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US 6,747,024 B1Granted
Heterocyclic compounds and their use as medicines
AssigneeSociete de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S.)
InventorsSerge Auvin, Pierre-Etienne Chabrier de Lassauniere
Life of this patent
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Abstract
The present invention relates to new heterocyclic derivatives having an inhibitory activity on calpains and/or a trapping activity on reactive oxygen species, of formula in which A, X, Y, R1, R2 and Het represent variable groups. The invention also relates to their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular as inhibitors of calpains and/or traps of reactive oxygen species, selectively or non-selectively.
Claims17
A compound of the formula
- in racemic, enantiomeric or diastereoisomeric form and all combinations of these forms, wherein
- R1 is selected from the group consisting of hydrogen, —OR3, —SR3, oxo and cyclic acetal,
- R3 is selected from the group consisting of hydrogen, alkyl, aralalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl and aralkylcarbonyl, the akyl, aryl or heterocycloalkyl unsubstituted or substituted by at least one member selected from the group consisting of alkyl, —OH, alkoxy, nitro, cyano, halogen and —NR4R5;
- R4 and R5 are independently selected from the group consisting of hydrogen or alkyl, or R4 and R5 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
- R2 is selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl, the aryl group being unsubstituted or substituted by at least one member selected from the group consisting of —OR6, —NR7R8, halogen, cyano, nitro and alkyl,
- R6, R7, and R8 are independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkylcarbonyl, arylcarbonyl and aralkylcarbonyl,
- A is
- wherein R9, R10, R11, R12, R13 are independently selected from the group consisting of hydrogen, halogen, —OH, alkyl, alkoxy, cyano, nitro and —NR15R16,
- R15 and R16 are independently selected from the group consisting of hydrogen, alkyl and —COR17, or R15 and R16 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
- R17 is selected from the group consisting of hydrogen, alkyl, alkoxy and —NR18R19,
- R18 and R19 are independently selected from the group consisting of hydrogen or alkyl, or R18 and R19 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
- R14 is hydrogen, alkyl and —COR20,
- R20 is selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aralkyl, heterocycloalkyl and —NR21R22,
- in which the alkyl, aryl or heterocycloalkyl are unsubstituted or substituted by at least one member selected from the group consisting of alkyl, —OH, alkoxy, nitro, cyano, halogen, and —NR4R5;
- R21 and R22 are independently selected from the group consisting of hydrogen and alkyl, or R21 or R22 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
- W is S,
- X is selected from the group consisting of —(CH2)n—, —(CH2)n—CO—, —N(R45)—CO—(CH2)n—CO—, —N(R45)—CO—D—CO—, —CO—N(R45)—D—CO—, —CO—D—CO—, —CH═CH—(CH2)n—CO—,
- —N(R45)—(CH2)n—CO—, —N(R45)—CO—C—(R46R47)—CO—, —O—(CH2)n—CO—, —N(R45)—CO—NH—C(R46R47) —CO—,—CO—N(R45)—C(R46R47)—CO—, —S—(CH2)n—CO— and —Z—CO—;
- D is phenylene unsubstituted or substituted by at least one member of the group consisting of alkyl, alkoxy, —OH, nitro, halogen, cyano, and carboxyl optionally esterified by alkyl;
- Z is heterocycle,
- R45 is hydrogen or alkyl,
- R46 and R47 are independently selected from the group consisting of the group consisting of hydrogen, alkyl, aryl and aralkyl, the alkyl and aryl groups are unsubstituted or substituted by at least one member selected from the group consisting of —OH, —SH, halogen, nitro, alkyl, alkoxy, alkylthio, aralkoxy, aryl-alkylthio, —NR48R49 and carboxyl optionally esterified by alkyl;
- R48 and R49 are independently selected from the group consisting of hydrogen, alkyl, and —COR50, R48 and R49 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle;
- R50 is hydrogen, alkyl, alkoxy and —NR51R52.
- R51 and R52 are independently hydrogen or alkyl, or R51 and R52 together with the nitrogen atom to which they are attached, form an optionally substituted heterocycle;
- n is an integer between 0 and 6;
- Y is —(CH2)p—;
- P is O;
- Het is a heterocycle or a pharmaceutically acceptable addition salt with acids or bases thereof,
- with the exception of the compounds of formula (I) wherein Het is tetrahydrofuran or tetrahydropyran, R1 is OR3, R3 is selected from the group consisting of hydrogen, alkyl, arylalkyl, heterocycloalkylcarbonyl, the heterocycloalkyl being connected by a carbon atom, alkylcarbonyl, arylcarbonyl or aralkylcarbonyl, R2 is hydrogen and Y is —(CH2)p— with p=0, the X is —CO—N(R45)—C—(R46R47)—CO— with R45=R46=H and with the exclusion of the compound wherein
- i) X represents —CH2—C(O)— and Het 4-oxo-4H-1-benzopyran-2-yl;
- ii) X represents —NH—C(O)—C(O)— and Het phenothiazin-1-yl;
- iii) X represents —CH2— and Het 1-azabicyclo[2.2.2] oct-3yl.
30 more elements
A compound selected from the group consisting of
- N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide;
- (3S)-3({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)-amino]pentanoyl}amino)tetrahydro-2-furanyl acetate;
- N-[(3S)-2-hydroxytetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;
- N-[4({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;
- N-[(1S)-1-({[(3S)-2-hydroxytetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-1-carboxamide;
- (3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)tetrahydro-2-furanyl pivalate;
- (3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino)-tetrahydro-2-furanyl3,3-dimethylbutanoate;
- (3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino) tetrahydro-2-furanyl benzoate;
- (3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino) tetrahydro-2-furanyl phenylacetate;
- (3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino) tetrahydro-2-furanyl(2S)-2-(dimethylamino)-3-phenylpropanoate;
- and
- (3S)-3-({(2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoyl}amino) tetrahydro-2-furanyl 4-morpholinecarboxylate.
9 more elements
A compound selected from the group consisting of
- methyl (2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoate;
- (2S)-4-methyl-2-[(10H-phenothiazin-2-ylcarbonyl)amino]pentanoic acid;
- N-[(1S)-3-methyl-1-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)butyl]-10-phenothiazine-2-carboxamide;
- ethyl 2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxylate;
- 2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxylic acid;
- N-[(3S)-2-oxotetrahydro-3-furanyl]-2-(10H-phenothiazin-2-yl)-1,3-thiazol-4-carboxamide;
- methyl 4-[(10H-phenothiazin-2-ylcarbonyl)amino]benzoate;
- 4-[(10H-phenothiazin-2-ylcarbonyl)amino]benzoic acid;
- N-[4-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)phenyl]-10H-phenothiazine-2-carboxamide;
- methyl (2S)-4-methyl-2-[(10H-phenothiazin-1-ylcarbonyl)amino]pentanoate;
- (2S)-4-methyl-2-[(10H-phenothiazin-1-ylcarbonyl)amino]pentanoic acid;
- N-[(1S)-1-({[(3S)-2-oxotetrahydro-3-furanyl]amino}carbonyl)-3-methylbutyl]-10H-phenothiazine-carboxamide;
- and
- N-[(1S)-1-(1,4-dioxa-7-azaspiro[4.4]non-7-ylcarbonyl)-3-methylbutyl]-10H-phenothiazine-2-carboxamide.
11 more elements
A method of inhibiting calpain and/or reactive oxygen species in warm-blooded animals comprising administering to warm-blooded animals in need thereof a calpain inhibiting and/or reactive oxygen species inhibiting amount of a compound of the formula
- in racemic, enantiomeric, diastereoisomeric form or all combinations of these forms,
- wherein R1 is hydrogen, —OR3, —SR3, oxo and cyclic acetal,
- R3 is hydrogen, alkyl, arylalkyl, heterocycloalkylcarbonyl, alkylcarbonyl, arylcarbonyl and aralkylcarbonyl,
- in which the alkyl, aryl or heterocycloalkyl are unsubstituted or substituted by at least one member selected from the group consisting of alkyl, —OH, alkoxy, nitro, cyano, halogen and —NR4R5;
- R4 and R5 are independently hydrogen or alkyl, or R4 and R5 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
- Ra2 is hydrogen, alkyl, aryl and aralkyl, the aryl being unsubstituted or substituted by at least one member selected from the group consisting of —OR6, —NR7R8, halogen, cyano, nitro and alkyl,
- R6, R7 and R8 are independently hydrogen, alkyl, aryl, aralkyl, alkylcabonyl, arylcarbonyl and aralkylcarbonyl;
- Aa is
- wherein R9, R10, R11, R12, R13 are independently selected from the group consisting of hydrogen, halogen, —OH, alkyl, alkoxy, cyano, nitro and —NR15R16,
- R15 and R16 are independently selected from the group consisting of hydrogen, alkyl and —COR17, or R15 and R16 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
- R17 is selected from the group consisting of hydrogen, alkyl, alkoxy and —NR18R19,
- R18 and R19 are independently hydrogen or alkyl, or R18 and R19 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
- R14 is hydrogen or alkyl or —COR20,
- R20 is hydrogen, alkyl, alkoxy, aryl, aralkyl, heterocycloalkyl and —NR21R12,
- the alkyl, aryl or heterocycloalkyl are unsubstituted or substituted by at least one member selected from the group consisting of alkyl, OH, alkoxy, nitro, cyano, halogen and —NR4R5;
- R21 and R22 are independently hydrogen or alkyl, or R21and R22 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
- W is S;
- Xa is —(CH2)n—, —(CH2)n—CO—, —N(R45)—CO—(CH2)n—CO—, —N(R45)—CO—D—CO—, —CO—N(R45)—D—CO—, —CO—D—CO—, —CH═CH—(CH2)n—CO—, —N(R45)—(CH2)n—CO—, —N(R45)—CO—C(R46R47)—CO—, —O—(CH2)n—CO—, —N(R45)—CO—NH—C(R46R47)—CO—,—CO—N(R45)—C(R46R47)—CO—,—S—(CH2)n—CO— and —Z—CO—;
- D is phenylene unsubstituted or substituted by at least one member selected from the group consisting of alkyl, alkoxy, —OH, nitro, halogen, cyano and carboxyl optionally esterified by an alkyl radical;
- Z is a heterocycle,
- R45 is hydrogen or alkyl;
- R46 and R47 are independently selected from the group consisting of hydrogen, alkyl, aryl and aralkyl, the alkyl and aryl groups are unsubstituted or substituted by at least one member of the group consisting of —OH —SH, halogen, nitro, alkyl, alkoxy, alkylthio, aralkoxy, aryl-alkylthio, —NR48R49 and carboxyl optionally esterified by alkyl;
- R48 and R49 are independently selected from the group consisting of hydrogen, alkyl and —COR50, or R48 and R49 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle,
- R50 is selected from the group consisting of hydrogen, alkyl, alkoxy and —NR51R52,
- R51 and R52 are independently selected from the group consisting of hydrogen or alkyl, or R51 and R52 together with the nitrogen atom to which they are attached form an optionally substituted heterocycle;
- n is an integer between 0 and 6;
- Ya—(CH2)p—;
- P is O;
- Heta is a heterocycle,
- and pharmaceutically acceptable addition salts thereof with acids or bases.
27 more elements
Dependencies are inferred from the claim text.