Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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1
Novel Diazabicyclononene Derivatives
The invention relates to novel compounds of the general formula I. The
invention
also concerns related aspects including processes for the preparation of the
compounds, pharmaceutical compositions containing one or more compounds of
formula I and especially their use as renin inhibitors in cardiovascular
events and
renal insufficiency. Furthermore, these compounds can be regarded as
inhibitors
l0 of other aspartyl proteases and might therefore be useful as inhibitors of
plasmepsins to treat malaria and as inhibitors of Candida albicans secreted
aspartyl proteases to treat fungal infections.
In the renin-angiotensin system (RAS) the biologically active angiotensin II
(Ang
II) is generated by a two-step mechanism. The highly specific enzyme renin
cleaves angiotensinogen to angiotensin I (Ang I), which is then further
processed
to Ang II by the less specific angiotensin-converting enzyme (ACE). Ang II is
known to work on at least two receptor subtypes called AT1 and AT2. Whereas
AT1 seems to transmit most of the known functions of Ang II, the role of AT2
is
still unknown.
Modulation of the RAS represents a major advance in the treatment of
cardiovascular diseases. ACE inhibitors and AT1 blockers have been accepted to
treat hypertension (Waeber B. 'et al., "The renin-angiotensin system: role in
experimental and human hypertension", in Berkenhager W. H., Reid J. L. (eds):
Hypes°tension, Amsterdam, Elsevier Science Publishing Co, 1996,
4~9-519;
Weber M. A., Am. J. Hypef~tens., 1992, 5, 2475). In addition, ACE inhibitors
are
used for renal protection (Rosenberg M. E. et al., Kidney
Inter°national, 1994, 45,
403; Breyer J. A. et al., Kidney Intey~national, 1994, 45, 5156), in the
prevention
of congestive heart failure (Vaughan D. E. et al., Cap°diovasc. Res.,
1994, 28, 159;
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2
Fouad-Tarazi F. et al., Am. J. Med., 1988, 84 (Suppl. 3A), 83) and myocardial
infarction (Pfeffer M. A. et al., N. Engl. J. Med.,1992, 327, 669).
The rationale to develop renin inhibitors is the specificity of renin
(Kleinert H. D.,
Ca~diovasc. Drugs, 1995, 9, 645). The only substrate known for renin is
angiotensinogen, which can only be processed (under physiological conditions)
by
renin. In contrast, ACE can also cleave bradykinin besides Ang I and can be by-
passed by chymase, a serine.protease (Husain A., J. Hypertens., 1993, 11,
1155).
In patients inhibition of ACE thus leads to bradykinin accumulation causing
l0 cough (5-20%) and potentially life-threatening angioneurotic edema (0.1-
0.2%)
(Israili Z. H. et al., Ahhals of l~cternal Medicine, 1992, 117, 234). Chyrnase
is not
inhibited by ACE inhibitors. Therefore, the formation of Ang II is still
possible in
patients treated with ACE inhibitors. Blockade of the ATl receptor (e.g. by
losartan) on the other hand overexposes other AT-receptor subtypes to Ang II,
whose concentration is dramatically increased by the blockade of ATl
receptors.
This may raise serious questions regarding the safety and efficacy profile of
ATl
receptor antagonists. In summary, renin inhibitors are not only expected to be
different from ACE inhibitors and ATl blockers with regard to safety, but more
importantly also with regard to their efficacy to block the RAS.
Only limited clinical experience (Azizi M. et al., J. Hypes°tens.,
1994, 12, 419;
Neutel J. M. et al., Am. Heart, 1991, 122, 1094) has been created with renin
inhibitors because of their insufficient oral activity due to their
peptidomimetic
character (Kleinert H. D., Cardiovasc. Drugs, 1995, 9, 645). The clinical
development of several compounds has been stopped because of this problem
together with the high cost of goods. Only one compound containing four chiral
centers has entered clinical trials (Rahuel J. et al., Chem. Biol., 2000, 7,
493;
Mealy N. E., Drugs of the Future, 2001, 26, 1139). Thus, metabolically stable,
orally bioavailable and sufficiently soluble renin inhibitors that can be
prepaxed on
a large scale are missing and sought. Recently, the first non-peptide renin
inhibitors were described which show high in vitro activity (Oefner C. et al.,
!J
Chem. Biol., 1999, 6, 127; Patent Application W097109311; Marki H. P. et al.,
Il
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Farrnaco, 2001, 56, 21). However, the development status of these compounds is
not known.
The present invention relates to the identification of renin inhibitors of a
non-
peptidic nature and of low molecular weight. Orally active renin inhibitors of
long duration of action which are active in indications beyond blood pressure
regulation where the tissular renin-chymase system may be activated leading to
pathophysiologically altered local functions such as renal, cardiac and
vascular
remodeling, atherosclerosis, and possibly restenosis are described.
to
The present invention describes non-peptidic renin inhibitors.
In particular, the present invention relates to novel compounds of the general
formula I,
M
/Q
~ ~V
..-~ Formula I
W
k
wherein
2o W is a six-membered, non benzofused, phenyl or heteroaryl ring, substituted
by V
in naeta or para position;
V represents -O-CH2-CH(OCH3)-CHa-O-; -O-CH2-CH(CH3)-CH2-O-; -O-CHZ-
CH(CF3)-CH2-O ; -O-CH2-C(CH3)2-CH2-O-; -O-CH2-C(CH3)2-O-; -O-C(CH3)a-
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CH2-O-; -O-CH2-CH(CH3)-O-; -O-CH(CH3)-CH2-O-; -O-CH2-C(CH2CH2)-O-; -
O-C(CHZCHa)-CH2-O-;
U represents aryl; heteroaryl;
T represents -CONRI-; -(CHZ)pOCO-; -(CH2)pN(Rl)CO-; -(CH2)pN(Rl)SOZ-; or
-COO-;
Q represents lower alkylene; lower alkenylene;
to
M represents hydrogen; cycloalkyl; aryl; heterocyclyl; heteroaryl;
L represents -R3; -COR3; -COORS; -CONRZR3; -SOZR3; -SOZNR2R3;
-COCH(Aryl)2;
R1 represents hydrogen; lower alkyl; lower alkenyl; lower alkinyl; cycloalkyl;
aryl; cycloalkyl - lower alkyl;
R2 and R2' independently represent hydrogen; lower alkyl; lower alkenyl;
2o cycloalkyl; cycloalkyl - lower alkyl;
R3 represents hydrogen; lower alkyl; lower alkenyl; cycloalkyl; aryl;
heteroaryl;
heterocyclyl; cycloalkyl - lower alkyl; aryl - lower alkyl; heteroaryl - lower
alkyl;
heterocyclyl - lower alkyl; aryloxy - lower alkyl; heteroaryloxy - lower
alkyl,
whereby these groups may be unsubstituted or mono-, di- or trisubstituted with
hydroxy, -OCOR2, -COOR2, lower alkoxy, cyano, -CONRZRZ', -CO-morpholin-4-
yl, -CO-((4-loweralkyl)piperazin-1-yl), -NH(NH)NH2, -NR4R4' or lower alkyl,
with the proviso that a carbon atom is attached at the most to one heteroatom
in
case this carbon atom is spa-hybridized;
R4 and R4' independently represent hydrogen; lower alkyl; cycloalkyl;
cycloalkyl -
lower alkyl; hydroxy - lower alkyl; -COOR2; -CONH2;
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k is the integer 0 or 1;
m and n represent the integer 0 or 1, with the proviso that in case m
represents the
integer 1, n is the integer 0, and in case n represents the integer l, m is
the integer
5 0; in case k represents the integer 0, n represents the integer 0;
p is the integer 1, 2, 3 or 4;
and optically pure enantiomers, mixtures of enantiomers such as racemates,
l0 diastereomers, mixtures of diastereomers, diastereomeric racemates,
mixtures of
diastereomeric racemates, and the meso-form; as well as pharmaceutically
acceptable salts, solvent complexes and morphological forms.
In the definitions of general formula I - if not otherwise stated - the term
lower
alkyl, alone or in combination with other groups, means saturated, straight
and
branched chain groups with one to seven carbon atoms, preferably one to four
carbon atoms that can be optionally substituted by halogens. Examples of lower
alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-
butyl,
tert-butyl, pentyl, hexyl and heptyl. The methyl, ethyl nad isopropyl groups
are
2o preferred.
The term lower alkoxy refers to a R-O group, wherein R is a lower alkyl.
Examples of lower alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, iso-
butoxy, sec-butoxy and tent-butoxy.
The term lower alkenyl, alone or in combination with other groups, means
straight and branched chain groups comprising an olefinic bond and consisting
of
two to seven carbon atoms, preferably two to four carbon atoms, that can be
optionally substituted by halogens. Examples of lower alkenyl are vinyl,
propenyl
or butenyl.
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The term lower alkinyl, alone or in combination with other groups, means
straight
and branched chain groups comprising a triple bond and consisting of two to
seven carbon atoms, preferably two to four carbon atoms, that can be
optionally
substituted by halogens. Examples of lower alkinyl are ethinyl, propinyl or
butinyl.
The term lower alkylene, alone or in combination with other groups, means
straight and branched divalent chain groups with one to , seven carbon atoms,
preferably one to four carbon atoms, that can be optionally substituted by
1 o halogens. Examples of lower alkylene are ethylene, propylene or butylene.
The term lower alkenylene, alone or in combination with other groups, means
straight and branched divalent chain groups 'comprising an olefinic bond and
consisting of two to seven carbon atoms, preferably two to four carbon atoms,
that
can be optionally substituted by halogens. Examples of lower alkenylene are
vinylene, propenylene and butenylene.
The term lower alkylenedioxy, refers to a lower alkylene substituted at each
end
by an oxygen atom. Examples of lower alkylenedioxy groups are preferably
2o methylenedioxy and ethylenedioxy.
The term lower alkylenoxy refers to a lower alkylene substituted at one end by
an
oxygen atom. Examples of lower alkylenoxy groups are preferably methylenoxy,
ethylenoxy and propylenoxy.
The term halogen means fluorine, chlorine, bromine or iodine, preferably
fluorine, chlorine and bromine.
The term cycloalkyl alone or in combination, means a saturated cyclic
3o hydrocarbon ring system with 3 to 7 carbon atoms, e.g. cyclopropyl,
cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl, which can be optionally mono- or
multisubstituted by lower alkyl, lower alkenyl, lower alkenylene, lower
alkoxy,
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lower alkylenoxy, lower alkylenedioxy, hydroxy, halogen, -CF3, -NRIRI',
-NRIC(O)RI', -NRIS(OZ)RI', -C(O)NRIRI', lower alkylcarbonyl, -COORI, -SRI,
-SORI, -SOZRI, -SOaNRIR~' whereby RI' represents hydrogen; lower alkyl; lower
alkenyl; lower alkinyl; cycloalkyl; aryl; cycloalkyl - lower alkyl. The
cyclopropyl
group is a preferred group.
The term aryl, alone or in combination, relates to the phenyl, the naphthyl or
the
indanyl group, preferably the phenyl group, which can be optionally mono- or
multisubstituted by lower alkyl, lower alkenyl, lower alkinyl, lower
alkenylene or
l0 lower alkylene forming with the aryl ring a five- or six-membered ring,
lower
alkoxy, lower alkylenedioxy, lower alkylenoxy, hydroxy, hydroxy-lower alkyl,
halogen, cyano, -CF3, -OCF3, -NRIRI', -NRIRI' - lower alkyl, -NR~C(O)RI',
-NR~S(02)RI, -C(O)NRIRI', -NO2, lower alkylcarbonyl, -COORI, -SRI, -SORI,
-SOZRI, -S02NRIRI', benzyloxy, whereby R~' has the meaning given above.
Preferred substituents are halogen, lower alkoxy, lower alkyl, CF3, OCF3.
The term aryloxy refers to an Ar-O group, wherein Ar is an aryl. An example of
a lower aryloxy group is phenoxy.
The term heterocyclyl, alone or in combination, means saturated or unsaturated
(but not aromatic) five-, six- or seven-membered rings containing one or two
nitrogen, oxygen or sulfur atoms which may be the same or different and which
rings can be optionally substituted with lower alkyl, hydroxy, lower alkoxy
and
halogen. The nitrogen atoms, if present, can be substituted by a -COORZ group.
Examples of such rings are piperidinyl, morpholinyl, thiomorpholinyl,
piperazinyl, tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl,
tetrahydrofuranyl, dihydropyrrolyl, imidazolidinyl, dihydropyrazolyl,
pyrazolidinyl, dihydroquinolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl.
The term heteroaryl, alone or in combination, means six-membered aromatic
rings containing one to four nitrogen atoms; benzofused six-membered aromatic
rings containing one to three nitrogen atoms; five-membered aromatic rings
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containing one oxygen, one nitrogen or one sulfur atom; benzofused five-
membered aromatic rings containing one oxygen, one nitrogen or one sulfur
atom;
five-membered aromatic rings containing one oxygen and one nitrogen atom and
benzofused derivatives thereof; five-membered aromatic rings containing a
sulfur
and a nitrogen or an oxygen atom and benzofused derivatives thereof; five-
membered aromatic rings containing two nitrogen atoms and benzofused
derivatives thereof; five-membered aromatic rings containing three nitrogen
atoms
and benzofused derivatives thereof, or a tetrazolyl ring. Examples of such
ring
systems are furanyl, thiophenyl, pyrrolyl, pyridinyl, pyrimidinyl, indolyl,
l0 quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, thiazolyl,
isothiazolyl,
pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, coumarinyl, benzothiophenyl,
quinazolinyl, quinoxalinyl. Such rings may be adequatly substituted with lower
alkyl, lower alkenyl, lower alkinyl, lower alkylene, lower alkenylene, lower
alkylenedioxy, lower alkyleneoxy, hydroxy-lower alkyl, lower alkoxy, hydroxy,
halogen, cyano, -CF3, -OCF3, -NRIRI', -NRIRI' - lower alkyl, -N(RI)CORI,
-N(RI)S02RI, -CONRIRI', -N02, lower alkylcarbonyl, -COORI, -SRI, -SORI,
-S02RI, -S02NRIRI', another aryl, another heteroaryl or another heterocyclyl
and
the like, whereby RI' has the meaning given above.
2o The term heteroaryloxy refers to a Het-O group, wherein Het is a
heteroaryl.
The term spa-hybridized refers to a carbom atom and means that this carbon
atom forms four bonds to four substituents placed in a tetragonal fashion
around
this carbon atom.
The expression pharmaceutically acceptable salts encompasses either salts with
inorganic acids or organic acids like hydrochloric or hydrobromic acid,
sulfuric
acid, phosphoric acid, citric acid, formic acid, acetic acid, malefic acid,
tartaric
acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, and the like
that
are non toxic to living organisms or in case the compound of formula I is
acidic in
nature with an inorganic base like an alkali or earth alkali base, e.g. sodium
hydroxide, potassium hydroxide, calcium hydroxide and the like.
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Compounds of the invention also include nitrosated compounds of the general
formula I that have been nitrosated through one or more sites such as oxygen
(hydroxyl condensation), sulfur (sulffiydryl condensation) andlor nitrogen.
The
nitrosated compounds of the present invention can be prepared using
conventional
methods known to one skilled in the art. For example, known methods for
nitrosating compounds are described in U.S. Pat. Nos. 5,380,758 and 5,703,073;
WO 97/27749; WO 98/19672; WO 98/21193; WO 99/00361 and Oae et al, Org.
Prep. Proc. Int., 15(3): 165-198 (1983), the disclosures of each of which are
to incorporated by reference herein in their entirety.
The compounds of the general formula I can contain two or more asymmetric
carbon atoms and may be prepared in form of optically pure enantiomers,
mixtures of enantiomers such as racemates, diastereomers, mixtures of
diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates,
and the meso-form and pharmaceutically acceptable salts thereof.
The present invention encompasses all these forms. Mixtures may be separated
in
a manner known pe~° se, i.e. by column chromatography, thin layer
chromatography, HPLC or crystallization.
A group of preferred compounds are compounds of general formula I wherein W,
V, U, T, Q, L, and M are as defined in general formula I above and wherein
2s k is 1
nis0and
m is 1.
Another group of preferred compounds of general formula I are those wherein W,
3o V, U, T, Q, M, k, m, and n are as defined in general formula I above and
L represents H; -COR3"; -COORS"; -CONR2"R3";
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whereby RZ" and R3" represent independently lower alkyl, lower cycloalkyl
- lower alkyl, v~hich lower alkyl and lower cycloallcyl - lower alkyl groups
are
unsubstituted or monosubstituted with halogen, cyano, hydroxy, -OCOCH3,
5 -CONH~,, -COOH, -NHZ, with the proviso that a carbon atom is attached at the
most to one heteroatom in case this carbon atom is spa-hybridized.
Another group of preferred compounds of general formula I above are those
wherein W, V, U, L, k, m, and n are as defined in general formula I and
to
T is -CONR1-;
Q is methylene;
M is aryl, heteroaryl.
Another group of even more preferred compounds of general formula I are those
wherein W, U, L, T, Q, M, k, m, and n are as defined in general formula I
above
and
V represents -O-CH2-CH(CH3)-CH2-O-; -O-CHZ-C(CH3)2-CH2-O- .
2o
Another group of also more preferred compounds of general formula I are those
wherein V, U, T, Q, M, L, k, m, and n are as defined in general formula I
above
and
W represents a 1,4-disubstituted phenyl ring.
Another group of even more preferred compounds of general formula I are those
wherein W, V, Q, T, M, L, k, m, and n are as defined in general formula I
above
and
U is a mono-, di-, or trisubstituted phenyl or heteroaryl, wherein the
substituents
are halogen, lower alkyl, lower alkoxy, CF3.
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Especially preferred compounds of general formula I ar e:
(1R, SS)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluorophenoxy)propoxy]-phenyl}-3,9
diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3
dichlorobenzyl)amide;
(IS, SR)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluoro-phenoxy)propoxy]phenyl}-3,9-
diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-
dichlorobenzyl)amide;
to a mixture of (1R, SS)-7- f 4-[(2S)-2-methyl-3-(2,3,6-
trifluorophenoxy)propoxy]-
phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-(2,3-
dichlorobenzyl)amide and (1S, SR)-7- f 4-[(2S)-2-methyl-3-(2,3,6-trifluoro-
phenoxy)propoxy]phenyl}-3,9-diazabicyclo-[3.3.1]non-6-ene-6-carboxylic acid
cyclopropyl-(2,3-dichlorobenzyl)amide.
The compounds of general formula I and their pharmaceutically acceptable salts
may be used as therapeutics e.g. in form of pharmaceutical compositions. These
pharmaceutical compositions containing at least one compound of general
formula
I and usual carrier materials and adjuvants may especially be used for the
2o treatment or prophylaxis of disorders which are associated with a
dysregulation of
the renin angiotensin system (RAS), comprising cardiovascular and renal
diseases.
Examples of such diseases are hypertension, coronary diseases, cardiac
insufficiency, renal insufficiency, renal and myocardial ischemia, and renal
failure. They can also be used to prevent restenosis after balloon or stmt
. angioplasty, to treat erectile dysfunction, glomerulonephritis, renal colic,
and
glaucoma. Furthermore, they can be used in the therapy and the prophylaxis of
diabetic complications, complications after vascular or cardiac surgery,
restenosis,
complications of treatment with immunosuppresive agents after organ
transplantation, complications of cyclosporin treatment, as well as other
diseases
3o presently known to be related to the RAS.
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In another embodiment, the invention relates to a method for the treatment
and/or
prophylaxis of diseases which are related to the RAS such as hypertension,
congestive heart failure, pulmonary hypertension, cardiac insufficiency, renal
insufficiency, renal or myocardial ischemia, atherosclerosis, renal failure,
erectile
dysfunction, glomerulonephritis, renal colic, glaucoma, diabetic
complications,
complications after vascular or cardiac surgery, restenosis, complications of
treatment with immunosuppresive agents after organ transplantation, and other
diseases which are related to the R.AS, which method comprises administering a
compound according of formula I to a human being or animal.
The invention further relates to the use of compounds of general formula I as
defined above for the treatment and/or prophylaxis of diseases which are
associated with the RAS such as hypertension, congestive heart failure,
pulmonary
hypertension, cardiac insufficiency, renal insufficiency, renal or myocardial
ischemia, atherosclerosis, renal failure, erectile dysfunction,
glomerulonephritis,
renal colic, glaucoma, diabetic complications, complications after vascular or
cardiac surgery, restenosis, complications of treatment with immunosuppresive
agents after organ transplantation, and other diseases presently known to be
related to the RAS.
In addition, the invention relates to the use of compounds as defined above
for the
preparation of medicaments for the treatment and/or prophylaxis of diseases
which are associated with the RAS such as hypertension, coronaxy diseases,
cardiac insufficiency, renal insufficiency, renal and myocardial ischemia, and
renal failure. These medicaments may be prepared in a manner known per se.
The compounds of formula I may also be used in combination with one or more
other pharmacologically active compounds e. g. with other renin inhibitors,
with
ACE-inhibitors, angiotensin II receptor antagonists, endothelin receptor
3o antagonists, vasodilators, calcium antagonists, potassium activators,
diuretics,
sympatholitics, beta-adrenergic antagonists, alpha-adrenergic antagonists, and
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neutral endopeptidase inhibitors, for the treatment of disorders as above-
mentioned.
All forms of prodrugs leading to an active component comprised by general
s formula I above are included in the present invention.
The compounds of general formula I can be manufactured by the methods
outlined below, by the methods described in the examples or by analogous
methods.
' 10,
Chemistry
The chemistry necessary to prepare the compounds included in general formula I
might be taken from earlier patent applications, for instance WO 03/093267 or
15 WO 04/002957. The linkers included under V in general formula I can be
prepared from a commercially available glycerol derivative, from commercially
available 3-hydroxy-2,2-dimethylpropionic acid methyl ester, from (R)- or (S~-
3-
hydroxy-2-methylpropionic acid (Locher, T.; et al.; PCT Int. Appl. WO 0022153
A1 20000420, 2000; Vogel, G.; et al.; Chemistry af2d Physics of Lipids, 1990,
52,
20 99; Seebach, D.; et al.; Helv. Claim. Acta, 1986, 69, 1147), or from (R)-
or (S~-3-
hydroxy-2-(trifluoromethyl)propionic acid (Goetzoe, S. P.; et al.; Chimia,
1996,
50, 20). Also, methyl 1-hydroxy-1-cyclopropane carboxylate or any derivative
of
lactic acid can be used as starting materials. All these starting materials
can be
converted into a precuror for the segment V-U by a combination of protecting
25 steps, coupling steps with a phenol derivative, a hydroxyheterocycle, a
hydroxycycloalkyl, or a hydroxyheteroaryl (typically via a Mitsunobu
coupling),
reductive steps, and/or deprotection steps. For instance a compound of type A
can
be prepared from one of the here above mentionned compound, whereas the Ra-
and Rb-groups are as defined in general formula I (or precursors to such a
group),
3o and COOR° is a suitable ester, typically a methyl, an ethyl, or a
benzyl ester. A
reduction of the ester can lead to a compound of type B, then a Mitsunobu
coupling can lead to a compound of type C. During the process, the protecting
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14
group (PG) can be cleaved and replaced by a more suitable one (PG') for the
following chemistry, leading to a compound of type D. Coupling to known vinyl
triflate E can lead to a bicyclononene of type F. Protecting group
manipulation
can lead to a compound of type G, then deprotection to a bicyclononene of type
H. A next step, for instance a Mitsunobu coupling, can lead to a bicyclononene
of
type J, where the V-U segment is completely in place. Saponification can lead
to
a compound of type K, then an amide coupling for instance to a compound of
type
L. Removal of the Boc-protecting group, then alkylation or acylation, can lead
to
a bicyclononene of type M, then deprotection to a desired final compound of
type
to N.
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Scheme 1
O O
HO Ra Rb ORb PG~O~ OR° ~ PG~O OH
Ra Rb
A
Br
O a/\ b 0Rd
Ra = PG: C R R my
Ra=PG': D
h
G Ra, F
O
N~Boc
G
F PG~ __
-U
--U
P
E ~ ,
--
PG~
-U
M-~
H
PG~
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16
The compounds of formula I and their pharmaceutically acceptable acid addition
salts can be used as medicaments, e. g. in the form of pharmaceutical
preparations
for enteral, parenteral, or topical administration. They can be administered,
for
example, perorally, e. g. in the form of tablets, coated tablets, dragees,
hard and
soft gelatine capsules, solutions, emulsions or suspensions, rectally, e. g.
in the
form of suppositories, parenterally, e. g. in the form of injection solutions
or
infusion solutions, or topically, e. g. in the form of ointments, creams or
oils.
The production of pharmaceutical preparations can be effected in a manner
which
' to will be familiar to any person skilled in the art by bringing the
described
compounds of formula I and their pharmaceutically acceptable acid addition
salts,
optionally in combination with other therapeutically valuable substances, into
a
galenical administration form together with suitable, non-toxic, inert,
therapeutically compatible solid or liquid carrier materials and, if desired,
usual
pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also
organic
Garner materials. Thus, for example, lactose, corn starch or derivatives
thereof,
talc, stearic acid or its salts can be used as carrier materials for tablets,
coated
2o tablets, dragees and hard gelatine capsules. Suitable carrier materials for
soft
gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid
and
liquid poyols (depending on the nature of the active ingredient no carriers
are,
however, required in the case of soft gelatine capsules). Suitable carrier
materials
for the production of solutions and syrups are, for example, water, polyols,
sucrose, invert sugar and the like. Suitable carrier materials for injections
are, for
example, water, alcohols, polyols, glycerols and vegetable oils. Suitable
carrier
materials for suppositories are, for example, natural or hardened oils, waxes,
fats
and semi-liquid or liquid polyols. Suitable carrier materials for topical
preparations are glycerides, semi-synthetic and synthetic glycerides,
hydrogenated
oils, liquid waxes, liquid paraffms, liquid fatty alcohols, sterols,
polyethylene
glycols and cellulose derivatives.
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Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-
improving agents, flavour-improving agents, salts for varying the osmotic
pressure, buffer substances, solubilizers, colorants and masking agents and
antioxidants come into consideration as pharmaceutical adjuvants.
s
The dosage of compounds of formula I can vary within wide limits depending on
the disease to be controlled, the age and the individual condition of the
patient and
the mode of administration, and will, of course, be fitted to the individual
requirements in each particular case. For adult patients a daily dosage of
about 1
to mg to about 1000 mg, especially about 50 mg to about 500 mg, comes into
consideration.
The pharmaceutical preparations conveniently contain about 1 - 500 mg,
preferably 5 - 200 mg of a compound of formula I.
The following examples serve to illustrate the present invention in more
detail.
They are, however, not intended to limit its scope in any manner.
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1~
Example
Abbreviations
ACE Angiotensin Converting Enzyme
AcOH Acetic acid
Ang Angiotensin
aq. aqueous
Bn Benzyl
l0 Boc teft-Butyloxycarbonyl
BSA Bovine serum albumine
BuLi n-Butyllithium
DIBAL diisobutylaluminiumhydride
DIPEA Diisopropylethylamine
DMAP 4-N,N Dimethylaminopyridine
DMSO Dimethylsulfoxide
EDC~HCI Ethyl-N,N dimethylaminopropylcarbodiimide
hydrochloride
EIA Enzyme immunoassay
eq. equivalent
Et Ethyl
EtOAc Ethyl acetate
FC Flash Chromatography
HOBt Hydroxybenzotriazol
LC-MS Liquid Chromatography - Mass Spectroscopy
MeOH Methanol
org. organic
PG protecting group
Ph Phenyl
RAS Renin Angiotensin System
rt room temperature
sol. Solution
TBAF tetra-h-butyl ammonium fluoride
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TBDMS test-Butyldimethylsilyl
Tf Trifluoromethylsulfonyl
THF Tetrahydrofuran
TMAD N,N,N',N'-Tetramethylazodicarboxamide
Precursor
(R)-3-(tef~t butyldiphenylsilanyloxy)-2-methylpropionic acid methyl ester (A)
l0 To a mixture of (-)-methyl D-(3-hydroxyisobutyrate (5.54 mL, 50 mmol) and
imidazole (8.51 g, 125 mmol) in CH2Cl2 (150 mL) was added tert-
butyldiphenylsilyl chloride (19.5 mL, 75 mmol). After stirring for 18 h, the
mixture was diluted with CH2C12 and washed with a saturated aq. NH4C1 solution
and brine. The org. extracts were dried over MgS04, filtered, and the solvent
was
removed under reduced pressure. Purification by FC (heptane/EtOAc 100:0 -~
90:10) yielded the title compound (15.32 g, 86%).
(,S~-3-(tent butyldiphenylsilanyloxy)-2-methylpropan-1-of (B)
2o To a solution of DIBAL (1M in hexane; 113.2 mL, 113.2 mmol), further
diluted
with THF (400 mL), was added a solution of compound A (13.44 g, 37.7 mmol)
in THF (150 mL), at -78°C. The solution was stirred for 30 min at -
78°C and then
MeOH (11.3 mL) was added slowly. The mixture was allowed to warm up. A
saturated aq. NH4C1 solution was added slowly until a granulous solid was
formed. The mixture was filtered over a pad of NaZSO4. Purification by FC
(heptanelEtOAc 98/2 ~ 95/5 90:10-~ 80:20) yielded the title compound (11.6
g, 93%). LC-MS; Rt = 1.12, ES+: 329.28.
(,f)-[3-(4-bromophenoxy)-2-methylpropoxy]-test butyldiphenylsilane (C)
4-Bromophenol (7.07g, 40.2 mmol) and DIPEA (0.58 mL, 3.3 mmol) were added
to a solution of compound B (11g, 33.48 mmol) in toluene (335 mL).
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Azodicarboxylic dipiperidide (12.67 g, 50.2 mmol) was added, followed by h-
tributylphosphine (16.52 ml, 67 mmol) at 0°C. The reaction mixture was
stirred
for 1 h at RT and then 2 h at 60 °C. It was allowed to cool to RT, and
then water
was added. The mixture was extracted with EtOAc. The org. extracts were dried
5 over MgSO4, filtered, and the solvents were removed under reduced pressure.
Purification by FC (heptane/EtOAc 95/5) yielded the title compound ( 16.0 g,
99%). LC-MS; Rt = 1.29min.
(S)-[3-(4-bromophenoxy)-2-methylpropoxy]-tent-butyldimethylsilane (D)
to
To a solution of compound C (13.1g, 27 mmol) in THF (200 mL) was added
TBAF (1M solution in THF, 54 mL, 54 mmol) at 0°C. The cooling bath
was
removed and the reaction mixture was stirred for 2h. AcOEt and a saturated.
aq.
NHøCl solution were added. The aqueous phase was extracted with AcOEt and the
15 org. extracts were dried over MgS04, filtered, and the solvents were
removed
under reduced pressure. Purification by FC (heptane/EtOAc 80/20 -~ 50/50-~
0/100) yielded the title compound (3.79 g, 57%).
To a mixture of the previously obtained compound (3.79 mL, 15.5 mmol) and
imidazole (2.63 g, 3 8.7 mmol) in CH2C12 (45 mL) was added teYt
20 butyldimethylsilyl chloride (3.5 g, 23.2 mmol). After stirring for 3 h, the
mixture
was diluted with CH2Cl2 and washed with a saturated aq. NH4Cl solution and
brine. The org. extracts were dried over MgS04, filtered, and the solvent was
removed under reduced pressure. Purification by FC (heptane/EtOAc 98/2 ~
95/5) yielded the title compound (3.1 g, 56%). LC-MS; Rt =.1.24min.
1:1 Mixture of (1R, SS)-7-{(2S)-4-[3-(tent butyldimethylsilanyloxy)-2-
methylpropoxy] phenyl}-9-methyl-3,9-diazabicyclo [3.3.1] non-6-ene-3,6-
dicarboxylic acid 3-test butyl ester 6-ethyl ester and (IS, SR)-7-{(2S)-4-[3-
(tert butyldimethylsilanyloxy)-2-methylpropoxy]phenyl}-9-methyl-3,9-
diazabicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid 3-tent-butyl ester 6-ethyl
ester (~
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21
BuLi (1.6M in hexane, 3.2 mL, 5.12 mmol) was added to a sol. of compound D
(1.8 g, 5 mmol) in THF (4 mL) at -78 °C. The mixture was stirred for 30
min at
this temperature, and ZnCl2 (1M in THF, prepared from ZnCl2 dried at 160
°C for
3 h and THF, 6 mL, 6 mmol) was added. The mixture was allowed to warm to rt
and a sol. of bicyclononene E (0.91 g, 2 mmol) in THF (6 ml), then Pd(PPh3)ø
(58
mg, 0.05 mmol) were added. The mixture was heated to 40 °C and stirred
at this
temperature for 30 min. A saturated aq. NH4C1 solution was added. The mixture
was extracted with EtOAc (3 times) and washed with brine. The org. extracts
were dried over MgS04, filtered, and the solvents were removed under reduced
to pressure. Purification by FC (heptane/AcOEt 50:50 ~ 0/100 then EtOAc/MeOH
95/5) yielded the title compounds (0.49 g, 41%). LC-MS; Rt =1.03 ES+: 589.36.
1:1 Mixture of (1R, SS)-7-{(2SJ-4-[3-(tent-butyldimethylsilanyloxy)-2-methyl-
propoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3-
tent butyl ester 6-ethyl ester 9-(2,2,2-trichloro-1,1-dimethylethyl) ester and
(IS, SR)-7-](2S)-4-[3-(tef~t-butyldimethylsilanyloxy)-2-methyl-propoxy]-
phenyl)-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3-tent butyl
ester 6-ethyl ester 9-(2,2,2-trichloro-1,1-dimethylethyl) ester (G)
A sol. of bicyclononene F (0.49 g, 0.83 mmol) and (3,(3,/3-trichloro-te~t-
butylchloroformate (1 g, 4.15 mmol) in CH2C1CH2C1 (10 ml) was heated to reflux
for 4 h. The mixture was allowed to cool to rt and the solvents were removed
under reduced pressure. Purification of the residue by FC (EtOAc/heptane 5/95
10/90) yielded the title compound (0.40 g, 61 %). LC-MS: Rt = 1.33
ES+:777.25.
1:1 Mixture of (1R, SS)-7-[4-((2R)-3-hydroxy-2-methylpropoxy)phenyl]-3,9-
diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3-tart butyl ester 6-
ethyl
ester 9-(2,2,2-trichloro-1,1-dimethylethyl) ester and (1S, SR)-7-[4-((2S)-3-
hydroxy-Z-methylpropoxy)phenyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-
tricarboxylic acid 3-tart butyl ester 6-ethyl ester 9-(2,2,2-trichloro-1,1-
dimethylethyl) ester (H)
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To a solution of bicyclononene G (0.40 g, 0.51 mmol) in THF (5 mL) was added
TBAF (1M solution in THF, 0.76 mL, 0.76 mmol) at 0°C. The ice bath
was
removed and the reaction mixture was stirred for 4 h. AcOEt and a saturated.
aq.
NH4C1 solution were added. The aqueous phase was extracted with AcOEt and the
org. extracts were dried over MgS04, filtered, and the solvents were removed
under reduced pressure. Purification by FC (heptane/EtOAc 30/70 -~ 50/50 2/1 )
yielded the title compound (0.26 g, 78%).
LC-MS; Rt = 1.95 min.
l0 1:1 Mixture of (1R, SS)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluorophenoxy)
propoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3
tert butyl ester 6-ethyl ester 9-(2,2,2-trichloro-1,1-dimethylethyl) ester and
(IS, SR)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluorophenoxy)propoxy]phenyl}-3,9
diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3-tent butyl ester 6-
ethyl
ester 9-(2,2,Z-trichloro-1,1-dimethylethyl) ester (J)
2,3,6-Trifluorophenol (0.07 g, 0.48 mmol) and DIPEA (0.007 mL, 0.04 mmol)
were added to a solution of compound H (0.26 g, 0.4 mmol) in toluene (5 mL).
Azodicarboxylic dipiperidide (0.15 g, 0.6 mmol) was added, followed by
2o tributylphosphine (0.20 ml, 0.8 mmol) at 0°C. The reaction mixture
was stirred
for 20 min. at RT and then 1 h at 80 °C. The reaction mixture was
allowed to cool
to RT and water was added. The mixture was extracted with EtOAc. The org.
extracts were dried over MgS04, filtered, and the solvents were removed under
reduced pressure. Purification by FC (heptane/EtOAc 20/80) yielded the title
compound (0.28 g, 89%).
LC-MS; Rt = 1.26, ES+: 795.08.
1:1 Mixture of (1R, SS)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluorophenoxy)-
propoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3-
test butyl ester 9-(2,2,2-trichloro-1,1-dimethylethyl) ester and (IS, SR)-7-{4-
[(2S)-2-methyl-3-(2,3,6-trifluorophenoxy)-propoxy] phenyl}-3,9-diazabicyclo-
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23
[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3-tent-butyl ester 9-(2,2,2-
trichloro-
1,1-dimethylethyl) ester (I~
A mixture of bicyclononene J (0.28 g, 0.36 mmol) in EtOH (5 ml) and aq. 1M
NaOH (3.6 mL, 3.6 mmol)) was stirred at 80 °C for 2.5 h. The
mixture was
allowed to cool to rt and was acidified with aq 1 M HCl. The mixture was
extracted with EtOAc (3x) and the org. extracts were dried over MgS04,
filtered,
and the solvents were removed under reduced pressure. Purification of the
crude
by FC (heptane/EtOAc 30/70-~ 50/50) yielded the title compound (0.20 g 72%).
1o LC-MS: Rt = 1.19; MS-: 765.17.
1:1 Mixture of ~ (1R, SS)-6-[cyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-7-{4-
[(2S)-2-methyl-3-(2,3,6-trifluorophenoxy)propoxy]phenyl}-3,9-diazabicyclo-
[3.3.1]non-6-ene-3,9-dicarboxylic acid 3-tef°t butyl ester 9-(2,2,2-
trichloro-l,l-
dimethylethyl) ester and (IS, SR)-6-[cyclopropyl-(2,3-dichlorobenzyl)-
carbamoyl]-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluorophenoxy)propoxy]phenyl}-
3,9-diazabicyclo-[3.3.1]non-6-ene-3,9-dicarboxylic acid 3-tent butyl ester 9-
(2,2,2-trichloro-1,1-dimethylethyl) ester (L)
A mixture of bicyclononene K (0.20 g, 0.26 mmol), (2,3-
dichlorobenzyl)cyclopropylamine (0.17 mg, 0.78 mmol), DMAP (0.004 g, 0.06
mmol), DIPEA (0.18 mL, 1.0 mmol), HOBt (0.04 g, 0.32 mmol) and EDC~HCI
(0.074 g, 0.39 mmol) in CH2C12 (5 mL) was stirred for 2 days. EDC.HCI (0.074
g,
0.39 mmol) and DIPEA (0.07 mL, 0.39 mmol) were then added and stirring was
continued for 2 days. The mixture was diluted with CH2C12 and washed with aq.
1M HCl (2x). The org. extracts were dried over MgSO4, filtered, and the
solvents
were removed under reduced pressure. Purification by FC (heptane/EtOAc 20:80
-~ 30/70) yielded the title compound (0.11 g, 44%). LC-MS: Rt = 1.34; ES+:
964.19.
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Example
1:1 Mixture of (1R, SS)-7-{4-[(2S)-2-methyl-3-(2,3,6-trifluorophenoxy)-
propoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid
cyclopropyl-(2,3-dichlorobenzyl)amide and (IS, SR)-7-{4-[(2S)-2-methyl-3-
(2,3,6-trifluorophenoxy)propoxy]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-
carboxylic acid cyclopropyl-(2,3-dichlorobenzyl)amide
The bicyclononene L (0.11 g, 0.11 mmol) was dissolved in THF (3 mL) and
' 10 AcOH (0.3 mL) and treated with zinc (0.14 g, 2.2 mmol.). The suspension
was
stirred for 2 h and filtered through a Titan~ HPLC filter. The filtrate was
evaporated under reduced pressure and the residue was used in the next step
without further purification.
A sol. of the former obtained material (0.08 g, 0.11 mmol) in CHZC12 (2 mL)
was
cooled to 0°C. 4M HCl/dioxane (2 mL) was added. After 2.5 h at rt, the
solvents
were removed under reduced pressure and the residue dried under high vacuum.
The title compound was purified by prep.-HPLC. LC-MS: Rt = 0.80; ES+: 660.38
The following assay was carried out in order to determine the activity of the
compounds of general formula I and their salts.
Inhibition of human recombinant renin by the compounds of the
invention
The enzymatic in vitro assay was performed in 384-well polypropylene plates
(Nunc). The assay buffer consisted of 10 mM PBS (Gibco BRL) including 1 mM
EDTA aild 0.1 % BSA. The incubates were composed of 50 ~.L per well of an
enzyme mix and 2.5 q,L of renin inhibitors in DMSO. The enzyme mix was
premixed at 4°C and consists of the following components:
~ human recombinant renin (0.16 ng/mL) ~ synthetic human angiotensin(1-14)
(0.5
~,M)
~ hydroxyquinoline sulfate (1 mM)
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The mixtures were then incubated at 37°C for 3 h.
To determine the enzymatic activity and its inhibition, the accumulated Ang I
was
detected by an enzyme immunoassay (EIA) in 3~4-well plates (Nunc). 5 ~,L of
the
incubates or standards were transferred to immuno plates which were previously
5 coated with a covalent complex of Ang I and bovine serum albumin (Ang I -
BSA). 75 ~,L of Ang I-antibodies in essaybuffer above including 0.01 % Tween
20
were added and a primary incubation made at 4 °C overnight. The plates
were
washed 3 times with PBS including 0.01% Tween 20, and then incubated for 2 h
at rt with an antirabbit-peroxidase coupled antibody (WA 934, Amersham). After
' to washing the plates 3 times, the peroxidase substrate ABTS (2.2'-azino-di-
(3-ethyl-
benzthiazolinsulfonate), was added and the plates incubated for 60 min at room
temperature. After stopping the reaction with 0.1 M citric acid pH 4.3 the
plate
was evaluated in a microplate reader at 405 nm. The percentage of inhibition
was
calculated of each concentration point and the concentration of renin
inhibition
15 was determined that inhibited the enzyme activity by 50% (ICSO). The ICSO-
values
of all compounds tested are below 100 nM. However selected compounds exhibit
a very good bioavailibility and are metabolically more stable than prior art
compounds.
