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Definitions

• Endothelins are peptides, that exist in three isoforms ET-1, ET-2, and ET-3, each encoded by a distinct gene. They have been originally discovered in the conditioned medium of porcine endothelial cells in 1988 by Yanagisawa (Yanagisawa M; Kurihara H; Kimura S; Tomobe Y; Kobayashi M; Mitsui Y; Yazaki Y; Goto K; Masaki T: A novel potent vasoconstrictor peptide produced by vascular endothelial cells [see comments]. NATURE (1988 Mar 31), 332(6163), 411-5.). The active ETs are peptides of 21 amino acids with two intramolecular disulfide bridges.
• big-ETs are produced from preproproteins of 203 to 212 amino acids which are processed by furin-like endopeptidases to the biologically inactive big-endothelin (big-ET).
• the big-ETs are specifically processed to mature ETs by a hydrolytic cleavage between amino acids 21 and 22 that are Trp 21 -Val 22 (big-ET-1, big ET-2) and Trp 21 -Ile 22 in big-ET-3 respectively.
• Trp 21 -Val 22 big-ET-1, big ET-2
• Trp 21 -Ile 22 in big-ET-3 respectively.
• a specific metalloprotease was postulated to be responsible for this specific cleavage.
• ECE-1 endothelin converting enzyme-1
• bovine adrenal Xu D, Emoto N, Giaid A, Slaughter C, Kaw S, de Witt D, Yanagisawa M: ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1.
• Cell (1994) 78: 473-485) ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1.
• ECE-1 is a membrane bound type II zinc-endopeptidase with a neutral pH optimum and a zinc binding motif HExxHx(>20)E. It belongs to subfamily M13 and has a large 681 amino acid ectodomain that comprises the active site. Other members of the M13 family are NEP24.11 (neutral endopeptidase), PEX, a phosphate regulating neutral endopeptidase, and Kell blood group protein that has recently been described as a big-ET-3 processing enzyme. Members of the M13 family of human origin are characterized by a high molecular weight (>80 kDa) a number of conserved disulfide bridges and a complex glycosylation pattern.
• the structure of NEP has recently been solved. (Oefner et al, J. Mol. Biol. 2000, 296, 341-349).
• the catalytic domain of ECE and related human M13 proteinases are significantly larger (>650 amino acids) than members of matrix metalloproteases (MMPs).
• MMPs matrix metalloproteases
• Unlike the family of the MMPs which belong to the metzincins and display a typical HExxHxxGxxH pattern members of the M13 family are gluzincins comprising a HExxHx(>20)E pattern.
• These two families are clearly different in size of catalytic domains, structure and zinc coordinating pattern of ligands. Active sites of the two families show clear differences which has clear impact on type of inhibitors and the potential selectivity.
• the present invention relates to compounds of formula (I)
• R 1 is hydrogen, alkylcarbonyl, or arylcarbonyl
• R 2 is alkyl, alkenyl, alkinyl, cyanoalkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonyl, alkylcarbonylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylsulfonyl, aryl, arylalkyl, arylalkoxyalkyl, aryl(alkoxycarbonyl) alkyl, arylcarbamoyl, diarylalkyl, aryl(carboxyalkyl)amide, arylamino, arylcarbonyl, arylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, or the group YR 2 is heterocyclyl or R 2 is a group of the formula
• R 3 is alkyl, alkylcycloalkyl, alkylcycloalkylalkyl, cycloalkyl, halogenalkyl, carboxyalkyl, aminoalkyl, dialkylaminoalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkinyl, aryl, arylalkyl, arylalkyl(alkoxycarbonyl)alkyl, arylcarbonylalkyl, aryloxyalkyl, arylalkenyl, aryl(alkoxycarbonyl)alkyl, heteroaryl, heteroarylalkyl, heterocyclyl or hetercycylalkyl, and R 3 is hydroxy in case of X is SO 2 ;
• R 5 is hydrogen, alkyl, aryl, or carboxyalkyl
• R 6 is hydrogen, alkyl, aryl, carboxyalkyl, arylcarbonyl, alkylcarbonyl, arylalkoxycarbonyl, or arylalkyl;
• R 7 is hydrogen, aryl, alkyl, arylalkyl, heterocyclylalkyl, arylamino, alkyl(arylalkyl)amino, alkoxycarbonylalkyl, carboxyalkyl, or alkylthioalkyl;
• R 8 is hydroxy, alkyl, aryl, cyanoalkyl, alkoxy, arylalkyl, arylalkoxy, mono- or dialkylamino, arylamino, aryl(alkyl)amino, cyanoalkylamino, arylalkyl(alkyl)amino, heteroaryl, heteroarylalkyl, or heterocyclyl; and
• X is —S(O) 2 —, —S(O) 2 —NH—, —C(O)—, —C(O)NR 5 —, C(O)O—;
• Y is —CH 2 , —O—, —NR 6 — or —S—;
• n and q independently are 0 or 1
• n and q independently are 1, 2 or 3 and o is 0, 1 or 2 with the proviso that the sum of n, o and p is >2 and ⁇ 3;
• the present invention is directed to compounds which are useful as inhibitors of metalloproteases, e.g. zinc proteases, particularly zinc hydrolases, and which are effective in the prophylaxis and treatment of disease states which are associated with vasoconstriction of increasing occurrences.
• metalloproteases e.g. zinc proteases, particularly zinc hydrolases
• examples of such disorders are high blood pressure, coronary disorders, cardiac insufficiency, renal and myocardial ischaemia, renal insufficiency, dialysis, cerebral ischaemia, cardiac infarct, migraine, subarachnoid haemorrhage, Raynaud syndrome and pulmonary high pressure.
• the compounds are useful as cytostatic and cerebroprotective agents for inhibition of graft rejection, for organ protection and for treatment of ophthalmological diseases.
• R 1 is hydrogen, alkylcarbonyl, or arylcarbonyl
• R 2 is alkyl, alkenyl, alkinyl, cyanoalkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonyl, alkylcarbonylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylsulfonyl, aryl, arylalkyl, arylalkoxyalkyl, aryl(alkoxycarbonyl)alkyl, arylcarbamoyl, diarylalkyl, aryl(carboxyalkyl)amide, arylamino, arylcarbonyl, arylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, or the group YR 2 is heterocyclyl or R is a group of the formula
• R 3 is alkyl, , alkylcycloalkyl, alkylcycloalkylalkyl, cycloalkyl, halogenalkyl, carboxyalkyl, aminoalkyl, dialkylaminoalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkinyl, aryl, arylalkyl, arylalkyl(alkoxycarbonyl)alkyl, arylcarbonylalkyl, aryloxyalkyl, arylalkenyl, aryl(alkoxycarbonyl)alkyl, heteroaryl, heteroarylalkyl, heterocyclyl or hetercycylalkyl, and R 3 is hydroxy in case of X is SO 2 ;
• R 5 is hydrogen, alkyl, aryl, or carboxyalkyl
• R 6 is hydrogen, alkyl, aryl, carboxyalkyl, arylcarbonyl, alkylcarbonyl, arylalkoxycarbonyl, or arylalkyl;
• R 7 is hydrogen, aryl, alkyl, arylalkyl, heterocyclylalkyl, arylamino, alkyl(arylalkyl)amino, alkoxycarbonylalkyl, carboxyalkyl, or alkylthioalkyl;
• R 8 is hydroxy, alkyl, aryl, cyanoalkyl, alkoxy, arylalkyl, arylalkoxy, mono- or dialkylamino, arylamino, aryl(alkyl)amino, cyanoalkylamino, arylalkyl(alkyl)amino, heteroaryl, heteroarylalkyl, or heterocyclyl;
• X is —S(O) 2 —, —S(O) 2 —NH—, —C(O)—, —C(O)NR 5 —, C(O)O—;
• Y is —CH 2 , —O—, —NR 6 — or —S—;
• n and q independently are 0 or 1
• n and q independently are 1, 2 or 3 and 0 is 0, 1 or 2 with the proviso that the sum of n, o and p is ⁇ 2 and ⁇ 3;
• alkyl alone or in combination, means a straight-chain or branched-chain alkyl group containing a maximum of 7, preferably a maximum of 4, carbon atoms, e.g., methyl, ethyl, n-propyl, 2-methylpropyl (iso-butyl), 1-methylethyl (iso-propyl), n-butyl, and 1,1-dimethylethyl (t-butyl).
• carbamoyl refers to the group —C(O)NH 2 .
• carbonyl refers to the group —C(O)—.
• halogen refers to the group fluoro, bromo, chloro and iodo.
• sulfonyl refers to the group —S(O 2 )—.
• alkenyl refers to a hydrocarbon chain as defined for alkyl having at least one olefinic double bond (including for example, vinyl, allyl and butenyl).
• alkinyl refers to a hydrocarbon chain as defined for alkyl having at least one olefinic triple bond (including for example propinyl, butin-(1)-yl, etc.
• alkoxy alone or in combination, means an alkyl ether group in which the term ‘alkyl’ has the significance given earlier, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.butoxy, tert.butoxy and the like.
• alkoxycarbonyl refers to a group of the formula —C(O)R c wherein R c is alkoxy as defined above.
• hydroxy refers to the group —OH, the term “cyano” to the group —CN.
• hydroxyalkyl means an alkyl group as defined above which is substituted by a hydroxy group.
• thioalkyl and cyanoalkyl refer to an alkyl group as defined above which is substituted by a —SH group or an —CN group, respectively.
• halogenalkyl refers to an alkyl group as defined above which is substituted by one to three halogen atoms, preferably fluoro, e.g. trifluoromethyl, 2,2,2-trifluoroethyl, etc.
• alkylthioalkyl is a group of the formula alkyl-S-alkyl.
• Carboxyalkyl means an alkyl as defined above which is substituted by a HOOC-group.
• alkylcarbonyl alone or in combination, means an acyl group derived from an alkanecarboxylic acid, i.e. alkyl-C(O)—, such as acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl etc.
• cycloalkyl signifies a saturated, cyclic hydrocarbon group with 3-8, preferably 3-6 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and the like.
• amino refers to the group —NH 2 .
• aryl for R 2 —alone or in combination—, refers to an aromatic carbocyclic radical, i.e. a 6 or 10 membered aromatic or partially aromatic ring, e.g. phenyl, naphthyl or tetrahydronaphthyl, preferably phenyl or naphthyl, and most preferably phenyl.
• the aryl moiety is optionally substituted with one or more groups independently selected from halogen, preferably fluoro, alkoxycarbonyl, e.g.
• the most preferred aromatic groups are 2,5-difluorobenzyl and 2,4,5-trifluorobenzyl.
• aryl for R 3 —alone or in combination—, refers to an aromatic carbocyclic radical, i.e. a 6 or 10 membered aromatic or partially aromatic ring, e.g. phenyl, naphthyl or tetrahydronaphthyl, preferably phenyl or naphthyl, and most preferably phenyl.
• the aryl moiety is optionally substituted with one or more groups independently selected from halogen, alkoxycarbonyl, e.g.
• aromatic groups are phenyl, 4-fluorobenzyl, 4-carboxybenzyl, 2,3-dihydrobenzo[1,4]dioxinyl, 2-bromophenyl, 2-fluorophenyl, 2-methoxycarbonylphenyl, naphthyl and 4-methoxyphenyl.
• aryl for R 4 to R 10 —alone or in combination—refers to an aromatic carbocyclic radical, i.e. a 6 or 10 membered aromatic or partially aromatic ring, e.g. phenyl, naphthyl or tetrahydronaphthyl, preferably phenyl or naphthyl, and most preferably phenyl.
• the aryl moiety is optionally substituted with one or more groups independently selected from halogen, preferably fluor, alkoxycarbonyl, e.g.
• methylcarbonyl carboxy, cyano, alkyl, alkoxy, phenyl, phenoxy, trifluormethyl, trifluormethoxy, hydroxy, alkylamido, e.g. acetamido, nitro, alkylsulfonyl, e.g. methylsulfonyl, more preferably alkyl or alkoxy.
• aryloxy refers to an aryl group as defined above attached to a parent structure via an oxy radical, i.e., aryl-O—.
• heteroaryl for R 2 and R 4 to R 10 —alone or in combination—refers to an aromatic mono- or bicyclic radical having 5 to 10, preferably 5 to 6 ring atoms, containing one to three heteroatoms, preferably one heteroatom, e.g. independently selected from nitrogen, oxygen or sulfur.
• heteroaryl groups are thiophenyl, isoxazolyl, thiazolyl, pyridinyl, pyrrolyl, imidazolyl, tetrazolyl, preferably pyridinyl, isoxazolyl or thiazolyl.
• the heteroaryl group can be mono-, di- or tri-substituted, independently, with phenyl, alkyl, alkylcarbonyl, alkoxycarbonyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonylalkyl, preferably alkyl.
• heteroaryl for R 3 —alone or in combination—refers to an aromatic mono- or bicyclic radical having 5 to 10, preferably 5 to 6 ring atoms, containing one to three heteroatoms, preferably one heteroatom, e.g. independently selected from nitrogen, oxygen or sulfur.
• heteroaryl groups are pyridinyl, thiophenyl, isoxyzolyl, isoquinolyl, quinolyl, and 1H-benzo[d][1,3]oxazin-2,4-dione and indolyl, pyrimidine, pyridazine, and pyrazine, preferably pyridinyl, thiophenyl, isoxazolyl, isoquinolyl, quinolyl, and 1H-benzo[d][1,3]oxazin-2,4-dione and indolyl.
• the heteroaryl group can be mono-, di- or tri-substituted, independently, with phenyl, alkyl, alkylcarbonyl, alkoxycarbonyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, oxo, alkoxycarbonylalkyl, preferably alkyl.
• heterocyclyl refers to a non-aromatic mono- or bicyclic radical having 5 to 10, preferably 5 to 6 ring atoms, containing one to three heteroatoms, preferably one heteroatom, e.g. independently selected from nitrogen, oxygen or sulfur.
• the heterocyclic ring can be substituted by a group independently selected from halogen, alkyl, alkoxy, oxocarboxy, alkoxycarbonyl, etc. and/or on a secondary nitrogen atom (i.e. —NH—) by alkyl, arylalkoxycarbonyl, alkylcarbonyl or on a tertiary nitrogen atom (i.e. ⁇ N—) by oxido.
• heterocyclic groups are morpholinyl, pyrrolidinyl, piperidyl, etc., and especially for R 2 alkyl-pyran-triol-yl.
• dimeric form means a compound wherein the two R 1 groups of two identical compounds of formula I have been replaced by a common single bond or wherein R 1 is glutathione-S— or cysteine-S— or ester and/or alkylcarbonyl or arylcarbonyl derivatives thereof, e.g. acetylcysteine-S— or benzoylcysteine-S—, preferably glutathione-S—, cysteine-S—, acetylcysteine-S— or benzoylcysteine-S—.
• R 1 is glutathione-S— or cysteine-S— or ester and/or alkylcarbonyl or arylcarbonyl derivatives thereof, e.g. acetylcysteine-S— or benzoylcysteine-S—, preferably glutathione-S—, cysteine-S—, acetylcysteine-S— or benzoylcystein
• salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
• the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.
• salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
• Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymine resins and the like.
• “Pharmaceutically acceptable esters” means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.
• the compounds of formula (I) are useful in inhibiting mammalian metalloprotease activity, particularly zinc hydrolase activity. More specifically, the compounds of formula (I) are useful as medicaments for the treatment and prophylaxis of disorders which are associated with diseases caused by endothelin-converting enzyme (ECE) activity.
• ECE endothelin-converting enzyme
• Inhibiting of this enzyme would be useful for treating myocardial ischaemia, congestive heart failure, arrhythmia, hypertension, pulmonary hypertension, asthma, cerebral vasospasm, subarachnoid haemorrhage, pre-eclampsia, kidney diseases, atherosclerosis, Buerger's disease, Takayasu's arthritis, diabetic complications, lung cancer, prostatic cancer, gastrointestinal disorders, endotoxic shock and septicaemia, and for wound healing and control of menstruation, glaucoma.
• the compounds are useful as cytostatic and cerebroprotective agents for inhibition of graft rejection, for organ protection and for treatment of ophthalmological diseases.
• the present invention comprises compounds of formula (I) wherein m and p are 0, n, o and q are 1. More specifically, the present invention comprises the above defined compounds of general formula (III).
• R 1 , R 2 , R 3 , R 4 , X and Y are as defined as above.
• R 1 is hydrogen or alkylcarbonyl, preferably hydrogen or acetyl, and more preferably hydrogen.
• R 2 is aryl, arylalkyl, arylalkoxyalkyl, arylcarbamoyl, arylamino, arylcarbonyl, arylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylalkyl or heteroarylalkyl, more preferably aryl, arylalkyl, arylcarbamoyl, arylamino, arylcarbonyl, arylsulfonyl or heteroarylalkyl.
• R 2 is arylalkyl and specifically phenylalkyl optionally substituted with 2 to 3 halogen atoms, e.g. 2,4,5-trifluoro-benzyl or 2,5-difluoro-benzyl.
• R 3 is preferably alkyl, halogenalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, cycloalkyl, halogenalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkinyl, aryl, arylalkyl, arylalkyl(alkoxycarbonyl)alkyl, arylcarbonylalkyl, aryloxyalkyl, arylalkenyl, aryl(alkoxycarbonyl)alkyl, heteroaryl, heteroarylalkyl or heterocyclyl, more preferably alkyl, arylalkyl, arylcarbonylalkyl, aryloxylakyl, alkylcycloalkyl, alkylcycloylkylalkyl, cycloalkyl, heteroarylalkyl or halogenalkyl and most preferably alkyl, arylalkyl, alkoxycarbonyl
• R 4 is hydrogen
• X is preferably —S(O) 2 —, —S(O) 2 —NH—, —C(O)NR 5 — or C(O)O—, and more preferably —S(O) 2 —, —C(O)NH— or C(O)O—.
• the invention comprises compounds as defined above, wherein R 5 is hydrogen, alkyl or carboxyalkyl, preferably hydrogen.
• R 6 in the compounds described above is preferably hydrogen, alkyl or arylalkyl and more preferably hydrogen.
• R 7 is hydrogen or aryl and R 8 is hydroxy or alkoxy.
• Y preferably is —O— or —NH—.
• the invention comprises the above compounds wherein R 1 is hydrogen or alkylcarbonyl, R 2 is phenylalkyl substituted with 2 to 3 halogen; R 3 is alkyl, aryl, arylalkyl, aryloxyalkyl or halogenalkyl, e.g. e.g.
• X is —SO 2 —, —CONH—, —C(O)—O—; and Y is —NH— or —O—.
• the present invention comprises compounds as defined above with the stereochemistry shown in formula (IV)
• R 1 , R 2 , R 3 , R 4 , X and Y are as defined above.
• the invention comprises compounds of formula (IV) wherein R 1 is hydrogen or acetyl and R 2 is difluorobenzyl or trifluorobenzyl, e.g. 2,4,5-trifluoro-benzyl or 2,5-difluoro-benzyl- and R 3 is phenoxy-ethyl, 2,2,2-trifluoro-ethyl, 4-fluoro-benzyl, 4-carboxy-benzyl, 2,3-dihydrobenzo[1,4]dioxin-5-yl, 2-bromophenyl, butane-1-yl, methyl, benzyl, tert-butyl, 2-fluoro-phenyl, 4-fluoro-phenyl, 2-methoxy-carbonylphenyl, isopropyl, naphthalen-2-yl, naphthalen-2-yl, or 4-methoxy-phenyl and R 4 is hydrogen, X is —S, benzyl, n
• Preferred embodiments of the present invention are the compounds exemplified in the examples. Especially, the invention comprises the following compounds selected from the group consisting of
• the invention also refers to pharmaceutical compositions containing a compound as defined above and a pharmaceutically acceptable excipient.
• a further embodiment of the present invention refers to the use of compounds as defined above as active ingredients in the manufacture of medicaments comprising a compound as defined above for the prophylaxis and treatment of disorders which are caused by endothelin-converting enzyme (ECE) activity especially myocardial ischaemia, congestive heart failure, arrhythmia, hypertension, pulmonary hypertension, asthma, cerebral vasospasm, subarachnoid haemorrhage, pre-eclampsia, kidney diseases, atherosclerosis, Buerger's disease, Takayasu's arthritis, diabetic complications, lung cancer, prostatic cancer, gastrointestinal disorders, endotoxic shock and septicaemia, and for wound healing and control of menstruation, glaucoma, graft rejection, diseases associated with cytostatic, ophthalmological, and cerebroprotective indications, and organ protection.
• EAE endothelin-converting enzyme
• the invention refers to the use of compounds as described above for the treatment or prophylaxis of diseases which are associated with myocardial ischaemia, congestive head failure, arrhythmia, hypertension, pulmonary hypertension, asthma, cerebral vasospasm, subarachnoid haemorrhage, pre-eclampsia, kidney diseases, atherosclerosis, Buerger's disease, Takayasu's arthritis, diabetic complications, lung cancer, prostatic cancer, gastrointestinal disorders, endotoxic shock and septicaemia, and for wound healing and control of menstruation, glaucoma, graft rejection, diseases associated with cytostatic, ophthalmological, and cerebroprotective indications, and organ protection.
• diseases which are associated with myocardial ischaemia, congestive head failure, arrhythmia, hypertension, pulmonary hypertension, asthma, cerebral vasospasm, subarachnoid haemorrhage, pre-eclampsia, kidney diseases, atherosclerosis
• the invention comprises compounds as described above for use as therapeutic active substances, in particular in context with diseases which are associated with zinc hydrolase activity such as myocardial ischaemia, congestive heart failure, arrhythmia, hypertension, pulmonary hypertension, asthma, cerebral vasospasm, subarachnoid haemorrhage, pre-eclampsia, kidney diseases, atherosclerosis, Buerger's disease, Takayasu's arthritis, diabetic complications, lung cancer, prostatic cancer, gastrointestinal disorders, endotoxic shock and septicaemia, and for wound healing and control of menstruation, glaucoma, graft rejection, diseases associated with cytostatic, ophthalmological, and cerebroprotective indications, and organ protection.
• diseases which are associated with zinc hydrolase activity such as myocardial ischaemia, congestive heart failure, arrhythmia, hypertension, pulmonary hypertension, asthma, cerebral vasospasm, subarachnoid haemorrhage, pre-eclampsi
• the invention also comprises a method for the therapeutic and/or prophylactic treatment of myocardial ischaemia, congestive heart failure, arrhythmia, hypertension, pulmonary hypertension, asthma, cerebral vasospasm, subarachnoid haemorrhage, pre-eclampsia, kidney diseases, atherosclerosis, Buerger's disease, Takayasu's arthritis, diabetic complications, lung cancer, prostatic cancer, gastrointestinal disorders, endotoxic shock and septicaemia, and for wound healing and control of menstruation, glaucoma, graft rejection, diseases associated with cytostatic, ophthalmological, and cerebroprotective indications, and organ protection, which method comprises administering a compound as defined above to a human being or animal.
• the invention also relates to the use of compounds as defined above for the inhibition of zinc hydrolase activity.
• the invention also refers to the above compounds whenever manufactured by a process as described below.
• Step a) of scheme I describes the persilylation of hydroxy- and amino groups, e.g. by reaction of compound 1 with hexamethyldisilazan/140° C. followed by reaction with R 3 SO 2 Cl in THF or di-t-butyldicarbonate/NaHCO 3 in dioxane/H 2 O (BOC protection).
• R 3 SO 2 Cl in THF
• di-t-butyldicarbonate/NaHCO 3 dioxane/H 2 O (BOC protection).
• the resulting alcohol 2 is treated with MeSO 3 H/Ph 3 P/DIAD in toluene (room temperature to 80° C.) or (via bromide) with LiBr/DEAD/Ph 3 P in THF (4° C.
• alcohol 2 can be transformed to a compound of formula 3 by reaction with MeSO 2 Cl/pyridine/DMAP (0° C. to room temperature).
• a compound of formula 8 or 9 maybe mesylated (1.1 eq MeSO 2 Cl/1.5 pyridine/1 eq DMAP; in case Y is an amine the reaction is performed with e.g. 1 eq NaI, amine neat 100° C., for Y R 2 is pyrrole, imidazole or X is S, the reaction is performed with 1 eq NaI, NaH in DMF at 0° C. to room temperature, followed by thiol deprotection, e.g. by treatment with TFA/Et 3 SiH, 0° C.
• R 1 is Trt
• R 1 is PMB
• the azide may be BOC deprotected by reaction with TFA, CH 2 Cl 2 at ⁇ 20° C. to room temperature, followed by reaction with ClCO 2 R 3 , iPr 2 NEt, CH 2 Cl 2 or R 3 NCO in THF at 0° C. to room temperature (or conversion to all other R 3 X described later), followed by reduction of the azide (e.g. Ph 3 P, THF, H 2 O or NaBH 4 , MeOH), followed by reductive amination (e.g. aldehyde, SnCl 2 , NaBH 3 CN, MeOH).
• R 6 has to be introduced the compound is treated with R 6 Br/K 2 CO 3 in acetonitrile at room temperature followed by thiol deprotection (e.g. Et 3 SiH, TFA, 0° C. to room temperature or Et 3 SiH, TFA, MeCN at room temperature or, for selective trityl-thiol deprotection in the presence of BOC by for example treatment with iPr 3 SiH in TFA/CH 2 Cl 2 , 0° C. to room temperature).
• thiol deprotection e.g. Et 3 SiH, TFA, 0° C. to room temperature or Et 3 SiH, TFA, MeCN at room temperature or, for selective trityl-thiol deprotection in the presence of BOC by for example treatment with iPr 3 SiH in TFA/CH 2 Cl 2 , 0° C. to room temperature.
• the aldehyde e.g. with (COCl) 2 /DMSO/iPr 2 NEt at ⁇ 65° C. to room temperature in CH 2 Cl 2
• an imine formation e.g. corresponding primary amine/MgSO 4 , room temperature, 16 hours in CH 2 Cl
• BOC-deprotection e.g. TFA in CH 2 Cl 2 , 0° C. to room temperature
• R 3 NHSO 2 Cl in e.g. iPr 2 NEt, 0° C. to room temperature
• FMOC-deprotection e.g. Et 2 NH in THF
• thiol deprotection e.g. Et 3 SiH in TFA at 80° C.
• Compounds wherein YR 2 is triazol may be prepared via step g by reaction of the above mentioned azide with the corresponding alkyl/amineCOCH 2 keton/ester/amide/aryl and K 2 CO 3 (in DMSO, 40° C. for 3 days) followed by thiol deprotection (e.g. Et 3 SiH, TFA, 0° C. to room temperature or Et 3 SiH, TFA, MeCN, room temperature).
• thiol deprotection e.g. Et 3 SiH, TFA, 0° C. to room temperature or Et 3 SiH, TFA, MeCN, room temperature.
• An alternative is the reaction of the corresponding azide with alkyl/amineCOCH 2 ester, K 2 CO 3 , DMSO, 40° C. for 3 days, followed by hydrolysis of the ester(e.g. LiOH, THF) and thiol deprotection as described above.
• the corresponding compound may be prepared via step g by BOC deprotection (TFA, CH 2 Cl 2 , ⁇ 20° C. to room temperature), followed by reaction with a compound of formula R 3 OCOCl and iPr 2 NEt/CH 2 Cl 2 or conversion to all other R 3 X described later.
• YR 2 represents a phenolether
• the phenol may be introduced via step g under Mitsunobu conditions (e.g. DEAD/Ph 3 P/PhOH in THF) and in case R 1 is Trt followed by reaction with e.g. TFA/Et 3 SiH at 0° C. to room temperature or, in case R 1 is PMB, followed by reaction with e.g. TFA/Et 3 SiH, at 0 to 80° C.
• Mitsunobu conditions e.g. DEAD/Ph 3 P/PhOH in THF
• R 1 is Trt followed by reaction with e.g. TFA/Et 3 SiH at 0° C. to room temperature or, in case R 1 is PMB, followed by reaction with e.g. TFA/Et 3 SiH, at 0 to 80° C.
• the corresponding compounds 5 may by obtained via step g by reaction with isocyanate/NMM in toluene at room temperature followed optionally by reaction with the corresponding alkyl-, cycloalkyl-halogenide, alkylbromoacetate with NaH in DMF at 0° C. to room temperature. If YR 2 represents an ether the corresponding compounds 5 may be obtained via step g by O-alkylation (e.g. NaH, R 2 -halogenide, DMF 0° C. to room temperature) or by O-alkylation with phase transfer conditions (e.g. R 2 -halogenide/50% NaOH, Bu 4 NHSO 4 ).
• O-alkylation e.g. NaH, R 2 -halogenide, DMF 0° C. to room temperature
• phase transfer conditions e.g. R 2 -halogenide/50% NaOH, Bu 4 NHSO 4
• This reaction may be followed by reaction with e.g. TFA/Et 3 SiH at 0° C. to room temperature (R 1 is Trt) or, in case R 3 is PMB, followed by reaction with e.g. TFA/Et 3 SiH, at 0 to 80° C.
• Compounds containing a group of formula (II) may be prepared via step g by reaction of the corresponding starting compound 8 or 9 with NaH, R 2 -halogenide/NaI, DMF and in case R 2 contains a COOtBu (a) reaction with TFA in CH 2 Cl 2 at ⁇ 20° C. and (b) reaction with EDCI/HOBT amine in CH 2 Cl 2 for formation of the corresponding amide- or, in case 2 R contains a COO-alkyl- (a) reaction with 1N NaOH in THF/EtOH to give the acid. Both pathways are completed by reaction with Et 3 SiH in TFA at 0° C. to room temperature.
• R 3 X is a carbamate these starting compounds may be reacted with R 3 OCOCl/pyridine in THF or by reaction with (a) R 3 OH/Cl 3 COCl/quinoline (formation of the chloroformate) followed by reaction with NaH.
• R 3 X is a sulfonamide the starting compounds may be reacted with R 3 SO 2 Cl/(i-Pr) 2 EtN/cat DMAP in ClCH 2 CH 2 Cl at room temperature.
• R 3 X is urea the starting compounds may be reacted with isocyanate in EtOH at room temperature.
• R 3 X is an alkylated urea, (i.e.
• the starting compounds may be reacted with isocyanate in EtOH at room temperature followed by reaction with the corresponding alkylhalogenide/K-OtBu at 0° C. to room temperature.
• R 3 X is an amide
• the starting compounds may be reacted with RCOOH/EDCI/DMAP (with an hydride formation, and subsequent addition of the starting amine, ⁇ 10° C. to room temperature) or as alternative with RCOOH/EDCI/DMAP at room temperature.
• R 3 X is a sulfamide (for R 3 is NH 2 ) the starting compounds may be reacted with sulfamic acid 2,4,6-trichlorophenylester/Et 3 N in CH 2 Cl 2 at 40° C. or with other methods which are known in the art.
• R 3 X is SO 2 OH the starting compounds maybe reacted with chlorosuphonic acid/2-picoline.
• R 3 X is an alkylated sulfamide (i.e. introduction of R 5 ) the starting compounds maybe reacted with NaH/alkyl halide in DMF at 0° C. at room temperature. Thiol liberation can than be achieved by reaction in TFA/Et 3 SiH at room temperature.
• Step h of scheme 1 includes a reaction pathway for the preparation of further derivatives by reaction of compounds of formula 4 with (a) NaH/ reactive R 2 Br in DMF at 0° C. to room temperature followed by (b) reaction with KSAc in DMF at 100° C.
• the corresponding thiols could be obtained by reaction of the the above compounds with LiOH aqueous in EtOH at 0° C. to room temperature.
• Step i of scheme 1 shows the preparation of compounds of formula 5 wherein Y is C.
• Compounds of formula 4 are treated with NaOH in EtOH at room temperature, followed by formation of a Weinreb amide (e.g. by reaction with HCl.H 2 NOMe/NMM, EDCI, HOBT at 0° C. to room temperature), followed by formation of the corresponding ketone (e.g. by reaction with R 2 —MgBr in THF, at 0° C. to room temperature), BOC deprotection (e.g. TFA in CH 2 Cl 2 , at ⁇ 20° C.
• Step c comprises the reaction of compound 2 with LiBH 4 in THF at ⁇ 20° C. to room temperature or LAH at ⁇ 15° C. in ether to obtain compounds 4.
• step d of scheme 2 shows the introduction of a phthalimide under Mitsunobu conditions (e.g. phthalimide, DEAD/Ph 3 P in THF, 3 to 80° C. This may be followed by t-butyldimethylsilylether deprotection (e.g. for t-BuMe 2 Si: reaction with TBAF in THF at room temperature), followed by reaction with e.g. MeSO 3 H/DIAD/Ph 3 P in toluene at room temperature ⁇ 80° C., followed by e.g.
• a phthalimide under Mitsunobu conditions e.g. phthalimide, DEAD/Ph 3 P in THF, 3 to 80° C.
• t-butyldimethylsilylether deprotection e.g. for t-BuMe 2 Si: reaction with TBAF in THF at room temperature
• reaction with KSCOCH 3 in DMF at 100° C. followed by phthalimide deprotection and disulfide formation (e.g. by reaction with CH 3 NH 2 , EtOH for 2 days at room temperature which may be followed by reaction with R 2 SO 2 Cl or R 2 COCl, DMAP in CH 2 Cl 2 or R 2 CO 2 H, TPTU or N-alkylation by reaction with R 2 Br and N-methylmorpholine in CH 2 Cl 2 .
• This may be followed by side chain manipulation e.g. hydrolysis with LiOH in THF/H 2 O.
• Step e of scheme 2 shows the reduction of the disulfide to the thiol (e.g. by nBu 3 P/CF 3 CH 2 OH/H 2 O at 0° C. or DTT, 2 M K 2 CO 3 , MeCN).
• R 2 Y is R 2 O: Compounds of this type may be obtained by reaction shown in step f and g. These reaction may comprise (step f) reaction of compounds 4 with R 2 Br/NaH in DMSO at room temperature or benzyl-2,2,2-trichloroacetimidate/CF 3 SO 3 H in CH 2 Cl 2 /cyclohexane at room temperature (here the R 2 -side chains may be manipulated by reaction with 10% Pd/C/H 2 in EtOH/dioxane) or the reaction is performed with PhOH/Ph 3 P/DIAD in THF at room temperature. All reactions may be followed by removal of the t-Bu-ether in TFA at 0° C. to room temperature.
• Mitsunobu conditions e.g. CH 3 COSH/Ph 3 P/DIAD in T
• Step a comprises the preparation of compounds 2 by reaction of compounds 1 with e.g. R 3 SO 2 Cl/DMAP in CH 2 Cl 2 at room temperature or Et 3 N in CH 2 Cl 2 (reflux)) followed by monohydrolysis (e.g. 1 M NaOH in MeOH/H 2 O for 20 min reflux and reduction of the acid with e.g. BH 3 .THF in THF at 0° C.
• Step c shows an alkylation (e.g. with R 2 Br/NaH in DMSO at room temperature) followed by ester reduction (e.g. LAH at ⁇ 15° C. in ether).
• Step e comprises the formation of the thioacetate (e.g. by CH 3 COSH/Ph 3 P/DIAD in THF at 0° C. to room temperature followed by formation of the thiol (e.g. with MeONa in MeOH at 0° C.
• Step f shows the reduction of both esters (e.g. with LAH in THF at 0° C.) followed by monoalkylation (e.g. with R 2 Br/NaH in DMF at ⁇ 15° C., step g).
• This pathway may be continued by formation of the mesylate (e.g. with MeSO 2 Cl/Et 3 N in Et 2 O at ⁇ 20° C. to room temperature), formation of the thioacetate (e.g.
• Step h depicts an additional way for preparing a mono-p-tosylate (e.g. with p-TosCl/Et 3 N/cat DMAP in THF at room temperature) followed by introduction of the tritylthiolate (e.g. with Ph 3 CSH/KOt-Bu in DMF at room temperature), formation of the mesylate (step i, with MeSO 2 Cl/Et 3 N in THF at 0° C. to room temperature) followed by the formation of the phenolether (e.g.
• Scheme 4 shows in step a the selective protection of the thiol group (e.g. by reaction with Ac 2 O/pyridine in CH 2 Cl 2 at room temperature; the starting compound can be received by a deprotection of a STrt or SPMB protected alcohol described above, e.g. Et 3 SiH in TFA).
• the S-acetylated alcohol was then reacted with (a) 1,2,3,4-tetra-O-acetyl-t-deoxy-beta-L-mannospyranose/trimethylsilyl-trifluoromethanesulphonate in CH 2 Cl 2 at 0° C. followed by cleavage of all acetyl group with NaOMe in MeOH at 0° C.
• Scheme 5 shows the reaction pathway for the synthesis of sterically hindered thiols.
• Step a represents a Swern-oxidation of the starting material which is known in the art (e.g. (COCl) 2 /DMSO/Et(i-Pr) 2 N in CH 2 Cl 2 ).
• Step b shows the methylene introduction by a Wittig reaction (e.g. with Kt-BuO/CH 3 PPh 3 Br in THF at room temperature to 70° C.
• Step c shows a reduction via a mixed anhydride (e.g. with iBuOCOCl/NMM in THF at ⁇ 5° C. to room temperature, then the mixture is added to NaBH 4 in water at 0° C.
• Step d represents the formation of an epoxide (e.g. with mCPBA in CH 2 Cl 2 at room temperature) followed by the formation of a thiirane (e.g. with KSCN in EtOH/H 2 O at room temperature or PO(OMe) 2 SCl in CH 2 Cl 2 ).
• a thiirane e.g. with KSCN in EtOH/H 2 O at room temperature or PO(OMe) 2 SCl in CH 2 Cl 2 .
• the resulting diastereomers are separable with methods known in the art.
• Step e shows the opening of the thiirane (e.g. with LiHBEt 3 in THF and LAH) and reduction of the resulting disulfide (e.g. with P(Bu) 3 /H 2 O in trifluoroethanol/CH 2 Cl 2 ).
• Step a comprises the N-acylation (protection of NH, e.g. with AcCl, iPr 2 NEt, 4-(N-benzyl-N-methylamino)pyridine polymer-supported, CH 2 Cl 2 ) or by N-CBz-Protection (e.g. with BnOCOCl, iPr 2 NEt, 4-Benzyl-N-methylamino)pyridine polymer supported, CH 2 Cl 2 ), followed by selective BOC deprotection (e.g. with TFA, CH 2 Cl 2 at ⁇ 20° C. to room temperature) and reaction with a reactive R 3 derivative (e.g.
• step e of scheme 6 shows formation of S-compounds of thiol inhibitors of formula (I) by (a) reaction of the free thiol with for example AcCl in pyridine or PhCOCl in pyridine at 0° C. to room temperature or (b) a S-derivative synthesis (e.g.
• the present invention also refers to the above described processes, especially to processes for the preparation of a compound of the present invention comprising reaction of a compound of formula V
• R 1 , R 3 , R 4 , X, Y, m, n, o, q and p are as defined above and A is a HS-protecting group
• Dimeric forms of a compound of formula I may be prepared by oxidative treatment of the formula I monomers.
• the compounds of formula I can be used as medicaments for the treatment and prophylaxis of disorders which are associated with vasoconstriction of increasing occurrences.
• disorders are high blood pressure, coronary disorders, cardiac insufficiency, renal and myocardial ischaemia, renal insufficiency, dialysis, cerebral ischaemia, cardiac infarct, migraine, subarachnoid haemorrhage, Raynaud syndrome and pulmonary high pressure.
• Atherosclerosis the prevention of restenosis after balloon-induced vascular dilation, inflammations, gastric and duodenal ulcers, ulcus cruris, gram-negative sepsis, shock, glomerulonephtritis, renal colic, glaucoma, asthma, in the therapy and prophylaxis of diabetic complications and complications in the administration of cyclosporin, as well as other disorders associated with endothelin activities.
• ECV304 human umbilical vein endothelial cell line
• cell factories as described until confluency (Schweizer et al. 1997, Biochem. J. 328: 871-878).
• trypsin/EDTA solution was detached with a trypsin/EDTA solution and collected by low speed centrifugation.
• the cell pellet was washed once with phosphate buffered saline pH 7.0 and stored at ⁇ 80° C. until use.
• the final membrane preparation was homogenized in 50 ml of buffer B (buffer A+0.5% Tween 20 (v/v), 0.5% CHAPS (w/v), 0.5% Digitonin (w/v)) and stirred at 4° C. for 2 hours. Thereafter the remaining membrane fragments were sedimented as described. The resulting clear supernatant containing the solubilized ECE was stored in 1.0 ml aliquots at ⁇ 120° C. until use.
• buffer B buffer A+0.5% Tween 20 (v/v), 0.5% CHAPS (w/v), 0.5% Digitonin (w/v)
• the assay measured the production of ET-1 from human big ET-1.
• the enzyme reaction and the radioimmunological detection of the produced ET- 1 was performed in the same well, using a specifically developed and optimized coating technique.
• Fluoronunc Maxisorp White (code 437796) 96 well plates were irradiated with 1 joule for 30 minutes in a UV Stratalinker 2400 (Stratagene). The 96 well plates were then fill with 300 ⁇ l protein A solution (2 ⁇ g/ml in 0.1 M Na 2 CO 3 pH 9.5) per well and incubated for 48 hours at 4° C. Coated plates can be stored for up to 3 weeks at 4° C. until use.
• Test compounds are solved and diluted in DMSO. 10 ⁇ l of DMSO was placed in the wells, followed by 125 ⁇ l of assay buffer (50 mM Tris/HCl, pH 7.0, 1 ⁇ M Thiorphan, 0,1% NaN 3 , 0.1% BSA) containing 200 ng big ET-1. The enzyme reaction was started by the addition of 50 ⁇ l of solubilized ECE (diluted in assay buffer 1:30 to 1:60 fold (v/v)). The enzyme reaction was carried out for 30 minutes at 37° C. The enzyme reaction was stopped by addition of 10 ⁇ l 150 mM ETDA, pH 7.0.
• the ET-1 RIA was performed principally as described earlier (Loffler, B. -M. and Maire, J. -P. 1994, Endothelium 1: 273-286).
• 25 ⁇ l of assay buffer containing 20000 cpm (3-( 125 I)Tyr)-endothelin-1 and 25 ⁇ l of the ET specific antiserum AS-3 (dilution in assay buffer 1:1000) was added. Plates were incubated under mixing at 4° C. over night. Thereafter, the liquid phase was sucked with a plate washer and plates were washed once with bidestilled water.
• To the washed plates 200 ⁇ l scintillation cocktail (Microscint 40 LSC-Cocktail, Packard, code 6013641) was added and plates were counted for 2 minutes per well in a Topcount.
• Standard curves were prepared in plates with synthetic ET-1 with final concentrations of 0 to 3000 pg ET-1 per well. In all plates controls for maximal ECE activity (in the presence of 10 ⁇ l DMSO) and for background production of ET-1 immunoreactivity (in the presence of 10 mM EDTA or 100 ⁇ M phosphoramidon) were performed. Assays were run in triplicate.
• the described assay format could be used to determine the kinetic characteristics of the used ECE preparation as well as different ECE inhibitors (i.e. Km, Ki) by variation of the substrate concentration used in the assay.
• ECE-1c Human ECE-1c was stable expressed in MDCK cells as described (Schweizer et al. 1997, Biochem. J. 328: 871-878). Cells were cultured in 24 well plates to confluency in Dulbecco's modified Eagles's medium (DMEM) supplemented with 10% (v/v) fetal bovine serum (FBS), 0.8 mg/ml geneticin, 100 i.u./ml penicillin and 100 ⁇ g/ml streptomycin in a humidified air/CO 2 (19:1) atmosphere. Before ECE assay the medium was replaced by 0.5 ml DMEM-HBSS 1:1, 10 mM HEPES pH 7.0 supplemented with 0.1% (w/v) BSA.
• DMEM Dulbecco's modified Eagles's medium
• FBS fetal bovine serum
• the inhibitors were added in DMSO at a final concentration of 1%.
• the enzyme reaction was started by the addition of 0.42 ⁇ M human big ET-1 and performed for 1.5 hours at 37° C. in an incubator. At the end of incubation, the incubation medium was quickly removed and aliquots were analysed by radioimmunoassay for produced ET-1 as described above.
• the ECE screening assay was validated by the measurement of the characteristic inhibitor constants of phosphoramidon (IC 50 0.8 ⁇ 0.2 ⁇ M) and CGS 314447 (IC 50 20 ⁇ 4 nM) [De Lombaert, Stephane; Stamford, Lisa B.; Blanchard, Louis; Tan, Jenny; Hoyer, Denton; Diefenbacher, Clive G.; Wei, Dongchu; Wallace, Eli M.; Moskal, Michael A.; et al. Potent non-peptidic dual inhibitors of endothelin-converting enzyme and neutral endopeptidase 24.11. Bioorg. Med. Chem. Lett. (1997), 7(8), 1059-1064].
• the compounds of the present invention show activity values in the radioimmunoassay (E and F) of about 0.5 nM to about 100 ⁇ M.
• the preferred compounds show values of 0.5 nM to 100 nM.
• medicaments containing a compound of formula I are also an object of the present invention as is a process for the manufacture of such medicaments, which process comprises bringing one or more compounds of formula I and, if desired, one or more other therapeutically valuable substances into a galenical administration form.
• compositions may be administered orally, for example in the form of tablets, coated tablets, drages, hard or soft gelatin capsules, solutions, emulsions or suspensions. Administration can also be carried out rectally, for example using suppositories; locally or percutaneously, for example using ointments, creams, gels or solutions; or parenterally, for example using injectable solutions.
• the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients.
• suitable excipients for tablets, dragees or hard gelatin capsules include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof.
• Suitable excipients for use with soft gelatin capsules include for example vegetable oils, waxes, fats, semi-solid or liquid polyols etc. According to the nature of the active ingredients, it may, however, be the case that no excipient is needed at all for soft gelatin capsules.
• excipients which may be used include for example water, polyols, saccharose, invert sugar and glucose.
• excipients which may be used include for example water, alcohols, polyols, glycerin, and vegetable oils.
• excipients which may be used include for example natural or hardened oils, waxes, fats and semi-solid or liquid polyols.
• compositions may also contain preserving agents, antioxidants, solubilising agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for the variation of osmotic pressure, buffers, coating agents or antioxidants. They may also contain other therapeutically valuable agents.
• the dosages in which the compounds of formula I are administered in effective amounts depend on the nature of the specific active ingredient, the age and the requirements of the patient and the mode of application. In general, dosages of 0.1-100 mg/kg body weight per day come into consideration, although the upper limit quoted can be exceeded when this is shown to be indicated.
• Method 1 TFA/triethylsilane deprotection for labile p-methoxy-benzylsulfanyl compounds: A solution of 0.15 mmol p-methoxy-benzylsulfanyl was dissolved in 2 ml TFA, cooled to 0° C. and treated with 0.24 ml (1.5 mmol) triethylsilane, stirred for 22 h at room temperature (the reaction was followed by TLC, if necessary treated again with 0.24 ml (1.51 mmol) triethylsilane and stirred for 30 h). The evaporated residue was purified by flash silica gel column to give the thiol compound.
• Method 2 TFA/triethylsilane deprotection for not labile p-methoxy-benzylsulfanyl compounds: A solution of 0.25 mmol p-methoxy-benzylsulfanyl and 0.4 ml (2.5 mmol) triethylsilane was heated for 1 min-1.5 h at 80° C. (followed by TLC), cooled to RT and evaporated. Crystallization from Et 2 O/pentane gave the thiol-compound.
• Trityl deprotection for single compound A solution of 0.58 mmol tritylsulfanyl in 5.8 ml TFA was treated at 0° C. with 0.92 ml (5.78 mmol) triethylsilane and after 10 min at room temperature evaporated and purified by flash chromatography on silica gel (Hexane/EtOAc 4:1) to give the thiol-compound.
• Trityl deprotection for parallel synthesis A solution of 0.32 mmol trityl-protected compound was dissolved in 1.5 ml acetonitril/0.4 ml TFA/0.1 ml triethylsilane and after 1 night at room temperature purified by preparative HPLC (RP18, CH 3 CN/H 2 O 80:20 to 95:5) to give the free thiols.
• Trityl deprotection in the presence of BOC 1 eq Trityl-protected compound in CH 2 Cl 2 (15-20 ml/mmol) was treated with 10 eq triisopropyl silane and 10 eq TFA at 0° C. or RT until no starting material could be detected. The solution was poured on saturated NaHCO 3 solution and the inorganic phase was extracted with CH 2 Cl 2 , the organic phases were washed with brine, dried over Na 2 SO 4 and evaporated and purified by flash chromatography to give the free amine.
• reaction was heated for 1.3 h at 100° C., cooled, evaporated to 400 ml and extracted with 250 ml aqueous saturated NH 4 Cl/EtOAc (3 ⁇ 300). The organic phases were washed with aq. 10% NaCl, dried (Na 2 SO 4 ) and evaporated.
• (2S,4R)-4-hydroxy-1-methanesulfonyl-pyrrolidine-2-carboxylic acid benzyl ester gave after 5 h at 80° C.
• (2S,4S)-1-methanesulfonyl-4-methanesulfonyloxy-pyrrolidine-2-carboxylic acid benzyl ester which was heated for 30 min with 4-methoxybenzylthiol/potassium tert-butylate to give (2S,4S)-1-methanesulfonyl-4-methanesulfonyloxy-pyrrolidine-2-carboxylic acid benzyl ester, mp 91-92° C., MS: 453 (M+NH 4 + ).
• Triphenylphosphine oxide was removed by crystallization from EtOAc/hexane and the mother liquid was purified by colum chromatography on silica gel with hexane: EtOAc 3:1 yielding 13.4 g (62%) of (2S,4S)-4-bromo-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl ester as colorless solid, mp 97-98° C., MS: 473 (MH + ).
• (2S,4R)-2-diazo-1-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-yl]-ethanone was obtained from (2S,4R)-1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid (with 2.3 eq. Trimethylsilyldiazomethane) in 57% yield, MS: 621 (M+NH 4 + ).
• Method A 200 mg (0.31 mmol) Methanesulfonic acid (2S,4R)-1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-ylmethyl ester and 47 mg (0.31 mmol, 1.0 eq) sodium iodide were dissolved in 5 ml ethyl isonipecotate, heated to 100° C. for 3 h and the excess of the amine was removed under vacuum. The resulting residue was dissolved in EtOAc and 5% aqueous NaHCO 3 solution, the layers were separated, the organic one was extracted with water (3 ⁇ ) and washed with brine, dried over Na 2 SO 4 , and evaporated.
• Method B A slurry of 300 mg (0.73 mmol) (2S,4R)-methanesulfonic acid 1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-ylmethyl ester and 109 mg (0.73 mmol) of NaI in 5 ml benzylamine was heated in the oil bath to 100° C., evaporated in the kugelrohr at 50-70° C./1 Torr and extracted with aqueous saturated NaHCO 3 solution/Et 2 O (3 ⁇ ). The organic phase was dried over Na 2 SO 4 , evaporated and the residue was crystallized from Et 2 O/pentane at ⁇ 20° C.
• Method C A solution of 130 mg (0.257 mmol) (2R,4R)-2-(3-methane-sulfonyloxy-propyl)-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid butyl ester, 0.037 ml (0.514 mmol) pyrrole and 38.6 mg (0.257 mmol) NaI in 0.4 ml DMF was treated at 0° C. with 22.4 mg (0.514 mmol) 55% NaH and warmed up over night to room temperature. The reaction was neutralized with cooled aqueous saturated NH 4 Cl and extracted (EtOAc 3 ⁇ ).
• (2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl with TFA in CH 2 Cl 2 gave (2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine as light yellow oil, MS: 501 (MH + ).
• (2S,4R)-2-aminomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid benzyl ester and 2,5-difluorobenzaldehyde and subsequent cleavage of the trityl protecting group analogously to reductive amination and deprotection gave (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid benzyl ester as colorless oil, MS: 393 (MH + ).
• the solution was stirred at room temperature for 48 h, 1M KHSO 4 was added, the layers were separated and the inorganic one was extracted with CH 2 Cl 2 . The combined organic layers were washed with 1M KHSO 4 and brine, dried over Na 2 SO 4 and evaporated.
• the crude product was dissolved in 4.2 ml Et 2 NH:THF (1:1) at 0° C. and stirred 5 h at room temperature. The solvent was evaporated, the residue redissolved and evaporated twice with hexane and dried in vacuum. The brown oil was dissolved in 4 ml TFA and 0.7 ml (4.2 mmol) Et 3 SiH and stirred at 80° C. for 2h.
• (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester was treated with 2,5-difluoro-benzylbromide to give (2S,4R)-2- ⁇ [bis-(2,5-difluoro-benzyl)-amino]-methyl ⁇ -4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester which was treated with TFA according to general method B (variation 0° C.
• (2S,4R)-2-[[benzyloxycarbonyl-(2,5-difluoro-benzyl)-amino]-methyl]-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester was treated according to trityl cleavage (method 5) to give (2S,4R)-2-[[benzyloxycarbonyl-(2,5-difluoro-benzyl)-amino]-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless oil, MS: 493 (MH + ).
• Methylamine Amides and Sulfonamides
• the suspension was heated to 80° C. for 6 h and stirred at room temperature overnight. After diluting the mixture with EtOAc and water, the phases were separated, and the inorganic one was extracted with EtOAc and CH 2 Cl 2 , the combined organic phases were washed with 1M KHSO 4 and brine, dried over Na 2 SO 4 and evaporated.
• Method A 9.07 g (20 mmol) of (2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-yl)-methanol and 9.5 ml (80 mmol) of benzylbromide were dissolved in 660 ml DMF, cooled to 0° C. and treated with 1.4 g (32 mmol) of 55% NaH over 15 min in 4 portions. The reaction was warmed up over night and treated with 4.75 ml (40 mmol) benzylbromide/700 mg (16 mmol) 55% NaH and 6 h later again with the same amount of benzylbromide/NaH.
• Method B A solution of 0.41 g (0.91 mmol) in 20 ml (bromomethyl)cyclohexane was mixed with 20 ml aqueous 50% NaOH and a catalytic amount of tetrabutyl-ammonium hydrogen sulfate and stirred vigorously over night. The organic phase was separated, and evaporated on the Kugelrohr. Flash-chromatography on silica gel (hexane/EtOAc 95:5) gave 0.3 g (60%) of (2S,4R)-2-cyclohexylmethoxymethyl-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidine, MS: 550 (MH + ).
• Trityl deprotection (Method 3) (7 h at 0° C.) gave (2S,4R)-2-benzyloxymethyl-4-mercapto-pyrrolidine-1-carboxylic acid phenyl ester, MS: 343 (M).
• Trityl deprotection (Method 3) gave (2S,4R)-4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2-fluoro-phenyl ester, MS: 416 (MH + ).
• Trityl deprotection (Method 3) of (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid (S)- and (R)-1-isopropoxycarbonyl-3-methyl-butyl ester gave (2S,4R)-4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid (S)- and (R)-1-isopropoxycarbonyl-3-methyl-butyl ester, MS: 478 (MH + ).
• Trityl deprotection (Method 3): (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid (S)- or (R)-1-carboxy-3-methyl-butyl ester gave (2S,4R)-4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid (S)- or (R)-1-carboxy-3-methyl-butyl ester, MS: 434 (M ⁇ H ⁇ ) and (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid (R)- or (S)-1-carboxy-3-methyl-butyl ester gave (2S,4R)-4-mercapto-2-(2,4,5-trifluoro-benzyl
• Trityl deprotection (following Method 3) gave: (R)- or (S)-[(2S,4R)-4-mercapto-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-phenyl-acetic acid methyl ester, MS: 359 (M) and (S)- or (R)-[(2S,4R)-4-mercapto-1-methanesulfonyl-pyrrolidin-2-ylmethoxy]-phenyl-acetic acid methyl ester, MS: 359 (M).
• Trityl deprotection (following Method 3) gave (2S,4R)-[4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidin-1-yl]-pyrrolidin-1-yl-methanone, MS: 374 (M).
• Trityl deprotection (Method 3) (2S,4R)-4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfonic acid amide, MS: 355 (M ⁇ H) ⁇ .
• Trityl deprotection (Method 3) gave (2S,4R)-2-benzyloxymethyl-4-mercapto-pyrrolidine-1-sulfonic acid methylamide, MS: 315 (M ⁇ H) ⁇ .
• Acetic acid ethyl ester (2S,4R)-[2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-sulfonylamino]-acetic acid ethyl ester; yield: 85%, MS: 682 (M ⁇ H) ⁇ ;
• Benzyl-acetic acid t-butyl ester ⁇ Benzyl-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-sulfonyl]-amino ⁇ -acetic acid-tert-butyl ester; yield: 77%;
• Phenyl (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfonic acid phenylamide; yellowish oil; yield: quant., MS: 431 (M ⁇ H) ⁇ ;
• Phenethyl (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfonic acid phenethylamide; colorless oil; yield: 53%, MS: 459 (M ⁇ H) ⁇ ;
• Phenoxyethyl (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfonic acid (2-phenoxy-ethyl)-amide; colorless oil; yield: quant., MS: 475 (M ⁇ H) ⁇ ;
• Benzyl-acetic acid ⁇ Benzyl-[4-mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfonyl]-amino ⁇ -acetic acid; colorless oil; yield: 88%, MS: 503 (M ⁇ H) ⁇ ;
• LAH reduction To a slurry of lithium aluminium hydride (0.72 g) in Et 2 O (120 ml) was added a solution of (2S,4R)-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl ester (9.0 g) in Et 2 O (80 ml) dropwise at ⁇ 15° C. within 0.5 h. The suspension was stirred for 2 h at the same temperature, then a saturated solution of potassium-sodium tartrate (10 ml) was added dropwise. The slurry was filtered through a pad of filter aid and was washed with Et 2 O.
• 6-ring To rac-cis-Piperidine-2,5-dicarboxylic acid dimethyl ester [Frank J., J. Heterocyclic Chem. 32, 857-861 (1995)] (36.2 g) dissolved in dichloromethane (720 ml) were added 4-dimethylaminopyridine (33.0 g) and, dropwise, methanesulphonyl chloride (28.6 g) within 10 minutes and room temperature. The temperature rose to 35° C.
• (3RS,4RS)-[4-Benzyloxymethyl-1-(naphthalene-2-sulfonyl)-pyrrolidin-3-yl]-methanethiol was obtained (quant.) from (3RS,4RS)-1-(naphthalene-2-sulfonyl)-3-benzyloxymethyl-4-tritylsulfanylmethyl-pyrrolidine as a colorless oil, MS: 428 (MH + ).
• Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester were prepared from BOC-Hyp-OH following literature procedure [Baldwin, Jack E.; Field, Robert A.; Lawrence, Christopher C.; Merritt, Kristen D.; Schofield, Christopher J.; Tetrahedron Lett.; 34; 1993; 7489-7492; and Herdewijn, Piet; Claes, Paul J.; Vanderhaeghe, Hubert; Can.J.Chem.; 60; 1982; 2903-2907;]
• Tablets containing the following ingredients can be manufactured in a conventional manner: Ingredients Per tablet Compound of formula I 10.0-100.0 mg Lactose 125.0 mg Maize starch 75.0 mg Talc 4.0 mg Magnesium stearate 1.0 mg
• Capsules containing the following ingredients can be manufactured in a conventional manner: Ingredients Per capsule Compound of formula I 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg
• Injection solutions can have the following composition: Compound of formula I 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Water for injection solutions ad 1.0 ml

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