U.S. patent application number 12/566928 was filed with the patent office on 2010-01-28 for macrocyclic lactams and pharmaceutical use thereof.
This patent application is currently assigned to NOVARTIS AG. Invention is credited to Yves AUBERSON, Claudia Betschart, Ralf Glatthar, Kurt Laumen, Rainer MacHauer, Marina Tintelnot-Blomley, Thomas J. Troxler, Siem Jacob Veenstra.
Application Number | 20100022500 12/566928 |
Document ID | / |
Family ID | 29725994 |
Filed Date | 2010-01-28 |
United States Patent
Application |
20100022500 |
Kind Code |
A1 |
AUBERSON; Yves ; et
al. |
January 28, 2010 |
Macrocyclic Lactams and Pharmaceutical Use Thereof
Abstract
The present invention relates to novel macrocyclic compounds of
the formula ##STR00001## wherein R.sub.1, R.sub.2, R.sub.3, U, V,
W, X, Y, Z and n are as defined in the specification, the number of
ring atoms included in the macrocyclic ring being 14, 15, 16 or 17,
in free base form or in acid addition salt form, to their
preparation, to their use as pharmaceuticals and to pharmaceutical
compositions comprising them.
Inventors: |
AUBERSON; Yves; (Allschwil,
CH) ; Betschart; Claudia; (Basel, CH) ;
Glatthar; Ralf; (Bad Sackingen, DE) ; Laumen;
Kurt; (March, DE) ; MacHauer; Rainer;
(Freiburg, DE) ; Tintelnot-Blomley; Marina;
(Maulburg, DE) ; Troxler; Thomas J.; (Wahlen,
CH) ; Veenstra; Siem Jacob; (Lorrach, DE) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
NOVARTIS AG
|
Family ID: |
29725994 |
Appl. No.: |
12/566928 |
Filed: |
September 25, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10577260 |
Jun 2, 2006 |
7612055 |
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PCT/EP2004/012497 |
Nov 4, 2004 |
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12566928 |
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Current U.S.
Class: |
514/183 ;
540/454; 540/460 |
Current CPC
Class: |
C07D 273/00 20130101;
A61P 43/00 20180101; C07D 255/00 20130101; C07D 245/02 20130101;
A61P 9/00 20180101; C07D 471/08 20130101; C07D 281/00 20130101;
A61P 25/28 20180101; C07D 513/08 20130101; A61P 25/00 20180101;
A61P 35/04 20180101; A61P 35/00 20180101 |
Class at
Publication: |
514/183 ;
540/460; 540/454 |
International
Class: |
A61K 31/395 20060101
A61K031/395; C07D 245/02 20060101 C07D245/02; C07D 291/02 20060101
C07D291/02; A61P 25/00 20060101 A61P025/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 5, 2003 |
GB |
0325830.8 |
Claims
1. A compound of the formula ##STR00011## in which R.sub.1 is
CH(R.sub.e)C(.dbd.O)N(R.sub.a)R.sub.b or
(CH.sub.2).sub.kN(R.sub.c)R.sub.d, wherein k is 0, 1 or 2; R.sub.a
and R.sub.b, independently, are hydrogen or an optionally
substituted (C.sub.1-8)alkyl, (C.sub.3-7)cycloalkyl,
(C.sub.3-7)cycloalkyl(C.sub.1-4)alkyl, aryl, aryl(C.sub.1-4)alkyl,
heteroaryl or heteroaryl(C.sub.1-4)alkyl group, R.sub.c and
R.sub.d, independently, are hydrogen or an optionally substituted
(C.sub.1-8)alkyl, (C.sub.3-7)cycloalkyl,
(C.sub.3-7)cycloalkyl(C.sub.1-4)alkyl, aryl, aryl(C.sub.1-4)alkyl,
heteroaryl, hetero-aryl(C.sub.1-4)alkyl, chroman-4-yl,
isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl,
1,1-dioxo-1lambda*6*-thiochroman-4-yl,
2,2-dioxo-2lambda*6*-isothiochroman-4-yl,
1,2,3,4-tetrahydro-quinolin-4-yl,
1,2,3,4-tetrahydro-isoquinolin-4-yl,
1,2,3,4-tetrahydro-naphthalen-1-yl,
1,1-dioxo-1,2,3,4-tetrahydro-1lambda*6*-benzo[e][1,2]thiazin-4-yl,
2,2-dioxo-1,2,3,4-tetrahydro-2lambda*6*-benzo[c][1,2]thiazin-4-yl,
1,1-dioxo-3,4-dihydro-1H-1 lambda*6*-benzo[c][1,2]oxathiin-4-yl,
2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1,2]oxathiin-4-yl,
2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl or
1,3,4,5-tetrahydro-benzo[c]oxepin-5-yl group, or R.sub.a and
R.sub.b, or R.sub.c and R.sub.d, together with the nitrogen to
which they are attached, form an optionally substituted
pyrrolidinyl, 1-piperidinyl, 4-morpholinyl or piperazinyl group;
and R.sub.e is optionally substituted (C.sub.1-8)alkyl,
(C.sub.1-4)alkoxy(C.sub.1-4)alkyl, (C.sub.3-7)cycloalkyl or
(C.sub.3-7)cycloalkyl(C.sub.1-4)alkyl; R.sub.2 is hydrogen or
(C.sub.1-4)alkyl; R.sub.3 is hydrogen, (C.sub.1-6)alkyl or an
optionally substituted (C.sub.1-6)alkylOC(.dbd.O)NH,
(C.sub.3-7)cyclo-alkylOC(.dbd.O)NH,
(C.sub.3-7)cycloalkyl(C.sub.1-4)alkylOC(.dbd.O)NH,
aryl(C.sub.1-4)alkylOC(.dbd.O)NH,
heteroaryl(C.sub.1-4)alkylOC(.dbd.O)NH,
(C.sub.1-4)alkylC(.dbd.O)NH, (C.sub.3-7)cycloalkylC(.dbd.O)NH,
arylC(.dbd.O)NH, aryl(C.sub.1-4)alkylC(.dbd.O)NH,
heteroarylC(.dbd.O)NH or heteroaryl(C.sub.1-4)alkylC(.dbd.O)NH
group; U is a bond, CF.sub.2, CF.sub.2CF.sub.2, CHF, CHFCHF,
cycloprop-1,2-ylene, (C.sub.1-3)alkylenoxy, (C.sub.1-8)alkylene,
NR.sub.g or an aromatic or heteroaromatic ring, which ring is
optionally substituted with halogen, (C.sub.1-4)alkoxy, hydroxy or
(C.sub.1-4)alkyl, whereby Z and V are in ortho- or meta-position to
each other, wherein R.sub.g is hydrogen, (C.sub.1-8)alkyl or
(C.sub.3-7)cycloalkyl; V is CH.dbd.CH, cycloprop-1,2-ylene,
CH.sub.2CH(OH), CH(OH)CH.sub.2 or CR.sub.hR.sub.hCR.sub.hR.sub.h,
wherein each R.sub.h, independently, is hydrogen, fluorine or
(C.sub.1-4)alkyl; W is (C.sub.1-6)alkylene, O, S, S(.dbd.O).sub.2,
C(.dbd.O), C(.dbd.O)O, OC(.dbd.O), N(R.sub.f)C(.dbd.O),
C(.dbd.O)NR.sub.f or NR.sub.f, wherein R.sub.f is hydrogen or
(C.sub.1-4)alkyl; X is an optionally substituted
(C.sub.1-4)alkanylylidene, (C.sub.1-4)alkylene,
(C.sub.3-7)cycloalkylene, piperidin-diyl, pyrrolidin-diyl,
benzothiazole-4,6-diyl, benzoxazole-4,6-diyl,
1H-benzotriazole-4,6-diyl, imidazo[1,2-a]pyridine-6,8-diyl,
benzo[1,2,5]oxadiazole-4,6-diyl, benzo[1,2,5]thiadiazole-4,6-diyl,
1H-indole-5,7-diyl, 1H-indole-4,6-diyl, 1H-benzimidazole-4,6-diyl
or 1H-indazole-1,6-diyl group or an optionally substituted aromatic
or heteroaromatic ring, whereby Y and C(.dbd.O)NR.sub.2 are in
meta-position to each other; Y is a bond, O, S(.dbd.O).sub.2,
S(.dbd.O).sub.2NR.sub.g, N(R.sub.g)S(.dbd.O).sub.2, NR.sub.g,
C(R.sub.g)OH, C(.dbd.O)NR.sub.g, N(R.sub.g)C(.dbd.O),
C(.dbd.O)N(R.sub.g)O or ON(R.sub.g)C(.dbd.O), wherein R.sub.g is
hydrogen, (C.sub.1-8)alkyl or (C.sub.3-7)cycloalkyl; Z is O,
CH.sub.2, CF.sub.2, CHF, cycloprop-1,2-ylene or a bond; and n is 0
to 5, the number of ring atoms included in the macrocyclic ring
being 14, 15, 16 or 17, in free base form or in acid addition salt
form.
2. A process for the preparation of a compound as defined in claim
1 of the formula I, in free base form or in acid addition salt
form, comprising the steps of cyclisation by metathesis of a
compound of the formula ##STR00012## in which R.sub.1, R.sub.2,
R.sub.3, U, W, X, Y, Z and n are as defined for the formula I, in
the presence of a catalyst, for instance a ruthenium, tungsten or
molybdenum complex, optionally followed by reduction, oxidation or
functionalisation of the resulting carbon-carbon-double bond, and
of recovering the so obtainable compound of the formula I in free
base form or in acid addition salt form.
3. A compound according to claim 1, in free base form or in
pharmaceutically acceptable acid addition salt form, for use as a
pharmaceutical.
4. A compound according to claim 1, in free base form or in
pharmaceutically acceptable acid addition salt form, for use in the
treatment of neurological or vascular disorders related to
beta-amyloid generation and/or aggregation.
5. A pharmaceutical composition comprising a compound as claimed in
claim 1, in free base form or in pharmaceutically acceptable acid
addition salt form, as active ingredient and a pharmaceutical
carrier or diluent.
6. The use of a compound as claimed in claim 1, in free base form
or in pharmaceutically acceptable acid addition salt form, as a
pharmaceutical for the treatment of neurological or vascular
disorders related to beta-amyloid generation and/or
aggregation.
7. The use of a compound as claimed in claim 1, in free base form
or in pharmaceutically acceptable acid addition salt form, for the
manufacture of a medicament for the treatment of neurological or
vascular disorders related to beta-amyloid generation and/or
aggregation.
8. A method for the treatment of neurological or vascular disorders
related to beta-amyloid generation and/or aggregation in a subject
in need of such treatment, which comprises administering to such
subject a therapeutically effective amount of a compound as claimed
in claim 1, in free base form or in pharmaceutically acceptable
acid addition salt form.
9. A combination comprising a therapeutically effective amount of a
compound as claimed in claim 1, in free base form or in
pharmaceutically acceptable acid addition salt form, and a second
drug substance, for simultaneous or sequential administration.
Description
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
[0001] This application is a Divisional of U.S. application Ser.
No. 10/577,260, filed Jun. 2, 2006, which is the National Stage of
International Application No. PCT/EP2004/012497, filed Nov. 4,
2004, which is based upon and claims the benefit of priority from
prior United Kingdom Patent Application No. 0325830.8, filed Nov.
5, 2003, the entire contents of all of which are incorporated
herein by reference in their entirety.
[0002] The present invention relates to novel macrocyclic
compounds, to their preparation, to their use as pharmaceuticals
and to pharmaceutical compositions comprising them.
[0003] More particularly the invention relates to compounds of the
formula
##STR00002##
in which [0004] R.sub.1 is CH(R.sub.e)C(.dbd.O)N(R.sub.a)R.sub.b or
(CH.sub.2).sub.kN(R.sub.c)R.sub.d, wherein [0005] k is 0, 1 or 2;
[0006] R.sub.a and R.sub.b, independently, are hydrogen or an
optionally substituted (C.sub.1-8)alkyl, (C.sub.3-7)cycloalkyl,
(C.sub.3-7)cycloalkyl(C.sub.1-4)alkyl, aryl, aryl(C.sub.1-14)alkyl,
heteroaryl or heteroaryl(C.sub.1-4)alkyl group, [0007] R.sub.c and
R.sub.d, independently, are hydrogen or an optionally substituted
(C.sub.1-8)alkyl, (C.sub.3-7)cycloalkyl,
(C.sub.3-7)cycloalkyl(C.sub.1-4)alkyl, aryl, aryl(C.sub.1-4)alkyl,
heteroaryl, hetero-aryl(C.sub.1-4)alkyl, chroman-4-yl,
isochroman-4-yl, thiochroman-4-yl, isothiochroman-4-yl,
1,1-dioxo-1lambda*6*-thiochroman-4-yl,
2,2-dioxo-2lambda*6*-isothiochroman-4-yl,
1,2,3,4-tetrahydro-quinolin-4-yl,
1,2,3,4-tetrahydro-isoquinolin-4-yl,
1,2,3,4-tetrahydro-naphthalen-1-yl, 1,1-dioxo-1,2,3,4-tetrahydro-1
lambda*6*-benzo[e][1,2]thiazin-4-yl,
2,2-dioxo-1,2,3,4-tetrahydro-2lambda*6*-benzo[c][1,2]thiazin-4-yl,
1,1-dioxo-3,4-dihydro-1H-1 lambda*6*-benzo[c][1,2]oxathiin-4-yl,
2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1,2]oxathiin-4-yl,
2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl or
1,3,4,5-tetrahydro-benzo[c]oxepin-5-yl group, or [0008] R.sub.a and
R.sub.b, or R.sub.c and R.sub.d, together with the nitrogen to
which they are attached, form an optionally substituted
pyrrolidinyl, 1-piperidinyl, 4-morpholinyl or piperazinyl group;
and [0009] R.sub.e is optionally substituted (C.sub.1-8)alkyl,
(C.sub.1-4)alkoxy(C.sub.1-4)alkyl, (C.sub.3-7)cycloalkyl or
(C.sub.3-7)cycloalkyl(C.sub.1-4)alkyl; [0010] R.sub.2 is hydrogen
or (C.sub.1-4)alkyl; [0011] R.sub.3 is hydrogen, (C.sub.1-6)alkyl
or an optionally substituted (C.sub.1-6)alkylOC(.dbd.O)NH,
(C.sub.3-7)cyclo-alkylOC(.dbd.O)NH,
(C.sub.3-7)cycloalkyl(C.sub.1-4)alkylOC(.dbd.O)NH,
aryl(C.sub.1-4)alkylOC(.dbd.O)NH,
heteroaryl(C.sub.1-4)alkylOC(.dbd.O)NH,
(C.sub.1-4)alkylC(.dbd.O)NH, (C.sub.3-7)cycloalkylC(.dbd.O)NH,
arylC(.dbd.O)NH, aryl(C.sub.1-4)alkylC(.dbd.O)NH,
heteroarylC(.dbd.O)NH or heteroaryl(C.sub.1-4)alkylC(.dbd.O)NH
group; [0012] U is a bond, CF.sub.2, CF.sub.2CF.sub.2, CHF, CHFCHF,
cycloprop-1,2-ylene, (C.sub.1-3)alkylenoxy, (C.sub.1-8)alkylene,
NR.sub.g or an aromatic or heteroaromatic ring, which ring is
optionally substituted with halogen, (C.sub.1-4)alkoxy, hydroxy or
(C.sub.1-4)alkyl, whereby Z and V are in ortho- or meta-position to
each other, wherein R.sub.g is hydrogen, (C.sub.1-8)alkyl or
(C.sub.3-7)cycloalkyl; [0013] V is CH.dbd.CH, cycloprop-1,2-ylene,
CH.sub.2CH(OH), CH(OH)CH.sub.2 or CR.sub.hR.sub.hCR.sub.hR.sub.h,
wherein each R.sub.h, independently, is hydrogen, fluorine or
(C.sub.1-4)alkyl; [0014] W is (C.sub.1-6)alkylene, O, S,
S(.dbd.O).sub.2, C(.dbd.O), C(.dbd.O)O, OC(.dbd.O),
N(R.sub.f)C(.dbd.O), C(.dbd.O)NR.sub.f or NR.sub.f, wherein [0015]
R.sub.f is hydrogen or (C.sub.1-4)alkyl; [0016] X is an optionally
substituted (C.sub.1-4)alkanylylidene, (C.sub.1-4)alkylene,
(C.sub.3-7)cycloalkylene, piperidin-diyl, pyrrolidin-diyl,
benzothiazole-4,6-diyl, benzoxazole-4,6-diyl,
1H-benzotriazole-4,6-diyl, imidazo[1,2-a]pyridine-6,8-diyl,
benzo[1,2,5]oxadiazole-4,6-diyl, benzo[1,2,5]thiadiazole-4,6-diyl,
1H-indole-5,7-diyl, 1H-indole-4,6-diyl, 1H-benzimidazole-4,6-diyl
or 1H-indazole-1,6-diyl group or an optionally substituted aromatic
or heteroaromatic ring, whereby Y and C(.dbd.O)NR.sub.2 are in
meta-position to each other; [0017] Y is a bond, O,
S(.dbd.O).sub.2, S(.dbd.O).sub.2NR.sub.g,
N(R.sub.g)S(.dbd.O).sub.2, NR.sub.g, C(R.sub.g)OH,
C(.dbd.O)NR.sub.g, N(R.sub.g)C(.dbd.O), C(.dbd.O)N(R.sub.g)O or
ON(R.sub.g)C(.dbd.O), wherein [0018] R.sub.g is hydrogen,
(C.sub.1-8)alkyl or (C.sub.3-7)cycloalkyl; [0019] Z is O, CH.sub.2,
CF.sub.2, CHF, cycloprop-1,2-ylene or a bond; and [0020] n is 0 to
5, the number of ring atoms included in the macrocyclic ring being
14, 15, 16 or 17, in free base form or in acid addition salt
form.
[0021] On account of the asymmetrical carbon atoms present in the
compounds of the formula I and their salts, the compounds may exist
in optically active form or in the form of mixtures of optical
isomers, e.g. in the form of racemic mixtures. All optical isomers
and their mixtures, including the racemic mixtures, are part of the
present invention.
[0022] Halogen denotes fluorine, bromine, chlorine or iodine.
[0023] Optional substituents on alkyl, alkoxy or cycloalkyl groups
or moieties, or, when R.sub.a and R.sub.b, or R.sub.c and R.sub.d,
together with the nitrogen to which they are attached form a
substituted pyrrolidinyl, 1-piperidinyl, 4-morpholinyl or
piperazinyl group, on the last mentioned substituted groups, may be
one to three groups independently selected from hydroxy,
hydroxy(C.sub.1-4)alkyl, (C.sub.1-4)alkoxy,
(C.sub.1-4)alkoxy(C.sub.1-4)alkyl,
(C.sub.1-4)alkoxy(C.sub.1-4)alkoxy, (C.sub.1-4)alkylsulfanyl,
(C.sub.1-4)alkoxycarbonyl, (C.sub.1-4)alkylcarbonyloxy,
(C.sub.1-4)alkylcarbonyl, (C.sub.1-4)alkylsulfonyl, cyano, oxo and
(C.sub.3-7)cycloalkyl.
[0024] Optional substituents on chroman-4-yl, isochroman-4-yl,
thiochroman-4-yl, isothiochroman-4-yl,
1,1-dioxo-1lambda*6*-thiochroman-4-yl,
2,2-dioxo-2lambda*6*-isothiochroman-4-yl,
1,2,3,4-tetrahydro-quinolin-4-yl,
1,2,3,4-tetrahydro-isoquinolin-4-yl,
1,2,3,4-tetrahydro-naphthalen-1-yl,
1,1-dioxo-1,2,3,4-tetrahydro-1lambda*6*-benzo[e][1,2]thiazin-4-yl,
2,2-dioxo-1,2,3,4-tetrahydro-2lambda*6*-benzo[c][1,2]thiazin-4-yl,
1,1-dioxo-3,4-dihydro-1H-1lambda*6*-benzo[c][1,2]oxathiin-4-yl,
2,2-dioxo-3,4-dihydro-2H-2lambda*6*-benzo[e][1,2]-oxathiin-4-yl,
2,3,4,5-tetrahydro-benzo[b]oxepin-5-yl or
1,3,4,5-tetrahydro-benzo[c]oxepin-5-yl, benzothiazole-4,6-diyl,
benzoxazole-4,6-diyl, 1H-benzotriazole-4,6-diyl,
imidazo-[1,2-a]pyridine-6,8-diyl, benzo[1,2,5]oxadiazole-4,6-diyl,
benzo[1,2,5]thiadiazole-4,6-diyl, 1H-indole-5,7-diyl,
1H-indole-4,6-diyl, 1H-benzimidazole-4,6-diyl,
1H-indazole-1,6-diyl, aryl or heteroaryl rings or moieties are one
to four, especially one to three, groups independently selected
from hydroxy, (C.sub.1-8)alkyl, (C.sub.1-6)alkoxy,
S(.dbd.O).sub.2(C.sub.1-4)alkyl, (C.sub.3-7)cycloalkyl,
(C.sub.3-7)cycloalkyl(C.sub.1-4)alkyl, cyano, nitro,
trifluoromethyl, halogen, aryl, heteroaryl and optionally
substituted carbamoyl.
[0025] When R.sub.c, and/or R.sub.d is substituted aryl or
heteroaryl, optional substituents may further be one to three
groups selected from benzyloxy, phenoxy, S(.dbd.O).sub.2NH.sub.2,
N(H)S(.dbd.O).sub.2(C.sub.1-3)alkyl, carboxy,
(C.sub.1-4)alkoxycarbonyl, (C.sub.1-4)alkylcarbamoyl,
(C.sub.1-4)alkylsulfonyl, (C.sub.1-4)alkylcarbonyloxy,
(C.sub.1-4)alkylcarbonyl, hydroxy(C.sub.1-4)alkyl and optionally
substituted amino.
[0026] Optional substituents on alkanylylidene, alkylene,
alkylenoxy, cycloalkylene, piperidin-diyl or pyrrolidin-diyl groups
or moieties may be one to three groups independently selected from
hydroxy, hydroxy(C.sub.1-4)alkyl, (C.sub.1-4)alkoxy,
(C.sub.1-4)alkoxy(C.sub.1-4)alkyl,
(C.sub.1-4)alkoxy(C.sub.1-4)alkoxy, (C.sub.1-4)alkylsulfanyl,
(C.sub.1-4)alkoxycarbonyl, (C.sub.1-4)alkylcarbonyloxy,
(C.sub.1-4)alkylcarbonyl, (C.sub.1-4)alkylsulfonyl, cyano, oxo,
carboxy, carbamoyl and (C.sub.3-7)cycloalkyl.
[0027] Optional substituents on amino groups can be one or two
groups independently selected from (C.sub.1-4)alkyl,
(C.sub.1-4)alkoxy(C.sub.1-4)alkyl, (C.sub.1-4)alkoxycarbonyl,
aryl(C.sub.1-4)alkoxycarbonyl and
heteroaryl(C.sub.1-4)alkoxycarbonyl.
[0028] Optional substituents on carbamoyl can be one or two groups
selected from (C.sub.1-4)alkyl and
(C.sub.1-4)alkoxy(C.sub.1-4)alkyl.
[0029] Aryl is naphthyl or preferably phenyl.
[0030] Heteroaryl is an aromatic 5- or 6-membered ring, in which 1,
2 or 3 ring atoms are hetero atoms independently selected from O, N
and S, such as thiazolyl, oxazolyl or preferably pyridyl.
[0031] Any non-cyclic carbon containing group or moiety with more
than 1 carbon atom is straight-chain or branched.
[0032] Unless defined otherwise, carbon containing groups, moieties
or molecules contain 1 to 8, preferably 1 to 6, more preferably 1
to 4, most preferably 1 or 2, carbon atoms.
[0033] In preferred embodiments, the invention relates to a
compound of the formula I, in free base form or in acid addition
salt form, in which
[0034] (1) R.sub.1 is CH(R.sub.e)C(.dbd.O)N(R.sub.a)R.sub.b and
R.sub.a, R.sub.b and R.sub.e have one of the meanings defined
herein-before;
[0035] (2) R.sub.1 is CH(R.sub.e)C(.dbd.O)N(R.sub.a)R.sub.b,
R.sub.b and R.sub.e have one of the meanings defined hereinbefore
and R.sub.a is hydrogen;
[0036] (3) R.sub.1 is CH(R.sub.e)C(.dbd.O)N(R.sub.a)R.sub.b,
R.sub.a and R.sub.e have one of the meanings defined hereinbefore
and R.sub.b is (C.sub.1-8)alkyl, preferably (C.sub.1-5)alkyl, more
preferably n-butyl;
[0037] (4) R.sub.1 is CH(R.sub.e)C(.dbd.O)N(R.sub.a)R.sub.b,
R.sub.a and R.sub.b have one of the meanings defined hereinbefore
and R.sub.e is (C.sub.1-8)alkyl, preferably (C.sub.1-4)alkyl, more
preferably methyl;
[0038] (5) R.sub.1 is (CH.sub.2).sub.kN(R.sub.c)R.sub.d and
R.sub.c, R.sub.d and k have one of the meanings defined
hereinbefore;
[0039] (6) R.sub.1 is (CH.sub.2).sub.kN(R.sub.c)R.sub.d, R.sub.c,
and R.sub.d have one of the meanings defined hereinbefore and k is
0;
[0040] (7) R.sub.1 is (CH.sub.2).sub.kN(R.sub.c)R.sub.d, k and
R.sub.d have one of the meanings defined hereinbefore and R.sub.c
is hydrogen;
[0041] (8) R.sub.1 is (CH.sub.2).sub.kN(R.sub.c)R.sub.d, k and
R.sub.c have one of the meanings defined hereinbefore and R.sub.d
is an optionally substituted aryl(C.sub.1-4)alkyl,
heteroaryl(C.sub.1-4)alkyl or chroman-4-yl group, preferably an
optionally substituted phenyl(C.sub.1-4)alkyl,
pyridyl(C.sub.1-4)alkyl or chroman-4-yl group, more preferably an
optionally substituted phenyl(C.sub.1-2)alkyl,
pyridyl(C.sub.1-2)alkyl or chroman-4-yl group,
more preferably a phenyl(C.sub.1-2)alkyl, pyridyl(C.sub.1-2)alkyl
or chroman-4-yl group optionally substituted by 1 to 4
substituents, independently selected from the group, consisting of
(C.sub.1-8)alkyl, (C.sub.1-4)alkoxy, (C.sub.3-7)cycloalkyl and
halogen, preferably phenyl(C.sub.1-2)alkyl substituted by 1 or 2
substituents, independently selected from the group, consisting of
(C.sub.1-8)alkyl, (C.sub.1-4)alkoxy and (C.sub.3-7)cycloalkyl,
preferably 3-(C.sub.1-8)alkyl-benzyl, more preferably
3-isopropylbenzyl, preferably 3-(C.sub.1-4)alkoxybenzyl, more
preferably 3-methoxybenzyl, preferably
3-(C.sub.3-7)cycloalkylbenzyl, more preferably 3-cyclopropylbenzyl,
preferably 2-(3,4-di(C.sub.1-4)alkoxyphenyl)ethyl, more preferably
2-(3,4-dimethoxyphenyl)ethyl, preferably pyridyl(C.sub.1-2)alkyl
optionally monosubstituted by halogen or (C.sub.3-7)cycloalkyl,
preferably unsubstituted 2-(pyrid-4-yl)ethyl, preferably
5-halogenopyrid-3-ylmethyl, more preferably
5-bromopyrid-3-ylmethyl, preferably
5-(C.sub.3-7)cycloalkylpyrid-3-ylmethyl, more preferably
5-cyclopropylpyrid-3-ylmethyl, preferably
2-(C.sub.3-7)cycloalkylpyrid-4-ylmethyl, more preferably
2-cyclopropylpyrid-4-ylmethyl, preferably chroman-4-yl substituted
by 1 to 4, more preferably by 1 to 3, substituents, independently
selected from the group, consisting of (C.sub.1-8)alkyl, more
preferably of (C.sub.1-4)alkyl, preferably
2,2,6-tri(C.sub.1-4)alkylchroman-4-yl, more preferably
2,2-dimethyl-6-isopropyl-chroman-4-yl;
[0042] (9) R.sub.2 is hydrogen;
[0043] (10) R.sub.3 is hydrogen, (C.sub.1-6)alkyl or an optionally
substituted (C.sub.1-6)alkylOC(.dbd.O)NH,
(C.sub.1-4)alkylC(.dbd.O)NH or heteroarylC(.dbd.O)NH group,
preferably hydrogen, (C.sub.1-4)alkyl or an unsubstituted
(C.sub.1-6)alkylOC(.dbd.O)NH, (C.sub.1-4)alkylC(.dbd.O)NH or
pyridylC(.dbd.O)NH group, more preferably hydrogen,
(C.sub.1-2)alkyl or an unsubstituted (C.sub.1-4)alkylOC(.dbd.O)NH,
(C.sub.1-2)alkylC(.dbd.O)NH or pyridylC(.dbd.O)NH group, preferably
hydrogen, preferably ethyl, preferably tert-butoxycarbonylamino,
preferably acetylamino, preferably pyrid-4-ylcarbonylamino;
[0044] (11) U is a bond, (C.sub.1-3)alkylenoxy,
(C.sub.1-8)alkylene, NH or an aromatic ring, which ring is
optionally substituted with (C.sub.1-4)alkyl, whereby Z and V are
in ortho- or meta-position to each other,
preferably a bond, (C.sub.1-3)alkylenoxy, (C.sub.1-8)alkylene, NH
or a 1,2- or 1,3-phenylene group, which group is optionally
substituted with (C.sub.1-4)alkyl, more preferably a bond,
(C.sub.1-3)alkylenoxy, (C.sub.1-6)alkylene, NH, unsubstituted
1,2-phenylene or 1,3-phenylene optionally monosubstituted with
(C.sub.1-4)alkyl, preferably a bond, preferably CH.sub.2,
preferably CH.sub.2CH.sub.2, preferably CH.sub.2CH.sub.2CH.sub.2,
preferably CH(CH.sub.3)CH.sub.2, preferably CH.sub.2CH(CH.sub.3),
preferably CH(CH.sub.3), preferably CH(CH.sub.2CH.sub.3),
preferably CH(CH.sub.2CH.sub.2CH.sub.3)CH.sub.2, preferably
OCH.sub.2CH.sub.2CH.sub.2, preferably NH, preferably unsubstituted
1,2-phenylene, preferably unsubstituted 1,3-phenylene, preferably
5-methyl-1,3-phenylene;
[0045] (12) V is CH.dbd.CH or preferably CH.sub.2CH.sub.2;
[0046] (13) W is (C.sub.1-6)alkylene, preferably
(C.sub.1-4)alkylene, more preferably (C.sub.1-2)alkylene,
preferably CH(CH.sub.3);
[0047] (14) X is optionally substituted (C.sub.1-4)alkylene or an
optionally substituted aromatic or hetero-aromatic ring, whereby Y
and C(.dbd.O)NR.sub.2 are in meta-position to each other,
preferably unsubstituted (C.sub.1-4)alkylene or a 1,3-phenylene or
2,4-pyridylene group, which group is optionally substituted with
(C.sub.1-4)alkyl, (C.sub.1-6)alkoxy,
S(.dbd.O).sub.2(C.sub.1-4)alkyl or heteroaryl, more preferably
unsubstituted (C.sub.1-3)alkylene or a 1,3-phenylene or
2,4-pyridylene group, which group is optionally monosubstituted
with (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy,
S(.dbd.O).sub.2(C.sub.1-4)alkyl or oxazolyl,
preferably CH.sub.2, preferably CH.sub.2CH.sub.2, preferably
CH.sub.2CH.sub.2CH.sub.2, preferably CH.sub.2CH(CH.sub.3),
preferably CH(CH.sub.3), preferably unsubstituted 1,3-phenylene,
preferably 5-methyl-1,3-phenylene, preferably
5-methoxy-1,3-phenylene, preferably 5-ethoxy-1,3-phenylene,
preferably 5-isopropoxy-1,3-phenylene, preferably
5-methylsulfonyl-1,3-phenylene, preferably
5-oxazol-2-yl-1,3-phenylene, preferably 6-methyl-2,4-pyridylene,
preferably 6-methoxy-2,4-pyridylene, preferably
6-ethoxy-2,4-pyridylene;
[0048] (15) Y is O, S(.dbd.O).sub.2, N(R.sub.g)S(.dbd.O).sub.2,
NR.sub.g, C(.dbd.O)NR.sub.g, N(R.sub.g)C(.dbd.O) or
ON(R.sub.g)C(.dbd.O), wherein R.sub.g is hydrogen, (C.sub.1-8)alkyl
or (C.sub.3-7)cycloalkyl,
preferably O, S(.dbd.O).sub.2, N(R.sub.g)S(.dbd.O).sub.2, NH,
C(.dbd.O)NR.sub.g, N(R.sub.g)C(.dbd.O) or ON(R.sub.g)C(.dbd.O),
wherein R.sub.g is hydrogen, (C.sub.1-4)alkyl or cyclopropyl,
preferably O, preferably S(.dbd.O).sub.2, preferably
N(CH.sub.3)S(.dbd.O).sub.2, preferably NH, preferably C(.dbd.O)NH,
preferably C(.dbd.O)NCH.sub.3, preferably N(H)C(.dbd.O), preferably
N(CH.sub.3)C(.dbd.O), preferably N(CH.sub.2CH.sub.3)C(.dbd.O),
preferably N(CH.sub.2CH.sub.2CH.sub.3)C(.dbd.O), preferably
N(cyclopropyl)C(.dbd.O), preferably
ON(CH.sub.2CH.sub.3)C(.dbd.O);
[0049] (16) Z is O, CH.sub.2 or a bond, preferably O, preferably
CH.sub.2, preferably a bond;
[0050] (17) n is 0 to 4, preferably 0, preferably 1, preferably 2,
preferably 3, preferably 4;
[0051] (18) the number of ring atoms included in the macrocyclic
ring is 14;
[0052] (19) the number of ring atoms included in the macrocyclic
ring is 15;
[0053] (20) the number of ring atoms included in the macrocyclic
ring is 16;
[0054] (21) the number of ring atoms included in the macrocyclic
ring is 17.
[0055] In especially preferred embodiments, the invention relates
to one or more than one of the compounds of the formula I mentioned
in the Examples hereinafter, in free base form or in acid addition
salt form.
[0056] In a further aspect, the invention relates to a process for
the preparation of the compounds of the formula I and their salts,
comprising the steps of cyclisation by metathesis of a compound of
the formula
##STR00003##
in which R.sub.1, R.sub.2, R.sub.3, U, W, X, Y, Z and n are as
defined for the formula I, in the presence of a catalyst, for
instance a ruthenium, tungsten or molybdenum complex, optionally
followed by reduction, oxidation or functionalisation of the
resulting carbon-carbon-double bond, and of recovering the so
obtainable compound of the formula I in free base form or in acid
addition salt form.
[0057] The reaction can be effected according to conventional
methods, for example as described in the Examples.
[0058] The working-up of the reaction mixtures and the purification
of the compounds thus obtainable may be carried out in accordance
with known procedures.
[0059] Acid addition salts may be produced from the free bases in
known manner, and vice-versa.
[0060] Compounds of the formula I can also be prepared by further
conventional processes, which processes are further aspects of the
invention, e.g. as described in the Examples.
[0061] For example, compounds of the formula I, in which R.sub.1 is
(CH.sub.2).sub.kN(R.sub.c)R.sub.d and k is 0, can be prepared by
reaction of a compound of the formula
##STR00004##
in which R.sub.2, R.sub.3, U, V, W, X, Y, Z and n are as defined
for the formula I, with an amine of the formula HN(R.sub.c)R.sub.d
(IV), in which R.sub.c and R.sub.d are as defined for the formula
I, and by recovering the so obtainable compound of the formula I in
free base form or in acid addition salt form.
[0062] For example, compounds of the formula I, in which R.sub.1 is
CH(R.sub.e)C(.dbd.O)N(R.sub.a)R.sub.b, can be prepared by reaction
of a compound of the formula
##STR00005##
in which R.sub.2, R.sub.3, R.sub.e, U, V, W, X, Y, Z and n are as
defined for the formula I, with an amine of the formula
HN(R.sub.a)R.sub.b (VI), in which R.sub.a and R.sub.b are as
defined for the formula I, and by recovering the so obtainable
compound of the formula I in free base form or in acid addition
salt form.
[0063] The starting materials of the formulae II, III, IV, V and VI
are known or may be prepared according to conventional procedures
starting from known compounds, for example as described in the
Examples.
[0064] Compounds of the formula I and their pharmaceutically
acceptable acid addition salts, hereinafter referred to as agents
of the invention, exhibit valuable pharmacological properties when
tested in vitro and in animals, and are therefore useful as
pharmaceuticals.
[0065] The agents of the invention are inhibitors of aspartic
proteases and can be used for the treatment of disorders involving
processing by such enzymes. Particularly they inhibit
beta-secretase and as such inhibit the generation of beta-amyloid
and the subsequent aggregation into oligomers and fibrils.
Test 1: Inhibition of Human BACE
[0066] Recombinant BACE (extracellular domain, expressed in
baculovirus and purified using standard methods) at 6 nM
concentration is incubated with the test compound at various
concentrations for 1 hour at room temperature in 100 mM acetate
buffer, pH 4.5, containing 0.1% CHAPS. Synthetic peptide substrate
Mca-Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-Lys(DNP) is added to a
final concentration of 3 .mu.M and the increase in fluorescence is
recorded at excitation of 325 nm and emission at 400 nm in a
microplate spectro-fluorimeter for 20 minutes in 1-minute
intervals. IC.sub.50 values are calculated from percentage of
inhibition of BACE-activity as a function of the test compound
concentration.
Test 2: Inhibition of Human BACE-2
[0067] Recombinant BACE-2 (extracellular domain, expressed in
baculovirus and purified using standard methods) at 2.5 nM
concentrations is incubated with the test compound at various
concentrations for 1 hour at room temperature in 100 mM acetate
buffer, pH 4.5, containing 0.1% CHAPS. Synthetic peptide substrate
Mca-Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-Lys(DNP) is added to a
final concentration of 3 .mu.M and the increase in fluorescence is
recorded at excitation of 325 nm and emission at 400 nm in a
microplate spectro-fluorimeter for 20 minutes in 1-minute
intervals. IC.sub.50 values are calculated from percentage of
inhibition of BACE-2-activity as a function of the test compound
concentration.
Test 3: Inhibition of Human Cathepsin D
[0068] Recombinant cathepsin D (expressed as procathepsin D in
baculovirus, purified using standard methods and activated by
incubation in sodium formate buffer pH 3.7) is incubated with the
test compound at various concentrations for 1 hour at room
temperature in 100 mM sodium formate buffer, pH 3.1. Synthetic
peptide substrate
Mca-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(DNP)-D-Arg-NH.sub.2 is
added to a final concentration of 2 .mu.M and the increase in
fluorescence is recorded at excitation of 325 nm and emission at
400 nm in a microplate spectro-fluorimeter for 20 minutes in
1-minute intervals. IC.sub.50 values are calculated from percentage
of inhibition of cathepsin D-activity as a function of the test
compound concentration.
Test 4: Inhibition of Cellular Release of Amyloid Peptide 1-40
[0069] Chinese hamster ovary cells are transfected with the gene
for amyloid precursor protein. Cells are plated at a density of
8000 cells/well in a 96-well microtiter plate and cultivated for 24
hours in DMEM cell culture medium containing 10% FCS. The test
compound is added to the cells at various concentrations, and cells
are cultivated for 24 hours in the presence of the test compound.
The supernatants are collected, and the concentration of amyloid
peptide 1-40 is determined using sandwich ELISA. The potency of the
compound is calculated from the percentage of inhibition of amyloid
peptide release as a function of the test compound
concentration.
[0070] In at least one of the above-indicated tests, the agents of
the invention show activity at concentrations below 20 .mu.M.
[0071] The agents of the invention are therefore useful e.g. for
the treatment and/or prevention of neurological and vascular
disorders related to beta-amyloid generation and/or aggregation,
such as neurodegenerative diseases like Alzheimer's disease, Down's
Syndrome, memory and cognitive impairment, dementia, amyloid
neuropathies, brain inflammation, nerve and brain trauma, vascular
amyloidosis, or cerebral haemorrhage with amyloidosis.
[0072] Some of the agents of the invention also inhibit BACE2
(beta-site APP-cleaving enzyme 2) or Cathepsin D, close homologues
of the pepsin-type aspartyl proteases and of beta-secretase. Due to
the correlation of BACE2 and CathD expression with a more
tumorigenic and metastatic potential of tumor cells, such
inhibitors are useful for the suppression of the metastasis process
associated with tumor cells.
[0073] For the above-mentioned indications, the appropriate dosage
will of course vary depending upon, for example, the compound
employed, the host, the mode of administration and the nature and
severity of the condition being treated. However, in general,
satisfactory results in animals are indicated to be obtained at a
daily dosage of from about 0.1 to about 100, preferably from about
1 to about 50, mg/kg of animal body weight. In larger mammals, for
example humans, an indicated daily dosage is in the range from
about 10 to about 2000, preferably from about 10 to about 200, mg
of an agent of the invention conveniently administered, for
example, in divided doses up to four times a day or in sustained
release form.
[0074] The agent of the invention may be administered by any
conventional route, in particular enterally, preferably orally, for
example in the form of tablets or capsules, or parenterally, for
example in the form of injectable solutions or suspensions.
[0075] In accordance with the foregoing, the present invention also
provides an agent of the invention, for use as a pharmaceutical,
e.g. for the treatment of neurological or vascular disorders
related to beta-amyloid generation and/or aggregation.
[0076] The present invention furthermore provides a pharmaceutical
composition comprising an agent of the invention in association
with at least one pharmaceutical carrier or diluent. Such
compositions may be manufactured in conventional manner. Unit
dosage forms contain, for example, from about 1 to about 1000,
preferably from about 1 to about 500, mg of an agent of the
invention.
[0077] The agents of the invention can be administered alone or in
combination with other pharmaceutical agents effective in the
treatment of conditions mentioned above.
[0078] The pharmaceutical combination may be in the form of a unit
dosage form, whereby each unit dosage will comprise a predetermined
amount of the two components, in admixture with suitable
pharmaceutical carriers or diluents. Alternatively, the combination
may be in form of a package containing the two components
separately, e.g. a pack or dispenser-device adapted for the
concomitant or separate administration of the two active agents,
wherein these agents are separately arranged.
[0079] Moreover the present invention provides the use of an agent
of the invention, for the manufacture of a medicament for the
treatment of any neurological or vascular disorders related to
beta-amyloid generation and/or aggregation.
[0080] In still a further aspect, the present invention provides a
method for the treatment of any neurological or vascular disorders
related to beta-amyloid generation and/or aggregation, in a subject
in need of such treatment, which comprises administering to such
subject a therapeutically effective amount of an agent of the
invention.
[0081] The following Examples illustrate the invention, but do not
limit it.
EXAMPLES
Abbreviations
[0082] aq. aqueous
[0083] BOC tert-butoxycarbonyl
[0084] CDCl3 deuterated chloroform
[0085] conc. concentrated
[0086] DBU diazabicycloundecene
[0087] DCM dichloromethane
[0088] DIPEA diisopropylethylamine
[0089] DMPU N,N'-dimethylpropylene urea
[0090] d6-DMSO deuterated dimethylsulfoxide
[0091] EDC.HCl 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide
hydrochloride
[0092] ES electron spray
[0093] Et.sub.2O diethyl ether
[0094] EtOAc ethyl acetate
[0095] EtOH ethanol
[0096] h hour
[0097] HCl hydrochloric acid
[0098] HMDS 1,1,1,3,3,3-hexamethyl-disilazane
[0099] HOBt hydroxybenzotriazole
[0100] HPLC high pressure liquid chromatography
[0101] LC liquid chromatography
[0102] LHMDS lithium hexamethyldisilazide
[0103] MeCN acetonitrile
[0104] min minute
[0105] Mp melting point
[0106] MS mass spectroscopy
[0107] PL-CHO polymer supported benzaldehyde (3 mmol/g)
[0108] PPTS pyridinium-para-toluenesulfonate
[0109] Rf retention factor (thin layer chromatography)
[0110] rt room temperature
[0111] TBME tert-butyl methyl ether
[0112] TFA trifluoroacetic acid
[0113] THF tetrahydrofuran
Example 1
(3S,14R)-16-[1-Hydroxy-2-(3-methyl-benzylamino)-ethyl]-3,4,14-trimethyl-1,-
4-diaza-cyclohexadecane-2,5-dione
[0114] A solution of 67 mg (0.2 mmol)
3(S),4,14(R)-trimethyl-16(R/S)-oxiranyl-1,4-diaza-cyclohexa-decane-2,5-di-
one in 92 mg (0.76 mmol) 3-methyl-benzylamine is heated at
65.degree. C. for 2 h. The mixture is diluted with DCM, 961 mg
PL-CHO (2.88 mmol) and 1 drop of glacial acetic acid are added and
the mixture is shaken at rt for 4 h. The resin is filtered off and
the filtrate evaporated. Purification of the residue by preparative
thin layer chromatography or HPLC gives a thick brownish oil.
[0115] Rf: (DCM/methanol/acetic acid=90/9/1): 0.36
[0116] MS (EI): [MH].sup.+=460.0
[0117] The starting material can be prepared as described
hereafter:
a)
(3S,14R)-3,4,14-Trimethyl-16-oxiranyl-1,4-diaza-cyclohexadecane-2,5-dio-
ne
[0118] To a solution of 718 mg (1.91 mmol)
(3S,14R)-16-(2-chloro-1-hydroxy-ethyl)-3,4,14-trimethyl-1,4-diaza-cyclohe-
xadecane-2,5-dione in 3.8 ml THF is added 2.3 ml 1 M NaOH dropwise
at 0.degree. C. and the reaction mixture is stirred for 2 h at
0.degree. C. Water is added and the mixture is extracted with DCM,
the combined organic layers are washed with saturated ammonium
chloride and brine, dried with sodium sulfate and evaporated to
give the product as a brownish oil (mixture of diastereomers).
[0119] Rf: (DCM/methanol=95/5): 0.52
[0120] MS (EI): [MH].sup.+=339.3, [MNa].sup.+=361.3
b)
(3S,14R)-16-(2-Chloro-1-hydroxy-ethyl)-3,4,14-trimethyl-1,4-diaza-cyclo-
hexadecane-2,5-dione
[0121] A solution of 1.24 g (3.32 mmol) of
(E)-(3S,14R)-16-(2-chloro-1-hydroxy-ethyl)-3,4,14-trimethyl-1,4-diaza-cyc-
lohexadec-10-ene-2,5-dione in 33 ml EtOH is stirred at rt in the
presence of 332 mg 10% Pd/C under a hydrogen atmosphere for 1 h.
More catalyst is added (332 mg) and the hydrogenation is continued
for 4 h. The catalyst is filtered off and the filtrate evaporated.
The residue is purified by chromatography on silica gel
(DCM/methanol 95/5) and gives the title compound as a brownish foam
(mixture of diastereomers).
[0122] Rf: (DCM/methanol=95/5): 0.40
[0123] MS (LC/MS): [MH].sup.+=375.0/377.0,
[MNa].sup.+=396.9/398.9
c)
(E)-(3S,14R)-16-(2-Chloro-1-hydroxy-ethyl)-3,4,14-trimethyl-1,4-diaza-c-
yclohexadec-10-ene-2,5-dione
[0124] A solution of 1.38 g (3.44 mmol) hept-6-enoic acid
{(S)-1-[(R)-1-(2-chloro-1-hydroxy-ethyl)-3-methyl-hept-6-enylcarbamoyl]-e-
thyl}-methyl-amide in 17 ml DCM is added dropwise within an hour to
a refluxing solution of 146 mg
[1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)-dichloro(phenylme-
thylene)-(tricyclohexylphosphine)ruthenium] (Grubbs II catalyst) in
340 ml DCM. The mixture is refluxed for an additional hour and the
solvent evaporated. The residue is purified by chromatography on
silica gel (DCM/methanol 95/5), giving the desired product as a
brownish foam (mixture of diastereomers).
[0125] Rf: (DCM/methanol=95/5): 0.39
d) Hept-6-enoic acid
{(S)-1-[(R)-1-(2-chloro-1-hydroxy-ethyl)-3-methyl-hept-6-enyl-carbamoyl]--
ethyl}-methyl-amide
[0126] A solution of 3.15 g (5 mmol) hept-6-enoic acid
{(S)-1-[(R)-1-(2-chloro-acetyl)-3-methyl-hept-6-enylcarbamoyl]-ethyl}-met-
hyl-amide in 110 ml ethanol is added to a suspension of 378 mg (10
mmol) sodium borohydride in 30 ml ethanol at -78.degree. C. The
temperature is kept below -75.degree. C. during the addition and
the mixture is stirred for an additional hour. The reaction is
quenched with 25 ml 1 M HCl at -78.degree. C. and the mixture is
allowed to warm to rt. After evaporation of the ethanol and
addition of 50 ml 1 M HCl the mixture is extracted with EtOAc. The
organic layer is washed with 1 M HCl and a half-saturated aqueous
sodium chloride solution, dried with sodium sulfate and evaporated.
Purification by chromatography on silica gel (cyclohexane/EtOAc
70/30 to 50/50) gives the desired product as a brown oil (mixture
of diastereomers).
[0127] Rf: (cyclohexane/EtOAc=50/50): 0.30
[0128] MS (LC/MS): [MH].sup.+=400.9/402.9,
[MNa].sup.+=422.9/424.9
e) Hept-6-enoic acid
{(S)-1-[(R)-1-(2-chloro-acetyl)-3-methyl-hept-6-enylcarbamoyl]-ethyl}-met-
hyl-amide
[0129] A solution of 1.9 g (5.0 mmol)
(R)-2-[(S)-2-(hept-6-enoyl-methyl-amino)-propionylamino]-4-methyl-oct-7-e-
noic acid methyl ester in 37 ml THF is cooled at -78.degree. C. and
1.45 ml (20 mmol) chloroiodomethane is added. A 1.57 M THF solution
of LDA (15.9 ml, 25 mmol) is added dropwise while the temperature
of the reaction mixture is maintained below -68.degree. C., and the
mixture is stirred for an additional 30 min. The reaction is
carefully quenched with 7.46 ml glacial acetic acid (130 mmol)
while the temperature is maintained below -65.degree. C. After
stirring for 15 min at -78.degree. C. the mixture is allowed to
warm to 0.degree. C. and 75 ml of a half-saturated aqueous sodium
chloride solution are added. The mixture is extracted with TBME,
washed with 1 M sodium bicarbonate, 1 M sodium sulfite and water,
dried with sodium sulfate and evaporated. The product (mixture of
diastereomers) is used for the next step without further
purification.
[0130] Rf: (cyclohexane/EtOAc=50/50): 0.45
[0131] MS (LC/MS): [MNa].sup.+=420.9/422.9
f)
(R)-2-[(S)-2-(Hept-6-enoyl-methyl-amino)-propionylamino]-4-methyl-oct-7-
-enoic acid methyl ester
[0132] To a solution of 2.63 g (20.5 mmol) 6-heptenoic acid and
4.12 g (26.1 mmol) HOBt in 100 ml DCM at 0.degree. C. are added
4.29 g (22.37 mmol) EDC.HCl, after 10 minutes followed by 5.04 g
(18.64 mmol)
(R)-4-methyl-2-((S)-2-methylamino-propionylamino)-oct-7-enoic acid
methyl ester. The mixture is allowed to warm to rt and stirring is
continued for 3 days. The reaction mixture is cooled to 0.degree.
C., 186 ml 0.5 M HCl is added and the layers separated. The aqueous
phase is extracted with DCM/ethanol 8:2 twice, the combined organic
layers are washed with 1 M potassium bicarbonate, water, dried with
sodium sulfate and evaporated. Purification by chromatography on
silica gel (DCM/methanol 98/2) gives the product as a brownish oil
(mixture of diastereomers).
[0133] Rf: (DCM/methanol=95/5): 0.73
[0134] MS (EI+): [MNa].sup.+=403.3
[0135] .sup.1H-NMR (400 MHz, d6-DMSO): 8.09-8.00 (m, 1H), 5.83-5.68
(m, 2H), 5.04-4.89 (m, 4H), 4.37-4.26 (m, 1H), 3.61 (s, 1.5H), 3.60
(s, 1.5H), 2.85-2.69 (m, 3H), 2.34-2.23 (m, 2H), 2.09-1.93 (m, 4H),
1.75-1.60 (m, 1H), 1.55-1.08 (m, 7H), 1.18 (d, 3H), 0.89-0.79 (m,
3H)
g) (R)-4-Methyl-2-((S)-2-methylamino-propionylamino)-oct-7-enoic
acid methyl ester
[0136] To a solution of 7.84 g (22.4 mmol)
[(S)-1-((R)-1-cyano-3-methyl-hept-6-enylcarbamoyl)-ethyl]-methyl-carbamic
acid tert-butyl ester in 67 ml methanol is added slowly 138 ml of a
6.5 M solution of HCl in Et.sub.2O (896 mmol) at 0.degree. C. The
mixture is stirred at rt for 1 h. The mixture is cooled with an ice
bath and water is added. The pH of the reaction mixture is adjusted
to pH 8 by addition of 89.7 g (896 mmol) potassium bicarbonate. The
mixture is extracted with DCM three times, the combined organic
layers are dried with sodium sulfate and evaporated. The product is
obtained as a brownish oil (mixture of diastereomers) and used for
the next step without further purification.
[0137] Rf: (DCM/methanol=95/5): 0.22
[0138] MS (EI): [MH].sup.+=271.0
[0139] .sup.1H-NMR (400 MHz, d6-DMSO, 2 diastereomers): 8.08 (d,
0.5H), 8.02 (d, 0.5H), 5.81-5.68 (m, 1H), 5.02-4.88 (m, 2H),
4.42-4.38 (m, 1H), 3.62 (s, 1.5H), 3.61 (s, 1.5H), 2.99-2.89 (m,
1H), 2.19 (s, 1.5H), 2.18 (s, 1.5H), 2.11-1.89 (m, 3H), 1.75-1.61
(m, 1H), 1.58-1.12 (m, 4H), 1.10 (d, 1.5H), 1.08 (d, 1.5H), 0.88
(d, 1.5H), 0.84 (d, 1.5H)
h)
[(S)-1-((R)-1-Cyano-3-methyl-hept-6-enylcarbamoyl)-ethyl]-methyl-carbam-
ic acid tert-butyl ester
[0140] To a solution of 5.01 g (24.64 mmol)
BOC-N-methyl-(L)-alanine and 4.95 g (31.36 mmol) HOBt in 100 ml DCM
at 0.degree. C. is added 5.15 g (26.88 mmol) EDC.HCl, after 10 min
followed by 3.41 g (22.4 mmol)
(R)-2-Amino-4-methyl-oct-7-enenitrile. After stirring for 17 h at
rt the mixture is cooled to 0.degree. C., 224 ml 0.5 M HCl is added
and the layers are separated. The aqueous phase is extracted with
DCM/ethanol=80/20 twice, the combined organic layers are washed
with 1 M potassium bicarbonate, water, dried with sodium sulfate
and evaporated to yield the product as a yellowish oil (mixture of
diastereomers), which is used in the next step without further
purification.
[0141] Rf: (DCM/methanol=95/5): 0.66
[0142] MS (EI): [MNa].sup.+=360.4
[0143] .sup.1H-NMR (400 MHz, d6-DMSO, 2 diastereomers): 8.58 (d,
0.5H), 8.51 (d, 0.5H), 5.82-5.71 (m, 1H), 5.04-4.91 (m, 2H),
4.79-4.71 (m, 1H), 4.55-4.45 (br m, 0.5H), 4.32-4.15 (br m, 0.5H),
2.78 (s, 1.5H), 2.75 (s, 1.5H), 2.12-1.94 (m, 2H), 1.91-1.79 (m,
1H), 1.65-1.14 (m, 5H), 1.39 (s, 9H), 1.25 (br d, 3H), 0.89 (d,
1.5H), 0.85 (m, 1.5H)
i) (R)-2-Amino-4-methyl-oct-7-enenitrile
[0144] A solution of 6.22 g (116.3 mmol) ammonium chloride and 5.58
g (85.7 mmol) sodium cyanide in 36.8 ml conc. aq. ammonium
hydroxide and 20 ml methanol is cooled to 0.degree. C. and ammonia
is bubbled through for 10 min. A solution of 7.34 g (52.6 mmol)
(R)-3-methyl-hept-6-enal in 50 ml methanol is added at 0.degree. C.
The mixture is stirred at rt for 2 days. Excess ammonia is
evaporated, the mixture cooled to 0.degree. C. and acidified by
addition of 105 ml 0.5 M HCl. The mixture is washed with diethyl
ether twice and the combined organic layers are backwashed with 105
ml 0.5 M HCl. The acidic aqueous layers are combined, the pH
adjusted to 8 by addition of 6 M aq. ammonium hydroxide and
extracted with DCM twice. The combined DCM layers are backwashed
with water, dried with sodium sulfate and evaporated to yield the
product as a brownish oil (mixture of diastereomers), which is used
for the next step without further purification.
[0145] Rf: (DCM/methanol=98/2): 0.29
[0146] MS (EI): [MH].sup.+=153.1
[0147] 1H-NMR (400 MHz, d6-DMSO): 5.84-5.70 (m, 1H), 4.98 (d, 1H),
4.90 (d, 1H), 5.67 (br d, 1H), 2.24 (br s, 2H), 2.12-1.90 (m, 2H),
1.70-1.53 (m, 2H), 1.48-1.32 (m, 2H), 1.27-1.12 (m, 2H), 0.91-0.83
(m, 3H)
j) (R)-3-Methyl-hept-6-enal
[0148] To a solution of 9.06 g (52.6 mmol)
(R)-7,7-dimethoxy-5-methyl-hept-1-ene) in 50 ml chloroform is added
26.3 ml TFA/water (1:1) at 0.degree. C., and the mixture is stirred
at 8.degree. C. for 17 h. The reaction mixture is cooled to
0.degree. C. again and the pH adjusted to ca. 8.5 by addition of
15.5 g (184 mmol) sodium bicarbonate. After addition of water the
mixture is extracted with DCM twice. The combined organic extracts
are washed with water, dried with sodium sulfate and evaporated.
The product is obtained as a volatile pale yellow oil and used for
the next step without further purification.
[0149] .sup.1H-NMR (400 MHz, CDCl.sub.3): 9.77 (t, 1H), 5.88-5.73
(m, 1H), 5.09-4.93 (m, 2H), 2.44 (dd, 1H), 2.30-2.22 (m, 1H),
2.19-2.01 (m, 3H), 1.52-1.29 (m, 2H), 0.99 (d, 3H)
k) (R)-7,7-Dimethoxy-5-methyl-hept-1-ene
[0150] To a suspension of 1.96 g (5.5 mmol)
methyltriphenylphosphonium bromide in 5 ml THF is added 617 mg (5.5
mmol) potassium tert-butoxide at 0.degree. C. The mixture is
stirred for 15 min at rt, then cooled to 0.degree. C. and a
solution of 1.59 g (5 mmol) (R)-6,6-dimethoxy-4-methyl-hexanal in
2.5 ml THF is added dropwise. After stirring for 2 h at rt the
reaction mixture is poured onto 15 ml ice-water and extracted with
diethyl ether. The combined organic extracts are dried with sodium
sulfate and the solvent is evaporated. The residue is taken up in
10 ml hexane and stirred for 30 min. The precipitated
triphenylphosphine oxide is filtered off and the filtrate is
directly poured onto a chromatography column. Purification by
chromatography on silica gel (n-hexane/diethyl ether 95/5) gives
the product as a colorless oil.
[0151] Rf: (n-hexane/diethyl ether=70/30): 0.36
[0152] .sup.1H-NMR (400 MHz, CDCl.sub.3): 5.74-5.60 (m, 1H), 4.89
(d, 1H), 4.82 (d, 1H), 4.35 (t, 1H), 3.20 (1, 3H), 3.18 (s, 3H),
2.05-1.85 (m, 2H), 1.58-1.41 (m, 2H), 1.36-1.21 (m, 2H), 1.19-1.05
(m, 1H), 0.79 (d, 3H)
l) (R)-6,6-Dimethoxy-4-methyl-hexanal
[0153] A mixture of 17.7 g (88.2 mmol)
(R)-8,8-dimethoxy-2,6-dimethyl-oct-2-ene and 3.7 g (44.1 mmol)
sodium bicarbonate in 265 ml DCM/methanol (4:1) is cooled to
-78.degree. C. and ozone is bubbled through the mixture. After 1 h
20 min the pale yellow solution turns pale blue and 34.8 g (132
mmol) triphenylphosphine is added at -78.degree. C. The mixture is
warmed to rt and stirred for 30 min. The solvent is evaporated and
the residue taken up in 176 ml hexane and stirred for 30 min. The
precipitated triphenylphosphine oxide is removed by filtration and
the solvent evaporated. The product is obtained as a pale yellow
oil and used for the next step without further purification.
[0154] Rf: (n-hexane/diethyl ether=70/30): 0.24
m) (R)-8,8-Dimethoxy-2,6-dimethyl-oct-2-ene
[0155] A solution of 18.39 g (119.2 mmol)
(R)-3,7-dimethyl-oct-6-enal (R-citronellal), 30.1 ml (275 mmol)
trimethyl orthoformate, 315 mg (3.93 mmol) ammonium nitrate and 180
mg (0.715 mmol) PPTS in 60 ml methanol is stirred at rt for 17 h.
The mixture is poured on 300 ml saturated aqueous sodium
bicarbonate and extracted with diethyl ether twice. The combined
organic extracts are dried with sodium sulfate and the solvent is
evaporated. The product is obtained as a pale yellow oil and used
for the next step without further purification.
[0156] Rf: (n-hexane/diethyl ether=90/10): 0.36
[0157] .sup.1H-NMR (400 MHz, CDCl.sub.3): 5.11 (t, 1H), 4.48 (t,
1H), 3.30 (s, 3H), 3.33 (s, 3H), 2.08-1.92 (m, 2H), 1.70 (s, 3H),
1.69-1.55 (m, 2H), 1.60 (s, 3H), 1.43-1.31 (m, 2H), 1.14-1.27 (m,
1H), 0.93 (d, 3H)
[0158] The following compounds can be obtained by a similar
procedure, using 3-methoxy-benzylamine, 2-pyridin-4-yl-ethylamine,
2-(3,4-dimethoxy-phenyl)-ethylamine or 3-isopropyl-benzylamine
instead of 3-methyl-benzylamine:
Example 1a
(3S,14R)-16-[1-Hydroxy-2-(3-methoxy-benzylamino)-ethyl]-3,4,14-trimethyl-1-
,4-diaza-cyclohexadecane-2,5-dione
[0159] Mixture of diastereomers
[0160] Rf: (DCM/methanol 95:5): 0.33
[0161] MS (LC/MS): [MH].sup.+=476.0
Example 1b
(3S,14R)-16-[1-Hydroxy-2-(2-pyridin-4-yl-ethylamino)-ethyl]-3,4,14-trimeth-
yl-1,4-diaza-cyclohexadecane-2,5-dione
[0162] Mixture of diastereomers
[0163] Rf: (DCM/methanol/NH.sub.3=90:10:1): 0.25
[0164] MS (LC/MS): [MH].sup.+=461.0
Example 1c
(3S,14R)-16-{2-[2-(3,4-Dimethoxy-phenyl)-ethylamino]-1-hydroxy-ethyl}-3,4,-
14-trimethyl-1,4-diaza-cyclohexadecane-2,5-dione
[0165] Mixture of diastereomers
[0166] Rf: (DCM/methanol/NH.sub.3 90:9:1): 0.30
[0167] MS (LC/MS): [MH].sup.+=520.0
Example 1d
(3S,14R)-16-[1-Hydroxy-2-(3-methyl-benzylamino)-ethyl]-3,14-dimethyl-1,4-d-
iaza-cyclohexadecane-2,5-dione
[0168] The title compound is prepared similarly to Example 1, using
Boc-N-(L)-alanine instead of Boc-N-methyl-(L)-alanine in step
h.
[0169] Mixture of diastereomers
[0170] LC (Atlantis dC-18, 19.times.100 mm, 5 .mu.M, 10% MeCN+10%
H.sub.2O (2 min) 10-100%
[0171] MeCN+10% H.sub.2O (12 min), 100% MeCN+10% H.sub.2O (3 min)
20 ml/min): 11.1 min
[0172] MS (LC/MS): [MH].sup.+=446.3
Example 1e
(3S,14R)-16-[1-Hydroxy-2-(3-methoxy-benzylamino)-ethyl]-3,14-dimethyl-1,4--
diaza-cyclohexadecane-2,5-dione
[0173] Mixture of diastereomers
[0174] LC (Atlantis dC-18, 19.times.100 mm, 5 .mu.M, 10% MeCN+10%
H.sub.2O (2 min) 10-100% MeCN+10% H.sub.2O (12 min), 100% MeCN+10%
H.sub.2O (3 min) 20 ml/min): 3.8 min
[0175] MS (LC/MS): [MH].sup.+=462.3
Example 1f
(3S,14R)-16-[1-Hydroxy-2-(3-isopropyl-benzylamino)-ethyl]-3,14-dimethyl-1,-
4-diaza-cyclohexadecane-2,5-dione
[0176] Mixture of diastereomers
[0177] LC (Atlantis dC-18, 19.times.100 mm, 5 .mu.M, 10% MeCN+10%
H.sub.2O (2 min) 10-100% MeCN+10% H.sub.2O (12 min), 100% MeCN+10%
H.sub.2O (3 min) 20 ml/min): 11.9 min
[0178] MS (LC/MS): [MH].sup.+=474.4
Example 1g
(3S,14R)-16-[1-Hydroxy-2-(2-pyridin-4-yl-ethylamino)-ethyl]-3,14-dimethyl--
1,4-diaza-cyclohexadecane-2,5-dione
[0179] Mixture of diastereomers
[0180] LC (Atlantis dC-18, 19.times.100 mm, 5 .mu.M, 10% MeCN+10%
H.sub.2O (2 min) 10-100% MeCN+10% H.sub.2O (12 min), 100% MeCN+10%
H.sub.2O (3 min) 20 ml/min): 10.7 min
[0181] MS (LC/MS): [MH].sup.+=447.3
Example 2
(3S,14R,16S)-16-[(1R)-1-Hydroxy-2-(3-isopropyl-benzylamino)-ethyl]-3,4,14--
trimethyl-1,4-diaza-cyclohexadecane-2,5-dione
[0182] The title compound can be prepared similarly to Example 1,
using the pure diastereomer
(3S,14R,16S)-16-((S)-2-chloro-1-hydroxy-ethyl)-3,4,14-trimethyl-1,4-diaza-
-cyclohexadecane-2,5-dione instead of the diastereomeric mixture
(3S,14R)-16-(2-chloro-1-hydroxy-ethyl)-3,4,14-trimethyl-1,4-diaza-cyclohe-
xadecane-2,5-dione in step b, and in the last step
3-isopropyl-benzylamine instead of 3-methyl-benzylamine with a
modified work-up procedure: A solution of 34 mg (0.1 mmol)
3(S),4,14(R)-trimethyl-16(S)--(S)-oxiranyl-1,4-diaza-cyclohexadecane-2,5--
dione in 57 mg (0.38 mmol) 3-isopropyl-benzylamine is heated to
80.degree. C. for 8 h. Excess 3-isopropyl-benzylamine is removed by
repeated co-evaporation with toluene. Purification of the residue
by preparative thin layer chromatography or HPLC gives a thick
colorless oil.
[0183] Rf: (DCM/methanol/14N NH.sub.3=90/9/1): 0.5
[0184] MS (EI): [MH].sup.+=488
[0185] 1H-NMR (400 MHz, d6-DMSO, major conformer): 8.90 (br s, 1H),
7.67 (d, 1H), 7.42-7.25 (m, 4H), 5.58 (br s, 1H), 4.92 (q, 1H),
4.10 (br t, 2H), 3.78-3.69 (m, 1H), 3.64-3.52 (m, 1H), 2.94-2.84
(m, 2H), 2.81 (s, 3H), 2.75-2.63 (m, 1H), 2.11-2.02 (m, 1H),
1.70-1.59 (m, 1H), 1.45-1.11 (m, 23H), 1.04 (d, 3H), 0.74 (d,
3H)
[0186] The starting material can be prepared as described
hereafter:
a) Hept-6-enoic acid
{(S)-1-[(1S,3R)-1-((S)-2-chloro-1-hydroxy-ethyl)-3-methyl-hept-6-enylcarb-
amoyl]-ethyl}-methyl-amide
[0187] To an ice-cold solution of 141 mg (1.1 mmol) hept-6-enoic
acid, 221 mg (1.1 mmol) HOBt.H.sub.2O, 230 mg (1.2 mmol) EDC.HCl
and 327 mg (1.0 mmol)
{1(S)-[1(S)-(2-chloro-1(S)-hydroxy-ethyl)-3(R)-methyl-hept-6-enylca-
rbamoyl]-ethyl}-methyl amino hydrochloride in 12 ml DCM are added
0.172 ml (1.0 mmol) DIPEA. The mixture is stirred at rt for 17 h.
After cooling with ice 10 ml of 0.5 M HCl are added and the layers
are separated. The organic layer is washed with 1 M potassium
bicarbonate, water, dried with sodium sulfate and evaporated. The
residue is purified by chromatography on silica gel
(cyclohexane/EtOAc 70/30) and gives the product as yellow
solid.
[0188] Rf: (cyclohexane/EtOAc=60/40): 0.24
[0189] MS (EI-): 399 [MH].sup.-
[0190] .sup.1H-NMR (400 MHz, d6-DMSO, major rotamer): 7.31 (d, 1H),
5.85-5.70 (m, 2H), 5.28 (d, 1H), 5.04-4.78 (m, 5H), 3.88-3.73 (m,
1H), 3.63-3.46 (m, 2H), 3.43-3.34 (m, 1H), 2.82 (s, 3H), 2.31 (t,
2H), 2.07-1.93 (m, 4H), 1.57-1.12 (m, 9H) 1.18 (d, 3H), 0.79 (d,
3H)
b)
{1(S)-[1(S)-(2-Chloro-1(S)-hydroxy-ethyl)-3(R)-methyl-hept-6-enylcarbam-
oyl]-ethyl}-methyl amino hydrochloride
[0191] A solution of 814 mg (2.08 mmol)
{1(S)-[1(S)-(2-chloro-1(S)-hydroxy-ethyl)-3(R)-methyl-hept-6-enylcarbamoy-
l]-ethyl}-methyl-carbamic acid tert-butyl ester in 4 ml DCM is
cooled to 0.degree. C. and 6.3 ml 5 M HCl in Et.sub.2O (31.3 mmol)
are added. The mixture is stirred at rt for 1.5 h. The solvent is
evaporated to yield the product as pale brownish powder, which is
used for the next step without further purification.
[0192] Rf: (cyclohexane/EtOAc=60/40): 0.0
[0193] MS (EI+): 291 [MH]+
[0194] .sup.1H-NMR (400 MHz, d6-DMSO): 8.97 (br, 1H), 8.78 (br,
1H), 8.35 (d, 1H), 5.83-5.71 (m, 1H), 5.47 (d, 1H), 5.03-4.88 (m,
2H), 3.98-3.86 (m, 1H), 3.79-3.69 (m, 1H), 3.62-3.53 (m, 2H),
3.51-3.43 (m, 1H), 2.46 (s, 3H), 2.10-1.95 (m, 2H), 1.56-1.17 (m,
5H), 1.38 (d, 3H), 0.85 (d, 3H)
c)
{1(S)-[1(S)-(2-Chloro-1(S)-hydroxy-ethyl)-3(R)-methyl-hept-6-enylcarbam-
oyl]-ethyl}-methyl-carbamic acid tert-butyl ester
[0195] To an ice-cold solution of 519 mg (2.55 mmol)
Boc-N-methyl-(L)-alanine, 513 mg (3.25 mmol) HOBt.H.sub.2O, 534 mg
(2.78 mmol) EDC.HCl and 566 mg (2.32 mmol)
1(S)-(2-chloro-1(S)-hydroxy-ethyl)-3(R)-methyl-hept-6-enyl
hydrochloride in 12 ml DCM is added 0.399 ml (2.32 mmol) DIPEA. The
mixture is stirred at rt for 17 h. After cooling with an ice bath
23 ml of 0.5 M HCl are added and the layers are separated. The
organic layer is washed with 1 M potassium bicarbonate, water,
dried with sodium sulfate and evaporated. The residue is purified
by chromatography on silica gel (cyclohexane/EtOAc 70/30) and gives
the product as yellow oil.
[0196] Rf: (cyclohexane/EtOAc=60/40): 0.39
[0197] MS (EI-): 389 [MH].sup.-
[0198] .sup.1H-NMR (400 MHz, d6-DMSO): 7.43 (br, 1H), 5.82-5.71 (m,
1H), 5.30 (d, 1H), 5.01-4.87 (m, 2H), 4.44 (br, 1H), 3.83-3.74 (m,
1H), 3.51-3.46 (m, 2H), 3.41-3.35 (m, 1H), 2.72 (s, 3H), 2.09-1.93
(m, 1H), 1.50-1.13 (m, 9H) 1.39 (s, 9H), 0.79 (d, 3H)
d) 1(S)-(2-Chloro-1(S)-hydroxy-ethyl)-3(R)-methyl-hept-6-enyl amino
hydrochloride
[0199] A solution of 709 mg (2.32 mmol)
[1(S)-(2-Chloro-1(S)-hydroxy-ethyl)-3(R)-methyl-hept-6-enyl]-carbamic
acid tert-butyl ester in 5 ml DCM is cooled to 0.degree. C. and 7.0
ml 5 M HCl in Et.sub.2O (35 mmol) are added. The mixture is stirred
at rt for 1.5 h. The solvent is evaporated to yield the product as
pale brownish powder, which is used for the next step without
further purification.
[0200] Rf: (cyclohexane/EtOAc=80/20): 0.0
[0201] MS (LC/MS): 205.9 [MH]+
e)
[1(S)-(2-Chloro-1(S)-hydroxy-ethyl)-3(R)-methyl-hept-6-enyl]-carbamic
acid tert-butyl ester
[0202] A solution of 224 mg (5.91 mmol) sodium borohydride in 65 ml
ethanol is cooled to -78.degree. C., a solution of 1.41 g (2.96
mmol) [1(S)-(2-chloro-acetyl)-3(R)-methyl-hept-6-enyl]-carbamic
acid tert-butyl ester in 18 ml ethanol is added dropwise,
maintaining the internal temperature below -75.degree. C. The
mixture is allowed to warm to rt and stirred for 17 h. The mixture
is cooled to -78.degree. C. and 14.8 ml of 1 M HCl are added
dropwise. Ethanol is evaporated and the residue is taken up in 1 M
HCl and EtOAc, the layers are separated and the aqueous layer is
extracted with EtOAc, the combined organic layers are dried with
sodium sulfate and evaporated. The residue is purified by
chromatography on silica gel (cyclohexane/EtOAc 80/20) and gives
the product as pale brown amorphous solid.
[0203] Rf: (cyclohexane/EtOAc=80/20): 0.25
[0204] MS (EI-): 304 [MH].sup.-
[0205] .sup.1H-NMR (400 MHz, d6-DMSO): 6.57 (d, 1H), 5.82-5.71 (m,
1H), 5.21 (d, 1H), 5.02-4.87 (m, 2H), 3.58 (d, 1H), 3.50-3.38 (m,
3H), 2.06-1.92 (m, 2H), 1.53-1.15 (m, 5H), 1.38 (s, 9H), 0.82 (d,
3H)
f) [1(S)-(2-Chloro-acetyl)-3(R)-methyl-hept-6-enyl]-carbamic acid
tert-butyl ester
[0206] A solution of 844 mg (2.96 mmol)
2(S)-tert-butoxycarbonylamino-4(R)-methyl-oct-7-enoic acid methyl
ester in 30 ml THF is cooled at -78.degree. C. and 0.86 ml (11.8
mmol) chloroiodo-methane are added. A 1.59 M THF solution of LDA
(9.3 ml, 14.8 mmol) is added dropwise while the temperature of the
reaction mixture is maintained below -75.degree. C., and the
mixture is stirred for an additional 1 h. The reaction is carefully
quenched with 4.41 ml (76.89 mmol) glacial acetic acid while the
temperature is maintained below -65.degree. C. After stirring for
15 min at -78.degree. C. the mixture is allowed to warm to
0.degree. C. and 44 ml of a half-saturated aqueous sodium chloride
solution is added. The mixture is extracted with TBME, the organic
layer washed with 1 M sodium bicarbonate and 1 M sodium sulfite,
dried with sodium sulfate and evaporated. The product is used for
the next step without further purification.
[0207] Rf: (cyclohexane/EtOAc=80/20): 0.44
[0208] MS (LC/MS): [MNa].sup.+=325.9
g) 2(S)-tert-Butoxycarbonylamino-4(R)-methyl-oct-7-enoic acid
methyl ester
[0209] To an ice-cooled solution of 1.15 g (4.25 mmol)
2(S)-tert-butoxycarbonylamino-4(R)-methyl-oct-7-enoic acid in 5 ml
DMF is added 850 mg (8.49 mmol) potassium bicarbonate and 0.422 ml
(6.79 mmol) MeI. The mixture is stirred at rt for 2 days. Toluene
and water are added to the mixture, the layers are separated and
the aqueous layer is extracted with toluene/iso-propanol (85/15)
twice. The combined organic layers are washed with half-saturated
aqueous sodium chloride, dried with sodium sulfate and evaporated.
The residue is purified by chromatography on silica gel
(cyclohexane/EtOAc 90/10) and gives the product as colorless
oil.
[0210] Rf: (cyclohexane/EtOAc=80/20): 0.39
[0211] [.alpha.].sub.D.sup.25+3.06.degree. (c=1.09, CHCl.sub.3)
[0212] MS (EI): [MH].sup.+=286, [MNa].sup.+=308
[0213] .sup.1H-NMR (400 MHz, d6-DMSO): 7.19 (d, 1H), 5.82-5.70 (m,
1H), 5.03-4.89 (m, 2H), 4.04-3.95 (m, 1H), 3.60 (s, 3H), 2.10-1.90
(m, 2H), 1.68-1.44 (m, 2H), 1.42-1.27 (m, 2H), 1.38 (s, 9H),
1.25-1.15 (m, 1H), 0.83 (d, 3H)
h) 2(S)-tert-Butoxycarbonylamino-4(R)-methyl-oct-7-enoic acid
[0214] A solution of 11.3 g lyophilized
2(S)-amino-4(R)-methyl-oct-7-enoic acid (includes phosphate salts)
in 113 ml water and 23 ml THF is cooled to 0.degree. C. and 1.04 g
(9.825 mmol) sodium car and 1.61 g (7.369 mmol) Boc.sub.2O are
added. The mixture is allowed to warm to rt and stirred for 19 h.
After cooling with an ice bath the mixture is acidified by the
addition of 162 ml 0.5 M HCl. The mixture is extracted with EtOAc
twice, the combined EtOAc layers are washed with half-saturated
aqueous sodium chloride, dried with sodium sulfate and evaporated
to yield the product as pinkish oil, which is used for the next
step without further purification.
[0215] Rf: (DCM/methanol=95/5): 0.26
[0216] MS (LC/MS): [MH].sup.-=270.1
i) 2(S)-Amino-4(R)-methyl-oct-7-enoic acid
[0217] The pH of the remaining aqueous phase is re-adjusted to pH
8, and CoCl.sub.3.times.6H.sub.2O (5 mg, 0.021 mmol) and 125 mg
acylase Amano (ACV12502) are added. The mixture is stirred at room
temperature for 24 h. TLC indicates complete conversion. The
mixture is lyophilized and the solid residue used for the next step
without further purification. Analytical data obtained from
analytical samples:
[0218] Rf: (acetonitrile/ethanol/water/acetic acid)=70/20/5/5):
0.41
[0219] [.alpha.].sub.D.sup.20+2.05.degree. (c=0.95, 1 M HCl)
[0220] MS (EI): [MH].sup.+=172
j) 2(S)-Acetylamino-4(R)-methyl-oct-7-enoic acid
[0221] To 11.26 g (49.54 mmol)
(R)-2-Acetylamino-4-methyl-oct-7-enoic acid methyl ester in 75 ml
(33 mM) phosphate buffer pH 7.5 are added 200 .mu.l of Alcalase 2.5
L (Novo Nordisk PMN04666). Under continuous stirring at room
temperature the pH of the mixture is kept constant by adding 1 M
sodium hydroxide solution from an auto burette. After 3 hours, the
conversion reaches about 50%. The pH is adjusted to 8.0 and the
mixture extracted with DCM (3.times.50 ml). The organic phase is
dried with magnesium sulfate and the solvent removed under reduced
pressure yielding the un-desired diastereomeric methyl ester. The
acid remaining in the aqueous solution is used in the next step
without further purification. Analytical data are obtained from
analytical samples:
Acid:
[0222] Rf: (acetonitrile/ethanol/water/acetic acid)=70/20/5/5):
0.68
[0223] [.alpha.].sub.D.sup.20; -5.19.degree. (c=0.924,
methanol)
[0224] MS (EI): [MH].sup.+=214
[0225] .sup.1H-NMR (400 MHz, d6-DMSO): 8.25 (d, 1H), 6.05-5.93 (m,
1H), 5.25-5.10 (m, 2H), 4.47-4.39 (m, 1H), 2.33-2.14 (m, 2H), 2.04
(s, 3H), 1.85-1.76 (m, 1H), 1.75-1.50 (m, 3H), 1.47-1.37 (m, 1H),
1.03 (d, 3H)
Methyl Ester:
[0226] LC (Chiralpak AD-H, 250.times.4.6 mm, hexane/ethanol 95/5, 1
ml/min): 9.01 min
[0227] .sup.1H-NMR (400 MHz, d6-DMSO): 8.20 (d, 1H), 5.65-5.75 (m,
1H), 4.95 (m, 1H), 4.90 (m, 1H), 4.20 (m, 1H), 3.55 (s, 3H), 1.75
(s, 3H), 1.8-2.0 (m, 1H), 1.55 (m, 1H), 1.30-1.45 (m, 3H),
1.00-1.10 (m, 1H), 0.8 (d, 3H)
k) (R)-2-Acetylamino-4-methyl-oct-7-enoic acid methyl ester
[0228] A solution of 4.92 g (25.0 mmol)
N--((R)-1-cyano-3-methyl-hept-6-enyl)-acetamide in 75 ml methanol
is cooled to 0.degree. C., 150 ml 5 M HCl in Et.sub.2O are added
and the mixture is stirred at rt for 1 h. After cooling with ice
350 ml water is added and the mixture is extracted three times with
DCM. The combined organic layers are washed with 1 M potassium
bicarbonate and water, dried with sodium sulfate and evaporated.
The residue is purified by chromatography on silica gel
(cyclohexane/EtOAc 70/30 to 60/40) and gives the product as
yellowish oil (mixture of diastereomers).
[0229] Rf: (cyclohexane/EtOAc=60/40): 0.16
[0230] MS (EI): [MH].sup.+=228
[0231] .sup.1H-NMR (400 MHz, d6-DMSO, 2 diastereomers): 8.21 (d,
0.5H), 8.18 (d, 0.5H), 5.82-5.68 (m, 1H), 5.03-4.89 (m, 2H),
4.32-4.22 (m, 1H), 3.60 (s, 3H), 2.10-1.89 (m, 2H), 1.84 (s, 1.5H),
1.83 (s, 1.5H), 1.67-1.58 (m, 1H), 1.53-1.08 (m, 4H), 0.88 (d,
1.5H), 0.82 (d, 1.5H)
l) N--((R)-1-Cyano-3-methyl-hept-6-enyl)-acetamide
[0232] To a solution of 3.81 g (25.0 mmol)
(R)-2-amino-4-methyl-oct-7-enenitrile (step i, example 1) and 6.45
ml (37.5 mmol) DIPEA in 50 ml DCM at 0.degree. C. are added
dropwise 2.31 ml (32.5 mmol) acetyl chloride. The mixture is
stirred at rt for 1 h. Upon cooling with ice the mixture is
quenched with a half-saturated aqueous solution of ammonium
chloride. The mixture is extracted with DCM, the extract washed
with water, dried with sodium sulfate and evaporated to yield the
product as brownish oil (mixture of diastereomers), which is used
for the next step without further purification.
[0233] Rf: (DCM/methanol=98/2): 0.21
[0234] MS (LC/MS): [MH].sup.+=195.0
[0235] The following compounds can be obtained by a similar
procedure, using 3-cyclopropyl-benzylamine,
C-(5-bromo-pyridine-3-yl)-methylamine,
C-(5-cyclopropyl-pyridine-3-yl)-methylamine,
C-(2-cyclopropyl-pyridine-4-yl)-methylamine,
6-isopropyl-2,2-dimethyl-chroman-4(R/S)-ylamine,
3-tert-butyl-benzylamine or 3-(2,2-dimethyl-propyl)-benzylamine
instead of 3-isopropyl-benzylamine:
Example 2a
(3S,14R,16S)-16-[(1R)-2-(3-Cyclopropyl-benzylamino)-1-hydroxy-ethyl]-3,4,1-
4-trimethyl-1,4-diaza-cyclohexadecane-2,5-dione
[0236] Rf (toluene/ethanol/NH3=90/9.9/0.1): 0.24
[0237] MS (EI): [MH].sup.+=486
Example 2b
(3S,14R,16S)-16-{(1R)-2-[(5-Bromo-pyridin-3-ylmethyl)-amino]-1-hydroxy-eth-
yl}-3,4,14-trimethyl-1,4-diaza-cyclohexadecane-2,5-dione
[0238] Rf (DCM/methanol/NH3=90/9/1): 0.40
[0239] MS (EI): [MH].sup.+=527
Example 2c
(3S,14R,16S)-16-{(1R)-2-[(5-Cyclopropyl-pyridin-3-ylmethyl)-amino]-1-hydro-
xy-ethyl}-3,4,14-trimethyl-1,4-diaza-cyclohexadecane-2,5-dione
[0240] Rf (toluene/ethanol/NH3=90/9.9/0.1): 0.16
[0241] MS (EI): [MH].sup.+=487
Example 2d
(3S,14R,16S)-16-{(1R)-2-[(2-Cyclopropyl-pyridin-4-ylmethyl)-amino]-1-hydro-
xy-ethyl}-3,4,14-trimethyl-1,4-diaza-cyclohexadecane-2,5-dione
[0242] Rf (DCM/methanol=90/10): 0.34
[0243] MS (EI): [MH].sup.+=487
Example 2e
(3S,14R,16S)-16-[(1R)-2-(2,2-Dimethyl-6-isopropyl-chroman-4-ylamino)-1-hyd-
roxy-ethyl]-3,4,14-trimethyl-1,4-diaza-cyclohexadecane-2,5-dione
[0244] Rf (DCM/methanol/NH3=97/2.7/0.3): 0.17
[0245] MS (EI): [MH].sup.+=558
Example 2f
(3S,14R,16S)-16-[(1R)-2-(3-tert-Butyl-benzylamino)-1-hydroxy-ethyl]-3,4,14-
-trimethyl-1,4-diaza-cyclohexadecane-2,5-dione
[0246] Rf (DCM/methanol=90/10): 0.37
[0247] MS (EI): [MH].sup.+=502
Example 2g
(3S,14R,16S)-16-{(1R)-2-[3-(2,2-Dimethyl-propyl)-benzylamino]-1-hydroxy-et-
hyl}-3,4,14-trimethyl-1,4-diaza-cyclohexadecane-2,5-dione
[0248] Rf: (DCM/methanol=90/10): 0.41
[0249] MS (EI): [MH].sup.+=516.5
Example 2h
(3S,15R,17S)-17-[(1R)-1-Hydroxy-2-(3-isopropyl-benzylamino)-ethyl]-3,4,15--
trimethyl-1,4-diaza-cycloheptadecane-2,5-dione
[0250] The title compound can be prepared similarly to Example 2,
using oct-7-enoic acid in step a instead of hept-6-enoic acid.
[0251] Rf: (DCM/methanol=90/10): 0.34
[0252] MS (EI): [MH].sup.+=502
Example 21
(6S,9S,11R)-9-[(1R)-1-Hydroxy-2-(3-isopropyl-benzylamino)-ethyl]-5,6,11-tr-
imethyl-1-oxa-5,8-diaza-cyclohexadecane-4,7-dione
[0253] The title compound can be prepared similarly to Example 2,
using 3-allyloxy-propionic acid in step a instead of hept-6-enoic
acid.
[0254] Rf (DCM/methanol/NH3=90/9/1): 0.46
[0255] MS (EI): [MH].sup.+=490
Example 21
(3S,8S,14R,16S)-16-[(1R)-1-Hydroxy-2-(3-isopropyl-benzylamino)-ethyl]-3,4,-
8,14-tetramethyl-1,4-diaza-cyclohexadecane-2,5-dione
[0256] The title compound can be prepared similarly to Example 2,
using 4(R)-methyl-hept-6-enoic acid (Acid Ib) in step a instead of
hept-6-enoic acid.
[0257] Rf: (DCM/methanol=90/10): 0.43
[0258] MS (EI): [MH].sup.+=502.5
Example 3
(3S,6S,8R)-6-[(1R)-1-Hydroxy-2-(3-isopropyl-benzylamino)-ethyl]-3,8-dimeth-
yl-1,1-dioxo-1 lambda*6*-thia-5-aza-cyclohexadecan-4-one
[0259] The title compound can be prepared similarly to Example 2,
using (S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid (Acid
Ia) in step c instead of BOC-N-methyl-(L)-alanine, followed by the
usual procedure for ring-closing metathesis and thereafter.
[0260] Rf: (DCM/methanol/14N NH.sub.3=90/9/1): 0.45
[0261] MS (EI): [MH].sup.+=509
[0262] The following compound can be obtained by a similar
procedure, using instead of
3-(hex-5-ene-1-sulfonyl)-2(S)-methyl-propionic acid in Example
32(S)-methyl-3-(pent-4-ene-1-sulfonyl)-propionic acid (Acid
IIb):
Example 3a
(3S,6S,8R)-6-[(1R)-1-Hydroxy-2-(3-isopropyl-benzylamino)-ethyl]-3,8-dimeth-
yl-1,1-dioxo-1 lambda*6*-thia-5-aza-cyclopentadecan-4-one
[0263] Rf: (DCM/methanol/Et.sub.3N=94/5/1): 0.90
[0264] MS (LC-MS): [MH].sup.+=495; [MNa].sup.+=517
Example 4
(4S,6R)-12-Ethyl-4-[(1R)-1-hydroxy-2-(3-isopropyl-benzylamino)-ethyl]-6-me-
thyl-3,12-diaza-bicyclo[12.3.1]octadeca-1(17),14(18),15-triene-2,13-dione
[0265] The title compound can be prepared similarly to Example 2,
using N-allyl-N-ethyl-isophthalamic acid (Acid IIIa) in step c
instead of BOC-N-methyl-(L)-alanine, followed by the usual
procedure for ring-closing metathesis and thereafter.
[0266] Rf: (DCM/methanol=5/1): 0.56
[0267] MS (LC-MS): [MH].sup.+=508; [MNa].sup.+=530
Example 5
(9R,11S)-11-[(1R)-1-Hydroxy-2-(3-isopropyl-benzylamino)-ethyl]-9,16-dimeth-
yl-2,12,17-triaza-bicyclo[12.3.1]octadeca-1(18),14,16-trien-13-one
[0268] The title compound can be prepared similarly to Example 2,
using 2-but-3-enylamino-6-methyl-isonicotinic acid (Acid IIIa) in
step c instead of Boc-N-methyl-(L)-alanine, followed by the usual
procedure for ring-closing metathesis and thereafter.
[0269] Rf: (DCM/methanol=5/1): 0.4
[0270] MS (LC-MS): [MH].sup.+=481
[0271] .sup.1H-NMR (400 MHz, D.sub.3COD): 7.30-7.17 (m, 5H), 6.60
(s, 1H), 6.49 (s, 1H), 3.95-3.90 (m, 1H), 3.84 (d, 1H), 3.78 (d,
1H), 3.66-3.61 (m, 1H), 3.35-3.20 (m, 2H), 2.98-2.87 (m, 1H),
2.80-2.70 (m, 2H), 2.38 (s, 3H), 1.80-1.64 (m, 3H), 1.60-1.20 (m,
10H), 1.26 (s, 3H), 1.28 (s, 3H), 0.98 (d, 3H)
Example 6
[(3S,6S,14R,16S)-16-((1S,3R)-3-Butylcarbamoyl-1-hydroxy-butyl)-3,14-dimeth-
yl-2,5-dioxo-1,4-diaza-cyclohexadec-6-yl]-carbamic acid tert-butyl
ester
[0272] A solution of 199 mg (0.35 mmol)
[(3S,6S,14R,16S)-16-((1S,3R)-3-butylcarbamoyl-1-hydroxy-butyl)-3,14-dimet-
hyl-2,5-dioxo-1,4-diaza-cyclohexadec-10-en-6-yl]-carbamic acid
tert-butyl ester in 10 ml THF and 10 ml EtOH is stirred in the
presence of 20 mg 10% Pd--C under an hydrogen atmosphere for 1 h.
The mixture is filtered over a pad of celite and the solvent
evaporated. This yields the title compound as a white powder.
[0273] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.28 min; MS (ES)
[MNa].sup.+=591.4
[0274] The starting material can be prepared as described
hereafter:
a)
[(3S,6S,14R,16S)-16-((1S,3R)-3-Butylcarbamoyl-1-hydroxy-butyl)-3,14-dim-
ethyl-2,5-dioxo-1,4diaza-cyclohexadec-10-en-6-yl]-carbamic acid
tert-butyl ester
[0275] A solution of 183 mg (0.37 mmol)
[(3S,6S,14R,16S)-3,14-dimethyl-16-((2S,4R)-4-methyl-5-oxo-tetrahydro-fura-
n-2-yl)-2,5-dioxo-1,4diaza-cyclohexadec-10-en-6-yl]-carbamic acid
tert-butyl ester in 1.5 ml butylamine is heated to 65.degree. C.
under nitrogen for two hours. The reaction mixture is evaporated,
the residue taken up in toluene and evaporated to dryness to yield
the title compound.
[0276] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.00 min; MS (ES)
[MNa].sup.+=589.4
b)
[(3S,6S,14R,16S)-3,14-Dimethyl-16-((2S,4R)-4-methyl-5-oxo-tetrahydro-fu-
ran-2-yl)-2,5-dioxo-1,4-diaza-cyclohexadec-10-en-6-yl]-carbamic
acid tert-butyl ester
[0277] To a refluxing solution of 6 mg
tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-
-2-ylidene][benzylidine]ruthenium(IV)dichloride (`Grubbs 2`
catalyst) in 300 ml DCM under a nitrogen atmosphere are slowly
added 210 mg (0.402 mmol)
((S)-1-{(S)-1-[(1S,3R)-3-methyl-1-((2S,4R)-4-methyl-5-oxo-tetrahydr-
o-furan-2-yl)-hept-6-enylcarbamoyl]-ethylcarbamoyl}-hex-5-enyl)-carbamic
acid tert-butyl ester in 50 ml degassed DCM. After 3 h the mixture
is cooled to rt, quenched with 0.05 ml butyl vinyl ether, stirred
with 200 mg activated charcoal and purified via chromatography on
silica gel (EtOAc/hexane 1:1) to yield the product (mixture of
double bond isomers).
[0278] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.19 min; MS (ES)
[MNa].sup.+=516.4
c)
((S)-1-{(S)-1-[(1S,3R)-3-Methyl-1-((2S,4R)-4-methyl-5-oxo-tetrahydro-fu-
ran-2-yl)-hept-6-enylcarbamoyl]-ethylcarbamoyl}-hex-5-enyl)-carbamic
acid tert-butyl ester
[0279] A solution of 194 mg (0.489 mmol) of
{(S)-1-[(1S,3R)-3-methyl-1-((2S,4R)-4-methyl-5-oxo-tetrahydro-furan-2-yl)-
-hept-6-enylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester in 2
ml 4N HCl in dioxane is kept 3 h at rt and then concentrated in
vacuo. The residue is taken up in 3 ml DCM and treated with 187 mg
(0.734 mmol) (2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid, 79
mg (0.516 mmol) HOBt.H.sub.2O, 140 mg (0.734 mmol) EDC.HCl and 0.27
ml (1.95 mmol) Et.sub.3N. After 18 h at rt the mixture is diluted
with EtOAc and washed successively with water, 5% aqueous citric
acid, water, 5% aqueous NaHCO.sub.3 and water (4.times.).
Evaporation of the mixture and chromatography on silica gel
(EtOAc/hexane 1:2 and 1:1) gives the product. LC/MS (Nucleosil
C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN (6 min), 100% MeCN
(1.5 min)): 5.94 min; MS (ES) [MNa].sup.+=544.4
d)
{(S)-1-[(1S,3R)-3-Methyl-1-((2S,4R)-4-methyl-5-oxo-tetrahydro-furan-2-y-
l)-hept-6-enylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester
[0280] A solution of 1.0 g (3.08 mmol) of
[(R)-3-methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-carba-
mic acid tert-butyl ester (mixture of diastereomers) in 6 ml 4N HCl
in dioxane is kept 3 h at rt and concentrated in vacuo. The residue
is taken up in 10 ml DCM and treated with 582 mg (3.08 mmol)
Boc-Ala-OH, 499 mg (3.26 mmol) HOBt.H.sub.2O, 882 mg (4.62 mmol)
EDC.HCl and 1.72 ml (12.3 mmol) Et.sub.3N and stirred overnight.
The mixture is diluted with EtOAc and washed successively with
water, 5% aqueous citric acid, water, 5% aqueous NaHCO.sub.3 and
water (4.times.). Evaporation of the mixture and chromatography on
silica gel (EtOAc/hexane 1:7, 1:6 and 1:3) gives the faster eluting
diastereomer and then
{(S)-1-[(1S,3R)-3-methyl-1-((2S,4R)-4-methyl-5-oxo-tetrahydro-furan-2-yl)-
-hept-6-enylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester as a
colorless oil.
[0281] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.29 min; MS (ES)
MNa.sup.+=419.4
e)
[(R)-3-Methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-car-
bamic acid tert-butyl ester (mixture of diastereomers)
[0282] At -78.degree. C. under nitrogen atmosphere a solution of
3.8 g (12.2 mmol) of
[(R)-3-methyl-1-(5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-carbamic
acid tert-butyl ester (mixture of diastereomers) and 2.2 ml (18.3
mmol) DMPU in 50 ml THF are treated with 67.8 ml (25.6 mmol) of a
0.41 M solution of LHMDS in THF. After 50 min 1.30 ml (20.7 mmol)
methyl iodide are added in one portion. Then after 45 min the
reaction is quenched with 4.56 ml (61 mmol) propionic acid and the
mixture is allowed to warm to rt and diluted with EtOAc and water.
The organic phase is washed successively with 5% aqueous citric
acid, water, 5% aqueous NaHCO3 and water (4.times.). Evaporation of
the mixture and chromatography on silica gel (EtOAc/hexane 1:6)
gives the product as a colorless oil that solidifies upon
standing.
[0283] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 6.04 min; MS (ES)
[MNa].sup.+=348.2
f)
[(R)-3-Methyl-1-(5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-carbamic
acid tert-butyl ester (mixture of diastereomers)
[0284] A solution of 10.18 g (30 mmol) of
[(R)-3,7-dimethyl-1-(5-oxo-tetrahydro-furan-2-yl)-oct-6-enyl]-carbamic
acid tert-butyl ester (mixture of diastereomers) in 300 ml DCM and
100 ml MeOH is cooled to -75.degree. C. After addition of 1.26 g
(15 mmol) NaHCO.sub.3 a stream of O.sub.3 in O.sub.2 is passed
through the stirred mixture till a blue color persists. The excess
ozone is removed by flushing with O.sub.2. After addition of 9.44 g
(36 mmol) triphenylphosphine the mixture is allowed to warm to rt
and stirred for 4 h. The mixture is filtered and concentrated in
vacuo. Chromatography on silica gel (EtOAc/Hexane 1:1) gives
aldehyde contaminated with 20% triphenylphosphine oxide. A
suspension of 11.8 g (33 mmol) methyl triphenylphosphonium bromide
and 3.36 g (30 mmol) tBuOK in 150 ml toluene is stirred 1 h at rt,
cooled with an ice bath and treated with a solution of the
abovementioned aldehyde in 70 ml THF. After 30 min the mixture is
quenched with saturated aqueous NaHCO.sub.3. The organic phase is
washed with brine, dried with sodium sulfate and evaporated. Column
chromatography of the residue on silica gel (EtOAc/hexane 1:5)
gives the product as a solidifying oil (mixture).
[0285] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.73 min; MS (ES)
MNa.sup.+=334.2
g)
[(R)-3,7-Dimethyl-1-(5-oxo-tetrahydro-furan-2-yl)-oct-6-enyl]-carbamic
acid tert-butyl ester (mixture of diastereomers)
[0286] A solution of 20.2 g (60 mmol) of
[(R)-3,7-dimethyl-1-(5-oxo-2,5-dihydro-furan-2-yl)-oct-6-enyl]-carbamic
acid tert-butyl ester (mixture of diastereomers) in 200 ml THF is
stirred under an atmosphere of hydrogen in the presence of 2 g
Raney nickel. When the take-up of hydrogen has ceased the reaction
mixture is filtered carefully (Raney nickel is pyrophoric!) via a
pad of celite. Evaporation of the solvent gives the product as a
colorless oil.
[0287] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 6.24 min; MS (ES)
MNa.sup.+=362
h)
[(1S,3R)-3,7-Dimethyl-1-((S)-5-oxo-2,5-dihydro-furan-2-yl)-oct-6-enyl]--
carbamic acid tert-butyl ester and
[(1R,3R)-3,7-dimethyl-1-((R)-5-oxo-2,5-dihydro-furan-2-yl)-oct-6-enyl]-ca-
rbamic acid tert-butyl ester (mixture)
[0288] A solution of 20.67 g (128 mmol) HMDS in 200 ml dry THF is
cooled at -70.degree. C. and 80 ml of a 1.6 M solution of BuLi in
hexane (128 mmol) are added dropwise. After 10 min a solution of
10.75 g (128 mmol) 5H-furan-2-one in 5 ml dry THF is added
dropwise. After addition the mixture is warmed at -40.degree. C. to
prevent the formation of a precipitate and added via a canula to a
stirred solution of 50.1 g (122 mmol)
[(R)-3,7-dimethyl-1-(toluene-4-sulfonyl)-oct-6-enyl]-carbamic acid
tert-butyl ester in 300 ml dry THF at -70.degree. C. After stirring
the mixture at this temperature for 1 h the mixture is poured
directly into a stirred mixture of 500 ml water and 500 ml EtOAc.
The organic phase is washed successively with 5% aqueous citric
acid, water, 5% aqueous sodium bicarbonate and water (4.times.).
The reaction mixture is evaporated and the residue chromatographed
over silica gel (EtOAc/hexane 1:5) to yield a mixture of the
products as a colorless oil that solidifies upon standing.
[0289] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 65-100%
MeCN (6 min), 100% MeCN (1.5 min)): 2.99 min; MS (ES)
[MNa].sup.+=360.2
i) [(R)-3,7-Dimethyl-1-(toluene-4-sulfonyl)-oct-6-enyl]-carbamic
acid tert-butyl ester
[0290] A mixture of 21.34 g (131.4 mmol) R-(+)-Citronellal, 14.63 g
(125 mmol) carbamic acid tert-butyl ester, 24.6 g (138 mmol) sodium
4-methyl-benzenesulfinate and 7.5 ml (200 mmol) formic acid in 100
ml acetonitrile are stirred at rt for 4 days. The mixture is
diluted with 300 ml EtOAc and 300 ml water. The organic phase is
successively washed with 5% aqueous citric acid, water, 5% aqueous
sodium bicarbonate and four times with water. After addition of 5
ml EtOH the solution is concentrated in vacuo yielding the title
compound as a colorless oil that solidifies upon standing.
[0291] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 6.85 min; MS (ES)
[MNa].sup.+=432.2
[0292] The following compounds can be obtained by a similar
procedure:
Example 6a
(2R,4S)--N-Butyl-4-((2S,5S,7R)-2,7-dimethyl-3,15-dioxo-1,4-diaza-cyclopent-
adec-5-yl)-4-hydroxy-2-methyl-butyramide
[0293] The compound can be prepared according to a similar
procedure as example 6 except for using hex-5-enoic acid instead of
(2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step c.
[0294] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.32 min; MS (ES)
[MNa].sup.+=462.4
Example 6b
(2R,4S)--N-Butyl-4-((2S,5S,7R)-2,7-dimethyl-3,16-dioxo-1,4-diaza-cyclohexa-
dec-5-yl)-4-hydroxy-2-methyl-butyramide
[0295] The compound can be prepared according to a similar
procedure as example 6 except for using hept-6-enoic acid instead
of (2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step c.
[0296] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.68 min; MS (ES)
[MNa].sup.+=476.4
Example 6c
(2R,4S)--N-Butyl-4-((2S,5S,7R)-2,7-dimethyl-3,17-dioxo-1,4-diaza-cyclohept-
adec-5-yl)-4-hydroxy-2-methyl-butyramide
[0297] The compound can be prepared according to a similar
procedure as example 6 except for using oct-7-enoic acid instead of
(2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step C.
[0298] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.05 min; MS (ES)
[MNa].sup.+=490.4
Example 6d
[(3S,6S,12R,14S)-14-((1S,3R)-3-Butylcarbamoyl-1-hydroxy-butyl)-3,12-dimeth-
yl-2,5-dioxo-1,4-diaza-cyclotetradec-6-yl]-carbamic acid tert-butyl
ester
[0299] The compound can be prepared according to a similar
procedure as example 6 except for using
(S)-2-tert-butoxycarbonylamino-pent-4-enoic acid instead of
(2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step c.
[0300] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.70 min; MS (ES)
[MNa].sup.+=563.4
Example 6e
(2R,4S)--N-Butyl-4-((2S,5S,7R)-2,7-dimethyl-3,14-dioxo-1,4-diaza-cyclotetr-
adec-5-yl)-4-hydroxy-2-methyl-butyramide
[0301] The compound can be prepared according to a similar
procedure as example 6 except for using pent-4-enoic acid instead
of (2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step c.
[0302] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.02 min; MS (ES)
[MNa].sup.+=448.4
Example 6f
(2R,4S)--N-Butyl-4-((6S,9S,11R)-6,11-dimethyl-4,7-dioxo-1-oxa-5,8-diaza-cy-
clohexadec-9-yl)-4-hydroxy-2-methyl-butyramide
[0303] The compound can be prepared according to a similar
procedure as example 6 except for using 3-allyloxy-propionic acid
instead of (2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in
step c.
[0304] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.92 min; MS (ES)
[MNa].sup.+=478.4
Example 6g
(2R,4S)--N-Butyl-4-((5S,8S,10R)-5,10-dimethyl-3,6-dioxo-1-oxa-4,7-diaza-cy-
clopentadec-8-yl)-4-hydroxy-2-methyl-butyramide
[0305] The compound can be prepared according to a similar
procedure as example 6 except for using allyloxy-acetic acid
instead of (2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in
step c.
[0306] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.11 min; MS (ES)
[MNa].sup.+=464.4
Example 6h
(2R,4S)--N-Butyl-4-((5S,8S,10R)-5,10-dimethyl-3,6-dioxo-1-oxa-4,7-diaza-cy-
clohexadec-8-yl)-4-hydroxy-2-methyl-butyramide
[0307] The compound can be prepared according to a similar
procedure as example 6 except for using but-3-enyloxy-acetic acid
instead of (2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in
step c.
[0308] LCMS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 4.44 min; MS (ES)
[MNa].sup.+=478.4
Example 61
(2R,4S)--N-Butyl-4-((3S,14R,16S)-3,14-dimethyl-2,5-dioxo-1,4,8-triaza-cycl-
ohexadec-16-yl)-4-hydroxy-2-methyl-butyramide
[0309] The compound can be prepared according to a similar
procedure as example 6 except for using
3-(allyl-benzyloxycarbonyl-amino)-propionic acid (Acid Ia) instead
of (2S)-tert-butoxy-carbonyl-2-amino-6-heptenoic acid in step d.
The cbz protecting group is removed in the last hydrogenation
step.
[0310] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 2.85 min; MS (ES)
[MH].sup.+=455.4, [MNa].sup.+=477.4
Example 61
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((2S,5S,7R)-1,2,7-trimethyl-3,15-dio-
xo-1,4-diaza-cyclopentadec-5-yl)-butyramide
[0311] The compound can be prepared according to a similar
procedure as example 6 except for using L-Boc-N-methylalanine
instead of L-Boc-alanine in step d and hex-5-enoic acid instead of
(2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step c. LCMS
(Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN (6 min),
100% MeCN (1.5 min)): 4.58 min; MS (ES) [MNa].sup.+=476.4
Example 6k
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((2S,5S,7R)-1,2,7-trimethyl-3,16-dio-
xo-1,4-diaza-cyclohexadec-5-yl)-butyramide
[0312] The compound can be prepared according to a similar
procedure as example 6 except for using L-Boc-N-methylalanine
instead of L-Boc-alanine in step d and hept-6-enoic acid instead of
(2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step c.
[0313] LCMS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 5.09 min; MS (ES) [MH].sup.+=468.4,
[MNa].sup.+=490.4
Example 61
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((2S,5S,7R)-1,2,7-trimethyl-3,17-dio-
xo-1,4-diaza-cycloheptadec-5-yl)-butyramide
[0314] The compound can be prepared according to a similar
procedure as example 6 except for using L-Boc-N-methylalanine
instead of L-Boc-alanine in step d and oct-7-enoic acid instead of
(2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step c.
[0315] LCMS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 5.42 min; MS (ES) [MH].sup.+=482.4,
[MNa].sup.+=504.4
Example 6m
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((5S,8S,10R)-4,5,10-trimethyl-3,6-di-
oxo-1-oxa-4,7-diaza-cyclohexadec-8-yl)-butyramide
[0316] The compound can be prepared according to a similar
procedure as example 6 except for using L-Boc-N-methylalanine
instead of L-Boc-alanine in step d and but-3-enyloxy-acetic acid
instead of (2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in
step c.
[0317] LCMS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 4.48 min; MS (ES) [MH].sup.+=470.4,
[MNa].sup.+=492.4
Example 6n
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((2S,5S,7R,13S)-1,2,7,13-tetramethyl-
-3,16-dioxo-1,4-diaza-cyclohexadec-5-yl)-butyramide
[0318] The compound can be prepared according to a similar
procedure as example 6 except for using L-Boc-N-methylalanine
instead of L-Boc-alanine in step d and (R)-4-methyl-hept-6-enoic
acid (Acid Ib) instead of
(2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step c.
[0319] LCMS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 5.44 min; MS (ES) [MH].sup.+=482.4,
[MNa].sup.+=504.4
Example 6o
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((2S,5S,7R,13R)-1,2,7,13-tetramethyl-
-3,16-dioxo-1,4-diaza-cyclohexadec-5-yl)-butyramide
[0320] The compound can be prepared according to a similar
procedure as example 6 except for using L-Boc-N-methylalanine
instead of L-Boc-alanine in step d and (S)-4-methyl-hept-6-enoic
acid instead of (2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid
in step c.
[0321] LCMS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 5.52 min; MS (ES) [MH].sup.+=482.4,
[MNa].sup.+=504.4
Example 6p
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((2S,5S,7R,14R)-1,2,7,14-tetramethyl-
-3,16-dioxo-1,4-diaza-cyclohexadec-5-yl)-butyramide
[0322] The compound can be prepared according to a similar
procedure as example 6 except for using L-Boc-N-methylalanine
instead of L-Boc-alanine in step d and (R)-3-methyl-hept-6-enoic
acid instead of (2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid
in step c.
[0323] LCMS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 5.57 min; MS (ES) [MH].sup.+=482.4,
[MNa].sup.+=504.4
Example 6g
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((5S,8S,10R)-4,5,10,15-tetramethyl-3-
,6-dioxo-1-oxa-4,7-diaza-cyclohexadec-8-yl)-butyramide (Mixture of
Diastereomers)
[0324] The compound can be prepared according to a similar
procedure as example 6 except for using L-Boc-N-methylalanine
instead of L-Boc-alanine in step d and
(2-methyl-but-3-enyloxy)-acetic acid (Acid Ic) instead of
(2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step c.
[0325] LCMS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 4.93 min; MS (ES) [MH].sup.+=484.4,
[MNa].sup.+=506.4
Example 6r
(2R,4S)--N-Butyl-4-((5S,8S,10R)-16-ethyl-4,5,10-trimethyl-3,6-dioxo-1-oxa--
4,7-diaza-cyclohexadec-8-yl)-4-hydroxy-2-methyl-butyramide (Mixture
of Diastereomers)
[0326] The compound can be prepared according to a similar
procedure as example 6 except for using L-Boc-N-methylalanine
instead of L-Boc-alanine in step d and
(1-ethyl-but-3-enyloxy)-acetic acid (Acid Id) instead of
(2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step c. LC
(Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN (6 min),
100% MeCN (1.5 min)): 4.95 min; MS (ES) [MH].sup.+=498.3
Example 6s
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((5S,8S,10R)-4,5,10-trimethyl-3,6-di-
oxo-17-propyl-1-oxa-4,7-diaza-cycloheptadec-8-yl)-butyramide
(Mixture of Diastereomers)
[0327] The compound can be prepared according to a similar
procedure as example 6 except for using L-Boc-N-methylalanine
instead of L-Boc-alanine in step d and
(1-propyl-pent-4-enyloxy)-acetic acid (Acid Ie) instead of
(2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step c.
[0328] LC (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 5.69 min; MS (ES)
[MH].sup.+=526.4
Example 7
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((5S,8S,10R)-4,5,10-trimethyl-3,6-di-
oxo-1,4,7-triaza-cyclohexadec-8-yl)-butyramide
[0329] The compound is prepared according to a similar procedure as
example 6 except for using
[(R)-3-methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hex-5-enyl]-carbam-
ic acid tert-butyl ester instead of
[(R)-3-methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-carba-
mic acid tert-butyl ester and L-Boc-N-methylalanine instead of
L-Boc-alanine in step d and (benzyl-pent-4-enyl-amino)-acetic acid
instead of (2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in
step c.
[0330] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.04 min; MS (ES)
[MH].sup.+=469.4
[0331] The starting material can be prepared as follows:
a)
[(R)-3-Methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hex-5-enyl]-carb-
amic acid tert-butyl ester (Mixture of Diastereomers)
[0332] At -78.degree. C. under nitrogen atmosphere a solution of
2.65 g (8.9 mmol) of a mixture of
[(1S,3R)-3-methyl-1-((S)-5-oxo-tetrahydro-furan-2-yl)-hex-5-enyl]-carbami-
c acid tert-butyl ester and
[(1R,3R)-3-methyl-1-((R)-5-oxo-tetrahydro-furan-2-yl)-hex-5-enyl]-carbami-
c acid tert-butyl ester and 3.2 ml (26.7 mmol) DMPU in 30 ml THF is
treated with 17.8 ml of a 1.0 M solution of LHMDS in THF. After 50
min 0.83 ml (13.3 mmol) methyl iodide are added in one portion.
After 45 min the reaction is quenched with 3.3 ml propionic acid
and the mixture is allowed to warm to rt and diluted with EtOAc and
water. The organic phase is washed successively with 5% aqueous
citric acid, water, 5% aqueous NaHCO3 and water (4.times.).
Evaporation of the mixture and chromatography on silica gel
(EtOAc/hexane 1:4) gives the title compound as a colorless oil
(diastereomeric mixture).
[0333] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.60 min; MS (ES)
[MNa].sup.+=334.2
b)
[(R)-3-Methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hex-5-enyl]-carb-
amic acid tert-butyl ester (Mixture of Diastereomers)
[0334] Under nitrogen atmosphere to 20 ml thoroughly degassed
toluene are subsequently added 0.63 g (0.31 mmol)
hydrido(triphenylphosphine)copper(1) hexamer, 2.9 ml
polymethylhydrosiloxane and a (degassed) solution of 5.7 g (19.3
mmol)
[(R)-3-methyl-1-(5-oxo-2,5-dihydro-furan-2-yl)-hex-5-enyl]-carbamic
acid tert-butyl ester in toluene. After stirring for 2 h at
25.degree. C. 6 mg (0.01 mmol) of
R(+)-2,2'-bis-(diphenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl are
added as an accelerating ligand for the copper complex. After 12 h
the mixture is diluted with ethyl acetate and washed with water, 5%
aqueous citric acid and 5% aqueous NaHCO.sub.3. Chromatography on
silica gel (EtOAc/hexane 1:9, then 1:3) provides the title compound
as a diastereomeric mixture.
[0335] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.28 min; MS (ES)
[MNa].sup.+=320.2
c) [(R)-3-M
ethyl-1-(5-oxo-2,5-dihydro-furan-2-yl)-hex-5-enyl]-carbamic acid
tert-butyl ester (Mixture of Diastereomers)
[0336] A solution of 17.15 g (46.7 mmol) of
((R)-1-benzenesulfonyl-3-methyl-hex-5-enyl)-carbamic acid
tert-butyl ester in 100 ml dry THF under nitrogen atmosphere is
cooled to -75.degree. C. A solution A containing lithium
furan-2-olate in THF is added over a period of 10 minutes via a
canula using positive nitrogen pressure. Solution A is prepared as
follows. A solution of 9.85 ml (46.7 mmol) HMDS in 100 ml dry THF
under nitrogen atmosphere is cooled at -70.degree. C. and 29.2 ml
of a 1.6 M solution of BuLi in hexane (46.7 mmol) are added
dropwise. After 30 minutes 3.92 g (46.7 mmol) 5H-furan-2-one in 2
ml dry THF are added dropwise and the temperature is kept at
-40.degree. C. After addition the reaction mixture is stirred at
-75.degree. C. for 1.5 h and then poured directly, with stirring,
in 200 ml water and 200 ml EtOAc. The organic phase is washed
successively with 5% aqueous citric acid, water (2.times.), 5%
aqueous NaHCO3 solution and water (4.times.). The reaction mixture
is evaporated and the residue chromatographed over silica gel
(EtOAc/hexane 1:3) to yield the title compound as an oil.
[0337] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.20 min; MS (ES)
[MNa].sup.+=318.2
d) ((R)-1-Benzenesulfonyl-3-methyl-hex-5-enyl)-carbamic acid
tert-butyl ester
[0338] A solution of 4.72 g (12.06 mmol)
(R)-4-isopropyl-3-((R)-3-methyl-hex-5-enoyl)-5,5-diphenyl-oxazolidin-2-on-
e in 50 ml THF and 125 ml MeOH is cooled at +4.degree. C. and
treated with 5.23 g (60.3 mmol) LiBr and 3.6 ml (24.1 mmol) DBU
while stirring at 25.degree. C. After 18 h the mixture is filtered,
diluted with MTBE, washed with 1N HCl and brine and dried with
MgSO.sub.4.H.sub.2O. The filtrate is concentrated under reduced
pressure and triturated with pentane. The solid is removed and the
solvent is distilled off at atmospheric pressure. This yields the
(R)-3-methyl-hex-5-enoic acid methyl ester as a colorless
liquid.
[0339] .sup.1H-NMR (400 MHz, CDCl.sub.3): 5.84-5.72 (m, 1H),
5.08-5.01 (m, 2H), 3.68 (s, 3H), 2.40-2.33 (m, 1H), 2.16-1.97 (m,
4H), 0.97 (d, 3H)
[0340] The product (1.2 g, 8.44 mmol) is dissolved in 2 ml THF and
cooled to -90.degree. C. A 1 M solution of DibalH in DCM (10.1 ml)
is added dropwise over 15 minutes. After 1 h at -90.degree. C. the
mixture is quenched with 0.34 ml MeOH, warmed to 25.degree. C. and
washed with 5% aqueous citric acid. The organic phase is carefully
concentrated under reduced pressure, dissolved in 3 ml MeCN and
treated immediately with 0.987 g (8.44 mmol) carbamic acid
tert-butyl ester, 1.50 g (8.44 mmol) sodium
4-methyl-benzenesulfinate and 0.44 ml (11.7 mmol) formic acid.
After stirring for 2 days the mixture is diluted with 50 ml EtOAc
and 50 ml water. The organic phase is successively washed with 5%
aqueous citric acid, water, 5% aqueous NaHCO.sub.3 solution and
four times with water. Concentration in vacuo yields the title
compound as a colorless oil that solidifies upon standing.
[0341] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.94 min; MS (ES)
[MNa].sup.+=390.2
e)
(R)-4-Isopropyl-3-((R)-3-methyl-hex-5-enoyl)-5,5-diphenyl-oxazolidin-2--
one
[0342] To a stirred suspension of 22.35 g (117 mmol) CuI in 400 ml
THF at -40.degree. C. are added dropwise 70 ml (140 mmol) of a 2M
THF solution of allylmagnesium chloride. After 1 h the mixture is
cooled to -78.degree. C. and 17.7 ml (140 mmol) BF3.OEt2 are added
in 15 minutes. Then a solution of 41 g (117 mmol)
(R)-3-((E)-but-2-enoyl)-4-isopropyl-5,5-diphenyl-oxazolidin-2-one
in 100 ml THF is added as quickly as possible. The temperature
rises to -40.degree. C. Stirring is continued for 1 h and then the
mixture is quenched with 500 ml 10% aqueous NH4Cl. The mixture is
stirred for 1 h at 25.degree. C. and filtered over celite and
washed with 150 ml TBME. The organic phase is washed successively
with water, 10% aqueous NaHCO3, water, 5% citric acid and water.
Chromatography (silica gel, EE/hexane 1:10) of the crude product
yields the
(R)-4-isopropyl-3-((R)-3-methyl-hex-5-enoyl)-5,5-diphenyl-oxazolidin-2-on-
e.
[0343] [.alpha.].sub.D+171.7.degree. (c=1, DCM)
[0344] .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.52-7.27 (m, 10H),
5.79-5.68 (m, 1H), 5.42 (d, 1H), 5.03-4.98 (m, 2H), 2.89-2.65 (m,
2H), 2.10-1.96 (m, 4H), 0.92 (d, 3H), 0.79 (d, 6H)
[0345] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 7.11 min; MS (ES)
[MNa].sup.+=414.2
[0346] The following compounds can be obtained by a similar
procedure:
Example 7a
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((2S,5S,7R,12R)-2,7,12-trimethyl-3,1-
5-dioxo-1,4-diaza-cyclopentadec-5-yl)-butyramide
[0347] The compound is prepared according to a similar procedure as
example 6 except for using
[(R)-3-methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hex-5-enyl]-carbam-
ic acid tert-butyl ester instead of
[(R)-3-methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-carba-
mic acid tert-butyl ester in step d and (S)-4-methyl-hept-6-enoic
acid instead of (2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid
in step c.
[0348] LCMS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 4.61 min; MS (ES)
MNa.sup.+=476.4
Example 7b
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((2S,5S,7R,12S)-2,7,12-trimethyl-3,1-
5-dioxo-1,4-diaza-cyclopentadec-5-yl)-butyramide
[0349] The compound is prepared according to a similar procedure as
example 6 except for using
[(R)-3-methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hex-5-enyl]-carbam-
ic acid tert-butyl ester instead of
[(R)-3-methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-carba-
mic acid tert-butyl ester in step d and (R)-4-methyl-hept-6-enoic
acid (Acid Ib) instead of
(2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step c.
[0350] LCMS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 4.62 min; MS (ES)
MNa.sup.+=476.4
Example 8
(2R,4S)-4-((2S,5S,7R,15S)-15-Acetylamino-2,7-dimethyl-3,16-dioxo-1,4-diaza-
-cyclohexadec-5-yl)-N-butyl-4-hydroxy-2-methyl-butyramide
[0351] A solution of 45 mg (0.079 mmol)
[(3S,6S,14R,16S)-16-((1S,3R)-3-butylcarbamoyl-1-hydroxy-butyl)-3,14-dimet-
hyl-2,5-dioxo-1,4diaza-cyclohexadec-6-yl]-carbamic acid tert-butyl
ester (example 6) in 1 ml 4N HCl/dioxane is kept for 3 h and then
evaporated. The residue is taken up in 3 ml THF and 1 ml EtOH and 1
ml 10% aqueous sodium carbonate, cooled to 0.degree. C. and stirred
vigorously. 0.112 ml (1.6 mmol) acetyl chloride are added and
stirring is continued for 1 h. The solvents are evaporated and the
residue is stirred with water and TBME/hexane for 30 min. The
mixture is filtered to yield the title compound.
[0352] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.06 min; MS (ES)
[MNa].sup.+=533.4
Example 9
N-[(3S,6S,14R,16S)-16-((1S,3R)-3-Butylcarbamoyl-1-hydroxy-butyl)-3,14-dime-
thyl-2,5-dioxo-1,4-diaza-cyclohexadec-6-yl]-isonicotinamide
[0353] A solution of 45 mg (0.079 mmol)
[(3S,6S,14R,16S)-16-((1S,3R)-3-butylcarbamoyl-1-hydroxy-butyl)-3,14-dimet-
hyl-2,5-dioxo-1,4-diaza-cyclohexadec-6-yl]-carbamic acid tert-butyl
ester (example 6) in 1 ml 4N HCl/dioxane is kept for 3 h and then
evaporated. The residue is taken up in 2 ml THF and 2 ml EtOH and
treated subsequently with 14 mg (0.118 mmol) isonicotinic acid, 13
mg (0.095 mmol) HOBt, 22 mg (0.118 mmol) EDCl and 0.055 ml (0.4
mmol) Et.sub.3N. After 24 h the mixture is diluted with EtOAc,
washed subsequently with water, 5% citric acid, water, saturated
aqueous sodium bicarbonate and water. The organic phase is
evaporated, the residual solid is washed with EtOAc and filtered to
yield the product as a white powder.
[0354] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.69 min; MS (ES)
[MNa].sup.+=596.4
Example 10
(2R,4S)--N-Butyl-4-((3S,6S,8R)-3,8-dimethyl-1,1,4-trioxo-1
lambda*6*-thia-5-aza-cyclohexadec-6-yl)-4-hydroxy-2-methyl-butyramide
[0355] A solution of 74 mg (0.15 mmol)
(2R,4S)--N-butyl-4-(-(3S,6S,8R)-3,8-dimethyl-1,1,4-trioxo-1
lambda*6*-thia-5-aza-cyclohexadec-11-en-6-yl)-4-hydroxy-2-methyl-butyrami-
de in 5 ml MeOH is stirred in the presence of 20 mg 10% Pd--C under
a hydrogen atmosphere for 1 h. The mixture is filtered over a pad
of celite and the solvent evaporated. The residue is crystallized
from toluene and the title compound is isolated as a white
powder.
[0356] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.88 min; MS (ES)
[MNa].sup.+=511.4
[0357] The starting material can be prepared as described
hereafter:
a) (2R,4S)--N-Butyl-4-((3S,6S,8R)-3,8-dimethyl-1,1,4-trioxo-1
lambda*6*-thia-5-aza-cyclohexadec-11-en-6-yl)-4-hydroxy-2-methyl-butyrami-
de
[0358] A solution of 99 mg (0.21 mmol)
(3S,6S,8R)-3,8-dimethyl-6-((2S,4R)-4-methyl-5-oxo-tetra-hydro-furan-2-yl)-
-1-dioxo-1 lambda*6*-thia-5-aza-cyclohexadec-11-en-4-one in 1.5 ml
butylamine is heated at 65.degree. C. for two hours. The mixture is
evaporated and the residue chromatographed on silica gel
(EtOAc/hexane 1:1) to yield the title compound as a white
solid.
[0359] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.64 min; MS (ES)
[MNa].sup.+=509.4
b)
(3S,6S,8R)-3,8-Dimethyl-6-((2S,4R)-4-methyl-5-oxo-tetrahydro-furan-2-yl-
)-1,1-dioxo-lambda*6*-thia-5-aza-cyclohexadec-11-en-4-one
[0360] Under a nitrogen atmosphere to 200 ml refluxing DCM is added
a solution of 10 mg (0.01 mmol)
tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-
-2-ylidene] [benzylidine]ruthenium(IV)dichloride (`Grubbs 2`
catalyst) in 1 ml DCM, followed by the dropwise addition of a
solution of 100 mg (0.218 mmol)
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-N-[(1S,3R)-3-methyl-1-((2S,4R)-4-me-
thyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-propionamide in 5 ml
DCM. After 2 h the mixture is cooled to rt and quenched by the
addition of 0.05 ml butyl vinyl ether and 0.2 g activated charcoal.
The mixture is passed through a pad of silica gel (EtOAc/hexane
1:1) to yield the title compound as a solid.
[0361] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.87 min; MS (ES)
[MNa].sup.+=436.2
c)
(S)-3-(Hex-5-ene-1-sulfonyl)-2-methyl-N-[(1S,3R)-3-methyl-1-((2S,4R)-4--
methyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-propionamide
[0362] A solution of 162 mg (0.5 mmol) of
[(R)-3-Methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-carba-
mic acid tert-butyl ester (mixture of diastereomers, Example 6,
step f) in 2 ml 4N HCl in dioxane is kept 3 h at rt and
concentrated in vacuo. The residue is taken up in 10 ml DCM and
treated with 157 mg (0.675 mmol)
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid (Acid Ia), 91
mg (0.59 mmol) HOBt.H.sub.2O, 129 mg (0.675 mmol) EDC.HCl and 0.383
ml (2.75 mmol) Et.sub.3N and stirred overnight. The mixture is
diluted with EtOAc and washed successively with water, 5% aqueous
citric acid, water, 5% aqueous NaHCO.sub.3 and water (4.times.).
Evaporation of the mixture and chromatography on silica gel
(EtOAc/hexane 1:3, 1:2 and 1:1) gives the faster eluting
diastereomer and then the title product.
[0363] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.64 min; MS (ES)
[MNa].sup.+=464.2
[0364] The following compounds can be obtained via a similar
procedure:
Example 10a
N-Butyl-4-((8R)-3,8-dimethyl-1,1,4-trioxo-1
lambda*6*-thia-5-aza-cyclo-pentadec-6-yl)-4-hydroxy-2-methyl-butyramide
[0365] The title compound is obtained as a mixture of diastereomers
using racemic 2-methyl-3-(pent-4-ene-1-sulfonyl)-propionic acid
(Acid IIb) instead of
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in step c.
[0366] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.49 and 4.61 min (2
diastereomers); MS (ES) [MNa.sub.2-H].sup.+=497.2
Example 10b
(2R,4S)--N-Butyl-4-((3S,6S,8R)-3,8-dimethyl-1,1,4-trioxo-1
lambda*6*-thia-5-aza-cyclotetradec-6-yl)-4-hydroxy-2-methyl-butyramide
[0367] The title compound is obtained using
2-methyl-3-(pent-4-ene-1-sulfonyl)-propionic acid (Acid IId)
instead of (S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in
step c.
[0368] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.25 min; MS (ES)
[MNa].sup.+=483.2
Example 10c
(2R,4S)--N-Butyl-4-((3S,6S,8R)-3,8-dimethyl-1,1,4-trioxo-1
lambda*6*-thia-5-aza-cycloheptadec-6-yl)-4-hydroxy-2-methyl-butyramide
[0369] The title compound is obtained using
(S)-3-(hept-6-ene-1-sulfonyl)-2-methyl-propionic acid (Acid IIe)
instead of (S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in
step c.
[0370] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.18 min; MS (ES)
[MNa].sup.+=525.4
Example 10d
N-Butyl-4-hydroxy-2-methyl-4-((7R)-7-methyl-1,1,3-trioxo-1
lambda*6*-thia-4-aza-cyclohexadec-5-yl)-butyramide
[0371] The title compound is obtained as a mixture of diastereomers
using 2-methyl-3-(pent-4-ene-1-sulfonyl)-propionic acid (Acid IIf)
instead of (S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in
step c.
[0372] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.22 and 5.40 min (2
diastereomers); MS (ES) [MNa].sup.+=497.2 and 497.2
Example 10e
N-Butyl-4-hydroxy-2-methyl-4-((8R)-8-methyl-1,1,4-trioxo-1lambda*6*-thia-5-
-aza-cyclohexadec-6-yl)-butyramide
[0373] The title compound is obtained as a mixture of diastereomers
using 3-(hex-5-ene-1-sulfonyl)-propionic acid (Acid IIg) instead of
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in step c.
[0374] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.71 and 4.83 min (2
diastereomers); MS (ES) [MNa].sup.+=497.2 and 497.2
Example 10f
N-Butyl-4-hydroxy-2-methyl-4-((9R)-9-methyl-1,1,5-trioxo-1lambda*6*-thia-6-
-aza-cyclohexadec-7-yl)-butyramide
[0375] The title compound is obtained as a mixture of diastereomers
using 3-(hex-5-ene-1-sulfonyl)-propionic acid (Acid IIh) instead of
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in step c.
[0376] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.25 and 4.34 min (1:1
diastereomeric mixture); MS (ES) [MNa].sup.+=497.2
Example 11
N-Butyl-4-hydroxy-4-((9R)-16-methoxy-9-methyl-13-oxo-2,12,17-triaza-bicycl-
o[12.3.1]octadeca-1(17),14(18),15-trien-11-yl)-2-methyl-butyramide
[0377] A solution of
16-methoxy-9-methyl-11-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-2,12,17-tri-
aza-bicyclo[12.3.1]octadeca-1(17),14(18),15-trien-13-one (49 mg,
0.12 mmol) in 1.2 ml butylamine is stirred at 50.degree. for 3 h.
Excess butylamine is evaporated and the residue purified by
chromatography on silica gel to afford the title compound (mixture
of diastereomers) as a slightly yellow powder.
[0378] Mp 178-182.degree. C.
[0379] HPLC (XTerra 4.5 cm, 95% CH.sub.3CN, 50.degree. C.): 3.98
min. MS (LC/MS): [MH].sup.+=477.3
[0380] The starting material can be prepared as follows:
a)
16-Methoxy-9-methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-2,12,17-tr-
iaza-bicyclo[12.3.1]octadeca-1(17),14(18),15-trien-13-one
[0381] A solution of 60 mg (0.15 mmol)
16-methoxy-9-methyl-11-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-2,12,17-tri-
aza-bicyclo[12.3.1]octadeca-1 (17),5,14(18),15-tetraen-13-one in 2
ml MeOH is hydrogenated under 1 atm hydrogen in the presence of 9
mg Pd/C for 2 h at rt. Filtration and evaporation yields the title
compound as a brownish foam.
b)
16-Methoxy-9-methyl-11-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-2,12,17-t-
riaza-bicyclo[12.3.1]octadeca-1(17),5,14(18),15-tetraen-13-one
[0382] A solution of 90 mg (0.21 mmol)
2-but-3-enylamino-6-methoxy-N-[3-methyl-1-(4-methyl-5-oxo-tetrahydro-fura-
n-2-yl)-hept-6-enyl]-isonicotinamide in 6 ml DCM is added dropwise
over 30 min to a refluxing solution of 3.5 mg
tricyclohexylphosphine
[1,3-bis(2,4,6-trimethyl-phenyl)-4,5-dihydroimidazol-2-ylidene]
[benzylidene] ruthenium (IV) dichloride (`Grubbs second generation
catalyst`) in 6 ml DCM and then stirred for 1 h at reflux. LC/MS
shows that only little product has been formed, therefore, 7 mg
catalyst are added and the mixture stirred for 18 h at reflux.
Again, 11 mg catalyst are added and heating continued for 4 h. The
reaction mixture is directly chromatographed on silica gel and
eluted with DCM/MeOH 98:2 to yield the title compound (mixture of
diastereomers) as a greenish foam.
[0383] HPLC (XTerra 4.5 cm, 95% CH.sub.3CN, 50.degree. C.): 3.85
min and 4.45 min (diastereoisomers). MS (LC/MS): 402.4
c)
2-But-3-enylamino-6-methoxy-N-[3-methyl-1-(4-methyl-5-oxo-tetrahydro-fu-
ran-2-yl)-hept-6-enyl]-isonicotinamide
[0384] A solution of 155 mg (0.7 mmol)
2-but-3-enylamino-6-methoxy-isonicotinic acid (Acid IIIb), 105 mg
(0.47 mmol)
(R)-3-methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]--
carbamic acid tert-butyl ester and 63 mg (0.42 mmol) HOBt.H.sub.2O
in 8 ml DMF is cooled to 0.degree., treated with 107 mg (0.56 mmol)
EDC.HCl and stirred at rt for 3 h. The reaction mixture is diluted
with EtOAc and washed with 0.5 N aqueous citric acid, 2 M
KHCO.sub.3 and brine, then dried over Na.sub.2SO.sub.4, filtered
and evaporated. Chromatography on silica gel yields the title
product as a colorless oil.
[0385] HPLC (XTerra 4.5 cm, 95% CH.sub.3CN, 50.degree. C.): 4.25
min. MS (LC/MS): [MH].sup.+=430.5
[0386] The following compounds can be obtained via a similar
procedure:
Example 11a
N-Butyl-4-hydroxy-4-((9R)-16-methoxy-9-methyl-13-oxo-2,12-diaza-bicyclo[12-
.3.1]octadeca-1(17),14(18),15-trien-11-yl)-2-methyl-butyramide
[0387] The title compound is obtained as a mixture of diastereomers
using 3-(benzyloxycarbonyl-but-3-enyl-amino)-5-methoxy-benzoic acid
(Acid IIIc) instead of
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in step c.
[0388] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.21 min; MS (ES)
[MNa].sup.+=498.4
Example 11b
N-Butyl-4-hydroxy-2-methyl-4-((11R)-11-methyl-15-oxo-2-oxa-14-aza-bicyclo[-
14.3.1]icosa-1(19),16(20),17-trien-13-yl)-butyramide
[0389] The title compound is obtained as a mixture of diastereomers
using 3-hex-5-enyloxy-benzoic acid (Acid IIId) instead of
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in step c.
[0390] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 6.04 and 6.13 min (mixture of
diastereomers); MS (ES) [MNa].sup.+=497.4
Example 11c
N-Butyl-4-hydroxy-2-methyl-4-((9R)-9-methyl-13-oxo-2-oxa-12-aza-bicyclo[12-
.3.1]octadeca-1(17),14(18),15-trien-11-yl)-butyramide
[0391] The title compound is obtained as a mixture of diastereomers
using 3-but-3-enyloxy-benzoic acid (Acid IIIe) instead of
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in step c.
[0392] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.44 min; MS (ES)
[MNa].sup.+=469.2
Example 11d
N-Butyl-4-hydroxy-2-methyl-4-((10R)-10-methyl-14-oxo-2-oxa-13-aza-bicyclo[-
13.3.1]nonadeca-1(18),15(19),16-trien-12-yl)-butyramide
[0393] The title compound is obtained as a mixture of diastereomers
using 3-pent-4-enyloxy-benzoic acid (Acid IIIf) instead of
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in step c.
[0394] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.87 min; MS (ES)
[MNa].sup.+=483.2
Example 11e
N-Butyl-4-((6R)-6,12-dimethyl-2,13-dioxo-3,12-diaza-bicyclo[12.3.1]octa-de-
ca-1(18),14,16-trien-4-yl)-4-hydroxy-2-methyl-butyramide
[0395] The title compound is obtained as a mixture of diastereomers
using N-allyl-N-methyl-iso-phthalamic acid (Acid IVa) instead of
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in step c.
[0396] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.35 min; MS (ES)
[MNa].sup.+=496.4
Example 11f
N-Butyl-4-((6R)-12-ethyl-6-methyl-2,13-dioxo-3,12-diaza-bicyclo[12.3.1]-oc-
tadeca-1(18),14,16-trien-4-yl)-4-hydroxy-2-methyl-butyramide
[0397] The title compound is obtained as a mixture of diastereomers
using N-allyl-N-ethyl-iso-phthalamic acid (Acid IVb) instead of
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in step c.
[0398] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.64 min; MS (ES)
[MNa].sup.+=510.4
Example 11a
N-Butyl-4-hydroxy-2-methyl-4-((6R)-6-methyl-2,13-dioxo-12-propyl-3,12-diaz-
a-bicyclo[12.3.1]octadeca-1(18),14,16-trien-4-yl)-butyramide
[0399] The title compound is obtained as a mixture of diastereomers
using N-allyl-N-propyl-iso-phthalamic acid (Acid IVc) instead of
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in step c.
[0400] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.01 min; MS (ES)
[MNa].sup.+=524.4
Example 11h
N-Butyl-4-((6R)-12-cyclopropyl-6-methyl-2,13-dioxo-3,12-diaza-bicyclo[12.3-
.1]octadeca-1(18),14,16-trien-4-yl)-4-hydroxy-2-methyl-butyramide
[0401] The title compound is obtained as a mixture of diastereomers
using N-allyl-N-cyclopropyl-isophthalamic acid (Acid IVd) instead
of (S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in step
c.
[0402] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.68 min; MS (ES)
MH.sup.+=500.4, [MNa].sup.+=522.4
Example 11i
N-Butyl-4-hydroxy-4-((6R)-16-methoxy-6,12-dimethyl-2,13-dioxo-3,12-di-aza--
bicyclo[12.3.1]octadeca-1(18),14,16-trien-4-yl)-2-methyl-butyramide
[0403] The title compound is obtained as a mixture of diastereomers
using N-allyl-N-methyl-5-methoxy-isophthalamic acid (Acid IVe)
instead of (S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in
step c.
[0404] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.82 min; MS (ES)
[MNa].sup.+=526.4
Example 11j
N-Butyl-4-((6R)-12-ethyl-16-methoxy-6-methyl-2,13-dioxo-3,12-diaza-bicyclo-
[12.3.1]octadeca-1(18),14,16-trien-4-yl)-4-hydroxy-2-methyl-butyramide
[0405] The title compound is obtained as a mixture of diastereomers
using N-allyl-N-ethyl-5-methoxy-isophthalamic acid (Acid IVf)
instead of (S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in
step c.
[0406] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.82 min; MS (ES)
MH.sup.+=518.4, [MNa].sup.+=540.4
Example 11k
N-Butyl-4-((6R)-12-propyl-16-methoxy-6-methyl-2,13-dioxo-3,12-diaza-bicycl-
o[12.3.1]octadeca-1(18),14,16-trien-4-yl)-4-hydroxy-2-methyl-butyramide
[0407] The title compound is obtained as a mixture of diastereomers
using N-allyl-N-propyl-5-methoxy-isophthalamic acid (Acid IVg)
instead of (S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in
step c.
[0408] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.19 min; MS (ES)
MH.sup.+=532.4, [MNa].sup.+=554.4
Example 111
N-Butyl-4-hydroxy-2-methyl-4-((6R)-6-methyl-2,14-dioxo-3,13-diaza-bicyclo[-
13.3.1]nonadeca-1(18),15(19),16-trien-4-yl)-butyramide
[0409] The title compound is obtained as a mixture of diastereomers
using N-but-3-enyl-iso-phthalamic acid (Acid IVh) instead of
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in step c.
[0410] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.34 min; MS (ES)
MH.sup.+=474.4, [MNa].sup.+=496.4
Example 11m
N-Butyl-4-hydroxy-2-methyl-4-((9R)-9-methyl-2,2,13-trioxo-2lambda*6*-thia--
12-aza-bicyclo[12.3.1]octadeca-1(17),14(18),15-trien-11-yl)-butyramide
[0411] The title compound is obtained as a mixture of diastereomers
using 3-(but-3-ene-1-sulfonyl)-benzoic acid (Acid IIIg) instead of
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid in step c.
[0412] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.65 min; MS (ES)
[MNa].sup.+=517.2
Example 12
N-Butyl-4-hydroxy-2-methyl-4-((6R)-6-methyl-2,13-dioxo-3,12-diaza-bicyclo[-
12.3.1]octadeca-1(18),14,16-trien-4-yl)-butyramide
[0413] The title compound is obtained as a mixture of diastereomers
and prepared according to a similar procedure as example 11 except
for using
[(R)-3-methyl-1-(4-methyl-5-oxo-tetra-hydro-furan-2-yl)-hex-5-enyl]-carba-
mic acid tert-butyl ester (for preparation see example 7) instead
of
[(R)-3-methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-carba-
mic acid tert-butyl ester (described in example 6) and
N-but-3-enyl-isophthalamic acid (Acid IVh) instead of
2-but-3-enylamino-6-methoxy-isonicotinic acid (Acid IIIb) in step
c.
[0414] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.95 min; MS (ES)
[MNa].sup.+=482.4
[0415] The following compounds can be prepared via a similar
procedure:
Example 12a
N-Butyl-4-((9R)-3-ethyl-9-methyl-2,13-dioxo-4-oxa-3,12-diaza-bicyclo-[12.3-
.1]octadeca-1(17),14(18),15-trien-11-yl)-4-hydroxy-2-methyl-butyramide
[0416] The title compound is obtained as a mixture of diastereomers
using N-allyloxy-N-ethyl-iso-phthalamic acid (Acid IVi) instead of
N-but-3-enyl-isophthalamic acid.
[0417] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.14 min; MS (ES)
[MNa].sup.+=556.4
Example 12b
N-Butyl-4-((6R)-11-ethyl-15-methoxy-6-methyl-2,12-dioxo-3,11-diaza-bicyclo-
[11.3.1]heptadeca-1(17),8,13,15-tetraen-4-yl)-4-hydroxy-2-methyl-butyramid-
e
[0418] The title compound is obtained as a mixture of diastereomers
using N-allyl-N-ethyl-5-methoxy-isophthalamic acid (Acid IVf)
instead of N-but-3-enyl-isophthalamic acid. Under the hydrogenation
conditions used in the last step the C.dbd.C double bond is not
reduced.
[0419] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.33 min; MS (ES)
[MNa].sup.+=524.4
Example 13
(2R,4S)--N-Butyl-4-((10R,12S)-17-ethoxy-10-methyl-14-oxo-2,13,18-triaza-bi-
cyclo[13.3.1]nonadeca-1(18),15(19),16-trien-12-yl)-4-hydroxy-2-methyl-buty-
ramide
[0420] The title compound is obtained similarly to Example 11 as a
single diastereomer, using 2-ethoxy-6-pent-4-enylamino-isonicotinic
acid (Acid IIIh) instead of
2-but-3-enylamino-6-methoxy-isonicotinic acid in step c and using
diastereomerically pure
[(1S,3R)-3-methyl-1-((2S,4R)-4-methyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-
-enyl]-carbamic acid tert-butyl ester in step c.
[0421] LC (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 5.00 min; MS (ES)
[MH].sup.+=505.2
[0422] The starting material can be obtained as follows:
a)
[(1S,3R)-3-Methyl-1-((2S,4R)-4-methyl-5-oxo-tetrahydro-furan-2-yl)-hept-
-6-enyl]-carbamic acid tert-butyl ester
[0423] The title compound is obtained in analogy to example 6 using
diastereomerically pure
[(1S,3R)-3,7-dimethyl-1-((S)-5-oxo-2,5-dihydro-furan-2-yl)-oct-6-enyl]-ca-
rbamic acid tert-butyl ester in step g.
[0424] Rf: (hexane/ethyl acetate 3:1) 0.36
[0425] .sup.1H-NMR (400 MHz, CDCl.sub.3): 5.86-5.76 (m, 1H),
5.08-4.95 (m, 2H), 4.55-4.05 (m, 1H), 4.37 (d, 1H), 2.78-2.68 (m,
1H), 2.49-2.66 (m, 1H), 2.18-2.02 (m, 2H), 2.01-1.92 (m, 1H),
1.74-1.66 (m, 1H), 1.59-1.26 (m, 4H), 1.47 (s, 9H), 1.31 (t, 3H),
0.97 (t, 3H)
[0426] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 40-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.94 min; MS (ES)
[MNa].sup.+=348.2
b)
[(1S,3R)-3,7-Dimethyl-1-((S)-5-oxo-2,5-dihydro-furan-2-yl)-oct-6-enyl]--
carbamic acid tert-butyl ester
[0427] 61.6 g (0.4 mol) R-(+)-citronellal, 44.46 g (0.38 mol)
carbamic acid tert-butyl ester, 74.76 g (0.42 mol) sodium
4-methyl-benzenesulfinate and 22.6 ml (0.6 mol) formic acid are
stirred in 300 ml acetonitrile at 25.degree. C. for 4 days. The
mixture is diluted with 700 ml EtOAc and 1000 ml water. The organic
phase is successively washed with 5% aqueous citric acid, water, 5%
aqueous NaHCO.sub.3 solution and four times with water. After
addition of 20 ml EtOH the solution is concentrated in vacuo
yielding
[(R)-3,7-dimethyl-1-(toluene-4-sulfonyl)-oct-6-enyl]-carbamic acid
tert-butyl ester as a colorless oil that solidifies upon
standing.
[0428] Rf (EtOAc/hexane 1:3) 0.49
[0429] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 6.82 min; MS (ES)
[MNa].sup.+=432.2
[0430] This material is dissolved in 500 ml THF under nitrogen
atmosphere and cooled to -75.degree. C. A solution A containing
lithium furan-2-olate in THF is added over a period of 20 minutes
via a canula using positive nitrogen pressure. Solution A is
prepared as follows. 78 ml (0.368 mol) HMDS in 500 ml dry THF under
nitrogen atmosphere are cooled at -70.degree. C. and 230 ml of a
1.6 M solution of BuLi in hexane (0.368 mol) are added dropwise.
After 30 minutes 30.92 g (0.368 mol) 5H-furan-2-one in 10 ml dry
THF are added dropwise and the temperature is kept below
-40.degree. C. Solution A is stirred at -40.degree. C. to prevent
the formation of a precipitate before it is added. After addition
the reaction mixture is stirred at -75.degree. C. for 1.5 h and
then poured directly into a stirred mixture of 1000 ml water and
1000 ml EtOAc. The organic phase is washed successively with 5%
aqueous citric acid, water, 5% aqueous NaHCO3 solution and water.
The reaction mixture is evaporated and the residue chromatographed
over silica gel (EtOAc/hexane 1:5) to yield an oily product. After
crystallization from hexane results a mixture of
[(1S,3R)-3,7-dimethyl-1-((S)-5-oxo-2,5-dihydro-furan-2-yl)-oct-6-enyl]-ca-
rbamic acid tert-butyl ester and
[(1R,3R)-3,7-dimethyl-1-((R)-5-oxo-2,5-dihydro-furan-2-yl)-oct-6-enyl]-ca-
rbamic acid tert-butyl ester as a white powder. Both diastereomers
are quantitatively separated over a Chiralpak AD column (5.times.50
cm) with hexane/isopropanol=97:3 as eluent. The slower moving
diastereomer is isolated and after evaporation of the eluent the
pure diastereomer
[(1S,3R)-3,7-dimethyl-1-((S)-5-oxo-2,5-dihydro-furan-2-yl)-oct-6-enyl]-ca-
rbamic acid tert-butyl ester is obtained as a white powder. Mp.
58-61.degree. C.
[0431] .sup.13C-NMR (100 MHz, CDCl.sub.3): 173.2, 155.2, 154.8,
131.4, 124.1, 121.3, 84.8, 79.6, 49.1, 39.6, 36.1, 29.1, 28.1,
25.6, 25.1, 19.5, 17.5
[0432] The following compounds can be prepared via a similar
procedure:
Example 13a
(2R,4S)--N-Butyl-4-((9R,11S)-9,16-dimethyl-13-oxo-2,12,17-triaza-bicyclo-[-
12.3.1]octadeca-1(17),14(18),15-trien-11-yl)-4-hydroxy-2-methyl-butyramide
[0433] The title compound is obtained using
2-but-3-enylamino-6-methyl-isonicotinic acid (Acid IIIa) instead of
2-ethoxy-6-pent-4-enylamino-isonicotinic acid (Acid IIIh).
[0434] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.59 min; MS (ES)
[MH].sup.+=461.4
Example 13b
(2R,4S)--N-Butyl-4-((9R,11S)-3-ethyl-16-methoxy-9-methyl-13-oxo-2,12,17-tr-
iaza-bicyclo[12.3.1]octadeca-1(17),14(18),15-trien-11-yl)-4-hydroxy-2-meth-
yl-butyramide
[0435] The title compound is obtained using
2-(1-ethyl-but-3-enylamino)-6-methoxy-isonicotinic acid (Acid IIIi)
instead of 2-ethoxy-6-pent-4-enylamino-isonicotinic acid (Acid
IIIh). LC (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 4.72 min; MS (ES)
[MH].sup.+=505.4
Example 13c
(2R,4S)--N-Butyl-4-((4S,6R)-16-ethoxy-12-ethyl-6-methyl-2,13-dioxo-3,12-di-
aza-bicyclo[12.3.1]octadeca-1(18),14,16-trien-4-yl)-4-hydroxy-2-methyl-but-
yramide
[0436] The title compound is obtained using
N-allyl-N-ethyl-5-ethoxy-isophthalamic acid (Acid IVj) instead of
2-ethoxy-6-pent-4-enylamino-isonicotinic acid (Acid IIIh).
[0437] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.11 min; MS (ES)
MH.sup.+=532.4, [MNa].sup.+=554.4
Example 13d
(2R,4S)--N-Butyl-4-((4S,6R)-12-ethyl-16-isopropoxy-6-methyl-2,13-dioxo-3,1-
2-diaza-bicyclo[12.3.1]octadeca-1(18),14,16-trien-4-yl)-4-hydroxy-2-methyl-
-butyramide
[0438] The title compound is obtained using
N-allyl-N-ethyl-5-isopropoxy-isophthalamic acid (Acid IVk) instead
of 2-ethoxy-6-pent-4-enylamino-isonicotinic acid (Acid IIIh).
[0439] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.35 min; MS (ES)
MH.sup.+=546.4, [MNa].sup.+=568.4
Example 13e
(2R,4S)--N-Butyl-4-((4S,6R)-12-ethyl-6,16-dimethyl-2,13-dioxo-3,12-diaza-b-
icyclo[12.3.1]octadeca-1(18),14,16-trien-4-yl)-4-hydroxy-2-methyl-butyrami-
de
[0440] The title compound is obtained using
N-allyl-5-methyl-N-ethyl-isophthalamic acid (Acid IVl) instead of
2-ethoxy-6-pent-4-enylamino-isonicotinic acid (Acid IIIh).
[0441] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.98 min; MS (ES)
[MH].sup.+=502.4, [MNa].sup.+=524.4
Example 13f
(2R,4S)--N-Butyl-4-((4S,6R)-12-ethyl-16-methanesulfonyl-6-methyl-2,13-diox-
o-3,12-diaza-bicyclo[12.3.1]octadeca-1(18),14,16-trien-4-yl)-4-hydroxy-2-m-
ethyl-butyramide
[0442] The title compound is obtained using
N-allyl-N-ethyl-5-methanesulfonyl-isophthalamic acid (Acid IVm)
instead of 2-ethoxy-6-pent-4-enylamino-isonicotinic acid (Acid
IIIh).
[0443] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.49 min; MS (ES)
[MH].sup.+=566.4
Example 13g
(2R,4S)--N-Butyl-4-((4S,6R)-12-ethyl-6-methyl-16-oxazol-2-yl-2,13-dioxo-3,-
12-diaza-bicyclo[12.3.1]octadeca-1(18),14,16-trien-4-yl)-4-hydroxy-2-methy-
l-butyramide
[0444] The title compound is obtained using
N-allyl-N-ethyl-5-oxazol-2-yl-isophthalamic acid (Acid IVn) instead
of 2-ethoxy-6-pent-4-enylamino-isonicotinic acid (Acid IIIh).
[0445] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.82 min; MS (ES)
[MH].sup.+=555.4
Example 13h
(2R,4S)--N-Butyl-4-((4S,6R)-13-ethyl-6-methyl-2,14-dioxo-3,13-diaza-bicycl-
o[13.3.1]nonadeca-1(18),15(19),16-trien-4-yl)-4-hydroxy-2-methyl-butyramid-
e
[0446] The title compound is obtained using
N-but-3-enyl-N-ethyl-isophthalamic acid (Acid IVo) instead of
2-ethoxy-6-pent-4-enylamino-isonicotinic acid (Acid IIIh).
[0447] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.90 min; MS (ES)
[MH].sup.+=502.4, [MNa].sup.+=524.4
Example 13i
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((4S,6R)-6-methyl-2,14-dioxo-13-prop-
yl-3,13-diaza-bicyclo[13.3.1]nonadeca-1(18),15(19),16-trien-4-yl)-butyrami-
de
[0448] The title compound is obtained using
N-but-3-enyl-N-propyl-isophthalamic acid (Acid IVp) instead of
2-ethoxy-6-pent-4-enylamino-isonicotinic acid (Acid IIIh).
[0449] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.27 min; MS (ES)
[MH].sup.+=516.4, [MNa].sup.+=538.4
Example 14
(2R,4S)--N-Butyl-4-((10R,12S)-2,10-dimethyl-1,1,14-trioxo-1lambda*6*-thia--
2,13-diaza-cyclohexadec-12-yl)-4-hydroxy-2-methyl-butyramide
[0450] The title compound is obtained similarly to Example 11 as a
single diastereomer, using
3-(methyl-pent-4-enyl-sulfamoyl)-propionic acid (Acid Va) instead
of 2-but-3-enylamino-6-methoxy-isonicotinic acid in step c and
using diastereomerically pure
[(1S,3R)-3,7-dimethyl-1-((S)-5-oxo-2,5-dihydro-furan-2-yl)-oct-6-enyl]-ca-
rbamic acid tert-butyl ester in step c.
[0451] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.66 min; MS (ES)
[MNa].sup.+=512.4
[0452] The following compound can be prepared via a similar
procedure:
Example 14a
(2R,4S)-4-Hydroxy-2-methyl-N-(3-methyl-butyl)-4-((7S,9R)-9-methyl-2,5-diox-
o-1,6-diaza-cyclopentadec-7-yl)-butyramide
[0453] The title compound is obtained using N-but-3-enyl-succinamic
acid (Acid Vb) instead of 2-ethoxy-6-pent-4-enylamino-isonicotinic
acid (Acid IIIh).
[0454] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.15 min; MS (ES)
[MNa].sup.+=462.4
Example 15
(2R,4S)--N-Butyl-4-((5S,8S,10R)-5,10-dimethyl-3,3,6-trioxo-3lambda*6*-thia-
-7-aza-bicyclo[11.3.1]heptadeca-1(17),
13,15-trien-8-yl)-4-hydroxy-2-methyl-butyramide
[0455] The title compound is obtained in a similar manner as
Example 10, starting from
(5S,8S,10S)-5,10-dimethyl-8-((2S,4R)-4-methyl-5-oxo-tetrahydro-furan-2-yl-
)-3,3-dioxo-3lambda*6*-thia-7-aza-bicyclo[11.3.1]heptadeca-1(17),11,13,15--
tetraen-6-one instead of
[(R)-3-Methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-carba-
mic acid tert-butyl ester (mixture of diastereomers, Example 6,
step f) in step c.
[0456] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.34 min; MS (ES)
[MNa].sup.+=517.2
[0457] The starting material can be prepared as follows:
a)
(5S,8S,10S)-5,10-Dimethyl-8-((2S,4R)-4-methyl-5-oxo-tetrahydro-furan-2--
yl)-3,3-dioxo-3lambda*6*-thia-7-aza-bicyclo[11.3.1]heptadeca-1(17),11,13,1-
5-tetraen-6-one
[0458] The title compound is prepared following the procedure
described for step b of example 10. LC/MS (Nucleosil C-18HD,
4.times.70 mm, 3 .mu.M, 20-100% MeCN (6 min), 100% MeCN (1.5 min)):
4.45 min; MS (ES) [MNa].sup.+=442.2
b)
(S)-2-Methyl-N-[(1S,3S)-3-methyl-1-((2S,4R)-4-methyl-5-oxo-tetrahydro-f-
uran-2-yl)-pent-4-enyl]-3-(3-vinyl-phenylmethanesulfonyl)-propionamide
[0459] The title compound is prepared following the procedure
described for step c of example 10 using
(S)-2-methyl-3-(3-vinyl-phenylmethanesulfonyl)-propionic acid (Acid
IIi) instead of (S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic
acid (Acid Ia).
[0460] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.15 min; MS (ES)
[MNa].sup.+=470.2
c)
[(S)-3-Methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-pent-4-enyl]-car-
bamic acid tert-butyl ester
[0461] The title compound is prepared following the procedure
described for step e of example 6. LC/MS (Nucleosil C-18HD,
4.times.70 mm, 3 .mu.M, 20-100% MeCN (6 min), 100% MeCN (1.5 min)):
4.09 min; MS (ES) [MNa].sup.+=320.2
d)
[(S)-3-Methyl-1-(5-oxo-tetrahydro-furan-2-yl)-pent-4-enyl]-carbamic
acid tert-butyl ester
[0462] A mixture of 2.19 g (6.67 mmol)
(R)-6-tert-butoxycarbonylamino-4-methyl-6-(5-oxo-tetra-hydro-furan-2-yl)--
hexanoic acid, 0.293 g (1.46 mmol) copper(II)acetate monohydrate,
0.2 ml pyridine and 5.4 g (12.0 mmol) Pb(OAc).sub.4 in 45 ml
benzene is refluxed under nitrogen for 18 h. The mixture is cooled
to rt, water is added and the organic phase is washed with water
and 5% aqueous NaHCO.sub.3. The organic phase is dried with
Na.sub.2SO.sub.4, filtered and evaporated. The residue is purified
by chromatography on silica gel (EtOAc/hexane 1:6 and 1:4) to yield
the title compound.
[0463] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.60 min; MS (ES)
[MNa].sup.+=306.2
e)
(R)-6-tert-Butoxycarbonylamino-4-methyl-6-(5-oxo-tetrahydro-furan-2-yl)-
-hexanoic acid
[0464] A mixture of 2.09 g (6.67 mmol)
[(R)-3-Methyl-6-oxo-1-(5-oxo-tetrahydro-furan-2-yl)-hexyl]-carbamic
acid tert-butyl ester, 1.2 g (10 mol) NaH.sub.2PO.sub.4, 50 ml
tBuOH and 10 ml water is subsequently treated with 20 ml of a 2M
THF solution of 2-methyl-2-butene and 2.35 g (20.6 mmol)
NaClO.sub.2 (technical, 80%). After stirring for 10 min the mixture
is diluted with EtOAc and brine. The organic phase is dried with
MgSO.sub.4, filtered and evaporated to yield the title compound as
a resin which is used in the next step without purification.
[0465] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.71 min; MS (ES)
[MNa].sup.+=352.2
f)
[(R)-3-Methyl-6-oxo-1-(5-oxo-tetrahydro-furan-2-yl)-hexyl]-carbamic
acid tert-butyl ester
[0466] A solution of 5.4 g (15.9 mmol) of
[(R)-3,7-dimethyl-1-(5-oxo-tetrahydro-furan-2-yl)-oct-6-enyl]-carbamic
acid tert-butyl ester (preparation of aldehyde in step g of example
6) in a mixture 200 ml DCM and 10 ml MeOH is cooled to -70.degree.
C. After addition of 0.63 g (7.5 mmol) NaHCO.sub.3 a stream of
O.sub.3 in O.sub.2 is passed through the stirred mixture till a
blue color persists. The excess ozone is removed by passing through
more oxygen. After addition of 5.0 g (19 mmol) triphenylphosphine
the mixture is allowed to warm up at rt and stirred for 4 h. The
mixture is filtered and concentrated in vacuo. Chromatography on
silica gel (EtOAc/Hexane 1:1) gives the title aldehyde.
[0467] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.14 min; MS (ES)
[MNa].sup.+=336.2
[0468] The following compound can be prepared via a similar
procedure:
Example 15a
(2R,4S)--N-Butyl-4-hydroxy-2-methyl-4-((5S,8S,10R)-5,10,15-trimethyl-3,3,6-
-trioxo-3lambda*6*-thia-7-aza-bicyclo[11.3.1]heptadeca-1(17),13,15-trien-8-
-yl)-butyramide
[0469] The title compound can be obtained by using
(S)-2-methyl-3-(3-methyl-5-vinyl-phenyl-methane-sulfonyl)-propionic
acid (Acid IIi) instead of
(S)-2-methyl-3-(3-vinyl-phenyl-methane-sulfonyl)-propionic acid
(Acid IIj).
[0470] Rf: (DCM/methanol=95:5) 0.36
[0471] MS (LC/MS): [MNa].sup.+=531
[0472] 1H-NMR (400 MHz, CDCl.sub.3): 7.09 (s, 1H), 7.03 (s, 1H),
6.92 (s, 1H), 6.03 (d, 1H), 5.75 (t, 1H), 4.31 (d, 1H), 4.16 (d,
1H), 4.15-4.05 (m, 1H), 3.90 (t, 1H), 3.68 (t, 1H), 3.43-3.20 (m,
2H), 3.06 (dd, 1H), 2.83-2.50 (m, 4H), 2.87 (s, 3H), 1.82 (t, 1H),
1.65-1.0 (m, 11H), 1.48 (d, 3H), 1.22 (d, 3H), 0.95 (t, 3H), 0.88
(d, 3H)
Example 16
(2R,4S)--N-Butyl-4-((9S,12S,14R)-9,14-dimethyl-7,10-dioxo-6,7,8,9,10,11,12-
,
13,14,15,16,17-dodecahydro-5-oxa-8,11-diaza-benzocyclopentadecen-12-yl)--
4-hydroxy-2-methyl-butyramide
[0473] The title compound is prepared similarly to Example 6, using
(2-allyl-phenoxy)-acetic acid instead of
(2S)-tert-butoxycarbonyl-2-amino-6-heptenoic acid in step c and
starting from
[(S)-3-methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-pent-4-enyl]--
carbamic acid tert-butyl ester (example 15, step d) instead of
{(S)-1-[(1S,3R)-3-methyl-1-((2S,4R)-4-methyl-5-oxo-tetrahydro-furan-2-yl)-
-hept-6-enylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester in
step d.
[0474] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 4.78 min; MS (ES)
[MNa].sup.+=512.4
Example 17
(2R,4S)--N-Butyl-4-((5S,8S,10R)-5,10-dimethyl-3,3,6-trioxo-3lambda*6*-thia-
-7-aza-bicyclo[12.3.1]octadeca-1(18),14,16-trien-8-yl)-4-hydroxy-2-methyl--
butyramide
[0475] The title compound is obtained in a similar manner as
Example 10, starting from
[(R)-3-methyl-1-(5-oxo-2,5-dihydro-furan-2-yl)-hex-5-enyl]-carbamic
acid tert-butyl ester (mixture of diastereomers, step c of example
7) instead of
[(R)-3-methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-ca-
rbamic acid tert-butyl ester (mixture of diastereomers, step f of
example 6) in step c.
[0476] Rf: (DCM/methanol=95:5) 0.35
[0477] MS (LC/MS): [MNa].sup.+=531
Building Blocks
##STR00006##
[0479] R.dbd.H, Me, Et, Pr
[0480] X=bond, --O--, --NCbz, --NBn
[0481] n=1-4
[0482] m=1-4
a) 3-(Allyl-benzyloxycarbonyl-amino)-propionic acid
[0483] To a solution of 2.5 g (11.2 mmol)
3-benzyloxycarbonylamino-propionic acid in 30 ml DMF and 30 ml THF
are added 1.34 g (33.6 mmol, 60% suspension in mineral oil) NaH and
the mixture is heated at 60.degree. C. for 3 h. After cooling down
1.42 ml (16.8 mmol) allyl bromide are added. After stirring for 40
h at rt the mixture is diluted with 10% citric acid and extracted
three times with EtOAc. The combined organic layers are washed with
water, dried with sodium sulfate and the volatiles are removed in
vacuo. The residue is chromatographed on silica gel (hexane/EtOAc
3:1), yielding the title product.
[0484] 1H-NMR (400 MHz, CDCl.sub.3): 7.41-7.30 (m, 5H), 5.88-5.74
(m, 1H), 5.27-5.12 (m, 4H), 4.02-3.93 (m, 2H), 3.63-3.53 (m, 2H),
2.75-2.61 (m, 2H)
[0485] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 31M, 20-100% MeCN (6
min), 100% MeCN (1.5 min)): 4.13 min; MS (ES) [MNa].sup.+=286.2
b) (R)-4-Methyl-hept-6-enoic acid
[0486] This compound is prepared analogously to its known mirror
image (S)-4-methyl-hept-6-enoic acid.
c) (2-methyl-but-3-enyloxy)-acetic acid
[0487] Under nitrogen atmosphere a suspension of 0.5 g (5.81 mmol)
2-methyl-3-buten-1-ol and 0.348 g (8.71 mmol, 60% suspension in
mineral oil) NaH in 10 ml THF are stirred 3 h at rt. Solid sodium
iodo acetate (1.81 g, 8.71 mmol) is added and stirring is continued
for 2 h. The mixture is diluted with water and brine, acidified
with 1N HCl and extracted with EtOAc. The organic phase is dried
with sodium sulfate and concentrated the residue is kugelrohr
distilled at ca 1 mbar (70-110.degree. C.) to yield the title
compound as a colorless liquid.
[0488] 1H-NMR (400 MHz, CDCl.sub.3): 5.85-5.76 (m, 1H), 5.16-5.05
(m, 2H), 4.17 (s, 2H), 3.53-3.42 (m, 2H), 2.60-2.50 (m, 1H), 1.07
(d, 3H)
[0489] MS (neg) [M-H].sup.-143.1
d) (1-Ethyl-but-3-enyloxy)-acetic acid
[0490] The title compound is obtained by a similar procedure as Ic
from hex-5-en-3-ol instead of 2-methyl-3-buten-1-ol.
[0491] MS (neg) [M-H].sup.- 157
e) (1-Propyl-pent-4-enyloxy)-acetic acid
[0492] The title compound is obtained by a similar procedure as Ic
from oct-7-en-4-ol instead of 2-methyl-3-buten-1-ol.
[0493] MS (neg) [M-H].sup.- 185
f) (Benzyl-pent-4-enyl-amino)-acetic acid
[0494] The title compound is obtained by sodium hydroxide
saponification of the corresponding methyl ester and used as its
sodium salt.
##STR00007##
[0495] R.dbd.H, Me
a) (S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid example 3
example 10, step c
[0496] A solution of 1.62 g (10 mmol)
(S)-3-acetylsulfanyl-2-methyl-propionic acid in 20 ml MeOH is
treated with 7.5 ml 4N NaOH and 1.63 g (10 mmol) 6-bromo-hex-1-ene.
After being stirred for 1 h at rt the mixture is diluted with 50 ml
EtOAc and acidified with 25 ml 1N HCl. The organic phase is washed
with brine, dried with sodium sulfate and concentrated in vacuo to
yield (S)-3-hex-5-enylsulfanyl-2-methyl-propionic acid as an oil
which is used without purification for the next step.
[0497] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 5.03 min; MS (ES)
[MNa.sub.2-H].sup.+=247
[0498] The product is dissolved in 20 ml MeOH and 10 ml water,
cooled at +4.degree. C. and treated with 7.35 g (22 mmol)
Oxone.RTM.. The mixture is stirred at rt for 18 h, diluted with 20
ml 1N HCl and extracted with EtOAc (3.times.). The combined organic
phases are dried with sodium sulfate, evaporated and crystallized
from TBME/hexane to yield the title compound as a white powder.
[0499] Mp 51-54.degree. C.
[0500] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.58 min; MS (ES)
[MNa].sup.+=257
b) (S)-2-Methyl-3-(pent-4-ene-1-sulfonyl)-propionic acid Example
3a
[0501] The title compound is obtained by a similar procedure as IIa
using 5-bromo-pent-1-ene instead 6-bromo-hex-1-ene.
[0502] 1H-NMR (400 MHz, CDCl.sub.3): 5.84-5.74 (m, 1H), 5.14-5.09
(m, 2H), 3.63-3.58 (m, 1H), 3.29-3.20 (m, 1H), 3.06-2.98 (m, 3H),
2.28-2.23 (m, 2H), 2.04-1.96 (m, 2H), 1.49 (d, 3H)
[0503] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 2.91 min; MS (ES)
[MNa].sup.+=243
c) 2-Methyl-3-(pent-4-ene-1-sulfonyl)-propionic acid Example
10a
[0504] The title compound is obtained by a similar procedure as IIa
using 5-bromo-pent-1-ene instead 6-bromo-hex-1-ene and racemic
3-acetylsulfanyl-2-methyl-propionic acid instead of
(S)-3-acetylsulfanyl-2-methyl-propionic acid.
d) (S)-3-(But-3-ene-1-sulfonyl)-2-methyl-propionic acid Example
10b
[0505] The title compound is obtained by a similar procedure as IIa
using 4-bromo-but-1-ene instead 6-bromo-hex-1-ene.
[0506] .sup.1H-NMR (400 MHz, CDCl3): 5.91-5.81 (m, 1H), 5.23-5.16
(m, 2H), 3.66-3.60 (m, 1H), 3.63 (dd, 1H), 3.15-3.11 (m, 2H), 3.02
(dd, 1H), 2.68-2.62 (m, 2H), 1.49 (d, 3H)
[0507] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 5-100% MeCN
(6 min), 100% MeCN (1.5 min)): 3.47 min; MS (ES)
[MNa].sup.+=229.0
e) (S)-3-(Hept-6-ene-1-sulfonyl)-2-methyl-propionic acid Example
10c
[0508] The title compound can be obtained by a similar procedure as
IIa using toluene-4-sulfonic acid hept-6-enyl ester instead of
6-bromo-hex-1-ene.
f) (Hept-6-ene-1-sulfonyl)-acetic acid Example 10d
[0509] The title compound can be obtained by a similar procedure as
IIa using toluene-4-sulfonic acid hept-6-enyl ester instead of
6-bromo-hex-1-ene and mercapto-acetic acid instead of
(S)-3-acetylsulfanyl-2-methyl-propionic acid.
g) 3-(Hex-5-ene-1-sulfonyl)-propionic acid Example 10e
[0510] The title compound can be obtained by a similar procedure as
IIa using 3-mercapto-propionic acid instead of
(S)-3-acetylsulfanyl-2-methyl-propionic acid.
[0511] 1H-NMR (400 MHz, CDCl.sub.3): 5.86-5.76 (m, 1H), 5.10-5.01
(m, 2H), 3.33 (t, 2H), 3.08-3.01 (m, 2H), 2.98 (t, 2H), 2.18-2.10
(m, 2H), 2.94-2.87 (m, 2H), 1.63-1.55 (m, 2H)
h) 4-(Pent-4-ene-1-sulfonyl)-butyric acid Example 10f
[0512] An ice cold solution of 0.584 g (6.66 mmol) 4-penten-1-ol
and 1.11 ml (14.0 mmol) pyridine in 5 ml DCM is treated with 0.866
ml (6.77 mmol) benzene sulfonyl chloride. After 30 minutes at
0.degree. C. the mixture is stirred overnight at rt. The mixture is
diluted with DCM, washed with 5% aqueous citric acid, water and 5%
aqueous NaHCO3, dried with sodium sulfate and evaporated, yielding
the benzenesulfonic acid pent-4-enyl ester as a colorless oil that
is used without further purification.
[0513] 1H-NMR (400 MHz, CDCl.sub.3): 7.97-7.92 (m, 2H), 7.72-7.66
(m, 1H), 7.63-7.56 (m, 2H), 5.76-5.66 (m, 1H), 5.01-4.95 (m, 2H),
4.08 (t, 2H), 2.11 (q, 2H), 1.79 (quintet, 2H)
[0514] A mixture of this ester (1.11 g, 4.89 mmol), 0.5 g (4.89
mmol) thiobutyrolactone and 2.45 ml (9.78 mmol) 4N NaOH is stirred
for 7 days. The mixture is acidified with 3.5 ml 4N HCl and
extracted with EtOAc. The organic phase is dried with sodium
sulfate and chromatographed on silica gel (EtOAc/hexane 1:3, 1:2
and 1:1), yielding the 4-pent-4-enylsulfanyl-butyric acid as a
colorless oil.
[0515] .sup.1H-NMR (300 MHz, CDCl.sub.3): 5.84-5.69 (m, 1H),
5.06-4.93 (m, 2H), 2.60-2.44 (m, 6H), 2.20-2.11 (m, 2H), 1.97-1.84
(m, 2H), 1.72-1.60 (m, 2H)
[0516] This acid is dissolved in 20 ml MeOH and 10 ml water, cooled
at +4.degree. C. and treated with 3.52 g (10.84 mmol) Oxone.RTM..
The mixture is stirred 1 h at 0.degree. C. and 18 h at rt. The
mixture is diluted with 10 ml 1N HCl and extracted with EtOAc. The
organic phase is washed with aqueous sodium sulfite, dried with
sodium sulfate, evaporated and crystallized from EtOAc/hexane to
yield the title compound as a white powder.
[0517] Mp 104-107.degree. C.
[0518] 1H-NMR (300 MHz, CDCl.sub.3): 5.81-5.67 (m, 1H), 5.10-5.02
(m, 2H), 3.10-3.03 (m, 2H), 3.01-2.94 (m, 2H), 2.61 (t, 2H),
2.27-2.10 (m, 4H), 2.01-1.89 (m, 2H)
i) (S)-2-Methyl-3-(3-vinyl-phenylmethanesulfonyl)-propionic acid
example 15
[0519] A mixture of 1.84 g (5 mmol), 5 ml 1N NaOH, 1.38 g (10 mmol)
K.sub.2CO.sub.3 and 0.072 mg Pd(PPh.sub.3).sub.4 (0.25 mmol) in 5
ml water and 50 ml DME is heated at 80.degree. C. under nitrogen.
After cooling down the mixture is acidified with 20 ml 2N HCl and
extracted with 150 ml TBME. The organic phase is dried with
Na.sub.2SO.sub.4, filtered and evaporated to yield the title
compound that is used in the next step without purification.
[0520] LC (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 3.75 min; MS (API-ES)
[M-H].sup.-=267.0
[0521] The starting material can be prepared as follows:
1) (S)-3-(3-Iodo-phenylmethanesulfonyl)-2-methyl-propionic acid
[0522] The title compound is prepared similarly to
(S)-3-(hex-5-ene-1-sulfonyl)-2-methyl-propionic acid (IIa), but
starting from (S)-3-(3-iodo-benzylsulfanyl)-2-methyl-propionic acid
instead of (S)-3-hex-5-enylsulfanyl-2-methyl-propionic acid.
[0523] LC (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 3.97 min; MS (API-ES)
[M-H].sup.-=367.0
2) (S)-3-(3-Iodo-benzylsulfanyl)-2-methyl-propionic acid
[0524] The title compound is prepared similarly to
(S)-3-hex-5-enylsulfanyl-2-methyl-propionic acid (IIa), using
1-bromomethyl-3-iodo-benzene instead of 6-bromo-hex-1-ene. LC
(Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN (6 min),
100% MeCN (1.5 min)): 5.11 min; MS (API-ES) [M-H].sup.-=335.0
j)
(S)-2-Methyl-3-(3-methyl-5-vinyl-phenylmethanesulfonyl)-propionic
acid Example 15a
[0525] Potassium vinyltrifluoroborate (247 mg, 1.8 mmol),
triethylamine (0.21 ml, 1.5 mmol) and
[1,1'-bis(diphenylphosphino-.kappa.P)ferrocene]dichloro-palladium
(24 mg) are added to
(S)-3-(3-bromo-5-methyl-phenylmethanesulfonyl)-2-methyl-propionic
acid (0.5 g, 1.5 mmol) in 25 ml propanol. The mixture is stirred
under argon for 2.5 hrs at reflux. After cooling to rt the mixture
is diluted with EtOAc, washed with 0.5 N aqueous hydrochloric acid
and brine, dried over magnesium sulfate, and the solvents are
evaporated. The residue is purified by chromatography on silica gel
(flashmaster, DCM to DCM/methanol 9/1) followed by crystallization
from DCM/diethyl ether/hexane to give the title compound as
off-white crystals.
[0526] Rf: (DCM/methanol=9:1) 0.45
[0527] MS (LC-MS): [MNa].sup.+=305
[0528] The starting material can be prepared as described
hereafter:
x)
(S)-3-(3-Bromo-5-methyl-phenylmethanesulfonyl)-2-methyl-propionic
acid
[0529] To a solution of 6.48 g (21 mmol)
(S)-3-(3-bromo-5-methyl-benzylsulfanyl)-2-methyl-propionic acid in
70 ml acetonitrile and 35 ml water is added 65.7 g (107 mmol)
Oxone.RTM.. After stirring for 2.5 hrs at rt the mixture is diluted
with EtOAc and water to get a clear solution. The organic layer is
washed with brine, dried over magnesium sulfate and the solvent is
evaporated. Crystallization from DCM/diethyl ether and a little
methanol gives the title compound as white crystals.
[0530] Rf: (DCM/methanol=95:5) 0.34
[0531] MS (LC-MS): [MNa].sup.+=357/359
xx) 1-Bromo-3-bromomethyl-5-methyl-benzene
[0532] To a solution of 5 ml (36.8 mmol) 5-bromo-m-xylene and 6.55
g (36.8 mmol) N-bromo-succinimide in 35 ml tetrachloromethane is
added 0.138 ml (0.74 mmol) tert-butyl-perbenzoate. The mixture is
irridiated using a heating lamp and stirred for 3 hrs at reflux
temperature. The mixture is cooled to room temperature, filtered
and evaporated. The product is isolated by chromatography on silica
gel (flashmaster, hexane) to give the title compound as white
crystals.
[0533] Rf: (hexane) 0.38
[0534] MS (EI-MS): 262/264/266 [M+, characteristic pattern for
tribromo compound]
xxx) (S)-3-(3-Bromo-5-methyl-benzylsulfanyl)-2-methyl-propionic
acid
[0535] A solution of 5.55 g (21 mmol)
1-bromo-3-bromomethyl-5-methyl-benzene and 2.90 ml (21 mmol)
(S)-3-acetylsulfanyl-2-methyl-propionic acid in 32 ml methanol is
cooled in an ice bath and 4N aqueous sodium hydroxide (15.8 ml, 63
mmol) are added. The reaction mixture is stirred at rt for 3 hrs.
EtOAc is added to the mixture and the organic layer is washed with
water and brine and evaporated. Filtration over silica gel
(flashmaster, hexane to hexane/EtOAc 4/6) gives the title
compound.
[0536] Rf: (hexane/EtOAc=7/3) 0.36
[0537] 1H-NMR (400 MHz, CDCl.sub.3): 7.30 (s, 1H), 7.25 (s, 1H),
7.08 (s, 1H), 3.68 (s, 2H), 2.79 (dd, 1H), 2.74-2.65 (m, 1H), 2.52
(dd, 1H), 2.35 (s, 3H), 1.30 (d, 3H)
##STR00008## [0538] R.sub.1=Allyl, But-3-enyl, Pent-4-enyl [0539]
Y.dbd.O, NH, NMe, SO.sub.2 [0540] X.dbd.H, Me, OMe, OEt
a) 2-But-3-enylamino-6-methyl-isonicotinic acid Examples 5 and
13a
[0541] A solution of 86 mg (0.33 mmol)
2-but-3-enylamino-6-methyl-isonicotinic acid tert-butyl ester in 2
ml TFA is stirred for 18 h and evaporated. The title compound thus
obtained is used in the next step without further purification.
[0542] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.20 (s, 1H), 7.00 (s,
1H), 5.87-5.71 (m, 1H), 5.21-5.10 (m, 2H), 3.42 (t, 2H), 2.58 (s,
3H), 2.47 (q, 2H)
[0543] LC (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 1.23 min. MS (ES)
[MH].sup.+=207.2
[0544] The starting material can be prepared as follows:
x) 2-But-3-enylamino-6-methyl-isonicotinic acid tert-butyl
ester
[0545] Under rigorous exclusion of oxygen a mixture of 200 mg (0.88
mmol) 2-chloro-6-methyl-isonicotinic acid tert-butyl ester, 10 mg
palladium(II)acetate (0.044 mmol), 27 mg (0.44 mol) BINAP
(R(+)-2,2-bis(diphenylphosphino)-1,1-binaphtalene) and 62 mg (0.88
mmol) but-3-enylamine in 10 ml toluene is heated at 60.degree. C.
for 4 h. The mixture is diluted with EtOAc, washed with 10% aqueous
NaHCO3 and water, dried with sodium sulfate and evaporated.
Chromatography of the product on silica gel (hexane/EtOAc 9:1)
yields the title compound.
[0546] .sup.1H-NMR (300 MHz, CDCl.sub.3): 6.86 (s, 1H), 6.67 (s,
1H), 5.87-5.71 (m, 1H), 5.16-5.05 (m, 2H), 4.6 (br, 1H), 3.31 (q,
2H), 2.4-2.31 (m, 2H), 2.38 (s, 3H), 1.55 (s, 9H) LC (Nucleosil
C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN (6 min), 100% MeCN
(1.5 min)): 3.75 min
xx) 2-Chloro-6-methyl-isonicotinic acid tert-butyl ester
[0547] A suspension of 0.2 g (1.17 mmol)
2-chloro-6-methyl-isonicotinic acid in 5 ml toluene is treated with
2 drops of DMF and 0.17 ml (2.33 mmol) SOCl2 and refluxed for 4 h.
The mixture is concentrated under reduced pressure and the residue
is taken up in 1.5 ml DCM, 0.22 ml tBuOH and 0.24 ml Et3N and
stirred in the presence of 7 mg (0.06 mmol) DMAP for 18 h. The
mixture is diluted with DCM, washed with 10% aqueous citric acid,
water and 10% aqueous NaHCO3, dried with sodium sulfate and
evaporated. Chromatography of the pro-duct on silica gel
(hexane/EtOAc 4:1 and 3:1) yields the title compound as a yellowish
solid.
[0548] .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.65 (s, 1H), 7.60 (s,
1H), 2.82 (s, 3H), 1.62 (s, 9H) LC (Nucleosil C-18HD, 4.times.70
mm, 3 .mu.M, 20-100% MeCN (6 min), 100% MeCN (1.5 min)): 5.83
min
b) 2-But-3-enylamino-6-methoxy-isonicotinic acid Step c of Example
11
[0549] A mixture of 1.0 g (5.3 mmol)
2-chloro-6-methoxy-isonicotinic acid, 4.4 g (53 mmol, 86% pure by
NMR) but-3-enylamine and 85 mg (0.53 mmol) CuSO.sub.4 in 10 ml
H.sub.2O is stirred in a pressurized reaction vessel for 36 h at
140.degree. C. The reaction mixture is diluted with an 0.5 M
aqueous citric acid and extracted two times with EtOAc. The
combined extracts are washed with citric acid solution, water and
brine, dried over Na.sub.2SO.sub.4, filtered and the solvent is
evaporated. Chromatography on silica gel yields the title compound
as an off-white powder.
[0550] HPLC (XTerra 4.5 cm, 95% CH.sub.3CN, 50.degree. C.): 3.64
min. MS (LC/MS): [MH].sup.+=223.3
c) 3-(Benzyloxycarbonyl-but-3-enyl-amino)-5-methoxy-benzoic acid
Example 11a
[0551] A mixture of 0.75 g (2.38 mmol)
3-benzyloxycarbonylamino-5-methoxy-benzoic acid, 1.07 g (2.85 mmol)
NaI, 2.3 g (7.14 mmol) Cs.sub.2CO.sub.3 and ca. 1 ml (10 mmol)
4-bromo-but-1-ene in 2 ml DMF is heated at 40.degree. C. for 18 h.
After cooling down the reaction mixture is diluted with TBME and
washed with water. The organic phase is dried with sodium sulfate
and evaporated. Purification of the crude product by chromatography
on silica gel (hexane EtOAc 5:1) gives the
3-(benzyloxycarbonyl-but-3-enyl-amino)-5-methoxy-benzoic acid
methyl ester. LC (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 6.07 min. MS (ES)
[MNa].sup.+=392.2
[0552] This ester (118 mg, 0.32 mmol) is dissolved in 2 ml MeOH and
treated with 2 ml 1N NaOH for 18 h. The mixture is acidified with 1
N HCl and extracted with EtOAc. The organic phase is dried with
sodium sulfate and evaporated to yield the title compound.
[0553] LC (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 5.14 min. MS (ES) [MNa].sup.+=378.2,
[M-H+Na.sub.2].sup.+=400.2
d) 3-Hex-5-enyloxy-benzoic acid Example 11b
[0554] The title compound is prepared similarly to
3-(9-decenyloxy)benzoic acid in Lin, H--C et al Macromolecules
1998, 31, 7298.
[0555] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.73-7.10 (m, 4H),
5.90-5.76 (m, 1H), 5.08-4.95 (m, 2H), 4.02 (t, 2H), 3.14 (q, 2H),
1.90-1.78 (m, 2H), 1.66-1.54 (m, 2H)
[0556] LC (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 5.33 min. MS (ES)
[M-H+Na.sub.2].sup.+=265.2
e) 3-But-3-enyloxy-benzoic Acid Example 11c
[0557] The title compound is prepared similarly to
3-(9-decenyloxy)benzoic acid in Lin, H--C et al Macromolecules
1998, 31, 7298.
[0558] .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.71 (d, 1H), 7.63-7.60
(m, 1H), 7.37 (t, 1H), 7.16 (dd, 1H), 5.97-5.87 (m, 1H), 5.22-5.12
(m, 2H), 4.09 (t, 2H), 2.61-2.56 (m, 2H)
[0559] LC (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 4.55 min. MS (ES)
[MNa.sub.2-H].sup.+=237.0
f) 3-Pent-4-enyloxy-benzoic acid Example 11d
[0560] The title compound is prepared similarly to
3-(9-decenyloxy)benzoic acid in Lin, H--C et al Macromolecules
1998, 31, 7298.
[0561] .sup.1H-NMR (400 MHz, CDCl.sub.3): 7.71 (d, 1H), 7.62 (s,
1H), 7.37 (t, 1H), 7.16 (d, 1H), 5.92-5.82 (m, 1H), 5.11-5.01 (m,
2H), 4.04 (t, 2H), 2.30-2.25 (m, 2H), 1.96-1.90 (m, 2H) LC
(Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN (6 min),
100% MeCN (1.5 min)): 5.00 min. MS (ES)
[MNa.sub.2-H].sup.+=251.0
g) 3-(But-3-ene-1-sulfonyl)-benzoic acid Example 11m
[0562] The title compound is obtained by a similar procedure as IIa
using 4-bromo-but-1-ene instead 6-bromo-hex-1-ene and
3-mercapto-benzoic acid instead of
(S)-3-acetylsulfanyl-2-methyl-propionic acid.
[0563] .sup.1H-NMR (400 MHz, CDCl.sub.3): 8.71 (s, 1H), 8.45 (d,
1H), 8.22 (d, 1H), 7.58 (t, 1H), 5.82-5.72 (m, 1H), 5.14-5.09 (m,
2H), 3.29-3.22 (m, 2H), 2.58-2.50 (m, 2H)
[0564] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.43 min; MS (ES)
[MNa].sup.+=263.0
h) 2-Ethoxy-6-pent-4-enylamino-isonicotinic acid Example 13
[0565] The title compound is prepared by stirring
2-ethoxy-6-pent-4-enylamino-isonicotinic acid tert-butyl ester 18 h
in neat trifluoroacetic acid. Evaporation of the TFA gives the
title compound that is used in the next step without
purification.
[0566] The starting material can be prepared with methods described
for examples IIIa and IIIb.
x) 2-Ethoxy-6-pent-4-enylamino-isonicotinic acid tert-butyl
ester
[0567] .sup.1H-NMR (300 MHz, CDCl.sub.3): 6.47 (s, 2H), 5.89-5.76
(m, 1H), 5.10-4.97 (m, 2H), 4.28 (q, 2H), 3.30 (t, 3H), 2.20 (q,
2H), 1.79-1.67 (m, 2H), 1.57 (s, 9H), 1.39 (t, 3H)
[0568] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 6.66 min; MS (API-ES)
[M-H]-=305.2
i) 2-(1-Ethyl-but-3-enylamino)-6-methoxy-isonicotinic acid example
13b
[0569] The title compound is prepared by stirring
2-ethoxy-6-pent-4-enylamino-isonicotinic acid tert-butyl ester 18 h
in neat trifluoroacetic acid. Evaporation of the TFA gives the
title compound that is used in the next step without
purification.
[0570] The starting material can be prepared with methods described
for example IIIa and IIIb.
x) 2-(1-Ethyl-but-3-enylamino)-6-methoxy-isonicotinic acid
tert-butyl ester
[0571] .sup.1H-NMR (400 MHz, CDCl.sub.3): 6.49 (s, 2H), 5.91-5.80
(m, 1H), 5.16-5.08 (m, 2H), 4.4 (br, 1H), 3.89 (s, 3H), 3.85-3.76
(m, 1H), 2.42-2.29 (m, 2H), 1.72-1.51 (m, 2H), 1.58 (s, 9H), 0.99
(t, 3H)
[0572] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 6.64 min
xx) 1-Ethyl-but-3-enylamine, hydrochloride
[0573] A stirred mixture of 23.4 g (149 mmol)
(1-ethyl-but-3-enyl)-carbamic acid methyl ester, 33.4 g (0.6 mol)
powdered KOH in 50 ml diethylene glycol is heated at 100.degree. C.
After the development of gas ceases the mixture is further heated
at 118.degree. C. for 1 hour while methanol is distilled of. After
cooling down the mixture is diluted with water, extracted twice
with TBME. The combined organic phases are washed with 10% aqueous
NaCO3 solution, dried with K.sub.2CO.sub.3 and extracted with 75 ml
2N HCl. The aqueous phase is concentrated in vacuo and the residue
crystallised from EtOAc/TBME to yield the title compound
(hydrochloride salt).
[0574] 1H-NMR (400 MHz, D.sub.2O): 5.76-5.64 (m, 1H), 5.18-5.11 (m,
2H), 3.19-3.11 (m, 1H), 2.42-2.33 (m, 1H), 2.25-2.16 (m, 1H),
1.64-1.47 (m, 2H), 0.86 (t, 3H)
xxx) (1-Ethyl-but-3-enyl)-carbamic acid methyl ester
[0575] To a cooled solution of 11.6 g (0.2 mol) propionaldehyde, 15
g (0.2 mol) carbamic acid methyl ester and 22.92 g allyl trimethyl
silane in 200 ml acetonitrile are added dropwise 28.4 g (0.2 mol)
boron trifluoride etherate. After the addition the mixture is
neutralised with 10% aqueous Na.sub.2CO.sub.3 and extracted with
EtOAc. The organic phase is washed with water, dried with sodium
sulfate, evaporated and distilled at 1 mbar, yielding the title
compound as a colorless liquid.
[0576] Bp: 59-61.degree. C.
[0577] 1H-NMR (400 MHz, CDCl.sub.3): 5.86-5.74 (m, 1H), 5.14-5.08
(m, 2H), 4.5 (br, 1H), 3.76-3.63 (m, 1H), 3.70 (s, 3H), 2.23-2.17
(m, 2H), 1.63-1.51 (m, 1H), 1.47-1.38 (m, 1H), 0.95 (t, 3H)
##STR00009##
[0578] R.sub.1.dbd.H, Me, Et, Pr, cPr
[0579] R.sub.2=Allyl, But-3-enyl
[0580] X.dbd.H, Me, OMe, OEt, OiPr, SO.sub.2Me, Oxazol-2-yl
a) N-allyl-N-methyl-isophthalamic acid Example 1e
[0581] A solution of 2.5 g (13.9 mmol) isophthalic acid mono methyl
ester in 25 ml THF, cooled at -30.degree. C. is treated with 2.32
ml (16.9 mmol) Et.sub.3N followed by 2.0 ml (15.3 mmol) isobutyl
chloroformate. After 30 min at -20.degree. C. are added 1.4 ml
(13.9 mmol) methyl allyl amine to the white suspension. After 4 h
at -20.degree. C. the mixture is poured into 50 ml water and
extracted with EtOAc. The organic phase is washed with water, dried
with Na.sub.2SO.sub.4 and evaporated. The residue is purified via
chromatography on silica gel (EtOAc/hexane 1:2), yielding the
methyl ester of the title compound. This ester is taken up in 5 ml
MeOH and 5 ml 1N NaOH. After stirring for 2 h the mixture is
acidified with 6 ml 1N HCl and extracted with EtOAc. The organic
layer is dried with Na.sub.2SO.sub.4 and evaporated to yield the
title compound as a white solid.
[0582] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 2.92 min; MS (ES)
[MNa].sup.+=242.2
b) N-allyl-N-ethyl-isophthalamic acid Example 11f
[0583] The title compound is obtained by a similar procedure as IVa
using allyl-ethyl-amine instead of allyl-methyl-amine.
[0584] Mp. 118-121.degree. C.
[0585] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.29 min; MS (ES)
MH.sup.+=234.2, MNa.sup.+=256.2, [M-H]Na.sub.2.sup.+=278.2
[0586] The starting material can be obtained as follows:
x) Allyl Ethyl Amine Hydrochloride
[0587] At 10.degree. C. 28.9 g allyl-ethyl-carbamic acid tert-butyl
ester (156 mmol) are dissolved in 200 ml 4N HCl in dioxane and
slowly warmed to room temperature. When the development of gas has
ceased the mixture is warmed at 30.degree. C. for 1 h. The mixture
is concentrated under reduced pressure and crystallized from
EtOH/TBME to yield the hydrochloric acid salt of allyl ethyl amine
as white plates.
[0588] Mp: 188.5-189.degree. C.
[0589] .sup.1H-NMR (400 MHz, D.sub.2O): 5.85-5.74 (m, 1H),
5.40-5.33 (m, 2H), 3.52 (d, 2H), 2.97 (q, 2H), 1.15 (t, 3H)
xx) Allyl-Ethyl-Carbamic Acid Tert-Butyl Ester
[0590] A solution of 31.44 g allyl-carbamic acid tert-butyl ester
(200 mmol) in 300 ml DMF and 30 ml dry THF is treated with 12 g
(300 mmol) NaH (60% suspension in mineral oil). The temperature is
kept below 40.degree. C. with an cold water bath. When the
development of hydrogen gas ceased the reaction mixture is treated,
under ice cooling, with 24 ml (300 mmol) ethyl iodide. After 16 h
the mixture is diluted with 1 l water and extracted with TBME. The
organic layer is washed extensively with water, concentrated under
reduced pressure and distilled at 0.3 mmHg, bp. 38-390, to yield
the allyl-ethyl-carbamic acid tert-butyl ester.
[0591] Rf: (hexane/ethyl acetate 6:1) 0.45
[0592] .sup.1H-NMR (400 MHz, CDCl.sub.3): 5.87-5.75 (m, 1H),
5.19-5.12 (m, 2H), 3.83 (br, 2H), 3.16 (br, 2H), 1.48 (s, 9H), 1.11
(t, 3H)
c) N-allyl-N-propyl-isophthalamic acid Example 11g
[0593] The title compound is made using methods described for Acid
IVb. LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 2.92 min; MS (ES) [MH].sup.+=248.2,
[MNa].sup.+=270.2
d) N-allyl-N-cyclopropyl-isophthalamic acid Example 11h
[0594] A solution of 0.3 g (1.37 mmol) N-cyclopropyl-isophthalamic
acid in 10 ml THF is treated with 142 mg (3.55 mmol) NaH (60%
suspension in mineral oil) and stirred at 25.degree. C. After 2 h
0.27 ml (3.23 mmol) allylbromide is added and after 18 h the
reaction is quenched with water. The mixture is acidified with 2N
HCl and extracted with EtOAc. The organic phase is washed with
brine, dried with sodium sulfate and evaporated to yield the title
compound that is used in the next step without purification.
[0595] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.47 min; MS (ES)
MH.sup.+=246.2, MNa.sup.+=268.2 The starting material can be
prepared as follows:
x) N-cyclopropyl-isophthalamic acid
[0596] A solution of 0.5 g (2.77 mmol) isophthalic acid mono methyl
ester, 5 ml toluene and 0.8 ml SOCl2 is treated with one drop DMF
and heated to 80.degree. C. till the evolution of gas ceases.
[0597] After cooling down the mixture is evaporated, dissolved in 2
ml DCM and added to an at 0.degree. C. stirred mixture of 5 ml 10%
aqueous Na.sub.2CO.sub.3, 0.21 ml (3.0 mmol) cyclopropyl amine and
5 ml DCM. After 1 h the layers are separated and the organic layer
is washed with 1N HCl, brine, dried with sodium sulfate and
evaporated. The crude product is crystallized (EtOAc, hexane) to
yield N-cyclopropyl-isophthalamic acid methyl ester as off-white
crystals.
[0598] .sup.1H-NMR (400 MHz, CDCl.sub.3): 8.33 (s, 1H), 8.18 (d,
1H), 8.05 (d, 1H), 7.55 (t, 1H), 6.41 (br, 1H), 3.97 (s, 3H),
3.00-2.91 (m, 1H), 0.98-0.85 (m, 2H), 0.75-0.62 (m, 2H)
e) N-allyl-N-methyl-5-methoxy-isophthalamic acid Example 11i
[0599] The title compound is made using methods described for Acid
IVb. LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 3.15 min; MS (ES) [MH].sup.+=250.0,
[MNa].sup.+=272.0
f) N-allyl-N-ethyl-5-methoxy-isophthalamic acid Example 11j
[0600] The title compound is made using methods described for Acid
IVb. LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 3.55 min; MS (ES) [MH].sup.+=264.2,
[MNa].sup.+=286.2
g) N-allyl-N-propyl-5-methoxy-isophthalamic acid Example 11k
[0601] The title compound is made using methods described for Acid
IVb. LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 3.97 min; MS (ES) [MH].sup.+=278.2,
[MNa].sup.+=300.2
h) N-but-3-enyl-isophthalamic acid Example 11l
[0602] The title compound is made using methods described for Acid
IVa. LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 2.99 min; MS (ES) [MH].sup.+=220.2,
[MNa].sup.+=242.2
i) N-allyloxy-N-ethyl-isophthalamic acid Example 12a
[0603] The title compound is made using methods described for Acids
IVb, IVc and IVj. LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M,
20-100% MeCN (6 min), 100% MeCN (1.5 min)): 4.10 min; MS (ES)
[MH].sup.+=294.2, [MNa].sup.+=316.2, [MNa.sub.2-H].sup.+=338.2
j) N-Allyl-N-ethyl-5-ethoxy-isophthalamic acid Example 13c
[0604] A solution of 1.0 g (4.45 mmol) 5-ethoxy-isophthalic acid
mono methyl ester, 10 ml toluene and 0.5 ml SOCl2 is treated with
one drop DMF and heated to 80.degree. C. till the evolution of gas
ceases. After cooling down the mixture is evaporated, dissolved in
5 ml DCM and added to an at 0.degree. C. stirred mixture of 10 ml
10% aqueous Na.sub.2CO.sub.3, 0.81 g (6.7 mmol) allyl ethyl amine
hydrochloride (see IVb) and 5 ml DCM. After 1 h the layers are
separated and the organic layer is washed with 1N HCl, brine, dried
with sodium sulfate and evaporated to yield the
N-allyl-5-ethoxy-N-ethyl-isophthalamic acid methyl ester. This
ester is dissolved in 20 ml MeOH, treated with 15 ml 1N NaOH and
stirred for 18 h. The methanol is evaporated, the residue acidified
with 1N HCl and extracted with TBME. The organic layer is dried
with sodium sulfate and evaporated to yield the title compound.
[0605] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.95 min; MS (ES)
[MH].sup.+=278.2, [MNa].sup.+=300.2
[0606] The starting material can be obtained as follows:
x) 5-Ethoxy-isophthalic acid mono methyl ester
[0607] A suspension of 11.0 g (46.1 mmol) 5-ethoxy-isophthalic acid
dimethyl ester in 100 ml MeOH and 20 ml THF is treated with 18.4 ml
2N NaOH and stirred overnight. The clear solution is concentrated,
diluted with some water and washed with TBME. The aqueous phase is
acidified with 2N HCl and extracted with TBME. The organic phase is
dried with sodium sulfate and evaporated to give the mono
ester.
[0608] .sup.1H-NMR (400 MHz, CDCl.sub.3): 8.38 (s, 1H), 7.84 (s,
2H), 4.18 (q, 2H), 3.98 (s, 3H), 1.37 (t, 3H)
xx) 5-Ethoxy-isophthalic acid dimethyl ester
[0609] To a suspension of 10 g (47.57 mmol) 5-hydroxy-isophthalic
acid dimethyl ester and 9.86 g (71.36 mmol) K.sub.2CO.sub.3 in 50
ml DMF is added dropwise 7.67 ml (95.1 mmol) ethyl iodide. After
the addition the mixture is stirred for 5 h, diluted with water and
extracted with TBME. The organic phase is washed with water, dried
with sodium sulfate and evaporated to give the title compound.
[0610] .sup.1H-NMR (400 MHz, CDCl.sub.3): 8.29 (s, 1H), 7.77 (s,
2H), 4.15 (q, 2H), 3.95 (s, 6H), 1.47 (t, 3H)
k) N-Allyl-N-ethyl-5-isopropoxy-isophthalamic acid Example 13d
[0611] The title compound is made using methods described for Acid
IVj. LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 4.23 min; MS (ES) [MH].sup.+=292.2,
[MNa].sup.+=314.2
l) N-Allyl-5-methyl-N-ethyl-isophthalamic acid Example 13e
[0612] The title compound is made using methods described for Acid
IVj. LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 3.74 min; MS (ES) [MH].sup.+=248.2,
[MNa].sup.+=270.2
m) N-Allyl-N-ethyl-5-methanesulfonyl-isophthalamic acid Example
13f
[0613] The title compound is made using methods described for Acid
IVj from 5-methanesulfonyl-isophthalic acid.
[0614] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.03 min; MS (ES)
[MH].sup.+=312.0, [MNa].sup.+=334.0
n) N-Allyl-N-ethyl-5-oxazol-2-yl-isophthalamic acid Example 13g
[0615] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.52 min; MS (ES)
[MH].sup.+=301.2, [MNa].sup.+=323.2
o) N-But-3-enyl-N-ethyl-isophthalamic acid Example 13h
[0616] The title compound is made using methods described for Acid
IVc. LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100% MeCN
(6 min), 100% MeCN (1.5 min)): 3.63 min; MS (ES) [MH].sup.+=248.2,
[MNa].sup.+=270.2
##STR00010##
[0617] X.dbd.SO.sub.2, C.dbd.O
[0618] R.dbd.H, Me
[0619] n=1-4
[0620] m=1-3
a) 3-(Methyl-pent-4-enyl-sulfamoyl)-propionic acid Example 14
[0621] To a stirred suspension of 1.03 g (12.0 mmol)
pent-4-enylamine, 8 ml DCM and 5 ml 10% aqueous Na.sub.2CO.sub.3 at
0.degree. C. are added dropwise 2.25 g (12.0 mmol)
3-chlorosulfonyl-propionic acid methyl ester. After stirring for 2
h at 25.degree. C. the phases are separated and the organic phase
is dried with sodium sulfate and evaporated. Chromatography on
silica gel (EtOAc, hexane 1:2) gives the
3-pent-4-enylsulfamoyl-propionic acid methyl ester. This ester is
dissolved in 2 ml DMF and heated to 65.degree. C. in the presence
of 1.58 g (11.5 mmol) K.sub.2CO.sub.3 and 0.716 ml methyl iodide
for 5 h. The mixture is diluted with EtOAc and washed with water,
dried with sodium sulfate and evaporated. Chromatography on silica
gel (EtOAc, hexane 1:4) gives the
3-(methyl-pent-4-enyl-sulfamoyl)-propionic acid methyl ester.
Hydrolysis of this ester with LiOH in water/MeOH gives the title
compound.
[0622] .sup.1H-NMR (400 MHz, CDCl.sub.3): 5.89-5.78 (m, 1H),
5.11-5.01 (m, 2H), 3.27 (t, 2H), 3.20 (t, 2H), 2.64 (t, 2H), 2.63
(s, 3H), 2.13 (q, 2), 1.77-1.69 (m, 2H)
[0623] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 3.45 min; MS (ES),
[MNa].sup.+=258.0
b) N-But-3-enyl-succinamic acid Example 14a
[0624] A mixture of 0.71 g (10 mmol) but-3-enylamine and 1.0 g (10
mmol) succinic anhydride in 10 ml DCM is stirred for 16 h. The
mixture is poured into 25 ml 1N NaOH, washed with TBME, acidified
with 6 ml 6N HCl, saturated with NaCl and extracted with THF/EtOAc
twice. The combined organic layers are dried with sodium sulfate
and evaporated to yield the title compound.
[0625] .sup.1H-NMR (400 MHz, CDCl.sub.3): 5.86 (br, 1H), 5.86-5.74
(m, 1H), 5.17-5.10 (m, 2H), 3.38 (q, 2H), 2.74 (t, 2H), 2.54 (t,
2H), 2.30 (q, 3H)
[0626] LC/MS (Nucleosil C-18HD, 4.times.70 mm, 3 .mu.M, 20-100%
MeCN (6 min), 100% MeCN (1.5 min)): 1.29 min; MS (ES),
[MNa].sup.+=194.0
* * * * *