# US 7,612,103 B2 · Pleuromutilin derivatives as antimicrobials

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- Number: US 7,612,103 B2
- Document ID: US7612103B2
- Status: Granted
- Kind: B2
- Application number: 10/521,926
- Filed: 2003-07-23
- Published: 2005-11-10
- Granted: 2009-11-03
- Earliest claimed: 2002-07-24
- Assignees: Nabriva Therapeutics AG
- Inventors: Heinz Berner; Gabriele Kerber
- Web page: https://patentgrep.com/patent/US7612103B2

## CPC

- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/45: having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- C07D 207/12: Oxygen or sulfur atoms
- C07D 211/20: with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D 211/54: Sulfur atoms
- C07D 211/56: Nitrogen atoms (nitro radicals C07D211/38)
- C07D 211/58: attached in position 4
- C07D 211/60: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 211/72: with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D 223/06: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms (halogen atoms C07D223/04)
- C07D 493/04: Ortho-condensed systems
- 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)

## Abstract

Compounds of formula wherein R1 and R1′ are hydrogen or deuterium, R2, R3 and R4 are hydrogen or deuterium, R5 is the residue of an amino acid, X is S or N-ALK, is piperidinyl or tetrahydropyridinyl, ALK is (C1-4)alkyl, and R6 is hydrogen, hydroxy or (C2-12)acyloxy, and their use as antimicrobials.

## Claims

### Claim 1

A compound of formula
wherein
R1 and R1′ are hydrogen or deuterium,
R2, R3 and R4 are hydrogen or deuterium,
R5 is the residue of an alpha amino acid, wherein the N which is part of the ring in formula I is acylated by the carboxylic group of said amino acid and wherein the carbonyl group of said amino acid is bound to the nitrogen of the group of formula
and the —OH group of said amino acid function is missing,
X is S or N-ALK, the group of formula
is piperidinyl or tetrahydropyridinyl,
ALK is (C1-4)alkyl, and
R6 is hydrogen, hydroxy or (C2-12)acyloxy,
with the proviso that if the group
is piperidinyl and X is S, then R6 is other than hydrogen.

### Claim 2 (depends on 1)

A compound according to claim 1 which is selected from the group consisting of
14-O-[4-hydroxy-N-valyl-piperidin-3-yl]-sulfanylacetylmutilin,
14-O-[3-hydroxy-N-valyl-piperidin-4-yl]-sulfanylacetylmutilin,
14-O-[3-hydroxy-N-histidinyl-piperidin-4-yl]-sulfanylacetylmutilin,
14-O-[3-hydroxy-N-valyl-piperidin-4-yl]-methylaminoacetylmutilin,
14-O-[4-hydroxy-N-valyl-piperidin-3-yl]-methylaminoacetylmutilin,
14-O—[N-valyl)-1,2,3,6-tetrahydropyridin-3-yl]-sulfanylacetylmutilin, and
14-O—[N-valyl)-1,4,5,6-tetrahydropyridin-4-yl]-sulfanylacetylmutilin.

### Claim 3

A compound of formula
wherein
R1 and R1′ are hydrogen or deuterium,
R2, R3 and R4 are hydrogen or deuterium,
R7 is a protecting group or the residue of an alpha amino acid, wherein the N which is part of the ring in formula II is acylated by the carboxylic group of said amino acid and wherein the carbonyl group of said amino acid is bound to the nitrogen of the group of formula
and said amino acid function is devoid of the —OH group, and wherein the amino group is protected,
X is S or N-ALK, the group of formula
is piperidinyl or tetrahydropyridinyl,
ALK is (C1-4)alkyl, and
R8 is hydrogen, hydroxy or (C2-12)acyloxy,
with the proviso that if the group of formula
is piperidinyl and X is S, then R8 is other than hydrogen.

### Claim 4 (depends on 3)

A compound according to claim 3 selected from the group consisting of
14-O—[N-BOC-4-hydroxy-piperidin-3-yl]-sulfanylacetylmutilin,
14-O—[N-BOC-3-hydroxy-piperidin-4-yl]-sulfanylacetylmutilin,
14-O-[4-hydroxy-N-BOC-piperidin-3-yl]-methylaminoacetylmutilin,
14-O-[3-hydroxy-N-BOC-piperidin-4-yl]-methylaminoacetylmutilin,
14-O—[N-BOC-1,4,5,6-tetrahydropyridin-4-yl]-sulfanylacetylmutilin,
14-O-[4-hydroxy-N—(N-BOC-valyl)-piperidin-3-yl]-sulfanylacetylmutilin,
14-O-[3-hydroxy-N—(N-BOC-valyl)-piperidin-4-yl]-sulfanylacetylmutilin,
14-O-[4-acetoxy-N—(N-BOC-valyl)-piperidin-3-yl]-sulfanylacetylmutilin,
14-O-[3-acetoxy-N—(N-BOC-valyl)-piperidin-4-yl]-sulfanylacetylmutilin,
14-O-[3-hydroxy-N—(N-BOC-histidinyl)-piperidin-4-yl]-sulfanylacetylmutilin,
14-O-[3-hydroxy-N—(N-BOC)-valyl-piperidin-4-yl]- methylaminoacetylmutilin,
14-O-[4-hydroxy-N—(N-BOC)-valyl-piperidin-3-yl]- methylaminoacetylmutilin,
14-O—[N—(N-BOC-valyl)-1,4,5,6-tetrahydropyridin-4-yl]- sulfanylacetylmutilin,
14-O—[N—(N-BOC-valyl)-1,2,3,6-tetrahydropyridin-3-yl]- sulfanylacetylmutilin.

### Claim 5 (depends on 1)

A compound of claim 1 in the form of a salt.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 in association with at least one pharmaceutical excipient.

### Claim 7 (depends on 6)

A pharmaceutical according to claim 6 further comprising another pharmaceutically active agent.

### Claim 8 (depends on 1)

A method of treatment of microbial diseases comprising administering to a subject in need of such treatment an effective amount of a compound of claim 1.