# US 8,784,775 B2 · Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors

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- Number: US 8,784,775 B2
- Document ID: US8784775B2
- Status: Granted
- Kind: B2
- Application number: 12/256,957
- Filed: 2008-10-23
- Published: 2009-07-30
- Granted: 2014-07-22
- Earliest claimed: 2007-10-26
- Assignees: Piramal Imaging SA
- Applicants: Lutz Lehmann; Andrea Thiele; Tobias Heinrich; Thomas Brumby; Christer Halldin; Balazs Gulyas; Sangram Nag
- Inventors: Lutz Lehmann; Andrea Thiele; Tobias Heinrich; Thomas Brumby; Christer Halldin; Balazs Gulyas; Sangram Nag
- Web page: https://patentgrep.com/patent/US8784775B2

## CPC

- C07D 291/08: condensed with carbocyclic rings or ring systems
- A61K 51/04: Organic compounds
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/16: Anti-Parkinson drugs
- 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
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07B 59/00: Introduction of isotopes of elements into organic compounds {; Labelled organic compounds per se}
- C07C 211/42: with six-membered aromatic rings being part of the condensed ring systems
- C07C 309/66: Methanesulfonates
- C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- A61K 49/0433: {containing an organic halogenated X-ray contrast-enhancing agent}
- A61K 51/00: Preparations containing radioactive substances for use in therapy or testing in vivo
- C07C 2602/08: the other ring being five-membered, e.g. indane
- C07C 2602/10: the other ring being six-membered, e.g. tetraline
- 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)
- 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)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

This invention relates to novel compounds suitable for labeling or already labeled by 18F, methods of preparing such a compound, compositions comprising such compounds, kits comprising such compounds or compositions and uses of such compounds, compositions or kits for diagnostic imaging by positron emission tomography (PET).

## Claims

### Claim 1

A compound of formula Ia
wherein
W is —CH2—C≡CH;
A is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, G4-(C2-C4)alkynyl-, G4-(C1-C4)alkoxy-, (G4-(C1-C4)alkyl)aryl-, or G4-(C1-C4)alkoxy)aryl-,
G1, G2, G3 and G4 are, independently and individually, at each occurrence, hydrogen, (C1-C4)alkyl, L, or —(C1-C6)alkyl-L,
with the proviso that exactly one of G1-G4 is L or —(C1-C6)alkyl-L,
L is a leaving group, or L is F,
n is an integer from 0 to 6, and
m is an integer from 1 to 4,
or a pharmaceutically acceptable salt, ester, amide, or complex thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein A is substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, G4-(C3-C4)alkynyl-, G4-(C1-C3)alkoxy-, (G4-(C1-C3)alkyl)phenyl-, or (G4-(C1-C3)alkoxy)phenyl-.

### Claim 3 (depends on 2)

The compound according to claim 2, wherein A is substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, (G4-(C1-C3)alkyl)phenyl-, (G4-(C1-C3)alkoxy)phenyl-, hydroxy-phenyl, halo-phenyl, methoxy-phenyl, dimethoxy-phenyl, trifluormethyl-phenyl, or ((C1-C4)alkyl)-phenyl.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein A is substituted or unsubstituted phenyl, (G4-(C1-C3)alkoxy)phenyl-, hydroxyl-phenyl, fluorophenyl, methoxyphenyl, or methylphenyl.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein G1, G2, G3 and G4 are independently and individually, at each occurrence, hydrogen, (C1-C4)alkyl, L, or —(C1-C4)alkyl-L, with the proviso that exactly one of G1-G4 is L or —(C1-C4)alkyl-L.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein G1, G2, G3 and G4 are independently and individually, at each occurrence, hydrogen, methyl, L, or —(C1-C2)alkyl-L, with the proviso that exactly one of G1-G4 is L or —(C1-C2)alkyl-L.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein G1, G2, G3 and G4 are independently and individually, at each occurrence, hydrogen, methyl, L, or -methyl-L, with the proviso that exactly one of G1-G4 is L or -methyl-L.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein L is halo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, or (4-methoxy-phenyl)sulfonyloxy.

### Claim 9 (depends on 8)

The compound according to claim 8, wherein L is chloro, bromo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, or (2,4,6-tri-isopropyl-phenyl) sulfonyloxy.

### Claim 10 (depends on 1)

The compound according to claim 1 which is

### Claim 11 (depends on 1)

The compound according to claim 1, wherein L is not F.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein L is 18F.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein L is 19F.

### Claim 14 (depends on 1)

A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 15 (depends on 12)

A composition comprising a compound according to claim 12 and a pharmaceutically acceptable carrier or diluent.

### Claim 16 (depends on 13)

A composition comprising a compound according to claim 13 and a pharmaceutically acceptable carrier or diluent.

### Claim 17 (depends on 11)

A composition comprising a compound according to claim 11 and a pharmaceutically acceptable carrier or diluent.

### Claim 18 (depends on 11)

A kit comprising a sealed vial containing a predetermined quantity of a compound according to claim 11.

### Claim 19 (depends on 12)

A method for detecting the presence of monoamine oxidase in a patient's body, comprising: introducing into said patient's body a detectable amount of a compound according to claim 12 and detecting said compound by positron emission tomography (PET).

### Claim 20 (depends on 1)

A method of treatment of a disease of the central nervous system comprising the step of introducing into a patient a suitable quantity of a compound according to claim 1.

### Claim 21 (depends on 12)

A method of treatment of a disease of the central nervous system comprising the step of introducing into a patient a suitable quantity of a compound according to claim 12.

### Claim 22 (depends on 13)

A method of treatment of a disease of the central nervous system comprising the step of introducing into a patient a suitable quantity of a compound according to claim 13.

### Claim 23 (depends on 13)

The compound according to claim 13, wherein said compound contains exactly one 19F-atom and the 19F-atom is attached to an sp3-hybridized carbon atom.

### Claim 24 (depends on 1)

The compound according to claim 1, wherein n is 1-3.

### Claim 25 (depends on 1)

The compound according to claim 1, wherein n is 1-2.

### Claim 26 (depends on 1)

The compound according to claim 1, wherein m is 1 to 2.

### Claim 27 (depends on 19)

The method according to claim 19, wherein said method is for imaging a disease of the central nervous system in said patient.

### Claim 28 (depends on 12)

The compound according to claim 12, wherein said compound is selected from the following compounds:

### Claim 29 (depends on 13)

The compound according to claim 13, wherein said compound is selected from the following compounds:

### Claim 30 (depends on 12)

A method of synthesizing a compound according to claim 12, comprising reacting one or more compounds of formula Ia wherein L is a leaving group with an F-fluorinating agent in which F is 18F.

### Claim 31 (depends on 30)

The method according to claim 30, wherein L is halo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl) sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, or (4-methoxy-phenyl)sulfonyloxy.

### Claim 32 (depends on 30)

The method according to claim 30, wherein L is chloro, bromo, or iodo.

### Claim 33 (depends on 30)

The method according to claim 30, wherein said one or more compounds of formula Ia is or includes a compound wherein G2 is L, and L is chloro, bromo, or iodo.

### Claim 34 (depends on 33)

The method according to claim 33, wherein the compound synthesized is one wherein G1 is —(C1-C6)alkyl-L.

### Claim 35 (depends on 33)

The method according to claim 33, wherein the compound synthesized is one wherein G1 is -methyl-L.

### Claim 36 (depends on 30)

The method according to claim 30, wherein said F-fluorinating agent is 4, 7, 13, 16, 21, 24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, KF, HF, KH F2, CsF, NaF or a tetraalkylammonium salt, wherein F is 18F.

### Claim 37 (depends on 13)

A method of synthesizing a compound according to claim 13, comprising reacting one or more compounds of formula Ia wherein L is a leaving group with an F-fluorinating agent in which F is 19F.

### Claim 38 (depends on 37)

The method according to claim 37, wherein L is halo, mesyloxy, tosyloxy, trifluormethylsulfonyloxy, nona-fluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl)sulfonyloxy, (4-tertbutyl-phenyl)sulfonyloxy, or (4-methoxy-phenyl)sulfonyloxy.

### Claim 39 (depends on 37)

The method according to claim 37, wherein L is chloro, bromo, or iodo.

### Claim 40 (depends on 37)

The method according to claim 37, wherein said one or more compounds of formula Ia is or includes a compound wherein G2 is L, and L is chloro, bromo, or iodo.

### Claim 41 (depends on 40)

The method according to claim 40, wherein the compound synthesized is one wherein G1 is —(C1-C6)alkyl-L.

### Claim 42 (depends on 40)

The method according to claim 40, wherein the compound synthesized is one wherein G1 is -methyl-L.

### Claim 43 (depends on 37)

The method according to claim 37, wherein said F-fluorinating agent is 4, 7, 13, 16, 21, 24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane K F, KF, HF, KH F2, CsF, NaF or a tetraalkylammonium salt, wherein F is 19F.

### Claim 44 (depends on 30)

The method according to claim 30, wherein a mixture of the following compounds 42 and 43
is reacted with a 18F-fluorinating agent to obtain a mixture of the following compounds 13 and 39