U.S. patent application number 13/967719 was filed with the patent office on 2013-12-12 for acetylene derivatives having mglur 5 antagonistic activity.
This patent application is currently assigned to Novartis AG. The applicant listed for this patent is Yves Auberson, Fabrizio Gasparini, Terance W. Hart, Silvio Ofner, Kaspar Zimmermann. Invention is credited to Yves Auberson, Fabrizio Gasparini, Terance W. Hart, Silvio Ofner, Kaspar Zimmermann.
Application Number | 20130331568 13/967719 |
Document ID | / |
Family ID | 9926969 |
Filed Date | 2013-12-12 |
United States Patent
Application |
20130331568 |
Kind Code |
A1 |
Gasparini; Fabrizio ; et
al. |
December 12, 2013 |
ACETYLENE DERIVATIVES HAVING MGLUR 5 ANTAGONISTIC ACTIVITY
Abstract
The invention provides compounds of formula I ##STR00001##
wherein n, A, R, R', R'', R.sub.0, X and Y are as defined in the
description, and their preparation. The compounds of formula I are
useful as pharmaceuticals.
Inventors: |
Gasparini; Fabrizio;
(Lausen, CH) ; Auberson; Yves; (Allschwil, CH)
; Ofner; Silvio; (Muenchenstein, CH) ; Hart;
Terance W.; (Cambridge, GB) ; Zimmermann; Kaspar;
(Oberwil, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gasparini; Fabrizio
Auberson; Yves
Ofner; Silvio
Hart; Terance W.
Zimmermann; Kaspar |
Lausen
Allschwil
Muenchenstein
Cambridge
Oberwil |
|
CH
CH
CH
GB
CH |
|
|
Assignee: |
Novartis AG
Basel
CH
|
Family ID: |
9926969 |
Appl. No.: |
13/967719 |
Filed: |
August 15, 2013 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13239467 |
Sep 22, 2011 |
8536229 |
|
|
13967719 |
|
|
|
|
12040081 |
Feb 29, 2008 |
|
|
|
13239467 |
|
|
|
|
10497363 |
Oct 26, 2004 |
7348353 |
|
|
PCT/EP02/13670 |
Dec 3, 2002 |
|
|
|
12040081 |
|
|
|
|
Current U.S.
Class: |
544/128 ;
544/363; 546/170; 546/278.1; 548/454; 548/470; 548/510; 560/29;
564/221 |
Current CPC
Class: |
A61P 25/32 20180101;
C07D 209/44 20130101; A61P 25/14 20180101; A61P 25/00 20180101;
A61P 25/08 20180101; A61P 25/30 20180101; C07D 209/08 20130101;
A61P 25/36 20180101; A61P 25/34 20180101; C07D 215/08 20130101;
A61P 43/00 20180101; C07C 271/16 20130101; A61P 25/28 20180101;
C07D 405/12 20130101; A61P 25/16 20180101; C07D 401/06 20130101;
C07D 405/06 20130101; A61P 25/18 20180101; A61P 25/24 20180101;
C07D 215/20 20130101; C07D 401/04 20130101; A61P 9/10 20180101;
A61P 25/04 20180101; A61P 25/22 20180101; A61P 29/00 20180101 |
Class at
Publication: |
544/128 ;
548/510; 548/454; 548/470; 546/170; 560/29; 564/221; 546/278.1;
544/363 |
International
Class: |
C07D 405/12 20060101
C07D405/12; C07D 401/04 20060101 C07D401/04; C07D 215/08 20060101
C07D215/08; C07C 271/16 20060101 C07C271/16; C07D 209/08 20060101
C07D209/08; C07D 209/44 20060101 C07D209/44 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 4, 2001 |
GB |
0128996.6 |
Claims
1. A compound of formula I ##STR00005## wherein m is 0 or 1, n is 0
or 1 and A is hydroxy X is hydrogen and Y is hydrogen, or A forms a
single bond with X or with Y; R.sub.0 is hydrogen.
(C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, trifluoromethyl, halogen,
cyano, nitro, --COOR.sub.1 wherein R.sub.1 is (C.sub.1-4)alkyl or
--COR.sub.2 wherein R.sub.2 is hydrogen or (C.sub.1-4)alkyl, and R
is --COR.sub.3, --COOR.sub.3, --CONR.sub.4R.sub.5 or
--SO.sub.2R.sub.6, wherein R.sub.3 is (C.sub.1-4)alkyl,
(C.sub.3-7)cycloalkyl or optionally substituted phenyl, 2-pyridyl
or 2-thienyl, R.sub.4 and R.sub.5, independently, are hydrogen or
(C.sub.1-4)alkyl and R.sub.3 is (C.sub.1-4alkyl,
(C.sub.3-7)cycloalkyl or optionally substituted phenyl, R' is
hydrogen or (C.sub.1-4)alkyl and R'' is hydrogen or
(C.sub.1-4)alkyl, or R' and R'' together form a group
--CH.sub.2--(CH.sub.2).sub.p-- wherein p is 0, 1 or 2, in which
case one of n and p is different from 0, with the proviso that
R.sub.0 is different from hydrogen, trifluoromethyl and methoxy
when m is 1, n is 0, A is hydroxy, X and Y are both hydrogen, R is
COOEt and R' and R'' together form a group --(CH.sub.2).sub.2--, in
free base or acid addition salt form.
Description
[0001] The present invention relates to novel acetylene
derivatives, their preparation, their use as pharmaceuticals and
pharmaceutical compositions containing them.
[0002] More particularly the invention provides a compound of
formula I
##STR00002##
wherein [0003] m is 0 or 1, [0004] n is 0 or 1 and [0005] A is
hydroxy [0006] X is hydrogen and [0007] Y is hydrogen, or [0008] A
forms a single bond with X or with Y; [0009] R.sub.0 is hydrogen,
(C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, trifluoromethyl, halogen,
cyano, nitro, --COOR.sub.1 wherein R.sub.1 is (C.sub.1-4)alkyl or
--COR.sub.2 wherein R.sub.2 is hydrogen or (C.sub.1-4)alkyl, and
[0010] R is --COR.sub.3, --COOR.sub.3, --CONR.sub.4R.sub.5 or
--SO.sub.2R.sub.6, wherein R.sub.3 is (C.sub.1-4)alkyl,
(C.sub.3-7)cycloalkyl or optionally substituted phenyl, 2-pyridyl
or 2-thienyl, R.sub.4 and R.sub.5, independently, are hydrogen or
(C.sub.1-4)alkyl and R.sub.6 is (C.sub.1-4)alkyl,
(C.sub.3-7)cycloalkyl or optionally substituted phenyl, [0011] R'
is hydrogen or (C.sub.1-4)alkyl and [0012] R'' is hydrogen or
(C.sub.1-4)alkyl, or [0013] R' and R'' together form a group
--CH.sub.2--(CH.sub.2).sub.p-- [0014] wherein p is 0, 1 or 2, in
which case one of n and p is different from 0, with the proviso
that R.sub.0 is different from hydrogen, trifluoromethyl and
methoxy when m is 1, n is 0, A is hydroxy, X and Y are both
hydrogen, R is COOEt and R' and R'' together form a group
--(CH.sub.2).sub.2--, in free base or acid addition salt form.
[0015] On account of the asymmetrical carbon atoms present in the
compounds of formula I and their salts, the compounds may exist in
optically active form or in form of mixtures of optical isomers,
e.g. in form of racemic mixtures. All optical isomers and their
mixtures including the racemic mixtures are part of the present
invention.
[0016] In a further aspect, the invention provides a process for
the production of the compounds of formula I and their salts, which
comprises the step of [0017] a) for the production of a compound of
formula I wherein A is hydroxy, reacting a compound of formula
II
[0017] ##STR00003## [0018] wherein m, n, R, R' and R'' are as
defined above, with a compound of formula III
[0018] ##STR00004## [0019] wherein R.sub.0 is as defined above, or
[0020] b) for the production of a compound of formula I wherein A
forms a single bond with X or with Y, dehydrating a compound of
formula I wherein A is hydroxy, and recovering the resulting
compound of formula I in free base or acid addition salt form.
[0021] The reaction of process a) can be effected according to
conventional methods, e.g. as described in Examples 1 (step e), 2
(step d), 5 (step b) and 8.
[0022] The dehydratation of process b) leads to a mixture of a
compound of formula I wherein A forms a single bond with X and a
compound of formula I wherein A forms a single bond with Y, which
are subsequently separated according to conventional methods, e.g.
as described in Examples 6, 9 and 10.
[0023] A so obtained compound of formula I can be converted into
another compound of formula I according to conventional methods,
e.g, as described in Examples i (steps f and g), 4 and 7.
[0024] Working up the reaction mixtures according to the above
processes and purification of the compounds thus obtained may be
carried out in accordance to known procedures.
[0025] Acid addition salts may be produced from the free bases in
known manner, and vice versa.
[0026] Compounds of formula I in optically pure form can be
obtained from the corresponding racemates according to well-known
procedures. Alternatively, optically pure starting materials can be
used.
[0027] The starting materials of formulae II and III are known or
may be obtained from known compounds, using conventional
procedures.
[0028] Compounds of formula I obtained in accordance with the
above-described process can be converted into other compounds of
formula I in customary manner.
[0029] Resulting acid addition salts can be converted into other
acid addition salts or into the free bases in a manner known per
se.
[0030] The compounds of formula I, including their acid addition
salts, may also be obtained in the form of hydrates or may include
the solvent used for crystallization.
[0031] Compounds of formula I and their pharmaceutically acceptable
acid addition salts, hereinafter referred to as agents of the
invention, exhibit valuable pharmacological properties and are
therefore useful as pharmaceuticals.
[0032] In particular, the agents of the invention exhibit a marked
and selective modulating, especially antagonistic, action at human
metabotropic glutamate receptors (mGluRs). This can be determined
in vitro for example at recombinant human metabotropic glutamate
receptors, especially PLC-coupled subtypes thereof such as mGluR5,
using different procedures like, for example, measurement of the
inhibition of the agonist induced elevation of intracellular
Ca.sup.2+ concentration in accordance with L. P. Daggett et al.,
Neuropharm, Vol. 34, pages 871-886 (1995), P. J. Flor at al., J.
Neurochem, Vol. 67, pages 58-53 (1996) or by determination to what
extent the agonist induced elevation of the inositol phosphate
turnover is inhibited as described by T. Knoepfel et al., Eur. J.
Pharmacol. Vol. 288, pages 389-392 (1994), L. P. Daggett et al.,
Neuropharm. Vol. 67, pages 58-83 (1996) and references cited
therein. Isolation and expression of human mGluR subtypes are
described in U.S. Pat. No. 5,521,297. Selected agents of the
invention show IC.sub.50values for the inhibition of the
quisqualate-induced inositol phosphate turnover, measured in
recombinant cells expressing hmGluR5a of about 1 nM to about 50
.mu.M.
[0033] The agents of the invention are therefore useful in the
treatment of disorders associated with irregularities of the
glutamatergic signal transmission, and of nervous system disorders
mediated full or in part by mGluR5.
[0034] Disorders associated with irregularities of the
glutamatergic signal transmission are for example epilepsy,
cerebral ischemias, especially acute ischemias, ischemic diseases
of the eye, muscle spasms such as local or general spasticity and,
in particular, convulsions or pain.
[0035] Nervous system disorders mediated full or in part by mGluR5
are for example acute, traumatic and chronic degenerative processes
of the nervous system, such as Parkinson's disease, senile
dementia, Alzheimer's disease, Huntington's chorea, amyotrophic
lateral sclerosis and multiple sclerosis, psychiatric diseases such
as schizophrenia and anxiety, depression, pain, itch and drug
abuse, e,g, alcohol and nicotine abuse and cocaine use
disorders.
[0036] The usefulness of the agents of the invention in the
treatment of the above-mentioned disorders can be confirmed in a
range of standard tests including those indicated below.
[0037] Activity of the agents of the invention in anxiety can be
demonstrated in standard models such as the stress-induced
hyperthermia in mice [cf. A. Lecci et al., Psychopharmacol, 101,
255-261]. At doses of about 0.1 to about 39 mg/kg p.o., the agents
of the invention reverse the stress-induced hyperthermia.
[0038] At doses of about 4 to about 50 mg/kg p,o., the agents of
the invention show reversal of Freund complete adjuvant (FCA)
induced hyperalgesia [cf. J. Donnerer et al., Neuroscience 49,
693-698 (1992) and C. J. Woolf, Neuroscience 62, 327-331
(1994)].
[0039] For all the above mentioned indications, the appropriate
dosage will of course vary depending upon, for example, the
compound employed, the host, the mode of administration and the
nature and severity of the condition being treated. However, in
general, satisfactory results in animals are indicated to be
obtained at a daily dosage of from about 0.5 to about 100 mg/kg
animal body weight, in larger mammals, for example humans, an
indicated daily dosage is in the range from about 5 to 1500 mg,
preferably about 10 to about 1000 mg of the compound conveniently
administered in divided doses up to 4 times a day or in sustained
release form.
[0040] In accordance with the foregoing, the present invention also
provides an agent of the invention for use as a pharmaceutical,
e.g. in the treatment of disorders associated with irregularities
of the glutamatergic signal transmission, and of nervous system
disorders mediated full or in part by mGluR5.
[0041] The invention also provides the use of an agent of the
invention, in the treatment of disorders associated with
irregularities of the glutamatergic signal transmission, and of
nervous system disorders mediated full or in part by mGluR5.
[0042] Furthermore the invention provides the use of an agent of
the invention for the manufacture of a pharmaceutical composition
designed for the treatment of disorders associated with
irregularities of the glutamatergic signal transmission, and of
nervous system disorders mediated full or in part by mGluR5.
[0043] In a further aspect the invention relates to a method of
treating disorders mediated full or in part by mGluR5, which method
comprises administering to a warm-blooded organism in need of such
treatment a therapeutically effective amount of an agent of the
invention.
[0044] Moreover the invention relates to a pharmaceutical
composition comprising an agent of the invention in association
with at least one pharmaceutical carrier or diluent.
[0045] The pharmaceutical compositions according to the invention
are compositions for enteral, such as nasal, rectal or oral, or
parenteral, such as intramuscular or intravenous, administration to
warm-blooded animals (human beings and animals) that comprise an
effective dose of the pharmacological active ingredient alone or
together with a significant amount of a pharmaceutically acceptable
carrier. The dose of the active ingredient depends on the species
of warm-blooded animal, body weight, age and individual condition,
individual pharmacokinetic data, the disease to be treated and the
mode of administration.
[0046] The pharmaceutical compositions comprise from approximately
1% to approximately 95%, preferably from approximately 20% to
approximately 90%, active ingredient. Pharmaceutical compositions
according to the invention may be, for example, in unit dose form,
such as in the form of ampoules, vials, suppositories, dragoes,
tablets or capsules.
[0047] The agents of the invention may alternatively be
administered e.g, topically in the form of a cream, gel or the
like, or by inhalation, e,g, in dry powder form.
[0048] Examples for compositions comprising an agent of the
invention include, e.g, a solid dispersion, an aqueous solution,
e,g, containing a solubilising agent, a microemulsion and a
suspension of an agent of the invention. The composition may be
buffered to a pH in the range of e.g. from 3.5 to 9.5, by a
suitable buffer.
[0049] The pharmaceutical compositions of the present invention are
prepared in a manner known per as, for example by means of
conventional dissolving, lyophilizing, mixing, granulating or
confectioning processes.
[0050] The agents of the invention can be administered either
alone, or in combination with other pharmaceutical agents effective
in the treatment of conditions mentioned above.
[0051] For the indication pain, the agents of this invention can be
used in combination with analgesic agents (opiates) or with
nonsteroidal anti-inflammatory drugs (NSAIDs) such as Rofecoxib
(Vioxx.RTM.), Celecoxib (Celebrex.RTM.) or Lumiracoxib
(Prexige.RTM.).
[0052] For the indication nicotine use disorders, the agents of the
invention can be used in combination with bupropione
(Zyban.RTM.).
[0053] The preferred agents of the invention include the (-)-(3aR,
4S, 7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic
acid methyl ester in free base or pharmaceutically acceptable acid
addition salt form.
[0054] Said compound inhibits the quisqualate-induced inositol
phosphate turnover in hmGlu5 expressing cells with an IC.sub.50
concentration of 30 nM. With the same compound, a stress-induced
hyperthermia of 0.92.+-.0.09.degree. C. was reduced to
0.56.+-.0.06.degree. C. at 0.1 mg/kg p.o., to 0.42.+-.0.06.degree.
C. at 1 mg/kg p.o. and to 0.18.+-.0.05.degree. C. at 10 mg/kg p.o.
(p<0.001 in each case).
[0055] The following non-limiting Examples illustrate the
invention.
EXAMPLE 1
(-)-(3aR, 4S,
7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid
methyl eater
[0056] 1,5,6,7-Tetrahydro-indol-4-one (38.4 g, 28.1 mmol),
di-tert-butyldicarbonate (66 g; 302 mmol) and potassium
tart-butylate (6 g; 62.5 mmol) in 1 l tetrahydrofuran are heated
under reflux for 2 h. After cooling, at room temperature the
reaction mixture is poured on brine (1 l) and extracted with
tert.-butylmethylether (4.times.600 ml). The combined organic
phases are dried over Na.sub.2SO.sub.4, filtered and evaporated in
vacuo. 51 g of yellowish oil are isolated and purified by column
chromatography on silica gel (600 g; eluent hexane/ethylacetate 8:2
v/v). 30.5 g (92%) of 1,5,6,7-Tetrahydro-indol-4-one-1-carboxylic
acid tert.butyl ester as white crystals are isolated (mp
84-86.degree. C.). [0057] b)
1,5,6,7-Tetrahydro-indol-4-one-1-carboxylic acid tert-butyl ester
(60 g; 255 mmol) and 15 g of 5% Pt on charcoal (given in three
portions of 5 g each; 24 h, 48, 72 h) in 1 l of methanol are
hydrogenated (1 bar) at room temperature under stirring for 92 h.
The mixture is filtered and the solvent evaporated in vacuo. The
residual brownish oil is purified by chromatography on silica gel
to yield (3aRS,4SR,7aRS)-4-hydroxy-octahydro-indole-1-carboxylic
acid tert-butyl ester as a yellowish oil (41.3 g; yield 67%).
[0058] c) To a solution of oxalylchloride (1.54 ml; 17.6 mmol) in
THF (320 ml) cooled to -60.degree. C. a solution of DMSO (2.28 ml;
32 mmol) in THF (32 ml) is added dropwise under stirring. After 5
min a solution of
(3aRS,4SR,7aRS)-4-hydroxy-octahydro-indole-1-carboxylic acid
tert-butyl ester (3.96 g; 16.4 mmol) in THF (64 mil is added and
the reaction mixture stirred for 100 min at -60.degree. C.
Triethylamine (11.2 ml; 80 mmol) is added and the cooling bath
removed and the reaction mixture stirred for further 60 min. The
reaction mixture is diluted with ethylacetate (1 l) and washed with
sat, NaHCO.sub.3 (150 ml). The water phase is extracted with
ethylacetate (300 ml). The combined organic phases are dried over
Na.sub.2SO.sub.4, filtered and evaporated in vacuo. The residue is
purified by column chromatography on silica gel (150 g) and the
fractions containing the desired compound are collected and
evaporated in vacuo to yield
(3aRS,7aRS)-4-Oxo-octahydro-indole-1-carboxylic acid tert-butyl
ester (2.51 g; yield=65%). [0059] d1) 4 g of
(3aRS,7aRS)-4-oxo-octahydro-indole-1-carboxylic acid tert-butyl
ester are dissolved in 200 ml of hexane-ethanol 80:20 (v/v). This
solution is injected via the pump on a 5 cm by 50 cm Chiralpak AD
column (Daicel Chemical Industries). The chromatography is achieved
at room temperature at a flow-rate of 100 ml/min and UV detection
is performed at 210 nm. The mobile phase consists of a mixture of
hexane-ethanol 80:20 (v/v). Under the applied chromatographic
conditions, the (+)-enantiomer is isolated from a first fraction
collected between 11 and 18 min, and the (-)enantiomer from a
second fraction collected between 20 and 40 min. After 6 injections
of a total of 27 g of racemate, the fractions containing the
corresponding enantiomers are combined to yield 12.55 g of
(+)-enantiomer and 12.23 g of (+)-enantiomer, with an enantiomeric
purity of 99% and 99.9%, respectively. The enantiomeric: purity is
determined on an analytical Chiralpak AD column (0.4.times.25 cm);
mobile phase, hexane-ethanol 90:10 (v/v).
(-)-(3aR,7aR)-4-oxo-octahydro-indole-1-carboxylic acid tert-butyl
ester
([.alpha.].sub.D=-111.6);--(+)-(3aS,7aS)-4-oxo-octahydro-indole-1-carboxy-
lic add ted-butyl ester ([.alpha.].sub.D=+105.2). [0060] d2a)
Alternatively (-)-(3aR,7aR)-oxo-octahydro-indole-1-carboxylic acid
tert-butyl ester can be obtained via the following procedure:
[0061] To 11.76 g (47.16 mmol)
(3aRS,4SR,7aRS)-4-hydroxy-octahydro-indole-1-carboxylic acid
tert-butyl ester in 50 ml TBME and 30 g (34.8 mmol) vinyl acetate,
0.5 g of immobilized lipase from Candida antarctica (Novozyme 435)
is added and the mixture is stirred at room temperature for 24 h.
After filtration of the mixture, the solvent is removed and the
obtained oily residue is purified by flash chromatography. The
acetate (3aS,4R,7aS)-4-acetoxy-octahydro-indole-1-carboxylic acid
tert-butyl ester is isolated in 47% yield with an optical purity of
>99% (GC, [.alpha.].sub.D.sup.20=54.6.degree. c=1, MeOH). The
recovered alcohol
(3aR,4S,7aR)-4-hydroxyoctahydro-indole-1-carboxylic acid tert-butyl
ester is obtained in 51% yield and >95% e.e. (GC,
[.alpha.].sub.D.sup.20=-41.3.degree. c=1, MeOH). Further
purification by Mae, affords the alcohol with 99.5% purity and
99.5% e.e. [0062] d2b) The alcohol
(3aR,4S,7aR)-4-hydroxy-actahydro-indole-1-carhoxylic acid
tert-butyl ester is oxidized to the ketone as described in Example
1c) to yield (-)-(3aR,7aR)-4-oxo-octahydro-indole-1-carboxylic acid
tert-butyl ester. [0063] e) To a solution of
1-ethynyl-3-methyl-benzene (3.248 g; 28 mmol) THF (168 ml) cooled
to -20.degree. C., a solution of butyllithium (17.5 ml; 28 mmol;
1.6M in hexane) is added. The reaction mixture is stirred at
-20.degree. C., for 2 h then a solution of
(-)-4-oxo-octahydro-indole-1-carboxylic acid tert-butyl ester
(3.346 g; 14 mmol) THF (70 ml) is added and the reaction Mixture
further stirred at 0-5.degree. C. After 2 h the reaction mixture is
diluted with ethylacetate (900 ml) and washed with sat. NaHCO.sub.3
(2.times.90 ml). The aqueous phase is extracted with ethylacetate
(400 ml). The combined organic phases are dried over
Na.sub.2SO.sub.4, filtered and evaporated in vacuo. The residue is
purified by column chromatography on silica gel (360 g) and the
fractions containing the desired compound are collected and
evaporated in vacuo to yield
(-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic
acid tert-butyl ester (4.27 g; yield=85%). 1H-NMR (400 MHz;
DMSO-D6): .delta. 7.3-7.1 (m, 4H), 5.5 (d, J=5 Hz, 1H), 3.85-3.55
(m, 1H), 3.35-3.25 (m, 1H), 3.25-3.1 (m, 1H), 2.6-2-45 (m, 1H),
2.28 (s, 3H), 1.9-1.4 (m, 7H), 1.36 (s, 9H), 1.13-0.98 (m, 1H).
[0064] f)
(-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic
acid tert-butyl ester (4.27 g; 12 mmol) is dissolved in a solution
of 1M HCl in ethylacetate, (240 ml) end stirred at room temperature
for 6 h. After completion of of the hydrolysis (TLC) the solvent is
evaporated in vacuo to yield
(-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole
hydrochloride (3.39 g; yield=93%) m.p.=181-183.degree. C. [0065] g)
(-),(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole
hydrochloride (3.38 g; 11.6 mmol) is suspended in CH.sub.2Cl.sub.2
(174 ml), triethylamine (3.6 ml; 25.52 mmol) is added and the
mixture is cooled to 5.degree. C. Methylchloroformate (1.2 ml;
15.08 mmol) is added dropwise. After completion of the addition,
the cooling bath is removed and the solution stirred for 2 h. The
reaction mixture is diluted with CH.sub.2Cl.sub.2 (250 ml) and
washed with brine (1.times.50 ml). The aqueous phase is extracted
with CH.sub.2Cl.sub.2 (50 ml), the combined organic phases are
dried over Na.sub.2SO.sub.4, filtered and the solvent evaporated in
vacuo. The residue is column chromatographed on silica gel (240 g),
eluent toluene/acetone 9:1 v/v. The fractions containing the
desired compound are collected and evaporated in vacuo to yield
3.39 g
(-)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic
acid methyl ester (yield=90%). M.p.=110-112.degree. C.,
[.alpha.].sub.D=-20.6 (c=1, methanol).
[0066] Following the same procedure, the following compounds are
obtained:
EXAMPLE 1a
(-)-(3aR,4S,7aR)-4-Hydroxy4-m-tolylethynyl-octahydro-indole-1-carboxylic
acid ethyl ester
[0067] M.p.=118-121.degree. C.
EXAMPLE 1b
(-)-(3aR,4S,7aR)-Furan-2-yl-(4-hydroxy-4-m-tolylethynyl-octahydro-indol-1--
yl)-methanone
[0068] M.p.=195.5-196.5.degree. C.
EXAMPLE 1c
(.+-.)-(3aRS,4SR,7aRS)-4-(3-Chlorophenylethynlyl)-4-hydroxy-octahydro-indo-
le-1-carboxylic acid ethyl ester
[0069] 1H NMR (400 MHz; CDCl3): 1.27(t, 3H), 1.60-1.80(m, 4H),
1.88-2.11(m, 5H), 2.27(m, 1H), 3.38(m, 1H), 3.54(m, 1H), 4.10(m,
2H), 7.22-7.31(m, 3H), 7.40(m, 1H).
EXAMPLE 1d
(.+-.)-(3aRS,4SR,7aRS)-4-(3-Fluoro-phenylethynyl)-4-hydroxy-octahydro-indo-
le-1-carboxylic acid ethyl ester
[0070] HPLC-MS; 354 (M+Na).
EXAMPLE 1e
(3aRS,4SR
7aRS)-4-Hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylic
acid(S)(tetrahydrofuran-3-yl)ester
[0071] ES-MS (+): 356 (M+1).
EXAMPLE 1f
(3aRS,4SR,7aRS)-4-Hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylic
acid(R)(tetrahydrofuran-3-ester
[0072] ES-MS (+): 356 (M+1).
EXAMPLE 1g
(3aRS,4SR,7aRS)-4-Hydroxy-4-(3-chlorophenylethynyl)-octahydro-indol-1-carb-
oxylic acid-(S)(tetrahydrofuran-3yl)ester
[0073] 1H NMR (400 MHz CHCl3): 7.39 (s, 1H), 7.25 (m, 3H), 5.27 (m,
1H),4.10-3.85 (m, 5H), 3.55 (m, 1H), 3.4 (m, 1H), 2.7 (m, 1H), 2.3
(a, 1H), 2.2-1.9 (m, 6H), 1.8-1.0 (m, 3H), 1.07 (m, 1H).
EXAMPLE 1h
(.+-.)-(3aRS,4SR,7aRS)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carbo-
xylic acid ethyl ester
[0074] ES-MS (+): 328.2 [M+1], m.p.=123-124.degree. C.
EXAMPLE 1i
(.+-.)-(3aRS,4SR,7aRS)-4-(4-Fluoro-phenylethynyl)-4-hydroxy-octahydro-indo-
le-1-carboxylic acid ethyl ester
[0075] ES-MS (+): 332.2, m.p.=115-116.degree. C.
EXAMPLE 1j
(.+-.)-(3aRS,4SR,7aRS)-4-(3-chlorophenylethynyl)-4-hydroxy-1-methanesulfon-
yl-octahydro-indole
[0076] NMR (CDCl3): 7.41 (s,1H), 7.30 (m, 3H), 3.93 (m, 1H), 3.57
(m, 1H), 3.35 (m, 1H), 2.85 (s,3H), 2.69 (m, 1H), 2.35 (bs,1H),
2.14 (m, 1H), 2.0 (m, 1H), 1.90, m,1H), 1.82-1.65 (m, 4H), 1.35 (m,
1H). HPLC: 1 peak, 99%
EXAMPLE 2
(.+-.)-(3aRS,7aRS)-4-Phenylethynyl-2,3
3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester and
(.+-.)-(3aRS,7aRS)-4-phenylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carbox-
ylic acid ethyl ester
[0077] A solution of
4-hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylic acid ethyl
ester (1.0 g, 3.19 mmol), triethylamine (2.2 ml, 16 mmol) and
phosphorous oxychloride 0.877 ml, 10 mmol) is heated to 40.degree.
C. for 4 hours. The dark mixture is coded to 0.degree. C. and
treated with 1M sodium hydroxide (5 ml) and then acidified with a
10% aqueous citric add solution. The mixture is extracted with
dichloromethane, the organic extracts are washed with brine, dried
over anhydrous magnesium sulfate and evaporated in vacuo. The
residue is chromatographed on silica with hexane and diethyl ether
(4:1 v/v). The first product containing fractions afforded
(.+-.)-(RS)-4-phenylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic
acid ethyl ester (10 mg, 1%) as a yellowish oil. 1H-NMR (400 MHz
CDCl3): 7.44 (m, 2H), 7.32 (m, 3H), 4.24-3.97 (m, 3H), 3.8 (m, 1H),
3.25 (m, 1H), 2.93 (m, 1H), 2.56 (m, 1H), 2.28 (m, 2H), 1.90 (m,
1H), 1.60 (m, 2H), 1.28 (t, J=7 Hz, 3H), 1.14 (m, 1H), ES-MS (+):
296.1. After collecting a mixture of the two products (475 mg,
50%), the third product containing fractions yielded
(.+-.)-(3RS,7aRS)-4-phenylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carbox-
ylic acid ethyl ester (64 mg, 7%) as a yellowish oil. 1H-NMR (400
MHz; CDCl3): 7.43 (m, 2H), 7.31 (m, 3H), 6.27 (m, 1H), 4.15 (m,
2H), 4.01-3.83 (m, 1H), 3.46(m, 2H), 2.82 (m, 1H), 2.37-1.82 (m,
5H), 1.57(m, 1H), 1.27 (t, J=7 Hz, 3H). ES-MS (+): 296.2.
[0078] Following the same synthetic procedure the following
examples can be made:
EXAMPLE 2a
(.+-.)-(3RS,7aRS)-2,2,2-Trifluoro-1-(4-phenylethynyl-2,3,3a,6,7,7a-hexahyd-
ro-indol-1-yl)-ethanone
[0079] ES-MS (+): 320.3 (M+1), R.sub.f=0.62 (TLC silica gel,
hexane/ethyl acetate 2:1).
EXAMPLE 2b
(.+-.)-(RS)-4-m-Tolylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic
acid ethyl ester
[0080] ES-MS (+): 310.2 (M+1), R.sub.f=0.55 (TLC silica gel,
hexane/ethyl acetate 2:1).
EXAMPLE 2c
(.+-.)-(3RS,7aRS)-4-m-Tolylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carbox-
ylic acid ethyl ester
[0081] ES-MS (+): 310.2 (M+1), R.sub.f=0.59 (TLC silica gel,
hexane/ethyl acetate 2:1).
EXAMPLE 2d
(.+-.)-(3RS,7aRS)-4-(4-Chloro-phenylethynyl)-2.3,3a,6,7,7a-hexahydro-indol-
e-1-carboxylic acid ethyl ester
[0082] ES-MS (+): 330.2 (M+1), R.sub.f=0.56 (TLC silica gel,
hexane/ethyl acetate 2:1).
EXAMPLE 2e
(.+-.)-(3RS,7aRS)-4-(2-Fluoro-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indol-
e-1-carboxylic acid ethyl ester
[0083] ES-MS (+): 314.2 (M+1), R.sub.f=0.42 (TLC silica gel,
hexane/ethyl acetate 2:1).
EXAMPLE 2f
(.+-.)-(3RS,7aRS)-4-(3-Fluoro-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indol-
e-1-carboxylic acid ethyl ester
[0084] ES-MS (+): 314.2 (M+1).
EXAMPLE 2g
(.+-.)-(RS)-4-(3-Fluoro-phenylethenyl)-2,3,5,6,7,7a-hexahydro-indole-1-car-
boxylic acid ethyl ester
[0085] ES-MS (+): 336.2 (M+Na).
EXAMPLE 2h
(.+-.)-(3RS,7aRS)-4-(3-Methoxy-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indo-
le-1-carboxylic acid ethyl ester
[0086] ES-MS (+): 348.2 (M+Na).
EXAMPLE 2i
(.+-.)-(RS)-4-(3-Methoxy-phenylethynyl)-2,3,5,6,7,7a-hexahydro-indole-1-ca-
rboxylic acid ethyl ester
[0087] ES-MS (+): 348.2 (M+Na),
EXAMPLE 3
(.+-.)-(3aRS,4RS,7aSR)-4-Hydroxy-4-phenylethynyl-octahydro-indole-2-carbox-
ylic acid ethyl ester
[0088] a) A solution of 716 g acetic acid
(.+-.)-(3aRS,4RS,7aRS)-2-benzyl-1,3-dioxo-2,3,3a4,7,7a-hexahydro-1H-isoin-
dol-4-yl ester [CAN 153255-27-7, see J. Chem. Soc. Perkin Trans I
(1993), 1925-1929] in 3.5 l tetrahydrofuran is added dropwise to
300 g lithium aluminum hydride in 3.5 l tetrahydrofuran at
50.degree. C. Thereafter the mixture is refluxed for 1 h, then
cooled to 0.degree. C., 800 ml water, followed by 300 ml aqueous
sodium hydroxide solution and again 600 ml water is added at max.
15.degree. C. After filtration about 550 g slightly brown
crystallizing oil, consisting of
(.+-.)-(3aRS,4SR,7aSR)-2-benzyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ol
is obtained. M.p, 69-71C. [0089] b) 1020 g
(.+-.)-(3aRS,4SR,7aSR)-2-benzyl-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ol
and 560 g oxalic acid dihydrate are dissolved in 18 l water, then
hydrogenated using 200 g 10% palladium on charcoal catalyst at
100.degree. C., 100 atm for 16 h. After filtration of the catalyst
the solution is concentrated to a volume of 6 l and 4.5 l
dichloromethane are added, 810 g potassium hydroxide pellets are
added portionwise, then ethyl chloro formate is added dropwise at a
temperature not exceeding 30.degree. C. The reaction mixture is
extracted with dichloromethane, evaporated to yield 827 g
(.+-.)-(3aRS,4SR,7aSR)-4-hydroxy-octahydro-isoindole-2-carboxylic
acid ethyl ester as slightly brown oil; purity by GC: 98.6%. [0090]
c) To 6.6 g oxalic chloride in 300 tetrahydrofuran at -60.degree.
C. 7.4 g dimethylsulfoxide are added, then stirred for 15 min. 10 g
(.+-.)-(3aRS,4SR,7aSR)4-hydroxy-octahydro-isoindole-2-carboxylic
acid ethyl ester in 50 ml tetrahydrofuran is added at -50.degree.
C., followed by 23 g triethylamine and allowed to warm at rt. The
suspension is filtered, 400 ml ethyl acetate is added to the
filtrate and the mixture washed with 3 times 400 ml water. Organic
phases are dried with sodium sulfate and evaporated yielding 9.9 g
(.+-.)-(3aRS,7aSR)-4-oxo-octahydro-isoindole-2-carboxylic acid
ethyl ester as crude brown oil. ES-MS(-): 210 (M-1), RP-HPLC:
single peak. [0091] d) 2.1 g
(.+-.)-(3aRS,7aSR)-4-oxo-octahydro-isoindole-2-carboxylic acid
ethyl ester in 10 ml tetrahydrofuran is added at -10.degree. C. to
20 ml of 1M lithium phenylacetylide in tetrahydrofuran within 10
min. After 16 h at room temperature 100 ml saturated aqueous
ammonium chloride solution is added, the mixture extracted with
ethyl acetate, solvents dried over sodium sulfate and evaporated.
The product is flash-chromatographed on silica gel with
hexane/ethyl acetate (2:1). 2.2 g
(.+-.)-(3aRS,4RS,7aSR)-4-hydroxy-4-phenylethynyl-octahydro-isoindole-2--
carboxylic acid ethyl ester are obtained as brown oil ES-MS(+): 314
(M+1), RP-HPLC: single peak.
[0092] Following the same procedure the following compounds are
obtained:
EXAMPLE 3a
(.+-.)-(3aR,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-car-
boxylic acid ethyl ester
[0093] ES-M(+): 328 (M+1), RP-HPLC: single peak.
EXAMPLE 3b
(.+-.)-(3aRS,4RS,7aSR)-4-Hydroxy-4-p-tolylethynyl-octahydro-isoindole-2-ca-
rboxylic acid ethyl ester
[0094] HPLC-MS: single peak, 350 (M+Na).
EXAMPLE 3c
(.+-.)-(3aR,4RS,7aSR)-4-(3-Cyano-phenylethynyl)-4-hydroxy-octahydro-isoind-
ole-2-carboxylic acid ethyl ester
[0095] HPLC-MS.: single peak, 351 (M+Na).
EXAMPLE 3d
(.+-.)-(3aR,4RS,7aSR)-4-Hydroxy-4-(3-methoxy-phenylethynyl)-octahydro-isoi-
ndole-2-carboxylic acid ethyl ester
[0096] ES-MS(+): 344 (M+1), HPLC: single peak.
EXAMPLE 3e
(.+-.)-(3aRS,
4RS,7aSR)-4-(3-Fluoro-phenylethynyl)-4-hydroxy-octahydro-isoindole-2-carb-
oxylic acid ethyl ester
[0097] ES-MS(+): 332 (M+1), HPLC: single peak.
EXAMPLE 4
(.+-.)-(3aRS,4RS,7aSR)-4-Hydroxy-4-phenylethynyl-isoindole-2-carboxylic
acid tert-butyl ester
[0098] a) Crude
(.+-.)-(3aRS,7aSR)-4-oxo-octahydro-isoindole-2-carboxylic acid
tert-butyl ester is prepared in a 4-step procedure without
purification: Starting from
(3aSR,7aRS)-4-oxo-octahydro-isoindole-2-carboxylic acid ethyl
ester: 1) Ketal formation with ethylene glycole in toluene/p-TsOH.
2) Removal of the ethyl carbamate using KOH in MeOH in sealed tube
at 100.degree. C. 3) Removal of ketal using 4N aqueous hydrochloric
acid in acetone at room temperature. 4) Formation of the
tert.-butyl carbamate using BOC-anhydride, K.sub.2CO.sub.3, in
dichloromethane. [0099] b) Reaction to
(.+-.)-(3aRS,4RS,7aSR)-4-hydroxy-4-phenylethynyl-octahydro-isoindole-2-ca-
rboxylic acid tert-butyl ester as described in Example 3d).
ES-MS(+): 342 (M+1), RP-HPLC: single peak.
[0100] Following the same procedure, the following compound is
obtained:
EXAMPLE 4a
(.+-.)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-ca-
rboxylic acid tert-butyl ester
[0101] ES-MS(+): 356 (M+1), RP-HPLC: single peak.
EXAMPLE 5
(.+-.)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-ca-
rboxylic acid methyl ester
[0102] a) 1 g of
(.+-.)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-c-
arboxylic acid tert-butyl ester is treated with ca. 1N HCl in ethyl
acetate at room temperature for 18 h, then washed with saturated
sodium hydrogencarbonate solution. The organic phase is dried over
Na2SO4 and evaporated. Purification by prep-HPLC.
(.+-.)-(3aRS,4RS,7aSR)-4-m-tolylethynyl-octahydro-isoindol-4-ol is
obtained. [0103] b) 60 mg of
(.+-.)-(3aRS,4RS,7aSR)-4-m-tolylethynyl-octahydro-isoindol-4-ol, 25
mg methyl chloroformate and 250 mg polymer-supported H0nig's base
in 5 ml dichloromethane are stirred at room temperature for 18 h,
then filtered and evaporated, followed by prep-HPLC purification to
yield
(.+-.)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-c-
arboxylic acid methyl ester. HPLC-MS: 336 (M+Na).
[0104] Following the same procedure, the following compounds are
obtained:
EXAMPLE 5a
(.+-.)-(3aRS,4RS,7aSR)-Furan-2-yl-(4-hydroxy-4-m-tolylethynyl-octahydro-is-
oindol-2-yl)-methanone
[0105] HPLC-MS: 372 (M+Na).
EXAMPLE 5b
(.+-.)-(3aRS,4RS,7aSR)-Cyclopropyl-(4-hydroxy-4-m-tolylethynyl-octahydro-i-
soindol-1-yl)-methanone
[0106] HPLC-MS: 346 (M+1Na).
EXAMPLE 5c
(.+-.)-(3aRS,4RS,7aSR)-(4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-y-
l)-pyridin-3-yl-methanone
[0107] HPLC-MS: 361 (M+1), 383 (M+Na).
EXAMPLE 6
(.+-.)-((1SR,3SR)-3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-methyl-carbamic
acid methyl ester and
(.+-.)-((1RS,3SR)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-methyl-carbamic
acid methyl ester
[0108] a) To a solution of 3-methylamino-cyclohex-2-wane (1.35 g,
10.8 mmol; CAS 55998-74-8) and triethylamine (4.5 ml, 32.4 mmol)
dichloromethane (20 ml) is added methyl chloroformate (2.5 ml, 32.4
mmol) at 0.degree. C. during 15 minutes. After 45 minutes the
reaction mixture is diluted with dichloromethane and washed three
times with citric acid (10% w/v). The organic phase is concentrated
in vacuo and the residue is treated with K.sub.2CO.sub.3 (3.0 g,
21.6 mmol) in water/methanol (1:1 v/v, 20 ml) for 15 minutes. The
reaction mixture is concentrated in vacuo and the residue
partitioned between water and dichloromethane and after
concentration in vacuo the mixture is chromatographed on silica gel
(100 g) with hexane/ethyl acetate (1:1 v/v) as eluent. The product
methyl-(3-oxo-cyclohex-1-enyl)-carbamic acid methyl ester is
obtained as a pale orange oil. NMR (400 MHz; CDCl.sub.3: 5.68 (s,
1H), 3.79 (s, 3H), 3.20 (s,3H), 2.82 (t, J=6.5 Hz, 2H). 2.39 (t,
J=6.5 Hz, 2H), 2.00 (quint., J=6.5 Hz, 2H). [0109] b). A solution
of methyl-(3-oxo-cyclohex-1-enyl)-carbamic acid methyl ester (412
mg, 2.2 mmol) in methanol (20 ml) is hydrogenated with Pd/C (10%,
80 mg, 1 bar). After filtration the crude product is
chromatographed on silica gel (30 g) with hexane/ethyl acetate 0:1
v/v) as eluent. Methyl-(3-oxo-cyclohexyl)-carbamic acid methyl
ester is obtained as a colorless oil. NMR (400 MHz; CDCl.sub.3):
4.23 (br, 1H), 3.69 (s, 3H), 2.83 (br, s, 3H), 2.57-2.34 (m, 3H),
2.21 (td, J=14 Hz, J=6 Hz, 1H), 2.05 (m, 1H), 1.91 (m, 1H), 1.80
(qd, J=12.5 Hz, J=3.5 Hz, 1H), 1.6 (m, 1H). [0110] c) The reaction
of methyl-(3-oxo-cyclohexyl)-carbamic acid methyl ester with
lithium m-tolylacetylide is performed as in example 1. After
chromatography on silicagel with hexane/ethyl acetate (gradient 4:1
to 1:1 v/v) as eluent the title compound
(.+-.)-((1SR,3SR)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-methyl-carbamic
acid methyl ester (yield 24%) is first eluted (R.sub.f=0.62 (TLC
silica gel, hexane/ethyl acetate 1:1), HPLC-MS: 324.2 (M+Na).sup.+)
followed by
(.+-.)-((1RS,3SR)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-methyl-carbamic
acid methyl ester (yield 50%, R.sub.f=0.49 (TLC silica gel,
hexane/ethyl acetate 1:1). HPLC-MS: 324.2 (M+Na).sup.+).
[0111] Following the same procedure the following compounds are
obtained;
EXAMPLE 6a
(.+-.)-(1RS,3SR)-((3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-(4-methoxy-benzy-
l)-carbamic acid ethyl ester
[0112] HPLC-MS: 444.2 (M+Na).sup.+.
EXAMPLE 6b
(.+-.)-(1RS,3RS)-((3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-(4-methoxy-benzy-
l)-carbamic acid ethyl ester.
[0113] HPLC-MS: 444.2 (M+Na).sup.+.
EXAMPLE 6c
(.+-.)-[(1RS,3SR)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-5,5-dimethyl-cyclo-
hexyl]-methyl-carbamic acid methyl ester
[0114] HPLC-MS: 368.2 (M+Na).sup.+.
EXAMPLE 6d
(.+-.)-(1RS,3SR)-(3-Hydroxy-5,5-dimethyl-3-m-tolylethynyl-cyclohexyl)-meth-
yl-carbamic acid methyl ester
[0115] HPLC-MS: 352.2 (M+Na).sup.+.
EXAMPLE 6e
(.+-.)-[(1RS,3SR)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-5,5-dimethyl-cycloh-
exyl]-methyl-carbamic acid methyl ester
[0116] HPLC-MS: 356.2 (M+Na).sup.+.
EXAMPLE 6f
(.+-.)-[(1RS,3RS)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl--
carbamic acid methyl ester
[0117] HPLC-MS: 328.2 (M+Na).sup.+.
EXAMPLE 6g
(.+-.)-[(1RS,3SR)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl--
carbamic acid methyl ester
[0118] HPLC-MS: 328.2 (M+Na).sup.+.
EXAMPLE 6h
(.+-.)-[(1RS,3RS)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-methyl-
-carbamic acid methyl ester
[0119] HPLC-MS: 340.2 (M+Na).sup.+.
EXAMPLE 6i
(.+-.)-[(1RS,3SR)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-methyl-
-carbamic acid methyl ester
[0120] HPLC-MS: 340.2 (M+Na).sup.+.
EXAMPLE 6j
(.+-.)-[(1RS,3RS)-3-(3-Chloro-phenylethynyl-3-hydroxy-cyclohexyl]-methyl-c-
arbamic acid methyl ester
[0121] R.sub.f=0.31 (TLC silica gel, hexane ethyl acetate 1:1).
EXAMPLE 6k
(.+-.)-[(1RS,3SR)-3-(3-Chloro-phenylethynyl)3-hydroxy-cyclohexyl]-methyl-c-
arbamic acid methyl ester
[0122] R.sub.f=0.22 (TLC silica gel, hexane/ethyl acetate 1:1).
EXAMPLE 6l (.+-.)-(1RS,3RS)-N-(b
3-hydroxy-3-m-tolylethynyl-cyclohexyl]-acetamide HPLC-MS: 294.2
(M+Na)
EXAMPLE 6m
[0123]
(.+-.)-(1RS,3SR)-N-(3-hydroxy-3-m-tolylethynyl-cyclohexyl)-acetamid-
e
[0124] M.p. 152-155.degree. C.
EXAMPLE 6n
(.+-.)-(1RS,3RS)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic
acid ethyl ester
[0125] HPLC-MS: 324.2 (M+Na).
EXAMPLE6o
(.+-.)-(1RS,3SR)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic
acid ethyl ester
[0126] M.p. 106-107.degree. C.
EXAMPLE 6o
(.+-.)-(1RS,3RS)-[3-(3-Fluoro-phenylethynyl-3-hydroxy-cyclohexyl]-carbamic
acid ethyl ester
[0127] HPLC-MS: 328.2 (M+Na).
EXAMPLE 6q
(.+-.)-(1RS,3SR)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbami-
c acid ethyl ester
[0128] M.p. 121-123.degree. C.
EXAMPLE 6r
(.+-.)-(1RS,3RS)-[3-(3-Methoxy-phenylethynyl)-3-hydroxy-cyclohexyl]-carbam-
ic acid ethyl ester
[0129] HPLC-MS: 340 2 (M+Na).
EXAMPLE 6s
(.+-.)-(1RS,3RS)-N-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-aceta-
mide HPLC-MS: 340.2 (M+Na).
EXAMPLE 6t
(.+-.)-(1RS,3SR)-N-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-aceta-
mide
[0130] HPLC-MS: 276.2 (M+1), 298.2 (M+Na),
EXAMPLE 6u
(.+-.)-(1RS,3SR)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbam-
ic acid ethyl ester
[0131] HPLC-MS; 340.2 (M+Na).
EXAMPLE 6v
(.+-.)-(1RS,3RS)-N-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-acet-
amide HPLC-MS: 288.2 (M +1), 310.2 (M+11a),
EXAMPLE 6w
(.+-.)-(1RS,3SR)-N-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-acet-
amide
[0132] HPLC-MS: 288.2 (M-1), 310.2 (M+Na).
EXAMPLE 6x
(.+-.)-(1RS,3RS)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbam-
ic acid tert-butyl ester
[0133] HPLC-MS: 368.2 (M+Na).
EXAMPLE 6y
(.+-.)-(1RS,3SR)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbam-
ic acid tert-butyl ester
[0134] HPLC-MS: 368.2 (M+Na).
EXAMPLE 6z
(.+-.)-(1RS,3RS)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic
acid tert-butyl ester
[0135] HPLC-MS: 352.2 (M+Na).
EXAMPLE 6aa
(.+-.)-(1RS,3SR)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic
acid tert-butyl ester
[0136] HPLC-MS: 352.1 (M+Na).
EXAMPLE 6ab
(.+-.)-(1RS,3RS)-(3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbami-
c acid tert-butyl ester
[0137] HPLC-MS: 356.2 (M+Na).
EXAMPLE 6ac
(.+-.)-(1RS,3SR)-(3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbami-
c acid tert-butyl ester
[0138] HPLC-MS: 356.2 (M+Na).
EXAMPLE 6ad
(.+-.)-(1RS,3RS)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbami-
c acid methyl ester
[0139] HPLC-MS: 314.2 (M+Na).
EXAMPLE 6ae
(.+-.)-(1RS,3SR)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbami-
c acid methyl ester
[0140] HPLC-MS: 314.2 (M+Na).
EXAMPLE 7
(.+-.)-(3-Phenylethynyl-cyclohex-2-enyl)-carbamic acid ethyl ester
and (.+-.)-3-phenylethyl-cyclohex-3-enyl)-carbamic acid ethyl
ester
[0141] 100 mg (0.35 mmol)
(3-hydroxy-3-phenylethynyl-cyclohexyl)-carbamic acid ethyl ester
(diasteromeric mixture 2) in 15 mL toluene are treated with 10 mg
p-toluene sulfonic acid and stirred 6 hours at 120", After cooling
and addition of 50 ml ethyl acetate, the product is washed with
water containing a small amount of sodium bicarbonate, and saline.
The organic phase is dried with sodium sulfate, concentrated and
column chromatographed using a 3:1 mixture of petroleum ether and
ethyl acetate. The first product to come out of the column is
(3-phenylethynyl-cyclohex-2-enyl)-carbamic acid ethyl ester (yield,
23%), followed by (3-phenylethynyl-cyclohex-3-enyl)-carbamic acid
ethyl ester (yield: 48%) Racemate 1: .sup.1H-NMR (400 MHz) delta
7.41 (m, 2H); 7.30 (m, 3H); 6.04 (a, 1H); 4.63 (broad s, 1H); 4.35
(broad s, 1H): 4.10 (q, 2H): 2.20 (a, 2H); 1.90 (m, 1H); 1.70, (m,
2H); 1.50 (m, 1H); 1.23 (t, 3H).
[0142] Racemate 2; .sup.1H-NMR (400 MHz); delta 7.40 (m, 2H); 7.30
(m, 3H); 6.19 (s, 1H); 4.68 (broad s, 1H); 4.10 (q, 2H); 3.92
(broad s, 1H); 2.81 (d, 1H); 2.28 (broad a, 2H); 2.12, 1.85, 1.59
(3 m, 3H); 1.23 (t, 3H).
EXAMPLE 8
(.+-.)-Methyl-(3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl
ester
[0143] 22 mg (0.082 mmol)
(3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl ester are
dissolved in 2 ml DMF and 1 THF. 8 mg (0.165 mmol) of a 60%
dispersion of NaH in oil is added and the mixture stirred under
argon for 90 minutes at room temperature. The reaction mixture is
cooled to 0.degree., and 16 microliters Mel in 0.5 ml THF are added
dropwise. After stirring one hour at room temperature, the reaction
mixture is cooled to 0.degree. again, ice is added and the crude
product extracted with ethyl acetate, washed with water and saline,
dried with sodium sulfate and column chromatographed using a 4:1
mixture of petroleum ether and ethyl acetate. Yield: 43%.
[0144] .sup.1H-NMR (400 MHz): delta 7.40 (m, 2H); 7.30 (m, 3H);
6.18 (s, 1H); 4.22 (broad m, 1H); 4.15 (q, 2H); 2.8 (broad s, 3H);
2.35 (broad s, 4H); 1.80-1.60 (m, 1H): 1.15 (t, 3H).
EXAMPLE 9
(.+-.)-(4aRS,5RS,8aSR)-5-Hydroxy-5-phenylethynyl-octahydro-quinoline-1-car-
boxylic acid ethyl ester
[0145] a) To the mixture of
(.+-.)-(4aRS,8aSR)-octahydro-quinolin-5-one oxalate (1.50 g, 8.17
mmol), toluene (5 ml) and water (5 ml) is added solid potassium
carbonate. After stirring for a few minutes ethyl chloroformate
(0.71 ml, 7.4 mmol) is added and the reaction mixture is then
stirred at room temperature for 3 hours. The organic phase is
separated and the aqueous phase extracted with dichloromethane
(3.times.10 ml). The combined organic phases are dried over
magnesium sulphate and concentrated in vacuo to yield 1.22 g (88%)
of (.+-.)-(4aRS,8aSR)-5-Oxo-octahydro-quinoline-1-carboxylic acid
ethyl ester. 1H NMR (400 MHz; CDCl3): 1.28 (t, 3H), 1.40 1.70 (m,
3H), 1.72-1.90 (m, 1H), 2.0-2.20 (m, 3H), 2.30-2.48 (m, 3H), 2.55
(td, 1H), 3.32 (td, 1H), 3.50 (m, 2H), 4.12 (q, 2H). [0146] b) To a
solution of
(.+-.)-(4aRS,8aSR)-5-oxo-octahydro-quinoline-1-carboxylic acid
ethyl ester (0.372 g, 1.65 mmol) in THF (15 ml) is added a solution
of lithium phenylacetylide in THF (3.30 ml, 3.30 mmol; 1.0M
solution in THF) at -50 C. The reaction mixture is then stirred for
1.5 hours at -50C and then allowed to warm to room temperature. The
reaction mixture is diluted with diethyl ether (100 ml), washed
with saturated sodium bicarbonate solution (2.times.10 ml), water
(10 ml), dried over magnesium sulfate and then concentrated in
vacuo. Purification of the crude product (0.860 g) using silica gel
chromatography (ethylacetate/hexane 1:3 v/v) give
(.+-.)-(4aRS,5RS,8aSR)-5-hydroxy-5-phenylethynyl-octahydro-quinoline-1-ca-
rboxylic acid ethyl ester.(0.144 g, 26.7%).
[0147] Following the same procedure the following compounds are
obtained:
EXAMPLE 9a
(.+-.)-1(4aRS,5SR,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-qui-
nolin-1-yl]-furan-2-yl-methanone
[0148] NMR (DMSO-D6, 500 MHz): 7.84 (s,1H), 7.45 (m, 4H), 6.95
(d,1H), 6.63 (d,1H), 5.51 (s,1H), 4.03 (m, 1H), 3.94 (m, 1H), 3.32
(m, 1H), 2.06 (m, 1H), 2.04 (m, 1H), 1.96 (m, 1H), 1.94 (m, 1H),
1.85 (m, 1H), 1.74 (m.2H), 1.71 (m, 1H), 1.60 (m, 1H), 1.50 (m,
1H), 1.41 (m, 1H).
EXAMPLE 9b
(.+-.)-[(4aRS,5RS,8aSR)-5-(3-Chloro-phenylethynyl-5-hydroxy-octahydro-quin-
olin-1-yl]-furan-2-yl-methanone
[0149] NMR (DMSO-D6, 500 MHz): 7.83 (s,1H), 7.43 (m, 4H), 6.95
(d,1H), 6.62 (m, 1H), 5.77 (s,1H), 3.99 (m, 1H), 3.90 (m, 1H), 3.31
(m, 1H), 2.12 (m, 1H), 2.06 (m, 1H), 1.97 (m, 1H), 1.88 (m, 1H),
1.83 (m, 1H), 1.77 (m, 1H), 1.66 (m, 1H), 1.59 (m, 2H), 1.46 (m,
1H), 1.22 (m, 1H).
EXAMPLE 9c
(.+-.)-(4aRS,5RS,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quin-
oline-1-carboxylic acid tert-butyl ester
[0150] NMR (CDCl3): 7.42 (d, J=1.1 Hz, 1H), 7.32 (m, 3H), 3.55 (m,
1H), 3.48 (m, 1H), 3.10 (m, 1H), 2.08 (m, 3H), 1.90 (m, 1H),
1.8-1.6 (m, 7H), 1.46 (s, 9H), 1.38 (m, 1H).
EXAMPLE 9d
(.+-.)-[(4aRS,5SR,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-qui-
nolin-1-yl]-morpholin-4yl-methanone
[0151] LC-MS, M+1=403.1
EXAMPLE 9e
(.+-.)-(4aRS,5RS,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quin-
olin-1-yl]-(4-methyl-piperazin-1yl)-methanone
[0152] LC-MS, M+1=416.2
EXAMPLE 10
(.+-.)-(4aRS,5RS,8aRS)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quin-
oline-1-carboxylic acid ethyl ester and
(.+-.)-(4aRS,5SR,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-qui-
noline-1-carboxylic acid ethyl ester
[0153] a) To a solution of trimethylsilylacetylene (1.54 ml, 10.8
mmol) in THF (10 ml), is added a solution of n-butyllithium in
hexane (6.75 ml, 10.8 mmol; 1.6M in hexane) at 0.degree.. The
reaction mixture is stirred at 0.degree. C. for 45 minutes and then
at room temperature for 20 hours. The reaction mixture is diluted
with diethyl ether (100 ml), washed with saturated sodium
bicarbonate solution (2.times.10 ml), dried over magnesium sulfate
and concentrated in vacuo. Purification of the crude product (2.0
g) using silica gel chromatography (ethylacetate/hexane gradient
0-40% v/v) give
(.+-.)-(4aRS,5RS,8aSR)-5-hydroxy-5-trimethylsilanylettlynyl-octahydro-qui-
noline-1-carboxylic acid ethyl ester, (1.48, 84%); 1H NMR (400 MHz;
CDCl3): 1H NMR 0.1 (s-overlap, 9H), 1.05 (t, 3H), 1.10-1.30 (m,
2H), 1.30-1.60 (m, 6H), 1.60-1.95 (m, 4H), 2.80-3.0 (m, 1H),
3.25-3.50(m, 1H), 3.50-3.65 (m, 1H), 3.95(m, 2H). Further
chromatographic fractions all contain variable mixtures of
(.+-.)-(4aRS,5RS,8a9R)-5-hydroxy-5-trimethylsilanylethynyl-octahydro-quin-
oline-1-carboxylic acid ethyl ester and
(.+-.)-(4aRS,5SR,8a8R)-6-hydroxy-5-trimethylsilanylethynyl-octahydro-quin-
oline-1-carboxylic acid ethyl ester. [0154] b) A mixture
(approximately 5:1) of
(.+-.)-(4aRS,5RS,8SR)-5-hydroxy-5-trimethylsilanylethynyl-octahyd-
ro-quinoline-1-carboxylic acid ethyl ester and
(.+-.)-(4aRS,5SR,8aSR)-5-hydroxy-5-trimethylsilanylethynyl-octahydro-quin-
oline-1-carboxylic acid ethyl ester (0.272 g, 0.84 mmol),
1-bromo-3-chloro-benzene (0.161 g, 0.84 mmol), copper(I)iodide
(0.016 g, 0.093 mmol), triphenylphosphine (0.02 g,0.074 mmol),
potassium carbonate (0.127 g, 0.02 mmol), palladium on carbon (10%)
(10 mg) in dimethoxyethane (2 ml) and water (1 ml) are combined
together and heated at 55.degree. C. for 24 hours under argon
atmosphere. The reaction mixture is cooled to room temperature,
filtered through celite, washed with diethyl ether and concentrated
in in vacuo to yield a crude oil The crude di (0.181 g) is purified
using silica gel chromatography (ethylacetate r hexane gradient
0-30%) and fractions containing the desired compounds are collected
and evaporated in vacuo to yield the first product
(.+-.)-(4aRS,5RS,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-qui-
noline-1-carboxylic acid ethyl ester. (140 mg, 46%). .sup.1H NMR
(400 MHz; CDCl3); 1.28 (t, 3H), 1.2 8-1.50 (m, 2H), 1.50-2.00 (m,
2.0-2.20 (m, 3H), 3.08 (m, 1H) 3.55 (tm, 1H), 3.80 (m, 1H), 4.15
(q, 2H),7.24-7.40(m, 4H) and the second product
(.+-.)-(4aRS,5SR,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-qui-
noline-1-carboxylic acid ethyl ester (30 mg, 10%), .sup.1H NMR (400
MHz; CDCI3): 1.29 (t, 3H), 1.41-1.58(m, 2H), 1.58-2.00(m, 8H),
2.08-2.18 (m, 2H), 3.16 (m, 1H), 3.61 (m, 1H), 3.70 (m, 1H), 4.10
(m, 2H),7.16-7.30(m, 4H).
[0155] Following the same procedure the following compounds are
obtained:
EXAMPLE 10a
(.+-.)-(4aRS,5SR,8aSR)-5-Hydroxy-5-m-tolylethynyl-octahydro-quinoline-1-ca-
rboxylic acid ethyl ester
[0156] .sup.1H NMR (400 MHz; CDCl3): 1.25 (t, 3H), 1.39-1.56 (m,
2H), 1.56-1.98 (m, 8H), 1.98-2.23 (m, 2H) 2.35 (a, 3H), 3.15 (m,
1H), 3.55-3.79 (m, 2H), 4.04-4.20 (m, 2H),7.10 (m, 1H)7.15-7.25 (m,
3H)
EXAMPLE 10b
(.+-.)-(4aRS.,5RS,8aSR)-5-Hydroxy-5-m-tolylethynyl-octahydro-quinoline-1-c-
arboxylic acid ethyl ester
[0157] .sup.1H NMR (400 MHz CDCl3): 1.25 (t, 3H), 1.30-1.50 (m,
2H), 1.56-2.20 (m, 8H), 220-2.44 (m, 3H), 2.85-3.19(m, 1H),
3.54-3.63 (m, 1H), 3.69-3.84 (m, 1H), 4.07-4.19 (m, 2H),7.05-7.27
(m, 4H).
EXAMPLE 11
(.+-.)-Ethyl-((1SR,3SR)-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamic
acid methyl ester and
(.+-.)-ethyl-((1SR,3RS)-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamic
acid methyl ester
[0158] a) To a solution of 3-methoxy-cyclopent-2-enone (800 mg,
7.13 mmol) in 30 ml of an ethylamine solution to THF, (2.0 M, 60
mmol) acetic acid (200 .mu.l) is added and the mixture stirred at
70 .degree. C. for 2 h. The reaction mixture is concentrated in
vacuo and the residue is filtered through silica gel with acetone.
The resulting solid is crystallized from dichloromethane/other to
yield 3-ethylamino-cyclopent-2-enone as white crystals, m.p.
136-138.5*C. [0159] b) To a solution of
3-ethylamino-cyclopent-2-enone (500 mg, 4 mmol) in 4 ml THF and 1
ml DMF, sodium hydride (12 mmol) is added. After stirring the
reaction mixture for 20 minutes at room temperature, methyl
chloroformate (615 .mu.l, 8 mmol) is added. After stirring for 16
minutes, the reaction mixture is quenched with saturated aqueous
ammonium chloride solution and concentrated in vacuo. The residue
is partitioned between brine and dichloromethane. The organic
extracts are chromatographed on silica gel (30 g) with
dichloromethane/methanol (95:5 v/v) as eluent to afford
ethyl-(3-oxo-cyclopent-1-enyl)-carbamic acid methyl ester which is
crystallized from dichloromethane/ether, m.p. 68-68.degree. C.
[0160] c) Ethyl-(3-oxo-cyclopent-1-enyl)-carbamic acid methyl ester
(400 mg, 2.16 mmol) is hydrogenated in methanol with Pd/C (10%, 80
mg) to yield (.+-.)-ethyl-((R,S)-3-oxo-cyclophentyl)-carbamic acid
methyl ester as a yellowish oil. [0161] d) The reaction of
(.+-.)-ethyl-(R,S)-3-oxo-cyclopentyl)-carbamic acid methyl ester
with lithium m-tolylacetylide is performed as in example 1. After
chromatography on silicagel with hexane/acetone (5:1 v/v) as
eluent, the title compound
(.+-.)-ethyl-((1SR,3RS)-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamic
acid methyl ester is first eluted [R.sub.f=0.48 (TLC silica gel,
hexane/ethyl acetate 1:1), HPLC-MS: 324.2 (M+Na).sup.+] followed by
(.+-.)-ethyl-((1SR,3SR)-3-hydroxy-3-m-tolylethynyl-cyclopentyl)-carbamic
acid methyl ester [R.sub.f=0.39 (TLC silica gel, hexane/ethyl
acetate 1:1), HPLC-MS: 324.2 (M+Na).sup.+], both as pale yellow
oils.
* * * * *