Synthesis and application of microbubble-forming compounds

Patent metadata

Field	Value
Publication number	US-11554094-B2
Application number	US-202017079381-A
Country	US
Kind code	B2
Filing date	Oct 23, 2020
Priority date	Jun 18, 2015
Publication date	Jan 17, 2023
Grant date	Jan 17, 2023

Abstract

The present disclosure is directed to fatty-acid glycerol ester derivative compounds containing a targeting bisphosphonate group. The disclosure further includes pharmaceutical or biomedical compositions comprising these compounds, and methods of using these compounds and compositions forming microbubbles. The microbubbles have affinity for metal-containing, especially calcium-containing, bodies and/or biological targets. In certain embodiments, these compositions are useful for providing targeted placement of microbubbles capable of cavitation on application of high frequency energy.

First claim

We claim:

1. A method for binding a physiological plaque, the method comprising the step of delivering an effective amount of a compound to a subject in need thereof, wherein the compound has the formula selected from the group consisting of formula (I), formula (Ia), formula (II), formula (III), formula (IV) and formula (V):

wherein:
each n is independently selected from 0-7;
each m is independently selected from 0-26;
each p is independently selected from 7-26;
each q is independently selected from 1-90;
each R 1 is independently selected from the group consisting of: hydrogen, C 1 -C 26 alkyl, C 1 -C 26 substituted alkyl, C 1 -C 26 alkenyl, C 1 -C 26 substituted alkenyl, C 1 -C 26 alkynyl, C 1 -C 26 substituted alkynyl, C 1 -C 26 alkyl aryl, C 1 -C 26 substituted alkyl aryl, C 1 -C 26 alkenyl aryl, C 1 -C 26 substituted alkenyl aryl, C 1 -C 26 alkynyl aryl, C 1 -C 26 substituted alkynyl aryl;
each R 2 is independently selected from the group consisting of: hydrogen, C 1 -C 26 alkyl, C 1 -C 26 substituted alkyl, C 1 -C 26 alkenyl, C 1 -C 26 substituted alkenyl, C 1 -C 26 alkynyl, C 1 -C 26 substituted alkynyl, C 1 -C 26 alkyl aryl, C 1 -C 26 substituted alkyl aryl, C 1 -C 26 alkenyl aryl, C 1 -C 26 substituted alkenyl aryl, C 1 -C 26 alkynyl aryl, C 1 -C 26 substituted alkynyl aryl, C 3 -C 8 cycloalkyl, C 3 -C 8 substituted cycloalkyl, C 3 -C 8 aryl, C 3 -C 8 substituted aryl, C 3 -C 8 heterocycloalkyl, C 3 -C 8 substituted heterocycloalkyl, C 3 -C 8 heteroaryl, C 3 -C 8 substituted heteroaryl, acyl, aminoacyl, thioacyl, aminocarbonyl, aminoacyl carbonyloxy, aminothiocarbonyl, aminosulfonyl, amidino, substituted sulfonyl, substituted sulfinyl, carboxy ester, phthalimido, SO 3 H and PO 3 H;
C is selected from the group consisting of:

B is selected from the group consisting of: a covalent bond, ethylene glycol, and polyethylene glycol;
A is selected from the group consisting of: a covalent bond, acyl, acylamino, aminoacyl, acyloxy, thioacyl, aminocarbonyl, aminoacyl carbonyloxy, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyloxy, aminosulfonylamino, aminosulfonyl, amidino, and carboxy ester, wherein any of these functional groups listed for A may be covalently bonded on either side to the

 moiety;
Y is selected from the group consisting of: a covalent bond, acyl, acylamino, aminoacyl, acyloxy, thioacyl, aminocarbonyl, aminoacyl carbonyloxy, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyloxy, aminosulfonylamino, aminosulfonyl, amidino, and carboxy ester, wherein any of these functional groups listed for A may be covalently bonded on either side to either one of the

 moieties;
X is selected from the group consisting of: hydrogen, silyl, acyl, aminoacyl, thioacyl, aminocarbonyl, aminoacyl carbonyloxy, aminothiocarbonyl, aminosulfonyl, amidino, substituted sulfonyl, substituted sulfinyl, carboxy ester, phthalimido, SO 3 H and POSH;
W is selected from the group consisting of: O, NR 2 , and S;
Z is selected from the group consisting of: a covalent bond, CH 2 , O, NR 2 , and S;
M is selected from the group consisting of: a covalent bond, CH 2 —CH 2 , CH 2 —CH 2 —Z, CH 2 —Z and CH 2 ;

or a tautomer and/or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the formula is the formula (II).

3. The method of claim 1 , wherein the formula is the formula (III).

4. The method of claim 1 , wherein the formula is the formula (IV).

5. The method of claim 1 , wherein the formula is the formula (V).

6. The method of claim 1 selected from the group consisting of:

7. The method of claim 1 , wherein each p is independently selected from 14-22; X is silyl, and each R 2 is hydrogen or C 1 -C 8 alkyl.

8. The method of claim 1 , wherein the formula is the formula (I) or the formula (Ia).

9. The method of claim 1 , wherein the compound in a pharmaceutical composition, wherein the compound forms a microbubble.

10. The method of claim 9 , further comprising the step of applying energy to the microbubble.

11. The method of claim 10 , wherein the energy is the form of electromagnetic or ultrasound energy and is sufficient to cause cavitation of the microbubble.

12. The method of claim 11 , wherein the cavitation releases sufficient energy to cause destruction of a cell, a tissue, or a calcium-containing mass at a site within the subject.

13. The method of claim 1 , wherein the subject is diagnosed to have the physiological plague, wherein the physiological plague is selected from a kidney stone, biliary stone and atheromatous plague.

Assignees

• California Inst Of Techn

Inventors

• Marx Vanessa M
• Grubbs Robert H

Classifications

• A61N5/02

  using microwaves · CPC title

• A61K9/0009 Primary

  involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis · CPC title

• C07B43/06

  of amide groups · CPC title

• A61K9/107

  Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)} · CPC title

• A61K9/1075

  Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence) · CPC title