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Pyrazolo piperidine and pyrazolo pyrimidine derivatives for treatment of neuropsychiatric systemic lupus erythematosus

A technology of drugs and compounds, applied in the field of pyrazolopiperidine derivatives and pyrazolopyrimidine derivatives for the treatment of neuropsychiatric systemic lupus erythematosus, can solve the problems of high medical demand, no NPSLE treatment method, etc.

Inactive Publication Date: 2020-07-17
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is currently no known therapy available for the treatment of NPSLE, including CNS lupus, and there is a high medical need for such treatments

Method used

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  • Pyrazolo piperidine and pyrazolo pyrimidine derivatives for treatment of neuropsychiatric systemic lupus erythematosus
  • Pyrazolo piperidine and pyrazolo pyrimidine derivatives for treatment of neuropsychiatric systemic lupus erythematosus
  • Pyrazolo piperidine and pyrazolo pyrimidine derivatives for treatment of neuropsychiatric systemic lupus erythematosus

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0157] Preparation of compounds for use in the present invention:

[0158] The synthesis of compounds of formula (I) and formula (II) has been described in US Pat. No. 9,126,999 and PCT application WO 2018 / 047081, respectively. Accordingly, both US 9,126,999 and WO 2018 / 047081 are incorporated by reference.

[0159] Existing Technology and Significance:

[0160] Recently, anti-interferon receptor type 1 (IFNAR) antibodies have shown efficacy in Ph2b studies in lupus patients (published by R. Furie et al., Arthritis and Rheumatology, 69, 376-386, 2017 ). Blockade of IFNAR also reduced the autoimmune phenotype in the lupus 564Igi murine model. In this model, follicular dendritic cells (FDCs) have been identified as the main source of IFNα: autoantibodies and nucleolar immune complexes elicit IFNα from FDCs via the endosomal receptor TLR7 (by A. Das et al., Immunity [Immunology] 46, 106-119, published in 2017).

[0161] In a related study in the 564Igi model, anti-IFNAR trea...

Embodiment 1a

[0205] Embodiment 1a. A method of treating and / or preventing NPSLE comprising administering to a patient in need thereof an effective amount of a compound of formula (II):

[0206]

[0207] in

[0208] L is -CH 2 -or-CH 2 CH 2 -;

[0209] R 1 is -NHC(=O)R 6 , -NHC(=O)(CH 2 ) n R 6 , -NHC(=O)(CH 2 ) m NHR 5 , -NHC(=O)(CH 2 ) m N(R 5 ) 2 , -NHC(=O)(CHR 7 ) m NHR 5 , -NHC(=O)(CH 2 ) m NH 2 , -NHC(=O)(CH 2 ) n OR 7 , -NHC(=O)OR 7 , -NHC(=O)(CHR 7 ) n R 6 , -NHC(=O)(CHR 7 ) n N(R 8 ) 2 , -NHC(=O)(CHR 7 ) n NHR 8 , -NR 7 C(=O)OR 11 , -NHC(=O)(CH 2 ) n N(CD 3 ) 2 , -NR 7 C(=O)R 5 , -NR 7 C(=O)(CH 2 ) n R 5 , -NR 7 C(=O)OR 5 , -NHS(=O) 2 R 5 , -NHC(=O)(CH 2 ) n NR 7 C(=O)R 5 , or -NHC(=O)(CH 2 ) n NR 7 S(=O) 2 R 5 ;

[0210] R 2 is H, C 1 -C 6 Alkyl or C 1 -C 6 haloalkyl;

[0211] R 3 is H, C 1 -C 6 Alkyl or -CD 3 ;

[0212] R 4 is H, NH 2 , C 1 -C 6 Alkyl or halogenated;

[0213] each R 5 independently se...

Embodiment 2a

[0220] Embodiment 2a. The method of Embodiment 1a, wherein the compound is a compound of Formula (IIa):

[0221]

[0222] in

[0223] R 2 is H, C 1 -C 6 Alkyl or C 1 -C 6 Haloalkyl;

[0224] R 3 is H, C 1 -C 6 Alkyl or -CD 3 ;

[0225] R 4 is H, NH 2 、C 1 -C 6 Alkyl or halo;

[0226] R 6 is C 3 -C 6 Cycloalkyl or have independently selected from N, NH, N (C 1 -C 6 Alkyl) and 1 to 2 ring members of O, unsubstituted or replaced by 1-2 R 9 4-6 membered heterocycloalkyl group substituted;

[0227] each R 9 independently selected from C 1 -C 6 Alkyl, hydroxyl, halo and C substituted by 1 to 3 -OH 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.

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PUM

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Abstract

The present invention relates to the use of certain pyrazolo piperidine derivatives in the treatment of diseases and conditions associated with the interaction of the toll like receptor. More particularly, the said treatment pertains to the treatment of NPSLE.

Description

technical field [0001] The present invention relates to the use of certain pyrazole derivatives in the treatment of diseases and disorders potentially associated with interactions with Toll-like receptors. More specifically, the treatment relates to the treatment of neuropsychiatric lupus erythematosus (NPSLE), including central nervous system (CNS)-lupus. Background technique [0002] US 9,126,999 B2 and WO 2018 / 047081 describe the synthesis and some utility of certain pyrazolo-piperidine derivatives. The compounds are known to antagonize Toll-like receptors 7 and 8 (TLR7, TLR8) and are useful in the treatment of SLE and lupus nephritis. However, US 9,126,999 B2 and WO 2018 / 047081 are silent on the treatment of NPSLE. [0003] The underlying pathophysiological mechanisms of NPSLE, including CNS-lupus, remain largely unknown. [0004] However, several pathogenic pathways have been identified, including a type I interferon-dependent pathway (see Bialas et al, Nature, Jun 2...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/437A61K31/519A61K31/5377A61K45/06A61P25/00A61P37/00
CPCA61K31/437A61K31/519A61K31/5377A61P37/00
Inventor J·迪恩T·尤特P·勒切尔B·尼斯莱因-希尔德斯海姆B·温
Owner NOVARTIS AG
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