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Definitions

• Elevated calpain levels have been measured in various pathophysiological processes, for example: ischemias of the heart (e.g. myocardial infarction), the kidney, the lung, the liver or the central nervous system (e.g. stroke), inflammations, muscular dystrophies, cataracts of the eyes, diabetes, HIV disorders, injuries to the central nervous system (e.g. brain trauma), Alzheimer's, Huntington's, Parkinson's diseases, multiple sclerosis etc. (see K.K. Wang, above) and infectious diseases such as malaria (IM Medana et al, Neuropath and Appl. Neurobiol. 2007, 33, pp.179-192). It is assumed that there is a connection between these diseases and generally or persistently elevated intracellular calcium levels. This results in calcium-dependent processes becoming hyperactivated and no longer being subject to normal physiological control. A corresponding hyperactivation of calpains can also trigger pathophysiological processes.
• ischemias of the heart e.g. myocardial infarction
• the kidney e.g.
• NFTs neurofibrillary tangles
• interleukin-la The release of interleukin-la is likewise inhibited by calpain inhibitors (N. Watanabe et al, Cytokine 1994, 6(6), pp. 597-601). It has additionally been found that calpain inhibitors show cytotoxic effects on tumor cells (E. Shiba et al. 20th Meeting Int. Ass. Breast Cancer Res., Sendai Jp, 1994, 25.-28.Sept., Int. J. Oncol. S(Suppl), 1994, 381).
• kidney diseases such as chronic kidney diseases, e.g. diabetic nephropathy
• calpain inhibitor calpastatin is down regulated during renal ischemia reperfusion (Am. J. Physiol. Renal Physiol. 2000, 279, pp. 509-517).
• A. Dnyanmote et al, Toxicology and Applied Pharmacology 2006, 215, pp.146-157 have shown that inhibition of calpain via overexpression of calpastatin reduces the progression of DCVC-induced renal injury in a model of acute renal failure.
• Calpain has also been identified as a central mediator essential for parasitic activity.
• Parasites like Plasmodium falciparum and Toxoplasma gondii exploit host cell calpains to facilitate escape from the intracellular parasitophorous vacuole and/or host plasma membrane. Inhibition of calpain- 1 in hypotonically lysed and resealed erythrocytes prevented the escape of P. falciparum parasites, which was restored by adding purified calpain- 1.
• efficient egress of T. gondii from mammalian fibroblasts was blocked by either small interfering RNA-mediated suppression or genetic deletion of calpain activity and could be restored by genetic complementation (D. Greenbaum et al, Science 324, 794 (2009). Because parasites that fail to escape from their host cells are unable to proliferate, suggesting a strategy for anti-parasitic therapeutics.
• WO 08/080969 describes nicotinamides of 3-amino-2-oxo carboxylic acid derivatives that in position 2 of the pyridine ring are linked to a substituted pyrazole via a nitrogen atom.
• WO 03/080182 describes the use of the aforementioned amides for the treatment of pulmonary diseases.
• the nonpeptide calpain inhibitors mentioned therein also have a number of disadvantages, in particular a low or absent selectivity in respect of related cysteine proteases, such as various cathepsins, likewise possibly leading to unwanted side effects.
• WO 07/016589 and WO 08/106130 describe 2-oxo carboxylic acid derivatives carrying a N-acylated 2-pyrrolidinecarboxylamido group in the 3-position. Also disclosed is their use for treating hepatitis C virus infections.
• Carboxamides comprising an a-ketoamide moiety in the amine component, in particular those described in WO 08/080969, have been demonstrated to be highly effective and selective calpain inhibitors. However, as found out by the inventors of the present invention, in some cases they have limited cytosolic stability, namely in humans, possibly resulting in their premature clearance from the cytosol. As a consequence, the pharmacokinetics of these compounds may be insufficient.
• X indicates, independently of each other, indicate a single bond or a double bond
• X indicates a single bond or an oxygen atom
• Ci-Ce-alkoxy Ci-C 6 -haloalkoxy, C 3 -C 7 -cycloalkyloxy, Ci-
• R lb radicals may together form a Ci-C4-alkylene group, or 2 R lb radicals bonded to adjacent C atoms of cycloalkyl may form together with the carbon atoms to which they are bonded also a benzene ring, is selected independently of one another from OH, SH, halogen, N0 2 , H 2 , CN, COOH, OCH 2 COOH, Ci-C 6 -alkyl, Ci-C 6 -alkoxy, Ci-C 6 -alkoxy-Ci-C 4 - alkyl, Ci-C6-alkylthio, where the alkyl moieties in the last 4 substituents mentioned may be partly or completely halogenated and/or have 1, 2 or 3 substituents R la ,
• R al , R bl and R cl are independently of one another H, Ci-C 6 -alkyl, Ci-C 6 - haloalkyl, Ci-C 6 -alkyl which has 1, 2 or 3 substituents R la , or C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, C 3 -C7-cycloalkyl, C 3 -C7-cycloalkyl-Ci-C 4 - alkyl, C 3 -C7-heterocycloalkyl-C i -C 4 -alkyl, C i -C 6 -alkoxy-C i -C 4 -alkyl, aryl, aryl-Ci-C 4 -alkyl, hetaryl or hetaryl-Ci-C 4 -alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1,
• R a2 , R b2 and R c2 are independently of one another H, Ci-C 6 -alkyl, Ci-C 6 - haloalkyl, Ci-C 6 -alkyl which has 1, 2 or 3 substituents R la , or C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-Ci-C 4 - alkyl, C 3 -C 7 -heterocycloalkyl-C i -C 4 -alkyl, C i -C 6 -alkoxy-C i -C 4 -alkyl, aryl, aryl-Ci-C 4 -alkyl, hetaryl or hetaryl-Ci-C 4 -alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstit
• R b3 and R c3 are independently of one another H, Ci-C6-alkyl, Ci-C 6 - haloalkyl, Ci-C 6 -alkyl which has 1, 2 or 3 substituents R la , or C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C 4 - alkyl, C3-C7-heterocycloalkyl-Ci-C4-alkyl, Ci-C6-alkoxy-Ci-C4-alkyl, aryl, aryl-Ci-C4-alkyl, hetaryl or hetaryl-Ci-C4-alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents R ld , or
• the two radicals R a2 and R a3 , or R b2 and R b3 or R c2 and R c3 form together with the N atom a 3 to 7-membered, optionally substituted nitrogen heterocycle which may optionally have 1, 2 or 3 further different or identical heteroatoms from the group of O, N, S as ring members,
• R M and R c4 are independently of one another Ci-C 6 -alkyl, Ci-C 6 - haloalkyl, Ci-C 6 -alkyl which has 1, 2 or 3 substituents R la , or C 2 -C 6 - alkenyl, C 2 -C 6 -alkynyl, C3-C7-cycloalkyl, C3-C7-cycloalkyl-Ci-C 4 - alkyl, C3 -C7-heterocycloalkyl-C 1 -C4-alkyl, C 1 -C 6 -alkoxy-C 1 -C4-alkyl, aryl, aryl-Ci-C4-alkyl, hetaryl or hetaryl-Ci-C4-alkyl, where aryl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents R ld , and
• R b6 and R c6 are independently of one another H, Ci-C 6 -alkyl, Ci-C 6 - alkoxy, Ci-C 6 -haloalkyl, Ci-C 6 -alkyl which has 1, 2 or 3 substituents R la , or C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 7 -cycloalkyl, C3-C7- cycloalkyl-C 1 -C4-alkyl, C3 -C7-heterocycloalkyl-C 1 -C4-alkyl, C 1 -Ce- alkoxy-C i-C 4 -alkyl, CO-Ci-C 6 -alkyl, CO-0-Ci-C 6 -alkyl, S0 2 -Ci-C 6 - alkyl, aryl, hetaryl, O-aryl, OCH 2 -aryl, ary
• R lb or two radicals R lc bonded to adjacent C atoms form together with the C atoms to which they are bonded a 4, 5, 6 or 7- membered, optionally substituted carbocycle or an optionally substituted heterocycle which has 1, 2 or 3 different or identical heteroatoms from the group of O, N and S as ring members;
• R ld is selected from halogen, OH, SH, N0 2 , COOH, C(0) H 2 , CHO, CN, H 2 , OCH 2 COOH, d-Ce-alkyl, Ci-Ce-haloalkyl, Ci-C 6 -alkoxy, Ci-C 6 - haloalkoxy, d-Ce-alkylthio, Ci-C 6 -haloalkylthio, CO-d-Ce-alkyl, CO-O- Ci-Ce-alkyl, NH-d-Ce-alkyl, HCHO, H-C(0)Ci-C 6 -alkyl, and S0 2 -Ci- Ce-alkyl; is Ci-C 6 -alkyl, Ci-C6-haloalkyl, Ci-C 6 -alkyl which has 1, 2 or 3 substituents R *3 , C 3 -C 7 -cycloalkyl, C 3 -C 7 -heter
• R 3 and R 4 are selected independently of one another from halogen, H 2 , CN, CF 3 ,
• R and R are selected independently of one another from hydrogen and C 1 -C4- alkyl; m is 0, 1 or 2; and n is 0, 1 or 2.
• the present invention therefore relates to the carboxamide compounds of the general formula I, their tautomers, the hydrates thereof, the pharmaceutically suitable salts of the carboxamide compounds I, the prodrugs of I and the pharmaceutically suitable salts of the prodrugs, tautomers or hydrates of I.
• the carboxamide compounds of the invention of the formula I, their salts, their prodrugs, their hydrates and their tautomers effectively inhibit calpain even at low concentrations. They are additionally distinguished by a high selectivity in relation to the inhibition of the calpain compared with other cysteine proteases, such as cathepsin B, cathepsin K, cathepsin L and cathepsin S, and by their improved stability against cytosolic degradation.
• carboxamide compounds of the invention of the formula I, their salts, their prodrugs, their hydrates and their tautomers are therefore particularly suitable for treating disorders and conditions in creatures, especially human creatures, which are associated with an elevated calpain activity.
• the invention therefore also relates to the use of carboxamide compounds of the formula I, their tautomers, their hydrates and their pharmaceutically suitable salts for the manufacture of a medicament, in particular of a medicament which is suitable for the treatment of a disorder or a condition which is associated with an elevated calpain activity.
• the invention further relates to a medicament, in particular a medicament which is suitable for the treatment of a disorder or a condition which is associated with an elevated calpain activity.
• the medicament comprises at least one carboxamide compound of the formula I, as described herein, the tautomer, the hydrate or a prodrug of compound I, or a pharmaceutically suitable salt of compound I or of the tautomer, the hydrate or a prodrug of I.
• This carboxamide compound, its salts, prodrugs, hydrates and tautomers like the compunds of formula I effectively inhibit calpain even at low concentrations. They are additionally distinguished by a high selectivity in relation to the inhibition of the calpain compared with other cysteine proteases, such as cathepsin B, cathepsin K, cathepsin L and cathepsin S, and by their improved stability against cytosolic degradation.
• these carboxamide compounds are particularly suitable for treating disorders and conditions in creatures, especially human creatures, which are associated with an elevated calpain activity.
• the invention therefore also relates to the use of these carboxamide compounds, their tautomers, their hydrates and their pharmaceutically suitable salts for the manufacture of a medicament, in particular of a medicament which is suitable for the treatment of a disorder or a condition which is associated with an elevated calpain activity as described herein for the compounds of formula I.
• the tautomers, the hydrates, the pharmaceutically suitable salts or the prodrugs reference is made to the compounds of formula I.
• the carboxamide compounds of the formula I may be present in the form of the oc- ketoamide, as shown in the formula I. Alternatively they may also be present in the form of a hydrate, i.e. the keto group in the a-position relative to the amide moiety in the amine component is transformed into two geminal hydroxy groups, as shown in the formula I-H below.
• R 1 , R 2 , R 3 , R 4 , X, m and n in formula I-H have the aforementioned meanings.
• both the a- ketoamide form and the hydrate form are present in a mixture.
• a-ketoamide form is indicated in the following formulae and descriptions, it is intended to include also the hydrate and mixtures thereof with the a- ketoamide form unless indicated otherwise. Hydrates and a-ketoamide forms are equally suitable as calpain inhibitors.
• the carboxamide compounds of the invention of the formula I are also able to form tautomers which are equally suitable as calpain inhibitors.
• Particular examples of tautomers to be mentioned are the compounds of the formula I-T:
• prodrug refers to a compound which is transformed under metabolic conditions into a compound of the formula I.
• prodrugs of the compounds I include the compounds of the formula I, wherein the oxygen atom of the keto group in a-position to the amide moiety is replaced with a group O-Alk-0, S-Alk- O or S-Alk-S, where Alk is linear C 2 -C 5 -alkandiyl, which may be unsubstituted or substituted with 1, 2, 3 or 4 radicals selected from Ci-C4-alkyl or halogen, examples for such groups including 0(CH 2 ) 2 0, 0(CH 2 ) 5 0, 0(CH 2 ) 4 0, S(CH 2 ) 2 0, S(CH 2 ) 5 0, S(CH 2 ) 4 0, etc.
• the aforementioned prodrugs are transformed into the corresponding a-ketoamide compounds of the formula I or into the corresponding hydrates of formula I-H.
• prodrugs and their pharmaceutically acceptable salts are also part of the invention.
• physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, organic sulfonic acids having 1 to 12 carbon atoms, e.g.
• Ci-C4-alkylsulfonic acids such as methanesulfonic acid, cycloaliphatic sulfonic acids such as S-(+)-10-camphorsulfonic acids, and aromatic sulfonic acids such as benzenesulfonic acid and toluenesulfonic acid, di- and tricarboxylic acids and hydroxy carboxylic acids having 2 to 10 carbon atoms, such as oxalic acid, malonic acid, maleic acid, fumaric acid, mucic acid, lactic acid, tartaric acid, citric acid, glycolic acid and adipic acid, as well as cis- and trans- cinnamic acid, furan-2-carboxylic acid and benzoic acid.
• physiologically tolerated salts of the compounds of the formula I may be in the form of mono-, di-, tri- or tetrasalts, meaning that they may comprise 1, 2, 3 or 4 of the aforementioned acid molecules per molecule of the formula I.
• the acid molecules may be present in their acidic form or as anion.
• the compounds of the invention may be in the form of a mixture of diastereomers, or of a mixture of diastereomers in which one of the two diastereomers is enriched, or of essentially diastereomerically pure compounds (diastereomeric excess de > 90%).
• the compounds are preferably in the form of essentially diastereomerically pure compounds (diastereomeric excess de > 90%).
• the compounds I of the invention may furthermore be in the form of a mixture of enantiomers (for example as racemate), of a mixture of enantiomers in which one of the two enantiomers is enriched, or essentially in enantiomerically pure compounds (enantiomeric excess ee > 90%).
• the compounds of the invention are frequently prone to racemization in relation to the stereochemistry of the carbon atom which carries the radical R 1 , so that mixtures are frequently obtained in relation to this carbon atom, or compounds which exhibit a uniform stereochemistry in relation to this C atom form mixtures under physiological conditions.
• alkyl In the context of the present description, unless stated otherwise, the terms “alkyl”, “alkoxy”, “alkylthio”, “haloalkyl”, “haloalkoxy”, “haloalkylthio”, “alkenyl”, “alkynyl”, “alkylene” and radicals derived therefrom always include both unbranched and branched “alkyl”, “alkoxy”, “alkylthio”, “haloalkyl”, “haloalkoxy”, “haloalkylthio”, “alkenyl”, “alkynyl” and “alkylene”, respectively.
• C n -C m - indicates the respective number of carbons in the hydrocarbon unit.
• halogenated substituents preferably have one to five identical or different halogen atoms, especially fluorine atoms or chlorine atoms.
• C 0 - Alkylene or (CH 2 )o or similar expressions in the context of the description designate, unless indicated otherwise, a single bond.
• halogen designates in each case, fluorine, bromine, chlorine or iodine, specifically fluorine, chlorine or bromine.
• chloromethyl dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2- bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl,
• Alkynyl straight-chain or branched hydrocarbon groups having two or more C atoms, e.g. 2 to 4, 2 to 6 or 2 to 10 carbon atoms and one or two triple bonds in any position but nonadjacent, e.g. C2-C 6 -alkynyl such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, l-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3 -pentynyl,
• Alkoxy or alkoxy moieties for example in alkoxyalkyl are Alkoxy or alkoxy moieties for example in alkoxyalkyl:
• Haloalkoxy alkoxy as described above, in which the hydrogen atoms of these groups are partly or completely replaced by halogen atoms, i.e. for example Ci-C 6 -haloalkoxy, such as chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2- difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy
• Alkoxyalkyl an alkyl radical ordinarily having 1 to 4 C atoms, in which one hydrogen atom is replaced by an alkoxy radical ordinarily having 1 to 6 or 1 to 4 C atoms.
• Examples thereof are CH 2 -OCH 3 , CH 2 -OC 2 H 5 , n-propoxymethyl, CH 2 -OCH(CH 3 ) 2 , n-butoxymethyl, (l-methylpropoxy)methyl, (2-methylpropoxy)methyl, CH 2 -OC(CH 3 ) 3 , 2-(methoxy)ethyl, 2-(ethoxy)ethyl, 2-(n-propoxy)ethyl, 2-(l-methylethoxy)ethyl, 2-(n-butoxy)ethyl, 2-( 1 -methylpropoxy)ethyl, 2-(2-methylpropoxy)ethyl,
• Alkylthio alkyl as defined above preferably having 1 to 6 or 1 to 4 C atoms, which is linked via an S atom, e.g. methylthio, ethylthio, n-propylthio and the like.
• Haloalkylthio haloalkyl as defined above preferably having 1 to 6 or 1 to 4 C atoms, which is linked via an S atom, e.g. fluoromethylthio, difluoromethylthio,
• Aryl a mono-, bi- or tricyclic aromatic hydrocarbon radical such as phenyl or naphthyl, especially phenyl.
• Heterocyclyl a heterocyclic radical which may be saturated or partly unsaturated or aromatic and which ordinarily has 3, 4, 5, 6, 7 or 8 ring atoms, where ordinarily 1, 2, 3 or 4, in particular 1, 2 or 3, of the ring atoms are heteroatoms such as N, S or O, besides carbon atoms as ring members.
• saturated heterocycles are in particular:
• Heterocycloalkyl i.e. a saturated heterocyclic radical which ordinarily has 3, 4, 5, 6 or 7 ring atoms, where ordinarily 1, 2 or 3 of the ring atoms are heteroatoms such as N, S or O, besides carbon atoms as ring members.
• heterocycloalkyl i.e. a saturated heterocyclic radical which ordinarily has 3, 4, 5, 6 or 7 ring atoms, where ordinarily 1, 2 or 3 of the ring atoms are heteroatoms such as N, S or O, besides carbon atoms as ring members.
• N-bonded, 5-membered saturated rings such as:
• N-bonded, 6-membered saturated rings such as:
• Unsaturated heterocyclic radicals which ordinarily have 4, 5, 6 or 7 ring atoms, where ordinarily 1, 2 or 3 of the ring atoms are heteroatoms such as N, S or O, besides carbon atoms as ring members. These include for example:
• Hetaryl a 5- or 6-membered aromatic heterocyclic radical which ordinarily has 1, 2, 3 or 4 nitrogen atoms or a heteroatom selected from oxygen and sulfur and, if appropriate, 1, 2 or 3 nitrogen atoms as ring members besides carbon atoms as ring members: for example
• R is Ci-Cio-alkyl, preferably C 3 -C 8 -alkyl, which may be partly or completely halogenated and/or have 1, 2 or 3 substituents R la as defined herein, where R la is in particular selected from Ci-C 4 -alkoxy and Ci-C 4 -haloalkoxy; C 3 -C7-cycloalkyl-methyl, where the cycloalkyl moiety may have 1, 2, 3 or 4 radicals R , as defined herein, where R is in particular selected from halogen, Ci-C 3 -alkyl, Ci-C 4 -haloalkyl, Ci-C 4 -alkoxy or Ci-C 4 -haloalkoxy; or benzyl or hetaryl-methyl, where phenyl and hetaryl in the last 2 radicals mentioned may be unsubstituted or carry 1, 2, 3 or 4 identical or different radicals R lc as defined herein, where R lc is in particular selected from
• R 1 is benzyl, where the phenyl group of benzyl may be unsubstituted or carry 1 or 2 identical or different radicals R lc as defined herein, where R lc is in particular selected from halogen, specifically fluorine and chlorine, Ci-C4-alkyl, Ci-C 4 -haloalkyl, Ci-C 4 -alkoxy, d-C 4 -haloalkoxy and (CH 2 ) p NR c6 R c7 , where p is 0 or 1 and R c6 and R c7 are as defined above, and in particular are selected form hydrogen and Ci-C4-alkyl or NR c6 R c7 together form a saturated N-bound heterocycle such as 4-morpholinyl, 1-pyrrolidinyl, 1-piperidinyl or 1-piperazinly or 4-methylpiperazin-l-yl and where R lc is especially selected from fluorine, chlorine, methyl, methoxy,
• R la , R lb and R lc where present have the aforementioned meanings.
• R la , R lb and R lc where present have the aforementioned meanings.
• R la is Ci-C4-alkoxy or Ci-C4-haloalkoxy
• R lb is halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy or C1-C4- haloalkoxy;
• R lc is halogen, Ci-C 4 -alkyl, OH, SH, CN, Ci-C 4 -haloalkyl, Ci-C 4 -haloalkoxy, COOH, 0-CH 2 -COOH, Ci-C 6 -alkoxy, Ci-C 6 -alkylthio, C 3 -C 7 -cycloalkyl, COO-Ci-Ce-alkyl, CONH 2 , CONH-Ci-C 6 -alkyl, S0 2 NH-Ci-C 6 -alkyl, CON- (Ci-C 6 -alkyl) 2 , S0 2 N-(Ci-C 6 -alkyl) 2 , NH-S0 2 -Ci-C 6 -alkyl, NH-CO-Ci-C 6 - alkyl, S0 2 -Ci-C 6 -alkyl,
• R c6 , R c7 are independently of one another hydrogen or Ci-C 6 -alkyl, or together with the nitrogen atom to which they are bonded, are a morpholine, piperidine, pyrrolidine, azetidine or piperazine residue, where the last 5 radicals mentioned are unsubstituted or may carry 1, 2, 3 or 4 radicals selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy or C 1 -C 4 - haloalkoxy.
• R lc is particularly preferred halogen, specifically fluorine and chlorine, Ci- C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy and
• R c6 R c7 (CH 2 )p R c6 R c7 , where p is 0 or 1 and R c6 and R c7 are as defined above, and in particular are selected form hydrogen and Ci-C4-alkyl or R c6 R c7 together form a saturated N-bound heterocycle such as 4-morpholinyl, 1- pyrrolidinyl, 1-piperidinyl or 1-piperazinyl or 4-methylpiperazin-l-yl and where R lc is especially selected from halogen, Ci-C4-alkyl, such as methyl, CF 3 , CHF 2 , CH 2 F, Ci-C 4 -alkoxy, such as methoxy, 0-CF 3 , 0-CHF 2 and O- CH 2 F.
• Ci-C4-alkyl such as methyl, CF 3 , CHF 2 , CH 2 F
• Ci-C 4 -alkoxy such as methoxy, 0-CF 3 , 0-CHF
• R xb and R xd independently of one another, are CN, halogen, Ci-C 4 -alkyl, Ci-C 4 - haloalkyl, Ci-C 4 -alkoxy or Ci-C 4 -haloalkoxy.
• R 2 is selected from Ci-C 6 -alkyl, Ci-C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-Ci-C 4 -alkyl, C 3 -C 6 - heterocycloalkyl-Ci-Cs-alkyl, (Ci-C 4 -alkylene)-COOR al , Ci-C 4 -alkoxy-Ci-C 2 - alkyl, phenyl, phenyl-Ci-C 3 -alkyl, hetaryl and hetaryl-Ci-C 3 -alkyl, where phenyl and hetaryl in the last four mentioned radicals is unsubstituted or carries 1, 2 or 3 substituents R xd and where R al and R xd are as
• X is O. In another particular embodiment, X indicates a single bond.
• X is O and R 2 is selected from the group consisting of Ci-C 6 -alkyl, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl or tert.
• X indicates a single bond and R 2 is selected from the group consisting of Ci-C 6 -alkyl, specifically methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. -butyl or tert.
• C 2 -C4-alkynyl such as 2- propynyl, C3-C 5 -cycloalkyl, in particular C3-C4-cycloalkyl, specifically cyclopropyl, cyclobutyl or cyclopentyl
• C3-C4-cycloalkyl-methyl specifically cyclopropylmethyl
• morpholin-4-yl-Ci-C3-alkyl specifically 2-(morpholin-4-yl)- ethyl or 3-(morpholin-4-yl)-propyl
• (Ci-C 2 -alkylene)-COO-Ci-C4-alkyl such as CH 2 -C(0)OCH 3 , CH(CH 3 )-C(0)OCH 3 , CH 2 -C(0)OC 2 H 5 or
• benzimidazol-2-yl-methyl oxazol-2-yl-Ci-C3-alkyl, such as oxazol-2-yl-methyl
• benzoxazolyl-Ci-C3-alkyl such as l,3-benzoxazol-2-yl-methyl.
• X indicates a single bond and R 2 is selected from the group consisting of methyl, ethyl, propyl, butyl, propenyl, specifically allyl, but-2-en-l-yl, but-3-en-l-yl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopropyl-methyl, morpholin-4-yl-propyl, phenyl, benzyl, phenyl-ethyl, pyridin-2-ylmethyl, pyridin-2-yl ethyl, pyridin-2-ylpropyl, l,3-benzoxazol-2-yl- methyl, benzimidazol-2-yl-methyl, oxazol-2-yl-methyl and CH 2 -C(0)OCH 3 .
• -X-R 2 is methyl, ethyl, propyl, butyl, allyl, cyclopropyl, cyclobutyl, cyclopropyl-methyl, benzyl, phenyl-ethyl, pyridin-2-ylmethyl, pyridin-2-ylethyl, pyridin-2-ylpropyl, CH 2 -C(0)OCH 3 , methoxy, ethoxy, 2-propen-l-yloxy, but-2- en-l-yloxy, but-3-en-l-yloxy, 2-propynyloxy, cyclopropoxy, cyclopropyl- methoxy, phenoxy, benzyloxy and 0-CH 2 -C(0)OCH 3 .
• R 3 is in particular halogen, specifically fluorine or chlorine, CN, CF 3 , CHF 2 , CH 2 F, Ci-C 2 -alkyl or Ci-C 2 -alkoxy.
• R 3 and R 4 are independently of one another fluorine, chlorine, methyl, ethyl or methoxy, and specifically fluorine is 0 or 1 and specifically 0; and n is 0 or 1 and specifically 0.
• radicals R ld , R al , R bl , R cl , R a2 , R b2 , R c2 , R a3 , R b3 , R c3 , R a4 , R M , R c4 , R R b5 , R c5 , R a6 , R b6 , R c6 , R a7 , R b7 , R c7 , R and R have, unless otherwise indicated, independently of one another preferably one of the following meanings:
• R al , R bl , R cl independently of one another: hydrogen, Ci-C 6 -alkyl, Ci-C6-haloalkyl, phenyl, benzyl, hetaryl or hetarylmethyl, where phenyl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents which are selected from halogen, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy.
• R a2 , R b2 , R c2 independently of one another: hydrogen, Ci-C 6 -alkyl, phenyl, benzyl, hetaryl or hetarylmethyl, where phenyl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents which are selected from halogen, C1-C4- alkyl, Ci-C 4 -haloalkyl, Ci-C 4 -alkoxy and Ci-C 4 -haloalkoxy.
• R a4 , R M , R c4 independently of one another: Ci-C 6 -alkyl, phenyl, benzyl, hetaryl or hetarylmethyl, where phenyl and hetaryl in the last 4 radicals mentioned are
• R a6 , R b6 , R c6 independently of one another: hydrogen, Ci-C 6 -alkyl, phenyl, benzyl, hetaryl or hetarylmethyl, where phenyl and hetaryl in the last 4 radicals mentioned are unsubstituted or have 1, 2 or 3 substituents which are selected from halogen, C 1 -C 4 - alkyl, Ci-C 4 -haloalkyl, Ci-C 4 -alkoxy and Ci-C 4 -haloalkoxy.
• R a7 , R b7 , R c7 independently of one another: hydrogen or Ci-C 6 -alkyl, or R a6 with R a7 (and likewise R b6 with R b7 and R c6 with R c7 ) together with the nitrogen atom to which they are bonded are a morpholine, piperidine, pyrrolidine, azetidine or piperazine residue, where the last 5 radicals mentioned are unsubstituted or may carry 1, 2, 3 or 4 radicals selected from Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, Ci-C 4 -alkoxy and C 1 -C 4 - haloalkoxy.
• R and R' independently of one another: hydrogen, methyl or ethyl.
• R 1 , R 2 , R 3 , R 4 , n and m are as defined herein, and where R 1 , R 2 , R 3 , R 4 , X, m and n, alone or in combination, have in particular the preferred or special meanings.
• Carboxamide compounds of the formula la that are present in the hydrate form shown in formula I-H are named herein compounds of formula Ia-H.
• R 1 , R 2 , R 3 , R 4 , n and m are as defined herein, and where R 1 , R 2 , R 3 , R 4 , X, m and n, alone or in combination, have in particular the preferred or special meanings.
• Carboxamide compounds of the formula lb that are present in the hydrate form shown in formula I-H are named herein compounds of formula Ib-H.
• the compounds of the formula I are predominately in the S-configuration at the carbon atom carrying the radical R 1 , and according to a particular preferred embodiment the compounds I are completely S-configurated at said position.
• the hydrogen atom linked to the carbon atom carrying the radical R 1 of a compound I is replaced by a deuterium atom, as shown in formula I-D below.
• R 1 , R 2 , R 3 , R 4 , X, m and n in formula I-H have the aforementioned meanings, and where R 1 , R 2 , R 3 , R 4 , X, m and n, alone or in combination, have in particular the preferred or special meanings.
• the degree of deuteration at said position usually exceeds 80%, preferably exceeds 90% and in particular exceeds 95%.
• the deuterated diasteromers of formula I-D often show a markedly higher stability against racematisation than their counterparts of formula I, probably due to a kinetic isotope effect (see F. Maltais et al. J. Med. Chem, DOI 10.1021/jm901023f).
• the compounds of the invention of the general formula I and the starting materials used to prepare them can be prepared in analogy to known processes of organic chemistry as are described in standard works of organic chemistry, e.g. Houben-Weyl, “Methoden der Organischen Chemie”, Thieme-Verlag, Stuttgart, Jerry March “Advanced Organic Chemistry", 5 th edition, Wiley & Sons and the literature cited therein, and R. Larock, "Comprehensive Organic Transformations", 2 nd edition, Weinheim, 1999 and the literature cited therein.
• the carboxamide compounds of the invention of the general formula I are advantageously prepared by the methods described below and/or in the experimental section.
• Step i) is ordinarily carried out at temperatures in the range from -20°C to +25°C.
• hydroxy diamide compound IV is oxidized to the carboxamide compound ⁇ of the invention.
• Various conventional oxidation reactions are suitable for this (see R. C. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 604 et seq.) such as, for example, Swern oxidation and Swern analogous oxidations (T.T. Tidwell, Synthesis 1990, pp. 857-870) or Pfitzner-Moffatt oxidation.
• Suitable coupling reagents are known to those skilled in the art and are selected, for example, from carbodiimides such as DCC, EDC, CDI (carbonyldiimidazole), carbonyldipyrazole and DCI (diisopropylcarbodiimide), benzotriazole derivatives such as 1- hydroxybenzotriazole, HBTU ((0-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) and HCTU (l-[bis(dimethylamino)methylene]-5-chloro-lH- benzotriazolium tetrafluoroborate), pyridinotriazole derivatives such as HATU (2-(7- aza-lH-benzotriazol-l-yl)-l, 1,3,3 -tetramethyluronium hexafluorophosphate), and phosphonium activators
• the activator is used in excess.
• the benzotriazole and phosphonium coupling reagents are generally used in a basic medium, e.g. in the presence of an amine different from VIII, preferably a non- nucleophilic amine, such as tertiary aliphatic amines, in particular diisopropyl- ethylamine, and alicyclic amines.
• the reaction conditions usually correspond to those given above for step i) of scheme 1.
• the resulting compound IX is then converted to the target compound I" with a procedure analogous to the one described for step ii) of scheme 1.
• the amines VII and the hydroxylamines VIII are either commercially available or can be prepared according to established processes.
• the carboxylic acid II can be prepared by hydrolyzing the carboxylic ester XI with acids or bases under generally customary conditions.
• the hydrolysis preferably takes place with bases such as alkali metal or alkaline earth metal hydroxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide in aqueous medium, such as a mixture of water and organic solvents, e.g. alcohols such as methanol or ethanol, ethers such as tetrahydrofuran or dioxane, at room temperature or elevated temperature such as 25-100°C.
• bases such as alkali metal or alkaline earth metal hydroxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide in aqueous medium, such as a mixture of water and organic solvents, e.g. alcohols such as methanol or ethanol, ethers such as tetrahydrofuran or dioxane, at room temperature or elevated temperature such as 25-100°C.
• R 3 , R 4 , m and n have the aforementioned meanings.
• R 6 is alkyl, preferably Ci-C 6 -alkyl.
• LG represents a nucleophilically displaceable leaving group.
• suitable nucleophilically displaceable leaving groups are halogen, e.g. chlorine or bromine, or tosylate.
• R 6 is alkyl, preferably Ci-C6-alkyl.
• R 3 , R 4 , m and n have the aforementioned meanings.
• an ester XII is reacted with an appropriate indazole compound of the formula XIII.
• the reaction is ordinarily carried out under conventional conditions in the presence of a base in an inert solvent at elevated temperature. It may be advantageous, where appropriate, to carry out the reaction in the presence of catalytically active amounts of a transition metal, in particular of a metal of group 10 or 1 1 in the periodic table.
• the reaction is preferably carried out at elevated temperature without diluent or in an inert solvent such as an ether, e.g. tetrahydrofuran or dioxane, carboxamides such as N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide or N-methylpyrrolidone, or an aromatic hydrocarbon such as benzene, toluene or o-, m- or p-xylene.
• an inert solvent such as an ether, e.g. tetrahydrofuran or dioxane, carboxamides such as N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide or N-methylpyrrolidone, or an aromatic hydrocarbon such as benzene, toluene or o-, m- or p-xylene.
• Suitable inorganic bases are alkali metal or alkaline earth metal amides such as sodium amide, alkali metal or alkaline earth metal carbonates such as potassium carbonate or cesium carbonate or alkali metal hydrides such as sodium hydride.
• Suitable organic bases are tertiary amines, such as, for example, trimethylamine or triethylamine.
• a suitable crown ether is 18-crown-6.
• a Cu(I) salt such as, for example, Cul, CuCN, Cu 2 0 is added, where appropriate, as catalyst (see, for example, US 4,826,835 and WO 88/00468).
• the nicotinic acid ester derivatives XII and the indazole compounds XIII can be purchased or can be prepared by conventional methods.
• reaction mixtures are worked up in a conventional way, e.g. by mixing with water, separating the phases and, where appropriate, purifying the crude products by chromatography.
• the intermediates and final products in some cases result in the form of colorless or pale brownish, viscous oils which are freed of volatiles or purified under reduced pressure and at moderately elevated temperature. If the intermediates and final products are obtained as solids, the purification can also take place by recrystallization or digestion.
• the compounds of the invention exhibit extremely low Ki values in relation to the inhibition of calpain and thus permit efficient inhibition of calpain, especially calpain I, at low serum levels.
• the compounds of the invention ordinarily exhibit Ki values in relation to the inhibition of calpain in vitro of ⁇ 1500 nM, preferably ⁇ 800 nM, in particular ⁇ 400 nM and specifically ⁇ 250 nM.
• the compounds of the invention are therefore particularly suitable for the treatment of disorders associated with an elevated calpain activity.
• the compounds of the invention are selective calpain inhibitors, i.e. the inhibition of other cysteine proteases such as cathepsin B, cathepsin K, cathepsin L or cathepsin S takes place only at concentrations which are distinctly higher than the concentrations necessary for inhibition of calpain. Accordingly, the compounds of the invention ought to show distinctly fewer side effects than the prior art compounds which are comparatively unselective in relation to inhibition of calpain and likewise inhibit other cysteine proteases.
• Compounds preferred according to the invention accordingly have a selectivity in relation to inhibition of cathepsin K, expressed in the form of the ratio of the Ki for inhibition of cathepsin K to the Ki for inhibition of calpain of > 5, in particular > 9 and specifically > 30.
• Compounds preferred according to the invention accordingly have a selectivity in relation to inhibition of cathepsin L, expressed in the form of the ratio of the Ki for inhibition of cathepsin L to the Ki for inhibition of calpain of > 5, in particular > 10 and specifically > 50.
• the compounds of the present invention feature an improved stability in the cytosole of human cells, which markedly contributes to their good overall metabolic stability.
• the cytosolic stability can be measured for example by incubating a solution of a compound of the invention with liver cytosole from particular species (for example rat, dog, monkey or human) and determining the half-life of the compound under these conditions. It is possible to conclude from larger half-lives that the metabolic stability of the compound is improved.
• the stability in the presence of human liver cytosole is of particular interest because it makes it possible to predict the metabolic degradation of the compound in the human liver. Compounds with enhanced cytosolic stability therefore are likely to be degraded at reduced rates in the liver.
• the compounds of the invention remain in the cytosol for extended periods, i.e. have a decreased cytosolic clearance, and therefore ought to show enhanced human pharmacokinetics.
• Compounds preferred according to the invention accordingly have, after an incubation in human hepatocytes for 4 hours, a concentration ratio of the hydroxyamide metabolite to their corresponding parent compound of formula I of ⁇ 5, in particular ⁇ 2 and specifically ⁇ 0.5.
• neurodegenerative disorders especially those neurodegenerative disorders occuring as a result of a chronic brain supply deficit, of an ischemia (stroke) or of a trauma such as brain trauma, and the neurodegenerative disorders Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease, also multiple sclerosis and the damage to the nervous system associated therewith, especially damage to the optic nerve (optic neuritis) and the nerves which control the movement of the eye.
• preferred embodiments of the invention relate to the treatment of neurodegenerative disorders, especially of the aforementioned neurodegenerative disorders in humans, and to the use of the compounds of the invention of the formula I, their tautomers and their pharmaceutically suitable salts for the manufacture of a medicament for the treatment of these disorders.
• Disorders associated with an elevated calpain activity also include epilepsy.
• the compounds of the invention can be used in creams, ointments or lotions for topical administration.
• the tablets may be coated with sucrose, a cellulose derivative or another suitable substance or be treated otherwise in order to display a prolonged or delayed activity and in order to release a predetermined amount of the active basic ingredient continuously.
• the active basic ingredient may also be formulated as microcapsules or
• reaction was carried out in analogy to reaction step 3.1 by reacting 2-(6- trifluoromethyl-2H-indazol-2-yl)nicotinamido] -2-hydroxy-4-phenylbutanoic acid and O-methylhydroxylamine hydrochloride.
• the "Sel. cat. K” column indicates the Ki(cathepsin K)/Ki(calpain) ratio.
• +++ means a Ki(cathepsin K)/Ki(calpain) ratio of > 30, ++ means 9 ⁇
• the "Sel. cat. S” column indicates the Ki(cathepsin S)/Ki(calpain) ratio.
• +++ means a Ki(cathepsin S)/Ki(calpain) ratio of > 50
• ++ means 10 ⁇ Ki(cathepsin S)/Ki(calpain) ⁇ 50
• + means 5 ⁇ Ki(cathepsin S)/Ki(calpain) ⁇ 10
• o means Ki(cathepsin S)/Ki(calpain) ⁇ 5.
• molt-4 cells are maintained in RPMI 1640 + GlutamaxTM I medium (Gibco) with 10% FCS and 50 ⁇ g/ml gentamicin at 37°C, 5% C0 2 and split 1 : 15 twice a week.
• Test mixture for each mixture, 10 6 cells (see above) are introduced into a 1.5 ml Eppendorf tube. To these are added in each case 150 ⁇ of the diluted substances (final cone. 10-5 M; 2.5 x 10 "6 M and 6.25 x 10 “7 M) and thoroughly mixed. A negative control and a positive control are used as controls. In this case, initially only 150 ⁇ of HBS buffer is pipetted onto the cells. All the mixtures are incubated at 37°C, 5% C0 2 in an incubator for 10 min. Thereafter, except for the negative control, in each case CaCl 2 (final cone. 5 mM) and ionomycin (final cone.
• SDS-PAGE electrophoresis 10 ⁇ g of total protein from each mixture are put into a new Eppendorf tube and, after pipetting in the same volume of 2x Tris-glycine SDS sample buffer (Invitrogen) and 1/10 volume of 1M DTT, thoroughly mixed and heated at 95°C for 15 min. The solutions are briefly centrifuged and loaded onto a 6% SDS gel (Invitrogen). The gel is run at 100V with l x Tris-glycine laemmli buffer (Biomol) until the lower band of the marker has reached the base of the gel.
• 0.5 ⁇ of a compound to be tested was incubated with lmg/ml of human liver cytosol as well as monkey liver cytosol at 37°C in 0.5 M of phosphate buffer at pH 7.5 while shaking (commercial sources: female cynomolgus liver cytosol from Tebu bio, human liver cytosol from BDgentest).
• moderately stable from about 1/3 to about 2/3 of the hepatic plasma flow
• instable more than 2/3 of the hepatic plasma flow. Based on this adjustment the following qualifiers were assigned to evaluate the cytosolic stabilities of the compounds tested: cytCL symbol human cynomolgus
• Each compound to be tested (10 ⁇ ) was incubated in monkey and also in human hepatocytes to determine the concentration ratio of hydroxyamide metabolite to the compound of formula I as parent compound. Incubations were carried out at 37°C for 0 and 4 hours in a 24-well plate, each well holding 0.5 ml hepatocyte medium with about 500,000 cells/ml. At the end of each time point, 1 ml of acetonitrile/ethanol (1/1, v/v) was added to each well to quench the reaction. The solutions were vortexed and mixed thoroughly. An aliquot was subjected to LC-UV-MS/MS analysis at UV wavelength of 254 nm.
• the tested compounds were prepared as a solution for either intravenous or oral administration to groups of female cynomolgus monkeys.
• the compounds were prepared in a 10% DMSO / PEG-400 vehicle at a concentration of 2 mg/ml.
• For oral dosing the compounds were prepared in a lipid based vehicle at a concentration of 3 mg/ml.
• Groups of three monkeys received either a 1 mg/kg (0.5 ml/kg) intravenous dose or a 3 mg/kg (1 ml/kg) oral dose.
• the intravenous dose was administered as a slow bolus in a saphenous vein; the oral dose was administered by gastric intubation and was followed by ⁇ 5 ml water.
• Serial blood samples were obtained from each animal at selected time points up to 24 hours after drug administration.
• Plasma was separated from the blood by centrifugation and stored frozen ( ⁇ -15C) until analysis.
• Parent compounds I and the selected metabolites were separated from plasma using protein precipitation with mixture of methanol, acetonitrile and water. The supernatant was evaporated to dryness with a stream of dry nitrogen. The samples were reconstituted with an aliquot of mobile phase, followed by quantification by FIPLC- MS/MS. Standard curves for both parent and the selected metabolites were prepared from authentic standards in blank monkey plasma; standards were analyzed
• the plasma concentration of each sample was calculated by least squares linear regression analysis of the peak area ratio (parent or metabolite/internal standard) of the spiked plasma standards versus concentration.
• Peak plasma concentrations (Cma X ) and the time to peak plasma concentration (Tma X ) were read directly from the plasma concentration data for each monkey.
• the plasma concentration data for both parent and metabolite were submitted to multi-exponential curve fitting using WinNonlin.
• the area under the plasma concentration-time curve from 0 to t hours (time of the last measurable plasma concentration) after dosing (AUCo- t ) was calculated using the linear trapezoidal rule for the plasma concentration- time profiles.
• the apparent total plasma clearance (CL P ) was calculated by dividing the administered dose by the AUCo-inf.
• the volume of distribution at steady state, V ss was estimated as a product of the plasma clearance (CL P ) and the mean residence time (MRT); the terminal-phase volume of distribution (V ), was derived from the plasma clearance value (CL P ) divided by the plasma elimination rate constant ( ⁇ ).
• the bioavailability was calculated as the dose-normalized AUCo-inf from the oral dose divided by the corresponding value derived from the intravenous dose.
• Metabolite to parent ratios were calculated as the C max (metabolite)/C max (parent) or AUC(metabolite)/AUC(parent) for the peak concentrations and area under the curve, respectively. Results obtained in these ways are shown in Table 3.
• N-(3 - Amino- 1 -benzyl-2, 3 -dioxopropyl)-2-(2H-indazol-2-yl)nicotinamide (as described in Example 78 of WO 08/080969) was used as a comparative example also carrying a 2H-indazol-2-yl substitent in position 2 of the nicotimamide moiety and having an unsubstituted carboxamide moiety.

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