N-acyl derivatives of the LL-E33288 antitumor antibiotics

Abstract: The invention is N-acyl and dihydro-N-acyl analogs of the family of antibacterial and antitumor agents known collectively as the E33288 complex.

Description: Lee et al, J. Am. Chem. Soc. 1987, 109, 3464 -3466, describes a novel family of antitumor antibiotics referred to as the calichemicins. There is a reference to calicheinicin γ 1 I and N-acetylcalichemicin γ 1 I , (which latter has been referred to also in the following teaching) but it is believed that the paper does not provide an enabling disclosure of the compounds of the present invention. EP-A-0289030 (Bristol-Myers Squibb) discloses N-acetyl derivatives designated N-acetylesperamicins A 1 . A 2 and A 1b . It is stated that these derivatives exhibit both antimicrobial and antitumor activity. SUMMARY OF THE INVENTION The invention describes certain N-acyl derivatives of the α 2 Br , β 1 Br , γ 1 Br , α 2 I , β 1 I , γ 1 I , and δ 1 I components and of the N-acyl-dihydro derivatives of the α 2 Br , β 1 Br , γ 1 Br , α 2 I , β 1 I , γ 1 I , and δ 1 I components of the LL-E33288 antibiotic complex prepared by reacting the antibiotic with an unsubstituted or substituted acid anhydride acyl cation equivalent or acid chloride. These N-acyl derivatives are effective antibacterial and antitumor agents. European Patent No 392376B (of which this application is a divisional) discloses N-acetyl-LL-E33288δ 1 I N-formyl-LL-E33288δ 1 I N-acetyl-LL-E33288γ 1 I and N-acetyl-dihydro-LL-E332887γ 1 I , and their preparation. DETAILED DESCRIPTION OF THE INVENTION The family of antibacterial and antitumor agents, known collectively as the LL-E33288 complex, are described and claimed in European Patent Application Number EP-A-182152 and are used to prepare the N-acyl derivatives of this invention. The above application describes the LL-E33288 complex, the components thereof, namely, LL-E33288α 1 Br , LL-E33288α 2 Br , LL-E33288α 3 Br , LL-E33288α 4 Br , LL-E33288β 1 Br , LL-E33288β 2 Br , LL-E33288 γ 1 Br , LL-E33288α 1 I , LL-E33288α 2 I , LL-E33288α 3 I , LL-E32288β 1 I , LL-E33288β 2 I , LL-E33288γ 1 I and LL-E33288δ 1 I and methods for their production by aerobic fermentation utilizing a new strain of Micromonospora echinospora ssp. calichensis or natural or derived mutants thereof. The proposed chemical structures of some of the above named components are disclosed in European Patent Application Number EP-A-182152 and are reproduced in Table I below: As can be seen from the structures disclosed in Table I, the α 2 Br , β 1 Br , γ 1 Br , α 2 I , β 1 I , γ 1 I , and δ 1 I components of the LL-E33288 antibiotic complex each contain a secondary amino group which is part of a substituted 4-aminopentose unit. It has now been discovered that the reaction of any of the above components with an unsubstituted or substituted, saturated or unsaturated alkyl or aryl acid anhydride, acid chloride or acyl cation equivalent results in the introduction of an acyl moiety on the secondary amino group as shown in Scheme I below. wherein W is the substituent attached to R 2 NH- of the aminopentose in Table I, R is hydrogen or a branched or unbranched alkyl (C 1 -C 10 ) or alkylene (C 1 -C 10 ) group, an aryl or heteroaryl group, or an aryl-alkyl (C 1 -C 5 ) or heteroaryl-alkyl (C 1 -C 5 ) group, all optionally substituted by one or more hydroxy, amino, carboxy, halo, nitro, lower (C 1 -C 3 ) alkoxy, or lower (C 1 -C 5 ) thioalkoxy groups. N-Acyl derivatives are also prepared from the dihydro derivatives of the LL-E33288 antibiotics, namely, dihydro-LL-E33288α 2 Br , dihydro-LL-E33288β 1 Br , dihydro-E33288γ 1 Br , dihydro-LL-E33288α 2 I , dihydro-LL-E33288β 1 I , dihydro-LL-E33288γ 1 I , and dihydro-LL-E33288δ 1 I , of parent application Serial No. 004,154. As an example, reaction of LL-E33288γ 1 I with acetic anhydride in methanol produces N-acetyl-LL-E33288 γ 1 I while the reaction of LL-E33288 δ 1 I with the mixed anhydride of acetic acid and formic acid produces N-formyl-LL-E33288 δ 1 I , both potent new antitumor antibiotics. The reaction of dihydro-LL-E33288 E33288γ 1 I with acetic anhydride in methanol produces N-acetyl-dihydro-LL-E33288 γ 1 I . N-Acetyl-dihydro-LL-E33288 γ 1 I is also produced by the reaction of N-acetyl-LL-E33288 γ 1 I with sodium borohydride under the conditions described European Patent Application Number EP-A-276485. The present invention provides N-acyl derivatives of LL-E33288 and dihydro LL-E33288 antibiotics of the formula wherein W is R is hydrogen or a branched or unbranched alkyl (C 1 -C 10 ) or alkylene (C 1 -C 10 ) group, an aryl or heteroaryl group, or an aryl-alkyl (C 1 -C 5 ) or heteroaryl-alkyl (C 1 -C 5 ) group, all optionally substituted by one or more hydroxy, amino, carboxy, halo, nitro, lower (C 1 -C 3 ) alkoxy, or lower (C 1 -C 5 ) thioalkoxy groups; R 1 is H or R 2 is CH 3 , C 2 H 5 or CH(CH 3 ) 2 ; R 4 is OH when R 5 is H or R 4 and R 5 taken together are a carbonyl; and X is an iodine or bromine atom, excluding: N-acetyl-LL-E33288δ 1 I ; N-formyl-LL-E33288δ 1 I ; N-acetyl-LL-E33288γ 1 I and N-acetyl-dihydro-LL-E33288γ 1 I . The N-acyl derivatives of the LL-E33288 antitumor antibiotics are most conveniently characterized by high-performance liquid chromatography (HPLC) and by thin-layer chromatography (TLC). The N-acyl derivatives of the LL-E33288 antitumor antibiotics are useful as antibacterial agents and are also active as antitumor agents as determined in the Biochemical Induction Assay (BIA), a bacterial assay system which specifically measures the ability of an agent to directly or indirectly initiate DNA damage. This invention also provides a compound. of formula: as defined above, for use in treating bacterial infections in warm-blooded animals, or for use in treating tumors in warm-blooded animals. This invention also provides use of a compound of formula: as defined above, in the preparation of a medicament for treating bacterial infections or for treating tumors in warm-blooded animals.

Claims: A compound of the formula wherein W is R is hydrogen or a branched or unbranched alkyl (C 1 -C 10 ) or alkylene (C 1 -C 10 ) group, an aryl or heteroaryl group, or an aryl-alkyl (C 1 -C 5 ) or heteroaryl-alkyl (C 1 -C 5 ) group, all optionally substituted by one or more hydroxy, amino, carboxy, halo, nitro, lower (C 1 -C 3 ) alkoxy, or lower (C 1 -C 5 ) thioalkoxy groups; R 1 is H or R 2 is CH 3 , C 2 H 5 or CH(CH 3 ) 2 ; R 4 is OH when R 5 is H or R 4 and R 5 taken together are a carbonyl; and X is an iodine or bromine atom, excluding: N-acetyl-LL-E33288δ 1 I ; N-formyl-LL-E33288δ 1 I ; N-acetyl-LL-E33288γ 1 I and N-acetyl-dihydro-LL-E33288γ 1 I . A compound according to Claim 1 for use in treating bacterial infections in warm-blooded animals. A compound according to Claim 1 for use in treating tumors in warm-blooded animals. Use of a compound according to Claim 1 in the preparation of a medicament for treating bacterial infections. Use of a compound according to Claim 1 in the preparation of a medicament for treating tumors in warm-blooded animals.

Inventors: LEE MAY DEAN-MING, LEE, MAY DEAN-MING
Applicants: WYETH CORP, WYETH HOLDINGS CORPORATION
Application year: 1990
Main classification: C07H15
IPC codes: C07H15, A61K31, A61P35, A61P31