Novel Diazabicyclononene Derivatives and Use
The invention relates to novel five-membered heteroaryl derivatives of the general formula (T). 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.
In the renin-angiotensin system (RAS) the biologically active angiotensin EL (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 ATl and AT2- Whereas
ATi 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 ATi 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): Hypertension, Amsterdam, Elsevier Science Publishing Co, 1996, 489-519; Weber M. A., Am. J. Hypertens., 1992, 5, 247S). In addition, ACE inhibitors are used for renal protection (Rosenberg M. E. et al, Kidney International, 1994, 45, 403; Breyer J. A. et al, Kidney International, 1994, 45, SI56), in the prevention of congestive heart failure (Vaughan D. E. et al, Cardiovasc. Res., 1994, 28,159; Fouad-Tarazi F. et al, Am. 1 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., Cardiovasc. 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 bypassed by chymase, a serine protease (Husain A., J. Hypertens., 1993, 77, 1155). In patients inhibition of ACE thus leads to bradykinin accumulation causing cough (5-20%) and potentially life-threatening angioneurotic edema (0.1-0.2%) (Israili Z. H. et al, Annals of Internal Medicine, 1992, 777, 234). Chymase 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 (e.g. AT2) to Ang II, whose concentration is significantly increased by the blockade of ATl
receptors- In summary, renin inhibitors are expected to demonstrate a different pharmaceutical profile than ACE inhibitors and ATl blockers with regard to
efficacy in blocking the RAS and in safety aspects.
Only limited clinical experience (Azizi M. et al, J. Hypertens., 1994, 72, 419; Neutel J. M. et al, Am. Heart, 1991, 722, 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.9 Drugs of the Future, 2001, 26, 1139). Thus, renin inhibitors with good oral bioavailability and long duration of action are required. Recently, the first non-peptide renin inhibitors were described which show high in vitro activity (Oefeer C. et al, Chem. BioL, 1999, 6, 127; Patent Application WO97/09311; Marki H. P. et al, 77 Farmaco, 2001, 55, 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. Described are 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. So, the present invention describes these non-peptidic renin inhibitors.
The present invention describes non-peptidic renin inhibitors.
In particular, the present invention relates to novel compounds of the general formula I,

wherein
X and W represent independently a nitrogen atom or a -CH- group;
V represents -(CH^r; -A-(CH2)S-; -CH2-A-(CH2)r; -(CH2)S-A-; -(CH2)2-A-(CH2)uS -A-(CH2)V-Bs -CH2-CH2-CH2-A-CH2-; -A-CH2-CH2-B-CH2-; -CH2-A-CH2-CH2-B-; -CH2~CH2~CH2-A-CH2-CH2-; -CH2-CH2»CH2-CH2«A-CH2s -A-CH2-CH2-B-CH2-CH2s -CH2^A-CH2-CH2-B-CH2-; ^CH2-A«CH2-CH2-CH2-B-; or -CH2-CH2-A-CH2-CH2-B-;
A and B independently represent -O-; -S-; -SO-; -SO2-; U represents aryl; heteroaryl;
T represents -CONR1-; -(CH2)POCO-; -(CH^pNCR^CO-; -(CH^pNCR^SC^s or -COO-;

Q represents lower alkylene; lower alkenylene;
M represents aryl-O(CH2)vR7; heteroaryl-O(CH2)vR7; aryl-O(CH2)vO(CH2)wR7;
heteroaryl-(CH2)vO(CH2)wR7; aryl-OCH2CH(R6)CH2R5; heteroaryl-
OCH2CH(R6)CH2R5;
L represents -R3; -COR3; -COOR3; -CONR2R3; -SO2R3; -SO2NR2R3; -COCHCAryTfc;
R1 represents hydrogen; lower alkyl; lower alkenyl; lower alkinyl; cycloalkyl; aryl; cycloalkyl - lower alkyl;
R2 and R2t independently represent hydrogen; lower alkyl; lower alkenyl; cycloalkyl; cycloalkyl - lower alkyl;
R 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 tmsubstituted or mono-, di- or trisubstituted with hydroxy, -OCOR2, -COOR2, lower alkoxy, cyano, -CONR2R2f, CO-morpholin-4-yl, CO-((4-loweralkyl)piperazin-l-yl)3 -NH(NH)NH2, -NR^R4' or lower alkyl, with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
R4 and R4t independently represent hydrogen; lower alkyl; cycloalkyl; cycloalkyl -lower alkyl; hydroxy - lower alkyl; -COOR2; -CONH2;
R5 represents -OH, lower alkoxy, -OCOR2, -COOR2, -NR2R2>, -OCONR2R2f, -NCONR2R2', cyano, -CONR2R2\ SO3H, -SONR2R2', -CO-morpholin-4-yl, -CO-((4-loweralkyl)piperazin-l-yl), -NH(NH)NH2, -NR4R4', with the proviso that a

carbon atom is attached at fee most to one heteroatom in case this carbon atom is sp3-hybridized;
R6 represents -OH, OR2; OCOR2; OCOOR2; or R6 and R5 form together with the carbon atoms to which they are attached a 1,3-dioxolane ring which is substituted in position 2 with R2 and R2'; or R6 and R5 form together with the carbon atoms to which they are attached a l,3-dioxolan-2-one ring;
R represents lower alkoxy;
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 1, m is the integer
0;
p is the integer 1,2,3 or 4;
r is the integer 3, 4, 5, or 6;
s is the integer 2, 3,4, or 5;
t is the integer 1, 2,3, or 4;
u is the integer 1,2, or 3;
v is the integer 1,2, 3, or 4;
w is the integer 1 or 2;
z is the integer 0 or 1 "~
and optically pure enantiomers, mixtures of enantiomers such as racemates, 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 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 tert-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.
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 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 andbutenylene.

The term lower alkylenedioxy, refers to a lower alkylene substituted at each end by an oxygen atom. Examples of lower alkylenedioxy groups are preferably 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 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, lower alkylenoxy, lower alkylenedioxy., hydroxy, halogen, -CF3, -NR1]*.1', -NR^CCC^R1', -NR1S(O2)Rlf) -C(O)NR1Rlf, lower alkylcarbonyl, -COOR1, -SR1, -SOR1, -SO2R1, -SO2NR1Rl1 whereby Rlf 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 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, -NI^R1', -NRV' - lower alkyl, -NR^OJR1', -NRiS(O2)R15 -C(O)NRxRlf, -NO2, lower alkylcarbonyl, -COOR1, -SR1, -SOR1, -SQ2R1, -SO2NRIRIt, benzyloxy, whereby R1' has the meaning given above. Preferred substituents are halogen, lower alkoxy, lower alkyl, CF3, OCF3.

The term aryloxy refers to an Ar-0 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 lings can be optionally substituted with lower alkyl, hydroxy, lower alkoxy and halogen. The nitrogen atoms, if present, can be substituted by a -COOR group. Examples of such rings are piperidinyl, morpholinyl, thiomorpholinyl, piperazdnyl, tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, imidazolidinyl, dihydropyrazolyl, pyrazolidinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl.
The term heteroary], 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 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, 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, -NR1^', -NR1^1 - lower alkyl, -NCR^COR1, -NCR^SOaR1, -CON^R1', -NO2, lower alkylcarbonyl, -COOR1, -SR1, -SOR1,

-SO2R1, -S02NR1Rlf» another aryl, another heteroaryl or another heterocyclyl and
the like, whereby R1' has the meaning given above.
The term heteroaryloxy refers to a Het-0 group, wherein Het is a heteroaryl.
The term cycloalkyl - lower alkyl refers to a cycloalkyl group which is
substituted with a lower alkyl group as defined above.
The term aryl - lower alkyl refers to aryl group which is substituted with a lower
alkyl group as defined above.
The term heteroaryl - lower alkyl refers to a heteroalkyl group which is
substituted with a lower alkyl group as defined above.
The term heterocyclyl - lower alkyl refers to a heterocyclyl group which is
substituted with a lower alkyl group as defined above.
The term aryloxy - lower alkyl refers to aryloxy group which is substituted with a
lower alkyl group as defined above.
The term heteroaryloxy - lower alkyl refers to a heteroaryloxy group which is
substituted with a lower alkyl group as defined above.
The term hydroxy - lower alkyl refers to a lower alkyl group which is substituted
with a hydroxyl group.
The term lower alkylcarbonyl refers to a-CO-lower aUcyl group.
The term sp3-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, maleic 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.
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-foim and pharmaceutically acceptable salts therof. The present invention encompasses all these forms. Mixtures may be separated in a manner known per se, i.e. by column chromatography, thin layer chromatography, HPLC or crystallization.
A group of preferred compounds are compounds of general formula I wherein X, W, V, U, T, Q, L, and M are as defined in general formula I above and wherein
zis 1 n is 0 and mis 1.
Another group of preferred compounds of general formula I are those wherein X, W, V, U, T, Q, M, m, and n are as defined in general formula I above and
z is 1 and
L represents H; -COR3"; -COOR3"; -CONR2"R3";
whereby R2" and R3" represent independently lower alkyl, lower cycloalkyl -lower alkyl, which lower alkyl and lower cycloalkyl - lower alkyl groups are unsubstituted or monosubstituted with halogen, cyano, hydroxy, -OCOCH3, -CONH2, -COOH, -NH2, with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3 -hybridized.
Another group of preferred compounds of general formula I above are those wherein X, W, V, U, L5 m, n, and z are as defined in general formula I and
T is -CONR1-; Q is methylene;

M is aryl-O(CH2)vR7; heteroaryl-O(CH2)vR7; aryl-OCH2CH(R6)CH2R5; heteroaryl-OCH2CH{R6)CH2R5.
Another group of even more preferred compounds of general formula I are those wherein X, W, U, L, T, Q, M, m, n, and z are as defined in general formula I above and
V is -CH2CH2O-; -CH2CH2CH2O-; -OCH2CH2O-.
Another group of also more preferred compounds of general formula I are those wherein V, U3 T, Q? M, L, m, n, and z are as defined in general formula I above and
X and W represent -CH-.
Another group of also more preferred compounds of general formula I are those wherein X, W, V, Q, T, M, L, m, n, and z are as defined in general formula I above and
U is a mono-, di-, or trisubstituted phenyl wherein the substituents are halogen; lower alkyl or lower alkoxy.
Most preferred compounds of general formula I are those wherein X and W represent a -CH- group;
V represents -A-(CH2)s -;
A represents -O-;
U represents phenyl, trisubstituted with halogen;
T represents - CONR1- ;
Q represents C1-C4 alkyl;
M represents phenyl - O - (CH2)v R7 or pyridyl- O - (CH2)v R7;
L represents R3;
R1 represents cycloalkyl;

R3 represents hydrogen, C1-C4 alkyl;
R7 represents C1-C4 alkoxy;
m represents the integer 1;
n represents the integer 0;
z represents the integer 1;
s represents the integer 3;
v represents the integer 2 ;
and optically pure enantiomers, mixtures of enantiomers such as racemates,
diastereomers, mixtures of diastereomers, diastereomeric racernates, mixtures of
diastereomeric racemates, and the meso-form; as well as pharmaceutically
acceptable salts, solvent complexes and morphological forms.
Most preferred compounds of general formula I are also those wherein
X and W represent a -CH- group;
V represents -O-CH2-CH2 -CH2-;
U represents phenyl, trisubstituted independently with Fluoro and Chloro;
T represents - CONR1- ;
Q represents - CH2-;
M represents phenyl - O - (CH2)v R7 or pyridyl- O - (CH2)v R7;
L represents R3;
R1 represents cyclopropyl;
R3 represents hydrogen;
R represents methoxy;
m represents the integer 1;
n represents the integer 0;
z represents the integer 1;
s represents the integer 3;
v represents the integer 2 ;
and optically pure enantiomers, mixtures of enantiomers such as racemates,
diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of

Claims
1. Compounds of the general formula I

wherein
X and W represent independently a nitrogen atom or a -CH- group;
V represents -(CH2)r; -A-(CH2)S-; -CH2-A-(CH2)t-; -(CH2)S-A-; -(CH2)2-A-(CH2)U-; -A-(CH2)V-B-; -CH2-CH2-CH2-A-CH2-; -A-CH2-CH2-B-CH2-; -CH2-A-CH2-CH2-B-; -CH2-CH2-CH2-A-CH2-CH2-; -CH2-CH2-CH2-CH2-A-CH2-; -A-CH2-CH2-B-CH2-CH2-; -CH2-A-CH2-CH2-B-CH2-; -CH2-A-CH2-CH2-CH2-B-; or -CH2-CH2-A-CH2-CH2-B-;
A and B independently represent -O-; -S-; -SO-; -SO2-; U represents aryl; heteroaryl;
T represents -CONR1-; -(CH2)POCO-; -(CH2JpNCR^CO-; -(CH2)PN(RI)SO2-; or -COO-;
Q represents lower alkylene; lower alkenylene;

M represents aryl-O(CH2)vR7; heteroaryl-O(CH2)vR7; aryl-O(CH2)vO(CH2)wR7;
heteroaryl-(CH2)vO(CH2)wR7; aryl-OCHsCHCR^CEbR5; heteroaryl-
OCH2CH(R6)CH2R5;
L represents -R3; -COR3; -COOR3; -CONR2R3; -SO2R3; -SO2NR2R3; -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; cycloalkyl; cycloalkyl - lower alkyl;
i
R 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, -CONR2R2\ -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 sp3-hybridized;
R4 and R4f independently represents hydrogen; lower alkyl; cycloalkyl; cycloalkyl - lower alkyl; hydroxy - lower alkyl; -COOR2; -CONH2;
R5 represents -OH, lower alkoxy, -OCOR2, -COOR2, -NR2Rr, -OCONR2R2\ -NCONR2R2% cyano, -CONR2R2f, SO3H, -SONR2R2', -CO-morphoIin-4-yl, -CO-((4-loweralkyI)piperazin-l-yl), -NH(NH)NH2, -NR^4', with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;

R6 represents -OH, OR2; OCOR2; OCOOR2; or R6 and R5 form together with the carbon atoms to which they are attached a 1,3-dioxolane ring which is substituted in position 2 with R2 and R2'; or R6 and R5 form together with the carbon atoms to which they are attached a l,3-dioxolan-2-one ring;
R7 represents lower alkoxy;
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 1, rn is the integer 0;
p is the integer 1,2, 3 or 4; r is the integer 3,4, 5, or 6; s is the integer 2, 3,4, or 5; t is the integer 1,2, 3, or 4; u is the integer 1,2, or 3; v is the integer 1,2, 3, or 4; w is the integer 1 or 2; z is the integer 0 or 1;
and optically pure enantiomers, mixtures of enantiomers such as racemates, 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.
2. Compounds of general formula I wherein X, W, V, U, T, Q, L, and M are as defined in general formula I and
zis 1 nisO mis 1,

and optically pure enantiomers, mixtures of enantiomers such as racemates, 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.
3. Compounds of general formula I wherein X, W, V, U, T, Q, M, m, and n are as
defined in general formula I and
zis 1
L represents -COR3"; -COOR3"; -CONR2"R3";
R2fl and R3?t represent independently lower alkyl; lower cycloalkyl - lower alkyl, which lower alkyl and lower cycloalkyl-lower alkyl are undubstituted or mono-substituted with halogen, -CN, -OH, -OCOCH3, -CONH2,-COOH, or -NH2, with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized,
and optically pure enantiomers, mixtures of enantiomers such as racemates, 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.
4. Compounds of general formula I wherein X, W, V, U, L, m, n, and z are as
defined in general formula I and
T represents -CONR1-;
Q represents methylene;
M represents aryl-O(CH2)vR7; heteroaryl-O(CH2)vR7; aryl-OCH2CH(R6)CH2R5;
heteroaryl-OCH^HCR^CH^5;
and optically pure enantiomers, mixtures of enantiomers such as racemates, 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.
5. Compounds of general formula I wherein X, W, U, L, T, Q, M, m, n, and z are
as defined in general formula I and
V represents -CH2CH2O-; -CH2CH2CH2O-; -OCH2CH20;
and optically pure enantiomers, mixtures of enantiomears such as racemates, 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.
6. Compounds of general formula I wherein V, U, T, Q, M, L, m, n, and z are as
defined in general formula I and
X and W represent a -CH- group
and optically pure enantiomers, mixtures of enantiomers such as racemates, 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.
7. Compounds of general formula I wherein X, W, V, Q, T, M, L, m, n, and z are
as defined in general formula I and
U is a mono-, di-, or trisubstituted phenyl whereby the substituents are halogen; lower alkyl or lower alkoxy
and optically pure enantiomers, mixtures of enantiomers such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of

diastereomeric racemates, and the meso-form; as well as pharmaceuticaUy acceptable salts, solvent complexes and morphological forms.
8. Compounds according to claim 1 of general formula I, wherein
X and W represent a -CH- group;
V represents -A-(CH2)s -;
A represents -O- ;
U represents phenyl, trisubstituted with halogen;
T represents - CONR1-;
Q represents C1-C4 alkyl;
M represents phenyl - O - (CH2)v R7 or pyridyl- O - (CH2)v R7;
L represents R3;
R1 represents cycloalkyl;
R3 represents hydrogen, C1-C4 alkyl;
R7 represents C1-C4 alkoxy;
m represents the integer 1;
n represents the integer 0;
z represents the integer 1;
s represents the integer 3;
v represents the integer 2 ;
and optically pure enantiomers, mixtures of enantiomers such as racemates,
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.
9. Compounds according to claiml of general formula I, wherein
X and W represent a -CH- group;
V represents -O-CH2-CH2 -CH2-;
U represents phenyl, trisubstituted independently with Fluoro and Chloro; T represents - CONR1-; Q represents - CH2-;

M represents phenyl - O - (CH2)v R7 or pyridyl- O - (CH2)v R7;
L represents R3;
R1 represents cyclopropyl;
R represents hydrogen;
R7 represents methoxy;
m represents the integer 1;
n represents the integer 0;
z represents the integer 1;
s represents the integer 3;
v represents the integer 2 ;
and optically pure enantiomers, mixtures of enantiomers such as racemates,
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.
10. The compounds according to any one of claims 1-9 selected from the group
consisting of
(rac.)-(ii?*, JiS'*)-7-{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-[2-(2-methoxy-ethoxy)-3-methylpyridin-4-ylniethyl]amide3 and
(rac.)-(lR*, 5iS'*)-7»{4-[3-(2-chloro-3,6-difluorophenoxy)propyl]phenyl}-3,9-diazabicyclo[3.3.1]non-6-ene-6-carboxylic acid cyclopropyl-[3-(2-methoxy-ethoxy)-2-methylbenzyl]amide.
11. Pharmaceutical compositions containing at least one compound of any one of
claims 1-10 and usual carrier materials and adjuvants for the treatment or
prophylaxis of disorders which are associated with a dysregulation of the renin-
angiotensin system (RAS), comprising cardiovascular and renal diseases
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 immunosuppressive agents after organ transplantation, and other diseases known to be related to the RAS.
12. A method for the treatment or prophylaxis of diseases which are related to the
RAS comprising 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 immunosuppressive agents after organ
transplantation, and other diseases which are related to the RAS, which method
comprises administrating a compound according to any one of claims 1 to 10 to a
human being or animal.
13. The use of compounds according to any one of claims 1 to 10 for the
treatment or prophylaxis of diseases which are associated with the RAS
comprising 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 immunosuppressive agents after organ
transplantation, and other diseases known to be related to the RAS.
14. The use of one or more compounds of any one of claims 1 to 10 in combination with other pharmacologically active compounds comprising ACE inhibitors, angiotensin II receptor antagonists, endothelin receptor antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholitics, beta-adrenergic antagonists, alpha-adrenergic antagonists, for the treatment of disorders as set forth in any one of claims 11 to 13.
Dated this 5 day of July 2006