# US 2014/0154182 A1 · N,n-substituted guanidine compound

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- Number: US 2014/0154182 A1
- Document ID: US20140154182A1
- Status: Published application
- Kind: A1
- Application number: 14/122,691
- Filed: 2012-05-30
- Published: 2014-06-05
- Earliest claimed: 2011-05-31
- Assignees: Stichting Vu-Vumc
- Inventors: Pieter Jacob Klein; Athansios Metaxas; Albert Dirk Windhorst; Johannes Antonius Maria Christiaans; Bart Nicolaas Maria van Berckel
- Web page: https://patentgrep.com/patent/US20140154182A1

## CPC

- C07C 279/18: having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
- A61K 31/155: Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
- A61K 51/04: Organic compounds
- C07B 59/001: {Acyclic or carbocyclic compounds}
- C07C 277/08: of substituted guanidines
- C07C 319/20: by reactions not involving the formation of sulfide groups
- C07C 323/44: X or Y being nitrogen atoms
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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 is directed to a N,N-substituted guanidine compound or a salt or solvate thereof according to formula (1), R1RNC(NH)NR2R3, wherein R1 is methyl and R2 is hydrogen. R3 is a organic group comprising a halogen and thiomethyl substituted phenyl group. R is an organic group comprising a substituted aryl group Z wherein the substituent group is —Y—R4, wherein Y is a heteroatom chosen from the group consisting of O, S and N and R4 is a fluorinated organic group.

## Claims

### Claim 1

A N,N-substituted guanidine compound or a salt or solvate thereof according to formula (1)
wherein R4 is a fluorinated organic group, Y is O, S or N,
Z is a substituted aryl group,
R1 is methyl,
R2 is hydrogen,
R5 is Cl or Br and
R6 is a thiomethyl group.

### Claim 2 (depends on 1)

Compound according to claim 1, wherein the fluorinated organic group R4 has 1 to 5 carbon atoms.

### Claim 3 (depends on 2)

Compound according to claim 2, wherein R4—Y— is a mono, bi or tri-fluorinated methoxy group.

### Claim 4 (depends on 1)

Compound according to claim 1, wherein Z is a phenyl group substituted at its 3-position with the R4—Y— group.

### Claim 5 (depends on 1)

Compound according to claim 1, wherein Y is O.

### Claim 6 (depends on 1)

Compound according to claim 1, wherein R5 is Cl.

### Claim 7 (depends on 1)

Compound according to claim 1, wherein R4—Y— is a mono, bi or tri-fluorinated methoxy group, Z is a phenyl group substituted at its 3-position with the R4—Y— group and R5 is Cl.

### Claim 8 (depends on 7)

Compound according to claim 7, wherein R4—Y is a bi-fluorinated methoxy group or a tri-fluorinated methoxy group.

### Claim 9 (depends on 1)

Compound according to claim 1, wherein at least one of groups R1, R2, R4, R5, R6 or the guanidine group contains a radio-isotope selected from 3H, 11C, 18F, 76Br, 123I, 124I, 125I or 131I.

### Claim 10 (depends on 9)

Compound according to claim 9, wherein one fluor atom in group R4 is the radio-isotope 18F or wherein the carbon of methyl group R1 is the radio-isotope 11C.

### Claim 11 (depends on 1)

Compound according to claim 1 for use as an ion channel blocker of the N-methyl-D-aspartate (NMDA) receptor.

### Claim 12 (depends on 9)

A radiopharmaceutical formulation comprising the compound according to claim 9.

### Claim 13 (depends on 9)

A radiopharmaceutical formulation comprising the compound according to claim 9 for use as an in vivo diagnostic or imaging method.

### Claim 14 (depends on 9, 12)

A method for the in vivo diagnosis or imaging of NMDA related disease in a subject, preferably a human, comprising administration of a compound according to claim 9 or a formulation according to claim 12.

### Claim 15 (depends on 10)

Process for the preparation of a N,N-substituted guanidine compound according to claim 10 by
(i) reaction of a precursor in a suitable solvent and in the presence of a base with an [18F]fluoroalkyl-L, wherein L is a leaving group; wherein the precursor is a compound according to formula (I) wherein the hydrogen group R2 is optionally exchanged by an amine protecting group and wherein on the R4-Y position a hydroxyl group is present on the aryl group Z, and
(ii) removal of the protection amine group in a suitable solvent and protective group removing reagent provided that R2 is exchanged by an amine protecting group.

### Claim 16 (depends on 15)

Process according to claim 15, wherein the precursor is 3-(2-chloro-5-(methylthio)phenyl)-1-(3-hydroxyphenyl)-1-methylguanidine.

### Claim 17 (depends on 15)

Process according to claim 15, wherein the leaving group L is a chlorine, bromine, iodine or a sulphonate ester leaving group.

### Claim 18 (depends on 10)

A method comprising use of 3-(2-chloro-5-(methylthio)phenyl)-1-(3-hydroxyphenyl)-1-methylguanidine to prepare a 18F labelled compound according to claim 10.

### Claim 19

A compound selected from 1-(2-chloro-5-(methylthio)phenyl)-3-(3-(difluoromethoxy)phenyl)guanidine or 1-(2-chloro-5-(methylthio)phenyl)-3-(3-(trifluoromethoxy)phenyl)guanidine or 3-(2-chloro-5-(methylthio)phenyl)-1-(3-hydroxyphenyl)-1-methylguanidine.

### Claim 20

A method comprising use of 1-(2-chloro-5-(methylthio)phenyl)-3-(3-(difluoromethoxy)phenyl)guanidine or 1-(2-chloro-5-(methylthio)phenyl)-3-(3-(trifluoromethoxy)phenyl)guanidine to prepare a 11C labeled 1-(2-chloro-5-(methylthio)phenyl)-3-11C-methyl-3-(3-(difluoromethoxy)phenyl)guanidine or 1-(2-chloro-5-(methylthio)phenyl)-3-11C-methyl-3-(3-(trifluoromethoxy)phenyl)guanidine respectively.