EP1622906A1 - Derives de diazabicyclononene et de tetrahydropyridine utilises comme inhibiteurs de la renine - Google Patents

Derives de diazabicyclononene et de tetrahydropyridine utilises comme inhibiteurs de la renine

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Publication number
EP1622906A1
EP1622906A1 EP04729415A EP04729415A EP1622906A1 EP 1622906 A1 EP1622906 A1 EP 1622906A1 EP 04729415 A EP04729415 A EP 04729415A EP 04729415 A EP04729415 A EP 04729415A EP 1622906 A1 EP1622906 A1 EP 1622906A1
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European Patent Office
Prior art keywords
ene
rac
phenyl
carboxylic acid
acetyl
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EP04729415A
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German (de)
English (en)
Inventor
Olivier Bezencon
Daniel Bur
Walter Fischli
Lubos Remen
Sylvia Richard-Bildstein
Thomas Weller
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Actelion Pharmaceuticals Ltd
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Actelion Pharmaceuticals Ltd
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Priority to EP04729415A priority Critical patent/EP1622906A1/fr
Priority claimed from PCT/EP2004/004373 external-priority patent/WO2004096804A1/fr
Publication of EP1622906A1 publication Critical patent/EP1622906A1/fr
Withdrawn legal-status Critical Current

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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 ATi 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 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).
  • 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 ATi 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,
  • Z, Y, X and W represent independently a nitrogen atom or a -CH- group; at least two of the Z, Y, X and W represent a -CH- group;
  • V represents a bond; -(CH 2 ) r ; -A-(CH 2 ) S -; -CH 2 -A-(CH 2 ) r ; -(CH 2 ) S -A-; -(CH 2 ) 2 -
  • a and B independently represent -O-; -S-; -SO-; -SO 2 -;
  • U represents aryl; heteroaryl;
  • T represents -CONR 1 -; -(CH 2 ) p OCO-; -(CH 2 ) p N(R 1 )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 2 and R 2 ' 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
  • k is the integer 0 or 1 ;
  • n represents the integer 0 or 1, with the proviso that in case m represents the integer 1, n is the integer 0; in case n represents the integer 1, m is the integer 0; in case k represents the integer 0, n represents the integer 0;
  • 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 and isopropyl groups are preferred.
  • lower alkoxy refers to a R-O-group, wherein 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.
  • Examples of 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'R 1 ', -NR 1 C(O)R 1 ', - 1 S(O 2 )R 1 ', -C(O)NR 1 R 1 ', lower alkylcarbonyl, -COOR 1 , -SR 1 , -SOR 1 , -SO 2 R', -SO 2 NR l R'' whereby R 1 ' represents hydrogen; lower alkyl; lower alkenyl,
  • 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'R 1 ' - lower alkyl, -NR 1 C(O)R 1 ', -NR 1 S(O 2 )R 1 , -NO 2 , lower alkylcarbonyl, -COOR 1 , -SR 1 , -SOR 1 , -S0 2 R', -COOR
  • 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 l R l ⁇ -NR'R 1 ' - lower alkyl, -N ⁇ COR 1 , -N(R')SO 2 R', -CONR'R 1 ', -NO 2 , lower alkylcarbonyl, -COOR 1 , -SR 1 , -SOR 1 , -SO 2 R', -SO ⁇ R'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.
  • 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.
  • 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.
  • 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 Z, Y, X, W, V, U, T, Q, L, and M are as defined in general formula I above and wherein
  • Another group of preferred compounds of general formula I are those wherein Z, Y, X, 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 ";
  • 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 or -NH , 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 Z, Y, X, W, V, U, L, k, m, and n are as defined in general formula I and
  • 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
  • Z, Y, X and W represent -CH-
  • Another group of also more preferred compounds of general formula I are those wherein Z, Y, X, 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, CF 3 .
  • Especially preferred compounds of general formula I are those selected from the group consisting of:
  • 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 in 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, congestive heart failure, pulmonary heart failure, coronary diseases, cardiac insufficiency, renal insufficiency, renal or myocardial ischemia, atherosclerosis, 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. Furthermore, they can be used in the therapy and the prophylaxis of diabetic complications, complications after vascular or cardiac surgery, complications of treatment with immunosuppresive agents after organ transplantation, complications of cyclosporin treatment, as well as other diseases presently known to be related to the RAS.
  • the invention relates to a method for the treatment and/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 administering a compound according to general 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 disorders which are associated with the Renin Angiotensin System (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.
  • RAS Renin Angiotensin System
  • 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.
  • the compounds of formula I may also be used in combination with one or more 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, and neutral endopeptidase inhibitors, for the treatment of the above-mentioned diseases or disorders.
  • ACE inhibitors angiotensin II receptor antagonists
  • endothelin receptor antagonists vasodilators
  • calcium antagonists potassium activators
  • diuretics sympatholitics
  • beta- adrenergic antagonists beta- adrenergic antagonists
  • alpha-adrenergic antagonists alpha-adrenergic antagonists
  • neutral endopeptidase inhibitors for the treatment of the above-mentioned diseases or disorders.
  • Precursors are compounds which were prepared as key intermediates and/or building blocks and which were suitable for further transformations in parallel chemistry.
  • Bicyclononanone A was prepared from (4-benzyl-6-ethoxycarbonylmethyl-l- methylpiperazin-2-yl)acetic acid ethyl ester (Patent Application WO92/05174) as described in Scheme 1. Derivative A might also be present as enol form. In order to allow a coupling at the 7-position of bicyclononane A with aryl bromides, the vinyl triflate derivative B was prepared.
  • Compound B can be then transformed into compounds of type C by a Negishi coupling (Scheme 2), whereas R b represents a side chain precursor suitable to construct the V-U-chain through one or several elementary chemical transformations.
  • the R b -substituent can be modified during the synthesis.
  • L 1 -substituent can be put in place (compounds of type E), whereas L 1 represents a substituent L as defined in general formula I, or a precursor of such a substituent.
  • the ester functional group can be saponified to compounds of type F. After an amide coupling for instance precursors of type G can be obtained.
  • heterocyclic systems may be prepared according to the literature existing for similar compounds.
  • pyridine derivative H could be prepared from 2,6-dibromopyridine, wherein R a is a substituent that may be easily transformed into a chain U-V as described in Formula I (Scheme 3; Bitman, R., et al.; J. Org. Chem., 2000, 65, 7634).
  • Pyridine J could be prepared by addition of a Grignard reagent on 4-bromopyridine, followed by oxidation (see Comins, D.; et al.; J. Org. Chem., 1985, 50, 4410). From known 3,5-dibromopyridine a compound of type K could be prepared.
  • pyridines of type L could be prepared from commercially available 2-(pyridin-4-yl)-alcohol, according to the literature described for similar compounds (Taylor, S. L.; et. al.; J. Org. Chem., 1983, 48, 4156).
  • a palladium-catalized coupling of 2,4-dibromopyrimidine with bicyclononene B could lead to an intermediate of type T, which could be transformed into an intermediate of type U (Scheme 6).
  • 6-Chloropyrazin-2-ylamine could be transformed in several steps into a pyrazine of type V (see Ghosh, A. K.; et al.; J. Med. Chem., 1993, 36, 2300 or Jovanovic, M. V., Heterocycles, 1983, 20, 2011, or Hartman, G. D.; et al.; J. Heteroclyclic Chem.; 1983, 20, 1089).
  • Pyrimidines of type W could be prepared according to standard procedures.
  • a compounds of type X can be prepared from 4,6-dichloropyrimidine.
  • X Pyridazinyl derivatives may be prepared as described in Scheme 7.
  • 2-pyridazin-3-ylethanol Y Rodriguez, L.; et al; Synlett, 1990, 227) could be transformed into a pyridazinyl derivative Z following known chemistry (Sauer, J.; et al; Tetrahedron, 1998, 54, 4297).
  • Known 6-bromo-pyridazine-4-carboxylic acid ethyl ester AA Dulayyi, A.; et al; Tetrahedron, 1998, 54, 12897; Barlin, G. B.; et al; Australian J.
  • Precursors G were transformed into the corresponding aryl ethers (Scheme 8), using the Mitsunobu reaction conditions. After deprotection, the final compounds are obtained.
  • 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.
  • 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 polyols (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.
  • the compounds were characterized at least by LC-MS and ' H-NMR. Only the LC-MS data are given here.
  • EDCHC1 Ethyl-N N-dimethylaminopropylcarbodiimide hydrochloride
  • BuLi (1.6M in hexane, 19.2 mL, 30.7 mmol) was added to a sol. of [2-(4-bromo- phenoxy)ethoxy]-tert-butyldimethylsilane (9.40 g, 28.4 mmol, Morita, C; et al, Heterocycles, 2000, 52, 1 163) in THF (55 mL) at -78 °C. The mixture was stirred for 30 min at this temperature, and ZnCl 2 (IM in THF, prepared from ZnCl 2 dried at 160 °C for 3 h and THF, 35.5 mL, 35.5 mmol) was added. The mixture was allowed to warm to rt and a sol.
  • the precursor (0.05 mmol) was dissolved or suspended in toluene (1.00 mL).
  • the phenol derivative (0.075 mmol) in toluene (0.50 mL) was added.
  • TMAD (0.075 mmol) in toluene (0.50 mL) was added, followed by tributylphosphine (0.15 mmol).
  • the reaction mixture was stirred for 2 h at rt and then 2 h at 60 °C. Sometimes, it was necessary to add a second portion of tributylphosphine and to stir overnight. Sometimes, THF was necessary as cosolvent to dissolve the reactants.
  • the reaction mixture was allowed to cool to rt, then water was added.
  • the mixture was extracted with EtOAc, and the org. extracts were evaporated under reduced pressure.
  • 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)
  • 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 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 was determined that inhibited the enzyme activity by 50% (ICs 0 ). The ICso-values of all compounds tested are below 10 ⁇ M.

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Abstract

L'invention concerne des dérivés de 3,9-diazabicyclo[3.3.1]nonène, des dérivés de tétrahydropyridine et des composés relatifs et des utilisations de ceux-ci comme principes actifs dans la préparation de compositions pharmaceutiques. L'invention concerne également des procédés de préparation des composés, des compositions pharmaceutiques renfermant un ou plusieurs composés et, notamment, l'utilisation de ceux-ci comme inhibiteurs de la rénine.
EP04729415A 2003-04-28 2004-04-26 Derives de diazabicyclononene et de tetrahydropyridine utilises comme inhibiteurs de la renine Withdrawn EP1622906A1 (fr)

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EP0304393 2003-04-28
PCT/EP2004/004373 WO2004096804A1 (fr) 2003-04-28 2004-04-26 Derives de diazabicyclononene et de tetrahydropyridine utilises comme inhibiteurs de la renine
EP04729415A EP1622906A1 (fr) 2003-04-28 2004-04-26 Derives de diazabicyclononene et de tetrahydropyridine utilises comme inhibiteurs de la renine

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