# US 9,428,431 B2 · Compositions comprising CB receptor agonists, uses thereof and methods for their preparation

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- Number: US 9,428,431 B2
- Document ID: US9428431B2
- Status: Granted
- Kind: B2
- Application number: 13/122,662
- Filed: 2009-10-11
- Published: 2011-11-03
- Granted: 2016-08-30
- Earliest claimed: 2008-10-06
- Assignees: Yissum Research Development Company of the Hebrew University of Jerusalem
- Applicants: Itai Bab; Raphael Mechoulam; Aviva Breuer; Naama Mussai
- Inventors: Itai Bab; Raphael Mechoulam; Aviva Breuer; Naama Mussai
- Web page: https://patentgrep.com/patent/US9428431B2

## CPC

- C07C 43/23: containing hydroxy or O-metal groups
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07C 41/26: by introduction of hydroxy or O-metal groups
- C07C 67/14: from carboxylic acid halides
- C07C 67/29: by introduction of oxygen-containing functional groups
- C07C 67/293: by isomerisation; by change of size of the carbon skeleton
- C07B 2200/07: Optical isomers
- C07C 2601/16: the ring being unsaturated
- C07C 2602/42: the bicyclo ring system containing seven carbon atoms
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Provided are compositions including (3R, 4R, 6R)-stereoisomers of phenyl substituted pinenes having CB receptor agonist properties, methods of treating diseases or disorders with the pharmaceutical compositions, and processes for their preparation are also provided.

## Claims

### Claim 1

A composition comprising the (3R, 4R, 6R)-diastereomer of a compound of general formula (II):
wherein
is a double bond;
R1 is independently selected from —R2OR3, —C(═O)R4, and —OC(═O)R5;
R2 is a C1-C5 straight or branched alkylene;
R3 is selected from the group consisting of H, —C(═O)OH, straight or branched C1-C5 alkyl, straight or branched C1-C5 acyl, and straight or branched C1-C5 amide;
R4, and R5 are independently selected from the group consisting of H, OH, straight or branched C1-C5 alkyl, straight or branched C1-C5alkoxy, and straight or branched C1-C5 amine;
R6 and R7 are each independently selected from H, and —OR8 wherein R8 is a straight or branched C1-C5 alkyl, provided that at least one of R6 and R7 is different than H; and
R9 is independently selected from an optionally substituted straight or branched C6-C12 alkyl, an optionally substituted straight or branched C5-C9 alkoxy, and an optionally substituted straight or branched C1-C7 ether.

### Claim 2 (depends on 1)

The composition according to claim 1, wherein R1 is —R2OR3.

### Claim 3 (depends on 1)

The composition according to claim 1, wherein R1 is —R2OR3, and R2 is —CH2—.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R6 is H, R7 is —OR8, and R8 is a straight or branched —C1-C5 alkyl.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R7 is H, R6 is —OR8, and R8 is a straight or branched —C1-C5 alkyl.

### Claim 6 (depends on 1)

The composition according to claim 1, wherein R6 and R7 are each independently —OR8, and R8 is a straight or branched —C1-C5 alkyl.

### Claim 7 (depends on 1)

The composition according to claim 1, wherein R9 is an optionally substituted branched —C6-C12 alkyl.

### Claim 8 (depends on 1)

The composition according to claim 1, wherein the compound of formula (II) is:

### Claim 9 (depends on 1)

The composition according to claim 1, wherein the composition is a pharmaceutical composition.

### Claim 10 (depends on 1)

The composition according to claim 1, capable of binding to a CB receptor.

### Claim 11 (depends on 1)

The composition according to claim 1, capable of binding to a CB2 receptor.

### Claim 12 (depends on 1)

A method of stimulating bone growth, bone mass, bone repair or prevention of bone loss, comprising administering to a subject in need thereof, a therapeutically effective amount of the composition according to claim 1.

### Claim 13 (depends on 1)

A method for treating osteopenia and osteoporosis, comprising administering to a subject in need thereof, a therapeutically effective amount of the composition according to claim 1.

### Claim 14 (depends on 1)

A method for preparing a compound of formula (II) as defined in claim 1, comprising:
esterifying a compound of formula (V) with an acyl chloride to obtain compound (VI):
oxidizing compound (VI) to obtain 4-oxo-substituted compound (VII):
reducing 4-oxo-substituted compound (VII) to the 4-hydroxy-substituted compound (VIII):
condensing 4-hydroxy-substituted compound (VIII) with compound (IX) to obtain condensed compound (X):
and reducing an ester group of condensed compound (X) to obtain the compound of formula (II):