# US 7,612,037 B2 · Cross-linked glycopeptide-cephalosporin antibiotics

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- Number: US 7,612,037 B2
- Document ID: US7612037B2
- Status: Granted
- Kind: B2
- Application number: 11/977,604
- Filed: 2007-10-25
- Published: 2008-05-08
- Granted: 2009-11-03
- Earliest claimed: 2001-10-12
- Assignees: Theravance, Inc.
- Inventors: Paul R. Fatheree; Martin S. Linsell; Daniel D. Long; Daniel Marquess; Edmund J. Moran; Matthew B. Nodwell; S. Derek Turner; James Aggen
- Web page: https://patentgrep.com/patent/US7612037B2

## CPC

- A61K 31/545: Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: [IMAGE cpc-sch-A61K-0953.gif] , e.g. cephalosporins, {cefaclor, or cephalexine}
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- C07D 277/40: Unsubstituted amino or imino radicals
- C07D 277/42: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 407/12: linked by a chain containing hetero atoms as chain links
- C07D 407/14: containing three or more hetero rings
- C07D 501/00: Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: [IMAGE cpc-sch-C07D-0993.gif] , e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D 501/46: with the 7-amino radical acylated by carboxylic acids containing hetero rings
- C07K 9/008: {directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

This invention provides cross-linked glycopeptide-cephalosporin compounds and pharmaceutically acceptable salts thereof which are useful as antibiotics. This invention also provides pharmaceutical compositions containing such compounds; methods for treating bacterial infections in a mammal using such compounds; and processes and intermediates useful for preparing such compounds.

## Claims

### Claim 1

A compound of the formula:
or a salt thereof, wherein
X1 and X2 are independently selected from the group consisting of hydrogen and chloro;
R1 is —Ya—(W)n—Yb—;
W is selected from the group consisting of —O—, —N(Rd)—, —S—, —S(O)—, —S(O)2—, C3-6 cycloalkylene, C6-10 arylene and C2-9 heteroarylene; wherein each arylene, cycloalkylene and heteroarylene group is optionally substituted with 1 to 3 substituents independently selected from Rb;
Ya and Yb are independently C1-5 alkylene, or when W is cycloalkylene, arylene or heteroarylene, Ya and Yb are independently selected from the group consisting of a covalent bond and C1-5 alkylene; wherein each alkylene group is optionally substituted with 1 to 3 substituents independently selected from —ORd, —NRdRe, —CO2Rd, —C(O)NRdRe and —S(O)2NRdRe;
R2 is hydrogen or C1-6 alkyl;
one of R4 and R5 is hydroxy and the other is hydrogen;
R6 and R7 are independently hydrogen or methyl;
R8 is hydrogen or a group of formula (i):
each Ra is independently selected from the group consisting of —ORd, halo, —SRd, —S(O)Rd, —S(O)2Rd, —S(O)2ORd, —S(O)2NRdRe, —NRdRe, —CO2Rd, —OC(O)Rd, —C(O)NRdRe, —NRdC(O)Re, —OC(O)NRdRe, —NRdC(O)ORe, —NRdC(O)NRdRe, —CF3 and —OCF3;
each Rb is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and Ra;
each Rc is independently selected from the group consisting of C3-6 cycloalkyl, C6-10 aryl, C2-9 heteroaryl and C3-6 heterocyclic; wherein each cycloalkyl, aryl, heteroaryl and heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and Rf;
each Rd and Re is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-10 aryl, C2-9 heteroaryl and C3-6 heterocyclic; or Rd and Re are joined, together with the atoms to which they are attached, to form a C3-6 heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur; wherein each alkyl, alkenyl and alkynyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Re and Rf; and each aryl, cycloalkyl, heteroaryl and heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and Rf;
each Rf is independently selected from the group consisting of —OH, —OC1-6 alkyl, —SC1-6 alkyl, —F, —Cl, —NH2, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, —OC(O)C1-6 alkyl, —C(O)OC1-6 alkyl, —NHC(O)C1-6 alkyl, —C(O)OH, —C(O)NH2, —C(O)NHC1-6 alkyl, —C(O)N(C1-6 alkyl)2, —CF3 and —OCF3; and
n is 0 or 1.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein n is 0 and Ya and Yb are independently C1-5 alkylene groups wherein each alkylene group is optionally substituted with 1 to 3 substituents independently selected from —ORd, —NRdRe, —CO2Rd, —C(O)NRdRe and —S(O)2NRdRe.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein n is 0 and Ya and Yb are joined together to form a —(CH2)2-8— group.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein n is 0 and Ya and Yb are joined together to form a —CH2)2—, —(CH2)3—, —(CH2)4—, —(CH2)5— or —(CH2)6— group.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein n is 0 and Ya and Yb are joined together to form a —(CH2)3— group.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein n is 1 and Ya and Yb are the same or different and each is selected from the group consisting of a covalent bond and C1-5 alkylene optionally substituted with 1 to 3 substituents selected from —ORd, —NRdRe, —CO2Rd, —C(O)NRdRe and —S(O)2NRdRe.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein W is C6-10 arylene or —O—.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein n is 1 and Ya and Yb are both —CH2— and W is C6-10 arylene optionally substituted with 1 to 3 substituents independently selected from Rb.

### Claim 9 (depends on 8)

The compound according to claim 8, wherein W is phenylene.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein n is 1 and Ya and Yb are both —CH2CH2— and W is —O—.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein R2 is hydrogen.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein R4 is hydroxy; R5 is hydrogen; R6 is hydrogen; R7 is methyl; R8 is hydrogen; and X1 and X2 are both chloro.

### Claim 13 (depends on 12)

The compound according to claim 12, wherein R1 is —Ya—(W)n—Yb—, where n is 0 and Ya and Yb are joined together to form a —(CH2)3— group; and R2 is hydrogen.