Substituted fullerenes and their use as inhibitors of cell death

• US 20060247152A1
• Filed: 05/02/2005
• Published: 11/02/2006
• Est. Priority Date: 05/02/2005
• Status: Abandoned Application

• Current Assignee: Luna Innovations, Inc.
• Original Assignee: Luna Innovations, Inc.
• Inventors: Rosenblum, Michael G., Lebovitz, Russ
• Application Number:
  US11/120,168
• Publication Number:
  US 20060247152A1
• Time in Patent Office: Days
• US Class Current: 548/400
• CPC Class Codes: A61K 31/235 having an aromatic ring attached to a carboxyl group
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate

Abstract

This patent discloses the use of water-soluble substituted fullerenes as inhibitors of cell death. The substituted fullerenes comprise a fullerene core (Cn) and at least one of: (i) from 1 to 6 (>CX¹X²) groups bonded to the fullerene core; (ii) from 1 to 18 -X³ groups bonded to the fullerene core; (iii) from 1 to 6 -X⁴- groups bonded to the fullerene core; or (iv) from 1 to 6 dendrons bonded to the fullerene core.

Claims

1. A method of inhibiting cell death, comprising:

administering to a mammal an effective amount of a composition comprising a substituted fullerene, wherein the substituted fullerene comprises a fullerene core (Cn), wherein n is an even integer greater than or equal to 60, and at least one of i-iv;

(i) m (>

CX¹X²) groups bonded to the fullerene core, wherein;

(i-a) m is an integer from 1 to 6, inclusive,

(i-b) each X¹ and X² is independently selected from —

H;

—

COOH;

—

CONH₂;

—

CONHR′

;

—

CONR′

₂;

—

COOR′

;

—

CHO;

—

(CH₂)_dOR¹¹;

a peptidyl moiety;

—

R;

—

RCOOH;

—

RCONH₂;

—

RCONHR′

;

—

RCONR′

₂;

—

RCOOR′

;

—

RCHO;

—

R(CH₂)_dOR¹¹;

a heterocyclic moiety;

a branched moiety comprising one or more terminal —

OH, —

NH₂, triazole, tetrazole, or sugar groups;

or a salt thereof, wherein each R is a hydrocarbon moiety having from 1 to about 6 carbon atoms and each R′

is independently a hydrocarbon moiety having from 1 to about 6 carbon atoms, an aryl-containing moiety having from 6 to about 18 carbon atoms, a hydrocarbon moiety having from 1 to about 6 carbon atoms and a terminal carboxylic acid or alcohol, or an aryl-containing moiety having from 6 to about 18 carbon atoms and a terminal carboxylic acid or alcohol, and d is an integer from 0 to about 20, and each R¹¹ is independently —

H, a charged moiety, or a polar moiety;

(ii) p -X³ groups bonded to the fullerene core, wherein;

(ii-a) p is an integer from 1 to 18, inclusive; and

(ii-b) each -X³ is independently selected from —

N⁺(R²)(R³)(R⁴), wherein R², R³, and R⁴ are independently —

H or —

(CH₂)_d—

CH₃, wherein d is an integer from 0 to about 20;

—

N⁺(R²)(R³)(R⁸), wherein R² and R³ are independently —

H or —

(CH₂)_d—

CH₃, wherein d is an integer from 0 to about 20, and each R⁸ is independently —

(CH₂)_f—

SO₃⁻

, —

(CH₂)_f—

PO₄⁻

, or —

(CH₂)_f—

COO⁻

, wherein f is an integer from 1 to about 20;

—

C(R⁵)(R⁶)(R⁷), wherein R⁵, R⁶, and R⁷ are independently —

COOH, —

H, —

CH(═

O), —

CH₂OH, or a peptidyl moiety;

wherein each R¹⁰ is independently >

O, >

C(R²)(R³), wherein R² and R³ are independently —

H or —

(CH₂)_d—

CH₃, wherein d is an integer from 0 to about 20, >

CHN⁺(R²)(R³)(R⁴), wherein R², R³, and R⁴ are independently —

H or —

(CH₂)_d—

CH₃, wherein d is an integer from 0 to about 20, or >

CHN⁺(R²)(R³)(R⁸), wherein R² and R³ are independently —

H or —

(CH₂)_d—

CH₃, wherein d is an integer from 0 to about 20, and each R⁸ is independently —

(CH₂)_f—

SO₃⁻

, —

(CH₂)_f—

PO₄⁻

, or —

(CH₂)_f—

COO—

, wherein f is an integer from 1 to about 20;

—

C(R²)(R³)(R⁸), wherein R² and R³ are independently —

H or —

(CH₂)_d—

CH₃, wherein d is an integer from 0 to about 20, and each R⁸ is independently —

(CH₂)_f—

SO₃⁻

, —

(CH₂)_f—

PO₄⁻

, or —

(CH₂)_f—

COO⁻

, wherein f is an integer from 1 to about 20;

—

(CH₂)_e—

COOH, —

(CH₂)_e—

CONH₂, —

(CH₂)_e—

COOR′

, wherein e is an integer from 1 to about 6 and each R′

is independently a hydrocarbon moiety having from 1 to about 6 carbon atoms, an aryl-containing moiety having from 6 to about 18 carbon atoms, a hydrocarbon moiety having from 1 to about 6 carbon atoms and a terminal carboxylic acid or alcohol, or an aryl-containing moiety having from 6 to about 18 carbon atoms and a terminal carboxylic acid or alcohol;

a peptidyl moiety;

or an aromatic heterocyclic moiety containing a cationic nitrogen;

(iii) q -X⁴- groups bonded to the fullerene core, wherein

(iii-a) q is an integer from 1 to 6, inclusive; and

(iii-b) each -X⁴- group is independently

 

wherein R² is independently —

H or —

(CH₂)_d—

CH₃, d is an integer from 0 to about 20, and R⁸ is independently —

(CH₂)_f—

SO₃⁻

, —

(CH₂)_f—

PO₄⁻

, or —

(CH₂)_f—

COO⁻

, and f is an integer from 1 to about 20;

 

wherein each R² and R³ is independently —

H or —

(CH₂)_d—

CH₃ and d is an integer from 0 to about 20;

wherein each R² is independently —

H or —

(CH₂)_d—

CH₃, d is an integer from 0 to about 20, and each R⁹ is independently —

H, —

OH, —

OR′

, —

NH₂, —

NHR′

, —

NHR′

₂, or —

(CH₂)_dOH, wherein each R′

is independently a hydrocarbon moiety having from 1 to about 6 carbon atoms, an aryl-containing moiety having from 6 to about 18 carbon atoms, a hydrocarbon moiety having from 1 to about 6 carbon atoms and a terminal carboxylic acid or alcohol, or an aryl-containing moiety having from 6 to about 18 carbon atoms and a terminal carboxylic acid or alcohol.

(iv) r dendrons bonded to the fullerene core and s nondendrons bonded to the fullerene core, wherein;

(iv-a) r is an integer from 1 to 6, inclusive;

(iv-b) s is an integer from 0 to 18, inclusive;

(iv-b) each dendron has at least one protic group which imparts water solubility, and

(iv-d) each nondendron independently comprises at least one drug, amino acid, peptide, nucleotide, vitamin, or organic moiety,

wherein the cell death is induced by a non-free-radical agent.

2. The method of claim 1, wherein the mammal suffers or is susceptible to cell death caused by heat, radiation, mechanical injury, a chemical toxin, a bacterial toxin, a viral toxin, a plant toxin, a biological toxin, or two or more thereof.

3. The method of claim 2, wherein the biological toxin is an autoimmune toxin

4. The method of claim 2, wherein the autoimmune toxin is a cytokine.

5. The method of claim 4, wherein the cytokine is TNF-α

.

6. The method of claim 1, wherein the mammal suffers or is susceptible to cell death by apoptosis.

7. The method of claim 1, wherein the composition further comprises a pharmaceutically-acceptable carrier.

8. The method of claim 1, wherein the substituted fullerene comprises a fullerene core (Cn) having 60 carbon atoms or 70 carbon atoms.

9. The method of claim 1, wherein the substituted fullerene has the structure: