WO2004096116A2 - Diazabicyclononene derivatives - Google Patents
Diazabicyclononene derivatives Download PDFInfo
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- WO2004096116A2 WO2004096116A2 PCT/EP2004/004372 EP2004004372W WO2004096116A2 WO 2004096116 A2 WO2004096116 A2 WO 2004096116A2 EP 2004004372 W EP2004004372 W EP 2004004372W WO 2004096116 A2 WO2004096116 A2 WO 2004096116A2
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
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- A61P3/00—Drugs for disorders of the metabolism
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- 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.
- these compounds can be regarded as inhibitors 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.
- renin-angiotensin II 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 ATl and AT2- Whereas ATi seems to transmit most of the known functions of Ang II, the role of AT2 is still unknown.
- ACE inhibitors and ATl 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).
- ACE inhibitors are used for renal protection (Rosenberg M. E. et al, Kidney International, 1994, 45, 403; Breyer J. A.
- renin inhibitors 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.
- ACE can also cleave bradykinin besides Ang I and can be bypassed by chymase, a serine protease (Husain A., J. Hypertens., 1993, 11, 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%)) (Konili Z. H.
- 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.
- 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.
- the present invention describes non-peptidic renin inhibitors.
- the present invention relates to novel compounds of the general formula I,
- W is a six-membered, non benzofused, phenyl or heteroaryl ring, substituted by V in meta ox para position;
- V represents -O-CH 2 -CH(OCH 3 )-CH 2 -O-; -O-CH 2 -CH(CH 3 )-CH 2 -O-; -O-CH 2 - CH(CF 3 )-CH 2 -O-; -O-CH 2 -C(CH 3 ) 2 -CH 2 -O-; -O-CH 2 -C(CH 3 ) 2 -O-; -O-C(CH 3 ) 2 - CH 2 -O-; -O-CH 2 -CH(CH 3 )-O-; -O-CH(CH 3 )-CH 2 -O-; -O-CH 2 -C(CH 2 CH 2 )-O-; O-C(CH 2 CH 2 )-CH 2 -O-;
- U represents aryl; heteroaryl;
- T represents -CONR 1 -; -(CH 2 ) p OCO-; -(CH 2 ) p N(R')CO-; -(CH 2 ) p N(R 1 )SO 2 -; or -COO-;
- Q represents lower alkylene; lower alkenylene;
- M represents hydrogen; cycloalkyl; aryl; heterocyclyl; heteroaryl;
- L represents -R 3 ; -COR 3 ; -COOR 3 ; -CONR 2 R 3 ; -SO 2 R 3 ; -SO 2 NR 2 R 3 ; -COCH(Aryl) 2 ;
- R 1 represents hydrogen; lower alkyl; lower alkenyl; lower alkinyl; cycloalkyl; aryl; cycloalkyl - lower alkyl;
- R and R ' independently represent hydrogen; lower alkyl; lower alkenyl; cycloalkyl; cycloalkyl - lower alkyl;
- R 3 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, -OCOR 2 , -COOR 2 , lower alkoxy, cyano, -CONR 2 R 2 ', -CO-morpholin-4- yl, -CO-((4-loweralkyl)piperazin-l-yl), -NH(NH)NH 2 , -NR 4 R 4 ' 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
- R 4 and R 4 * independently represent hydrogen; lower alkyl; cycloalkyl; cycloalkyl lower alkyl; hydroxy - lower alkyl; -COOR 2 ; -CONH 2 ; k is the integer 0 or 1 ;
- n 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; in case k represents the integer 0, n represents the integer 0;
- p is the integer 1, 2, 3 or 4;
- 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.
- lower alkyl 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.
- 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.
- lower alkoxy refers to a R-O group, wherein R is a lower alkyl.
- R is a lower alkyl.
- lower alkoxy groups are methoxy, ethoxy, propoxy, iso-propoxy, iso- butoxy, sec-butoxy and tert-butoxy.
- 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.
- lower alkenyl are vinyl, propenyl or butenyl.
- 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.
- lower alkinyl are ethinyl, propinyl or butinyl.
- 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.
- 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.
- 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.
- 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.
- halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.
- 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, -CF 3 , -NR ⁇ 1 ', -NR 1 C(O)R 1 ', -NR 1 S(O 2 )R 1, 5 -C(O)NR 1 R 1 ', lower alkylcarbonyl, -COOR 1 , -SR 1 , -SOR 1 , -SO 2 R 1 , -SO2NR 1 R 1 ' whereby R 1 ' represents hydrogen; lower alkyl; lower alkenyl; lower al
- 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, -CF 3 , -OCF 3 , -NR ⁇ R 1 ', -NR ⁇ - lower alkyl, -NR 1 C(O)R 1 ', -C(O)NR 1 R 1 ', -NO 2 , lower alkylcarbonyl, -COOR 1 , -SR 1 , -SOR 1 , -SO 2 R 1 , -SO 2 NR 1 ,
- aryloxy refers to an Ar-O group, wherein Ar is an aryl.
- An example of a lower aryloxy group is phenoxy.
- 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 -COOR 2 group.
- rings are piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1 ,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, imidazolidinyl, dihydropyrazolyl, pyrazolidinyl, dihydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl.
- 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 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, -CF 3 , -OCF 3 , -NR'R 1 ', -NR'R 1 ' - lower alkyl, -NflR ⁇ COR 1 , -NOR ⁇ SOaR 1 , -CONR'R 1 ', -NO 2 , lower alkylcarbonyl, -COOR 1 , -SR 1 , -SOR 1 , -SO 2 R 1 , -SO 2 NR I R 1 ', another aryl, another heteroaryl or another heterocyclyl and the like, whereby R 1 ' has the meaning given above.
- heteroaryloxy refers to a Het-O group, wherein Het is a heteroaryl.
- 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.
- 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.
- 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
- nitrosated compounds of the general formula I that have been nitrosated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulffiydryl condensation) and/or 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 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.
- 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 W, V, U, T, Q, L, and M are as defined in general formula I above and wherein
- k 1 n is 0 and m is 1.
- Another group of preferred compounds of general formula I are those wherein W, V, U, T, Q, M, k, m, and n are as defined in general formula I above and
- L represents H; -COR 3 "; -COOR 3 "; -CONR 2 "R 3 "; whereby R 2 " and R 3 " 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, -OCOCH 3 , -CONH 2 , -COOH, -NH 2 , with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3 -hybridized.
- T is -CONR 1 -;
- M is aryl, heteroaryl.
- V represents -O-CH 2 -CH(CH 3 )-CH 2 -O-; -O-CH 2 -C(CH 3 ) 2 -CH 2 -O- .
- 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.
- U is a mono-, di-, or trisubstituted phenyl or heteroaryl, wherein the substituents are halogen, lower alkyl, lower alkoxy, CF 3 .
- substituents are halogen, lower alkyl, lower alkoxy, CF 3 .
- Especially preferred compounds of general formula I are:
- 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 treatment or prophylaxis of disorders which are associated with a dysregulation of the renin angiotensin system (RAS), comprising cardiovascular and renal diseases.
- RAS renin angiotensin system
- 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 stent angioplasty, to treat erectile dysfunction, glomerulonephritis, renal colic, and glaucoma.
- 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 RAS, which method comprises administering a compound according of formula I to a human being or animal.
- 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
- 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.
- 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,
- 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, coronary diseases, cardiac insufficiency, renal insufficiency, renal and myocardial ischemia, and renal failure.
- diseases which are associated with the RAS such as hypertension, coronary 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 antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholitics, beta-adrenergic antagonists, alpha-adrenergic antagonists, and neutral endopeptidase inhibitors, for the treatment of disorders as above- mentioned.
- other pharmacologically active compounds e. g. with other renin inhibitors, with ACE-inhibitors, angiotensin II receptor antagonists, endothelin receptor antagonists, vasodilators, calcium antagonists, potassium activators, diuretics, sympatholitics, beta-adrenergic antagonists, alpha-adrenergic antagonists, and neutral endopeptidase inhibitors, for the treatment of disorders as above- mentioned.
- 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.
- 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 WO 04/002957.
- the linkers included under V in general foraiula 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 Al 20000420, 2000; Vogel, G.; et al; Chemistry and Physics ofLipids, 1990, 52, 99; Seebach, D.; et al; Helv. Chim.
- Ada 1986, 69, 1147
- (R)- or (S)-3- hydroxy-2-(rrifluoromethyl)propionic acid (Goetzoe, S. P.; et al.; Chimia, 1996, 50, 20).
- 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 steps, coupling steps with a phenol derivative, a hydroxyhetero cycle, a hydroxycycloalkyl, or a hydroxyheteroaryl (typically via a Mitsunobu coupling), reductive steps, and/or deprotection steps.
- a compound of type A can be prepared from one of the here above mentionned compound, whereas the R a - and R -groups are as defined in general formula I (or precursors to such a group), and COOR 0 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.
- the protecting 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 N.
- 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 forai 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.
- compositions can be effected in a manner which 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 carrier materials.
- lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated 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 paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
- 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.
- 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 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.
- 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 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 MgSO 4 , filtered, and the solvents were removed under reduced pressure. Purification by FC (heptane/EtOAc 20/80) yielded the title compound (0.28 g, 89%).
- the bicyclononene L (0.11 g, 0.11 mmol) was dissolved in THF (3 mL) and 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.
- 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 and 0.1% BSA.
- the incubates were composed of 50 ⁇ L per well of an enzyme mix and 2.5 ⁇ 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(l-14) (0.5 ⁇ M) • hydroxyquinoline sulfate (1 mM) The mixtures were then incubated at 37°C for 3 h.
- the accumulated Ang I was detected by an enzyme immunoassay (EIA) in 384-well plates (Nunc). 5 ⁇ L of the incubates or standards were transferred to immuno plates which were previously 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%o 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).
- EIA enzyme immunoassay
- 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 was detemained that inhibited the enzyme activity by 50% (IC 50 ). The IC 50 -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.
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/555,382 US20060223795A1 (en) | 2003-05-02 | 2004-04-26 | Novel diazabicyclononene derivatives |
BRPI0409882-0A BRPI0409882A (en) | 2003-05-02 | 2004-04-26 | compounds, pharmaceutical compositions, method for the treatment or prophylaxis of diseases, and uses of compounds and one or more compounds in combination with other pharmacologically active compounds |
EP04729414A EP1622564A2 (en) | 2003-05-02 | 2004-04-26 | Diazabicyclononene derivatives |
JP2006505261A JP2006525259A (en) | 2003-05-02 | 2004-04-26 | New diazabicyclononene derivatives |
AU2004233577A AU2004233577A1 (en) | 2003-05-02 | 2004-04-26 | Diazabicyclononene derivatives |
MXPA05011711A MXPA05011711A (en) | 2003-05-02 | 2004-04-26 | Diazabicyclononene derivatives. |
CA002521898A CA2521898A1 (en) | 2003-05-02 | 2004-04-26 | Diazabicyclononene derivatives |
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EP0304622 | 2003-05-02 | ||
EPPCT/EP03/04622 | 2003-05-02 |
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WO2004096116A2 true WO2004096116A2 (en) | 2004-11-11 |
WO2004096116A3 WO2004096116A3 (en) | 2005-03-24 |
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PCT/EP2004/004372 WO2004096116A2 (en) | 2003-05-02 | 2004-04-26 | Diazabicyclononene derivatives |
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EP (1) | EP1622564A2 (en) |
JP (1) | JP2006525259A (en) |
KR (1) | KR20060015573A (en) |
CN (1) | CN1780838A (en) |
AU (1) | AU2004233577A1 (en) |
BR (1) | BRPI0409882A (en) |
CA (1) | CA2521898A1 (en) |
MX (1) | MXPA05011711A (en) |
RU (1) | RU2005137571A (en) |
WO (1) | WO2004096116A2 (en) |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005040165A1 (en) * | 2003-10-13 | 2005-05-06 | Actelion Pharmaceuticals Ltd | Diazabicyclononene derivatives and their use as renin inhibitors |
WO2005040173A1 (en) * | 2003-10-23 | 2005-05-06 | Actelion Pharmaceuticals Ltd | Diazabicyclononene and tetrahydropyridine derivatives as renin inhibitors |
WO2005054244A2 (en) * | 2003-12-05 | 2005-06-16 | Actelion Pharmaceuticals Ltd | Azabicyclooctene and other tetrahydropyridine derivatives with a new side-chain |
WO2006021403A1 (en) * | 2004-08-25 | 2006-03-02 | Actelion Pharmaceuticals Ltd | Bicyclononene derivatives |
WO2006058546A1 (en) * | 2004-12-01 | 2006-06-08 | Actelion Pharmaceuticals Ltd | Novel lactame derivatives as renin inhibitors |
WO2006064484A1 (en) * | 2004-12-17 | 2006-06-22 | Actelion Pharmaceuticals Ltd | Azabicyclononene derivatives as renin inhibitors |
WO2006079988A1 (en) * | 2005-01-28 | 2006-08-03 | Actelion Pharmaceuticals Ltd | 7- {4- [2- (2 , 6-dichl0r0-4-methylphen0xy) ethoxy] phenyl}-3 , 9-diazabicyclo [3 .3 . 31] non - 6-ene- s- carboxylic acid cyclopropyl- (2 , 3-dimethylbenzyd amide as inhibitors of renin for the treatment of hypertension |
WO2006131884A2 (en) * | 2005-06-07 | 2006-12-14 | Actelion Pharmaceuticals Ltd | Thiazole substituted diazabicyclononane or-nonene derivatives as renin inhibitors |
WO2007104652A2 (en) * | 2006-03-16 | 2007-09-20 | Nicox S.A. | Non-peptidic renin inhibitors nitroderivatives |
US8084450B2 (en) | 2004-12-30 | 2011-12-27 | Novartis Ag | Organic compounds |
US8129411B2 (en) | 2005-12-30 | 2012-03-06 | Novartis Ag | Organic compounds |
US8138340B2 (en) | 2004-08-25 | 2012-03-20 | Actelion Pharmaceuticals Ltd. | Bicyclononene derivatives |
US8163773B2 (en) | 2005-07-11 | 2012-04-24 | Novartis Ag | Organic compounds |
US8334308B2 (en) | 2007-08-20 | 2012-12-18 | Merck Sharp & Dohme Corp. | Renin inhibitors |
US8343968B2 (en) | 2007-05-24 | 2013-01-01 | Merck Canada Inc. | Case of renin inhibitors |
US8383650B2 (en) | 2007-06-25 | 2013-02-26 | Novartis Ag | Organic compounds |
WO2013038936A1 (en) * | 2011-09-13 | 2013-03-21 | タカラバイオ株式会社 | Method for terminating peroxidase reaction, and terminating agent for said reaction |
US8889714B2 (en) | 2008-05-05 | 2014-11-18 | Actelion Pharmaceuticals Ltd. | 3,4-substituted piperidine derivatives as renin inhibitors |
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WO2004002957A1 (en) * | 2002-06-27 | 2004-01-08 | Actelion Pharmaceuticals Ltd | Novel tetrahydropyridine derivatives as renin inhibitors |
-
2004
- 2004-04-26 CN CNA2004800116500A patent/CN1780838A/en active Pending
- 2004-04-26 EP EP04729414A patent/EP1622564A2/en not_active Withdrawn
- 2004-04-26 BR BRPI0409882-0A patent/BRPI0409882A/en not_active Application Discontinuation
- 2004-04-26 KR KR1020057020788A patent/KR20060015573A/en not_active Application Discontinuation
- 2004-04-26 RU RU2005137571/04A patent/RU2005137571A/en not_active Application Discontinuation
- 2004-04-26 WO PCT/EP2004/004372 patent/WO2004096116A2/en active Application Filing
- 2004-04-26 MX MXPA05011711A patent/MXPA05011711A/en not_active Application Discontinuation
- 2004-04-26 AU AU2004233577A patent/AU2004233577A1/en not_active Abandoned
- 2004-04-26 CA CA002521898A patent/CA2521898A1/en not_active Abandoned
- 2004-04-26 JP JP2006505261A patent/JP2006525259A/en active Pending
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WO1997009311A1 (en) * | 1995-09-07 | 1997-03-13 | F. Hoffmann-La Roche Ag | New 4-(oxyalkoxyphenyl)-3-oxy-piperidines for treating heart and kidney insufficiency |
WO2003093267A1 (en) * | 2002-04-29 | 2003-11-13 | Actelion Pharmaceuticals Ltd | 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene derivatives and their use as renin inhibitors in the treatment of hypertension, cardiovascular or renal diseases |
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EL-ABBADY S A ET AL: "ENHANCED REACTIVITY OF PYRIDIN-3-OL TOWARDS 4-PHENYL-1,2,4-TRIAZOLINE 3,5-DIONE: FMO TREATMENT OF THE CYCLOADDITION PROCESS BY ASED-MO CALCULATIONS METHOD" ZAGAZIG JOURNAL OF PHARMACEUTICAL SCIENCES, FACULTY OF PHARMACY ZAGAZIG UNIVERSITY, CAIRO, EG, vol. 5, no. 1, June 1996 (1996-06), pages 68-74, XP001154254 ISSN: 1110-5089 * |
Cited By (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005040165A1 (en) * | 2003-10-13 | 2005-05-06 | Actelion Pharmaceuticals Ltd | Diazabicyclononene derivatives and their use as renin inhibitors |
WO2005040173A1 (en) * | 2003-10-23 | 2005-05-06 | Actelion Pharmaceuticals Ltd | Diazabicyclononene and tetrahydropyridine derivatives as renin inhibitors |
WO2005054244A2 (en) * | 2003-12-05 | 2005-06-16 | Actelion Pharmaceuticals Ltd | Azabicyclooctene and other tetrahydropyridine derivatives with a new side-chain |
WO2005054244A3 (en) * | 2003-12-05 | 2005-08-04 | Actelion Pharmaceuticals Ltd | Azabicyclooctene and other tetrahydropyridine derivatives with a new side-chain |
WO2006021403A1 (en) * | 2004-08-25 | 2006-03-02 | Actelion Pharmaceuticals Ltd | Bicyclononene derivatives |
US8138340B2 (en) | 2004-08-25 | 2012-03-20 | Actelion Pharmaceuticals Ltd. | Bicyclononene derivatives |
WO2006059304A2 (en) * | 2004-12-01 | 2006-06-08 | Actelion Pharmaceuticals Ltd | Novel lactame derivatives as renin inhibitors |
WO2006058546A1 (en) * | 2004-12-01 | 2006-06-08 | Actelion Pharmaceuticals Ltd | Novel lactame derivatives as renin inhibitors |
WO2006059304A3 (en) * | 2004-12-01 | 2006-10-12 | Actelion Pharmaceuticals Ltd | Novel lactame derivatives as renin inhibitors |
WO2006063610A1 (en) * | 2004-12-17 | 2006-06-22 | Actelion Pharmaceuticals Ltd | Heteroaryl substituted diazabicyclononene derivatives |
WO2006064484A1 (en) * | 2004-12-17 | 2006-06-22 | Actelion Pharmaceuticals Ltd | Azabicyclononene derivatives as renin inhibitors |
US8178559B2 (en) | 2004-12-30 | 2012-05-15 | Novartis Ag | Organic compounds |
US8084450B2 (en) | 2004-12-30 | 2011-12-27 | Novartis Ag | Organic compounds |
WO2006079988A1 (en) * | 2005-01-28 | 2006-08-03 | Actelion Pharmaceuticals Ltd | 7- {4- [2- (2 , 6-dichl0r0-4-methylphen0xy) ethoxy] phenyl}-3 , 9-diazabicyclo [3 .3 . 31] non - 6-ene- s- carboxylic acid cyclopropyl- (2 , 3-dimethylbenzyd amide as inhibitors of renin for the treatment of hypertension |
US7915259B2 (en) | 2005-01-28 | 2011-03-29 | Actelion Pharmaceuticals Ltd. | Diazabicyclononene derivatives and use thereof |
WO2006131884A2 (en) * | 2005-06-07 | 2006-12-14 | Actelion Pharmaceuticals Ltd | Thiazole substituted diazabicyclononane or-nonene derivatives as renin inhibitors |
WO2006131884A3 (en) * | 2005-06-07 | 2007-03-15 | Actelion Pharmaceuticals Ltd | Thiazole substituted diazabicyclononane or-nonene derivatives as renin inhibitors |
US8163773B2 (en) | 2005-07-11 | 2012-04-24 | Novartis Ag | Organic compounds |
US8129411B2 (en) | 2005-12-30 | 2012-03-06 | Novartis Ag | Organic compounds |
WO2007104652A3 (en) * | 2006-03-16 | 2008-01-10 | Nicox Sa | Non-peptidic renin inhibitors nitroderivatives |
WO2007104652A2 (en) * | 2006-03-16 | 2007-09-20 | Nicox S.A. | Non-peptidic renin inhibitors nitroderivatives |
US8343968B2 (en) | 2007-05-24 | 2013-01-01 | Merck Canada Inc. | Case of renin inhibitors |
US8383650B2 (en) | 2007-06-25 | 2013-02-26 | Novartis Ag | Organic compounds |
US8497286B2 (en) | 2007-06-25 | 2013-07-30 | Novartis Ag | Organic compounds |
US8334308B2 (en) | 2007-08-20 | 2012-12-18 | Merck Sharp & Dohme Corp. | Renin inhibitors |
US8889714B2 (en) | 2008-05-05 | 2014-11-18 | Actelion Pharmaceuticals Ltd. | 3,4-substituted piperidine derivatives as renin inhibitors |
WO2013038936A1 (en) * | 2011-09-13 | 2013-03-21 | タカラバイオ株式会社 | Method for terminating peroxidase reaction, and terminating agent for said reaction |
Also Published As
Publication number | Publication date |
---|---|
JP2006525259A (en) | 2006-11-09 |
CA2521898A1 (en) | 2004-11-11 |
BRPI0409882A (en) | 2006-05-23 |
RU2005137571A (en) | 2006-05-10 |
KR20060015573A (en) | 2006-02-17 |
EP1622564A2 (en) | 2006-02-08 |
AU2004233577A1 (en) | 2004-11-11 |
WO2004096116A3 (en) | 2005-03-24 |
CN1780838A (en) | 2006-05-31 |
MXPA05011711A (en) | 2006-01-23 |
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