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Claims for Patent: 5,079,233

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Claims for Patent: 5,079,233

Title: N-acyl derivatives of the LL-E33288 antitumor antibiotics, composition and methods for using the same
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.
Inventor(s): Lee; May D. M. (Monsey, NY)
Assignee: American Cyanamid Company (Stamford, CT)
Application Number:07/338,928
Patent Claims: 1. A compound of the formula ##STR6## wherein R is hydrogen or a branched or unbranched alkyl (C.sub.1 -C.sub.10) optionally substituted by one or more hydroxy, or carboxy;

R.sub.2 is CH.sub.3, C.sub.2 H.sub.5 or CH(CH.sub.3).sub.2 ;

W is ##STR7## wherein R.sub.1 is H or ##STR8## R.sub.4 is OH when R.sub.5 is H or R.sub.4 and R.sub.5 taken together are a carbonyl; and X is an iodine or bromine atom.

2. A compound according to claim 1 of the formula: ##STR9## which is the antitumor antibiotic N-acetyl LL-E33288.delta..sub.1.sup.I, wherein W is as defined in claim 1; R is CH.sub.3 ; R.sub.1 is ##STR10## R.sub.2 is CH.sub.3 ; R.sub.4 and R.sub.5 taken together is a carbonyl; X is iodine and having:

a) a proton magnetic resonance spectrum as shown in Figure I;

b) a molecular weight of 1395 as determined by FABMS;

c) a molecular formula of C.sub.56 H.sub.74 N.sub.3 O.sub.22 IS.sub.4 with an exact mass for M+K as determined by high resolution FAB-MS to be 1420.217 for C.sub.56 H.sub.74 N.sub.3 O.sub.22 IS.sub.4 K;

d) a retention time of 4.5 minutes by HPLC using a Analytichem Sepralyte C.sub.18, 5u, 4,6 mm.times.25 cm column with a mobile phrase of 0.2 M aqueous ammonium acetate at pH 6.0 made 1:1 with acetonitrile and having a flow rate of 1.5 ml/minute with UV detection at 254 nm and 280 nm; and

e) a Rf of 0.25 on Whatman High Performance TLC (HPTLC) plates, type LHP-KF using ethyl acetate saturated with 0.1 M aqueous phosphate buffer at pH 7.0, visualized using a 254 nm UV lamp.

3. A compound according to claim 1 of the formula: ##STR11## which is the antitumor antibiotic N-formyl LL-E33288.delta..sub.1.sup.I, wherein W is as defined in claim 1; R is H; R.sub.1 is ##STR12## R.sub.2 is CH.sub.3 ; R.sub.4 and R.sub.5 taken together is a carbonyl; X is iodine and having:

a) a protonmagnetic resonance spectrum as shown in Figure II;

b) a molecular weight of 1381 as determined by FAB-MS;

c) a molecular formula of C.sub.55 H.sub.72 N.sub.3 O.sub.22 IS.sub.4 with an exact mass for M+K as determined by high resolution FAB-MS to be 1420.2172 for C.sub.55 H.sub.72 N.sub.3 O.sub.22 IS.sub.4 K;

d) a retention time of 4.2 minutes by HPLC using an Analytichem Sepralyte C.sub.18, 5u, 4.6 mm .times.25 cm column with a mobile phase of 0.2 M aqueous ammonium acetate at pH 6.0, made 1:1 with acetonitrile and having a flow rate of 1.5 ml/minute with UV detection at 254 nm and 280 nm; and

e) a Rf of 0.31 on Whatman High Performance TLC (HPTLC) plates, Type LHP-KF using ethyl acetate saturated with 0.1 M aqueous phosphate buffer at pH 7.0, visualized using a 254 nm UV lamp.

4. A compound according to claim 1 of the formula: ##STR13## which is the antitumor antibiotic N-acetyl-LL-E33288.delta..sub.1.sup.I, wherein W is as defined in claim 1; R is CH.sub.3 ; R.sub.1 is ##STR14## R.sub.2 is C.sub.2 H.sub.5 ; R.sub.4 and R.sub.5 taken together is a carbonyl; X is iodine and having:

a) a ultraviolet spectrum as shown in Figure III;

b) an infrared absorption spectrum as shown in Figure IV;

c) a proton magnetic resonance spectrum as shown in Figure V; and

d) a carbon-13 magnetic resonance spectrum as shown in Figure VI with significant peak listed as:

e) a molecular weight of 1409 as determined by FAB-MS;

f) a molecular formula of C.sub.57 H.sub.76 N.sub.3 O.sub.22 IS.sub.4 with an exact mass for M+H as determined by high resolution FAB-MS to be 1410.2954 for C.sub.57 H.sub.76 N.sub.3 O.sub.22 IS.sub.4 ;

g) a retention time of 6.6 minutes by HPLC using an Analytichem Sepralyte C.sub.18, 5u, 4.6 mm.times.25 cm column with a mobile phase of 0.2M aqueous ammonium acetate at pH 6.0, made 1:1 with acetonitrile and having a flow rate of 1.5 ml/minute with UV detection at 254 mm and 280 nm; and

h) a Rf of 0.53 on Whatman High Performance TLC (HPTLC) plates, type LHP-KF using ethyl acetate saturated with 0.1 M aqueous phosphate buffer at pH 7.0, visualized using a 254 nm UV lamp.

5. A compound according to claim 1 of the formula: ##STR15## which is the antitumor antibiotic N-formyl-LL-E33288.delta..sub.1.sup.I, wherein W is as defined in claim 1; R is H; R.sub.1 is ##STR16## R.sub.2 is C.sub.2 H.sub.5 ; R.sub.4 and R.sub.5 taken together is a carbonyl; and X is iodine and having:

a) a retention time of 6.2 minutes by HPLC using an Analytichem Sepralyte C.sub.18, 5u, 4.6 mm.times.25 cm column with a mobile phase of 0.2M aqueous ammonium acetate at pH 6.0, made 1:1 with acetonitrile and having a flow rate of 1.5 ml/minute with UV detection at 254 nm and 280 nm; and

b) a Rf of 0.53 on Whatman High Performance TLC (HPTLC) plates, Type LHP-KF using ethyl acetate saturated with 0.1 M aqueous phosphate buffer at pH 7.0, visualized using a 254 nm UV lamp.

6. A compound according to claim 1 of the formula: ##STR17## which is the antitumor antibiotic N-acetyl-dihydro-LL-333288.gamma..sub.1.sup.I, wherein W is as defined in claim 1; R is CH.sub.3 ; R.sub.1 is ##STR18## R.sub.2 is C.sub.2 H.sub.5 ; R.sub.4 is H; X is iodine; and having a) a ultraviolet absorption spectrum as shown in Figure VII;

b) a proton magnetic resonance spectrum as shown in Figure VIII, and

c) a Rf of 0.38 on Whatman High Performance TLC (HPTLC) plates, type LHP-KF using ethyl acetate saturated with 0.1 M aqueous phosphate buffer at pH 7.0, visualized using a 254 nm UV lamp.

7. A compound according to claim 1 of the formula: ##STR19## which is the antitumor antibiotic N-monomethyl-succinyl-LL-E33288.gamma..sub.1.sup.I, wherein W is as defined in claim 1; R is --CH.sub.2 CH.sub.2 CO.sub.2 CH.sub.3 ; R.sub.1 is ##STR20## R.sub.2 is C.sub.2 H.sub.5 ; R.sub.4 and R.sub.5 taken together is a carbonyl; X is iodine; and having:

a) a Rf of 0.42 on Whatman High Performance TLC (HPTLC) plates, type LHP-KF using ethyl acetate saturated with 0.1 M aqueous phosphate buffer at pH 7.0, visualized using a 254 nm UV lamp.

8. A process for producing a compound of the formula: ##STR21## wherein W is ##STR22## R.sub.1 is H or ##STR23## R.sub.4 is OH when R.sub.5 is H and x is an iodine or bromine atom comprising reacting ##STR24## wherein W is as defined above except R.sub.4 and R.sub.5 are taken together to form a ketone with sodium borohydride in an alcoholic solution at -5.degree. C. to about +5.degree. C. from 5 minutes to 5 hours.

9. A process for producing a compound of the formula: ##STR25## wherein W is ##STR26## R.sub.1 is H or ##STR27## R.sub.4 is OH when R.sub.5 is H and X is an iodine or bromine atom comprising reacting ##STR28## wherein W is as defined above except R.sub.4 and R.sub.5 are taken together to form a ketone with sodium borohydride in an alcoholic solution at -5.degree. C. to about +5.degree. C. from 5 minutes to 5 hours.

10. A process for producing a compound of the formula: ##STR29## wherein W is ##STR30## R.sub.1 is H or ##STR31## R.sub.4 is OH or when R.sub.5 is H and X is an iodine or bromine atom comprising reacting ##STR32## wherein w is as defined above except R.sub.4 and R.sub.5 are taken together to form a ketone with sodium borohydride in an alcoholic solution at -5.degree. C. to about +5.degree. C. from 5 minutes to 5 hours.

11. A process for producing a compound of the formula: ##STR33## wherein W is ##STR34## R.sub.1 is H or ##STR35## R.sub.4 is OH when R.sub.5 is H and X is an iodine or bromine atom comprising reacting ##STR36## wherein W is as defined above except R.sub.4 and R.sub.5 are taken together to form a ketone with sodium borohydride in an alcoholic solution at -5.degree. C. to about +5.degree. C. from 5 minutes to 5 hours.

12. A process for producing a compound of the formula: ##STR37## wherein W is ##STR38## R.sub.1 is H or ##STR39## R.sub.4 is OH when R.sub.5 is H and X is an iodine or bromine atom comprising reacting ##STR40## wherein W is as defined above except R.sub.4 and R.sub.5 are taken together to form a ketone with sodium borohydride in an alcoholic solution at -5.degree. C. to about +5.degree. C. from 5 minutes to 5 hours.

13. A process for producing a compound of the formula ##STR41## wherein W is ##STR42## R.sub.1 is H or ##STR43## R.sub.4 is OH when R.sub.5 is H and X is an iodine or bromine atom comprising reacting ##STR44## wherein W is as defined above except R.sub.4 and R.sub.5 are taken together to form a ketone with sodium borohydride in an alcoholic solution at -5.degree. C. to about +5.degree. C. from 5 minutes to 5 hours.

14. A process for producing a compound of the formula: ##STR45## wherein W is ##STR46## R.sub.1 is H or ##STR47## R.sub.4 is OH when R.sub.5 is H and X is an iodine or bromine atom comprising reacting ##STR48## wherein W is as defined above except R.sub.4 and R.sub.5 are taken together to form a ketone with sodium borohydride in an alcoholic solution at -5.degree. C. to about +5.degree. C. from 5 minutes to 5 hours.

15. A process for producing a compound of the formula: ##STR49## wherein W is ##STR50## R.sub.1 is H or ##STR51## R.sub.4 is OH when R.sub.5 is H and X is an iodine or bromine atom comprising reacting ##STR52## wherein W is as defined above except R.sub.4 and R.sub.5 are taken together to form a ketone with sodium borohydride in an alcoholic solution at -5.degree. C. from 5 minutes to 5 hours.

16. A process for producing a compound of the formula: ##STR53## wherein W is ##STR54## R.sub.1 is H or ##STR55## R.sub.4 is OH when R.sub.5 is H and X is an iodine or bromine atom comprising reacting ##STR56## wherein W is as defined above except R.sub.4 and R.sub.5 are taken together to form a ketone with sodium borohydride in an alcoholic solution at -5.degree. C. to about +5.degree. C. from 5 minutes to 5 hours.

17. A method of treating bacterial infections in warm-blooded animals which comprises administering to said animals an antibacterially effective amount of a compound of the formula: ##STR57## wherein W is ##STR58## R is hydrogen or a branched or unbranched alkyl (C.sub.1 -C.sub.10) optionally substituted by one or more hydroxy, or carboxy; R.sub.1 is H or ##STR59## R.sub.2 is CH.sub.3, C.sub.2 H.sub.5 or CH(CH.sub.3).sub.2 ; R.sub.4 is OH when R.sub.5 is H or R.sub.4 and R.sub.5 taken together are a carbonyl; and X is an iodine or bromine atom.

18. A method of testing the growth of tumors in warm-blooded animals which comprises administering to said animals an oncolytic amount of a compound of the formula: ##STR60## wherein W is ##STR61## R is hydrogen or a branched or unbranched alkyl (C.sub.1 -C.sub.10) optionally substituted by one or more hydroxy, or carboxy; R.sub.1 is H or ##STR62## R.sub.2 is CH.sub.3, C.sub.2 H.sub.5 or CH(CH.sub.3).sub.2 ; R.sub.4 is OH when R.sub.5 is H or R.sub.4 and R.sub.5 taken together are a carbonyl; and X is an iodine or bromine atom.
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