This invention relates to the prepn. of novel carbacyclic indolocarbazoles, such as I [R1 = NR13R14; R2 = H, CN, alkyl, aryl, heteroaryl, acyl, carboxy, carboxamido; R1R2 = spiro nitrogen contg. heterocycle, such as spirohydantoyl; R3 = H, OR13, OCOR13, OCONHR13, OCONR13R14; R1R3 = fused heterocycle, such as -OSO2O-, and R2 = H; R4, R6 = H, CN, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, acyl, carboxy. carboxamido, etc.; R8R9, R10R11 = H2, O, S; R8 = H, R9 = OH; R10 = H, R11 = OH; R12 = H, alkyl, cycloalkyl, benzyl aryl heteroaryl, acyl, carboxy, etc.; R13, R14 = H, alkyl, cycloalkyl, acyl, aryl, etc.], for therapeutic use as protein kinase inhibitors with advantageous pharmaceutical properties. These indolocarbazoles are claimed for use in the treatment of CNS diseases, non-insulin-dependent diabetes mellitus, acute stroke and other neuro-traumatic injuries, diabetes mellitus, malignant diseases, diseases caused by malfunctioning of specific signaling pathways and neurodegenerative diseases, such as Alzheimer's disease. Thus, indolocarbazole II (R1 = β-NH2, R2 = α-H, R3 = H) was prepd. starting from cyclopentadiene, 4-methoxybenzyl amine, dichloromaleic anhydride, and indole via a multistep synthetic sequence which included a reaction of 12,13-dihydro-6-[(4-methoxyphenyl)methyl]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione with cis-3,5-dibromocyclopentene using NaH in THF to form II (R1R3 = bond, R2 = H) in 90.4% yield. II (R1R3 = bond, R2 = H), which contains the target ring skeleton, further underwent an hydroxylation sequence using BH2.THF followed by NaOH and H2O2 to form alc. II (R1 = α-OH, R2 = β-H, R3 = H), oxidn. of the alc. to the corresponding ketone II (R1R2 = O, R3 = H), reaction of the ketone with benzylamine to give N-benzyl amine II (R1 = β-NHCH2Ph, R2 = α-H, R3 = H) and, finally, N-debenzylation to give the desired indolocarbazole II (R1 = β-NH2, R2 = α-H, R3 = H). The prepd. indolocarbazoles were assayed for inhibiting the activity of a group of protein kinases consisting of extracellular signal regulated kinase 2 (ERK2), protein kinase A (PKA), protein kinase C (PKC) and glycogen synthase kinase 3β (GSK3β).

Preparation of N,N-bridged, nitrogen-substituted carbacyclic indolocarbazoles for use in pharmaceutical compositions as protein kinase inhibitors / B. Monse, T. Braxmeier, S. Ferrand, S. Gordon, H. Klafki, G. Lahu, H. Roder, H. Sahagun-Krause, P. Seneci, O. Thillaye du Boullay.

Preparation of N,N-bridged, nitrogen-substituted carbacyclic indolocarbazoles for use in pharmaceutical compositions as protein kinase inhibitors

P. Seneci
Penultimo
;
2004

Abstract

This invention relates to the prepn. of novel carbacyclic indolocarbazoles, such as I [R1 = NR13R14; R2 = H, CN, alkyl, aryl, heteroaryl, acyl, carboxy, carboxamido; R1R2 = spiro nitrogen contg. heterocycle, such as spirohydantoyl; R3 = H, OR13, OCOR13, OCONHR13, OCONR13R14; R1R3 = fused heterocycle, such as -OSO2O-, and R2 = H; R4, R6 = H, CN, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, acyl, carboxy. carboxamido, etc.; R8R9, R10R11 = H2, O, S; R8 = H, R9 = OH; R10 = H, R11 = OH; R12 = H, alkyl, cycloalkyl, benzyl aryl heteroaryl, acyl, carboxy, etc.; R13, R14 = H, alkyl, cycloalkyl, acyl, aryl, etc.], for therapeutic use as protein kinase inhibitors with advantageous pharmaceutical properties. These indolocarbazoles are claimed for use in the treatment of CNS diseases, non-insulin-dependent diabetes mellitus, acute stroke and other neuro-traumatic injuries, diabetes mellitus, malignant diseases, diseases caused by malfunctioning of specific signaling pathways and neurodegenerative diseases, such as Alzheimer's disease. Thus, indolocarbazole II (R1 = β-NH2, R2 = α-H, R3 = H) was prepd. starting from cyclopentadiene, 4-methoxybenzyl amine, dichloromaleic anhydride, and indole via a multistep synthetic sequence which included a reaction of 12,13-dihydro-6-[(4-methoxyphenyl)methyl]-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione with cis-3,5-dibromocyclopentene using NaH in THF to form II (R1R3 = bond, R2 = H) in 90.4% yield. II (R1R3 = bond, R2 = H), which contains the target ring skeleton, further underwent an hydroxylation sequence using BH2.THF followed by NaOH and H2O2 to form alc. II (R1 = α-OH, R2 = β-H, R3 = H), oxidn. of the alc. to the corresponding ketone II (R1R2 = O, R3 = H), reaction of the ketone with benzylamine to give N-benzyl amine II (R1 = β-NHCH2Ph, R2 = α-H, R3 = H) and, finally, N-debenzylation to give the desired indolocarbazole II (R1 = β-NH2, R2 = α-H, R3 = H). The prepd. indolocarbazoles were assayed for inhibiting the activity of a group of protein kinases consisting of extracellular signal regulated kinase 2 (ERK2), protein kinase A (PKA), protein kinase C (PKC) and glycogen synthase kinase 3β (GSK3β).
NAD AG, MUNICH, GERMANY
C07D487-16
WO 2004048384
ERK-2 ; INDOLOCARBAZOLES ; kinases ; alzheimer's disease
Settore CHIM/06 - Chimica Organica
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/13 - Biologia Applicata
Preparation of N,N-bridged, nitrogen-substituted carbacyclic indolocarbazoles for use in pharmaceutical compositions as protein kinase inhibitors / B. Monse, T. Braxmeier, S. Ferrand, S. Gordon, H. Klafki, G. Lahu, H. Roder, H. Sahagun-Krause, P. Seneci, O. Thillaye du Boullay.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/186823
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