Note: Descriptions are shown in the official language in which they were submitted.
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APD62599PC 1
AS ORIGINALLY FILED
Substituted N-cyclohexyl imidazolinones having an
MCH-modulatory effect
The invention relates to substituted N-cyclohexylheterocycles and to the
physiologically
tolerated salts and physiologically functional derivatives thereof.
Compounds similar in their overall structure to the heteroatom-substituted
cyclohexylimidazolinones described herein and having a pharmacological effect
have been
described in the prior art. Thus, for example, WO 03/057220 describes
imidazolone
derivatives (cyclic urea derivatives) having 5-HT2~ receptor activity which
can be used for
the treatment of disorders of the central nervous system, such as depression
and anxiety,
and gastrointestinal complaints. These compounds each have an aromatic group
as
substituent on the central nitrogen atoms.
The non-prior-published application with earlier priority and the file number
DE 102 33 817.5 (WO 2004/11438) likewise relates to cyclic urea derivatives
each having
an aromatic group as substituent on the central nitrogen atoms, where one of
the aromatic
groups has at least one nitrogen-containing substituent. The aryl-substituted
cyclic urea
derivatives have an MCH-modulatory effect. The compounds are suitable for
example as
anorectic agents.
In addition, EP-A 0 503 548 and EP-A 0 587 134 describe similar compounds
having a
pharmacological effect. EP 0 503 548 and EP 0 587 134 relate to cyclic urea
derivatives
which have aggregation-inhibiting effects, to medicaments comprising these
compounds
and to processes for their preparation.
Compounds having an MCH-antagonistic effect for the treatment of obesity are
described
in the prior art (examples: WO 2001021577, WO 2003035624, WO 2002089729,
WO 2002006245, WO 2002002744, WO 2002057233, WO 2003045313,
WO 2003097047, WO 2002010146, WO 2003087044).
CA 02554233 2006-07-24
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The invention was based on the object of providing compounds which bring about
a weight
reduction in mammals and which are suitable for the prevention and treatment
of obesity
and diabetes.
A series of compounds which modulate the activity of MCH receptors has
surprisingly
been found. The compounds are distinguished in particular by antagonism of the
MCH 1 R.
The invention therefore relates to compounds of the formula I,
R 1 E ~ G A-Q
wK~ vX~N N
R2
to ~ ( )~ I
in which the meanings are
R1 H, (C,-C8)-alkyl, (C~-C4)-alkoxy-(C,-C4)-alkyl, (C3-C&)-alkenyl, (C~-Cg)-
alkynyl, a 3 to 10-membered mono-, bi- or spirocyclic ring which may
include 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and
sulfur, where the ring system may be additionally substituted by F, Cl, Br,
CF3, NOZ, CN, (C1-C6)-alkyl, O-(C1-C8)-alkyl, S-(C1-Cg)-alkyl, (C1-Cø)-
alkoxy-(C1-C4)-alkyl, (Co-Cg)-alkylene-aryl, oxo, CO(R3), CON(R4)(RS),
hydroxy, hydroxy-(C,-C4)-alkyl, COO(R6), N(R7)CO(C,-C6)-alkyl,
N(R8)(R9) or SOZCH3;
R3, R4, R5, R6, R7, R8, R9,
independently of one another H, (C1-C6)-alkyl;
K a group of the formula -(CR 1 OR 11 )Z , in which one or more -(CR l OR 11 )-
groups may be replaced by Z to result in a chemically reasonable radical, a
bond, C-_-C, C=C;
Z O, CO, N(R59), S, SO, SOZ;
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APD62599PC 3
R10, R11 independently of one another H, (C1-Cg)-alkyl, hydroxy-(Ci-C4)-alkyl,
hydroxy, (C~-C4)-alkoxy-(C1-C4)-alkyl, where R10 and R11 in the z groups
may in each case have the same or different meanings;
z 1,2,3,4,5,6;
R59 H, (C1-Cg)-alkyl;
E 3-14 membered bivalent carbo- or heterocyclic ring structure having 0-4
heteroatoms from the group of N, O and S, which may optionally have
substituents from the group of H, F, Cl, Br, I, OH, CF3, N02, CN, OCF3,
oxo, O-(C,-C6)-alkyl, O-(C,-C4)-alkoxy-(CI-C4)-alkyl, S-(C~-C6)-alkyl, (C1-
C6)-alkyl, (CZ-C6)-alkenyl, (C3-Cg)cycloalkyl, O-(C3-Cg)cycloalkyl, (C3-
C8)cycloalkenyl, O-(C3-C8)cycloalkenyl, (C2-C6)-alkynyl, (Co-Cg)-alkylene-
aryl, O-(Co-Cg)-alkylene-aryl, S-aryl, N(R12)(R13), SOZ-CH3, COOH,
COO-(C,-C6)-alkyl, CON(R14)(R15), N(R16)CO(R17), N(R18)SOZ(R19),
CO(R20) and be mono or bicyclic; preferably 3-I4 membered bivalent
carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of
N, O and S, which may optionally have substituents from the group of H, F,
Cl, Br, I, OH, CF3, NO2, CN, OCF3, oxo, O-(C,-C6)-alkyl, O-(C~-C4)-
alkoxy-(C,-C4)-alkyl, S-(Cf-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl,
N(R 12)(R 13), S02-CH3, N(R 16)CO(R 17), N(R 18)S02(R 19), CO(R20) and
be mono- or bicyclic;
R12, R13, R14, R15, R16, R18
independently of one another H, (C1-Cg)-alkyl;
or
R 12 and R 13, R 14 and R 15
independently of one another, optionally together with the nitrogen atom to
which they are bonded, a 5-6 membered ring which, apart from the nitrogen
atom, may also include 0-1 further heteroatoms from the group of N-(C,-
C6)-alkyl, oxygen and sulfur;
R 17, R 19, R20
CA 02554233 2006-07-24
API)62599PC 4
independently of one another H, (C,-Cg)-alkyl, aryl;
X a bond, a group of the formula -(CR21R22)y-, in which one or more
-(CR21R22)- groups may be replaced by Y to result in a chemically
_5 reasonable radical;
Y O, CO, N(R23), S, SO, 502;
R21, R22 independently of one another H, (C1-C~)-alkyl, where R21 and R22 in
the y
groups may in each case have the same or different meanings;
y l, 2, 3, 4, 5, 6; preferaby 2, 3, 4, 5, 6;
R23 H, (C~-Cg)-alkyl;
D, G CH or N;
R2 OH, O-(C1-C6)-alkyl, O-(C1-C4)-alkoxy-(C1-C4)-alkyl, (C,-C6)-alkyl;
n 0, l, 2, 3, 4;
Q N(R24)(R25), a 3 to 8-membered ring which may include 0 to 3
heteroatoms selected from the group of oxygen, nitrogen and sulfur, where
the ring system may additionally be substituted by (Co-C4)-alkylene-
N(R24)(R25), preferably N(R24)(R25); F, Cl, Br, CF3, N02, CN, (C1-C6)-
alkyl, O-(C1-Cg)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (Co-Cg)-alkylene-aryl,
oxo, CO(R26), CON(R27)(R28), hydroxy, hydroxy-(C,-Ca)-alkyl,
COO(R29), N(R30)CO(C1-C6)-alkyl or S02CH3;
R26, R27, R28, R29, R30
independently of one another H, (C,-C6)-alkyl;
A a group of the formula -(C(R31)(R32))m-, in which 0-2 members may be
replaced by an element from the group of O, S, N(R33), CO, S02;
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APD62599PC 5
m 0, 1, 2, 3, 4, 5;
R31, R32, R33
independently of one another H, (C1-C6)-alkyl, aryl;
R24, R25 independently of one another H, (C,-C8)-alkyl, -(CR34R35)o-R36, (C~-
C4)-
alkoxy-(C1-C4)-alkyl, (C3-Cg)-alkenyl, (C3-C8)-alkynyl, CO-(C1-C8)-alkyl, -
CO-(CH2)Q -R36, CO(C(R37)(R38))qN(R39)(R40),
CO(C(R41)(R42))SO(R43); or R24 and R25 form together with the nitrogen
atom to which they are bonded a 4 to 10-membered mono-, bi- or
spirocyclic ring which, apart from the nitrogen atom, may include 0 to 4
additional heteroatoms selected from the group of oxygen, nitrogen and
sulfur, where the heterocyclic ring system~may additionally be substituted
by F, Cl, Br, CF3, N02, CN, (Cl-C6)-alkyl, O-(Ct-Cg)-alkyl, (C~-C4)-
alkoxy-(C1-Cd)-alkyl, hydroxy-(CI-C4)-alkyl, (Co-Cg)-alkylene-aryl, oxo,
CO(R44), CON(R45)(R46), hydroxy, COO(R47), N(R48)CO(Ci-C6)-alkyl,
N(R49)(R50) or S02CH3;
0 0, 1, 2, 3, 4, 5, 6;
q, s independently of one another 0, 1, 2, 3, 4;
R34, R35 independently of one another H, (CI-C8)-alkyl, hydroxy-(C1-C4)-alkyl,
OH,
(C1-C4)-alkoxy-(C1-C4)-alkyl;
R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50
independently of one another H, (Cl-C6)-alkyl;
R39 and R40, R45 and R46, R49 and R50
independently of one another, optionally together with the nitrogen atom to
which they are bonded a 5-6 membered ring which, apart from the nitrogen
atom, may also include 0-1 further heteroatoms from the group of N-(C1-
C6)-alkyl, oxygen and sulfur;
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APD62599PC 6
R36 OH, O-(C1-C6)-alkyl, O-(Co-CA)-alkylene-aryl, CON(R51)(R52),
N(R53)(R54), 3-12 membered mono-, bi- or spirocyclic ring which may
comprise one or more heteroatoms from the group of N, O and S, and the 3-
12 membered ring may comprise further substituents such as F, Cl, Br, I,
OH, CFA, NOz, CN, OCF3, oxo, O-(C,-C6)-alkyl, (C,-C4)-alkoxy-(C1-C4)
alkyl, S-(C1-C6)-alkyl, (C,-C6)-alkyl, (C2-C6)-alkenyl, (C~-Cg)cycloalkyl, O
(C3-Cg)cycloalkyl, (C3-C8)cycloalkenyl, O-(C3-Cg)cycloalkenyl, (CZ-C6)
alkynyl, O-(Co-Cg)-alkylene-aryl, (Co-Cg)-alkylene-aryl, N(R55)(R56),
CO(C,-C6)-alkyl, COO(R57) and S(O)" (R58);
a 0, 1, 2;
R51, 52 independently of one another H, (C,-C8)-alkyl, (C2-C6)-alkenyl, (Co-
Cg)-
l 5 alkylene-aryl;
R53, R54 independently of one another H, (C1-C6)-alkyl;
R55, R56 independently of one another H, (C,-Cg)-alkyl;
R57 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (Co-C8)-alkylene-aryl;
R58 (C1-C6)-alkyl, 5-10 membered aromatic ring system which may comprise 0
2 further heteroatoms from the group of nitrogen, oxygen and sulfur and be
substituted by F, Cl, Br, CF3, N02, CN, (C,-Cg)-alkyl, O-(C1-C8)-alkyl;
and the physiologically tolerated salts thereof.
The radicals R 1 and R2, the index n and the groups K, E, X, D=G, Q and A
preferably
have, independently of one another, the following meanings:
R1 H, (C~-Cg)-alkyl, (C,-C4)-alkoxy-(C,-C4)-alkyl, a 3-8 membered
monocyclic ring which may include 0 to 3 heteroatoms selected from the
group of oxygen, nitrogen and sulfur, where the ring system may
CA 02554233 2006-07-24
APD62599PC 7
additionally be substituted by F, Cl, Br, (C1-C6)-alkyl, O-(C,-Cg)-alkyl, (C~-
C4)-alkoxy-(C ~-C4)-alkyl;
preferably (C1-C8)-alkyl, a 3-7 membered monocyclic ring which may
include 0 to 2 heteroatoms selected from the group of oxygen, nitrogen and
sulfur, where the ring system may additionally be substituted by F, Cl, Br,
(C,-C6)-alkyl, O-(Cl-Cg)-alkyl;
particularly preferably (C,-C6)-alkyl, (C~-C7)-cycloalkyl and phenyl.
K O, a bond, C=_C, CO, OCH2, OCH2CH2,
preferably O, a bond;
l5 particularly preferably O.
E a 5-6 membered monocyclic bivalent carbo- or heterocyclic ring structure
having 0-2 heteroatoms from the group of N, O and S, which may
optionally have substituents from the group of H, F, Cl, Br, oxo, O-(C1-C6)
alkyl, O-(C~-C4)-alkoxy-(C,-C4)-alkyl, (C,-C6)-alkyl;
preferably a para- or meta-substituted 6 membered aromatic or
heteroaromatic ring structure which may optionally have 1-2 substituents
from the group of F, Cl, Br, O-(C,-C6)-alkyl, (Cl-C6)-alkyl;
particularly preferably an unsubstituted 1,4-phenylene or 2,5-pyridylene
unit.
X a bond, CH2CH2, CH2CHZCH2, OCH2CH2;
preferably a bond, CHZCHZ;
particularly preferably a bond.
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APD62599PC 8
D=G CH=CH, CH=N, N=CH;
preferably CH=CH, N=CH;
particularly preferably CH=CH.
R2 OH, O-(C~-C6)-alkyl, (C,-C6)-alkyl;
preferably OH, (C,-C6)-alkyl;
particularly preferably (C~-C6)-alkyl.
n 0, 1, 2;
preferably 0, l;
particularly preferably 0.
Q a group of the formula N(R24)(R25), a 3 to 8-membered ring having
0-3 heteroatoms from the group of oxygen, nitrogen and sulfur, where the
ring system may additionally be substituted by N(R24)(R25), F, Cl, Br, CF3,
N02, CN, (C1-C6)-alkyl, O-(C1-Cg)-alkyl, (C1-C4)-alkoxy-(C~-C4)-alkyl,
(Co-Cg)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy,
COO(R29), N(R30)CO(C,-C6)-alkyl, or SO2CH3;
preferably a group of the formula N(R24)(R25), a nitrogen-containing 4 to
8-membered ring which, apart from the nitrogen atom, may also comprise
further 0-2 heteroatoms from the group of oxygen, nitrogen and sulfur, and
where the ring system may additionally be substituted by N(R24)(R25), F,
(C1-C6)-alkyl, O-(C1-C8)-alkyl, (C,-C4)-alkoxy-(C,-C4)-alkyl, (Co-C8)-
alkylene-aryl, oxo, CO(R26), N(R30)CO(C1-C6)-alkyl, or SOZCH3;
particularly preferably a group of the formula N(R24)(R25), a nitrogen-
containing 5 to 8-membered ring which, apart from the nitrogen atom, may
CA 02554233 2006-07-24
APD62599PC 9
also comprise further 0-1 heteroatoms from the group of oxygen, nitrogen
and sulfur, and where the ring system may additionally be substituted by
N(R24)(R25), (C,-C6)-alkyl, O-(C1-Cg)-alkyl, (Co-C8)-alkylene-aryl, oxo,
CO(R26), N(R30)CO(C1-C6)-alkyl, or SOZCH3;
very particularly preferably a group of the formula N(R24)(R25), a
nitrogen-containing 5 to 8-membered ring which, apart from the nitrogen
atom, may also comprise further 0-l heteroatoms from the group of oxygen,
nitrogen and sulfur, and where the ring system may additionally be
substituted by N(R24)(R25), (CI-C6)-alkyl or N(R30)CO(C1-C6)-alkyl;
R24, R25 independently of one another H, (C1-Cg)-alkyl, -(CR34R35)o R36, (C,-
C4)-
alkoxy-(CI-C4)-alkyl, (C3-Cs)-alkenyl, (C3-Cg)-alkynyl, CO-(C,-Cg)-alkyl,
-CO-(CH2)o-R36, or R24 and R25 form together with the nitrogen atom to
which they are bonded a 4 to 8-membered monocyclic ring which, apart
from the nitrogen atom, may include 0 to 2 additional heteroatoms selected
from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring
system may additionally be substituted by F, (C1-C6)-alkyl, O-(C1-Cg)-alkyl,
(C,-C4)-alkoxy-(CI-C4)-alkyl, hydroxy-(Cl-C4)-alkyl, (Co-Cg)-alkylene-aryl,
oxo, CO(R44), N(R48)CO(C~-C6)-alkyl, N(R49)(R50) or S02CH3;
preferably independently of one another H, (C1-Cg)-alkyl, (C~-C4)-alkoxy-
(C,-C4)-alkyl, CO-(C,-C8)-alky, or R24 and R25 form together with the
nitrogen atom to which they are bonded a 4 to 8-membered monocyclic ring
which, apart from the nitrogen atom, may include 0 or 1 additional
heteroatoms selected from the group of oxygen, nitrogen and sulfur, where
the heterocyclic ring system may additionally be substituted by (C1-C6)-
alkyl, N(R48)CO(C1-C6)-alkyl or N(R49)(R50);
particularly preferably independently of one another H, (C1-Cg)-alkyl,
CO-(C1-Cg)-alkyl, or R24 and R25 form together with the nitrogen atom to
which they are bonded a 5 to 7-membered monocyclic ring which, apart
from the nitrogen atom, may also comprise a further nitrogen atom, where
the heterocyclic ring system may additionally be substituted by (C,-C6)-
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APD62599PC I 0
alkyl, N(R48)CO(Cl-C6)-alkyl or N(R49)(R50);
0 0, l, 2, 3, 4, 5;
preferably 0, 1, 2, 3, 4;
particularly preferably 0, l, 2, 3;
R34, R35 independently of one another H, (C1-Cg)-alkyl, hydroxy-(C1-C4)-alkyl,
OH,
(C,-C4)-alkoxy-(C1-C4)-alkyl;
preferably H, (C1-Cg)-alkyl;
particularly preferably H;
R44, R48, R49, R50
independently of one another H, (C1-C6)-alkyl;
R49 and R50
optionally together with the nitrogen atom to which they are bonded a
5-6 membered ring which, apart from the nitrogen atom, may also include
0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and
sulfur;
R36 O-(C~-C6)-alkyl, 5-8 membered monocyclic ring which may comprise 0-2
heteroatoms from the group of N, O and S, and the 5-8 membered ring may
comprise further substituents such as F, Cl, Br, oxo, O-(C1-C6)-alkyl, (C,-
C4)-alkoxy-(Cl-C4)-alkyl, (Cl-C6)-alkyl, (Co-C8)-alkylene-aryl,
N(R55)(R56);
preferably O-(C~-C6)-alkyl;
R55, R56 independently of one another H, (C1-Cg)-alkyl;
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APD62599PC 11
R26, R30 independently of one another H, (CI-C6)-alkyl.
A a group of the formula -(C(R31 )(R32))m-, in which one member may be
replaced by an element from the group of O, N(R33);
preferably a bond or a group of the formula -(C(R31)(R32))m in which one
member is replaced by an element from the group of O, N(R33);
particularly preferably a bond, or a group of the formula -(C(R31)(R32))m-
in which one member is replaced by an element from the group of O,
N(R33), and the group bonds via the heteroatom in position 4 (relative to
the cyclic urea) on the cyclohexane ring of the formula I;
m 0, 1,2,3;
preferably 0, 1, 3;
R31, R32, R33 independently of one another H, (C~-C6)-alkyl, aryl.
If radicals or substituents may occur more than once in the compounds of the
formula I,
such as, for example, R2, they may all, independently of one another, have the
indicated
meanings and be identical or different.
The invention relates to compounds of the formula I in the form of their
racemates,
enantiomer-enriched mixtures and pure enantiomers, and to their diastereomers
and
mixtures thereof.
The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4,
R5, R6, R7, R8,
R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24,
R25,
R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40,
R41, R42,
R43, R44, R45, R46, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56,
R57, R58
and R59 may be either straight-chain, branched or optionally halogenated.
In a further embodiment, the alkyl, alkenyl and alkynyl radicals in the
substituents R1, R2,
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APD62599PC 12
R3, R4, R5, R6, R7, R8, R9, R 10, R 11, R 12, R 13, R 14, R 15, R 16, R 17, R
18, R 19, R20,
R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35,
R36, R37,
R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52,
R53, R54,
R55, R56, R57, R58 and R59 may be both straight-chain, branched and/or
optionally
substituted by substituents such as aryl, heteroaryl, alkoxy or halogen. This
also applies if
the alkyl, alkenyl and alkynyl radicals are part of another group, for example
part of an
alkoxy group (such as (Ci-C4)-alkoxy-(C,-C4)-alkyl)). Suitable halogens are
fluorine,
chlorine, bromine and iodine, preferably fluorine, chlorine and bromine,
particularly
preferably fluorine.
Examples of alkyl groups are: methyl, ethyl, propyl, butyl, pentyl, hexyl,
heptyl and octyl.
Included therein are both the n isomers of these radicals and branched isomers
such as
isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, neopentyl, 3,3-
dimethylbutyl etc.
Unless described otherwise, the term alkyl additionally includes alkyl
radicals which are
unsubstituted or optionally substituted by one or more further radicals, for
example 1, 2, 3
or 4 identical or different radicals such as aryl, heteroaryl, alkoxy or
halogen. It is
moreover possible for the additional substituents to occur in any position of
the alkyl
radical.
Cycloalkyl means for the purposes of the present application cycloalkyl and
cycloalkyl-
alkyl (alkyl which is substituted in turn by cycloalkyl, e.g.
cyclopropylmethyl), where
cycloalkyl has at least 3 carbon atoms. Examples of cycloalkyl radicals are:
cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and
cyclodecyl.
Optional possibilities are also polycyclic ring systems such as decalinyl,
norbornanyl,
bornanyl or adamantanyl. The cycloalkyl radicals may be unsubstituted or
optionally
substituted by one or more further radicals as listed above by way of example
for the alkyl
radicals.
Examples of alkenyl and alkynyl groups are: vinyl, 1-propenyl, 2-propenyl
(allyl),
2-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, ethynyl, 1-propynyl, 2-
propynyl
(propargyl), 1-butynyl, 2-butynyl or 3-butynyl.
Cycloalkenyl means for the purposes of the present application cycloalkenyl
radicals and
cycloalkenyl-alkyl radicals (alkyl which is substituted by cycloalkenyl),
which comprise at
CA 02554233 2006-07-24
APD62599PC 13
least three carbon atoms. Examples of cycloalkenyl are: cyclopentenyl,
cyclohexenyl,
cycloheptenyl and cyclooctenyl.
The alkenyl radicals and cycloalkenyl radicals may have one to three
conjugated or
unconjugated double bonds (thus also alk-dienyl and alk-trienyl radicals),
preferably one
double bond in a straight or branched chain. The same applies to the triple
bonds in alkynyl
radicals. The alkenyl and alkynyl radicals may be unsubstituted or optionally
substituted by
one or more further radicals as listed above by way of example for the alkyl
radicals.
Aryl refers in the present invention to radicals derived from monocyclic or
bicyclic
aromatic compounds comprising no ring heteroatoms. Where aryl refers to
systems which
are not monocyclic, the saturated form (perhydroform) or the partially
unsaturated from
(for example the dihydroform or tetrahydroform) is also possible, where the
respective
forms are known and stable, for the second ring. The term aryl also includes
in the present
invention for example bicyclic radicals in which both rings are aromatic and
bicyclic
radicals in which only one ring is aromatic. Examples of aryl are: phenyl,
naphthyl,
indanyl, 1,2-dihydronaphthenyl, 1,4-dihydronaphthenyl, indenyl or
1,2,3,4-tetrahydronaphthyl. Aryl is particularly preferably phenyl or
naphthyl. The term
"aryl" thus means in particular a phenyl or naphthyl group.
Heteroaryl radicals mean radicals derived from monocyclic or bicyclic aromatic
compounds comprising ring heteroatoms, preferably N, O or S. Otherwise, the
statements
made about aryl radicals apply to heteroaryl radicals.
The aryl and heteroaryl radicals may be unsubstituted or substituted by one or
more further
radicals. Suitable further radicals are listed by way of example above for the
alkyl radicals.
The compounds of the formula I may comprise one or more centers of asymmetry.
The
compounds of the formula I may therefore be in the form of their racemates,
enantiomer-
enriched mixtures, pure enantiomers, diastereomers and diastereomer mixtures.
The
present invention includes all these isomeric forms of the compounds of the
formula I.
These isomeric forms can be obtained by known methods even if not expressly
described
in some cases.
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APD62599PC 14
Mono-, bi- or spirocyclic rings may be saturated, partially saturated or
unsaturated and also
bridged.
C=C means a group of the formula R'C=CR" in which R' and R" are independently
of one
another H, (C~-Cs)-alkyl, preferably H.
Pharmaceutically acceptable salts are, because their solubility in water is
greater than that
of the initial or basic compounds, particularly suitable for medical
applications. These salts
must have a pharmaceutically acceptable anion or cation. Suitable
pharmaceutically
acceptable acid addition salts of the compounds of the invention are salts of
inorganic acids
such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric,
sulfonic and
sulfuric acid, and of organic acids such as, for example, acetic acid,
benzenesulfonic,
benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic,
lactic, lactobionic,
malefic, malic, methanesulfonic, trifluoromethanesulfohic, succinic, p-
toluenesulfonic,
tartaric and trifluoroacetic acid. For medical purposes the chlorine salt is
particularly
preferably used. Suitable pharmaceutically acceptable basic salts are ammonium
salts,
alkali metal salts (such as sodium and potassium salts), alkaline earth metal
salts (such as
magnesium and calcium salts) and salts of trometamol (2-amino-2-hydroxymethyl-
1,3-propanediol), diethanolamine, lysine or ethylenediamine.
Salts with a pharmaceutically unacceptable anion likewise belong within the
framework of
the invention as useful intermediates for the preparation or purification of
pharmaceutically
acceptable salts andlor for use in nontherapeutic, for example in vitro,
applications.
The term "physiologically functional derivative" used herein refers to any
physiologically
tolerated derivative of a compound of the formula I of the invention, for
example an ester,
which on administration to a mammal such as, for example, a human is able to
form
(directly or indirectly) a compound of the formula I or an active metabolite
thereof.
Physiologically functional derivatives include prodrugs of the compounds of
the invention,
as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-
61. Such
prodrugs can be metabolized in vivo to a compound of the invention. These
prodrugs may
themselves be active or not.
CA 02554233 2006-07-24
APD62599PC 15
The compounds of the invention may also exist in various polymorphous forms,
for
example as amorphous and crystalline polymorphous forms. All polymorphous
forms of
the compounds of the invention belong within the framework of the invention
and are a
further aspect of the invention.
All references to "compound(s) of formula (I)" hereinafter refer to compounds)
of the
formula (I) as described above, and their salts, solvates and physiologically
functional
derivatives as described herein.
If radicals or substituents may occur more than once in the compounds of the
formula I,
they may all, independently of one another, have the indicated meanings and be
identical
or different.
In a further preferred embodiment, the meanings for the radicals R1, R2, the
index n and
L 5 the groups K, E, X, D, G, A and Q are as follows:
R1 (Ci-Cg)-alkyl, (C,-C4)-alkoxy-(Ci-C4)-alkyl, a 3 to 10-membered mono-, bi-
or spirocyclic ring which may include 0 to 3 heteroatoms selected from the
group of oxygen, nitrogen and sulfur, where the ring system may be
additionally substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O-(C,-Cg)-
alkyl, (Co-CZ)-alkylene-aryl, oxo, CO(R3), CON(R4)(RS), hydroxy,
N(R7)CO(C,-C6)-alkyl, N(R8)(R9) or SOZCH3;
preferably (C~-Cg)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, a 3 to 10-membered
mono- or bicyclic ring which may include 0 to 2 heteroatoms selected from
the group of oxygen, nitrogen and sulfur, where the ring system may be
additionally substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O-(C1-Cg)-
alkyl, oxo, CO(R3), CON(R4)(RS), N(R7)CO(C1-C6)-alkyl, or S02CH3;
R3, R4, R5, R7, R8, R9
independently of one another H, (C ~-Cg)-alkyl;
K a bond, OCHZ, CH20, (C(R 10)(R 11 ))Z, Cue;
z l, 2, 3, 4; preferably 1, 2, 3; particularly preferably 1,2;
CA 02554233 2006-07-24
APD62599PC I 6
R10, R11 independently of one another H, (C1-Cg)-alkyl;
E 3-8 membered bivalent carbo- or heterocyclic ring structure having 0-4
heteroatoms from the group of N, O and S, which may optionally have
substituents from the group of H, F, CI, Br, OH, CF3, N02, CN, OCF3, O-
(C,-C6)-alkyl, O-(C,-C4)-alkoxy-(C,-C4)-alkyl, S-(C1-C6)-alkyl, (C,-C6)-
alkyl, (CZ-C6)-alkenyl, O-(C3-Cg)cycloalkyl, (C3-C8)cycloalkenyl, (C2-C6)-
alkynyl, (Co-C8)-alkylene-aryl, O-(Co-Cg)-alkylene-aryl, S-aryl,
N(R12)(R13), S02-CH3, N(R16)CO(R17), N(R18)S02(R19), CO(R20) and
be mono- or bicyclic;
preferably 5-7 membered bivalent carbo- or heterocyclic ring structure
having 0-3 heteroatoms from the group of N, O and S, which may optionally
have substituents from the group of H, F, CI, Br, OH, CF3, NO~, CN, OCF3,
I S O-(C,-C6)-alkyl, S-(C,-C6)-alkyl, (C~-C6)-alkyl, (C2-C6)-alkenyl, O-(Co-
Cg)-
alkylene-aryl, S-aryl, N(R12)(R13), S02-CH3, N(R16)CO(R17), CO(R20)
and be mono- or bicyclic;
particularly preferably 5-7 membered bivalent carbo- or heterocyclic ring
structure having 0-2 heteroatoms from the group of N, O and S, which may
optionally have substituents from the group of H, F, Cl, Br, OH, CF3, N02,
OCF3, O-(C,-C6)-alkyl, (C,-C6)-alkyl, (C2-C6)-alkenyl, N(R12)(R13), S02-
CH3, CO(R20),
e.g. E is selected from the group consisting of
CA 02554233 2006-07-24
APD62599PC l7
O
/ \ S \ / \ / N-N
v
N /~ \
-N~ - ~N N-
S , ~ '
N N\
N '~ /
, S > > ,
N N N-O and ~ /
which may optionally have substituents from the group of H, F, Cl, Br, OH,
CF3, NO2,
OCF3, O-(C,-C6)-alkyl, (C,-C6)-alkyl, (C2-C6)-alkenyl, N(R12)(R13), S02-CH3,
CO(R20),
preferably H, F, Cl, Br, O-(C1-C6)-alkyl, (C~-C6)-alkyl, CO(R20);
preferably
O S
\ / \ / ~ -N N-
N-N ~ ,
' ,
N
\ ~ N
N f N ~ / and ~ /
which may optionally have the aforementioned substituents;
particularly preferably
CA 02554233 2006-07-24
APD62599PC 18
;ii' ~/ ~ ~\ ~ , ~,1 / \
i4
and
'! r~/~' ~.~', i
R12, R13, R16, R18
independently of one another H, (Ci-Cg)-alkyl;
R 17, R 19, R20
independently of one another H, (C1-Cg)-alkyl, aryl; preferably
independently of one another H, (C1-Cg)-alkyl;
X a bond, -CH2-CH2-; preferably a bond;
D, G either D is N and G is CH or D is CH and G is N or D and G are both CH; D
and G are preferably both CH;
R2 OH, O-(C~-C6)-alkyl, O-(C~-C4)-alkoxy-(C1-C4)-alkyl, (C1-C6)-alkyl;
preferably O-(C,-C6)-alkyl, (C1-C6)-alkyl;
n 0, 1, 2; preferably 0 or 1;
Q N(R24)(R25), a 3 to 8-membered monocyclic ring which may include 0 to 3
heteroatoms selected from the group of oxygen, nitrogen and sulfur, where
the ring system may be additionally substituted by N(R24)(R25), F, Cl, Br,
CF3, N02, CN, (CI-C6)-alkyl, O-(C,-C8)-alkyl, (C,-C4)-alkoxy-(C1-C4)-
alkyl, (Co-C8)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy,
hydroxy-(CI-C4)-alkyl, COO(R29), N(R30)CO(C1-C6)-alkyl or S02CH3,
preferably N(R24)(R25), F, Cl, (C~-C6)-alkyl, O-(C1-Cg)-alkyl, (C1-C4)-
alkoxy-(Cl-C4)-alkyl, (Co-Cg)-alkylene-aryl, oxo, CO(R26), N(R30)CO(C1-
C6)-alkyl or S02CH3;
R26, R27, R28, R29, R30
independently of one another H, (C,-C6)-alkyl; preferably (CI-C6)-alkyl;
CA 02554233 2006-07-24
APD62599PC 19
A a group of the formula -(C(R31 )(R32))m- in which 0-2 members may be
replaced by an element from the group of O, N(R33), CO; preferably a
group of the formula -(C(R31)(R32))m- in which 1 member may be replaced
by an element from the group of O, N(R33);
m 0, 1, 2, 3, 4; preferably 0, 1, 3 or 4;
R31, R32, R33
independently of one another H, (CI-C6)-alkyl, aryl; preferably H;
R24, R25 independently of one another H, (C1-Cg)-alkyl, -(CH2)o-R36, CO-(C1-
Cg)-
alkyl, or R24 and R25 form together with the nitrogen atom to which they
are bonded a 4 to 10-membered, mono-, bi- or spirocyclic ring which, apart
from the nitrogen atom, may include 0 to 2 additional heteroatoms selected
from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring
system may additionally be substituted by F, Cl, (C1-C6)-alkyl, O-(C~-Cg)-
alkyl, oxo, CO(R44), CON(R45)(R46), hydroxy, N(R48)CO(C1-C6)-alkyl or
N(R49)(R50), preferably F, (CI-C6)-alkyl, O-(Ci-Cg)-alkyl, oxo, CO(R44),
N(R48)CO(C1-C6)-alkyl or N(R49)(R50);
0 0, 1, 2, 3, 4;
R36 OH, 5-10 membered mono- or bicyclic ring which may comprise one or
more heteroatoms from the group of N, O and S, and the 5-10 membered
ring may comprise further substituents such as F, Cl, Br, OH, CF3, oxo, O-
(C1-C6)-alkyl, (C1-C6)-alkyl, O-(Co-C2)-alkylene-aryl, (Co-C2)-alkylene-aryl
and N(R55)(R56); preferably a 5-8 membered monocyclic ring which may
comprise 0-2 heteroatoms from the group of N, O and S, and the 5-8
membered ring may comprise further substituents such as F, oxo, O-(C,-
C6)-alkyl, (C~-C6)-alkyl, (Co-CZ)-alkylene-aryl and N(R55)(R56);
R44, R45, R46, R48, R49, R50
independently of one another H, (C~-C6)-alkyl;
CA 02554233 2006-07-24
APD62599PC 20
R55, R56 independently of one another H, (C1-Cg)-alkyl.
It is very particularly preferred for D and G in the aforementioned compounds
of the
formula I each to be CH.
In a further preferred embodiment, the present invention relates to compounds
of the
formula I in which the substituents of the cyclohexylene group are in para
position relative
to one another, i.e. the compounds of the formula I have the following
structure Ia:
R1 E D=GN
~X~N
A~Q
O
(R2)~ Ia
where the radicals R1 and R2, the index n and the groups K, E, X, D, G, A and
Q have the
aforementioned meanings.
L 5 In addition, very particularly preferred compounds of the formula I are
those in which the
group Q comprises at least one nitrogen atom, where the nitrogen atom may be
present in
ring Q andlor in a substituent of ring Q.
Particularly preferred compounds of the formula I are those in which the group
A-Q has
one of the following meanings:
if:
A is a group of the formula -(C(R31 )(R32))m in which 0-2 members may be
replaced by an element from the group of O, N(R33), CO; preferably a
group of the formula -(C(R31)(R32))m in which 1 member may be replaced
by an element from the group of O, N(R33);
where
m is 1, 2, 3, 4; preferably 1, 3 or 4;
CA 02554233 2006-07-24
APD62599PC 21
and
R31, R32, R33
are independently of one another H, (C,-C6)-alkyl, aryl; preferably H;
then
Q is N(R24)(R25);
where
R24, R25 are independently of one another H, (Cl-Cg)-alkyl, -(CH2)o-R36, CO-
(CI-
Cg)-alkyl, or R24 and R25 form together with the nitrogen atom to which
they are bonded a 4 to 10-membered mono-, bi- or spirocyclic ring which,
apart from the nitrogen atom, may include 0 to 2 additional heteroatoms
selected from the group of oxygen, nitrogen and sulfur, where the
heterocyclic ring system may additionally be substituted by F, Cl, (C,-C6)-
alkyl, O-(C1-Cg)-alkyl, oxo, CO(R44), CON(R45)(R46), hydroxy,
N(R48)CO(C,-C6)-alkyl or N(R49)(R50), preferably F, (C1-C6)-alkyl,
O-(C,-Cg)-alkyl, oxo, CO(R44), N(R48)CO(C,-C6)-alkyl or N(R49)(R50);
o is 0, 1, 2, 3, 4;
R36 is OH, 5-10 membered mono- or bicyclic ring which may comprise one or
more heteroatoms from the group of N, O and S, and the 5-10 membered
ring may comprise further substituents such as F, CI, Br, OH, CF3, oxo, O-
(Cl-C6)-alkyl, (C1-C6)-alkyl, O-(Co-C2)-alkylene-aryl, (Co-CZ)-alkylene-aryl
and N(R55)(R56), preferably a 5-8 membered monocyclic ring which may
comprise 0-2 heteroatoms from the group of N, O and S, and the 5-8
membered ring may comprise further substituents such as F, oxo, O-(CI-
C6)-alkyl, (C,-C6)-alkyl, (Co-CZ)-alkylene-aryl and N(R55)(R56);
R44, R45, R46, R48, R49, R50
are independently of one another H, (C1-C6)-alkyl;
and
R55, R56 are independently of one another H, (C~-Cg)-alkyl;
CA 02554233 2006-07-24
APD62599PC 22
if:
A is a group of the formula -(C(R31)(R32))m in which 0-2 members may be
replaced by an element from the group of O, N(R33), CO; preferably a
group of the formula -(C(R31)(R32))m in which 1 member may be replaced
by an element from the group of O, N(R33);
where
m is 0, 1, 2, 3, 4; preferably 0 or 1;
and
R31, R32, R33
are independently of one another H, (C1-C6)-alkyl, aryl; preferably H;
where A very particularly preferably is a bond or N(R33);
then
Q is a 3 to 8-membered monocyclic ring which may include 0 to 3
heteroatoms selected from the group of oxygen, nitrogen and sulfur, where
the ring system may additionally be substituted by F, Cl, Br, CF3, N02, CN,
(C~-C6)-alkyl, O-(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (Co-Cg)
alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, hydroxy-(C,-C4)
alkyl, COO(R29), N(R30)CO(Cl-C6)-alkyl or S02CH3; preferably a 5 to 7
membered monocyclic ring which comprises one or two nitrogen atoms,
where the ring system may additionally be substituted by (CI-C6)-alkyl, (C1
C4)-alkoxy-(CI-C4)-alkyl or (Co-C2)-alkylene-aryl;
where
R26, R27, R28, R29, R30
are independently of one another H, (C1-C6)-alkyl; preferably (C1-C6)-alkyl;
if:
A is a group of the formula -(C(R31 )(R32))m in which 0-2 members may be
replaced by an element from the group of O, N(R33), CO; preferably a
group of the formula -(C(R31)(R32))m in which 1 member may be replaced
CA 02554233 2006-07-24
APD62599PC 2=~
by an element from the group of O, N(R33);
where
m is 0, 1, 2, 3, 4; preferably 0 or l;
and
R31, R32, R33
are independently of one another H, (C~-C6)-alkyl, aryl; preferably H;
l0 where A very particularly preferably is a bond or N(R33);
then
Q is a 3 to 8-membered monocyclic ring which may include 0 to 3 heteroatoms
selected from the group of oxygen, nitrogen and sulfur, where the ring
l5 system is additionally substituted by N(R24)(R25) and may additionally be
substituted by F, Cl, Br, CFA, N02, CN, (C,-C6)-alkyl, O-(C,-C8)-alkyl, (C,-
C4)-alkoxy-(C,-C4)-alkyl, (Co-Cg)-alkylene-aryl, oxo, CO(R26),
CON(R27)(R28), hydroxy, hydroxy-(C1-C4)-alkyl, COO(R29),
N(R30)CO(Cl-C6)-alkyl or S02CH3; preferably a 3 to 8-membered
20 monocyclic ring which may include 0 to 1 heteroatom selected from the
group of oxygen, nitrogen and sulfur, where the ring system is additionally
substituted by N(R24)(R25) and may additionally be substituted by F, Cl,
Br, CF3, NO2, CN, (C1-C6)-alkyl, O-(C~-Cg)-alkyl, (C1-C4)-alkoxy-(C,-C4)-
alkyl, (Co-Cg)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy,
25 hydroxy-(C~-C4)-alkyl, COO(R29), N(R30)CO(C,-C6)-alkyl or SOZCH3,
preferably F, (C,-C6)-alkyl, O-(C1-Cg)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl,
(Co-Cg)-alkylene-aryl, oxo, CO(R26), N(R30)CO(C1-C6)-alkyl or SOZCH3;
where
30 R26, R27, R28, R29, R30
are independently of one another H, (C1-C6)-alkyl; preferably (C~-C6)-alkyl;
and
R24, R25 are independently of one another H, (C~-C8)-alkyl, -(CHZ)o R36, CO-
(C1-
CA 02554233 2006-07-24
APD62599PC 24
Cs)-alkyl, or R24 and R25 form together with the nitrogen atom to which
they are bonded a 4 to 10-membered mono-, bi- or spirocyclic ring which,
apart from the nitrogen atom, may include 0 to 2 additional heteroatoms
selected from the group of oxygen, nitrogen and sulfur, Where the
heterocyclic ring system may additionally be substituted by F, Cl, (C~-C6)-
alkyl, O-(C1-Cg)-alkyl, oxo, CO(R44), CON(R45)(R46), hydroxy,
N(R48)CO(C,-C6)-alkyl or N(R49)(R50), preferably F, (C~-C6)-alkyl,
O-(C1-Cg)-alkyl, oxo, CO(R44), N(R48)CO(Cl-C6)-alkyl or N(R49)(R50);
o is 0, 1, 2, 3, 4;
R36 is OH, 5-10 membered mono- or bicyclic ring which may comprise one or
more heteroatoms from the group of N, O and S and the 5-10 membered
ring may comprise further substituents such as F, Cl, Br, OH, CF3, oxo, O-
(C~-C6)-alkyl, (C,-C6)-alkyl, O-(Co-CZ)-alkylene-aryl, (Co-C2)-alkylene-aryl
and N(R55)(R56), preferably a 5-8 membered monocyclic ring which may
comprise 0-2 heteroatoms from the group of N, O and S, and the 5-8
membered ring may comprise further substituents such as F, oxo, O-(C~-
C6)-alkyl, (C1-C6)-alkyl, (Co-C2)-alkylene-aryl and N(R55)(R56);
R44, R45, R46, R48, R49, R50
are independently of one another H, (C1-C6)-alkyl;
and
R55, R56 are independently of one another H, (C,-Cg)-alkyl.
Examples of particularly preferred A-Q groups are listed below:
\Het~~~C~R31~~R32Om-1 N~R24OR25~
in which Het is O, S, N(R33), preferably O, N(R33), and m is 3 or 4
CA 02554233 2006-07-24
APD62599PC 25
R24
i
-N
R25
~Subst
N
-N N-Subst . ~N~
U
in which Subst is H, (C,-C6)-alkyl, hydroxy-C1-C4)-alkyl, preferably H, (C~-
C6)-alkyl
~'N -N'
N-R25 ~N-R25
R24 R24
in which the radicals R24, R25, R31, R32 and R33 have the aforementioned
meanings.
In a further particularly preferred embodiment, the present invention relates
to compounds
of the formula Iaa
--''''.
,,~ ~' - A
~~,! v . i ' /' y
! ':
1
,,
in which
W is CH or N, and
the radical R l and the groups A and Q have the aforementioned meanings.
The compounds of the invention of the formula I can be prepared for example by
processes
analogous to the preparation processes disclosed in WO 03/057220, for example
by
cyclization and/or coupling reactions. Suitable starting substances can be
prepared by
processes known to the skilled worker, and some are commercially available.
In a preferred embodiment, the compounds of the formula I are prepared by a
process
CA 02554233 2006-07-24
APD62599PC 26
including the following steps:
a) preparation of a compound of the formula II: the basic structure
(1,4-dioxaspiro[4.5]decan-8-one) is commercially available. Substituted
variants can be prepared by processes known from the literature (see, for
example, Nakamura, M. et al.; J. Am. Chem. Soc. 2003, 125(21), 6362-6363;
Kawafuchi, H. et al.; Tetrahedron Lett. 2002, 43(11), 2051-2054; Beauhaire, J.
et al.; Tetrahedron Lett. 1995, 36(7), 1043-1046)
O
O
O
~R2~n
II
b) reaction of the compound of the formula II with
i
under reductive amination conditions, where R = lower alkyl, preferably ethyl
or methyl, to give a compound of the formula III
R~
H
y.
''~R2~r EI~
c) coupling of the compound of the formula III with phosgene (or a known
phosgene equivalent, for example carbonyldiimidazole) and a primary amine of
the formula
R1 ~K~E~X~NH2
and subsequent deprotection of the acetals, with simultaneous cyclization
resulting in a compound of the formula IV
CA 02554233 2006-07-24
APD62599PC 2~
X
N N
R1 U (R2)~
IV
d) reaction with a primary or secondary amine under reductive amination
conditions, resulting in compounds of the formula I whose A-Q group is linked
via a nitrogen atom to the cyclohexylene ring
A-Q
X
~K~E~ N N
R1 U (R2)~
I.
Further compounds of the invention of the formula I can be obtained by
analogous
processes, the skilled worker being aware how the process described above must
be altered
in order to obtain further compounds of the formula I.
Suitable reaction conditions and reagents for carrying out steps a) to d) of
the process of
the invention are known to the skilled worker.
Two preparation routes for compounds of the formula I are indicated by way of
example
below:
Exemplary route 1
CA 02554233 2006-07-24
APD62599PC 2~
y
Qt
i.,y-...._,. H
I J'~i_t0' . .. ,_ ,
_.....___... _...
(reductive
t
-. amination) C -', I '~ ,,
-'' '-~~ ~ w!f-_
'- _:,--.
L.' ,
n~ ; :.
_4 . __.. _.. .._-- _ ' y
Kl4 '~.~~1
R1-_~ f ,
acid P'
_w 1. ~ ~1 ~ _ _
'. (reductive -- ,..tJ.. "'f,~;: ' ,
amination)
Exemplary route 2
o~t
.'_ r !,
._
K K ~ r;y base i Cfj Cfia!.base ,~__~ o
:',,P'fN -___._ _~~.. ,~ i ...1: __~
-1_i~i _~'.I ' ..'y.,:......~ ' -.n .hJ.W .,
i.171 S--__
' :~; acid
In exemplary routes 1 and 2, R1, K and Q have the aforementioned meanings.
Use
This invention further relates to the use of compounds of the formula I and
their
pharmaceutical compositions as MCH receptor ligands. The MCH receptor ligands
of the
invention are particularly suitable as modulators of the activity of the
MCH1R.
The role of MCH in regulating the energy balance has now been well documented
(Qu, D.
et al.; Nature 1996, 380, 243-7; Shimada, M. et al. Nature 1998, 396, 670-4;
Chen, Y et al.
Endocrinology 2002, 143, 2469-77; Endocrinology 2003, 144, 4831-40; Review: G.
Hervieu, Expert Opin. Ther. Targets 2003, 7, 495-511 ).
There are also indications that MCH antagonists can have a beneficial
influence on
centrally related disorders such as, for example, depression (Borowsky, B. et
al.; Nature
Medicine 2002, 8, 825-30; Review: G. Hervieu, Expert Opin. Ther. Targets 2003,
7, 495-
511).
Compounds of this type are particularly suitable for the treatment and/or
prevention of
CA 02554233 2006-07-24
APD62599PC
1. Obesity
2. Diabetes mellitus, especially type 2 diabetes, including the prevention of
the sequelae
associated therewith.
Particular aspects in this connection are
- hyperglycemia,
- improvement in insulin resistance,
- improvement in glucose tolerance,
1 U - protection of the pancreatic 13 cells
- prevention of macro- and microvascular disorders
3. Dyslipidemias and their sequelae such as, for example, atherosclerosis,
coronary heart
disease, cerebrovascular disorders etc, especially those (but not restricted
thereto)
which are characterized by one or more of the following factors:
- high plasma triglyceride concentrations, high postprandial plasma
triglyceride
concentrations,
- low HDL cholesterol concentration
4. Various other conditions which may be associated with the metabolic
syndrome, such
as:
- thromboses, hypercoagulable and prothrombotic stages (arterial and venous)
- high blood pressure
- heart failure such as, for example (but not restricted thereto), following
myocardial
infarction, hypertensive heart disease or cardiomyopathy
5. Psychiatric indications such as
- depressions
- anxiety states
- disturbances of the circadian rhythm
- affection disorders
- schizophrenia
- addictive disorders
CA 02554233 2006-07-24
APD62599PC 30
Formulations
The amount of a compound of formula (I) necessary to achieve the desired
biological effect
depends on a number of factors, for example the specific compound chosen, the
intended
use, the mode of administration and the clinical condition of the patient. The
daily dose is
generally in the range from 0.001 mg to 100 mg, preferably 0.3 mg to 100 mg
(typically
from 0.01 mg to 50 mg, preferably 3 mg to 50 mg) per day and per kilogram of
bodyweight, for example 0.1-10 mg/kg/day, preferably 3-10 mg/kg.day. An
intravenous
dose may be, for example, in the range from 0.001 mg to 1.0 mg/kg, preferably
0.3 mg to
1.0 mg/kg, which can suitably be administered as infusion of 10 ng to 100 ng
per kilogram
and per minute. Suitable infusion solutions for these purposes may contain,
for example,
from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single
doses may
contain, for example, from 1 mg to 10 g of the active ingredient. Single doses
may contain,
for example, from 1 mg to 10 g of the active ingredient. Thus, ampoules for
injections may
contain, for example, from 1 mg to 100 mg, and single-dose formulations which
can be
administered orally, such as, for example, tablets or capsules, may contain,
for example,
from 0.05 to 1000 mg, typically from 0.5 to 600 mg, or in a further embodiment
from 1.0
to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically
acceptable salts,
the aforementioned weight data are based on the weight of the free compound
from which
the salt is derived. For the prophylaxis and therapy of the abovementioned
conditions, the
compounds of formula (I) may be used as the compound itself, but they are
preferably in
the form of a pharmaceutical composition with an acceptable carrier. The
carrier must, of
course, be acceptable in the sense that it is compatible with the other
ingredients of the
composition and is not harmful for the patient's health. The carrier may be a
solid or a
liquid or both and is preferably formulated with the compound as a single
dose, for
example as a tablet, which may contain from 0.05% to 95% by weight of the
active
ingredient. Other pharmaceutically active substances may likewise be present,
including
other compounds of formula (I). The pharmaceutical compositions of the
invention can be
produced by one of the known pharmaceutical methods, which essentially consist
of
mixing the ingredients with pharmacologically acceptable carriers and/or
excipients.
Pharmaceutical compositions of the invention are those suitable for oral,
rectal, topical,
peroral (for example sublingual) and parenteral (for example subcutaneous,
intramuscular,
intradermal or intravenous) administration, although the most suitable mode of
CA 02554233 2006-07-24
APD62599PC 31
administration depends in each individual case on the nature and severity of
the condition
to be treated and on the nature of the compound of formula (I) used in each
case. Coated
formulations and coated slow-release formulations also belong within the
framework of the
invention. Preference is given to acid- and gastric juice-resistant
formulations. Suitable
_5 coatings resistant to gastric juice comprise cellulose acetate phthalate,
polyvinyl acetate
phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of
methacrylic
acid and methyl methacrylate.
Suitable pharmaceutical preparations for oral administration may be in the
form of separate
units such as, for example, capsules, cachets, suckable tablets or tablets,
each of which
contain a defined amount of the compound of formula (I); as powders or
granules; as
solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-
water or water-
in-oil emulsion. These compositions may, as already mentioned, be prepared by
any
suitable pharmaceutical method which includes a step in which the active
ingredient and
I S the carrier (which may consist of one or more additional ingredients) are
brought into
contact. The compositions are generally produced by uniform and homogeneous
mixing of
the active ingredient with a liquid and/or finely divided solid carrier, after
which the
product is shaped if necessary. Thus, for example, a tablet can be produced by
compressing
or molding a powder or granules of the compound, where appropriate with one or
more
additional ingredients. Compressed tablets can be produced by tableting the
compound in
free-flowing form such as, for example, a powder or granules, where
appropriate mixed
with a binder, glidant, inert diluent and/or one or more surface-
active/dispersing agents) in
a suitable machine. Molded tablets can be produced by molding the compound,
which is in
powder form and is moistened with an inert liquid diluent, in a suitable
machine.
Pharmaceutical compositions which are suitable for peroral (sublingual)
administration
comprise suckable tablets which contain a compound of formula (I) with a
flavoring,
normally sucrose and gum arabic or tragacanth, and pastilles which comprise
the
compound in an inert base such as gelatin and glycerol or sucrose and gum
arabic.
Pharmaceutical compositions suitable for parenteral administration comprise
preferably
sterile aqueous preparations of a compound of formula (I), which are
preferably isotonic
with the blood of the intended recipient. These preparations are preferably
administered
intravenously, although administration may also take place by subcutaneous,
intramuscular
CA 02554233 2006-07-24
APD62599PC 32
or intradermal injection. These preparations can preferably be produced by
mixing the
compound with water and making the resulting solution sterile and isotonic
with blood.
Injectable compositions of the invention generally contain from 0.1 to 5% by
weight of the
active compound.
Pharmaceutical compositions suitable for rectal administration are preferably
in the form of
single-dose suppositories. These can be produced by mixing a compound of the
formula (I)
with one or more conventional solid carriers, for example cocoa butter, and
shaping the
resulting mixture.
l0
Pharmaceutical compositions suitable for topical use on the skin are
preferably in the form
of ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can
be used are
petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or
more of
these substances. The active ingredient is generally preseht in a
concentration of from 0.1
I S to 15% by weight of the composition, for example from 0.5 to 2%.
Transdermal administration is also possible. Pharmaceutical compositions
suitable for
transdermal uses can be in the form of single plasters which are suitable for
long-term
close contact with the patient's epidermis. Such plasters suitably contain the
active
20 ingredient in an aqueous solution which is buffered where appropriate,
dissolved and/or
dispersed in an adhesive or dispersed in a polymer. A suitable active
ingredient
concentration is about 1% to 35%, preferably about 3% to 15%. A particular
possibility is
for the active ingredient to be released by electrotransport or iontophoresis
as described,
for example, in Pharmaceutical Research, 2(6): 318 ( 1986).
The compounds of the formula I are distinguished by beneficial effects on
lipid
metabolism, and they are particularly suitable for weight reduction and for
maintaining a
reduced weight after weight reduction has taken place in mammals and as
anorectic agents.
The compounds are distinguished by their low toxicity and their few side
effects. The
compounds can be employed alone or in combination with other weight-reducing
or
anorectic active ingredients. Further anorectic active ingredients of this
type are mentioned,
for example, in the Rote Liste, chapter Ol under weight-reducing
agents/appetite
suppressants, and they also include active ingredients which increase the
energy turnover
of the organism and thus lead to weight reduction or else those which
influence the general
CA 02554233 2006-07-24
APD62599PC 33
metabolism of the organism in such a way that an increased calorie intake does
not lead to
an enlargement of the fat depots and a normal calorie intake leads to a
reduction of the fat
depots of the organism. The compounds are suitable for the prophylaxis and, in
particular,
for the treatment of excessive weight or obesity. The compounds are further
suitable for the
prophylaxis and, in particular, for the treatment of type II diabetes, of
arteriosclerosis and
for normalizing lipid metabolism and for the treatment of high blood pressure.
Combinations with other medicaments
In a further aspect of the invention the compounds of the formula I can be
administered
alone or in combination with one or more further pharmacologically active
substances
which have, for example, favorable effects on metabolic disturbances or
disorders
frequently associated therewith. Examples of such medicaments are
1. medicaments which lower blood glucose, antidiabetics,
2. active ingredients for the treatment of dyslipidemias,
3. antiatherosclerotic medicaments,
4. antiobesity agents,
5. antiinflammatory active ingredients
6. active ingredients for the treatment of malignant tumors
7. antithrombotic active ingredients
8. active ingredients for the treatment of high blood pressure
9. active ingredients for the treatment of heart failure and
10. active ingredients for the treatment and/or prevention of complications
caused by
diabetes or associated with diabetes.
They can be combined with the compounds of the invention of the formula I in
particular
for a synergistic improvement in the effect. Administration of the active
ingredient
combination can take place either by separate administration of the active
ingredients to the
patient or in the form of combination products in which a plurality of active
ingredients are
present in one pharmaceutical preparation.
Further particularly suitable pharmacologically active substances are:
Antidiabetics
CA 02554233 2006-07-24
~1PD62599PC 34
All antidiabetics disclosed for example in the Rote Liste 2001, chapter 12.
They can be
combined with the compounds of the invention of the formula I in particular
for a
synergistic improvement in the effect. Administration of the active ingredient
combination
can take place either by separate administration of the active ingredients to
the patient or in
the form of combination products in which a plurality of active ingredients
are present in
one pharmaceutical preparation. Most of the active ingredients listed below
are disclosed in
the USP Dictionary of USAN and International Drug Names, US Pharmacopeia,
Rockville
2001.
Suitable antidiabetics include all insulins and insulin derivatives, such as,
for example,
Lantus~ or HMR 1964 or Apidra~, and other fast-acting insulins (see, for
example US 6
221 633), amylin, GLP-l and GLP-2 derivatives, as described in WO 01/04146 or
else
such as those disclosed in WO 98/08871 of Novo Nordisk A/S, and orally
effective
hypoglycemic active ingredients.
The orally effective hypoglycemic active ingredients include, preferably,
sulfonylureas,
biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones,
glucosidase
inhibitors, glucagon-receptor-antagonists, GLP-1 agonists, DPP-IV inhibitors,
potassium
channel openers such as, for example, those disclosed in WO 97/26265 and WO
99/03861
of Novo Nordisk A/S, insulin sensitizers, activators of the insulin receptor
kinase GSK3-
beta inhibitors, inhibitors of liver enzymes involved in the stimulation of
gluconeogenesis
and/or glycogenolysis, for example inhibitors of glycogen phosphorylase,
modulators of
glucose uptake and glucose excretion, compounds which alter lipid metabolism
and lead to
a change in the blood lipid composition, such as antihyperlipidemic active
ingredients and
antilipidemic active ingredients, e.g. HMGLoA reductase inhibitors, inhibitors
of
cholesterol transport/ of cholesterol uptake, inhibitors of bile acid
reabsorption or inhibitors
of microsomal triglyceride transfer protein (MTP), compounds which reduce food
intake
and/or food absorption, PPAR and RXR agonists and active ingredients which act
on the
ATP-dependent potassium channel of the beta cells.
In one embodiment of the invention, the present compounds are administered in
combination with insulin.
CA 02554233 2006-07-24
APDfi2599PC 35
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with substances which influence hepatic glucose production such
as, for
example, glycogen phosphorylase inhibitors (see: WO 01/94300, WO 02/096864, WO
03/084923, WO 03/084922, WO 03/104188).
In one embodiment, the compounds of the formula I are administered in
combination with
a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or
glimepiride.
In one embodiment, the compounds of the formula I are administered in
combination with
an active ingredient which acts on the ATP-dependent potassium channel of the
beta cells,
such as, for example, tolbutamide, glibenclamide, glipizide, glimepiride or
repaglinide.
In one embodiment, the compounds of the formula I are administered in
combination with
a biguanide such as, for example, metformin.
IS
In a further embodiment, the compounds of the formula I are administered in
combination
with a meglitinide such as, for example, repaglinide.
In one embodiment, the compounds of the formula I are administered in
combination with
a thiazolidinedione such as, for example, ciglitazone, pioglitazone,
rosiglitazone or the
compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in
particular
5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-
thiazolidinedione.
In one embodiment, the compounds of the formula I are administered in
combination with
a DPPIV inhibitor as described, for example, in W098/19998, W099/61431,
W099/67278, W099/67279, WO01/72290, WO 02/38541, W003/040174, in particular P
93/01 (1-cyclopentyl-3-methyl-1-oxo-2-pentanammonium chloride), P-31/98,
LAF237 (1-
[2-[3-hydroxyadamant-1-ylamino)acetyl]pyrrolidine-2-(S)-carbonitrile), TS021
((2S, 4S)-
4-fluoro-1-[[(2-hydroxy-l,l-dimethylethyl)amino]-acetyl]pyrrolidine-2-
carbonitrile
monobenzenesulfonate).
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a PPARgamma agonist such as, for example, rosiglitazone,
pioglitazone.
CA 02554233 2006-07-24
APD62599PC 36
In one embodiment, the compounds of the formula I are administered in
combination with
compounds with an inhibitory effect on SGLT-1 and/or 2, as disclosed directly
or
indirectly for example in PCT/EP03/06841, PCT/EP03/13454 and PCT/EP03/13455.
In one embodiment, the compounds of the formula I are administered in
combination with
an a-glucosidase inhibitor such as, for example, miglitol or acarbose.
In one embodiment, the compounds of the formula I are administered in
combination with
more than one of the aforementioned compounds, e.g. in combination with a
sulfonylurea
and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin
and a
sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and
lovastatin, etc.
Lipid modulators
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an HMGCoA reductase inhibitor such as lovastatin,
fluvastatin,
pravastatin, simvastatin, ivastatin, itavastatin, atorvastatin, rosuvastatin.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a bile acid reabsorption inhibitor (see, for example, US
6,245,744, US
6,221,897, US 6,277,831, EP 0683 773, EP 0683 774).
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a polymeric bile acid adsorbent such as, for example,
cholestyramine or
colesevelam.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a cholesterol absorption inhibitor as described for example
in
WO 0250027, or ezetimibe, tiqueside, pamaqueside.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an LDL receptor inducer (see, for example, US 6,342,512).
CA 02554233 2006-07-24
APD62599PC 37
In one embodiment, the compounds of the formula I are administered in
combination with
bulking agents, preferably insoluble bulking agents (see, for example,
carob/Caromax~
(Zunft H J; et al., Carob pulp preparation for treatment of
hypercholesterolemia,
ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6.) Caromax is a carob-
s containing product from Nutrinova, Nutrition Specialties & Food Ingredients
GmbH,
Industriepark Hoechst, 65926 Frankfurt/Main)). Combination with Caromax~ is
possible
in one preparation or by separate administration of compounds of the formula I
and
Caromax~. Caromax~ can in this connection also be administered in the form of
food
products such as, for example, in bakery products or muesli bars.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a PPARalpha agonist.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a fibrate such as, for example, fenofibrate, gemfibrozil,
clofibrate,
bezafibrate.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with nicotinic acid or niacin.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a CETP inhibitor, e.g. CP- 529, 414 (torcetrapib).
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an ACAT inhibitor.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an MTP inhibitor such as, for example, implitapide.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an antioxidant.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a lipoprotein lipase inhibitor.
CA 02554233 2006-07-24
APD62599PC 38
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with an ATP-citrate lyase inhibitor.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a squalene synthetase inhibitor.
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a lipoprotein(a) antagonist.
(0
Antiobesity agents
In one embodiment of the invention, the compounds of the formula I are
administered in
combination with a lipase inhibitor such as, for example, orlistat.
In one embodiment, the further active ingredient is fenfluramine or
dexfenfluramine.
In another embodiment, the further active ingredient is sibutramine.
In another embodiment, the further active ingredient is rimonabant.
In a further embodiment, the compounds of the formula I are administered in
combination
with CART modulators (see "Cocaine-amphetamine-regulated transcript influences
energy
metabolism, anxiety and gastric emptying in mice" Asakawa, A, et al., M.:
Hormone and
Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g. naphthalene-
1-sulfonic
acid { 4-[(4-aminoquinazolin-2-ylamino)methyl]- cyclohexylmethyl } amide
hydrochloride
(CGP 71683A)), MC4 agonists (e.g. 1-amino-1,2,3,4-tetrahydronaphthalene-2-
carboxylic
acid [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-
5-yl)-1-
(4-chlorophenyl)-2-oxoethyl]-amide; (WO 01/91752)), orexin antagonists (e.g. 1-
(2-
methylbenzoxazol-6-yl)-3-(1,5]naphthyridin-4-ylurea hydrochloride (SB-334867-
A)), CBI
antagonists/inverse agonists, H3 antagonists/inverse agonists (e.g. 3-
cyclohexyl-1-(4,4-
dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-y1)propan-1-one oxalic acid
salt
(WO 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6-
trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585)), CRF
BP
antagonists (e.g. urocortin), urocortin agonists, X33 agonists (e.g. 1-(4-
chloro-3-
CA 02554233 2006-07-24
APD62599PC 39
methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1 H-indol-6-yloxy)ethylamino]-
ethanol
hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists,
CCK-A
agonists (e.g. {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-
cyclohexylethyl)thiazol-2-
ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt (WO
99/15525)),
S serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed serotoninergic
and
noradrenergic compounds (e.g. WO 00/71549), SHT agonists e.g. 1-(3-
ethylbenzofuran-7-
yl)piperazine oxalic acid salt (WO 01/09111), BRS3 agonists, galanin
antagonists, ghrelin
antagonists, MCH antagonists, mGluRS antagonists, opioid antagonists, growth
hormone
(e.g. human growth hormone), growth hormone-releasing compounds (6-benzyloxy-1-
(2-
diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid
tertiary
butyl ester (WO 01/85695)), (NTF, CNTF derivatives (e.g. Axokine), TRH
agonists (see,
for example, EP 0 462 884), uncoupling protein 2 or 3 modulators, leptin
agonists (see, for
example, Ixe, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina;
Grasso,
Patricia. Leptin agonists as a potential approach to the treatment of obesity.
Drugs of the
I 5 Future (2001 ), 26(9), 873-881 ), DA agonists (e.g. bromocriptine,
Doprexin),
lipaselamylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO
00/78312),
RXR modulators or TR-(3 agonists.
In one embodiment of the invention, the further active ingredient is leptin.
In one embodiment, the further active ingredient is dexamphetamine,
amphetamine,
mazindole or phentermine.
In one embodiment, the compounds of the formula I are administered in
combination with
medicaments having effects on the coronary circulation and the vascular
system, such as,
for example, ACE inhibitors (e.g. ramipril), medicaments which act on the
angiotensin-
renine system, calcium antagonists, beta Mockers etc.
In one embodiment, the compounds of the formula I are administered in
combination with
medicaments having an antiinflammatory effect.
In one embodiment, the compounds of the formula I are administered in
combination with
medicaments which are employed for cancer therapy and cancer prevention.
CA 02554233 2006-07-24
APD62599PC 40
It will be appreciated that every suitable combination of the compounds of the
invention
with one or more of the aforementioned compounds and optionally one or more
other
pharmacologically active substances is regarded as falling within the
protection conferred
by the present invention.
In two articles which appeared simultaneously in Nature (Nature 400, 261-264,
1999;
Nature 400, 265-269, 1999), two research groups separately described a highly
specific
receptor for melanin concentrating hormone (MCH). MCH assumes important
functions in
controlling food intake. Compounds which act on the MCH receptor therefore
have an
anorectic effect and are suitable for the treatment of obesity. Testing for an
anorectic effect
of the compounds of the invention of the formula I was therefore carried out
as follows.
Functional measurements to determine IC50 values
I 5 Cloning of the cDNA for the human MCH receptor, preparation of a
recombinant HEK293
cell line which expresses the human MCH receptor, and functional measurements
with the
recombinant cell line took place in analogy to the description by Audinot et
al. (J. Biol.
Chem. 276, 13554-13562, 2001). A difference from the reference was, however,
the use of
the plasmid pEAK8 from EDGE Biosystems (USA) for the construction of the
expression
vector. The host used for the transfection was a transformed HEK cell line
named "PEAK
Stable Cells" (likewise from EDGE Biosystems). Functional measurements of the
cellular
calcium flux after addition of agonist (MCH) in the presence of ligand of the
invention
took place with the aid of the FLIPR apparatus from Molecular Devices (USA),
using
protocols of the apparatus manufacturer.
Biological activity testing
The IC50 values measured for exemplary compounds 1, 2, 5 and 8 under the
aforementioned conditions were of the order of 0.01 to 2 ~M. Exemplary
compounds 3, 6
and 9 showed IC50 values of from 2 to 10 ~,M.
The examples and preparation methods detailed below serve to illustrate the
invention
CA 02554233 2006-07-24
APU62599PC 41
without, however, restricting it.
Examples
S General explanations
a) Mode of drawing the structural formulae
Only non-hydrogen atoms are depicted for clarity in the structural formulae of
the
examples given.
b) Salt forms
Many of the compounds of the invention are bases and can form salts with
appropriately
strong acids. In particular, after purification of the compounds by HPLC
chromatography
using a trifluoroacetic acid-containing mobile phase 'they may be in the form
of
L 5 hydrotrifluoroacetates. These can be converted into the free bases shown
by simple
treatment of a solution of the salts for example with sodium carbonate
solution.
c) Units of the characterizing data
The unit of the stated molecular weights is "g/mol". Peaks observed in the
mass spectrum
are indicated as integral quotient of the molar molecular ion mass and of the
charge on the
molecular ion (m/z).
Abbreviations
Unless indicated otherwise, the abbreviations in the examples hereinafter have
the
following meaning:
NaBH3CN = sodium cyanoborohydride
DMF = N,N-dimethylformamide
EDC = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
THF = tetrahydrofuran
DMSO = dimethyl sulfoxide
HOBt = 1-hydroxybenzotriazole
HOAt = 1-hydroxy-7-azabenzotriazole
CA 02554233 2006-07-24
A PD62599PC 42
HCl = hydrochloric acid
f-1PLC = high performance liquid chromatography
PyBOP = benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate
CDI = carbonyldiimidazole
Example 1
(R)-N-( 1- { 4-[2-oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazol-1-
yl)cyclohexyl } pyrrolidin-3-yl)acetamide
O
O N~''~N O
N- _N
U
Method A
A mixture of 1-(4-oxocyclohexyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one
(348
mg), (R)-N-pyrrolidin-3-ylacetamide ( 128 mg) and dichloroethane (5 mL) was
mixed with
sodium triacetoxyborohydride (295 mg) and stirred for 48 hours. Sodium
hydroxide
solution ( 1 M) was added, and the mixture was extracted with ethyl acetate.
The organic
phase was dried over magnesium sulfate, filtered and concentrated. The residue
was
purified by preparative HPLC. The product with a molecular weight of 460.58
(C27H32N4O3) was obtained in this way; MS (ESI): 461 ([M+H]+).
1-(4-oxocyclohexyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one
Method B
A solution of 4-phenoxyaniline (2.0 g) in DMF ( 10 mL) was added to a solution
of
carbonyldiimidazole ( 1.8 g) in DMF (30 mL) at 0°C. After 30 minutes,
(2,2-
diethoxyethyl)-(1,4-dioxaspiro[4.5]dec-8-yl)amine (3.0 g) in DMF (10 mL) was
added, and
the mixture was heated at 80°C for 30 minutes. Trifluoroacetic acid (5
mL) was added, and
the mixture was kept at 80°C for a further S hours. After cooling, the
mixture was diluted
with water and extracted with ethyl acetate. The organic phase was dried over
magnesium
sulfate, filtered and concentrated. The product with the molecular weight of
348.41
(C2,H2oN203) was obtained in this way; MS (ESI]: 349 ([M+H]+).
CA 02554233 2006-07-24
nYD62599PC 43
Analogously, 1-(4-cyclopentyloxyphenyl)-3-(4-oxocyclohexyl)-1,3-
dihydroimidazol-2-one
was obtained from 4-cyclopentyloxyaniline, 1-(6-cyclopentyloxypyridin-3-yl)-3-
(4-
oxocyclohexyl)-1,3-dihydroimidazol-2-one was obtained from 6-
cyclopentyloxypyridin-3-
ylamine and 1-(4-butoxyphenyl)-3-(4-oxocyclohexyl)-1,3-dihydroimidazol-2-one
was
obtained from 4-butoxyaniline.
(2,2-Diethoxyethyl)-( 1,4-dioxaspiro[4.5]dec-8-yl)-amine
1,4-Dioxaspiro[4.5]decan-8-one (1.0 g) was reacted with 2,2-diethoxyethylamine
(0.85 g)
by method A. The product with the molecular weight of 273.38 (C,4HZ7N04) was
obtained
l0 in this way; MS (ESI): 274 ([M+H]+).
6-Cyclopentyloxypyridin-3-ylamine
A mixture of 5-nitropyridin-2-of ( 14.0 g), bromocyclopentane (8.0 g),
potassium carbonate
( 14 g) and DMF (200 mL) was heated at 80°C for 6 hours. After cooling,
the reaction
mixture was diluted with water and extracted with ethyl acetate. The organic
phase was
washed with water, dried over magnesium sulfate and concentrated. The residue
was
purified by chromatography on silica gel. The resulting product (2-
cyclopentyloxy-5-
nitropyridine) was hydrogenated in ethanol using palladium(II) hydroxide as
catalyst. The
product with the molecular weight of 178.24 (C10H14N20) was obtained in this
way; MS
(ESI): 179 (M+H+).
4-Cyclopentyloxyaniline
A mixture of 4-nitrophenol (63.7 g), bromocyclopentane (68.2 g), potassium
carbonate
(63.3 g) and DMF (300 mL) was heated at 80°C for 24 hours. After
cooling, it was diluted
with water and extracted with ethyl acetate. The organic phase was washed with
water,
dried over magnesium sulfate and concentrated. The residue was hydrogenated in
ethanol
using palladium(II) hydroxide as catalyst. The product with the molecular
weight of 177.25
(C 11 H 15N0) was obtained in this way; MS (ESIJ: 178 (M+H+).
Example 2
Trans-1-(4-cyclopentyloxy-phenyl)-3-[4-(2-dimethylaminoethoxy)cyclohexyl]-
1,3-dihydroimidazol-2-one
CA 02554233 2006-07-24
APD62599PC 44
,rte
;W..
f
., J ~; ~~ ,
Sodium hydride (42 mg) was added to a mixture of traps-1-(4-
cyclopentyloxyphenyl)-3-(4-
hydroxycyclohexyl)-1,3-dihydroimidazol-2-one (0.30 g) and DMF (10 ml) and,
after gas
evolution ceased, dimethylaminoethyl chloride (94 mg) was added. After eight
hours, the
reaction solution was diluted with water, and the mixture was extracted with
ethyl acetate.
The organic phase was dried over magnesium sulfate, filtered and concentrated.
The
residue was purified by preparative HPLC. The product with the molecular
weight of
413.56 (C24H35N~03) was obtained in this way; MS (ESI): 414 ([M+H]+).
Traps-1-(4-cyclopentyloxyphenyl)-3-(4-hydroxycyclohexyl)-1,3-dihydroimidazol-2-
one
Traps-4-aminocyclohexanol was reacted by method B with CDI and
(4-cyclopentyloxyphenyl)(2,2-diethoxyethyl)amine. The isolated crude product
was mixed
with DMF (2 ml) and TFA (2 ml) and left to stand for 12 hours. The reaction
solution was
I S diluted with water, and the mixture was extracted with ethyl acetate. The
organic phase
was dried over magnesium sulfate, filtered and concentrated. The residue was
purified by
preparative HPLC. The product with the molecular weight of 342.44 (CZOH26N2O3)
was
obtained in this way; MS (ESI): 343 ([M+H]+)
(4-Cyclopentyloxyphenyl)(2,2-diethoxyethyl)amine
A suspension of 4-cyclopentyloxyaniline (8.86 g), bromoacetaldehyde diethyl
acetal
( 13 g), potassium carbonate ( 13.8 g) and dimethylformamide ( 100 ml) was
heated at 80°C
for 6 hours. Cooling was followed by filtration and concentration of the
filtrate. The
residue was purified by chromatography on silica gel (eluent: heptane/ethyl
acetate 2:1).
The product with the molecular weight of 293.41 (C17H27N03) was obtained in
this way;
MS (ESI): 294 ([M+H]+)
The following compounds were prepared by method A using the appropriate
ketones and
amines:
CA 02554233 2006-07-24
APD62599PC 45
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