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Dihydro- 1H- pyrrolo [1,2-a] indol-1-yl carboxylic derivatives which act as S1P1 agonists

A solvate, C1-C6 technology, used in anti-inflammatory agents, drug combinations, antiviral agents, etc., can solve problems such as β-cell toxicity and discomfort

Inactive Publication Date: 2011-02-23
ARENA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although they are effective in delaying or inhibiting transplant rejection, classical immunosuppressants such as cyclosporine A and FK506 are known to cause several undesirable side effects, including nephrotoxicity, neurotoxicity, β-cell toxicity, and gastrointestinal discomfort

Method used

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  • Dihydro- 1H- pyrrolo [1,2-a] indol-1-yl carboxylic derivatives which act as S1P1 agonists
  • Dihydro- 1H- pyrrolo [1,2-a] indol-1-yl carboxylic derivatives which act as S1P1 agonists
  • Dihydro- 1H- pyrrolo [1,2-a] indol-1-yl carboxylic derivatives which act as S1P1 agonists

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preparation example Construction

[0590] for the active level of 125 The synthetic method that I is combined in the target molecule comprises:

[0591] A. Sandmeyer and similar reactions: This method converts aryl or heteroaryl amines into diazonium salts, such as diazonium tetrafluoroborate, and the subsequent use of Na 125 I convert to 125 I labeled compound. A representative method is reported by Zhu, G-D and colleagues in J. Org. Chem., 2002, 67, 943-948.

[0592] B. The ortho iodine of phenol ( 125 I)ization: This method allows 125 I was bound in the ortho position to the phenol as reported by Collier, T.L and co-workers in J. Labelled Compd. Radiopharm., 1999, 42, S264-S266.

[0593] C. For aryl bromides and heteroaryl bromides 125 I Exchange: The method is usually a two-step process. The first step is to convert the aryl or heteroaryl bromide to the corresponding trialkyltin intermediate using, for example, the following method: 3 ) 3 SnSn(CH 3 ) 3 ] in the presence of Pd-catalyzed reactions ...

Embodiment 1

[0599] Embodiment 1: the synthesis of compound of the present invention

[0600] Exemplary syntheses for compounds of the invention are shown in Figures 7 to 12 , where the symbols have the same definitions as those used throughout this specification.

[0601] The compounds of the present invention and their synthesis are further illustrated by the following examples. The following examples are provided to further define the invention without, however, limiting the invention to the specifics of these examples. Compounds described before and after this application were named according to AutoNom version 2.2 or CS ChemDraw Ultra version 9.0.7. In some instances, common names are used, and it is understood that such common names will be known to those skilled in the art.

[0602] Chemistry: Proton NMR ( 1 H NMR) spectra were recorded on a Bruker Avance-400 equipped with QNP (Quad Nucleus Probe) or BBI (Broad Band Inverse) and z-gradient. Chemical shifts are given in parts p...

Embodiment 11

[0604] Example 1.1: Preparation of 2-(7-(5-(6-cyanopyridin-3-yl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-pyrrole and[1,2-a]indol-1-yl)acetic acid (compound 3).

[0605] Step A: Preparation of 2-(7-(5-(6-cyanopyridin-3-yl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-pyrrolo [1,2-a]indol-1-yl) tert-butyl acetate.

[0606] To 2-(7-(N'-hydroxyamidino)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid tert-butyl ester (50mg, 0.152mmol ) in dioxane (914μl) and 6-cyanonicotinic acid (45.0mg, 0.304mmol), successively add TEA (212μL, 1.518mmol) and 1-propyl phosphoric acid cyclic anhydride (49.2μL, 0.167 mmol). The reaction mixture was stirred for 30 min, heated at reflux for 18 h, then diluted with water. The resulting precipitate was filtered off and washed with water to give the title compound as a yellow solid (43mg). LCMS m / z=442.4[M+H] + .

[0607]Step B: Preparation of 2-(7-(5-(6-cyanopyridin-3-yl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-pyrrolo [1,2-a]indol-1-yl)acetic acid (compo...

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Abstract

The present invention relates to certain (1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl carboxylic acid derivatives of Formula (Ia) and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists of the S1P1 receptor. Also provided by the present invention are pharmaceutical compositions containing compounds of the invention, and methods of using the compounds and compositions of the invention in the treatment of S1P1 associated disorders, for example, psoriasis, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, sepsis, myocardial infarction, ischemic stroke, acne, microbial infections or diseases and viral infections or diseases.

Description

technical field [0001] The present invention relates to certain (1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylcarboxylates of formula (Ia) Acid derivatives and pharmaceutically acceptable salts thereof, which exhibit useful pharmacological properties, for example, as agonists of the S1P1 receptor. The invention also provides pharmaceutical compositions comprising the compounds of the invention, and methods of using the compounds and compositions of the invention to treat S1P1-related disorders, e.g., psoriasis, rheumatoid arthritis , Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes diabetes), sepsis, myocardial infarction, ischemic stroke, acne, microbial infection or disease, and viral infection or disease. Background technique [0002] The present invention relates to compounds as S1P1 receptor agonists, which have at least one immunosuppressive, anti-inflammatory and / or or hemos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P17/10A61P29/00A61P19/02A61K31/4245A61P31/12A61P17/06A61P31/04A61P43/00C07D487/04
CPCC07D487/04A61P1/04A61P3/10A61P9/10A61P17/06A61P17/10A61P19/02A61P25/28A61P29/00A61P31/00A61P31/04A61P31/12A61P35/00A61P37/00A61P37/06A61P43/00
Inventor 罗伯特·M·琼斯丹尼尔·J·布扎德安德鲁·M·卡瓦萨基路易斯·A·洛佩斯珍妮·V·穆迪拉斯·托雷森布雷特·厄尔曼
Owner ARENA PHARMA