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Fully synthetic macrocycles with constrained conformation

A technology for compounds and compositions, applied in the field of conformationally constrained fully synthesized macrocyclic compounds, capable of solving complex quality control and development process issues

Active Publication Date: 2018-09-25
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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  • Fully synthetic macrocycles with constrained conformation
  • Fully synthetic macrocycles with constrained conformation
  • Fully synthetic macrocycles with constrained conformation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0943] Data of Example 1: C 31 h 40 FN 3 o 7 Si (613.7). LC-MS (Method 7):

[0944] R t =1.45(41), 614([M+H] + ); 1.47(44), 614([M+H] + ).

[0945] 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 m, 7H), 2.84, 2.70, 2.66 (s, 3H), 0.97-0.82 (m, 2H), 0.03, 0.02, 0.00 (s 9H).

Embodiment 2

[0946] Core 02: Synthetic Example 2 (Scheme 11)

[0947] Synthesis of protected macrocyclic lactam embodiment 2

[0948] Over 2 hours, T3P (50%, in EtOAc, 0.75 mL, 1.27 mmol) and iso-Pr 2 NEt (0.36 mL, 2.2 mmol) in anhydrous CH 2 Cl 2 (20mL) solution was added amino acid 98 (250mg, 0.43mmol) in anhydrous CH 2 Cl 2 (730 mL) solution. The solution was stirred at room temperature for 20 h, then washed with saturated Na 2 CO 3 Aqueous extraction. Dry the organic phase (Na 2 SO 4 ), filtered and concentrated. FC(CH 2 Cl 2 / MeOH 100:0 to 95:5), providing Example 2 (187 mg, 77%).

[0949] Data of Example 2: C 30 h 36 FN 3 o 7 (569.6) LC-MS (Method 7):

[0950] R t =1.35(62), 570([M+H] + ); 1.39(15), 570([M+H] + )

[0951] 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 (m 10H; s at 2.82, 2.69, 2.64), 1.44-1.41 (3s, 9H).

[0952] Core 03: Synthes...

Embodiment 3

[0960] 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), 4.35-4.11(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 m, 5H), 1.76 (td, J=8.2, 12.7, 1H), 1.36 (s, 9H).

[0961] Synthetic acid embodiment 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 whose parent application is Chinese invention patent application 200980160767.8. technical field [0002] Macrocyclic natural and synthetic products are in the development of 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,J.A.Robinson,F.Bernardini,C.Bisang,S.J.DeMarco,K.Moehle,F.O.Gombert,Curr.Med.Chem.2009 , 16,42-65), as anticancer drugs and in other therapeutic areas (C.E.Ballard, H.Yu, B.Wang, Curr.Med.Chem.2002,9, 471-498; F.Sarabia, S.Chammaa , A.S.Ruiz, L.M.Ortiz, F.J.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 (L.A.Wessjohann, E.Ruijter, D.Garcia-Rivera, W.Brandt, Mol.Divers. 2005,9,171 -186; D.J. Newman, G.M. Gragg, K.M. Snader, J. Nat. Prod. 2003, 66, 1022-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/04C07D498/08C07D498/18A61K31/407A61K31/4985A61K31/439A61K31/4748A61P1/06A61P1/00A61P25/06A61P25/18A61P27/02A61P15/06A61P25/24
CPCY02P20/55
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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