# US 2018/0021368 A1 · Bolaamphiphilic compounds, compositions and uses thereof

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- Number: US 2018/0021368 A1
- Document ID: US20180021368A1
- Status: Published application
- Kind: A1
- Application number: 15/639,425
- Filed: 2017-06-30
- Published: 2018-01-25
- Earliest claimed: 2012-09-04
- Assignees: Lauren Sciences LLC
- Applicants: Lauren Sciences LLC
- Inventors: Charles LINDER; Eliahu HELDMAN; Sarina GRINBERG
- Web page: https://patentgrep.com/patent/US20180021368A1

## CPC

- A61K 31/724: Cyclodextrins
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Bolaamphiphilic compounds are provided according to formula I: HG2-L1-HG1 I where HG1, HG2 and L1 are as defined herein. Provided bolaamphilphilic compounds and the pharmaceutical compositions thereof are useful for delivering biologically active drugs into animal or human brain.

## Claims

### Claim at position 1

-88. (canceled)

### Claim 89

A pharmaceutical composition or a formulation comprising a bolaamphiphile complex, a sub-micron sized vesicle, or nano-sized vesicle; wherein the bolaamphiphile complex or nano-sized vesicles comprises one or more bolaamphiphilic compounds and a biologically active compound, wherein the bolaamphiphilic compound is a compound according to formula I:
HG2-L1-HG1 I
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof;
wherein:
each HG1 and HG2 is independently a hydrophilic head group; and
L1 is alkylene, alkenyl, heteroalkylene, or heteroalkenyl linker; unsubstituted or substituted with C1-C20 alkyl, hydroxyl, or oxo.

### Claim 90 (depends on 89)

The pharmaceutical composition according to claim 89, wherein
L1 is heteroalkylene, or heteroalkenyl linker comprising C, N, and O atoms; unsubstituted or substituted with C1-C20 alkyl, hydroxyl, or oxo.

### Claim 91 (depends on 89)

The pharmaceutical composition according to claim 89, wherein the bolaamphiphilic compound is a compound according to formula II, III, IV, V, or VI:
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof;
wherein:
each HG1 and HG2 is independently a hydrophilic head group;
each Z1 and Z2 is independently —C(R3)2—, —N(R3)— or —O—;
each R1a, R1b, R3, and R4 is independently H or C1-C8 alkyl;
each R2a and R2b is independently H, C1-C8 alkyl, OH, alkoxy, or O-HG1 or O-HG2;
each n8, n9, n11, and n12 is independently an integer from 1-20;
n10 is an integer from 2-20; and
each dotted bond is independently a single or a double bond.

### Claim 92 (depends on 91)

The pharmaceutical composition according to claim 91, wherein the bolaamphiphilic compound is a compound according to formula II, III, IV, V, or VI; and each n8 and n12 is independently 1, 2, 3, or 4.

### Claim 93 (depends on 91)

The pharmaceutical composition according to claim 91, wherein the bolaamphiphilic compound is a compound according to formula II, III, IV, V, or VI; and each R2a and R2b is independently H, OH, alkoxy, or O-HG1 or O-HG2.

### Claim 94 (depends on 91)

The pharmaceutical composition according to claim 91, wherein the bolaamphiphilic compound is a compound according to formula II, III, IV, V, or VI; and each R1a and R1b is independently H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, sec-Bu, n-pentyl, isopentyl, n-hexyl, n-heptyl, or n-octyl.

### Claim 95 (depends on 91)

The pharmaceutical composition according to claim 91, wherein the bolaamphiphilic compound is a compound according to formula II, III, IV, or V; n10 is an integer from 2-16.

### Claim 96 (depends on 91)

The pharmaceutical composition according to claim 91, wherein the bolaamphiphilic compound is a compound according to formula II, III, IV, V, or VI; and each Z1 and Z2 is —O—.

### Claim 97 (depends on 89)

The pharmaceutical composition according to claim 89, wherein the bolaamphiphilic compound is a compound according to formula II, III, IV, V, or VI; and each HG1 and HG2 is independently selected from:
wherein:
X is —NR5aR5b, or —N+R5aR5bR5c; each R5a, and R5b is independently H or substituted or unsubstituted C1-C20 alkyl or R5a and R5b may join together to form an N containing substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycle;
each R5C is independently substituted or unsubstituted C1-C20 alkyl;
each R8 is independently H, substituted or unsubstituted C1-C20 alkyl, alkoxy, or carboxy;
m1 is 0 or 1; and
each n13, n14, and n15 is independently an integer from 1-20.

### Claim 98 (depends on 89)

The pharmaceutical composition according to claim 89, wherein the bolaamphiphilic compound is a compound according to formula VIIIa, VIIIb, VIIIc, or VIIId:
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof;
wherein:
each X is —NR5aR5b, or —N+R5aR5bR5c; each R5a, and R5b is independently H or substituted or unsubstituted C1-C20 alkyl or R5a and R5b may join together to form an N containing substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycle;
each R5C is independently substituted or unsubstituted C1-C20 alkyl;
n10 is an integer from 2-20; and
each dotted bond is independently a single or a double bond.

### Claim 99 (depends on 97)

The pharmaceutical composition according to claim 97, wherein each R5a, R5b, and R5c is independently substituted or unsubstituted C1-C20 alkyl.

### Claim 100 (depends on 97)

The pharmaceutical composition according to claim 97, wherein X is —N(Me)-CH2CH2—OAc or —N+(Me)2-CH2CH2—OAc.

### Claim 101 (depends on 97)

The pharmaceutical composition according to claim 97, wherein X is a headgroup comprising NK1R antagonist.

### Claim 102 (depends on 97)

The pharmaceutical composition according to claim 97, wherein X is a headgroup comprising NK1R antagonist, and the NK1R antagonist is I, II, or III:
I {1-[4-(1H-tetrazol-5-yl)butyl]indol-3-yl}carbonyl-Hyp-Nal- N(methyl)-Bz1, (Hyp = (R)-4-hydroxy-L-proline; Nal = 3- L-(β-naphthyl)-alanine)
II CP-99,994
III (+)-[2R,3R,4R,8R,9(3′R)-2-{1-[1(3,5bis(tri- fluoromethyl)phenyl]ethyl)oxy}-4(-3carboxy- 3-methylpiperidinlyl)-3-phenyl-methyltetra- hydropyran

### Claim 103 (depends on 89)

The pharmaceutical composition according to claim 89, wherein the bolaamphiphilic compound is a pharmaceutically acceptable salt.

### Claim 104 (depends on 89)

The pharmaceutical composition according to claim 89, wherein the bolaamphiphilic compound is in a form of a quaternary salt.

### Claim 105 (depends on 89)

The pharmaceutical composition of claim 89, wherein the biologically active compound is a drug active against brain tumor.

### Claim 106 (depends on 89)

The pharmaceutical composition of claim 89, wherein the biologically active compound is CPT-11, or BCNU (Carmustine).