U.S. patent application number 13/030419 was filed with the patent office on 2011-06-16 for alcanoic acid amides substituted by saturated o-heterocycles.
Invention is credited to Peter Herold, Stjepan Jelakovic, Robert Mah, Christiane Marti, Aleksandar Stojanovic, Stefan Stutz, Vincenzo Tschinke.
Application Number | 20110144197 13/030419 |
Document ID | / |
Family ID | 37847050 |
Filed Date | 2011-06-16 |
United States Patent
Application |
20110144197 |
Kind Code |
A1 |
Herold; Peter ; et
al. |
June 16, 2011 |
ALCANOIC ACID AMIDES SUBSTITUTED BY SATURATED O-HETEROCYCLES
Abstract
Compounds of the general formula (formula I) ##STR00001## in
which the meanings of the substituents R.sup.1 and R.sup.6 are as
indicated in claim 1, have renin-inhibiting properties and can be
used as medicines.
Inventors: |
Herold; Peter; (Allschwil,
CH) ; Mah; Robert; (Allschwil, CH) ; Tschinke;
Vincenzo; (Allschwil, CH) ; Stutz; Stefan;
(Allschwil, CH) ; Stojanovic; Aleksandar;
(Allschwil, CH) ; Jelakovic; Stjepan; (Allschwil,
CH) ; Marti; Christiane; (Allschwil, CH) |
Family ID: |
37847050 |
Appl. No.: |
13/030419 |
Filed: |
February 18, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11992127 |
Mar 17, 2008 |
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PCT/EP2006/066368 |
Sep 14, 2006 |
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13030419 |
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Current U.S.
Class: |
514/459 ;
514/469; 514/471; 549/426; 549/463; 549/467; 549/493 |
Current CPC
Class: |
A61K 31/335 20130101;
A61P 9/00 20180101; A61P 9/12 20180101; A61P 9/04 20180101; A61P
27/06 20180101; A61P 9/10 20180101; A61P 13/12 20180101 |
Class at
Publication: |
514/459 ;
514/471; 549/493; 549/426; 549/463; 514/469; 549/467 |
International
Class: |
A61K 31/341 20060101
A61K031/341; C07D 307/14 20060101 C07D307/14; C07D 309/06 20060101
C07D309/06; A61K 31/351 20060101 A61K031/351; C07D 307/00 20060101
C07D307/00; A61K 31/343 20060101 A61K031/343; C07D 307/93 20060101
C07D307/93; A61P 9/00 20060101 A61P009/00; A61P 27/06 20060101
A61P027/06; A61P 9/12 20060101 A61P009/12; A61P 9/10 20060101
A61P009/10; A61P 13/12 20060101 A61P013/12 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 17, 2005 |
CH |
01518/05 |
Claims
1-8. (canceled)
9. A compound of the formula ##STR00009## or a pharmaceutically
useful salt thereof; in which R.sup.1 is an optionally substituted
tetrahydrofuranyl, optionally substituted tetrahydrofuranylmethyl,
optionally substituted tetrahydropyranyl or optionally substituted
tetrahydropyranylmethyl; R.sup.2 and R.sup.3 are independently of
one another hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl or
C.sub.2-6alkynyl, or the two radicals together with the carbon atom
to which they are bonded are C.sub.3-8cycloalkyl; R.sup.4 and
R.sup.5 are independently of one another hydrogen, C.sub.1-6alkyl,
C.sub.2-6alkenyl or C.sub.2-6alkynyl or the two radicals together
with the carbon atom to which they are bonded are
C.sub.3-8cycloalkyl; R.sup.6 is a group --CH.sub.2--R.sup.7,
--CH.sub.2--CO--R.sup.7, --CH.sub.2--CH.sub.2--R.sup.7,
--CH.sub.2--NR.sup.8--CO--R.sup.7,
--CH.sub.2--CO--NR.sup.8--CH.sub.2--R.sup.7,
--CH.sub.2--CH.sub.2--NR.sup.8--R.sup.7,
--CH.sub.2--CO--NR.sup.8--R.sup.7 or
--CO--NR.sup.8--CH.sub.2--R.sup.7; R.sup.7 is an optionally
substituted cyclic radical; and R.sup.8 is hydrogen, C.sub.1-6alkyl
or C.sub.1-6alkanoyl.
10. A compound of the formula ##STR00010## or a salt thereof,
especially a pharmaceutically useful salt thereof; in which R.sup.1
is an optionally substituted tetrahydrofuranyl, optionally
substituted tetrahydrofuranylmethyl, optionally substituted
tetrahydropyranyl or optionally substituted
tetrahydropyranylmethyl; R.sup.2 and R.sup.3 are independently of
one another hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl or
C.sub.2-6alkynyl, or the two radicals together with the carbon atom
to which they are bonded are C.sub.3-8cycloalkyl; R.sup.4 and
R.sup.5 are independently of one another hydrogen, C.sub.1-6alkyl,
C.sub.2-6alkenyl or C.sub.2-6alkynyl or the two radicals together
with the carbon atom to which they are bonded are
C.sub.3-8cycloalkyl; R.sup.6 is a group --CH.sub.2--R.sup.7,
--CH.sub.2--CO--R.sup.7, --CH.sub.2--CH.sub.2--R.sup.7,
--CH.sub.2--NR.sup.8--CO--R.sup.7,
--CH.sub.2--CO--NR.sup.8--CH.sub.2--R.sup.7,
--CH.sub.2--CH.sub.2--NR.sup.8--R.sup.7,
--CH.sub.2--CO--NR.sup.8--R.sup.7 or
--CO--NR.sup.8--CH.sub.2--R.sup.7; R.sup.7 is an optionally
substituted cyclic radical; and R.sup.8 is hydrogen, C.sub.1-6alkyl
or C.sub.1-6alkanoyl.
11. A compound according to claim 10 of the formula ##STR00011## or
a salt thereof; in which R.sup.1, R.sup.4, R.sup.5 and R.sup.6 have
the meaning as indicated for the compound of the formula (I)
according to claim 10.
12. A pharmaceutically useful salt of a compound according to claim
11.
13. A method for the prevention, for delaying the progression or
for the treatment of high blood pressure, heart failure, glaucoma,
myocardial infarction, renal failure or restenoses, which comprises
administering a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically useful salt thereof according to
claim 9, to a patient in need thereof.
14. A pharmaceutical composition, comprising a compound of the
formula (I) or a pharmaceutically useful salt thereof, according to
claim 9, and a pharmaceutically inert excipient.
15. A pharmaceutical combination in the form of a product or of a
kit comprising individual components a) of a compound of the
formula (I) or a pharmaceutically useful salt thereof, according to
claim 9, and b) of at least one pharmaceutical form whose active
ingredient has a cardiovascular effect.
16. A compound according to claim 10, of the formula ##STR00012##
or a pharmaceutically useful salt thereof.
Description
[0001] The present invention relates to the use of specific
alkanamides as medicines, in particular as renin inhibitors, to a
process for their preparation and to novel compounds of this
type.
[0002] Alkanamides for use as medicines are disclosed for example
in EP 678503. In relation especially to the renin inhibition,
however, there is still a need for active ingredients of high
potency. The priority in this is to improve the pharmacokinetic
properties. These properties, which aim at better bioavailability,
are for example absorption, metabolic stability, solubility or
lipophilicity.
[0003] The invention therefore provides compounds and the use of
compounds of the general formula
##STR00002##
in which R.sup.1 is saturated heterocyclyl or saturated
heterocyclyl-C.sub.1-4alkyl, where in each case the heterocycle is
an oxygen-heterocycle having 1 or 2 oxygen atoms, is bonded via a C
atom and is unsubstituted or substituted one or more times by
C.sub.1-6alkanoyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkoxy-C.sub.1-6alkoxy,
C.sub.1-6alkoxy-C.sub.1-6alkyl, C.sub.1-6alkoxycarbonylamino,
C.sub.0-6alkylcarbonylamino, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylenedioxy, optionally N-mono- or
N,N-di-C.sub.1-6alkylated amino, aryl, optionally N-mono- or
N,N-di-C.sub.1-6alkylated carbamoyl, optionally esterified carboxy,
cyano, C.sub.3-8cycloalkoxy, C.sub.3-8cycloalkyl-C.sub.0-6alkyl,
halogen, halo-C.sub.1-6alkoxy, halo-C.sub.1-6alkyl, heteroaryl,
unsaturated, partially saturated or saturated heterocyclyl,
hydroxy, nitro or oxo; R.sup.2 and R.sup.3 are independently of one
another hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl or
C.sub.2-6alkynyl, or the two radicals together with the carbon atom
to which they are bonded are C.sub.3-8cycloalkyl; R.sup.4 and
R.sup.5 are independently of one another hydrogen, C.sub.1-6alkyl,
C.sub.2-6alkenyl or C.sub.2-6alkynyl or the two radicals together
with the carbon atom to which they are bonded are
C.sub.3-8cycloalkyl; R.sup.6 is a group --CH.sub.2--R.sup.7,
--CH.sub.2--CO--R.sup.7, --CH.sub.2--CH.sub.2--R.sup.7,
--CH.sub.2--NR.sup.8--CO--R.sup.7,
--CH.sub.2--CO--NR.sup.8--CH.sub.2--R.sup.7,
--CH.sub.2--CH.sub.2--NR.sup.8--R.sup.7,
--CH.sub.2--CO--NR.sup.8--R.sup.7 or
--CO--NR.sup.6--CH.sub.2--R.sup.7; R.sup.7 is an optionally
substituted cyclic radical; R.sup.8 is hydrogen, C.sub.1-6alkyl or
C.sub.1-6alkanoyl; and salts, especially pharmaceutically useful
salts thereof.
[0004] The term saturated oxygen-heterocycle refers to
3-16-membered, mono- or bicyclic saturated heterocyclic radicals
having 1 or 2 oxygen atoms. Preferred radicals have 3-8 members,
particularly preferably 5 or 6 members, and are monocyclic and are
optionally fused to a 3-8-membered ring which may be carbocyclic or
heterocyclic. A further preferred group of saturated
oxygen-heterocyclic radicals are bicyclic saturated
oxygen-heterocycles which have a spirocyclic or bridged ring.
Preferred oxygen-heterocyclic radicals have in each ring 1 oxygen
atom or 1-2 oxygen atoms, with at least two, preferably 2-7, carbon
atoms being present in each ring. Examples of saturated
oxygen-heterocyclyl radicals are dioxanyl, [1,4]dioxepanyl,
dioxolanyl, oxepanyl, tetrahydropyranyl and tetrahydrofuranyl.
Examples of bicyclic saturated oxygen-heterocyclyl radicals are
2,5-dioxabicyclo[4.1.0]heptanyl, 2-oxa-bicyclo[2.2.1]heptanyl,
2-oxabicyclo[4.1.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl,
7-oxa-bicyclo[2.2.1]heptanyl, 2-oxabicyclo[3.1.0]hexanyl,
3-oxabicyclo[3.1.0]hexanyl, 1-oxaspiro[2.5]octanyl,
6-oxaspiro[2.5]octanyl or 3-oxabicyclo[3.3.1]nonanyl.
Oxygen-heterocyclyl may be unsubstituted or substituted one or more
times, e.g. once or twice, by C.sub.1-6alkanoyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.1-6alkoxy, C.sub.1-6alkoxy-C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonylamino, C.sub.1-6alkyl,
C.sub.0-6alkylcarbonylamino, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylenedioxy, optionally N-mono- or
N,N-di-C.sub.1-6-alkylated amino, aryl, optionally N-mono- or
N,N-di-C.sub.1-6-alkylated carbamoyl, optionally esterified
carboxy, cyano, C.sub.3-8cycloalkoxy,
C.sub.3-8cycloalkyl-C.sub.0-6alkyl, halogen, halo-C.sub.1-6alkoxy,
halo-C.sub.1-6alkyl, heteroaryl, unsaturated, partially saturated
or saturated heterocyclyl, hydroxy, nitro, oxide or oxo.
[0005] The term saturated heterocyclyl refers to 3-16-membered,
mono- or bicyclic saturated heterocyclic radicals having 1 to 4
nitrogen and/or 1 or 2 sulphur or oxygen atoms. Preferred radicals
have 3-8 members, particularly preferably 5 or 6 members, and are
monocyclic and are optionally fused to a 3-8-membered ring which
may be carbocyclic or heterocyclic. A further preferred group of
saturated heterocyclic radicals are bicyclic saturated heterocycles
which have a spirocyclic or bridged ring. Preferred heterocyclic
radicals have in each ring 1 nitrogen, oxygen or sulphur atom or
1-2 nitrogen atoms and 1-2 oxygen atoms 1-2 nitrogen atoms and 1-2
sulphur atoms, with at least one, preferably 1-7, carbon atom(s)
being present in each ring. Examples of saturated heterocyclyl
radicals are azepanyl, azetidinyl, aziridinyl, dioxanyl,
[1,4]dioxepanyl, dioxolanyl, dithianyl, dithiolanyl, morpholinyl,
oxathianyl, oxepanyl, piperazinyl, piperidinyl, pyrrolidinyl,
tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothio-phenyl,
tetrahydrothiopyranyl, thiepanyl or thiomorpholinyl. Examples of
bicyclic saturated heterocyclyl radicals are
2,5-dioxabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.1]heptanyl,
2-oxabicyclo[4.1.0]heptanyl, 3-oxabicyclo[4.1.0]heptanyl,
7-oxabicyclo[2.2.1]heptanyl, 2-oxabicyclo[3.1.0]hexanyl,
3-oxabicyclo[3.1.0]hexanyl, 1-oxaspiro[2,5]octanyl,
6-oxaspiro[2,5]octanyl or 3-oxabicyclo[3.3.1]nonanyl. Heterocyclyl
may be unsubstituted or substituted one or more times, e.g. once or
twice, by C.sub.1-6alkanoyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.1-6alkoxy, C.sub.1-6alkoxy-C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonylamino, C.sub.1-6alkyl,
C.sub.0-6alkylcarbonylamino, C.sub.1-6alkylcarbonyloxy,
C.sub.1-6alkylenedioxy, optionally N-mono- or
N,N-di-C.sub.1-6-alkylated amino, aryl, optionally N-mono- or
N,N-di-C.sub.1-6-alkylated carbamoyl, optionally esterified
carboxy, cyano, C.sub.3-8cycloalkoxy,
C.sub.3-8cycloalkyl-C.sub.0-6alkyl, halogen, halo-C.sub.1-6alkoxy,
halo-C.sub.1-6alkyl, heteroaryl, unsaturated, partially saturated
or saturated heterocyclyl, hydroxy, nitro, oxide or oxo.
[0006] The term cyclic radical refers to carbocyclic and
heterocyclic radicals. These radicals may be saturated, partially
saturated, unsaturated or aromatic. Examples of substituents on
R.sup.7 are acetamidinyl-C.sub.1-6alkyl,
3-acetamidomethylpyrrolidinyl, acyl-C.sub.1-6alkoxy-C.sub.1-6alkyl,
(N-acyl)-C.sub.1-6alkoxy-C.sub.1-6alkylamino, C.sub.1-6alkanoyl,
C.sub.3-5alkenyloxy-C.sub.1-6alkyl, C.sub.1-6alkoxy,
C.sub.1-6alkoxy-C.sub.1-6alkoxy,
C.sub.1-6alkoxy-C.sub.1-6alkoxy-C.sub.1-6alkyl,
C.sub.1-6alkoxy-C.sub.1-6alkyl,
(N--C.sub.1-6alkoxy)-C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkoxy,
(N--C.sub.1-6alkoxy)-C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkyl,
C.sub.1-6alkoxy-C.sub.1-6alkylcarbamoyl,
C.sub.1-6alkoxy-C.sub.1-6alkylcarbonyl,
C.sub.1-6alkoxy-C.sub.1-6alkylcarbonylamino,
1-C.sub.1-6alkoxy-C.sub.1-6alkylimidazol-2-yl,
2-C.sub.1-6alkoxy-C.sub.1-6alkyl-4-oxo-imidazol-1-yl,
3-C.sub.1-6alkoxy-C.sub.1-6alkyl-pyrrolidinyl,
1-C.sub.1-6alkoxy-C.sub.1-6alkyltetrazol-5-yl,
5-C.sub.1-6alkoxy-C.sub.1-6alkyltetrazol-1-yl,
C.sub.1-6alkoxyaminocarbonyl-C.sub.1-6alkoxy,
C.sub.1-6alkoxyaminocarbonyl-C.sub.1-6alkyl,
C.sub.1-6alkoxycarbonyl, C.sub.1-6alkoxycarbonyl-C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonyl-C.sub.1-6-alkyl,
C.sub.1-6alkoxycarbonylamino,
C.sub.1-6alkoxycarbonylamino-C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonylamino-C.sub.1-6alkyl, C.sub.1-6alkyl,
(N--C.sub.1-6alkyl)-C.sub.1-6alkoxy-C.sub.1-6alkylcarbamoyl,
(N--C.sub.1-6alkyl)-C.sub.1-6alkoxy-C.sub.1-6alkylcarbonylamino,
(N--C.sub.1-6alkyl)-C.sub.1-6-alkoxycarbonylamino,
(N--C.sub.1-6alkyl)-C.sub.0-6alkylcarbonylamino-C.sub.1-6alkoxy,
(N--C.sub.1-6alkyl)-C.sub.0-6alkylcarbonylamino-C.sub.1-6alkyl,
(N--C.sub.1-6alkyl)-C.sub.1-6alkylsulphonylamino-C.sub.1-6alkoxy,
(N--C.sub.1-6alkyl)-C.sub.1-6alkylsulphonylamino-C.sub.1-6alkyl,
C.sub.1-6alkylamidinyl, C.sub.1-6alkylamino,
di-C.sub.1-6alkylamino, C.sub.1-6alkylamino-C.sub.2-6alkoxy,
di-C.sub.1-6alkylamino-C.sub.2-6alkoxy,
C.sub.1-6alkylamino-C.sub.1-6alkyl, C.sub.1-6alkylaminocarbonyl,
C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkoxy,
di-C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkoxy,
C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkoxy-C.sub.1-6alkyl,
C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkyl,
C.sub.1-6alkylaminocarbonylamino-C.sub.1-6alkoxy,
C.sub.1-6alkylaminocarbonylamino-C.sub.1-6alkyl,
di-C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkyl,
di-C.sub.1-6alkylamino-C.sub.1-6alkyl, C.sub.1-6alkylcarbamoyl,
di-C.sub.1-6alkylcarbamoyl, C.sub.0-6alkylcarbonylamino,
C.sub.0-6alkylcarbonylamino-C.sub.1-6alkoxy,
C.sub.0-6alkylcarbonylamino-C.sub.1-6alkyl,
C.sub.1-6alkylcarbonyloxy-C.sub.1-6alkoxy,
C.sub.1-6alkylcarbonyloxy-C.sub.1-6alkyl, C.sub.1-6alkylsulphonyl,
C.sub.1-6alkylsulphonyl-C.sub.1-6alkoxy,
C.sub.1-6alkylsulphonyl-C.sub.1-6alkyl,
C.sub.1-6alkylsulphonylamino-C.sub.1-6alkoxy,
C.sub.1-6alkylsulphonylamino-C.sub.1-6alkyl, amino-C.sub.2-7alkoxy,
amino-C.sub.1-6alkyl, carbamoyl, carbamoyl-C.sub.1-6alkoxy,
carbamoyl-C.sub.1-6alkyl, carboxy-C.sub.1-6alkoxy,
carboxy-C.sub.1-6alkoxy-C.sub.1-6alkyl, carboxy-C.sub.1-6alkyl,
cyano, cyano-C.sub.1-6alkoxy, cyano-C.sub.1-6alkyl,
C.sub.3-8cycloalkyl-C.sub.0-6alkoxy,
C.sub.3-8cycloalkyl-C.sub.1-6alkyl,
C.sub.3-8cycloalkylcarbonylamino,
C.sub.3-8cycloalkylcarbonylamino-C.sub.1-6alkoxy,
C.sub.3-8cycloalkylcarbonylamino-C.sub.1-6alkyl,
3,4-dihydroxypyrrolidinyl,
O,N-dimethylhydroxylamino-C.sub.1-6alkyl, 2,6-dimethylmorpholinyl,
3,5-dimethylmorpholinyl, dioxanyl, dioxolanyl,
4,4-dioxothio-morpholinyl, dithianyl, dithiolanyl, halogen,
halo-C.sub.1-7alkoxy, halo-C.sub.1-6alkyl,
hydroxy-C.sub.1-6alkoxy-C.sub.1-6alkoxy,
hydroxy-C.sub.1-6alkoxy-C.sub.1-6alkyl, hydroxy-C.sub.1-6alkyl,
(N-hydroxy)-C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkoxy,
(N-hydroxy)-C.sub.1-6alkylaminocarbonyl-C.sub.1-6alkyl,
(N-hydroxy)aminocarbonyl-C.sub.1-6alkoxy,
(N-hydroxy)aminocarbonyl-C.sub.1-6alkyl,
2-hydroxymethylpyrrolidinyl, 4-hydroxy-piperidinyl,
3-hydroxypyrrolidinyl, imidazolyl-C.sub.1-4alkoxy,
imidazolyl-C.sub.1-4alkyl, 2-methylimidazolyl-C.sub.1-4alkoxy,
2-methylimidazolyl-C.sub.1-4alkyl,
3-methyl-[1,2,4]-oxadiazol-5-yl-C.sub.1-4alkoxy,
5-methyl-[1,2,4]-oxadiazol-3-yl-C.sub.1-4alkoxy,
3-methyl-[1,2,4]-oxadiazol-5-yl-C.sub.1-4alkyl,
5-methyl-[1,2,4]-oxadiazol-3-yl-C.sub.1-4alkyl,
O-methyloximyl-C.sub.1-6alkyl, 4-methylpiperazinyl,
5-methyltetrazol-1-yl-C.sub.1-4alkoxy,
5-methyltetrazol-1-yl-C.sub.1-4alkyl, morpholinyl,
[1,2,4]-oxadiazol-5-yl-C.sub.1-4alkoxy,
[1,2,4]-oxadiazol-5-yl-C.sub.1-4alkyl, oxazol-4-yl-C.sub.1-4alkoxy,
oxazol-4-yl-C.sub.1-4alkyl, oxide, oxo, 2-oxoimidazolidinyl,
2-oxo-[1,3]oxazinyl, 2-oxo-oxazolidinyl,
2-oxooxazolidinyl-C.sub.1-4alkoxy,
2-oxooxazolidinyl-C.sub.1-4alkyl, 4-oxopiperidinyl,
2-oxopyrrolidinyl, 2-oxopyrrolidinyl-C.sub.1-4alkoxy,
2-oxopyrrolidinyl-C.sub.1-4alkyl, 2-oxotetrahydro-pyrimidinyl,
4-oxothiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl,
pyrrolyl, tetrazol-1-yl-C.sub.1-4alkoxy,
tetrazol-2-yl-C.sub.1-4alkoxy, tetrazol-5-yl-C.sub.1-4alkoxy,
tetrazol-1-yl-C.sub.1-4alkyl, tetrazol-2-yl-C.sub.1-4alkyl,
tetrazol-5-yl-C.sub.1-4alkyl, thiazol-4-yl-C.sub.1-4alkoxy,
thiazol-4-yl-C.sub.1-4alkyl, thiomorpholinyl,
[1,2,4]-triazol-1-yl-C.sub.1-4alkoxy,
[1,2,4]-triazol-4-yl-C.sub.1-4alkoxy,
[1,2,4]-triazol-1-yl-C.sub.1-4alkyl or
[1,2,4]-triazol-4-yl-C.sub.1-4alkyl.
[0007] Carbocyclic saturated radicals are for example
C.sub.3-8cycloalkyl radicals or else bicyclic (including
spirocyclic) and polycyclic radicals having up to 20 carbon
atoms.
[0008] Carbocyclic partially saturated radicals are derived from
the saturated radicals mentioned and have at least one double
bond.
[0009] Carbocyclic aromatic radicals are for example phenyl or
naphthyl or else mono-, bi- or polycyclic radicals having up to 20
carbon atoms.
[0010] Heterocyclic partially saturated radicals are derived from
the saturated or unsaturated radicals mentioned and have at least
one double bond. They are for example
2,3-dihydro-benzoimidazol-1-yl, 3,4-dihydro-2H-1,4-benzoxazin-4-yl,
3,4-dihydro-2H-1,4-benzothiazin-4-yl,
3,4-dihydro-2H-1,3-benzothiazin-1-yl,
5,6-dihydrophenanthridin-5-yl,
3,4,5,6,7,8-hexahydro-2H-1,4-benzoxazin-4-yl,
3,4,5,6,7,8-hexahydro-2H-1,4-benzothiazin-4-yl,
2,3,4,5-tetrahydro-1H-1-benzo[6,7-b]azepin-1-yl,
1,2,3,4-tetrahydro-1,3-benzodiazin-1-yl or -3-yl,
1,2,3,4-tetrahydro-1,4-benzodiazin-1-yl,
1,2,3,4-tetrahydroquinol-1-yl or
1,2,3,4-tetrahydroisoquinol-2-yl.
[0011] Heterocyclic aromatic radicals are for example benzofuranyl,
benzoimidazolyl, benzo-oxazinyl, benzooxazolyl, benzothiazinyl,
benzothiazolyl, benzo[b]thienyl, quinazolinyl, quinolyl,
quinoxalinyl, furanyl, imidazolyl, imidazopyridinyl,
imidazopyrimidinyl, indazolyl, indolyl, isobenzofuranyl,
isoquinolyl, naphthyridyl, oxazolyl, phthalazinyl, pyranyl,
pyrazinyl, pyridooxazinyl, pyridyl, pyrimidinyl, pyrrolizinyl,
pyrrolopyridyl, thiazolyl, thienyl, triazolyl, pyrrolyl, pyrazolyl,
triazinyl or triazolopyridinyl.
[0012] C.sub.1-6Alkyl may be straight-chain or branched and/or
bridged and is for example methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, secondary butyl, tertiary butyl or a pentyl or hexyl
group.
[0013] C.sub.1-6Alkylamino is, for example, methylamino,
ethylamino, propylamino or butylamino.
[0014] Di-C.sub.1-6alkylamino is, for example, dimethylamino,
N-methyl-N-ethylamino, diethylamino, N-methyl-N-propylamino or
N-butyl-N-methylamino.
[0015] C.sub.2-6alkenyl may be straight-chain or branched and is,
for example, allyl or vinyl.
[0016] C.sub.2-6alkynyl may be straight-chain or branched and is,
for example, ethynyl.
[0017] C.sub.1-6alkoxy is, for example, methoxy, ethoxy, propyloxy,
isopropyloxy, butyloxy, isobutyloxy, secondary butyloxy, tertiary
butyloxy, pentyloxy or hexyloxy.
[0018] C.sub.1-6Alkoxycarbonylamino is preferably
C.sub.2-C.sub.5alkoxycarbonylamino such as ethoxycarbonylamino,
propyloxycarbonylamino, isopropyloxycarbonylamino,
butyloxycarbonylamino, isobutyloxycarbonylamino, secondary
butyloxycarbonylamino or tertiary butyloxycarbonylamino.
[0019] C.sub.1-6alkylcarbonyloxy is, for example, acetyloxy,
propionyloxy, propylcarbonyloxy, isopropyl-carbonyloxy,
butylcarbonyloxy, isobutylcarbonyloxy, secondary butylcarbonyloxy,
tertiary butylcarbonyloxy, pentylcarbonyloxy or
hexylcarbonyloxy.
[0020] C.sub.0-6alkylcarbonylamino is, for example, formylamino,
acetylamino, propionylamino, propyl-carbonylamino,
isopropylcarbonylamino, butylcarbonylamino, isobutylcarbonylamino,
secondary butylcarbonylamino, tertiary butylcarbonylamino,
pentylcarbonylamino or hexylcarbonylamino.
[0021] Halogen is, for example, fluorine, chlorine, bromine or
iodine, preferably fluorine or chlorine.
[0022] Halo-C.sub.1-6alkoxy is, for example, alkoxy substituted one
or more times by fluorine, chlorine, bromine or iodine, including
mixed, e.g. fluorine and chlorine, substitutions, with preference
for perfluorinated radicals such as trifluoromethoxy.
[0023] Halo-C.sub.1-6alkyl is, for example, alkyl substituted one
or more times by fluorine, chlorine, bromine or iodine, including
mixed, e.g. fluorine and chlorine, substitutions, with preference
for perfluorinated radicals such as trifluoromethyl.
[0024] C.sub.1-6Alkylenedioxy is, for example, methylenedioxy,
ethylenedioxy, 1,3-propylenedioxy or 1,2-propylenedioxy.
[0025] Optionally N-mono- or N,N-di-C.sub.1-8-alkylated carbamoyl
is, for example, carbamoyl, methyl-carbamoyl, ethylcarbamoyl,
N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl or
propyl-carbamoyl.
[0026] Optionally esterified carboxy is, for example, carboxy
esterified with C.sub.0-6alkyl, such as carboxy or
C.sub.1-6alkoxycarbonyl.
[0027] C.sub.3-8Cycloalkoxy is preferably 3-, 5- or 6-membered
cycloalkoxy such as cyclopropyloxy, cyclopentyloxy and
cyclohexyloxy.
[0028] C.sub.3-8Cycloalkyl-C.sub.0-6alkyl is preferably 3-, 5- or
6-membered cycloalkyl such as cyclopropyl, cyclopropylmethyl,
cyclopentyl and cyclohexyl.
[0029] Cyano-C.sub.1-4alkoxy is, for example, cyanomethoxy,
2-cyanoethoxy, 2- or 3-cyanopropyloxy or 4-cyanobutyloxy,
especially cyanomethoxy.
[0030] Cyano-C.sub.1-4alkyl is, for example, cyanomethyl,
2-cyanoethyl, 2- or 3-cyanopropyl, 2-cyano-2-methylpropyl or
4-cyanobutyl, especially cyanomethyl.
[0031] N,N-Di-C.sub.1-4alkylamino is, for example, dimethylamino,
N-methyl-N-ethylamino, diethylamino, N-methyl-N-propylamino or
N-butyl-N-methylamino.
[0032] N,N-Di-C.sub.1-4alkylamino-C.sub.1-4alkoxy is
2-dimethylaminoethoxy, 3-dimethylaminopropyloxy,
4-dimethylaminobutyloxy, 2-diethylaminoethoxy,
2-(N-methyl-N-ethylamino)ethoxy or
2-(N-butyl-N-methylamino)ethoxy.
[0033] N,N-Di-C.sub.1-4alkylamino-C.sub.1-4alkyl is, for example,
2-dimethylaminoethyl, 3-dimethylamino-propyl, 4-dimethylaminobutyl,
2-diethylaminoethyl, 2-(N-methyl-N-ethylamino)ethyl or
2-(N-butyl-N-methylamino)ethyl.
[0034] N,N-Di-C.sub.1-4alkylcarbamoyl-C.sub.1-4alkoxy is, for
example, methyl- or dimethylcarbamoyl-C.sub.1-4alkoxy such as
N-methyl-, N-butyl- or N,N-dimethylcarbamoylmethoxy,
2-(N-methyl-carbamoyl)ethoxy, 2-(N-butylcarbamoyl)ethoxy,
2-(N,N-dimethylcarbamoyl)ethoxy, 3-(N-methylcarbamoyl)propyloxy,
3-(N-butylcarbamoyl)propyloxy, 3-(N,N-dimethylcarbamoyl)propyloxy
or 4-(N-methylcarbamoyl)butyloxy, 4-(N-butylcarbamoyl)butyloxy or
4-(N,N-dimethylcarbamoyl)butyloxy, especially N-methyl-, N-butyl-
or N,N-dimethyl-carbamoylmethoxy.
[0035] N,N-Di-C.sub.1-4alkylcarbamoyl-C.sub.1-4alkyl is, for
example, 2-dimethylcarbamoylethyl, 3-dimethyl-carbamoylpropyl,
2-dimethylcarbamoylpropyl, 2-(dimethylcarbamoyl)-2-methylpropyl or
2-(dimethylcarbamoyl)butyl.
[0036] Optionally partially hydrogenated pyridyl- or
N-oxidopyridyl-C.sub.1-4alkoxy is, for example, pyridyl- or
N-oxidopyridylmethoxy, 2-pyridylethoxy, 2- or 3-pyridylpropyloxy or
4-pyridylbutyloxy, especially 3- or 4-pyridylmethoxy.
[0037] Optionally partially hydrogenated pyridyl- or
N-oxidopyridyl-C.sub.1-4alkyl is, for example, pyridyl- or
N-oxidopyridylmethyl, 2-pyridylethyl, 2- or 3-pyridylpropyl or
4-pyridylbutyl, especially 3- or 4-pyridylmethyl.
[0038] Morpholino-C.sub.1-4alkoxy may be N-oxidized and is, for
example, 1-morpholinoethoxy, 3-morpholinopropyloxy or
1-(morpholino-2-methyl)propyloxy.
[0039] Morpholino-C.sub.1-4alkyl may be N-oxidized and is, for
example, morpholinomethyl, 2-morpholinoethyl, 3-morpholinopropyl or
1- or 2-(4-morpholino)butyl.
[0040] Piperazino-C.sub.1-4alkyl is, for example, piperazinomethyl,
2-piperazinoethyl or 3-piperazinopropyl.
[0041] Piperidino-C.sub.1-4alkoxy is, for example,
piperidinomethoxy, 2-piperidinoethoxy or 3-piperidinopropyloxy.
[0042] Piperidino-C.sub.1-4alkyl is, for example, piperidinomethyl,
2-piperidinoethyl or 3-piperidinopropyl.
[0043] Pyrrolidino-C.sub.1-4alkoxy is, for example,
2-pyrrolidinoethoxy or 3-pyrrolidinopropyloxy.
[0044] Pyrrolidino-C.sub.1-4alkyl is, for example,
pyrrolidinomethyl, 2-pyrrolidinoethyl or 3-pyrrolidinopropyl.
[0045] S-Oxothiomorpholino-C.sub.1-4alkyl is, for example,
S-oxothiomorpholinomethyl or 2-(S-oxothio-morpholino)ethyl.
[0046] Thiazolyl-C.sub.1-4alkoxy is, for example, thiazolylmethoxy,
2-thiazolylethoxy or 3-thiazolyl-propyloxy.
[0047] Thiomorpholino-C.sub.1-4alkyl or
S,S-dioxothiomorpholino-C.sub.1-4alkyl is, for example,
thiomorpholino-C.sub.1-4alkyl such as -methyl or -ethyl, or
S,S-dioxothiomorpholino-C.sub.1-4alkyl such as -methyl or
-ethyl.
[0048] Depending on the presence of asymmetric carbon atoms, the
compounds of the invention may be in the form of mixtures of
isomers, specifically as racemates, or in the form of pure isomers,
specifically of optical antipodes. The invention includes all these
forms. Mixtures of diastereomers, diastereomeric racemates or
mixtures of diastereomeric racemates can be fractionated by
conventional methods, e.g. by column chromatography, thin-layer
chromatography, HPLC and the like.
[0049] Salts of compounds with salt-forming groups are in
particular acid addition salts, salts with bases or, if a plurality
of salt-forming groups is present, optionally also mixed salts or
inner salts.
[0050] Salts are primarily the pharmaceutically acceptable or
non-toxic salts of compounds of the formula (I). Such salts are
formed for example by compounds of the formula (I) having an acidic
group, e.g. a carboxy or sulpho group, and are for example their
salts with suitable bases, such as non-toxic metal salts derived
from metals of group Ia, Ib, IIa and IIb of the Periodic Table of
the Elements, e.g. alkali metal, in particular lithium, sodium or
potassium, salts, alkaline earth metal salts, for example magnesium
or calcium salts, furthermore zinc salts or ammonium salts, also
those salts formed with organic amines such as optionally
hydroxy-substituted mono-, di- or trialkylamines, especially mono-,
di- or tri-lower-alkyl-amines, or with quaternary ammonium bases,
e.g. methyl-, ethyl-, diethyl- or triethylamine, mono-, bis- or
tris(2-hydroxy-lower-alkyl)amines such as ethanol-, diethanol- or
triethanol-amine, tris(hydroxymethyl)methylamine or
2-hydroxy-tertiary-butylamine,
N,N-di-lower-alkyl-N-(hydroxy-lower-alkyl)amine, such as
N,N-dimethyl-N-(2-hydroxyethyl)amine, or N-methyl-D-glucamine, or
quaternary ammonium hydroxides such as tetrabutylammonium
hydroxide.
[0051] Under lower-alkyl is understood an alkyl group having 1 to 6
C-atoms. The compounds of the formula I having a basic group, e.g.
an amino group, can form acid addition salts, e.g. with suitable
inorganic acids, e.g. hydrohalic acid such as hydrochloric acid,
hydrobromic acid, sulphuric acid with replacement of one or both
protons, phosphoric acid with replacement of one or more protons,
e.g. orthophosphoric acid or metaphosphoric acid, or pyrophosphoric
acid with replacement of one or more protons, or with organic
carboxylic, sulphonic or phosphonic acids or N-substituted
sulphamic acids, e.g. acetic acid, propionic acid, glycolic acid,
succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid,
fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric
acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid,
mandelic acid, salicylic acid, 4-aminosalicylic acid,
2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid,
nicotinic acid, isonicotinic acid, furthermore amino acids such as,
for example, the .alpha.-amino acids mentioned hereinbelow, and
methane-sulphonic acid, ethanesulphonic acid,
2-hydroxyethanesulphonic acid, ethane-1,2-disulphonic acid,
benzenesulphonic acid, 4-toluenesulphonic acid,
naphthalene-2-sulphonic acid, 2- or 3-phosphoglycerate, glucose
6-phosphate, N-cyclohexylsulphamic acid (to form cyclamates) or
with other acidic organic compounds such as ascorbic acid.
Compounds of the formula (I) having acidic and basic groups may
also form inner salts.
[0052] Pharmaceutically unsuitable salts may also be used for
isolation and purification.
[0053] The compounds of the formula (I) also include compounds in
which one or more atoms are replaced by their stable,
non-radioactive isotopes; for example a hydrogen atom by
deuterium.
[0054] Prodrug derivatives of the compounds described herein are
derivatives thereof which on in vivo use liberate the original
compound by a chemical or physiological process. A prodrug may for
example be converted into the original compound when a
physiological pH is reached or by enzymatic conversion. Possible
examples of prodrug derivatives are esters of freely available
carboxylic acids, S- and O-acyl derivatives of thiols, alcohols or
phenols, the acyl group being defined as herein. Preferred
derivatives are pharmaceutically acceptable ester derivatives which
are converted by solvolysis in physiological medium into the
original carboxylic acid, such as, for example, lower alkyl esters,
cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or
disubstituted lower alkyl esters such as lower .omega.-(amino,
mono- or dialkylamino, carboxy, lower alkoxycarbonyl)-alkyl esters
or such as lower .alpha.-(alkanoyloxy, alkoxycarbonyl or
dialkylaminocarbonyl)-alkyl esters; conventionally,
pivaloyloxymethyl esters and similar esters are used as such.
[0055] Because of the close relationship between a free compound, a
prodrug derivative and a salt compound, a particular compound in
this invention also includes its prodrug derivative and salt form,
where this is possible and appropriate.
[0056] The groups of compounds mentioned hereinafter are not to be
regarded as closed; on the contrary, it is possible for parts of
these groups of compounds to be interchanged or replaced by the
definitions given above, or omitted, in a worthwhile manner, e.g.
to replace general by more specific definitions.
[0057] Preferred saturated oxygen-heterocyclyl radicals for R.sup.1
are 4-16-membered, mono- or bicyclic saturated oxygen-heterocyclic
radicals having 1 or 2 oxygen atoms. Preference is given to
4-8-membered, and particular preference to 5- or 6-membered,
monocyclic radicals which optionally have a fused-on 3-8-membered
ring which may be carbocyclic or heterocyclic. A further preferred
group of oxygen-heterocyclic radicals for R.sup.1 are bicyclic
saturated oxygen-heterocycles which have for example a spirocyclic
or bridged ring. Preferred heterocyclic radicals for R.sup.1 have
in each ring 1 oxygen atom or 1-2 oxygen atoms, with at least one,
preferably 2-7, carbon atoms being present per ring.
[0058] R.sup.1 is particularly preferably optionally substituted
tetrahydrofuranyl, optionally substituted tetrahydrofuranylmethyl,
optionally substituted tetrahydropyranyl or optionally substituted
tetrahydropyranylmethyl.
[0059] R.sup.6 is preferably a group --CH.sub.2--R.sup.7,
--CH.sub.2--CO--R.sup.7 or --CH.sub.2--NR.sup.8--CO--R.sup.7.
[0060] R.sup.7 is preferably an optionally substituted aromatic or
partially saturated heterocyclic radical.
[0061] R.sup.7 is particularly preferably an optionally substituted
phenyl, 2,3-dihydro-benzo[1,4]oxazinyl,
2,3-dihydro-benzo[1,4]thiazinyl or 1,2,3,4-tetrahydroquinolyl.
[0062] Examples of preferred substituents on R.sup.7 in the meaning
of phenyl are C.sub.1-6-alkyl, halogen, trifluoromethyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
C.sub.1-4-alkoxy-C.sub.1-4-alkoxy-C.sub.1-4-alkyl, C.sub.1-6-alkoxy
and C.sub.1-4-alkoxy-C.sub.1-6-alkoxy.
[0063] Examples of preferred substituents on R.sup.7 in the meaning
of partially saturated heterocyclic are
C.sub.1-4-alkoxycarbonylamino such as methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino
or butoxycarbonylamino,
C.sub.1-4-alkoxy-C.sub.1-4-alkoxy-C.sub.1-4-alkyl, such as
methoxy-C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
ethoxy-C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
propoxy-C.sub.1-4-alkoxy-C.sub.1-4-alkyl,
isopropoxy-C.sub.1-4-alkoxy-C.sub.1-4-alkyl or
butoxy-C.sub.1-4-alkoxy-C.sub.1-4-alkyl, where C.sub.1-4-alkoxy is,
for example, methoxy, ethoxy, propoxy or butoxy, and
C.sub.1-4-alkyl is, for example, methyl, ethyl, propyl or butyl, in
particular methoxymethoxymethyl, 2-methoxyethoxymethyl or
3-methoxypropoxymethyl, C.sub.1-4-alkoxy-C.sub.1-4-alkyl, such as
methoxy-C.sub.1-4-alkyl, ethoxy-C.sub.1-4-alkyl,
propoxy-C.sub.1-4-alkyl, isopropoxy-C.sub.1-4-alkyl,
butoxy-C.sub.1-4-alkyl, isobutoxy-C.sub.1-4-alkyl,
sec-butoxy-C.sub.1-4-alkyl or tert-butoxy-C.sub.1-4-alkyl, where
C.sub.1-4-alkyl is, for example, methyl, ethyl, propyl or butyl, in
particular ethoxymethyl or 2-methoxyethyl, or
N--C.sub.1-4-alkylcarbamoyl, such as N-methylcarbamoyl,
N-ethylcarbamoyl, N-propylcarbamoyl or N-butylcarbamoyl.
[0064] R.sup.6 is particularly preferably a group
--CH.sub.2--R.sup.7 with R.sup.7 being phenyl.
[0065] Preference is further given to compounds of the general
formula
##STR00003##
in which
[0066] R.sup.1, R.sup.4, R.sup.5 and R.sup.6 have the meaning as
indicated for the compound of the formula (I).
[0067] Particular preference is given in each case to those
compounds of the formula (I') in which at least one, for example
one, two, three or preferably all asymmetric carbon atoms of the
main chain have the absolute stereochemistry shown in formula (I'A)
("S" in each case), where the substituents each have the meanings
indicated above and their pharmaceutically acceptable salts.
##STR00004##
[0068] The above-mentioned preferences for the individual
substituents or groups of substituents apply in the same way also
to the compounds of the formulae (I') and (I'A).
[0069] The compounds of the formula (I), (I') and formula (I'A) can
be prepared in an analogous manner to the preparation process
disclosed in the literature (see WO 2002008172 and WO 2002/002508
and literature cited therein). Further preparation processes are
described for example in EP 678503, EP 702004, WO 01/09079, WO
01109083, WO 02/02487, EP 716007, WO 02/02500, WO 02/092828 and in
Helvetica Chemica Acta 86 (2003), 2848-2870 and literature cited
therein.
[0070] Details of the specific preparation variants can be found in
the examples.
[0071] The compounds of the formula (I) can also be prepared in
optically pure form. Separation into antipodes can take place by
methods known per se, either preferably at an early stage in the
synthesis by salt formation with an optically active acid such as,
for example, (+)- or (-)-mandelic acid and separation of the
diastereomeric salts by fractional crystallization or preferably at
a rather late stage by derivatizing with a chiral auxiliary
component such as, for example, (+)- or (-)-camphanoyl chloride,
and separation of the diastereomeric products by chromatography
and/or crystallization and subsequent cleavage of the linkage to
the chiral auxiliary. The pure diastereomeric salts and derivatives
can be analysed to determine the absolute configuration of the
contained piperidine by conventional spectroscopic methods, with
X-ray spectroscopy on single crystals representing a particularly
suitable method.
[0072] The compounds of the formula (I), and of the formula (I'A),
and their pharmaceutically acceptable salts have an inhibitory
effect on the natural enzyme renin. The latter passes from the
kidneys into the blood and there brings about the cleavage of
angiotensinogen to form the decapeptide angiotensin I which is then
cleaved in the lung, the kidneys and other organs to the
octapeptide angiotensin II. Angiotensin II raises the blood
pressure both directly by arterial constriction, and indirectly by
releasing the hormone aldosterone, which retains sodium ions, from
the adrenals, which is associated with an increase in the
extracellular fluid volume. This increase is attributable to the
effect of angiotensin II itself or of the heptapeptide angiotensin
III formed therefrom as cleavage product. Inhibitors of the
enzymatic activity of renin bring about a reduction in the
formation of angiotensin I and, as a consequence thereof, the
formation of a smaller amount of angiotensin II. The reduced
concentration of this active peptide hormone is the direct cause of
the blood pressure-lowering effect of renin inhibitors.
[0073] The effect of renin inhibitors is detected inter alia
experimentally by means of in vitro tests where the reduction in
the formation of angiotensin I is measured in various systems
(human plasma, purified human renin together with synthetic or
natural renin substrate). The following in vitro test of Nussberger
et al. (1987) J. Cardiovascular Pharmacol., Vol. 9, pp. 39-44, is
used inter alia. This test measures the formation of angiotensin I
in human plasma. The amount of angiotensin I formed is determined
in a subsequent radio-immunoassay. The effect of inhibitors on the
formation of angiotensin I is tested in this system by adding
various concentrations of these substances. The IC.sub.50 is
defined as the concentration of the particular inhibitor which
reduces the formation of angiotensin I by 50%. The compounds of the
present invention show inhibitory effects in the in vitro systems
at minimal concentrations of about 10.sup.-6 to about 10.sup.-10
mol/l.
[0074] The compound having Example number 1 shows an IC.sub.50 of
2.610.sup.-9 mol/l.
[0075] Renin inhibitors bring about a fall in blood pressure in
salt-depleted animals. Human renin differs from renin of other
species. Inhibitors of human renin are tested using primates
(marmosets, Callithrix jacchus) because human renin and primate
renin are substantially homologous in the enzymatically active
region. The following in vivo test is employed inter alia: the test
compounds are tested on normotensive marmosets of both sexes with a
body weight of about 350 g, which are conscious, unrestrained and
in their normal cages. Blood pressure and heart rate are measured
with a catheter in the descending aorta and are recorded
radiometrically. Endogenous release of renin is stimulated by
combining a low-salt diet for 1 week with a single intramuscular
injection of furosemide
(5-(aminosulphonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic
acid) (5 mg/kg). 16 hours after the furosemide injection, the test
substances are administered either directly into the femoral artery
by means of a hypodermic needle or as suspension or solution by
gavage into the stomach, and their effect on blood pressure and
heart rate is evaluated. The compounds of the present invention
have a blood pressure-lowering effect in the described in vivo test
with i.v. doses of about 0.003 to about 0.3 mg/kg and with oral
doses of about 0.3 to about 30 mg/kg.
[0076] The blood pressure-reducing effect of the compounds
described herein can be tested in vivo using the following
protocol:
[0077] The investigations take place in 5 to 6-week old, male
double transgenic rats (dTGR), which overexpress both human
angiotensinogen and human renin and consequently develop
hypertension (Bohlender J. et al., J Am Soc Nephrol 2000; 11:
2056-2061). This double transgenic rat strain was produced by
crossbreeding two transgenic strains, one for human angiotensinogen
with the endogenous promoter and one for human renin with the
endogenous promoter. Neither single transgenic strain was
hypertensive. The double transgenic rats, both males and females,
develop severe hypertension (mean systolic pressure, approximately
200 mm Hg) and die after a median of 55 days if untreated. The fact
that human renin can be studied in the rat is a unique feature of
this model. Age-matched Sprague-Dawley rats serve as
non-hypertensive control animals. The animals are divided into
treatment groups and receive test substance or vehicle (control)
for various treatment durations. The applied doses for oral
administration may range from 0.5 to 100 mg/kg body weight.
Throughout the study, the animals receive standard feed and tap
water ad libitum. The systolic and diastolic blood pressure, and
the heart rate are measured telemetrically by means of transducers
implanted in the abdominal aorta, allowing the animals free and
unrestricted movement.
[0078] The effect of the compounds described herein on kidney
damage (proteinuria) can be tested in vivo using the following
protocol:
[0079] The investigations take place in 4-week old, male double
transgenic rats (dTGR), as described above. The animals are divided
into treatment groups and receive test substance or vehicle
(control) each day for 7 weeks. The applied doses for oral
administration may range from 0.5 to 100 mg/kg body weight.
Throughout the study, the animals receive standard feed and tap
water ad libitum. The animals are placed periodically in metabolism
cages in order to determine the 24-hour urinary excretion of
albumin, diuresis, natriuresis, and urine osmolality. At the end of
the study, the animals are sacrificed and the kidneys and hearts
may also be removed for determining the weight and for
immunohistological investigations (fibrosis, macrophage/T cell
infiltration, etc.).
[0080] The pharmacokinetic properties of the compounds described
herein can be tested in vivo using the following protocol:
[0081] The investigations take place in pre-catheterized (carotid
artery) male rats (300 g.+-.20%) that can move freely throughout
the study. The compound is administered intravenously and orally
(gavage) in separate sets of animals. The applied doses for oral
administration may range from 0.5 to 50 mg/kg body weight; the
doses for intravenous administration may range from 0.5 to 20 mg/kg
body weight. Blood samples are collected through the catheter
before compound administration and over the subsequent 24-hour
period using an automated sampling device (AccuSampler, DiLab
Europe, Lund, Sweden). Plasma levels of the compound are determined
using a validated LC-MS analytical method. The pharmacokinetic
analysis is performed on the plasma concentration-time curves after
averaging all plasma concentrations across time points for each
route of administration. Typical pharmacokinetics parameters to be
calculated include: maximum concentration (C.sub.max), time to
maximum concentration (t.sub.max), area under the curve from 0
hours to the time point of the last quantifiable concentration
(AUC.sub.0-t), area under the curve from time 0 to infinity
(AUC.sub.0-inf), elimination rate constant (K), terminal half-life
(t.sub.1/2), absolute oral bioavailability or fraction absorbed
(F), clearance (CL), and Volume of distribution during the terminal
phase (Vd).
[0082] The compounds of the formula (I), and preferably of the
formula (I'A), and their pharmaceutically acceptable salts can be
used as medicines, e.g. in the form of pharmaceutical products. The
pharmaceutical products can be administered enterally, such as
orally, e.g. in the form of tablets, lacquered tablets,
sugar-coated tablets, hard and soft gelatine capsules, solutions,
emulsions or suspensions, nasally, e.g. in the form of nasal
sprays, rectally, e.g. in the form of suppositories, or
transdermally, e.g. in the form of ointments or patches. However,
administration is also possible parenterally, such as
intramuscularly or intravenously, e.g. in the form of solutions for
injection.
[0083] Tablets, lacquered tablets, sugar-coated tablets and hard
gelatine capsules can be produced by processing the compounds of
the formula (I), or preferably of the formula (I'A), and their
pharmaceutically acceptable salts with pharmaceutically inert
inorganic or organic excipients. Excipients of these types which
can be used for example for tablets, sugar-coated tablets and hard
gelatine capsules are lactose, maize starch or derivatives thereof,
talc, stearic acid or salts thereof etc.
[0084] Excipients suitable for soft gelatine capsules are, for
example, vegetable oils, waxes, fats, semisolid and liquid polyols
etc.
[0085] Excipients suitable for producing solutions and syrups are,
for example, water, polyols, sucrose, invert sugar, glucose
etc.
[0086] Excipients suitable for solutions for injection are, for
example, water, alcohols, polyols, glycerol, vegetable oils, bile
acids, lecithin etc.
[0087] Excipients suitable for suppositories are, for example,
natural or hardened oils, waxes, fats, semiliquid or liquid polyols
etc.
[0088] The pharmaceutical products may in addition comprise
preservatives, solubilizers, viscosity-increasing substances,
stabilizers, wetting agents, emulsifiers, sweeteners, colorants,
aromatizers, salts to alter the osmotic pressure, buffers, coating
agents or antioxidants. They may also comprise other substances of
therapeutic value.
[0089] The present invention further provides the use of the
compounds of the formula (I), or preferably of the formula (I'A),
and their pharmaceutically acceptable salts in the treatment or
prevention of high blood pressure, heart failure, glaucoma,
myocardial infarction, renal failure and restenoses.
[0090] The compounds of the formula (I), and preferably of the
formula (I'A), and their pharmaceutically acceptable salts can also
be administered in combination with one or more agents having
cardiovascular activity, e.g. .alpha.- and .beta.-blockers such as
phentolamine, phenoxy-benzamine, prazosin, terazosin, tolazine,
atenolol, metoprolol, nadolol, propranolol, timolol, carteolol
etc.; vasodilators such as hydralazine, minoxidil, diazoxide,
nitroprusside, flosequinan etc.; calcium antagonists such as
amrinone, bencyclan, diltiazem, fendiline, flunarizine,
nicardipine, nimodipine, perhexiline, verapamil, gallopamil,
nifedipine etc.; ACE inhibitors such as cilazapril, captopril,
enalapril, lisinopril etc.; potassium activators such as pinacidil;
antiserotoninergics such as ketanserine; thromboxane synthetase
inhibitors; neutral endopeptidase inhibitors (NEP inhibitors);
angiotensin II antagonists; and diuretics such as
hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride,
bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone,
metolazone, spironolactone, triamterene, chlorthalidone etc.;
sympatholytics such as methyldopa, clonidine, guanabenz, reserpine;
and other agents suitable for the treatment of high blood pressure,
heart failure or vascular disorders associated with diabetes or
renal disorders such as acute or chronic renal failure in humans
and animals. Such combinations can be used separately or in
products which comprise a plurality of components.
[0091] Further substances which can be used in combination with the
compounds of the formulae (I) or (I'A) are the compounds of classes
(i) to (ix) on page 1 of WO 02/40007 (and the preferences and
examples detailed further therein) and the substances mentioned on
pages and 21 of WO 03/027091.
[0092] The dosage may vary within wide limits and must of course be
adapted to the individual circumstances in each individual case. In
general, a daily dose appropriate for oral administration ought to
be from about 3 mg to about 3 g, preferably about 10 mg to about 1
g, e.g. approximately 300 mg per adult person (70 kg), divided into
preferably 1-3 single doses, which may be for example of equal
size, although the stated upper limit may also be exceeded if this
proves to be indicated, and children usually receive a reduced dose
appropriate for their age and body weight.
EXAMPLES
[0093] The following examples illustrate the present invention. All
temperatures are stated in degrees Celsius and pressures in mbar.
Unless mentioned otherwise, the reactions take place at room
temperature. The abbreviation "Rf=xx (A)" means for example that
the Rf is found in solvent system A to be xx. The ratio of amounts
of solvents to one another is always stated in parts by volume.
Chemical names for final products and intermediates have been
generated on the basis of the chemical structural formulae with the
aid of the AutoNom 2000 (Automatic Nomenclature) program. Unless
mentioned otherwise, the absolute stereochemistry of all four
asymmetric C atoms in the main chain is "S" in each case.
[0094] HPLC gradients on Hypersil BDS C-18 (5 um); column:
4.times.125 mm
90% water*/10% acetonitrile* to 0% water*/100% acetonitrile* in 5
minutes+2.5 minutes(1.5 ml/min) I
95% water*/5% acetonitrile* to 0% water*/100% acetonitrile* in 40
minutes(0.8 ml/min) II
* contains 0.1% trifluoroacetic acid
[0095] The following abbreviations are used: [0096] Rf ratio of
distance migrated by a substance to the distance of the solvent
front from the starting point in thin-layer chromatography [0097]
Rt retention time of a substance in HPLC (in minutes) [0098] M.p.
melting point (temperature)
General Method A: (Azide Reduction)
[0099] A solution of 1 mmol of "azide derivative" in 10-20 ml of
ethanol and ethanolamine (1 equiv) is hydrogenated in the presence
of 200-400 mg of Pd/C 10% (moist) at 0.degree. C. for 1-3 hours.
The reaction mixture is clarified by filtration and the catalyst is
washed with ethanol. The filtrate is evaporated. The title compound
is obtained from the residue by flash chromatography (SiO.sub.2 60
F).
General Method B: (Lactone Amidation I)
[0100] A mixture of 1 mmol of "lactone", "amine" (10-30 equiv.) and
2-hydroxypyridine (1 equiv.) is stirred at 65.degree. C. for 2-24
hours. The reaction mixture is cooled to room temperature,
evaporated, mixed with 1 M aqueous sodium bicarbonate solution and
extracted with tert-butyl methyl ether (2.times.). The combined
organic phases are washed with water and brine, dried with sodium
sulphate and evaporated. The title compound is obtained from the
residue by flash chromatography (SiO.sub.2 60 F).
General Method C: (Lactone Amidation II)
[0101] A solution of 1.2 mmol of "amine" in 1-2 ml of toluene is
added to a solution of 1.1 mmol of trimethylaluminium solution (2 M
in heptane) at -78.degree. C. The reaction mixture is warmed to
room temperature, stirred for a further 30-60 minutes and then
evaporated. A solution of 1 mmol of "lactone" in 2 ml of toluene is
added to the residue, and the mixture is stirred at 80.degree. C.
for 2-4 hours. The reaction mixture is cooled to room temperature
and, after addition of ml of 1N HCl, stirred for 30 minutes. The
reaction mixture is diluted with brine and extracted with toluene
(2.times.)--the combined organic phases are dried with sodium
sulphate and evaporated. The title compound is obtained from the
residue by flash chromatography (SiO.sub.2 60 F).
General Method D: (Desilylation)
[0102] 1.5 mmol of tetrabutylammonium fluoride solution (1M in
tetrahydrofuran) are added to a solution of 1 mmol of "silyl ether"
in 10-15 ml of tetrahydrofuran at 0.degree. C. The reaction mixture
is stirred at room temperature for 2-4 hours, poured into 1 M
aqueous sodium bicarbonate solution and extracted with tert-butyl
methyl ether (2.times.). The combined organic phases are washed
with brine, dried with sodium sulphate and evaporated. The title
compound is obtained from the residue by flash chromatography
(SiO.sub.2 60 F).
General Method E: (Chloro Enamine Coupling)
[0103] 1.2-1.8 mmol of (1-chloro-2-methylpropenyl)dimethylamine
(chloro enamine) are added to a solution of 1 mmol of "acid" in 10
ml of dichloromethane at 0.degree. C. After 2-4 hours, the reaction
mixture is evaporated and the residue is dissolved in 6 ml of
dichloromethane--this solution is added dropwise to the solution of
1.25 mmol of "amine" and 1.1 mmol of triethylamine in 6 ml of
dichloromethane at 0.degree. C. over the course of 2-10 minutes.
The reaction mixture is stirred at room temperature for 1-2 hours,
poured into water and extracted with tert-butyl methyl ether
(2.times.). The combined organic phases are washed with brine,
dried with sodium sulphate and evaporated. The title compound is
obtained from the residue by flash chromatography (SiO.sub.2 60
F).
General Method F: (Lactone Opening/Silylation)
[0104] A solution of 1 mmol of "lactone" in 5 ml of dioxane is
mixed with 5 ml of water and 1.1 mmol of lithium hydroxide
monohydrate. After 4-6 hours, the reaction mixture is mixed with
ice and 1M aqueous citric acid solution and extracted with
tert-butyl methyl ether (3.times.). The combined organic phases are
washed with cold water and cold brine, dried with sodium sulphate
and evaporated at room temperature. The residue is dissolved
without delay in 8 ml of N,N-di-methylformamide and then 5 mmol of
tert-butylchlorodimethylsilane and 8.8 mmol of imidazole are added.
After 10-20 hours, the reaction mixture is evaporated--the residue
is mixed with diethyl ether and water and adjusted to pH 4 with 1M
aqueous citric acid solution and then the organic phase is
separated off. The aqueous phase is extracted again with diethyl
ether (3.times.)--the combined organic phases are washed with
brine, dried with sodium sulphate and evaporated. The residue is
dissolved in 3 ml of tetrahydrofuran, and 3 ml of water and 9 ml of
acetic acid are successively added. After 3-4 hours, the reaction
mixture is poured into ice-water and extracted with diethyl ether
(2.times.)--the combined organic phases are washed with water and
brine, dried with sodium sulphate and evaporated. The title
compound is obtained from the residue by flash chromatography
(SiO.sub.2 60 F).
General Method G: (Grignard Reaction)
[0105] A solution of 1.33 mmol of "aryl bromide" in 2.70 ml of
tetrahydrofuran is cooled to -78.degree. C., and 2 mmol of
N-methylmorpholine are added. Then 1.33 mmol of butyllithium
solution (1.6 M in hexane) are added at -78.degree. C. The reaction
mixture is stirred at -78.degree. C. for 5 minutes, and 2 mmol of
magnesium bromide solution (0.3 M, freshly prepared from 2 mmol of
Mg turnings and 2 mmol of 1,2-dibromoethane in 6.67 ml of
tetrahydrofuran at 60.degree. C.) are added. The reaction mixture
is stirred at -78.degree. C. and, after 5 minutes, a solution of 1
mmol of
2-[2-azido-2-(4-isopropyl-5-oxotetrahydrofuran-2-yl)ethyl]-3-methylbutyra-
ldehyde [173154-02-4] in 1 ml of tetrahydrofuran is added at
-78.degree. C. The reaction mixture is then stirred at -78.degree.
C. for minutes and quenched with 1 M aqueous ammonium chloride
solution. It is extracted with tert-butyl methyl ether (3.times.).
The combined organic phases are washed with brine, dried with
sodium sulphate and evaporated. The title compound is obtained from
the residue by flash chromatography (SiO.sub.2 60 F).
General Method H: (Alcohol Methoxyacetylation)
[0106] 2.6 mmol of pyridine, 2.4 mmol of methoxyacetyl chloride and
0.1 mmol of 4-dimethylamino-pyridine are successively added to a
solution of 1 mmol of "alcohol" in 13.5 ml of toluene at 0.degree.
C. The ice bath is removed and the reaction mixture is stirred at
room temperature for 2 hours. The reaction mixture is poured into
0.5 M HCl and then the organic phase is separated off. The aqueous
phase is extracted again with diethyl ether (3.times.)--the
combined organic phases are washed with brine, dried with sodium
sulphate and evaporated. The title compound is obtained from the
residue by flash chromatography (SiO.sub.2 60 F).
General Method I: (Azide and Methoxyacetoxy Reduction)
[0107] A solution of 1 mmol of "azide methoxyacetoxy derivative" in
25 ml of ethanol and ethanol-amine (1 mmol) is hydrogenated in the
presence of 600 mg of Pd/C 10% (dry) at room temperature for 2-5
hours. The reaction mixture is clarified by filtration and the
catalyst is washed with ethanol. The filtrate is evaporated. The
residue is treated with 1 M sodium bicarbonate solution and
extracted with tert-butyl methyl ether (3.times.)--the combined
organic phases are dried with sodium sulphate and evaporated. The
title compound is obtained from the residue by flash chromatography
(SiO.sub.2 60 F).
General Method J: (Boc Protection of Amine)
[0108] 2 mmol of N,N-diisopropylethylamine and 2 mmol of
di-tert-butyl dicarbonate are successively added to a solution of 1
mmol of "amine" in 22 ml of dichloromethane at 0.degree. C. The
reaction mixture is warmed to room temperature and stirred at room
temperature overnight. The reaction mixture is poured into water
and then the organic phase is separated off. The aqueous phase is
again extracted with dichloromethane (2.times.)--the combined
organic phases are washed with brine, dried with sodium sulphate
and evaporated. The title compound is obtained from the residue by
flash chromatography (SiO.sub.2 60 F).
General Method K: (Boc Deprotection of Amine)
[0109] 50 mmol of trifluoroacetic acid are added to a solution of 1
mmol of "amine" in 20 ml of dichloromethane at 0.degree. C. The
reaction mixture is stirred at 0.degree. C. for 1-3 hours. The
reaction mixture is neutralized with 1M sodium bicarbonate
solution, and the aqueous phase is extracted with tert-butyl methyl
ether (3.times.)--the combined organic phases are washed with
brine, dried with sodium sulphate and evaporated. The title
compound is obtained from the residue by flash chromatography
(SiO.sub.2 60 F).
General Method L: (Phenol Alkylation)
[0110] A solution of 1 mmol of "phenol" in 2 ml of
dimethylformamide is mixed with 1.5 mmol of potassium carbonate and
1.1 mmol of 1-chloro-3-methoxypropane. The reaction mixture is
stirred at 100.degree. C. for 11 hours. The reaction mixture is
filtered and evaporated. The residue is partitioned between ethyl
acetate and water/brine 9:1. The phases are separated, the aqueous
phase is extracted with ethyl acetate (2.times.)--the combined
organic phases are washed with brine, dried with sodium sulphate
and evaporated. The title compound is obtained from the residue by
flash chromatography (SiO.sub.2 60 F).
Example 1
##STR00005##
[0111]
5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benz-
yl]-8-methyl-N-(tetrahydrofuran-2(R)-ylmethyl)nonamide
[0112] The title compound is prepared as a yellowish oil in analogy
to Method A from 0.36 g of
5-azido-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8--
methyl-N-(tetrahydrofuran-2(R)-ylmethyl)nonamide. Rf=0.40
(dichloromethane/methanol/conc. ammonia 25% 200:20:1). Rt=3.78
(gradient I).
[0113] The starting materials are prepared as follows:
a)
5-Azido-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]--
8-methyl-N-(tetrahydrofuran-2(R)-ylmethyl)nonamide
[0114] 0.46 g of
5-azido-4-(tert-butyldimethylsilanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-me-
thoxy-propoxy)benzyl]-8-methyl-N-(tetrahydrofuran-2(R)-ylmethyl)nonamide
is reacted in analogy to Method D. The title compound is obtained
as a colourless oil. Rf=0.29 (EtOAc/heptane 3:1); Rt=4.85 (gradient
I).
b)
5-Azido-4-(tert-butyldimethylsilanyloxy)-2-isopropyl-7-[4-methoxy-3-(3--
methoxy-propoxy)benzyl]-8-methyl-N-(tetrahydrofuran-2(R)-ylmethyl)nonamide
[0115] 0.40 g of
5-Azido-4-(tert-butyldimethylsilanyloxy)-2-isopropyl-7-[4-methoxy-3-(3-me-
thoxy-propoxy)benzyl]-8-methylnonanoic acid and 0.10 ml of
C-(tetrahydrofuran-2(R)-yl)methylamine are reacted in analogy to
Method E. The crude title compound is obtained as a yellow oil.
c)
5-Azido-4-(tert-butyldimethylsilanyloxy)-2-isopropyl-7-[4-methoxy-3-(3--
methoxy-propoxy)benzyl]-8-methylnonanoic acid
[0116] 0.933 g of
5-{1-azido-3-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl}-3-iso-
propyldihydrofuran-2-one [324763-46-4] is reacted in analogy to
Method F. The title compound is obtained as a yellowish oil.
Rf=0.40 (EtOAc/heptane 1:1); Rt=6.54 (gradient I).
[0117] The following compounds are prepared in an analogous manner
to the process described in Example 1:
2
5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-
-methyl-N-(tetrahydropyran-3(S)-ylmethyl)nonamide
##STR00006##
[0119] The starting material is prepared as follows:
a) C-(Tetrahydropyran-3S-yl)methylamine
[0120] A solution of 0.9 mmol of tetrahydropyran-3R-carbaldehyde
[143810-10-0] in 5 ml of ethanol is mixed with a solution of 1.8
mmol of hydroxylamine hydrochloride in 0.5 ml of water and heated
to reflux overnight. The reaction mixture is concentrated and
partitioned between saturated sodium carbonate solution and diethyl
ether. The phases are separated and the aqueous phase is extracted
with diethyl ether (2.times.). The combined organic phases are
dried with sodium sulphate and evaporated. The residue is dissolved
in 5 ml of ethanol and, over the course of 2 hours, small portions
of 12.8 mmol of zinc dust and of 0.8 ml of glacial acetic acid are
added alternately. The internal temperature must not exceed
50.degree. C. during the addition. The reaction mixture is stirred
at room temperature for 12 hours and filtered through Hyflo, and
the filter cake is washed with cold ethanol. The solution is
evaporated and the residue is partitioned between 4M NaOH and
diethyl ether. The phases are separated and the aqueous phase is
extracted with diethyl ether (2.times.). The combined organic
phases are dried with sodium sulphate and evaporated. The title
compound is identified from the residue on the basis of its Rf by
flash chromatography (SiO.sub.2 60 F).
3
5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-
-methyl-N-(7-oxabicyclo[2.2.1]hept-2(R,S)-yl)nonamide
##STR00007##
[0122] The starting material is prepared as follows:
a) 7-Oxabicyclo[2.2.1]hept-2(R,S)-ylamine
[0123] A solution of 0.398 mmol of
7-oxabicyclo[2.2.1]heptane-2(R,S)-carboxylic acid [19800-01-2] and
0.995 mmol of triethylamine in 4 ml of tetrahydrofuran is cooled to
0.degree. C., and 0.796 mmol of ethyl chloroformate is added. The
reaction mixture is stirred at 0.degree. C. for 1 hour and then a
solution of 7.96 mmol of sodium azide in 2 ml of water is added at
0.degree. C. The reaction solution is stirred at 0.degree. C. for
45 minutes. It is diluted with water and ethyl acetate, and the
organic phase is washed with water (2.times.), dried with sodium
sulphate and evaporated. The residue is taken up in 2 ml of toluene
and heated at 115.degree. C. for 2 hours. The reaction mixture is
cooled to room temperature, mixed with 4N HCl and vigorously
stirred at room temperature for 2 hours. The reaction mixture is
evaporated. The crude title compound is identified from the residue
on the basis of its Rf.
[0124] The starting material can alternatively be prepared as
follows:
[0125] A solution of 29.4 mmol of
2(R,S)-nitro-7-oxabicyclo[2.2.1]heptane [89210-62-8], [58564-86-6]
in 60 ml of methanol and 147 mmol of ammonium formate is mixed with
235 mmol of Pd/C 10% and stirred at room temperature for 4 hours.
It is filtered through Hyflo and the filtrate is evaporated. The
residue is mixed with water and diethyl ether, the phases are
separated, and the aqueous phase is extracted with diethyl ether
(3.times.). The combined organic phases are washed with water and
brine, dried with sodium sulphate and evaporated. The title
compound is identified from the residue on the basis of the Rf by
flash chromatography (SiO.sub.2 60 F).
4
5-Amino-4-hydroxy-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-
-methyl-N--((Z)-3-oxabicyclo[3.1.0]hex-1-ylmethyl)nonamide
##STR00008##
[0127] The starting materials are prepared as follows:
a) C--((Z)-3-Oxabicyclo[3.1.0]hex-1-yl)methylamine
[0128] A solution of 2.62 mmol of
1-azidomethyl-((Z)-3-oxabicyclo[3.1.0]hexane) in 150 ml of methanol
is hydrogenated in the presence of 0.03 mmol of Pd/C 10% (moist)
until conversion is complete. The reaction mixture is clarified by
filtration and the catalyst is washed with ethanol. The filtrate is
evaporated. The crude title compound is identified from the residue
on the basis of its Rf.
b) 1-Azidomethyl-((Z)-3-oxabicyclo[3.1.0]hexane)
[0129] A solution of 5 mmol of
(Z)-3-oxabicyclo[3.1.0]hex-1-ylmethyl methanesulphonate and 55 mmol
of sodium azide in 50 ml of dimethyl sulphoxide is stirred at room
temperature for hours. It is then diluted with water and tert-butyl
methyl ether and washed with brine. The aqueous phase is extracted
with tert-butyl methyl ether (2.times.). The combined organic
phases are dried with sodium sulphate and evaporated. The title
compound is identified from the residue on the basis of its Rf.
c) (Z)-3-Oxabicyclo[3.1.0]hex-1-ylmethyl methanesulphonate
[0130] 50 mmol of triethylamine and 20 mmol of methanesulphonyl
chloride are successively added to a solution of 10 mmol of
((Z)-3-oxabicyclo[3.1.0]hex-1-yl)methanol in 100 ml of
dichloro-methane at 0.degree. C. The mixture is stirred at
0.degree. C. for 1 hour, diluted with dichloromethane and washed
with M HCl. The organic phase is dried with sodium sulphate and
evaporated. The crude title compound is identified from the residue
on the basis of its Rf.
d) ((Z)-3-Oxabicyclo[3.1.0]hex-1-yl)methanol
[0131] 0.42 mmol of
tert-butyldimethyl-((Z)-3-oxabicyclo[3.1.0]hex-1-ylmethoxy)silane
is reacted in analogy to Method D. The title compound is identified
on the basis of its Rf.
e)
tert-Butyldimethyl-((Z)-3-oxabicyclo[3.1.0]hex-1-ylmethoxy)silane
[0132] 5.07 mmol of diethyl zinc and 10.02 mmol of
chloroiodomethane are successively added dropwise to a solution of
2.52 mmol of tert-butyl(2,5-dihydrofuran-3-ylmethoxy)dimethylsilane
[144186-63-0] in 12.5 ml of dichloroethane at 0.degree. C. The
reaction mixture is stirred at 0.degree. C. for minutes and then
cautiously quenched with saturated ammonium chloride solution at
0.degree. C.
[0133] The mixture is warmed to room temperature and vigorously
stirred for 10 minutes. It is extracted with tert-butyl methyl
ether (3.times.), and the combined organic phases are washed with
water and brine, dried with sodium sulphate and evaporated. The
title compound is identified from the residue on the basis of its
Rf by flash chromatography (SiO.sub.2 60 F).
* * * * *