Substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero- heteraphanes and metallocenes useful for treating HCV infections

Patent metadata

Field	Value
Publication number	US-10092547-B2
Application number	US-201715804842-A
Country	US
Kind code	B2
Filing date	Nov 6, 2017
Priority date	May 27, 2011
Publication date	Oct 9, 2018
Grant date	Oct 9, 2018

Abstract

Certain substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes disclosed herein are potent and/or selective inhibitors of viral replication, particularly Hepatitis C virus replication. Pharmaceutical compositions/and combinations containing one or more substituted aliphanes, cyclophanes, heteraphanes, heterophanes, hetero-heteraphanes and metallocenes and a pharmaceutically acceptable carrier are also provided by this disclosure. Methods for treating viral infections, including Hepatitis C viral infections are provided by the disclosure.

First claim

What is claimed is:

1. A process for preparing a compound of formula (I):

or HCl salt thereof;
comprising steps:
(a) converting compound (i) to compound (ii):

(b) reacting 4-bromo-1,2-diaminobenzene with compound (ii) to form compound (iii):

(c) converting compound (iii) to compound (iv) in the presence of acetic acid:

(d) converting compound (iv) to compound (v):

(e) reacting compound (v) with compound (vi) to form compound (vii):

(f) converting compound vii to compound (viii) or HCl salt of compound (viii):

and
(g) coupling compound (viii) or the HCl salt of compound (viii) with (S)-2-(methoxycarbonyl)amino)-3-methylbutanoic acid to form the compound of formula (I):

2. The process of claim 1 , wherein compound (vi) is formed by reacting [2.2]paracyclophane with Br 2 and iron powder:

3. The process of claim 1 , wherein step (b) occurs in the presence of 1-ethyl-3-(3dimethylaminopropyl)carbodiimide (EDCI) to form the compound of formula (iii).

4. The process of claim 1 , wherein step (d) is conducted by stirring a mixture of compound (iv) with bis(pinacolato)diborane, potassium acetate, and (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (Pd(dppf)Cl 2 ) in anhydrous 1,4-dioxane.

5. The process of claim 1 , wherein step (e) is conducted by stirring a mixture of compound (v), compound (vi), Cs 2 CO 3 , tetrakis(triphenylphosphine)palladium (0) (Pd(PPh 3 ) 4 ), and dimethylformamide (DMF) in water.

6. The process of claim 1 , wherein step (f) is conducted by cooling a solution of compound (vii) in dichloromethane/methanol (DCM/MeOH) and adding HCl/dioxane solution.

7. The process of claim 1 , wherein compound (vii) is converted to the HCl salt of compound (viii).

8. The process of claim 1 , wherein step (g) is conducted with EDCI and hydroxybenzotriazole (HOBt) monohydrate in acetonitrile.

9. A process for preparing a compound of formula (I):

or HCl salt thereof;
comprising steps:
(a) reacting compound (v) with compound (vi) to form compound (vii):

(b) converting compound (vii) to c pound (viii) or HCl salt of compound (viii):

and
(c) coupling compound (viii) or the HCl salt of compound (viii) with (S)-2-(methoxycarbonyl)amino)-3-methylbutanoic acid to form the compound of formula (I):

10. The process of claim 9 , wherein compound (vi) is formed by reacting [2.2]paracyclophane with Br 2 and iron powder:

11. The process of claim 9 , wherein step (a) is conducted by stirring a mixture of compound (v), compound (vi), Cs 2 CO 3 , Pd(PPh 3 ) 4 , and DMF in water.

12. The process of claim 9 , wherein step (b) is conducted by cooling a solution of compound (vii) in DCM/MeOH and adding HCl/dioxane solution.

13. The process of claim 9 , wherein compound (vii) is converted to the HCl salt of compound (viii).

14. The process of claim 9 , wherein step (c) is conducted with EDCI and HOBt monohydrate in acetonitrile.

Assignees

• Achillion Pharmaceuticals Inc

Inventors

• Wiles Jason Allan
• Wang Qiuping
• Hashimoto Akihiro
• Pais Godwin
• Wang Xiangzhu
• Gadhachanda Venkat
• Phadke Avinash
• Deshpande Milind
• Chen Dawei

Classifications

• C07D471/08

  Bridged systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/422

  not condensed and containing further heterocyclic rings · CPC title

• C07D491/10

  Spiro-condensed systems · CPC title

• C07D491/113

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title