Bifunctional antifungal agents and methods of treating fungal infection

Patent metadata

Field	Value
Publication number	US-2019209572-A1
Application number	US-201716325634-A
Country	US
Kind code	A1
Filing date	Aug 18, 2017
Priority date	Aug 19, 2016
Publication date	Jul 11, 2019
Grant date	—

Abstract

The present invention is directed to bifunctional compounds which are useful in the treatment of fungal infections. The present compounds contains at least one fungal binding moiety (FBM) which is linked to at least one antibody binding moiety (ABM or ABT group) through a linker group, which optionally comprises a connector group. Compounds according to the present invention are useful in the treatment of fungal infections as described herein.

First claim

1 . A compound according to the chemical structure:

Wherein each R 1 is independently H, C 1 -C 3 alkyl or a group;

Each R 2 is H, a group or a group, with the proviso that at

least one R 2 group is a group;
Each n′ is independently 1-6;

Each R 3 is independently H, Cl or a group;
Where R N is H or a C 1 -C 3 alkyl group optionally substituted with one or two hydroxyl groups;
Each R 5 is independently H, CO 2 R E , SO 3 H, L-P G or L-ABT;
R E is H, a C 1 -C 6 alkyl group or a L-ABT group;
P G is a protecting group;

Each R 4 is independently H, Cl, a L-ABT group or a

group with the proviso that at least one R 4 is a L-ABT group or a group;
Where R N and n′ are the same as above; and
R 1 is H, P G or a L-ABT group;
Where L is a linker group optionally containing at least one connector group CT; and
ABT is an antibody binding moiety comprising a hapten which is capable of binding to an antibody present in a patient prior to the administration of the compound to the patient, or a pharmaceutically acceptable salt, stereoisomer, enantiomer, solvate or polymorph thereof.

2 . The compound according to claim 1 wherein R 1 and R N are each H.

3 . The compound according to claim 1 wherein each R 2 group is

4 . The compound according to claim 1 wherein R 3 is a

group where R 5 is H, SO 3 H, CO 2 R E or L-ABT.

5 . The compound according to claim 4 wherein each R 5 group is L-ABT.

6 . The compound according to claim 5 wherein said R 4 groups are substituted on the phenyl group at the ortho and para position (positions 2 and 4 of the phenyl group).

7 . The compound according to claim 5 wherein said R 4 groups are substituted on the phenyl group at the ortho and meta positions.

8 . The compound according to claim 7 wherein said R 4 groups are substituted on the phenyl group at positions 2 and 4 of the phenyl ring.

9 . The compound according to claim 1 wherein

where X L is N(R 1 ), O, S, S(O), SO 2 , S(O) 2 O, —OS(O) 2 , or OS(O) 2 O; and
R 1 is H, a C 1 -C 3 alkyl group or a —C(O)(C 1 -C 3 ) group, preferably H;
each n and n′ is independently 1 to 25, 1 to 15, 1 to 12, 2 to 11, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4 and 2 to 3 or 1, 2, 3, 4, 5, 6, 7, or 8; and
each n″ is independently 0 to 8, often 1 to 7, or 1, 2, 3, 4, 5 or 6 (preferably 3).

10 . The compound according to claim 1 wherein L is a linker group based upon polyethyleneglycol (PEG) linkages, polypropylene glycol linkages, or polyethyleneglycol-co-polypropylene oligomers of up to 100 ethyhlene glycole or propylene glycol units (about 1 to 75, about 1 to 60, about 1 to 50, about 1 to 35, about 1 to 25, about 1 to 20, about 1 to 15, 2 to 10, about 4 to 12, about 1 to 8, 1 to 3, 1 to 4, 2 to 6, 1 to 5, etc.).

11 . The compound according to claim 1 wherein L is a linker group according to the chemical structure:

where each n and n′ is independently 1 to 25, 1 to 15, 1 to 12, 2 to 11, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4 and 2 to 3 or 1, 2, 3, 4, 5, 6, 7, or 8.

12 . The compound according to claim 1 wherein L is a linker group according to the chemical structure:

where each n and n′ is independently 1 to 25, 1 to 15, 1 to 12, 2 to 11, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4 and 2 to 3 or 1, 2, 3, 4, 5, 6, 7, or 8; and
each n″ is independently 0 to 8, often 1 to 7, or 1, 2, 3, 4, 5 or 6.

13 . The compound according to claim 1 wherein L is a polyamino acid optionally comprising one or two connector groups CT comprising up to 100 (preferably about 1 to 75, about 1 to 60, about 1 to 50, about 1 to 45, about 1 to 35, about 1 to 25, about 1 to 20, about 1 to 15, 2 to 10, about 4 to 12, about 5 to 10, about 4 to 6, about 1 to 8, about 1 to 6, about 1 to 5, about 1 to 4, about 1 to 3) amino acid residues wherein said amino acid residues are selected from naturally occurring D and L amino acids or L is a group according to the chemical structure:

Where R a and R a′ are each independently H, C 1 -C 3 alkyl, alkanol, aryl or benzyl
or each forms a cyclic ring with R 3 or R 3′ on an adjacent carbon respectively (to form proline or hydroxyproline) or R 3 , R 3′ and R 3″ are each independently a side chain derived from an amino acid preferably selected from the group consisting of alanine (methyl), arginine (propyleneguanidine), asparagine (methylenecarboxyamide), aspartic acid (ethanoic acid), cysteine (thiol, reduced or oxidized di-thiol), glutamine (ethylcarboxyamide), glutamic acid (propanoic acid), glycine (H), histidine (methyleneimidazole), isoleucine (1-methylpropane), leucine (2-methylpropane), lysine (butyleneamine), methionine (ethylmethylthioether), phenylalanine (benzyl), proline, hydroxylproline (R 3 or R 3′ forms a cyclic ring with R a or R a′ and the adjacent nitrogen group to form a pyrrolidine group for proline or a hydroxypyrrolidine for hydroxyproline), serine (methanol), threonine (ethanol, 1-hydroxyethane), tryptophan (methyleneindole), tyrosine (methylene phenol) or valine (isopropyl); and m and m′ (within the context of this use) is each independently an integer from 1 to 100, 1 to 75, 1 to 60, 1 to 55, 1 to 50, 1 to 45, 1 to 40, 2 to 35, 3 to 30, 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1, 2, 3, 4 or 5.

14 . The compound according to claim 1 wherein L is a linker group according to the chemical formula:

Where Z and Z′ are each independently a bond, —(CH 2 ) i —O, —(CH 2 ) i —S, —(CH 2 ) i —N—R,

wherein said —(CH 2 ) i group, if present in Z or Z′, is bonded to a connector (CT), an alternative linker, A B M and/or UPAR B M;
Each R is H, or a C 1 -C 3 alkyl or alkanol group;
Each R 2 is independently H or a C 1 -C 3 alkyl group;
Each Y is independently a bond, O, S or N—R;

Assignees

• Univ Yale
• Merck Sharp & Dohme

Inventors

• Spiegel David A
• Chirkin Egor
• Roemer Terry
• Nantermet Philippe

Classifications

• C07D251/68

  Triazinylamino stilbenes · CPC title

• A61P31/10

  Antimycotics · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/10

  Sulfides; Sulfoxides; Sulfones · CPC title

• A61K31/53 Primary

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title