# US 9,517,279 B2 · 2-alkoxy-11-hydroxyaporphine derivatives and uses thereof

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- Number: US 9,517,279 B2
- Document ID: US9517279B2
- Status: Granted
- Kind: B2
- Application number: 13/640,426
- Filed: 2011-04-14
- Published: 2013-08-15
- Granted: 2016-12-13
- Earliest claimed: 2010-04-14
- Assignees: The McLean Hospital Corporation
- Applicants: John L. Neumeyer; Yu-Gui Si; Anna W. Sromek
- Inventors: John L. Neumeyer; Yu-Gui Si; Anna W. Sromek
- Web page: https://patentgrep.com/patent/US9517279B2

## CPC

- C07D 221/18: Ring systems of four or more rings
- A61K 51/0455: {having six-membered rings with one nitrogen as the only ring hetero atom}
- C07B 59/002: {Heterocyclic compounds}
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The invention features 2-alkoxy-11-hydroxyaporphine derivatives that selectively bind D2high receptors. The compounds are useful for imaging D2high receptors and for the treatment of diseases, such as Parkinson's disease, sexual dysfunction, and depressive disorders.

## Claims

### Claim 1

A compound of formula I:
or a pharmaceutically acceptable salt thereof,
wherein
X1 is 2-fluoroethyl, 3-fluoro-n-propyl, 2-iodoethyl, or 3-iodo-n-propyl;
R1 is H, CH3, CH2CH3, or CH2CH2CH3;
R2 is H or OY2;
each of Y1 and Y2 is, independently, selected from H, C(O)—R3, and fatty acid acyl, and
R3 is selected from H, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C2-6 heterocyclyl, C6-12 aryl, C7-14 alkaryl, C3-10 alkheterocyclyl, and C1-7 heteroalkyl,
wherein said compound has an in vitro affinity of between 0.5 nM and 35 nM at D2high receptors.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X1 is a 2-fluoroethyl or 3-fluoro-n-propyl substituent, and wherein said 2-fluoroethyl or 3-fluoro-n-propyl substituent comprises a radioactive fluorine atom.

### Claim 3 (depends on 1)

The compound of claim 1, wherein said compound is selected from R(−)-2-(2-fluoroethoxy)-11-hydroxy-N-methyl-noraporphine, R(−)-2-(3-fluoro-n-propanoxy)-11-hydroxy-N-methyl-noraporphine, R(−)-2-(2-fluoroethoxy)-11-hydroxy-N-ethyl-noraporphine, R(−)-2-(3-fluoro-n-propanoxy)-11-hydroxy-N-ethyl-noraporphine, R(−)-2-(2-fluoroethoxy)-11-hydroxy-N-propyl-noraporphine, R(−)-2-(3-fluoro-n-propanoxy)-11-hydroxy-N-propyl-noraporphine, esters thereof, and pharmaceutically acceptable salts thereof.

### Claim 4 (depends on 1)

The compound of claim 1, wherein said compound is selected from R(−)-2-(2-fluoroethoxy)-10-hydroxy-11-hydroxy-N-methyl-noraporphine, R(−)-2-(3-fluoro-n-propanoxy)-10-hydroxy-11-hydroxy-N-methyl-noraporphine, R(−)-2-(2-fluoroethoxy)-10-hydroxy-11-hydroxy-N-ethyl-noraporphine, R(−)-2-(3-fluoro-n-propanoxy)-10-hydroxy-11-hydroxy-N-ethyl-noraporphine, R(−)-2-(2-fluoroethoxy)-10-hydroxy-11-hydroxy-N-propyl-noraporphine, R(−)-2-(3-fluoro-n-propanoxy)-10-hydroxy-11-hydroxy-N-propyl-noraporphine, monoesters thereof, diesters thereof, and pharmaceutically acceptable salts thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein said compound has no observable affinity at D1high receptors.

### Claim 6 (depends on 1)

A method of imaging D2high receptors in a subject, said method comprising (i) administering to said subject a radiolabeled compound of claim 1, and (ii) following the specific binding of said radiolabeled compound to said D2high receptors, monitoring the distribution of said radiolabeled compound in said subject.

### Claim 7 (depends on 6)

The method of claim 6, wherein said radiolabeled compound comprises a radioactive fluorine atom.

### Claim 8 (depends on 7)

The method of claim 7, wherein said distribution of said radiolabeled compound in said subject is monitored using PET.

### Claim 9 (depends on 6)

The method of claim 6, wherein said radiolabeled compound comprises a radioactive iodine atom.

### Claim 10 (depends on 9)

The method of claim 9, wherein said distribution of said radiolabeled compound in said subject is monitored using SPECT.

### Claim 11 (depends on 6)

The method of claim 6, further comprising diagnosing a dopamine-related disorder in said subject on the basis of the results of said imaging.

### Claim 12 (depends on 6)

The method of claim 6, wherein in said imaging is repeated to monitor the progression of a dopamine-related disorder in said subject.

### Claim 13 (depends on 11)

The method of claim 11, wherein said dopamine-related disorder is selected from psychoses, schizophrenia, Parkinson's disease, and progressive supranuclear palsy.

### Claim 14 (depends on 11)

The method of claim 11, wherein said dopamine-related disorder is dopamine supersensitivity.

### Claim 15 (depends on 1)

A method of treating Parkinson's disease in a subject, said method comprising administering to said subject an effective amount of a compound of claim 1.

### Claim 16 (depends on 1)

The compound of claim 1, wherein X1 is 2-fluoroethyl, R1 is CH2CH2CH3, R2 is H, and Y1 is H, or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

The compound of claim 1, wherein X1 is 2-fluoroethyl, R1 is CH2CH2CH3, R2 is OH, and Y1 is H, or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

The compound of claim 1, wherein X1 is 3-fluoro-n-propyl, R1 is CH2CH2CH3, R2 is H, and Y1 is H, or a pharmaceutically acceptable salt thereof.