# US 2019/0167669 A1 · Methods of treating neurofibromatosis with perillyl alcohol

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- Number: US 2019/0167669 A1
- Document ID: US20190167669A1
- Status: Published application
- Kind: A1
- Application number: 16/313,388
- Filed: 2017-06-30
- Published: 2019-06-06
- Earliest claimed: 2010-08-27
- Assignees: NeOnc Technologies, Inc.
- Applicants: NeOnc Technologies, Inc.
- Inventors: Thomas CHEN
- Web page: https://patentgrep.com/patent/US20190167669A1

## CPC

- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 9/0043: {Nose}
- A61K 31/045: Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K 31/366: having six-membered rings, e.g. delta-lactones
- A61K 31/4015: having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
- A61K 31/415: 1,2-Diazoles
- A61K 31/4188: condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/54: the modifying agent being an organic compound
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/543: {Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine}
- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- C07B 59/00: Introduction of isotopes of elements into organic compounds {; Labelled organic compounds per se}
- C07C 33/14: containing six-membered rings
- C07D 207/26: 2-Pyrrolidones
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 487/04: Ortho-condensed systems
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07C 2601/16: the ring being unsaturated
- 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)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present methods treat neurofibromatosis by a administering to a subject perillyl alcohol or iso-perillyl alcohol. The present methods also treat neurofibromatosis by administering to a subject a carbamate of perillyl alcohol, or a carbamate of iso-perillyl alcohol. The perillyl alcohol carbamate may comprise perillyl alcohol conjugated with rolipram or temozolomide.

## Claims

### Claim 1

A method of treating neurofibromatosis, comprising administering to a subject a therapeutically effective amount of perillyl alcohol, an iso-perillyl alcohol, or a combination thereof.

### Claim 2

A method of treating neurofibromatosis, comprising administering to a subject a therapeutically effective amount of a carbamate of perillyl alcohol, a carbamate of an iso-perillyl alcohol, or a combination thereof.

### Claim 3 (depends on 2)

The method of claim 2, wherein the carbamate of perillyl alcohol is perillyl alcohol conjugated with temozolomide or rolipram.

### Claim 4 (depends on 2)

The method of claim 2, wherein the carbamate of perillyl alcohol is 4-(3-cyclopentyloxy-4-methoxy phenyl)-2-oxo-pyrrolidine-1-carboxylic acid 4-isopropenyl cyclohex-1-enylmethyl ester.

### Claim 5 (depends on 2)

The method of claim 2, wherein the carbamate of perillyl alcohol is 3-methyl 4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl-carbamic acid-4-isopropenyl cyclohex-1-enylmethyl ester.

### Claim 6 (depends on 1, 2)

The method of claims 1 or 2, further comprising administering temozolomide or rolipram to the subject.

### Claim 7 (depends on 1, 2)

The method of claims 1 or 2, further comprising administering to the subject a statin selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin and rosuvastatin.

### Claim 8 (depends on 1, 2)

The method of claims 1 or 2, further comprising administering prostratin to the subject.

### Claim 9 (depends on 1, 2)

The method of claims 1 or 2, wherein the administration is by inhalation, intranasally, orally, intravenously, subcutaneously or intramuscularly.

### Claim 10

A method of inhibiting or decreasing Ras level and/or activity in a cell, comprising administering to the cell perillyl alcohol, an iso-perillyl alcohol, or a combination thereof.

### Claim 11

A method of inhibiting or decreasing Ras level and/or activity in a cell, comprising administering to the cell a carbamate of perillyl alcohol, a carbamate of an iso-perillyl alcohol, or a combination thereof.

### Claim 12

A method of inhibiting or decreasing Ras level and/or activity in a subject, comprising administering to the subject an effective amount of perillyl alcohol, an iso-perillyl alcohol, or a combination thereof.

### Claim 13

A method of inhibiting or decreasing Ras level and/or activity in a subject, comprising administering to the subject an effective amount of a carbamate of perillyl alcohol, a carbamate of an iso-perillyl alcohol, or a combination thereof.

### Claim 14 (depends on 11, 13)

The method of claims 11 or 13, wherein the carbamate of perillyl alcohol is perillyl alcohol conjugated with temozolomide or rolipram.

### Claim 15 (depends on 11, 13)

The method of claims 11 or 13, wherein the carbamate of perillyl alcohol is 4-(3-cyclopentyloxy-4-methoxy phenyl)-2-oxo-pyrrolidine-1-carboxylic acid 4-isopropenyl cyclohex-1-enylmethyl ester.

### Claim 16 (depends on 11, 13)

The method of claims 11 or 13, wherein the perillyl alcohol carbamate is 3-methyl 4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl-carbamic acid-4-isopropenyl cyclohex-1-enylmethyl ester.

### Claim 17 (depends on 10, 11, 12, 13)

The method of any of claims 10-13, further comprising administering temozolomide or rolipram.

### Claim 18 (depends on 10, 11, 12, 13)

The method of any of claims 10-13, further comprising administering a statin selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin and rosuvastatin.

### Claim 19 (depends on 10, 11, 12, 13)

The method of any of claims 10-13, further comprising administering prostratin.

### Claim 20 (depends on 12, 13)

The method of claims 12 or 13, wherein said administration is by inhalation, intranasally, orally, intravenously, subcutaneously or intramuscularly.

### Claim 21

A method of treating neurofibromatosis, comprising administering to a subject a therapeutically effective amount of perillyl alcohol.

### Claim 22 (depends on 21)

The method of claim 21, further comprising administering rolipram to the subject.

### Claim 23 (depends on 21)

The method of claim 21, further comprising administering a statin selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin and rosuvastatin.

### Claim 24 (depends on 23)

The method of claim 23, wherein the statin is lovastatin.

### Claim 25 (depends on 21)

The method of claim 21, further comprising administering prostratin to the subject.

### Claim 26

A method of treating neurofibromatosis, comprising administering to a subject a therapeutically effective amount of iso-perillyl alcohol.

### Claim 27 (depends on 26)

The method of claim 26, further comprising administering rolipram to the subject.

### Claim 28 (depends on 26)

The method of claim 26, further comprising administering a statin selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, simvastatin and rosuvastatin.

### Claim 29 (depends on 28)

The method of claim 28, wherein the statin is lovastatin.