Inflammation imaging and therapy

Patent metadata

Field	Value
Publication number	US-10016518-B2
Application number	US-201314421943-A
Country	US
Kind code	B2
Filing date	Aug 15, 2013
Priority date	Aug 17, 2012
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

Abstract

An imaging agent comprising a conjugate of an oligosaccharide moiety with an imaging moiety. The oligosaccharide is Lewis A or Lewis B or a mimetic thereof, or a pharmaceutically acceptable salt or PEGylated form of Lewis A or Lewis B or its mimetics. Lewis A and Lewis B and its mimetics are also provided for use in the therapeutic treatment of inflammatory diseases, autoimmune diseases and cancer.

First claim

The invention claimed is:

1. An imaging agent comprising a conjugate of an oligosaccharide with an imaging moiety, wherein the oligosaccharide is of formula (I) or a pharmaceutically acceptable salt or PEGylated form thereof:

wherein each Z is the same or different and is selected from OH, hydrogen, halogen, C 1-6 alkoxy, —NR′R″, —NR′COR″, —N(COR′)(COR″), —SR′, —COR′, —COOR′, —OC(O)R′,—OC(O)OR′, —OC(O)NR′R″, —OC(O)SR′, —OP(O)(OR′)(OR″), —OSO 3 H, or C 1-12 alkyl, C 2-12 alkenyl or C 2-12 alkynyl, which is optionally substituted with one or more substituents selected from halogen, NH 2 , N 3 , CN, COOH, COO(C 1-4 alkyl), OH and C 1-4 alkoxy;
each X is the same or different and is selected from OH, hydrogen, halogen, C 1-6 alkoxy, —NR′R″, —NR′COR″, —N(COR′)(COR″), —SR′, —COR′, —COOR′, —OC(O)R′, —OC(O)OR′, —OC(O)NR′R″, —OC(O)SR′, —OP(O)(OR′)(OR″), —OSO 3 H, or C 1-12 alkyl, C 2-12 alkenyl or C 2-12 alkynyl, which is optionally substituted with one or more substituents selected from halogen, NH 2 , N 3 , CN, COOH, COO(C 1-4 alkyl), OH and C 1-4 alkoxy;
each A is the same or different and is selected from CR′R″, O, S and NR′;
n is 0, 1, 2, 3 or 4; a dotted line indicates a bond selected from a saturated bond and an unsaturated bond; Y is either a group Z as defined above or a saccharide unit of formula (II):

wherein X, Z and A are as defined above;
R represents the point of attachment to the imaging moiety; and
R′ and R″ are identical or different and are selected from hydrogen and C 1-12 alkyl groups which are optionally substituted with one or more substituents selected from halogen, NH 2 , N 3 , CN, COOH, COO(C 1-4 alkyl), OH and C 1-4 alkoxy.

2. An imaging agent according to claim 1 , wherein either all groups Z are OH, or one, two, three or four groups Z are other than OH and the remainder represent OH; either all groups X are hydrogen or one, two or three groups X are other than hydrogen and the remainder represent hydrogen; either each A is —O— or one, two or three A groups are other than —O— and the remainder represent —O—; and n is 0, 1, 2 or 3.

3. An imaging agent according to claim 1 , wherein each Z is the same or different and is selected from OH, hydrogen, halogen, methoxy, ethoxy, —NH 2 , (C 1-2 alkyl)amine, di(C 1-2 alkyl)amine, (C 1-2 acetyl)amine, di(C 1-2 acetyl)amine, mercapto, methylthio, ethylthio and —OP(O)(OH) 2 .

4. An imaging agent according to claim 1 , wherein each X is the same or different and is hydrogen or halogen.

5. An imaging agent according to claim 1 , wherein each carbon atom that carries a group Z other than OH also carries a group X that represents OH, hydrogen, halogen, methoxy, ethoxy, —NH 2 , (C 1-2 alkyl)amine, di(C 1-2 alkyl)amine, (C 1-2 acetyl)amine, di(C 1-2 acetyl)amine, mercapto, methylthio, ethylthio or —OP(O)(OH) 2 .

6. An imaging agent according to claim 1 , wherein each A is the same or different and is —O—, —SH—, —NH— or —N(Me)-.

7. An imaging agent according to claim 1 , wherein the oligosaccharide is of formula (Ia) or (Ib) or a pharmaceutically acceptable salt or PEGylated form thereof:

wherein:
each Z is the same or different and is selected from OH, hydrogen, halogen, methoxy, ethoxy, —NH 2 , (C 1-2 alkyl)amine, di(C 1-2 alkyl)amine, (C 1-2 acetyl)amine, di(C 1-2 acetyl)amine, mercapto, methylthio, ethylthio and —OP(O)(OH) 2 , wherein either all groups Z are OH, or one or two groups are other than OH and the remainder are OH;
each X is the same or different and is selected from hydrogen or halogen, or in the case where a group Z carried on the same carbon atom as X is other than OH, then X represents OH, hydrogen, halogen, methoxy, ethoxy, —NH 2 , (C 1-2 alkyl)amine, di(C 1-2 alkyl)amine, (C 1-2 acetyl)amine, di(C 1-2 acetyl)amine, mercapto, methylthio, ethylthio or —OP(O)(OH) 2 , wherein either all groups X are hydrogen, or one or two groups are other than hydrogen and the remainder are hydrogen;
each A is the same or different and is selected from —O—, —SH—, —NH— and —N(Me)-; wherein either all groups A are —O— or one A group is other than —O— and the remainder represent —O—;
n is 2;
the bond Cl(R)-A is saturated; and
R represents the point of attachment to the imaging moiety.

8. An imaging agent according to claim 1 , wherein the oligosaccharide is Lewis A or Lewis B or a pharmaceutically acceptable salt thereof.

9. An imaging agent according to claim 1 , wherein the oligosaccharide is Lewis A or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising an imaging agent as claimed in claim 1 and a pharmaceutically acceptable carrier or diluent.

11. An imaging method comprising the steps of:
(i) administering to a subject an imaging agent according to claim 1 or a pharmaceutical composition according to claim 10 ; and
(ii) carrying out medical imaging on the subject, wherein carrying out medical imaging comprises carrying out magnetic resonance imaging, Positron Emission Tomography or Single-Photon-Emission-Computed Tomography.

12. An imaging agent according to claim 1 , wherein the contrast agent is selected from the group consisting of magnetic resonance imaging contrast agent, positron emission tomography contrast agent.

13. An imaging agent according to claim 12 , wherein the magnetic resonance imaging contrast agent is selected from the group consisting of a Gd(III)-containing contrast agent, iron containing colloidal particles, and manganese containing particles.

Assignees

• Isis Innovation
• Univ Oxford Innovation Ltd

Inventors

• Anthony Daniel
• Davis Benjamin Guy
• Bort Guillaume

Classifications

• A61K31/702

  Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages · CPC title

• A61K49/101

  the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals · CPC title

• A61K49/10 Primary

  Organic compounds · CPC title

• C07H23/00

  Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12 (esters with inorganic acids C07H11/00) · CPC title

• A61K49/1845

  the small organic molecule being a carbohydrate (monosaccharides, discacharides) · CPC title