety by identical or
different substituents selected from among chlorine or fluorine
atoms or C.sub.1-3-alkyl, CF.sub.3, HO, CH.sub.3O or CHF.sub.2O--
groups, [0171] R.sup.5 denotes a hydrogen atom, a straight-chain or
branched C.sub.1-4-alkyl group, a propargyl or
C.sub.1-3-alkyloxy-C.sub.1-3-alkyl group, or [0172] R.sup.4 and
R.sup.5 together with the carbon atom to which they are bound form
[0173] a C.sub.5-6-cycloalkenyl or C.sub.3-7-cycloalkyl group,
[0174] wherein one of the methylene groups of a
C.sub.4-7-cycloalkyl group may be replaced by an oxygen or sulphur
atom or a sulphonyl group, or [0175] 1 to 2 carbon atoms of a
C.sub.3-7-cycloalkyl group may optionally be substituted
independently of one another by in each case one or two fluorine
atoms, or one or two C.sub.1-5-alkyl groups, or a hydroxy,
C.sub.1-5-alkyloxy, formyloxy, nitrile, carboxy,
C.sub.1-5-alkyloxycarbonyl, aminocarbonyl,
C.sub.1-5-alkylaminocarbonyl, di-(C.sub.1-5-alkyl)-aminocarbonyl or
C.sub.4-7-cycloalkyleneiminocarbonyl group, [0176] with the proviso
that a C.sub.3-7-cycloalkyl group of this kind formed from R.sup.4
and R.sup.5 together, [0177] wherein one of the methylene groups of
the cyclic group which is linked directly to the carbon atom to
which the groups R.sup.4 and R.sup.5 are bound, is replaced by an
oxygen or sulphur atom, [0178] is excluded, and M denotes a
thiophene ring according to formula (III),
[0178] ##STR00012## [0179] which is bound to the carbonyl group in
formula (I) via the 2-position and is substituted by R.sup.2 in the
5-position, where [0180] R.sup.2 denotes a chlorine or bromine atom
or an ethynyl group, and [0181] R.sup.6 denotes a hydrogen atom,
wherein the alkyl, alkenyl, alkynyl and alkyloxy groups contained
in the previously mentioned definitions which have more than two
carbon atoms may, unless otherwise stated, be straight-chain or
branched and the alkyl groups in the previously mentioned
dialkylated groups, for example the dialkylamino groups, may be
identical or different, the tautomers, enantiomers, diastereomers,
mixtures and salts thereof.
[0182] A 6th embodiment of the present invention includes those
compounds of general formula (I), corresponding to embodiments 1,
2, 3, 4 or 5, wherein the group
D denotes a substituted bicyclic ring system of formula (II),
##STR00013## [0183] wherein [0184] K.sup.1 and K.sup.4 [0185] each
independently of one another represent a --CH.sub.2, --CHR.sup.7a
or a --CR.sup.7bR.sup.7c-- group, where [0186]
R.sup.7a/R.sup.7b/R.sup.7c [0187] each independently of one another
denote a C.sub.1-2-alkyl group, [0188] K.sup.2 and K.sup.3 [0189]
each denote a --CH.sub.2 group, [0190] X denotes an NR.sup.1 group,
wherein [0191] R.sup.1 denotes a hydrogen atom or [0192] a
C.sub.1-5-alkyl or C.sub.3-6-cycloalkyl group, [0193] wherein in
the methylene and methyl groups present in the above-mentioned
groups one to three hydrogen atoms may be replaced by fluorine
atoms, provided that the methylene or methyl groups are not
directly bound to the nitrogen atom, [0194] and wherein [0195]
A.sup.1 denotes CR.sup.10, [0196] A.sup.2 denotes CR.sup.11, [0197]
A.sup.3 denotes CR.sup.12, [0198] where R.sup.10, R.sup.11 and
R.sup.12 each independently of one another represent [0199] a
hydrogen, fluorine or chlorine atom, or a C.sub.1-3-alkyl,
CF.sub.3, HO, CH.sub.3O-- group, [0200] or D denotes the group
(II-4)
[0200] ##STR00014## [0201] wherein the groups A1, A2, A3, K1, K2,
K3, K4 are as hereinbefore defined, and the anion in (II-4) may be
selected from among fluoride, chloride, bromide, iodide, sulphate,
phosphate, benzoate, salicylate, succinate, citrate or tartrate,
the tautomers, enantiomers, diastereomers, mixtures and salts
thereof.
[0202] A 7th embodiment of the present invention includes those
compounds of general formula (I), corresponding to embodiments 1,
2, 3, 4, 5 or 6, wherein neither
R.sup.4 nor R.sup.5 may represent a hydrogen atom, the tautomers,
enantiomers, diastereomers, mixtures and salts thereof.
[0203] An 8th embodiment of the present invention includes those
compounds of general formula (I), corresponding to embodiments 1,
2, 3, 4, 5 or 6, wherein
R.sup.4 and R.sup.5 together with the carbon atom to which they are
bound, [0204] form a C.sub.5-6-cycloalkenyl or C.sub.3-7-cycloalkyl
group, [0205] wherein one of the methylene groups of a
C.sub.4-7-cycloalkyl group may be replaced by an oxygen or sulphur
atom, [0206] with the proviso that a C.sub.3-7-cycloalkyl group of
this kind formed from R.sup.4 and R.sup.5 together, [0207] wherein
one of the methylene groups of the cyclic group, which is linked
directly to the carbon atom, to which the groups R.sup.4 and
R.sup.5 are bound, is replaced by an oxygen or sulphur atom, [0208]
is excluded, the tautomers, enantiomers, diastereomers, mixtures
and salts thereof.
[0209] The following ring systems are mentioned as particularly
preferred examples of the cyclic groups which may be formed from
R.sup.4/R.sup.5 and the carbon atom to which they are bound:
##STR00015##
[0210] The following preferred compounds of general formula (I) are
mentioned by way of example, both as the tautomers, enantiomers,
diastereomers, mixtures and salts thereof: [0211]
3-[(5-bromo-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro--
1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic acid amide,
[0212]
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro-
-1H-benzo[d]azepin-7-yl)tetrahydrofuran-3-carboxylic acid amide,
[0213] 5-chloro-thiophene-2-carboxylic
acid-N-[1-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-1--
methyl-ethyl]-amide, [0214]
5-ethynyl-N-[1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7--
ylcarbamoyl)-ethyl]-thiophene-2-carboxylic acid amide, [0215]
5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcar-
bamoyl]-ethyl}-amide, [0216] 5-bromo-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcar-
bamoyl]-ethyl}-amide, [0217] 5-chloro-thiophene-2-carboxylic
acid-N-[2-methoxy-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylca-
rbamoyl)-ethyl]-amide, [0218]
1-[(5-bromo-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro--
1H-benzo[d]azepin-7-yl)-cyclopentane-1-carboxylic acid amide,
[0219]
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro-
-1H-benzo[d]azepin-7-yl)-cyclopentane-1-carboxylic acid amide,
[0220]
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro-
-1H-benzo[d]azepin-7-yl)-tetrahydrothiophene-3-carboxylic acid
amide, [0221]
1-[(5-chloro-thiophen-2-yl)carbonylamino]-N-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-yl)-cyclobutane-1-carboxylic acid amide,
[0222]
1-[(5-bromo-thiophen-2-yl)carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro-1-
H-benzo[d]azepin-7-yl)-cyclopent-3-ene-1-carboxylic acid amide,
[0223]
1-[(5-chloro-thiophen-2-yl)carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro--
1H-benzo[d]azepin-7-yl)-cyclohexane-1-carboxylic acid amide, [0224]
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-benzyloxy-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl-
carbamoyl)-ethyl]-amide, [0225] 5-chloro-thiophene-2-carboxylic
acid-N-[2-benzyloxy-1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]az-
epin-7-ylcarbamoyl)-ethyl]-amide, [0226]
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-hydroxy-1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azep-
in-7-ylcarbamoyl)-ethyl]-amide, [0227]
5-bromo-thiophene-2-carboxylic
acid-N-[3-hydroxy-1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azep-
in-7-ylcarbamoyl)-propyl]-amide, [0228]
5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-3-dimethylaminocarbonyl-1-(3-methyl-2,3,4,5-tetrahydro-1-
H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide, [0229]
5-chloro-thiophene-2-carboxylic
acid-N-[2-(4-hydroxy-phenyl)-1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-b-
enzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide, [0230]
5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-y-
lcarbamoyl)-ethyl]-amide, [0231] 5-chloro-thiophene-2-carboxylic
acid-N-{1-methyl-1-[3-methyl-5-(4-aminophenyl)-2,3,4,5-tetrahydro-1H-benz-
o[d]azepin-7-ylcarbamoyl]-ethyl}-amide, [0232]
5-chloro-thiophene-2-carboxylic
acid-N-[2-ethoxy-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcar-
bamoyl)-ethyl]-amide, [0233] 5-chloro-thiophene-2-carboxylic
acid-N-[3-methoxy-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylca-
rbamoyl)-propyl]-amide, [0234] 5-chloro-thiophene-2-carboxylic
acid-N-[2-isopropyloxy-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
-ylcarbamoyl)-ethyl]-amide, [0235]
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-benzyloxy-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl-
carbamoyl)-propyl]-amide, [0236]
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-3,4-dimethoxy-N-(3-methyl-2,3,-
4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-cyclopentane-1-carboxylic
acid amide, [0237] 5-chloro-thiophene-2-carboxylic
acid-N--[C-(1-methyl-pyrazol-3-yl)-C-(3-methyl-2,3,4,5-tetrahydro-1H-benz-
o[d]azepin-7-ylcarbamoyl)-methyl]-amide, [0238]
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-phenyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcar-
bamoyl)-ethyl]-amide, [0239] (R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-(furan-2-yl)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
-ylcarbamoyl)-ethyl]-amide, [0240] 5-chloro-thiophene-2-carboxylic
acid-N-[2-(4-methoxyphenyl)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]aze-
pin-7-ylcarbamoyl)-ethyl]-amide, [0241]
5-chloro-thiophene-2-carboxylic
acid-N-[2-(4-hydroxy-3-nitro-phenyl)-1-(3-methyl-2,3,4,5-tetrahydro-1H-be-
nzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide, [0242]
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-(4-hydroxy-phenyl)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]az-
epin-7-ylcarbamoyl)-ethyl]-amide, [0243]
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-cyclohexyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-y-
lcarbamoyl)-ethyl]-amide, [0244]
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-aminocarbonyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin--
7-ylcarbamoyl)-propyl]-amide, [0245]
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-acetylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7--
ylcarbamoyl)-ethyl]-amide, [0246]
(R)-5-bromo-thiophene-2-carboxylic
acid-N-[2-benzoylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
-ylcarbamoyl)-ethyl]-amide, [0247]
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-(2-hydroxycarbonyl-ethyl)carbonylamino-1-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide, [0248]
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-(2-hydroxycarbonyl-ethyl)carbonylamino-1-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide, [0249]
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-(4-methoxycarbonyl-butyl)carbonylamino-1-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide, [0250]
5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3,3-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepinium--
7-ylcarbamoyl]-ethyl}-amide iodide, [0251]
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3,5-dimethyl-2,3,4,5-tetrah-
ydro-1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic acid
amide.
[0252] The invention also relates to physiologically acceptable
salts of the compounds according to the embodiments defined above
and the Examples.
[0253] The invention also relates to pharmaceutical compositions
containing a compound or a physiologically acceptable salt of a
compound according to the embodiments defined above and the
Examples, optionally together with one or more inert carriers
and/or diluents.
[0254] The invention also relates to the use of a compound or a
physiologically acceptable salt of a compound according to the
embodiments defined above and the Examples, for preparing a
pharmaceutical composition with an inhibitory effect on factor Xa
and/or an inhibitory effect on related serine proteases.
[0255] The invention also relates to a process for preparing a
pharmaceutical composition, characterised in that by a non-chemical
method a compound or a physiologically acceptable salt of a
compound according to the embodiments defined above and the
Examples is incorporated in one or more inert carriers and/or
diluents.
[0256] According to the invention the compounds of general formula
(I) are obtained by methods known per se, for example by the
following methods:
(a) The preparation of a compound of general formula (Ia)
##STR00016## [0257] wherein A.sup.1 to A.sup.3, K.sup.1 to K.sup.4,
X and R.sup.1 to R.sup.6 are defined as in embodiment 1, [0258] and
which may optionally be protected at any amino, hydroxy, carboxy or
thiol groups present by the usual protective groups such as for
example those described in T. W. Greene, P. G. M. Wuts in
"Protective Groups in Organic Synthesis" and the protective groups
of which may be cleaved in a manner known from the literature,
[0259] is described in the exemplifying embodiments or may be
carried out for example according to one of the following formula
schemes 1 and 2:
##STR00017##
[0259] ##STR00018## [0260] where [0261] Q denotes a hydroxy or
C.sub.1-4-alkyloxy group, a halogen atom or a alkyloxycarbonyloxy
or acyloxy group and [0262] PG denotes a hydrogen atom or a
protective group for the amino function known from the literature
such as for example a tert.-butoxycarbonyl, benzyloxycarbonyl or a
trifluoroacetyl group. [0263] The reaction steps i)-iii) described
in Scheme 1 and 2 may for example be carried out as described in
the Examples or under conditions known from the literature, as
follows: [0264] i) acylation of an amine (IV) or (VII) with an
optionally activated carboxylic acid (V) or (VI) or (VIII) [0265]
The acylation is expediently carried out with a corresponding
halide or anhydride in a solvent such as methylene chloride,
chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane,
benzene, toluene, acetonitrile, dimethylformamide, sodium hydroxide
solution or sulpholane, optionally in the presence of an inorganic
or organic base at temperatures between -20 and 200.degree. C., but
preferably at temperatures between -10 and 160.degree. C. [0266]
The acylation may however also be carried out with the free acid,
optionally in the presence of an acid-activating agent or a
dehydrating agent, for example in the presence of isobutyl
chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen
chloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonic
acid, phosphorus trichloride, phosphorus pentoxide,
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),
N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/camphorsulphonic acid,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or
1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium
tetrafluoroborate/N-methylmorpholine,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate/N-ethyldiisopropylamine,
O-pentafluorophenyl-N,N,N',N'-tetramethyluronium-hexafluorophosphate/trie-
thylamine, N,N'-thionyldiimidazole or triphenylphosphine/carbon
tetrachloride, at temperatures between -20 and 200.degree. C., but
preferably at temperatures between -10 and 160.degree. C. [0267]
The acylation may also be carried out with a carboxylic acid ester
(V) or (VI) and the amine (IV) by activation with
trimethylaluminium. [0268] The acylation of a compound of general
formula (IV) may however also be carried out with a reactive
carboxylic acid derivative of general formula (IX)
[0268] ##STR00019## [0269] wherein R.sup.4 to R.sup.6 and R.sup.2
are defined as in embodiment 1. The acylation is then conveniently
carried out in a solvent such as for example toluene,
tetrahydrofuran or dimethylformamide, with the addition of an acid
such as acetic acid or camphorsulphonic acid or optionally in the
presence of a Lewis acid such as zinc chloride or
copper(II)chloride and optionally by the addition of amine bases
such as for example diisopropylethylamine, triethylamine or
N-methylmorpholine, at temperatures between -10 and 100.degree. C.,
for example using a microwave oven or as described in P. Wipf et
al., Helvetica Chimica Acta, 69, 1986, 1153. [0270] Compounds of
general formula (IX) may be prepared from compounds of general
formula (V), expediently in a solvent or mixture of solvents such
as dichloromethane, trichloromethane, carbon tetrachloride,
benzene, chlorobenzene, toluene, xylene, hexamethyldisiloxane,
ether, tetrahydrofuran, dioxane, acetonitrile, pyridine, optionally
in the presence of N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or
1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium
tetrafluoroborate/N-methylmorpholine,
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate/N-ethyldiisopropylamine, or in acetic anhydride
at temperatures between -20 and 200.degree. C., but preferably at
temperatures between -10 and 100.degree. C. [0271] Other methods of
amide coupling are described for example in P. D. Bailey, I. D.
Collier, K. M. Morgan in "Comprehensive Functional Group
Interconversions", Vol. 5, page 257ff., Pergamon 1995 or in
Supplementary Volume 22 to Houben-Weyl, Thieme Verlag, 2003 and
literature cited therein. [0272] ii) or iii) Cleaving a protective
group [0273] The optional subsequent cleaving of any protective
group used is carried out hydrolytically, for example, in an
aqueous solvent, e.g. In water, isopropanol/water,
tetrahydrofuran/water or dioxane/water, in the presence of an acid
such as trifluoroacetic acid, hydrochloric acid or sulphuric acid
or in the presence of an alkali metal base such as lithium
hydroxide, sodium hydroxide or potassium hydroxide or by ether
cleavage, e.g. In the presence of iodotrimethylsilane, at
temperatures between 0 and 100.degree. C., preferably at
temperatures between 10 and 50.degree. C. [0274] A benzyl,
methoxybenzyl or benzyloxycarbonyl group may, however, be cleaved
hydrogenolytically, e.g. with hydrogen in the presence of a
catalyst such as palladium/charcoal in a solvent such as methanol,
ethanol, ethyl acetate, dimethylformamide,
dimethylformamide/acetone or glacial acetic acid, optionally with
the addition of an acid such as hydrochloric acid at temperatures
between 0 and 50.degree. C., but preferably at room temperature,
and under a hydrogen pressure of 1 to 7 bar, but preferably 1 to 5
bar. [0275] A protective group may however also be cleaved by the
methods described in T. W. Greene, P. G. M. Wuts in "Protective
Groups in Organic Synthesis". (b) The components of general
formula
[0275] ##STR00020## [0276] wherein A.sup.1, A.sup.2, A.sup.3,
K.sup.1, K.sup.2, K.sup.3, K.sup.4, X and R.sup.3 are defined as in
embodiment 1, and [0277] and which may optionally be protected at
any amino, hydroxy, carboxy or thiol groups present by the usual
protective groups such as for example those described in T. W.
Greene, P. G. M. Wuts in "Protective Groups in Organic Synthesis"
and the protective groups of which may be cleaved in a manner known
from the literature in the course of the synthesis sequence to form
compounds of formula (I), [0278] are known from the literature, or
their synthesis is described in the exemplifying embodiments, or
they may be prepared for example using methods of synthesis known
from the literature or analogously to methods of synthesis known
from the literature as described for example in DE4429079, U.S.
Pat. No. 4,490,369, DE3515864, U.S. Pat. No. 5,175,157, DE1921861,
WO85/00808 or in G. Bobowski et al., J. Heterocyclic Chem. 16,
1525, 1979 or in P. D. Johnson et al., Bioorg. Med. Chem. Lett
2003, 4197. [0279] Fragments bridged in the azepine moiety as shown
in formula II-1 or II-2 may for example be prepared analogously to
J. W. Coe et al. J. Med. Chem., 2005, 48, 3474 or J. W. Coe et al.,
US Patent application US2005/0020616. [0280] The benzazepine
modifications in formula II-3 or II-4 may for example be prepared
by oxidation using meta-chloroperbenzoic acid or alkylation with an
alkyl halide from suitable benzepine precursors as described in the
experimental section.
[0281] For example, a compound of general formula (IV), wherein
R.sup.3 denotes a hydrogen atom and A1, A2, A3, K1, K2, K3, K4 and
X are defined as in embodiment 1, may be prepared by reduction of
the nitro group of a compound of general formula (III)
##STR00021## [0282] wherein A1, A2, A3, K1, K2, K3, K4 and X are
defined as in embodiment 1, as follows. [0283] The reduction of the
nitro group is for example conveniently carried out in a solvent or
mixture of solvents such as water, aqueous ammonium chloride
solution, hydrochloric acid, sulphuric acid, phosphoric acid,
formic acid, acetic acid, acetic anhydride with base metals such as
iron, zinc, tin or sulphur compounds such as ammonium sulphide,
sodium sulphide or sodium dithionite or by catalytic hydrogenation
with hydrogen, for example under a pressure between 0.5 and 100
bar, but preferably between 1 and 50 bar, or with hydrazine as
reducing agent, conveniently in the presence of a catalyst such as
for example Raney nickel, palladium charcoal, platinum oxide,
platinum on mineral fibres or rhodium, or with complex hydrides
such as lithium aluminium hydride, sodium borohydride, sodium
cyanoborohydride, diisobutylaluminium hydride, conveniently in a
solvent or mixture of solvents such as water, methanol, ethanol,
isopropanol, pentane, hexane, cyclohexane, heptane, benzene,
toluene, xylene, ethyl acetate, methylpropionate, glycol,
glycoldimethylether, diethyleneglycoldimethylether, dioxane,
tetrahydrofuran, N-methylpyrrolidinone, or
N-ethyl-diisopropylamine, N--C.sub.1-5-alkylmorpholine,
N--C.sub.1-5-alkylpiperidine, N--C.sub.1-5-alkylpyrrolidine,
triethylamine, pyridine, for example at temperatures between -30
and 250.degree. C., but preferably between 0 and 150.degree. C. (c)
The components of general formula
[0283] ##STR00022## [0284] wherein R.sup.4, R.sup.5, R.sup.6 and
R.sup.2 are defined as in embodiment 1, and where Q denotes a
hydroxy or C.sub.1-4-alkyloxy group, a halogen atom or a
alkyloxycarbonyloxy or acyloxy group [0285] which may optionally be
protected at any amino, hydroxy, carboxy or thiol groups present by
the usual protective groups such as for example those described in
T. W. Greene, P. G. M. Wuts in "Protective Groups in Organic
Synthesis" and the protective groups of which may be cleaved in a
manner known from the literature in the course of the synthesis
sequence to form compounds of formula (I), [0286] are known from
the literature, or their synthesis is described in the exemplifying
embodiments, or they may be prepared for example using methods of
synthesis known from the literature or analogously to methods of
synthesis known from the literature as described for example in
WO04/46138.
[0286] ##STR00023## [0287] For example they may also be prepared
according to Scheme 3 by reacting a compound (VIII) with an amine
(VI-1), where Q denotes a hydroxy or C.sub.1-4-alkyloxy group, a
halogen atom or an alkyloxycarbonyloxy or acyloxy group and Q-I
denotes a hydroxy or C.sub.1-4-alkyloxy group, which may optionally
be converted into Q after the acylation step by saponification and
activation as described above. The acylation may be carried out
according to the acylation conditions described above. [0288] The
amino acid derivatives (VI-1) are known from the literature or may
be prepared analogously to methods known from the literature as
described in the Examples, for example, from commercially
obtainable amino acid derivatives.
[0289] In the reactions described hereinbefore any reactive groups
present such as hydroxy, carboxy, amino, alkylamino or imino groups
may be protected during the reaction by conventional protective
groups which are cleaved again after the reaction.
[0290] For example a protecting group for a hydroxy group might be
the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl,
tert.-butyl, trityl, benzyl or tetrahydropyranyl group.
[0291] Protecting groups for a carboxyl group might be the
trimethylsilyl, methyl, ethyl, tert.-butyl, benzyl or
tetrahydropyranyl group.
[0292] A protecting group for an amino, alkylamino or imino group
might be the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,
tert.-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or
2,4-dimethoxybenzyl group and additionally, for the amino group,
the phthalyl group.
[0293] For example a protecting group for an ethynyl group might be
the trimethylsilyl, diphenylmethylsilyl, tert.butyldimethylsilyl or
a 1-hydroxy-1-methyl-ethyl group.
[0294] Other protective groups which may be used and their removal
are described in T. W. Greene, P. G. M. Wuts, "Protective Groups in
Organic Synthesis", Wiley, 1991 and 1999.
[0295] Any protective group used is optionally subsequently cleaved
for example by hydrolysis in an aqueous solvent, e.g. In water,
isopropanol/water, tetrahydrofuran/water or dioxane/water, in the
presence of an acid such as trifluoroacetic acid, hydrochloric acid
or sulphuric acid or in the presence of an alkali metal base such
as lithium hydroxide, sodium hydroxide or potassium hydroxide or by
means of ether splitting, e.g. In the presence of
iodotrimethylsilane, at temperatures between 0 and 100.degree. C.,
preferably at temperatures between 10 and 50.degree. C.
[0296] A benzyl, methoxybenzyl or benzyloxycarbonyl group, however,
is cleaved by hydrogenolysis, for example, e.g. with hydrogen in
the presence of a catalyst such as palladium/charcoal in a solvent
such as methanol, ethanol, ethyl acetate, dimethylformamide,
dimethylformamide/acetone or glacial acetic acid, optionally with
the addition of an acid such as hydrochloric acid at temperatures
between 0 and 50.degree. C., but preferably at room temperature,
and under a hydrogen pressure of 1 to 7 bar, but preferably 1 to 5
bar.
[0297] A methoxybenzyl group may also be cleaved in the presence of
an oxidising agent such as cerium(IV) ammonium nitrate in a solvent
such as methylene chloride, acetonitrile or acetonitrile/water at
temperatures between 0 and 50.degree. C., but preferably at room
temperature.
[0298] A methoxy group is conveniently cleaved in the presence of
boron tribromide in a solvent such as methylene chloride at
temperatures between -35 and -25.degree. C.
[0299] A 2,4-dimethoxybenzyl group, however, is preferably cleaved
in trifluoroacetic acid in the presence of anisol.
[0300] A tert.-butyl or tert.-butyloxycarbonyl group is preferably
cleaved by treatment with an acid such as trifluoroacetic acid or
hydrochloric acid, optionally using a solvent such as methylene
chloride, dioxane or ether.
[0301] A phthalyl group is preferably cleaved in the presence of
hydrazine or a primary amine such as methylamine, ethylamine or
n-butylamine in a solvent such as methanol, ethanol, isopropanol,
toluene/water or dioxane at temperatures between 20 and 50.degree.
C.
[0302] An allyloxycarbonyl group is cleaved by treatment with a
catalytic amount of tetrakis-(triphenylphosphine)-palladium(0),
preferably in a solvent such as tetrahydrofuran and preferably in
the presence of an excess of a base such as morpholine or
1,3-dimedone at temperatures between 0 and 100.degree. C.,
preferably at room temperature and under inert gas, or by treatment
with a catalytic amount of tris-(triphenylphosphine)-rhodium(I)
chloride in a solvent such as aqueous ethanol and optionally in the
presence of a base such as 1,4-diazabicyclo[2,2,2]octane at
temperatures between 20 and 70.degree. C.
[0303] Moreover, the compounds of general formula I obtained may be
resolved into their enantiomers and/or diastereomers.
[0304] Thus, for example, the compounds of general formula I
obtained which occur as racemates may be separated by methods known
per se (cf. Allinger N. L. And Eliel E. L. In "Topics in
Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their
optical enantiomers and compounds of general formula I with at
least 2 asymmetric carbon atoms may be resolved into their
diastereomers on the basis of their physical-chemical differences
using methods known per se, e.g. By chromatography and/or
fractional crystallisation, and, if these compounds are obtained in
racemic form, they may subsequently be resolved into the
enantiomers as mentioned above.
[0305] The enantiomers are preferably separated by column
separation on chiral phases or by recrystallisation from an
optically active solvent or by reacting with an optically active
substance which forms salts or derivatives such as e.g. Esters or
amides with the racemic compound, particularly acids and the
activated derivatives or alcohols thereof, and separating the
diastereomeric mixture of salts or derivatives thus obtained, e.g.
on the basis of their differences in solubility, whilst the free
antipodes may be released from the pure diastereomeric salts or
derivatives by the action of suitable agents. Optically active
acids in common use are e.g. The D- and L-forms of tartaric acid or
dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid,
mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid
or quinic acid. An optically active alcohol may be, for example,
(+) or (-)-menthol and an optically active acyl group in amides,
for example, may be a (+)- or (-)-menthyloxycarbonyl.
[0306] Furthermore, the compounds of formula (I) obtained may be
converted into the salts thereof, particularly for pharmaceutical
use into the physiologically acceptable salts with inorganic or
organic acids. Acids which may be used for this purpose include for
example hydrochloric acid, hydrobromic acid, sulphuric acid,
methanesulphonic acid, phosphoric acid, fumaric acid, succinic
acid, lactic acid, citric acid, tartaric acid or maleic acid.
[0307] Moreover, if the new compounds of formula (I) contain a
carboxy group, they may subsequently, if desired, be converted into
the salts thereof with inorganic or organic bases, particularly for
pharmaceutical use into the physiologically acceptable salts
thereof. Suitable bases for this purpose include for example sodium
hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine,
diethanolamine and triethanolamine.
[0308] As already mentioned hereinbefore, the compounds of general
formula (I) and the tautomers, enantiomers, diastereomers and
physiologically acceptable salts thereof have valuable
pharmacological properties, particularly an antithrombotic activity
which is preferably based on an effect on thrombin or factor Xa,
for example on a thrombin-inhibiting or factor Xa-inhibiting
activity, on a prolonging effect on the aPTT time and on an
inhibitory effect on related serine proteases such as e.g.
urokinase, factor Vila, factor IX, factor XI and factor XII.
[0309] The compounds listed in the Experimental Section were
investigated for their effect on the inhibition of factor Xa as
follows:
Method:
[0310] Enzyme-kinetic measurement with chromogenic substrate. The
quantity of p-nitroaniline (pNA) released from the colourless
chromogenic substrate by human factor Xa is determined
photometrically at 405 nm. It is proportional to the activity of
the enzyme used. The inhibition of the enzyme activity by the test
substance (in relation to the solvent control) is determined at
various concentrations of test substance and from this the
IC.sub.50 is calculated, as the concentration which inhibits the
factor Xa used by 50%.
Material:
[0311] Tris(hydroxymethyl)-aminomethane buffer (100 mMol) and
sodium chloride (150 mMol), pH 8.0 plus 1 mg/ml Human Albumin
Fraction V, protease-free Factor Xa (Calbiochem), spec. Activity:
217 IU/mg, final concentration: 7 IU/ml for each reaction
mixture
[0312] Substrate S 2765 (Chromogenix), final concentration: 0.3
mM/l (1 KM) for each reaction mixture
[0313] Test substance: final concentration 100, 30, 10, 3, 1, 0.3,
0.1, 0.03, 0.01, 0.003, 0.001 .mu.Mol/l
Procedure:
[0314] 10 .mu.l of a 23.5-times concentrated starting solution of
the test substance or solvent (control), 175 .mu.l of TRIS/HSA
buffer and 25 .mu.l of a 65.8 U/L Factor Xa working solution are
incubated for 10 minutes at 37.degree. C. After the addition of 25
.mu.l of S 2765 working solution (2.82 mMol/l) the sample is
measured in a photometer (SpectraMax 250) at 405 nm for 600 seconds
at 37.degree. C.
Evaluation:
[0315] 1. Determining the maximum increase (deltaOD/minutes) over
21 measuring points. 2. Determining the % inhibition based on the
solvent control. 3. Plotting a dosage/activity curve (% inhibition
vs substance concentration). 4. Determining the IC.sub.50 by
interpolating the X-value (substance concentration) of the
dosage/activity curve at Y=50% inhibition.
[0316] All the compounds tested had an IC.sub.50 value of less than
100 .mu.mol/L.
[0317] The compounds prepared according to the invention are
generally well tolerated.
[0318] In view of their pharmacological properties the new
compounds and the physiologically acceptable salts thereof are
suitable for the prevention and treatment of venous and arterial
thrombotic diseases, such as for example the prevention and
treatment of deep leg vein thrombosis, for preventing reocclusions
after bypass operations or angioplasty (PT(C)A), and occlusion in
peripheral arterial diseases, and for preventing and treating
pulmonary embolism, disseminated intravascular coagulation and
severe sepsis, for preventing and treating DVT in patients with
exacerbated COPD, for treating ulcerative colitis, for preventing
and treating coronary thrombosis, for preventing stroke and the
occlusion of shunts.
[0319] In addition, the compounds according to the invention are
suitable for antithrombotic support in thrombolytic treatment, such
as for example with alteplase, reteplase, tenecteplase,
staphylokinase or streptokinase, for preventing long-term
restenosis after PT(C)A, for the prevention and treatment of
ischaemic events in patients with all forms of coronary heart
disease, for preventing metastasis and the growth of tumours and
inflammatory processes, e.g. In the treatment of pulmonary
fibrosis, for preventing and treating rheumatoid arthritis, for
preventing and treating fibrin-dependent tissue adhesions and/or
the formation of scar tissue and for promoting wound healing
processes.
[0320] In view of their pharmacological properties the new
compounds and the physiologically acceptable salts thereof are also
suitable for the treatment of Alzheimer's and Parkinson's disease.
One explanation for this arises for example from the following
findings, from which it can be concluded that thrombin inhibitors
or factor Xa inhibitors, by inhibiting thrombin formation or
thrombin activity, may be valuable drugs for treating Alzheimer's
and Parkinson's disease. Clinical and experimental studies indicate
that neurotoxic mechanisms, for example the inflammation which is
associated with the activation of proteases of the clotting
cascade, are involved in the dying of neurones following brain
injury. Various studies point to the involvement of thrombin in
neurodegenerative processes, for example following a stroke,
repeated bypass operations or traumatic brain injury. An increased
thrombin activity has been demonstrated some days after peripheral
nerve damage, for example. It has also been shown that thrombin
causes a neurite retraction, as well as glia proliferation, and
apoptosis in primary cultures of neurones and neuroblastoma cells
(for a summary see: Neurobiol. Aging 2004, 25(6), 783-793).
Moreover, various in vitro studies on the brains of patients with
Alzheimer's disease indicated that thrombin plays a role in the
pathogenesis of this disease (Neurosci. Lett. 1992, 146, 152-54). A
concentration of immune-reactive thrombin has been detected in
neurite plaques in the brains of Alzheimer's patients. It has been
demonstrated in vitro that thrombin also plays a part in the
regulation and stimulation of the production of the "Amyloid
Precursor Protein" (APP) as well as in the cleaving of the APP into
fragments which can be detected in the brains of Alzheimer's
patients. Moreover, it has been demonstrated that the
thrombin-induced microglial activation leads in vivo to the
degeneration of nigral dopaminergic neurones. These findings lead
one to conclude that microglial activation, triggered by endogenous
substance(s) such as thrombin, for example, are involved in the
neuropathological process of the cell death of dopaminergic
neurones of the kind which occurs in patients with Parkinson's
disease (J. Neurosci. 2003, 23, 5877-86).
[0321] The dosage required to achieve such an effect is
appropriately 0.01 to 3 mg/kg, preferably 0.03 to 1.0 mg/kg by
intravenous route, and 0.03 to 30 mg/kg, preferably 0.1 to 10 mg/kg
by oral route, in each case administered 1 to 4 times a day.
[0322] For this purpose, the compounds of formula I prepared
according to the invention may be formulated, optionally together
with other active substances, with one or more inert conventional
carriers and/or diluents, e.g. with corn starch, lactose, glucose,
microcrystalline cellulose, magnesium stearate,
polyvinylpyrrolidone, citric acid, tartaric acid, water,
water/ethanol, water/glycerol, water/sorbitol, water/polyethylene
glycol, propylene glycol, cetylstearyl alcohol,
carboxymethylcellulose or fatty substances such as hard fat or
suitable mixtures thereof, to produce conventional galenic
preparations such as plain or coated tablets, capsules, powders,
suspensions or suppositories.
[0323] The new compounds and the physiologically acceptable salts
thereof may be used therapeutically in conjunction with
acetylsalicylic acid, with inhibitors of platelet aggregation such
as fibrinogen receptor antagonists (e.g. abciximab, eptifibatide,
tirofiban, roxifiban), with physiological activators and inhibitors
of the clotting system and the recombinant analogues thereof (e.g.
Protein C, TFPI, antithrombin), with inhibitors of ADP-induced
aggregation (e.g. Clopidogrel, ticlopidine), with P.sub.2T receptor
antagonists (e.g. Cangrelor) or with combined thromboxane receptor
antagonists/synthetase inhibitors (e.g. Terbogrel).
Experimental Section
[0324] The Examples that follow are intended to illustrate the
invention, without restricting its scope.
[0325] As a rule, melting points and/or IR, UV, .sup.1H-NMR and/or
mass spectra have been obtained for the compounds prepared. Unless
otherwise stated, R.sub.f values were determined using ready-made
silica gel 60 F.sub.254 TLC plates (E. Merck, Darmstadt, Item no.
1.05714) without chamber saturation. The R.sub.f values given under
the heading Alox were determined using ready-made aluminium oxide
60 F.sub.254 TLC plates (E. Merck, Darmstadt, Item no. 1.05713)
without chamber saturation. The R.sub.f values given under the
heading Reversed-phase-8 (RP-8) were determined using ready-made
RP-8 F.sub.254s TLC plates (E. Merck, Darmstadt, Item no. 1.15684)
without chamber saturation. The ratios given for the eluants refer
to units by volume of the solvents in question. For
chromato-graphic purification silica gel made by Messrs Millipore
(MATREX.TM., 35-70 .mu.m) was used. Unless more detailed
information is provided as to the configuration, it is not clear
whether the products are pure stereoisomers or mixtures of
enantiomers and diastereomers.
[0326] The following abbreviations are used in the test
descriptions: [0327] BOC tert.-butoxycarbonyl [0328] DIPEA
N-ethyl-diisopropylamine [0329] DMF N,N-dimethylformamide [0330]
sat. saturated [0331] h hour(s) [0332] HATU
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophospha-
te [0333] NaHMDS sodium hexamethyldisilazide [0334] i. vac. in
vacuo [0335] conc. concentrated [0336] min minute(s) [0337] NMM
N-methyl-morpholine [0338] R.sub.f retention factor [0339] R.sub.t
retention time [0340] TBTU
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate [0341] TEA triethylamine [0342] TFA
trifluoroacetic acid [0343] THF tetrahydrofuran.
[0344] The term "thiophen-2-yl" or "thien-2-yl" denotes the group
shown in the box:
##STR00024##
[0345] The HPLC-MS data were obtained under the following
conditions:
Method 1:
[0346] Waters ZQ2000 mass spectrometer, Gilson G215 Autosampler,
HP1100 HPLC and diode array detector.
[0347] The mobile phase used was:
A: water with 0.10% TFA B: acetonitrile with 0.10% TFA
TABLE-US-00001 time in min % A % B flow rate in ml/min 0.00 95 5
1.00 0.40 95 5 1.00 4.00 2 98 1.00 4.35 2 98 1.00 4.50 95 5
1.00
[0348] The stationary phase used was an X-Terra MS C18 column, 3.5
.mu.m, 4.6 mm.times.50 mm.
[0349] The diode array detection was carried out at a wavelength
range of 210-500 nm.
Method 2:
Waters Alliance 2695, PDA Detector 2996, ZQ 2002
[0350] The mobile phase used was:
A: water with 0.10% TFA B: acetonitrile with 0.10% TFA
TABLE-US-00002 time in min % A % B flow rate in ml/min 0.00 95 5
1.00 0.10 95 5 1.00 3.10 2 98 1.00 4.50 2 98 1.00 5.00 95 5
1.00
[0351] The stationary phase used was a Waters X-Terra MS C18
column, 2.5 .mu.m, 4.6 mm.times.30 mm
Method 3:
Waters Alliance 2695, PDA Detector 2996
[0352] The mobile phase used was:
A: water with 0.13% TFA B: acetonitrile with 0.10% TFA
TABLE-US-00003 time in min % A % B flow rate in ml/min 0.00 95 5
1.00 0.75 95 5 1.00 5.25 2 98 1.00 5.75 2 98 1.00 6.05 95 5 1.00
6.55 95 5 1.00
[0353] The stationary phase used was a Varian Microsorb 100 C18
column; 3.5 .mu.m; 4.6 mm.times.50 mm
[0354] Method 3a
Waters Alliance 2695, PDA Detector 2996
[0355] The mobile phase used was:
A: water with 0.1% TFA B: acetonitrile with 0.1% TFA
TABLE-US-00004 time in min % A % B flow rate in ml/min 0.00 95 5
1.00 0.1 95 5 1.00 3.1 2 98 1.00 4.5 2 98 1.00 5.0 95 5 1.00
[0356] The stationary phase used was a Varian Microsorb 100 C18
column; 2.5 .mu.m; 4.6 mm.times.30 mm
Method 4:
Agilent 1100
[0357] The mobile phase used was:
A: water with 0.10% formic acid B: acetonitrile with 0.10% formic
acid
TABLE-US-00005 time in min % A % B flow rate in ml/min 0.00 95 5
1.60 4.50 10 90 1.60 5.00 10 90 1.60 5.50 90 10 1.60
[0358] The stationary phase used was a Zorbax StableBond C18
column; 3.5 .mu.m; 4.6 mm.times.75 mm
Method 5:
Waters Alliance 2695, PDA Detector 2996
[0359] The mobile phase used was:
A: water with 0.1% TFA B: acetonitrile with 0.1% TFA
TABLE-US-00006 time in min % A % B flow rate in ml/min 0.00 95 5
5.00 0.20 95 5 5.00 1.35 2 98 5.00 1.55 2 98 5.00 1.65 95 5 5.00
1.85 95 5 5.00
[0360] The stationary phase used was an Interchim HS Strategy 5
C18-2 column; 5 .mu.m; 4.6 mm.times.50 mm
Method 6:
Waters Alliance 26905, PDA Detector 996
[0361] The mobile phase used was:
A: water with 0.1% TFA B: acetonitrile with 0.1% TFA
TABLE-US-00007 time in min % A % B flow rate in ml/min 0.00 95 5
2.00 0.10 95 5 2.00 2.10 2 98 2.00 3.00 2 98 2.00 3.25 95 5
2.00
[0362] The stationary phase used was a MerckChromolith SpeedRod
RP-18e column; 4.6 mm.times.50 mm
EXAMPLE 1
3-[(5-bromo-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro-1-
H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic acid amide
##STR00025##
[0363] (a) 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d][azepine
[0364] 8.4 g (29.0 mmol)
3-trifluoroacetyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine are
suspended under a nitrogen atmosphere in 80 ml of methanol and
combined with 5 ml NaOH solution (50%) and stirred for 2 h at
70.degree. C.
[0365] The methanol is distilled off using the rotary evaporator,
the residue is combined with water and extracted with
tert.-butylethylether. The organic phase is washed with NaOH
solution (50%) and sat. Sodium chloride solution, dried on sodium
sulphate and evaporated to dryness i. vac.
[0366] Yield: 5.1 g (91%)
[0367] R.sub.f value: 0.28 (aluminium oxide;
dichloromethane/ethanol=95:5)
[0368] C.sub.10H.sub.12N.sub.2O.sub.2 (192.22)
[0369] Mass spectrum: (M+H).sup.+=193
(b) 3-methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
[0370] 5.0 g (26.0 mmol)
7-nitro-2,3,4,5-tetrahydro-1H-benzo[d][azepine are mixed in 9.8 ml
(260.1 mol) formic acid with 15.5 ml (208.1 mmol) formalin solution
in water (37%), with stirring, at room temperature, and stirred
overnight at 70.degree. C. The reaction mixture is made alkaline
with NaOH solution (50%) while cooling with an ice bath and
extracted with tert.-butylmethylether. The organic phase is dried
on sodium sulphate and evaporated to dryness i. vac.
[0371] Yield: 4.8 g (90%)
[0372] R.sub.f value: 0.65 (aluminium oxide;
dichloromethane/ethanol=95:5)
[0373] C.sub.11H.sub.14N.sub.2O.sub.2 (206.24)
[0374] Mass spectrum: (M+H).sup.+=207
(c) 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine
[0375] 4.8 g (23.2 mmol)
3-methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine are
dissolved in 45 ml of methanol and combined with 400 mg Pd/C 10%.
The mixture is hydrogenated in a Parr apparatus at room temperature
at 3 bar hydrogen pressure for 5 hours. Then the catalyst is
filtered off and the filtrate is evaporated down i. vac.
[0376] Yield: 3.9 g (96%)
[0377] R.sub.f value: 0.36 (aluminium oxide;
dichloromethane/ethanol=98:2)
[0378] C.sub.11H.sub.16N.sub.2 (176.26)
[0379] Mass spectrum: (M+H).sup.+=177
(d) 3-amino-tetrahydro-furan-3-carboxylic acid-hydrochloride
[0380] 3.5 g (15.1 mmol)
3-tert.-butoxycarbonylamino-tetrahydro-furan-3-carboxylic acid are
dissolved in 150 ml of 1-molar hydrochloric acid and stirred for 1
h at room temperature. Then the reaction mixture is
lyophilised.
[0381] Yield: 2.5 g (100%)
[0382] C.sub.5H.sub.9NO.sub.3*HCl (167.59)
[0383] Mass spectrum: (M+H).sup.+=132
(e)
3-[(5-bromo-thiophen-2-yl)-carbonylamino]-tetrahydro-furan-3-carboxyli-
c acid
[0384] 3.1 g (14.9 mmol) 5-bromo-thiophene-2-carboxylic acid in 50
ml dichloromethane are combined with 5.4 ml (74.6 mmol) thionyl
chloride with stirring at room temperature and stirred for 3.5 h at
reflux temperature. Then the reaction mixture is evaporated to
dryness.
[0385] 2.5 g (14.9 mmol) 3-amino-tetrahydro-furan-3-carboxylic
acid-hydrochloride are dissolved in 2.0 ml (14.9 mmol) TEA and 150
ml acetonitrile and combined with 5.9 ml (22.4 mmol)
N,O-bis-(trimethylsilyl)-trifluoro-acetamide with stirring and
refluxed for 4 h with stirring. The reaction mixture is combined
with 4.1 ml (29.8 mmol) TEA and the solution of the prepared acid
chloride in 50 ml acetonitrile, stirred for 15 min at reflux
temperature and then cooled slowly to room temperature. Then the
mixture is evaporated to dryness i. vac., the residue is combined
with water and 2-molar sodium carbonate solution and washed with
diethyl ether. The aqueous phase is adjusted to pH 1 with 20 ml
conc. Hydrochloric acid, the precipitate is suction filtered and
dried at 50.degree. C. in the vacuum drying cupboard.
[0386] Yield: 3.6 g (75%)
[0387] C.sub.10H.sub.10BrNa.sub.4S (320.16)
[0388] Mass spectrum: (M-H).sup.-=318/320 (bromine isotopes)
(f)
3-[(5-bromo-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahyd-
ro-1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic acid
amide
[0389] 700.0 mg (2.19 mmol)
3-[(5-bromo-thiophen-2-yl)-carbonylamino]-tetrahydro-furan-3-carboxylic
acid are combined with 890.0 mg (2.34 mmol) HATU and 601.0 .mu.l
(5.47 mmol) NMM in 10 ml DMF with stirring at room temperature and
stirred for 10 min. Then 385.0 mg (2.19 mmol)
3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine are added
and the mixture is stirred overnight at 65.degree. C. The reaction
mixture is combined with water and sat. Sodium hydrogen carbonate
solution, the precipitate is filtered off and purified by
chromatography on aluminium oxide (eluant: dichloromethane/ethanol
100:0 to 98:2).
[0390] Yield: 850.0 mg (81%)
[0391] R.sub.f value: 0.62 (aluminium oxide;
dichloromethane/ethanol=95:5)
[0392] C.sub.21H.sub.24BrN.sub.3O.sub.3S (478.40)
[0393] Mass spectrum: (M+H).sup.+=478/480 (bromine isotopes)
EXAMPLE 2
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro--
1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic acid amide
##STR00026##
[0394] (a) benzyl
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-tetrahydro-furan-3-carboxylate
[0395] 1.59 g (9.8 mmol) 5-chloro-thiophene-2-carboxylic acid is
dissolved in 30 ml DMF and stirred with 3.61 g (10.7 mmol) benzyl
3-amino-tetrahydro-furan-3-carboxylate and 3.46 g (10.8 mmol) TBTU
and 4.3 ml (39 mmol) NMM at room temperature for 20 h. Then the
mixture is evaporated down and purified by chromatography on silica
gel (eluant: dichloromethane/ethanol 100:0 to 94:6).
[0396] Yield: quantitative
[0397] R.sub.f value: 0.59 (silica gel;
dichloromethane/ethanol=9:1)
[0398] C.sub.17H.sub.16ClNO.sub.4S (365.83)
[0399] Mass spectrum: (M+H).sup.+=366/368 (chlorine isotopes)
(b)
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-tetrahydro-furan-3-carboxyl-
ic acid
[0400] 3.6 g (9.8 mmol) benzyl
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-tetrahydro-furan-3-carboxylate
are dissolved in 60 ml of ethanol and combined with 39.1 ml (39.1
mmol) 1-molar aqueous sodium hydroxide solution and stirred for 6 h
at room temperature. After evaporation i. vac. The residue is
combined with 1-molar aqueous hydrochloric acid while cooling with
an ice bath, the precipitate is suction filtered and dried at
60.degree. C. in the vacuum drying cupboard.
[0401] Yield: 2.5 g (91%)
[0402] R.sub.f value: 0.13 (silica gel; dichloromethane/ethanol
9:1)
[0403] C.sub.10H.sub.10ClNO.sub.4S (275.71)
[0404] Mass spectrum: (M-H).sup.-=274/276 (chlorine isotopes)
(c)
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahy-
dro-1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic acid
amide
[0405] Prepared analogously to Example 2(a) from
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-tetrahydro-furan-3-carboxylic
acid and 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine
with TBTU and TEA in THF at room temperature with subsequent
purification by chromatography with aluminium oxide (eluant:
dichloromethane/ethanol 100:0 to 97:3).
[0406] Yield: 67%
[0407] R.sub.f value: 0.63 (aluminium oxide;
dichloromethane/ethanol=95:5)
[0408] C.sub.21H.sub.24ClN.sub.3O.sub.3S (433.95)
[0409] Mass spectrum: (M+H).sup.+=434/436 (chlorine isotopes)
EXAMPLE 3
5-chloro-thiophene-2-carboxylic
acid-N-[1-(3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamo-
yl)-1-methyl-ethyl]-amide
##STR00027##
[0410] (a)
2-(5-chloro-thiophen-2-yl)-4,4-dimethyl-4H-oxazol-5-one
[0411] 1.0 g (4.0 mmol)
2-[(5-chloro-thiophen-2-yl)-carbonylamino]-2-methyl-propionic acid
in 30 ml acetic anhydride are stirred for 1 h at 85.degree. C. Then
the reaction mixture is evaporated to dryness.
[0412] Yield: 927.3 mg (100%)
[0413] C.sub.9H.sub.8ClNO.sub.2S (229.68)
[0414] Mass spectrum: (M+H).sup.+=230
(b) 5-chloro-thiophene-2-carboxylic
acid-N-[1-(3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamo-
yl)-1-methyl-ethyl]-amide
[0415] 200.0 .mu.l (10.0 .mu.mol) of a 0.05 molar
2-(5-chloro-thiophen-2-yl)-4,4-dimethyl-4H-oxazol-5-one solution in
toluene/acetic acid 9:1 are combined with 200.0 .mu.l (10.0
.mu.mol) of a 0.05-molar
3-cyclopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine
solution in DMF and 1.7 .mu.l (10.0 .mu.mol) DIPEA, heated to
80.degree. C. overnight and left to stand for 2 days at room
temperature. The reaction solution is filtered through basic
aluminium oxide and the filtrate is evaporated down i. vac.
[0416] Yield: quantitative
[0417] R.sub.t value: 3.31 min (HPLC-MS, method 1)
[0418] C.sub.22H.sub.26ClN.sub.3O.sub.2S (431.99)
[0419] Mass spectrum: (M+H).sup.+=432/434 (chlorine isotopes)
EXAMPLE 4
5-chloro-thiophene-2-carboxylic
acid-N-{1-methyl-1-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-benz-
o[d]azepin-7-ylcarbamoyl]ethyl}-amide
##STR00028##
[0420] (a)
2-[(5-chloro-thiophen-2-yl)-carbonylamino]-2-methyl-propionic
acid
[0421] 4.5 g (27.7 mmol) 5-chloro-thiophene-2-carboxylic acid are
combined with 8.0 ml (110.7 mmol) thionyl chloride in 250 ml
dichloromethane with stirring at room temperature and stirred for 3
h at reflux temperature. Then the reaction mixture is evaporated to
dryness.
[0422] 2.9 g (27.7 mmol) 2-amino-isobutyric acid are combined with
8.0 ml (30.4 mmol) N,O-bis-(trimethylsilyl)-trifluoro-acetamide in
300 ml acetonitrile with stirring and stirred for 3.5 h at reflux
temperature. The reaction mixture is combined with 8.5 ml (60.9
mmol) TEA and the solution of the prepared acid chloride in 75 ml
acetonitrile, stirred for 15 min at reflux temperature and then
slowly cooled to room temperature. The reaction mixture is
evaporated to dryness i. vac., the residue is mixed with water and
2-molar sodium carbonate solution and washed with diethyl ether.
The aqueous phase is adjusted to pH 1 with 20 ml conc. Hydrochloric
acid, the precipitate is suction filtered and dried at 50.degree.
C. in the vacuum drying cupboard.
[0423] Yield: 5.9 g (86%)
[0424] C.sub.9H.sub.10ClNO.sub.3S (247.70) [0425] Mass spectrum:
(M+H).sup.+=248/250 (chlorine isotopes)
(b) 5-chloro-thiophene-2-carboxylic
acid-N-{1-methyl-1-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-benz-
o[d]azepin-7-ylcarbamoyl]-ethyl}-amide
[0426] Prepared analogously to Example 2-c from
2-[(5-chloro-thiophen-2-yl)-carbonylamino]-2-methyl-propionic acid
and
3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-amin-
e with TBTU and NMM in DMF at room temperature with subsequent
filtration through aluminium oxide.
[0427] Yield: (95%)
[0428] R.sub.f value: 0.65 (silica gel;
dichloromethane/ethanol=9:1)
[0429] C.sub.21H.sub.21ClF.sub.3N.sub.3O.sub.3S (487.92)
[0430] Mass spectrum: (M-H).sup.-=486/488 (chlorine isotopes)
EXAMPLE 5
5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-e-
thyl]-amide
##STR00029##
[0432] 500.0 mg (1.03 mmol) 5-chloro-thiophene-2-carboxylic
acid-N-{1-methyl-1-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-benz-
o[d]azepin-7-ylcarbamoyl]-ethyl}-amide are combined with 637.0 mg
(4.61 mmol) potassium carbonate in 15 ml of methanol and 10 ml of
water with stirring at room temperature and stirred for 3 h at
reflux temperature. The reaction mixture is evaporated down i.
vac., the residue is combined with water, the precipitate is
filtered off and dried in the vacuum drying cupboard at 50.degree.
C.
[0433] Yield: 340.0 mg (85%)
[0434] R.sub.f value: 0.20 (silica gel;
dichloromethane/methanol/conc. Ammonia solution=80:20:2)
[0435] C.sub.19H.sub.22ClN.sub.3O.sub.2S (391.92)
[0436] Mass spectrum: (M+H).sup.-=390/392 (chlorine isotopes)
EXAMPLE 6
5-chloro-thiophene-2-carboxylic
acid-N-[1-(3-acetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-1-
-methyl-ethyl]-amide
##STR00030##
[0438] 100.0 mg (0.26 mmol) 5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-e-
thyl]-amide are combined with 43.0 .mu.l (0.31 mmol) TEA and 27.0
.mu.l (0.29 mmol) acetic anhydride in 5 ml THF with stirring at
room temperature and stirred for 2 h at room temperature. The
reaction mixture is mixed with water, the precipitate is filtered
off and dried in the vacuum drying cupboard at 50.degree. C.
[0439] Yield: 80.0 mg (72%)
[0440] R.sub.f value: 0.90 (silica gel;
dichloromethane/methanol/conc. Ammonia solution=80:20:2)
[0441] C.sub.21H.sub.24ClN.sub.3O.sub.3S (433.95)
[0442] Mass spectrum: (M+H).sup.+=434/436 (chlorine isotopes)
EXAMPLE 7
5-chloro-thiophene-2-carboxylic
acid-N-[1-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-1--
methyl-ethyl]-amide
##STR00031##
[0444] 100.0 mg (0.26 mmol) 5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-e-
thyl]-amide in 5 ml acetone are combined with 74.0 mg (0.54 mmol)
potassium carbonate and 21.0 .mu.l (0.26 mmol) iodoethane with
stirring at room temperature and stirred for 3 h at reflux
temperature. The reaction mixture is mixed with water at room
temperature, the precipitate is filtered off and dried in the
vacuum drying cupboard at 50.degree. C.
[0445] Yield: 60.0 mg (56%)
[0446] R.sub.f value: 0.30 (silica gel;
dichloromethane/methanol/conc. Ammonia solution=80:20:2)
[0447] C.sub.21H.sub.26ClN.sub.3O.sub.2S (419.97)
[0448] Mass spectrum: (M+H).sup.+=420/422 (chlorine isotopes)
EXAMPLE 8
5-ethynyl-N-[1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-y-
lcarbamoyl)-ethyl]-thiophene-2-carboxylic acid amide
##STR00032##
[0449] (a) ethyl
5-trimethylsilylethynyl-thiophene-2-carboxylate
[0450] Under an argon atmosphere a solution of 32.5 g (138.0 mmol)
ethyl 5-bromo-thiophene-2-carboxylate in 320 ml acetonitrile and
640 ml THF is combined with 1.3 g (7.0 mmol) copper-(I)-iodide and
39.0 g (276.0 mmol) trimethyl-silylacetylene with stirring, the
mixture is stirred for 5 min and then 5.6 g (7.0 mmol)
1,1-bis-(diphenylphosphino)-ferrocene-dichloropalladium(II))-PdCl.sub.2
in a complex with CH.sub.2Cl.sub.2 1/1 and 57.4 ml (414.0 mmol) TEA
are added. The reaction mixture is stirred overnight at room
temperature, evaporated down i. vac., the residue is combined with
ethyl acetate and washed with ammonia solution (5%) and water. The
organic phase is dried on sodium sulphate and evaporated to dryness
i. vac. The residue is combined with diethyl ether, the precipitate
is suction filtered and dried.
[0451] Yield: quantitative
[0452] R.sub.f value: 0.71 (silica gel; petroleum ether/ethyl
acetate=8:2)
[0453] C.sub.12H.sub.16O.sub.2SSi (252.41)
[0454] Mass spectrum: (M+H).sup.+=253
(b) 5-ethynyl-thiophene-2-carboxylic acid
[0455] The solution of 36.2 g (114.0 mmol) ethyl
5-trimethylsilanylethynyl-thiophene-2-carboxylate in 185 ml of
ethanol is combined with 730.0 ml (1.46 mol) 2-molar aqueous sodium
hydroxide solution and stirred overnight at 50.degree. C. The
reaction mixture is evaporated to dryness i. vac., combined with
water and washed with dichloromethane. The aqueous phase is
acidified with 6-molar aqueous hydrochloric acid while cooling with
an ice bath, the precipitate is filtered off and dried at
50.degree. C. in the vacuum drying cupboard.
[0456] Yield: 8.9 g (41%)
[0457] R.sub.f value: 0.64 (RP-8; methanol/NaCl solution
(5%)=6:4)
[0458] C.sub.7H.sub.4O.sub.2S (152.17)
[0459] Mass spectrum: (M-H).sup.-=151
(c) methyl
2-[(5-ethynyl-thiophen-2-yl)-carbonylamino]-2-methyl-propionate
[0460] A solution of 6.0 g (39.4 mmol)
5-ethynyl-thiophene-2-carboxylic acid in 180 ml THF is combined
with 20.6 ml (118.3 mmol) DIPEA and 13.9 g (43.3 mmol) TBTU with
stirring and stirred for 10 min. Then 6.1 g (39.4 mmol) methyl
2-amino-isobutyrate hydrochloride is added and the mixture is
stirred overnight at room temperature. The reaction mixture is
evaporated to dryness i. vac., mixed with ethyl acetate and washed
with water and sodium hydrogen carbonate solution (5%). The organic
phase is dried with sodium sulphate and evaporated down i.vac.
[0461] Yield: 9.3 g (94%)
[0462] R.sub.f value: 0.71 (silica gel;
dichloromethane/ethanol=9:1)
[0463] C.sub.12H.sub.13NO.sub.3S (251.30)
[0464] Mass spectrum: (M+H).sup.+=252
(d) 2-[(5-ethynyl-thiophen-2-yl)-carbonylamino]-2-methyl-propionic
acid
[0465] 9.3 g (37.1 mmol) methyl
2-[(5-ethynyl-thiophen-2-yl)-carbonylamino]-2-methyl-propionate are
dissolved in 550 ml of water and 370 ml THF and combined with 74.2
ml (74.2 mmol) 1-molar aqueous lithium hydroxide solution and
stirred for 2 h at room temperature. THF is distilled off i. vac.
And the residue is extracted with dichloromethane. The aqueous
phase is acidified with 3-molar aqueous hydrochloric acid, the
precipitate is filtered off and dried at 50.degree. C. in the
vacuum drying cupboard.
[0466] Yield: 8.4 g (95%)
[0467] R.sub.f value: 0.20 (silica gel;
dichloromethane/ethanol=9:1)
[0468] C.sub.11H.sub.11NO.sub.3S (237.28)
[0469] Mass spectrum: (M+H).sup.+=238
e) 2-(5-ethynyl-thiophen-2-yl)-4,4-dimethyl-4H-oxazol-5-one
[0470] Prepared analogously to Example 3-a from
2-[(5-ethynyl-thiophen-2-yl)-carbonylamino]-2-methyl-propionic acid
in acetic anhydride at 65.degree. C. with subsequent purification
by chromatography on silica gel with the eluant (petroleum
ether/ethyl acetate=2:1).
[0471] Yield: 3.1 g (84%)
[0472] R.sub.f value: 0.67 (silica gel; petroleum ether/ethyl
acetate=7:3)
[0473] C.sub.11H.sub.9NO.sub.2S (219.26)
[0474] Mass spectrum: (M+H).sup.+=220
f)
5-ethynyl-N-[1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin--
7-ylcarbamoyl)-ethyl]-thiophene-2-carboxylic acid amide
[0475] A solution of 150.0 mg (0.7 mmol)
2-(5-ethynyl-thiophen-2-yl)-4,4-dimethyl-4H-oxazol-5-one in 7.5 ml
of toluene and 850.0 .mu.l acetic acid is combined with a solution
of 134.2 mg (0.8 mmol)
3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in 8.5 ml
DMF with stirring and stirred overnight at 65.degree. C. The
reaction mixture is evaporated to dryness i. vac., dissolved in
dichloromethane and ethanol and filtered through aluminium oxide.
The filtrate is combined with water, the precipitate is suction
filtered and dried at 55.degree. C. in the vacuum drying
cupboard.
[0476] Yield: 260.0 mg (96%)
[0477] R.sub.f value: 0.43 (RP-8; methanol/NaCl solution
(5%)=6:4)
[0478] C.sub.22H.sub.25N.sub.3O.sub.2S (395.52)
[0479] Mass spectrum: (M+H).sup.+=396
EXAMPLE 9
5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbam-
oyl)-1-methyl-ethyl]-amide/5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbam-
oyl)-1-methyl-ethyl]-amide
##STR00033##
[0480] (a)
3-trifluoroacetyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
[0481] 12.5 g (51.39 mmol)
3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine in 30 ml
acetic anhydride are dissolved in 18.9 ml (352.0 mmol) sulphuric
acid (conc.) and at -5.degree. C. to 0.degree. C. slowly combined
with 3.6 ml (51.39 mmol) nitric acid (65%) and stirred for 1 h at
0.degree. C. The reaction mixture is added to water, extracted with
ethyl acetate, the organic phase is dried on sodium sulphate and
evaporated to dryness. The residue is recrystallised from
ethanol.
[0482] Yield: 10.4 g (70%)
[0483] R.sub.f value: 0.78 (silica gel;
dichloromethane/ethanol=95:5)
[0484] C.sub.12H.sub.11F.sub.3N.sub.2O.sub.3 (288.22)
[0485] Mass spectrum: (M+H).sup.+=289
(b) tert. Butyl
7-nitro-2,3,4,5-tetrahydro-benzo[y]azepin-3-carboxylate
[0486] 5.0 g (17.34 mmol)
3-trifluoroacetyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine in
50 ml THF are combined with 10.4 ml (20.81 mmol) 2-molar sodium
hydroxide solution and stirred for 30 min at room temperature. The
reaction solution is combined with 1.88 g (17.69 mmol) sodium
carbonate and 5.0 ml of water and while cooling with an ice bath a
solution of 3.98 g (18.21 mmol) di-tert-butyl-dicarbonate in 15 ml
THF is metered in and the mixture is stirred for 1 h at room
temperature. Then the insoluble matter is filtered off, the
filtrate is combined with ethyl acetate and washed with sat. Sodium
chloride solution. The organic phase is dried on sodium sulphate
and the filtrate is evaporated to dryness i. vac.
[0487] Yield: quantitative
[0488] R.sub.f value: 0.81 (silica gel;
dichloromethane/ethanol=95:5)
[0489] C.sub.15H.sub.20N.sub.2O.sub.4 (292.33)
[0490] Mass spectrum: (M-isobuten+H).sup.+=237
(c)
8-nitro-1,3,4,5-tetrahydro-benzo[d]azepin-2-one/7-nitro-1,3,4,5-tetrah-
ydro-benzo[d]azepin-2-one
[0491] 5.1 g (17.3 mmol) tert. Butyl
7-nitro-2,3,4,5-tetrahydro-benzo[d]azepine-3-carboxylate in 50 ml
of ethyl acetate and 70 ml of water are combined with 8.9 g (41.63
mmol) sodium metaperiodate, 0.54 g (2.60 mmol) ruthenium
chloride*H.sub.2O with vigorous stirring and stirred for 3.5 h at
room temperature. Then the insoluble matter is filtered off, the
filtrate is combined with ethyl acetate and washed with sodium
disulphite solution (10%) and sat. Sodium chloride solution. The
organic phase is dried on sodium sulphate and the filtrate is
evaporated to dryness i. vac. The residue is dissolved in 60 ml
dichloromethane, 6.0 ml TFA are added and the mixture is stirred
overnight. The reaction solution is evaporated to dryness i. vac.,
combined with dichloromethane, washed with water and sat sodium
hydrogen carbonate solution, dried on sodium sulphate and
evaporated to dryness i. vac.
[0492] Yield: 2.3 g (65%)
[0493] R.sub.f value: 0.52 (silica gel;
dichloromethane/ethanol=9:1)
[0494] C.sub.10H.sub.10N.sub.2O.sub.3 (206.20)
[0495] Mass spectrum: (M+H).sup.+=207
(d)
8-amino-1,3,4,5-tetrahydro-benzo[d]azepin-2-one/7-amino-1,3,4,5-tetrah-
ydro-benzo[d]azepin-2-one
[0496] 2.3 g (11.2 mmol)
8-nitro-1,3,4,5-tetrahydro-benzo[d]azepin-2-one/7-nitro-1,3,4,5-tetrahydr-
o-benzo[d]azepin-2-one are dissolved in 40 ml of methanol and
combined with 300 mg Pd/C 10%. The mixture is hydrogenated in a
Parr apparatus at room temperature at 3 bar hydrogen pressure for
17 hours. Then the catalyst is filtered off and the filtrate is
evaporated down i. vac.
[0497] Yield: 1.51 g (77%)
[0498] R.sub.f value: 0.10 (silica gel;
dichloromethane/ethanol=95:5)
[0499] C.sub.10H.sub.12N.sub.2O (176.22)
[0500] Mass spectrum: (M+H).sup.+=177
(e) 5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(4-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbam-
oyl)-1-methyl-ethyl]-amide/5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbam-
oyl)-1-methyl-ethyl]-amide
[0501] Prepared analogously to Example 1 from
2-[(5-chloro-thiophen-2-yl)-carbonylamino-2-methyl-propionic acid
with HATU, NMM and
8-amino-1,3,4,5-tetrahydro-benzo[d]azepin-2-on/7-amino-1,3,4,5-tetrahydro-
-benzo[d]azepin-2-one in DMF with subsequent purification by
chromatography on silica gel with the eluant
(dichloromethane/ethanol 100:0 to 92:8).
[0502] Yield: quantitative
[0503] R.sub.f value: 0.40 (silica gel;
dichloromethane/ethanol=9:1)
[0504] C.sub.19H.sub.20ClN.sub.3O.sub.3S (405.90)
[0505] Mass spectrum: (M+H).sup.+=406/408 (chlorine isotopes)
[0506] The following compounds may be prepared analogously to
Example 1:
TABLE-US-00008 Structural formula Yield R.sub.f value or No. Name
Last Step Mass peak(s) R.sub.t 10 ##STR00034##
5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(1,1,3-trimethyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl]-ethyl}-amide 68% (M +
H).sup.+ = 434/436 (chlorine isotopes) 0.33 (RP-8; methanol: 5%
NaCl solution = 6:4) 11 ##STR00035##
5-chloro-thiophene-2-carboxylic
acid-N-[1-(7-ethyl-6,7,8,9-tetrahydro-5H-
pyrazino[2,3-d]azepin-2-ylcarbamoyl)-1-methyl-ethyl]-amide 1% (M +
H).sup.+ = 422/424 (chlorine isotopes) 0.17 (RP-8; methanol: 5%
NaCl solution = 6:4) 12 ##STR00036##
5-chloro-thiophene-2-carboxylic
acid-N-[1-(1,1,3-trimethyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-7-ylcarbamoyl]-ethyl}-amide 100% (M + H).sup.+ =
420/422 (chlorine isotopes) 3.29 min (HPLC-MS) method 1 13
##STR00037## 5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-
1H-benzo[d]azepin-7-ylcarbamoyl]-ethyl}-amide 64% (M + H).sup.+ =
406/408 (chlorine isotopes) 0.40 (RP-8; methanol: 5% NaCl solution
= 6:4) 14 ##STR00038## 5-bromo-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-
1H-benzo[d]azepin-7-ylcarbamoyl]-ethyl}-amide 99% (M + H).sup.+ =
450/452 (bromine isotopes) 0.40 (RP-8; methanol: 5% NaCl solution =
6:4) 18 ##STR00039##
1-[(5-bromo-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro--
1H- benzo[d]azepin-7-yl)-cyclopentane-1-carboxylic acid amide 42%
(M + H)+ = 476/78 (bromine isotopes) 0.61 (aluminium oxide;
dichloro- methane/ ethanol = 95:5) 19 ##STR00040##
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro-
-1H- benzo[d]azepin-7-yl)-cyclopentane-1-carboxylic acid amide 75%
(M + H)+ = 432/34 (chlorine isotopes) 0.32 (RP-8; methanol/ 5% NaCl
solution = 6:4) 20 ##STR00041##
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro-
-1H- benzo[d]azepin-7-yl)-tetrahydrothiophene-3-carboxylic acid
amide 62% (M + H)+ = 450/52 (chlorine isotopes) 21 ##STR00042##
5-chloro-thiophene-2-carboxylic
acid-N-[1-(3-methyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-7-ylcarbamoyl]-ethyl}-amide 48% (M + H)+ = 392/94
(chlorine isotopes) 22 ##STR00043##
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[1-(3-methyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-7-ylcarbamoyl]-1-phenyl-methyl}-amide 26% (M - H)- =
452/4 (chlorine isotopes) 0.45 (RP-8; methanol/ 5% NaCl solution =
6:4) 23 ##STR00044## 5-chloro-thiophene-2-carboxylic
acid-N-[3-tert.-butoxycarbonyl-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl]-propyl}-amide
57% (M + H)+ = 506/08 (chlorine isotopes) 24 ##STR00045##
5-chloro-thiophene-2-carboxylic
acid-N-[2-hydroxy-1-(3-methyl-2,3,4,5-tetrahydro-
1H-benzo[d]azepin-7-ylcarbamoyl]-ethyl}-amide 2% (M + H)+ = 408/10
(chlorine isotopes) 0.48 (RP-8; methanol/ 5% NaCl solution = 6:4)
25 ##STR00046## 5-chloro-thiophene-2-carboxylic
acid-N-[3-hydroxy-1-(3-methyl-2,3,4,5-tetrahydro-
1H-benzo[d]azepin-7-ylcarbamoyl]-propyl}-amide 20% (M + H)+ =
422/24 (chlorine isotopes) 0.51 (RP-8; methanol/ 5% NaCl solution =
6:4) 26 ##STR00047## 5-chloro-thiophene-2-carboxylic
acid-N-[1-(3-methyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-7-ylcarbamoyl]-but-3-enyl}-amide 71% (M + H)+ =
418/20 (chlorine isotopes) 27 ##STR00048##
5-chloro-thiophene-2-carboxylic
acid-N-[2-(1,2,4-triazol-1-yl)-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl]-ethyl}-amide 55% (M +
H)+ = 459/61 (chlorine isotopes) (M - H)- = 457/9 (chlorine
isotopes) 0.46 (RP-8; methanol/ 5% NaCl solution = 6:4) 28
##STR00049## 5-chloro-thiophene-2-carboxylic
acid-N-[2-(1-benzyl-imidazol-4-yl)-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl]-ethyl}-amide 29
##STR00050## 5-chloro-thiophene-2-carboxylic
acid-N-[3-methylsulphanyl-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl]-propyl}-amide 54% (M +
H)+ = 452/54 (chlorine isotopes) 34 ##STR00051##
1-[(5-chloro-thiophen-2-yl)carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro--
1H- benzo[d]azepin-7-yl)-cyclohexane-1-carboxylic acid amide 8% (M
+ H)+ = 446/8 (chlorine isotopes) 0.79 (aluminium oxide; dichloro-
methane/ ethanol = 95:5)
[0507] The following compounds may be prepared analogously to
Example 2:
TABLE-US-00009 Structural formula Yield R.sub.f value or No. Name
Last Step Mass peak(s) R.sub.t 15 ##STR00052##
5-chloro-thiophene-2-carboxylic
acid-N-[2-methoxy-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 86% (M +
H).sup.+ = 422/424 chlorine isotopes 0.52 (aluminium oxide;
dichloro- methane/ ethanol = 95:5) 30 ##STR00053##
1-[(5-chloro-thiophen-2-yl)carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro--
1H- benzo[d]azepin-7-yl)-cyclopropane-1-carboxylic acid amide 40%
(M + H).sup.+ = 404/406 chlorine isotopes 0.41 (RP-8; methanol/ 5%
NaCl solution = 6:4) 31 ##STR00054##
1-[(5-chloro-thiophen-2-yl)carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro--
1H- benzo[d]azepin-7-yl)-cyclobutane-1-carboxylic acid amide 60% (M
+ H).sup.+ = 418/420 chlorine isotopes 0.62 (silica gel dichloro-
methane/ ethanol/ ammonia = 80:20:2) 32 ##STR00055##
1-[(5-chloro-thiophen-2-yl)carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro--
1H- benzo[d]azepin-7-yl)-cyclopent-3-ene-1-carboxylic acid amide
70% (M + H)+ = 430/32 (chlorine isotopes) (M - H)- = 428/30
(chlorine isotopes 0.34 (RP-8; methanol/ 5% NaCl solution = 6:4) 33
##STR00056##
1-[(5-bromo-thiophen-2-yl)carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro-1-
H- benzo[d]azepin-7-yl)-cyclopent-3-ene-1-carboxylic acid amide 85%
(M + H)+ = 474/6 (bromine isotopes) 0.32 (RP-8; methanol/ 5% NaCl
solution = 6:4)
[0508] The following compounds may be prepared analogously to
Example 8:
TABLE-US-00010 Structural formula Yield No. Name Last Step Mass
peak(s) R.sub.f value or R.sub.t 16 ##STR00057## quantitative (M +
H).sup.+ = 422 3.27 min (HPLC-MS; method 2)
5-ethynyl-N-[1-(3-cyclopropyl-2,3,4,5-tetrahydro-4H-benzo[d]azepin-7-
ylcarbamoyl)-1-methyl-ethyl]-thiophene-2-carboxylic acid amide 17
##STR00058## quantitative (M + H).sup.+ = 424 3.29 min (HPLC-MS;
method 2)
5-ethynyl-N-[1-methyl-1-(1,1,3-trimethyl-2,3,4,5-tetrahydro-4H-benzo[d]az-
epin-7- ylcarbamoyl)-ethyl]-thiophene-2-carboxylic acid amide
EXAMPLE 35
5-chloro-thiophene-2-carboxylic
acid-N-[3-hydroxycarbonyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepi-
n-7-ylcarbamoyl]propyl-amide
##STR00059##
[0510] 93 mg (0.15 mmol) 5-chloro-thiophene-2-carboxylic
acid-N-[3-tert.-butoxycarbonyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]-
azepin-7-ylcarbamoyl]-propyl}-amide are combined with 1 ml
trifluoroacetic acid in 1 ml dichloromethane with stirring at RT
and stirred for 1.5 h at room temperature and concentrated by
evaporation.
[0511] Yield: 78.0 mg (92%)
[0512] C.sub.21H.sub.24ClN.sub.3O.sub.4S (449.959)
[0513] Mass spectrum: (M+H).sup.+=450/52 (chlorine isotopes)
EXAMPLE 36
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-(1H-tetrazol-5-yl)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]az-
epin-7-ylcarbamoyl)-propyl]-amide
##STR00060##
[0514] (a) (R)-2-tert.-butoxycarbonylamino-4-cyano-butyric acid
[0515] 5.0 g (20.3 mmol)
(R)--N-.alpha.-(tert.-butoxycarbonyl)-D-glutamine are combined with
2.30 ml (24.3 mmol) acetic anhydride in 55 ml of pyridine with
stirring at room temperature and stirred for 20 h. The reaction
mixture is evaporated down i. vac., the residue is combined with
ethyl acetate and washed 3 times with 5% citric acid and 3 times
with sat. NaCl solution. The organic phase is dried on sodium
sulphate and concentrated by evaporation i.vac. Then it is purified
by chromatography on silica gel (eluant: dichloromethane/methanol
90:10).
[0516] Yield: 3.16 g (68%)
[0517] R.sub.f value: 0.3 (silica gel;
dichloromethane/methanol=9:1)
[0518] C.sub.10H.sub.16N.sub.2O.sub.4 (228.25)
[0519] Mass spectrum: (M-H).sup.-=227
(b) tert.butyl
(R)-[3-cyano-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamo-
yl)-propyl]-carbamate
[0520] 1.0 g (4.0 mmol)
(R)-2-tert.-butoxycarbonylamino-4-cyano-butyric acid is dissolved
in 10 ml DMF and stirred with 1.29 g (4.03 mmol) TBTU and 2.79 ml
(20.1 mmol) TEA at room temperature for 30 min. Then 1.0 g (4.01
mmol) 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine is
added and the mixture is stirred overnight at 35.degree. C. The
reaction mixture is evaporated to dryness i. vac. And extracted
with ethyl acetate. The organic phase is dried with sodium sulphate
and evaporated down i. vac. Then it is purified by chromatography
on silica gel (eluant: dichloromethane/methanol 95:5).
[0521] Yield: 450 mg (29%)
[0522] R.sub.f value: 0.15 (silica gel;
dichloromethane/methanol=95:5)
[0523] C.sub.21H.sub.30N.sub.4O.sub.3 (386.49)
[0524] Mass spectrum: (M+H).sup.+=387
(c) tert.butyl
(R)-[1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-3-(1-
H-tetrazol-5-yl)-propyl]-carbamate
[0525] 200 mg (0.52 mmol) tert.butyl
(R)-[3-cyano-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamo-
yl)-propyl]carbamate are placed in 1 ml DMF and combined with 80 mg
(1.23 mmol) sodium azide and 66 mg (1.23 mmol) ammonium chloride.
The reaction mixture is stirred overnight at 100.degree. C., then
acidified with TFA and separated using RP material (eluant:
water/acetonitrile 95:5=>5:95).
[0526] Yield: 49.8 mg (18%)
[0527] C.sub.21H.sub.31N.sub.7O.sub.3 (429.53)
[0528] Mass spectrum: (M+H).sup.+=430
(d)
(R)-2-amino-N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-4-(-
1H-tetrazol-5-yl)-butyramide
[0529] 49.8 mg (90 .mu.mol) tert.butyl
(R)-[1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-3-(1-
H-tetrazol-5-yl)-propyl]-carbamate are stirred in 1 ml of 2 molar
aqueous hydrochloric acid at 50.degree. C. for 2.5 h and then
evaporated to dryness.
[0530] Yield: 32.7 mg (89%)
[0531] C.sub.16H.sub.23N.sub.7O (329.41)
[0532] Mass spectrum: (M+H).sup.+=330
(e) (R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-(1H-tetrazol-5-yl)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]az-
epin-7-ylcarbamoyl)-propyl]-amide
[0533] 13 mg (0.08 mmol) 5-chloro-thiophene-2-carboxylic acid are
dissolved in 0.5 ml DMF, mixed at room temperature with 26 mg (0.08
mmol) TBTU and 50 .mu.l (0.45 mmol) NMM and stirred for 15 min. A
solution of 32 mg (0.08 mmol)
(R)-2-amino-N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-4-(1H--
tetrazol-5-yl)-butyramide in 1 ml DMF is added to the reaction
mixture and it is stirred overnight at room temperature. The
reaction mixture is acidified with TFA, separated by chromatography
through RP material (eluant: water/acetonitrile 95:5=>5:95) and
then freeze-dried.
[0534] Yield: 18.8 mg (40%)
[0535] R.sub.t value: 2.29 min (HPLC-MS; method 2)
[0536] C.sub.21H.sub.24ClN.sub.7O.sub.2S (473.99)
[0537] Mass spectrum: (M+H).sup.+=474/6 (chlorine isotopes)
EXAMPLE 37
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-benzyloxy-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl-
carbamoyl)-ethyl]-amide
##STR00061##
[0538] (a) (R)
2-amino-3-benzyloxy-N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl-
)-propionamide
[0539] 0.117 g (0.60 mmol)
(R)-3-benzyloxy-2-tert.-butoxycarbonylamino-propionic acid are
reacted analogously to Example 2 (a) with 0.116 g (0.66 mmol)
3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine, TBTU,
DIPEA in THF. Then the BOC protective group is cleaved analogously
to Example 1 (d), made basic with sodium hydroxide and extracted
with ethyl acetate.
[0540] Yield: quantitative
[0541] R.sub.f value: 0.48 (RP-8; methanol/5% NaCl
solution=6:4)
[0542] C.sub.21H.sub.27N.sub.3O.sub.2 (353.46)
[0543] Mass spectrum: (M+H).sup.+=354
(b)(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-benzyloxy-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl-
carbamoyl)-ethyl]-amide
[0544] 0.117 g (0.72 mmol) 5-chloro-thiophene-2-carboxylic acid are
combined with 0.26 ml (3.60 mmol) thionyl chloride and 0.01 ml DMF
in 15 ml dichloromethane with stirring at room temperature and
refluxed for 2 h with stirring. Then the reaction mixture is
evaporated down i.vac.
[0545] 0.230 g (0.65 mmol) of (R)
2-amino-3-benzyloxy-N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl-
)-propionamide in 10 ml THF are combined with 0.27 ml (1.95 mmol)
TEA and the solution of the prepared acid chloride in 10 ml THF at
room temperature with stirring and stirred for 15 h. Then the
mixture is diluted with ethyl acetate, washed with water, dried on
sodium sulphate and concentrated by evaporation i.vac. The
purification is carried out by chromatography through aluminium
oxide (eluant: dichloromethane/ethanol 100:0=>98.5:1.5)
[0546] Yield: 0.14 g (43%)
[0547] R.sub.f value: 0.81 (aluminium oxide;
dichloromethane/ethanol=95:5)
[0548] C.sub.26H.sub.28ClN.sub.3O.sub.2S (498.04)
[0549] Mass spectrum: (M+H).sup.+=498/00 (chlorine isotopes)
EXAMPLE 38
5-chloro-thiophene-2-carboxylic
acid-N-[1-(3-isopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl-
)-1-methyl-ethyl]-amide
##STR00062##
[0550] (a)
3-isopropyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
[0551] 0.96 g (5.00 mmol)
7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 0.404 ml (5.50
mmol) acetone are dissolved in 20 ml THF, then 0.414 ml (7.50 mmol)
acetic acid and 0.10 g p-toluenesulphonic acid are added and the
mixture is stirred for 30 min at room temperature. At room
temperature 1.378 g (6.50 mmol) sodium triacetoxyborohydride are
added and stirred for 23 h. Then the mixture is made alkaline with
sat. Sodium hydrogen carbonate solution and extracted with ethyl
acetate, then the organic phase is dried with sodium sulphate and
concentrated by evaporation i.vac.
[0552] Yield: quantitative
[0553] C.sub.13H.sub.18N.sub.2O.sub.2 (234.29)
[0554] Mass spectrum: (M+H).sup.+=235
(b) 3-isopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine
[0555] Prepared analogously to Example 1 (c) from
3-isopropyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine in
methanol with Pd/C 10% at room temperature. Then the product is
concentrated by evaporation.
[0556] Yield: 0.920 g (89%)
[0557] R.sub.f value: 0.14 (silica gel;
dichloromethane/ethanol=9:1)
[0558] C.sub.13H.sub.20N.sub.2 (204.31)
[0559] Mass spectrum: (M+H).sup.+=205
(c) 5-chloro-thiophene-2-carboxylic
acid-N-[1-(3-isopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl-
)-1-methyl-ethyl]-amide
[0560] Prepared analogously to Example 1(f) from
3-isopropyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and
2-[(5-chloro-thiophen-2-yl)-carbonylamino]-2-methyl-propionic acid
with HATU and NMM in DMF at room temperature with subsequent
chromatography through aluminium oxide (eluant:
dichloromethane/ethanol 98:2) and through RP material (Zorbax
StableBond C18; 7 .mu.m 220 g; eluant: water/acetonitrile/formic
acid=95:5:0.1=>10:90:0.1) and lyophilisation.
[0561] Yield: 0.386 g (40%)
[0562] R.sub.f value: 0.70 (aluminium oxide;
dichloromethane/ethanol=95:5)
[0563] C.sub.22H.sub.28ClN.sub.3O.sub.2S (434.0)
[0564] Mass spectrum: (M+H)+=434/6 (chlorine isotopes)
EXAMPLE 39
5-chloro-thiophene-2-carboxylic
acid-N-[1-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylca-
rbamoyl)-1-methyl-ethyl]-amide
##STR00063##
[0565] (a)
2,2,2-trifluoro-1-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d-
]azepin-3-yl)-ethanone
[0566] 1.30 g (4.27 mmol) of
2,2,2-trifluoro-1-(7-hydroxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3--
yl)-ethanone are dissolved in 20 ml DMF. At room temperature 0.59 g
(4.27 mmol) potassium carbonate and 0.26 ml (4.27 mmol)
methyliodide are added and the mixture is stirred overnight. Then
it is filtered and the filtrate is concentrated by evaporation
i.vac., the residue is triturated with water and suction filtered
and dried in the circulating air dryer at 45.degree. C.
[0567] Yield: 1.30 g (96%)
[0568] R.sub.f value: 0.59 (silica gel; petroleum
ether/ethylacetate=1:1)
[0569] C.sub.13H.sub.13F.sub.3N.sub.2O.sub.4 (318.25)
[0570] Mass spectrum: (M+H)+=319
(b) 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
[0571] 1.30 g (4.08 mmol)
2,2,2-trifluoro-1-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3--
yl)-ethanone and 3.06 ml (6.13 mmol) 2 molar sodium hydroxide
solution are dissolved in 20 ml THF at room temperature and stirred
for 3 h. Then the mixture is concentrated by evaporation i.vac.,
diluted with water and extracted with tert.-butyl-methylether. The
organic phase is washed with 50% sodium hydroxide solution and sat.
NaCl solution, dried on sodium sulphate and concentrated by
evaporation i.vac.
[0572] Yield: 0.87 g (96%)
[0573] R.sub.f value: 0.15 (silica gel; petroleum ether/ethyl
acetate=1:1)
[0574] C.sub.11H.sub.14N.sub.2O.sub.3 (222.24)
[0575] Mass spectrum: (M+H)+=223
(c)
7-methoxy-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
[0576] Prepared analogously to Example 1 (b) from
7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine and aqueous
formalin solution in formic acid.
[0577] Yield: 0.80 g (86%)
[0578] R.sub.f value: 0.59 (aluminium oxide;
dichloromethane/ethanol=95:5)
[0579] C.sub.12H.sub.16N.sub.2O.sub.3 (236.27)
[0580] Mass spectrum: (M+H)+=237
(d)
8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine
[0581] Prepared analogously to Example 1 (c) from
7-methoxy-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
with Pd/C 10% in methanol.
[0582] Yield: 0.67 g (96%)
[0583] R.sub.f value: 0.63 (aluminium oxide;
dichloromethane/ethanol=95:5)
[0584] C.sub.12H.sub.18N.sub.2O (236.27)
[0585] Mass spectrum: (M+H)+=207
(e) 5-chloro-thiophene-2-carboxylic
acid-N-[1-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylca-
rbamoyl)-1-methyl-ethyl]-amide
[0586] Prepared analogously to Example 1 (f) from
8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine
and 2-[(5-chloro-thiophen-2-yl)-carbonylamino]-2-methyl-propionic
acid with HATU and NMM in DMF at room temperature. Then the mixture
is concentrated by evaporation i.vac. And purified by
chromatography through silica gel (eluant: dichloromethane/ethanol
100:0=>98:2).
[0587] Yield: 0.55 g (63%)
[0588] R.sub.f value: 0.61 (aluminium oxide;
dichloromethane/ethanol=95:5)
[0589] C.sub.21H.sub.26ClN.sub.3O.sub.3S (435.97)
[0590] Mass spectrum: (M+H)+=436/8 (chlorine isotopes)
EXAMPLE 40
5-chloro-thiophene-2-carboxylic
acid-N-[1-(8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylca-
rbamoyl)-1-methyl-ethyl]-amide
##STR00064##
[0591] (a)
1-(7-benzyloxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)--
2,2,2-trifluoro-ethanone
[0592] 1.30 g (4.27 mmol)
2,2,2-trifluoro-1-(7-hydroxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3--
yl)-ethanone are placed in 20 ml DMF and at room temperature 0.65 g
(4.70 mmol) potassium carbonate and 0.508 ml (4.27 mmol)
benzylbromide are added and the mixture is stirred for 3 h. Then it
is filtered and the filtrate is concentrated by evaporation i.vac.,
the residue is triturated with water, suction filtered and dried at
45.degree. C. in the circulating air dryer.
[0593] Yield: 1.67 g (99%)
[0594] R.sub.f value: 0.64 (silica gel; petroleum ether/ethyl
acetate=7:3)
[0595] C.sub.19H.sub.17F.sub.3N.sub.2O.sub.4 (394.34)
[0596] Mass spectrum: (M+NH.sub.4)+=412
(b) 7-benzyloxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
[0597] Prepared analogously to Example 39 (b) from
1-(7-benzyloxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-2,2,2-trif-
luoro-ethanone.
[0598] Yield: 1.04 g (83%)
[0599] R.sub.f value: 0.46 (silica gel; petroleum ether/ethyl
acetate=3:7)
[0600] C.sub.17H.sub.18N.sub.2O.sub.3 (298.34)
[0601] Mass spectrum: (M+H)+=299
(c)
7-benzyloxy-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
[0602] Prepared analogously to Example 1 (b) from
7-benzyloxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine and
aqueous formalin solution in formic acid.
[0603] Yield: 1.08 g (99%)
[0604] R.sub.f value: 0.8 (aluminium oxide;
dichloromethane/ethanol=95:5)
[0605] C.sub.18H.sub.20N.sub.2O.sub.3 (312.36)
[0606] Mass spectrum: (M+H)+=313
(d) 8-amino-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol
[0607] 0.50 g (1.60 mmol)
7-benzyloxy-3-methyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
are dissolved in 20 ml of methanol and combined with 100 mg Pd/C
10%. Hydrogenation is carried out in a Parr apparatus at room
temperature at 3 bar hydrogen pressure for 2 h. Then the catalyst
is filtered off and the filtrate is concentrated by evaporation
i.vac.
[0608] Yield: 0.26 g (84%)
[0609] R.sub.f value: 0.1 (aluminium oxide;
dichloromethane/ethanol=95:5)
[0610] C.sub.11H.sub.16N.sub.20 (192.26)
[0611] Mass spectrum: (M+H)+=193
(e) 5-chloro-thiophene-2-carboxylic
acid-N-[1-(8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylca-
rbamoyl)-1-methyl-ethyl]-amide
[0612] Prepared analogously to Example 1 (f) from
8-amino-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol and
2-[(5-chloro-thiophen-2-yl)-carbonylamino]-2-methyl-propionic acid
with HATU and NMM in DMF at room temperature. Then the mixture is
concentrated by evaporation i.vac. And purified by chromatography
through RP material (Zorbax StableBond C18; 8 .mu.m; eluant: water
with 1.5% formic acid/acetonitrile=95:5=>5:95).
[0613] Yield: 0.30 g (49%)
[0614] R.sub.f value: 0.40 (aluminium oxide;
dichloromethane/ethanol=95:5)
[0615] C.sub.20H.sub.24ClN.sub.3O.sub.3S (421.95)
[0616] Mass spectrum: (M+H)+=422/4 (chlorine isotopes)
[0617] The following compounds may be prepared from optionally
protected amino acid derivatives, benzazepine derivatives and
thiophenecarboxylic acid derivatives analogously to the methods of
synthesis described in the foregoing Examples:
TABLE-US-00011 Structural formula Yield No. Name (last Step) Mass
peak(s) R.sub.f value or R.sub.t 41 ##STR00065## 32% (M + H).sup.+
= 446/448 (chlorine isotopes) Rt = 2.50 min HPLC-method 3a
5-chloro-thiophene-2-carboxylic
acid-N-[1-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-7-ylcarbamoyl)-1-methyl-ethyl]-amide 42 ##STR00066##
46% (M + H).sup.+ = 472/474 (chlorine isotopes) Rt = 2.66 min
HPLC-method 3a
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-cyclobutyl-2,3,4,5-tetrah-
ydro-1H- benzo[d]azepin-7-yl)-cyclopentane-1-carboxylic acid amide
43 ##STR00067## 49% (M - H)+ = 458/460 (chlorine isotopes) Rt =
4.41 min HPLC-method 3
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-cyclopropyl-2,3,4,5-tetra-
hydro-1H- benzo[d]azepin-7-yl)-cyclopentane-1-carboxylic acid amide
44 ##STR00068## 70% (M + H).sup.+ = 464 0.31 (RP-8; methanol/5%
NaCl solution = 6:4) (S)-thiophene-2-carboxylic
acid-N-[2-benzyloxy-1-(3-methyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 45 ##STR00069## 11% (M +
H).sup.+ = 374 0.60 (RP-8; methanol/5% NaCl solution = 6:4)
(S)-thiophene-2-carboxylic
acid-N-[2-hydroxy-1-(3-methyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 46 ##STR00070## 54% (M -
H)- = 386 0.63 (aluminium oxide; dichloromethane/ ethanol = 95:5)
5-methyl-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-
1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 47 ##STR00071## 42%
(M + H).sup.+ = 300 0.66 (aluminium oxide; dichloromethane/ ethanol
= 95:5) 5-formyl-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-
1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 48 ##STR00072## 38%
(M + H).sup.+ = 378/380 0.86 min (HPLC-MS; method 5)
5-chloro-thiophene-2-carboxylic
acid-N-[(3-methyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-7-ylcarbamoyl)-methyl]-amide 49 ##STR00073## 29% (M
+ H).sup.+ = 422/424 (bromine isotopes) 0.88 min (HPLC-MS; method
5) 5-bromo-thiophene-2-carboxylic
acid-N-[(3-methyl-2,3,4,5-tetrahydro-1H
benzo[d]azepin-7-ylcarbamoyl)-methyl]-amide 50 ##STR00074## 34% (M
- H)- = 358 0.82 min (HPLC-MS; method 5)
5-methyl-thiophene-2-carboxylic
acid-N-[(3-methyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-7-ylcarbamoyl)-methyl]-amide 51 ##STR00075## 29% (M
+ H).sup.+= 470 0.89 min (HPLC-MS; method 5)
5-iodo-thiophene-2-carboxylic
acid-N-[(3-methyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-7-ylcarbamoyl)-methyl]-amide
EXAMPLE 52
3-[(5-chloro-thiophen-2-yl)carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro-1-
H-benzo[d]azepin-7-yl)-1-oxo-tetrahydro-thiophene-3-carboxylic acid
amide
##STR00076##
[0619] 90 mg (0.16 mmol)
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro-
-1H-benzo[d]azepin-7-yl)-tetrahydrothiophene-3-carboxylic acid
amide (Ex. 20) are dissolved in 3.4 ml dichloromethane and 0.34 ml
glacial acetic acid and 39.3 mg (0.16 mmol) 3-chloroperoxybenzoic
acid are added at -5.degree. C. Then the mixture is stirred for 1 h
at 0.degree. C., then heated to room temperature and stirred for 3
h. The reaction is washed with 5% sodium hydrogen carbonate
solution and the organic phase is dried with sodium sulphate and
concentrated by evaporation. The crude product is purified with RP
material (Zorbax StableBond C18; 3.5 .mu.m; 4.6.times.75 mm eluant:
water/acetonitrile/formic acid=95:5:0.1=>10:90:0.1).
[0620] Yield: 14.6 mg (18%)
[0621] R.sub.f value: 0.25 (silica gel;
dichloromethane/ethanol/ammonia=8:2:0.2)
[0622] C.sub.21H.sub.24ClN.sub.3O.sub.3S.sub.2 (466.02)
[0623] Mass spectrum: (M+H).sup.+=466/468 (chlorine isotopes)
EXAMPLE 53
3-[(5-chloro-thiophen-2-yl)carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro-1-
H-benzo[d]azepin-7-yl)-1,1-dioxo-tetrahydro-thiophene-3-carboxylic
acid amide
##STR00077##
[0624] was isolated as a by-product in the preparation of Example
52.
[0625] Yield: 1.8 mg (2%)
[0626] R.sub.f value: 0.11 (silica gel;
dichloromethane/ethanol/ammonia=8:2:0.2)
[0627] C.sub.21H.sub.24ClN.sub.3O.sub.4S.sub.2 (482.02)
[0628] Mass spectrum: (M+H).sup.+=482/484 (chlorine isotopes)
EXAMPLE 54
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro--
1H-benzo[d]azepin-7-yl)-pyrrolidin-1-tert.butoxycarbonyl-3-carboxylic
acid amide
##STR00078##
[0630] The title compound was prepared analogously to the synthesis
sequence in Example 1e/1f from
3-amino-pyrrolidin-1-tert.butoxycarbonyl-3-carboxylic acid,
5-chlorothiophene-2-carboxylic acid chloride and
3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine.
[0631] Yield: 15.5 mg
[0632] R.sub.f value: 0.34 (RP-8; methanol/5% NaCl
solution=6:4)
[0633] C.sub.26H.sub.33ClN.sub.4O.sub.4S (533.09)
[0634] Mass spectrum: (M+H).sup.+=533/535 (chlorine isotopes)
EXAMPLE 55
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro--
1H-benzo[d]azepin-7-yl)-pyrrolidin-3-carboxylic acid amide
##STR00079##
[0636] 10 mg (0.02 mmol)
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro-
-1H-benzo[d]azepin-7-yl)-pyrrolidin-1-tert.
butoxycarbonyl-3-carboxylic acid amide are dissolved in 0.25 ml THF
and at room temperature 0.3 ml of 6 molar hydrochloric acid are
added and the mixture is stirred for 1 h.
[0637] Then it is concentrated by evaporation i.vac.
[0638] Yield: 10 mg (80%)
[0639] R.sub.f value: 0.44 (RP-8; methanol/5% NaCl
solution=6:4)
[0640] C.sub.21H.sub.25ClN.sub.4O.sub.2S (432.98)
[0641] Mass spectrum: (M+H).sup.+=433/435 (chlorine isotopes)
[0642] The following compounds may be prepared from amino acid
derivatives, benzazepine derivatives and thiophenecarboxylic acid
derivatives analogously to the methods of synthesis described in
the foregoing Examples or known from the literature:
TABLE-US-00012 Structural formula Yield No. Name Last Step Mass
peak(s) R.sub.f value or R.sub.t 56 ##STR00080## 68% (M + H).sup.+
= 448/450 (chlorine isotopes) 2.7 min (HPLC-MS; method 4)
4-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetra-
hydro-1H-benzo[d]azepin-7-yl)-tetrahydro-pyran-4-carboxylic acid
amide 57 ##STR00081## 25% (M + H).sup.+ = 434/436 (chlorine
isotopes) 0.31 (RP-8; methanol/5% NaCl solution = 6:4)
5-chloro-thiophene-2-carboxylic
acid-N-[1-ethyl-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide 59
##STR00082## 45% (M + H).sup.+ = 454/456 (chlorine isotopes) 0.3
(silica gel; dichloromethane/ ethanol/glacial acetic acid =
90:10:1) 5-chloro-thiophene-2-carboxylic
acid-N-[1-(3-methyl-2,3,4,5-tetrahydro-
1H-benzo[d]azepin-7-ylcarbamoyl)-1-(prop-2-ynyl)-but-3-ynyl]-amide
EXAMPLE 58
5-chloro-thiophene-2-carboxylic
acid-N-[2-methoxy-1-methoxymethyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo-
[d]azepin-7-ylcarbamoyl)-ethyl]-amide
##STR00083##
[0643] (a) 5-chloro-thiophene-2-carboxylic
acid(1-hydroxymethyl-2-methoxy-1-methoxymethyl-ethyl)-amide
[0644] 1.14 g (6.16 mmol)
2-amino-3-methoxy-2-methoxymethyl-propan-1-ol are suspended in 9 ml
THF, cooled in the ice bath and combined with 2.56 ml (18.4 mmol)
TEA. 1.12 g (6.19 mmol) 5-chlorothiophene-2-carboxylic acid
chloride are dissolved in 6 ml THF and added dropwise. After 1.5 h
the mixture is filtered and the filtrate is concentrated by
evaporation i.vac. Then it is purified by chromatography through RP
material (Microsorb C18 Varian; eluant:
water/acetonitrile/trifluoroacetic
acid=90:10:0.1=>0:100:0.1).
[0645] Yield: 0.20 g (8%)
[0646] R.sub.t value: 4.25 min (HPLC-MS method 3)
[0647] C.sub.11H.sub.16ClNO.sub.4S (293.77)
[0648] Mass spectrum: (M+H).sup.+=294/296 (chlorine isotopes)
(b)
2-[(5-chloro-thiophene-2-carbonyl)-amino]-3-methoxy-2-methoxymethyl-pr-
opionic acid
[0649] 0.20 g (0.49 mmol) 5-chloro-thiophene-2-carboxylic
acid(1-hydroxymethyl-2-methoxy-1-methoxymethyl-ethyl)-amide are
dissolved at room temperature in 3 ml of water/3 ml acetonitrile
and combined with 0.08 g (0.51 mmol)
2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) and 0.13 g
(1.55 mmol) sodium hydrogen carbonate. Then 1.5 ml (3.14 mmol) of
13% sodium hypochlorite is added dropwise and the mixture is
stirred for 2 h. The reaction mixture is concentrated by
evaporation i.vac. And purified by chromatography through RP
material (Microsorb C18 Varian; eluant:
water/acetonitrile/trifluoroacetic
acid=90:10:0.1=>0:100:0.1).
[0650] Yield: 0.10 g (66%)
[0651] R.sub.t value: 4.16 min (HPLC-MS method 3)
[0652] C.sub.11H.sub.14ClNO.sub.5S (307.75)
[0653] Mass spectrum: (M+H).sup.+=306/308 (chlorine isotopes)
(c) 5-chloro-thiophene-2-carboxylic
acid-N-[2-methoxy-1-methoxymethyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo-
[d]azepin-7-ylcarbamoyl)-ethyl]-amide
[0654] 0.05 g (0.16 mmol)
2-[(5-chloro-thiophene-2-carbonyl)-amino]-3-methoxy-2-methoxymethyl-propi-
onic acid are dissolved in 1.5 ml THF and at room temperature 0.04
g (0.16 mmol) 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ)
are added. After 30 min, 0.029 g (0.16 mmol) of
3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine is added
and the mixture is stirred for 12 h at 40.degree. C. Then it is
concentrated by evaporation i.vac. And purified by chromatography
through RP material (Microsorb C18 Varian; eluant:
water/acetonitrile/trifluoroacetic
acid=90:10:0.1=>0:100:0.1).
[0655] Yield: 13.9 mg (15%)
[0656] R.sub.t value: 4.09 min (HPLC-MS method 3)
[0657] C.sub.22H.sub.28ClN.sub.3O.sub.4S (466.00)
[0658] Mass spectrum: (M+H).sup.+=466/468 (chlorine isotopes)
EXAMPLE 60
5-chloro-thiophene-2-carboxylic
acid-N-[3-methoxy-1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azep-
in-7-ylcarbamoyl)-propyl]-amide
##STR00084##
[0659] (a) ethyl 2-benzhydrilidenamino-4-methoxy-butanoate
[0660] 15.0 g (56 mmol) N-(diphenylmethylene)glycmethylester are
cooled to -78.degree. C. in 150 ml THF, combined with 60 ml 1M
NaHMDS solution and stirred for 1 h. Then 11 ml (117 mmol)
1-bromo-2-methoxyethane are added and the mixture is slowly heated
to 5.degree. C. After filtration the mixture is purified by
repeated chromatography (silica gel, petroleum ether:ethyl acetate
9:1).
[0661] Yield: 8.1 g
(b) ethyl 2-benzhydrilidenamino-4-methoxy-2-methylbutanoate
[0662] Analogously to Example 60 (a)
2-benzhydrilidenamino-4-methoxy-butanoic acid is reacted with
methyliodide to produce the title compound.
[0663] C.sub.21H.sub.25NO.sub.3 (339.43)
[0664] Mass spectrum: (M+H).sup.+=340
(c) 5-chloro-thiophene-2-carboxylic
acid-N-(1-ethoxycarbonyl-3-methoxy-1-methyl-propyl)-amide
[0665] 0.57 g of ethyl
2-benzhydrilidenamino-4-methoxy-2-methylbutanoate in 2.5 ml THF are
combined with 0.7 ml of 4M HCl and stirred for 2 h at room
temperature. Then the mixture is combined with ethyl acetate and 1
M HCl. The aqueous phase is extracted three times with ethyl
acetate and then freeze-dried. The crude product is reacted with
5-chlorothiophenecarboxylic acid chloride analogously to Example
1(e) to produce the title compound.
[0666] C.sub.21H.sub.25NO.sub.3 (339.43)
[0667] Mass spectrum: (M+H).sup.+=340
(d) 5-chloro-thiophene-2-carboxylic
acid-N-[3-methoxy-1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azep-
in-7-ylcarbamoyl)-propyl]-amide
[0668] 0.60 ml of a 2M solution of trimethylaluminium in toluene
are added to a mixture of 130 mg (0.738 mmol)
3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in
dichloromethane and stirred for 15 min. Then the mixture is added
to 233 mg (0.729 mmol) 5-chloro-thiophene-2-carboxylic
acid-N-(1-ethoxycarbonyl-3-methoxy-1-methyl-propyl)-amide and
stirred for 3 days. Then it is poured onto ice water/2 N NaOH,
extracted several times with ethyl acetate and dried with sodium
sulphate. The crude product is purified by chromatography.
[0669] R.sub.t value: 2.53 min (HPLC-MS method 2)
[0670] C.sub.22H.sub.28ClN.sub.3O.sub.3S (450)
[0671] Mass spectrum: (M+H).sup.+=450/452 (chlorine isotopes)
EXAMPLE 61
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-methoxy-1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azep-
in-7-ylcarbamoyl)-ethyl]-amide
##STR00085##
[0673] A mixture of 1.5 g (6.8 mmol)
N-tert.butoxycarbonyl-.alpha.-methylserine in 100 ml acetonitrile
is combined with in each case one-fifth of 7.8 g (34 mmol) of
silver oxide and 4.3 ml (68 mmol) iodomethane, with vigorous
stirring, at hourly intervals within 5 h and the mixture is stirred
for 4 days. Then it is filtered and the crude product is reacted
with 3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and
5-chlorothiophene-2-carboxylic acid chloride analogously to the
reaction conditions described in Example 1f, 55 and 58a to obtain
the title compound.
[0674] R.sub.f value: 0.63 (aluminium oxide;
dichloromethane/ethanol=95:5)
[0675] C.sub.21H.sub.26ClN.sub.3O.sub.3S (435.97)
[0676] Mass spectrum: (M+H).sup.+=436/438 (chlorine isotopes)
[0677] The following compounds may be prepared from amino acid
derivatives, benzazepine derivatives and thiophenecarboxylic acid
derivatives analogously to the methods of synthesis described in
the foregoing Examples:
TABLE-US-00013 Structural formula Yield No. Name Last Step Mass
peak(s) R.sub.f value or R.sub.t 62 ##STR00086## 57% (M + H).sup.+
= 512/514 (chlorine isotopes) Rt: 2.8 min HPLC-method 3a
5-chloro-thiophene-2-carboxylic
acid-N-[2-benzyloxy-1-methyl-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 63
##STR00087## 4% (M + H).sup.+ = 422/424 (chlorine isotopes) 2.25
min (HPLC; method 2) (R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-hydroxy-1-methyl-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
EXAMPLE 64
5-bromo-thiophene-2-carboxylic
acid-N-[3-hydroxy-1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azep-
in-7-ylcarbamoyl)-propyl]-amide
##STR00088##
[0678] (a) methyl
2-[(5-bromo-thiophene-2-carbonyl)-amino]-propionate
[0679] 5.18 g (25.30 mmol) 5-bromothiophene-2-carboxylic acid are
stirred in 20 ml of thionyl chloride for 1 h at 60.degree. C. and
then the mixture is concentrated by evaporation i.vac.
[0680] 3.52 g (25.26 mmol) DL-OMe-Ala-HCL are placed in 100 ml
dichloromethane with 20 ml (142.25 mmol) TEA, then at 0.degree. C.
the acid chloride is added dropwise to 20 ml dichloromethane. At
room temperature the mixture is stirred for 16 h and concentrated
by evaporation i.vac. Then sodium hydrogen carbonate solution is
added and the mixture is extracted 3.times. with ethyl acetate. The
organic phase is washed 1.times. with 1 molar hydrochloric acid and
1.times. with sat. Sodium hydrogen carbonate solution and dried
with sodium sulphate. Then it is concentrated by evaporation i.vac.
And purified by chromatography through silica gel (eluant: ethyl
acetate/petroleum ether 1:3=>1:2).
[0681] Yield: 6.0 g (82%)
[0682] R.sub.f value: 0.17 (silica gel; ethyl acetate/petroleum
ether=30:70)
[0683] C.sub.9H.sub.10BrNO.sub.3S (292.15)
[0684] Mass spectrum: (M+H).sup.+=290/292 (bromine isotopes)
(b) 5-bromo-thiophene-2-carboxylic
acid-N-(3-methyl-2-oxo-tetrahydro-furan-3-yl)-amide (prepared
analogously to J. Org. Chem., 1993, 58, 6966)
[0685] 1.90 ml (22.62 mmol) diisopropylamine and 5.00 ml (33.34
mmol) N,N,N,N-tetramethyl-ethylenediamine (TMEDA) are placed in 110
ml THF at 0.degree. C. and slowly combined with 14.2 ml (22.62
mmol) 1.6 M n-butyllithium in n-hexane. Then the mixture is stirred
for 20 min and cooled to -78.degree. C., then 2.12 g (7.26 mmol)
methyl 2-[(5-bromo-thiophene-2-carbonyl)-amino]-propionate in 50 ml
THF are slowly added dropwise and the mixture is stirred for 1 h.
In a two-necked flask 4.0 ml (80.91 mmol) ethylene oxide are
condensed at -78.degree. C. and this is then added to the reaction
mixture. The mixture is stirred for 20 h at room temperature. Then
nitrogen is passed through the reaction vessel in order to expel
excess ethylene oxide, then the reaction mixture is combined with
aqueous ammonium chloride solution and concentrated by evaporation
i.vac. The residue is combined with 1 M hydrochloric acid and THF
and extracted with ethyl acetate. The organic phase is dried with
sodium sulphate and purified by chromatography through RP material
(eluant: water/acetonitrile 90:10=>0:100).
[0686] Yield: 0.20 g (9%)
[0687] R.sub.f value: 0.52 (silica gel; ethyl acetate/petroleum
ether=30:10)
[0688] C.sub.10H.sub.10BrNO.sub.3S (304.16)
[0689] Mass spectrum: (M+H).sup.+=304/306 (bromine isotopes)
(c) 5-bromo-thiophene-2-carboxylic
acid-N-[3-hydroxy-1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azep-
in-7-ylcarbamoyl)-propyl]-amide
[0690] 0.16 g (0.66 mmol)
3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine are suspended at
room temperature in 3 ml dichloromethane, 1.30 ml (2.60 mmol) 2M
trimethylaluminium solution in toluene are added dropwise thereto
and the mixture is stirred for 30 min. 0.20 g (0.66 mmol)
5-bromo-thiophene-2-carboxylic acid
(3-methyl-2-oxo-tetrahydro-furan-3-yl)-amide in 6 ml THF are added
dropwise to the reaction mixture. It is then stirred for 20 h at
room temperature. Then the reaction is poured onto 60 ml of 2 M
sodium hydroxide solution and extracted 3.times. with ethyl
acetate. The combined organic phases are dried with sodium sulphate
and purified by chromatography through RP material (Microsorb C18
Varian eluant: water/acetonitrile 90:10=>0:100).
[0691] Yield: 0.14 g (38%)
[0692] R.sub.t value: 2.22 min (HPLC-MS; method 3a)
[0693] C.sub.21H.sub.26BrN.sub.3O.sub.3S (480.43)
[0694] Mass spectrum: (M+H).sup.+=480/482 (bromine isotopes)
EXAMPLE 65
5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-3-dimethylaminocarbonyl-1-(3-methyl-2,3,4,5-tetrahydro-1-
H-benzo[d]azepin-7-ylcarbamoyl)-propyl]amide
##STR00089##
[0696] 0.20 g (0.77 mmol) N-BOC-.alpha.-methyl-D,L-glutamic acid in
5 ml THF are combined with 0.24 g (0.77 mmol) TBTU and 0.10 ml
(0.77 mmol) TEA with stirring at room temperature and stirred for 5
min. Then 0.38 ml (0.77 mmol) dimethylamine 2M in THF are and the
mixture is stirred for 15 h at room temperature. The reaction
mixture is concentrated by evaporation i.vac. And reacted
analogously to the foregoing Examples to form the title
compound.
[0697] R.sub.f value: 0.3 (silica gel;
dichloromethane/ethanol/ammonia 80:20:2)
[0698] C.sub.24H.sub.31ClN.sub.4O.sub.3S (491.05)
[0699] Mass spectrum: (M+H).sup.+=491/493 (chlorine isotopes)
[0700] The following compounds may be prepared from amino acid
derivatives, benzazepine derivatives and thiophenecarboxylic acid
derivatives analogously to the methods of synthesis described in
the foregoing Examples:
TABLE-US-00014 66 ##STR00090## (M + H).sup.+ = 493/495 (chlorine
isotopes) Rt: 2.5 min HPLC-method 2
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-dimethylaminocarbonyloxy-1-
methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-
ethyl]-amide 67 ##STR00091## (M + H).sup.+ = 498/500 (chlorine
isotopes) Rf: 0.48; silica gel; CH.sub.2Cl.sub.2/ethanol/ NH.sub.3
= 80:20:2 5-chloro-thiophene-2-carboxylic
acid-N-[2-(4-hydroxy-phenyl)-1-methyl-
1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-
amide 68 ##STR00092## (M + H).sup.+ = 472/474 (chlorine isotopes)
Rf: 0.5; silica gel; CH.sub.2Cl.sub.2/ethanol = 80:20
5-chloro-thiophene-2-carboxylic
acid-N-[2-(1H-imidazol-4-yl)-1-methyl-
1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-
amide
EXAMPLE 69
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-(3-methoxycarbonyl-propyloxy)-1-methyl-1-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
##STR00093##
[0701] (a) tert.butyl
(R)--N-[2-(3-methoxycarbonyl-prop-2-enyloxy)-1-methyl-1-(3-methyl-2,3,4,5-
-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-carbamate
[0702] A mixture of 120 mg (0.226 mmol) tert.butyl
(R)--N-[2-(prop-2-enyloxy)-1-methyl-1-(3-methyl-2,3,4,5-tetrahydro-1H-ben-
zo[d]azepin-7-ylcarbamoyl)ethyl]-carbamate (prepared from
(R)--O-allyl-.alpha.-methyl-N-butoxycarbonylserine and
3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine) in
methylene chloride is rinsed for 30 min with argon, combined with
0.42 ml (4.66 mmol) methyl acrylate and 2nd generation Grubbs
catalyst and heated to boiling for 4 h. Then the mixture is
concentrated by evaporation and purified by chromatography.
[0703] R.sub.t value: 2.53 min (HPLC-MS; method 2)
(b) (R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-(3-methoxycarbonyl-propyloxy)-1-methyl-1-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]amide
[0704] Tert.butyl
(R)--N-[2-(3-methoxycarbonyl-prop-2-enyloxy)-1-methyl-1-(3-methyl-2,3,4,5-
-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-carbamate is
reacted by a 3-step synthesis sequence analogously to Example 1(c),
35 and 1(f) to form the title compound.
[0705] R.sub.t value: 1.79 min (method 6)
[0706] C.sub.25H.sub.32ClN.sub.3O.sub.5S (522.06)
[0707] Mass spectrum: (M+H).sup.+=522/524 (chlorine isotopes)
EXAMPLE 70
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-(3-hydroxycarbonyl-propyloxy)-1-methyl-1-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
##STR00094##
[0708] is prepared from Example 69 by saponification with lithium
hydroxide analogously to Example 8 (d).
[0709] R.sub.t value: 2.4 min (HPLC-MS; method 2)
[0710] C.sub.24H.sub.30ClN.sub.3O.sub.5S (508.03)
[0711] Mass spectrum: (M+H).sup.+=508/510 (chlorine isotopes)
EXAMPLE 71
5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-y-
lcarbamoyl)-ethyl]-amide
##STR00095##
[0712] (a)
3,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and
3,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-8-ylamine
[0713] Starting from 1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine
a mixture of the two title compounds may be prepared by the
synthesis sequence of Leuckart-Wallach reaction analogously to
Example 1(b), nitrogenation analogously to Example 9(a) and
reduction analogously to Example 9(d), and the mixture may be
purified by chromatography (silica gel, methylene
chloride/(ethanol: ammonia 95:5) 99/1->8/2):
3,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine
[0714] R.sub.f value: 0.70 (silica gel; methylene
chloride/methanol/ammonia 80/20/2)
[0715] C.sub.12H.sub.18N.sub.12 (190.29)
[0716] Mass spectrum: (M+H).sup.+=191
3,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-8-ylamine
[0717] R.sub.f value: 0.75 (silica gel; methylene
chloride/methanol/ammonia 80/20/2)
[0718] C.sub.12H.sub.18N.sub.2 (190.29)
[0719] Mass spectrum: (M+H).sup.+=191
(b) 5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-y-
lcarbamoyl)-ethyl]-amide
[0720] is prepared by reacting
3,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine
analogously to Example 1(f).
[0721] R.sub.f value: 0.6 (silica gel; methylene
chloride/methanol/ammonia 80/20/2)
[0722] C.sub.21H.sub.26ClN.sub.3O.sub.2S (419.97)
[0723] Mass spectrum: (M+H).sup.+=420/422 (chlorine isotopes)
EXAMPLE 72
5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-8-y-
lcarbamoyl)-ethyl]-amide
##STR00096##
[0724] is prepared from
3,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-8-ylamine (see
Example 71a) analogously to Example 1(f).
[0725] R.sub.f value: 0.8 (silica gel; methylene
chloride/methanol/ammonia 80/20/2)
[0726] C.sub.21H.sub.26ClN.sub.3O.sub.2S (419.97)
[0727] Mass spectrum: (M+H).sup.+=420/422 (chlorine isotopes)
EXAMPLE 73
5-chloro-thiophene-2-carboxylic
acid-N-{1-methyl-1-[3-methyl-5-(4-aminophenyl)-2,3,4,5-tetrahydro-1H-benz-
o[d]azepin-7-ylcarbamoyl]-ethyl}-amide
##STR00097##
[0728] (a)
3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine
[0729] 1.00 g (4.48 mmol)
1-phenyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine is taken up in 1.7
ml formic acid and combined with 1.22 ml of 37% formalin solution,
then heated to 70.degree. C. for 2 h. The reaction mixture is
concentrated, made basic with 10 M NaOH and extracted with ethyl
acetate. The organic phases are dried with sodium sulphate, then
filtered and evaporated down.
[0730] R.sub.f value: 0.35 (silica gel; methylene
chloride/methanol/ammonia 95/5/0.5)
[0731] C.sub.17H.sub.19N (237.34)
[0732] Mass spectrum: (M+H).sup.+=238
(b)
3-methyl-5-(4-nitrophenyl)-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepi-
ne
[0733] 3-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine is
nitrogenated analogously to Example 9(a) and purified by
chromatography (silica gel: petroleum ether/ethyl acetate
1/1->1/100)
[0734] R.sub.f value: 0.2 (silica gel; ethyl acetate)
[0735] C.sub.17H.sub.17N.sub.3O.sub.4 (327.33)
[0736] Mass spectrum: (M+H).sup.+=328
(c) 5-chloro-thiophene-2-carboxylic
acid-N-{1-methyl-1-[3-methyl-5-(4-aminophenyl)-2,3,4,5-tetrahydro-1H-benz-
o[d]azepin-7-ylcarbamoyl]-ethyl}-amide
[0737] is prepared by hydrogenation of
3-methyl-5-(4-nitrophenyl)-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine
analogously to Example 1(c) and subsequent reaction with
2-[(5-chloro-thiophen-2-yl)-carbonylamino]-2-methyl-propionic acid
analogously to Example 1(f).
[0738] R.sub.f value: 0.6 (aluminium oxide; methylene
chloride/ethanol 95/5)
[0739] C.sub.26H.sub.29ClN.sub.4O.sub.2S (497.05)
[0740] Mass spectrum: (M+H).sup.+=497/499 (chlorine isotopes)
[0741] The following compounds may be prepared from amino acid
derivatives, benzazepine derivatives and thiophenecarboxylic acid
derivatives analogously to the methods of synthesis described in
the Examples or known from the literature:
TABLE-US-00015 74 ##STR00098## (M + H).sup.+ = 420/422 (chlorine
isotopes) Rt: 2.63 min HPLC-method 2
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[1-(3-methyl-2,3,4,5-tetrahydro-
1H-benzo[d]azepin-7-ylcarbamoyl)-butyl]-amide 75 ##STR00099## (M +
H).sup.+ = 436/438 (chlorine isotopes) Rt: 2.56 min HPLC-method 2
5-chloro-thiophene-2-carboxylic
acid-N-[2-ethoxy-1-(3-methyl-2,3,4,5-tetra-
hydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 76 ##STR00100##
(M + H).sup.+ = 436/438 (chlorine isotopes) Rt: 0.92 min
HPLC-method 5 5-chloro-thiophene-2-carboxylic
acid-N-[3-methoxy-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide 77
##STR00101## (M + H).sup.+ = 450/452 (chlorine isotopes) Rt: 2.63
min HPLC-method 2 5-chloro-thiophene-2-carboxylic
acid-N-[2-propyloxy-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 78
##STR00102## (M + H).sup.+ = 464/466 (chlorine isotopes) Rt: 4.62
min HPLC-method 3 5-chloro-thiophene-2-carboxylic
acid-N-[2-isobutyloxy-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 79
##STR00103## (M + H).sup.+ = 450/452 (chlorine isotopes) Rt: 4.32
min HPLC-method 3 5-chloro-thiophene-2-carboxylic
acid-N-[2-isopropyloxy-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 80
##STR00104## (M + H).sup.+ = 432/434 (chlorine isotopes) Rt: 4.30
min HPLC-method 3 5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-but-3-enyl]-amide 81
##STR00105## (M + H).sup.+ = 512/514 (chlorine isotopes) Rt: 0.25;
silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 90:10:1
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-benzyloxy-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide
82 ##STR00106## (M + H).sup.+ = 512/514 (chlorine isotopes) Rt:
4.82 min HPLC-method 3 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-phenethyloxy-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
EXAMPLE 83
5-chloro-thiophene-2-carboxylic
acid-N-[2-(2-methoxyethyloxy)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]a-
zepin-7-ylcarbamoyl)-ethyl]amide
##STR00107##
[0742] (a) methyl
N-(5-chlorothiophen-2-yl)carbonyl-aziridine-2-carboxylate
[0743] A mixture of 4.40 g (43.5 mmol) methyl
aziridine-2-carboxylate and 13.5 ml (97.3 mmol) triethylamine in 30
ml methylene chloride is combined with 8.80 g (48.6 mmol)
5-chlorothiophenecarboxylic acid chloride in 30 ml methylene
chloride while cooling with ice and subsequently after removal of
the cooling bath stirred for 3 h at room temperature. Then the
mixture is diluted with water, extracted with methylene chloride,
dried with sodium sulphate, concentrated and purified by
chromatography (silica gel, petroleum ether/ethyl acetate
80/15->80/20) to obtain the slightly contaminated title
compound.
[0744] R.sub.f value: 0.42 (silica gel; methylene chloride/methanol
80/20)
[0745] C.sub.9H.sub.8ClNO.sub.3S (245.68)
[0746] Mass spectrum: (M+H).sup.+=246/248 (chlorine isotopes)
(b) methyl
2-(5-chlorothiophen-2-yl)carbonylamino-3-(2-methoxyethyloxy)pro-
pionate
[0747] A mixture of 0.30 g (about 1 mmol) methyl
N-(5-chlorothiophen-2-yl)carbonyl-aziridine-2-carboxylate and 0.29
ml (3.7 mmol) 2-methoxyethanol in 4 ml methylene chloride is slowly
combined with 0.16 ml boron trifluoride etherate and stirred for 3
h. The reaction mixture is concentrated and purified by
chromatography (silica gel, petroleum ether/ethyl acetate
80/20->40/60).
[0748] R.sub.f value: 0.05 (silica gel; methylene chloride/methanol
80/20)
[0749] C.sub.12H.sub.16ClNO.sub.5S (321.78)
[0750] Mass spectrum: (M+H).sup.+=322/324 (chlorine isotopes)
(c) 5-chloro-thiophene-2-carboxylic
acid-N-[2-(2-methoxyethyloxy)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]a-
zepin-7-ylcarbamoyl)-ethyl]-amide
[0751] The title compound is prepared from methyl
2-(5-chlorothiophen-2-yl)carbonylamino-3-(2-methoxyethyloxy)propionate
by lithium hydroxide saponification and subsequent reaction with
3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine with EEDQ
analogously to Example 58(c).
[0752] R.sub.t value: 3.98 min (method 3)
[0753] C.sub.22H.sub.28ClN.sub.3O.sub.4S (465.99)
[0754] Mass spectrum: (M+H).sup.+=466/468 (chlorine isotopes)
EXAMPLE 84 AND 85
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-3,4-dihydroxy-N-(3-methyl-2,3,4-
,5-tetrahydro-1H-benzo[d]azepin-7-yl)-cyclopentane-1-carboxylic
acid amide (84) and
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-3-formyloxy-4-hydroxy-
-N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-cyclopentane-1-car-
boxylic acid amide (85)
##STR00108##
[0756] A mixture of 0.10 g (0.348 mmol)
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-3,4-epoxy-cyclopentane-1-carbo-
xylic acid, 0.113 g (0.352 mmol) TBTU and 0.116 ml (1.055 mmol) NMM
in 1.5 ml DMF is stirred for 30 min and then combined with 62 mg
(0.352 mmol)
3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and stirred
overnight. Water is added, the mixture is extracted with ethyl
acetate, concentrated and the residue is taken up in DMF and
trifluoroacetic acid and purified by chromatography by HPLC.
EXAMPLE 84
[0757] R.sub.t value: 3.53 min (method 3)
[0758] C.sub.22H.sub.26ClN.sub.3O.sub.4S (463.98)
[0759] Mass spectrum: (M+H).sup.+=464/466 (chlorine isotopes)
EXAMPLE 85
[0760] R.sub.t value: 3.72 min (method 3)
[0761] C.sub.23H.sub.26ClN.sub.3O.sub.5S (491.99)
[0762] Mass spectrum: (M+H).sup.+=492/494 (chlorine isotopes)
EXAMPLE 86
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-3,4-dimethoxy-N-(3-methyl-2,3,4-
,5-tetrahydro-1H-benzo[d]azepin-7-yl)-cyclopentane-1-carboxylic
acid amide
##STR00109##
[0763] (a) methyl
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-3,4-epoxy-cyclopentane-1-carbo-
xylate
[0764] A mixture of 0.85 g (2.9 mmol) methyl
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-cyclopent-3-ene-1-carboxylate
and 20 ml methylene chloride is combined with 0.92 g 70%
meta-chloroperbenzoic acid at 0.degree. C. and stirred for 3 h at
room temperature. The mixture is washed with sat. Sodium hydrogen
carbonate solution and concentrated.
[0765] C.sub.12H.sub.12ClNO.sub.4S (301.75)
[0766] Mass spectrum: (M+H).sup.+=302/304 (chlorine isotopes)
(b) methyl
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-3,4-dihydroxy-cyclop-
entane-1-carboxylate
[0767] A mixture of 0.76 g (1.84 mmol) methyl
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-3,4-epoxy-cyclopentane-1-carbo-
xylate, 3.0 ml acetic acid and 0.38 g potassium hydrogen sulphate
are stirred for 4 h at 40.degree. C. Then the mixture is
concentrated by evaporation, dissolved in DMF, acidified with
trifluoroacetic acid and purified by preparative HPLC.
[0768] C.sub.12H.sub.14ClNO.sub.5S (319.76)
[0769] Mass spectrum: (M+H).sup.+=320/322 (chlorine isotopes)
(c)
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-3,4-dimethoxy-N-(3-methyl-2-
,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-cyclopentane-1-carboxylic
acid amide
[0770] The title compound was prepared from methyl
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-3,4-dihydroxy-cyclopentane-1-c-
arboxylate by methylation analogously to Example 61 and subsequent
saponification with LiOH and reaction with
3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine.
[0771] R.sub.t value: 4.09 min (HPLC-MS; method 3)
[0772] C.sub.24H.sub.30ClN.sub.3O.sub.4S (492.04)
[0773] Mass spectrum: (M+H).sup.+=492/494 (chlorine isotopes)
EXAMPLE 87
(R)-5-bromo-thiophene-2-carboxylic
acid-N-[2-(5-methyl-oxazol-2-yl)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[-
d]azepin-7-ylcarbamoyl)-ethyl]-amide
##STR00110##
[0775] A mixture of 0.70 g (2.5 mmol) methyl
(R)-2-tert.butoxycarbonylamino-3-propargylaminocarbonyl-propionate,
10 mg gold trichloride and 9.0 ml acetonitrile is stirred for 16 h
at 50.degree. C. Then the mixture is filtered, concentrated by
evaporation and purified by HPLC. The crude product is reacted
analogously to Example 64(c) with
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine, then
subjected to BOC cleaving and reaction with
5-bromothiophenecarboxylic acid analogously to Example 1(f) to form
the title compound.
[0776] R.sub.t value: 2.52 min (HPLC-MS; method 2)
[0777] C.sub.23H.sub.25BrN.sub.4O.sub.3S (517.45)
[0778] Mass spectrum: (M+H).sup.+=517/519 (bromine isotopes)
[0779] The following compounds may be prepared from amino acid
derivatives, benzazepine derivatives and thiophenecarboxylic acid
derivatives analogously to the methods of synthesis described in
the Examples or known from the literature:
TABLE-US-00016 88 ##STR00111## (M + H).sup.+ = 473/475 (chlorine
isotopes) Rt: 2.48 min HPLC-method 2
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-(5-methyl-oxazol-2-yl)-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 89
##STR00112## (M + H).sup.+ = 561/563 (chlorine isotopes) Rf: 0.37;
silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 90:10:1
5-chloro-thiophene-2-carboxylic
acid-N-[C-(1-tert.cndot.butoxycarbonylpiperidin-4-yl)-C-
(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-methyl]-ami-
de 90 ##STR00113## (M + H).sup.+ = 461/463 (chlorine isotopes) Rf:
0.42; RP8; MeOH/5% NaCl solution = 6/4
5-chloro-thiophene-2-carboxylic
acid-N-[C-(piperidin-4-yl)-C-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-methyl]-amide 91
##STR00114## (M + H).sup.+ = 456/458 (chlorine isotopes) Rf: 0.35;
RP8; MeOH/5% NaCl solution = 6/4 5-chloro-thiophene-2-carboxylic
acid-N-[C-(pyrazin-2-yl)-C-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-methyl]-amide 92
##STR00115## (M + H).sup.+ = 458/460 (chlorine isotopes) Rf: 0.6;
silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
5-chloro-thiophene-2-carboxylic
acid-N-[C-(1-methyl-pyrazol-3-yl)-C-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-methyl]-amide
93 ##STR00116## (M + H).sup.+ = 455/457 (chlorine isotopes) Rf:
0.54; Alox; CH.sub.2Cl.sub.2/ethanol = 95/5
5-chloro-thiophene-2-carboxylic
acid-N-[C-(pyridin-3-yl)-C-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-methyl]-amide 94
##STR00117## (M + H).sup.+ = 498/500 (chlorine isotopes) Rf: 0.75;
silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
5-chloro-thiophene-2-carboxylic
acid-N-[C-(3,4-methylendioxophenyl)-C-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-methyl]-amide
95 ##STR00118## (M + H).sup.+ = 448/450 (chlorine isotopes) Rt:
2.72 min HPLC-method 4 5-chloro-thiophene-2-carboxylic
acid-N-[C-(tetrahydrofuran-3-yl)-C-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-methyl]-amide
96 ##STR00119## (M + H).sup.+ = 468/470 (chlorine isotopes) Rf:
0.79; Alox; CH.sub.2Cl.sub.2/ethanol = 95/5
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-phenyl-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 97
##STR00120## (M + H).sup.+ = 475/477 (chlorine isotopes) Rf: 0.56;
Alox; CH.sub.2Cl.sub.2/ethanol = 95/5
5-chloro-thiophene-2-carboxylic
acid-N-[2-(thiazol-4-yl)-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 98
##STR00121## (M + H).sup.+ = 458/460 (chlorine isotopes) Rf: 0.77;
Alox; CH.sub.2Cl.sub.2/ethanol = 95/5
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-(furan-2-yl)-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 99
##STR00122## (M + H).sup.+ = 469/471 (chlorine isotopes) Rf: 0.54;
silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-(pyridin-3-yl)-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 100
##STR00123## (M + H).sup.+ = 528/530 (chlorine isotopes) Rf: 0.27;
silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 90:10:1
5-chloro-thiophene-2-carboxylic
acid-N-[2-(3,5-dimethoxyphenyl)-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
101 ##STR00124## (M + H).sup.+ = 528/530 (chlorine isotopes) Rf:
0.7; silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
5-chloro-thiophene-2-carboxylic
acid-N-[2-(3,4-dimethoxyphenyl)-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
102 ##STR00125## (M + H).sup.+ = 498/500 (chlorine isotopes) Rf:
0.7; silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
5-chloro-thiophene-2-carboxylic
acid-N-[2-(4-methoxyphenyl)-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
103 ##STR00126## (M + H).sup.+ = 529/531 (chlorine isotopes) Rf:
0.18; silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
5-chloro-thiophene-2-carboxylic
acid-N-[2-(4-hydroxy-3-nitro-phenyl)-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
104 ##STR00127## (M + H).sup.+ = 499/501 (chlorine isotopes) Rf:
0.30; silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
5-chloro-thiophene-2-carboxylic
acid-N-[2-(4-hydroxy-3-amino-phenyl)-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
105 ##STR00128## (M + H).sup.+ = 484/486 (chlorine isotopes) Rf:
0.5; silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-(4-hydroxy-phenyl)-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
106 ##STR00129## (M + H).sup.+ = 474/476 (chlorine isotopes) Rf:
0.18; silica gel; CH.sub.2Cl.sub.2/ethanol = 80:20
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-cyclohexyl-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 107
##STR00130## (M + H).sup.+ = 475/477 (chlorine isotopes) Rt: 2.7
min HPLC-method 4 5-chloro-thiophene-2-carboxylic
acid-N-[2-(thiazol-2-yl)-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 108
##STR00131## (M + H).sup.+ = 493/495 (chlorine isotopes) Rt: 4.14
min HPLC-method 3 5-chloro-thiophene-2-carboxylic
acid-N-[3-dimethylaminocarbonyloxy-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide
109 ##STR00132## (M + H).sup.+ = 522/524 (chlorine isotopes) Rf:
0.74; silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
5-chloro-thiophene-2-carboxylic
acid-N-[2-tert.cndot.butyloxycarbonylmethyloxy-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
110 ##STR00133## (M + H).sup.- = 464/466 (chlorine isotopes) Rf:
0.45; RP8; MeOH/5% NaCl solution = 6/4
5-chloro-thiophene-2-carboxylic
acid-N-[2-hydroxycarbonylmethyloxy-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
111 ##STR00134## (M + H).sup.+ = 436/438 (chlorine isotopes) Rf:
0.65; RP8; MeOH/5% NaCl solution = 6/4
5-chloro-thiophene-2-carboxylic
acid-N-[2-hydroxycarbonyl-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 112
##STR00135## (M + H).sup.+ = 435/437 (chlorine isotopes) Rf: 0.25;
silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-aminocarbonyl-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 113
##STR00136## (M + H).sup.+ = 463/465 (chlorine isotopes) Rf: 0.6;
silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
5-chloro-thiophene-2-carboxylic
acid-N-[2-dimethylaminocarbonyl-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
114 ##STR00137## (M + H).sup.+ = 449/451 (chlorine isotopes) Rf:
0.2; silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-aminocarbonyl-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide 115
##STR00138## (M + H).sup.+ = 477/479 (chlorine isotopes) Rf: 0.3;
silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
5-chloro-thiophene-2-carboxylic
acid-N-[3-dimethylaminocarbonyl-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide
116 ##STR00139## (M + H).sup.+ = 464/466 (chlorine isotopes) Rt:
0.94 min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-methyloxycarbonyl-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide
117 ##STR00140## (M + H).sup.+ = 535/537 (chlorine isotopes) Rt:
0.90 min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-(N-methyloxycarbonylmethyl-N-
methyl-aminocarbonyl)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-propyl]-amide 118 ##STR00141## (M + H).sup.+ = 549/551
(chlorine isotopes) Rt: 0.89 min HPLC-method 5
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-(N-(2-methyloxycarbonyl-ethyl)-N-
methyl-aminocarbonyl)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-propyl]-amide 119 ##STR00142## (M + H).sup.+ = 563/565
(chlorine isotopes) Rt: 0.89 min HPLC-method 5
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-(N-(3-methyloxycarbonyl-propyl)-N-
methyl-aminocarbonyl)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-propyl]-amide 120 ##STR00143## (M + H).sup.+ = 521/523
(chlorine isotopes) Rt: 0.84 min HPLC-method 5
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-(N-hydroxycarbonylmethyl-N-
methyl-aminocarbonyl)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-propyl]-amide 121 ##STR00144## (M + H).sup.+ = 549/551
(chlorine isotopes) Rt: 0.85 min HPLC-method 5
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-(N-(3-hydroxycarbonyl-propyl)-N-
methyl-aminocarbonyl)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-propyl]-amide 122 ##STR00145## (M + H).sup.+ = 535/537
(chlorine isotopes) Rt: 0.84 min HPLC-method 5
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-(N-(2-hydroxycarbonyl-ethyl)-N-
methyl-aminocarbonyl)-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-propyl]-amide 123 ##STR00146## (M + H).sup.+ = 478/480
(chlorine isotopes) Rt: 2.55 min HPLC-method 2
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[4-methyloxycarbonyl-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-butyl]-amide
124 ##STR00147## (M + H).sup.+ = 464/466 (chlorine isotopes) Rt:
3.87 min HPLC-method 3 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[4-hydroxycarbonyl-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-butyl]-amide
125 ##STR00148## (M + H).sup.+ = 506/508 (chlorine isotopes) Rt:
2.71 min HPLC-method 2 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[5-ethyloxycarbonyl-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-pentyl]-amide
126 ##STR00149## (M + H).sup.+ = 478/480 (chlorine isotopes) Rt:
3.96 min HPLC-method 3 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[5-hydroxycarbonyl-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-pentyl]-amide
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-tert.cndot.butyloxycarbonylamino-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
128 ##STR00150## (M + H).sup.+ = 541/543 (chlorine isotopes) Rt:
1.03 min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-benzyloxycarbonylamino-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
129 ##STR00151## (M + H).sup.+ = 449/451 (chlorine isotopes) Rt:
0.84 min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-acetylamino-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 130
##STR00152## (M + H).sup.+ = 555/557 (bromine isotopes) Rt: 0.98
min HPLC-method 5 (R)-5-bromo-thiophene-2-carboxylic
acid-N-[2-benzoylamino-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 131
##STR00153## (M + H).sup.+ = 522/524 (bromine isotopes) Rt: 0.90
min HPLC-method 5 (R)-5-bromo-thiophene-2-carboxylic
acid-N-[2-ethylaminocarbonylamino-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
132 ##STR00154## (M + H).sup.+ = 478/480 (chlorine isotopes) Rt:
0.88 min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-ethylaminocarbonylamino-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide
133 ##STR00155## (M + H).sup.+ = 511/513 (chlorine isotopes) Rt:
0.97 min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-benzoylamino-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 134
##STR00156## (M + H).sup.+ = 493/495 (bromine isotopes) Rt: 0.85
min HPLC-method 5 (R)-5-bromo-thiophene-2-carboxylic
acid-N-[2-acetylamino-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 135
##STR00157## (M + H).sup.+ = 521/523 (chlorine isotopes) Rt: 3.99
min HPLC-method 3 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[2-(2-methoxycarbonyl-
ethyl)carbonylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-ethyl]-amide 136 ##STR00158## (M + H).sup.+ = 493/495
(chlorine isotopes) Rt: 3.61 min HPLC-method 3
(R)-5-chloro-thiophene-2-carboxylic acid-N-[2-
hydroxycarbonylmethylcarbonylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 137 ##STR00159## (M +
H).sup.+ = 507/509 (chlorine isotopes) Rt: 3.64 min HPLC-method 3
(R)-5-chloro-thiophene-2-carboxylic acid-N-[2-(2-hydroxycarbonyl-
ethyl)carbonylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-ethyl]-amide 138 ##STR00160## (M + H).sup.+ = 521/523
(chlorine isotopes) Rt: 3.66 min HPLC-method 3
(R)-5-chloro-thiophene-2-carboxylic acid-N-[2-(3-hydroxycarbonyl-
propyl)carbonylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-ethyl]-amide 139 ##STR00161## (M + H).sup.+ = 535/537
(chlorine isotopes) Rt: 3.71 min HPLC-method 3
(R)-5-chloro-thiophene-2-carboxylic acid-N-[2-(4-hydroxycarbonyl-
butyl)carbonylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-ethyl]-amide 140 ##STR00162## (M + H).sup.+ = 507/509
(chlorine isotopes) Rt: 3.83 min HPLC-method 3
(R)-5-chloro-thiophene-2-carboxylic acid-N-[2-
methoxycarbonylmethylcarbonylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-
benzo[d]azepin-7-ylcarbamoyl)-ethyl]-amide 141 ##STR00163## (M +
H).sup.+ = 549/551 (chlorine isotopes) Rt: 4.04 min HPLC-method 3
(R)-5-chloro-thiophene-2-carboxylic acid-N-[2-(4-methoxycarbonyl-
butyl)carbonylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-ethyl]-amide 142 ##STR00164## (M + H).sup.+ = 535/537
(chlorine isotopes) Rt: 3.95 min HPLC-method 3
(R)-5-chloro-thiophene-2-carboxylic acid-N-[2-(3-methoxycarbonyl-
propyl)carbonylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-ethyl]-amide 143 ##STR00165## (M + H).sup.+ = 421/423
(chlorine isotopes) Rt: 0.77 min HPLC-method 5
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-amino-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide 144
##STR00166## (M + H).sup.+ = 521/523 (chlorine isotopes) Rt: 1.02
min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-tert.cndot.butoxycarbonylamino-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide
145 ##STR00167## (M + H).sup.+ = 507/509 (chlorine isotopes) Rt:
0.97 min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-isopropyloxycarbonylamino-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide
146 ##STR00168## (M + H).sup.+ = 479/481 (chlorine isotopes) Rt:
0.90 min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-methyloxycarbonylamino-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide
147 ##STR00169## (M + H).sup.+ = 534/536 (chlorine isotopes) Rt:
0.87 min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-(morpholine-4-yl)carbonylamino-1-
(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-ami-
de 148 ##STR00170## (M + H).sup.+ = 525/527 (chlorine isotopes) Rt:
0.97 min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-benzoylamino-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide 149
##STR00171## (M + H).sup.+ = 463/465 (chlorine isotopes) Rt: 0.85
min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-acetylamino-1-(3-methyl-2,3,4,5-
tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide 150
##STR00172## (M + H).sup.+ = 492/494 (chlorine isotopes) Rt: 0.88
min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-ethylaminocarbonylamino-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide
151 ##STR00173## (M + H).sup.+ = 493/495 (chlorine isotopes) Rt:
0.88 min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-methyloxymethylcarbonylamino-1-
(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-ami-
de 152 ##STR00174## (M + H).sup.+ = 563/565 (chlorine isotopes) Rt:
0.94 min HPLC-method 5 (R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-(3-ethyloxycarbonyl-
propyl)carbonylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-propyl]-amide 153 ##STR00175## (M + H).sup.+ = 537/539
(chlorine isotopes) Rt: 0.89 min HPLC-method 5
(R)-5-chloro-thiophene-2-carboxylic acid-N-[3-(2-methyloxy-
ethyl)methylcarbonylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepi-
n-7- ylcarbamoyl)-propyl]-amide 154 ##STR00176## (M + H).sup.+ =
535/537 (chlorine isotopes) Rt: 0.85 min HPLC-method 5
(R)-5-chloro-thiophene-2-carboxylic acid-N-[3-(3-hydroxycarbonyl-
propyl)carbonylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-
ylcarbamoyl)-propyl]-amide 155 ##STR00177## (M + H).sup.+ = 517/519
(chlorine isotopes) Rt: 0.98 min HPLC-method 5
(R)-5-chloro-thiophene-2-carboxylic
acid-N-[3-trifluormethylcarbonylamino-1-(3-
methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-propyl]-amide
156 ##STR00178## (M + H).sup.+ = 478/480 (chlorine isotopes) Rf:
0.2; silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
5-chloro-thiophene-2-carboxylic
acid-N-[4-aminocarbonylamino-1-(3-methyl-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl)-butyl]-amide
EXAMPLE 157
5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3,3-dimethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepinium--
7-ylcarbamoyl]-ethyl}-amide iodide
##STR00179##
[0781] A mixture of 0.50 g (2.43 mmol)
3-methyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine, 0.44 ml
(7.0 mmol) iodomethane and 2.0 ml acetonitrile are stirred for 1 h
at room temperature and for 1 h at boiling temperature. The
precipitate formed is suction filtered and dried. Then the mixture
is hydrogenated analogously to Example 1(c) and reacted to form the
title compound analogously to 1(f).
[0782] R.sub.t value: 2.7 min (HPLC-MS; method 4)
[0783] C.sub.21H.sub.27ClN.sub.3O.sub.2S I(547.88)
[0784] Mass spectrum: =420/422 (chlorine isotopes)
EXAMPLE 158
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-3-oxy-2,3,4,5-tetra-
hydro-1H-benzo[d]azepin-7-yl)-cyclopentane-1-carboxylic acid
amide
##STR00180##
[0786] A mixture of 0.20 g (0.46 mmol)
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetrahydro-
-1H-benzo[d]azepin-7-yl)-cyclopentane-1-carboxylic acid amide, 0.12
ml 70% meta-chloroperbenzoic acid and 10.0 ml chloroform are
stirred for 2 h at room temperature. The mixture is diluted with
water and a few drops of 2 N NaOH and ethyl acetate. The mixture is
kept overnight in the freezer, and after thawing a crystalline
layer is found between the two phases, which is filtered off and
dried.
[0787] R.sub.t value: 3.14 min (HPLC-MS; method 4)
[0788] C.sub.22H.sub.26ClN.sub.3O.sub.3S (447.98)
[0789] Mass spectrum: (M+H).sup.+=448/450 (chlorine isotopes)
EXAMPLE 159
5-chloro-thiophene-2-carboxylic
acid-N-[1-(7-benzyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-ylcarba-
moyl)-1-methyl-ethyl]-amide
##STR00181##
[0790] (a) 1-benzyl-5-chloro-azepan-4-carbaldehyde
[0791] 310 ml (4 mol) DMF are taken and at 10-20.degree. C. 273 ml
(3 mol) phosphorus oxychloride are added dropwise thereto over a
period of 40 min, then the mixture is stirred for 30 min and then
combined with 400 ml dichloromethane and 239.7 g (1 mol)
1-benzyl-hexahydro-4H-azepinone and stirred for 4 h. It is poured
onto 31 of ice water and stirred for 30 min, after which it is
extracted with dichloromethane. The organic phase is dried and
concentrated by evaporation i.vac., then the crude product is
triturated with acetone.
[0792] Yield: 177.8 g (62%)
[0793] R.sub.f value: 0.69 (silica gel: dichloromethane/ethyl
acetate/ethanol=4:2:0.1)
[0794] C.sub.14H.sub.16ClNO (249.74)
(b)
7-benzyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-ylamine
[0795] 4.60 g (0.20 mol) sodium are dissolved in 250 ml of ethanol
and at room temperature combined with 5.90 g (0.10 mmol) guanidine
hydrochloride and 24.97 g (0.10 mol)
1-benzyl-5-chloro-azepan-4-carbaldehyde. Then the mixture is
refluxed for 5 h, then stirred for 15 h at room temperature. It is
then concentrated by evaporation i.vac., combined with 500 ml
dichloromethane and washed 3 times with 400 ml of water. It is
purified by chromatography through silica gel (eluant:
dichloromethane/methanol 95:5), concentrated by evaporation i.vac.
And triturated with ethanol.
[0796] Yield: 1.97 g (8%)
[0797] C.sub.15H.sub.18N.sub.4 (254.33)
[0798] Mass spectrum: (M+H)+=255
(c) 5-chloro-thiophene-2-carboxylic
acid-N-[1-(7-benzyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-ylcarba-
moyl)-1-methyl-ethyl]-amide
[0799] 0.63 g (2.75 mmol)
2-(5-chloro-thiophen-2-yl)-4,4-dimethyl-4H-oxazol-5-one and 0.70 g
(2.75 mmol)
7-benzyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-ylamine are
suspended in 0.350 ml glacial acetic acid, 3.15 ml of toluene and
3.5 ml DMF and stirred for 20 h at 110.degree. C. The mixture is
separated by chromatography through silica gel
(eluant:dichloromethane/ethanol 100:0=>93:7). Then it is
combined with ethyl acetate and washed with 5% sodium hydrogen
carbonate solution and water, dried with sodium sulphate and
concentrated by evaporation i.vac.
[0800] Yield: 0.20 g (15%)
[0801] R.sub.f value: 0.5 (silica gel;
dichloromethane/ethanol=90:10)
[0802] C.sub.24H.sub.26ClN.sub.5O.sub.2S (484.01)
[0803] Mass spectrum: (M-H)-=482/4 (chlorine isotopes)
EXAMPLE 160
5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ylcarbamo-
yl)-ethyl]amide
##STR00182##
[0804] (a) 6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ylamine
[0805] 1.2 g (3.68 mmol)
7-benzyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ylamine are
dissolved in 20 ml of methanol and combined with 0.12 g palladium
oxide. The mixture is hydrogenated in a Parr apparatus at
50.degree. C. at 1 bar hydrogen pressure. Then the catalyst is
filtered off and the filtrate is concentrated by evaporation i.vac.
It is recrystallised from methanol.
[0806] Yield: 0.50 g (57%)
[0807] R.sub.f value: 0.21 (silica gel;
dichloromethane/methanol/ammonia=5:1:0.1)
[0808] melting point: 290.degree. C.
[0809] C.sub.9H.sub.13N.sub.3 (163.22)
(b) tert.-butyl
2-amino-5,6,8,9-tetrahydro-pyrido[2,3-d]azepin-7-carboxylate
[0810] 0.38 g (1.61 mmol)
6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ylamine are suspended
in 10 ml dichloromethane, then 0.667 g (4.83 mmol) potassium
carbonate are added and the mixture is stirred at room temperature
for 10 min. Then 0.369 g (1.69 mmol) BOC-anhydride in 10 ml
dichloromethane is slowly added dropwise while cooling with ice,
after which the mixture is stirred for 17 h at room temperature,
diluted with 20 ml dichloromethane and washed with water. The crude
product is dried with sodium sulphate, concentrated by evaporation
and purified by chromatography through silica gel (eluant:
dichloromethane/ethanol 98:2=>90:10).
[0811] Yield: 0.20 g (47%)
[0812] R.sub.f value: 0.5 (silica gel;
dichloromethane/ethanol=90:10)
[0813] C.sub.14H.sub.21N.sub.3O.sub.2 (263.34)
(c) tert-butyl
2-{2-[(5-chloro-thiophen-2-yl)-carbamylamino]-2-methyl-propionylamino}-5,-
6,8,9-tetrahydro-pyrido[2,3-d]azepine-7-carboxylate
[0814] Prepared analogously to Example 1(f) from tert.-butyl
2-amino-5,6,8,9-tetrahydro-pyrido[2,3-d]azepin-7-carboxylate and
2-[(5-chloro-thiophen-2-yl)-carbonylamino]-2-methyl-propionic acid
with HATU and NMM in DMF at 70.degree. C. and subsequent
purification through silica gel (eluant: dichloromethane/ethanol
100:0=>97:3).
[0815] Yield: 0.15 g (40%)
[0816] R.sub.f value: 0.65 (silica gel;
dichloromethane/ethanol=90:10)
[0817] C.sub.23H.sub.29ClN.sub.4O.sub.4S (493.02)
(d) 5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ylcarbamo-
yl)-ethyl]-amide
[0818] 0.150 g (0.30 mmol) tert-butyl
2-{2-[(5-chloro-thiophen-2-yl)-carbamylamino]-2-methyl-propionylamino}-5,-
6,8,9-tetrahydro-pyrido[2,3-d]azepine-7-carboxylate are dissolved
at room temperature in 2 ml dichloromethane, combined with 0.40 ml
(5.23 mmol) trifluoroacetic acid and stirred for 2 h. Then the
mixture is concentrated by evaporation i.vac. And purified by
chromatography through RP material (Zorbax StableBond C18, 3.5
.mu.m; eluant: water/acetonitrile/formic
acid=80:20:0.1=>10:90:0.1).
[0819] Yield: 0.080 g (52%)
[0820] R.sub.f value: 0.25 (silica gel;
dichloromethane/ethanol/ammonia=90:10:1)
[0821] C.sub.18H.sub.21ClN.sub.4O.sub.2S (392.91)
[0822] Mass spectrum: (M+H)+=393/5 (chlorine isotopes)
EXAMPLE 161
5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(7-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2--
ylcarbamoyl)-ethyl]-amide
##STR00183##
[0824] 70 mg (0.14 mmol) 5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ylcarbamo-
yl)-ethyl]-amide are dissolved in 1 ml (26.50 mmol), then 15.0
.mu.l (0.20 mmol) 37% formaldehyde solution in water are added and
the mixture is stirred for 3 h at 90.degree. C. Then it is
concentrated by evaporation i.vac.
[0825] Yield: 40 mg (56%)
[0826] R.sub.f value: 0.25 (silica gel;
dichloromethane/ethanol/ammonia=80:20:2)
[0827] C.sub.19H.sub.23ClN.sub.4O.sub.2S (604.94)
[0828] Mass spectrum: (M+H)+=407/9 (chlorine isotopes)
[0829] The following compounds may be prepared from amino acid
derivatives, benzazepine derivatives and thiophenecarboxylic acid
derivatives analogously to the methods of synthesis described in
the Examples or known from the literature:
TABLE-US-00017 162 ##STR00184## (M + H).sup.+ = 440/442/444
(dichlorine isotope pattern) Rf: 0.33; RP8; MeOH/5% NaCl solution =
6/4
5-chloro-thiophene-2-carboxylicacid-N-[1-methyl-1-(3-methyl-9-chloro-
2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylcarbamoyl]-ethyl}-amide
163 ##STR00185## (M + H).sup.+ = 448/450 (chlorine isotopes) Rf:
0.75; silica gel; CH.sub.2Cl.sub.2/ethanol/ ammonia = 80:20:2
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3,5-dimethyl-2,3,4,5-tetra-
hydro-1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic acid
amide
EXAMPLE 164
##STR00186##
[0830]
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-yl)-cyclopentane-3-tert.butoxy-1-carboxylic
acid amide
EXAMPLE 165
##STR00187##
[0831]
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-yl)-cyclopentane-3-hydroxy-1-carboxylic
acid amide
EXAMPLE 166
##STR00188##
[0832]
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-yl)-cyclopentane-3-oxo-1-carboxylic acid
amide
EXAMPLE 167
##STR00189##
[0833]
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-5-hydroxy-2,-
3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic
acid amide
EXAMPLE 168
##STR00190##
[0834]
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-5-oxo-2,3,4,-
5-tetrahydro-1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic
acid amide
EXAMPLE 169
##STR00191##
[0835]
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(7-methyl-6,7,8,9-tetr-
ahydro-5H-pyrido[2,3-d]azepin-3-yl)-cyclopentane-1-carboxylic acid
amide
EXAMPLE 170
##STR00192##
[0836]
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-1-methoxy-2,-
3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic
acid amide
EXAMPLE 171
##STR00193##
[0837]
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-1-hydroxy-2,-
3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic
acid amide
EXAMPLE 172
##STR00194##
[0838]
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-1-oxo-2,3,4,-
5-tetrahydro-1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic
acid amide
EXAMPLE 173
##STR00195##
[0839]
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-5-methoxy-2,-
3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic
acid amide
EXAMPLE 174
##STR00196##
[0840]
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-1-fluoro-2,3-
,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic
acid amide
EXAMPLE 175
##STR00197##
[0841]
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-1,1-difluoro-
-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic
acid amide
EXAMPLE 176
##STR00198##
[0842]
3-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-5-fluoro-2,3-
,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-tetrahydrofuran-3-carboxylic
acid amide
EXAMPLE 177
##STR00199##
[0843] 5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3-methyl-9-cyano-2,3,4,5-tetrahydro-1H-benzo[d]azepin-
-7-ylcarbamoyl]-ethyl}-amide
EXAMPLE 178
##STR00200##
[0844] 5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(10-methyl-10-aza-tricyclo[6,3,2,02,7]trideca-2(7),3,5-
-trien-4-ylcarbamoyl]-ethyl}-amide
EXAMPLE 179
##STR00201##
[0845] 5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(10-methyl-10-aza-tricyclo[6,3,1,02,7]dodeca-2(7),3,5--
trien-4-ylcarbamoyl]-ethyl}-amide
EXAMPLE 180
##STR00202##
[0846] 5-chloro-thiophene-2-carboxylic
acid-N-[4-methylsulphonylamino-1-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]-
azepin-7-ylcarbamoyl)-butyl]-amide
EXAMPLE 181
##STR00203##
[0847]
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-yl)-3-cyano cyclopentane-1-carboxylic
acid amide
EXAMPLE 182
##STR00204##
[0848]
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-yl)-3-dimethylaminocarbonyl
cyclopentane-1-carboxylic acid amide
EXAMPLE 183
##STR00205##
[0849]
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-yl)-3-methoxycarbonyl
cyclopentane-1-carboxylic acid amide
EXAMPLE 184
##STR00206##
[0850]
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-yl)-3-hydroxycarbonyl
cyclopentane-1-carboxylic acid amide
EXAMPLE 185
##STR00207##
[0851] 5-chloro-thiophene-2-carboxylic
acid-N-[1-methyl-1-(3-methyl-9-cyano-2,3,4,5-tetrahydro-1H-benzo[d]azepin-
-7-ylcarbamoyl]-ethyl}-amide
EXAMPLE 186
##STR00208##
[0852]
1-[(5-chloro-thiophen-2-yl)-carbonylamino]-N-(3-methyl-2,3,4,5-tetr-
ahydro-1H-benzo[d]azepin-7-yl)-3-cyano cyclopentane-1-carboxylic
acid amide
[0853] The Examples that follow describe the preparation of
pharmaceutical formulations which contain as active substance any
desired compound of general formula I.
EXAMPLE A
TABLE-US-00018 [0854] Dry ampoule containing 75 mg of active
substance per 10 ml Composition: Active substance 75.0 mg Mannitol
50.0 mg water for injections ad 10.0 ml
[0855] Preparation:
[0856] Active substance and mannitol are dissolved in water. After
packaging the solution is freeze-dried. To produce the solution
ready for use for injections, the product is dissolved in
water.
EXAMPLE B
TABLE-US-00019 [0857] Dry ampoule containing 35 mg of active
substance per 2 ml Composition: Active substance 35.0 mg Mannitol
100.0 mg water for injections ad 2.0 ml
[0858] Preparation:
[0859] Active substance and mannitol are dissolved in water. After
packaging, the solution is freeze-dried.
[0860] To produce the solution ready for use for injections, the
product is dissolved in water.
EXAMPLE C
TABLE-US-00020 [0861] Tablet containing 50 mg of active substance
Composition: (1) Active substance 50.0 mg (2) Lactose 98.0 mg (3)
Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium
stearate 2.0 mg 215.0 mg
[0862] Preparation:
[0863] (1), (2) and (3) are mixed together and granulated with an
aqueous solution of (4). (5) is added to the dried granulated
material. From this mixture tablets are pressed, biplanar, faceted
on both sides and with a dividing notch on one side.
[0864] Diameter of the tablets: 9 mm.
EXAMPLE D
TABLE-US-00021 [0865] Tablet containing 350 mg of active substance
Composition: (1) Active substance 350.0 mg (2) Lactose 136.0 mg (3)
Maize starch 80.0 mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium
stearate 4.0 mg 600.0 mg
[0866] Preparation:
[0867] (1), (2) and (3) are mixed together and granulated with an
aqueous solution of (4). (5) is added to the dried granulated
material. From this mixture tablets are pressed, biplanar, faceted
on both sides and with a dividing notch on one side.
[0868] Diameter of the tablets: 12 mm.
EXAMPLE E
TABLE-US-00022 [0869] Capsules containing 50 mg of active substance
Composition: (1) Active substance 50.0 mg (2) Dried maize starch
58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 2.0 mg
160.0 mg
[0870] Preparation:
[0871] (1) is triturated with (3). This trituration is added to the
mixture of (2) and (4) with vigorous mixing.
[0872] This powder mixture is packed into size 3 hard gelatine
capsules in a capsule filling machine.
EXAMPLE F
TABLE-US-00023 [0873] Capsules containing 350 mg of active
substance Composition: (1) Active substance 350.0 mg (2) Dried
maize starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium
stearate 4.0 mg 430.0 mg
[0874] Preparation:
[0875] (1) is triturated with (3). This trituration is added to the
mixture of (2) and (4) with vigorous mixing.
[0876] This powder mixture is packed into size 0 hard gelatine
capsules in a capsule filling machine.
EXAMPLE G
TABLE-US-00024 [0877] Suppositories containing 100 mg of active
substance 1 suppository contains: Active substance 100.0 mg
Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W.
6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 mg 2,000.0
mg
[0878] Preparation:
[0879] The polyethyleneglycol is melted together with
polyethylenesorbitan monostearate. At 40.degree. C. the ground
active substance is homogeneously dispersed in the melt. It is
cooled to 38.degree. C. and poured into slightly chilled
suppository moulds.
* * * * *