Lincomycin analogs

Abstract

Compounds of the formula: ##STR1## are disclosed, wherein R 1 taken independently is hydrogen; R 2 taken independently is the moiety ##STR2## wherein Ac is carboxacyl or an acyl group of formula: ##STR3## wherein Z is hydrogen, lower alkyl or a protective group removable by hydrogenolysis; R 5 is lower alkyl; R 1 and R 2 when together are the divalent group; ##STR4## wherein Z and R 5 are as defined above; R 3 is hydrogen when R 1 and R 2 are taken together and is a monovalent thio group of formula: ##STR5## located in the 7(S)-position when R 1 and R 2 are taken independently, A represents hydrogen or hydroxyl, B represents hydrogen or hydroxyalkyl, n is the integer 0 when B is hydroxyalkyl and n is an integer of 0 to 1, inclusive, when B is hydrogen, X is oxygen .[.or sulfur.]., D is the acyl radical of a lower hydrocarbon carboxylic acid; R 4 is lower alkyl and Y is carboxacyl or hydrogen. Disclosed also are methods of making and using the novel compounds of the invention, which are useful intermediates in the chemical synthesis of useful antibacterial lincomycin analogs. Certain of the compounds of the invention are also active as antibacterial agents.

I claim: 
     
       1. A compound of the formula: ##STR32## wherein R 1  when taken independently represents hydrogen; R 2  when takene independently represents the monovalent moiety ##STR33## wherein Ac is selected from carboxyacyl of from 2 to 18 carbon atoms, inclusive, and an acyl radical of formula: ##STR34## wherein Z is selected from hydrogen, lower alkyl and an amino protecting group removable by hydrogenolysis; R 5  is lower alkyl; R 1  and R 2  when taken together form the divalent group of the formula: ##STR35## wherein Z and R 5  are as defined above; R 3  is hydrogen when R 1  and R 2  are taken together and when R 1  and R 2  are taken independently, R 3  is a monovalent thio group in the 7(S)-position, having the formula: ##STR36## wherein A is selected from hydrogen and hydroxy, B is selected from hydrogen and monohydroxyloweralkyl, n is the integer 0 when B is monohydroxyloweralkyl and an integer of from 0 to 1 when B is hydrogen, X is .[.selected from.]. oxygen .[.and sulfur.]., D is an acyl radical of a lower hydrocarbon carboxylic acid; R 4  represents lower alkyl; and Y is selected from carboxacyl of from 2 to 18 carbon atoms, inclusive, and hydrogen. 
     
     
       2. A compound of the formula: ##STR37## wherein A is selected from hydrogen and hydroxyl; B is selected from hydrogen and monohydroxyloweralkyl; n is the integer 0 when B is monohydroxyloweralkyl and n is an integer of from 0 to 1, inclusive, when B is hydrogen; X is .[.selected from.]. oxygen .[.and sulfur.].; D is the acyl radical of a lower hydrocarbon carboxylic acid; Ac 1  is selected from carboxacyl of from 2 to 18 carbon atoms, inclusive, and an acyl radical of the formula: ##STR38## wherein Z is selected from hydrogen, lower alkyl and an amino protecting group removable by hydrogenolysis; and R 5  is lower alkyl; R 4  represents lower alkyl; and Y is selected from carboxacyl of from 2 to 18 carbon atoms, inclusive, and hydrogen. 
     
     
       3. A process for preparing compounds of the formula: ##STR39## wherein A is selected from hydrogen and hydroxy; B is selected from hydrogen and monohydroxyloweralkyl; n is the integer 0 when B is monohydroxyloweralkyl and n is an integer of from 0 to 1, inclusive, when B is hydrogen; X is .[.selected from.]. oxygen .Iadd..[.and sulfur.]..Iaddend.; D is the acyl radical of a lower hydrocarbon carboxylic acid; Ac 1  is selected from carboxyacyl of from 2 to 18 carbon atoms, inclusive, and an acyl radical of formula: ##STR40## wherein G is selected from lower alkyl and an amino protecting group removable by hydrogenolysis and R 5  is lower alkyl; R 4  represents lower alkyl; and Y is selected from carboxacyl of from 2 to 18 carbon atoms, inclusive, and hydrogen, which comprises bringing together 
     
     
       1. the corresponding alkyl N-acyl-6,7-aziridino-6-deamino-7-deoxy-α-thiolincosaminide of formula: ##STR41## 
     
     
        wherein AC 1 , R 4  and Y are as defined above; 2. an anhydrous lower hydrocarbon carboxylic acid; and 3. a corresponding sulfur compound of formula: ##STR42## wherein X, A, B, and n are as defined above.   
     
     
       4. A compound of the formula: ##STR43## wherein A is selected from hydrogen and hydroxyl; B is selected from hydrogen and monohydroxyloweralkyl; n is the integer 0 when B is monohydroxyloweralkyl and n is an integer of from 0 to 1, inclusive, when B is hydrogen; X is .[.selected from.]. oxygen .[.and sulfur.].; D is the acyl radical of a lower hydrocarbon carboxylic acid; Y is selected from carboxacyl of from 2 to 18 carbon atoms, inclusive, and hydrogen; R 4  and R 5  are each lower alkyl. 
     
     
       5. A compound according to claim 4 which is methyl N-(trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio-.alpha.-thiolincosaminide. 
     
     
       6. A compound of the formula: ##STR44## wherein A is selected from hydrogen and hydroxyl; B is selected from hydrogen and monohydroxyloweralkyl; n is the integer 0 when B is monohydroxyloweralkyl and n is an integer of from 0 to 1, inclusive, when B is hydrogen; X is .[.selected from.]. oxygen .[.and sulfur.].; Y is selected from carboxacyl of from 2 to 18 carbon atoms, inclusive, and hydrogen, R 4 , R 5  and R 6  are each lower alkyl. 
     
     
       7. A compound according to claim 6 wherein Y is hydrogen. 
     
     
       8. A compound according to claim 6 which is methyl N-(1-methyl-trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio-α-thiolincosaminide. 
     
     
       9. A compound of the formula: ##STR45## wherein G is selected from lower alkyl and an amino protecting group removable by hydrogenolysis; R 4  and R 5  each represent lower alkyl and Y is selected from carboxacyl of from 2 to 18 carbon atoms, inclusive, and hydrogen. 
     
     
       10. The compound of claim 9 wherein Y is hydrogen. 
     
     
       11. A compound according to claim 9 which is methyl N-(1-carbobenzoxy-trans-4-propyl-L-prolyl)-6,7-aziridino-6-deamino-7-deoxy-α-thiolincasminide. 
     
     
       12. A process for preparing compounds of the formula: ##STR46## wherein G is selected from lower alkyl and an amino protecting group removable by hydrogenolysis; R 4  and R 5  are each lower alkyl, Y is selected from carboxacyl of from 2 to 18 carbon atoms, inclusive, and hydrogen which comprises N-acylating a thiolincosaminide compound of formula: ##STR47## wherein Y and R 4  are as defined above; with a mixed anhydride of formula: ##STR48## wherein G and R 5  are as defined above; b is an integer of from 1 to 3, at a temperature of from about -10° C. to 5° C. 
     
     
       13. A process according to claim 12 wherein said thiolincosaminide is solubilized in an aliphatic alcohol having a molecular weight of at least about 60 prior to N-acylation. 
     
     
       14. A process according to claim 12 wherein said thiolinocosaminide compound reactant is methyl 6(R),7(R)-aziridino-6-deamino-7-deoxy-α-thiolincosaminide, said mixed anhydride in N-[1-carbobenzoxy-trans-4-propyl-L-prolyl]-butylcarbonic anhydride and the product of the process is methyl N-[1-carbobenzoxy-trans-4-propyl-L-propyl-6(R),7(R)-aziridino-6-deamino-7-deoxy-α-thiolinocosaminide. 
     
     
       15. A process for preparing compounds of the formula: ##STR49## wherein G is selected from lower alkyl and a amino protecting group removable by hydrogenolysis; R 4  and r 5  are each lower alkyl; Y is selected from hydrogen and carboxacyl of from 2 to 18 carbon atoms, inclusive; A is selected from hydrogen and hydroxyl; B is selected from hydrogen and monohydroxyloweralkyl; n is the integer 0 when B is monohydroxyloweralkyl and n is an integer of from 0 to 1, inclusive, when B is hydrogen; X is .[.selected from.]. oxygen .[.and sulfur.]., and D is the acyl radical of a lower hydrocarbon carboxylic acid, which comprises: 
     
     
       1. reacting together an appropriate aziridine of formula: ##STR50## wherein Y and R 4  are as defined above; and an appropriate mixed anhydride of formula: ##STR51## wherein G and R 5  are as previously defined and b is an integer of from 1 to 3, inclusive; at a temperature of from about -10° C. to about 5° C.; 
     
     
       2. warming the reaction mixture so obtained to a temperature of from about 25° C. to about 180° C.; and 3. adding to said warmed reaction mixture (I) an appropriate sulfur compound of the formula: ##STR52## wherein A, B, X and n are as defined above and (II) an anhydrous lower hydrocarbon carboxylic acid.   
     
     
       16. The process of claim 15 wherein methyl 6(R),7(R)-aziridino-6-deamino-7-deoxy-α-thiolincosaminide is reacted with N-[1-carbobenzoxy-trans-4-propyl-L-prolyl]-butylcarbonic anhydride in step (1.) and the product thereof is added to 1,3-oxathiolane and acetic acid in step (3.) whereby there is obtained) methyl N-(1-carbobenzoxy-trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio-α-thiolincosaminide. 
     
     
       17. A process for preparing compounds of the formula: ##STR53## wherein R 4  and R 5  each represent lower alkyl; Y is selected from carboxacyl of from 2 to 18 carbon atoms, inclusive, and hydrogen; A is selected from hydrogen and hydroxy; B is selected from hydrogen and monohydroxyloweralkyl; n is the integer 0 when B is monohydroxyloweralkyl and n is an integer of from 0 to 1, inclusive, when B is hydrogen; X is .[.selected from.]. oxygen .[.and sulfur.].; and D is the acyl radical of a lower hydrocarbon carboxylic acid, which comprises: 
     
     
       1. reacting together in appropriate aziridine compound of formula: ##STR54## wherein Y and r 4  are as defined above; and an appropriate mixed anhydride of formula: ##STR55##wherein R 5  is as defined above, J is an amino protecting group removable by hydrogenolysis and b is an integer of from 1 to 3, inclusive; at a temperature of from about -10° C. to about 5° C.; 
     
     
       2. warming the reaction mixture so obtained to a temperature of from about 25° C. to about 50° C.; 3. subjecting said warmed reaction mixture to catalytic hydrogenation; and   4. adding to said hydrogenated mixture (I) an appropriate sulfur compound of the formula: ##STR56## wherein A, B, X and n are as defined above and (II) an anhydrous lower hydrocarbon carboxylic acid.   
     
     
       18. A compound of the formula: ##STR57## wherein R 4  and R 5  are each lower alkyl and Y is selected from hydrogen and carboxyacyl of from 2 to 18 carbon atoms, inclusive. 
     
     
       19. A compound according to claim 18 which is methyl N-[trans-4-propyl-L-prolyl]-6(R),7(R)-aziridino-6-deamino-7-deoxy-α-thiolincosaminide. 
     
     
       20. A compound according to claim 2 which is methyl N-(1-carbobenzoxy-trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio-α-thiolincosaminide. 
     
     
       21. A compound according to claim 9 which is methyl N-(1-methyl-trans-4-propyl-L-prolyl)-6(R),7(R)-aziridino-6-deamino-7-deoxy-α-thiolincosaminide.