Macrolide antibiotics

• US 20040077557A1
• Filed: 11/19/2003
• Published: 04/22/2004
• Est. Priority Date: 12/21/2000
• Status: Abandoned Application

• Current Assignee: Glaxo Group Limited (GSK plc), PLIVA dd (Teva Pharmaceutical Industries Limited)
• Original Assignee: Glaxo Group Limited (GSK plc)
• Inventors: Ciraco, Manuela, Ali, Sulejman, Terreni, Silvia, Biondi, Stefano, Mingardi, Anna, Damiani, Federica, Andreotti, Daniele, Tarsi, Luca, Lociuro, Sergio, Cardullo, Francesca, Seri, Catia, Tibasco, Jessica, Arista, Luca, Merlo, Giancarlo, Pozzan, Alfonso, Paio, Alfredo, Niccolai, Daniela, Marchioro, Carla, Piga, Elisabetta
• Application Number:
  US10/450,893
• Publication Number:
  US 20040077557A1
• Time in Patent Office: Days
• US Class Current: 514/28
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: C07H 17/08 Hetero rings containing eight or more ring members, e.g. erythromycins
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to 11,12 γ lactone ketolides of formula (I) wherein R, R¹, R², R³ are as defined herein and pharmaceutically acceptable salts and solvates thereof, to process for their preparation and their use in therapy or prophylaxis of systemic or topical bacterial infections in a human or animal body.

Claims

1. A compound of formula (I)

2. A compound as claimed in claim 1 wherein R is (CH₂)_nA-X—

R₄ or (CH₂)_nR₅.

3. A compound as claimed in claim 1 or 2 wherein R₁ is methyl or 2-propenyl.

4. A compound as claimed in any claims 1 to 3 wherein R₂ is hydrogen.

5. A compound as claimed in any claims 1 to 4 wherein R₃ is hydrogen or fluorine.

6. A compound as claimed in any claims 1 to 5 wherein A is selected from —

NH—

, —

NHC(O)—

or —

NHC(Y)NH—

.

7. A compound as claimed in any claims 1 to 6 wherein X is a C_1-4 alkylene chain which is optionally interrupted by a bivalent radical selected from —

O—

, —

NH—

, —

C(O)—

, —

NHC(O)—

, —

S(O)₂—

—

S— and

/or such a C_1-4 alkylene chain is optionally substituted by one group selected from NH₂, C_1-4 alkyl, oxo or N—

OH.

8. A compound as claimed in any claims 1 to 7 wherein R₄ is phenyl (optionally substituted by 1 to 3 groups which may be the same or different selected from nitro, amino, methyl, C_1-4 alkoxy ie methoxy or hydroxy), 1-imidazolyl (optionally substituted by 1 to 3 groups which may be the same or different selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, phenyl, m-nitrophenyl, dichlorophenyl, C_1-4 alkyl i.e methyl, trifluoromethylphenyl, thiophen-2-yl, thiazol-2-yl), 3-trifluoromethylpyraol-4-yl, 1-pyrazolyl (optionally substituted by 1 to 3 groups which may be the same or different selected from alogen (i.e. chlorine, fluorine), pyridin-2-yl, pyridin-4-yl, quinolin-2-yl, quinolin-4-yl, quinoxalin-2-yl, pyrimidin-4-yl, C_1-4 alkyl i.e methyl, 1,3 benzooxazol-2-yl, p-chloro phenyl, difluoro phenyl, pyrazin-2-yl thiazol-5-yl) 1H-indol-3-yl, 1H-indol-2-yl, 3-methoxy-quinoxalin-2-yl, 2-quinolinyl 3-quinolinyl, 4-quinolinyl, 4-pyridinyl, 3-pyridinyl(optionally substituted by one amino), 5methyl furan-2-yl, 3-thiophenyl, 6-methoxy-7H-purin-7-yl, quinoxalin-2-yl, 3-methoxy quinoxalin-2-yl 6-methoxy-2-oxo-1,3-benzoxazol-3(2H)-yl, 1H-pyrrolo [2,3-b]pyridin-1-yl, 2-(methylthio)-1H-benzimidazol-1-yl, 1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl, 6-methoxy-2-oxo-1,3-benzoxazol-3(2H)-yl, 3H-imidazo[4,5-b]pyridin-3-yl, 1,3-benzoxazol-2-yl, benzothiazol-2-yl, 1,3 benzo[1,3]dioxolyl, 3-(5-cyano-3,4-dimethylthien-2-yl)-1H-1,2,4-triazol-1-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 2,4-dimethyl-1,3-thiazol-5-yl or 4-oxo-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl.

9. A compound as claimed in any claims 1 to 8 wherein R₁ is methyl, R₂ or R₃ is hydrogen, A is —

NH—

, —

NHC(O), X is C_1-4 alkylene chain which is optionally interrupted by a bivalent radical selected from —

O—

, —

NH—

, —

C(O)—

, —

NHC(O)—

, —

S(O)₂—

—

S— and

/or such a C_1-4 alkylene chain is optionally substituted by one group selected from NH₂, C_1-4 alkyl, oxo or N—

OH, R₄ is a group selected from 4-(pyridin-3-yl)-imidazol-1-yl, 4-(pyridin-3-yl)-imidazol-1-yl, quinoxalin-2-yl, quinoxalin-2-yl, quinolin-4-yl, quinoxalin-2-yl, -(2,3-dihydro-benzo[1,4]dioxin-6-yl, 4-oxo-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl, 4-methoxy-3-nitro-phenyl, 2-hydroxy-4,5-dimethoxy-phenyl, 3-hydroxy-4-methoxy-phenyl, 3,4-dimethoxy-phenyl, 4-hydroxy-3-methoxy-phenyl, 3-methoxy-quinoxalin-2-yl, 3-amino-4-methoxy-phenyl, 4-(pyridin-3-yl)-imidazol-1-yl, quinolin-4-yl, 4-pyrimidin-4-yl-pyrazol-1-yl, 2-(methylthio)-1H-benzimidazol-1-yl, -[3-(4-chlorophenyl)-1H-pyrazol-5-yl]propylamino) -methylene], 6-methoxy-2-oxo-1,3-benzoxazol-3(2H)-yl, 1H-pyrrolo[2,3-b]pyridin-1-yl, 3-(2,4-dimethyl-1,3-thiazol-5-yl)-1H-pyrazol-1-yl, 4-phenyl-1H-imidazol-1-yl, 4-pyridin-4-yl 1H-imidazol-1-yl, thiophen-2-yl, 3-(5-cyano-3,4-dimethylthien-2-yl)-1H-1,2,4-triazol-1-yl, quinolin-3-yl, 1,3-thiazol-2-yl and n is 0 or 1.

11. A process for the preparation of a compound of formula (I) which comprises:

a) reacting a compound of formula (II)

wherein R₁, R₂, R₃ have the meanings defined in claim 1, R₁₁ is a cladinose derivative of formula (III), in which R_2a is a hydroxy protecting group, or hydroxy, R₁₂ is hydrogen or R₁₁ together R₁₂ is an oxygen atom, with a suitable activated derivative of the acid (IV) HOC(O)XR₄ (IV) or with a suitable activated derivative of the sulfonic acid (V) HOS(O)₂XR₄ (V) respectively wherein R₄ and X have the meanings defined in claim 1, to produce a compound of formula (I) wherein R is (CH₂)_nA-X—

R₄, A is —

N(R₆)C(O)—

or —

N(R₆)S(O)₂—

X and n have the meanings defined in claim 1;

b) reacting a compound of formula (II) with a compound of formula R₄XN(R₇)C(Y)L (VI), wherein L is a suitable leaving group, R₆ is phenyl or C_1-4 alkyl, R₄ and X have the meanings defined in claim 1, to produce a compound of formula (I) wherein R is (CH₂)_nA -X—

R₄, A is —

N(R₆)C(Y)N(R₇)—

and X and n have the meanings defined in claim 1;

c) reacting a compound of formula (II) with a compound of formula R₄XN═

C(Y) (VII), wherein R₄ and X have the meanings defined in claim 1, to produce a compound of formula (I) wherein R is (CH₂)_nA-X—

R₄, A is —

N(R₆)C(Y)NH—

, X and n have the meanings defined in claim 1;

d) reacting a compound of formula (II) with a compound of formula R₄XL (VIII), wherein R₄ and X have the meanings defined in claim 1 and L is suitable leaving group, to produce a compound of formula (I) wherein R is (CH₂)_nA-X—

R₄, A is —

N(R₆)—

, X and n have the meanings defined in claim 1;

e) reacting a compound of formula (II) with a compound of formula R₄XOC(O)L (IX) wherein L is a suitable leaving group such as halogen (e.g. chlorine or bromine), R₄ and X have the meanings defined in claim 1, to produce a compound of formula (I) wherein R is (CH₂)_nA-X—

R₄, A is N(R₆)C(O)O, X and n have the meanings defined in claim 1;

f) reacting a compound of formula (II) with a compound of formula R₄XCHO (X), wherein R₄ and X have the meanings defined in claim 1, to produce a compound of formula (I) wherein R is (CH₂)_nA-X—

R₄, A is N═

C(R₆), X and n have the meanings defined in claim 1;

g) reacting a compound of formula (XI), in which R₁₁ and R₁₂ have the meaning as defined for compounds of formula (II), wherein R₁, R₂, R₃, R₄ and X have the meanings defined in claim 1, with a compound of formula R₆COOH (XIa),

to produce a compound of formula (I) wherein R is (CH₂)_nA-X—

R₄, A is N═

C(R₆), X and n have the meanings defined in claim 1;

h) decarboxylation of a compound of formula (XII), wherein R₁, R₂ and R₃ have the meanings defined in claim 1, R₁₁ and R₁₂ have the meaning as defined for compounds of formula (II),

to produce a compound of formula (I) wherein R is hydrogen;

i) cyclisation of chlorine derivatives (I wherein R₁, R₂ and R₃ have the meanings defined in claim 1, R₁₁ and R₁₂ have the meaning as defined for compounds of formula (II),

to produce a compound of formula (I) wherein R is cyano;

l) reacting a compound of formula (XVII), wherein R₁, R₂ and R₃ have the meanings defined in claim 1, R₁ and R₁₂ have the meaning defined in formula (II) and R₁₃ is C_1-4 alkyl, with an aldehyde of formula

wherein R₄, X and n have the meanings defined in claim 1, to produce a compound of formula(I) wherein R is (CH₂)_nAXR₄ A and X have the meanings defined in claim 1;

and n is an integer from 2 or 3;

m) reacting a compounds of formula (I) in which R₁ has the meanings defined in claim 1, R₃ is hydrogen and R₂ is hydroxy protecting group with a halogenating agent to produce a compound of formula (I) wherein R₃ is halogen;

n) cyclisation of a compound of formula (XXXII), wherein L is suitable leaving group such halogen (i.e chlorine or bromine), R₁, R₂, R₃ have the meanings defined in claim 1, R₁₁ and R₁₂ have the meaning defined in formula (II), X is C_4-5 alkylene chain optionally substituted by one or two groups selected from oxo, 9 or 10 membered fused bicyclic heterocyclic having at least one heteroatom selected from oxygen, sulphur or nitrogen,

to produce a compound of formula (I) wherein R₁ is (CH₂)_nR₅;

and thereafter, if required, subjecting the resulting compound to one or more of the following operations;

i) hydrolysis of the cladinose derivative (III);

ii) conversion of the 3-hydroxy group into the 3-oxo,

iii) removal of the protecting group R₂ and

iv) conversion of the resultant compound of formula (I) into a pharmaceutically acceptable salt and solvates thereof.

12. A compound as claimed in any claims 1 to 10 for use in therapy.

13. The use of a compound as claimed in any claims 1 to 10 in the preparation of a medicament for use in the therapy of systemic or topical bacterial infections in a human or animal body.

14. The use of a compound as claimed in any claims 1 to 10 for use in the treatment or prophylaxis of systemic or topical bacterial infections in a human or animal body.

15. A pharmaceutical composition comprising a compound as claimed in any claims 1 to 10 in admixture with one or more pharmaceutically acceptable carriers or excipients.

16. A method for the treatment of the human or non human animal body to combat bacterial infection comprising administration of an effective amount of a compound as claimed in in any claims 1 to 10.

10. A compounds selected from:

(11S,21S)-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-2-(4-pyridin-3-yl)-imidazol-1-yl)-ethylamino)-methylene]-erythromycin A;

(11S,21S)-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-2(quinolin-4-yl)-ethylamino)-methylene]-erythromycin A;

(11S,21S)-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(3-(4-(pyridin-3-yl)-imidazol-1-yl)-propylamino)-methylene]-erythromycin A;

(11S,21 S)-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(2(quinoxalin-2-ylsulfanyl)-acetamido)-methylene]-erythromycin A;

(11S, 21S)-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-((4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-4-oxo)-butyramido)-methylene]-erythromycin A;

(11S,21S)-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-methoxy-3-nitro-phenyl)-4-oxo-butyramido)-methylene]-erythromycin A;

(11S,21 S)-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(2-hydroxy-4,5-dimethoxy-phenyl)-4-oxo-butyramido)-methylene]-erythromycin A;

(11S,21S)-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-oxo-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-4-oxo-butyramido)-methylene]-erythromycin A;

(11S,21 S)-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-3-(4-quinolin-2-yl-1H-pyrazol-1-yl)-propylamino)-methylene]-erythromycin A;

(11S,21S)-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(3,4-dimethoxy-phenyl)-4-oxo-butyramido)-methylene]-erythromycin A;

(11S, 21S)-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(4-(4-hydroxy-3-methoxy-phenyl)-4-oxo-butyramido)-methylene]-erythromycin A;

(11 S, 21S)-3-decladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-[oxycarbonyl-(3-(4-(thiophen-2-yl)-imidazol-1-yl)-propylamino)-methylene]-erythromycin A.