# US 2008/0188562 A1 · Treating tinnitus using prodrugs of gabapentin and pregabalin > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2008/0188562 A1 - Document ID: US20080188562A1 - Status: Published application - Kind: A1 - Application number: 11/939,517 - Filed: 2007-11-13 - Published: 2008-08-07 - Earliest claimed: 2006-11-14 - Inventors: Noa Zerangue - Web page: https://patentgrep.com/patent/US20080188562A1 ## CPC - A61K 31/195: having an amino group - A61K 31/197: the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205) - A61P 27/00: Drugs for disorders of the senses - A61P 27/16: Otologicals - 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) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Methods of using prodrugs of gabapentin or pregabalin and pharmaceutical compositions thereof to treat tinnitus, and pharmaceutical compositions of prodrugs of gabapentin or pregabalin useful in treating tinnitus are disclosed. ## Claims ### Claim 1 A method of treating tinnitus in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound chosen from Formula (I) and Formula (II): a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of any of the foregoing, and a pharmaceutically acceptable N-oxide of any of the foregoing, wherein: R1 is chosen from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R2 and R3 are independently chosen from hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or R2 and R3 together with the carbon atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring; and R4 is chosen from acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. ### Claim 2 (depends on 1) The method of claim 1, wherein R1 is hydrogen. ### Claim 3 (depends on 1) The method of claim 1, wherein at least one of R2 and R3 is other than hydrogen. ### Claim 4 (depends on 1) The method of claim 1, wherein R2 and R3 are independently chosen from hydrogen and C1-6 alkyl. ### Claim 5 (depends on 1) The method of claim 1, wherein R3 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl, and R2 is hydrogen. ### Claim 6 (depends on 1) The method of claim 1, wherein R4 is chosen from C1-6 alkyl and C1-6 substituted alkyl. ### Claim 7 (depends on 1) The method of claim 1, wherein R4 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, and 1,1-diethoxyethyl. ### Claim 8 (depends on 1) The method of claim 1, wherein R1 and R2 are each hydrogen, R3 is C1-6 alkyl, and R4 is chosen from C1-6 alkyl and C1-6 substituted alkyl. ### Claim 9 (depends on 1) The method of claim 1, wherein R1 and R2 are each hydrogen, R3 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and sec-butyl, and R4 is chosen from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, and 1,1-diethoxyethyl. ### Claim 10 (depends on 1, 6) The method of any one of claims 1, 6, and 8, wherein each substituent is independently chosen from halogen, —NH2, —OH, —CF3, —CN, —COOH, —C(O)NH2, —C(O)OR5, and —NR53+ wherein each R5 is independently C1-3 alkyl. ### Claim 11 (depends on 1) The method of claim 1, wherein the compound is a compound of Formula (I) chosen from: 1-{[(α-Acetoxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Propanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Butanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Pivaloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Acetoxymethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Propanoyloxymethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Butanoyloxymethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Isobutanoyloxymethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Pivaloxymethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Acetoxypropoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Propanoyloxypropoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Butanoyloxypropoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Isobutanoyloxypropoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Pivaloxypropoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Acetoxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Propanoyloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Butanoyloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Isobutanoyloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Pivaloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Acetoxybutoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Propanoyloxybutoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Butanoyloxybutoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; 1-{[(α-Isobutanoyloxybutoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; and 1-{[(α-Pivaloxybutoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid; a pharmaceutically acceptable salt of any of the foregoing, a pharmaceutically acceptable solvate of any of the foregoing, and a pharmaceutically acceptable N-oxide of any of the foregoing. ### Claim 12 (depends on 1) The method of claim 1, wherein the compound is a compound of Formula (I) and is 1-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid or a pharmaceutically acceptable salt thereof, a pharmaceutical acceptable solvate of any of the foregoing, or a pharmaceutically acceptable N-oxide of any of the foregoing. ### Claim 13 (depends on 12) The method of claim 12, wherein the 1-{[α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid is crystalline. ### Claim 14 (depends on 13) The method of claim 13, wherein the crystalline 1-{[α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid has characteristic absorption peaks at 7.0°±0.3°, 8.2°±0.3°, 10.5°±0.3°, 12.8°±0.3°, 14.9°±0.3°, 16.4°±0.3°, 17.9°±0.3°, 18.1°±0.3°, 18.9°±0.3°, 20.9°±0.3°, 23.3°±0.3°, 25.3°±0.3°, and 26.6°±0.3° in an X-ray powder diffractogram. ### Claim 15 (depends on 13) The method of claim 13, wherein the crystalline 1-{[α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid has a melting point range from about 63° C. to about 66° C. ### Claim 16 (depends on 1) The method of claim 1, wherein the compound is a compound of Formula (II) chosen from: 3-{[(α-Acetoxyethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Propanoyloxyethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Butanoyloxyethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Pivaloxyethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Acetoxymethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Propanoyloxymethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Butanoyloxymethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Isobutanoyloxymethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Pivaloxymethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Acetoxypropoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Propanoyloxypropoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Butanoyloxypropoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Isobutanoyloxypropoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Pivaloxypropoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Acetoxyisopropoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Propanoyloxyisopropoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Butanoyloxyisopropoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Isobutanoyloxyisopropoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Pivaloxyisopropoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Acetoxybutoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Propanoyloxybutoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Butanoyloxybutoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; 3-{[(α-Isobutanoyloxybutoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; and 3-{[(α-Pivaloxybutoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid; a pharmaceutically acceptable salt of any of the foregoing, a pharmaceutically acceptable solvate of any of the foregoing, and a pharmaceutically acceptable N-oxide of any of the foregoing. ### Claim 17 (depends on 1) The method of claim 1, wherein the compound is a compound of Formula (II) and is 3-{[(α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-methyl hexanoic acid or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of any of the foregoing, or a pharmaceutically acceptable N-oxide of any of the foregoing. ### Claim 18 (depends on 1) The method of claim 1, wherein the compound is a compound of Formula (I) and is administered in an amount from about 10 mg-equivalents to about 3,600 mg-equivalents of gabapentin per day. ### Claim 19 (depends on 1) The method of claim 1, wherein the compound is a compound of Formula (II) and is administered in an amount from about 10 mg-equivalents to about 1,200 mg-equivalents of pregabalin per day. ### Claim 20 (depends on 1) The method of claim 1, wherein the compound is administered orally. ### Claim 21 (depends on 20) The method of claim 20, comprising orally administering the compound in a sustained release oral dosage form. ### Claim 22 (depends on 21) The method of claim 21, wherein a therapeutically effective amount of gabapentin or pregabalin is maintained in the plasma of the patient for a period of at least about 4 hours after administrating the compound. ### Claim 23 (depends on 21) The method of claim 21, wherein the therapeutically effective amount of gabapentin or pregabalin is maintained in the plasma of the patient for a period of at least about 8 hours after administrating the compound. ### Claim 24 (depends on 21) The method of claim 21, wherein the therapeutically effective amount of gabapentin or pregabalin is maintained in the plasma of the patient for a period of at least 12 hours after administrating the compound.