Maytansinoids

• US 4,364,866 A
• Filed: 09/17/1980
• Issued: 12/21/1982
• Est. Priority Date: 09/21/1979
• Status: Expired due to Term

• Current Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Inventors: Izawa, Motowo, Asai, Mitsuko, Nakahama, Kazuo
• Primary Examiner(s): Bond, Robert T.
• Application Number:
  US06/188,238
• Time in Patent Office: 825 Days
• Field of Search: 260/239.3 P, 424/248.54, 260/239.3 T
• US Class Current: 540/462
• CPC Class Codes: C07D 498/18 Bridged systems
• CPC Class Codes: C12N 1/205 Bacterial isolates
• CPC Class Codes: C12P 17/188 Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms ergot-alcaloids C12P17/183
• CPC Class Codes: C12R 2001/14 Chainia
• CPC Class Codes: C12R 2001/465 Streptomyces
• CPC Class Codes: C12R 2001/62 Streptosporangium
• CPC Class Codes: Y10S 435/872 Nocardia

Abstract

Antibiotic C-15003 PHO of the formula: ##STR1## wherein R₁ is H, hydroxyl, alkanoyloxy, alkenylcarbonyloxy or arylcarbonyloxy; R₂ is H, hydroxyl or alkanoyloxy; R₃ is H or alkanoyloxy is produced by introducing a hydroxyl group into 15-position of a maytansinoid compound, and, if desired, thus obtained compound is subjected to deacylation or acylation.

Antibiotic C-15003 PHO is useful as antiprotozoal or antitumor agent.

Claims

1. A maytansinoid compound of the formula:

##STR26## wherein when R₃ designates hydrogen or alkanoyl containing not more than 5 carbon atoms except ##STR27## R₁ is hydroxyl and R₂ is hydrogen;

when R₃ designates hydrogen or alkanoyl containing not more than 5 carbon atoms, R₁ is hydrogen and R₂ is hydroxyl;

when R₃ designates hydrogen or alkanoyl of 2 to 5 carbon atoms other than ##STR28## R₂ is hydrogen and R₁ is formyloxy, alkanoyloxy of 2 to 7 carbon atoms, alkenylcarbonyloxy of 3 to 5 carbon atoms or ArCOO, Ar being selected from the group consisting of phenyl, benzyl, cinnamyl, phenethyl and styryl, and wherein the said alkanoyloxy, alkenylcarbonyloxy or ArCOO may optionally be substituted by at most three substituents X and the radical Ar may be optionally substituted with 1 to 3 C_1-4 -alkyl groups;

when R₃ designates ##STR29## R₂ is hydrogen, and R₁ is formyloxy, acetoxy, alkanoyloxy of 3 to 7 carbon atoms, alkenylcarbonyloxy of 3 to 5 carbon atoms, or ArCOO, Ar being selected from the group consisting of phenyl, benzyl, cinnamyl, phenethyl and styryl, and wherein said alkanoyloxy, alkenylcarbonyloxy or ArCOO may optionally be substituted by at most three substituents X and the radical Ar may be optionally substituted with 1 to 3 C_1-4 -alkyl groups; and

when R₃ designates hydrogen or alkanoyl containing not more than 5 carbon atoms, R₁ is hydrogen and R₂ is alkanoyloxy of 2 to 5 carbon atoms;

wherein X is selected from the group consisting of C_1-4 -alkoxy, C_2-4 alkanoyl, C_2-4 alkanoyloxy, C_2-4 alkoxycarbonyl, halogen, nitro, cyano, trifluoromethyl, di-C_1-4 -alkylamino, C_1-4 alkylthio, methylsulfinyl, methylsulfonyl, oxo, thioxo, C_1-4 alkanoylamino and carboxyl.

2. A compound as claimed in claim 1, wherein R₁ is alkanoyloxy of 2 to 7 carbon atoms, alkenylcarbonyloxy of 3 to 5 carbon atoms or ArCOO, R₂ is hydrogen and R₃ is isovaleryl.

3. A compound as claimed in claim 1, when R₁ is alkanoyloxy of 3 to 7 carbon atoms, alkenylcarbonyloxy of 3 to 5 carbon atoms, ArCOO, chloroacetoxy, dichloroacetoxy or trichloroacetoxy, R₂ is hydrogen and R₃ is isobutyryl.

4. A compound as claimed in claim 1, wherein R₁ is hydrogen, R₂ is alkanoyloxy of 2 to 5 carbon atoms and R₃ is isobutyryl.

5. A compound as claimed in claim 1, wherein R₁ is hydroxyl, R₂ is hydrogen and R₃ is hydrogen.

6. A compound as claimed in claim 1, wherein R₁ is hydroxyl, R₂ is hydrogen and R₃ is acetyl.

7. A compound as claimed in claim 1, wherein R₁ is hydroxyl, R₂ is hydrogen and R₃ is propionyl.

8. A compound as claimed in claim 1, wherein R₁ is hydroxyl, R₂ is hydrogen and R₃ is isovaleryl.

9. A compound as claimed in claim 1, wherein R₁ is hydrogen, R₂ is hydroxyl and R₃ is isobutyryl.

10. A compound as claimed in claim 1, wherein R₁ is propionyloxy, R₂ is hydrogen and R₃ is isobutyryl.

11. A compound as claimed in claim 1, wherein R₁ is n-butyryloxy, R₂ is hydrogen and R₃ is isobutyryl.

12. A compound as claimed in claim 1, wherein R₁ is n-valeryloxy, R₂ is hydrogen and R₃ is isobutyryl.

13. A compound as claimed in claim 1, wherein R₁ is acetoxy, R₂ is hydrogen and R₃ is isovaleryl.

14. A compound as claimed in claim 1, wherein R₁ is benzoyloxy, R₂ is hydrogen and R₃ is isobutyryl.

15. A compound as claimed in claim 1, wherein R₁ is monochloroacetoxy, R₂ is hydrogen and R₃ is isobutyryl.

16. A compound as claimed in claim 1, wherein R₁ is crotonoyloxy, R₂ is hydrogen and R₃ is isobutyryl.

17. A compound as claimed in claim 1, wherein R₁ is acryloyloxy, R₂ is hydrogen and R₃ is isobutyryl.

18. A compound as claimed in claim 1, wherein R₁ is isobutyryloxy, R₂ is hydrogen and R₃ is isobutyryl.

19. A compound as claimed in claim 1, wherein R₁ is isovaleryloxy, R₂ is hydrogen and R₃ is isobutyryl.

20. A compound as claimed in claim 1, wherein R₁ is hydrogen, R₂ is acetoxy and R₃ is isobutyryl.