6-mercapto-cyclodextrin derivatives:reversal agents for drug-induced neuromuscular block

• US RE44,733 E1
• Filed: 03/28/2012
• Issued: 01/28/2014
• Est. Priority Date: 11/29/1999
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme BV (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme BV (Merck & Co., Inc.)
• Inventors: Zhang, Mingiang, Palin, Ronald, Bennett, Jonathan
• Primary Examiner(s): MAIER, LEIGH C
• Application Number:
  US13/432,742
• Time in Patent Office: 671 Days
• Field of Search: None
• US Class Current: 514/58
• CPC Class Codes: N/A

Abstract

Disclosed is a 6-mercapto-cyclodextrin derivative having general formula (I) wherein m is 0-7 and n is 1-8 and m+n=7 or 8; R is (C_1-6)alkylene, optionally substituated with 1-3 OH groups, or (CH₂)_o-phenylene-(CH₂)_p—; o and p are independently 0-4; X is COOH, CONHR₁, NHCOR₂, SO₂OH, PO(OH)₂, O(CH₂—CH₂—O)_q—H, OH or tetrazol-5-yl; R₁ is H or (C_1-3)alkyl; R₂ is carboxyphenyl; q is 1-3; or pharmaceutically acceptable salts thereof. The 6-mercaptocyclodextrin derivative is highly suitable for use in the reversal of drug-induced neuromuscular block.

Claims

1. A 6-mercapto-cyclodextrin derivative having the general formula I

2. The 6-mercapto-cyclodextrin derivative according to claim 1, wherein R, m and n are defined as in claim 1 and X is COOH or SO₂OH;

or a pharmaceutically acceptable salt thereof.

3. The 6-mercapto-cyclodextrin derivative according to claim 1, wherein m is 0;

n is 8;

R is (C_1-6)alkylene or (CH₂)_o-phenylene-(CH₂)_p;

o and p are independently 0-4; and

X is COOH or SO₂OH;

or a pharmaceutically acceptable salt thereof.

4. A 6-mercapto-cyclodextrin derivative according to claim 1 selected from the group consisting of:

6-per-deoxy-6-per-(2-carboxyethyl)thio-γ

-cyclodextrin;

6-per-deoxy-6-per-(3-carboxypropyl)thio-γ

-cyclodextrin;

6-per-deoxy-6-per-(4-carboxyphenyl)thio-γ

-cyclodextrin;

6-per-deoxy-6-per-(4-carboxyphenylmethyl)thio-γ

-cyclodextrin;

6-per-deoxy-6-per-(2-carboxypropyl)thio-γ

-cyclodextrin; and

6-per-deoxy-6-per-(2-sulfoethyl)thio-γ

-cyclodextrin;

or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a 6-mercapto-cyclodextrin derivative having the general formula I

6. A kit for providing neuromuscular block and its reversal comprising (a) a neuromuscular blocking agent, and (b) a 6-mercapto-cyclodextrin derivative according to the general formula I

7. The kit according to claim 6, wherein the neuromuscular blocking agent is selected from the group consisting of rocuronium, vecuronium, pancuronium, rapacuronium, mivacurium, (cis)atracurium, tubocurarine and suxamethonium.

8. The kit according to claim 6, wherein the neuromuscular blocking agent is rocuronium.

10. The kit according to claim 6, wherein the neuromuscular blocking agent is vecuronium.

9. A method for reversal of drug-induced neuromuscular block in a patient, which comprises parenterally administering to said patient an effective amount of a 6-mercaptocyclodextrin derivative according to the general formula I

11. 6-Per-deoxy-6-per-(2-carboxyethyl)thio-γ

-cyclodextrin, or a pharmaceutically acceptable salt thereof.

12. 6-Per-deoxy-6-per-(2-carboxyethyl)thio-γ

-cyclodextrin, sodium salt.

13. A pharmaceutical composition comprising 6-per-deoxy-6-per-(2-carboxyethyl)thio-γ

-cyclodextrin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically suitable auxiliary.

14. A pharmaceutical composition comprising 6-per-deoxy-6-per-(2-carboxyethyl)thio-γ

-cyclodextrin, sodium salt, and a pharmaceutically suitable auxiliary.

15. A kit for providing neuromuscular block and its reversal comprising (a) a neuromuscular blocking agent, and (b) 6-per-deoxy-6-per-(2-carboxyethyl)thio-γ

-cyclodextrin, or a pharmaceutically acceptable salt thereof.

17. The kit according to claim 15, wherein the neuromuscular blocking agent is selected from the group consisting of rocuronium, vecuronium, pancuronium, rapacuronium, mivacurium, (cis)atracurium, tubocurarine and suxamethonium.

18. The kit according to claim 15, wherein the neuromuscular blocking agent is rocuronium.

19. The kit according to claim 15, wherein the neuromuscular blocking agent is vecuronium.

16. A kit for providing neuromuscular block and its reversal comprising (a) a neuromuscular blocking agent, and (b) 6-per-deoxy-6-per-(2-carboxyethyl)thio-γ

-cyclodextrin, sodium salt.

20. A method for reversal of drug-induced neuromuscular block in a subject, which comprises parenterally administering to said subject an effective amount of 6-per-deoxy-6-per-(2-carboxyethyl)thio-γ

-cyclodextrin, or a pharmaceutically acceptable salt thereof.

21. A method for reversal of drug-induced neuromuscular block in a subject, which comprises parenterally administering to said subject an effective amount of 6-per-deoxy-6-per-(2-carboxyethyl)thio-γ

-cyclodextrin, sodium salt.