U.S. patent application number 12/585584 was filed with the patent office on 2010-02-04 for heterocyclic compounds and their use as aldosterone synthase inhibitors.
Invention is credited to Peter Herold, Robert Mah, Michael Quirmbach, Christoph Schumacher, Vincenzo Tschinke.
Application Number | 20100029694 12/585584 |
Document ID | / |
Family ID | 35033774 |
Filed Date | 2010-02-04 |
United States Patent
Application |
20100029694 |
Kind Code |
A1 |
Herold; Peter ; et
al. |
February 4, 2010 |
Heterocyclic compounds and their use as aldosterone synthase
inhibitors
Abstract
Heterocyclic compounds of the general formula (I) ##STR00001##
in which R, R.sup.1, R.sup.2, W, X, Y, Z and n have the meanings
defined in the description, a process for their preparation and the
use of these compounds as medicaments, in particular as aldosterone
synthase inhibitors.
Inventors: |
Herold; Peter; (Basel,
CH) ; Mah; Robert; (Muttenz, CH) ; Tschinke;
Vincenzo; (Binningen, CH) ; Schumacher;
Christoph; (Bettingen, CH) ; Quirmbach; Michael;
(Basel, CH) |
Correspondence
Address: |
WENDEROTH, LIND & PONACK, L.L.P.
1030 15th Street, N.W.,, Suite 400 East
Washington
DC
20005-1503
US
|
Family ID: |
35033774 |
Appl. No.: |
12/585584 |
Filed: |
September 18, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11597620 |
Nov 27, 2006 |
7612088 |
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PCT/EP2005/052417 |
May 27, 2005 |
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12585584 |
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Current U.S.
Class: |
514/266.2 ;
514/300 |
Current CPC
Class: |
A61P 1/16 20180101; A61P
3/12 20180101; A61P 9/04 20180101; A61P 7/10 20180101; A61P 19/04
20180101; A61P 5/40 20180101; A61P 43/00 20180101; C07D 417/04
20130101; A61P 9/10 20180101; A61P 3/04 20180101; A61P 9/00
20180101; C07D 471/04 20130101; A61P 13/12 20180101; A61P 9/12
20180101 |
Class at
Publication: |
514/266.2 ;
514/300 |
International
Class: |
A61K 31/517 20060101
A61K031/517; A61K 31/437 20060101 A61K031/437; A61P 5/40 20060101
A61P005/40 |
Foreign Application Data
Date |
Code |
Application Number |
May 28, 2004 |
CH |
00916/04 |
Claims
1-14. (canceled)
15. A method for the prevention, for delaying the progression or
for the treatment of pathological states which are caused or partly
caused by hyperaldosteronism in a patient, which comprises
administering a therapeutically effective amount of a compound of
formula (I) to a patient in need thereof, ##STR00007## W is C or,
if Z is a bond and X is C, is also N; X is C or, if Z is a bond, is
also N; Y is C or, if Z is C, is also N; Z is C or a bond; R a) is
hydrogen; or b) is C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkoxy,
halogen or trifluoromethyl; R.sup.1 a) is
C.sub.3-C.sub.8-cycloalkyl-C.sub.0-C.sub.4-alkyl or
heterocyclyl-C.sub.0-C.sub.4-alkyl, where the heterocyclyl radical
is at least partially saturated and the radicals are unsubstituted
or substituted by 1-4 C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-alkyl,
C.sub.0-C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-alkylsulfonyl,
aryl-C.sub.0-C.sub.4-alkoxycarbonyl, aryl, cyano, halogen,
unsaturated heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or
tri-C.sub.1-C.sub.4-alkylsilyl; or b), if W is N, is also
C.sub.1-C.sub.8-alkyl, C.sub.2-C.sub.8-alkenyl or
C.sub.2-C.sub.8-alkynyl; R.sup.2 a) is hydrogen; or b) is
C.sub.1-C.sub.8-alkyl, C.sub.0-C.sub.8-alkylcarbonyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.0-C.sub.4-alkyl or
heterocyclyl-C.sub.0-C.sub.4-alkyl, where the heterocyclyl radical
is at least partially saturated and the radicals are unsubstituted
or substituted by 1-4 C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-alkyl,
CO--C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-alkylsulfonyl,
aryl-CO--C.sub.4-alkoxycarbonyl, aryl, cyano, halogen, unsaturated
heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or
tri-C.sub.1-C.sub.4-alkylsilyl; n is 0-2; and its salt or compound
in which one or more atoms are replaced by their stable,
nonradioactive isotopes, where, if W, X, Y and Z are C, R.sup.1 is
not an C.sub.1-C.sub.8-alkyl substituted piperazinyl radical and
where aryl stands for an aromatic hydrocarbon radical which
comprises 5-14 carbon atoms and where heterocyclyl stands for a
saturated, partially saturated or unsaturated, 4-8-membered,
monocyclic ring system, for a saturated, partially saturated or
unsaturated, 7-12-membered bicyclic ring system and also for a
saturated, partially saturated or unsaturated, 7-12-membered
tricyclic ring system, in each case comprising an N, O or S atom in
at least one ring, it also being possible for an additional N, O or
S atom to be present in one ring.
16. A method for the prevention, for delaying the progression or
for the treatment of pathological states which are caused or partly
caused by excessive cortisol release in a patient, which comprises
administering a therapeutically effective amount of a compound of
formula (I) to a patient in need thereof, ##STR00008## W is C or,
if Z is a bond and X is C, is also N; X is C or, if Z is a bond, is
also N; Y is C or, if Z is C, is also N; Z is C or a bond; R a) is
hydrogen; or b) is C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkoxy,
halogen or trifluoromethyl; R.sup.1 a) is
C.sub.3-C.sub.8-cycloalkyl-CO--C.sub.4-alkyl or
heterocyclyl-CO--C.sub.4-alkyl, where the heterocyclyl radical is
at least partially saturated and the radicals are unsubstituted or
substituted by 1-4 C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-alkyl,
C.sub.0-C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-alkylsulfonyl,
aryl-CO--C.sub.4-alkoxycarbonyl, aryl, cyano, halogen, unsaturated
heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or
tri-C.sub.1-C.sub.4-alkylsilyl; or b), if W is N, is also
C.sub.1-C.sub.8-alkyl, C.sub.2-C.sub.8-alkenyl or
C.sub.2-C.sub.8-alkynyl; R.sup.2 a) is hydrogen; or b) is
C.sub.1-C.sub.8-alkyl, CO--C.sub.8-alkylcarbonyl,
C.sub.3-C.sub.8-cycloalkyl-CO--C.sub.4-alkyl or
heterocyclyl-C.sub.0-C.sub.4-alkyl, where the heterocyclyl radical
is at least partially saturated and the radicals are unsubstituted
or substituted by 1-4 C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-alkyl,
C.sub.0-C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-alkylsulfonyl,
aryl-C.sub.0-C.sub.4-alkoxycarbonyl, aryl, cyano, halogen,
unsaturated heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or
tri-C.sub.1-C.sub.4-alkylsilyl; n is 0-2; and its salt or compound
in which one or more atoms are replaced by their stable,
nonradioactive isotopes, where, if W, X, Y and Z are C, R.sup.1 is
not an C.sub.1-C.sub.8-alkyl substituted piperazinyl radical and
where aryl stands for an aromatic hydrocarbon radical which
comprises 5-14 carbon atoms and where heterocyclyl stands for a
saturated, partially saturated or unsaturated, 4-8-membered,
monocyclic ring system, for a saturated, partially saturated or
unsaturated, 7-12-membered bicyclic ring system and also for a
saturated, partially saturated or unsaturated, 7-12-membered
tricyclic ring system, in each case comprising an N, O or S atom in
at least one ring, it also being possible for an additional N, O or
S atom to be present in one ring.
17. A pharmaceutical combination in the form of a product or of a
kit comprising individual components consisting a) of a compound of
formula (I), and b) at least one pharmaceutical form whose active
ingredient has a blood pressure-lowering, an inotropic, a metabolic
or a lipid-lowering effect, ##STR00009## W is C or, if Z is a bond
and X is C, is also N; X is C or, if Z is a bond, is also N; Y is C
or, if Z is C, is also N; Z is C or a bond; R a) is hydrogen; or b)
is C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkoxy, halogen or
trifluoromethyl; R.sup.1 a) is
C.sub.3-C.sub.8-cycloalkyl-CO--C.sub.4-alkyl or
heterocyclyl-CO--C.sub.4-alkyl, where the heterocyclyl radical is
at least partially saturated and the radicals are unsubstituted or
substituted by 1-4 C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-alkyl,
CO--C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-alkylsulfonyl,
aryl-CO--C.sub.4-alkoxycarbonyl, aryl, cyano, halogen, unsaturated
heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or
tri-C.sub.1-C.sub.4-alkylsilyl; or b), if W is N, is also
C.sub.1-C.sub.8-alkyl, C.sub.2-C.sub.8-alkenyl or
C.sub.2-C.sub.8-alkynyl; R.sup.2 a) is hydrogen; or b) is
C.sub.1-C.sub.8-alkyl, C.sub.0-C.sub.8-alkylcarbonyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.0-C.sub.4-alkyl or
heterocyclyl-C.sub.0-C.sub.4-alkyl, where the heterocyclyl radical
is at least partially saturated and the radicals are unsubstituted
or substituted by 1-4 C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-alkyl,
C.sub.0-C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-alkylsulfonyl,
aryl-C.sub.0-C.sub.4-alkoxycarbonyl, aryl, cyano, halogen,
unsaturated heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or
tri-C.sub.1-C.sub.4-alkylsilyl; n is 0-2; and its salt or compound
in which one or more atoms are replaced by their stable,
nonradioactive isotopes, where, if W, X, Y and Z are C, R.sup.1 is
not an C.sub.1-C.sub.8-alkyl substituted piperazinyl radical and
where aryl stands for an aromatic hydrocarbon radical which
comprises 5-14 carbon atoms and where heterocyclyl stands for a
saturated, partially saturated or unsaturated, 4-8-membered,
monocyclic ring system, for a saturated, partially saturated or
unsaturated, 7-12-membered bicyclic ring system and also for a
saturated, partially saturated or unsaturated, 7-12-membered
tricyclic ring system, in each case comprising an N, O or S atom in
at least one ring, it also being possible for an additional N, O or
S atom to be present in one ring.
18. A method for the prevention, for delaying the progression or
for the treatment of pathological states which are caused or partly
caused by hyperaldosteronism in a patient, which comprises
administering a therapeutically effective amount of a compound of
formula (Ia), (Ib), (Ic) or (Id) to a patient in need thereof,
##STR00010## where the meanings of the substituents R, R.sup.1 and
R.sup.2 are as indicated for compounds of the formula (I) according
to claim 15.
19. A method for the prevention, for delaying the progression or
for the treatment of pathological states which are caused or partly
caused by excessive cortisol release in a patient, which comprises
administering a therapeutically effective amount of a compound of
formula (Ia), (Ib), (Ic) or (Id) to a patient in need thereof,
##STR00011## where the meanings of the substituents R, R.sup.1 and
R.sup.2 are as indicated for compounds of the formula (I) according
to claim 16.
20. A pharmaceutical combination in the form of a product or of a
kit comprising individual components consisting a) of a compound of
formula (Ia), (Ib), (Ic) or (Id), and b) at least one
pharmaceutical form whose active ingredient has a blood
pressure-lowering, an inotropic, a metabolic or a lipid-lowering
effect, ##STR00012## where the meanings of the substituents R,
R.sup.1 and R.sup.2 are as indicated for compounds of the formula
(I) according to claim 17.
Description
[0001] The invention relates to novel heterocycles, to a process
for preparing the compounds of the invention, to pharmaceutical
products containing them, and to their use as active pharmaceutical
ingredients, in particular as aldosterone synthase inhibitors.
[0002] The present invention relates firstly to compounds of the
general formula
##STR00002##
in which W is C or, if Z is a bond and X is C, is also N; X is C
or, if Z is a bond, is also N; Y is C or, if Z is C, is also N; Z
is C or a bond; R a) is hydrogen; or [0003] b) is
C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8alkoxy, halogen or
trifluoromethyl;
[0004] R.sup.1 a) is
C.sub.3-C.sub.8cycloalkyl-C.sub.0-C.sub.4-alkyl or
heterocyclyl-C.sub.0-C.sub.4-alkyl, where the heterocydyl radical
is at least partially saturated and the radicals are unsubstituted
or substituted by 1-4 C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-alkylsulfonyl,
aryl-C.sub.0-C.sub.4-alkoxycarbonyl, aryl, cyano, halogen,
unsaturated heterocyclyl, oxo, trifluoromethoxy, trifluoromethyl or
tri-C.sub.1-C.sub.4-alkylsilyl; or [0005] b), if W is N, is also
C.sub.1-C.sub.8-alkyl, C.sub.2-C.sub.8-alkenyl or
C.sub.2-C.sub.8-alkynyl; R.sup.2 a) is hydrogen; or [0006] b) is
C.sub.1-C.sub.8-alkyl, C.sub.0-C.sub.8-alkylcarbonyl,
C.sub.3-C.sub.8-cycloalkyl-C.sub.0-C.sub.4-alkyl or
heterocyclyl-C.sub.0-C.sub.4-alkyl, where the heterocyclyl radical
is at least partially saturated and the radicals are unsubstituted
or substituted by 14 C.sub.1-C.sub.8-alkoxy,
C.sub.1-C.sub.8-alkoxycarbonyl, C.sub.1-C.sub.8-alkyl,
C.sub.1-C.sub.8-alkylcarbonyl, C.sub.1-C.sub.8-alkylsulfonyl,
aryl-C.sub.0-C.sub.4-alkoxycarbonyl, aryl, cyano, halogen,
unsaturated heterocydyl, oxo, trifluoromethoxy, trifluoromethyl or
tri-C.sub.1-C.sub.4-alkylsilyl; n is 0-2; and the salts thereof,
preferably the pharmaceutically usable salts thereof. where, if W,
X, Y and Z are C, R.sup.1 is not an C.sub.1-C.sub.8-alkyl
substituted piperazinyl radical.
[0007] The term aryl stands for an aromatic hydrocarbon radical
which generally comprises 5-14, preferably 6-10, carbon atoms and
is, for example, phenyl, indenyl, e.g. 2- or 4-indenyl, or
naphthyl, e.g. 1- or 2-naphthyl. Aryl having 6-10 carbon atoms is
preferred, especially phenyl or 1- or 2-naphthyl. Said radicals may
be unsubstituted or substituted one or more times, e.g. once or
twice, it being possible for the substituent to be in any position,
e.g. in the o, m or p position of the phenyl radical or in the 3 or
4 position of the 1- or 2-naphthyl radical, and it also being
possible for a plurality of identical or different substituents to
be present.
[0008] Aryl-C.sub.0-C.sub.4-alkyl is, for example, phenyl, naphthyl
or benzyl.
[0009] The term heterocyclyl stands for a saturated, partially
saturated or unsaturated, 4-8-membered, particularly preferably
5-membered, monocyclic ring system, for a saturated, partially
saturated or unsaturated, 7-12-membered, particularly preferably
9-membered, bicyclic ring system and also for a saturated,
partially saturated or unsaturated, 7-12-membered tricydic ring
system, in each case comprising an N, O or S atom in at least one
ring, it also being possible for an additional N, O or S atom to be
present in one ring. Said radicals may be unsubstituted or
substituted one or more times, e.g. once or twice, it also being
possible for a plurality of identical or different substituents to
be present.
[0010] Unsaturated monocyclic heterocyclyl-C.sub.0-C.sub.4-alkyl
is, for example, pyrrole, thiophene, thiazole or oxazole.
[0011] An example of saturated monocyclic
heterocyclyl-C.sub.0-C.sub.4-alkyl is pyrrolidinyl or
tetrahydrofuranyl.
[0012] Unsaturated bicyclic heterocyclyl-C.sub.0-C.sub.4-alkyl is
for example benzofuranyl, benzothiophenyl, indazolyl, indolyl,
isoquinolinyl or quinolinyl.
[0013] Partially saturated bicydic
heterocyclyl-C.sub.0-C.sub.4-alkyl is for example 4, 5, 6,
7-tetrahydrobenzofuranyl or 4,5,6,7-tetrahydrobenzothiazolyl.
[0014] C.sub.3-C.sub.8-Cycloalkyl-C.sub.1-C.sub.4-alkyl is
preferably 3-, 5- or 6-membered cycloalkyl-C.sub.0-C.sub.4-alkyl
such as cyclopropyl, cyclopentyl or cyclohexyl.
[0015] C.sub.1-C.sub.8-Alkyl 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, hexyl or heptyl group.
[0016] C.sub.2-C.sub.8-Alkenyl is, for example, ethenyl, propenyl,
isopropenyl, butenyl, isobutenyl, secondary butenyl, tertiary
butenyl, or a pentenyl, hexenyl or heptenyl group.
[0017] C.sub.2-C.sub.8-Alkynyl is, for example, ethynyl, propynyl,
butynyl, or a pentynyl, hexynyl or heptynyl group.
[0018] C.sub.1-C.sub.8-Alkoxy is, for example,
C.sub.1-C.sub.5-alkoxy such as methoxy, ethoxy, propyloxy,
isopropyloxy, butyloxy, isobutyloxy, secondary butyloxy, tertiary
butyloxy or pentyloxy, but may also be a hexyloxy or heptyloxy
group.
[0019] C.sub.1-C.sub.8-Alkoxycarbonyl is preferably
C.sub.1-C.sub.5-alkoxycarbonyl such as methoxycarbonyl,
ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl,
butyloxycarbonyl, isobutyloxycarbonyl, secondary butyloxycarbonyl
or tertiary butyloxycarbonyl.
[0020] C.sub.0-C.sub.8-Alkylcarbonyl is, for example, formyl,
acetyl, propionyl, propylcarbonyl, isopropylcarbonyl,
butylcarbonyl, isobutylcarbonyl, secondary butylcarbonyl or
tertiary butylcarbonyl.
[0021] Halogen is, for example, fluorine, chlorine, bromine or
iodine.
[0022] The compound groups mentioned below are not to be regarded
as closed; on the contrary, parts of these compound groups may be
replaced by one another or by the definitions given above, or be
omitted, in a meaningful way, e.g. to replace general by more
specific definitions.
[0023] Preferred compounds of the formula (I) are compounds of the
general formulae
##STR00003##
where the meanings of the substituents R, R.sup.1 and R.sup.2 are
as indicated for compounds of the formula (I).
[0024] R is preferably hydrogen or C.sub.1-C.sub.8-alkyl,
particularly preferably hydrogen or methyl.
[0025] R.sup.1 is preferably
C.sub.3-C.sub.8-cycloalkyl-C.sub.0-C.sub.4-alkyl or heterocydyl,
very particularly preferably optionally monosubstituted cyclohexyl,
pyrrolidinyl, 4,5,6,7-tetrahydroisobenzofuranyl or
4,5,6,7-tetrahydrobenzothiazolyl.
[0026] R.sup.2 is preferably hydrogen, halogen,
C.sub.1-C.sub.8-alkyl or C.sub.0-C.sub.8-alkylcarbonyl.
[0027] n is preferably a number 0 to 1.
[0028] Preferred substituents for
C.sub.3-C.sub.8-cycloalkyl-C.sub.0-C.sub.4-alkyl or heterocydyl are
halogen, cyano, trifluoromethyl, heterocyclyl or
C.sub.0-C.sub.8-alkylcarbonyl. Very particularly preferred
substituents for C.sub.3-C.sub.8-cycloalkyl-C.sub.0-C.sub.4-alkyl
or heterocydyl are fluorine, bromine, chlorine, cyano, thiophenyl,
thiazolyl, oxazolyl or acetyl.
[0029] The compounds of the formula (I) which have at least one
asymmetric carbon atom can exist in the form of optically pure
enantiomers, mixtures of enantiomers or as racemates. Compounds
having a second asymmetric carbon atom can exist in the form of
optically pure diastereomers, mixtures of diastereomers,
diastereomeric racemates, mixtures of diastereomeric racemates or
as meso compounds. The invention includes all these forms. Mixtures
of enantiomers, racemates, mixtures of diastereomers,
diastereomeric racemates or mixtures of diastereomeric racemates
can be fractionated by conventional methods, e.g. by racemate
resolution, column chromatography, thin-layer chromatography, HPLC
and the like.
[0030] The term "pharmaceutically usable salts" includes salts with
inorganic or organic acids, such as hydrochloric acid, hydrobromic
acid, nitric acid, sulphuric acid, phosphoric acid, citric acid,
formic acid, maleic acid, acetic acid, succinic acid, tartaric
acid, methanesulphonic acid, p-toluenesulphonic acid and the like.
Salts of compounds having 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.
[0031] The compounds of the formula (I) can be prepared in a manner
analogous to preparation processes disclosed in the literature.
Details of the specific preparation variants can be found in the
examples.
[0032] The compounds of the formula (I) can also be prepared in
optically pure form. Separation into antipodes is possible by
methods known per se, either preferably at an early stage of 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 derivatization with a chiral auxiliary
component such as, for example, (+) or (-)-camphanyl chloride, and
separation of the diastereomeric products by chromatography and/or
crystallization and subsequent deavage of the linkage to the chiral
auxiliary. The pure diastereomeric salts and derivatives can be
analyzed to determine the absolute configuration of the contained
compound using conventional spectroscopic methods, a particularly
suitable method being single-crystal X-ray spectroscopy.
[0033] Salts are primarily the pharmaceutically usable or nontoxic
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, salts thereof
with suitable bases, such as nontoxic metal salts derived from
metals of group Ia, Ib, IIa and IIb of the Periodic Table of
Elements, e.g. alkali metal, in particular lithium, sodium or
potassium salts, alkaline earth metal salts, for example magnesium
or calcium salts, also zinc salts or ammonium salts, and those
salts formed with organic amines such as optionally
hydroxy-substituted mono-, di- or trialkylamines, in particular
mono-, di- or tri-lower-alkylamines, 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 triethanolamine, 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. 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, also amino
acids such as, for example, the abovementioned .alpha.-amino acids,
and methanesulphonic 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 acids.
Compounds of the formula (I) having acidic and basic groups can
also form inner salts.
[0034] Pharmaceutically unsuitable salts can also be used for
isolation and purification.
[0035] The compounds of the formula (I) also include compounds in
which one or more atom's are replaced by their stable,
nonradioactive isotopes; for example a hydrogen atom by
deuterium.
[0036] Prodrug derivatives of the compounds described above are
derivatives thereof which on use in vivo release the original
compound through a chemical or physiological process. A prodrug may
be converted into the original compound for example when a
physiological pH is reached or by enzymatic conversion. Examples of
possible prodrug derivatives are esters of freely available
carboxylic acids, S- and O-acyl derivatives of thiols, alcohols or
phenols, where the acyl group is as defined above. Preference is
given to pharmaceutically usable 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; pivaloyloxymethyl esters and
similar esters are conventionally used as such.
[0037] Because of the close relationship between a free compound, a
prodrug derivative and a salt compound, a defined compound in this
invention also includes its prodrug derivative and salt form where
this is possible and appropriate.
[0038] Aldosterone is a steroidal hormone which is synthesized in
the zona glomerulosa cells of the adrenal cortex by the enzyme
aldosterone synthase (CYP11B2). Aldosterone production and
secretion is controlled by the adrenocorticotropic hormone (ACTH),
angiotensin II, potassium and sodium ions. The primary biological
function of aldosterone is to regulate the salt balance, since
aldosterone controls the reabsorption of sodium ions from the renal
filtrate and the secretion of potassium ions into the renal
filtrate. The state of excessive aldosterone secretion, also called
hyperaldosteronism, may lead to high blood pressure, hypokalaemia,
alkalosis, muscle weakness, polyuria, polydipsia, oedemas,
vasculitis, increased collagen formation, fibrosis and endothelial
dysfunction.
[0039] The chemical compounds described in this invention inhibit
the cytochrome P450 enzyme aldosterone synthase (CYP11B2) and can
therefore be used to treat states induced by aldosterone. The
described compounds can be employed for the prevention, for
delaying the progression, or for the treatment of states such as
hypokalaemia, hypertension, congestive heart failure, acute and, in
particular, chronic renal failure, cardiovascular restenosis,
atherosclerosis, metabolic syndrome (syndrome X), adiposity
(obesity), vasculitis, primary and secondary hyperaldosteronism,
proteinuria, nephropathy, diabetic complications such as diabetic
nephropathy, myocardial infarction, coronary heart disease,
increased collagen formation, fibrosis, vascular and coronary
tissue changes (remodelling) secondary to hypertension, endothelial
dysfunction and oedemas secondary to cirrhosis, nephrosis and
congestive heart failure.
[0040] Cortisol is a steroidal hormone which is synthesized almost
exclusively in the zona fasciculata cells of the adrenal cortex by
the cytochrome P450 enzyme 11-.beta.-hydroxylase (CYP11B1).
Cortisol production is controlled by ACTH. The primary biological
function of cortisol is to regulate the production and the
availability of carbohydrates for the brain and other metabolically
active tissues. Increased cortisol production and secretion is a
normal physiological response to stress and leads to the essential
mobilization of fats, proteins and carbohydrates to meet an
increased demand for energy by the body. Chronically excessive
cortisol release describes the condition of Cushing's syndrome.
Cushing's syndrome may be produced on the one hand by
hypersynthesis of cortisol, which may be generated by an
adrenocortical tumour, or be produced on the other hand as the
consequence of excessive stimulation of the adrenal cortex by ACTH.
The first form is referred to as primary hypercortisolism, and the
second form as secondary hypercortisolism. An excessive and
persistent cortisol secretion may also accompany a stress response,
which may lead to depression, hyperglycemia and to suppression of
the immune system.
[0041] The chemical compounds described in this invention inhibit
the enzyme 11-.beta.-hydroxylase (CYP11B1) and can therefore, due
to the inhibition of cortisol synthesis, be employed for the
prevention, delaying the progression or treatment of Cushing's
syndrome and of the physical and mental consequences of excessive
and persistent cortisol secretion in states of stress. Therefore,
these compounds may be useful for the treatment and prevention of
conditions such as the ectopic adrenocorticotropic (ACTH) hormone
syndrome, adrenal incidentaloma, primary pigmented nodular
adrenocortical disease (PPNAD) and Carney complex (CNC), anorexia
nervosa, chronic alcohol abuse, cigarette smoking, nicotine and
cocaine withdrawal, post-traumatic stress disorder, cognitive
dysfunction after stroke and cortisol-mediated mineralcorticoid
excess.
[0042] Inhibition of aldosterone synthase (Cyp11B2) and of
11-.beta.-hydroxylase (Cyp11B1) and of aromatase (Cyp19), by the
compounds described above can be determined by the following in
vitro assay:
[0043] The cell line NCI-H295R was originally isolated from an
adrenocortical carcinoma and has been characterized in the
literature through the stimulative secretion of steroid hormones
and the presence of the key enzymes necessary for steroidogenesis.
These include Cyp11A (cholesterol side-chain cleavage), Cyp11B1
(steroid 11.beta.-hydroxylase), Cyp11B2 (aldosterone synthetase),
Cyp17 (steroid 17.alpha.-hydroxylase and/or 17,20 lyase), Cyp19
(aromatase), Cyp21B2 (steroid 21-hydroxylase) and 30-HSD
(hydroxysteroid dehydrogenase). The cells have the physiological
characteristics of zonally undifferentiated human fetal adrenal
cells, with the ability to produce the steroid hormones of each of
the three phenotypically distinct zones found in the adult adrenal
cortex.
[0044] The NCI-295R cells (American Type Culture Collection, ATCC,
Rockville, Md., USA) are cultured in Dulbecco's Modified Eagle'Ham
F-12 medium (bME/F12) that is supplemented with Ultroser SF serum
(Soprachem, Cergy-Saint-Christophe, France) as well as insulin,
transferrin, selenit (I-T-S, Becton Dickinson Biosiences, Franklin
Lakes, N.J., USA) and antibiotics in 75 cm.sup.2 cell culture
flasks at a temperature of 37.degree. C. and a 95% air/5% CO2
humidified atmosphere. The cells are subsequently transferred in a
24-well plate and seeded in presence of DME/F12 medium that is
supplemented with 0.1% bovine serum albumin instead of Ultroser SF
serum. The experiment is initiated by incubating the cells for 72
hours in DME/F12 medium supplemented with 0.1% bovine serum albumin
and test compounds in the presence or absence of cell stimulatory
agents. The test compound is added in a concentration range of 0.2
nanomolar to 20 millimolar. Angiotensin-II (at 10 or 100 nanomolar
concentration), potassium ions (at 16 millimolar), forskolin (at 10
micromolar) or a combination of two agents may serve as
cell-stimulatory agents. The cellular secretion of aldosterone,
cortisol, corticosterone and estradiol/estrone into the cell
culture medium can be quantitatively assessed with commercially
available immuno-assays and specific monoclonal antibodies
according to the manufacturer's instructions.
[0045] The degree of secretion of a selective steroid is used as a
measure of enzyme activity, respectively enzyme inhibition in the
presence of absence of a test compound. The dose-dependent enzyme
inhibitory activity of a compound is reflected in a inhibition
curve that is characterized by an IC50 value. The IC50 values for
active test compounds are generated by simple linear regression
analysis to establish inhibition curves without data weighing. The
inhibition curve is generated by fitting a 4-parameter logistic
function to the raw data of the samples using the least squares
approach. The function is described as follows:
Y=(d-a)/((1+(x/c).sup.-b))+a
with: a=minimum b=slope c=IC50 d=maximum x=inhibitor
concentrations
[0046] The compounds of the present invention show inhibitory
effects in in vitro systems with minimal concentrations of about
10.sup.-3 to about 10.sup.-10 mol/l.
[0047] The aldosterone-reducing effect of the compounds described
herein can be tested in vivo by the following protocol:
[0048] Adult male Sprague Dawley rats, weighing between 125 and 150
grams, are kept, housed singly, under the usual conditions of light
and temperature. At 16.00 h on the first day of the experiment, the
animals receive a subcutaneous injection of the depot ACTH product
in a dose of 1.0 mg/kg of weight (SYNACTEN-Depot, Novartis, Basel,
CH). Pilot studies showed that this ACTH dose increased plasma
aldosterone and corticosterone significantly by 15-fold and 25-fold
respectively over a period of at least 18 hours. At 8.00 h in the
morning of the second day, the animals, divided into test groups of
5 animals, receive administration either of water orally or of a
compound in a variable dose range of 0.01-10 mg/kg orally by
gavage. Two hours later, blood is taken in EDTA-treated Eppendorf
vessels. Plasma samples are obtained by centrifugation of the blood
and can be stored at -20.degree. C. An alternative method to
stimulate the aldosterone secretion consists in subjecting adult
male catherized Wistar rats of 250 to 350 grams weight for 48 hours
to a low salt diet and 16 hours prior the start of the experiment
with an subcutaneous or intraperitoneal application of furosemide
at 10 mg/kg. The furosemide application may be repeated 2 hours
prior to the start of the experiment Pilot studies indicated that
this treatment results in a 5 to 20 fold increase in plasma
aldosterone levels over a period of 12 to 24 hours. The catheters
are chronically implanted in the carotid of the animals and allow
thus the periodical sampling of up to 0.2 ml of blood using an
AccuSampler (DiLab Europe, Lund, Sweden). The experiment starts
with the oral administration of test compound in a dose range of
0.01 to 10 mg/kg. The blood sampling with the AccuSampler occurs 1
hour before the administration of test compound and 2, 4, 6, 8, 12,
16 and 24 hours thereafter. The blood samples are anticoagulated
with heparin and centrifuged.
[0049] The plasma samples derived form both protocols are tested
for the steroid content in previously described radioimmunoassays.
The reduction in the steroid levels, such as, for example,
aldosterone, serves as a measure of the in vivo bioavailability and
enzyme inhibiting activity of the compounds described herein.
[0050] The reduction of cardiac damage upon inhibition of the
aldosterone synthase with the herein described compounds may be
evaluated with the following protocol. The protocol corresponds
largely to the protocol described in the publication by Rocha et
al. (Endocrinology, Vol. 141, pp 3871-3878, 2000). Adult male
Wistar rats are housed in individual cages and given 0.9% saline as
drinking fluid ad libitum throughout the experiment. Three days
later, rats are placed on one of the three dosing protocols. Group
I (control group with 8 animals) receives for 14 days the nitric
oxide synthase inhibiting agent L-NAME (N-nitro-L-arginine
methylester, SIGMA, St. Louis, Mo., USA). On day 11 of L-NAME
treatment, an osmotic minipump containing only saline is implanted
in each animal subcutaneously. Group II (L-NAME/Ang II with 8
animals) receives L_NAME for 14 days, and on day 11 of L-NAME
treatment, an osmotic minipump containing Ang II is implanted in
each animal subcutaneaously. Group III (L-NAME/Ang II/test compound
with 8 animals) is treated similarly to group 11 but receives test
compound in a daily dose range of 0.2 to 10 mg/kg rat weight. The
test compound is dissolved in distilled water and given by oral
gavage; whereas groups I and II receive the vehicle without test
compound. The experiment is concluded on day 14 of L-NAME treatment
L-NAME is administered in 0.9% saline containing drinking water at
a concentration of 60 mg/100 ml which results in a daily intake of
approximately 60 mg/kg. Angiotensin II is administered via Alzet
osmotic mini pumps (model 2001, Alza Corp, Palo Alto, Calif., USA).
The mini-pimp is implanted subcutaneously at the nape of the neck.
Angiotensin II (human, 99% peptide purity) is purchased from Sigma
Chemical Corp., St Louis, Mo., USA and administered at a dose of
225 ug/kg/day in saline. The concentration of angiotensin II used
to fill the pumps is calculated based upon: a) the mean pump rate
provided by the manufacturer; b) the body weight of the animals on
the day before implantation of the pumps and c) the planned dose.
The rats are sacrificed on day 14. Their hearts are removed and
sliced through the ventricle/atrium in a "bread-loaf" manner,
yielding three samples from the following gross cardiac regions:
superior, middle and inferior. The samples are fixed in 10%
buffered formalin. Paraffin sections are cut and stained with
hematoxyliin/eosin. A single investigator who is blinded to the
experimental groups views slides. One slide from each of the three
gross cardiac sample regions is analyzed per rat. Cardiac sites
(left and right ventricles and the septum) are evaluated
separately. The entire section is assessed histologically for the
presence of myocardial damage (regardless of the severity) as
evidenced by the presence of myocyte necrosis, inflammatory cells,
hemorrhages and general tissue disruption. Evaluation of the
histological data is made by comparing groups II and III, i.e.
Angiotensin II with or without test compound. The evaluation of the
samples may occur semi-quantitatively and can be illustrated with a
score table.
[0051] The lowering of blood pressure and the reduction of cardiac
damage and nephropathy upon inhibition of the aldosterone synthase
with the herein described compounds may be evaluated with following
protocol. The experiments occur in 4 week old male double
transgenic rats (dTGR) that overexpress human angiotensinogen as
well as human renin and therefore develop hypertension. Age-paired
Sprague-Dawley (SD) rats serve as non-hypertensive control animals.
The animals are separated in test groups that receive either test
compound or vehicle (control group) for 34 weeks. The animals are
fed standard chow and get drinking water ad libitum during the
whole experiment. The systolic and diastolic blood pressure as well
as the heart rate are monitored with implanted telemetric
transducers whereby the animals are free and unrestricted to move.
The rats are transferred once a week for 24 hours into a metabolic
cage in order to measure the 24 hour urinary albumin excretion. The
dimensions of the heart (left ventricular mass, end-diastolic
diameter and wall thickness, thickness of the septum, shortening
fraction) and the diastolic filling are determined by
echocardiography at the beginning and the end of the treatment
under isofluran anesthesia (M-mode monitoring in the short axis and
tissue Doppler representation using a commercial echocardiogram
instrument that is equipped with a 15 MHz probe). The animals are
sacrificed at the end of the study and the kidneys and heart
removed for weighing and immuno-histochemical assessment (fibrosis,
macrophage/T-cell infiltration, etc.).
[0052] In order to achieve the desired effects in a patient to be
treated, the compounds of the present invention can be administered
orally or enterally, such as, for example, intravenously,
intraperitoneally, intramuscularly, rectally, subcutaneously or
else by direct injection of the active substance locally in tissues
or tumours. The term patient encompasses warm-blooded species and
mammals such as, for example, human, primate, bovine, dog, cat,
horse, sheep, mouse, rat and pig. The compounds can be administered
as pharmaceutical product or be incorporated into an administration
device which ensures permanent release of the compound. The amount
of substance to be administered can vary over a wide range and
represent every effective dose. Depending on the patient to be
treated or the condition to be treated and mode of administration,
the dose of the effective substance each day can be between about
0.005 and 50 milligrams per kilogram of body weight, but is
preferably between about 0.05 and 5 milligrams per kilogram of body
weight each day.
[0053] For oral administration, the compounds can be formulated in
solid or liquid pharmaceutical forms such as, for example, as
capsules, pills, tablets, coated tablets, granules, powders,
solutions, suspensions or emulsions. The dose of a solid
pharmaceutical form can be one usual hard gelatin capsule which may
be filled with active ingredients and excipients such as lubricants
and fillers, such as, for example, lactose, sucrose and maize
starch. Another form of administration may be represented by
tableting of the active substance of the present invention. The
tableting can take place with conventional tableting excipients
such as, for example, lactose, sucrose, maize starch, combined with
binder from gum acacia, maize starch or gelatin, disintegrants such
as potato starch or crosslinked polyvinylpyrrolidone (PVPP) and
lubricants such as stearic acid or magnesium stearate.
[0054] Examples of excipients suitable for soft gelatin capsules
are vegetable oils, waxes, fats, semisolid and liquid polyols
etc.
[0055] Examples of excipients suitable for producing solutions and
syrups are water, polyols, sucrose, invert sugar, glucose etc.
[0056] For rectal administration, the compounds can be formulated
in solid or liquid pharmaceutical forms such as, for example,
suppositories. Examples of excipients suitable for suppositories
are natural or hardened oils, waxes, fats, semiliquid or liquid
polyols etc.
[0057] For parenteral administration, the compounds can be
formulated as injectable dosage of the active ingredient in a
liquid or suspension. The preparations usually comprise a
physiologically tolerated sterile solvent which may comprise a
water-in-oil emulsion, with or without surfactant, and other
pharmaceutically acceptable excipients. Oils which can be used for
such preparations are paraffins and triglycerides of vegetable,
animal or synthetic origin, such as, for example, peanut oil, soya
oil and mineral oil. Injectable solutions generally comprise liquid
carriers such as, preferably, water, saline, dextrose or related
sugar solutions, ethanol and glycols such as propylene glycol or
polyethylene glycol.
[0058] The substances may be administered as transdermal patch
system, as depot injection or implant if the formulation makes
sustained delivery of the active ingredient possible. The active
substance can be compressed as granules or to narrow cylinders and
be administered subcutaneously or intramuscularly as depot
injection or implant. The pharmaceutical products may in addition
also comprise preservatives, solubilizers, viscosity-increasing
substances, stabilizers, wetting agents, emulsifiers, sweeteners,
colorants, aromatizing agents, salts to change the osmotic
pressure, buffers, coating agents or antioxidants. They may also
comprise other therapeutically valuable substances too.
[0059] The compounds of the invention described herein permit the
following methods of use: [0060] as therapeutic combination in the
form of a product or of a kit which is composed of individual
components consisting of a compound described herein, in free form
or as pharmaceutically usable salt, and at least one pharmaceutical
form whose active ingredient has a blood pressure-lowering, an
inotropic, an antidiabetic, an obesity educing or a lipid-lowering
effect, which can be used either simultaneously or sequentially.
The product and the kit may comprise instructions for use. [0061]
as method for combined use, such as, for example, in simultaneous
or sequential succession, of a therapeutically effective amount of
a compound described herein, in free or in pharmaceutically usable
salt form, and of a second active ingredient with blood
pressure-lowering, inotropic, antidiabetic, obesity-reducing or
lipid-lowering effect.
[0062] The compounds described herein and their pharmaceutically
usable salts can be used in combination with
(i) one or more blood pressure-lowering active ingredients, as such
for example: [0063] renin inhibitors such as aliskiren; [0064]
angiotensin II receptor blockers such as candesartan, irbesartan,
olmesartan, losartan, valsartan, telmisartan etc.; [0065] ACE
inhibitors such as quinapril, ramipril, trandolapril, lisinopril,
captopril, enalapril etc.; [0066] calcium antagonists such as
nifedipine, nicardipine, verapamil, isradipine, nimodipine,
amlodipine, felodipine, nisoldipine, diltiazem, fendiline,
flunarizine, perhexyline, gallopamil etc.; [0067] diuretics such as
hydrochlorthiazide, chlorothiazide, acetazolamide, amiloride,
bumetanide, benzthiazide, etacrynic acid, furosemide, indacrinone,
metolazone, triamterene, chlortalidone, etc.; [0068] aldosterone
receptor blockers such as spironolactone, eplerenone; [0069]
endothelin receptor blockers such as bosentan; [0070]
phosphodiesterase inhibitors such as aminone, sildenafil; [0071]
direct vasodilators such as dihydralazine, minoxidil, pinacidil,
diazoxide, nitroprusside, flosequinan etc., [0072] .alpha.- and
.beta.-receptor blockers such as phentolamine, phenoxybenzamine,
prazosin, doxazosin, terazosin, carvedilol, atenolol, metoprolol,
nadolol, propranolol, timolol, carteolol etc.; [0073] neutral
endopeptidase (NEP) inhibitors; [0074] sympatholytics such as
methyldopa, donidine, guanabenz, reserpine (ii) one or more agents
having inotropic activity, as such for example: [0075] cardiac
glycosides such as digoxin; [0076] .beta.-receptor stimulators such
as dobutamine [0077] thyroid hormone such as thyroxine (iii) one or
more agents having antidiabetic activity, as such for example:
[0078] insulins such as insulin aspart, insulin human, insulin
lispro, insulin glargine and further fast-, medium- and long-acting
insulin derivatives and combinations [0079] insulin sensitizers
such as rosiglitazone, pioglitazone; [0080] sulphoicnylureas such
as glimepiride, chlorpropamide, glipizide, glyburide etc.; [0081]
biguanides such as metformin; [0082] glucosidase inhibitors such as
acarbose, miglitol; [0083] meglitinides such as repaglinide,
nateglinide; (iv) one or more obesity-reducing ingredients, as such
for example: [0084] lipase inhibitors such as orlistate; [0085]
appetite suppressants such as sibutramine, phentermine; (v) one or
more lipid-lowering active ingredients, such as, for example,
[0086] HMG-CoA reductase inhibitors such as lovastatin,
fluvastatin, pravastatin, atorvastatin, simvastatin, rosuvastatin
etc.; [0087] fibrate derivatives such as fenofibrate, gemfibrozil
etc.; [0088] bile acid-binding active ingredients such as
colestipol, colestyramine, colesevelam [0089] cholesterol
absorption inhibitors such as ezetimibe [0090] nicotinic acid such
as niacin and other agents which are suitable for the treatment of
high blood pressure, heart failure or vascular disorders associated
with diabetes and 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] The presently described compounds and the pharmaceutically
usable salts thereof may find use as combinations with [0092] (i) a
diagnostic test system, that allows the quantitative determination
of the plasma renin concentration (PRC) [0093] (ii) a diagnostic
test system, that allows the quantitative determination of the
plasma aldosterone concentration (PAC) [0094] (iii) a diagnostic
test system, that allows the quantitative determination of the
plasma renin activity (PRA) [0095] (iv) a diagnostic test system,
that allows the quantitative determination of the plasma
aldosterone to renin concentration ratio (ARC) [0096] (v) a
diagnostic test system, that allows the quantitative determination
of the plasma aldosterone to renin activity ratio (ARR) [0097] (vi)
a diagnostic test system, that allows the quantitative
determination of the plasma cortisol concentration (PCC)
[0098] Such combination of a diagnostic test system and a therapy
may be used separately or in preparation with individual
components.
[0099] The following examples illustrate the present invention. All
temperatures are stated in degrees Celsius, 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 have the value xx. The ratio
amounts of solvents to one another is always stated in proportions
by volume. Chemical names of final products and intermediates were
generated with the aid of the AutoNom 2000 (Automatic Nomenclature)
program.
[0100] HPLC gradients on Hypersil BDS C-18 (5 .mu.m); column:
4.times.125 mm:
95% water*/5% acetonitrile* to 0% water*/100% acetonitrile* in 10
minutes+2 minutes (1 ml/min) [0101] contains 0.1% trifluoroacetic
acid
[0102] The following abbreviations are used: [0103] Rf ratio of the
distance migrated by a substance to the distance of the solvent
from the starting point in thin-layer chromatography [0104] Rt
retention time of a substance in HPLC (in minutes) [0105] m.p.
melting point (temperature)
EXAMPLE 1
##STR00004##
[0106]
4-(5,6,7,8-Tetrahydroimidazo[1,5-a]pyridin-5-yl)cyclohexanecarbonit-
rile
[0107] A solution of 0.56 g of
N-tert-butyl-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)-cyclohexane-
carboxamide and 1 ml of thionyl chloride in 30 ml of chloroform is
stirred under reflux for 6 hours. The reaction mixture is cooled to
room temperature and evaporated. The residue is taken up in
dichloromethane and mixed with saturated aqueous sodium bicarbonate
solution. The organic phase is separated off, and the aqueous phase
is extracted with dichloromethane (2.times.). The combined organic
phases are dried with sodium sulphate and evaporated. The title
compound is obtained as a yellow oil from the residue by flash
chromatography (SiO.sub.2 60F). Rf=0.45
(dichloromethane:methanol=95:5); Rt=4.66.
[0108] The starting materials are prepared as follows:
a)
N-tert-Butyl-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)cyclohexan-
ecarboxamide
[0109] A solution of 0.56 g of
4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)cyclohexanecarboxylic
acid and 7.5 ml of thionyl chloride is stirred under reflux for 30
minutes. The reaction mixture is cooled to room temperature and
evaporated. The residue is dissolved in dichloromethane, cooled to
0.degree. C., and then 2 ml of tert-butylamine are added, and the
reaction mixture is subsequently stirred for a further 15 hours.
The reaction mixture is diluted with dichloromethane and mixed with
saturated aqueous sodium bicarbonate solution. The organic phase is
separated off, and the aqueous phase is extracted with
dichloromethane (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 60F).
b)
4-(5,6,7,8-Tetrahydroimidazo[1,5-a]pyridin-5-yl)cyclohexanecarboxylic
Acid
[0110] A solution of 1.5 g of
4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzoic acid
[93178-73-5] in 5 ml of acetic acid is hydrogenated (50 bar) in the
presence of 0.05 g of Nishimura catalyst at room temperature. The
reaction mixture is clarified by filtration, and the filtrate is
evaporated. The crude title compound is obtained from the
residue.
EXAMPLE 2
##STR00005##
[0111]
1-[3-(5,6,7,8-Tetrahydroimidazo[1,5-a]pyridin-8-yl)pyrrolidin-1-yl]-
ethanone
[0112] 0.15 ml of acetyl chloride is added dropwise to a solution
of 0.38 g
8-pyrrolidin-3-yl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, 0.16 ml
of pyridine and 2 ml of chloroform at 0.degree. C., and the mixture
is then warmed to room temperature. After 18 hours, water is added
to the reaction mixture, and it is extracted with ethyl acetate
(3.times.)--the combined organic phases are dried with sodium
sulphate and evaporated. The title compound is identified from the
residue by flash chromatography (SiO.sub.2 60F) on the basis of the
Rf.
[0113] The starting materials are prepared as follows:
a) 8-Pyrrolidin-3-yl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine
[0114] 0.14 ml of conc. H.sub.2SO.sub.4 are added dropwise to a
suspension of 0.19 g of lithiumaluminium hydride and 10 ml of
tetrahydrofran at 0.degree. C. After stirring for 30 minutes a
solution of 0.41 g of
3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)pyrrolidin-2-one
and 10 ml of tetrahydrofuran is added dropwise, and the mixture is
then warmed to room temperature. After 1 hour, the reaction mixture
is cooled to 0.degree. C. and quenched successively with 1 ml of
tetrahydrofuran/water (1:1) and 3 ml of 5% NaOH. The precipitate is
filtered off and washed with tetrahydrofuran (2.times.)--the
combined organic phases are dried with sodium sulphate and
evaporated. The crude title compound is obtained from the
residue.
b)
3-(5,6,7,8-Tetrahydroimidazo[1,5-a]pyridin-8-yl)pyrrolidin-2-one
[0115] A solution of 0.41 g of
3-(6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-ylidene)pyrrolidin-2-one
and 10 ml of methanol is hydrogenated in the presence of 0.1 g of
Pd(OH).sub.2/C 20% at room temperature. The reaction mixture is
clarified by filtration, and the filtrate is evaporated. The title
compound is identified from the residue by flash chromatography
(SiO.sub.2 60F) on the basis of the Rf.
c)
3-(6,7-Dihydro-5H-imidazo[1,5-a]pyridin-8-ylidene)pyrrolidin-2-one
[0116] 0.23 ml of phosphorus oxychloride are added dropwise to a
solution of 0.50 g of
3-(8-hydroxy-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)pyrrolidin-2-on-
e and 7.5 ml of pyridine at 0.degree. C., and the reaction mixture
is then warmed to room temperature. After 1 hour, 1.02 ml of
1,8-diazabicyclo[5.4.0]undec-7-ene are added. After 3 hours water
is added to the reaction mixture, and it is extracted with
dichloromethane (3.times.)--the combined organic phases are washed
successively with 1N NaOH and water, dried with sodium sulphate and
evaporated. The title compound is identified from the residue by
flash chromatography (SiO.sub.2 60F) on the basis of the Rf.
d)
3-(8-Hydroxy-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)pyrrolidin-2--
one
[0117] 1.25 ml of n-butyllithium (1.6M in hexane) are added
dropwise to a solution to 0.29 ml of diisopropylamine and 2 ml of
tetrahydrofuran at -78.degree. C. After 30 minutes, a solution,
cooled to -78.degree. C., of 0.31 g of
1-trimethylsilanylpyrrolidin-2-one and 5 ml of tetrahydrofuran is
added dropwise. The mixture is stirred for a further 30 minutes and
then a solution of 0.27 g of
6,7-dihydro-5H-imidazo[1,5a]pyridin-8-one [426219-51-4] and 5 ml
tetrahydrofuran is added dropwise. The reaction mixture is stirred
at -78.degree. C. for 1 hour and then at 0.degree. C. for 2 hours.
The mixture is quenched with saturated aqueous ammonium chloride
solution/water (1:1), the tetrahydrofuran is evaporated, and the
residue is extracted with dichloromethane (3.times.). The combined
organic phases are dried with sodium sulphate and evaporated. The
title compound is identified from the residue by flash
chromatography (SiO.sub.2 60F) on the basis of the Rf.
EXAMPLE 3
##STR00006##
[0118]
5-(4,5,6,7-Tetrahydrobenzothiazol-5-yl)-5,6,7,8-tetrahydroquinazoli-
ne
[0119] A solution of 0.27 g of
5-(6,7-dihydro-4H-benzothiazol-5-ylidene)-5,6,7,8-tetrahydro-quinazoline,
15 ml of ethanol and 4 ml conc. HCl is hydrogenated in the presence
of 0.5 g of Pd/C 10% at room temperature for 4 hours. The reaction
mixture is clarified by filtration, and the filtrate is evaporated.
The title compound is identified from the residue by flash
chromatography (SiO.sub.2 60F) on the basis of the Rf.
[0120] The starting materials are prepared as follows:
a)
5-(6,7-Dihydro-4H-benzothiazol-5-ylidene)-5,6,7,8-tetrahydroquinazoline
[0121] 1.06 g of benzenesulphonyl chloride is added to a solution
of 0.66 g of
5-(5-hydroxy-5,6,7,8-tetrahydroquinazolin-5-yl)-4,5,6,7-tetrahydrobe-
nzothiazole-5-carboxylic acid and 20 ml of pyridine at 0.degree. C.
After 20 hours at 0.degree. C., the reaction mixture is poured into
ice-water--the resulting solid is filtered off, dried, dissolved in
1 ml of 2,4,6-trimethylpyridine and then heated to 140.degree. C.
After 90 minutes, the reaction mixture is cooled to room
temperature, mixed with hot water, stirred for 10 minutes and then
the water is decanted off. This "water-treatment process" is
repeated twice more. The solid is then dried and purified by flash
chromatography (SiO.sub.2 60F). The title compound is identified on
the basis of the Rf.
b)
5-(5-Hydroxy-5,6,7,8-tetrahydroquinazolin-5-yl)-4,5,6,7-tetrahydrobenzo-
thiazole-5-carboxylic Acid
[0122] 2.5 ml of n-butyllithium (1.6M in hexane) are added to a
solution of 0.58 ml of diisopropylamine and 4 ml of tetrahydrofuran
at 40.degree. C. The mixture is warmed to -15.degree. C. and then
cooled again to .about.40.degree. C. After this, a solution, cooled
to -40.degree. C., of 0.36 g of
4,5,6,7-tetrahydrobenzothiazole-5-carboxylic acid and 5 ml of
tetrahydrofuran is added dropwise. The reaction mixture is warmed
to 50.degree. C., stirred for 2 hours, cooled to -40.degree. C. and
then a solution of 0.30 g of 7,8-dihydro-6H-quinazolin-5-one
[21599-28-0] and 5 ml of tetrahydrofuran is added dropwise. The
reaction mixture is stirred further at -40.degree. C. for 2 hours
and at room temperature for 16 hours, poured onto ice and washed
with diethyl ether (3.times.). The combined organic phases are
extracted with water. The combined aqueous phases are acidified
with 1N HCl and extracted with dichloromethane (2.times.)--the
combined organic phases are washed with brine, dried with sodium
sulphate and evaporated. The title compound is identified from the
residue by flash chromatography (SiO.sub.2 60F) on the basis of the
Rf.
c) 4,5,6,7-Tetrahydrobenzothiazole-5-carboxylic Acid
[0123] 6 ml of 2N NaOH are added to a solution of 0.42 g of ethyl
4,5,6,7-tetrahydrobenzothiazole-5-carboxylate [95203-30-8] and 24
ml of MeOH at room temperature. After 6 hours, the reaction mixture
is evaporated. The residue is acidified with 4N HCl, diluted with
water and extracted with ethyl acetate (2.times.)--the combined
organic phases are dried with sodium sulphate and evaporated. The
crude title compound is obtained from the residue.
[0124] The following compound is prepared in an analogous manner to
the processes described in
EXAMPLE 3
EXAMPLE
5-(4,5,6,7-Tetrahydrobenzothiazol-6-yl)-5,6,7,8-tetrahydroquinazoline
[0125] starting from ethyl
4,5,6,7-tetrahydrobenzothiazole-6-carboxylate [77528-74-6]
* * * * *