Synthesis and application of microbubble-forming compounds

Patent metadata

Field	Value
Publication number	US-10945946-B2
Application number	US-202016831781-A
Country	US
Kind code	B2
Filing date	Mar 26, 2020
Priority date	Jun 18, 2015
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

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 compound of a formula, 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 compound of claim 1 , wherein the formula is the formula (II).

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

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

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

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

7. The compound of claim 4 , wherein each p is independently selected from 14-22; X is silyl, and each R2 is hydrogen or C1-C8 alkyl.

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

Assignees

• California Inst Of Techn

Inventors

• Marx Vanessa M
• Grubbs Robert H

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C08G65/3355

  having phosphorus bound to carbon and oxygen · CPC title

• 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

• 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