US2006019371A1PendingUtilityA1

Macrolide analogs

55
Assignee: KHOSLA CHAITANPriority: Sep 20, 1993Filed: Jan 14, 2005Published: Jan 26, 2006
Est. expirySep 20, 2013(expired)· nominal 20-yr term from priority
Inventors:Chaitan KhoslaGary AshleyCamilla KaoRobert Mcdaniel
C12N 9/93C12P 17/08C12P 17/06C07D 407/06C07D 309/36C07D 311/92C12N 15/52C12P 7/26C07D 313/00C07D 323/00C07H 17/08C12P 17/162C40B 40/00
55
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Claims

Abstract

Combinatorial libraries of polyketides can be obtained by suitable manipulation of a host modular polyketide synthase gene cluster such as that which encodes the PKS for erythromycin. The combinatorial library is useful as a source of pharmaceutically active compounds. In addition, novel polyketides and antibiotics are prepared using this method.

Claims

exact text as granted — not AI-modified
1 . A compound of the formula:  
       
         
           
           
               
               
           
         
         wherein R1, R2, R3, R4, R5, and R6 are independently selected from Q wherein Q is selected from the group consisting of (a) —H, (b) —Me, (c) —Et, and (d) —OH;  
         L1 and L2 are independently —H or —OH;  
         L3 is D-desosamine or —OH; and  
         L4 is L-mycarose, L-cladinose or —OH  
         with the proviso that when R 1 -R 5  are —ME, R 6  is other than —H or —Me.  
       
     
     
         2 . The compound of  claim 1  wherein Q is selected from the group consisting of (a), (b), and (c) and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         3 . The compound of  claim 1  wherein Q is selected from the group consisting of (a), (b), and (d) and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         4 . The compound of  claim 1  wherein Q is selected from the group consisting of (a), (c), and (d) and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         5 . The compound of  claim 1  wherein Q is selected from the group consisting of (b), (c), and (d) and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         6 . The compound of  claim 1  wherein Q is selected from the group consisting of (a) and (b) and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         7 . The compound of  claim 1  wherein Q is selected from the group consisting of (a) and (c) and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         8 . The compound of  claim 1  wherein Q is selected from the group consisting of (a) and (d) and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         9 . The compound of  claim 1  wherein Q is selected from the group consisting of (b) and (c) and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         10 . The compound of  claim 1  wherein Q is selected from the group consisting of (b) and (d) and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         11 . The compound of  claim 1  wherein Q is selected from the group consisting of (c) and (d) and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         12 . The compound of  claim 1  wherein Q is (a) and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         13 . The compound of  claim 1  wherein Q is (c) and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         14 . The compound of  claim 1  wherein Q is (d) and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         15 . The compound of  claim 1  wherein 
 (a) R 6  and R 1  are —H and R 2 , R 3 , R 4  and R 5  are —Me,    (b) R 5  and R 1  are —H and R 2 , R 3 , R 4  and R 6  are —Me,    (c) R 4  and R 1  are —H and R 2 , R 3 , R 5  and R 6  are —Me,    (d) R 3  and R 1  are —H and R 2 , R 4 , R 5  and R 6  are —Me,    (e) R 2  and R 1  are —H and R 3 , R 4 , R 5  and R 6  are —Me,    (f) R 6  and R 2  are —H and R 1 , R 3 , R 4  and R 5  are —Me,    (g) R 5  and R 2  are —H and R 1 , R 3 , R 4  and R 6  are —Me,    (h) R 4  and R 2  are —H and R 1 , R 3 , R 5  and R 6  are —Me,    (i) R 3  and R 2  are —H and R 1 , R 4 , R 5  and R 6  are —Me,    (j) R 6  and R 3  are —H and R 1 , R 2 , R 4  and R 5  are —Me,    (k) R 5  and R 3  are —H and R 1 , R 2 , R 4  and R 6  are —Me,    (l) R 4  and R 3  are —H and R 1 , R 2 , R 5  and R 6  are —Me,    (m) R 6  and R 4  are —H and R 1 , R 2 , R 3  and R 5  are —Me,    (n) R 5  and R 4  are —H and R 1 , R 2 , R 3  and R 6  are —Me,    (o) R 6  and R 5  are —H and R 1 , R 2 , R 3  and R 4  are —Me, and    L 1 , L 2 , L 3  and L 4  are as defined therein.    
     
     
         16 . The compound of  claim 15  wherein (a)-(o) are as defined therein, L 1  and L 2  are —OH, L 3  is D-desosamine and L 4  is L-cladinose.  
     
     
         17 . The compound of  claim 1  wherein 
 (a) R 6 , R 2  and R 1  are —H and R 3 , R 4  and R 5  are —Me,    (b) R 5 , R 2  and R 1  are —H and R 3 , R 4  and R 6  are —Me,    (c) R 4 , R 2  and R 1  are —H and R 3 , R 5  and R 6  are —Me,    (d) R 3 , R 2  and R 1  are —H and R 4 , R 5  and R 6  are —Me,    (e) R 6 , R 3  and R 1  are —H and R 2 , R 4  and R 5  are —Me,    (f) R 5 , R 3  and R 1  are —H and R 2 , R 4  and R 6  are —Me,    (g) R 4 , R 3  and R 1  are —H and R 2 , R 5  and R 6  are —Me,    (h) R 6 , R 4  and R 1  are —H and R 2 , R 3  and R 5  are —Me,    (i) R 5 , R 4  and R 1  are —H and R 2 , R 3  and R 6  are —Me,    (j) R 6 , R 5  and R 1  are —H and R 2 , R 3  and R 4  are —Me,    (k) R 6 , R 3  and R 2  are —H and R 1 , R 4  and R 5  are —Me,    (l) R 5 , R 3  and R 2  are —H and R 1 , R 4  and R 6  are —Me,    (m) R 4 , R 3  and R 2  are —H and R 1 , R 5  and R 6  are —Me,    (n) R 6 , R 4  and R 2  are —H and R 1 , R 3  and R 5  are —Me,    (o) R 5 , R 4  and R 2  are —H and R 1 , R 3  and R 6  are —Me,    (p) R 6 , R 5  and R 2  are —H and R 1 , R 3  and R 4  are —Me,    (q) R 6 , R 4  and R 3  are —H and R 1 , R 2  and R 5  are —Me,    (r) R 5 , R 4  and R 3  are —H and R 1 , R 2  and R 6  are —Me,    (s) R 6 , R 5  and R 3  are —H and R 1 , R 2  and R 4  are —Me, or    (t) R 6 , R 5  and R 4  are —H and R 1 , R 2  and R 3  are —Me, and    L 1 , L 2 , L 3  and L 4  are as defined therein.    
     
     
         18 . The compound of  claim 17  wherein (a)-(t) are as defined therein, L 1  and L 2  are —OH, L 3  is D-desosamine and L 4  is L-cladinose.  
     
     
         19 . The compound of  claim 1  wherein 
 (a) R 6 , R 3 , R 2  and R 1  are —H and R 5 , and R 4  are —Me,    (b) R 5 , R 3 , R 2  and R 1  are —H and R 6 , and R 4  are —Me,    (c) R 4 , R 3 , R 2  and R 1  are —H and R 5 , and R 6  are —Me,    (d) R 6 , R 4 , R 2  and R 1  are —H and R 3 , and R 5  are —Me,    (e) R 5 , R 4 , R 2  and R 1  are —H and R 3 , and R 6  are —Me,    (f) R 6 , R 5 , R 2  and R 1  are —H and R 3 , and R 4  are —Me,    (g) R 6 , R 4 , R 3  and R 1  are —H and R 2 , and R 5  are —Me,    (h) R 5 , R 4 , R 3  and R 1  are —H and R 2 , and R 6  are —Me,    (i) R 6 , R 5 , R 4  and R 1  are —H and R 2 , and R 3  are —Me,    (j) R 2 , R 4 , R 3  and R 1  are —H and R 5 , and R 6  are —Me,    (k) R 6 , R 4 , R 3  and R 2  are —H and R 1 , and R 5  are —Me,    (l) R 5 , R 4 , R 3  and R 2  are —H and R 1 , and R 6  are —Me,    (m) R 6 , R 5 , R 3  and R 2  are —H and R 1 , and R 4  are —Me, or    (n) R 6 , R 5 , R 4  and R 3  are —H and R 1 , and R 2  are —Me, and    L 1 , L 2 , L 3  and L 4  are as defined therein.    
     
     
         20 . The compound of  claim 19  wherein (a)-(n) are as defined therein, L 1  and L 2  are —OH, L 3  is D-desosamine and L 4  is L-cladinose.  
     
     
         21 . The compound of  claim 1  wherein 
 (a) R 5 , R 4 , R 3 , R 2  and R 1  are —H and R 6  is —Me,    (b) R 6 , R 4 , R 3 , R 2  and R 1  are —H and R 5  is —Me,    (c) R 6 , R 5 , R 3 , R 2  and R 1  are —H and R 4  is —Me,    (d) R 6 , R 5 , R 4 , R 2  and R 1  are —H and R 3  is —Me,    (e) R 6 , R 5 , R 4 , R 3  and R 1  are —H and R 2  is —Me, or    (f) R 6 , R 5 , R 4 , R 3  and R 2  are —H and R 1  is —Me, and    L 1 , L 2 , L 3  and L 4  are as defined therein.    
     
     
         22 . The compound of  claim 21  wherein (a)-(f) are as defined therein, L 1  and L 2  are —OH, L 3  is D-desosamine and L 4  is L-cladinose.  
     
     
         23 . The compound of  claim 1  wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are —H and L 1 , L 2 , L 3  and L 4  are as defined therein.  
     
     
         24 . The compound of  claim 23  wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are as defined therein, L 1  and L 2  are —OH, L 3  is D-desosamine and L 4  is L-cladinose.  
     
     
         25 . The compound of  claim 1  selected from the group consisting of 6,10-didesmethyl-6-ethylerythromycin A; 10,12-didesmethyl-12-deoxy-12-ethylerythromycin A; 10,12-didesmethyl-12-deoxy-10-hydroxyerythromycin A: 6,10,12-tridesmethyl-6,12-diethylerythromycin A, and 6,10,12-tridesmethyl-6-deoxy-6,12-diethylerythromycin A.  
     
     
         26 . The compound of  claim 1  selected from the group consisting of 10-desmethylerythronolide B, 10-desmethyl-6-deoxyerythronolide B, 12-desmethylerythronolide B, 12-desmethyl-6-deoxyerythronolide B, 12-desmethyl-12-ethylerythronolide B, 6-desmethyl-6-deoxy-6-ethylerythronolide B, 10-desmethylerythromycin A, 10-desmethyl-12-deoxyerythromycin A, 10-desmethyl-6,12-dideoxyerythromycin A, 12-desmethylerythromycin A, 12-desmethyl-12-deoxyerythromycin A, 12-desmethyl-6,12-dideoxyerythromycin A, 6-desmethyl-6-ethylerythromycin A, 12-desmethyl-12-ethylerythromycin A, 12-desmethyl-12-deoxy-12-ethylerythromycin A, 10-desmethyl- 10-hydroxyerythromycin A, 12-desmethyl-12-epihydroxyerythromycin A, 10,12-didesmethylerythromycin A, 10,12-didesmethyl-12-deoxyerythromycin A, and 10,12-didesmethyl-6,12-dideoxyerythromycin A.  
     
     
         27 . The compound of  claim 1  selected from the group consisting of 10-desmethylerythronolide B, 10-desmethyl-6-deoxyerythronolide B, 12-desmethylerythronolide B, 12-desmethyl-6-deoxyerythronolide B, 10-desmethylerythromycin A, 10-desmethyl-12-deoxyerythromycin A, 10-desmethyl-6,12-dideoxyerythromycin A, 12-desmethylerythromycin A, 12-desmethyl-12-deoxyerythromycin A, 12-desmethyl-6,12-dideoxyerythromycin A, 10,12-didesmethylerythromycin A, 10,12-didesmethyl-12-deoxyerythromycin A, and 10,12-didesmethyl-6,12-dideoxyerythromycin A.  
     
     
         28 . A compound selected from the group consisting of 10-desmethylerythromycin A, 10-desmethyl-12-deoxyerythromycin A, and 12-desmethyl-12-deoxyerythromycin A.  
     
     
         29 . The compound 6-desmethyl-6-ethylerythromycin A.

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