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Carbamate-substituted pyrazolopyridines

A compound and hydrate technology, which is applied in the direction of pharmaceutical combination, organic chemistry, medical preparations containing active ingredients, etc.

Inactive Publication Date: 2005-09-07
ADVERIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds have been shown to have some disadvantages with regard to their in vivo properties, such as, for example, their hepatic behavior, their pharmacokinetic behaviour, their dose-response relationship or their metabolic pathways

Method used

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  • Carbamate-substituted pyrazolopyridines
  • Carbamate-substituted pyrazolopyridines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0227] 4-Amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl-(methyl)carbamate

[0228]

[0229] Under argon, 0.80 g (2.61 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine from Example 6A, 0.51 g ( 2.86mmol) sodium (E)-2-cyano-2-[(methoxycarbonyl)(methyl)amino]ethenate from Example 10A and 0.53g 0.73ml (5.23mmol) triethylamine were added to 50ml of toluene. The mixture was heated to reflux for 9 hours. It was then recooled to RT, and it was mixed and extracted with dichloromethane and water. The organic phase was dried over magnesium sulfate, filtered and concentrated under vacuum on a rotary evaporator. The residue was mixed with 5 ml of diethyl ether and subsequently crystallized. The crystals were filtered off with suction, dried and purified by preparative RP-HPLC.

[0230] Yield: 20.2 mg (2% of theory)

[0231] LC / MS (Method 2): Rt = 3.01 min

[0232] MS(EI): m / z=408(M+H) +

[0233] 1 H-NMR (300MHz, DMSO-d 6 ): δ=3...

Embodiment 2

[0235] 4,6-Diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate

[0236]

[0237] 107.35 mg (0.31 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6 from Example 8A - Pyrimidinetriamine trihydrochloride was added to 5 ml of pyridine and the mixture was cooled to 0°C. To this was added 33.25 mg (0.31 mmol) ethyl chloroformate and the reaction was stirred overnight at RT. Pyridine was evaporated under vacuum with a rotary evaporator and the residue was purified with preparative RP-HPLC.

[0238] Yield: 56.2 mg (43% of theory)

[0239] LC / MS (Method 1): Rt = 2.66 min

[0240] MS(EI): m / z=423(M+H) +

[0241] 1 H-NMR (300MHz, DMSO-d 6 ): δ=1.17-1.33(m, 3H), 3.97-4.14(m, 2H), 5.80(s, 2H), 6.14(broad singlet, 4H), 7.07-7.17(m, 2H), 7.22(t , 1H).7.29-7.40(m, 2H), 7.97(broad singlet, 1H), 8.60(d, 1H), 9.07(d, 1H).

Embodiment 3

[0243] 4,6-Diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate isopropyl ester

[0244]

[0245] Similar to Example 2 with 150 mg (0.43 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- 4,5,6-Pyrimidinetriamine trihydrochloride, 7.5 ml pyridine and 52.47 mg (0.43 mmol) isopropyl chloroformate. The residue was taken up in a dichloromethane / methanol mixture, filtered and dried.

[0246] Yield: 165 mg (88% of theory)

[0247] LC / MS (Method 1): Rt = 2.84 min

[0248] MS(EI): m / z=437(M+H) +

[0249] 1 H-NMR (300MHz, DMSO-d 6 ): δ=1.26(d, 6H), 4.82(quintet, 1H), 5.92(s, 2H), 7.07-7.20(m, 2H), 7.25(t, 1H).7.31-7.43(m, 2H ), 7.47-7.57 (m, 1H), 8.16 (broad singlet, 1H), 8.74 (dd, 1H), 8.98 (dd, 1H).

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Abstract

The present invention relates to compounds which stimulate soluble guanylate cyclase, to the preparation thereof and to the use thereof as medicaments, in particular as medicaments for the treatment of cardiovascular disorders and / or sexual dysfunction.

Description

[0001] technical content [0002] The present invention relates to compounds stimulating soluble guanylate cyclase, their preparation and their use as medicaments, in particular as medicaments for the treatment of cardiovascular disorders and / or sexual dysfunction. Background technique [0003] One of the most important cellular delivery systems in mammalian cells is cyclic guanosine-phosphate (cGMP). Together with nitric oxide (NO), which is released from the endothelium and transmits hormonal and mechanical signals, it forms the NO / cGMP system. Guanylate cyclase catalyzes the biosynthesis of cGMP from guanosine triphosphate (GTP). Representatives of this family of substances disclosed so far are divided into two groups according to structural features and ligand types: particulate guanylate cyclases that can be stimulated by natriuretic peptides and soluble guanosines that can be stimulated by NO acid cyclase. Soluble guanylate cyclase is composed of two subunits and most...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61K45/06A61P9/00A61P9/02A61P9/10A61P9/12A61P13/00A61P15/00A61P15/10A61P19/10A61P25/00A61P25/16A61P25/24A61P25/28A61P27/06C07D471/04
CPCC07D471/04A61K45/06A61K31/506A61P13/00A61P15/00A61P15/08A61P15/10A61P19/10A61P25/00A61P25/16A61P25/24A61P25/28A61P27/06A61P9/00A61P9/02A61P9/10A61P9/12A61K2300/00
Inventor C·阿隆索·阿利亚E·比肖夫K·明特尔J·-P·施塔斯E·施塔尔S·维甘德A·福伊雷尔
Owner ADVERIO PHARMA
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