# US 2012/0059007 A1 · Pharmacologically-active vanilloid carbamates

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- Number: US 2012/0059007 A1
- Document ID: US20120059007A1
- Status: Published application
- Kind: A1
- Application number: 12/882,351
- Filed: 2010-09-15
- Published: 2012-03-08
- Earliest claimed: 2009-09-15
- Assignees: Rutgers, The State University of New Jersey; University of Medicine and Dentistry of New Jersey; Lehigh University
- Inventors: Jeffrey D. Laskin; Diane E. Heck; Carl Jeffrey Lacey; Erik Aponte; Mou-Tuan Huang; Ned D. Heindel
- Web page: https://patentgrep.com/patent/US20120059007A1

## CPC

- C07C 271/24: with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07C 271/12: to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C 271/16: to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
- C07C 271/22: to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
- C07D 277/16: Sulfur atoms
- C07D 295/13: to an acyclic saturated chain
- C07C 2601/14: The ring being saturated
- C07C 2602/08: the other ring being five-membered, e.g. indane
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

This application relates to pharmacologically-active vanilloid compounds which are useful for the treatment of various anti-inflammatory states characterized by inhibition of FAAH, such as, Alzheimer's dementia, Parkinson's disease, depression, pain, rheumatoid arthritis, pathophysiology of mood disorders, multiple sclerosis, and inflammation, or antagonism of TRPV1, such as, for example, Huntington's disease, hypertension, arthritis, allergic airway inflammation, Crohn's disease, ulcerative colitis, and neuropathic pain.

## Claims

### Claim 1

The compound of the formula (I)
wherein
R1, R2, and R* are hydrogen, (C1-C15)alkyl, (C1-C15)alkyl(C1-C6)alkoxy, aryl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, (C1-C6)alkaryl, heterocyclic, (C1-C6)alkyl heterocyclic, and amino acyl and pharmaceutically acceptable addition salts thereof and optical and geometric isomers or racemic mixtures thereof.

### Claim 2 (depends on 1)

The compound of claim 1 wherein
R1 and R2 are alike or different and selected from hydrogen, (C1-C15)alkyl, (C1-C15)alkyl(C1-C6)alkoxy, aryl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, (C1-C6)alkaryl, heterocyclic, (C1-C6)alkyl heterocyclic, and amino acyl;
R* is (C1-C6)alkyl or aryl; and
pharmaceutically acceptable acid addition salts thereof and optical and geometric isomers or racemic mixtures thereof.

### Claim 3 (depends on 2)

The compound of claim 2 wherein
R1 is hydrogen or (C1-C15)alkyl;
R2 is hydrogen, (C1-C15)alkyl, (C1-C15)alkyl(C1-C6)alkoxy, aryl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, (C1-C6)alkaryl, heterocyclic, (C1-C6)alkyl heterocyclic, and amino acyl; and
R* is (C1-C6)alkyl.

### Claim 4 (depends on 3)

The compound of claim 3 wherein
R1 is hydrogen or n-butyl;
R2 is ethyl, n-butyl, n-hexyl, n-octyl, n-heptyl, 2-ethylhexyl, n-dodecyl, cyclohexyl, cyclohexylmethyl, 2-phenoxyethyl, phenethyl, 2-indanyl, 2-methoxyethyl, 3,3-dmethylbutyl, 2-(4-morpholino)ethyl, ethyl 2-glycinyl or ethyl 2-valinyl; and
R* is methyl.

### Claim 5 (depends on 4)

The compound of claim 4 which is
4-{[(cyclohexylcarbamoyl)oxy]methyl}-2-methoxyphenyl acetate,
4-{[(butylcarbamoyl)oxy]methyl}-2-methoxyphenyl acetate,
4-{[(hexylcarbamoyl)oxy]methyl}-2-methoxyphenyl acetate,
4-{[(octylcarbamoyl)oxy]methyl}-2-methoxyphenyl acetate,
4-{[(decylcarbamoyl)oxy]methyl}-2-methoxyphenyl acetate,
2-methoxy-4-({[(2-methoxyethyl)carbamoyl]oxy}methyl)phenyl acetate,
4-(acetyloxy)-3-methoxybenzyl 2-thioxo-1,3-thiazolidine-3-carboxylate,
4-{[(heptylcarbamoyl)oxy]methyl}-2-methoxyphenyl acetate,
4-{[(dibutylcarbamoyl)oxy]methyl}-2-methoxyphenyl acetate,
4-{[(benzylcarbamoyl)oxy]methyl}-2-methoxyphenyl acetate,
4-{[(2-ethylhexylcarbamoyl)oxy]methyl}-2-methoxyphenyl acetate,
4-{[(dodecylcarbamoyl)oxy]methyl}-2-methoxyphenyl acetate,
2-methoxy-4-({[(2-phenoxyethyl)carbamoyl]oxy}methyl)phenyl acetate,
2-methoxy-4-({[(2-phenylethyl)carbamoyl]oxy}methyl)phenyl acetate,
4-({[(cyclohexylmethyl)carbamoyl]oxy}methyl)-2-methoxyphenyl acetate,
4-{[(2,3-dihydro-1H-inden-2-ylcarbamoyl)oxy]methyl}-2-methoxyphenyl acetate,
4-({[(3,3-dimethylbutyl)carbamoyl]oxy}methyl)-2-methoxyphenyl acetate,
2-methoxy-4-[({[2-(morpholin-4-yl)ethyl]carbamoyl}oxy)methyl]phenyl acetate,
4-{[(ethylcarbamoyl)oxy]methyl}-2-methoxyphenyl acetate,
ethyl [({[4-(acetyloxy)-3-methoxybenzyl]oxy}carbonyl)amino]acetate, or
ethyl 2 [({[4-(acetoxy)-3-methoxybenzyl]oxy}carbonyl)amino]-3-methylbutanoate.

### Claim 6 (depends on 1)

A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compound of claim 1.

### Claim 7 (depends on 1)

A method of treating Alzheimer's dementia, Parkinson's disease, depression, pain, rheumatoid arthritis, pathophysiology of mood disorders, multiple sclerosis, or inflammation which comprises administering to a patient an effective amount of the compound of claim 1.

### Claim 8 (depends on 1)

A method of treating Huntington's disease, hypertension, arthritis, allergic airway inflammation, Crohn's disease, ulcerative colitis, or neuropathic pain which comprises administering to a patient an effective amount of the compound of claim 1.

### Claim 9

A method of preparing a compound of formula (I)
wherein
R1, R2, and R* are hydrogen, (C1-C15)alkyl, (C1-C15)alkyl(C1-C6)alkoxy, aryl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, (C1-C6)alkaryl, heterocyclic, (C1-C6)alkyl heterocyclic, and amino acyl and pharmaceutically acceptable addition salts thereof and optical and geometric isomers or racemic mixtures thereof, which comprises
reacting a benzyl alcohol compound of formula (a)
with an isocyanate of formula (b)
RNCO (b); and
obtaining the compound of formula (I).

### Claim 10

A method of preparing a compound of formula (I)
wherein
R1, R2, and R* are hydrogen, (C1-C15)alkyl, (C1-C15)alkyl(C1-C6)alkoxy, aryl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, (C1-C6)alkaryl, heterocyclic, (C1-C6)alkyl heterocyclic, and amino acyl and pharmaceutically acceptable addition salts thereof and optical and geometric isomers or racemic mixtures thereof, which comprises
reacting a benzyl alcohol compound of formula (a)
with carbonyldiimidazole (CDI) of formula (c)
to obtain the compound of formula (d)
reacting the compound of formula (d) with NHR1R2 and
obtaining the compound of formula (I).

### Claim 11

A method of preparing a compound of formula (I)
wherein
R1, R2, and R* are hydrogen, (C1-C15)alkyl, (C1-C15)alkyl(C1-C6)alkoxy, aryl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C6)alkyl, (C1-C6)alkaryl, heterocyclic, (C1-C6)alkyl heterocyclic, and amino acyl and pharmaceutically acceptable addition salts thereof and optical and geometric isomers or racemic mixtures thereof, which comprises
reacting a benzyl alcohol compound of formula (a)
with N-chloroformylthiazolidine-2-thione of formula (e)
to obtain the compound of formula (f)
reacting the compound of formula (f) with NHR1R2 and
obtaining the compound of formula (I).