Note: Descriptions are shown in the official language in which they were submitted.
CA 02531060 2005-12-29
Heterocyclically-Substituted Pentanol Derivatives, Process for their
Production
and their Use as Anti-inflammatory Agents
The invention relates to heterocyclically-substituted pentanol derivatives, in
particular pentanol derivatives that are substituted by quinazoline,
quinoxaline,
cinnoline, indazole, phthalazine, naphthyridine, benzothiazole,
dihydroindolone,
dihydroisoindolone, benzimidazole or indole, process for their production and
their use
as anti-inflammatory agents.
From the prior art of WO 00/32584, DE 100 38 639 A1 and WO 02/10143, anti-
inflammatory agents of the general formula
R' RZ HO R3
~I)
are known, whereby the Ar radical comprises phthalides, thiophthalides,
benzoxazinones
or phthalazinones. In the experiment, these compounds show dissociations of
action
between anti-inflammatory and undesirable metabolic actions and are superior
to the
previously described nonsteroidal glucocorticoids or exhibit at least just as
good an
action.
In addition, compounds in which Q represents an aromatic carbocyclic radical
are known from W003/059899.
The selectivity of the compounds of the prior art compared to the other
steroid
receptors still requires improvement. however.
It was therefore the object of this invention to make available compounds
whose
selectivity is improved compared to the other steroid receptors.
CA 02531060 2005-12-29
This object is achieved by the compounds according to the claims.
This invention therefore relates to compounds of general formula I
R~ Rz Rs
~ ~ N
A'\ v/ 'B~ ~Q
HO (I)
in which
A stands for an aryl, a benzyl or a phenethyl group, whereby the aryl, benzyl
or phenethyl group optionally can be substituted by one or more radicals
from the group Cl-CS-alkyl, C,-CS-alkoxy, C~-CS-alkylthio, C~-CS-
perfluoroalkyl, halogen, hydroxy, cyano, nitro,-O-(CH2)n-O-, -O-(CHZ)n-
CH2-, -O-CH=CH-, or -(CHZ)~+2-~ whereby n = 1 or 2, and the terminal
oxygen atoms and/or carbon atoms are linked to directly adjacent ring-
carbon atoms,
or NR4R5,
whereby R4 and R5, independently of one another, can be hydrogen, CI-
CS-alkyl or (CO)-Cl-CS-alkyl,
RI and R2, independently of one another, mean a hydrogen atom, a methyl or
ethyl group, or together with the carbon atom mean the chain of a C3-C6-
cycloalkyl ring,
R3 means a CI-Cg-alkyl group that is optionally substituted, independently of
one another, by one or more groups selected from halogen, hydroxy or
Cl-C;-alkoxy, or an optionally partially or completely fluorinated C,-C3-
alkyl group, an optionally substituted group that is selected from CZ-C6-
alkenyl, CZ-C6-alkinyl, C3-Cg-cycloalkyl, C3-C~-heterocyclyl, aryl,
CA 02531060 2005-12-29
heteroaryl, (CI-C8-alkyl)C3-Cg-cycloalkyl, (C~-C$-alkyl)aryl, or (C,-Cg-
alkyl)heteroaryl,
B means a methylene group or a carbonyl group that is optionally
substituted by a methyl or ethyl group, and
Q means a quinazolinyl, quinoxalinyl, cinnolinyl, indazolyl, phthalazinyl,
naphthyridinyl, benzothiazolyl, dihydroindolonyl, dihydroisoindolonyl,
benzimidazole or indolyl group that is linked via any position and that
optionally can be substituted by one or more radicals from the group C~-
CS-alkyl, C,-CS-alkoxy, C,-CS-alkylthio, C,-CS-perfluoroalkyl, halogen,
hydroxy, cyano, nitro, or NR4R5,
whereby R4 and R5, independently of one another, can be hydrogen, Cl-
CS-alkyl or (CO)-C~-CS-alkyl,
whereby phthalazinones are excluded,
as well as their racemates or separately present stereoisomers, and optionally
their
physiologically compatible salts.
In view of the prior art WO 98/54159 and WO 00/32584, phthalazinones were
excluded. They are produced by the definition in claim 1 of Q = phthalazine in
combination with the possible substituent hydroxy, since hydroxyphthalazines
are at a
tautomeric equilibrium with phthalazinones.
Compounds of general formula I in which
A stands for an aryl group, a benzyl group or a phenethyl group,
whereby the aryl, benzyl or phenethyl group optionally can be
substituted by one or more radicals from the group of C~-C;-alkyl, C,-CS-
alkoxy, C~-C;-alkylthio, C,-C;-perfluoroalkyl, halogen, hydroxy, cyano,
nitro, -O-(CHZ)"-O-, -O-(CHZ)~-CH~-. -O-CH=CH-, or -(CHZ)~+2-,
~
CA 02531060 2005-12-29
4
whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms
are linked to directly adjacent ring-carbon atoms,
or NR4R5,
whereby R4 and R5, independently of one another, can be hydrogen, C~-
CS-alkyl or (CO)-C,-CS-alkyl,
R1 and R2, independently of one another, mean a hydrogen atom, a methyl or
ethyl group, or together with the carbon atom of the chain mean a C3-C6-
cycloalkyl ring,
R3 means a C1-C3-alkyl group or an optionally partially or completely
fluorinated C~-C3-alkyl group,
B means a methylene group or a carbonyl group that is optionally
substituted by a methyl or ethyl group, and
Q means a quinazolinyl, quinoxalinyl, cinnolinyl, indazolyl, phthalazinyl,
naphthyridinyl or benzothiazolyl group that is linked via any position and
that optionally can be substituted by one or more radicals from the group
of C~-CS-alkyl, C,-CS-alkoxy, C~-CS-alkylthio, C~-C5-perfluoroalkyl,
halogen, hydroxy, cyario, nitro or NR4R5,
whereby R4 and R5, independently of one another, can be hydrogen, Cl-
CS-alkyl or (CO)-C~-CS-alkyl,
whereby phthalazinones are excluded,
as well as their racemates or separately present stereoisomers, and optionally
their
physiologically compatible salts
are one aspect of the invention.
Compounds of general formula I in which
A stands for an aryl group, a benzyl group or a phenethyl group,
CA 02531060 2005-12-29
whereby the aryl, benzyl or phenethyl group optionally can be substituted
by one or more radicals from the group of C~-CS-alkyl, C,-CS-alkoxy, C,-
CS-alkylthio, C~-CS-perfluoroalkyl, halogen, hydroxy, cyano, vitro,-O-
(CHZ)~-O-, -O-(CHZ)n-CH2, -O-CH=CH-, -(CHZ)n+2-,
whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms
are linked to directly adjacent ring-carbon atoms,
or NR4R5,
whereby R4 and R5, independently of one another, can be hydrogen, Cl-
CS-alkyl or (CO)-C,-CS-alkyl,
R' and RZ, independently of one another, mean a hydrogen atom, a methyl or
ethyl group, or together with the carbon atom of the chain mean a C3-C6-
cycloalkyl ring,
R3 means a C1-C3-alkyl group or an optionally partially or completely
fluorinated C1-C3-alkyl group,
B means a methylene group or a carbonyl group that is optionally
substituted by a methyl or ethyl group, and
means a quinazolinyl, quinoxalinyl, einnolinyl, indazolyl, naphthyridinyl
or benzothiazolyl group that is linked via any position,
which optionally can be substituted by one or more radicals from the
group of C,-CS-alkyl, C,-CS-alkoxy, CI-CS-alkylthio, C~-C;-
perfluoroalkyl, halogen, hydroxy, eyano, vitro or NR4R5,
whereby R4 and R5, independently of one another, can be hydrogen, C,-
C;-alkyl or (CO)-Ci-C;-alkyl,
as well as their racemates or separately present stereoisomers, and optionally
their
physiologically compatible salts
CA 02531060 2005-12-29
6
are a subject of the invention.
Compounds of general formula I in which R3 represents a CI-Cg-alkyl group that
is optionally substituted, independently of one another, by one or more groups
selected
from halogen, hydroxy or Cl-C3-alkoxy, or an optionally partially or
completely
fluorinated C~-C3-alkyl group are a subject of the invention.
Compounds of general formula I in which R3 is a C1-C3-alkyl group or an
optionally partially or completely fluorinated Cl-C3-alkyl group are a special
subject of
the invention. Preferred are the CF3 group and the CZFS group.
The C~-CS- or CI-Cg-alkyl groups can be straight-chain or branched and can
stand for a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-
butyl, or n-pentyl,
2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group. A methyl or ethyl
group is
preferred.
For a partially or completely fluorinated C1-C3-alkyl group, for example, the
following partially or completely fluorinated straight chain or branched
groups are
considered: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-
difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, and
pentafluoroethyl. Of the latter, the trifluoromethyl group or the
pentafluoroethyl group
is preferred.
A C~-CS-perfluoroalkyl group is defined as a completely fluorinated straight
chain or branched alkyl group, such as, e.g., CF3, CZFS, C3F~, C4F9, or CSFn.
Alkyl radicals R' and RZ together with the carbon atom of the chain can form a
3-
to 6-membered ring. The methyl group or the ethyl group is preferred for R'
and RZ.
As alkyl radicals R4 and R5, C,-C3-alkyl is preferred, whereby the C,-C3-alkyl
group can be straight-chain or branched.
CA 02531060 2005-12-29
The CI-CS-alkoxy groups in A and Q can be straight-chain or branched and stand
for, for example, a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-
butoxy,
tert.-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-
methylbutoxy
group. A methoxy or ethoxy group is preferred.
The C1-CS-alkylthio groups in A and Q can be straight-chain or branched and
stand for a methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio,
iso-butylthio,
tert.-butylthio or n-pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio or
3-
methylbutylthio group. A methylthio or ethylthio group is preferred.
The designation halogen atom or halogen means a fluorine, chlorine, bromine or
iodine atom. A fluorine, chlorine or bromine atom is preferred.
The NR4R5 group can mean, for example, NH2, N(H)CH3, N(CH3)2,
N(H)(CO)CH3, N(CH3)(CO)CH3, N[(CO)CH3]2, N(H)COZCH3, N(CH3)C02CH3, or
N(COZCH3)2.
As acyl radicals R4 and R5, (CO)-C1-C3-alkyl is preferred, whereby the C,-C3-
alkyl radical can be straight-chain or branched.
The CZ-C6- or CZ-CS-alkenyl group is straight-chain or branched; for example,
vinyl, propenyl, isopropenyl, butenyl, or isobutenyl is suitable.
The CZ-C6- or CZ-CS-alkinyl group is straight-chain or branched; for example,
C---C, propinyl, isopropinyl, butinyl, or isobutinyl is suitable.
For a cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl or cyclooctyl is considered.
The Cl-Cg-alkyl(C3-C8)cycloalkyl group can be, for example, cyclobutylmethyl,
cyclopentylmethyl, cyclohexylmethyl, or cycloheptylmethyl. The linkage with
the chain
is carried out via the alkyl group.
CA 02531060 2005-12-29
The heterocyclyl group is not aromatic and can be, for example, pyrrolidine,
imidazolidine, pyrazolidine, or piperidine.
For an aryl group, phenyl and naphthyl are considered, and for (C~-
Cg)alkylaryl,
benzyl and homobenzyl are considered. If the aryl group stands for A, the
phenyl group
is preferred.
Heteroaryl comprises, for example, furanyl, thienyl, thiazolyl, oxazolyl,
imidazolyl, triazolyl, pyridyl and pyrimidyl.
(Ci-C8-Alkyl)heteroaryl comprises all combinations from the definition of
alkyl
given above with monocyclic aromatic heterocyclic compounds, in particular the
heterocyclic compounds that are mentioned by name. The linkage with the chain
is
carried out via the alkyl group, which in turn is linked to any chemically
possible
position of the heterocyclic compound.
The substituents of groups in R3 can be Ci-C6-alkyl, CZ-C6-alkenyl, CZ-C6-
alkinyl, C1-C6-alkoxy, halogen, hydroxy, and NR4R5.
In the ring, the substituted aryl, benzyl or phenethyl groups carry 1-4 or 1-3
substituents, preferably 2 substituents.
The substituents for A can be selected, independently of one another, from the
group that consists of C~-C;-alkyl, C,-C;-alkoxy, C1-C;-alkylthio, C,-C;-
perfluoroalkyl,
halogen, hydroxy, cyano, nitro, -O-(CHZ)"-O-, -O-(CHZ)~-CHZ-, -O-CH=CH-,
-(CHZ)~+i-, (whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon
atoms are
linked to directly adjacent ring-carbon atoms), or NR4R5 (whereby R4 and R5,
independently of one another, are hydrogen, C,-C;-alkyl or (CO)-Ci-C;-alkyl).
C,-C;-Alkyl, C,-C;-alkoxy, C,-C;-alkylthio, C,-C;-perfluoroalkyl, halogen,
hydroxy, -O-(CHI)"-O-, -O-(CHZ)"-CHZ-, -O-CH=CH- and -(CHZ)~+z- are preferred.
CA 02531060 2005-12-29
C~-C5-Alkyl, C~-CS-alkoxy, C,-CS-alkylthio, C1-CS-perfluoroalkyl, halogen,
hydroxy, -O-(CHZ)n-O- and -O-(CHZ)"-CHZ- are especially preferred. In
particular,
compounds whose substituents of A are selected from the group of Cy-CS-alkyl,
CI-CS-
alkoxy, C1-CS-alkylthio, C~-CS-perfluoroalkyl, halogen and hydroxy are a
subject of the
invention.
Compounds whose substituents of A are selected from the group of
-O-(CH2)-O-, -O-(CH2)n-CHZ-, -O-CH=CH- and --(CHZ)~+2-, preferably -O-(CHZ)~-O-
and -O-(CH2)~-CH2-, are another subject of the invention.
Compounds of formula t, in which A means a phenyl radical and whose
substituents are selected from the group of hydroxy, CI-CS-alkoxy and halogen,
are
another subject of the invention.
The following definitions and substitution patterns in ring A are a special
subject
of the invention: 2,5-disubstituted phenyl derivatives and 2,4-disubstituted
phenyl
derivatives.
For radical B, the unsubstituted methylene group and the carbonyl group are
preferred.
Compounds of formula I according to claim 1, in which B stands for a methylene
group that is optionally substituted by a methyl or ethyl group, are a special
subject of
the invention.
Compounds according to claim 1, in which Q means a benzothiazolyl,
quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-
naphthyridinyl,
indazolyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl
group that
is linked via any position, are a subject of the invention.
CA 02531060 2005-12-29
10
Compounds of formula I in which Q means a benzothiazolyl, quinazolinyl,
quinoxalinyl, cinnolinyl, indazolyl, phthalazinyl or a 1,7- or 1,8-
naphthyridinyl group
that is linked via an position are another subject of the invention.
Preferred radicals Q are quinazoline, benzothiazole, naphthyridine, indazole,
indolone, benzimidazole, and isoindolone. Especially preferred are
quinazoline,
indazole and benzimidazole.
Radical Q can be linked via any ring-carbon atom to the (NH)-group of the
chain. 5- and 8-positions are preferred for the quinazoline ring, the
quinoxaline ring, the
cinnoline ring and the phthalazine ring; 3- and 5-positions are preferred for
the
naphthyridine ring, and 7- and 4-positions are preferred for the
dihydroindolone,
dihydroisoindolone, benzimidazole, indazole, indole and the benzothiazole
ring.
For the purposes of this invention, the expression that Q "can be linked via
any
ring-carbon atom or any position" means any possible chemical linkage between
one of
the carbon atoms of the heterocyclic compound Q and the NH group of the
compound of
formula I.
Q can be substituted by one or more radicals from the group of C~-CS-alkyl, Cl-
CS-alkoxy, C~-CS-alkylthio, CI-CS-perfluoroalkyl, halogen, hydroxy, cyano,
nitro or
NR4R5,
whereby R4 and R5, independently of one another, can be hydrogen, C1-CS-alkyl
or
(CO)-C ~-CS-alkyl.
The C~-C3-alkyl group, the C1-CS-alkoxy group, the hydroxy group, the C~-CS-
perfluoroalkyl group and halogen atoms are preferred. The C,-C3-alkyl group,
the
hydroxy group and halogen atoms are especially prefa-red.
Anther subject of this invention follows from the meanings for A, R~, R2, R3,
R'~,
R5, B and Q, disclosed in the Examples, and all possible combinations thereof.
CA 02531060 2005-12-29
The compounds of general formula I according to the invention can be present
as
different stereoisomers because of the presence of asymmetry centers. Both the
racemates and the separately present stereoisomers are part of the subject of
this
W vention.
With respect to their active strength, the separately present stereoisomers,
i.e.,
(+)-enantiomers and (-)-enantiomers, are a special subject of this invention.
In the case that the compounds of general formula I are present as salts, the
latter
can be in the form of, for example, hydrochloride, sulfate, nitrate,
phosphate, pivalate,
maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate, which
can be
obtained according to the methods that are known to one skilled in the art.
The process for the production of the compounds of W098/54159, WO00/32584
and W002/10143 can also be used for the production of the compounds according
to the
invention. For the linkage of the benzothiazole, quinazoline, quinoxaline,
cinnoline,
indazole, phthalazine, 1,7- and 1,8-naphthyridine, dihydroindolone,
dihydroisoindolone,
benzimidazole or indole groups that are characteristic of the compounds
according to the
invention, the following process steps can be performed:
Al)
fnrR=rn
r~ '"NCO H x ~ ltl;:a k !dH~t?
p ;'Rz9~.~i..R~ tKf
i~3
[or)
A 0-keto acid of general formula (II), in which A, R' and R' have the meanings
that are indicated for formula (I), is converted with an aminobenzothiazole,
CA 02531060 2005-12-29
12
aminoquinazoline, aminoquinoxaline, aminocinnoline, or aminophthalazine
derivatives
(Q-NH2) into D-ketoamide (III), whereby A, Rl and R2 have the above-indicated
meanings, in the way that is known to one skilled in the art. For example, ~-
ketoamide
(III) is obtained with use of dehydrating coupling reagents, as they are known
from
peptide chemistry, e.g., dicyclohexylcarbodiimide or 1-(3-
dimethylaminopropyl~3-
ethylcarbodiimides, or by upstream conversion of the acid into an acid
chloride, e.g.,
with thionyl chloride or POC13 and subsequent reaction with Q-NH2.
R' Rz ~
A\~<~ N H-Q
(III) O
Compound (III) is reacted either with an alkyl metal compound R3 -M, in which
R3 has the above-indicated meanings and M stands for an alkali metal (lithium,
sodium
or potassium) or MgX or ZnX with X = halogen (chlorine, bromine, or iodine),
or by
reaction with compound (IV),
(R6)3S1-R3
(IV)
whereby R3 has the above-indicated meaning, and R6 refers to a Cl-CS-alkyl
group, and
the three R6 groups must not be the same, in the presence of a catalyst, e.g.,
fluoride salts
or bases, such as, for example, alkali carbonates (J. Am. Chem. Soc. 1989,
lll, 393), to
form title compound (I).
CA 02531060 2005-12-29
13
forB=CO
,R ~ Ra
R,~ R' ~ ; tern R x :~ti-Q
~~"'.~'~CO~1 ~ O~~z~ ~ ~~ O
2, i~°~r~ R'
i~' 3 v~~~trn 1~~9 S
[Key: verestern = esterification
verseifen = saponification]
As an alternative, D-keto acids (II) can also be esterified to compounds (V),
R' R2 O
A\ v _COZR'
(V)
in which A, R' and R2 are defined as described above, and R' is C1-C4-alkyl,
according
to commonly used methods, e.g., with thionyl chloride in methanol or ethanol
or with
methyl iodide and alkali carbonate, and can be reacted analogously to reaction
sequence
Al) from (III) to (I) with alkyl compounds of formula R3-M, in which R3 has
the above-
indicated meanings, and M stands for an alkali metal (lithium, sodium or
potassium) or
MgX or ZnX with X = halogen (chlorine, bromine, or iodine),
or with (R6)3Si-R3 to form compound (VI).
R' RZ Rs
A\ v/ _COZR'
HO
(VI)
The ester (VI) is saponified under standard conditions, for example aqueous
alkali hydroxide solution, to acid (VIa; R' = H).
The acid (VIa) is reacted for coupling with an aminoquinazoline,
aminoquinoxaline, aminocinnoline, aminoindazole, aminophthalazine,
aminonaphthyridine, aminobenzothiazole, aminodihydroindolone,
" ~~ CA 02531060 2005-12-29
14
aminodihydroisoindolone, aminobenzimidazole or aminoindole with use of a
conventional activating reagent, e.g., thionyl chloride, optionally in the
presence of a
catalyst such as dimethylaminopyridine, to form title compound (I).
B)
for B = a methylene group that is optionall~substituted by methyl or ethyl
~ ~ ,NH-Q
R, Rz R3 a) R, R\
A\ v o:B A
3
R~ Rz R3 c) R' Rz R
g~NHz ~ A\~g .NH-O
OH OH
R~ Rz Rs R~ RZ Rs
A O d-~ A N H-Q
O ~8 ~8
a)
A compound of general formula (VII) or (VIII),
3
R~ Rz R3 R~ R~
~ ~ ~LG
A\ voiB A HO B
(VII) (VIII)
in which A, B and R', Rz and R3 have the above-indicated meanings, and LG
means any
CA 02531060 2005-12-29
leaving group such as halide or sulfonate, is reacted with a compound of
general formula
(IX) or (X)
Q-NH-R9 Q-N=C=O
(IX) (X)
in which R9 means a hydrogen atom, a CI-CS-acyl group or alkoxy or
aryloxycarbonyl
group, and Q has the above-indicated meaning, whereby radical R9 is cleaved
off, or an
intermediately formed oxazolid'inone (cf., e.g., S. J. Brickner, D. K.
Hutchinson, M. R.
Barbachyn, P. R. Manninen, D. A. Ulanowicz, S. A. Garmon, K. C. Grega, S. K.
Hendges, D. S. Toops, C. W. Ford, G. E. Zurenko J. Med. Chem. 1996, 39, 673)
is
cleaved with, for example, aqueous alkali hydroxides to produce title compound
(I).
b)
Another method consists in reacting compounds of formula (VII) or (VIII) with
nitrogen nucleophiles, for example azide salts or ammonia, whereby in the
first case, a
reduction step follows in the way that is known to one skilled in the art,
e.g., with
complex hydride reagents, such as lithium aluminum hydride, or by a transition
metal-
catalyzed hydrogenolysis to produce compounds of formula (XI).
R' Rz R3
A\~g~NHz
HO
(XI)
Radicals R'-R3, A and B are equally important as indicated above.
CA 02531060 2005-12-29
16
c)
Compound (XI) can be converted under base catalysis, e.g., in the presence of
tertiary amine bases or alkali carbonates or alkali hydroxides, or under
transition metal
catalysis, e.g., palladium catalysis (J. P. Wolfe, S. Wagaw, J.-F. Marcoux, S.
L.
Buchwald Acc. Chem. Res. 1998, 31, 805; J. F. Hartwig Acc. Chem. Res. 1998,
31, 852);
with a halogenated quinazoline, quinoxaline, cinnoline, indazole, phthalazine,
naphthyridine, benzothiazole, dihydroindolone, dihydroisoindolone,
benzimidazole or
indole, into title compound (I).
d)
Finally, title compound (I) can also be synthesized with Q-NHZ by reductive
amination of a compound of formula (XII), which can be obtained by means of
reduction or alkylation from compound (VI) according to the methods that are
known to
one skilled in the art, whereby, e.g., sodium cyanoborohydride, sodium
triacetoxy
borohydride or hydrogen is considered as a reducing agent under palladium
catalysis.
R' RZ Ra
A ~~~~0
-HO'' Ra
(XI I)
R8 means hydrogen, methyl or ethyl according to the substituents that are
defined
for the methylene group in B.
In the case that the compounds of general formula I are present as salts, this
can
be, for example, in the form of hydrochloride, sulfate, nitrate, phosphate,
pivalate,
maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.
If the compounds according to the invention are present as racemic mixtures,
they can be separated into pure, optically active forms according to the
methods of
CA 02531060 2005-12-29
17
racemate separation that are familiar to one skilled in the art. For example,
the racemic
mixtures can be separated by chromatography on an even optically active
carrier
material (CHIRALPAK AD~) into the pure isomers. It is also possible to
esterify the
free hydroxy group in a racemic compound of general formula I with an
optically active
acid. The diastereoisomeric esters that are obtained can be separated by
fractionated
crystallization or by chromatography. The separated esters are then saponified
in each
case to the optically pure isomers. As an optically active acid, for example,
mandelic
acid, camphorsulfonic acid or tartaric acid can be used.
The binding of the substances to the glucocorticoid receptor (GR) and other
steroid hormone receptors (mineral corticoid receptor (MR), progesterone
receptor (PR)
and androgen receptor (AR)) is examined with the aid of recombinantly produced
receptors. Cytosol preparations of Sf~ cells, which had been infected with
recombinant
baculoviruses, which code for the GR, are used for the binding studies. In
comparison
to reference substance ~[3H]-dexamethasone, the substances show a high to very
high
affinity to GR.
Moreover, the compounds of formula (I) substituted by quinazolines,
quinoxalines, cinnolines, indazoles, phtlialazines, naphthyridines,
benzothiazoles,
dihydroindolones, dihydroisoindolones, benzimidazoles and indoles that are
described
here show a high selectivity for the glucocorticoid receptor. Example 2 thus
shows, e.g.,
the following profile: ICSO(GR) = 1.8 nmol; ICSO(MR), ICSO(PR), ICSO(AR) > 1
~mol,
and the compound of Example 52: ICSO(GR) = 10 nmol; ICSO(MR), ICSO(PR),
ICSO(AR)
> 1 ~mol.
As an essential, molecular mechanism for the anti-inflammatory action of
glucocorticoids, the GR-mediated inhibition of the transcription of cytokines,
adhesion
molecules, enzymes and other pro-inflammatory factors is considered. This
inhibition is
CA 02531060 2005-12-29
18
produced by an interaction of the GR with other transcription factors, e.g.,
AP-1 and NF-
kappa-B (for a survey, see Cato, A. C. B. and Wade, E., BioEssays 18, 371-378,
1996).
The compounds of general formula I according to the invention inhibit the
secretion of cytokine IL-8 into the human monocyte cell line THP-1 that is
triggered by
lipopolysaccharide (LPS). The concentration of the cytokines was determined in
the
supernatant by means of commercially available ELISA kits.
The anti-inflammatory action of the compounds of general formula I was tested
in the animal experiment by tests in the croton oil-induced inflammation in
rats and mice
(J. Exp. Med. (1995), 182, 99-108). To this end, croton oil in ethanolic
solutioW vas
applied topically to the animals' ears. The test substances were also applied
topically or
systemically at the same time or two hours before the croton oil. After 16-24
hours, the
ear weight was measured as a yardstick for inflammatory edema, the peroxidase
activity
as a yardstick for the invasions of granulocytes, and the elastase activity as
a yardstick
for the invasion of neutrophilic granulocytes. In this test, the compounds of
general
formula I inhibit the three above-mentioned inflammation parameters both after
topical
administration and after systemic administration.
One of the most frequent undesirable actions of a glucocorticoid therapy is
the
so-called "steroid diabetes" [cf., Hatz, H. J., Glucocorticoide:
Immunologische
Grundlagen, Pharmakologie and Therapierichtlinien, [Glucocorticoids:
Immunological
Bases, Pharmacology and Therapy Guidelines], Wissenschaftliche
Verlagsgesellschaft
mbH, Stuttgart, 1998]. The reason for this is the stimulation of
gluconeogenesis in the
liver by induction of the enzymes responsible in this respect and by free
amino acids,
which are produced from the degradation of proteins (catabolic action of
glucocorticoids). A key enzyme of the catabolic metabolism in the liver is
tyrosinamino
transferase (TAT). The activity of this enzyme can be determined from liver
CA 02531060 2005-12-29
19
homogenates by photometry and represents a good measurement of the undesirable
metabolic actions of glucocorticoids. To measure the TAT induction, the
animals are
sacrificed 8 hours after the test substances are administered, the livers are
removed, and
the TAT activity is measured in the homogenate. In this test, at doses in
which they
have an anti-inflammatory action, the compounds of general formula I induce
little or
no tyrosinamino transferase.
Because of their anti-inflammatory and, in addition, anti-allergic,
immunosuppressive and antiproliferative action, the compounds of general
formula I
according to the invention can be used as medications for treatment or
prophylaxis of the
following pathologic conditions in mammals and humans: In this case, the term
"DISEASE" stands for the following indications:
(i) Lung diseases that are accompanied by inflammatory, allergic and/or
proliferative
processes:
- Chronic, obstructive lung diseases of any origin, primarily bronchial
asthma
- Bronchitis of different origins
- All forms of restrictive lung diseases, primarily allergic alveolitis,
- All forms of pulmonary edema, primarily toxic pulmonary edema
- Sarcoidoses and granulomatoses, especially Boeck's disease
(ii) Rheumatic diseases/autoimmune diseases/joint diseases that are
accompanied by inflammatory, allergic and/or proliferative processes:
- All forms of rheumatic diseases, especially rheumatoid arthritis, acute
rheumatic fever, polymyalgia rheumatica
- Reactive arthritis
- Inflammatory soft-tissue diseases of other origins
" ~ CA 02531060 2005-12-29
- Arthritic symptoms in the case of degenerative joint diseases (arthroses)
- Traumatic arthritides
- Collagenoses of any origin, e.g., systemic lupus erythematodes,
sclerodermia, polymyositis, dermatomyositis, Sjogren's syndrome, Still's
syndrome, Felty's syndrome
(iii) Allergies that are accompanied by inflammatory and/or proliferative
processes:
- All forms of allergic reactions, e.g., Quincke's edema, hay fever, insect
bites, allergic reactions to pharmaceutical agents, blood derivatives,
contrast media, etc., anaphylactic shock, urticaria, contact dermatitis
(iv) Vascular inflammations (vasculitides)
- Panarteritis nodosa, temporal arteritis, erythema nodosum
(v) Dermatological diseases that are accompanied by inflammatory, allergic
and/or
proliferative processes:
- Atopic dermatitis (primarily in children)
- Psoriasis
- Pityriasis rubra pilaris
- Erythematous diseases, triggered by different noxae, e.g., radiation,
chemicals, burns, etc.
- Bullous dermatoses
Diseases of the lichenoid group,
- Pruritis (e.g., of allergic origin)
- Seborrheal eczema
- Rosacea
- Pemphigus vulgaris
- Ervthema exudativum multiforme
' CA 02531060 2005-12-29
21
- Balanitis
- Vulvitis
- Hair loss such as alopecia areata
- Cufaneous T-cell lymphoma
(vi) Kidney diseases that are accompanied by inflammatory, allergic and/or
proliferative processes:
- Nephrotic syndrome
- All nephritides
(vii) Liver diseases that are accompanied by inflammatory, allergic and/or
proliferative
processes:
- Acute liver cell decomposition
- Acute hepatitis of different origins, -e.g., viral, toxic, pharmaceutical
agent-induced
- Chronic aggressive hepatitis and/or chronic intermittent hepatitis
(viii) Gastrointestinal diseases that are accompanied by inflammatory,
allergic and/or
proliferative processes:
- Regional enteritis (Crohn's disease)
- Colitis ulcerosa
- Gastritis
- Reflux esophagitis
- Ulcerative colitis of other origins, e.g., native sprue
(ix) Proctologic diseases that are accompanied by inflammatory, allergic
and/or
proliferative processes:
- Anal eczema
- Fissures
CA 02531060 2005-12-29
22
- Hemorrhoids
- Idiopathic proctitis
(x) Eye diseases that are accompanied by inflammatory, allergic and/or
proliferative
processes:
- Allergic keratitis, uveitis, iritis
- Conjunctivitis
- Blepharitis
- Optic neuritis
- Chorioiditis
- Sympathetic ophthalmic
(xi) Diseases of the ear-nose-throat area that are accompanied by
inflammatory, allergic
and/or proliferative processes:
- Allergic rhinitis, hay fever
- Otitis externa, e.g., caused by contact dermatitis, infection, etc.
- Otitis media
(xii) Neurological diseases that are accompanied by inflammatory, allergic
and/or
proliferative processes:
- Cerebral edema, primarily tumor-induced cerebral edema
- Multiple sclerosis
- Acute encephalomyelitis
- Meningitis
- Various forms of convulsions, e.g., infantile nodding spasms
(xiii) Blood diseases that are accompanied by inflammatory, allergic and/or
proliferative processes:
- Acquired hemolytic anemia
CA 02531060 2005-12-29
23
- Idiopathic thrombocytopenia
(xiv) Tumor diseases that are accompanied by inflammatory, allergic and/or
proliferative processes:
- Acute lymphatic leukemia
- Malignant lymphoma
- Lymphogranulomatoses
- Lymphosarcoma
Extensive metastases, mainly in breast, bronchial and prostate cancers
(xv) Endocrine diseases that are accompanied by inflammatory, allergic and/or
proliferative processes:
- Endocrine orbitopathy
- Thyreotoxic crisis
- De Quervain's thyroiditis
- Hashimoto's thyroiditis
- Basedow's disease
(xvi) Organ and tissue transplants, graft-versus-host disease
(xvii) Severe shock conditions, e.g., anaphylactic shock, systemic
inflammatory
response syndrome (SIRS)
(xviii) Substitution therapy in:
- Innate primary suprarenal insufficiency, e.g., congenital adrenogenital
syndrome
- Acquired primary suprarenal insufficiency, e.g., Addison's disease,
autoimmune adrenalitis, meta-infective tumors, metastases, etc.
Innate secondary suprarenal insufficiency, e.g., congenital
hypopituitarism
CA 02531060 2005-12-29
24
- Acquired secondary suprarenal insufficiency, e.g., meta-infective tumors,
etc.
(xix) Vomiting that is accompanied by inflammatory, allergic and/or
proliferative
processes:
- e.g., in combination with a 5-HT3 antagonist in cytostatic-agent-induced
vomiting
(xx) Pains of inflammatory origins, e.g., lumbago.
Moreover, the compounds of general formula I according to the invention can be
used for treatment and prophylaxis of additional pathologic conditions that
are not
mentioned above, for which synthetic glucocorticoids are now used (see in this
respect
Hatz, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie and
Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart,
1998).
All previously mentioned indications (i) to (xx) are described in more detail
in
Hatz, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie and
Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart,
1998.
For the therapeutic actions in the above-mentioned pathologic conditions, the
suitable dose varies and depends on, for example, the active strength of the
compound of
general formula I, the host, the type of administration, and the type and
severity of the
conditions that are to be treated, as well as the use as a prophylactic agent
or therapeutic
agent.
In addition, the invention provides:
(i) The use of one of the compounds of general formula I according to the
invention or mixture thereof for the production of a medication for treating
a DISEASE;
- ' CA 02531060 2005-12-29
(ii) A process for treating a DISEASE, said process comprises an
administration of an amount of the compound according to the invention,
whereby the amount suppresses the disease and whereby the amount of
compound is given to a patient who requires such a medication;
(iii) A pharmaceutical composition for treating a DISEASE, said treatment
comprises one of the compounds according to the invention or mixture
thereof and at least one pharmaceutical adjuvant and/or vehicle.
In general, satisfactory results can be expected in animals when the daily
doses
comprise a range of 1 pg to 100,000 ~g of the compound according to the
invention per
kg of body weight. In the case of larger mammals, for example the human, a
recommended daily dose lies in the range of 1 p.g to 100,000 pg per kg of body
weight.
Preferred is a dose of 10 to 30,000 pg per kg of body weight, and more
preferred is a
dose of 10 to 10,000 p.g per kg of body weight. For example, this dose is
suitably
administered several times daily. For treating acute shock (e.g., anaphylactic
shock),
individual doses can be given that are significantly above the above-mentioned
doses.
The formulation of the pharmaceutical preparations based on the new compounds
is carried out in a way that is known in the art by the active ingredient
being processed
with the vehicles that are commonly used in galenicals, fillers, substances
that influence
decomposition, binding agents, moisturizers, lubricants, absorbents, diluents,
flavoring
correctives, coloring agents, etc., and converted into the desired form of
administration.
In this case, reference is made to Remington's Pharmaceutical Science, 15'x'
Edition,
Mack Publishing Company, East Pennsylvania (1980).
For oral administration, especially tablets, coated tablets, capsules, pills.
powders, granulates, lozenges, suspensions, emulsions or solutions are
suitable.
For parenteral administration, injection and infusion preparations are
possible.
CA 02531060 2005-12-29
26
For intra-articular injection, correspondingly prepared crystal suspensions
can be
used.
For intramuscular injection, aqueous and oily injection solutions or
suspensions
and corresponding depot preparations can be used.
For rectal administration, the new compounds can be used in the form of
suppositories, capsules, solutions (e.g., in the form of enemas) and ointments
both for
systemic and for local treatment.
For pulmonary administration of the new compounds, the latter can be used in
the form of aerosols and inhalants.
For local application to eyes, outer ear channels, middle ears, nasal
cavities, and
paranasal sinuses, the new compounds can be used as drops, ointments and
tinctures in
corresponding pharmaceutical preparations.
For topical application, formulations in gels, ointments; fatty ointments,
creams,
pastes, powders, milk and tinctures are possible. The dosage of the compounds
of
general formula I should be 0.01 %-20% in these preparations to achieve a
sufficient
pharmacological action.
The invention also comprises the compounds of general formula I according to
the invention as therapeutic active ingredients.
In addition, the compounds of general formula I are part of the invention as
therapeutic active ingredients together with pharmaceutically compatible and
acceptable
adjuvants and vehicles. The invention also comprises a pharmaceutical
composition that
contains one or more of the pharmaceutically active compounds according to the
invention
or mixtures thereof or a pharmaceutically compatible salt thereof or
pharmaceutically
compatible adjuvants and vehicles.
CA 02531060 2005-12-29
27
The examples below are used for a more detailed explanation of the invention
without intending that it be limited thereto. The syntheses of important
precursors, which
are not disclosed within the scope of the experiments, are already prior art
and can be
derived from, for example, WO 98/54159, (WO 00/32584) or WO 02/10143.
CA 02531060 2005-12-29
28
Experiments
Example 1
~O OH H I N~ N
_ N /
FC
/ 3 /
F
4-(5-Fluoro-2-methoxyphenyl 4-methyl-1-(phthalazin-5-ylamino)-2-
(trifluoromethyl)-
pentan-2-of
4-(5-Fluoro-2-methoxy phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl pentanal
0.81 ml (8.67 mmol) of oxalyl chloride is cooled in 15 ml of dichloromethane
to
-60°C and mixed with 1.6 ml (22.6 mmol) of dimethyl sulfoxide in 10 ml
of
dichloromethane. After 15 minutes, 1.0 g (3.22 mmol) of 4-(5-fluoro-2-methoxy-
phenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol (WO 00/32584) in 10 ml of
dichloromethane is added, and the mixture is stirred for one hour at -
60°C. 4.1 ml (29
mmol) of triethylamine is added, and the mixture is allowed to heat over 30
minutes to
room temperature. It is poured into 50 ml of water and extracted with CH2C12.
The
combined organic extracts are washed with saturated NaCI solution, dried
(Na2S04) and
concentrated by evaporation in a vacuum. After chromatography on silica gel
with
hexane-ethyl acetate (0-30%), 600 mg of the product is obtained.
'H-NMR (CDC13); 8 = 1.38 (s, 3H), 1.47 (s, 3H), 2.23 (d, 1H), 3.36 (d, 1H),
3.86
(s, 3H), 6.77 (dd, 1 H), 6.87 (dd, 1 H), 6.91 (ddd, 1 H), 9.05 (s, 1 H).
200 mg (0.65 mmol) of 4-(5-fluoro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-
trifluoromethyl-pentanal in 5 ml of toluene is added to 70 mg (0.48 mmol) of 5-
aminophthalazine (I. A. Shaikh, F. Johnson, A. P. Grollman, J. Med. Chem.
1986. 26,
1329-1340) in 2 ml of acetic acid. The reaction solution is refluxed with
water being
separated off for 6 hours and refluxed on a molecular sieve (4 A) for another
4 hours.
CA 02531060 2005-12-29
29
The solvent is removed in a vacuum, and acetic acid residue is eliminated by
azeotropic
codistillation with toluene. After chromatography on silica gel with hexane-
ethyl
acetate (0-70%), 40 mg of 4-(5-fluoro-2-methoxyphenyl}-4-methyl-1-(phthalazin-
5-
ylimino)-2-(trifluoromethyl)-pentan-2-of is obtained. 20 mg of palladium on
carbon is
added to 10 mg of imine in 10 ml of ethyl acetate and 1 ml of triethylamine,
and it is
shaken for 2 hours under a hydrogen atmosphere at normal pressure. Catalyst is
removed from the solution by means of filtration, and it is concentrated by
evaporation.
After chromatography on silica gel with hexane-ethyl acetate (0-70%), 4 mg of
the
desired product is obtained.
'H-NMR (CDC13); 8 = 1.44 (s, 3H), 1.66 (s, 3H), 2.07 (d, 1H), 3.07 (d, 1H),
3.16
(d, 1 H), 3.24 (d, 1 H), 3.85 (s, 3H), 6.42 (d, 1 H), 6.76 (m, 2H), 7.11 (dd,
1 H), 7.30 (d,
1 H), 7.66 (dd, 1 H), 9.3 8 (s, 1 H), 9.48 (s, 1 H).
Example 2
N
~O OH
N I ~N
\ ul~
F3C
F
4-(5-Fluoro-2-methoxyphen r~1~4-methyl-~2-methylquinazolin-5-ylamino)-2-
(trifluoromethyl)-pentan-2-of
5-Amino-2-methylquinazoline
12.7 g (mmol) of 2-methyl-5-nitro-3H-quinazolin-4-one (M. T. Bogert, V. J.
Chambers J. Org Chem. 1905, 649-658) and 37.5 g of phosphorus pentachloride
are
refluxed in 75 ml of phosphoryl chloride over 20 hours. After cooling, it is
poured into
saturated NaHCO; solution and extracted with ethyl acetate. The organic phase
is dried,
and the solvent is removed. 14 g of 4-chloro-2-methyl-5-nitroquinazoline, of
which 4.5
' CA 02531060 2005-12-29
g (20.2 mmol) in 225 ml of ethyl acetate and 22.5 ml of triethylamine are
dissolved, is
obtained. 2 g of palladium on carbon is added, and it is stirred while being
cooled with
ice for 4 hours under a hydrogen atmosphere at normal pressure. Catalyst is
removed
from the solution by means of filtration on Celite, whereby washing is
continued with
200 ml of ethanol, and it is concentrated by evaporation. After chromatography
on silica
gel with ethyl acetate-ethanol (0-10%), 530 mg of the product is obtained. 'H-
NMR
(CDC13); 8 = 2.87 (s, 3H), 4.52 (br., 2H), 6.77 (d, 1H), 7.33 (d, 1H), 7.65
(t, 1H), 9.40 (s,
1 H).
I 80 mg (0.48 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-
(trifluoromethyl)pentanal and 50 mg of 5-amino-2-methylquinazoline are
concentrated
to 5 ml in 20 ml of dichloroethane and 2 ml of acetic acid with continuous
slow removal
of the solvent over 5 hours. The residual solvent is removed in a vacuum, and
acetic
acid residue is eliminated by azeotropic codistillation with toluene. After
chromatography on silica gel with hexane-ethyl acetate (0-70%), 58 mg of 4-(5-
fluoro-
2-methoxyphenyl~4-methyl-1-(2-methylquinazolin-5-ylimino)-2-(trifluoromethyl)-
pentan-2-of is obtained. 20 mg of palladium on carbon is added to the imine in
10 ml of
ethyl acetate and 1 ml of triethylamine, and it is shaken for 2 hours under a
hydrogen
atmosphere at normal pressure. Catalyst is removed from the solution by means
of
filtration, and it is concentrated by evaporation. It is taken up in 5 ml of
chloroform, and
200 mg of activated manganese dioxide is added and stirred for 30 minutes. It
is filtered
on Celite and concentrated by evaporation in a vacuum. After chromatography on
silica
gel with hexane-ethyl acetate (0-70%), 22 mg of the product is obtained. 'H-
NMR
(CDCI;); 8 = 1.47 (s, 3H), 1.56 (s, 3H), 2.38 (d, IH), 2.77 (d, IH), 2.83 (s,
3H), 3.16 (dd,
I H), 3.33 (dd, 1 H), 3.85 (s, 3H), 4.70 (br., 1 H), 6.05 (d, 1 H), 6.77 (dd,
I H), 6.88 (ddd,
1 H), 7.09 (dd, I H), 7.24 (d, I H), 7..56 (t, I H), 9.16 (s, 1 H).
CA 02531060 2005-12-29
31
Example 3
N
OH OH
~N
\ ~I~
/ F3C
F
4-(5-Fluoro-2-hydroxyphenyl~4-meth 1-~l-_(2-methylquinazolin-5-ylamino)-2-
~trifluoromethyl)-pentan-2-of
103 mg (0.23 mmol) of 4-(5-fluoro-2-methoxyphenyl~4-methyl-1-(2-
methylquinazolin-5-ylamino)-2-(trifluoromethyl)-pentan-2-of in 10 ml of CHZC12
is
mixed at 0°C with 5 ml of 1 M boron tribromide-CHZC12 solution. After
10 hours,
another 5 ml of I M boron tribromide-CH2C12 solution is added, and at room
temperature, the batch is poured into saturated NaHC03 after 72 hours, stirred
for 20
minutes and extracted with CHZCIz. The combined organic extracts are washed
with
water, dried (NazS04) and concentrated by evaporation in a vacuum.
Chromatography
with hexane-2-propanol (0-20%) on silica gel yields 80 mg of the product.
'H-NMR (CDC13); 8 = 1.51 (s, 3H), 1.58 (s, 3H), 2.37 (d, 1H), 2.81 (s, 3H),
2.91
(d, 1 H), 3.25 (dd, I H), 3.43 (dd, 1 H), 5.05 (br., I H), 6.20 (d, 1 H); 6.54
(dd, 1 H), 6.69
(m, 1 H), 7.05 (dd, 1 H), 7.23 (d, 1 H), 7.59 (d, 1 H), 7.58 (d, 1 H), 8.32
(d, I H), 8.68 (d,
1 H).
CA 02531060 2005-12-29
32
Example 4
N
F OH
~N
\ ~Iv
F3C
F
4-(2 5-Difluorophenvl)-4-methyl-1-(2-methylquinazolin-5-ylamino)-2-
(trifluoromethyl)-
pentan-2-of
4-(2,5-Difluorophenyl)-2-hydrozy-4-methyl-2-tr~uoromethyl pentanal
5.4 g (15.5 mmol) of 4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-
trifluoromethyl-valeric acid ethyl ester (WO 02/10143) is dissolved at
0°C in diethyl
ether and mixed within 20 minutes with 1.76 g (46.5 mmol) of lithium aluminum
hydride. It is allowed to stir at room temperature for 4 hours, and enough
saturated
NaHC03 solution is carefully added until no more gas generation is observed.
The
mixture is diluted with ethyl acetate, stirred for another 15 minutes, and
then the
precipitate that is formed is filtered off. It is concentrated .by evaporation
and
chromatographed on silica gel with hexane/ethyl acetate (50%). 2.45 g of 2,5-
difluorophenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol is obtained as a
pale
yellowish crystallizing oil. 800 mg (2.8 mmol) of 4-(2,5-difluorophenyl)-4-
methyl-2-
trifluoromethyl-pentane-1,2-diol is introduced into 20 ml of dichloromethane,
and at
0°C, 9.5 ml of DMSO and 1.95 ml of triethylamine are added. The
solution is slowly
mixed with 1.34 g (8.4 mmol) of S03-pyridine complex, and it is stirred for 2
hours at
0°C. The mixture is dispersed between saturated ammonium chloride
solution and
MTBE, the phases are separated, and the aqueous phase is extracted with MTBE.
The
combined organic phases are washed with water and saturated NaCI solution and
dried
CA 02531060 2005-12-29
33
with NaS04. It is concentrated by evaporation and chromatographed on silica
gel with
hexane/ethyl acetate (30%). 710 mg of the desired product is obtained. 1H-NMR
(CDC13): 8 = 1.41 (s, 3H), 1.48 (s, 3H), 2.39 (d, 2H), 3.02 (d, 1H), 3.61 (s,
1H), 6.84-
7.18 (m, 3H), 9.23 (s, 1H).
240 mg (0.84 mmol) of 4-(2,5-difluoro-phenyl)-2-hydroxy-4-methyl-2-
trifluoromethyl-pentanal and 200 mg (1.26 mmol) of 5-amino-2-methyl-
quinazoline are
reacted first analogously to Example 2. After chromatography on silica gel
with hexane-
ethyl acetate (0-70%), 80 mg of 4-(2,5-difluorophenyl)-4-methyl-1-(2-
methylquinazolin-
5-ylimino)-2-(trifluoromethyl)-pentan-2-of is obtained and is taken up again
in ethyl
acetate/ethanol 1:1 and hydrogenated with 10 mg of palladium catalyst (10% on
activated carbon) under hydrogen atmosphere (1 atm). After 5 hours at room
temperature, the catalyst is suctioned off, and the filtrate is concentrated
by evaporation.
The residue is taken up again in chloroform and reacted with manganese dioxide
analogously to Example 2. After chromatographic purification, 15 mg of the
desired
product is obtained as a reddish-brown film. MS (ESI): 440 (M+H); IH-NMR
(CDC13):
8 = 1.48 (s, 3H), 1.62 (s, 3H), 2.29 (d, 1H), 2.61 (d, 1H), 2.79 (s, 3H), 3.19-
3.35 (m,
2H), 3.61 (s, 1 H), 4.69-4.73 (m, 1 H), 6.00 (d, 1 H), 6.83-6.91 (m, 2H), 7.08-
7.14 (m,
1 H), 7:23 (d, 1 H), 7.52 (dd, 1 H), 9.14 (d, 1 H).
Example 5
~O OH H S
N ~ N
r F3C
F
CA 02531060 2005-12-29
34
4-(5-Fluoro-2-methoxyphenyl~4-methyl-I -(2-methylbenzothiazol-7-ylamino)-2-
(trifluoromethyl)-pentan-2-of
200 mg (0.65 mmol) of 4-(5-fluoro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-
trifluoromethyl-pentanal and 126 mg (0.77 mmol) of 7-amino-2-
methylbenzothiazole
(Libeer et al. Bull. Soc. Chim. Belg.; 1971; 80; 43-47) are heated in 8 ml of
acetic acid
over 5 hours to 125°C. After cooling to room temperature, it is mixed
with 214 mg
(1.01 mmol) of sodium triacetoxy borohydride and allowed to stir for 16 hours.
After
another 100 mg (0.47 mmol) of sodium triacetoxy borohydride is added, and
after 2
hours of stirring, toluene is added, and it is concentrated by evaporation in
a vacuum.
The residue is taken up in ethyl acetate, the organic phase is washed with
saturated
sodium bicarbonate and saturated sodium chloride solution, and it is dried on
sodium
sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-50%),
221 mg
of the product is obtained. 'H-NMR (CDCl3); 8 = 1.45 (s, 3H), 1.58 (s, 3H),
2.25 (d,
1 H), 2.78 (d, 1 H), 2.82 (s, 3H), 3. I 4 (s, I H), 3. I 6 (dd, 1 H), 3.28
(dd, I H), 3.48 (dd, I H),
3 .84 (s, 3 H), 4.23 (d, 1 H), 5 .97 (d, I H), 6. 82 (dd, 1 H), 6.96 (ddd, I
H), 7.15 (dd, 1 H),
7.21 (t, 1 H), 7.42 (d, 1 H).
Example 6
OH OH H S
N N
w
FC
F
4-(5-Fluoro-2-hydroxyphenyl?-4-methyl-1-(2-methylbenzothiazol-7-ylamino)-2-
(trifluoromethyl)pentan-2-of
. ' CA 02531060 2005-12-29
Analogously to Example 3, 150 mg (0.13 mmol) of 4-(5-fluoro-2-
methoxyphenyI~4-methyl-1-(2-methylbenzothiazol-7-ylamino)-2-(trifluoromethyl)-
pentan-2-of in 15 ml of CHZC12 is reacted with 6.8 ml of 1 M boron tribromide-
CHZC12
solution. After chromatography on silica gel with hexane-ethyl acetate (0-
70%), 102 mg
of the product is obtained. 'H-NMR (CDCl3); 8 = 1.50 (s, 3H), 1.59 (s, 3H),
2.31 (d,
1 H), 2.79 (d, 1 H), 2.80 (s, 3 H), 3.27 (m, 2H), 3.40 (dd, 1 H), 3.54 (dd, 1
H), 6.02 (d, 1 H),
6.11 (br., 1 H), 6.65 (dd, 1 H), 6.82 (ddd, 1 H), 7.12 (dd, 1 H), 7.18 (t, 1
H), 7.40 (d, 1 H).
Example 7
~O OH H N
N ~ ~N
vp
F3C
F
1-(Quinoxalin-5-ylaminol-4-(5-fluoro-2-methoxyphenyl~-4-methyl-2-
(trifluoromethyl)-
pentan-2-of
140 mg (0.46 mmol) of 4-(5-fluoro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-
trifluoromethyl-pentanal; dissolved in 5 ml of dichloroethane, is added to 80
mg (0.55
mmol) of 5-aminoquinoxaline (J. Salon, V. Milata, N. Pronayova, J. Lesko
Monatsh.
Chem. 2000, 131, 293-299) in 2 ml of acetic acid. The reaction solution is
refluxed for 5
hours on a molecular sieve (4 A). The mixture is dispersed between water and
dichloromethane and extracted (CHZC12). The combined organic phases are washed
(saturated NaCI solution), dried (Na2S04) and concentrated by evaporation.
After
chromatographic purification on silica gel with hexane/ethyl acetate (0-50%),
82 mg of
1-(quinoxalin-5-ylimino)-4-(5-fluoro-2-methoxyphenyl~4-methyl-2-
(trifluoromethyl)-
pentan-2-ol, which is taken up in 3 ml of methanol and mixed with 100 ~1 of
acetic acid
and 10 mg (0.26 mmol) of NaBH4, is obtained. The reaction mixture is stirred
for 2
CA 02531060 2005-12-29
36
days at room temperature, and here, another 10 mg of NaBH4 is added twice in
each
case. The mixture is dispersed between water and dichloromethane and extracted
(CHZC12). The combined organic phases are washed (saturated NaCI solution),
dried
(Na2S04) and concentrated by evaporation. The crude product is purified by
chromatography on silica gel with hexane/ethyl acetate (10-50%). 40 mg of the
desired
product, which can be recrystallized from hexane/diethyl ether, is obtained.
MS (ESI):
438 (M+H);'H-NMR (CDC13): 8= 1.46 (s, 3H), 1.61 (s, 3H), 2.26 (d, 1H), 2.80
(d, 1H),
2.99 (s, 1H), 3.22-3.49 (m, 3H), 3.85 (s, 3H), 6.07 (d, 1H), 6.81 (dd, 1H),
6.91-6.99 (m,
1 H), 7.19 (dd, 1 H), 7.36 (dd, 1 H), 7.46 (d, 1 H), 8.61 (d, 1 H), 8.80 (d, 1
H).
Example 8
OH OH H N
N ~ ~N
\ ~Iv
F3C
F
1-(Quinoxalin-5-ylamino)-4-(5-fluoro-2-hydroxyphenyl~4-methyl-2-
(trifluoromethyl)-
pentan-2-of
Analogously to Example 3, 30 mg (68 ~mol) of 1-(quinoxalin-5-ylamino)-4-(5-
fluoro-2-methoxyphenyl}-4-methyl-2-(trifluoromethyl)-pentan-2-ol, dissolved in
3 ml of
dichloromethane, is reacted with 3 ml of boron tribromide solution ( 1 M in
CH2C12) and
stirred at room temperature for 24 hours. The mixture is dispersed between
ethyl acetate
and saturated NaHC03 solution and extracted with ethyl acetate. The combined
organic
phases are washed (saturated NaCI solution), dried (NaZS04) and concentrated
by
evaporation. The crude product is purified by chromatography on silica gel
with
hexane/ethyl acetate (20%). 15 mg of the desired product is obtained. MS
(ESI): 424
' CA 02531060 2005-12-29
37
(M+H);'H-NMR (CDC13): 8 = 1.46 (s, 3H), 1.53 (s, 3H), 2.28 (d, 1H), 2.58 (d,
1H),
2.97 (br, 1 H), 3.30-3.56 (m, 4H), 6.18 (d, 1 H), 6.56 (dd, 1 H), 6.76-6.83
(m, 1 H), 7.15
(dd, 1 H), 7.36 (d, 1 H), 7.46 (d, 1 H), 8.65 (d, 1 H), 8.83 (d, 1 H).
Example 9
CI OH H N
N ~N
F3C
F
~-[(Quinoxalin-5-ylamino)methyl-1-(2-chloro-5-fluorophenyl)-0-
(trifluoromethyl)
c~lobutane ethanol
I -(2-Chloro-5 fluorophenyl)-ahydroxy-Q(trifluoromethyl)cyclobutane propanal
3.1 g (8.7 mmol) of 1-(2-chloro-5-fluorophenyl)-D-hydroxy-D-(trifluoromethyl)
cyclobutanepropionie acid ethyl ester (WO 02/10143) is reacted analogously to
Example
4 with 990 mg (26.1 mmol) of lithium aluminum hydride. 1.80 g of 1-(2-chloro-5-
fluorophenyl)-0-(hydroxy~0-(trifluoromethyl)cyelobutane propanol is obtained
as a
pale yellowish oil. 493 ~l (2.56 mmol) of oxalyl chloride is introduced into
20 ml of
dichloromethane. At-75°C, 802 ~1 (11.3 mmol) of DMSO is added in drops,
and after
15 minutes of stirring, a solution of 800 mg (2.56 mmol) of I-[(chloro-5-
fluorophenyl~
~-(hydroxy~0-(trifluoromethyl)cyclobutane propanol in 10 ml of dichloromethane
is
added in drops. After another 15 minutes, 2.20 ml ( I 5.8 mmol) of
triethylamine is
added in drops and stirred for another 30 minutes at -60°C and for 30
minutes at 0°C.
The reaction is completed by adding water, the phases are separated and
extracted with
dichloromethane. The combined organic phases are washed with water and
saturated
NaCI solution and dried with NaS04. It is concentrated by evaporation and
~
CA 02531060 2005-12-29
38
chromatographed on silica gel with hexane/ethyl acetate (30%). 810 mg of the
desired
product is obtained. MS (CI): 342 (M+NH4); IH-NMR (CDC13): S = 1.74-1.92 (m,
IH),
2.00-2.70 (m, SH), 2.86 (d, 1 H), 3.19 (d, 1 H), 3.52 (s, 1 H), 6.79-6.93 (m,
1 H), 7.10-7.24
(m, 2H), 8.94 (s, 1 H).
200 mg (0.64 mmol) of 1-j2-chloro-5-fluorophenyl)-0-hydroxy-~-
(trifluoromethyl)cyclobutane propanal in 2 ml of toluene is added to 325 mg
(0.96
mmol) of 5-aminoquinoxaline (J. Salon, V. Milata, N. Pronayova, J. Lesko
Monatsh.
Chem. 2000, 131, 293-299) in 3 ml of acetic acid, and it is stirred for 24
hours at room
temperature. The solution is dispersed between toluene and water, the aqueous
phase is
extracted with toluene, the combined organic phases are washed with saturated
NaCI
solution, dried (NaZS04), and the solvent is removed. The crude ~-[(quinoxalin-
5-
ylimino)methyl]-1-(2-chloro-5-fluorophenyl)-0-(trifluoromethyl)cyclobutane
ethanol is
taken up in methanol/acetic acid 1:1 and mixed with 100 mg (2.66 mmol) of
NaBH4.
After 6 hours of stirring at room temperature, the reaction is brought to a
halt by adding
saturated NH4C1 solution, and the mixture is diluted with dichloromethane.
After
extraction with dichloromethane, the combined organic phases are washed
(saturated
NaCI solution), dried (Na2S04), and the solvent is removed. 280 mg of product
is
obtained as a dark red resin, which can be crystallized from hexane/diethyl
ether. MS
(ESI): 454 (M+H).
Example 10
OMe GH H
N ~N
/ FsC ~ i N
F
CA 02531060 2005-12-29
39
4-(5-Fluoro-2-methoxyphenyl~-4-methyl-1-(2-methyl-1 8-naphthyridin-5-ylamino)-
2-
(trifluoromethyl)-pentan-2-of
1-Amino-4-(5 Jluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)propan-2-of
1.0 g (3.4 mmol) of 2-[2-(5-fluoro-2-methoxyphenyl-2-methylpropyl]-2-
(trifluoromethyl)oxirane (WO 00/32584) in 68 ml of THF is refluxed with 1.1 g
of
sodium azide and 180 mg of ammonium chloride in 14 ml of water and 26 ml of
ethanol
for 6 hours. The batch is concentrated by evaporation, diluted with ether,
washed with
water, dried (Na2S04) and concentrated by evaporation. Chromatography on
silica gel
with hexane-ethyl acetate (0-15%) yields 950 mg of 1-azido-4-(5-fluoro-2-
methoxyphenyl~4-methyl-2-(trifluoromethyl)propan-2-ol. The latter is dissolved
in 29
ml of THF and mixed at 0°C in portions with 270 mg of lithium aluminum
hydride.
After 1 hour, the batch is treated with ethyl acetate and water and filtered
on Celite. The
ethyl acetate phase is dried (Na2S04) and concentrated by evaporation in a
vacuum. 920
mg of amine is obtained.
1H-NMR (CDCl3): 8 = 1.4 (s, 3H), 1.5 (s, 3H), 2.15 (d, 1H), 2.45 (d, 1H), 2.55
(d, 1 H), 2.75 (d, 1 H), 2.80 (m), 3.8 (s, 3H), 6.8 (dd, 1 H), 6.9 (td, 1 H),
7.05 (dd, 1 H)
202 mg (1.13 mmol) of 5-chloro-2-methyl-1,8-naphthyridine (E. V. Brown, J.
Org. Chem 1965, 1607-1609) is added to 350 mg (1.13 mmol) of 1-amino-4-(5-
fluoro-2-
methoxyphenyl~4-methyl-2-(trifluoromethyl)-pentan-2-of and 128 mg (1.13 mmol)
of
DABCO. It is heated for 1.5 hours to 150°C. After chromatography of the
cooled melts
on silica gel with dichloromethane/methanol (0-10%), 385 mg of the desired
product is
obtained. 'H-NMR (CDCl3); 8 = 1.46 (s, 3H), 1.58 (s, 3H), 2.45 (d, 1H), 2.68
(s, 3H),
2.72 (d, 1 H), 3.20 (d, 1 H), 3.38 (d, 1 H), 3.83 (s, 3H), 5.86 (d, 1 H), 6.77
(dd, 1 H), 6.92
(ddd, 1 H), 7.08 (dd, 1 H), 7.11 (d, I H), 7.71 (d, 1 H), 8.50 (d, 1 H).
CA 02531060 2005-12-29
Example 11
OH OH
_ N ~ ,N
F Cv ~ , N
3
F
4~5-Fluoro-2-hydroxyphenyl)-4-methyl-1-(2-methyl-1 8-naphthyridin-5-ylamino)-2-
(trifluoromethyl)-pentan-2-of
Analogously to Example 3, mg (0.13 mmol) of 4-(5-fluoro-2-methoxyphenyl~4-
methyl-1-(2-methyl-1,8-naphthyridin-5-ylamino)-2-(trifluoromethyl)-pentan-2-of
in 15 ml of CHZC12 is reacted with ml of 1 M boron tribromide-CHZC12 solution.
After
chromatography on silica gel with hexane-ethyl acetate (0-70%), 102 mg of the
product
is obtained. 'H-NMR (CDCl3); 8 = 1.50 (s, 3H), 1.59 (s, 3H), 2.31 (d, IH),
2.79 (d, IH),
2.80 (s, 3H), 3.27 (m, 2H), 3.40 (dd, I H), 3.54 (dd, 1 H), 6.02 (d, 1 H), 6.
I I (br., 1 H),
6.65 (dd, 1 H), 6.82 (ddd, 1 H), 7.12 (dd, 1 H), 7.18 (t, 1 H), 7. (d, 1 H).
Example 12
\O OH ~ N
~N
vp
F3C
F
1-f Cinnolin-5-ylamino)-4-(5-fluoro-2-hydroxyphenyl~-4-methyl-2-
(trifluoromethyl)-
pentan-2-of
240 mg (0.78 mmol) of 4-(5-fluoro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-
trifluoromethyl-pentanal and 170 mg (1.17 mmol) of 5-aminocinnoline (J. R.
Elkins, E.
V. Brown J. Heterocycl. Chem. 1968. 639-646) are dissolved in 10 ml of
CA 02531060 2005-12-29
41
dichloroethane. 1 ml of acetic acid and 30 mg of powdered molecular sieve (4
A) are
added and refluxed for 6 hours on a molecular sieve (4 A). The reaction
mixture is
dispersed between dichloromethane and water, the phases are separated, the
aqueous
phase is extracted with CHZCIZ, the combined organic phases are washed with
saturated
NaHC03 solution and saturated NaCI solution and dried with Na2S04. It is
concentrated
by evaporation and chromatographed on silica gel with hexane/ethyl acetate (20
to
50%). 70 mg of 1-(cinnolin-5-ylimino)-4-(5-fluoro-2-hydroxyphenyl~4-methyl-2-
(trifluoromethyl)-pentan-2-of is obtained, of which 30 mg is taken up in THF
and mixed
with 10 mg (0.16 mmol) of sodium cyanoborohydride and 100 ~1 of acetic acid.
After 6
hours of stirring at room temperature, it is dispersed between water and
CHZC12, and the
phases are separated. The aqueous phase is extracted with CH2CI2, the combined
organic phases are washed with saturated NaCI solution and dried with NaZS04.
It is
concentrated by evaporation, the residue is taken up again in chloroform, a
spatula tip
full of activated manganese dioxide is added, and it is stirred for 2 hours at
room
temperature. Then, the manganese dioxide is filtered off, and the filtrate is
concentrated
by evaporation. The crude product is chromatographed on silica gel with
hexane/ethyl
acetate (20 to 50%). 3.3 mg of the desired product is obtained as a red film.
MS (ESI):
438 (M+H); 'H-NMR (CDC13): 8 = 1.48 (s, 3H), 1.53 (s, 3H), 2.59 (dd, 2H), 3.13
(s,
1 H), 3.24 (dd, 1 H), 3.37 (dd, 1 H), 3.89 (s, 3H), 4.80-4.84 (m, 1 H), 6.47
(d, 1 H), 6.83
(dd, 1 H), 6.91-6.99 (m, 1 H), 7.05 (dd, 1 H), 7.76-7.87 (m, 2H), 8.11 (d, 1
H), 9.08 (d,
1 H).
CA 02531060 2005-12-29
42
Example 13
N
~O OH
~N
F3C
F
F
4 ~5-Fluoro-2-methoxyphenyl)-4-methyl-1-(8-fluoro-2-methylquinazolin-5-
ylamino)-2-
(trifluoromethyl)-pentan-2-of
5-Amino-8-fluoro-2-methylquinazoline
A solution of 2.4 g (18.6 mmol) of 2,5-difluoroaniline in 11 ml of water and
1.6
ml of concentrated hydrochloric acid (37%) that is 50°C is added to a
solution of 3.35 g
(20.25 mmol) of chloral hydrate and 21.27 g (149.7 mmol) of sodium sulfate in
72 ml of
water, which was already stirred at this temperature for 1 hour. It is stirred
for another
30 minutes at room temperature, and after 4.09 g (58.9 mmol) of hydroxyl
ammonium
chloride in 19 ml of water is added, it is heated over 45 minutes to
125°C and kept at
this temperature for 5 minutes. After cooling and after another hour, the
precipitated
light brown precipitate is filtered off, washed with water and dried. 3.0 g
(15.0 mmol)
of the hydroxylimine is obtained as an intermediate product, which is
dissolved in
portions in 15 ml of concentrated sulfuric acid at 60°C. After the
addition is completed,
it is heated for 2 hours to 80°C and for 4 hours to 90°C. It is
allowed to cool off, and the
solution is poured onto 100 g of ice. It is extracted with ethyl acetate, the
organic phase
is washed with water, dried on sodium sulfate and concentrated by evaporation.
After
chromatography on silica gel with hexane-ethyl acetate (0-45%), 1.2 g (7.1
mmol) of the
4,7-difluoroisatin is obtained. 1.8 ml of a 30% hydrogen peroxide solution is
added in
drops to the isatin in 30 ml of a 1 molar sodium hydroxide solution over 10
minutes.
After 2 hours of stirring at room temperature, it is cooled to 0°C, and
5 ml of a 4 molar
hydrochloric acid is added and diluted with 50 ml of water. It is extracted
with ethyl
CA 02531060 2005-12-29
43
acetate, dried on sodium sulfate, concentrated by evaporation, and 1.27 g of
3,6-
difluoroanthranilic acid, which is reacted without further purification, is
thus obtained
quantitatively. The 3,6-difluoroanthranilic acid is heated in 8 ml of acetic
acid
anhydride for 45 minutes to 100°C. After cooling, the acetic acid and
excess acetic acid
anhydride that are produced are removed azeotropically with toluene in a
vacuum. The
residue is mixed with 40 ml of a 25% ammonia solution while being cooled with
ice and
stirred for 72 hours. It is diluted with water and acidified with acetic acid.
It is
extracted with ethyl acetate, the organic phase is washed with water, dried on
sodium
sulfate and concentrated by evaporation. The thus obtained 1.03 g (5.25 mmol)
of 5,8-
difluoro-2-methyl-3H-quinazolin-4-one and 6 g of phosphorus pentachloride are
heated
in 20 ml of phosphoryl chloride for 12 hours to 125°C. After cooling,
it is poured into
saturated NaHC03 solution and extracted with ethyl acetate. The organic phase
is dried,
and the solvent is removed. 1.7 g of 4-chloro-5,8-difluoro-2-
methylquinazoline, which
is dissolved in 60 ml of ethyl acetate and 5 ml of triethylamine, is obtained
quantitatively. 600 mg of palladium is added to carbon and shaken for 2 hours
(480 ml
of hydrogen absorption) under a hydrogen atmosphere at normal pressure.
Catalyst is
removed from the solution by means of filtration on Celite, whereby it was
rewashed
with 100 ml of ethanol and concentrated by evaporation. After chromatography
on
silica gel with hexane-ethyl acetate-ethanol (0-40%), 550 mg of 5,8-difluoro-2-
methylquinazoline is obtained. 890 mg (13.7 mmol) of sodium azide is added to
240 mg
(1.3 mmol) of 5,8-difluoro-2-methylquinazoline and 300 mg (1.13 mmol) of 18-
crown-6
in 10 ml of DMF, and the mixture is heated for 8 hours to 125°C. The
solvent is
removed in a vacuum, and it is chromatographed on silica gel with ethyl
acetate, and 52
mg of product is obtained. 1H-NMR (CDC13); 8 = 2.92 (s, 3H), 4.31 (br., 2H),
6.67 (dd,
1 H), 7.38 (dd, 1 H), 9.37 (s, I H).
CA 02531060 2005-12-29
44
In dichloroethane, 50 mg of sodium acetate, 0.05 ml of trifluoroacetic acid
and
0.1 ml of acetic acid are added to 200 mg (0.48 mmol) of 4-(5-fluoro-2-
methoxyphenyl~
2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 40 mg (0.23 mmol) of 5-
amino-8-
fluoro-2-methylquinazoline. It is refluxed, and after 4 hours, the solvent is
removed in a
vacuum with the addition of toluene. After chromatography on silica gel with
hexane-
ethyl acetate (0-70%), 58 mg of 4-(5-fluoro-2-methoxyphenyl~4-methyl-1-(8-
fluoro-2-
methylquinazolin-5-ylimino)-2-(trifluoromethyl)-pentan-2-of is obtained. 20 mg
of
palladium on carbon is added to the imine in 10 ml of ethyl acetate and 1 ml
of
triethylamine, and it is shaken for 1 hour under hydrogen atmosphere at normal
pressure.
Catalyst is removed from the solution by means of filtration, and it is
concentrated by
evaporation. It is taken up in 5 ml of chloroform, and 200 mg of activated
manganese
dioxide is added, and it is stirred for 30 minutes. It is filtered on Celite
and concentrated
by evaporation in a vacuum. After chromatography on silica gel with hexane-
ethyl
acetate (0-70%), 12 mg of the product is obtained. 'H-NMR (CDCI;); 8 = 1.46
(s, 3H),
1.55 (s, 3H), 2.37 (d, 1 H), 2.76 (d, 1 H), 2.90 (s, 3H), 3.13 (dd, 1 H), 3.27
(dd, 1 H), 3.85
(s, 3H), 4.50 (br., 1 H), 5.94 (dd, 1 H), 6.77 (dd, 1 H), 6.91 (ddd, 1 H),
7.08 (dd, 1 H), 7.30
(dd, 1 H), 9.16 (s, 1 H).
Example 14
OH OH N
N I N
\ ~I~
F3C
F
F
4-(5-Fluoro-2-hydroxvoxyphenyl~4-methyl-1-~8-fluoro-2-methylquinazolin-5-
ylamino)-2-(trifluoromethyl]~entan-2-of
CA 02531060 2005-12-29
Analogously to Example 3, 20 mg (43 pmol) of 4-(5-fluoro-2-methoxyphenyl~
4-methyl-1-(8-fluoro-2-methylquinazolin-5-ylamino)-2-(trifluoromethyl)-pentan-
2-of
in 4 ml of CHZC12 is reacted with 2 ml of 1 M boron tribromide-CHZCl2
solution. After
chromatography on silica gel with hexane/2-propanol (10%), 17 mg of the
product is
obtained. 'H-NMR (CDC13); 8 = 1.50 (s, 3H), 1.57 (s, 3H), 2.35 (d, 1H), 2.86
(s, 3H),
2.90 (d, 1 H), 3 .21 (dd, 1 H), 3.3 6 (dd, 1 H), 4.72 (br., 1 H), 6.08 (dd, 1
H), 6.54 (dd, 1 H),
6.68 (ddd, 1 H), 7.03 (dd, 1 H), 7.3 3 (dd, 1 H), 9.19 (s, 1 H).
Example 15
N
~O OH
_ N I ~N
3C O
F
~2-Methylguinazolin-5-yl)-4-(5-fluoro-2-methoxyphenyl~2-hydroxy-4-methyl-2-
(trifluoromethyl)pentanoic acid amide
104 mg (0.41 mmol) of 4-(5-fluoro-2-methoxyphenyl~4-methyl-2-oxopentanoic
acid (WO 00/32584) and 100 mg (0.63 mmol) of 5-amino-2-methylquinazoline in 2
ml
of DMF are mixed at room temperature under argon with 102 mg (4.49 mmol) of
dicyclohexylcarbodiimide. It is allowed to stir for 3 hours at room
temperature, the
reaction mixture is poured into water, extracted with ethyl acetate, the
organic phase is
washed with water and dried (Na2S04). After chromatography on silica gel with
hexane-ethyl acetate (0-70%), 64.9 mg of N-(2-methylquinazolin-5-yl)-4-(5-
fluoro-2-
methoxyphenyl~4-methyl-2-oxopentanoic acid amide is obtained, which is
dissolved in
2.2 ml of DMF and cooled to 0°C. The solution is mixed with 0.18 ml of
(trifluoromethyl)trimethylsilane and 243 mg of cesium carbonate and stirred
for 6 hours
at room temperature. Water is added, it is extracted with ethyl acetate. the
organic phase
CA 02531060 2005-12-29
46
is washed with water and dried on sodium sulfate. The intermediate product
that is
concentrated by evaporation is taken up in 2 ml of THF, and 100 pl of a 1 M
solution of
tetrabutylammonium fluoride is added. It is stirred for 30 minutes, water is
added, it is
extracted with ethyl acetate, the organic phase is washed with water and dried
on sodium
sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-65%),
14.7 mg
of product is obtained. 'H-NMR (CDC13); 8 = 1.44 (s, 3H), 1.46 (s, 3H), 2.85
(d, 1 H),
2.91 (s, I H), 3.04 (d, I H), 3.89 (s, 3H), 4.18 (s, 1 H), 6.77 (m, 2H), 6.94
(dd, 1 H), 7.79
(d, I H), 7.86 (t, 1 H), 8.05 (d, 1 H), 9.08 (s, I H), 9. I 2 (s, 1 H).
Example 16
~O OH -N
_ H NH
N
F C~
3
F
4-(5-Fluoro-2-methoxyphenyl~l-(1H indazol-4-ylamino)-4-methyl-2-
(trifluoromethyl)pentan-2-of
154 mg of 4-(5-fluoro-2-methoxyphenyl~2-hydroxy-4-methyl-2-
(trifluoromethyl)pentanal and 80 mg of 1H-indazol-4-ylamine (from Auwers Chem.
Ber., 1920, 53, 1213) are dissolved in 10 mI of toluene and 1.5 ml of acetic
acid and
stirred for 16 hours at room temperature. It is mixed with ethyl acetate and
sodium
bicarbonate solution, the ethyl acetate phase is washed twice with sodium
bicarbonate
solution, dried on sodium sulfate and concentrated by evaporation. After
chromatography on silica gel with hexane/ethyl acetate (1.5+1), 172 mg of4-(5-
fluoro-
2-methoxyphenyl)-I-(1H indazol-4-ylimino)-4-methyl-2-(trifluoromethyl)pentan-2-
of is
obtained. MS(EI+):423/424.
CA 02531060 2005-12-29
47
148 mg of imine is dissolved in 5 ml of methanol and 0.5 ml of acetic acid,
combined with 60 mg of sodium cyanoborohydride, and stirred for 2 hours at
0°C and
for 6 hours at room temperature. It is mixed with ethyl acetate and sodium
bicarbonate
solution, the ethyl acetate phase is washed twice with sodium bicarbonate
solution, dried
and concentrated by evaporation. After chromatography on silica gel with
hexane/ethyl
acetate (1.5+I), 130 mg of 4-(S-fluoro-2-methoxyphenyl~l-(1H-indazol-4-
ylamino)- 4-
methyl-2-(trifluoromethyl)pentan-2-of is obtained. MS(EI+): 425/426; 'H-NMR
{CDC13); 8 = 1.45 (s, 3H), 1.58 (s, 3H), 2.27 (d, 1H), 2.78 (d, IH), 3.18 (d,
1H), 3.35 (d,
1 H), ), 3.85 (s, 3 H), 5.67 (d, 1 I-I), 6.83 (dd, 1 H), 6.85 (d, I H), 6.95
(ddd, 1 H), 7.12 (dd,
1 H), 7.15 (dd, 1 H), 7.86 (br, 1 H).
Example 17
OH OH -N
NH
N
vp
/ F3C
F
4-(5-Fluoro-2-hydrox~rphenyl~-1 ~ 1 H indazol-4-ylamino)-4-methyl-2-
(trifluoromethyl)pentan-2-of
Analogously to Example 3, 127 mg of4-(5-fluoro-2-methoxyphenyl~l-(1H
indazol-4-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-of is reacted with 10
ml of
1 M boron tribromide-CHZCIz solution. After chromatography on silica gel with
hexane/ethyl acetate (40%), 60 mg of 4-(5-fluoro-2-hydroxyphenyl~l-(1H indazol-
4-
ylamino)- 4-methyl-2-(trifluoromethyl)pentan-2-of is obtained. Flash point:
164-165°C.
MS(EI+): 411/412 'H-NMR (D6-DMSO); 8 = 1.37 (s, 3H), 1.55 (s, 3H), 1.92 (d,
1H),
2.92 (dd, 1 H), 3 .03-3 .18 (2H), 5 .16 (t(br), 1 H). 5.5 8 (d, 1 H), 5.82 (s,
1 H), 6.65 (d, 1 H),
CA 02531060 2005-12-29
48
6.81 (dd, 1 H), 6.85 (ddd, 1 H), 6.95 (dd, 1 H), 7.00 (dd, 1 H), 7.97 (s, 1
H), 9.75 (s, 1 H),
12.7 (s, 1 H)
Example 18
~O OH -N
_ H
N
w
FC
F
4-(5-Fluoro-2-methoxyphenyl~-4-methyl-1-(1-methyl-1H indazol-4-ylamino)-2-
~rifluoromethvl)pentan-2-of
154 mg of 4-(5-fluoro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-
(trifluoromethyl)pentanal and 91 mg of 1-methyl-1H-indazol-4-ylamine (Sureau
Chimia,
1961, I5, 195) are reacted, as described in Example 15, to form 4-(5-fluoro-2-
methoxyphenyl~4-methyl-1-(1-methyl-1H indazol-4-ylimino)-2-
(trifluoromethyl)pentan-2-of MS(EI+): 437/438 and further reduced with sodium
cyanoborohydride to 4-(5-fluoro-2-methoxyphenyl~ 4-methyl-1-(1-methyl-1H
indazol-
4-ylamino)-2-(trifluoromethyl)pentan-2-ol. MS(EI+): 439/440, 'H-NMR (CDCl3); 8
=
1.46 (s, 3H), 1.59 (s, 3H), 2.27 (d, 1H), 2.77 (d, IH), 3.05-3.20 (3H), 3.38
(d, 1H), 3.82
(s, 3 H), 4.00 (s, 3 H), 5.60 (d, 1 H), 6.75 (d, 1 H), 6.84 (dd, 1 H), 6.95
(ddd, 1 H), 7.12 (dd,
1 H), 7.16 (dd, 1 H), 7.75 (s, 1 H).
Example 19
OH OH -N
H N_
N
up w
FsC
F
CA 02531060 2005-12-29
49
4-(5-Fluoro-2-h~~henyl~4-methyl-1-(1-methyl-1H indazol-4-ylamino)-2-
(trifluoromethyl)pentan-2-of
Analogously to Example 3, 22 mg of 4-(5-fluoro-2-hydroxyphenyl}-4-methyl-1-
(1-methyl-IH indazol-4-ylamino)-2-(trifluoromethyl)pentan-2-of is obtained
from 84
mg of 4-(5-fluoro-2-methoxyphenyl~4-methyl-1-( 1-methyl-I H-indazol-4-ylamino)-
2-
(trifluoromethyl)pentan-2-ol. Flash point: 193-194°C, MS(EI+): 425/426,
'H-NMR (D6-
DMSO); 8 = 1.40 (s, 3H), 1.53 (s, 3H), 1.91 (d, IH), 2.95 (dd, IH), 3.09-3.20
(2H), 3.90
(s, 3H), 5.26 (t(br), 1 H),), 5.62 (d, 1 H), 5.83 (s, I H), 6.73 (d, 1 H),
6.80 (dd, 1 H), 6.85
(ddd, 1 H), 6.99-7.05 (2H), 7.93 (s, I H), 9.75 (s, 1 H)
Example 20
O~ OH
iN
\ ~I~
FsC
F
4-(5-Fluoro-2-methoxyphen~~4-methyl-1-(2-methyl-2H indazol-4-ylamino)-2-
(trifluoromethyl)pentan-2-of
154 mg of 4-(5-fluoro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-
(trifluoromethyl)pentanal and 91 mg of 2-methyl-2H-indazol-4-ylamine (Sureau
Chimia, 1961, 15, 195) are reacted, as described in Example 15, to form 4-(5-
fluoro-2-
methoxyphenyl~4-methyl-I-(2-methyl-2H indazol-4-ylimino)-4-methyl-2-
(trifluoromethyl)pentan-2-of [flash point: 92-94°C, MS(EI+): 437/438]
and further
reduced with sodium cyanoborohydride to 4-(5-fluoro-2-methoxyphenyl)-4-methyl-
I-(2-
methyl-2H-indazol-4-ylamino)-2-(trifluoromethyl)pentan-2-ol. MS(EI+): 439/440,
'H-
NMR (CDC13); ~ = 1.47 (s, 3H), 1.56 (s, 3H), 2.30 (d, 1H), 2.75 (d, 1H), 3.14
(d, IH),
, CA 02531060 2005-12-29
3.29 (d(br), 1H), 3.33 (s(br), 1H), 3.75 (s(br), 1H), 3.85 (s, 3H), 4.15 (s,
3H), 5.55 (d,
1 H), 6.86 (d, 1 H), 6.95-7.07 (2H), 7.10 (dd, 1 H), 7.15 (dd, 1 H), 7.66 (s,
1 H)
Example 21
OH OH N
H '
N ~ ,N
F3C
F
4-(5-Fluoro-2-hydroxyphenyl)-4-methyl-1-(2-methyl-2H indazol-4-ylarnino)-2-
(trifluoromethyl)pentan-2-of
Analogously to Example 3, 100 mg of 4-(5-fluoro-2-hydroxyphenyl~4-methyl-1-
(2-methyl-2H indazol-4-ylamino)-2-(trifluoromethyl)pentan-2-of is obtained
from 132
mg of 4-(5-fluoro-2-methoxyphenyl~4-methyl-1-(2-methyl-2H indazol-4-ylamino)-2-
(trifluoromethyl)pentan-2-ol. Flash point: 182°C, MS(EI+): 425/426, 'H-
NMR (D6-
DMSO); 8 = 1.40 (s, 3H), 1.55 (s, 3H), 1.93 (d, 1H), 2.89 (dd, 1H), 3.05-3.17
(2H), 4.07
(s, 3H), 5.00 (t(br), 1 H), 5.38 (d, 1 H), 5.85 (s, 1 H), 6.72-6.90 (4H), 6.99
(dd, 1 H), 8.16
(s, 1 H), 9.73 (s, 1 H)
Example 22
F OH -N
_ H NH
N
W
FC
F
4-(2.5-Difluorophenyl)-1-(1H indazol-4-vlamino)-4-methyl-2-
(trifluoromethvl)pentan-
2-0l
CA 02531060 2005-12-29
51
Analogously to Example 3, 207 mg (0.73 mmol) of 4-(2,5-difluorophenyl)-2-
hydroxy-4-methyl-2-trifluoromethyl-pentanal is reacted with 150 mg (1.10 mmol)
of
1 H-indazol-4-ylamine (from Auwers Chem. Ber., 1920, 53, 1213). 110 mg of 4-
(2,5-
difluorophenyl)-1-(1H indazol-4-ylimino)-4-methyl-2-(trifluoromethyl)pentan-2-
of is
obtained. 50 mg (0.12 mmol) thereof is reduced analogously to Example 7 with
27 mg
(0.72 mmol) of NaBH4. After chromatography on silica gel with hexane/ethyl
acetate
(20-30%), 18 mg of the desired product is obtained.
'H-NMR (300 MHz, CDC13): D = 1.48 (s, 3H), 1.62 (s, 3H), 2.27 (d, 1H), 2.52
(d, 1H), 3.23-3.38 (m, 2H), 5.67 (d, 1H), 6.83-7.01 (m, 3H), 7.08-7.18 (m,
2H), 7.89 (s,
1 H)
Example 23
O~ OH -N
_ H NH
N
FC ~
3
Bf
4-(4-Bromo-2-methoxyphenyl~2-hydroxy- N-(1 H indazol-4-yl)-4-methyl-2-
(trifluoromethyl)pentanoic acid amide
122 mg of 4-dimethylaminopyridine is dissolved in the heat in 3 ml of
Sulfolan~,
cooled to room temperature and combined with 0.0525 ml of thionyl chloride.
After 45
minutes at room temperature, it is mixed with 192 mg of 4-(4-bromo-2-
methoxyphenyl}-
2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid (WO 98/54159) and stirred
again
for 45 minutes at room temperature. It is mixed with 90 mg of I H indazol-4-
ylamine
(from Auwers Chem. Ber., 1920, 53, 1213), heated for 1 hour to 80°C and
combined
with sodium bicarbonate solution and ethyl acetate. The ethyl acetate phase is
washed
four times with water, dried and concentrated by evaporation. After
chromatography on
CA 02531060 2005-12-29
52
silica gel with hexane/ethyl acetate (50%), 150 mg of 4-(4-bromo-2-
methoxyphenyl~2-
hydroxy-N-(IH indazol-4-yl)- 4-methyl -2-(trifluoromethyl)pentanoic acid amide
is
obtained. MS(EI+): 499/501 'H-NMR (D6-DMSO); 8 = 1.38 (s, 3H), 1.50 (s, 3H),
2.17
(d, I H), 3.10 (d, 1 H), 3.83 (s, 3H), 6.65 (dd, 1 H), 6.97 (d, 1 H), 7.03 (d,
1 H), 7.08 (s,
1 H), 7.10 (d, 1 H), 7.27 (dd, 1 H), 7.31 (d, 1 H), 7.92 (s, 1 H), 9.45 (s, 1
H), 13 .1 (s, 1 H)
Example 24
OH OH -N
H NH
N
F3C O
Br
4-(4-Bromo-2-hydroxyphenyl)-2-hydroxy-N~IH indazol-4-yl)-4-methyl-2-
(trifluoromethyl)Qentanoic acid amide
Analogously to Example 3, 55 mg of 4-(4-bromo-2-hydroxyphenyl~2-hydroxy-
N-(1 H indazol-4-yl)- 4-methyl -2-(trifluoromethyl)pentanoic acid amide is
obtained
from 100 mg of 4-(4-bromo-2-methoxyphenyl}-2-hydroxy-N-(IH indazol-4-yl)- 4-
methyl-2-(trifluoromethyl)pentanoic acid amide. MS(ET'): 485/487, 'H-NMR (D6-
DMSO); 8 = 1.42 (s, 3H), 1.48 (s, 3H), 2.23 (d, 1 H), 3.15 (d, 1 H), 6.54 (dd,
1 H), 6.83 (d,
1 H), 6.95 (d, 1 H), 7.00 (s, 1 H), 7.10 (d, 1 H), 7.25 (dd, 1 H), 7.30 (d, 1
H), 7.95 (s, 1 H),
9.61 (s, 1 H), 9.95 (s, 1 H), 13.12 (s, 1 H)
Example 25
~O OH N
_ N ~ ~N
\ FC
3 /
F F
CA 02531060 2005-12-29
.~
53
4~5-Fluoro-2-methox~oxyphenyl~4-methy~7-fluoro-2-methylquinazolin-5-
ylamino)-2-~rifluoromethyl)-pentan-2-of
5-Amino-7 fluoro-2-methylquinazoline
17 g (70.5 mmol) of 3,6-difluoro-2-N-pivaloylaminobenzaldehyde (L. Florvall,
I.
Fagervall, L.-G- Larsson, S. B. Ross, Eur. J. Med. Chem. 3~1 (1999) 137-151 ),
9.2 g of
acetamidine hydrochloride, 13.4 g of potassium carbonate and 10.4 g of
molecular sieve
(4A) are added together in 70 ml of butyronitrile. It is heated for 17 hours
to 145°C
while being stirred vigorously, and the solvent is removed in a vacuum. After
chromatography of the residue on silica gel with hexane/ethyl acetate (0-70%),
4.5 g of
7-fluoro-5-N-pivaloylamino-2-methylquinazoline is obtained.
1 g (3.82 mmol) of 7-fluoro-5-N-pivaloylamino-2-methylquinazoline is dissolved
in 74 ml of toluene and cooled to -70°C. Over 30 minutes, 9.5 ml (11.4
mmol) of a 1.2
M diisobutyl aluminum hydride solution in toluene is added in drops. The
reaction
mixture is allowed to heat to -40°C and stirred for 4 hours at
~0°C. Water is slowly
added, and it is stirred for 30 minutes at room temperature until a
precipitate forms,
which is removed by means of filtration through Celite. The phases are
separated,
washed with saturated sodium chloride solution and dried on sodium sulfate.
After
chromatography on silica gel with hexane-ethyl acetate (0-100%), 64 mg of the
product
is obtained. 1H-NMR (CDCl3); b = 2.83 (s, 3H), 4.67 (br., 2H), 6.50 (dd, 1 H),
6.93 (dd,
1 H), 9.23 (s, 1 H).
0.1 ml of titanium tetraethylate is added to 22 mg (0.07 mmol) of 4-(5-fluoro-
2-
methoxyphenyl~2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 11 mg (0.06
mmol) of 5-amino-7-fluoro-2-methylquinazoline in 4 ml of toluene, and the
mixture is
heated over 2.5 hours to 100°C. After cooling, it is poured into water.
and vigorous
stirring is continued. The suspension is filtered through Celite, and rewashed
thoroughly
CA 02531060 2005-12-29
54
with ethyl acetate. The phases of the filtrate are separated, and it is
extracted again with
ethyl acetate. It is dried on sodium sulfate, and the solvent is removed in a
vacuum. The
4-(5-fluoro-2-methoxyphenyl)-1-(7-fluoro-2-methylquinazolin-5-y limino)-4-
methyl-2-
(trifluoromethyl)-pentan-2-of that is thus obtained in crude form is in 8 ml
of ethyl
acetate, in 5 ml of ethyl acetate and 0.5 ml of triethylamine, 20 mg of
palladium on
carbon is added, and it is shaken for 1 hour under a hydrogen atmosphere at
normal
pressure. Catalyst is removed from the solution by means of filtration, and it
is
concentrated by evaporation. It is taken up in 5 ml of chloroform, 50 mg of
activated
manganese dioxide is added, and it is stirred for 20 minutes. It is filtered
on Celite and
concentrated by evaporation in a vacuum. After chromatography on silica gel
with
hexane-ethyl acetate (0-70%), 18 mg of the product is obtained. 'H-NMR
(CDCl3); b =
1.47 (s, 3H), 1.54 (s, 3H), 2.44 (d, 1H), 2.70 (d, 1H), 2.81 (s, 3H), 3.15
(dd, 1H), 3.30
(dd, 1 H), 3.86 (s, 3H), 4.97 (br., 1 H), 5.83 (dd, 1 H), 6.79 (dd, 1 H), 6.85
(dd, 1 H), 6.92
(ddd, 1 H), 7.06 (dd, 1 H), 8.98 (s, 1 H).
Example 26
~O OH -N
NH
N
/ F3C
F
4-(5-Fluoro-2-methoxyphenyl~l-(6-methoxyl-1H indazol-4-ylamino)-4-methyl-2-
(trifluoromethyl)pentan-2-of
Analogously to Example 16, the desired product is obtained from 4-(5-fluoro-2-
methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 6-methyl-1H-
indazol-4-ylamine (from Auwers Chem. Ber., 1920, 53, 1213). iH-NMR (CD;OD); 8
=
CA 02531060 2005-12-29
SS
1.45 (s, 3H), 1.64 (s, 3H), 2.01 (d, 1H), 2.23 (s, 3H), 2.78 (d, IH), 3.01 (d,
1H), 3.21 (d,
1 H), 3.86 (s, 3H), 5.96 (s, I H), 6.93 (m, 2H), 7. I 4 (dd, 1 H), 7.21 (s, I
H), 7.73 (s, 1 H).
Example 27
~O OH N
F ~ N I ~N
F3C I /
4-~3-Fluoro-2-methoxyphenyl~ 1-(2-meth~rlguinazolin-5-ylamino~4-methyl-2-
Lrifluoromethyl)pentan-2-of
2, 6-Difluoroanisole
20 g (153.74 mmol) of 2,6-difluorophenol is dissolved in 200 ml of acetone and
mixed under nitrogen with 42.5 g (307.48 mmol) of potassium carbonate. After I
9.1 ml
of methyl iodide (2 equivalents) is added, it is refluxed for three and one-
half hours.
After cooling, the reaction mixture is filtered, the filter residue is washed
with acetone,
and the filtrate is spun in until a dry state is reached. The residue is
chromatographed on
silica gel (mobile solvent ethyl acetatelhexane). 17.27 g (77.9%) of the
desired product
is obtained. It should be noted that the product is slightly volatile. The
bath temperature
should not exceed 30°C and is to be adapted to the vacuum of the rotary
evaporator.
2-(3-Fluoro-2-methoxyphenyl)-2-methylpropanenitrile
10 g (69.39 mol) of 2,6-difluoroanisole is dissolved in 200 ml of toluene and
mixed at room temperature with 5.75 g (83.27 mmol) of isobutyric acid nitrite.
Within
35 minutes, 166.5 ml of a 0.5 molar solution of potassium hexamethyl
disilazide in
toluene is added in drops. In this case, a slight temperature rise to
27.5°C takes place.
After 16 hours of stirring at room temperature, the reaction mixture is mixed
with 200
CA 02531060 2005-12-29
56
ml of water and 400 ml of ethyl acetate and acidified with 10% sulfuric acid
to a pH of
4. The organic phase is separated, and the aqueous phase is shaken once with
ethyl
acetate (200 ml). The combined organic extracts are shaken with water and
brine. After
the solvent is dried, filtered, and spun off, the residue is chromatographed
on silica gel
(mobile solvent ethyl acetate/hexane). 7.66 g (57.1%) of the desired compound
is
isolated.
2-(3-Fluoro-2-methoxyphenyl)-2-methylpropanal
7.66 g (39.64 mmol) of the above-described nitrite is dissolved in 158 ml of
toluene. At -65 to -60°C and within 40 minutes, 49.5 ml of a I .2 molar
solution of
DIBAH in toluene is added in drops. After one hour of stirnng at this
temperature is
begun, 493 ml of a I 0% L-(+)-tartaric acid solution is to be added in drops.
After 100
milliliters, the temperature is increased to -10°C. The remainder of
the tartaric acid
solution is quickly added, and the batch is stirred vigorously for two hours
at room
temperature. The reaction mixture is shaken twice with 400 ml of diethyl ether
each.
The combined organic extracts are shaken with water and brine, dried, and the
solvent is
spun off. The residue that is obtained (7.8 g = 102%) is incorporated in crude
form into
the next stage.
(ElZ)-4-(3-Fluoro-2-methoxyphenyl)-4-methylpent-2-enoic acid ethyl ester
21.3 ml of a 2 molar LDA solution in THF is added in drops to a solution of
9.87
g (39.75 mmol) of 2-ethoxy-phosphonoacetic acid triethyl ester in 40 ml of
absolute
THF at 0°C. After 30 minutes of stirnng at 0°C, 7.8 g (39.75
mmol) of 2-(3-fluoro-2-
methoxyphenyl~2-methylpropanal, dissolved in 26 ml of THF, is quickly added in
drops at 0°C. The cold bath is removed, and the batch is stirred for 16
hours at room
CA 02531060 2005-12-29
57
temperature. The reaction mixture is poured into water and extracted twice
with ethyl
acetate. The combined organic extracts are washed with water and brine, dried,
and
after the desiccant is filtered off, the solvent is spun off. The residue is
chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 8.39 g
(68.2%) of
the desired compound is isolated.
(ElZ)-4-(3-Fluoro-2-methoxyphenyl)-4-methylpent-2-enoic acid
8.39 g (27.03 mmol) of (E/Z)-4-(3-fluoro-2-methoxyphenyl}-4-methylpent-2-
enoic acid ethyl ester is mixed with 270 ml of 1 N NaOH in ethanol/water (2:1
) and
stirred for two days at room temperature. The ethanol is drawn off in a rotary
evaporator, and the residue is extracted twice with 150 ml of diethyl ether
each. The
combined organic extracts are washed with water and discarded after monitoring
by
TLC. The aqueous phases are acidified with concentrated hydrochloric acid to
pH 3 and
extracted twice with 300 ml each of diethyl ether. The ether extracts are
washed with
water and brine, dried, the solvent is spun off, and the residue (5.89 g =
77.2%) is
incorporated in crude form into the next stage.
4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-oxo pentanoic acid
5.89 g (20.86 mmol) of (E/Z)-4-(3-fluoro-2-methoxyphenyl}-4-methylpent-2-
enoic acid is mixed at room temperature with 126 ml of a 1 molar sulfuric
acid, and after
21 ml of glacial acetic acid is added, it is stirred for 15 hours at a bath
temperature of
90°C. The reaction mixture is mixed with solid potassium carbonate to a
pH of 9 while
being cooled carefully in an ice bath (heavily foaming). It is extracted twice
with
diethyl ether. The combined organic extracts are washed with water and
discarded after
TLC. The combined aqueous phases are acidified with concentrated hydrochloric
acid
CA 02531060 2005-12-29
58
to a pH of 4 and extracted twice with 300 ml each of diethyl ether. The ether
extracts
are washed with water and brine, dried, and the solvent is spun off. Since the
residue
still contains acetic acid, it is spun off twice with 100 ml each of toluene.
The remaining
residue (4.14 g = 78.1 %) is incorporated in crude form into the next stage.
4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-oxo pentanoic acid ethyl ester
4:14 g (16.28 mmol) of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic
acid is dissolved in 97 ml of ethanol, mixed with 1.79 ml of sulfuric acid,
and refluxed
for four hours. The ethanol is drawn off in a rotary evaporator, and the
residue is
carefully mixed with co-saturated sodium bicarbonate solution until a pH of 9
is
reached. It is extracted twice with 100 ml each of ethyl acetate, and the
combined
organic extracts are washed with water and then with brine. After the
desiccant is dried
and filtered off, and after the solvent is spun in, the residue is
chromatographed on silica
gel (mobile solvent ethyl acetate/hexane). 4.16 g (90.6%) of the desired
compound is
isolated.
4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-2-trimethylsilyloxy
pentanoic
acid ethyl ester
4.16 g ( 14.74 mmol) of 4-(3-fluoro-2-methoxyphenyl}-4-methyl-2-oxo-pentanoic
acid ethyl ester is dissolved in 24 ml of THF and mixed at 0°C with
2.51 g ( 17.68 mmol)
of (trifluoromethyl)-trimethylsilane and 36.1 mg of tetrabutylammonium
fluoride. After
two and one-half hours of stirring between 0 and 5°C, the batch is
poured into 50 ml of
ice water. It is extracted twice with 150 ml each of diethyl ether, and the
combined
organic extracts are worked up as usual. After chromatography on silica gel
(mobile
solvent ethyl acetate/hexane), 5.24 g (83.8%) of the desired compound is
obtained.
CA 02531060 2005-12-29
59
4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-tr~uoromethyl-2-trimethylsilyloxy
pentan-1-
of
5.24 g (12.34 mmol) of 4-(3-fluoro-2-methoxyphenyl~4-methyl-2-
trifluoromethyl-2-trimethylsilyloxy-pentanoic acid ethyl ester is dissolved in
45 ml of
diethyl ether and mixed at 0 to 5°C in portions with 936.9 mg (24.69
mmol) of LiAlH4.
After four and one-half hours of stirnng at room temperature, the reaction
mixture is
carefully mixed with saturated NaHCO3 while being cooled in an ice bath, and
it is
stirred for one hour under cold conditions and overnight at room temperature.
After the
usual working-up, 4.11 g (87.1 %) of a mixture that consists of the desired
compound
and the compound are obtained, in which the silyl ether has migrated. The
mixture is
incorporated in crude form into the next stage.
4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-triJluoromethyl pentane-1,2-diol
4.11 g (10.75 mmol) of 4-(3-fluoro-2-methoxyphenyl}-4-methyl-2-
trifluoromethyl-2-trimethylsilyloxy-pentan-I-of is dissolved in 61 ml of THF,
mixed
with 3.39 g (10.746 mmol) of Bu4NF trihydrate, and stirred for one hour at
room
temperature. The reaction mixture is poured into water and extracted twice
with diethyl
ether. The organic phases are washed as usual with water and brine. After the
desiccant
is dried and filtered off, and after the solvent is spun in, the remaining
residue is
chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 2.71 g
(81.4%) of
the desired compound is isolated.
4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl pentanal
765 mg (6.03 mmol) of oxalyl chloride in 13 ml of dichloromethane is
introduced into a heated flask. At -78°C, 0.855 ml of DMSO, dissolved
in 2.5 ml of
CA 02531060 2005-12-29
60
dichloromethane, is added in drops, and the batch is stirred for five more
minutes. Then,
1.7 g (5.48 mmol) of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-
pentane-1,2-diol, dissolved in 5 ml of dichloromethane, is added in drops.
After 15
minutes of stirring, the batch is carefully mixed with 3.79 ml (27.40 mmol) of
triethylamine, stirred for five minutes at -78°C and slowly allowed to
come to room
temperature. 20 ml of water is added, and the batch is stirred for another
hour at room
temperature. After phase separation, the aqueous phase is shaken once with 100
ml of
dichloromethane. The combined organic extracts are washed with 1% sulfuric
acid, 5%
sodium bicarbonate solution and brine. According to the usual procedure, 1.617
g
(96.2%) of the aldehyde is obtained, which is incorporated in crude form into
the next
stage.
Analogously to Example 25, the desired product is obtained from 4-(3-fluoro-2-
methoxyphenyl~2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 5-amino-2-
methylquinazoline. 1H-NMR (300 MHz, CDC13): 0 = 1.45 (3H), 1.57 (3H), 2.35
(IH),
2.75 (IH), 2.82 ( 3H), 3.00-3.40 (3H), 4.00 (3H), 4.75 (1H), 6.10 (1H), 6.90-
7.02 (2H),
7.05-7.18 (1H), 7.25 (1H), 7.55 (1H), 9.10 (IH).
Example 28
~O OH -N
F ~ N ~ NH
/ F3C I /
4-(3-Fluoro-2-methoxyphenyl~l-(1H indazol-4- lamino)-4-methyl-2-
(trifluoromethyl)pentan-2-of
Analogously to Example 16, the desired product is obtained from 4-(3-fluoro-2-
methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 1H-indazol-4-
CA 02531060 2005-12-29
61
ylamine. 'H-NMR (300 MHz, CDC13): 0 = 1.49 (3H), 1.60 (3H), 2.30 (1H), 2.71
(1H),
3.18 (1H), 3.30 (1H), 4.05 (3H), 5,75 (1H), 6.85 (1H), 6.90-7.20 (4H), 7.80
(1H).
Example 29
OH OH -N
H NH
F ~ W FsC N ~ /
4-(3-Fluoro-2-hydroxyphenyl~-I-(1H indazol-4-amino)-4-methyl-2-
~rifluorometh,_yl)pentan-2-of
Analogously to Example 3, the desired product is obtained from 4-(3-fluoro-2-
methoxyphenyl~l-(1H indazol-4-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-
ol.
1H-NMR (300 MHz, DMSO-d6): 0 = 1.42 (3H), 1.59 (3H), I.95 (1H), 2.85-2.95
(1H), 3.03-3.18 (2H), 5.15 (IH), 5.55 (1H), 5.80 (1H), 6.65 (1H), 6.70-6.80
(1H), 6.90
( 1 H), 6.90-7.13 (2H), 7.95 ( 1 H), 9. 80 ( 1 H), 12.70 ( 1 H).
Example 30
~O OH -N
H NH
F ~ / FsC N
C~
2-[(5-Chloro-1H indazol-4-ylamino)-methyl]-1,1,1-trifluoro-4-(3-fluoro-2-
methoxyphen~l-4-methylpentan-2-of
5-Chloro-4-vitro-IH indazole
2.24 g (12 mmol) of 4-chloro-2-methyl-3-nitrophenylamine, produced according
to literature (Mori et al., Chem. Pharm. Bull. 1986, 34, 4859 ff. as well as
Brand and
Zoller, Chem. Ber. 1907, 3324 ff.) is dissolved in 100 ml of acetic acid. At
10°C, 6.0 ml
of a 2 molar aqueous sodium nitrite solution is added in drops. Then, the
suspension is
CA 02531060 2005-12-29
62
added within 15 minutes to boiling acetic acid (150 ml), and the reaction
mixture is
allowed to reflux for 4 hours. After the acetic acid is removed in a vacuum,
the residue
is taken up in ethyl acetate and saturated sodium bicarbonate solution. The
organic
phase is washed with saturated sodium chloride solution and dried on sodium
sulfate.
After the solvent is removed in a vacuum, the crude product (1.81 g, 76%) is
further
reacted.
1H-NMR (300 MHz, DMSO-d6): 8 = 7.65 (d, 1 H), 7.97 (d, 1 H), 8.32 (s, 1 H),
13.97 (s, 1 H).
5-Chloro-I H indazol-4 ylamine
A solution that consists of 5-chloro-4-nitro-IH indazole (872 mg, 4.41 mmol)
is
mixed with 150 mg of palladium on carbon (10%) and stirred under hydrogen
atmosphere at room temperature. After 45 minutes, the catalyst is suctioned
off on one
frit and washed with methanol. The filtrate is concentrated by evaporation,
and the
residue is taken up in 200 ml of ethyl acetate and heated. After renewed
suctioning and
concentration by evaporation of the filtrate, the purification is carried out
on silica gel
with hexane/ethyl acetate (100-33% hexane). 296 mg (40% of theory) of the
product is
obtained.
1H-NMR (300 MHz, DMSO-d6): b = 5.97 (s, 2H), 6.66 (d, 1H), 7.05 (d, 1H),
8.19 (s, I H), 12.83 (s, 1 H).
2-((5-Chloro-IH indazol-4 ylimino)-methylJ-l,l,l-trifluoro-4-(3 fluoro-2-
methoxyphenyl)-4-methyl pentan-2-of
A solution that consists of 4-(3-fluoro-2-methoxvphenyl)-2-hydroxy-4-methyl-2-
trifluoro-methylpentanal (278 mg, 0.9 mmol) and ~-chloro-1H-indazol-4-ylamine
(121
~' CA 02531060 2005-12-29
63
mg, 0.72 mmol) in 20 ml of xylene is mixed with titanium(IV)ethylate (0.42 ml,
2.0
mmol) and refluxed for 10 hours. After cooling to room temperature, xylene is
distilled
off, and the residue is purified on silica gel with hexane/ethyl acetate (30-
100% ethyl
acetate). 123 mg (37% of theory) of the product is obtained.
'H-NMR (400 MHz, CDC13): b = 1.43 (s, 3H), 1.57 (s, 3H), 2.38 (d, 1H), 3.22
(d,
IH), 3.94 (d, 3H), 4.91 (s, 1H), 6.41-6.52 (m, 2H), 6.90 (d, 1H), 7.28 (d,
1H), 7.38 (d,
I H), 7.56 (s, 1 H), 7.72 (s, I H), I 0.26 (br, 1 H).
2-~(5-Chloro-I H indazol-4 ylamino)-methylJ-1,1,1-trifluoro-4-(3 fluoro-2-
methoxyphenyl)-4-methylpentan-2-of
A solution that consists of 2-[(5-chloro-1H-indazol-4-ylimino)-methyl]-I,I,I-
trifluoro-4-(3-fluoro-2-methoxyphenyl~4-methylpentan-2-of (49 mg, 0.1 I mmol)
in 5.0
ml of methanol is mixed with I S mg of sodium borohydride and stirred at room
temperature. Then, a total of 300 mg of sodium borohydride was added in
portions
within 4 days. The reaction mixture is neutralized with 10% acetic acid. After
the
solvent is removed, the residue is taken up in saturated sodium bicarbonate
solution and
ethyl acetate. It is extracted with ethyl acetate, the combined organic phases
are washed
with saturated sodium chloride solution and dried on sodium sulfate. After the
solvent is
removed in a vacuum and after the residue is purified by means of preparative
thin-layer
chromatography on silica gel with hexane/ethyl acetate (50% ethyl acetate), 24
mg
(47%) of the product is obtained.
'H-NMR (300 MHz, CDC13): 8 = 1.48 (s, 3H), 1.59 (s, 3H), 2.39 (d, IH), 2.72
(d,
1 H), 3.55-3.59 (m, 2H), 4.01 (d, 3H), 4.80-4.84 (m, 1 H), 6.80 (d, 1 H), 6.86-
6.98 (m,
2H), 7. I I (d, I H), 7.22 (d, 1 H), 7.70 (s, 1 H).
CA 02531060 2005-12-29
64
Example 31
~O OH -N
H NH
/ F3C N
1,1, I -Trifluoro-4-(3-fluoro-2-methoxyphenyl~-4-meth~[(5-methyl-1 H indazol-4-
ylamino)-methyl]-pentan-2-of
5-Methyl-1 H-indazol-4 ylamine
It is mixed with 5.0 ml of fuming nitric acid at 0°C into a solution
that consists of
2,4-dimethylaniline (12.4 ml, 100 mmol) in 80 ml of concentrated sulfuric
acid, and it is
stirred for 20 minutes at 4°C, and then for 30 minutes at room
temperature. The reaction
mixture is poured into 600 ml of ice water, and set at pH 10 with 5N sodium
hydroxide
solution. The precipitate is suctioned off, washed with water and dried. 15.72
g (95%
of theory) of 2,4-dimethylnitrophenylamine is obtained as a mixture of
regioisomers.
Analogously to the production of 5-chloro-4-nitro-1H indazole, 1.14 g (57% of
theory) of the product was obtained as a mixture of the two regioisomers in
the reaction
of 2,4-dimethylnitrophenylamine (2.0 g, 12 mmol) with 6.0 ml of a 2 molar
aqueous
sodium nitrite solution in acetic acid (250 ml).
MS (ES+, acetonitrile/water 1:1 + 0.01% formic acid): m/z(%) 178 (M+1, 100).
Analogously to the production of 5-chloro-1H indazol-4-ylamine, the
regioisomeric mixture of the previous reaction ( 1.0 g, 5.64 mmol) is reacted
with 100
mg of palladium on carbon in methanol under hydrogen atmosphere for 16 hours
at
room temperature. After purification on silica gel with hexane/ethyl acetate
(33%
hexane, then 100% ethyl acetate), 53 mg (6% of theory) of 5-methyl-1H indazol-
4-
ylamine is obtained.
~
CA 02531060 2005-12-29
65
'H-NMR (300 MHz, DMSO-d6): ~ = 2.12 (s, 3H), 5.41 (s, 2H), 6.57 (d, 1H),
6.90 (d, 1 H), 8.10 (s, 1 H), 12.5 (s, 1 H).
4-(3-Fluoro-2-methoxyphenyl~2-hydroxy-4-methyl-2-trifluoro-methylpentanal
(308 mg, 1.0 mmol) and 5-methyl-1H indazol-4-ylamine (148 mg, 1.0 mmol) are
introduced into 15.0 ml of xylene and mixed with titanium(IV) ethylate (0.42
ml, 2.0
mmol). After 3 hours under reflux, the reaction mixture is allowed to cool to
room
temperature. After ethyl acetate and saturated sodium chloride solution are
added, it is
vigorously stirred for 30 minutes at room temperature. The deposited
precipitate is
suctioned off, the aqueous phase is separated, and the organic phase is dried
on sodium
sulfate. The purification is carried out by means of chromatography on silica
gel with
hexane/ethyl acetate (30-40% ethyl acetate). 345 mg (79% of theory) of 1,1,1-
trifluoro-
4-(3-fluoro-2-methoxyphenyl}-4-methyl-2-[(5-methyl-1H indazol-4-
ylimino)methyl]-
pentan-2-of is obtained.
A solution that consists of 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-
methyl-2-[(5-methyl-1H indazol-4-ylimino)-methyl]-pentan-2-of (151 mg, 0.34
mmol)
in 20 ml of methanol is dissolved, mixed with 30 mg of palladium on carbon
(10%) and
stirred at room temperature under hydrogen atmosphere. After 20 hours, 30 mg
of
palladium on carbon is added, and the reaction mixture is allowed to stir for
another 28
hours at room temperature. The catalyst is filtered off on Celite and washed
with
methanol. After the filtrate is concentrated by evaporation and after the
residue is
purified by means of preparative thin-layer chromatography on silica gel with
hexane/ethyl acetate (50% ethyl acetate), 28 mg (19% of theory) of the product
is
obtained. 'H-NMR (400 MHz, CDCI;): 8 = 1.47 (s, 3H), 1.60 (s, 3H), 2.18 (s,
3H), 2.37
(d, 1H), 2.70 (d, 1H), 3.48 (s, 2H), 4.00 (d, 3H), 6.88-6.97 (m, 3H), 7.07 (d,
1H), 7.11
(d, 1 H), 7.67 (s, 1 H).
CA 02531060 2005-12-29
66
Example 32
'-O OH N
O ~ N I ~N
/ F3C I /
~BenzoLl ,3ldioxol-4-yl)-4-meth-1-(2-methychinazolin-5-ylamino)-2-
~trifluoromethyl~entan-2-of
1-(Benzo~l,3Jdioxol-4 yl)-1-methylethanol
25.5 g of 4-acetylbenzo[1,3]dioxole is mixed at room temperature under argon
with 57.2 ml of methylmagnesium chloride solution (3M in THF) in 375 ml THF.
It is
stirred for 16 hours at room temperature and added to ice/2H hydrochloric
acid. It is
extracted with ethyl acetate, and the organic phase is washed with water and
brine, and it
is dried (NaZS04). 27.89 g of 1-[benzo(1,3)dioxol-4-yl]-1-methylethanol is
obtained as
a brown oil.
1H-NMR (CDC13), 0 (ppm) = 1.6 (s, 6H), 5.95 (s, 2H), 6.76 (dd, 1H), 6.82 (t,
1 H), 6.91 (dd, 1 H)
4-(Benzo~l,3Jdioxol-4 yl)-4-methyl-2-oxo pentanoic acid ethyl ester
5.0 g of 1-(benzo[1,3]dioxol-4-yl)-1-methylethanol and 7.8 g of 2-
trimethylsilyloxy-acrylic acid-ethyl ester are mixed in 100 ml of
dichloromethane at
-70°C with 2.4 ml of tin(IV) chloride. After S minutes, the solution is
added to
potassium carbonate solution and vigorously stirred. It is f ltered through
diatomaceous
earth, the phases are separated, and the aqueous phase is extracted with
dichloromethane. The organic phase is washed with water and brine, dried
(Na2S04)
and concentrated by evaporation. After chromatography on silica gel
(hexane/ethyl
acetate 0 -> 10%), 3.4 g of the title compound is obtained as a colorless oil.
CA 02531060 2005-12-29
67
1H-NMR (CDC13), G (ppm) = 1.25 (t, 3H), 1.44 (s, 6H), 3.31 (s, 2H), 4.12 (q,
2H), 5.92 (s, 2H), 6.7 - 6.82 (m, 3H)
4-(Benzo~l,3Jdioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl pentanoic acid
ethyl
ester
4.42 g of 4-(benzo[1,3)dioxol-4-yl)-4-methyl-2-oxo-pentanoic acid ethyl ester
and 6.9 ml of trifluoromethyl-trimethylsilane in 95 ml of THF are slowly mixed
at -70°C
with 3.2 ml of TBAF solution ( 1 H in THF). It is stirred for 1 hour at -
70°C and for 2
hours at room temperature, and a spatula tip full of solid tetrabutylammonium
fluoride
(TBAF) is added. After 1 hour of stirring, it is added to 0.1 N hydrochloric
acid and
extracted with ethyl acetate. The organic phase is washed with water and
brine, dried
(Na2S04) and concentrated by evaporation. After chromatography on silica gel
(hexane/
ethyl acetate 0-> 10%), 4.55 g of the title compound is obtained as a yellow
oil.
'H-NMR (CDC13), ~ (ppm) = 1:19 (t, 3H), 1.39 (s, 3H), 1.46 (s, 3H), 2.29 (d,
1 H), 2.74 (d, 1 H), 3.59 (dq, 1 H), 4.05 (dq, 1 H), 5.92 (s, 1 H), 5.98 (s, 1
H), 6.68 - 6.85
(m, 3 H)
4-(Benzo~l,3Jdioxol-4 yl)-2-hydroxy-4-methyl-2-trifluoromethyl pentanol
2.92 g of4-(benzo[1,3)dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-
pentanoic acid ethyl ester in 100 ml of diethyl ether is mixed in portions at
0°C with 478
mg of lithium aluminum hydride. After stirring for 10 hours, it is added to
saturated
bicarbonate solution and filtered through diatomaceous earth. The phases are
separated,
and the aqueous phase is extracted with ethyl acetate. The organic phase is
washed with
water and brine, dried (NaZS04) and concentrated by evaporation. After
CA 02531060 2005-12-29
68
chromatography on silica gel (hexane/ethyl acetate 0 -> 10%), 2.44 g of the
title
compound is obtained as a yellow oil.
'H-NMR (CDCl3), 0 (ppm) = 1.42 (s, 3H), 1.51 (s, 3H), 2.22 (d, 1H), 2.36 (d,
1 H), 2.9 (bs, 1 H), 3.41 (d, 1 H), 3.51 (d, 1 H), 5.92 (s, 1 H), 5.95 (s, 1
H), 6.69 - 6.85 (m,
3 H)
4-(Benzo(l,3Jdioxol-4-yl)-2-hydroxy-4-methyl-2-trifluormethyl pentanal
0.650 ml of oxalyl chloride in 16.0 ml of dichloromethane is mixed at -
78°C with
1.2 ml of DMSO in 3.0 ml of dichloromethane. After 5 minutes, 2 g of 4-
(benzo[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanol in 7.0
ml of
dichloromethane is added in drops at -78°C. After 15 minutes, it is
mixed with 4.6 ml of
triethylamine and slowly heated to room temperature. It is washed with water
and brine,
dried with sodium sulfate and concentrated by evaporation in a vacuum. After
chromatography on silica gel (hexane/ethyl acetate 0 -> 5%), 1.64 g of the
title
compound is obtained as. a yellow oil.
'H-NMR (CDC13), 0 (ppm) = 1.40 (s, 3H), 1.44 (s, 3H), 2.24 (d, 1H), 3.1 (d,
1 H), 3.64 (bs; 1 H), 5.94 (s, 1 H), 5.99 (s, 1 H), 6.67 - 6.9 (m, 3H), 9.05
(s, 1 H)
Analogously to the production of Example 2, the corresponding imine is
obtained
from 125 mg of 5-amino-2-methylquinazoline and 237 mg of 4-(benzo[1,3]dioxol-4-
yl)-
2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and reduced with palladium on
activated
carbon. The reoxidation is achieved by heating the product in xylene in the
presence of
palladium on activated carbon in the air. 61 mg of the title compound is
obtained. ~H-
NMR (CDC13), 0 (ppm) = 1.48 (s, 3H), 1.56 (s, 3H), 2.35 (d, 1H), 2.53 (d, 1H),
2.85 (s,
3H), 3.23 (dd, 1 H), 3.41 (dd, 1 H), 4.74 (bt, 1 H), 5.90 (s, 1 H), 5.93 (s, 1
H), 6.17 (d, 1 H),
6.78 (dd, 1 H), 6.84-6.93 (m, 2H), 7.28 (d, 1 H), 7.58 (t, 1 H), 9.21 (s, 1 H)
" ~~ CA 02531060 2005-12-29
69
Example 33
'-O OH N
O ~ N I N
F3C I /
F
4-(Benzo [ 1,3ldioxol-4-yl)-4-methyl-1-(8-fluoro-2-methylquinazolin-5-ylamino)-
2-
~trifluoromethyl)-pentan-2-of
Analogously to Example 25, 90 mg of 4-(benzo[1,3]dioxol-4-yl)-2-hydroxy-4-
methyl-2-(trifluoromethyl)pentanal and 50 mg of 5-amino-8-fluoro-2-
methylquinazoline
in 10 ml of toluene are reacted: After chromatography on silica gel with
hexane-ethyl
acetate (0-70%), 58 mg of 4-(benzo[1,3]dioxol-4-yl)-4-methyl-1-(2-
methylquinazolin-5-
ylimino)-2-(trifluoromethyl)-pentan-2-of is obtained. 20 mg of palladium on
carbon is
added to the imine in 10 ml of ethyl acetate and 1 ml of triethylamine, and it
is shaken
for 2 hours under a hydrogen atmosphere at normal pressure. Catalyst is
removed from
the solution by means of filtration, and it is concentrated by evaporation. It
is taken up
in 5 ml of chloroform, and 200 mg of activated manganese dioxide is added and
stirred
for 10 minutes. It is filtered on Celite and concentrated by evaporation in a
vacuum.
After chromatography on silica gel with hexane-ethyl acetate (0-70%), 15 mg of
the
product is obtained. IH-NMR (CDCl3); 8 = 1.26 (s, 3H), 1.48 (s, 3H), 2.34 (d,
1H), 2.54
(d, 1 H), 2.91 (s, 3 H), 3.19 (dd, 1 H), 3.34 (dd, 1 H), 4.58 (br., 1 H), 5.89
(d, 1 H), 5.94 (d,
1 H), 6.05 (dd, 1 H), 6.71-6.85 (m, 3H), 7.32 (dd, 1 H), 9.27 (s, 1 H).
Example 34
~-O OH -N
O \ N \ NH
F3C
CA 02531060 2005-12-29
4-(Benzof 1,31dioxol-4-yl)-4-methyl-1-(1H indazol-4-vlamino)-2-
(trifluoromethyl)-
pentan-2-of
Analogously to the production of Example 30, the corresponding imine that
consists of 168 mg of 4-amino-1H indazole and 383 mg of 4-(benzo[1,3]dioxol-4-
yl)-2-
hydroxy-4-methyl-2-trifluoromethyl-pentanal is obtained and further reduced
with 488
mg of sodium cyanoborohydride to 240 mg of the title compound. 1H-NMR (CDC13),
~
(ppm) = 1.44 (s, 3H), 1.58 (s, 3H), 2.27 (d, 1 H), 2.54 (d, 1 H), 3.22 (dd, 1
H), 3.41 (dd,
1 H), 4.01-4.17 (m, 1 H), 5.81 (d, 1 H), 5.92 s, 2H), 6.73-6.99 (m, 4H), 7.12
(t, 1 H), 7.88
(s, 1 H)
Examples 35 and 36
(-)-4-(Benzo[1,31dioxol-4-yl)-4-methyl-1-(1H indazol-4-ylamino)-2-
(trifluoromethyl)-
pentan-2-of and (+)-4-(Benzo[1,3]dioxol-4-yl)-4-methyl-1-(1H indazol-4-
ylamino~ 2-
(trifluoromethyl)-pentan-2-of
Separation of (+/-)-4-(benzo[1,3]dioxol-4-yl)-4-methyl-1-(1H indazol-4-
ylamino)-2-
(trifluoromethyl)-pentan-2-ol:
The enantiomer mixture is separated by chromatography on chiral carrier
material (CHIRALPAK AD~, DAICEL Company) with hexane/ethanol (90 : 10, wv).
Thus obtained are
(-)-enantiomer: MS (esi): M++1 = 422, [~]D -50.9° °(c = 1.0,
CHC13) and
(+)-enantiomer: MS (esi): M++1 = 422, [~]D +54.3° °(c = 1.0,
CHC13)
,, ~ CA 02531060 2005-12-29
71
Example 37
~-O OH -N
H NH
O ( ~ F3C N
/
4-(Benzo[ 1,3 ]dioxol-4-yl)-1-(6-methyl-1 H-indazol-4-ylamino)-4-methyl-2-
(trifluoromethyl)pentan-2-of
Analogously to Example 16, the desired product is obtained from 4-
(benzo[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 6-
methyl-
1 H-indazol-4-ylamine (from Auwers Chem. Ber., 1920, 53, 1213). 'H-NMR
(CD30D);
8 = 1.44 (s, 3H), 1.65 (s, 3H), 2.06 (d, 1H), 2.23 (s, 3H), 2.8 (d, 2H), 3.09
(d, 1H), 5.89
(s, 1 H), 5.91 (s, 1 H), 6.05 (s, 1 H), 6.75 (dd, 1 H), 6.86 (t, 1 H), 6.94
(dd, 1 H), 7.22 (s,
1 H), 7.73 (s, 1 H).
Example 38
/-O OH H S
N
O ~ \ F'C N
~Benzo [ 1,3ldioxol-4-~1)-4-methyl-1-(2-methyl-benzothiazol-7-ylamino)-2-
(trifluoromethyl)-pentan-2-of
Analogously to the production of Example 30, the corresponding imine is
obtained from 100 mg of 7-amino-2-methylbenzothiazole (Libeer et al. Bull.
Soc. Chim.
Belg.; 1971; 80; 43-47) and 154 mg of 4-(benzo[1,3]dioxol-4-yl)-2-hydroxy-4-
methyl-2-
trifluoromethyl-pentanal, and-further reduced with 63 mg of sodium
cyanoborohydride
to 8 mg of the title compound. 'H-NMR (CDC13), L~ (ppm) = 1.42 (s, 3H), 1.53
(s, 3H),
CA 02531060 2005-12-29
77
2.01 (d, 1 H), 2.10 (d, 1 H), 2.78 (s, 3H), 5.29 (d, 1 H), 5.67 (d, 1 H), 6.00
(s, 2H), 6.13 (s,
1H), 6.63-6.82 (m, 3H), 7.18-7.30 (m, 2H)
Example 39
/-O OH \
O \ N ( N
F3C ~ ~ N
4-(Benzo[1,3]dioxol-4-yl -4-methyl-1-(2-methyl-1,8-naphthyridin-5-ylamino)-2-
~trifluoromethyl)-pentan-2-of
Analogously to Example 10, 1-amino-4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-
(trifluoromethyl)propan-2-of is reacted with 5-chloro-2-methyl-1,8-
naphthyridine to
form the desired product. ~NMR (CDC13) ~ (ppm) = 1.49 (s, 3H), 1.57 (s, 3H),
2.41 (d,
1 H), 2.49 (d, 1 H), 2.74 (s, 3H), 3.32 (d, 1 H), 3.50 (d, 1 H), 5.89 (s, 1
H), 5.93 (s, 1 H),
6.06 (d, 1 H), 6.76-6.92 (m, 3H), 7.23 (d, 1 H), 8.05 (d, 1 H), 8.61 (d, 1 H)
Example 40
O OH -N
H NH
N \
\ ulv
F3C
42,3-Dihydrobenzofuranyl 4-methyl-1-(1H indazol-4-ylamino)-2-(trifluoromethyl)-
pentan-2-of
4-(2, 3-Dihydrobenzofuranyl)-2-hydrozy-4-methyl-2-(trifluoromethyl)pentanal
Analogously to the described method of synthesis of4-(benzo[1,3]dioxol-4-yl)-
2-hydroxy-4-methyl-2-trifluoromethyl-pentanol (Example 32), starting from 513
mg of
4-(2,3-dihydrobenzofuranyl~4-methyl-2-oxo-pentanoic acid ethyl ester (WO
00/32584),
142 mg of 4-(2,3-dihydrobenzofuranyl~2-hydroxy-4-methyl-2-(trifluoromethyl)-
w, CA 02531060 2005-12-29
73
pentanol as fraction 2 and 84 mg of the title compound as fraction 1 are
obtained as
colorless oils.
Fraction I: IH-NMR (CDC13), 0 (ppm) =1.39 (s, 3H), 1.45 (s, 3H), 2.18 (d, 1H),
3 . I 9 (t, 2H), 3.34 (d, 1 H), 3.62 (bs, I H), 4.5 I - 4.63 (m, 2H), 6.8 (t,
1 H), 6.91 (d , 1 H),
7. I 1 (d, I H), 8.96 (s, 1 H)
Fraction 2: 1H-NMR (CDC13), ~ (ppm) = 1.41 (s, 3H), 1.48 (s, 3H), 2.25 (d, I
H),
2.48 (d, 1 H), 3.2 (t, 2H), 3.42 (bs, 1 H), 4.56 (t, 2H), 6.85 (t, 1 H), 7.06 -
7.15 (m, 2H)
Analogously to the production of Example 30, the corresponding imine is
obtained from 32 mg of 4-amino-1H indazole and 75 mg of 4-(2,3-
dihydrobenzofuranyl}-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and
further
reduced with 134 mg of sodium cyanoborohydride to 64 mg of the title compound.
~H-
NMR (CDCl3), D (ppm) = 1.45 (s, 3H), 1.57 (s, 3H), 2.31 (d, 1H), 2.64 (d, IH),
3.05-
3 .19 (m, 2H), 3 .21 (d, I H), 3.3 9 (d, 1 H), 4.48-4.63 (m, 2H), 5.76 (d, I
H), 6. 85 (d, 1 H),
6.92 (t, 1H), 7.05-7.23 (m, 3H), 7.85 (s, 1H)
Example 41
~O OH -N
CI ~ N NH
ul~
F3C
4-(,3-Chloro-2-methoxyphenyl~-I-(IH indazol-4-ylamino)-4-methyl-2-
(trifluoromethyl)pentan-2-of
3-Chloro-2-methoxybenzylcyanide
39.4 g (221.3 mmol) of NBS and 100 mg of benzoyl peroxide are added to 31.6 g
(201.7 mmol) of 3-chloro-2-methoxytoluene in 500 ml of CC14. It is refluxed
for 16
hours, allowed to cool, and filtered. Solvent is removed from the filtrate and
dissolved
" ~~ CA 02531060 2005-12-29
74
in 214 ml of dimethylformamide and 142 ml of water. 20.9 g (322.1 mmol) of
potassium cyanide is added at 0°C and stirred over 16 hours. The
reaction mixture is
diluted with water and extracted several times with tert-butyl-methyl ether.
The organic
phase is washed several times with saturated sodium chloride solution and
dried on
sodium sulfate. The solvent is removed in a vacuum, and after chromatographic
purification on silica gel (hexane/ethyl acetate 20%), 29.7 g of product is
obtained. ~H-
NMR (CDC13): b = 3.76 (s, 2H), 3.95 (s, 3H), 7.08 (t, 1 H), 7.31 (d, 1 H),
7.37 (d, 1 H)
4-(3-Chloro-2-methoxy phenyl)-4-methyl-2-trifluoromethyl pentane-1,2-diol
29.7 g (163.7 mmol) of 4-chloro-2-methoxybenzylcyanide and 46.5 g (327.4
mmol) of methyl iodide in 260 ml of DMF are mixed in portions at 0°C
with 13.2 g
(327.4 mmol) of sodium hydride (60% in oil). It is stirred overnight and then
mixed
with water and ethyl acetate. The phases are separated, and the aqueous phase
is
extracted several times with ethyl acetate. It is washed with water and
saturated sodium
chloride solution, dried with sodium sulfate and concentrated by evaporation
in a
vacuum. After chromatography on silica gel (hexane/ethyl acetate 95:5), 32.4 g
of 2-(4-
chloro-2-methoxy-phenyl)-2-methylpropionitrile is obtained as a colorless oil.
7 g (33.4
mmol) of nitrile is slowly mixed in toluene at -78°C with 41.6 ml (50.1
mmol) of
diisobutylaluminum hydride solution (20% in toluene), and 5.55 ml of
isopropanol is
added in drops after 3 hours at -78°C. It is allowed to heat to -
5°C, and 380 ml of a 10%
aqueous tartaric acid solution is added. After dilution with ether, it is
stirred vigorously,
the organic phase is separated, and the aqueous phase is extracted several
times with
ether. It is washed with brine, dried with sodium sulfate and concentrated by
evaporation in a vacuum. After chromatography on silica gel (hexane/ethyl
acetate
95:5), 7.1 g of 2-(4-chloro-methoxy-phenyl)-2-methylpropanal is obtained as a
colorless
" ~~ CA 02531060 2005-12-29
oil. A solution of 8.95 g (33.4 mmol) of 2-diethylphosphono-2-ethoxyacetic
acid ethyl
ester in 30 ml of tetrahydrofuran is mixed with 19 ml (38 mmol) of a 2 M
solution of
lithium diisopropylamide in tetrahydrofuran-heptane-toluene while being cooled
with
ice within 20 minutes, and it is stirred for 15 minutes at 0°C. A
solution of 7.1 g (33.4
mmol) of 2-(3-chloro-2-methoxyphenyl~2-methylpropanal in 27 ml of
tetrahydrofuran
is added in drops at 0°C within 30 minutes. After 20 hours at room
temperature, water is
added, and it is extracted several times with ether and ethyl acetate. It is
washed with
saturated ammonium chloride solution, dried (Na2S04) and concentrated by
evaporation.
The crude product is purified by column chromatography on silica gel
(hexane/ethyl
acetate 10%), and 8.5 g of 4-(3-chloro-2-methoxy-phenyl)-4-methyl-3-ethoxy-2-
ene-
valeric acid ethyl ester is obtained. The intermediate product is saponified
with 80 ml of
3 M sodium hydroxide solution/160 ml of ethanol. 5.3 g of acid, which is
stirred with
ml of 2N sulfuric acid at 90°C over 16 hours, is obtained. After
cooling, it is made
basic with potassium carbonate, washed with ether and acidified with
hydrochloric acid.
After extraction with ethyl acetate, washing with saturated sodium chloride
solution and
removal of the solvent, 4.0 g of 4-(3-chloro-2-methoxyphenyl~4-methyl-2-oxo-
valeric
acid is obtained. 6.6 g (24.3 mmol) of 4-(3-chloro-2-methoxy-phenyl)-4-methyl-
2-oxo-
valeric acid and 2.74 ml (51.4 mmol) of sulfuric acid (96%) are refluxed in
150 ml of
ethanol for 5 hours. The batch is concentrated by evaporation in a vacuum, and
the
residue is taken up in saturated sodium bicarbonate solution. It is extracted
several times
with ethyl acetate, washed with saturated sodium bicarbonate solution, dried
(sodium
sulfate) and concentrated by evaporation in a vacuum. After chromatographic
purification on silica gel (hexane/ethyl acetate 10%), 5.9 g of 4-(3-chloro-2-
methoxv-
phenyl)-4-methyl-2-oxo-valeric acid-ethyl ester is obtained. This ester and
3.4 g (23.8
mmol) of (trifluoromethyl)-trimethylsilane in 34 ml of THF are mixed with 49
mg of
" ~ CA 02531060 2005-12-29
76
tetrabutylammonium fluoride at 0°C. It is stirred for 16 hours at room
temperature and
then the reaction mixture is added to water. It is extracted several times
with ethyl
acetate, washed with saturated sodium chloride solution, dried with sodium
sulfate and
concentrated by evaporation in a vacuum. 2.96 g of 4-(3-chloro-2-methoxy-
phenyl)-2-
hydroxy-4-methyl-2-trifluoromethyl-valeric acid-ethyl ester is obtained as a
yellow oil.
This oil is mixed in 24 ml of diethyl ether at 0°C with 510 mg of
lithium aluminum
hydride and stirred for 4 more hours at room temperature. 20 ml of saturated
sodium
bicarbonate solution is carefully added at 0°C to the batch, and it is
vigorously stirred for
1 more hour. It is extracted several times with tert-butyl methyl ether,
washed with
water and saturated sodium chloride solution, dried with sodium sulfate and
concentrated by evaporation in a vacuum. The crude product is mixed in 33 ml
of THF
with 1.83 (5.79 mmol) of tetrabutylammonium fluoride trihydrate and stirred
for 16
hours. It is poured into ice water, extracted several times with tert-butyl
methyl ether,
washed with saturated sodium chloride solution, dried with sodium sulfate and
concentrated by evaporation in a vacuum. After chromatographic purification on
silica
gel (hexane/ethyl acetate 25%), 1.81 g of 4-(3-chloro-2-methoxy-phenyl)-4-
methyl-2-
trifluoromethyl-pentane-1,2-diol is obtained. 'H-NMR (CDC13), 0 (ppm) = 1.47
(s, 3H),
1.56 (s, 3H), 2.21 (d, 1 H), 2.54 (d, 1 H), 2.91 (s, 1 H), 3.31 (dd, 1 H),
3.42 (d, 1 H), 4.01 (s,
3H), 7.00 (t, 1H), 7.20-7.35 (m, 2H)
4-(3-Chloro-2-methoxy phenyl)=2-hydroxy-4-methyl-2-trifluoromethyl pentanal
1.87 g ( 18.5 mmol) of triethylamine and, in portions over 10 minutes, 1.17 g
(7.4
mmol) of pyridine S03 complex are added to 1.2 g (3.7 mmol) of diol in 24 ml
of
dichloromethane and 6.4 ml of DMSO. It is stirred over 5 hours, and 30 ml of
saturated
ammonium chloride solution is added. The mixture is stirred for another 15
minutes, the
CA 02531060 2005-12-29
77
phases are separated, and it is extracted with tert.-butyl ethyl ether. It is
washed with
water and dried on sodium sulfate. The solvent is removed in a vacuum, and
after
chromatographic purification on silica gel (hexane/ethyl acetate, 0-50%), 0.98
g of
product is obtained. 'H-NMR (CDCl3): 8 = 1.44. (s, 3H), 1.50 (s, 3H), 2.29 (d,
2H), 3.28
(d, 1 H), 3.55 (s, 1 H), 4.01 (s, 3H), 6.95 (t, 1 H), 7.07 (dd, 1 H), 7.30
(dd, 1 H), 8.90 (s,
1 H).
Analogously to Example 16, the desired product is obtained from 4-(3-chloro-2-
methoxyphenyl~2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 1 H-indazol-4-
ylamine.
'H-NMR (300 MHz, CD30D): D = 1.49 (3H), 1.68 (3H), 2.03 (1H), 3.00 (1H),
3.25 (1H), 3.35 (1H), 3.95 (3H), 5.60 (1H), 6.73-6.83 (2H), 7.D3 (1H), 7.18
(1H), 7.30
(1H), 7.95 (1H).
Example 42
OH OH -N
C~ ~ N NH
ul~
F3C
4-(3-Chloro-2-hydroxyphenyl~-1-(1H indazol-4-ylamino~4-methyl-2-
(trifluoromethyl)pentan-2-of
Analogously to Example 3, the desired product is obtained from 4-(3-chloro-2-
methoxyphenyl}-1-(1H indazol-4-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-
ol.
'H-NMR (300 MHz, CD30D): ~ = 1.50 (3H), 1.70 (3H), 2.03 (1H), 3.00 (1H), 3.25
(1H), 3.35 (1H), 5.60 (1H), 6.73-6.83 (2H), 7.03 (1H), 7.18 (1H), 7.30 (1H),
7.95 (1H).
CA 02531060 2005-12-29
78
Example 43 .
~O OH -N
H NH
y N
F3C
F
4-(4-Fluoro-2-methoxyphen~l)-4-methyl-1-(1H indazol-4-ylamino)-2-
(trifluoromethyl)-
pentan-2-of
4-(9-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol
and 4-
(2 fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol
Both products are obtained analogously to the method of synthesis of 4-(4-
chloro-2-methoxyphenyl~2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol and 4-(2-
chloro-4-methoxyphenyl}-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol
(Example
45) from 3-fluoroanisole and 2-hydroxy-4-methylene-2-(trifluoromethyl)valeric
acid
ethyl ester and the subsequent reaction with lithium aluminum hydride. The
separation
is carried out by chromatography on silica gel.
1st Fraction: 1H-NMR (CDC13), ~ (ppm) = 1.40 (s, 3H), 1.52 (s, 3H), 2.25 (d,
I H), 2.50 (d, 1 H), 2.83 (bs, 1 H), 3.36 (d, I H), 3.46 (d, 1 H), 3.85 (s,
3H), 6.54 - 6.69 (m,
2H), 7.19 - 7.3 0 (m, 1 H)
2nd Fraction: iH-NMR (CDCl3), D (ppm) = I .41 (s, 3H), 1.53 (s, 3H), 2.17 (d,
1 H), 2.3 (d, 1 H), 2.89 (bs, 1 H), 3.34 (bd, 1 H), 3.53 (d, 1 H), 3.78 (s,
3H), 6.58 (dd, 1 H),
6.63 (dd, I H), 7.22 (t, 1 H)
4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
Analogously to the synthesis of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-
methyl-2-(trifluoromethyl)pentanal, 1.81 g of the title compound is obtained
as a cloudy
" ~ CA 02531060 2005-12-29
79
oil starting from 3 g of 4-(4-fluoro-2-methoxyphenyl~2-hydroxy-4-methyl-2-
(trifluoromethyl)pentanol.
1H-NMR (CDCI3), 0 (ppm) = 1.38 (s, 3H), 1.46 (s, 3H), 2.19 (d, IH), 3.37 (d,
1 H), 3.58 (s, 1 H), 3.87 (s, 3H), 6.55 - 6.64 (m, 2H), 7.06 (dd, 1 H), 8.97
(s, 1 H)
Analogously to the production of Example 30, the corresponding imine is
obtained from 64 mg of 4-amino-1H indazole and 150 mg of 4-(4-fluoro-2-
methoxyphenyl~2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and further
reduced
with 141 mg of sodium cyanoborahydride to 53 mg of the title compound. 'H-NMR
(CDC13), ~ (ppm) = I .44 (s, 3H), 1.59 (s, 3H), 2.29 (d, 1 H), 2.70 (d, 1 H),
3.18 (d, 1 H),
3.33 (d, 1 H), 3.84 (s, 3H), 5.64 (d, 1 H), 6.65 (dd, 1 H), 6.71 (dt, 1 H),
6.88 (d, 1 H), 7.12
(t, 1 H), 7.3 7 (dd, 1 H), 7.90 (s, 1 H)
Example 44
OH OH -N
NH
N
FsC ~ /
F
4-(4-Fluoro-2-hydroxyphenyl~4-methyl-1-(1H indazol-4-ylamino)-2-
(trifluoromethyl)-
pentan-2-of
Analogously to the production of Example 3, 4 mg of the title compound is
obtained from the reaction of 45 mg of 4-(4-fluoro-2-methoxyphenyl~4-methyl-1-
(1H
indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-of and 1.65 ml of boron
tribromide (1
M in dichloromethane). 'H-NMR (CDC13), D (ppm) = 1.48 (s, 3H), 1.52 (s, 3H),
2.26
(d, 1 H), 2.84 (d, I H), 3.25 (d, 1 H), 3.41 (d, 1 H), 4.23 (bs, 1 H), 5.72
(d, 1 H), 6.44 (dd,
1 H), 6.64 (dt, 1 H), 6.83 (d, 1 H). 7.12 (t, 1 H), 7.3 3 (dd, 1 H), 7.96 (s,
1 H)
.. CA 02531060 2005-12-29
Example 45
~O OH -N
H NH
N
FsC
CI
4-(4-Chloro-2-methoxyphenyl~-4-methyl-1-(1H indazol-4-ylamino)-2-
(trifluoromethyl)-
pentan-2-of
4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol
and 4-
(2-chloro-4-metho~.yphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol
A solution of 3 g of 2-hydroxy-4-methylene-2-(trifluoromethyl)valeric acid
ethyl
ester in 22 ml of 3-chloroanisole is mixed in portions with aluminum
trichloride at room
temperature. It is stirred for 48 hours and then mixed with 2N hydrochloric
acid and
hexane and stirred for 1 hour. It is washed with 2N hydrochloric acid and
water, and
excess 3-chloroanisole is distilled off in a vacuum. The remaining residue is
purified by
chromatography on silica gel (hexane/ethyl acetate 0-10%). 2.85 g of a mixture
of 4-(4-
chloro-2-methoxyphenyl~2-hydroxy-4-methy-2-(trifluoromethyl)valeric acid ethyl
ester
and 4-(2-chloro-4-methoxyphenyl)-2-hydroxy-4-methy-2-(trifluoromethyl)valeric
acid
ethyl ester is obtained as a yellow oil. This substance mixture is mixed in 90
ml of ether
at 0°C with 445 mg of lithium aluminum hydride and stirred for 12
hours. The batch is
added to saturated sodium bicarbonate solution, filtered through diatomaceous
earth, the
phases are separated, and the aqueous phase is extracted with ethyl acetate.
It is washed
with water and brine, dried with sodium sulfate, and concentrated by
evaporation in a
vacuum. After chromatography on silica gel (hexane/ethyl acetate 95:5), 1.87
mg of 4-
(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-of
as a 1St
fraction and 160 mg of 4-(2-chloro-4-methoxyphenyl~2-hydroxy-4-methyl-2-
(trifluoromethyl)pentan-1-of as a 2°d fraction are obtained as
colorless oils.
.. CA 02531060 2005-12-29
81
lst Fraction:'H-NMR (CDC13), ~ (ppm) = 1.41 (s, 3H), 1.51 (s, 3H), 2.24 (d,
1 H), 2.51 (d, 1 H), 2.84 (bs, 1 H), 3.36 (d, 1 H), 3.48 (d, I H), 3.85 (s,
3H), 6.88 (d, 1 H),
6.92 (dd, I H), 7.24 (d, 1 H)
2nd Fraction: IH-NMR (CDC13), 0 (ppm) = I .52 (s, 3H), I .62 (s, 3H), 2.18 (d,
1 H), 2.76 (d, I H), 2.93 (bs, 1 H), 3.33 (d, I H), 3.55 (d, I H), 3.80 (s,
3H), 6.78 (dd, I H),
6.90 (d, 1 H), 7.3 8 (d, l H)
4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
0.425 ml of oxalyl chloride in 10 ml of dichloromethane is mixed at -
78°C with
0.77 ml of DMSO in 2.0 ml of dichloromethane. After 5 minutes, I .38 g of 4-(4-
chloro-
2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-of in 6.0 ml
of
dichloromethane is added in drops at -78°C. After 15 minutes, it is
mixed with 2.9 ml of
triethylamine and slowly heated to room temperature. It is washed with water
and brine,
dried with sodium sulfate and concentrated by evaporation in a vacuum. After
chromatography on silica gel (hexane/ethyl acetate 98:2), 1.16 g of 4-(4-
chloro-2-
methoXyphenyl~2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal is obtained as a
colorless oil. ~H-NMR (CDC13), ~ (ppm) =1.38 (s, 3H), 1.44 (s, 3H), 2.21 (d,
IH), 3.34
(d, I H), 3.57 (bs, I H), 3.89 (s, 3H), 6.84 (d, 1 H), 6.87 (d, 1 H), 7.04 (d,
1 H), 9.02 (s, 1 H)
Analogously to the production of 4-(5-fluoro-2-methoxyphenyl}-4-methyl-I-(2-
methylphthalazin-I-on-5-ylamino)-2-(trifluoromethyl)-pentan-2-of (Example 27),
the
corresponding imine is obtained from 168 mg of 4-amino-1H indazole and 410 mg
of 4-
(4-chloro-2-methoxyphenyl~2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and
further reduced with 580 mg of sodium cyanoborohydride to 303 mg of the title
compound. 'H-NMR (CDC13), ~ (ppm) = 1.44 (s, 3H), 1.59 (s, 3H), 2.26 (d, 1H),
2.70
" ~~ CA 02531060 2005-12-29
82
(d, 1 H), 3.17 (dd, I H), 3.31 (dd, 1 H), 3.85 (s, 3H), 4.08 (bs, 1 H), 5.53
(d, 1 H), 6.86 (d,
1 H), 6.89 (d, 1 H), 6.99 (dd, 1 H), 7.14 (t, 1 H), 7.34 (d, 1 H), 7.86 (s, 1
H)
Examples 46 and 47
(-)-4-(4-Chloro-2-methoxyphenyll-4-methyl-1-( 1 H-indazol-4-ylaminol-2-
~ifluoromethyl)-pentan-2-of and (+)-)-4-(4-Chloro-2-methoxyphenyl)-4-methyl 1
H
indazol-4-ylamino)-2-~trifluoromethyl)-pentan-2-of
Separation of (+/-)-4-(4-chloro-2-methoxyphenyl~4-methyl-1-(1H indazol-4-
ylamino)-
2-(trifluoromethyl)-pentan-2-ol:
The enantiomer mixture is separated by chromatography on chiral carrier
material (CHIRALPAK AD~, DAICEL Company) with hexane/ethanol (80 : 20, vw).
Thus obtained are
(-)-Enantiomer: MS (esi): M++1 = 442/444, [~]D -60.8° °(c = 1.0,
CHC13) and
(+)-Enantiomer: MS (esi): M++1 = 442/444, [0]D +43.0° °(c = 1.0,
CHC13)
Examples 48 and 49
OH OH -N
NH
N
CI
~-)-4-(4-Chloro-2-hydroxyphenyl~4-methyl-1-(1H indazol-4-ylamino)-2-
(trifluoromethyl)=pentan-2-of
Analogously to the production of Example 3, 11 mg of the title compound is
obtained from the reaction of 100 mg of (-)-4-(4-chloro-2-methoxyphenyl~4-
methyl-1-
( 1 H-indazol-4-ylamino)-2-{trifluoromethyl)-pentan-2-of and 3.6 ml of boron
tribromide
( 1 M in dichloromethane).
.. " CA 02531060 2005-12-29
83
IH-NMR (CDC13), 0 (ppm) = 1.49 (s, 3H), 1.62 (s, 3H), 2.25 (d, 1H), 2.82 (d,
1 H), 3.25 (d, 1 H), 3.40 (d, 1 H), 5.63 (d, 1 H), 6.72 (d, 1 H), 6.84 (d, 1
H), 6.93 (d, 1 H),
7.14 (t, 1 H), 7.31 (d, 1 H), 7.95 (s, 1 H)
(+)-4-(4-Chloro-2-hydroxyphenYl 4-methyl~l-(1H indazol-4-ylamino)-2-
(trifluoromethyl)-~entan-2-of
Analogously to the production of Example 3, 2.17 g of the title compound is
obtained from the reaction of 5.3 g of (+)-4-(4-chloro-2-methoxyphenyl~4-
methyl-1-
(1H indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-of and 190 ml of boron
tribromide
( 1 M in dichloromethane).
'H-NMR (CDCl3), ~ (ppm) = 1.49 (s, 3H), 1.62 (s, 3H), 2.25 (d, 1H), 2.82 (d,
1 H), 3.25 (d, 1 H), 3.40 (d, 1 H), 5.63 (d, 1 H), 6.72 (d, 1 H), 6.84 (d, 1
H), 6.93 (d, 1 H),
7.14 (t, 1 H), 7.31 (d, 1 H), 7.95 (s, 1 H)
Example 50
~O OH N
N I ~N
CI
4-(4-Chloro-2-methoxyphenyl~-4-methy~2-methylquinazolin-5-ylaminol-2-
(trifluoromethyl)-pentan-2-of
Analogously to the production of Example 2, the corresponding imine is
obtained
from 395 mg of 5-amino-2-methylquinazoline and 299 mg of 4-(4-chloro-2-
methoxyphenyl~2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, and it is
reduced with
palladium on activated carbon. The reoxidation is achieved by heating the
product in
xylene in the presence of palladium on activated carbon in air. I 1 mg of the
title
CA 02531060 2005-12-29
84
compound is obtained. 1H-NMR (CDC13), D (ppm) = I .50 (s, 3H), I .59 (s, 3H),
2.45 (d,
I H), 2.68 (d, 1 H), 2.86 (s, 3H), 3.18 (dd, 1 H), 3.36 (dd, 1 H), 3.89 (s,
3H), 6.08 (d, 1 H),
6.92 (d, 1 H), 6.98 (t, I H), 7.36 (d, I H), 7.54 (d, I H), 9. I 1 (s, 1 H)
Example 51
~O OH N
N I ~N
FsC
CI ~ ~ F
4-(4-Chloro-2-methoxyphenyl~l-(8-fluoro-2-methylq-uinazolin-5-ylaminol-4-
methyl-2-
(trifluoromethyl~-pentan-2-of
I .72 g (5.30 mmol) of 4-(4-chloro-2-methoxyphenyl~2-hydroxy-4-methyl-2-
trifluoromethyl-pentanal and 0.85 g (4.80 mmol) of 5-amino-8-fluoro-2-methyl-
quinazoline are first reacted analogously to Example 2 in 64 ml of
dichloromethane and
13 ml of acetic acid. 600 mg of purified intermediate product is obtained.
200 mg (0.42 mmol) of this imine is dissolved in 7 ml of THF, and 60 mg (0.84
mmol) of sodium cyanoborohydride is added at 0°C. After 1 hour, several
drops of
methanol/acetic acid (1:1) as well as another 15 mg (0.21 mmol) of sodium
cyanoborohydride are added and stirred for another 2 hours. The reaction is
brought to a
halt by adding saturated ammonium chloride solution and worked up analogously
to
Example 26. The crude product is chromatographed on silica gel (eluant
hexane/ethyl
acetate 20%). This product is taken up in a little chloroform, mixed with a
spatula tip
full of manganese dioxide and stirred for 1 hour. The manganese dioxide is
filtered off,
the filtrate is concentrated by evaporation and chromatographed with a little
silica gel
with hexane,iethyl acetate 20-50%. 5 mg of the desired product is obtained. 'H-
NMR
(CDC1;), L~ (ppm) = 1.49 (s, 3H), 1.56 (s, 3H), 2.45 (d, IH), 2.68 (d, IH),
2.88 (s, 3H),
" ~' CA 02531060 2005-12-29
3.16 (dd, 1 H), 3.30 (dd, 1 H), 3.89 (s, 3H), 5.92 (dd, 1 H), 6.85 (d, 1 H),
6.92 (dd, I H),
7.30 (dd, 1 H), 7.36 (d, 1 H), 9.19 (s, 1 H); MS (CI): 486/488 (M+H).
Example 52
~O OH
I
N ~N
F3C I ~ N
CI
4-(4-Chloro-2-methoxyphenyl~4-methyl-1-(2-methyl-1 8-naphthyridin-5-ylamino)-2-
(trifluoromethyl~entan-2-of
Analogously to Example 10, 1-amino-4-(4-chloro-2-methoxyphenyl~4-methyl-
2-(trifluoromethyl)propan-2-of is reacted with 5-chloro-2-methyl-1,8-
naphthyridine to
form the desired product. 'H-NMR (CDC13); 8 = 1.46 (s, 3H), 1.56 (s, 3H), 2.46
(d,
1 H), 2.62 (d, 1 H), 2.70 (s, 3 H), 3.22 (d, 1 H), 3.3 8 (dd, 1 H), 3.84 (s,
3H), 5 .89 (d, 1 H),
6.87 (d, 1 H), 6.94 (dd, 1 H), 7.14 (d, 1 H), 7.27 (d, 1 H), 7.82 (d, 1 H),
8.58 (s, 1 H).
Example 53
r OH OH
N I ~N
~N
CI
4-(4-Chloro-2-hydroxyphenyl~4-methyl-1-(2-methyl-1 8-naphthyridin-5-ylamino)-2-
(trifluoromethyl)~pentan-2-of
Analogously to Example 3, 4-(4-chloro-2-methoxyphenyl~4-methyl-1-(2-
methyl-1,8-naphthyridin-5-ylamino)-2-(trifluoromethyl)pentan-2-of is reacted
to form
the desired product. ~H-NMR (CD;OD); 8 = 1.47 (s, 3H), 1.66 (s, 3H), 2.02 (d,
1H),
.. CA 02531060 2005-12-29
86
2.18 (d, 1 H), 2.72 (s, 3 H), 3.14 (d, 1 H), 3.24 (dd, 1 H), 5 .94 (d, 1 H),
6.65 (d, 1 H), 6.76
(dd, 1 H), 7.31 (d, 1 H), 7.40 (d, I H), 8.26 (d, I H), 8.3 5 (s, 1 H).
Example 54
F OH -N
H NH
N
w ~I~
F3C
4-(2-Fluoro-4-methoxyphenyl)-4-methyl-1-(1H indazol-4-ylamino)-2-
(trifluoromethyl)-
pentan-2-of
4-(2-Fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
Analogously to the synthesis of 4-(4-chloro-2-methoxyphenyl~2-hydroxy-4-
methyl-2-(trifluoromethyl)pentanal (Example 45), 1.73 g of the title compound
is
obtained as a colorless oil starting from 3 g of 4-(2-fluoro-4-methoxyphenyl~2-
hydroxy-
4-methyl-2-(trifluoromethyl)pentanol (Example 47).
'H-NMR (CDC13), ~ (ppm) = 1.39 (s, 3H), 1.46 (s, 3H), 2.26 (d, 1H), 3.09 (d,
1 H), 3.63 (s, 1 H), 3.78 (s, 3H), 6.52 - 6.65 (m, 2H), 7.03 (t, 1 H), 9.04
(s, 1 H)
Analogously to the production of Example 30, the corresponding imine is
obtained from 82 mg of 4-amino-IH indazole and 192 mg of 4-(2-fluoro-4-
methoxyphenyl~2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and further
reduced
with 281 mg of sodium cyaonoborohydride to 152 mg of the title compound. 'H-
NMR
(CDC13), ~ (ppm) = I .47 (s, 3H), I .61 (s, 3H), 2.23 (d, 1 H), 2.50 (d, 1 H),
3.24 (dd, 1 H),
3.37 (dd, 1 H), 3.78 (s, 3H), 4.00-4.1 I (m, 1 H), 5.70 (d, I H), 6.61 (dd, 1
H), 6.72 (dd,
1 H), 6.87 (d, I H), 7.08 (t, 1 H), 7.33 (t, 1 H), 7.90 (s, I H)
~~
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87
Example 5~
F OH -N
H NH
_ N
/ 3C
HO
4-(2-Fluoro-4-hydroxyphenyl}-4-methyl-I -( I H indazol-4-ylamino)-2-
(trifluoromethyl)-
pentan-2-of
Analogously to the production of Example 3, 76 mg of the title compound is
obtained from the reaction of 80 mg of 4-(2-fluoro-4-methoxyphenyl~4-methyl-1-
(IH
indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-of and 3 ml of boron
tribromide (I M
in dichloromethane). 1H-NMR (CDC13), 0 (ppm) = I .44 (s, 3H), 1.60 (s, 3H),
2.22 (d,
1 H), 2.49 (d, I H), 3.28 (d, 1 H), 3.37 (d, I H), 5.83 (d, I H), 6.58 (dd, 1
H), 6.66 (dd, 1 H),
6.85 (d, 1 H), 7. I 6 (t, 1 H), 7.27 (d, 1 H), 7. 88 (s, 1 H)
Example 56
CI OH -N
H NH
N
F3C
/ /
4-(2-Chloro-4-methoxyphenyl~4-methyl-I-(1H indazol-4- lamino)-2-
(trifluoromethyl)-
pentan-2-of
4-(2-Chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
Analogously to the synthesis of 4-(4-chloro-2-methoxyphenyl}-2-hydroxy-4-
methyl-2-(trifluoromethyl)pentanal (Example 45), 141 mg of the title compound
is
obtained as a yellow oil starting from 1 ~0 mg of 4-(2-chloro-4-methoxyphenyl}-
2-
hydroxy-4-methyl-2-(trifluoromethyl)pentanol. IH-NMR (CDC13), C (ppm) = 1.~2
(s,
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88
3H), 1.54 (s, 3H), 2.24 (d, 1 H), 3.60 (d, 1 H), 3.65 (s, 1 H), 3.79 (s, 3H),
6.72 (dd, 1 H),
6.88 (d, 1 H), 7.19 (d, 1 H), 9.11 (s, 1 H)
Analogously to the production of Example 30, the corresponding imine is
obtained from 36 mg of 4-amino-1H-indazole and 90 mg of 4-(2-chloro-4-
methoxyphenyl~2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and further
reduced to
54 mg of the title compound with 114 mg of sodium cyanoborohydride. 1H-NMR
(CDC13), ~ (ppm) = 1.56 (s, 1H), 1.71 (s, 3H), 2.19 (d, 1H), 3.01 (d, 1H),
3.28 (d, 1H),
3.37 (d, 1 H), 3.79 (s, 3H), 5.56 (d, 1 H), 6.83 (dd, 1 H), 6.86 (d, 1 H),
7.06 (t, 1 H), 7.49 (d,
1 H), 7.90 (s, 1 H)
Example 57
CI OH -N
H NH
_ N
3C
w0
4-(2-Chloro-4-hydroxyphen~~4-methyl-1-(1H indazol-4-ylamino)-2-
(trifluoromethyl)-
pentan-2-of
Analogously to the production of Example 3, 11 mg of the title compound is
obtained from the reaction of 27 mg of 4-(2-chloro-4-methoxyphenyl)-4-methyl-1-
(1H
indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-of and 0.93 ml of boron
tribromide
(1 M in dichloromethane). 'H-NMR (CDCl3), 0 (ppm) = 1.54 (s, 3H), 1.69 (s,
3H), 2.19
(d, 1 H), 3.00 (d, 1 H), 3.25-3.46 (m, 2H), 4.01 (bs, 1 H), 5.75 (d, 1 H),
6.77 (dd, 1 H), 6.82
(d, 1 H), 6.92 (d, 1 H), 7.11 (t, 1 H), 7.41 (d, 1 H), 7.86 (s, 1 H)
.. CA 02531060 2005-12-29
89
Example 58
~O OH -N
H ~N H
N
\ ~I~
F3C
Br
4-~4-Bromo-2-methoxyphenyl)-4-methy~ 1 H-indazol-4=ylamino)-2-
(trifluoromethyl~
pentan-2-of
4-(4-Bromo-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl) pentane-1,2-diol
2.55 g (6.17 mmol) of 4-(4-bromo-2-methoxyphenyl}-2-hydroxy-4-methyl-2-
(trifluoromethyl)-pentanoic acid ethyl ester (synthesized in two stages
starting from 4-
(4-bromo-2-methoxyphenyl}-2-oxopentanoic acid (WO 98/54159)) is dissolved in
102
ml of diethyl ether, mixed in portions at 0 to -5°C with 351.3 mg
(9.256 mmol) of
lithium aluminum hydride and stirred for three and one-half hours at room
temperature.
The reaction mixture is mixed drop by drop with saturated sodium bicarbonate
solution
while being cooled in an ice bath, and stirred for 15 minutes at 5°C
and then for one
hour at room temperature. The deposited precipitate is suctioned off, rewashed
with
diethyl ether, and the filtrate is concentrated by evaporation in a rotary
evaporator. The
residue is chromatographed on silica gel (mobile solvent ethyl
acetate/hexane). In
addition to 308 mg of aldehyde (see next stage), 2.025 g (88.4%) of the diol
is obtained.
4-(4-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl) pentanal
2.03 g (5.442 mmol) of 4-(4-bromo-2-methoxyphenyl~4-methyl-2-
(trifluoromethyl)-pentane-1,2-diol is oxidized to aldehyde according to Swern
as
described in Example 49. 1.839 g (91.4%) of the desired compound is isolated.
1H-
NMR (300 MHz, CDC1;): C~ = 1.39 (3H), 1.45 (3H), 2.23 (1H), 3.35 (1H), 3.58
(1H),
3.90 (3H), 6.93-7.09 (3H) 9.03 (1H).
CA 02531060 2005-12-29
Analogously to the production of Example 30, the corresponding imine is
obtained from I 81 mg of 4-amino-1H indazole and 500 mg of 4-(4-bromo-2-
methoxyphenyl}-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and further
reduced to
190 mg of the title compound with 334 mg of sodium cyanoborohydride. 'H-NMR
(CDC13), D (ppm) = 1.44 (s, 3H), 1.59 (s, 3H), 2.24 (d, 1H), 2.71 (d, 1H),
3.17 (dd, 1H),
3 .31 (dd, 1 H), 3 .87 (s, 3 H), 4.01-4.10 (m, 1 H), 5.52 (d, 1 H), 6.68 (d, 1
H), 7.05 (d, I H),
7.15 (dd, 1 H), 7.15 (t, 1 H), 7.27 (d, 1 H), 7.88 (s, 1 H)
Example 59
OH OH -N
_ H NH
N
3C
Br
4 ~4-Bromo-2-hydroxyphenyl~4-methy~lH-indazol-4-ylamino)-2-(trifluoromethyl)-
pentan-2-of
Analogously to the production of Example 3, 14 mg of the title compound is
obtained from the reaction of 90 mg of 4-(4-bromo-2-methoxyphenyl~4-methyl-1-
(1H
indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-of and 3.8 ml of boron
tribromide ( I M
in dichloromethane). ~H-NMR (CDC13), 0 (ppm) = 1.48 (s, 3H), 1.60 (s, 3H),
2.22 (d,
1 H), 2.86 (d, 1 H), 3 .23 (d, 1 H), 3 .3 9 (d, 1 H), 4.22 (bs, 1 H), 5 .6 5
(d, 1 H), 6.83 (d, 1 H),
6.85 (d, 1 H), 7.04 (dd, 1 H); 7.15 (t, 1 H), 7.23 (d, 1 H), 7.95 (s, 1 H)
Example 60
~O OH -N
H NH
N
C1
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91
4-(5-Chloro-2-methoxyphenyl)1-(1H indazol-4-ylamino)-4-methyl-2-
(trifluoromethyl)pentan-2-of
4-(5-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
2 g (6.12 mmol) of 4-(5-chloro-2-methoxyphenyl~4-methyl-2-trifluoromethyl-
pentane-1,2-diol is oxidized with 854.6 mg (6.733 mmol) of oxalyl chloride and
1.05 ml
(14.812 mmol) of DMSO according to Swern as described in Example 49. After the
working-up, 1.95 g (98.4%) of the desired aldehyde, which is incorporated in
crude form
into the next stage, is obtained. IH-NMR (300 MHz, CDCI3): 0 = 1.39 (3H), 1.49
(3H),
2.27 (1H); 3.32 (1H), 3.59 (1H), 3.88 (3H), 6.78 (1H), 7.10 (1H), 7.20 (1H),
9.09 (IH).
Analogously to Example 16, the desired product is obtained from 4-(5-chloro-2-
methoxyphenyl~2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 1 H-indazol-4-
ylamine.
'H-NMR (300 MHz, CDCI3): ~ = 1.45 (3H), 1.60 (3H), 2.25 (1H), 2.78 (1H),
3 .13 ( 1 H), 3.3 5 ( 1 H), 3 .83 (3 H), 5.60 ( 1 H), 6. 82 ( 1 H), 6.87 (2H),
7.15 ( 1 H), 7.25 ( I H),
7.40 (1H), 7.86 (1H).
Example 61
~O OH N
N I ~N
F
F
4-(6-Fluoro-2-methoxyoxyphenyl~4-methyl-1-(7-fluoro-2-methylquinazolin-5-
ylamino)-2-(trifluoromethyl)-pentan-2-of
Analogously to Example 25, 4-(6-fluoro-2-methoxyphenyl~2-hydroxy-4-methyl-
2-trifluoromethyl-pentanal is reacted with 5-amino-7-fluoro-2-
methylquinazoline to
form the desired prcduct. 'H-NMR (CDC1;); 8 = 1.~9 (d, 3H), 1.69 (d, 3H), 2.3~
(d,
~~ CA 02531060 2005-12-29
92
1 H), 2.65 (d, I H), 2.80 (s, 3H), 3.21 (dd, 1 H), 3.41 (dd, I H), 3.86 (s,
3H), 5.02 (br., 1 H),
5.89 (dd, 1 H), 6.62 (dd, 1 H), 6.67 (d, I H), 6.83 (dd, 1 H), 7.14 (ddd, I
H), 8.98 (s, 1 H).
Example 62
OH OH N
N I N
F C~
F 3
F
4-(6-Fluoro-2-hydroxyoxyphenyl?-I-(7-fluoro-2-methylquinazolin-5-ylamino~ 4-
methyl-2-(trifluoromethyl)pentan-2-of
Analogously to Example 3, 4-(6-fluoro-2-methoxyphenyl~4-methyl-1-(8-fluoro-
2-methylquinazolin-5-ylamino~2-(trifluoromethyl)-pentan-2-of is reacted to
form the
desired product. 'H-NMR (CDC13); ~ = 1.64 (d, 3H), 1.73 (d, 3H), 2.40 (d, 1H),
2.73 (d,
1 H), 2.78 (s, 3H), 3.32 (dd, 1 H), 3.49 (dd, 1 H), 3 .84 (s, 1 H), 5. I 3
(br., 1 H), 5.98 (dd,
I H), 6.48 (d, 1 H), 6.54 (dd, 1 H), 6.80 (dd, I H), 6.93 (ddd, 1 H), 8.97 (s,
1 H).
Example 63
~O OH N
N I ~N
F3C
F / F
4-(6-Fluoro-2-methoxyphenyl~4-methyl-I ~8-fluoro-2-methylquinazolin-5-
yIamino~2-
~trifluoromethyl)-pentan-2-of
Analogously to Example 25, 4-(6-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-
2-trifluoromethyl-pentanal is reacted with 5-amino-8-fluoro-2-
methylquinazoline to
form the desired product. 1H-NMR (CDC13); 8 = 1.58 (d, 3H), 1.68 (d, 3H), 2.35
(d,
1 H), 2.69 (d, 1 H), 2.90 (s, 3H), 3.04 (s, 1 H), 3.23 (dd, 1 H), 3.40 (dd, 1
H), 3.85 (s, 3H),
~~
CA 02531060 2005-12-29
93
4.56 (br., 1H), 6.05 (dd, 1H), 6.58-6.68 (m, 2H), 7.14 (ddd, 1H), 7.30 (dd,
1H), 9.17 (s,
1 H).
Example 64
OH OH N
N I ~N
\ ~I~
F3C
/ F / F
4-(6-Fluoro-2-hydroxyphenyl~-4-methyl-1-(8-fluoro-2-methylquinazolin-5-
ylamino)-2-
(trifluoromethyl)-pentan-2-of
Analogously to Example 3, 4-(6-fluoro-2-methoxyphenyl~4-methyl-1-(8-fluoro-
2-methylquinazolin-5-ylamino)-2-(trifluoromethyl)-pentan-2-of is reacted to
form the
desired product. 1H-NMR (CDCl3); 8 = 1.62 (d, 3H), 1.74 (d, 3H), 2.26 (d, 1H),
2.85 (d,
1 H), 2.63 (s, 1 H), 2.89 (s, 3H), 3.32 (dd, 1 H), 3.44 (dd, 1 H), 4.64 (br.,
1 H), 6.10 (dd,
1 H), 6.46-6.5 8 (m, 2H), 6.93 (ddd, 1 H), 7.31 (dd, 1 H), 9.22 (s, 1 H).
Example 65
~O OH -N
F \ N NH
F3C
F
~3,5-Difluoro-2-methoxyphenyl~-4-methyl-1-(1H indazol-4-ylamino)-2-
(trifluoromethyl)-pentan-2-of
4-(3, 5-Difluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-
(trifluoromethyl)pentanal
Analogously to the described method of synthesis of 4-(benzo[1,3]dioxol-4-yl)-
2-hydroxy-4-methyl-2-trifluoromethyl-pentanal, 90 mg of the title compound is
obtained
., CA 02531060 2005-12-29
94
as a colorless oil. 'H-NMR (CDC13), D (ppm) = 1.39 (s, 3H), I .45 (s, 3H),
2.33 (d, 1 H),
3.18 (d, 1 H), 3.59 (s, 1 H), 3.98 (d, 3 H), 6.15 (dm, 1 H), 6.72 - 6.82 (m, 1
H), 9.24 (s, 1 H)
Analogously to the production of Example 30, the corresponding imine is
obtained from 35 mg of 4-amino-1H indazole and 85 mg of 4-(3,5-difluoro-2-
methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and further
reduced to
43 mg of the title compound with 99 mg of sodium cyanoborohydride. IH-NMR
(CDCl3), ~ (ppm) = 1.45 (s, 1 H), 1.59 (s, 3H), 2.26 (d, 1 H), 2.71 (d, 1 H),
3.22 (d, 1 H),
3.34 (d, 1H), 4.01 (d, 3H), 5.81 (d, 1H), 6.78 (ddd, 1H), 6.88 (d, 1H), 6.93
(ddd, 1H),
7.15 (t, 1 H), 7.90 (s, 1 H)
Example 66
OH OH -N
F ~ N NH
FsC ~ /
F
4~3 5-Difluoro-2-hydroxyphenyl~-4-methyl-1-(1H indazol-4-ylamino)-2-
~trifluoromethvl)-pentan-2-of
Analogously to the production of Example 3, 14 mg of the title compound is
obtained from the reaction of 37 mg of 4-(3,5-difluoro-2-methoxyphenyl~4-
methyl-1-
( 1 H indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-of and 1.3 ml of boron
tribromide
(1 M in dichloromethane). 1H-NMR (CDCl3), D (ppm) = 1.50 (s, 3H), 1.62 (s,
3H), 2.30
(d, 1 H), 2.81 (d, 1 H), 3.27 (d, 1 H), 3.39 (d, I H), 5.73 (d, 1 H), 6.78
(dt, 1 H), 6.87 (d,
1 H), 6.94 (dt, I H), 7. I 2 (t, 1 H), 7.89 (s, 1 H)
CA 02531060 2005-12-29
Example 67
O OH -N
NH
N
F3C
4-(2,3-Dihydrobenzofuranyl~4-methyl-1-(1H indazol-4-ylamino)-2-
(trifluoromethyl)-
pentan-2-of
Analogously to the production of Example 30, the corresponding imine is
obtained from 32 mg of 4-amino-1H indazole and 75 mg of 4-(2,3-
dihydrobenzofuranyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and
further
reduced with 134 mg of sodium cyanoborohydride to 64 mg of the title compound.
'H-
NMR (CDC13), 0 (ppm) = 1.45 (s, 3H), 1.57 (s, 3H), 2.31 (d, 1H), 2.64 (d, 1H),
3.05-
3.19 (m; 2H), 3.21 (d, 1 H), 3.39 (d, 1 H), 4.48-4.63 (m, 2H), 5.76 (d, 1 H),
6.85 (d, 1 H),
6.92 (t, 1H), 7.05-7.23 (m, 3H), 7.85 (s, 1H)
Example 68
~O OH -N
NH
N
F3C
F
F
4-(4,5-Difluoro-2-methoxyphenyl~4-methyl-1-(1H indazol-4 ylamino)-2-
(trifluoromethyl)-pentan-2-of
4-(4, 5-Difluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-
(trifluoromethyl)pentanal
Analogously to the described method of synthesis of 4-(benzo[1,3]dioxol-4-yl)-
2-hydroxy-4-methyl-2-trifluoromethyl-pentanal, 695 mg of the title compound is
obtained as a colorless oil. 'H-NMR (CDCI;), C (ppm) = 1.38 (s, 3H), 1.44 (s,
3H), 2.23
., CA 02531060 2005-12-29
96
(d, 1 H), 3.29 (d, 1 H), 3.56 (s, I H), 3.83 (s, 3H), 6.76 (dd, 1 H), 6.96
(dd, 1 H), 9.08 (s,
1 H)
Analogously to the production of Example 30, the corresponding imine is
obtained from 82 mg of 4-amino-1H indazole and 200 mg of 4-(4,5-difluoro-2-
methoxyphenyl}-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and further
reduced
with 319 mg of sodium cyanoborohydride to 155 mg of the title compound. 'H-NMR
(CDC13), 0 (ppm) = I .44 (s, 3H), 1.58 (s, 3H), 2.24 (d, I H), 2.71 (d, 1 H),
3.19 (d, I H),
3 .32 (bd, 1 H), 3.82 (s, 3H), 5.63 (d, 1 H), 6.70 (dd, 1 H), 6.87 (d, 1 H),
7. I 3 (t, 1 H), 7.24
(dd, 1 H), 7.87 (s, I H)
Example 69
~O OH -N
H NH
N
y v
F3C
CI
F
4-(4-Chloro-5-fluoro-2-methox~phenyl~-4-methyl-1~1H indazol-4-ylamino~2-
~rifluoromethyl~-pentan-2-of
4-(4-Chloro-S fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-
(trifluoromethyl)pentanal
Analogously to the described method of synthesis of 4-(benzo[1,3]dioxol-4-yI)-
2-hydroxy-4-methyl-2-trifluoromethyl-pentanol, 1.55 g of 4-(4-chloro-5-fluoro-
2-
methoxyphenyl~2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is obtained as
fraction
1 and 1.32 g of 4-(4-chloro-5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-
(trifluoromethyl)pentanol is obtained as fraction 2.
Fraction I: ~H-NMR (CDC13), 0 (ppm) = 1.36 (s, 3H), 1.43 (s, 3H), 2.28 (d,
1H),
3.27 (d, I H), 3.57 (s, 1 H), 3.85 (s, 3H), 6.84 (d, 1 H), 6.93 (d, 1 H), 9. I
1 (s, I H)
~~
CA 02531060 2005-12-29
97
Fraction 2: IH-NMR (CDC13), 0 (ppm) = 1.4 (s, 3H), 1.48 (s, 3H), 2.23 (d, IH),
2.47 (d, 1 H), 2.91 (s, 1 H), 3.3 5 (dd, 1 H), 3. S dd, 1 H), 3.83 (s, 3H),
6.87 (d, 1 H), 7. I (d,
1 H)
Analogously to the production of Example 30, the corresponding imine is
obtained from 78 mg of 4-amino-IH indazole and 200 mg of 4-(4-chloro-5-fluoro-
2-
methoxyphenyl}-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and further
reduced to
116 mg of the title compound with 280 mg of sodium cyanoborohydride. IH-NMR
(CDCl3), D (ppm) = 1.43 (s, 3H), 1.58 (s, 3H), 2.23 (d, 1H), 2.71 (d, 1H),
3.19 (d, 1H),
3.31 (bd, 1 H), 3.83 (s, 3H), 5.55 (d, 1 H), 6.85 (s, 1 H), 6.87 (d, 1 H), 7.
I 4 (t, 1 H), 7.21 (d,
1H), 7.88 (s, 1H)
Example 70
OH OH -N
H NH
N
FsC
CI
F
4-(4-Chloro-5-fluoro-2-hydroxyphenyl~-4-methyl-1-(1H indazol-4-ylamino,-2-
(trifluoromethyl),pentan-2-of
Analogously to the production of Example 3, 30 mg of the title compound is
obtained from the reaction of 100 mg of 4-(4-chloro-5-fluoro-2-methoxyphenyl~4-
methyl-1-(1H indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-of and 3.3 ml of
boron
tribromide (1 M in dichloromethane). Flash point = 171-173°C
,. CA 02531060 2005-12-29
98
Example 71
N
~O OH
~N
F3C ~ /
CI / F
F
4-(4-Chloro-5-fluoro-2-methoxyoxyphe ~l)-4-methyl-1-(8-fluoro-2-
methylguinazolin-
S-ylamino~2-(trifluoromethyl)-pentan-2-of
Analogously to Example 25, 4-(4-chloro-5-fluoro-2methoxyphenyl~2-hydroxy-
4-methyl-2-trifluoromethyl-pentanal is reacted with 5-amino-8-fluoro-2-
methylquinazoline to form the desired product. 'H-NMR (CDC13); b = 1.45 (s,
3H),
1.56 (s, 3H), 2.30 (d, 1 H), 2.73 (d, I H), 2.90 (s, 3H), 2.99 (s, 1 H), 3. I
4 (dd, 1 H), 3.22
(dd, I H), 3.83 (s, 3 H), 4.48 (br., 1 H), 5.88 (dd, 1 H), 6.79 (d, 1 H), 7. I
7 (d, I H), 7.31 (dd,
1 H), 9.20 (s, 1 H).
Example 72
N
OH
N ~ ~N
F3C
4-Methyl-1-~2-methylguinazolin-5-ylamino)- 4-phenyl-2-(trifluoromethyl)-pentan-
2-of
2-Hydroxy-4-methyl-4 phenyl-2-trifluoromethyl pentanal
10.4 g of 4-methyl-2-oxo-4-phenylpentanoic acid (W098/54159) in 250 ml of
dimethylformamide is mixed at -5°C with 4.1 ml of thionyl chloride and
after I 5
minutes with 4 ml of methanol. After 15 hours at room temperature, the batch
is diluted
with water and extracted with ethyl acetate. The organic extracts are washed
with water,
dried (Na2S04) and concentrated by evaporation, whereby 9.3 g of 4-methyl-2-
oxo-4-
phenylpentanoic acid-methyl ester is obtained. The latter are mixed in 558 ml
of DMF
~~
CA 02531060 2005-12-29
99
at -5°C with 15.5 ml (104.63 mmol) of (trifluoromethyl)trimethylsilane
and 20.5 g
(63.28 mmol) of cesium carbonate and stirred for 16 hours at room temperature.
Water
is added, extracted with ethyl acetate, the organic phase is washed with water
and dried
(NaZS04). The intermediate product that is concentrated by evaporation is
taken up in
200 ml of THF, and 50 ml of a 1 M solution of tetrabutylammonium fluoride in
THF is
added. It is stirred for 2 hours, water is added, extracted with ethyl
acetate, the organic
phase is washed with water and dried (Na2S04). After chromatography on silica
gel
with hexane-ethyl acetate (0-30%), 8.35 g of 2-hydroxy-4-methyl-4-phenyl-2-
(trifluoromethyl)pentanoic acid=methyl ester is obtained. The ester (8.3 g,
28.59 mmol)
is dissolved in I 80 ml of THF, and over a period of 2.5 hours, 1.52 g (36.20
mmol) of
lithium aluminum hydride is added in small portions. After conversion is
completed, 5
ml of ethyl acetate is added in drops, and after another 10 minutes, 10 ml of
water is
carefully added. The precipitate that is formed is filtered out and washed
carefully with
ethyl acetate. After chromatography on silica gel with hexane-ethyl acetate (0-
35%),
5.40 g of 4-methyl-4-phenyl-2-(trifluoromethyl)pentane-1,2-diol is obtained.
5.7 ml
(40.3 mmol) of triethylamine and, in portions over 20 minutes, 5 g of pyridine
S03
complex are added to 2.5 g (9.53 mmol) of dioI in 75 ml of dichloromethane and
28 ml
of DMSO. It is stirred over 2 hours, and 40 ml of saturated ammonium chloride
solution
is added: The mixture is stirred for another 15 minutes, the phases are
separated, and it
is extracted with dichloromethane. It is washed with water and dried on sodium
sulfate.
The solvent is removed in a vacuum, and 3 g of product is obtained. 'H-NMR
(CDCl3):
~ = 1.34 (s, 3H), 1.44 (s, 3H), 2.34 (d, 2H), 2.66 (d, 1 H), 3.64 (s, 1 H),
7.03-7.41 (m,
4H), 8.90 (s, 1 H).
CA 02531060 2005-12-29
100
Analogously to Example 25, 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-
pentanal is reacted with S-amino-2-methylquinazoline to form the desired
product.
'H-NMR (CDC13); b = 1.46 (s, 3H), 1.59 (s, 3H), 2.30 (d, IH), 2.3? (d, IH),
2,84
(s, 3 H), 3 . I 0 (dd, 1 H), 3.27 (dd, 1 H), 4.70 (br., 1 H), 6.12 (d, I H),
7.26 (d, 1 H), 7.28 (t,
1 H), 7.39 (t, 2H), 7.48 (d, 2H), 7.5 8 (t, 1 H), 9.22 (s, 1 H).
Example 73
F ON H S
N N
F C~
3
F
4 X2,5-Difluorophenyl)-4-methyl-I -(2-methyl-benzothiazol-7-ylamino)-2-
(trifluoromethyl~pentan-2-of
110 mg (0.66 mmol) of 2-methyl-benzothiazol-7-ylamine in 1 ml of acetic acid
is
mixed with I50 mg (0.53 mmol) of 4-(2,5-difluoro-phenyl)-2-hydroxy-4-methyl-2-
trifluoromethyl-pentanal, dissolved in I 0 ml of dichloroethane, refluxed for
4 hours on a
molecular sieve (4 A) and stirred for another 16 hours at room temperature.
The mixture
was dispersed between water and dichloromethane, extracted with
dichloromethane, and
the combined organic phases were washed (saturated NaCI solution), dried
(NaZS04)
and concentrated by evaporation. The intermediate product (97 mg) obtained
after
chromatography on silica gel with hexane/ethyl acetate (20°I°)
is taken up in acetic acid,
mixed with I 0 mg of NaBH4, and the mixture is stirred for 4 hours at room
temperature.
It is dispersed between water and dichloromethane, extracted, the combined
organic
phases (saturated NaCI solution) are washed. dried (Na2S04) and concentrated
by
evaporation. 90 mg of product, which can be crystallized from hexane/diethyl
ether, is
~~
CA 02531060 2005-12-29
101
obtained. MS (CI): 445 (M+H);'H-NMR (CDC13): 8 = 1.61 (s, br, 6H), 2.26 (d,
1H),
2.50 (d, 1 H), 2.83 (s, 3H), 3.15 (s, 1 H), 3.27 (d, br, 2H), 3.49 (m, I H),
6.02 (d, 1 H),
6.82-7.02 (m, 2H), 7.10-7.25 (m, 2H), 7.45 (dd, 1 H).
Example 74
CI OH H S
N N
W
FC
4-(2-Chlorophenyl)-4-methyl-1-(2-methyl-benzothiazol-7-ylamino)-
2~trifluoromethyl)-
pentan-2-of
Analogously to Example 5, the desired product is obtained from 7-amino-2-
methylbenzothiazole (Libeer et al. Bull. Soc. Chim. Belg.; 1971; 80; 43-47)
and 4-(2-
chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal. 'H-NMR (300 MHz,
CDC13): O = 1.60 (3H), 1.73 (3H), 2.20 (1H), 2.80 (3H), 3.09 (1H), 3.18 (1H),
3.23
(4H), 5.78 ( 1 H), 7.13 ( 1 H), 7.20-7.3 5 (2H), 7.3 7-7.45 (2H), 7.60 ( I H).
Example 75
~O OH -N
H NH
N
4-(2-Methoxyphenyl~4-methyl-1-(IH indazol-4-ylamino~2-(trifluoromethyl)-Qentan-
2-
of
4-(2-Methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal
Analogously to the described method of synthesis of 4-(benzo[1,3)dioxol-4-yl)-
2-hydroxy-4-methyl-2-trifluoromethyl-pentanal (Example 32), 7.9 mg of the
title
~~ CA 02531060 2005-12-29
102
compound is obtained as a colorless oil starting from 28.6 g of 4-(2-
methoxyphenyl~4-
methyl-2-oxo-pentanoic acid ethyl ester (WO 98/54159). 1H-NMR (CDC13), D (ppm)
_
1.40 (s, 3H), 1.47 (s, 3H), 2.2 (d, 1H), 3.46 (d, 1H), 3.60 (s, 1H), 3.88 (s,
3H), 6.83
6.94 (m, 2H), 7.13 (dd, 1 H), 7.24 (dt, 1 H), 8.94 (s, 1 H)
Analogously to the production of Example 30, the corresponding imine is
obtained from 139 mg of 4-amino-1H indazole and 300 mg of 4-(2-methoxyphenyl~2-
hydroxy-4-methyl-2-(trifluoromethyl)penfanal and further reduced with 627 mg
of
sodium cyanoborohydride to 310 mg of the title compound.
1H-NMR (CDC13); 0 (ppm) = 1.48 (s, 3H), 1.60 (s, 3H), 2.33 (d, 1 H), 2.77 (d,
1 H), 3.17 (dd, 1 H), 3.36 (dd, 1 H), 3.88 (s, 3H), 3.98-4.08 (m, 1 H), 5.66
(d, 1 H), 6.83 (d,
1 H), 6.94 (dd, 1 H), 7.04 (dt, 1 H), 7.09 (t, 1 H), 7.32 (dt, 1 H), 7.43 (dd,
1 H), 7.86 (s, 1 H)
Example 76
OH OH -N
NH
N
4-(2-Hydroxyphenyl~4-methyl-1-(1H indazol-4-ylamino)-2-(trifluoromethyl)-
pentan-2-
of
Analogously to the production of Example 3, 15 mg of the title compound is
obtained from the reaction of 20 mg of 4-(2-methoxyphenyl~4-methyl-1-(1H
indazol-4-
ylamino)-2-(trifluoromethyl)-pentan-2-of and 0.75 ml of boron tribromide (1 M
in
dichloromethane).
~H-NMR (CDC13), C (ppm) = 1.52 (s, 3H), 1.62 (s, 3H), 2.32 (d, 1H), 2.90 (d,
1 H), 3.23 (d, 1 H), 3.43 (dd, 1 H), 4.22 (bs, 1 H), 5.75 (d, I H), 6. 72 (d,
I H), 6.79 (d, I H),
6.97 (t, 1 H), 7.04-7. I 6 (m, 2H), 7.39 (d, 1 H), 7.93 (s, 1 H)
.. CA 02531060 2005-12-29
103
Examples 77 and 78
~)-~2-Hydroxyphenyl)-4-methy~lH indazol-4-ylamino)-2-(trifluoromethyl)-
pentan-2-of and (+)-4~2-Hydroxyphenyl~-4-methyl-1-~ I H-indazol-4-ylamino)-2-
(trifluoromethy 1)-pentan-2-of
Separation of (+/-)-4-(2-Hydroxyphenyl~4-methyl-1-(1H indazol-4-ylamino)-2-
(trifluoromethyl)-pentan-2-of
The enantiomer mixture is separated by chromatography on chiral carrier
material (CHIRALPAK AD~, DAICEL Company) with hexane/ethanol (70 : 30, vvv).
Thus obtained are
Enantiomer A: MS (ei) M+ = 392 and
Enantiomer B. MS (ei) M+= 392
Example 79
OH rN
H NH
N
vp
F3C I /
CI /
4~4-Chlorophenyl)-4-methyl-1-(1H indazol-4-ylamino)-2-(trifluoromethyl)-pentan-
2-al
2-(4-Chlorophenyl)-2-methylpropanal
g of 4-chlorobenzyl cyanide and 14.3 ml of methyl iodide in 140 ml DMF are
mixed at 0°C in portions with sodium hydride (60°I° in
oil). It is stirred overnight and
then mixed with water and ethyl acetate. The phases are separated, and the
aqueous
phase is extracted with ethyl acetate.
~
. CA 02531060 2005-12-29
1~4
It is thoroughly extracted with water, washed with brine, dried with sodium
sulfate and concentrated by evaporation in a vacuum. After chromatography on
silica
gel (hexane/ethyl acetate 95:5), 11.73 g of 2-(4-chlorophenyl)-2-
methylpropionitrile is
obtained as a colorless oil. The latter is slowly mixed in toluene at -
78°C with 55.4 ml
of diisobutylaluminum hydride solution (20% in toluene), and after 4 hours at -
78°C, 50
ml of ethyl acetate was added in drops. It is stirred overnight while being
heated to
room temperature, and water is added. After filtration through diatomaceous
earth, the
phases are separated, and the aqueous phase is extracted with ethyl acetate.
It is washed
with water and brine, dried with sodium sulfate and concentrated by
evaporation in a
vacuum. After chromatography on silica gel (hexane/ethyl acetate 95:5), 10.2 g
of 2-(4-
chlorophenyl)-2-methylpropanal is obtained as a colorless oil. IH-NMR (CDC13),
~
(ppm) = I .46 (s, 6H), 7.20 (d, I H), 7.29-7.43 (m, 3H), 9.48 (s, 1 H)
4-(4-Chlorophenyl)-4-methyl-2-oxo-valeric acid
A solution of I 5.04 g of 2-diethylphosphono-2-ethoxyacetic acid-ethyl ester
in
50 ml of tetrahydrofuran is mixed with 30 ml of a 2 M solution of lithium
diisopropylamide in tetrahydrofuran-heptane-toluene while being cooled with
ice within
20 minutes and stirred for I S minutes at 0°C. Within 30 minutes, a
solution of 10.2 g of
2-(4-chlorophenyl)-2-methylpropanal in 50 ml of tetrahydrofuran at 0°C
is added
thereto. After 20 hours at room temperature, 2N sulfuric acid is added,
extracted with
ethyl acetate, dried (Na2S04) and concentrated by evaporation. The crude
product is
saponified with 200 ml of 2 M sodium hydroxide solution/400 ml of ethanol.
13.8 g of
acid, which is refluxed for 3 hours with 300 ml of 2N sulfuric acid and 100 ml
of glacial
acetic acid while being stirred vigorously, is obtained. After extraction with
ethyl
CA 02531060 2005-12-29
105
acetate and washing with water, 10.9 g of 4-(4-chlorophenyl)-4-methyl-2-oxo-
valeric
acid is obtained as a red oil.
'H-NMR (CDC13), D (ppm) = 1.47 (s, 6H), 3.28 (s, 2H), 7.28 (m, 4H), 7.73 (bs,
1 H)
4-(4-Chlorophenyl)-2-hydro~.y-4-methyl-2-(trifluoromethyl) pentan-I-al
Analogously to the synthesis of 4-(3-chloro-2-methoxy-phenyl)-2-hydroxy-4-
methyl-2-trifluoromethyl-pentanal (Example 45), 4.22 g of 4-(4-chlorophenyl)-2-
hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-of is obtained as a colorless oil
by
esterification of 10.9 g of 4-(4-chlorophenyl)-4-methyl-2-oxo-valeric acid in
ethanol/sulfuric acid, reaction of the product with
(trifluoromethyl)trimethylsilane and
tetrabutylammonium fluoride and reduction of the formed hydroxy ester
with.lithium
aluminum hydride.
1H-NMR (CDCl3), 0 (ppm) = 1.39 (s, 3H), 1.49 (s, 3H), 2.07 (d, 1H), 2.19 (d,
1 H), 2.83 (bs, 1 H), 3.27 (d, 1 H), 3.41 (d, 1 H), 7.26-7.3 8 (m, 4H).
6.8 ml (33.3 mmol) of triethylamine and, in portions over 20 minutes, 1.5 g of
pyridine S03 complex are added to 2 g (6.7 mmol) of diol in 50 ml of
dichloromethane
and 22 ml of DMSO. It is stirred over 5 hours, and 40 ml of saturated ammonium
chloride solution is added. The mixture is stirred for another 15 minutes, the
phases are
separated, and it is extracted with dichloromethane. It is washed with water
and dried on
sodium sulfate. The solvent is removed in a vacuum, and after chromatography
on silica
gel (hexane/ethyl acetate 0-30%), 1.27 g of product is obtained. 'H-NMR
(CDC13): 8 =
1.34 (s, 3H), 1.44 (s, 3H), 2.34 (d, 2H), 2.66 (d, 1H), 3.64 (s, 1H), 7.23-
7.31 (m, 4H),
8.90 (s, 1 H). Analogously to the production of Example 30, the corresponding
imine is
obtained from 158 mg of 4-amino-1H indazole and 350 mg of 4-(4-chlorophenyl)-2-
", '~ CA 02531060 2005-12-29
106
hydroxy-4-methyl-2-(trifluoromethyl)pentanal, and 100 mg of the imine was
further
reduced with 216 mg of sodium cyanoborohydride to 68 mg of the title compound.
~H-
NMR (CDCl3), 0 (ppm) = 1.42 (s, 3H), 1.59 (s, 3H), 2.19 (d, 1H), 2.31 (d, 1H),
3.11 (d,
1 H), 3.22 (d, 1 H), 5.67 (d, 1 H), 6.90 (d, 1 H), 7.18 (t, 1 H), 7.3 5 (d,
2H), 7.42 (d, 2H),
7.89 (s, 1 H)
Example 80
N
OH
N I ~N
F3C
CI - ~ ~ F
4-(4-Chlorophenyl)-4-methyl-1-(8-fluoro-2-methylquinazolin-5-ylamino)-2-
(trifluoromethyl)-pentan-2-of
Analogously to Example 25, 4-(4-chlorophenyl)-2-hydroxy-4-methyl-2-
trifluoromethyl-pentanal is reacted with 5-amino-8-fluoro-2-methylquinazoline
to form
the desired product.
~H-NMR (CDC13); 8 = 1.45 (s, 3H), 1.58 (s, 3H), 2.29 (d, 1H), 2.36 (d, 1H),
2.79
(br., 1 H), 2.90 (s, 3 H), 3.05 (dd, 1 H), 3.20 (dd, 1 H), 4.37 (br., 1 H),
5.98 (dd, 1 H), 7.29
(dd, 1 H), 7.38 (t, 2H), 7.49 (d, 2H), 9.21 (s; 1 H).
Example 81
O
~O OH H
_ N NH
F C~
F
CA 02531060 2005-12-29
107
4-{ [4-(5-Fluoro-2-methoxyphenyl~2-hydroxy-4-methyl-2-(trifluoromethyl)-
pentyl]amino }-1,3-dihydroindol-2-one
Dimethyl-2-(2, 6-dinitrophenyl)-malonate
42.9 g (311.03 mmol) of dimethylmalonate is dissolved in 300 ml of N,N-
dimethylformamide and mixed in portions with 35.15 g (296.22 mmol) of
potassium-
tent. butylate. After the tert-butanol that was produced was distilled off,
the reaction
mixture is cooled to 20°C. 30 g (148.11 mmol) of 2,6-dichlorbenzene is
quickly added
in portions to the mixture. After three hours of stirnng at 90°C, it is
stirred overnight at
room temperature. The reaction mixture is added to 800 ml of 1 % NaOH solution
(cooled with ice) and extracted three times with methyl-tert. butyl ether. The
combined
ether phases are discarded after TLC monitoring. The aqueous phase is
carefully
acidified while being cooled in an ice bath with concentrated nitric acid (w =
65%).
After being extracted six times with methyl-tert-butyl ether, conventional
working-up of
the combined organic extracts (water, brine, drying, filtering and spinning-
off of the
solvent) yields a residue that is chromatographed on silica gel (mobile
solvent ethyl
acetatelhexane). 12.09 g (27:09%) of the desired compound is isolated.
Methyl-(2, 6-Dinitrophenyl)-acetate
10.08 g (33.8 mmol) of dimethyl-2-(2,6-dinitrophenyl)-malonate is mixed in 54
ml of glacial acetic acid with 2.7 ml of perchloric acid and refluxed at
125°C. In this
case, the ethyl acetate that is produced was distilled off. After 90 minutes,
the reaction
is brought to a halt since starting material is no longer present according to
TLC
monitoring. The reaction mixture is poured into ice water and extracted three
times with
ethyl acetate. The combined organic extracts are shaken with 5% sodium
bicarbonate
~~ CA 02531060 2005-12-29
108
solution, with water and with brine. After the organic phase is dried, the
desiccant is
filtered off and the solvent is spun off, a residue that is chromatographed on
silica gel
(mobile solvent ethyl acetate/hexane) remains. 4.69 g of the (2,6-
dinitrophenyl)-acetic
acid is isolated which then is esterified with methanol (16 ml) and
concentrated sulfuric
acid (0.4 ml). To this end, the acid and the reagents are refluxed for seven
hours. The
methanol is spun off, and the residue is worked up in the usual way. After
chromatography on silica gel (mobile solvent ethyl acetate/hexane), 4.43 g
(89%) of the
desired ester is obtained.
4-Amino-l, 3-dihydroindol-2-one
4.43 g (18.45 mmol) of methyl-(2,6-dinitrophenyl)-acetate is added to 38.8 ml
of
glacial acetic acid and I 1 ml of water and mixed with 3.75 g of iron powder
and stirred
for four more hours. In this case, heating to 40 to 60°C takes place.
The reaction
mixture is added to ice water, mixed with ethyl acetate and stirred vigorously
for ten
minutes. The mixture is filtered with a glass-fiber filter, the organic phase
is separated,
and the aqueous phase is extracted twice more with ethyl acetate. The combined
organic
extracts are washed with brine, dried, and the solvent is spun off after the
desiccant is
filtered off. The residue is chromatographed on silica gel (mobile solvent
methanol/dichloromethane). 2.38 g of the 4-nitro-indol-2-one is isolated. The
nitro
compound, however, is mixed in glacial acetic acid/water with 2.7 g of iron
powder and
passes through the above-described cycle another time. I .63 g of the desired
amine is
now isolated.
Analogously to Example 27, 4-(5-fluoro-2-methoxyphenyl~2-hydroxy-2-
trifluoromethyl-pentanal is reacted with 4-amino-1,3-dihydroindol-I-one to
form the
desired product.
~~ CA 02531060 2005-12-29
109
'H-NMR (CDC13): 8 = 1.44 (s, 3H), 1.58 (s, 3H), 2.23 (d, 1H), 2.70 (d, 1H),
3.04
(s, 1 H), 3.09 (d, 1 H), 3.19 (s, 2H), 3.21 (d, 1 H), 3.85 (s, 3H), 5.71 (d, 1
H), 6.32 (d, 1 H),
6.84 (dd, 1 H), 6.92-7.01 (m, 2H), 7.14 (dd, 1 H), 7.78 (s, br, 1 H)
Example 82
O
~O OH
N NH
up w
FsC ~ /
CI
F
4-~,L4-~5-Chloro-2-methoxyphenyl~-2-hydroxy-4-methyl-2-
ftrifluorometh~~pentyl~amino -1,3-dihydro-6-fluoroindol-2-one
180 mg (0.60 mmol) of 4-(4-chloro-2-methoxyphenyl~2-hydroxy-4-methyl-2-
trifluoromethyl-pentanal and 100 mg (0.60 mmol) of 4-amino-6-fluoroindol-2-one
are
introduced into 1 S ml of dichloroethane and 3 ml of acetic acid, about 100 mg
of
powdered molecular sieve (4 ~) is added, and the mixture is refluxed for 6
hours. After
cooling, it is filtered off, the filtrate is dispersed between dichloromethane
and saturated
NaHC03 solution, and the phases are separated. The aqueous phase is extracted
several
times with dichloromethane, the combined organic phases are washed with water
and
saturated NaCI solution, and dried with Na2S04. The solvent is removed, and
the crude
product is chromatographed on silica gel (eluant hexane/ethyl acetate 20-
100%). 40 mg
of imine, which is taken up in 5 ml of methanol, is obtained, mixed with a few
drops of
acetic acid and about 20 mg of sodium cyanoborohydride and stirred for 2 hours
at room
temperature. The mixing is brought to a halt by adding saturated NaHC03
solution. It is
extracted with dichloromethane. washed with saturated NaCI solution and dried
with
NaZSO.~. Chromatographic purification of the crude product (silica gel, eluant
. " ' ' CA 02531060 2005-12-29
110
hexane/ethyl acetate 20-100%) yields 4 mg of the desired product. MS (ESI):
475/477
(M+H); 'H-NMR (CDC13): 8 = 1.46 (s, 3H), 1.57 (s, 3H), 2.29 (d, 1 H), 2.60 (d,
1 H),
2.78 (s, I H), 2.99-3.21 (m, 4H), 3.47 (t, br, 1 H), 3.88 (s, 3H), 5.52 (dd, 1
H), 6.08 (dd,
1 H), 6.89 (d, 1 H), 7.00 (dd, 1 H), 7.32 (dd, 1 H), 7.68 (s, br, 1 H).
Examples 83 - 92
General Operating Instructions for the Production of N-Methyl-benzimidazole
Derivatives:
0.70 mmol of the substituted pentanal and 1.05 mmol of the amine component
(4-methyl-1H benzimidazol-4-ylamine, cf., e.g., V. Milata, D. Ilavsky, J.
Saloo,Bull.
Soc. Chim. Belg. 1997, 106, 731-732; 3-methyl-3H-benzimidazol-4-ylamine, cf.,
e.g.,
M. Kamel, M. I. Ali, M. M. Kamel, Tetrahedron 1966, 22, 3351-3354 ) are
introduced
with about 80 mg of molecular sieve (4 ~, powdered) into 10 ml of
dichloroethane and 1
ml of acetic acid and refluxed for about 7 hours. After the cooling, the
mixture is mixed
with phosphate buffer solution (1 M, pH 7) and dichloromethane, filtered off,
and the
phases are separated. The aqueous phase is extracted several times with
dichloromethane, the combined organic phases are washed with water and
saturated
NaCI solution and dried with Na2S04. The solvents are removed in a rotary
evaporator,
and the intermediate product is purified by chromatography on silica gel
(eluant
hexane/ethyl acetate). The imine that is formed is further taken up in a
little methanol,
some drops of acetic acid are added, and NaCNBH3 (2-3 equivalents) is added.
The
solution is stirred for 3 hours at room temperature, the reaction is completed
by adding
phosphate buffer solution (1 M, pH 7) and extracted with dichloromethane. The
combined organic phases are washed with water and saturated NaCI solution and
dried
with NaZS04. The crude product is filtered on silica gel with hexane/ethyl
acetate.
CA 02531060 2005-12-29
Example Name Structure Yield MS H-NMR (300 MHz)
1,1,1-Trifluoro-4- 'O OH H N=~ 38% 456/458 1.36 (s, 3H), 1.53 (s, 3H),
N \ N,
(4-chloro-2- c~ I ~ F,c I ~ +
(M H, 2.01 (d, 1 H), 2.86 (d, 1 H),
methoxy-phenyl)- CI) 2.84-2.93 (m, 1 H), 3.02-
4-methyl-2-(4- 3.10 (m, IH), 3.75 (s, 3H),
methyl-1H- 3.84 (s, 3H), 5.01 (t, br,
benzimidazol-4- 1 H), 5.76 (d, 1 H), 6.22 (s,
ylamine) 1 H), 6.74 (d, 1 H), 6.85-6.99
(m, 3H), 7.25 (d, 1H), 7.99
(s, 1 H). (db-DMSO)
1,1,1-Trifluoro-4- 'o off ~ N-~ 3 8% 1.42 (s, 3H), I .64 (s, 3 H),
H N
N
(4-chloro-2- c~ I ~ F3c I ~ 2.00 (d, 1 H), 2.77 (d, 1 H),
methoxy-phenyl)- 3.00 (d, 1 H), 3. I 3 (d, 1 H),
4-methyl-2-(3- 3.81 (s, 3H), 4.11 (s, 3H),
methyl-3H- 5.70 (d, 1 H), 6.84-7.07 (m;
benzimidazol-4- 4H), 7.33 (d, IH), 8.04 (s,
ylamine) 1 H). (CD30D)
1,1,1-Trifluoro-4- 'o OH H N=~ 28% 440 1.43 (s, 3H), 1.62 (s, 3H),
N \ N
(5-fluoro-2- I ~ F,c I ~ (M+H, 2.08 (d, 1 H), 3.01 d, 1 H
(
F
methoxy-phenyl)- ESI) 3.07 (d, 1 H), 3.19 (d, I H),
4-methyl-2-(4- 3.82 (s, 3H), 3.87 (s, 3H),
methyl-1H- 5.79 (d, 1H), 6.73-6.88 (m,
benzimidazol-4- 3H), 7.03-7.13 (m, 2H),
ylamine) I 8. I 1 (s, I H). (CD30D)
i
CA 02531060 2005-12-29
112
Example Name Structure YieldMS 'H-NMR (300 MHz)
1,1,1-Trifluoro-4-~o off ~N-~ 18% 1.56 (s, 3H), 1.70
(s, 3H),
H
5-fluoro-2- N
2
( I 28 (d
F 1 H)
c I 3
01 (d
1 H
~ .
, ,
~ ,
.
,
),
methoxy-phenyl)-F 3.06 (d, 1 H), 3.25
(d, 1 H),
4-methyl-2-(3- 3.94 (s, 3H), 4.14
(s, 3H),
methyl-3H- 5.94 (d, 1 H), 6.88
(dd, 1 H),
benzimidazol-4- 6.97-7.05 (m, 1 H),
7.12 (dd,
ylamine) 1 H), 7.22 (dd, 1
H), 7.28 (d,
1 H), 7.82 (s, 1
H). (CDCI3)
1,1,1-Trifluoro-4-F OH H N N_ 40% 427 1.42 (s, 3H), 1.50
N ~ (s, 3H),
2 5-difluoro- ~ ~ F,c I ~ M EI 2.21 d 1 H 2.45 d
( ~ ( ~ ) 1 H
( ~ )~ (
F
phenyl)-4-methyl- 3.21 (m, 2H), 3.76
(s, 3H),
2-(4-methyl-1 5.25 (t, br, 1 H),
H- 5.98 (d,
benzimidazol-4- 1 H), 6.55 (s, 1
H), 6.76 (d,
ylamine) 1 H), 6.93-7.16 (m,
4H),
7.98 (s, 1 H). (db-DMSO)
1,1,1-Trifluoro-4-F off ~N-~ 90% 428 1.47 (s, 3H), 1.60
H \ (s, 3H),
N
(2 N (M+H 2
5-difluoro- I ~ F 25 (d
c I ~ 1 H)
2
57 (d
1 H)
, , , .
,
,
.
,
,
phenyl)-4-methyl-F ESI) 3.09 (d, 1 H), 3.19
(d, 1 H),
2-(3-methyl-3H- 4.02 (s, 3H), 5.94
(d, 1H),
benzimidazol-4- 6.80-6.93 (m, 2H),
6.99-
ylamine) 7.13 (m, 2H), 7.25
(d, 1 H),
7.88 (s, 1 H). (CDC13)
" , ~ ~ CA 02531060 2005-12-29
113
General Operating Instructions for Methyl Ether Cleavage in N-
Methylbenzimidazole
Derivatives:
About 0.1 mmol of the methyl ether is introduced into about 3 ml of
dichloromethane, and about 1 ml of a BBr3 solution (1 M in dichloromethane) is
added.
It is stirred for 2 hours at room temperature, diluted with ethyl acetate, the
solution is
added to saturated NaHC03 solution, the phases are separated and extracted
with ethyl
acetate. The combined organic phases are washed with water and saturated NaCI
solution and dried with NaZS04. The crude product is crystallized from diethyl
ether/hexane. Yields of about SO% are obtained.
Name Structure MS 'H-NMR (300 MHz, CDC13)
1,1,1-Trifluoro-4-OH OH H N N_ 442/4441.32 (s, 3H), 1.64
N (s, 3H),
I
FCC
(4-chloro-2- , (M+H, 2.02 (m, 2H), 3.00-3.16
~~ (m,
hydroxy-phenyl)-4- ESI) 2H), 4.04 (s, 3H),
5.98 (d,
methyl-2-(4- I H), 6.68-6.74 (m,
I H), 7.04
methyl-1H- (d, IH), 7.23-7.33
(m, 3H),
benzimidazol-4- 8.98 (s, 1 H). (CD30D)
ylamine)
1,1,1-Trifluoro-4-off off ~N-~ 442/444
H
N
N
(4-chloro-2- I ~ F,c I ~ (M+H,
~~
hydroxy-phenyl)-4- ESI)
methyl-2-(3-
methy I-3 H-
benzimidazol-4-
ylamine)
" ~ ~ ~ CA 02531060 2005-12-29
114
Name Structure MS 1H-NMR (300 MHz, CDC13)
1,1,1-Trifluoro-4-OH OH H N='\ 426 1.47 (s, 3H), 1.64
N ~ N (s, 3H),
5-fluoro-2- ~ ~ F'~ ~ ~ M+H 1.97-2.03 m
( ( , ( , 2H), 3.06 (d,
F
hydroxy-phenyl)-4- ESI) 1 H), 3.27 (d, 1 H),
3.85 (s,
methyl-2-(4- 3H), 5.86 (d, 1 H),
6.57-6.82
methyl-1H- (m, 3H), 6.98-7.06
(m, 2H),
benzimidazol-4- 8.01 (s, 1 H). (CD30D)
ylamine)
1,1,1-Trifluoro-4-OH OH ~N-~ 426 1.47 (s, 3H), 1.63
' (s, 3H),
(5-fluoro-2- N (M+H 1
N 92-2
~ ~ F 04 (m
c i ~ 1 H)
2
87
d
, , .
.
,
,
.
(
,
hydroxy-phenyl)-4-F ESI) 1 H), 3.09-3.18 (m,
1 H), 4.15
methyl-2-(3- (s, 3H), 5.84 (d,
1 H), 6.40
methyl-3H- (dd, 1 H), 6.50-6.57
(m, 1 H),
benzimidazol-4- 6.92-7.06 (m, 3H),
8.09 (s,
ylamine) 1H). (CD30D)
~
~ CA 02531060 2005-12-29
115
Example 93
H
~O OH N
H
N ~ ~O
F3C I /
F
4 ~[4 ~5-Fluoro-2-methoxyphenyl~2-hydroxy-4-methyl-2-
(trifluoromethyl)pentyllamino~-2,3-dihydroisoindolon-1 (2H~ one
2-Methyl-3-nitrobenzoic acid methyl ester
30 g (165.6 mmol) of 2-methyl-3-nitrobenzoic acid is added to 150 ml of
methanol, and it is refluxed for two days after 2.9 ml of concentrated
sulfuric acid is
added. After cooling, the crystallizate (22.55 g = 79%) is suctioned off and
used in the
next stage.
2-(Bromomethyl)-3-nitrobenzoic acid methyl ester
25.55 g (130.9 mmol) of 2-methyl-3-nitrobenzoic acid methyl ester is added to
300 ml of carbon tetrachloride, and mixed with 25.6 g (141.7 mmol) of N-
bromosuccinimide and 62.8 mg of benzoyl peroxide. After seven days of
refluxing, the
succinimide is suctioned off after cooling, and then the filtrate is spun in
to the dry state.
The desired compound that is incorporated in crude form into the next stage
remains.
2-(Azidomethyl)-3-nitrobenzoic acid methyl ester
g (36.5 mmol) of 2-(bromomethyl)-3-nitrobenzoic acid methyl ester is mixed
with 36 ml of N,N-dimethylformamide and 24 ml of water. After 3.54 g of sodium
azide is added, the batch is stirred overnight. The reaction mixture is
diluted with
methyl-tert butyl ether, and washed twice with water and once with brine.
After drying
~
~ CA 02531060 2005-12-29
116
on sodium sulfate, it is filtered, and the solvent is spun off. The desired
azide is
obtained in a yield of 89.6% (7.72 g) and further used in crude form.
4-Amino-2, 3-dihydroisoindol-l -one
1 g (4.2 mmol) of 2-(azidomethyl)-3-nitrobenzoic acid methyl ester is added to
ml of ethanol and 2 ml of glacial acetic acid and mixed with 148.5 mg of PdIC.
After
stirring overnight at room temperature under a hydrogen atmosphere, the
catalyst is
suctioned off via a glass-fiber filter, and the filtrate is concentrated by
evaporation until
a dry state is reached. The residue is chromatographed on silica gel (ethyl
acetate).
391.5 mg (62.4%) of the desired compound is isolated.
Analogously to Example 30, 4-(5-fluoro-2-methoxyphenyl~-2-hydroxy-2-
trifluoromethyl-pentanal is reacted with 4-amino-2,3-dihydroisoindol-1-one to
form the
desired product.
'H-NMR (DMSOD6): & = 1.37 (s, 3H), 1.54 (s, 3H), 2.03 (d, 1H), 2.81 (d, 1H),
2.81 (d, I H), 2.90 (dd, 1 H), 3.02 (dd, 1 H), 3.33 (s, 1 H), 3.81 (s, 3 H),
4.01-4.14 (m, 2H),
4.77 (br., 1 H), 5.76 (s, 1 H), 6.17 (d, 1 H), 6.88 (d, 1 H); 7.01-7. I 6 (m ,
4H), 8.35 (s, I H)
Example 94
OH OH H
N NH
w
F3C
F
4-(5-Fluoro-2-hydroxyoxyphenyl~ I -( 1 H-indol-4-ylamino)-4-methyl-2-
(trifluoromethyl)pentan-2-of
Analogously to Example 3, 4-(5-fluoro-2-methoxyphenyl~4-methyl-1-(1H-
indol-~-ylamino)-2-(trifluoromethyl)-pentan-2-of is reacted to form the
desired product.
. . CA 02531060 2005-12-29
117
IH-NMR (CDC13); 8 = 1.49 (s, 3H), 1.61 (s, 3H), 2.31 (d, 1H), 2.75 (d, 1H),
3.26
(d, 1 H), 3.43 (d, 1 H), 3.60 (s, 1 H), 5.67 (d, 1 H), 6.33 (rn, 1 H), 6.63
(dd, 1 H), 6.86-6.97
(m, 3H), 7.10 (dd, 1 H), 7.15 (dd, 1 H), 8.14 (br, 1 H)
Example 95
C f F .~D1~
~s
O V 1 r fl
F
1 1 1-Trifluoro-2-f (8-fluoro-2-methyl-quinazolin-S-ylamino)-methyll-4-f 3-
methoxy-
phenyl)-4-methyl-pentan-2-of
Starting from the corresponding precursors, the compound was synthesized
analogously to what is described in Example 13. 26.9 mg (17.8%) of the desired
compound was isolated in the last step.
'H-NMR (300 MHz, CD30D): 0 = 1.49 (3H), 1.69 (3H), 2.19 (1H), 2.56 (1H),
2.85 (3H), 2.93 (1H), 3.12 (1H), 3.64 (3H), 5.90 (1H), 6.58 (1H), 7.00 (1H),
7.03-7.20
(2H), 7.38 (1H), 9.38 (1H).
Example 96
g ~ F ,~ NY
H f is
Hp ;~ ~ N71
~Y J ''~~ ~'V
1 ~ ~f
3-~4 4 4-Trifluoro-3-[~8-fluoro-2-methyl-cLuinazolin-5-ylamino)-methyl-3-
hydroxy-1,1-
dimethyl-butvl ~-phenol
Starting from ether, described in Example 95, the compound was obtained by
ether cleavage with BBr3. 6 mg (29.5%) of the desired compound was isolated in
the
last step.
" . , ~ ~ CA 02531060 2005-12-29
118
'H-NMR (300 MHz, CD30D): 0 = 1.49 (3H), 1.65 (3H), 2.15 (IH), 2.50 (1H),
2.82 (3H), 2.95 (IH), 3.17 (1H), 6.02 (1H), 6.53 (1H), 6.90-7.13 (3H), 7.39
(IH), 9.38
(1H).
Example 97
F
F F
O N
x
(+)-1, I , I -Trifluoro-2-((8-fluoro-2-methyl-cinazolin-5-ylamino)-methyl]'-4-
(3-methoxy-
phenyl -4-methyl-pentan-2-of
The compound that is produced according to Example 95 is separated into
enantiomers thereof on a chiral column (Chiralpak AD 200, mobile solvent
hexane/isopropanol).
(+)-Enantiomers: Example 97;
(-)-Enantiomers: Example 98.
Example 98
f i F rN
F
(-)-1,1,1-Trifluoro-2-f (8-fluoro-2-methyl-cinazolin-5 ylamino)-meth~~-4-(3-
methoxy-
phenyl)-4-methyl-pentan-2-of
For conditions for the racemate cleavage, see Example 97.
, CA 02531060 2005-12-29
119
Example 99
~~w
F.;; .1
F F ~F
3-(~3-Chloro-2-methoxy-phenyl)-cyclohexyl]-1,1,1-trifluoro-2 ~~(8-fluoro-2-
methyl-
guinazolin-5-ylamino)-methyl]-~ropan-2-of
The compound was synthesized starting from the corresponding precursors and
analogously to what is described in the examples above. 32 mg (31.9%) of the
desired
compound was isolated in the last step.
'H-NMR (CDCl3): b = 1.00-2.50 (12H), 2.60-3.30 (6H), 3.79 (3H), 4.15-4.55
( 1 H), 5.60-5 . 8 5 ( 1 H), 6. 82 ( 1 H), 6.95 ( 1 H), 7.10-7.50 (2H), 9.10 (
1 H).
Example 100
~,o r~r o
xH
~»
E
~~-4-[4 ~4-Chloro-2-methoxy-phenyl)-2-hy_droxy-4-methyl-2-trifluoromethyl-
pentylamino]-1,3-dihydro-indol-2-one
The compound was synthesized starting from the corresponding precursors and
analogously to what is described in the examples above. 117.1 mg (97.7%) of
the
desired compound was isolated as a racemate in the last step.
1H-NMR (300 MHz, CDC13); 0 = 1.44 (3H), 1.58 (3H), 2.09 (1H), 2.20 (1H),
2.65 (1H), 2.95-3.27 (3H), 3.88 (3Hh), 5.99 (1H), 6.34 (1H), 6.85-7.08 (3H),
7.32 (1H),
7.99 (1H).
Then, a racemate cleavage was performed. After chromatography on a chiral
column (Chiralpak AD 20C, mobile solvent hexane/ethanol), the two enantiomers
were
obtained.
. ~ CA 02531060 2005-12-29
120
(-)-Enantiomer: Example 100;
(+)-Enantiomer: Example 101.
Example 101
'o
ef ~ t~
~+)-4-f 4-(4-Chloro-2-methoxy_-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-
pentylaminoL 1 3-dihydro-indol-2-one
For conditions for the racemate cleavage, see Example 1 O1.
Example 102
a.!"H. # E~ 1
t1M
E MO
l
~f
~~-4-[4-(4-Chloro-2-hydroxy,~he~l)-2-h dY- roxy-4-methyl-2-trifluoromethyl-
pentylaminol I ,3-dihydro-indol-2-one
The compound was synthesized by ether cleavage of the compound that is
described in Example 100.
'H-NMR (300 MHz, CD30D): ~ = 1.32 (3H), 1.49 (3H), 2.43 (1H), 2.59 (1H),
3.10 (1H), 3.21-3.40 (3H), 5.87 (1H), 6.24 (1H), 6.58 (1H), 6.69 (IH), 6.95
(IH), 7.18
( 1 H).
Example 103
Ff F
off ~ ~1' w
/=~~ f~~ /~p .,4 Htl
CIJ/ly H t ~O
r' /
. . CA 02531060 2005-12-29
121
(+)-4-[4-(4-Chloro-2-hydroxy-phen~)-2-hydroxy-4-methyl-2-trifluoromethyl-
pen laminol 1,3-dih~rdro-indol-2-one
The compound was synthesized by ether cleavage of the compound that is
described in Example 101. For ~NMR data, see Example 102.
Example 104
WO FF F H
Hp H ~~~0
7F
6-Fluoro-4-j4-(2-fluoro-6-methoxy phenyl)-2-h d~ -~yl-2-trifluoromethyl-
pentylamino [-2,3-dihydro-isoindol-1-one
The compound was synthesized starting from the corresponding precursors,
analogously to what is described in the examples above. 62.5 mg (77.8%) of the
desired
compound was isolated in the last step.
'H-NMR (300 MHz, CD30D~: D = 1.53 (3H), I .79 (3H), 1.98 (1H), 2.95-3.12
(2H), 3 .25 ( 1 H), 3 .90 (3 H), 4.09-4.28 (2H), 6.00 ( I H), 6.62 ( 1 H),
6.71 ( 1 H), 6.83 ( I H),
7.19 (1H).
Example 105
PF ~
OH
#10 H O
F
F
6-Fluoro-4-j4-(2-fluoro-6-hydroxy-phenyl)-2-hydrox~4-methyl-2-trifluoromethyl-
~entylamino~-2,3-dihydro-isoindol-1-one
The compound was obtained by ether cleavage of the compound, described in the
preceding example. with BBr;. 37.5 mg (69.7%) of the desired compound was
isolated.
CA 02531060 2005-12-29
122
1H-NMR (300 MHz, CD30D): 0 = 1.54 (3H), 1.82 (3H), 1.89 (1H), 3.05 (1H),
3.20-3.40 (2H), 4.10-4.28 (2H), 6.05 ( 1 H), 6.47 ( 1 H), 6.5 8 ( 1 H), 6.70 (
1 H), 6.98 ( 1 H).
Example 106
., r ~ ~
1,1,1-Trifluoro-4-(2-fluoro-6-methoxy-phenyl)-2-[( 1 H-indazol-4-ylamino)-
methyl)-4-
methyl-pentan-2-of
The compound was synthesized starting from the corresponding precursors,
analogously to what was described in the examples above. 51.2 mg (72.8%) of
the
desired compound was isolated in the last step.
'H-NMR (300 MHz, CD30D): ~ = 1.54 (3H), 1.80 (3H), 2.03 (1H), 3.00-3.19
(2H), 3.35 (1H), 3.85 (3H), 5.65 (1H), 6.63 (1H), 6.70-6.84 (2H), 7.08 (1H),
7.18 (1H),
7.93 ( 1 H).
Example 107
E~ c
N
'~
1,1,1-Trifluoro-4-(2-fluoro-6-hydroxy_phen~)-2-[( 1 H-indazol-4-ylamino~
methyll-4-
methyl-pentan-2-of
The compound was obtained by ether cleavage of the compound, described in
Example 106, with BBr3. 20.8 mg (54.2%) of the desired compound was isolated
~H-NMR (300 MHz, CD30D): ~ = 1.57 (3H), 1.80 (3H), 1.92 (1H), 3.15 (1H),
3.20-3.50 (2H), 5.70 ( 1 H), 6.40-6.60 (2H), 6.75 ( 1 H), 6.88-7.10 (2H), 7.90
( 1 H).
