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Heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators

A halogen and compound technology, applied in the field of formula heterocyclic derivatives and as prostaglandin receptor modulators, can solve problems such as limited efficacy

Inactive Publication Date: 2014-08-27
IDORSIA PHARM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Often, treatment with antihistamines and leukotriene antagonists has limited efficacy, and long-term use of corticosteroids is often associated with undesired side effects

Method used

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  • Heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators
  • Heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators
  • Heterocyclyl derivatives and their use as prostaglandin d2 receptor modulators

Examples

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preparation example Construction

[1165] The following examples illustrate the preparation of the compounds of the invention but do not limit their scope in any way. Whenever used in the experimental part, general structures 1, 2, 3, etc. refer to the respective structures described in the preceding general description of the preparation of compounds of formula (I) below.

[1166] General method for preparing compounds of formula (I):

[1167] Saponification

[1168] To (±)-(3-{5-fluoro-2-[trans-2-(4-fluoro-phenyl)-cyclopropanecarbonyl]-1,2,3,4-tetrahydro-isoquinoline-8 To a solution of ethyl}-4-methoxy-phenyl)-acetate in DMF (1 mL) was added 2M aqueous NaOH (1 mL). The mixture was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (ca. 1 mL), purified by preparative HPLC (column: Atlantis, 18 x 50 mm, 10 μm, UV / MS, acidic conditions) and concentrated in vacuo to afford the desired acid as a white solid.

[1169] Listed in Table 1 below are examples of compounds of formula (I) prep...

example 169

[1232] Example 169: Benzyl 8-(5-carboxymethyl-2-methoxy-phenyl)-5-cyano-3,4-dihydro-1H-isoquinoline-2-carboxylate (C27H24N2O5, MW =456.17)

[1233] To an ice-cooled suspension of 5-cyano-8-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (73 mg, 0.24 mmol, 1.0 eq.) in DCM (4.4 mL) Triethylamine (99 μL, 0.71 mmol, 3.0 eq.) and trifluoromethanesulfonic anhydride (61 μL, 0.355 mmol, 1.5 eq.) were sequentially added to the solution. The reaction mixture was stirred at 0 °C for 30 min and at r.t. for another 45 min. The mixture was diluted with DCM (10 mL) and washed with saturated NaHCO 3Aqueous (2x) washes. The organic layer was washed with MgSO 4 Dry, filter and concentrate in vacuo. To triflate, [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] - ethyl acetate (97mg, 0.24mmol, 1.0eq.) and sodium carbonate (100mg, 0.95mmol, 4.0eq.) in toluene / EtOH / water 20:4:1 (4.8mL) in N 2 To the mixture below was added tetrakis(triphenylphosphine)pal...

example 170

[1235] Example 170: Benzyl 8-(5-carboxymethyl-2-methoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (C26H25NO5, MW=431.17)

[1236] To an ice-cooled solution of benzyl 8-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (113 mg, 0.40 mmol, 1.00 eq.) in DCM (1 mL) was added NEt in sequence 3 (0.17mL, 1.20mmol, 3.00eq.) and trifluoromethanesulfonic anhydride (0.10mL, 0.60mmol, 1.50eq.). The reaction mixture was stirred at 0 °C for 30 min and at r.t. for another 45 min. The mixture was diluted with DCM (50 mL) and washed with saturated NaHCO 3 Wash with aqueous solution (2 x 25 mL). The organic layer was washed with MgSO 4 Dry and concentrate in vacuo. To triflate, [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl] - ethyl acetate (128mg, 0.40mmol, 1.00eq.) and sodium carbonate (170mg, 1.60mmol, 4.00eq.) in toluene / EtOH / water 20:4:1 (2.5mL) in N 2 To the lower mixture was added tetrakis(triphenylphosphine)palladium(0) (23mg, 0.02mmol, 0.05eq.). The m...

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Abstract

The present invention relates to phenyl-substituted heterocyclyl derivatives of the formula (I) wherein Z, n, m, R1, R2, R3, R4, R5, R6, R7 and R8 are as described in the description and their use as prostaglandin receptor modulators, most particularly as prostaglandin D2 receptor modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation.

Description

technical field [0001] The present invention relates to heterocyclic derivatives of formula (I) and their use as prostaglandin receptor modulators, most particularly as prostaglandin D 2 Use of receptor ("DP receptor") modulators in the treatment of various prostaglandin-mediated diseases and conditions, pharmaceutical compositions containing such compounds and methods for their preparation. Specifically, these derivatives can be used alone or in the form of pharmaceutical compositions for the treatment of chronic and acute allergic / immune diseases / disorders such as asthma, allergic asthma, eosinophilic asthma, severe asthma, rhinitis, allergic Rhinitis, angioedema, insect venom allergy, drug allergy, allergic sinusitis, allergic nephritis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorder, anaphylactic shock, urticaria Measles, eczema, ulcerative colitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/44C07D217/06C07D223/06C07D223/16C07D401/06C07D401/12C07D405/06C07D413/06C07D417/06A61K31/47
CPCC07D405/06C07D223/16C07D223/06C07D209/44C07D217/06C07D401/06C07D401/12C07D417/06C07D413/06A61P1/04A61P7/00A61P7/10A61P11/00A61P11/02A61P11/06A61P11/08A61P13/12A61P17/04A61P19/02A61P29/00A61P35/00A61P35/02A61P37/08A61P43/00
Inventor 哈马德·艾斯奥伊克里斯多夫·博斯西尔维娅·理查德-比尔德斯滕罗曼·西格里斯特
Owner IDORSIA PHARM LTD
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