U.S. patent application number 11/176901 was filed with the patent office on 2005-12-08 for substituted cyclohexane derivatives.
Invention is credited to Ackermann, Jean, Aebi, Johannes, Dehmlow, Henrietta, Hirth, Georges, Maerki, Hans-Peter, Morand, Olivier.
Application Number | 20050272774 11/176901 |
Document ID | / |
Family ID | 8179485 |
Filed Date | 2005-12-08 |
United States Patent
Application |
20050272774 |
Kind Code |
A1 |
Ackermann, Jean ; et
al. |
December 8, 2005 |
Substituted cyclohexane derivatives
Abstract
The present invention provides compounds of formula (I) 1
wherein A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5, A.sup.6,
A.sup.7, A.sup.8 , A.sup.9, A.sup.10, U, V, W, m, n and p-are as
indicated in the specification, and pharmaceutically acceptable
salts thereof. The compounds are useful for the treatment and/or
prophylaxis of diseases which are associated with
2,3-oxidosqualene-lanosterol cyclase such as hypercholesterolemia
and hyperlipemia.
Inventors: |
Ackermann, Jean; (Riehen,
CH) ; Aebi, Johannes; (Basle, CH) ; Dehmlow,
Henrietta; (Grenzach-Wyhlen, DE) ; Hirth,
Georges; (Huningue, FR) ; Maerki, Hans-Peter;
(Basle, CH) ; Morand, Olivier; (Hegenheim,
FR) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
8179485 |
Appl. No.: |
11/176901 |
Filed: |
July 7, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11176901 |
Jul 7, 2005 |
|
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10315770 |
Dec 10, 2002 |
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6953806 |
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Current U.S.
Class: |
514/317 ;
546/229 |
Current CPC
Class: |
C07D 211/46 20130101;
C07D 233/56 20130101; C07C 271/52 20130101; C07C 311/17 20130101;
A61P 43/00 20180101; C07D 205/04 20130101; A61P 3/06 20180101; C07C
311/18 20130101; A61P 35/00 20180101; A61P 1/16 20180101; C07C
2601/14 20170501; C07D 231/12 20130101; C07D 295/135 20130101; C07D
249/08 20130101; C07D 295/084 20130101; C07D 295/088 20130101; A61P
33/00 20180101; A61P 9/10 20180101; C07D 207/08 20130101; A61P 9/00
20180101; A61P 31/10 20180101; A61P 3/00 20180101; A61P 3/10
20180101 |
Class at
Publication: |
514/317 ;
546/229 |
International
Class: |
C07D 211/26; A61K
031/445 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 12, 2001 |
EP |
01129271.1 |
Claims
1. A compound of formula (I) 20wherein U is O or a lone pair, V is
O, S, --CH.dbd.CH--, --CH.dbd.CH--CH.sub.2-O--, or --C.ident.C--, W
is CO, COO, CONR.sup.1, CSO, CSNR.sup.1, or SO.sub.2NR.sup.1, m and
n independently from each other are from 0 to 7 and m+n is from 0
to 7, with the proviso that m is not 0 if V is O or S, A.sup.1 is
hydrogen, lower-alkyl, hydroxy-lower-alkyl, or lower-alkenyl,
A.sup.2 is cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl,
lower-alkynyl, heteroaryl, substituted heteroaryl, or lower-alkyl
optionally substituted by R.sup.2, or A.sup.1 and A.sup.2 are
bonded to each other to form a ring with the N atom to which they
are attached, and -A.sup.1-A- is lower-alkylene or
lower-alkenylene, optionally substituted by R.sup.2, in which one
--CH.sub.2-- group of -A.sup.1-A.sup.2- can optionally be replaced
by NR.sup.3, S, or O, or -A.sup.1-A.sup.2- is --CH=N--CH.dbd.CH--
which can optionally be substituted by lower-alkyl, A.sup.3 and
A.sup.4 independently from each other are hydrogen or lower-alkyl,
or A.sup.3 and A.sup.4 are bonded to each other to form a ring
together with the carbon atom to which they are attached and
-A.sup.3-A.sup.4- is --(CH.sub.2).sub.2-5--, A.sup.5, A.sup.6,
A.sup.7 and A.sup.8 independently from each other are hydrogen or
lower-alkyl, A.sup.9 is hydrogen, lower-alkyl, lower-alkenyl, or
aryl-lower-alkyl, A.sup.10 is lower-alkyl, cycloalkyl,
aryl-lower-alkyl, substituted aryl-lower alkyl, heteroaryl,
substituted heteroaryl, heteroaryl-lower-alkyl, or substituted
heteroaryl-lower alkyl, p is 0 or 1, R.sup.2 is hydroxy,
hydroxy-lower-alkyl, lower-alkoxy, lower-alkoxycarbonyl,
N(R.sup.4,R.sup.5), thio-lower-alkoxy or halogen, R.sup.1, R.sup.3,
R.sup.4 and R.sup.5 independently from each other are hydrogen or
lower-alkyl, substituted aryl and substituted heteroaryl are aryl
and heteroaryl, respectively, substituted by 1 to 3 substituents
independently selected from the group consisting of lower-alkyl,
lower-alkynyl, dioxo-lower-alkylene (forming e.g. a benzodioxyl
group), halogen, hydroxy, CN, CF.sub.3, NH.sub.2, N(H,
lower-alkyl), N(lower-alkyl).sub.2, aminocarbonyl, carboxy,
NO.sub.2, lower-alkoxy, thio-lower-alkoxy, lower-alkylcarbonyl,
lower-alkylcarbonyloxy, lower-alkoxycarbonyl, phenyl, and
phenyloxy, and pharmaceutically acceptable salts thereof, with the
proviso that the compound of formula (I) is not
trans-naphthalene-1-sulfonic acid methyl-(4-methylaminomethyl--
cyclohexylmethyl)-amide.
2. The compound according to claim 1, wherein U is a lone pair.
3. The compound according to claim 1, wherein V is O, CH.dbd.CH--,
--CH.dbd.CH--CH.sub.2--O--, or --C.ident.C--.
4. (canceled)
5. (canceled)
6. The compound according to claim 3, wherein V is
--CH.dbd.CH--.
7. The compound according to claim 3, wherein V is
--C.ident.C--.
8. The compound according to claim 1, wherein W is COO.
9. (canceled)
10. The compound according to claim 1, wherein m is from 0 to 4 and
n is from 0 to 1.
11. The compound according to claim 10, wherein m is 0.
12. The compound according to claim 10, wherein n is 0.
13. The compound according to claim 1, wherein A.sup.1 is hydrogen,
lower-alkyl or hydroxy-lower-alkyl.
14. The compound according to claim 13, wherein A.sup.1 is methyl,
ethyl, or 2-hydroxy-ethyl.
15. The compound according to claim 1, wherein A.sup.2 is
lower-alkenyl, 2-methyl-pyrimidinyl, or lower-alkyl optionally
substituted by R.sup.2, wherein R.sup.2 is hydroxy.
16. The compound according to claim 15, wherein A.sup.2 is methyl
or 2-hydroxy-ethyl.
17. The compound according to claim 1, wherein A.sup.1 and A.sup.2
are bonded to each other to form a ring with the N atom to which
they are attached, and -A.sup.1-A.sup.2- is lower-alkylene
optionally substituted by R.sup.2, in which one --CH.sub.2-- group
of -A.sup.1-A.sup.2- can optionally be replaced by NR.sup.3 or O,
or -A.sup.1-A.sup.2- is --CH=N--CH.dbd.CH--, wherein R.sup.2 is
hydroxy or hydroxy-lower-alkyl, and R.sup.3 is hydrogen or
lower-alkyl.
18. The compound according to claim 17, wherein -A.sup.1-A.sup.2-
is --(CH.sub.2).sub.4-- or --(CH.sub.2).sub.5--.
19. The compound according to claim 1, wherein A.sup.3 and A.sup.4
are hydrogen.
20. The compound according to claim 1, wherein A.sup.5 and A.sup.6
are hydrogen.
21. The compound according to claim 1, wherein A.sup.7 and A.sup.8
are hydrogen.
22. The compound according to claim 1, wherein A.sup.9 is
lower-alkyl.
23. The compound according to claim 22, wherein A.sup.9 is
methyl.
24. (canceled)
25. The compound according to claim 1, wherein A.sup.10 is phenyl
optionally substituted with halogen or CF.sub.3.
26. The compound according to claim 25, wherein A.sup.10 is
4-chloro-phenyl or 4-trifluoromethyl-phenyl.
27. The compound according to claim 1, selected from the group
consisting of
trans-Methyl-[4-(2-piperidin-1-yl-ethyl)-cyclohexylmethyl]-carbamic
acid 4-chloro-phenyl ester,
trans-N-Methyl-N-[4-(2-piperidin-1-yl-ethyl)--
cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide,
trans-N-(4-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-cyclohexylmethyl)-N-me-
thyl-4-trifluoromethyl-benzenesulfonamide,
trans-[2-(4-Dimethylaminomethyl-
-cyclohexyl)-ethyl]-methyl-carbamic acid 4-trifluoromethyl-phenyl
ester,
trans-[2-(4-{[Ethyl-(2-hydroxy-ethyl)-amino]-methyl}-cyclohexyl)-ethyl]-m-
ethyl-carbamic acid 4-trifluoromethyl-phenyl ester,
trans-Methyl-[2-(4-piperidin-1-ylmethyl-cyclohexyl)-ethyl]
-carbamic acid 4-trifluoromethyl-phenyl ester,
trans-Methyl-{2-[4-(3-piperidin-1-yl-(E)--
propenyl)-cyclohexyl]-ethyl}-carbamic acid 4-chloro-phenyl ester,
trans-Methyl-{2-[4-(3-pyrrolidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-ca-
rbamic acid 4-chloro-phenyl ester,
trans-(4-{5-[Bis-(2-hydroxy-ethyl)-amin-
o]-pentyl}-cyclohexylmethyl)-methyl-carbamic acid
4-trifluoromethyl-phenyl ester,
trans-(4-{3-[Ethyl-(2-hydroxy-ethyl)-amino]-prop-1-ynyl}-cyclohexy-
lmethyl)-methyl-carbamic acid 4-trifluoromethyl-phenyl ester, and
trans-N-(4-{3-[Ethyl-(2-hydroxy-ethyl)-amino]-propyl}-cyclohexylmethyl)-N-
-methyl-4-trifluoromethyl-benzenesulfonamide, and pharmaceutically
acceptable salts thereof.
28. A pharmaceutical composition comprising a compound according to
claim 1 and a pharmaceutically acceptable carrier.
29. A method of treatment of hypercholesterolemia or hyperlipemia,
comprising administering from 1 to 1000 mg per day of a compound or
a salt thereof according to claim 1, to a patient in need of
treatment.
30. A compound of formula (I) 21wherein U is a lone pair, V is
--CH.dbd.CH--, or --C.ident.C--, W is COO, m and n independently
from each other are from 0 to 3 and m+n is from 0 to 3, A.sup.1 is
hydroxy lower-alkyl, or lower-alkyl, A.sup.2 is hydroxy lower-alkyl
or lower-alkyl, or A.sup.1 and A.sup.2 are bonded to each other to
form a ring with the N atom to which they are attached, and
-A.sup.1-A.sup.2- is lower-alkylene, A.sup.3 and A.sup.4 are each
hydrogen, A.sup.5, A.sup.6, A.sup.7 and A.sup.8 are each hydrogen,
A.sup.9 is lower-alkyl, A.sup.10 is phenyl substituted with
chlorine or --CF.sub.3, p is 0 or 1, and pharmaceutically
acceptable salts thereof.
31. The compound according to claim 30, wherein hydroxy lower-alkyl
for each of A.sup.1 and A.sup.2 is --CH.sub.2CH.sub.2OH.
32. The compound according to claim 30, wherein lower alkyl for
each of A.sup.1 and A.sup.2 is independently selected from the
group consisting of --CH.sub.3 and --CH.sub.2CH.sub.3.
33. The compound according to claim 30, wherein A.sup.9 is
--CH.sub.3.
Description
PRIORITY TO RELATED APPLICATIONS
[0001] This application is a Division of Ser. No. 10/315,770, filed
Dec. 10, 2002 which is now allowed
BACKGROUND OF THE INVENTION
[0002] The microsomal enzyme, 2,3-oxidosqualene-lanosterol cyclase
(EC 5.4.99.), is required for the biosynthesis of cholesterol,
ergosterol and other sterols. Causal risk factors that directly
promote the development of coronary and peripheral atherosclerosis
include elevated low-density lipoprotein cholesterol (LDL-C), low
high-density lipoprotein cholesterol (HDL-C), hypertension,
cigarette smoking and diabetes mellitus. Other synergistic risk
factors include elevated concentrations of triglyceride (TG)-rich
lipoproteins, small, dense low-density lipoprotein particles,
lipoprotein (a) (Lp(a)), and homocysteine. Predisposing risk
factors modify the causal or conditional risk factors and thus
affect atherogenesis indirectly. The predisposing risk factors are
obesity, physical inactivity, family history of premature CVD, and
male sex. The strong connection between coronary heart disease
(CHD) and high LDL-C levels in plasma, and the therapeutic
advantage of lowering elevated LDL-C levels are now well
established (Gotto et al., Circulation 81, 1990, 1721-1733; Stein
et al., Nutr. Metab. Cardiovasc. Dis. 2, 1992, 113-156;
Illingworth, Med. Clin. North. Am. 84, 2000, 23-42).
Cholesterol-rich, sometimes unstable, atherosclerotic plaques lead
to the occlusion of blood vessels resulting in an ischemia or an
infarct. Studies with respect to primary prophylaxis have shown
that a lowering of plasma LDL-C levels in plasma reduces the
frequency of non-fatal incidences of CHD, while the overall
morbidity remainis unchanged. The lowering of plasma LDL-C levels
in patients with pre-established CHD (secondary intervention)
reduces CHD mortality and morbidity; meta-analysis of different
studies shows that this decrease is proportional to the reduction
of the LDL-C (Ross et al., Arch. Intern. Med. 159, 1999,
1793-1802).
[0003] The clinical advantage of cholesterol lowering is greater
for patients with pre-established CHD than for asymptomatic persons
with hypercholesterolemia. According to current guidelines,
cholesterol lowering treatment is recommended for patients who had
survived a myocardial infarct or patients suffering from angina
pectoris or another atherosclerotic disease, with a target LDL-C
level of 100 mg/dl.
[0004] Preparations such as bile acid sequestrants, fibrates,
nicotinic acid, probucol as well as statins, i.e. HMG-Co-A
reductase inhibitors such as simvastatin and atorvastatin, are used
for usual standard therapies. The best statins reduce plasma LDL-C
effectively by at least 40%, and also plasma triglycerides, a
synergistic risk factor, but less effectively. In contrast,
fibrates reduce plasma triglycerides effectively, but not LDL-C.
Combination of a statin and a fibrate proved to be very efficacious
in lowering LDL-C and triglycerides (Ellen and McPherson, J.
Cardiol. 81, 1998, 60B-65B), but safety of such a combination
remains an issue (Shepherd, Eur. Heart J. 16, 1995, 5-13). A single
drug with a mixed profile combining effective lowering of both
LDL-C and triglycerides would provide additional clinical benefit
to asymptomatic and symptomatic patients.
[0005] In humans, statins are well tolerated at standard dosage,
but reductions in non-sterol intermediates in the cholesterol.
synthesis pathway, such as isoprenoids and coenzyme Q, may be
associated with adverse clinical events at high doses (Davignon et
al., Can. J. Cardiol. 8, 1992, 843-864; Pederson and Tobert, Drug
Safety 14, 1996, 11-24).
[0006] This has stimulated the search for, and development of
compounds that inhibit cholesterol biosynthesis, yet act distal to
the synthesis of these important, non-sterol intermediates.
2,3-oxidosqualene:lanosterol cyclase (OSC), a microsomal enzyme,
represents a unique target for a cholesterol-lowering drug (Morand
et al., J. Lipid Res., 38, 1997, 373-390; Mark et al., J. Lipid
Res. 37, 1996, 148-158). OSC is downstream of
farnesyl-pyrophosphate, beyond the synthesis of isoprenoids and
coenzyme Q. In hamsters, pharmacologically active doses of an OSC
inhibitor showed no adverse side-effects, in contrast to a statin
which reduced food-intake and body weight, and increased plasma
bilirubin, liver weight and liver triglyceride content (Morand et
al., J. Lipid Res., 38, 1997, 373-390). The compounds described in
European Patent Application No. 636 367, which inhibit OSC and
which lower the total cholesterol in plasma, belong to these
substances.
[0007] OSC inhibition does not trigger the overexpression of HMGR
because of an indirect, negative feed-back regulatory mechanism
involving the production of 24(S),25-epoxycholesterol (Peffley et
al., Biochem. Pharmacol. 56, 1998, 439-449; Nelson et al., J. Biol.
Chem. 256, 1981, 1067-1068; Spencer et al., J. Biol. Chem. 260,
1985, 13391-13394; Panini et al., J. Lipid Res. 27, 1986,
1190-1204; Ness et al., Arch. Biochem. Biophys. 308, 1994,
420-425). This negative feed-back regulatory mechanism is
fundamental to the concept of OSC inhibition because (i) it
potentiates synergistically the primary inhibitory effect with an
indirect down-regulation of HMGR, and (ii) it prevents the massive
accumulation of the precursor monooxidosqualene in the liver. In
addition, 24(S),25-epoxycholesterol was found to be one of the most
potent agonists of the nuclear receptor LXR (Janowski et al., Proc.
Natl. Acad. Sci. USA, 96, 1999, 266-271). Considering that
24(S),25-epoxycholesterol is a by-product of inhibition of OSC it
is hypothesized that OSC inhibitors could also indirectly activate
LXR-dependent pathways such as (i) cholesterol-7alpha-hydroxylase
to increase the consumption of cholesterol via the bile acid route,
(ii) expression of ABC proteins with the potential to stimulate
reverse cholesterol transport and increase plasma HDL-C levels
(Venkateswaran et al., J. Biol. Chem. 275, 2000, 14700-14707;
Costet et al., J. Biol. Chem. June 2000, in press; Ordovas, Nutr
Rev 58, 2000, 76-79, Schmitz and Kaminsky, Front Biosci 6, 2001,
D505-D514), and/or inhibit intestinal cholesterol absorption
(Mangelsdorf, XIIth International Symposium on Atherosclerosis,
Stockholm, June 2000). In addition, possible cross talks between
fatty acid and cholesterol metabolism mediated by liver LXR have
been hypothesized (Tobin et al., Mol. Endocrinol. 14, 2000,
741-752).
SUMMARY OF THE INVENTION
[0008] The present invention provides compounds of formula (I)
2
[0009] wherein
[0010] U is O or a lone pair,
[0011] V is a single bond, O, S, --CH.sub.2--, --CH.dbd.CH--,
--CH.dbd.CH--CH.sub.2--O--, or --C.ident.C--,
[0012] W is CO, COO, CONR.sup.1, CSO, CSNR.sup.1, SO.sub.2, or
SO.sub.2NR.sup.1,
[0013] m and n independently from each other are from 0 to 7 and
m+n is from 0 to 7, with the proviso that m is not 0 if V is O or
S,
[0014] A.sup.1 is hydrogen, lower-alkyl, hydroxy-lower-alkyl, or
lower-alkenyl,
[0015] A.sup.2 is cycloalkyl, cycloalkyl-lower-alkyl,
lower-alkenyl, lower-alkynyl, heteroaryl, substituted heteroaryl,
or lower-alkyl optionally substituted by R.sup.2, or
[0016] A.sup.1 and A.sup.2 are bonded to each other to form a ring
with the N atom to which they are attached, and -A.sup.1-A.sup.2-
is lower-alkylene or lower-alkenylene, optionally substituted by
R.sup.2, in which one --CH.sub.2-- group of
[0017] -A.sup.1-A.sup.2- can optionally be replaced by NR.sup.3, S,
or O, or -A.sup.2-A.sup.2- is
[0018] --CH.dbd.N--CH.dbd.CH-- which can optionally be substituted
by lower-alkyl,
[0019] A.sup.3 and A.sup.4 independently from each other are
hydrogen or lower-alkyl, or
[0020] A.sup.3 and A.sup.4 are bonded to each other to form a ring
together with the carbon atom to which they are attached and
-A.sup.3-A.sup.4- is --(CH.sub.2).sub.2-5--,
[0021] A.sup.5, A.sup.6, A.sup.7 and A.sup.8 independently from
each other are hydrogen or lower-alkyl,
[0022] A.sup.9 is hydrogen, lower-alkyl, lower-alkenyl, or
aryl-lower-alkyl,
[0023] A.sup.10 is lower-alkyl, cycloalkyl, aryl, substituted aryl,
aryl-lower-alkyl, substituted aryl-lower-alkyl, heteroaryl,
substituted heteroaryl, heteroaryl-lower-alkyl, or substituted
heteroaryl-lower alkyl,
[0024] p is 0 or 1,
[0025] R.sup.2 is hydroxy, hydroxy-lower-alkyl, lower-alkoxy,
lower-alkoxycarbonyl, N(R.sup.4,R.sup.5), thio-lower-alkoxy or
halogen,
[0026] R.sup.1, R.sup.3, R.sup.4 and R.sup.5 independently from
each other are hydrogen or lower-alkyl, substituted aryl and
substituted heteroaryl are aryl and heteroaryl, respectively,
substituted by 1 to 3 substituents independently selected from the
group consisting of lower-alkyl, lower-alkynyl,
dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen,
hydroxy, CN, CF.sub.3, NH.sub.2, N(H, lower-alkyl),
N(lower-alkyl).sub.2, aminocarbonyl, carboxy, NO.sub.2,
lower-alkoxy, thio-lower-alkoxy, lower-alkylcarbonyl,
lower-alkylcarbonyloxy, lower-alkoxycarbonyl, phenyl, and
phenyloxy,
[0027] and pharmaceutically acceptable salts thereof,
[0028] with the proviso that the compound of formula (I) is not
trans-naphthalene-1-sulfonic acid
methyl-(4-methylaminomethyl-cyclohexylm- ethyl)-amide.
[0029] The compounds of the present invention are useful for the
treatment and/or prophylaxis of diseases associated with
2,3-oxidosqualine-lanoster- ol cyclase such as hypercholesterolemia
and hyperlipemia.
DETAILED DESCRIPTION OF THE INVENTION
[0030] The present invention provides compounds of formula (I)
3
[0031] wherein
[0032] U is O or a lone pair,
[0033] V is a single bond, O, S, --CH.sub.2--, --CH.dbd.CH--,
--CH.dbd.CH--CH.sub.2--O--, or --C.ident.C--,
[0034] W is CO, COO, CONR.sup.1, CSO, CSNR.sup.1, SO.sub.2, or
SO.sub.2NR.sup.1,
[0035] m and n independently from each other are from 0 to 7 and
m+n is from 0 to 7, with the proviso that m is not 0 if V is O or
S,
[0036] A.sup.1 is hydrogen, lower-alkyl, hydroxy-lower-alkyl, or
lower-alkenyl,
[0037] A.sup.2 is cycloalkyl, cycloalkyl-lower-alkyl,
lower-alkenyl, lower-alkynyl, heteroaryl, substituted heteroaryl,
or lower-alkyl optionally substituted by R.sup.2, or
[0038] A.sup.1 and A.sup.2 are bonded to each other to form a ring
with the N atom to which they are attached, and -A.sup.1-A.sup.2-
is lower-alkylene or lower-alkenylene, optionally substituted by
R.sup.2, in which one --CH.sub.2-- group of
[0039] -A.sup.1-A.sup.2- can optionally be replaced by NR.sup.3, S,
or O, or -A.sup.1-A.sup.2- is
[0040] --CH.dbd.N--CH.dbd.CH-- which can optionally be substituted
by lower-alkyl,
[0041] A.sup.3 and A.sup.4 independently from each other are
hydrogen or lower-alkyl, or
[0042] A.sup.3 and A.sup.4 are bonded to each other to form a ring
together with the carbon atom to which they are attached and
-A.sup.3-A.sup.4- is --(CH.sub.2).sub.2-5--,
[0043] A.sup.5, A.sup.6, A.sup.7 and A.sup.8 independently from
each other are hydrogen or lower-alkyl,
[0044] A.sup.9 is hydrogen, lower-alkyl, lower-alkenyl, or
aryl-lower-alkyl,
[0045] A.sup.10 is lower-alkyl, cycloalkyl, aryl, substituted aryl,
aryl-lower-alkyl, substituted aryl-lower-alkyl, heteroaryl,
substituted heteroaryl, heteroaryl-lower-alkyl, or substituted
heteroaryl-lower alkyl,
[0046] p is 0 or 1,
[0047] R.sup.2 is hydroxy, hydroxy-lower-alkyl, lower-alkoxy,
lower-alkoxycarbonyl, N(R.sup.4,R.sup.5), thio-lower-alkoxy or
halogen,
[0048] R.sup.1, R.sup.3, R.sup.4 and R.sup.5 independently from
each other are hydrogen or lower-alkyl, substituted aryl and
substituted heteroaryl are aryl and heteroaryl, respectively,
substituted by 1 to 3 substituents independently selected from the
group consisting of lower-alkyl, lower-alkynyl,
dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen,
hydroxy, CN, CF.sub.3, NH.sub.2, N(H, lower-alkyl),
N(lower-alkyl).sub.2, aminocarbonyl, carboxy, NO.sub.2,
lower-alkoxy, thio-lower-alkoxy, lower-alkylcarbonyl,
lower-alkylcarbonyloxy, lower-alkoxycarbonyl, phenyl, and
phenyloxy,
[0049] and pharmaceutically acceptable salts thereof,
[0050] with the proviso that the compound of formula (I) is not
trans-naphthalene-1-sulfonic acid
methyl-(4-methylaminomethyl-cyclohexylm- ethyl)-amide.
[0051] The present compounds of formula I inhibit OSC and therefore
also inhibit the biosynthesis of cholesterol, ergosterol and other
sterols, and reduce the plasma cholesterol levels. They can
therefore be used in the therapy and prophylaxis of
hypercholesterolemia, hyperlipemia, arteriosclerosis and vascular
diseases in general. Furthermore, they can be used in the therapy
and/or prevention of mycoses, parasite infections, gallstones,
cholestatic liver disorders, tumors and hyperproliferative
disorders, e.g. hyperproliferative skin and vascular disorders. In
addition, it has unexpectedly been found that the compounds of the
present invention can also be of therapeutical use to improve
glucose tolerance in order to treat and/or prevent related diseases
such as diabetes. The compounds of the present invention further
exhibit improved pharmacological properties compared to known
compounds.
[0052] Unless otherwise indicated the following definitions are set
forth to illustrate and define the meaning and scope of the various
terms used to describe the invention herein. In this specification
the term "lower" is used to mean a group consisting of one to
seven, preferably of one to four carbon atom(s).
[0053] The term "lone pair" refers to an unbound electron pair, in
particular to the unbound electron pair of a nitrogen atom in e.g.
an amine.
[0054] The term "halogen" refers to fluorine, chlorine, bromine and
iodine, with fluorine, chlorine and bromine being preferred.
[0055] The term "alkyl", alone or in combination with other groups,
refers to a branched or straight-chain monovalent saturated
aliphatic hydrocarbon radical of one to twenty carbon atoms,
preferably one to sixteen carbon atoms, more preferably one to ten
carbon atoms. Lower-alkyl groups as described below also are
preferred alkyl groups.
[0056] The term "lower-alkyl", alone or in combination with other
groups, refers to a branched or straight-chain monovalent alkyl
radical of one to seven carbon atoms, preferably one to four carbon
atoms. This term is further exemplified by such radicals as methyl,
ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the
like.
[0057] The term "cycloalkyl" refers to a monovalent carbocyclic
radical of 3 to 10 carbon atom(s), preferably 3 to 6 carbon atoms,
such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
[0058] The term "alkoxy" refers to the group R'--O--, wherein R' is
an alkyl. The term "lower-alkoxy" refers to the group R'--O--,
wherein R' is a lower-alkyl. The term "thio-alkoxy" refers to the
group R'--S--, wherein R' is an alkyl. The term "thio-lower-alkoxy"
refers to the group R'--S--, wherein R' is a lower-alkyl.
[0059] The term "alkenyl", alone or in combination with other
groups, stands for a straight-chain or branched hydrocarbon residue
comprising an olefinic bond and up to 20, preferably up to 16
carbon atoms, more preferrably up to 10 carbon atoms. Lower-alkenyl
groups as described below also are preferred alkenyl groups. The
term "lower-alkenyl" refers to a straight-chain or branched
hydrocarbon residue comprising an olefinic bond and up to 7,
preferably up to 4 carbon atoms, such as e.g. 2-propenyl.
[0060] The term "alkynyl", alone or in combination with other
groups, stands for a straight-chain or branched hydrocarbon residue
comprising a triple bond and up to 20, preferably up to 16 carbon
atoms, more preferably up to 10 carbon atoms. Lower-alkynyl groups
as described below also are preferred alkynyl groups. The term
"lower-alkynyl" refers to a straight-chain or branched hydrocarbon
residue comprising a triple bond and up to 7, preferably up to 4
carbon atoms, such as e.g. 2-propinyl.
[0061] The term "alkylene" refers to a straight chain or branched
divalent saturated aliphatic hydrocarbon group of 1 to 20 carbon
atoms, preferably 1 to 16 carbon atoms, more preferrably up to 10
carbon atoms. Lower-alkylene groups as described below also are
preferred alkylene groups. The term "lower-alkylene" refers to a
straight chain or branched divalent saturated aliphatic hydrocarbon
group of 1 to 7, preferably 1 to 6 or 3 to 6 carbon atoms. Straight
chain alkylene or lower-alkylene groups are preferred.
[0062] The term "alkenylene" refers to a straight chain or branched
divalent hydrocarbon group comprising an olefinic bond and up to 20
carbon atoms, preferably up to 16 carbon atoms, more preferrably up
to 10 carbon atoms. Lower-alkenylene groups as described below also
are preferred alkenylene groups. The term "lower-alkenylene" refers
to a straight chain or branched divalent hydrocarbon group
comprising an olefinic bond and up to 7, preferably up to 5,
C-atoms. Straight chain alkenylene or lower-alkenylene groups are
preferred.
[0063] The term "aryl" relates to the phenyl or naphthyl group,
preferably the phenyl group. "Substituted phenyl" is aryl
substituted by 1 to 3 substituents independently selected from the
group consisting of lower-alkyl, lower-alkynyl,
dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen,
hydroxy, CN, CF.sub.3, NH.sub.2, N(H, lower-alkyl),
N(lower-alkyl).sub.2, aminocarbonyl, carboxy, NO.sub.2,
lower-alkoxy, thio-lower-alkoxy, lower-alkylcarbonyl,
lower-alkylcarbonyloxy, lower-alkoxycarbonyl, phenyl, phenyloxy.
Preferred substituents are halogen, CF.sub.3, CN, lower-alkyl
and/or lower-alkoxy. More preferred substituents are chlorine and
CF.sub.3.
[0064] The term "heteroaryl" refers to an aromatic 5- or 6-membered
ring which can comprise 1, 2 or 3 atoms selected from nitrogen,
oxygen and/or sulphur, such as, for example, furyl, pyridyl,
pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl,
imidazolyl, or pyrrolyl. "Substituted heteroaryl" is heteroaryl
which is substituted by 1 to 3 substituents independently selected
from the group consisting of lower-alkyl, lower-alkynyl,
dioxo-lower-alkylene (forming e.g. a benzodioxyl group), halogen,
hydroxy, CN, CF.sub.3, NH.sub.2, N(H, lower-alkyl),
N(lower-alkyl).sub.2, aminocarbonyl, carboxy, NO.sub.2,
lower-alkoxy, thio-lower-alkoxy, lower-alkylcarbonyl,
lower-alkylcarbonyloxy, lower-alkoxycarbonyl, phenyl, phenyloxy.
Preferred substituents are halogen, CF.sub.3, CN, lower-alkyl
and/or lower-alkoxy. More preferred substituents are chlorine and
CF.sub.3. A preferred heteroaryl group is pyrimidinyl; a preferred
substituted heteroaryl is heteroaryl substituted with methyl.
[0065] The term "pharmaceutically acceptable salts" embraces salts
of the compounds of formula (I) with inorganic or organic acids
such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric
acid, phosphoric acid, citric acid, formic acid, maleic acid,
acetic acid, fumaric acid, succinic acid, tartaric acid,
methanesulphonic acid, p-toluenesulphonic acid and the like, which
are non toxic to living organisms. Preferred salts are formates,
hydrochlorides, hydrobromides and methanesulfonic acid salts.
[0066] Preferred are compounds of formula (I) and/or
pharmaceutically acceptable salts thereof. Other preferred
embodiments relate to compounds of formula (I) wherein U is a lone
pair or to compounds of formula (I) wherein U is 0.
[0067] Compounds of formula (I) as described above, in which V is a
single bond, O, --CH.sub.2--, --CH.dbd.CH--,
--CH.dbd.CH--CH.sub.2--O--, or --C.ident.C-- relate to a preferred
embodiment of the present invention. More preferred compounds as
defined above are those, wherein V is a single bond. Other more
preferred compounds as defined above are those, wherein V is
--CH.sub.2--. Other more preferred compounds as defined above are
those, wherein V is --CH.dbd.CH--. Other more preferred compounds
as defined above are those, wherein V is --C.ident.C--. In
addition, compounds of formula (I) as defined above, in which W is
COO relate to a preferred embodiment of the present invention.
Compounds in which W is SO.sub.2 are also preferred.
[0068] In a further preferred embodiment of the present invention,
m is 0 to 4 and n is 0 to 1. Compounds of formula (I), in which m
is 0 and/or n is 0 are also preferred. Compounds as described
above, in which the number of carbon atoms of (CH.sub.2).sub.m, V
and (CH.sub.2).sub.n together is 7 or less, are also preferred.
[0069] Other preferred compounds of the present invention are those
in which A.sup.1 represents hydrogen, lower-alkyl or
hydroxy-lower-alkyl, preferrably those in which A.sup.1 is methyl,
ethyl or 2-hydroxy-ethyl. Another group of preferred compounds of
the present invention are those in which A.sup.2 represents
lower-alkenyl, 2-methyl-pyrimidinyl, or lower-alkyl optionally
substituted by R.sup.2, wherein R.sup.2 is hydroxy, with those
compounds wherein A.sup.2 represents methyl or 2-hydroxy-ethyl
being especially preferred.
[0070] Compounds of formula (I), wherein A.sup.1 and A.sup.2 are
bonded to each other to form a ring and -A.sup.1-A.sup.2- is
lower-alkylene optionally substituted by R.sup.2, in which one
--CH.sub.2-- group of -A.sup.1-A.sup.2- can optionally be replaced
by NR.sup.3 or O, or -A.sup.1-A.sup.2- is --CH.dbd.N--CH.dbd.CH--,
wherein R.sup.2 is hydroxy or hydroxy-lower-alkyl, and R.sup.3 is
hydrogen or lower-alkyl are also preferred, with those compounds,
wherein -A.sup.1-A.sup.2- is --(CH.sub.2).sub.4-- or
--(CH.sub.2).sub.5-- being especially preferred. In compounds
wherein A.sup.1 and A.sup.2 are bonded to each other to form a
ring, said ring is preferrably a 4-, 5-, or 6-membered ring such as
e.g. piperidinyl or pyrrolidinyl.
[0071] A further preferred embodiment of the present invention
relates to compounds of formula (I), wherein A.sup.3 and A.sup.4
represent hydrogen. Other preferred compounds of formula (I) as
defined above are those wherein A.sup.5 and A.sup.6 represent
hydrogen. Other preferred compounds of formula (I) as defined above
are those wherein A.sup.7 and A.sup.8 represent hydrogen.
[0072] Compounds of formula (I), wherein A.sup.9 is lower-alkyl
also relate to a preferred embodiment of the present invention,
with those compounds, wherein A.sup.9 is methyl relating to a
particularly preferred embodiment. Other preferred compounds are
those in which A.sup.10 is aryl, more preferrably wherein A.sup.10
is phenyl optionally substituted with halogen or CF.sub.3.
Compounds of formula (I) as defined above, wherein A.sup.10 is
4-chloro-phenyl or 4-trifluoromethyl-phenyl are most preferred.
[0073] Preferred compounds of general formula (I) are those
selected from the group consisting of
trans-N-{4-[5-(Allyl-methyl-amino)-pentyl]-cycloh-
exylmethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-{4-[5-(4-Hydroxy-piperidin-1-yl)-pentyl]-cyclohexylmethyl}-N-meth-
yl-4-trifluoromethyl-benzenesulfonamide,trans-N-[4-(5-Dimethylamino-pentyl-
)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexylmethyl)-N-
-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-(4-{5-[Bis-(2-hydrox-
y-ethyl)-amino]-pentyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benze-
nesulfonamide,
trans-{4-[5-(Allyl-methyl-amino)-pentyl]-cyclohexylmethyl}--
methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
trans-[4-(5-Dimethylamino-pentyl)-cyclohexylmethyl]-methyl-carbamic
acid 4-trifluoromethyl-phenyl ester,
trans-(4-{5-[Ethyl-(2-hydroxy-ethyl)-amin-
o]-pentyl}-cyclohexylmethyl)-methyl-carbamic acid
4-trifluoromethyl-phenyl ester,
trans-{4-[5-(4-Hydroxy-piperidin-1-yl)-pentyl]-cyclohexylmethyl}-m-
ethyl-carbamic acid 4-trifluoromethyl-phenyl ester,
trans-(4-{5-[Bis-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexylmethyl)-methy-
l-carbamic acid 4-trifluoromethyl-phenyl ester,
trans-N-Methyl-N-[4-(5-pip-
eridin-1-yl-pentyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide-
,
trans-N-Methyl-N-[4-(5-pyrrolidin-1-yl-pentyl)-cyclohexylmethyl]-4-trifl-
uoromethyl-benzenesulfonamide,
trans-N-(4-{4-[Ethyl-(2-hydroxy-ethyl)-amin-
o]-butyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-[4-(4-Dimethylamino-butyl)-cyclohexylmethyl]-N-methyl-4-trifluoro-
methyl-benzenesulfonamide,
trans-N-[4-(4-Diethylamino-butyl)-cyclohexylmet-
hyl]-N-methyl-4-trifluoromethyl-benzene-sulfonamide, trans-N-{4-[4-
(Allyl-methyl-amino)-butyl]-cyclohexylmethyl}-N-methyl-4-trifluoromethyl--
benzenesulfonamide,
trans-N-(4-{4-[Bis-(2-hydroxy-ethyl)-amino]-butyl}-cyc-
lohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-{4-[4-(Allyl-methyl-amino)-butyl]-cyclohexylmethyl}-methyl-carbamic
acid 4-chloro-phenyl ester,
trans-Methyl-[4-(4-piperidin-1-yl-butyl)-cycl-
ohexylmethyl]-carbamic acid 4-chloro-phenyl ester,
trans-(4-{4-[Ethyl-(2-h-
ydroxy-ethyl)-amino]-butyl}-cyclohexyl-methyl)-methyl-carbamic acid
4-chloro-phenyl ester,
trans-N-(4-Dimethylaminomethyl-cyclohexylmethyl)-N-
-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-{4-[(Allyl-methyl-am-
ino)-methyl]-cyclohexylmethyl}-N-methyl-4-trifluoromethyl-benzenesulfonami-
de,
trans-N-(4-{[Ethyl-(2-hydroxy-ethyl)-amino]-methyl}-cyclohexylmethyl)--
N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-(4-Diethylaminometh-
yl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzene-sulfonamide,
trans-N-(4-{[Bis-(2-hydroxy-ethyl)-amino]-methyl}-cyclohexylmethyl)-N-met-
hyl-4-trifluoromethyl-benzenesulfonamide,
trans-(4-Dimethylaminomethyl-cyc- lohexylmethyl)-methyl-carbamic
acid 4-chloro-phenyl ester,
trans-{4-[(Allyl-methyl-amino)-methyl]-cyclohexylmethyl}-methyl-carbamic
acid 4-chloro-phenyl ester,
trans-(4-Diethylaminomethyl-cyclohexylmethyl)- -methyl-carbamic
acid 4-chloro-phenyl ester, trans-(4-{[Ethyl-(2-hydroxy-e-
thyl)-amino]-methyl}-cyclohexylmethyl)-methyl-carbamic acid
4-chloro-phenyl ester,
trans-(4-{[Bis-(2-hydroxy-ethyl)-amino]-methyl}-cy-
clohexylmethyl)-methyl-carbamic acid 4-chloro-phenyl ester,
trans-N-(4-Ethylaminomethyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl--
benzenesulfonamide,
trans-N-Methyl-N-(4-piperidin-1-ylmethyl-cyclohexylmet-
hyl)-4-trifluoromethyl-benzenesulfonamide,
trans-N-(4-Azetidin-1-ylmethyl--
cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-Methyl-N-(4-pyrrolidin-1-ylmethyl-cyclohexylmethyl)-4-trifluorome-
thyl-benzenesulfonamide,
trans-Methyl-(4-piperidin-1-ylmethyl-cyclohexylme- thyl)-carbamic
acid 4-chloro-phenyl ester, trans-Methyl-(4-pyrrolidin-1-yl-
methyl-cyclohexylmethyl)-carbamic acid 4-chloro-phenyl ester
trans-N-{4-[3-(Allyl-methyl-amino)-propyl]-cyclohexylmethyl}-N-methyl-4-t-
rifluoromethyl-benzenesulfonamide,
trans-N-(4-{3-[Ethyl-(2-hydroxy-ethyl)--
amino]-propyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfona-
mide,
trans-N-[4-(3-Allylamino-propyl)-cyclohexylmethyl]-N-methyl-4-triflu-
oromethyl-benzenesulfonamide,
trans-N-Methyl-N-[4-(3-methylamino-propyl)-c-
yclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide,
trans-{4-[3-(Allyl-methyl-amino)-propyl]-cyclohexylmethyl}-methyl-carbami-
c acid 4-chloro-phenyl ester,
trans-Methyl-[4-(3-piperidin-1-yl-propyl)-cy-
clohexylmethyl]-carbamic acid 4-chloro-phenyl ester,
trans-(4-{3-[Ethyl-(2-hydroxy-ethyl)-amino]-propyl}-cyclohexylmethyl)-met-
hyl-carbamic acid 4-chloro-phenyl ester,
trans-(4-{3-[Bis-(2-hydroxy-ethyl-
)-amino]-propyl}-cyclohexylmethyl)-methyl-carbamic acid
4-chloro-phenyl ester,
trans-{4-[2-(Allyl-methyl-amino)-ethyl]-cyclohexylmethyl}-methyl-c-
arbamic acid 4-chloro-phenyl ester,
trans-Methyl-[4-(2-piperidin-1-yl-ethy-
l)-cyclohexylmethyl]-carbamic acid 4-chloro-phenyl ester,
trans-N-Methyl-N-[4-(2-piperidin-1-yl-ethyl)-cyclohexylmethyl]-4-trifluor-
omethyl-benzenesulfonamide,
trans-N-(4-{2-[Ethyl-(2-hydroxy-ethyl)-amino]--
ethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-(4-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-cyclohexylmethyl)-N-me-
thyl-4-trifluoromethyl-benzenesulfonamide,
trans-(4-{2-[Ethyl-(2-hydroxy-e-
thyl)-amino]-ethyl}-cyclohexylmethyl)-methyl-carbamic acid
4-chloro-phenyl ester,
trans-N-{4-[2-(Allyl-methyl-amino)-ethyl]-cyclohexylmethyl}-N-meth-
yl-4-trifluoromethyl-benzenesulfonamide,
trans-(RS,RS)-N-(4-{2-[Bis-(2-hyd-
roxy-propyl)-amino]-ethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-be-
nzenesulfonamide,
trans-(2-{4-[3-(Allyl-methyl-amino)-propyl]-cyclohexyl}--
ethyl)-methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
trans-[2-(4-{3-[Ethyl-(2-hydroxy-ethyl)-amino]-propyl}-cyclohexyl)-ethyl]-
-methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
trans-Methyl-{2-[4-(3-morpholin-4-yl-propyl)-cyclohexyl]-ethyl}-carbamic
acid 4-trifluoromethyl-phenyl ester,
trans-Methyl-{2-[4-(3-piperidin-1-yl-
-propyl)-cyclohexyl]-ethyl}-carbamic acid 4-trifluoromethyl-phenyl
ester,
trans-{2-[4-(3-Dimethylamino-propyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid 4-trifluoromethyl-phenyl ester,
trans-{2-[4-(3-Diethylamino-propyl)--
cyclohexyl]-ethyl}-methyl-carbamic acid 4-trifluoromethyl-phenyl
ester,
trans-Methyl-(2-{4-[3-(methyl-propyl-amino)-propyl]-cyclohexyl}-ethyl)-ca-
rbamic acid 4-trifluoromethyl-phenyl ester, trans-
[2-(4-{3-[Bis-(2-hydrox-
y-ethyl)-amino]-propyl}-cyclohexyl)-ethyl]-methyl-carbamic acid
4-trifluoromethyl-phenyl ester,
trans-Methyl-(2-{4-[3-(4-methyl-piperazin-
-1-yl)-propyl]-cyclohexyl}-ethyl)-carbamic acid
4-trifluoromethyl-phenyl ester,
trans-N-(2-{4-[(Allyl-methyl-amino)-methyl]-cyclohexyl}-ethyl)-N-m-
ethyl-4-trifluoromethyl-benzenesulfonamide,
trans-(2-{4-[(Allyl-methyl-ami-
no)-methyl]-cyclohexyl}-ethyl)-methyl-carbamic acid
4-trifluoromethyl-phenyl ester,
trans-[2-(4-Dimethylaminomethyl-cyclohexy-
l)-ethyl]-methyl-carbamic acid 4-trifluoromethyl-phenyl ester,
trans-[2-(4-{[Ethyl-(2-hydroxy-ethyl)-amino]-methyl}-cyclohexyl)-ethyl]-m-
ethyl-carbamic acid 4-trifluoromethyl-phenyl ester,
trans-Methyl-{2-[4-(4-methyl-piperazin-1-ylmethyl)-cyclohexyl]-ethyl}-car-
bamic acid 4-trifluoromethyl-phenyl ester,
trans-(2-{4-[(2-Hydroxy-ethylam-
ino)-methyl]-cyclohexyl}-ethyl)-methyl-carbamic acid
4-trifluoromethyl-phenyl ester,
trans-(2-{4-[(2-Hydroxy-1,1-dimethyl-ethy-
lamino)-methyl]-cyclohexyl}-ethyl)-methyl-carbamic acid
4-trifluoromethyl-phenyl ester,
trans-[2-(4-Allylaminomethyl-cyclohexyl)-- ethyl]-methyl-carbamic
acid 4-trifluoromethyl-phenyl ester,
trans-Methyl-[2-(4-methylaminomethyl-cyclohexyl)-ethyl]-carbamic
acid 4-trifluoromethyl-phenyl ester,
trans-N-[2-(4-Dimethylaminomethyl-cyclohe-
xyl)-ethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-[2-(4-{[Ethyl-(2-hydroxy-ethyl)-amino]-methyl}-cyclohexyl)-ethyl]-
-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-Methyl-N-{2-[4-(4--
methyl-piperazin-1-ylmethyl)-cyclohexyl]-ethyl}-4-trifluoromethyl-benzenes-
ulfonamide,
trans-N-(2-{4-[(2-Hydroxy-ethylamino)-methyl]-cyclohexyl}-ethy-
l)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-Methyl-N-[2-(4-m-
ethylaminomethyl-cyclohexyl)-ethyl]-4-trifluoromethyl-benzenesulfonamide,
trans-N-(2-{4-[(2-Hydroxy-1,1-dimethyl-ethylamino)-methyl]-cyclohexyl}-et-
hyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-[2-(4-Allylaminomethyl-cyclohexyl)-ethyl]-N-methyl-4-trifluoromet-
hyl-benzenesulfonamide, trans-N-Methyl-N-[2-
(4-piperidin-1-ylmethyl-cyclo-
hexyl)-ethyl]-4-trifluoromethyl-benzenesulfonamide,
trans-Methyl-[2-(4-piperidin-1-ylmethyl-cyclohexyl)-ethyl]-carbamic
acid 4-trifluoromethyl-phenyl ester,
trans-Methyl-[2-(4-piperidin-1-ylmethyl-c-
yclohexyl)-ethyl]-carbamic acid 4-chloro-phenyl ester,
trans-[2-(4-{[Ethyl-(2-hydroxy-ethyl)-amino]-methyl}-cyclohexyl)-ethyl]-m-
ethyl-carbamic acid 4-chloro-phenyl ester,
trans-[2-(4-Ethylaminomethyl-cy- clohexyl)-ethyl]-methyl-carbamic
acid 4-chloro-phenyl ester,
trans-[2-(4-Dimethylaminomethyl-cyclohexyl)-ethyl]-methyl-carbamic
acid 4-chloro-phenyl ester,
trans-(2-{4-[(Allyl-methyl-amino)-methyl]-cyclohex-
yl}-ethyl)-methyl-carbamic acid 4-chloro-phenyl ester,
trans-Methyl-[2-(4-pyrrolidin-1-ylmethyl-cyclohexyl)-ethyl]-carbamic
acid 4-chloro-phenyl ester,
trans-Methyl-[2-(4-methylaminomethyl-cyclohexyl)-e- thyl]-carbamic
acid 4-chloro-phenyl ester, trans-4-Chloro-N-methyl-N-[2-(4-
-piperidin-1-ylmethyl-cyclohexyl)-ethyl]-benzenesulfonamide,
trans-4-Chloro-N-[2-(4-dimethylaminomethyl-cyclohexyl)-ethyl]-N-methyl-be-
nzenesulfonamide,
trans-4-Chloro-N-methyl-N-[2-(4-pyrrolidin-1-ylmethyl-cy-
clohexyl)-ethyl]-benzenesulfonamide,
trans-N-(2-{4-[(Allyl-methyl-amino)-m-
ethyl]-cyclohexyl}-ethyl)-4-chloro-N-methyl-benzenesulfonamide,
trans-4-Chloro-N-methyl-N-[2-(4-methylaminomethyl-cyclohexyl)-ethyl]-benz-
enesulfonamide,
trans-4-Chloro-N-[2-(4-{[ethyl-(2-hydroxy-ethyl)-amino]-me-
thyl}-cyclohexyl)-ethyl]-N-methyl-benzenesulfonamide,
trans-4-Chloro-N-[2-(4-ethylaminomethyl-cyclohexyl)-ethyl]-N-methyl-benze-
nesulfonamide,
trans-(2-{4-[(6-Hydroxy-hexylamino)-methyl]-cyclohexyl}-eth-
yl)-methyl-carbamic acid 4-chloro-phenyl ester,
trans-(2-{4-[(5-Hydroxy-pe-
ntylamino)-methyl]-cyclohexyl}-ethyl)-methyl-carbamic acid
4-chloro-phenyl ester,
trans-4-Chloro-N-(2-{4-[(5-hydroxy-pentylamino)-methyl]-cyclohexyl-
}-ethyl)-N-methyl-benzenesulfonamide,
trans-4-Chloro-N-(2-{4-[(6-hydroxy-h-
exylamino)-methyl]-cyclohexyl}-ethyl)-N-methyl-benzenesulfonamide,
trans-[2-(4-{[Ethyl-(2-hydroxy-ethyl)-amino]-methyl}-cyclohexyl)-ethyl]-m-
ethyl-carbamic acid 4-trifluoromethyl-phenyl ester,
trans-N-{4-[4-(Allyl-methyl-amino)-butoxy]-cyclohexylmethyl}-4-chloro-N-m-
ethyl-benzenesulfonamide,
cis-N-{4-[4-(Allyl-methyl-amino)-butoxy]-cyclohe-
xylmethyl}-4-chloro-N-methyl-benzenesulfonamide,
trans-{4-[4-(Allyl-methyl-
-amino)-butoxy]-cyclohexylmethyl}-methyl-carbamic acid
4-chloro-phenyl ester,
trans-N-{4-[4-(Allyl-methyl-amino)-butoxy]-cyclohexylmethyl}-N-met-
hyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-(4-{4-[Ethyl-(2-hydroxy--
ethyl)-amino]-butoxy}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzene-
sulfonamide,
trans-Methyl-{2-[4-(3-piperidin-1-yl-(E)-propenyl)-cyclohexyl-
]-ethyl}-carbamic acid 4-chloro-phenyl ester,
trans-N-Methyl-N-[4-(3-piper-
idin-1-yl-(E,Z)-propenyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfo-
namide,
trans-N-(4-{3-[Ethyl-(2-hydroxy-ethyl)-amino]-(E,Z)-propenyl}-cycl-
ohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-(2-{4-[3-(Allyl-methyl-amino)-(E)-propenyl]-cyclohexyl}-ethyl)-N--
methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-{2-[4-(3-Dimethylamin-
o-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfo-
namide,
trans-N-Methyl-N-{2-[4-(3-piperidin-1-yl-(E)-propenyl)-cyclohexyl]-
-ethyl}-4-trifluoromethyl-benzenesulfonamide,
trans-N-{2-[4-(3-Ethylamino--
(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl-benzenesulfona-
mide,
trans-(2-{4-[3-(Allyl-methyl-amino)-(E)-propenyl]-cyclohexyl}-ethyl)-
-methyl-carbamic acid 4-chloro-phenyl ester, trans-{2-[4-(3
-Dimethylamino-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid 4-chloro-phenyl ester,
trans-{2-[4-(3-Ethylamino-(E)-propenyl)-cyclohexyl-
]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester,
trans-Methyl-{2-[4-(3-pyrrolidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-ca-
rbamic acid 4-chloro-phenyl ester,
trans-N-Methyl-N-[4-(4-piperidin-1-yl-(-
E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfona-
mide,
trans-N-Methyl-N-[4-(4-pyrrolidin-1-yl-(E)-but-2-enyloxymethyl)-cycl-
ohexylmethyl]-4-trifluoromethyl-benzenesulfonamide,
trans-N-(4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-(E)-but-2-enyloxymethyl}-cy-
clohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-{4-[4-(Allyl-methyl-amino)-(E)-but-2-enyloxymethyl]-cyclohexylmet-
hyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-(4-{4-[Bis-(2-hydroxy-ethyl)-amino]-(E)-but-2-enyloxymethyl}-cycl-
ohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-Methyl-N-[4-(4-methylamino-(E)-but-2-enyloxymethyl)-cyclohexylmet-
hyl]-4-trifluoromethyl-benzenesulfonamide,
trans-N-(4-{4-[(2-Hydroxy-ethyl-
)-methyl-amino]-(E)-but-2-enyloxymethyl}-cyclohexylmethyl)-N-methyl-4-trif-
luoromethyl-benzenesulfonamide,
trans-N-Methyl-N-[4-(4-morpholin-4-yl-(E)--
but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamid-
e,
trans-N-Methyl-N-[4-(4-piperazin-1-yl-(E)-but-2-enyloxymethyl)-cyclohex-
ylmethyl]-4-trifluoromethyl-benzenesulfonamide,
trans-N-Methyl-N-[4-(4-pip-
eridin-1-yl-butoxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfo-
namide,
trans-N-(4-{4-[(2-Hydroxy-ethyl)-methyl-amino]-butoxymethyl}-cyclo-
hexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-Methyl-N-[4-(4-pyrrolidin-1-yl-butoxymethyl)-cyclohexylmethyl]-4--
trifluoromethyl-benzenesulfonamide,
trans-N-{4-[4-(Allyl-methyl-amino)-but-
oxymethyl]-cyclohexylmethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide-
,
trans-N-(4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxymethyl}cyclohexylmet-
hyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-[4-(4-Dimethylamino-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-tr-
ifluoromethyl-benzenesulfonamide,
trans-N-(4-{4-[Bis-(2-hydroxy-ethyl)-ami-
no]-butoxymethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulf-
onamide,
trans-N-{4-[4-((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-butoxymethyl]-
-cyclohexylmethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-Methyl-[4-(4-pyrrolidin-1-yl-butoxymethyl)-cyclohexylmethyl]-carbam-
ic acid 4-chloro-phenyl ester,
trans-Methyl-[4-(4-piperidin-1-yl-butoxymet-
hyl)-cyclohexylmethyl]-carbamic acid 4-chloro-phenyl ester,
trans-(4-{4-[(2-Hydroxy-ethyl)-methyl-amino]-butoxymethyl}-cyclohexylmeth-
yl)-methyl-carbamic acid 4-chloro-phenyl ester,
trans-(4-{4-[Bis-(2-hydrox-
y-ethyl)-amino]-butoxymethyl}-cyclohexylmethyl)-methyl-carbamic
acid 4-chloro-phenyl ester,
trans-[4-(4-Dimethylamino-butoxymethyl)-cyclohexyl-
methyl]-methyl-carbamic acid 4-chloro-phenyl ester,
trans-(4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxymethyl}-cyclohexylmethy-
l)-methyl-carbamic acid 4-chloro-phenyl ester,
trans-Methyl-{2-[4-(2-piper-
idin-1-yl-ethyl)-cyclohexyl]-ethyl}-carbamic acid 4-chloro-phenyl
ester,
trans-4-Chloro-N-methyl-N-{2-[4-(2-piperidin-1-yl-ethyl)-cyclohexyl]-ethy-
l}-benzenesulfonamide,
trans-(2-{4-[2-(Allyl-methyl-amino)-ethyl]-cyclohex-
yl}-ethyl)-methyl-carbamic acid 4-chloro-phenyl ester,
trans-{2-[4-(2-Dimethylamino-ethyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid 4-chloro-phenyl ester,
trans-{2-[4-(2-Ethylamino-ethyl)-cyclohexyl]--
ethyl}-methyl-carbamic acid 4-chloro-phenyl ester,
trans-[2-(4-{2-[Ethyl-(-
2-hydroxy-ethyl)-amino]-ethyl}-cyclohexyl)-ethyl]-methyl-carbamic
acid 4-chloro-phenyl ester,
trans-Methyl-{2-[4-(2-methylamino-ethyl)-cyclohexy-
l]-ethyl}-carbamic acid 4-chloro-phenyl ester,
trans-(2-{4-[2-(6-Hydroxy-h-
exylamino)-ethyl]-cyclohexyl}-ethyl)-methyl-carbamic acid
4-chloro-phenyl ester,
trans-(2-{4-[2-(5-Hydroxy-pentylamino)-ethyl]-cyclohexyl}-ethyl)-m-
ethyl-carbamic acid 4-chloro-phenyl ester,
trans-4-Chloro-N-{2-[4-(2-dimet-
hylamino-ethyl)-cyclohexyl]-ethyl}-N-methyl-benzenesulfonamide,
trans-N-(2-{4-[2-(Allyl-methyl-amino)-ethyl]-cyclohexyl}-ethyl)-4-chloro--
N-methyl-benzenesulfonamide,
trans-4-Chloro-N-methyl-N-{2-[4-(2-methylamin-
o-ethyl)-cyclohexyl]-ethyl}-benzenesulfonamide,
trans-4-Chloro-N-{2-[4-(2--
ethylamino-ethyl)-cyclohexyl]-ethyl}-N-methyl-benzenesulfonamide,
trans-4-Chloro-N-[2-(4-{2-[ethyl-(2-hydroxy-ethyl)-amino]-ethyl}-cyclohex-
yl)-ethyl]-N-methyl-benzenesulfonamide,
trans-Methyl-[4-(3-piperidin-1-yl--
prop-1-ynyl)-cyclohexylmethyl]-carbamic acid 4-chloro-phenyl ester,
trans-(4-{3-[Ethyl-(2-hydroxy-ethyl)-amino]-prop-1-ynyl}-cyclohexylmethyl-
)-methyl-carbamic acid 4-chloro-phenyl ester,
trans-N-Methyl-N-[4-(3-piper-
idin-1-yl-prop-1-ynyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonam-
ide,
trans-N-(4-{3-[Ethyl-(2-hydroxy-ethyl)-amino]-prop-1-ynyl}-cyclohexyl-
methyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-Methyl-[4-(3-piperidin-1-yl-prop-1-ynyl)-cyclohexylmethyl]-carbamic
acid 4-trifluoromethyl-phenyl ester,
trans-(4-{3-[Ethyl-(2-hydroxy-ethyl)-
-amino]-prop-1-ynyl}-cyclohexylmethyl)-methyl-carbamic acid
4-trifluoromethyl-phenyl ester,
trans-{2-[4-(3-Imidazol-1-yl-propyl)-cycl-
ohexyl]-ethyl}-methyl-carbamic acid 4-chloro-phenyl ester,
trans-N-[2-(4-Imidazol-1-ylmethyl-cyclohexyl)-ethyl]-N-methyl-4-trifluoro-
methyl-benzenesulfonamide,
trans-N-(4-Imidazol-1-ylmethyl-cyclohexylmethyl-
)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-N-[4-(3-Imidazol-1--
yl-(E,Z)-propenyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesul-
fonamide,
trans-N-[4-(2-Imidazol-1-yl-ethyl)-cyclohexylmethyl]-N-methyl-4--
trifluoromethyl-benzenesulfonamide,
trans-N-[4-(4-Imidazol-1-yl-(E)-but-2--
enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfona-
mide,
trans-N-Methyl-N-(4-{4-[methyl-(2-methyl-pyrimidin-4-yl)-amino]-(E)--
but-2-enyloxymethyl}-cyclohexylmethyl)-4-trifluoromethyl-benzenesulfonamid-
e,
rac-trans-ethyl(2-hydroxyethyl)({4-[2-(methyl{[4-(trifluoromethyl)pheno-
xy]carbonyl}amino)-ethyl]cyclohexyl}methyl)ammoniumolate,
trans-Methyl-{4-[3-(methyl-propyl-amino)-prop-1-ynyl]-cyclohexylmethyl}-c-
arbamic acid 4-fluoro-phenyl ester,
trans-(4-{3-[Ethyl-(2-hydroxy-ethyl)-a-
mino]-prop-1-ynyl}-cyclohexylmethyl)-methyl-carbamic acid
4-fluoro-phenyl ester, and
trans-[4-(3-Dimethylamino-prop-1-ynyl)-cyclohexylmethyl]-methy-
l-carbamic acid 4-fluoro-phenyl ester, and pharmaceutically
acceptable salts thereof.
[0074] Particularly preferred compounds of general formula (I) are
those selected from the group consisting of
trans-Methyl-[4-(2-piperidin-1-yl-e-
thyl)-cyclohexylmethyl]-carbamic acid 4-chloro-phenyl ester,
trans-N-Methyl-N-[4-(2-piperidin-1-yl-ethyl)-cyclohexylmethyl]-4-trifluor-
omethyl-benzenesulfonamide,
trans-N-(4-{2-[Bis-(2-hydroxy-ethyl)-amino]-et-
hyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide,
trans-[2-(4-Dimethylaminomethyl-cyclohexyl)-ethyl]-methyl-carbamic
acid 4-trifluoromethyl-phenyl ester,
trans-[2-(4-{[Ethyl-(2-hydroxy-ethyl)-ami-
no]-methyl}-cyclohexyl)-ethyl]-methyl-carbamic acid
4-trifluoromethyl-phenyl ester,
trans-Methyl-[2-(4-piperidin-1-ylmethyl-c-
yclohexyl)-ethyl]-carbamic acid 4-trifluoromethyl-phenyl ester,
trans-Methyl-{2-[4-(3-piperidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-car-
bamic acid 4-chloro-phenyl ester,
trans-Methyl-{2-[4-(3-pyrrolidin-1-yl-(E-
)-propenyl)-cyclohexyl]-ethyl}-carbamic acid 4-chloro-phenyl ester,
trans-(4-{5-[Bis-(2-hydroxy-ethyl)-amino]-pentyl}-cyclohexylmethyl)-methy-
l-carbamic acid 4-trifluoromethyl-phenyl ester,
trans-(4-{3-[Ethyl-(2-hydr-
oxy-ethyl)-amino]-prop-1-ynyl}-cyclohexylmethyl)-methyl-carbamic
acid 4-trifluoromethyl-phenyl ester, and
trans-N-(4-{3-[Ethyl-(2-hydroxy-ethyl-
)-amino]-propyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfo-
namide, and pharmaceutically acceptable salts thereof.
[0075] Preferred compounds of formula (I) include: 4
[0076] wherein
[0077] U is a lone pair,
[0078] V is --CH.sub.2--, --CH.dbd.CH--, or --C.ident.C--,
[0079] W is COO or SO.sub.2,
[0080] m and n independently from each other are from 0 to 3 and
m+n is from 0 to 3,
[0081] A.sup.1 is hydroxy lower-alkyl, or lower-alkyl,
[0082] A.sup.2 is hydroxy lower-alkyl or lower-alkyl, or
[0083] A.sup.1 and A.sup.2 are bonded to each other to form a ring
with the N atom to which they are attached, and -A.sup.1-A.sup.2-
is lower-alkylene,
[0084] A.sup.3 and A.sup.4 are each hydrogen,
[0085] A.sup.5, A.sup.6, A.sup.7 and A.sup.8 are each hydrogen,
[0086] A.sup.9 is lower-alkyl,
[0087] A.sup.10 is phenyl substituted with chlorine or
--CF.sub.3,
[0088] p is 0 or 1,
[0089] and pharmaceutically acceptable salts thereof.
[0090] Compounds of formula (I) can have one or more asymmetric
carbon atoms and can exist in the form of optically pure
enantiomers or as racemates. The invention embraces all of these
forms. Compounds of formula (I) which are trans-isomers (with
reference to the cyclohexyl ring) are preferred.
[0091] It will be appreciated that the compounds of general formula
(I) in this invention may be derivatised at functional groups to
provide derivatives which are capable of conversion back to the
parent compound in vivo.
[0092] The present invention also relates to a process for the
manufacture of compounds of formula (I) as described above, which
process comprises
[0093] a) reacting a compound of formula (II) 5
[0094] with a compound (A.sup.1, A.sup.2, U)N--C(A.sup.3,
A.sup.4)-(CH.sub.2).sub.m-M, wherein V is O or S, M is mesylate,
tosylate, triflate, Cl, Br or I, and U, A.sup.1, A.sup.2, A.sup.3,
A.sup.4, A.sup.5, A.sup.6, A.sup.7, A.sup.8, A.sup.9, A.sup.10, W,
m, n and p are as defined above, or wherein HV is mesylate,
tosylate, triflate, Cl, Br or I, and M is OH or SH,
[0095] or b) reacting a compound of formula (III) 6
[0096] with a compound NHA.sup.1A.sup.2, wherein M is mesylate,
tosylate, triflate, Cl, Br or I, and A.sup.1, A.sup.2, A.sup.3,
A.sup.4, A.sup.5, A.sup.6, A.sup.7, A.sup.8, A.sup.9, A.sup.10, V,
W, m, n and p are as defined above,
[0097] and optionally converting a compound of formula (I) as
defined above to a pharmaceutically acceptable salt,
[0098] and optionally converting a compound of formula (I) as
defined above, wherein U is a lone pair, to a corresponding
compound wherein U is O.
[0099] Reactions of a compound of formula (II) with a compound
(A.sup.1, A.sup.2, U)N--C(A.sup.3, A.sup.4)-(CH.sub.2).sub.m-M can
be carried out by procedures known in the art and described in the
Scheme 8 in a solvent like N,N-dimethylformamide,
N,N-dimethylacetamide or nitromethane in the presence of a base
like sodium hydride or 2,6-di-tert-butylpyridine in a temperature
range of e.g. 0.degree. C. to 80.degree. C. Reactions of a compound
of formula (III) with a compound NHA.sup.1A.sup.2 can be carried
out by procedures known in the art and described in the examples
preferentially in solvents like N,N-dimethylacetamide,
N,N-dimethylformamide or methanol, preferentially between room
temperature and 80.degree. C.
[0100] A compound as defined above can be converted to a
pharmaceutically acceptable salt by procedures known in the art
such as by a treatment with a corresponding acid in a solvent like
ethanol, methanol or dichloromethane in a temperature range of e.g.
e.g. -20.degree. C. and +40.degree. C. A compound as defined above,
wherein U is a lone pair can be converted to a compound wherein U
is O by procedures known in the art such as by reaction with a
mixture of hydrogen peroxide, urea adduct and phthalic anhydride in
dichloromethane at room temperature.
[0101] The invention further relates to compounds of formula (I) as
defined above, when manufactured according to a process as defined
above.
[0102] As described above, the compounds of formula (I) of the
present invention can be used for the treatment and/or prophylaxis
of diseases which are associated with OSC such as
hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular
diseases, mycoses, parasite infections and gallstones, and/or
treatment and/or prophylaxis of impaired glucose tolerance,
diabetes, tumors and/or hyperproliferative disorders, preferably
for the treatment and/or prophylaxis of hypercholesterolemia and/or
hyperlipemia. Hyperproliferative skin and vascular disorders
particularly come into consideration as hyperproliferative
disorders.
[0103] The invention therefore also relates to pharmaceutical
compositions comprising a compound as defined above and a
pharmaceutically acceptable carrier and/or adjuvant.
[0104] Further, the invention relates to compounds as defined above
for use as therapeutic active substances, particularly as
therapeutic active substances for the treatment and/or prophylaxis
of diseases which are associated with OSC such as
hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular
diseases, mycoses, parasite infections, gallstones, tumors and/or
hyperproliferative disorders, and/or treatment and/or prophylaxis
of impaired glucose tolerance and diabetes, preferably for the
treatment and/or prophylaxis of hypercholesterolemia and/or
hyperlipemia.
[0105] In another embodiment, the invention relates to a method for
the treatment and/or prophylaxis of diseases which are associated
with OSC such as hypercholesterolemia, hyperlipemia,
arteriosclerosis, vascular diseases, mycoses, parasite infections,
gallstones, tumors and/or hyperproliferative disorders, and/or
treatment and/or prophylaxis of impaired glucose tolerance and
diabetes, preferably for the treatment and/or prophylaxis of
hypercholesterolemia and/or hyperlipemia, which method comprises
administering a compound as defined above to a human being or
animal.
[0106] The invention further relates to the use of compounds as
defined above for the treatment and/or prophylaxis of diseases
which are associated with OSC such as hypercholesterolemia,
hyperlipemia, arteriosclerosis, vascular diseases, mycoses,
parasite infections, gallstones, tumors and/or hyperproliferative
disorders, and/or treatment and/or prophylaxis of impaired glucose
tolerance and diabetes, preferably for the treatment and/or
prophylaxis of hypercholesterolemia and/or hyperlipemia.
[0107] In addition, the invention relates to the use of compounds
as defined above for the preparation of medicaments for the
treatment and/or prophylaxis of diseases which are associated with
OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis,
vascular diseases, mycoses, parasite infections, gallstones, tumors
and/or hyperproliferative disorders, and/or treatment and/or
prophylaxis of impaired glucose tolerance and diabetes, preferably
for the treatment and/or prophylaxis of hypercholesterolemia and/or
hyperlipemia. Such medicaments comprise a compound as defined
above.
[0108] The compounds of formula (I) can be manufactured by the
methods given below, by the methods given in the examples or by
analogous methods. Appropriate reaction conditions for the
individual reaction steps are known to the person skilled in the
art. Starting materials are either commercially available or can be
prepared by methods analogous to the methods given below or in the
examples or by methods known in the art. 7
[0109] Trans-(4-methylaminomethyl-cyclohexyl)-methanol (7-trans
with A.sup.5, A.sup.6=H; A.sup.9=Me) can be obtained from
trans-(4-hydroxymethyl-cyclohexylmethyl)-carbamic acid tert-butyl
ester [U.S. (2000) U.S. Pat. No. 6,022,969 A] by treatment with
lithium aluminum hydride in tetrahydrofuran between room
temperature and the reflux temperature of the tetrahydrofuran (step
g). Introduction of a tert-butoxycarbonyl protective function by
treatment with di-tert-butyl-dicarbonate in methanol/triethylamine
between -10.degree. C. and room temperature gives compound 8
(A.sup.5, A.sup.6=H; A.sup.9=Me) (step h). Compounds with variable
alkyl groups A.sup.5, A.sup.6 and A.sup.9 are prepared from
cyclohexane-1,4-dicarboxylic acid mono alkyl esters, preferentially
mono isopropyl esters, by first introduction of the first alkyl
group A.sup.5 by conversion of the acid moiety in 1 into the
corresponding acid chlorides and treatment with a di-alkyl cuprates
in solvents like ether or tetrahydrofuran preferentially at
-78.degree. C. (step a). Reductive amination of the ketones 2 with
ammonium formiate and sodium cyanoborohydride in solvents like
methanol or ethanol preferentially at room temperature then gives
amines 4 with A.sup.6 equal H (step b). If the ketones 2 are
treated with an alkyllithium reagent in the presence of titanium
tetrachloride in ether as described in Tetrahedron 42(11),
2931-2935 (1986), then tertiary alkohols 3 are formed (step c). The
tertiary alkohols 3 are then reacted with trimethylsilylazide in
the presence of borontrifluoride etherate in a solvent like benzene
to from the azides as described in Tetrahedron Letters 28(51),
6513-6516 (1987); the azides are subsequently hydrogenated with
hydrogen gas and e.g. a palladium catalyst in solvents like
methanol, ethanol or tetrahydrofuran to the primary amines 4 (step
d). Introduction of a tert-butoxycarbonyl protective function at
the primary amino moiety of compounds 4 leads then to compounds 5
(step e). Compounds 5 can be N-alkylated at the primary
tert-butoxycarbonyl protected amino function with an alkyl halide
in the presence of a base like sodium hydride in a solvent like
N,N-dimethylformamide or acetonitrile at temperatures between room
temperature and 80.degree. C. to introduce substituents A.sup.9;
after reduction of the ester function with e.g. lithium aluminum
hydride in solvents like tetrahydrofuran at temperatures between
-50.degree. C. and room temperature, the compounds 8 are obtained
(step f). Compounds 8 are subsequently oxidized to the
corresponding aldehydes 9 by using e.g. Swern conditions: oxalyl
chloride/dimethylsulfoxide/triethylamine in dichloromethane,
-78.degree. C. to room temperature (step i). 8
[0110]
[4-(Tert-butyl-dimethyl-silanyloxymethyl)-cyclohexyl]-methanol
compounds 1 are prepared from the corresponding bis-hydroxymethyl
cyclohexane derivatives by treatment with one equivalent of n-butyl
lithium in tetrahydrofuran at -78.degree. C. followed by one
equivalent of tert-butyl-dimethyl-chlorosilane at -65.degree. C. to
room temperature. Mesylation of
[4-(tert-butyl-dimethyl-silanyloxymethyl)-cycl- ohexyl]-methanols 1
(methanesulfonyl chloride in dichloromethane and triethylamine at
0-10.degree. C.) gives the corresponding methanesulfonates, which
are treated with sodium cyanide in N,N-dimethylformamide at
80.degree. C. to give the cyano compounds 2 with A.sup.5, A.sup.6
equal to hydrogen (step a). Direct reduction of the cyano compounds
2 e.g. by hydrogenation with a platinum catalyst in acidic methanol
gives the primary amines 5 with A.sup.5, A.sup.6, A.sup.7 and
A.sup.8 equal to hydrogen and without tert-butyl-dimethyl-silyl
protective function (step b). Alternatively, alkyl groups A.sup.5
and/or A.sup.6 can be introduced into cyano compounds 2 by
treatment with a base like potassium tert-butoxide or sodium
hydride in solvents like tetrahydrofuran or 1,2-dimethoxyethane
followed by addition of one or sequentially two different alkyl
halides, a reaction preferentially performed between 0.degree. C.
and 80.degree. C. Mono and/or dialkyl cyano compounds 2 can be
reduced to compounds 5 as described above (step b). Alternatively,
cyano compounds 2 can be reacted with alkyl Grignard reagents in
solvents like ether or tetrahydrofuran between 0.degree. C. and the
reflux temperature of the solvent to form the corresponding alkyl
ketones 3 (step c). Reductive amination of the ketones 3 with
ammonium formiate and sodium cyanoborohydride in solvents like
methanol or ethanol preferentially at room temperature followed by
removal of the tert-butyl-dimethyl-silyl protective function with
aqueous hydrofluoric acid in a water/acetonitrile mixture at room
temperature gives amines 5 with A.sup.8 equal to H (step e).
Treatment of ketones 3 with a second alkyl Grignard reagent under
conditions similar to those just described gives tertiary alcohols
4 (step d). The tertiary alkohols 4 are then reacted with
trimethylsilylazide in the presence of borontrifluoride etherate in
a solvent like benzene to form the corresponding azide as described
in Tetrahedron Letters 28(51), 6513-6516 (1987) and the azide is
hydrogenated with hydrogen gas and e.g. a palladium catalyst in
solvents like methanol, ethanol or tetrahydrofuran to the primary
amines 5 without tert-butyl-dimethyl-silyl protective function,
which gets lost under the conditions of the azide formation (step
f). Treatment of the amino-alcohols 5 first with
di-tert-butyl-dicarbonate in dichloromethane in the presence of
triethylamine followed by acetic anhydride and pyridine in
dichloromethane gives the di-protected compounds 6 (step g).
Compounds 6 can be N-alkylated at the primary tert-butoxycarbonyl
protected amino function with an alkyl halide in the presence of a
base like sodium hydride in a solvent like N,N-dimethylformamide or
acetonitril at temperatures between room temperature and 80.degree.
C. to introduce substituents A.sup.9 and give, after basic cleavage
of the acetate function, the primary hydroxy compounds 7 (step h).
The primary hydroxy compounds 7 can be oxidized subsequently to the
corresponding aldehydes 8 by using e.g. Swern conditions: oxalyl
chloride/dimethylsulfoxide/triethylamine in dichloromethane,
-78.degree. C. to room temperature (step i). 9
[0111] Aldehydes 1 undergo Wittig reactions with a variety of
ylids. Thus, treatment with (benzyloxyalkyl or
haloalkyl)triphenylphosphonium salts, e.g.
4-(bromobutyl)triphenylphosphonium bromide or
3-benzyloxypropyl)triphenylphosphonium bromide, preferentially with
finely milled potassium carbonate as base in solvents like
2-methyl-2-butanol or tert-amyl alcohol at temperatures between
room temperature and the reflux temperature of the solvents, yields
[4-(5-bromo-(E,Z)-pent-1-enyl)-cyclohexylalkyl]-alkyl-carbamic acid
tert-butyl esters 2 or
[4-(4-benzyloxy-(E,Z)-but-1-enyl)-cyclohexylalkyl]- -alkyl-carbamic
acid tert-butyl esters 5 (step a). Optionally, the double bond
present can be reduced by hydrogenation leading to compounds 3 and
6 (step b and e). If a benzyloxy function has been present in the
phosphonium salt and the corresponding olefin, then, the
hydrogenolytic removal of the benzyl group reduces the double bond
at the same time (step e). After removal of the tert-butoxycarbonyl
protective function with acid (steps c and f), the corresponding
amine compounds 4 and 7 are converted into compounds 8 and 9
carrying the NA.sup.9WA.sup.10 groups by the following procedures
(steps d and g):
[0112] a) NA.sup.9WA.sup.10=Sulfonamides or carbamates: treatment
with an aryl-sulfonyl chloride or with an aryl chloroformate
preferentially in the presence of diisopropyl-ethylamine, potassium
carbonate, tetrahydrofuran and water between -10.degree. C. and
room temperature.
[0113] b) NA.sup.9WA.sup.10=Thiocarbamates: The amines may be
reacted with A.sup.10OOCSCl in solvents like dioxane,
dichloromethane or tetrahydrofuran in the presence of a base like
diisopropyl-ethylamine or aqueous potassium carbonate.
[0114] c) NA.sup.9WA.sup.10=Ureas: The amines may be reacted with
isocyanate in dioxane at room temperature.
[0115] d) NA.sup.9WA.sup.10=Thioureas: The amines may be reacted
with isothiocyanate in dioxane at room temperature.
[0116] e) NA.sup.9WA.sup.10=Amides: The amines may be reacted with
A.sup.10COCl/Huenigsbase in CH.sub.2Cl.sub.2,
A.sup.10COOH/EDCI/DMAP (via formation of the symmetrical anhydride,
and subsequent addition of the starting amine at -10.degree. C. to
room temperature) or alternatively with A.sup.10COOH/EDCI/DMAP or
A.sup.10COOH/Huenig's base or NMM/EDCI/HOBT in DMF, dioxane or
CH.sub.2Cl.sub.2 at room temperature.
[0117] f) NA.sup.9WA.sup.10=Sulfamides: The amines may be reacted
with sulfamoyl chlorides in dioxane in the presence of an excess of
triethylamine. The sulfamoyl chlorides can be prepared from
A.sup.10NH.sub.2 and chlorosulfonic acid in CH.sub.2Cl.sub.2 at
0.degree. C. to room temperature followed by reaction with
PCl.sub.5 in toluene at 75.degree. C. Alternatively, the sulfamoyl
chlorides can be synthesized in acetonitrile with A.sup.10NH.sub.2
and sulfuryl chloride at 0.degree. C. to 65.degree. C.
[0118] Compounds 9, which contain a hydroxy function, are converted
into the corresponding methanesulfonates by treatment with
methanesulfonyl chloride in dichloromethane and triethylamine at
0-10.degree. C. (step h).
[0119] Amination of halides 8 and methanesulfonates 10 with amines
A.sup.1A.sup.2NH is preferentially being performed in
N,N-dimethylacetamide or in N,N-dimethylformamide, between room
temperature and 80.degree. C., or in methanol and optionally
1,8-diazabicyclo[5.4.0]undec-7-ene at room temperature to reflux
and yields the final amine compounds 11 (q=1 or 2) (step i). Amines
11 may optionally be converted into a salt or into the N-oxides
using a mixture of hydrogen peroxide urea adduct and phthalic
anhydride in dichloromethane at room temperature. In case
A.sup.1A.sup.2N (U absent) signifies imidazol-1-yl, then the
transformation of halides 8 and methanesulfonates 10 is performed
with imidazole, sodium hydride in a solvent like
N,N-dimethylformamide preferentially at temperatures between
0.degree. C. and room temperature. If A.sup.1=H, heteroaromatic
moieties A.sup.1 may be introduced into compounds 11 by treatment
with halo heteroaromatics in the presence of Huenig's base in
N,N-dimethylformamide between room temperature and 100.degree. C.
(Ger. Offen. (1990), DE3905364 A1). Alternatively, Buchwald
conditions e.g. Pd(OAc).sub.2, 2-(Dicyclohexylphosphino) biphenyl,
NaOtBu in toluene might be applied (John P. Wolfe, Hiroshi Tomori,
Joseph P. Sadighi, Jingjun Yin, and Stephen L. Buchwald, J. Org.
Chem., 65 (4), 1158-1174, 2000). 101112
[0120] Primary alcohols 1 are treated with hydrogen chloride in
dioxane at room temperature to remove the tert-butoxycarbonyl
protective function; the primary or secondary amine thus formed
then converted into groups NA.sup.9WA.sup.10 as described in Scheme
3 (step a). Conversion of the primary alcohols 2 into the
corresponding methanesulfonate esters 3 is then performed as
described above (step b). Transformation of methanesulfonates 3
into final compounds 4 is then performed as described in Scheme 3
(step c).
[0121] Aldehydes 5 react with (triphenyl-phosphoranylidene)-acetic
acid esters in dichloromethane or toluene between room temperature
and 110.degree. C. to the corresponding unsaturated ester compounds
6 (step d). Optionally, the double bond in the unsaturated ester
compounds 6 can be hydrogenated using a palladium catalyst in a
solvent like methanol or ethanol preferentially at room temperature
(step e). Subsequently, the ester function can be reduced using
lithium aluminium hydride or diisobutyl aluminium hydride in
tetrahydrofuran or 1,2-dimethoxyethane at temperatures between
-78.degree. C. and the reflux temperature of the solvents giving
the primary alcohol compounds 8 (step f). Removal of the
tert-butoxycarbonyl protective function with acid and treatment of
the corresponding amine compounds as described in Scheme 3 gives
the corresponding compounds 9 carrying groups NA.sup.9WA.sup.10
(step g). The primary alcohol compounds 9 are then transformed into
the corresponding methanesulfonate esters 10 as described above
(step h), a process which leads to mixtures of methanesulfonate
esters and chlorides or pure chlorides, if the double bond is still
present. Transformation of methanesulfonate esters, mixtures of
methanesulfonate esters and chlorides or pure chlorides 10 into
final compounds 11 is then performed as described in Scheme 3.
131415
[0122] Aminoalkohols 1 can be protected a the amino-function e.g.
by treatment with N-(benzyloxycarbonyloxy)-succinimide in methanol
to give the Z-protected analogues 2 (step a). The Z-protected
analogues 2 are subsequently oxidized to the corresponding
aldehydes 3 by using e.g. Swern conditions: oxalyl
chloride/dimethylsulfoxide/triethylamine in dichloromethane,
-78.degree. C. to room temperature (step b). Wittig reaction with
(methoxymethyl)triphenylphosphonium chloride and potassium
tert-butylate in tetrahydrofuran, preferentially between
-10.degree. C. and room temperature, gives enol ethers 4 (step c)
and after hydrolysis with 2N aqueous hydrochloric acid in
tetrahydrofuran aldehydes 5 (step d). Reduction to the primary
alcohols 6 with sodium borohydride in methanol followed by
hydrolytic removal of the Z-protective function then leads to
primary alcohols 7 (step e and f), which are converted into amino
compounds 10 as described for aminoalkhols 7 in Scheme 3 (steps g,
h, i). 16
[0123] 4-(Hydroxy-alkoxy)-benzoic acid esters 3 can be prepared
from 4-hydroxy-benzoic acid esters 1 by various well known methods,
e.g. Mitsunobu ether formation (diethyl-azo-dicarboxylate,
triphenylphosphine in tetrahydrofuran between -10.degree. C. and
the reflux temperature of the tetrahydrofuran) with a mono-benzyl
protected dihydroxy-alkane (r=2-8) and subsequent deprotection
(hydrogenolysis with hydrogen gas and a palladium catalyst in
methanol at room temperature) or by direct alkylation with a
suitable bromo- or chloro-hydroxy alkane in the presence of a base
like potassium carbonate in solvents like acetone, acetonitrile or
N,N-dimethylformamide between room temperature and 100.degree. C.
(steps a and b). Catalytic hydrogenation of
4-(hydroxy-alkoxy)-benzoic acid esters 3 using a rhodium catalyst
and hydrogen gas at temperatures between room temperature and
80.degree. C. and pressures of hydrogen between normal pressure and
20 bar in solvents like ethanol or methanol and optionally a
tertiary base like triethylamine gives mixtures of cis and trans
4-(hydroxy-alkoxy)-cyclohex- ane carboxylic acid esters 4 with a
strong preference for the cis isomers (step c). Isomerization to a
cis/trans mixture close to 1:1 can be achieved after reintroduction
of the benzyl group (e.g. with benzyl 2,2,2-trichloro-acetimidate,
trifluoroacetic acid in dichloromethane/cyclohexane at room
temperature, step d) by quenching the enolate formed with lithium
diisopropylamide at -78.degree. C. in tetrahydrofuran by treatment
with methanol at the same temperature (step e). This mixture of cis
and trans 4-(benzyloxy-alkoxy)-cyclohexane carboxylic acid esters 6
can be separated by chromatography into the pure cis and trans
isomers 8 and 7 (step f). 17
[0124] Pure cis or trans 4-(benzyloxy-alkoxy)-cyclohexane
carboxylic acid esters 1 can be converted into the corresponding
N-alkyl amides 3 by well known procedures of saponification and
amide formation via the corresponding acid chloride as intermediate
(steps a and b). N-Alkyl amides 3 can then be reduced to the
corresponding N-alkyl amines 4 with lithium aluminium hydride in
tetrahydrofuran between room temperature and the reflux temperature
of tetrahydrofuran (step c). Optionally, a tert-butoxycarbonyl
protective function can be introduced with
di-tert-butyl-dicarbonate as reagent before removal of the
benzyloxy function (steps e and f). Compounds 5 with either a two
carbon chain between cyclohexane ring and the amino function and/or
substituents A.sup.5, A.sup.6, A.sup.7, A.sup.8 different from
hydrogen are prepared from the carboxylic acid 2 as described in
Schemes 1 and 2: i) the carboxylic acids 2 are modified in analogy
to the procedures described for the carboxylic acids 1 in Scheme 1;
or ii) the carboxylic acids 2 are reduced to the corresponding
primary alcohol with borane-tetrahydrofuran complex in
tetrahydrofuran between -10.degree. C. and the reflux temperature
of tetrahydrofuran and then transformed in analogy to the
procedures described for the hydroxy methyl compounds 1 in Scheme
2, leading to the primary amines 5 (step d). After introduction of
a tert-butoxycarbonyl protective function into primary amines 4 and
5, the tert-butoxycarbonyl protected nitrogen function can be
alkylated as described above leading to compounds 6 (step e).
Hydrogenolytic removal of the benzyl function and removal of the
tert-butoxycarbonyl protective function under acidic conditions
leads to cis or trans amino alcohol compounds 8 (steps f and g).
Cis or trans amino alcohol compounds 8 are subsequently converted
into analogues 9 carrying a group NA.sup.9WA.sup.10 as described in
Scheme 3 (step h). Conversion of the primary alcohols 9 into the
corresponding methanesulfonate esters 10 is then performed as
described above (step i). Transformation of methanesulfonate esters
10 into final compounds 11 is then performed as described in Scheme
3 (step k). 18
[0125] Primary alcoholes 1 are reacted with 1,4-dibromo-2-butene in
a vigorously stirred mixture of dichloromethane and 50% w/w sodium
hydroxide in the presence of tetrabutylammonium hydrogensulfate
preferentially at room temperature to yield bromides 2 (step a).
Transformation of bromides 2 into final compounds 3 is then
performed as described in Scheme 3 (step b).
[0126] Primary alcohols 1 are converted to amines 4 by attaching
the pre-assembled fragment
A.sup.1A.sup.2NC(A.sup.3A.sup.4)(CH.sub.2).sub.m--- OH, which can
be synthesized by known methods (step c): Primary alcohols 1 are
first converted into the corresponding methanesulfonates; fragments
A.sup.1A.sup.2NC(A.sup.3A.sup.4)(CH.sub.2).sub.m--OH are treated
with sodium hydride in N,N-dimethylformamide at 0.degree. C. to
room temperature, then, the methanesulfonates are added and the
condensation performed between 0.degree. C. and 80.degree. C. to
give amines 4. Alternatively, primary alcohols 1 are converted to
the corresponding triflates (with trifluoromethansulfonic
anhydride/2,6-di-tert-butylpyridi- ne in dichloromethane at
0.degree. C.). These triflates are then reacted in situ with
alcohols A.sup.1A.sup.2NC(A.sup.3A.sup.4)(CH.sub.2).sub.m--O- H in
the presence of 2,6-di-tert-butylpyridine as base in nitromethane
at room temperature to 60.degree. C. to yield amines 4 [following a
procedure of Belostotskii, Anatoly M.; Hassner, Alfred. Synthetic
methods. 41. Etherification of hydroxysteroids via triflates.
Tetrahedron Lett. (1994), 35(28), 5075-6]. 19
[0127] Aldehydes 1 can be treated with triphenylphosphine,
tetrabromomethane and triethylamine in dichloromethane at 0.degree.
C. to room temperature to yield 2,2-dibromo-vinyl derivatives 2
(step a). Rearrangement with n-buyl-lithium (ca 1.6 M in hexane) in
tetrahydrofuran at -78.degree. C., followed by reaction with
formaldehyde (-78.degree. C. to room temperature) gives the
propargyl alcohols 5 [step b and c; following conditions described
in: Marshall, James A.; Bartley, Gary S.; Wallace, Eli M. Total
Synthesis of the Pseudopterane (-)-Kallolide B, the Enantiomer of
Natural (+)-Kallolide B. J. Org. Chem. (1996), 61(17), 5729-5735;
and Baker, Raymond; Boyes, Alastair L.; Swain, Christopher J.
Synthesis of talaromycins A, B, C, and E. J. Chem. Soc., Perkin
Trans. 1 (1990), (5), 1415-21]. For longer side chains, the
rearrangement is performed with n-butyl lithium (ca 1.6 M in
hexane) in tetrahydrofuran at -78.degree. C. as above, followed by
addition of a co-solvent such as
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinon and reaction with
O-protected .omega.-bromo-alcohols 4 (s=2-7) (step b and d; e.g.
1-bromo-.omega.-tetrahydropyranyloxyalkane) to give after removal
of the O-protective function (e.g. with pyridinium
p-toluenesulfonate in methanol at room temperature to 50.degree.
C.) compounds 6. Conversion of compounds 5 and 6 into final
compounds 8 can be performed as described in Scheme 3 (steps e and
f).
[0128] The following tests were carried out in order to determine
the activity of the compounds of formula I and their salts.
[0129] Inhibition of Human Liver Microsomal
2,3-oxidosqualene-lanosterol Cyclase (OSC)
[0130] Liver microsomes from a healthy volunteer were prepared in
sodium phosphate buffer (pH 7.4). The OSC activity was measured in
the same buffer, which also contained lmM EDTA and 1 mM
dithiothreitol. The microsomes were diluted to 0.8 mg/ml protein in
cold phosphate buffer. Dry [.sup.14C]R,S-monooxidosqualene (MOS,
12.8 mCi/mmol) was diluted to 20 nCi/.mu.l with ethanol and mixed
with phosphate buffer-1% BSA (bovine serum albumin). A stock
solution of 1 mM test substance in DMSO was diluted to the desired
concentration with phosphate buffer-1% BSA. 40 .mu.l of microsomes
were mixed with 20 .mu.l of the solution of the test substance and
the reaction was subsequently started with 20 .mu.l of the
[.sup.14C]R,S-MOS solution. The final conditions were: 0.4 mg/ml of
microsomal proteins and 30 .mu.l of [.sup.14C]R,S-MOS in phosphate
buffer, pH 7.4, containing 0.5% albumin, DMSO<0.1% and
ethanol<2%, in a total volume of 80 .mu.l.
[0131] After 1 hour at 37.degree. C. the reaction was stopped by
the addition of 0.6 ml of 10% KOH-methanol, 0.7 ml of water and 0.1
ml of hexane:ether (1:1, v/v) which contained 25 .mu.g of
non-radioactive MOS and 25 .mu.g of lanosterol as carriers. After
shaking, 1 ml of hexane:ether (1:1, v/v) was added to each test
tube, these were again shaken and then centrifuged. The upper phase
was transferred into a glass test tube, the lower phase was again
extracted with hexane:ether and combined with the first extract.
The entire extract was evaporated to dryness with nitrogen, the
residue was suspended in 50 .mu.l of hexane:ether and applied to a
silica gel plate. Chromatographic separation was effected in
hexane:ether (1:1, v/v) as the eluent. The Rf values for the MOS
substrate and the lanosterol product were 0.91 and, respectively,
0.54. After drying, radioactive MOS and lanosterol were observed on
the silica gel plate. The ratio of MOS to lanosterol was determined
from the radioactive bands in order to determine the yield of the
reaction and OSC inhibition.
[0132] The test was carried out on the one hand with a constant
test substance concentration of 100 nM and the percentage OSC
inhibition against controls was calculated. The more preferred
compounds of the present invention exhibit inhibitions larger than
50%. In addition, the test was carried out with different test
substance concentrations and subsequently the IC.sub.50 value was
calculated, i.e. the concentration required to reduce the
conversion of MOS into lanosterol to 50% of the control value. The
preferred compounds of the present invention exhibit IC.sub.50
values of 1 nM to 10 .mu.M, preferrably of 1-100 nM.
[0133] The compounds of formula I and/or their pharmaceutically
acceptable salts can be used as medicaments, e.g. in the form of
pharmaceutical preparations for enteral, parenteral or topical
administration. They can be administered, for example, perorally,
e.g. in the form of tablets, coated tablets, drages, hard and soft
gelatine capsules, solutions, emulsions or suspensions, rectally,
e.g. in the form of suppositories, parenterally, e.g. in the form
of injection solutions or infusion solutions, or topically, e.g. in
the form of ointments, creams or oils. Oral administration is
preferred.
[0134] The production of the pharmaceutical preparations can be
effected in a manner which will be familiar to any person skilled
in the art by bringing the described compounds of formula I and/or
their pharmaceutically acceptable salts, optionally in combination
with other therapeutically valuable substances, into a galenical
administration form together with suitable, non-toxic, inert,
therapeutically compatible solid or liquid carrier materials and,
if desired, usual pharmaceutical adjuvants.
[0135] Suitable carrier materials are not only inorganic carrier
materials, but also organic carrier materials. Thus, for example,
lactose, corn starch or derivatives thereof, talc, stearic acid or
its salts can be used as carrier materials for tablets, coated
tablets, drages and hard gelatine capsules. Suitable carrier
materials for soft gelatine capsules are, for example, vegetable
oils, waxes, fats and semi-solid and liquid polyols (depending on
the nature of the active ingredient no carriers might, however, be
required in the case of soft gelatine capsules). Suitable carrier
materials for the production of solutions and syrups are, for
example, water, polyols, sucrose, invert sugar and the like.
Suitable carrier materials for injection solutions are, for
example, water, alcohols, polyols, glycerol and vegetable oils.
Suitable carrier materials for suppositories are, for example,
natural or hardened oils, waxes, fats and semi-liquid or liquid
polyols. Suitable carrier materials for topical preparations are
glycerides, semi-synthetic and synthetic glycerides, hydrogenated
oils, liquid waxes, liquid paraffins, liquid fatty alcohols,
sterols, polyethylene glycols and cellulose derivatives.
[0136] Usual stabilizers, preservatives, wetting and emulsifying
agents, consistency-improving agents, flavor-improving agents,
salts for varying the osmotic pressure, buffer substances,
solubilizers, colorants and masking agents and antioxidants come
into consideration as pharmaceutical adjuvants.
[0137] The dosage of the compounds of formula I can vary within
wide limits depending on the disease to be controlled, the age and
the individual condition of the patient and the mode of
administration, and will, of course, be fitted to the individual
requirements in each particular case. For adult patients a daily
dosage of about 1 to 1000 mg, especially about 1 to 100 mg, comes
into consideration. Depending on severity of the disease and the
precise pharmacokinetic profile the compound could be administered
with one or several daily dosage units, e.g. in 1 to 3 dosage
units.
[0138] The pharmaceutical preparations conveniently contain about
1-500 mg, preferably 1-100 mg, of a compound of formula I.
[0139] The following Examples serve to illustrate the present
invention in more detail. They are, however, not intended to limit
its scope in any manner.
EXAMPLES
General Remarks
[0140] All reactions were performed under argon.
Example 1
[0141] 1.1
[0142] 2.90 g (11.0 mmol)
trans-(4-hydroxymethyl-cyclohexylmethyl)-carbami- c acid tert-butyl
ester [U.S. (2000) U.S. Pat. No. 6,022,969 A] dissolved in 15 ml of
tetrahydrofuran were added slowly to a suspension of 0.92 g of
lithium aluminium hydride in 10 ml of tetrahydrofuran. The reaction
mixture was then stirred at 50.degree. C. for 4 hours, cooled to
0.degree. C., treated with 2 g of ice, stirred at room temperature
for 30 min., diluted with ethyl acetate, dried over sodium sulfate,
filtered and evaporated. Thus, crude
trans-(4-methylaminomethyl-cyclohexyl)-methanol was obtained [MS:
158 (MH.sup.+)], which was dissolved in 20 ml of methanol, cooled
to -10.degree. C. and treated at once with 2.77 g
di-tert-butyl-dicarbonate. Then, the reaction mixture was stirred
at -10.degree. C. for 30 min. and at room temperature for 1 hour.
Subsequently, 5 ml of water and 5 ml of triethylamine were added
and the reaction mixture evaporated under reduced pressure. It was
then poured into 100 ml of an ice/water mixture and extracted 3
times with 100 ml of dichloromethane. The combined dichloromethane
phases were dried over magnesium sulfate and evaporated under
reduced pressure. The residue formed was chromatographed on silica
gel with a 1:1 v/v mixture of dichloromethane and ethylacetate as
the eluent giving 2.5 g (82%)
trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid
tert-butyl ester as colorless viscous oil, MS: 257 (M.sup.+).
[0143] 1.2
[0144] 0.45 ml of oxalyl chloride in 5.0 ml of dichloromethane were
cooled to -78.degree. C.; then, 0.41 g of dimethylsulfoxide in 2.0
ml of dichloromethane were slowly added and the reaction mixture
stirred at -78.degree. C. for 10 minutes. Then, 0.680 g (2.64 mmol)
trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid
tert-butyl ester dissolved in 5.0 ml of dichloromethane were added
and the reaction mixture stirred at -78.degree. C. for 10 minutes.
Subsequently, 1.84 ml of triethylamine were added at the same
temperature, the reaction mixture stirred 30 minutes at -78.degree.
C., warmed to room temperature and stirred for 1 hour. It was then
poured into 50 ml of an ice/water mixture and extracted 3 times
with 50 ml of dichloromethane. The combined dichloromethane phases
were washed with dilute hydrochloric acid, sodium hydrogen
carbonate solution and with water, dried over magnesium sulfate and
evaporated under reduced pressure. The residue formed was
chromatographed on silica gel with a 4:1 v/v mixture of
dichloromethane and ether as the eluent giving 0.615 g (91.1%)
trans-(4-formyl-cyclohexyl- methyl)-methyl-carbamic acid tert-butyl
ester as colorless amorphous solid, MS: 273 (MNH.sub.4.sup.+).
[0145] 1.3
[0146] 0.590 g (2.31 mmol)
trans-(4-formyl-cyclohexylmethyl)-methyl-carbam- ic acid tert-butyl
ester, 1.325 g (2.77 mmol) 4-(bromobutyl)triphenylphosp- honium
bromide and 1.28 g (9.24 mmol) potassium carbonate were suspended
in 10 ml of tert-amyl alcohol and the reaction mixture heated at
reflux for 2 hours. It was then cooled to room temperature, diluted
with ethyl acetate, filtered and evaporated under reduced pressure.
The residue formed was chromatographed on silica gel with a 95:5
v/v mixture of dichloromethane and ether as the eluent giving 0.635
g (73.4%)
trans-E/Z-[4-(5-bromo-pent-1-enyl)-cyclohexylmethyl]-methyl-carbamic
acid tert-butyl ester as colorless viscous oil, MS: 373 (M.sup.+,
1Br).
[0147] 1.4
[0148] 1.15 g (3.07 mmol)
trans-E/Z-[4-(5-bromo-pent-1-enyl)-cyclohexylmet-
hyl]-methyl-carbamic acid tert-butyl ester dissolved in 15 ml of
ethanol were added to a suspension of 300 mg platinum dioxide
freshly reduced to platinum by hydrogenation immediately prior to
use. Hydrogenation was then continued at ambient pressure until 95%
of the calculated amount of hydrogen had been consumed. Then, the
reaction mixture was filtered over celite and evaporated giving
0.950 g (82%) trans-[4-(5-bromo-pentyl)-cycl-
ohexylmethyl]-methyl-carbamic acid tert-butyl ester as colorless
viscous oil, MS: 375 (M.sup.+, 1Br).
[0149] 1.5
[0150] 0.950 g (2.52 mmol)
trans-[4-(5-bromo-pentyl)-cydohexylmethyl]-meth- yl-carbamic acid
tert-butyl ester were dissolved in 6 ml of 4 N hydrogen chloride
solution in dioxane and the reaction mixture stirred at room
temperature for 4 hours. It was then evaporated under reduced
pressure, re-suspended in tert-butyl methyl ether and filtered.
There were thus obtained 0.724 g (91.7%)
trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-meth- yl-amine
hydrochloride as colorless amorphous solid, MS: 276 (MH.sup.+,
1Br).
[0151] 1.6
[0152] 0.786 ml Diisopropyl-aethylamine, 0.619 g (2.53 mmol)
4-trifluoromethyl-benzene sulfochloride and 0.952 mg potassium
carbonate (dissolved in the minimal amount of water) were added to
a solution of 0.718 g (2.30 mmol)
trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-methyl-am- ine
hydrochloride in 15.0 ml of tetrahydrofuran kept at -10.degree. C.
The reaction mixture was then intensively stirred for 1 hour at
-10.degree. C. and for 1 hour at room temperature. It was
subsequently evaporated, poured into 50 ml of an ice/water mixture
and extracted 3 times with 50 ml of dichloromethane. The combined
dichloromethane phases were dried over magnesium sulfate and
evaporated under reduced pressure. The residue formed was
chromatographed on silica gel with dichloromethane as the eluent
giving 1.03 g (92.6%) trans-N-[4-(5-bromo-pentyl)-cyclohexylmethyl-
]-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless
amorphous solid, MS: 404 [(M-Br).sup.+].
[0153] 1.7
[0154] 0.515 ml Diisopropyl-aethylamine, 0.674 g (3.00 mmol)
4-trifluoromethylphenyl chloroformate [Org. Lett. (2000), 2(8),
1049-1051] and 0.828 mg potassium carbonate (dissolved in the
minimal amount of water) were added to a suspension of 0.625 g
(2.00 mmol)
trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-methyl-amine
hydrochloride in 20.0 ml of tetrahydrofuran kept at -10.degree. C.
The reaction mixture was then intensively stirred for 1 hour at
-10.degree. C. and for 3 hour at room temperature. 0.200 g
4-trifluoromethylphenyl chloroformate were added and stirring at
room temperature continued for additional 2 hours. The reaction
mixture was subsequently acidified with dilute hydrogen chloride
solution. It was then evaporated, poured into 50 ml of an ice/water
mixture and extracted 3 times with 50 ml of dichloromethane. The
combined dichloromethane phases were dried over magnesium sulfate
and evaporated under reduced pressure. The residue formed was
chromatographed on silica gel with a 1:1 v/v mixture of hexane and
dichloromethane as the eluent giving 0.90 g (96.9%)
trans-[4-(5-bromo-pentyl)-cyclohexylmethyl]-- methyl-carbamic acid
4-trifluoromethyl-phenyl ester as colorless viscous oil, MS: 464
(MH.sup.+, 1Br).
Example 2
[0155] 2.1
[0156] 153 mg (0.315 mmol)
trans-N-[4-(5-bromo-pentyl)-cyclohexylmethyl]-N-
-methyl-4-trifluoromethyl-benzenesulfonamide (example 1.6)
dissolved in 2.0 ml of methanol were treated with 0.5 ml of
N-allyl-methyl-amine and the reaction mixture stirred for 6 h at
50.degree. C. It was then evaporated, poured into 50 ml of an
ice/water mixture and extracted 3 times with 50 ml of
dichloromethane. The combined dichloromethane phases were washed
with sodium carbonate solution, dried over magnesium sulfate and
evaporated under reduced pressure. The residue formed was
chromatographed on silica gel with a 9:1:0.1 v/v/v mixture of
dichloromethane, methanol and saturated ammonia solution as the
eluent giving 0.110 g (73.3%)
trans-N-{4-[5-(allyl-methyl-amino)-pentyl]-cyclohe-
xylmethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as
colorless solid, MS: 475 (MH.sup.+).
[0157] In analogy to the method described in example 2.1, alkyl
bromides were treated with secondary or primary amines in methanol
or N,N-dimethylacetamide to yield tertiary or secondary amine
products as listed in the following table.
1 Example Product MS MH.sup.+ Bromide Amine 2.2
trans-N-{4-[5-(4-Hydroxy- 505 trans-N-[4-(5-Bromo- 4-Hydroxy-
piperidin-1-yl)-pentyl]- pentyl)- piperidine
cyclohexylmethyl}-N-methyl- cyclohexylmethyl]-N- 4-trifluoromethyl-
methyl-4- benzenesulfonamide trifluoromethyl- benzenesulfonamide
2.3 trans-N-[4-(5- 449 trans-N-[4-(5-Bromo- Dimethyl-amine
Dimethylamino-pentyl)- pentyl)- cyclohexylmethyl]-N-methyl-
cyclohexylmethyl]-N- 4-trifluoromethyl- methyl-4-
benzenesulfonamide trifluoromethyl- benzenesulfonamide 2.4
trans-N-(4-{5-[Ethyl-(2- 493 trans-N-[4-(5-Bromo- Ethyl-(2-hydroxy-
hydroxy-ethyl)-amino]- pentyl)- ethyl)-amine
pentyl}-cyclohexylmethyl)-N- cyclohexylmethyl]-N-
methyl-4-trifluoromethyl- methyl-4- benzenesulfonamide
trifluoromethyl- benzenesulfonamide 2.5 trans-N-(4-{5-[Bis-(2- 509
trans-N-[4-(5-Bromo- Bis-(2-hydroxy- hydroxy-ethyl)-amino]-
pentyl)- ethyl)-amine pentyl}-cyclohexylmethyl)-N-
cyclohexylmethyl]-N- methyl-4-trifluoromethyl- methyl-4-
benzenesulfonamide trifluoromethyl- benzenesulfonamide 2.6
trans-{4-[5-(Allyl-methyl- 455 trans-[4-(5-Bromo- N-Allyl-methyl-
amino)-pentyl]- pentyl)- amine cyclohexylmethyl}-methyl-
cyclohexylmethyl]- carbamic acid 4- methyl-carbamic acid
trifluoromethyl-phenyl ester 4-trifluoromethyl- phenyl ester 2.7
trans-[4-(5-Dimethylamino- 429 trans-[4-(5-Bromo- Dimethyl-amine
pentyl)-cyclohexylmethyl]- pentyl)- methyl-carbamic acid 4-
cyclohexylmethyl]- trifluoromethyl-phenyl ester methyl-carbamic
acid 4-trifluoromethyl- phenyl ester 2.8 trans-(4-{5-[Ethyl-(2- 473
trans-[4-(5-Bromo- Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]-
pentyl)- ethyl)-amine pentyl}-cyclohexylmethyl)- cyclohexylmethyl]-
methyl-carbamic acid 4- methyl-carbamic acid trifluoromethyl-phenyl
ester 4-trifluoromethyl- phenyl ester 2.9 trans-{4-[5-(4-Hydroxy-
485 trans-[4-(5-Bromo- 4-Hydroxy- piperidin-1-yl)-pentyl]- pentyl)-
piperidine cyclohexylmethyl}-methyl- cyclohexylmethyl]- carbamic
acid 4- methyl-carbamic acid trifluoromethyl-phenyl ester
4-trifluoromethyl- phenyl ester 2.10 trans-(4-{5-[Bis-(2-hydroxy-
489 trans-[4-(5-Bromo- Bis-(2-hydroxy- ethyl)-amino]-pentyl}-
pentyl)- ethyl)-amine cyclohexylmethyl)-methyl- cyclohexylmethyl]-
carbamic acid 4- methyl-carbamic acid trifluoromethyl-phenyl ester
4-trifluoromethyl- phenyl ester 2.11 trans-N-Methyl-N-[4-(5- 489
trans-N-[4-(5-Bromo- Piperidine piperidin-1-yl-pentyl)- pentyl)-
cyclohexylmethyl]-4- cyclohexylmethyl]-N- trifluoromethyl-
methyl-4- benzenesulfonamide trifluoromethyl- benzenesulfonamide
2.12 trans-N-Methyl-N-[4-(5- 475 trans-N-[4-(5-Bromo- Pyrrolidine
pyrrolidin-1-yl-pentyl)- pentyl)- cyclohexylmethyl]-4-
cyclohexylmethyl]-N- trifluoromethyl- methyl-4- benzenesulfonamide
trifluoromethyl- benzenesulfonamide
Example 3
[0158] 3.1
[0159] 0.700 g (1.42 mmol) of
3-benzyloxypropyl)triphenylphosphonium bromide, 0.305 g (1.18 mmol)
of trans-(4-formyl-cyclohexylmethyl)-methyl-- carbamic acid
tert-butyl ester (example 1.2) and 0.662 g of finely milled
potassium carbonate were suspended in 10.0 ml of 2-methyl-2-butanol
and the reaction mixture intensively stirred at 100.degree. C. for
2 hours. It was then evaporated, poured into 50 ml of an ice/water
mixture and extracted 3 times with 50 ml of ethylacetate. The
combined ethylacetate phases were dried over magnesium sulfate and
evaporated under reduced pressure. The residue formed was
chromatographed on silica gel with a 95:5 v/v mixture of
dichloromethane and ether as the eluent giving 0.364 g (78.6%)
trans-[4-(4-benzyloxy-[E/Z 1:9]but-1-enyl)-cyclohexylmethyl]-me-
thyl-carbamic acid tert-butyl ester as colorless viscous oil, MS:
331 [M-C.sub.4H.sub.8).sup.+].
[0160] 3.2
[0161] 0.350 g (0.903 mmol) of trans-[4-(4-benzyloxy-[E/Z
1:9]but-1-enyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl
ester were dissolved in 10.0 ml of ethylacetate. 0.3 g palladium on
charcoal (5%) were added and the reaction mixture hydrogenated at
normal pressure for 24 hours. Then, it was filtered over celite,
evaporated and the residue formed was chromatographed on silica gel
with a 4:1 v/v mixture of dichloromethane and ether as the eluent
giving 0.23 g (85%) of
trans-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-methyl-carbamic acid
tert-butyl ester as colorless viscous oil, MS: 300 (MH.sup.+).
[0162] 3.3
[0163] In analogy to the sequence described in examples 1.5 and 1.6
trans-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-methyl-carbamic acid
tert-butyl ester was treated with hydrogen chloride solution in
methanol/water followed by acylation with
4-trifluoromethyl-benzenesulfoc- hloride giving
trans-N-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-N-methyl-4-t-
rifluoromethyl-benzenesulfonamide as colorless amorphous solid, MS:
no MH.sup.+ or M.sup.+ signal; 145, 198, 209, 252 (fragments).
[0164] 3.4
[0165] 1.22 g (3.0 mmol)
trans-N-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-N--
methyl-4-trifluoromethyl-benzenesulfonamide were dissolved in 4.0
ml of pyridine, cooled to -10.degree. C. and treated with 0.687 g
methanesulfochloride. The reaction mixture was then stirred at room
temperature for 2 hours. It was subsequently poured into 50 ml of
an ice/water/diluted hydrogen chloride mixture and extracted 3
times with 50 ml of dichloromethane. The combined dichloromethane
phases were dried over magnesium sulfate and evaporated under
reduced pressure giving 1.35 g (92.8%) trans-methanesulfonic acid
4-(4-{[methyl-(4-trifluoromethyl-ben-
zenesulfonyl)-amino]-methyl}-cyclohexyl)-butyl ester as colorless
solid, MS: 486 (MH.sup.+).
[0166] 3.5
[0167] In analogy to the reactions described in examples 1.5 and
1.7 trans-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-methyl-carbamic
acid tert-butyl ester (example 3.2) was treated with hydrogen
chloride solution in methanol/water followed by acylation with
4-chlorophenyl chloroformate giving
trans-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-methyl-- carbamic acid
4-chloro-phenyl ester as colorless viscous oil, MS: 354 (MH.sup.+,
1Cl).
[0168] 3.6
[0169] In analogy to the reaction described in example 3.4,
trans-[4-(4-hydroxy-butyl)-cyclohexylmethyl]-methyl-carbamic acid
4-chloro-phenyl ester was treated with methanesulfochloride in
pyridine to yield trans-methanesulfonic acid
4-(4-{[(4-chloro-phenoxycarbonyl)-met-
hyl-amino]-methyl}-cyclohexyl)-butyl ester as colorless viscous
oil, MS: 432 (MH.sup.+, 1Cl).
Example 4
[0170] In analogy to the method described in example 2.1,
methanesulfonic acid esters were treated with secondary or primary
amines in methanol or N,N-dimethylacetamide to yield tertiary or
secondary amine products as listed in the following table.
2 MS Methanesulfonic acid Example Product MH.sup.+ esters Amine 4.1
trans-N-(4-{4-[Ethyl-(2- 479 trans-Methanesulfonic
Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]- acid 4-(4-{[methyl-(4-
ethyl)-amine butyl]}-cyclohexylmethyl)-N- trifluoromethyl-
methyl-4-trifluoromethyl- benzenesulfonyl)- benzenesulfonamide
amino]-methyl}- cyclohexyl)-butyl ester 4.2 trans-N-[4-(4- 435
trans-Methanesulfonic Dimethyl-amine Dimethylamino-butyl)- acid
4-(4-{[methyl-(4- cyclohexylmethyl]-N-methyl- trifluoromethyl-
4-trifluoromethyl- benzenesulfonyl)- benzenesulfonamide
amino]-methyl}- cyclohexyl)-butyl ester 4.3
trans-N-[4-(4-Diethylamino- 463 trans-Methanesulfonic Diethyl-amine
butyl)-cyclohexylmethyl]-N- acid 4-(4-{[methyl-(4-
methyl-4-trifluoromethyl- trifluoromethyl- benzenesulfonamide
benzenesulfonyl)- amino]-methyl}- cyclohexyl)-butyl ester 4.4
trans-N-{4-[4-(Allyl-methyl- 461 trans-Methanesulfonic
N-Allyl-methyl- amino)-butyl]- acid 4-(4-{[methyl-(4- amine
cyclohexylmethyl}-N-methyl- trifluoromethyl- 4-trifluoromethyl-
benzenesulfonyl)- benzenesulfonamide amino]-methyl}-
cyclohexyl)-butyl ester 4.5 trans-N-(4-{4-[Bis-(2- 495
trans-Methanesulfonic Bis-(2-hydroxy- hydroxy-ethyl)-amino]- acid
4-(4-{[methyl-(4- ethyl)-amine butyl}-cyclohexylmethyl)-N-
trifluoromethyl- methyl-4-trifluoromethyl- benzenesulfonyl)-
benzenesulfonamide amino]-methyl}- cyclohexyl)-butyl ester 4.6
trans-{4-[4-(Allyl-methyl- 407 trans-Methanesulfonic
N-Allyl-methyl- amino)-butyl]- (1 Cl) acid 4-(4-{[(4-chloro- amine
cyclohexylmethyl}-methyl- phenoxycarbonyl)- carbamic acid 4-chloro-
methyl-amino]- phenyl ester methyl}-cyclohexyl)- butyl ester 4.7
trans-Methyl-[4-(4- 421 trans-Methanesulfonic Piperidine
piperidin-1-yl-butyl)- (1 Cl) acid 4-(4-{[(4-chloro-
cyclohexylmethyl]-carbamic phenoxycarbonyl)- acid 4-chloro-phenyl
ester methyl-amino]- methyl}-cyclohexyl)- butyl ester 4.8
trans-(4-{4-[Ethyl-(2- 425 trans-Methanesulfonic Ethyl-(2-hydroxy-
hydroxy-ethyl)-amino]- (1 Cl) acid 4-(4-{[(4-chloro- ethyl)-amine
butyl}-cyclohexylmethyl)- phenoxycarbonyl)- methyl-carbamic acid 4-
methyl-amino]- chloro-phenyl ester methyl}-cyclohexyl)- butyl
ester
Example 5
[0171] 5.1
[0172] In analogy to the procedure described in examples 1.6,
trans-(4-methylaminomethyl-cyclohexyl)-methanol (example 1.1) was
acylated with 4-trifluoromethyl-benzene sulfochloride giving
trans-N-(4-hydroxymethyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-ben-
zenesulfonamide as colorless solid, MS: 366 (MH.sup.+).
[0173] 5.2
[0174] In analogy to the procedure described in example 3.4,
trans-N-(4-hydroxymethyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-ben-
zenesulfonamide is treated with methanesulfonyl chloride to yield
trans-methanesulfonic acid
4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-
-amino]-methyl}-cyclohexylmethyl ester as colorless solid, MS: 443
(M.sup.+).
[0175] 5.3
[0176] In analogy to the procedure described in examples 1.7,
trans-(4-methylaminomethyl-cyclohexyl)-methanol (example 1.1) was
acylated with 4-chlorophenyl chloroformate [Org. Lett. (2000),
2(8), 1049-1051] giving
trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbami- c acid
4-chloro-phenyl ester as colorless viscous oil, MS: 311
(M.sup.+).
[0177] 5.4
[0178] In analogy to the procedure described in example 3.4, the
trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid
4-chloro-phenyl ester was treated with methanesulfonyl chloride to
yield trans-methanesulfonic acid
4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-m-
ethyl}-cyclohexylmethyl ester as colorless viscous oil, MS: 390
(MH.sup.+).
Example 6
[0179] In analogy to the method described in example 2.1,
methanesulfonic acid esters were treated with secondary or primary
amines in methanol or N,N-dimethylacetamide to yield tertiary or
secondary amine products as listed in the following table.
3 MS Methanesulfonic acid Example Product MH.sup.+ esters Amine 6.1
trans-N-(4- 393 trans-Methanesulfonic Dimethyl-amine
Dimethylaminomethyl- acid 4-{[methyl-(4-
cyclohexylmethyl)-N-methyl- trifluoromethyl- 4-trifluoromethyl-
benzenesulfonyl)- benzenesulfonamide amino]-methyl}-
cyclohexylmethyl ester 6.2 trans-N-{4-[(Allyl-methyl- 419
trans-Methanesulfonic N-Allyl-methyl- amino)-methyl]- acid
4-{[methyl-(4- amine cyclohexylmethyl}-N-methyl- trifluoromethyl-
4-trifluoromethyl- benzenesulfonyl)- benzenesulfonamide
amino]-methyl}- cyclohexylmethyl ester 6.3 trans-N-(4-{[Ethyl-(2-
437 trans-Methanesulfonic Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]-
acid 4-{[methyl-(4- ethyl)-amine methyl}-cyclohexylmethyl)-
trifluoromethyl- N-methyl-4-trifluoromethyl- benzenesulfonyl)-
benzenesulfonamide amino]-methyl}- cyclohexylmethyl ester 6.4
trans-N-(4- 421 trans-Methanesulfonic Dimethyl-amine
Diethylaminomethyl- acid 4-{[methyl-(4- cyclohexylmethyl)-N-methyl-
trifluoromethyl- 4-trifluoromethyl- benzenesulfonyl)-
benzenesulfonamide amino]-methyl}- cyclohexylmethyl ester 6.5
trans-N-(4-{[Bis-(2-hydroxy- 453 trans-Methanesulfonic
Bis-(2-hydroxy- ethyl)-amino]-methyl}- acid 4-{[methyl-(4-
ethyl)-amine cyclohexylmethyl)-N-methyl- trifluoromethyl-
4-trifluoromethyl- benzenesulfonyl)- benzenesulfonamide
amino]-methyl}- cyclohexylmethyl ester 6.6 trans-(4- 339
trans-Methanesulfonic Dimethyl-amine Dimethylaminomethyl- (1 Cl)
acid 4-{[(4-chloro- cyclohexylmethyl)-methyl- phenoxycarbonyl)-
carbamic acid 4-chloro- methyl-amino]- phenyl ester methyl}-
cyclohexylmethyl ester 6.7 trans-{4-[(Allyl-methyl- 365
trans-Methanesulfonic N-Allyl-methyl- amino)-methyl]- (1 Cl) acid
4-{[(4-chloro- amine cyclohexylmethyl}-methyl- phenoxycarbonyl)-
carbamic acid 4-chloro- methyl-amino]- phenyl ester methyl}-
cyclohexylmethyl ester 6.8 trans-(4- 367 trans-Methanesulfonic
Dimethyl-amine Diethylaminomethyl- (1 Cl) acid 4-{[(4-chloro-
cyclohexylmethyl)-methyl- phenoxycarbonyl)- carbamic acid 4-chloro-
methyl-amino]- phenyl ester methyl}- cyclohexylmethyl ester 6.9
trans-(4-{[Ethyl-(2-hydroxy- 383 trans-Methanesulfonic
Ethyl-(2-hydroxy- ethyl)-amino]-methyl}- (1 Cl) acid 4-{[(4-chloro-
ethyl)-amine cyclohexylmethyl)-methyl- phenoxycarbonyl)- carbamic
acid 4-chloro- methyl-amino]- phenyl ester methyl}-
cyclohexylmethyl ester 6.10 trans-(4-{[Bis-(2-hydroxy- 399
trans-Methanesulfonic Bis-(2-hydroxy- ethyl)-amino]-methyl}- (1 Cl)
acid 4-{[(4-chloro- ethyl)-amine cyclohexylmethyl)-methyl-
phenoxycarbonyl)- carbamic acid 4-chloro- methyl-amino]- phenyl
ester methyl}- cyclohexylmethyl ester 6.11 trans-N-(4- 393
trans-Methanesulfonic Ethylamine Ethylaminomethyl- acid
4-{[methyl-(4- cyclohexylmethyl)-N-methyl- - trifluoromethyl-
4-trifluoromethyl- benzenesulfonyl)- benzenesulfonamide
amino]-methyl}- cyclohexylmethyl ester 6.12 trans-N-Methyl-N-(4-
433 trans-Methanesulfonic Piperidine piperidin-1-ylmethyl- acid
4-{[methyl-(4- cyclohexylmethyl)-4- trifluoromethyl-
trifluoromethyl- benzenesulfonyl)- benzenesulfonamide
amino]-methyl}- cyclohexylmethyl ester 6.13 trans-N-(4-Azetidin-1-
405 trans-Methanesulfonic Azetidine ylmethyl-cyclohexylmethyl)-
acid 4-{[methyl-(4- N-methyl-4-trifluoromethyl- trifluoromethyl-
benzenesulfonamide benzenesulfonyl)- amino]-methyl}-
cyclohexylmethyl ester 6.14 trans-N-Methyl-N-(4- 419
trans-Methanesulfonic Pyrrolidine pyrrolidin-1-ylmethyl- acid
4-{[methyl-(4- cyclohexylmethyl)-4- trifluoromethyl-
trifluoromethyl- benzenesulfonyl)- benzenesulfonamide
amino]-methyl}- cyclohexylmethyl ester 6.15
trans-Methyl-(4-piperidin-1- 379 trans-Methanesulfonic Piperidine
ylmethyl-cyclohexylmethyl)- (1 Cl) acid 4-{[(4-chloro- carbamic
acid 4-chloro- phenoxycarbonyl)- phenyl ester methyl-amino]-
methyl}- cyclohexylmethyl ester 6.16 trans-Methyl-(4-pyrrolidin-
365 trans-Methanesulfonic Pyrrolidine 1-ylmethyl- (1 Cl) acid
4-{[(4-chloro- cyclohexylmethyl)-carbamic phenoxycarbonyl)- acid
4-chloro-phenyl ester methyl-amino]- methyl}- cyclohexylmethyl
ester
Example 7
[0180] 7.1
[0181] 0.532 g (1.59 mmol) of methyl (triphenylphosphoranylidene)
acetate and 0.370 g (1.45 mmol) of
trans-(4-formyl-cyclohexylmethyl)-methyl-carba- mic acid tert-butyl
ester (example 1.2) were suspended in 10.0 ml of toluene and the
reaction mixture heated at 90.degree. C. for 1 hour. It was then
evaporated and the residue formed was chromatographed on silica gel
with a 9:1 v/v mixture of dichloromethane and ether as the eluent
giving 0.370 g (82%)
trans-3-{4-[(tert-butoxycarbonyl-methyl-amino)-methy-
l]-cyclohexyl}-(E,Z)-acrylic acid methyl ester (E:Z=9:1) as
colorless viscous oil, MS: 312 (MH.sup.+).
[0182] 7.2
[0183] 1.17 g (3.75 mmol) of
trans-3-{4-[(tert-butoxycarbonyl-methyl-amino-
)-methyl]-cyclohexyl}-(E,Z)-acrylic acid methyl ester (E:Z=9:1)
were dissolved in 15.0 ml of ethylacetate. 2 times 0.3 g palladium
on charcoal (5%) were then added and the reaction mixture
hydrogenated at normal pressure until the consumption of hydrogen
came to an end. Then, it was filtered over celite, evaporated and
the residue formed was chromatographed on silica gel with a 95:5
v/v mixture of dichloroniethane and ether as the eluent giving 1.00
g (84.9% ) of trans-3-{4-[(tert-butox-
ycarbonyl-methyl-amino)-methyl]-cyclohexyl}-propionic acid methyl
ester as colorless viscous oil, MS: 313 (M.sup.+).
[0184] 7.3
[0185] 0.990 g (3.16 mmol)
trans-3-{4-[(tert-butoxycarbonyl-methyl-amino)--
methyl]-cyclohexyl}-propionic acid methyl ester and 660 mg
potassium hydroxide were dissolved in 5.0 ml of ethanol and the
reaction mixture heated at reflux for 3 hours. It was then
evaporated, subsequently poured into 50 ml of an ice/water mixture,
acidified with aqueous hydrochloric acid to pH 5 and extracted 3
times with 50 ml of dichloromethane. The combined dichloromethane
phases were dried over magnesium sulfate and evaporated under
reduced pressure giving 0.900 g (95%)
trans-3-{4-[(tert-butoxy-carbonyl-methyl-amino)-methyl]-cyclohexyl}-propi-
onic acid as colorless viscous oil, MS: 299 (M.sup.+).
[0186] 7.4
[0187] 0.898 g (3.0 mmol) of
trans-3-{4-[(tert-butoxycarbonyl-methyl-amino-
)-methyl]-cyclohexyl}-propionic acid dissolved in 10.0 ml of
tetrahydrofunan were added slowly and at 0.degree. C. to 4.5 ml of
an 1M solution of boran-tetrahydrofuran-complex in tetrahydrofuran.
The reaction mixture was then stirred at room temperature for 1
hour. Subsequently, 10 ml of methanol were added and the reaction
mixture evaporated. It was then poured into 50 ml of an
ice/water/aqueous sodium hydrogen carbonate mixture and extracted 3
times with 50 ml of dichloromethane. The combined dichloromethane
phases were dried over magnesium sulfate and evaporated under
reduced pressure. The residue formed was chromatographed on silica
gel with a 4:1 v/v mixture of dichloromethane and ether as the
eluent giving 0.690 g (80.6%)
trans-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-methyl-carbamic acid
tert-butyl ester as colorless viscous oil, MS: 286 (MH.sup.+).
[0188] 7.5
[0189] In analogy to the sequence described in examples 1.5 and
1.6, trans-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-methyl-carbamic
acid tert-butyl ester was treated with hydrogen chloride solution
in methanol/water followed by acylation with
4-trifluoromethyl-benzenesulfoc- hloride to yield
trans-N-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-N-methyl--
4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 393
(M.sup.+).
[0190] 7.6
[0191] In analogy to the procedure described in example 3.4,
trans-N-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethy-
l-benzenesulfonamide was treated with methanesulfonyl chloride to
yield trans-methanesulfonic acid
3-(4-{[methyl-(4-trifluoromethyl-benzenesulfon-
yl)-amino]-methyl}-cyclohexyl)-propyl ester as colorless solid, MS:
472 (M.sup.+).
[0192] 7.7
[0193] In analogy to the sequence described in examples 1.5 and
1.6, trans-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-methyl-carbamic
acid tert-butyl ester was treated with hydrogen chloride solution
in methanol/water followed by acylation with 4-chlorophenyl
chloroformate [Org. Lett. (2000), 2(8), 1049-1051] to yield
trans-[4-(3-hydroxy-propyl)- -cyclohexylmethyl]-methyl-carbamic
acid 4-chloro-phenyl ester as colorless viscous oil, MS: 340
(MH.sup.+, 1Cl).
[0194] 7.8
[0195] In analogy to the procedure described in example 3.4,
trans-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-methyl-carbamic acid
4-chloro-phenyl ester was treated with methanesulfonyl chloride to
yield trans-methanesulfonic acid
3-(4-{[(4-chloro-phenoxycarbonyl)-methyl-amino-
]-methyl}-cyclohexyl)-propyl ester as colorless solid, MS: 418
(MH.sup.+, 1Cl).
Example 8
[0196] In analogy to the method described in example 2.1,
methanesulfonic acid esters were treated with secondary or primary
amines in methanol or N,N-dimethylacetamide to yield tertiary or
secondary amine products as listed in the following table.
4 MS Methanesulfonic acid Example Product MH.sup.+ esters Amine 8.1
trans-N-{4-[3-(Allyl-met- hyl- 447 trans-Methanesulfonic
N-Allyl-methyl- amino)-propyl]- acid 3-(4-{[methyl-(4- amine
cyclohexylmethyl}-N-methyl- trifluoromethyl- 4-trifluoromethyl-
benzenesulfonyl)- benzenesulfonamide amino]-methyl}-
cyclohexyl)-propyl ester 8.2 trans-N-(4-{3-[Ethyl-(2- 465
trans-Methanesulfonic Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]- acid
3-(4-{[methyl-(4- ethyl)-amine propyl}-cyclohexylmethyl)-
trifluoromethyl- N-methyl-4-trifluoromethyl- benzenesulfonyl)-
benzenesulfonamide amino]-methyl}- cyclohexyl)-propyl ester 8.3
trans-N-[4-(3-Allylamino- 433 trans-Methanesulfonic N-Allyl-amine
propyl)-cyclohexylmethyl]- acid 3-(4-{[methyl-(4-
N-methyl-4-trifluoromethyl- trifluoromethyl- benzenesulfonamide
benzenesulfonyl)- amino]-methyl}- cyclohexyl)-propyl ester 8.4
trans-N-Methyl-N-[4-(3- 407 trans-Methanesulfonic Methylamine
methylamino-propyl)- acid 3-(4-{[methyl-(4- cyclohexylmethyl]-4-
trifluoromethyl- trifluoromethyl- benzenesulfonyl)-
benzenesulfonamide amino]-methyl}- cyclohexyl)-propyl ester 8.5
trans-{4-[3-(Allyl-methyl- 393 trans-Methanesulfonic
N-Allyl-methyl- amino)-propyl]- (1 Cl) acid 3-(4-{[(4-chloro- amine
cyclohexylmethyl}-methyl- phenoxycarbonyl)- carbamic acid 4-chloro-
methyl-amino]- phenyl ester methyl}-cyclohexyl)- propyl ester 8.6
trans-Methyl-[4-(3- 407 trans-Methanesulfonic Piperidine
piperidin-1-yl-propyl)- 1 Cl) acid 3-(4-{[(4-chloro-
cyclohexylmethyl]-carbamic phenoxycarbonyl)- acid 4-chloro-phenyl
ester methyl-amino]- methyl}-cyclohexyl)- propyl ester 8.7
trans-(4-{3-[Ethyl-(2- 411 trans-Methanesulfonic Ethyl-(2-hydroxy-
hydroxy-ethyl)-amino]- 1 Cl) acid 3-(4-{[(4-chloro- ethyl)-amine
propyl}-cyclohexylmethyl)- phenoxycarbonyl)- methyl-carbamic acid
4- methyl-amino]- chloro-phenyl ester methyl}-cyclohexyl)- propyl
ester 8.8 trans-(4-{3-[Bis-(2-hydroxy- 427 trans-Methanesulfonic
Bis-(2-hydroxy- ethyl)-amino]-propyl}- (1 Cl) acid
3-(4-{[(4-chloro- ethyl)-amine cyclohexylmethyl)-methyl-
phenoxycarbonyl)- carbamic acid 4-chloro- methyl-amino]- phenyl
ester methyl}-cyclohexyl)- propyl ester
Example 9
[0197] 9.1
[0198] 2.1 g (13.35 mmol)
trans-(4-methylaminomethyl-cyclohexyl)-methanol (example 1.1) were
dissolved in 20 ml methanol. 3.32 g (13.35 mmol)
N-(benzyloxycarbonyloxy)-succinimide were added and the solution
was stirred at room temperature for 2 hours, then for 1 hour at
50.degree. C. Afterwards, the solvent was evaporated under reduced
pressure and the residue was partitioned between dichloromethane
and water. The organic phase was washed with water (2 times), then
with brine and finally dried over magnesium sulfate and evaporated
under reduced pressure. The residue was chromatographed on silica
gel with a 4:1 v/v mixture of dichloromethane and diethyl ether as
the eluent. 1.67 g (42.9%)
trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid
benzyl ester were obtained as colorless oil, M: 289 (M).
[0199] 9.2
[0200] In analogy to the method described in example 1.2, 1.65 g
(5.66 mmol) of
trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid
benzyl ester were treated with dimethylsulfoxide/triethylamine in
dichloromethane between -78.degree. C. and room temperature to
yield 1.6 g (97.6%)
trans-(4-formyl-cyclohexylmethyl)-methyl-carbamic acid benzyl ester
as colorless oil, MS: 289 (M).
[0201] 9.3
[0202] 2.27 g (6.63 mmol) (methoxymethyl)triphenylphosphonium
chloride were suspended in 20 ml of absolute tetrahydrofuran, the
temperature being maintained at -10.degree. C. 0.75 g (6.63 mmol)
of potassium tert.-butylate were added while stirring, thus a
homogenous solution was obtained. After 0.5 hour, 1.6 g (5.52 mmol)
trans-(4-formyl-cyclohexylmet- hyl)-methyl-carbamic acid benzyl
ester dissolved in 10 ml of tetrahydrofuran were added, and
stirring was continued for 2 hours at -10.degree. C., then for 1
hour at room temperature. Afterwards, the solvent was evaporated
under reduced pressure, the residue was dissolved in 3 ml of
dichloromethane and then chromatographed on silica gel with a 98:2
v/v mixture of dichloromethane and diethyl ether as the eluent,
yielding 0.81 g (42.9%)
trans-[4-(E,Z)-(2-methoxy-vinyl)-cyclohexylmethyl-
]-methyl-carbamic acid benzyl ester as colorless oil, M: 318
(MH.sup.+).
[0203] 9.4
[0204] 0.8 g (2.52 mmol)
trans-[4-(E,Z)-(2-methoxy-vinyl)-cyclohexylmethyl-
]-methyl-carbamic acid benzyl ester were dissolved in 10 ml of
tetrahydrofuran; 1 ml of a 2N aqueous hydrochloric acid solution
was added and the mixture was heated to reflux for 2 hours. Then,
the reaction mixture was neutralized by addition of aqueous sodium
bicarbonate solution and extracted with dichloromethane. The
organic phase was washed with brine, then dried over magnesium
sulfate and evaporated under reduced pressure.
Trans-methyl-[4-(2-oxo-ethyl)-cyclohex- ylmethyl]-carbamic acid
benzyl ester was obtained in quantitative yield as colorless,
viscous oil, M: 304 (MH.sup.+).
[0205] 9.5
[0206] A stirred solution of 0.75 g (2.47 mmol)
trans-methyl-[4-(2-oxo-eth- yl)-cyclohexylmethyl]-carbamic acid
benzyl ester in 15 ml of methanol was cooled to 0-5.degree. C. 0.14
g (3.7 mmol) of sodium borohydride were added in four equal
portions, at intervals of 10 minutes. Stirring was continued for 1
hour at room temperature. Afterwards, a 1N aqueous hydrochloric
acid solution was dropped into the solution until the medium was
acidic; it was then made neutral by addition of aqueous sodium
bicarbonate solution. The reaction mixture was subsequently
extracted 3 times with 25 ml of dichloromethane. The combined
organic phases were dried over magnesium sulfate and evaporated
under reduced pressure. The residue obtained was chromatographed on
silica gel with a 95:5 v/v mixture of dichloromethane and methanol
as the eluent. 0.63 g (83%)
trans-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-methyl-carbamic acid
benzyl ester were obtained as colorless oil, MS: 306
(MH.sup.+).
[0207] 9.6
[0208] 0.62 g (2.03 mmol)
trans-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-met- hyl-carbamic acid
benzyl ester dissolved in 10 ml of tetrahydrofuran were submitted
to a hydrogenation over 0.3 g of 5% palladium on charcoal as
catalyst, at normal pressure and ambient temperature. The cleavage
of the benzyloxycarbonyl group was complete after 3 hours. After
removal of the catalyst by filtration and evaporation of the
solvent, 0.33 g (95%) of
trans-2-(4-methylaminomethyl-cyclohexyl)-ethanol were obtained as a
colorless oil, MS: 172 (MH.sup.+).
[0209] 9.7
[0210] In analogy to the procedure described in example 1.7, 0.325
g (1.90 mmol) of trans-2-(4-methylaminomethyl-cyclohexyl)-ethanol
were acylated with 0.54 g (2.84 mmol) of 4-chlorophenyl
chloroformate to yield 0.34 g (55%)
trans-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-methyl-carbamic acid
4-chloro-phenyl ester as colorless viscous oil, MS: 326 (MH.sup.+,
1Cl).
[0211] 9.8
[0212] In analogy to the procedure described in example 3.4,
trans-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-methyl-carbamic acid
4-chloro-phenyl ester was treated with methanesulfonyl chloride to
yield trans-methanesulfonic acid
2-(4-{[(4-chloro-phenoxycarbonyl)-methyl-amino-
]-methyl}-cyclohexyl)-ethyl ester as colorless viscous oil, MS: 404
(MH.sup.+, 1Cl).
[0213] 9.9
[0214] In analogy to the procedure described in example 1.6,
trans-2-(4-methylaminomethyl-cyclohexyl)-ethanol was acylated with
4-trifluoromethyl-benzene sulfochloride to yield
trans-N-[4-(2-hydroxy-et-
hyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide
as colorless solid, MS: 380 (MH.sup.+).
[0215] 9.10
[0216] In analogy to the procedure described in example 3.4,
trans-N-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-
-benzenesulfonamide was treated with methanesulfonyl chloride to
yield trans-methanesulfonic acid
2-(4-{[methyl-(4-trifluoromethyl-benzenesulfon-
yl)-amino]-methyl}-cyclohexyl)-ethyl ester as colorless solid, MS:
358 (MH.sup.+).
Example 10
[0217] In analogy to the method described in example 2.1,
methanesulfonic acid esters were treated with secondary or primary
amines in methanol or N,N-dimethylacetamide to yield tertiary or
secondary amine products as listed in the following table.
5 MS Methanesulfonic acid Example Product MH.sup.+ esters Amine
10.1 trans-{4-[2-(Allyl-meth- yl- 379 trans-Methanesulfonic
N-Allyl-methyl- amino)-ethyl]- (1 Cl) acid 2-(4-{[(4-chloro- amine
cyclohexylmethyl}-methyl- phenoxycarbonyl)- carbamic acid 4-chloro-
methyl-amino]- phenyl ester methyl}-cyclohexyl)- ethyl ester 10.2
trans-Methyl-[4-(2- 393 trans-Methanesulfonic Piperidine
piperidin-1-yl-ethyl)- (1 Cl) acid 2-(4-{[(4-chloro-
cyclohexylmethyl]-carbamic phenoxycarbonyl)- acid 4-chloro-phenyl
ester methyl-amino]- methyl}-cyclohexyl)- ethyl ester 10.3
trans-N-Methyl-N-[4-(2- 447 trans-Methanesulfonic Piperidine
piperidin-1-yl-ethyl)- acid 2-(4-{[methyl-(4- cyclohexylmethyl]-4-
trifluoromethyl- trifluoromethyl- benzenesulfonyl)-
benzenesulfonamide amino]-methyl}- cyclohexyl)-ethyl ester 10.4
trans-N-(4-{2-[Ethyl-(2- 451 trans-Methanesulfonic
Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]- acid 2-(4-{[methyl-(4-
ethyl)-amine ethyl}-cyclohexylmethyl)-N- trifluoromethyl-
methyl-4-trifluoromethyl- benzenesulfonyl)- benzenesulfonamide
amino]-methyl}- cyclohexyl)-ethyl ester 10.5 trans-N-(4-{2-[Bis-(2-
467 trans-Methanesulfonic Bis-(2-hydroxy- hydroxy-ethyl)-amino]-
acid 2-(4-{[methyl-(4- ethyl)-amine ethyl}-cyclohexylmethyl)-N-
trifluoromethyl- methyl-4-trifluoromethyl- benzenesulfonyl)-
benzenesulfonamide amino]-methyl}- cyclohexyl)-ethyl ester 10.6
trans-(4-{2-[Ethyl-(2- 397 trans-Methanesulfonic Ethyl-(2-hydroxy-
hydroxy-ethyl)-amino]- (1 Cl) acid 2-(4-{[(4-chloro- ethyl)-amine
ethyl}-cyclohexylmethyl)- phenoxycarbonyl)- methyl-carbamic acid 4-
methyl-amino]- chloro-phenyl ester methyl}-cyclohexyl)- ethyl ester
10.7 trans-N-{4-[2-(Allyl-methyl- 433 trans-Methanesulfonic
N-Allyl-methyl- amino)-ethyl]- acid 2-(4-{[methyl-(4- amine
cyclohexylmethyl}-N-methyl- trifluoromethyl- 4-trifluoromethyl-
benzenesulfonyl)- benzenesulfonamide amino]-methyl}-
cyclohexyl)-ethyl ester 10.8 trans-(RS,RS)-N-(4-{2-[Bis- 495
trans-Methanesulfonic Bis-(2-hydroxy- (2-hydroxy-propyl)-amino]-
acid 2-(4-{[methyl-(4- propyl)-amine ethyl}-cyclohexylmethyl)-N-
trifluoromethyl- methyl-4-trifluoromethyl- benzenesulfonyl)-
benzenesulfonamide amino]-methyl}- cyclohexyl)-ethyl ester
Example 11
[0218] 11.1
[0219] To a dry-ice cooled solution of 30.0 g (208 mmol)
trans-(4-hydroxymethyl-cyclohexyl)-methanol in 450 ml
tetrahydrofuran was dropped at -60.degree. C. to -67.degree. C.,
within 30 minutes, 130 ml (208 mmol) 1.6 M butyllithium solution
(1.6 M in hexane). After stirring for 30 minutes at -78.degree. C.,
32.3 g (208 mmol) of tert-butyl-dimethyl-chlorosilane was added
within 10 minutes. After stirring the reaction mixture for 15
minutes at -65.degree. C., it was stirred over night at room
temperature and then partitioned between ether, 1N hydrogen
chloride solution and water. The organic layer was dried over
magnesium sulfate, concentrated under reduced pressure and the
residue then chromatographed on silica gel with a 3:1 v/v mixture
of hexane and ethylacetate as the eluent giving 27.7 g (51.4%) of
pure
trans-[4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexyl]-methanol
as colorless viscous oil, MS: 259 (MH.sup.+).
[0220] 11.2
[0221] To an ice-cooled solution of 27.6 g (107 mmol)
trans-[4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclohexyl]-methanol
and 9.99 ml (128 mmol) of methanesulfonyl chloride in 350 ml of
dichloromethane was added under stirring at 0-10.degree. C. 29.6 ml
(213 mmol) triethylamine within 20 minutes. The reaction-mixture
was then stirred for 1 hour at room temperature. It was then
partitioned between dichloromethane, 1N HCl and water. The
dichloromethane-phase was dried over magnesium sulfate and
concentrated to yield 38.2 g crude trans-methanesulfonic acid
4-(tert-butyl-dimethyl-silanyloxymethyl)-cyclo- hexylmethyl ester
as colorless viscous oil, MS: 354 (M+NH.sub.4.sup.+).
[0222] 11.3
[0223] 38.2 g of crude trans-methanesulfonic acid
4-(tert-butyl-dimethyl-s- ilanyloxymethyl)-cyclohexylmethyl ester
and 16.7 g (340 mmol) of sodium cyanide dissolved in 380 ml of
N,N-dimethylformamide were stirred for 2 hours at 80.degree. C.
After cooling the reaction mixture down to room temperature, it was
partitioned between ether and water. The organic layer was dried
over magnesium sulfate and concentrated under reduced pressure and
the residue then chromatographed on silica gel with a 9:1 v/v
mixture of hexane and ethylacetate as the eluent giving 24.2 g
(79.7% over two steps) of pure
trans-[4-(tert-butyl-dimethyl-silanyloxymethyl)-c-
yclohexyl]-acetonitrile as colorless viscous oil, MS: 290
(MNa.sup.+).
[0224] 11.4
[0225] A solution of 24.2 g (90.5 mmol)
trans-[4-(tert-butyl-dimethyl-sila-
nyloxymethyl)-cyclohexyl]-acetonitrile, of 22 ml (270 mmol)
chloroform and of 2.4 g platinum dioxide (Degussa 223) in 250 ml
ethanol was stirred at room temperature for 20 hours under a
hydrogen atmosphere. The catalyst was then removed by filtration
and the solvent evaporated under reduced pressure giving 17.1 g
(97.3%) of pure trans-[4-(2-amino-ethyl)-cyclohexy- l]-methanol
HCl-salt as colorless solid, MS: 158 (MH.sup.+).
[0226] 11.5
[0227] To a solution of 17.6 g (90.9 mmol)
trans-[4-(2-amino-ethyl)-cycloh- exyl]-methanol HCl-salt and 13.9
ml (100 mmol) triethylamine in 120 ml dichloromethane was added
under stirring within 10 minutes at room temperature a solution of
21.8 g (100 mmol) of di-tert-butyl-dicarbonate in 70 ml of
dichloromethane. After stirring for 3 hours at room temperature,
the reaction-mixture was partitioned between dichloromethane, 1N
hydrogen chloride solution and water. Then, the
dichloromethane-phase was dried over magnesium sulfate and
concentrated to yield 27.9 of crude
trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-carba- mic acid
tert-butyl ester as colorless viscous oil, MS: 275
(MNH.sub.4.sup.+).
[0228] 11.6
[0229] A solution of 27.9 g (86.7 mmol)
trans-[2-(4-hydroxymethyl-cyclohex- yl)-ethyl]-carbamic acid
tert-butyl ester, 41 ml (434 mmol) acetic anhydride and 35 ml (434
mmol) of pyridine in 140 ml of dichloromethane was stirred at room
temperature for 16 hours. The reaction-mixture was then taken up in
ether and washed with 1N hydrogen chloride solution, sodium
hydrogen carbonate solution and water. Then, the ether-phase was
dried over magnesium sulfate and concentrated to yield 26.0 g crude
trans-acetic acid
4-(2-tert-butoxycarbonylamino-ethyl)-cyclohexylmethyl ester as
colorless viscous oil, MS: 200 [(M-(tert-butoxycarbonyl))H.sup.+-
].
[0230] 11.7
[0231] To an ice-cooled and stirred solution of the crude 26.0 g
trans-acetic acid
4-(2-tert-butoxycarbonylamino-ethyl)-cyclohexylmethyl ester and
5.77 ml (92.6 mmol) methyliodide in 300 ml of N,N-dimethylformamide
was added within 15 minutes 4.04 g (92.58 mmol) sodium hydride (55%
in oil). After stirring over night at room temperature, additional
1.65 ml (26.5 mmol) methyliodide and 1.16 g (26.5 mmol) of sodium
hydride were added and the reaction-mixture was then stirred for
another 1 hour at room temperature. It was then partitioned between
ether, 1N hydrogen chloride solution and water. The organic layer
was dried over magnesium sulfate and concentrated under reduced
pressure and the residue then chromatographed on silica gel with a
4:1 v/v mixture of hexane and ethylacetate as the eluent giving
18.7 g (67.7% over 3 steps) of pure trans-acetic acid
4-[2-(tert-butoxycarbonyl-methyl-amino)-- ethyl]-cyclohexylmethyl
ester as colorless viscous oil, MS: 214
[(M-(tert-butoxycarbonyl))H.sup.+].
[0232] 11.8
[0233] To a solution of 18.7 g (59.7 mmol) of trans-acetic acid
4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl
ester in 110 ml of methanol was added 41.25 g (298.5 mmol) of
potassium carbonate. The reaction mixture was then stirred for 2
hours at room temperature. The excess of potassium carbonate was
removed by filtration and the methanol was removed by evaporation
under reduced pressure. The crude residue was partitioned between
ether, 1N hydrogen chloride solution and water. The organic layer
was dried over magnesium sulfate and concentrated under reduced
pressure and the residue then chromatographed on silica gel with a
2:1 v/v mixture of hexane and ethylacetate as the eluent giving
13.9 g (86.0%) of pure trans-[2-(4-hydroxymethyl-cyclohexyl-
)-ethyl]-methyl-carbamic acid tert-butyl ester as colorless viscous
oil, MS 272 (MH.sup.+).
[0234] 11.9
[0235] 1.56 ml (18.2 mmol) of oxalylchloride were added to a
dry-ice-cooled solution of 2 ml (28 mmol) of dimethylsulfoxide in
30 ml dichloromethane at -78.degree. C. After stirring for 15
minutes at -78.degree. C., a solution of 3.8 g (14 mmol)
trans-2-(4-hydroxymethyl-cy- clohexyl)-ethyl]-methyl-carbamic acid
tert-butyl ester in 10 ml of dichloromethane was added within 10
minutes at -78.degree. C. to the reaction mixture. After stirring
for 15 minutes under dry-ice-cooling, 9.76 ml (70 mmol) of
triethylamine was added. The dry ice-cooling was then removed and
the reaction mixture was stirred for further 3 hours at room
temperature. It was then taken up in ether and washed with 1N
hydrogen chloride solution and water. The organic layer was dried
over magnesium sulfate and concentrated under reduced pressure
giving 4.02 g of crude
trans-[2-(4-formyl-cyclohexyl)-ethyl]-methyl-carbamic acid
tert-butyl ester as colorless viscous oil, MS: 269 (M.sup.+).
[0236] 11.10
[0237] A solution of 4.02 g (14.9 mmol)
trans-[2-(4-formyl-cyclohexyl)-eth- yl]-methyl-carbamic acid
tert-butyl ester and 5.47 g (14.9 mmol) of
(triphenyl-phosphoranylidene)-acetic acid ethyl ester in 40 ml of
dichloromethane was stirred at room temperature for 60 hours. After
concentration under reduced pressure, the crude product was
chromatographed on silica gel with a 9:1 v/v mixture of hexane and
ethylacetate as the eluent giving 3.82 g (75.4%) of pure
trans-3-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-(E)-a-
crylic acid ethyl ester as colorless viscous oil, MS: 340
(MH.sup.+).
[0238] 11.11
[0239] A suspension of 3.8 g (11.2 mmol)
trans-3-{4-[2-(tert-butoxycarbony-
l-methyl-amino)-ethyl]-cyclohexyl}-(E)-acrylic acid ethyl ester and
400 mg of palladium (10% on carbon) in 40 ml of methanol was
stirred for 20 hours at room temperature under a hydrogen
atmosphere. The catalyst was removed by filtration and the solvent
evaporated under reduced pressure to give 3.67 g of crude
trans-3-{4-[2-(tert-butoxycarbonyl-methyl-amino)--
ethyl]-cyclohexyl}-propionic acid ethyl ester as colorless viscous
oil, MS: 359 (MNH.sub.4.sup.+).
[0240] 11.12
[0241] To a solution of
trans-3-{4-[2-(tert-butoxycarbonyl-methyl-amino)-e-
thyl]-cyclohexyl}-propionic acid ethyl ester in 40 ml of
tetrahydrofuran was added under ice-cooling 547 mg (14.0 mmol) of
lithium aluminium hydride in small portions. The reaction mixture
was then stirred for 1 hour at room temperature. To destroy the
excess of lithium aluminium hydride, 50 ml of brine was added to
the reaction mixture under ice-cooling. It was then partitioned
between ether and water, the organic layer was dried over magnesium
sulfate and concentrated under reduced pressure giving 3.35 g (100%
over 2 stepts) nearly pure
trans-{2-[4-(3-hydroxy-propyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid tert-butyl ester as colorless viscous oil, MS. 317
(MNH.sub.4.sup.+).
[0242] 11.13
[0243] To a solution of 3.35 g (11.20 mmol)
trans-{2-[4-(3-hydroxy-propyl)- -cyclohexyl]-ethyl}-methyl-carbamic
acid tert-butyl ester and 1.54 ml (13.4 mmol) of methanesulfonyl
chloride in 35 ml dichloromethane was added under ice-cooling
within 5 minutes a solution of 1.87 ml (13.4 mmol) triethylamine in
5 ml of dichloromethane. The reaction mixture was then stirred for
1 hour at room temperature. It was subsequently partitioned between
ether, water and 1N hydrogen chloride solution. The organic layer
was dried over magnesium sulfate and concentrated under reduced
pressure giving 4.06 g (96.1%) almost pure trans-methanesulfonic
acid
3-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-propyl
ester as colorless viscous oil, MS: 395 (MNH.sub.4.sup.+).
[0244] 11.14
[0245] 30 ml of 4N hydrogen chloride solution in dioxan was added
to 4.06 g (10.8 mmol) of trans methanesulfonic acid
3-{4-[2-(tert-butoxycarbonyl--
methyl-amino)-ethyl]-cyclohexyl}-propyl ester. After stirring of
the reaction mixture for 3 hours at room temperature, it was
concentrated under reduced pressure. The residue formed was stirred
in ether and the crystals formed were filtered off and washed with
ether. After drying under reduced pressure and at and 45.degree.
C., 3.12 g (92.4%) trans-methanesulfonic acid
3-[4-(2-methylamino-ethyl)-cyclohexyl]-propyl ester HCl salt could
be isolated as colorless crystals, MS: 278 (MH.sup.+).
[0246] 11.15
[0247] To an ice-cooled solution of 1.5 g (4.78 mmol) of
trans-methanesulfonic acid
3-[4-(2-methylamino-ethyl)-cyclohexyl]-propyl ester HCl salt and
1.23 g (5.5 mmol) of 4-trifluoromethyl-phenyl-chlorofo- rmate in 30
ml of dichloromethane was added 4.06 ml (23.9 mmol) of diisopropyl
ethylamine. The reaction mixture was then stirred for 1 hour at
room temperature and partitioned between ether, 1N hydrogen
chloride solution and water. The organic layer was dried over
magnesium sulfate and concentrated under reduced pressure and the
residue then chromatographed on silica gel with a 2:1 v/v mixture
of hexane and ethylacetate as the eluent giving 1.94 g (87.2%)
trans-methanesulfonic acid
3-(4-{2-[methyl-(4-trifluoromethyl-phenoxycarbonyl)-amino]-ethyl}-cy-
clohexyl)-propyl ester as colorless viscous oil, MS: 466
(MH.sup.+).
[0248] 11.16
[0249] In analogy to the procedure described in example 11.15,
trans-methanesulfonic acid
3-[4-(2-methylamino-ethyl)-cyclohexyl]-propyl ester HCl salt was
reacted with 4-chloro-phenyl-chloroformate to yield
trans-methanesulfonic acid
3-(4-{2-[(4-chloro-phenoxycarbonyl)-methyl-ami-
no]-ethyl}-cyclohexyl)-propyl ester as colorless viscous oil, MS:
432 (MH.sup.+, 1Cl).
Example 12
[0250] 12.1
[0251] A solution of 200 mg (0.43 mmol) trans-methanesulfonic acid
3-(4-{2-[methyl-(4-trifluoromethyl-phenoxycarbonyl)-amino]-ethyl}-cyclohe-
xyl)-propyl ester and 0.204 ml (2.15 mmol) of allyl methyl amine in
2 ml of N,N-dimethylacetamide was stirred over night at 60.degree.
C. The reaction mixture was then taken up in ether and the ether
phases were washed with water. The organic layer was dried over
magnesium sulfate, concentrated under reduced pressure and the
residue then chromatographed on silica gel with a 9:1 v/v mixture
of dichloromethane and iN ammonia in methanol as the eluent giving
124 mg (65.5%) trans-(2-{4-[3-(allyl-methyl-
-amino)-propyl]-cyclohexyl}-ethyl)-methyl-carbamic acid
4-trifluoromethyl-phenyl ester as colorless viscous oil, MS: 441
(MH.sup.+).
[0252] In analogy to the method described in example 12.1,
methanesulfonic acid esters were reacted with secondary or primary
amines in N,N-dimethylacetamide to yield tertiary or secondary
amine products as listed in the following table:
6 MS Methanesulfonic acid Example Product MH.sup.+ esters Amine
12.2 trans-[2-(4-{3-[Ethyl-(- 2- 459 trans-Methanesulfonic
Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]- acid 3-(4-{2-[methyl-
ethyl)-amine propyl}-cyclohexyl)-ethyl]- (4-trifluoromethyl-
methyl-carbamic acid 4- phenoxycarbonyl)- trifluoromethyl-phenyl
ester amino]-ethyl}- cyclohexyl)-propyl ester 12.3
trans-Methyl-{2-[4-(3- 457 trans-Methanesulfonic Morpholine
morpholin-4-yl-propyl)- acid 3-(4-{2-[methyl-
cyclohexyl]-ethyl}-carbamic (4-trifluoromethyl- acid
4-trifluoromethyl-phenyl phenoxycarbonyl)- ester amino]-ethyl}-
cyclohexyl)-propyl ester 12.4 trans-Methyl-{2-[4-(3- 455
trans-Methanesulfonic Piperidine piperidin-1-yl-propyl)- acid
3-(4-{2-[methyl- cyclohexyl]-ethyl}-carbamic (4-trifluoromethyl-
acid 4-trifluoromethyl-phenyl phenoxycarbonyl)- ester
amino]-ethyl}- cyclohexyl)-propyl ester 12.5 trans-{2-[4-(3- 415
trans-Methanesulfonic Dimethyl-amine Dimethylamino-propyl)- acid
3-(4-{2-[methyl- cyclohexyl]-ethyl}-methyl- (4-trifluoromethyl-
carbamic acid 4- phenoxycarbonyl)- trifluoromethyl-phenyl ester
amino]-ethyl}- cyclohexyl)-propyl ester 12.6
trans-{2-[4-(3-Diethylamino- 443 trans-Methanesulfonic
Diethyl-amine propyl)-cyclohexyl]-ethyl}- acid 3-(4-{2-[methyl-
methyl-carbamic acid 4- (4-trifluoromethyl- trifluoromethyl-phenyl
ester phenoxycarbonyl)- amino]-ethyl}- cyclohexyl)-propyl ester
12.7 trans-Methyl-(2-{4-[3- 443 trans-Methanesulfonic 3-(Methyl-
(methyl-propyl-amino)- acid 3-(4-{2-[methyl- propyl-amine
propyl]-cyclohexyl}-ethyl)- (4-trifluoromethyl- carbamic acid 4-
phenoxycarbonyl)- trifluoromethyl-phenyl ester amino]-ethyl}-
cyclohexyl)-propyl ester 12.8 trans-[2-(4-{3-[Bis-(2- 475
trans-Methanesulfonic Bis-(2-hydroxy- hydroxy-ethyl)-amino]- acid
3-(4-{2-[methyl- ethyl)-amine propyl}-cyclohexyl)-ethyl]-
(4-trifluoromethyl- methyl-carbamic acid 4- phenoxycarbonyl)-
trifluoromethyl-phenyl ester amino]-ethyl}- cyclohexyl)-propyl
ester 12.9 trans-Methyl-(2-{4-[3-(4- 470 trans-Methanesulfonic
1-Methyl- methyl-piperazin-1-yl)- acid 3-(4-{2-[methyl- piperazine
propyl]-cyclohexyl}-ethyl)- (4-trifluoromethyl- carbamic acid 4-
phenoxycarbonyl)- trifluoromethyl-phenyl ester amino]-ethyl}-
cyclohexyl)-propyl ester
Example 13
[0253] 13.1
[0254] In analogy to the procedures described in examples 11.13 and
11.14, trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic
acid tert-butyl ester (example 11.8) was reacted with
methanesulfonyl chloride to give trans-methanesulfonic acid
4-[2-(tert-butoxycarbonyl-methyl-amino- )-ethyl]-cyclohexylmethyl
ester, which was subsequently treated with 4N hydrogen chloride in
dioxan to yield trans-methanesulfonic acid
4-(2-methylamino-ethyl)-cyclohexylmethyl ester HCl salt as
colorless solid, MS: 250 (MH.sup.+).
[0255] 13.2
[0256] In analogy to the procedure described in example 11.15,
trans-methanesulfonic acid 4-(2-methylamino-ethyl)-cyclohexylmethyl
ester HCl salt was reacted with 4-(trifluoromethyl) benzene
sulphonyl chloride to yield trans-methanesulfonic acid
4-{2-[methyl-(4-trifluoro-methyl-benz-
enesulfonyl)-amino]-ethyl}-cyclohexylmethyl ester as colorless
viscous oil, MS: 475 (MNH.sub.4.sup.+).
[0257] 13.3
[0258] In analogy to the procedure described in example 11.15,
trans-methanesulfonic acid 4-(2-methylamino-ethyl)-cyclohexylmethyl
ester HCl salt was reacted with
4-trifluoromethyl-phenyl-chloroformate to yield
trans-methanesulfonic acid
4-{2-[methyl-(4-trifluoromethyl-phenoxycarbony-
l)-amino]-ethyl}-cyclohexylmethyl ester as colorless viscous oil,
MS: 455 (MNH.sub.4.sup.+).
[0259] 13.4
[0260] In analogy to the procedure described in example 11.15,
trans-methanesulfonic acid 4-(2-methylamino-ethyl)-cyclohexylmethyl
ester HCl salt was reacted with 4-chloro-benzene sulphonyl chloride
to yield trans-methanesulfonic acid
4-{2-[(4-chloro-benzenesulfonyl)-methyl-amino]-
-ethyl}-cyclohexylmethyl ester as colorless viscous oil, MS: 424
(MH.sup.+, 1Cl).
[0261] 13.5
[0262] In analogy to the procedure described in example 11.15,
trans-methanesulfonic acid 4-(2-methylamino-ethyl)-cyclohexylmethyl
ester HCl salt was reacted with 4-chloro-phenyl-chloroformate to
yield trans-methanesulfonic acid
4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-
-ethyl}-cyclohexylmethyl ester as colorless viscous oil, MS: 404
(MH.sup.+, 1Cl).
Example 14
[0263] In analogy to the method described in example 12.1,
methanesulfonic acid esters were reacted with secondary or primary
amines in N,N-dimethylacetamide to yield tertiary or secondary
amine products as listed in the following table:
7 MS Methanesulfonic acid Example Product MH.sup.+ esters Amine
14.1 trans-N-(2-{4-[(Allyl-m- ethyl- 433 trans-Methanesulfonic
N-Allyl-methyl- amino)-methyl]-cyclohexyl}- acid 4-{2-[methyl-(4-
amine ethyl)-N-methyl-4- trifluoromethyl- trifluoromethyl-
benzenesulfonyl)- benzenesulfonamide amino]-ethyl}-
cyclohexylmethyl ester 14.2 trans-(2-{4-[(Allyl-methyl- 413
trans-Methanesulfonic N-Allyl-methyl- amino)-methyl]-cyclohexyl}-
acid 4-{2-[methyl-(4- amine ethyl)-methyl-carbamic acid
trifluoromethyl- 4-trifluoromethyl-phenyl phenoxycarbonyl)- ester
amino]-ethyl}- cyclohexylmethyl ester 14.3 trans-[2-(4- 387
trans-Methanesulfonic Dimethylamine Dimethylaminomethyl- acid
4-{2-[methyl-(4- cyclohexyl)-ethyl]-methyl- trifluoromethyl-
carbamic acid 4- phenoxycarbonyl)- trifluoromethyl-phenyl ester
amino]-ethyl}- cyclohexylmethyl ester 14.4 trans-[2-(4-{[Ethyl-(2-
431 trans-Methanesulfonic Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]-
acid 4-{2-[methyl-(4- ethyl)-amine methyl}-cyclohexyl)-ethyl]-
trifluoromethyl- methyl-carbamic acid 4- phenoxycarbonyl)-
trifluoromethyl-phenyl ester amino]-ethyl}- cyclohexylmethyl ester
14.5 trans-Methyl-{2-[4-(4- 442 trans-Methanesulfonic 1-Methyl-
methyl-piperazin-1- acid 4-{2-[methyl-(4- piperazine
ylmethyl)-cyclohexyl]-ethyl}- trifluoromethyl- carbamic acid 4-
phenoxycarbonyl)- trifluoromethyl-phenyl ester amino]-ethyl}-
cyclohexylmethyl ester 14.6 trans-(2-{4-[(2-Hydroxy- 403
trans-Methanesulfonic 2-Hydroxy- ethylamino)-methyl]- acid
4-{2-[methyl-(4- ethylamine cyclohexyl}-ethyl)-methyl-
trifluoromethyl- carbamic acid 4- phenoxycarbonyl)-
trifluoromethyl-phenyl ester amino]-ethyl}- cyclohexylmethyl ester
14.7 trans-(2-{4-[(2-Hydroxy-1,1- 431 trans-Methanesulfonic
2-Amino-2- dimethyl-ethylamino)- acid 4-{2-[methyl-(4-
methyl-propanol methyl]-cyclohexyl}-ethyl)- trifluoromethyl-
methyl-carbamic acid 4- phenoxycarbonyl)- trifluoromethyl-phenyl
ester amino]-ethyl}- cyclohexylmethyl ester 14.8 trans-[2-(4- 399
trans-Methanesulfonic Allyl-amine Allylaminomethyl- acid
4-{2-[methyl-(4- cyclohexyl)-ethyl]-methyl- trifluoromethyl-
carbamic acid 4- phenoxycarbonyl)- trifluoromethyl-phenyl ester
amino]-ethyl}- cyclohexylmethyl ester 14.9 trans-Methyl-[2-(4- 373
trans-Methanesulfonic Methyl-amine methylaminomethyl- acid
4-{2-[methyl-(4- cyclohexyl)-ethyl]-carbamic trifluoromethyl- acid
4-trifluoromethyl-phenyl phenoxycarbonyl)- ester amino]-ethyl}-
cyclohexylmethyl ester 14.10 trans-N-[2-(4- 407
trans-Methanesulfonic Dimethyl-amine Dimethylaminomethyl- acid
4-{2-[methyl-(4- cyclohexyl)-ethyl]-N-methyl- trifluoromethyl-
4-trifluoromethyl- benzenesulfonyl)- benzenesulfonamide
amino]-ethyl}- cyclohexylmethyl ester 14.11
trans-N-[2-(4-{[Ethyl-(2- 451 trans-Methanesulfonic
Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]- acid 4-{2-[methyl-(4-
ethyl)-amine methyl}-cyclohexyl)-ethyl]- trifluoromethyl-
N-methyl-4-trifluoromethyl- benzenesulfonyl)- benzenesulfonamide
amino]-ethyl}- cyclohexylmethyl ester 14.12
trans-N-Methyl-N-{2-[4-(4- 462 trans-Methanesulfonic 1-Methyl-
methyl-piperazin-1- acid 4-{2-[methyl-(4- piperazine
ylmethyl)-cyclohexyl]-ethyl}- trifluoromethyl- 4-trifluoromethyl-
benzenesulfonyl)- benzenesulfonamide amino]-ethyl}-
cyclohexylmethyl ester 14.13 trans-N-(2-{4-[(2-Hydroxy- 423
trans-Methanesulfonic 2-Hydroxy- ethylamino)-methyl]- acid
4-{2-[methyl-(4- ethylamine cyclohexyl}-ethyl)-N-methyl-
trifluoromethyl- 4-trifluoromethyl- benzenesulfonyl)-
benzenesulfonamide amino]-ethyl}- cyclohexylmethyl ester 14.14
trans-N-Methyl-N-[2-(4- 393 trans-Methanesulfonic Methyl-amine
methylaminomethyl- acid 4-{2-[methyl-(4- cyclohexyl)-ethyl]-4-
trifluoromethyl- trifluoromethyl- benzenesulfonyl)-
benzenesulfonamide amino]-ethyl}- cyclohexylmethyl ester 14.15
trans-N-(2-{4-[(2-Hydroxy- 451 trans-Methanesulfonic 2-Amino-2-
1,1-dimethyl-ethylamino)- acid 4-{2-[methyl-(4- methyl-propanol
methyl]-cyclohexyl}-ethyl)- trifluoromethyl-
N-methyl-4-trifluoromethyl- benzenesulfonyl)- benzenesulfonamide
amino]-ethyl}- cyclohexylmethyl ester 14.16 trans-N-[2-(4- 419
trans-Methanesulfonic Allyl-amine Allylaminomethyl- acid
4-{2-[methyl-(4- cyclohexyl)-ethyl]-N-met- hyl- trifluoromethyl-
4-trifluoromethyl- benzenesulfonyl)- benzenesulfonamide
amino]-ethyl}- cyclohexylmethyl ester 14.17 trans-N-Methyl-N-[2-(4-
447 trans-Methanesulfonic Piperidine piperidin-1-ylmethyl- acid
4-{2-[methyl-(4- cyclohexyl)-ethyl]-4- trifluoromethyl-
trifluoromethyl- benzenesulfonyl)- benzenesulfonamide
amino]-ethyl}- cyclohexylmethyl ester 14.18 trans-Methyl-[2-(4- 427
trans-Methanesulfonic Piperidine piperidin-1-ylmethyl- acid
4-{2-[methyl-(4- cyclohexyl)-ethyl]-carbamic trifluoromethyl- acid
4-trifluoromethyl-phenyl phenoxycarbonyl)- ester amino]-ethyl}-
cyclohexylmethyl ester 14.19 trans-Methyl-[2-(4- 393
trans-Methanesulfonic Piperidine piperidin-1-ylmethyl- (1 Cl) acid
4-{2-[(4-chloro- cyclohexyl)-ethyl]-carbamic phenoxycarbonyl)- acid
4-chloro-phenyl ester methyl-amino]-ethyl}- cyclohexylmethyl ester
14.20 trans-[2-(4-{[Ethyl-(2- 397 trans-Methanesulfonic
Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]- (1 Cl) acid
4-{2-[(4-chloro- ethyl)-amine methyl}-cyclohexyl)-ethyl]-
phenoxycarbonyl)- methyl-carbamic acid 4- methyl-amino]-ethyl}-
chloro-phenyl ester cyclohexylmethyl ester 14.21 trans-[2-(4- 353
trans-Methanesulfonic Ethylamine Ethylaminomethyl- (1 Cl) acid
4-{2-[(4-chloro- cyclohexyl)-ethyl]-methyl- phenoxycarbonyl)-
carbamic acid 4-chloro- methyl-amino]-ethyl}- phenyl ester
cyclohexylmethyl ester 14.22 trans-[2-(4- 353 trans-Methanesulfonic
Dimethylamine Dimethylaminomethyl- (1 Cl) acid 4-{2-[(4-chloro-
cyclohexyl)-ethyl]-methyl- phenoxycarbonyl)- carbamic acid
4-chloro- methyl-amino]-ethyl}- phenyl ester cyclohexylmethyl ester
14.23 trans-(2-{4-[(Allyl-methyl- 379 trans-Methanesulfonic
N-Allyl-methyl- amino)-methyl]-cyclohexyl}- (1 Cl) acid
4-{2-[(4-chloro- amine ethyl)-methyl-carbamic acid
phenoxycarbonyl)- 4-chloro-phenyl ester methyl-amino]-ethyl}-
cyclohexylmethyl ester 14.24 trans-Methyl-[2-(4- 379
trans-Methanesulfonic Pyrrolidine pyrrolidin-1-ylmethyl- (1 Cl)
acid 4-{2-[(4-chloro- cyclohexyl)-ethyl]-carbamic phenoxycarbonyl)-
acid 4-chloro-phenyl ester methyl-amino]-ethyl}- cyclohexylmethyl
ester 14.25 trans-Methyl-[2-(4- 339 trans-Methanesulfonic
Methylamine methylaminomethyl- (1 Cl) acid 4-{2-[(4-chloro-
cyclohexyl)-ethyl]-carbamic phenoxycarbonyl)- acid 4-chloro-phenyl
ester methyl-amino]-ethyl}- cyclohexylmethyl ester 14.26
trans-4-Chloro-N-methyl-N- 413 trans-Methanesulfonic Piperidine
[2-(4-piperidin-1-ylmethyl- (1 Cl) acid 4-{2-[(4-chloro-
cyclohexyl)-ethyl]- benzenesulfonyl)- benzenesulfonamide
methyl-amino]-ethyl}- cyclohexylmethyl ester 14.27
trans-4-Chloro-N-[2-(4- 373 trans-Methanesulfonic Dimethylamine
dimethylaminomethyl- (1 Cl) acid 4-{2-[(4-chloro-
cyclohexyl)-ethyl]-N-methyl- benzenesulfonyl)- benzenesulfonamide
methyl-amino]-ethyl}- cyclohexylmethyl ester 14.28
trans-4-Chloro-N-methyl-N- 399 trans-Methanesulfonic Pyrrolidine
[2-(4-pyrrolidin-1-ylmethyl- (1 Cl) acid 4-{2-[(4-chloro-
cyclohexyl)-ethyl]- benzenesulfonyl)- benzenesulfonamide
methyl-amino]-ethyl}- cyclohexylmethyl ester 14.29
trans-N-(2-{4-[(Allyl-methyl- 399 trans-Methanesulfonic
N-Allyl-methylamine amino)-methyl]-cyclohex- yl}- (1 Cl) acid
4-{2-[(4-chloro- ethyl)-4-chloro-N-methyl- benzenesulfonyl)-
benzenesulfonamide methyl-amino]-ethyl}- cyclohexylmethyl ester
14.30 trans-4-Chloro-N-methyl-N- 359 trans-Methanesulfonic
Methylamine [2-(4-methylaminomethyl- (1 Cl) acid 4-{2-[(4-chloro-
cyclohexyl)-ethyl]- benzenesulfonyl)- benzenesulfonamide
methyl-amino]-ethyl}- cyclohexylmethyl ester 14.31
trans-4-Chloro-N-[2-(4- 417 trans-Methanesulfonic Ethyl-(2-hydroxy-
{[ethyl-(2-hydroxy-ethyl)- (1 Cl) acid 4-{2-[(4-chloro-
ethyl)-amine amino]-methyl}-cyclohexyl)- benzenesulfonyl)-
ethyl]-N-methyl- methyl-amino]-ethyl}- benzenesulfonamide
cyclohexylmethyl ester 14.32 trans-4-Chloro-N-[2-(4- 373
trans-Methanesulfonic Ethylamine ethylaminomethyl- (1 Cl) acid
4-{2-[(4-chloro- cyclohexyl)-ethyl]-N-methyl- benzenesulfonyl)-
benzenesulfonamide methyl-amino]-ethyl}- cyclohexylmethyl ester
14.33 trans-(2-{4-[(6-Hydroxy- 425 trans-Methanesulfonic 6-Hydroxy-
hexylamino)-methyl]- (1 Cl) acid 4-{2-[(4-chloro- hexylamine
cyclohexyl}-ethyl)-methyl- phenoxycarbonyl)- carbamic acid
4-chloro- methyl-amino]-ethyl}- phenyl ester cyclohexylmethyl ester
14.34 trans-(2-{4-[(5-Hydroxy- 411 trans-Methanesulfonic 5-Hydroxy-
pentylamino)-methyl]- (1 Cl) acid 4-{2-[(4-chloro- pentylamine
cyclohexyl}-ethyl)-methyl- phenoxycarbonyl)- carbamic acid
4-chloro- methyl-amino]-ethyl}- phenyl ester cyclohexylmethyl ester
14.35 trans-4-Chloro-N-(2-{4-[(5- 431 trans-Methanesulfonic
5-Hydroxy- hydroxy-pentylamino)- (1 Cl) acid 4-{2-[(4-chloro-
pentylamine methyl]-cyclohexyl}-ethyl)- benzenesulfonyl)- N-methyl-
methyl-amino]-ethyl}- benzenesulfonamide cyclohexylmethyl ester
14.36 trans-4-Chloro-N-(2-{4-[(6- 445 trans-Methanesulfonic
6-Hydroxy- hydroxy-hexylamino)- (1 Cl) acid 4-{2-[(4-chloro-
hexylamine methyl]-cyclohexyl}-ethyl)- benzenesulfonyl)- N-methyl-
methyl-amino]-ethyl}- benzenesulfonamide cyclohexylmethyl ester
14.37 trans-[2-(4-{[Ethyl-(2- 431 trans-Methanesulfonic
Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]- acid 4-{2-[methyl-(4-
ethyl)-amine methyl}-cyclohexyl)-ethyl- trifluoromethyl-
methyl-carbamic acid 4- phenoxycarbonyl)- trifluoromethyl-phenyl
ester; amino]-ethyl}- hydrochloride cyclohexylmethyl ester
Example 15
[0264] 15.1
[0265] A solution of 14.36 g (82.5 mmol) of
diethyl-azo-dicarboxylate in 50 ml of tetrahydrofuran was added
within 30 minutes to a solution of 11.4 g (75.0 mmol)
4-hydroxy-benzoic acid methyl ester, 20.65 g (78.8 mmol) of
triphenylphosphin and 13.5 g (75.0 mmol) of 4-benzyloxy-1-butanol
dissolved in 100 ml of tetrahydrofuran. The reaction mixture was
then stirred for 1 hour at room temperature, 1 g of
triphenylphosphin was added and stirring continued for 1 hour at
room temperature and for 30 minutes at reflux. The reaction mixture
was then diluted with 200 ml of hexane and filtered. The filtrate
was poured into 200 ml of a saturated potassium carbonate solution
and extracted 3 times with 200 ml of ethylacetate. The combined
ethylacetate phases were washed with brine, dried over magnesium
sulfate and evaporated under reduced pressure. The residue formed
was chromatographed on silica gel with a 98:2 v/v mixture of
dichloromethane and ether as the eluent giving 21.8 g (92.4%)
4-(4-benzyloxy-butoxy)-benzoic acid methyl ester as colorless
viscous oil, MS: 314 (M.sup.+).
[0266] 15.2
[0267] 2.7 g (8.6 mmol) of 4-(4-benzyloxy-butoxy)-benzoic acid
methyl ester were dissolved in 15.0 ml of methanol. 0.3 g palladium
on charcoal (10%) were added and the reaction mixture hydrogenated
at normal pressure until the consumption of hydrogen came to an
end. Then, it was filtered over celite and evaporated giving 1.79 g
(93%) of 4-(4-hydroxy-butoxy)-be- nzoic acid methyl ester as
colorless solid, MS: 224 (M.sup.+).
[0268] 15.3
[0269] 4.0 g (17.8 mmol) of 4-(4-hydroxy-butoxy)-benzoic acid
methyl ester were dissolved in 200.0 ml of methanol. 0.4 ml of
triethylamine and 4.0 g of rhodium on charcoal (5%) were added and
the reaction mixture hydrogenated at 10 bar hydrogen pressure and
room temperature until the consumption of hydrogen came to an end.
Then, it was filtered over celite and evaporated. The residue
formed was chromatographed on silica gel with a 95:5 v/v mixture of
dichloromethane and methanol as the eluent giving 3.1 g (75.4%) of
cis- and trans-4-(4-hydroxy-butoxy)-cyclohexanecarboxyli- c acid
methyl ester (9:1) as colorless viscous oil, MS: 231
(MH.sup.+).
[0270] 15.4
[0271] 1.6 ml of trifluoroacetic acid were slowly added to a
solution 1.45 g (6.3 mmol) cis- and
trans-4-(4-hydroxy-butoxy)-cyclohexanecarboxylic acid methyl ester
(9:1) arid of 1.9 g (7.55 mmol) benzyl 2,2,2-trichloro-acetimidate
dissolved in 5 ml of dichloromethane and 5 ml of cyclohexane. After
stirring the reaction mixture for 1 hour at room temperature, it
was filtered and the filtrate was poured into 50 ml of a saturated
sodium hydrogencarbonate solution and extracted 3 times with 50 ml
of dichloromethane. The combined dichloromethane phases were washed
with brine, dried over magnesium sulfate and evaporated under
reduced pressure. The residue formed was chromatographed on silica
gel with a 95:5 v/v mixture of dichloromethane and ether as the
eluent giving 1.0 g (49.5%) cis- and
trans-4-(4-benzyloxy-butoxy)-cyclohexanecarboxylic acid methyl
ester (9:1) as colorless viscous oil, MS: 229
[(M-91(C.sub.7H.sub.7)).sup.+], 214
[(M-106(C.sub.7H.sub.6O)).sup.+].
[0272] 15.5
[0273] 1 ml (1.6 mmol) of an 1 M solution of n-butyl lithium in
hexane were added at -78.degree. C. to a solution of 0.2 g (1.3
mmol) of diisopropylamine dissolved in 5 ml of tetrahydrofuran and
the reaction mixture was stirred for 15 minutes at this
temperature. Then, a solution of 0.480 g (1.50 mmol) cis- and
trans-4-(4-benzyloxy-butoxy)-cyclohexanec- arboxylic acid methyl
ester (9:1) dissolved in 2 ml of tetrahydrofuran were slowly added
at -78.degree. C. After stirring for 15 minutes at -78.degree. C.,
0.5 ml of methanol were added and the reaction mixture poured into
50 ml of a saturated sodium hydrogencarbonate solution and
extracted 3 times with 100 ml of ether. The combined ether phases
were washed with brine, dried over magnesium sulfate and evaporated
under reduced pressure. The residue formed, cis- and
trans-4-(4-benzyloxy-butox- y)-cyclohexanecarboxylic acid methyl
ester (58:42), was chromatographed on silica gel with a 9:1 v/v
mixture of dichloromethane and ether as the eluent giving 0.231 g
(48.1%) cis-4-(4-benzyloxy-butoxy)-cyclohexanecarbo- xylic acid
methyl ester as colorless viscous oil, MS: 229
[(M-91(C.sub.7H.sub.7)).sup.+], 214
[(M-106(C.sub.7H.sub.6O)).sup.+] and 0.152 g (31.7%)
trans-4-(4-benzyloxy-butoxy)-cyclohexanecarboxylic acid methyl
ester as colorless viscous oil, MS: 229 [(M-91(C.sub.7H.sub.7)).su-
p.+], 214 [(M-106(C.sub.7H.sub.6O)).sup.+].
[0274] 15.6
[0275] 0.730 g (18.3 mmol) of sodium hydroxide dissolved in 3 ml of
water were added to a solution of 2.48 g (7.73 mmol)
trans-4-(4-benzyloxy-butox- y)-cyclohexanecarboxylic acid methyl
ester in 25 ml of dioxane. After stirring the reaction mixture for
2 hours at reflux, it was cooled to room temperature and poured
into 100 ml of an ice/4N aqueous hydrogen chloride mixture,
evaporated in part and then extracted 3 times with 100 ml of
dichloromethane. The combined dichloromethane phases were washed
with brine, dried over magnesium sulfate and evaporated under
reduced pressure. The were thus obtained 2.25 g (95%)
trans-4-(4-benzyloxy-butoxy- )-cyclohexanecarboxylic acid as a
light brown viscous oil, MS: 305 [(M-H).sup.-].
[0276] 15.7
[0277] 2.22 g (7.25 mmol)
trans-4-(4-benzyloxy-butoxy)-cyclohexanecarboxyl- ic acid were
dissolved in 10 ml thionylchloride and the reaction mixture stirred
at reflux for 1 hour. It was then evaporated and the residue formed
dissolved in 10 ml of dichloromethane. This solution was slowly
added to a vigorously stirred mixture of 10 ml of methylamine in
water (40%) and 50 ml of dichloromethane kept at -5.degree. C.
Intense stirring was continued at room temperature for 1 hour.
Then, the phases were separated and the aqueous phase extracted
again 2 times with 50 ml of dichloromethane. The combined
dichloromethane phases were washed with sodium hydrogencarbonate
solution and brine, dried over magnesium sulfate and evaporated
under reduced pressure. The were thus obtained 2.27 g (98%)
trans-4-(4-benzyloxy-butoxy)-cyclohexanecarboxylic acid methylamide
as a light brown viscous oil, MS: 320 (MH.sup.+).
[0278] 15.8
[0279] 2.2 g (6.88 mmol)
trans-4-(4-benzyloxy-butoxy)-cyclohexanecarboxyli- c acid
methylamide dissolved in 10 ml of tetrahydrofuran were added slowly
to a suspension of 0.261 g of lithium aluminium hydride in 10 ml of
tetrahydrofuran. The reaction mixture was then stirred at
50.degree. C. for 2 hours, cooled to 0.degree. C., treated with 2 g
of ice, stirred at room temperature for 30 minutes, diluted with
ethyl acetate, dried over sodium sulfate, filtered and evaporated
to give 2.05 g (97.4%)
trans-[4-(4-benzyloxy-butoxy)-cyclohexylmethyl]-methyl-amine as
light brown viscous oil, MS: 306 (MH.sup.+).
[0280] 15.9
[0281] 2.05 g (6.71 mmol)
trans-[4-(4-benzyloxy-butoxy)-cyclohexylmethyl]-- methyl-amine were
dissolved in 15 ml of methanol, cooled to -10.degree. C. and
treated at once with 1.61 g (7.38 mmol) di-tert-butyl-dicarbonate.
Then, the reaction mixture was stirred at -10.degree. C. for 30
minutes and at room temperature for 2 hours. Subsequently, 2 ml of
water and 1 ml of triethylamine were added and the reaction mixture
evaporated under reduced pressure. It was then poured into 50 ml of
an ice/water mixture and extracted 3 times with 50 ml of
dichloromethane. The combined dichloromethane phases were dried
over magnesium sulfate and evaporated under reduced pressure. The
residue formed was chromatographed on silica gel with a 9:1 v/v
mixture of dichloromethane and ether as the eluent giving 2.15 g
(79%) trans-[4-(4-benzyloxy-butoxy)-cyclohexylmethyl]-methy-
l-carbamic acid tert-butyl ester as colorless viscous oil, MS: 406
(MH.sup.+).
[0282] 15.10
[0283] 2.15 g (5.3 mmol) of
trans-[4-(4-benzyloxy-butoxy)-cyclohexylmethyl- ]-methyl-carbamic
acid tert-butyl ester were dissolved in 20.0 ml of methanol, 0.3 g
palladium on charcoal (10%) were added and the reaction mixture
hydrogenated at normal pressure until the consumption of hydrogen
came to an end. Then, it was filtered over celite and evaporated
giving 1.60 g (95.6%) of
trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-ca- rbamic
acid tert-butyl ester as colorless viscous oil, MS: 315
(M.sup.+).
[0284] 15.11
[0285] In analogy to the sequence described in examples 1.5 and
1.6, trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic
acid tert-butyl ester was treated with hydrogen chloride solution
in methanol/water followed by acylation with
4-trifluoromethyl-benzenesulfoc- hloride giving
trans-N-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-N-methyl-4--
trifluoromethyl-benzenesulfonamide as colorless solid, MS: 424
(M.sup.+).
[0286] 15.12
[0287] In analogy to the procedure described in example 3.4,
trans-N-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-N-methyl-4-trifluoromethy-
l-benzenesulfonamide was treated with methanesulfonyl chloride to
yield trans-methanesulfonic acid
4-(4-{[methyl-(4-trifluoromethyl-benzenesulfon-
yl)-amino]-methyl}-cyclohexyloxy)-butyl ester as colorless solid,
MS: 502 (M.sup.+).
[0288] 15.13
[0289] In analogy to the sequence described in examples 1.5 and
1.6, trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic
acid tert-butyl ester was treated with hydrogen chloride solution
in methanol/water followed by acylation with
4-chloro-benzenesulfochloride giving
trans-4-chloro-N-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-N-methyl--
benzenesulfonamide as colorless viscous oil, MS: 390 (MH.sup.+,
1Cl).
[0290] 15.14
[0291] In analogy to the procedure described in example 3.4,
trans-4-chloro-N-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-N-methyl-benzene-
sulfonamide was treated with methanesulfonyl chloride to yield
trans-methanesulfonic acid
4-(4-{[(4-chloro-benzenesulfonyl)-methyl-amino-
]-methyl}-cyclohexyloxy)-butyl ester as colorless solid, MS: 468
(MH.sup.+, 1Cl).
[0292] 15.15
[0293] In analogy to the sequence described in examples 1.5 and
1.7, trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic
acid tert-butyl ester was treated with hydrogen chloride solution
in methanol/water followed by acylation with 4-chlorophenyl
chloroformate giving
trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic acid
4-chloro-phenyl ester as colorless viscous oil, MS: 370 (MH.sup.+,
1Cl).
[0294] 15.16
[0295] In analogy to the procedure described in example 3.4,
trans-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic acid
4-chloro-phenyl ester was treated with methanesulfonyl chloride to
yield trans-methanesulfonic acid
4-(4-{[(4-chloro-phenoxy-carbonyl)-methyl-amin-
o]-methyl}-cyclohexyloxy)-butyl ester as colorless viscous, MS: 448
(MH.sup.+, 1Cl).
[0296] 15.17
[0297] In analogy to the sequence described in examples 15.6, 15.7,
15.8, 15.9 and 15.10,
cis-4-(4-benzyloxy-butoxy)-cyclohexanecarboxylic acid methyl ester
(example 15.5) was hydrolysed with sodium hydroxide in
water/dioxane, then, the acid formed was converted into its
N-methyl-amide, which was reduced with lithium aluminium hydride,
treated with di-tert-butyl-dicarbonate and hydrogenated giving
cis-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic acid
tert-butyl ester as colorless viscous oil, MS: 316 (MH.sup.+).
[0298] 15.18
[0299] In analogy to the sequence described in examples 1.5 and
1.6, cis-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-methyl-carbamic
acid tert-butyl ester was treated with hydrogen chloride solution
in methanol/water followed by acylation with
4-chloro-benzenesulfochloride giving
cis-4-chloro-N-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-N-methyl-be-
nzene-sulfonamide as colorless viscous oil, MS: 300
[(M-89(C.sub.4H.sub.9O.sub.2)).sup.+, 1 Cl].
[0300] 15.19
[0301] In analogy to the procedure described in example 3.4,
cis-4-chloro-N-[4-(4-hydroxy-butoxy)-cyclohexylmethyl]-N-methyl-benzenesu-
lfonamide was treated with methanesulfonyl chloride to yield
cis-methanesulfonic acid
4-(4-{[(4-chloro-benzenesulfonyl)-methyl-amino]--
methyl}-cyclohexyloxy)-butyl ester as colorless viscous oil, MS:
468 (MH.sup.+, 1Cl).
Example 16
[0302] In analogy to the method described in example 2.1,
methanesulfonic acid esters were treated with secondary or primary
amines in methanol or N,N-dimethylacetamide to yield tertiary or
secondary amine products as listed in the following table.
8 MS Methanesulfonic acid Example Product MH.sup.+ esters Amine
16.1 trans-N-{4-[4-(Allyl-methyl- 443 trans-Methanesulfonic
N-Allyl-methyl- amino)-butoxy]- (1 Cl) acid 4-(4-{[(4-chloro- amine
cyclohexylmethyl}-4-chloro- benzenesulfonyl)- N-methyl-
methyl-amino]- benzenesulfonamide methyl}- cyclohexyloxy)-butyl
ester 16.2 cis-N-{4-[4-(Allyl-methyl- 443 cis-Methanesulfonic
N-Allyl-methyl- amino)-butoxy]- (1 Cl) acid 4-(4-{[(4-chloro- amine
cyclohexylmethyl}-4-chloro- benzenesulfonyl)- N-methyl-
methyl-amino]- benzenesulfonamide methyl}- cyclohexyloxy)-butyl
ester 16.3 trans-{4-[4-(Allyl-methy- l- 423 trans-Methanesulfonic
N-Allyl-methyl- amino)-butoxy]- (1 Cl) acid 4-(4-{[(4-chloro- amine
cyclohexylmethyl}-methyl- phenoxycarbonyl)- carbamic acid 4-chloro-
methyl-amino]- phenyl ester methyl}- cyclohexyloxy)-butyl ester
16.4 trans-N-{4-[4-(Allyl-methyl- 477 trans-Methanesulfonic
N-Allyl-methyl- amino)-butoxy]- acid 4-(4-{[methyl-(4- amine
cyclohexylmethyl}-N-methyl- trifluoromethyl- 4-trifluoromethyl-
benzenesulfonyl)- benzenesulfonamide amino]-methyl}-
cyclohexyloxy)-butyl ester 16.5 trans-N-(4-{4-[Ethyl-(2- 495
trans-Methanesulfonic Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]- acid
4-(4-{[methyl-(4- ethyl)-amine butoxyl}-cyclohexylmethyl)-
trifluoromethyl- N-methyl-4-trifluoromethyl- benzenesulfonyl)-
benzenesulfonamide amino]-methyl}- cyclohexyloxy)-butyl ester
Example 17
[0303] 17.1
[0304] To a dry ice-cooled solution of 4 g (11.8 mmol)
trans-3-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-(E)-a-
crylic acid ethyl ester (example 11.10) in 50 ml of tetrahydrofuran
was added at -75.degree. C. to -63.degree. C. within 15 minutes
23.6 ml (28.3 mmol) of a solution of diisobutyl-aluminium hydride
(1.2M in toluene). After the reaction mixture was stirred for 2
hours at -75.degree. C., 20 ml of methanol was added at -75.degree.
C. to this mixture. The temperature was raised to 20.degree. C. and
20 ml 1N hydrogen chloride solution was added. The reaction mixture
was partitioned between ether, 1N hydrogen chloride solution,
sodium hydrogen carbonate solution and water. The organic layer was
dried over magnesium sulfate and concentrated under reduced
pressure giving 3.61 g of
trans-{2-[4-(3-hydroxy-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid tert-butyl ester as slightly yellow viscous oil, MS: 298
(MH.sup.+).
[0305] 17.2
[0306] A solution of 200 mg (0.672 mmol)
trans{2-[4-(3-hydroxy-(E)-propeny-
l)-cyclohexyl]-ethyl}-methyl-carbamic acid tert-butyl ester in 2 ml
4M hydrogen chloride solution in dioxane was stirred for 30 minutes
at room temperature. The reaction mixture was then concentrated
under reduced pressure. The crude HCl-salt was triturated two times
with dry ether and the crystalline product then dried for several
hours at 45.degree. C. and 15 mbar to give 155 mg (98.6%) of pure
trans-3-[4-(2-methylamino-ethyl)-c- yclohexyl]-(E)-prop-2-en-1-ol
HCl-salt as colorless cristalls, MS: 198 (MH.sup.+).
[0307] 17.3
[0308] To a solution of 150 mg (0.642 mmol)
trans-3-[4-(2-methylamino-ethy- l)-cyclohexyl]-(E)-prop-2-en-1-ol
HCl-salt and 125 mg (0.654 mmol) 4-chlorophenyl chloroformate in
1.5 ml of dichloromethane was added at room temperature 0.55 ml
(3.21 mmol) diisopropyl ethyl amine. The reaction mixture was
stirred for 1 hour at room temperature, taken up in ether and
washed with iN hydrogen chloride solution and water. The organic
layer was dried over magnesium sulfate and concentrated under
reduced pressure and the residue then chromatographed on silica gel
with a 2:1 v/v mixture of hexane and ethylacetate as the eluent
giving 146 mg (64.7%)
trans-{2-[4-(3-hydroxy-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-ca-
rbamic acid 4-chloro-phenyl ester, MS: 369 (MNH.sub.4.sup.+,
1Cl).
[0309] 17.4
[0310] To an ice-cooled solution of 135 mg (0.384 mmol)
trans-{2-[4-(3-hydroxy-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid 4-chloro-phenyl ester and 0.089 ml (0.77 mmol) 2,6-lutidine in
2 ml of dichloromethane was added under stirring 0.033 ml (0.422
mmol) methane sulfonylchloride. The reaction mixture was stirred
for 20 hours at room temperature, then taken up in ether and washed
with 1N hydrogen chloride solution and water. The organic layer was
dried over magnesium sulfate and concentrated under reduced
pressure and the residue then chromatographed on silica gel with a
4:1 v/v mixture of hexane and ethylacetate as the eluent giving 90
mg (63.4%) of
trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid 4-chloro-phenyl ester as colorless viscous oil, MS: 370
(MH.sup.+, 2Cl).
[0311] 17.5
[0312] In analogy to the sequence described in examples 17.1 and
17.2,
trans-3-{4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-cyclohexyl}-(E,Z)--
acrylic acid methyl ester (E:Z=9:1) (example 7.1) was reduced with
diisobutyl-aluminiurn hydride followed by the removal of the
protective tert-butoxycarbonyl function with 4M hydrogen chloride
solution in dioxane to yield
trans-3-(4-methylaminomethyl-cyclohexyl)-(E,Z)-prop-2-en- -1-ol
(E:Z=9:1) as colorless viscous oil, which was used without further
characterization.
[0313] 17.6
[0314] In analogy to the sequence described in examples 1.6 and
17.4,
trans-3-(4-methyl-aminomethyl-cyclohexyl)-(E,Z)-prop-2-en-1-ol
(E:Z=9:1) was reacted with 4-trifluoromethyl-benzene sulfochloride
and potassium carbonate (dissolved in the minimal amount of water)
in tetrahydrofuran to yield
trans-N-[4-(3-hydroxy-(E,Z)-propenyl)-cyclohexyl-methyl]-N-methy-
l-4-trifluoromethyl-benzenesulfonamide (E:Z=9:1) as colorless
viscous oil, MS: 409 (MNH.sub.4.sup.+). It was subsequently treated
with methane sulfonylchloride and 2,6-lutidine in dichloromethane
to yield
trans-N-[4-(3-chloro-(E,Z)-propenyl)-cyclohexyl-methyl]-N-methyl-4-triflu-
oromethyl-benzenesulfonamide (E:Z=9:1) as colorless viscous oil,
MS: 410 (MH.sup.+, 1Cl).
[0315] 17.7
[0316] In analogy to the sequence described in examples 17.3 and
17.4,
trans-3-[4-(2-methylamino-ethyl)-cyclohexyl]-(E)-prop-2-en-1-ol HCl
was reacted with 4-trifluoro-methyl-benzene sulfochloride in
dichloromethane in the presence of diisopropyl ethyl amine followed
by treatment with methane sulfonylchloride and 2,6-lutidine in
dichloromethane to yield
trans-N-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifl-
uoromethyl-benzenesulfonamide as colorless viscous oil, MS: 424
(MH.sup.+, 1Cl).
Example 18
[0317] 18.1
[0318] In analogy to the method described in example 12.1,
trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid 4-chloro-phenyl ester was reacted with piperidine in
N,N-dimethylacetamide at room temperature to yield
trans-methyl-{2-[4-(3-piperidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-car-
bamic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 419
(MH.sup.+, 1Cl).
[0319] 18.2
[0320] In analogy to the method described in example 12.1,
trans-N-[4-(3-chloro-(E,Z)-propenyl)-cyclohexylmethyl]-N-methyl-4-trifluo-
romethyl-benzenesulfonamide (E:Z=9:1) was reacted with piperidine
in N,N-dimethylacetamide at room temperature to yield
trans-N-methyl-N-[4-(3-piperidin-1-yl-(E,Z)-propenyl)-cyclohexylmethyl]-4-
-trifluoromethyl-benzenesulfonamide (E:Z=9:1) as yellow solid, MS:
459 (MH.sup.+).
[0321] 18.3
[0322] In analogy to the method described in example 12.1,
trans-N-[4-(3-chloro-(E,Z)-propenyl)-cyclohexylmethyl]-N-methyl-4-trifluo-
romethyl-benzenesulfonamide (E:Z=9:1) was reacted with
ethyl-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at room
temperature to yield
trans-N-(4-{3-[ethyl-(2-hydroxy-ethyl)-amino]-(E,Z)--
propenyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide
(E:Z=9:1) as colorless solid, MS: 463 (MH.sup.+).
[0323] 18.4
[0324] In analogy to the method described in example 12.1,
trans-N-{2-
[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl--
benzenesulfonamide was reacted with N-allyl-methyl-amine in
N,N-dimethylacetamide at room temperature to yield
trans-N-(2-{4-[3-(allyl-methyl-amino)-(E)-propenyl]-cyclohexyl}-ethyl)-N--
methyl-4-trifluoromethyl-benzenesulfonamide as colorless viscous
oil, MS: 459 (MH.sup.+).
[0325] 18.5
[0326] In analogy to the method described in example 12.1,
trans-N-{2-
[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifluoromethyl--
benzenesulfonamide was reacted with dimethyl-amine in
N,N-dimethylacetamide at room temperature to yield
trans-N-{2-[4-(3-dimethylamino-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl--
4-trifluoromethyl-benzenesulfonamide as colorless viscous oil, MS:
433 (MH.sup.+).
[0327] 18.6
[0328] In analogy to the method described in example 12.1,
trans-N-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifl-
uoromethyl-benzenesulfonamide was reacted with piperidine in
N,N-dimethylacetamide at room temperature to yield
trans-N-methyl-N-{2-[4-(3-piperidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-
-4-trifluoromethyl-benzenesulfonamide as colorless viscous oil, MS:
473 (MH.sup.+).
[0329] 18.7
[0330] In analogy to the method described in example 12.1,
trans-N-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-trifl-
uoromethyl-benzenesulfonamide was reacted with ethylamine in
N,N-dimethylacetamide at room temperature to yield
trans-N-{2-[4-(3-ethylamino-(E)-propenyl)-cyclohexyl]-ethyl}-N-methyl-4-t-
rifluoromethyl-benzenesulfonamide as colorless viscous oil, MS: 433
(MH.sup.+).
[0331] 18.8
[0332] In analogy to the method described in example 12.1,
trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid 4-chloro-phenyl ester was reacted with N-allyl-methyl-amine in
N,N-dimethylacetamide at room temperature to yield
trans-(2-{4-[3-(allyl-methyl-amino)-(E)-propenyl]-cyclohexyl}-ethyl)-meth-
yl-carbamic acid 4-chloro-phenyl ester as light yellow viscous oil,
MS: 405 (MH.sup.+, 1Cl).
[0333] 18.9
[0334] In analogy to the method described in example 12.1,
trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid 4-chloro-phenyl ester was reacted with dimethylamine in
N,N-dimethylacetamide at room temperature to yield
trans-{2-[4-(3-dimethylamino-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carb-
amic acid 4-chloro-phenyl ester as light yellow viscous oil, MS:
379 (MH.sup.+, 1Cl).
[0335] 18.10
[0336] In analogy to the method described in example 12.1,
trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid 4-chloro-phenyl ester was reacted with ethylamine in
N,N-dimethylacetamide at room temperature to yield
trans-{2-[4-(3-ethylamino-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbami-
c acid 4-chloro-phenyl ester as light yellow viscous oil, MS: 379
(MH.sup.+, 1Cl).
[0337] 18.11
[0338] In analogy to the method described in example 12.1,
trans-{2-[4-(3-chloro-(E)-propenyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid 4-chloro-phenyl ester was reacted with pyrrolidine in
N,N-dimethylacetamide at room temperature to yield
trans-methyl-{2-[4-(3-pyrrolidin-1-yl-(E)-propenyl)-cyclohexyl]-ethyl}-ca-
rbamic acid 4-chloro-phenyl ester as yellow viscous oil, MS: 405
(MH.sup.+, 1Cl).
Example 19
[0339] 19.1
[0340] A heterogenous mixture of 1.59 g (4.35 mmol) of
trans-N-(4-hydroxymethyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-ben-
zenesulfonamide (example 5.1), 5.0 ml of dichloromethane, 37.2 g
(174 mmol) of (E)-1,4-dibromo-2-butene, 15.0 ml of 50% w/w sodium
hydroxide solution and 0.44 g (1.3 mmol) of tetrabutylammonium
hydrogensulfate was stirred vigorously at room temperature for 3
days. Afterwards, 30 ml of deionized water were added and the
reaction mixture was extracted with 3 portions of n-hexane. rhe
combined organic phases were then washed with water (3 times), 1 N
aqueous hydrochloric acid solution, saturated aqueous sodium
bicarbonate solution, brine and were finally dried over magnesium
sulfate and evaporated under reduced pressure. The excess of the
(E)-1,4-dibromo-2-butene was distilled off under reduced pressure
(0.5 torr) at 100.degree. C. The residue thus obtained was
chromatographed on silicagel with a 3:1 v/v mixture of
dichloromethane and hexane as the eluent giving 1.51 g (69.6 %) of
trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-
-trifluoromethyl-benzenesulfonamide as pale yellow solid, MS: 515
(MNH.sub.4.sup.+, 1Br).
[0341] 19.2
[0342] In analogy to the method described in example 19.1,
trans-N-(4-hydroxymethyl-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-ben-
zenesulfonamide (example 5.1) was reacted with 1,4-dibromo-butane
in dichloromethane and aqueous sodium hydroxide solution in the
presence of tetrabutylammonium hydrogensulfate to yield
trans-N-[4-(4-bromo-butoxymet-
hyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide
as colorless solid, MS: 500 (MH.sup.+, 1Br).
[0343] 19.3
[0344] In analogy to the method described in example 19.1,
trans-(4-hydroxymethyl-cyclohexylmethyl)-methyl-carbamic acid
4-chloro-phenyl ester (example 5.3) was reacted with
1,4-dibromo-butane in dichloromethane and aqueous sodium hydroxide
solution in the presence of tetrabutylammonium hydrogensulfate to
yield trans-[4-(4-bromo-butoxyme-
thyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester
as colorless solid, MS: 446 (MH.sup.+, 1 Cl, 1Br).
Example 20
[0345] 20.1
[0346] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-
-trifluoromethyl-benzenesulfonamide was reacted with piperidine in
N,N-dimethylacetamide at room temperature to yield
trans-N-methyl-N-[4-(4-piperidin-1-yl-(E)-but-2-enyloxymethyl)-cyclohexyl-
methyl]-4-trifluoromethyl-benzenesulfonamide as yellow solid, MS:
503 (MH.sup.+).
[0347] 20.2
[0348] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-
-trifluoromethyl-benzenesulfonamide was reacted with pyrrolidine in
N,N-dimethylacetamide at room temperature to yield
trans-N-methyl-N-[4-(4-pyrrolidin-1-yl-(E)-but-2-enyloxymethyl)-cyclohexy-
lmethyl]-4-trifluoromethyl-benzenesulfonamide as light yellow
solid, MS: 489 (MH.sup.+).
[0349] 20.3
[0350] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-
-trifluoromethyl-benzenesulfonamide was reacted with
ethyl-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at room
temperature to yield
trans-N-(4-{4-[ethyl-(2-hydroxy-ethyl)-amino]-(E)-bu-
t-2-enyloxymethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesul-
fonamide as light yellow solid, MS: 507 (MH.sup.+).
[0351] 20.4
[0352] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-
-trifluoromethyl-benzenesulfonamide was reacted with
N-allyl-methyl-amine in N,N-dimethylacetamide at room temperature
to yield
trans-N-{4-[4-(allyl-methyl-amino)-(E)-but-2-enyloxymethyl]-cyclohexylmet-
hyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as light yellow
viscous oil, MS: 489 (MH.sup.+).
[0353] 20.5
[0354] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-
-trifluoromethyl-benzenesulfonamide was reacted with
bis-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at room
temperature to yield
trans-N-(4-{4-[bis-(2-hydroxy-ethyl)-amino]-(E)-but-2-enyloxymet-
hyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide
as light yellow solid, MS: 523 (MH.sup.+).
[0355] 20.6
[0356] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-
-trifluoromethyl-benzenesulfonamide was reacted with methylamine in
N,N-dimethylacetamide at room temperature to yield
trans-N-methyl-N-[4-(4-methylamino-(E)-but-2-enyloxymethyl)-cyclohexylmet-
hyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid,
MS: 449 (MH.sup.+).
[0357] 20.7
[0358] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-
-trifluoromethyl-benzenesulfonamide was reacted with
(2-hydroxy-ethyl)-methyl-amine in N,N-dimethylacetamide at room
temperature to yield
trans-N-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-(E)-b-
ut-2-enyloxymethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesu-
lfonamide as light yellow solid, MS: 493 (MH.sup.+).
[0359] 20.8
[0360] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-
-trifluoromethyl-benzenesulfonamide was reacted with morpholine in
N,N-dimethylacetamide at room temperature to yield
trans-N-methyl-N-[4-(4-morpholin-4-yl-(E)-but-2-enyloxymethyl)-cyclohexyl-
methyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid,
MS: 505 (MH.sup.+).
[0361] 20.9
[0362] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-
-trifluoromethyl-benzenesulfonamide was reacted with
1-tert-butoxycarbonyl piperazine in N,N-dimethylacetamide at room
temperature followed by treatment with trifluoroacetic acid at room
temperature to yield
trans-N-methyl-N-[4-(4-piperazin-1-yl-(E)-but-2-enyloxymethyl)-cyclohexyl-
methyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid,
MS: 504 (MH.sup.+).
[0363] 20.10
[0364] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluorom-
ethyl-benzenesulfonamide was reacted with piperidine in
N,N-dimethylacetamide at room temperature to yield
trans-N-methyl-N-[4-(4-piperidin-1-yl-butoxymethyl)-cyclohexylmethyl]-4-t-
rifluoromethyl-benzenesulfonamide as light yellow solid, MS: 505
(MH.sup.+).
[0365] 20.11
[0366] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluorom-
ethyl-benzenesulfonamide was reacted with
(2-hydroxy-ethyl)-methyl-amine in N,N-dimethylacetamide at room
temperature to yield
trans-N-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-butoxymethyl}-cyclohexylme-
thyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless
solid, MS: 495 (MH.sup.+).
[0367] 20.12
[0368] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluorom-
ethyl-benzenesulfonamide was reacted with pyrrolidine in
N,N-dimethylacetamide at room temperature to yield
trans-N-methyl-N-[4-(4-pyrrolidin-1-yl-butoxymethyl)-cyclohexylmethyl]-4--
trifluoromethyl-benzenesulfonamide as yellow solid, MS: 491
(MH.sup.+).
[0369] 20.13
[0370] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluorom-
ethyl-benzenesulfonamide was reacted with N-allyl-methyl-amine in
N,N-dimethylacetamide at room temperature to yield
trans-N-{4-[4-(allyl-methyl-amino)-butoxymethyl]-cyclohexylmethyl}-N-meth-
yl-4-trifluoromethyl-benzenesulfonamide as yellow solid, MS: 491
(MH.sup.+).
[0371] 20.14
[0372] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluorom-
ethyl-benzenesulfonamide was reacted with
ethyl-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at room
temperature to yield
trans-N-(4-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butoxymethyl}-cyclohexylmet-
hyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless
solid, MS: 509 (MH.sup.+).
[0373] 20.15
[0374] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluorom-
ethyl-benzenesulfonamide was reacted with dimethyl-amine in
N,N-dimethylacetamide at room temperature to yield
trans-N-[4-(4-dimethylamino-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-tr-
ifluoromethyl-benzenesulfonamide as colorless solid, MS: 465
(MH.sup.+).
[0375] 20.16
[0376] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluorom-
ethyl-benzenesulfonamide was reacted with
bis-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at room
temperature to yield
trans-N-(4-{4-[bis-(2-hydroxy-ethyl)-amino]-butoxymethyl}-cyclohexylmethy-
l)-N-methyl-4-trifluoromethyl-benzenesulfonamideas colorless solid,
MS: 525 (MH.sup.+).
[0377] 20.17
[0378] In analogy to the method described in example 12.1,
trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluorom-
ethyl-benzenesulfonamide was reacted with
(S)-2-hydroxymethyl-pyrrolidine in N,N-dimethylacetamide at room
temperature to yield
trans-N-{4-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-butoxymethyl]-cyclohe-
xylmethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as
colorless solid, MS: 521 (MH.sup.+).
[0379] 20.18
[0380] In analogy to the method described in example 12.1,
trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic
acid 4-chloro-phenyl ester was reacted with pyrrolidine in
N,N-dimethylacetamide at 50.degree. C. for 2 hours to yield
trans-methyl-[4-(4-pyrrolidin-1-yl-butoxymethyl)-cyclohexylmethyl]-carbam-
ic acid 4-chloro-phenyl ester as colorless viscous oil, MS: 437
(MH.sup.+, 1Cl).
[0381] 20.19
[0382] In analogy to the method described in example 12.1,
trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic
acid 4-chloro-phenyl ester was reacted with piperidine in
N,N-dimethylacetamide at 50.degree. C. for 2 hours to yield
trans-methyl-[4-(4-piperidin-1-yl-butoxymethyl)-cyclohexylmethyl]-carbami-
c acid 4-chloro-phenyl ester as colorless viscous oil, MS: 451
(MH.sup.+, 1Cl).
[0383] 20.20
[0384] In analogy to the method described in example 12.1,
trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic
acid 4-chloro-phenyl ester was reacted with
(2-hydroxy-ethyl)-methyl-amine in N,N-dimethylacetamide at
50.degree. C. for 3 hours to yield
trans-(4-{4-[(2-hydroxy-ethyl)-methyl-amino]-butoxymethyl}-cyclohexylmeth-
yl)-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous
oil, MS: 441 (MH.sup.+, 1Cl).
[0385] 20.21
[0386] In analogy to the method described in example 12.1,
trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic
acid 4-chloro-phenyl ester was reacted with
bis-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at 50.degree.
C. for 3 hours to yield
trans-(4-{4-[bis-(2-hydroxy-ethyl)-amino]-butoxymethyl}-cyclohexylmethyl)-
-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous
oil, MS: 471 (MH.sup.+, 1Cl).
[0387] 20.22
[0388] In analogy to the method described in example 12.1,
trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic
acid 4-chloro-phenyl ester was reacted with dimethylamine in
N,N-dimethylacetamide at 50.degree. C. for 3 hours to yield
trans-[4-(4-dimethylamino-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic
acid 4-chloro-phenyl ester as light yellow viscous oil, MS: 411
(MH.sup.+, 1Cl).
[0389] 20.23
[0390] In analogy to the method described in example 12.1,
trans-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-methyl-carbamic
acid 4-chloro-phenyl ester was reacted with
ethyl-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at
50.degree. C. for 3 hours to yield
trans-(4-{4-[ethyl-(2-hydroxy-ethyl)-amino]-butoxymethyl}-cyclohexylmethy-
l)-methyl-carbamic acid 4-chloro-phenyl ester as colorless viscous
oil, MS: 455 (MH.sup.+, 1Cl).
Example 21
[0391] 21.1
[0392] A solution of 12.64 g (36.17 mmol) of trans-methanesulfonic
acid
4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl
ester (example 13.1) and 4.51 g (92 mmol) of sodium cyanide in 100
ml of dimethylformamide was stirred for 6 hours at 110.degree. C.
The reaction mixture was then taken up in ether and washed four
times with water. The ether layer was dried over sodium sulfate and
concentrated under reduced pressure, giving 10.14 g of crude
trans-[2-(4-cyanomethyl-cyclohexyl)-eth- yl]-methyl-carbamic acid
tert-butyl ester as a colorless oil, which was used without further
purification.
[0393] 21.2
[0394] 90.4 ml (108.5 mmol) of diisobutylaluminium hydride (1.2M in
toluene) were dropped under stirring and dry-ice-cooling at
-70.degree. C. to -78.degree. C., within 20 minutes, to a solution
of 10.14 g (36.17 mmol) of crude
trans-[2-(4-cyanomethyl-cyclohexyl)-ethyl]-methyl-carbamic acid
tert-butyl ester in 90 ml of methylenechloride. The reaction
mixture was stirred for 4 hours at -70.degree. C. to -78.degree. C.
To this reaction mixture was then carefully added 40 ml of 4N HCl
(in water), within 10 minutes at -78.degree. C. The temperature was
slowly raised to room temperature. After stirring for 10 minutes at
room temperature, the reaction mixture was partitioned between
ether, 1N HCl and water. The ether-phase was dried over sodium
sulfate and concentrated under reduced pressure giving 10.14 g of
crude trans-methyl-{2-[4-(2-oxo-ethyl)-cyclohe-
xyl]-ethyl}-carbamic acid tert-butyl ester as colorless oil, which
was used without further purification.
[0395] 21.3
[0396] 800 mg (21 mmol) of lithium aluminium hydride were added
within 10 minutes to a solution of 4.5 g (15.87 mmol) crude
trans-methyl-{2-[4-(2-o- xo-ethyl)-cyclohexyl]-ethyl}-carbamic acid
tert-butyl ester in 40 ml of tetrahydrofuran. After stirring for 3
hours at room temperature, 40 ml of brine was dropped carefully
into the reaction mixture. The reaction mixture was stirred for
another 20 minutes at room temperature and then partitioned between
ether, 1N HCl and water. After drying of the ether phase over
sodium sulfate and concentration under reduced pressure, 4.26 g of
trans-{2-[4-(2-hydroxy-ethyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid tert-butyl ester was obtained, which was used without further
purification.
[0397] 21.4
[0398] In analogy to the procedures described in examples 11.13,
11.14 and 11.15,
trans-{2-[4-(2-hydroxy-ethyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid tert-butyl ester was reacted with methanesulfonyl chloride to
give trans-methanesulfonic acid
2-{4-[2-(tert-butoxycarbonyl-methyl-amino)-eth-
yl]-cydohexyl}-ethyl ester, which was subsequently treated with 4N
hydrogen chloride in dioxan to yield trans-methanesulfonic acid
2-[4-(2-methylamino-ethyl)-cyclohexyl]-ethyl ester HCl salt as
colorless solid; treatment of the trans-methanesulfonic acid
2-[4-(2-methylamino-ethyl)-cyclohexyl]-ethyl ester HCl salt with
4-chloro-benzene sulphonyl chloride then yielded
trans-methanesulfonic acid
2-(4-{2-[(4-chloro-benzenesulfonyl)-methyl-amino]-ethyl}-cyclohexyl)-
-ethyl ester as colorless oil, MS: 438 (MH.sup.+, 1Cl).
[0399] 21.5
[0400] In analogy to the procedures described in example 11.15,
trans-methanesulfonic acid
2-[4-(2-methylamino-ethyl)-cyclohexyl]-ethyl ester HCl salt was
treated with 4-chloro-phenyl-chloroformate to yield
trans-methanesulfonic acid
2-(4-{2-[(4-chloro-phenoxycarbonyl)-methyl-ami-
no]-ethyl}-cyclohexyl)-ethyl ester as colorless. oil, MS: 418
(MH.sup.+, 1Cl).
Example 22
[0401] In analogy to the method described in example 12.1,
methanesulfonic acid esters were reacted with secondary or primary
amines in N,N-dimethylacetamide to yield tertiary or secondary
amine products as listed in the following table:
9 MS Methanesulfonic acid Example Product MH.sup.+ esters Amine
22.1 trans-Methyl-{2-[4-(2- 407 trans-Methanesulfonic Piperidine
piperidin-1-yl-ethyl)- (1 Cl) acid 2-(4-{2-[(4-
cyclohexyl]-ethyl}-carbamic chloro- acid 4-chloro-phenyl ester
phenoxycarbonyl)- methyl-amino]-ethyl}- cyclohexyl)-ethyl ester
22.2 trans-4-Chloro-N-methyl-N- 427 trans-Methanesulfonic
Piperidine {2-[4-(2-piperidin-1-yl- (1 Cl) acid 2-(4-{2-[(4-
ethyl)-cyclohexyl]-ethyl}- chloro- benzenesulfonamide
benzenesulfonyl)- methyl-amino]-ethyl}- cyclohexyl)-ethyl ester
22.3 trans-(2-{4-[2-(Allyl-methyl- 393 trans-Methanesulfonic
N-Allyl-methyl- amino)-ethyl]-cyclohexyl}- (1 Cl) acid 2-(4-{2-[(4-
amine ethyl)-methyl-carbamic acid chloro- 4-chloro-phenyl ester
phenoxycarbonyl)- methyl-amino]-ethyl}- cyclohexyl)-ethyl ester
22.4 trans-{2-[4-(2- 367 trans-Methanesulfonic Dimethylamine
Dimethylamino-ethyl)- (1 Cl) acid 2-(4-{2-[(4-
cyclohexyl]-ethyl}-methyl- chloro- carbamic acid 4-chloro-
phenoxycarbonyl)- phenyl ester methyl-amino]-ethyl}-
cyclohexyl)-ethyl ester 22.5 trans-{2-[4-(2-Ethylamino- 367
trans-Methanesulfonic Ethylamine ethyl)-cyclohexyl]-ethyl}- (1 Cl)
acid 2-(4-{2-[(4- methyl-carbamic acid 4- chloro- chloro-phenyl
ester phenoxycarbonyl)- methyl-amino]-ethyl}- cyclohexyl)-ethyl
ester 22.6 trans-[2-(4-{2-[Ethyl-(2- 411 trans-Methanesulfonic
Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]- (1 Cl) acid 2-(4-{2-[(4-
ethyl)-amine ethyl}-cyclohexyl)-ethyl]- chloro- methyl-carbamic
acid 4- phenoxycarbonyl)- chloro-phenyl ester methyl-amino]-ethyl}-
cyclohexyl)-ethyl ester 22.7 trans-Methyl-{2-[4-(2- 353
trans-Methanesulfonic Methylamine methylamino-ethyl)- (1 Cl) acid
2-(4-{2-[(4- cyclohexyl]-ethyl}-carbamic chloro- acid
4-chloro-phenyl ester phenoxycarbonyl)- methyl-amino]-ethyl}-
cyclohexyl)-ethyl ester 22.8 trans-(2-{4-[2-(6-Hydroxy- 439
trans-Methanesulfonic 6-Hydroxy- hexylamino)-ethyl]- (1 Cl) acid
2-(4-{2-[(4- hexylamine cyclohexyl}-ethyl)-methyl- chloro- carbamic
acid 4-chloro- phenoxycarbonyl)- phenyl ester methyl-amino]-ethyl}-
cyclohexyl)-ethyl ester 22.9 trans-(2-{4-[2-(5-Hydroxy- 425
trans-Methanesulfonic 5-Hydroxy- pentylamino)-ethyl]- (1 Cl) acid
2-(4-{2-[(4- pentylamine cyclohexyl}-ethyl)-methyl- chloro-
carbamic acid 4-chloro- phenoxycarbonyl)- phenyl ester
methyl-amino]-ethyl}- cyclohexyl)-ethyl ester 22.10
trans-4-Chloro-N-{2-[4-(2- 387 trans-Methanesulfonic Dimethylamine
dimethylamino-ethyl)- (1 Cl) acid 2-(4-{2-[(4-
cyclohexyl]-ethyl}-N-methyl- chloro- benzenesulfonamide
benzenesulfonyl)- methyl-amino]-ethyl}- cyclohexyl)-ethyl ester
22.11 trans-N-(2-{4-[2-(Allyl- 413 trans-Methanesulfonic
N-Allyl-methyl- methyl-amino)-ethyl]- (1 Cl) acid 2-(4-{2-[(4-
amine cyclohexyl}-ethyl)-4-chloro- chloro- N-methyl-
benzenesulfonyl)- benzenesulfonamide methyl-amino]-ethyl}-
cyclohexyl)-ethyl ester 22.12 trans-4-Chloro-N-methyl-N- 373
trans-Methanesulfonic Methylamine {2-[4-(2-methylamino-ethyl)- (1
Cl) acid 2-(4-{2-[(4- cyclohexyl]-ethyl}- chloro-
benzenesulfonamide benzenesulfonyl)- methyl-amino]-ethyl}-
cyclohexyl)-ethyl ester 22.13 trans-4-Chloro-N-{2-[4-(2- 387
trans-Methanesulfonic Ethylamine ethylamino-ethyl)- (1 Cl) acid
2-(4-{2-[(4- cyclohexyl]-ethyl}-N-methyl- chloro-
benzenesulfonamide benzenesulfonyl)- methyl-amino]-ethyl}-
cyclohexyl)-ethyl ester 22.14 trans-4-Chloro-N-[2-(4-{2- 431
trans-Methanesulfonic Ethyl-(2-hydroxy- [ethyl-(2-hydroxy-ethyl)-
(1 Cl) acid 2-(4-{2-[(4- ethyl)-amine amino]-ethyl}-cyclohexyl)-
chloro- ethyl]-N-methyl- benzenesulfonyl)- benzenesulfonamide
methyl-amino]-ethyl}- cyclohexyl)-ethyl ester
Example 23
[0402] 23.1
[0403] A solution of 257.6 g (982 mmol) triphenylphosphine in 1 l
methylenechloride was treated with 162.8 g (491 mmol)
tetrabromomethane (the reaction was heated up to reflux and was
then cooled with an ice bath) and after 40 minutes at room
temperature treated with 157.4 ml (1129 mmol) triethylamine (the
reaction was heated up to reflux and became dark violet). After
cooling (0.degree. C.), 62.7 g (245.5 mmol) of
trans-(4-formyl-cyclohexylmethyl)-methyl-carbamic acid tert-butyl
ester (example 1.2) in 600 ml methylenechloride were added during
20 minutes. The solution was stirred for 20 hours at room
temperature, evaporated and filtered through silica gel
(deactivated with hexane/Et.sub.3N) with a 99:1 to 4:1 v/v mixture
of hexane and ether as eluent to yield 61.5 g (61%) of
trans-[4-(2,2-dibromo-vinyl)-cyclohexylmethyl]-methyl-carbamic acid
tert-butyl ester as brown oil, MS: 409 (M, 2Br).
[0404] 23.2
[0405] A solution of 32.9 g (80 mmol) of
trans-[4-(2,2-dibromo-vinyl)-cycl- ohexylmethyl]-methyl-carbamic
acid tert-butyl ester in 640 ml tetrahydrofuran was treated at
-78.degree. C. with 105 ml (168 mmol) of n-butyl-lithium (ca 1.6 M
in hexane). After 2 hours at this temperature, 24 g (800 mmol) of
paraformaldehyde were added. The reaction mixture was warmed up to
room temperature for 3 hours and after 0.5 hours at this
temperature extracted with water/ether (3.times.). The organic
phases were washed with aqueous 10% NaCl, dried over sodium sulfate
and evaporated. Purification by flash-chromatography on silica gel
(hexane/EtOAc 9:1 to 2:1) yielded 12.1 g (54%)
oftrans-[4-(3-hydroxy-prop-
-1-ynyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester as
orange viscous oil, MS: 282 (MH.sup.+).
[0406] 23.3
[0407] A solution of 8.16 g (29 mmol) of
trans-[4-(3-hydroxy-prop-1-ynyl)--
cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester in 230 ml
methylenechloride was treated at 0.degree. C. with 2.48 ml (31.9
mmol) of methanesulforiylchloride and 5.05 ml (43.5 mmol) of
2,6-lutidine. The reaction mixture was stirred over night to room
temperature. The reaction was cooled (0.degree. C.) and treated
again with 0.68 ml (8.7 mmol) of methanesulfonylchloride and 1.68
ml (14.5 mmol) of 2,6-lutidine and stirred for 24 hours. Water (35
ml) was added and the reaction was stirred for 5 minutes. After
extraction with aqueous saturated NaHCO.sub.3/ether (3.times.), the
organic phases were washed with aqueous 10% NaCl, dried over sodium
sulfate and evaporated to yield 12.5 g of crude
trans-methanesulfonic acid
3-{4-[(tert-butoxycarbonyl-methyl-amino)-
-methyl]-cyclohexyl}-prop-2-ynyl ester as brown oil, MS: 360
(MH.sup.+).
[0408] 23.4
[0409] A solution of 12.5 g (corresponds to 28.9 mmol) of crude
trans-methanesulfonic acid
3-{4-[(tert-butoxycarbonyl-methyl-amino)-methy-
l]-cyclohexyl}-prop-2-ynyl ester in 160 ml methylenechloride was
treated at 0.degree. C. with 78 ml of trifluoroacetic acid (for 30
minutes). After 15 minutes at this temperature, the reaction was
evaporated, redissolved in toluene and evaporated (4.times.) to
give 23.12 g of crude trans-methanesulfonic acid
3-(4-methylaminomethyl-cyclohexyl)-prop-2-ynyl ester
trifluoro-acetate as dark brown viscous oil, MS: 260
(MH.sup.+).
[0410] 23.5
[0411] A solution of 7.70 g (corresponds to 9.63 mmol) of crude
trans-methanesulfonic acid
3-(4-methylaminomethyl-cyclohexyl)-prop-2-ynyl ester
trifluoro-acetate in 60 ml methylenechloride was treated at
0.degree. C. with 1.61 ml (11.56 mmol) 4-chlorophenylchloroformate
and then during 3 minutes with 8.25 ml (48.17 mmol; 5 equivalents)
of Huenig's base. The reaction was stirred 45 hours at room
temperature and extracted with aqueous 10% KHSO.sub.4/ether
(3.times.). The organic phases were washed with aqueous 10% NaCl
and dried over sodium sulfate to yield 5.3 g of crude
trans-methanesulfonic acid 3-(4-{[(4-chloro-phenoxyc-
arbonyl)-methyl-amino]-methyl}-cyclohexyl)-prop-2-ynyl ester as
dark brown oil, MS: 414 (MH.sup.+, 1Cl).
[0412] 23.6
[0413] In analogy to example 23.5, trans-methanesulfonic acid
3-(4-methylaminomethyl-cyclohexyl)-prop-2-ynyl ester
trifluoro-acetate and 4-trifluoromethylbenzenesulfonyl chloride
gave trans-methanesulfonic acid
3-(4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyc-
lohexyl)-prop-2-ynyl ester as dark brown oil, MS: 468
(MH.sup.+).
[0414] 23.7
[0415] In analogy to example 23.5, trans-methanesulfonic acid
3-(4-methylaminomethyl-cyclohexyl)-prop-2-ynyl ester
trifluoro-acetate and 4-trifluorophenylchloroformate gave
trans-methanesulfonic acid
3-(4-{[methyl-(4-trifluoromethyl-phenoxycarbonyl)-amino]-methyl}-cyclohex-
yl)-prop-2-ynyl ester as dark brown oil, MS: 448 (MH.sup.+).
Example 24
[0416] 24.1
[0417] A solution of 222 mg (corresponds to 0.40 mmol) of crude
trans-methanesulfonic acid
3-(4-{[(4-chloro-phenoxycarbonyl)-methyl-amino-
]-methyl}-cyclohexyl)-prop-2-ynyl ester in 4 ml of methanol was
cooled to 0.degree. C., treated with 0.34 ml (4 mmol) of piperidine
and stirred over night at room temperature. The solvent was
evaporated and the residue extracted with aqueous saturated
NaHCO.sub.3/ether (3.times.). The organic phase was dried with
sodium sulfate, filtered and evaporated. Purification by flash
column chromatography on silica gel (methylenechloride /methanol
99:1 to 98:2) gave 92 mg (57%) of pure
trans-methyl-[4-(3-piperidin-1-yl-prop-1-ynyl)-cyclohexylmethyl]-carbamic
acid 4-chloro-phenyl ester as light yellow viscous oil, MS: 403
(MH.sup.+, 1Cl). The following compounds were prepared from the
corresponding mesylates and secondary amines:
10 MS Methanesulfonic acid Example Product MH.sup.+ esters Amine
24.2 trans-(4-{3-[Ethyl-(2- 407 trans-Methanesulfonic
Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]-pro- p- (1 Cl) acid
3-(4-{[(4-chloro- ethyl)-amine 1-ynyl}-cyclohexylmethyl)-
phenoxycarbonyl)- methyl-carbamic acid 4- methyl-amino]-
chloro-phenyl ester methyl}-cyclohexyl)- prop-2-ynyl ester 24.3
trans-N-Methyl-N-[4-(3- 457 trans-Methanesulfonic Piperidine
piperidin-1-yl-prop-1-ynyl)- acid 3-(4-{[methyl-(4-
cyclohexylmethyl]-4- trifluoromethyl- trifluoromethyl-
benzenesulfonyl)- benzenesulfonamide amino]-methyl}-
cyclohexyl)-prop-2- ynyl ester 24.4 trans-N-(4-{3-[Ethyl-(2- 461
trans-Methanesulfonic Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]-prop-
acid 3-(4-{[methyl-(4- ethyl)-amine 1-ynyl}-cyclohexylmethyl)-N-
trifluoromethyl- methyl-4-trifluoromethyl- benzenesulfonyl)-
benzenesulfonamide amino]-methyl}- cyclohexyl)-prop-2- ynyl ester
24.5 trans-Methyl-[4-(3- 437 trans-Methanesulfonic Piperidine
piperidin-1-yl-prop-1-ynyl)- acid 3-(4-{[methyl-(4-
cyclohexylmethyl]-carbamic trifluoromethyl- acid
4-trifluoromethyl-phenyl phenoxycarbonyl)- ester amino]-methyl}-
cyclohexyl)-prop-2- ynyl ester 24.6 trans-(4-{3-[Ethyl-(2- 441
trans-Methanesulfonic Ethyl-(2-hydroxy- hydroxy-ethyl)-amino]-prop-
acid 3-(4-{[methyl-(4- ethyl)-amine 1-ynyl}-cyclohexylmethyl)-
trifluoromethyl- methyl-carbamic acid 4- phenoxycarbonyl)-
trifluoromethyl-phenyl ester amino]-methyl}- cyclohexyl)-prop-2-
ynyl ester
Example 25
[0418] 25.1
[0419] To an ice-cooled solution of 200 mg (0.46 mmol)
trans-methanesulfonic acid
3-(4-{2-[(4-chloro-phenoxycarbonyl)-methyl-ami-
no]-ethyl}-cyclohexyl)-propyl ester (example 11.16) and 126 mg
(1.85 mmol) of imidazole in 3.5 ml of N,N-dimethylformamide was
added at 0.degree. C. 30.3 mg (0.69 mmol) of sodium hydride (55% in
oil). The reaction mixture was then stirred for 4 hours at room
temperature. After quenching with ammonium chloride solution, the
reaction mixture was partitioned between water and ether. The
combined ether phases were washed with brine, dried over magnesium
sulfate and evaporated under reduced pressure. The residue formed
was chromatographed on silica gel with a 95:5 v/v mixture of
ethylacetate and methanol as the eluent giving 103 mg (55%) of pure
trans-{2-[4-(3-imidazol-1-yl-propyl)-cyclohexyl]-ethyl}-methyl-carbamic
acid 4-chloro-phenyl ester as colorless viscous oil, MS: 404
(MH.sup.+).
[0420] 25.2
[0421] In analogy to the procedure described in example 25.1,
trans-methanesulfonic acid
4-{2-[methyl-(4-trifluoromethyl-benzenesulfony-
l)-amino]-ethyl}-cyclohexylmethyl ester (example 13.2) was reacted
with imidazole in N,N-dimethylformamide in the presence of sodium
hydride to yield
trans-N-[2-(4-imidazol-1-ylmethyl-cyclohexyl)-ethyl]-N-methyl-4-tri-
fluoromethyl-benzenesulfonamide as colorless viscous oil, MS: 430
(MH.sup.+).
[0422] 25.3
[0423] In analogy to the procedure described in example 25.1,
trans-methanesulfonic acid
4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-
-amino]-methyl}-cyclohexylmethyl ester (example 5.2) was reacted
with imidazole in N,N-dimethylformamide in the presence of sodium
hydride to yield
trans-N-(4-imidazol-1-ylmethyl-cyclohexylmethyl)-N-methyl-4-trifluo-
romethyl-benzenesulfonamide as colorless solid, MS: 416
(MH.sup.+).
[0424] 25.4
[0425] In analogy to the procedure described in example 25.1,
trans-N-[4-(3-chloro-(E,Z)-propenyl)-cyclohexylmethyl]-N-methyl-4-trifluo-
romethyl-benzenesulfonamide (E:Z=9:1) (example 17.6) was reacted
with imidazole in N,N-dimethylformamide in the presence of sodium
hydride to yield
trans-N-[4-(3-imidazol-1-yl-(E,Z)-propenyl)-cydohexylmethyl]-N-meth-
yl-4-trifluoromethyl-benzenesulfonamide (E:Z=9:1) as yellowish
solid, MS: 442 (MH.sup.+).
[0426] 25.5
[0427] In analogy to the procedure described in example 25.1,
trans-methanesulfonic acid
2-(4-{[methyl-(4-trifluoromethyl-benzenesulfon-
yl)-amino]-methyl}-cyclohexyl)-ethyl ester (example 9.10) was
reacted with imidazole in N,N-dimethylformamide in the presence of
sodium hydride to yield
trans-N-[4-(2-imidazol-1-yl-ethyl)-cyclohexylmethyl]-N-methyl-4-tri-
fluoromethyl-benzenesulfonamide as yellowish solid, MS: 430
(MH.sup.+).
[0428] 25.6
[0429] In analogy to the procedure described in example 25.1,
trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-
-trifluoromethyl-benzenesulfonamide (example 19.1) was reacted with
imidazole in N,N-dimethylformamide in the presence of sodium
hydride to yield
trans-N-[4-(4-imidazol-1-yl-(E)-but-2-enyloxymethyl)-cyclohexylmeth-
yl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as yellowish
solid, MS: 486 (MH.sup.+).
Example 26
[0430] 26.1
[0431] A solution of 77 mg (0.17 mmol)
trans-N-methyl-N-[4-(4-methylamino--
(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfon-
amide (example 20.6), 0.044 g (0.34 mmol) of
4-chloro-2-methyl-pyrimidine [Ger. Offen. (1990), DE3905364 A1] and
0.06 ml (0.34 mmol) N-ethyl-diisopropylamine in 1 ml of
N,N-dimethylformamide was stirred for 2 hours at 80.degree. C. The
reaction mixture was then cooled to room temperature, poured into
30 ml of ice-water and extracted 3 times with 10 ml of ether. The
combined ether phases were washed with brine, dried over magnesium
sulfate and evaporated under reduced pressure. The residue formed
was chromatographed on silica gel with a 95:5:1 v/v/v mixture of
dichloromethane, methanol and saturated aqueous ammonia as the
eluent giving 55 mg (59%)
trans-N-methyl-N-(4-{4-[methyl-(2-methyl-pyrimidin-4-y-
l)-amino]-(E)-but-2-enyloxymethyl}-cyclohexylmethyl)-4-trifluoromethyl-ben-
zenesulfonamide as yellowish viscous oil, MS: 541 (MH.sup.+).
Example 27
[0432] A mixture of 702 mg (1.63 mmol)
[trans-(2-(4-{[ethyl-(2-hydroxy-eth-
yl)-amino]-methyl}-cyclohexyl)-ethyl]-methyl-carbamic acid
4-trifluoromethyl-phenyl ester, 256.6 mg (1.8 mmol) of phthalic
anhydride and 335 mg (3.54 mmol) of Hydrogen peroxide-Urea adduct
in 7 ml of CH.sub.2Cl.sub.2, was stirred for two days at RT.
Additional 100 mg (1.06 mmol) of Hydrogen peroxide-Urea adduct and
50 mg (0.34 mmol) of phthalic anhydride were added to the reaction
mixture. After another 3 h at RT, 10 ml of aqueous saturated
NaHCO.sub.3 were added. After stirring for 10 min at RT, the
reaction-mixture was taken up in ether/water. The ether phase was
dried and evaporated under reduced pressure. The residue was
chromatographed on silica gel with a 9:1 v/v mixture of
methylenchloide/methanol as eluent giving 449 mg (62%) of pure
rac-trans-ethyl(2-hydroxyethyl)({4-[2-(methyl{[4-(trifluoromethyl)phenoxy-
]carbonyl}amino) ethyl]cyclohexyl}methyl)ammoniumolate, MS: 447
(MH.sup.+).
Example 28
[0433] 28.1
[0434] A solution of 10.6 g ( corresponds to 5.1 g, 14.2 mmol) of
crude trans-methanesulfonic acid
3-{4-[(tert-butoxycarbonyl-methyl-amino)-methy-
l]-cyclohexyl}-prop-2-ynyl ester in 210 ml ethanol was treated at
0.degree. C. with 18.1 ml (142 mmol) of 7.8 N HCl in ethanol. After
4 hours at room temperature, the reaction was evaporated to give
12.06 g of crude
trans-[4-(3-chloro-prop-1-ynyl)-cyclohexylmethyl]-methyl-amine. HCl
as brown semisolid, MS: 199 (MH.sup.+, 1Cl).
[0435] 28.2
[0436] A solution of 12.06 g (corresponds to 14.2 mmol) of crude
trans-[4-(3-chloro-prop-1-ynyl)-cyclohexylmethyl]-methyl-amine.HCl
in 100 ml methylenechloride was treated at 0.degree. C. with 2.97 g
(17.0 mmol) 4-fluorophenylchloroformate and then during 3 minutes
with 12.1 ml (70.9 mmol; 5 equivalents) of Huenig's base. The
reaction was stirred 2 hours at room temperature and extracted with
aqueous 10% KHSO.sub.4/ether (3.times.). The organic phases were
washed with aqueous 10% NaCl and dried over sodium sulfate to yield
5.53 g (98%) of
trans-[4-(3-chloro-prop-1-ynyl)-cyclohexylmethyl]-methyl-carbamic
acid 4-fluoro-phenyl ester as a brown oil, MS: 338 (MH.sup.+,
1Cl).
Example 29
[0437] 29.1
[0438] A solution of 250 mg (0.63 mmol) of
trans-[4-(3-chloro-prop-1-ynyl)- cyclohexylmethyl]-methyl-carbamic
acid 4-fluoro-phenyl ester with a catalytic amount of NaI in 7 ml
of methanol was treated with 0.65 ml (6.3 mmol) of
N-methylpropylamine and stirred over night at room temperature. The
solvent was evaporated and the residue extracted with aqueous
saturated NaHCO.sub.3 /ether (3.times.). The organic phase was
dried with sodium sulfate, filtered and evaporated. Purification by
flash column chromatography on silica gel
(methylenechloride/methanol 98:2) gave 218 mg (93%) of pure
trans-methyl-{4-[3-(methyl-propyl-amino)-prop-1-ynyl]-cy-
clohexylmethyl}-carbamic acid 4-fluoro-phenyl ester as light brown
oil, MS: 375 (MH.sup.+).
[0439] The following compounds were prepared from the corresponding
chloride and secondary amines:
11 MS Example Product MH.sup.+ Chloride Amine 29.2
trans-(4-{3-[Ethyl-(2- 391 trans-[4-(3-chloro- Ethyl-(2-hydroxy-
hydroxy-ethyl)-amino]-prop- prop-1-ynyl)- ethyl)-amine
1-ynyl}-cyclohexylmethyl)- cyclohexylmethyl]- methyl-carbamic acid
4- methyl-carbamic acid fluoro-phenyl ester 4-fluoro-phenyl ester
29.3 trans-[4-(3-Dimethylamino- 347 trans-[4-(3-chloro-
Dimethylamine prop-1-ynyl)- prop-1-ynyl)- cyclohexylmethyl]-methyl-
cyclohexylmethyl]- carbamic acid 4-fluoro- methyl-carbamic acid
phenyl ester 4-fluoro-phenyl ester
EXAMPLES
Example A
[0440] Film coated tablets containing the following ingredients can
be manufactured in a conventional manner:
12 Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg
200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous
60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch
glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel
Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl cellulose
3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg
2.6 mg Iron oxyde (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6
mg
[0441] The active ingredient is sieved and mixed with
microcristalline cellulose and the mixture is granulated with a
solution of polyvinylpyrrolidon in water. The granulate is mixed
with sodium starch glycolate and magesiumstearate and compressed to
yield kernels of 120 or 350 mg respectively. The kernels are
lacquered with an aqueous solution/suspension of the above
mentioned film coat.
Example B
[0442] Capsules containing the following ingredients can be
manufactured in a conventional manner:
13 Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose
150.0 mg Maize starch 20.0 mg Talc 5.0 mg
[0443] The components are sieved and mixed and filled into capsules
of size 2.
Example C
[0444] Injection solutions can have the following composition:
14 Compound of formula (I) 3.0 mg Polyethylene Glycol 400 150.0 mg
Acetic Acid q.s. ad pH 5.0 Water for injection solutions ad 1.0
ml
[0445] The active ingredient is dissolved in a mixture of
Polyethylene Glycol 400 and water for injection (part). The pH is
adjusted to 5.0 by Acetic Acid. The volume is adjusted to 1.0 ml by
addition of the residual amount of water. The solution is filtered,
filled into vials using an appropriate overage and sterilized.
Example D
[0446] Soft gelatin capsules containing the following ingredients
can be manufactured in a conventional manner:
15 Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0
mg Hydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant
oils 34.0 mg Soya bean oil 110.0 mg Weight of capsule contents
165.0 mg Gelatin capsule Gelatin 75.0 mg Glycerol 85% 32.0 mg
Karion 83 8.0 mg (dry matter) Titan dioxide 0.4 mg Iron oxide
yellow 1.1 mg
[0447] The active ingredient is dissolved in a warm melting of the
other ingredients and the mixture is filled into soft gelatin
capsules of appropriate size. The filled soft gelatin capsules are
treated according to the usual procedures.
Example E
[0448] Sachets containing the following ingredients can be
manufactured in a conventional manner:
16 Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mg
Microcristalline cellulose (AVICEL PH 102) 1400.0 mg Sodium
carboxymethyl cellulose 14.0 mg Polyvinylpyrrolidon K 30 10.0 mg
Magnesiumstearate 10.0 mg Flavoring additives 1.0 mg
[0449] The active ingredient is mixed with lactose,
microcristalline cellulose and sodium carboxymethyl cellulose and
granulated with a mixture of polyvinylpyrrolidon in water. The
granulate is mixed with magnesiumstearate and the flavouring
additives and filled into sachets.
* * * * *