# US 7,608,596 B2 · 10-substituted macrolide antibiotics

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- Number: US 7,608,596 B2
- Document ID: US7608596B2
- Status: Granted
- Kind: B2
- Application number: 10/539,759
- Filed: 2003-12-22
- Published: 2006-10-26
- Granted: 2009-10-27
- Earliest claimed: 2002-12-20
- Assignees: C10 Pharma AS
- Inventors: Kjell Undheim; Solvi Gunnes
- Web page: https://patentgrep.com/patent/US7608596B2

## CPC

- C07H 17/08: Hetero rings containing eight or more ring members, e.g. erythromycins
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed herein are 10-desmethyl, 10 substituted-macrolides, their preparation, pharmaceutical compositions containing them, their use and methods of treatment using them. The 10-desmethyl macrolides are particularly useful as antibiotics.

## Claims

### Claim 1

A 10-desmehtyl macrolide consisting of formula III:
(1) R is methyl substituted with one or more substituents selected from the group consisting of
(i) CN,
(ii) F,
(iii) CO2R3 wherein R3 is selected from hydrogen, C1-C3-alkyl or aryl substituted C1-C3-alkyl, or heteroaryl substituted C1-C3-alkyl,
(iv) OR4 wherein R4 is selected from hydrogen, C1-C4-alkyl or aryl substituted C1-C4-alkyl, or heteroaryl substituted C1-C4-alkyl, heterocycloalkyl and optionally substituted cycloalkyl, C1-C3-alkoxy-C1-C3-alkoxy, C2-C4-alkenyl or aryl substituted C2-C4-alkenyl, or heteroaryl substituted C2-C4-alkenyl, heterocycloalkyl and optionally substituted cycloalkyl, aryl or optionally substituted aryl, heteroaryl or optionally substituted heteroaryl,
(v) S(O)nR3 wherein n=0, 1 or 2 and R3 is as previously defined
(vi) NR4C(O)R3 wherein R3 and R4 are as previously defined
(vii) NR4C(O)NR5R6 wherein R4 is defined as defined previously, and R5 and R6 are independently selected from hydrogen, C1-C3-alkyl, C1-C3 alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl
(viii) NR7R8 wherein R7 and R8 are independently selected from the group consisting of
(a) hydrogen
(b) C1-C12-alkyl, and optionally substituted C1-C12-alkyl
(c) C2-C12-alkenyl, and optionally substituted C2-C12-alkenyl
(d) C2-C12-alkynyl, and optionally substituted C2-C12-alkynyl
(e) aryl, and optionally substituted aryl
(f) heteroaryl, and optionally substituted heteroaryl
(g) heterocycloalkyl, and optionally substituted heterocycloalkyl
(h) C1-C12 alkyl substituted with aryl, and optionally substituted with substituted aryl
(i) C1-C12 alkyl substituted with heteroaryl, and optionally substituted with substituted heteroaryl
(j) C1-C12 alkyl substituted with heterocycloalkyl, and with optionally substituted heterocycloalkyl, and
(k) R7 and R8 taken together with the atom to which they are attached from a 3-10- membered heterocycloalkyl ring which may contain one or more additional heteroatoms and may be substituted with one or more substituents independently selected from the group consisting of
(aa) halogen, hydroxy, C1-C3-alkoxy, alkoxy-C1-C3-alkoxy, oxo, C1-C3-alkyl, aryl and optionally substituted aryl, heteroaryl and optional substituted heteroaryl
(bb) CO2R3 wherein R3 is as previously defined, and
(cc) C(O)NR5R6 wherein R5 and R6 are as previously defined,
(ix) aryl, and optionally substituted aryl, and
(x) heteroaryl, and optionally substituted heteroaryl,
(2) C2-C10-alkyl,
(3) C2-C10-alkyl substituted with one or more substituents selected from the group consisting of
(i) halogen,
(ii) OR4 wherein R4 is as defined previously
(iii) —CHO,
(iv) oxo,
(v) NR7R8 wherein R7 and R8 are defined as previously
(vi) ═N—O—R4 is wherein R3 is as previously defined
(vii) —CN
(viii) —S(O)nR3 wherein n=0, 1 or 2 and R3 is as previously defined
(ix) aryl, and optionally substituted aryl
(x) heteroaryl, and optionally substituted heteroaryl
(xi) C3-C8-cycloalkyl, and optionally substituted C3-C8-cycloalkyl
(xii) heterocycloalkyl, and optionally substituted heterocycloalkyl
(xiii) NR4C(O)R3 where R3 and R4 are as previously defined
(xiv) NR4C(O)NR5R6 wherein R4, R5 and R6 are as previously defined
(xv) ═N—NR7R8 wherein R7 and R8 are as previously defined
(xvi) ═N—R4 wherein R4 is as previously defined
(xvii) ═N—NR4C(O)R3 wherein R3 and R4 are as previously defined, and
(xviii) ═N—NR4C(O)NR5R6 wherein R4, R5 and R6 are as previously defined,
(4) C2-C10-alkenyl,
(5) C2-C10-alkenyl substituted with one or more substituents selected from the group consisting of
(i) halogen,
(ii) OR4 wherein R4 is as previously defined
(iii) O—S(O)nR3 where n and R3 are as previously defined
(iv) —CHO,
(v) oxo,
(vi) —CO2R3 where R3 is as previously defined
(vii) —C(O)—R4 where R4 is as previously defined
(viii) —CN
(ix) aryl, and optionally substituted aryl
(x) heteroaryl, and optionally substituted heteroaryl
(xi) C3-C7-cycloalkyl
(xii) C1-C12-alkyl substituted with heteroaryl
(xiii) NR7R8 wherein R7 and R8 are as previously defined
(xiv) NR4C(O)R3 where R3 and R4 are as previously defined
(xv) NR4C(O)NR5R6 where R4, R5 and R6 are as previously defined
(xvi) ═N—O—R4 where R4 is as previously defined
(xvii) ═N—NR7R8 wherein R7 and R8 are as previously defined
(xviii) ═N—NR4 wherein R4 is as previously defined
(xix) ═N—NR4C(O)R3 wherein R3 and R4 are as previously defined, and
(xx) ═N—NR4C(O)NR5R6 wherein R4, R5 and R6 are as previously defined,
(6) C2-C10-alkynyl
(7) C2-C10-alkynyl substituted with one or more substituents selected from the group consisting of
(i) trialkylsilyl
(ii) halogen,
(iii) —CN
(iv) OR4 where R4 is defined as previously
(v) —CHO,
(vi) oxo,
(vii) —CO2R3 where R3 is as previously defined
(viii) —C(O)NR5R6 wherein R5 and R6 are as previously defined
(ix) NR7R8 wherein R7 and R8 are as previously defined
(x) O—S(O)nR3 where n and R3 are as previously defined
(xi) C3-C7-cycloalkyl
(xii) C1-C12-alkyl substituted with heteroaryl
(xiii) aryl, and optionally substituted aryl
(xiv) heteroaryl, and optionally substituted heteroaryl
(xv) NR4C(O)R3 where R3 and R4 are as previously defined
(xvi) NR4C(O)NR5R6 where R4, R5 and R6 are as previously defined
(xvii) ═N—O—R4 where R4 is as previously defined
(xviii) ═N—NR7R8 wherein R7 and R8 are as previously defined
(xix) ═N—NR4C(O)R3 wherein R3 and R4 are as previously defined, and
(xx) ═N—NR4C(O)NR5R6 wherein R4, R5 and R6 are as previously defined,
(8) cyclic substituents selected from the group consisting of
(i) aryl, and optionally substituted aryl
(ii) heteroaryl, and optionally substituted heteroaryl
(iii) heterocycloalkyl, and optionally substituted heterocycloalkyl, and
(iv) C3-C7-cycloalkyl, and optionally substituted C3-C7-cycloalkyl, and
(9) C1 substituents with the exception of 10-methyl derivatives which are part of the above definitions under (1)
(i) —CHO
(ii) —CN
(iii) CO2R3 wherein R3 is as previously defined
(iv) C(O)NR5R6 wherein R5 and R6 are as previously defined
(v) C(S)NR5R6 wherein R5 and R6 are as previously defined
(vi) C(NR4)NR5R6 wherein R4, N5 and R6 are as previously defined
(vii) CH═N—O—R4 wherein R4 is as previously defined
(viii) CH═N—R4 is wherein R4 is as previously defined
(ix) CH═N—NR7R8 wherein R7 and R8 are as previously defined
(x) CH═N—NR4C(O)R3 wherein R3 and R4 are as previously defined, and
(xi) CH═N—NR4C(O)NR5R6 wherein R4, R5 and R6 are as previously defined;
R1 is selected from the group consisting of
(1) H
(2) methyl
(3) methyl substituted with one or more substituents selected from the group consisting of
(i) F
(ii) —CN
(iii) —CO2R11 where R11 is C1-C3-alkyl or aryl substituted C1-C3-alkyl, or heteroalkyl substituted C1-C3-alkyl
(iv) —C(O)NR5R6 wherein R5 and R6 are defined as previously
(v) aryl, and optionally substituted aryl, and
(vi) heteroaryl, and optionally substituted heteroaryl
(4) C2-C10-alkyl
(5) substituted C2-C10-alkyl with one or more substituents selected from the group consisting of
(i) halogen,
(ii) OR4 where R4 is defined as previously
(iii) C1-C3-alkoxy-C1-C3-alkoxy
(iv) —CHO
(v) oxo
(vi) NR7R8 wherein R7 and R8 are as previously defined
(vii) ═N—O—R4 where R4 is as previously defined
(viii) —CN
(ix) —S(O)nR3 where n=0, 1, or 2 and R3 is as previously defined
(x) aryl, and optionally substituted aryl
(xi) heteroaryl, and optionally substituted heteroaryl
(xii) C3-C8-cycloalkyl, and optionally substituted C3-C8-cycloalkyl
(xiii) C1-C12-alkyl substituted with heteroaryl, and optionally substituted heteroaryl
(xiv) heterocycloalkyl
(xv) NHC(O)R3 where R3 is as previously defined
(xvi) NHC(O)NR5R6 where R5 and R6 are as previously defined
(xvii) ═N—NR7R8 wherein R7 and R8 are as previously defined
(xviii) ═N—R4 wherein R4 as previously defined, and
(xix) ═N—NHC(O)R3 wherein R3 is as previously defined,
(4) C1-C10-alkenyl substituted with one or more substituents selected from the group consisting of
(i) halogen,
(ii) OR4 where R4 is as previously defined
(iii) —CHO
(iv) oxo
(v) —S(O)nR3 where n and R3 are as previously defined
(vi) —CN
(vii) —CO2R3 where R3 is as previously defined
(viii) NR7R8 wherein R7 and R8 are as previously defined
(ix) ═N—O—R4 where R4 is as previously defined
(x) —C(O)—R4 where R4 is as previously defined
(xi) —C(O)NR5R6 wherein R5 and R6 are as previously defined
(xii) aryl, and optionally substituted aryl
(xiii) heteroaryl, and optionally substituted heteroaryl
(xiv) C3-C7-cycloalkyl
(xv) C1-C12-alkyl substituted with heteroaryl
(xvi) NHC(O)R3 where R3 is as previously defined
(xvii) NHC(O)NR5R6 where R5 and R6 are as previously defined
(xviii) ═N—NR7R8 wherein R7 and R8 are as previously defined
(xix) ═N—R4 wherein R4 is as previously defined,
(xx) ═N—NHC(O)R3 wherein R3 is as previously defined, and
(xxi) ═N—NHC(O)NR5R6 wherein R5 and R6 are as previously defined,
(5) C2-C10-alkynyl, and
(6) C2-C10-alkynyl substituted with one or more substituents selected from the group consisting of
(i) halogen,
(ii) OR4 where R4 is defined as previously
(iii) —CHO
(iv) oxo
(v) —CO2R3 where R3 is as previously defined
(vi) —C(O)NR5R6 wherein R5 and R6 are as previously defined
(vii) —CN
(viii) NR7R8 wherein R7 and R8 are as previously defined
(ix) ═N—O—R4 where R4 is as previously defined
(x) —S(O)nR3 where n and R3 are as previously defined
(xi) aryl, and optionally substituted aryl
(xii) heteroaryl, and optionally substituted heteroaryl
(xiii) C3-C7-cycloalkyl
(xiv) C1-C12-alkyl substituted with heteroaryl
(xv) NHC(O)R3 where R3 is as previously defined
(xvi) NHC(O)NR5R6 where R5 and R6 are as previously defined
(xvii) ═N—NR7R8 wherein R7 and R8 are as previously defined
(xviii) ═N—R4 wherein R4 is as previously defined
(xix) ═N—NHC(O)R3 wherein R3 is as previously defined, and
(xx) ═N—NHC(O)NR5R6 wherein R5 and R6 are as previously defined;
R2 is selected from the group consisting of
(1) hydrogen
(2) OH
(3) OR3 where R3 is as previously defined
(4) OC(O)R3 where R3 is as previously defined, and
(5) O(CO)OR3 where R3 is as previously defined;
and X and Y taken together are selected from the group consisting of
(1) O
(2) NOR4 wherein R4 is as defined previously
(3) N—O C(R9)(CR10)—O—R4 where R4 is as previously defined and
(i) R9 and R10 are each independently defined as R4, or
(ii) R9 and R10 are taken together with the atom to which they are attached form a C3-C12 cycloalkyl ring,
(4) NR4 wherein R4 is as previously defined, and
(5) N—NR7R8 wherein R7 and R8 are as previously defined, or one of X and Y is hydrogen and the other is selected from the group consisting of
(1) —OR4 wherein R4 is as previously defined, and
(2) —NR7R8 wherein R7 and R8 are as previously defined
RP is selected from the group consisting of
(1) hydrogen
(2) R3 as previously defined
(3) COR3 where R3 is as previously defined
wherein aryl groups have 5 to 10 ring atoms, and heteroaryl groups have 5 to 10 ring atoms including C and at least one of N, O or S.

### Claim 2 (depends on 1)

A pharmaceutical composition comprising an antibiotic 10-desmethyl macrolide of claim 1 and a pharmaceutical excipient.

### Claim 3 (depends on 1)

A method of treatment of a human or animal subject to combat bacterial infection thereof, which method comprises administering to said subject an antibiotic 10-desmethyl macrolide of claim 1.