U.S. patent application number 10/010058 was filed with the patent office on 2002-10-03 for novel piperazine derivatives.
Invention is credited to Adams, David Reginald, Bentley, Jonathan Mark, Davidson, James Edward Paul, Dawson, Claire Elizabeth, George, Ashley Roger, Mansell, Howard Langham, Mattei, Patrizio, Mizrahi, Jacques, Nettekoven, Matthias Heinrich, Pratt, Robert Mark, Roever, Stephan, Roffey, Jonathan Richard Anthony, Specklin, Jean-Luc, Stalder, Henri, Wilkinson, Kerry.
Application Number | 20020143020 10/010058 |
Document ID | / |
Family ID | 9905222 |
Filed Date | 2002-10-03 |
United States Patent
Application |
20020143020 |
Kind Code |
A1 |
Adams, David Reginald ; et
al. |
October 3, 2002 |
Novel piperazine derivatives
Abstract
The present invention is a chemical compound of formula (I) 1 or
a pharmaceutically acceptable salts, solvates and esters thereof,
wherein R.sup.1 to R.sup.4, A.sup.1, A.sup.2 m and n are as
described in the specification.
Inventors: |
Adams, David Reginald;
(Winnersh, GB) ; Bentley, Jonathan Mark;
(Winnersh, GB) ; Davidson, James Edward Paul;
(Winnersh, GB) ; Dawson, Claire Elizabeth;
(Winnersh, GB) ; George, Ashley Roger; (Winnersh,
GB) ; Mansell, Howard Langham; (Winnersh, GB)
; Mattei, Patrizio; (Riehen, CH) ; Mizrahi,
Jacques; (Basle, CH) ; Nettekoven, Matthias
Heinrich; (Grenzach-Wyhlen, DE) ; Pratt, Robert
Mark; (Winnersh, GB) ; Roever, Stephan;
(Inzlingen, DE) ; Roffey, Jonathan Richard Anthony;
(Winnersh, GB) ; Specklin, Jean-Luc;
(Kembs-Schaferhof, FR) ; Stalder, Henri; (Basle,
CH) ; Wilkinson, Kerry; (Winnersh, GB) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.
PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
|
Family ID: |
9905222 |
Appl. No.: |
10/010058 |
Filed: |
December 7, 2001 |
Current U.S.
Class: |
514/254.1 ;
514/255.01; 544/374; 544/389 |
Current CPC
Class: |
A61P 1/14 20180101; A61P
25/30 20180101; A61P 1/04 20180101; C07D 213/30 20130101; A61P
25/06 20180101; C07D 307/12 20130101; A61P 25/14 20180101; A61P
9/00 20180101; A61P 25/28 20180101; C07D 295/21 20130101; A61P
11/00 20180101; A61P 25/08 20180101; C07D 207/325 20130101; A61P
25/32 20180101; A61P 25/22 20180101; C07D 413/04 20130101; A61P
25/20 20180101; C07D 295/205 20130101; C07D 261/08 20130101; A61P
3/04 20180101; A61P 25/00 20180101; C07D 333/16 20130101; C07D
307/42 20130101; A61P 13/02 20180101; A61P 15/10 20180101; A61P
3/10 20180101; A61P 25/24 20180101; C07D 213/64 20130101; A61P
25/04 20180101; A61P 25/18 20180101; C07D 213/643 20130101; C07D
285/14 20130101; A61P 17/02 20180101; A61P 43/00 20180101; C07D
277/24 20130101; A61P 15/00 20180101; A61P 9/10 20180101; A61P 3/06
20180101 |
Class at
Publication: |
514/254.1 ;
514/255.01; 544/374; 544/389 |
International
Class: |
A61K 031/496; A61K
031/495; C07D 45/02; C07D 241/04 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 15, 2000 |
GB |
0030710.8 |
Claims
1. A compound of formula (I): 11wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen,
alkyl, cycloalkyl, aryl and aralkyl, or R.sup.1 and R.sup.2,
together with the carbon atom to which they are attached, form an
unsubstituted 3- to 8-membered carbocyclic ring or a 3 to 8
membered carbocyclic ring which is substituted with alkyl; R.sup.3
and R.sup.4 are independently selected from the group consisting of
hydrogen, alkyl, cycloalkyl, aryl and aralkyl; A.sup.1 is oxygen or
sulfur, wherein in case A.sup.1 is oxygen and A.sup.2 is
unsubstituted phenyl one of R.sup.1, R.sup.2, R.sup.3 and R.sup.4
is not hydrogen; A.sup.2 is unsubstituted aryl, unsubstituted
heteroaryl or unsubstituted cycloalkyl or aryl, heteroaryl or
cycloalkyl each substituted with at least one substituent
independently selected from the group consisting of halogen, alkyl,
cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy,
cyano, nitro, amino, alkoxycarbonyl, cycloalkoxycarbonyl,
aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl,
carbamoyl, cycloalkoxy, alkylsulfonyloxy, arylsulfonyloxy,
carbamoyloxy, heteroarylalkoxy, alkenyloxy,
tetrahydrofuranylalkoxy, alkynyloxy and cycloalkylalkoxy, or
wherein said alkyl, said cycloalkyl, said aryl, said aralkyl, said
alkoxy, said aralkoxy, said aryloxy, said alkoxycarbonyl, said
cycloalkoxycarbonyl, said aryloxycarbonyl, said aralkoxycarbonyl,
said heteroaryloxycarbonyl, said cycloalkoxy, said
alkylsulfonyloxy, said arylsulfonyloxy, said heteroarylalkoxy, said
alkenyloxy, said tetrahydrofuranylalkoxy, said alkynyloxy and said
cycloalkylalkoxy are substituted with betweenone and three
substituents independently selected from the group consisting of
alkyl, alkoxy, halogen, nitro, oxo, trifluoromethyl, alkoxy
substituted with between one and three halogen, thiophenyl, aryl,
amino, alkylcarbonyl and aryloxy, or two substituents of aryl,
heteroaryl or cycloalkyl form, together with the carbon atoms to
which they are attached, an unsubstituted 5- to 7-membered
carbocyclic ring or a substituted 5- to 7-membered carbocyclic ring
with at least one substituent independently selected from the group
consisting of alkyl, alkoxy and halogen; n is 1 or 2; and m is zero
or 1; or a pharmaceutically acceptable salt, solvate or ester
thereof; provided that 2-methyl-1-piperazinecarboxylic acid
(4-nitrophenyl)methyl ester and 1-piperazinecarboxylic acid
(4-(trifluoromethyl)phenyl)methyl ester are excluded.
2. A compound of formula I according to claim 1, wherein A.sup.2 is
unsubstituted aryl, unsubstituted heteroaryl, unsubstituted
cycloalkyl or aryl, heteroaryl, cycloalkyl each substituted with at
least one substituent independently selected from the group
consisting of halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy,
aralkoxy, aryloxy, hydroxy, cyano, nitro, amino, alkoxycarbonyl,
cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,
heteroaryloxycarbonyl and carbamoyl, or wherein said alkyl, said
cycloalkyl, said aryl, said aralkyl, said alkoxy, said aralkoxy,
said aryloxy, said alkoxycarbonyl, said cycloalkoxycarbonyl, said
aryloxycarbonyl, said aralkoxycarbonyl and said
heteroaryloxycarbonyl are substituted with between one and three
substituents independently selected from the group consisting of
alkyl, alkoxy, halogen and nitro, or two substituents of aryl,
heteroaryl or cycloalkyl form together with the carbon atoms to
which they are attached an unsubstituted 5- to 7-membered
carbocyclic ring or a 5- to 7-membered ring substituted with alkyl,
alkoxy or halogen; and m is zero.
3. A compound according to claim 1, wherein R.sup.3 and R.sup.4 are
independently selected from hydrogen or alkyl.
4. A compound according to claim 3, wherein R.sup.3 and R.sup.4 are
hydrogen.
5. A compound according to claim 3, wherein R.sup.3 and R.sup.4 are
methyl.
6. A compound according to claim 3, wherein one of R.sup.3 and
R.sup.4 is methyl or ethyl and the other of R.sup.3 and R.sup.4 is
hydrogen.
7. A compound according to of claim 1, wherein A.sup.1 is
oxygen.
8. A compound according to of claim 1, wherein A.sup.1 is
sulfur.
9. A compound according to claim 1, wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydrogen, alkyl
and aryl.
10. A compound according to claim 1, wherein A.sup.2 is
unsubstituted phenyl or phenyl substituted with between one and
four substituents independently selected from the group consisting
of halogen, alkoxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy,
alkynyloxy and cycloalkylalkoxy, or wherein said alkoxy, said
heteroarylalkoxy or said alkenyloxy are substituted with between
one and three substituents independently selected from alkyl or
halogen.
11. A compound according to claim 1, wherein A.sup.2 is
unsubstituted phenyl or phenyl substituted with between one and
three substituents independently selected from the group consisting
of fluoro, chloro, difluoromethoxy, propoxy,
3,5-dimethyl-isoxazol-4-ylmethoxy, 2-propenyloxy, 5-pentyloxy,
cyclopropylmethoxy, 2-propynyloxy and NH(R')--C(O)--O--, wherein R'
is selected from the group consisting of isopropyl, benzyl and
tert.-butyl.
12. A compound according to claim 1, wherein n is 1.
13. A compound according to claim 12, wherein m is zero.
14. A compound of formula I wherein the compound is selected from
the group consisting of: S-4-[(2-propylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate; S-4-[(benzylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
S-4-[(tert-butylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate; 2,6-difluoro-4-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
(R)-4-difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylate;
(R)-2,6-difluoro-4-propoxybenzyl 2-methylpiperazine-1-carboxylate;
cis-2,6-dimethyl-piperazine-1-carboxyli- c acid
4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester;
2-fluoro-5-(2-propenyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate- ;
(R)-2-fluoro-5-pentyloxybenzyl 2-methylpiperazine-1-carboxylate;
5-(cyclopropylmethyl)oxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carb- oxylate;
(R)-2-ethyl-piperazine-1-carboxylic acid 4-cyclopropylmethoxy-2,6-
-difluoro-benzyl ester; (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-propoxy-benzyl ester;
(R)-2-ethyl-piperazine-1-carboxylic acid
4-allyloxy-2,6-difluoro-benzyl ester;
(R)-2-ethyl-piperazine-1-carbo- xylic acid
2,6-difluoro-4-prop-2-ynyloxy-benzyl ester;
(R)-2-ethyl-piperazine-1-carboxylic acid
4-cyclopropylmethoxy-2-chloro-6-- fluoro-benzyl ester;
(R)-2-ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-propoxy-benzyl ester;
(R)-2-ethyl-piperazine-1-carbox- ylic acid
4-allyloxy-2-chloro-6-fluoro-benzyl ester; and
(R)-2-ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-prop-2-ynylo- xy-benzyl ester.
15. A compound of formula I wherein the compound is
S-4-[(2-propylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate.
16. A compound of formula I wherein the compound is
S-4-[(benzylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate.
17. A compound of formula I wherein the compound is
S-4-[(tert-butylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate.
18. A compound of formula I wherein the compound is
2,6-difluoro-4-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxy- late.
19. A compound of formula I wherein the compound is
(R)-4-difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylate.
20. A compound of formula I wherein the compound is
(R)-2,6-difluoro-4-propoxybenzyl
2-methylpiperazine-1-carboxylate.
21. A compound of formula I wherein the compound is
cis-2,6-dimethyl-piperazine-1-carboxylic acid
4-(3,5-dimethyl-isoxazol-4-- ylmethoxy)-2,6-difluoro-benzyl
ester.
22. A compound of formula I wherein the compound is
2-fluoro-5-(2-propenyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate- .
23. A compound of formula I wherein the compound is
(R)-2-fluoro-5-pentyloxybenzyl
2-methylpiperazine-1-carboxylate.
24. A compound of formula I wherein the compound is
5-(cyclopropylmethyl)oxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carb- oxylate.
25. A compound of formula I wherein the compound is
(R)-2-ethyl-piperazine-1-carboxylic acid
4-cyclopropylmethoxy-2,6-difluor- o-benzyl ester.
26. A compound of formula I wherein the compound is
(R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-propoxy-benzyl ester.
27. A compound of formula I wherein the compound is
(R)-2-ethyl-piperazine-1-carboxylic acid
4-allyloxy-2,6-difluoro-benzyl ester.
28. A compound of formula I wherein the compound is
(R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-prop-2-ynyloxy-be- nzyl ester.
29. A compound of formula I wherein the compound is
(R)-2-ethyl-piperazine-1-carboxylic acid
4-cyclopropylmethoxy-2-chloro-6-- fluoro-benzyl ester.
30. A compound of formula I wherein the compound is
(R)-2-ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-propoxy-benz- yl ester.
31. A compound of formula I wherein the compound is
(R)-2-ethyl-piperazine-1-carboxylic acid
4-allyloxy-2-chloro-6-fluoro-ben- zyl ester.
32. A compound of formula I wherein the compound is
(R)-2-ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-prop-2-ynylo- xy-benzyl ester.
33. A process for the preparation of a compound comprising
deprotecting a compound of formula 12wherein R.sup.1 to R.sup.4,
A.sup.1, A.sup.2, m and n are defined as in claim 1 and (P) is a
nitrogen protecting group.
34. A method of treating a disease alleviated by modulation of
5-HT2 receptors comprising administering a therapeutically
effective amount of a compound of formula I or a pharmaceutically
acceptable salt, solvate or ester thereof to a patient in need of
such treatment.
35. A pharmaceutical composition comprising a therapeutically
effective amount of compound of formula I or a pharmaceutically
acceptable salt, solvate or ester thereof and a therapeutically
inert carrier.
36. The pharmaceutical composition of claim 35 further comprising a
therapeutically effective amount of a lipase inhibitor.
37. The pharmaceutical composition of claim 36 wherein said lipase
inhibitor is orlistat.
38. A method of treating obesity comprising administering a
therapeutically effective amount of a compound of formula I or a
pharmaceutically acceptable salt, solvate or ester thereof to a
patient in need of such treatment.
39. The method of claim 38 further comprising the administration of
a therapeutically effective amount of a lipase inhibitor to the
patient.
40. The method of treatment of claim 39 wherein said lipase
inhibitor is orlistat.
41. A method of treatment of diabetes mellitus, Type I diabetes,
Type II diabetes, diabetes, diabetes secondary to pancreatic
disease, diabetes related to steroid use, Type III diabetes,
hyperglycaemia, diabetic complication and insulin resistance.
diabetes comprising administration of a therapeutically effective
amount of the compound of formula I or a pharmaceutically effective
salt solvate or ester thereof to a patient in need of such
treatment.
42. A method of treatment of type II diabetes comprises
administering a therapeutically effective amount of a compound of
formula I or a pharmaceutically acceptable salt, solvate or ester
thereof to a patient in need of such treatment.
43. The method of treatment of claim 42, further comprising
administration of a therapeutically effective amount of a lipase
inhibitor to the patient.
44. The method of claim 43 wherein said lipase inhibitor is
orlistat.
Description
BACKGROUND
[0001] It has been recognized that obesity is a disease process
influenced by environmental factors in which the traditional weight
loss methods of dieting and exercise need to be supplemented by
therapeutic products (S. Parker, "Obesity: Trends and Treatments",
Scrip Reports, PJB Publications Ltd, 1996).
[0002] Whether someone is classified as overweight or obese is
generally determined on the basis of their body mass index (BMI)
which is calculated by dividing body weight (kg) by height squared
(m.sup.2). Thus, the units of BMI are kg/m.sup.2 and it is possible
to calculate the BMI range associated with minimum mortality in
each decade of life. Overweight is defined as a BMI in the range
25-30 kg/m . Obesity is a BMI greater than 30 kg/m There are
problems with this definition in that it does not take into account
the proportion of body mass that is muscle in relation to fat
(adipose tissue). To account for this, obesity can also be defined
on the basis of body fat content: greater than 25% in males and
greater than 30% in females.
[0003] As the BMI increases there is an increased risk of death
from a variety of causes that is independent of other risk factors.
The most common diseases associated with obesity are cardiovascular
disease (particularly hypertension), diabetes (obesity aggravates
the development of diabetes), gall bladder disease (particularly
cancer) and reproductive diseases. Research has shown that even a
modest reduction in body weight can correspond to a significant
reduction in the risk of developing coronary heart disease.
[0004] Compounds marketed as anti-obesity agents include Orlistat
(XENICAL.RTM.) and Sibutramine. Orlistat (a lipase inhibitor)
inhibits fat absorption directly and tends to produce a high
incidence of unpleasant (though relatively harmless) side-effects
such as diarrhoea. Sibutramine (a mixed 5-HT/noradrenaline
re-uptake inhibitor) can increase blood pressure and heart rate in
some patients. The serotonin releaser/re-uptake inhibitors
fenfluramine (Pondimin.RTM.) and dexfenfluramine (Redux.TM.) have
been reported to decrease food intake and body weight over a
prolonged period (greater than 6 months). However, both products
were withdrawn after reports of preliminary evidence of heart valve
abnormalities associated with their use. There is therefore a need
for the development of a safer anti-obesity agent.
[0005] The non-selective 5-HT.sub.2C receptor agonists/partial
agonists m-chlorophenylpiperazine (mCPP) and
trifluoromethylphenylpiperazine (TFMPP) have been shown to reduce
food intake in rats (G. A. Kennett and G. Curzon, Psychopharmacol.,
1988, 96, 93-100; G. A. Kennett, C. T. Dourish and G. Curzon, Eur.
J. Pharmacol., 1987, 141, 429-435) and to accelerate the appearance
of the behavioural satiety sequence (S. J. Kitchener and C. T.
Dourish, Psychopharmacol., 1994, 113, 369-377). Recent findings
from studies with mCPP in normal human volunteers and obese
subjects have also shown decreases in food intake. Thus, a single
dose of mCPP decreased food intake in female volunteers (A. E. S.
Walsh et al., Psychopharmacol., 1994, 116, 120-122) and decreased
the appetite and body weight of obese male and female subjects
during subchronic treatment for a 14 day period (P. A. Sargeant et
al., Psychopharmacol., 1997, 133, 309-312). The anorectic action of
mCPP is absent in 5-HT.sub.2C receptor knockout mutant mice (L. H.
Tecott et al., Nature, 1995, 374, 542-546) and is antagonised by
the 5-HT.sub.2C receptor antagonist SB-242084 in rats (G. A.
Kennett et al., Neuropharmacol., 1997, 36, 609-620). It seems
therefore that mCPP decreases food intake via an agonist action at
the 5-HT.sub.2C receptor.
[0006] Other compounds which have been proposed as 5-HT.sub.2C
receptor agonists for use in the treatment of obesity include the
substituted 1-aminoethyl indoles disclosed in EP-A-0655440.
CA-2132887 and CA-2153937 disclose that tricyclic
1-aminoethylpyrrole derivatives and tricyclic 1-aminoethyl pyrazole
derivatives bind to 5-HT.sub.2C receptors and may be used in the
treatment of obesity. WO-A-98/30548 discloses aminoalkylindazole
compounds as 5-HT.sub.2C agonists for the treatment of CNS diseases
and appetite regulation disorders. WO 0035922 discloses
2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)ones as
5HT.sub.2C agonists. Aralkyloxycarbonyl-substituted piperazine
derivatives have been repeatedly described as nitrogen-protected
piperazine synthetic intermediates (e.g. Org. Lett., 2000, 2(8),
1049-1051.
SUMMARY
[0007] The present invention is a new piperazine derivative,
processes and intermediates for its preparation, to pharmaceutical
compositions containing the compound of the invention and to a
method of treatment using the compound. The active compound of the
present invention is useful in treating obesity and other
disorders.
[0008] The invention is a compound of formula I or a
pharmaceutically acceptable salt, solvate or ester therof 2
[0009] wherein
[0010] R.sup.1 and R.sup.2 are independently selected from
hydrogen, alkyl, cycloalkyl, aryl and aralkyl or R.sup.1 and
R.sup.2 together with the carbon atom to which they are attached
form an unsubstituted 3- to 8-membered carbocyclic ring or a 3- to
8-membered ring which is substituted with alkyl;
[0011] R.sup.3 and R.sup.4 are independently selected from
hydrogen, alkyl, cycloalkyl, aryl and aralkyl;
[0012] A.sup.1 is oxygen or sulfur, wherein in case A.sup.1 is
oxygen and A.sup.2 is unsubstituted phenyl one of R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 is not hydrogen
[0013] A.sup.2 is unsubstituted aryl, unsubstituted heteroaryl or
unsubstituted cycloalkyl or aryl, heteroaryl or cycloalkyl each
substituted with at least one substituent independently selected
from the group consisting of halogen, alkyl, cycloalkyl, aryl,
aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy, cyano, nitro, amino,
alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl,
aralkoxycarbonyl, heteroaryloxycarbonyl, carbamoyl, cycloalkoxy,
alkylsulfonyloxy, arylsulfonyloxy, carbamoyloxy, heteroarylalkoxy,
alkenyloxy, tetrahydrofuranylalkoxy, alkynyloxy and
cycloalkylalkoxy, or wherein said alkyl, said cycloalkyl, said
aryl, said aralkyl, said alkoxy, said aralkoxy, said aryloxy, said
alkoxycarbonyl, said cycloalkoxycarbonyl, said aryloxycarbonyl,
said aralkoxycarbonyl, said heteroaryloxycarbonyl, said
cycloalkoxy, said alkylsulfonyloxy, said arylsulfonyloxy, said
heteroarylalkoxy, said alkenyloxy, said tetrahydrofuranylalkoxy,
said alkynyloxy and said cycloalkylalkoxy are substituted with
betweenone and three substituents independently selected from the
group consisting of alkyl, alkoxy, halogen, nitro, oxo,
trifluoromethyl, alkoxy substituted with between one and three
halogen, thiophenyl, aryl, amino, alkylcarbonyl and aryloxy, or two
substituents of aryl, heteroaryl or cycloalkyl form, together with
the carbon atoms to which they are attached, an unsubstituted 5- to
7-membered carbocyclic ring or a substituted 5- to 7-membered
carbocyclic ring with at least one substituent independently
selected from the group consisting of alkyl, alkoxy and
halogen;
[0014] n is 1 or 2;
[0015] m is zero or 1;
[0016] wherein 2-methyl-1-piperazinecarboxylic acid
(4-nitrophenyl)methyl ester and 1-piperazinecarboxylic acid
(4-(trifluoromethyl)phenyl)methyl ester are excluded.
[0017] It is an object of this invention to provide selective,
directly acting 5HT.sub.2 receptor ligands for use in therapy and
particularly for use as anti-obesity agents. It is a further object
of this invention to provide directly acting ligands selective for
5-HT.sub.2C receptors, for use in therapy and particularly for use
as anti-obesity agents. It is a further object of this invention to
provide selective, directly acting 5-HT.sub.2C receptor ligands,
preferably 5-HT.sub.2C receptor agonists, for use in therapy and
particularly for use as anti-obesity agents.
DETAILED DESCRIPTION
[0018] The term "alkyl", alone or in combination, signifies a
straight-chain or branched-chain alkyl group with 1 to 10,
preferably 1 to 8 carbon atoms, more preferably a straight or
branched-chain alkyl group with 1-4 carbon atoms. Examples of
straight-chain and branched C.sub.1-C.sub.8 alkyl groups are
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the
isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the
isomeric octyls, preferably methyl, ethyl, propyl and isopropyl.
Particularly preferred are methyl and ethyl.
[0019] The term "cycloalkyl", alone or in combination, signifies a
cycloalkyl ring with 3 to 8 carbon atoms and preferably a
cycloalkyl ring with 3 to 6 carbon atoms. Examples of
C.sub.3-C.sub.8 cycloalkyl are cyclopropyl, methyl-cyclopropyl,
dimethylcyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl,
methyl-cyclopentyl, cyclohexyl, methylcyclohexyl,
dimethyl-cyclohexyl, cycloheptyl and cyclooctyl, preferably
cyclo-propyl and particularly cyclopentyl.
[0020] The term "alkoxy", alone or in combination, signifies a
group of the formula alkyl-O-- in which the term "alkyl" has the
previously given significance, such as methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, sec.butoxy and tert.butoxy,
preferably methoxy and ethoxy.
[0021] The term "cycloalkoxy", alone or in combination, signifies a
group of the formula cycloalkyl-O-- in which the term "cycloalkyl"
has the previously given significance, such as cyclohexyloxy.
[0022] The term "carbonyl" refer to a group of the formula
--C(O)--.
[0023] The term "aryl", alone or in combination, signifies a phenyl
or naphthyl group, preferably a phenyl group which optionally
carries one or more, preferably one to three substituents each
independently selected from halogen, trifluoromethyl, amino, alkyl,
aryloxy, alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl,
methylendioxy, carboxy, alkoxycarbonyl, hydroxycarbonyl,
aminocarbonyl, alkyaminocarbonyl, dialkylaminocarbonyl, hydroxy,
nitro and alkoxy, wherein alkoxy is optionally substituted with 1
to 3 halogen atoms. Preferred is phenyl.
[0024] The term "aryloxy", alone or in combination, signifies a
group of the formula aryl-O-- in which the term "aryl" has the
previously given significance. Phenyloxy is an example of such an
aryloxy group.
[0025] The term "heteroaryl", alone or in combination, signifies an
aromatic 5 to 10, preferably 5- or 6-membered ring comprising 1 to
3 atoms independently selected from nitrogen, oxygen or sulfur such
as e.g. furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl,
isoxazolyl, oxazolyl, pyrrolyl and benzothiadiazolyl. Preferred
examples are pyridyl, thienyl, pyrazinyl, furyl, isoxazole,
(1,2,4)oxadiazole and thiazolyl. Particularly preferred are pyridyl
and thienyl.
[0026] The term "heteroarylalkoxy", alone or in combination,
signifies an alkoxy group as defined before, wherein one or two,
preferably one hydrogen atom is replaced by a heteroaryl group as
defined before. Examples are pyridin-3-ylmethoxy,
isoxazol-4-ylmethoxy, (1,2,4)oxadiazol-3-ylmethoxy, 3-furylmethoxy,
thien-3-ylmethoxy, isoxazol-3-ylmethoxy, thien-2-methoxy,
(2,1,3)benzothiadiazolylmethoxy, 2-thiophen-2-yl-ethoxy,
2-pyrrol-1-yl-ethoxy and thiazol-4-ylmethoxy.
[0027] The term "aralkyl", alone or in combination, signifies an
alkyl or cycloalkyl group as previously defined in which one or
several, preferably one hydrogen atom has been replaced by an aryl
group as previously defined. Preferred is benzyl.
[0028] The term "3- to 8-membered carbocyclic ring" as used for the
definition of R.sup.1 and R.sup.2 signifies a 3- to 8-membered,
preferably 3 to 6 membered cycloalkane ring. Examples are
cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane
and cyclooctane, preferably cyclopropane.
[0029] The term "5- to 7-membered carbocyclic ring" as used for the
definition of A.sup.2 signifies a cycloalkane ring with 5 to 7,
preferably 6 carbon atoms optionally substituted with alkyl, alkoxy
or halogen. Examples are cyclopentane, methyl-cyclopentane,
cyclohexane, methylcyclohexane, dimethyl-cyclohexane and
cycloheptane preferably cyclohexane.
[0030] The term "aralkoxy", alone or in combination, signifies an
alkoxy or cycloalkoxy group as previously defined in which one or
several, preferably one hydrogen atom has been replaced by an aryl
group as previously defined. Preferred is benzyloxy.
[0031] The term "nitro", alone or in combination, signifies a
--NO.sub.2 group.
[0032] The term "cyano", alone or in combination, signifies a --CN
group.
[0033] The term "alkoxycarbonyl", alone or in combination,
signifies an alkoxy-C(O)-- group, wherein alkoxy is defined as
before.
[0034] The term "cycloalkoxycarbonyl", alone or in combination,
signifies an cycloalkoxy-C(O)-- group, wherein cycloalkoxy is
defined as before.
[0035] The term "aryloxycarbonyl", alone or in combination,
signifies an aryloxy-C(O)-- group, wherein aryloxy is defined as
before.
[0036] The term "aralkoxycarbonyl", alone or in combination,
signifies an aralkoxy-C(O)-- group, wherein aralkoxy is defined as
before.
[0037] The term "heteroaryloxycarbonyl", alone or in combination,
signifies a heteroaryl-O--C(O)-- group, wherein heteroaryl is
defined as before.
[0038] The term "amino", alone or in combination, signifies a
primary, secondary or tertiary amino group bonded via the nitrogen
atom, with the secondary amino group carrying an alkyl or
cycloalkyl substituent and the tertiary amino group carrying two
similar or different alkyl or cycloalkyl substituents or the two
nitrogen substitutents together forming a ring, such as, for
example, --NH.sub.2, methylamino, ethylamino, dimethylamino,
diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino
etc., preferably amino, dimethylamino and diethylamino and
particularly primary amino.
[0039] The term "halogen" signifies fluorine, chlorine, bromine or
iodine and preferably fluorine, chlorine or bromine and
particularly fluorine and chlorine.
[0040] The term "carbamoyl" alone or in combination refers to a
group of the formula NH(R')--C(O)--, wherein R' means hydrogen,
alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, adamantyl, alkenyl or
alkyl substituted with halogen. Preferably R' means alkyl or
aralkyl particularly preferred are isopropyl, benzyl and tert.
butyl.
[0041] The term "carbamoyloxy", alone or in combination, signifies
a carbamoyl-O-- group, wherein carbamoyl is defined as before.
[0042] The term "alkylsulfonyloxy", alone or in combination,
signifies a 3
[0043] group in which alkyl is as previously defined. An examples
is propylsulfonyloxy.
[0044] The term "arylsulfonyloxy", alone or in combination,
signifies a 4
[0045] group in which aryl is as previously defined. An examples is
phenylsulfonyloxy.
[0046] The term "alkenyl", alone or in combination, signifies a
straight-chain or branched-chain hydrocarbon group comprising an
carbon-carbon double bond and 1 to 10, preferably 1 to 8 carbon
atoms, more preferably 1-4 carbon atoms.
[0047] The term "alkenyloxy", alone or in combination, signifies an
alkenyl-O-- group, wherein alkenyl is defined as before.
[0048] The term "alkynyl", alone or in combination, signifies a
straight-chain or branched-chain hydrocarbon group comprising an
carbon-carbon triple bond and 1 to 10, preferably 1 to 8 carbon
atoms, more preferably 1-4 carbon atoms.
[0049] The term "alkynyloxy", alone or in combination, signifies an
alkynyl-O-- group, wherein alkynyl is defined as before.
[0050] The term "oxo", alone or in combination, signifies an .dbd.O
group.
[0051] Examples of pharmaceutically acceptable salts of the
compounds of formula I are salts with physiologically compatible
mineral acids such hydrochloric acid, sulfuric acid or phosphoric
acid; or with organic acids such as methanesulphonic acid, acetic
acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid,
tartaric acid, succinic acid or salicylic acid. Preferred salts of
compounds of formula I are hydrochloride salts, succinate salts and
fumarate salts. The compounds of formula I can also form salts with
physiologically compatible bases. Examples of such salts are alkali
metal, alkali earth metal, ammonium and alkylammonium salts such as
the Na, K, Ca or tetramethylammonium salt. The compound of formula
I can also be present in the form of zwitterions.
[0052] The invention expressly includes pharmaceutically acceptable
derivatives of the compounds of formula I. For example hydroxy
groups of compounds of formula I can be esterified. Examples of
such esters are formate, acetate, propionate, butyrate,
isobutyrate, valerate, 2-methylbutyrate, isovalerate and
N,N-dimethylaminoacetate. Preferred esters are acetate and
N,N-dimethylaminoacetate.
[0053] Also included are pharmaceutically acceptable solvates of
compounds according to formula I such as for example hydrates. The
solvation can be effected in the course of the manufacturing
process or can take place e.g. as a consequence of hygroscopic
properties of an initially anhydrous compound of formula I
(hydration).
[0054] The term "lipase inhibitor" refers to compounds that are
capable of inhibiting the action of lipases, for example gastric
and pancreatic lipases. For example, orlistat and lipstatin as
described in U.S. Pat. No. 4,598,089 are potent inhibitors of
lipases. Lipstatin is a natural product of microbial origin, and
orlistat is the result of a hydrogenation of lipstatin. Other
lipase inhibitors include a class of compound commonly referred to
as panclicins. Panclicins are analogues of orlistat (Mutoh et al,
1994). The term "lipase inhibitor" refers also to polymer bound
lipase inhibitors for example described in International Patent
Application WO99/34786 (Geltex Pharmaceuticals Inc.). These
polymers are characterised in that they have been substituted with
one or more groups that inhibit lipases. The term "lipase
inhibitor" also comprises pharmaceutically acceptable salts of
these compounds. The term "lipase inhibitor" preferably refers to
orlistat.
[0055] Orlistat is a known compound useful for the control or
prevention of obesity and hyperlipidemia. See, U.S. Pat. No.
4,598,089, issued Jul. 1, 1986, which also discloses processes for
making orlistat and U.S. Pat. No. 6,004,996, which discloses
appropriate pharmaceutical compositions. Further suitable
pharmaceutical compositions are described for example in
International Patent Applications WO 00/09122 and WO 00/09123.
Additional processes for the preparation of orlistat are disclosed
in European Patent Applications Publication Nos. 185,359, 189,577,
443,449, and 524,495.
[0056] Orlistat is preferably orally administered from 60 to 720 mg
per day in divided doses two to three times per day. Preferred is
wherein from 180 to 360 mg, most preferably 360 mg per day of a
lipase inhibitor is administered to a subject, preferably in
divided doses two or, particularly, three times per day. The
subject is preferably an obese or overweight human, i.e. a human
with a body mass index of 25 or greater. Generally, it is preferred
that the lipase inhibitor be administered within about one or two
hours of ingestion of a meal containing fat. Generally, for
administering a lipase inhibitor as defined above it is preferred
that treatment be administered to a human who has a strong family
history of obesity and has obtained a body mass index of 25 or
greater.
[0057] Orlistat can be administered to humans in conventional oral
compositions, such as, tablets, coated tablets, hard and soft
gelatin capsules, emulsions or suspensions. Examples of carriers
which can be used for tablets, coated tablets, drages and hard
gelatin capsules are lactose, other sugars and sugar alcohols like
sorbitol, mannitol, maltodextrin, or other fillers; surfactants
like sodium lauryl sulfate, Brij 96, or Tween 80; disintegrants
like sodium starch glycolate, maize starch or derivatives thereof;
polymers like povidone, crospovidone; talc; stearic acid or its
salts and the like. Suitable carriers for soft gelatin capsules
are, for example, vegetable oils, waxes, fats, semi-solid and
liquid polyols and the like. Moreover, the pharmaceutical
preparations can contain preserving agents, solubilizers,
stabilizing agents, wetting agents, emulsifying agents, sweetening
agents, coloring agents, flavoring agents, salts for varying the
osmotic pressure, buffers, coating agents and antioxidants. They
can also contain still other therapeutically valuable substances.
The formulations may conveniently be presented in unit dosage form
and may be prepared by any methods known in the pharmaceutical art.
Preferably, orlistat is administered according to the formulation
shown in the Examples and in U.S. Pat. No. 6,004,996,
respectively.
[0058] The compounds of formula I can contain several asymmetric
centers and can be present in the form of optically pure
enantiomers, mixtures of enantiomers such as, for example,
racemates, optically pure diastereioisomers, mixtures of
diastereoisomers, diastereoisomeric racemates or mixtures of
diastereoisomeric racemates. The optically active forms can be
obtained for example by resolution of the racemates, by asymmetric
synthesis or asymmetric chromatography (chromatography with a
chiral adsorbents or eluent).
[0059] The term "asymmetric carbon atom (C*) means a carbon atom
with four different substituents. According to the
Cahn-Ingold-Prelog-Convention the asymmetric carbon atom can be of
the "R" or "S" configuration.
[0060] Preferred are compounds according to formula I, wherein
[0061] R.sup.1 and R.sup.2 are independently selected from
hydrogen, alkyl, cycloalkyl, aryl and aralkyl or R.sup.1 and
R.sup.2 together with the carbon atom to which they are attached
form a 3- to 8-membered carbocyclic ring which is optionally
substituted with alkyl;
[0062] R.sup.3 and R.sup.4 are independently selected from
hydrogen, alkyl, cycloalkyl, aryl and aralkyl;
[0063] A.sup.1 is oxygen or sulfur, wherein in case A.sup.1 is
oxygen and A.sup.2 is unsubstituted phenyl, one of R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 is not hydrogen;
[0064] A.sup.2 is aryl, heteroaryl or cycloalkyl each optionally
substituted with one or more substituents independently selected
from halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy,
aryloxy, hydroxy, cyano, nitro, amino, alkoxycarbonyl,
cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,
heteroaryloxycarbonyl and carbamoyl, wherein alkyl, cycloalkyl,
aryl, aralkyl, alkoxy, aralkoxy, aryloxy, alkoxycarbonyl,
cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and
heteroaryloxycarbonyl are optionally substituted with one to three
substituents independently selected from alkyl, alkoxy, halogen and
nitro, or two substituents of aryl, heteroaryl or cycloalkyl form
together with the carbon atoms to which they are attached a 5- to
7-membered carbocyclic ring which is optionally substituted with
alkyl, alkoxy or halogen;
[0065] n is 1 or 2 and
[0066] m is zero.
[0067] More preferred compounds according to formula I are those
wherein R.sup.3 and R.sup.4 are independently selected from
hydrogen and alkyl,most preferably R.sup.3 and R.sup.4 are
hydrogen.
[0068] In another preferred embodiment, R.sup.3 and R.sup.4 are
both alkyl. Additional preferred compounds are those wherein
R.sup.3 and R.sup.4 are methyl. Most preferred are the compounds
according to formula I, wherein R.sup.3 and R.sup.4 are methyl and
both methyl groups have the cis configuration. Preferred are the
cis-2,6-dimethylpiperazine derivatives of the formula I, wherein
R.sup.3 and R.sup.4 are methyl and R.sup.1, R.sup.2, A.sup.1,
A.sup.2, m and n are defined as mentioned before.
[0069] A further preferred embodiment of the invention are
compounds according to formula I, wherein one of R.sup.3 and
R.sup.4 is methyl or ethyl and the other one is hydrogen.
[0070] Particularly preferred are chiral compounds of formula (Ia),
5
[0071] wherein R.sup.5 is alkyl, particularly methyl or ethyl, and
R.sup.1, R.sup.2, A.sup.1, A.sup.2, m and n are defined as before.
Formula Ia means that the asymmetric carbon atom C* 6
[0072] is of the R configuration.
[0073] Further preferred compounds of formula I are those, wherein
A.sup.1 is sulfur. Most preferred compounds of formula I are those
wherein A.sup.1 is oxygen.
[0074] Also preferred compounds of formula I are those wherein
R.sup.1 and R.sup.2 are independently selected from hydrogen,
alkyl, cycloalkyl, aryl and aralkyl or R.sup.1 and R.sup.2 together
with the carbon atom to which they are attached form a 3- to
8-membered cycloalkyl ring which is optionally substituted with
alkyl. A particularly preferred embodiment of the invention
comprises compounds of formula I, wherein R.sup.1 and R.sup.2 are
independently selected from hydrogen, alkyl and aryl, preferably
hydrogen, methyl and phenyl. Most preferred are those compounds,
wherein R.sup.1 and R.sup.2 are both hydrogen.
[0075] Preferred are compounds according to formula (I), wherein
A.sup.2 is aryl, heteroaryl or cycloalkyl each optionally
substituted with one or more, preferably one to four, particularly
preferred one to three substituents independently selected from
halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy,
aryloxy, hydroxy, cyano, nitro, amino, alkoxycarbonyl,
cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,
heteroaryloxycarbonyl, carbamoyl, cycloalkoxy, alkylsulfonyloxy,
arylsulfonyloxy, carbamoyloxy, heteroarylalkoxy, alkenyloxy,
tetrahydrofuranylalkoxy, alkynyloxy and cycloalkylalkoxy, wherein
alkyl, cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy,
alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl,
aralkoxycarbonyl, heteroaryloxycarbonyl, cycloalkoxy,
alkylsulfonyloxy, arylsulfonyloxy, heteroarylalkoxy, alkenyloxy,
tetrahydrofuranylalkoxy, alkynyloxy and cycloalkylalkoxy are
optionally substituted with one to three substituents independently
selected from alkyl, alkoxy, halogen, nitro, oxo, trifluoromethyl,
alkoxy substituted with one to three halogen, thiophenyl, aryl,
amino, alkylcarbonyl and aryloxy, or two substituents of aryl,
heteroaryl or cycloalkyl form together with the carbon atoms to
which they are attached a 5- to 7-membered carbocyclic ring which
is optionally substituted with one or more, preferably one to three
substituents independently selected from alkyl, alkoxy and
halogen.
[0076] Likewise preferred are compounds of the present invention,
wherein A.sup.2 is phenyl, naphthalenyl, cycloalkyl, pyridyl,
thienyl, pyrazinyl or furyl, each optionally substituted with one
or more, preferably one to four substituents, independently
selected from halogen, alkyl, cycloalkyl, aryl, aralkyl, alkoxy,
aralkoxy, aryloxy, hydroxy, cyano, nitro, amino, alkoxycarbonyl,
cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,
heteroaryloxycarbonyl and carbamoyl, wherein alkyl, cycloalkyl,
aryl, aralkyl, alkoxy, aralkoxy, aryloxy, alkoxycarbonyl,
cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl and
heteroaryloxycarbonyl are optionally substituted with one to three
substituents independently selected from alkyl, alkoxy, halogen and
nitro, or two substituents of aryl, heteroaryl or cycloalkyl form
together with the carbon atoms to which they are attached a 5- to
7-membered carbocyclic ring which is optionally substituted with
alkyl, alkoxy or halogen.
[0077] Preferred are compounds according to formula I, wherein
A.sup.2 is phenyl, naphthalenyl, cyclohexyl, pyridyl or thienyl
each optionally substituted with one or more, preferably one to
four substituents independently selected from halogen, alkyl,
cycloalkyl, aryl, aralkyl, alkoxy, aralkoxy, aryloxy, hydroxy,
cyano, nitro, amino, alkoxycarbonyl, cycloalkoxycarbonyl,
aryloxycarbonyl, aralkoxycarbonyl, heteroaryloxycarbonyl and
carbamoyl, wherein alkyl, cycloalkyl, aryl, aralkyl, alkoxy,
aralkoxy, aryloxy, alkoxycarbonyl, cycloalkoxycarbonyl,
aryloxycarbonyl, aralkoxycarbonyl and heteroaryloxycarbonyl are
optionally substituted with one to three substituents independently
selected from alkyl, alkoxy, halogen and nitro. Particularly
preferred examples of the above substituents of phenyl,
naphthalenyl, cyclohexyl, pyridyl and thienyl are
trifluoromethoxyl, fluoro, chloro, bromo, nitro, phenylmethoxy,
trifluoromethyl, methyl, tert-butyl, difluoromethoxy, cyano,
methoxycarbonyl, benzyloxy, fluoro-benzyloxy, chlorobenzyloxy and
nitrobenzyloxy.
[0078] Particularly preferred are compounds of formula I are those,
wherein A.sup.2 is phenyl, naphthalenyl, cyclohexyl, pyridyl or
thienyl each optionally substituted with one or more, preferably
one to four substituents independently selected from halogen,
alkyl, aryl, alkoxy, aralkoxy, cyano, nitro, alkoxycarbonyl,
wherein alkyl, alkoxy, aralkoxy and alkoxycarbonyl are optionally
substituted with one to three substituents independently selected
from halogen and nitro.
[0079] Other preferred compounds of formula I are those wherein A
is phenyl, optionally substituted with one to five, preferably one
to three substituents independently selected from halogen, alkyl,
aryl, alkoxy, aralkoxy, cyano, nitro, alkoxycarbonyl, wherein
alkyl, alkoxy and aralkoxy optionally substituted with one to three
substituents independently selected from halogen and nitro.
[0080] A further preferred object of the present invention are
compounds according to formula I, wherein n is 1.
[0081] Another preferred object of the present invention are
compounds according to formula I, wherein A.sup.2 is phenyl,
optionally substituted with one to four substituents independently
selected from halogen, alkoxy, carbamoyloxy, heteroarylalkoxy,
alkenyloxy, alkynyloxy and cycloalkylalkoxy, wherein alkoxy,
heteroarylalkoxy and alkenyloxy are optionally substituted with one
to three substituents independently selected from alkyl and
halogen. Particularly, preferred are compounds of formula I,
wherein A.sup.2 is phenyl, optionally substituted with one to three
substituents independently selected from fluoro, chloro,
difluoromethoxy, propoxy, 3,5-dimethyl-isoxazol-4-ylmethoxy,
2-propenyloxy, 5-pentyloxy, cyclopropylmethoxy, 2-propynyloxy and
NH(R')--C(O)--O--, wherein R' is isopropyl, benzyl or
tert.-butyl.
[0082] Additionally preferred compounds of formula I are those
wherein m is zero.
[0083] Examples of preferred compounds of formula I include:
[0084] Piperazine-1-carboxylic acid 4-trifluoromethoxy-benzyl
ester;
[0085] piperazine-1-carboxylic acid 3,4-difluoro-benzyl ester;
[0086] piperazine-1-carboxylic acid 4-fluoro-benzyl ester;
[0087] piperazine-1-carboxylic acid 4-bromo-benzyl ester;
[0088] piperazine-1-carboxylic acid 2-trifluoromethoxy-benzyl
ester;
[0089] piperazine-1-carboxylic acid 2-chloro-5-nitro-benzyl
ester;
[0090] piperazine-1-carboxylic acid 2-chloro-benzyl ester;
[0091] piperazine-1-carboxylic acid biphenyl-4-ylmethyl ester;
[0092] piperazine-1-carboxylic acid 3-methoxy-benzyl ester;
[0093] piperazine-1-carboxylic acid 3-trifluoromethyl-benzyl
ester;
[0094] piperazine-1-carboxylic acid 4-trifluoromethyl-benzyl
ester;
[0095] piperazine-1-carboxylic acid naphthalen-2-ylmethyl
ester;
[0096] piperazine-1-carboxylic acid naphthalen-1-ylmethyl
ester;
[0097] piperazine-1-carboxylic acid 2-methyl-benzyl ester;
[0098] piperazine-1-carboxylic acid 2,4-dichloro-benzyl ester;
[0099] piperazine-1-carboxylic acid 2,6-dichloro-benzyl ester;
[0100] piperazine-1-carboxylic acid 4-tert-butyl-benzyl ester;
[0101] piperazine-1-carboxylic acid
2-fluoro-4-trifluoromethyl-benzyl ester;
[0102] piperazine-1-carboxylic acid 2,4-difluoro-benzyl ester;
[0103] piperazine-1-carboxylic acid 2-chloro-4-fluoro-benzyl
ester;
[0104] piperazine-1-carboxylic acid
4-fluoro-2-trifluoromethyl-benzyl ester;
[0105] piperazine-1-carboxylic acid 4-difluoromethoxy-benzyl
ester;
[0106] piperazine-1-carboxylic acid 2,4-dimethyl-benzyl ester;
[0107] piperazine-1-carboxylic acid cyclohexylmethyl ester;
[0108] piperazine-1-carboxylic acid 2-fluoro-benzyl ester;
[0109] cis-2,6-dimethyl-piperazine-1-carboxylic acid
4-chloro-benzyl ester;
[0110] cis-2,6-dimethyl-piperazine-1-carboxylic acid 3-cyano-benzyl
ester;
[0111] cis-2,6-dimethyl-piperazine-1-carboxylic acid
4-methoxycarbonyl-benzyl ester;
[0112] piperazine-1-carboxylic acid 4-cyano-benzyl ester;
[0113] piperazine-1-carboxylic acid 2-trifluoromethyl-benzyl
ester;
[0114] piperazine-1-carboxylic acid 4-chloro-2-fluoro-benzyl
ester;
[0115] piperazine-1-carbothioic acid
S-(4-benzyloxy-benzyl)ester;
[0116] piperazine-1-carbothioic acid S-(4-bromo-benzyl)ester;
[0117] piperazine-1-carbothioic acid
S-(4-trifluoromethoxy-benzyl)ester;
[0118] piperazine-1-carbothioic acid S-(4-fluoro-benzyl)ester;
[0119] piperazine-1-carbothioic acid
S-(2,4-difluoro-benzyl)ester;
[0120] piperazine-1-carbothioic acid S-(4-methoxy-benzyl)ester;
[0121] piperazine-1-carbothioic acid
S-(2,4-dimethyl-benzyl)ester;
[0122] piperazine-1-carbothioic acid S-(2-fluoro-4-tri
fluoromethyl-benzyl)ester;
[0123] piperazine-1-carbothioic acid
S-[4-(4-fluoro-benzyloxy)-benzyl]este- r;
[0124] piperazine-1-carboxylic acid 4-benzyloxy-benzyl ester;
[0125] piperazine-1-carboxylic acid 4-(4-fluoro-benzyloxy)-benzyl
ester;
[0126] piperazine-1-carboxylic acid 4-methoxy-benzyl ester;
[0127] piperazine-1-carboxylic acid benzhydryl ester;
[0128] (RS)-piperazine-1-carboxylic acid 1-phenyl-ethyl ester;
[0129] piperazine-1-carboxylic acid phenethyl ester;
[0130] cis-2,6-dimethylpiperazine-1-carboxylic acid
5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester;
[0131] piperazine-1-carboxylic acid
5-[2-(3-chlorobenzyloxy)]pyridyl-methy- l ester;
[0132] cis-2,6-dimethylpiperazine-1-carboxylic acid
2-(2-thienyl)ethyl ester;
[0133] cis-2,6-dimethylpiperazine-1-carboxylic acid 2-fluoro-benzyl
ester;
[0134] piperazine-1-carbothioic acid S-[4-(3-nitrobenzyl)oxy]benzyl
ester;
[0135] piperazine-1-carboxylic acid 3-(2-phenethyloxy)-benzyl
ester
[0136] 3-[2-(3-chlorophenyl)]ethoxybenzyl
piperazine-1-carboxylate;
[0137] cis-2,6-dimethyl-piperazine-1-carboxylic acid
6-(2-fluoro-benzyloxy)-pyridin-3-ylmethyl ester;
[0138] 4-bromo-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0139] benzyl cis-2,6-dimethylpiperazine-1-carboxylate;
[0140] 2-chlorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate;
[0141] (R)-2-fluorobenzyl 2-methylpiperazine-1-carboxylate;
[0142] 2-fluoro-4-propylbenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0143] S-4-[(ethylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0144] S-4-[[(2-chloroethyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0145] S-4-[(butylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0146] S-4-[(2-propylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate- ;
[0147] S-4-[(benzylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0148] S-4-[[(2-methylbenzyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0149] 4-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0150] cis-2,6-dimethyl-piperazine-1-carboxylic acid
6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester;
[0151] cis-2,6-dimethyl-piperazine-1-carboxylic acid
6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester;
[0152] 4-ethyl-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0153] 2-fluoro-4-pentylbenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0154] S-4-[(tert-butylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxyla- te;
[0155] 2,5-difluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0156] 2,3-difluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0157] 2,6-difluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0158] 2,4-dimethylbenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0159] 2-4-[(propylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0160] S-4-[(cyclohexylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxyla- te;
[0161] 2-fluoro-4-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate;
[0162] 3-benzyloxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0163] 2,6-difluoro-4-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-c- arboxylate;
[0164] (+/-)-S-4-[(2-butylamino)carbonyl]oxybenzyl
piperazine-1-thiocarbox- ylate;
[0165] S-4-[(cyclopentylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxyl- ate;
[0166] S-4-[(1-adamantylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxyl- ate;
[0167] S-4-[(2-propenylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxyla- te;
[0168] S-4-[(phenylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0169] S-4-[[4-(2-propylphenyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0170] (+/-)-S-4-[[(1-phenylethyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0171]
S-4-[[[(4-ethoxycarbonyl)phenyl]amino]carbonyl]oxybenzylpiperazine--
1-thiocarboxylate;
[0172] S-4-[[(3-chloro-4-fluorophenyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0173]
S-4-[[(4-difluoromethoxyphenyl)amino]carbonyl]oxybenzylpiperazine-1-
-thiocarboxylate;
[0174] 4-methylbenzyl cis-2,6-dimethylpiperazine-1-carboxylate;
[0175] (+/-)-4-difluoromethoxybenzyl
2-ethylpiperazine-1-carboxylate;
[0176] S-4-[[(4-methoxyphenyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0177] S-4-[[(3-methylbenzyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0178] S-4-[[(4-methoxybenzyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0179] 2,6-difluoro-4-(2-propyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-car- boxylate;
[0180] S-4-(2-oxo-2-phenylethoxy)benzyl
piperazine-1-thiocarboxylate;
[0181] (R)-4-difluoromethoxybenzyl
2-ethylpiperazine-1-carboxylate;
[0182] S-4-benzenesulfonyloxybenzyl
piperazine-1-thiocarboxylate;
[0183] (+/-)-2,6-difluoro-4-propoxybenzyl
2-ethylpiperazine-1-carboxylate;
[0184] (+/-)-2,6-difluoro-4-difluoromethoxybenzyl
2-ethylpiperazine-1-carb- oxylate;
[0185] 2-fluoro-5-methoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0186] 3-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0187] S-4-propanesulfonyloxybenzyl
piperazine-1-thiocarboxylate;
[0188] cis-2,6-dimethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(pyridin-3-ylmethoxy)-benzyl ester;
[0189] (R)-2,6-difluoro-4-propoxybenzyl
2-methylpiperazine-1-carboxylate;
[0190] (R)-4-difluoromethoxybenzyl
2-methylpiperazine-1-carboxylate;
[0191] 5-benzyloxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate- ;
[0192] 2,6-difluoro-4-(3-phenyl)propoxybenzyl
cis-2,6-dimethylpiperazine-1- -carboxylate;
[0193] 4-bromo-2-fluorobenzyl piperazine-1-carboxylate;
[0194] 2,6-difluoro-4-(2-propenyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-c- arboxylate;
[0195] (R)-2,6-difluoro-4-difluoromethoxybenzyl
2-methylpiperazine-1-carbo- xylate;
[0196] 2-fluoro-5-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate;
[0197] 5-ethoxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0198] 2-fluoro-5-propoxybenzyl piperazine-1-carboxylate;
[0199] (R)-2-fluoro-5-propoxybenzyl
2-methylpiperazine-1-carboxylate;
[0200] 2-fluoro-5-propoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0201] 5-butoxy-2-fluorobenzyl piperazine-1-carboxylate;
[0202] (R)-5-butoxy-2-fluorobenzyl
2-methylpiperazine-1-carboxylate;
[0203] 5-butoxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0204] cis-2,6-dimethyl-piperazine-1-carboxylic acid
4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl
ester;
[0205] 2-fluoro-5-(2-methylpropyl)-oxybenzyl
cis-2,6-dimethylpiperazine-1-- carboxylate;
[0206] 2-chloro-6-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0207] (R)-2,6-difluorobenzyl 2-methylpiperazine-1-carboxylate;
[0208] (R,R)-4-difluoromethoxybenzyl
2,6-dimethylpiperazine-1-carboxylate;
[0209] (R)-2-fluoro-5-(2-propenyl)oxybenzyl
2-methylpiperazine-1-carboxyla- te;
[0210] 2-fluoro-5-(2-propenyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate;
[0211] 5-(cyclohexylmethyl)oxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1- -carboxylate;
[0212] 2-fluoro-5-(2-phenyl)ethoxybenzyl
cis-2,6-dimethylpiperazine-1-carb- oxylate;
[0213] 2-fluoro-1-(3-phenyl)propoxybenzyl
piperazine-1-carboxylate;
[0214] (R)-2-fluoro-5-(3-phenyl)propoxybenzyl
2-methylpiperazine-1-carboxy- late;
[0215] 2-fluoro-5-(3-phenyl)propoxybenzyl
cis-2,6-dimethylpiperazine-1-car- boxylate;
[0216] 2-fluoro-5-(3trifluoromethylbenzyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0217] 2-fluoro-5-(2-pyridylmethyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-- carboxylate;
[0218] 2-fluoro-5-(3-pyridylmethyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-- carboxylate;
[0219] (+/-)-2,6-difluoro-4-(2-pyridylmethyl)oxybenzyl
2-methylpiperazine-1-carboxylate;
[0220] (+/-)-2,6-difluoro-4-(3-pyridylmethyl)oxybenzyl
2-methylpiperazine-1-carboxylate;
[0221] (+/-)-2-methyl-piperazine-1-carboxylic acid
4-(3,5-dimethyl-isoxazo- l-4-ylmethoxy)-2,6-difluoro-benzyl
ester;
[0222] 5-tert-butylaminocarbonyloxy-2-fluorobenzyl
cis-2,6-dimethylpiperaz- ine-1-carboxylate;
[0223] 2-fluoro-5-(4-difluoromethoxybenzyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0224] piperazine-1-carboxylic acid
2,6-difluoro-4-(5-thiophen-2-yl-[1,2,4-
]oxadiazol-3-ylmethoxy)-benzyl ester;
[0225] (R)-2-methyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(5-thiophe-
n-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)-benzyl ester;
[0226] cis-2,6-dimethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(5-thiophen-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)-benzyl
ester;
[0227] 2,6-difluoro-4-(3-fluorobenzyl)oxybenzyl
cis-2,6-dimethylpiperazine- -1-carboxylate;
[0228] 2,6-difluoro-4-(3,4-difluorobenzyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0229] 2-fluoro-5-(2,4-difluorobenzyl)oxybenzyl
cis-2,6-dimethylpiperazine- -1-carboxylate;
[0230] 2-fluoro-5-(3,4-difluorobenzyl)oxybenzyl
cis-2,6-dimethylpiperazine- -1-carboxylate;
[0231] 2,6-difluoro-4-(3-furylmethyl)oxybenzyl
cis-2,6-dimethylpiperazine-- 1-carboxylate;
[0232] (+/-)-2,6-difluoro-4-(3-furylmethyl)oxybenzyl
2-ethylpiperazine-1-carboxylate;
[0233] (+/-)-piperazine-1-carboxylic acid
2,6-difluoro-4-(tetrahydro-furan- -2-ylmethoxy)-benzyl ester;
[0234] (+/-)-piperazine-1-carboxylic acid
2-fluoro-4-(tetrahydro-furan-2-y- lmethoxy)-benzyl ester;
[0235] 2,6-difluoro-4-(3-thienylmethyl)oxybenzyl
cis-2,6-dimethylpiperazin- e-1-carboxylate;
[0236] 2,6-difluoro-4-(3-thienylmethyl)oxybenzyl
piperazine-1-carboxylate;
[0237] (R)-2,6-difluoro-4-(3-thienylmethyl)oxybenzyl
2-methylpiperazine-1-carboxylate;
[0238] (+/-)-2,6-difluoro-4-(3-thienylmethyl)oxybenzyl
2-ethylpiperazine-1-carboxylate;
[0239] cis-2,6-dimethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(5-methyl-isoxazol-3-ylmethoxy)-benzyl ester;
[0240] cis-2,6-dimethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-benzyl
ester;
[0241] (+/-)-2-fluoro-5-(2-propenyl)oxybenzyl
2-ethylpiperazine-1-carboxyl- ate;
[0242] 2-fluoro-5-(2-propenyl)oxybenzyl
piperazine-1-carboxylate;
[0243] 2,6-difluoro-4-(2-thienylmethyl)oxybenzyl
piperazine-1-carboxylate;
[0244] (R)-2,6-difluoro-4-(2-thienylmethyl)oxybenzyl
2-methylpiperazine-1-carboxylate;
[0245] cis-2,6-dimethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(thiophen-2-ylmethoxy)-benzyl ester;
[0246] 5-butylaminocarbonyloxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1- -carboxylate;
[0247] 2-fluoro-5-(2-propynyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate;
[0248] 5-(5-[2,1,3]benzothiadiazolylmethyl)oxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0249] 2-fluoro-5-(3-fluorobenzyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-c- arboxylate;
[0250] (R)-2-fluoro-5-pentyloxybenzyl
2-methylpiperazine-1-carboxylate;
[0251] 5-(cyclopropylmethyl)oxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-- 1-carboxylate;
[0252] (R)-2-methyl-piperazine-1-carboxylic acid
2-fluoro-5-(2-thiophen-2-- yl-ethoxy)-benzyl ester;
[0253] cis-2,6-dimethyl-piperazine-1-carboxylic acid
3-bromo-2,6-difluoro-benzyl ester;
[0254] cis-2,6-dimethyl-piperazine-1-carboxylic acid
2,4-difluoro-2'-methoxy-biphenyl-3-ylmethyl ester;
[0255] cis-2,6-dimethyl-piperazine-1-carboxylic acid
2,4-difluoro-3',4'-dimethoxy-biphenyl-3-ylmethyl ester;
[0256] cis-2,6-dimethyl-piperazine-1-carboxylic acid
2,4-difluoro-3'-hydroxy-4'-methoxy-biphenyl-3-ylmethyl ester;
[0257] cis-2,6-dimethyl-piperazine-1-carboxylic acid
3'-amino-2,4-difluoro-biphenyl-3-ylmethyl ester;
[0258] cis-2,6-dimethyl-piperazine-1-carboxylic acid
4'-acetyl-2,4-difluoro-biphenyl-3-ylmethyl ester;
[0259] cis-2,6-dimethyl-piperazine-1-carboxylic acid
3'-acetyl-2,4-difluoro-biphenyl-3-ylmethyl ester;
[0260] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-methyl-benz- yl ester;
[0261] (R)-2-ethyl-piperazine-1-carboxylic acid 2,6-difluoro-benzyl
ester;
[0262] (R)-2-ethyl-piperazine-1-carboxylic acid
4-cyclopropylmethoxy-2,6-d- ifluoro-benzyl ester;
[0263] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-propoxy-ben- zyl ester;
[0264] (R)-2-ethyl-piperazine-1-carboxylic acid
4-allyloxy-2,6-difluoro-be- nzyl ester;
[0265] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-prop-2-ynyl- oxy-benzyl ester;
[0266] (R)-2-ethyl-piperazine-1-carboxylic acid
4-butoxy-2,6-difluoro-benz- yl ester;
[0267] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(2-methoxy-- ethoxy)-benzyl ester;
[0268] (R)-2-ethyl-piperazine-1-carboxylic acid
4-ethoxy-2,6-difluoro-benz- yl ester;
[0269] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(2-methyl-t- hiazol-4-ylmethoxy)-benzyl ester;
[0270] (R)-2-ethyl-piperazine-1-carboxylic acid
2-fluoro-5-methoxy-benzyl ester;
[0271] (R)-2-ethyl-piperazine-1-carboxylic acid
5-ethoxy-2-fluoro-benzyl ester;
[0272] (R)-2-ethyl-piperazine-1-carboxylic acid
2-fluoro-5-propoxy-benzyl ester;
[0273] (R)-2-ethyl-piperazine-1-carboxylic acid
5-butoxy-2-fluoro-benzyl ester;
[0274] (R)-2-ethyl-piperazine-1-carboxylic acid
2-fluoro-5-pentyloxy-benzy- l ester;
[0275] (R)-2-ethyl-piperazine-1-carboxylic acid
2-fluoro-5-(3-methyl-butox- y)-benzyl ester;
[0276] (R)-2-ethyl-piperazine-1-carboxylic acid
5-benzyloxy-2-fluoro-benzy- l ester;
[0277] (R)-2-ethyl-piperazine-1-carboxylic acid
2-fluoro-5-phenethyloxy-be- nzyl ester;
[0278] (R)-2-ethyl-piperazine-1-carboxylic acid
2-fluoro-5-(2-methyl-benzy- loxy)-benzyl ester;
[0279] (R)-2-ethyl-piperazine-1-carboxylic acid
2-fluoro-5-(3-methyl-benzy- loxy)-benzyl ester;
[0280] (R)-2-ethyl-piperazine-1-carboxylic acid
2-fluoro-5-(2-pyrrol-1-yl-- ethoxy)-benzyl ester;
[0281] (R)-2-ethyl-piperazine-1-carboxylic acid
5-cyclopropylmethoxy-2-flu- oro-benzyl ester;
[0282] (R)-2-ethyl-piperazine-1-carboxylic acid
5-cyclobutylmethoxy-2-fluo- ro-benzyl ester;
[0283] (R)-2-ethyl-piperazine-1-carboxylic acid
5-cyclohexylmethoxy-2-fluo- ro-benzyl ester;
[0284] (R)-2-ethyl-piperazine-1-carboxylic acid
5-(2-cyclohexyl-ethoxy)-2-- fluoro-benzyl ester;
[0285] (R)-2-ethyl-piperazine-1-carboxylic acid
2-fluoro-5-prop-2-ynyloxy-- benzyl ester;
[0286] (R)-2-ethyl-piperazine-1-carboxylic acid
5-allyloxy-2-fluoro-benzyl ester;
[0287] (R)-2-ethyl-piperazine-1-carboxylic acid
2-fluoro-5-(2-methoxy-etho- xy)-benzyl ester;
[0288] (R)-2-ethyl-piperazine-1-carboxylic acid
5-(2-ethoxy-ethoxy)-2-fluo- ro-benzyl ester;
[0289] (R)-2-ethyl-piperazine-1-carboxylic acid
2-fluoro-5-(3-phenoxy-prop- oxy)-benzyl ester;
[0290] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-methoxy-ben- zyl ester;
[0291] (R)-2-ethyl-piperazine-1-carboxylic acid
3-ethoxy-2,6-difluoro-benz- yl ester;
[0292] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-propoxy-ben- zyl ester;
[0293] (R)-2-ethyl-piperazine-1-carboxylic acid
3-butoxy-2,6-difluoro-benz- yl ester;
[0294] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-pentyloxy-b- enzyl ester;
[0295] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(3-methyl-b- utoxy)-benzyl ester;
[0296] (R)-2-ethyl-piperazine-1-carboxylic acid
3-benzyloxy-2,6-difluoro-b- enzyl ester;
[0297] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(3-phenyl-p- ropoxy)-benzyl ester;
[0298] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(4-methyl-b- enzyloxy)-benzyl ester;
[0299] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(3-methyl-b- enzyloxy)-benzyl ester;
[0300] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(2-methyl-b- enzyloxy)-benzyl ester;
[0301] (R)-2-ethyl-piperazine-1-carboxylic acid
3-(3,3-dimethyl-butoxy)-2,- 6-difluoro-benzyl ester;
[0302] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(2-pyrrol-1- -yl-ethoxy)-benzyl ester;
[0303] (R)-2-ethyl-piperazine-1-carboxylic acid
3-cyclopropylmethoxy-2,6-d- ifluoro-benzyl ester;
[0304] (R)-2-ethyl-piperazine-1-carboxylic acid
3-cyclobutylmethoxy-2,6-di- fluoro-benzyl ester;
[0305] (R)-2-ethyl-piperazine-1-carboxylic acid
3-(2-cyclohexyl-ethoxy)-2,- 6-difluoro-benzyl ester;
[0306] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-prop-2-ynyl- oxy-benzyl ester;
[0307] (R)-2-ethyl-piperazine-1-carboxylic acid
3-allyloxy-2,6-difluoro-be- nzyl ester;
[0308] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(2-methoxy-- ethoxy)-benzyl ester;
[0309] (R)-2-ethyl-piperazine-1-carboxylic acid
3-(2-ethoxy-ethoxy)-2,6-di- fluoro-benzyl ester;
[0310] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(3-phenoxy-- propoxy)-benzyl ester;
[0311] (R)-2-ethyl-piperazine--carboxylic
1-[2-fluoro-5-(3-methoxy-propoxy- )-benzyl]ester;
[0312] (R)-2-ethyl-piperazine-1-carboxylic acid
1-[2,6-difluoro-3-(3-metho- xy-propoxy)-benzyl]ester;
[0313] (R)-2-ethyl-piperazine-1-carboxylic acid
4-cyclopropylmethoxy-2-chl- oro-6-fluoro-benzyl ester;
[0314] (R)-2-ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-propox- y-benzyl ester;
[0315] (R)-2-ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-ethoxy- -benzyl ester;
[0316] (R)-2-ethyl-piperazine-1-carboxylic acid
4-butoxy-2-chloro-6-fluoro- -benzyl ester;
[0317] (R)-2-ethyl-piperazine-1-carboxylic acid
4-butoxy-2-chloro-6-fluoro- -benzyl ester;
[0318] (R)-2-ethyl-piperazine-1-carboxylic acid
4-allyloxy-2-chloro-6-fluo- ro-benzyl ester;
[0319] (R)-2-ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-prop-2- -ynyloxy-benzyl ester;
[0320] (R)-2-ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-(2-met- hoxy-ethoxy)-benzyl ester;
[0321] (R)-2-ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-(3-met- hoxy-propoxy)-benzyl ester;
[0322] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-(2-met- hyl-thiazol-4-ylmethoxy)-benzyl
ester.
[0323] Examples of particularly preferred compounds of formula I
are:
[0324] Piperazine-1-carboxylic acid 4-trifluoromethoxy-benzyl
ester;
[0325] piperazine-1-carboxylic acid 2-chloro-benzyl ester;
[0326] piperazine-1-carboxylic acid 4-difluoromethoxy-benzyl
ester;
[0327] piperazine-1-carboxylic acid 2-fluoro-benzyl ester;
[0328] cis-2,6-dimethyl-piperazine-1-carboxylic acid
4-chloro-benzyl ester;
[0329] piperazine-1-carbothioic acid
S-(4-benzyloxy-benzyl)ester;
[0330] piperazine-1-carbothioic acid
S-(2,4-difluoro-benzyl)ester;
[0331] piperazine-1-carbothioic acid S-(4-methoxy-benzyl)ester;
[0332] piperazine-1-carbothioic acid
S-[4-(4-fluoro-benzyloxy)-benzyl]este- r;
[0333] piperazine-1-carboxylic acid 4-(4-fluoro-benzyloxy)-benzyl
ester;
[0334] cis-2,6-dimethylpiperazine-1-carboxylic acid
2-(2-thienyl)ethyl ester;
[0335] cis-2,6-dimethylpiperazine-1-carboxylic acid 2-fluoro-benzyl
ester;
[0336] 4-bromo-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0337] 2-fluoro-4-propylbenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0338] S-4-[(butylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0339] S-4-[(2-propylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate- ;
[0340] S-4-[(benzylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0341] 4-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0342] 4-ethyl-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0343] S-4-[(tert-butylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxyla- te;
[0344] 2,6-difluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0345] 2-fluoro-4-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate;
[0346] 3-benzyl oxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0347] 2,6-difluoro-4-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-c- arboxylate;
[0348] (+/-)-4-difluoromethoxybenzyl
2-ethylpiperazine-1-carboxylate;
[0349] S-4-(2-oxo-2-phenylethoxy)benzyl
piperazine-1-thiocarboxylate;
[0350] (R)-4-difluoromethoxybenzyl
2-ethylpiperazine-1-carboxylate;
[0351] (R)-2,6-difluoro-4-propoxybenzyl
2-methylpiperazine-1-carboxylate;
[0352] (R)-4-difluoromethoxybenzyl
2-methylpiperazine-1-carboxylate;
[0353] 2-fluoro-5-propoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate;
[0354] cis-2,6-dimethyl-piperazine-1-carboxylic acid
4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl
ester;
[0355] (R)-2-fluoro-5-(2-propenyl)oxybenzyl
2-methylpiperazine-1-carboxyla- te;
[0356] 2-fluoro-5-(2-propenyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate;
[0357] (R)-2-fluoro-5-pentyloxybenzyl
2-methylpiperazine-1-carboxylate;
[0358] 5-(cyclopropylmethyl)oxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-- 1-carboxylate;
[0359] (R)-2-ethyl-piperazine-1-carboxylic acid
4-cyclopropylmethoxy-2,6-d- ifluoro-benzyl ester;
[0360] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-propoxy-ben- zyl ester;
[0361] (R)-2-ethyl-piperazine-1-carboxylic acid
4-allyloxy-2,6-difluoro-be- nzyl ester;
[0362] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-prop-2-ynyl- oxy-benzyl ester;
[0363] (R)-2-ethyl-piperazine-1-carboxylic acid
5-allyloxy-2-fluoro-benzyl ester;
[0364] (R)-2-ethyl-piperazine-1-carboxylic acid
3-allyloxy-2,6-difluoro-be- nzyl ester;
[0365] (R)-2-ethyl-piperazine-1-carboxylic acid
4-cyclopropylmethoxy-2-chl- oro-6-fluoro-benzyl ester;
[0366] (R)-2-ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-propox- y-benzyl ester;
[0367] (R)-2-ethyl-piperazine-1-carboxylic acid
4-allyloxy-2-chloro-6-fluo- ro-benzyl ester;
[0368] (R)-2-ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-prop-2- -ynyloxy-benzyl ester.
[0369] Most preferred compounds according to formula I are:
[0370] S-4-[(2-propylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate- ;
[0371] S-4-[(benzylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate;
[0372] S-4-[(tert-butylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxyla- te;
[0373] 2,6-difluoro-4-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-c- arboxylate;
[0374] (R)-4-difluoromethoxybenzyl
2-ethylpiperazine-1-carboxylate;
[0375] (R)-2,6-difluoro-4-propoxybenzyl
2-methylpiperazine-1-carboxylate;
[0376] cis-2,6-dimethyl-piperazine-1-carboxylic acid
4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl
ester;
[0377] 2-fluoro-5-(2-propenyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate;
[0378] (R)-2-fluoro-5-pentyloxybenzyl
2-methylpiperazine-1-carboxylate;
[0379] 5-(cyclopropylmethyl)oxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-- 1-carboxylate;
[0380] (R)-2-ethyl-piperazine-1-carboxylic acid
4-cyclopropylmethoxy-2,6-d- ifluoro-benzyl ester;
[0381] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-propoxy-ben- zyl ester;
[0382] (R)-2-ethyl-piperazine-1-carboxylic acid
4-allyloxy-2,6-difluoro-be- nzyl ester;
[0383] (R)-2-ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-prop-2-ynyl- oxy-benzyl ester;
[0384] (R)-2-ethyl-piperazine-1-carboxylic acid
4-cyclopropylmethoxy-2-chl- oro-6-fluoro-benzyl ester;
[0385] (R)-2-ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-propox- y-benzyl ester;
[0386] (R)-2-ethyl-piperazine-1-carboxylic acid
4-allyloxy-2-chloro-6-fluo- ro-benzyl ester and
[0387] (R)-2-ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-prop-2- -ynyloxy-benzyl ester.
[0388] Processes for the manufacture of the compounds according to
formula I are an object of the present invention. The substituents
and indices used in the following schemes have the significance
given above unless indicated to the contrary.
[0389] Compounds of formula (I) where R.sup.1 to R.sup.4, A.sup.1,
A.sup.2 and n are as previously defined may be conveniently
prepared according to Reaction Scheme 1. 7
[0390] A compound of formula (VI) can be prepared by reaction of
the piperazine carbamoyl chloride (III) with an alcohol (IV) or
thiol (V) in the presence of a suitable base such as sodium
hydride, triethylamine, PS-BEMP or pyridine in a solvent such as
acetonitrile, N-methylpyrrolidinone, dimethyl formamide,
tetrahydrofuran or dichloromethane. The piperazine may be protected
using a suitable protecting group (P) e.g. tert-butoxycarbonyl,
9-fluorenylmethoxycarbonyl- , allyloxycarbonyl, trimethylsilyl,
3,4-dimethoxybenzyl and trityl, preferably tert-butoxycarbonyl and
9-fluorenylmethoxycarbonyl. These protective groups may also be
bound to a polymeric resin, e.g., polystyrene-PEG-bound trityl.
[0391] The protected piperazine-carbamoyl chloride (III) may be
synthesized from a protected piperazine (II) by treatment with a
reagent such as phosgene, diphosgene or triphosgene in the presence
of a base such as pyridine in a suitable solvent, for instance
dichloromethane. Where necessary, protected piperazines (II) can be
synthesized from commercially available monoalkyl- or
dialkyl-piperazines by treatment with reagents known to introduce
the desired protecting group e.g. di-tert-butyl dicarbonate or
9-fluorenylmethyl chloroformate. The protection of the piperazines
may also be accomplished by covalent linkage of the appropriate
piperazine nitrogen to a polymeric resin, e.g.,
polystyrene-PEG-hydroxytrityl resin in the case of P=trityl, using
methods known in the art. Mono or dialkyl-piperazines may be
prepared by those skilled in the art via a variety of methods which
includes, but is not limited to: reduction of mono or
dialkylpyrazines using e.g. catalytic hydrogenation or dissolved
metal reagents; alkylation of ethylene diamine and alkylated
analogues with e.g. alkyl-substituted 1,2-dihaloethane compounds,
alkyl-substituted 1,2-ethanediol compounds or alkyl-substituted
ethane-1,2-dialkylsulfonate compounds; reduction of a monoalkyl
substituted 2,5-diketopiperazine with e.g. sodium or lithium
borohydride or lithium aluminium hydride.
[0392] The alcohol (IV) may be commercially available or
alternatively may be synthesized via reduction of an aldehyde,
carboxylic acid, ester or amide derivative with a reagent such as
sodium or lithium borohydride or lithium aluminium hydride in a
suitable solvent or alternatively via Grignard addition of alkyl-
or aryl-magnesium halides or alkyl- or aryl-lithium nucleophiles to
aldehydes or carboxylic esters or amides. The aldehydes, carboxylic
acids, esters and amides may be commercially available or
synthesized according to methods known to those skilled in the art.
Such methods include but are not limited to formylation of an aryl
or heteroaryl containing starting-material, vicarious nucleophilic
substitution, hydrolysis of an alkyl halide or oxidation of an
aryl-methyl (tolyl) group.
[0393] Thiols of formula (V) may be prepared from (IV) by a variety
of methods e.g. displacement of an activated derivative of the
hydroxyl of (IV) with a sulfur nucleophile such as thiolacetic acid
followed by treatment with a reducing agent such as lithium
aluminium hydride. Activated hydroxyl derivatives include, but are
not limited to, mesylates, tosylates and in situ activation with
phosphorus compounds such as triphenylphosphine.
[0394] Thiols of formula (V) may be replaced by xanthogenates,
which are prepared in situ from alcohol (IV) with carbon disulfide
and a base such as sodium or potassium hydroxide in a solvent such
as tetrahydrofuran or acetone.
[0395] Compounds of formula (I) may be prepared from compounds of
formula (VI) by reaction with a reagent known to selectively remove
the protecting group (P) e.g. tert-butoxycarbonyl, triphenylmethyl
and 3,4-dimethoxybenzyl may be removed using an acid such as
hydrochloric acid or trifluoroacetic acid and
9-fluorenylmethoxycarbonyl may be removed by treatment with a base
such as morpholine.
[0396] Alternatively compounds of formula (I) where A.sup.1.dbd.O
may be prepared via Reaction Scheme (2) below. 8
[0397] Reaction of a piperazine (II) with carbon dioxide in the
presence of a base such as tetraalkylammonium (for alkyl preferably
ethyl or butyl) hydrogencarbonate or potassium hydride or
butyl-lithium or a metal such as lithium may produce the
piperazine-carboxylate (VII). Treatment of (VII) with halide (VIII)
(X means Cl, Br or I) in a suitable solvent may give a compound of
formula (VI) where A.sup.1.dbd.O. Halides of formula (VIII) may be
synthesized if not commercially available by methods known to those
skilled in the art. Such methods include, but are not limited to,
conversion of an alcohol of formula (IV) where A.sup.1.dbd.O via
treatment with triphenylphosphine and a halogen such as bromine;
formation and displacement of an alkyl or arylsulfonate such as
mesylate or tosylate with a halide salt such as sodium bromide in a
solvent such as tetrahydrofuran or acetone and halogenation of an
aralkyl or heteroaralkyl compound with a reagent such as
N-bromosuccinimide optionally in the presence of a co-reagent such
as AIBN (2,2'-azobisisobutyronitrile) or benzoyl peroxide.
Compounds of formula (VI) can be transformed into compounds of
formula (I) by methods as described above in Reaction Scheme 1.
[0398] If, in any of the other processes mentioned herein, R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and the substituent groups attached to
A.sup.2 are other than the one required, the substituent group may
be converted to the desired substituent by known methods. R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and the substituent groups attached to
A.sup.2 may also need protecting against the conditions under which
the reaction is carried out. In such a case, the protecting group
may be removed after the reaction has been completed.
[0399] Alternatively compounds of formula (I) where A.sup.1.dbd.O
may be prepared via Reaction Scheme (3) below. 9
[0400] A compound of formula (VI) can be prepared by reaction of
the piperazine (II) with an activated derivative (IX) or (X) of
alcohol (IV) optionally in the presence of a suitable base such as
triethylamine, PS-BEMP or pyridine in a solvent such as
acetonitrile, N-methylpyrrolidinone, dimethyl formamide,
tetrahydrofuran or dichloromethane. The piperazine may be protected
using a suitable protecting group (P) e.g. tert-butoxycarbonyl,
9-fluorenylmethoxycarbonyl- , allyloxycarbonyl, trimethylsilyl,
3,4-dimethoxybenzyl and trityl, preferably tert-butoxycarbonyl and
9-fluorenylmethoxycarbonyl.
[0401] The activated derivative (IX) may be synthesizedsynthesized
from alcohol (IV) with 1-chloroalkyl chloroformate, preferably
1-chloroethyl chloroformate, in the presence of a suitable base
such as triethylamine, PS-BEMP or pyridine in a solvent such as
acetonitrile, N-methylpyrrolidinone, dimethyl formamide,
tetrahydrofuran or dichloromethane.
[0402] The activated derivative (X) is either commercially
available or may be synthesizedsynthesized from alcohol (IV) by
treatment with a reagent such as phosgene, diphosgene, or
triphosgene, optionally in the presence of a base such as pyridine,
in a suitable solvent, e. g., dichloromethane or
tetrahydrofuran.
[0403] Compounds of formula (I) may be prepared from compounds of
formula (VI) by reaction with a reagent known to selectively remove
the protecting group (P) e.g. tert-butoxycarbonyl and
3,4-dimethoxybenzyl may be removed using an acid such as
hydrochloric acid or trifluoroacetic acid and
9-fluorenylmethoxycarbonyl may be removed by treatment with a base
such as morpholine.
[0404] The processes as described above may be carried out to give
a compound of the invention in the form of a free base or as an
acid addition salt. If the compound of the invention is obtained as
an acid addition salt, the free base can be obtained by basifying a
solution of the acid addition salt. Conversely, if the product of
the process is a free base, an acid addition salt, particularly a
pharmaceutically acceptable acid addition salt, may be obtained by
dissolving the free base in a suitable organic solvent and treating
the solution with an acid, in accordance with conventional
procedures for preparing acid addition salts from basic
compounds.
[0405] A further object of the present invention is the process for
the preparation of a compound according to formula I comprising the
deprotection of a compound according to formula 10
[0406] wherein R.sup.1 to R.sup.4, A.sup.1, A.sup.2, m and n are
defined as before and (P) is a nitrogen protecting group. Examples
of nitrogen protecting groups are tert-butoxycarbonyl,
9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyl,
3,4-dimethoxybenzyl and trityl, preferably tert-butoxycarbonyl and
9-fluorenylmethoxycarbonyl.
[0407] Another preferred aspect of this invention are the following
intermediates:
[0408] Cis-4-chlorocarbonyl-2,6-dimethyl-piperazine-1-carboxylic
acid tert-butyl ester;
[0409] Piperazine-1,4-dicarboxylic acid tert-butyl ester
4-trifluoromethoxy-benzyl ester;
[0410] Piperazine-1,4-dicarboxylic acid tert-butyl ester
2-fluoro-benzyl ester;
[0411]
4-(4-Benzyloxy-benzylsulfanylcarbonyl)-piperazine-1-carboxylic acid
tert-butyl ester;
[0412]
4-[4-(4-Fluoro-benzyloxy)-benzylsulfanylcarbonyl]-piperazine-1-carb-
oxylic acid tert-butyl ester;
[0413] Piperazine-1,4-dicarboxylic acid 4-benzyloxy-benzyl ester
9H-fluoren-9-ylmethyl ester;
[0414] Piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester
4-(4-fluoro-benzyloxy)-benzyl ester;
[0415] Piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester
4-methoxy-benzyl ester;
[0416] Piperazine-1,4-dicarboxylic acid benzhydryl ester
9H-fluoren-9-ylmethyl ester;
[0417] (RS)-Piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl
ester 1-phenyl-ethyl ester;
[0418] cis-2,6-Dimethylpiperazine-1,4-dicarboxylic acid
5-(2-chloropyridyl)methyl ester tert-butyl ester;
[0419] cis-2,6-Dimethylpiperazine-1,4-dicarboxylic acid
5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester tert-butyl ester;
[0420] Piperazine-1,4-dicarboxylic acid
5-[2-(3-chlorobenzyloxy)]pyridyl-m- ethyl ester tert-butyl
ester;
[0421]
[(4-tert-Butyl-dimethylsilyloxy)benzylsulfanylcarbonyl]-piperazine--
4-carboxylic acid tert-butyl ester;
[0422] Piperazine-1,4-dicarboxylic acid
(3-tert-butyldimethylsilyloxy)benz- yl ester tert-butyl ester;
[0423] Piperazine-1,4-dicarboxylic acid (3-hydroxy)benzyl ester
tert-butyl ester;
[0424] Piperazine-1,4-dicarboxylic acid 3-(2-phenylethoxy)benzyl
ester tert-butyl ester;
[0425] 4-(4-Fluoro-benzyloxy)-phenyl-methanethiol;
[0426] (RS)-Carbonic acid 4-benzyloxy-benzyl ester 1-chloro-ethyl
ester;
[0427] (RS)-Carbonic acid 1-chloro-ethyl ester
4-(4-fluoro-benzyloxy)-benz- yl ester;
[0428] (RS)-Carbonic acid 1-chloro-ethyl ester 4-methoxy-benzyl
ester;
[0429] (RS)-Carbonic acid benzhydryl ester 1-chloro-ethyl
ester;
[0430] (RS)-Carbonic acid 1-chloro-ethyl ester 1-phenyl-ethyl
ester.
[0431] Use of the compounds of formula I as therapeutically active
substances is a further object of the invention.
[0432] A further object of the invention are compounds of formula I
as described above for the production of medicaments for the
prophylaxis and therapy of illnesses which are caused by disorders
associated with the 5-HT.sub.2 receptor, particularly with the
5-HT.sub.2a, 5-HT.sub.2b or 5-HT.sub.2c subtype. Most preferred is
the 5-HT.sub.2c subtype.
[0433] Likewise an object of the invention is a pharmaceutical
composition comprising a compound of formula I and a
therapeutically inert carrier.
[0434] A further object of the invention is a compound of formula I
for the production of pharmaceutical compositions for the treatment
and prophylaxis of eating disorders and obesity.
[0435] Also an object of the invention is the use of a compound
according to formula I for the production of medicaments for the
treatment of diabetes mellitus, Type I diabetes, Type II diabetes,
diabetes secondary to pancreatic disease, diabetes related to
steroid use, Type III diabetes, hyperglycaemia, diabetic
complications and insulin resistance.
[0436] Particularly, a further object of the invention is the use
of a compound of formula I for the production of medicaments for
the treatment of Type II diabetes.
[0437] Another object of the invention is the use of compounds in
accordance with formula I for the production of medicaments for the
treatment and prophylaxis of disorders of the central nervous
system, cardiovascular disorders, gastrointestinal disorders,
diabetes insipidus and sleep apnoea.
[0438] Particularly an object of the invention is the above method
of treatment, wherein the disorders of the central nervous system
are selected from depression, atypical depression, bipolar
disorders, anxiety disorders, obsessive-compulsive disorders,
social phobias or panic states, sleep disorders, sexual
dysfunction, psychoses, schizophrenia, migraine and other
conditions associated with cephalic pain or other pain, raised
intracranial pressure, epilepsy, personality disorders, age-related
behavioural disorders, behavioural disorders associated with
dementia, organic mental disorders, mental disorders in childhood,
aggressivity, age-related memory disorders, chronic fatigue
syndrome, drug and alcohol addiction, bulimia, anorexia nervosa,
premenstrual tension, trauma, stroke, neurodegenerative diseases,
encephalitis and meningitis.
[0439] A further preferred embodiment of the present invention is
the above mentioned method of treatment by administering the
compounds according to formula I, wherein the cardiovascular
disorder is thrombosis.
[0440] Also preferred is the mentioned use of the compounds
according to formula I, wherein the gastrointestinal disorder is
dysfunction of gastrointestinal motility.
[0441] A further object of the invention are compounds in
accordance with formula I, when manufactured according to the
described process.
[0442] A further embodiment of the present invention is a method
for the treatment and prophylaxis of disorders of the central
nervous system, cardiovascular disorders, gastrointestinal
disorders, diabetes insipidus, and sleep apnoea, which method
comprises administering an effective amount of a compound of
formula I as described. Preferred is this method, wherein the
disorders of the central nervous system are selected from
depression, atypical depression, bipolar disorders, anxiety
disorders, obsessive-compulsive disorders, social phobias or panic
states, sleep disorders, sexual dysfunction, psychoses,
schizophrenia, migraine and other conditions associated with
cephalic pain or other pain, raised intracranial pressure,
epilepsy, personality disorders, age-related behavioural disorders,
behavioural disorders associated with dementia, organic mental
disorders, mental disorders in childhood, aggressivity, age-related
memory disorders, chronic fatigue syndrome, drug and alcohol
addiction, bulimia, anorexia nervosa, premenstrual tension, trauma,
stroke, neurodegenerative diseases, encephalitis and
meningitis.
[0443] A preferred object of the invention is a method for the
treatment and prophylaxis of eating disorders and obesity, which
method comprises administering an effective amount of a compound of
formula I.
[0444] Another object of the present invention is a method for the
treatment and prophylaxis of disorders selected from diabetes
mellitus, Type I diabetes, Type II diabetes, diabetes secondary to
pancreatic disease, diabetes related to steroid use, Type III
diabetes, hyperglycaemia, diabetic complications and insulin
resistance, which method comprises administering an effective
amount of a compound in accordance with formula I. Particularly
preferred is the above method for the treatment and prophylaxis of
Type II diabetes.
[0445] Particularly preferred is a method for the treatment and
prophylaxis of Type II diabetes.
[0446] A further preferred object is a method of treatment of
obesity in a human in need of such treatment which comprises
administration to the human a therapeutically effective amount of a
compound according to formula I and a therapeutically effective
amount of a lipase inhibitor, particularly, wherein the lipase
inhibitor is orlistat.
[0447] Also an object of the invention are the method as described
above for the simultaneous, separate or sequential
administration.
[0448] A further object of the invention is the use of a compound
of formula I in the manufacture of a medicament for the treatment
and prevention of obesity in a patient who is also receiving
treatment with a lipase inhibitor and particularly, wherein the
lipase inhibitor is orlistat.
[0449] Another object of the invention is the use of a compound
according to formula I in the manufacture of a medicament for the
treatment and prevention of diabetes mellitus, Type I diabetes,
Type II diabetes, diabetes secondary to pancreatic disease,
diabetes related to steroid use, Type III diabetes, hyperglycaemia,
diabetic complications and insulin resistance in a patient who is
also receiving treatment with a lipase inhibitor and particularly,
wherein the lipase inhibitor is orlistat.
[0450] Particularly preferred is the use of a compound according to
formula I in the manufacture of a medicament for the treatment and
prevention of Type II diabetes in a patient who is also receiving
treatment with a lipase inhibitor and particularly, wherein the
lipase inhibitor is orlistat.
[0451] Also an object of the invention is the pharmaceutical
composition comprising a compound of formula I, a therapeutically
inert carrier and further a therapeutically effective amount of a
lipase inhibitor, particularly, wherein the lipase inhibitor is
orlistat.
[0452] The compounds of formula (I) may be used in the treatment
(including prophylactic treatment) of disorders associated with
5-HT.sub.2 receptor function. The compounds may act as receptor
agonists or antagonists. Preferably, the compounds may be used in
the treatment (including prophylactic treatment) of disorders
associated with 5-HT.sub.2b and/or 5-HT.sub.2c receptor function.
Preferably, the compounds may be used in the treatment (including
prophylactic treatment) of disorders where a 5-HT.sub.2c receptor
agonist is required.
[0453] The compositions of the present invention may be formulated
in a conventional manner using one or more pharmaceutically
acceptable carriers. Thus, the active compounds of the invention
may be formulated for oral, buccal, intranasal, parenteral (e.g.,
intravenous, intramuscular or subcutaneous) transdermal or rectal
administration or in a form suitable for administration by
inhalation or insufflation.
[0454] For oral administration, the pharmaceutical compositions may
take the form of, for example, tablets or capsules prepared by
conventional means with pharmaceutically acceptable excipients such
as binding agents (e.g. pregelatinised maize starch,
polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers
(e.g. lactose, microcrystalline cellulose or calcium phosphate);
lubricants (e.g. magnesium stearate, talc or silica); disintegrants
(e.g. potato starch or sodium starch glycollate); or wetting agents
(e.g. sodium lauryl sulfate). The tablets may be coated by methods
well known in the art. Liquid preparations for oral administration
may take the form of, for example, solutions, syrups or
suspensions, or they may be presented as a dry product for
constitution with water or other suitable vehicle before use. Such
liquid preparations may be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents
(e.g. sorbitol syrup, methyl cellulose or hydrogenated edible
fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous
vehicles (e.g. almond oil, oily esters or ethyl alcohol); and
preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic
acid).
[0455] For buccal administration the composition may take the form
of tablets or lozenges formulated in conventional manner.
[0456] The active compounds of the invention may be formulated for
parenteral administration by injection, including using
conventional catheterization techniques or infusion. Formulations
for injection may be presented in unit dosage form e.g. in ampoules
or in multi-dose containers, with an added preservative. The
compositions may take such forms as suspensions, solutions or
emulsions in oily or aqueous vehicles, and may contain formulating
agents such as suspending, stabilizing and/or dispersing
agents.
[0457] Alternatively, the active ingredient may be in powder form
for reconstitution with a suitable vehicle, e.g. sterile
pyrogen-free water, before use.
[0458] The active compounds of the invention may also be formulated
in rectal compositions such as suppositories or retention enemas,
e.g., containing conventional suppository bases such as cocoa
butter or other glycerides.
[0459] For intranasal administration or administration by
inhalation, the active compounds of the invention are conveniently
delivered in the form of a solution or suspension from a pump spray
container that is squeezed or pumped by the patient or as an
aerosol spray presentation from a pressurized container or a
nebulizer, with the use of a suitable propellant, e.g.
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount. The
pressurized container or nebulizer may contain a solution or
suspension of the active compound. Capsules and cartridges (made,
for example, from gelatin) for use in an inhaler or insufflator may
be formulated containing a powder mix of a compound of the
invention and a suitable powder base such as lactose or starch.
[0460] A proposed dose of the active compounds of the invention for
oral, parenteral or buccal administration to the average adult
human for the treatment of the conditions referred to above (e.g.,
obesity) is 0.1 to 500 mg of the active ingredient per unit dose
which could be administered, for example, 1 to 4 times per day.
[0461] The invention will now be described in detail with reference
to the following examples. It will be appreciated that the
invention is described by way of example only and modification of
detail may be made without departing from the scope of the
invention.
Assay Procedures
[0462] Binding to Serotonin Receptors
[0463] The binding of compounds of formula (I) to serotonin
receptors was determined in vitro by standard methods. The
preparations were investigated in accordance with the assays given
below.
[0464] Method (a): For the binding to the 5-HT.sub.2C receptor, the
5-HT.sub.2C receptors were radiolabeled with [.sup.3H]-5-HT. The
affinity of the compounds for 5-HT.sub.2C receptors in a CHO cell
line was determined according to the procedure of D. Hoyer, G.
Engel and H. O. Kalkman, European J. Pharmacol., 1985, 118,
13-23.
[0465] Method (b): For the binding to the 5-HT.sub.2B receptor, the
5-HT.sub.2B receptors were radiolabeled with [3H]-5-HT. The
affinity of the compounds for human 5-HT.sub.2B receptors in a CHO
cell line was determined according to the procedure of K. Schmuck,
C. Ullmer, P. Engels and H. Lubbert, FEBS Lett., 1994, 342,
85-90.
[0466] Method (c): For the binding to the 5-HT.sub.2A receptor, the
5-HT.sub.2A receptors were radiolabeled with [.sup.125I]-DOI. The
affinity of the compounds for 5-HT.sub.2A receptors in a CHO cell
line was determined according to the procedure of D. J. McKenna and
S. J. Peroutka, J. Neurosci., 1989, 9, 3482-90.
[0467] The thus determined activity of the compound presented as a
calculated Ki of the Example is shown in Table 1. The Ki value is
definied as an inhibition Constance and is determined from the IC50
value as described in Cheng, Yung-Chi and Prusoff, W. H., Biochem.
Pharmacol., 1973, 22(23), 3099-108.
1 TABLE 1 Method (a) Method (b) Method (c) Compound Ki (2C)/nM Ki
(2B)/nM Ki (2A)/nM 32 15 370 6 22 44 4000 44 63 33 8300 550 121 15
8400 200
[0468] Preferred Ki (2C) values are below 10000 nM; especially
preferred Ki (2C) values are below 1000 nM, particularly preferred
Ki (2C) values are below 100 nM. Most preferred Ki (2C) values are
below 50 nM.
[0469] Functional Activity
[0470] The functional activity of compounds of formula (I) was
assayed using a Fluorimetric Imaging Plate reader (FLIPR). CHO
cells expressing the human 5-HT.sub.2C or human 5-HT.sub.2A
receptors were counted and plated into standard 96 well microtitre
plates on the day before testing to give a confluent monolayer. The
cells were then dye loaded with the calcium sensitive dye,
Fluo-3-AM. Unincorporated dye was removed using an automated cell
washer to leave a total volume of 100 .mu.L/well of assay buffer
(Hanks balanced salt solution containing 20 mM Hepes and 2.5 mM
probenecid). The drug (dissolved in 50 .quadrature.L of the assay
buffer) was added at a rate of 70 .mu.L/sec to each well of the
FLIPR 96 well plate during fluorescence measurements. The
measurements were taken at 1 sec intervals and the maximum
fluorescent signal was measured (approx 10-15 secs after drug
addition) and compared with the response produced by 10 .mu.M 5-HT
(defined as 100%) to which it was expressed as a percentage
response (relative efficacy). Dose response curves were constructed
using Graphpad Prism (Graph Software Inc.).
2 TABLE 2 h5-HT.sub.2c h5-HT.sub.2A Relative Relative EC50 Efficacy
EC50 Efficacy Compound (nM) (%) (nM) (%) 32 38 65 560 22 22 100 56
220 24 63 33 74 370 25 121 22 91 550 11
[0471] The compounds of formula (I) have activity at the
h5-HT.sub.2C receptor in the range of 10,000 to 0.1 nM.
[0472] Preferred activities at the h5-HT.sub.2C receptor are below
10000 nM; especially preferred below 1000 nM, particularly
preferred activities are below 100 nM. Most preferred activity at
the h5-HT.sub.2C receptor are below 50 nM.
[0473] The compounds of formula (I) have maximum functional
activity at the h5-HT.sub.2C receptor in the range of 0 to
100%.
[0474] Preferred maximal functional activity at the h5-HT.sub.2C
receptor as described above are above 30%; especially preferred
above 50%, particularly preferred above 60%. Most preferred maximal
functional activity at the h5-HT.sub.2C receptor are above 70%.
[0475] Regulation of Feeding Behaviour
[0476] The in vivo activity of compounds of formula (1) was assayed
for ability to regulate feeding behaviour by assaying food
consumption in food deprived animals as follows.
[0477] Test compounds are assessed following acute administration.
Each study utilises a between-subjects design (typically n=8) and
compares the effects of doses of the test agent to those of vehicle
and a positive control.
[0478] The anorectic drug d-fenfluramine normally serves as a
positive control. The route of drug administration, drug volume and
injection-test-interval are dependent upon the compounds used. A
palatable wet mash, made by adding powdered lab chow and water in
aratio of 1:2 and mixing to a smooth consistency, is presented in
120 mL glass jars for 60 minutes each day. Intake is measured by
weighing before and after each session. Care is taken to collect
all spillage. Animals are allowed to habituate to the wet mash meal
for 10 days. After drug administration, animals are allowed to
consume the wet mash. Food consumption is assayed at pre-determined
time points (typically, 1, 2 and 4 hours after administration).
Food intake data are subjected to one-way analysis of variance
(ANOVA) with drug as a between-subjects factor. A significant main
effect is followed up by the performance of Dunnett's test in order
to assess which treatment mean(s) are significantly different from
the control mean. All statistical analyses were performed using
Statistica Software, Version 5.0 (Statsofr Inc.) and Microsoft
Excel 7.0 (Microsoft Corp.).
[0479] The thus determined activity of the Example indicated that
the compounds maintain significant hypophagia 3 hours after a dose
of 30 mg/kg per os.
EXAMPLES
[0480] Abbreviations
[0481] PS-BEMP:
2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3-
,2-diazo-phosphorine on polystyrene
[0482] PS-NH2: 4-(Aminomethyl)-polystyrene
[0483] TBME: tert-Butyl methyl ether
[0484] Starting Materials
[0485] 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl
ester was prepared following a modified procedure of document DE 25
50 111, Rhone-Poulenc.
(+/-)4-chlorocarbonyl-2-ethylpiperazine-1-carboxylic acid
tert-butyl ester was prepared using the method described in DE
2550111 according to the following procedure:
[0486] To a stirred solution of 2-ethylpiperazine dihydrochloride
(J. Org. Chem., 1987, 52(6), 1045, 5.0 g) and triethylamine (9.3
ml) in DCM (50 ml) at 0.degree. C. was added
di-tert-butyl-dicarbonate (6.5 g). The mixture was warmed to room
temperature, stirred for 2 h, washed successively with water,
dilute sodium hydroxide solution, water and brine then dried
(sodium sulfate) and concentrated in vacuo to give the product as a
clear oil (5.1 g); .delta..sub.H (400 MHz, CDCl.sub.3) 3.78 (1H,
m), 3.71 (1H, d, J 12.5 Hz), 2.81 (1H, dt, J 11.5, 2.5 Hz), 2.69
(1H, t, J 10.5 Hz), 2.48 (1H, td, J 11.5, 3 Hz), 2.29 (1H, m), 2.17
(1H, m), 1.39 (9H, s), 1.31 (1H, dd, J 7.5, 6 Hz), 1.25 (1H, dd, J
7.5, 6 Hz) and 0.87 (3H, t, J 7 Hz); GC (150.degree. C. -10
min-320.degree. C.) 93%, 5.13 min.
[0487] (+/-)4-Chlorocarbonyl-2-ethylpiperazine-1-carboxylic acid
tert-butyl ester: a solution of (RS)
4-tert-butoxycarbonyl-2-ethylpiperaz- ine (3.95 g) and pyridine
(1.64 ml) in DCM (35 ml) was added dropwise to a stirred solution
of triphosgene (2.1 g) in DCM (100 ml) at 0.degree. C. under Ar.
The mixture was warmed to room temperature, stirred for 30 min then
washed with water (100 ml) and brine (100 ml). The organic solution
was dried (sodium sulfate) and concentrated in vacuo. The residue
was dissolved in isohexane, filtered and concentrated in vacuo to
give the product as a clear oil (3.73 g) which was used without
further purification; .delta..sub.H (400 MHz, CDCl.sub.3) 4.39-3.80
(4H, m), 3.39-2.69 (3H, m), 1.66 (2H, m), 1.47 (9H, s), 0.96 (2.7H,
d, J 7 Hz) and 0.89 (0.3H, d, J 7 Hz); GC (150.degree. C. -10 min
-320.degree. C.) 83%, 8.72 min.
[0488] (+/-)4-chlorocarbonyl-2-methylpiperazine-1-carboxylic acid
tert-butyl ester and
(R)4-chlorocarbonyl-2-methylpiperazine-1-carboxylic acid tert-butyl
ester were prepared according to the above method from commercially
available racemic 2-methylpiperazine and (R)2-methylpiperazine
respectively.
[0489] Tetrabutylammonium hydrogencarbonate was prepared as
described in St. C. Cheng, Ch. A. Blaine, M. G. Hill, K. R. Mann,
Inorg. Chem. 35, 7704 (1996); C. Venturello, R. D'Aloisio,
Synthesis 1985, 33.
[0490] N-Boc-piperazine is commercially available.
[0491] N-Fmoc-piperazine hydrobromide is commercially
available.
[0492] 4-(4-Fluorobenzyloxy)-benzyl alcohol is commercially
available.
[0493] 4-(4-Fluoro-benzyloxy)-phenyl-methanethiol was prepared in
analogy to S. Vetter, Synth. Commun. 28, 3219 (1998).
[0494] cis-N-Boc-2,6-dimethylpiperazine was prepared as described
in A. Muehlebach, P. Pino, Helv. Chim. Acta 73, 839 (1990).
[0495] 2,6-Difluoro-4-hydroxybenzyl alcohol was prepared according
to the following procedure:
[0496] To a stirred solution of 3,5-difluorophenol (14.5 g) and
potassium hydroxide (85%, 7.4 g) in water (30 mL) at 60.degree. C.
was added dropwise over 1 hour a solution of aqueous formaldehyde
(37%, 15.3 mL) in added water (30 mL). The mixture was cooled to
40.degree. C., stirred for 18 hours then cooled to 0.degree. C. The
mixture was carefully acidified with conc. HCl during which time a
white precipitate appeared. The mixture was stirred for 30 minutes
at 0.degree. C. then filtered. The filter-cake was washed with
ice-cold water and dried to give the product as a white solid (8.1
g, 46%); .delta..sub.H (400 MHz, DMSO-d.sub.6) 10.23 (1H, m, OH),
6.44 (1H, t, J 4 Hz), 6.39 (1H, t, J 4 Hz), 4.95 (1H, t, J 5.5 Hz,
OH) and 4.38 (2H, d, J 5.5 Hz); HPLC (XTERRA, MeOH--NH.sub.4OAc,
50%.fwdarw.80%) 94% (0.62 min).
[0497] 2-Fluoro-5-hydroxybenzyl alcohol was prepared according to
the following procedure: 2-Fluoro-5-hydroxybenzaldehyde: to a
stirred solution of 2-fluoro-5-methoxybenzaldehyde (18.3 g) in
dichloromethane (200 mL) at 0.degree. C. was added dropwise a
solution of boron tribromide in dichloromethane (1M, 120 mL, 1
eq.). The mixture was stirred for 3 h then concentrated to a volume
of .about.50 mL and partitioned between ethyl acetate (500 mL) and
water (500 mL). The organic layer was washed (water), dried
(magnesium sulfate) and concentrated to give a red oil (22.7 g).
The oil was purified by column chromatography (SiO.sub.2,
DCM.fwdarw.DIPE) to give the product as a pink crystalline solid
(9.9 g, 59% yield);
[0498] 2-Fluoro-5-hydroxybenzyl alcohol: to a stirred solution of
2-fluoro-5-hydroxybenzaldehyde (4.1 g) in methanol (50 mL) at
0.degree. C. was added portionwise sodium borohydride (0.55 g). The
mixture was warmed to room temperature, stirred for 1 hour then
partitioned between water (200 mL) and ethyl acetate (2.times.200
mL). The combined organics were washed (brine), dried (magnesium
sulfate) and concentrated to give 2-fluoro-5-hydroxybenzyl alcohol
as a yellow oil which crystallised on standing overnight (4.1 g,
95% yield):
[0499] Alternatively 2-fluoro-5-hydroxybenzyl alcohol was prepared
according to the following procedure:
[0500] 2-Fluoro-5-hydroxybenzyl alcohol: to a stirred solution of
2-fluoro-5-methoxybenzaldehyde (1.0 g) in toluene (30 ml) at
0.degree. C. under Ar was added dropwise a solution of DIBAL-H (1.0
M, toluene, 3.2 ml). The mixture was stirred for 30 min then heated
to 100.degree. C. and stirred for 18 h. The mixture was cooled to
0.degree. C. and quenched by dropwise addition of ethyl acetate (5
ml), methanol (2 ml) and water (1 ml). The mixture was stirred for
30 min then partitioned between dil. hydrochloric acid (30 ml) and
ethyl acetate (2.times.30 ml). The combined organics were washed
(water, brine), dried (sodium sulfate) and concentrated in vacuo.
The residue was triturated with isohexane-DCM (10:1) to give the
product as a white solid (0.56 g, 61%): .delta..sub.H (400 MHz,
DMSO-d.sub.6) 9.24 (1H, m, OH), 6.90 (1H, dd, J 10, 9 Hz), 6.85
(1H, q, J 3 Hz), 6.60 (1H, m), 5.15 (1H, m, OH) and 4.46 (2H, s);
HPLC (XTERRA, 20/50, 280 nm) 93% (1.09 min).
[0501] (R)2-Methyl-piperazine, (RS)2-methylpiperazine and
(RS)2-ethylpiperazine were loaded onto solid-phase supports using
the following procedure:
[0502] A mixture of polystyrene-PEG-hydroxytrityl resin (4 g,
NovaBiochem, 0.26 mmol/g loading, 1.04 mmol), freshly distilled
acetyl chloride (5 mL, 56 mmol) and toluene (50 mL) was heated
under reflux for 3 h then cooled to room temperature. The resin was
filtered off and washed three times each with toluene, THF,
dichloromethane and toluene again. The resin was used in the next
step immediately.
[0503] To a 20 mL solid-phase tube was added approximately half of
the resin from the previous step (2 g, 0.52 mmol)) and dry THF (10
mL). The tube was shaken for 10 minutes then the solvent was
removed by suction filtration. More THF (10 mL) and
(R)2-methylpiperazine (0.18 g, 1.8 mmol) were added and the mixture
was sealed and shaken for 18 hours. The solvent was removed by
suction filtration and the resin was sequentially washed three
times with THF, methanol, dichloromethane and THF again then dried
under vacuum.
[0504] S-4-hydroxybenzyl piperazine-1-thiocarboxylate was prepared
according to the following procedure adapted from: M. R. Tremblay
et al, Bioorg. Med. Chem., (1999), 7, 1013-1023.
[0505] 4-(tert-butydimethylsilyloxy)-benzaldehyde: to a stirred
solution of 4-hydroxybenzaldehyde (25.0 g, 205 mmol) in dry DMF
(200 mL) was added imidazole (28.0 g, 410 mmol) and TBDMS-Cl (32.4
g, 215 mmol) under an argon atmosphere. The resulting mixture was
stirred for 4 h at room temperature (rt) then water was added and
the mixture was extracted with ether (2.times.300 mL) and
dichloromethane (2.times.300 mL). The combined organics were dried
(MgSO.sub.4), filtered and concentrated under vacuum. The crude oil
was purified by filtration through silica gel (eluting with
hexane--EtOAc, 95:5) to give the product as a colourless oil (48.0
g, 99%).
[0506] 4-(tert-Butydimethylsilyloxy)-benzyl alcohol: to a stirred
solution of 4-(tert-butydimethylsilyloxy)-benzaldehyde (48.0 g, 203
mmol) in methanol (200 ML) at 0.degree. C. was added sodium
borohydride (11.6 g, 305 mmol) and the reaction was stirred at
0.degree. C. for 45 min. Water (200 mL) was added and the methanol
was removed under reduced pressure. The mixture was extracted with
ether (2.times.200 mL) and ethyl acetate (2.times.200 mL). The
combined organics were dried (MgSO.sub.4), filtered and
concentrated under vacuum to give the crude product, which was used
without further purification (48 g, quantitative).
[0507] Ethanethioic acid,
S-[4-(tert-butyldimethylsilyloxy)benzyl]ester: To an efficiently
stirred solution of triphenylphosphine (81 g, 309 mmol) in THF (200
mL) was added diethyl azodicarboxylate (62.5 g, 309 mmol) at
0.degree. C. The mixture was stirred for 30 min, after which time a
thick white precipitate was obtained. The crude
4-(tert-butydimethylsilyloxy)-b- enzyl alcohol (48 g) in THF (100
mL) and thiolacetic acid (36.1 g, 474 mmol) were added dropwise
while the temperature was maintained below 10.degree. C. The
reaction was stirred overnight while keeping the internal
temperature below 10.degree. C. The solvent was removed in vacuo
and the residue was purified by flash column chromatography
[SiO.sub.2: isohexane-ethyl acetate (9:1)] to give the product as a
viscous brown oil (30.7 g, 50%).
[0508] 4-(tert-Butyldimethylsilyloxy)-benzenemethanethiol: to a
stirred solution of ethanethioic acid,
S-[4-(tert-butyldimethylsilyloxy)benzyl]es- ter (30.7 g, 104 mmol)
in dry THF (300 mL) at 0.degree. C. under an argon atmosphere was
added lithium aluminium hydride (5.9 g, 156 mmol). The reaction was
stirred for 3 h at 0.degree. C. The mixture was quenched by careful
addition of EtOAc then water. The pH was brought to 5 with an
aqueous solution of 10% HCl and the resulting slurry was filtered.
The filtrate was extracted with EtOAc (2.times.100 mL) and the
combined organic layers were washed successively with Rochelle's
salt, brine, dried (MgSO.sub.4), filtered and concentrated to give
the product as a green oil (22.1 g, 84%).
[0509] S-4-(tert-butyl-dimethylsilyloxy)benzyl
4-tert-butoxycarbonylpipera- zine-1-thiocarboxylate: to a stirred
solution of 4-(tert-butyldimethylsily- loxy)-benzenemethanethiol
(10.5 g, 41 mmol) and triethylamine (69 mmol, 9.6 mL) in THF (500
mL) at 0.degree. C. was added 4-tert-butoxycarbonyl-1-
-chlorocarbonylpiperazine (8.56 g, 34 mmol) and DMAP (6.9 mmol,
0.84 g). The reaction mixture was warmed to 50.degree. C. and
stirred for 3 h then poured into water (500 mL) and extracted with
EtOAc (2.times.250 mL). The combined organic extracts were washed
with water (250 mL) then brine (500 mL), then dried (MgSO.sub.4)
and concentrated to reveal a brown oil. Chromatography [SiO.sub.2:
90/10, hexane/EtOAc)] gave the product as a yellow oil which
crystallised on standing (13.4 g, 85%): m.p. 53-54.degree. C.
.sup.1H-NMR (400 MHz, CDCl.sub.3): 0.18 (6H, s), 0.96 (9H, s), 1.46
(9H, s), 3.42-3.51 (8H, m), 4.12 (2H, s), 6.75 (2H, d, J=8.5 Hz)
and 7.18 (2H, d, J=8.5 Hz).
[0510] S-4-hydroxybenzyl
4-tert-butoxycarbonylpiperazine-1-thiocarboxylate- : to a stirred
solution of S-4-(tert-butyl-dimethylsilyloxy)benzyl
4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (10 g, 22 mmol)
in THF (100 mL) was added a solution of TBAF in THF (1 N, 24 mL, 24
mmol). The mixture was stirred at room temperature for 40 min then
diluted with water (200 mL) and extracted with EtOAc (2.times.250
mL). The combined organic extracts were washed successively with
water (250 mL) and brine (500 mL) then dried (MgSO.sub.4), filtered
and concentrated to reveal a brown oil. Trituration with
EtOAc/hexane afforded the product as a white solid (3.7 g, 47%):
.sup.1H-NMR (400 MHz, d.sub.6-DMSO) 9.32 (1H, m), 7.11dt (2H, t, J
8.5, 2.5 Hz), 6.67 (2H, t, J 8.5, 2.5 Hz), 4.02 (2H, s), 3.43 (4H,
m), 3.33 (4H, m) and 1.40 (9H, s).
[0511] All other starting materials and reagents are commercially
available unless otherwise stated.
Example 1
[0512] Piperazine-1-carboxylic acid 4-trifluoromethoxy-benzyl ester
hydrochloride
[0513] Piperazine-1,4-dicarboxylic acid tert-butyl ester
4-trifluoromethoxy-benzyl ester: 652 mg (1.5 mmol) PS-BEMP and 373
mg (1.5 mmol) 4-chlorocarbonyl-piperazine-1-carboxylic acid
tert-butyl ester was added to a solution of 192 mg (1.0 mmol)
4-trifluoromethoxybenzyl alcohol in 5 ml acetonitrile. The mixture
was heated to reflux for 24 h then cooled to rt, diluted with 5 ml
acetonitrile, 666 mg (4.5 mmol) PS-NH2 added and shaken at rt for
16 h. After filtration and evaporation the crude product is
purified by flash chromatography on silica gel with hexane/AcOEt
50:50:180 mg colourless crystalline solid. .sup.1H-NMR
(CDCl.sub.3): 1.45 s, 9H, 3.35-3.55 m, 8H, 5.14 s, 2H, 7.20 d, 2H
and 7.40 d, 2H, AB-system.
[0514] Piperazine-1-carboxylic acid 4-trifluoromethoxy-benzyl ester
hydrochloride: A solution of 174 mg (0.49 mmol)
piperazine-1,4-dicarboxyl- ic acid tert-butyl ester
4-trifluoromethoxy-benzyl ester in 4.9 ml 1.5M HCl/Et2O and 0.98 ml
abs. MeOH was stirred at rt for 3 h. Evaporation of the reaction
mixture provided 189 mg as colourless powder. .sup.1H-NMR
(d.sub.6-DMSO): 3.10 m, 4H and 3.62 m, 4H; 5.13 2, 2H; 7.40 d, 2H
and 7.53 d, 2H, AB-system; 9.2 br, 2H. MS (ISP): 305.2
(M+H).sup.+.
[0515] In analogy to Example 1 the following carbamates of Examples
2-24 were prepared from the given starting material that is either
commercially available or described in the literature:
Example 2
[0516] Piperazine-1-carboxylic acid 3,4-difluoro-benzyl ester
hydrochloride was prepared from 3,4-difluorobenzyl alcohol; MS
(ISP): 257.1 MH.sup.+.
Example 3
[0517] Piperazine-1-carboxylic acid 4-fluoro-benzyl ester
hydrochloride was prepared from 4-fluorobenzyl alcohol; MS (ISP):
239.3 MH.sup.+.
Example 4
[0518] Piperazine-1-carboxylic acid 4-bromo-benzyl ester
hydrochloride was prepared from 4-bromobenzyl alcohol; MS (ISP):
299.1 MH.sup.+.
Example 5
[0519] Piperazine-1-carboxylic acid 2-trifluoromethoxy-benzyl ester
hydrochloride was prepared from 2-trifluoromethoxy-benzyl alcohol;
MS (ISP): 305.2 MH.sup.+.
Example 6
[0520] Piperazine-1-carboxylic acid 2-chloro-5-nitro-benzyl ester
hydrochloride was prepared from 2-chloro-5-nitro-benzyl alcohol; MS
(ISP): 300.3 MH.sup.+.
Example 7
[0521] Piperazine-1-carboxylic acid 2-chloro-benzyl ester
hydrochloride was prepared from 2-chlorobenzyl alcohol; MS (ISP):
255.1 MH.sup.+.
Example 8
[0522] Piperazine-1-carboxylic acid biphenyl-4-ylmethyl ester
hydrochloride was prepared from 4-biphenylmethanol; MS (ISP): 297.3
MH.sup.+.
Example 9
[0523] Piperazine-1-carboxylic acid 3-methoxy-benzyl ester
hydrochloride was prepared from 3-methoxybenzyl alcohol; MS (ISP):
250.2 MH.sup.+.
Example 10
[0524] Piperazine-1-carboxylic acid 3-trifluoromethyl-benzyl ester
hydrochloride was prepared from 3-(trifluoromethyl)-benzyl alcohol;
MS (ISP): 289.2 MH.sup.+.
Example 11
[0525] Piperazine-1-carboxylic acid 4-trifluoromethyl-benzyl ester
hydrochloride was prepared from 4-(trifluoromethyl)-benzyl alcohol;
MS (ISP): 289.1 MH.sup.+.
Example 12
[0526] Piperazine-1-carboxylic acid naphthalen-2-ylmethyl ester
hydrochloride was prepared from 2-naphthalenemethanol; MS (ISP):
271.3 MH.sup.+.
Example 13
[0527] Piperazine-1-carboxylic acid naphthalen-1-ylmethyl ester
hydrochloride was prepared from 1-naphthalenemethanol; MS (ISP):
271.3 MH.sup.+.
Example 14
[0528] Piperazine-1-carboxylic acid 2-methyl-benzyl ester
hydrochloride was prepared from 2-methylbenzyl alcohol; MS (ISP):
235.4 MH.sup.+.
Example 15
[0529] Piperazine-1-carboxylic acid 2,4-dichloro-benzyl ester
hydrochloride was prepared from 2,4-dichlorobenzyl alcohol; MS
(EI): 288.0 M.sup.+.
Example 16
[0530] Piperazine-1-carboxylic acid 2,6-dichloro-benzyl ester
hydrochloride was prepared from 2,6-dichlorobenzyl alcohol; MS
(ISP): 289.1 MH.sup.+.
Example 17
[0531] Piperazine-1-carboxylic acid 4-tert-butyl-benzyl ester
hydrochloride was prepared from 4-tert.-butyl-benzyl alcohol; MS
(ISP): 277.3 MH.sup.+.
Example 18
[0532] Piperazine-1-carboxylic acid
2-fluoro-4-trifluoromethyl-benzyl ester hydrochloride was prepared
from 2-fluoro-4-trifluoromethyl-benzyl alcohol; MS (ISP): 307.2
MH.sup.+.
Example 19
[0533] Piperazine-1-carboxylic acid 2,4-difluoro-benzyl ester
hydrochloride was prepared from 2,4-difluorobenzyl alcohol; MS
(ISP): 257.1 MH.sup.+.
Example 20
[0534] Piperazine-1-carboxylic acid 2-chloro-4-fluoro-benzyl ester
hydrochloride was prepared from 2-chloro-4-fluorobenzyl alcohol; MS
(ISP): 273.2 MH.sup.+.
Example 21
[0535] Piperazine-1-carboxylic acid
4-fluoro-2-trifluoromethyl-benzyl ester hydrochloride was prepared
from 4-fluoro-2-trifluoromethyl-benzyl alcohol; MS (ISP): 307.3
MH.sup.+.
Example 22
[0536] Piperazine-1-carboxylic acid 4-difluoromethoxy-benzyl ester
hydrochloride was prepared from 4-difluoromethoxy-benzyl alcohol;
MS (ISP): 287.2 MH.sup.+.
Example 23
[0537] Piperazine-1-carboxylic acid 2,4-dimethyl-benzyl ester
hydrochloride was prepared from 2,4-dimethyl-benzyl alcohol; MS
(ISP): 248.2 MH.sup.+.
Example 24
[0538] Piperazine-1-carboxylic acid cyclohexylmethyl ester
hydrochloride was prepared from hydroxymethyl-cyclohexane; MS (EI):
226.3 M.sup.+.
Example 25
[0539] Piperazine-1-carboxylic acid 2-fluoro-benzyl ester
hydrochloride: Piperazine-1,4-dicarboxylic acid tert-butyl ester
2-fluoro-benzyl ester: A solution of 4.47 g N-Boc-piperazine in 40
ml acetonitrile was saturated with dry carbon dioxide gas at rt. To
this solution was added dropwise in 5 min. a solution of 8.50 g (28
mmol) terabutylammonium hydrogencarbonate (dried at 50.degree. C.
at 0.1 mbar for 1 h) in 30 ml acetonitrile, and then carbon dioxide
gas bubbled into the stirred solution at rt for 1 h. Then 2.90 g
(20 mmol) 2-fluorobenzyl chloride was added drop-wise within 5 min.
After stirring at rt for 3 h the reaction mixture was evaporated,
150 ml of water added and extracted with AcOEt. The organic layer
was washed with brine, dried over Na.sub.2SO.sub.4 and evaporated.
Purification by flash chromatography on silica gel with
hexane/AcOEt 50:50 provided 4.29 g piperazine-1,4-dicarboxylic acid
tert-butyl ester 2-fluoro-benzyl ester as colourless powder.
.sup.1H-NMR(CDCl.sub.3): 1.46 s, 9H; 3.35-3.55 m, 8H; 5.21 s, 2H;
7.02-7.20 m, 2H and 7.27-7.45 m, 2H. MS (EI): 338.1 M.sup.+.
[0540] Piperazine-1-carboxylic acid 2-fluoro-benzyl ester
hydrochloridewas prepared in analogy to Example 1. Colourless
powder, .sup.1H-NMR (CDCl.sub.3): 3.18 sbr, 4H and 3.85 sbr, 4H;
5.21 s, 2H; 7.03-7.22 m, 2H and 7.30-7.46 m, 2H; 10.1 br, 2H. MS
(ISP): 239.3 (M+H).sup.+.
[0541] In analogy to Example 25 the carbamates of Examples 26-31
were be prepared from the given starting material that is either
commercially available or described in the literature:
Example 26
[0542] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
4-chloro-benzyl ester hydrochloride
[0543] Prepared in analogy to Example 25 with
cis-N-Boc-2,6-dimethyl-piper- azine and 4-chloro-benzyl chloride.
Colourless powder, 1H-NMR (d.sub.6-DMSO): 1.30 d 7.2 Hz, 6H;
3.0-3.25 m, 4H and 4.2-4.4m, 2H; 5.11 s, 2H; 7.35-7.55 AB-system,
4H; 9.5 br, 2H. MS (ISP): 283.1 (M+H).sup.+.
Example 27
[0544] cis-2,6-Dimethyl-piperazine-1-carboxylic acid 3-cyano-benzyl
ester was prepared from 1-Boc-cis-3,5-dimethyl-piperazine and
3-cyano-benzyl bromide; MS (ISP): 274.3 MH.sup.+.
Example 28
[0545] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
4-methoxycarbonyl-benzyl ester hydrochloride was prepared from
1-Boc-cis-3,5-dimethyl-piperazine and methyl
4-(bromomethyl)-benzoate; MS (ISP): 307.3 MH.sup.+.
Example 29
[0546] Piperazine-1-carboxylic acid 4-cyano-benzyl ester
hydrochloride was prepared from 4-cyano-benzyl bromide; MS (ISP):
246.3 MH.sup.+.
Example 30
[0547] Piperazine-1-carboxylic acid 2-trifluoromethyl-benzyl ester
hydrochloride was prepared from methanesulfonic acid
2-trifluoromethyl-benzyl ester that was prepared from
2-trifluoromethyl-benzyl alcohol and methanesulfonyl chloride
following a text book procedure; MS (ISP): 289.2 MH.sup.+.
Example 31
[0548] Piperazine-1-carboxylic acid 4-chloro-2-fluoro-benzyl ester
hydrochloride was prepared from 4-chloro-2-fluoro-benzyl bromide;
.sup.1H-NMR (d.sub.6-DMSO): 3.07 m, 4H and 3.59m, 4H, piperazine-H;
5.13 s, 2H, OCH.sub.2; MS (ISP): 273.2 MH.sup.+.
Example 32
[0549] Piperazine-1-carbothioic acid S-(4-benzyloxy-benzyl)ester
hydrochloride:
4-(4-Benzyloxy-benzylsulfanylcarbonyl)-piperazine-1-carbox- ylic
acid tert-butyl ester: Under argon 84 mg (1.5 mmol) of solid KOH
was dissolved at rt in 214 mg (1 mmol) 4-(benzyloxy)-benzyl alcohol
and 0.5 ml acetone. Then 76 mg (1.1 mmol) carbon disulfide was
added and the mixture thoroughly stirred for 2 h. 323 mg (1.3 mmol)
4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester was
added and the mixture heated at reflux for 8 h. The reaction
mixture was cooled to rt, 3 ml of water added and extracted with
TBME. The organic phase was washed with water and brine to pH 7,
dried over Na.sub.2SO.sub.4 and evaporated. Purification of the
crude product by preparative HPLC on a PRO C18 column with a
H.sub.2O/MeCN gradient provided 87 mg
4-(4-benzyloxy-benzylsulfanylcarbonyl)-piperazine-1-carboxylic acid
tert-butyl ester as colourless powder. .sup.1H-NMR (CDCl.sub.3):
1.46 s, 9H; 3.40-3.65 m, 8H; 4.13 s, 2H; 5.04 s, 2H; 6.90 d, 2H and
7.25-7.48 m, 7H.
[0550] Piperazine-1-carbothioic acid S-(4-benzyloxy-benzyl)ester
hydrochloride: A solution of 86 mg (0.19 mmol)
4-(4-benzyloxy-benzylsulfa- nylcarbonyl)-piperazine-1-carboxylic
acid tert-butyl ester in 2.2 ml 1.5M HCl/Et.sub.2O and 0.45 ml abs.
MeOH was stirred at rt for 4 h. Evaporation of the reaction mixture
provided 64 mg product as colourless powder.
.sup.1H-NMR(d.sub.6-DMSO): 3.03-3.17 m, 4H and 3.58-3.73 m, 4H;
4.09 s, 2H; 5.08 s, 2H; 6.95 d, J=7.5 Hz, 2H and 7.26 d, J=7.5 Hz,
2H (AB-system) and 7.30-7.50 m, 5H; 9.2 br, 2H. MS (ISP): 343.2
(M+H).sup.+.
[0551] In analogy to Example 32 the following thiocarbamates of
Examples 33-39 were prepared from the given starting material that
is either commercially available or described in the
literature:
Example 33
[0552] Piperazine-1-carbothioic acid S-(4-bromo-benzyl)ester
hydrochloride was prepared from 4-bromobenzyl alcohol; .sup.1H-NMR
(d.sub.6-DMSO): 3.10 m, 4H and 3.68 m, 4H, piperazine-H; 4.12 s,
2H, SCH.sub.2; MS (ISP): 317.1 MH.sup.+.
Example 34
[0553] Piperazine-1-carbothioic acid
S-(4-trifluoromethoxy-benzyl)ester hydrochloride was prepared from
4-trifluoromethoxy-benzyl alcohol; .sup.1H-NMR (d.sub.6-DMSO): 3.12
m, 4H and 3.70 m, 4H, piperazine-H; 4.21 s, 2H, SCH.sub.2; MS
(ISP): 321.3 MH.sup.+.
Example 35
[0554] Piperazine-1-carbothioic acid S-(4-fluoro-benzyl)ester
hydrochloride was prepared from 4-fluoro-benzyl alcohol;
.sup.1H-NMR (d.sub.6-DMSO): 3.10 m, 4H and 3.68 m, 4H,
piperazine-H; 4.14 s, 2H, SCH.sub.2; MS (ISP): 255.1 MH.sup.+.
Example 36
[0555] Piperazine-1-carbothioic acid S-(2,4-difluoro-benzyl)ester
hydrochloride was prepared from 2,4-difluoro-benzyl alcohol;
.sup.1H-NMR (d.sub.6-DMSO): 3.10 m, 4H and 3.68 m, 4H,
piperazine-H; 4.14 s, 2H, SCH.sub.2; MS (ISP): 273.2 MH.sup.+.
Example 37
[0556] Piperazine-1-carbothioic acid S-(4-methoxy-benzyl)ester
hydrochloride was prepared from 4-methoxy-benzyl alcohol;
.sup.1H-NMR (d.sub.6-DMSO): 3.10 m, 4H and 3.67 m, 4H,
piperazine-H; 3.72 s, 3H, OCH.sub.3; 4.09 s, 2H, SCH.sub.2; MS
(ISP): 267.3MH.sup.+.
Example 38
[0557] Piperazine-1-carbothioic acid S-(2,4-dimethyl-benzyl)ester
hydrochloride was prepared from 2,4-dimethylbenzyl alcohol;
.sup.1H-NMR (d.sub.6-DMSO): 2.23 s, 3H, and 2.27 s, 3H,
2.times.CH.sub.3-aryl; 3.10 m, 4H and 3.66 m, 4H, piperazine-H;
4.10 s, 2H, SCH.sub.2; MS (ISP): 265.3 MH.sup.+.
Example 39
[0558] Piperazine-1-carbothioic acid
S-(2-fluoro-4-trifluoromethyl-benzyl)- ester hydrochloride was
prepared from 2-fluoro-4-trifluoromethyl-benzyl alcohol;
.sup.1H-NMR (d.sub.6-DMSO): 3.10 m, 4H and 3.67 m, 4H,
piperazine-H; 4.24 s, 2H, SCH.sub.2; MS (ISP): 323.3 MH.sup.+.
Example 40
[0559] Piperazine-1-carbothioic acid
S-[4-(4-fluoro-benzyloxy)-benzyl]este- r hydrochloride:
4-(4-Fluoro-benzyloxy)-phenyl-methanethiol in analogy to S. Vetter,
Synth. Commun. 28, 3219 (1998): A mixture of 6.00 (26 mmol)
4-(4-fluorobenzyloxy)-benzyl alcohol and 3.93 g (52 mmol) thiourea
was dissolved at 50.degree. C. in water/acetone 1:1.5. To this
solution 7.75 ml 5N HCl was added dropwise and the mixture stirred
at 50.degree. C. for 16 h. Then the solution was cooled and
extracted quickly twice with Et.sub.2O, the aqueous layer made
alkaline by addition of 3.1 g (78 mmol) NaOH pellets and heated to
reflux for 3 h. Acidification of the reaction mixture at rt with 5N
HCl, extraction with AcOEt, drying with Na.sub.2SO.sub.4 and
evaporation furnished 6.25 g 4-(4-fluoro-benzyloxy)--
phenyl-methanethiol as a colourless powder: mp. 77-80.degree. C.
.sup.1H-NMR (d.sub.6-DMSO): 2.77 t, J=7.5 Hz, 1H; 3.68 d, J=7.5 Hz,
2H; 5.06 s, 2H; 6.94 d, 2H and 7.18-7.32 m, 4H and 7.45-7.58 m,
2H.
[0560]
4-[4-(4-Fluoro-benzyloxy)-benzylsulfanylcarbonyl]-piperazine-1-carb-
oxylic acid tert-butyl ester: 5.84 g (23.5 mmol)
4-chlorocarbonyl-piperazi- ne-1-carboxylic acid tert-butyl ester
were added to a solution of 6.0 g (24.2 mmol)
4-(4-fluoro-benzyloxy)-phenyl-methanethiol in 14.6 ml pyridine. The
solution was heated to 100.degree. C. for 3.5 h, then cooled to rt,
10 ml of water added and the volume reduced to a third. The
resulting precipitate is collected, washed with water and dried.
The crude product is re-crystallized from hexane/AcOEt. Flash
chromatography on silica gel provided 4.90 g
4-[4-(4-fluoro-benzyloxy)-benzylsulfanylcar-
bonyl]-piperazine-1-carboxylic acid tert-butyl ester as colourless
powder, mp: 123-124.degree. C. 1H-NMR (CDCl.sub.3): 1.46 s, 9H;
3.38-3.60 m, 8H; 4.13 s, 2H; 5.00 s, 2H; 6.89 d, 2H, 7.06 t, 2H,
7.28 d, 2H and 7.40 dd, 2H.
[0561] Piperazine-1-carbothioic acid
S-[4-(4-fluoro-benzyloxy)-benzyl]este- r hydrochloride: A solution
of 4.89 g (10.6 mmol) 4-[4-(4-fluoro-benzyloxy-
)-benzylsulfanylcarbonyl]-piperazine-1-carboxylic acid tert-butyl
ester in 120.6 ml 1.5M HCl/Et.sub.2O and 24.1 ml abs. MeOH was
stirred at rt for 6 h. Evaporation of the reaction mixture provided
3.96 g piperazine-1-carbothioic acid
S-[4-(4-fluoro-benzyloxy)-benzyl]ester hydrochloride as colourless
powder, mp. 169-169.5.degree. C. .sup.1H-NMR(d.sub.6-DMSO): 3.05 m,
4H and 3.58-3.75 m, 4H; 4.09 s, 2H; 5.06 s, 2H; 6.94 d, 2H,
7.17-7.30 m, 4H and 7.43-7.55 m, 2H; 9.2 br, 2H. MS (ISP): 361.2
(M+H).sup.+.
Example 41
[0562] Piperazine-1-carboxylic acid 4-benzyloxy-benzyl ester
[0563] (RS)-Carbonic acid 4-benzyloxy-benzyl ester 1-chloro-ethyl
ester: A solution of 1.07 g (5.0 mmol) 4-benzyloxybenzyl alcohol
and 0.786 g (5.5 mmol) 1-chloroethyl chloroformate in 25 ml
CH.sub.2Cl.sub.2 is cooled to 0.degree. C. and 0.435 g (5.5 mmol)
pyridine added. After stirring at rt for 2 h the reaction mixture
is quenched with 1N HCl, the organic phase separated and washed
with sat. NaHCO.sub.3 solution and brine, dried over
Na.sub.2SO.sub.4 and evaporated: 1.58 g (98%) (RS)-carbonic acid
4-benzyloxy-benzyl ester 1-chloro-ethyl ester as light yellow oil.
.sup.1H-NMR (CDCl.sub.3): 1.81 d, J=6 Hz, 3H; 5.07 s, 2H; 5.14 and
5.17, AB-system J=15 Hz, 2H; 6.43 q, J=6 Hz, 1H; 6.97 d, J=8.5 Hz,
2H and 7.30-7.45 m, 7H.
[0564] Piperazine-1,4-dicarboxylic acid 4-benzyloxy-benzyl ester
9H-fluoren-9-ylmethyl ester: A solution of 1.47 g (4.7 mmol)
N-Fmoc-piperazine (obtained from N-Fmoc-piperazine hydrobromide by
treatment with aqueous NaHCO.sub.3 and extraction with TBME, drying
the organic layer over Na.sub.2SO.sub.4 and evaporation under
reduced pressure at <30.degree. C.) in 18 ml CH.sub.2Cl.sub.2 at
0.degree. C. was added dropwise to a solution of 1.51 g (4.7 mmol)
(RS)-carbonic acid 4-benzyloxy-benzyl ester 1-chloro-ethyl ester in
57 ml of CH.sub.2Cl.sub.2 . The reaction is slightly exothermic and
a colourless precipitate is formed. After 1 h at 0.degree. C. the
mixture was allowed to warm to rt and stirred for further 62 h.
Then the reaction is quenched with 2.35 ml 4M K.sub.2CO.sub.3,
filtered over a plug of Na.sub.2SO.sub.4 and evaporated. The crude
product (2.67 g) was purified by flash-chromatography on silica gel
with hexane/AcOEt 50:50 as eluent: 1.54 g (60%) RO-72-0160/000 as
yellow solid. IR (Nujol): 1699 cm.sup.-1. .sup.1H-NMR (CDCl.sub.3):
3.25-3.60 br, 8H; 4.23 t, J=6.4 Hz, 1H; 4.48 d, J=6.4 Hz, 2H; 5.06
s and 5.07 s, 4H; 6.97 d, J=8.4 Hz, 2H, 7.26-7.45, m 11H, 7.55 d,
J=7.6 Hz, 2H and 7.76 d, J=7.6 Hz, 2H. MS (ISP): 566.4
(M+NH.sub.4).sup.+; 571.4 (M+Na).sup.+.
[0565] Piperazine-1-carboxylic acid 4-benzyloxy-benzyl ester: A
solution of 274 mg (0.5 mmol) piperazine-1,4-dicarboxylic acid
4-benzyloxy-benzyl ester 9H-fluoren-9-ylmethyl ester in 13 ml
morpholine was stirred at rt for 1 h. Then 23 ml of chilled water
was added, the suspension filtered and the filtrate extracted with
TBME. The organic layer was washed with water, brine, dried over
Na.sub.2SO.sub.4 and evaporated: 54 mg piperazine-1-carboxylic acid
4-benzyloxy-benzyl ester as light yellow, waxy solid. MIR: 3300
cm.sup.-1, 1688 cm.sup.-1. .sup.1H-NMR (CDCl.sub.3): 1.77 br, 1H;
2.75-2.90 m, 4H and 3.40-3.50 m, 4H; 5.06 s and 5.07 s, 4H; 6.96 d,
J=8.8 Hz, 2H and 7.28-7.44 m, 7H. MS (ISP): 327.3 (M+H).sup.+.
[0566] In analogy to Example 41 the following carbamates of
Examples 42-45 were prepared from the given starting material that
is either commercially available or described in the
literature.
Example 42
[0567] Piperazine-1-carboxylic acid 4-(4-fluoro-benzyloxy)-benzyl
ester (RS)-Carbonic acid 1-chloro-ethyl ester
4-(4-fluoro-benzyloxy)-benzyl ester: Prepared in analogy to
(RS)-carbonic acid 4-benzyloxy-benzyl ester 1-chloro-ethyl ester
(Example 41) from 4-(4-fluoro-benzyloxy)-benzyl alcohol and
1-chloroethyl chloroformate: light yellow oil. .sup.1H-NMR
(CDCl.sub.3): 1.81 d, J=5.5 Hz, 3H; 5.03 s, 2H; 5.13 and 5,18 J=5.5
Hz, AB-system, 2H; 6.43 q, 1H; 6.95 d, J=8.4 Hz, 2H, 7.07 t J=8.4
Hz, 2H, 7.28-7.45 m, 4H.
[0568] Piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester
4-(4-fluoro-benzyloxy)-benzyl ester: Prepared in analogy to
piperazine-1,4-dicarboxylic acid 4-benzyloxy-benzyl ester
9H-fluoren-9-ylmethyl ester (Example 41) from (RS)-carbonic acid
1-chloro-ethyl ester 4-(4-fluoro-benzyloxy)-benzyl ester) and
N-Fmoc-piperazine: yellow solid. .sup.1H-NMR (CDCl.sub.3): 3.3-3.6
m, 8H; 4.23 t, J=6 Hz, 1 H; 4.48 d, J=6 Hz, 2H; 5.03 s, 2H; 5.08 s,
2H; 6.95 d, J=8.5 Hz, 2H, 7.08 t, J=8.5 Hz, 2H, 7.25-7.46 m, 8H,
7.55 d, J=7 Hz, 2H and 7.77 d, J=7 Hz, 2H.
[0569] Piperazine-1-carboxylic acid 4-(4-fluoro-benzyloxy)-benzyl
ester: Prepared in analogy to piperazine-1-carboxylic acid
4-benzyloxy-benzyl ester (Example 41) from
piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester
4-(4-fluoro-benzyloxy)-benzyl ester and morpholine: colourless,
waxy solid: IR (Nujol): 3341 cm.sup.-1, 1689 cm.sup.-1. .sup.1H-NMR
(CDCl.sub.3): 1.75 br, 1H; 2.85-2.90 m, 4H and 3.40-3.55 m, 4H;
5.02 s, 2H; 5.07 s, 2H; 6.94 d, J=8.4 Hz, 2H, 7.07 t, J=8.8 Hz, 2H,
7.30 d, J=8.4 Hz, 2H and 7.38-7.42 m, 2H. MS (EI): 344.3
M.sup.+.
Example 43
[0570] Piperazine-1-carboxylic acid 4-methoxy-benzyl ester
hydrochloride was prepared from 4-methoxy-benzyl alcohol via the
Following Intermediates
[0571] (RS)-Carbonic acid 1-chloro-ethyl ester 4-methoxy-benzyl
ester: .sup.1H-NMR (CDCl.sub.3): 1.81 d, J=8.2 Hz, 3H; 3.81 s, 3H;
5.14 and 5.18 AB-system, J=16 Hz, 2H; 6.42 1, J=8.2 Hz, 1H; 6.90 d,
J=8 Hz, 2H and 7.36 d, J=8 Hz, 2H. MS (EI): 244.1 M.sup.+.
[0572] Piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl ester
4-methoxy-benzyl ester: .sup.1H-NMR (CDCl.sub.3): 3.32-3.58 br, 8H;
3,81 s, 3H; 4.24 t, J=6 Hz, 1H; 4.58 d, J=6 Hz, 2H; 5.07 s, 2H;
6.92 d, J=8 Hz, 2H, 7.54-7.46 m, 6H, 7.54 d, J=8 Hz, 2H, 7.78 d,
J=8 Hz, 2H.
[0573] Piperazine-1-carboxylic acid 4-methoxy-benzyl ester
hydrochloride: Deprotection with morpholine led to
piperazine-1-carboxylic acid 4-methoxy-benzyl ester. The
hydrochloride was prepared by addition of HCl/Et.sub.2O to a
solution of the free base in Et.sub.2O followed by evaporation.
.sup.1H-NMR (d6-DMSO): 3.10 m, 4H and 3.60 m, 4H, piperazine-H;
5.02 s, 2H. MS (ISP): 251.2 MH.sup.+.
Example 44
[0574] Piperazine-1-carboxylic acid benzhydryl ester was Prepared
from diphenyl carbinol via he Following Intermediates
[0575] (RS)-Carbonic acid benzhydryl ester 1-chloro-ethyl ester:
.sup.1H-NMR (CDCl.sub.3): 1.83 d, J=5.8 Hz, 3H; 6.41 q, J=5.8 Hz,
1H; 6.75 s, 1H; 7.25-7.43 m, 10H.
[0576] Piperazine-1,4-dicarboxylic acid benzhydryl ester
9H-fluoren-9-ylmethyl ester: .sup.1H-NMR (CDCl.sub.3): 3.32-3.68
br, 8H; 4.24 t, J=6 Hz, 1H; 4.48 d, J=6 Hz, 2H; 6.82 s, 1H;
7.25-7.44 m, 14H and 7.56 d, J=8 Hz, 2H and 7.78 d, J=8 Hz, 2H.
[0577] Piperazine-1-carboxylic acid benzhydryl ester: .sup.1H-NMR
(CDCl.sub.3): 1.70 br, 1H; 2.80-2.85 m, 4H and 3.40-3.70 m, 4H,
piperazine-H; 6.82 s, 1H; 7.25-7.35 m, 10H. MS (ISP): 297.3
MH.sup.+.
Example 45
[0578] (RS)-Piperazine-1-carboxylic acid 1-phenyl-ethyl ester was
Prepared from (RS)-1-phenylethanol via the Following
Intermediates
[0579] (RS)-Carbonic acid 1-chloro-ethyl ester 1-phenyl-ethyl
ester: .sup.1H-NMR (CDCl.sub.3): 1.62 d, J=6.5 Hz and 1.64 d, J=6.5
Hz, 3H; 1.79 d, J=5.8 Hz and 1.64 d, J=5.8 Hz, 3H; 5.77 q, J=6.5 Hz
and 5.80 q, J=6.5 Hz, 1H; 6.37 q, J=5.8 Hz and 6.41 q, J=5.8 Hz,
1H; 7.37 m, 5H.
[0580] (RS)-Piperazine-1,4-dicarboxylic acid 9H-fluoren-9-ylmethyl
ester 1-phenyl-ethyl ester: .sup.1H-NMR (CDCl.sub.3): 1.56 d, J=6.5
Hz, 3H; 3.32-3.58 br, 8H; 4.24 t, J=6 Hz, 1H; 4.68 d, J=6 Hz, 2H;
5.83 d, J=6.5 Hz, 1H; 7.25-7.44 m, 9H and 7.56 d, J=8 Hz, 2H and
7.78 d, J=8 Hz, 2H.
[0581] (RS)-Piperazine-1-carboxylic acid 1-phenyl-ethyl ester:
.sup.1H-NMR (CDCl.sub.3): 1.54 d, J=4 Hz, 3H; 1.68 br, 1H;
2.75-2.85 m, 4H and 3.40-3.55 m, 4H, piperazine-H; 5.82 q, J=4 Hz,
1H; 7.25-7.38 m, 5H. MS (EI): 234.2 M.sup.+.
Example 46
[0582] Piperazine-1-carboxylic acid phenethyl ester
[0583] Phenethyl alcohol (2 eq), triethylamine (3 eq) and pyridine
(1 eq) was added to a solution of
4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester in
dichloromethane (30 vol.) and the mixture was shaken at 25.degree.
C. for 6 days. The mixture was evaporated, and the resultant crude
material purified by preparative HPLC [C18, 10 mM aqueous
NH.sub.4OAc solution:MeOH] to afford the intermediate product,
which was used immediately in the next step.
[0584] A solution of HCl in dioxane (4 M, 10 eq) was added to a
solution of the above intermediate in methanol (50 volumes) and the
mixture was shaken for 16 h. Evaporation to dryness afforded the
desired product.
[0585] .sup.1H-NMR (400 MHz, d.sub.6-DMSO): 2.90 (2H, t, J=6.5 Hz),
2.99-3.06 (4H, m), 3.52-3.59 (4H, m), 4.22 (2H, t, J=6.5 Hz),
7.19-7.34 (5H, m) and 9.29-9.43 (2H, br s); HPLC: [XTERRA;
methanol-10 mM aqueous NH.sub.4OAc (40:60); 2 mL/min; 210 nm] 100%
(0.98 min).
Example 47
[0586] cis-2,6-Dimethylpiperazine-1-carboxylic acid
5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester fumarate
[0587] cis-2,6-Dimethylpiperazine-1,4-dicarboxylic acid
5-(2-chloropyridyl)-methyl ester tert-butyl ester: A solution of
2-chloro-5-(hydroxymethyl)pyridine (2.6 g, 18 mmol),
1-tert-butoxycarbonyl-2,6-dimethyl-4-chlorocarbonylpiperazine (3.8
g, 14 mmol), pyridine (1.5 mL, 19 mmol) and triethylamine (7.6 mL,
52 mmol) in dichloromethane (100 mL) was stirred for 96 h. The
mixture was concentrated in vacuo then partitioned between water
(100 mL) and ethyl acetate (3.times.50 mL). The combined organic
extracts were washed with water and brine, then dried over sodium
sulfate, concentrated in vacuo and purified by flash column
chromatography [SiO.sub.2; isohexane--ethyl acetate (4:1)] to give
the product as a white solid (1.7 g, 32%), m.p. 75-76.degree. C.
.sup.1H-NMR (400 MHz, CDCl.sub.3): 8.40 (1H, d, J=2.5 Hz), 7.67
(1H, dd, J=2.5, 8 Hz), 7.33 (1H, d, J=8 Hz), 5.14 (2H, s),
4.23-4.14 (2H, m), 4.04-3.82 (2H, m), 3.04-2.86 (2H, m), 1.47 (9H,
s) and 1.23 (6H, d, J=7 Hz).
[0588] cis-2,6-Dimethylpiperazine-1,4-dicarboxylic acid
5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester tert-butyl ester:
Tris-[2-(2-methoxyethoxy)ethyl]amine (0.02 g, 0.007 mmol) was added
to a stirred mixture of cis-2,6-Dimethylpiperazine-1,4-dicarboxylic
acid 5-(2-chloropyridyl)methyl ester tert-butyl ester(0.25 g, 0.7
mmol), 3-chlorobenzyl alcohol (0.14 g, 1.0 mmol), potassium
carbonate (0.09 g, 0.7 mmol) and powdered potassium hydroxide (85%,
0.17 g, 2.6 mmol) in toluene (10 mL). The mixture was heated to
120.degree. C., stirred for 4 h, cooled to room temperature, poured
into water (20 mL) and extracted with ether (3.times.30 mL). The
combined organic extracts were washed with water and brine, then
dried over sodium sulfate, concentrated in vacuo and purified by
flash column chromatography [SiO.sub.2; isohexane--ethyl acetate
(9:1) to (3:1)] to give the product as a viscous oil (0.13 g, 40%).
.sup.1H-NMR (400 MHz, CDCl.sub.3): 8.16 (1H, d, J=2.5 Hz), 7.63
(1H, dd, J=2.5, 8.5 Hz), 7.45 (1H, s), 7.34-7.27 (3H, m), 6.81 (1H,
d, J=8.5 Hz), 5.36 (2H, s), 5.08 (2H, s), 4.22-4.14 (2H, m),
4.05-3.80 (2H, m), 3.08-2.84 (2H, m), 1.47 (9H, s) and 1.22 (6H, d,
J=7 Hz); HPLC [Xterra, 2.0 mL/min; methanol-10 mM aqueous ammonium
acetate solution (50:50) to (80:20) over 5 min then (80:20)] 97%
(7.81 min).
[0589] cis-2,6-Dimethylpiperazine-1-carboxylic acid
5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester fumarate: a solution
of hydrogen chloride in dioxan (4 M, 0.61 mL, 2.4 mmol) was added
drop-wise to a stirred solution of
cis-2,6-Dimethylpiperazine-1,4-dicarboxylic acid
5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester tert-butyl ester
(0.12 g, 0.24 mmol) in methanol (5 mL). The mixture was stirred for
18 h then concentrated in vacuo. The residue was partitioned
between ether (2.times.10 mL) and aqueous sodium hydroxide solution
(2 M, 10 mL). The combined organic layers were washed with water
and brine then dried over sodium sulfate, concentrated in vacuo,
dissolved in warm 2-propanol (1 mL) and added drop-wise to a
stirred solution of fumaric acid (0.033 g, 0.28 mmol) in warm
2-propanol (1 mL). The mixture was cooled to 0.degree. C., stirred
for 30 min then filtered. The filter-cake was washed with
2-propanol and ether then dried in vacuo to give the product as a
white solid (0.071 g, 57%), m.p. 172.degree. C. (dec.). .sup.1H-NMR
(400 MHz, d.sub.6-DMSO): 8.18 (1H, d, J=2.5 Hz), 7.76 (1H, dd,
J=2.5, 8.5 Hz), 7.50 (1H, s), 7.42-7.36 (3H, m), 6.93 (1H, d, J=8.5
Hz), 6.59 (2H, s), 5.37 (2H, s), 5.04 (2H, s), 4.01-3.93 (2H, m),
2.77 (2H, d, J=12 Hz), 2.70 (2H, dd, J 4, 12 Hz) and 1.18 (6H, d,
J=7 Hz).
Example 48
[0590] Piperazine-1-carboxylic acid
5-[2-(3-chlorobenzyloxy)]pyridyl-methy- l ester fumarate
[0591] 6-(3-Chlorobenzyloxy)nicotinic acid: 6-chloronicotinic acid
(1.0 g, 6.3 mmol)) was added portion-wise over 30 min to a stirred
suspension of sodium hydride (60%, 0.76 g, 19 mmol) in toluene (10
mL. The mixture was stirred for 30 min then cooled to 0.degree. C.
A solution of 3-chloro-benzyl alcohol (0.69 g, 6.4 mmol) in toluene
(5 mL) was added drop-wise over 10 min. The mixture was warmed to
room temperature, DMF (20 mL) was added and the mixture was heated
to 95.degree. C. and stirred for 18 h. The mixture was cooled to
room temperature then poured into water (30 mL). The aqueous
mixture was acidified to pH 2 and extracted with ethyl acetate
(2.times.30 mL). The combined organic extracts were washed with
water and brine, then dried over sodium sulfate and concentrated in
vacuo to give a yellow solid (2.36 g). The residue was
re-crystallised [2-propanol-water, (2:1)] to give the product as a
white solid (0.85 g, 51%), m.p. 158.degree. C. (dec.). .sup.1H-NMR
(400 MHz, CDCl.sub.3): 8.93 (1H, d, J=2.5 Hz), 8.24 (1H, dd, J=2.5,
8.5 Hz), 7.46 (1H, s), 7.35-7.29 (3H, m), 6.87 (1H, dd, J=1, 8.5
Hz) and 5.45 (2H, s).
[0592] 2-(3-Chlorobenzyloxy)-5-(hydroxymethyl)pyridine:
6-(3-chlorobenzyloxy)nicotinic acid (0.60 g, 2.3 mmol)was added
portionwise to a stirred suspension of lithium aluminium hydride
(0.14 g, 3.7 mmol) in THF (10 mL) at 0.degree. C. under Ar. The
mixture was warmed to room temperature, stirred for 2 h then cooled
to 0.degree. C. Saturated aqueous sodium potassium tartrate
solution (1 mL) was added dropwise followed by sodium sulfate
decahydrate (2 g). The mixture was diluted with ether (30 mL),
stirred for 1 h then filtered through kieselguhr. The filter-cake
was washed with ether (10 mL); the combined filtrates were
concentrated in vacuo and purified by flash column chromatography
[SiO.sub.2; isohexane--ethyl acetate (4:1) to (1:1)] to give the
product as a viscous oil (0.25 g, 44%). .sup.1H-NMR (400 MHz,
CDCl.sub.3): 8.11 (1H, d, J=2.5 Hz), 7.63 (1H, dd, J=2.5, 8.5 Hz),
7.45 (1H, s), 7.33-7.25 (3H, m), 6.82 (1H, d, J=8.5 Hz), 5.35 (2H,
s), 4.62 (2H, d, J=4 Hz) and 1.87 (1H, t, J=4 Hz, --OH). HPLC:
[Xterra, 2.0 mL/min; methanol-10 mM aqueous ammonium acetate
solution (50:50) to (80:20) over 5 min then (80:20)] 98% (3.95
min).
[0593] Piperazine-1,4-dicarboxylic acid
5-[2-(3-chlorobenzyloxy)]pyridyl-m- ethyl ester tert-butyl ester: a
solution of 2-(3-chlorobenzyloxy)-5-(hydro- xymethyl)pyridine (0.22
g, 0.9 mmol) in DMF (1 mL) was added drop-wise to a stirred
suspension of sodium hydride (60%, 0.042 g, 1.1 mmol) in DMF (2
mL). The mixture was stirred for 30 min then a solution of
1-tert-butoxycarbonyl-4-chlorocarbonylpiperazine (0.22 g, 0.9 mmol)
in DMF (1 mL) was added. The mixture was stirred for 18 h then
poured into water (10 mL) and extracted with ether (2.times.10 mL).
The combined organic extracts were washed with water and brine,
then dried over sodium sulfate, concentrated in vacuo and purified
by flash column chromatography [SiO.sub.2; isohexane--ethyl acetate
(9:1) to (3:1)] to give the product as a viscous oil (0.17 g, 41%).
.sup.1H-NMR (400 MHz, CDCl.sub.3): 8.16 (1H, d, J=2.5 Hz), 7.63
(1H, dd, J=2.5, 8.5 Hz), 7.45 (1H, s), 7.34-7.26 (3H, m), 6.81 (1H,
d, J=8.5 Hz), 5.36 (2H, s), 5.08 (2H, s), 3.48-3.36 (8H, m) and
1.46 (9H, s). HPLC: [Xterra, 2.0 mL/min; methanol-10 mM aqueous
ammonium acetate solution (50:50) to (80:20) over 5 min then
(80:20)] 97% (7.35 min).
[0594] Piperazine-1-carboxylic acid
5-[2-(3-chlorobenzyloxy)]pyridyl-methy- l ester fumarate: a
solution of hydrogen chloride in dioxan (4 M, 0.9 mL, 3.6 mmol) was
added drop-wise to a stirred solution of
Piperazine-1,4-dicarboxylic acid
5-[2-(3-chlorobenzyloxy)]pyridyl-methyl ester tert-butyl ester
(0.16 g, 0.35 mmol) in methanol (5 mL). The mixture was stirred for
18 h then concentrated in vacuo. The residue was partitioned
between ether (2.times.10 mL) and aqueous sodium hydroxide solution
(2 M, 10 mL). The combined organic layers were washed with water
and brine then dried over sodium sulfate, concentrated in vacuo,
dissolved in warm 2-propanol (2 mL) and added dropwise to a stirred
solution of fumaric acid (0.047 g, 0.41 mmol) in warm 2-propanol (2
mL). The mixture was cooled to 0.degree. C., stirred for 30 min
then filtered. The filter-cake was washed with 2-propanol and ether
then dried in vacuo to give the product as a white solid (0.089 g,
54%), m.p. 148.degree. C. (dec.). .sup.1H-NMR (400 MHz,
d.sub.6-DMSO): 8.19 (1H, d, J=2.5 Hz), 7.77 (1H, dd, J=2.5, 8.5
Hz), 7.50 (1H, s), 7.42-7.36 (3H, m), 6.92 (1H, d, J=8.5 Hz), 6.52
(2H, s), 5.36 (2H, s), 5.04 (2H, s), 3.45-3.40 (4H, m) and
2.86-2.80 (4H, m).
Example 49
[0595] cis-2,6-Dimethylpiperazine-1-carboxylic acid
2-(2-thienyl)ethyl ester
[0596] 2-(2-thienyl)ethanol (2 eq), triethylamine (3 eq) and
pyridine (1 eq) was added to a solution of
cis-4-chlorocarbonyl-2,6-dimethyl-piperazi- ne-1-carboxylic acid
tert-butyl ester in dichloromethane (30 vol.) and the mixture was
shaken at 25.degree. C. for 6 days. The mixture was evaporated, and
the resultant crude material purified by preparative HPLC [C18, 10
mM aqueous NH.sub.4OAc solution:MeOH] to afford the intermediate
product, which was used immediately in the next step.
[0597] A solution of HCl in dioxane (4 M, 10 eq) was added to a
solution of the above intermediate in methanol (50 volumes) and the
mixture was shaken for 16 h. Evaporation to dryness afforded the
desired product. HPLC: [XTERRA; methanol-10 mM aqueous NH.sub.4OAc
(60:40); 2 mL/min; 210 nm] 94.5% (0.83 min); MS(ISP): 269
MH.sup.+.
[0598] cis-4-chlorocarbonyl-2,6-dimethyl-piperazine-1-carboxylic
acid tert-butyl ester was prepared in analogy to
4-chlorocarbonyl-piperazine-1- -carboxylic acid tert-butyl ester
from cis-2,6-dimethylpiperazine-1-carbox- ylic acid tert-butyl
ester (A. Muehlebach, P. Pino, Helv. Chim. Acta 73, 839 (1990)) by
a modified procedure of Rhone-Poulenc DE 25 50 111
(Rhone-Poulenc).
Example 50
[0599] cis-2,6-Dimethylpiperazine-1-carboxylic acid 2-fluorobenzyl
ester
[0600] 2-fluorobenzyl alcohol (2 eq), triethylamine (3 eq) and
pyridine (1 eq) was added to a solution of
cis-4-chlorocarbonyl-2,6-dimethyl-piperazi- ne-1-carboxylic acid
tert-butyl ester in dichloromethane (30 vol.) and the mixture was
shaken at 25.degree. C. for 6 days. The mixture was evaporated, and
the resultant crude material purified by preparative HPLC [C18, 10
mM aqueous NH.sub.4OAc solution:MeOH] to afford the intermediate
product, which was used immediately in the next step.
[0601] A solution of HCl in dioxane (4 M, 10 eq) was added to a
solution of the above intermediate in methanol (50 volumes) and the
mixture was shaken for 16 h. Evaporation to dryness afforded the
desired product. HPLC: [XTERRA; methanol-10 mM aqueous NH.sub.4OAc
(60:40); 2 mL/min; 210 nm] 96.8% (0.88 min); MS (ISP): 267
MH.sup.+.
[0602] cis-4-chlorocarbonyl-2,6-dimethyl-piperazine-1-carboxylic
acid tert-butyl ester was prepared in analogy to
4-chlorocarbonyl-piperazine-1- -carboxylic acid tert-butyl ester
from cis-2,6-dimethylpiperazine-1-carbox- ylic acid tert-butyl
ester (A. Muehlebach, P. Pino, Helv. Chim. Acta 73, 839 (1990)) by
a modified procedure of Rhone-Poulenc DE 25 50 111
(Rhone-Poulenc).
Example 51
[0603] Piperazine-1-carbothioic acid S-[4-(3-nitrobenzyl)oxy]benzyl
ester
[0604] Piperazine-1-carbothioic acid S-[4-(3-nitrobenzyl)oxy]benzyl
ester: A mixture
[(4-tert-butyl-dimethylsilyloxy)benzylsulfanylcarbonyl]-piperaz-
ine-4-carboxylic acid tert-butyl ester (0.05 g), 3-nitrobenzyl
bromide (0.028 g), cesium fluoride (0.033 g) and DMF (1 mL) was
shaken for 48 h then partitioned between water (2 mL) and
dichloromethane (2 mL). The separated organic layer was
concentrated in vacuo then suspended in trifluoroacetic
acid--dichloromethane (1:1, 1 mL) and shaken for 18 h. The mixture
was concentrated in vacuo and purified by preparative HPLC [C1 8,
10 mM aqueous NH.sub.4OAc solution: MeOH] to afford the product
(0.011 g, 25%). HPLC: [Xterra, 2.0 mL/min; methanol-10 mM aqueous
ammonium acetate solution (50:50) to (80:20) over 5 min then
(80:20)] 98% (5.1 min); MS (ISP): 387 MH.sup.+.
Example 52
[0605] Piperazine-1-carboxylic acid 3-(2-phenylethoxy)-benzyl ester
hydrochloride
[0606] Piperazine-1,4-dicarboxylic acid
(3-tert-butyldimethylsilyloxy)benz- yl ester tert-butyl ester: A
solution of 3-tert-butyldimethylsilyloxybenzy- l alcohol
(Tetrahedron Lett. 26, 681 (1985)) (5.0 g), triethylamine (8.7 mL),
pyridine (1.65 mL) and 4-chlorocarbonyl-piperazine-1-carboxylic
acid tert-butyl ester (5.1 g) in dichloromethane (200 mL) was
stirred for 96 h. 4-Dimethylaminopyridine (0.20 g) was added and
the mixture was heated to reflux for 4 h. The mixture was cooled to
room temperature, washed with water (100 mL), brine (100 mL), dried
over magnesium sulfate and concentrated in vacuo. The residue was
purified by column chromatography [SiO.sub.2; dichloromethane,
isopropyl ether: (100:0) to (80:20)] to give the product as a
yellow oil (3.8 g, 41%). .sup.1H-NMR (400 MHz, CDCl.sub.3): 0.19
(6H, s), 0.98 (9H, s), 1.46 (9H, s), 3.36-3.43 (4H, m), 3.44-3.50
(4H, m), 5.08 (2H, s), 6.78 (1H, dd, J=2.5, 8 Hz), 6.82 (1H, t, J=2
Hz), 6.92 (1H, d, J=8 Hz) and 7.20 (1H, t, J=8 Hz).
[0607] Piperazine-1,4-dicarboxylic acid (3-hydroxy)benzyl ester
tert-butyl ester: a solution of tetrabutylammonium fluoride in THF
(1 M, 4.4 mL, 4.4 mmol) and glacial acetic acid (0.76 mL, 13.3
mmol) were added sequentially to a stirred solution of
piperazine-1,4-dicarboxylic acid
(3-tert-butyldimethylsilyloxy)benzyl ester tert-butyl ester (0.50
g, 1.1 mmol) in anhydrous THF (10 mL) at 0.degree. C . The mixture
was stirred for 1 h then poured into water (40 mL) and extracted
with ethyl acetate (3.times.20 mL). The combined organic extracts
were washed with water (3.times.25 mL), saturated aqueous sodium
hydrogencarbonate solution (25 mL) and brine (25 mL) then dried
over magnesium sulfate and concentrated in vacuo to give the
product as a colourless oil which solidified on standing (0.38 g,
100%). .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.46 (9H, s), 3.38-3.44
(4H, m), 3.45-3.50 (4H, m), 5.09 (2H, s), 6.79 (1H, dd, J 2.5, 8
Hz), 6.83 (1H, m, OH), 6.90 (1H, d, J=8 Hz), 7.22 (1H, t, J=8 Hz)
and 7.26 (1H, s). HPLC [Xterra, 2.0 mL/min; methanol-10 mM aqueous
ammonium acetate solution (50:50) to (80:20) over 5 min then
(80:20)] 100% (3.59 min).
[0608] Piperazine-1,4-dicarboxylic acid 3-(2-phenylethoxy)benzyl
ester tert-butyl ester: potassium carbonate (0.072 g, 0.52 mmol)
was added to a solution of piperazine-1,4-dicarboxylic acid
(3-hydroxy)benzyl ester tert-butyl ester (0.16 g, 0.48 mmol) in
acetone (5 mL) at 0.degree. C. and the reaction mixture was stirred
at 0.degree. C. for 30 min. (2-Bromoethyl)-benzene (0.097 g, 0.52
mmol) was added and the reaction mixture was allowed to warm to
room temperature and then heated under reflux for 24 h. After
cooling, the reaction mixture was concentrated in vacuo and the
residue was partitioned between water (20 mL) and ethyl acetate (20
mL). The organic phase was separated, washed with saturated brine
(25 mL), dried (MgSO.sub.4) and concentrated in vacuo to give an
oil which was purified by column chromatography [SiO.sub.2;
heptane-ethyl acetate (3:1)] to yield the title compound (0.10 g,
48%) as a colourless oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): 1.46
(9H, s), 3.10 (2H, t, J=7.0 Hz), 3.40 (4H, m), 3.46 (4H, m), 4.18
(2H, t, J=7.0 Hz), 5.09 (2H, s), 6.84 (1H, m), 6.88 (1H, m), 6.91
(1H, m) and 7.22-7.34 (6H, m).
[0609] Piperazine-1-carboxylic acid 3-(2-phenylethoxy)-benzyl ester
hydrochloride: 4M HCl in 1,4-dioxane (2.3 mL, 9.2 mmol) was added
to a solution of piperazine-1,4-dicarboxylic acid
3-(2-phenylethoxy)benzyl ester tert-butyl ester (0.10 g, 0.23 mmol)
in methanol (2 mL) and ether (2 mL) and the solution was left to
stand with occasional swirling at room temperature for 3 h. The
solution was concentrated in vacuo and the residue was triturated
with ether to yield the title compound (0.08 g, 93%) as a white
solid. .sup.1H-NMR (400 MHz, d.sub.6-DMSO): 3.03 (2H, t, J=6.8 Hz),
3.08 (4H, m), 3.61 (4H, m), 4.19 (2H, t, J=7.0 Hz), 5.06 (2H, s),
6.88-6.94 (3H, m), 7.20-7.33 (6H, m) and 9.19 (2H, br s).
Example 53
[0610] 3-[2-(3-Chlorophenyl)ethyl]oxybenzylpiperazine-1-carboxylate
hydrochloride
[0611]
3-[2-(3-Chlorophenyl)ethyl]oxybenzyl-4-tert-butoxycarbonylpiperazin-
e-1-carboxylate was prepared from piperazine-1,4-dicarboxylic acid
(3-hydroxy)benzyl ester tert-butyl ester and
(2-bromoethyl)-3-chlorobenze- ne using the method described for
Example 52 to yield the product (0.24 g, 85%) as a colourless oil;
.sup.1H NMR (400 MHz, CDCl.sub.3) 1.46 (9H, s), 3.25 (2H, t, J 7.0
Hz), 3.41 (4H, m), 3.46 (4H, m), 4.20 (2H, t, J 7.0 Hz), 5.10 (2H,
s), 6.84 (1H, m), 6.88 (1H, m), 6.92 (1H, m), 7.14-7.24 (3H, m) and
7.28-7.36 (2H, m); HPLC retention time 8.12 min (.lambda.=220
nm).
[0612] 3-[2-(3-Chlorophenyl)ethyl]oxybenzylpiperazine-1-carboxylate
hydrochloride was prepared from
3-[2-(3-chlorophenyl)ethyl]oxybenzyl-4-te-
rt-butoxycarbonylpiperazine-1-carboxylate using the method
described for Example 52 to yield the title compound (0.14 g, 67%)
as a white solid; .sup.1H NMR (400 MHz, d.sub.6-DMSO) 3.05 (2H, t,
J 7.0 Hz), 3.08 (4H, m), 3.62 (4H, m), 4.20 (2H, t, J 6.5 Hz), 5.06
(2H, s), 6.88-6.95 (3H, m), 7.25-7.35 (4H, m), 7.42 (1H, m) and
9.20 (2H, br s); HPLC retention time 5.67 min (.lambda.=220
nm).
Example 54
[0613] cis-2,6-dimethyl-piperazine-1-carboxylic acid
6-(2-fluoro-benzyloxy)-pyridin-3-ylmethyl ester hemifumarate
[0614] 6-(2-Fluorobenzyloxy)nicotinic acid: to a stirred suspension
of sodium hydride (60%, 0.63 g) in DMF (10 ml) at 0.degree. C. was
added portionwise over 10 min 6-chloronicotinic acid (1.0 g). The
mixture was stirred for 30 min then a solution of 2-fluorobenzyl
alcohol (0.84 g) in DMF (5 ml) was added dropwise over 10 min. The
mixture was warmed to room temperature, stirred for 1 h then heated
to 100.degree. C. and stirred for a further 18 h then cooled to
room temperature. To the mixture were added dropwise water (10 ml)
and hydrochloric acid (2M, 10 ml). The emerging precipitate was
washed with water and dried to give the product as an off-white
solid (1.34 g); .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta..sub.H
8.75 (1H, dd, J 2.5, 1 Hz), 8.17 (1H, dd, J 8.5, 2.5 Hz), 7.56 (1H,
dt, J 7.5, 1.5 Hz), 7.43 (1H, m), 7.27 (1H, dd, J 8.5, 1 Hz), 7.22
(1H, dd, J 7.5, 1 Hz), 6.97 (1H, dd, J 8.5, 1 Hz) and 5.48 (2H, s);
[XTERRA; methanol-10 mM aqueous NH.sub.4OAc (50:50); 2 mL/min; 220
nm] 98%, 0.80 min.
[0615] 2-(2-Fluorobenzyloxy)-5-pyridylmethanol: to a stirred
solution of 6-(2-fluorobenzyloxy)nicotinic acid (0.89 g) in THF (10
ml) at 0.degree. C. under Ar was addded dropwise a solution of
lithium aluminium hydride (1.0 M, 5.5 ml). The mixture was warmed
to room temperature and stirred for 2 h. Saturated potassium sodium
tartrate solution (1 ml) was added to the mixture followed by ethyl
acetate (10 ml). The mixture was stirred for 30 min, filtered and
concentrated in vacuo to give the product as a clear oil (0.63 g)
which was used without further purification; .delta..sub.H (400
MHz, CDCl.sub.3) 8.14 (1H, d, J 1.5 Hz), 7.63 (1H, dd, J 8.5, 2.5
Hz), 7.49 (1H, dt, J 7.5, 1 Hz), 7.29 (1H, m), 7.13 (1H, dt, J 7.5,
1 Hz), 7.02 (1H, dt, J 10, 1 Hz), 6.81 (1H, d, J 8 Hz), 5.45 (2H,
s) and 4.63 (2H, s); LC 73 %, 2.24 min.
[0616] cis-2,6-dimethyl-piperazine-1-carboxylic acid
6-(2-fluoro-benzyloxy)-pyridin-3-ylmethyl ester: to a stirred
suspension of sodium hydride (0.084 g) in DMF (2 ml) was added
dropwise a solution of 2-(2-fluorobenzyloxy)-5-pyridylmethanol
(0.41 g) and cis
1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine (0.45
g) in DMF (4 ml). The mixture was stirred for 18 h then poured into
water (20 ml). The aqueous layer was extracted with two portions of
ethyl acetate (20 ml). The combined organic extracts were washed
(water, brine), dried (sodium sulfate) and concentrated in vacuo.
The residue was purified by flash column chromatography [SiO.sub.2;
toluene--ether (4:1)] to give the product as a pale oil (0.28 g);
1H-NMR (400 MHz, CDCl.sub.3) .delta..sub.H 8.19 (1H, d, J 2 Hz),
7.62 (1H, dd, J 8.5, 2.5 Hz), 7.50 (1H, dt, J 7.5, 1.5 Hz), 7.30
(1H, m), 7.14 (1H, dt, J 7.5, 1 Hz), 7.08 (1H, ddd, J 10, 8.5, 1.5
Hz), 6.80 (1H, d, J 8.5 Hz), 5.45 (2H, s), 5.09 (2H, s), 4.20 (2H,
m), 4.05-3.80 (2H, m), 3.10-2.80 (2H, m), 1.48 (9H, s) and 1.22
(6H, d, J 6.5 Hz); HPLC [XTERRA; methanol-10 mM aqueous NH.sub.4OAc
(50:50); 2 mL/min; 220 nm] 98%, 7.24 min.
[0617] cis-2,6-dimethyl-piperazine-1-carboxylic acid
6-(2-fluoro-benzyloxy)-pyridin-3-ylmethyl ester hemifumarate:
cis-2,6-dimethyl-piperazine-1-carboxylic acid
6-(2-fluoro-benzyloxy)-pyri- din-3-ylmethyl ester (0.25 g) and
HCl-dioxane (4M, 0.6 ml) were combined as described below for
Example 58 to give the product as a white solid (0.18 g);
.sup.1H-NMR (400 MHz, DMSO-d.sub.6) 8.20 (1H, d, J 2 Hz), 7.75 (1H,
d, J 8.5, 2.5 Hz), 7.53 (1H, dt, J 7.5, 1.5 Hz), 7.40 (1H, dddd, J
9, 7.5, 5.5, 1.5 Hz), 7.25 (1H, dd, J 9.5, 1 Hz), 7.20 (1H, dd, J
7.5, 1 Hz), 6.89 (1H, d, J 8.5 Hz), 6.57 (1H, s), 5.40 (2H, s),
5.04 (2H, s), 3.95 (2H, m), 2.74 (2H, d, J 12 Hz), 2.68 (2H, dd, J
12, 4.5 Hz) and 1.18 (6H, d, J 7 Hz); HPLC [XTERRA; methanol-10 mM
aqueous NH.sub.4OAc (50:50); 2 mL/min; 220 nm] 99%, 4.23 min.
Example 55
[0618] 4-Bromo-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was
synthesized from cis 1-chlorocarbonyl-2,6-dimethyl-4-te-
rt-butoxycarbonylpiperazine and 4-bromo-2-fluorobenzyl alcohol
according to the methods described in Examples 52 and 54 to give
the product as a white solid: .delta..sub.H (400 MHz, DMSO-d.sub.6)
1.3 (6H, d J, 7.2 Hz), 3.0-3.2 (4H, m), 4.3 (2H, sextet, J 7.2 Hz),
5.15 (2H, s), 7.42 (2H, m), 7.6 (1H, m), 9.15 (1H, br) and 9.80
(1H, br); LC (XTERRA, 50/80, 220 nm) 89.8% (3.62 min).
Example 56
[0619] Benzyl cis-2,6-dimethylpiperazine-1-carboxylate
hydrochloride was prepared from cis
1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpipe- razine and
benzyl alcohol according to the methods described for Examples 52
and 54 to give the product as a cream solid (0.0833 g, 15%
overall); .nu..sub.max (nujol)/cm-1 2776, 2672, 2568, 2527, 1706,
1581, 1415, and 1329; .delta..sub.H (400 MHz, DMSO-d.sub.6) 9.89 (1
H, br), 9.19 (1 H, br), 7.41-7.31(5 H, m), 5.13 (2 H, s), 4.34 (2
H, m), 3.17-3.08 (4 H, m), and 1.31 (6 H, d, J 7.2).
Example 57
[0620] 2-Chlorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate
hydrochloride was prepared from cis
1-chlorocarbonyl-2,6-dimethyl-4-tert-- butoxycarbonylpiperazine and
2-chloro-benzyl alcohol according to the methods described for
Examples 52 and 54 to give the product as a white solid (0.0901 g,
14% overall); .nu..sub.max (nujol)/cm-1 3375, 2689, 2577, 1699,
1592, 1380, 1328, and 1300; .delta..sub.H (400 MHz, DMSO-d.sub.6)
9.62 (2 H, br), 7.50 (2 H, m), 7.40 (2 H, m), 5.19 (2 H, s), 4.33
(2 H, m), 3.18-3.06 (4 H, m), and 1.31 (6 H, d, J 7.2).
Example 58
[0621] (R)-2-Fluorobenzyl 2-methylpiperazine-1-carboxylate
hydrochloride
[0622] To a stirred solution of
(R)1-tert-butoxycarbonyl-4-chlorocarbonyl-- 2-methylpiperazine (348
mg, 1.32 mmol), triethylamine (550 uL, 3 eq) and 2-fluorobenzyl
alcohol (420 uL, 2 eq) in dichloromethane (8 mL) were added
pyridine (110 uL, 1 eq) and DMAP (cat.). The resultant mixture was
stirred at ambient temperature for 5 days. Purification by flash
column chromatography [SiO.sub.2; ethyl acetate--heptane (1:3)]
afforded a colourless oil (692 mg). This material was dissolved in
MeOH (12 mL) and treated with a solution of HCl in dioxane (4 M;
3.3 mL, .about.10 equiv.), with overnight stirring. Purification by
flash column chromatography [SiO.sub.2; ethyl
acetate--methanol--ammonium hydroxide (90:8:2)] afforded a
colourless oil. Dissolution in dichloromethane (4 mL) and treatment
with HCl in dioxane (4 M; 1 mL) afforded, after evaporation the
desired product (368 mg, 79%) as a white solid: .delta..sub.H(400
MHz; d.sub.6-DMSO) 1.26 (3H, d, J 7.0 Hz), 2.81-2.94 (1H, m),
3.01-3.27 (4H, m), 3.90-3.98 (1H, m), 4.31-4.40 (1H, m), 5.13 (1H,
d, J 12.5 Hz), 5.17 (1H, d, J 12.5 Hz), 7.20-7.26 (2H, m),
7.38-7.50 (2H, m), 9.13 (1H, br s) and 9.59 (1H, br s); LC (XTERRA,
30/70, 210 nm) 99.6% (2.01 min).
Example 59
[0623] 2-Fluoro-4-propylbenzyl
cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride
[0624] 2-Fluoro-4-propylbenzyl
4-tert-butoxycarbonyl-cis-2,6-dimethylpiper- azine-1-carboxylate:
tetrakis(triphenylphosphine)palladium(O) (0.029 g) was added to a
solution of 4-bromo-2-fluorobenzyl 4-tert-butoxycarbonyl-2-
,6-dimethylpiperazine-1-carboxylate (from Example 55, 0.223 g, 0.5
mmol) and n-propylzinc bromide (0.5 M THF, 3.0 ml) in dry THF (5
ml) under Ar. The reaction mixture was heated to reflux for 19 h,
then cooled to ambient temperature and partitioned between ethyl
acetate (50 ml) and saturated aqueous ammonium chloride solution
(50 ml). The organic phase was separated, washed with water and
brine, dried (sodium sulfate) and the solvent evaporated under
reduced pressure to afford the crude product as an oil, which was
purified by silica gel chromatography (DIPE:heptane, 1:1) and used
immediately.
[0625] 2-Fluoro-4-propylbenzyl
cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared
from 2-fluoro-4-propylbenzyl
4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate
according to the method described in Example 52: .delta..sub.H(400
MHz; d.sub.6-DMSO) 0.9 (3H, t, J 7.3 Hz), 1.3 (6H, d, J 7.2 Hz),
1.59 (2H, sextet, J 7.3 Hz), 2.58 (2H, t, J 7.3 Hz), 3.0-3.2 (4H,
m), 4.25 (2H, sextet, J 7.2 Hz), 5.15 (2H, s), 7.0-7.1 (2H, m),
7.38 (1H, t, J 7.9 Hz) and 9.0-10.0 (2H, br); HPLC (XTERRA, 50/80,
220 nm) 91% (4.93 min).
Example 60
[0626] S-4-[(Ethylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpi-
perazine-1-thiocarboxylate and ethyl isocyanate according to the
method described in Example 71 to give the product as a white solid
(58.6%); melting point 153.1-157.6.degree. C.; NMR .delta..sub.H
(400 MHz, DMSO-d.sub.6) 1.069 (3H, t, J 7.0 Hz), 3.116 (6H, m),
3.667(4H, bs), 4.140(2H, s), 7.020(2H, d, J 8.5 Hz), 7.325(2H, d, J
8.5 Hz), 7.744(1H, t, J 5.5 Hz) and 9.117(2H, bs).
Example 61
[0627] S-4-[[(2-Chloroethyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate
and 2-chloroethyl isocyanate according to the method described in
Example 71 to give the product as a white solid (73.8%); melting
point 206.3-206.4.degree. C.; NMR .delta..sub.H (400 MHz,
DMSO-d.sub.6) 3.120(4H, bt), 3.385 (3H, q, J 6.0 Hz), 3.367(6H, m),
4.146(2H, s), 7.040(2H, d, J 9.0 Hz), 7.337(2H, d, J 8.5 Hz),
8.045(1H, t, J 5.5 Hz) and 8.987(2H, bs).
Example 62
[0628] S-4-[(Butylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpi-
perazine-1-thiocarboxylate and butyl isocyanate according to the
method described in Example 71 to give the product as a white solid
(65.7%); melting point 176.7-177.7.degree. C.; NMR .delta.H (400
MHz, DMSO-d.sub.6) 0.884(3H, t, J 7.0 Hz), 1.310(2H, m), 1.436(2H,
m), 3.041(2H, q, J 6.0 Hz), 3.105(4H, bt), 3.638(4H, bs), 4.132(2H,
s), 7.015(2H, d, J 8.5 Hz), 7.323(2H, d, J 9.0 Hz) 7.736(2H, t, J
6.0 Hz) and 8.733(2H, bs).
Example 63
[0629] S-4-[(2-Propylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpi-
perazine-1-thiocarboxylate and propyl isocyanate according to the
method described in Example 71 to give the product as a white solid
(83.7%); HPLC (XTERRA, 50/80, 220 nm) 87% (1.15 min), NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 1.113(6H, d, J 6.5 Hz),
3.108(4H, bt), 3.638(5H, bm), 4.138(2H, s), 7.020(2H, d, J 8.5 Hz),
7.321(2H, d, J 8.5 Hz), 7.682(1H, bd) and 8.721(2H, bs).
Example 64
[0630] S-4-[(Benzylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpi-
perazine-1-thiocarboxylate and benzyl isocyanate according to the
method described in Example 71 to give the product as a white solid
(62.1%); HPLC (XTERRA, 50/80, 220 nm) 89% (1.15 min); NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 3.113(4H, bs), 3.634(4H, bs),
4.144(2H, s), 4.256(2H, s), 7.110(2H, d, J 8.5 Hz), 7.328(7H, m),
8.328(1H, bs) and 8.890(2H, bs).
Example 65
[0631] S-4-[[(2-Methylbenzyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate
and 2-methylbenzyl isocyanate according to the method described in
Example 71 to give the product as a white solid (62.1%); HPLC
(XTERRA, 50/80, 220 nm) 89% (1.15 min); NMR .delta..sub.H (400 MHz,
DMSO-d.sub.6) 3.113(4H, bs), 3.634(4H, bs), 4.144(2H, s), 4.256(2H,
s), 7.110(2H, d, J 8.5 Hz), 7.328(7H, m), 8.328(1H, bs) and
8.890(2H, bs).
Example 66
[0632] 4-Difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride
[0633] 4-Difluoromethoxybenzyl alcohol: to a stirred solution of
4-difluoromethoxybenzaldehyde (1.0 g) in methanol (20 ml) was added
sodium borohydride (0.11 g). The mixture was stirred for 2 h then
concentrated in vacuo and partitioned between dichloromethane (50
ml) and dilute aqueous sodium hydroxide solution (50 ml). The
organic layer was washed (water, brine), dried (sodium sulfate) and
concentrated in vacuo to give the product as an oil (0.89 g), which
was used without further purification.
[0634] 4-Difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared
from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert--
butoxycarbonylpiperazine and 4-difluoromethoxybenzyl alcohol
according to the methods described for Examples 52 and 54 to give
the product as a white solid (0.202 g, 58% overall); (Found: C,
51.4; H, 6.2; N, 8.0%. C.sub.15H.sub.20F.sub.2N.sub.2O.sub.3.HCl
requires C, 51.4; H, 6.0; N, 8.0%); .delta..sub.H (400 MHz,
DMSO-d.sub.6) 9.87 (2H, br), 7.44 (2H, d, J 8.8 Hz), 7.24 (1H, t, J
74 Hz), 7.19 (2H, d, J 8.8 Hz), 5.11 (2H, s), 4.32 (2H, m), 3.14
(2H, d, J 13.2 Hz), 3.06 (2H, dd, J 5.2 and 13.2 Hz), and 1.31 (6H,
d, J 7.2 Hz).
Example 67
[0635] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester fumarate
[0636] 6-(3-Methylbutoxy)nicotinic acid was prepared from
6-chloronicotinic acid (0.50 g), 3-methyl-1-butanol (0.36 ml) and
sodium hydride (60%, 0.32 g) according to the method described in
Example 54 to give the product as a white solid (0.25 g, 38%):
.delta..sub.H (400 MHz, DMSO-d.sub.6) 12.97 (1H, m), 8.71 (1H, d, J
2.5 Hz), 8.12 (1H, dd, J 8.5, 2.5 Hz), 6.87 (1H, d, J 8.5 Hz), 4.36
(2H, t, J 7 Hz), 1.75 (1H, nonet, J 6.5 Hz), 1.62 (2H, 1, J 6.5 Hz)
and 0.93 (6H, d, J 6.5 Hz); HPLC (XTERRA, 20/50, 220 nm) 99% (3.90
min).
[0637] [6-(3-Methyl-butoxy)-pyridin-3-yl]-methanol was prepared
from 6-(3-methylbutoxy)nicotinic acid (0.24 g) and lithium
aluminium hydride (0.5M, THF, 3.5 ml) according to the method
described in Example 54 to give the product as a yellow oil (0.19
g, 86%): .delta..sub.H (400 MHz, CDCl.sub.3) 8.08 (1H, d, J 2.5
Hz), 7.59 (1H, dd, J 8.5, 2.5 Hz), 6.71 (1H, d, J 8.5 Hz), 4.60
(2H, s), 4.30 (2H, t, J 6.5 Hz), 1.81 (1H, nonet, J 6.7 Hz), 1.66
(3H, q, J 7 Hz) and 0.96 (6H, d, J 6.5 Hz); HPLC (XTERRA, 50/80,
235 nm) 86% (2.54 min).
[0638] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester was prepared from
[6-(3-Methyl-butoxy)-pyridin-3-yl]-methanol (0.19 g), sodium
hydride (60%, 0.048 g) and
4-tert-butoxycarbonyl-1-chlorocarbonyl-cis-2,6-dimethy- lpiperazine
(0.25 g) according to the method described in Example 54 to give
the product as a pale oil (0.052 g, 13%): .delta..sub.H (400 MHz,
CDCl.sub.3) 8.15 (1H, d, J 2.5 Hz), 7.58 (1H, dd, J 8.5, 2.5 Hz),
6.71 (1H, d, J 8.5 Hz), 5.07 (2H, s), 4.32 (2H, t, J 7 Hz), 4.18
(2H, m), 3.95 (2H, m), 2.95 (2H, m), 1.81 (1H, nonet, J 7 Hz), 1.67
(2H, q, J 7 Hz), 1.47 (9H, s), 1.22 (6H, d, J 7 Hz) and 0.96 (6H,
d, J 6.5 Hz); HPLC (XTERRA, 50/80, 235 nm) 91% (7.19 min).
[0639] cis-2,6-dimethyl-piperazine-1-carboxylic acid
6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester fumarate was prepared
from cis-2,6-dimethyl-piperazine-1-carboxylic acid
6-(3-methyl-butoxy)-pyridin- -3-ylmethyl ester (0.05 g) and HCl
(4M, dioxane, 0.2 ml) according to the method described in Example
48 to give the product as a white solid (0.012 g, 28%):
.quadrature..sub.H (400 MHz, DMSO-d.sub.6) 8.15 (1H, d, J 2.5 Hz),
7.69 (1H, dd, J 8.5, 2 Hz), 6.79 (1H, d, J 8.5 Hz), 6.60 (2H, s),
5.02 (2H, s), 4.27 (2H, t, J 7 Hz), 3.95 (2H, m), 2.75 (2H, d, J 12
Hz), 2.68 (2H, dd, J 12, 4 Hz), 1.74 (1H, nonet, J 6.7 Hz), 1.60
(2H, q, J 7 Hz), 1.18 (6H, d, J 7 Hz) and 0.92 (6H, d, J 6.5 Hz);
HPLC (XTERRA, 50/80, 235 nm) 95% (4.46 min).
Example 68
[0640] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester hemifumarate
[0641] 6-(Cyclohexylmethoxy)nicotinic acid was prepared from
6-chloronicotinic acid (0.50 g), cyclohexylmethanol (0.41 ml) and
sodium hydride (60%, 0.32 g) according to the method described in
Example 54 to give the product as a white solid (0.42 g, 56%):
.delta..sub.H (400 MHz, DMSO-d.sub.6) 12.97 (1H, br), 8.70 (1H, d,
J 2.5 Hz), 8.12 (1H, dd, J 8.5, 2.5 Hz), 6.88 (1H, d, J 8.5 Hz),
4.14 (2H, d, J 6 Hz), 1.81-1.60 (6H, m), 1.20 (3H, sept of
triplets, J 12, 2.5 Hz) and 1.03 (2H, dq, J 11, 2.5 Hz); HPLC
(XTERRA, 50/80, 220 nm) 100% (1.47 min).
[0642] [5-(2-Cyclohexylmethoxy)pyridyl]methanol was prepared from
6-cyclohexylmethoxynicotinic acid (0.39 g) and lithium aluminium
hydride (0.5M, THF, 3.5 ml) according to the procedure described
for Example 54 to give the product as a yellow oil (0.36 g, 96%):
.delta..sub.H (400 MHz, CDCl.sub.3) 8.07 (1H, d, J 2.5 Hz), 7.60
(1H, dd, J 8.5, 2.5 Hz), 6.72 (1H, d, J 8.5 Hz), 4.60 (2H, s), 4.08
(2H, d, J 6.5 Hz), 1.88-1.67 (6H, m), 1.24 (3H, septet of triplets,
J 12, 3 Hz) and 1.04 (2H, dq, J 12, 3 Hz); HPLC (XTERRA, 50/80, 235
nm) 77% (4.49 min).
[0643] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester was prepared from
[5-(2-cyclohexylmethoxy)pyridyl]methanol (0.36 g), sodium hydride
(60%, 0.77 g) and
4-tert-butoxycarbonyl-1-chlorocarbonyl-cis-2,6-dimethylpipera- zine
(0.40 g) according to the method described for Example 54 to give
the product as a pale oil (0.035 g, 5%): .delta..sub.H (400 MHz,
CDCl.sub.3) 8.14 (1H, d, J 2.5 Hz), 7.58 (1H, dd, J 8.5, 2.5 Hz),
6.72 (1H, d, J 8.5 Hz), 5.07 (2H, s), 4.18 (2H, m), 4.09 (2H, d, J
6.5 Hz), 3.92 (2H, m), 2.95 (2H, m), 1.88-1.65 (6H, m), 1.47 (9H,
s), 1.25 (3H, septet of triplets, J 12.5, 3 Hz), 1.22 (6H, d, J 7
Hz) and 1.05 (2H, dq, J 13, 3 Hz); HPLC (XTERRA, 50/80, 235 nm) 91%
(8.06 min).
[0644] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
6-(3-methyl-butoxy)-pyridin-3-ylmethyl ester hemifumarate was
prepared from [5-(2-cyclohexylmethoxy)pyridyl]methyl
4-tert-butoxycarbonyl-cis-2,6- -dimethylpiperazine-1-carboxylate
(0.03 g) and HCl (4M, dioxane, 0.2 ml) according to the method
described in Example 48 to give the product as a white solid (0.011
g, 45%): .delta..sub.H (400 MHz, DMSO-d.sub.6) 8.14 (1H, d, J 2.5
Hz), 7.69 (1H, dd, J 8.5, 2.5 Hz), 6.80 (1H, d, J 8.5 Hz), 6.58
(1H, s), 5.01 (2H, s), 4.06 (2H, d, J 6 Hz), 3.93 (2H, m), 2.73
(2H, d, J 12 Hz), 2.67 (2H, dd, J 12, 4.5 Hz), 1.80-1.60 (6H, m),
1.19 (3H, septet of triplets, J 12, 3 Hz), 1.17 (6H, d, J 7 Hz) and
1.02 (2H, m); HPLC (XTERRA, 50/80, 235 nm) 100% (5.83 min).
Example 69
[0645] 4-Ethyl-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate
[0646] 4-Ethyl-2-fluorobenzyl
4-tert-butoxycarbonyl-cis-2,6-dimethylpipera- zine-1-carboxylate
was prepared from 4-bromo-2-fluorobenzyl
4-tert-butylpiperazine-1-carboxylate and diethylzinc according to
the method described for Example 59.
[0647] 4-Ethyl-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate was prepared from
4-ethyl-2-fluorobenzyl 4-tert-butoxycarbonyl-cis-2,6-dimeth-
ylpiperazine-1-carboxylate according to the methods described for
Example 54 to give the product as a yellow oil: .delta..sub.H (400
MHz, DMSO-d.sub.6) 1.18 (3H, t, J 7.7 Hz), 1.28 (6H, d, J 7.2 Hz),
2.62 (2H, q, J 7.7 Hz), 3.05-3.2 (4H, m), 4.28 (2H, sextet, J 7.1
Hz), 5.15 (2H, s), 7.05-7.1 (2H, m), 7.39 (1H, t, J 7.9 Hz) and
9.0-10.0 (2H, br); HPLC (XTERRA, 50/80, 220 nm) 96% (3.65 min).
Example 70
[0648] 2-Fluoro-4-pentylbenzyl
cis-2,6-dimethylpiperazine-1-carboxylate
[0649] 2-Fluoro-4-pentylbenzyl
4-tert-butoxycarbonyl-cis-2,6-dimethylpiper- azine-1-carboxylate
was prepared from 4-bromo-2-fluorobenzyl
4-tert-butylpiperazine-1-carboxylate and dipentylzinc according to
the method described for Example 59.
[0650] 2-Fluoro-4-pentylbenzyl
cis-2,6-dimethylpiperazine-1-carboxylate was prepared from
2-fluoro-4-pentylbenzyl 4-tert-butoxycarbonyl-cis-2,6-d-
imethylpiperazine-1-carboxylate according to the methods described
for Example 54 to give the product as a yellow oil: .delta..sub.H
(400 MHz, DMSO-d.sub.6) 0.85 (3H, t, J 7.0 Hz), 1.27 (10H, m), 1.55
(2H, sextet, J 7.0 Hz), 2.60 (2H, t, J 7.0 Hz), 3.03-3.2 (4H, m),
4.30 (2H, sextet, J 7.1 Hz), 5.15 (2H, s), 7.05-7.1 (2H, m), 7.39
(1H, t, J 7.9 Hz) and 8.8-9.8 (2H, br); HPLC (XTERRA, 50/80, 220
nm) 96% (6.46 min).
Example 71
[0651] S-4-[(tert-Butylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxyla- te hydrochloride
[0652] S-4-[(tert-Butylamino)carbonyl]oxybenzyl
4-tert-butoxycarbonylpiper- azine-1-thiocarboxylate: to a stirred
solution of S-4-hydroxybenzyl
4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (1.35 g, 3.7
mmol) in dichloromethane (50 mL) were added tert-butyl isocyanate
(0.85 ml, 7.4 mmol) and triethylamine (0.1 ml). The mixture was
stirred for 18 h then diluted with isohexane (30 mL) and
concentrated in vacuo. The solid residue was washed with isohexane
to give the crude product as a white solid (1.74 g, >100%) which
was used without further purification.
[0653] To a stirred solution of the crude product from above (3.7
mmol) in methanol (10 mL) was added dropwise HCl-dioxane (4M, 9.2
ml, 10 eq.). The mixture was stirred at room temperature for 4 h
then concentrated in vacuo. Diethyl ether (10 mL) was added to the
residue which was left to stand for 18 h. The precipitate formed
was filtered-off, washed with ether and dried to give the title
compound as a white, crystalline solid (1.15 g, 80%): HPLC (XTERRA,
50/80, 220 nm) 91.4% (1.81 min); NMR .delta..sub.H (400 MHz,
DMSO-d.sub.6) 1.269(9H, s), 3.119(4H, bt), 3.673(4H, bs), 4.141(2H,
s), 6.998(2H, d, J 8.5 Hz), 7.322(2H, d, J 8.5 Hz) and 7.522(1H,
s).
Example 72
[0654] 2,5-Difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate
hydrochloride was prepared from cis
1-chlorocarbonyl-2,6-dimethyl-4-tert-- butoxycarbonylpiperazine and
2,5-difluorobenzyl alcohol according to the methods described for
Examples 52 and 54 to give the product as a white solid (0.247 g,
77% overall); (Found: C, 52.5; H, 6.1; N, 8.7%.
C.sub.14H.sub.18F.sub.2N.sub.2O.sub.2.HCl requires C, 52.4; H, 6.0;
N, 8.7%); .delta..sub.H (400 MHz, DMSO-d.sub.6), 9.98 (2H, br),7.29
(3H, m), 5.15 (2H, s), 4.31 (2H, m), 3.15 (2H, d, J 12.8 Hz), 3.06
(2H, dd, J 5 and 13 Hz), and 1.31 (6H, d, J 7.2 Hz).
Example 73
[0655] 2,3-Difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate
hydrochloride was prepared from cis
1-chlorocarbonyl-2,6-dimethyl-4-tert-- butoxycarbonylpiperazine and
2,3-difluorobenzyl alcohol according to the methods described for
Examples 52 and 54 to give the product as a white solid (0.1846 g,
57% overall); (Found: C, 52.4; H, 6.0; N, 8.6%.
C.sub.14H.sub.18F.sub.2N.sub.2O.sub.2.HCl requires C, 52.4; H, 6.0;
N, 8.7%); .delta..sub.H (400 MHz, DMSO-d.sub.6) 10.07 (1H, br),
9.33 (1H, br), 7.44 (1H, m), 7.28 (2H, m), 5.21 (2H, s), 4.30 (2H,
m), 3.14 (2H, d, J 13.2 Hz), 3.06 (2H, m), and 1.31(6 H, d, J 7.2
Hz).
Example 74
[0656] 2,6-Difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate
hydrochloride
[0657] 2,6-Difluorobenzyl
4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine- -1-carboxylate
was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert--
butoxycarbonylpiperazine and 2,6-difluorobenzyl alcohol according
to the method described for Example 54 to give the product as a
colourless gum (0.251 g, 65%); Rf (Silica, isopropyl ether) 0.35;
.delta..sub.H (400 MHz, CDCl.sub.3) 7.29 (1H, m), 6.90 (2H, m),
5.23 (2H, s), 4.16 (2H, m), 3.92 (2H, br), 2.95 (2H, br), 1.47 (9H,
s), 1.21 (6H, d, J 6.8 Hz).
[0658] 2,6-Difluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate
hydrochloride was prepared from 2,6-difluorobenzyl
4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate
according to the method described for Example 52 to give the title
compound as a white solid (0.1585 g, 76%); (Found: C, 52.5; H, 6.3;
N, 8.7%. C.sub.14H.sub.18F.sub.2N.sub.2O.sub.2.HCl requires C,
52.4; H, 6.0; N, 8.7%); .delta..sub.H (400 MHz, DMSO-d.sub.6) 10.02
(1H, br, s), 9.29 (1H, br, s), 7.51 (1H, m), 7.16 (2H, m), 5.18
(2H, s), 4.24 (2H, m), 3.12 (2H, d, J 12.8 Hz), 3.04 (2H, dd, J 5
and 12.8 Hz), and 1.28 (6H, d, J 7.2 Hz).
Example 75
[0659] 2,4-Dimethylbenzyl cis-2,6-dimethylpiperazine-1-carboxylate
hydrochloride was prepared from cis
1-chlorocarbonyl-2,6-dimethyl-4-tert-- butoxycarbonylpiperazine and
2,4-dimethylbenzyl alcohol according to the methods described for
Examples 52 and 54 to give the product as a hygroscopic white solid
(0.1384 g, 44% overall); (Found: C, 60.9; H, 8.1; N, 8.9%.
C.sub.16H.sub.24N.sub.2O.sub.2.HCl.0.25H.sub.2O requires C, 60.6;
H, 8.1; N, 8.8%); .delta..sub.H (400 MHz, DMSO-d.sub.6) 9.53 (2H,
br), 7.19 (1H, d, J 7.6 Hz), 7.03 (1H, s), 6.99 (1H, d, J 7.6 Hz),
5.07 (2H, s), 4.29 (2H, m), 3.13 (2H, d, J 13.2 Hz), 3.04 (2H, dd,
J 5.2 and 13.2 Hz), 2.27 (3H, s), 2.26 (3H, s) and 1.29 (6H, d, J
7.2 Hz).
Example 76
[0660] S-4-[(Propylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydroxide was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpipera-
zine-1-thiocarboxylate and propyl isocyanate according to the
method described in Example 71 to give the product as a white solid
(25.3%); HPLC (XTERRA, 50/80) 98% (1.18 min); NMR .delta..sub.H
(400 MHz, DMSO-d.sub.6) 0.877(3H, t, J 7.5 Hz), 1.470(2H, m),
3.006(2H, q, J 6.5 Hz), 3.112(4H, bt), 3.673(4H, bt), 4141(2H, s),
7.017(2H, d, J8.5 Hz), 7.323(2H, d, J 8.5 Hz), 7.715(1H, t) and
9.126 (2H, bs).
Example 77
[0661] S-4-[(Cyclohexylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxyla- te hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate
and cyclohexyl isocyanate according to the method described in
Example 71 to give the product as a white solid (41.4%); HPLC
(XTERRA, 50/80) 89% (3.63 min); NMR .delta..sub.H (400 MHz,
DMSO-d.sub.6) 1.234(6H, m), 1.554(1H, bd), 1.700(2H, bd), 1.808(2H,
bd), 3.113(4H, bt), 3.677(4H, bs), 4.142(2H,s), 7.012(2H, d, J 8.5
Hz), 7.316(2H, d, J 8.0 Hz), 7.661(1H, d) and 9.189(1H, bs).
Example 78
[0662] 2-Fluoro-4-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate fumarate
[0663] 2-Fluoro-4-hydroxybenzyl alcohol: to a stirred solution of
3-fluorophenol (10.4 g) and potassium hydroxide (85%, 6.1 g) in
water (20 ml) at 60.degree. C. was added dropwise over 1 h a
solution of 37% aqueous formaldehyde solution (14.3 ml) in added
water (20 ml). The mixture was cooled to 40.degree. C., stirred for
18 h then cooled to room temperature and acidified with dilute
hydrochloric acid. The mixture was extracted with ethyl acetate
(2.times.100 ml). The combined organic extracts were washed (water,
brine), dried (sodium sulfate), concentrated in vacuo and purified
by column chromatography (SiO.sub.2; ethyl acetate--isohexane, 1:1)
to give the product as a white, crystalline solid (1.0 g, 8%):
.delta..sub.H (400 MHz, DMSO-d.sub.6) 9.70 (1H, m, OH), 7.21 (1H,
t, J 8.5 Hz), 6.58 (1H, dd, J 8, 2, Hz), 6.51 (1H, dd, J 12, 2 Hz),
4.98 (1H, m, OH) and 4.41 (2H, s); HPLC (XTERRA, 50/80, 235 nm) 93%
(0.54 min).
[0664] 4-Difluoromethoxy-2-fluorobenzyl alcohol: to a stirred
solution of powdered potassium hydroxide (85%, 2.2 g) in 2-propanol
(20 ml) was added dropwise a solution of 2-fluoro-4-hydroxybenzyl
alcohol (1.0 g) in 2-propanol (5 ml). The mixture was cooled to
-10.degree. C. and chlorodifluoromethane was bubbled into the
stirred mixture for 10 min. The reaction vessel was sealed and the
mixture was stirred for 30 min at -10.degree. C. then warmed slowly
to room temperature and stirred for 18 h. The mixture was
partitioned between ethyl acetate (2.times.30 ml) and water (30
ml). The combined organic extracts were washed (water, brine),
dried (sodium sulfate), concentrated in vacuo and purified by
column chromatography [SiO.sub.2, isohexane-ethyl acetate
(9:1.fwdarw.4:1)] to give the product as a clear oil (0.47 g, 35%):
.delta..sub.H (400 MHz, CDCl.sub.3) 7.43 (1H, t, J 8 Hz), 6.94 (1H,
dd, J 8, 2.5 Hz), 6.87 (1H, dd, J 10.5, 2.5 Hz), 6.50 (1H, t, J 73
Hz) and 4.74 (2H, d, J 6 Hz).
[0665] 4-Difluoromethoxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate fumarate was prepared
from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-
-butoxycarbonylpiperazine and 4-difluoromethoxy-2-fluorobenzyl
alcohol according to the methods described for Example 48 to give
the product as an off-white solid (0.072 g, 41% overall);
.nu..sub.max (nujol)/cm-1 3391, 2595, 1702, 1630, 1511, 1420, 1378,
and 1342; .delta..sub.H (400 MHz, DMSO-d.sub.6) 7.48 (1H, m), 7.30
(1H, t), 7.18-7.14 (2H, m), 6.58 (2H, s), 5.10 (2H, s), 3.97 (2H,
t, J 6 Hz), 2.79 (2H, d, J 12.5 Hz), 2.72 (2 H, dd, J 4.3 and 12.3
Hz), and 1.19 (6 H, d,J6.9 Hz).
Example 79
[0666] 3-Benzyloxybenzyl cis-2,6-dimethylpiperazine-1-carboxylate
hydrochloride was prepared from cis
1-chlorocarbonyl-2,6-dimethyl-4-tert-- butoxycarbonylpiperazine and
3-benzyloxybenzyl alcohol according to the methods described for
Examples 52 and 54 to give the product as a white solid (0.254 g,
65% overall); .nu..sub.max (nujol)/cm-1 3320, 2684, 2587, 1716,
1694, 1599, 1415, and 1312; .delta..sub.H (400 MHz, DMSO-d.sub.6)
10.02 (1H, br), 9.27 (1H, br), 7.45-7.28 (6H, m), 7.01-6.94 (3H,
m), 5.11 (2H, s), 5.09 (2H, s), 4.33 (2H, m), 3.15 (2H, d, J 13.2
Hz), 3.07 (2H, m), and 1.31 (6H, d, J 7.6 Hz).
Example 80
[0667] 2,6-Difluoro-4-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-c- arboxylate hydrochloride
[0668] 2,6-Difluoro-4-difluoromethoxybenzyl alcohol: to a stirred
solution of powdered potassium hydroxide (85%, 7.2 g) in 2-propanol
(60 ml) was added dropwise a solution of
2,6-difluoro-4-hydroxybenzyl alcohol (3.5 g) in 2-propanol (20 ml).
The mixture was cooled to -10.degree. C. and chlorodifluoromethane
was bubbled into the stirred mixture for 10 min. The reaction
vessel was sealed and the mixture was stirred for 30 min at
-10.degree. C. then warmed slowly to room temperature and stirred
for 18 h. The mixture was partitioned between ethyl acetate
(2.times.100 ml) and water (100 ml). The combined organic extracts
were washed (water, brine), dried (sodium sulfate), concentrated in
vacuo and purified by column chromatography [SiO.sub.2,
isohexane-ethyl acetate (9:1.fwdarw.4:1)] to give the product as a
clear oil (1.83 g, 40%): .delta..sub.H (400 MHz, CDCl.sub.3) 6.74
(1H, t, J 4 Hz), 6.70 (1H, t, J 4 Hz), 6.51 (1H, t, J 73 Hz) and
4.75 (2H, d, J 6.5 Hz).
[0669] 2,6-Difluoro-4-difluoromethoxybenzyl
cis-2,6-dimethyl-4-tert-butoxy- carbonyl-piperazine-1-carboxylate
hydrochloride: to a stirred suspension of sodium hydride (60%, 86
mg, 1.5 eq.) in DMF (2 mL) at 0.degree. C. was added dropwise a
solution of cis-2,6-dimethyl-1-(chlorocarbonyl)-4-(tert--
butoxycarbonyl)piperazine (0.40 g, 1 eq.) and
4-difluoromethoxy-2,6-difluo- robenzyl alcohol (0.30 g, 1 eq.) in
DMF (5 mL). The mixture was warmed to room temperature, stirred for
2 hours then partitioned between water (20 mL) and ethyl acetate
(2.times.20 mL). The combined organic layers were washed (water,
brine), dried (sodium sulfate) and concentrated to give a yellow
oil (0.72 g), which was used without further purification.
[0670] 2,6-Difluoro-4-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-c- arboxylate hydrochloride was
prepared from cis 1-chlorocarbonyl-2,6-dimeth-
yl-4-tert-butoxycarbonylpiperazine and
2,6-difluoro-4-difluoromethoxybenzy- l alcohol according to the
method described for Example 54 to give the product as a, white
solid (0.1406 g, 65% overall); .nu..sub.max (nujol)/cm-1 3342,
1684, 1640, 1599, 1378, 1308, 1166, and 1089; .delta..sub.H (400
MHz, DMSO-d.sub.6) 9.69 (2H, br), 7.38 (1H, t, J 73 Hz), 7.15-7.10
(2H, m), 5.14 (2H, s), 4.24 (2H, m), 3.13 (2H, d, J 13 Hz), 3.05
(2H, dd, J 5.2 and 13 Hz), and 1.27 (6H, d, J 7.2 Hz).
Example 81
[0671] (+/-)-S-4-[(2-Butylamino)carbonyl]oxybenzyl
piperazine-1-thiocarbox- ylate hydrochloride, was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate
and (+/-)sec-butyl isocyanate according to the method described in
Example 71 to give the product as a white solid (41.2%); melting
point 185.7-205.6.degree. C.; NMR .delta..sub.H (400 MHz,
DMSO-d.sub.6) 0.871(3H, t, J 7.5 Hz), 1.090(3H, d, J 7.0 Hz),
1.440(2H, m), 3.115(4H, t), 3.455(1H, m), 3.672(4H, bt) 4.142(2H,
s), 7.012(2H, d, J 8.5 Hz), 7.325(2H, d, J 8.5 Hz), 7.584(1H, d)
and 9.085(1H, bs).
Example 82
[0672] S-4-[(Cyclopentylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxyl- ate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate
and cyclopentyl isocyanate according to the method described in
Example 71 to give the product as a white solid (88.2%); melting
point 196.5-197.6.degree. C.; NMR .delta..sub.H (400 MHz,
DMSO-d.sub.6) 1.499(4H, m), 1.652(2H, m), 1.828(2H, m), 3.116(4H,
bt), 3.312(5H, bs), 3.678(4H, bt), 3.818(1H, m), 4.142(2H, s),
7.017(2H, d, J 8.0 Hz), 7.321(2H, d, J 8.5 Hz), 7.736(1H, d) and
9.157(2H, bs).
Example 83
[0673] S-4-[(1-Adamantylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxyl- ate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate
and adamantanyl isocyanate according to the method described in
Example 71 to give the product as a white solid (38.2%); melting
point 200.7-200.8.degree. C.; NMR .delta..sub.H (400 MHz,
DMSO-d.sub.6) 1.612(6H, m), 1.905(6H, m), 2.027(3H, bs), 3.119(4H,
bt), 3.669(4H, bs), 4.138(2H, s), 6.987(2H, d, J 8.5 Hz), 7.321(2H,
d, J 8.5 Hz), 7.449(1H, bs) and 9.070(2H, s).
Example 84
[0674] S-4-[(2-Propenylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxyla- te hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate
and allyl isocyanate according to the method described in Example
71 to give the product as a white solid (18.6%); melting point
193.8-193.9.degree. C.; NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
3.101(4H, bt), 3.689(4H, bs), 3.757(2H, bs), 4.147(2H, s),
5.102(1H, dd, J 1.5, 10.5 Hz), 5.201(1H, d, J 1.5, 17.5 Hz),
7.026(2H, d, J 8.5 Hz), 7.332(2H, d, J 8.5 Hz), 7.925(1H, t) and
9.431(2H, bs).
Example 85
[0675] S-4-[(Phenylamino)carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpi-
perazine-1-thiocarboxylate and cyclohexyl isocyanate according to
the method described in Example 71 to give the product as a white
solid (8.0%); melting point 177.9-201.9.degree. C.; NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 3.127(4H, bt), 3.687(4H, bs),
4.180(2H, s), 7.055(1H, t, J 7.5 Hz), 7.144(2H, d, J 8.5 Hz),
7.323(2H, t, J 8.5 Hz), 7.391(2H, d, J 8.5 Hz), 7.495(2H, d, J 7.5
Hz), 9.078(2H, s) and 10.191(1H, s).
Example 86
[0676] S-4-[[4-(2-Propyl)phenylamino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate
and 4-(2-propyl)phenyl isocyanate according to the method described
in Example 71 to give the product as a white solid (4.8%); melting
point 234.2-234.3.degree. C.; NMR .delta..sub.H (400 MHz,
DMSO-d.sub.6) 1.179(6H, d, J 7.0 Hz), 3.121(4H, bt), 3.647(4H, bs),
4.168(2H, s), 7.141(2H, d, J 8.5 Hz), 7.183(2H, d, J 8.5 Hz),
7.387(4H, m), (9.019(2H, bs) and 10.089(1H, s).
Example 87
[0677] (+/-)-S-4-[[(1-Phenylethyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate
and 1-phenylethyl isocyanate according to the method described in
Example 71 to give the product as a white solid (54.2%); melting
point 231.9-232.0.degree. C.; NMR .delta..sub.H (400 MHz,
DMSO-d.sub.6) 1.411(3H, d, J 7.0 Hz), 3.101(4H, bt), 3.668(4H, bs)
4.132(2H, s), 4.701(1H, m), 7.00(2H, d, J 8.0 Hz), 7.327(6H, m),
8.297(1H, bd) and 9.175(2H, bs).
Example 88
[0678]
S-4-[[(4-Ethoxycarbonyl)phenylamino]carbonyl]oxybenzylpiperazine-1--
thiocarboxylate hydrochloride was prepared from S-4-hydroxybenzyl
4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and
4-(ethoxycarbonyl)phenyl isocyanate according to the method
described in Example 71 to give the product as a white solid
(77.3%); melting point 201.0-201.5.quadrature.C; NMR .delta.H (400
MHz, DMSO-d.sub.6) 1.308(3H, t, J 7.0 Hz), 3.122(4H, bt), 3.680(4H,
bt), 4.175(2H, s), 4.277(2H, q, J 7.0 Hz), 7.183(2H, d, J 8.5 Hz),
7.396(2H, d, J 8.5 Hz), 7.626(2H, d, J 9.0 Hz), 7.923(2H, d, J 9.0
Hz), 9.085(2H, bs) and 10.619(1H, bs).
Example 89
[0679] S-4-[[(3-Chloro-4-fluorophenyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate
and 3-chloro-4-fluorophenyl isocyanate according to the method
described in Example 71 to give the product as a white solid
(39.5%); melting point 204.1-204.2.quadrature.C; NMR .delta..sub.H
(400 MHz, DMSO-d.sub.6) 3.113(4H, bt), 3.686(4H, bs), 4.168(2H, s),
7.401(2H, d, J 8.5 Hz), 7.593(4H, m), 7.718(1H, dd, J 2.5, 7.0 Hz),
9.229(2H, bs) and 10.458(1H, bs).
Example 90
[0680]
S-4-[[(4-Difluoromethoxyphenyl)amino]carbonyl]oxybenzylpiperazine-1-
-thiocarboxylate hydrochloride was prepared from S-4-hydroxybenzyl
4-tert-butoxycarbonylpiperazine-1-thiocarboxylate and
4-difluoromethoxyphenyl isocyanate according to the method
described in Example 71 to give the product as a white solid
(30.7%); melting point 203.7-203.8.quadrature.C; NMR .delta..sub.H
(400 MHz, DMSO-d.sub.6) 3.116(4H, bt), 3.683(4H, bs), 4.171(2H, s),
7.155(4H, d, J 8.5 Hz), 7.387(2H, d, J 8.5 Hz), 7.520(2H, d, J 9.0
Hz), 9.206(2H, s) and 10.285(1H, bs).
Example 91
[0681] 4-Methylbenzyl cis-2,6-dimethylpiperazine-1-carboxylate
hydrochloride was prepared from cis
1-chlorocarbonyl-2,6-dimethyl-4-tert-- butoxycarbonylpiperazine and
4-methylbenzyl alcohol according to the methods described for
Examples 52 and 54 to give the product as a white solid (0.2614 g,
87% overall); .lambda..sub.max (diffuse reflectance)/cm-1 2749,
2656, 2541, 1697, 1594, 1518, 1330, and 1112; .delta..sub.H (400
MHz, DMSO-d.sub.6) 10.05 (1H, br), 9.32 (1H, br), 7.26 (2H, d, J
8.0 Hz), 7.18 (2H, d, J 8.0 Hz), 5.07 (2H, s), 4.30 (2H, m), 3.14
(2H, d, J 12.8 Hz), 3.05 (2H, m), 2.30 (3H, s), and 1.30 (6H, d, J
7.2 Hz).
Example 92
[0682] (+/-)-4-Difluoromethoxybenzyl
2-ethylpiperazine-1-carboxylate fumarate
[0683] (RS) 4-Tert-butoxycarbonyl-2-ethylpiperazine: to a stirred
solution of 2-ethylpiperazine dihydrochloride (J.Org.Chem., 1987,
52(6), 1045, 5.0 g) and triethylamine (9.3 ml) in DCM (50 ml) at
0.degree. C. was added di-tert-butyl-dicarbonate (6.5 g). The
mixture was warmed to room temperature, stirred for 2 h, washed
successively with water, dilute sodium hydroxide solution, water
and brine then dried (sodium sulfate) and concentrated in vacuo to
give the product as a clear oil (5.1 g); .delta..sub.H (400 MHz,
CDCl.sub.3) 3.78 (1H, m), 3.71 (1H, d, J 12.5 Hz), 2.81 (1H, dt, J
11.5, 2.5 Hz), 2.69 (1H, t, J 10.5 Hz), 2.48 (1H, td, J 11.5, 3
Hz), 2.29 (1H, m), 2.17 (1H, m), 1.39 (9H, s), 1.31 (1H, dd, J 7.5,
6 Hz), 1.25 (1H, dd, J 7.5, 6 Hz) and 0.87 (3H, t, J 7 Hz); GC
(150.degree. C. -10 min-32.degree. C.) 93%, 5.13 min.
[0684] (RS)
1-Chlorocarbonyl-2-ethyl-4-tert-butoxycarbonylpiperazine: a
solution of (RS)4-tert-butoxycarbonyl-2-ethylpiperazine (3.95 g)
and pyridine (1.64 ml) in DCM (35 ml) was added dropwise to a
stirred solution of triphosgene (2.1 g) in DCM (100 ml) at
0.degree. C. under Ar. The mixture was warmed to room temperature,
stirred for 30 min then washed with water (100 ml) and brine (100
ml). The organic solution was dried (sodium sulfate) and
concentrated in vacuo. The residue was dissolved in isohexane,
filtered and concentrated in vacuo to give the product as a clear
oil (3.73 g) which was used without further purification;
.delta..sub.H (400 MHz, CDCl.sub.3) 4.39-3.80 (4H, m), 3.39-2.69
(3H, m), 1.66 (2H, m), 1.47 (9H, s), 0.96 (2.7H, d, J 7 Hz) and
0.89 (0.3H, d, J 7 Hz); GC (150.degree. C. -10 min-320.degree. C.)
83%, 8.72 min.
[0685]
(+/-)4-Difluoromethoxybenzyl-2-ethyl-4-tert-butoxycarbonylpiperazin-
e-1-carboxylate: sodium borohydride (0.11 g) was added to stirred
4-difluoromethoxybenzaldehyde (1.0 g) in methanol (20 ml). The
mixture was stirred for 2 h then concentrated in vacuo. The residue
was partitioned between DCM (30 ml) and aqueous sodium hydroxide
solution (2M, 30 ml). The organic layer was filtered through a PTFE
membrane and concentrated in vacuo to give a clear oil (0.89 g).
The residue was combined with (RS)
1-chlorocarbonyl-2-ethyl-4-tert-butoxycarbonylpiperazi- ne (1.1 g)
and sodium hydride (0.31 g) according to the method described for
Example 54 to give the product as a yellow oil (1.46 g), which was
used without further purification.
[0686] (+/-)-4-Difluoromethoxybenzyl
2-ethylpiperazine-1-carboxylate fumarate:
(+/-)4-difluoromethoxybenzyl-2-ethyl-4-tert-butoxycarbonylpiper-
azine-1-carboxylate (0.045 g) and HCl-dioxane (4M, 0.2 ml) were
combined according to the method described for Example 48 to give
the product as a white solid (0.023 g); .delta..sub.H (400 MHz,
DMSO-d.sub.6) 7.41 (1H, d, J 8 Hz), 7.21 (1H, t, J 74 Hz), 7.17
(1H, d, J 8.5 Hz), 6.56 (2H, s), 5.08 (1H, d, J 13 Hz), 5.04 (1H,
d, J 13 Hz), 3.91 (lH, m), 3.78 (1H, m), 2.90 (3H, m), 2.73 (1H,
m), 2.57 (1H, m), 1.70 (1H, m), 1.62 (1H, m) and 0.77 (3H, t, J 7
Hz).
Example 93
[0687] S-4-[[(4-Methoxyphenyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate
and 4-methoxyphenyl isocyanate according to the method described in
Example 71 to give the product as a white solid (22.4%); NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 2.272(3H, s), 3.354(4H, bm),
3.445(4H, bs), 4.162(2H, s), 6.860(1H, d, J 7.5 Hz), 7.139(2H, d, J
9.0 Hz), 7.192(1H, t, J 7.5 Hz), 7.293(2H, d, J 8.5 Hz), 7.370(2H,
d, J 8.5 Hz) and 10.104(1H, bs).
Example 94
[0688] S-4-[ [(3-Methylbenzyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate
and 3-methylbenzyl isocyanate according to the method described in
Example 71 to give the product as a white solid (58.4%); NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 2.302(3H, s), 3.344(4H, bm),
3.436(4H, bs), 4.125(2H, s), 4.231(2H, d, J 6.5 Hz), 7.071(5H, m),
7.228(1H, t, J 7.5 Hz), 7.318(2H, d, J 8.5 Hz) and 8.232(1H, t, J
6.5 Hz).
Example 95
[0689] S-4-[[(4-Methoxybenzyl)amino]carbonyl]oxybenzyl
piperazine-1-thiocarboxylate hydrochloride was prepared from
S-4-hydroxybenzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate
and 4-difluoromethoxyphenyl isocyanate according to the method
described in Example 71 to give the product as a white solid
(66.0%); .delta..sub.H (400 MHz, DMSO-d.sub.6) 3.338(4H, bm),
3.437(4H, bs), 3.737(3H, s), 4.116(2H, s), 4.184(2H, d, J 6.0 Hz),
6.902(2H, d, J 8.5 Hz), 7.024(2H, d, J 8.5 Hz), 7.227(2H, d, J 9.0
Hz), 7.318(2H, d, J 8.5 Hz) and 8.193(1H, t, J 6.0 Hz).
Example 96
[0690] 2,6-Difluoro-4-(2-propyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-car- boxylate fumarate
[0691] 2,6-Difluoro-4-(2-propoxy)benzyl alcohol: a mixture of
2,6-difluoro-4-hydroxybenzyl alcohol (0.20 g), cesium carbonate
(0.22 g) and 2-iodopropane (0.14 ml) in DMF (10 ml) was heated to
40.degree. C. and stirred for 18 h. The mixture was cooled to room
temperature then poured into water (30 ml) and extracted with ethyl
acetate (2.times.20 ml). The combined organic extracts were washed
(water, brine), dried (sodium sulfate) and concentrated in vacuo to
give the product as a yellow oil (0.25 g) which was used without
further purification: .delta..sub.H (400 MHz, CDCl.sub.3) 6.44 (1H,
t, J 4 Hz), 6.40 (1H, t, J 4 Hz), 4.69 (2H, d, J 5.5 Hz), 4.48 (1H,
hept., J 6 Hz) and 1.33 (6H, d, J 6 Hz).
[0692] 2,6-Difluoro-4-(2-propoxy)benzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate fumarate was prepared
from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-
-butoxycarbonylpiperazine and 2,6-difluoro-4-(2-propoxy)benzyl
alcohol according to the methods described for Examples 48 and 54
to give the product as a white solid: .delta..sub.H (400 MHz,
DMSO-d.sub.6) 1.16 (6H, d, J 6.9 Hz), 1.26 (6H, d, J 6.0 Hz),
2.65-2.8 (4H, m), 3.90 (2H, m), 4.68 (1H, heptet, J 6.0 Hz), 5.02
(2H, s), 6.6 (2H, s, fumarate) and 6.75 (2H, m), NH not observed;
HPLC (XTERRA, 50/80, 220 nm) 94% (4.00 min).
Example 97
[0693] S-4-(2-Oxo-2-phenylethoxy)benzyl
piperazine-1-thiocarboxylate
[0694] 4-(2-Oxo-2-phenylethoxy)benzyl
4-tert-butoxycarbonylpiperazine-1-th- iocarboxylate: a mixture of
4-hydroxybenzyl 4-tert-butoxycarbonylpiperazin- e-1-thiocarboxylate
(100 mg, 0.28 mmol), cesium carbonate (140 mg, 1.5 eq) and
a-bromoacetophenone (84 mg, 1.5 eq) in DMF was shaken at ambient
temperature for 16 h. The reaction mixture was poured into water
(30 mL) and extracted with ethyl acetate (3.times.20 mL). The
organic extracts were washed with water (30 mL), dried (MgSO.sub.4)
and condensed to give the desired product (129 mg, 96%) as a yellow
oil: NMR .delta..sub.H(400 MHz; d.sub.6-DMSO) 1.40 (9H, s),
3.30-3.36 (4H, m), 3.43 (4H, br s), 4.07 (2H, s), 5.54 (2H, s),
6.86-6.91 (2H, m), 7.20-7.26 (2H, m), 7.54-7.60 (2H, m) and
7.66-7.72 (1H, m); HPLC (XTERRA, 50/80, 220 nm) 96.1% (6.56
min).
[0695] 4-(2-Oxo-2-phenylethoxy)benzyl piperazine-1-thiocarboxylate:
a solution of HCl in dioxane (4 M; 380 uL, 10 eq) was added to a
solution of 4-(2-oxo-2-phenylethoxy)benzyl
4-tert-butoxycarbonylpiperazine-1-thioc- arboxylate (72.1 mg) in
ethyl acetate (2 mL) and the resultant mixture was shaken at
ambient temperature for 16 h. The solvent was removed in vacuo and
the resultant crude material was suspended in dichloromethane (4
mL) and shaken with MP-CO.sub.3 (1 g, 17 eq) at ambient temperature
for 1 h. Purification by ion-exchange chromatography [SCX-2 (500
mg); DCM, MeOH, NH.sub.3-MeOH] afforded the desired product (44.7
mg, 79%) as a colourless oil: NMR .delta..sub.H(400 MHz;
CDCl.sub.3) 2.82-2.86 (4H, m), 3.41-3.63 (4H, br s), 4.12 (2H, s),
5.23 (2H, s), 6.84-6.90 (2H, m), 7.24-7.29 (2H, m), 7.46-7.52 (2H,
m) and 7.58-7.64 (1H, m); HPLC (XTERRA, 50/80, 235 nm) 97.7% (2.05
min).
Example 98
[0696] (R)-4-Difluoromethoxybenzyl 2-ethylpiperazine-1-carboxylate
fumarate
[0697]
(R)4-Difluoromethoxybenzyl-2-ethyl-4-tert-butoxycarbonylpiperazine--
1-carboxylate: a sample of crude
(+/-)4-difluoromethoxybenzyl-2-ethyl-4-te-
rt-butoxycarbonylpiperazine-1-carboxylate (Example 92, 0.1 g) in
solution in isohexane--2-propanol (9:1, 0.7 ml) was separated by
HPLC [Chiralcel AD; isohexane--2-propanol (9:1)] to give the
product as a clear oil (0.053 g); .delta..sub.H (400 MHz,
CDCl.sub.3) 7.35 (2H, d, J8.5 Hz), 7.11 (1H, d, J8.5 Hz), 6.51 (1H,
t, J74 Hz), 5.13 (1H, d, J 12.5 Hz), 5.09 (1H, d, J 12.5 Hz),
4.19-3.82 (4H, m), 3.09-2.70 (3H, m), 1.57 (2H, m), 1.46 (9H, m)
and 0.88 (3H, m); HPLC [Chiralcel AD 300.times.4.6 mm;
hexane--2-propanol (9:1), 1.0 ml/min, 220 nm] 98% (10.51 min).
[0698] (R)4-Difluoromethoxybenzyl-2-ethylpiperazine-1-carboxylate
fumarate:
(R)4-difluoromethoxybenzyl-2-ethyl-4-tert-butoxycarbonylpiperaz-
ine-1-carboxylate (0.045 g) was prepared from
(R)4-difluoromethoxybenzyl-2-
-ethyl-4-tert-butoxycarbonylpiperazine-1-carboxylate according to
the method described in Example 48 to give the product as a white
solid (0.023 g); m.p. 164.degree. C. (decomp.); .delta..sub.H (400
MHz, DMSO-d.sub.6) 7.41 (1H, d, J 8 Hz), 7.21 (1H, t, J 74 Hz),
7.17 (1H, d, J 8.5 Hz), 6.56 (2H, s), 5.08 (1H, d, J 13 Hz), 5.04
(1H, d, J 13 Hz), 3.91 (1H, m), 3.78 (1H, m), 2.90 (3H, m), 2.73
(1H, m), 2.57 (1H, m), 1.70 (1H, m), 1.62 (1H, m) and 0.77 (3H, t,
J 7 Hz).
Example 99
[0699] S-4-Benzenesulfonyloxybenzyl piperazine-1-thiocarboxylate
hydrochloride
[0700] 4-Benzenesulfonyloxybenzyl
4-tert-butoxycarbonylpiperazine-1-thioca- rboxylate:
[0701] triethylamine (57 uL, 0.41 mmol) and benzenesulfonyl
chloride (38 uL) was added to a stirred solution of 4-hydroxybenzyl
4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (0.10 g) in
dichloromethane (3 mL) at ice-bath temperature. The reaction
mixture was warmed to room temperature and stirred for 4 hours. The
mixture was diluted with water (25 mL) and extracted with
dichloromethane (2.times.30 mL). The combined organics were dried
(MgSO.sub.4), filtered and concentrated under vacuum to reveal a
brown gum. Trituration with isohexane afforded the product as a
white solid (44 mg, 32%) which was used without further
purification.
[0702] 4-Benzenesulfonyloxybenzyl piperazine-1-thiocarboxylate
hydrochloride: to a stirred solution of 4-benzenesulfonyloxybenzyl
4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (44 mg) in ethyl
acetate (2 mL) was added hydrogen chloride solution (4M, dioxane,
0.23 mL). The mixture was stirred for 18 h then concentrated under
vacuum to give the product as a white crystalline solid (31 mg,
78%): HPLC (XTERRA, 50/80, 220 nm) 98.4% (2.54 min); NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 3.100(4H, bt), 3.672(4H, bt),
4.123(2H, s), 6.976(2H, d, J 8.5 Hz), 7.341(2H, d, J 9.0 Hz),
7.680(2H, t, J 8.0 Hz), 7.826(1H, t, J 7.5 Hz), 7.870(2H, d, J 7.0
Hz) and 9.258(2H, bs).
Example 100
[0703] (+/-)-2,6-Difluoro-4-propoxybenzyl
2-ethylpiperazine-1-carboxylate fumarate was prepared from
(+/-)1-chlorocarbonyl-2-ethyl-4-tert-butoxycar- bonylpiperazine,
1-iodopropane and 2,6-difluoro-4-hydroxybenzyl alcohol according to
the methods described for Examples 54 and 96 to give the product as
a white solid (0.13 g, 42%); m.p. 145-165.degree. C. (decomp.);
.delta..sub.H (400 MHz, DMSO-d.sub.6) 6.77 (1H, t, J 3.5 Hz), 6.73
(1H, t, J, 3.5 Hz), 5.07 (1H, d, J 12 Hz), 5.01 (1H, d, J 12 Hz),
3.97 (2H, t, J 6.5 Hz), 3.85 (1H, m), 3.72 (1H, m), 2.95-2.85 (3H,
m), 2.74 (1H, dd, J 13, 4.5 Hz), 2.57 (1H, td, J 12.5, 3 Hz), 1.71
(2H, sept., J 7 Hz), 1.70 (1H, m), 1.57 (1H, sept. J 6.5 Hz), 0.96
(3H, t, J 7 Hz) and 0.73 (3H, t, J 6.5 Hz).
Example 101
[0704] (+/-)-2,6-Difluoro-4-difluoromethoxybenzyl
2-ethylpiperazine-1-carb- oxylate fumarate was prepared from
(+/-)1-chlorocarbonyl-2-ethyl-4-tert-bu- toxycarbonylpiperazine and
2,6-difluoro-4-difluoromethoxybenzyl alcohol according to the
methods described for Examples 54 to give the product as a white
solid (0.084 g, 38%); m.p. 145.degree. C. (decomp.); Found: C,
49.04; H, 4.78; N, 5.87%. C.sub.19H.sub.22F.sub.4N.sub.2O.sub.7
requires: C, 48.93; H, 4.75; N, 6.00%.
Example 102
[0705] 2-Fluoro-5-methoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride
[0706] 2-Fluoro-5-methoxybenzyl alcohol: sodium borohydride (0.061
g) was added to stirred 2-fluoro-5-methoxybenzaldehyde (0.5 g) in
methanol (10 ml). The mixture was stirred for 2 h then concentrated
in vacuo. The residue was partitioned between DCM (2.times.15 ml)
and aqueous sodium hydroxide solution (2M, 10 ml). The combined
organic layers were washed (water, brine), dried (sodium sulfate)
and concentrated in vacuo to give a clear oil (0.5 g), which was
used without further purification.
[0707] 2-Fluoro-5-methoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared
from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert--
butoxycarbonylpiperazine and 2-fluoro-5-methoxybenzyl alcohol
according to the methods described for Examples 54 to give the
product as white crystals (0.2714 g, 82% overall); (Found: C,
53.95; H, 6.7; N, 8.3%. C.sub.15H.sub.21FN.sub.2O.sub.3.HCl
requires C, 54.1; H, 6.7; N, 8.4%); .delta..sub.H (400 MHz,
DMSO-d.sub.6) 9.84 (2H, br), 7.16 (1H, t, J 9.2 Hz), 6.99 (1H, m),
6.94 (1H, m), 5.13 (2H, s), 4.31 (2H, m, J 6 Hz), 3.73 (3H, s),
3.14 (2H, d, J 13 Hz), 3.06 (2H, dd, J 5.2 and 13 Hz), and 1.31
(6H, d, J 7.2 Hz).
Example 103
[0708] 3-Difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate fumarate was prepared from
cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butox- ycarbonylpiperazine
and 3-difluoromethoxybenzyl alcohol according to the methods
described for Examples 48 and 54 to give the product as a white
solid (0.2816 g, 65% overall); (Found: C, 53.0; H, 5.8; N, 6.4%.
C.sub.15H.sub.20F.sub.2N.sub.2O.sub.3.C.sub.4H.sub.4O.sub.4
requires C, 53.0; H, 5.6; N, 6.5%); .delta..sub.H (400 MHz,
DMSO-d.sub.6) 7.43 (1H, t, J 8.0 Hz), 7.24 (1H, s), 7.21 (1H, t, J
74 Hz), 7.13(2H, m, J 8.0 Hz), 6.59 (2H, s), 5.11 (2H, s), 4.02
(2H, m, J 6 Hz), 2.82-2.72 (4 H, m), and 1.22 (6H, d, J 6.8
Hz).
Example 104
[0709] S-4-Propanesulfonyloxybenzyl piperazine-1-thiocarboxylate
hydrochloride was prepared from S-4-hydroxybenzyl
4-tert-butoxycarbonylpi- perazine-1-thiocarboxylate and
1-propylsulfonyl chloride according to the method described in
Examples 71 and 99 to give the product as a colourless gum (51.6%);
HPLC (XTERRA, 50/80, 220 nm) 96.3% (1.11 min); .delta..sub.H (400
MHz, DMSO-d.sub.6) 1.033(3H, t, J 7.5 Hz), 1.846(2H, m), 3.117(4H,
bs), 3.480(2H, t, J 7.5 Hz), 3.685(4H, bs), 4.179(2H, s), 7.269(2H,
d, J 9.0 Hz), 7.438(2H, d, J 8.5 Hz) and 9.236(2H, bs).
Example 105
[0710] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(pyridin-3-ylmethoxy)-benzyl ester fumarate was
prepared from 2,6-difluoro-4-hydroxybenzyl alcohol, 3-picolyl
chloride hydrochloride and cis
1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonyl- piperazine
according to the methods described for Examples 54 and 96 to give
the product as a white solid: .delta..sub.H (400 MHz, DMSO-d.sub.6)
1.25 (6H, d, J 6.9 Hz), 2.78-2.90 (4H, m), 4.04 (2H, m), 5.05 (2H,
s), 5.10 (2H, s), 6.55 (2H, m), 7.34 1H, dd, J 0.8, 4.8 Hz), 7.75
(1H, m), 8.62 (1H, dd, J 1.6, 4.8 Hz) and 8.67 (1H, m), NH not
observed; HPLC (XTERRA, 50/80, 220 nm) 99.6% (1.82 min).
Example 106
[0711] (R)-2,6-Difluoro-4-propoxybenzyl
2-methylpiperazine-1-carboxylate fumarate was prepared from
(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarb- onylpiperazine,
1-iodopropane and 2,6-difluoro-4-hydroxybenzyl alcohol according to
the methods described for Examples 54 and 96 to give the product as
a white solid (19.2%); melting point 193.9-194.0.degree. C.; NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 0.958(3H, t, J 7.5 Hz),
1.140(3H, d, J 7.0 Hz), 1.715(2H, m), 2.817(2H, m), 2.982(2H, m),
3.687(2H, m), 4.097(1H, bs), 5.027(2H, q, J 11.0 Hz), 6.573(2H, s)
and 6.773(2H, d, J 10.0 Hz).
Example 107
[0712] (R)-4-Difluoromethoxybenzyl 2-methylpiperazine-1-carboxylate
fumarate was prepared from
(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarb- onylpiperazine and
4-difluoromethoxybenzyl alcohol according to the methods described
for Examples 48 and 54 to give the product as a white solid
(24.0%); melting point 123.9-124.520 C.; NMR .delta..sub.H (400
MHz, DMSO-d.sub.6) 1.174(3H, d, J 7.0 Hz), 2.622(1H, m), 3.003(2H,
m), 3.766(1H, dd, J 2.5, 13 Hz), 4.187(1H, m), 5.067(2H, m), 6.542
(2H, s), 7.178(2H, d, J 9.0 Hz), 7.244(1H, t, J 74.0) and 7.424(2H,
d, J 8.5 Hz).
Example 108
[0713] 5-Benzyloxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared
from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert--
butoxycarbonylpiperazine, benzyl chloride and
2-fluoro-5-hydroxybenzyl alcohol according to the methods described
for Examples 52, 54 and 96 to give the product as a white solid
(0.229 g, 56% overall);(Found; C, 61.5; H, 6.5; N, 6.8%.
C.sub.21H.sub.25FN.sub.2O.sub.3.HCl requires C, 61.7; H, 6.4; N,
6.85%); .delta..sub.H (400 MHz, DMSO-d.sub.6) 9.86 (1H, br), 9.17
(1H, br), 7.45-7.33 (5H, m), 7.17 (1H, t, J 9 Hz), 7.08 (1H, m, J
2.8 Hz), 7.02 (1H, m), 5.12 (2H, s), 5.09 (2H, s), 4.29 (2H, m),
3.15 (2H, d, J 12.8 Hz), 3.06 (2H, dd, J 4.8 and 12.8 Hz), and 1.29
(6H, d, J 7.2 Hz).
Example 109
[0714] 2,6-Difluoro-4-(3-phenyl)propoxybenzyl
cis-2,6-dimethylpiperazine-1- -carboxylate fumarate was prepared
from 2,6-difluoro-4-hydroxybenzyl alcohol, 3-phenylpropyl bromide
and cis 1-chlorocarbonyl-2,6-dimethyl-4-t-
ert-butoxycarbonylpiperazine according to the methods described for
Examples 48, 54 and 96 to give the product as a white solid:
.delta..sub.H (400 MHz, DMSO-d.sub.6) 1.25 (6H, d, J 6.9 Hz), 2.00
(2H, m), 2.64-2.80 (6H, m), 3.88, (2H, m), 4.02 (2H, t, J 6.4 Hz),
5.03 (2H, s), 6.60 (2H, s, fumarate), 6.76 (2H, m) and 7.18-7.30
(5H, m), NH not observed; HPLC (XTERRA, 50/80, 220 nm) 99% (6.75
min).
Example 110
[0715] 4-Bromo-2-fluorobenzyl piperazine-1-carboxylate
hydrochloride was prepared from 4-bromo-2-fluorobenzyl alcohol and
1-chlorocarbonyl-4-tert-- butoxycarbonylpiperazine according to the
methods described for Examples 52 and 54 to give the product as a
white solid (26.5%); melting point 209.5-209.6.degree. C.; NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 3.078(4H, bt), 3.594(4H, bt),
5.118(2H, s), 7.455(2H, m), 7.592(1H, m) and 9.147(2H, bs).
Example 111
[0716] 2,6-Difluoro-4-(2-propenyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-c- arboxylate was prepared from
2,6-difluoro-4-hydroxybenzyl alcohol, allyl bromide and cis
1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpipera- zine
according to the methods described for Examples 54 and 96: NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 1.25 (6H, d, J 6.9 Hz),
2.75-2.87 (4H, m), 4.04 (2H, m), 4.51 (2H, dt, J 5.3, 1.5 Hz), 5.14
(2H, s), 5.32 (1H, dq, J 10.5, 1.5 Hz), 5.41 (1H, dq, J 17.3, 1.5
Hz), 6.00 (1H, ddt, J 17.3, 10.5, 5.3 Hz) and 6.45 (2H, m), NH not
observed; HPLC (XTERRA, 50/80, 220 nm) 97.3% (3.89 min).
Example 112
[0717] (R)-2,6-Difluoro-4-difluoromethoxybenzyl
2-methylpiperazine-1-carbo- xylate fumarate was prepared from
2,6-difluoro-4-difluoromethoxybenzyl alcohol and
(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine
according to the methods described for Examples 54 to give the
product as a white solid (2.9%); HPLC (XTERRA, 50/80, 220 nm) 86.0%
(1.55 min); NMR .delta..sub.H (400 MHz, DMSO-d.sub.6) 1.154(3H, d,
J 7.0 Hz), 2.639(1H, bm), 2.863(2H, bm), 3.007(2H, bm), 3.714(1H,
bd), 4.122(1H, bs), 5.106(2H, q), 6.590(2H, s), 7.108(2H, d, J 8.5
Hz) and 7.360(1H, t, J 73 Hz).
Example 113
[0718] 2-Fluoro-5-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate hydrochloride
[0719] 2-Fluoro-5-difluoromethoxybenzyl alcohol: to a stirred
solution of powdered potassium hydroxide (85%, 6.56 g) in
2-propanol (70 ml) was added dropwise a solution of
2-fluoro-5-hydroxybenzyl alcohol (1.43 g) in 2-propanol (5 ml). The
mixture was cooled to -10.degree. C. and chlorodifluoromethane was
bubbled into the stirred mixture for 10 min. The reaction vessel
was sealed and the mixture was stirred for 30 min at -10.degree. C.
then warmed slowly to room temperature and stirred for 18 h. The
mixture was partitioned between isopropyl ether (2.times.100 ml)
and water (350 ml). The combined organic extracts were washed
(water, brine), dried (sodium sulfate), concentrated in vacuo and
purified by column chromatography [SiO.sub.2, isopropyl
ether-pentane (1:4.fwdarw.1:0)] to give the product as a clear oil
(0.86 g, 44%): .delta..sub.H (400 MHz, CDCl.sub.3) 7.25 (1H, m),
7.03 (2H, m), 6.46 (1H, t, J 74 Hz), 4.76 (2H, d, J 6 Hz) and 1.85
(1H, t, J 6 Hz).
[0720] 2-Fluoro-5-difluoromethoxybenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate hydrochloride was
prepared from 2-fluoro-5-difluoromethoxybenzyl alcohol and cis
1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpipera- zine
according to the methods described for Examples 52 and 54 to give
the product as a white solid (0.1473 g, 84%); .nu..sub.max (diffuse
reflectance)/cm.sup.-1 2780, 2314, 1697, 1593, 1501, 1327, 1209,
and 1101; .delta..sub.H (400 MHz, DMSO-d.sub.6) 9.74 (1H, br), 9.18
(1H, br), 7.35-7.22 (3H, m), 7.20 (1H, t, J 74 Hz), 5.17 (2H, s),
4.31 (2H, m, J 6.4 Hz), 3.16 (2H, d, J 13 Hz), 3.08 (2H, dd, J 5.2
and 13 Hz), and 1.30 (6H, d, J 7.2 Hz).
Example 114
[0721] 5-Ethoxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate fumarate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, ethyl iodide and cis
1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine
according to the methods described for Examples 54 and 96 to give
the product as a white solid (23.4%); melting point
142.9-143.3.degree. C.; NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
1.046(3H, d, J 6.0 Hz), 1.98(6H, d, J 7.0 Hz), 1.306(3H, t, J 7.0
Hz), 2.745(4H, m), 3.985(4H, m), 5.080(2H, s), 6.584(2H, s),
6.917(2H, m) and 7.129(1H, t, J 9.0 Hz).
Example 115
[0722] 2-Fluoro-5-propoxybenzyl piperazine-1-carboxylate fumarate
was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 1-iodopropane
and 1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine according to
the methods described for Examples 54 and 96 to give the product as
a white solid (28.9%); melting point 155.9-156.1.degree. C.; NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 0.966(3H, t, J 7.5 Hz),
1.711(2H, m), 2.793(4H, bt), 3.397(4H, bt), 3.897(2H, t, J 6.5 Hz),
5.077(2H, s), 6.549(2H, s), 6.937(2H, m) and 7.129(1H, t, J 9.0
Hz).
Example 116
[0723] (R)-2-Fluoro-5-propoxybenzyl
2-methylpiperazine-1-carboxylate fumarate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, 1-iodopropane and
(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiper- azine
according to the methods described for Examples 54 and 96 to give
the product as a white solid (26.4%); melting point
162.6-162.7.degree. C.; NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
0.963(3H, t, J 7.5 Hz), 1.173(3H, d, J 7.0 Hz), 1.709(2H, m),
2.582(1H, m), 2.801(2H, bs), 2.991(2H, bm), 3.731(1H, bdd),
3.895(2H, t, J 6.5 Hz), 4.142(1H, bm), 5.077(2H,q), 6.556(2H, s),
6.931(2H, m) and 7.126(1H, t, J 9.0 Hz).
Example 117
[0724] 2-Fluoro-5-propoxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate fumarate diethyl etherate
was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 1-iodopropane
and 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butox-
ycarbonylpiperazine according to the methods described for Examples
54 and 96 to give the product as a white solid (14.4%); melting
point 142.6-144.1.degree. C.; NMR .delta..sub.H (400 MHz,
DMSO-d.sub.6) 0.958(3H, t, J 7.0 Hz), 1.039(2H, d, J 6.0 Hz),
1.199(6H, d, J 7.0 Hz), 1.707(2H, m), 2.756(4H, bm), 3.891(2H, t, J
6.5 Hz), 3.978(2H, bm), 5.083(2H, s), 6.571(2H, s), 6.932(2H, m)
and 7.126(1H, t, J 9.0 Hz).
Example 118
[0725] 5-Butoxy-2-fluorobenzyl piperazine-1-carboxylate fumarate
was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 1-iodobutane
and 1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine according to
the methods described for Examples 54 and 96 to give the product as
a white solid (15.2%); melting point 142.4-143.5.degree. C.; NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 0.927(3H, t, J 7.5 Hz),
1.423(2H, m, J 7.5 Hz), 1.679(2H, m, J 8.0 Hz), 2.798(4H, bt),
3.402(4H, bt), 3.939(3H, t, J 6.5 Hz), 6.537(2H, s), 6.928(2H, m)
and 7.125(1H, t, J 9.0 Hz).
Example 119
[0726] (R)-5-Butoxy-2-fluorobenzyl 2-methylpiperazine-1-carboxylate
fumarate was prepared from 2-fluoro-5-hydroxybenzyl alcohol,
1-iodobutane and
(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine
according to the methods described for Examples 54 and 96 to give
the product as a white solid (18%); melting point
171.6-171.7.degree. C.; NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
0.928(3H, t, J 7.0 Hz), 1.167(3H, d, J 7.0 Hz), 1.421(2H, m, J 7.5
Hz), 1.676(2H, m, J 7.5 Hz), 2.564(2H, bm), 2.787(2H, bs),
2.982(2H, bm), 3.717(1H, bdd), 3.931(2H, t, J 6.5 Hz), 4.122(1H,
bm), 5.078(2H, q), 6.566(2H, s), 6.929(2H, m) and 7.123(1H, t, J
9.0 Hz).
Example 120
[0727] 5-Butoxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate fumarate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, 1-iodobutane and
1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine
according to the methods described for Examples 54 and 96 to give
the product as a white solid (24.4%); melting point
153.2-153.5.degree. C.; NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
0.923(3H, t, J7.5 Hz), 1.199(6H, d, J 7.0 Hz), 1.418(2H, m, J 7.5
Hz), 1.675(2H, m, J 7.5 Hz), 2.761(4H, bm), 3.960(4H, bm),
5.084(2H, s), 6.586(2H, s), 6.935(2H, m) and 7.125(1H, t, J 9.5
Hz).
Example 121
[0728] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl
esterfumarate
[0729]
[4-(3,5-Dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-phenyl]-methano-
l: PS-BEMP (1.5 g, 2 eq) was added to a solution of
2,6-difluoro-4-hydroxybenzyl alcohol (400 mg, 1.5 eq) in
acetonitrile (4 mL) and the mixture was shaken for 5 min.
4-(Chloromethyl)-3,5-dimethylis- oxazole (210 uL, 1.67 mmol) was
added and the resultant mixture was shaken at ambient temperature
for 16 h. The mixture was filtered, the resin washed with
dichloromethane (4.times.4 mL) and evaporated to afford the desired
product (380 mg, 85%) as a white solid: NMR .delta..sub.H(400 MHz;
d.sub.6-DMSO) 2.20 (3H, s), 2.40 (3H, s), 4.42 (2H, d, J 5.5 Hz),
5.95 (2H, s), 5.08 (1H, t, J 5.5 Hz) and 6.76-6.83 (2H, m); HPLC
(XTERRA, 50/80, 220 nm) 94.5% (1.03 min).
[0730] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl ester: a
solution of
4-tert-butoxycarbonyl-1-chlorocarbonyl-2,6-dimethylpiperazine (307
mg, 1 eq) and 4-[4-(3,5-dimethylisoxazolyl)]methoxybenzyl alcohol
(300 mg, 1.11 mmol) in DMF (3 mL) was added to a suspension of
sodium hydride (60%; 67 mg, 1.5 eq) in DMF (2 mL) pre-cooled in
dry-ice for 2 min. The vented mixture was left shaking at ambient
temperature for 16 h. The reaction mixture was poured onto
ice-water (15 mL) and the resultant solid was filtered and washed
with water (2.times.10 mL). Drying in a vacuum oven afforded the
desired product (489 mg, 87%) as a low-melting pale yellow solid:
NMR .delta..sub.H(400 MHz; d.sub.6-DMSO) 1.08 (6H, d, J 6.5 Hz),
1.40 (9H, s), 2.21 (3H, s), 2.41 (3H, s), 2.48-2.52 (2H, m),
3.68-3.85 (2H, br d, J 12 Hz), 3.95-4.06 (2H, m), 4.97 (2H, s),
5.07 (2H, s) and 6.83-6.92 (2H, m); HPLC (XTERRA, 50/80, 220 nm)
85.7% (6.26 min).
[0731] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
4-(3,5-dimethyl-isoxazol-4-ylmethoxy)-2,6-difluoro-benzyl
esterfumarate: a solution of HCl in dioxane (4 M; 2.3 mL, 10 eq)
was added to a solution cis-2,6-dimethyl-piperazine-1-carboxylic
acid 4-(3,5-dimethyl-isoxazol-4-- ylmethoxy)-2,6-difluoro-benzyl
ester (463 mg, 0.91 mmol) in methanol (15 mL) and the resultant
mixture was stirred at ambient temperature for 8 h. The solvent was
removed in vacuo and the residue was suspended in aqueous sodium
hydroxide solution (2 N; 30 mL) and extracted with diethyl ether
(2.times.20 mL) and ethyl acetate (1.times.20 mL). The combined
organics were washed with brine (20 mL), dried (MgSO.sub.4) and
concentrated in vacuo to afford the free-base (195 mg) as a pale
yellow solid. This material was dissolved in hot IPA (3 mL) and
added to a stirred solution of fumaric acid (78 mg, 1.5 eq) in hot
IPA (2 mL). The resultant suspension was allowed to cool to ambient
temperature, then cooled in ice-water. Diethyl ether (5 mL) was
added and the suspension was heated to give a solution, then
allowed to cool. The resultant solution was cooled in ice-water and
filtration afforded the desired product (155 mg, 32%) as a white,
crystalline solid: NMR .delta..sub.H(400 MHz; d.sub.6-DMSO) 1.17
(6H, d, J 7.0 Hz), 2.21 (3H, s), 2.41 (3H, s), 2.71 (2H, dd, J
12.5, 4.5 Hz), 2.77 (2H, d, J 12.5 Hz), 3.88-3.96 (2H, m), 4.97
(2H, s), 5.06 (2H, s), 6.58 (2H, s) and 6.83-6.91 (2H, m); HPLC
(XTERRA, 50/80, 220 nm) 99% (2.39 min).
Example 122
[0732] 2-Fluoro-5-(2-methylpropyl)-oxybenzyl
cis-2,6-dimethylpiperazine-1-- carboxylate fumarate was prepared
from 2-fluoro-5-hydroxybenzyl alcohol, 1-iodo-2-methylpropane and
1-chlorocarbonyl-4-tert-butoxycarbonylpiperazi- ne according to the
methods described for Examples 54 and 96 to give the product as a
white solid (31.3%); melting point 178.6-178.7.degree. C.; NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 0.961(6H, d, J 7.0 Hz),
1.193(6H, d, J 7.0 Hz), 1.994(1H, m, J 6.5 Hz), 2.726(4H, bm),
3.709(2H, d J 6.5 Hz), 3.966(2H, q), 5.084(2H, s), 6.593(2H, s),
6.933(2H, m) and 7.124(1H, t, J 9.0 Hz).
Example 123
[0733] 2-Chloro-6-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared
from 2-chloro-6-fluorobenzyl alcohol and
1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine
according to the methods described for Examples 52 and 54 to give
the product as a white solid (0.2713 g, 80% overall); (Found: C,
49.8; H, 5.7; N, 8.0%. C.sub.14H.sub.18ClN.sub.2O.sub.2.HCl
requires C, 49.9; H, 5.7; N, 8.3%); .delta..sub.H (400 MHz,
DMSO-d.sub.6) 10.01 (1H, br), 9.27 (1H, br), 7.49 (1H, m, J 8.0
Hz), 7.40 (1H, d, J 8.0 Hz), 7.30 (1H, t, J 9 Hz), 5.22 (2H, d, J
1.6 Hz), 4.24 (2H, m, J 6.5 Hz), 3.17-3.06 (4H, m), and 1.28 (6H,
d, J 7.2 Hz).
Example 124
[0734] (R)-2,6-Difluorobenzyl 2-methylpiperazine-1-carboxylate
hydrochloride was prepared from 2,6-difluorobenzyl alcohol and
(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine
according to the methods described for Examples 52 and 54 to give
the product as a white solid (0.217 g, 70% overall); (Found: C,
50.7; H, 5.65; N, 9.0. C.sub.13H.sub.16F.sub.2N.sub.2O.sub.2.HCl
requires C, 50.9; H, 5.6; N, 9.1%); .delta..sub.H (400 MHz,
DMSO-d.sub.6) 9.39 (2H, br), 7.50 (1H, m), 7.18-7.12 (2H, m), 5.17
(2H, m, J 12.4 Hz), 4.29 (2H, m), 3.88 (1H, d, J 13 Hz), 3.24-3.03
(4H, m, J 13 Hz), 2.86 (1H, m, J 12.4 Hz), and 1.24 (3H, d, J 7.2
Hz).
Example 125
[0735] (R,R)-4-Difluoromethoxybenzyl
2,6-dimethylpiperazine-1-carboxylate
[0736] (S) N-Benzyl-1-amino-2-propanol hydrochloride: a mixture of
(S) 1-amino-2-propanol (9.0 g), benzaldehyde (14.7 ml), magnesium
sulfate and THF (200 ml) was stirred for 18 h then filtered and
concentrated in vacuo. The residue was dissolved in ethanol (200
ml) and sodium borohydride (1.1 g) was added. The mixture was
stirred for 2 h then a further portion of sodium borohydride (1.1
g) was added. The mixture was stirred for 18 h then concentrated in
vacuo. The residue was partitioned between dilute hydrochloric acid
(2M, 200 ml) and ether (100 ml). The aqueous layer was basified
with sodium hydroxide solution and extracted with two portions of
ethyl acetate (100 ml). The combined ethyl acetate layers were
washed (water), dried (sodium sulfate) and concentrated in vacuo.
The residue was dissolved in ether (50 ml) and HCl-dioxane (4M, 35
ml) was added dropwise. The precipitate was filtered off, washed
with ether and dried to give the product as a white solid (17.0 g);
8 H (400 MHz, DMSO-d.sub.6) 9.43 (1H, m), 9.12 (1H, m), 7.58 (2H,
dd, J 7.5, 2 Hz), 7.45-7.39 (3H, m), 5.35 (1H, m), 4.14 (2H, s),
4.01 (1H, m), 2.87 (1H, d, J 12 Hz), 2.67 (1H, t, J 8.5 Hz) and
1.08 (3H, d, J 6 Hz); HPLC [XTERRA; NH.sub.4OAc.sub.(aq)--MeOH
(9:1)] 97% (1.08 min).
[0737] (S) N-Benzyl-1-amino-2-propanol (R)
N-tert-butoxycarbonyl-alanine amide: carbonyldiimidazole (12.1 g)
was added to a stirred solution of (R)
N-tert-butoxycarbonyl-alanine (14.1 g) in DCM (200 ml). The mixture
was stirred for 90 min then (S) N-benzyl-1-amino-2-propanol
hydrochloride (15.0 g) was added portionwise. The mixture was
stirred for 96 h then concentrated in vacuo. The residue was
purified by flash column chromatography [SiO.sub.2; ethyl
acetate--isohexane(1:1)] to give the product as a gum (11.5 g);
.delta..sub.H (400 MHz, CDCl.sub.3) 7.39-7.16 (5H, m), 5.37 (1H,
m), 4.90-4.55 (3H, m), 4.09 (0.5H, m), 3.97 (0.5H, m), 3.59 (1H,
m), 3.42 (1H, m), 3.22 (1H, m), 1.44 (4.5H, s), 1.42 (4.5H, s),
1.36 (1.5H, d, J 6.5 Hz), 1.26 (1.5H, d, J 6.5 Hz), 1.20 (1.5H, d,
J 6 Hz) and 1.12 (1.5H, d, J 6 Hz); HPLC (XTERRA, 50/80, 220 nm)
97% (1.77 min).
[0738] (R,R)1-Benzyl-3,5-dimethylpiperazine-2-one: trifluoroacetic
acid (50 ml) was added dropwise to a stirred solution of
(S)N-benzyl-1-amino-2-propanol (R)N-tert-butoxycarbonyl-alanine
amide (10.7 g) in DCM (100 ml) at 0.degree. C. The mixture was
stirred for 2 h then concentrated in vacuo. The residue was
partitioned between sodium hydroxide solution (2M, 200 ml) was
dichloromethane (200 ml). The organic layer was washed (water),
dried (sodium sulfate) and concentrated in vacuo to give a viscous
oil (7.15 g). To the oil were added triphenylphosphine (9.4 g) and
THF (150 ml) and the stirred mixture was cooled to 0.degree. C.
under Ar. To the stirred solution was added
di-tert-butyldiazodicarboxylate (8.6 g). The mixture was warmed to
room temperature, stirred for 18 h then concentrated in vacuo.
Dilute hydrochloric acid (1M, 100 ml) and conc. hydrochloric acid
(10 ml) were added to the mixture. The mixture was stirred for 3 h
then filtered. The filtrate was washed with ether (50 ml) then made
basic using sodium hydroxide solution and extracted with two
portions of ethyl acetate (100 ml). The combined ethyl acetate
extracts were washed (water, brine), dried (sodium sulfate),
concentrated in vacuo and purified by flash column chromatography
[SiO.sub.2; ethyl acetate--methanol--NH.sub.4OH
(95:5).fwdarw.(79:20:1)] to give the product as clear oil (1.38 g);
67 .sub.H (400 MHz, CDCl.sub.3) 7.35-7.22 (5H, m), 4.66 (1H, d, J
14.5 Hz), 4.49 (1H, d, J 14.5 Hz), 3.78 (1H, q, J 7 Hz), 3.33 (1H,
m), 3.16 (1H, dd, J 12, 4 Hz), 2.97 (1H, dd, J 12,9 Hz) and 1.49
(3H, d, J 7 Hz); LC 96%, 0.67 min.
[0739] (R,R)1-Benzyl-3,5-dimethylpiperazine: a solution of
(R,R)1-benzyl-3,5-dimethylpiperazine-2-one (1.3 g) in THF (10 ml)
was added dropwise to a stirred suspension of lithium aluminium
hydride (0.68 g) in THF (30 ml) at 0.degree. C. under Ar. The
mixture was stirred for 30 min then heated under reflux for a
further 18 h. The mixture was cooled to 0.degree. C. and diluted
with ether (50 ml). To the stirred mixture were added water (2 ml)
sodium hydroxide solution (2 ml) and water (2 ml). The mixture was
stirred for 1 h then filtered through a pad of kieselguhr, washing
with DCM. The filtrate was concentrated in vacuo to give the
product as a clear oil (0.99 g); .delta..sub.H (400 MHz,
CDCl.sub.3) 7.35-7.20 (5H, m), 3.48 (1H, d, J 13 Hz), 3.38 (1H, d,
J 13 Hz), 3.19 (1H, m), 2.49 (2H, dd, J 10.5, 3 Hz), 2.09 (2H, dd,
J 10, 6.5 Hz) and 1.14 (6H, d, J 6.5 Hz); LC 93%, 1.91 min.
[0740] (R,R)2,6-Dimethylpiperazine dihydrochloride: a mixture of
(R,R)4-Benzyl-2,6-dimethylpiperazine (0.95 g), palladium
hydroxide/carbon (20%, 0.35 g) and methanol (30 ml) was shaken
under hydrogen (45 p.s.i.) for 18 h. The mixture was filtered
through a pad of kieselguhr, washing with methanol. The filtrate
was treated with HCl-dioxane (4M, 5 ml), left to stand for 30 min
then concentrated in vacuo. The residue was crystallised under
diisopropyl ether to give the product as an off-white crystalline
solid (0.17 g); .delta..sub.H (400 MHz, DMSO-d.sub.6) 10.02-9.72
(4H, m), 3.72 (2H, m), 3.33 (2H, dd, J 13.5, 4 Hz), 3.15 (2H, dd, J
13.5, 7 Hz) and 1.40 (6H, d, J 7 Hz); .delta..sub.C (167 MHz,
DMSO-d.sub.6) 43.8, 43.7 and 14.3.
[0741]
(R,R)1-Chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine;
to a stirred mixture of (R,R)2,6-dimethylpiperazine dihydrochloride
(0.50 g) and triethylamine (0.93 ml) in DCM (50 ml) at 0.degree. C.
was added dropwise a solution of di-tert-butyl-dicarbonate (0.58 g)
in DCM (5 ml). The mixture was warmed to room temperature, stirred
for 2 h then concentrated in vacuo. The residue was dissolved in
ethyl acetate, filtered through a PTFE membrane and concentrated in
vacuo to give a clear oil (0.47 g). To the oil were added pyridine
(0.6 ml) and DCM (6 ml). The mixture was added dropwise to a
stirred solution of triphosgene (0.25 g) in DCM (20 ml) at
0.degree. C. The mixture was stirred for 1 h, washed with two
portions of water (20 ml) then dried over sodium sulfate and
concentrated in vacuo to give the product as a yellow oil (0.43 g);
.delta..sub.H (400 MHz, CDCl.sub.3) 4.29 (1.6H, m), 4.07 (0.4H, m),
3.62 (2H, m), 3.54 (2H, m), 1.49 (7H, s), 1.48 (2H, s), 1.37 (2.5H,
m) and 1.23 (0.5H, m).
[0742]
(R,R)4-Difluoromethoxybenzyl-2,6-dimethylpiperazine-1-carboxylate
fumarate was prepared from
(R,R)1-chlorocarbonyl-2,6-dimethyl-4-tert-buto-
xycarbonylpiperazine (0.20 g) and 4-difluoromethoxybenzyl alcohol
(0.13 g) according to the procedures described for Example 48 to
give the product as a white solid (0.14 g); .delta..sub.H (400 MHz,
DMSO-d.sub.6) 7.43 (2H, d, J 9 Hz), 7.23 (1H, t, J 74 Hz), 7.18
(2H, d, J 9 Hz), 6.53 (2H, s), 5.10 (1H, d, J 12.5 Hz), 5.03 (1H,
d, J 12.5 Hz), 3.92 (2H, m), 3.16 (2H, dd, J 13, 4 Hz), 2.84 (2H,
dd J 12.5, 3.5 Hz) and 1.23 (6H, d, J 6.5 Hz); HPLC (XTERRA, 50/80,
220 nm) 96% (1.22 min).
Example 126
[0743] (R)-2-Fluoro-5-(2-propenyl)oxybenzyl
2-methylpiperazine-1-carboxyla- te
[0744] In a sealed 7 mL glass vial a mixture of
2-fluoro-5-hydroxybenzyl alcohol (50 mg, 0.35 mmol), PS-BEMP (2 g,
2.2 mmol/g, 0.46 mmol) and acetonitrile (3 mL) was shaken for 30
minutes. allyl bromide (18 uL, 0.22 mmol) was added and the mixture
was shaken for 18 h. The mixture was filtered through a PTFE frit,
washing with dichloromethane. The filtrate was concentrated under
vacuum to give the product as a colourless oil which was used
without further purification.
[0745] To a stirred solution of disuccinimidyl carbonate (3 mmol)
in acetonitrile (18 mL) was added 2-fluoro-5-(2-propenyl)benzyl
alcohol (3 mmol) then triethylamine (6 mmol). The mixture was
stirred for 150 minutes at room temperature. To a polypropylene 10
mL tube were sequentially added (R)2-methylpiperazine loaded resin
(0.2 g, 0.05 mmol) and a portion of the benzyl alcohol/DSC mixture
(3 mL, 5 mmol). The mixture was heated to 60.degree. C. and
agitated for 16 h. The mixture was cooled to room temperature then
drained. The resin was washed 3.times. each with THF, methanol and
dichloromethane using the following automated sequence: 5 mL
solvent added, wash for 5 minutes, drain for 2 minutes. To the
washed resin was added 5% trifluoroacetic acid in dichloromethane
(5 mL). The mixture was agitated for 1 h then drained. More TFA/DCM
(5 mL) was added and the mixture was agitated for a further hour
then drained again. The combined TFA/DCM washes were concentrated
under vacuum to give the product as a pale brown solid (7.5%); HPLC
(XTERRA, 50/80, 220 nm) 86.2% (1.91 min); NMR .delta..sub.H (400
MHz, DMSO-d.sub.6) 1.149(3H, d, J 7.0 Hz), 2.455(1H, td, J 3.5, 8.5
Hz), 2.676(2H, d, J 3.0 Hz), 2.834(1H, bdd), 2.938(1H, td),
3.645(1H, dd), 4.045(1H, m), 4.542(2H, dt, J 1.5, 5.5 Hz),
5.064(2H, m), 5.240(1H, m), 5.380(1H, m), 6.020(1H, m), 6.937(2H,
m) and 7.136(1H, t, J 9.0 Hz).
Example 127
[0746] 2-Fluoro-5-(2-propenyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, allyl bromide and
1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine
according to the methods described for Examples 54 and 121 to give
the product as a yellow oil (8.4%); HPLC (XTERRA, 50/80, 220 nm)
95.7% (2.87 min); NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
1.183(6H, d, J 6.5 Hz), 2.673(4H, m), 3.294(2H, bs), 3.910(2H, m),
4.572(2H, m), 5.078(2H, s), 5.252(1H, m), 5.371(1H, m), 6.022(1H,
m), 6.948(2H, m) and 7.138(1H, t, J 9.5 Hz).
Example 128
[0747] 5-Cyclohexylmethoxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-car- boxylate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, cyclohexylmethyl bromide and
1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-but- oxycarbonylpiperazine
according to the methods described for Examples 54 and 121 to give
the product as a yellow oil (10.8%); HPLC (XTERRA, 50/80, 220 nm)
91.4% (6.77 min); NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
1.016(2H, m), 1.204(8H, m), 1.735(5H, m), 2.681(4H, m), 3.291(2H,
s) 3.737(2H, d, J 6.5 Hz), 3.905(2H, m) 5.078(2H, s), 6.931(2H, m)
and 7.119(1H, t, J 9.0 Hz).
Example 129
[0748] 2-Fluoro-5-(2-phenyl)ethoxybenzyl
cis-2,6-dimethylpiperazine-1-carb- oxylate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, 2-phenylethyl bromide and
1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpipera- zine
according to the methods described for Examples 54 and 121 to give
the product as a yellow oil (2.2%); HPLC (XTERRA, 50/80, 220 nm)
87.7% (5.58 min); NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
1.168(6H, d, J 7.0 Hz), 2.685(4H, m), 3.020(2H, t, J 7.0 Hz),
3.915(2H, m), 4.175(2H, t, J 7.0 Hz), 5.079(2H, s), 6.940(2H, m),
7.132(1H, t, J 9.0 Hz), 7.224(1H, m) and 7.308(4H, m).
Example 130
[0749] 2-Fluoro-5-(3-phenyl)propoxybenzyl piperazine-1-carboxylate
was prepared from 2-fluoro-5-hydroxybenzyl alcohol, 3-phenylpropyl
bromide and piperazine resin according to the methods described for
Example 126 to give the product as a yellow oil (12.8%); HPLC
(XTERRA, 50/80, 220 nm) 95.6% (5.30 min); NMR .delta..sub.H (400
MHz, DMSO-d.sub.6) 2.006 (2H, m), 2.621 (4H, bs), 2.727 (2H, t, J
7.5 Hz), 3.282 (5H, bt), 3.936 (2H, t, J 6.5 Hz), 5.068 (2H, s),
6.932 (2H, m) and 7.167 (6H, m).
Example 131
[0750] (R)-2-Fluoro-5-(3-phenyl)propoxybenzyl
2-methylpiperazine-1-carboxy- late was prepared from
2-fluoro-5-hydroxybenzyl alcohol, 3-phenylpropyl bromide and
(R)-2-methylpiperazine resin according to the methods described for
Example 126 to give the product as a yellow oil (6.5%); HPLC
(XTERRA, 50/80, 220 nm) 89.0% (5.68 min); NMR .delta..sub.H (400
MHz, DMSO-d.sub.6) 1.142 (3H, d. J 7.0 Hz), 2.001 (2H, m), 2.439
(1H, m), 2.657 (2H, m), 2.730 (2H, t, J 6.5 Hz), 2.845 (1H, bd),
2.930 (2H, bt), 3.633 (1H, bd), 3.939 (2H, t, J 6.5 Hz), 4.010 (1H,
m), 5.065 (2H, m), 6.922 (2H, m) and 7.207 (6H, m).
Example 132
[0751] 2-Fluoro-5-(3-phenyl)propoxybenzyl
cis-2,6-dimethylpiperazine-1-car- boxylate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, 3-phenylpropyl bromide and
1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butox- ycarbonylpiperazine
according to the methods described for Examples 54 and 121 to give
the product as a yellow oil (2.3%); HPLC (XTERRA, 50/80, 220 nm)
91.1% (6.29 min); NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
7.32-7.10 (6H, m), 6.95 (1H, q, J 3 Hz), 6.91 (1H, dt, J 9, 4Hz),
5.08 (2H, s), 3.93 (2H, t, J 6.5 Hz), 3.91 (2H,m), 2.73 (2H, t, J 7
Hz), 2.71 (2H, d, J 8.5 Hz), 2.65 (2H, dd, J 12.5, 4.5 Hz), 2.00
(2H, m) and 1.18 (6H, d, J 7 Hz).
Example 133
[0752] 2-Fluoro-5-(3-trifluoromethylbenzyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, 3-trifluoromethylbenzyl bromide
and
1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine
according to the methods described for Examples 54 and 121 to give
the product as a yellow oil (10.5%); HPLC (XTERRA, 50/80, 220 nm)
96.9% (6.20 min); NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
1.164(6H, d, J 6.5 Hz), 2.668(4H, m), 3.889(2H, m), 5.082(2H, s),
5.199(2H, s), 7.057(2H, m), 7.175(1H, t, J 6.5 Hz) and 7.688(4H,
m).
Example 134
[0753] 2-Fluoro-5-(2-pyridylmethyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-- carboxylate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, 2-pyridylmethyl chloride
hydrochloride and 1-chlorocarbonyl-cis-2,6-dimet-
hyl-4-tert-butoxycarbonylpiperazine according to the methods
described for Examples 54 and 121 to give the product as a yellow
oil (10.4%); HPLC (XTERRA, 50/80, 220 nm) 91.1% (2.02 min); NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 1.174 (6H, d, J 6.5 Hz),
2.676 (4H, m), 3.902 (2H, m), 5.069 (2H, s), 5.165 (2H, s), 7.018
(2H, m), 7.161 (1H, t, J 9.0 Hz), 7.350 (1H, m), 7.493 (1H, d, J
7.0 Hz), 7.825 (1H, m) and 8.575 (1H, m).
Example 135
[0754] 2-Fluoro-5-(3-pyridylmethyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-- carboxylate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, 3-pyridylmethyl chloride
hydrochloride and 1-chlorocarbonyl-cis-2,6-dimet-
hyl-4-tert-butoxycarbonylpiperazine according to the methods
described for Examples 54 and 121 to give the product as a yellow
oil (5.4%); HPLC (XTERRA, 50/80, 220 nm) 91% (1.64 min);
.delta..sub.H (400 MHz, DMSO-d.sub.6) 1.172 (6H, d, J 7.0 Hz),
2.673 (4H, m), 3.294 (3H, s), 3.900 (2H, m), 5.075 (2H, s), 5.138
(2H, s), 7.052 (2H, m), 7.172 (1H, t, J 9.0 Hz), 7.424 (1H, m),
7.849 (1H, m), 8.546 (1H, m) and 8.654 (1H, m).
Example 136
[0755] (+/-)-2,6-Difluoro-4-(2-pyridylmethyl)oxybenzyl
2-methylpiperazine-1-carboxylate was prepared from
2,6-difluoro-4-hydroxybenzyl alcohol, 2-pyridylmethyl chloride
hydrochloride and (+/-)2-methylpiperazine resin according to the
methods described for Example 126 to give the product as a yellow
oil: .delta..sub.H (400 MHz, DMSO-d.sub.6) 1.19 (3H, d, J 7.1 Hz),
2.85 (1H, m), 3.05-3.20 (4H, m), 3.90 (1H, m), 4.35 (1H, m), 5.10
(2H, m), 5.28 (2H, s), 6.92 (2H, m), 7.48 (1H, m), 7.62 (1H, m),
7.96 (1H, m), 8.65 (1H, m) and 9.15 (1H, br); HPLC (XTERRA, 50/80,
220 nm) 92% (1.35 min).
Example 137
[0756] (+/-)-2,6-Difluoro-4-(3-pyridylmethyl)oxybenzyl
2-methylpiperazine-1-carboxylate was prepared from
2,6-difluoro-4-hydroxybenzyl alcohol, 3-pyridylmethyl chloride
hydrochloride and (+/-)2-methylpiperazine resin according to the
methods described for Example 126 to give the product as a yellow
oil: .delta..sub.H (400 MHz, DMSO-d.sub.6) 1.19 (3H, d, J 7.1 Hz),
2.85 (1H, m), 3.05-3.20 (4H, m), 3.90 (1H, m), 4.35 (1H, m), 5.10
(2H, m), 5.28 (2H, s), 6.92 (2H, m), 7.78 (1H, m), 8.25 (1H, m),
8.78 (1H, m), 8.84 (1H, m) and 9.20 (1H, br); HPLC (XTERRA, 50/80,
220 nm) 90.5% (1.12 min).
Example 138
[0757] (+/-)-2-Methyl-piperazine-1-carboxylic acid
4-(3,5-dimethyl-isoxazo- l-4-ylmethoxy)-2,6-difluoro-benzyl ester
was prepared from 2,6-difluoro-4-hydroxybenzyl alcohol,
4-(3,5-dimethylisoxazolylmethyl chloride and
(+/-)2-methylpiperazine resin according to the methods described
for Example 126 to give the product as a yellow oil: .delta..sub.H
(400 MHz, DMSO-d.sub.6) 1.20 (3H, d, J 7.1 Hz), 2.22 (3H, s), 2.42
(3H, s), 2.85 (1H, m), 3.05-3.20 (4H, m), 3.90 (1H, m), 4.35 (1H,
m), 5.0 (2H, s), 5.10 (2H, m), 6.89 (2H, m), 8.60 (1H, br) and 9.20
(1H, br); HPLC (XTERRA, 50/80, 220 nm) 87.7% (1.61 min).
Example 139
[0758] 5-tert-Butylaminocarbonyloxy-2-fluorobenzyl
cis-2,6-dimethylpiperaz- ine-1-carboxylate hydrochloride
[0759] 2-Fluoro-5-[2-(trimethylsilyl)ethoxymethoxy]benzyl alcohol:
to a stirred mixture of 2-fluoro-5-hydroxybenzaldehyde (0.28 g),
N,N-di-isopropylethylamine (0.52 ml) and DCM (2 ml) at 0.degree. C.
was added dropwise 2-(trimethylsilyl)ethoxymethyl chloride (0.45
ml). The mixture was stired 1 h then partitioned between DCM (25
ml) and water (25 ml). The organic layer was washed (water, brine),
dried (sodium sulfate) and concentrated in vacuo. The residue was
dissolved in 2-propanol (20 ml) and sodium borohydride (0.15 g) was
added. The mixture was stirred 1 h then partitioned between
isopropyl ether (2.times.50 ml) and water (50 ml). The combined
organics were washed (water), concentrated in vacuo and purified by
column chromatography [SiO.sub.2; DCM-isopropyl
ether(1:0.fwdarw.0:1)] to give the product as a colourless oil
(0.54 g, 99%) which was used without further purification.
[0760]
2-Fluoro-5-[2-(trimethylsilyl)ethoxymethoxy]benzyl-4-tert-butoxycar-
bonyl-cis-2,6-dimethylpiperazine-1-carboxylate was prepared from
2-fluoro-5-[2-(trimethylsilyl)ethoxymethoxy]benzyl alcohol and
1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine
according to the procedures described for Example 54 to give the
product as a clear oil which was used immediately without further
purification.
[0761]
2-Fluoro-5-hydroxybenzyl-cis-2,6-dimethylpiperazine-1-carboxylate
hydrochloride: a mixture of crude
2-fluoro-5-[2-(trimethylsilyl)ethoxymet-
hoxy]benzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate
(0.61 g) hydrogen chloride solution (4.0 M, dioxane, 2 ml) and
methanol (4 ml) was stirred for 3 h then concentrated in vacuo. The
residue was left to stand under ether (10 ml) for 1 h; the white
precipitate was filtered off, washed with ether and dried to give
the product as a white solid (0.23 g, 71%): .delta..sub.H (400 MHz,
DMSO-d.sub.6) 9.84 (1H, br), 9.51 (1H, br), 9.15 (1H, br), 7.01
(1H, t, J 9 Hz), 6.81 (1H, dd, J 6, 3 Hz), 6.73 (1H, m), 5.08 (2H,
s), 4.30 (2H, m), 3.16 (2H, d, J 11 Hz), 3.10 (2H, m) and 1.30(6H,
d, J 7 Hz).
[0762]
2-Fluoro-5-hydroxybenzyl-cis-2,6-dimethyl-4-tert-butylcarbonylpiper-
azine-1-carboxylate: to a stirred solution of
2-fluoro-5-hydroxybenzyl-cis- -2,6-dimethylpiperazine-1-carboxylate
(free-base, 1.93 g) in DCM (70 ml) was added dropwise di-tert-butyl
di-carbonate (1.68 ml). The mixture was stirred for 18 h then
concentrated in vacuo and purified by column chromatography
[SiO.sub.2; isopropyl ether--isohexane (2:3.fwdarw.1:0)] to give
the product as a white solid (2.24 g, 84%): .delta..sub.H (400 MHz,
DMSO-d.sub.6) 6.92 (1H, t, J 9 Hz), 6.87 (1H, m), 6.76 (1H, m),
6.10 (1H, m, OH), 5.15 (2H, s), 4.20 (2H, t, J 5.5 Hz), 3.93 (2H,
m), 2.97 (2H, m), 1.48 (9H, s) and 1.23 (6H, d, J 7 Hz); HPLC
XTERRA, 50-80%, 220 nm, 98.5% (4.86 min).
[0763]
5-tert-Butylaminocarbonyloxy-2-fluorobenzyl-4-tert-butoxycarbonyl-c-
is-2,6-dimethylpiperazine-1-carboxylate: triethylamine (0.02 ml)
was added to a stirred mixture of
2-fluoro-5-hydroxybenzyl-cis-2,6-dimethyl-4-tert--
butylcarbonylpiperazine-1-carboxylate (0.19 g) and
tert-butylisocyanate (0.12 ml) in DCM (2 ml). The mixture was
stirred 18 h the concentrated in vacuo and purified by column
chromatography [SiO.sub.2: isopropyl ether--isohexane
(2:3.fwdarw.1:0)] to give the product as a colourless partially
solidified gum (0.2445 g, 102%). Rf (Silica, isopropyl ether) 0.20;
.delta..sub.H (400 MHz, CDCl.sub.3) 7.14 (1H, m), 7.06-7.03 (2H,
m), 5.18 (2H, s), 4.98 (1H, br), 4.20 (2H, br), 3.96 (1H, br), 3.87
(1H, br), 3.00 (1H, br), 2.93 (1H, br), 1.48 (9H, s), 1.38 (9H, s),
and 1.24 (6H, d, J 6.4 Hz).
[0764] 5-tert-Butylaminocarbonyloxy-2-fluorobenzyl
cis-2,6-dimethylpiperaz- ine-1-carboxylate hydrochloride was
prepared from 5-tert-butylaminocarbony-
loxy-2-fluorobenzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-car-
boxylate according to the method described for Example 52 to give
the product as a white solid (0.1538 g, 72% overall); (Found: C,
54.4; H, 7.0; N, 9.9%. C.sub.19H.sub.28FN.sub.3O.sub.4.HCl requires
C, 54.6; H, 7.0; N, 10.05%); .delta..sub.H (400 MHz, DMSO-d.sub.6)
9.8 (1H, br), 9.2 (1H, br), 7.64 (1H, s), 7.24 (1H, t, J 9.2 Hz),
7.18 (1H, m), 7.11 (1H, br), 5.15 (2H, s), 4.30 (2H, m, J 6 Hz),
3.16 (2H, d, J 13 Hz), 3.07 (2H, dd, J 5 and 13 Hz), and 1.30-1.27
(15H, m).
Example 140
[0765] 2-Fluoro-5-(4-difluoromethoxybenzyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared
from 2-fluoro-5-hydroxybenzyl alcohol, 4-difluoromethoxybenzyl
chloride and
1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine
according to the methods described for Examples 52 and 54 to give
the product as a white solid (0.224 g, 94% overall); (Found: C,
55.7; H, 5.7; N, 5.9. C.sub.22H.sub.25F.sub.3N.sub.2O.sub.4.HCl
requires C, 55.6; H, 5.5; N, 5.9%); .delta..sub.H(400 MHz,
DMSO-d.sub.6) 9.8 (1H, br), 9.3 (1H, br), 7.50 (2H, d, J 8.4 Hz),
7.26(1H, t, J 74 Hz), 7.21-7.15 (3H, m), 7.09 (1H, m), 7.03 (1H, m,
J 3.2 Hz), 5.12 (2H, s), 5.08 (2H, s), 4.28 (2H, m, J 6 Hz), 3.15
(2H, d, J 13 Hz), 3.06 (2H, dd, J 5 and 13 Hz), and 1.29 (6H, d, J
7.2 Hz).
Example 141
[0766] Piperazine-1-carboxylic acid
2,6-difluoro-4-(5-thiophen-2-yl-[1,2,4-
]oxadiazol-3-ylmethoxy)-benzyl ester was prepared from
2,6-difluoro-4-hydroxybenzyl alcohol,
3-chloromethyl-5-thiophen-2-yl-[1,2- ,4]oxadiazole and piperazine
resin according to the methods described for Example 126 to give
the product as a yellow oil: .delta..sub.H (400 MHz; d.sub.6-DMSO)
2.60 (4H, br s), 3.30 (4H, br s), 5.04 (2H, s), 5.42 (2H, s),
6.92-7.01 (2H, m), 7.36 (1H, dd, J 5.0, 4 Hz), 8.06 (1H, dd, J 4, 1
Hz) and 8.12 (1H, dd, J 5.0, 1 Hz); HPLC (XTERRA, 50-80%, 235 nm)
99.4% (3.71 min).
Example 142
[0767] (R)-2-Methyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(5-thiophe-
n-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)-benzyl ester was prepared from
2,6-difluoro-4-hydroxybenzyl alcohol,
3-chloromethyl-5-thiophen-2-yl-[1,2- ,4]oxadiazole and
(R)2-methylpiperazine resin according to the methods described for
Example 126 to give the product as a yellow oil: .delta..sub.H(400
MHz; d.sub.6-DMSO) 1.10 (3H, d, J 7.0 Hz), 2.40 (1H, td, J 12.0,
3.5 Hz), 2.62 (2H, br d, J, 2.5 Hz), 2.75-2.82 (1H, br d, J 12 Hz),
2.88 (1H, td, J 12.5, 3.5 Hz), 3.55 (1H, br d, J12 Hz), 3.96 (1H,
br s), 5.02 (1H, d, J 12.5 Hz), 5.07 (1H, d, J 12.5 Hz), 5.42 (2H,
s), 6.93-7.01 (2H, m), 7.36 (1H, dd, J 5.0 and 4 Hz), 8.06 (1H, dd,
J 4, 1.0 Hz) and 8.12 (1H, dd, J 5.0, 1 Hz); HPLC (XTERRA, 50-80%,
235 nm) 99.8% (4.22 min).
Example 143
[0768] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(5-thiophen-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)-benzyl
ester was prepared from 2,6-difluoro-4-hydroxybenzyl alcohol,
3-chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole and
cis-1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine
according to the methods described for Example 54 and 121 to give
the product as a yellow oil: .delta..sub.H(400 MHz; d.sub.6-DMSO)
1.14 (6H, d, J 6.5 Hz), 2.60 (2H, dd, J 12, 5 Hz), 2.66 (2H, d, J
12 Hz), 3.77-3.87 (2H, m), 5.05 (2H, s), 5.42 (2H, s), 6.93-7.01
(2H, m), 7.36 (1H, dd, J 5.0, 4 Hz), 8.06 (1H, dd, J 4,1.0 Hz) and
8.12 (1H, dd, J 5.0, 1.0 Hz); HPLC (XTERRA, 50-80%, 235 nm) 99.4%
(5.04 min).
Example 144
[0769] 2,6-Difluoro-4-(3-fluorobenzyl)oxybenzyl
cis-2,6-dimethylpiperazine- -1-carboxylate was prepared from
2,6-difluoro-4-hydroxybenzyl alcohol, 3-fluorobenzyl chloride and
1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxyca- rbonylpiperazine
according to the methods described for Example 54 and 121 to give
the product as a yellow oil: .delta..sub.H (400 MHz; d.sub.6-DMSO)
1.13 (6H, d, J 7.0 Hz), 2.60 (2H, dd, J 12, 4.5 Hz), 2.66 (2H, d, J
12 Hz), 3.77-3.86 (2H, m), 5.03 (2H, s), 5.18 (2H, s), 6.84-6.93
(2H, m), 7.16-7.22 (1H, m), 7.27-7.32 (2H, m) and 7.42-7.49 (1H,
m); HPLC (XTERRA, 50-80%, 220 nm) 99.8% (5.96 min).
Example 145
[0770] 2,6-Difluoro-4-(3,4-difluorobenzyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carboxylate was prepared from
2,6-difluoro-4-hydroxybenzyl alcohol, 3,4-difluorobenzyl chloride
and 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine
according to the methods described for Example 54 and 121 to give
the product as a yellow oil: .delta..sub.H (400 MHz; d.sub.6-DMSO)
1.13 (6H, d, J 7.0 Hz), 2.60 (2H, dd, J 12.0, 4.5 Hz), 2.66 (2H, d,
J 12.0 Hz), 3.77-3.85 (2H, m), 5.04 (2H, s), 5.13 (2H, s),
6.84-6.92 (2H, m), 7.29-7.35 (1H, m), 7.48 (1H, dt, J 11.0, 8.5 Hz)
and 7.55 (1H, ddd, J 11.5, 7.5, 2.5 Hz); HPLC (XTERRA, 50-80%, 220
nm) 99.5% (6.17 min).
Example 146
[0771] 2-Fluoro-5-(2,4-difluorobenzyl)oxybenzyl
cis-2,6-dimethylpiperazine- -1-carboxylate was prepared from
2,6-difluoro-4-hydroxybenzyl alcohol, 2,4-difluorobenzyl chloride
and 1-chlorocarbonyl-2,6-dimethyl-4-tert-buto- xycarbonylpiperazine
according to the methods described for Example 54 and 121 to give
the product as a yellow oil: .delta..sub.H (400 MHz; d.sub.6-DMSO)
1.26 (6H, d, J 6.9 Hz), 2.75-2.90 (4H, m), 4.10 (2H, br), 4.98 (2H,
s), 5.20 (2H, s), 6.85 (1H, m), 6.98 (2H, m) and 7.10-7.30 (3H, m),
NH not observed; HPLC (XTERRA, 50/80%, 220 nm) 93.8% (5.68
min).
Example 147
[0772] 2-Fluoro-5-(3,4-difluorobenzyl)oxybenzyl
cis-2,6-dimethylpiperazine- -1-carboxylate was prepared from
2,6-difluoro-4-hydroxybenzyl alcohol, 3,4-difluorobenzyl chloride
and 1-chlorocarbonyl-2,6-dimethyl-4-tert-buto- xycarbonylpiperazine
according to the methods described for Example 54 and 121 to give
the product as a yellow oil: .delta..sub.H (400 MHz; d6-DMSO) 1.29
(6H, d, J 6.9 Hz), 2.77-2.90 (4H, m), 4.10 (2H, br), 5.04 (2H, s),
5.18 (2H, s), 6.80-7.02 (5H, m) and 7.42 (1H, m), NH not observed;
HPLC (XTERRA, 50/80%, 220 nm) 89.5% (5.5 min).
Example 148
[0773] 2,6-Difluoro-4-(3-furylmethyl)oxybenzyl
cis-2,6-dimethylpiperazine-- 1-carboxylate fumarate
[0774] 2,6-Difluoro-4-(furan-3-methoxy)benzyl alcohol:
methanesulfonyl chloride (0.9 ml) was added dropwise to a stirred
solution of 3-furan-methanol (1.0 g) and triethylamine (2.1 ml) in
dichloromethane (30 ml) at 0.degree. C . The mixture was stirred
for 30 min. then warmed to room temperature and stirred for a
further 2 h. The mixture was partitioned between ether (100 ml) and
water (100 ml). The organic layer was washed (water, brine), dried
(sodium sulfate) and concentrated in vacuo to give a pale yellow
oil (0.77 g). To the oil were added 2,6-difluoro-4-hydroxybenzyl
alcohol (0.56 g), cesium carbonate (1.1 g) and DMF (30 ml). The
mixture was stirred for 18 h then partitioned between ethyl acetate
(20 ml) and water (50 ml). The layers were separated; the aqueous
layer was extracted with more ethyl acetate (20 ml). The combined
organic layers were washed (water, brine), dried (sodium sulfate)
and concentrated in vacuo. The residue was purified by flash column
chromatography [SiO.sub.2: isohexane--ethyl acetate (3:1)] to give
the product as a clear oil (0.16 g); .delta..sub.H (400 MHz,
CDCl.sub.3) 7.51 (1H, d, J 1 Hz), 7.45 (1H, t, J 2 Hz), 6.54 (1H t,
J 4 Hz), 6.50 (1H, t, J 4 Hz), 6.47 (1H, d, J 1.5 Hz), 4.91 (2H, s)
and 4.71 (2H, d, J 6.5 Hz); HPLC (XTERRA, 50/80, 220 nm) 1.76 min
(74%).
[0775]
2,6-Difluoro-4-(3-furanmethoxy)benzyl-2,6-dimethylpiperazine-1-carb-
oxylate fumarate: to a stirred suspension of sodium hydride (60%,
0.015 g) in DMF (1 ml) was added dropwise a solution of
2,6-difluoro-4-(furan-3-me- thoxy)benzyl alcohol (0.06 g) and cis
1-chlorocarbonyl-2,6-dimethyl-4-tert- -butoxycarbonylpiperazine
(0.07 g) in DMF (2 ml). The mixture was stirred for 2 h then
partitioned between ethyl acetate (20 ml) and water (20 ml). The
organic layer was washed (water, brine), dried (sodium sulfate) and
concentrated in vacuo to give a yellow oil (0.11 g). To the residue
were added methanol (2 ml) and hydrogen chloride in dioxane (4M,
0.3 ml). The mixture was stirred for 4 h then partitioned between
water (20 ml) and ether (20 ml). The aqueous layer was basified
with aqueous sodium hydroxide solution (2M, 5 ml) and extracted
with ethyl acetate (20 ml). The ethyl acetate layer was washed
(water, brine), dried (sodium sulfate) and concentrated in vacuo to
give a pale oil (0.036 g). To the oil were added fumaric acid
(0.013 g) and 2-propanol (1 ml). The mixture was heated to reflux
then cooled to room temperature and diluted with ether (5 ml). The
emerging precipitate was filtered-off, washed (ether) and dried to
give the product as a white solid (0.027 g); .delta..sub.H (400
MHz, DMSO-d.sub.6) 7.81 (1H, t, J 1.5 Hz), 7.67 (1H, t, J 2 Hz),
6.86 (1H, t, J 3 Hz), 6.82 (1H, t, J 3 Hz), 6.59 (2H, s), 6.57 (1H,
d, J 1.5 Hz), 5.04 (2H, s), 5.01 (2H, s), 3.95-3.86 (2H, m),
2.80-2.65 (4H, m) and 1.16 (6H, d, J 7 Hz); HPLC (XTERRA, 50/80,
220 nM) 82% (4.00 min).
Example 149
[0776] (+/-)-2,6-Difluoro-4-(3-furylmethyl)oxybenzyl
2-ethylpiperazine-1-carboxylate fumarate was prepared from
1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine (0.07
g), and 2,6-difluoro-4-(furan-3-methoxy)benzyl alcohol (0.06 g)
according to the procedures described for Example 148 to give the
product as a white solid (0.03 g); .quadrature..sub.H (400 MHz,
DMSO-d.sub.6) 7.81 (1H, d, J 1 Hz), 7.67 (1H, t, J 2 Hz), 6.86 (1H,
t, J 3.5 Hz), 6.82 (1H, t, J 3.5 Hz), 6.57 (3H, s), 4.07 (1H, d, J
11 Hz), 5.01 (2H, s), 5.00 (1H, d, J 11 Hz), 3.81 (1H, m),
2.91-2.80 (4H, m), 2.74-2.66 (1H, m), 2.59-2.50 (1H, m), 1.76-1.63
(1H, m), 1.61-1.48 (1H, m) and 0.73 (3H, t, J 7.5 Hz); HPLC
(XTERRA, 50/80, 220 nM) 86% (3.71 min).
Example 150
[0777] (+/-)-Piperazine-1-carboxylic acid
2,6-difluoro-4-(tetrahydro-furan- -2-ylmethoxy)-benzyl ester
fumarate
[0778]
(+/-)-[2,6-Difluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenyl]-methan-
ol: a stirred mixture of 2,6-difluoro-4-hydroxybenzyl alcohol (0.5
g), (+/-)-tetrahydrofurfuryl bromide (0.36 ml), cesium carbonate
(0.56 g) and sodium iodide (0.005 g) in DMF (5 ml) was heated to
60.degree. C. for 18 h then cooled to room temperature. The mixture
was partitioned between ethyl acetate (30 ml) and aqueous sodium
hydroxide solution (2M, 30 ml). The organic layer was washed
(water, brine), dried (sodium sulfate) and concentrated in vacuo.
The residue was purified by flash column chromatography [SiO.sub.2;
isohexane--ethyl acetate (4:1)] to give the product as a clear oil
(0.17 g); .delta..sub.H (400 MHz, CDCl.sub.3) 6.50 (1H, t, J 3.5
Hz), 6.46 (1H, t, J 3.5 Hz), 4.69 (2H, d, J 6.5 Hz), 4.28-4.21 (1H,
m), 3.92 (2H, d, J 5 Hz), 3.92 (1H, dd, J 15, 6.5 Hz), 3.83 (1H,
dt, J 15, 6.5 Hz), 2.12-2.03 (1H, m), 2.00-1.90 (2H, m), 1.83 (1H,
t, J 6 Hz) and 1.78-1.69 (1H, m); HPLC (XTERRA, 50/80, 220 nM) 98%
(0.91 min).
[0779] (+/-)-Piperazine-1-carboxylic acid
2,6-difluoro-4-(tetrahydro-furan- -2-ylmethoxy)-benzyl ester
fumarate was prepared from
1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine (0.076 g), and
(+/-)-[2,6-Difluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenyl]-methanol
(0.075 g) according to the procedures described for Example 148 to
give the product as a white solid (0.058 g); m.p. 199.degree. C.
(decomp.); Found: C, 52.81; H, 5.65; N, 5.78%.
C.sub.21H.sub.26F.sub.2N.sub.2O.sub.8- .0.25H.sub.2O requires: C,
52.88; H, 5.60; N, 5.87%.
Example 151
[0780] (+/-)-Piperazine-1-carboxylic acid
2-fluoro-4-(tetrahydro-furan-2-y- lmethoxy)-benzyl ester
fumarate
[0781]
(+/-)-[2-Fluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenyl]-methanol
was prepared from 2-fluoro-5-hydroxybenzyl alcohol (0.50 g) and
(+/-)-tetrahydrofurfuryl bromide (0.40 ml) according to the
procedure described for Example 150 to give the product as a clear
oil (0.17 g); .delta..sub.H (400 MHz, CDCl.sub.3)
.quadrature..sub.H 6.98 (1H, q, J 3 Hz), 6.94 (1H, t, J 9 Hz), 6.79
(1H, dt, J 9, 3 Hz), 4.71 (2H, d, J 4.5 Hz), 4.25 (1H, tt, J 7, 5
Hz), 3.94 (1H dt, J8.5,6.5 Hz), 3.93 (2H, d, J 5 Hz), 3.82 (1H, dt,
J 8.5,7 Hz), 2.11-2.03 (1H, m), 2.01-1.88 (2H, m) and 1.80-1.71
(1H, m); HPLC (XTERRA, 50/80, 220 nM) 96% (0.88 min).
[0782] (+/-)-Piperazine-1-carboxylic acid
2-fluoro-4-(tetrahydro-furan-2-y- lmethoxy)-benzyl ester fumarate
was prepared from (+/-)-[2-Fluoro-4-(tetra-
hydro-furan-2-ylmethoxy)-phenyl]-methanol (0.075 g) and
1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine
(0.092 g) using the procedures described in Example 148 to give the
product as a white, crystalline solid (0.086 g); m.p.
141-147.degree. C. (decomp.); Found: C, 57.01; H, 6.58; N, 5.98%.
C.sub.2H.sub.27FN.sub.2O.sub.8 requires: C, 57.25; H, 6.48; N,
5.81%.
Example 152
[0783] 2,6-Difluoro-4-(3-thienylmethyl)oxybenzyl
cis-2,6-dimethylpiperazin- e-1-carboxylate fumarate
[0784] [2,6-Difluoro-4-(thiophen-3-ylmethoxy)-phenyl]-methanol: to
a stirred solution of thiophene-3-methanol (1.0 g) and
triethylamine (1.8 ml) in DCM (10 ml) at 0.degree. C. was added
dropwise methanesulfonyl chloride (0.75 ml). The mixture was warmed
to room temperature and stirred for 2 h then washed with water (20
ml), filtered through a PTFE membrane and concentrated in vacuo. To
the residue were added 2,6-difluoro-4-hydroxybenzyl alcohol (0.5
g), cesium carbonate (0.75 g), sodium iodide (0.01 g) and DMF (5
ml). The mixture was heated to 60.degree. C. and stirred for 18 h.
The mixture was cooled to room temperature then partitioned between
ethyl acetate (40 ml) and water (20 ml). The organic layer was
washed (water), dried (sodium sulfate) and concentrated in vacuo.
The residue was purified by flash column chromatography [SiO.sub.2;
isohexane--ethyl acetate (4:1)] to give the product as a clear oil
(0.68 g); .delta..sub.H (400 MHz, CDCl.sub.3) 7.35 (1H, dd, J 5, 3
Hz), 7.31 (1H, m), 7.12 (1H, dd, J 5, 1.5 Hz), 6.54 (1H, t, J 3.5
Hz), 6.50 (1H, t, J 3.5 Hz), 5.04 (2H, s) and 4.70 (2H, d, J 6 Hz);
HPLC (XTERRA, 50/80, 220 nM) 94% (2.51 min).
[0785] 2,6-Difluoro-4-(3-thienylmethyl)oxybenzyl
cis-2,6-dimethylpiperazin- e-1-carboxylate fumarate was prepared
from [2,6-difluoro-4-(thiophen-3-ylm- ethoxy)-phenyl]-methanol
(0.15 g) and cis 1-chlorocarbonyl-2,6-dimethyl-4--
tert-butoxycarbonylpiperazine (0.16 g) according to the procedures
described in Example 148 to give the product as a white,
crystalline solid (0.084 g); m.p. 162-186.degree. C. (decomp.);
.delta..sub.H (400 MHz, DMSO-d.sub.6) 7.61 (1H, m), 7.56 (1H, dd, J
5, 3 Hz), 7.17 (1H, dd, J 5, 1 Hz), 5.14 (2H, s), 5.04 (2H, s),
3.90 (2H, m), 2.76 (2H, t, J 11 Hz), 2.68 (2H, dd, J 12, 4.5 Hz)
and 1.16 (6H, d, J 7 Hz).
Example 153
[0786] 2,6-Difluoro-4-(3-thienylmethyl)oxybenzyl
piperazine-1-carboxylate fumarate was prepared from
[2,6-difluoro-4-(thiophen-3-ylmethoxy)-phenyl]- -methanol (0.15 g)
and 1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine (0.15 g)
according to the procedures described for Example 148 to give the
product as a white, crystalline solid (0.084 g); m.p.
161-162.degree. C. (decomp.); .delta..sub.H (400 MHz, DMSO-d.sub.6)
7.62 (1H, dd, J 3, 1.5 Hz), 7.57 (1H, dd, J 5, 3 Hz), 7.17 (1H, dd,
J 5, 1.5 Hz), 6.87 (1H, t, J 3.5 Hz), 6.83 (1H, t, J 3.5 Hz), 6.54
(2H, s), 5.14 (2H, s), 5.04 (2H, s), 3.35 (4H, m) and 2.77 (4H,
m).
Example 154
[0787] (R)-2,6-Difluoro-4-(3-thienylmethyl)oxybenzyl
2-methylpiperazine-1-carboxylate fumarate was prepared from
[2,6-difluoro-4-(thiophen-3-ylmethoxy)-phenyl]-methanol (0.15 g)
and (R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine
(0.15 g) according to the procedures described for Example 148 to
give the product as a white, crystalline solid (0.028 g); m.p.
121-143.degree. C. (decomp.); .delta..sub.H (400 MHz, DMSO-d.sub.6)
7.62 (1H, dd, J 3, 1.5 Hz), 7.57 (1H, dd, J 5, 3 Hz), 7.17 (1H, dd,
J 5, 1 Hz), 6.87 (1H, t, J 3.5 Hz), 6.83 (1H, t, J 3.5 Hz), 6.57
(2H, s), 5.14 (2H, s), 5.07 (1H, d, J 12 Hz), 5.01 (1H, d, J 12
Hz), 4.04 (1H, m), 3.63 (1H, m), 3.00-2.86 (3H, m), 2.76 (1H, m),
2.54 (1H, m) and 1.13 (3H, d, J 7 Hz).
Example 155
[0788] (+/-)-2,6-Difluoro-4-(3-thienylmethyl)oxybenzyl
2-ethylpiperazine-1-carboxylate fumarate was prepared from
[2,6-difluoro-4-(thiophen-3-ylmethoxy)-phenyl]-methanol (0.15 g)
and (+/-)1-chlorocarbonyl-2-ethyl-4-tert-butoxycarbonylpiperazine
(0.16 g) according to the procedures described for Example 148 to
give the product as a white, crystalline solid (0.057 g); m.p.
133-134.degree. C. (decomp.); .delta..sub.H (400 MHz, DMSO-d.sub.6)
7.61 (1H, dd, J 3, 1.5 Hz), 7.56 (1H, dd, J 5, 3 Hz), 7.17 (1H, dd,
J 4.5, 1 Hz), 5.14 (2H, s), 5.06 (1H, d, J 12 Hz), 5.01 (1H, d, J
12 Hz), 3.92-3.66 (2H, m), 2.94-2.80 (3H, m), 2.76-2.66 (1H, m),
2.62-2.50 (1H, m), 1.78-1.64 (1H, m), 1.63-1.48 (1H, m) and 0.72
(3H, d, J 7.5 Hz).
Example 156
[0789] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(5-methyl-isoxazol-3-ylmethoxy)-benzyl ester was
prepared from 2,6-difluoro-4-hydroxybenzyl alcohol,
3-chloromethyl-5-methyl-isoxaz- ole and
1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine
according to the procedures described for Example 54 and 121 to
give the product as a yellow oil: .delta..sub.H (400 MHz;
d.sub.6-DMSO) 1.14 (6H, d, J 6.5 Hz), 2.41 (H, d, J 1.0 Hz), 2.63
(2H, dd, J 12, 4.5 Hz), 2.68 (2H, d, J 12 Hz), 3.80-3.88 (2H, m),
5.04 (2H, s), 5.21 (2H, s), 6.34 (1H, d, J 1.0 Hz), and 6.84-6.92
(2H, m); HPLC (XTERRA, 50/80%, 220 nm) 96.8% (2.38 min).
Example 157
[0790] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-benzyl
esterwas prepared from 2,6-difluoro-4-hydroxybenzyl alcohol,
(5-methyl-3-phenyl-isoxazol-4-yl)-methanol and
1-chlorocarbonyl-cis-2,6-d- imethyl-4-tert-butoxycarbonylpiperazine
according to the procedures described for Example 54 and 121 to
give the product as a yellow oil: .delta..sub.H (400 MHz;
d.sub.6-DMSO) 1.15 (6H, d, J 7.0 Hz), 2.53 (3H, s), 2.62 (2H, dd, J
12.0, 4.5 Hz), 2.68 (2H, d, J 12.0 Hz), 3.80-3.88 (2H, m),
5.01-5.08 (4H, m), 6.84-6.91 (2H, m), 7.48-7.53 (3H, m) and
7.64-7.68 (2H, m).
Example 158
[0791] (+/-)-2-Fluoro-5-(2-propenyl)oxybenzyl
2-ethylpiperazine-1-carboxyl- ate fumarate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, allyl bromide and
(+/-)2-ethyl-1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine
according to the procedures described for Example 148 to give the
product as a white solid (5.1%); HPLC (XTERRA, 50-80%, 220 nm)
96.8% (2.30 min); NMR .delta..sub.H (400MHz, DMSO-d.sub.6) 0.765
(2H, t, J 7.5 Hz), 1.650 (2H, m), 2.708 (1H, m), 2.878 (2H, bt),
3.767 (1H, bd), 3.883 (1H, bs), 4.536 (2H, d, J 5.0 Hz), 5.069 (2H,
q), 5.247 (1H, bd), 5.377 (1H, bd), 6.013 (1H, bs), 6.586 (2H, s),
6.955 (2H, m) and 7.138 (1H, t, J 9.0 Hz).
Example 159
[0792] 2-Fluoro-5-(2-propenyl)oxybenzyl piperazine-1-carboxylate
fumarate was prepared from 2-fluoro-5-hydroxybenzyl alcohol, allyl
bromide and 1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine
according to the procedures described for Example 148 to give the
product as a white solid (8.5%); HPLC (XTERRA, 50-80%, 220 nm) 98%
(1.29 min); NMR .delta..sub.H (400 MHz, DMSO-d.sub.6) 2.774(4H,
bs), 3.381(4H, bs), 4.545(2H, d), 5.072(2H, s), 5.251(1H, m),
5.378(1H, m), 6.018(1H, m), 6.557(2H, s), 6.964(2H, m) and
7.139(1H, t, J 9.0 Hz).
Example 160
[0793] 2,6-Difluoro-4-(2-thienylmethyl)oxybenzyl
piperazine-1-carboxylate fumarate was prepared from
2,6-difluoro-4-hydroxybenzyl alcohol, 2-thiophenemethanol and
1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine according to the
procedures described for Example 152 to give the product as a white
solid (0.6%); HPLC (XTERRA, 50-80%, 220 nm) 90.6% (3.53 min); NMR
.delta..sub.H (400 MHz, DMSO-d.sub.6) 2.852(4H, bs), 3.400(4H, bs),
5.058(2H, s), 5.354(2H, s), 6.589(6H, s), 6.884(2H, d J 10 Hz),
7.052(1H, m), 7.249(1H, bd) and 7.583(1H, dd, J 1.5, 5.0 Hz).
Example 161
[0794] (R)-2,6-Difluoro-4-(2-thienylmethyl)oxybenzyl
2-methylpiperazine-1-carboxylate fumarate was prepared from
2,6-difluoro-4-hydroxybenzyl alcohol, 2-thiophenemethanol and
(R)1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine
according to the procedures described for Example 152 to give the
product as a white solid (0.24%); HPLC (XTERRA, 50/80%, 220 nm)
100% (4.36 min); NMR .delta..sub.H (400 MHz, DMSO-d.sub.6)
1.128(3H, d. J 7.0 Hz), 2.931(1H, bm), 3.655(4H, bd), 4.073(2H,
bs), 5.036(2H, q), 5.340(2H, s), 6.60(4H, s), 6.880(1H, d, J 7.0
Hz), 7.05 1(1H, m), 7.248(2H, m) and 7.58 1(1H, m).
Example 162
[0795] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(thiophen-2-ylmethoxy)-benzyl ester fumarate was
prepared from 2,6-difluoro-4-hydroxybenzyl alcohol,
2-thiophenemethanol and
1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine
according to the procedures described for Example 152 to give the
product as a white solid (1.8%); HPLC (XTERRA, 50/80%, 220 nm) 94%
(5.05 min); NMR .delta..sub.H (400 MHz, DMSO-d.sub.6) 1.160(6H, d,
J 7.0 Hz), 2.733(4H, bm), 3.912(2H, bs), 5.042(2H, s), 5.348(2H,
s), 6.611(3H, s), 6.884(2H, d, J 10 Hz), 7.050(1H, m), 7.242(1H, m)
and 7.582(1H, dd, J 1.5, 5.0 Hz).
Example 163
[0796] 5-Butylaminocarbonyloxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1- -carboxylate hydrochloride
[0797]
5-Butylaminocarbonyloxy-2-fluorobenzyl-4-tert-butoxycarbonyl-cis-2,-
6-dimethylpiperazine-1-carboxylate was prepared from
5-hydroxy-2-fluorobenzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-
-1-carboxylate and butyl isocyanate according to the method
described for Example 139 to give the product as a colourless gum
(0.177 g, 92%); Rf (Silica, isopropyl ether) 0.175; .delta..sub.H
(400 MHz, CDCl.sub.3) 7.14 (1H, m), 7.07-7.01 (2H, m), 5.18 (2H,
s), 5.01 (1H, br), 4.20 (2H, br), 3.95 (H, br), 3.26 (2H, m, J 7
Hz), 2.96 (2H, br), 1.56 (2H, m, J 7.2 Hz), 1.48 (9H, s), 1.39 (2H,
m, J 8 Hz), 1.23 (6H, d, J 7.0 Hz), and 0.96 (3H, t, J 7.3 Hz).
[0798] 5-Butylaminocarbonyloxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1- -carboxylate hydrochloride was
prepared from 5-butylaminocarbonyloxy-2-flu-
orobenzyl-4-tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate
according to the procedure described in Example 52 to give the
product as a white solid (0.1223 g, 85%); (Found: C, 54.6; H, 7.1;
N, 9.9%. C.sub.19H.sub.28FN.sub.3O.sub.4.HCl requires C, 54.6; H,
7.0; N, 10.05%); NMR .delta..sub.H (400 MHz, DMSO-d.sub.6) 9.7 (1H,
br), 9.3 (1H, br), 7.76 (1H, t, J 5.6 Hz), 7.24 (1H, t, J 9.2 Hz),
7.20 (1H, m), 7.12 (1H, m, J 4.0 Hz), 5.15 (2H, s), 4.30 (2H, m),
3.15 (2H, d, J 13 Hz), 3.09-3.02 (4H, m), 1.45 (2H, m, J 7.2 Hz),
1.36-1.29 (8H, m, J 7.2 Hz), and 0.89 (3H, t, J 7.2 Hz).
Example 164
[0799] 2-Fluoro-5-(2-propynyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate hydrochloride
[0800]
2-Fluoro-5-(2-propynyl)oxybenzyl-4-tert-butoxycarbonyl-cis-2,6-dime-
thylpiperazine-1-carboxylate was prepared from
5-hydroxy-2-fluorobenzyl-4--
tert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate and
propargyl bromide to give the product as a colourless gum (0.191 g,
>100%). Rf (Silica, isopropyl ether) 0.25; .delta..sub.H (400
MHz, CDCl.sub.3) 7.00-6.98 (2H, m), 6.90 (1H, m), 5.18 (2H, s),
4.66 (2H, d, J 0.24 Hz), 4.21 (2H, m, J 5.6 Hz), 3.95 (2H, br),
2.97 (2H, br), 2.51 (1H, t, J 0.24 Hz), 1.48 (9H, s), and 1.24 (6H,
d, J 6.8 Hz).
[0801] 2-Fluoro-5-(2-propynyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-carbo- xylate hydrochloride as
prepared from 2-fluoro-5-(2-propynyl)oxybenzyl-4-t-
ert-butoxycarbonyl-cis-2,6-dimethylpiperazine-1-carboxylate
according to the procedures described in Example 52 to give the
product as a white solid (0.1352 g, 95% overall); .nu..sub.max
(diffuse reflectance)/cm-1 3507, 3292, 3242, 2125, 1700, 1594,
1506, and 1209; .delta..sub.H (400 MHz, DMSO-d.sub.6)10.0-9.0 (2H,
br), 7.19 (1H, t, J 9.2 Hz), 7.06 (1H, m), 7.00 (1H, m), 5.13 (2H,
s), 4.79 (2H, d, J 0.24 Hz), 4.31 (2H, m, J 6 Hz), 3.57 (1H, t, J
0.24 Hz), 3.15 (2H, d, J 13.2 Hz), 3.07 (2H, dd, J 5 and 13.2 Hz),
and 1.31 (6H, d, J 7.2 Hz).
Example 165
[0802] 5-(5-[2,1,3]Benzothiadiazolylmethyl)oxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-1-carboxylate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, 5-[2,1,3]benzothiadiazolylmethyl
chloride and
1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiper- azine
according to the procedures described for Examples 121 and 54 to
give the product as a yellow oil: .delta..sub.H (400 MHz,
DMSO-d.sub.6) 1.25 (6H, d, J 7.0 Hz), 2.78-2.95 (4H, m), 4.10 (2H,
br), 5.20 (2H, s), 5.22 (2H, s), 6.90-7.08 (3H, m), 7.65 (1H, m)
and 8.03 (2H, m), NH not observed; HPLC (XTERRA, 50/80%, 220 nm)
90.7% (4.84 min).
Example 166
[0803] 2-Fluoro-5-(3-fluorobenzyl)oxybenzyl
cis-2,6-dimethylpiperazine-1-c- arboxylate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, 3-fluorobenzyl bromide and
1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butox- ycarbonylpiperazine
according to the procedures described for Examples 121 and 54 to
give the product as a yellow oil: .delta..sub.H (400 MHz,
DMSO-d.sub.6) 1.28 (6H, d, J 6.9 Hz), 2.77-2.90 (4H, m), 4.10 (2H,
br), 5.03 (2H, s), 5.17 (2H, s), 6.85 (1H, m), 6.95-7.10 (3H, m),
7.15 (2H, m) and 7.35 (1H, m), NH not observed; HPLC (XTERRA,
50/80%, 220 nm) 85% (4.83 min).
Example 167
[0804] (R)-2-Fluoro-5-pentyloxybenzyl
2-methylpiperazine-1-carboxylate was prepared from
2-fluoro-5-hydroxybenzyl alcohol, 1-iodopentane and
(R)2-methylpiperazine resin according to the procedures described
for Example 126 to give the product as a yellow oil: .delta..sub.H
(400 MHz, DMSO-d.sub.6) 0.89 (3H, t, J 7.0 Hz), 1.24 (3H, d, J 7.1
Hz), 1.30-1.45 (4H, m), 1.70 (2H, pent, J 6.7 Hz), 2.90 (1H, m),
3.0-3.20 (4H, m), 3.92 (3H, m), 4.38 (1H, m), 5.07 (1H, d, J 12.5
Hz), 5.12 (1H, d, J 12.5 Hz), 6.93 (1H, m), 6.98 (1H, m), 7.14 (1H,
m), 8.90 (1H, br) and 9.40 (1H, br); HPLC (XTERRA, 50/80%, 220 nm)
84.6% (4.85 min).
Example 168
[0805] 5-(Cyclopropylmethyl)oxy-2-fluorobenzyl
cis-2,6-dimethylpiperazine-- 1-carboxylate fumarate was prepared
from 2-fluoro-5-hydroxybenzyl alcohol, cyclopropylmethyl bromide
and 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-bu-
toxycarbonylpiperazine according to the procedures described for
Examples 121 and 54 to give the product as a white solid:
.delta..sub.H(400 MHz, DMSO-d.sub.6) 7.13 (1H, t, J 9 Hz), 6.95
(1H, q, J 3 Hz), 6.90 (1H, dt, J 9, 3.5 Hz), 6.58 (2H, s), 5.08
(2H, s), 3.98 (2H, m), 3.78 (2H, d, J 7 Hz), 2.80 (2H, d, J 12 Hz),
2.72 (2H, dd, J 12, 4.5 Hz), 1.20 (6H, d, J 7 Hz), 0.56 (2H, ddd, J
8, 6, 4.5 Hz) and 0.30 (2H, dt, J 6, 4.5 Hz).
Example 169
[0806] (R)-2-Methyl-piperazine-1-carboxylic acid
2-fluoro-5-(2-thiophen-2-- yl-ethoxy)-benzyl ester fumarate
[0807] 2-Fluoro-5-[2-(2-thienyl)]ethoxybenzyl alcohol was prepared
from 2-thiophene-ethanol (0.5 g) and 2-fluoro-5-hydroxybenzyl
alcohol according to the procedure described in Example 152 to give
the product as a clear oil (0.12 g); .delta..sub.H (400 MHz,
CDCl.sub.3) 7.16 (1H, dd, J 5, 1.5 Hz), 6.98-6.92 (3H, m), 6.91
(1H, m), 6.78 (1H, dt, J 9, 3.5 Hz), 4.70 (2H, d, J 6 Hz), 4.15
(2H, t, J 6.5 Hz) and 3.28 (2H, dt, J 6.5, 1 Hz); HPLC (XTERRA,
50/80%, 220 nm) 97% (3.49 min).
[0808] (R)-2-Methyl-piperazine-1-carboxylic acid
2-fluoro-5-(2-thiophen-2-- yl-ethoxy)-benzyl ester fumarate was
prepared from 2-fluoro-5-[2-(2-thieny- l)]ethoxybenzyl alcohol and
(R)1-chlorocarbonyl-2-methyl 4-tert-butoxycarbonylpiperazine
according to the procedures described in Example 152 to give the
product as a white, crystalline solid (0.047 g); .delta..sub.H (400
MHz, DMSO-d.sub.6) 7.53 (1H, dd, J 5, 1 Hz), 7.25-7.09 (3H, m),
7.02 (1H, m), 6.91 (1H, m), 6.58 (2H, s), 4.74 (2H, s), 4.56 (2H,
s), 4.26 (1H, m), 3.82 (1H, m), 3.14 (1H, m), 3.00 (1H, m),
2.91-2.80 (2H, m), 2.67 (1H, m) and 1.28 (3H, d, J 6.5 Hz); HPLC
(XTERRA, 50/80%, 220 nm) 99% (4.15 min).
Example 170
[0809] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
3-bromo-2,6-difluoro-benzyl ester hydrochloride
[0810] 1-Bromo-3-(bromomethyl)-2,4-difluoro-benzene
1-Bromo-2,4-difluoro-3-methyl-benzene (22 g, 0.106 M) and
N-bromosuccinimide (22.7 g, 0.128 M) were dissolved in
tetrachloromethane (800 mL). Dibenzoylperoxide (0.52 g, 2 mM) was
added and the mixture was irradiated for 1 h. Succinimide was
removed by filtration of the cooled mixture and the filtrate was
washed with water. The water phase was extracted with
dichloromethane. Organic phases were pooled, dried with MgSO4 and
and evaporated to yield a yellowish oil (32 g). The residue was
purified by column chromatography (silica gel; n-hexane) to yield
28.4 g (94%) of the title compound as a colorless oil. MS (EI):
286.0 (M).sup.+. (3-Bromo-2,6-difluoro-phenyl)-methanol
[0811] 1-Bromo-3-(bromomethyl)-2,4-difluoro-benzene (45.2 g, 0.158
M) was dissolved in dioxane (800 mL), water (800 mL) and calcium
carbonate (80 g, 0.80 M) were added and the mixture was refluxed
for 16 h. The mixture was cooled, acidified with 2N HCl and
extracted with dichloromethane. Organic phases were pooled, dried
with Na2SO4 and and evaporated to yield a brownish oil (40.3 g).
The residue was purified by column chromatography (silica gel;
n-hexane/ethyl acetate 9:1) to yield 31.2 g (88%) of the title
compound as a colorlesss solid. MS (EI): 224.0 (M).sup.+.
cis-2,6-Dimethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(3-bromo-2,6-difluoro-benzyl)ester
[0812] The compound was prepared from
(3-bromo-2,6-difluoro-phenyl)-methan- ol and
4-chlorocarbonyl-cis-3,5-dimethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedures described in Example
121 and 54 to give the product as a colorless oil (9.75 g); MS
(ISP): 482.3 (M+NH4).sup.+.
cis-2,6-Dimethyl-piperazine-1-carboxylic acid
3-bromo-2,6-difluoro-benzyl ester hydrochloride
[0813] The compound was prepared from
cis-2,6-dimethyl-piperazine-1,4-dica- rboxylic acid 4-tert-butyl
ester 1-(3-bromo-2,6-difluoro-benzyl)ester according to the
procedures described in Example 121 and 54 to give the product as a
colorless solid (0.159 g); m.p.: 207-210.degree. C.; MS (ISP):
365.1 (M+H).sup.+.
Example 171
[0814] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
2,4-difluoro-2'-methoxy-biphenyl-3-ylmethyl ester
[0815] A mixture of 46.33 mg (0.1 mmol)
cis-2,6-dimethyl-piperazine-1,4-di- carboxylic acid
1-(3-bromo-2,6-difluoro-benzyl)ester 4-tert-butyl ester, 16.71 mg
(0.11 mmol) 2-methoxyphenylboronic acid, 3.65 mg (0.005 mmol)
dichloro
(1,1'-bis(diphenylphosphino)ferrocene)palladium(II)dichlorometha-
ne adduct and 0.11 ml of a 2M Na.sub.2CO.sub.3 aq. solution in 1.2
ml dioxane was heated for 17 h to 85.degree. C. The mixture was
filtered and 0.15 ml 4N HCl in dioxane was added and the mixture
heated for 3 h to 65.degree. C. After cooling to ambient
temperature 0.2 ml triethylamine and water were added to dissolve
the mixture. The solution was subjected to reversed phase
preparative HPLC eluting with a water/acetonitrile gradient to
yield after evaporation of the solvents 28.2 mg (66%) of the title
compound. MS (ISP): 391 MH.sup.+.
[0816] In analogy to Example 171 the following Examples 172-176 can
be prepared from given starting material that is either
commercially available or described in the literature:
Example 172
[0817] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
2,4-difluoro-3',4'-dimethoxy-biphenyl-3-ylmethyl ester
hydrochloride
[0818] Following the general procedure of example 171 the title
compound was synthesized from
cis-2,6-dimethyl-piperazine-1,4-dicarboxylic acid
1-(3-bromo-2,6-difluoro-benzyl)ester 4-tert-butyl ester and
3,4-dimethoxyphenyl boronic acid. MS (ISP): 421 MH.sup.+
Example 173
[0819] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
2,4-difluoro-3'-hydroxy-4'-methoxy-biphenyl-3-ylmethyl ester
hydrochloride
[0820] Following the general procedure of example 171 the title
compound was synthesized from
cis-2,6-dimethyl-piperazine-1,4-dicarboxylic acid
1-(3-bromo-2,6-difluoro-benzyl)ester 4-tert-butyl ester and
2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol.
MS (ISP): 407 MH.sup.+
Example 174
[0821] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
3'-amino-2,4-difluoro-biphenyl-3-ylmethyl ester hydrochloride
[0822] Following the general procedure of example 171 the title
compound was synthesized from
cis-2,6-dimethyl-piperazine-1,4-dicarboxylic acid
1-(3-bromo-2,6-difluoro-benzyl)ester 4-tert-butyl ester and
3-aminophenyl boronic acid. MS (ISP): 376 MH.sup.+
Example 175
[0823] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
4'-acetyl-2,4-difluoro-biphenyl-3-ylmethyl ester hydrochloride
[0824] Following the general procedure of example 171 the title
compound was synthesized from
cis-2,6-dimethyl-piperazine-1,4-dicarboxylic acid
1-(3-bromo-2,6-difluoro-benzyl)ester 4-tert-butyl ester and
4-acetyl-phenylboronic acid. MS (ISP): 403 MH.sup.+
Example 176
[0825] cis-2,6-Dimethyl-piperazine-1-carboxylic acid
3'-acetyl-2,4-difluoro-biphenyl-3-ylmethyl ester hydrochloride
[0826] Following the general procedure of example 171 the title
compound was synthesized from
cis-2,6-dimethyl-piperazine-1,4-dicarboxylic acid
1-(3-bromo-2,6-difluoro-benzyl)ester 4-tert-butyl ester and
3-acetyl-phenylboronic acid. MS (ISP): 403 MH.sup.+
Example 177
[0827] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-methyl-benz- yl ester
[0828] (R)-2-Ethyl-piperazine dihydrochloride
[0829] (3R)-3-Ethyl-1-(phenylmethyl)-piperazine (30.7 g, 0.15 M)
was dissolved in ethanol (650 mL), palladium on carbon (10%; 11.5
g) was added and the mixture was hydrogenated (3 bar) at room
temperature. The catalyst was removed by filtration and 5.5 N HCl
in Ethanol (60 mL) was added to the filtrate. The product
crystallized and was filtered off after evaporation of 400 mL of
the solvent and subsequent addition of diethylether (400 mL). White
solid (25.9 g; 92%); MS (EI): 114.2 (M).sup.+.
[0830] (R)-3-Ethyl-piperazine-1-carboxylic acid tert-butyl
ester
[0831] (R)-2-Ethyl-piperazine dihydrochloride (25.9 g, 01.38 M) was
dissolved in dichloromethane (700 mL) and cooled to 0.degree. C.
Triethylamine (48.2 mL, 0.346 M) was added and subsequently
di-tert-butyl-dicarbonate (30.2 g, 0.138 M) dissolved in
dichloromethane (50 mL) was added within 30 min with cooling
(0-5.degree. C.) and stirring. Stirring was continued for another 3
h at room temperature. The mixture was washed with water, the water
phase was extracted twice with dichloromethane, organic phases were
pooled, dried with Na2SO4 and evaporated to yield a colorless oil
(31 g). The residue was purified by column chromatography (silica
gel; dichoromethane/methanol 90:10) to yield 26.5 g (89%) of a
colorless oil. MS (ISP): 215.5 (M+H).sup.+.
[0832] (R)-4-Chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester
[0833] Bis-(trichloromethyl)-carbonate (13.9 g, 47 mM) was
dissolved in dichloromethane (500 mL) and cooled to 0.degree.0 C. A
mixture of (R)-3-ethyl-piperazine-1-carboxylic acid tert-butyl
ester (26.5 g; 0.124 M) and pyridine (10.9 mL, 0.136 M) in
dichloromethane (150 mL) was added dropwise with stirring
(0-3.degree. C.). Stirring was continued for another 1/2 h at room
temperature. The mixture was washed with water and brine, the water
phases were extracted with dichloromethane, organic phases were
pooled, dried with Na2SO4 and evaporated to yield a brown oil (34
g, 99%) which crystallized upon standing; MS (EI): 276.2
(M).sup.+.
[0834] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(3-bromo-2,6-difluoro-benzyl)ester
[0835] The compound was prepared from
(3-bromo-2,6-difluoro-phenyl)-methan- ol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedures described in Example
121 and 54 to give the product as a colorless oil (9.22 g); MS
(ISP): 480.3, 482.3 (M+H).sup.+.
[0836] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-methyl-benzyl)ester
[0837] A mixture of (R)-2-ethyl-piperazine-1,4-dicarboxylic acid
4-tert-butyl ester 1-(3-bromo-2,6-difluoro-benzyl)ester (226 mg),
tetrakis(triphenylphosphine)palladium (56 mg), trimethylboroxine
(122 mg) and potassium carbonate (200 mg) in dioxane (5 mL) was
heated to reflux with stirring for 6 h. The cooled was mixture was
partitioned between water and ethylacetate. The water phase was
extracted once with ethylacetate, organic phases were pooled and
dried with Na2SO4 to yield after evaporation a dark oil (259 mg).
This residue was purified by column chromatography (silica gel;
n-hexane/ethylacetate gradient) to yield 160 mg (82%) of a yellow
oil. MS (ISP): 416.4 (M+H).sup.+.
[0838] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-methyl-benz- yl ester
[0839] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-methyl-benzyl)ester (160 mg) was dissolved
in methanol (3 mL), 500 .mu.L 4 N HCl in dioxane was added and the
mixture was stirred for 18 h at room temperature. The mixture was
added to water (10 mL) made alkaline with 1 N NaOH and extracted
with ethylacetate. Organic phases were pooled, dried with Na2SO4
and evaporated to give the product as a yellowish oil (120 mg); MS
(ISP): 299.4 (M+H).sup.+.
Example 178
[0840] (R)-2-Ethyl-piperazine-1-carboxylic acid 2,6-difluoro-benzyl
ester
[0841] This compound was prepared from
(R)-4-chlorocarbonyl-3-ethyl-pipera- zine-1-carboxylic acid
tert-butyl ester and 2,6-difluorobenzylalcohol via
(R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester
1-(2,6-difluoro-benzyl)ester according to the procedures described
in Example 177 to give the product as a yellowish oil (69 mg); MS
(ISP): 285.2 (M+H).sup.+.
Example 179
[0842] (R)-2-Ethyl-piperazine-1-carboxylic acid
4-cyclopropylmethoxy-2,6-d- ifluoro-benzyl ester
3,5-Difluoro-4-hydroxymethyl -phenol
[0843] 3,5-Difluorophenol (67.2 g, 0.48 M) was added to a solution
of potassium hydroxide (35.1 g, 0.53 M) in water (145 mL). The
mixture was heated to 60.degree. C. and a mixture of formaldehyde
(74 mL, 36% in water) and water (145 mL) was added dropwise. The
mixture was stirred for 20 h at 40.degree. C. After cooling to
0-5.degree. C. concentrated HCl (60 mL, 36%) was added. The product
precipitated, was filtered off and dried. Colorless solid (35.9 g,
41%); m.p.: 156-160.degree. C. dec.; MS (ISN): 159.2
(M-H).sup.-.
[0844] 4-Cyclopropylmethoxy-2,6-difluoro-benzylalcohol
[0845] Sodium hydride (82 mg, 55%, 1.87 mM) was added to a solution
of 3,5-difluoro-4-hydroxymethyl-phenol (300 mg, 1.87 mM) in
dimethylformamide (4 mL). After 1 h stirring at room temperature
cyclopropylmethylbromide (135 mg, 1.87 mM) was added and stirring
continued for 24 h. The mixture was partitioned between water and
diethylether. Organic phases were pooled, washed with brine and
dried with MgSO4 to yield after evaporation a yellow oil (673 mg).
This residue was purified by column chromatography (silica gel;
n-hexane/ethylacetate gradient) to yield 287 mg (71%) of the
product as a yellowish oil. MS (EI): 214.1 (M).sup.+.
[0846] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(4-cyclopropylmethoxy-2,6-difluoro-benzyl)ester
[0847] A mixture of 4-cyclopropylmethoxy-2,6-difluoro-benzylalcohol
(270 mg, 1.26 mM) and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester (349 mg, 1.26 mM) in dimethylformamide (2 mL) was
added slowly to a suspension of sodium hydride (83 mg, 55%, 1.89
mM) in dimethylformamide (2 mL). The mixture was stirred at room
temperature for 5 h and partitioned between water and diethylether.
Organic phases were pooled, washed with brine and dried with MgSO4
to yield after evaporation a yellow oil (585 mg). This residue was
purified by column chromatography (silica gel;
n-hexane/ethylacetate gradient) to yield 406 mg (71%) of the
product as a yellowish oil. MS (ISP): 477.3 (M+H).sup.+.
[0848] (R)-2-Ethyl-piperazine-1-carboxylic acid
4-cyclopropylmethoxy-2,6-d- ifluoro-benzyl ester
[0849] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(4-cyclopropylmethoxy-2,6-difluoro-benzyl)ester (400 mg)
was dissolved in methanol (5 mL), 1100 .mu.L 4 N HCl in dioxane was
added and the mixture was stirred for 18 h at room temperature. The
mixture was made alkaline with 2 N NaOH and eluted with
ethylacetate over a column containing 10 g ChemElut CE1010. The
filtrate was collected, solvent was evaporated to give a yellowish
oil (237 mg). This residue was purified by column chromatography
(silica gel; dichloromethane/methanol gradient) to yield 186 mg
(59%) of the product as a colorless oil. MS (ISP): 355.4
(M+H).sup.+.
Example 180
[0850] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-propoxy-ben- zyl ester
[0851] 2,6-Difluoro-4-propoxy-benzylalcohol
[0852] This compound was prepared from
3,5-difluoro-4-hydroxymethyl-phenol and propylbromide according to
the procedure described in Example 179 to give the product as a
yellowish oil (168 mg, 44%); MS (EI): 202.1 (M).sup.+.
[0853] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-4-propoxy-benzyl)ester
[0854] This compound was prepared from
2,6-difluoro-4-propoxy-benzylalcoho- l and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (257 mg; 78%); MS (ISP):
465.4 (M+Na).sup.+.
[0855] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-propoxy-ben- zyl ester
[0856] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(2,6-difluoro-4-propoxy-benzyl)ester according to the procedure
described in Example 179 to give the product as a colorless oil
(133 mg; 69%); MS (ISP): 343.4 (M+H).sup.+.
Example 181
[0857] (R)-2-Ethyl-piperazine-1-carboxylic acid
4-allyloxy-2,6-difluoro-be- nzyl ester
4-Allyloxy-2,6-difluoro-benzylalcohol
[0858] This compound was prepared from
3,5-difluoro-4-hydroxymethyl-phenol and allylbromide according to
the procedure described in Example 179 to give the product as a
yellowish oil (229 mg, 61%); MS (EI): 200.1 (M).sup.+.
[0859] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(4-allyloxy-2,6-difluoro-benzyl)ester
[0860] This compound was prepared from
4-allyloxy-2,6-difluoro-benzylalcoh- ol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (230 mg; 47%); MS (ISP):
441.4 (M+H).sup.+.
[0861] (R)-2-Ethyl-piperazine-1-carboxylic acid
4-allyloxy-2,6-difluoro-be- nzyl ester
[0862] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(4-allyloxy-2,6-difluoro-benzyl)ester according to the procedure
described in Example 179 to give the product as a colorless oil
(101 mg; 59%); MS (ISP): 341.4 (M+H).sup.+.
Example 182
[0863] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-prop-2-ynyl- oxy-benzyl ester
2,6-Difluoro-4-prop-2-ynyloxy-benzylalcohol
[0864] This compound was prepared from
3,5-difluoro-4-hydroxymethyl-phenol and propargylbromide according
to the procedure described in Example 179 to give the product as a
yellowish oil (229 mg, 62%); MS (EI): 197.1 (M).sup.+.
[0865] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-4-prop-2-ynyloxy-benzyl)ester
[0866] This compound was prepared from
2,6-difluoro-4-prop-2-ynyloxy-benzy- lalcohol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (336 mg; 67%); MS (ISP):
456.5 (M+NH4).sup.+.
[0867] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-prop-2-ynyl- oxy-benzyl ester
[0868] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(2,6-difluoro-4-prop-2-ynyloxy-benzyl)ester according to the
procedure described in Example 179 to give the product as a
colorless oil (195 mg; 76%); MS (ISP): 339.3(M+H).sup.+.
Example 183
[0869] (R)-2-Ethyl-piperazine-1-carboxylic acid
4-butoxy-2,6-difluoro-benz- yl ester
4-Butoxy-2,6-difluoro-benzylalcohol
[0870] This compound was prepared from
3,5-difluoro-4-hydroxymethyl-phenol and butylbromide according to
the procedure described in Example 179 to give the product as a
yellowish oil (279 mg, 69%); MS (EI): 216.1 (M).sup.+.
[0871] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(4-butoxy-2,6-difluoro-benzyl)ester
[0872] This compound was prepared from
4-butoxy-2,6-difluoro-benzylalcohol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (454 mg; 80%); MS (ISP):
479.4 (M+Na).sup.+.
[0873] (R)-2-Ethyl-piperazine-1-carboxylic acid
4-butoxy-2,6-difluoro-benz- yl ester
[0874] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(4-butoxy-2,6-difluoro-benzyl)ester according to the procedure
described in Example 179 to give the product as a colorless oil
(240 mg; 68%); MS (ISP): 357.4 (M+H).sup.+.
Example 184
[0875] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(2-methoxy-- ethoxy)-benzyl ester
[0876] 2,6-Difluoro-4-(2-methoxy-ethoxy)-benzylalcohol
[0877] This compound was prepared from
3,5-difluoro-4-hydroxymethyl-phenol and methoxyethyl bromide
according to the procedure described in Example 179 to give the
product as a colorless oil (159 mg, 39%); MS (EI): 218.1
(M).sup.+.
[0878] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-4-(2-methoxy-ethoxy)-benzyl)ester
[0879] This compound was prepared from
2,6-difluoro-(2-methoxy-ethoxy)-ben- zylalcohol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (172 mg; 55%); MS (ISP):
481.4 (M+Na).sup.+.
[0880] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(2-methoxy-- ethoxy)-benzyl ester
[0881] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(2,6-difluoro-4-(2-methoxy-ethoxy)-benzyl)e- ster according to
the procedure described in Example 179 to give the product as a
colorless oil (75 mg; 56%); MS (ISP): 359.3(M+H).sup.+.
Example 185
[0882] (R)-2-Ethyl-piperazine-1-carboxylic acid
4-ethoxy-2,6-difluoro-benz- yl ester
[0883] 4-Ethoxy-2,6-difluoro-benzylalcohol
[0884] This compound was prepared from
3,5-difluoro-4-hydroxymethyl-phenol and ethylbromide according to
the procedure described in Example 179 to give the product as a
yellowish oil (241 mg, 68%); MS (EI): 188.1 (M).sup.+.
[0885] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(4-ethoxy-2,6-difluoro-benzyl)ester
[0886] This compound was prepared from
4-ethoxy-2,6-difluoro-benzylalcohol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (478 mg; 81%); MS (ISP):
429.6 (M+H).sup.+.
[0887] (R)-2-Ethyl-piperazine-1-carboxylic acid
4-ethoxy-2,6-difluoro-benz- yl ester
[0888] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(4-ethoxy-2,6-difluoro-benzyl)ester according to the procedure
described in Example 179 to give the product as a colorless oil
(167 mg; 46%); MS (ISP): 329.3 (M+H).sup.+.
Example 186
[0889] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(2-methyl-t- hiazol-4-ylmethoxy)-benzyl ester
[0890]
2,6-Difluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzylalcohol
[0891] This compound was prepared from
3,5-difluoro-4-hydroxymethyl-phenol and
4-chlormethyl-2-methylthiazol according to the procedure described
in Example 179 to give the product as a colorless oil (369 mg,
73%); MS (ISP): 272.3 (M+H).sup.+.
[0892] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester
1-(2,6-difluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzyl)ester
[0893] This compound was prepared from
2,6-difluoro-(2-methyl-thiazol-4-yl- methoxy)-benzylalcohol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carbo- xylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (447 mg; 66%); MS (ISP):
534.3 (M+Na).sup.+.
[0894] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-4-(2-methyl-t- hiazol-4-ylmethoxy)-benzyl ester
[0895] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(2,6-difluoro-4-(2-methyl-thiazol-4-ylmetho- xy)-benzyl)ester
according to the procedure described in Example 179 to give the
product as a colorless oil (204 mg; 57%); MS (ISP): 412.4
(M+H).sup.+.
Example 187
[0896] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-fluoro-5-methoxy-benzyl ester hydrochloride
2-Fluoro-5-iodo-benzylalcohol
[0897] 2-Fluoro-5-iodo-benzaldehyde (23.4 g, 0.093 M) was dissolved
in methanol (150 mL). Sodium borohydride (1.8 g, 0.047 M) was added
in portions with cooling (5.degree. C.) and stirring. The mixture
was stirred for 1 h at room temperature, poured into ice-water (600
mL) and extracted into ethylacetate. Organic phases were pooled,
washed with brine and dried with MgSO4. The solvent was evaporated
to yield a yellowish oil (24.2 g). This residue was purified by
column chromatography (silica gel; n-hexane/ethylacetate 4:1) to
yield 23.9 g (quant.) of the product as a colorless oil. MS (EI):
252.0 (M).sup.+.
[0898] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-iodo-benzyl)ester
[0899] A mixture of 2-fluoro-5-iodo-benzylalcohol (5.0 g, 19.8 mM)
and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester (5.5 g, 19.8 mM) in dimethylformamide (70 mL) was
added slowly to a suspension of sodium hydride (1.3 g, 55%, 1.89
mM) in dimethylformamide (30 mL). The mixture was stirred at room
temperature for 5 h and partitioned between water and diethylether.
Organic phases were pooled, washed with brine and dried with Na2SO4
to yield after evaporation a yellow oil (11.2 g). This residue was
purified by column chromatography (silica gel;
n-hexane/ethylacetate 3:1) to yield 9.4 g (97%) of the product as a
yellowish oil. MS (ISP): 510.3 (M+NH4).sup.+.
[0900] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester
[0901] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-iodo-benzyl)ester (8.9 g, 18 mM) was dissolved
in tetrahydrofuran (150 mL), trisopropylborate (6.7 g, 36 mM) was
added and the mixture was cooled to -78.degree. C. At this low
temperature n-butyllithium (16.9 mL, 1.6N) was added drop by drop
with stirring. The mixture was stirred for 45 min at -78.degree.
C., for another 45 min at -50.degree. C. and for 15 min at
0.degree. C. Acetic acid (9.5 mL, 50%) was added slowly with
stirring (0-5.degree. C.), followed by hydrogen peroxide (2.75 mL,
35%). Stirring continued with cooling for another 45 min and for 1
h at room temperature. The mixture was partitioned between water
and diethylether, organic phases were pooled, washed with water,
sodium thiosulfate solution (5%), brine and dried with Na2SO4 to
yield after evaporation a light yellow oil (8.5 g). This residue
was purified by column chromatography (silica gel;
n-hexane/ethylacetate 1:1) to yield 3.0 g (43%) of the product as a
yellowish oil. MS (ISP): 400.5 (M+NH4).sup.+.
[0902] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-fluoro-5-methoxy-benzyl ester hydrochloride
[0903] A mixture of 6.27 mg (0.157 mmol) NaH (60% suspension in
mineral oil) and 40 mg (0.105 mmol)
(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester
1-(2-fluoro-5-hydroxy-benzyl)ester in 1 ml DMF was stirred for 30
min at room temperature under argon. 16.4 mg (0.115 mmol)
methyliodide was added and the mixture was stirred 30 min at room
temperature. After addition of 60 ul HCl (37%) the mixture was
purified with preparative HPLC eluting with an acetonitrile/water
gradient. The fractions containing the desired intermediate were
combined and 0.05 ml HCl (37%) was added before evaporation to
dryness. The residue was taken up in 1 ml dioxane and 0.15 ml HCl
(37%) and stirred for 30 min at 60.degree. C. Evaporation of the
mixture yielded 20 mg (57%) of the title compound. MS (ISP): 297
(M+H).sup.+.
Example 188
[0904] (R)-2-Ethyl-piperazine-1-carboxylic acid
5-ethoxy-2-fluoro-benzyl ester hydrochloride
[0905] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and ethyl bromide. MS
(ISP): 311 (M+H).sup.+.
Example 189
[0906] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-fluoro-5-propoxy-benzyl ester hydrochloride
[0907] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and propyl bromide. MS
(ISP): 325 (M+H).sup.+.
Example 190
[0908] (R)-2-Ethyl-piperazine-1-carboxylic acid
5-butoxy-2-fluoro-benzyl ester hydrochloride
[0909] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and butyl bromide. MS
(ISP): 339 (M+H).sup.+.
Example 191
[0910] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-fluoro-5-pentyloxy-benzy- l ester hydrochloride
[0911] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and pentyl bromide. MS
(ISP): 353 (M+H).sup.+.
Example 192
[0912] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-fluoro-5-(3-methyl-butox- y)-benzyl ester hydrochloride
[0913] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and 3-methyl-butyl
bromide. MS (ISP): 353 (M+H).sup.+.
Example 193
[0914] (R)-2-Ethyl-piperazine-1-carboxylic acid
5-benzyloxy-2-fluoro-benzy- l ester
[0915] According to example 187 the title compound was synthesized
from (R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and benzyl bromide. MS
(ISP): 373 (M+H).sup.+.
Example 194
[0916] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-fluoro-5-phenethyloxy-be- nzyl ester
[0917] According to example 187 the title compound was synthesized
from (R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and phenethyl bromide. MS
(ISP): 387 (M+H).sup.+.
Example 195
[0918] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-fluoro-5-(2-methyl-benzy- loxy)-benzyl ester hydrochloride
[0919] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and 2-methylbenzyl
bromide. MS (ISP): 387 (M+H).sup.+.
Example 196
[0920] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-fluoro-5-(3-methyl-benzy- loxy)-benzyl ester hydrochloride
[0921] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and 3-methylbenzyl
bromide. MS (ISP): 387 (M+H).sup.+.
Example 197
[0922] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-fluoro-5-(2-pyrrol-1-yl-- ethoxy)-benzyl ester
[0923] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and 2-pyrrol-1-yl-ethyl
bromide. MS (ISP): 375 (M+H).sup.+.
Example 198
[0924] (R)-2-Ethyl-piperazine-1-carboxylic acid
5-cyclopropylmethoxy-2-flu- oro-benzyl ester hydrochloride
[0925] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and cyclopropylmethyl
bromide. MS (ISP): 337 (M+H).sup.+.
Example 199
[0926] (R)-2-Ethyl-piperazine-1-carboxylic acid
5-cyclobutylmethoxy-2-fluo- ro-benzyl ester hydrochloride
[0927] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and cyclobutylmethyl
bromide. MS (ISP): 351 (M+H).sup.+.
Example 200
[0928] (R)-2-Ethyl-piperazine-1-carboxylic acid
5-cyclohexylmethoxy-2-fluo- ro-benzyl ester hydrochloride
[0929] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and cyclohexylmethyl
bromide. MS (ISP): 379 (M+H).sup.+.
Example 201
[0930] (R)-2-Ethyl-piperazine-1-carboxylic acid
5-(2-cyclohexyl-ethoxy)-2-- fluoro-benzyl ester hydrochloride
[0931] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and 2-cyclohexyl-ethyl
bromide. MS (ISP): 393 (M+H).sup.+.
Example 202
[0932] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-fluoro-5-prop-2-ynyloxy-- benzyl ester
[0933] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and prop-2-ynyl bromide.
MS (ISP): 337 (M+H).sup.+.
Example 203
[0934] (R)-2-Ethyl-piperazine-1-carboxylic acid
5-allyloxy-2-fluoro-benzyl ester
[0935] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and allyl bromide. MS
(ISP): 323 (M+H).sup.+.
Example 204
[0936] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-fluoro-5-(2-methoxy-etho- xy)-benzyl ester hydrochloride
[0937] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and 2-methoxy-ethyl
bromide. MS (ISP): 341 (M+H).sup.+.
Example 205
[0938] (R)-2-Ethyl-piperazine-1-carboxylic acid
5-(2-ethoxy-ethoxy)-2-fluo- ro-benzyl ester hydrochloride
[0939] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and 2-ethoxy-ethyl
bromide. MS (ISP): 355 (M+H).sup.+.
Example 206
[0940] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-fluoro-5-(3-phenoxy-prop- oxy)-benzyl ester hydrochloride
[0941] According to example 187 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-fluoro-5-hydroxy-benzyl)ester and 3-phenoxy-propyl
bromide. MS (ISP): 417 (M+H).sup.+.
Example 207
[0942] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-methoxy-ben- zyl ester hydrochloride
[0943] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester
[0944] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(3-bromo-2,6-difluoro-benzyl)ester (3.9 g, 8 mM) was
dissolved in tetrahydrofuran (120 mL), trisopropylborate (3.1 g, 17
mM) was added and the mixture was cooled to -78.degree. C. At this
low temperature n-butyllithium (7.8 mL, 1.6N) was added drop by
drop with stirring. The mixture was stirred for 45 min at
-78.degree. C., for another 45 min at -50.degree. C. and for 15 min
at 0.degree. C. Acetic acid (4.4 mL, 50%) was added slowly with
stirring (0-5.degree. C.), followed by hydrogen peroxide (1.3 mL,
35%). Stirring continued with cooling for another 45 min and for 1
h at room temperature. The mixture was partitioned between water
and diethylether, organic phases were pooled, washed with water,
sodium thiosulfate solution (5%), brine and dried with Na2SO4 to
yield after evaporation a light yellow oil (4.1 g). This residue
was purified by column chromatography (silica gel;
n-hexane/ethylacetate 1:1) to yield 0.93 g (28%) of the product as
a colorless oil. MS (ISP): 418.2 (M+NH4).sup.+.
[0945] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-methoxy-ben- zyl ester hydrochloride
[0946] A mixture of 5.03 mg (0.126 mmol) NaH (60% suspension in
mineral oil) and 33.6 mg (0.084 mmol)
(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester
1-(2,6-difluoro-3-hydroxy-benzyl)ester in 1 ml DMF was stirred for
30 min at room temperature under argon. 13.1 mg (0.092 mmol)
methyliodide was added and the mixture was stirred 30 min at room
temperature. After addition of 0.06 ml HCl (37%) the mixture was
purified with preparative HPLC eluting with an acetonitrile/water
gradient. The fractions containing the desired intermediate were
combined and evaporated to dryness. The residue was taken up in 1
ml dioxane and 0.125 ml HCl (37%) and stirred for 30 min at
60.degree. C. Evaporation of the mixture yielded 22 mg (75%) of the
title compound. MS (ISP): 315 (M+H).sup.+.
Example 208
[0947] (R)-2-Ethyl-piperazine-1-carboxylic acid
3-ethoxy-2,6-difluoro-benz- yl ester hydrochloride
[0948] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and ethyl bromide. MS
(ISP): 329 (M+H).sup.+.
Example 209
[0949] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-propoxy-ben- zyl ester hydrochloride
[0950] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and propyl bromide. MS
(ISP): 343 (M+H).sup.+.
Example 210
[0951] (R)-2-Ethyl-piperazine-1-carboxylic acid
3-butoxy-2,6-difluoro-benz- yl ester hydrochloride
[0952] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and butyl bromide. MS
(ISP): 357 (M+H).sup.+.
Example 211
[0953] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-pentyloxy-b- enzyl ester hydrochloride
[0954] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and pentyl bromide. MS
(ISP): 371 (M+H).sup.+.
Example 212
[0955] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(3-methyl-b- utoxy)-benzyl ester hydrochloride
[0956] According to example 207 the title compound was synthesized
from (R)-2-Ethyl- piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and 3-methyl-butyl
bromide. MS (ISP): 371 (M+H).sup.+.
Example 213
[0957] (R)-2-Ethyl-piperazine-1-carboxylic acid
3-benzyloxy-2,6-difluoro-b- enzyl ester hydrochloride
[0958] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and benzyl bromide. MS
(ISP): 391 (M+H).sup.+.
Example 214
[0959] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(3-phenyl-p- ropoxy)-benzyl ester hydrochloride
[0960] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and 3-phenyl-propyl
bromide. MS (ISP): 419 (M+H).sup.+.
Example 215
[0961] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(4-methyl-b- enzyloxy)-benzyl ester
hydrochloride
[0962] According to example 207 the title compound was synthesized
from (R)-2-Ethyl- piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and 4-methyl-benzyl
bromide. MS (ISP): 405 (M+H).sup.+.
Example 216
[0963] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(3-methyl-b- enzyloxy)-benzyl ester
hydrochloride
[0964] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and 3-methyl-benzyl
bromide. MS (ISP): 405 (M+H).sup.+.
Example 217
[0965] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(2-methyl-b- enzyloxy)-benzyl ester
hydrochloride
[0966] According to example 207 the title compound was synthesized
from (R)-2-Ethyl- piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and 2-methyl-benzyl
bromide. MS (ISP): 205 (M+H).sup.+.
Example 218
[0967] (R)-2-Ethyl-piperazine-1-carboxylic acid
3-(3,3-dimethyl-butoxy)-2,- 6-difluoro-benzyl ester
hydrochloride
[0968] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and 3,3-dimethylbutyl
bromide. MS (ISP): 385 (M+H).sup.+.
Example 219
[0969] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(2-pyrrol-1- -yl-ethoxy)-benzyl ester
hydrochloride
[0970] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and
2-pyrrol-1-yl-ethyl bromide. MS (ISP): 394 (M+H).sup.+.
Example 220
[0971] (R)-2-Ethyl-piperazine-1-carboxylic acid
3-cyclopropylmethoxy-2,6-d- ifluoro-benzyl ester hydrochloride
[0972] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and
3-cyclopropylmethyl bromide. MS (ISP): 355 (M+H).sup.+.
Example 221
[0973] (R)-2-Ethyl-piperazine-1-carboxylic acid
3-cyclobutylmethoxy-2,6-di- fluoro-benzyl ester hydrochloride
[0974] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and 3-cyclobutylmethyl
bromide. MS (ISP): 369 (M+H).sup.+.
Example 222
[0975] (R)-2-Ethyl-piperazine-1-carboxylic acid
3-(2-cyclohexyl-ethoxy)-2,- 6-difluoro-benzyl ester
hydrochloride
[0976] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and 2-cyclohexyl-ethyl
bromide. MS (ISP): 411 (M+H).sup.+.
Example 223
[0977] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-prop-2-ynyl- oxy-benzyl ester hydrochloride
[0978] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and prop-2-ynyl
bromide. MS (ISP): 339 (M+H).sup.+.
Example 224
[0979] (R)-2-Ethyl-piperazine-1-carboxylic acid
3-allyloxy-2,6-difluoro-be- nzyl ester hydrochloride
[0980] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and allyl bromide. MS
(ISP): 341 (M+H).sup.+.
Example 225
[0981] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(2-methoxy-- ethoxy)-benzyl ester hydrochloride
[0982] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and 2-methoxy-ethyl
bromide. MS (ISP): 359 (M+H).sup.+.
Example 226
[0983] (R)-2-Ethyl-piperazine-1-carboxylic acid
3-(2-ethoxy-ethoxy)-2,6-di- fluoro-benzyl ester hydrochloride
[0984] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and 2-ethoxy-ethyl
bromide. MS (ISP): 373 (M+H).sup.+.
Example 227
[0985] (R)-2-Ethyl-piperazine-1-carboxylic acid
2,6-difluoro-3-(3-phenoxy-- propoxy)-benzyl ester hydrochloride
[0986] According to example 207 the title compound was synthesized
from (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2,6-difluoro-3-hydroxy-benzyl)ester and 3-phenoxy-propyl
bromide. MS (ISP): 435 (M+H).sup.+.
Example 228
[0987] (R)-2-Ethyl-piperazine-1-carboxylic
1-[2-fluoro-5-(3-methoxy-propox- y)-benzyl]ester
[0988] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-[2-fluoro-5-(3-methoxy-propoxy)-benzyl]ester
[0989] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(2-fluoro-5-hydroxy-benzyl)ester and toluene-4-sulfonic acid
3-methoxy-propyl ester according to the procedure described in
Example 187 to give the product as a colorless oil (342 mg; 94%);
MS (ISP): 472.4 (M+NH4).sup.+.
[0990] (R)-2-Ethyl-piperazine-1-carboxylic
1-[2-fluoro-5-(3-methoxy-propox- y)-benzyl]ester
[0991] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-[2-fluoro-5-(3-methoxy-propoxy)-benzyl]este- r according to the
procedure described in Example 187 to give the product as a
colorless oil (154 mg; 64%); MS (ISP): 355.4 (M+H).sup.+.
Example 229
[0992] (R)-2-Ethyl-piperazine-1-carboxylic acid
1-[2,6-difluoro-3-(3-metho- xy-propoxy)-benzyl]ester
[0993] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-[2,6-difluoro-3-(3-methoxy-propoxy)-benzyl]ester
[0994] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(2,6-difluoro-3-hydroxy-benzyl)ester and toluene-4-sulfonic acid
3-methoxy-propyl ester according to the procedure described in
Example 207 to give the product as a colorless oil (117 mg; 97%);
MS (ISP): 490.4 (M+NH4).sup.+.
[0995] (R)-2-Ethyl-piperazine-1-carboxylic acid
1-[2,6-difluoro-3-(3-metho- xy-propoxy)-benzyl]ester
[0996] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-[2,6-difluoro-3-(3-methoxy-propoxy)-benzyl]- ester according to
the procedure described in Example 207 to give the product as a
colorless oil (44 mg; 56%); MS (ISP): 373.4 (M+H).sup.+.
Example 230
[0997] (R)-2-Ethyl-piperazine-1-carboxylic acid
4-cyclopropylmethoxy-2-chl- oro-6-fluoro-benzyl ester
[0998] 3-Chloro-5-fluoro-4-hydroxymethyl-phenol
[0999] This compound was prepared from 3-chloro-5-fluoro-phenol and
formaldehyde according to the procedure described in Example 179 to
give the product as a colorless solid (26.4 g, 48%); m.p.:
125-127.degree. C.; MS (EI): 176.1 (M).sup.+.
[1000] 2-Chloro-4-cyclopropylmethoxy-6-fluoro-benzylalcohol
[1001] This compound was prepared from
3-Chloro-5-fluoro-4-hydroxymethyl-p- henol and
cyclopropylmethylbromide according to the procedure described in
Example 179 to give the product as a yellowish oil (305 mg, 77%);
MS (EI): 230.1 (M).sup.+.
[1002] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-chloro-4-cyclopropylmethoxy-6-fluoro-benzyl)ester
[1003] This compound was prepared from
2-Chloro-4-cyclopropylmethoxy-6-flu- oro-benzylalcohol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (580 mg; 95%); MS (ISP):
488.4 (M+NH4).sup.+.
[1004] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-4-cyclopropylmeth- oxy-6-fluoro-benzyl ester
[1005] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(2-chloro-4-cyclopropylmethoxy-6-fluoro-ben- zyl)ester according
to the procedure described in Example 179 to give the product as a
colorless oil (284 mg, 63%); MS (ISP): 371.3 (M+H).sup.+.
Example 231
[1006] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-propox- y-benzyl ester
[1007] 2-Chloro-6-fluoro-4-propoxy-benzylalcohol
[1008] This compound was prepared from
3-Chloro-5-fluoro-4-hydroxymethyl-p- henol and propylbromide
according to the procedure described in Example 179 to give the
product as a yellowish oil (259 mg, 69%); MS (EI): 218.1
(M).sup.+.
[1009] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-chloro-6-fluoro-4-propoxy-benzyl)ester
[1010] This compound was prepared from
2-chloro-6-fluoro-4-propoxy-benzyla- lcohol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (499 mg; 93%); MS (ISP):
476.3 (M+NH4).sup.+.
[1011] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-propox- y-benzyl ester
[1012] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(2-chloro-6-fluoro-4-propoxy-benzyl)ester according to the
procedure described in Example 179 to give the product as a
colorless oil (262 mg, 68%); MS (ISP): 359.3 (M+H).sup.+.
Example 232
[1013] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-ethoxy- -benzyl ester
[1014] 2-Chloro-6-fluoro-4-ethoxy-benzylalcohol
[1015] This compound was prepared from
3-chloro-5-fluoro-4-hydroxymethyl-p- henol and ethylbromide
according to the procedure described in Example 179 to give the
product as a yellowish oil (209 mg, 60%); MS (EI): 204.1
(M).sup.+.
[1016] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-chloro-6-fluoro-4-ethoxy-benzyl)ester
[1017] This compound was prepared from
2-chloro-6-fluoro-4-ethoxy-benzylal- cohol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (418 mg; 94%); MS (ISP):
462.4 (M+NH4).sup.+.
[1018] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-ethoxy- -benzyl ester
[1019] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(2-chloro-6-fluoro-4-ethoxy-benzyl)ester according to the
procedure described in Example 179 to give the product as a
colorless oil (205 mg, 64%); MS (ISP): 345.4 (M+H).sup.+.
Example 233
[1020] (R)-2-Ethyl-piperazine-1-carboxylic acid
4-butoxy-2-chloro-6-fluoro- -benzyl ester
[1021] 4-Butoxy-2-chloro-6-fluoro-benzylalcohol
[1022] This compound was prepared from
3-chloro-5-fluoro-4-hydroxymethyl-p- henol and butylbromide
according to the procedure described in Example 179 to give the
product as a yellowish oil (277 mg, 70%); MS (EI): 232.1
(M).sup.+.
[1023] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(4-butoxy-2-chloro-6-fluoro-benzyl)ester
[1024] This compound was prepared from
4-butoxy-2-chloro-6-fluoro-benzylal- cohol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (505 mg; 90%); MS (ISP):
490.4 (M+NH4).sup.+.
[1025] (R)-2-Ethyl-piperazine-1-carboxylic acid
4-butoxy-2-chloro-6-fluoro- -benzyl ester
[1026] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(4-butoxy-2-chloro-6-fluoro-benzyl)ester according to the
procedure described in Example 179 to give the product as a
colorless oil (286 mg; 73%); MS (ISP): 373.4 (M+H).sup.+.
Example 234
[1027] (R)-2-Ethyl-piperazine-1-carboxylic acid
4-allyloxy-2-chloro-6-fluo- ro-benzyl ester
[1028] 4-Allyloxy-2-chloro-6-fluoro-benzylalcohol
[1029] This compound was prepared from
3-chloro-5-fluoro-4-hydroxymethyl-p- henol and allylbromide
according to the procedure described in Example 179 to give the
product as a yellowish oil (221 mg, 60%); MS (EI): 216.1
(M).sup.+.
[1030] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(4-allyloxy-2-chloro-6-fluoro-benzyl)ester
[1031] This compound was prepared from
4-allyloxy-2-chloro-6-fluoro-benzyl- alcohol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (405 mg; 87%); MS (ISP):
474.4 (M+NH4).sup.+.
[1032] (R)-2-Ethyl-piperazine-1-carboxylic acid
4-allyloxy-2-chloro-6-fluo- ro-benzyl ester
[1033] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(4-allyloxy-2-chloro-6-fluoro-benzyl)ester according to the
procedure described in Example 179 to give the product as a
colorless oil (242 mg; 78%); MS (ISP): 357.3 (M+H).sup.+.
Example 235
[1034] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-prop-2- -ynyloxy-benzyl ester
[1035] 2-Chloro-6-fluoro-4-prop-2-ynyloxy-benzylalcohol
[1036] This compound was prepared from
3-chloro-5-fluoro-4-hydroxymethyl-p- henol and propargylbromide
according to the procedure described in Example 179 to give the
product as a yellowish oil (212 mg, 58%); MS (EI): 214.1
(M).sup.+.
[1037] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-chloro-6-fluoro-4-prop-2-ynyloxy-benzyl)ester
[1038] This compound was prepared from
2-chloro-6-fluoro-4-prop-2-ynyloxy-- benzylalcohol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (357 mg; 80%); MS (ISP):
472.3 (M+NH4).sup.+.
[1039] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-prop-2- -ynyloxy-benzyl ester
[1040] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(2-chloro-6-fluoro-4-prop-2-ynyloxy-benzyl)- ester according to
the procedure described in Example 179 to give the product as a
colorless oil (203 mg; 74%); MS (ISP): 355.3 (M+H).sup.+.
Example 236
[1041] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-(2-met- hoxy-ethoxy)-benzyl ester
[1042] 2-Chloro-6-fluoro-4-(2-methoxy-ethoxy)-benzylalcohol
[1043] This compound was prepared from
3-chloro-5-fluoro-4-hydroxymethyl-p- henol and (2-bromoethyl)methyl
ether according to the procedure described in Example 179 to give
the product as a yellowish oil (209 mg, 52%); MS (EI): 234.1
(M).sup.+.
[1044] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-chloro-6-fluoro-4-(2-methoxy-ethoxy)-benzyl)ester
[1045] This compound was prepared from
2-chloro-6-fluoro-4-(2-methoxy-etho- xy)-benzylalcohol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (370 mg; 89%); MS (ISP):
492.3 (M+NH4).sup.+.
[1046] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-(2-met- hoxy-ethoxy)-benzyl ester
[1047] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(2-chloro-6-fluoro-4-(2-methoxy-ethoxy)-ben- zyl)ester according
to the procedure described in Example 179 to give the product as a
colorless oil (214 mg; 75%); MS (ISP): 375.4 (M+H).sup.+.
Example 237
[1048] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-(3-met- hoxy-propoxy)-benzyl ester
[1049] 2-Chloro-6-fluoro-4-(3-methoxy-propoxy)-benzylalcohol
[1050] This compound was prepared from
3-chloro-5-fluoro-4-hydroxymethyl-p- henol and toluene-4-sulfonic
acid 3-methoxy-propyl ester according to the procedure described in
Example 179 to give the product as a yellowish oil (382 mg, 90%);
MS (EI): 248.1 (M).sup.+.
[1051] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester 1-(2-chloro-6-fluoro-4-(3-methoxy-propoxy)-benzyl)ester
[1052] This compound was prepared from
2-chloro-6-fluoro-4-(3-methoxy-prop- oxy)-benzylalcohol and
(R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxyli- c acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (576 mg; 77%); MS (ISP):
506.4 (M+NH4).sup.+.
[1053] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-(3-met- hoxy-propoxy)-benzyl ester
[1054] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(2-chloro-6-fluoro-4-(3-methoxy-propoxy)-be- nzyl)ester according
to the procedure described in Example 179 to give the product as a
colorless oil (254 mg; 56%); MS (ISP): 389.3 (M+H).sup.+.
Example 238
[1055] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-(2-met- hyl-thiazol-4-ylmethoxy)-benzyl
ester
[1056]
2-Chloro-6-fluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzylalcohol
[1057] This compound was prepared from
3-chloro-5-fluoro-4-hydroxymethyl-p- henol and
4-chloromethyl-2-thiazol according to the procedure described in
Example 179 to give the product as a yellowish oil (421 mg, 86%);
MS (EI): 287.0 (M).sup.+.
[1058] (R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl
ester
1-(2-chloro-6-fluoro-4-(2-methyl-thiazol-4-ylmethoxy)-benzyl)ester
[1059] This compound was prepared from
2-chloro-6-fluoro-4-(2-methyl-thiaz- ol-4-ylmethoxy)-benzylalcohol
and (R)-4-chlorocarbonyl-3-ethyl-piperazine-- 1-carboxylic acid
tert-butyl ester according to the procedure described in Example
179 to give the product as a colorless oil (582 mg; 75%); MS (ISP):
528.2 (M+H).sup.+.
[1060] (R)-2-Ethyl-piperazine-1-carboxylic acid
2-chloro-6-fluoro-4-(2-met- hyl-thiazol-4-ylmethoxy)-benzyl
ester
[1061] This compound was prepared from
(R)-2-ethyl-piperazine-1,4-dicarbox- ylic acid 4-tert-butyl ester
1-(2-chloro-6-fluoro-4-(2-methyl-thiazol-4-yl-
methoxy)-benzyl)ester according to the procedure described in
Example 179 to give the product as a colorless oil (413 mg; 89%);
MS (ISP): 428.5 (M+H).sup.+.
EXAMPLE A
[1062] Tablets containing the following ingredients can be
manufactured in a conventional manner:
3 Ingredients Per tablet Compound of formula I 10.0-300.0 mg
Lactose 125.0 mg Maize starch 75.0 mg Talc 4.0 mg Magnesium
stearate 1.0 mg
EXAMPLE B
[1063] Capsules containing the following ingredients can be
manufactured in a conventional manner:
4 Ingredients Per capsule Compound of formula I 100.0 mg Lactose
150.0 mg Maize starch 20.0 mg Talc 5.0 mg
EXAMPLE C
[1064] Injection solutions can have the following composition:
5 Compound of formula I 10.0 mg Sodium chloride q.s mg Water for
injection solutions ad 2.0 ml
* * * * *