U.S. patent application number 17/198606 was filed with the patent office on 2022-01-20 for blood-brain barrier-penetrant dopamine- -hydroxylase inhibitors.
The applicant listed for this patent is BIAL - PORTELA & CA, S.A.. Invention is credited to Alexander Beliaev, Laszlo Erno Kiss, Pedro Nuno Leal Palma, Tino Rossi, Patricio Soares Da Silva.
Application Number | 20220017523 17/198606 |
Document ID | / |
Family ID | |
Filed Date | 2022-01-20 |
United States Patent
Application |
20220017523 |
Kind Code |
A1 |
Soares Da Silva; Patricio ;
et al. |
January 20, 2022 |
BLOOD-BRAIN BARRIER-PENETRANT DOPAMINE- -HYDROXYLASE INHIBITORS
Abstract
This invention relates to: (a) compounds of formula I (with
R.sub.1 to R.sub.5, n and A as defined herein) and pharmaceutically
acceptable salts or solvates thereof that are useful as
dopamine-.beta.-hydroxylase inhibitors; (b) pharmaceutical
compositions comprising such compounds, salts or solvates; (c) the
use of such compounds, salts or solvates in therapy; (d)
therapeutic methods of treatment using such compounds, salts or
solvates; and (e) processes and intermediates useful for the
synthesis of such compounds. ##STR00001##
Inventors: |
Soares Da Silva; Patricio;
(Sao Mamede Do Coronado, PT) ; Rossi; Tino; (Sao
Mamede Do Coronado, PT) ; Kiss; Laszlo Erno; (Sao
Mamede Do Coronado, PT) ; Beliaev; Alexander; (Sao
Mamede Do Coronado, PT) ; Leal Palma; Pedro Nuno;
(Sao Mamede Do Coronado, PT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BIAL - PORTELA & CA, S.A. |
Sao Mamede Do Coronado |
|
PT |
|
|
Appl. No.: |
17/198606 |
Filed: |
March 11, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16335521 |
Mar 21, 2019 |
10975083 |
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PCT/PT2017/050022 |
Sep 22, 2017 |
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17198606 |
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International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 207/06 20060101 C07D207/06; C07D 207/08 20060101
C07D207/08; C07D 207/27 20060101 C07D207/27; C07D 405/04 20060101
C07D405/04; C07D 409/04 20060101 C07D409/04; A61P 25/34 20060101
A61P025/34; A61P 25/36 20060101 A61P025/36; A61P 25/32 20060101
A61P025/32; A61P 9/12 20060101 A61P009/12; A61P 9/04 20060101
A61P009/04 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 23, 2016 |
GB |
1616201.8 |
Aug 29, 2017 |
GB |
1713779.5 |
Claims
1. A pharmaceutical composition comprising (i) a compound of
formula I, or a pharmaceutically acceptable salt or solvate
thereof: ##STR00266## and (ii) a pharmaceutically acceptable
excipient, wherein: R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl,
partially or fully deuterated C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 cyanoalkyl,
C.sub.1-C.sub.6 mercaptoalkyl or amino; R.sub.2 is hydrogen or
C.sub.1-C.sub.3 alkyl; R.sub.3 is hydrogen or oxo; or R.sub.2 and
R.sub.3 combine to form a structure of formula Ia: ##STR00267##
wherein: X is CH.sub.2, CR.sub.6 or N; is a double bond when X is
CR.sub.6 or N and is a single bond when X is CH.sub.2; R.sub.4 is
hydrogen or C.sub.1-C.sub.3 alkyl; R.sub.5 is hydrogen or
C.sub.1-C.sub.2 alkyl; or R.sub.4 and R.sub.5 combine, together
with the carbon atom to which they are attached, to form a
cyclopropyl ring wherein the CH.sub.2 moiety is optionally
substituted with two deuterium atoms; R.sub.6 is hydrogen; A is
C.sub.5-C.sub.7 cycloalkyl, furanyl, thiophenyl, methylthiophenyl
or ##STR00268## wherein: X.sub.1 is hydrogen, halo or methyl;
X.sub.1' is hydrogen or halo; X.sub.2 is hydrogen, halo or methyl;
X.sub.2' is hydrogen or halo; X.sub.3 is hydrogen or fluoro; n is 0
or 1, and when n is 0 a single or double bond joins the carbon
atoms to which R.sub.3 and R.sub.4 are attached.
2. A compound of formula I, or a pharmaceutically acceptable salt
or solvate thereof: ##STR00269## wherein: R.sub.1 is hydrogen,
C.sub.1-C.sub.6 alkyl, partially or fully deuterated
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6
cyanoalkyl, C.sub.1-C.sub.6 mercaptoalkyl or amino; R.sub.2 is
hydrogen or C.sub.1-C.sub.3 alkyl; R.sub.3 is hydrogen or oxo; or
R.sub.2 and R.sub.3 combine to form a structure of formula Ia:
##STR00270## wherein: X is CH.sub.2, CR.sub.6 or N; is a double
bond when X is CR.sub.6 or N and is a single bond when X is
CH.sub.2; R.sub.4 is hydrogen or C.sub.1-C.sub.3 alkyl; R.sub.5 is
hydrogen or C.sub.1-C.sub.2 alkyl; or R.sub.4 and R.sub.5 combine,
together with the carbon atom to which they are attached, to form a
cyclopropyl ring wherein the CH.sub.2 moiety is optionally
substituted with two deuterium atoms; R.sub.6 is hydrogen; A is
C.sub.5-C.sub.7 cycloalkyl, furanyl, thiophenyl, methylthiophenyl
or ##STR00271## wherein: X.sub.1 is hydrogen, halo or methyl;
X.sub.1' is hydrogen or halo; X.sub.2 is hydrogen, halo or methyl;
X.sub.2' is hydrogen or halo; X.sub.3 is hydrogen or fluoro; n is 0
or 1, and when n is 0 a single or double bond joins the carbon
atoms to which R.sub.3 and R.sub.4 are attached with the proviso
that the following compounds are excluded: ##STR00272##
3. A pharmaceutical composition according to claim 1, wherein:
R.sub.2 is hydrogen or C.sub.1-C.sub.3 alkyl; and R.sub.3 is
hydrogen or oxo.
4. A pharmaceutical composition according to claim 1, wherein:
R.sub.2 and R.sub.3 combine to form a structure of formula Ia:
##STR00273## wherein: X is CH.sub.2, CR.sub.6 or N; is a double
bond when X is CR.sub.6 or N and is a single bond when X is
CH.sub.2.
5. A pharmaceutical composition according to claim 4, wherein is a
double bond and X is CR.sub.6.
6. A pharmaceutical composition according to claim 1, wherein n is
0 and a single bond joins the carbon atoms to which R.sub.3 and
R.sub.4 are attached.
7. A pharmaceutical composition according to claim 1, wherein
R.sub.4 and R.sub.5 combine, together with the carbon atom to which
they are attached, to form a cyclopropyl ring wherein the CH.sub.2
moiety is optionally substituted with two deuterium atoms.
8. A pharmaceutical composition according to claim 1, wherein more
than 50% of substituents R.sub.5 and A have the stereochemical
configuration of formula Id ##STR00274##
9. A pharmaceutical composition according to claim 1, wherein more
than 50% of substituents R.sub.5 and A have the stereochemical
configuration of formula Ie ##STR00275##
10. A pharmaceutical composition according to claim 1, wherein A is
##STR00276## wherein X.sub.1, X.sub.1', X.sub.2, X.sub.2' and
X.sub.3 are as defined in claim 1.
11. A pharmaceutical composition according to claim 1, wherein
R.sub.1 is hydrogen, methyl, d3-methyl, propyl, cyclopropyl,
cyanomethyl, mercaptoethyl or amino.
12. A pharmaceutical composition according to claim 3, wherein
R.sub.2 is hydrogen or methyl.
13. A pharmaceutical composition according to claim 3, wherein
R.sub.3 is hydrogen.
14. A pharmaceutical composition according to claim 1, wherein
R.sub.4 is hydrogen or methyl.
15. A pharmaceutical composition according to claim 1, wherein
R.sub.5 is hydrogen or methyl.
16. A pharmaceutical composition according to claim 1, wherein A is
##STR00277## wherein: X.sub.1 is hydrogen, fluoro, chloro or
methyl; X.sub.1' is hydrogen, fluoro or chloro; X.sub.2 is
hydrogen, fluoro, chloro, bromo or methyl; X.sub.2' is hydrogen,
fluoro, chloro or bromo; X.sub.3 is hydrogen or fluoro.
17-18. (canceled)
19. A method for treating or preventing conditions ameliorated by
inhibition of dopamine-beta-hydroxylase within the central nervous
system comprising administering a therapeutically effective amount
of a compound of formula I, as defined in claim 1, or a
pharmaceutically acceptable salt or solvate thereof, to a patient
in need thereof.
20. A pharmaceutical composition comprising (i) a therapeutically
effective amount of a compound of formula I, as defined in claim 2,
or a pharmaceutically acceptable salt or solvate thereof; and (ii)
a pharmaceutically acceptable excipient.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation Application of U.S.
application Ser. No. 16/335,521, filed on Mar. 21, 2019, which is
the U.S. national stage filing, under 35 U.S.C. .sctn. 371(c), of
International Application No. PCT/PT2017/050022, filed on Sep. 22,
2017, which claims priority to United Kingdom Patent Application
No. 1713779.5, filed on Aug. 29, 2017; and United Kingdom Patent
Application No. 1616201.8, filed on Sep. 23, 2016.
FIELD OF THE INVENTION
[0002] This invention relates to: (a) compounds and
pharmaceutically acceptable salts or solvates thereof that are
useful as dopamine-.beta.-hydroxylase inhibitors; (b)
pharmaceutical compositions comprising such compounds, salts or
solvates; (c) the use of such compounds, salts or solvates in
therapy; (d) therapeutic methods of treatment using such compounds,
salts or solvates; and (e) processes and intermediates useful for
the synthesis of such compounds.
BACKGROUND OF THE INVENTION
[0003] The enzyme dopamine-.beta.-hydroxylase (D.beta.H), also
known as dopamine .beta.-monooxygenase, is expressed both in the
periphery and the central nervous system (CNS). D.beta.H catalyses
the specific hydroxylation of dopamine (DA) to produce
norepinephrine, also known as noradrenaline (NA). As such,
inhibitors of D.beta.H can inhibit the biosynthesis of NA, limiting
its concentration and increasing DA levels.
[0004] Conventionally, interest in the development of inhibitors of
D.beta.H had centred on the hypothesis that inhibition of this
enzyme may provide significant clinical improvements in patients
suffering from cardiovascular disorders such as hypertension or
chronic heart failure. The rationale for the use of D.beta.H
inhibitors is based on their capacity to inhibit the biosynthesis
of NA, which is achieved via enzymatic hydroxylation of DA.
Reduction of the biosynthesis of NA via inhibition of D.beta.H can
directly dampen sympathetic nerve function, the activation of which
is the principal clinical manifestation of congestive heart failure
(Parmley, W. W., Clin. Cardiol., 18: 440-445, 1995). Therefore,
peripheral D.beta.H inhibitors reduce sympathetic drive.
[0005] D.beta.H inhibitors may also find application in disorders
of the CNS, including drug addiction, psychiatric disorders,
reduced cognition or dementia. For example, cocaine primarily acts
through inhibition of presynaptic dopamine (DA) transporters as
well as the serotonin and norepinephrine transporters. Increased
levels of synaptic DA and, thereby, DA receptor binding following
cocaine administration is a key mechanism through which cocaine is
reinforcing. Cocaine also modulates the endogenous opioid system,
especially p.-opioid receptors (MOR), .kappa.-opioid receptors
(KOR), and preprodynorphin. Whereas stimulation of dopaminergic
pathways may be sufficient to cause the reinforcing effects of
cocaine, DA transporter gene deletion studies have shown that this
pathway is not essential to the development of cocaine
self-administration. Selective gene disruption of the MOR will,
however, prevent the development of cocaine
self-administration.
[0006] Disulfiram (Antabuse), which inhibits aldehyde dehydrogenase
(ALDH) and has been used for more than 50 years in the treatment of
alcoholism (Fuller, R. K. et al., J. Amer. Med. Assoc., 256:
1449-55, 1986), was found to reduce alcohol and cocaine intake in
co-dependent patient population (Carroll, K. M. et al., Arch. Gen.
Psychiatry, 61: 264-72, 2000; Carroll, K. M. et al., Addiction, 93:
713-27, 1998; Carroll, K. M. et al., J. Stud. Alcohol, 54: 199-208,
1993). Surprisingly, further studies revealed that disulfiram was
at least as effective at treating cocaine addicts who do not
consume alcohol, and may even be more effective (Carroll, K. M. et
al., Arch. Gen. Psychiatry, 61: 264-72, 2004; George, T. P. et al.,
Biol Psychiatry, 47: 1080-6, 2000; Petrakis, I. L. et al.,
Addiction, 95: 219-28, 2000). Therefore, an ALDH-independent
mechanism must be responsible for the ability of disulfiram to
promote cocaine abstinence (Gaval-Cruz, M. et al., Mol. Interv., 9:
175-87, 2009; Weinshenker, D. et al., Neuropsychopharmacology, 32:
1433-51, 2007). Subsequently, Schroeder et al. tested the effects
of disulfiram on cocaine and food self-administration behaviour and
drug-primed reinstatement of cocaine seeking in rats (Schroeder, J.
P. et al., Neuropsychopharmacology, 35: 2440-9, 2010). Their
results suggest that disulfiram's efficacy in the treatment of
cocaine addiction is associated with the inhibition of D.beta.H and
interference with the ability of environmental stimuli to trigger
relapse (Schroeder, J. P. et al., Neuropsychopharmacology, 35:
2440-9, 2010).
[0007] Furthermore, the noradrenergic system plays a role in a
number of cognitive domains, including working memory, attention,
and memory consolidation (Coull, J. T. et al., NeuroImage, 10:
705-15, 1999; McGaugh, J. L. et al., Psychopharmacology, 202: 3-14,
2009; Sara, S. J., Neuroscience, 10: 211-23, 2009). However,
noradrenergic system activity in excess may impair cognition.
Animal studies have shown associations between excess noradrenergic
activity and impairments in attention and working memory (Arnsten,
A. F., Nat. Rev. Neurosci., 10: 410-22, 2009; Sara, S. J.,
Neuroscience, 10: 211-23, 2009). Other studies show decreased
cognitive performance in people placed under stress conditions,
suggesting excess noradrenergic activity affects human cognition as
well (Campbell, H. L. et al., Pharmacol. Biochem. Behay., 88:
222-9, 2008; Hermans, E. J. et al., Science, 334: 1151-3, 2011).
Given this association between cognitive performance and
noradrenergic system activity, there remains the question of
whether differences in basal levels of activity may relate to
differences in cognitive performance and whether this relationship
is also influenced by age. Noradrenergic system activity appears
higher in older compared with younger adults, both peripherally and
in the CNS (Featherstone, J. A. et al., J. Gerontol., 42, 271-6,
1987; Lawlor, B. A. et al., Biol. Psychiatry, 38: 185-8, 1995;
Supiano, M. A. et al., Am. J. Physiol., 259: E422-31, 1990).
Previously it has been demonstrated that the concentration of
cerebrospinal fluid NA was higher in older compared with younger
adults, but it is not known whether noradrenergic system age
differences may be a factor in cognitive differences. Numerous
studies have linked excess noradrenergic activity with cognitive
impairment. As such, D.beta.H inhibitors may find application in
enhancing cognition, especially in those suffering from dementia,
including frontotemporal dementia (FTD), Parkinson disease and
Alzheimer disease (AD), or Mild Cognitive Impairment (MCI).
[0008] Several inhibitors of D.beta.H have been thus far reported
in the literature. Early first and second generation examples such
as disulfiram (Goldstein, M. et al., Life Sci., 3:763, 1964) and
diethyldithiocarbamate (Lippmann, W. et al., Biochem. Pharmacol.,
18: 2507, 1969) or fusaric acid (Hidaka, H. Nature, 231, 1971) and
aromatic or alkyl thioureas (Johnson, G. A. et al, J. Pharmacol.
Exp. Ther., 171: 80, 1970) were found to be of low potency,
exhibited poor selectivity for D.beta.H and caused toxic side
effects. The third generation of D.beta.H inhibitors, however, were
found to have much greater potency, such as, for example,
nepicastat (RS-25560-197, IC.sub.50 9 nM) (Stanley, W. C., et al.,
Br. J. Pharmacol., 121: 1803-1809, 1997), which was developed to
early clinical trials. Although it was initially developed for
peripheral indications (hypertension and congestive heart failure),
an important discovery was that nepicastat was found to cross the
blood-brain barrier (BBB), and was thereby able to cause central as
well as peripheral effects.
[0009] Nepicastat and its analogues are disclosed in WO95/29165.
Furthermore, WO 2004/033447 and WO 2008/136695 disclose D.beta.H
inhibitors having high potency and significantly reduced brain
access, giving rise to potent and peripherally selective D.beta.H
inhibitors. However, these compounds would either not exhibit an
effect in the CNS or would act primarily in the periphery,
potentially resulting in unwanted secondary effects in the
cardiovascular system or systemic tissues such as reduced
sympathetic drive. A review of the mechanism, substrates and
inhibitors of D.beta.H, is given by Beliaev, A., et al. in Current
Enzyme Inhibition, 5, 27-43, 2009.
[0010] Therefore, there remains an unfulfilled clinical requirement
for a potent, non-toxic and CNS-penetrant/active inhibitor of
D.beta.H with suitable pharmacokinetic properties, which could be
used for treatment of certain CNS disorders, including cocaine
addiction, alcohol addiction, adjunct opioid addiction, cognition
decline in FTD, cognition decline in MCI, cognition decline in AD,
attention deficit-hyperactive disorder (ADHD), post-traumatic
stress disorder (PTSD) and unipolar depression. A D.beta.H
inhibitor with similar or even greater potency than nepicastat and
with beneficial CNS effects--including the ability to cross the BBB
and exhibit a long residence time in the brain so as to provide a
long duration of D.beta.H inhibition in the CNS--would provide a
significant improvement over all D.beta.H inhibitor compounds thus
far described in the prior art. Additionally, such compounds would
preferably be orally bioavailable and easier and cheaper to
synthesise.
[0011] During a SciFinder search, the following compounds were
identified as commercially available. However, no reference was
made to their disclosure in the scientific or patent
literature.
##STR00002##
[0012] Sejtosztodas Farmakologiaja (1979), 8(1), 79-100 discusses
the antimicrobial effect of certain 1,2,4-triazoles and discloses
the compound
6-(4-chlorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c]-1,2,4-tr-
iazole-3-thione which is not within the scope of the present
invention.
[0013] WO 2014/127350 A1 discloses a genus of compounds that are
modulators, such as positive allosteric modulators, of one or more
subclasses of vasopressin receptors. The genus disclosed in this
publication overlaps to a small extent with the genus of the
present invention. However, multiple selections of non-preferred
embodiments within the genus of WO 2014/127350 A1 would be required
to arrive at a compound of the present invention.
SUMMARY OF THE INVENTION
[0014] The present invention provides a compound of formula I, or a
pharmaceutically acceptable salt or solvate thereof:
##STR00003##
wherein:
[0015] R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl, partially or
fully deuterated C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.2-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 mercaptoalkyl or
amino;
[0016] R.sub.2 is hydrogen or C.sub.1-C.sub.3 alkyl;
[0017] R.sub.3 is hydrogen or oxo;
[0018] or R.sub.2 and R.sub.3 combine to form a structure of
formula Ia:
##STR00004##
[0019] wherein:
[0020] X is CH.sub.2, CR.sub.6 or N;
[0021] is a double bond when X is CR.sub.6 or N and is a single
bond when X is CH.sub.2;
[0022] R.sub.4 is hydrogen or C.sub.1-C.sub.3 alkyl;
[0023] R.sub.5 is hydrogen or C.sub.1-C.sub.2 alkyl;
[0024] or R.sub.4 and R.sub.5 combine, together with the carbon
atom to which they are attached, to form a cyclopropyl ring wherein
the CH.sub.2 moiety is optionally substituted with two deuterium
(D) atoms;
[0025] R.sub.6 is hydrogen;
[0026] A is C.sub.5-C.sub.7 cycloalkyl, furanyl, thiophenyl,
methylthiophenyl or
##STR00005##
[0027] wherein:
[0028] X.sub.1 is hydrogen, halo or methyl;
[0029] X.sub.1' is hydrogen or halo;
[0030] X.sub.2 is hydrogen, halo or methyl;
[0031] X.sub.2' is hydrogen or halo;
[0032] X.sub.3 is hydrogen or fluoro;
[0033] n is 0 or 1, and when n is 0 a single or double bond joins
the carbon atoms to which R.sub.3 and R.sub.4 are attached;
[0034] for use in therapy.
[0035] This invention is also directed to compounds of formula I,
as defined above, or a pharmaceutically acceptable salt or solvate
thereof, per se, provided that the following compounds are
excluded:
##STR00006##
[0036] This invention is also directed to compounds of formula I,
as defined above, or a pharmaceutically acceptable salt or solvate
thereof, for use in the treatment of conditions ameliorated by
inhibition of D.beta.H within the CNS.
[0037] This invention is also directed to compounds of formula I,
as defined above, or a pharmaceutically acceptable salt or solvate
thereof, in the manufacture of a medicament for treatment of
conditions ameliorated by inhibition of D.beta.H within the
CNS.
[0038] This invention is also directed to a method for treating or
preventing conditions ameliorated by inhibition of D.beta.H within
the CNS comprising administering a therapeutically effective amount
of a compound of formula I, as defined above, or a pharmaceutically
acceptable salt or solvate thereof, to a patient in need
thereof.
[0039] This invention is also directed to a pharmaceutical
composition comprising (i) a therapeutically effective amount of a
compound of formula I, as defined above, or a pharmaceutically
acceptable salt or solvate thereof; and (ii) a pharmaceutically
acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] FIG. 1 shows mean concentration-time profile of the compound
of Example 54 in plasma and brain after oral administration of 10
mg/kg to Wistar rats. Each point represents mean.+-.SD of 4
rats.
[0041] FIG. 2 shows mean concentration-time profile of the
compounds of Example 54, 61, 73, 74, 86 and 113 in rat plasma after
oral administration of 10 mg/kg to Wistar rats. Each point
represents mean.+-.SD of 4 rats.
[0042] FIG. 3 shows mean concentration-time profile of the
compounds of Example 54, 61, 73, 74, 86 and 113 in rat brain after
oral administration of 10 mg/kg to Wistar rats. Each point
represents mean.+-.SD of 4 rats.
[0043] FIG. 4 shows D.beta.H activity in rat ADR after oral
administration of 10 mg/kg of compounds of Example 54, 61, 73, 74,
86 and 113. Each point represents mean.+-.SD of 4 rats.
DETAILED DESCRIPTION OF THE EMBODIMENTS
A. DEFINITIONS
[0044] "C.sub.1-C.sub.6 alkyl" means a monovalent unsubstituted
saturated straight-chain or branched-chain hydrocarbon radical
having from 1 to 6 carbon atoms. "C.sub.1-C.sub.2 alkyl",
"C.sub.1-C.sub.3 alkyl", "C.sub.1-C.sub.4 alkyl" and
"C.sub.1-C.sub.5 alkyl" have analogous meanings.
[0045] "partially or fully deuterated C.sub.1-C.sub.6 alkyl" means
a C.sub.1-C.sub.6 alkyl wherein some or all of the hydrogen atoms,
respectively, have been selectively replaced by deuterium.
[0046] "C.sub.3-C.sub.6 cycloalkyl" means a monovalent
unsubstituted saturated cyclic hydrocarbon radical having from 3 to
6 carbon atoms. "C.sub.5-C.sub.7 cycloalkyl" has analogous
meaning.
[0047] "C.sub.2-C.sub.6 cyanoalkyl" means a monovalent
cyano-substituted saturated straight-chain or branched-chain
hydrocarbon radical having from 2 to 6 carbon atoms including that
which forms the cyano group.
[0048] "C.sub.1-C.sub.6 mercaptoalkyl" means a monovalent
thiol-substituted saturated straight-chain or branched-chain
hydrocarbon radical having from 1 to 6 carbon atoms.
[0049] "oxo" means an oxo radical, and may be depicted as
.dbd.O.
[0050] "halo" means a fluorine (which may be depicted as --F),
chlorine (which may be depicted as --Cl), bromine (which may be
depicted as --Br) or iodine (which may be depicted as --I)
radical.
[0051] "amino" means --NH.sub.2.
[0052] "Pharmaceutically acceptable salt" means a salt such as
those described in standard texts on salt formation, see for
example: P. Stahl, et al., Handbook of Pharmaceutical Salts:
Properties, Selection and Use (VCHA/Wiley-VCH, 2002), or S. M.
Berge, et al., "Pharmaceutical Salts" (1977) Journal of
Pharmaceutical Sciences, 66, 1-19.
[0053] "Pharmaceutically acceptable solvate" means a molecular
complex comprising the compound of the invention and one or more
pharmaceutically acceptable solvent molecules, for example, water
or ethanol. The term "hydrate" may be employed when said solvent is
water. Pharmaceutically acceptable solvates include hydrates and
other solvates wherein the solvent of crystallization may be
isotopically substituted, e.g. D.sub.2O, d.sub.6-acetone,
d.sub.6-DMSO.
[0054] "Pharmaceutically acceptable excipient" means any ingredient
of a pharmaceutical composition other than the compound(s) of the
invention, or other known pharmacologically active components. The
choice of excipient will to a large extent depend on factors such
as the particular mode of administration, the effect of the
excipient on solubility and stability, and the nature of the dosage
form.
[0055] "Therapy", "treatment" and "treating" include both
preventative and curative treatment of a condition, disease or
disorder. It also includes slowing, interrupting, controlling or
stopping the progression of a condition, disease or disorder. It
also includes preventing, curing, slowing, interrupting,
controlling or stopping the symptoms of a condition, disease or
disorder.
[0056] Other variations to the disclosed embodiments can be
understood and effected by those skilled in the art in practicing
the claimed invention, from a study of the disclosure, and the
appended claims. In the claims, the word "comprising" does not
exclude other elements or steps, and the indefinite article "a" or
"an" does not exclude a plurality. The mere fact that certain
measures are recited in mutually different dependent claims does
not indicate that a combination of these measures cannot be used to
advantage.
B. COMPOUNDS
[0057] The invention provides a compound of formula I, as defined
above, or a pharmaceutically acceptable salt or solvate
thereof:
##STR00007##
with the proviso that the following compounds are excluded:
##STR00008##
B0. Core Structures
[0058] In some embodiments R.sub.2 is hydrogen or C.sub.1-C.sub.3
alkyl; and R.sub.3 is hydrogen or oxo to form a structure of
formula I1 to I4:
##STR00009##
[0059] Structure I2 is particularly preferred.
[0060] In some embodiments R.sub.2 and R.sub.3 of formula I combine
to form a structure of formula Ia:
##STR00010##
[0061] wherein:
[0062] X is CH.sub.2, CR.sub.6 or N;
[0063] is a double bond when X is CR.sub.6 or N and is a single
bond when X is CH.sub.2.
[0064] In some of these embodiments is a double bond and X is
N.
[0065] In some of these embodiments is a double bond and X is
CR.sub.6. This embodiment is particularly preferred.
[0066] In some of these embodiments is a single bond and X is
CH.sub.2.
[0067] In some embodiments of formula I, n is 0 and a single bond
joins the carbon atoms to which R.sub.3 and R.sub.4 are attached to
form a structure of formula Ib
##STR00011##
[0068] In some embodiments of formula I, R.sub.4 and R.sub.5
combine, together with the carbon atom to which they are attached,
to form a structure of formula Ic having a cyclopropyl ring wherein
the CH.sub.2 moiety is optionally substituted with two deuterium
atoms:
##STR00012##
[0069] In some embodiments more than 50%, preferably more than 90%,
more preferably more than 95% and even more preferably more than
99% of substituents R.sub.5 and A of compounds of formula I have
the stereochemical configuration of formula Id
##STR00013##
[0070] In some embodiments more than 50%, preferably more than 90%,
more preferably more than 95% and even more preferably more than
99% of substituents R.sub.5 and A of compounds of formula I have
the stereochemical configuration of formula Ie
##STR00014##
[0071] Preferred embodiments of formula I include compounds of
formula If, Ig and Ih. Formula Ih is particularly preferred.
##STR00015##
[0072] In some particularly preferred embodiments of formula If, Ig
and Ih more than 50%, preferably more than 90%, more preferably
more than 95% and even more preferably more than 99% have the
stereochemical configuration of formulas Is, It and Iu. Formula Iu
is particularly preferred.
##STR00016##
[0073] Other preferred embodiments of formula I include compounds
of formula Ii, Ij and Ik. Formula Ik is particularly preferred.
##STR00017##
[0074] In some particularly preferred embodiments of formula Ii, Ij
and Ik more than 50%, preferably more than 90%, more preferably
more than 95% and even more preferably more than 99% have the
stereochemical configuration of formulas II, Im and In. Formula In
is particularly preferred.
##STR00018##
B1. Substituent R.sub.1
[0075] R.sub.1 is selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, partially or fully deuterated
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6
cyanoalkyl, C.sub.1-C.sub.6 mercaptoalkyl and amino.
[0076] R.sub.1 is preferably selected from the group consisting of
hydrogen and C.sub.1-C.sub.6 alkyl. [0077] In some embodiments
R.sub.1 is hydrogen. [0078] In some embodiments R.sub.1 is
C.sub.1-C.sub.6 alkyl. [0079] In some embodiments R.sub.1 is
partially deuterated C.sub.1-C.sub.6 alkyl. [0080] In some
embodiments R.sub.1 is fully deuterated C.sub.1-C.sub.6 alkyl.
[0081] In some embodiments R.sub.1 is C.sub.3-C.sub.6 cycloalkyl.
[0082] In some embodiments R.sub.1 is C.sub.2-C.sub.6 cyanoalkyl.
[0083] In some embodiments R.sub.1 is C.sub.1-C.sub.6
mercaptoalkyl. [0084] In some embodiments R.sub.1 is amino.
[0085] R.sub.1 is preferably selected from the group consisting of
hydrogen, methyl, d.sub.3-methyl, propyl, cyclopropyl, cyanomethyl,
mercaptoethyl and amino.
[0086] R.sub.1 is more preferably selected from the group
consisting of hydrogen and methyl. [0087] In some embodiments
R.sub.1 is preferably hydrogen. [0088] In some embodiments R.sub.1
is preferably methyl. [0089] In some embodiments R.sub.1 is
preferably d.sub.3-methyl. [0090] In some embodiments R.sub.1 is
preferably propyl. [0091] In some embodiments R.sub.1 is preferably
cyclopropyl. [0092] In some embodiments R.sub.1 is preferably
cyanomethyl. [0093] In some embodiments R.sub.1 is preferably
mercaptoethyl. [0094] In some embodiments R.sub.1 is preferably
amino.
[0095] R.sub.1 is most preferably hydrogen.
B2. Substituent R.sub.2 (When Not Combined with R.sub.3)
[0096] R.sub.2 is selected from the group consisting of hydrogen
and C.sub.1-C.sub.3 alkyl. [0097] In some embodiments R.sub.2 is
hydrogen. [0098] In some embodiments R.sub.2 is C.sub.1-C.sub.3
alkyl.
[0099] R.sub.2 is preferably selected from the group consisting of
hydrogen and methyl. [0100] In some embodiments R.sub.2 is
preferably hydrogen. [0101] In some embodiments R.sub.2 is
preferably methyl.
[0102] R.sub.2 is most preferably hydrogen.
B3. Substituent R.sub.3 (When Not Combined with R.sub.2)
[0103] R.sub.3 is selected from the group consisting of hydrogen
and oxo. [0104] In some embodiments R.sub.3 is hydrogen. [0105] In
some embodiments R.sub.3 is oxo.
[0106] R.sub.3 is preferably hydrogen.
B4. Substituent R.sub.4 (When Not Combined with R.sub.5)
[0107] R.sub.4 is selected from the group consisting of hydrogen
and C.sub.1-C.sub.3 alkyl. [0108] In some embodiments R.sub.4 is
hydrogen. [0109] In some embodiments R.sub.4 is C.sub.1-C.sub.3
alkyl.
[0110] R.sub.4 is preferably selected from the group consisting of
hydrogen and methyl. [0111] In some embodiments R.sub.4 is
preferably hydrogen. [0112] In some embodiments R.sub.4 is
preferably methyl.
[0113] R.sub.4 is most preferably hydrogen.
B5. Substituent R.sub.5 (When Not Combined with R.sub.4)
[0114] R.sub.5 is selected from the group consisting of hydrogen
and C.sub.1-C.sub.2 alkyl. [0115] In some embodiments R.sub.5 is
hydrogen. [0116] In some embodiments R.sub.5 is C.sub.1-C.sub.2
alkyl.
[0117] R.sub.5 is preferably selected from the group consisting of
hydrogen and methyl. [0118] In some embodiments R.sub.5 is
preferably hydrogen. [0119] In some embodiments R.sub.5 is
preferably methyl.
[0120] R.sub.5 is most preferably hydrogen.
B6. Substituent R.sub.6
[0121] R.sub.6 is hydrogen.
B7. Substituent A
[0122] A is selected from the group consisting of C.sub.5-C.sub.7
cycloalkyl, furanyl, thiophenyl, methylthiophenyl and
##STR00019##
[0123] wherein: [0124] X.sub.1 is hydrogen, halo or methyl; [0125]
X.sub.1' is hydrogen or halo; [0126] X.sub.2 is hydrogen, halo or
methyl; [0127] X.sub.2' is hydrogen or halo; and [0128] X.sub.3 is
hydrogen or fluoro.
[0129] Preferably A is
##STR00020##
[0130] wherein X.sub.1, X.sub.1', X.sub.2, X.sub.2' and X.sub.3 are
as defined above.
[0131] More preferably A is
##STR00021##
[0132] wherein: [0133] X.sub.1 is hydrogen, fluoro, chloro or
methyl; [0134] Xi' is hydrogen, fluoro or chloro; [0135] X.sub.2 is
hydrogen, fluoro, chloro, bromo or methyl; [0136] X.sub.2' is
hydrogen, fluoro, chloro or bromo; and [0137] X.sub.3 is hydrogen
or fluoro. [0138] In one preferred embodiment not all of X.sub.1,
X.sub.1', X.sub.2, X.sub.2' and X.sub.3 are hydrogen.
[0139] Preferably A is selected from the group consisting of
##STR00022##
[0140] Most preferably A is selected from the group consisting
of
##STR00023##
B8. Specific Embodiments of Compounds of Formula I
[0141] Various embodiments of substituents R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.5, R.sub.6, A, X, X.sub.1, X.sub.1',
X.sub.2, X.sub.2' and X.sub.3 have been discussed in B1 to B7
above. These "substituent" embodiments can be combined with any of
the "core structure" embodiments, discussed in B0 above, to form
further embodiments of compounds of formula I. All embodiments of
compounds of formula I formed by combining the "substituent"
embodiments and "core structure" embodiments, discussed above, are
within the scope of Applicants' invention, and some preferred
further embodiments of the compounds of formula I are provided
below.
[0142] In some embodiments of formula I, structures of formula If,
Ii, and Il are highly preferred
##STR00024##
wherein:
[0143] R.sub.1 is selected from the group consisting of hydrogen
and methyl;
[0144] R.sub.3 is selected from the group consisting of hydrogen
and oxo;
[0145] R.sub.4 (if present) is selected from the group consisting
of hydrogen and methyl;
[0146] R.sub.5 (if present) is selected from the group consisting
of hydrogen and methyl; and
[0147] A is selected from the group consisting of
##STR00025##
[0148] In some embodiments of formula I, structures of formula Ih,
Ik, and In (in particular formula Ih) are highly preferred
##STR00026##
wherein:
[0149] R.sub.1 is selected from the group consisting of hydrogen
and methyl;
[0150] R.sub.4 (if present) is selected from the group consisting
of hydrogen and methyl;
[0151] R.sub.5 (if present) is selected from the group consisting
of hydrogen and methyl;
[0152] R.sub.6 is hydrogen; and
[0153] A is selected from the group consisting of
##STR00027##
[0154] In some embodiments of formula I, structures of formula Ih
wherein more than 50%, preferably more than 90%, more preferably
more than 95% and even more preferably more than 99% have the
stereochemical configuration of formula Iu are even more highly
preferred
##STR00028##
wherein:
[0155] R.sub.1 is selected from the group consisting of hydrogen
and methyl;
[0156] R.sub.4 is selected from the group consisting of hydrogen
and methyl;
[0157] R.sub.5 is selected from the group consisting of hydrogen
and methyl;
[0158] R.sub.6 is hydrogen; and
[0159] A is selected from the group consisting of
##STR00029##
[0160] In some embodiments of formula I, structures of formula Io,
Ip and Iq (in particular formula Io) are even more highly
preferred
##STR00030##
wherein:
[0161] A is selected from the group consisting of
##STR00031##
[0162] In some embodiments of formula I, structures of formula Io
wherein more than 50%, preferably more than 90%, more preferably
more than 95% and even more preferably more than 99% have the
stereochemical configuration of formula Iv are even more highly
preferred
##STR00032##
wherein:
[0163] A is selected from the group consisting of
##STR00033##
[0164] The following compounds represent specific embodiments of
the invention: [0165] 3-Phenylpyrrolidine-1-carbothioamide; [0166]
3-(thiophen-2-yl)pyrrolidine-1-carbothioamide; [0167]
3-(4-Fluorophenyl)pyrrolidine-1-carbothioamide; [0168]
3-phenylpiperidine-1-carbothioamide; [0169]
3-(2,4-difluorophenyl)pyrrolidine-1-carbothioamide; [0170]
(S)-3-phenylpyrrolidine-1-carbothioamide; [0171]
3-methyl-3-phenylpyrrolidine-1-carbothioamide; [0172]
1-phenyl-3-azabicyclo[3.1.0]hexane-3-carbothioamide; [0173]
3-cyclohexylpyrrolidine-1-carbothioamide; [0174]
3-(5-methylthiophen-2-yl)pyrrolidine-1-carbothioamide; [0175]
(R)-3-phenylpyrrolidine-1-carbothioamide; [0176]
3-(3,5-Difluorophenyl)pyrrolidine-1-carbothioamide; [0177]
3-o-tolylpyrrolidine-1-carbothioamide; [0178]
3-m-tolylpyrrolidine-1-carbothioamide; [0179]
3-(thiophen-3-yl)pyrrolidine-1-carbothioamide; [0180]
3-(furan-3-yl)pyrrolidine-1-carbothioamide; [0181]
3-(furan-2-yl)pyrrolidine-1-carbothioamide; [0182]
3-(2,5-difluorophenyl)pyrrolidine-1-carbothioamide; [0183]
3-(2,4,5-trifluorophenyl)pyrrolidine-1-carbothioamide; [0184]
3-(3,4-difluorophenyl)pyrrolidine-1-carbothioamide; [0185]
(5)-3-(2,4,6-trifluorophenyl)pyrrolidine-1-carbothioamide; [0186]
3-(2,3,4-trifluorophenyl)pyrrolidine-1-carbothioamide; [0187]
3-(2,3,5,6-Tetrafluorophenyl)pyrrolidine-1-carbothioamide; [0188]
3-(2,3,5-trifluorophenyl)pyrrolidine-1-carbothioamide; [0189]
(5)-3-(3,5-difluorophenyl)pyrrolidine-1-carbothioamide; [0190]
(R)-3-(3,5-difluorophenyl)pyrrolidine-1-carbothioamide; [0191]
(1S,5S)-1-(thiophen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide;
[0192]
(1R,5R)-1-(thiophen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carbothioami-
de; [0193] 3-(perfluorophenyl)pyrrolidine-1-carbothioamide; [0194]
(1S,5R)-1-(3,5-Difluorophenyl)-N-methyl-3-azabicyclo[3.1.0]hexane-3-carbo-
thioamide; [0195] N-methyl-3-phenylpyrrolidine-1-carbothioamide;
[0196] 3-(3,5-difluorophenyl)-N-methylpyrrolidine-1-carbothioamide;
[0197]
N-methyl-3-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carbothioamide;
[0198]
1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide;
[0199]
(1R,5S)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboth-
ioamide; [0200]
(1S,5R)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide-
; [0201]
1-(2,4-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide-
; [0202]
1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide-
; [0203]
(1S,5R)-1-(3,5-Difluorophenyl)-N-propyl-3-azabicyclo[3.1.0]hexane-
-3-carbothioamide; [0204]
1-(2,5-difluorophenyl)-N-(2-mercaptoethyl)-3-azabicyclo[3.1.0]hexane-3-ca-
rbothioamide; [0205]
(1S,5R)-1-(3,5-difluorophenyl)-N-methyl-4-oxo-3-azabicyclo[3.1.0]hexane-3-
-carbothioamide; [0206]
4-(3,5-difluorophenyl)-N-methyl-2-oxopyrrolidine-1-carbothioamide;
[0207]
1-(3,5-Difluorophenyl)-N-methyl-4-oxo-3-azabicyclo[3.1.0]hexane-3-carboth-
ioamide; [0208]
6-Phenyltetrahydro-1H-pyrrolo[1,2-c]imidazole-3(2H)-thione; [0209]
1-(3,5-Difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothiohydrazide;
[0210]
1-(3,5-Difluorophenyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexane-3-ca-
rbothioamide; [0211]
N-(cyanomethyl)-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbot-
hioamide; [0212]
3-(3,5-Difluorophenyl)-N-methyl-2,3-dihydro-1H-pyrrole-1-carbothioamide;
[0213]
6-phenyl-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione;
[0214]
6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H-
)-thione; [0215]
6-(2,4-Difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thion-
e; [0216]
6-(2,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(-
5H)-thione; [0217]
5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]-
imidazole-3(2H)-thione; [0218]
(5aS,6aR)-5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione; [0219] (5aS,6
aR)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,-
2-c]imidazole-3(2H)-thione; [0220]
(5aS,6aR)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione; [0221]
(5aR,6aS)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione; [0222]
(R)-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-t-
hione; [0223]
(S)-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-t-
hione; [0224]
(5aS,6aR)-5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[2,1-c][1,2,4]triazole-3(2H)-thione; [0225]
(S)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole--
3(5H)-thione; [0226]
(R)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole--
3(5H)-thione; [0227]
(5aS,6aR)-5a-(2,3,5-trifluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]p-
yrrolo[1,2-c]imidazole-3(2H)-thione; [0228] (5aS,6
aR)-5a-(2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,-
2-c]imidazole-3(2H)-thione; [0229]
(5aR,6aS)-5a-(2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione; [0230]
(5aS,6aR)-5a-(2,3-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione; [0231]
(5aR,6aS)-5a-(2,3-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione; [0232]
(5aS,6aR)-5a-(2,3,6-trifluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]p-
yrrolo[1,2-c]imidazole-3(2H)-thione; [0233]
(5aR,6aS)-5a-(2,3,6-trifluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]p-
yrrolo[1,2-c]imidazole-3(2H)-thione; [0234]
(5aS,6aR)-5a-(2,4-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione; [0235]
(5aS,6aR)-5a-(3,4-difluorophenyl)-5,5a6,6a-tetrahydrocyclopropa[3,4]pyrro-
lo[1,2-c]imidazole-3(2H)-thione; [0236]
(5aS,6aR)-5a-(2,4,5-trifluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]p-
yrrolo[1,2-c]imidazole-3(2H)-thione; [0237]
(5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4-
]pyrrolo[1,2-c]imidazole-3(2H)-thione; [0238]
(5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4-
]pyrrolo[1,2-c]imidazole-3(2H)-thione; [0239]
(5aS,6aR)-5a-(2-chloro-5-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4-
]pyrrolo[1,2-c]imidazole-3(2H)-thione; [0240]
(5aS,6aR)-5a-(3,5-difluorophenyl)-2-methyl-5,5a,6,6a-tetrahydrocyclopropa-
[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione; [0241]
(5aS,6aR)-2-cyclopropyl-5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclo-
propa [3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione; [0242]
6-cyclohexyl-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione;
[0243]
(S)-6-(2,3,5-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazo-
le-3-thione; [0244]
(R)-6-(2,3,5-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazo-
le-3-thione; [0245]
(S)-6-(2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole--
3-thione, [0246]
(S)-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]i-
midazole-3-thione; [0247]
(R)-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]i-
midazole-3-thione; [0248]
(R)-6-(2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole--
3-thione; [0249]
(5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa-
[3,4]pyrrolo[2,1-c][1,2,4]triazole-3(2H)-thione; [0250]
(5aS,6aR)-5a-(2-chloro-6-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4-
]pyrrolo[1,2-c]imidazole-3(2H)-thione; [0251]
(5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa-
[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione; [0252]
(5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4-
]pyrrolo[1,2-c]imidazole-3(2H)-thione-5,5-d.sub.2; [0253]
(5aS,6aR)-5a-(3-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4-
]pyrrolo[1,2-c]imidazole-3(2H)-thione; [0254]
(5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]-
pyrrolo[1,2-c]imidazole-3(2H)-thione; [0255]
(5aS,6aR)-5a-(3-bromo-5-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]-
pyrrolo[1,2-c]imidazole-3 (2H)-thione; [0256]
(5aS,6aS)-5a-(5-chloro-2-fluorophenyl)-2-(methyl-d.sub.3)-5,5a,6,6a-tetra-
hydrocyclopropa [3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione; [0257]
5a-(5-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1-
,2-c]imidazole-3(2H)-thione-6,6,6a-d.sub.3; [0258]
(5aR,6aS)-5a-(3-chloro-2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa-
[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione; [0259]
(5aS,6aS)-5a-(3,5-difluorophenyl)-2,5,5a,6,6a,7-hexahydro-3H-cyclopropa[d-
]imidazo[1,5-a]pyridine-3-thione; [0260]
(6/R,7S)-7-methyl-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyr-
rolo[1,2-c]imidazole-3-thione; [0261]
(6/R,7R)-7-methyl-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyr-
rolo[1,2-c]imidazole-3-thione; [0262]
(5aS,6aR)-5a-(3,5-dichlorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione; [0263]
(5aR,6aS)-5a-(5-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4-
]pyrrolo[1,2-c]imidazole-3(2H)-thione; [0264]
(6R)-6-(2,3,5,6-tetrafluorophenyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-3-
(2H)-thione; [0265]
(S)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazo-
le-3-thione; [0266]
(R)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazo-
le-3-thione; [0267]
(R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[-
1,2-c]imidazole-3-thione; [0268]
(5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[-
3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione; [0269]
(5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-5,5a,6,6a-tetrahydrocyclo-
propa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione; [0270]
(S)-6-(3-bromo-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]im-
idazole-3-thione; [0271]
(R)-6-(3-bromo-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]im-
idazole-3-thione; [0272]
(5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[-
3,4]pyrrolo[2,1-c][1,2,4]triazole-3(2H)-thione; and [0273]
(5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]-
pyrrolo[2,1-c][1,2,4]triazole-3(2H)-thione.
C. COMPOSITIONS
[0274] The compounds of the invention intended for pharmaceutical
use may be administered alone or in combination with one or more
other compounds of the invention or in combination with one or more
other drugs (or as any combination thereof). Generally, they will
be administered as a formulation in association with one or more
pharmaceutically acceptable excipients. Accordingly, the present
invention is also directed to a pharmaceutical composition
comprising (i) a therapeutically effective amount of a compound of
formula I, as defined above, or a pharmaceutically acceptable salt
or solvate thereof; and (ii) a pharmaceutically acceptable
excipient.
[0275] Pharmaceutical compositions suitable for the delivery of
compounds of the present invention and methods for their
preparation will be readily apparent to those skilled in the art.
Such compositions and methods for their preparation may be found,
for example, in "Remington's Pharmaceutical Sciences", 19th Edition
(Mack Publishing Company, 1995).
D. METHODS OF USE
[0276] This invention is also directed to compounds of formula I,
as defined above, or a pharmaceutically acceptable salt or solvate
thereof, for use in therapy, in particular for the treatment of
conditions ameliorated by inhibition of D.beta.H within the
CNS.
[0277] This invention is also directed to the use of compounds of
formula I, as defined above, or a pharmaceutically acceptable salt
or solvate thereof, in the manufacture of a medicament for
treatment of conditions ameliorated by inhibition of D.beta.H
within the CNS.
[0278] This invention is also directed to a method for treating
conditions ameliorated by inhibition of dopamine-beta-hydroxylase
within the CNS comprising administering a therapeutically effective
amount of a compound of formula I, as defined in claim 1, or a
pharmaceutically acceptable salt or solvate thereof, to a patient
in need thereof.
[0279] Conditions ameliorated by inhibition of D.beta.H within the
CNS can include, but are not limited to: cocaine addiction, alcohol
addiction, adjunct opioid addiction, cognition decline in FTD,
cognition decline in MCI, cognition decline in AD, ADHD, PTSD and
unipolar depression.
E. GENERAL SYNTHETIC METHODOLOGY
[0280] The methods used for the synthesis of the compounds of the
invention are illustrated by the schemes below. The starting
materials and reagents used in preparing these compounds are
available from commercial suppliers or can be prepared by methods
obvious to those skilled in the art. To make the schemes easier to
read, the option to incorporate deuterium at certain positions is
not shown. Specifically, deuterated products can be produced using
specifically deuterated starting materials, including, but not
limited to, those used in Examples 1-121.
[0281] Compounds of formula I2 can generally be synthesised by the
methods outlined in Scheme 1.
##STR00034##
[0282] Compounds of formula I4 can generally be synthesised by the
method outlined in Scheme 2:
##STR00035##
[0283] Compounds of formula Ia, where X.dbd.CH.sub.2 can generally
be synthesised by the method outlined in Scheme 3:
##STR00036##
[0284] Compounds of formula Ia, where X.dbd.CR.sub.6 can generally
be synthesised by the method outlined in Scheme 4:
##STR00037##
[0285] When R.sub.6.dbd.H, the starting material in Scheme 4 can
generally be synthesised by the method outlined in Scheme 5:
##STR00038##
[0286] The starting material for Scheme 5, when n=0, can generally
be synthesised by the method outlined in Scheme 6 as either
enriched enantiomers or racemates:
##STR00039##
[0287] When R.sub.6.dbd.H and R.sub.4 and R.sub.5 combine to form a
cyclopropyl group, the starting material in Scheme 4 can generally
be synthesised by the method outlined in Scheme 7:
##STR00040##
[0288] The starting material for Scheme 7 can generally be
synthesised by the method outlined in Scheme 8:
##STR00041##
[0289] Compounds of formula Ia, where X.dbd.N can generally be
synthesised by the method outlined in Scheme 9:
##STR00042##
[0290] The starting material for Scheme 9, when n=0 and R.sub.4 and
R.sub.5 combine to form a cyclopropyl group, can generally be
synthesised by the method outlined in Scheme 10:
##STR00043##
[0291] In turn, the starting material for Schemes 8 and 10 can
generally be synthesised by the method outlined in Scheme 11 as
either enriched enantiomers or racemates and including specific
deuteration:
##STR00044##
[0292] In accordance with this synthetic methodology, the invention
provides a process for the preparation of compounds of formulae I2
or Ia wherein is a double bond and X is CR.sub.6
##STR00045##
which comprises reacting a compound of formula II2 or IIa wherein
n, R.sub.4, R.sub.5, R.sub.6 and A are as defined for formula I
above
##STR00046##
with a compound of formula R.sup.1--N.dbd.C.dbd.S.
[0293] Compounds of formula II2 and IIa wherein n, R.sub.4,
R.sub.5, R.sub.6 and A are as defined for formula I above are thus
useful intermediates representing further embodiments of the
present invention.
F. EXAMPLES
[0294] All compounds and intermediates were characterised by NMR.
The spectra were recorded on a Bruker Avance III 600 MHz
spectrometer with solvent used as internal standard. .sup.13C
spectra were recorded at 150 MHz and .sup.1H spectra were recorded
at 600 MHz. Data are reported in the following order: approximate
chemical shift (ppm), number of protons, multiplicity (br, broad;
d, doublet; m, multiplet; s, singlet; t, triplet) and coupling
constant (Hz).
[0295] Room temperature in the following protocols means the
temperature ranging from 20.degree. C. to 25.degree. C.
Example 1
3-Phenylpyrrolidine-1-carbothioamide
Step 1: N-(3-phenylpyrrolidine-1-carbonothioyl)benzamide
##STR00047##
[0297] To a solution of ammonium thiocyanate (62 mg, 0.815 mmol) in
acetone (2 mL) was added benzoyl chloride (0.087 mL, 0.747 mmol) at
room temperature with stirring. After being stirred for 10 min. the
resulting precipitate was filtered off and 3-phenylpyrrolidine (CAS
#936-44-7) (100 mg, 0.679 mmol) was added to the filtrate in
portions. The reaction mixture was stirred at ambient temperature
for 20 h, and then evaporated to dryness. Chromatography (petroleum
ether-ethyl acetate, 4:1) gave
N-(3-phenylpyrrolidine-1-carbonothioyl)benzamide as an off-white
powder (0.067 g, 32% yield).
Step 2: 3-phenylpyrrolidine-1-carbothioamide
##STR00048##
[0299] To a solution of
N-(3-phenylpyrrolidine-1-carbonothioyl)benzamide (0.06 g, 0.193
mmol) in methanol (2 mL) was added 20% aq. sodium hydroxide (0.317
mL, 1.933 mmol) and the mixture was refluxed for 6 h. Thereupon,
the reaction was diluted with water (4 mL) and then the organics
were removed under vacuum to give the product as an oil that
solidified on standing in the cold (5.degree. C.). The crystals
were collected, washed with water and dried to give
3-phenylpyrrolidine-1-carbothioamide as an off-white powder (0.018
g, 45% yield).
[0300] .sup.1H NMR (DMSO-d6): 7.33 (2H, t, J=7.3 Hz), 7.29 (2H, d,
J=7.2 Hz), 7.24 (1H, t, J=7.2 Hz), 7.19 (2H, br s), 4.12 (0.5H, m),
3.90 (0.5H, m), 3.78 (0.5H, m), 3.44-3.61 (2H, m), 3.26 (0.5H, m),
2.34 (0.5H, s br), 2.20 (0.5H, s br), 2.11 (0.5H, m), 1.97 (0.5H,
m).
[0301] .sup.13C NMR (DMSO-d6): 178.5, 141.2, 141.1, 128.5, 127.1,
126.8, 126.7, 57.5, 53.9, 51.3, 47.5, 44, 42.4, 33,0, 31.9.
Example 2
3-(thiophen-2-yl)pyrrolidine-1-carbothioamide
##STR00049##
[0303] 3-(Thiophen-2-yl)pyrrolidine (CAS #125067-53-0) was
converted to 3-(thiophen-2-yl)pyrrolidine-1-carbothioamide by a
similar procedure as described for Example 1 and the product was
isolated as an off-white powder.
[0304] .sup.1H NMR (DMSO-d6): 7.39 (1H, d, J=4.4 Hz), 7.19 (2H, br,
s), 6.98 (1H, dd, J=5.0, 3.5 Hz), 6.96 (1H, d, J=2.9 Hz), 4.10
(0.5H, br s), 3.86 (0.5H, br s), 3.80(1H, br s), 3.66 (0.5H, br s),
3.53 (1.5H, m), 3.38 (0.5H, m), 3.29 (0.5H, br s), 2.39 (0.5H, m),
2.26 (0.5H, br s), 2.09 (0.5H, br s), 1.95 (0.5H, br s).
[0305] .sup.13C NMR (DMSO-d6): 178.5, 144.7, 127, 124.1, 124.1,
124, 58.1, 54.6, 51, 47.2, 39.2, 37.9, 34.1, 33.0.
Example 3
3-(4-Fluorophenyl)pyrrolidine-1-carbothioamide
##STR00050##
[0307] To a solution of 1,1'-thiocarbonyldiimidazole (0.570 g, 3.20
mmol) in tetrahydrofuran (6 mL) was added a solution of
3-(4-fluorophenyl)pyrrolidine (CAS #144620-11-1) (0.48 g, 2.91
mmol) in tetrahydrofuran (6.00 mL). The mixture was then stirred
for 1 h at room temperature and for an additional 2 h at
55-60.degree. C. Thereupon, tetrahydrofuran was removed under
vacuum and the residue was dissolved in methanol (12 mL). The thus
obtained solution was treated with 25% aq. ammonia (3.26 mL, 43.6
mmol) and then the mixture was stirred at room temperature for 5
days. The reaction was diluted with 1M HCl, the resulting
precipitate was collected, washed with a mixture of methanol-water
(1:1) and dried under vacuum at 50.degree. C. to give
3-(4-fluorophenyl)pyrrolidine-1-carbothioamide as a white powder
(0.22 g, 34% yield).
[0308] .sup.1H NMR (DMSO-d6): 7.33 (2H, m), 7.15 (2H, m), 6.70-7.60
(2H, br s), 4.11 (0.5H, m), 3.90 (0.5H, m), 3.77 (0.5H, m), 3.52
(1.5H, m), 3.40 (1.5H, m), 3.23 (0.5H, m), 2.33 (0.5H, br s), 2.18
(0.5H, br s), 2.09 (0.5H, m), 1.96 (0.5H, m).
[0309] .sup.13C NMR (DMSO-d6): 178.4, 161.8, 160.2, 137.2, 129,
129, 115.3, 115.1, 57.5, 54, 51.3, 47.4, 43.3, 41.7, 33.1,
31.9.
Example 4
3-phenylpiperidine-1-carbothioamide
##STR00051##
[0311] 3-Phenylpiperidine (CAS #3973-62-4) was converted to
3-phenylpiperidine-1-carbothioamide by a similar procedure as
described for Example 3 and the product was isolated as a white
powder.
[0312] .sup.1H NMR (DMSO-d6): 7.38 (2H, br s), 7.32 (2H, t, J=7.8
Hz), 7.29 (2H, d, J=7.8 Hz), 7.23 (1H, mt, J=7.1 Hz), 4.59 (2H, m),
2.96 (2H, m), 2.64 (1H, m), 1.90 (1H, m), 1.70(2H, m), 1.50 (1H,
m).
[0313] .sup.13C NMR (DMSO-d6): 180.5, 143.3, 128.4, 127.1, 126.5,
53.7, 47.6, 42.0, 31.3, 25.0,
Example 5
3-(2,4-difluorophenyl)pyrrolidine-1-carbothioamide
##STR00052##
[0315] 3-(2,4-Difluorophenyl)pyrrolidine (CAS #1092108-80-9) was
converted to 3-(2,4-difluorophenyl)pyrrolidine-1-carbothioamide by
a similar procedure as described for Example 3 and the product was
isolated as a beige powder.
[0316] .sup.1H NMR (DMSO-d6): 7.39 (1H, m), 7.19 (1H, ddd, J=11.0,
9.2, 2.6 Hz), 7.09 (2H, br s), 7.07 (1H, ddt, J=1.0, 2.6, 8.5 Hz),
3.34-4.24 (5H, m), 2.28 (1H, br s), 2.09 (1H, br s).
[0317] .sup.13C NMR (DMSO-d6): 178.6, 178.5, 162, 161.9, 161.2,
160.4, 160.3, 159.6, 129.4, 129.2, 129, 129, 124.9, 124.1, 115.3,
115.1, 111.7, 111.5, 104.1, 103.9, 103.8, 56.1, 52.5, 50.9, 37.1,
35.5, 31.6, 30.4.
Example 6
(S)-3-phenylpyrrolidine-1-carbothioamide
##STR00053##
[0319] (S)-3-phenylpyrrolidine (CAS #62624-46-8) was converted to
(S)-3-phenylpyrrolidine-1-carbothioamide by a similar procedure as
described for Example 3 and the product was isolated as a beige
powder.
[0320] .sup.1H NMR (DMSO-d6): 7.33 (2H, t, J=7.2 Hz), 7.29 (2H, d,
J=7.4 Hz), 7.24 (1H, t, J=7.1 Hz), 7.21 (2H, br s), 4.12 (0.5H, m),
3.90 (0.5H, m), 3.78 (0.5H, m), 3.44-3.61 (2H, m), 3.26 (0.5H, m),
2.34 (0.5H, s br), 2.20 (0.5H, s br), 2.11 (0.5H, m), 1.97 (0.5H,
m).
[0321] .sup.13C NMR (DMSO-d6): 178.4, 141.2, 141.1, 128.5, 127.1,
126.7, 126.7, 57.5, 53.9, 51.3, 47.5, 44, 42.4, 33,0, 31.9.
Example 7
3-methyl-3-phenylpyrrolidine-1-carbothioamide
##STR00054##
[0323] 3-Methyl-3-phenylpyrrolidine (CAS #56606-73-6) was converted
to 3-methyl-3-phenylpyrrolidine-1-carbothioamide by a similar
procedure as described for Example 3 and the product was isolated
as a white solid.
[0324] .sup.1H NMR (DMSO-d6): 6.80-7.60 (7H, m), 3.89 and 3.82 (1H,
2 br d, J=11.4 Hz), 3.68 (1H, m), 3.60 and 3.54 (1H, 2 br d, J=10.8
Hz), 3.45 (0.5H, m), 2.27 (0.5H, m), 2.21 (0.5H, m), 2.10(1H,
m).
[0325] .sup.13C NMR (DMSO-d6): 178.9, 178.6, 146.8, 146.6, 128.4,
126.3, 126.2, 125.7, 125.5, 62.3, 58.9, 50.1, 46.4, 46.2, 44.5,
37.7, 36.2, 27.5, 27.1.
Example 8
1-phenyl-3-azabicyclo[3.1.0]hexane-3-carbothioamide
##STR00055##
[0327] 1-phenyl-3-azabicyclo[3.1.0]hexane (CAS #67644-21-7) was
converted to 1-phenyl-3-azabicyclo[3.1.0]hexane-3-carbothioamide by
a similar procedure as described for Example 3 and the product was
isolated as a white powder.
[0328] .sup.1H NMR (DMSO-d6): 6.8-7.9 (2H, br s), 7.31 (2H, t,
J=7.6 Hz), 7.31 (3H, m), 4.39 (0.5H, br s), 4.09 (0.5H, br s), 3.95
(0.5H, br s), 3.47-3.80 (2.5H, m), 1.90-2.21 (1H, m), 1.10 (1H, br
dd, J=7.6, 5.0 Hz), 0.72 (1H, t, J=4.6 Hz).
[0329] .sup.13C NMR (DMSO-d6): 179.9, 140.9, 128.4, 126.4, 126.2,
57.3, 54, 53.5, 50.2, 31.8, 30.2, 24.5, 23.6, 19.5.
Example 9
3-cyclohexylpyrrolidine-1-carbothioamide
##STR00056##
[0331] 3-cyclohexylpyrrolidine (CAS #78813-85-1) was converted to
3-cyclohexylpyrrolidine-1-carbothioamide by a similar procedure as
described for Example 3 and the product was isolated as a white
powder.
[0332] .sup.1H NMR (DMSO-d6): 7.08 (2H, br s), 3.87 (0.5H, br t,
J=9 Hz), 3.81 (0.5H, br t, J=9.7 Hz), 3.51 (0.5H, br t, J=8.5 Hz),
3.43 (0.5H, m), 3.32 (0.5H, m), 3.18 (0.5H, m), 3.03 (0.5H, H, t,
J=10.8 Hz), 2.86 (0.5H, J=10 Hz), 2.07 (0.5H, m), 1.94 (1H, m),
1.82 (0.5H, m), 1.57-1.77 (5.5H, m), 1.42 (0.5H, m), 1.17 (4.0 H,
m), 0.94 (2H, m).
[0333] .sup.13C NMR (DMSO-d6): 178.2, 55.6, 51.9, 51.5, 47.7, 45.4,
43.6, 41.1, 40.8, 31.5, 31.4, 30.8, 30,0, 28.9, 25.6, 25.5.
Example 10
3-(5-methylthiophen-2-yl)pyrrolidine-1-carbothioamide
##STR00057##
[0335] To a stirred solution of 1,1'-thiocarbonyldiimidazole (0.469
g, 2.63 mmol) in dry tetrahydrofuran (9 mL) was added a solution of
3-(5-methylthiophen-2-yl)pyrrolidine (CAS #1260863-70-4) (0.44 g,
2.63 mmol) in dry tetrahydrofuran (9 mL). The reaction was stirred
for 1 h at room temperature and for an additional 2 h at
55-60.degree. C. After being cooled to room temperature, the
organics were evaporated to dryness under vacuum and the residue
was treated with 2 M ethanolic ammonia solution (7.89 mL, 15.78
mmol). The reaction was stirred for 16 h in a sealed vial at
70.degree. C. The mixture was then cooled again and quenched water
(2 mL). The resulting crystals were collected, washed with a
mixture of ethanol-water (1:1) and dried under vacuum at 50.degree.
C. to give 3-(5-methylthiophen-2-yl)pyrrolidine-1-carbothioamide as
a white powder (0.3 g, 1.325 mmol, 50.4% yield).
[0336] .sup.1H NMR (DMSO-d6): 6.84 (2H, br d, J=3.5 Hz), 6.71 (1H,
d, J=3.2 Hz), 6.63 (1H, m), 4.04 (0.5H, br s), 3.83 (0.5H, br s),
3.72 (1H, m), 3.50 (2H, m), 3.35 (0.5H, m), 3.25 (0.5H, m), 2.39
(3H, m), 2.30 (0.5H, m), 2.22 (0.5H, br s), 2.04 (0.5H, br s), 1.90
(0.5H, br s).
[0337] .sup.13C NMR (DMSO-d6): 178.6, 178.5, 142.3, 142.3, 137.3,
137.2, 125,0, 123.8, 58.0, 54.4, 51.0, 47.1, 39.4, 38.0, 34.0,
32.9, 15.0,
Example 11
(R)-3-phenylpyrrolidine-1-carbothioamide
##STR00058##
[0339] (R)-3-phenylpyrrolidine (CAS #61586-40-7) was converted to
(R)-3-phenylpyrrolidine-1-carbothioamide by a similar procedure as
described for Example 10 and the product was isolated as a white
powder
[0340] .sup.1H NMR (DMSO-d6): 7.33 (2H, t, J=7.2 Hz), 7.29 (2H, d,
J=7.4 Hz), 7.24 (1H, t, J=7.1 Hz), 7.21 (2H, br s), 4.12 (0.5H, m),
3.90 (0.5H, m), 3.78 (0.5H, m), 3.44-3.61 (2H, m), 3.26 (0.5H, m),
2.34 (0.5H, s br), 2.20 (0.5H, s br), 2.11 (0.5H, m), 1.97 (0.5H,
m).
[0341] .sup.13C NMR (DMSO-d6): 178.5, 141.2, 141.1, 128.5, 127.1,
126.8, 126.7, 57.5, 53.9, 51.3, 47.5, 44, 42.4, 33, 31.9.
Example 12
3-(3,5-Difluorophenyl)pyrrolidine-1-carbothioamide
##STR00059##
[0343] 3-(3,5-Difluorophenyl)pyrrolidine (CAS #1092108-82-1) was
converted to 3-(3,5-Difluorophenyl)pyrrolidine-1-carbothioamide by
a similar procedure as described for Example 10 and the product was
isolated as a white powder.
[0344] .sup.1H NMR (DMSO-d6): 7.21 (2H, br s), 7.09 (3H, m), 4.12
(0.5H, br m), 3.89 (0.5H, br m), 3.79 (0.5H, br m), 3.45 (3H, br
m), 3.27 (0.5H, m), 2.34 (0.5H, br m), 2.20 (0.5H, br m), 2.14
(0.5H, br m), 1.99 (0.5H, br m).
[0345] .sup.13C NMR (DMSO-d6): 178.5, 163.3, 163.2, 161.7, 161.6,
145.9, 110.6, 110.6, 110.5, 110.4, 102.4, 102.2, 102, 57, 53.4,
51.2, 47.3, 43.6, 42.1, 32.6, 31.4.
Example 13
3-o-tolylpyrrolidine-1-carbothioamide
##STR00060##
[0347] 3-(o-Tolyl)pyrrolidine (CAS #954220-67-8) was converted to
3-o-tolylpyrrolidine-1-carbothioamide by a similar procedure as
described for Example 10 and the product was isolated as a white
powder
[0348] .sup.1H NMR (DMSO-d6): 6.87-7.43 (6H, m), 4.02 (0.5H, m),
3.85 (0.5H, m), 3.75 (0.5H, m), 3.67 (0.5H, m), 3.51-3.62 (1.5H,
m), 3.47 (0.5H, m), 3.40 (0.5H, m), 3.23 (0.5H, m), 2.32 (3H, s),
2.30 (0.5H, m), 2.14 (0.5H, m), 2.07 (0.5H, m), 1.98 (0.5H, m).
[0349] .sup.13C NMR (DMSO-d6): 178.4, 139.5, 139.2, 135.9, 130.3,
126.5, 126.4, 126.2, 125.2, 125.1, 56.8, 53.2, 51, 47.1, 40.1,
38.5, 32.3, 30.9, 19.3.
Example 14
3-m-tolylpyrrolidine-1-carbothioamide
##STR00061##
[0351] 3-(m-Tolyl)pyrrolidine (CAS #954220-64-5) was converted to
3-m-tolylpyrrolidine-1-carbothioamide by a similar procedure as
described for Example 10 and the product was isolated as an
off-white solid.
[0352] .sup.1H NMR (DMSO-d6): 6.56-7.60 (2H, br s), 7.21 (1H, t,
J=7.5 Hz), 7.11 (1H, br s), 7.07 (1H, br d, J=6.3 Hz), 7.05 (1H, br
d, J=7.5 Hz), 4.11 (0.5H, m), 3.90 (0.5H, m), 3.77 (0.5H, m), 3.52
(1H, m), 3.44 (1H, m), 3.35 (1H, m), 3.24 (0.5H, m), 2.32 (0.5H,
m), 2.28 (3H, s), 2.18 (0.5H, m), 2.08 (0.5H, m), 1.96 (0.5H,
m).
[0353] .sup.13C NMR (DMSO-d6): 178.4, 178.4, 141.1, 141, 137.6,
128.4, 127.8, 127.4, 127.3, 124.1, 57.5, 53.9, 51.4, 47.5, 44,
42.3, 33,0, 31.8, 21.1.
Example 15
3-(thiophen-3-yl)pyrrolidine-1-carbothioamide
##STR00062##
[0355] 3-(Thiophen-3-yl)pyrrolidine (CAS #1231007-58-6) was
converted to 3-(thiophen-3-yl)pyrrolidine-1-carbothioamide by a
similar procedure as described for Example 10 and the product was
isolated as a white powder.
[0356] .sup.1H NMR (DMSO-d6): 7.51 (1H, m), 7.28 (1H, m), 7.18 (2H,
br s), 7.09(1H, m), 4.08 (0.5H, br s), 3.85 (0.5H, br s), 3.74
(0.5H, m), 3.39-3.65 (2.5H, m), 3.32 (0.5H, m), 3.25 (0.5H, m),
2.34 (0.5H, br s), 2.18 (0.5H, br s), 2.09 (0.5H, m), 1.95 (0.5H,
m).
[0357] .sup.13C NMR (DMSO-d6): 178.5, 178.4, 142.2, 127.2, 127.1,
126.5, 126.4, 120.7, 120.5, 57.2, 53.7, 51.2, 47.3, 39.8, 38.2,
32.9, 31.8.
Example 16
3-(furan-3-yl)pyrrolidine-1-carbothioamide
##STR00063##
[0359] 3-(Furan-3-yl)pyrrolidine (CAS #1260650-66-5) was converted
to 3-(furan-3-yl)pyrrolidine-1-carbothioamide by a similar
procedure as described for Example 10 and the product was isolated
as a dark beige solid.
[0360] .sup.1H NMR (DMSO-d6): 7.61 (1H, s), 7.54 (1H, s), 7.12(2H,
m), 6.49(1H, dd, J=1.8, 0.7 Hz), 4.01 (0.5H, m), 3.81 (0.5H, m),
3.67 (0.5H, m), 3.31-3.57 (2.5H, m), 3.24 (0.5H, br s), 3.19 (0.5H,
m), 2.27 (0.5H, br s), 2.12 (0.5H, br s), 1.99 (0.5H, m), 1.87
(0.5H, m).
[0361] .sup.13C NMR (DMSO-d6): 178.5, 178.4, 143.5, 143.5, 138.9,
125.2, 110, 109.9, 57, 53.4, 51.1, 47.3, 35.1, 33.6, 32.5,
31.5.
Example 17
3-(furan-2-yl)pyrrolidine-1-carbothioamide
##STR00064##
[0363] 3-(Furan-2-yl)pyrrolidine (CAS #1082926-03-1) was converted
to 3-(furan-2-yl)pyrrolidine-1-carbothioamide by a similar
procedure as described for Example 10 and the product was isolated
as a white solid.
[0364] .sup.1H NMR (DMSO-d6): 7.57 (1H, s), 7.28(2H, br s),
6.38(1H, m), 6.21 (1H, d, J=3.1 Hz), 3.97 (0.5H, br s), 3.77 (0.5H,
br s), 3.69 (0.5H, br s), 3.52-3.66 (1.5H, m), 3.30-3.51 (2H, m),
2.31 (0.5H, br s), 2.16 (0.5H, m), 2.13 (0.5H, m), 1.99 (0.5H, br
s).
[0365] .sup.13C NMR (DMSO-d6): 178.6, 155.0, 154.8, 142.0, 110.4,
105.2, 105.0, 55.4, 51.8, 50.8, 47.0, 37.7, 36.1, 30.8, 29.6.
Example 18
3-(2,5-difluorophenyl)pyrrolidine-1-carbothioamide
##STR00065##
[0367] 3-(2,5-Difluorophenyl)pyrrolidine (CAS #1203797-48-1) was
converted to 3-(2,5-difluorophenyl)pyrrolidine-1-carbothioamide by
a similar procedure as described for Example 10 and the product was
isolated as a white solid.
[0368] .sup.1H NMR (DMSO-d6): 6.82-7.61 (5H, m), 4.09 (0.5H, m),
3.90 (0.5H, m), 3.76 (0.5H, m), 3.71 (0.5H, m), 3.46-3.64 (1H, m),
3.38 (1H, m), 2.33 (0.5H, m), 2.18 (1H, m), 2.03 (0.5H, m).
[0369] .sup.13C NMR (DMSO-d6): 178.5, 159.1, 157.6, 157.4, 155.7,
129.9, 117.0, 116.8, 114.9, 56.0, 52.4, 51.0, 47.0, 37.4, 35.9,
31.4, 30.3.
Example 19
3-(2,4,5-trifluorophenyl)pyrrolidine-1-carbothioamide
##STR00066##
[0371] 3-(2,4,5-Trifluorophenyl)pyrrolidine (CAS #1260814-64-9) was
converted to 3-(2,4,5-trifluorophenyl)pyrrolidine-1-carbothioamide
by a similar procedure as described for Example 10 and the product
was isolated as a white solid.
[0372] .sup.1H NMR (DMSO-d6): 7.55 (2H, m), 7.24 (2H, br s), 4.09
(0.5H, m), 3.90 (0.5H, m), 3.76 (0.5H, m), 3.69 (0.5H, m), 3.52
(2H, m), 3.37 (0.5H, m), 3.29 (0.5H, m), 2.31 (0.5H, m), 2.17(1H,
m), 2.03 (0.5H, m).
[0373] .sup.13C NMR (DMSO-d6): 178.5, 156.4, 154.8, 148.8, 147,
145.4, 125.1, 124.9, 116.5, 116.4, 116.3, 106.2, 106.0, 106.0,
105.8, 56.0, 52.5, 51.0, 47.0, 36.9, 35.4, 31.5, 30.4.
Example 20
3-(3,4-difluorophenyl)pyrrolidine-1-carbothioamide
##STR00067##
[0375] 3-(3,4-Difluorophenyl)pyrrolidine (CAS #848822-98-0) was
converted to 3-(3,4-difluorophenyl)pyrrolidine-1-carbothioamide by
a similar procedure as described for Example 10 and the product was
isolated as a light orange solid.
[0376] .sup.1H NMR (DMSO-d6): 7.41 (2H, br m), 7.16 (1H, br s),
6.59-7.86 (2H, m), 4.12 (0.5H, m), 3.90 (0.5H, m), 3.78 (0.5H, m),
3.51 (1.5H, m), 3.42 (1.5H, m 1H, s), 3.24 (0.5H, m), 2.32 (0.5H,
m), 2.18 (0.5H, m), 2.11 (0.5H, m), 1.98 (0.5H, m).
[0377] .sup.13C NMR (DMSO-d6): 178.4, 150.2, 150.2, 149.1, 149.0,
148.6, 148.5, 147.5, 147.4, 139.0, 138.9, 124.0, 117.4, 117.3,
116.3, 116.2, 57.3, 53.8, 51.3, 47.4, 43.3, 41.7, 32.8, 31.7.
Example 21
(S)-3-(2,4,6-trifluorophenyl)pyrrolidine-1-carbothioamide
##STR00068##
[0379] (S)-3-(2,4,6-Trifluorophenyl)pyrrolidine (CAS #1335508-11-6)
was converted to
(S)-3-(2,4,6-trifluorophenyl)pyrrolidine-1-carbothioamide by a
similar procedure as described for Example 10 and the product was
isolated as a white solid.
[0380] .sup.1H NMR (DMSO-d6): 7.22 (2H, m), 6.50-8.0 (2H, m br),
4.03 (0.5H, br m), 3.96 (0.5H, br s), 3.81 (0.5H, br m), 3.68 (1H,
br m), 3.51-3.58 (1.5H, m), 3.42 (0.5H, br s), 3.38 (0.5H, br s),
2.28 (1H, m), 2.13 (1H, br s).
[0381] .sup.13C NMR (DMSO-d6): 178.6, 162.1, 162, 160.5, 160.4,
112.2, 101.4, 101.2, 101.0, 54.6, 51.2, 50.8, 47.5, 33.7, 32.4,
30.8, 29.7.
Example 22
3-(2,3,4-trifluorophenyl)pyrrolidine-1-carbothioamide
##STR00069##
[0383] 3-(2,3,4-Trifluorophenyl)pyrrolidine (CAS #1260884-52-3) was
converted to 3-(2,3,4-trifluorophenyl)pyrrolidine-1-carbothioamide
by a similar procedure as described for Example 10 and the product
was isolated as an off-white solid.
[0384] .sup.1H NMR (DMSO-d6): 6.15-8.25 (2H, s br), 7.33 (1H, br
s), 7.21 (1H, br s), 4.09 (0.5H, br s), 3.88 (0.5H, br s), 3.76
(1H, m), 3.56 (1.5H, m), 3.50 (0.5H, br s), 3.30-3.50 (1H, m), 2.37
(0.5H, m), 2.18 (1H, m), 2.03 (0.5H, br s).
[0385] .sup.13C NMR (DMSO-d6): 178.6, 178.5, 149.9, 149.7, 148.3,
148.1, 139.8, 138.2, 126.1, 122.4, 112.7, 55.9, 52.4, 50.9, 47.0,
37.0, 35.5, 31.6, 30.4.
Example 23
3-(2,3,5,6-Tetrafluorophenyl)pyrrolidine-1-carbothioamide
##STR00070##
[0387] 3-(2,3,5,6-Tetrafluorophenyl)pyrrolidine (CAS #1260865-90-4)
was converted to
3-(2,3,5,6-Tetrafluorophenyl)pyrrolidine-1-carbothioamide by a
similar procedure as described for Example 10 and the product was
isolated as an off-white powder.
[0388] .sup.1H NMR (DMSO-d6): 7.84 (1H, br s), 7.26 (2H, br s),
4.10 (0.5H, m), 3.95 (1H, m), 3.78 (1H, m), 3.47 (2H, m), 3.41
(0.5H, m), 2.0-2.40 (2H, m).
[0389] .sup.13C NMR (DMSO-d6): 178.6, 146.5, 146.4, 146.3, 145.5,
144.8, 144.8, 144.7, 143.9, 143.8, 119.4, 105.6, 105.4, 54.3, 51.1,
50.6, 47.4, 34.7, 33.3, 30.7, 29.6.
Example 24
3-(2,3,5-trifluorophenyl)pyrrolidine-1-carbothioamide
##STR00071##
[0391] 3-(2,3,5-Trifluorophenyl)pyrrolidine (CAS #1260885-09-3) was
converted to 3-(2,3,5-trifluorophenyl)pyrrolidine-1-carbothioamide
by a similar procedure as described for Example 10 and the product
was isolated as a white powder.
[0392] .sup.1H NMR (DMSO-d6): 7.45 (1H, br s), 7.25 (2H, br s),
7.13 (1H, m), 4.10 (0.5H, m), 3.90 (0.5H, m), 3.78 (1H, m), 3.63
(0.5H, m), 3.53 (1.5H, m), 3.41 (0.5H, m), 3.35 (0.5H, m), 2.35
(0.5H, m), 2.19 (1H, m), 2.04 (0.5H, m).
[0393] .sup.13C NMR (DMSO-d6): 178.5, 158.2, 158.1, 156.6, 156.5,
150.5, 150.4, 150.3, 148.9, 148.8, 148.7, 145.8, 144.2, 131.5,
110.1, 104.3, 55.8, 52.3, 50.9, 47, 37.3, 35.8, 31.5, 30.3.
Example 25
(S)-3-(3,5-difluorophenyl)pyrrolidine-1-carbothioamide
##STR00072##
[0395] (S)-3-(3,5-difluorophenyl)pyrrolidine (CAS #1336142-75-6)
was converted to
(S)-3-(3,5-difluorophenyl)pyrrolidine-1-carbothioamide by a similar
procedure as described for Example 10 and the product was isolated
as a white powder.
[0396] .sup.1H NMR (DMSO-d6): 7.21 (2H, br s), 7.07 (3H, m), 4.12
(0.5H, m), 3.89 (0.5H, m), 3.78 (0.5H, m), 3.35-3.63 (3H, m), 3.27
(0.5H, m), 2.34 (0.5H, m), 2.20 (0.5H, m), 2.14 (0.5H, m), 1.99
(0.5H, m).
[0397] .sup.13C NMR (DMSO-d6): 178.5, 163.3, 163.2, 161.7, 161.6,
146, 145.8, 110.6, 110.6, 110.5, 110.4, 102.3, 102.2, 102.0, 57,
53.4, 51.2, 47.3, 43.7, 42.1, 32.6, 31.4.
Example 26
(R)-3-(3,5-difluorophenyl)pyrrolidine-1-carbothioamide
##STR00073##
[0399] (R)-3-(3,5-difluorophenyl)pyrrolidine (CAS #1334824-24-6)
was converted to
(R)-3-(3,5-difluorophenyl)pyrrolidine-1-carbothioamide by a similar
procedure as described for Example 10 and the product was isolated
as a white powder.
[0400] .sup.1H NMR (DMSO-d6): 7.21 (2H, br s), 7.07 (3H, m), 4.12
(0.5H, m), 3.89 (0.5H, m), 3.78 (0.5H, m), 3.35-3.63 (3H, m), 3.27
(0.5H, m), 2.34 (0.5H, m), 2.20 (0.5H, m), 2.14 (0.5H, m), 1.99
(0.5H, m).
[0401] .sup.13C NMR (DMSO-d6): 178.5, 163.3, 163.2, 161.7, 161.6,
146, 145.8, 110.6, 110.5, 110.4, 102.4, 102.2, 102.0, 57.0, 53.4,
51.2, 47.3, 43.7, 42.1, 32.6, 31.4.
Example 27
(1S,5S)-1-(thiophen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
##STR00074##
[0403] (1S,5S)-1-(thiophen-2-yl)-3-azabicyclo[3.1.0]hexane (CAS
#1046141-90-5) was converted to
(1S,5S)-1-(thiophen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
by a similar procedure as described for Example 10 and the product
was isolated as a beige semi-solid.
[0404] .sup.1H NMR (CDCl.sub.3): 7.14 (1H, br d, J=4.4 Hz), 6.93
(1H, dd, J=5.1, 3.5 Hz), 6.89 (1H, br), 5.81 (2H, br s), 4.56
(0.5H, m), 4.29 (0.5H, m), 4.02 (0.5H, m), 3.94 (0.5H, m), 3.85
(0.5H, m), 3.73 (1H, m), 3.60 (0.5H, br s), 1.97 (0.5H, br s), 1.92
(0.5H, br s), 1.39 (1H, m), 0.96 (1H, m).
[0405] .sup.13C NMR (CDCl.sub.3): 180.2, 144.1, 143.8, 127, 124.2,
123.8, 123.6, 123.5, 58.9, 55.0, 54.8, 50.5, 28.6, 27.5, 27.2,
26.3, 20.1.
Example 28
(1R,5R)-1-(thiophen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
##STR00075##
[0407] (1R,5R)-1-(thiophen-2-yl)-3-azabicyclo[3.1.0]hexane (CAS
#1046141-89-2) was converted to
(1R,5R)-1-(thiophen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
by a similar procedure as described for Example 10 and the product
was isolated as a beige solid.
[0408] .sup.1H NMR (DMSO-d6): 7.14 (1H, br d, J=4.4 Hz), 6.93 (1H,
dd, J=5.1, 3.5 Hz), 6.89 (1H, br), 5.75 (2H, br s), 4.57 (0.5H, m),
4.30 (0.5H, m), 4.03 (0.5H, m), 3.95 (0.5H, m), 3.85 (0.5H, m),
3.73 (1H, m), 3.59 (0.5H, br s), 1.98 (0.5H, br s), 1.93 (0.5H, br
s), 1.39 (1H, m), 0.96 (1H, m).
[0409] .sup.13C NMR (DMSO-d6): 180.3, 144.1, 143.8, 127, 124.2,
123.8, 123.6, 123.5, 58.9, 55.0, 54.8, 50.5, 28.6, 27.5, 27.3,
26.3, 20.1.
Example 29
3-(perfluorophenyl)pyrrolidine-1-carbothioamide
##STR00076##
[0411] 3-(Perfluorophenyl)pyrrolidine (CAS #1260650-30-3) was
converted to 3-(perfluorophenyl)pyrrolidine-1-carbothioamide by a
similar procedure as described for Example 10 and the product was
isolated as a white powder.
[0412] .sup.1H NMR (DMSO-d6): 7.27 (2H, br s), 4.09 (0.5H, br s),
3.94 (1H, br s), 3.77 (1H, br s), 3.58 (1.5H, br s), 3.46 (0.5H, br
s), 3.40 (0.5H, br s), 2.37 (0.5H, br s), 2.29 (0.5H, br s), 2.23
(0.5H, br s), 2.13 (0.5H, br s).
[0413] .sup.13C NMR (DMSO-d6): 178.6, 145.9, 144.3, 54.3, 51.1,
50.6, 47.3, 34.2, 32.8, 30.7, 29.7.
Example 30
(1S,5R)-1-(3,5-Difluorophenyl)-N-methyl-3-azabicyclo[3.1.0]hexane-3-carbot-
hioamide
##STR00077##
[0415] A solution of
(1S,5R)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane (Feng Xu
et al.: Org. Lett. 8(17), 3885-3888, 2006) (0.215 g, 1.1 mmol) and
methyl isothiocyanate (0.088 g, 1.210 mmol) in acetonitrile (5 mL)
was stirred at room temperature for 4 h and then concentrated under
reduced pressure. The residue was chromatographed (ethyl
acetate-petroleum ether) to give
(1S,5R)-1-(3,5-difluorophenyl)-N-methyl-3-azabicyclo[3.1.0]hexane-3-carbo-
thioamide as a yellowish solid (0.148 g, 50% yield).
[0416] .sup.1H NMR (CDCl.sub.3): 6.60-6.71 (3H, m), 5.51 (1H, br
s), 4.29 (1H, br s), 3.96 (1H, m), 3.81 (1H, br d, J=8.9 Hz), 3.75
(1H, d, J=7.5 Hz), 3.13 (3H, d, J=4.5 Hz), 2.02(1H, dt, J=8.4, 4.4
Hz), 1.21 (1H, dd, J=5.4, 8.3), 0.94 (1H, t, J=4.9 Hz).
[0417] .sup.13C NMR (CDCl.sub.3): 181, 163.9, 163.8, 162.3, 162.2,
144.4, 144.4, 109.6, 109.5, 109.4, 109.4, 102.2, 102.1, 101.9,
55.5, 51.6, 32.4, 31.1, 24.7, 20.4.
Example 31
N-methyl-3-phenylpyrrolidine-1-carbothioamide
##STR00078##
[0419] 3-Phenylpyrrolidine (CAS #936-44-7) was converted to
N-methyl-3-phenylpyrrolidine-1-carbothioamide by a similar
procedure as described for Example 30 and the product was isolated
as a white solid.
[0420] .sup.1H NMR (CDCl.sub.3): 7.34 (2H, t, J=7.8 Hz), 7.27 (1H,
m), 7.23 (2H, d, J=7.9 Hz), 5.32 (1H, br s), 3.68-4.46 (2H, m),
3.62 (1H, br s), 3.49 (1H, br s), 3.17 (3H, d, J=4.55 Hz), 2.40
(1H, br s), 2.07-2.20 (1H, m).
[0421] .sup.13C NMR (CDCl.sub.3): 179.8, 140.4, 128.7, 127.1,
126.9, 55.6, 49.2, 43.7, 32.7, 32.4.
Example 32
3-(3,5-difluorophenyl)-N-methylpyrrolidine-1-carbothioamide
##STR00079##
[0423] 3-(3,5-Difluorophenyl)pyrrolidine (CAS #1092108-82-1) was
converted to
3-(3,5-difluorophenyl)-N-methylpyrrolidine-1-carbothioamide by a
similar procedure as described for Example 30 and the product was
isolated as a white solid.
[0424] .sup.1H NMR (DMSO-d6): 7.31 (1H, br q, J=4.0 Hz), 7.11 (1H,
tt, J=2.3, 9.3 Hz), 7.07 (2H, m), 3.98 (1H, br s), 3.73 (1H, br m),
3.48 (2H, br m), 3.39 (1H, m), 2.89(3H, d, J=4.3 Hz), 2.28 (1H, br
m), 2.07 (1H, br m).
[0425] .sup.13C NMR (DMSO-d6): 179.4, 163.8, 163.7, 162.2, 162.1,
146.5, 146.5, 146.4, 111, 110.9, 102.8, 102.6, 102.5, 56.2, 50.3,
43.1, 32.4, 32.1.
Example 33
N-methyl-3-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carbothioamide
##STR00080##
[0427] 3-(2,3,5,6-Tetrafluorophenyl)pyrrolidine (CAS #1260865-90-4)
was converted to
N-methyl-3-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carbothioamide
by a similar procedure as described for Example 30 and the product
was isolated as a white powder.
[0428] .sup.1H NMR (DMSO-d6): 7.83 (1H, m), 7.36 (1H, br q, J=3.7
Hz), 3.99 (1H, br s), 3.83 (1H, m), 3.77 (1H, br s), 3.60 (1H, m),
3.48 (1H, m), 2.89 (3H, d, J=4.1 Hz), 2.31 (1H, br s), 2.25 (1H, br
m).
[0429] .sup.13C NMR (DMSO-d6): 179.1, 146.5, 146.4, 146.3, 145.5,
145.4, 144.9, 144.8, 144.7, 143.9, 143.8, 119.5, 119.4, 119.3,
105.7, 105.5, 105.3, 52.8, 48.4, 33.6, 32.0, 30.0.
Example 34
1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
##STR00081##
[0431] 1-(3,5-Difluorophenyl)-3-azabicyclo[3.1.0]hexane (Feng Xu et
al.: Org. Lett. 8(17), 3885-3888, 2006) was converted to
1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
by a similar procedure as described for Example 10 and the product
was isolated as a white powder.
[0432] .sup.1H NMR (DMSO-d6): 7.30 (2H, br s), 7.07 (1H, br t,
J=9.2 Hz), 6.94 (2H, br s), 4.39 (0.5H, br s), 4.07 (0.5H, br s),
3.92 (0.5H, br s), 3.58-3.80 (2H, m), 3.53 (0.5H, br s), 2.21
(0.5H, br s), 2.12 (0.5H, br s), 1.20(1H, br s), 0.78 (1H, br
s).
[0433] .sup.13C NMR (DMSO-d6): 179.9, 163.4, 163.3, 161.7, 161.6,
145.9, 145.9, 145.8, 109.8, 109.7, 109.5, 109.4, 101.8, 101.6,
101.5, 56.5, 53.7, 52.8, 49.9, 31.7, 30.1, 25.4, 24.7, 20.4,
20.0.
Example 35
(1R,5S)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
##STR00082##
[0435] (1R,5S)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane
(Feng Xu et al.: Org. Lett. 8(17), 3885-3888, 2006) was converted
to
(1R,5S)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
by a similar procedure as described for Example 10 and the product
was isolated as a white powder.
[0436] .sup.1H NMR (DMSO-d6): 7.30 (2H, br s), 7.07 (1H, br t,
J=9.2 Hz), 6.94 (2H, br s), 4.39 (0.5H, br s), 4.07 (0.5H, br s),
3.92 (0.5H, br s), 3.58-3.80 (2H, m), 3.53 (0.5H, br s), 2.21
(0.5H, br s), 2.12 (0.5H, br s), 1.20(1H, br s), 0.78 (1H, br
s).
[0437] .sup.13C NMR (DMSO-d6): 179.9, 163.4, 163.3, 161.7, 161.6,
145.9, 145.9, 145.8, 109.7, 109.5, 101.8, 101.6, 101.4, 56.5, 53.7,
52.7, 50.0, 31.7, 30.2, 25.4, 24.7, 20.4, 20.0.
Example 36
(1S,5R)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
##STR00083##
[0439] (1S,5R)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane
(Feng Xu et al.: Org. Lett. 8(17), 3885-3888, 2006) was converted
to
(1S,5R)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
by a similar procedure as described for Example 10 and the product
was isolated as a white powder.
[0440] .sup.1H NMR (DMSO-d6): 7.30 (2H, br s), 7.07 (1H, br t,
J=9.2 Hz), 6.94 (2H, br s), 4.39 (0.5H, br s), 4.07 (0.5H, br s),
3.92 (0.5H, br s), 3.58-3.80 (2H, m), 3.53 (0.5H, br s), 2.21
(0.5H, br s), 2.12 (0.5H, br s), 1.20(1H, br s), 0.78 (1H, br
s).
[0441] .sup.13C NMR (DMSO-d6): 179.9, 163.4, 163.3, 161.7, 161.6,
145.9, 145.9, 109.7, 109.5, 101.8, 101.6, 101.4, 56.5, 53.7, 52.8,
50, 31.7, 30.2, 25.5, 24.7, 20.4, 20.0,
Example 37
1-(2,4-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
##STR00084##
[0443] 1-(2,4-Difluorophenyl)-3-azabicyclo[3.1.0]hexane (Feng Xu et
al.: Org. Lett. 8(17), 3885-3888, 2006) was converted to
1-(2,4-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
by a similar procedure as described for Example 10 and the product
was isolated as a white powder.
[0444] .sup.1H NMR (DMSO-d6): 7.42 (1H, m), 7.24 (1H, br t, J=9.3
Hz), 7.05 (1H, br t, J=7.5 Hz), 6.80-7.60 (2H, br s), 4.30 (0.5H,
m), 4.09 (0.5H, m), 3.87 (0.5H, m), 3.71 (0.5H, m), 3.66 (0.5H, m),
3.58 (0.5H, m), 3.48 (0.5H, m), 3.35 (0.5H, m), 2.09 (0.5H, m),
1.93 (0.5H, m), 1.10(1H, br s), 0.70 (1H, t, J=4.7 Hz).
[0445] .sup.13C NMR (DMSO-d6): 179.8, 162.7, 162.6, 162.3, 162.2,
161, 160.9, 160.7, 160.6, 131.9, 123.5, 111.5, 111.3, 104.2, 104.0,
103.9, 57.9, 54.1, 53.9, 50.0, 27.6, 26.2, 22.8, 21.8, 16.8,
16.7.
Example 38
1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
##STR00085##
[0447] 1-(2,5-Difluorophenyl)-3-azabicyclo[3.1.0]hexane (Feng Xu et
al.: Org. Lett. 8(17), 3885-3888, 2006) was converted to
1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothioamide
by a similar procedure as described for Example 10 and the product
was isolated as a white powder.
[0448] .sup.1H NMR (DMSO-d6): 7.20-7.28 (2H, m), 7.16 (1H, m),
6.60-8.00 (2H, br s), 4.33 (0.5H, br m), 4.09 (0.5H, br m), 3.90
(0.5H, br m), 3.71 (0.5H, br m), 3.65 (0.5H, br m), 3.46-3.61 (1H,
m), 3.40 (0.5H, br m), 2.18 (0.5H, br m), 2.03 (0.5H, br m),
1.14(1H, br s), 0.73 (1H, t, J=4.8 Hz).
[0449] .sup.13C NMR (DMSO-d6): 179.8, 158.8, 157.2, 129.2, 117,
117, 116.9, 116.8, 115.4, 115.3, 57.5, 53.8, 49.9, 28.2, 26.7, 23,
22.1, 17.4, 17.1.
Example 39
(1S,5R)-1-(3,5-Difluorophenyl)-N-propyl-3-azabicyclo[3.1.0]hexane-3-carbot-
hioamide
Step 1:
((1S,5R)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)(1H--
imidazol-1-yl)methanethione
##STR00086##
[0451] To a solution of 1,1'-thiocarbonyldiimidazole (0.329 g,
1.844 mmol) in dry tetrahydrofuran (6 mL) was added a solution of
(1S,5R)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane (Feng Xu
et al.: Org. Lett. 8(17), 3885-3888, 2006) (0.36 g, 1.844 mmol) in
dry tetrahydrofuran (6 mL). The solution was stirred at room
temperature for 1 h and then at 50-55.degree. C. for 2 h. After
being cooled to room temperature, the solution was concentrated
under reduced pressure. The residue was chromatographed (ethyl
acetate-petroleum ether) to give
((1S,5R)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)(1H-imidazo-
l-1-yl)methanethione (0.31 g, 55% yield).
Step 2:
(1S,5R)-1-(3,5-Difluorophenyl)-N-propyl-3-azabicyclo[3.1.0]hexane--
3-carbothioamide
##STR00087##
[0453] To a solution of
((1S,5R)-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-3-yl)(1H-imidazo-
l-1-yl)methanethione (0.15 g, 0.491 mmol) in dry tetrahydrofuran (3
mL) was added propan-1-amine (0.081 mL, 0.982 mmol) and the mixture
was stirred at 65.degree. C. for 16 h. The solvents were evaporated
off and then the residue was chromatographed (petroleum ether ethyl
acetate) to give
(1S,5R)-1-(3,5-difluorophenyl)-N-propyl-3-azabicyclo[3.1.0]hexane-3--
carbothioamide as a yellowish viscous oil (0.093 g, 64% yield).
[0454] .sup.1H NMR (CDCl.sub.3): 6.65-6.74 (3H, m), 5.30 (1H, t,
J=4.7 Hz), 4.29 (1H, br m), 3.96 (1H, br m), 3.82 (1H, br d, J=8.9
Hz), 3.76 (1H, br d, J=7.0 Hz), 3.60 (2H, m), 2.03 (1H, dt, J=4.3,
8.3 Hz), 1.65 (2H, m), 1.23 (1H, d m, J=5.3 Hz), 0.97 (3H, t, J=7.5
Hz), 0.97 (1H, m).
[0455] .sup.13C NMR (CDCl.sub.3): 180.2, 164, 163.9, 162.3, 162.2,
144.5, 144.4, 144.4, 109.7, 109.6, 109.5, 109.5, 102.3, 102.1,
102.0, 55.4, 51.5, 47.4, 31.1, 24.7, 22.5, 20.3, 11.4.
Example 40
1-(2,5-difluorophenyl)-N-(2-mercaptoethyl)-3-azabicyclo[3.1.0]hexane-3-car-
bothioamide
##STR00088##
[0457] 1-(2,5-Difluorophenyl)-3-azabicyclo[3.1.0]hexane (Feng Xu et
al.: Org. Lett. 8(17), 3885-3888, 2006) was converted to
1-(2,5-difluorophenyl)-N-(2-mercaptoethyl)-3-azabicyclo[3.1.0]hexane-3-ca-
rbothioamide by a similar procedure as described for Example 39 and
the product was isolated as a colourless oil.
[0458] .sup.1H NMR (DMSO-d6): 7.56 (1H, t br, J=4.5 Hz), 7.24 (2H,
m), 7.16 (1H, m), 4.17 (1H, s br), 3.91 (1H, s br), 3.67 (1H, m),
3.56 (2H, m), 3.50 (1H, br s), 2.63 (2H, q, J=7.1 Hz), 2.39 (1H,
m), 2.14 (1H, br s), 1.13 (1H, dd, J=8.0, 5.1 Hz), 0.76 (1H, t,
J=4.8 Hz).
[0459] .sup.13C NMR (DMSO-d6): 179.3, 158.8, 158.7, 157.2, 157.1,
129.3, 129.3, 129.2, 129.2, 117.0, 117.0, 117.0, 116.9, 116.9,
116.8, 115.5, 115.4, 115.3, 115.2, 53.6, 49.6, 47.8, 47, 27.1,
22.8, 22.2, 17.6.
Example 41
(1S,5R)-1-(3,5-difluorophenyl)-N-methyl-4-oxo-3-azabicyclo[3.1.0]hexane-3--
carbothioamide
##STR00089##
[0461] To a solution of
(1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one
(Example 60, step 2) (0.628 g, 3 mmol) in dry tetrahydrofuran (15
mL) was added sodium hydride (60% in mineral oil) (0.180 g, 4.5
mmol) at 0-5.degree. C. in portions. The mixture was stirred for 30
min at room temperature, and methyl isothiocyanate (0.329 g, 4.5
mmol) was then added at -78.degree. C. The mixture was allowed to
reach room temperature over 3 h, then carefully quenched with aq.
ammonium chloride solution, and extracted with a mixture of ethyl
acetate petroleum ether (2:1). The organic phase was dried over
MgSO.sub.4 and evaporated to dryness. The residue was triturated
with petroleum ether, then filtered, washed with petroleum ether,
and dried under vacuum. Chromatography (ethyl acetate-petroleum
ether; 1:4) afforded
(1S,5R)-1-(3,5-difluorophenyl)-N-methyl-4-oxo-3-azabicyclo[3.1.0]hexane-3-
-carbothioamide as a white powder (0.036 g, 4% yield).
[0462] .sup.1H NMR (DMSO-d6): 10.37 (1H, br s), 7.18 (2H, m), 7.15
(1H, tt, J=2.3, 9.3 Hz), 4.50 (1H, dd, J=11.4, 1.7 Hz), 4.16 (1H,
d, J=11.3 Hz), 3.02 (3H, d, J=2.8 Hz), 2.76 (1H, ddd, J=1.7, 3.5,
9.1 Hz), 1.68(1H, dd, J=9.1, 4.8 Hz), 1.43(1H, dd, J=4.8, 3.6
Hz).
[0463] .sup.13C NMR (DMSO-d6): 180.5, 174.4, 163.3, 163.2, 161.7,
161.6, 143.3, 143.3, 143.2, 111.0, 111.0, 110.9, 110.8, 102.9,
102.7, 102.6, 56.1, 32.1, 30.1, 26.8, 26.7, 26.7, 20.7.
Example 42
4-(3,5-difluorophenyl)-N-methyl-2-oxopyrrolidine-1-carbothioamide
##STR00090##
[0465] 4-(3,5-Difluorophenyl)pyrrolidin-2-one (CAS #1604786-89-1)
was converted to
4-(3,5-difluorophenyl)-N-methyl-2-oxopyrrolidine-1-carbothioamide
by a similar procedure as described for Example 41 and the product
was isolated as a beige powder.
[0466] .sup.1H NMR (DMSO-d6): 10.51 (1H, br q, J=4.5 Hz), 7.10-7.20
(3H, m), 4.54(1H, dd, J=10.7, 8.2 Hz), 3.85 (1H, dd, J=10.8, 9.0
Hz), 3.68 (1H, quin, J=9.0 Hz), 3.05 (3H, d, J=4.5 Hz), 2.95-3.05
(2H, m).
[0467] .sup.13C NMR (DMSO-d6): 180.1, 174.7, 163.3, 163.3, 161.7,
161.6, 145.5, 145.4, 145.3, 110.8, 110.7, 110.6, 110.6, 102.7,
102.5, 102.4, 56.7, 40.3, 35.1, 32.2.
Example 43
1-(3,5-Difluorophenyl)-N-methyl-4-oxo-3-azabicyclo[3.1.0]hexane-3-carbothi-
oamide
##STR00091##
[0469] 5-(3,5-Difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one was
converted to
1-(3,5-Difluorophenyl)-N-methyl-4-oxo-3-azabicyclo[3.1.0]hexane-3-carb-
othioamide by a similar procedure as described for Example 41 and
the product was isolated as a beige powder.
[0470] .sup.1H NMR (DMSO-d6): 10.37 (1H, q, J=4.5 Hz), 7.18 (2H,
m), 7.15 (1H, tt, J=2.3, 9.3 Hz), 4.50 (1H, dd, J=11.4, 1.7 Hz),
4.16 (1H, d, J=11.3 Hz), 3.02(3H, d, J=4.5 Hz), 2.76 (1H, ddd,
J=1.7, 3.5, 9.1 Hz), 1.68 (1H, dd, J=9.1, 4.8 Hz), 1.43 (1H, dd,
J=4.8, 3.6 Hz).
[0471] .sup.13C NMR (DMSO-d6): 180.5, 174.4, 163.3, 163.2, 161.7,
161.6, 143.3, 143.3, 143.2, 111.0, 111.0, 110.9, 110.8, 102.9,
102.7, 102.5, 56.1, 32.1, 30.1, 26.7, 26.7, 20.7.
Example 44
6-Phenyltetrahydro-1H-pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00092##
[0473] A solution of 1,1'-thiocarbonyldiimidazole (0.159 g, 0.894
mmol) in dichloromethane (2 mL) was added dropwise to a solution of
(4-phenylpyrrolidin-2-yl)methanamine (CAS #82256-70-0) (0.150 g,
0.851 mmol) in dichloromethane (2 mL) at room temperature. The thus
obtained orange solution was allowed to stir at room temperature
for 1 h, diluted with dichloromethane, and then washed with water.
The organic layer was dried over MgSO.sub.4 and evaporated under
vacuum to give the crude product as an orange oil. Chromatography
(dichloromethane-methanol) followed by trituration (petroleum
ether-ethyl acetate) afforded
6-phenyltetrahydro-1H-pyrrolo[1,2-c]imidazole-3(2H)-thione as a
beige solid (0.076 g, 41% yield).
[0474] .sup.1H NMR (DMSO-d6): 8.61 (1H, s), 7.31 (2H, t, J=7.5 Hz),
7.25 (2H, d, J=8.6 Hz), 7.22 (1H, t m, J=7.2 Hz), 4.17 (1H, m,
J=10.1, 4.5 Hz), 3.74 (1H, dd, J=7.3, 10.3 Hz), 3.67 (1H, t, J=9.8
Hz), 3.60 (1H, t, J=9.3 Hz), 3.55 (1H, m), 3.44 (1H, dd, J=3.7,
10.4 Hz), 2.26 (1H, m), 1.50 (1H, q, J=11.3 Hz).
[0475] .sup.13C NMR (DMSO-d6): 186.3, 142.6, 128.6, 127.1, 126.5,
63.1, 54.2, 46.2, 45, 39.2.
Example 45
1-(3,5-Difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothiohydrazide
Step 1: benzyl
2-(1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbonothioyl)hydra-
zinecarboxylate
##STR00093##
[0477] To a solution of 1,1'-thiocarbonyldiimidazole (201 mg, 1.127
mmol) in anhydrous tetrahydrofuran (2.6 mL) was added dropwise a
solution of 1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane (Feng
Xu et al.: Org. Lett. 8(17), 3885-3888, 2006) (200 mg, 1.025 mmol)
in anhydrous tetrahydrofuran (2.6 mL) at room temperature. The
reaction was stirred at room temperature for 1 h, then heated at
55.degree. C. for 2 h. Thereupon, the solvent was evaporated off
and the resulting yellow oil was dissolved in methanol (2.5 mL)
followed by addition of benzyl carbazate (341 mg, 2.049 mmol) in
one portion. The reaction was heated at reflux temperature for 24
h, the solvent was then evaporated off and the residue was
dissolved in dichloromethane, washed with water, dried over
MgSO.sub.4, filtered and evaporated to dryness. The thus obtained
yellow oil was purified by chromatography (dichloromethane
methanol) to give benzyl
2-(1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbonothioy-
l)hydrazinecarboxylate as a yellow oil (0.27 g, 0.67 mmol, 65%
yield).
Step 2:
1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothiohydraz-
ide
##STR00094##
[0479] To a stirred solution of benzyl
2-(1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbonothioyl)hydra-
zinecarboxylate (270 mg, 0.67 mmol) in dichloromethane (5 mL) was
added dropwise boron tribromide (0.19 mL, 2.008 mmol) at
-78.degree. C. under nitrogen. The solution was stirred in the cold
for 5 min, then was allowed to warm up to room temperature
naturally and stirred for 1.5 h. The mixture was then cooled again
to 0-5.degree. C. followed by quenching with water. The resulting
emulsion then was extracted with a mixture of 30% 2-propanol in
dichloromethane, the organic phase was washed with water, dried
over MgSO.sub.4, filtered and evaporated to dryness. The thus
obtained yellow oil was purified by chromatography
(dichloromethane-methanol), Recrystallization from 2-propanol
afforded
1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbothiohydrazide
as a pink solid (0.015 g, 8% yield).
[0480] .sup.1H NMR (DMSO-d6): 8.80 (1H, s), 7.08 (1H, tt, J=9.4,
2.4 Hz), 6.95 (2H, m), 4.64 (2H, br s), 4.17 (1H, br d, J=10.9 Hz),
3.89 (1H, br d, J=11.0 Hz), 3.68(1H, d, J=10.9 Hz), 3.59 (1H, br
dd, J=10.9, 4.2 Hz), 2.18 (1H, dt, J=8.3, 4.2 Hz), 1.19 (1H, dd,
J=8.0, 5.1 Hz), 0.77 (1H, t, J=4.8 Hz).
[0481] .sup.13C NMR (DMSO-d6): 180.7, 163.4, 163.3, 161.8, 161.7,
146, 145.9, 145.8, 109.7, 109.7, 109.6, 109.5, 101.8, 101.7, 101.5,
54.4, 51.7, 30.4, 24.6, 20.3.
Example 46
1-(3,5-Difluorophenyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbothioa-
mide
##STR00095##
[0483] To a solution of 1,1'-thiocarbonyldiimidazole (201 mg, 1.127
mmol) in anhydrous tetrahydrofuran (2.6 mL) was added dropwise a
solution of 1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane (Feng
Xu et al.: Org. Lett. 8(17), 3885-3888, 2006) (200 mg, 1.025 mmol)
in anhydrous tetrahydrofuran (2.6 mL) at room temperature. The
solution was stirred at room temperature for 1 h, then was heated
at 55.degree. C. for 2 h. The solvent was evaporated off under
vacuum and the oily residue was dissolved in methanol (4.1 mL),
followed by addition of 1,1-dimethylhydrazine (0.13 mL 1.690 mmol).
The mixture was then heated to reflux and stirred for 24 h, and
then cooled to room temperature, whereupon the solvent was
evaporated off. The yellow oily residue was dissolved in
dichloromethane, washed with water, dried over MgSO.sub.4, filtered
and evaporated to dryness. Chromatography (petroleum ether-ethyl
acetate) afforded
1-(3,5-difluorophenyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbothio-
amide as a light yellow oil (0.124 g, 26% yield).
[0484] .sup.1H NMR (CDCl.sub.3): 6.70 (2H, m), 6.67 (1H, tt, J=2.3,
8.9 Hz), 4.59 (1H, d, J=11.0 Hz), 4.16 (1H, d, J=11.0 Hz), 3.72
(1H, dd, J=3.6, 10.9 Hz), 3.71 (1H, dd, J=1.2, 10.9 Hz), 3.13 (6H,
m), 1.84(1H, m), 1.07(1H, m), 0.98(1H, m).
[0485] .sup.13C NMR (CDCl.sub.3): 191.7, 163.9, 163.8, 162.3,
162.2, 144.8, 109.7, 109.7, 109.6, 109.6, 102.1, 101.9, 101.7,
57.2, 54.4, 43.2, 30.0, 24.3, 17.4.
Example 47
N-(cyanomethyl)-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboth-
ioamide
##STR00096##
[0487] 1-(2,5-Difluorophenyl)-3-azabicyclo[3.1.0]hexane (Feng Xu et
al.: Org. Lett. 8(17), 3885-3888, 2006) was converted to
N-(cyanomethyl)-1-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carbot-
hioamide by a similar procedure as described for Example 30 and the
product was isolated as a brownish red solid.
[0488] .sup.1H NMR (DMSO-d6): 7.99 (1H, br s), 7.25 (2H, m),
7.17(1H, m), 4.45 (2H, br d, J=5.1 Hz), 3.44-4.40 (4H, br m), 2.19
(1H, br s), 1.16 (1H, m), 0.80 (1H, m).
[0489] .sup.13C NMR (DMSO-d6): 179.7, 158.8, 158.7, 157.2, 157.1,
129.1, 129.1, 129.0, 129.0, 129.0, 129.0, 117.6, 117.1, 117.0,
117.0, 116.9, 116.8, 116.8, 115.5, 115.5, 115.4, 115.3, 58.3, 54.5,
53.6, 49.9, 33.2, 28.1, 26.4, 23, 21.6, 17.8.
Example 48
3-(3,5-Difluorophenyl)-N-methyl-2,3-dihydro-1H-pyrrole-1-carbothioamide
Step 1:
4-(3,5-difluorophenyl)-2-hydroxy-N-methylpyrrolidine-1-carbothioam-
ide
##STR00097##
[0491] To a solution of
4-(3,5-difluorophenyl)-N-methyl-2-oxopyrrolidine-1-carbothioamide
(Example 42) (0.270 g, 1 mmol) in dry toluene (5 mL) was added
dropwise 1 M diisobutylaluminum hydride (2.70 mL, 2.70 mmol) in
toluene at 0-5.degree. C. and the reaction was stirred for 1 h in
the cold. Thereupon, the mixture was quenched with ice-water,
stirred for 1 h in the cold, diluted with ethyl acetate (20 mL) and
then filtered through a celite plug. The organic phase was dried
over MgSO.sub.4 and evaporated to dryness. Purification by
chromatography (petroleum ether-ethyl acetate) afforded
4-(3,5-difluorophenyl)-2-hydroxy-N-methylpyrrolidine-1-carbothioamide
as a white powder (0.14 g, 51% yield).
Step 2:
3-(3,5-Difluorophenyl)-N-methyl-2,3-dihydro-1H-pyrrole-1-carbothio-
amide
##STR00098##
[0493] To a solution of
4-(3,5-difluorophenyl)-2-hydroxy-N-methylpyrrolidine-1-carbothioamide
(0.2 g, 0.734 mmol) in dry toluene (5 mL) was added 2,6-lutidine
(0.428 mL, 3.67 mmol) followed by addition of 2,2,2-trifluoroacetic
anhydride (0.23 mL, 1.76 mmol) at -10.degree. C. under nitrogen.
The reaction was allowed to warm up to room temperature and stirred
for 20 h. Thereupon, the mixture was quenched with water (10 mL)
and stirred for 30 min. The organic phase was evaporated to
dryness, the residue was then dissolved in ethanol (15 mL) and
treated with 5 M sodium hydroxide (0.3 mL, 1.469 mmol) at room
temperature for 1 h. Thereupon, the mixture was evaporated to
dryness and the residue was partitioned between dichloromethane and
water. The organic phase was dried over MgSO.sub.4, evaporated to
dryness under vacuum and chromatographed (petroleum ether-ethyl
acetate) to give
3-(3,5-difluorophenyl)-N-methyl-2,3-dihydro-1H-pyrrole-1-carbothioamide
as a white powder (0.063 g, 33% yield).
[0494] .sup.1H NMR (DMSO-d6): 7.80 (1H, br s), 7.41 (1H, br d,
J=2.3 Hz), 7.11 (1H, m), 6.93 (2H, m), 5.37 (1H, dd, J=4.1, 2.6
Hz), 4.37 (1H, m), 4.23 (1H, t, J=11.2 Hz), 3.70 (1H, dd, J=11.6,
5.7 Hz), 2.91 (3H, d, J=4.3 Hz).
[0495] .sup.13C NMR (DMSO-d6): 176.6, 163.5, 163.4, 161.8, 161.8,
148.5, 148.4, 148.3, 133.4, 112.2, 110.4, 110.2, 102.6, 102.4,
102.2, 55.9, 46.6, 31.9.
Example 49
6-phenyl-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione
Step 1: 2-phenylpent-4-enenitrile
##STR00099##
[0497] To a stirred solution of 2-phenylacetonitrile (3.15 mL, 27.3
mmol) in tetrahydrofuran (136 mL) was added lithium
hexamethyldisilazane (30 mL, 30.0 mmol) dropwise at -78.degree. C.
The resulting yellow solution was allowed to stir in the cold for
30 min, whereupon 3-bromoprop-1-ene (2.3 mL, 27.2 mmol) was added
dropwise and the mixture was stirred at room temperature. The
solvent was then removed under vacuum and the product was purified
by chromatography (petroleumether-ethyl acetate; 1:0, 9:1, then
6:1) and isolated as a yellow oil. (Yield: 2.62g, 63%).
Step 2: 2-phenylpent-4-en-1-amine
##STR00100##
[0499] To a stirred solution of 2-phenylpent-4-enenitrile (2.82 g,
17.94 mmol) in dry tetrahydrofuran (60 mL) was added lithium
aluminum hydride (1.362 g, 35.9 mmol) portionwise at 0.degree. C.
The thus obtained pink suspension was allowed to stir at room
temperature for 5 min and then at 60.degree. C. overnight.
Thereupon, water (1.5 mL) was added followed by slow addition of a
mixture of 50% sodium hydroxide (1.5 mL) and water (3 mL) at
0.degree. C. The organic layer was diluted with a mixture of
dichloromethane-2-propanol (7:3), dried over MgSO.sub.4 and
filtered through a celite plug. The filtrate was evaporated to
dryness under vacuum to give a clear oil. The product was purified
by chromatography (dichloromethane-methanol) and isolated as a dark
yellow oil. (Yield:1.13 g, 39%).
Step 3: 4-methyl-N-(2-phenylpent-4-en-1-yl)benzenesulfonamide
##STR00101##
[0501] To a stirred solution of 2-phenylpent-4-en-1-amine (1.13 g,
7.01 mmol) and triethylamine (1.074 mL, 7.71 mmol) in
dichloromethane (35 mL) was added tosyl chloride (1.336 g, 7.01
mmol) portionwise at room temperature. The resulting yellow
solution was allowed to stir at room temperature overnight. The
reaction was then diluted with dichloromethane and quenched with
water. The organic layer was separated, dried over MgSO.sub.4 and
evaporated to dryness under vacuum to give a yellow oil. The
product was purified by chromatography (petroleum ether-ethyl
acetate 1:0, 9:1, 6:1, then 4:1) and isolated as a yellow oil.
(Yield: 1.03 g, 44%).
Step 4: (4-phenyl-1-tosylpyrrolidin-2-yl)methanol
##STR00102##
[0503] 3-Chlorobenzoperoxoic acid (0.676 g, 3.92 mmol) was added
portionwise to a stirred solution of
4-methyl-N-(2-phenylpent-4-enyl)benzenesulfonamide (1.03 g, 3.27
mmol) in dichloromethane (16 mL) at 0.degree. C. The reaction
mixture was allowed to warm up to room temperature and stirred for
2 days. Thereupon, water was added, the organic layer was diluted
with dichloromethane, separated, dried over MgSO.sub.4 and
evaporated to dryness under reduced pressure. The product was
purified by chromatography (petroleum ether-ethyl acetate; 1:1) and
isolated as a clear oil. (Yield: 0.215 g, 20%).
Step 5: (4-phenylpyrrolidin-2-yl)methanol
##STR00103##
[0505] Lithium aluminium hydride (0.223 g, 5.88 mmol) was added
portionwise to a stirred solution of
(4-phenyl-1-tosylpyrrolidin-2-yl)methanol (0.487 g, 1.469 mmol) in
dry terahydrofuran (7 mL) at 0.degree. C. under nitrogen. The thus
obtained grey suspension was allowed to stir at room temperature
overnight, whereupon the reaction was quenched with water (0.3 mL)
followed by dropwise addition of a mixture of 50% NaOH (0.3 mL) and
water (0.6 mL). The mixture was then dried over MgSO.sub.4 and
filtered through a celite plug. The filtrate was evaporated to
dryness under vacuum to give a semisolid on trituration with ethyl
acetate. The solid was suspended in ethyl acetate, filtered off and
the filtrate was evaporated to dryness to leave a clear oil.
(Yield: 0.318 g, 122% (intermediate not purified prior to next
step)).
Step 6: tert-butyl
2-(hydroxymethyl)-4-phenylpyrrolidine-1-carboxylate
##STR00104##
[0507] To a stirred solution of (4-phenylpyrrolidin-2-yl)methanol
(0.260 g, 1.467 mmol) in ethanol (3 mL) was added di-tert-butyl
dicarbonate (0.352 g, 1.614 mmol) at 0.degree. C. The resulting
yellow solution was allowed to stir at room temperature overnight.
The solvent was then evaporated to dryness under vacuum and the
thus obtained mixture was separated by chromatography (petroleum
ether-ethyl acetate (1:0, 3:1, 2:1, then 1:1). The product was
isolated as a clear oil. (Yield: 0.298 g, 73%).
Step 7: tert-butyl 2-formyl-4-phenylpyrrolidine-1-carboxylate
##STR00105##
[0509] Dess-Martin periodinane
(3-oxo-1.lamda..sup.5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl
triacetate) (0.443 g, 1.046 mmol) was added in one portion to a
stirred solution of tert-butyl
2-(hydroxymethyl)-4-phenylpyrrolidine-1-carboxylate (0.290 g, 1.046
mmol) in dichloromethane (13 mL) at room temperature and the
reaction was then stirred for 3 h. Thereupon, the solvent was
evaporated off and the resulting residue was azeotroped with
toluene. The product was purified by chromatography (petroleum
ether-ethyl acetate; 1:0, 4:1, 3:1, 2:1, 1:1) and isolated as a
clear oil. (Yield: 0.234 g, 81%).
Step 8: 4-phenylpyrrolidine-2-carbaldehyde hydrochloride
##STR00106##
[0511] A 2 M solution of HCl (3.34 mL, 6.68 mmol) in diethyl ether
was added to tert-butyl 2-formyl-4-phenylpyrrolidine-1-carboxylate
(0.230 g, 0.835 mmol) at room temperature and the thus obtained
yellow mixture was allowed to stir at room temperature for 3 h. The
solvent was then evaporated off under vacuum to leave a yellow oil.
(Yield: 0.177 g, 100%).
Step 9:
6-phenyl-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione
##STR00107##
[0513] To a stirred solution of 4-phenylpyrrolidine-2-carbaldehyde
hydrochloride (0.177 g, 0.836 mmol) in dimethyl formamide (3.5 mL)
was added potassium thiocyanate (0.163 g, 1.672 mmol) and the thus
obtained yellow solution was allowed to stir at 100.degree. C. for
1 h and 45 min to give a brown solution. The reaction mixture was
allowed to cool to room temperature, and then diluted with water (3
mL) and diethyl ether, respectively. The aqueous layer was
extracted with ethyl acetate (3 times) and the combined organic
layers were washed with water (twice), dried over MgSO.sub.4 and
evaporated to dryness under vacuum to give a brown solid.
Recrystallization from isopropanol afforded a beige solid. (Yield:
24 mg, 12%).
[0514] .sup.1H NMR (DMSO-d6): 11.78 (1H, br s), 7.15-7.45 (5H, m),
6.63 (1H, s), 4.17(1H, dd, J=11.2, 8.1 Hz), 4.08 (1H, quin, J=8.1
Hz), 3.67 (1H, dd, J=11.2, 8.1 Hz), 3.24 (1H, ddd, J=15.0, 7.9, 0.7
Hz), 2.86 (1H, ddd, J=15.4, 8.5, 1.5 Hz).
[0515] .sup.13C NMR (DMSO-d6): 155.9, 141.3, 132.7, 128.7, 127.2,
127.0, 106.7, 50.4, 47.0, 31.2.
Example 50
6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione
##STR00108##
[0517] 2-(3,5-difluorophenyl)acetonitrile was converted to
6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thion-
e by a similar procedure as described for Example 49 and the
product was isolated as a dark beige solid.
[0518] .sup.1H NMR (DMSO-d6): 11.81 (1H, br s), 7.11-7.18 (3H, m),
6.64(1H, m), 4.19(1H, dd, J=11.2, 7.9 Hz), 4.12 (1H, quin, J=8.3
Hz), 3.70 (1H, dd, J=11.2, 8.5 Hz), 3.23 (1H, ddd, J=15.3, 7.9, 0.9
Hz), 2.90 (1H, ddd, J=15.3, 8.9, 1.6 Hz).
[0519] .sup.13C NMR (DMSO-d6): 163.3, 163.2, 161.7, 161.6, 156.0,
145.5, 145.4, 145.4, 132.3, 110.8, 110.8, 110.7, 110.7, 106.8,
102.7, 102.5, 102.3, 49.9, 46.6, 30.8.
Example 51
6-(2,4-Difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione
Step 1:
(E)-N-(2-(2,4-difluorophenyl)-3-(dimethylamino)allylidene)-N-methy-
lmethanaminium hexafluorophosphate(V)
##STR00109##
[0521] Phosphoryl trichloride (8.12 mL, 87 mmol) was added dropwise
to N,N-dimethylformamide (8.32 mL, 107 mmol) at 0.degree. C. to
give a clear viscous solution. The mixture was allowed to warm up
to room temperature and stirred for 1 h before adding a solution of
2-(2,4-difluorophenyl)acetic acid (5 g, 29.0 mmol) in
N,N-dimethylformamide (15 mL). The resulting yellow solution was
allowed to stir at 70.degree. C. overnight. The thus obtained brown
reaction mixture was cooled to room temperature and slowly poured
onto a mixture of ice-water (60 mL) and a solution of potassium
hexafluorophosphate(V) (8.02 g, 43.6 mmol) in water (20 mL). The
resulting yellow precipitate was filtered off, washed with cold
water and dried under vacuum. (Yield: 10 g, 85%).
Step 2: ethyl 4-(2,4-difluorophenyl)-1H-pyrrole-2-carboxylate
##STR00110##
[0523] To a stirred solution of ethyl 2-aminoacetate hydrochloride
(5.45 g, 39.0 mmol) and
(E)-N-(2-(2,4-difluorophenyl)-3-(dimethylamino)allylidene)-N-methylmethan-
aminium hexafluorophosphate(V) (10 g, 26.0 mmol) in
N,N-dimethylformamide (240 mL) was added
1,4-diazabicyclo[2.2.2]octane (7.30 g, 65.1 mmol) at room
temperature and the thus obtained yellow suspension was allowed to
stir at 100.degree. C. overnight. The mixture was then poured onto
ice-water (ca. 400 mL) and allowed to stir at room temperature for
1 h. The resulting precipitate was filtered off, washed with water
to give the product as a brown solid. (Yield: 4.5 g, 65%).
Step 3: 1-tert-butyl 2-ethyl
4-(2,4-difluorophenyl)-1H-pyrrole-1,2-dicarboxylate
##STR00111##
[0525] To a stirred solution of ethyl
4-(2,4-difluorophenyl)-1H-pyrrole-2-carboxylate (4.5 g, 17.91 mmol)
and di-tert-butyl dicarbonate (4.30 g, 19.70 mmol) in acetonitrile
(90 mL) was added N,N-dimethylpyridin-4-amine (0.219 g, 1.791 mmol)
at room temperature. The resulting clear solution was allowed to
stir at room temperature overnight. Thereupon, the reaction mixture
was quenched with water, the organic layer was diluted with
dichloromethane, separated, dried over MgSO.sub.4 and evaporated to
dryness under vacuum to give a brown oil. The product was purified
by chromatography (petroleum ether-ethyl acetate; 1:0, 8:1, then
6:1) and isolated as a yellow oil. (Yield: 5.46 g, 82%).
Step 4: 1-tert-butyl 2-ethyl
4-(2,4-difluorophenyl)pyrrolidine-1,2-dicarboxylate
##STR00112##
[0527] A solution of 1-tert-butyl 2-ethyl
4-(2,4-difluorophenyl)-1H-pyrrole-1,2-dicarboxylate (4.5 g, 12.81
mmol) in ethanol (128 mL) was added to 10% palladium on charcoal
(0.341 g, 0.320 mmol) at room temperature under nitrogen. The
mixture was allowed to stir at 60.degree. C. under 10 bar of
hydrogen for 3h. Thereupon, the mixture was cooled to room
temperature, purged with argon, filtered through a celite plug and
washed with dichloromethane. The filtrate was evaporated to dryness
under vacuum to give a clear oil. (Yield: 5.38g, 93%).
Step 5: (3-(2, 4-difluorophenyl)pyrrolidin-2-yl)methanol
##STR00113##
[0529] To a stirred solution of 1-tert-butyl 2-ethyl
4-(2,4-difluorophenyl)pyrrolidine-1,2-dicarboxylate (5.38 g, 15.14
mmol) and lithium chloride (2.246 g, 53.0 mmol) in a mixture of
methanol (38 mL) and tetrahydrofuran (38 mL) was added sodium
borohydride (2.005 g, 53.0 mmol) at 0.degree. C. The thus obtained
white suspension was allowed to stir at room temperature overnight.
Thereupon, a second crop of lithium chloride (1 g) and sodium
borohydride (1 g) was added and the mixture was allowed to stir for
additional 48 h. Water was then added, whereupon the organic layer
was diluted with dichloromethane, separated, dried over MgSO.sub.4
and evaporated to dryness under vacuum. The product was purified by
chromatography (petroleum ether-ethyl acetate) and then isolated as
a yellow oil. (Yield: 1.96g, 41%).
Step 6: tert-butyl
4-(2,4-difluorophenyl)-2-formylpyrrolidine-1-carboxylate
##STR00114##
[0531] To a stirred solution of tert-butyl
4-(2,4-difluorophenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate
(1.96 g, 6.26 mmol) in dichloromethane (78 mL) was added
Dess-Martin periodinane
(3-oxo-1.lamda..sup.5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl
triacetate) (2.65 g, 6.26 mmol) at room temperature. The thus
obtained pale pink suspension was allowed to stir at room
temperature for 4 h. The solvent was then evaporated off under
vacuum and the product was purified by chromatography (petroleum
ether-ethyl acetate; 1:0, 8:1, 6:1, 4:1, then 2:1). The product was
isolated as a colourless oil. (Yield: 1.5 g, 90%).
Step 7: 4-(2,4-difluorophenyl)pyrrolidine-2-carbaldehyde
hydrochloride
##STR00115##
[0533] A 2 M solution of HCl (19.27 mL, 38.5 mmol) in diethyl ether
was added to tert-butyl
4-(2,4-difluorophenyl)-2-formylpyrrolidine-1-carboxylate (1.5 g,
4.82 mmol) at room temperature and the yellow solution was allowed
to stir at room temperature for 4 h. The solvent was then
evaporated off under vacuum to give the product as a yellow oil.
(Yield: 1.19 g, 100%).
Step 8:
6-(2,4-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H-
)-thione
##STR00116##
[0535] To a stirred solution of
4-(2,4-difluorophenyl)pyrrolidine-2-carbaldehyde hydrochloride
(1.19 g, 4.80 mmol) in N,N-dimethylformamide (24 mL) was added
potassium thiocyanate (0.934 g, 9.61 mmol) at room temperature,
whereupon the resulting brown solution was allowed to stir at
100.degree. C. for 90 min. Thereupon, water was added and the
organic layer was diluted with diethyl ether containing few drops
of ethyl acetate. The organic layer was separated and the aqueous
layer was extracted again. The combined organic layers were washed
with water (three times), dried over MgSO.sub.4 and evaporated to
dryness under vacuum to give a brown semisolid. Recrystallisation
from ethanol afforded the product as a beige solid. (Yield: 0.08g,
6%).
[0536] .sup.1H NMR (DMSO-d6): 11.83 (1H, br s), 7.45 (1H, td,
J=8.7, 6.7 Hz), 7.28 (1H, ddd, J=2.7, 9.4, 11.5 Hz), 7.09 (1H, dt,
J=2.6, 8.6 Hz), 6.64 (1H, s), 4.24 (1H, quin, J=8.0 Hz), 4.15 (1H,
dd, J=11.1, 8.1 Hz), 3.72 (1H, dd, J=11.3, 7.8 Hz), 3.24 (1H, dd,
J=8.2, 15.2 Hz), 2.90 (1H, ddd, J=15.5, 8.3, 1.5 Hz).
[0537] .sup.13C NMR (DMSO-d6): 162.3, 162.2, 161.1, 161, 160.6,
160.5, 159.5, 159.4, 156, 132.2, 129.9, 129.8, 129.8, 129.8, 124.3,
124.3, 124.2, 124.2, 111.8, 111.8, 111.7, 111.7, 106.9, 104.3,
104.2, 104.0, 49.3, 40.1, 30.1.
Example 52
6-(2,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione
##STR00117##
[0539] 2-(2,5-Difluorophenyl)acetic acid was converted to
6-(2,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thion-
e by a similar procedure as described for Example 51 and the
product was isolated as a beige solid.
[0540] .sup.1H NMR (DMSO-d6): 11.83 (1H, br s), 7.30 (2H, m),
7.19(1H, m), 6.65 (1H, s), 4.27(1H, quin, J=8.1 Hz), 4.16 (1H, dd,
J=11.2, 8.2 Hz), 3.75 (1H, dd, J=8.1, 11.2 Hz), 3.24 (1H, dd,
J=15.5, 8.0 Hz), 2.94 (1H, br dd, J=15.3, 8.4 Hz).
[0541] .sup.13C NMR (DMSO-d6): 159, 157.5, 157.2, 156, 155.6,
132.1, 129.8, 129.7, 129.7, 129.6, 117.2, 117.1, 117.0, 117.0,
115.5, 115.5, 115.4, 115.4, 115.4, 115.3, 115.3, 115.2, 106.9,
49.1, 40.5, 29.9.
Example 53
5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]i-
midazole-3(2H)-thione
Step 1:
(2-(aminomethyl)-2-(3,5-difluorophenyl)cyclopropyl)methanol
##STR00118##
[0543] To a stirred solution of 3,5-difluorophenylacetonitrile (3
g, 19.59 mmol) in dry terahydrofuran (30 mL), was added
2-(chloromethyl)oxirane (1.839 mL, 23.51 mmol) at room temperature,
under nitrogen, The reaction was then cooled to 0.degree. C. and 2
M sodium bis(trimethylsilyl)amide in terahydrofuran (17.14 mL, 34.3
mmol) was added, dropwise at 0-5.degree. C. Thereupon, the thus
obtained red mixture was allowed to warm up to room temperature and
stirred for 3 h. The reaction was diluted with dry terahydrofuran
(30 mL), cooled to 0.degree. C., whereupon sodium borohydride (2.96
g, 78 mmol) was added, followed by dropwise addition of boron
trifluoride diethyl etherate (9.93 mL, 78 mmol). The mixture was
allowed to warm up to room temperature and stirred overnight. The
resulting pale yellow suspension was cooled to 0.degree. C. and
carefully quenched with 2 M HCl (58.8 mL, 118 mmol). The
terahydrofuran was then evaporated off and the aqueous phase was
washed with diethyl ether. The pH of the aqueous phase was set to
pH=10 by adding 3 M sodium hydroxide and then extracted with
dichloromethane. The organic phase was dried over MgSO.sub.4,
filtered and evaporated to dryness under vacuum to leave a yellow
oil. (Yield: 3.01 g, 65%).
Step 2: tert-butyl
(1-(3,5-difluorophenyl)-2-(hydroxymethyl)cyclopropyl)methylcarbamate
##STR00119##
[0545] To an ice-cold solution of
(2-(aminomethyl)-2-(3,5-difluorophenyl)cyclopropyl)methanol (3 g,
14.07 mmol) in ethanol (32 mL) was added di-tert-butyl dicarbonate
(3.38 g, 15.48 mmol). The solution was stirred at room temperature
for 4 h and then the solvent was evaporated off under vacuum. The
resulting yellow oil was purified by chromatography
(dichloromethane-methanol). The product was isolated as a pale
yellow oil. (Yield: 3.9 g, 88%).
Step 3: tert-butyl
1-(3,5-difluorophenyl)-4-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate
##STR00120##
[0547] To a stirred solution of oxalyl dichloride (1.194 mL, 13.69
mmol) in dry dichloromethane (33 mL), was added dropwise a solution
of dimethylsulfoxide (1.945 mL, 27.4 mmol) in dry dichloromethane
(6 mL) at -78.degree. C. The reaction mixture was stirred in the
cold for 5 min, and then a solution of tert-butyl
(1-(3,5-difluorophenyl)-2-(hydroxymethyl)cyclopropyl)methylcarbamate
(3.9 g, 12.45 mmol) in dry dichloromethane (12 mL) was added
dropwise. The mixture was stirred at -78.degree. C. for 45 min and
then triethylamine (8.67 mL, 62.2 mmol) was added. The reaction was
allowed to warm up gradually to room temperature and stirred at
room temperature for 2 h. Thereupon, the mixture was washed three
times with water, dried over MgSO.sub.4, filtered and evaporated to
dryness to give a yellow oil. (Yield: 3.96 g, 82%).
Step 4: tert-butyl
4-cyano-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
##STR00121##
[0549] To a stirred solution of tert-butyl
1-(3,5-difluorophenyl)-4-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate
(3.9 g, 12.53 mmol) in dry dichloromethane (260 mL) was added
trimethylsilanecarbonitrile (4.46 mL, 33.4 mmol) at room
temperature under nitrogen. The solution was then cooled to
-78.degree. C. and boron trifluoride etherate (4.62 mL, 36.7 mmol)
was added dropwise. The reaction mixture was stirred in the cold
for 4 h. and then saturated solution of sodium bicarbonate was
added and the mixture was allowed to warm up to room temperature.
The organic phase was separated and aqueous phase was extracted
with dichloromethane. The combined organic phases were dried over
MgSO.sub.4, filtered and evaporated to dryness to leave a pinkish
oil. (Yield: 3.88 g, 77%).
Step 5:
3-(tert-butoxycarbonyl)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]-
hexane-2-carboxylic acid
##STR00122##
[0551] To a stirred solution of tert-butyl
4-cyano-1-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate
(3.6 g, 11.24 mmol) in ethanol (36 mL), was added a solution of 3 M
sodium hydroxide (18.73 mL, 56.2 mmol) at room temperature. The
solution was heated at 80.degree. C. for 3 h. and then was cooled
to room temperature. Thereupon, ethanol was evaporated off and the
aqueous phase was acidified with 2 M HCl solution and then
extracted with ethyl acetate. The organic phase was dried over
MgSO.sub.4, filtered and evaporated to dryness to leave a yellow
solid. (Yield: 2.95 g, 66%).
Step 6: tert-butyl 3-tert-butyl 2-methyl
5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate
##STR00123##
[0553] To a stirred solution of
3-(tert-butoxycarbonyl)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane--
2-carboxylic acid (1.8 g, 5.30 mmol) in N,N-dimethylforamide (18
mL) was added potassium carbonate (2.133 g, 15.44 mmol) followed by
addition of methyl iodide (1.658 mL, 26.5 mmol). The reaction was
stirred at room temperature for 6 h, water was then added and the
mixture was extracted with ethyl acetate. The organic phase was
dried over MgSO.sub.4, filtered and evaporated to dryness. The thus
obtained yellow oil was purified by chromatography (petroleum
ether-ethyl acetate). The product was isolated as a pale yellow
oil. (Yield: 1.36 g, 69%).
Step 7: tert-butyl
1-(3,5-difluorophenyl)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carb-
oxylate
##STR00124##
[0555] To a stirred solution of 3-tert-butyl 2-methyl
5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate
(1.35 g, 3.82 mmol) in a mixture of methanol (10 mL) and dry
tetrahydrofuran (10 mL), was added lithium chloride (0.274 mL,
13.37 mmol) at 0.degree. C. followed by addition of sodium
borohydride (0.506 g, 13.37 mmol). The resulting white suspension
was allowed to warm up to room temperature and stirred overnight.
Water was then added and the mixture was extracted with
dichloromethane. The organic phase was dried over MgSO.sub.4,
filtered and evaporated to dryness to leave the product as a pale
yellow oil. (Yield: 1.23 g, 94%).
Step 8: tert-butyl
1-(3,5-difluorophenyl)-4-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate
##STR00125##
[0557] To a stirred solution of tert-butyl
1-(3,5-difluorophenyl)-4-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carb-
oxylate (1.23 g, 3.78 mmol) in dichloromethane (45 mL) was added,
Dess-Martin periodinane
(3-oxo-1.lamda..sup.5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl
triacetate) (1.603 g, 3.78 mmol) at room temperature and the
reaction was stirred for 24 h. The mixture was then evaporated to
small volume and separated by chromatography (petroleum ether-ethyl
acetate). The product was isolated as a pale yellow oil. (Yield:
0.96 g, 79%).
Step 9:
5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carbaldehyde
hydrochloride
##STR00126##
[0559] 2 M HCl in diethyl ether (10.64 mL, 21.28 mmol) was added to
tert-butyl
difluorophenyl)-4-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate
(0.86g, 2.66 mmol) to give a colourless solution. The solution was
stirred at room temperature for 3 h, whereupon the solvent was
evaporated off and the residues was azeotroped with toluene to
leave the product as a yellow oil. (Yield: 0.690 g, 90%).
Step 10:
5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrol-
o[1,2-c]imidazole-3(2H)-thione
##STR00127##
[0561] To a stirred solution of
5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carbaldehyde
hydrochloride (690 mg, 2.66 mmol) in N,N-dimethylformamide (13 mL)
was added potassium thiocyanate (516 mg, 5.31 mmol), at room
temperature, The solution was then heated at 100.degree. C. for 90
min. Thereupon, the mixture was cooled to room temperature, water
was added and then extracted with diethyl ether. The organic phase
was washed with water, dried over MgSO.sub.4, filtered and
evaporated to dryness to leave a brown oil. Chromatography
(dichloromethane-methanol) followed by recrystallization from
2-propanol afforded the product as a beige solid. (Yield: 0.068 g,
8%).
[0562] .sup.1H NMR (DMSO-d6): 11.75 (1H, br s), 7.12 (3H, m), 6.67
(1H, s), 4.22 (1H, d, J=12.2 Hz), 4.05 (1H, d, J=12.2 Hz), 3.00
(1H, dd, J=8.3, 4.3 Hz), 1.67 (1H, dd, J=8.4, 5.3 Hz), 1.19 (1H, t,
J=4.8 Hz).
[0563] .sup.13C NMR (DMSO-d6): 163.4, 163.3, 161.8, 161.7, 156.8,
144.8, 144.8, 144.7, 134.5, 110.1, 110.1, 110.0, 109.9, 105.9,
102.3, 102.1, 101.9, 50.6, 36.4, 25.3, 23.0.
Example 54
(5aS,6aR)-5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrro-
lo[1,2-c]imidazole-3(2H)-thione
##STR00128##
[0565] 3,5-Difluorophenylacetonitrile and
(R)-2-(chloromethyl)oxirane was converted to
(5aS,6aR)-5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a beige
solid.
[0566] .sup.1H NMR (DMSO-d6): 11.75 (1H, br s), 7.12 (3H, m), 6.67
(1H, s), 4.22 (1H, d, J=12.2 Hz), 4.05 (1H, d, J=12.2 Hz), 3.00
(1H, dd, J=8.3, 4.3 Hz), 1.67 (1H, dd, J=8.4, 5.3 Hz), 1.19 (1H, t,
J=4.8 Hz).
[0567] .sup.13C NMR (DMSO-d6): 163.4, 163.3, 161.8, 161.7, 156.8,
144.9, 144.8, 144.7, 134.5, 110.1, 110.1, 110, 109.9, 105.9, 102.3,
102.1, 101.9, 50.6, 36.4, 25.3, 23.0.
Example 55
5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]i-
midazole-3(2H)-thione
##STR00129##
[0569] 2,5-Difluorophenylacetonitrile and 2-(chloromethyl)oxirane
was converted to
5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]-
imidazole-3(2H)-thione by a similar procedure as described for
Example 53 and the product was isolated as a beige solid.
[0570] .sup.1H NMR (DMSO-d6): 11.77 (1H, br s), 7.30 (2H, m), 7.21
(1H, m), 6.69(1H, s), 4.11 (1H, d, J=12.4 Hz), 3.83 (1H, d, J=12.2
Hz), 2.89 (1H, dd, J=8.3, 4.2 Hz), 1.66 (1H, dd, J=8.4, 5.3 Hz),
1.18 (1H, m).
[0571] .sup.13C NMR (DMSO-d6): 158.8, 158.7, 157.2, 157.1, 156.6,
134.5, 128.6, 128.6, 128.5, 128.4, 117.2, 117.1, 117.0, 117.0,
117.0, 116.8, 116.8, 115.9, 115.9, 115.8, 115.7, 106.2, 51.4, 51.4,
32.7, 22.3, 21.0.
Example 56
(5aS,6aR)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrro-
lo[1,2-c]imidazole-3(2H)-thione
##STR00130##
[0573] 2,5-Difluorophenylacetonitrile and
(R)-2-(chloromethyl)oxirane was converted to
(5aS,6aR)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a beige
solid.
[0574] .sup.1H NMR (DMSO-d6): 11.77 (1H, br s), 7.30 (2H, m), 7.21
(1H, m), 6.69(1H, d, J=2 Hz), 4.11 (1H, d, J=12.4 Hz), 3.83 (1H, d,
J=12.2 Hz), 2.89 (1H, dd, J=8.3, 4.2 Hz), 1.66 (1H, dd, J=8.4, 5.3
Hz), 1.18 (1H, m).
[0575] .sup.13C NMR (DMSO-d6): 158.8, 158.7, 157.2, 157.2, 157.1,
157.1, 156.7, 134.5, 128.6, 128.5, 128.5, 128.4, 117.2, 117.1,
117.0, 117.0, 116.9, 116.8, 116.8, 115.9, 115.9, 115.8, 115.7,
106.1.
Example 57
(5aR,6aS)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrro-
lo[1,2-c]imidazole-3(2H)-thione
##STR00131##
[0577] 2,5-Difluorophenylacetonitrile and
(S)-2-(chloromethyl)oxirane was converted to
(5aR,6aS)-5a-(2,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a beige
solid.
[0578] .sup.1H NMR (DMSO-d6): 11.77 (1H, br s), 7.30 (2H, m), 7.21
(1H, m), 6.69(1H, s), 4.11 (1H, d, J=12.4 Hz), 3.83 (1H, d, J=12.2
Hz), 2.89 (1H, dd, J=8.3, 4.2 Hz), 1.66 (1H, dd, J=8.4, 5.3 Hz),
1.18 (1H, m).
[0579] .sup.13C NMR (DMSO-d6): 158.8, 158.7, 158.7, 157.2, 157.1,
156.6, 134.5, 128.6, 128.6, 128.5, 128.4, 117.2, 117.1, 117.0,
117.0, 117.0, 116.8, 116.8, 115.9, 115.9, 115.8, 115.7, 106.2,
51.4, 51.4, 32.7, 22.3, 21.0.
Example 58
(R)-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-th-
ione
Step 1: (E)-1,3-difluoro-5-(2-nitrovinyl)benzene
##STR00132##
[0581] To a solution of methanol (72 mL), water (36 mL), and 2.5 M
sodium hydroxide (32.4 mL, 81 mmol) was added a solution of
3,5-difluorobenzaldehyde (10 g, 70.4 mmol) and nitromethane (4.36
mL, 81 mmol) in methanol (12.00 mL) dropwise over 30 min at
5.degree. C., while the internal temperature was maintained between
5 and 10.degree. C. with external cooling. The reaction was then
agitated in the cold for an additional 0.5 h, and then a solution
of cc. HCl (11.73 mL, 141 mmol) in water (36 mL) was added in one
portion at 0-10.degree. C. with stirring. The resulting crystals
were collected, washed with water and dried to give the product as
a light yellow powder. (Yield: 7.0 g, 54%).
Step 2: (R)-diethyl
2-(1-(3,5-difluorophenyl)-2-nitroethyl)malonate
##STR00133##
[0583] To a stirred solution of
(E)-1,3-difluoro-5-(2-nitrovinyl)benzene (7.4 g, 40.0 mmol) in dry
tetrahydrofuran (75 mL) was added
4-((S)-hydroxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
(CAS #70877-75-7) (0.620 g, 1.999 mmol) at room temperature with
stirring followed by addition of diethyl malonate (8.65 mL, 56.7
mmol). The mixture was cooled to -5 to -7.degree. C. under inert
atmosphere and stirred for 20 h in the cold. Thereupon, the mixture
was evaporated to dryness under vacuum and the residue was taken up
in dichloromethane (100 mL), washed with 1 M HCl, brine, dried over
MgSO.sub.4 and filtered on a silica pad. The filtrate was
concentrated to 20 mL, and the residue was crystallized on dilution
with petroleum ether (ca. 50 mL). The mixture was further diluted
with petroleum ether (120 mL), and aged at 5-10.degree. C. The
resulting solid was collected, washed with petroleum ether, and
dried to give the product as an off-white powder. (Yield: 9.1 g,
70%).
Step 3: (4R)-ethyl
4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylate
##STR00134##
[0585] To a suspension of (R)-diethyl
2-(1-(3,5-difluorophenyl)-2-nitroethyl)malonate (9 g, 26.1 mmol) in
methanol (150 mL) was added nickel(II) chloride hexahydrate (6.20
g, 26.1 mmol) followed by addition of sodium borohydride (7.89 g,
209 mmol) in portions with ice cooling. The mixture was stirred for
6 h at room temperature, then quenched with ammonium chloride
solution (250 mL), diluted with dichloromethane (150 mL), acidified
with 6 M HCl to pH=2, and stirred for 16 h. Thereupon, the mixture
was extracted with dichloromethane, the organic phase was dried
over MgSO.sub.4 and evaporated to dryness to give the product as a
beige powder. (Yield: 6.87 g, 98%).
Step 4: (4R)-4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylic
acid
##STR00135##
[0587] To a stirred solution of (4R)-ethyl
4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylate (6.85 g, 25.4
mmol) in ethanol (100 mL) was added 1 M sodium hydroxide (30.5 mL,
30.5 mmol). The resulting suspension was stirred for 1 h, the
organics were then removed under vacuum, and the residue was
dissolved in water (250 mL). The product was crystallized on
acidification with 6 M HCl. The resulting crystals were collected,
washed with cold water and dried under vacuum at 50.degree. C. to
give the product as a beige powder Yield: 5.2 g, 21, 85%.
Step 5: (R)-4-(3,5-difluorophenyl)pyrrolidin-2-one
##STR00136##
[0589] A solution of
(4R)-4-(3,5-difluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (5.2
g, 21.56 mmol) in toluene (300 mL) was stirred under reflux for 3
h, whereupon the mixture was evaporated to dryness, Crystallization
from petroleum ether afforded beige powder. Yield: 4.06 g, 96%.
Step 6: (R)-tert-butyl
4-(3,5-difluorophenyl)-2-oxopyrrolidine-1-carboxylate
##STR00137##
[0591] To a stirred solution of
(R)-4-(3,5-difluorophenyl)pyrrolidin-2-one (4.05 g, 20.54 mmol) in
dry dichloromethane (15 mL) was added at room temperature
di-tert-butyl dicarbonate (6.72 g, 30.8 mmol) followed by addition
of N,N-dimethylpyridin-4-amine (2.509 g, 20.54 mmol) and triethyl
amine (2.86 mL, 20.54 mmol). The mixture was then stirred at room
temperature for 3 h, and then concentrated under vacuum.
Chromatography (petroleum ether-ethyl acetate; 4:1) gave an oil
which was crystallized from petroleum ether (60 mL), The product
was isolated as a white powder. Yield: 6.24 g, 88%.
Step 7: (4R)-tert-butyl
4-(3,5-difluorophenyl)-2-hydroxypyrrolidine-1-carboxylate
##STR00138##
[0593] To a stirred solution of (R)-tert-butyl
4-(3,5-difluorophenyl)-2-oxopyrrolidine-1-carboxylate (2 g, 6.73
mmol) in dry diethyl ether (30 mL) was added dropwise 65% RED-Al
(bis(2-methoxyethoxy)aluminum(III) sodium hydride) (1.212 mL, 4.04
mmol) in toluene at 0-5.degree. C. under nitrogen and the mixture
was stirred for 30 min. in the cold. Thereupon, the mixture was
quenched with sodium bicarbonate solution and stirred for 30 min.
The organic phase was dried over MgSO.sub.4, and evaporated to
dryness to give the product as colourless oil. (Yield: 2.07 g,
93%).
Step 8: (4R)-tert-butyl
2-cyano-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate
##STR00139##
[0595] To a stirred solution of (4R)-tert-butyl
4-(3,5-difluorophenyl)-2-hydroxypyrrolidine-1-carboxylate (2 g,
6.68 mmol) in dry dichloromethane (50 mL) was added
trimethylsilanecarbonitrile (1.792 mL, 13.36 mmol) followed by
addition of boron trifluoride diethyl etherate (1.863 mL, 14.70
mmol) at -70.degree. C. The mixture was stirred for 4 h in the
cold, quenched with sodium bicarbonate solution, and then allowed
to warm up with stirring to room temperature. The organic phase was
dried over MgSO.sub.4, filtered and evaporated to dryness under
vacuum. Chromatography (petroleum ether-ethyl acetate; 9:1)
afforded the compound as a colourless oil. (Yield: 1.36 g,
66%).
Step 9:
(4R)-1-(tert-butoxycarbonyl)-4-(3,5-difluorophenyl)pyrrolidine-2-c-
arboxylic acid
##STR00140##
[0597] To a stirred solution of (4R)-tert-butyl
2-cyano-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate (1.35 g,
4.38 mmol) in ethanol (15 mL) was added 3 M sodium hydroxide (7.30
mL, 21.89 mmol) and the solution was gently refluxed (oil bath at
80.degree. C.) for 3 h. Thereupon, ethanol was removed under vacuum
and the residue was diluted with water (10 mL), and then acidified
with 2 M HCl to pH=2 at 10-15.degree. C. The mixture was extracted
with dichloromethane (40 mL), the insoluble materials in both
phases was filtered off, whereupon the organic phase was washed
with brine, dried over MgSO.sub.4 and evaporated to dryness to give
0.89 g of yellowish oil. (Yield: 62%).
Step 10: (4R)-tert-butyl
4-(3,5-difluorophenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate
##STR00141##
[0599] To a stirred solution of
(4R)-1-(tert-butoxycarbonyl)-4-(3,5-difluorophenyl)pyrrolidine-2-carboxyl-
ic acid (0.45 g, 1.375 mmol) in isopropyl acetate (2 mL) was added
sodium borohydride (0.083 g, 2.200 mmol) at 0-5.degree. C. followed
by addition of boron trifluoride diethyl etherate (0.348 mL, 2.75
mmol. The mixture was stirred for 2 h in the cold, then quenched
with 0.5 M sodium hydroxide (9.90 mL, 4.95 mmol), and allowed to
stir at room temperature for 30 min. The organic phase was
separated, dried over MgSO.sub.4, evaporated to dryness to leave an
oil. Purification by chromatography (petroleum ether-EtOAc; 4:1,
then 2:1). The product was isolated as a yellowish oil. (Yield:
0.29 g, 67%).
Step 11: (4R)-tert-butyl
4-(3,5-difluorophenyl)-2-formylpyrrolidine-1-carboxylate
##STR00142##
[0601] To a stirred solution of (4R)-tert-butyl
4-(3,5-difluorophenyl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate
(0.28 g, 0.894 mmol) in dry dichloromethane (8 mL) was added
Dess-Martin periodinane
(3-oxo-1.lamda..sup.5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyltriacetate)
(0.379 g, 0.894 mmol) in one portion to give a clear solution.
Thereupon, the mixture was stirred at room temperature for 3 h,
concentrated to approximately one third and subjected to
chromatography (petroleum ether-ethyl acetate 9:1, then 4:1). The
product was isolated as yellowish oil. (Yield: 0.25 g, 90%).
Step 12:
(R)-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-
-3(5H)-thione
##STR00143##
[0603] A solution of (4R)-tert-butyl
4-(3,5-difluorophenyl)-2-formylpyrrolidine-1-carboxylate (0.24 g,
0.771 mmol) in 2 M HCl (3.08 mL, 6.17 mmol) in diethyl ether was
stirred at room temperature for 16 h. whereupon diethyl ether was
evaporated off under reduced pressure, and the residue dissolved in
a mixture of ethanol (5 mL) and water (5 mL). Thereupon, potassium
thiocyanate (0.082 g, 0.848 mmol) was added followed by addition of
cc. HCl (0.032 mL, 0.385 mmol) and the solution was stirred under
reflux for 5 h. The mixture was then cooled in ice-water bath, the
resulting solid was collected by filtration, washed with water,
isopropanol and petroleum ether, and then dried at 50.degree. C.
under vacuum to give the product as a beige powder. (Yield: 0.12 g,
62%).
[0604] .sup.1H NMR (DMSO-d6): 11.81 (1H, br s), 7.15 (3H, m), 6.65
(1H, s), 4.20(1H, dd, J=11.0, 8.1 Hz), 4.13 (1H, quin, J=8.3 Hz),
3.72 (1H, dd, J=11.2, 8.5 Hz), 3.24 (1H, ddd, J=15.3, 7.9, 0.9 Hz),
2.92 (1H, ddd, J=15.3, 9.0, 1.8 Hz).
[0605] .sup.13C NMR (DMSO-d6): 163.3, 163.2, 161.7, 161.6, 156,
145.5, 145.5, 145.4, 132.3, 110.8, 110.8, 110.7, 110.7, 106.9,
102.7, 102.5, 102.3, 49.9, 46.6, 30.8.
Example 59
(S)-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-th-
ione
##STR00144##
[0607] (E)-1,3-Difluoro-5-(2-nitrovinyl)benzene (using
4-((R)-hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #524-63-0)) was converted to
(S)-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-t-
hione by a similar procedure as described for Example 58 and the
product was isolated as a dark beige powder
[0608] .sup.1H NMR (DMSO-d6): 11.81 (1H, br s), 7.15 (3H, m), 6.65
(1H, s), 4.20 (1H, dd, J=11.0, 8.1 Hz), 4.13 (1H, quin, J=8.3 Hz),
3.72 (1H, dd, J=11.2, 8.5 Hz), 3.24 (1H, ddd, J=15.3, 7.9, 0.9 Hz),
2.92 (1H, ddd, J=15.3, 9.0, 1.8 Hz).
[0609] .sup.13C NMR (DMSO-d6): 163.3, 163.2, 161.7, 161.6, 156,
145.5, 145.5, 145.4, 132.3, 110.9, 110.8, 110.7, 110.7, 106.9,
102.7, 102.5, 102.4, 49.9, 46.6, 30.8.
Example 60
(5aS,6aR)-5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrro-
lo[2,1-c][1,2,4]triazole-3(2H)-thione
Step 1: (1S,5R)-tert-butyl
1-(3,5-difluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate
##STR00145##
[0611] To an ice-cooled stirred solution of chromium (VI) oxide
(2.137 g, 21.37 mmol) in water (3.77 mL) was added dropwise
sulfuric acid (1.125 mL, 21.10 mmol). Thereupon, the obtained
orange solution was added dropwise to an ice-cooled solution of
tert-butyl
(((1S,2R)-1-(3,5-difluorophenyl)-2-(hydroxymethyl)cyclopropyl)methyl)carb-
amate (2.85 g, 9.10 mmol) in acetone (57 mL) (prepared according to
step 1-3 of Example 53 from 2-(3,5-difluorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane). The reaction was stirred in the cold
for 1 h, and then 25 mL of isopropanol was added, followed by
addition of water. The thus obtained dark aqueous phase was
extracted with dichloromethane, whereupon the organic phase was
washed with water and evaporated to dryness to give the product as
a semi-solid mass. Trituration with disopropyl ether afforded the
product as a white powder. (Yield: 1.813 g, 64%).
Step 2:
(1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one
##STR00146##
[0613] To a stirred solution of (1S,5R)-tert-butyl
1-(3,5-difluorophenyl)-4-oxo-3-azabicyclo[3.1.0]hexane-3-carboxylate
(1.8 g, 5.82 mmol) in dichloromethane (50 mL) was added
2,2,2-trifluoroacetic acid (3.59 mL, 46.6 mmol) dropwise. The
reaction was allowed stir at room temperature for 2 h. Thereupon,
the solvent was removed under vacuum, the residue was dissolved in
dichloromethane, washed with potassium carbonate solution and
evaporated to dryness to leave an off-white crystalline product.
Trituration with diethyl ether afforded white crystals. (Yield:
1.135 g, 93%).
Step 3:
(1S,5R)-1-(3,5-difluorophenyl)-4-methoxy-3-azabicyclo[3.1.0]hex-3--
ene
##STR00147##
[0615] To a stirred solution of
(1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexan-2-one (1.0
g, 4.78 mmol) in dry dichloromethane (24 mL) was added
trimethyloxonium tetrafluoroborate (0.714 g, 4.83 mmol) under inert
atmosphere and the solution was stirred at room temperature for 5
h. The thus obtained turbid solution was treated with saturated
aqueous sodium bicarbonate, whereupon the organic phase was washed
again with sodium bicarbonate, dried over MgSO.sub.4, filtered and
evaporated to dryness to give the product as a colourless oil.
(Yield: 1.07 g, 95%).
Step 4: methyl
2-((1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hex-2-en-2-yl)hydraz-
inecarbodithioate
##STR00148##
[0617] To a stirred solution of
(1S,5R)-1-(3,5-difluorophenyl)-4-methoxy-3-azabicyclo[3.1.0]hex-3-ene
(1.07 g, 4.79 mmol) in methanol (10 mL) was added methyl
hydrazinecarbodithioate (0.586 g, 4.79 mmol) in portions. The
solution was stirred at room temperature for 1 h, and then
evaporated to dryness to leave a colourless foam. (Yield: 1.5 g,
90%).
Step 5: methyl
(5aS,6aR)-5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[2,1-c][1,2,4]triazole-3(2H)-thione
##STR00149##
[0619] A stirred solution of methyl
2-((1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hex-2-en-2-yl)hydraz-
inecarbodithioate (1.5 g, 4.79 mmol) in N,N-dimethylformamide (25
mL) was heated at reflux under inert atmosphere for 1 h. The
mixture was then cooled to room temperature, poured onto ice and
stirred for 30 min. The resulting precipitate was filtered off, the
filter cake was washed with water and dissolved in ethyl acetate.
The organic phase was washed with water again, dried over
MgSO.sub.4, filtered and evaporated to dryness. Chromatography
(dichloromethane-methanol; 98:2) followed by trituration with a
mixture of petroleum ether-diethyl ether afforded the product as an
off-white solid. (Yield: 0.104 g, 7%).
[0620] .sup.1H NMR (DMSO-d6): 13.19 (1H, br s), 7.20 (2H, m), 7.15
(1H, tt, J=2.3, 9.3 Hz), 4.25 (1H, dd, J=11.9, 0.7 Hz), 4.09 (1H,
d, J=11.9 Hz), 3.13 (1H, ddd, J=0.8, 4.4, 8.7 Hz), 1.80 (1H, dd,
J=8.7, 5.6 Hz), 1.47 (1H, dd, J=5.6, 4.3 Hz).
[0621] .sup.13C NMR (DMSO-d6): 163.7, 163.3, 163.2, 161.7, 161.6,
157.9, 143.6, 143.6, 143.5, 110.6, 110.6, 110.5, 110.4, 102.7,
102.5, 102.4, 49.1, 36.9, 23.0, 21.0.
Example 61
(S)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3-
(5H)-thione
##STR00150##
[0623] (E)-1,2,4,5-terafluoro-5-(2-nitrovinyl)benzene (using
4-((R)-hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #524-63-0)) was converted to
(S)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole--
3(5H)-thione by a similar procedure as described for Example 59 and
the product was isolated as a dark beige powder.
[0624] .sup.1H NMR (DMSO-d6): 11.86 (1H, br s), 7.86 (1H, m), 6.64
(1H, s), 4.54(1H, quin, J=8.5 Hz), 4.20 (1H, dd, J=11.6, 9.2 Hz),
3.79 (1H, dd, J=11.7, 7.6 Hz), 3.33 (1H, m), 2.97(1H, dd, J=16.0,
7.6 Hz).
[0625] .sup.13C NMR (DMSO-d6): 155.9, 146.3, 145.3, 144.7, 143.6,
132.0, 120.5, 120.4, 120.3, 106.7, 105.9, 105.7, 105.6, 48.4, 35.8,
29.4.
Example 62
(R)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3-
(5H)-thione
##STR00151##
[0627] (E)-1,2,4,5-terafluoro-5-(2-nitrovinyl)benzene (using
4-((S)-hydroxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #70877-75-7)) was converted to
(R)-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole--
3(5H)-thione by a similar procedure as described for Example 58 and
the product was isolated as a beige powder.
[0628] .sup.1H NMR (DMSO-d6): 11.86 (1H, br s), 7.85 (1H, tt,
J=10.4, 7.6 Hz), 6.64 (1H, m), 4.54 (1H, m), 4.20 (1H, dd, J=11.7,
9.2 Hz), 3.79 (1H, dd, J=11.7, 7.6 Hz), 3.33(1H, m), 2.97 (1H, ddd,
J=1.2, 8.0, 16 Hz).
[0629] .sup.13C NMR (DMSO-d6): 155.9, 146.4, 146.3, 146.3, 145.3,
145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 132, 120.5, 106.7, 105.9,
105.7, 105.6, 48.4, 35.8, 29.4.
Example 63
(5aS,6aR)-5a-(2,3,5-trifluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]py-
rrolo[1,2-c]imidazole-3(2H)-thione
##STR00152##
[0631] 2,3,5-Trifluorophenylacetonitrile and
(R)-2-(chloromethyl)oxirane was converted to
(5aS,6aR)-5a-(2,3,5-trifluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]p-
yrrolo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a beige
solid.
[0632] .sup.1H NMR (DMSO-d6): 11.78 (1H, br s), 7.50 (1H, m),
7.19(1H, m), 6.70(1H, d, J=2.1 Hz), 4.12 (1H, d, J=12.0 Hz), 3.88
(1H, d, J=12.0 Hz), 2.95 (1H, dd, J=8.5, 4.3 Hz), 1.67(1H, dd,
J=8.4, 5.5 Hz), 1.22 (1H, m).
[0633] .sup.13C NMR (DMSO-d6): 157.8, 157.8, 156.7, 156.2, 156.2,
150.5, 150.4, 150.3, 148.9, 148.8, 148.7, 147.3, 147.2, 147.2,
147.2, 145.7, 145.6, 145.6, 145.5, 134.3, 130.2, 130.1, 130.0,
112.3, 112.2, 106.3, 105.3, 105.2, 105.1, 105.0, 51.2, 51.2, 32.6,
32.5, 22.5, 21.1.
Example 64
(5aS,6aR)-5a-(2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrro-
lo[1,2-c]imidazole-3(2H)-thione
##STR00153##
[0635] 2,6-Difluorophenylacetonitrile and
(R)-2-(chloromethyl)oxirane was converted to
(5aS,6aR)-5a-(2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a beige
solid.
[0636] .sup.1H NMR (DMSO-d6): 11.78 (1H, br s), 7.43 (1H, m), 7.13
(2H, m), 6.70 (1H, s), 4.05 (1H, d, J=12.2 Hz), 3.70 (1H, d, J=12.2
Hz), 2.71 (1H, dd, J=8.3, 4.3 Hz), 1.65 (1H, dd, J=8.2, 5.6 Hz),
1.28 (1H, t, J=4.9 Hz).
[0637] .sup.13C NMR (DMSO-d6): 162.7, 162.6, 161, 161, 156.6,
134.6, 130.5, 130.4, 130.3, 115.2, 115.1, 115.0, 112, 112.0, 111.8,
111.8, 106.4, 51.6, 26.4, 21.7, 21.4.
Example 65
(5aR,6aS)-5a-(2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrro-
lo[1,2-c]imidazole-3(2H)-thione
##STR00154##
[0639] 2,6-Difluorophenylacetonitrile and
(S)-2-(chloromethyl)oxirane was converted to (5aR,6aS)-5a-(2,
6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,2-c]imidaz-
ole-3 (2H)-thione by a similar procedure as described for Example
53 and the product was isolated as a beige solid.
[0640] .sup.1H NMR (DMSO-d6): 11.78 (1H, br s), 7.43 (1H, m), 7.13
(2H, m), 6.70 (1H, s), 4.05 (1H, d, J=12.2 Hz), 3.70 (1H, d, J=12.2
Hz), 2.71 (1H, dd, J=8.3, 4.3 Hz), 1.65 (1H, dd, J=8.2, 5.6 Hz),
1.28 (1H, t, J=4.9 Hz).
[0641] .sup.13C NMR (DMSO-d6): 162.7, 162.6, 161, 161, 156.6,
134.6, 130.5, 130.4, 130.3, 115.2, 115.1, 115, 112, 112, 111.9,
111.8, 106.4, 51.6, 26.4, 21.7, 21.4.
Example 66
(5aS,6aR)-5a-(2,3-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrro-
lo[1,2-c]imidazole-3(2H)-thione
##STR00155##
[0643] 2,3-Difluorophenylacetonitrile and
(R)-2-(chloromethyl)oxirane was converted to
(5aS,6aR)-5a-(2,3-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a light
yellow solid.
[0644] .sup.1H NMR (DMSO-d6): 11.77 (1H, br s), 7.39 (1H, m), 7.23
(1H, m), 7.20 (1H, m), 6.70 (1H, d, J=2.2 Hz), 4.12 (1H, d, J=12.2
Hz), 3.85 (1H, d, J=12.2 Hz), 2.87 (1H, dd, J=8.4, 4.3 Hz),
1.65(1H, dd, J=8.4, 5.4 Hz), 1.21 (1H, t, J=4.8 Hz).
[0645] .sup.13C NMR (DMSO-d6): 156.7, 150.7, 150.6, 150.4, 150.3,
149, 148.9, 148.7, 148.6, 134.5, 129.1, 129.1, 125.6, 124.9, 124.9,
124.9, 124.8, 116.9, 116.8, 106.2, 51.5, 51.5, 32.5, 32.5, 22.1,
20.9.
Example 67
(5aR,6aS)-5a-(2,3-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrro-
lo[1,2-c]imidazole-3(2H)-thione
##STR00156##
[0647] 2,3-Difluorophenylacetonitrile and
(S)-2-(chloromethyl)oxirane was converted to
(5aR,6aS)-5a-(2,3-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a beige
solid.
[0648] .sup.1H NMR (DMSO-d6): 11.77 (1H, br s), 7.39 (1H, m), 7.23
(1H, m), 7.20 (1H, m), 6.70 (1H, d, J=2.2 Hz), 4.12 (1H, d, J=12.2
Hz), 3.85 (1H, d, J=12.2 Hz), 2.87 (1H, dd, J=8.4, 4.3 Hz), 1.65
(1H, dd, J=8.4, 5.4 Hz), 1.21 (1H, t, J=4.8 Hz).
[0649] .sup.13C NMR (DMSO-d6): 156.7, 150.6, 150.6, 150.4, 150.3,
149, 148.9, 148.7, 148.6, 134.5, 129.1, 129.1, 125.6, 124.9, 124.8,
124.8, 124.8, 116.9, 116.7, 106.2, 51.5, 51.5, 32.5, 32.4, 22.1,
20.9.
Example 68
(5aS,6aR)-5a-(2,3,6-trifluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]py-
rrolo[1,2-c]imidazole-3(2H)-thione
##STR00157##
[0651] 2,3,6-Trifluorophenylacetonitrile and
(R)-2-(chloromethyl)oxirane was converted to
(5aS,6aR)-5a-(2,3,6-trifluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]p-
yrrolo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a light
beige solid.
[0652] .sup.1H NMR (DMSO-d6): 11.79 (1H, br s), 7.50 (1H, m, J=9.4,
5.0 Hz), 7.17 (1H, m), 6.71 (1H, d, J=2.2 Hz), 4.06 (1H, d, J=12.2
Hz), 3.76 (1H, d, J=12.2 Hz), 2.77 (1H, dd, J=8.3, 4.3 Hz), 1.69
(1H, dd, J=8.2, 5.6 Hz), 1.31 (1H, t, J=5.0 Hz).
[0653] .sup.13C NMR (DMSO-d6): 158.1, 158.1, 156.6, 156.5, 156.5,
150.2, 150.2, 150.1, 150.1, 148.6, 148.5, 148.5, 148.4, 147.4,
147.3, 145.8, 145.7, 134.3, 117.2, 117.2, 117.2, 117.1, 117.1,
117.1, 117.0, 117.0, 111.7, 111.6, 111.6, 111.6, 111.5, 111.5,
111.5, 111.4, 106.5, 51.4, 26.5, 21.5, 21.3.
Example 69
(5aR,6aS)-5a-(2,3,6-trifluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]py-
rrolo[1,2-c]imidazole-3(2H)-thione
##STR00158##
[0655] 2,3,6-Trifluorophenylacetonitrile and
(S)-2-(chloromethyl)oxirane was converted to
(5aR,6aS)-5a-(2,3,6-trifluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]p-
yrrolo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a beige
solid.
[0656] .sup.1H NMR (DMSO-d6): 11.79 (1H, br s), 7.50 (1H, m, J=9.4,
5.0 Hz), 7.17 (1H, m), 6.71 (1H, d, J=2.2 Hz), 4.06 (1H, d, J=12.2
Hz), 3.76 (1H, d, J=12.2 Hz), 2.77 (1H, dd, J=8.3, 4.3 Hz), 1.69
(1H, dd, J=8.2, 5.6 Hz), 1.31 (1H, t, J=5.0 Hz).
[0657] .sup.13C NMR (DMSO-d6): 158.1, 156.6, 156.5, 150.2, 150.2,
150.1, 150.1, 148.6, 148.5, 148.5, 148.4, 147.3, 147.3, 145.8,
145.6, 134.3, 117.2, 117.2, 117.1, 117.1, 117.0, 117.0, 117.0,
111.6, 111.4, 106.5, 51.3, 26.5, 21.5, 21.3.
Example 70
(5aS,6aR)-5a-(2,4-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrro-
lo[1,2-c]imidazole-3(2H)-thione
##STR00159##
[0659] 2,4-Difluorophenylacetonitrile and
(R)-2-(chloromethyl)oxirane was converted to
(5aS,6aR)-5a-(2,4-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a beige
solid.
[0660] .sup.1H NMR (DMSO-d6): 11.76 (1H, br s), 7.47 (1H, td,
J=8.7, 6.6 Hz), 7.29 (1H, ddd, J=10.9, 9.2, 2.6 Hz), 7.08 (1H, tdd,
J=1.0, 2.8, 8.6 Hz), 6.68 (1H, d, J=2.2 Hz), 4.08 (1H, d, J=12.0
Hz), 3.77 (1H, d, J=12.2 Hz), 2.77 (1H, dd, J=8.3, 4.2 Hz), 1.62
(1H, dd, J=8.3, 5.4 Hz), 1.15 (1H, t, J=4.8 Hz).
[0661] .sup.13C NMR (DMSO-d6): 162.7, 162.6, 162.6, 162.6, 161.1,
161, 161, 160.9, 156.6, 134.7, 131.8, 131.8, 131.8, 131.7, 123.1,
123, 123, 122.9, 111.6, 111.5, 111.4, 111.4, 106.1, 104.4, 104.2,
104, 51.7, 32.2, 21.8, 20.7.
Example 71
(5aS,6aR)-5a-(3,4-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrro-
lo[1,2-c]imidazole-3(2H)-thione
##STR00160##
[0663] 3,4-Difluorophenylacetonitrile and
(R)-2-(chloromethyl)oxirane was converted to
(5aS,6aR)-5a-(3,4-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrr-
olo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a beige
solid.
[0664] .sup.1H NMR (DMSO-d6): 11.74 (1H, br s), 7.48 (1H, ddd,
J=12.1, 7.7, 2.1 Hz), 7.39 (1H, dt, J=10.5, 8.7 Hz), 7.21 (1H, m),
6.66 (1H, s), 4.20 (1H, d, J=12.2 Hz), 3.99 (1H, d, J=12.2 Hz),
2.89 (1H, dd, J=8.3, 4.2 Hz), 1.64(1H, dd, J=8.2, 5.3 Hz), 1.13
(1H, t, J=4.8 Hz).
[0665] .sup.13C NMR (DMSO-d6): 156.7, 150.2, 150.1, 149.2, 149.1,
148.6, 148.5, 147.6, 147.5, 137.9, 137.9, 137.8, 137.8, 134.8,
123.9, 123.9, 123.8, 123.8, 117.5, 117.4, 116.4, 116.3, 105.9,
51.2, 36.1, 24.4.
Example 72
(5aS,6aR)-5a-(2,4,5-trifluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]py-
rrolo[1,2-c]imidazole-3(2H)-thione
##STR00161##
[0667] 2,4,5-Trifluorophenylacetonitrile and
(R)-2-(chloromethyl)oxirane was converted to
(5aS,6aR)-5a-(2,4,5-trifluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]p-
yrrolo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a beige
solid.
[0668] .sup.1H NMR (DMSO-d6): 11.76 (1H, br s), 7.59 (2H, m), 6.69
(1H, d, J=2.1 Hz), 4.08 (1H, d, J=12.0 Hz), 3.81 (1H, d, J=12.0
Hz), 2.86 (1H, dd, J=8.3, 4.2 Hz), 1.65 (1H, dd, J=8.4, 5.4 Hz),
1.17 (1H, t, J=4.8 Hz).
[0669] .sup.13C NMR (DMSO-d6): 157.9, 157.8, 156.6, 156.2, 156.2,
149.5, 149.4, 149.4, 147.9, 147.8, 147.7, 146.6, 146.6, 145.0,
145.0, 134.5, 123.8, 123.8, 123.8, 123.7, 118.7, 118.7, 118.6,
118.6, 106.4, 106.3, 106.2, 106.1, 51.5, 51.4, 32.2, 22.2,
21.0.
Example 73
(5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]-
pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00162##
[0671] 2-(3-Chloro-5-fluorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane was converted to
(5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4-
]pyrrolo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a beige
solid.
[0672] .sup.1H NMR (DMSO-d6): 11.74 (1H, br s), 7.31 (2H, m), 7.26
(1H, ddd, J=1.7, 2.2, 10.1 Hz), 6.67 (1H, d, J=2.2 Hz), 4.23 (1H,
d, J=12.2 Hz), 4.04 (1H, d, J=12.0 Hz), 3.01 (1H, dd, J=8.4, 4.3
Hz), 1.67(1H, dd, J=8.4, 5.3 Hz), 1.17(1H, dd, J=4.4, 5.2 Hz).
[0673] .sup.13C NMR (DMSO-d6): 163.1, 161.4, 156.8, 144.8, 144.7,
134.5, 134.2, 134.1, 123.1, 123.1, 114.3, 114.2, 113, 112.8, 105.9,
50.7, 36.3, 36.3, 25.1, 22.8.
Example 74
(5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]-
pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00163##
[0675] 2-(5-Chloro-2-fluorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane was converted to
(5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4-
]pyrrolo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a light
yellow solid.
[0676] .sup.1H NMR (DMSO-d6): 11.76 (1H, br s), 7.49 (1H, dd,
J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.7, 4.3, 2.8 Hz), 7.30 (1H, dd,
J=9.9, 8.9 Hz), 6.69 (1H, s), 4.10 (1H, d, J=12.0 Hz), 3.81 (1H, d,
J=12.2 Hz), 2.89 (1H, dd, J=8.3, 4.2 Hz), 1.67(1H, dd, J=8.4, 5.4
Hz), 1.17(1H, t, J=4.8 Hz).
[0677] .sup.13C NMR (DMSO-d6): 161.3, 159.7, 156.6, 134.6, 130.2,
130.1, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 117.6, 117.4,
106.2, 51.5, 51.5, 32.6, 22.1, 20.9.
Example 75
(5aS,6aR)-5a-(2-chloro-5-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]-
pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00164##
[0679] 2-(2-Chloro-5-fluorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane was converted to
(5aS,6aR)-5a-(2-chloro-5-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4-
]pyrrolo[1,2-c]imidazole-3(2H)-thione by a similar procedure as
described for Example 53 and the product was isolated as a light
yellow solid.
[0680] .sup.1H NMR (DMSO-d6): 11.76 (1H, br s), 7.56 (1H, dd,
J=8.8, 5.1 Hz), 7.39 (1H, dd, J=9.2, 3.1 Hz), 7.24 (1H, td, J=8.5,
3.1 Hz), 6.69 (1H, d, J=2.2 Hz), 4.08 (1H, d, J=12.2 Hz), 3.76 (1H,
d, J=12.0 Hz), 2.77 (1H, dd, J=8.4, 4.3 Hz), 1.69 (1H, dd, J=8.4,
5.4 Hz), 1.20(1H, dd, J=5.3, 4.4 Hz).
[0681] .sup.13C NMR (DMSO-d6): 161.5, 159.9, 156.5, 139.2, 139.1,
134.9, 131.2, 131.2, 130.4, 130.4, 118.9, 118.8, 116.6, 116.4,
106.2, 51.2, 36.4, 22.1, 21.8.
Example 76
(5aS,6aR)-5a-(3,5-difluorophenyl)-2-methyl-5,5a,6,6a-tetrahydrocyclopropa[-
3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
Step 1:
(5a5,6aR)-5a-(3,5-difluorophenyl)-1-hydroxy-2-methylhexahydrocyclo-
propa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00165##
[0683] To a solution of
(1R,5S)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carbaldehyde
hydrochloride (analogous to Example 53 step 10) (0,460 g, 1,771
mmol) in dichloromethane (4.4 mL) was added isothiocyanatomethane
(0.155 g, 2.126 mmol) and triethylamine (0.299 mL, 2.126 mmol). The
reaction mixture was stirred at room temperature for 24 h.
Thereupon, the mixture was quenched with water and extracted with
dichloromethane. The organic phase was dried over MgSO.sub.4,
filtered and evaporated to dryness. Chromatography (ethyl
acetate-petroleum ether; 1:6) afforded the product as a brown
solid. (Yield: 0.129 g, 29%).
Step 2:
(5aS,6aR)-5a-(3,5-difluorophenyl)-2-methyl-5,5a,6,6a-tetrahydrocyc-
lopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00166##
[0685] To a stirred solution of
(5aS,6aR)-5a-(3,5-difluorophenyl)-1-hydroxy-2-methylhexahydrocyclopropa[3-
,4]pyrrolo[1,2-c]imidazole-3(2H)-thione) (0.095 g, 0.321 mmol) in a
mixture of ethanol (0.801 mL) and water (0.801 mL) was added 6 M
HCl (0.107 mL, 0.641 mmol). The reaction mixture was heated at
reflux for 2 h. Thereupon, the mixture was cooled down to room
temperature, and ethanol was removed under vacuum. The residue was
extracted with dichloromethane, whereupon the organic phase was
dried over MgSO.sub.4, filtrated, concentrated under reduced
pressure to give a brown solid which was purified by chromatography
(ethyl acetate-petroleum ether; 1:1). The product was isolated as
brown solid. (Yield: 0.067 g, 54%).
[0686] .sup.1H NMR (CDCl.sub.3): 6.78 (2H, m), 6.74 (1H, m), 6.44
(1H, s), 4.31 (1H, d, J=12.2 Hz), 4.20 (1H, d, J=12.3 Hz), 3.57
(3H, s), 2.62 (1H, dd, J=8.3, 4.0 Hz), 1.69 (1H, dd, J=8.2, 5.6
Hz), 1.18(1H, dd, J=5.4, 4.3 Hz).
[0687] .sup.13C NMR (CDCl.sub.3): 164.1, 164, 162.4, 162.3, 158,
143.3, 143.2, 143.1, 133.3, 110.3, 110.2, 110.1, 110.1, 109.7,
103.1, 103, 102.8, 52.7, 36.2, 34.8, 24.2, 23.2.
Example 77
(5aS,6aR)-2-cyclopropyl-5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclop-
ropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00167##
[0689]
(1R,5S)-5-(3,5-Difluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carbalde-
hyde hydrochloride was converted to
(5aS,6aR)-2-cyclopropyl-5a-(3,5-difluorophenyl)-5,5a,6,6a-tetrahydrocyclo-
propa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione by a similar
procedure as described for Example 76 and the product was isolated
as a brown solid.
[0690] .sup.1H NMR (DMSO-d6): 7.12 (3H, m), 6.79 (1H, s), 4.25 (1H,
d, J=12.2 Hz), 4.08 (1H, d, J=12.2 Hz), 3.37 (1H, m), 3.00 (1H, dd,
J=8.4, 4.3 Hz), 1.68 (1H, dd, J=8.4, 5.3 Hz), 1.20 (1H, t, J=4.8
Hz), 0.93 (2H, m), 0.86 (2H, m).
[0691] .sup.13C NMR (DMSO-d6): 163.4, 163.3, 161.7, 161.7, 158.7,
144.7, 144.6, 144.6, 132.8, 110.2, 110.2, 110.1, 110.0, 107.6,
102.3, 102.2, 102.0, 51.4, 35.8, 35.8, 29.5, 25.1, 23.0, 6.4,
6.4.
Example 78
(5aS,6aR)-5a-(2,5-difluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[-
3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00168##
[0693] Compound was prepared in an analogous manner to Example 80
from
(5S)-3-(tert-butoxycarbonyl)-5-(2,5-difluorophenyl)-3-azabicyclo[3.1.0]he-
xane-2-carboxylic acid and methylmagnesium iodide and isolated as a
yellow solid.
[0694] .sup.1H NMR (DMSO-d6): 11.66 (1H, br s), 7.28 (2H, m), 7.20
(1H, m), 4.06 (1H, d, J=12.0 Hz), 3.78 (1H, d, J=12.0 Hz), 2.86
(1H, dd, J=8.2, 4.3 Hz), 2.09 (1H, m), 2.04 (3H, s), 1.63 (1H, dd,
J=8.1, 5.4 Hz), 1.13 (1H, t, J=4.8 Hz).
[0695] .sup.13C NMR (DMSO-d6): 158.8, 158.7, 157.2, 157.1, 155.7,
130.3, 128.8, 128.8, 128.8, 128.7, 128.6, 117.2, 117.1, 117.0,
116.9, 116.8, 115.9, 115.8, 115.7, 115.7, 114.8, 51.5, 32.5, 22.4,
20.3, 9.4.
Example 79
(5aS,6aR)-5a-(3,5-difluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopropa[-
3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00169##
[0697] Compound was prepared in an analogous manner to Example 80
from
(5S)-3-(tert-butoxycarbonyl)-5-(3,5-difluorophenyl)-3-azabicyclo[3.1.0]he-
xane-2-carboxylic acid and methylmagnesium iodide and isolated as a
yellow solid.
[0698] .sup.1H NAIR (DMSO-d6): 1.63 (1H, br s), 7.10 (3H, m), 4.17
(1H, d, J=12.0 Hz), 4.00 (1H, d, J=12.2 Hz), 2.97 (1H, dd, J=8.3,
4.3 Hz), 2.03 (3H, s), 1.65 (1H, dd, J=8.2, 5.1 Hz), 1.15(1H,
m).
[0699] .sup.13C NMR (DMSO-d6): 163.4, 163.3, 161.8, 161.7, 156,
145, 130.2, 114.5, 110, 110, 109.9, 109.9, 102.1, 50.7, 36.1, 25.4,
22.4, 9.4.
Example 80
(S)-1-butyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole--
3(5H)-thione
Step 1: (4S)-tert-butyl
4-(3,5-difluorophenyl)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxyl-
ate
##STR00170##
[0701] To a solution of
(4S)-1-(tert-butoxycarbonyl)-4-(3,5-difluorophenyl)pyrrolidine-2-carboxyl-
ic acid (analogous to Example 58 step 9) (0.982 g, 3 mmol) in dry
dichloromethane (10 mL) was added di(1H-imidazol-1-yl)methanone
(0.584 g, 3.60 mmol) in portions at room temperature and the
mixture was stirred for 30 min. Thereupon,
N,O-dimethylhydroxylamine hydrochloride (0.351 g, 3.60 mmol) was
added and the stirring was continued at room temperature for 40 h.
The reaction was then washed with water, the organic phase was
dried over MgSO.sub.4 and concentrated under vacuum. Chromatography
(petroleum ether-ethyl acetate; 2:1) afforded the product as an
off-white solid. (Yield: 0.92 g, 83%).
Step 2: tert-butyl
(4S)-4-(3,5-difluorophenyl)-2-pentanoylpyrrolidine-1-carboxylate
##STR00171##
[0703] To a solution of (4S)-tert-butyl
4-(3,5-difluorophenyl)-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxyl-
ate (0.40 g, 1.08 mmol) in dry tetrahydrofuran (2 mL) was added 2 M
butylmagnesium bromide (1.62 mL, 3.24 mmol) at 0-5.degree. C. under
nitrogen. The mixture was allowed to warm up to room temperature
and stirred for 3 h. Thereupon, the mixture was poured onto 1 M HCl
and then extracted with diethyl ether. The organic phase was washed
with brine, dried over MgSO.sub.4, and evaporated to dryness.
Chromatography (petroleum ether-ethyl acetate; 9:1) afforded the
product as a colourless oil. (Yield: 0.2 g, 50%).
Step 3:
(S)-1-butyl-6-(3,5-difluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]im-
idazole-3(5H)-thione
##STR00172##
[0705] A mixture of (4S)-tert-butyl
4-(3,5-difluorophenyl)-2-pentanoylpyrrolidine-1-carboxylate (0.19
g, 0.517 mmol) and 4 M HCl (2.59 mL, 10.34 mmol) in dioxane was
stirred at room temperature overnight. The mixture was then cooled
to room temperature and evaporated to dryness. The thus obtained
oily residue was dissolved in a mixture of ethanol (2 mL) and water
(2 mL), followed by addition of potassium thiocyanate (0.055 g,
0.569 mmol) and 6 M HCl (0.043 mL, 0.259 mmol). The mixture was
stirred under reflux for 1 h, then stirred at room temperature for
30 min. The obtained solid was collected by filtration, washed with
a mixture of ethanol water (1:1) and dried under vacuum at
50.degree. C. to give the product as a light beige powder. (Yield:
0.12 g, 75%).
[0706] .sup.1H NMR (DMSO-d6): 11.71 (1H, s), 7.13 (3H, m), 4.14
(1H, dd, J=11.2, 7.9 Hz), 4.07 (1H, quin, J=8.1 Hz), 3.67 (1H, dd,
J=11.1, 8.3 Hz), 3.20 (1H, dd, J=15.0, 7.8 Hz), 2.84 (1H, dd,
J=15.1, 8.8 Hz), 2.35 (2H, t, J=7.5 Hz), 1.50 (2H, m), 1.26 (2H,
m), 0.86(3H, t, J=7.4 Hz).
[0707] .sup.13C NMR (DMSO-d6): 163.3, 163.2, 161.7, 161.6, 155.1,
145.8, 145.7, 145.6, 127.6, 120, 110.8, 110.7, 110.6, 110.6, 102.6,
102.5, 102.3, 49.9, 46.5, 30.4, 29.8, 23.6, 21.5, 13.6.
Example 81
6-cyclohexyl-6,7-dihydro-2H-pyrrolo[1,2-c]imidazole-3(5H)-thione
##STR00173##
[0709] Compound was prepared in an analogous manner to Example 58
from diethyl 2-(1-cyclohexyl-2-nitroethyl)malonate (Liu, Jin-ming;
Wang, Xin; Ge, Ze-mei; Sun, Qi; Cheng, Tie-ming; Li, Run-tao
Tetrahedron (2011), 67(3), 636-640) and isolated as a beige
powder.
[0710] .sup.1H NMR (DMSO-d6): 11.68 (1H, br s), 6.52 (1H, s), 3.84
(1H, dd, J=11.3, 7.9 Hz), 3.33 (1H, dd, J=9.0, 11.5 Hz), 2.86 (1H,
ddd, J=0.8, 7.8, 15.1 Hz), 2.57 (1H, m), 2.47 (1H, m), 1.65 (5H,
m), 1.43(1H, m), 1.18(3H, m), 0.96 (2H, m).
[0711] .sup.13C NMR (DMSO-d6): 155.6, 133.2, 106.3, 48.4, 47.8, 41,
30.7, 30.4, 27.5, 25.9, 25.5.
Example 82
(S)-6-(2,3,5-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-
e-3-thione
##STR00174##
[0713] Compound was prepared in an analogous manner to Example 59
from (E)-1,2,5-trifluoro-3-(2-nitrovinyl)benzene using
4-((R)-hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst CAS #524-63-0) and isolated as a beige powder.
[0714] .sup.1H NMR (DMSO-d6): 11.84 (1H, br s), 7.48 (1H, m), 7.21
(1H, m), 6.65 (1H, m), 4.33 (1H, quin, J=8.2 Hz), 4.17 (1H, dd,
J=11.3, 8.1 Hz), 3.77 (1H, dd, J=11.4, 8.1 Hz), 3.26 (1H, ddd,
J=15.4, 8.2, 0.9 Hz), 2.94 (1H, ddd, J=15.4, 8.5, 1.5 Hz).
[0715] .sup.13C NMR (DMSO-d6): 158.1, 158.1, 158.0, 158.0, 156.5,
156.5, 156.4, 156.4, 156.1, 150.6, 150.5, 150.4, 148.9, 148.8,
148.7, 145.7, 145.7, 145.6, 145.6, 144.1, 144.1, 144.0, 144.0,
131.9, 131.5, 131.4, 131.4, 131.3, 110.7, 110.5, 107.0, 104.9,
104.7, 104.7, 104.5, 49.0, 40.3, 30.0.
Example 83
(R)-6-(2,3,5-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-
e-3-thione
##STR00175##
[0717] Compound was prepared in an analogous manner to Example 58
from (E)-1,2,5-trifluoro-3-(2-nitrovinyl)benzene using
4-((S)-hydroxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #70877-75-7) and isolated as a beige powder.
[0718] .sup.1H NMR (DMSO-d6): 11.84 (1H, br s), 7.48 (1H, m), 7.21
(1H, m), 6.65 (1H, m), 4.33 (1H, quin, J=8.2 Hz), 4.17 (1H, dd,
J=11.3, 8.1 Hz), 3.77 (1H, dd, J=11.4, 8.1 Hz), 3.26 (1H, ddd,
J=15.4, 8.2, 0.9 Hz), 2.94 (1H, ddd, J=15.4, 8.5, 1.5 Hz).
[0719] .sup.13C NMR (DMSO-d6): 158.1, 158.1, 158.0, 158.0, 156.5,
156.5, 156.4, 156.4, 156.1, 150.6, 150.5, 150.4, 148.9, 148.8,
148.7, 145.7, 145.7, 145.6, 145.6, 144.1, 144.1, 144.0, 144.0,
131.9, 131.5, 131.4, 131.4, 131.3, 110.7, 110.5, 107.0, 104.9,
104.7, 104.7, 104.5, 49.1, 40.3, 30.0.
Example 84
(S)-6-(2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-
-thione
##STR00176##
[0721] Compound was prepared in an analogous manner to Example 59
from (E)-1,3-difluoro-2-(2-nitrovinyl)benzene using
4-((R)-hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #524-63-0) and isolated as a greenish powder.
[0722] .sup.1H NMR (DMSO-d6): 11.84 (1H, br s), 7.41 (1H, m), 7.13
(2H, m), 6.63 (1H, m), 4.47 (1H, quin, J=8.7 Hz), 4.17 (1H, dd,
J=10.8, 9.8 Hz), 3.73 (1H, dd, J=11.4, 8.2 Hz), 3.29 (1H, dd,
J=15.8, 9.3 Hz), 2.92 (1H, dd, J=15.8, 8.4 Hz).
[0723] .sup.13C NMR (DMSO-d6): 161.6, 161.6, 160.0, 159.9, 155.9,
132.3, 129.8, 129.7, 129.7, 116.7, 116.6, 116.4, 112.3, 112.2,
112.1, 112.1, 106.6, 48.6, 35.3, 29.6.
Example 85
(S)-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]im-
idazole-3-thione
##STR00177##
[0725] Compound was prepared in an analogous manner to Example 59
from (E)-1-chloro-2,4-difluoro-3-(2-nitrovinyl)benzene using
4-((R)-hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #524-63-0) and isolated as a white powder.
[0726] .sup.1H NMR (DMSO-d6): 11.85 (1H, br s), 7.61 (1H, td,
J=8.7, 5.6 Hz), 7.22 (1H, dt, J=1.6, 9.6 Hz), 6.63 (1H, s), 4.50
(1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.5, 9.3 Hz), 3.75 (1H, dd,
J=11.7, 7.7 Hz), 3.31 (1H, dd, J=9.4, 16 Hz), 2.93 (1H, dd, J=15.8,
7.8 Hz).
[0727] .sup.13C NMR (DMSO-d6): 160.2, 160.1, 158.5, 158.5, 156.6,
156.5, 155.8, 155, 154.9, 132.3, 129.7, 129.7, 118.9, 118.8, 118.7,
116.1, 116.1, 116, 113.3, 113.3, 113.1, 113.1, 106.6, 48.5, 35.7,
29.5.
Example 86
(R)-6-(3-chloro-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]im-
idazole-3-thione
##STR00178##
[0729] Compound was prepared in an analogous manner to Example 58
from (E)-1-chloro-2,4-difluoro-3-(2-nitrovinyl)benzene using
4-((S)-hydroxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #70877-75-7) and isolated as a white powder.
[0730] .sup.1H NMR (DMSO-d6): 11.85 (1H, br s), 7.61 (1H, td,
J=8.7, 5.6 Hz), 7.22 (1H, dt, J=1.6, 9.6 Hz), 6.63 (1H, s), 4.50
(1H, quin, J=8.5 Hz), 4.18 (1H, dd, J=11.5, 9.3 Hz), 3.75 (1H, dd,
J=11.7, 7.7 Hz), 3.31 (1H, dd, J=9.4, 16 Hz), 2.93 (1H, dd, J=15.8,
7.8 Hz).
[0731] .sup.13C NMR (DMSO-d6): 160.2, 160.1, 158.5, 158.5, 156.6,
156.5, 155.8, 155, 154.9, 132.2, 129.7, 129.6, 118.9, 118.8, 118.7,
116.1, 116.1, 116, 115.9, 113.3, 113.2, 113.1, 113.1, 106.6, 48.5,
35.7, 29.5.
Example 87
(R)-6-(2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazole-3-
-thione
##STR00179##
[0733] Compound was prepared in an analogous manner to Example 58
from (E)-1,3-difluoro-2-(2-nitrovinyl)benzene using
4-((S)-hydroxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #70877-75-7) and isolated as a white powder.
[0734] .sup.1H NMR (DMSO-d6): 11.84 (1H, br s), 7.41 (1H, m), 7.13
(2H, t, J=8.1 Hz), 6.63 (1H, s), 4.47(1H, quin, J=8.7 Hz), 4.17
(1H, m), 3.73 (1H, dd, J=11.4, 8.2 Hz), 3.29 (1H, dd, J=15.7, 9.2
Hz), 2.92 (1H, br dd, J=15.7, 8.4 Hz).
[0735] .sup.13C NMR (DMSO-d6): 161.6, 161.6, 160.0, 159.9, 155.8,
132.3, 129.8, 129.8, 129.7, 116.7, 116.6, 116.4, 112.3, 112.2,
112.1, 112.1, 106.6, 48.6, 35.3, 29.6.
Example 88
(5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[-
3,4]pyrrolo[2,1-c][1,2,4]triazole-3(2H)-thione
##STR00180##
[0737] Compound was prepared in an analogous manner to Example 60
from tert-butyl
(((1S,2R)-1-(3-chloro-2,6-difluorophenyl)-2-(hydroxymethyl)cyclopropyl)me-
thyl)carbamate and isolated as a pink solid.
[0738] .sup.1H NMR (DMSO-d6): 13.30 (1H, s), 7.67 (1H, td, J=8.7,
5.6 Hz), 7.24 (1H, td, J=9.1, 1.4 Hz), 4.12 (1H, d, J=12.6 Hz),
3.86 (1H, d, J=12.2 Hz), 2.95 (1H, dd, J=8.9, 4.2 Hz), 1.81 (1H,
dd, J=8.8, 5.9 Hz), 1.68 (1H, m).
[0739] .sup.13C NMR (DMSO-d6): 163.6, 161.2, 161.1, 159.5, 159.5,
157.8, 157.7, 157.5, 156.1, 156.0, 130.8, 130.7, 116.1, 116.0,
115.9, 115.8, 115.8, 115.7, 115.7, 113.0, 113.0, 112.9, 112.8,
49.5, 27.3, 20.1, 19.6.
Example 89
(5aS,6aR)-5a-(2-chloro-6-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]-
pyrrolo[1.2-c]imidazole-3(2H)-thione
##STR00181##
[0741] Compound was prepared in an analogous manner to Example 53
from 2-(2-chloro-6-fluorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane and isolated as a beige solid.
[0742] .sup.1H NMR (DMSO-d6): 11.78 (1H, br s), 7.42 (1H, m), 7.38
(1H, m), 7.27(1H, ddd, J=9.7, 8.3, 1.2 Hz), 6.72 (1H, d, J=2.2 Hz),
4.04 (1H, br d, J=12.0 Hz), 3.67 (1H, d, J=12.0 Hz), 2.73 (1H, m),
1.67 (1H, br s), 1.34 (1H, t, J=5.1 Hz).
[0743] .sup.13C NMR (DMSO-d6): 162.7, 161.1, 156.5, 136.4, 134.7,
130.7, 130.6, 125.7, 125.7, 124.8, 124.7, 115.1, 114.9, 106.4, 51,
29.9, 22.8, 22.7, 22.7.
Example 90
(5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[-
3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00182##
[0745] Compound was prepared in an analogous manner to Example 53
from 2-(3-chloro-2,6-difluorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane and isolated as an orange solid.
[0746] .sup.1H NMR (DMSO-d6): 11.80 (1H, br s), 7.64 (1H, m), 7.22
(1H, t, J=8.8 Hz), 6.72 (1H, d, J=2.1 Hz), 4.06 (1H, d, J=12.2 Hz),
3.76 (1H, d, J=12.2 Hz), 2.77 (1H, dd, J=8.3, 4.3 Hz), 1.69 (1H,
dd, J=8.1, 5.6 Hz), 1.31 (1H, t, J=5.0 Hz).
[0747] .sup.13C NMR (DMSO-d6): 161.3, 161.2, 159.6, 159.6, 157.8,
157.8, 156.6, 156.2, 156.1, 134.3, 130.3, 130.3, 117.1, 117.0,
116.8, 115.8, 115.7, 115.6, 115.6, 112.9, 112.9, 112.8, 112.8,
106.5, 51.4, 26.7, 21.6, 21.5.
Example 91
(5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]-
pyrrolo[1,2-c]imidazole-3(2H)-thione-5,5-d.sub.2
##STR00183##
[0749] Compound was prepared from
2-(5-chloro-2-fluorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane using NaBD.sub.4 as reducing agent
(Example 53 step 1) and isolated as an off-white solid.
[0750] .sup.1H NMR (DMSO-d6): 11.76 (1H, br s), 7.49 (1H, dd,
J=6.5, 2.6 Hz), 7.43 (1H, ddd, J=8.6, 4.3, 2.8 Hz), 7.30 (1H, t,
J=9.4 Hz), 6.68 (1H, s), 2.88 (1H, dd, J=8.3, 4.2 Hz), 1.67 (1H,
dd, J=8.3, 5.4 Hz), 1.17 (1H, t, J=4.8 Hz).
[0751] .sup.13C NMR (DMSO-d6): 161.3, 159.7, 156.6, 134.6, 130.1,
130.1, 129.3, 129.3, 128.8, 128.7, 128.3, 128.3, 117.5, 117.4,
106.1, 50.9, 32.4, 22.1, 20.8.
Example 92
(5aS,6aR)-5a-(3-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]-
pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00184##
[0753] Compound was prepared in an analogous manner to Example 53
from 2-(3-chloro-2-fluorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane and isolated as a beige solid.
[0754] .sup.1H NMR (DMSO-d6): 11.77 (1H, br s), 7.54 (1H, m),
7.39(1H, m), 7.21 (1H, t, J=7.8 Hz), 6.69 (1H, d, J=2.2 Hz), 4.11
(1H, d, J=12.0 Hz), 3.83 (1H, d, J=12.2 Hz), 2.86 (1H, dd, J=8.4,
4.3 Hz), 1.65 (1H, dd, J=8.4, 5.3 Hz), 1.20 (1H, t, J=4.8 Hz).
[0755] .sup.13C NMR (DMSO-d6): 157.8, 156.7, 156.2, 134.5, 129.9,
129.4, 129.4, 128.6, 128.5, 125.4, 125.4, 119.9, 119.8, 106.2,
51.6, 51.5, 32.8, 22.1, 20.9.
Example 93
(5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]p-
yrrolo[1,2-c]imidazole-3(2H)-thione
##STR00185##
[0757] Compound was prepared in an analogous manner to Example 53
from 2-(5-bromo-2-fluorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane and isolated as a beige solid.
[0758] .sup.1H NMR (DMSO-d6): 11.76 (1H, br s), 7.61 (1H, dd,
J=6.7, 2.5 Hz), 7.55 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.24 (1H, dd,
J=10.1, 8.8 Hz), 6.68 (1H, d, J=2.2 Hz), 4.09 (1H, d, J=12.0 Hz),
3.80 (1H, d, J=12.0 Hz), 2.88 (1H, dd, J=8.4, 4.3 Hz), 1.67 (1H,
dd, J=8.4, 5.4 Hz), 1.16 (1H, t, J=4.8 Hz).
[0759] .sup.13C NMR (DMSO-d6): 161.8, 160.2, 156.6, 134.6, 133.0,
133.0, 132.4, 132.3, 129.2, 129.1, 118.0, 117.8, 116.2, 116.2,
106.2, 51.5, 51.5, 32.6, 22.1, 20.9.
Example 94
(5aS,6aR)-5a-(3-bromo-5-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]p-
yrrolo[1,2-c]imidazole-3(2H)-thione
##STR00186##
[0761] Compound was prepared in an analogous manner to Example 53
from 2-(3-bromo-5-fluorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane and isolated as a dark yellow
solid.
[0762] .sup.1H NMR (DMSO-d6): 11.74 (1H, br s), 7.43 (1H, s), 7.43
(1H, m), 7.29(1H, dt, J=10.0, 1.9 Hz), 6.66 (1H, d, J=2.2 Hz), 4.23
(1H, d, J=12.0 Hz), 4.02 (1H, d, J=12.2 Hz), 3.01 (1H, dd, J=8.4,
4.3 Hz), 1.67 (1H, dd, J=8.3, 5.4 Hz), 1.16 (1H, t, J=4.8 Hz).
[0763] .sup.13C NMR (DMSO-d6): 163.0, 161.4, 156.8, 145.0, 145.0,
134.6, 126.0, 125.9, 122.2, 122.1, 117.1, 117.0, 113.4, 113.3,
105.9, 50.8, 36.3, 36.3, 25.1, 22.8.
Example 95
(S)-6-(3,5-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]im-
idazole-3-thione
Step 1: ((4S)-tert-butyl
2-(cyano(hydroxy)methyl)-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate
##STR00187##
[0765] To a stirred solution of (4S)-tert-butyl
4-(3,5-difluorophenyl)-2-formylpyrrolidine-1-carboxylate (1.2 g,
3.85 mmol) in a mixture of tetrahydrofuran (10 mL) and water (5 mL)
was added potassium cyanide (0.301 g, 4.63 mmol) followed by
addition of cc HCl (0.319 mL, 3.85 mmol). The mixture was stirred
for 8 h, then extracted with dichloromethane. The organic phase was
washed with brine, dried over MgSO.sub.4 and evaporated to dryness
to give (4S)-tert-butyl
2-(cyano(hydroxy)methyl)-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate
as a yellowish oil. (Yield: 1.44 g, 99%).
Step 2: (4S)-tert-butyl
4-(3,5-difluorophenyl)-2-(2-ethoxy-1-hydroxy-2-oxoethyl)pyrrolidine-1-car-
boxylate
##STR00188##
[0767] A mixture of (4S)-tert-butyl
2-(cyano(hydroxy)methyl)-4-(3,5-difluorophenyl)pyrrolidine-1-carboxylate
(1.43 g, 3.80 mmol) and 2 M HCl (28.5 mL, 57.1 mmol) was stirred
under reflux for 16 h. After cooling to room temperature the
mixture was filtered through a celite plug to remove insoluble
coloured precipitate and then the filtrate was evaporated to
dryness under vacuum. The residue was azeotroped twice with dry
ethanol and the residue was taken up in abs. ethanol (20 mL). The
thus obtained solution was treated with 4 M HCl (9.51 mL, 38.0
mmol) in dioxane and stirred under reflux for 2 h. The mixture was
evaporated to dryness, and then azeotroped with abs. ethanol. The
resulting semisolid was taken up in abs. ethanol (30 mL),
neutralized by addition of triethylamine to pH=6-7, then a second
crop of triethylamine (0.530 mL, 3.80 mmol) was added followed by
addition of di-tert-butyl dicarbonate (0.830 g, 3.80 mmol). The
reaction was allowed to stir at room temperature for 2 h, and then
evaporated to dryness at 40.degree. C. The residue was partitioned
between dichloromethane and water, the organic phase was dried over
MgSO.sub.4 and concentrated under reduced pressure. Chromatography
(petroleum ether-ethyl acetate; 9:1, then 4:1) gave the product as
a yellow oil. (Yield: 1.16 g, 79%).
Step 3: (4S)-tert-butyl
4-(3,5-difluorophenyl)-2-(2-ethoxy-2-oxoacetyl)pyrrolidine-1-carboxylate
##STR00189##
[0769] To a stirred solution of (4S)-tert-butyl
4-(3,5-difluorophenyl)-2-(2-ethoxy-1-hydroxy-2-oxoethyl)pyrrolidine-1-car-
boxylate (1.15 g, 2.98 mmol) in dry dichloromethane (25 mL) was
added Dess-Martin periodinane
(3-oxo-1.lamda..sup.5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl
triacetate) (1.266 g, 2.98 mmol) at room temperature in one portion
and the mixture was stirred for 2 h. The reaction mixture was
concentrated under vacuum, whereupon the reside was purified by
chromatography (petroleum ether-ethyl acetate; 4:1). The product
was isolated as a yellowish oil. (1.08 g, 94% yield).
Step 4: ethyl
2-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-oxoacetate
hydrochloride
##STR00190##
[0771] To a stirred solution of (4S)-tert-butyl
4-(3,5-difluorophenyl)-2-(2-ethoxy-2-oxoacetyl)pyrrolidine-1-carboxylate
(0.4 g, 1.043 mmol) in 4 M HCl (5.22 mL, 20.87 mmol) in dioxane was
stirred at room temperature for 4 h. The reaction mixture was
diluted with a mixture of diethyl ether (20 mL) and petroleum ether
(5 mL) and stirred for 30 min, Thereupon, the resulting precipitate
was collected, washed with diethyl ether, petroleum ether and dried
under vacuum at 50.degree. C. to give ethyl
2-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-oxoacetate
hydrochloride as a white powder. (Yield: 0.34 g, 92%).
Step 5: (S)-ethyl
6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imida-
zole-1-carboxylate
##STR00191##
[0773] A solution of ethyl
2-((4S)-4-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-oxoacetate
hydrochloride (0.33 g, 1.032 mmol), 6 M HCl (0.086 mL, 0.516 mmol)
and potassium thiocyanate (0.110 g, 1.135 mmol) in a mixture of
ethanol (5 mL) and water (5 mL) was stirred under reflux for 30
min. The reaction was then cooled to room temperature, and the
resulting solid was collected, washed with a mixture of ethanol and
water (1:1), and dried under vacuum at 50.degree. C. to give
(S)-ethyl
6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imida-
zole-1-carboxylate as a white solid. (Yield: 0.28 g, 84%).
Step 6:
S)-6-(3,5-difluorophenyl)-1-methyl-6,7-dihydro-2H-pyrrolo[1,2-c]im-
idazole-3(5H)-thione
##STR00192##
[0775] To a solution of (9-ethyl
6-(3,5-difluorophenyl)-3-thioxo-3,5,6,7-tetrahydro-2H-pyrrolo[1,2-c]imida-
zole-1-carboxylate (0.1 g, 0.308 mmol) in dry tetrahydrofuran (2
mL) was added sodium borohydride (0.058 g, 1.542 mmol) followed by
addition of boron trifluoride etherate (0.195 mL, 1.542 mmol) with
ice-water bath cooling. The mixture was allowed to warm up to room
temperature and stirred for 16 h. Thereupon, the mixture was cooled
again to 0-5.degree. C., and quenched with 2 M HCl (1.233 ml, 2.467
mmol). The organic solvents were removed under vacuum, and then the
residue extracted with ethyl acetate. The organic phase was dried
over MgSO.sub.4, filtered and evaporated to dryness. Chromatography
(petroleum ether-ethyl acetate; 1:1 gave
(S)-6-(3,5-difluorophenyl)-1-methyl-6,7-dihydro-2H-pyrrolo[1,2-c]imi-
dazole-3(5H)-thione as a white powder (0.021 g, 0.079 mmol, 25.6%
yield).
[0776] .sup.1H NMR (DMSO-d6): 11.69 (1H, br s), 7.13 (3H, m),
5.76(1H, s), 4.15 (1H, dd, J=11.2, 7.9 Hz), 4.07 (1H, quin, J=7.8
Hz), 3.66 (1H, dd, J=11.2, 8.4 Hz), 3.18 (1H, m), 2.82 (1H, ddd,
J=15.0, 8.9, 1.3 Hz), 1.98 (3H, s).
[0777] .sup.13C NMR (DMSO-d6): 163.3, 163.2, 161.7, 161.6, 155.1,
145.7, 145.7, 145.6, 127.8, 115.4, 110.8, 110.7, 110.6, 110.6,
102.6, 102.5, 102.3, 50.0, 46.5, 30.0, 9.4.
Example 96
(R)-1-methyl-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1-
,2-c]imidazole-3-thione
##STR00193##
[0779] Compound was prepared in an analogous manner to Example 80
from
(4R)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-c-
arboxylic acid and methylmagnesium iodide and isolated as an
off-white powder.
[0780] .sup.1H NMR (DMSO-d6): 11.74 (1H, br s), 7.85 (1H, m), 4.49
(1H, quin, J=8.5 Hz), 4.42 (1H, m), 4.15 (1H, dd, J=11.6, 9.2 Hz),
3.76 (1H, dd, J=11.7, 7.8 Hz), 3.27 (1H, dd, J=15.6, 9.2 Hz), 2.89
(1H, dd, J=15.4, 7.9 Hz), 1.97 (3H, s).
[0781] .sup.13C NMR (DMSO-d6): 155.0, 146.4, 146.3, 146.3, 145.3,
145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 127.5, 120.5, 120.4,
120.3, 115.3, 105.9, 105.7, 105.6, 48.4, 35.9, 28.6, 9.3.
Example 97
(S)-1-methyl-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1-
,2-c]imidazole-3-thione
##STR00194##
[0783] Compound was prepared in an analogous manner to Example 80
from
(4S)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-c-
arboxylic acid and methylmagnesium iodide and isolated as a light
beige powder.
[0784] .sup.1H NMR (DMSO-d6): 11.74 (1H, br s), 7.85 (1H, m),
4.49(1H, quin, J=8.5 Hz), 4.15 (1H, dd, J=11.6, 9.2 Hz), 3.76 (1H,
dd, J=11.7, 7.8 Hz), 3.27 (1H, dd, J=15.6, 9.2 Hz), 2.89 (1H, dd,
J=15.4, 7.9 Hz), 1.97 (3H, s).
[0785] .sup.13C NMR (DMSO-d6): 155, 146.4, 146.3, 146.3, 145.3,
145.2, 144.8, 144.7, 144.6, 143.7, 143.6, 127.5, 120.5, 120.4,
120.3, 115.3, 105.9, 105.7, 105.6, 48.7, 48.4, 35.9, 28.6, 9.3.
Example 98
(S)-6-(2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]im-
idazole-3-thione
##STR00195##
[0787] Compound was prepared in an analogous manner to Example 80
from
(4S)-1-(tert-butoxycarbonyl)-4-(2,6-difluorophenyl)pyrrolidine-2-carboxyl-
ic acid and methylmagnesium iodide and isolated as a light beige
powder.
[0788] .sup.1H NMR (DMSO-d6): 11.72 (1H, br s), 7.40 (1H, m), 7.13
(2H, m), 4.41 (1H, quin, J=8.7 Hz), 4.12 (1H, br t, J=10.1 Hz),
3.70 (1H, dd, J=8.8, 10.8 Hz), 3.21 (1H, br dd, J=15.3, 9.2 Hz),
2.84 (1H, br dd, J=15.2, 8.6 Hz), 1.97 (3H, s).
[0789] .sup.13C NMR (DMSO-d6): 161.6, 161.6, 160.0, 159.9, 155.0,
129.8, 129.7, 129.7, 127.8, 116.6, 116.5, 116.4, 115.2, 112.3,
112.2, 112.1, 112.1, 48.6, 35.4, 28.8, 9.3.
Example 99
(5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclop-
ropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00196##
[0791] Compound was prepared in an analogous manner to Example 80
from tert-butyl
(1S,5R)-1-(5-chloro-2-fluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabic-
yclo[3.1.0]hexane-3-carboxylate and methylmagnesium iodide. The
product was isolated as a beige solid.
[0792] .sup.1H NMR (DMSO-d6): 11.65 (1H, br s), 7.47 (1H, dd,
J=6.5, 2.6 Hz), 7.42 (1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.29 (1H, dd,
J=10.0, 8.9 Hz), 4.06 (1H, d, J=11.7 Hz), 3.77 (1H, d, J=12.0 Hz),
2.87 (1H, dd, J=8.2, 4.3 Hz), 2.04 (3H, m), 1.64 (1H, dd, J=8.1,
5.4 Hz), 1.12 (1H, t, J=4.8 Hz).
[0793] .sup.13C NMR (DMSO-d6): 161.3, 159.7, 155.7, 130.3, 130.1,
130.1, 129.3, 129.3, 129.0, 128.9, 128.3, 128.3, 117.6, 117.4,
114.8, 51.5, 51.5, 32.3, 22.3, 20.2, 9.4.
Example 100
(5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-1-(methyl-d.sub.3)-5,5a,6,6a-tetrah-
ydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00197##
[0795] Compound was prepared in an analogous manner to Example 80
from tert-butyl
(1S,5R)-1-(5-chloro-2-fluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabic-
yclo[3.1.0]hexane-3-carboxylate and methyl-d.sub.3-magnesium
iodide. The product was isolated as a light orange solid.
[0796] .sup.1H NMR (DMSO-d6): 11.65 (1H, s), 7.47 (1H, dd, J=6.6,
2.8 Hz), 7.42 (1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.29 (1H, m), 4.06
(1H, d, J=11.9 Hz), 3.77 (1H, d, J=12.0 Hz), 2.87 (1H, dd, J=8.3,
4.3 Hz), 1.64(1H, dd, J=8.3, 5.4 Hz), 1.12(1H, t, J=4.8 Hz).
[0797] .sup.13C NMR (DMSO-d6): 161.3, 159.7, 155.7, 155.6, 130.3,
130.1, 130.1, 129.3, 129.3, 129.0, 128.9, 128.3, 128.3, 117.6,
117.4, 114.7, 114.6, 51.5, 51.5, 32.3, 22.3, 20.2.
Example 101
(5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-(methyl-d.sub.3)-5,5a,6,6a-tetrah-
ydrocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00198##
[0799] Compound was prepared in an analogous manner to Example 76
from
(1R,5S)-5-(5-chloro-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-carbaldeh-
yde hydrochloride and isothiocyanatomethane-d.sub.3 and isolated as
a yellow oil.
[0800] .sup.1H NMR (DMSO-d6): 7.50 (1H, dd, J=6.5, 2.5 Hz), 7.43
(1H, m), 7.30 (1H, t, J=9.5 Hz), 6.93 (1H, s), 4.13 (1H, br d,
J=12.0 Hz), 3.84 (1H, d, J=12.0 Hz), 2.92(1H, dd, J=8.2, 4.1 Hz),
1.69 (1H, dd, J=8.3, 5.5 Hz), 1.17 (1H, t, J=4.8 Hz).
[0801] .sup.13C NMR (DMSO-d6): 161.3, 159.7, 157.2, 132.9, 130.2,
130.2, 129.4, 129.4, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4,
110.4, 52.3, 52.3, 32, 22.1, 20.9.
Example 102
5a-(5-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrrolo[1,-
2-c]imidazole-3(2H)-thione-6,6,6a-d.sub.3
##STR00199##
[0803] Compound was prepared in an analogous manner to Example 53
from 2-(5-chloro-2-fluorophenyl)acetonitrile and
2-(chloromethyl-d2)oxirane-2,3,3-d3 and isolated as a beige
solid.
[0804] .sup.1H NMR (DMSO-d6): 11.76 (1H, br s), 7.49 (1H, dd,
J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.8, 4.4, 2.8 Hz), 7.30 (1H, dd,
J=10.0, 8.8 Hz), 6.68 (1H, d, J=2.3 Hz), 4.10 (1H, dd, J=12.0, 1.8
Hz), 3.81 (1H, d, J=12.0 Hz).
[0805] .sup.13C NMR (DMSO-d6): 161.3, 159.7, 156.6, 134.5, 130.2,
130.2, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 117.6, 117.4,
106.2, 51.5, 51.4, 32.4, 21.6, 21.4, 21.2, 20.6, 20.5, 20.3.
Example 103
(5aR,6aS)-5a-(3-chloro-2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[-
3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00200##
[0807] Compound was prepared in an analogous manner to Example 53
from 2-(3-chloro-2,6-difluorophenyl)acetonitrile and
(S)-2-(chloromethyl)oxirane and isolated as a beige solid.
[0808] .sup.1H NMR (DMSO-d6): 11.79 (1H, br s), 7.64 (1H, m), 7.21
(1H, t, J=8.7 Hz), 6.71 (1H, d, J=2.2 Hz), 4.05 (1H, d, J=12.2 Hz),
3.76 (1H, d, J=12.3 Hz), 2.76 (1H, dd, J=8.4, 4.4 Hz), 1.69(1H, dd,
J=8.2, 5.6 Hz), 1.30(1H, t, J=5.0 Hz).
[0809] .sup.13C NMR (DMSO-d6): 161.3, 161.2, 159.6, 159.6, 157.8,
157.8, 156.6, 156.2, 156.1, 134.3, 130.3, 130.3, 117.1, 117.0,
116.8, 115.8, 115.7, 115.7, 115.6, 113.0, 112.9, 112.8, 112.8,
106.5, 51.4, 26.7, 21.6, 21.5.
Example 104
(R)-6-(3-chloro-2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo-
[1,2-c]imidazole-3-thione
##STR00201##
[0811] Compound was prepared in an analogous manner to Example 80
from
(4S)-1-(tert-butoxycarbonyl)-4-(3-chloro-2,6-difluorophenyl)pyrrolidine-2-
-carboxylic acid and methylmagnesium iodide and isolated as an
off-white powder.
[0812] .sup.1H NMR (DMSO-d6): 11.73 (1H, br s), 7.61 (1H, td,
J=8.8, 5.6 Hz), 7.21 (1H, t, J=9.5 Hz), 4.44 (1H, quin, J=8.6 Hz),
4.13 (1H, dd, J=11.4, 9.2 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.23
(1H, m), 2.84 (1H, dd, J=15.5, 8.1 Hz), 1.97 (3H, s).
[0813] .sup.13C NMR (DMSO-d6): 160.2, 160.1, 158.5, 158.5, 156.6,
156.5, 155, 154.9, 154.9, 129.7, 129.7, 127.7, 118.9, 118.7, 118.6,
116.1, 116.1, 116.0, 116.0, 115.2, 113.3, 113.3, 113.1, 113.1,
48.5, 35.8, 28.7, 9.4.
Example 105
(S)-6-(3-chloro-2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo-
[1,2-c]imidazole-3-thione
##STR00202##
[0815] Compound was prepared in an analogous manner to Example 80
from
(4R)-1-(tert-butoxycarbonyl)-4-(3-chloro-2,6-difluorophenyl)pyrrolidine-2-
-carboxylic acid and methylmagnesium iodide and isolated as a light
beige powder.
[0816] .sup.1H NMR (DMSO-d6): 11.73 (1H, br s), 7.61 (1H, td,
J=8.8, 5.6 Hz), 7.21 (1H, t, J=9.5 Hz), 4.44 (1H, quin, J=8.6 Hz),
4.13 (1H, dd, J=11.4, 9.2 Hz), 3.72 (1H, dd, J=11.6, 7.9 Hz), 3.23
(1H, m), 2.84 (1H, dd, J=15.5, 8.1 Hz), 1.97 (3H, s).
[0817] .sup.13C NMR (DMSO-d6): 160.2, 160.1, 158.5, 158.5, 156.6,
156.5, 154.9, 154.9, 129.7, 129.6, 127.7, 118.9, 118.7, 118.6,
116.1, 116.1, 116.0, 115.9, 115.2, 113.3, 113.3, 113.1, 113.1,
48.5, 35.7, 28.7, 9.4.
Example 106
(5aS,6aS)-5a-(3,5-difluorophenyl)-2,5,5a,6,6a,7-hexahydro-3H-cyclopropa[d]-
imidazo[1,5-a]pyridine-3-thione
Step 1:
((1R,2S)-2-(((tert-butoxycarbonyl)amino)methyl)-2-(3,5-difluorophe-
nyl)cyclopropyl)methyl 4-methylbenzenesulfonate
##STR00203##
[0819] To a stirred solution of tert-butyl
((1S,2R)-1-(3,5-difluorophenyl)-2-(hydroxymethyl)cyclopropyl)methylcarbam-
ate (1.0 g, 3.19 mmol) (prepared according to Example 53 from
2-(3,5-difluorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane)) in dry dichloromethane (10 mL) was
added triethylamine (0.89 mL, 6.38 mmol) followed by addition of
N,N-dimethylpyridin-4-amine (0.039 g, 0.319 mmol) and tosyl
chloride (0.730 g, 3.83 mmol) at 0-5.degree. C. under nitrogen. The
mixture was stirred for 2 h in ice and then allowed to warm up
naturally to room temperature over 30 min. Thereupon, the mixture
was washed with sodium bicarbonate solution, 10% citric acid, then
dried over MgSO.sub.4 and finally evaporated to give the crude
product as a light brown oil (1.37 g, 73% yield).
Step 2: tert-butyl
(((1S,2S)-2-(cyanomethyl)-1-(3,5-difluorophenyl)cyclopropyl)methyl)carbam-
ate
##STR00204##
[0821] To a solution of sodium cyanide (0.204 g, 4.16 mmol) in
dimethyl sulfoxide (12 mL) was added
((1R,2S)-2-((tert-butoxycarbonylamino)methyl)-2-(3,5-difluorophenyl)cyclo-
propyl)methyl 4-methylbenzenesulfonate (1.35 g, 2.310 mmol) and the
mixture was stirred at room temperature for 4 h. The reaction was
then diluted with water (30 mL) followed by extraction with diethyl
ether. The organic phase was washed with brine, dried over
MgSO.sub.4 and evaporated to dryness. The resulting oil was
crystallised from petroleum ether, filtered and dried under vacuum
to give tert-butyl
((1S,2S)-2-(cyanomethyl)-1-(3,5-difluorophenyl)cyclopropyl)methylcarbamat-
e as a light beige powder (0.57 g, 77% yield).
Step 3: tert-butyl
(((1S,2S)-2-(2-amino-2-oxoethyl)-1-(3,5-difluorophenyl)cyclopropyl)methyl-
)carbamate
##STR00205##
[0823] To a solution of tert-butyl
((1S,2S)-2-(cyanomethyl)-1-(3,5-difluorophenyl)cyclopropyl)methylcarbamat-
e (1.69 g, 5.24 mmol) in a mixture of acetone (30 mL) and water (10
mL) was added urea hydrogen peroxide addition complex (2.466 g,
26.2 mmol) followed by addition of potassium carbonate (0.145 g,
1.049 mmol) and the mixture was stirred at room temperature for 20
h. Acetone was then removed under vacuum and the residue was
partitioned between water and a mixture of ethyl acetate and
petroleum ether (1:1). The organic phase was dried over MgSO.sub.4
and evaporated to dryness to give the title product as a colourless
oil (1.98 g, 100% yield).
Step 4:
(1S,6S)-1-(3,5-difluorophenyl)-3-azabicyclo[4.1.0]heptan-4-one
##STR00206##
[0825] tert-Butyl
((1S,2S)-2-(2-amino-2-oxoethyl)-1-(3,5-difluorophenyl)cyclopropyl)methylc-
arbamate (1.78 g, 5.23 mmol) was stirred under reflux with 2 M HCl
(39 mL, 78 mmol) for 2 h. Thereupon, the mixture was evaporated to
dryness and then azeotroped with abs. ethanol. The oily residue was
dissolved in abs. ethanol (80 mL) followed by addition of 4 M HCl
(13.0 mL, 52.1 mmol) in dioxane. The thus obtained solution was
stirred under reflux for 30 min and evaporated to dryness. The
residue was taken up in methanol (20 mL), and then pH was adjusted
to 9-10 by addition of 25% sodium methoxide in methanol. The
mixture was stirred overnight at 50-55.degree. C. Methanol was then
removed under vacuum, and the residue crystallized form water. The
resulting solid was collected, washed with water and dried to give
(1S,6S)-1-(3,5-difluorophenyl)-3-azabicyclo[4.1.0]heptan-4-one as a
beige powder (0.9 g, 77% yield).
Step 5: tert-butyl
(1S,6S)-1-(3,5-difluorophenyl)-4-oxo-3-azabicyclo[4.1.0]heptane-3-carboxy-
late
##STR00207##
[0827] To a solution of
(1S,6S)-1-(3,5-difluorophenyl)-3-azabicyclo[4.1.0]heptan-4-one
(0.88 g, 3.94 mmol) and N,N-dimethylpyridin-4-amine (0.482 g, 3.94
mmol) in dry dichloromethane (3 mL) was added di-tert-butyl
dicarbonate (1.291 g, 5.91 mmol) at room temperature in portions.
The mixture was stirred for 4 h at room temperature, then diluted
with dichloromethane to 50 mL and finally washed with 10% citric
acid (25 mL). The organic phase was dried over MgSO.sub.4, filtered
on a silica pad, and then the filtrate evaporated to dryness to
give (1S,6S)-tert-butyl
1-(3,5-difluorophenyl)-4-oxo-3-azabicyclo[4.1.0]heptane-3-carboxylate
as a light beige powder (1.18 g, 93% yield).
Step 6: tert-butyl
(1S,6S)-1-(3,5-difluorophenyl)-4-hydroxy-3-azabicyclo[4.1.0]heptane-3-car-
boxylate
##STR00208##
[0829] To a solution of (1S,6S)-tert-butyl
1-(3,5-difluorophenyl)-4-oxo-3-azabicyclo[4.1.0]heptane-3-carboxylate
(1.17 g, 3.62 mmol) in a mixture of dry diethyl ether (18 mL) and
tetrahydrofuran (6 mL) was added dropwise 65% RED-Al
(bis(2-methoxyethoxy)aluminum(III) sodium hydride) (2.17 mL, 7.24
mmol) in toluene at 0-5.degree. C. and the mixture was stirred for
30 min. under nitrogen. The mixture was then quenched with a cold
solution of saturated sodium bicarbonate and allowed to stir at
ambient for 30 min. The organic phase was separated, and the
aqueous phase was extracted with diethyl ether. The combined
organic phases were dried over MgSO.sub.4 and evaporated to dryness
to give (1S,6S)-tert-butyl
1-(3,5-difluorophenyl)-4-hydroxy-3-azabicyclo[4.1.0]heptane-3-carboxylate
as a yellowish oil.(1.15 g, 98% yield).
Step 7 tert-butyl
(1S,6S)-1-(3,5-difluorophenyl)-4-methoxy-3-azabicyclo[4.1.0]heptane-3-car-
boxylate
##STR00209##
[0831] To a solution of (1S,6S)-tert-butyl
1-(3,5-difluorophenyl)-4-hydroxy-3-azabicyclo[4.1.0]heptane-3-carboxylate
(1.14 g, 3.50 mmol) in methanol (35 mL) was added
4-methylbenzenesulfonic acid hydrate (0.067 g, 0.350 mmol) at room
temperature and the solution was stirred for 24 h. Thereupon, the
mixture was neutralized with 1 M sodium hydroxide (0.35 mL, 0.350
mmol) and evaporated to dryness. The residue was taken up in a
mixture of petroleum ether and ethyl acetate (4:1), then
chromatographed in a mixture of petroleum ether-ethyl acetate
(9:1), to give (1S,6S)-tert-butyl
1-(3,5-difluorophenyl)-4-methoxy-3-azabicyclo[4.1.0]heptane-3-carboxylate
as a colourless oil (0.71 g, 60% yield).
Step 8 tert-butyl
(1S,6S)-4-cyano-1-(3,5-difluorophenyl)-3-azabicyclo[4.1.0]heptane-3-carbo-
xylate
##STR00210##
[0833] To a solution of (1S,6S)-tert-butyl
1-(3,5-difluorophenyl)-4-methoxy-3-azabicyclo[4.1.0]heptane-3-carboxylate
(0.71 g, 2.092 mmol) in dry dichloromethane (15 mL) was added
trimethylsilanecarbonitrile (0.561 mL, 4.18 mmol) followed by
addition of boron trifluoride etherate (0.58 mL, 4.60 mmol) at
-70.degree. C. The mixture was stirred for 4 h in the cold, and
then quenched with aqueous sodium bicarbonate and allowed to warm
up to room temperature. The organic phase was dried over MgSO.sub.4
and evaporated to dryness. Chromatography petroleum ether-ethyl
acetate; 9:1) afforded the product as a colourless oil (0.095 g,
13%).
Step 9 tert-butyl
(1S,6S)-4-carbamoyl-1-(3,5-difluorophenyl)-3-azabicyclo[4.1.0]heptane-3-c-
arboxylate
##STR00211##
[0835] To a solution of (1S,6S)-tert-butyl
4-cyano-1-(3,5-difluorophenyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate
(0.09 g, 0.269 mmol) in a mixture of acetone (1.5 mL) and water
(0.5 mL) was added urea hydrogen peroxide addition complex (0.127
g, 1.346 mmol) followed by addition of potassium carbonate (0.0074
mg, 0.054 mmol) and the solution was stirred at room temperature
for 16 h. Acetone was then removed under vacuum, the oily residue
was diluted with water (2 mL) and then extracted with a mixture of
petroleum ether-ethyl acetate (1:1). The organic phase was dried
over MgSO.sub.4 and evaporated to dryness to give
(1S,6S)-tert-butyl
4-carbamoyl-1-(3,5-difluorophenyl)-3-azabicyclo[4.1.0]heptane-3-carboxyla-
te (0.09 g, 95% yield).
Step 10
(1S,6S)-3-(tert-butoxycarbonyl)-1-(3,5-difluorophenyl)-3-azabicycl-
o[4.1.0]heptane-4-carboxylic acid
##STR00212##
[0837] A suspension of (1S,6S)-tert-butyl
4-carbamoyl-1-(3,5-difluorophenyl)-3-azabicyclo[4.1.0]heptane-3-carboxyla-
te (0.09 g, 0.255 mmol) in 2 M HCl (1.92 mL, 3.83 mmol) was stirred
under reflux for 3 h. The reaction mixture was concentrated under
vacuum, the residue was dissolved in water and then the pH was
adjusted to 7 by adding 1 M sodium hydroxide (0.511 mL, 0.511
mmol). The solution was concentrated to 2 mL, followed by addition
of methanol (2 mL) and di-tert-butyl dicarbonate (0.123 g, 0.562
mmol). The mixture was stirred for 45 min, whereupon a second crop
of di-tert-butyl dicarbonate (0.347 g, 1.592 mmol) was added and
the reaction was stirred for 1 h. Thereupon, methanol was removed
under vacuum, the residue was diluted with water (10 mL) and washed
with petroleum ether. The aqueous phase was acidified to pH=2 by
adding 2 M HCl, and then extracted with dichloromethane. The
organic phase was dried over MgSO.sub.4, filtered and evaporated to
dryness to give the product as an off-white powder (0.07 g, 78%
yield).
Step 11 tert-butyl
(1S,6S)-1-(3,5-difluorophenyl)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]hepta-
ne-3-carboxylate
##STR00213##
[0839] To a solution of
(1S,6S)-3-(tert-butoxycarbonyl)-1-(3,5-difluorophenyl)-3-azabicyclo[4.1.0-
]heptane-4-carboxylic acid (0.07 g, 0.198 mmol) in isopropyl
acetate (1.5 mL) was added sodium borohydride (0.018 g, 0.475 mmol)
at 0-5.degree. C. followed by addition of boron trifluoride
etherate (0.075 mL, 0.594 mmol). The mixture was stirred in the
cold for 2 h, then a second crop of sodium borohydride (0.018 g,
0.475 mmol) and boron trifluoride etherate (0.075 mL, 0.594 mmol)
was added. After being stirred for 30 min. in the cold the reaction
mixture was quenched with 1 M sodium hydroxide (1.070 mL, 1.070
mmol) and stirred at room temperature for 30 min. The organic phase
was separated, dried over MgSO.sub.4 and evaporated to dryness to
give (1S,6S)-tert-butyl
1-(3,5-difluorophenyl)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-car-
boxylate as a white powder (0.066 g, 98% yield).
Step 12 tert-butyl
(1S,6S)-1-(3,5-difluorophenyl)-4-formyl-3-azabicyclo[4.1.0]heptane-3-carb-
oxylate
##STR00214##
[0841] To a solution of (1S,6S)-tert-butyl
1-(3,5-difluorophenyl)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-car-
boxylate (0.066 g, 0.194 mmol) in dry dichloromethane (2 mL) was
added Dess-Martin periodinane
(3-oxo-1.lamda..sup.5-benzo[d][1,2]iodaoxole-1,1,1(3H)-triyl
triacetate) (0.082 g, 0.194 mmol) in one portion to give a clear
solution. The mixture was stirred for 2 h at room temperature, and
then concentrated under vacuum. Chromatography (petroleum
ether-ethyl acetate; 9:1, then 4:1) gave (1S,6S)-tert-butyl
1-(3,5-difluorophenyl)-4-formyl-3-azabicyclo[4.1.0]heptane-3-carboxylate
as a yellowish oil (0.054 g, 82% yield).
Step 13
(5aS,6a5)-5a-(3,5-difluorophenyl)-2,5,5a,6,6a,7-hexahydro-3H-cyclo-
propa[d]imidazo[1,5-a]pyridine-3-thione
##STR00215##
[0843] A solution of (1S,6S)-tert-butyl
1-(3,5-difluorophenyl)-4-formyl-3-azabicyclo[4.1.0]heptane-3-carboxylate
(0.054 g, 0.160 mmol) in 4 M HCl (0.6 mL, 2.401 mmol) in dioxane
was stirred at room temperature for 2 h. The mixture was then
diluted with petroleum ether (10 mL) and stirred for 1 h. The
resulting oily precipitate was dissolved in a mixture of ethanol (1
mL) and water (1 mL), and potassium thiocyanate (0.017 g, 0.176
mmol) was then added followed by addition of 6 M HCl (0.013 mL,
0.080 mmo) and the solution was stirred under reflux for 1 h. The
product crystallized on cooling to room temperature. The mixture
was then stirred at room temperature for 30 min, the crystals were
collected and washed with a mixture of ethanol-water (1:1) to give
(5aS,6aS)-5a-(3,5-difluorophenyl)-5a,6,6a,7-tetrahydro-2H-cyclopropa[d]im-
idazo[1,5-c]pyridine-3(5H)-thione as alight beige powder (0.023 g,
0.083 mmol, 52% yield).
[0844] .sup.1H NMR (DMSO-d6): 12.06 (1H, br s), 7.15 (3H, m), 6.71
(1H, t, J=1.8 Hz), 4.61 (1H, d, J=13.1 Hz), 3.92 (1H, d, J=13.1
Hz), 3.11 (1H, ddd, J=2.0, 3.3, 15.9 Hz), 2.99 (1H, dd, J=2.2, 15.9
Hz), 1.68 (1H, m), 1.05 (1H, dd, J=8.9, 5.8 Hz), 0.52 (1H, t, J=5.7
Hz).
[0845] .sup.13C NMR (DMSO-d6): 163.4, 163.3, 161.7, 161.7, 159.4,
147.2, 147.2, 147.1, 123.9, 110.9, 110.9, 110.8, 110.7, 110.1,
102.4, 102.3, 102.1, 44.3, 23.5, 20.5, 18.6, 11.6.
Example 107
(6R,7S)-7-methyl-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrro-
lo[1,2-c]imidazole-3-thione
##STR00216##
[0847] Compound was prepared in an analogous manner to Example 58
from (E)-1,2,4,5-tetrafluoro-3-(2-nitrovinyl)benzene and diethyl
2-methylmalonate using
4-((S)-hydroxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst CAS #70877-75-7). The title compound was isolated as an
off-white powder.
[0848] .sup.1H NMR (DMSO-d6): 11.87 (1H, br s), 7.89 (1H, m), 6.70
(1H, t, J=2.0 Hz), 4.20 (1H, dd, J=), 4.04 (1H, q, J=9.1 Hz), 3.84
(1H, dd, J=11.2, 9.4 Hz), 3.40 (1H, m), 1.23 (3H, d, J=6.6 Hz).
[0849] .sup.13C NMR (DMSO-d6): 156.0, 146.5, 146.4, 146.3, 145.6,
145.5, 144.8, 144.8, 144.7, 144.0, 143.8, 136.7, 118.4, 118.3,
118.2, 106.7, 106.2, 106.1, 105.9, 47.5, 44.6, 37.6, 17.1.
Example 108
(6R,7R)-7-methyl-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrro-
lo[1,2-c]imidazole-3-thione
##STR00217##
[0851] Compound was prepared in an analogous manner to Example 58
from (E)-1,2,4,5-tetrafluoro-3-(2-nitrovinyl)benzene and diethyl
2-methylmalonate using
4-((S)-hydroxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst CAS #70877-75-7). The title compound was isolated as a
light beige powder.
[0852] .sup.1H NMR (DMSO-d6): 11.77 (1H, br s), 7.86 (1H, m), 6.63
(1H, m), 4.56(1H, td, J=8.5, 4.4 Hz), 4.19 (1H, dd, J=12.3, 8.3
Hz), 4.04 (1H, dd, J=12.3, 4.4 Hz), 3.74(1H, quin, J=7.2 Hz), 0.87
(3H, d, J=7.0 Hz).
[0853] .sup.13C NMR (DMSO-d6): 155.8, 146.4, 146.3, 146.2, 145.5,
145.4, 144.8, 144.7, 144.6, 143.8, 143.7, 137.2, 118.7, 118.5,
118.4, 106.2, 106.0, 105.9, 105.7, 47.7, 41.7, 34.3, 14.2.
Example 109
(5aS,6aR)-5a-(3,5-dichlorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]pyrro-
lo[1,2-c]imidazole-3(2H)-thione
##STR00218##
[0855] Compound was prepared in an analogous manner to Example 53
from 2-(3,5-dichlorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane and isolated as a yellow solid.
[0856] .sup.1H NMR (DMSO-d6): 11.74 (1H, br s), 7.49 (1H, t, J=1.8
Hz), 7.44 (2H, d, J=1.8 Hz), 6.67 (1H, s), 4.24 (1H, d, J=12.2 Hz),
4.02 (1H, d, J=12.0 Hz), 3.03 (1H, dd, J=8.4, 4.3 Hz), 1.68 (1H,
dd, J=8.4, 5.3 Hz), 1.16 (1H, t, J=4.8 Hz).
[0857] .sup.13C NMR (DMSO-d6): 156.8, 144.4, 134.6, 134.2, 126.4,
105.9, 50.8, 36.3, 24.9, 22.6.
Example 110
(5aR,6aS)-5a-(5-chloro-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]-
pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00219##
[0859] Compound was prepared in an analogous manner to Example 53
from 2-(5-chloro-2-fluorophenyl)acetonitrile and
(S)-2-(chloromethyl)oxirane and isolated as a beige solid.
[0860] .sup.1H NMR (DMSO-d6): 11.76 (1H, br s), 7.49 (1H, dd,
J=6.5, 2.7 Hz), 7.43 (1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.30 (1H, dd,
J=10.0, 8.8 Hz), 6.69 (1H, d, J=2.3 Hz), 4.10 (1H, d, J=12.0 Hz),
3.81 (1H, d, J=12.2 Hz), 2.89 (1H, dd, J=8.3, 4.2 Hz), 1.67 (1H,
dd, J=8.4, 5.4 Hz), 1.17 (1H, t, J=4.7 Hz).
[0861] .sup.13C NMR (DMSO-d6): 161.3, 159.7, 156.6, 134.6, 130.2,
130.1, 129.4, 129.3, 128.8, 128.7, 128.3, 128.3, 117.6, 117.4,
106.2, 51.5, 51.5, 32.6, 22.1, 20.9.
Example 111
(6R)-6-(2,3,5,6-tetrafluorophenyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-3(-
2H)-thione
Step 1: tert-butyl
(4R)-2-((1,3-dioxoisoindolin-2-yl)methyl)-4-(2,3,5,6-tetrafluorophenyl)py-
rrolidine-1-carboxylate
##STR00220##
[0863] To a stirred solution of (4R)-tert-butyl
2-(hydroxymethyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-1-carboxylate
(analogous to Example 58 step 10) (0.49 g, 1.262 mmol), phtalimide
(0.312 g, 2.121 mmol) and triphenylphosphine (0.546 g, 2.083 mmol)
in tetrahydrofuran (10 mL) was added dropwise under nitrogen at
0-5.degree. C. with stirring diethyl (E)-diazene-1,2-dicarboxylate
(0.32 mL, 2.02 mmol). The mixture was allowed to warm up naturally
to room temperature and stirred for 64 h. The mixture was then
evaporated to dryness under vacuum and the residue was purified by
chromatography (petroleum ether ethyl acetate; 9:1, then 4:1) to
give (4R)-tert-butyl
2-((1,3-dioxoisoindolin-2-yl)methyl)-4-(2,3,5,6-tetrafluorophenyl)pyrroli-
dine-1-carboxylate as a foam (0.502 g, 83% yield),
Step 2:
((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)methanamine
dihydrochloride
##STR00221##
[0865] A mixture of (4R)-tert-butyl
2-((1,3-dioxoisoindolin-2-yl)methyl)-4-(2,3,5,6-tetrafluorophenyl)pyrroli-
dine-1-carboxylate (0.49 g, 1.024 mmol) and 8 M HCl (16 mL, 128
mmol) was stirred under reflux for 7 h. The solution was then
cooled to room temperature and evaporated to dryness. The residue
was slurried in tetrahydrofuran, the resulting solid was collected,
washed with tetrahydrofuran, and petroleum ether, and dried under
vacuum at 50.degree. C. to give
((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)methanamine
dihydrochloride as a white powder (0.265 g, 81% yield).
Step 3:
(6R)-6-(2,3,5,6-tetrafluorophenyl)hexahydro-3H-pyrrolo[1,2-c]imida-
zole-3-thione
##STR00222##
[0867] To a mixture of
((4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidin-2-yl)methanamine
dihydrochloride (0.24 g, 0.747 mmol) and triethylamine (0.229 mL,
1.644 mmol) in dry tetrahydrofuran (7.5 mL) was added in portions
with stirring di(1H-imidazol-1-yl)methanethione (0.133 g, 0.747
mmol) and the mixture was stirred at room temperature for 30 min.
Tetrahydrofuran was then removed under vacuum, the residue was
suspended in 1 M HCl (20 mL) with sonication. The thus obtained
solid was collected, washed with water and dried under vacuum at
50.degree. C. The crude product was filtered through a short silica
pad in a mixture of ethyl acetate-dichloromethane to give
(6R)-6-(2,3,5,6-tetrafluorophenyl)tetrahydro-1H-pyrrolo[1,2-c]imi-
dazole-3(2H)-thione as a white powder (0.12 g, 55% yield).
[0868] .sup.1H NMR (DMSO-d6): 8.87 (0.7H, s), 8.62 (0.3H, s), 7.80
(1H, m), 4.44 (0.7H, dd, J=11.9, 8.5 Hz), 4.29 (0.7H, qd, J=8.2,
2.9 Hz), 4.21 (0.3H, m), 3.93 (0.6H, m), 3.71(1H, m), 3.55 (1H, m),
3.45 (0.3H, dd, J=10.5, 3.7 Hz), 3.39 (0.7H, m), 3.12 (0.7H, dd,
J=11.7, 8.9 Hz), 2.18 (1H, m), 2.06 (0.7H, m), 1.73 (0.3H, m).
[0869] .sup.13C NMR (DMSO-d6): 186.5, 186.3, 146.4, 146.3, 146.2,
145.2, 145.1, 144.8, 144.7, 144.6, 143.6, 143.5, 121.5, 121.4,
121.3, 120.9, 120.8, 120.7, 105.4, 105.3, 105.2, 105.2, 105.1,
105.0, 62.7, 60.8, 52.2, 51.1, 47.4, 36.6, 35.9, 34.2, 31.7.
Example 112
(S)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-
e-3-thione
##STR00223##
[0871] Compound was prepared in an analogous manner to Example 59
from (E)-2,3,6-trifluoro-5-(2-nitrovinyl)benzene using
4-((R)-hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #524-63-0) and isolated as a light khaki
powder.
[0872] .sup.1H NMR (DMSO-d6): 11.85 (1H, br s), 7.47 (1H, qd,
J=9.5, 4.9 Hz), 7.18 (1H, tdd, J=9.6, 9.6, 3.8, 1.9 Hz), 6.63 (1H,
d, J=1.9 Hz), 4.49 (1H, quin, J=8.6 Hz), 4.19 (1H, dd, J=11.3, 9.4
Hz), 3.75 (1H, dd, J=11.6, 7.8 Hz), 3.32 (1H, dd, J=15.9, 9.3 Hz),
2.94 (1H, dd, J=15.9, 7.8 Hz).
[0873] .sup.13C NMR (DMSO-d6): 157.0, 156.9, 155.9, 155.4, 155.3,
155.3, 155.3, 149.1, 149.1, 149.0, 149.0, 147.6, 147.5, 147.5,
147.4, 147.4, 147.3, 146, 145.9, 145.9, 145.9, 132.2, 119, 118.9,
118.9, 118.8, 116.5, 116.5, 116.4, 116.3, 112.0, 112.0, 112.0,
111.9, 111.8, 111.8, 111.8, 111.8, 106.6, 48.5, 35.7, 29.5.
Example 113
(R)-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-
e-3-thione
##STR00224##
[0875] Compound was prepared in an analogous manner to Example 58
from (E)-2,3,6-trifluoro-5-(2-nitrovinyl)benzene using
4-((S)-hydroxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #70877-75-7) and isolated as a light khaki
powder.
[0876] .sup.1H NMR (DMSO-d6): 11.84 (1H, br s), 7.46 (1H, qd,
J=9.5, 5.1 Hz), 7.17 (1H, ddt, J=1.9, 3.9, 9.8 Hz), 6.62 (1H, d,
J=2.1 Hz), 4.48 (1H, quin, J=8.6 Hz), 4.17 (1H, dd, J=11.3, 9.4
Hz), 3.74 (1H, dd, J=11.6, 7.9 Hz), 3.31 (1H, dd, J=9.6, 16 Hz),
2.93 (1H, dd, J=15.8, 7.9 Hz).
[0877] .sup.13C NMR (DMSO-d6):157, 157, 156.9, 156.9, 155.9, 155.4,
155.4, 155.3, 155.3, 149.1, 149.1, 149, 149, 147.6, 147.6, 147.5,
147.4, 147.4, 147.3, 146, 146, 145.9, 145.9, 132.2, 119, 118.9,
118.9, 118.8, 116.5, 116.5, 116.4, 116.3, 112, 112, 112, 112,
111.9, 111.8, 111.8, 111.8, 106.6, 48.5, 35.7, 29.5.
Example 114
(R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1-
,2-c]imidazole-3-thione
Step 1: (4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic
acid
##STR00225##
[0879] A suspension of
(4R)-1-(tert-butoxycarbonyl)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-c-
arboxylic acid (0.45 g, 1.239 mmol) (analogous to Example 58 step
10) in 2 M HCl (9.29 mL, 18.58 mmol) was stirred under reflux for 2
h. Thereupon, the mixture was concentrated under vacuum, the
residue was dissolved in water, and then pH was adjusted to 7 with
5 M sodium hydroxide. The resulting precipitate was collected,
washed with water and dried to give
(4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid as
an off-white powder (0.2 g, 61% yield).
Step 2:
(6R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxohexahydro-1H-p-
yrrolo[1,2-c]imidazol-1-one
##STR00226##
[0881] To a solution of
(4R)-4-(2,3,5,6-tetrafluorophenyl)pyrrolidine-2-carboxylic acid
(0.18 g, 0.684 mmol) in 0.5 M sodium carbonate (10.94 mL, 5.47
mmol) and dioxane (11 mL) was added methyl isothiocyanate (0.100 g,
1.368 mmol). The mixture was stirred for 1 h at room temperature,
then heated at 50-60.degree. C. to give clear solution. Thereupon,
the reaction was allowed to cool down naturally to room
temperature, and then acidified to pH=1-2 by adding cc HCl. The
reaction was heated under reflux for 1 h, and then evaporate to ca.
5 mL of volume and the separated oily product crystallised on
standing. Thereupon, the mixture was diluted with water (10 mL),
stirred at 0-5.degree. C. for 30 min, the resulting solid was
collected, washed with water and dried under vacuum to give
(6R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxohexahydro-1H-pyrrolo[-
1,2-c]imidazol-1-one as a light cream powder (0.20 g, 92%
yield).
Step 3:
(R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-2,5,6,7-tetrahydro-3H-p-
yrrolo[1,2-c]imidazole-3-thione
##STR00227##
[0883] To a solution of
(6R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-3-thioxohexahydro-1H-pyrrolo[-
1,2-c]imidazol-1-one (0.17 g, 0.534 mmol) in dry tetrahydrofuran (3
mL) was added 65% RED-Al (bis(2-methoxyethoxy)aluminum(III) sodium
hydride) (0.104 mL, 0.347 mmol) in toluene dropwise at 0-5.degree.
C. under nitrogen and the mixture was allowed to stir in the cold
for 30 min. Thereupon, the mixture was quenched with cc HCl (0.445
mL, 5.34 mmol), and allowed to warm up naturally room temperature
and stirred for 1 h. The solvents were then evaporated off, and the
residue was taken up in ethyl acetate. The organic phase was dried
over MgSO.sub.4, filtered, and evaporated to dryness.
Chromatography (petroleum ether-ethyl acetate; 2:1, then 1:1)
afforded
(R)-2-methyl-6-(2,3,5,6-tetrafluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]i-
midazole-3(5H)-thione as a white powder (0.094 g, 58% yield).
[0884] .sup.1H NMR (DMSO-d6): 7.86 (1H, m), 6.88 (1H, s), 4.52 (1H,
quin, J=8.4 Hz), 4.23 (1H, dd, J=11.4, 9.5 Hz), 3.83 (1H, dd,
J=11.7, 7.5 Hz), 3.36 (1H, dd, J=9.4, 16.1 Hz), 3.34 (3H, s),
2.99(1H, dd, J=16.1, 7.6 Hz).
[0885] .sup.13C NMR (DMSO-d6): 156.5, 146.4, 146.4, 146.3, 146.3,
146.2, 145.3, 145.3, 145.3, 145.3, 145.3, 145.2, 145.2, 145.2,
144.8, 144.8, 144.7, 144.7, 144.7, 144.6, 144.6, 143.7, 143.7,
143.7, 143.6, 143.6, 143.6, 130.4, 120.6, 120.5, 120.4, 110.8,
105.9, 105.7, 105.6, 49.3, 35, 34.1, 29.4.
Example 115
(5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3-
,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00228##
[0887] Compound was prepared in an analogous manner to Example 53
from 2-(3-bromo-2,6-difluorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane and isolated as a white solid.
[0888] .sup.1H NMR (DMSO-d6): 11.78 (1H, s), 7.74 (1H, td, J=8.4,
5.9 Hz), 7.16 (1H, dt, J=1, 9.2 Hz), 6.71 (1H, d, J=2.2 Hz), 4.05
(1H, d, J=12.2 Hz), 3.75 (1H, d, J=12.2 Hz), 2.75 (1H, dd, J=8.4,
4.4 Hz), 1.69 (1H, dd, J=8.3, 5.6 Hz), 1.29 (1H, t, J=4.9 Hz).
[0889] .sup.13C NMR (DMSO-d6): 162, 161.9, 160.3, 160.3, 158.9,
158.8, 157.2, 157.2, 156.6, 134.4, 133.1, 133.1, 117.1, 117, 116.8,
113.5, 113.5, 113.4, 113.4, 106.6, 103.8, 103.7, 103.6, 103.6,
51.4, 26.8, 21.8, 21.6.
Example 116
(5aS,6aR)-5a-(5-chloro-2-fluorophenyl)-2-methyl-5,5a,6,6a-tetrahydrocyclop-
ropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00229##
[0891] Compound was prepared in an analogous manner to Example 114
from
(1R,5S)-3-(tert-butoxycarbonyl)-5-(5-chloro-2-fluorophenyl)-3-azabicyclo[-
3.1.0]hexane-2-carboxylic acid and isolated as a light beige
solid.
[0892] .sup.1H NMR (DMSO-d6): 7.50 (1H, dd, J=6.5, 2.7 Hz), 7.43
(1H, ddd, J=8.8, 4.4, 2.7 Hz), 7.30 (1H, dd, J=9.9, 8.9 Hz), 6.93
(1H, s), 4.13 (1H, d, J=11.9 Hz), 3.84 (1H, d, J=12.0 Hz), 2.92
(1H, dd, J=8.4, 4.2 Hz), 1.69(1H, dd, J=8.4, 5.4 Hz), 1.17(1H, t,
J=4.8 Hz).
[0893] .sup.13C NMR (DMSO-d6): 161.3, 159.7, 157.2, 132.9, 130.2,
130.2, 129.4, 129.4, 128.7, 128.6, 128.3, 128.3, 117.6, 117.4,
110.4, 52.3, 52.3, 34.1, 31.9, 22.1, 20.9.
Example 117
(S)-6-(3-bromo-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imi-
dazole-3-thione
##STR00230##
[0895] (E)-1-bromo-2,4-difluoro-3-(2-nitrovinyl)benzene (using
4-((R)-hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #524-63-0)) was converted to
(S)-6-(3-bromo-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]im-
idazole-3-thione by a similar procedure as described for Example 59
and the product was isolated as a light khaki powder.
[0896] .sup.1H NMR (DMSO-d6): 11.85 (1H, br s), 7.72 (1H, ddd,
J=8.9, 8.1, 5.8 Hz), 7.16 (1H, t, J=9.4 Hz), 6.63 (1H, s), 4.50
(1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.5, 9.3 Hz), 3.74 (1H, dd,
J=11.7, 7.7 Hz), 3.31 (1H, dd, J=16.1, 9.5 Hz), 2.92 (1H, dd,
J=15.9, 7.8 Hz).
[0897] .sup.13C NMR (DMSO-d6): 160.8, 160.8, 159.2, 159.1, 157.6,
157.5, 155.9, 155.9, 155.8, 132.5, 132.4, 132.3, 118.9, 118.8,
118.6, 113.8, 113.8, 113.6, 113.6, 106.6, 104.1, 104.1, 103.9,
103.9, 48.6, 35.7, 29.5.
Example 118
(R)-6-(3-bromo-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imi-
dazole-3-thione
##STR00231##
[0899] (E)-1-bromo-2,4-difluoro-3-(2-nitrovinyl)benzene (using
4-((S)-hydroxy((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #70877-75-7)) was converted to
(R)-6-(3-bromo-2,6-difluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]im-
idazole-3-thione by a similar procedure as described for Example 58
and the product was isolated as a light beige powder.
[0900] .sup.1H NMR (DMSO-d6): 11.85 (1H, br s), 7.72 (1H, ddd,
J=8.9, 8.1, 5.8 Hz), 7.16 (1H, t, J=9.4 Hz), 6.63 (1H, s), 4.50
(1H, quin, J=8.5 Hz), 4.17 (1H, dd, J=11.5, 9.3 Hz), 3.74 (1H, dd,
J=11.7, 7.7 Hz), 3.31 (1H, dd, J=16.1, 9.5 Hz), 2.92 (1H, dd,
J=15.9, 7.8 Hz).
[0901] .sup.13C NMR (DMSO-d6): 160.8, 160.8, 159.2, 159.1, 157.6,
157.5, 155.9, 155.9, 155.8, 132.5, 132.4, 132.3, 118.9, 118.8,
118.6, 113.8, 113.8, 113.6, 113.6, 106.6, 104.1, 104.1, 103.9,
103.9, 48.6, 35.7, 29.5.
Example 119
(5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3-
,4]pyrrolo[2,1-c][1,2,4]triazole-3(2H)-thione
##STR00232##
[0903] Compound was prepared in an analogous manner to Example 60
from tert-butyl
(((1S,2R)-1-(3-bromo-2,6-difluorophenyl)-2-(hydroxymethyl)cyclopropyl)met-
hyl)carbamate and isolated as a pink solid.
[0904] .sup.1H NMR (DMSO-d6): 13.29 (1H, s), 7.78 (1H, td, J=8.5,
5.9 Hz), 7.18 (1H, td, J=9.2, 1.3 Hz), 4.12 (1H, d, J=12.2 Hz),
3.85 (1H, d, J=12.2 Hz), 2.94 (1H, dd, J=8.8, 4.3 Hz), 1.81 (1H,
dd, J=8.8, 5.9 Hz), 1.67 (1H, d, J=4.7 Hz).
[0905] .sup.13C NMR (DMSO-d6): 163.6, 161.8, 161.8, 160.2, 160.2,
158.8, 158.7, 157.6, 157.1, 157.1, 133.5, 133.5, 116.1, 116.0,
115.9, 113.6, 113.5, 113.4, 113.4, 103.8, 103.8, 103.6, 103.6,
49.5, 27.4, 20.1, 19.7.
Example 120
(5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-5,5a,6,6a-tetrahydrocyclopropa[3,4]p-
yrrolo[2,1-c][1,2,4]triazole-3(2H)-thione
##STR00233##
[0907] Compound was prepared in an analogous manner to Example 60
from tert-butyl
(((1S,2R)-1-(5-bromo-2-fluorophenyl)-2-(hydroxymethyl)cyclopropyl)methyl)-
carbamate and isolated as a pale brown solid.
[0908] .sup.1H NMR (DMSO-d6): 7.69 (1H, dd, J=6.7, 2.5 Hz), 7.58
(1H, ddd, J=8.8, 4.5, 2.6 Hz), 7.26 (1H, dd, J=10.0, 8.8 Hz), 4.15
(1H, d, J=11.9 Hz), 3.87 (1H, d, J=11.9 Hz), 3.08 (1H, dd, J=8.9,
4.0 Hz), 1.78 (1H, dd, J=8.7, 5.6 Hz), 1.51 (1H, dd, J=4.3, 5.5
Hz).
[0909] .sup.13C NMR (DMSO-d6): 163.6, 161.8, 160.1, 157.9, 133.2,
133.2, 132.7, 132.7, 128.3, 128.1, 118.0, 117.9, 116.2, 49.7, 33,
20.6, 19.1.
Example 121
(5aS,6aR)-5a-(3-bromo-2,6-difluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyc-
lopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00234##
[0911] Compound was prepared in an analogous manner to Example 80
from 2-(3-bromo-2,6-difluorophenyl)acetonitrile and
(R)-2-(chloromethyl)oxirane and isolated as a white solid.
[0912] .sup.1H NMR (DMSO-d6): 11.68 (1H, br s), 7.74 (1H, td,
J=8.4, 5.9 Hz), 7.15 (1H, td, J=9.2, 1.2 Hz), 4.01 (1H, d, J=12.3
Hz), 3.71 (1H, d, J=12.0 Hz), 2.72 (1H, dd, J=8.3, 4.5 Hz), 2.05
(3H, s), 1.65 (1H, dd, J=8.2, 5.6 Hz), 1.25 (1H, t, J=5.0 Hz).
[0913] .sup.13C NMR(DMSO-d6): 161.9, 161.9, 160.3, 160.2, 158.8,
158.8, 157.2, 157.1, 155.7, 133.0, 133.0, 130.0, 117.2, 117.1,
115.1, 113.5, 113.3, 103.7, 103.7, 103.6, 51.4, 26.5, 21.8, 20.9,
9.4.
Example 122
(5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclopr-
opa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00235##
[0914] Step 1:
((1R,2S)-2-(aminomethyl)-2-(5-bromo-2-fluorophenyl)cyclopropyl)methanol
##STR00236##
[0916] To a stirred solution of
2-(5-bromo-2-fluorophenyl)acetonitrile (10 g, 46.7 mmol) in dry
tetrahydrofuran (100 mL), was added (R)-2-(chloromethyl)oxirane
(4.38 mL, 56.1 mmol) at room temperature, under inert atmosphere,
The reaction was then cooled to 0.degree. C. and 2 M sodium
bis(trimethylsilyl)amide in tetrahydrofuran (40.9 mL, 82 mmol) was
added dropwise keeping the temperature between 0-5.degree. C.
Thereupon, the obtained red mixture was allowed to warm up to room
temperature and stirred for 3 h. The reaction was diluted with dry
tetrahydrofuran (100 mL), cooled to 0.degree. C. and sodium
borohydride (7.07 g, 187 mmol) was added, followed by dropwise
addition of boron trifluoride etherate (23.68 mL, 187 mmol). The
mixture was allowed to warm to room temperature naturally and
stirred overnight. The obtained pale yellow suspension was then
cooled to 0.degree. C. and carefully quenched with 2 M HCl (140 ml,
280 mmol). The tetrahydrofuran was evaporated off under vacuum, the
aqueous phase was washed with diethyl ether (discarded), then was
basified to pH=10 (3 M NaOH) and extracted with dichloromethane.
The organic phase was dried over MgSO.sub.4, filtered and
evaporated to leave a yellow oil. Yield: 11.75 g, 73%.
Step 2: tert-butyl
(((1S,2R)-1-(5-bromo-2-fluorophenyl)-2-(hydroxymethyl)cyclopropyl)methyl)-
carbamate
##STR00237##
[0918] To an ice-cooled solution of
((1R,2S)-2-(aminomethyl)-2-(5-bromo-2-fluorophenyl)cyclopropyl)methanol
(11.75 g, 42.9 mmol) in ethanol (145 mL), was added di-tert-butyl
dicarbonate (9.35 g, 42.9 mmol). The solution was stirred at room
temperature for 4 h. Then the solvent was evaporated and the
residue was separated on a column. The titled compound was isolated
as a yellow foam. Yield: 10.1 g, 56%.
Step 3: tert-butyl
(1S,5R)-1-(5-bromo-2-fluorophenyl)-4-hydroxy-3-azabicyclo[3.1.0]hexane-3--
carboxylate
##STR00238##
[0920] To a stirred solution of oxalyl dichloride (2.60 mL, 29.7
mmol) in dry dichloromethane (62.8 mL), was added dropwise a
solution of DMSO (4.21 mL, 59.4 mmol) in dry dichloromethane (12.5
mL) at -78.degree. C. over 30 min. The reaction mixture was stirred
for 5 min in the cold, and then a solution of tert-butyl
(((1S,2R)-1-(5-bromo-2-fluorophenyl)-2-(hydroxymethyl)cyclopropyl)methyl)-
carbamate (10.1 g, 27.0 mmol) in dry dichloromethane (25 mL) was
added, dropwise over 30 min. The mixture was stirred at -78.degree.
C. for 1 h, and then triethylamine (18.8 mL, 135 mmol) was added.
The reaction was allowed to warm up gradually to room temperature
and stirred for 2 h. Thereupon the mixture was washed three times
with water, dried over MgSO.sub.4, filtered and evaporated to give
a yellow oil. Yield: 10.1 g, 85 %.
Step 4: tert-butyl
(1S,5R)-1-(5-bromo-2-fluorophenyl)-4-cyano-3-azabicyclo[3.1.0]hexane-3-ca-
rboxylate
##STR00239##
[0922] To a stirred solution of tert-butyl
(1S,5R)-1-(5-bromo-2-fluorophenyl)-4-hydroxy-3-azabicyclo[3.1.0]hexane-3--
carboxylate (10.1 g, 27.1 mmol) in dry dichloromethane (133 mL) was
added trimethylsilanecarbonitrile (9.71 mL, 72.4 mmol) at room
temperature under inert atmosphere. Then, the solution was cooled
to -78.degree. C. and boron trifluoride diethyl etherate (10.08 mL,
80.0 mmol) was added dropwise. The reaction mixture was stirred at
-78.degree. C. for 4 h., and then saturated solution of NaHCO.sub.3
was added and the mixture was allowed to warm to room temperature.
The organic phase was separated and aqueous phase was extracted
with dichloromethane. The combined organic phases were dried over
MgSO.sub.4, filtered and evaporated to give 10.3 g of yellow oil.
Yield: 85%.
Step 5:
(1R,5S)-5-(5-bromo-2-fluorophenyl)-3-(tert-butoxycarbonyl)-3-azabi-
cyclo[3.1.0]hexane-2-carboxylic acid
##STR00240##
[0924] To a stirred solution of tert-butyl
(1S,5R)-1-(5-bromo-2-fluorophenyl)-4-cyano-3-azabicyclo[3.1.0]hexane-3-ca-
rboxylate (10.3 g, 27.0 mmol) in ethanol (93 mL), at room
temperature was added a solution of 3 M NaOH (45 mL, 135 mmol). The
solution was heated at 80.degree. C. for 3 h. Then, the reaction
was cooled to room temperature, ethanol was evaporated and the aq.
phase was acidified with 2N HCl solution, the resulting solid was
filtered off, dissolved in a mixture of dichloromethane-isopropanol
(7:3). The organic phase was dried over MgSO.sub.4, filtered and
evaporated to give the titled product as a yellow semi-solid.
Yield: 10.5 g, 78%.
Step 6: tert-butyl
(1S,5R)-1-(5-bromo-2-fluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabicy-
clo[3.1.0]hexane-3-carboxylate
##STR00241##
[0926] To a stirred solution of
((1R,5S)-5-(5-bromo-2-fluorophenyl)-3-(tert-butoxycarbonyl)-3-azabicyclo[-
3.1.0]hexane-2-carboxylic acid (2.5 g, 6.25 mmol) in anhydrous
dichloromethane (36 mL) was added di(1H-imidazol-1-yl)methanone
(1.215 g, 7.50 mmol) portion wise under nitrogen and the reaction
stirred for 30 min. Thereupon, N,O-dimethylhydroxylamine
hydrochloride (0.731 g, 7.50 mmol) was added and the mixture was
stirred overnight. The reaction mixture was then diluted with
dichloromethane (ca. to 60 mL) and washed with water. The organic
phase was dried over MgSO.sub.4, filtered and evaporated to give
the titled product as a yellow yellow oil. Yield: 1.57 g, 45%.
Step 7: tert-butyl
(1S,5R)-4-acetyl-1-(5-bromo-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-c-
arboxylate
##STR00242##
[0928] To a stirred solution of (1S,5R)-tert-butyl
1-(5-bromo-2-fluorophenyl)-4-(methoxy(methyl)carbamoyl)-3-azabicyclo[3.1.-
0]hexane-3-carboxylate (1.57 g, 3.54 mmol) in anhydrous
tetrahydrofuran (15 mL) was added methylmagnesium iodide (3.54 ml,
10.62 mmol) dropwise at 0.degree. C. The reaction mixture was
stirred in the cold for 1 h, and then quenched by addition of 1 M
HCl (14.17 ml, 14.17 mmol). The mixture was extracted with a
mixture of ethyl acetate-petroleum ether (1:1). The organic phase
was washed with brine, dried over MgSO.sub.4, filtered and
evaporated to give 1.34 g of yellow oil. Yield: 86%.
Step 8:
1-((1R,5S)-5-(5-bromo-2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-y-
l)ethan-1-one hydrochloride
##STR00243##
[0930] To a stirred solution of (1S,5R)-tert-butyl
4-acetyl-1-(5-bromo-2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxyla-
te (1.33 g, 3.34 mmol) was added 4 M HCl in dioxane (6.68 mL, 26.7
mmol) and then the mixture was stirred at room temperature for 2 h.
Thereupon, diethyl ether was added and the mixture was evaporated
to dryness to give an orange oil. Yield: 1.2 g, 91%.
Step 9:
(5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-methyl-5,5a,6,6a-tetrahydr-
ocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00244##
[0932] To a stirred solution of
1-((1R,5S)-5-(5-bromo-2-fluorophenyl)-3-azabicyclo[3.1.0]hexan-2-yl)ethan-
one hydrochloride (1.1 g, 3.29 mmol) in a mixture of ethanol (13.5
mL) and water (13.5 mL) was added potassium thiocyanate (0.351 g,
3.62 mmol) followed by addition of cc. HCl (0.135 mL, 1.644 mmol).
The solution was heated at reflux for 1 h. The reaction was cooled
to room temperature, and then ethanol was removed. The aqueous
phase was extracted with dichloromethane, the organic phase was
dried over MgSO.sub.4, filtered and evaporated. Chromatography in a
mixture of dichloromethane-methanol afforded the titled compound as
a beige foam. Yield: 0.9 g, 77%.
[0933] .sup.1H NMR (DMSO-d6): 11.65 (1H, s), 7.59 (1H, dd, J=6.7,
2.5 Hz), 7.55 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.24 (1H, dd, J=10.1,
8.7 Hz), 4.05 (1H, d, J=12.0 Hz), 3.76 (1H, d, J=12.0 Hz), 2.87
(1H, dd, J=8.3, 4.3 Hz), 2.04 (3H, s), 1.64 (1H, dd, J=8.2, 5.3
Hz), 1.12(1H, t, J=4.8 Hz).
[0934] .sup.13C NMR (DMSO-d6): 161.8, 160.2, 155.7, 132.9, 132.9,
132.3, 132.2, 130.2, 129.4, 129.3, 118, 117.8, 116.2, 116.2, 114.8,
51.5, 51.5, 32.2, 22.2, 20.2, 9.3.
Example 123
(5aS,6aR)-5a-(3-chloro-2,6-difluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocy-
clopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00245##
[0936] Compound was prepared in an analogous manner to Example 122
from 2-(3-chloro-2,6-difluorophenyl)acetonitrile. The product was
isolated as a beige solid.
[0937] .sup.1H NMR (DMSO-d6): 11.68 (1H, s), 7.63 (1H, td, J=8.6,
5.8 Hz), 7.21 (1H, t, J=8.6 Hz), 4.01 (1H, d, J=12.2 Hz), 3.72 (1H,
d, J=12.2 Hz), 2.73 (1H, dd, J=8.2, 4.4 Hz), 2.05 (3H, s), 1.65
(1H, dd, J=8.2, 5.6 Hz), 1.25 (1H, t, J=5.0 Hz).
[0938] .sup.13C NMR (DMSO-d6): 161.2, 161.2, 159.6, 159.6, 157.8,
157.8, 156.2, 156.1, 155.7, 130.3, 130.2, 129.9, 117.2, 117.1, 117,
115.7, 115.7, 115.6, 115.6, 115.1, 112.9, 112.9, 112.8, 112.8,
51.4, 26.4, 21.7, 20.8, 9.4.
Example 124
(R)-6-(3-bromo-2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[-
1,2-c]imidazole-3-thione
##STR00246##
[0940] Compound was prepared in an analogous manner to Example 129
from 3-bromo-2,6-difluorobenzaldehyde and isolated as a beige
powder.
[0941] .sup.1H NMR (DMSO-d6): 11.73 (1H, br s), 7.72 (1H, ddd,
J=8.9, 8.1, 5.8 Hz), 7.16 (1H, m), 4.44 (1H, quin, J=8.6 Hz), 4.13
(1H, dd, J=11.5, 9.2 Hz), 3.71 (1H, dd, J=11.6, 7.9 Hz), 3.23 (1H,
dd, J=15.5, 9.3 Hz), 2.84 (1H, dd, J=15.4, 8.1 Hz), 1.97 (3H,
s).
[0942] .sup.13C NMR (DMSO-d6): 160.8, 160.8, 159.2, 159.1, 157.5,
157.5, 155.9, 155.8, 155, 132.4, 132.4, 127.7, 118.8, 118.7, 118.6,
115.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5,
35.8, 28.7, 9.3.
Example 125
(S)-6-(3-bromo-2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[-
1,2-c]imidazole-3-thione
##STR00247##
[0944] Compound was prepared in an analogous manner to Example 129
from 3-bromo-2,6-difluorobenzaldehyde using
4-((R)-hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #524-63-0) and isolated as a beige powder.
[0945] .sup.1H NMR (DMSO-d6): 11.72 (1H, br s), 7.72 (1H, ddd,
J=8.9, 8.1, 5.8 Hz), 7.16 (1H, m), 4.44 (1H, t, J=8.7 Hz), 4.13
(1H, dd, J=11.5, 9.2 Hz), 3.71 (1H, dd, J=11.6, 7.9 Hz), 3.23 (1H,
dd, J=15.5, 9.3 Hz), 2.84 (1H, dd, J=15.5, 8.1 Hz), 1.97 (3H,
s).
[0946] .sup.13C NMR (DMSO-d6): 160.8, 160.8, 159.2, 159.1, 157.5,
157.5, 155.9, 155.8, 155, 132.4, 132.4, 127.7, 118.8, 118.7, 118.6,
115.1, 113.8, 113.8, 113.6, 113.6, 104.1, 104, 103.9, 103.9, 48.5,
35.8, 28.7, 9.3.
Example 126
(5aS,6aR)-5a-(3-chloro-5-fluorophenyl)-1-methyl-5,5a,6,6a-tetrahydrocyclop-
ropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00248##
[0948] Compound was prepared in an analogous manner to Example 122
from 2-(3-chloro-5-fluorophenyl)acetonitrile. The product was
isolated as a beige solid.
[0949] .sup.1H NMR (DMSO-d6): 11.64 (1H, s), 7.30 (1H, dt, J=8.7,
2.1 Hz), 7.28 (1H, t, J=1.6 Hz), 7.23 (1H, dt, J=10.0, 1.8 Hz),
4.19 (1H, d, J=12.2 Hz), 3.99 (1H, d, J=12.0 Hz), 3.00 (1H, dd,
J=8.3, 4.3 Hz), 2.03 (3H, s), 1.64 (1H, dd, J=8.3, 5.2 Hz), 1.14
(1H, t, J=4.8 Hz).
[0950] .sup.13C NMR (DMSO-d6): 163.1, 161.4, 156, 145, 144.9,
134.1, 134.1, 130.2, 123, 123, 114.5, 114.3, 114.1, 112.9, 112.8,
50.8, 36, 36, 25.2, 22.2, 9.3.
Example 127
(5aS,6aR)-5a-(5-bromo-2-fluorophenyl)-1-(methyl-d.sub.3)-5,5a,6,6a-tetrahy-
drocyclopropa[3,4]pyrrolo[1,2-c]imidazole-3(2H)-thione
##STR00249##
[0952] Compound was prepared in an analogous manner to Example 122
from 2-(5-bromo-2-fluorophenyl)acetonitrile. The product was
isolated as a beige solid.
[0953] .sup.1H NMR (DMSO-d6): 11.65 (1H, s), 7.59 (1H, dd, J=6.7,
2.6 Hz), 7.55 (1H, ddd, J=8.7, 4.5, 2.6 Hz), 7.23 (1H, dd, J=10.1,
8.7 Hz), 4.05 (1H, d, J=12.0 Hz), 3.76 (1H, d, J=12.0 Hz), 2.87
(1H, dd, J=8.2, 4.3 Hz), 1.64 (1H, dd, J=8.3, 5.4 Hz), 1.12 (1H, t,
J=4.8 Hz).
[0954] .sup.13C NMR (DMSO-d6): 161.8, 160.2, 155.7, 132.9, 132.9,
132.3, 132.2, 130.3, 129.4, 129.3, 118, 117.8, 116.2, 116.2, 114.7,
51.5, 51.5, 32.3, 22.2, 20.2.
Example 128
(S)-6-(5-bromo-2-fluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2--
c]imidazole-3-thione
##STR00250##
[0956] Compound was prepared in an analogous manner to Example 129
from 5-bromo-2-fluorobenzaldehyde using
4-((R)-hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #524-63-0) and isolated as an off-white solid.
[0957] .sup.1H NMR(DMSO-d6): 11.70 (1H, br s), 7.58 (1H, dd, J=6.7,
2.5 Hz), 7.53 (1H, ddd, J=8.7, 4.5, 2.5 Hz), 7.23 (1H, dd, J=10.3,
8.8 Hz), 4.20 (1H, quin, J=8.1 Hz), 4.11 (1H, dd, J=10.9, 8.1 Hz),
3.71 (1H, dd, J=11.3, 7.9 Hz), 3.18 (1H, dd, J=15.2, 8.1 Hz), 2.85
(1H, ddd, J=15.2, 8.3, 1.2 Hz), 1.98 (3H, s).
[0958] .sup.13C NMR(DMSO-d6): 160.3, 158.7, 155.1, 131.8, 131.8,
131.4, 131.4, 130.6, 130.5, 127.5, 118, 117.9, 116.5, 116.4, 115.4,
49, 40.5, 29, 9.3.
Example 129
(R)-1-methyl-6-(2,3,6-trifluorophenyl)-6,7-dihydro-2H-pyrrolo[1,2-c]imidaz-
ole-3(5H)-thione
##STR00251##
[0959] Step 1: (E)-1,2,4-trifluoro-3-(2-nitrovinyl)benzene
##STR00252##
[0961] To a solution of methanol (90 mL) and 1.5 M sodium hydroxide
(131 mL, 197 mmol) was added a solution of
2,3,6-trifluorobenzaldehyde (30 g, 187 mmol) and nitromethane (16
mL, 299 mmol) in methanol (60 mL) dropwise over 40 min at 5.degree.
C., while the internal temperature was maintained between 5 and
10.degree. C. with external cooling. The reaction was then agitated
in the cold for 30 min., and then a solution of acetic acid (16 mL,
281 mmol) was added in one portion at 0-10.degree. C. with
stirring. The resulting mixture extracted with dichloromethane (ca.
200 mL), the organic phase was washed with brine, dried
(MgSO.sub.4), filtered to give
1-(2,3,6-trifluorophenyl)-2-nitroethanol solution in
dichloromethane. Thereupon, the above solution (ca. 270 mL) was
treated with N,N-dimethylpyridin-4-amine (2.289 g, 18.74 mmol)
followed by addition of acetic anhydride (21.26 ml, 225 mmol) and
the mixture was stirred at room temperature overnight. The reaction
mixture was then washed with water and sodium bicarbonate solution,
respectively. The organic phase was dried over MgSO.sub.4, filtered
and evaporated to dryness. The crude product was crystallized from
a mixture of isopropanol and water to give a light brownish solid.
Yield: 38.1 g, 88%.
Step 2: diethyl
(R)-2-(2-nitro-1-(2,3,6-trifluorophenyl)ethyl)malonate
##STR00253##
[0963] To a cold solution of
(E)-1,2,4-trifluoro-3-(2-nitrovinyl)benzene (5 g, 24.62 mmol) and
1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(dimethylamino)cyclohexyl-
)thiourea (CAS #620960-26-1) (0.305 g, 0.738 mmol) in dry toluene
(40 ml) was added diethyl malonate (4.88 mL, 32.0 mmol) and the
solution was kept for 16 h at -20.degree. C. (in the freezer), the
reaction was then warmed up to room temperature, washed with 30 mL
of 1 M HCl solution, dried over MgSO.sub.4, filtered through a
silica pad and evaporated to dryness to give (R)-diethyl
2-(2-nitro-1-(2,3,6-trifluorophenyl)ethyl)malonate as a yellowish
oil. Yield: 10.3 g, 98%.
Step 3: ethyl
(4R)-2-oxo-4-(2,3,6-trifluorophenyl)pyrrolidine-3-carboxylate
##STR00254##
[0965] To a suspension of (R)-diethyl
2-(2-nitro-1-(2,3,6-trifluorophenyl)ethyl)malonate (10.3 g, 22.68
mmol) in methanol (115 mL) was added nickel(II) chloride
hexahydrate (5.39 g, 22.68 mmol) followed by addition of sodium
borohydride (6.86 g, 181 mmol) in portions with ice cooling over 30
min. The mixture was stirred for 5 h at room temperature, then
quenched with 2 M HCl solution (60 mL) followed by addition of cc.
ammonia (5 mL). The mixture was then diluted with dichloromethane
(150 mL), acidified with 6 M HCl to pH=2, and stirred for 16 h to
give a clear solution. Thereupon, the mixture was extracted with
dichloromethane, the organic phase was dried over MgSO.sub.4,
filtered and evaporated to dryness. Crystallization from petroleum
ether gave the titled product as a light beige powder. (Yield: 6.19
g, 95%).
Step 4:
(4R)-2-oxo-4-(2,3,6-trifluorophenyl)pyrrolidine-3-carboxylic
acid
##STR00255##
[0967] To a stirred solution (4R)-ethyl
2-oxo-4-(2,3,6-trifluorophenyl)pyrrolidine-3-carboxylate (6 g,
20.89 mmol) in ethanol (90 mL) was added 1 M sodium hydroxide (25.1
mL, 25.1 mmol). The resulting suspension was stirred for 2 h at
room temperature, the organics were then removed under vacuum, and
the residue was dissolved in water (50 mL). The product was
crystallized on acidification with 6 M HCl. The resulting crystals
were collected, washed with cold water and dried under vacuum at
50.degree. C. to give the product as a beige powder. Yield: 4.75 g,
88%.
Step 5: (R)-4-(2,3,6-trifluorophenyl)pyrrolidin-2-one
##STR00256##
[0969] A solution of
(4R)-2-oxo-4-(2,3,6-trifluorophenyl)pyrrolidine-3-carboxylic acid
(4.64 g, 17.90 mmol) in toluene (150 mL) was stirred under reflux
for 3 h, thereupon, the mixture was evaporated to 30 mL followed by
addition of petroleum ether afforded the titled product as a beige
powder. Yield: 3.45 g, 90%.
Step 6: tert-butyl
(R)-2-oxo-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate
##STR00257##
[0971] To a stirred solution of
(R)-4-(2,3,6-trifluorophenyl)pyrrolidin-2-one (3.35 g, 15.57 mmol))
in dry dichloromethane (14 mL) was added at room temperature
di-tert-butyl dicarbonate (5.10 g, 23.35 mmol) followed by addition
of N,N-dimethylpyridin-4-amine (1.902 g, 15.57 mmol). The mixture
was then stirred at room temperature for 24 h at room temperature,
and then diluted with dichloromethane to 80 mL washed with 10%
citric acid (80 mL). The organic phase was dried (MgSO.sub.4),
filtered through silica pad, and then the filtrate was evaporated
to dryness. Crystallization from petroleum ether afforded
(R)-teat-butyl
2-oxo-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate as an
off-white powder. Yield: 4.15 g, 85%.
Step 7: tert-butyl
(4R)-2-hydroxy-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate
##STR00258##
[0973] To a stirred solution of (R)-tert-butyl
2-oxo-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate (4 g,
12.69 mmol) in a mixture of dry diethyl ether (39 mL) and
tetrahydrofuran (13 mL) was added dropwise 65% RED-Al
(bis(2-methoxyethoxy)aluminum(III) sodium hydride) (2.67 mL, 8.88
mmol) in toluene at 5-7.degree. C. under nitrogen and the mixture
was stirred for 1 h in the cold. Thereupon, the mixture was
quenched with sodium bicarbonate solution (ca. 40 mL) and stirred
for 30 min. The organic phase was dried over MgSO.sub.4, filtered
and evaporated to dryness to give the product as a yellowish oil.
(Yield: 4.55 g, 96%).
Step 8: tert-butyl
(4R)-2-cyano-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate
##STR00259##
[0975] To a stirred solution of (4R)-tert-butyl
2-methoxy-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate (4.33
g, 11.76 mmol) in dry dichloromethane (90 mL) was added
trimethylsilanecarbonitrile (3.15 mL, 23.52 mmol) followed by
addition of boron trifluoride diethyl etherate (3.28 mL, 25.9 mmol)
at -70.degree. C. The mixture was stirred for 4 h in the cold,
quenched with sodium bicarbonate solution, and then allowed to warm
up with stirring to room temperature. The organic phase was dried
over MgSO.sub.4, filtered and evaporated to dryness under vacuum to
give the titled compound as a yellowish oil. (Yield: 4.41 g,
98%).
Step 9: tert-butyl
(4R)-2-carbamoyl-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate
##STR00260##
[0977] To a stirred solution of (4R)-tert-butyl
2-cyano-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate (4.4 g,
11.46 mmol) in a mixture of acetone (54 mL) and water (18 mL) was
added urea hydrogen peroxide complex (5.39 g, 57.3 mmol) followed
by potassium carbonate (0.317 g, 2.292 mmol) and the reaction was
stirred at room temperature for 16 h. Acetone was then partially
removed under vacuum until oil separation. The mixture was diluted
with water and petroleum ether, aged with stirring for 1 h at
5-7.degree. C. (crystallization occurred). The solid was collected,
washed with water, petroleum ether and dried to give
(4R)-tert-butyl
2-carbamoyl-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate.
Yield: 3.46 g, 88%.
Step 10:
(4R)-1-(tert-butoxycarbonyl)-4-(2,3,6-trifluorophenyl)pyrrolidine-
-2-carboxylic acid
##STR00261##
[0979] A stirred suspension of (4R)-tert-butyl
2-carbamoyl-4-(2,3,6-trifluorophenyl)pyrrolidine-1-carboxylate
(3.36 g, 9.76 mmol) in 2 M HCl (73 mL, 146 mmol) was refluxed for 3
h to give a clear solution with minimum amount of dark insoluble
material. After being cooled to room temperature the solid was
filtered off and the filtrate was concentrated under vacuum. The
residue was dissolved in water (ca. 50 mL), the pH was adjusted to
7 by addition of 1 M NaOH (19.52 mL, 19.52 mmol). The solution was
then concentrated to approx. 50 mL and methanol (55 mL) was added
followed by addition of di-tert-butyl dicarbonate (2.343 g, 10.73
mmol) and the mixture was stirred for 45 min. Methanol was then
removed under vacuum, the residue was diluted with water (25 mL)
and washed with petroleum ether. The aqueous phase was acidified to
pH=1-2 by addition of 2 M HCl, and then extracted with DCM (50 ml).
The organic phase was dried over MgSO.sub.4, filtered and
evaporated to dryness to give
(4R)-1-(tert-butoxycarbonyl)-4-(2,3,6-trifluorophenyl)pyrrolidine-2-carbo-
xylic acid as a light beige powder. Yield: 2.8 g, 83%.
Step 11-14:
(R)-1-methyl-6-(2,3,6-trifluorophenyl)-2,5,6,7-tetrahydro-3H-pyrrolo[1,2--
c]imidazole-3-thione
##STR00262##
[0981] Compound was prepared in an analogous manner to Example 122
(Steps 6-9) from
(4R)-1-(tert-butoxycarbonyl)-4-(2,3,6-trifluorophenyl)pyrrolidi-
ne-2-carboxylic acid and isolated as an off-white powder.
[0982] .sup.1H NMR (DMSO-d6): 11.72 (1H, br s), 7.47 (1H, qd,
J=9.4, 5.0 Hz), 7.17 (1H, tdd, J=9.6, 9.6, 3.7, 1.9 Hz), 4.43 (1H,
quin, J=8.7 Hz), 4.14 (1H, dd, J=11.3, 9.2 Hz), 3.73 (1H, dd,
J=11.5, 8.1 Hz), 3.24 (1H, dd, J=15.6, 9.2 Hz), 2.86 (1H, dd,
J=15.4, 8.4 Hz), 1.97 (3H, s).
[0983] .sup.13C NMR (DMSO-d6): 156.9, 156.9, 156.9, 156.9, 155.3,
155.3, 155.3, 155.3, 155, 149.1, 149, 149, 148.9, 147.5, 147.5,
147.4, 147.4, 147.3, 147.3, 145.9, 145.9, 145.8, 145.8, 127.6,
118.9, 118.8, 118.8, 118.7, 116.5, 116.4, 116.3, 116.3, 115.2, 112,
112, 111.9, 111.9, 111.8, 111.8, 111.8, 111.7, 48.4, 35.7, 28.6,
9.3.
Example 130
(R)-6-(5-bromo-2-fluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2--
c]imidazole-3-thione
##STR00263##
[0985] Compound was prepared in an analogous manner to Example 129
from 5-bromo-2-fluorobenzaldehyde and isolated as an off-white
solid.
[0986] .sup.1H NMR (DMSO-d6): 11.70 (1H, br s), 7.58 (1H, dd,
J=6.6, 2.5 Hz), 7.53 (1H, ddd, J=8.7, 4.5, 2.5 Hz), 7.23 (1H, dd,
J=10.3, 8.7 Hz), 4.20 (1H, quin, J=8.1 Hz), 4.11 (1H, dd, J=10.9,
8.2 Hz), 3.71 (1H, dd, J=11.3, 7.9 Hz), 3.18 (1H, dd, J=15.2, 8.1
Hz), 2.85 (1H, ddd, J=15.2, 8.4, 1.1 Hz), 1.98 (3H, s).
[0987] .sup.13C NMR (DMSO-d6): 160.3, 158.7, 155.1, 131.8, 131.8,
131.4, 131.4, 130.6, 130.5, 127.6, 118, 117.9, 116.5, 116.4, 115.4,
49, 40.5, 29, 9.3.
Example 131
(R)-6-(2,6-difluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]im-
idazole-3-thione
##STR00264##
[0989] Compound was prepared in an analogous manner to Example 129
from 2,6-difluorobenzaldehyde and isolated as an off-white
solid.
[0990] .sup.1H NMR (DMSO-d6): 11.72 (1H, br s), 7.40 (1H, tt,
J=8.4, 6.6 Hz), 7.13 (2H, m), 4.41 (1H, quin, J=8.8 Hz), 4.12 (1H,
m), 3.70 (1H, dd, J=11.4, 8.4 Hz), 3.21 (1H, dd, J=15.2, 9.2 Hz),
2.84 (1H, dd, J=15.4, 8.7 Hz), 1.97 (3H, s).
[0991] .sup.13C NMR (DMSO-d6): 161.6, 161.6, 160, 159.9, 155,
129.8, 129.7, 129.7, 127.8, 116.6, 116.5, 116.4, 115.2, 112.3,
112.2, 112.1, 112.1, 48.6, 35.4, 28.8, 9.3.
Example 132
(S)-6-(5-chloro-2-fluorophenyl)-1-methyl-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-
-c]imidazole-3-thione
##STR00265##
[0993] Compound was prepared in an analogous manner to Example 129
from 5-chloro-2-fluorobenzaldehyde using
4-((R)-hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol
as catalyst (CAS #524-63-0) and isolated as a beige solid.
[0994] .sup.1H NMR (DMSO-d6): 11.70 (1H, br s), 7.46 (1H, dd,
J=6.5, 2.7 Hz), 7.40 (1H, ddd, J=8.8, 4.4, 2.6 Hz), 7.29 (1H, dd,
J=10.1, 8.8 Hz), 4.20 (1H, quin, J=8.1 Hz), 4.11 (1H, dd, J=10.8,
8.1 Hz), 3.72 (1H, dd, J=11.3, 7.9 Hz), 3.18 (1H, dd, J=15.1, 8.1
Hz), 2.85 (1H, ddd, J=15.2, 8.3, 1.2 Hz), 1.98 (3H, s).
[0995] .sup.13C NMR (DMSO-d6): 159.8, 158.2, 155.1, 130.2, 130.1,
128.9, 128.8, 128.5, 128.5, 127.6, 117.6, 117.4, 115.5, 49.1, 49.1,
40.5, 29, 9.3.
G. DOPAMINE-.beta.-HYDROXYLASE INHIBITION ASSAYS
[0996] The ability of a compound to inhibit D.beta.H activity may
be assessed using the following cell assay. For the purposes of the
present invention, a compound is considered to be a "D.beta.H
inhibitor" if it exhibits activity in "% of control" of .ltoreq.20%
at 10 .mu.m in this cell assay. Preferred compounds of the present
invention (including most of the specific Examples above) exhibit
activity in "% of control" of .ltoreq.50% at 1.0 .mu.m in this cell
assay. More preferred compounds of the present invention exhibit
activity in "% of control" of .ltoreq.20% at 1.0 .mu.m in this cell
assay. Especially preferred compounds of the present invention
exhibit activity in "% of control" of .ltoreq.50% at 100 nm in this
assay.
[0997] SK-N-SH cells (ATCC HTB-11), obtained from LGC Standards
(Teddington, UK) were cultured in Eagle's minimum essential medium
supplemented with 25 mM Hepes, 100 U/mL penicillin G, 0.25 .mu.g/mL
amphotericin B, 100 .mu.g/mL streptomycin and 10% Gibco.RTM. fetal
bovine serum. Cells were grown in T162 cm flasks (Corning, N.Y.) in
a humidified atmosphere of 5% CO.sub.2-95% air at 37.degree. C.
Fetal bovine serum was removed from cells for 4 h prior to
collection.
[0998] For the preparation of cellular homogenates, media was
removed and cell monolayers were washed with 50 mM Tris-HCl pH 7.4.
Cells were subsequently scrapped off the flasks and were
resuspended in 50 mM Tris pH 7.4. Cell suspensions were homogenized
with SilentCrusher M (Heidolph) for a short stroke and resultant
homogenates were aliquoted and stored frozen at -80.degree. C.
[0999] Total protein was quantified in cellular homogenates with
BioRad Protein Assay (BioRad) using a standard curve of BSA (50-250
.mu.g/mL).
[1000] D.beta.H activity was measured by a modification of the
method of Nagatsu and Udenfriend (Nagatsu, T. and S. Udenfriend:
"Photometric assay of dopamine-hydroxylase activity in human
blood." Clin. Chem. 18(9): 980-3, 1972) which is based on the
enzymatic hydroxylation of tyramine into octopamine. The octopamine
formed is subsequently oxidized to p-hydroxybenzaldehyde and
measured by spectrophotometry. In brief, reaction mixture (total
volume 500 .mu.l) contained: cellular homogenate (75 .mu.g total
protein) sodium acetate pH 5.0 (200 mM), NEM (30 mM), CuSO.sub.4 (5
.mu.M), catalase aqueous solution (0.5 mg/mL), pargyline-HCl (1
mM), sodium fumarate (10 mM), ascorbic acid (10 mM), inhibitor or
vehicle and tyramine (25 mM). After a 10 min pre-incubation period
at 37.degree. C., the reaction was initiated by the addition of
tyramine. Reaction was carried out for 45 min at 37.degree. C.
before termination with 50 .mu.l PCA (2 M). Samples were
centrifuged for 3 min at 16100 g and supernatants were subjected to
solid phase extraction. Solid phase extraction was performed using
either SPE cartridges ISOLUTE SCX-3 (100 mg, 1 mL) or SPE 2 mL
fixed 96 well plates ISOLUTE SCX-3 (100 mg) previously equilibrated
with MilliQ water. Columns/plates were centrifuged at 150 g for 2
min. Eluate was discarded and matrix was washed with 1 mL of MilliQ
water after which octopamine was eluted with 2.times. 0.25 mL
ammonium hydroxide (4 M). The oxidation of octopamine to
p-hydroxybenzaldehyde was carried out for 6 min with 100 .mu.l
sodium periodate (2%) and was stopped with 100 .mu.l sodium
metabisulfite (10%). Absorbance was measured at 330 nm on a
Spectramax microplate reader (Molecular Devices, Sunnyvale,
Calif.). All enzymatic reactions were performed in duplicate.
Results are reported in the table below as activity in % of control
at the inhibitor concentration tested.
[1001] Furthermore, the ability of a compound to inhibit D.beta.H
activity may be assessed in human plasma using the following assay.
For the purposes of the present invention, a compound is considered
to be a "D.beta.H inhibitor" if it exhibits activity in "% of
control" of .ltoreq.20% at 10 .mu.m in this assay. Preferred
compounds of the present invention (including most of the specific
Examples above) exhibit activity in "% of control" of .ltoreq.50%
at 1.0 .mu.m in this cell assay. More preferred compounds of the
present invention exhibit activity in "% of control" of .ltoreq.20%
at 1.0 .mu.m in this cell assay. Especially preferred compounds of
the present invention exhibit activity in "% of control" of
.ltoreq.50% at 100 nm in this assay.
[1002] Dopamine beta hydroxylase activity in human plasma was
measured by the method previously developed (Nagatsu, T. and
Udenfriend, S. Photometric assay of dopamine-.beta.-hydroxylase
activity in human blood. Clin. Chem. 18(9) 980-983, 1972) with
minor modifications. Catalase, N-ethylmaleimide, tyramine, disodium
fumarate, pargyline, sodium acetate, ascorbic acid, copper sulfate
and octopamine were obtained from Sigma Chemical Co., St. Louis,
Mo. 63178. Human plasma samples were obtained from healthy donors
(Instituto Portugu s do Sangue Transplantacao, Centro Sangue
Transplantacao, Porto, Portugal). From date of collection, plasma
was stored at -80.degree. C. until use. Test compounds were
initially prepared in dimethyl sulfoxide at a concentration of 10
mM and diluted in dimethyl sulfoxide to the required
concentrations. Test compounds were further diluted in ultrapure
water to a concentration 20-fold to that of the final concentration
to be tested. Final concentrations of test compounds were 10, 100
and 1000 nM. The various reagents used to make up the incubation
buffer were premixed and consisted of the following components:
sodium acetate buffer (1 M, pH 5.0, 18 ml), sodium fumarate (0.2 M,
4.5 ml), ascorbic acid (0.2 M, 4.5 ml, freshly prepared), pargyline
(20 mM, freshly prepared, 4.5 ml), N-ethylmaleimide (0.2 M, 4.5
ml), catalase (10 000 U/ml, 9 ml), copper sulfate (20 .mu.M, 4.5
ml) and 4.5 ultrapure water. The standard incubation mixture (total
volume, 950 .mu.l) contained: 50 .mu.L of compound or vehicle
(dimethyl sulfoxide 2%); 700 .mu.L of incubation buffer; 125 .mu.l
of plasma (or saline for blank reaction or standard curve); 75
.mu.l of saline. The reaction mixture was placed in water bath,
shaking at 37.degree. C. and pre-incubated for 10 minutes. Tyramine
(0.5 M) was added and incubation proceeded for 45 minutes. The
reaction contents were exposed to air. A sample of enzyme
preparation (with 125 .mu.l of plasma) that had been added
perchloric acid 2 M at the end of the pre-incubation period was
used as blank. A blank for each of the tested compounds was used.
For octopamine standard curve, perchloric acid 2 M was replaced by
increasing concentrations of octopamine prepared in perchloric acid
2 M (0.5, 1, 2.5, 5, 7.5, 10, 15, 20 ng/ml, final concentration).
The incubation was stopped by adding 200 .mu.l of 2 M molar
perchloric acid, and the mixture was centrifuged at 9000 g for 5
min. The supernatant fluid (800 .mu.L) was transferred to a column
(SPE cartridge ISOLUTE SCX-3, 100 mg) and centrifuged at 150 g for
2 min. The column was washed two more times with 0.5 ml of
ultrapure water by centrifuging at 150 g for 2 min. The adsorbed
octopamine was eluted twice with 0.3 ml of 4 M ammonium hydroxide
by centrifuging at 150 g for 2 min. Octopamine in the eluate was
then converted to p-hydroxybenzaldehyde by adding 200 .mu.l of
sodium periodate (2%) and incubating for 6 min. Excess periodate
was than reduced by adding 200 .mu.l of sodium metabisulfite (10%).
Absorbance was measured at 330 mm in a 96-well plate by use of a
SpectraMAX plus 384 (Molecular Devices) with software SOFTmax.RTM.
PRO Software 5.3 spectrophotometer. Absorbance was linear with
octopamine concentration from 0.5 to 20 ng/ml. Dopamine beta
hydroxylase activity is determined as nmol of octopamine formed/ml
of plasma/hour and effect of compounds is presented as control.
[1003] Results are reported in the table below (inside brackets) as
activity in % of control at the inhibitor concentration tested.
H. MDCK PERMEABILITY SCREENING ASSAY
[1004] Madin-Darby canine kidney (MDCK) is a common cell line to
assess membrane permeability of compounds. In this experiment, a
value of -6 Log(cm/s) is indicative of a compound which is poorly
permeable (e.g. Atenolol Log P.sub.app=-6.2 Log(cm/s)) whilst a
value of -4 Log(cm/s) is indicative of a compound which is highly
permeable (e.g. Propranolol Log P.sub.app=-4.2 Log(cm/s)).
Preferred compounds of the present invention (including some of the
specific Examples above (other Examples have not been tested))
exhibit a Log P.sub.app higher than -6 Log(cm/s) in this assay.
More preferred compounds of the present invention exhibit a
P.sub.app higher than -5 Log(cm/s) in this assay. Especially
preferred compounds of the present invention exhibit a Log
P.sub.app higher than -4.5 Log(cm/s) in this assay.
[1005] MDCK-II cells (canine) were grown in MEM supplemented with
100 U/mL penicillin G, 0.25 .mu.g/mL amphotericin B, 100 .mu.g/mL
streptomycin, 10% fetal bovine serum and 25 nM Hepes and maintained
in a humified atmosphere of 5% CO.sub.2-95% air at 37.degree. C.
for 4 to 5 days. Transport experiments are performed in collagen
treated 0.4 .mu.m polycarbonate filter support (12 mm ID,
transwell, Costar-Corning) with compounds being applied from the
apical (AP) cell border. The upper and lower chambers contained 400
and 1000 .mu.L of Hank's Balance Salt Solution (HBSS),
respectively. On the day of the experiments, cells were washed with
HBSS, pH 7.4 and after a 5 min. pre-incubation period under gentle
agitation, experiments were started by the addition of test
compounds. Compounds are diluted in HBSS in order to have a final
concentration of 50 .mu.M with less than 1% DMSO. After 30 min.
incubation, 250 .mu.L of medium was taken from the lower side to
determine the optical transport. Samples were mixed with equal
volume of acetonitrile with 0.1% formic acid and injected directly
onto the LC-MS column.
[1006] Apparent permeability coefficients (P.sub.app) were
calculated using the following equation:
P app = V AC 0 .times. dC dt ##EQU00001##
Where V is the volume of the solution in the receiving compartment,
A is the membrane surface area, C.sub.0 is the initial
concentration and dC/dt is the change in the drug concentration in
the receiver over time. (Balimane, P. V.; Chong, S and Morrison, R.
A.: J. Pharmacol. Toxicol. Methods, 44(1), 301-312, 2000). Results
are reported as Log P.sub.app in Log(cm/s).
I. EVALUATION OF PHARMACOKINETIC PROFILE
[1007] Adult male Wistar rats were kept under controlled
environmental conditions (12 h light/dark cycle, room temperature
22.+-.1.degree. C. and humidity 50.+-.5%, food and tap water ad
libitum). On the day before the experiment, the animals were
fasted. In experiments designed to evaluate the pharmacokinetic
profile of the compound of Examples 54, 61, 73, 74, 86 and 113,
rats (n=4 per group) were administered orally (p.o.) with compounds
(10 mg/kg/4 ml; vehicle: 40% kleptose) and plasma and brain samples
were collected from anaesthetized animals at 0.5, 1, 2, 4, 8, 15
and 24 h post-dosing. Animals were anaesthetized by intraperitoneal
administration of sodium pentobarbital (60 mg/kg). Blood was
collected from cardiac punction into heparinised tubes and kept on
ice until centrifugation at 1,500 g for 15 min at 4.degree. C.
Plasma and brain samples were stored at less than -20.degree. C.
until analysis.
[1008] After thawing, 200 .mu.l of acetonitrile with 0.1% formic
acid was added to 100 .mu.L of plasma. The samples were vortexed
and centrifuged for 10 min at 10 000 g. Supernatant was filtered
and injected into a mass spectrometer.
[1009] After thawing and weighing, water was added to the brain to
give a tissue concentration of 0.1 mg/ml. The samples were then
homogenized using a Heidolph DIAX 900 mixer and transferred to
plastic tubes. Following centrifugation at 10 000 g for 20 min,
supernatant was taken and treated as described for plasma.
J. D.beta.H ACTIVITY IN RAT ADRENAL GLAND HOMOGENATES
[1010] Dopamine beta hydroxylase activity in rat adrenal gland
homogenates was measured by the method previously developed
(Nagatsu, T. and Udenfriend, S. Photometric assay of
dopamine-.beta.-hydroxylase activity in human blood. Clin. Chem.
18(9) 980-983, 1972) with minor modifications. Catalase,
N-ethylmaleimide, tyramine, disodium fumarate, pargyline, sodium
acetate, ascorbic acid, copper sulfate and octopamine were obtained
from Sigma Chemical Co., St. Louis, Mo. 63178. Test compounds were
prepared in kleptose 40% at a concentration of 0.75, 2.5 or 7.5
mg/mL to be administered at a dose of 10 mg/kg. Compounds and
vehicle (kleptose 40%) were administered to wistar rats and
adrenals were collected 0.5 h, 1 h, 2 h, 4 h, 8 h, 15 h and 24 h
after administration. Samples were constituted by the right and
left adrenals of each animal. Adrenals were stored in 200 .mu.L of
50 mM Tris pH 7.4 at -30.degree. C., from date of collection. The
samples were homogenized and homogenates were then quantified for
protein. Protein concentration was adjusted to 1.6 mg/ml. The
various reagents used to make up the incubation buffer were
premixed and consisted of the following components: sodium acetate
buffer (1 M, pH 5.0, 6.0 mL), sodium fumarate (0.2 M, 1.5 mL),
ascorbic acid (0.2 M, 1.5 mL, freshly prepared), pargyline (20 mM,
freshly prepared, 1.5 mL), N-ethylmaleimide (0.2 M, 1.5 mL),
catalase (55 000 U/ml, 3 mL), copper sulfate (90 .mu.M, 1.67 mL)
and ultrapure water (1.33 mL). The standard incubation mixture
(total volume, 500 .mu.L) contained: 350 .mu.L of incubation
buffer; 125 .mu.L of protein sample (or buffer for blank reaction
or standard curve). The reaction mixture was placed in water bath
with shaking at 37.degree. C. and pre-incubated for 10 minutes.
Tyramine (0.4 M, 25 .mu.L) was added and incubation proceeded for
45 minutes. The reaction contents were exposed to air. A sample of
enzyme preparation (with 125 .mu.L of protein sample) that had been
added perchloric acid 2 M at the end of the pre-incubation period
was used as blank. A blank for each of the tested compounds was
used. For octopamine standard curve, perchloric acid 2 M was
replaced by increasing concentrations of octopamine prepared in
perchloric acid 2 M (0.5, 1, 2.5, 5, 7.5, 10 .mu.g/mL, final
concentration). The incubation was stopped by adding 50 .mu.L of 2
M molar perchloric acid, and the mixture was centrifuged at 16000 g
for 3 min. The supernatant fluid (500 .mu.L) was transferred to a
column (SPE cartridge ISOLUTE SCX-3, 100 mg) and centrifuged at 150
g for 2 min. The column was washed two more times with 0.5 ml of
ultrapure water by centrifuging at 150 g for 2 min. The adsorbed
octopamine was eluted twice with 250 .mu.L of 4 M ammonium
hydroxide by centrifuging at 150 g for 2 min. Octopamine in the
eluate was then converted to p-hydroxybenzaldehyde by adding 100
.mu.L of sodium periodate (2%) and incubating for 6 min. Excess
periodate was than reduced by adding 100 .mu.l of sodium
metabisulfite (10%). Absorbance was measured at 330 mm in a 96 well
plate by use of a SpectraMAX plus 384 (Molecular Devices) with
software SOFTmax.RTM. PRO Software 5.3 spectrophotometer.
Absorbance was linear with octopamine concentration from 0.5 to 10
.mu.g/mL. Dopamine beta hydroxylase activity is determined as nmol
of octopamine formed/mg of protein/hour and effect of compounds is
presented as % of control.
K. BIOLOGICAL DATA
In Vitro Experiments:
TABLE-US-00001 [1011] D.beta.H activity in D.beta.H activity in
D.beta.H activity in MDCK Permeability % of Ctrl % of Ctrl % of
Ctrl LogP.sub.app Example (0.1 .mu.M) (1 .mu.M) (10 .mu.M)
(Log(cm/s)) 1 75.6 42.4 4 -4.2 2 54.9 0 -3.9 3 89.0 53.8 3.9 4 18.6
5 83.2 0.8 6 97.6 50.3 3.3 7 84.8 37.7 7.5 -4 8 14.5 2.2 -3.9 9
30.9 5.3 -3.6 10 54.9 2.7 0 -3.9 11 86.4 31.4 1.5 12 63.0 11.5 0
-4.1 13 7.2 14 13.1 15 50.1 9.3 -4.1 16 55.5 17 56.8 -4.1 18 57.0
6.4 19 33.4 20 44.8 21 17.5 22 27.4 23 5.9 0 -4 24 40.2 15.9 -4 25
46.1 6.7 -4 26 21.4 -4 27 20.8 -3.9 28 0.2 3.3 29 26.9 30 3.3 2.8
-3.9 31 15.8 -4.1 32 57.3 4.7 -4 33 11.8 1.0 34 12.3 0 -4.2 35 95.0
34.3 0 36 4.0 0 37 59.7 2.4 -4.1 38 3.3 0 -4.1 39 40.4 0.3 40 87.9
41 29.8 0 42 44.1 -4 43 43.6 0 -3.7 44 70.9 13.7 45 29.1 46 31.6 47
45.3 48 43.0 49 60.6 -4 50 89.3 36.6 6.8 -3.9 51 54.4 -4 52 27.3 -4
53 66.5 11.8 -4.6 54 44.3 8.2 -4.6 55 61.0 0.4 -4.1 56 41.7 7.8
-4.8 57 97.9 58.6 9.2 -4.2 58 106.5 59.8 -3.9 59 100.1 27.8 -3.6 60
60.2 61 52.2 8.4 62 43.1 9.8 63 13.9 64 39.9 7.2 65 17.9 66 51.1
7.9 67 36.1 68 5.1 69 14.6 70 35.7 71 48.5 72 35.0 73 41.7 5.1 74
21.9 1.8 75 18.1 76 17.4 77 23.0 78 10.9 79 13.0 80 56.7 81 59.4 82
90.0 20.0 83 84.0 33.1 84 96.9 41.9 85 0 0 86 25.3 0 87 36.5 0 88
45.8 6.2 89 29.8 90 1.8 1.0 91 22.0 0 92 2.0 0 93 0 0 94 18.1 0 95
28.9 96 32.0 (57.3)* 15.0 97 41.9 (74.1)* 7.9 98 39.9 99 31.6
(38.3)* 1 100 0 0 101 14.5 0 102 32.0 0 103 63.4 10.3 104 47.5 6.0
105 17.4 0 106 16.3 107 54.7 108 38.8 109 67.5 17.2 110 73.8 15.9
111 48.3 112 70 10.1 113 39.6 0 114 70.8 15.2 115 0.5 0 116 24.8 0
117 6.4 0 118 33.8 0 119 49.1 4.5 120 86.4 21.8 121 5.2 0 122
(9.8)* 123 (4.7)* 124 (23.8)* 125 (12.1)* 126 (49.9)* 127 (10.0)*
128 (39.1)* 129 (27.7)* 130 (88.8)* 131 (0.5)* 132 (67.0)* *numbers
in brackets represent activity in % of control in human plasma
assay
In Vivo Experiments:
[1012] Mean concentration-time profile of the compound of Example
54 in plasma and brain after oral administration of 10 mg/kg, to
Wistar rats is shown in FIG. 1. Each point represents mean.+-.SD of
4 rats.
[1013] Mean concentration-time profile of the compounds of Example
54, 61, 73, 74, 86 and 113 in plasma after oral administration of
10 mg/kg to Wistar rats is shown in FIG. 2. Each point represents
mean.+-.SD of 4 rats.
[1014] Mean concentration-time profile of the compounds of Example
54, 61, 73, 74, 86 and 113 in brain after oral administration of 10
mg/kg to Wistar rats is shown in FIG. 3. Each point represents
mean.+-.SD of 4 rats.
[1015] D.beta.H activity in ADR after oral administration of 10
mg/kg of compounds of Example 54, 61, 73, 74, 86 and 113 is shown
in FIG. 4. Each point represents mean.+-.SD of 4 rats.
* * * * *