Synthesis and application of microbubble-forming compounds

Patent metadata

Field	Value
Publication number	US-10646432-B2
Application number	US-201615737705-A
Country	US
Kind code	B2
Filing date	Jun 20, 2016
Priority date	Jun 18, 2015
Publication date	May 12, 2020
Grant date	May 12, 2020

Abstract

The present disclosure is directed to fatty-acid glycerol ester derivative compounds containing a targeting bisphosphonate group. The disclosure further include 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 pharmaceutical or biomedical composition comprising one or more compounds of 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 PO 3 H;
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 pharmaceutical or biomedical composition of claim 1 , wherein the composition is a suspension, a colloid, an emulsion, an aerosol, a sol, a gel, a foam, or in the form of microbubbles.

3. The pharmaceutical or biomedical composition of claim 2 , wherein the composition is in the form of microbubbles having a diameter of about 1 micron to about 10 microns, optionally wherein the microbubbles have an affinity for metal-containing material.

4. The pharmaceutical or biomedical composition of claim 2 , wherein the composition is in the form of microbubbles, the microbubbles comprising a core containing a fluid having a normal boiling point less than about 30° C., optionally wherein the fluid is air, CO 2 , a fluorinated C 1-6 hydrocarbon, or any combination thereof.

5. The pharmaceutical or biomedical composition of claim 4 , wherein the fluid is a fluorinated C 1-6 hydrocarbon and wherein the fluorinated C 1-6 hydrocarbon is perfluoropropane or perfluoropentane.

6. The pharmaceutical or biomedical composition of claim 1 , wherein the composition further comprises one or more pharmaceutically acceptable excipients.

7. The pharmaceutical or biomedical composition of claim 6 , wherein the composition comprises sterilized water or a sterilized physiological fluid.

8. The pharmaceutical or biomedical composition of claim 2 , wherein the composition is in the form of microbubbles, and wherein the microbubbles have a diameter of about 1 micron to about 10 microns.

9. The pharmaceutical or biomedical composition of claim 1 , wherein the compound of Formula V is selected from:

Assignees

• Califorina Institute Of Tech
• Marx Vanessa M
• Grubbs Robert H
• California Inst Of Techn

Inventors

• Marx Vanessa M
• Grubbs Robert H

Classifications

• C07F9/3873

  containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S) · CPC title

• C08G65/3355

  having phosphorus bound to carbon and oxygen · CPC title

• A61K9/0009 Primary

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

• A61N5/02

  using microwaves · CPC title

• A61K9/12

  Aerosols; Foams {(A61K9/0043, A61K9/0056, A61K9/006, A61K9/0073 take precedence; spray-films A61K9/7015)} · CPC title