Taggable heteroaromatic drugs and conjugates thereof

Patent metadata

Field	Value
Publication number	US-10420845-B2
Application number	US-201615737247-A
Country	US
Kind code	B2
Filing date	Jun 16, 2016
Priority date	Jun 18, 2015
Publication date	Sep 24, 2019
Grant date	Sep 24, 2019

Abstract

The present disclosure provides heteroarene-based drug derivatives having a “clickable” ketone group, as well as conjugates of said drug derivatives with targeting moieties capable of binding to extracellular antigens; and pharmaceutical compositions comprising them.

First claim

What is claimed is:

1. A compound of the formula I:
Y—CF 2 —(CR 1 R 2 ) n —X—(CR 1 R 2 ) m —R 1   I

wherein
Y is a drug or a bioactive reagent, comprising a heteroaromatic ring and linked via a carbon atom of said heteroaromatic ring;
X is carbonyl, or cyclic ketal substituted with 1 to 4 groups each independently is phenyl or naphtyl substituted ortho to the carbon of attachment with —NO 2 , and optionally further substituted at any position other than ortho to the carbon of attachment with one or more groups each independently selected from the group consisting of —O—(C 1 -C 8 ), —(C 1 -C 8 )alkyl, —N(R′) 2 , and halogen, wherein R′ each independently is —(C 1 -C 8 )alkyl or H;
R 1 and R 2 each independently is H, halogen, —OR 3 , —CO—R 3 , —CO—OR 3 , —OCO—OR 3 , —OCO—N(R 3 ) 2 , —CN, —NO 2 , —SR 3 , —N(R 3 ) 2 , —CO—N(R 3 ) 2 , —(C 1 -C 8 )alkyl, —(C 2 -C 8 )alkenyl, —(C 2 -C 8 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 6 -C 14 )aryl, or 4-12-membered heterocyclyl;
R 3 is H, —(C 1 -C 18 )alkyl, —(C 2 -C 18 )alkenyl, or —(C 2 -C 18 )alkynyl; and
n and m each independently is an integer of 1-8,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein:
(i) R 1 and R 2 each independently is H, halogen, —OR 3 , —CO—R 3 , —CO—OR 3 , —OCO—OR 3 , —OCO—N(R 3 ) 2 , —CN, —NO 2 , —SR 3 , —N(R 3 ) 2 , —CO—N(R 3 ) 2 , —(C 1 -C 4 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 4 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 6 -C 14 )aryl, or 4-12-membered heterocyclyl, wherein R 3 is H, methyl, ethyl or propyl;
(ii) n is 3, 4, or 5; or
(iii) m is 1, 2, or 3.

3. The compound of claim 1 , wherein R 1 and R 2 each independently is H, halogen, —OR 3 , —CO—R 3 , —CO—OR 3 , —OCO—OR 3 , —OCO—N(R 3 ) 2 , —CN, —NO 2 , —SR 3 , —N(R 3 ) 2 , —CO—N(R 3 ) 2 , —(C 1 -C 4 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 4 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 6 -C 14 )aryl, or 4-12-membered heterocyclyl, wherein R 3 is H, methyl, ethyl or propyl; n is 3, 4, or 5; and m is 1, 2, or 3.

4. The compound of claim 3 , wherein R 1 and R 2 are H.

5. The compound of claim 1 , wherein Y is an anticancer drug, antineoplastic drug, antifungal drug, antibacterial drug, antiviral drug, cardiac drug, neurological drug, psychoactive drug, alkaloid, antibiotic, bioactive peptide, steroid, steroid hormone, peptide hormone, interferon, interleukin, narcotic, nucleic acid, pesticide, or prostaglandin.

6. The compound of claim 5 , wherein said anticancer drug is a chemotherapeutic drug; or said antineoplastic drug is an alkylating antineoplastic agent.

7. The compound of claim 1 , wherein X is (i) carbonyl; or (ii) cyclic ketal substituted with 1 or 2 phenyl groups each independently substituted ortho to the carbon of attachment with —NO 2 , and optionally further substituted at any position other than ortho to the carbon of attachment with one or more groups each independently is —O—(C 1 -C 8 ).

8. The compound of claim 7 , wherein X is cyclic ketal substituted with 4,5-dimethoxy,2-nitrophenyl group.

9. A conjugate of the formula II:

Y is a drug or a bioactive reagent, comprising a heteroaromatic ring and linked via a carbon atom of said heteroarimatic ring;
R 1 and R 2 each independently is H, halogen, —OR 3 , —CO—R 3 , —CO—OR 3 , —OCO—OR 3 , —OCO—N(R 3 ) 2 , —CN, —NO 2 , —SR 3 , —N(R 3 ) 2 , —CO—N(R 3 ) 2 , —(C 1 -C 8 )alkyl, —(C 2 -C 8 )alkenyl, —(C 2 -C 8 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 6 -C 14 )aryl, or 4-12-membered heterocyclyl;
R 3 is H, —(C 1 -C 18 )alkyl, —(C 2 -C 18 )alkenyl, or —(C 2 -C 18 )alkynyl;
R 4 is absent, or is selected from the group consisting of —NH—(CH 2 ) p —, —NH—CO—(CH 2 ) p —, —NH—CO—NH—(CH 2 ) p —, —NH—CO—O—(CH 2 ) p —, —O—(CH 2 ) p —, —O—CO—(CH 2 ) p —, —O—CO—NH—(CH 2 ) p —, and —O—CO—O—(CH 2 ) p —;
R 5 is a polymer-, protein-, peptide-, or carbohydrate moiety;
R 6 is H, —(CH 2 ) y —OH, —(CH 2 ) y —SH, —(CH 2 ) y —NH 2 , —(CH 2 ) y —COOH, —(CH 2 ) y —SO 3 H, or a divalent radical selected from the group consisting of —(CH 2 ) y —O—, —(CH 2 ) y —S—, —(CH 2 ) y —NH—, —(CH 2 ) y —OCO— and —(CH 2 ) y —SO 3 —;
n and m each independently is an integer of 1-8;
p and y each independently is an integer of 0-8; and
T is absent, or is a targeting moiety capable of binding to an extracellular antigen and linked via a functional group thereof, provided that when T is absent R 6 is not a divalent radical, and when T is a targeting moiety R 6 is a divalent radical,
or a pharmaceutically acceptable salt thereof.

10. The conjugate of claim 9 , wherein:
(i) R 1 and R 2 each independently is H, halogen, —OR 3 , —CO—R 3 , —CO—OR 3 , —OCO—OR 3 , —OCO—N(R 3 ) 2 , —CN, —NO 2 , —SR 3 , —N(R 3 ) 2 , —CO—N(R 3 ) 2 , —(C 1 -C 4 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 4 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 6 -C 14 )aryl, or 4-12-membered heterocyclyl, wherein R 3 is H, methyl, ethyl or propyl;
(ii) n is 3, 4, or 5;
(iii) m is 1, 2, or 3;
(iv) R 4 is —NH—CO—(CH 2 ) p — or —NH—CO—NH—(CH 2 ) p —;
(v) R 5 is a polymer moiety, and said polymer is linear or branched polyethylene glycol (PEG) or copolymers thereof; a pseudo PEG interrupted by at least one group each independently selected from the group consisting of —NH—CO—, —CO—NH—, and (C 3 -C 8 )alkylene interrupted by at least two groups each independently selected from the group consisting of —NH—CO— and —CO—NH—; poly(lactic acid) or copolymers thereof; polyesters selected from the group consisting of polylactide (PLA), polyglycolide (PGA), polycaprolactone (PCL) and copolymers thereof; or polyamides based on polymethacrylamide or copolymers thereof;
(vi) R 5 is a protein moiety, and said protein is albumin, a modified albumin, or a protein containing globin-like domains having long half-life in circulation;
(vii) R 5 is a peptide moiety;
(viii) R 5 is a carbohydrate moiety;
(ix) Y is an anticancer drug, antineoplastic drug, antifungal drug, antibacterial drug, antiviral drug, cardiac drug, neurological drug, psychoactive drug, alkaloid, antibiotic, bioactive peptide, steroid, steroid hormone, peptide hormone, interferon, interleukin, narcotic, nucleic acid, pesticide, or prostaglandin; or
(x) said targeting moiety is a protein, peptide, polypeptide, glycoprotein, lipoprotein, lipid, phospholipid, oligonucleotide or a mimic thereof, steroid, hormone, lymphokine, growth factor, albumin, cytokine, enzyme, coenzyme, vitamin, cofactor, human antigen, hapten, receptor protein, antibody or a fragment thereof, a substance used or modified such that it functions as a targeting moiety, or a combination thereof, preferably a vitamin such as vitamin B9 (folic acid).

11. The conjugate of claim 10 , wherein said polymer is linear or branched PEG; or a pseudo PEG having the structure (—CH 2 —CH 2 —O) 3 —(CH 2 ) 3 —NH—CO—(CH 2 ) 2 —CO—NH—(CH 2 ) 3 —(O—CH 2 —CH 2 -) 3 .

12. The conjugate of claim 10 , wherein said anticancer drug is a chemotherapeutic drug; or said antineoplastic drug is an alkylating antineoplastic agent.

13. The conjugate of claim 9 wherein R 1 and R 2 each independently is H, halogen, —OR 3 , —CO—R 3 , —CO—OR 3 , —OCO—OR 3 , —OCO—N(R 3 ) 2 , —CN, —NO 2 , —SR 3 , —N(R 3 ) 2 , —CO—N(R 3 ) 2 , —(C 1 -C 4 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 4 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 6 -C 14 )aryl, or 4-12-membered heterocyclyl, wherein R 3 is H, methyl, ethyl or propyl; n is 3, 4, or 5; m is 1, 2, or 3; R 4 is —NH—CO—(CH 2 ) p — or —NH—CO—NH—(CH 2 ) p —; and R 5 is a PEG moiety or a pseudo PEG moiety interrupted

Assignees

• Univ Ramot

Inventors

• Shabat Doron
• Satchi-Fainaro Ronit
• Gnaim Samer
• Scomparin Anna

Classifications

• C07D491/22

  in which the condensed system contains four or more hetero rings · CPC title

• C07D215/44

  with aryl radicals attached to said nitrogen atoms · CPC title

• A61K31/436

  the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin · CPC title

• A61K47/54

  the modifying agent being an organic compound · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title