# US 2014/0193337 A1 · 18f-saccharide-folates

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- Number: US 2014/0193337 A1
- Document ID: US20140193337A1
- Status: Published application
- Kind: A1
- Application number: 14/239,275
- Filed: 2012-08-21
- Published: 2014-07-10
- Earliest claimed: 2011-08-22
- Assignees: Merck & Cie
- Inventors: Roger Schibli; Rudolf Moser; Cristina Magdalena Muller; Simon Mensah Ametamey; Cindy Ramona Fischer; Viola Groehn
- Web page: https://patentgrep.com/patent/US20140193337A1

## CPC

- A61K 51/0491: {Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers}
- C07B 59/005: {Sugars; Derivatives thereof; Nucleosides; Nucleotides; Nucleic acids}
- G01N 33/60: involving radioactive labelled substances
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- 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)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present invention is directed towards new 18F-folate radiopharmaceuticals, wherein the 18F isotope is linked via a prosthetic group, more specifically via a prosthetic group having a saccharide group, such as a cyclic mono- or oligosaccharide, preferably based on a pyranoside or furanoside, which is covalently linked to the glutamate portion of a folate or derivative thereof, a method of their preparation, as well as their use in diagnosis and monitoring of cancer and inflammatory and autoimmune diseases and therapy thereof.

## Claims

### Claim 1

Compounds of formula I,
wherein
Z is a pteroate or derivative thereof,
Y1,Y2 are independently of each other O, N or S,
m is 1, 2 or 3, and
Q1, Q2 are independently of each other H, a protecting group or a group of formula
-L-A-L′-18F,
wherein
L,L′ are independently of each other a linking group, such as a covalent bond or a straight-chain or branched C(1-8)alkyl, which is unsubstituted or substituted by at least one CN, Hal, OH, NH2, CO2H, NO2, and wherein one or more of the non-adjacent CH2 groups may independently be replaced by a group selected from —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C—, —O—CO—O—, —S—R′—, —SO3R′—, or a five- or six-membered heterocycle, wherein R′ represents H or C(1-8)alkyl, and
A is a saccharide group,
with the proviso that at least one of Q1 and Q2 is a group of formula -L-A-L′-18F.

### Claim 2 (depends on 1)

Compounds according to claim 1 having formula Ia, Ib, Ic,
wherein
Z is a pteroate or derivative thereof,
Y1,Y2 are independently of each other O, N or S,
m is 1, 2 or 3,
L1,L1′,L2,L2′ are independently of each other a linking group, such as a covalent bond or a straight-chain or branched C(1-50)alkyl, which is unsubstituted or substituted by at least one CN, Hal, OH, NH2, CO2H, NO2, and wherein one or more of the non-adjacent CH2 groups may independently be replaced by a group selected from —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C—, —O—CO—O—, —S—R′—, —SO3R′—, or a five- or six-membered heterocycle, wherein R′ represents H or C(1-8)alkyl,
A1,A2 are independently of each other a saccharide group, and
B1,B2 are independently of each other H, or a protecting group.

### Claim 3 (depends on 1)

Compound according to claim 1 having formula II
wherein
X1 to X5 are independently of each other C, N or O, preferably N or O,
R1, R2 are independently of each other H, halogen, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR5, —COR5, —COOR5, —NHR, —CONHR5, —CONHR5, wherein R5 represents H, halo, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR′, —COR′, —COOR′, or —NHR′, wherein R′ is H or C(1-8)alkyl,
R3, R4 are independently of each other H, nitroso, C(1-12)alkyl, —OR′, —COR′ or halosubstituted —COR′, wherein R′ represents H or C(1-8)alkyl,
Y1,Y2 are independently of each other O, N or S,
m is 1, 2 or 3,
r has a value of 1 to 7,
p is 0 or 1,
Q1, Q2 are independently of each other H, protecting group or a group of formula
-L-A-L′-18F,
wherein
L,L′ are independently of each other a linking group, such as a covalent bond or a straight-chain or branched C(1-50)alkyl, which is unsubstituted or substituted by at least one CN, Hal, OH, NH2, CO2H, NO2, and wherein one or more of the non-adjacent CH2 groups may independently be replaced by a group selected from —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C—, —O—CO—O—, —S—R′—, —SO3R′—, or a five- or six-membered heterocycle, wherein R′ represents H or C(1-8)alkyl, and
A is a saccharide group,
with the proviso that at least one of Q1 and Q2 is a group of formula -L-A-L′-18F.

### Claim 4 (depends on 1)

Compound according to claim 1 having formulae IIa, IIb, IIc
wherein
X1 to X5 are independently of each other C, N or O, preferably N or O,
R1, R2 are independently of each other H, halogen, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR5, —COR5, —COOR5, —NHR5, —CONHR5, —CONHR5, wherein R5 represents H, halo, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR′, —COR′, —COOR′, or —NHR′, wherein R′ is H or C(1-8)alkyl,
R3, R4 are independently of each other H, nitroso, C(1-12)alkyl, —OR′, —COR′ or halosubstituted —COR′, wherein R′ represents H or C(1-8)alkyl,
Y1,Y2 are independently of each other O, N or S,
m is 1, 2 or 3,
r has a value of 1 to 7,
p is 0 or 1,
L1,L1′,L2,L2′ are independently of each other a linking group, such as a covalent bond or a straight-chain or branched C(1-50)alkyl, which is unsubstituted or substituted by at least one CN, Hal, OH, NH2, CO2H, NO2, and wherein one or more of the non-adjacent CH2 groups may independently be replaced by a group selected from —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C—, —O—CO—O—, —S—R′—, —SO3R′—, or a five- or six-membered heterocycle, wherein R′ represents H or C(1-8)alkyl,
A1,A2 are independently of each other a saccharide group, and
B1,B2 are independently of each other H, or a protecting group.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein the saccharide group is a cyclic monosaccharide or a cyclic oligosaccharide based on a pyranoside, preferably selected from allose, altrose, glucose, mannose, gulose, idose, galactose and talose, or a furanoside, preferably selected from ribose, arabinose, xylose, and lyxose.

### Claim 6 (depends on 1)

A compound according to claim 1, wherein the saccharide group is a cyclic monosaccharide selected from glucose and galactose.

### Claim 7 (depends on 1)

A compound according to claim 1, having formulae IIIa, IIIb, IIIc,
wherein
X1 to X5 are independently of each other C, N or O, preferably N or O,
R1, R2 are independently of each other H, halogen, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR5, —COR5, —COOR5, —NHR5, —CONHR5, —CONHR5, wherein R5 represents H, halo, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR′, —COR′, —COOR′, or —NHR′, wherein R′ is H or C(1-8)alkyl,
R3, R4 are independently of each other H, nitroso, C(1-12)alkyl, —OR′, —COR′ or halosubstituted —COR′, wherein R′ represents H or C(1-8)alkyl,
Y1,Y2 are independently of each other O, N or S,
m is 1, 2 or 3,
r has a value of 1 to 7,
p is 0 or 1,
L1,L1′,L2,L2′ are independently of each other a linking group, such as a covalent bond or a straight-chain or branched C(1-8)alkyl, which is unsubstituted or substituted by at least one CN, Hal, OH, NH2, CO2H, NO2, and wherein one or more of the non-adjacent CH2 groups may independently be replaced by a group selected from —O—, —CO—, —CO—O—, —O—CO—, —NR′—, —NR′—CO—, —CO—NR′—, —NR′—CO—O—, —O—CO—NR′—, —NR′—CO—NR′—, —CH═CH—, —C—, —O—CO—O—, —S—R′—, —SO3R′—, or a five- or six-membered heterocycle, wherein R′ represents H or C(1-8)alkyl,
B1,B2 are independently of each other H, or a protecting group,
R6,R9 is H or C(1-8)alkyl, and
R7,R8,R10,R11 are independently of each other H, —OH, or —OC(1-8)alkyl.

### Claim 8 (depends on 2)

Compound according to claim 2, wherein L1 and L2 are independently of each other straight-chain or branched C(1-24)alkyl, which is unsubstituted or substituted by at least one group selected from Hal, OH, NHR′, CO2R′, and wherein one or more of the non-adjacent CH2 groups may independently be replaced by a group selected from —O—, —CO—O—, —O—CO—, —NR′—, —NR′—CO—, —CO—NR′, or a five- or six-membered heterocycle, preferably a five-membered azaheterocycle, wherein R′ represents H or C(1-8)alkyl.

### Claim 9 (depends on 2)

A compound according to claim 2, wherein L1 and L2 are independently of each other a group of formulae (a), (b), (c) or (d)
wherein
R″ is H or a straight-chain or branched C(1-8)alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2,
Spis a spacer (linked to Y1 and/or Y2) such as a straight-chain or branched C(1-8)alkyl, which is unsubstituted or wherein at least one of the —CH2— groups is substituted with —OH, —NHR′, or —COOR′, wherein R′ represents H or C(1-8)alkyl and,
q is 0, 1, 2, 3 or 4.

### Claim 10 (depends on 2)

Compound according to claim 2, wherein L1′ and L2′ are preferably a covalent bond or a straight-chain or branched C(1-24)alkyl, more preferably C(1-12)alkyl, most preferably C(1-6)alkyl, which is unsubstituted or substituted by at least one group selected from Hal, OH, NHR′, CO2R′, and wherein one or more of the non-adjacent CH2 groups may independently be replaced by a group selected from —O—, —CO—O—, —O—CO—, —NR′—, —NR′—CO—, —CO—NR′, wherein R′ represents H or C(1-8)alkyl.

### Claim 11 (depends on 1)

Compound according to claim 1, wherein Y1 and/or Y2 is N and B2 is a carboxamide protecting group.

### Claim 12 (depends on 1)

A compound according to claim 1 having formulae IVa, IVb, IVc, IVd
wherein
X1 to X5 are independently of each other C, N or O, preferably N or O,
R1, R2 are independently of each other H, halogen, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR5, —COR5, —COOR5, —NHR5, —CONHR5, wherein R5 represents H, halo, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR′, —COR′, —COOR′, or —NHR′, wherein R′ is H or C(1-8)alkyl,
R3, R4 are independently of each other H, nitroso, C(1-12)alkyl, —OR′, —COR′ or halosubstituted —COR′, wherein R′ represents H or C(1-8)alkyl,
m is 1, 2 or 3,
r has a value of 1 to 7,
p is 0 or 1,
Y1 is O, N or S,
B1 is H, or a protecting group,
R″ is H or a straight-chain or branched C(1-8)alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2,
L2′ is a covalent bond or a straight-chain or branched C(1-6)alkyl, wherein one or more of the non-adjacent CH2 groups may independently be replaced by a group selected from —O—, —CO—O—, —O—CO—, —NR′—, —NR′—CO—, —CO—NR′, wherein R′ represents H or C(1-8)alkyl,
Spis a spacer such as a straight-chain or branched C(1-8)alkyl, which is unsubstituted or wherein at least one of the —CH2— groups is substituted with —OH, —NHR′, or —COOR′, wherein R′ represents H or C(1-8)alkyl,
q is 0, 1, 2, 3 or 4,
R6 is H or C(1-8)alkyl, and
R7,R8 are independently of each other H, —OH, or —OC(1-8)alkyl.

### Claim 13 (depends on 1)

A compound according to claim 1 having formulae Va, Vb, Vc, Vd
wherein
X1 to X5 are independently of each other C, N or O, preferably N or O,
R1, R2 are independently of each other H, halogen, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR5, —COR5, —COOR5, —NHR5, —CONHR5, wherein R5 represents H, halo, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR′, —COR′, —COOR′, or —NHR′, wherein R′ is H or C(1-8)alkyl,
R3, R4 are independently of each other H, nitroso, C(1-12)alkyl, —OR′, —COR′ or halosubstituted —COR′, wherein R′ represents H or C(1-8)alkyl,
m is 1, 2 or 3,
r has a value of 1 to 7,
p is 0 or 1,
Y2 is O, N or S,
B2 is H, or a protecting group,
R″ is H or a straight-chain or branched C(1-8)alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2,
Spis a spacer such as a straight-chain or branched C(1-8)alkyl, which is unsubstituted or wherein at least one of the —CH2— groups is substituted with —OH, —NHR′, or —COOR′, wherein R′ represents H or C(1-8)alkyl,
L1′ is a covalent bond or a straight-chain or branched C(1-6)alkyl, wherein one or more of the non-adjacent CH2 groups may independently be replaced by a group selected from —O—, —CO—O—, —O—CO—, —NR′—, —NR′—CO—, —CO—NR′, wherein R′ represents H or C(1-8)alkyl,
q is 0, 1, 2, 3 or 4,
R9 is H or C(1-8)alkyl, and
R10,R11 are independently of each other H, —OH, or —OC(1-8)alkyl.

### Claim 14 (depends on 1)

A compound according to claim 1 having formulae VIa, VIb, VIc, VId
wherein
X1 to X5 are independently of each other C, N or O, preferably N or O,
R1, R2 are independently of each other H, halogen, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR5, —COR5, —COOR5, —NHR5, —CONHR5, wherein R5 represents H, halo, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR′, —COR′, —COOR′, or —NHR′, wherein R′ is H or C(1-8)alkyl,
R3, R4 are independently of each other H, nitroso, C(1-12)alkyl, —OR′, —COR′ or halosubstituted —COR′, wherein R′ represents H or C(1-8)alkyl,
m is 1, 2 or 3,
r has a value of 1 to 7,
p is 0 or 1,
R″ is H or a straight-chain or branched C(1-8)alkyl, which is unsubstituted or substituted by at least one CN, Hal, or NO2,
Sp is a spacer such as a straight-chain or branched C(1-8)alkyl, which is unsubstituted or wherein at least one of the —CH2— groups is substituted with —OH, —NHR′, or —COOR′, wherein R′ represents H or C(1-8)alkyl,
L1′,L2′ are independently of each other a covalent bond or a straight-chain or branched C(1-6)alkyl, wherein one or more of the non-adjacent CH2 groups may independently be replaced by a group selected from —O—, —CO—O—, —O—CO—, —NR′—, —NR′—CO—, —CO—NR′, wherein R′ represents H or C(1-8)alkyl,
q is 0, 1, 2, 3 or 4
R6,R9 is H or C(1-8)alkyl, and
R7,R8,R10,R11 are independently of each other H, —OH, or —OC(1-8)alkyl.

### Claim 15 (depends on 1)

A compound according to claim 1 wherein m is 2.

### Claim 16 (depends on 9)

A compound according to claim 9, wherein q is 0.

### Claim 17 (depends on 1)

A compound according to claim 1 having formulae VIIa, VIIb, VIIc, VIId
wherein
Y3, Y4 are independently of each other selected from H, halo, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR′, —COR′, —COOR′, and —NHR′, wherein R′ is H or C(1-8)alkyl,
Y5 is selected from H, nitroso, C(1-12)alkyl, —OR′, —COR′, and halosubstituted —COR′, wherein R′ is H or C(1-12)alkyl,
m is 1, 2 or 3,
Y1 is O, N or S,
B1 is H, or a protecting group,
Spis a spacer such as a straight-chain or branched C(1-8)alkyl, which is unsubstituted or wherein at least one of the —CH2— groups is substituted with —OH, —NHR′, or —COOR′, wherein R′ represents H or C(1-8)alkyl,
L2′ is a covalent bond or a straight-chain or branched C(1-6)alkyl, wherein one or more of the non-adjacent CH2 groups may independently be replaced by a group selected from —O—, —CO—O—, —O—CO—, —NR′—, —NR′—CO—, —CO—NR′, wherein R′ represents H or C(1-8)alkyl,
q is 0, 1, 2, 3 or 4,
R6 is H or C(1-8)alkyl, and
R7,R8 are independently of each other H, —OH, or —OC(1-8)alkyl.

### Claim 18 (depends on 1)

A compound according to claim 1 having formulae VIIIa, VIIIb, VIIIc, VIIId
wherein
Y3, Y4 are independently of each other selected from H, halo, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR′, —COR′, —COOR′, and —NHR′, wherein R′ is H or C(1-8)alkyl,
Y5 is selected from H, nitroso, C(1-12)alkyl, —OR′, —COR′, and halosubstituted —COR′, wherein R′ is H or C(1-12)alkyl,
m is 1, 2 or 3,
Y2 is O, N or S,
B2 is H, or a protecting group,
Spis a spacer such as a straight-chain or branched C(1-8)alkyl, which is unsubstituted or wherein at least one of the —CH2— groups is substituted with —OH, —NHR′, or —COOR′, wherein R′ represents H or C(1-8)alkyl,
L1′ is a covalent bond or a straight-chain or branched C(1-6)alkyl, wherein one or more of the non-adjacent CH2 groups may independently be replaced by a group selected from —O—, —CO—O—, —O—CO—, —NR′—, —NR′—CO—, —CO—NR′, wherein R′ represents H or C(1-8)alkyl,
q is 0, 1, 2, 3 or 4,
R9 is H or C(1-8)alkyl, and
R10,R11 are independently of each other H, —OH, or —OC(1-8)alkyl.

### Claim 19 (depends on 1)

A compound according to claim 1 having formulae IXa, IXb, IXc, IXd
wherein
Y3, Y4 are independently of each other selected from H, halo, C(1-12)alkyl, C(2-12)alkenyl, C(2-12)alkynyl, —OR′, —COR′, —COOR′, and —NHR′, wherein R′ is H or C(1-8)alkyl,
Y5 is selected from H, nitroso, C(1-12)alkyl, —OR′, —COR′, and halosubstituted —COR′, wherein R′ is H or C(1-12)alkyl,
m is 1, 2 or 3,
Sp are independently of each other a spacer such as a straight-chain or branched C(1-8)alkyl, which is unsubstituted or wherein at least one of the —CH2— groups is substituted with —OH, —NHR′, or —COOR′, wherein R′ represents H or C(1-8)alkyl,
L1′,L2′ are independently of each other a covalent bond or a straight-chain or branched C(1-6)alkyl, wherein one or more of the non-adjacent CH2 groups may independently be replaced by a group selected from —O—, —CO—O—, —O—CO—, —NR′—, —NR′—CO—, —CO—NR′, wherein R′ represents H or C(1-8)alkyl,
q is 0, 1, 2, 3 or 4,
R6,R9 are independently of each other H or C(1-8)alkyl, and
R7,R8,R10,R11 are independently of each other H, —OH, or —OC(1-8)alkyl

### Claim 20 (depends on 1)

Pharmaceutical composition comprising at least one compound according to claim 1.

### Claim 21 (depends on 1)

Use of a compound according to claim 1 or a pharmaceutical composition for diagnostic imaging of a cell or population of cells expressing a folate-receptor in vitro or in vivo.

### Claim 22 (depends on 1)

Use of a compound according to claim 1 or a pharmaceutical composition for convenient and effective administration to a subject in need for diagnostic imaging.

### Claim 23 (depends on 1)

Method for diagnostic imaging of a cell or population of cells expressing a folate-receptor, said method comprising the steps of administering at least one compound according to claim 1 in a diagnostic imaging amount, and obtaining a diagnostic image of said cell or population of cells.

### Claim 24 (depends on 23)

Method according to claim 23, wherein the diagnostic imaging is performed of a cell or population of cells expressing a folate-receptor in vitro or in vivo.

### Claim 25 (depends on 1)

Method for in vitro detection of a cell expressing the folate receptor in a tissue sample which includes contacting said tissue sample with a compound according to claim 1 in effective amounts and for sufficient time and conditions to allow binding to occur and detecting such binding by PET imaging.

### Claim 26 (depends on 1)

Method of diagnostic imaging and/or monitoring a subject comprising the steps of (i) administering at least one compound according to claim 1 in a diagnostic imaging amount, and (ii) performing diagnostic imaging using PET by detecting a signal from said at least one compound.

### Claim 27 (depends on 1)

Method of monitoring cancer therapy in a subject comprising the steps of (i) administering to a subject in need thereof at least one compound according to claim 1 in a diagnostic imaging amount in combination with a therapeutically active compound of choice, and (ii) performing diagnostic imaging using PET by detecting a signal from said at least one compound to follow the course of cancer therapy.

### Claim 28 (depends on 26)

Method of claim 26 used in combination with any other methods of cancer diagnosis or therapy.