U.S. patent application number 09/928593 was filed with the patent office on 2002-03-28 for mevinolin derivatives.
Invention is credited to Baenteli, Rolf, Bauer, Wilfried, Cottens, Sylvain, Ehrhardt, Claus, Hommel, Ulrich, Kallen, Joerg, Meingassner, Josef Gottfried, Nuninger, Francois, Weitz Schmidt, Gabriele.
Application Number | 20020037895 09/928593 |
Document ID | / |
Family ID | 26315146 |
Filed Date | 2002-03-28 |
United States Patent
Application |
20020037895 |
Kind Code |
A1 |
Baenteli, Rolf ; et
al. |
March 28, 2002 |
Mevinolin derivatives
Abstract
Mevinolin derivatives wherein the lactone ring is modified have
interesting pharmaceutical properties, particularly in preventing
or treating disorders or diseases mediated by LFA-1/ICAM-1
interactions.
Inventors: |
Baenteli, Rolf; (Basel,
CH) ; Bauer, Wilfried; (Lampenberg, CH) ;
Cottens, Sylvain; (Witterswil, CH) ; Ehrhardt,
Claus; (Loerrach, DE) ; Hommel, Ulrich;
(Muellheim, DE) ; Kallen, Joerg; (Basel, CH)
; Meingassner, Josef Gottfried; (Perchtoldsdorf, AT)
; Nuninger, Francois; (Wittenheim, FR) ; Weitz
Schmidt, Gabriele; (Bad Krozingen, DE) |
Correspondence
Address: |
THOMAS HOXIE
NOVARTIS CORPORATION
PATENT AND TRADEMARK DEPT
564 MORRIS AVENUE
SUMMIT
NJ
079011027
|
Family ID: |
26315146 |
Appl. No.: |
09/928593 |
Filed: |
August 13, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09928593 |
Aug 13, 2001 |
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PCT/EP00/01191 |
Feb 14, 2000 |
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Current U.S.
Class: |
514/228.8 ;
514/317; 514/540; 544/97; 546/206; 560/256 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 27/02 20180101; A61P 37/06 20180101; C07C 235/30 20130101;
A61P 1/04 20180101; A61P 17/04 20180101; A61P 17/00 20180101; A61P
29/00 20180101; A61P 37/02 20180101; C07D 211/76 20130101; A61P
17/08 20180101; A61P 9/10 20180101; A61P 17/02 20180101; C07C
271/12 20130101; A61P 5/14 20180101; A61P 17/14 20180101; A61P
17/06 20180101; A61P 31/04 20180101; A61P 37/00 20180101; A61P
37/08 20180101; A61P 11/00 20180101; C07C 2602/28 20170501; A61P
13/12 20180101; A61P 25/28 20180101; C07C 235/26 20130101; A61P
3/10 20180101; A61P 3/06 20180101; C07C 237/18 20130101; A61P 21/04
20180101; C07D 265/10 20130101; A61P 9/00 20180101 |
Class at
Publication: |
514/228.8 ;
514/317; 514/540; 544/97; 546/206; 560/256 |
International
Class: |
C07D 265/10; C07D
211/06; C07C 215/42; A61K 031/445; A61K 031/535 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 16, 1999 |
GB |
9903546.1 |
Nov 25, 1999 |
GB |
9927880.6 |
Claims
1. A compound of formula I 36wherein each of a-b and .alpha.-.beta.
independently, is either a single bond or a double bond; R.sub.1 is
. . . H, . . . C.sub.1-4alkyl or --OR.sub.a wherein R.sub.a is H,
C.sub.1-6alkyl optionally substituted by OH or C.sub.1-4alkoxy,
C.sub.2-6alkenyl or aryl-0.sub.14alkyl; R.sub.2 is OH;
--O--CO--R.sub.5 wherein R.sub.5 is C.sub.1-8alkyl,
C.sub.3-7cycloalkyl, C.sub.3-7cycloalkyl-C.sub.1-4alkyl, aryl or
aryl-C.sub.1-4alkyl; or --O--R.sub.6 wherein R.sub.6 is the residue
of an .alpha.-amino-acid attached to O through its carbonyl residue
or --CHR.sub.7COR.sub.8 wherein R.sub.7 is H, C.sub.1-4alkyl,
heteroC.sub.1-4alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-4alkyl, aryl or aryl-C.sub.1-4alkyl and
R.sub.8 is OH, C.sub.1-4alkoxy or NR.sub.9R.sub.10 wherein each of
R.sub.9 and R.sub.10 independently is H, C.sub.1-4alkyl or R.sub.9
and R.sub.10 form together with the nitrogen to which they are
bound, a heteroaryl group; R.sub.3 is a substituted lactam,
piperidyl, linear amino alcohol or cyclic carbamate, or a residue
of formula (i) 37wherein R.sub.13 is OH; C.sub.1-6alkoxy;
--O--CO--C.sub.1-6alkyl; or --CO--NHC.sub.1-6alkyl; R.sub.14 is OH;
C.sub.1-4alkoxy; C.sub.1-4alkyl;
C.sub.1-4alkoxy-carbonyl-C.sub.1-4alkoxy- ;
hydroxy-C.sub.1-5alkoxy; C.sub.1-4alkoxy-C.sub.1-5alkoxy;
C.sub.1-4alkoxy-carbonyl-C.sub.1-4alkyl; or
NR.sub.9aR.sub.10a-C.sub.1-5a- lkoxy wherein each of R.sub.9a and
R.sub.10a independently has one of the significances given for
R.sub.9 and R.sub.10; R.sub.15 is H or C.sub.1-4alkyl; and R.sub.16
is CONR.sub.17R.sub.18 wherein one of R.sub.17 and R.sub.18 is H
and the other is C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl,
C.sub.3-7cycloalkyl-C.sub.1-4alkyl or aryl-C.sub.1-4alkyl; or
C.sub.1-6alkoxy-carbonyl; each of a-b and .alpha.-.beta. being a
single bond when each of R.sub.13 or R.sub.14 is OH; and R.sub.4 is
H or OR.sub.19 wherein R.sub.19 is C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl, C.sub.1-4alkoxy-C.sub.1-6alkyl,
aryl-C.sub.1-4alkyl or C.sub.1-4alkoxycarbonyl-C.sub.1-4alkyl, and
wherever "aryl" appears as is or in the significances of
"aryl-C.sub.1-4alkyl" in the above definition, it is "phenyl" or
"naphthyl" optionally substituted by halogen, OH,
NR.sub.11R.sub.12, COOH, CF.sub.3, C.sub.1-4alkoxy, C.sub.1-4alkyl,
hydroxy-C.sub.1-4alkyl, hydroxy-C.sub.1-4alkoxy,
C.sub.1-4alkoxy-carbonyl, cyano or CONR.sub.11R.sub.12, each of
R.sub.11 and R.sub.12 independently being H, C.sub.1-4alkyl,
phenyl, naphthyl, phenyl-C.sub.1-4alkyl or naphthyl-C.sub.1-4alkyl
or R.sub.11 and R.sub.12 together with the nitrogen to which they
are bound forming heteroaryl; and wherever "heteroaryl" appears, it
is a 5- or 6-membered heterocyclic residue optionally fused to a
benzene ring; in free form or in salt form.
2. A compound according to claim 1 wherein R.sub.3 is a radical of
formula (a), (b), (c.sub.1) or (C.sub.2) 38wherein R.sub.30 is
C.sub.1-8alkyl; C.sub.3-7cycloalkyl; aryl;
C.sub.3-7cycloalkyl-C.sub.1-4alkyl; aryl-C.sub.1-4alkyl;
heteroaryl; or heteroaryl-C.sub.1-4alkyl; R.sub.31 is OH;
C.sub.1-4alkoxy; C.sub.1-4alkyl; C.sub.1-4alkoxy-carbonyl-C.sub.1--
4alkoxy; hydroxy-C.sub.1-5alkoxy; C.sub.1-4alkoxy-C.sub.1-5alkoxy;
C.sub.1-4alkoxy-carbonyl-C.sub.1-4alkyl; amino-C.sub.1-4alkoxy;
HOOC-C.sub.1-4alkoxy; HOOC-C.sub.1-4alkyl; or
NR.sub.9aR.sub.10a-C.sub.1-- 5alkoxy wherein each of R.sub.9a and
R.sub.10a independently is H, C.sub.1-4alkyl or R.sub.9a and
R.sub.10a form together with the nitrogen to which they are bound,
a heteroaryl group; R.sub.40 has one of the significances given for
R.sub.30; R.sub.41 has one of the significances given for R.sub.31
or is --O--CO--C.sub.1-8alkyl; either each of X and Y is H or X and
Y form together 39each of R.sub.50, independently is H;
C.sub.1-8alkyl; C.sub.3-7cycloalkyl; aryl;
C.sub.3-7cycloalkyl-C.sub.1-4a- lkyl; aryl-C.sub.1-4alkyl;
heteroaryl; heteroaryl-C.sub.1-4alkyl; C.sub.1-4alkyl-carbonyl;
aryl-carbonyl; heteroaryl-carbonyl; aryl-C.sub.1-4alkyl-carbonyl or
heteroaryl-C.sub.1-4alkyl-carbonyl, and each of R.sub.51,
independently is H; C.sub.1-4alkyl; hydroxy-C.sub.1-4alkyl;
amino-C.sub.1-4alkyl; C.sub.1-4alkoxy-C.sub.1-4al- kyl;
C.sub.1-4alkoxy-carbonyl-C.sub.1-4alkyl wherein C.sub.1-4alkoxy is
optionally substituted by amino, C.sub.1-4alkyl-amino or
di-(C.sub.1-4alkyl)-amino; HOOC-C.sub.1-4alkyl; or
R.sub.23R.sub.24N--CO--C.sub.1-4alkyl wherein R.sub.23 is H,
C.sub.1-4alkyl, hydroxy-C.sub.1-4alkyl, polyhydroxy-C.sub.1-8alkyl,
heteroaryl, heteroaryl-C.sub.1-4alkyl, amino-C.sub.1-4alkyl,
C.sub.1-4alkylamino-C.sub.1-4alkyl,
di-(C.sub.1-4alkyl)amino-C.sub.1-4alk- yl or aryl-C.sub.1-4alkyl
and R.sub.24 is H, C.sub.1-4alkyl or hydroxy-C.sub.1-4alkyl, at
least one of R.sub.50 and R.sub.51 being other than H.
3. A compound according to claim 2 wherein R.sub.3 is a radical of
formula (a); R.sub.30 being benzyl or naphthyl-methyl wherein the
phenyl or naphthyl ring is optionally substituted by OH,
C.sub.1-4alkoxy, hydroxy-C.sub.1-4alkoxy or hydroxy-C.sub.1-4alkyl,
or morpholino, pyridyl, indolyl or quinolyl; and R.sub.31 being OH,
C.sub.1-4alkoxy, hydroxy-C.sub.1-4alkoxy,
C.sub.1-4alkoxy-carbonyl-C.sub.1-4alkoxy or
HOOC-C.sub.1-4alkoxy.
4. A compound according to claim 2 wherein R.sub.3 is a radical of
formula (c.sub.1) or (C.sub.2) wherein X and Y form together
--CO--; R.sub.50 being benzyl or naphthyl-methyl wherein the phenyl
or naphthyl ring is optionally substituted by OH, C.sub.1-4alkoxy,
hydroxy-C.sub.1-4alkoxy or hydroxy-C.sub.1-4alkyl; and R.sub.51
being hydroxy-C.sub.1-4alkyl; amino-C.sub.1-4alkyl;
C.sub.1-4alkoxy-C.sub.1-4alkyl;
C.sub.1-4alkoxy-carbonyl-C.sub.1-4alkyl; HOOC-C.sub.1-4alkyl; or
R.sub.23R.sub.24N--CO--C.sub.1-4alkyl wherein R.sub.23 and R.sub.24
are as defined in claim 2.
5. A compound according to claim 1 which is (S)-2-methyl-butyric
acid
(S)-(3R,7S,8aR)-8-{(S)-2-[(4R,6R)-3-(4-hydroxy-3-methoxy-benzyl)-4-methyl-
carbamoylmethyl-2-oxo-[1,3]oxazinan-6-yl]-ethyl}3,7-dimethyl-1,2,3,7,8,8a--
hexahydro-naphthalen-1-yl ester or (S)-2-methyl-butyric acid
(1S,3R,7S,8S,8aR)-8-{2-[(2S,4R)-4-hydroxy-1-(5-hydroxymethyl-6-methoxy-na-
phthalen-2-ylmethyl)-6oxo-pipeddin-2-yl]-ethyl}-3,7-dimethyl-1,2,3,7,8,8a--
hexahydronaphthalen-1-yl ester.
6. A compound according to any one of claims 1 to 5, in free form
or in pharmaceutically acceptable salt form, for use as a
pharmaceutical.
7. A pharmaceutical composition comprising a compound of formula I
according to any one of claims 1 to 5, in free form or in
pharmaceutically acceptable salt form, in association with a
pharmaceutically aceptable diluent or carrier therefor.
8. A pharmaceutical composition according to claim 7, for use in
combination with at least one pharmaceutical composition comprising
an immunosuppressant, immunomodulatory or anti-inflammatory
drug.
9. A method for preventing or treating disorders or diseases
mediated by LFA-1/ICAM1 interactions in a subject in need of such
treatment, which method comprises administering to said subject an
effective amount of a compound of formula I according to any one of
claims 1 to 5 or a pharmaceutically acceptable salt thereof.
Description
[0001] The present invention relates to mevinolin derivatives, a
process for their production, their use as a pharmaceutical and
pharmaceutical preparations containing them.
[0002] More particularly the present invention provides a compound
of formula I 1
[0003] wherein
[0004] each of a-b and .alpha.-.beta. independently, is either a
single bond or a double bond;
[0005] R.sub.1 is
[0006] . . . H, . . . C.sub.1-4alkyl or --OR.sub.a
[0007] wherein R.sub.a is H; C.sub.1-6alkyl optionally substituted
by OH or C.sub.1-4alkoxy; C.sub.2-6alkenyl; or
aryl-C.sub.1-4alkyl;
[0008] R.sub.2 is OH; --O--CO--R.sub.5 wherein R.sub.5 is
C.sub.1-8alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-4alkyl, aryl or aryl-C.sub.1-4alkyl; or
--O--R.sub.6 wherein R.sub.6 is the residue of an
.alpha.-amino-acid attached to O through its carbonyl residue or
--CHR.sub.7--COR.sub.8 wherein R.sub.7 is H, C.sub.1-4alkyl,
heteroC.sub.1-4alkyl, C.sub.3-7cycloalkyl,
C.sub.3-7cycloalkyl-C.sub.1-4a- lkyl, aryl or aryl-C.sub.1-4alkyl
and R.sub.8 is OH, C.sub.1-4alkoxy or NR.sub.9R.sub.10 wherein each
of R.sub.9 and R.sub.10 independently is H, C.sub.1-4alkyl or
R.sub.9 and R.sub.10 form together with the nitrogen to which they
are bound, a heteroaryl group;
[0009] R.sub.3 is a substituted lactam, piperidyl, linear amino
alcohol or cyclic carbamate, or a residue of formula (i) 2
[0010] wherein
[0011] R.sub.13 is OH; C.sub.1-6alkoxy; --O--CO--C.sub.1-6alkyl; or
--O13 CO--NHC.sub.1-6alkyl;
[0012] R.sub.14 is OH; C.sub.1-4alkoxy; C.sub.1-4alkyl;
C.sub.1-4alkoxy-carbonyl-C.sub.1-4alkoxy;
hydroxy-C.sub.1-5alkoxy;
[0013] C.sub.1-4alkoxy-C.sub.1-5alkoxy;
C.sub.1-4alkoxy-carbonyl-C.sub.1-4- alkyl; or
NR.sub.9aR.sub.10a-C.sub.1-5alkoxy wherein each of R.sub.9a and
R.sub.10a independently has one of the significances given for
R.sub.9 and R.sub.10;
[0014] R.sub.15 is H or C.sub.1-4alkyl; and
[0015] R.sub.16 is CONR.sub.17R.sub.18 wherein one of R.sub.17 and
R.sub.18 is H and the other is C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkyl, C.sub.3-7cycloalkyl-C.sub.1-4alkyl or
aryl-C.sub.1-4alkyl; or C.sub.1-6alkoxy-carbonyl;
[0016] each of a-b and .alpha.-.beta. being a single bond when each
of R.sub.13 or R.sub.14 is OH; and
[0017] R.sub.4 is H or OR.sub.19 wherein R.sub.19 is
C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl,
C.sub.1-4alkoxy-C.sub.1-6alkyl, aryl-C.sub.1-4alkyl or
C.sub.1-4alkoxycarbonyl-C.sub.1-4alkyl,
[0018] and wherever "aryl" appears as is or in the significances of
"aryl-C.sub.1-4alkyl" in the above definition, it is "phenyl" or
"naphthyl" optionally substituted by halogen, OH,
NR.sub.11R.sub.12, COOH, CF.sub.3, C.sub.1-4alkoxy, C.sub.1-4alkyl,
hydroxy-C.sub.1-4alkyl, hydroxy-C.sub.1-4alkoxy,
C.sub.1-4alkoxy-carbonyl, cyano or CONR.sub.11R.sub.12, each of
R.sub.11 and R.sub.12 independently being H, C.sub.1-4alkyl,
phenyl, naphthyl, phenyl-C.sub.1-4alkyl or naphthyl-C.sub.1-4alkyl
or R.sub.11 and-R.sub.12 together with the nitrogen to which they
are bound forming heteroaryl; and wherever "heteroaryl" appears, it
is a 5- or 6-membered heterocyclic residue optionally fused to a
benzene ring;
[0019] in free form or in salt form.
[0020] Alkyl groups or alkyl moieties may be branched or straight
chain. Cycloalkyl groups or moieties are preferably cyclopentyl or
cyclohexyl. Heteroalkyl includes e.g. halogenated alkyl such as
CF.sub.3. Polyhydroxy-C.sub.1-4alkyl may comprise up to 6 hydroxy
groups.
[0021] Preferably the phenyl or naphthyl moiety in aryl or
aryl-C.sub.1-4alkyl, when substituted, bears up to 3 substituents
as disclosed above, more preferably selected from C.sub.1-4alkoxy,
e.g. methoxy or ethoxy, hydroxy-C.sub.1-4alkoxy,
hydroxy-C.sub.1-4alkyl and OH. When the phenyl moiety is
disubstituted, the 2 substitutents are preferably in positions meta
and para. Aryl-C.sub.1-4alkyl is preferably benzyl, phenethyl or
naphthyl-CH.sub.2--, the phenyl or naphthyl moiety being optionally
substituted as indicated above.
[0022] Examples of heteroaryl include pyrrolyl, imidazolyl, furyl,
thienyl, pyrrolidinyl, piperidyl, piperazinyl, morpholino, pyridyl,
indolyl or quinolyl. Heteroaryl as formed by R.sub.9 and R.sub.10
together with the nitrogen to which they are attached, may comprise
a further heteroatom, e.g. O or N, and is preferably pyrrolidinyl,
piperidyl, piperazinyl or morpholino. In heteroaryl-C.sub.1-4alkyl,
the alkyl moiety preferably is C.sub.1 or C.sub.2alkyl.
[0023] The significances given above for "aryl" and "heteroaryl"
also applies to the radicals of formulae (a), (b), (c.sub.1) or
(c.sub.2) hereinafter.
[0024] When R.sub.6 is the residue of an .alpha.-amino acid, it may
be the residue of a natural or unnatural .alpha.-amino acid
residue, e.g. Ala, Leu, lIe, Val, Pro, wherein the terminal amino
group may be substituted or unsubstituted, e.g. by an amino
protecting group.
[0025] When R.sub.3 is a substituted lactam residue, it is
preferably a 6-membered ring wherein the nitrogen of the lactam may
be substituted and/or comprising a further substituent on the ring,
e.g. on the carbon atom opposite to the nitrogen. Preferably the
lactam residue is disubstituted. A suitable example of a
substituted lactam as R.sub.3 includes e.g. a radical of formula
(a) 3
[0026] wherein
[0027] R.sub.30 is C.sub.1-8alkyl; C.sub.3-7cycloalkyl; aryl;
C.sub.3-7clcoalkyl-C.sub.1-4alkyl; aryl-C.sub.1-4alkyl; heteroaryl;
or heteroaryl-C.sub.1-4alkyl;
[0028] R.sub.31 is OH; C.sub.1-4alkoxy; C.sub.1-4alkyl;
C.sub.1-4alkoxy-carbonyl-C.sub.1-4alkoxy; hydroxy-C.sub.1-5alkoxy;
C.sub.1-4alkoxy-C.sub.1-5alkoxy;
C.sub.1-4alkoxy-carbonyl-C.sub.1-4alkyl; amino-C.sub.1-4alkoxy;
HOOC-C.sub.1-4alkoxy; HOOC.sub.1-4alkyl; or
NR.sub.9aR.sub.10a-C.sub.1-5alkoxy wherein each of R.sub.9a and
R.sub.10a independently has one of the significances given for
R.sub.9 and R.sub.10.
[0029] When R.sub.3 is a substituted piperidyl residue, the
nitrogen of the piperidyl may be substituted and/or a further
substituent may be present on the ring, e.g. on the carbon atom
opposfte to the nitrogen. Preferably the piperidyl residue is
disubsfituted. A suitable example of a subsbtuted piperidyl residue
includes e.g. a radical of formula (b) 4
[0030] wherein
[0031] R.sub.40 has one of the significances given for R.sub.30;
and
[0032] R.sub.41 has one of the significances given for R.sub.31 or
is --O--CO--C.sub.1-8alkyl.
[0033] When R.sub.3 is a substituted amino alcohol residue, the
amino group thereof may be monosubstituted, e.g. by a substituent
such as aryl-C.sub.1-4alkyl or aryl-C.sub.1-4alkyl-carbonyl, and/or
a further substituent may be present on the chain, e.g. on the
carbon atom adjacent to the alcohol or amino group. Cyclisation of
the substituted amino alcohol residue leads to a corresponding
substituted cyclic carbamate. A suitable example of a substituted
amino alcohol and of the corresponding substituted cyclic carbamate
includes e.g. a radical of formula (c.sub.1) or (c.sub.2) 5
[0034] wherein
[0035] either each of X and Y is H or X and Y form together 6
[0036] each of R.sub.50, independently is H; C.sub.1-8alkyl;
C.sub.3-7cycloalkyl; aryl; C.sub.3-7cycloalkyl-C.sub.1-4alkyl;
aryl-C.sub.1-4alkyl; heteroaryl; heteroaryl-C.sub.1-4alkyl;
C.sub.1-4alkyl-carbonyl; aryl-carbonyl; heteroaryl-carbonyl;
aryl-C.sub.1-4alkyl-carbonyl or heteroaryl-C.sub.1-4alkyl-carbonyl,
and
[0037] each of R.sub.51, independently is H; C.sub.1-4alkyl;
hydroxy-C.sub.1-4alkyl; amino-C.sub.1-4alkyl;
C.sub.1-4alkoxy-C.sub.1-4al- kyl;
C.sub.1-4alkoxy-carbonyl-C.sub.1-4alkyl wherein C.sub.1-4alkoxy is
optionally substituted by amino, C.sub.1-4alkyl-amino or
di-(C.sub.1-4alkyl)-amino; HOOC-C.sub.1-4alkyl; or
R.sub.23R.sub.24N--CO--C.sub.1-4alkyl wherein R.sub.23 is H,
C.sub.1-4alkyl, hydroxy-C.sub.1-4alkyl, polyhydroxy-C.sub.1-8alkyl,
heteroaryl, heteroaryl-C.sub.1-4alkyl, amino-C.sub.1-4alkyl,
C.sub.1-4alkylamino-C.sub.1-4alkyl,
di-(C.sub.1-4alkyl)amino-C.sub.1-4alk- yl or aryl-C.sub.1-4alkyl
and R.sub.24 is H, C.sub.1-4alkyl or hydroxy-C.sub.1-4alkyl, at
least one of R.sub.50 and R.sub.51 being other than H.
[0038] Preferred compounds of formula I are those wherein R.sub.3
is substituted lactam, substituted linear amino alcohol,
substituted cyclic carbamate, preferably substituted lactam or
substituted cyclic carbamate, e.g. as disclosed above, more
preferably a radical of formula (a) or (c.sub.1) or (C.sub.2)
wherein X and Y are --CO--.
[0039] In the compounds of formula I, the following significances
are preferred individually or in any sub-combination:
[0040] 1. R.sub.1 is H or CH.sub.3, preferably CH.sub.3;
[0041] 2. R.sub.2 is --O--CO--R.sub.5, preferably wherein R.sub.5
is C.sub.4-8alkyl, particularly --CH(CH.sub.3)--CH.sub.2--CH.sub.3,
--CH(CH.sub.2--CH.sub.2--CH.sub.3).sub.2,
--CH(CH.sub.2--CH.sub.3).sub.2,
--C(CH.sub.3).sub.2--CH.sub.2--CH.sub.3 or
--CH(CH.sub.2--CH.sub.3)--CH.s- ub.2--CH.sub.2--CH.sub.3.
[0042] 3. a-b is a double bond;
[0043] 4. .alpha.-.beta. is a double bond;
[0044] 5. R.sub.4 is H;
[0045] 6. R.sub.3 is a radical of formula (i);
[0046] 7. R.sub.16 is CO--NR.sub.17R.sub.18; preferably one of
R.sub.17 and R.sub.18 is H;
[0047] 8. Each of R.sub.13 and R.sub.14 is OH and each of a-b and
.alpha.-.beta. is a single bond;
[0048] 9. Each of R.sub.13 and R.sub.14 is other than OH;
[0049] 10. R.sub.3 is a radical of formula (a);
[0050] 11. R.sub.30 in (a) is aryl-C.sub.1-4alkyl or
heteroaryl-C.sub.1-4alkyl, preferably benzyl or naphthyl-methyl
wherein the phenyl or naphthyl ring is optionally substituted by
OH, C.sub.1-4alkoxy, hydroxy-C.sub.1-4alkoxy or
hydroxy-C.sub.1-4alkyl, or morpholino, pyridyl, indolyl or
quinolyl;
[0051] 12. R.sub.31 in (a) is OH, C.sub.1-4alkoxy,
hydroxy-C.sub.1-4alkoxy- , C.sub.1-4alkoxy-carbonyl-C.sub.1-4alkoxy
or HOOC--C.sub.1-4alkoxy;
[0052] 13. R.sub.3 is a radical of formula (c.sub.1) or (c.sub.2)
wherein X and Y form together --CO--;
[0053] 14. R.sub.50 in (c.sub.1) or (C.sub.2) wherein X and Y form
together --CO--, is aryl-C.sub.1-4alkyl or
heteroaryl-C.sub.1-4alkyl, preferably benzyl or naphthyl-methyl
wherein the phenyl or naphthyl ring is optionally substituted by
OH, C.sub.1-4alkoxy, hydroxy-C.sub.1-4alkoxy or
hydroxy-C.sub.1-4alkyl;
[0054] 15. R.sub.51 in (c.sub.1) or (c.sub.2) wherein X and Y form
together --CO--, is hydroxy-C.sub.1-4alkyl; amino-C.sub.1-4alkyl;
C.sub.1-4alkoxy-C.sub.1-4alkyl;
C.sub.1-4alkoxy-carbonyl-C.sub.1-4alkyl; HOOC--C.sub.1-4alkyl; or
R.sub.23R.sub.24N--CO--C.sub.1-4alkyl.
[0055] Compounds of formula I may exist in free form or in salt
form, e.g. as acid addition salts with e.g. organic or inorganic
acids, for example, hydrochlorides, or salts when a COOH is
present, as salts with bases e.g. alkali salts such as sodium or
potassium, or substituted or unsubstituted ammonium salts.
[0056] It will be appreciated that the radicals of formulae (i),
(a), (b), (c.sub.1) and (c.sub.2) may comprise at least one
asymetric carbon atom, e.g. the carbon atom which bears R.sub.15
and R.sub.16, R.sub.31, R.sub.41 or R.sub.51, respectively, for
example 7
[0057] Where the stereochemistry of any part of a compound of the
invention is not specified, it is to be understood that the present
invention embraces individual enantiomers and their mixtures.
Similar considerations apply in relation to starting materials
exhibiting asymetric carbon atoms as mentioned above. Where
compounds of the invention exist in isomeric form as
aforementioned, individual isomers may be obtained in conventional
manner, e.g. employing optically active starting materials or by
separation of initially obtained mixtures, for example using
conventional chromatographic techniques.
[0058] The present invention also includes a process for the
production of a compound of formula I, comprising
[0059] a) for the production of a compound of formula I wherein
R.sub.3 is a residue of formula (i) submitting mevinolin or
compactin or the corresponding tetrahydro-mevinolin or -compactin
to ring opening, e.g. by reaction with a corresponding amine, e.g.
arylamine; or
[0060] b) for the production of a compound of formula I wherein
R.sub.3 is a radical of formula (c.sub.1) wherein each of X and Y
is H, submitting to reductive aminafion the carbonyl function in
R".sub.3 in a compound of formula IV 8
[0061] wherein R.sub.1, R.sub.2, R.sub.4, a-b and .alpha.-.beta.
and R.sub.1 are as defined above, and R".sub.3 is a radical of
formula (C.sub.1A) 9
[0062] wherein R.sub.51 is as defined above; or
[0063] c) for the production of a compound of formula I wherein
R.sub.3 is a residue of formula (c.sub.2) wherein each of X and Y
is H, submitting mevinolin or compactin wherein the lactone ring
has been converted into a conjugated .alpha.,.beta. unsaturated
lactone, to 1,4-addition e.g. with an amine, e.g. veratrylamine,
and concomitant ring opening with an alcohol, e.g. methanol; or
[0064] d) for the production of a compound of formula I wherein
R.sub.3 is a residue of formula (c.sub.1) or (c.sub.2) wherein each
of X and Y is --CO--, submitting to cyclisation a compound of
formula I wherein R.sub.3 is a residue of formula (c.sub.1) or
(c.sub.2) wherein each of X and Y is H; or
[0065] e) for the production of a compound of formula I wherein
R.sub.3 is a substituted lactam, e.g. a residue of formula (a),
submitting a compound of formula I wherein R.sub.3 is a residue of
formula (i) wherein R.sub.13 is OH oxidised to a ketone and
R.sub.16 is CONHR.sub.18, to a reductive amination and concomitant
ring closure; or converting the free OH group in R.sub.3 in a
compound of formula I wherein R.sub.3 is a residue of formula (i)
wherein R.sub.16 is CONHR.sub.18, into a leaving group, e.g. by
mesylation, and then submitting the resulting compound to a basic
treatment; or
[0066] f) for the production of a compound of formula I wherein
R.sub.3 is a substituted piperidyl, e.g. a residue of formula (b),
reducing a coripound of formula I wherein R.sub.3 is a substituted
lactam, e.g. a residue of formula (a);
[0067] and, where required, removing the protecting group where
present, and converting the resulting compound of formula I in free
form or in salt form.
[0068] Where OH groups are present in the starting products which
are not to participate in the reaction, they may be protected, in
accordance with known methods. OH protecting groups are known in
the art, e.g. tert.-butyl-dimethyl-silanyl.
[0069] Process steps (a) to (f) may be effected analogously to
methods known in the art or as disclosed in the Examples below. The
cyclisation in step (d) may conveniently be carried out in the
presence of a cyclisation agent, e.g. carbonyl duimidazole.
[0070] Compounds of formula IV may be prepared by opening of the OH
protected lactone ring according to known procedures, e.g. by
reaction with an amine and then oxidation of the resulting hydroxy
group into a ketone. Insofar as the production of the starting
materials is not particularly described, the compounds are known or
may be prepared analogously to methods known in the art or as
disclosed in WO 99/11258, e.g. starting from mevinolin or compactin
or tetrahydro-mevinolin or -compactin. The
--O--CO--CH(CH.sub.3)--C.sub.2H.sub.5 of mevinolin, compactin or
tetrahydro-mevinolin or -compactin may also be reduced to OH and
then esterifled to another --O--CO--R.sub.5 group.
[0071] The following Examples are illustrative of the invention.
Following abbreviations are used:
[0072] Boc=tert.-butoxy-carbonyl
[0073] rt=room temperature
[0074] OMe=methoxy
[0075] ThF=tetrahydrofurane
[0076] DMF=dimethylformamide
[0077] DCC=N,N'-dicyclohexylcarbodiimide
[0078] Pro=proline
[0079] TBDMS=tert-butyldimethylsilyl
[0080] DMAP=dimethylaminopyridine
[0081] CDI=caibonyldiimidazole
[0082] TBME=tert-butylmethylether
[0083] CHX=cyclohexane
EXAMPLE 1
[0084] (S)-2-Methyl-butyric acid
(S)-(3R,7S,8aR)8-{(S)-2-[(4R,6R)-3-(4-hyd-
roxy-3-methoxy-benzyl)-4-[(2-hydroxy-ethylcarbamoyl)methyl]-2-oxo-[1,3]oxa-
-zinan-6-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl
ester 10
[0085] a) To a solution of 40.4 g mevinolin ((S)-2Methyl-butyric
acid
(1S,3R,7S,8S,8aR)-8-[2-((1R,3R)-4-hydroxy-6-oxo-tetrahydro-pyran-2yl)-eth-
yl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester) in
100 ml of CH.sub.2Cl.sub.2 are added 24.4 g DMAP, then slowly 15.0
g Ac.sub.2O. The mixture is stirred overnight at rt. The reaction
is controlled by TLC, TBME/CHX, 3:2. The reaction mixture is
diluted with TBME, washed successively with water, ca. 15% citric
acid, brine, then dried over sodium sulfate. The organic phase is
concentrated and the product cristallized by addition of
diisopropylether. The precipitate is filtred, washed with
duisopropylether and dried, yielding the .alpha.,.beta. unsaturated
lactone derivative (S)-2-methyl-butyric acid
(S)-(3R,7S,8aR)-7methyl-3-methyl-8-[(S)-2-((R)-6-oxo-3,6-dihydro-2H-pyran-
-2yl)-ethyl]-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester. MS
(FAB-MS), 387 (MH+)
[0086] b) To 15.5 g of compound a) in 250 ml MeOH is added 14.4 g
of the 4-(tert-butyl-dimethyl-silanyloxy)-3-methoxy-benzylamine and
the mixture is stirred overnight. TLC control in TBME. The reaction
mixture is completely evaporated and the crude product separated by
flash-chromatography on silica gel (CHX.fwdarw.TBME.fwdarw.MeOH).
The desired methylester (S)-2-methyl-butyric acid
(S)-(3R,7S,8aR)-8{(R)-(3R,5-
R)-5-[4-(tert-butyl-dimethyl-silanyloxy)3-methoxy-benzylamino]-3-hydroxy-6-
-methylcarbamoyl-hexyl}-7-methyl-3-methyl-1,2,3,7,8,8a-hexahydro-naphthale-
n-1-yl ester is obtained. MS, (ESI), 686.5 (MH+)
[0087] c) A solution of 12.5 g of the compound as obtained in b),
in 25 ml DMF is treated with 4.1 g CDI and stirred for ca. 5 h. at
rt. TLC control in TBME/CHX, 3:2. The reaction mixture is diluted
with TBME, extracted with water and then brine, the organic phase
dried over sodium sulfate and evaporated. The crude product is
purified by RP-18 chromatography, MeOH/H2O.fwdarw.MeOH. After
rechromatography on silica gel, TBME/CHX.fwdarw.TBME, the cyclic
carbamate (S)-2-Methyl-butyric acid
(S)-(3R,7S,8aR)-8-((S)-2-{(4R,6R)-3-[4-(tert-butyl-dimethyl-silanyloxy)-3-
-methoxy-benzyl]-4-methylcarbamoylmethyl-2-oxo-[1,3]oxazinan-6-yl}-ethyl)--
7-methyl-3-methyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester is
obtained as a foam. MS (ESI), 712.5 (MH+)
[0088] d) To a solution of 6.0 g of the compound as obtained in c)
in 25 ml MeOH is added a total of 5.5 g 2-amino-ethanol and the
mixture is heated at reflux, for ca. 40 hrs., until completion (TLC
control in moist ethyl acetate). The reaction mixture is diluted
with ethyl acetate, extracted with citric acide and brine, then
dried over sodium sulfate and evaporated. The crude product is
purified as above, first by RP-18 chromatography then on silica
gel. The title product is obtained as a white foam. MS (ESI): 627.4
(MH+)
EXAMPLE 2
[0089] (S)-2-Methylbutyric acid
(S)-(3R,7S,8aR)-8-{(S)-2-[(4R,6R)-3-(4-hyd-
roxy-3-methoxy-benzyl)-4-methylcarbamoylmethyl-2-oxo-[1,3]oxazinan-6-yl]-e-
thyl}-7-methyl-3-methyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl
ester 11
[0090] 3.6 g of the compound as obtained in Example 1c) is
dissolved in 100 ml of a solution of ca. 30% methylamine in MeOH
and stirred at rt for ca. 24 hrs. (TLC control in moist ethyl
acetate). The reaction mixture is evaporated and the crude product
purified by silica gel chromatography (TMBE/CHX.fwdarw.ethyl
acetate). Pure fractions are combined, evaporated and the title
compound is obtained as a foam. MS (ESI): 597.4 (MH+)
[.alpha.].sub.D.sup.20=+234.7.degree. (c=1 in methanol)
[0091] By following the same procedure, but using the appropriate
starting material, the diastereomer wherein the carbamate ring has
the configuration 12
[0092] is also obtained.
[0093] By following the procedure as disclosed in Examples 1 and 2,
the compounds of formula X 13
[0094] wherein R.sub.50 and R.sub.51 are as defined in Table 1
below, may be prepared.
1TABLE 1 Ex R.sub.50 R.sub.51 M.S. (ESI) 3* 3-OMe-4-OH-benzyl
--CH.sub.2--CO--NH--CH.sub.2-(4'-OH-3'-OMe- 717 [M - H] phenyl) 4
3-OMe-4-(2-hydroxy-ethoxy)-
--CH.sub.2--CO--NH--CH.sub.2-[3'-OMe-4'-(.beta.- 851 [M + HCOO-]
benzyl hydroxy-ethoxy)-phenyl] 5 3,4-di-OMe-benzyl
--CH.sub.2--CO--NHCH.sub.3 611 [MH+] 6 3,4-di-OMe-benzyl
--CH.sub.2--COOH 596 [M - H] 7 3-OMe-4-OH-benzyl
--CH.sub.2--CO--OCH.sub.3 596 [M - H] 8 3-OMe-4-OH-benzyl
--CH.sub.2--COOH 582 [M - H] 9 3-OMe-4-OH-benzyl
--CH.sub.2--CO--N(CH.sub.3).sub.2 609 [M - H] 10 3-OMe-4-OH-benzyl
--CH.sub.2--CH.sub.2--OH 570 [MH+] 11 3,4-di-OH-benzyl
--CH.sub.2--CO--NH--CH.sub.2-(3',4'-di-OH-phenyl) 689 [M - H] 12
3,4-di-OMe-benzyl --CH.sub.2--CO--N--CH(CH.sub.2OH).sub.2 669 [M -
H] 13 3-OMe-4-(2-hydroxy-ethoxy)- --CH.sub.2--CO--NHCH.sub.3 639 [M
- H] benzyl 14 3-OMe-4-OH-benzyl --CH.sub.2--CO--NH--CH.sub.2---
CH(OH)--CH.sub.2OH 655 [M - H] 15 3,4-di-OH-benzyl
--CH.sub.2--CO--OCH.sub.3 582 [M - H] 16 3,4-di-OH-benzyl
--CH.sub.2--CO--NHCH.sub.2CH.sub.2OH 611 [M - H] 17
3-OMe-4-OH-benzyl --CH.sub.2--CO--NH--CH(CH.sub.2--OH).sub.2 655 [M
- H] 18 3,4-di-OMe-benzyl --CH.sub.2--CO--NH--CH.sub.2--CH.sub.2OH
640 [M - H] 19 14 --CH.sub.2--CO--NH--CH.sub.2--CH.sub.2OH 689 [M -
H] 20 3-OMe-4-OH-benzyl --CH.sub.2--CO--NH--CH.s-
ub.2--(CHOH).sub.4--CH.sub.2OH 745 [M - H] 21 3-OMe-4-OH-benzyl
--CH.sub.2--CO--N--(CH.sub.2CH.sub.2OH).sub.2 669 [M - H] 22
3-OMe-4-OH-benzyl
--CH.sub.2--CO--NH--(CH.sub.2).sub.2--N(CH.sub.3).sub.2 654 [MH+]
23 4-OMe-3-OH-benzyl --CH.sub.2--CO--NH--CH.sub.2--CH.su- b.2OH 671
[M + HCOO-] 24 3,4-di-OMe-benzyl --CH.sub.2--CO--NH--(3,4-
-di-OMe-benzyl) 721 [MH+] *The diastereoisomer of the compound of
Ex. 3, wherein the cyclic carbamate residue has the
configuration
[0095] 15
[0096] is also prepared by following the same procedure.
[0097] By following the procedure below the compounds of formula
X.sub.1 may be prepared. The OH protected lactone ring of mevinolin
or compactin may also be submitted to ring opening, e.g. by
reaction with an amine, then treatment of the resulting
hydroxyamine with carbonyl-diimodazole leads to the carbamate.
16
[0098] wherein R.sub.50, R.sub.51 are as defined in Table 2
below.
2TABLE 2 Ex R.sub.50 R.sub.51 M.S. (ESI) 25* 3,4-di-OMe-
--CH.sub.2--CO--NHCH.sub.3 611 (M + H) benzyl 26 3,4-di-OMe-
--CH.sub.2--CO--O--(CH.sub.2).sub.2--N(CH.su- b.3).sub.2 668 (M +
H) benzyl *The diasteromer of the compound of Ex. 25, wherein the
cyclic carbamate residue has the configuration
[0099] 17
[0100] is also prepared by following the same procedure.
EXAMPLE 27
[0101] (S)-2-Methyl-butyric acid
(S)-(3S,4aS,7S,5S,8S,8aS)-8-{(S)-2-[(4R,6-
R)-3-(4-hydroxy-3-methoxy-benzyl)-4-[(2-hydroxy-ethylcarbamoyl)-methyl]-2o-
xo-[1,3]oxazinan-6-yl]-ethyl}-3,7-dimethyl-decahydro-naphthalen-1-yl
ester
[0102] By following the first step of the procedure to prepare
example 28 (to obtain trans tetrahydro mevinolin) and then the
procedure (step a) to d) as disclosed in Example 1, the compound of
formula 18
[0103] is obtained. MS (ESI): 629 [M-H].
EXAMPLE 28
[0104] (S)-2-Methyl-butyric acid
(S)-(3S,4aS,7S,8S,8aS)-8-[(3R,5R)-6-(3,4--
dimethoxy-benzylcarbamoyl)-3,5-dihydroxy-hexyl]-3,7dimethyl-decahydro-naph-
thalen-1-yl ester 19
[0105] a) To a solution of 40 g (0.098 mol) of mevinolin in 3 l
ethyl acetate is added 10 g Pt/Al2O3. The mixture is hydrognated
under an H.sub.2 atmosphere under 2.6 bar pressure for 16 h. The
mixture is filtered and the solvent evaporated. The residue is
purified by silical gel chromatography using ethyl
acetatelcyclohexane 8/2 as a solvent. First eluted is the undesired
cis isomer, followed by a side product with one double bond.
Finally the desired trans isomer is eluted. Several
crystallizations yielded the desired trans tetrahydromevinolin
((S)-2-Methyl-butyric acid
(S)-(3S,4aS,7S,5S,8S,8aS)-8-[2-((2R,4R)-4-hydr-
oxy-6-oxo-tetrahydro-pyran-2yl)-ethyl]-3-methyl-7-methyl-decahydro-naphtha-
len-1-yl ester).
[0106] b) To a solution of 2 g (5.0 mmol) of the trans tetrahydro
mevinolin obtained in a) in 12 ml ethanol is added 3.7 ml (25.0
mmol) 3,4-dimethoybenzylamine. The reaction mixture is stirred for
20 h at rt, then it is diluted with 300 ml diethyl ether with and
washed with 100 ml of water. The organic extract is dried with
MgSO.sub.4 and evaporated. The residue is purified by
chromatography on silicagel using ethyl acetate as elueht to give
the title compound. MS (ESI): 598 (M+Na), 574 (M-H)
[0107] The compound of Example 29 is obtained by silylating
mevinolin, following step b) of the procedure of Example 28,
reacting with ethyl isocyanate and desilylating according to
conventional methods. The compound of example 30 is obtained by
reacting mevinolin with ethyl diazoacetate and rhodium acetate and
then following step b) of the procedure of Example 28. 20
EXAMPLE 29
[0108] The compound of Example 31 is prepared by following step a)
and b) of the procedure of Example 1 and desilylating the compound
resulting from step b). The compounds of Examples 32 and 33 are
obtained by submitting the appropriate starting materials to step
a) and a modified version of step b) (in the absence of methanol):
21
EXAMPLE 34
[0109] (S)-2-Methyl-butyric acid
(1S,3R,7S,8S,8aR)-8-{2-[(2S,4R)-4-hydroxy-
-1-(5-hydroxymethyl-6-methoxy-naphthalen-2-ylmethyl)-6-oxo-piperdin-2-yl]--
ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester
22
[0110] a) To a stirred solution of 22 g (37 mmol) of silylated
mevinolin (obtained by standard silylation of mevinolin in the 4
position) ((S)-2-Methyl-butyric acid
(3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-(tert-butyl-dim-
ethyl-silanyloxy)-6-oxo-tetrahydro-pyran-2-yl]-ethyl}-3,7-dimethyl-1,2,3,7-
,8,8a-hexahydro-naphthalen-1-yl ester) in 65 ml THF at rt are added
18 g (56 mmol) of
C-[5-(tert-butyl-dimethyl-silanyloxymethyl)-6-methoxy-naphth-
alen-2yl]-methylamine (prepared from
2-bromo-6-methoxy-naphthalene). After 18 hours the reaction mixture
is diluted wvith 250 ml methyl-tbutyl other and washed successively
with 10% aqueous citric acid, saturated aqueous sodium bicarbonate
and brine. The organic phase is dried over sodium sulfate and the
solvent evaporated. The crude product is purified by silica gel
chromatography (hexane/ethyl acetate 4/1 to 3/2) to afford the
hydroxyamide 2-methyl-butyric acid
8-(5-(tert-butyl-dimethyl-silanyloxy)--
6-{[-5-tert-butyl-dimethyl-silanyloxymethyl)-6-methoxy-naphthalen-2-ylmeth-
yl]-carbamoyl}-3-hydroxy-hexyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphth-
alen-1-yl ester as a white foam. MS (ESI, -Q1MS) 894.6; 884.3;
848.5
[0111] b) To a stirred, cooled (0.degree. C.) solution of 4.3 g
(5.0 mmol) of the compound obtained under 34a) above and 1.4 ml (10
mmol) trethylamine in 40 ml THF are added 0.51 ml (6.6 mmol) of
methanesulfonyl chloride. After 30 minutes 6.5 ml (13 mmol) of a 2M
solution of sodium bis(trimethylsilyl)amide in THF are added. The
mixture is stirred for 1 hour at 0.degree. C. the reaction is
quenched with 10% aqueous citric acid and diluted with
methyl-t-butyl ether. The phases are separated and the aqueous
phase is extracted twice with methyl-t-butyl ether. The organic
phases are combined, washed successively with saturated aqueous
sodium bicarbonate and brine, dried over sodium sulfate and the
solvent is evaporated. The crude product is purified by silica gel
chromatography (hexane/ethyl acetate 95/5 to 4/1) to afford the
lactam 2-methyl-butyric acid
8-(2-{4-(tert-butyl-dimethyl-silanyloxy)-1-[5-(tert-butyl-dimethyl-s-
ilanyloxymethyl)-6-methoxy-naphthalen-2-ylmethyl]-6-oxo-piperidin-2-yl}-et-
hyl)3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1yl ester as a
white foam. MS (ESI, +Q1MS) 832.6; 598.4
[0112] c) To a stirred solution of 106 mg (0.13 mmol) of the
compound obtained under 34b) above in 2 ml THF at room temperature
are added 606 .mu.l (0.62 mmol) of a 1N aqueous HCl solution. After
18 hours the reaction is quenched with saturated aqueous sodium
bicarbonate and diluted with methyl-t-butyl ether. The phases are
separated and the aqueous phase is extracted twice with
methyl-t-butyl ether. The combined organic phases are washed with
brine, dned over sodium sulfate and the solvent is evaporated. The
crude product is purified by silica gel chromatography
(hexane:ethyl acetate 1:1 to 1:4) to afford the pure title compound
as a white foam.
[0113] MS (ESl, -Q1MS) 648.4; 602.5
[.alpha.].sub.D.sup.20=+119.3.degree. (c=1 in methanol) m.p.
145.degree. C.
[0114] The compounds of formula X.sub.2 23
[0115] wherein R.sub.30 and R.sub.31, have the significances given
in Table 3, are prepared analogously to procedure as disclosed in
Example 34.
3TABLE 3 Ex R.sub.30 R.sub.31 M.S 35 24 OH 545 [MH+] 36* 25 OH 545
[MH+] 37 4-(2'-OH-ethoxy)-3-OCH.sub.3-benzyl OH 628 [M + HCOO-] 38
3,5-di-(OCH.sub.3)-benzyl OH 554 [MH+] 39
3,4-di-(OCH.sub.2CH.sub.3)-phenyl OH 568 [MH+] 40
.beta.-naphthyl-CH.sub.2-- OH 544 [MH+] 41 4-di-ethyl-carbamoyl-be-
nzyl OH 593 [MH+] 42 3-OCH.sub.3-4-OH-benzyl OH 538 [M - H] 43
4-morpholinocarbonyl-benzyl OH 607 [MH+] 44 26 OH 619 [M + HCOO-]
45 4-ethoxy-carbonyl-benzyl OH 566 [MH+] 46* 27 OH 519 [MH+] 47**
(3,4-dimethoxy)-benzyl OH 554 [M + H] 48 4-pyridyl-CH.sub.2-- OH
495 (M + H) 49** 3-pyridyl-CH.sub.2-- OH 494 (M) (El) 50 CH.sub.3
OH 418 (M + H) 51 3-benzoxy-benzyl OH 600 (M + H) 52*
3-benzoxy-benzyl OH 600 (M + H) 53 3-isopropoxy-benzyl OH 596 (M +
HCOO) 54* 3-isopropoxy-benzyl OH 552 (M + H) 55
(3,4-dimethoxy)-phenethyl OH 568 (M + H) 56 p-CF.sub.3-benzyl OH
562 (M + H) 57 p-tert.-butoxy-benzyl OH 594 (M + H) 58 28 OCH.sub.3
640 [MNa+] 59** m-methoxy-benzyl OH 523 (M) (EI) 60* benzyl
OCH.sub.3 508 (M + H) 61 3-OCH.sub.3-4-(2'-OH-ethoxy)-benzyl
O--CH.sub.2--CO--OC.sub.2H.sub.5 715 [M + HCOO-] 62
3-OCH.sub.3-4-(2'-OH-ethoxy)-benzyl O--CH.sub.2--CH.sub.2--OH 628
[MH+] 63* benzyl OCH.sub.2CH.sub.2OH 538 (M + H) 64* benzyl
O-CH.sub.2--COOH 552 (M + H) *In these compounds the lactam moiety
has the following configuration:
[0116] 29
[0117] **Both diastereoisomers are obtained and each can be
isolated.
[0118] The systhesis of compounds of Examples 61 to 64*
additionally comprise a treatment with ethyl diazoacetate and
rhodium acetate, followed for the compounds of Examples 62* and
63*, by a reduction.
[0119] By following the procedure of Example 34 but using as
starting material the corresponding tetrahydro-mevinolin derivative
and 3,4-dimethoxy-benzylamine, the following compound is obtained:
30 31
[0120] Compounds of Ex. 66 and 67 may be obtained from mevinolin as
follows: ester cleavage of mevinolin and oxidation of the newly
generated hydroxy position to the oxo compound. The neighbouring
hydroxy substituent is then introduced via the formation of the
silylenolate and treatment with meta-chloroperbenzoic acid.
Selective alkylation of the newly formed hydroxy position is
achieved by treatment with Meerwein salt. The ester group is
introduced via its anhydride. Then the procedure as described for
Ex. 34 is followed. 32
EXAMPLE 68
[0121] (S)-2-Methyl-butyric acid
(1S,3R,7S,8S,8aR)-8-[2-((R)-1-benzyl-4-me-
thyl-6-oxo-piperidin-2-yl)-ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naph-
thalen-1-yl ester
[0122] Mevinolin is treated with acetic anhydride to give the
.alpha.,.beta.-unsaturated lactone. This is treated with cuprous
bromide dimethylsulfide complex and methyl lithium to affect
conjugate addition. The methylated lactone compound is treated with
methanol and diazabicycloundecane to give the ring opened
methylated hydroxy ester. The hydroxy group of which is then
oxidized with sulfur trioxide pyridine complex to the corresponding
ketone.
[0123] The ketone reductively aminated (as described for Example
76b) to give the title compound. MS(El): 491 (M)
[0124] The procedure of Example 68, but using the appropriate
starting materials, the compounds of formula X.sub.3 33
[0125] wherein R.sub.1 and Y-Z are as defined in Table 4 below, may
be prepared:
4 TABLE 4 Example Y-Z R.sub.1 MS (EI) 68 C--C --CH.sub.2-phenyl see
above 69 CC --CH.sub.2--CH(CH.sub.3).sub.2 457 (M) 70 CC
--CH.sub.2--CH(CH.sub.3).sub.2 457 (M)
EXAMPLE 71
[0126] (S)-2-Methyl-butyric acid
(1S,3R,7S,8S,8aR)-8-{2-[(2S,4S)-1-(3,4-di-
methoxy-benzyl)-4-hydroxy-6-oxo-piperidin-2-yl]-ethyl}-3,7-dimethyl-1,2,3,-
7,8,8a-hexahydro-naphthalen-1-yl ester
[0127] a) To a stirred solution of 600 mg (1.1 mmol) of
2-methyl-butyric acid
8{2-[1-(3,4-dimethoxy-benzyl)-4-hydroxy-6-oxo-piperidin-2-yl]ethyl}--
3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester in 15 ml
of THF at rt are added 2 ml of a 65% RedAl.RTM. solution in
toluene. After 3 hours, the reacbon is quenched by the addition of
1 ml of methanol. The organic phase is extracted twice with 15 ml
of 2N HCl. The aqueous phases are combined, brought to pH 12 with
1N NaOH and extracted three times with ethyl acetate. The organic
phases are combined, dried over sodium sulfate and the solvent
evaporated. The residue is purTfied by silea gel chromatography
(t-butyl methyl ether/methanol 9/1) to afford pure
1-(3,4-Dimethoxy-benzyl)-2-[2-(8-hydroxy-2,6-dimethyl-1,2,6,7,8,8a-hexahy-
dro-naphthalen-1-yl)-ethyl]-pipeddin-4-ol as a white foam. MS (ESl)
456 (M+H)
[0128] b) The above compound is treated with diethylacetic
anhydride in the presence of catalytic amounts of
4-dimethylaminopyridine in dichloromethane at rt for 16 h to give a
diacylated compound. The undesired acyl group on the lactone moiety
is cleaved by transesterification with methanol at 55.degree. C.
for 5 h to give the title compound. MS (ESl): 554 (M+H). See
formula below in Table 5.
[0129] By following the procedure of Example 71, but using the
appropriate starting materials, the compounds of fornula X.sub.4
34
[0130] wherein R.sub.1-R.sub.3 and Y-Z are as defined in Table 5
below, may be prepared
5TABLE 5 Ex R.sub.1 R.sub.2 R.sub.3 Y-Z MS(ESI) 71 OH
3,4-dimethoxy-benzyl (CH.sub.3--CH.sub.2).sub.2CH--CO-- CC see
above 72 OH 3,4-dimethoxy-benzyl (CH.sub.3--CH.sub.2).sub.2-
CH--CO-- CC 554 (M + H) 73 (CH.sub.3--CH.sub.2).sub.2CH--CO--O--
3,4-dimethoxy-benzyl (CH.sub.3--CH.sub.2).sub.2CH--CO-- CC 674 (M +
Na) 74 (CH.sub.3--CH.sub.2).sub.2CH--CO--O-- 3,4-dimethoxy-benzyl
(CH.sub.3--CH.sub.2).sub.2CH--CO-- CC 652 (M + H) 75
(CH.sub.3--CH.sub.2).sub.2CH--CO--O-- 3,4-dimethoxy-benzyl H CC 554
(M + H)
[0131] Compound of Ex. 73 is obtained from compound of Ex. 71
starting from compound of Ex. 47. Compound of Ex. 74 is obtained
from compound of Ex. 72 starting from the diastereoisomer of Ex.
50**.
EXAMPLE 76
[0132] (S)-2-Methyl-butyric acid
(1S,3R,7S,8S,8aR)-8-[(3R,5R)-3-(3,4-dimet-
hoxy-benzylamino)-5-hydroxy-6-methylcarbamoyl-hexyl]-3,7-dimethyl-1,2,3,7,-
8,8a-hexahydronaphthalen-1-yl ester
[0133] a) To a solution of 900 mg (1.65 mmol) of 2-methyl-butyric
acid
8-[5-(tert.-butyl-dimethyl-silanyloxy)-6-methylcarbamoyl-3-oxo-hexyl]-3,7-
-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1yl ester in 5 ml of
THF are added 700 mg (11.7 mmol) of acetic acid and 1.0 g (3.2
mmol) of tetrabutylammonium fluoride trihydrate. The reaction
mixture is stirred for 3 hours at rt. It is then diluted with 30 ml
of ethyl acetate and washed successively with a saturated aqueous
sodium bicarbonate solution and water. The organic phase is dried
over sodium sulfate and the solvent evaporated. The residue is
crystallized from diethyl ether to afford the desired product
2-methyl-butyric acid 8-(5-hydroxy-6-methylcarbamoyl-3-ox-
o-hexyl)-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester
as white crystals. MS (FAB) 440 (M+Li)
[0134] b) To a solution of 300 mg (0.69 mmol) of the compound of
formula 76a) in 2 ml of dichloroethane are added 200 mg (1.2 mmol)
of veratrylamine, 244 mg (1.15 mmol) of sodium triacetoxyborohydrde
and 60 mg (1.0 mmol) of acetic acid. The reaction mixture is
stirred overnight at room temperature. It is then diluted with 20
ml of ethyl acetate and washed successively with a saturated
aqueous sodium bicarbonate solution, water and brine. The organic
phase is dried over sodium sulfate and the solvent evaporated. The
residue is purified by silica gel chromatography (tert.-butyl
methyl ether/methanol/NH.sub.4OH.sub.aq 90/9/1) to afford the title
compound as a white foam. MS (ESl) 585 (M+H)
[0135] By following the procedure of Example 76, but using the
appropriate starting materials, the compounds of formula X.sub.5
35
[0136] wherein R.sub.1 and R.sub.2 are as defined in Table 6 below,
may be prepared.
6 TABLE 6 Ex R.sub.1 R.sub.2 MS (ESI) 76 CH.sub.3
-(3,4-dimethoxy)-benzyl see above 77 CH.sub.3 benzyl 525 (M + H) 78
CH.sub.3 diphenyl-methyl 601 (M + H) 79 CH.sub.3
CH(CH.sub.3)-phenyl 539 (M + H)
[0137] The compounds of formula I, in free form or in
pharmaceutically acceptable salt form exhibit valuable
pharmacological properties, e.g. inhibiting activity of
LFA-1/ICAM-1 or ICAM3 interactions or inhibiting inflammation, e.g.
as indicated in in vitro and in vivo tests and are therefore
indicated for therapy.
[0138] A. In vitro:
[0139] i) Cell Free Assay
[0140] The assay measures the binding of soluble human ICAM-1 to
immobilized human LFA-1. LFA-1 is purified from JY cells, a human
lymphoblastoid B cell-line, by immunoaffinity chromatography as
described by Dustin et al. (J. Immunol. 148, 2654-2663, 1992).
ICAM1 mouse Cx fusion protein (ICAM-1) is produced using the
baculovirus system as described by Weitz-Schmidt et al. (Anal.
Biochem.238,1 84-190, 1996). Purified LFA-1 is diluted 1:20 in
phosphate buffered saline (PBS) containing 2 mM MgCl.sub.2, pH 7.4
and coated onto microtitre plates (Nunc) at 37.degree. C. for 3h.
Plates are blocked with 1% heat-treated BSA in PBS for 2 hours at
37.degree. C. followed by a washing step using PBS, 2 mM
MgCl.sub.2, 1% fetal calf serum, pH 7.4 (assay buffer). Compounds
dissolved at 10 mM in DMSO are diluted in assay buffer and added to
the plates. Biotinylated recombinant ICAM-1 in assay buffer (6
.mu.g/ml) is added and allowed to bind at 37.degree. C. for one
hour. After incubation, wells are washed with assay buffer.
Streptavidin-peroxidase diluted 1:5000 in assay buffer is added and
incubated for 45 min at 37.degree. C. Plates are then washed with
assay buffer and 2.2'-azino-bis(3-ethylbenzothiazoline-6 sulfonic
acid) diammonium salt substrate solution is added to each well. The
reaction is stopped after 20 min and bound ICAM-1 is determined by
measuring the optical density at 405 nm in a microplate reader.
[0141] In this assay, compounds of formula I inhibit adhesion of
LFA-1 to ICAM-1 with an IC.sub.50.ltoreq.30 .mu.M, preferably 0.05
to 30 .mu.M.
[0142] ii) Human Mixed Lymphocyte Reaction (MLR)
[0143] Peripheral blood mononuclear cells (PBMC) are isolated from
human buffy coats. In each experiment, PBMC from three different
donors (A, B, and C) are set up in three individual 2-way reactions
(A-B, A-C, B-C). Cells are cocultured for six days and
proliferation is determined by pulsing the cells with
.sup.3H-thymidine. The concentration of compounds of formula I
which results in 50% inhibition of cell proliferation (IC.sub.50)
is calculated. In this assay, compounds of formula I inhibit the
MLR with an IC.sub.50 in the range of 0.2 to 4 .mu.M.
[0144] B. In vivo
[0145] i) Murine Thioglycollate Induced Peritonitis
[0146] Thioglycollate is injected i.p. to mice and immediately
thereafter the compound to be tested is given s.c.. The mice are
killed after 4 hours, the peritoneal cavity lavaged and total
number of neutrophils in the lavage fluid is determined. In this
assay, the compounds of formula I inhibit thioglycollate induced
neutrophil migration when administered s.c. at a dose of from
0.001-50 .mu.g/kg.
[0147] ii) Allergic Contact Dermatitis (ACD)
[0148] Groups of oxazolone-sensitized mice are challenged with 10
.mu.l of 0.2 or 2.0% oxazolone on the inner surface of the right to
eliciate ACD. The low concentration of oxazolone is used for
testing compounds on systemic activity whereas the high
concentration is applied for topical testing. The unchallenged left
ears serve as normal controls and dermatitis is evaluated from the
individual differences in pinnal weight, which is taken as a
measure of increase in inflammatory swelling 24 h after the
challenge. Dermatitis is evaluated in test- and for comparison in
control groups. The test groups are treated with the test compounds
either orally (twice, 2 h and immediately before challenge),
subcutaneously (immediately before challenge) or topically (30 min
after challenge at the site of elicitation of the ACD); the
controls are treated similarly with the vehicles alone. For oral
and subcutaneous administration the compounds are administered in
an oil in water emulsion, for topical administration the compounds
are prepared in a mixture of ethanol, acetone and
dimethylacetamide. The data of the test- and the vehicle-treated
control groups are statistically analysed by ANOVA followed by
Dunnet T-test (normal distribution or data) or by H and U-test,
respectively. When administered p.o. at a dose of from 0.1 to 10
mg/kg, compounds of formula I inhibit the elicitation phase of
allergic contact dermatitis.
[0149] iii) Transplantation: Heterotopic mouse heart allograft
[0150] The strain combination used: BALB/cC3H (H-2d H-2k) comprises
MHC and non-MHC mismatch. Female animals are anaesthetised using
inhalational isofluorane. Following heparinisation of the donor
BALB/c mouse through the abdominal inferior vena cava with
simultaneous exsanguination via the aorta, the chest is opened and
the heart rapidly cooled. The aorta is ligated and divided distal
to the first branch and the brachiocephalic trunk is divided at the
first bifurcation. The left pulmonary artery is ligated and divided
and the right side divided but left open. All other vessels are
dissected free, ligated and divided and the donor heart is removed
into iced saline.
[0151] The recipientC3H is prepared by dissection and
cross-clamping of the infra-renal abdominal aorta and vena cava.
The graft is implanted with end-to-side anastomoses, using 11/0
monofilament suture, between the donor brachiocephalic trunk and
the recipient aorta and the donor right pulmonary artery to the
recipient vena cava. The clamps are removed, the graft tethered
retroabdominaly, the abdominal contents washed with warm saline and
the animal is closed and allowed to recover under a heating lamp.
Graft survival is monitored by daily palpation of the beating donor
heart through the abdominal wall. Rejection is considered to be
complete when heart beat stops. Improvements of graft function are
obtained in animals treated with a compound of formula I
administered orally at a daily dose of 30 mg/kg. Significant
improvement is obtained when the compound of formula I is
administered wit an immunosuppressive agent, e.g. cyclosporin A, at
a daily dose of 10 mg/kg.
[0152] The compounds of formula I are, therefore, useful in the
treatment and/or prevention of diseases or disorders mediated by
LFA-1/lCAM-1 or ICAM-3 interactions e.g. ischemia/reperfusion
injury e.g. myocardial infarction, stroke, gut ischemia, renal
failure or hemorrhage shock, acute or chronic rejection of organ or
tissue allo- or xenografts, e.g. heart, lung, combined heart-lung,
kidney, liver, bowel, bone marrow or pancreatic islets, infection
diseases such as septic shock, adult respiratory distress syndrome,
or traumatic shock. The compounds of formula I are also useful in
the treatment and/or prevention of acute or chronic inflammatory
diseases or disorders or autoimmune diseases e.g. rheumatoid
arthritis, systemiclupus erythematosus,
hashimoto's-thyroidis,-multiple sclerosis, myasthenia gravis,
diabetes type I and uveitis, cutaneous manifestations of
immunologically-mediated illnesses, inflammatory and
hyperproliferative skin diseases (such as psoriasis, atopic
dermatitis, alopecia aerata, allergic contact dermatitis, irritant
contact dermatitis and further eczematous dermatitises, seborrhoeic
dermatitis, lichen planus, pemphigus, bullous pemphigoid,
epidermolysis bullosa, urticaria, angioedemas, vasculitides,
erythema multiforme, cutaneous eosinophilias, lupus erythematosus,
acne, granuloma annulare, pyoderma gangrenosum, sun bums or toxic
epidermal necrolysis), inflammatory bowel disease, ophthalmic
inflammatory diseases or immune-mediated conditions of the eye,
such as auto-immune diseases, e.g. keratoplasty and chronic
keratitis, allergic conditions, e.g. vernal conjunctivitis,
inflammatory conditions and comeal transplants. Compounds of
formula I are useful as immunosuppressive agents.
[0153] For the above uses the required dosage will of course vary
depending on the mode of administration, the particular condition
to be treated and the effect desired. In general, satisfactory
results are indicated to be obtained systemically at daily dosages
of from about 0.1 to about 10 mg/kg body weight An indicated daily
dosage in the larger mammal is in the range from about 0.5 mg to
about 80 mg, conveniently administered, for example, in divided
doses up to four times a day or in retard form.
[0154] For topical use satisfactory results are obtained with local
administration of a 1-3% concentration of active substance several
times daily, e.g. 2 to 5 times daily.
[0155] The compounds of formula I may be administered systemically
or topically, by any conventional route, in particular enterally,
e.g. orally, e.g. in the form of tablets or capsules, topically,
e.g. in the form of lotions, gels, ointments or creams, or in a
nasal or a suppository form. Percutaneous administration via
patches or other delivery systems may also be a possible route for
prevention or treatment of above diseases.
[0156] Pharmaceutical compositions comprising a compound of formula
I in association with at least one pharmaceutical acceptable
carrier or diluent may be manufactured in conventional manner by
mixing with a pharmaceutically acceptable carrier or diluent. Unit
dosage forms contain, for example, from about 0.1 mg to about 40 mg
of active substance.
[0157] Topical administration is e.g. to the skin. A further form
of topical administration is to the eye.
[0158] The compounds of formula I may be administered in free form
or in pharmaceutically acceptable salt form e.g. as indicated
above. Such salts may be prepared in conventional manner and
exhibit the same order of actMty as the free compounds.
[0159] In accordance with the foregoing the present invention
further provides:
[0160] 1.1 A method for preventing or treating disorders or
diseases mediated by LFA-1IACAM1 interactions, e.g. such as
indicated above, in a subject in need of such treatment, which
method comprises administering to said subject an effective amount
of a compound of formula I or a pharmaceutically acceptable salt
thereof;
[0161] 1.2 A method for preventing or treating acute or chronic
inflammatory diseases or disorders or autoimmune diseases, e.g. as
indicated above, in a subject in need of such treatment, which
method comprises administering to said subject an effective amount
of a compound of formula I or a pharmaceutically acceptable salt
thereof;
[0162] 2. A compound of formula I, in free form or in a
pharmaceutically acceptable salt form for use as a pharmaceutical,
e.g. in any of the methods as indicated under 1.1 and 1.2
above.
[0163] 3. A pharmaceutical composition for use in any of the
methods as in 1.1 and 1.2 above comprising a compound of formula I
in free form or pharmaceutically acceptable salt form in
association with a pharmaceutically acceptable diluent or carder
therefor.
[0164] 4. A compound of formula I or a pharmaceutically acceptable
salt thereof for use in the preparation of a pharmaceutical
composition for use in any of the method as in 1.1 and 1.2
above.
[0165] The compounds of formula I may be administered as the sole
active ingredient or in conjunction with, e.g. as an adjuvant to,
other drugs in immunomodulating regimens or other anti-inflammatory
agents for the treatment or prevention of allo- or xenograft acute
or chronic rejection or inflammatory or autoimmune disorders. For
example, the compounds of formula I may be used in combination with
cyclosporins, rapamycins or ascomycins, or their immunosuppressive
analogs, e.g. cyclosporin A, cyclosporin G, FK-506, ABT-281,
ASM981, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin etc.;
corticosteroids; cyclophosphamide; azathioprene; methotrexate;
FTY720; leflunomide; mizoribine; mycophenolic acid; mycophenolate
mofetil; 15-deoxyspergualine; immunosuppressive monoclonal
antibodies, e.g., monoclonal antibodies to leukocyte receptors,
e.g., MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD40, CD45 or CD58
or their ligands; or other immunomodulatory compounds, e.g.
CTLA41g, or other adhesion molecule inhibitors, e.g. mAbs or low
molecular weight inhibitors including Selectin antagonists and VLA4
antagonists. A preferred composition is with Cyclosporin A, FK506,
rapamycin or 40-O-(2-hydroxy)ethy-rapamycin.
[0166] Where the compounds of formula I are administered in
conjunction with other immunosuppressive/immunomodulatory or
anti-inflammatory therapy, e.g. for preventing or treating chronic
rejection as hereinabove specified, dosages of the co-administered
immunosuppressant, immunomodulatory or anti-inflammatory compound
will of course vary depending on the type of co-drug employed, e.g.
whether it is a steroid or a cyclosporin, on the specific drug
employed, on the condition being treated and so forth. In
accordance with the foregoing the present invention provides in a
yet further aspect:
[0167] 5. A method as defined above comprising co-administration,
e.g. concomitantly or in sequence, of a therapeutically effective
amount of a compound of formula I in free form or in
pharmaceutically acceptable salt form, and a second drug substance,
said second drug substance being an immunosuppressant,
imnmunomodulatory or anti-inflammatory drug, e.g. as indicated
above.
[0168] 6. A therapeutic combination, e.g. a kit, for use in any
method as defined under 1.1 or 1.2 above, comprising a compound of
formula I, in free form or in pharmaceutically acceptable salt
form, with at least one pharmaceutical composition comprising an
immunosuppressant, immunomodulatory or anti-inflammatory drug. The
kit may comprise instructions for its administration.
[0169] Compounds of Examples 2, 28 and 34 are preferred,
particularly for use in the treatment of inflammatory skin
diseases, e.g. as indicated above. In one test run, following
results were obtained: an IC.sub.50 of 0.05, 0.79 and 0.19 .mu.M,
respectively for the compounds of Ex. 2, 28 and 34, in the test
Ai); an IC.sub.50 of 0.2 .mu.M for the compound of Ex. 2 in the MLR
test Aii); an ED.sub.50 of 0.1 .mu.g/kg p.o. for the compound of
Ex. 2 in the test Bi); in Bii) compound of Ex. 2 has an inhibiting
effect of 41% when administered p.o. at a dose of 2.times.3 mg/kg
and compound of Ex. 34 inhibits inflammatory swelling by 41% at
2.times.1 mg/kg p.o.
[0170] Preferred compounds of formula I are those inhibiting HMG
CoA Reductase activity with an IC.sub.50.gtoreq.1 .mu.M, e.g.
.gtoreq.50 .mu.M, in the in vitro Microsomal assay as disclosed in
WO 99/11258.
* * * * *