U.S. patent application number 12/401938 was filed with the patent office on 2009-07-09 for substituted 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine-2-yl compounds and 5,6,7,8-tetrahydro-quinazoline-2-yl compounds.
This patent application is currently assigned to GRUENENTHAL GmbH. Invention is credited to Edward BIJSTERVELD, Michael HAURAND, Hagen-Heinrich HENNIES, Stefan OBERBORSCH, Bernd SUNDERMANN, Corinna SUNDERMANN.
Application Number | 20090176811 12/401938 |
Document ID | / |
Family ID | 34965850 |
Filed Date | 2009-07-09 |
United States Patent
Application |
20090176811 |
Kind Code |
A1 |
OBERBORSCH; Stefan ; et
al. |
July 9, 2009 |
Substituted 5,6,7,8-Tetrahydro-pyrido[4,3-d]pyrimidine-2-yl
Compounds and 5,6,7,8-Tetrahydro-quinazoline-2-yl Compounds
Abstract
Substituted 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds, corresponding to
formula I ##STR00001## processes for the production thereof,
pharmaceutical preparations containing these compounds the use
thereof for the production of pharmaceutical preparations and
related method of treating or inhibiting certain disorders or
conditions, including pain.
Inventors: |
OBERBORSCH; Stefan; (Aachen,
DE) ; SUNDERMANN; Bernd; (Aachen, DE) ;
SUNDERMANN; Corinna; (Aachen, DE) ; HAURAND;
Michael; (Aachen, DE) ; HENNIES; Hagen-Heinrich;
(Simmerath, DE) ; BIJSTERVELD; Edward; (CB
Nijmegen, NL) |
Correspondence
Address: |
CROWELL & MORING LLP;INTELLECTUAL PROPERTY GROUP
P.O. BOX 14300
WASHINGTON
DC
20044-4300
US
|
Assignee: |
GRUENENTHAL GmbH
Aachen
DE
|
Family ID: |
34965850 |
Appl. No.: |
12/401938 |
Filed: |
March 11, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11588238 |
Oct 27, 2006 |
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12401938 |
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PCT/EP2005/004489 |
Apr 27, 2005 |
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11588238 |
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Current U.S.
Class: |
514/264.11 ;
544/279 |
Current CPC
Class: |
A61P 25/16 20180101;
A61P 25/18 20180101; C07D 409/12 20130101; A61P 25/04 20180101;
A61P 25/30 20180101; A61P 25/14 20180101; A61P 13/02 20180101; A61P
21/00 20180101; A61P 1/00 20180101; A61P 25/22 20180101; A61P 25/06
20180101; A61P 3/04 20180101; A61P 25/24 20180101; A61P 25/28
20180101; A61P 23/00 20180101; A61P 25/36 20180101; A61P 17/04
20180101; A61P 9/00 20180101; C07D 239/84 20130101; C07D 471/04
20130101; A61P 25/32 20180101; A61P 1/12 20180101; A61P 11/00
20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/264.11 ;
544/279 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 471/04 20060101 C07D471/04 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 28, 2004 |
DE |
10 2004 020 908.1 |
Claims
1. A process for preparing a substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-2-yl compound
corresponding to formula I: ##STR00034## wherein X represents an
NR.sup.2a group; R.sup.1 represents a --C(.dbd.O)--R.sup.3 group or
a --C(.dbd.O)--O--R.sup.4 group; R.sup.2a represents a
--C(.dbd.O)--R.sup.5 group or an --S(.dbd.O).sub.2--R.sup.6 group;
R.sup.3 represents a linear or branched, unsubstituted or at least
monosubstituted, saturated or unsaturated aliphatic group, which
may comprise at least one heteroatom as a chain link; an
unsubstituted or at least monosubstituted, saturated or unsaturated
cycloaliphatic group, which may comprise at least one heteroatom as
a ring member, which group may be attached via a linear or
branched, unsubstituted or at least monosubstituted alkylene group,
which may comprise at least one heteroatom as a chain link; or an
unsubstituted or at least monosubstituted aryl or heteroaryl group,
which may be attached via a linear or branched, unsubstituted or at
least monosubstituted alkylene group; R.sup.4 represents an
unsubstituted or at least monosubstituted aryl or heteroaryl group,
which may be attached via a linear or branched, unsubstituted or at
least monosubstituted alkylene group; R.sup.5 represents a linear
or branched, unsubstituted or at least monosubstituted, saturated
or unsaturated aliphatic group, which may comprise at least one
heteroatom as a chain link; an unsubstituted or at least
monosubstituted, saturated or unsaturated cycloaliphatic group,
which may comprise at least one heteroatom as a ring member, which
group may be attached via a linear or branched, unsubstituted or at
least monosubstituted alkylene group, which may comprise at least
one heteroatom as a chain link or may be fused with an
unsubstituted or at least monosubstituted, mono- or polycyclic ring
system; an unsubstituted or at least monosubstituted aryl or
heteroaryl group, which may be attached via a linear or branched,
unsubstituted or at least monosubstituted alkylene, alkenylene or
alkynylene group, which may comprise at least one heteroatom as a
chain link or may be fused with an unsubstituted or at least
monosubstituted, mono- or polycyclic ring system; a
--C(.dbd.O)--R.sup.7 group, which may be attached via a linear or
branched, unsubstituted or at least monosubstituted alkylene group;
a --C(.dbd.O)--R.sup.8 group, which may be attached via a linear or
branched, unsubstituted or at least monosubstituted alkylene group,
or an --N(H)--C(.dbd.O)--O--R.sup.9 group, which may be attached
via a linear or branched, unsubstituted or at least monosubstituted
alkylene group, which may comprise at least one --N(H)--C(.dbd.O)
or at least one --C(.dbd.O)--N(H) grouping as a chain link; R.sup.6
represents an --NR.sup.10R.sup.11 group; a linear or branched,
unsubstituted or at least monosubstituted, saturated or unsaturated
aliphatic group, which may comprise at least one heteroatom as a
chain link; an unsubstituted or at least monosubstituted, saturated
or unsaturated cycloaliphatic group, which may comprise at least
one heteroatom as a ring member, and which may be fused with an
unsubstituted or at least monosubstituted mono- or polycyclic ring
system, which group may be attached via a linear or branched,
unsubstituted or at least monosubstituted alkylene group, which may
comprise at least one heteroatom as a chain link or may be bridged
with a linear or branched alkylene group; or an unsubstituted or at
least monosubstituted aryl or heteroaryl group, which may be
attached via a linear or branched, unsubstituted or at least
monosubstituted alkylene group or may be fused with an
unsubstituted or at least monosubstituted mono- or polycyclic ring
system; R.sup.7 represents a linear or branched, unsubstituted or
at least monosubstituted alkyl group, an unsubstituted or at least
monosubstituted aryl or heteroaryl group, an unsubstituted or at
least monosubstituted, saturated or unsaturated cycloaliphatic
group, which may comprise at least one heteroatom as a ring member,
which group may be fused with an unsubstituted or at least
monosubstituted mono- or polycyclic ring system, or an
--NR.sup.7aR.sup.7b group, wherein R.sup.7a and R.sup.7b,
identically or differently, in each case, represent a linear or
branched alkyl group, R.sup.8 represents a linear or branched,
unsubstituted or at least monosubstituted alkyl group or an
unsubstituted or at least monosubstituted aryl or heteroaryl group,
which may be attached by a linear or branched alkylene group,
R.sup.9 represents a linear or branched, unsubstituted or at least
monosubstituted alkyl group, an unsubstituted or at least
monosubstituted aryl or heteroaryl group, which may be attached via
a linear or branched alkylene group, or an unsubstituted or at
least monosubstituted, saturated or unsaturated cycloaliphatic
group, which may be fused with at least one unsubstituted or at
least monosubstituted mono- or polycyclic ring system, R.sup.10 and
R.sup.11, identically or differently, in each case, represent a
linear or branched alkyl group, or a salt thereof, said process
comprising: reacting a protected piperidin-4-one corresponding to
formula II, ##STR00035## wherein PG represents a protective group,
with a dimethoxy-methyl-dimethyl-amine corresponding to formula III
##STR00036## in an organic reaction medium to yield a compound
corresponding to formula IV, ##STR00037## and optionally purifying
or isolating said compound corresponding to formula IV, and
reacting said compound corresponding to formula IV with guanidine
corresponding to formula V, ##STR00038## which guanidine
corresponding to formula V may be present in the form of a salt, in
an organic reaction medium, which step of reacting may include the
presence of at least one base, to yield a compound corresponding to
formula VI, ##STR00039## and optionally purifying or isolating said
compound corresponding to formula VI, and reacting said compound
corresponding to formula VI in an organic reaction medium, which
may optionally include at least one base or at least one catalyst,
with a compound corresponding to the formula
R.sup.3--C(.dbd.O)--X.sup.1 or a compound corresponding to the
formula (R.sup.3--C(.dbd.O)).sub.2O, or reacting said compound
corresponding to formula VI with a compound corresponding to the
formula R.sup.3--C(.dbd.O)--OH in an organic reaction medium in the
presence of at least one coupling agent, which may include at least
one base, or reacting said compound corresponding to formula VI
with a compound corresponding to formula
R.sup.4--O--C(.dbd.O)--X.sup.1a in an organic reaction medium,
which may include at least one base, wherein X.sup.1 and X.sup.1a
in each case denote a leaving group, to yield a compound
corresponding to formula VII, ##STR00040## and optionally purifying
or isolating said compound corresponding to formula VII, and
eliminating the protective group PG to yield a compound
corresponding to formula VIII, ##STR00041## or a salt thereof, and
optionally purifying or isolating the compound corresponding to
formula VIII or the salt thereof and reacting said compound
corresponding to formula VIII or the salt thereof with a compound
of corresponding to the formula R.sup.5--C(.dbd.O)--X.sup.2 or
(R.sup.5--C(.dbd.O)).sub.2O, in an organic reaction medium,
optionally including at least one base or at least one catalyst, or
reacting said compound corresponding to formula VIII or the salt
thereof with a compound corresponding to the formula
R.sup.6--SO.sub.2--X.sup.3, wherein X.sup.3 represents a leaving
group, in an organic reaction medium, optionally including at least
one base, or reacting said compound corresponding to formula VIII
or the salt thereof with a compound corresponding to the formula
R.sup.5--COOH, in an organic reaction medium, in the presence of at
least one suitable coupling agent, optionally including at least
one base, to yield a compound corresponding to formula IX
##STR00042## and optionally purifying or isolating said compound
corresponding to formula IX and optionally converting said compound
corresponding to formula IX to yield a corresponding salt and
optionally purifying or isolating the corresponding salt of said
compound corresponding to formula IX, or reacting a piperidin-4-one
corresponding to formula X ##STR00043## or a salt thereof, with a
compound corresponding to the formula R.sup.5--C(.dbd.O)--X.sup.2
or (R.sup.5--C(.dbd.O)).sub.2O, wherein X.sup.2 represents a
leaving group, in an organic reaction medium, which may include at
least one base or at least one catalyst, or with a compound of
corresponding to the formula R.sup.6--SO.sub.2--X.sup.3, wherein
X.sup.3 represents a leaving group, in an organic reaction medium,
which may include at least one base, or with a compound
corresponding to the formula R.sup.5--COOH, in the presence of a
suitable coupling agent, and in an organic reaction medium, which
may include at least one base, to yield a compound corresponding to
formula XI, ##STR00044## and optionally purifying or isolating the
compound corresponding to formula XI, and reacting said compound
corresponding to formula XI with a dimethoxy-methyl-dimethyl-amine
corresponding to formula III ##STR00045## in an organic reaction
medium to form a compound corresponding to formula XII,
##STR00046## and optionally purifying or isolating said compound
corresponding for formula XII, and reacting said said compound
corresponding for formula XII with a guanidine corresponding to
formula V, ##STR00047## or a salt thereof, in an organic reaction
medium which may include at least one base, to yield a compound
corresponding to formula XIII ##STR00048## and optionally purifying
or isolating said compound corresponding to formula XIII and
reacting said compound corresponding to formula XIII in an organic
reaction medium, which may include at least one base or at least
one catalyst, with a compound corresponding to the formula
R.sup.3--C(.dbd.O)).sub.2O or with a compound corresponding to the
formula R.sup.3--C(.dbd.O)--X.sup.1, or with a compound
corresponding to the formula R.sup.3--COOH, in an organic reaction
medium which may include at least one base and in the presence of
at least one coupling agent, or with a compound corresponding to
the formula R.sup.4--O--C(.dbd.O)--Xla in an organic reaction
medium, which may include at least one base, wherein X.sup.1 and
X.sup.1a in each case represent a leaving group, to yield a
compound corresponding to formula XIV ##STR00049## and optionally
purifying or isolating the compound corresponding to formula XIV
and optionally converted compound corresponding to formula XIV to
yield a corresponding salt and optionally purifying or isolating
the salt of the compound corresponding to formula XIV.
2. A method of noradrenalin receptor regulation, 5-HT receptor
regulation, mGluR5 receptor regulation or batrachotoxin receptor
regulation, said method comprising administering to a subject in
need thereof a pharmaceutically effective amount of a compound
corresponding to formula I: ##STR00050## wherein X represents an
NR.sup.2a group; R.sup.1 represents a --C(.dbd.O)--R.sup.3 group or
a --C(.dbd.O)--O--R.sup.4 group; R.sup.2a represents a
--C(.dbd.O)--R.sup.5 group or an --S(.dbd.O).sub.2--R.sup.6 group;
R.sup.3 represents a linear or branched, unsubstituted or at least
monosubstituted, saturated or unsaturated aliphatic group, which
may comprise at least one heteroatom as a chain link; an
unsubstituted or at least monosubstituted, saturated or unsaturated
cycloaliphatic group, which may comprise at least one heteroatom as
a ring member, which group may be attached via a linear or
branched, unsubstituted or at least monosubstituted alkylene group,
which may comprise at least one heteroatom as a chain link; or an
unsubstituted or at least monosubstituted aryl or heteroaryl group,
which may be attached via a linear or branched, unsubstituted or at
least monosubstituted alkylene group; R.sup.4 represents an
unsubstituted or at least monosubstituted aryl or heteroaryl group,
which may be attached via a linear or branched, unsubstituted or at
least monosubstituted alkylene group; R.sup.5 represents a linear
or branched, unsubstituted or at least monosubstituted, saturated
or unsaturated aliphatic group, which may comprise at least one
heteroatom as a chain link; an unsubstituted or at least
monosubstituted, saturated or unsaturated cycloaliphatic group,
which may comprise at least one heteroatom as a ring member, which
group may be attached via a linear or branched, unsubstituted or at
least monosubstituted alkylene group, which may comprise at least
one heteroatom as a chain link or may be fused with an
unsubstituted or at least monosubstituted, mono- or polycyclic ring
system; an unsubstituted or at least monosubstituted aryl or
heteroaryl group, which may be attached via a linear or branched,
unsubstituted or at least monosubstituted alkylene, alkenylene or
alkynylene group, which may comprise at least one heteroatom as a
chain link or may be fused with an unsubstituted or at least
monosubstituted, mono- or polycyclic ring system; a
--C(.dbd.O)--R.sup.7 group, which may be attached via a linear or
branched, unsubstituted or at least monosubstituted alkylene group;
a --C(.dbd.O)--R.sup.8 group, which may be attached via a linear or
branched, unsubstituted or at least monosubstituted alkylene group,
or an --N(H)--C(.dbd.O)--O--R.sup.9 group, which may be attached
via a linear or branched, unsubstituted or at least monosubstituted
alkylene group, which may comprise at least one --N(H)--C(.dbd.O)
or at least one --C(.dbd.O)--N(H) grouping as a chain link; R.sup.6
represents an --NR.sup.10R.sup.11 group; a linear or branched,
unsubstituted or at least monosubstituted, saturated or unsaturated
aliphatic group, which may comprise at least one heteroatom as a
chain link; an unsubstituted or at least monosubstituted, saturated
or unsaturated cycloaliphatic group, which may comprise at least
one heteroatom as a ring member, and which may be fused with an
unsubstituted or at least monosubstituted mono- or polycyclic ring
system, which group may be attached via a linear or branched,
unsubstituted or at least monosubstituted alkylene group, which may
comprise at least one heteroatom as a chain link or may be bridged
with a linear or branched alkylene group; or an unsubstituted or at
least monosubstituted aryl or heteroaryl group, which may be
attached via a linear or branched, unsubstituted or at least
monosubstituted alkylene group or may be fused with an
unsubstituted or at least monosubstituted mono- or polycyclic ring
system; R.sup.7 represents a linear or branched, unsubstituted or
at least monosubstituted alkyl group, an unsubstituted or at least
monosubstituted aryl or heteroaryl group, an unsubstituted or at
least monosubstituted, saturated or unsaturated cycloaliphatic
group, which may comprise at least one heteroatom as a ring member,
which group may be fused with an unsubstituted or at least
monosubstituted mono- or polycyclic ring system, or an
--NR.sup.7aR.sup.7b group, wherein R.sup.7a and R.sup.7b,
identically or differently, in each case, represent a linear or
branched alkyl group, R.sup.8 represents a linear or branched,
unsubstituted or at least monosubstituted alkyl group or an
unsubstituted or at least monosubstituted aryl or heteroaryl group,
which may be attached by a linear or branched alkylene group,
R.sup.9 represents a linear or branched, unsubstituted or at least
monosubstituted alkyl group, an unsubstituted or at least
monosubstituted aryl or heteroaryl group, which may be attached via
a linear or branched alkylene group, or an unsubstituted or at
least monosubstituted, saturated or unsaturated cycloaliphatic
group, which may be fused with at least one unsubstituted or at
least monosubstituted mono- or polycyclic ring system, R.sup.10 and
R.sup.11, identically or differently, in each case, represent a
linear or branched alkyl group, or a pharmaceutically acceptable
salt thereof.
3. The method of claim 2, wherein said method is effective for
inhibiting noradrenalin reuptake or for inhibiting
5-hydroxy-tryptophan reuptake.
4. A method of treating or inhibiting a condition mediated at least
in part by at least one receptor selected from the group consisting
of noradrenalin-receptors, 5-HT receptors, mGluR5 receptors and
batrachotoxin receptors, said method comprising administering to a
subject in need thereof a pharmaceutically effective amount of a
compound corresponding to formula I: ##STR00051## wherein X
represents an NR.sup.2a group; R.sup.1 represents a
--C(.dbd.O)--R.sup.3 group or a --C(.dbd.O)--O--R.sup.4 group;
R.sup.2a represents a --C(.dbd.O)--R.sup.5 group or an
--S(.dbd.O).sub.2--R.sup.6 group; R.sup.3 represents a linear or
branched, unsubstituted or at least monosubstituted, saturated or
unsaturated aliphatic group, which may comprise at least one
heteroatom as a chain link; an unsubstituted or at least
monosubstituted, saturated or unsaturated cycloaliphatic group,
which may comprise at least one heteroatom as a ring member, which
group may be attached via a linear or branched, unsubstituted or at
least monosubstituted alkylene group, which may comprise at least
one heteroatom as a chain link; or an unsubstituted or at least
monosubstituted aryl or heteroaryl group, which may be attached via
a linear or branched, unsubstituted or at least monosubstituted
alkylene group; R.sup.4 represents an unsubstituted or at least
monosubstituted aryl or heteroaryl group, which may be attached via
a linear or branched, unsubstituted or at least monosubstituted
alkylene group; R.sup.5 represents a linear or branched,
unsubstituted or at least monosubstituted, saturated or unsaturated
aliphatic group, which may comprise at least one heteroatom as a
chain link; an unsubstituted or at least monosubstituted, saturated
or unsaturated cycloaliphatic group, which may comprise at least
one heteroatom as a ring member, which group may be attached via a
linear or branched, unsubstituted or at least monosubstituted
alkylene group, which may comprise at least one heteroatom as a
chain link or may be fused with an unsubstituted or at least
monosubstituted, mono- or polycyclic ring system; an unsubstituted
or at least monosubstituted aryl or heteroaryl group, which may be
attached via a linear or branched, unsubstituted or at least
monosubstituted alkylene, alkenylene or alkynylene group, which may
comprise at least one heteroatom as a chain link or may be fused
with an unsubstituted or at least monosubstituted, mono- or
polycyclic ring system; a --C(.dbd.O)--R.sup.7 group, which may be
attached via a linear or branched, unsubstituted or at least
monosubstituted alkylene group; a --C(.dbd.O)--R.sup.8 group, which
may be attached via a linear or branched, unsubstituted or at least
monosubstituted alkylene group, or an --N(H)--C(.dbd.O)--O--R.sup.9
group, which may be attached via a linear or branched,
unsubstituted or at least monosubstituted alkylene group, which may
comprise at least one --N(H)--C(.dbd.O) or at least one
--C(.dbd.O)--N(H) grouping as a chain link; R.sup.6 represents an
--NR.sup.10R.sup.11 group; a linear or branched, unsubstituted or
at least monosubstituted, saturated or unsaturated aliphatic group,
which may comprise at least one heteroatom as a chain link; an
unsubstituted or at least monosubstituted, saturated or unsaturated
cycloaliphatic group, which may comprise at least one heteroatom as
a ring member, and which may be fused with an unsubstituted or at
least monosubstituted mono- or polycyclic ring system, which group
may be attached via a linear or branched, unsubstituted or at least
monosubstituted alkylene group, which may comprise at least one
heteroatom as a chain link or may be bridged with a linear or
branched alkylene group; or an unsubstituted or at least
monosubstituted aryl or heteroaryl group, which may be attached via
a linear or branched, unsubstituted or at least monosubstituted
alkylene group or may be fused with an unsubstituted or at least
monosubstituted mono- or polycyclic ring system; R.sup.7 represents
a linear or branched, unsubstituted or at least monosubstituted
alkyl group, an unsubstituted or at least monosubstituted aryl or
heteroaryl group, an unsubstituted or at least monosubstituted,
saturated or unsaturated cycloaliphatic group, which may comprise
at least one heteroatom as a ring member, which group may be fused
with an unsubstituted or at least monosubstituted mono- or
polycyclic ring system, or an --NR.sup.7aR.sup.7b group, wherein
R.sup.7a and R.sup.7b, identically or differently, in each case,
represent a linear or branched alkyl group, R.sup.8 represents a
linear or branched, unsubstituted or at least monosubstituted alkyl
group or an unsubstituted or at least monosubstituted aryl or
heteroaryl group, which may be attached by a linear or branched
alkylene group, R.sup.9 represents a linear or branched,
unsubstituted or at least monosubstituted alkyl group, an
unsubstituted or at least monosubstituted aryl or heteroaryl group,
which may be attached via a linear or branched alkylene group, or
an unsubstituted or at least monosubstituted, saturated or
unsaturated cycloaliphatic group, which may be fused with at least
one unsubstituted or at least monosubstituted mono- or polycyclic
ring system, R.sup.10 and R.sup.11, identically or differently, in
each case, represent a linear or branched alkyl group, or a
pharmaceutically acceptable salt thereof.
5. A method according to claim 4, wherein said condition comprises
pain in a mammal, said method comprising administering to said
mammal an effective pain alleviating amount of said compound
corresponding to formula I.
6. A method according to claim 4, wherein said condition is
selected from the group consisting of migraine, depression, urinary
incontinence, coughing, neurodegenerative diseases, food intake
disorders, cognitive dysfunction, cognitive deficiency states,
disorders of the nervous system, epilepsy, schizophrenia, cerebral
ischaemia, muscle spasms, cramps, diarrhea, pruritus,
gastro-oesophageal reflux syndrome, panic attacks, alcohol or drug
abuse or abuse of medicines, alcohol or drug dependency or
dependency on medicines, withdrawal symptoms associated with
alcohol or drug dependency or dependency on medicines, tolerance to
medicines, locomotor activity disorders, irregularaties of the
cardiovascular system, pain, anxiety, decreased vigilance,
decreased libido, diuresis, and antinatriuresis, said method
comprising administering to a subject in need thereof a
pharmaceutically effective amount of said compound corresponding to
formula I.
7. A method according to claim 6, wherein said condition is a
neurodegenerative disease selected from the group consisting of
Parkinson's disease, Huntington's chorea, Alzheimer's disease and
multiple sclerosis; or a food intake disorder selected from the
group consisting of bulimia, anorexia, obesity and cachexia; or a
cognitive memory disorder; or a tolerance opioids.
8. A method of preparing a pharmaceutical formulation for
noradrenalin receptor regulation, for 5-HT receptor regulation, for
mGluR5 receptor regulation or for batrachotoxin receptor regulation
comprising combining a pharmaceutically effective amount of a
compound corresponding to formula I: ##STR00052## wherein X
represents an NR.sup.2a group; R.sup.1 represents a
--C(.dbd.O)--R.sup.3 group or a --C(.dbd.O)--O--R.sup.4 group;
R.sup.2a represents a --C(.dbd.O)--R.sup.5 group or an
--S(.dbd.O).sub.2--R.sup.6 group; R.sup.3 represents a linear or
branched, unsubstituted or at least monosubstituted, saturated or
unsaturated aliphatic group, which may comprise at least one
heteroatom as a chain link; an unsubstituted or at least
monosubstituted, saturated or unsaturated cycloaliphatic group,
which may comprise at least one heteroatom as a ring member, which
group may be attached via a linear or branched, unsubstituted or at
least monosubstituted alkylene group, which may comprise at least
one heteroatom as a chain link; or an unsubstituted or at least
monosubstituted aryl or heteroaryl group, which may be attached via
a linear or branched, unsubstituted or at least monosubstituted
alkylene group; R.sup.4 represents an unsubstituted or at least
monosubstituted aryl or heteroaryl group, which may be attached via
a linear or branched, unsubstituted or at least monosubstituted
alkylene group; R.sup.5 represents a linear or branched,
unsubstituted or at least monosubstituted, saturated or unsaturated
aliphatic group, which may comprise at least one heteroatom as a
chain link; an unsubstituted or at least monosubstituted, saturated
or unsaturated cycloaliphatic group, which may comprise at least
one heteroatom as a ring member, which group may be attached via a
linear or branched, unsubstituted or at least monosubstituted
alkylene group, which may comprise at least one heteroatom as a
chain link or may be fused with an unsubstituted or at least
monosubstituted, mono- or polycyclic ring system; an unsubstituted
or at least monosubstituted aryl or heteroaryl group, which may be
attached via a linear or branched, unsubstituted or at least
monosubstituted alkylene, alkenylene or alkynylene group, which may
comprise at least one heteroatom as a chain link or may be fused
with an unsubstituted or at least monosubstituted, mono- or
polycyclic ring system; a --C(.dbd.O)--R.sup.7 group, which may be
attached via a linear or branched, unsubstituted or at least
monosubstituted alkylene group; a --C(.dbd.O)--R.sup.8 group, which
may be attached via a linear or branched, unsubstituted or at least
monosubstituted alkylene group, or an --N(H)--C(.dbd.O)--O--R.sup.9
group, which may be attached via a linear or branched,
unsubstituted or at least monosubstituted alkylene group, which may
comprise at least one --N(H)--C(.dbd.O) or at least one
--C(.dbd.O)--N(H) grouping as a chain link; R.sup.6 represents an
--NR.sup.10R.sup.11 group; a linear or branched, unsubstituted or
at least monosubstituted, saturated or unsaturated aliphatic group,
which may comprise at least one heteroatom as a chain link; an
unsubstituted or at least monosubstituted, saturated or unsaturated
cycloaliphatic group, which may comprise at least one heteroatom as
a ring member, and which may be fused with an unsubstituted or at
least monosubstituted mono- or polycyclic ring system, which group
may be attached via a linear or branched, unsubstituted or at least
monosubstituted alkylene group, which may comprise at least one
heteroatom as a chain link or may be bridged with a linear or
branched alkylene group; or an unsubstituted or at least
monosubstituted aryl or heteroaryl group, which may be attached via
a linear or branched, unsubstituted or at least monosubstituted
alkylene group or may be fused with an unsubstituted or at least
monosubstituted mono- or polycyclic ring system; R.sup.7 represents
a linear or branched, unsubstituted or at least monosubstituted
alkyl group, an unsubstituted or at least monosubstituted aryl or
heteroaryl group, an unsubstituted or at least monosubstituted,
saturated or unsaturated cycloaliphatic group, which may comprise
at least one heteroatom as a ring member, which group may be fused
with an unsubstituted or at least monosubstituted mono- or
polycyclic ring system, or an --NR.sup.7aR.sup.7b group, wherein
R.sup.7a and R.sup.7b, identically or differently, in each case,
represent a linear or branched alkyl group, R.sup.8 represents a
linear or branched, unsubstituted or at least monosubstituted alkyl
group or an unsubstituted or at least monosubstituted aryl or
heteroaryl group, which may be attached by a linear or branched
alkylene group, R.sup.9 represents a linear or branched,
unsubstituted or at least monosubstituted alkyl group, an
unsubstituted or at least monosubstituted aryl or heteroaryl group,
which may be attached via a linear or branched alkylene group, or
an unsubstituted or at least monosubstituted, saturated or
unsaturated cycloaliphatic group, which may be fused with at least
one unsubstituted or at least monosubstituted mono- or polycyclic
ring system, R.sup.10 and R.sup.11, identically or differently, in
each case, represent a linear or branched alkyl group, or a
pharmaceutically acceptable salt thereof, with at least one
physiologically acceptable auxiliary substance, and forming the
combined substances into a pharmaceutically administrable dosage
form.
9. A method according to claim 8, wherein said pharmaceutical
formulation is effective for inhibiting noradrenalin reuptake or
for inhibiting 5-hydroxy-tryptophan reuptake.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of co-pending application
Ser. No. 11/588,238, filed Oct. 27, 2006, now U.S. Pat. No. ______,
which in turn is a continuation of International patent application
Serial No. PCT/EP2005/004489 filed Apr. 27, 2005 designating the
United States of America, and published in German on Nov. 10, 2005
as WO 2005/105759, which claims benefit of Federal Republic of
Germany patent application no. DE 10 2004 020 908.1, filed Apr. 28,
2004, the entire disclosures of which are incorporated herein in
their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-2-yl and
5,6,7,8-tetrahydroquinazolin-2-yl compounds, processes for the
production thereof, pharmaceutical formulation containing these
compounds, methods of producing such pharmaceutical formulation,
and related methods of treating or inhibiting certain conditions or
disorders, including pain.
BACKGROUND OF THE INVENTION
[0003] Pain is one of the basic clinical symptoms. There is a
worldwide need for effective pain treatments. The urgency of the
requirement for therapeutic methods for providing tailored and
targeted treatment of chronic and non-chronic pain, this being
taken to mean pain treatment which is effective and satisfactory
from the patient's standpoint, is also evident from the large
number of scientific papers relating to applied analgesia and to
basic nociception research which have appeared in recent times.
[0004] Conventional opioids, such as for example morphine, are
effective in the treatment of severe to very severe pain, but they
often lead to unwanted accompanying symptoms, such as for example
respiratory depression, vomiting, sedation, constipation or the
development of tolerance. Moreover, they are frequently
insufficiently effective in the case of neuropathic pain, suffered
in particular by tumor patients.
SUMMARY OF THE INVENTION
[0005] One object of the present invention was accordingly to
provide novel compounds which are suitable in particular as
pharmaceutical active ingredients in pharmaceutical preparations,
preferably in pharmaceutical preparations for the prevention and/or
treatment of pain, in particular acute pain, chronic pain,
neuropathic or visceral pain.
[0006] It has now surprisingly been found that the substituted
5,6,7,8-tetrahydro-pyrido-[4,3-d]pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the general formula
I stated hereinafter are suitable for noradrenalin receptor
regulation, in particular for inhibiting noradrenalin reuptake
(noradrenalin uptake), for 5-HT receptor regulation, in particular
for inhibiting 5-hydroxy tryptophan reuptake (5-HT uptake), for
mGluR5 receptor regulation and/or for batrachotoxin (BTX) receptor
regulation and may therefore be used in particular as
pharmaceutical active ingredients in pharmaceutical preparations
for preventing and/or treating disorders or diseases associated
with these receptors or processes.
[0007] The present invention accordingly provides substituted
5,6,7,8-tetrahydro-pyrido-[4,3-d]pyrimidin-2-yl and
5,6,7,8-tetrahydroquinazolin-2-yl compounds of the general formula
I,
##STR00002##
[0008] in which
[0009] X denotes a C(H)(NHR.sup.2) group or an NR.sup.2a group,
[0010] R.sup.1 denotes a --C(.dbd.O)--R.sup.3 group or a
--C(.dbd.O)--O--R.sup.4 group,
[0011] R.sup.2, R.sup.2a, mutually independently, in each case
denote a --C(.dbd.O)--R.sup.5 group or an
--S(.dbd.O).sub.2--R.sup.6 group,
[0012] R.sup.3 denotes a linear or branched, unsubstituted or at
least monosubstituted, saturated or unsaturated aliphatic residue,
optionally comprising at least one heteroatom as a chain link, an
unsubstituted or at least monosubstituted, saturated or unsaturated
cycloaliphatic residue, optionally comprising at least one
heteroatom as a ring member, which residue may be attached via a
linear or branched, unsubstituted or at least monosubstituted
alkylene group, optionally comprising at least one heteroatom as a
chain link, or an unsubstituted or at least monosubstituted aryl or
heteroaryl residue, which may be attached via a linear or branched,
unsubstituted or at least monosubstituted alkylene group,
[0013] R.sup.4 denotes an unsubstituted or at least monosubstituted
aryl or heteroaryl residue, which may be attached via a linear or
branched, unsubstituted or at least monosubstituted alkylene
group,
[0014] R.sup.5 denotes a linear or branched, unsubstituted or at
least monosubstituted, saturated or unsaturated aliphatic residue,
optionally comprising at least one heteroatom as a chain link,
[0015] an unsubstituted or at least monosubstituted, saturated or
unsaturated cycloaliphatic residue, optionally comprising at least
one heteroatom as a ring member, which residue may be attached via
a linear or branched, unsubstituted or at least monosubstituted
alkylene group, optionally comprising at least one heteroatom as a
chain link, and/or be fused with an unsubstituted or at least
monosubstituted, mono- or polycyclic ring system,
[0016] an unsubstituted or at least monosubstituted aryl or
heteroaryl residue, which may be attached via a linear or branched,
unsubstituted or at least monosubstituted alkylene, alkenylene or
alkynylene group, optionally comprising at least one heteroatom as
a chain link and/or be fused with an unsubstituted or at least
monosubstituted, mono- or polycyclic ring system,
[0017] a --C(.dbd.O)--R.sup.7 residue, which may be attached via a
linear or branched, unsubstituted or at least monosubstituted
alkylene group,
[0018] a --C(.dbd.O)--R.sup.8 residue, which may be attached via a
linear or branched, unsubstituted or at least monosubstituted
alkylene group, or
[0019] an --N(H)--C(.dbd.O)--O--R.sup.9 residue, which may be
attached via a linear or branched, unsubstituted or at least
monosubstituted alkylene group, optionally comprising at least one
--N(H)--C(.dbd.O) or at least one --C(.dbd.O)--N(H) grouping as a
chain link,
[0020] R.sup.6 denotes a group --NR.sup.10R.sup.11,
[0021] a linear or branched, unsubstituted or at least
monosubstituted, saturated or unsaturated aliphatic residue,
optionally comprising at least one heteroatom as a chain link,
[0022] an unsubstituted or at least monosubstituted, saturated or
unsaturated cycloaliphatic residue, optionally comprising at least
one heteroatom as a ring member, optionally fused with an
unsubstituted or at least monosubstituted mono- or polycyclic ring
system, which residue may be attached via a linear or branched,
unsubstituted or at least monosubstituted alkylene group,
optionally comprising at least one heteroatom as a chain link
and/or be bridged with a linear or branched alkylene group, or
[0023] an unsubstituted or at least monosubstituted aryl or
heteroaryl residue, which may be attached via a linear or branched,
unsubstituted or at least monosubstituted alkylene group and/or be
fused with an unsubstituted or at least monosubstituted mono- or
polycyclic ring system,
[0024] R.sup.7 denotes a linear or branched, unsubstituted or at
least monosubstituted alkyl residue, an unsubstituted or at least
monosubstituted aryl or heteroaryl residue, an unsubstituted or at
least monosubstituted, saturated or unsaturated cycloaliphatic
residue, optionally comprising at least one heteroatom as a ring
member, which residue may be fused with an unsubstituted or at
least monosubstituted mono- or polycyclic ring system, or an
--NR.sup.7aR.sup.7b residue, in which the residues R.sup.7a and
R.sup.7b, identical or different, in each case denote a linear or
branched alkyl residue,
[0025] R.sup.8 denotes a linear or branched, unsubstituted or at
least monosubstituted alkyl residue or an unsubstituted or at least
monosubstituted aryl or heteroaryl residue, optionally attached via
a linear or branched alkylene group,
[0026] R.sup.9 denotes a linear or branched, unsubstituted or at
least monosubstituted alkyl residue, an unsubstituted or at least
monosubstituted aryl or heteroaryl residue, optionally attached via
a linear or branched alkylene group, or an unsubstituted or at
least monosubstituted, saturated or unsaturated cycloaliphatic
residue, which may be fused with at least one unsubstituted or at
least monosubstituted mono- or polycyclic ring system, and
[0027] R.sup.10, R.sup.11, identical or different, in each case
denote a linear or branched alkyl residue,
[0028] in each case optionally in the form of one of the pure
stereoisomers thereof, in particular enantiomers or diastereomers,
the racemates thereof or in the form of a mixture of stereoisomers,
in particular the enantiomers and/or diastereomers, in any desired
mixing ratio, or in each case in the form of corresponding salts or
in each case in the form of corresponding solvates.
[0029] If one or more of the substituents R.sup.3 and
R.sup.5-R.sup.9 denote a saturated or unsaturated aliphatic
residue, i.e. an alkyl, alkenyl or alkynyl residue, which is mono-
or polysubstituted, for example 1, 2, 3, 4, 5, 6, 7, 8 or 9 times,
the substituents thereof may, in each case mutually independently,
preferably be selected from the group consisting of F, Cl, Br,
--OH, --SH and --NH.sub.2. Alkenyl residues comprise at least one
C--C double bond and alkynyl residues at least one C--C triple
bond.
[0030] Examples of suitable alkyl, alkenyl and alkynyl residues,
which may be mono- or polysubstituted, are methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl,
iso-pentyl, neopentyl, n-hexyl, 2-hexyl, n-heptyl, n-octyl,
n-nonyl, n-decyl, --C(H)(C.sub.2H.sub.5).sub.2,
--C(H)(n-C.sub.3H.sub.7).sub.2,
--CH.sub.2--CH.sub.2--C(H)(CH.sub.3)--(CH.sub.2).sub.3--CH.sub.3,
vinyl, ethynyl, propenyl, allyl, propynyl, butenyl, butynyl,
pentenyl, pentynyl, hexenyl, hexynyl,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3 and
--CH.sub.2--CH.sub.2--CH.dbd.CH.sub.2.
[0031] If one or more of the substituents R.sup.3, R.sup.5 and
R.sup.6 denote a saturated or unsaturated aliphatic residue, i.e.
an alkyl, alkenyl or alkynyl residue, which comprises one or more,
for example 1, 2, 3, 4 or 5, heteroatoms as chain link(s), these
heteroatoms, in each case mutually independently, may preferably be
selected from the group consisting of oxygen, sulfur and nitrogen
(NH). Preferably, these heteroatoms are located in a non-terminal
position of the respective residue. Residues such as
--CH.sub.2--CH.sub.2--S--CH.sub.3,
--CH.sub.2--O--CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--O--CH.sub.3 or --CH.sub.2--CH.sub.2--O--CH.sub.3 may be
mentioned by way of example.
[0032] If one or more of the substituents R.sup.3, R.sup.5-R.sup.7
and R.sup.9 denote a cycloaliphatic residue or comprises a
cycloaliphatic residue, which is mono- or polysubstituted, for
example 1, 2, 3, 4 or 5 times, the substituents thereof may, in
each case mutually independently, preferably be selected from the
group consisting of --C.sub.1-5 alkyl,
--C(.dbd.O)--O--C.sub.1-5-alkyl, --C(.dbd.O)--CF.sub.3,
--S(.dbd.O).sub.2--C.sub.1-5-alkyl, --S(.dbd.O).sub.2-phenyl, oxo
(.dbd.O) and phenyl, wherein the C.sub.1-5 alkyl residue may in
each case be linear or branched and the phenyl residue may in each
case be mono- or polysubstituted, for example 1, 2, 3, 4 or 5
times, identically or differently, with a substituent selected from
the group consisting of F, Cl, Br and I. Particularly preferably,
the substituents, in each case mutually independently, may be
selected from the group consisting of --C(.dbd.O)--O-tert-butyl,
--C(.dbd.O)--CF.sub.3, --S(.dbd.O).sub.2-methyl,
--S(.dbd.O).sub.2-phenyl, oxo, and phenyl, wherein the phenyl
residue may in each case be mono- or polysubstituted, for example
1, 2, 3, 4 or 5 times, identically or differently, with a
substituent selected from the group consisting of F, Cl and Br.
[0033] If the cycloaliphatic residues comprise one or more, for
example 1, 2 or 3, heteroatoms as ring members, these, in each case
mutually independently, may preferably be selected from the group
consisting of nitrogen, oxygen and sulfur.
[0034] Examples of suitable cycloaliphatic residues, which may be
mono- or polysubstituted, are cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl,
cycloheptenyl, cyclooctenyl, imidazolidinyl, tetrahydrofuranyl
(tetrahydrofuryl), piperidinyl, piperazinyl, morpholinyl and
dithiolanyl.
[0035] If one or more of the substituents R.sup.3-R.sup.9 denote an
aryl or heteroaryl residue or comprise an aryl or heteroaryl
residue, which is mono- or polysubstituted, for example 1, 2, 3, 4
or 5 times, the substituents thereof may, in each case mutually
independently, preferably be selected from the group consisting of
halogen, --CN, --NO.sub.2, --OH, --SH, C.sub.1-5 alkyl, C.sub.1-5
alkoxy, --S--C.sub.1-5-alkyl, --CF.sub.3, --CHF.sub.2, --CH.sub.2F,
--O--CF.sub.3, --O--CHF.sub.2, --O--CH.sub.2F,
--C(.dbd.O)--CF.sub.3, --S--CF.sub.3, --S--CHF.sub.2,
--S--CH.sub.2F, --S(.dbd.O).sub.2-phenyl,
--S(.dbd.O).sub.2--C.sub.1-5 alkyl,
N(C.sub.1-5alkyl)(C.sub.1-5-alkyl),
--C(.dbd.O)--O--C.sub.1-5-alkyl, --CH.sub.2--O--C(.dbd.O)-phenyl,
--O--C(.dbd.O)-phenyl, --NH--C(.dbd.O)--C.sub.1-5-alkyl,
--C.ident.C-phenyl, --C.ident.C-naphthyl, --C.ident.C-pyrrolyl,
--C.ident.C-indolyl, --C.ident.C-furyl (--C.ident.C-furanyl),
--C.ident.C-benzo[b]furanyl, --C.ident.C-thienyl
(--C.ident.C-thiophenyl), --C.ident.C-benzo[b]thienyl,
--C.ident.C-pyrazolyl, --C.ident.C-imidazolyl,
--C.ident.C-thiazolyl, --C.ident.C-thiadiazolyl,
--C.ident.C-triazolyl, --C.ident.C-oxazolyl,
--C.ident.C-isoxazolyl, --C.ident.C-pyridinyl,
--C.ident.C-pyridazinyl, --C.ident.C-pyrimidinyl,
--C.ident.C-pyrazinyl, --C.ident.C-pyranyl, --C.ident.C-indazolyl,
--C.ident.C-purinyl, --C.ident.C-indolizinyl,
--C.ident.C-quinolinyl, --C.ident.C-isoquinolinyl,
--C.ident.C-quinazolinyl, pyrazolyl, phenyl, furyl (furanyl),
thiadiazolyl, thiophenyl (thienyl), phenoxy and benzyl, wherein the
cyclic substituents may themselves in each case be mono- or
polysubstituted, for example 1, 2, 3, 4 or 5 times, identically or
differently, with a substituent selected from the group consisting
of F, Cl, Br, I.
[0036] Particularly preferably, the substituents, in each case
mutually independently, may be selected from the group consisting
of F, Cl, Br, I, --CN, --NO.sub.2, --OH, --SH, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
n-pentyl, neopentyl, methoxy, ethoxy, n-propoxy, iso-propoxy,
n-butyloxy, iso-butyloxy, sec-butyloxy, tert-butyloxy, --S-methyl,
--S-ethyl, --CF.sub.3, --CHF.sub.2, --CH.sub.2F, --O--CF.sub.3,
--O--CHF.sub.2, --O--CH.sub.2F, --C(.dbd.O)--CF.sub.3,
--S--CF.sub.3, --S--CHF.sub.2, --S--CH.sub.2F,
--S(.dbd.O).sub.2-phenyl, pyrazolyl, phenyl, --N(CH.sub.3).sub.2,
--N(C.sub.2H.sub.5).sub.2, --CH.sub.2--O--C(.dbd.O)-phenyl,
--C(.dbd.O)--O--CH.sub.3, --C(.dbd.O)--O--C.sub.2H.sub.5,
--NH--C(.dbd.O)--CH.sub.3, --O--C(.dbd.O)-phenyl,
--C.ident.C-phenyl, --C.ident.C-furyl (--C.ident.C-furanyl),
--C.ident.C-thiadiazolyl, --C.ident.C-thiophenyl
(--C.ident.C-thienyl), phenyl, furyl (furanyl), thiadiazolyl,
thiophenyl (thienyl), phenoxy and benzyl, wherein the cyclic
substituents may themselves in each case be mono- or
polysubstituted, for example 1, 2, 3, 4 or 5 times, identically or
differently, with a substituent selected from the group consisting
of F, Cl, Br, I.
[0037] Examples of suitable aryl residues which may be mentioned
are phenyl, 1-naphthyl and 2-naphthyl.
[0038] If one or more of the substituents R.sup.3-R.sup.9 denote a
heteroaryl residue or comprise a heteroaryl residue, the
heteroatom(s) thereof may, in each case mutually independently,
preferably be selected from the group consisting of oxygen, sulfur
and nitrogen. For example, the heteroaryl residues may comprise 1,
2, 3, 4 or 5 heteroatoms.
[0039] Suitable heteroaryl residues which may be mentioned are, for
example, pyrrolyl, indolyl, furyl (furanyl), benzo[b]furanyl,
thienyl (thiophenyl), benzo[b]thienyl, pyrazolyl, imidazolyl,
thiazolyl, thiadiazolyl, triazolyl, oxazolyl, isoxazolyl,
pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl,
purinyl, indolizinyl, quinolinyl, isoquinolinyl and
quinazolinyl.
[0040] For the purposes of the present invention, a mono- or
polycyclic ring system should be understood to mean mono- or
polycyclic hydrocarbon residues which may be saturated, unsaturated
or aromatic and optionally comprise one or more, for example 1, 2,
3, 4 or 5, heteroatoms as ring members. Such a mono- or polycyclic
ring system may, for example, be fused (anellated) with a
cycloaliphatic residue, an aryl residue or a heteroaryl
residue.
[0041] If a polycyclic ring system is present, the different rings
may, in each case mutually independently, exhibit a different
degree of saturation, i.e. be saturated, unsaturated or aromatic.
The heteroatoms of each ring may, in each case identically or
differently, preferably be selected from the group consisting of
oxygen, nitrogen and sulfur. Preferably, the respective rings of
the mono- or polycyclic ring system are 5- or 6-membered.
Preferably, polycyclic ring systems should be understood to mean
bicyclic ring systems.
[0042] If one or more of the substituents R.sup.5, R.sup.6, R.sup.7
and R.sup.9 comprise a monocyclic or polycyclic ring system which
is mono- or polysubstituted, for example 1, 2, 3, 4 or 5 times, the
substituents thereof may, in each case mutually independently,
preferably be selected from the group consisting of halogen, --CN,
--NO.sub.2, --OH, --SH, C.sub.1-5 alkyl, C.sub.1-5 alkoxy,
--S--C.sub.1-5-alkyl, --CF.sub.3, --CHF.sub.2, --CH.sub.2F,
--O--CF.sub.3, --O--CHF.sub.2, --O--CH.sub.2F,
--C(.dbd.O)--CF.sub.3, --S--CF.sub.3, --S--CHF.sub.2,
--S--CH.sub.2F, --S(.dbd.O).sub.2-phenyl,
--S(.dbd.O).sub.2--C.sub.1-5-alkyl, N(C.sub.1-5alkyl)(C.sub.1-5
alkyl), --C(.dbd.O)--O--C.sub.1-5-alkyl,
--CH.sub.2--O--C(.dbd.O)-phenyl, --O--C(.dbd.O)-phenyl,
--NH--C(.dbd.O)--C.sub.1-5-alkyl, --C.ident.C-phenyl,
--C.ident.C-naphthyl, --C.ident.C-pyrrolyl, --C.ident.C-indolyl,
--C.ident.C-furyl (--C.ident.C-furanyl),
--C.ident.C-benzo[b]furanyl, --C.ident.C-thienyl
(--C.ident.C-thiophenyl), --C.ident.C-benzo[b]thienyl,
--C.ident.C-pyrazolyl, --C.ident.C-imidazolyl,
--C.ident.C-thiazolyl, --C.ident.C-thiadiazolyl,
--C.ident.C-triazolyl, --C.ident.C-oxazolyl,
--C.ident.C-isoxazolyl, --C.ident.C-pyridinyl,
--C.ident.C-pyridazinyl, --C.ident.C-pyrimidinyl,
--C.ident.C-pyrazinyl, --C.ident.C-pyranyl, --C.ident.C-indazolyl,
--C.ident.C-purinyl, --C.ident.C-indolizinyl, --C.ident.C--
quinolinyl, --C.ident.C-isoquinolinyl, --C.ident.C-quinazolinyl,
pyrazolyl, phenyl, furyl (furanyl), thiadiazolyl, thiophenyl
(thienyl), phenoxy and benzyl, wherein the cyclic substituents may
themselves in each case be mono- or polysubstituted, for example 1,
2, 3, 4 or 5 times, identically or differently, with a substituent
selected from the group consisting of F, Cl, Br, I. Particularly
preferably, the substituents, in each case mutually independently,
may be selected from the group consisting of F, Cl, Br, I, --CN,
--NO.sub.2, --OH, --SH, methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl,
methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, iso-butyloxy,
sec-butyloxy, tert-butyloxy, --S-methyl, --S-ethyl, --CF.sub.3,
--CHF.sub.2, --CH.sub.2F, --O--CF.sub.3, --O--CHF.sub.2,
--O--CH.sub.2F, --C(.dbd.O)--CF.sub.3, --S--CF.sub.3,
--S--CHF.sub.2, --S--CH.sub.2F, --S(.dbd.O).sub.2-phenyl,
pyrazolyl, phenyl, --N(CH.sub.3).sub.2, --N(C.sub.2H.sub.5).sub.2,
--CH.sub.2--O--C(.dbd.O)-phenyl, --C(.dbd.O)--O--CH.sub.3,
--C(.dbd.O)--O--C.sub.2H.sub.5, --NH--C(.dbd.O)--CH.sub.3,
--O--C(.dbd.O)-phenyl, furyl (furanyl), thiadiazolyl, thiophenyl
(thienyl), phenoxy and benzyl, wherein the cyclic substituents may
themselves in each case be mono- or polysubstituted, for example 1,
2, 3, 4 or 5 times, identically or differently, with a substituent
selected from the group consisting of F, Cl, Br, I.
[0043] If one of the above-stated substituents R.sup.3-R.sup.6
comprises a linear or branched alkylene, alkenylene or alkynylene
group, which is mono- or polysubstituted, for example 1, 2, 3, 4 or
5 times, the substituents thereof may, in each case mutually
independently, preferably be selected from the group consisting of
F, Cl, Br, hydroxy and unsubstituted phenyl.
[0044] If the alkylene, alkenylene or alkynylene group comprises
one or more, for example 1, 2, 3, 4 or 5, heteroatoms as chain
link(s), these may preferably be selected from the group consisting
of oxygen, sulfur and nitrogen (NH).
[0045] Examples which may be stated are alkylene, alkenylene or
alkynylene groups such as --(CH.sub.2)--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--,
--C(H)(CH.sub.2phenyl), --C(H)(phenyl),
--C(H)(C)(H)(CH.sub.3).sub.2), --C(C.sub.2H.sub.5)(H)--,
--(CH.sub.2)--O--, --(CH.sub.2).sub.2--O--,
--(CH.sub.2).sub.3--O--, --(CH.sub.2).sub.4--O--,
--O--(CH.sub.2)--, --O--(CH.sub.2).sub.2--,
--O--(CH.sub.2).sub.3--, --O--(CH.sub.2).sub.4--,
--C(C.sub.2H.sub.5)(H)--O--, --O--C(C.sub.2H.sub.5)(H)--,
--CH.sub.2--O--CH.sub.2--, --CH.sub.2--S--CH.sub.2--,
--C(CH.sub.3).sub.2--, --C(H)(CH.sub.3)--, --CH.dbd.CH-- and
--C.ident.C--.
[0046] Preferred substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the above-stated
general formula I are those
[0047] in which
[0048] X denotes a C(H)(NHR.sup.2) group or an NR.sup.2a group,
[0049] R.sup.1 denotes a --C(.dbd.O)--R.sup.3 group or a
--C(.dbd.O)--O--R.sup.4 group,
[0050] R.sup.2, R.sup.2a, mutually independently, in each case
denote a --C(.dbd.O)--R.sup.5 group or an
--S(.dbd.O).sub.2--R.sup.6 group,
[0051] R.sup.3 denotes a linear or branched, unsubstituted or at
least monosubstituted, saturated or unsaturated aliphatic C.sub.1-8
residue, optionally comprising at least one heteroatom as a chain
link, an unsubstituted or at least monosubstituted, saturated or
unsaturated 3- to 8-membered cycloaliphatic residue, optionally
comprising at least one heteroatom as a ring member, which residue
may be attached via a linear or branched, unsubstituted or at least
monosubstituted C.sub.1-3 alkylene group, optionally comprising at
least one heteroatom as a chain link, or an unsubstituted or at
least monosubstituted 5- to 14-membered aryl or heteroaryl residue,
which may be attached via a linear or branched, unsubstituted or at
least monosubstituted C.sub.1-3 alkylene group,
[0052] R.sup.4 denotes an unsubstituted or at least monosubstituted
5- to 14-membered aryl or heteroaryl residue, which may be attached
via a linear or branched, unsubstituted or at least monosubstituted
C.sub.1-3 alkylene group,
[0053] R.sup.5 denotes a linear or branched, unsubstituted or at
least monosubstituted, saturated or unsaturated aliphatic
C.sub.1-10 residue, optionally comprising at least one heteroatom
as a chain link,
[0054] an unsubstituted or at least monosubstituted, saturated or
unsaturated 3- to 8-membered cycloaliphatic residue, optionally
comprising at least one heteroatom as a ring member, which residue
may be attached via a linear or branched, unsubstituted or at least
monosubstituted C.sub.1-6 alkylene group, optionally comprising at
least one heteroatom as a chain link and/or be fused with an
unsubstituted or at least monosubstituted, mono- or polycyclic ring
system,
[0055] an unsubstituted or at least monosubstituted 5- to
14-membered aryl or heteroaryl residue, which may be attached via a
linear or branched, unsubstituted or at least monosubstituted
C.sub.1-6 alkylene, C.sub.2-6 alkenylene or C.sub.2-6 alkynylene
group, optionally comprising at least one heteroatom as a chain
link and/or be fused with an unsubstituted or at least
monosubstituted, mono- or polycyclic ring system,
[0056] a --C(.dbd.O)--R.sup.7 residue, which may be attached via a
linear or branched, unsubstituted or at least monosubstituted
C.sub.1-3 alkylene group,
[0057] a --C(.dbd.O)--R.sup.8 residue, which may be attached via a
linear or branched, unsubstituted or at least monosubstituted
C.sub.1-3 alkylene group, or
[0058] an --N(H)--C(.dbd.O)--O--R.sup.9 residue, which may be
attached via a linear or branched, unsubstituted or at least
monosubstituted C.sub.1-8 alkylene group, optionally comprising at
least one --N(H)--C(.dbd.O) or at least one --C(.dbd.O)--N(H)
grouping as a chain link,
[0059] R.sup.6 denotes a group --NR.sup.10R.sup.11,
[0060] a linear or branched, unsubstituted or at least
monosubstituted, saturated or unsaturated aliphatic C.sub.1-10
residue, optionally comprising at least one heteroatom as a chain
link,
[0061] an unsubstituted or at least monosubstituted, saturated or
unsaturated cycloaliphatic residue, optionally comprising at least
one heteroatom as a ring member, optionally fused with an
unsubstituted or at least monosubstituted mono- or polycyclic ring
system, which residue may be attached via a linear or branched,
unsubstituted or at least monosubstituted C.sub.1-6 alkylene group,
optionally comprising at least one heteroatom as a chain link
and/or be bridged with a linear or branched C.sub.1-6 alkylene
group, or
[0062] an unsubstituted or at least monosubstituted 5- to
14-membered aryl or heteroaryl residue, which may be attached via a
linear or branched, unsubstituted or at least monosubstituted
C.sub.1-6 alkylene group and/or be fused with an unsubstituted or
at least monosubstituted mono- or polycyclic ring system,
[0063] R.sup.7 denotes a linear or branched, unsubstituted or at
least monosubstituted C.sub.1-3 alkyl residue, an unsubstituted or
at least monosubstituted 5- to 14-membered aryl or heteroaryl
residue, an unsubstituted or at least monosubstituted, saturated or
unsaturated 5-, 6- or 7-membered cycloaliphatic residue, optionally
comprising at least one heteroatom as a ring member, which residue
may be fused with an unsubstituted or at least monosubstituted
mono- or polycyclic ring system, or denotes an --NR.sup.7aR.sup.7b
residue, in which the residues R.sup.7a and R.sup.7b, identical or
different, in each case denote a linear or branched C.sub.1-5 alkyl
residue,
[0064] R.sup.8 denotes a linear or branched, unsubstituted or at
least monosubstituted C.sub.1-3 alkyl residue or an unsubstituted
or at least monosubstituted 5- or 6-membered aryl or heteroaryl
residue, optionally attached via a linear or branched C.sub.1-3
alkylene group,
[0065] R.sup.9 denotes a linear or branched, unsubstituted or at
least monosubstituted C.sub.1-3 alkyl residue, an unsubstituted or
at least monosubstituted 5- or 6-membered aryl or heteroaryl
residue, optionally attached via a linear or branched C.sub.1-3
alkylene group, or an unsubstituted or at least monosubstituted,
saturated or unsaturated 5- or 6-membered cycloaliphatic residue,
which may be fused with at least one unsubstituted or at least
monosubstituted mono- or polycyclic ring system, and,
[0066] R.sup.10, R.sup.11, identical or different, in each case
denote a linear or branched C.sub.1-5 alkyl residue,
[0067] in each case optionally in the form of one of the pure
stereoisomers thereof, in particular enantiomers or diastereomers,
the racemates thereof or in the form of a mixture of stereoisomers,
in particular the enantiomers and/or diastereomers, in any desired
mixing ratio, or in each case in the form of corresponding salts or
in each case in the form of corresponding solvates.
[0068] Also preferred are substituted
5,6,7,8-tetrahydro-pyrido[4,3-(d)]pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the above-stated
general formula I, in which R.sup.3 denotes a linear or branched,
unsubstituted or at least monosubstituted C.sub.1-8 alkyl residue,
optionally comprising one or more oxygen atoms and/or one or more
NH groups as chain link(s), an unsubstituted or at least
monosubstituted, saturated or unsaturated 5-, 6- or 7-membered
cycloaliphatic residue, optionally comprising at least one
heteroatom as a ring member, which residue may be attached via a
linear or branched, unsubstituted or at least monosubstituted
C.sub.1-3 alkylene group, optionally comprising at least one
heteroatom as a chain link, or an unsubstituted or at least
monosubstituted phenyl residue, thiophenyl residue (thienyl
residue), furanyl residue (furyl residue), pyridinyl residue or
naphthyl residue, which may be attached via a linear or branched,
unsubstituted or at least monosubstituted C.sub.1-3 alkylene
group,
[0069] preferably a methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl or tert-butyl residue, an unsubstituted,
saturated or unsaturated 5-, 6- or 7-membered cycloaliphatic
residue, optionally comprising one or more oxygen atoms and/or one
or more nitrogen atoms as ring member(s), which residue may be
attached via a --(CH.sub.2)--, --(CH.sub.2).sub.2 or
--(CH.sub.2).sub.3 group, or a phenyl residue, thiophenyl residue
(thienyl residue), furanyl residue (furyl residue), pyridinyl
residue or naphthyl residue, which may be attached via a
--(CH.sub.2)--, --(CH.sub.2).sub.2 or --(CH.sub.2).sub.3 group
and/or be mono- or polysubstituted, identically or differently,
with a substituent selected from the group consisting of methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,
tert-butyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,
iso-butoxy, sec-butoxy, tert-butoxy, F, Cl, Br, I, --CN and
--CF.sub.3,
[0070] and the respective remaining residues X, R.sup.1, R.sup.2,
R.sup.2a and R.sup.4 to R.sup.11 have the above-stated meaning, in
each case optionally in the form of one of the pure stereoisomers
thereof, in particular enantiomers or diastereomers, the racemates
thereof or in the form of a mixture of stereoisomers, in particular
the enantiomers and/or diastereomers, in any desired mixing ratio,
or in each case in the form of corresponding salts, or in each case
in the form of corresponding solvates.
[0071] Also preferred are substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the above-stated
general formula I, in which the residue R.sup.4 denotes a phenyl
residue optionally attached via a --(CH.sub.2), --(CH.sub.2).sub.2
or --(CH.sub.2).sub.3 bridge, wherein the phenyl ring,
unsubstituted or at least monosubstituted, identical or different,
may be substituted with a substituent selected from among the group
consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy,
iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, F, Cl,
Br, I, --CN and --CF.sub.3,
[0072] preferably an unsubstituted benzyl residue,
[0073] and the respective remaining residues X, R.sup.1, R.sup.2,
R.sup.2a, R.sup.3 and R.sup.5 to R.sup.11 have the above-stated
meaning, in each case optionally in the form of one of the pure
stereoisomers thereof, in particular enantiomers or diastereomers,
the racemates thereof or in the form of a mixture of stereoisomers,
in particular the enantiomers and/or diastereomers, in any desired
mixing ratio, or in each case in the form of corresponding salts,
or in each case in the form of corresponding solvates.
[0074] Likewise preferred are substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the above-stated
general formula I, in which R.sup.5 denotes a linear or branched
C.sub.1-10 alkyl residue, optionally comprising one or more oxygen
atoms and/or optionally one or more sulfur atoms and/or optionally
one or more --N(H) groups as chain link(s), a linear or branched
C.sub.2-10 alkenyl residue, optionally comprising one or more
oxygen atoms and/or optionally one or more sulfur atoms and/or
optionally one or more --N(H) groups as chain link(s), a linear or
branched C.sub.2-10 alkynyl residue, optionally comprising one or
more oxygen atoms and/or optionally one or more sulfur atoms and/or
optionally one or more --N(H) groups as chain link(s),
[0075] an unsubstituted or at least monosubstituted, saturated or
unsaturated 3- to 8-membered cycloaliphatic residue, optionally
comprising one or more heteroatoms, mutually independently,
selected from the group consisting of oxygen, sulfur and nitrogen
as ring member(s), which residue may be attached via a
--(CH.sub.2)--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --C(C.sub.2H.sub.5)(H)--, --(CH.sub.2)--O--,
--(CH.sub.2).sub.2--O--, --(CH.sub.2).sub.3--O--,
--(CH.sub.2).sub.4--O--, --O--(CH.sub.2)--,
--O--(CH.sub.2).sub.2--, --O--(CH.sub.2).sub.3--,
--O--(CH.sub.2).sub.4--, --C(C.sub.2H.sub.5)(H)--O--,
--O--C(C.sub.2H.sub.5)(H)--, --CH.sub.2--O--CH.sub.2--,
--CH.sub.2--S--CH.sub.2--, --C(CH.sub.3).sub.2 or --C(H)(CH.sub.3)
group and/or be fused with an unsubstituted or at least
monosubstituted, 5- or 6-membered monocyclic ring system,
[0076] an unsubstituted or at least monosubstituted, 5- or
6-membered aryl or heteroaryl residue, which may be attached via a
--(CH.sub.2)--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --C(C.sub.2H.sub.5)(H)--, --(CH.sub.2)--O--,
--(CH.sub.2).sub.2--O--, --(CH.sub.2).sub.3--O--,
--(CH.sub.2).sub.4--O--, --O--(CH.sub.2)--,
--O--(CH.sub.2).sub.2--, --O--(CH.sub.2).sub.3--,
--O--(CH.sub.2).sub.4--, --C(C.sub.2H.sub.5)(H)--O--,
--O--C(C.sub.2H.sub.5)(H)--, --CH.sub.2--O--CH.sub.2--,
--CH.sub.2--S--CH.sub.2--, --C(CH.sub.3).sub.2--,
--C(H)(CH.sub.3)-- or --CH.dbd.CH-- group and/or be fused with an
unsubstituted or at least monosubstituted 5- or 6-membered,
monocyclic ring system,
[0077] a --C(.dbd.O)--R.sup.7 residue, which may be attached via a
--(CH.sub.2)--, --(CH.sub.2).sub.2 or --(CH.sub.2).sub.3 group,
[0078] a --C(.dbd.O)--R.sup.8 residue, which may be attached via a
linear or branched C.sub.1-3 alkylene group which is unsubstituted
or mono- or polysubstituted with a phenyl residue, or
[0079] an --N(H)--C(.dbd.O)--O--R.sup.9 residue, which may be
attached via a linear or branched C.sub.1-8 alkylene group which is
unsubstituted or mono- or polysubstituted with a phenyl residue and
optionally comprises at least one --N(H)--C(.dbd.O) or at least one
--C(.dbd.O)--N(H) grouping as a chain link,
[0080] preferably
[0081] a residue selected from the group consisting of methyl,
ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl,
n-pentyl, neopentyl, iso-pentyl, --C(H)(C.sub.2H.sub.5).sub.2,
--C(H)(n-C.sub.3H.sub.7).sub.2--, --CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.sub.2--CH.dbd.CH.sub.2,
--CH.sub.2--CH.sub.2--C(H)(CH.sub.3)--(CH.sub.2).sub.3--CH.sub.3,
--CH.sub.2--O--CH.sub.3 and
--CH.sub.2--O--CH.sub.2--CH.sub.2--O--CH.sub.3,
[0082] a residue selected from the group consisting of cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl
(tetrahydrofuryl), dithiolanyl, 1,2,3,4-tetrahydroindolyl,
1,2,3,4-tetrahydronaphthyl, 1,3-dihydroisoindolyl, benzooxazolyl
and imidazolidinyl, wherein the cyclic residue in each case may be
attached via a --(CH.sub.2)--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--,
--C(C.sub.2H.sub.5)(H)--, --(CH.sub.2)--O--,
--(CH.sub.2).sub.2--O--, --(CH.sub.2).sub.3--O--,
--(CH.sub.2).sub.4--O--, --O--(CH.sub.2)--,
--O--(CH.sub.2).sub.2--, --O--(CH.sub.2).sub.3--,
--O--(CH.sub.2).sub.4--, --C(C.sub.2H.sub.5)(H)--O--,
--O--C(C.sub.2H.sub.5)(H)--, --CH.sub.2--O--CH.sub.2--,
--CH.sub.2--S--CH.sub.2--, --C(CH.sub.3).sub.2--, or
--C(H)(CH.sub.3) group and/or be mono- or polysubstituted,
identically or differently, with a substituent selected from the
group consisting of phenyl, --C(.dbd.O)--O-tert-butyl, oxo
(.dbd.O), --S(.dbd.O).sub.2-methyl and --S(.dbd.O).sub.2-phenyl,
wherein the above-stated phenyl residue may in each case be mono-
or polysubstituted, identically or differently, with a substituent
selected from the group consisting of F, Cl, Br and I,
[0083] a residue selected from the group consisting of phenyl,
naphthyl, furanyl (furyl), thiophenyl (thienyl), pyridinyl,
isoxazolyl, triazolyl, pyrazolyl, thiazolyl,
benzo[1,2,5]-oxadiazolyl, 2,3-dihydrobenzofuranyl, quinolinyl,
chromanyl, chromenyl, benzo[b]furanyl, benzo[b]thiophenyl,
benzo[1,3]-dioxinyl, indolyl, 2,3-dihydro-indolyl,
3,4-dihydro-benzo[1,4]oxazinyl and 1,2,3,4-tetrahydroisoquinolinyl,
wherein the cyclic residue may in each case be attached via a
--(CH.sub.2)--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --C(C.sub.2H.sub.5)(H)--, --(CH.sub.2)--O--,
--(CH.sub.2).sub.2--O--, --(CH.sub.2).sub.3--O--,
--(CH.sub.2).sub.4--O--, --O--(CH.sub.2)--,
--O--(CH.sub.2).sub.2--, --O--(CH.sub.2).sub.3--,
--O--(CH.sub.2).sub.4--, --C(C.sub.2H.sub.5)(H)--O--,
--O--C(C.sub.2H.sub.5)(H)--, --CH.sub.2--O--CH.sub.2--,
--CH.sub.2--S--CH.sub.2--, --C(CH.sub.3).sub.2--, --C(H)(CH.sub.3)
or --CH.dbd.CH-- group and/or be mono- or polysubstituted,
identically or differently, with a substituent selected from the
group consisting of F, Cl, Br, I, --CN, --NO.sub.2, --OH, --SH,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,
tert-butyl, n-pentyl, iso-pentyl, neopentyl, methoxy, ethoxy,
n-propoxy, iso-propoxy, n-butyloxy, iso-butyloxy, sec-butyloxy,
tert-butyloxy, --S-methyl, --S-ethyl, --CF.sub.3, --CHF.sub.2,
--CH.sub.2F, --O--CF.sub.3, --O--CHF.sub.2, --O--CH.sub.2F,
--S--CF.sub.3, --S--CHF.sub.2, --S--CH.sub.2F,
--S(.dbd.O).sub.2-phenyl, pyrazolyl, phenyl, --N(CH.sub.3).sub.2,
--N(C.sub.2H.sub.5).sub.2, --CH.sub.2--O--C(.dbd.O)-phenyl,
--O--C(.dbd.O)-phenyl, furyl (furanyl), thiadiazolyl, thiophenyl
(thienyl), phenoxy and benzyl, and wherein the cyclic substituents
may themselves in each case be mono- or polysubstituted,
identically or differently, with a substituent selected from the
group consisting of F, Cl, Br, I,
[0084] a --C(.dbd.O)--R.sup.7 residue, which may be attached via a
--(CH.sub.2)--, --(CH.sub.2).sub.2 or --(CH.sub.2).sub.3 group,
[0085] a --C(.dbd.O)--O--R.sup.8 residue, which may be attached via
a --(CH.sub.2)--, --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3 or
[0086] --C(H)(phenyl) group, or
[0087] an --N(H)--C(.dbd.O)--O--R.sup.9 residue, which may be
attached via a --(CH.sub.2)--, --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--,
--C(H)(CH.sub.2-phenyl), --C(H)(phenyl),
--C(H)(C(H)(CH.sub.3).sub.2) or
--C(H)(CH.sub.2--CH(CH.sub.3).sub.2)--NH--C(.dbd.O)--CH.sub.2
group,
[0088] and the respective remaining residues X, R.sup.1, R.sup.2,
R.sup.2a, R.sup.3, R.sup.4 and R.sup.6 to R.sup.11 have the
above-stated meaning, in each case optionally in the form of one of
the pure stereoisomers thereof, in particular enantiomers or
diastereomers, the racemates thereof or in the form of a mixture of
stereoisomers, in particular the enantiomers and/or diastereomers,
in any desired mixing ratio, or in each case in the form of
corresponding salts, or in each case in the form of corresponding
solvates.
[0089] Also preferred are substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the above-stated
general formula I, in which R.sup.6 is
[0090] a group --NR.sup.10R.sup.11,
[0091] a linear or branched, unsubstituted C.sub.1-10 alkyl
residue, a linear or branched, unsubstituted C.sub.2-10 alkenyl
residue, a linear or branched, unsubstituted, C.sub.2-10 alkynyl
residue,
[0092] an unsubstituted or at least monosubstituted, saturated or
unsaturated 3-, 4-, 5-, 6-, 7- or 8-membered cycloaliphatic
residue, which may be attached via a linear or branched C.sub.1-3
alkylene group and/or be bridged with a linear or branched
C.sub.1-3 alkylene group,
[0093] an unsubstituted or at least monosubstituted 5- to
6-membered aryl or heteroaryl residue, which may be attached via a
linear or branched C.sub.1-6 alkylene group and/or be fused with an
unsubstituted or at least monosubstituted 5- or 6-membered
monocyclic ring system,
[0094] preferably
[0095] a group --NR.sup.10R.sup.11,
[0096] a linear or branched, unsubstituted C.sub.1-5 alkyl residue,
a linear or branched, unsubstituted C.sub.2-5 alkenyl residue, a
linear or branched, unsubstituted, C.sub.2-5 alkynyl residue,
[0097] an unsubstituted or at least monosubstituted, saturated or
unsaturated, 5-, 6- or 7-membered cycloaliphatic residue, which may
be attached via a --(CH.sub.2)--, --(CH.sub.2).sub.2, or
--(CH.sub.2).sub.3 group and/or be bridged with a
--(C)(CH.sub.3).sub.2) group, or
[0098] an unsubstituted or at least monosubstituted, 5- or
6-membered aryl or heteroaryl residue, which may be attached via a
--(CH.sub.2)--, --(CH.sub.2).sub.2--, or --(CH.sub.2).sub.3 group
and/or be fused with an unsubstituted or at least monosubstituted,
5- or 6-membered monocyclic ring system, optionally containing one
or more oxygen atoms as ring member(s) and/or one or more nitrogen
atoms as ring member(s),
[0099] particularly preferably
[0100] a group --NR.sup.10R.sup.11,
[0101] a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl or tert-butyl residue,
[0102] a 7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptyl residue optionally
attached via a --(CH.sub.2)--, --(CH.sub.2).sub.2 or
--(CH.sub.2).sub.3 group, or
[0103] a phenyl, naphthyl, thiophenyl (thienyl), furanyl, (furyl),
thiazolyl, pyrazolyl, 2,3-dihydro-benzo[1,4]-dioxinyl,
1,2,3,4-tetrahydroiso-quinolinyl or 3,4-dihydrobenzo[1,4]oxazinyl
residue, which may be attached via a --(CH.sub.2),
--(CH.sub.2).sub.2, or --(CH.sub.2).sub.3 group and/or be mono- or
polysubstituted, identically or differently, with a substituent
selected from the group consisting of F, Cl, Br, I, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
n-pentyl, iso-pentyl, neopentyl, methoxy, ethoxy, --CN, --CF.sub.3,
--CF.sub.2H, --CFH.sub.2, --NO.sub.2, --C(.dbd.O)--CF.sub.3,
--O--CF.sub.3, --C(.dbd.O)--O--CH.sub.3,
--C(.dbd.O)--O--C.sub.2H.sub.5, --NH--C(.dbd.O)--CH.sub.3,
--S(.dbd.O).sub.2--CH.sub.3 and phenyl,
[0104] and the respective remaining residues X, R.sup.1, R.sup.2,
R.sup.2a, R.sup.3, R.sup.5 and R.sup.7 to R.sup.11 have the
above-stated meaning, in each case optionally in the form of one of
the pure stereoisomers thereof, in particular enantiomers or
diastereomers, the racemates thereof or in the form of a mixture of
stereoisomers, in particular the enantiomers and/or diastereomers,
in any desired mixing ratio, or in each case in the form of
corresponding salts, or in each case in the form of corresponding
solvates.
[0105] Moreover, those substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the above-stated
general formula I are preferred, in which the residue R.sup.7
denotes a linear or branched, unsubstituted C.sub.1-3 alkyl
residue, an unsubstituted, 5- or 6-membered aryl or heteroaryl
residue, an unsubstituted, saturated or unsaturated 5-, 6- or
7-membered cycloaliphatic residue, optionally comprising a nitrogen
atom as a ring member, which residue may be fused with an
unsubstituted, 6-membered monocyclic ring system, or an
--NR.sup.7aR.sup.7b residue, in which the residues R.sup.7a and
R.sup.7b, identical or different, in each case denote a linear or
branched C.sub.1-3 alkyl residue,
[0106] preferably a methyl, ethyl, n-propyl, phenyl, indolyl,
2,3-dihydroindolyl, dimethylamino or diethylamino residue,
[0107] and the respective remaining residues X, R.sup.1, R.sup.2,
R.sup.2a, R.sup.3 to R.sup.6 and R.sup.8 to R.sup.11 have the
above-stated meaning, in each case optionally in the form of one of
the pure stereoisomers thereof, in particular enantiomers or
diastereomers, the racemates thereof or in the form of a mixture of
stereoisomers, in particular the enantiomers and/or diastereomers,
in any desired mixing ratio, or in each case in the form of
corresponding salts, or in each case in the form of corresponding
solvates.
[0108] Likewise preferred are substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the above-stated
general formula I, in which R.sup.8 denotes a linear or branched,
unsubstituted C.sub.1-3 alkyl residue or a phenyl residue
optionally attached via a linear or branched C.sub.1-3 alkylene
group,
[0109] particularly preferably a methyl, ethyl, phenyl or benzyl
residue,
[0110] and the respective remaining residues X, R.sup.1, R.sup.2,
R.sup.2a, R.sup.3 to R.sup.7 and R.sup.9 to R.sup.11 have the
above-stated meaning, in each case optionally in the form of one of
the pure stereoisomers thereof, in particular enantiomers or
diastereomers, the racemates thereof or in the form of a mixture of
stereoisomers, in particular the enantiomers and/or diastereomers,
in any desired mixing ratio, or in each case in the form of
corresponding salts, or in each case in the form of corresponding
solvates.
[0111] Also preferred are substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the above-stated
general formula I, in which R.sup.9 denotes a linear or branched,
unsubstituted C.sub.1-3 alkyl residue, an unsubstituted 5- or
6-membered aryl or heteroaryl residue, optionally attached via a
linear or branched C.sub.1-3 alkylene group, or an unsubstituted or
at least monosubstituted, saturated or unsaturated, 5- or
6-membered cycloaliphatic residue, which may be fused with at least
one unsubstituted, 6-membered monocyclic ring system,
[0112] preferably a methyl, ethyl, n-propyl, iso-propyl, n-butyl,
iso-butyl, sec-butyl, tert-butyl, or a phenyl or fluorenyl residue
optionally attached via a --(CH.sub.2) group,
[0113] and the respective remaining residues X, R.sup.1, R.sup.2,
R.sup.2a, R.sup.3 to R.sup.8 and R.sup.10 and R.sup.11 have the
above-stated meaning, in each case optionally in the form of one of
the pure stereoisomers thereof, in particular enantiomers or
diastereomers, the racemates thereof or in the form of a mixture of
stereoisomers, in particular the enantiomers and/or diastereomers,
in any desired mixing ratio, or in each case in the form of
corresponding salts, or in each case in the form of corresponding
solvates.
[0114] Likewise preferred are substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the above-stated
general formula I, in which the residues R.sup.10 and R.sup.11,
identical or different, in each case denote a methyl, ethyl,
n-propyl or iso-propyl residue, and the respective remaining
residues X, R.sup.1, R.sup.2, R.sup.2a and R.sup.3 to R.sup.9 have
the above-stated meaning, in each case optionally in the form of
one of the pure stereoisomers thereof, in particular enantiomers or
diastereomers, the racemates thereof or in the form of a mixture of
stereoisomers, in particular the enantiomers and/or diastereomers,
in any desired mixing ratio, or in each case in the form of
corresponding salts, or in each case in the form of corresponding
solvates.
[0115] Particularly preferred are substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the general formula
I,
##STR00003##
[0116] in which
[0117] X denotes a C(H)(NHR.sup.2) group or an NR.sup.2a group,
[0118] R.sup.1 denotes a --C(.dbd.O)--R.sup.3 group or a
--C(.dbd.O)--O--R.sup.4 group,
[0119] R.sup.2, R.sup.2a, mutually independently, in each case
denote a --C(.dbd.O)--R.sup.5 group or an
--S(.dbd.O).sub.2--R.sup.6 group,
[0120] R.sup.3 denotes a methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl or tert-butyl residue, an
unsubstituted, saturated or unsaturated 5-, 6- or 7-membered
cycloaliphatic residue, optionally comprising one or more oxygen
atoms and/or one or more nitrogen atoms as ring member(s), which
residue may be attached via a --(CH.sub.2), --(CH.sub.2).sub.2 or
--(CH.sub.2).sub.3 group, or a phenyl residue, thiophenyl residue
(thienyl residue), furanyl residue (furyl residue), pyridinyl
residue or naphthyl residue, which may be attached via a
--(CH.sub.2), --(CH.sub.2).sub.2 or --(CH.sub.2).sub.3 group and/or
be mono- or polysubstituted, identically or differently, with a
substituent selected from the group consisting of methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,
sec-butoxy, tert-butoxy, F, Cl, Br, I, --CN and --CF.sub.3,
[0121] R.sup.4 denotes an unsubstituted benzyl residue,
[0122] R.sup.5 denotes a residue selected from the group consisting
of methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,
tert-butyl, n-pentyl, iso-pentyl, neopentyl,
--C(H)(C.sub.2H.sub.5).sub.2, --C(H)(n-C.sub.3H.sub.7).sub.2,
--CH.dbd.CH--CH.dbd.CH--CH.sub.3,
--CH.sub.2--CH.sub.2--CH.dbd.CH.sub.2,
--CH.sub.2--CH.sub.2--C(H)(CH.sub.3)--(CH.sub.2).sub.3--CH.sub.3,
--CH.sub.2--O--CH.sub.3 and
--CH.sub.2--O--CH.sub.2--CH.sub.2--O--CH.sub.3,
[0123] a residue selected from the group consisting of cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl
(tetrahydrofuryl), dithiolanyl, 1,2,3,4-tetrahydroindolyl,
1,2,3,4-tetrahydronaphthyl, 1,3-dihydroisoindolyl, benzooxazolyl
and imidazolidinyl, wherein the cyclic residue may in each case be
attached via a --(CH.sub.2), --(CH.sub.2).sub.2,
--(CH.sub.2).sub.3, --(CH.sub.2).sub.4, --C(C.sub.2H.sub.5)(H),
--(CH.sub.2)--O, --(CH.sub.2).sub.2--O, --(CH.sub.2).sub.3--O,
--(CH.sub.2).sub.4--O, --O--(CH.sub.2), --O--(CH.sub.2).sub.2,
--O--(CH.sub.2).sub.3, --O--(CH.sub.2).sub.4,
--C(C.sub.2H.sub.5)(H)--O, --O--C(C.sub.2H.sub.5)(H),
--CH.sub.2--O--CH.sub.2, --CH.sub.2--S--CH.sub.2,
--C(CH.sub.3).sub.2, or --C(H)(CH.sub.3) group and/or be mono- or
polysubstituted, identically or differently, with a substituent
selected from the group consisting of phenyl,
--C(.dbd.O)--O-tert-butyl, oxo (.dbd.O), --S(.dbd.O).sub.2-methyl
and --S(.dbd.O).sub.2-phenyl, and wherein the above-stated phenyl
residues may in each case be mono- or polysubstituted, identically
or differently, with a substituent selected from the group
consisting of F, Cl, Br and I,
[0124] a residue selected from the group consisting of phenyl,
naphthyl, furanyl (furyl), thiophenyl (thienyl), pyridinyl,
isoxazolyl, triazolyl, pyrazolyl, thiazolyl,
benzo[1,2,5]-oxadiazolyl, 2,3-dihydrobenzofuranyl, quinolinyl,
chromanyl, chromenyl, benzo[b]furanyl, benzo[b]thiophenyl,
benzo[1,3]-dioxinyl, indolyl, 2,3-dihydro-indolyl,
3,4-dihydro-benzo[1,4]oxazinyl and 1,2,3,4-tetrahydroisoquinolinyl,
wherein the cyclic residue may in each case be attached via a
--(CH.sub.2), --(CH.sub.2).sub.2, --(CH.sub.2).sub.3,
--(CH.sub.2).sub.4, --C(C.sub.2H.sub.5)(H), --(CH.sub.2)--O,
--(CH.sub.2).sub.2--O, --(CH.sub.2).sub.3--O,
--(CH.sub.2).sub.4--O, --O--(CH.sub.2)--, --O--(CH.sub.2).sub.2--,
--O--(CH.sub.2).sub.3, --O--(CH.sub.2).sub.4,
--C(C.sub.2H.sub.5)(H)--O, --O--C(C.sub.2H.sub.5)(H),
--CH.sub.2--O--CH.sub.2, --CH.sub.2--S--CH.sub.2,
--C(CH.sub.3).sub.2, --C(H)(CH.sub.3) or --CH.dbd.CH-- group and/or
be mono- or polysubstituted, identically or differently, with a
substituent selected from the group consisting of F, Cl, Br, I,
--CN, --NO.sub.2, --OH, --SH, methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl,
methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, iso-butyloxy,
sec-butyloxy, tert-butyloxy, --S-methyl, --S-ethyl, --CF.sub.3,
--CHF.sub.2, --CH.sub.2F, --O--CF.sub.3, --O--CHF.sub.2,
--O--CH.sub.2F, --S--CF.sub.3, --S--CHF.sub.2, --S--CH.sub.2F,
--S(.dbd.O).sub.2-phenyl, pyrazolyl, phenyl, --N(CH.sub.3).sub.2,
--N(C.sub.2H.sub.5).sub.2, --CH.sub.2--O--C(.dbd.O)-phenyl,
--O--C(.dbd.O)-phenyl, furyl (furanyl), thiadiazolyl, thiophenyl
(thienyl), phenoxy and benzyl, and wherein the cyclic substituents
may themselves in each case be mono- or polysubstituted,
identically or differently, with a substituent selected from the
group consisting of F, Cl, Br, I,
[0125] denotes a --C(.dbd.O)--R.sup.7 residue, which may be
attached via a --(CH.sub.2)--, --(CH.sub.2).sub.2 or
--(CH.sub.2).sub.3 group,
[0126] a --C(.dbd.O)--O--R.sup.8 residue, which may be attached via
a --(CH.sub.2), --(CH.sub.2).sub.2, --(CH.sub.2).sub.3 or
--C(H)(phenyl) group, or
[0127] an --N(H)--C(.dbd.O)--O--R.sup.9 residue, which may be
attached via a --(CH.sub.2), --(CH.sub.2).sub.2,
--(CH.sub.2).sub.3, --(CH.sub.2).sub.4, --(CH.sub.2).sub.5,
--C(H)(CH.sub.2-phenyl), --C(H)(phenyl),
--C(H)(C(H)(CH.sub.3).sub.2) or
--C(H)(CH.sub.2--CH(CH.sub.3).sub.2)--NH--C(.dbd.O)--CH.sub.2
group,
[0128] R.sup.6 denotes a group --NR.sup.10R.sup.11,
[0129] a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl or tert-butyl residue,
[0130] a 7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptyl residue optionally
attached via a --(CH.sub.2)--, --(CH.sub.2).sub.2 or
--(CH.sub.2).sub.3 group, or
[0131] a phenyl, naphthyl, thiophenyl (thienyl), furanyl, (furyl),
thiazolyl, pyrazolyl, 2,3-dihydro-benzo[1,4]-dioxinyl,
1,2,3,4-tetrahydroiso-quinolinyl or 3,4-dihydrobenzo[1,4]oxazinyl
residue, which may be attached via a --(CH.sub.2),
--(CH.sub.2).sub.2, or --(CH.sub.2).sub.3 group and/or be mono- or
polysubstituted, identically or differently, with a substituent
selected from the group consisting of F, Cl, Br, I, methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,
n-pentyl, iso-pentyl, neopentyl, methoxy, ethoxy, --CN, --CF.sub.3,
--CF.sub.2H, --CFH.sub.2, --NO.sub.2, --C(.dbd.O)--CF.sub.3,
--O--CF.sub.3, --C(.dbd.O)--O--CH.sub.3,
--C(.dbd.O)--O--C.sub.2H.sub.5, --NH--C(.dbd.O)--CH.sub.3,
--S(.dbd.O).sub.2--CH.sub.3 and phenyl,
[0132] R.sup.7 denotes a methyl, ethyl, n-propyl, phenyl, indolyl,
2,3-dihydroindolyl, dimethylamino or diethylamino residue
[0133] R.sup.8 denotes a methyl, ethyl, phenyl or benzyl
residue,
[0134] R.sup.9 denotes a methyl, ethyl, n-propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, tert-butyl, or a phenyl or fluorenyl
residue optionally attached via a --(CH.sub.2) group,
[0135] R.sup.10, R.sup.11, identical or different, in each case
denote a methyl, ethyl, n-propyl or iso-propyl residue,
[0136] in each case optionally in the form of one of the pure
stereoisomers thereof, in particular enantiomers or diastereomers,
the racemates thereof or in the form of a mixture of stereoisomers,
in particular the enantiomers and/or diastereomers, in any desired
mixing ratio, or in each case in the form of corresponding salts or
in each case in the form of corresponding solvates.
[0137] Very particularly preferred are substituted
5,6,7,8-tetrahydropyrido-[4,3-d]pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the general formula
I selected from the group consisting of [0138] [1]
3-fluoro-N-[6-(4-fluoro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidi-
n-2-yl]-benzamide, [0139] [2]
3,5-dichloro-N-[6-(3-fluoro-4-methoxy-benzoyl)-5,6,7,8-tetrahydro-pyrido--
[4,3-d]pyrimidin-2-yl]-benzamide, [0140] [3]
4-tert-butyl-N-(6-hexanoyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl-
)-benzamide, [0141] [4]
N-(6-acetyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-3,4-dichloro--
benzamide, [0142] [5]
3,5-dichloro-N-[6-(3-trifluoromethyl-benzoyl)-5,6,7,8-tetrahydro-pyrido-[-
4,3-d]pyrimidin-2-yl]-benzamide, [0143] [6]
3-chloro-N-[6-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-5,6,7,8-tetrahy-
dro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide, [0144] [7]
N-[6-(2-ethoxy-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-3-
-fluoro-benzamide, [0145] [8]
3-chloro-N-[6-(3-phenyl-propionyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrim-
idin-2-yl]-benzamide, [0146] [9]
4-tert-butyl-N-[6-(isoxazole-5-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]-
-pyrimidin-2-yl]-benzamide, [0147] [10]
N-[6-(2-benzylsulfanyl-acetyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin--
2-yl]-2-methoxy-benzamide, [0148] [11] thiophene-2-carboxylic acid
{6-[2-(4-chloro-phenyl)-2-methyl-propionyl]-5,6,7,8-tetrahydro-pyrido[4,3-
-d]pyrimidin-2-yl}-amide, [0149] [12]
N-(6-benzoyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-3-methyl-ben-
zamide, [0150] [13]
N-[6-(2,3-dihydro-benzofuran-5-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]-
-pyrimidin-2-yl]-2-fluoro-benzamide, [0151] [14]
thiophene-2-carboxylic acid
[6-(3,4,5-trimethoxy-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-2-y-
l]-amide, [0152] [15] naphthalene-1-carboxylic acid
[6-(3-methyl-5-phenyl-isoxazole-4-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-
-d]pyrimidin-2-yl]-amide, [0153] [16]
3-chloro-N-{6-[2-(5-methyl-2-phenyl-thiazol-4-yl)-acetyl]-5,6,7,8-tetrahy-
dro-pyrido[4,3-d]pyrimidin-2-yl}-benzamide, [0154] [17]
N-[6-(4-chloro-2,5-dimethyl-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,-
3-d]pyrimidin-2-yl]-2-trifluoromethyl-benzamide, [0155] [18]
N-[6-(1-benzenesulfonyl-1H-indole-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4-
,3-d]pyrimidin-2-yl]-3-methoxy-benzamide, [0156] [20]
N-[6-(5-methyl-1-phenyl-1H-pyrazole-4-sulfonyl)-5,6,7,8-tetrahydro-pyrido-
[4,3-d]pyrimidin-2-yl]-2-trifluoromethyl-benzamide, [0157] [21]
N-[6-(3-chloro-2-methyl-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-(d-
)]pyrimidin-2-yl]-3-fluoro-benzamide, [0158] [22]
3,5-dichloro-N-[6-(3,5-dimethyl-isoxazole-4-carbonyl)-5,6,7,8-tetrahydro--
pyrido[4,3-d]pyrimidin-2-yl]-benzamide, [0159] [23]
thiophene-2-carboxylic acid
[6-(4-trifluoromethoxy-benzenesulfonylamino)-5,6,7,8-tetrahydro-quin-
azolin-2-yl]-amide, [0160] [25]
N-[6-(furan-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-3-
-methoxy-benzamide, [0161] [26]
N-{6-[4-(2,3-dihydro-indol-1-yl)-4-oxo-butyryl]-5,6,7,8-tetrahydro-pyrido-
[4,3-d]pyrimidin-2-yl}-3-methyl-benzamide, [0162] [27]
N-{6-[2-(4-methyl-cyclohexyl)-acetyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyr-
imidin-2-yl}-2-trifluoromethyl-benzamide, [0163] [28]
3,4-difluoro-N-[6-(6-phenoxy-pyridine-3-carbonyl)-5,6,7,8-tetrahydro-pyri-
do[4,3-d]pyrimidin-2-yl]-benzamide, [0164] [29]
4-tert-butyl-N-[6-(2-phenyl-thiazole-4-carbonyl)-5,6,7,8-tetrahydro-pyrid-
o[4,3-d]pyrimidin-2-yl]-benzamide, [0165] [30]
3,5-dichloro-N-[6-(2-trifluoromethyl-benzenesulfonyl)-5,6,7,8-tetrahydro--
pyrido[4,3-d]pyrimidin-2-yl]-benzamide, [0166] [31]
thiophene-2-carboxylic acid
[6-(3-bromo-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl-
]-amide, [0167] [32]
N-[6-(2-chloro-pyridine-4-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2-yl]-3-methoxy-benzamide, [0168] [33]
4-fluoro-N-[6-(2-methanesulfonyl-benzenesulfonylamino)-5,6,7,8-tetrahydro-
-quinazolin-2-yl]-benzamide, [0169] [35]
N-(6-dimethylsulfamoyl-5,6,7,8-tetrahydro-pyrido[4,3-(d)]pyrimidin-2-yl)--
3-fluoro-benzamide, [0170] [36]
3-fluoro-N-{6-[2-(4-trifluoromethyl-phenyl)-acetyl]-5,6,7,8-tetrahydro-py-
rido[4,3-(d)]pyrimidin-2-yl}-benzamide, [0171] [37]
N-{6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetyl]-5,6,7,8-tetrahydro--
pyrido[4,3-(d)]pyrimidin-2-yl}-2-trifluoromethyl-benzamide, [0172]
[38] thiophene-2-carboxylic acid
{6-[4-(4-chloro-2-methyl-phenoxy)-butyrylamino]-5,6,7,8-tetrahydro-quinaz-
olin-2-yl}-amide, [0173] [39]
N-[6-(butane-1-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-(d)]pyrimidin-2-yl-
]-3-fluoro-benzamide, [0174] [40]
2-methoxy-N-[6-(2-propyl-pentanoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2-yl]-benzamide, [0175] [41]
N-[6-(4,5-dichloro-thiophene-2-sulfonylamino)-5,6,7,8-tetrahydro-quinazol-
in-2-yl]-4-fluoro-benzamide, [0176] [42]
4-chloro-N-[6-(2-trifluoromethyl-benzenesulfonyl)-5,6,7,8-tetrahydro-pyri-
do[4,3-d]pyrimidin-2-yl]-benzamide, [0177] [43]
thiophene-2-carboxylic acid
[6-(4-methoxy-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2--
yl]-amide, [0178] [44]
5-[2-(3,4-difluoro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-(d)]pyrimidin--
6-yl]-5-oxo-valeric acid methyl ester, [0179] [45]
N-[6-(benzo[b]thiophene-3-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2-yl]-4-chloro-benzamide, [0180] [46]
N-[6-(5-bromo-2-methoxy-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazol-
in-2-yl]-4-fluoro-benzamide, [0181] [47]
4-fluoro-N-[6-(4-fluoro-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazol-
in-2-yl]-benzamide, [0182] [48]
N-{6-[2-(1H-indol-3-yl)-2-oxo-acetyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyr-
imidin-2-yl}-2-trifluoromethyl-benzamide, [0183] [49]
5-tert-butyl-2-methyl-furan-3-carboxylic acid
{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-yl}-ami-
de, [0184] [50]
N-[6-(2,5-dimethoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyri-
midin-2-yl]-3-methoxy-benzamide, [0185] [51] benzoic acid
2-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-ylcar-
bamoyl}-benzyl ester, [0186] [52]
3,4-difluoro-N-(6-hexanoyl-5,6,7,8-tetrahydro-pyrido[4,3-(d)]pyrimidin-2--
yl)-benzamide, [0187] [53]
4-ethyl-N-[6-(tetrahydro-furan-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3--
d]pyrimidin-2-yl]-benzamide, [0188] [54]
N-[6-(2-chloro-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-
-2-yl]-3-fluoro-benzamide, [0189] [55]
4-tert-butyl-N-[6-(5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-5,6,7,8--
tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide, [0190] [56]
3-methoxy-N-[6-(4-methoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3--
d]pyrimidin-2-yl]-benzamide, [0191] [57]
{2-[2-(3,4-difluoro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-
-yl]-2-oxo-1-phenyl-ethyl}-carbamic acid benzyl ester, [0192] [58]
5-phenyl-oxazole-4-carboxylic acid
{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-yl}-ami-
de, [0193] [59]
4-chloro-N-(6-dimethylsulfamoyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-
-2-yl)-benzamide, [0194] [60]
4-tert-butyl-N-[6-(2-fluoro-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,-
3-d]pyrimidin-2-yl]-benzamide, [0195] [61]
4-chloro-N-[6-(3-cyclopentyl-propionyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]p-
yrimidin-2-yl]-benzamide, [0196] [62]
4-chloro-N-[6-(4-phenyl-butyryl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidi-
n-2-yl]-benzamide, [0197] [63]
4-tert-butyl-N-[6-(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-5,6,7-
,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide, [0198] [64]
2-chloro-N-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazoli-
n-6-yl}-isonicotinamide, [0199] [66]
N-[6-(5-chloro-thiophene-2-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyri-
midin-2-yl]-3-fluoro-benzamide, [0200] [67]
N-[6-(4-diethylamino-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-
-yl]-3-methoxy-benzamide, [0201] [68]
N-[6-(2,4-dimethyl-thiazole-5-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]p-
yrimidin-2-yl]-3-methyl-benzamide, [0202] [69]
4-chloro-N-[6-naphthalene-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyr-
imidin-2-yl]-benzamide, [0203] [70]
N-[6-(2,4-difluoro-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2-yl]-2-methoxy-benzamide, [0204] [71]
3,4-dichloro-N-[6-(4-chloro-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,-
3-d]pyrimidin-2-yl]-benzamide, [0205] [72]
3,4-difluoro-N-[6-(thiophene-2-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]-
pyrimidin-2-yl]-benzamide, [0206] [74]
4-ethyl-N-[6-(4-pyrazol-1-yl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyr-
imidin-2-yl]-benzamide, [0207] [75]
N-[6-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-ylmethanesulfonylamino)-5,6-
,7,8-tetrahydro-quinazolin-2-yl]-butyramide, [0208] [76]
5-oxo-5-phenyl-valeric acid
(2-butyrylamino-5,6,7,8-tetrahydro-quinazolin-6-yl)-amide, [0209]
[77]
3-[2-(4-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]--
3-oxo-propionic acid methyl ester, [0210] [78]
N-{6-[5-(4-chloro-phenyl)-2-methyl-furan-3-carbonyl]-5,6,7,8-tetrahydro-p-
yrido[4,3-d]pyrimidin-2-yl}-2-methoxy-benzamide, [0211] [79]
4-chloro-N-[6-(2,4-dimethyl-thiazole-5-sulfonyl)-5,6,7,8-tetrahydro-pyrid-
o[4,3-d]pyrimidin-2-yl]-benzamide, [0212] [80]
N-[6-(2,3-difluoro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-y-
l]-3-methoxy-benzamide, [0213] [81]
4-chloro-N-{6-[2-(2-methoxy-ethoxy)-acetyl]-5,6,7,8-tetrahydro-pyrido[4,3-
-d]pyrimidin-2-yl}-benzamide, [0214] [82]
2-[2-(2-ethoxy-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-sul-
fonyl]-benzoic acid methyl ester, [0215] [83]
4-tert-butyl-N-[6-(4-nitro-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-
-d]pyrimidin-2-yl]-benzamide, [0216] [86]
N-[6-(5-chloro-thiophene-2-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyri-
midin-2-yl]-2-methoxy-benzamide, [0217] [87]
4-fluoro-N-[6-(furan-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidi-
n-2-yl]-benzamide, [0218] [88]
4-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-ylcar-
bamoyl}-piperidine-1-carboxylic acid tert-butyl ester, [0219] [89]
1-(4-chloro-phenyl)-cyclopropanecarboxylic acid
(2-butyrylamino-5,6,7,8-tetrahydro-quinazolin-6-yl)-amide, [0220]
[90]
N-(6-ethanesulfonyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-3-met-
hoxy-benzamide, [0221] [91] 5-methyl-thiophene-2-carboxylic acid
(2-butyrylamino-5,6,7,8-tetrahydro-quinazolin-6-yl)-amide, [0222]
[92]
4-tert-butyl-N-[6-(4-methyl-3-nitro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,-
3-d]pyrimidin-2-yl]-benzamide, [0223] [94]
4-fluoro-N-[6-(3-phenyl-propionylamino)-5,6,7,8-tetrahydro-quinazolin-2-y-
l]-benzamide, [0224] [95]
3,4-dichloro-N-[6-(2,4,6-trimethyl-benzenesulfonyl)-5,6,7,8-tetrahydro-py-
rido[4,3-d]pyrimidin-2-yl]-benzamide, [0225] [96]
N-[6-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-5,6,7,8-tetra-
hydro-pyrido[4,3-d]pyrimidin-2-yl]-nicotinamide, [0226] [97]
thiophene-2-carboxylic acid
[6-(3,5-difluoro-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-amide,
[0227] [98]
N-[6-(2,4-difluoro-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2--
yl]-butyramide, [0228] [99] thiophene-2-carboxylic acid
[6-(2,3,5,6-tetramethyl-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]-
pyrimidin-2-yl]-amide, [0229] [101]
N-[6-(3,4-dichloro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-y-
l]-4-ethyl-benzamide, [0230] [102]
N-[6-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-ylmethanesulfonyl)-5,6,7,8--
tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-3-fluoro-benzamide, [0231]
[103]
N-[6-(6-fluoro-4H-benzo[1,3]dioxin-8-carbonyl)-5,6,7,8-tetrahydro-pyrido[-
4,3-d]pyrimidin-2-yl]-2-trifluoromethyl-benzamide, [0232] [104]
[5-(2-butyrylamino-5,6,7,8-tetrahydro-quinazolin-6-ylcarbamoyl)-pentyl]-c-
arbamic acid benzyl ester, [0233] [105]
2-ethoxy-N-[6-(4-oxo-pentanoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-
-2-yl]-benzamide, [0234] [106] naphthalene-1-carboxylic acid
[6-(propane-1-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-a-
mide, [0235] [107]
N-[6-(5-fluoro-2-methyl-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]-
pyrimidin-2-yl]-4-methyl-benzamide, [0236] [109]
3-chloro-N-[6-(2-methyl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidi-
n-2-yl]-benzamide, [0237] [110] thiophene-2-carboxylic acid
[6-(3-chloro-benzo[b]thiophene-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3--
d]pyrimidin-2-yl]-amide, [0238] [112] thiophene-2-carboxylic acid
[6-(2-cyclopentyl-acetylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-amide,
[0239] [113]
N-[6-(3,4-dichloro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-y-
l]-2-fluoro-benzamide, [0240] [114]
N-[6-(2-chloro-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-
-2-yl]-4-ethyl-benzamide, [0241] [115] thiophene-2-carboxylic acid
[6-(4-bromo-3-methyl-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-am-
ide, [0242] [116]
3-methyl-N-[6-(toluene-3-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimi-
din-2-yl]-benzamide, [0243] [117] naphthalene-1-carboxylic acid
[6-(5-chloro-thiophene-2-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimi-
din-2-yl]-amide, [0244] [118]
N-(2-butyrylamino-5,6,7,8-tetrahydro-quinazolin-6-yl)-2,6-difluoro-benzam-
ide, [0245] [119]
3-chloro-N-[6-(3,4-dimethoxy-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyr-
imidin-2-yl]-benzamide, [0246] [120]
N-[6-(3-chloro-benzo[b]thiophene-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,-
3-d]pyrimidin-2-yl]-benzamide, [0247] [121]
4-ethyl-N-[6-(thiophene-3-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2-yl]-benzamide, [0248] [123]
2-ethoxy-N-[6-(2-ethylsulfanyl-pyridine-3-carbonyl)-5,6,7,8-tetrahydro-py-
rido[4,3-d]pyrimidin-2-yl]-benzamide, [0249] [124]
3-[2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]--
3-oxo-propionic acid ethyl ester, [0250] [125]
N-[6-(3-bromo-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin--
2-yl]-3-chloro-benzamide, [0251] [126]
3,4-dichloro-N-{6-[2-(4-chloro-phenyl)-acetyl]-5,6,7,8-tetrahydro-pyrido[-
4,3-d]pyrimidin-2-yl}-benzamide, [0252] [127]
3-chloro-N-[6-(2-chloro-6-fluoro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d-
]pyrimidin-2-yl]-benzamide, [0253] [128]
4-fluoro-N-(6-hexanoylamino-5,6,7,8-tetrahydro-quinazolin-2-yl)-benzamide-
, [0254] [129]
N-[6-(5-bromo-2-methoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]-
pyrimidin-2-yl]-3-methoxy-benzamide, [0255] [132]
N-[6-(3-cyclopentyl-propionyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin--
2-yl]-isonicotinamide, [0256] [133] 5-benzyl-furan-2-carboxylic
acid (2-butyrylamino-5,6,7,8-tetrahydro-quinazolin-6-yl)-amide
[0257] [134]
3,4-dichloro-N-[6-(4-trifluoromethoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-
-pyrido[4,3-d]pyrimidin-2-yl]-benzamide, [0258] [135]
[(2-butyrylamino-5,6,7,8-tetrahydro-quinazolin-6-ylcarbamoyl)-phenyl-meth-
yl]-carbamic acid benzyl ester, [0259] [136]
N-[6-(3,4-dimethoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyri-
midin-2-yl]-4-fluoro-benzamide, [0260] [137]
2-fluoro-N-[6-(2-methyl-5-phenyl-furan-3-carbonyl)-5,6,7,8-tetrahydro-pyr-
ido[4,3-d]pyrimidin-2-yl]-benzamide, [0261] [138]
thiophene-2-carboxylic acid
(6-pent-4-enoylamino-5,6,7,8-tetrahydro-quinazolin-2-yl)-amide,
[0262] [139]
(2-methyl-1-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazol-
in-6-ylcarbamoyl}-propyl)-carbamic acid 9H-fluoren-9-ylmethyl
ester, [0263] [140]
(5-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-ylca-
rbamoyl}-pentyl)-carbamic acid tert-butyl ester,
[0264] [141]
3-fluoro-N-[6-(1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-5,6,7,8-tetrahy-
dro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide, [0265] [142]
4-chloro-N-{6-[2-(2,5-dioxo-imidazolidin-4-yl)-acetyl]-5,6,7,8-tetrahydro-
-pyrido[4,3-d]pyrimidin-2-yl}-benzamide, [0266] [143]
3-fluoro-N-[6-(toluene-4-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimi-
din-2-yl]-benzamide, [0267] [144]
3,5-dichloro-N-[6-(4-thiophen-2-yl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-
-d]pyrimidin-2-yl]-benzamide, [0268] [145]
N-[6-(3-chloro-thiophene-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyri-
midin-2-yl]-2-ethoxy-benzamide, [0269] [146]
N-[6-(toluene-3-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-butyra-
mide, [0270] [147] thiophene-2-carboxylic acid
{6-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl-
amino]-5,6,7,8-tetrahydro-quinazolin-2-yl}-amide, [0271] [148]
4-methyl-N-[6-(4-trifluoromethylsulfanyl-benzoyl)-5,6,7,8-tetrahydro-pyri-
do[4,3-d]pyrimidin-2-yl]-benzamide, [0272] [149]
(2-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-ylca-
rbamoyl}-ethyl)-carbamic acid tert-butyl ester, [0273] [150]
2-fluoro-N-[6-(2-methyl-5-nitro-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrid-
o[4,3-d]pyrimidin-2-yl]-benzamide, [0274] [151]
N-[6-(4-methoxy-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-
-butyramide, [0275] [152]
4-chloro-N-[6-(2,4-difluoro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyri-
midin-2-yl]-benzamide [0276] [153]
4-methyl-N-(6-pent-4-enoyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl-
)-benzamide, [0277] [154] naphthalene-1-carboxylic acid
[6-(3-fluoro-4-methyl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin--
2-yl]-amide, [0278] [155]
N-{6-[2-(4-trifluoromethyl-phenyl)-acetyl]-5,6,7,8-tetrahydro-pyrido[4,3--
d]pyrimidin-2-yl}-benzamide, [0279] [156]
N-[6-(3,4-dichloro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-y-
l]-nicotinamide, [0280] [157]
4-ethyl-N-{6-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline--
7-sulfonyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl}-benzamide,
[0281] [158]
2-methoxy-N-[6-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-5,6,7,8-tetrah-
ydro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide, [0282] [159]
4-ethyl-N-[6-(2-methoxy-acetyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-
-2-yl]-benzamide, [0283] [160]
4-fluoro-N-[6-(propane-1-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2-y-
l]-benzamide, [0284] [162]
N-[6-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-ylmethanesulfonylamino)-5,6-
,7,8-tetrahydro-quinazolin-2-yl]-butyramide, [0285] [163]
N-{6-[2-(2,5-dimethyl-phenyl)-acetylamino]-5,6,7,8-tetrahydro-quinazolin--
2-yl}-4-fluoro-benzamide, [0286] [165] thiophene-2-carboxylic acid
(6-phenylmethanesulfonylamino-5,6,7,8-tetrahydro-quinazolin-2-yl)-amide,
[0287] [166]
N-[6-(3,4-dimethoxy-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2-
-yl]-butyramide, [0288] [167]
N-{6-[4-(1,1-dimethyl-propyl)-benzenesulfonylamino]-5,6,7,8-tetrahydro-qu-
inazolin-2-yl}-butyramide, [0289] [168]
N-(2-butyrylamino-5,6,7,8-tetrahydro-quinazolin-6-yl)-3-(3-trifluoromethy-
l-phenyl)-acrylamide, [0290] [169]
N-[6-(butane-1-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-4-fluor-
o-benzamide, [0291] [170] naphthalene-1-carboxylic acid
(6-acetyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-amide,
[0292] [171]
3,5-dichloro-N-[6-(3-diethylcarbamoyl-propionyl)-5,6,7,8-tetrahydro-
-pyrido[4,3-d]pyrimidin-2-yl]-benzamide, [0293] [172]
4-ethyl-N-[6-(4-methoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]-
pyrimidin-2-yl]-benzamide, [0294] [173]
4-ethyl-N-[6-(quinoline-6-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2-yl]-benzamide, [0295] [174]
N-[6-(2-cyclopropyl-acetyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-y-
l]-2-fluoro-benzamide, [0296] [175]
N-[6-(2H-chromene-3-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-
-yl]-3,4-difluoro-benzamide, [0297] [176]
N-{6-[2-(4-chloro-phenyl)-propionyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyri-
midin-2-yl}-benzamide, [0298] [177] thiophene-2-carboxylic acid
[6-(2-naphthalen-1-yl-acetylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-am-
ide, [0299] [178]
4-fluoro-N-(6-phenylmethanesulfonyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2-yl)-benzamide, [0300] [180] thiophene-2-carboxylic acid
[6-(2,5-dichloro-thiophene-3-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-
-2-yl]-amide, [0301] [181]
{5-[2-(4-fluoro-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-6-ylcarbamoyl-
]-pentyl}-carbamic acid benzyl ester, [0302] [182]
N-[6-(2,5-dimethyl-2H-pyrazole-3-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3--
d]pyrimidin-2-yl]-4-ethyl-benzamide, [0303] [183]
naphthalene-1-carboxylic acid
[6-(3-fluoro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl-
]-amide, [0304] [184]
N-[6-(benzo[b]thiophene-3-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2-yl]-4-tert-butyl-benzamide, [0305] [185]
4-fluoro-N-[6-(4-methoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d-
]pyrimidin-2-yl]-benzamide, [0306] [186]
4-tert-butyl-N-[6-(2,3-dihydro-benzo[1,4]dioxin-6-sulfonyl)-5,6,7,8-tetra-
hydro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide, [0307] [187]
3-chloro-N-{6-[2-(2,6-dichloro-phenyl)-acetyl]-5,6,7,8-tetrahydro-pyrido[-
4,3-d]pyrimidin-2-yl}-benzamide, [0308] [188]
thiophene-2-carboxylic acid
[6-(2,3-dihydro-benzo[1,4]dioxin-6-sulfonylamino)-5,6,7,8-tetrahydro-quin-
azolin-2-yl]-amide, [0309] [189]
N-{6-[2-(3-chloro-phenoxy)-acetyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimi-
din-2-yl}-4-methyl-benzamide, [0310] [190]
N-[6-(5-phenyl-pentanoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-
-benzamide, [0311] [191]
4-ethyl-N-[6-(2-ethyl-butyryl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin--
2-yl]-benzamide, [0312] [192]
3,5-dichloro-N-[6-(4-trifluoromethoxy-benzoyl)-5,6,7,8-tetrahydro-pyrido[-
4,3-d]pyrimidin-2-yl]-benzamide, [0313] [193]
naphthalene-1-carboxylic acid
[6-(4-methyl-octanoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-y-
l]-amide, [0314] [194]
4-[2-(4-fluoro-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-6-ylcarbamoyl]-
-piperidine-1-carboxylic acid tert-butyl ester, [0315] [195]
N-[6-(2-benzyloxy-acetyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-
-2-methoxy-benzamide, [0316] [196]
N-[6-(2-trifluoromethyl-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazol-
in-2-yl]-butyramide, [0317] [197]
N-[2-(4-fluoro-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-6-yl]-2-methyl-
-6-trifluoromethyl-nicotinamide, [0318] [198]
N-[6-(3-cyano-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-2--
trifluoromethyl-benzamide, [0319] [199]
3-methoxy-N-[6-(3-trifluoromethoxy-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-
-d]pyrimidin-2-yl]-benzamide, [0320] [200]
N-(6-butyryl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-2-fluoro-ben-
zamide, [0321] [201]
N-(6-benzenesulfonylamino-5,6,7,8-tetrahydro-quinazolin-2-yl)-4-fluoro-be-
nzamide, [0322] [202]
N-[6-(5-chloro-thiophene-2-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2-
-yl]-4-fluoro-benzamide, [0323] [203] naphthalene-1-carboxylic acid
(6-hexanoyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-amide,
[0324] [204]
N-(6-propionyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-2-tr-
ifluoromethyl-benzamide, [0325] [205]
N-[6-(2-ethyl-butyryl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-4--
methyl-benzamide, [0326] [206]
2-fluoro-N-[6-(3-trifluoromethyl-benzenesulfonyl)-5,6,7,8-tetrahydro-pyri-
do[4,3-d]pyrimidin-2-yl]-benzamide, [0327] [207]
5-benzyl-furan-2-carboxylic acid
{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-yl}-ami-
de, [0328] [208] thiophene-2-carboxylic acid
{6-[2-(2,5-dimethyl-phenyl)-acetylamino]-5,6,7,8-tetrahydro-quinazolin-2--
yl}-amide, [0329] [210]
4-fluoro-N-[6-(propane-1-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimi-
din-2-yl]-benzamide, [0330] [211]
2-[2-(3-fluoro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-sul-
fonyl]-benzoic acid methyl ester, [0331] [212]
3,5-dichloro-N-[6-(5-[1,2]dithiolan-3-yl-pentanoyl)-5,6,7,8-tetrahydro-py-
rido[4,3-d]pyrimidin-2-yl]-benzamide, [0332] [213]
thiophene-2-carboxylic acid
[6-(2-phenoxy-butyrylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-amid-
e, [0333] [214] thiophene-2-carboxylic acid
{6-[2-(4-methoxyphenyl)-acetylamino]-5,6,7,8-tetrahydro-quinazolin-2-yl}--
amide, [0334] [215]
N-(6-cyclohexanecarboxylic-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl-
)-2-trifluoromethyl-benzamide, [0335] [216]
N-[6-(2,4-dimethyl-thiazole-5-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]p-
yrimidin-2-yl]-2-trifluoromethyl-benzamide, [0336] [217]
2-thiophen-2-yl-thiazole-4-carboxylic acid
{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-yl}-ami-
de, [0337] [219] thiophene-2-carboxylic acid
{6-[3-(3-trifluoromethyl-phenyl)-acryloylamino]-5,6,7,8-tetrahydro-quinaz-
olin-2-yl}-amide, [0338] [220] thiophene-2-carboxylic acid
[6-(5-phenyl-pentanoylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-amide,
[0339] [221] thiophene-2-carboxylic acid
[6-(2-chloro-5-trifluoromethyl-benzoylamino)-5,6,7,8-tetrahydro-quinazoli-
n-2-yl]-amide, [0340] [222]
4-fluoro-N-[6-(2,3,5,6-tetramethyl-benzenesulfonylamino)-5,6,7,8-tetrahyd-
ro-quinazolin-2-yl]-benzamide, [0341] [223]
4-fluoro-N-[6-(4-methyl-octanoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimid-
in-2-yl]-benzamide, [0342] [224]
2-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-ylsul-
famoyl}-benzoic acid methyl ester, [0343] [225]
[(3-methyl-1-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazo-
lin-6-ylcarbamoyl}-butylcarbamoyl)-methyl]-carbamic acid benzyl
ester, [0344] [226]
3-chloro-N-(6-pentanoyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-b-
enzamide, [0345] [227]
4-fluoro-N-[6-(5-oxo-5-phenyl-pentanoylamino)-5,6,7,8-tetrahydro-quinazol-
in-2-yl]-benzamide, [0346] [228] thiophene-2-carboxylic acid
[6-(3-phenyl-acryloylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-amide,
[0347] [229]
N-[6-(5-[1,2]dithiolan-3-yl-pentanoylamino)-5,6,7,8-tetrahydro-quinazolin-
-2-yl]-4-fluoro-benzamide, [0348] [230] benzoic acid
2-(2-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-yl-
carbamoyl}-ethyl)-phenyl ester, [0349] [231]
4-fluoro-N-[6-(2-methyl-5-nitro-benzenesulfonylamino)-5,6,7,8-tetrahydro--
quinazolin-2-yl]-benzamide, [0350] [232]
4-chloro-N-[6-(2-phenoxy-acetyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidi-
n-2-yl]-benzamide, [0351] [234]
N-[6-(5-bromo-thiophene-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2-yl]-2-fluoro-benzamide, [0352] [235]
4-fluoro-N-[6-(5-fluoro-2-methyl-benzenesulfonylamino)-5,6,7,8-tetrahydro-
-quinazolin-2-yl]-benzamide, [0353] [236]
N-[6-(4-acetylamino-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2-
-yl]-4-fluoro-benzamide, [0354] [237] thiophene-2-carboxylic acid
[6-(2-trifluoromethyl-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-a-
mide, [0355] [238]
3,4-difluoro-N-[6-(quinoline-6-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]-
pyrimidin-2-yl]-benzamide, [0356] [239]
{1-[2-(4-fluoro-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-6-ylcarbamoyl-
]-2-phenyl-ethyl}-carbamic acid tert-butyl ester, [0357] [240]
thiophene-2-carboxylic acid
[6-(2-methyl-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-amide,
[0358] [241]
3-chloro-N-{6-[3-(2-oxo-benzooxazol-3-yl)-propionyl]-5,6,7,8-tetrahydro-p-
yrido[4,3-d]pyrimidin-2-yl}-benzamide, [0359] [242]
3-chloro-N-[6-(5-chloro-thiophene-2-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4-
,3-d]pyrimidin-2-yl]-benzamide, [0360] [243]
3,5-dichloro-N-[6-(4-methoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4-
,3-d]pyrimidin-2-yl]-benzamide, [0361] [244]
4-tert-butyl-N-[6-(5-methyl-isoxazole-3-carbonyl)-5,6,7,8-tetrahydro-pyri-
do[4,3-d]pyrimidin-2-yl]-benzamide, [0362] [245]
N-[6-(5-bromo-2-methoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]-
pyrimidin-2-yl]-4-methyl-benzamide, [0363] [246]
4-tert-butyl-N-{6-[3-(2-hydroxyphenyl)-propionyl]-5,6,7,8-tetrahydro-pyri-
do[4,3-d]pyrimidin-2-yl}-benzamide, [0364] [247]
4-fluoro-N-[6-(2-phenyl-butyrylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-
-benzamide, [0365] [248]
4-tert-butyl-N-[6-(4-propyl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyri-
midin-2-yl]-benzamide, [0366] [249] thiophene-2-carboxylic acid
[6-(2-bromo-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-amide,
[0367] [250]
2-methoxy-N-[6-(6-phenoxy-pyridine-3-carbonyl)-5,6,7,8-tetrahydro-pyrido[-
4,3-d]pyrimidin-2-yl]-benzamide, [0368] [251]
N-[6-(4-acetylamino-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyri-
midin-2-yl]-4-ethyl-benzamide, [0369] [252]
3,5-dichloro-N-[6-(4-fluoro-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,-
3-d]pyrimidin-2-yl]-benzamide, [0370] [253]
N-[6-(1-benzenesulfonyl-1H-indole-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4-
,3-d]pyrimidin-2-yl]-4-fluoro-benzamide, [0371] [255]
N-[6-(3-chloro-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]--
4-fluoro-benzamide,
[0372] in each case optionally in the form of one of the pure
stereoisomers thereof, in particular enantiomers or diastereomers,
the racemates thereof or in the form of a mixture of stereoisomers,
in particular the enantiomers and/or diastereomers, in any desired
mixing ratio, or in each case in the form of corresponding salts or
in each case in the form of corresponding solvates.
[0373] The present invention also provides a process for the
production of substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl-compounds of the
above-stated general formula I, in which X denotes an NR.sup.2a
group, according to which an N-protected piperidin-4-one of the
general formula II,
##STR00004##
[0374] in which PG denotes a protective group, is converted by
reaction with dimethoxy-methyl-dimethyl-amine of the formula
III
##STR00005##
[0375] in an organic reaction medium to yield a compound of the
general formula IV,
##STR00006##
[0376] in which PG has the above-stated meaning, this latter
compound is optionally purified and/or isolated, and is converted
by reaction with guanidine of the formula V,
##STR00007##
[0377] optionally in the form of a corresponding salt, in an
organic reaction medium, optionally in the presence of at least one
base to yield a compound of the general formula VI,
##STR00008##
[0378] in which PG has the above-stated meaning, this latter
compound is optionally purified and/or isolated, and is reacted in
an organic reaction medium, optionally in the presence of at least
one base and/or at least one catalyst, with a compound of the
general formula R.sup.3--C(.dbd.O)--X.sup.1 or a compound of the
general formula (R.sup.3--C(.dbd.O)).sub.2O, or by reaction with a
compound of the general formula R.sup.3--C(.dbd.O)--OH in an
organic reaction medium in the presence of at least one coupling
agent, optionally in the presence of at least one base, or by
reaction with a compound of the general formula
R.sup.4--O--C(.dbd.O)--X.sup.1a in an organic reaction medium,
optionally in the presence of at least one base, wherein R.sup.3
and R.sup.4 in each case have the above-stated meaning and X.sup.1
and X.sup.1a in each case denote a leaving group, to yield a
compound of the general formula VII,
##STR00009##
[0379] in which PG and R.sup.1 have the above-stated meaning, this
latter compound is optionally purified and/or isolated, and by
elimination of the protective group PG is converted to yield an
appropriately substituted compound of the general formula VIII,
##STR00010##
[0380] optionally in the form of a corresponding salt, this latter
compound is optionally purified and/or isolated, and is converted
by reaction with a compound of the general formula
R.sup.5--C(.dbd.O)--X.sup.2 or (R.sup.5--C(.dbd.O)).sub.2O, in
which R.sup.5 in each case has the above-stated meaning and X.sup.2
denotes a leaving group, in an organic reaction medium, optionally
in the presence of at least one base and/or in the presence at
least one catalyst,
[0381] or by reaction with a compound of the general formula
R.sup.6--SO.sub.2--X.sup.3, in which R.sup.6 has the above-stated
meaning and X.sup.3 denotes a leaving group, in an organic reaction
medium, optionally in the presence of at least one base, or by
reaction with a compound of the general formula R.sup.5--COOH, in
which R.sup.5 has the above-stated meaning, in an organic reaction
medium, in the presence of at least one suitable coupling agent,
optionally in the presence of at least one base, to yield a
compound of the general formula IX
##STR00011##
[0382] in which R.sup.1 and R.sup.2a have the above-stated meaning,
this latter compound is optionally purified and/or isolated, and
optionally converted to yield a corresponding salt and this is
optionally purified and/or isolated,
[0383] or piperidin-4-one of the general formula X
##STR00012##
[0384] optionally in the form of a corresponding salt, is converted
by reaction with a compound of the general formula
R.sup.5--C(.dbd.O)--X2 or (R.sup.5--C(.dbd.O))2O, in which R5 in
each case has the above-stated meaning and X2 denotes a leaving
group, in an organic reaction medium, optionally in the presence of
at least one base and/or in the presence of at least one catalyst,
or by reaction with a compound of the general formula R6-SO2-X3, in
which R6 has the above-stated meaning and X3 denotes a leaving
group, in an organic reaction medium, optionally in the presence of
at least one base, or by reaction with a compound of the general
formula R5-COOH, in which R5 has the above-stated meaning, in an
organic reaction medium, in the presence of a suitable coupling
agent, optionally in the presence of at least one base, to yield a
compound of the general formula XI,
##STR00013##
[0385] in which R.sup.2a has the above-stated meaning, this latter
compound is optionally purified and/or isolated, and is converted
by reaction with dimethoxy-methyl-dimethyl-amine of the formula
III
##STR00014##
[0386] in an organic reaction medium to yield a compound of the
general formula XII,
##STR00015##
[0387] in which R.sup.2a has the above-stated meaning, this
compound is optionally purified and/or isolated, and is converted
with guanidine of the formula V,
##STR00016##
[0388] optionally in the form of a corresponding salt, in an
organic reaction medium, optionally in the presence of at least one
base, to yield a compound of the general formula XIII
##STR00017##
[0389] this compound is optionally purified and/or isolated, and is
reacted in an organic reaction medium, optionally in the presence
of at least one base and/or at least one catalyst, with a compound
of the general formula R.sup.3--(C.dbd.O)--X.sup.1 or a compound of
the general formula (R.sup.3--C(.dbd.O)).sub.2O, or by reaction
with a compound of the general formula R.sup.3--COOH in an organic
reaction medium in the presence of at least one coupling agent,
optionally in the presence of at least one base, or by reaction
with a compound of the general formula
R.sup.4--O--C(.dbd.O)--X.sup.1a in an organic reaction medium,
optionally in the presence of at least one base, wherein R.sup.3
and R.sup.4 in each case have the above-stated meaning and X.sup.1
and X.sup.1a denote a leaving group, to yield a compound of the
general formula XIV
##STR00018##
[0390] in which R.sup.1 and R.sup.2a have the above-stated meaning,
and this latter compound is optionally purified and/or isolated,
and optionally converted to yield a corresponding salt and this
salt is optionally purified and/or isolated.
[0391] The process according to the invention for the production of
substituted 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl
compounds of the above-stated general formula I, in which X denotes
an --NR.sup.2a group starting from N-protected piperidin-4-one, is
also reproduced in the following scheme I.
##STR00019##
[0392] In Step 1, piperidin-4-one, which is provided on the
nitrogen atom with a protective group (PG), is firstly reacted with
dimethoxymethyl-dimethyl-amine in an organic reaction medium,
preferably toluene and/or benzene, to yield at least one compound
of the above-stated general formula IV, which is preferably used
without further working up in Step 2.
[0393] Dimethoxymethyl-dimethyl-amine, piperidin-4-one and
N-protected piperidone are commercially obtainable, but may also be
produced using conventional methods known to the person skilled in
the art. Examples of suitable protective groups which may be
considered for piperidone are trifluoroacetamide, methoxycarbonyl,
ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl,
allyloxycarbonyl or 9-fluorenylmethoxycarbonyl. Suitable reagents
and methods for introducing these protective groups are known to
the person skilled in the art.
[0394] In Step 2, the respective compound of the general formula IV
is reacted optionally in the presence of at least one organic base
and/or at least one organometallic base, preferably in the presence
of sodium ethanolate and/or sodium methanolate, in an organic
reaction medium, preferably methanol and/or ethanol, with guanidine
of the formula V, optionally in the form of a corresponding salt
such as for example guanidine hydrochloride, to yield the
respective compound of the above-stated general formula VI.
[0395] Guanidine and the corresponding salts thereof are
commercially obtainable, but may also be produced using
conventional methods known to the person skilled in the art.
[0396] In Step 3, the respective compound of the general formula VI
is reacted under conventional conditions known to the person
skilled in the art in an organic reaction medium such as for
example pyridine by acylation with at least one compound of the
general formula R.sup.3--C(.dbd.O)--X.sup.1 or at least one
compound of the general formula (R.sup.3--C(.dbd.O)).sub.2O,
optionally in the presence of at least one organic base and/or at
least one inorganic base, which may preferably be selected from the
group consisting of diisopropylethylamine, triethylamine, pyridine
and diethylamine, optionally in the presence of at least one
catalyst, preferably in the presence of dimethylaminopyridine
(DMAP), to yield the respective compound of the general formula
VII.
[0397] Alternatively, the reaction of the respective compound of
the general formula VI may also proceed with at least one
carboxylic acid of the general formula R.sup.3--COOH, in which
R.sup.3 in each case has the above-stated meaning, in an organic
reaction medium, preferably selected from the group consisting of
dichloromethane, DMF, THF and acetonitrile, optionally in the
presence of at least one conventional coupling agent known to the
person skilled in the art, preferably selected from the group
consisting of N,N'-carbonyldiimidazole (CDI),
N,N'-dicyclohexylcarbodiimide (DCC) and
N-ethyl-N'-[3-(dimethylamino)-propyl]-carbodiimide (EDCI), or in
the presence of 1-hydroxy-7-azabenzotriazole (HOAt) and at least
one organic base such as for example diisopropylethylamine
(DIPEA).
[0398] A further possible alternative is for the reaction to
proceed with at least one compound of the general formula
R.sup.4--O--C(.dbd.O)--X.sup.1a, in which R.sup.4 has the
above-stated meaning and X.sup.1a denotes a leaving group, in an
organic reaction medium such as for example acetonitrile, DMF or
dichloromethane, optionally in the presence of at least one base
for example selected from the group consisting of aqueous potassium
carbonate, sodium hydrogencarbonate, sodium hydroxide solution,
diisopropylethylamine, triethylamine, pyridine and
diethylamine.
[0399] The respective compound of the general formula VII is
converted by elimination of the respective protective group (PG) in
Step 4 under conventional conditions known to the person skilled in
the art to yield the respective compound of the above-stated
general formula VIII, optionally in the form of a corresponding
salt such as for example trifluoroacetate.
[0400] For example, elimination of the above-stated protective
groups may proceed in the presence of at least one inorganic base,
acid or Lewis acid, such as for example potassium carbonate,
lithium hydroxide, potassium hydroxide, sulfuric acid, hydrobromic
acid, hydrofluoric acid, hydrochloric acid, boron trifluoride
etherate or boron trichloride, at least one organic acid such as
for example trifluoroacetic acid, trifluoromethanesulfonic acid or
acetic acid, or in the presence of at least one organic base, such
as for example morpholine, triethylamine, diethylamine,
diisopropylethylamine or pyridine or by hydrogenation.
[0401] The respective compound of the above-stated general formula
VIII is reacted in Step 5 under conventional conditions known to
the person skilled in the art in an organic reaction medium, such
as for example pyridine, by acylation with at least one compound of
the general formula R.sup.5--C(.dbd.O)--X.sup.2 or at least one
compound of the general formula (R.sup.5--C(.dbd.O)).sub.2O, in
which R.sup.5 in each case has the above-stated meaning and X.sup.2
denotes a conventional leaving group familiar to the person skilled
in the art, preferably a halogen such as for example chlorine,
optionally in the presence of at least one organic base and/or at
least one inorganic base, preferably at least one base selected
from the group consisting of diisopropylethylamine, triethylamine,
pyridine and diethylamine, optionally in the presence of at least
one catalyst, preferably dimethylaminopyridine (DMAP), or by
sulfonylation with at least one sulfonyl compound of the general
formula R.sup.6--S(.dbd.O).sub.2--X.sup.3, in which R.sup.6 in each
case has the above-stated meaning and X.sup.3 denotes a
conventional leaving group familiar to the person skilled in the
art, preferably a halogen such as for example chlorine, optionally
in the presence of at least one organic base and/or at least one
inorganic base, preferably at least one base selected from the
group consisting of sodium hydrogencarbonate,
diisopropylethylamine, triethylamine, pyridine and diethylamine, or
by reaction with at least one carboxylic acid of the general
formula R.sup.5--COOH, in which R.sup.5 in each case has the
above-stated meaning, in an organic reaction medium, preferably
selected from the group consisting of dichloromethane, DMF, THF and
acetonitrile, optionally in the presence of at least one
conventional coupling agent known to the person skilled in the art,
preferably selected from the group consisting of
N,N'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC)
and N-ethyl-N'-[3-(dimethylamino)-propyl]-carbodiimide (EDCI), or
in the presence of 1-hydroxy-7-azabenzotriazole (HOAt) and at least
one organic base such as for example diisopropylethylamine (DIPEA)
to yield the respective substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl compound of the
above-stated general formula I.
[0402] Alternatively, the substituted
5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidin-2-yl compounds according
to the invention of the above-stated general formula I, in which X
denotes an --NR.sup.2a group, are produced starting from
piperidin-4-one. The corresponding process is illustrated in Scheme
II.
##STR00020##
[0403] The respective compound of the above-stated general formula
XI is obtained starting from piperidin-4-one of the general formula
X, optionally in the form of a corresponding salt such as for
example the hydrochloride, under conventional conditions known to
the person skilled in the art in an organic reaction medium, such
as for example pyridine, by acylation with at least one compound of
the general formula R.sup.5--C(.dbd.O)--X.sup.2 or
(R.sup.5--C(.dbd.O)).sub.2O in which R.sup.5 in each case has the
above-stated meaning and X.sup.2 denotes a conventional leaving
group familiar to the person skilled in the art, preferably a
halogen such as for example chlorine, optionally in the presence of
at least one organic base and/or at least one inorganic base,
preferably at least one base selected from the group consisting of
diisopropylethylamine, triethylamine, pyridine and diethylamine,
optionally in the presence of at least one catalyst, preferably
DMAP, or by sulfonylation with at least one compound of the general
formula R.sup.6--S(.dbd.O).sub.2--X.sup.3, in which R.sup.6 has the
above-stated meaning and X.sup.3 denotes a conventional leaving
group familiar to the person skilled in the art, preferably a
halogen such as for example chlorine, in the presence of at least
one organic base and/or at least one inorganic base, preferably at
least one base selected from the group consisting of sodium
hydrogencarbonate, diisopropylethylamine, triethylamine, pyridine
and diethylamine, or by reaction with a carboxylic acid of the
general formula R.sup.5--COOH in an organic reaction medium,
preferably selected from the group consisting of dichloromethane,
DMF, THF and acetonitrile, in the presence of a conventional
coupling agent known to the person skilled in the art, preferably
selected from the group consisting of CDI, DCC and EDCI, or
optionally in the presence of HOAt and at least one organic base
such as for example DIPEA.
[0404] The resultant compound of the above-stated general formula
XI is then reacted with dimethoxy-methyl-dimethyl-amine of the
formula III in an organic reaction medium, preferably toluene
and/or benzene, to yield the respective compound of the
above-stated general formula XII, which compound is preferably
converted without further working up in the presence of at least
one organic base and/or at least one organometallic base,
preferably sodium ethanolate and/or sodium methanolate, in an
organic reaction medium, preferably methanol and/or ethanol, with
guanidine of the above-stated formula V, optionally in the form of
a corresponding salt such as for example guanidine hydrochloride,
to yield the respective compound of the above-stated general
formula XIII.
[0405] Reaction of the respective compound of the general formula
XIII with at least one compound of the general formula
R.sup.4--O--(C.dbd.O)--X.sup.1a or at least one compound of the
general formula (R.sup.3--C(.dbd.O)).sub.2O or a compound of the
general formula R.sup.3--C(.dbd.O)--X.sup.1, in which R.sup.3 and
R.sup.4 in each case have the above-stated meaning and X.sup.1 and
X.sup.1a denote a conventional leaving group familiar to the person
skilled in the art, preferably a halogen such as for example
chlorine, in the presence of at least one base, preferably selected
from the group consisting of aqueous potassium carbonate, sodium
hydrogencarbonate, sodium hydroxide solution,
diisopropylethylamine, triethylamine, pyridine, diethylamine,
optionally in an organic reaction medium, preferably selected from
the group consisting of acetonitrile, DMF and dichloromethane, then
leads to the respective substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl compounds of the
above-stated general formula I, in which X denotes an --NR.sup.2a
group and R.sup.1 has the above-stated meaning.
[0406] Alternatively, reaction of the respective compound of the
general formula XIII may also proceed with at least one carboxylic
acid of the general formula R.sup.3--COOH, in which R.sup.3 in each
case has the above-stated meaning, in an organic reaction medium,
preferably selected from the group consisting of dichloromethane,
DMF, THF and acetonitrile, optionally in the presence of at least
one conventional coupling agent known to the person skilled in the
art, preferably selected from the group consisting of
N,N'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC)
and N-ethyl-N'-[3-(dimethylamino)-propyl]-carbodiimide (EDCI), or
in the presence of 1-hydroxy-7-azabenzotriazole (HOAt) and at least
one organic base such as for example diisopropylethylamine
(DIPEA).
[0407] The present invention also provides a process for the
production of substituted 5,6,7,8-tetrahydro-quinazolin-2-yl
compounds of the above-stated general formula I, in which X denotes
a C(H)(NHR.sup.2) group, according to which
1,4-dioxa-spiro[4.5]dec-8-yl-amine of the formula C
##STR00021##
[0408] is converted by reaction with a compound of the general
formula R.sup.5--C(.dbd.O)--X.sup.4 or (R.sup.5--C(.dbd.O)).sub.2O,
in which R.sup.5 in each case has the above-stated meaning and
X.sup.4 denotes a leaving group, in an organic reaction medium,
optionally in the presence of at least one base and/or in the
presence at least one catalyst, or by reaction with a compound of
the general formula R.sup.6--SO.sub.2--X.sup.5, in which R.sup.6
has the above-stated meaning and X.sup.5 denotes a leaving group,
in an organic reaction medium, optionally in the presence of at
least one base, or by reaction with a compound of the general
formula R.sup.5--COOH, in which R.sup.5 has the above-stated
meaning, in an organic reaction medium, in the presence of a
suitable coupling agent, optionally in the presence of at least one
base, to yield a compound of the general formula D
##STR00022##
[0409] in which R.sup.2 has the above-stated meaning, this latter
compound is optionally purified and/or isolated, and converted by
elimination of the acetal group in an organic reaction medium in
the presence of water and at least one acid to yield a compound of
the general formula E,
##STR00023##
[0410] in which R.sup.2 has the above-stated meaning, and this
latter compound is converted by introduction of a protective group
(PG.sup.1) in an organic reaction medium to yield the compound of
the general formula F
##STR00024##
[0411] in which R.sup.2 has the above-stated meaning and PG.sup.1
denotes a protective group, this latter compound is optionally
purified and/or isolated, and is converted by reaction with
dimethoxymethyl-dimethyl-amine of the general formula III
##STR00025##
[0412] in an organic reaction medium to yield a compound of the
general formula G
##STR00026##
[0413] in which R.sup.2 and PG.sup.1 have the above-stated meaning,
and this latter compound is optionally purified and/or isolated,
and optionally converted in the presence of at least one base in an
organic reaction medium with a guanidine compound of the formula V,
optionally in the form of a corresponding salt,
##STR00027##
[0414] to yield a compound of the general formula H
##STR00028##
[0415] this latter compound is optionally purified and/or isolated,
and is converted by introduction of a protective group (PG2) in an
organic reaction medium to yield a compound of the general formula
I
##STR00029##
[0416] in which R.sup.2 and PG.sup.2 have the above-stated meaning,
this latter compound is optionally purified and/or isolated, and
converted by reaction with a compound of the general formula
R.sup.3--C(.dbd.O)--X.sup.6 or a compound of the general formula
(R.sup.3--C(.dbd.O)).sub.2O, in which R.sup.3 in each case has the
above-stated meaning and X.sup.6 denotes a leaving group, or by
reaction with a compound of the general formula R.sup.3COOH, in
which R.sup.3 has the above-stated meaning, in an organic reaction
medium in the presence of a coupling agent, optionally in the
presence of at least one base, or by reaction with a compound of
the general formula R.sup.4--O--C(.dbd.O)--X.sup.1a in an organic
reaction medium, optionally in the presence of a base, to yield a
compound of the general formula J
##STR00030##
[0417] in which R.sup.2 and PG.sup.2 have the above-stated meaning
and R.sup.1 has the above-stated meaning, this latter compound is
optionally purified and/or isolated, and converted by elimination
of the protective group to yield a
5,6,7,8-tetrahydro-quinazolin-2-yl compound of the general formula
I, in which X denotes a C(H)(NHR.sup.2) group, this latter compound
is optionally purified and/or isolated and then optionally
converted to yield a corresponding salt, and this is optionally
purified and/or isolated.
[0418] The process according to the invention for the production of
substituted 5,6,7,8-tetrahydro-quinazolin-2-yl compounds of the
above-stated general formula I, in which X denotes a
C(H)(NHR.sup.2) group, is also reproduced in Scheme III below.
##STR00031##
[0419] 1,4-Dioxa-spiro[4.5]dec-8-yl-amine of the formula C may be
produced using conventional methods known to the person skilled in
the art, for example starting from 1,4-dioxa-spiro[4.5]decan-8-one,
which is converted via reductive amination with benzylamine in an
organic reaction medium, such as for example dichloromethane, in
the presence of sodium cyanoborohydride or sodium
triacetoxyborohydride or by reaction with hydroxylamine
hydrochloride in the presence of an organic base, such as
triethylamine or Amberlyst, in an organic reaction medium, such as
ethanol, to yield the compound of the general formula B, in which R
denotes a hydroxy group or a benzyl residue, which compound is
optionally purified and/or isolated, and is reacted in the presence
of at least one catalyst such as palladium on activated carbon
(Pd(C)) by hydrogenation or by reduction with at least one metal
hydride such as for example lithium aluminium hydride in an organic
reaction medium, preferably ethanol and/or THF, to yield
1,4-dioxa-spiro[4.5]dec-8-yl-amine of the formula C.
[0420] The compound 1,4-dioxa-spiro[4.5]dec-8-yl-amine of the
formula C is then reacted under conventional conditions known to
the person skilled in the art in an organic reaction medium, such
as for example pyridine, by acylation with a compound of the
general formula R.sup.5--C(.dbd.O)--X.sup.4 or
(R.sup.5--C(.dbd.O)).sub.2O, in which R.sup.5 has the above-stated
meaning, and X.sup.4 denotes a conventional leaving group known to
the person skilled in the art, preferably halogen, particularly
preferably chlorine, optionally in the presence of at least one
organic base and/or at least one inorganic base, preferably at
least one base selected from the group consisting of
diisopropylethylamine, triethylamine, pyridine and diethylamine,
optionally in the presence of at least one catalyst, preferably
DMAP, or by sulfonylation of the compound
1,4-dioxa-spiro[4.5]dec-8-yl-amine of the formula C with at least
one sulfonyl compound of the general formula
R.sup.6--SO.sub.2--X.sup.5, in which R.sup.6 has the above-stated
meaning, and X.sup.5 denotes a conventional leaving group known to
the person skilled in the art, preferably halogen, particularly
preferably chlorine, in an organic reaction medium, preferably
acetonitrile and/or dichloromethane, in the presence of at least
one organic base and/or at least one inorganic base, preferably in
the presence of at least one base selected from the group
consisting of potassium carbonate, sodium hydrogencarbonate,
diisopropylethylamine, triethylamine, pyridine and diethylamine, or
by reaction of the compound 1,4-dioxa-spiro[4.5]dec-8-yl-amine of
the formula C with at least one carboxylic acid of the general
formula R.sup.5--COOH, in which R.sup.5 has the above-stated
meaning, in at least one organic reaction medium, preferably
selected from the group consisting of dichloromethane, DMF, THF and
acetonitrile, in the presence of at least one conventional coupling
agent known to the person skilled in the art to yield the
corresponding compound of the general formula D.
[0421] Corresponding coupling agents which lead to the formation of
an amide grouping are for example CDI, DCC or EDCI. Alternatively,
HOAt, in conjunction with at least one organic base, such as for
example DIPEA, may also be considered.
[0422] The respective compound of the general formula D is then
converted by elimination of the acetal protective group under
conventional conditions known to the person skilled in the art to
yield a compound of the general formula E, preferably by
elimination of the acetal protective group in an organic reaction
medium, preferably dichloromethane and/or methanol, in the presence
of water with at least one inorganic acid and/or at least one
organic acid, preferably selected from the group consisting of
methanolic hydrochloric acid, hydrochloric acid, p-toluenesulfonic
acid, trifluoroacetic acid, acetic acid, and citric acid, or in the
presence of a Lewis acid.
[0423] Starting from a compound of the general formula E, the
respective compound F is obtained by introduction of a protective
group (PG1).
[0424] Suitable protective groups (PG1) are for example
trifluoroacetamide, methoxycarbonyl, ethoxycarbonyl,
tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl and
9-fluorenylmethoxycarbonyl. Suitable reagents and processes for
introducing these protective groups are known to the person skilled
in the art.
[0425] The respective compound of the general formula F is then
reacted with dimethoxymethyl-dimethyl-amine of the general formula
III in an organic reaction medium, preferably toluene and/or
benzene, to yield the corresponding compound of the general formula
G, which is preferably reacted without further working up in the
presence of at least one organic base or at least one
organometallic base, preferably in the presence of sodium
ethanolate and/or sodium methanolate, in an organic reaction
medium, preferably methanol and/or ethanol, with guanidine of the
general formula V, preferably in the form of a corresponding salt,
such as for example guanidine hydrochloride, to yield the
respective compound of the general formula H.
[0426] The protective group may optionally be partially eliminated
in the process and is reintroduced under conventional conditions
known to the person skilled in the art, such that the respective
compound of the formula I is obtained. The protective group (PG2)
introduced may be identical to or different from, preferably
identical to, the above-stated protective group (PG1).
[0427] The respective compound of the above-stated general formula
I is then reacted under conventional conditions known to the person
skilled in the art in an organic reaction medium such as for
example pyridine by acylation with at least one compound of the
general formula R.sup.3--C(.dbd.O)--X.sup.6 or a compound of the
general formula (R.sup.3--C(.dbd.O)).sub.2O, in which R.sup.3 in
each case has the above-stated meaning and X.sup.6 denotes a
conventional leaving group known to the person skilled in the art,
preferably halogen, particularly preferably chlorine, in an organic
reaction medium, optionally in the presence of at least one organic
base and/or at least one inorganic base, preferably a base selected
from the group consisting of diisopropylethylamine, triethylamine,
pyridine and diethylamine, optionally in the presence of at least
one catalyst, preferably DMAP, or by reaction with at least one
carboxylic acid R.sup.3--COOH, in which R.sup.3 has the
above-stated meaning, in an organic reaction medium, preferably
selected from the group consisting of dichloromethane, DMF, THF and
acetonitrile, in the presence of at least one conventional coupling
agent, preferably selected from the group consisting of CDI, DCC
and EDCI, or in the presence of HOAt and at least one organic base
such as for example DIPEA to yield the corresponding compound of
the general formula J.
[0428] A further possible alternative is for the reaction to
proceed with at least one compound of the general formula
R.sup.4--O--C(.dbd.O)--X.sup.1a, in which R.sup.4 has the
above-stated meaning and Xla denotes a leaving group, in an organic
reaction medium, such as for example acetonitrile, DMF or
dichloromethane, optionally in the presence of at least one base
for example selected from the group consisting of aqueous potassium
carbonate, sodium hydrogencarbonate, sodium hydroxide solution,
diisopropylethylamine, triethylamine, pyridine and
diethylamine.
[0429] The respective compound of the general formula J is then
converted by elimination of the protective group (PG2) under
conventional conditions known to the person skilled in the art to
yield the respective substituted 5,6,7,8-tetrahydro-quinazolin-2-yl
compound of the above-stated general formula I, in which X denotes
a C(H)(NHR.sup.2) group.
[0430] Elimination of the above-stated protective group (PG2) may
proceed for example in the presence of an inorganic base, acid or
Lewis acid, such as potassium carbonate, lithium hydroxide,
potassium hydroxide, sulfuric acid, hydrobromic acid, hydrofluoric
acid, hydrochloric acid, boron trifluoride etherate, boron
trichloride, an organic acid such as trifluoroacetic acid,
trifluoromethanesulfonic acid, acetic acid, or in the presence of
an organic base, such as morpholine, triethylamine, diethylamine,
diisopropylethylamine, pyridine or by hydrogenation.
[0431] The compounds of the general formulae
R.sup.3--C(.dbd.O)--X.sup.1, R.sup.5--C(.dbd.O)--X.sup.2,
R.sup.5--C(.dbd.O)--X.sup.4, R.sup.3--C(.dbd.O)--X.sup.6,
(R.sup.3--C(.dbd.O)).sub.2O, (R.sup.5--C(.dbd.O)).sub.2O,
R.sup.3--COOH, R.sup.5--COOH, R.sup.6--SO.sub.2--X.sup.3,
R.sup.6--SO.sub.2--X.sup.5 and R.sup.4--O--(C.dbd.O)--X.sup.1a are
in each case commercially obtainable and/or may be produced using
conventional methods known to the person skilled in the art.
[0432] The above-described reactions may in each case be performed
under conventional conditions familiar to the person skilled in the
art, for example with regard to temperature, pressure or the
sequence of addition of the components. Optimum control of the
process under the respective conditions may optionally be
established by the person skilled in the art by simple preliminary
testing.
[0433] The intermediate and final products obtained by the
above-described reactions may in each case, if desired and/or
necessary, be purified and/or isolated by conventional methods
known to the person skilled in the art. Suitable purification
methods are, for example, extraction methods and chromatographic
methods such as column chromatography or preparative
chromatography.
[0434] All the above-described process steps and in each case also
the purification and/or isolation of intermediate or final products
may be performed in part or entirely under an inert gas atmosphere,
preferably under a nitrogen atmosphere.
[0435] If the substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds according to the
invention of the above-stated general formula I are obtained after
production thereof in the form of a mixture of the stereoisomers
thereof, preferably in the form of the racemates thereof or other
mixtures of the various enantiomers and/or diastereomers thereof,
these may be resolved and optionally isolated using conventional
methods known to the person skilled in the art. Examples are
chromatographic separation processes, in particular liquid
chromatography processes at standard pressure or at elevated
pressure, preferably MPLC and HPLC processes, and fractional
crystallisation processes. Individual enantiomers, for example
diastereomeric salts formed by means of HPLC on a chiral phase or
by means of crystallisation with chiral acids, for instance
(+)-tartaric acid, (-)-tartaric acid or (+)-10-camphorsulfonic
acid, may here in particular be separated from one another.
[0436] The substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds according to the
invention of the above-stated general formula I and optionally in
each case corresponding stereoisomers may be obtained using
conventional methods known to the person skilled in the art in the
form of corresponding salts, in particular in the form of
corresponding physiologically acceptable salts, wherein the
pharmaceutical preparation according to the invention may comprise
one or more salts of one or more of these compounds.
[0437] The respective salts of the substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds according to the
invention of the above-stated general formula I and corresponding
stereoisomers may be obtained for example by reaction with one or
more inorganic acids and/or one or more organic acids. Suitable
acids may preferably be selected from the group consisting of
perchloric acid, hydrochloric acid, hydrobromic acid, sulfuric
acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid,
succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic
acid, citric acid, glutamic acid, saccharic acid,
cyclohexanesulfamic acid, aspartame, monomethylsebacic acid,
5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid,
2-aminobenzoic acid, 3-aminobenzoic acid or 4-aminobenzoic acid,
2,4,6-trimethylbenzoic acid, -lipoic acid, acetylglycine, hippuric
acid, phosphoric acid, maleic acid, malonic acid and aspartic
acid.
[0438] The substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds according to the
invention of the above-stated general formula I and optionally
corresponding stereoisomers and in each case the physiologically
acceptable salts thereof may be obtained using conventional methods
known to the person skilled in the art also in the form of the
solvates thereof, in particular in the form of the hydrates
thereof.
[0439] It has surprisingly been found that the substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds according to the
invention are suitable for noradrenalin receptor regulation, in
particular for inhibiting noradrenalin reuptake (noradrenalin
uptake), for 5-HT receptor regulation, in particular for inhibiting
5-hydroxy-tryptophan reuptake (5-HT uptake), for mGluR5 receptor
regulation and/or for batrachotoxin (BTX) receptor regulation and
may therefore be used in particular as pharmaceutical active
ingredients in pharmaceutical preparations for the prevention
and/or treatment of disorders or diseases associated with these
receptors or processes.
[0440] The substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl and
5,6,7,8-tetrahydro-quinazolin-2-yl compounds according to the
invention of the above-stated general formula I and optionally
corresponding stereoisomers and in each case the corresponding
salts and solvates are toxicologically safe and are therefore
suitable as pharmaceutical active ingredients in pharmaceutical
preparations.
[0441] The present invention accordingly also provides a
pharmaceutical preparation containing at least one substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl or
5,6,7,8-tetrahydro-quinazolin-2-yl compound according to the
invention of the above-stated general formula I, in each case
optionally in the form of one of the pure stereoisomers thereof, in
particular enantiomers or diastereomers, the racemates thereof or
in the form of a mixture of stereoisomers, in particular the
enantiomers and/or diastereomers, in any desired mixing ratio, or
in each case in the form of a corresponding salt, or in each case
in the form of a corresponding solvate, and optionally one or more
pharmaceutically acceptable auxiliary substances.
[0442] The pharmaceutical preparation according to the invention is
suitable for noradrenalin receptor regulation, in particular for
inhibiting noradrenalin reuptake (noradrenalin uptake), for 5-HT
receptor regulation, in particular for inhibiting
5-hydroxy-tryptophan reuptake (5-HT uptake), for mGluR5 receptor
regulation and/or for batrachotoxin (BTX) receptor regulation.
[0443] The pharmaceutical preparation according to the invention is
preferably suitable for the prevention and/or treatment of
disorders and/or diseases, which are mediated at least in part by
noradrenalin receptors, 5-HT receptors, mGluR5 receptors and/or
batrachotoxin (BTX) receptors.
[0444] The pharmaceutical preparation according to the invention is
particularly preferably suitable for the prevention and/or
treatment of pain, preferably of pain selected from the group
consisting of acute pain, chronic pain, neuropathic pain and
visceral pain, and/or for the prevention and/or treatment of
migraine, depression, urinary incontinence, coughing,
neurodegenerative diseases, preferably selected from the group
consisting of Parkinson's disease, Huntington's chorea, Alzheimer's
disease and multiple sclerosis, disorders of food intake,
preferably selected from the group consisting of bulimia, anorexia,
obesity and cachexia, cognitive dysfunction, preferably memory
disorders, cognitive deficiency states (attention deficit syndrome,
ADS), disorders of the nervous system, epilepsy, schizophrenia,
cerebral ischaemia, muscle spasms, cramps, diarrhoea, pruritus,
gastro-oesophageal reflux syndrome, panic attacks, alcohol and/or
drug (in particular nicotine and/or cocaine) abuse and/or abuse of
medicines, alcohol and/or drug (in particular nicotine and/or
cocaine) dependency and/or dependency on medicines, preferably for
the prevention and/or reduction of withdrawal symptoms associated
with alcohol and/or drug dependency and/or dependency on medicines,
for the prevention and/or reduction of a development of tolerance
to medicines, in particular medicines based on opioids, for
regulating food intake, for modulating locomotor activity, for
regulating the cardiovascular system, for local anaesthesia, for
anxiolysis, for increasing vigilance, for increasing libido, for
diuresis, and/or for antinatriuresis.
[0445] The pharmaceutical preparation according to the invention is
very particularly preferably suitable for the prevention and/or
treatment of pain, preferably acute pain, chronic pain, neuropathic
pain or visceral pain.
[0446] The present invention also provides the use of at least one
substituted 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl or
5,6,7,8-tetrahydro-quinazolin-2-yl compound according to the
invention of the above-stated general formula I, in each case
optionally in the form of one of the pure stereoisomers thereof, in
particular enantiomers or diastereomers, the racemates thereof or
in the form of a mixture of stereoisomers, in particular the
enantiomers and/or diastereomers, in any desired mixing ratio, or
in each case in the form of a corresponding salt, or in each case
in the form of a corresponding solvate, and optionally one or more
pharmaceutically compatible auxiliary substances for the production
of a pharmaceutical preparation for noradrenalin receptor
regulation, in particular for inhibiting noradrenalin reuptake
(noradrenalin uptake), for 5-HT receptor regulation, in particular
for inhibiting 5-hydroxy-tryptophan reuptake (5-HT uptake), for
mGluR5 receptor regulation and/or for batrachotoxin (BTX) receptor
regulation.
[0447] The use is preferred of at least one substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl or
5,6,7,8-tetrahydro-quinazolin-2-yl compound according to the
invention of the above-stated general formula I, in each case
optionally in the form of one of the pure stereoisomers thereof, in
particular enantiomers or diastereomers, the racemates thereof or
in the form of a mixture of stereoisomers, in particular the
enantiomers and/or diastereomers, in any desired mixing ratio, or
in each case in the form of a corresponding salt, or in each case
in the form of a corresponding solvate, and optionally one or more
pharmaceutically compatible auxiliary substances for the production
of a pharmaceutical preparation for the prevention and/or treatment
of disorders and/or diseases which are mediated at least in part by
noradrenalin receptors, 5-HT receptors, mGluR5 receptors and/or
batrachotoxin (BTX) receptors.
[0448] The use is particularly preferred of at least one
substituted 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl or
5,6,7,8-tetrahydro-quinazolin-2-yl compound according to the
invention of the above-stated general formula I, in each case
optionally in the form of one of the pure stereoisomers thereof, in
particular enantiomers or diastereomers, the racemates thereof or
in the form of a mixture of stereoisomers, in particular the
enantiomers and/or diastereomers, in any desired mixing ratio, or
in each case in the form of a corresponding salt, or in each case
in the form of a corresponding solvate, and optionally one or more
pharmaceutically compatible auxiliary substances for the production
of a pharmaceutical preparation for the prevention and/or treatment
of pain, preferably of pain selected from the group consisting of
acute pain, chronic pain, neuropathic pain and visceral pain,
and/or for the prevention and/or treatment of migraine, depression,
urinary incontinence, coughing, neurodegenerative diseases,
preferably selected from the group consisting of Parkinson's
disease, Huntington's chorea, Alzheimer's disease and multiple
sclerosis, disorders of food intake, preferably selected from the
group consisting of bulimia, anorexia, obesity and cachexia,
cognitive dysfunction, preferably memory disorders, cognitive
deficiency states (attention deficit syndrome, ADS), disorders of
the nervous system, epilepsy, schizophrenia, cerebral ischaemia,
muscle spasms, cramps, diarrhoea, pruritus, gastro-oesophageal
reflux syndrome, panic attacks, alcohol and/or drug abuse and/or
abuse of medicines, alcohol and/or drug dependency and/or
dependency on medicines, preferably for the prevention and/or
reduction of withdrawal symptoms associated with alcohol and/or
drug dependency and/or dependency on medicines, for the prevention
and/or reduction of the development of tolerance to medicines, in
particular medicines based on opioids, for regulating food intake,
for modulating locomotor activity, for regulating the
cardiovascular system, for local anaesthesia, for anxiolysis, for
increasing vigilance, for increasing libido, for diuresis, and/or
for antinatriuresis.
[0449] The use is very particularly preferred of at least one
substituted 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl or
5,6,7,8-tetrahydro-quinazolin-2-yl compound according to the
invention of the above-stated general formula I, in each case
optionally in the form of one of the pure stereoisomers thereof, in
particular enantiomers or diastereomers, the racemates thereof or
in the form of a mixture of stereoisomers, in particular the
enantiomers and/or diastereomers, in any desired mixing ratio, or
in each case in the form of a corresponding salt, or in each case
in the form of a corresponding solvate, and optionally one or more
pharmaceutically compatible auxiliary substances for the production
of a pharmaceutical preparation for the prevention and/or treatment
of pain, preferably of acute pain, chronic pain, neuropathic pain
or visceral pain.
[0450] The pharmaceutical preparation according to the invention is
suitable for administration to adults and children including small
children and babies.
[0451] The pharmaceutical preparation according to the invention
may be formulated as a liquid, semisolid or solid dosage form, for
example in the form of solutions for injection, drops, succi,
syrups, sprays, suspensions, tablets, patches, capsules, dressings,
suppositories, ointments, creams, lotions, gels, emulsions,
aerosols or in multiparticulate form, for example in the form of
pellets or granules, optionally pressed into tablets, packaged in
capsules or suspended in a liquid, and may also be administered as
such.
[0452] In addition to at least one substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl or
5,6,7,8-tetrahydro-quinazolin-2-yl compound according to the
invention of the above-stated general formula I, optionally in the
form of the pure stereoisomer thereof, in particular enantiomer or
diastereomer, the racemate thereof or in the form of mixtures of
the stereoisomers, in particular the enantiomers or diastereomers,
in any desired mixing ratio, or optionally in the form of a
corresponding salt or in each case in the form of a corresponding
solvate, the pharmaceutical preparation according to the invention
conventionally contains further physiologically acceptable
pharmaceutical auxiliary substances, which may preferably be
selected from the group consisting of matrix materials, fillers,
solvents, diluents, surface-active substances, dyes, preservatives,
disintegrants, slip agents, lubricants, aromas and binders.
[0453] Selection of the physiologically acceptable auxiliary
substances and the quantities thereof which are to be used depends
upon whether the pharmaceutical preparation is to be administered
orally, subcutaneously, parenterally, intravenously,
intraperitoneally, intradermally, intramuscularly, intranasally,
buccally, rectally or topically, for example onto infections of the
skin, mucous membranes or eyes. Preparations in the form of
tablets, coated tablets, capsules, granules, pellets, drops, succi
and syrups are preferred for oral administration, while solutions,
suspensions, readily reconstitutible dried preparations and sprays
are preferred for parenteral, topical and inhalatory
administration.
[0454] The substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl or
5,6,7,8-tetrahydro-quinazolin-2-yl compounds used in the
pharmaceutical preparation according to the invention in a depot in
dissolved form or in a dressing, optionally with the addition of
skin penetration promoters, are suitable percutaneous
administration preparations.
[0455] Orally or percutaneously administrable formulations may also
release the respective substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl or
5,6,7,8-tetrahydro-quinazolin-2-yl compounds in delayed manner.
[0456] Production of the pharmaceutical preparations according to
the invention proceeds with the assistance of conventional means,
devices, methods and processes known from the prior art, such as
are described for example in "Remington's Pharmaceutical Sciences",
ed. A. R. Gennaro, 17th ed., Mack Publishing Company, Easton, Pa.
(1985), in particular in part 8, chapters 76 to 93. The
corresponding description is hereby introduced as a reference and
is deemed to be part of the disclosure.
[0457] The quantity of the respective substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl or
5,6,7,8-tetrahydro-quinazolin-2-yl compound to be administered to
the patient may vary and is for example dependent on the weight or
age of the patient and on the mode of administration, the
indication and the severity of the complaint. Conventionally, 0.005
to 5000 mg/kg, preferably 0.05 to 500 mg/kg, particularly
preferably 0.05 to 75 mg/kg of patient body weight of at least one
such compound are administered.
Pharmacological Methods:
[0458] I. Method for Determining Noradrenalin and 5-HT Uptake
Inhibition:
[0459] Synaptosomes from rat brain regions are freshly isolated for
in vitro studies, as described in the publication "The isolation of
nerve endings from brain" by E. G. Gray and V. P. Whittaker, J.
Anatomy 96, pages 79-88, 1962. The corresponding literature
description is hereby introduced as a reference and is deemed to be
part of the disclosure.
[0460] The tissue (hypothalamus for the determination of
noradrenalin uptake inhibition and medulla and pons for the
determination of 5-HT uptake inhibition) is homogenised in
ice-cooled 0.32 M sucrose (100 mg of tissue/1 mL) in a glass
homogeniser with Teflon pestle using five complete up and down
strokes at 840 revolutions/minute.
[0461] The homogenate is centrifuged at 4.degree. C. for 10 minutes
at 1000 g. After subsequent centrifugation at 17000 g for 55
minutes, the synaptosomes (P.sub.2 fraction) are obtained, which
are resuspended in 0.32 M glucose (0.5 mL/100 mg of original
weight).
[0462] The particular uptake is measured in a 96-well microtitre
plate. The volume is 250 .mu.l and the incubation proceeds at room
temperature (approx. 20-25.degree. C.) under an O.sub.2
atmosphere.
[0463] The incubation time is 7.5 minutes for [.sup.3H]-NA and 5
minutes for [.sup.3H]-5-HT.
[0464] The 96 samples are then filtered through a Unifilter GF/B
microtitre plate (Packard) and washed with 200 mL of incubated
buffer using a "Brabdel MPXRI-96T Cell-Harvester". The Unifilter
GF/B plate is dried for 1 hour at 55.degree. C. The plate is then
sealed with a Back seal (Packard) and 35 .mu.l of scintillation
fluid are added per well (Ultima Gold, Packard). After sealing with
a top seal (Packard) and establishing an equilibrium (around 5
hours), radioactivity is determined in a "Trilux 1450 Microbeta"
(Wallac).
[0465] The quantity of protein used in the above determination
corresponds to the values known from the literature, as for example
described in "Protein measurement with the folin phenol reagent",
Lowry et al., J. Biol. Chem., 193, 265-275, 1951.
[0466] A detailed description of the method may additionally be
found in the literature, for example in M. Ch. Frink, H.-H.
Hennies, W. Engelberger, M. Haurand and B. Wilffert (1996)
Arzneim.-Forsch./Drug Res. 46 (III), 11, 1029-1036.
[0467] The corresponding literature descriptions are hereby
introduced in each case as a reference and are deemed to be part of
the present disclosure.
[0468] The following characteristics were determined for the NA or
5-HT transporter:
[0469] NA uptake: Km=0.32.+-.0.11 .mu.M
[0470] 5HT uptake: Km=0.084.+-.0.011 .mu.M
[0471] II. Method for Determining Affinity for the Batrachotoxin
(BTX) Binding Site of the Sodium Channel:
[0472] Binding site 2 of the sodium channel is the so-called
batrachotoxin (BTX) binding site. [.sup.3H]-Batrachotoxinin A20
benzoate (10 nM in the batch) is used as ligand. The ion channel
particles (synaptosomes) are enriched from rat cerebrocortex, as
described in the publication by Gray and Whittaker (E. G. Gray and
V. P. Whittaker (1962) J. Anat. 76, 79-88. The corresponding
description is hereby introduced as a reference and is deemed to be
part of the present disclosure. The radioactivity measured in the
presence of veratridine (3.times.10.sup.-4 M in the batch) is
defined as non-specific binding.
[0473] The assay conditions are as published by Pauwels, Leysen and
Laduron, as described in Eur. J. Pharmacol. 124, 291-298. The
corresponding description is hereby introduced as a reference and
is deemed to be part of the present disclosure.
[0474] At variance with this method, the total batch is reduced to
250 .mu.l, such that the assay may be performed on 96-well
microtitre plates. The incubation time in these microtitre plates
amounts to two hours at room temperature (approx. 20-25.degree.
C.).
[0475] The following characteristics were determined for the
K.sub.D value of the binding site:
[0476] K.sub.D: 24.63.+-.1.56 nM.
[0477] III. Method for Determining Affinity for the mGluR5
Receptor
[0478] Pig brain homogenate is produced by homogenisation (Polytron
Pt 3000, Kinematica AG, 10,000 rpm (revolutions per minute) for 90
seconds) of pig brain hemispheres without medulla, cerebellum and
pons in a buffer of pH 8.0 (30 mM Hepes, Sigma, order number
H3375+1 tablet Complete Roche Diagnostics, order number 1836145
made up to 100 ml) in a ratio of 1:20 (brain weight/volume) and
differential centrifugation at 900 g and 40,000 g. 450 .mu.g of
protein from brain homogenate is incubated in each case in 250
.mu.l incubation batches in 96-well microtitre plates with 15 nM
.sup.3[H]-MPEP (Tocris, order number R1212) and the compounds to be
investigated (in each case 10 .mu.M in the test) in the
above-stated buffer at room temperature for 60 minutes.
[0479] The batches are then filtered with the assistance of a
Brandel Cell Harvester (Brandel, Grade Robotic 9600) on Unifilter
plates with glass filter mats (Perkin Elmer, order number 6005177)
and then rewashed 3 times with buffer of the above-stated
composition using 250 .mu.l per sample. The filter plates are then
dried for 60 minutes at 55.degree. C. Then 30 .mu.l of Ultima Gold
scintillating material (Packard BioScience, order number 6013159)
is added per well and after 3 hours the samples are measured using
the B counter (Microbial, Perkin Elmer). Nonspecific binding is
determined by the addition of 10 .mu.M
2-methyl-6-(phenylethynyl)-pyridine (Tocris, order number
1212).
[0480] The invention is explained below with reference to Examples.
These explanations are given merely by way of example and do not
restrict the general concept of the invention.
EXAMPLES
[0481] The yields of the compounds produced have not been
optimised.
[0482] All temperatures are uncorrected.
[0483] The term "ether" means diethyl ether, "EE" ethyl acetate,
"DCM" dichloromethane, "DMF" dimethylformamide, "DME"
dimethoxyethane, "DMSO" dimethyl sulfoxide and "THF"
tetrahydrofuran. The term "equivalents" means molar equivalents,
"mp" melting point or melting range, "decomp." decomposition, "RT"
room temperature, i.e. approx. 20.degree. C., "abs." absolute
(anhydrous), "rac." racemic, "conc." concentrated, "min" minutes,
"h" hours, "d" days, "vol. %" percent by volume and "wt. %" weight
percent and "M" is an indication of concentration in mol/l.
[0484] Further abbreviations:
TABLE-US-00001 DIPEA diisopropylethylamine HOAt
1-hydroxy-7-azabenzotriazole EDCI
N-ethyl-N'-[3-(dimethylamino)-propyl]-carbodiimide DCC
N,N'-dicyclohexylcarbodiimide DMA dimethoxymethyl-dimethyl-amine
DMAP dimethylaminopyridine CDI N,N'-carbonyldiimidazole Pd(C)
palladium on activated carbon
[0485] The chemicals and solvents used were purchased from
conventional suppliers (Acros, Avocado, Aldrich, Bachem, Fluka,
Lancaster, Maybridge, Merck, Sigma, TCI, Oakwood etc.) or
synthesised by conventional methods familiar to the person skilled
in the art.
[0486] Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt, was
used as the stationary phase for the column chromatography.
[0487] Thin-layer chromatography was performed with pre-coated
silica gel 60 F 254 HPTLC plates from E. Merck, Darmstadt.
[0488] The mobile solvent mixture ratios for chromatographic
investigations are always stated in volume/volume.
[0489] Analysis was carried out by NMR and HPLC-MS.
General Method for the Production of Exemplary Substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl Compounds
##STR00032##
[0491] The synthesis of
2-amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid
tert-butyl ester of the formula VI (PG=tert-butyloxycarbonyl, BOC)
proceeded as described in detail hereinafter.
[0492] In Step 3 the compound VI was acylated by reaction with
carboxylic acid chlorides of the general formula
R.sup.3--(C.dbd.O)--Cl or carboxylic acid bromides of the general
formula R.sup.3--(C.dbd.O)--Br, wherein the respective carboxylic
acid chloride was optionally produced directly from the
corresponding carboxylic acid R.sup.3--(C.dbd.O)--OH.
[0493] To this end, in Step 3 oxalyl chloride (5 equivalents) and a
few drops of DMF were added to a solution of the respective
carboxylic acid (1 equivalent) in CH.sub.2Cl.sub.2 and stirring was
performed for 1 h at RT under nitrogen as inert gas. After removal
of the solvent, the respective carboxylic acid chloride was
dissolved in pyridine. If a carboxylic acid chloride or carboxylic
acid bromide was used, this (1 equivalent) was dissolved directly
in pyridine.
[0494] 2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic
acid tert-butyl ester of the formula VI (0.85 equivalents) was
added to this solution at 0.degree. C. and stirring was performed
for 2 h at 0.degree. C. and then for 2 h at RT under nitrogen as
inert gas. After the addition of aqueous 1 M NaOH and stirring for
20 minutes, CH.sub.2Cl.sub.2 was added and the aqueous phase
extracted with CH.sub.2Cl.sub.2. The combined organic phases were
dried over Na.sub.2SO.sub.4. After filtration and removal of the
solvent, purification was performed by means of column
chromatography and the respective compound of the general formula
VII was obtained.
[0495] In Step 4, trifluoroacetic acid (65 equivalents) was added
to a solution of the Boc-protected compound of the general formula
VII (1 equivalent) in CH.sub.2Cl.sub.2 under nitrogen as inert gas
and stirring was performed for 2 h at RT. After removal of the
solvent, the unprotected compounds of the general formula VIII were
obtained, which were used without further working up in Step 5.
[0496] In Step 5, acylation of the compounds of the general formula
VIII proceeded with carboxylic acid chlorides of the general
formula R.sup.5--C(.dbd.O)--Cl, carboxylic acid bromides of the
general formula R.sup.5--C(.dbd.O)--Br or by reaction with
carboxylic acids of the general formula R.sup.5--C(.dbd.O)--OH.
[0497] For acylation by means of a carboxylic acid in Step 5, the
respective compound VIII was dissolved in CH.sub.2Cl.sub.2 and
DIPEA and the respective carboxylic acid (1 equivalent) were added.
After cooling of the reaction mixture to 0.degree. C., EDCI (1
equivalent) and HOAt (20 mg, 0.15 equivalents) were added. The
reaction mixture was stirred for 1 h at 0.degree. C. and then
overnight at RT. After removal of the solvent, purification
proceeded via preparative HPLC or column chromatography and the
respective compound of the general formula IX was obtained.
[0498] For acylation by means of a carboxylic acid halide, the
respective compound of the general formula VIII (1 equivalent) was
dissolved in CH.sub.2Cl.sub.2, triethylamine (2 equivalents), a
catalytic quantity of DMAP and the respective carboxylic acid
halide (1 equivalent) were added and then stirring was performed
overnight at RT. After removal of the solvent, purification
proceeded via preparative HPLC or column chromatography and the
respective compound of the general formula IX was obtained.
[0499] In Step 5, sulfonylation of the compounds of the general
formula VIII proceeded with sulfonyl chlorides of the general
formula R.sup.6--S(.dbd.O).sub.2--Cl.
[0500] For sulfonylation, the respective compound of the general
formula VIII (1 equivalent) was dissolved in CH.sub.2Cl.sub.2 and
triethylamine (2 equivalents) and the respective sulfonyl chloride
(1 equivalent) were added at 0.degree. C. The reaction mixture was
stirred overnight at RT. After removal of the solvent, purification
proceeded via preparative HPLC or column chromatography and the
respective compound of the general formula IX was obtained.
[0501] Hereinafter, the above-described method for the production
of substituted 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl
compounds is explained in detail with reference to a number of
exemplary compounds:
Production of
2-amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic Acid
tert-butyl Ester
[0502] Dimethoxymethyl-dimethyl-amine (DMA) 35.5 ml (266 mmol) was
added to a solution of 4-oxo-piperidine-1-carboxylic acid
tert-butyl ester 10.59 g (53.14 mmol) in toluene (50 ml) with
stirring and with nitrogen as inert gas and refluxing was performed
for 3.5 h. After removal of the solvent, the product
3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid
tert-butyl ester was obtained, which was used in the subsequent
reaction without further purification.
[0503] Guanidine hydrochloride 7.07 g (74 mmol) was added at
0.degree. C. to a solution of sodium 1.65 g (74 mmol) in absolute
ethanol and stirring was performed for 2 h at RT under nitrogen as
inert gas. 60 ml (60 mmol) of this reaction mixture were added to
the solution of
3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid
tert-butyl ester in 100 ml of absolute ethanol and refluxing was
performed for 5 h. After removal of the solvent and purification by
means of column chromatography,
2-amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid
tert-butyl ester 5.72 g (43% of theoretical) was obtained.
Example 5
3,5-Dichloro-N-[6-(3-trifluoromethyl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,-
3-d]pyrimidin-2-yl]-benzamide
a) Production of
2-(3,5-dichloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-ca-
rboxylic Acid tert-butyl Ester
[0504] Oxalyl chloride 1184 .mu.l (13.8 mmol) and two drops of DMF
were added to a solution of 3,5-dichlorobenzoic acid 527 mg (2.76
mmol) in CH.sub.2Cl.sub.2 and stirring was performed for 1 h at RT
under nitrogen as inert gas. After removal of the solvent, the
3,5-dichlorobenzoyl chloride was dissolved in pyridine (30 ml).
2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid
tert-butyl ester 599 mg (2.39 mmol) was added to this solution at
0.degree. C. and stirring was performed for 2 h at 0.degree. C. and
then for 2 h at RT under nitrogen as inert gas. After the addition
of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes, CH2Cl2 (50
ml) was added and the aqueous phase extracted with CH2Cl2
(3.times.20 ml). The combined organic phases were dried over
Na2SO4. After filtration and removal of the solvent, purification
was performed by means of column chromatography and the product
2-(3,5-dichloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-ca-
rboxylic acid tert-butyl ester 573 mg (1.35 mmol, 57% of
theoretical) was obtained.
b)
3,5-Dichloro-N-[6-(3-trifluoromethyl-benzoyl)-5,6,7,8-tetra-hydropyrido-
[4,3-d]pyrimidin-2-yl]-benzamide
[0505] Trifluoroacetic acid 5.0 ml (65 mmol) was added to a
solution of
2-(3,5-dichloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-ca-
rboxylic acid tert-butyl ester 404 mg (0.954 mmol) in
CH.sub.2Cl.sub.2 (7 ml) under nitrogen as inert gas and stirring
was performed for 2 h at RT. After removal of the solvent, the
intermediate
(3,5-dichloro-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamid-
e trifluoroacetate) was dissolved in CH.sub.2Cl.sub.2 (10 ml) and
DIPEA 340 .mu.l and 3-trifluoromethylbenzoic acid 200 mg (1.05
mmol) were added. After cooling the reaction mixture to 0.degree.
C., EDCI 201 mg (1.05 mmol) and HOAt 20 mg (0.15 mmol) were added.
The reaction mixture was stirred for 1 h at 0.degree. C. and then
overnight at RT. After removal of the solvent, purification was
performed by means of column chromatography and the product
3,5-dichloro-N-[6-(3-trifluoromethyl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4-
,3-d]pyrimidin-2-yl]-benzamide 260 mg (0.53 mmol, 55% of
theoretical) was obtained.
Example 145
N-[6-(3-chloro-thiophene-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2-yl]-2-ethoxy-benzamide
a) Production of
2-(2-ethoxy-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carbox-
ylic Acid tert-butyl Ester
[0506] 2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic
acid tert-butyl ester 528 mg (2.11 mmol) was added at 0.degree. C.
to a solution of 2-ethoxybenzoic acid chloride 390 mg (2.11 mmol)
in pyridine (25 ml) and stirring was performed for 2 h at 0.degree.
C. and then for 72 h at RT under nitrogen as inert gas. After the
addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes,
CH.sub.2Cl.sub.2 (50 ml) was added and the aqueous phase extracted
with CH.sub.2Cl.sub.2 (3.times.20 ml). The combined organic phases
were dried over Na.sub.2SO.sub.4. After filtration and removal of
the solvent, purification was performed by means of column
chromatography and the product
2-(2-ethoxy-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carbox-
ylic acid tert-butyl ester 600 mg (1.51 mmol, 72% of theoretical)
was obtained.
b)
N-[6-(3-chloro-thiophene-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]py-
rimidin-2-yl]-2-ethoxy-benzamide
[0507] Trifluoroacetic acid 3.6 ml (49 mmol) was added to a
solution of
2-(2-ethoxy-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carbox-
ylic acid tert-butyl ester 300 mg (0.753 mmol) in CH.sub.2Cl.sub.2
(10 ml) under nitrogen as inert gas and stirring was performed for
2 h at RT. After removal of the solvent, the intermediate
(2-ethoxy-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide
trifluoroacetate) was dissolved in CH.sub.2Cl.sub.2 (10 ml) and
DIPEA 225 .mu.l and 3-chlorothiophene-2-carboxylic acid 129 mg
(0.791 mmol) were added. After cooling the reaction mixture to
0.degree. C., EDCI 158 mg (0.828 mmol) and HOAt 15 mg (0.11 mmol)
were added. The reaction mixture was stirred for 1 h at 0.degree.
C. and then overnight at RT. After removal of the solvent,
purification was performed by means of column chromatography and
the product
N-[6-(3-chloro-thiophene-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyri-
midin-2-yl]-2-ethoxy-benzamide 170 mg (0.38 mmol, 51% of
theoretical) was obtained.
Example 109
3-Chloro-N-[6-(2-methyl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-
-2-yl]-benzamide
a) Production of
2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carbox-
ylic Acid tert-butyl Ester
[0508] 2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic
acid tert-butyl ester 1202 mg (4.8 mmol) was added at 0.degree. C.
to a solution of 3-chlorobenzoic acid chloride 615 .mu.l (4.8 mmol)
in pyridine (25 ml) and stirring was performed for 2 h at 0.degree.
C. and then overnight at RT under nitrogen as inert gas. After the
addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes,
CH.sub.2Cl.sub.2 (50 ml) was added and the aqueous phase extracted
with CH.sub.2Cl.sub.2 (3.times.20 ml). The combined organic phases
were dried over Na.sub.2SO.sub.4. After filtration and removal of
the solvent, purification was performed by means of column
chromatography and the product
2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine--
6-carboxylic acid tert-butyl ester 790 mg (2.55 mmol, 53% of
theoretical) was obtained.
b) Production of
3-chloro-N-[6-(2-methyl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidi-
n-2-yl]-benzamide
[0509] Trifluoroacetic acid 4.0 ml (54 mmol) was added to a
solution of
2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carbox-
ylic acid tert-butyl ester 307 mg (0.789 mmol) in CH.sub.2Cl.sub.2
(8 ml) under nitrogen as inert gas and stirring was performed for 2
h at RT. After removal of the solvent, the intermediate
(3-chloro-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide
trifluoroacetate) was dissolved in CH.sub.2Cl.sub.2 (10 ml) and
DIPEA 380 .mu.l and 2-methylbenzoic acid 118 mg (0.868 mmol) were
added. After cooling the reaction mixture to 0.degree. C., EDCI 166
mg (0.868 mmol) and HOAt 16 mg (0.12 mmol) were added. The reaction
mixture was stirred for 1 h at 0.degree. C. and then overnight at
RT. After removal of the solvent, purification was performed by
means of column chromatography and the product
3-chloro-N-[6-(2-methyl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidi-
n-2-yl]-benzamide 260 mg (0.64 mmol, 81% of theoretical) was
obtained.
Example 121
4-Ethyl-N-[6-(thiophene-3-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimi-
din-2-yl]-benzamide
a) Production of
2-(4-ethyl-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxy-
lic Acid tert-butyl Ester
[0510] 2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic
acid tert-butyl ester 501 mg (2.0 mmol) was added at 0.degree. C.
to a solution of 4-ethylbenzoic acid chloride 296 .mu.l (2.0 mmol)
in pyridine (25 ml) and stirring was performed for 2 h at 0.degree.
C. and then overnight at RT under nitrogen as inert gas. After the
addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes,
CH.sub.2Cl.sub.2 (50 ml) was added and the aqueous phase extracted
with CH.sub.2Cl.sub.2 (3.times.20 ml). The combined organic phases
were dried over Na.sub.2SO.sub.4. After filtration and removal of
the solvent, purification was performed by means of column
chromatography and the product
2-(4-ethyl-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-
-carboxylic acid tert-butyl ester 640 mg (1.67 mmol, 84% of
theoretical) was obtained.
b) Production of
4-ethyl-N-[6-(thiophene-3-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2-yl]-benzamide
[0511] Trifluoroacetic acid 7.3 ml (96 mmol) was added to a
solution of
2-(4-ethyl-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxy-
lic acid tert-butyl ester 567 mg (1.48 mmol) in CH.sub.2Cl.sub.2
(10 ml) under nitrogen as inert gas and stirring was performed for
1.5 h at RT. After removal of the solvent, the intermediate
(4-ethyl-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide
trifluoroacetate) was dissolved in CH.sub.2Cl.sub.2 (10 ml). After
the addition of triethylamine 1150 .mu.l (8.20 mmol), the solution
was cooled to 0.degree. C. and 3-thiophene sulfonyl chloride 253 mg
(1.39 mmol) was added. The reaction mixture was stirred for 1 h at
0.degree. C. and then overnight at RT. After removal of the
solvent, purification was performed by means of column
chromatography and the product
4-ethyl-N-[6-(thiophene-3-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2-yl]-benzamide 400 mg (0.93 mmol, 63% of theoretical) was
obtained.
Example 125
N-[6-(3-bromo-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-
-yl]-3-chloro-benzamide
a) Production of
2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carbox-
ylic Acid tert-butyl Ester
[0512] 2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic
acid tert-butyl ester 1202 mg (4.8 mmol) was added at 0.degree. C.
to a solution of 3-chlorobenzoic acid chloride 615 .mu.l (4.8 mmol)
in pyridine (25 ml) and stirring was performed for 2 h at 0.degree.
C. and then overnight at RT under nitrogen as inert gas. After the
addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes,
CH.sub.2Cl.sub.2 (50 ml) was added and the aqueous phase extracted
with CH.sub.2Cl.sub.2 (3.times.20 ml). The combined organic phases
were dried over Na.sub.2SO.sub.4. After filtration and removal of
the solvent, purification was performed by means of column
chromatography and the product
2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine--
6-carboxylic acid tert-butyl ester 790 mg (2.55 mmol, 53% of
theoretical) was obtained.
b) Production of
N-[6-(3-bromo-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin--
2-yl]-3-chloro-benzamide
[0513] Trifluoroacetic acid 6.2 ml (81 mmol) was added to a
solution of
2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carbox-
ylic acid tert-butyl ester 487 mg (1.25 mmol) in CH.sub.2Cl.sub.2
(8 ml) under nitrogen as inert gas and stirring was performed for
1.5 h at RT. After removal of the solvent, the intermediate
(3-chloro-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide
trifluoroacetate) was dissolved in CH.sub.2Cl.sub.2 (15 ml). After
the addition of triethylamine 820 .mu.l (5.84 mmol), the solution
was cooled to 0.degree. C. and 3-bromo benzenesulfonyl chloride 311
mg (1.37 mmol) was added. The reaction mixture was stirred for 1 h
at 0.degree. C. and then overnight at RT. After removal of the
solvent, purification was performed by means of column
chromatography and the product
N-[6-(3-bromo-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin--
2-yl]-3-chloro-benzamide 525 mg (81% of theoretical) was
obtained.
General Method for the Production of Substituted
5,6,7,8-tetrahydro-quinazolin-2-yl Compounds
##STR00033##
[0515] The synthesis of 1,4-dioxa-spiro[4.5]dec-8-ylamine of the
formula C proceeded as described in detail hereinafter.
[0516] Sulfonylation of 1,4-dioxa-spiro[4.5]dec-8-ylamine of the
formula C proceeded by means of sulfonyl chlorides of the general
formula R.sup.6--S(.dbd.O).sub.2--Cl.
[0517] For sulfonylation, K.sub.2CO.sub.3 (5 equivalents) was added
to a solution of 1,4-dioxa-spiro[4.5]dec-8-ylamine of the formula C
(1 equivalent) in CH.sub.3CN. A solution of the respective sulfonyl
chloride (1 equivalent) in CH.sub.3CN was added and stirring was
performed at RT for 2 h under nitrogen as inert gas. The reaction
mixture was filtered and the residue washed with CH.sub.2Cl.sub.2.
After purification by column chromatography, the respective
compound of the general formula D was obtained.
[0518] Alternatively, for sulfonylation, triethylamine (2
equivalents) and the respective sulfonyl chloride (1 equivalent)
were added at 0.degree. C. to a solution of
1,4-dioxa-spiro[4.5]dec-8-ylamine of the formula C (1 equivalent)
in CH.sub.2Cl.sub.2. The reaction mixture was stirred overnight at
RT. The respective compound of the general formula D was obtained
after removal of the solvent and purification by means of
preparative HPLC or column chromatography.
[0519] Acylation of the compounds C proceeded with carboxylic acid
chlorides of the general formula R.sup.5--C(.dbd.O)--Cl, carboxylic
acid bromides of the general formula R.sup.5--C(.dbd.O)--Br or by
reaction with carboxylic acids of the general formula
R.sup.5--C(.dbd.O)--OH.
[0520] For acylation by means of a carboxylic acid, the compound C
(1 equivalent) was dissolved in CH.sub.2Cl.sub.2 and DIPEA and the
respective carboxylic acid (1 equivalent) were added. After cooling
of the reaction mixture to 0.degree. C., EDCI (1 equivalent) and
HOAt (0.15 equivalents) were added. The reaction mixture was
stirred for 1 h at 0.degree. C. and then overnight at RT. After
removal of the solvent, the respective compound of the formula D
was purified by means of column chromatography.
[0521] For acylation by means of a carboxylic acid halide, the
respective compound of the general formula D (1 equivalent) was
dissolved in CH.sub.2Cl.sub.2, triethylamine (2 equivalents), a
catalytic quantity of DMAP and the respective carboxylic acid
halide (1 equivalent) were added and then stirring was performed
overnight at RT. After removal of the solvent and purification by
means of column chromatography, the respective compound of the
general formula D was obtained.
[0522] Reaction to yield the compounds of the formulae D to I
proceeded as described in detail hereinafter.
[0523] Reaction of the respective compound I to yield the compounds
J proceeded by acylation with carboxylic acid chlorides of the
general formula R.sup.3--(C.dbd.O)--Cl, carboxylic acid bromides of
the general formula R.sup.3--(C.dbd.O)--Br or by reaction with
carboxylic acids of the general formula R.sup.3--(C.dbd.O)--OH.
[0524] For acylation by means of a carboxylic acid, the respective
compound I (1 equivalent) was dissolved in CH.sub.2Cl.sub.2 and
DIPEA and the respective carboxylic acid (1 equivalent) were added.
After cooling of the reaction mixture to 0.degree. C., EDCI (1
equivalent) and HOAt (0.15 equivalents) were added. The reaction
mixture was stirred for 1 h at 0.degree. C. and then overnight at
RT. After removal of the solvent, the respective compound of the
general formula J was purified by means of column
chromatography.
[0525] For acylation by means of a carboxylic acid halide, the
respective compound of the general formula I (1 equivalent) was
dissolved in CH.sub.2Cl.sub.2, triethylamine (2 equivalents), a
catalytic quantity of DMAP and the respective carboxylic acid
halide (1 equivalent) were added and then stirring was performed
overnight at RT. After removal of the solvent and purification by
means of column chromatography, the respective compound of the
general formula J was obtained.
[0526] Final elimination of the BOC protective group proceeded as
described in detail hereinafter.
Example 180
Thiophene-2-carboxylic acid
[6-(2,5-dichloro-thiophene-3-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-
-2-yl]-amide
a) Production of benzyl-(1,4-dioxa-spiro[4.5]dec-8-yl)-amine
[0527] Na(OAc).sub.3BH 2.03 g (9.6 mmol) was added to a solution of
1,4-dioxa-spiro[4.5]decan-8-one 1.0 g (6.4 mmol) and benzylamine
0.69 g (6.4 mmol) in CH.sub.2Cl.sub.2 (20 ml) under nitrogen as
inert gas and stirring was performed for 2 h at RT. After the
addition of CH.sub.2Cl.sub.2 (80 ml), the organic phase was washed
with aqueous saturated NaHCO.sub.3 solution. After drying of the
separated organic phases over Na.sub.2SO.sub.4 and filtration, the
solvent was removed by distillation and the product
benzyl-(1,4-dioxa-spiro[4.5]dec-8-yl)-amine 1.6 g (100% of
theoretical) was obtained.
b) Production of 1,4-dioxa-spiro[4.5]dec-8-ylamine
[0528] Benzyl-(1,4-dioxa-spiro[4.5]dec-8-yl)-amine (6.4 mmol) was
dissolved in EtOH (10 ml) and hydrogenated under nitrogen with
Pd(C) 340 mg (0.32 mmol) with stirring overnight at RT. The
reaction mixture was filtered out over Celite and washed with
CH.sub.2Cl.sub.2. After removal of the solvent, the product
1,4-dioxa-spiro[4.5]dec-8-ylamine 824 mg (82% of theoretical) was
obtained.
c) Production of 2,5-dichloro-thiophene-3-sulfonic acid
(1,4-dioxa-spiro[4.5]dec-8-yl)-amide
[0529] K.sub.2CO.sub.3 2.51 g (18.16 mmol) was added to a solution
of 1,4-dioxa-spiro[4.5]dec-8-ylamine 571 mg (3.63 mmol) in
CH.sub.3CN (10 ml). A solution of
3,5-dichlorothiophene-3-sulfonylchloride (914 mg, 3.63 mmol) in
CH.sub.3CN (10 ml) was added and stirring was performed at RT for
100 min under nitrogen as inert gas. The reaction mixture was
filtered and the residue washed with CH.sub.2Cl.sub.2. After
purification by column chromatography, the
2,5-dichloro-thiophene-3-sulfonic acid
(1,4-dioxa-spiro[4.5]dec-8-yl)-amide 914 mg (68% of theoretical)
was obtained.
d) Production of 2,5-dichloro-thiophene-3-sulfonic Acid
(4-oxo-cyclohexyl)-amide
[0530] p-TosOH.times.H.sub.2O 4 g (21.0 mmol) was added to a
solution of 2,5-dichloro-thiophene-3-sulfonic
acid-(1,4-dioxa-spiro[4.5]dec-8-yl)-amide 894 mg (2.40 mmol) in
acetone (10 ml) and water (1 ml) and stirring was performed for 6 h
at RT. After addition of aqueous 1M NaOH (100 ml) and aqueous
saturated NaCl solution (100 ml), extraction was performed with
CH.sub.2Cl.sub.2 (3.times.200 ml). After separation of the organic
phases, drying over Na.sub.2SO.sub.4 and filtration, the solvent
was removed by distillation. After purification by means of column
chromatography, the product 2,5-dichloro-thiophene-3-sulfonic acid
(4-oxo-cyclohexyl)-amide 634 mg (80% of theoretical) was
obtained.
[0531] e) Production of N-Boc-Protected
2,5-dichloro-thiophene-3-sulfonic Acid (4-oxo-cyclohexyl)-amide
[0532] Et.sub.3N 179 mg (1.77 mmol) and DMAP 29 mg (0.24 mmol) were
added to a solution of 2,5-dichloro-thiophene-3-sulfonic acid
(4-oxo-cyclohexyl)-amide 388 mg (1.18 mmol) in CH.sub.2Cl.sub.2 (10
ml). After cooling to 0.degree. C., Boc.sub.2O 386 mg (1.77 mmol)
was added and stirring was performed for 2 h under nitrogen as
inert gas. After removal of the solvent and purification by means
of column chromatography, the product N-Boc-protected
2,5-dichloro-thiophene-3-sulfonic acid (4-oxo-cyclohexyl)-amide 419
mg (83% of theoretical) was obtained.
f) Production of 2,5-dichloro-thiophene-3-sulfonic Acid
(2-amino-5,6,7,8-tetrahydro-quinazoline-6-yl)-amide
[0533] A reaction solution of N-Boc-protected
2,5-dichloro-thiophene-3-sulfonic acid (4-oxo-cyclohexyl)-amide 383
mg (0.89 mmol) and dimethoxymethyl-dimethyl-amine 533 mg (4.47
mmol) in toluene (10 ml) was refluxed for 4 h with stirring and
nitrogen as inert gas. After removal of the solvent, the crude
product N-Boc-protected 2,5-dichloro-thiophene-3-sulfonic acid
(3-dimethylamino-methylene-4-oxo-cyclohexyl)-amide was obtained,
which was used without further purification in the next step.
[0534] Guanidine hydrochloride 245 mg (2.56 mmol) was added to a
solution of sodium 59 mg (2.6 mmol) in absolute ethanol (26 ml) and
stirring was performed for 30 min at RT under nitrogen as inert
gas. 9 ml (60 mmol) of this reaction mixture was added to
N-Boc-protected 2,5-dichloro-thiophene-3-sulfonic acid
(3-dimethylaminomethylene-4-oxo-cyclohexyl)-amide (0.89 mmol) and
refluxing was performed for 8 h under nitrogen as inert gas. After
the addition of CH.sub.2Cl.sub.2 (5 ml) and TFA (5 ml) and stirring
for 1 h at RT and removal of the solvent, purification was
performed by means of column chromatography and the product
2,5-dichloro-thiophene-3-sulfonic acid
(2-amino-5,6,7,8-tetrahydro-quinazolin-6-yl)-amide 133 mg (39% of
theoretical) was obtained.
g) Production of N-Boc-Protected 2,5-dichloro-thiophene-3-sulfonic
Acid (2-amino-5,6,7,8-tetrahydro-quinazolin-6-yl)-amide
[0535] Boc.sub.2O 41 mg (0.188 mmol) and DMAP 2 mg (0.016 mmol) was
added at 0.degree. C. to a solution of
2,5-dichloro-thiophene-3-sulfonic acid
(2-amino-5,6,7,8-tetrahydro-quinazolin-6-yl)-amide 63 mg (0.17
mmol) in CH.sub.2Cl.sub.2 (10 ml) and stirring was performed under
nitrogen as inert gas for 3.5 h at 0.degree. C. After the addition
of Boc.sub.2O 20 mg and stirring for 30 min at 0.degree. C., the
solvent was removed by distillation. After purification by means of
column chromatography, the product N-Boc-protected
2,5-dichloro-thiophene-3-sulfonic acid
(2-amino-5,6,7,8-tetrahydro-quinazolin-6-yl)-amide 58 mg (73% of
theoretical) was obtained.
h) Production of N-Boc-Protected thiophene-2-carboxylic Acid
[6-(2,5-dichloro-thiophene-3-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-
-2-yl]-amide
[0536] Thiophene-2-carboxylic acid chloride 25 mg (0.17 mmol)
dissolved in (1 ml) was added at 0.degree. C. to a solution of
N-Boc-protected 2,5-dichloro-thiophene-3-sulfonic acid
(2-amino-5,6,7,8-tetrahydro-quinazolin-6-yl)-amide 54 mg (0.11
mmol) in CH.sub.2Cl.sub.2 (4 ml) and pyridine (5 ml) and stirring
was performed for 1 h at 0.degree. C. and overnight at RT and under
nitrogen as inert gas. After removal of the solvent and
purification by means of column chromatography, the product
N-Boc-protected thiophene-2-carboxylic acid
[6-(2,5-dichloro-thiophene-3-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-
-2-yl]-amide 21 mg (32% of theoretical) was obtained.
i) Production of thiophene-2-carboxylic Acid
[6-(2,5-dichloro-thiophene-3-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-
-2-yl]-amide
[0537] TFA (2 ml) was added to a solution of N-Boc-protected
thiophene-2-carboxylic acid
[6-(2,5-dichloro-thiophene-3-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-
-2-yl]-amide 21 mg (36 .mu.mol) in CH.sub.2Cl.sub.2 (1 ml) and
stirring was performed for 2 h at RT. After removal of the solvent
and purification by means of column chromatography, the product
thiophene-2-carboxylic acid
[6-(2,5-dichloro-thiophene-3-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-
-2-yl]-amide 12 mg (69% of theoretical) was obtained.
[0538] The production, not described in detail above, of the other
compounds according to the Examples stated below also proceeded in
accordance with the above-stated production methods, wherein the
educts used in each case are known to the person skilled in the art
on the basis of these methods.
TABLE-US-00002 Example Compound 1
3-fluoro-N-[6-(4-fluoro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimid-
in-2- yl]-benzamide 2
3,5-dichloro-N-[6-(3-fluoro-4-methoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 3
4-tert-butyl-N-(6-hexanoyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-y-
l)- benzamide 4
N-(6-acetyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-3,4-dichloro-
- benzamide 5
3,5-dichloro-N-[6-(3-trifluoromethyl-benzoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 6
3-chloro-N-[6-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-5,6,7,8-tetrah-
ydro- pyrido[4,3-d]pyrimidin-2-yl]-benzamide 7
N-[6-(2-ethoxy-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]--
3- fluoro-benzamide 8
3-chloro-N-[6-(3-phenyl-propionyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin- 2-yl]-benzamide 9
4-tert-butyl-N-[6-(isoxazole-5-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 10
N-[6-(2-benzylsulfanyl-acetyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidi-
n-2-yl]- 2-methoxy-benzamide 11 thiophene-2-carboxylic acid
{6-[2-(4-chloro-phenyl)-2-methyl-propionyl]-
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl}-amide 12
N-(6-benzoyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-3-methyl-
benzamide 13
N-[6-(2,3-dihydro-benzofuran-5-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-2-fluoro-benzamide 14
thiophene-2-carboxylic acid
[6-(3,4,5-trimethoxy-benzoylamino)-5,6,7,8-
tetrahydro-quinazolin-2-yl]-amide 15 naphthalene-1-carboxylic acid
[6-(3-methyl-5-phenyl-isoxazole-4-carbonyl)-
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-amide 16
3-chloro-N-{6-[2-(5-methyl-2-phenyl-thiazol-4-yl)-acetyl]-5,6,7,8-tetra-
hydro- pyrido[4,3-d]pyrimidin-2-yl}-benzamide 17
N-[6-(4-chloro-2,5-dimethyl-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-2-trifluoromethyl-benzamide 18
N-[6-(1-benzenesulfonyl-1H-indole-2-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-3-methoxy-benzamide 20
N-[6-(5-methyl-1-phenyl-1H-pyrazole-4-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-2-trifluoromethyl-benzamide 21
N-[6-(3-chloro-2-methyl-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-(d)]pyrimidin-2-yl]-3-fluoro-benzamide 22
3,5-dichloro-N-[6-(3,5-dimethyl-isoxazole-4-carbonyl)-5,6,7,8-tetrahydr-
o- pyrido[4,3-d]pyrimidin-2-yl]-benzamide 23 thiophene-2-carboxylic
acid [6-(4-trifluoromethoxy-benzenesulfonylamino)-
5,6,7,8-tetrahydro-quinazolin-2-yl]-amide 25
N-[6-(furan-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-
-3- methoxy-benzamide 26
N-{6-[4-(2,3-dihydro-indol-1-yl)-4-oxo-butyryl]-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl}-3-methyl-benzamide 27
N-{6-[2-(4-methyl-cyclohexyl)-acetyl]-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl}-2-trifluoromethyl-benzamide 28
3,4-difluoro-N-[6-(6-phenoxy-pyridine-3-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 29
4-tert-butyl-N-[6-(2-phenyl-thiazole-4-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 30
3,5-dichloro-N-[6-(2-trifluoromethyl-benzenesulfonyl)-5,6,7,8-tetrahydr-
o- pyrido[4,3-d]pyrimidin-2-yl]-benzamide 31 thiophene-2-carboxylic
acid [6-(3-bromo-benzenesulfonylamino)-5,6,7,8-
tetrahydro-quinazolin-2-yl]-amide 32
N-[6-(2-chloro-pyridine-4-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyr-
imidin- 2-yl]-3-methoxy-benzamide 33
4-fluoro-N-[6-(2-methanesulfonyl-benzenesulfonylamino)-5,6,7,8-tetrahyd-
ro- quinazolin-2-yl]-benzamide 35
N-(6-dimethylsulfamoyl-5,6,7,8-tetrahydro-pyrido[4,3-(d)]pyrimidin-2-yl-
)-3- fluoro-benzamide 36
3-fluoro-N-{6-[2-(4-trifluoromethyl-phenyl)-acetyl]-5,6,7,8-tetrahydro-
pyrido[4,3-(d)]pyrimidin-2-yl}-benzamide 37
N-{6-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetyl]-5,6,7,8-tetrahydr-
o- pyrido[4,3-(d)]pyrimidin-2-yl}-2-trifluoromethyl-benzamide 38
thiophene-2-carboxylic acid
{6-[4-(4-chloro-2-methyl-phenoxy)-butyrylamino]-
5,6,7,8-tetrahydro-quinazolin-2-yl}-amide 39
N-[6-(butane-1-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-(d)]pyrimidin-2--
yl]-3- fluoro-benzamide 40
2-methoxy-N-[6-(2-propyl-pentanoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 41
N-[6-(4,5-dichloro-thiophene-2-sulfonylamino)-5,6,7,8-tetrahydro-quinaz-
olin- 2-yl]-4-fluoro-benzamide 42
4-chloro-N-[6-(2-trifluoromethyl-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 43 thiophene-2-carboxylic
acid [6-(4-methoxy-benzenesulfonylamino)-5,6,7,8-
tetrahydro-quinazolin-2-yl]-amide 44
5-[2-(3,4-difluoro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-(d)]pyrimidi-
n-6- yl]-5-oxo-valeric acid methyl ester 45
N-[6-(benzo[b]thiophene-3-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-4-chloro-benzamide 46
N-[6-(5-bromo-2-methoxy-benzenesulfonylamino)-5,6,7,8-tetrahydro-
quinazolin-2-yl]-4-fluoro-benzamide 47
4-fluoro-N-[6-(4-fluoro-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinaz-
olin- 2-yl]-benzamide 48
N-{6-[2-(1H-indol-3-yl)-2-oxo-acetyl]-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl}-2-trifluoromethyl-benzamide 49
5-tert-butyl-2-methyl-furan-3-carboxylic acid
{2-[(thiophene-2-carbonyl)-
amino]-5,6,7,8-tetrahydro-quinazolin-6-yl}-amide 50
N-[6-(2,5-dimethoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-3-methoxy-benzamide 51 benzoic acid
2-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-
quinazolin-6-ylcarbamoyl}-benzyl ester 52
3,4-difluoro-N-(6-hexanoyl-5,6,7,8-tetrahydro-pyrido[4,3-(d)]pyrimidin--
2-yl)- benzamide 53
4-ethyl-N-[6-(tetrahydro-furan-2-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 54
N-[6-(2-chloro-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimid-
in-2- yl]-3-fluoro-benzamide 55
4-tert-butyl-N-[6-(5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl)-5,6,7,-
8- tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide 56
3-methoxy-N-[6-(4-methoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 57
{2-[2-(3,4-difluoro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-
-6- yl]-2-oxo-1-phenyl-ethyl}-carbamic acid benzyl ester 58
5-phenyl-oxazole-4-carboxylic acid
{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-
tetrahydro-quinazolin-6-yl}-amide 59
4-chloro-N-(6-dimethylsulfamoyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimid-
in-2- yl)-benzamide 60
4-tert-butyl-N-[6-(2-fluoro-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 61
4-chloro-N-[6-(3-cyclopentyl-propionyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 62
4-chloro-N-[6-(4-phenyl-butyryl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimi-
din-2- yl]-benzamide 63
4-tert-butyl-N-[6-(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-5,6-
,7,8- tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide 64
2-chloro-N-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazo-
lin-6- yl}-isonicotinamide 66
N-[6-(5-chloro-thiophene-2-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-3-fluoro-benzamide 67
N-[6-(4-diethylamino-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-
-2- yl]-3-methoxy-benzamide 68
N-[6-(2,4-dimethyl-thiazole-5-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-3-methyl-benzamide 69
4-chloro-N-[6-naphthalene-2-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 70
N-[6-(2,4-difluoro-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyr-
imidin- 2-yl]-2-methoxy-benzamide 71
3,4-dichloro-N-[6-(4-chloro-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 72
3,4-difluoro-N-[6-(thiophene-2-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 74
4-ethyl-N-[6-(4-pyrazol-1-yl-benzoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 75
N-[6-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-ylmethanesulfonylamino)-
5,6,7,8-tetrahydro-quinazolin-2-yl]-butyramide 76
5-oxo-5-phenyl-valeric acid
(2-butyrylamino-5,6,7,8-tetrahydro-quinazolin-6- yl)-amide 77
3-[2-(4-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl-
]-3- oxo-propionic acid methyl ester 78
N-{6-[5-(4-chloro-phenyl)-2-methyl-furan-3-carbonyl]-5,6,7,8-tetrahydro-
- pyrido[4,3-d]pyrimidin-2-yl}-2-methoxy-benzamide 79
4-chloro-N-[6-(2,4-dimethyl-thiazole-5-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 80
N-[6-(2,3-difluoro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-
-yl]-3- methoxy-benzamide 81
4-chloro-N-{6-[2-(2-methoxy-ethoxy)-acetyl]-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl}-benzamide 82
2-[2-(2-ethoxy-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-
sulfonyl]-benzoic acid methyl ester 83
4-tert-butyl-N-[6-(4-nitro-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 86
N-[6-(5-chloro-thiophene-2-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-2-methoxy-benzamide 87
4-fluoro-N-[6-(furan-2-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimi-
din-2- yl]-benzamide 88
4-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-
ylcarbamoyl}-piperidine-1-carboxylic acid tert-butyl ester 89
1-(4-chloro-phenyl)-cyclopropanecarboxylic acid
(2-butyrylamino-5,6,7,8- tetrahydro-quinazolin-6-yl)-amide 90
N-(6-ethanesulfonyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-3-
methoxy-benzamide 91 5-methyl-thiophene-2-carboxylic acid
(2-butyrylamino-5,6,7,8-tetrahydro- quinazolin-6-yl)-amide 92
4-tert-butyl-N-[6-(4-methyl-3-nitro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 94
4-fluoro-N-[6-(3-phenyl-propionylamino)-5,6,7,8-tetrahydro-quinazolin-2-
-yl]- benzamide 95
3,4-dichloro-N-[6-(2,4,6-trimethyl-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 96
N-[6-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine-7-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-nicotinamide 97
thiophene-2-carboxylic acid
[6-(3,5-difluoro-benzoylamino)-5,6,7,8-tetrahydro-
quinazolin-2-yl]-amide 98
N-[6-(2,4-difluoro-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazolin--
2-yl]- butyramide 99 thiophene-2-carboxylic acid
[6-(2,3,5,6-tetramethyl-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-amide 101
N-[6-(3,4-dichloro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin--
2-yl]-4- ethyl-benzamide 102
N-[6-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-ylmethanesulfonyl)-5,6,7-
,8- tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-3-fluoro-benzamide 103
N-[6-(6-fluoro-4H-benzo[1,3]dioxin-8-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-2-trifluoromethyl-benzamide 104
[5-(2-butyrylamino-5,6,7,8-tetrahydro-quinazolin-6-ylcarbamoyl)-pentyl-
]- carbamic acid benzyl ester 105
2-ethoxy-N-[6-(4-oxo-pentanoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimi-
din-2- yl]-benzamide
106 naphthalene-1-carboxylic acid
[6-(propane-1-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-amide 107
N-[6-(5-fluoro-2-methyl-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-4-methyl-benzamide 109
3-chloro-N-[6-(2-methyl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2- yl]-benzamide 110 thiophene-2-carboxylic acid
[6-(3-chloro-benzo[b]thiophene-2-carbonyl)-
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-amide 112
thiophene-2-carboxylic acid
[6-(2-cyclopentyl-acetylamino)-5,6,7,8-tetrahydro-
quinazolin-2-yl]-amide 113
N-[6-(3,4-dichloro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin--
2-yl]-2- fluoro-benzamide 114
N-[6-(2-chloro-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimi-
din-2- yl]-4-ethyl-benzamide 115 thiophene-2-carboxylic acid
[6-(4-bromo-3-methyl-benzoylamino)-5,6,7,8-
tetrahydro-quinazolin-2-yl]-amide 116
3-methyl-N-[6-(toluene-3-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyr-
imidin- 2-yl]-benzamide 117 naphthalene-1-carboxylic acid
[6-(5-chloro-thiophene-2-sulfonyl)-5,6,7,8-
tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-amide 118
N-(2-butyrylamino-5,6,7,8-tetrahydro-quinazolin-6-yl)-2,6-difluoro-ben-
zamide 119
3-chloro-N-[6-(3,4-dimethoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 120
N-[6-(3-chloro-benzo[b]thiophene-2-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 121
4-ethyl-N-[6-(thiophene-3-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]py-
rimidin- 2-yl]-benzamide 123
2-ethoxy-N-[6-(2-ethylsulfanyl-pyridine-3-carbonyl)-5,6,7,8-tetrahydro-
- pyrido[4,3-d]pyrimidin-2-yl]-benzamide 124
3-[2-(3-chloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-y-
l]-3- oxo-propionic acid ethyl ester 125
N-[6-(3-bromo-benzenesulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimid-
in-2- yl]-3-chloro-benzamide 126
3,4-dichloro-N-{6-[2-(4-chloro-phenyl)-acetyl]-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl}-benzamide 127
3-chloro-N-[6-(2-chloro-6-fluoro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 128
4-fluoro-N-(6-hexanoylamino-5,6,7,8-tetrahydro-quinazolin-2-yl)-benzam-
ide 129
N-[6-(5-bromo-2-methoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-3-methoxy-benzamide 132
N-[6-(3-cyclopentyl-propionyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimid-
in-2- yl]-isonicotinamide 133 5-benzyl-furan-2-carboxylic acid
(2-butyrylamino-5,6,7,8-tetrahydro- quinazolin-6-yl)-amide 134
3,4-dichloro-N-[6-(4-trifluoromethoxy-benzenesulfonyl)-5,6,7,8-tetrahy-
dro- pyrido[4,3-d]pyrimidin-2-yl]-benzamide 135
[(2-butyrylamino-5,6,7,8-tetrahydro-quinazolin-6-ylcarbamoyl)-phenyl-
methyl]-carbamic acid benzyl ester 136
N-[6-(3,4-dimethoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-4-fluoro-benzamide 137
2-fluoro-N-[6-(2-methyl-5-phenyl-furan-3-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 138 thiophene-2-carboxylic
acid (6-pent-4-enoylamino-5,6,7,8-tetrahydro-
quinazolin-2-yl)-amide 139
(2-methyl-1-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quina-
zolin- 6-ylcarbamoyl}-propyl)-carbamic acid 9H-fluoren-9-ylmethyl
ester 140
(5-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-
ylcarbamoyl}-pentyl)-carbamic acid tert-butyl ester 141
3-fluoro-N-[6-(1,2,3,4-tetrahydro-naphthalene-2-carbonyl)-5,6,7,8-tetr-
ahydro- pyrido[4,3-d]pyrimidin-2-yl]-benzamide 142
4-chloro-N-{6-[2-(2,5-dioxo-imidazolidin-4-yl)-acetyl]-5,6,7,8-tetrahy-
dro- pyrido[4,3-d]pyrimidin-2-yl}-benzamide 143
3-fluoro-N-[6-(toluene-4-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyr-
imidin-2- yl]-benzamide 144
3,5-dichloro-N-[6-(4-thiophen-2-yl-benzoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 145
N-[6-(3-chloro-thiophene-2-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-2-ethoxy-benzamide 146
N-[6-(toluene-3-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-
butyramide 147 thiophene-2-carboxylic acid
{6-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-
isoquinoline-7-sulfonylamino]-5,6,7,8-tetrahydro-quinazolin-2-yl}-amide
148
4-methyl-N-[6-(4-trifluoromethylsulfanyl-benzoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 149
(2-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-
ylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester 150
2-fluoro-N-[6-(2-methyl-5-nitro-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 151
N-[6-(4-methoxy-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2--
yl]- butyramide 152
4-chloro-N-[6-(2,4-difluoro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 153
4-methyl-N-(6-pent-4-enoyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-
-yl)- benzamide 154 naphthalene-1-carboxylic acid
[6-(3-fluoro-4-methyl-benzoyl)-5,6,7,8-
tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-amide 155
N-{6-[2-(4-trifluoromethyl-phenyl)-acetyl]-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl}-benzamide 156
N-[6-(3,4-dichloro-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin--
2-yl]- nicotinamide 157
4-ethyl-N-{6-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoli-
ne-7-
sulfonyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl}-benzamide
158
2-methoxy-N-[6-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-5,6,7,8-
tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide 159
4-ethyl-N-[6-(2-methoxy-acetyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimi-
din-2- yl]-benzamide 160
4-fluoro-N-[6-(propane-1-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin--
2-yl]- benzamide 162
N-[6-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-ylmethanesulfonylamino)-
5,6,7,8-tetrahydro-quinazolin-2-yl]-butyramide 163
N-{6-[2-(2,5-dimethyl-phenyl)-acetylamino]-5,6,7,8-tetrahydro-quinazol-
in-2- yl}-4-fluoro-benzamide 165 thiophene-2-carboxylic acid
(6-phenylmethanesulfonylamino-5,6,7,8-
tetrahydro-quinazolin-2-yl)-amide 166
N-[6-(3,4-dimethoxy-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazoli-
n-2- yl]-butyramide 167
N-{6-[4-(1,1-dimethyl-propyl)-benzenesulfonylamino]-5,6,7,8-tetrahydro-
- quinazolin-2-yl}-butyramide 168
N-(2-butyrylamino-5,6,7,8-tetrahydro-quinazolin-6-yl)-3-(3-trifluorome-
thyl- phenyl)-acrylamide 169
N-[6-(butane-1-sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-4-fl-
uoro- benzamide 170 naphthalene-1-carboxylic acid
(6-acetyl-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidin-2-yl)-amide
171
3,5-dichloro-N-[6-(3-diethylcarbamoyl-propionyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 172
4-ethyl-N-[6-(4-methoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 173
4-ethyl-N-[6-(quinoline-6-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]py-
rimidin- 2-yl]-benzamide 174
N-[6-(2-cyclopropyl-acetyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin--
2-yl]-2- fluoro-benzamide 175
N-[6-(2H-chromene-3-carbonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidi-
n-2- yl]-3,4-difluoro-benzamide 176
N-{6-[2-(4-chloro-phenyl)-propionyl]-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl}-benzamide 177 thiophene-2-carboxylic
acid [6-(2-naphthalen-1-yl-acetylamino)-5,6,7,8-
tetrahydro-quinazolin-2-yl]-amide 178
4-fluoro-N-(6-phenylmethanesulfonyl-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl)-benzamide 180 thiophene-2-carboxylic
acid [6-(2,5-dichloro-thiophene-3-sulfonylamino)-
5,6,7,8-tetrahydro-quinazolin-2-yl]-amide 181
{5-[2-(4-fluoro-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-6-ylcarbam-
oyl]- pentyl}-carbamic acid benzyl ester 182
N-[6-(2,5-dimethyl-2H-pyrazole-3-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-4-ethyl-benzamide 183
naphthalene-1-carboxylic acid
[6-(3-fluoro-benzoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-amide 184
N-[6-(benzo[b]thiophene-3-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-4-tert-butyl-benzamide 185
4-fluoro-N-[6-(4-methoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 186
4-tert-butyl-N-[6-(2,3-dihydro-benzo[1,4]dioxin-6-sulfonyl)-5,6,7,8-te-
trahydro- pyrido[4,3-d]pyrimidin-2-yl]-benzamide 187
3-chloro-N-{6-[2-(2,6-dichloro-phenyl)-acetyl]-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl}-benzamide 188 thiophene-2-carboxylic
acid [6-(2,3-dihydro-benzo[1,4]dioxin-6-
sulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2-yl]-amide 189
N-{6-[2-(3-chloro-phenoxy)-acetyl]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyr-
imidin- 2-yl}-4-methyl-benzamide 190
N-[6-(5-phenyl-pentanoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2--
yl]- benzamide 191
4-ethyl-N-[6-(2-ethyl-butyryl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimid-
in-2-yl]- benzamide 192
3,5-dichloro-N-[6-(4-trifluoromethoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 193 naphthalene-1-carboxylic
acid [6-(4-methyl-octanoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-amide 194
4-[2-(4-fluoro-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-6-ylcarbamo-
yl]- piperidine-1-carboxylic acid tert-butyl ester 195
N-[6-(2-benzyloxy-acetyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2--
yl]-2- methoxy-benzamide 196
N-[6-(2-trifluoromethyl-benzenesulfonylamino)-5,6,7,8-tetrahydro-quina-
zolin- 2-yl]-butyramide 197
N-[2-(4-fluoro-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-6-yl]-2-met-
hyl-6- trifluoromethyl-nicotinamide 198
N-[6-(3-cyano-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-
-2- trifluoromethyl-benzamide 199
3-methoxy-N-[6-(3-trifluoromethoxy-benzoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 200
N-(6-butyryl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-2-fluoro-
benzamide 201
N-(6-benzenesulfonylamino-5,6,7,8-tetrahydro-quinazolin-2-yl)-4-fluoro-
- benzamide 202
N-[6-(5-chloro-thiophene-2-sulfonylamino)-5,6,7,8-tetrahydro-quinazoli-
n-2- yl]-4-fluoro-benzamide 203 naphthalene-1-carboxylic acid
(6-hexanoyl-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidin-2-yl)-amide
204
N-(6-propionyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-2-
trifluoromethyl-benzamide 205
N-[6-(2-ethyl-butyryl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-
-4- methyl-benzamide 206
2-fluoro-N-[6-(3-trifluoromethyl-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 207
5-benzyl-furan-2-carboxylic acid
{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-
tetrahydro-quinazolin-6-yl}-amide 208 thiophene-2-carboxylic acid
{6-[2-(2,5-dimethyl-phenyl)-acetylamino]-5,6,7,8-
tetrahydro-quinazolin-2-yl}-amide 210
4-fluoro-N-[6-(propane-1-sulfonyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyr-
imidin- 2-yl]-benzamide 211
2-[2-(3-fluoro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-
sulfonyl]-benzoic acid methyl ester 212
3,5-dichloro-N-[6-(5-[1,2]dithiolan-3-yl-pentanoyl)-5,6,7,8-tetrahydro-
- pyrido[4,3-d]pyrimidin-2-yl]-benzamide 213 thiophene-2-carboxylic
acid [6-(2-phenoxy-butyrylamino)-5,6,7,8-tetrahydro-
quinazolin-2-yl]-amide 214 thiophene-2-carboxylic acid
{6-[2-(4-methoxyphenyl)-acetylamino]-5,6,7,8-
tetrahydro-quinazolin-2-yl}-amide 215
N-(6-cyclohexanecarboxylic-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-
-yl)-2- trifluoromethyl-benzamide 216
N-[6-(2,4-dimethyl-thiazole-5-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-2-trifluoromethyl-benzamide 217
2-thiophen-2-yl-thiazole-4-carboxylic acid
{2-[(thiophene-2-carbonyl)-amino]-
5,6,7,8-tetrahydro-quinazolin-6-yl}-amide 219
thiophene-2-carboxylic acid
{6-[3-(3-trifluoromethyl-phenyl)-acryloylamino]-
5,6,7,8-tetrahydro-quinazolin-2-yl}-amide 220
thiophene-2-carboxylic acid
[6-(5-phenyl-pentanoylamino)-5,6,7,8-tetrahydro-
quinazolin-2-yl]-amide 221 thiophene-2-carboxylic acid
[6-(2-chloro-5-trifluoromethyl-benzoylamino)-
5,6,7,8-tetrahydro-quinazolin-2-yl]-amide 222
4-fluoro-N-[6-(2,3,5,6-tetramethyl-benzenesulfonylamino)-5,6,7,8-tetra-
hydro- quinazolin-2-yl]-benzamide 223
4-fluoro-N-[6-(4-methyl-octanoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyri-
midin-2- yl]-benzamide 224
2-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quinazolin-6-
ylsulfamoyl}-benzoic acid methyl ester 225
[(3-methyl-1-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-quin-
azolin- 6-ylcarbamoyl}-butylcarbamoyl)-methyl]-carbamic acid benzyl
ester 226
3-chloro-N-(6-pentanoyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl-
)- benzamide 227
4-fluoro-N-[6-(5-oxo-5-phenyl-pentanoylamino)-5,6,7,8-tetrahydro-quina-
zolin- 2-yl]-benzamide 228 thiophene-2-carboxylic acid
[6-(3-phenyl-acryloylamino)-5,6,7,8-tetrahydro-
quinazolin-2-yl]-amide 229
N-[6-(5-[1,2]dithiolan-3-yl-pentanoylamino)-5,6,7,8-tetrahydro-quinazo-
lin-2- yl]-4-fluoro-benzamide 230 benzoic acid
2-(2-{2-[(thiophene-2-carbonyl)-amino]-5,6,7,8-tetrahydro-
quinazolin-6-ylcarbamoyl}-ethyl)-phenyl ester 231
4-fluoro-N-[6-(2-methyl-5-nitro-benzenesulfonylamino)-5,6,7,8-tetrahyd-
ro- quinazolin-2-yl]-benzamide 232
4-chloro-N-[6-(2-phenoxy-acetyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrim-
idin-2- yl]-benzamide 234
N-[6-(5-bromo-thiophene-2-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-2-fluoro-benzamide 235
4-fluoro-N-[6-(5-fluoro-2-methyl-benzenesulfonylamino)-5,6,7,8-tetrahy-
dro- quinazolin-2-yl]-benzamide 236
N-[6-(4-acetylamino-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazoli-
n-2- yl]-4-fluoro-benzamide 237 thiophene-2-carboxylic acid
[6-(2-trifluoromethyl-benzoylamino)-5,6,7,8-
tetrahydro-quinazolin-2-yl]-amide 238
3,4-difluoro-N-[6-(quinoline-6-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 239
{1-[2-(4-fluoro-benzoylamino)-5,6,7,8-tetrahydro-quinazolin-6-ylcarbam-
oyl]-2- phenyl-ethyl}-carbamic acid tert-butyl ester 240
thiophene-2-carboxylic acid
[6-(2-methyl-benzoylamino)-5,6,7,8-tetrahydro-
quinazolin-2-yl]-amide 241
3-chloro-N-{6-[3-(2-oxo-benzooxazol-3-yl)-propionyl]-5,6,7,8-tetrahydr-
o- pyrido[4,3-d]pyrimidin-2-yl}-benzamide 242
3-chloro-N-[6-(5-chloro-thiophene-2-sulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 243
3,5-dichloro-N-[6-(4-methoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 244
4-tert-butyl-N-[6-(5-methyl-isoxazole-3-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 245
N-[6-(5-bromo-2-methoxy-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-4-methyl-benzamide 246
4-tert-butyl-N-{6-[3-(2-hydroxyphenyl)-propionyl]-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl}-benzamide 247
4-fluoro-N-[6-(2-phenyl-butyrylamino)-5,6,7,8-tetrahydro-quinazolin-2--
yl]- benzamide 248
4-tert-butyl-N-[6-(4-propyl-benzoyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 249 thiophene-2-carboxylic
acid [6-(2-bromo-benzoylamino)-5,6,7,8-tetrahydro-
quinazolin-2-yl]-amide 250
2-methoxy-N-[6-(6-phenoxy-pyridine-3-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 251
N-[6-(4-acetylamino-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-4-ethyl-benzamide 252
3,5-dichloro-N-[6-(4-fluoro-benzenesulfonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-benzamide 253
N-[6-(1-benzenesulfonyl-1H-indole-2-carbonyl)-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-2-yl]-4-fluoro-benzamide 255
N-[6-(3-chloro-benzenesulfonylamino)-5,6,7,8-tetrahydro-quinazolin-2-y-
l]-4- fluoro-benzamide
Pharmacological Data:
[0539] The affinity of the substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]-pyrimidin-2-yl or
5,6,7,8-tetrahydro-quinazolin-2-yl compound according to the
invention for the batrachotoxin (BTX) binding site and for the
mGluR5-receptor and the inhibition of noradrenalin or 5-HT reuptake
was determined as described above.
[0540] The substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl or
5,6,7,8-tetrahydro-quinazolin-2-yl compounds according to the
invention exhibit good to very good inhibition of noradrenalin
reuptake and good to very good inhibition of 5-hydroxy-tryptophan
reuptake.
[0541] Furthermore, these compounds according to the invention also
exhibit excellent affinity for the batrachotoxin (BTX) binding site
of the sodium channel and the mGluR5 receptor.
[0542] Table I below gives the respective pharmacological data for
some exemplary substituted
5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl or
5,6,7,8-tetrahydro-quinazolin-2-yl compounds.
TABLE-US-00003 TABLE I Compound mGluR5 5-HT uptake, NA uptake,
according to (MPEP), 10 .mu.M BTX rat, 1 .mu.M, % rat, 10 .mu.M,
Example % inhibition inhibition inhibition % inhibition 29 40.51 68
35 69 64 70 73 71 69 47 74 72 31 41 74 66 54 43 78 41.06 31 79 34
80 54 82 36.33 38 32 83 39 77 86 62 32 92 75 66 35 94 47 95 77 59
72 97 30 99 78 41 56 101 68 65 84 102 63 103 65 107 38.23 73 36 39
109 30 92 110 40 96 75 113 31.26 38 45 67 114 82 50 73 115 34.26 82
56 49 116 53 31 52 117 37 32 31 119 34 72 120 48 92 78 121 57 52 92
124 65 125 66 43 70 126 70 55 89 127 30 35 71 128 33 129 51.14 76
132 58.08 72 133 39 134 64 58 59 137 43 139 31.02 62 141 63 54 55
143 37.25 61 53 144 81 42 67 145 84.43 46 146 39.64 147 48 148 85
32 149 32 150 49 54 152 34.01 55 33 154 30.72 50 155 62 156 45.96
50 157 63 43 61 158 74 55 36 160 40 162 29 163 28 165 35 167 51 32
168 33.45 39 46 171 32 172 70.12 57 57 85 173 69 175 49 32 46 176
38 177 41.98 39 178 45.31 180 86.74 46 34 181 36.39 183 31 63 184
87 48 69 185 36 186 77 46 82 187 43 29 100 189 39.49 55 46 53 190
56 36 73 192 87 47 73 193 51.83 84 38 43 194 45.64 195 35 31 197
32.15 199 48 52 202 33.07
[0543] The foregoing description and examples have been set forth
merely to illustrate the invention and are not intended to be
limiting. Since modifications of the described embodiments
incorporating the spirit and substance of the invention may occur
to persons skilled in the art, the invention should be construed
broadly to include all variations within the scope of the appended
claims and equivalents thereof.
* * * * *