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Conformation-constrained entirely-synthetic macrocyclic compounds

A compound and construction technology, applied in the field of conformationally restricted fully synthesized macrocyclic compounds, can solve complex quality control and development process problems

Active Publication Date: 2016-02-03
POLYPHOR AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] - Complex quality control and development processes

Method used

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  • Conformation-constrained entirely-synthetic macrocyclic compounds
  • Conformation-constrained entirely-synthetic macrocyclic compounds
  • Conformation-constrained entirely-synthetic macrocyclic compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0942] Data of Example 1: C 31 H 40 FN 3 O 7 Si (613.7). LC-MS (Method 7):

[0943] R t =1.45(41),614([M+H] + ); 1.47(44), 614([M+H] + ).

[0944] 1 H-NMR(DMSO-d 6 ): complex spectrum, several isomers; 7.45-7.01 (m, 8H), 6,78-6.58 (2m, 1H), 5.42-5.06 (m, 3H), 4.50-3.50 (several m, 7H) , 3.30-1.40 (several kinds of m, 7H), 2.84, 2.70, 2.66 (s, 3H), 0.97-0.82 (m, 2H), 0.03, 0.02, 0.00 (s9H).

Embodiment 2

[0945] Core 02: Synthesis Example 2 (Scheme 11)

[0946] Example 2 Synthesis of Protected Macrolide

[0947] In 2 hours, T3P (50%, EtOAc, 0.75mL, 1.27mmol) and iso-Pr 2 NEt (0.36mL, 2.2mmol) anhydrous CH 2 Cl 2 (20mL) Add amino acid 98 (250mg, 0.43mmol) in anhydrous CH to the solution 2 Cl 2 (730 mL) solution. Stir the solution at room temperature for 20 hours, then use saturated Na 2 CO 3 Aqueous extraction. Dry organic phase (Na 2 SO 4 ), filter and concentrate. FC(CH 2 Cl 2 / MeOH100:0 to 95:5), providing Example 2 (187 mg, 77%).

[0948] Data of Example 2: C 30 H 36 FN 3 O 7 (569.6)LC-MS (Method 7):

[0949] R t =1.35(62),570([M+H] + ); 1.39(15), 570([M+H] + )

[0950] 1 H-NMR(DMSO-d 6 ): complex spectrum, several isomers; 7.46-7.30 (m, 5H), 7.27-7.06 (m, 2H), 6.98-6.67 (4dd, 1H), 5.54-5.06 (m, 3H), 4.68-3.48 (m, 6H), 3.05-1.98 (m10H; s at 2.82, 2.69, 2.64), 1.44-1.41 (3s, 9H).

[0951] Core 03: Synthesis Example 3, Example 4, and Example 5 (Scheme 7)

[0952] Synthesis of Mitsunob...

Embodiment 3

[0959] Data of Example 3: C 33 H 41 FN 4 O 8 (640.7). HPLC(30%CH 3 CN): R t = 3.20 (96). LC-MS (Method 9c): R t =2.06,641([M+H] + ). 1 H-NMR(CDCl 3 ): 7.45-7.32 (m, 5H), 7.06 (m, 1H), 6.94-6.88 (m, 2H), 5.57 (dd, J=2.8, 12.6, 1H), 5.42 (width m, 1H), 5.26 ( d, J = 12.2, 1H), 5.15 (d, J = 12.2, 1H), 4.90 (dd, J = 2.5, 11.0, 1H), 4.34 (d, J = 17.2, 1H), 4.35 to 4.11 (m, 3H), 3.82 (width t, J about 8.5, 1H), 3.65 (d, J=17.3, 1H), 3.29 (t, J about 8.8, 1H), 3.14 (s, 3H), 2.65 (s, 3H) , 2.51-1.98 (several kinds of m, 5H), 1.76 (td, J=8.2, 12.7, 1H), 1.36 (s, 9H).

[0960] Synthesis acid example 4:

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Abstract

The invention relates to conformation-constrained entirely-synthetic macrocyclic compounds. A conformation-constrained, space-defined 12-30-member macrocyclic system (I) which is as shown in the description comprises three different constitution units: an aromatic template a, a confor1ation regulator b and a spaced part c, which are illustrated in the description and the claims. The macrocyclic compounds (I) can be easily prepared according to a parallel synthesis method or a combinatorial chemistry method, and are designed for realizing interaction with a specific biological target. Particularly, the compounds show agonistic or antagonistic activity to the following matters: a motilin receptor (MR), a 5-hydroxytryptamine receptor (5-HT2B receptor) of a subtype 5-HT2B, and a prostaglandin F2alpha receptor (FP receptor). Thus, the compounds are effectively used for treating gastrointestinal tract hypomotility disorder such as diabetic gastroparesis and constipation-predominant irritable bowel syndrome, CNS-related diseases such as migraine, schizophrenia, psychosis and depression, ocular hypertension such as glaucoma-related ocular hypertension, and premature delivery.

Description

[0001] This application is a divisional application of the Chinese invention patent application 200980160767.8. Technical field [0002] Macrocyclic natural and synthetic products are developing new drugs, especially anti-infectives (see Review: F. von Nussbaum, M. Brands, B. Hinzen, S. Weigand, D. Angew.Chem.Int.Ed.Engl. 2006, 45, 5072-5129; D. Obrecht, Jarobinson, F. Bernardini, C. Bisang, SJDeMarco, K. Moehle, FOGombert, Curr.Med.Chem. 2009 , 16, 42-65), as an anticancer drug and in other therapeutic fields (CE Ballard, H. Yu, B. Wang, Curr. Med. Chem. 2002, 9, 471-498; F. Sarabia, S. Chammaa, AS Ruiz, LMOrtiz, FJ Herrera, Curr. Med. Chem. 2004, 11, 1309-1332) play a key role. They often show significant biological activity, and many macrocycles or their derivatives have been successfully developed as drugs (LAWessjohann, E. Ruijter, D. Garcia-Rivera, W. Brandt, Mol. Divers. 2005, 9, 171 -186; DJ Newman, GM Gragg, KMSnader, J. Nat. Prod. 2003, 66, 1022-1037). The chemical d...

Claims

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Application Information

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IPC IPC(8): C07D498/04C07D498/08C07D498/18A61K31/407A61K31/4985A61K31/439A61K31/4748A61P1/06A61P1/00A61P25/06A61P25/18A61P27/02A61P15/06A61P25/24
CPCY02P20/55C07D498/04C07D498/08C07D498/18
Inventor D·奥伯莱希特P·厄尔玛特S·乌姆士F·拉什A·卢瑟尔K·马克斯K·默勒
Owner POLYPHOR AG
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