WO2004101494B1 - Calpain inhibitors - Google Patents

Calpain inhibitors

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Publication number
WO2004101494B1
WO2004101494B1 PCT/ES2004/070034 ES2004070034W WO2004101494B1 WO 2004101494 B1 WO2004101494 B1 WO 2004101494B1 ES 2004070034 W ES2004070034 W ES 2004070034W WO 2004101494 B1 WO2004101494 B1 WO 2004101494B1
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Prior art keywords
phenyl
biphenyl
amino
group
aryl
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PCT/ES2004/070034
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Spanish (es)
French (fr)
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WO2004101494A1 (en
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Garcia Bernardo Herradon
Cano Esperanza Benito
Lopez Antonio Chana
Morales Enrique Mann
Aguado Ana Montero
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Consejo Superior Investigacion
Garcia Bernardo Herradon
Cano Esperanza Benito
Lopez Antonio Chana
Morales Enrique Mann
Aguado Ana Montero
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Publication of WO2004101494A1 publication Critical patent/WO2004101494A1/en
Publication of WO2004101494B1 publication Critical patent/WO2004101494B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to compounds comprising a peptide-biphenyl hybrid structure and to associated compounds having a calpain inhibitor activity. One of the inventive compounds is a 2,2'-disubstituted biphenyl, with the substituents at positions 2 and 2' of the biphenyl skeleton being chains containing structures that are associated with amino acids, peptides and amides, which can be identical or different. The invention also relates to all of the conformational isomers (atropisomers) of the aforementioned compound having formula I. Compounds having formula I can be used for the preventive or therapeutic treatment of a degenerative disease.

Claims

REIVINDICACIONES MODIFICADAS MODIFIED CLAIMS
[Recibidas por la Oficina Internacional el 22 de noviembre de 2004 (22.11.2004): reivindicaciones 1 - 3, reemplazadas por las reivindicaciones modificadas 1 - 3, las demás reivindicaciones siguen igual] 1. Uso de un compuesto bifenilo-2,2'-disustiruido de fórmula I[Received by the International Bureau on November 22, 2004 (22.11.2004): claims 1-3, superseded by the modified claims 1-3, the other claims remain the same] 1. Use of a biphenyl-2,2 'compound -disustiruido of formula I
Figure imgf000002_0001
i en la que los grupos R1 y R2 pueden ser iguales o distintos, y pueden estar 5 independientemente seleccionados entre los grupos - NH2, - NHR3 en el que R3 representa un grupo alquilo o arilo, - NR4R5 en el que R4 y R5 representan dos grupos alquilo o arilo, idénticos o diferentes, o formando un sistema cíclico,
Figure imgf000002_0001
i wherein the groups R 1 and R 2 may be the same or different, and may be independently selected from the groups - NH 2 , - NHR 3 wherein R 3 represents an alkyl or aryl group, - NR 4 R 5 wherein R 4 and R 5 represent two alkyl or aryl groups, identical or different, or forming a cyclic system,
10 - CO2H, - CO2R6 en el que R6 es un grupo arilo o alquilo, - CONH2, - CONR7R8 en el que R7 y R8 representan dos grupos alquilo o arilo, idénticos o diferentes, o formando un sistema cíclico,10 - CO 2 H, - CO 2 R 6 wherein R 6 is an aryl or alkyl group, - CONH 2 , - CONR 7 R 8 in which R 7 and R 8 represent two identical or different alkyl or aryl groups , or forming a cyclic system,
15 - un grupo de fórmula II,15 - a group of formula II,
Figure imgf000002_0002
II en la que: - Ar representa un grupo arilo, carbocíclico o heterocíclico, distinto de imidazol,
Figure imgf000002_0002
II in which: - Ar represents an aryl, carbocyclic or heterocyclic group, other than imidazole,
20 - el asterisco (*) representa un centro estereogénico, de configuración (R) ó (S), indistintamente, - n tiene un valor entre O y ó, - X, representa un grupo OH, OR9 en el que R9 representa un grupo alquilo o arilo, IMΗ2, NHR10, en el que R10 representa un grupo alquilo o 54 arilo, NR R en el que R y R representan dos grupos alquilo o arilo, idénticos o diferentes, o formando un sistema cíclico, - aa es un residuo de amino ácido, de fórmula R1320 - the asterisk (*) represents a stereogenic center, of configuration (R) or (S), indistinctly, - n has a value between O and ó, - X, represents a group OH, OR 9 in which R 9 represents an alkyl or aryl group, IMΗ2, NHR 10 , wherein R 10 represents an alkyl group or Aryl, NR R in which R and R represent two alkyl or aryl groups, identical or different, or forming a cyclic system, - aa is an amino acid residue, of formula R 13
H o dónde el asterisco (*) indica un centro estereogénico de configuración (R) o (S), indistintamente, R13 se selecciona entre H, alquilo o arilo; ó de fórmulaH or where the asterisk (*) indicates a stereogenic center of configuration (R) or (S), indistinctly, R 13 is selected from H, alkyl or aryl; or formula
Figure imgf000003_0001
en la que los átomos de nitrógeno y el carbono en posición α- están formando un anillo entre 4 y 7 eslabones, los residuos de aminoácido (aa) están unidos a través de su grupo amino a la cadena representada por -C(O)NHCH(CH2Ar)CO-; - un grupo de fórmula III,
Figure imgf000003_0001
in which the nitrogen atoms and the carbon in position α- are forming a ring between 4 and 7 links, the amino acid residues (aa) are linked through their amino group to the chain represented by -C (O) NHCH (CH 2 Ar) CO-; - a group of formula III,
>V H Ar III en la que Ar representa un grupo arilo; - un grupo de fórmula IV,> VH Ar III in which Ar represents an aryl group; - a group of formula IV,
Figure imgf000003_0002
IV en la que: 55
Figure imgf000003_0002
IV in which: 55
- Ar representa un grupo arilo, - (*), y n tienen el significado descrito anteriormente, - aa, tiene el significado descrito anteriormente, pero ahora el residuo de aminoácido está unido a través de su grupo carbonilo a la cadena representada por -NH C(O)CH(CH2Ar)NH-, - X representa H, alquilo entre 1 y 6 átomos de carbono, COR14 dónde R14 es un grupo arilo o alquilo, CO2R15, dónde R15 es un grupo arilo o alquilo; - un grupo de fórmula V,- Ar represents an aryl group, - (*), and n have the meaning described above, - aa, has the meaning described above, but now the amino acid residue is linked through its carbonyl group to the chain represented by -NH C (O) CH (CH 2 Ar) NH-, - X represents H, alkyl between 1 and 6 carbon atoms, COR 14 where R 14 is an aryl or alkyl group, CO 2 R 15 , where R 15 is an aryl group or alkyl; - a group of formula V,
o Ar V en la que Ar representa un grupo arilo;or Ar V in which Ar represents an aryl group;
y en la que al menos uno de los grupos R , R tiene la estructura indicada por los grupos II, o III, o IV, o V; y cualquiera de los isómeros conformacionales (atropisómeros) de dicho compuesto de fórmula I; como inhibidor de calpaina.and wherein at least one of the groups R, R has the structure indicated by groups II, or III, or IV, or V; and any of the conformational isomers (atropisomers) of said compound of formula I; as a calpain inhibitor.
2. Un compuesto bifenilo-2,2'-disustituido de fórmula I2. A biphenyl-2,2'-disubstituted compound of formula I
Figure imgf000004_0001
Figure imgf000004_0001
I en la que los grupos R1 y R2 pueden ser iguales o distintos, y pueden estar independientemente seleccionados entre los grupos - NH2, - NHR3 en el que R3 representa un grupo alquilo o arilo, - NR4R5 en el que R4 y R5 representan dos grupos alquilo o arilo, idénticos o diferentes, o formando un sistema cíclico, 56I wherein the groups R 1 and R 2 may be the same or different, and may independently be selected from the groups - NH 2 , - NHR 3 wherein R 3 represents an alkyl or aryl group, - NR 4 R 5 in that R 4 and R 5 represent two alkyl or aryl groups, identical or different, or forming a cyclic system, 56
- CO2H.- CO 2 H.
- CO2R6 en el que R6 es un grupo arilo o alquilo,- CO 2 R 6 wherein R 6 is an aryl or alkyl group,
- CONH2,- CONH 2 ,
- CONR7R8 en el que R7 y R8 representan dos grupos alquilo o arilo, idénticos o diferentes, o formando un sistema cíclico,- CONR 7 R 8 in which R 7 and R 8 represent two alkyl or aryl groups, identical or different, or forming a cyclic system,
- un grupo de fórmula II,- a group of formula II,
Figure imgf000005_0001
II en la que: - Ar representa un grupo arilo, carbocíclico o heterocíclico, distinto de imidazol. - el asterisco (*) representa un centro estereogénico, de configuración (R) ó (S), indistintamente, - n tiene un valor entre O y ó, - X, representa un grupo OH, OR9 en el que R9 representa un grupo alquilo o arilo, NH2, NHR10. en el que R10 representa un grupo alquilo o τ^-_ 1 1 1 1 1 Λ arilo, NR R en el que R y R representan dos grupos alquilo o arilo, idénticos o diferentes, o formando un sistema cíclico, - aa es un residuo de amino ácido, de fórmula
Figure imgf000005_0001
II wherein: - Ar represents an aryl, carbocyclic or heterocyclic group, other than imidazole. - the asterisk (*) represents a stereogenic center, of configuration (R) or (S), indistinctly, - n has a value between O and ó, - X, represents a group OH, OR 9 in which R 9 represents a alkyl or aryl group, NH 2 , NHR 10 . wherein R 10 represents an alkyl group or τ 1 - 1 1 1 aryl, NR R in which R and R represent two identical or different alkyl or aryl groups, or forming a cyclic system, - aa is an amino acid residue, of formula
Figure imgf000005_0002
dónde el asterisco (*) indica un centro estereogénico de configuración (R) o (S), indistintamente, R13 se selecciona entre H, alquilo o arilo; ó de fórmula
Figure imgf000006_0001
en la que los átomos de nitrógeno y el carbono en posición α- están formando un anillo entre 4 y 7 eslabones, los residuos de aminoácido (aa) están unidos a través de su grupo amino a la cadena representada por -C(O)NHCH(CH2Ar)CO-; un grupo de fórmula III,
Figure imgf000005_0002
where the asterisk (*) indicates a stereogenic center of configuration (R) or (S), indistinctly, R 13 is selected from H, alkyl or aryl; or formula
Figure imgf000006_0001
in which the nitrogen atoms and the carbon in position α- are forming a ring between 4 and 7 links, the amino acid residues (aa) are linked through their amino group to the chain represented by -C (O) NHCH (CH2Ar) CO-; a group of formula III,
Figure imgf000006_0002
III en la que Ar representa un grupo arilo; un grupo de fórmula IV,
Figure imgf000006_0002
III in which Ar represents an aryl group; a group of formula IV,
Figure imgf000006_0003
ιv en la que: - Ar representa un grupo arilo, - (*), y n tienen el significado descrito anteriormente, - aa, tiene el significado descrito anteriormente, pero ahora el residuo de aminoácido está unido a través de su grupo carbonilo a la cadena representada por -NH C(O)CH(CH2Ar)NH-, - X representa H, alquilo entre 1 y 6 átomos de carbono, COR14 dónde R es un grupo arilo o alquilo, CO2R15, dónde R15 es un grupo arilo o alquilo;
Figure imgf000006_0003
ιv in which: - Ar represents an aryl group, - (*), and n have the meaning described above, - aa, has the meaning described above, but now the amino acid residue is linked through its carbonyl group to the chain represented by -NH C (O) CH (CH 2 Ar) NH-, - X represents H, alkyl between 1 and 6 carbon atoms, COR 14 where R is an aryl or alkyl group, CO 2 R 15 , where R 15 is an aryl or alkyl group;
- un grupo de fórmula V, 58 MγAr O V en la que Ar representa un grupo arilo- a group of formula V, 58 M γ Ar OV where Ar represents an aryl group
y en la que al menos uno de los grupos R , R tiene la estructura indicada por los grupos II, o III, o IV, o V; con la condición de que cuando R1 y R2 sean iguales sean grupos distintos de (4-nitrobenzoilo)amino ó 2-naftoiloamino; y cualquiera de los isómeros conformacionales (atropisómeros) de dicho compuesto de fórmula I.and wherein at least one of the groups R, R has the structure indicated by groups II, or III, or IV, or V; with the proviso that when R 1 and R 2 are the same they are different groups of (4-nitrobenzoyl) amino or 2-naphthoyloamino; and any of the conformational isomers (atropisomers) of said compound of formula I.
3. Un compuesto según la reivindicación 2 caracterizado porque es de fórmula I y seleccionado entre - (S,S)-3-Fenil-2-{[2'-(2-fenil-l-metoxicarbonyl-etilcarbamoil)-bifenil-2-carbonil]- amino} -propionato de metilo (1), - Ácido (S,S)-2- { [2 ' -( 1 -carboxi-2-fenil-etilcarb amoil)-bifenil-2-carbonil] -amino } -3 - fenil-propiónico (2), - (S3S)-3-(lH-mdol-3-ü)-2-({2'-[2-(lH-mdol-3-ü)-l-metoxicarbonil-etilcarbamoil]- bifenil-2-carbonil}-amino)-propionato de metilo (3), - (S,SS)-2-(2-{[2'-(l-Carboxi-2-fenil-etilcarbamoil)-bifenil-2-carbonil]-ammo}-3- fenil-propionilamino)-3-metil-butirato de metilo (4), - (S,S,S,S)-2-[3-Fenil-2-({2'-[2-fenil-l-(2-metil-l-metoxicarbonil-propilcarbamoil)- etilcarbamoil]-bifenil-2-carbonil}-amino)-propionilamino]-3-metil-butirato de metilo (4a), - (S,S)-(2-Fenil-l-{2'-[3-fenil-2-(9H-fluoren-9-ilmetoxicarbonilamino)- propionilamino]-bifenil-2-ilcarbamoil}-etil)-carb amato de 9H-fluoren-9-ilmetilo (5), - 2'-Amino-2-[2-(nafioil)amino]bifenilo (7), - (S,SS)-2-[2-({2'-Amino-bifenil-2-πcarbamoil)-2-fenil-etilcarbamoil]-bifenil-2- carbonil}-amino)-3-fenil-propionilamino]-3-metil-butirato de metilo (8), - (S,S,S,S)-3-(lH-Indol-3-ü)-2-{3-fenil-2-[(2'-{2-fenil-l-[2-(lH-mdol-3-ü)-l- metoxicarbonil-etilcarbamoil]-etilcarbamoil}-bifenil-2-carbonil)- amino]propionilamino}-propionato de metilo (9), 593. A compound according to claim 2 characterized in that it is of formula I and selected from - (S, S) -3-Phenyl-2 - {[2 '- (2-phenyl-l-methoxycarbonyl-ethylcarbamoyl) -biphenyl-2 -carbonyl] -methyl} -propionate methyl (1), - (S, S) -2- {[2 '- (1 -carboxy-2-phenyl-ethylcarbomethyl) -biphenyl-2-carbonyl] -amino acid } -3-phenyl-propionic (2), - (S 3 S) -3- (lH-mdol-3-ü) -2 - ({2 '- [2- (lH-mdol-3-ü) - methyl l-methoxycarbonyl-ethylcarbamoyl] -biphenyl-2-carbonyl} -amino) -propionate (3), - (S, SS) -2- (2 - {[2 '- (l-Carboxy-2-phenyl- ethylcarbamoyl) -biphenyl-2-carbonyl] -ammo} -3-phenyl-propionylamino) -3-methyl-butyrate methyl (4), - (S, S, S, S) -2- [3-Phenyl-2 - ({2 '- [2-phenyl-l- (2-methyl-l-methoxycarbonyl-propylcarbamoyl) -ethylcarbamoyl] -biphenyl-2-carbonyl} -amino) -propionylamino] -3-methyl-butyrate methyl (4a ), - (S, S) - (2-Phenyl-l- {2 '- [3-phenyl-2- (9H-fluoren-9-ylmethoxycarbonylamino) -propionylamino] -biphenyl-2-ylcarbamoyl} -ethyl) - 9H-Fluoren-9-ylmethyl carbonate (5), - 2'-Amino-2- [2- (naphioyl) amino] biphenyl (7), - (S, SS) -2- [2 - ({2'-Amino-biphenyl-2-πcarbamoyl) -2-phenyl-ethylcarbamoyl] -biphenyl-2-carbonyl} -amino) -3-phenyl-propionylamino] -3-methyl- Methyl butyrate (8), - (S, S, S, S) -3- (lH-Indol-3-ü) -2- {3-phenyl-2 - [(2 '- {2-phenyl-1 - [2- (lH-mdol-3-ü) -l-methoxycarbonyl-ethylcarbamoyl] -ethylcarbamoyl} -biphenyl-2-carbonyl) -amino] propionylamino} -propionate methyl (9), 59
- Ácido (S)-2'-[2-(4-hidroxi-fenil)-l-metoxicarbonil-etilcarbamoil]-bifenil-2- carboxílico (10), - (S,S,S)-2-[3-Fenil-2-({2'-[2-(4-hidroxi-fenil)-l-metoxicarbonil-etilcarbamoil]- bifenil-2-carbonil}-amino)-propionilamino]-4-metil-pentanoato de metilo (11), - (S,S,S)-2-({2'-[2-fenil-l-(3-metil-l-metilcarbamoil-butilcarbamoil)-etilcarbamoil]- bifenil-2-carbonil}-amino)-3-(4-hidroxifenil)-propionato de metilo (12), - (S,S,S)-2-[3-Fenil-2-({2'-[2-(4-hidroxi-fenil)-l-metoxicarbonil-etilcarbamoil]- bifenil-2-carbonil}-amino)-propionilamino]-4-metilsulfanil-butirato de metilo (13), - Ácido 2'-{(S)-[2-fenil-l-(R)-(2-fenil-l-metilcarbamoil-etilcarbamoil)- etilcarbamoil]}-bifenil-2-carboxílico (14), - (S)-2-[(S)-2-({2'-(S)-[2-Fenil-l-(R)-(2-fenil-l-metilcarbamoil-etilcarbamoil)- etilcarbamoil]-bifenil-2-carbonil}-amino)-4-metil-pentanoilamino]-4-metilsulfanil- butirato de metilo (15), - Ácido (S)-2'-[2-fenil-l-metoxicarbonil-etilcarbamoil]-bifenil-2-carboxílico (16), - (R)-(3-Fenil-2-{[2'-(S)-(2-fenil-l-metoxicarbonil-etilcarbamoil)-bifenil-2- carbonil]-amino})-propionato de metilo (17), - (S,S)-3-(4-Hidroxi-fenil)-2-( {2 '-[2-(4-hidroxi-fenil)- 1 -metoxicarbonil- etilcarbamoil]-bifenil-2-carbonil}-amino)-propionato de metilo (18), - (S,S)-N-( 1 -Ferrocenilmetil)-3-fenil-2-( {2 ' -[2-fenil- 1 -( 1 -ferrocenilmetilcarbamoil)]- etilcarbamoil)-bifenil-2-carbonil}-amino)-propionamida (19), - N,N'-Rt1s'-(2-fluoro-5-nitro-fenil)-bifenil-2,2'-dicarboxamida (20), - (S,S)-2- Amino-N- [2'-(2-amino-3 -fenil-propionilamino)-bifenil-2-il] -3 -fenil- propionamida (21), - (S,S)- { 1 -[ 1 -(2,-Amino-bifenil-2-ilcarbamoil)-2-fenil-etilcarbamoil]-3-metil-butil} - carbamato de 9H-fluoren-9-ilmetilo (22), - 2,2'-di-[(3,5-dinitrobenzoil)amino)-bifenilo (24), - 2-(2-Νaftoilammo)-2'-[(3,5-dinitrobenzoil)amino]-bifemlo (25), - 2-(2-Νaftoilamino)-2'-[(4-nitrobenzoil)amino]-bifenilo (26), y - (S,S5S,S)-2-(3-Fenil-2-{[2,-(2-Fenil-l-{2,-[2-(9H-Fluoren-9- ilmetoxicarbomlamino)-propionilamino]-bifenil-2-ilcarbamoil}-etilcarbamoil)- bifenil-2-carbonil] -amino }-propionilamino)-3-metil-butirato de metilo (27), y por que es un inhibidor de calpaina. 60- (S) -2 '- [2- (4-hydroxy-phenyl) -l-methoxycarbonyl-ethylcarbamoyl] -biphenyl-2-carboxylic acid (10), - (S, S, S) -2- [3- Phenyl-2 - ({2 '- [2- (4-hydroxy-phenyl) -l-methoxycarbonyl-ethylcarbamoyl] -biphenyl-2-carbonyl} -amino) -propionylamino] -4-methyl-pentanoate methyl (11) , - (S, S, S) -2 - ({2 '- [2-phenyl-l- (3-methyl-l-methylcarbamoyl-butylcarbamoyl) -ethylcarbamoyl] -biphenyl-2-carbonyl} -amino) -3 Methyl (4-hydroxyphenyl) -propionate (12), - (S, S, S) -2- [3-Phenyl-2 - ({2 '- [2- (4-hydroxy-phenyl) -l- methyl methoxycarbonyl-ethylcarbamoyl] -biphenyl-2-carbonyl} -amino) -propionylamino] -4-methylsulfanyl-butyrate (13), - 2 '- {(S) - [2-phenyl-1 - (R) - (2-phenyl-1-methylcarbamoyl-ethylcarbamoyl) -ethylcarbamoyl] -biphenyl-2-carboxylic acid (14), - (S) -2 - [(S) -2 - ({2 '- (S) - [2 - Phenyl-1- (R) - (2-phenyl-1-methylcarbamoyl-ethylcarbamoyl) -ethylcarbamoyl] -biphenyl-2-carbonyl} -amino) -4-methyl-pentanoylamino] -4-methylsulfanyl-butyrate methyl ester (15) ), - (S) -2 '- [2-phenyl-1-methoxycarbonyl-ethylcarbamoyl] -biphenyl-2-carboxylic acid (16), - (R) - (3-Phenyl-2 - {[2'- (S) - (2-phenyl-1-methoxycarbonyl-ethylcarbamoyl) -biphenyl-2-carbonyl] -amino}) - methyl propionate (17), - (S, S) -3- (4-Hydroxy-phenyl) -2- ({2 '- [2- (4-hydroxy-phenyl) -1-methoxycarbonyl-ethylcarbamoyl] -biphenyl-2-carbonyl} -amino) -propionate methyl (18), - (S, S) - N- (1-Ferrocenylmethyl) -3-phenyl-2- ({2 '- [2-phenyl-1- (1-ferrocenylmethylcarbamoyl)] - ethylcarbamoyl) -biphenyl-2-carbonyl} -amino) -propionamide (19) , - N, N'-Rt 1 s' - (2-fluoro-5-nitro-phenyl) -biphenyl-2,2'-dicarboxamide (20), - (S, S) -2- Amino-N- [ 2 '- (2-amino-3-phenyl-propionylamino) -biphenyl-2-yl] -3-phenyl-propionamide (21), - (S, S) - {1 - [1 - (2 , -Amino- biphenyl-2-ylcarbamoyl) -2-phenyl-ethylcarbamoyl] -3-methyl-butyl} -carbamic acid 9H-fluoren-9-ylmethyl (22), - 2,2'-di - [(3,5-dinitrobenzoyl) amino) -biphenyl (24), - 2- (2-Νaftoylammo) -2 '- [(3,5-dinitrobenzoyl) amino] -bipheme (25), - 2- (2-Ν-aftoylamino) -2' - [( 4-nitrobenzoyl) amino] -biphenyl (26), and - (S, S 5 S, S) -2- (3-Phenyl-2 - {[2 , - (2-Phenyl-l- {2 , - [ 2- (9H-Fluoren-9-ylmethoxycarbomlamino) -propionyl amino] -biphenyl-2-ylcarbamoyl} -ethylcarbamoyl) -biphenyl-2-carbonyl] -amino} -propionylamino) -3-methyl-butyrate (27), and because it is a calpain inhibitor. 60
4. Uso de un compuesto inhibidor de calpaína de fórmula I, definido en la reivindicación 1, para preparar un medicamento para el tratamiento preventivo o terapéutico de una enfermedad degenerativa.4. Use of a calpain inhibitor compound of formula I, defined in claim 1, for preparing a medicament for the preventive or therapeutic treatment of a degenerative disease.
5. Uso de un compuesto inhibidor de calpaína de fórmula I según la reivindicación 4 en el que la enfermedad degenerativa está seleccionada entre isquemia cerebral, isquemia cardiaca, Alzheimer, Parkinson, distrofia muscular, cataratas y enfermedades desmielinizantes.5. Use of a calpain inhibitor compound of formula I according to claim 4 wherein the degenerative disease is selected from cerebral ischemia, cardiac ischemia, Alzheimer's, Parkinson's, muscular dystrophy, cataracts and demyelinating diseases.
6. Uso de un compuesto inhibidor de calpaína de fórmula I según la reivindicación 5 en el que la enfermedad degenerativa desmielinizante es la esclerosis múltiple. 6. Use of a calpain inhibitor compound of formula I according to claim 5 wherein the demyelinating demyelinating disease is multiple sclerosis.
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ES2243131B1 (en) 2004-05-07 2007-02-01 Consejo Sup. Investig. Cientificas TIAMIDAS DERIVED FROM BIFENYL AS CALPAINA INHIBITORS.
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