Maytansinoids, pharmaceutical compositions thereof and method of use thereof

• US 4,308,269 A
• Filed: 06/06/1980
• Issued: 12/29/1981
• Est. Priority Date: 06/11/1979
• 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: Akimoto, Hiroshi, Miyashita, Osamu
• Primary Examiner(s): BOND, ROBERT
• Application Number:
  US06/157,091
• Time in Patent Office: 571 Days
• Field of Search: 260/239.3 P, 424/248.54
• US Class Current: 514/229.5
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 498/18 Bridged systems
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Novel maytansinoids of the formula: ##STR1## wherein X is H or Cl, and R is a hydrocarbon residue or an azaheterocyclic group, said R group having at least one of water-solubilizing substituents, have antimitotic, antitumor and antimicrobial activities.

Claims

1. A compound of the formula:

##STR6## wherein X is H or Cl, and

R is C_1-8 alkyl, phenyl, phenyl-C_1-4 alkyl or 5- or 6-membered azaheterocyclic group containing one to four of N, of the class consisting of pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolinyl, pyrazolinyl, imidazolinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl and triazolidinyl,

said R group having one or two substituents selected from the class consisting of carboxyl, sulfo, an amino group which is unsubstituted or mono-substituted by C_1-4 alkyl, C_3-4 alkenyl, benzyl, phenyl, C_1-4 alkylsulfonyl, benzenesulfonyl and p-toluenesulfonyl, and

a quaternary ammonio group of the formula;

##STR7## wherein each of R², R³ and R⁴ is independently C_1-4 alkyl, allyl pyrazolio, pyrrolinio, triazolio, tetrazolio, piperidinio, piperazinio, pyrrolidinio, pyrrolinio, imidazolinio, imidazolidinio, pyrazolinio and pyrazolidinio group.

2. A compound according to claim 1, wherein X is Cl.

3. A compound according to claim 1, wherein the azaheterocyclic group is pyridyl, piperazinyl, imidazolinyl or tetrazolyl.

4. A compound according to claim 1, wherein the quaternary ammonio group is trimethylammonio, allyldimethylammonio, benzyldimethylammonio, pyridinio, piperazinio, imidazolio or triazolio.

5. A compound according to claim 1, wherein R is C_1-8 alkyl, phenyl-C_1-4 alkyl or pyridyl, said groups having one or two substituents selected from the group consisting of carboxyl, pyridinio, amino and C_1-4 alkylamino.

6. A compound according to claim 5, wherein R is phenyl-C_1-4 alkyl substituted by amino.

7. The compound according to claim 1, which is maytansinol 3-α

-aminophenylacetate.

8. The compound according to claim 1, which is maytansinol 3-α

-amino-β

-phenylpropionate.

9. The compound according to claim 1, which is maytansinol 3-aminoacetate.

10. An antitumor composition which comprises as an active ingredient an amount effective to inhibit the growth of tumors of a compound of the formula:

##STR8## wherein X is H or Cl, and

R is C_1-8 alkyl, phenyl, phenyl-C_1-4 alkyl or 5- or 6-membered azaheterocyclic group containing one to four of N, of the class consisting of pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl triazolyl, tetrazolyl, pyrrolinyl, pyrazolinyl, imidazolinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl and triazolidinyl,

said R group having one or two substituents selected from the group consisting of carboxyl, sulfo, an amino group which is substituted or mono-substituted by C_1-4 alkyl, C_3-4 alkenyl, benzyl, phenyl, C_1-4 alkylsulfonyl, benzenesulfonyl and p-toluenesulfonyl, and

a quaternary ammonio group of the formula;

##STR9## wherein each of R², R³ and R⁴ is independently C_1-4 alkyl, allyl or benzyl, or the quaternary ammonio group if formed at the ring N of a pyridinio, pyrazinio, pyrimidinio, pyridazinio, imidazolio, pyrazolio, pyrrolinio, triazolio, tetrazolio, piperidinio, piperazinio, pyrrolidinio, pyrrolinio, imidazolinio, imidazolidinio, pyrazolinio and pyrazolidinio group.

11. A method of inhibiting the growth of tumor cells and prolonging the survival time of a tumor-bearing warm blooded animal, which comprises administering to said animal an amount effective to inhibit the growth of tumors of a compound of the formula:

##STR10## wherein X is H or Cl, and

R is C_1-8 alkyl, phenyl, phenyl-C_1-4 alkyl or 5- or 6-membered azaheterocyclic group containing one to four of N, of the class consisting of pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolinyl, pyrazolinyl, imidazolinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl and triazolidinyl,

said R group having one or two substituents selected from the class consisting of carboxyl, sulfo, an amino group which is unsubstituted or mono-substituted by C_1-4 alkyl, C_3-4 alkenyl, benzyl, phenyl, C_1-4 alkylsulfonyl, benzenesulfonyl and p-toluenesulfonyl, and a quaternary ammonio group of the formula;

##STR11## wherein each of R², R³ and R⁴ is independently C_1-4 alkyl, allyl or benzyl, or the quaternary ammonio group is formed at the ring N or a pyridinio, pyrazinio, pyrimidinio, pyridazinio, imidazolio, pyrazolio, pyrrolinio, trazolio, tetrazolio, piperidinio, piperazinio, pyrrolidinio, pyrrolinio, imidazolinio, imidazolidinio, pyrazolinio and pyrazolidinio group.