Acid labile immunoconjugate intermediates

• US 5,612,474 A
• Filed: 06/30/1994
• Issued: 03/18/1997
• Est. Priority Date: 06/30/1994
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Patel, Vinod F.
• Primary Examiner(s): Kunz, Gary L.
• Application Number:
  US08/269,493
• Time in Patent Office: 992 Days
• Field of Search: 536/25.5, 536/27.1, 536/25.3, 536/27.14, 536/7.1
• US Class Current: 536/27.14
• CPC Class Codes: C07H 19/16 Purine radicals

Abstract

Trityl derivatives useful as "linkers" for preparation of imunoconjugates comprising drugs end antibodies are provided. Immunoconjugates and processes for their preparation and use are also provided. This invention also provides for prodrugs comprising a substituted trityl group conjugated with a drug of choice as well as methods of using the imunoconjugates and prodrugs of this invention.

Claims

1. A compound of the formula:

##STR27## wherein;

R and R¹ are independently selected from the group consisting of;

--NO₂, --CHO, --COOH, --CO₂ X, --PO₂ X, --CBR₃, --CCl₃, --CF₃, --CI₃, --COX, --CN, --CONH₂, --OC(O)OX, --OC(O)NHX, --OC(O)NX₂, --CH₂ Cl, --CH₂ X, --CH₃, --CHX₂, --CX₃, --F, --Cl, --Br, --I, --H, --NH₂, --SH, --OPOX, --OH, --OX, --OCO₂ X, --SX, --SONH₂, --S(O)_n X, --SO₂ NH₂, --SO₂ NHX, --SONHX, --NHX, and --NX₂,

where X is C₁ -C₁₂ alkyl or aryl,

and n is 0-3;

D is a drug selected from the group consisting of doxorubicin, gemcitabine and 2-Amino-2'"'"'-deoxy-2'"'"',2'"'"'-difluoroadenosine;

A is ##STR28## wherein;

y is C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl, C₂ -C₁₂ alkynyl, C₁ -C₁₂ alkoxy, C₁ -C₁₂ alkylthio, C₁ -C₁₂ alkylamino, aryl, arylamino, aralkylamino, arylthio, aryloxy, aralkyl, aralkylamino, aralkalkyamino, aralkylthio, aralkoxy, or a peptide having from 2-6 amino acids,

or a salt or solvent thereof.

2. The compound of claim 1 wherein R and R'"'"' are independently selected from the group consisting of hydroxy, C₁ -C₁₂ alkoxy, C₁ -C₁₂ alkyl, C₁ -C₁₂ alkanoyl, di(C₁ -C₁₂ alkyl)amino, C₁ -C₁₂ alkylamino, trichloromethyl, and trifluoromethyl, or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 2 wherein R and R'"'"' are independently selected from the group consisting of hydroxy, C₁ -C₆ alkoxy, C₁ -C₆ alkyl, di(C₁ -C₆ alkyl)amino, and C₁ -C₆ alkylamino, or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 3 wherein R and R'"'"' are independently selected from the group consisting of hydroxy and C₁ -C₆ alkoxy, or a pharmaceutically acceptable salt or solvate thereof.

5. The compound of claim 1 wherein D is doxorubicin.

6. The compound of claim 1 wherein D is gemcitabine.

7. The compound of claim 1 wherein D is 2-Amino-2'"'"'-deoxy-2'"'"',2'"'"'-difluoroadenosine.

8. A compound of the formula:

##STR29## wherein;

R and R¹ are each --OCH₃ ;

A is ##STR30## and D is ##STR31##