Note: Descriptions are shown in the official language in which they were submitted.
CA 02598207 2007-08-16
Substituted chroman derivatives,
processes for their preparation
and their use as antiinflammatory agents
Introduction
The invention relates to substituted chroman
derivatives, processes for their preparation and their
use as antiinflammatory agents.
Open-chain non-steroidal antiinflammatory agents are
known in the art (DE 100 38 639, WO 03/082827 and
WO 02/10143). These compounds show experimentally
dissociations between antiinflammatory and unwanted
metabolic effects and are superior to non-steroidal
glucocorticoids described to date or exhibit at least
as good an effect.
The present invention provides further non-steroidal
antiinflammatory agents.
Brief description of the invention
The present invention relates to compounds of the
general formula (I)
R R~
Y Rs
R2
/ R5
R" R'2 3a Ra
R
CF ZR1a
OH
R3/NH
(1)
in which
CA 02598207 2007-08-16
- 2 -
R1 and R2 are independently of one another a hydrogen
atom, a hydroxy group, a halogen atom, an
optionally substituted (C1-Clo)-alkyl group, a
( C1-Clo )-alkoxy group, a (C1-C10 )-alkylthio group, a
(C1-C5)-perfluoroalkyl group, a cyano group, a
nitro group, or an -NR9R9a group,
or R' and R2 together form a group selected from the
groups -0- ( CH2 ) n-O-, -0- ( CHz ) n-CHz-, -O-CH=CH-,
- ( CH2 ) n+2- , -NH- ( CH2 ) +i-, -N ( C1-C3-al kyl ) - ( CH2 ) n+1-
and -NH-N=CH-,
where n is 1 or 2, and the terminal oxygen atoms
and/or carbon atoms and/or nitrogen atoms are
linked to directly adjacent ring carbon atoms,
R11 is a hydrogen atom, a hydroxy group, a halogen
atom, a cyano group, an optionally substituted
( C1-Clo )-alkyl group, a ( C1-Clo )-alkoxy group, a
(C1-Clo) -alkylthio group, or a (C1-CS) -
perfluoroalkyl group,
R12 is a hydrogen atom, a hydroxy group, a halogen
atom, a cyano group, an optionally substituted
( C1-C10 )-alkyl group, or a (C1-Clo )-alkoxy group,
R3 is a (C1-Clo) -alkyl group which is optionally
substituted by 1 to 3 hydroxy groups, 1 to 3
halogen atoms, and/or 1 to 3(C1-C5)-alkoxy groups,
an optionally substituted (C3-C7) -cycloalkyl group,
an optionally substituted heterocyclyl group,
an optionally substituted aryl group, or
a mono- or bicyclic heteroaryl group which is
optionally substituted by one or more groups which
are selected independently of one another from
(C1-CS)-alkyl groups which themselves may
optionally be substituted by 1 to 3
hydroxy or 1 to 3-COOR13 groups,
(C1-C5) -alkoxy groups,
halogen atoms, hydroxy groups, -NR9R9a groups,
(C1-CS)-perfluoroalkyl groups, nitro groups,
thiol groups, sulfoxyl groups, sulfonic acid
groups, sulfonamide groups, sulfonimine groups,
cyano groups or -(CO)-(C1-C5)-alkyl groups, and
CA 02598207 2007-08-16
- 3 -
exo methylene groups
and optionally comprises 1 to 4 nitrogen atoms
and/or 1 to 2 oxygen atoms and/or 1 to 2 sulfur
atoms and/or 1 to 2 keto groups, this group being
linked by any position to the nitrogen atom and
possibly being optionally hydrogenated at one or
more positions,
R3a is a hydrogen atom, a cyano group or an optionally
substituted (Cl-CS)-alkyl group;
R4, R5, R6 and R6a are independently of one
another a hydrogen atom, a halogen atom, a hydroxy
group, an -NR9R9a group, an optionally substituted
(C1-C10) -alkyl group, a (C1-C1 ) -alkoxy group or a
(C1-C10)-alkylthio group,
R9 and R9a are independently of one another a
hydrogen atom, a(C1-C5)-alkyl group or a-(CO)-
(C1-CS) -alkyl group,
R10 is a (C1-C10) -alkyl group or a - (CO) - (C1-C10) -alkyl
group,
R13 is a hydrogen atom or a(C1-C5)-alkyl group,
R14 is a hydrogen atom, a fluorine atom or a partly or
completely fluorinated (C1-CS)-alkyl group, and
Y is a methylene group, an oxygen atom, a sulfur
atom, an -S(0)n group (where n = 1 or 2), an
-S (0) (NR13) group, an -NH group or an -NR1
group;
in the form of any stereoisomer or of a mixture of
stereoisomers; or as pharmacologically acceptable
salt or derivative.
The present invention further relates to processes for
preparing compounds of the general formula (I) as
described herein.
The present invention further relates to pharmaceutical
compositions which include one or more compounds of the
general formula (I) in combination with one or more
pharmaceutical carriers or excipients.
CA 02598207 2007-08-16
- 4 -
The present invention additionally relates to the use
of the compounds of the general formula (I) for
manufacturing pharmaceutical compositions having an
antiinflammatory effect.
The present invention further relates to compounds of
the general formula (II)
R' R6a
~ Y s
R 2 R
5
R
R~~ R12 3a Ra
R
f OH CF2R'a
0
(II)
in which the substituents R1 to R14 and Y have the
abovementioned meanings, and to the use of these
compounds for preparing compounds of the general
formula (I) as described above.
Detailed description of the invention
Definitions
The term halogen atom or halogen means a fluorine,
chlorine, bromine or iodine atom. A fluorine, chlorine
or bromine atom is preferred.
The alkyl groups mentioned in the definitions of the
general formula (I) may be straight-chain or branched
and are for example a methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl,
2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl
group, and the hexyl, heptyl, nonyl, decyl group and
derivatives thereof branched in any way. Alkyl groups
which comprise 1 to 10, 1 to 8 or 1 to 5 carbon atoms
are preferred. A methyl or ethyl group is particularly
preferred.
CA 02598207 2007-08-16
- 5 -
The abovementioned alkyl groups may optionally be
substituted by 1 to 5, preferably 1 to 3, groups which
are selected independently of one another from hydroxy,
cyano, nitro, -COOR13, (C1-C5) -alkoxy groups, halogen
atoms, -NR9R9a, a partly or completely fluorinated
(C1-C3)-alkyl group. The alkyl groups may preferably be
substituted by 1 to 3 halogen atoms and/or 1 to 3
hydroxy and/or 1 to 3 cyano and/or 1 to 3-COOR13
groups. Fluorine atom, hydroxy, methoxy and/or cyano
groups represent a particularly preferred subgroup of
substituents.
1 to 3 hydroxy and/or 1 to 3-COOR13 groups are a
further particularly preferred group of substituents
for the alkyl groups. Hydroxy groups are particularly
preferred in this connection.
Examples of a suitable partly or completely fluorinated
alkyl group are the following partly or completely
fluorinated following groups: fluoromethyl,
difluoromethyl, trifluoromethyl, fluoroethyl,
1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoro-
ethyl, tetrafluoroethyl, pentafluoroethyl. Of these,
the trifluoromethyl or the pentafluoroethyl are
preferred. The completely fluorinated group is also
called perfluoroalkyl group. The reagents which are
optionally employed during the synthesis can be
purchased, or the published syntheses of the
corresponding reagents belong to the prior art, or
published syntheses can be applied analogously.
The alkoxy groups mentioned in the definitions of the
general formula (I) may be straight-chain or branched
and be for example a methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, tert-butoxy or
n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or
3-methylbutoxy group. C1-C5- and C1-C3-, C1-C$-, and
CA 02598207 2007-08-16
- 6 -
C1-Clo-alkoxy groups are preferred. A methoxy or ethoxy
group is particularly preferred.
The alkylthio groups mentioned in the definitions of
the general formula (I) may be straight-chain or
branched and are for example a methylthio, ethylthio,
n-propylthio, isopropylthio, n-butylthio, isobutylthio,
tert-butylthio or n-pentylthio, 2,2-dimethylpropylthio,
2-methylbutylthio or 3-methylbutylthio group.
C1-C5-Alkylthio groups are preferred. A methylthio or
ethylthio group is particularly preferred.
The alkoxy and alkylthio groups described above may
have on their alkyl groups the same substituents which
have been described hereinbefore for the alkyl groups
in general. Preferred substituents for alkoxy and
alkylthio groups are selected independently of one
another from halogen (especially fluorine and/or
chlorine), hydroxy and cyano.
The substituent -NR9R9a means for example -NH2, -NH (CH3) ,
-N ( CH3 ) 2, -NH ( C2Hs ) , -N ( C2H5 ) 2, -NH (C3H7) , -N (C3H7) 2,
-NH ( C9H9 ) . -N ( C4H9 ) 2, -NH (C5H11) ~ -N (C5H11) 2, -NH ( CO ) CH3 ,
NH ( CO ) C2H5, -NH ( CO ) C3H7, -NH ( CO ) C4H9r -NH ( CO ) C5H11.
The (C3-C7) -cycloalkyl group means a saturated cyclic
group which is optionally substituted by one or more
groups selected from hydroxy groups, halogen atoms,
(C1-C5) -alkyl groups, (C1-C5) -alkoxy groups, -NR9R9a
groups, -COOR13 groups, -CHO, cyano and have 3 to 7 ring
carbon atoms such as, for example, cyclopropyl, methyl-
cyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl,
methylcyclopentyl, cyclohexyl, methylcyclohexyl,
cycloheptyl, methylcycloheptyl.
An alkylidene or exo alkylidene group means a group
having 1 to 10 carbon atoms which is bonded via an exo
double bond to the system (ring or chain) . (C1-C5) - and
CA 02598207 2007-08-16
- 7 -
(C1-C3)-alkylidene is preferred, and exo methylene is
particularly preferred.
The heterocyclyl group is a cyclic, non-aromatic group
comprising one or more heteroatoms and may be for
example pyrrolidine, imidazolidine, pyrazolidine,
piperidine. Perhydroquinoline and perhydroisoquinoline
are also included in the heterocyclyl groups of the
invention.
Examples of suitable substituents for heterocyclyl and
heteroaryl groups are substituents from the following
group: optionally substituted C1-CS-alkyl groups,
hydroxy, (C1-CS) -alkoxy, -NR9R9a, halogen, cyano,
-COOR13, -CHO. The substituents may optionally also be
bonded to the nitrogen atom of the heterocyclyl or
heteroaryl group; N-oxides are also included in the
definition.
Aryl groups in the context of the invention are
aromatic or partly aromatic carbocyclic groups having 6
to 14 carbon atoms which have one ring, such as, for
example, phenyl or phenylene, or a plurality of fused
rings, such as, for example, naphthyl or anthranyl.
Examples which may be mentioned are phenyl, naphthyl,
tetralinyl, anthranyl, indanyl, and indenyl. The
optionally substituted phenyl group and the naphthyl
group are preferred.
The aryl groups may be substituted at any suitable
position leading to a stable compound by one or more
radicals from the group of hydroxy, halogen, C1-C5-alkyl
which is optionally substituted by 1 to 3 hydroxy
groups or COOR13 groups, or C1-C5-alkoxy, cyano, -CF3 and
nitro.
The aryl groups may be partly hydrogenated and then, in
addition or as alternative to the substituents detailed
above, also carry keto and/or exo alkylidene. Partly
CA 02598207 2007-08-16
- 8 -
hydrogenated phenyl means for example cyclohexadienyl,
cyclohexenyl, cyclohexyl. A partly hydrogenated
substituted naphthalene system is for example
1-tetralone or 2-tetralone.
The mono- or bicyclic heteroaryl group may optionally
comprise 1 to 9 groups selected from nitrogen atoms,
oxygen atoms, sulfur atoms or keto groups, of which a
maximum of 4 nitrogen atoms, a maximum of 2 oxygen
atoms, a maximum of 2 sulfur atoms and/or a maximum of
2 keto groups may be present. Every subcombination of
these groups is possible. The heteroaryl group may be
hydrogenated at one or more positions.
Monocyclic heteroaryl groups may be for example
pyridine, pyrazine, pyrimidine, pyridazine, triazine,
azaindolizine, 2H- and 4H-pyran, 2H- and 4H-thiopyran,
furan, thiophene, 1H- and 4H-pyrazole, 1H- and
2H-pyrrole, oxazole, thiazole, furazan, 1H- and
4H-imidazole, isoxazole, isothiazole, oxadiazole,
triazole, tetrazole, thiadiazole.
Bicyclic heteroaryl groups may be for example
phthalidyl, thiophthalidyl, indolyl, isoindolyl,
dihydroindolyl, dihydroisoindolyl, indazolyl,
benzothiazolyl, indolonyl, dihydroindolonyl,
isoindolonyl, dihydroisoindolonyl, benzofuranyl,
benzo[b]thienyl, benzo[c]thienyl, pyrazolo[1,5-a]-
pyridyl, benzimidazolyl, dihydroisoquinolinyl,
dihydroquinolinyl, benzoxazinonyl, phthalazinonyl,
dihydrophthalazinonyl, quinolinyl, isoquinolinyl,
quinolonyl, isoquinolonyl, quinazolinyl, quinoxalinyl,
cinnolinyl, phthalazinyl, dihydrophthalazinyl, 1,7- or
1,8-naphthyridinyl, coumarinyl, isocoumarinyl,
indolizinyl, isobenzofuranyl, azaindolyl,
azaisoindolyl, furanopyridyl, furanopyrimidinyl,
furanopyrazinyl, furanopyridazinyl,
dihydrobenzofuranyl, dihydrofuranopyridyl,
CA 02598207 2007-08-16
9 -
dihydrofuranopyrimidinyl, dihydrofuranopyrazinyl,
dihydrofuranopyridazinyl, dihydrobenzofuranyl group.
If the heteroaryl groups are partly or completely
hydrogenated, the present invention includes compounds
of the general formula (I) in which R3 is tetrahydro-
pyranyl, 2H-pyranyl, 4H-pyranyl, piperidyl,
tetrahydropyridyl, dihydropyridyl, 1H-pyridin-2-onyl,
1H-pyridin-4-onyl, 4-aminopyridyl, 1H-pyridin-4-
ylideneaminyl, chromanyl, isochromanyl, thiochromanyl,
decahydroquinolinyl, tetrahydroquinolinyl, dihydro-
quinolinyl, 5,6,7,8-tetrahydro-lH-quinolin-4-onyl,
decahydroisoquinolinyl, tetrahydroisoquinolinyl,
dihydroisoquinolinyl, 3,4-dihydro-2H-benz[1,4]oxazinyl,
1,2-dihydro[1,3]benzoxazin-4-onyl, 3,4-dihydrobenz-
[1,4]oxazin-4-onyl, 3,4-dihydro-2H-benzo[1,4]thiazinyl,
4H-benzo[1,4]thiazinyl, 1,2,3,4-tetrahydroquinoxalinyl,
1H-cinnolin-4-onyl, 3H-quinazolin-4-onyl, 1H-
quinazolin-4-onyl, 3,4-dihydro-lH-quinoxalin-2-onyl,
2,3-1,2,3,4-tetrahydro[1,5]naphthyridinyl, dihydro-lH-
[1,5]naphthyridyl, 1H-[1,5]naphthyrid-4-onyl, 5,6,7,8-
tetrahydro-lH-naphthyridin-4-onyl, 1,2-
dihydropyrido[3,2-d][1,3]oxazin-4-onyl, octahydro-1H-
indolyl, 2,3-dihydro-lH-indolyl, octahydro-2H-
isoindolyl, 1,3-dihydro-2H-isoindolyl,
1,2-dihydroindazolyl, 1H-pyrrolo[2,3-b]pyridyl,
2,3-dihydro-lH-pyrrolo[2,3-b]pyridyl, 2,2-dihydro-lH-
pyrrolo[2,3-b]pyridin-3-onyl.
The mono- or bicyclic heteroaryl group may optionally
be substituted by one or more substituents selected
from C1-C5-alkyl groups which are optionally substituted
by 1 to 3 hydroxy groups or 1 to 3-COOR13 groups, or
C1-C5-alkoxy groups, halogen atoms, and/or exo methylene
groups. The substituents may, if possible, optionally
also be bonded directly to the heteroatom (e.g. to the
nitrogen atom). The present invention also includes
N-oxides.
CA 02598207 2007-08-16
- 10 -
Suitable hydroxy protective groups which are necessary
where appropriate are all conventional hydroxy
protective groups known to the skilled worker, in
particular silyl ethers or esters of organic C1-Clo
acids, C1-CS ethers, benzyl ethers or benzyl esters.
Conventional hydroxy protective groups are described in
detail in T.W. Greene, P.G.M. Wuts "Protective Groups
in Organic Synthesis", 2nd edition, John Wiley & Sons,
1991). The protective groups are preferably alkyl-,
aryl- or mixed alkylaryl-substituted silyl groups, e.g.
the trimethylsilyl (TMS), triethylsilyl (TES), tert-
butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl
(TBDPS) or triisopropylsilyl groups (TIPS) or other
customary hydroxy protective groups (e.g.
methoxymethyl, methoxyethoxymethyl, ethoxyethyl,
tetrahydrofuranyl, tetrahydropyranyl groups).
The compounds of the invention of the general formula
(I) may, owing to the presence of centers of asymmetry,
exist as stereoisomers. The present invention relates
to all possible diastereoisomers both as racemates and
in enantiopure form. The term stereoisomers also
includes all possible diastereoisomers and regioisomers
and tautomers (e.g. keto-enol tautomers) in which the
stereoisomers of the invention may exist, and to which
the invention therefore likewise relates.
The compounds of the invention may also be in the form
of salts with pharmacologically acceptable anions, for
example in the form of the hydrochloride, sulfate,
nitrate, phosphate, pivalate, maleate, fumarate,
tartrate, benzoate, mesylate, citrate or succinate.
The invention also includes pharmacologically suitable
derivatives or prodrugs of the compounds of the general
formula (I). Derivatives or prodrugs refers for example
to esters, ethers or amides of the compounds of the
general formula (I) or other compounds which metabolize
in the body to compounds of the general formula (I).
CA 02598207 2007-08-16
- 11 -
Suitable compounds are listed for example in Hans
Bundgaard (Editor), Design of Prodrugs, Elsevier,
Amsterdam 1985.
Preferred embodiments
A subgroup of compounds of the invention of the general
formula (I) are those compounds in which R' and R2 are
independently of one another a hydrogen atom, a hydroxy
group, a halogen atom, an optionally substituted
(C1-Clo) -alkyl group, a (C1-Clo) -alkoxy group, a (C1-Clo) -
alkylthio group, a(C1-C5)-perfluoroalkyl group, a cyano
group, a nitro group, or an -NR9R9a group.
A preferred group of compounds of the general formula
(I) are those compounds in which Y is an oxygen atom, a
sulfur atom or a methylene group.
A further preferred group of compounds of the general
formula (I) are those compounds in which R3 is an
optionally substituted aryl or heteroaryl group. A more
preferred group of compounds of the general formula (I)
are those compounds in which R3 is an optionally
substituted aryl or heteroaryl group which is selected
from the group consisting of naphthyl, phthalidyl,
isoindolyl, dihydroindolyl, dihydroisoindolyl,
dihydroisoquinolinyl, thiophthalidyl, benzofuranyl,
benzoxazinonyl, phthalazinonyl, quinolinyl,
isoquinolinyl, quinolonyl, isoquinolonyl, chromanyl,
isochromanyl, indazolyl, benzothiazolyl, quinazolinyl,
quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or
1,8-naphthyridinyl, pyrazolo[1,5-a}pyridyl, dihydro-
indolonyl, dihydroisoindolonyl, benzimidazole or
indolyl group.
A further preferred group of compounds of the general
formula (I) are those compounds in which R3a is a
hydrogen atom or a(C1-CS)-alkyl group.
CA 02598207 2007-08-16
- 12 -
A further preferred group of compounds of the general
formula (I) are those compounds in which R4, R5, R6, and
R6a are independently of one another a hydrogen atom, a
halogen atom or an optionally substituted (C1-Clo)-alkyl
group.
A further preferred group of compounds of the general
formula (I) are those compounds in which R1 and R2 are
independently of one another a hydrogen atom, a halogen
atom or an optionally substituted (C1-Clo)-alkyl group.
A further preferred group of compounds of the general
formula (I) are those compounds in which the
substituents R11 and R12 are in each case a hydrogen
atom.
A further preferred group of compounds of the general
formula (I) are those compounds in which the
substituent R14 is a fluorine atom or a trifluoromethyl
group.
A particularly preferred group of compounds of the
general formula (I) are those compounds in which R1, R2,
R9, R6, and R6a are independently of one another a
hydrogen atom, a halogen atom or an optionally
substituted (C1-Clo) -alkyl group, Y is an oxygen atom, a
sulfur atom or a methylene group, R3a is a hydrogen atom
or a(C1-CS) -alkyl group, Rll and R12 are in each case a
hydrogen atom, R19 is a fluorine atom or a
trifluoromethyl group, and R3 is an optionally
substituted aryl or heteroaryl group which is selected
from the group consisting of naphthyl, phthalidyl,
isoindolyl, dihydroindolyl, dihydroisoindolyl,
dihydroisoquinolinyl, thiophthalidyl, benzofuranyl,
benzoxazinonyl, phthalazinonyl, quinolinyl,
isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl,
benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl,
phthalazinyl, 1,7- or 1,8-naphthyridinyl,
pyrazolo[1,5-a]pyridyl, dihydroindolonyl, chromanyl,
CA 02598207 2007-08-16
- 13 -
isochromanyl, dihydroisoindolonyl, benzimidazole or
indolyl group.
Every further possible combination of the
abovementioned subgroups and of substituents indicated
as preferred with their general andlor specific
meanings is likewise to be regarded as encompassed by
the present invention.
Biological activity
The antiinflammatory effect of the compounds of the
general formula (I) is tested in an animal experiment
by testing in the croton oil-induced inflammation in
the rat and mouse (J. Exp. Med. (1995), 182, 99-108).
For this purpose, croton oil is applied in ethanolic
solution topically to the ears of the animals. The test
substances are likewise administered topically or
systemically at the same time as or two hours before
the croton oil. After 16-24 hours, the ear weight is
measured as a measure of the inflammatory edema, the
peroxidase activity is measured as a measure of the
migration in of granulocytes and the elastase activity
is measured as a measure of the migration in of
neutrophilic granulocytes. In this test, the compounds
of the general formula (I) inhibit the three
abovementioned parameters of inflammation both after
topical and after systemic administration.
The binding of the substances to the glucocorticoid
receptor (GR) and further steroid hormone receptors
(mineral corticoid receptor (MR), progesterone receptor
(PR) and androgen receptor (AR)) is examined with the
aid of recombinantly prepared receptors. Cytosol
preparations of Sf9 cells which had been infected with
recombinant baculoviruses which code for the GR are
employed for the binding studies. Compared with the
reference substance [3H]-dexamethasone, the substances
show a high affinity for the GR. Thus, an IC50(GR) =
CA 02598207 2007-08-16
- 14 -
20 nM and IC50(PR) > 1 pM was measured for the compound
of example 1 and an IC50 (GR) = 30 nM and IC50 (PR) > 1}zM
was measured for the compound of example 2.
The essential molecular mechanism for the
antiinflammatory effect of glucocorticoids is regarded
as the GR-mediated inhibition of the transcription of
cytokines, adhesion molecules, enzymes and other pro-
inflammatory factors. This inhibition is brought about
by an interaction of the GR with other transcription
factors, e.g. AP-1 and NF-kappa-B (for review, see Cato
ACB and Wade E, BioEssays 18, 371-378 1996).
The compounds of the invention of the general formula
(I) inhibit the secretion, induced by
lipopolysaccharide (LPS), of the cytokine IL-8 in the
human THP-1 monocyte cell line. The concentration of
the cytokines was determined in the supernatant using a
commercially available ELISA kit.
One of the commonest unwanted effects of a
glucocorticoid therapy is the so-called \\steroid
diabetes" [cf. Hatz, HJ, Glucocorticoide:
Immunologische Grundlagen, Pharmakologie und
Therapierichtlinien, Wissenschaftliche
Verlagsgesellschaft mbH, Stuttgart, 1998]. The cause of
this is stimulation of gluconeogenesis in the liver by
induction of the enzymes responsible therefor and by
free amino acids resulting from the breakdown of
proteins (catabolic effect of the glucocorticoids). A
key enzyme in catabolic metabolism in the liver is
tyrosine aminotransferase (TAT). The activity of this
enzyme can be determined by photometry on liver
homogenates and represents a good measure of the
unwanted metabolic effects of glucocorticoids. To
measure the TAT induction, the animals are sacrificed
8 hours after administration of the test substances,
the livers are removed, and the TAT activity in the
homogenate is measured. In this test, the compounds of
CA 02598207 2007-08-16
- 15 -
the general formula (I) induce, in doses in which they
have antiinflammatory activity, tyrosine
aminotransferase to only a small extent or not at all.
Medical indications
Owing to their antiinflammatory and additional anti-
allergic, immunosuppressive and antiproliferative
effect, the compounds of the invention of the general
formula (I) can be used as medicaments for the
treatment or prophylaxis of the following pathological
states in patients, especially mammals and preferably
humans: in this connection, the term "DISORDER" stands
for the following indications:
(i) pulmonary disorders associated with
inflammatory, allergic and/or proliferative
processes:
- chronic obstructive lung disorders of any
origin, especially bronchial asthma
- bronchitis of varying origin
- all types of restrictive lung disorders,
especially allergic alveolitis,
- all types of pulmonary edema, especially
toxic pulmonary edema
- sarcoidoses and granulomatoses, especially
Boeck's disease
(ii) rheumatic disorders/autoimmune diseases/joint
disorders associated with inflammatory, allergic
and/or proliferative processes:
- all types of rheumatic disorders, especially
rheumatoid arthritis, acute rheumatic fever
polymyalgia rheumatica
- reactive arthritis
- inflammatory soft tissue disorders of other
origin
- arthritic symptoms associated with
degenerative joint disorders (arthroses)
- traumatic arthritides
CA 02598207 2007-08-16
- 16 -
- collagenoses of any origin, e.g. systemic
lupus erythematosus, scleroderma,
polymyositis, dermatomyositis, Sjogren's
syndrome, Still's syndrome, Felty's syndrome
(iii) allergies associated with inflammatory and/or
proliferative processes:
- all types of allergic reactions, e.g.
angioedema, hayfever, insect bite, allergic
reactions to drugs, blood derivatives,
contrast agents etc., anaphylactic shock,
urticaria, contact dermatitis
(iv) vessel inflammations (vasculitides)
- polyarteritis nodosa, temporal arteritis,
erythema nodosum
(v) dermatological disorders associated with
inflammatory, allergic and/or proliferative
processes:
- atopic dermatitis (especially in children)
- psoriasis
- pityriasis rubra pilaris
- erythematous disorders induced by various
noxae, e.g. radiation, chemicals, burns, etc.
- bullous dermatoses
- lichenoid disorders
- pruritus (e.g. of allergic origin)
- seborrheic eczema
- rosacea
- pemphigus vulgaris
- erythema multiforme exudativum
- balanitis
- vulvitis
- hair loss such as alopecia areata
- cutaneous T-cell lymphomas
(vi) renal disorders associated with inflammatory,
allergic and/or proliferative processes:
- nephrotic syndrome
- all nephritides
(vii) liver disorders associated with inflammatory,
allergic and/or proliferative processes:
CA 02598207 2007-08-16
- 17 -
- acute liver cell necrosis
- acute hepatitis of varying origin, e.g.
viral, toxic, drug-induced
- chronic aggressive and/or chronic
intermittent hepatitis
(viii) gastrointestinal disorders associated with
inflammatory, allergic and/or proliferative
processes:
- regional enteritis (Crohn's disease)
- ulcerative colitis
- gastritis
- reflux esophagitis
- gastroenteritides of other origin, e.g.
indigenous sprue
(ix) proctological disorders associated with
inflammatory, allergic and/or proliferative
processes:
- anal eczema
- fissures
- hemorrhoids
- idiopathic proctitis
(x) ocular disorders associated with inflammatory,
allergic and/or proliferative processes:
- allergic keratitis, uveitis, iritis,
- conjunctivitis
- blepharitis
- optic neuritis
- chorioditis
- sympathetic ophthalmia
(xi) ear-nose-throat disorders associated with
inflammatory, allergic and/or proliferative
processes:
- allergic rhinitis, hayfever
- otitis externa, e.g. caused by contact exema,
infection etc.
- otitis media
(xii) neurological disorders associated with
inflammatory, allergic and/or proliferative
processes:
CA 02598207 2007-08-16
- 18 -
- cerebral edema, especially tumor-related
cerebral edema
- multiple sclerosis
- acute encephalomyelitis
- meningitis
- various types of seizures, e.g. infantile
spasms
(xiii) blood disorders associated with inflammatory,
allergic and/or proliferative processes:
- acquired hemolytic anemia
- idiopathic thrombocytopenia
(xiv) neoplastic disorders associated with
inflammatory, allergic and/or proliferative
processes:
- acute lymphatic leukemia
- malignant lymphomas
- lymphogranulomatoses
- lymphosarcomas
- extensive metastases, especially associated
with breast, bronchial and prostate
carcinomas
(xv) endocrine disorders associated with
inflammatory, allergic and/or proliferative
processes
- endocrine orbitopathy
- thyrotoxic crisis
- de Quervain's thyroiditis
- Hashimoto's thyroiditis
- Basedow's disease
(xvi) organ and tissue transplantations, graft-versus-
hose disease
(xvii) severe states of shock, e.g. anaphylactic shock,
systemic inflammatory response syndrome (SIRS)
(xviii) emesis associated with inflammatory, allergic
and/or proliferative processes:
- e.g. in combination with a 5-HT3 antagonist
in cytostic-related vomiting.
(xix) pain of inflammatory origin, e.g. lumbago
(xx) replacement therapy for:
CA 02598207 2007-08-16
- 19 -
- congenital primary adrenal insufficiency,
e.g. congenital adrenogenital syndrome
- acquired primary adrenal insufficiency, e.g.
Addison's disease, autoimmune adrenalitis,
post-infection, tumors, metastases etc.
- congenital secondary adrenal insufficiency,
e.g. congenital hypopituitarism
- acquired secondary adrenal insufficiency,
e.g. post-infection, tumors etc.
Medicaments comprising stereoisomers of the general
formula I show a particular efficacy for the following
disorders:
1. lung disorders
2. rheumatic disorders/autoimmune diseases
3. dermatological disorders
4. degenerative joint disorders
5. vessel inflammations
6. graft versus host disease
7. severe states of shock
8. emesis associated with inflammatory, allergic
and/or proliferative processes
9. inflammation-related pain.
In addition, the compounds of the invention of the
general formula (I) can be employed for the therapy and
prophylaxis of further pathological states which are
not mentioned above but for which synthetic
glucocorticoids are currently used (concerning this,
see Hatz, HJ, Glucocorticoide: Immunologische
Grundlagen, Pharmakologie und Therapierichtlinien,
Wissenschafliche Verlagsgesellachaft mbH, Stuttgart,
1998).
All the aforementioned indications are described in
detail in Hatz, HJ, Glucocorticoide: Immunologische
Grundlagen, Pharmakologie und Therapierichtlinien,
CA 02598207 2007-08-16
- 20 -
Wissenschafliche Verlagsgesellachaft mbH, Stuttgart,
1998).
The suitable dose for a therapeutic effect in the
abovementioned pathological states varies and depends
for example on the potency of the compound of the
general formula (I), the patient (e.g. height, weight,
gender, etc.), the mode of administration and the
nature and severity of the conditions to be treated,
and the use as prophylactic or therapeutic agent.
The invention relates to the use of the claimed
compounds for manufacturing a pharmaceutical
composition.
The invention further provides:
(i) the use of one of the compounds of the
invention of the general formula (I) or mixture
thereof for manufacturing a pharmaceutical
composition for the treatment or prevention of
inflammatory processes, and especially for the
treatment of a DISORDER (as defined above);
(ii) a method for the treatment or prevention of
inflammatory processes, especially for the
treatment of a DISORDER (as defined above),
which method includes administration of a
pharmaceutically effective amount of a compound
of the general formula (I), where the amount
alleviates or suppresses the disease or the
symptoms, and where the compound is given to a
patient, preferably a mammal, in particular a
human, requiring such a treatment;
(iii) a pharmaceutical composition having an
antiinflammatory effect, in particular for the
treatment of a DISORDER (as defined above),
where the composition includes one of the
compounds of the invention or mixture thereof
and, where appropriate, at least one
pharmaceutical excipient and/or carrier.
CA 02598207 2007-08-16
- 21 -
Satisfactory results are generally to be expected in
animals when the daily doses include a range from 1 pg
to 100 000 pg of the compound of the invention per kg
of body weight. For larger mammals, for example humans,
a recommended daily dose is in the range from 1 pg to
100 000 pg per kg of body weight. A dose of 10 to
30 000 pg per kg of body weight is preferred, and a
dose of 10 to 10 000 pg per kg of body weight is more
preferred. This dose is for example expediently
administered more than once a day. For the treatment of
acute shock (e.g. anaphylactic shock) it is possible to
give single doses which are distinctly higher than the
abovementioned doses.
The pharmaceutical products based on the novel
compounds are formulated in a manner known per se by
processing the active ingredient with the carrier
substances, fillers, substances influencing
disintegration, binders, humectants, lubricants,
absorbents, diluents, masking flavors, colorants etc.
which are in use in pharmaceutical technology, and
converting into the desired administration form:
Reference should be made in this connection to
Remington's Pharmaceutical Science, 15th ed. Mack
Publishing Company, East Pennsylvania (1980).
Particularly suitable for oral administration are
tablets, coated tablets, capsules, pills, powders,
granules, pastilles, suspensions, emulsions or
solutions.
Preparations for injection and infusion are possible
for parenteral administration.
Appropriately prepared crystal suspensions can be used
for intraarticular injection.
CA 02598207 2007-08-16
- 22 -
Aqueous and oily solutions for injections or
suspensions and corresponding depot preparations can be
used for intramuscular injection.
The novel compounds can be used for rectal
administration in the form of suppositories, capsules,
solutions (e.g. in the form of enemas) and ointments
both for systemic and for local therapy.
The novel compounds can be used in the form of aerosols
and inhalations for pulmonary administration thereof.
For local use on eyes, the external auditory canal,
middle ear, nasal cavity and paranasal sinuses, the
novel compounds can be used as drops, ointments,
tinctures and gels in appropriate pharmaceutical
preparations.
Formulations possible for topical application are gels,
ointments, greasy ointments, creams, pastes, dusting
powders, suspensions, emulsions and solutions. The
dosage of the compounds of the general formula (I) in
these preparations should be 0.01% - 20% in order to
achieve an adequate pharmacological effect.
The invention likewise includes the compounds of the
invention of the general formula (I) as therapeutic
active ingredient. The invention further includes the
compounds of the invention of the general formula (I)
as therapeutic active ingredient together with one or
more pharmaceutically suitable and acceptable
excipients and/or carriers.
The compounds of the invention of the general formula
(I) can also where appropriate be formulated and/or
administered in combination with further active
ingredients.
CA 02598207 2007-08-16
- 23 -
The invention therefore also relates to combination
therapies or combined compositions in which a compounds
of the general formula (I) or a pharmaceutically
acceptable salt thereof, or a pharmaceutical
composition comprising a compound of the general
formula (I) or a pharmaceutically acceptable salt
thereof, is administered either simultaneously (where
appropriate in the same composition) or successively
together with one or more medicaments for the treatment
of one of the pathological states mentioned above. For
the treatment of rheumatoid arthritis, osteoarthritis,
COPD (chronic obstructive pulmonary disorder), asthma
or allergic rhinitis, for example, it is possible to
combine a compound of the general formula (I) of the
present invention with one or more medicaments for the
treatment of such a condition. Where such a combination
is administered by inhalation, the medicament to be
combined can be selected from the following list:
= a PDE4 inhibitor including an inhibitor of the
PDE4D isoform;
= a selective (3.sub2.adrenoceptor agonist such as,
for example, metaproterenol, isoproterenol,
isoprenaline, albuterol, salbutamol, formoterol,
salmeterol, terbutaline, orciprenaline, bitolterol
mesylate, pirbuterol or indacaterol;
= a muscarine receptor antagonist (for example an
Ml, M2 or M3 antagonist, such as, for example, a
selective M3 antagonist) such as, for example,
ipratropium bromide, tiotropium bromide,
oxitropium bromide, pirenzepine or telenzepine;
= a modulator of chemokine receptor function (such
as, for example, a CCR1 receptor antagonist); or
= an inhibitor of p38 kinase function.
CA 02598207 2007-08-16
- 24 -
For another aspect of the present invention, such a
combination with a compound of the general formula (I)
or a pharmaceutically acceptable salt thereof is
employed for the treatment of COPD, asthma or allergic
rhinitis and can be administered by inhalation or
orally in combination with xanthine (such as, for
example, aminophylline or theophylline), which can
likewise be administered by inhalation or orally.
Preparation processes
The compounds of the invention of the general formula
(I) can be obtained in various ways. The preparation
processes described below likewise form a part of the
present invention.
Unless indicated otherwise, the substituents used in
the process descriptions below have the same meaning as
above in the section "Brief description of the
invention", including the definitions stated in the
section "Detailed description of the invention".
In general, compounds of the general formula (I) are
prepared by reacting aldehydes of the general formula
(II) with amines of the general formula R3-NHZ and
subsequent reduction of the imines obtained thereby.
The reaction sequence is summarized in scheme 1 below.
CA 02598207 2007-08-16
- 25 -
SCHEME 1: Reaction of compounds of the general formula
(II) to give compounds of the general formula
(I)
R Rsa R Rsa
Y
R2 \ RS R3-NH2 R2 ~ Y Rs
/ R / R5
R Ri2 ~ Ra R~i ~2 Ra
R R Rsa
14
~ OH CF2R 1 OH CF2R14
0
R3/
(II)
Red.
RI sa
RRR F2R1a
NH
Rs/
(I)
The compounds of the general formula (II) used in this
sequence can be obtained by various processes according
to the invention.
Process A: Preparation of compounds of the general
formula (II) from compounds of the general formula (IX)
via intermediate (IIIA)
In the first step of process A, compounds of the
general formula (IX) in which R is preferably a C1-C5-
alkyl group are reacted to give compounds of the
general formula (VIII) (scheme 2) . Compounds of the
CA 02598207 2007-08-16
- 26 -
general formula (IX) are known in the art and can be
prepared by processes known to the skilled worker.
SCHEME 2: Preparation of compounds of the general
formula (VIII)
Rt Rsa
Rt Rsa
2 R6 Y R6
Rs R2 R5
R R2 R a
4 R 12 R
R 3a
R
COZR COZR
(IX) (VIII)
If R3a in the compounds of the general formula (VIII) is
a hydrogen atom, the reaction takes place by reduction,
e.g. by catalytic hydrogenation of the compound (IX)
with elemental hydrogen over suitable metal catalysts.
Compounds of the general formula (VIII) in which R3a is
a cyano or alkyl group are obtainable by reacting
compounds of the general formula (IX) with cyanide ions
or organometallic alkyl compounds (e.g. organocopper
compounds). These processes are known in the art.
In the next step, the carboxylic esters of the general
formula (VIII) obtained in this way are reduced with a
suitable reducing agent (e.g. lithium aluminum hydride)
by processes known in the art to alcohols of the
general formula (VII) (scheme 3).
CA 02598207 2007-08-16
- 27 -
SCHEME 3: Preparation of compounds of the general
formula (VII)
Rt Rsa
Rs R1 Y Rsa
2 Rs
R5 2
Rs
R R12 R3a R4 R~~ R~2 ~ R4
R
C02R
OH
(VIII) (VII)
The aldehydes of the general formula (VI) are obtained
by careful oxidation of the alcohols of the general
formula (VII) by processes known in the art (scheme 4):
SCHEME 4: Preparation of compounds of the general
formula (VI)
R R63 R1 R6a
Y Rs R5 R5
2 Y Rs Rz OU
R11 R12 Rsa RR1t RR3a Ra
OH p
(VII) (VI)
The aldehydes of the general formula (VI) can be
reacted with suitable organometallic reagents M-CF2R14,
thus making it possible to introduce the group -CF2R14
into the molecule (scheme 5), where M is an
electrophilic leaving group. Examples of suitable
organometallic reagents are compounds of the general
formula CF2n+i-Si (CH3) 3 in the presence of a catalyst.
Suitable as catalyst in this process step are fluoride
salts or basic compounds such as alkali metal
carbonates (J. Am. Chem. Soc. 1989, 111, 393).
Alternatively, organolithium or -magnesium compounds
1
can also be used to introduce the group -CF2R9. In this
CA 02598207 2007-08-16
- 28 -
case, the alcohols of the general formula (V) are
obtained.
SCHEME 5: Preparation of compounds of the general
formula (V)
R' R6a Ri R6a
Rs
2 Y R6 2 ~ ?3.
R5 R / R R11 R12 3a R4 Rii R12 4R R
0 HO CF2R14
(VI) (V)
Ketones of the general formula (IV) can be obtained by
oxidation of the alcohols of the general formula (V)
using processes known in the art (e.g. with Dess-Martin
periodinane as oxidizing agent) (scheme 6)
SCHEME 6: Preparation of compounds of the general
formula (IV)
R Y R RI Y R~
R2 R6 2 Rs
R
R5 R5
11 4 11 4
R R12 R~ R R R12 Rsa R
HO CF2R 14 O CF2R14
(V) (IV)
The ketones of the general formula (IV) are then
converted into the corresponding cyanohydrins of the
general formula (IIIA) (scheme 7). Reagents suitable
for this purpose are, for example, potassium, sodium or
copper cyanide, or else trimethylsilyl cyanide.
According to the reagent employed, R in the general
formula (IIIA) is a hydrogen atom or a trimethylsilyl
group.
CA 02598207 2007-08-16
- 29 -
SCHEME 7: Preparation of compounds of the general
formula (IIIA):
R 6a R'
R o Y RR2 Y RR5 R5
R Riz Rsa R4 R R~2 R3a Ra
0 CF2R14 RO CF2R14
CN
(IV) (IIIA)
The cyanohydrins of the general formula (IIIA) are
then, where appropriate after removal of the trimethyl-
silyl group - converted with a suitable reducing agent
(e.g. diisobutylaluminum hydride) into the aldehydes of
the general formula (II) (scheme 8).
SCHEME 8: Preparation of compounds of the general
formula (II) from compounds of the general
formula (IIIA)
R R6a Ri R6a
Y Y
R6 2 \ R6
R2
R5 R / Rs
R11 R12 3a R4 Rt1 R12 3a Ra
R R
RO CN CF2R14 HO CF2R'4
O
(IIIA) (II)
Process B: Preparation of compounds of the general
formula (II) from compounds of the general formula (IX)
via intermediates (IIIB)
Synthesis of the precursor compounds of the general
formulae (VIII), (VII), (VI), (V) and (IV) proceeds in
process B as in process A.
The aldehyde of the general formula (IV) is then
converted with a suitable organometallic reagent (e.g.
CA 02598207 2007-08-16
- 30 -
a Grignard compound such as, for example,
vinylmagnesium bromide) into an unsaturated alcohol of
the general formula (IIIB) (scheme 9).
SCHEME 9: Preparation of compounds of the general
formula (IIIB):
Rt Y Rsa Rt Y Rsa
2 R6 2 R6
R5 RS
R Ri2 Rsa R R11 R12 Raa Ra
O CF2R14 HO CF2R14
(IV) (IIIB)
Compounds of the general formula (II) can be obtained
by oxidizing the double bond in the compounds of the
general formula (IIIB) (e.g. by ozone or by transition
metal oxides such as, for example, osmium tetraoxide
with subsequent cleavage using a suitable oxidizing
agent such as, for example, sodium periodate)
(scheme 10).
SCHEME 10: Preparation of compounds of the general
formula (II) from compounds of the general
formula (IIIB)
R R6a R R6a
R2 Y R6 R2 Oe Y Rs
R5 R5
R11 R12 sa R4 R11 R~ Ra
R
HO CF2R14 HO CF2R14
O
(IIIB) (il)
CA 02598207 2007-08-16
- 31 -
Process C: Preparation of compounds of the general
formula (II) from compounds of the general formula
(XIII)
Compounds of the general formula (II) are prepared from
compounds of the general formula (XIII) known in the
art by firstly reacting the latter with a-keto esters
of the general formula R14CF2-C (=O) -COzR (where R is
preferably a C1-C5-alkyl group) with catalysis by -
optionally chiral - Lewis acids in an ene reaction to
give compounds of the general formula (XII) (scheme
11).
SCHEME 11: Preparation of compounds of the general
formula (XII)
R R6a R1 RBa
RZ Y R6 2 Y R6
Rs Rs
R11 R12 R4 R R~2
CFzR'4
OH C02R
(XIII) (XII)
The diol of the general formula (XI) can be obtained
from the compound of the general formula (XII) by
reducing the ester function by processes known in the
art (e.g. with lithium aluminum hydride) (scheme 12).
CA 02598207 2007-08-16
- 32 -
SCHEME 12: Preparation of compounds of the general
formula (XI)
Y R1 R6a
R~ R~ R s Y
Rz Rs
R5 Rz
R11 1z Rs
R 14 Ri, Riz
CF2R CFZR1a
COZR
OH OH
(XII) OH
(XI)
This diol (XI) can be converted into a compound of the
general formula (X) by reducing the double bond (e.g.
by catalytic hydrogenation with elemental hydrogen on a
suitable metal catalyst) (scheme 13).
SCHEME 13: Preparation of compounds of the general
formula (X)
Ri y Rsa R1 Rsa
RZ Rs Y z Rs
/ / Rs - R / R5
11
R R12 R1, R12
,a
CF2R CF2R14
OH OH
(XI) OH OH
(X)
Aldehydes of the general formula (II) in which the
substituents R3a and R 4 in the compounds of the general
formulae (I) and (II) have the meaning of a hydrogen
atom can be obtained from these diols of the general
formula (X) by oxidizing the terminal hydroxy group
(scheme 14).
CA 02598207 2007-08-16
- 33 -
SCHEME 14: Preparation of compounds of the general
formula (II) from compounds of the general
formula (X)
RI R6a RI Rsa
R2 R z Rs
Rs 5
R R12 R1i 12
CFzR ia CF2R14
OH OH
OH
(X) O
(II)
As an alternative to the reaction sequence indicated
above for process C, esters of the general formula
(XII) can also be reduced to the corresponding
aldehydes, which can be reacted directly with the
primary amines of the general formula R3-NH2.
Subsequently, the isolated double bond present in the
right-hand ring of the compound is hydrogenated with
suitable reducing agents. This alternative sequence
also results in compounds of the general formula (I) in
which the substituents R3a and R4 have the meaning of a
hydrogen atom.
Examples
Synthesis 1: Preparation of compounds of the general
formula (VII)
A. 2-(Chroman-4-yl)ethanol:
2.27 g of ethyl (2-chroman-4-yl) acetate (J. Med. Chem.
44, (2001), pp. 1085-1098) are stirred with 800 mg of
lithium aluminum hydride in 50 ml of THF at 0 C for
2 hours. Saturated ammonium chloride solution and ethyl
acetate are added to the mixture, which is then
filtered through kieselguhr. The aqueous phase is
extracted with ethyl acetate, and the combined organic
phases are washed with brine and dried with sodium
CA 02598207 2007-08-16
- 34 -
sulfate. 1.9 g of 2-(chroman-4-yl)ethanol are obtained
as crude yield.
1H NMR (CDC13): S 1.72-1.90 (m, 2H), 2.0-2.2 (m, 2H),
2.96-3.09 (m, 1H), 3.80 (t, 2H), 4.13-4.25 (m, 2H),
6.79 (d, 1H), 6.87 (t, 1H), 7.10 (t, 1H), 7.14 (d, 1H).
B. 2-(4-Methylchroman-4-yl)ethanol:
11.5 ml of methylmagnesium chloride solution [3.3M in
THF] are slowly added to 7.3 g of ethyl E/Z-(chroman-4-
ylidene)acetate (J. Med. Chem. 44, (2001), pp. 1085-
1098), 100 mg of copper(I) chloride and 5.1 ml of
chlorotrimethylsilane in 55 ml of THF at 0 C in such a
way that the temperature always remains below 5 C. The
mixture is stirred at 0 C for one hour and at room
temperature for 10 hours. Saturated ammonium chloride
solution is added to the mixture, which is then
extracted with ether. The combined organic phases are
washed with brine, dried with sodium sulfate and
concentrated in vacuo. Chromatography on silica gel
(hexane/ethyl acetate 100:0 -> 90:10) results in ethyl
2-(4-methylchroman-4-yl)acetate as crude product. This
is mixed in 50 ml of THF at 0 C with 1 g of lithium
aluminum hydride and stirred at 0 C for 1.5 hour. The
mixture is cautiously added to sat ammonium chloride
solution and diluted with ethyl acetate. It is filtered
through kieselguhr, and the aqueous phase is extracted
with ethyl acetate. The combined organic phases are
washed with brine, dried with sodium sulfate and
concentrated in vacuo. Chromatography on silica gel
(hexane/ethyl acetate 100:0 -> 60:40) results in 1.2 g
of 2-(4-methylchroman-4-yl)ethanol as colorless oil.
1H NMR (CDC13) : 8= 1.36 (s, 3H), 1.74 (ddd, 1H) , 1.91-
2.11 (m, 3H), 3.57-3.75 (m, 2H), 4.10-4.28 (m, 2H),
6.79 (d, 1H), 6.89 (t, 1H), 7.08 (t, 1H), 7.22 (d, 1H).
C. The following can likewise be prepared by the
described processes:
2-(6-methylchroman-4-yl)ethanol
2-(7-methylchroman-4-yl)ethanol
CA 02598207 2007-08-16
- 35 -
2-(6-fluorochroman-4-yl)ethanol
2-(6-methoxychroman-4-yl)ethanol
2-(7-methoxychroman-4-yl)ethanol
2-(1,2,3,4-tetrahydronaphthalen-1-yl)ethanol
2-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)ethanol
2-(4-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)ethanol
2-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)ethanol
2-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-
ethanol
2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)ethanol
2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)ethanol
2-(thiochroman-4-yl)ethanol:
2-(4-methylthiochroman-4-yl)ethanol
2-(4-ethylchroman-4-yl)ethanol
2-(4-propylchroman-4-yl)ethanol
Synthesis 2: Preparation of compounds of the general
formula (VI)
A. 2-(Chroman-4-yl)ethanal:
1.7 ml of DMSO in 25.0 ml of dichloromethane are added
to 1 ml of oxalyl chloride in 25.0 ml of
dichloromethane at -78 C. After 5 min, 1.9 g of
2-(chroman-4-yl)ethanol in 25.0 ml of dichloromethane
are added dropwise at -78 C. After 15 min, 7 ml of
triethylamine are added, and the mixture is slowly
warmed to RT. It is washed with water, brine, 1%
strength sulfuric acid and sat. sodium bicarbonate
solution, dried with sodium sulfate and concentrated in
vacuo. 1.81 g of the title compound are obtained as a
yellow oil.
1H NMR (CDC13): 6 1.73-1.86 (m, 1H), 2.11-2.28 (m, 1H),
2.75 (dd, 1H), 2.93 (dd, 1H), 3.43-3.56 (m, 1H), 4.11-
4.25 (m, 2H), 6.81 (d, 1H) , 6.87 (t, 1H), 7. 03-7 . 17 (m,
2H), 9.88 (1H).
B. 2-(4-Methylchroman-4-yl)ethanal:
1.0 ml of DMSO in 25.0 ml of dichloromethane are added
to 0.58 ml of oxalyl chloride in 25.0 ml of
CA 02598207 2007-08-16
- 36 -
dichloromethane at -78 C. After 5 min, 1.2 g of
2-(methylchroman-4-yl)ethanol in 25.0 ml of
dichloromethane are added dropwise at -78 C. After
15 min, 4 ml of triethylamine are added, and the
mixture is slowly warmed to room temperature. It is
washed with water, brine, 1% strength sulfuric acid and
sat. sodium bicarbonate solution, dried with sodium
sulfate and concentrated in vacuo. Chromatography on
silica gel (hexane/ethyl acetate 100:0 -> 90:10)
results in 970 mg of 2-(4-methylchroman-4-yl)ethanal as
colorless oil.
1H NMR (CDC13) 1.48 (s, 3H), 1.92 (ddd, 1H), 2.12
(ddd, 1H), 2.59 (dd, 1H), 2.69 (dd, 1H), 4.11-4.29 (m,
2H), 6.83 (d, 1H), 6.92 (t, 1H), 7.12 (t, 1H), 7.23 (d,
1H), 9.66 (s, 1H).
C. The following can likewise be prepared by the
processes described above:
2-(6-methylchroman-4-yl)ethanal
2-(7-methylchroman-4-yl)ethanal
2-(6-fluorochroman-4-yl)ethanal
2-(6-methoxychroman-4-yl)ethanal
2-(7-methoxychroman-4-yl)ethanal
2-(1,2,3,4-tetrahydronaphthalen-l-yl)ethanal
2-(2-methyl-1,2,3,4-tetrahydronaphthalen-l-yl)ethanal
2-(4-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)ethanal
2-(5-methoxy-1,2,3,4-tetrahydronaphthalen-l-yl)ethanal
2-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-l-yl)-
ethanal
2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)ethanal
2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)ethanal
2-(thiochroman-4-yl)ethanal
2-(4-methylthiochroman-4-yl)ethanal
2-(4-ethylchroman-4-yl)ethanal
2-(4-propylchroman-4-yl)ethanal
CA 02598207 2007-08-16
- 37 -
Synthesis 3: Preparation of compounds of the general
formula (V)
A. 2-(Chroman-4-yl)-1-trifluoromethylethanol:
2 ml of tetrabutylammonium fluoride solution (lM in
THF) are added to a solution of 1.8 g of 2-(chroman-4-
yl)ethanal and 4.6 ml of trifluoromethyltrimethylsilane
in 60 ml of THF at 0 C and stirred for 1 hour. A
spatula tip of solid tetrabutylammonium fluoride is
added once again, and water is added. The mixture is
extracted with ethyl acetate, and the organic phase is
washed with brine and dried with sodium sulfate.
Chromatography on silica gel (hexane/ethyl acetate 95:5
-> 90:10) results in 2.1 g of 2-(chroman-4-yl)-1-
trifluoromethylethanol as mixture of diastereomers.
1H NMR (CDC13, selected signals): 8= 1.76-1.97 (m, 2H),
1.98-2.34 (m, 2H), 3.08-3.25 (m, 1H), 4.03-4.35 (m,
3H), 6.88-6.95 (m, 2H), 7.06-7.21 (m, 2H).
B. 2-(4-Methylchroman-4-yl)-1-trifluoromethylethanol:
0.87 ml of tetrabutylammonium fluoride solution (1M in
THF) is added to a solution of 870 mg of 2-(4-
methylchroman-4-yl)ethanal and 2 ml of trifluoromethyl-
trimethylsilane in 30 ml of THF at 0 C and stirred for
1 hour. A spatula tip of solid tetrabutylammonium
fluoride is added once again, and water is added. The
mixture is extracted with ethyl acetate, and the
organic phase is washed with brine and dried with
sodium sulfate. 1.2 g of 2-(4-methylchroman-4-yl)-l-
trifluoromethylethanol are obtained as brown oil
(mixture of diastereomers).
1H NMR (CDC13, selected signals) : 8= 1.34 (s, 3H) , 1. 35
(s, 3H), 1.68 (ddd, 1H), 1.78 (ddd, 1H), 1.85 (dd, 1H),
1.90-2.04 (m), 2.05-2.14 (m), 2.31 (ddd, 1H), 3.73-3.83
(m, 1H), 3.97-4.22 (m), 6.77 (d, 1H, diaster. A+B),
6.80-6.87 (m, 1H, diaster. A+B), 7.0-7.1 (m), 7.17-7.21
(m).
CA 02598207 2007-08-16
- 38 -
C. The following can likewise be prepared by processes
described above:
2-(6-methylchroman-4-yl)-1-trifluoromethylethanol
2-(7-methylchroman-4-yl)-1-trifluoromethylethanol
2-(6-fluorochroman-4-yl)-l-trifluoromethylethanol
2-(6-methoxychroman-4-yl)-1-trifluoromethylethanol
2-(7-methoxychroman-4-y1)-1-trifluoromethylethanol
2-(1,2,3,4-tetrahydronaphthalen-l-yl)-1-
trifluoromethylethanol
2-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1-
trifluoromethylethanol
2-(4-methyl-1,2,3,4-tetrahydronaphthalen-l-yl)-1-
trifluoromethylethanol
2-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1-
trifluoromethylethanol
2-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-l-yl)-1-
trifluoromethylethanol
2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1-
pentafluoroethylethanol
2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-l-yl)-1-
trifluoromethylethanol
2-(thiochroman-4-yl)-1-trifluoromethylethanol:
2-(4-methylthiochroman-4-yl)-1-trifluoromethylethanol
2-(4-ethylchroman-4-yl)-l-trifluoromethylethanol
2-(4-propylchroman-4-yl)-1-trifluoromethylethanol
Synthesis 4: Preparation of compounds of the general
formula (IV)
A. 3-(Chroman-4-yl)-1,1,1-trifluoropropan-2-one:
54.0 g of Dess-Martin periodinane in 650 ml of
dichloromethane are mixed at room temperature with a
solution of 9.0 g of 2-(chroman-4-yl)-1-
trifluoromethylethanol in 65 ml of dichloromethane and
stirred for 10 hours. The mixture is mixed with sat.
sodium bicarbonate solution, diluted with diethyl ether
and stirred with sodium thiosulfate solution for
30 mi.n. The organic phase is separated off and washed
with water. It is dried with sodium sulfate and
CA 02598207 2007-08-16
- 39 -
concentrated in vacuo. 7.95 g of 3-(chroman-4-yl)-
1,1,1-trifluoropropan-2-one are obtained.
1H NMR (CDC13) : cS = 1.62-1.77 (m, 1H), 2.08-2.22 (m,
1H), 2.94 (dd, 1H), 3.11 (dd, 1H), 3.39-3.50 (m, 1H),
4. 02-4 . 20 (m, 2H), 6.75 (d, 1H), 6.81 (t, 1H), 6.97 (d,
1H), 7.05 (t, 1H).
B. 3-(4-Methychroman-4-yl)-1,1,1-trifluoropropan-2-one:
7.8 g of Dess-Martin periodinane in 100 ml of
dichloromethane are mixed at 0 C with a solution of
1.2 g of 2-(chroman-4-yl)-1-trifluoromethylethanol in
ml of dichloromethane and stirred at 0 C for 1 hour.
The mixture is mixed with sat. sodium bicarbonate
solution, diluted with diethyl ether and stirred with
15 sodium thiosulfate solution for 30 min. The organic
phase is separated off and washed with water. It is
dried with sodium sulfate and concentrated in vacuo.
1.1 g of 3-(4-methylchroman-4-yl)-1,1,1-trifluoro-
propan-2-one are obtained as brown oil.
20 1H NMR (CDC13): 6= 1.50 (s, 3H), 2.0 (ddd, 1H), 2.25
(ddd, 1H), 3.10 (s, 2H), 4.10-4.28 (m, 2H), 6.83 (d,
1H), 6.90 (t, 1H), 7.13 (t, 1H), 7.18 (d, 1H).
C. The following can likewise be prepared by processes
described above:
2-(6-methylchroman-4-yl)-1,1,1-trifluoropropan-2-one
2-(7-methylchroman-4-yl)-1,1,1-trifluoropropan-l-one
2-(6-fluorochroman-4-yl)-1,1,1-trifluoropropan-2-one
2-(6-methoxychroman-4-yl)-1,1,1-trifluoropropan-2-one
2-(7-methoxychroman-4-yl)-1,1,1-trifluoropropan-2-one
2-(1,2,3,4-tetrahydronaphthalen-1-yl)-1,1,1-
trifluoropropan-2-one
2-(2-methyl-1,2,3,4-tetrahydronaphthalen-l-yl)-1,1,1-
trifluoropropan-2-one
2-(4-methyl-1,2,3,4-tetrahydronaphthalen-l-yl)-1,1,1-
trifluoropropan-2-one
2-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1,1,1-
trifluoropropan-2-one
CA 02598207 2007-08-16
- 40 -
2-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-
1,1,1-trifluoropropan-2-one
4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-
1,1,1,2,2-pentafluorobutan-3-one
2-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-1,1,1-
trifluoropropan-2-one
2-(4-methylthiochroman-4-yl)-1,1,1-trifluoropropan-2-
one
2-(4-ethylchroman-4-yl)-1,1,1-trifluoropropan-2-one
2-(4-propylchroman-4-yl)-1,1,1-trifluoropropan-2-one
Synthesis 5: Preparation of compounds of the general
formula (IIIA)
3-(Chroman-4-yl)-2-trifluoromethyl-2-trimethylsilyloxy-
propionitrile
140 mg of 3-(chroman-4-yl)-1,1,1-trifluoropropan-2-one
in 2.5 ml of dichloromethane are mixed with 124 mg of
trimethylsilyl cyanide at room temperature and stirred
for 4 hours (J. Med. Chem. 2003, (46), pp. 2494-2501).
The mixture is added to water and extracted with ethyl
acetate. The combined organic phases washed with brine,
dried with sodium sulfate and concentrated in vacuo.
204 mg of the title compound are obtained as oil.
Synthesis 6: Preparation of compounds of the general
formula (II) from compounds of the general formula
(IIIA)
3-(Chroman-4-yl)-2-hydroxy-2-trifluoromethylpropion-
aldehyde
0.4 ml of DIBAL-H solution (1.5M in toluene) is added
to 204 mg of 3-(chroman-4-yl)-2-trifluoromethyl-
2-trimethylsilyloxypropionitrile in 5 ml of toluene at
-70 C, and the mixture is stirred at -70 C for 4 hours.
Addition of 1 ml of ethyl acetate is followed by
warming to room temperature, addition of 1M sulfuric
acid and stirring for 10 hours. The mixture is diluted
with water and extracted with ethyl acetate, and the
CA 02598207 2007-08-16
- 41 -
combined organic phases are washed with brine, dried
with sodium sulfate and concentrated in vacuo. The
remaining oil is taken up in 1 ml of THF, mixed with
tetrabutylammonium fluoride solution [1M in THF] and
stirred at room temperature for 6 hours. Addition of
water is followed by extraction with ethyl acetate,
washing with brine, drying and concentrating in vacuo.
124 mg of the title compound are obtained as an orange-
colored oil.
MS (ei) : M+ = 274
Synthesis 7: Preparation of compounds of the general
formula (IIIB)
A. 1-(Chroman-4-yl)-2-trifluoromethyl-3-buten-2-ol:
A solution of 7.4 g of 3-(chroman-4-yl)-1,1,1-
trifluoropropan-2-one in 75 ml of THF is added to
33.3 ml of vinylmagnesium bromide solution [1H in THF]
at room temperature. The mixture is stirred at room
temperature for 4 hours and then added to sat. ammonium
chloride solution. The mixture is extracted with ethyl
acetate, and the combined organic phases are washed
with brine, dried with sodium sulfate and concentrated
in vacuo. Chromatography on silica gel (hexane/ethyl
acetate 100:0 -> 90:10) results in 7.0 g of 1-(chroman-
4-yl)-2-trifluoromethyl-3-buten-2-ol as yellow oil
(mixture of diastereomers).
1H NMR (CDC13, selected signals): 1.8-1.9 (m), 1.97
(dd, 1H), 2.01-2.37 (m), 2.93-3.03 (m, 1H), 3.03-3.12
(m, 1H), 4.05-4.27 (m), 5.53 (d, 1H), 5.58-5.70 (m,
3H), 5.97-6.17 (m, 2H), 6.73-6.94 (m, 4H), 7.02 (d,
1H), 7.04-7.13 (m, 2H), 7.21 (d, 1H).
B. 1-(4-Methylchroman-4-yl)-2-trifluoromethyl-3-buten-
2-ol:
A solution of 1.1 g of 3-(4-methylchroman-4-yl)-1,1,1-
trifluoropropan-2-one in 30 ml of THF is added to
9.2 ml of vinylmagnesium bromide solution [1H in THF]
at room temperature. The mixture is stirred at room
CA 02598207 2007-08-16
- 42 -
temperature for 5 hours and then added to sat. ammonium
chloride solution. The mixture is extracted with ethyl
acetate, the combined organic phases are washed with
brine, dried with sodium sulfate and concentrated in
vacuo. Chromatography on silica gel (heaxane/ethyl
acetate 100:0 -> 95:5) results in 930 g of 1-(4-
methylchroman-4-yl)-2-trifluoromethyl-3-buten-2-ol as
oil.
MS (ei) : M+ = 286
C. The following can likewise be prepared by processes
described above:
1-(6-methylchroman-4-yl)-2-trifluoromethyl-3-buten-2-ol
1-(7-methylchroman-4-yl)-2-trifluoromethyl-3-buten-2-ol
1-(6-fluorochroman-4-yl)-2-trifluoromethyl-3-buten-2-o1
1-(6-methoxychroman-4-yl)-2-trifluoromethyl-3-buten-
2-ol
1-(7-methoxychroman-4-yl)-2-trifluoromethyl-3-buten-
2-ol
1-(1,2,3,4-tetrahydronaphthalen-1-yl)-2-trifluoro-
methyl-3-buten-2-ol
1-(2-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-2-tri-
fluoromethyl-3-buten-2-ol
1-(4-methyl-1,2,3,4-tetrahydronaphthalen-l-yl)-2-tri-
fluoromethyl-3-buten-2-ol
1-(5-methoxy-1,2,3,4-tetrahydronaphthalen-l-yl)-2-tri-
fluoromethyl-3-buten-2-ol
1-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-l-yl)-2-
trifluoromethyl-3-buten-2-ol
1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-
2-pentafluoroethyl-3-buten-2-ol
1-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-2-tri-
fluoromethyl-3-buten-2-ol
1-(4-methylthiochroman-4-yl)-2-trifluoromethyl-3-buten-
2-ol
1-(4-ethylchroman-4-yl)-2-trifluoromethyl-3-buten-2-ol
1-(4-propylchroman-4-yl)-2-trifluoromethyl-3-buten-2-ol
CA 02598207 2007-08-16
- 43 -
Synthesis 8: Preparation of compounds of the general
formula (II) from compounds of the general formula
(IIIB)
A. 3-(Chroman-4-yl)-2-hydroxy-2-trifluoromethylpropion-
aldehyde:
Ozone is passed into a solution of 7.0 g of 1-(chroman-
4-yl)-2-trifluoromethyl-3-buten-2-ol in 450 ml of
dichloromethane and 120 ml of methanol at -70 C until
the solution assumes a blue coloration. Argon is then
passed through the solution for one minute, 3.6 ml of
dimethyl sulfide are added, and the mixture is stirred
at -70 C for one hour. It is slowly warmed to room
temperature and then stirred for 10 hours. The mixture
is added to water and extracted with dichloromethane.
The combined organic phases are dried and concentrated
in vacuo. 6.6 g of 3-(chroman-4-yl)-2-hydroxy-
2-trifluoromethylpropionaldehyde are obtained as yellow
oil.
MS (ei) : M+ = 274
B. 2-Hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropionaldehyde:
Ozone is passed into a solution of 900 mg of 1-(4-
methylchroman-4-yl)-2-trifluoromethyl-3-buten-2-ol in
56 ml of dichloromethane and 14 ml of methanol at -70 C
until the solution assumes a blue coloration. Argon is
then passed through the solution for one minute,
0.42 ml of dimethyl sulfide is added, and the mixture
is stirred at -70 C for one hour. It is slowly warmed
to room temperature and then stirred for 10 hours. The
mixture is added to water and extracted with
dichloromethane. The combined organic phases are dried
and concentrated in vacuo. Chromatography on silica gel
(hexane/ethyl acetate 100:0 -> 96:4) results in 330 mg
of 2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropionaldehyde as yellow oil (mixture of
diastereomers).
CA 02598207 2007-08-16
- 44 -
1H NMR (CDC13, selected signals) 8 = 1.38 (s, 3H,
diaster. A), 1.43 (s, 3H, diaster. B), 1.57-1.65 (m,
2H), 1.81 (ddd, 1H), 2.13 (ddd, 1H), 2.37 (d, 1H,
diaster. B), 2.45-2.60 (m), 2.83 (d, 1H. diaster. B),
3.69 (s, 1H, diaster. A), 3.86 (s, 1H, diaster. B),
3.97 (dd, 1H, diaster. B), 4. 08-4 . 35 (m), 6.78-6.84 (m,
1H, diaster. A+B), 6.88-6.95 (m, 1H), 7.07-7.21 (m),
7.23-7.30 (m), 8.88 (s, 1H, diaster. B), 9.56 (s, 1H,
diaster. A).
C. The following can likewise be prepared by processes
described above:
2-hydroxy-3-(6-methylchroman-4-yl)-2-trifluoromethyl-
propionaldehyde
2-hydroxy-3-(7-methylchroman-4-yl)-2-trifluoromethyl-
propionaldehyde
3-(6-fluorochroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propionaldehyde
2-hydroxy-3-(6-methoxychroman-4-yl)-2-trifluoromethyl-
propionaldehyde
2-hydroxy-3-(7-methoxychroman-4-yl)-2-trifluoromethyl-
propionaldehyde
2-hydroxy-3-(1,2,3,4-tetrahydronaphthalen-l-yl)-2-tri-
fluoromethylpropionaldehyde
2-hydroxy-3-(2-methyl-1,2,3,4-tetrahydronaphthalen-
1-yl)-2-trifluoromethylpropionaldehyde
2-hydroxy-3-(4-methyl-1,2,3,4-tetrahydronaphthalen-
1-yl)-2-trifluoromethylpropionaldehyde
2-hydroxy-3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-
1-yl)-2-trifluoromethylpropionaldehyde
3-(5,7-dimethy-1,2,3,4-tetrahydronaphthalen-1-yl)-
2-hydroxy-2-trifluoromethylpropionaldehyde
2-hydroxy-3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-
1-yl)-2-pentafluoroethylpropionaldehyde
3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-l-yl)-
2-hydroxy-2-trifluoromethylpropionaldehyde
2-hydroxy-3-(4-methylthiochroman-4-yl)-2-trifluoro-
methylpropionaldehyde
CA 02598207 2007-08-16
- 45 -
3-(4-ethylchroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propionaldehyde
2-hydroxy-3-(4-propylchroman-4-yl)-2-trifluoromethyl-
propionaldehyde
Synthesis 9: Preparation of compounds of the general
formula (XIII)
4-Methylenethiochroman:
79.9 ml of n-butyllithium solution [1.6M in hexane] are
added dropwise to a solution of 40.9 g of inethyl-
triphenylphosphonium bromide in 470 ml of THF at -10 C.
The mixture is stirred for a further 45 minutes and
then 18.8 g of thiochroman-4-one are added. The mixture
is mixed with a further 330 ml of THF and stirred at
room temperature for 1 hour. The mixture is diluted
with water and extracted with ethyl acetate. The
combined organic phases are washed with water and
brine, dried with sodium sulfate and concentrated in
vacuo. Chromatography on silica gel (hexane/ethyl
acetate 100:0 -> 90:10) results in 11.7 g of
4-methylenethiochroman as oil.
1H NMR (CDC13) 6= 2.8-2.9 (m, 2H), 3.03-3.13 (m, 2H),
4.98 ( s , 1H) , 5. 5(s, 1H), 6. 98-7 .08 (m, 1H), 7. 08-7 . 17
(m, 2H), 7.54 (d, 1H).
Synthesis 10: Preparation of compounds of the general
formula (XII)
A. Ethyl 2-hydroxy-3-[(2H)thiochromen-4-yl]-2-tri-
fluoromethylpropionate:
3.54 g of binaphthol are added to a solution of 1.3 ml
of titanium tetraethoxide in 10 ml of toluene at room
temperature and stirred for one hour. A solution of
10 g of 4-methylenethiochroman in 60 ml of toluene and
15 ml of trifluoropyruvate is added to this solution.
The reaction solution is stirred at 120 C for 3 hours
and at room temperature for a further 10 hours. The
reaction solution is diluted with water and ethyl
CA 02598207 2007-08-16
- 46 -
acetate and filtered through kieselguhr. The organic
phase is washed with brine, dried over sodium sulfate
and concentrated in vacuo. Chromatography on silica gel
(hexane/ethyl acetate 100:0 -> 90:10) results in 19.8 g
of ethyl 2-hydroxy-3-[(2H)thiochromen-4-yl]-2-tri-
fluoromethylpropionate as brown oil.
1H NMR (CDC13) : b = 1.19 (t, 3H), 3.03 (d, 1H), 3.17
(dd, 1H), 3.30 (dd, 1H), 3.81 (s, 1H), 3.87-3.97 (m,
1H), 4.09-4.18 (m, 1H), 6.10 (t, 1H), 7.07-7.18 (m,
2H), 7.30 (d, 1H), 7.42 (d, 1H).
B. Ethyl 3-(2H-chromen-4-yl)-2-hydroxy-2-(trifluoro-
methyl)propionate
g (307 mmol) of zinc dust and 710 mg (2.5 mmol) of
15 lead(II) chloride are suspended in 200 ml of THF and,
at room temperature, 11.2 ml (100 mmol) of dibromo-
methane are added. The mixture is stirred for a further
60 minutes, and 33 ml (33 mmol) of a 1M titanium(IV)
chloride solution in dichloromethane are added dropwise
20 over the course of 40 minutes while cooling in ice.
After one hour, 4.4 g (30 mmol) of solid chroman-4-one
are added in several portions at room temperature, the
reaction warming to 30 C. The mixture is stirred at
room temperature for a further 3 hours. It is diluted
with diethyl ether and the reaction mixture is
cautiously added to a mixture 4M hydrochloric acid and
ice. Separation of the phases is followed by extraction
with diethyl ether, washing with water, drying over
sodium sulfate and removal of the solvent. The crude
product is purified by column chromatography on silica
gel (hexane/isopropyl ether 0-20%) to result in 2.75 g
of 4-methylenechroman.
0.60 ml (0.3 mmol) of a 0.5M titanium tetraisopropoxide
solution in toluene is added to 170 mg (0.60 mmol) of
1,1'-bi-2-naphthol, and the red solution is stirred at
room temperature for 2 hours. 1.0 g (6.8 mmol) of
4-methylenechroman and 2.3 (13.6 mmol) of ethyl
trifluoropyruvate are added, and the mixture is heated
CA 02598207 2007-08-16
- 47 -
at 110 C for 2 hours. Cooling is followed immediately
by purification by column chromatography on silica gel
(hexane/ethyl acetate 20%) to result in 1.15 g of ethyl
3-(2H-chromen-4-yl)-2-hydroxy-2-(trifluoromethyl)-
propionate.
Synthesis 11: Preparation of compounds of the general
formula (XI)
1,2-Dihydroxy-3-[(2H)thiochromen-4-yl]-2-trifluoro-
methylpropane:
8.7 g of lithium aluminum hydride are added to a
solution of 19.0 g of ethyl 2-hydroxy-3-
[(2H)thiochromen-4-yl]-2-trifluoromethylpropionate in
500 ml of THF at 0 C, and the mixture is stirred at 0 C
for 2 hours and at room temperature for 1 hour. The
mixture is cautiously mixed with sat. ammonium chloride
solution and extracted with ethyl acetate. The combined
organic phases are washed with water and brine, dried
over sodium sulfate and concentrated in vacuo.
Chromatography on silica gel (hexane/ethyl acetate
100:0 -> 80:20) results in 11 g of 1,2-dihydroxy-
3-[(2H)thiochromen-4-yl]-2-trifluoromethylpropane as
colorless oil.
1H NMR (CDC13): 8 = 2.86 (d, 1H), 3.02-3.11 (m, 2H),
3.23-3.33 (m, 2H), 3.54-3.70 (m, 2H), 6.13 (t, 1H),
7.11-7.21 (m, 2H), 7.35 (d, 1H), 7.46 (d, 1H).
Synthesis 12: Preparation of compounds of the general
formula (X)
1,2-Dihydroxy-3-(thiochroman-4-yl)-2-trifluoromethyl-
propane:
9 g of 1,2-dihydroxy-3-[(2H)thiochromen-4-yl]-2-tri-
fluoromethylpropane in 130 ml of ethanol are mixed with
9 g of Raney nickel and stirred under a hydrogen
atmosphere at 50 bar in an autoclave for 2 hours. 9 g
of Raney nickel are again added, and reaction with
hydrogen at 50 bar is continued for 5 hours. The
CA 02598207 2007-08-16
- 48 -
mixture is filtered with suction through kieselguhr and
concentrated in vacuo. 8.1 g of 1,2-dihydroxy-
3-(thiochroman-4-yl)-2-trifluoromethylpropane are
obtained as yellow oil (mixture of diastereomers).
'H NMR (CDC13, selected signals): 6 = 1.92 (dd, 1H),
1.95-2.07 (m), 2.18 (dd, 1H), 2.40-2.53 (m, 2H),
2.97-3.08 (m, 2H), 3.20-3.31 (m, 2H), 3.32-3.40 (m,
2H), 3.61 (t, 2H), 3.90 (d, 1H), 3.96 (d, 1H), 7.01-
7.08 (m), 7.09-7.20 (m).
Synthesis 13: Preparation of compounds of the general
formula (II) from compounds of the general formula (X)
2-Hydroxy-3-(thiochroman-4-yl)-2-trifluoromethyl-
propionaldehyde:
4.6 ml of DMSO in 80 ml of dichloromethane are added to
2.4 ml of oxalyl chloride in 240 ml of dichloromethane
at -78 C. After 5 min, 1.2 of 1,2-dihydroxy-
3-(thiochroman-4-yl)-2-trifluoromethylpropane in 80 ml
of dichloromethane are added dropwise at -78 C. After
15 min, 22.8 ml of triethylamine are added, and the
mixture is slowly warmed to room temperature. It is
with water and brine, dried with sodium sulfate and
concentrated in vacuo. Chromatography on silica gel
(hexane/ethyl acetate 100:0 -> 85:15) results in 4.0 g
of 2-hydroxy-3-(thiochroman-4-yl)-2-trifluoromethyl-
propionaldehyde as yellow oil (mixture of
diastereomers).
1H NMR (CDC13, selected signals): 6 = 1.75-1.93 (m),
1.95-2.03 (m), 2.12-2.28 (m), 2.60 (dd, 1H), 2.81-2.90
(m, 2H), 2.95-3.02 (m), 3.03-3.18 (m), 6.84-7.10 (m),
9.12 (s, 1H, diaster. A), 9.66 (s, 1H, diaster. B).
Synthesis 14: Preparation of imines from compounds of
the general formula (II)
A. 5-[3-(Chroman-4-yl)-2-hydroxy-2-
trifluoromethylpropylideneamino]quinolin-2[1H]-one:
CA 02598207 2007-08-16
, . .
- 49 -
0.76 ml of titanium tetraisopropoxide is added to a
solution of 600 mg of 3-(chroman-4-yl)-2-hydroxy-
2-trifluoromethylpropionaldehyde and 386 mg of
5-aminoquinolin-2[1H]-one in 22 ml of toluene, and the
mixture is heated at 110 C for 4 hours. The mixture is
added to sat. sodium carbonate solution and extracted
with ethyl acetate, and the combined organic phases are
washed with brine, dried over sodium sulfate and
concentrated in vacuo. Chromatography on silica gel
(hexane 100%, dichloromethane/isopropanol 100:0 ->
95:5) results in 275 mg of 5-[3-(chroman-4-yl)-2-
hydroxy-2-trifluoromethylpropylideneamino]quinolin-
2[1H]-one as beige foam (mixture of diastereomers).
1H NMR (CDC13, selected signals): 8 = 1.76-1.85 (m),
2.02-2.12 (m), 2.13-2.22 (m), 2.27 (d, 1H), 2.31 (d,
1H), 2.40-2.48 (m), 2.61 (d, 1H, diaster. A+B), 2.93-
3.01 (m, 1H, diaster. A), 3.22-3.31 (m, 1H, diaster.
B), 4.10-4.18 (m), 4.22-4.29 (m), 4.87 (bs, 1H,
diaster. A), 5.02 (bs, 1H, diaster. B), 6.64 (d, 1H,
diaster. B), 6.72 (d, 1H, diaster. A), 6.73-6.84 (m),
6.88-7.00 (m), 7.06-7.17 (m), 7.24-7.31 (m), 7.37-7.42
(m), 7.45-7.54 (m), 8.06-8.18 (m), 12.43 (bs, 1H,
diaster. A+B).
B. 5-[2-Hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropylideneamino]quinolin-2[1H]-one:
1.1 ml of titanium tetraisopropoxide are added to a
solution of 300 mg of 3-(4-methylchroman-4-yl)-
2-hydroxy-2-trifluoromethylpropionaldehyde and 160 mg
of 5-aminoquinolin-2[1H]-one in 10 ml of toluene, and
the mixture is heated at 110 C for 6 hours. The mixture
is added to sat. sodium bicarbonate solution and
extracted with ethyl acetate, and the combined organic
phases are washed with brine, dried over sodium sulfate
and concentrated in vacuo. Chromatography on silica gel
(hexane/ethyl acetate 100:0 -> 0:100) results in 300 mg
of 5-[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropylideneamino]quinolin-2[1H]-one as foam
(mixture of diastereomers).
CA 02598207 2007-08-16
- 50 -
1H NMR (CDC13, selected signals) b = 1.41 (s, 3H,
diaster. A), 1.46 (s, 3H, diaster. B), 1.65-1.77 (m,
1H, diaster. A), 1.81-1.94 (m, 1H, diaster. B), 2.3-2.4
(m, 1H, diaster. B), 2.43 (d, 1H, diaster. A+B), 2.61
(d, 1H, diaster. B), 2.61-2.73 (m, 2H, diaster. B),
2.87 (d, 1H, diaster. A), 3.98-4.27 (m), 4.31-4.41 (m,
1H, diaster. B), 4.82 (bs, 1H, diaster. B), 5.0 (bs,
1H, diaster. A), 5.93 (d, 1H, diaster. A), 6.49 (d, 1H,
diaster. A), 6.58 (d, 1H, diaster. B), 6.72 (d, 1H,
diaster. A), 6.74-6.93 (m), 7.03 (t, 1H, diaster. B),
7.2-7.34 (m), 7.38-7.50 (m, 2H, diaster. B), 8.0 (s,
1H, diaster. B), 8.05 (d, 1H, diaster. A), 8.13 (d, 1H,
diaster. B), 12.65 (bs, 1H, diaster. A+B).
C. 5-[2-Hydroxy-3-(thiochroman-4-yl)-2-
trifluoromethylpropylideneamino]quinolin-2[1H]-one:
2.6 ml of titanium tetraisopropoxide are added to a
solution of 700 mg of 2-hydroxy-3-(thiochroman-4-yl)-
2-trifluoromethylpropionaldehyde and 386 mg of
5-aminoquinolin-2[1H]-one in 20 ml of toluene, and the
mixture is heated at 110 C for 4 hours. The mixture is
added to sat. sodium bicarbonate solution and extracted
with ethyl acetate, and the combined organic phases are
washed with brine, dried over sodium sulfate and
concentrated in vacuo. Chromatography on silica gel
(hexane 100%, dichloromethane/isopropanol 100:0 ->
96:4) results in 600 mg of 5-[2-hydroxy-3-(thiochroman-
4-yl)-2-trifluoromethylpropylideneamino]quinolin-2[1H]-
one as foam (mixture of diastereomers).
'H NMR (CDC13, selected signals): S = 1.81-2.08 (m),
2.11-2.22 (m), 2.30-2.46 (m), 2.56 (dd, 1H), 2.87-2.96
(m), 3.01-3.40 (m), 4.93 (s, 1H, diaster. A+B), 6.28
(d, 1H), 6.69 (d, 1H), 6.77 (d, 1H, diaster. A+B), 6.86
(d, 1H), 6.99 (t, 1H), 7.01-7.11 (m), 7.13 (d, 1H),
7.18-7.27 (m), 7.31-7.43 (m), 7.74 (s, 1H), 8.08 (s,
1H), 8.10 (d, 1H), 8.18 (d, 1H), 12.01 (bs, 1H,
diaster. A+B).
CA 02598207 2007-08-16
- 51 -
D. 5-[3-(Chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propylideneamino]phthalazin-1[2H]-one:
0.76 ml of titanium tetraisopropoxide is added to a
solution of 600 mg of 3-(chroman-4-yl)-2-hydroxy-
2-trifluoromethylpropionaldehyde and 384 mg of
5-aminophthalazin-1[2H]-one in 22 ml of toluene, and
the mixture is heated at 110 C for 7 hours. The mixture
is added to sat. sodium bicarbonate solution and
extracted with ethyl acetate, and the combined organic
phases are washed with brine, dried over sodium sulfate
and concentrated in vacuo. Chromatography on silica gel
(hexane 100%, dichloromethane/isopropanol 100:0 ->
95:5) results in 818 mg of 5-[3-(chroman-4-yl)-2-
hydroxy-2-trifluoromethylpropylideneamino]phthalazin-
1[2H]-one as yellow foam (mixture of diastereomers).
1H NMR (CDC13, selected signals): 6 = 1.80-1.93 (m),
2.03-2.22 (m), 2.32 (d, 1H), 2.38 (d, 1H), 2.46 (d,
1H), 2.58-2.68 (m), 2.97-3.05 (m, 1H), 3.26-3.36 (m),
4.10-4.21 (m), 4.22-4.29 (m), 4.76 (s, 1H, diaster. A),
4.89 (s, 1H, diaster. B), 6.82-6.83 (m), 6.86-7.0 (m),
7.03-7.18 (m), 7.21 (d, 1H, diaster. A), 7.70-7.81 (m),
8.06 (s, 1H, diaster. B), 8.14 (s, 1H, diaster. A),
8.33-8.55 (m), 10.47 (bs, 1H, diaster. A+B).
E. 5-[3-(Chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propylideneamino]-8-fluoro-2-methylquinazoline:
0.31 ml of titanium tetraisopropoxide is added to a
solution of 250 mg of 3-(chroman-4-yl)-2-hydroxy-
2-trifluoromethylpropionaldehyde and 180 mg of 5-amino-
8-fluoro-2-methylquinazoline in 10 ml of toluene, and
the mixture is heated at 110 C for 6 hours. The mixture
is added to sat. sodium bicarbonate solution and
extracted with ethyl acetate, and the combined organic
phases are washed with brine, dried over sodium sulfate
and concentrated in vacuo. Chromatography on silica gel
dichloromethane/methanol 100:0 -> 60:40) results in
191 mg of 5-[3-(chroman-4-yl)-2-hydroxy-2-trifluoro-
methylpropylideneamino]-8-fluoro-2-methylquinazoline as
orange-colored foam (mixture of diastereomers).
CA 02598207 2007-08-16
- 52 -
1H NMR (CDC13): 8 = 1.80-1.92 (m, 1H), 2.02-2.22 (m),
2.33 (d, 1H), 2.38 (d, 1H), 2.46 (d, 1H), 2.63 (dd,
1H), 2.98 (s, 3H, diaster. A+B), 3.27-3.38 (m), 4.09-
4.18 (m), 4.23-4.30 (m), 4.79 (s, 1H, diaster. A), 4.91
(s, 1H, diaster. B), 6.71-6.78 (m), 6.79-6.87 (m),
6.89-6.97 (m), 7.03-7.13 (m), 7.47-7.57 (m), 8.09 (s,
1H, diaster. B), 8.18 (s, 1H, diaster. A).
F. The following can be prepared likewise:
5-[3-(chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propylideneamino]-2-methylquinazoline
4-[3-(chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propylideneamino]indazole
4-[3-(chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propylideneamino]-1,3-dihydroindol-2-one
5-[3-(chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propylideneamino]-2-methyl-iso-quinolin-l-one
5-[3-(chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propylideneamino]-iso-chromen-l-one
5-[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropylideneamino]phthalazin-1[2H]-one
5-[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropylideneamino]-2-methylquinoline
5-[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropylideneamino]-2-methylquinazoline
4-[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropylideneamino]indazole
5-[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropylideneamino]-iso-chromen-l-one
5-[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropylideneamino]-iso-chromen-l-one
4-[2-hydroxy-3-(4-thiochroman-4-yl)-2-trifluoromethyl-
propylideneamino]indazole
5-[2-hydroxy-3-(4-thiochroman-4-yl)-2-trifluoromethyl-
propylideneamino]phthalazin-1[2H]-one
8-fluoro-5-[2-hydroxy-3-(4-thiochroman-4-yl)-2-
trifluoromethylpropylideneamino]-2-methylquinazoline
4-[2-hydroxy-3-(6-methylchroman-4-yl)-2-trifluoro-
methylpropylideneamino]indazole
CA 02598207 2007-08-16
- 53 -
5-[2-hydroxy-3-(6-methylchroman-4-yl)-2-trifluoro-
methylpropylideneamino]-2-methylquinoline
4-[2-hydroxy-3-(7-methylchroman-4-yl)-2-trifluoro-
methylpropylideneamino]indazole
5-[2-hydroxy-3-(7-methylchroman-4-yl)-2-trifluoro-
methylpropylideneamino]-2-methylquinazoline
5-[3-(6-fluorochroman-4-yl)-2-hydroxy-2-trifluoro-
methylpropylideneamino]-2-methylquinazoline
5-[3-(6-fluorochroman-4-yl)-2-hydroxy-2-trifluoro-
methylpropylideneamino]phthalazin-1[2H]-one
5-[3-(6-fluorochroman-4-yl)-2-hydroxy-2-trifluoro-
methylpropylideneamino]-iso-chromen-l-one
5-[2-hydroxy-3-(6-methoxychroman-4-yl)-2-trifluoro-
methylpropylideneamino]-2-methylquinazoline
5-[2-hydroxy-3-(7-methoxychroman-4-yl)-2-trifluoro-
methylpropylideneamino]-2-methylquinazoline
5-[2-hydroxy-3-(1,2,3,4-tetrahydronaphthalen-1-yl)-
2-trifluoromethylpropylideneamino]quinolin-2[1H]-one
5-[2-hydroxy-3-(1,2,3,4-tetrahydronaphthalen-1-yl)-
2-trifluoromethylpropylideneamino]-2-methylquinoline
8-fluoro-5-[2-hydroxy-3-(1,2,3,4-tetrahydronaphthalen-
1-yl)-2-trifluoromethylpropylideneamino]-2-methyl-
quinazoline
5-[2-hydroxy-3-(2-methyl-1,2,3,4-tetrahydronaphthalen-
1-yl)-2-trifluoromethylpropylideneamino]-2-methyl-
quinoline
5-[2-hydroxy-3-(4-methyl-1,2,3,4-tetrahydronaphthalen-
1-yl)-2-trifluoromethylpropylideneamino]-2-methyl-
quinoline
5-[2-hydroxy-3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-
1-yl)-2-trifluoromethylpropylideneamino]-2-methyl-iso-
quinolin-l-one
5-[3-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-
2-hydroxy-2-trifluoromethylpropylideneamino]-2-methyl-
iso-quinolin-l-one
5-[2-hydroxy-3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-
1-yl)-2-pentafluoroethylpropylideneamino]quinolin-
2[1H]-one
CA 02598207 2007-08-16
- 54 -
5-[3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-
2-hydroxy-2-trifluoromethylpropylideneamino]quinolin-
2[1H]-one
5-[2-hydroxy-3-(4-methylthiochroman-4-yl)-2-trifluoro-
methylpropylideneamino]quinolin-2[1H]-one
5-[2-hydroxy-3-(4-methylthiochroman-4-yl)-2-trifluoro-
methylpropylideneamino]-2-methylquinazoline
5-[2-hydroxy-3-(4-methylthiochroman-4-yl)-2-trifluoro-
methylpropylideneamino]-2-methylquinoline
5-[3-(4-ethylchroman-4-yl)-2-hydroxy-2-trifluoro-
methylpropylideneamino]-2-methylquinoline
5-[3-(4-ethylchroman-4-yl)-2-hydroxy-2-trifluoro-
methylpropylideneamino]quinolin-2[1H]-one
5-[3-(4-ethylchroman-4-yl)-2-hydroxy-2-trifluoro-
methylpropylideneamino]phthalazin--1[2H]-one
5-[2-hydroxy-3-(4-propylchroman-4-yl)-2-trifluoro-
methylpropylideneamino]quinolin-2[1H]-one
Compounds of the general formula (I)
Example 1:
5-{[3-Chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propyl]amino}quinolin-2[1H]-one:
31 mg of sodium cyanoborohydride are added to a
solution of 15 mg of 5-[3-(chroman-4-yl)-2-hydroxy-2-
trifluoromethylpropylideneamino]quinolin-2[1H]-one in
1.5 ml of methanol and 0.3 ml of glacial acetic acid at
room temperature, and the mixture is stirred for
3.5 hours. The mixture is added to sat. sodium
bicarbonate solution and extracted with ethyl acetate,
and the combined organic phases are washed with brine,
dried over sodium sulfate and concentrated in vacuo.
Chromatography on silica gel (dichloromethane/methanol
100:0 -> 60:40) results in 12 mg of 5-{[3-(chroman-
4-yl)-2-hydroxy-2-trifluoromethylpropyl]amino}quinolin-
2[1H]-one as yellow foam (mixture of diastereomers).
1H NMR (CDC13, selected signals): 6 = 2.0-2.13 (m),
2.13-2.21 (m), 3.17-3.27 (m, 1H), 3.55 (s, 1H), 3.63
CA 02598207 2007-08-16
- 55 -
(s, 1H), 4.01-4.13 (m, 2H), 6.49 (d, 1H), 6.58 (t, 1H,
diaster. A+B), 6.62-6.79 (m, 3H), 6.99 (t, 1H, diaster.
A+B), 7.06 (d, 1H), 7.10 (d, 1H), 7.30-7.39 (m, 1H,
diaster. A+B), 8.12 (d, 1H, diaster. A+B).
Examples 2,3,4 and 5:
5-{[2-Hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}quinolin-2{1H]-one, diastereomer A,
(+) enantiomer;
5-{[2-Hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}quinolin-2{1H]-one, diastereomer B,
(-) enantiomer;
5-{[2-Hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}quinolin-2{1H]-one, diastereomer A,
(-) enantiomer;
5-{[2-Hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}quinolin-2{1H]-one, diastereomer B,
(+) enantiomer:
100 mg of sodium cyanoborohydride are added to a
solution of 50 mg of 5-[2-hydroxy-3-(4-methylchroman-
4-yl)-2-trifluoromethylpropylideneamino]quinolin-2[1H]-
one in 4.8 ml of methanol and 1.0 ml of glacial acetic
acid at room temperature, and the mixture is stirred
for 3.5 hours. The mixture is added to sat. sodium
bicarbonate solution and extracted with ethyl acetate,
and the combined organic phases are washed with brine,
dried over sodium sulfate and concentrated in vacuo.
HPLC chromatography (chiral pack AD-H, hexane/ethanol
95:5 -> 50:50) results in 1 mg of 5-{[2-hydroxy-3-(4-
methylchroman-4-yl)-2-trifluoromethylpropyl]amino}-
quinolin-2[1H]-one (fraction 1: diastereomer A, (+)
enantiomer), 5 mg of 5-{[2-hydroxy-3-(4-methylchroman-
4-yl)-2-trifluoromethylpropyl]amino}quinolin-2[1H]-one
(fraction 2: diastereomer B, (-) enantiomer), 7 mg of
5-{[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}quinolin-2[1H]-one (fraction 3:
diastereomer A, (-) enantiomer), and 8 mg of 5-{[2-
hydroxy-3-(4-methylchroman-4-yl)-2-trifluoromethyl-
propyl]amino}quinolin-2[1H]-one (fraction 4:
CA 02598207 2007-08-16
- 56 -
diastereomer B, (+) enantiomer), in each case as
colorless foams.
Example 2 (fraction 1): 'H NMR (CD3OD): 1.54 (s,
3H), 1.87 (ddd, 1H), 2.17 (d, 1H), 2.22 (d, 1H), 2.37
(ddd, 1H), 3.42 (d, 1H), 3.52 (d, 1H), 4.11 (ddd, 1H),
4.22 (ddd, 1H), 6.33 (d, 1H), 6.47 (d, 1H), 6.66 (dd,
1H), 6.78 ( t , 1H), 7. 0(dt, 1H), 7.27-7.33 (m, 2H), 8.0
(d, 1H).
Example 3 (fraction 2) : 'H NMR (CD3OD) : 8= 1.40 (s,
3H), 1.68-1.76 (m, 1H), 2.15 (d, 1H), 2.53 (d, 1H),
2.85 (d, 1H), 2.87-2.97 (m, 1H), 3.06 (d, 1H),
4.02-4.11 (m, 1H), 4.20-4.27 (m, 1H), 5.74 (d, 1H),
6.44 (d, 1H), 6.59 (d, 1H), 6.7 (d, 1H), 6.88 (t, 1H),
7.04 (t, 1H), 7.15 (t, 1H), 7.36 (d, 1H), 7.96 (d, 1H).
Example 4 (fraction 3): 'H NMR (CD30D): 6 = 1.54 (s,
3H), 1.87 (ddd, 1H), 2.17 (d, 1H), 2.22 (d, 1H), 2.37
(ddd, 1H), 3.42 (d, 1H), 3.52 (d, 1H), 4.11 (ddd, 1H),
4.22 (ddd, 1H), 6.33 (d, 1H), 6.47 (d, 1H), 6.66 (dd,
1H), 6.78 ( t , 1H), 7. 0(dt, 1H), 7.27-7.33 (m, 2H), 8.0
(d, 1H).
Example 5 (fraction 4): 'H NMR (CD30D): b= 1.40 (s,
3H), 1.68-1.76 (m, 1H), 2.15 (d, 1H), 2.53 (d, 1H),
2.85 (d, 1H), 2.87-2.97 (m, 1H), 3.06 (d, 1H),
4.02-4.11 (m, 1H), 4.20-4.27 (m, 1H), 5.74 (d, 1H),
6.44 (d, 1H), 6.59 (d, 1H), 6.7 (d, 1H), 6.88 (t, 1H),
7.04 (t, 1H), 7.15 (t, 1H), 7.36 (d, 1H), 7.96 (d, 1H).
Example 6:
5-{[2-Hydroxy-3-(thiochroman-4-yl)-2-trifluoromethyl-
propyl]amino}quinolin-2[1H]-one:
100 mg of sodium cyanoborohydride are added to a
solution of 50 mg of 5-[2-hydroxy-3-(thiochroman-4-yl)-
2-trifluoromethylpropylideneamino]quinolin-2[1H]-one in
4.8 ml of methanol and 1.0 ml of glacial acetic acid at
CA 02598207 2007-08-16
- 57 -
room temperature, and the mixture is stirred for
1 hour. The mixture is added to sat. sodium bicarbonate
solution and extracted with ethyl acetate, and the
combined organic phases are washed with brine, dried
over sodium sulfate and concentrated in vacuo. 44 mg of
5-{[2-hydroxy-3-(thiochroman-4-yl)-2-trifluoromethyl-
propyl]amino}quinolin-2[1H]-one are obtained as a
yellow foam (mixture of diastereomers).
1H NMR (CDC13, selected signals): 8 = 1.80-1.92 (m),
2.07-2.12 (m), 2.18 (dd, 1H), 2.30 (dd, 1H), 2.32-2.40
(m, 1H), 2.88-2.95 (m), 3.05-3.18 (m), 3.20-3.31 (m),
3.31-3.38 (m), 3.42 (dd, 1H), 4.11-4.23 (m), 6.17 (d,
1H), 6.22 (d, 1H), 6.44 (t, 1H), 6.54 (d, 1H), 6.60 (d,
1H), 6.85-7.20 (m), 7.51-7.57 (m), 11.25-11.44 (bd, 1H,
diaster. A+B).
Example 7:
3-(Chroman-4-yl)-1-[(2-methylquinolin-5-yl)amino]-
2-(trifluoromethyl)propan-2-ol
A. 1.15 g of ethyl 3-(2H-chromen-4-yl)-2-hydroxy-
2-(trifluoromethyl)propionate are taken up in 30 ml of
diethyl ether and cooled to -5 C. 275 mg (7.2 mmol) of
solid lithium aluminum hydride are added in portions
over the course of 10 minutes. The mixture is stirred
at this temperature for 2 hours and poured into
saturated ammonium chloride solution. The suspension is
filtered through Celite, washing thoroughly with ethyl
acetate. The phases of the filtrate are separated, and
ethyl acetate extraction is repeated. Washing with
saturated sodium chloride solution and drying over
sodium sulfate are followed by removal of the solvent
in vacuo. Chromatographic purification on silica gel
(hexane/ethyl acetate 25-33%) affords 620 mg of 3-(2H-
chromen-4-yl)-2-hydroxy-2-(trifluoromethyl)propanal.
1H NMR (300 MHz, CDC13); 6 = 3.06 (d, 1H), 3.26 (d,
1H), 3.89 (s, 1H), 4.67 (dd, 1H), 4.70 (dd, 1H), 5.74
(t, 1H), 6.80 (d, 1H), 6.93 (t, 1H), 7.15 (t, 1H), 7.21
(d, 1H), 9.63 (s, 1H).
CA 02598207 2007-08-16
- 58 -
B. 0.4 ml (2.0 mmol) of titanium tetraethoxide is added
to 245 mg (0.9 mmol) of 3-(2H-chromen-4-yl)-2-hydroxy-
2-(trifluoromethyl)propanal and 150 mg (0.95 mol) of
5-amino-8-methylquinoline in 10 ml of toluene, and the
mixture is heated at 100 C for 2 hours. After cooling,
it is poured into water and stirred vigorously. The
suspension is filtered through Celite, washing
thoroughly with ethyl acetate. The phases of the
filtrate are separated, and ethyl acetate extraction is
repeated. Drying over sodium sulfate is followed by
removal of the solvent in vacuo. Purification by
chromatography on silica gel (hexane/ethyl acetate 50%)
results in 180 mg of 3-(2H-chromen-4-yl)-1-[(2-
methylquinolin-5-yl)imino]-2-(trifluoromethyl)propan-2-
ol. 90 mg of the imine obtained in this way are taken
up in 4 ml of methanol and cooled to 0 C. 25 mg
(0.66 mmol) of solid sodium borohydride are added,
followed after 2 hours by dropwise addition pouring
into saturated ammonium chloride solution and vigorous
stirring. Extraction with ethyl acetate several times,
washing with saturated sodium chloride solution and
drying over sodium sulfate are followed by removal of
the solvent in vacuo. Separation by column
chromatography on silica gel (hexane/ethyl acetate 50%)
affords 80 mg of 3-(2H-chromen-4-yl)-1-[(2-
methylquinolin-5-yl)amino]-2-(trifluoromethyl)propan-
2-ol.
C. 30 mg of 3-(2H-chromen-4-yl)-1-[(2-methylquinolin-5-
yl)amino]-2-(trifluoromethyl)propan-2-ol are taken up
in 8 ml of methanol and, after addition of 10 mg of
palladium on carbon (10%), the suspension is shaken
under hydrogen at atmospheric pressure for 2 hours. The
mixture is filtered through Celite, washing thoroughly
with methanol. The solvent is removed in vacuo and,
after purification by chromatography on silica gel
(hexane/ethyl acetate 50%), 12 mg of the title compound
are obtained as mixture of diastereomers.
CA 02598207 2007-08-16
- 59 -
1H NMR (300 MHz, CDC13); 6 = 2.05-2.37 (m, 4H), 2.74
(s, 3H), 3.24-3.32 (m, 1H), 3.51 (dd, 0.5H), 3.50 (dd,
1H), 3.61-3.72 (m, 1.5H), 4.21 (m, 2H), 4.45 (br, 1H),
6.70 (dd, 0.5H), 6.75 (dd, 0.5H), 6.78-6.88 (m, 2H),
7.08-7.13 (m, 1.5H), 7.18 (d, 0.5H), 7.27 (d, 1H),
7.53-7.56 (m, 2H) , 8.04 (d, 0. 5H) , 8.06 (d, 0.5H).
The following can likewise be prepared by methods
described above:
3-(chroman-4-yl)-1-(2-methylquinolin-5-ylamino)-2-tri-
fluoromethylpropan-2-ol
5-{[3-(chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propyl]amino}phthalazin-1[2H]-one
5-{[3-(chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propyl]amino}-8-fluoro-2-methylquinazoline
5-{[3-(chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propyl]amino}-2-methylquinazoline
4-{[3-(chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propyl]amino}indazole
4-{[3-(chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propyl]amino}-1,3-dihydroindol-2-one
5-{[3-(chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propyl]amino}-2-methyl-iso-quinolin-l-one
5-{[3-(chroman-4-yl)-2-hydroxy-2-trifluoromethyl-
propyl]amino}-iso-chromen-l-one
5-{[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}phthalazin-1[2H]-one
5-{[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}-2-methylquinoline
5-{[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}-2-methylquinazoline
4-{[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}indazole
5-{[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}-iso-chromen-l-one
5-{[2-hydroxy-3-(4-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}-iso-chromen-l-one
4-{[2-hydroxy-3-(4-thiochroman-4-yl)-2-trifluoromethyl-
propyl]amino}indazole
CA 02598207 2007-08-16
- 60 -
5-{[2-hydroxy-3-(4-thiochroman-4-yl)-2-trifluoromethyl-
propyl]amino}phthalazin-1[2H]-one
8-fluoro-5-{[2-hydroxy-3-(4-thiochroman-4-yl)-2-tri-
fluoromethylpropyl]amino}-2-methylquinazoline
4-{[2-hydroxy-3-(6-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}indazole
5-{[2-hydroxy-3-(6-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}-2-methylquinoline
4-{[2-hydroxy-3-(7-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}indazole
5-{[2-hydroxy-3-(7-methylchroman-4-yl)-2-trifluoro-
methylpropyl]amino}-2-methylquinazoline
5-{[3-(6-fluorochroman-4-yl)-2-hydroxy-2-trifluoro-
methylpropyl]amino}-2-methylquinazoline
5-{[3-(6-fluorochroman-4-yl)-2-hydroxy-2-trifluoro-
methylpropyl]amino}phthalazin-1[2H]-one
5-{[3-(6-fluorochroman-4-yl)-2-hydroxy-2-trifluoro-
methylpropyl]amino}-iso-chromen-l-one
5-{[2-hydroxy-3-(6-methoxychroman-4-yl)-2-trifluoro-
methylpropyl]amino}-2-methylquinazoline
5-{[2-hydroxy-3-(7-methoxychroman-4-yl)-2-trifluoro-
methylpropyl]amino}-2-methylquinazoline
5-{[2-hydroxy-3-(1,2,3,4-tetrahydronaphthalen-1-yl)-
2-trifluoromethylpropyl]amino}quinolin-2[1]-one
5-{[2-hydroxy-3-(1,2,3,4-tetrahydronaphthalen-1-yl)-
2-trifluoromethylpropyl]amino}-2-methylquinoline
8-fluoro-5-{[2-hydroxy-3-(1,2,3,4-tetrahydronaphthalen-
1-yl)-2-trifluoromethylpropyl]amino}-2-methyl-
quinazoline
5-{[2-hydroxy-3-(2-methyl-1,2,3,4-tetrahydronaphthalen-
1-yl)-2-trifluoromethylpropyl]amino}-2-methylquinoline
5-{[2-hydroxy-3-(4-methyl-1,2,3,4-tetrahydronaphthalen-
1-yl)-2-trifluoromethylpropyl]amino}-2-methylquinoline
5-{[2-hydroxy-3-(5-methoxy-1,2,3,4-tetrahydro-
naphthalen-1-yl)-2-trifluoromethylpropyl]amino}-
2-methyl-iso-quinolin-l-one
5-{[3-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-l-yl)-
2-hydroxy-2-trifluoromethylpropyl]amino}-2-methyl-iso-
quinolin-l-one
CA 02598207 2007-08-16
- 61 -
5-{[2-hydroxy-3-(6-methoxy-1,2,3,4-tetrahydro-
naphthalen-1-yl)-2-pentafluoroethylpropyl]-
amino}quinolin-2[1H]-one
5-{[3-(6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)-
2-hydroxy-2-trifluoromethylpropyl]amino}quinolin-2[1H]-
one
5-{[2-hydroxy-3-(4-methylthiochroman-4-yl)-2-trifluoro-
methylpropyl]amino}quinolin-2[1H]-one
5-{[2-hydroxy-3-(4-methylthiochroman-4-yl)-2-trifluoro-
methylpropyl}amino}-2-methylquinazoline
5-{[2-hydroxy-3-(4-methylthiochroman-4-yl)-2-trifluoro-
methylpropyl]amino}-2-methylquinoline
5-{[3-(4-ethylchroman-4-yl)-2-hydroxy-2-trifluoro-
methylpropyl]amino}-2-methylquinoline
5-{[3-(4-ethylchroman-4-yl)-2-hydroxy-2-trifluoro-
methylpropyl]amino}quinolin-2[1H]-one
5-{[3-(4-ethylchroman-4-yl)-2-hydroxy-2-trifluoro-
methylpropyl]amino}phthalazin-1[2H]-one
5-{[2-hydroxy-3-(4-propylchroman-4-yl)-2-
trifluoromethylpropyl]amino}quinolin-2[lH]-one
