Note: Descriptions are shown in the official language in which they were submitted.
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Quinazolinones
The invention relates to substituted quinazolinones of the formula I
O
R ~ N/(CH2)n R2
R
(CH2)m N~ 3
N Rd R
Y
in which
R and R' are independently of each other H, A, OH, OA, OCH2-Ar, Hal,
NHz, NHA, NAZ, NOZ, CN, C(O)R2, CONH2, CONHA, CONAz,
COOH, COOA or SOzA,
Rz and R3 are independently of each other H, A, -C(=NH)-NH2 or solid
phase,
R4 is Ar, phenylalkyl, cycloalkyl or Het,
Y may be absent and, if present, is alkenyl having 2 to 4 carbon
atoms,
A is unbranched or branched alkyl having 1 to 6 carbon atoms,
Ar is phenyl, naphthyl, biphenyl or benzofuranyl, which is
unsubstituted or mono-, di- or trisubstituted by A, OH, OA,
CF3, OCF3, Hal, CN, COOH, CODA, NH2, NHA, NA2, NO2,
SOZNHz, S02NAH or S02NAz,
Het is a saturated, partially or completely unsaturated mono- or
bicyclic heterocyclic radical having 5 to 10 ring members,
where 1 or 2 N and/or 1 or 2 S or O atoms can be present and
the heterocyclic radical can be mono- or disubstituted by A,
Hal, OH, OA, CF3, OCF3, NH2, NHA, NA2, COOH, CODA,
phenyl which is unsubstituted or mono-, di- or trisubstituted by
A, OH, OA, CF3, OCF3, Hal, CN, COOH, CODA, NHz, NHA,
NA2, NOz, S02NH2, S02NAH or SOzNA2 or thiophenyl which is
unsubstituted or mono-, di- or trisubstituted by A, OH, OA,
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CF3, OCF3, Hal, CN, COOH, COOA, NH2, NHA, NAZ, N02,
SO2NH2, S02NAH or S02NA2,
Hal is F, CI, Br or I,
n is 0, 1, 2 or 3,
m is 0, 1, 2 or 3,
and their pharmaceutically tolerable salts and solvates.
Similar compounds having a quinazolinone parent structure as a
combinatorial library are disclosed in WO 98/11438. W.D. Dean et al, J.
Het. Chem. 1982, 1117-24 and L. Legrand et al, Bull. Soc. Chim. Fr. 1976,
1853-6 describes methods for the synthesis of similar quinazolinone
compounds.
The invention is based on the object of finding novel compounds having
valuable properties, in particular those which can be used for the
production of medicaments.
It has been found that the compounds of the formula I and their salts or
solvates have very valuable pharmacological properties together with good
tolerability.
They act especially as GPIbIX inhibitors, in particular inhibiting the
interaction of this receptor with the ligand von Willebrand factor (vWF). This
action can be demonstrated, for example, by a method which is described
by S. Meyer et al. in J. Biol. Chem. 1993, 268, 20555-20562. The property
as GPIbIX alpha-thrombin receptor (N.J. Greco, Biochemistry 1996, 35,
915-921 ) can also be blocked by the compounds mentioned.
The significance of GPIbIX as an adhesion receptor on platelets, which
mediates the primary interaction of platelets with an arteriosclerotically
modified vascular wall via binding to the vWF expressed there, has been
described by many authors (e.g. 2.M. Ruggeri in Thromb. Hemost. 1997,
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78, 611-616). The activation of another platelet adhesion receptor,
GPllbllla, following the GPIbIX-vWF interaction, leads to platelet
aggregation and thus to thrombotic vascular occlusion.
A GPIbIX antagonist can thus prevent the start of thrombus formation and
thus also release of active substances from the platelets which, for
example, promote thrombus growth and have an additional trophic action
on the vascular wall. This has been shown with inhibitory peptides or
antibodies in various experimental models (e.g. H Yamamoto et al.,
Thromb. Hemost. 1998, 79, 202-210).
In the case of higher shear forces, the blocking action of GPIbIX inhibitors
exerts its maximum effect, as described by J.J. Sixma et al. in
Arteriosclerosis, Thrombosis, and Vascular Biology 1996, 16, 64-71.
According to the flow chamber method used there, the compounds of the
formula I can be characterized as GPIbIX inhibitors in whole blood.
The inhibition of thrombus formation of the GPIbIX inhibitors can be
measured by a modified Born method (Nature 1962, 4832, 927-929) using
botrocetin or ristocetin as an aggregation stimulant.
The compounds of the formula I according to the invention can therefore be
employed as pharmaceutical active compounds in human and veterinary
medicine. They act as adhesion receptor antagonists, in particular as
glycoprotein IbIX antagonists, and are suitable for the prophylaxis and/or
therapy of thrombotic disorders and sequelae deriving therefrom. The
preferentially best action is to be expected in the case of thrombotic
disorders in the arterial vascular system, but GPIbIX inhibitors also have an
effect in the case of thrombotic disorders in the venous vascular bed. The
disorders are acute coronary syndromes, angina pectoris, myocardial
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infarct, peripheral circulatory disorders, stroke, transient ischaemic
attacks,
arteriosclerosis, reocclusion/restenosis after angioplasty/stent implantation.
The compounds can furthermore be employed as anti-adhesive substances
where the body comes into contact with foreign surfaces such as implants,
catheters or cardiac pacemakers.
Therefore, the invention relates further to compounds of the formula I
according to Claim 1 and their physiologically acceptable salts or solvates
as pharmaceutical active compounds.
The invention relates to compounds of the formula I according to Claim 1
and their physiologically acceptable salts or solvates as glycoprotein IbIX
antagonists.
Comparison medication introduced onto the market which may be
mentioned are aspirin and GPllbllla antagonists.
The invention relates to the compounds of the formula I and their salts or
solvates, and to a process for the preparation of these compounds and
their salts or solvates, characterized in that
a) a compound of the formula I is liberated from one of its functional
derivatives by treating with a solvolysing or hydrogenolysing agent,
or
b) in stage 1 ) a compound of the formula I I
COX
I I
Q
in which
X is CI, Br, OH or a reactive esterified OH group and
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Q is NHZ or NHA, either of which is optionally protected, and
R and R' are optionally protected when they are or contain NHz or NHA,
is reacted with a compound of the formula III
H2N-(CH2)n /R2 III
(CHz)m-N~
R3
in which R2, R3, n and m have the meanings indicated in Claim 1,
to give a compound of forumula IV
O
R
N/(CH2)n ~2 IV
R H (CH2)m N~
R3
Q
in which R, R', R2, R3, Q, n and m have the meanings indicated above,
and
in stage 2) a compound of formula IV as indicated above is if necessary
deprotected to give a compound of formula IV in which Q is NH2 or NHA
and is reacted with a compound of formula V
R4-Y-CHO V
in which R4 and Y have the meanings indicated in Claim 1,
or
c) a radical R, R', RZ, R3 and/or R4 is converted into another radical R, R',
R2, R3 and/or R4 by, for example
- converting an amino group into a guanidino group by reaction with
an amidinating agent,
- reducing a nitro group, sulfonyl group or sulfoxyl group,
- etherifying an OH group or subjecting an OA group to ether
cleavage,
- alkylating a primary or secondary amino group,
- partially or completely hydrolysing a CN group,
- cleaving an ester group or esterifying a carboxylic acid radical,
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- reacting an aryl bromide, aryl iodide, heteroaryl bromide or
heteroaryliodide to give the corresponding coupling products by
means of a Suzuki coupling with boronic acids,
- or carrying out a nucleophilic or electrophilic substitution,
and/or
a base or acid of the formula I is converted into one of its salts or
solvates.
The compounds of the formula I can have a chiral centre and therefore
occur in a number of stereoisomeric forms. All these forms (e.g. f~ and S
forms) and their mixtures (e.g. the RS forms) are included in the formula I.
The compounds according to the invention also include so-called prodrug
derivatives, i.e. compounds of the formula I modified with, for example,
alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved
in the body to give the active compounds according to the invention.
Furthermore, free amino groups as substituents of compounds of the
formula I can be provided with appropriate conventional protective groups.
Solvates of the compounds of the formula I are understood as meaning
adducts of inert solvent molecules to the compounds of the formula I which
are formed on account of their mutual power of attraction. Solvates are, for
example, mono- or dihydrates or alcoholates.
The abbreviations used have the following meanings:
BOC tert-butoxycarbonyl,
CBZ benzyloxycarbonyl,
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene,
DCC dicyclohexylcarbodiimide,
DCE dichloroethane,
DDQ 2,8-dichioro-5,6-dicyano-1,4-benzoquinone,
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DMA dimethylacetamide,
DMF dimethylformamide,
dppf 1,1'-bis(diphenylphosphino)ferrocene,
Et ethyl,
Fmoc fluorenylmethoxycarbonyl,
HBTU O-(benzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluoro
phosphate,
Me methyl,
Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl,
OBut tert-butyl ester,
OMe methyl ester,
OEt ethyl ester,
POA phenoxyacetyl,
Ph phenyl,
TEA triethylamine,
TFA trifluoroacetic
acid.
In the above formulae, A is alkyl and has 1 to 6, preferably 1, 2, 3 or 4 C
atoms. Alkyl is preferably methyl, furthermore ethyl, propyl, isopropyl,
butyl,
isobutyl, sec-butyl or tert-butyl, additionally also pentyl, 1-, 2- or
3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-,
3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or
2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or
1,2,2-trimethylpropyl.
A is preferentially methyl.
Alkenyl having 2 to 4 carbon atoms is preferably vinyl or buts-1,3-dienyl;
vinyl is particularly preferred.
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Ar is phenyl, naphthyl, biphenyl or benzofuranyl, which is unsubstituted or
mono-, di- or trisubstituted by A, OH, OA, CF3, OCF3, Hal, CN, COOH,
CODA, NH2, NHA, NA2, NO2, S02NH2, SOzNAH or SOZNA2.
Ar is preferentially phenyl, preferably - as indicated - mono- di- or
trisubstituted phenyl, specifically preferentially phenyl, 2-, 3- or
4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-propylphenyl, 2-, 3- or
4-isopropylphenyl, 2-, 3- or 4-tert-butylphenyl, 2-, 3- or 4-aminophenyl, 2-,
3- or 4-N,N-dimethylaminophenyl, 2-, 3- or 4-sulfonamidophenyi, 2-, 3- or
4-nitrophenyl, 2-, 3- or 4-hydroxyphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3-
or 4-ethoxyphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-
trifluoromethoxyphenyl, 2-, 3- or 4-carboxyphenyl, 2-, 3- or 4-cyanophenyl,
2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl.
Furthermore Ar is preferentially unsubstituted naphthyl, biphenyl or
benzofuran-5-yl.
Phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-tert-
butylphenyl, 4-dimethylaminophenyl, 4-methoxyphenyl, 3-methoxyphenyl,
3-chlorophenyl, 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 2,5-
dimethoxyphenyl, 3',5'-dimethoxybiphenyl-4-yl, 2',4'-dimethoxybiphenyl-4-
y1, biphenyl-4-yl, naphthalen-1-yl, naphthalen-2-yl or benzofuran-5-yl is
particularly preferred for Ar.
Cycloalkyl preferably has 3-7 C atoms and is preferably cyclopropyl or
cyclobutyl, furthermore preferably cyclopentyl or cyclohexyl, and further
also cycloheptyl; cyclohexyl is particularly preferred .
Hal is preferably F, CI or Br.
Net is a saturated, partially or completely unsaturated mono- or bicyclic
heterocyclic radical having 5 to 10 ring members, where 1 or 2 N and/or 1
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or 2 S or O atoms can be present and the heterocyclic radical can be
mono- or disubstituted by A, Hal, OH, OA, CF3, OCF3, NHZ, NHA, NA2,
COOH, COOA, phenyl which is unsubstituted or mono-, di- or trisubstituted
by A, OH, OA, CF3, OCF3, Hal, CN, COOH, COOA, NHz, NHA, NAZ, NO2,
SOZNH2, SOZNAH or SOZNAZ or thiophenyl which is unsubstituted or
mono-, di- or trisubstituted by A, OH, OA, CF3, OCF3, Hal, CN, COOH,
CODA, NH2, NHA, NA2, NOz, S02NH2, SOzNAH or SOZNA2.
Net is preferably substituted by A, OH, OA, CF3, OCF3, Hal, CN, COOH,
CODA, NH2, NHA, NA2, N02, SO2NH2, SOZNAH or SOzNA2 or thiophenyl
which is unsubstituted or mono-, di- or trisubstituted by A, OH, OA, CF3,
OCF3, Hal, CN, COOH, CODA, NHZ, NHA, NA2, NO2, S02NH2, SOZNAH or
S02NA2 or unsubstituted 2- or 3-furyl, 2- or 3-thiophenyl, 1-, 2- or
3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or
5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or
5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore
preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -4- or -5-yl,
1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or-5-yl, 1,2,4-oxadiazol-3- or
-5-yl, 1,3,4-thiadiazol-2-or-5-yl, 1,2,4-thiadiazol-3-or-5-yl,
1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3-
or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or
7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6-
or 7-1 H-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or
7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or
7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or
7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 1-, 2-, 3-, 4-,
5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-,
2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-acridinyl,
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3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl. The
heterocyclic radicals can also be partially or completely hydrogenated. Het
can thus also be 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-,
-3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl,
tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or
-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or
3-pyrrolidinyl, tetrahydro-1-, -2- or -3-pyrrolyl, tetrahydro-1-, -2- or
4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-, -5-, -6-, -7-1 H-indolyl,
2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3-
or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl,
1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl,
1,2,3,6-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or
4-piperidinyl, 1-, 2-, 3- or 4-azepanyl, 2-, 3- or 4-morpholinyl,
tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or
-5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or
-5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,
-4-, -5-, -6-, -7- or -8-quinolinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,
-4-, -5-, -6-, -7- or -8-isoquinolinyl.
2-Furyl, thiophen-2-yl, thiophen-3-yl, 5-(3,4-dimethoxyphenyl)-thiophen-2-yl
or 5-[2,2']bithiophenyl is particularly preferred for Het.
Phenylalkyl preferably has 7, 8, 9 or 10 carbon atoms and is preferably
phenylmethyl, phenylethyl, phenylpropyl or phenylbutyl; phenylethyl is
particularly preferred .
The term solid phase indicates a resin for solid-phase chemistry, especially
for combinatorial chemistry, i.e. by robot- and computer-assisted
syntheses, and subjected to mass screening as indicated in US 5,463,564;
M. A. Gallop et al., J. Med. Chem. 1994, 37, 1233-1251 and 1385-1401
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and M.J. Sofia, Drugs Discovery Today 1996, 1, 27-34). The polymeric
material of the solid phase is generally chosen from the group consisting of
cross-linked polystyrene, cross-linked polyacrylamide or other resins,
natural polymers or silicagels.
The group of cross-linked polystyrene, cross-linked polyacrylamide or other
resins includes e.g. polyacrylamide, polymethacrylamide,
polyhydroxyethylmethacrylate, polyamide, polystyrene, (meth)acrylate
copolymers, for instance from (methy)acrylic acid, esters of (meth)acrylic
acid and/or 2-methylene-succinic acid, but-2-enoic acid or malefic acid,
polyurethanes or other copolymers.
Suitable terminal functional groups or linkers on the surface of the resin
have to be chosen to attach the compounds to the resin. There exists a
variety of commercially available resins, e.g. in Novabiochem - The
Combinatorial Chemistry Catalog, March 99. Examples for sutitable resins
are carbonate resins with a modified carbonate group as terminal functional
group like p-nitrophenylcarbonate resin, halogenated resins like Merrifield
resin (chloromethylpolystyrene) or carboxy resins like carboxy polystyrene
resin or NovaSyn~ TG Carboxy Resin. p-Nitrophenylcarbonate resin is
particularly preferred. These and other types of resins well known in the art
can be used in the subject invention.
R and R' are independently of each other H, A, OH, OA, OCH2 Ar, Hal,
NH2, NHA, NAz, NO2, CN, C(O)Rz, CONH2, CONHA, CONA2, COOH,
CODA or SOzA, where A, Ar, Hal have a preferred meaning indicated
beforehand and RZ has a preferred meaning indicated in the following.
R is preferentially H.
R' is preferentially H, A, OA or Hal.
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The preferred position of R' is the 6- or 7-position of the quinazolinone ring
system.
Rz and R3 are independently of each other H, A, -C(=NH)-NH2 or a solid
phase, where A or solid phase have a preferred meaning indicated
beforehand.
R2 is preferentially H.
R3 is preferentially H or -C(=NH)-NH2, particularly preferred is H.
R4 is Ar, phenylalkyl, cycloalkyl or Het, where Ar, phenylalkyl, cycloalkyl or
Het have a preferred meaning indicated beforehand. R4 is preferentially
phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-tert-
butylphenyl, 4-dimethylaminophenyl, 4-methoxyphenyl, 3-methoxyphenyl,
3-chlorophenyl, 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 2,5-
dimethoxyphenyl, 3',5'-dimethoxybiphenyl-4-yl, 2',4'-dimethoxybiphenyl-4-
y1, biphenyl-4-yl, naphthalen-1-yl, naphthalen-2-yl or benzofuran-5-yl,
phenylethyl, cyclohexyl, 2-furyl, thiophen-2-yl, thiophen-3-yl, 5-(3,4-
dimethoxyphenyl)-thiophen-2-yl or 5-[2,2']bithiophenyl.
Y may be absent and, if present, is alkenyl having 2 to 4 carbon atoms. Y is
preferentially absent or vinyl.
n and m are each independently of each other 0, 1, 2 or 3, particularly
preferred 1.
Some preferred groups of compounds can be expressed by the following
subformulae la to Im, which correspond to the formula I and in which the
radicals not designated in greater detail have the meanings indicated in
formula I, but in which
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in la R is H and
R' is H, A, OA or Hal;
in Ib R is H,
R' is H, A, OA or Hal and
Y is absent;
in Ic R is H,
R' is H, A, OA or Hal and
Y is alkenyl having 2 to 4 carbon atoms;
in Id R is H,
R' is H, A, OA or Hal,
R2 is H and
R4 is Ar;
in 1e R is H,
R' is H, A, OA or Hal,
RZ is H and
R4 is phenylalkyl;
in If R is H,
R' is H, A, OA or Hal,
RZ is H and
R4 is cycloalkyl;
in Ig R is H,
R' is H, A, OA or Hal,
RZ is H and
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R4 is Het;
in Ih R is H,
R' is H, A, OA or Hal,
Rz is H,
R3 is H,
R4 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,
4-
tert-butylphenyl, 4-dimethylaminophenyl, 4-methoxyphenyl,
3-
methoxyphenyl, 3-chlorophenyl, 3,4,5-trimethoxyphenyi,
3,4-
dimethoxyphenyl, 2,5-dimethoxyphenyl, 3',5'-dimethoxy-
biphenyl-4-yl, 2',4'-dimethoxybiphenyl-4-yl,
biphenyl-4-yl,
naphthalen-1-yl, naphthalen-2-yl or benzofuran-5-yl,
phenylethyl, cyclohexyl, 2-furyl, thiophen-2-yl,
thiophen-3-yl,
5-(3,4-dimethoxyphenyl)-thiophen-2-yl or 5-[2,2']bithiophenyl,
n is 1 and
m is 1;
in Ik R is H,
R' is H, A, OA or Hal,
R2 is H,
R3 is H,
Y is -CH=CH-,
R4 is phenyl, 4-dimethylaminophenyl or 2,5-dimethoxyphenyl,
n is 1 and
m is 1;
in Im R is H,
R' is H, A, OA or Hal,
R2 is H,
R3 is H,
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Y is absent,
R4 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-
tert-butylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-
chlorophenyl, 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl,
3',5'-dimethoxybiphenyl-4-yl, 2',4'-dimethoxybiphenyl-4-yl,
biphenyl-4-yl, naphthalen-1-yl, naphthalen-2-yl or benzofuran-
5-yl, phenylethyl, cyclohexyl, 2-furyl, thiophen-2-yl, thiophen-
3-yl, 5-(3,4-dimethoxyphenyl)-thiophen-2-yl or 5-
[2,2')bithiophenyl,
n is 1 and
m is 1.
The compounds of the formula I and also the starting substances for their
preparation are otherwise prepared by methods known per se, such as are
described in the literature (e.g. in the standard works such as Houben-
Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry),
Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which
are known and suitable for the reactions mentioned. In this case, use can
also be made of variants which are known per se, but not mentioned here
in greater detail.
The starting substances, if desired, can also be formed in situ such that
they are not isolated from the reaction mixture, but immediately reacted
further to give the compounds of the formula I.
The compounds of the formula I can be obtained by liberating them from
their functional derivatives by solvolysis, in particular hydrolysis or by
hydrogenolysis.
Preferred starting substances for the solvolysis or hydrogenolysis are those
which otherwise correspond to the formula I, but instead of one or more
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free amino and/or hydroxyl groups contain corresponding protected amino
and/or hydroxyl groups, in particular those which instead of an H-N- group
carry an R'-N- group, in which R' is an amino protective group and/or those
which instead of the H atom of a hydroxyl group carry a hydroxyl protective
group, e.g. those which correspond to the formula I, but instead of a group
-COOH carry a group -COOR", in which R" is a hydroxyl protective group.
A number of - identical or different - protected amino and/or hydroxyl
groups can also be present in the molecule of the starting substance. If the
protective groups present are different from one another, in many cases
they can be removed selectively (lit.: T.W. Greene, P.G.M. Wuts, Protective
Groups in Organic Chemistry, 2nd ed., Wiley, New York 1991, P.J.
Kocienski, Protecting Groups, 1st ed. or Georg Thieme Verlag, Stuttgart -
New-York, 1994).
The expression "amino protective group" is generally known and relates to
groups which are suitable for protecting (for blocking) an amino group
against chemical reactions, but which are easily removable after the
desired chemical reaction has been carried out at other positions in the
molecule. Typical groups of this type are, in particular, unsubstituted or
substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino
protective groups are removed after the desired reaction (or reaction
sequence), their nature and size is otherwise not critical; however, those
having 1-20, in particular 1-8, C atoms are preferred. The expression "acyl
group" is to be interpreted in the widest sense in connection with the
present process. It includes acyl groups derived from aliphatic, araliphatic,
aromatic or heterocyclic carboxylic acids or sulfonic acids and, in
particular.
alkoxycarbonyl groups, aryloxycarbonyl groups and especially
aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl
such as acetyi, propionyi, butyryl; aralkanoyl such as phenylacetyl; aroyl
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such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl
such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,
BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ
("carbobenzoxy"), 4-methoxybenzyloxycarbonyl (MOZ), 4-Nitro-
benzyloxycarbonyl oder 9-fluorenylmethoxycarbonyl (Fmoc); 2-
(phenylsulfonyl)ethoxycarbonyl; trimethylsilylethoxycarbonyl (Teoc) or
arylsulfonyl such as 4-methoxy-2,3,6-trimethylphenyl-sulfonyl (Mtr).
Preferred amino protective groups are BOC, furthermore CBZ, Fmoc,
benzyl and acetyl; particularly preferred Fmoc.
The expression "hydroxyl protective group" is also generally known and
relates to groups which are suitable for protecting a hydroxyl group against
chemical reactions, but which are easily removable after the desired
chemical reaction has been carried out at other positions in the molecule.
Typical groups of this type are the abovementioned unsubstituted or
substituted aryl, aralkyl, aroyl or acyl groups, furthermore also alkylgroups,
alkyl-, aryl- or aralkylsilylgroups or O,O- or O,S-acetals. The nature and
size of the hydroxyl protective groups is not critical, since they are removed
again after the desired chemical reaction or reaction sequence; groups
having 1-20, in particular 1-10 C atoms, are preferred. Examples of
hydroxyl protective groups are, inter alia, benzyl, 4-methoxybenzyl oder
2,4-dimethoxybenzyl, aroyl groups such as benzoyl or p-nitrobenzoyl, acyl
groups such as acetyl or pivaloyl, p-toluolsulfonyl, alkyl groups such as
methyl or tert-butyl, but also allyl, alkylsilyl groups such as trimethylsilyl
(TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) or
triethylsilyl,
trimethylsilylethyl, aralkylsilyl groups such as tert-butyldiphenylsilyl
(TBDPS), cyclic acetals such as isopropylidene-, cyclopentylidene-,
cyclohexylidene-, benzylidene-, p-methoxybenzylidene- or o,p-
dimethoxybenzyiideneacetal, acyclic acetates such as tetrahydropyranyi
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(Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM),
benzyloxymethyl (BOM) or methylthiomethyl (MTM). Acetyl, benzyl, tert-
butyl or TBS being particularly preferred.
The liberation of the compounds of the formula I from their functional
derivatives depending on the protective group used is known in the present
literature such as T.W. Greene, P.G.M. Wuts, Protective Groups in Organic
Chemistry, 2nd ed., Wiley, New York 1991, P.J. Kocienski, Protecting
Groups, 1 st ed., Georg Thieme Verlag, Stuttgart - New-Yor k, 1994. In this
case, use can also be made of variants which are known per se, but not
mentioned here in greater detail.
The groups BOC and O-tert-butyl can preferably be removed, for example,
using TFA in dichloromethane or using approximately 3 to 5N HCI in
dioxane at 15-30°C, the Fmoc group using an approximately 5 to 50%
solution of dimethylamine, diethylamine or piperidine in DMF at 15-
30°C.
Preferred starting substances for the solvolysis or hydrogenolysis includes
also those which otherwise correspond to the formula I, but are attached to
a solid phase. The liberation of the compounds of the formula I from the
solid phase is known in the present literature such as Novabiochem - The
Combinatorial Chemistry Catalog, March 99 and cited literature.
The solid phase with a carbonate moiety as terminal functional group can
preferably be removed, for example, using TFA (50%) in dichloromethane.
The quinazolinones of formula I can also preferably be prepared, using
either solution or solid-phase techniques, by combining and reacting an
anthranilic acid of formula II with an amine of formula III and if necessary
deprotect the given formula IV in which Q is then NH2 or NHA and reacting
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the compound of formul IV in which Q is NHZ or NHA with an aldehyde of
formula V.
As a rule, the starting compounds of the formulae II, III and V are known or
commercially available.
The unknown compounds, however, can be prepared by methods known
per se. The compounds of the formula II are anthranilic acids. It is
furthermore possible to introduce appropriate substituents into the aromatic
by conventional electrophilic or alternatively nucleophilic substitutions.
Examples of Fmoc protected anthranilic acids, include, but are not limited
to, Fmoc protected anthranilic acid, Fmoc protected 3-methyl anthranilic
acid, Fmoc protected 3-methoxy anthranilic acid, Fmoc protected 3-chloro
anthranilic acid or Fmoc protected 4-chloro anthranilic acid.
Solid-phase techniques may be employed to condense anthranilic acids of
formula II and the amine component of formula III which is resin bound (R2
or R3 is solid phase).
The amines of formula III in which RZ or R3 are H, as a rule, are also
commercially available and can be attached to the suitable resin by
coupling procedures well known in the art and as described in the ensuing
Examples. Furthermore, syntheses for the preparation of amines of formula
III, such as, for example, the Gabriel synthesis, can be used.
The aldehydes of formula V, as a rule, are also commercially available.
Furthermore, syntheses for the preparation of aldehydes of formula V, such
as, for example, the oxidation of an alcohol, can be used.
As a rule, the reactions and the attachment to the resin are carried out in
an inert solvent. Depending on the conditions used, the reaction time is
between a few minutes and a number of days, the reaction temperature
3G between approximately 0° and 150°C, normally between
20° and 130°C.
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Suitable inert solvents are, for example, hydrocarbons such as hexane,
petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons
such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,
chloroform or dichloromethane; alcohols such as methanol, ethanol,
isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl
ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers
such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or
ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as
acetone or butanone; amides such as acetamide, N-methylpyrrolidone
(NMP), dimethylacetamide or dimethylformamide (DMF); nitrites such as
acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon
disulfide; carboxylic acids such as formic acid or acetic acid; nitro
compounds such as nitromethane or nitrobenzene; esters such as ethyl
acetate or mixtures of the solvents mentioned.
The reaction of the compounds of formula II with compounds of formula III
is analoguesly to the coupling of peptides. The condensation reaction of
formula II with formula III is preferrably carried out in an inert solvent as
indicated above in the presence of a dehydrating agent, such as,
dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethyl-
carbodiimide-hydrochlorid (EDC) or diisopropylcarbodiimide (DIC), further
for instance in the presence of an anhydride of propanphosphonic acid
(see Angew. Chem. 1980, 92, 129), diphenylphosphorylazide or 2-ethoxy-
N-ethoxycarbonyl-1,2-dihydroquinoline.
Particularly preferred is the presence of a coupling agent, such as TBTU
(O-(benzotriazol-1-yl)-N, N, N', N'-bis-(tetramethylene)-uron ium
tetrafluoroborate) or O-(benzotriazol-1-yl)-N,N,N',N'-bis-(tetramethylene)-
uronium hexafluorophosphate.
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A compound of formula II in which X is a reactive esterified OH group can
be synthesized by reacting a compound of formula II in which X is OH with
HOBt (1-hydroxybenzotriazole) or N-hydroxysuccinimide(e.g. in the
standard works such as Houben-Weyl, Methoden der organischen Chemie
[Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart).
For the preparation of compounds of the formula I in which RZ or R3 are
-C(=NH)-NH-, a compond of formula I in which RZ and R3 are H can be
treated with an amidinating agent. The preferred amidinating agent is
1-amidino-3,5-dimethylpyrazole (DPFN), which is employed, in particular, in
the form of its nitrate, or pyrazole-1-carboxamidine. The reaction is
expediently carried out with addition of a base such as triethylamine or
ethyldiisopropylamine in an inert solvent or solvent mixture, e.g. DMF at
temperatures between 0° and 150°C, preferably between 60°
and 120°C.
For the preparation of compounds of the formula I in which R4 is
unsubstituted or substituted biphenyl, 5-(3,4-dimethoxyphenyl)-thiophen-2-
yl or 5-[2,2']bithiophenyl, an appropriate compound of the formula I in which
R4 is phenyl chloride, phenyl bromide, phenyl iodide, thiophenyl chloride,
thiophenyl bromide or thiophenyl iodide can be reacted with the appropriate
boronic acid derivatives in a Suzuki type coupling reaction. This reaction is
expediently carried out under Palladium catalysis with different phosphines
as coordination ligands, e.g. Pd(P(Ph)3)z, Pd(II)Cl2dppf, PdOAc2 + P(R*)3
(R* = phenyl, cyclohexyl, tert-butyl) etc. in the presence of a base such as
potassium carbonate, caesium carbonate, DBU, NaOH, in an inert solvent
or solvent mixture, e.g. DMF or 1,4-dioxane at temperatures between 0°
and 150°, preferably between 60° and 120°. Depending on
the conditions
used, the reaction time is between a few minutes and a number of days.
The boronic acid derivatives can be prepared by conventional methods or
3C are commercially available. The reactions can be carried out in analogy to
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the methods indicated in Suzuki et al., J. Am. Chem. Soc. 1989, 111,
314ff., Suzuki et al., Chem. Rev. 1995, 95, 2457ff and G.C. Fu et al.
Angew. Chem 1998, 110, 3586.
A base of the formula I can be converted into the associated acid addition
salt using an acid, for example by reaction of equivalent amounts of the
base and of the acid in an inert solvent such as ethanol and subsequent
evaporation. Acids which give physiologically acceptable salts are
particularly suitable for this reaction. Thus inorganic acids can be used,
e.g.
sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or
hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic
acid, furthermore organic acids, in particular aliphatic, alicyclic,
araliphatic,
aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric
acids, e.g. formic acid, acetic acid, propionic acid, pivafic acid,
diethylacetic
acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malefic acid,
lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic
acid,
nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid,
p-toluenesulfonic acid, naphthalenemono- and disulfonic acids or
laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g.
picrates, can be used for the isolation andlor purification of the compounds
of the formula I.
On the other hand, compounds of the formula I with bases (e.g sodium or
potassium hydroxide or carbonate) can be converted into the
corresponding metal salts, in particular alkali metal or alkaline earth metal
salts, or into the corresponding ammonium salts.
The invention furthermore relates to pharmaceutical preparations
comprising at least one compound of the formula I and/or one of its
physiologically acceptable salts, which are prepared, in particular, in an
non-chemical way. In this case, the compounds of the formula I can be
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brought into a suitable dose form together with at least one solid, liquid
and/or semi-liquid excipient or auxiliary and, if appropriate, in combination
with one or more other active compounds.
These preparations can be used as medicaments in human or veterinary
medicine. Possible excipients are organic or inorganic substances which
are suitable for enteral (e.g. oral) or parenteral administration or topical
application and do not react with the novel compounds, for example water,
vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols,
glyceryl triacetate, gelatin, carbohydrates such as lactose or starch,
magnesium stearate, talc and petroleum jelly. Tablets, pills, coated tablets,
capsules, powders, granules, syrups, juices or drops are used, in particular,
for oral administration, suppositories are used for rectal administration,
solutions, preferably oily or aqueous solutions, furthermore suspensions,
emulsions or implants, are used for parenteral administration, and
ointments, creams or powders are used for topical application. The novel
compounds can also be lyophilized and the lyophilizates obtained used, for
example, for the production of injection preparations. The preparations
indicated can be sterilized and/or can contain auxiliaries such as lubricants,
preservatives, stabilizers and/or wetting agents, emulsifiers, salts for
affecting the osmotic pressure, buffer substances, colourants, flavourings
and/or one or more other active compounds, e.g. one or more vitamins.
The compounds of the formula I and their physiologically acceptable salts
act as adhesion receptor antagonists, in particular glycoprotein IbIX
antagonists, and can be employed for the prophylaxis and/or therapy of
thrombotic disorders and sequelae deriving therefrom. The disorders are
acute coronary syndromes, angina pectoris, myocardial infarct, peripheral
circulatory disorders, stroke, transient ischaemic attacks, arteriosclerosis
and reocclusion/restenosis after angioplasty/stent implantation.
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In this case, the substances according to the invention are as a rule
administered in the dose of the glycoprotein Ilbllla antagonist ReoPro~ of
preferably between approximately 1 and 500 mg, in particular between 5
and 100 mg, per dose unit. The daily dose is preferably between
approximately 0.02 and 10 mg/kg of body weight. The specific dose for
each patient depends, however, on all sorts of factors, for example on the
efficacy of the specific compound employed, on the age, body weight,
general state of health and sex, on the diet, on the time and route of
administration, and on the excretion rate, pharmaceutical combination and
severity of the particular disorder to which the therapy applies. Oral
administration is preferred.
Above and below, all temperatures are indicated in °C. In the
following
examples, "customary working-up" for solution reactions means: if
necessary, water is added, if necessary, depending on the constitution of
the final product, the mixture is adjusted to pHs between 2 and 10 and
extracted with ethyl acetate or dichloromethane, the organic phase is
separated off, dried over sodium sulfate and evaporated, and the residue is
purified by chromatography on silica gel and/or by crystallization.
"Customary working-up" for solid-phase reactions means: the crude
reaction is filtered and washed with DMF twice, then sucessively with
methanol and methylene chloride three times, and finally once with methyl
tert-butyl ether. The resin is then dried in vacuo.
Mass spectrometry (MS) apparatuses Kratos Maldi III and Finnigan LCQ.
(M+H)+ values or M+ values are determined.
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EXAMPLES
Example 1:
3 grams (1.62 mmol) of p-nitrophenylcarbonate resin (1) [Novabiochem:
0.54 mmol/g loading) is suspended in 30 ml of DMF then 8.1 mmol of C (3-
Aminomethyl-cyclohexyl)-methylamine is added at room temperature. The
reaction is then heated to 55° and left to stir for two days. The crude
reaction is then customary worked up for solid-phase reactions affording
the resin bound bis amine (2).
O
O2N ~ ~ O O (1)
H2N ~O (2)
N"O-
I
H
Analogously, by reaction of the p-nitrophenylcarbonate resin (1) with the bis
amines of formula III
HzN- (CH2)~ /R2 I I I
(CH2)m-N~R3
in which RZ and R3 are H, excluding C-(3-aminomethyl-cyclohexyl)-
methylamine, and n and m have the meanings indicated in Claim 1 the
following resin bound bis amines are obtained:
cyclohexane-1,3-diamine, resin bound;
3-aminomethyl-cyclohexylamine, resin bound;
3-aminoethyl-cyclohexylamine, resin bound;
3-aminopropyl-cyciohexylamine, resin bound;
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C-(3-aminoethyl-cyclohexyl)-methylamine, resin bound;
C-(3-aminopropyl-cyclohexyl)-methylamine, resin bound;
C-(3-aminoethyl-cyclohexyl)-ethylamine, resin bound;
C-(3-aminopropyl-cyclohexyl)-propylamine, resin bound;
cyclohexane-1,4-diamine, resin bound;
4-aminomethyl-cyclohexylamine, resin bound;
4-aminoethyl-cyclohexylamine, resin bound;
4-aminopropyl-cyclohexylamine, resin bound;
G-(4-aminomethyl-cyclohexyl)-methylamine, resin bound;
C-(4-aminoethyl-cyclohexyl)-methylamine, resin bound;
C-(4-aminopropyl-cyclohexyl)-methylamine, resin bound;
C-(4-aminoethyl-cyclohexyl)-ethylamine, resin bound and
C-(4-aminopropyl-cyclohexyl)-propylamine, resin bound.
Example 2:
1. Synthesis of Fmoc protected anthranilic acid
29.15 mmol of anthranilic acid is taken in 100 ml of 1,4 dioxane then 145
mmol of sodium bicarbonate in 20 ml of water is added. Next, 32 mmol of
Fmoc-CI is added and the reaction is left to stir overnight at room
temperature. The reaction is then concentrated in vacuo and customary
worked up for solution reactions. The resulting solid is triturated in ethyl
ether affording the pure product.
2. Coupling of Fmoc protected anthranilic acid to resin
1 gram of resin (2) is suspended in 10 ml of DMF. The reaction is then
treated with 1.62 mmol of Fmoc protected anthranilic acid, 1.62 mmol of
HBTU, and 1.62 mmol of triethyl amine. The reaction is then allowed to
shake overnight at room temperature. After customary working up, the
resin is dried in vacuo affording resin bound anthranilic acid (3).
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O
\ N O (3)
I OO
/ H N~O-
NH ~ O
~O H
O~O
3. Cleavage of Fmoc protected group
1 gram resin (3) is suspended in 10 ml of 20% piperidine/DMF and shaken
for 1.5 hours at room temperature. The reaction is then customary worked
up for solid-phase reactions affording the free aniline (4).
4. Aldehyde condensation and ring closure
100 mg resin (4) is suspended in 1 ml of dimethyl acetamide then 200 p,1 of
acetic acid is added followed by the addition of 2.16 mmol of
benzaldehyde. The reaction is then heated to 80° for two days. The
reaction is then cooled to toom temperature and customary worked up for
solid-phase reactions affording the resin (5).
O
O (5)
\ N ~ OO
~N~O-
I/ I O
N I \ H
H /
5. Oxidation to quinazolinone
100 mg resin (5) is suspended in 4 ml solution of 36 mg of DDQ in DMF.
Then the reaction is allowed to shake overnight at room temperature. The
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reaction is then customary worked up for solid-phase reactions affording
quinazolinone (6) resin bound.
O
O (6)
\ N ~ ~
'-N"O-
/ i \
N H
6. Cleavage of the final product 3-(3-aminomethyl-cyclohexylmethyl)-2-
phenyl-3H-quinazolin-4-one
100 mg of resin (6) is suspended in 2 ml of a 50% trifluoroacetic
acid/methylene chloride solution and shaken for 1.5 hours at room
temperature. Customary working up for solid-phase reactions afforded 3-(3-
aminomethyl-cyclohexylmethyl)-2-phenyl-3H-quinazolin-4-one;
MS calc.: 347.4 found: 348.2.
Example 3:
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila
COOH
R' I I a
/ N~H
O' 'O
30
cleavage of the Fmoc protecting group and reaction with benzaldehyde,
oxidation and cleavage from the solid phase, the following compounds are
obtained
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with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-chloro-2-phenyl-3H-quinazolin-4-
one;
MS calc.: 381.9 found: 382.2;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methyl-2-phenyl-3H-quinazolin-4-
one;
MS calc.: 361.5 found: 362.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-7-chloro-2-phenyl-3H-quinazolin-4-
one;
MS calc.: 381.9 found: 382.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methoxy-2-phenyl-3H-quinazolin-4-
one;
MS calc.:377.5.
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 2-
methyl-benzaldehyde, oxidation and cleavage from the solid phase, the
following compounds are obtained
with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-chloro-2-(2-methylphenyl)-3H-
quinazolin-4-one;
MS calc.: 395.9 found: 396.2;
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with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methyl-2-(2-methylphenyl)-3H-
quinazolin-4-one;
MS calc.: 375.5 found: 376.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-7-chloro-2-(2-methylphenyl)-3H-
quinazolin-4-one;
MS calc.: 395.9 found: 396.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methoxy-2-(2-methylphenyl)-3H-
quinazolin-4-one;
MS calc.: 391.5 found: 392.2;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(2-methylphenyl)-3H-quinazolin-4-
one;
MS calc.: 361.5 found: 362.2.
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 3-
methyl-benzaldehyde, oxidation and cleavage from the solid phase, the
following compounds are obtained
with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-chloro-2-(3-methylphenyl)-3H-
quinazolin-4-one;
MS calc.: 395.9 found: 396.2;
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with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methyl-2-(3-methylphenyl)-3H-
quinazolin-4-one;
MS calc.: 375.5 found: 376.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-7-chloro-2-(3-methylphenyl)-3H-
quinazolin-4-one;
MS calc.: 395.9 found: 396.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methoxy-2-(3-methylphenyl)-3H-
quinazolin-4-one;
MS calc.: 391.5 found: 392.2;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl-2-(3-methylphenyl)-3H-quinazolin-4-
one;
MS calc.: 361.5 found: 362.2.
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 4-
methyl-benzaldehyde, oxidation and cleavage from the solid phase, the
following compounds are obtained
with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-chloro-2-(4-methylphenyl)-3H-
quinazolin-4-one;
MS calc.: 395.9 found: 396.2;
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with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methyl-2-(4-methylphenyl)-3H-
quinazolin-4-one;
MS calc.: 375.5 found: 376.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-7-chloro-2-(4-methylphenyl)-3H-
quinazolin-4-one;
MS calc.: 395.9 found: 396.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methoxy-2-(4-methylphenyl)-3H-
quinazolin-4-one;
MS calc.: 391.5 found: 392.2;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl-2-(4-methylphenyl)-3H-quinazolin-4-
one;
MS calc.: 361.5 found: 362.2.
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 4-tert-
butyl-benzaldehyde, oxidation and cleavage from the solid phase, the
following compounds are obtained
with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-chloro-2-(4-tert-butylpheny1)-3H-
quinazolin-4-one;
MS calc.: 438.0 found: 438.2;
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with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methyl-2-(4-tert-butylphenyl)-3H-
quinazolin-4-one;
MS calc.: 417.6 found: 418.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-7-chloro-2-(4-tert-butylphenyl)-3H-
quinazolin-4-one;
N1S calc.: 438.0 found: 438.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methoxy-2-(4-tert-butylphenyl)-3H-
quinazolin-4-one;
MS calc.: 433.6 found: 434.2;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl-2-(4-tert-butylphenyl)-3H-quinazolin-4-
one;
MS calc.: 403.6 found: 404.3.
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 3-
chloro-benzaldehyde, oxidation and cleavage from the solid phase, the
following compounds are obtained
with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-chloro-2-(3-chlorophenyl)-3H-
quinazolin-4-one;
MS calc.: 416.4 found: 416.2;
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with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methyl-2-(3-chlorophenyl)-3H-
quinazolin-4-one;
MS talc.: 395.9 found: 396.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-7-chloro-2-(3-chlorophenyl)-3H-
quinazolin-4-one;
MS talc.: 416.3 found: 416.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methoxy-2-(3-chlorophenyl)-3H-
quinazolin-4-one;
MS talc.: 411.9 found: 412.1;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl-2-(3-chlorophenyl)-3H-quinazolin-4-
one;
MS talc.: 381.9 found: 382.2.
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 4-
methoxy-benzaldehyde, oxidation and cleavage from the solid phase, the
following compounds are obtained
with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-chloro-2-(4-methoxyphenyl)-3H-
quinazolin-4-one;
MS talc.: 411.9 found: 412.2;
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10
20
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methyl-2-(4-methoxyphenyl)-3H-
quinazolin-4-one;
MS calc.: 391.5 found: 392.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-7-chloro-2-(4-methoxyphenyl)-3H-
quinazolin-4-one;
MS caic.: 411.9 found: 412.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methoxy-2-(4-methoxyphenyl)-3H-
quinazolin-4-one;
MS calc.: 407.5 found: 408.2;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl-2-(4-methoxyphenyl)-3H-quinazolin-4-
one;
MS caic.: 377.5 found: 378.2.
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 3-
methoxy-benzaldehyde, oxidation and cleavage from the solid phase, the
following compounds are obtained
with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-chloro-2-(3-methoxyphenyl)-3H-
quinazolin-4-one;
MS calc.: 411.9 found: 412.1;
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with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methyl-2-(3-methoxyphenyl)-3H-
quinazolin-4-one;
MS calc.: 391.5 found: 392.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-7-chloro-2-(3-methoxyphenyl)-3H-
quinazolin-4-one;
w1S caic.: 411.9 found: 412.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methoxy-2-(3-methoxyphenyl)-3H-
quinazolin-4-one;
MS calc.: 407.5 found: 408.2;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl-2-(3-methoxyphenyl)-3H-quinazolin-4-
one;
MS calc.: 377.5 found: 378.2.
Example 4:
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila
COOH
R' Ila
/ N~H
O' _O
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cleavage of the Fmoc protecting group and reaction with 3,4,5-
trimethoxybenzaldehyde, oxidation and cleavage from the solid phase, the
following compounds are obtained
with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-chloro-2-(3,4,5-trimethoxyphenyl)-
3H-quinazolin-4-one;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methyl-2-(3,4,5-trimethoxyphenyl)-
3H-quinazolin-4-one;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-7-chloro-2-(3,4,5-trimethoxyphenyl)-
3H-quinazolin-4-one;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methoxy-2-(3,4,5-trimethoxyphenyl)-
3H-quinazolin-4-one;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(3,4, 5-trimethoxyphenyl)-3H-
quinazolin-4-one.
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 3,4-
dimethoxybenzaldehyde, oxidation and cleavage from the solid phase, the
following compounds are obtained
with R' = 3-CI in formula Ila
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3-(3-aminomethyl-cyclohexylmethyl)-6-chloro-2-(3,4-dimethoxyphenyl)-3H-
quinazolin-4-one;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methyl-2-(3,4-dimethoxyphenyl)-3H-
quinazolin-4-one;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-7-chloro-2-(3,4-dimethoxyphenyl)-3H-
quinazolin-4-one;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methoxy-2-(3,4-d imethoxyphenyl)-
3H-quinazolin-4-one;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(3,4-dimethoxyphenyl)-3H-
quinazolin-4-one.
Example 5:
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with
[2,2']bithiophenyl-5-carbaldehyde, oxidation and cleavage from the solid
phase, the following compounds are obtained
with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2,2']bithiophenyl-5-yl-6-chloro-3H-
quinazolin-4-one;
MS calc.: 470.1 found: 470.1;
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with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2,2']bithiophenyl-5-yl-6-methyl-3H-
quinazolin-4-one;
MS calc.: 449.6 found: 450.1;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2,2']bithiophenyl-5-yl-7-chloro-3H-
quinazolin-4-one;
MS cafe: 470.1 found: 470.1;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2,2']bithiophenyl-5-yl-6-methoxy-
3H-quinazolin-4-one;
MS calc.: 465.6 found: 466.1;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2,2']bithiophenyl-5-yl-3H-quinazolin-
4-one;
MS calc.: 435.6 found: 436.1.
Example 6:
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 3
furan-2-yl-propenal, oxidation and cleavage from the solid phase, the
following compounds are obtained
with R' = 3-CI in formula Ila
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3-(3-aminomethyl-cyclohexylmethyl)-6-chloro-2-(2-furan-2-yl-vinyl)-3H-
quinazolin-4-one;
MS calc.: 397.9 found: 398.2;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methyl-2-(2-furan-2-yl-vinyl)-3H-
quinazolin-4-one;
MS calc.: 377.5 found: 378.3;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-7-chloro-2-(2-furan-2-yl-vinyl)-3H-
quinazolin-4-one;
MS calc.: 397.9 found: 398.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methoxy-2-(2-furan-2-yl-vinyl)-3H-
quinazolin-4-one;
MS calc.: 393.5 found: 394.3;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(2-furan-2-yl-vinyl)-3H-quinazolin-4-
one;
MS calc.: 363.5 found: 364.2.
Example 7:
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with
cyclohexanecarbaldehyde, oxidation and cleavage from the solid phase,
the following compounds are obtained
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with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-chloro-2-cyclohexyl-3H-quinazolin-4-
one;
MS calc.: 388.0 found: 388.2;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methyl-2-cyclohexyl-3H-quinazolin-
4-one;
MS calc.: 367.5 found: 368.3;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-7-chloro-2-cyclohexyl-3H-quinazolin-4-
one;
MS calc.: 388.0 found: 388.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methoxy-2-cyclohexyl-3H-
quinazolin-4-one;
MS calc.: 383.5 found: 384.3;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-cyclohexyl-3H-quinazolin-4-one;
MS calc.: 353.5 found: 354.3.
Example 8:
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 3-
phenyl-propionaldehyde, oxidation and cleavage from the solid phase, the
following compounds are obtained
~C
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with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-chloro-2-phenylethyl-3H-quinazolin-
4-one;
MS calc.: 410.0 found: 410.3;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methyl-2-phenylethyl-3H-quinazolin-
4-one;
MS calc.: 389.5 found: 390.4;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-7-chloro-2-phenylethyl-3H-quinazolin-
4-one;
MS calc.: 410.0 found: 410.3;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-6-methoxy-2-phenylethyl-3H-
quinazolin-4-one;
MS calc.: 405.5 found: 406.3;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-phenylethyl-3H-quinazolin-4-one;
MS calc.: 375.5 found: 376.4.
Example 9:
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with
biphenyl-4-carbaldehyde, oxidation and cleavage from the solid phase, the
following compounds are obtained
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with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-biphenyl-4-yl-6-chloro-3H-
quinazolin-4-one;
MS calc.: 458.0 found: 458.2;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-biphenyl-4-yl-6-methyl-3H-
quinazolin-4-one;
MS caic.: 43 i .6 found: 438.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-biphenyl-4-yl-7-chloro-3H-
quinazolin-4-one;
MS calc.: 458.0 found: 458.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-biphenyl-4-yl-6-methoxy-3H-
quinazolin-4-one;
MS calc.: 453.6 found: 454.2;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-biphenyl-4-yl-3H-quinazolin-4-one;
MS calc.: 423.6 found: 424.2.
Example 10:
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with
thiophene-3-carbaldehyde, oxidation and cleavage from the solid phase,
the following compounds are obtained
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with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-thiophenyl-3-yl-6-chloro-3H-
quinazolin-4-one;
MS calc.: 387.9 found: 388.2;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-thiophenyl-3-yl-6-methyl-3H-
quinazolin-4-one;
MS calc.: 367.5 found: 368.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-thiophenyl-3-yl-7-chloro-3H-
quinazolin-4-one;
MS calc.: 387.9 found: 388.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-thiophenyl-3-yl-6-methoxy-3H-
quinazolin-4-one;
MS calc.: 383.5 ; found: 384.2;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-thiophenyl-3-yl-3H-quinazolin-4-one;
MS calc.: 353.5 found: 354.2.
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with
thiophene-2-carbaldehyde, oxidation and cleavage from the solid phase,
the following compounds are obtained
with R' = 3-CI in formula Ila
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3-(3-aminomethyl-cyclohexylmethyl)-2-thiophenyl-2-yl-6-chloro-3H-
quinazolin-4-one;
MS calc.: 387.9 found: 388.2;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-thiophenyl-2-yl-6-methyl-3H-
quinazolin-4-one;
MS calc.: 367.5 found: 368.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-thiophenyl-2-yl-7-chloro-3H-
quinazolin-4-one;
MS calc.: 387.9 found: 388.1;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-thiophenyl-2-yl-6-methoxy-3H-
quinazolin-4-one;
MS calc.: 383.5 found: 384.2;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-thiophenyl-2-yl-3H-quinazolin-4-one;
MS calc.: 353.5 found: 354.2.
Example 11:
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with
naphthalene-2-carbaldehyde, oxidation and cleavage from the solid phase,
the following compounds are obtained
with R' = 3-CI in formula Ila
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3-(3-aminomethyl-cyclohexylmethyl)-2-naphthalen-2-yl-6-chloro-3H-
quinazolin-4-one;
MS calc.: 432.0 found: 432.2;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-naphthalen-2-yl-6-methyl-3H-
quinazolin-4-one;
MS calc.: 411.6 found: 412.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-naphthalen-2-yl-7-chloro-3H-
quinazolin-4-one;
MS calc.: 432.0 found: 432.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-naphthalen-2-yl-6-methoxy-3H-
quinazolin-4-one;
MS calc.: 427.6 found: 428.2;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-naphthalen-2-yl-3H-quinazolin-4-
one;
MS calc.: 397.5 found: 398.2.
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with
naphthalene-1-carbaldehyde, oxidation and cleavage from the solid phase,
the following compounds are obtained
with R' = 3-CI in formula Ila
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3-(3-aminomethyl-cyclohexylmethyl)-2-naphthalen-1-yl-6-chloro-3H-
quinazolin-4-one;
MS calc.: 432.0 found: 432.2;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-naphthalen-1-yl-6-methyl-3H-
quinazolin-4-one;
MS calc.: 411.6 found: 412.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-naphthalen-1-yl-7-chloro-3H-
quinazolin-4-one;
MS calc.: 432.0 found: 432.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-naphthalen-1-yl-6-methoxy-3H-
quinazolin-4-one;
MS calc.: 427.6 found: 428.2;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-naphthalen-1-yl-3H-quinazolin-4-
one;
MS calc.: 397.5 found: 398.2.
Example 12:
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 3-
phenyi-propenal, oxidation and cleavage from the solid phase, the following
compounds are obtained
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with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-styryl-6-chloro-3H-quinazolin-4-one;
MS calc.: 407.9 found: 408.2;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-styryl-6-methyl-3H-quinazolin-4-one;
MS calc.: 387.5 found: 388.3;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-styryl-7-chloro-3H-quinazolin-4-one;
MS calc.: 407.9 found: 408.2;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-styryl-6-methoxy-3H-quinazolin-4-
one;
MS calc.: 403.5 found: 404.3;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-styryl-3H-quinazolin-4-one;
MS calc.: 373.5 found: 374.3.
Example 13:
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with
benzofuran-5-carbaldehyde, oxidation and cleavage from the solid phase,
the following compounds are obtained
with R' = 3-CI in formula Ila
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3-(3-aminomethyl-cyclohexylmethyl)-2-benzofuran-5-yl-6-chloro-3H-
quinazolin-4-one;
MS calc.: 421.9 found: 422.2;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-benzofuran-5-yl-6-methyl-3H-
quinazolin-4-one;
MS calc.: 401.5 found: 402.2;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-benzofuran-5-yl-7-chloro-3H-
quinazolin-4-one;
MS calc.: 421.9 found: 422.2;
~rvith R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-benzofuran-5-yl-6-methoxy-3H-
quinazolin-4-one;
MS calc.: 417.5 found: 418.1;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-benzofuran-5-yl-3H-quinazolin-4-
one;
MS calc.: 387.5 found: 388.2.
Example 14:
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 3-(4-
dimethylamino-phenyl)-propenal, oxidation and cleavage from the solid
phase, the following compounds are obtained
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with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2-(4-dimethylamino-phenyl)-vinyl]-6-
chloro-3H-quinazolin-4-one;
MS calc.:451.0;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(2-(4-dimethylamino-phenyl)-vinyl]-6-
methyl-3H-quinazolin-4-one;
MS calc.:430.6;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2-(4-dimethylamino-phenyl)-vinyl]-7-
chloro-3H-quinazolin-4-one;
MS calc.:451.0;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2-(4-dimethylamino-phenyl)-vinyl]-6-
methoxy-3H-quinazolin-4-one;
MS calc.:446.6;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2-(4-dimethylamino-phenyl)-vinyl]-
3H-quinazolin-4-one;
MS calc.:416.6.
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 3-(2,5-
dimethoxy-phenyl)-propenal, oxidation and cleavage from the solid phase,
the following compounds are obtained
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with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2-(2,5-dimethoxy-phenyl)-vinyl]-6-
chloro-3H-quinazolin-4-one;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2-(2,5-dimethoxy-phenyl)-vinyl]-6-
methyl-3H-quinazolin-4-one;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2-(2,5-dimethyoxy-phenyl)-vinyl]-7-
chloro-3H-quinazolin-4-one;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2-(2,5-dimethoxy-phenyl)-vinyl]-6-
methoxy-3H-quinazolin-4-one;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[2-(2,5-dimethoxy-phenyl)-vinyl]-3H-
quinazolin-4-one.
Example 15:
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 4-
bromo-benzaldehyde, Suzuki-reaction with 2,4-dimethoxyphenyl boronic
acid as indicated afterwards, oxidation and cleavage from the solid phase,
the following compounds are obtained
with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(2',4'-dimethoxy-biphenyl-4-yl)-6-
chloro-3H-quinazolin-4-one;
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with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(2',4'-dimethoxy-biphenyl-4-yl)-6-
methyl-3H-quinazolin-4-one;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(2',4'-dimethoxy-biphenyl-4-yl)-7-
chloro-3H-quinazolin-4-one;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(2',4'-dimethoxy-biphenyl-4-yl)-6-
methoxy-3H-quinazolin-4-one;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(2',4'-dimethoxy-biphenyl-4.-yl)-3H-
quinazolin-4-one.
Suzuki reaction according to G.C. Fu et al., Angew. Chem. 1998, 110,
3586-3587:
1 gram of resin bound 3-(3-aminomethyl-cyclohexylmethyl)-2-(4-
bromophenyl)-3H-quinazolin-4-one is suspended in 10 ml of 1,4-dioxane.
The reaction is then treated with 1.62 mmol CszC03, 1.62 mmol of 2,4-
dimethoxyphenyl boronic acid and 10 mol% ([Pdz(dba)3] + P(tert-Bu)3). The
reaction is then allowed to shake at 80° until conversion is complete.
After
cooling the reaction mixture, it is worked up as is customary.
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 4-
bromo-benzaldehyde, Suzuki-reaction with 3,5-dimethoxyphenyl boronic
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acid as indicated afterwards, oxidation and cleavage from the solid phase,
the following compounds are obtained
with R' = 3-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(3',5'-dimethoxy-biphenyl-4-yl)-6-
chloro-3H-quinazolin-4-one;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(3',5'-dimethoxy-biphenyl-4-yl)-6-
methyl-3H-quinazolin-4-one;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(3',5'-dimethoxy-biphenyl-4-yl)-7-
chloro-3H-quinazolin-4-one;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(3',5'-dimethoxy-biphenyl-4-yl)-6-
methoxy-3H-quinazolin-4-one;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-(3',5'-dimethoxy-biphenyl-4-yl)-3H-
quinazolin-4-one.
Analogously to example 2, by reaction of resin (2) with a compound of
formula Ila, cleavage of the Fmoc protecting group and reaction with 5-
bromo-thiophenyl-2-carbaldehyde, Suzuki-reaction with 3,4-
dimethoxyphenyl boronic acid as indicated afterwards, oxidation and
cleavage from the solid phase, the following compounds are obtained
with R' = 3-CI in formula Ila
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3-(3-aminomethyl-cyclohexylmethyl)-2-[5-(2,4-dimethoxy-phenyl)-2-
thiophenyl]-6-chloro-3H-quinazolin-4-one;
with R' = 3-CH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[5-(2,4-dimethoxy-phenyl)-2-
thiophenyl]-6-methyl-3H-quinazolin-4-one;
with R' = 4-CI in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[5-(2,4-dimethoxy-phenyl)-2-
thiophenyl]-7-chloro-3H-quinazolin-4-one;
with R' = 3-OCH3 in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[5-(2,4-dimethoxy-phenyl)-thiophen-
2-yl]-6-methoxy-3H-quinazolin-4-one;
with R' = H in formula Ila
3-(3-aminomethyl-cyclohexylmethyl)-2-[5-(2,4-dimethoxy-phenyl)-thiophen-
2-yl]-3H-quinazolin-4-one.
The following examples relate to pharmaceutical preparations:
Example A: Injection vials
A solution of 100 g of an active compound of the formula I and 5 g of
disodium hydrogenphosphate is adjusted to pH 6.5 in 3 I of double-distilled
water using 2N hydrochloric acid, sterile-filtered, dispensed into injection
vials, lyophilized under sterile conditions and aseptically sealed. Each
injection vial contains 5 mg of active compound.
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Example B: Suppositories
A mixture of 20 g of an active compound of the formula I is melted with
100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and
allowed to cool. Each suppository contains 20 mg of active compound.
Example C: Solution
A solution is prepared from 1 g of an active compound of the formula I,
9.38 g of NaH2P04.2Hz0, 28.48 g of Na2HP04.12H20 and 0.1 g of
benzalkonium chloride in 940 ml of double-distilled water. The mixture is
adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This
solution
can be used in the form of eye drops.
Example D: Ointment
500 mg of an active compound of the formula I is mixed with 99.5 g of
petroleum jelly under aseptic conditions.
Example E: Tablets
A mixture of 1 kg of active compound of the formula I, 4 kg of lactose,
1.2 kg of potato starch, 0.2 g of talc and 0.1 kg of magnesium stearate is
compressed in a customary manner to give tablets such that each tablet
contains 10 mg of active compound.
Example F: Coated tablets
Analogously to Example E, tablets are pressed which are then coated with
a coating of sucrose, potato starch, talc, tragacanth and colourant in a
customary manner.
Example G: Capsules
2 kg of active compound of the formula I are dispensed into hard gelatin
capsules in a customary manner such that each capsule contains 20 mg of
the active compound.
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Example H: Ampules
A solution of 1 kg of active compound of the formula I in 60 ml of double-
distilled water is sterile-filtered, dispensed into ampoules, lyophilized
under
sterile conditions and aseptically sealed. Each ampoule contains 10 mg of
active compound.
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