# US 10,308,595 B2 · Albicidin derivatives, their use and synthesis

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- Number: US 10,308,595 B2
- Document ID: US10308595B2
- Status: Granted
- Kind: B2
- Application number: 14/768,323
- Filed: 2014-02-14
- Published: 2015-12-31
- Granted: 2019-06-04
- Earliest claimed: 2013-02-15
- Assignees: Technische UniversitäT Berlin
- Applicants: Technische Universitaet Berlin
- Inventors: Roderich Suessmuth; Julian Kretz; Vivien Schubert; Alexander Pesic; Manuela Huegelland; Monique Royer; Stephane Cociancich; Philippe Rott; Dennis Kerwat; Stefan Graetz
- Web page: https://patentgrep.com/patent/US10308595B2

## CPC

- C07C 255/44: at least one of the singly-bound nitrogen atoms being acylated
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- C07C 233/83: of an acyclic saturated carbon skeleton
- C07C 237/42: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
- C07C 255/03: Mononitriles
- C07C 255/29: containing cyano groups and acylated amino groups bound to the carbon skeleton
- C07C 255/57: containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
- C07C 275/42: being further substituted by carboxyl groups
- C07C 311/21: having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 311/46: Y being a hydrogen or a carbon atom
- C07C 311/47: Y being a hetero atom
- C07D 207/34: 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
- C07D 209/34: in position 2
- C07D 213/81: Amides; Imides
- C07D 237/24: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 241/24: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 263/24: with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
- C07D 277/56: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 295/14: substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 295/155: with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 307/56: 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
- C07D 311/12: substituted in position 3 and unsubstituted in position 7
- C07D 317/08: having the hetero atoms in positions 1 and 3
- C07D 317/46: condensed with one six-membered ring
- C07D 333/38: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07F 9/062: {Organo-phosphoranes without P-C bonds}
- C07F 9/09: Esters of phosphoric acids
- C07F 9/12: with hydroxyaryl compounds
- C07C 2601/02: with a three-membered ring
- C07C 2601/08: the ring being saturated
- C07C 2601/14: The ring being saturated
- C07C 2601/18: with a ring being at least seven-membered
- C07C 2603/74: Adamantanes
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Antibiotically active compounds characterized by general formula (I), wherein X1, BB, BC, BD, BE and X2 are building blocks with D1, D2, D3, D4 or D5 being linkers which include carbon, sulphur, nitrogen, phosphor and/or oxygen atoms and which are covalently connecting the moities BA and BB, BB and BC, BC and BD, BD and BE and BE and BF, respectively, and wherein in particular the building block BC comprises an amino acid derivative. The compounds for use in a method of treatment of diseases, in particular for use in a method of treatment of bacterial infections are also disclosed.

## Claims

### Claim 1

A compound having formula (23)
a. with X1 being BA-D1 with BA being selected from
with R2 and R3 being selected, where applicable, independently from each other from —H, —F, —CN, —OH, a substituted or unsubstituted C1-C3 alkyl, a substituted or unsubstituted C1-C3 alkoxy or a C1-C3 haloalkyl,
with E being
a substituted or unsubstituted C1-C16 alkyl, a substituted or unsubstituted C1-C16 alkoxy, a substituted or unsubstituted C1-C16 carboxy, a substituted or unsubstituted C2-C16 alkenyl, a substituted or unsubstituted C2-C16 alkynyl, or a C1-C16 haloalkyl, —
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl,
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle,
a substituted or unsubstituted C5-C10 heteroaryl, or
with n of R1n being 0, 1, 2, 3, 4, or 5, and
with each R1 independently from any other R1 being selected from the group consisting of —OH, —F, —Cl, —Br, —I, —CCH, —CN, —N3, —OCH3, —OCF3, —NH2, —NHCH3, —N(CH3)2, —CH3, —CH2—CH3, —CF3, —OCONH2 or —NO2, B(ORa)(ORb), —(CH2)m—Ra, —(CH2)m—ORa, —(CH2)m—C(═O)Ra, —(CH2)m—C(═O)ORa, —(CH2)m—OC(═O)Ra, —(CH2)m—OC(═O)ORa, —(CH2)m—OC(═O)NRaRb, —(CH2)m—C(═O)NRaRb, —(CH2)m—C(═O)NRaRb, —(CH2)m—C(═O)NRb(ORa), —(CH2)m—C(═S)Ra, —(CH2)m—C(═S)ORa, —(CH2)m—OC(═S)Ra, —(CH2)m—OC(═S)ORa, —(CH2)m—OC(═S)NRaRb, —(CH2)m—C(═S)NRaRb, —(CH2)m—SRa, —(CH2)m—S(═O)Ra, —(CH2)m—S(O2)Ra, —(CH2)m—S(O2)ORa, —(CH2)m—OS(O2)Ra, —(CH2)m—OS(O2)ORa, —(CH2)m—NRaRb, —(CH2)m—NRcC(═O)Ra, —(CH2)m—NRcC(═O)NRaRb, —(CH2)m—NRcC(═O)ORa, —(CH2)m—NRcC(═S)Ra, —(CH2)m—NRcC(═S)NRaRb, —(CH2)m—NRcC(═S)ORa, —(CH2)m—NRcS(O2)Ra, —(CH2)m—P(═O)(ORb)(ORa), —(CH2)m—P(═O)(ORb)(Ra) or —(CH2)m—S(O2)NRbRa, —(CH2)m—O—C(═O)—(M)—C(═O)OH, —(CH2)m—O—C(═O)—(M)—C(═O)ORa, —(CH2)m—O—C(═O)—(M)—Ra, —(CH2)m—O—(CH2)q—P(═O)(Rba)(Raa), —(CH2)m—C(═O)O—(CH2)q—P(═O)(Rba)(Raa), —(CH2)m—C(═O)O—(CH2)q—S(O2)OH or —(CH2)m—C(═O)O—(CH2)q—S(O2)ORa,
with Raa being selected independently from each other being —Ra or —ORa,
with Rba being selected independently from each other being —Rb or —ORb,
with M being a substituted or unsubstituted C1-C8 alkyl,
with m being selected from 0, 1 or 2,
with q being selected from 0, 1 or 2, and
with each Ra, Rb or Rc being selected independently from each other from
hydrogen, —CN,
a substituted or unsubstituted C1-C16 alkyl, a substituted or unsubstituted C1-C16 alkoxy, a substituted or unsubstituted C1-C16 carboxy, a substituted or unsubstituted C2-C16 alkenyl, a substituted or unsubstituted C2-C16 alkynyl, or a C1-C16 haloalkyl, a substituted or unsubstituted C3-C10 cycloalkyl, or a substituted or unsubstituted C3-C10 halo cycloalkyl,
a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl,
a substituted or unsubstituted C3-C10 heterocycle or a substituted or unsubstituted C3-C10 halo heterocycle,
a substituted or unsubstituted C5-C10 heteroaryl,
a substituted or unsubstituted C6-C10 aryl;
b. with BC being selected from
with Y being selected from —CN, —C(═O)OH, —C(═O)OCH3, —C(═O)OCH2CH3, —C(═O)NHCH3, —C(═O)NHCH2CH3, —C(═O)N(CH3)2, —C(═O)N(CH2CH3)2, —C(═O)N(CH3)(CH2CH3), —CF3 or —C(═O)NH2, and
with Z being selected from —H, —OH, —CH3, —CH2CH3, —OCH3, —NH2, —NHCH3, —N(CH3)2, —N(CH3)3+;
c. with each R8 being
—H, or, with each R8 being selected independently from each other from —H, —CH3, —CH2CH3;
d. with n of R10n being 1 or 2; and
with each R10 independently from any other R10 being selected from
—OH, —F, —Cl, —Br, I, —CCH, —CN, —N3, —OCH3, —OCF3, —NH2, —NHCH3, —N(CH3)2, —CH3, —CH2—CH3, —CF3, or —NO2;
e. with n of R11n being 0, 1, 2, 3 or 4,
with each R11 being selected independently from any other from any other R11 from —OH, —F, —Cl, —Br, —I, —CCH, —CN, —N3, —OCH3, —OCF3, NH2, —NHCH3, —N(CH3)2, —CH3, —CH2CH3, —CH2OCH3, —CHCH2, —CH2OH, —SO2NH2, —SO2N(CH3)2, —SO2NHCH3, —CH3, —CF3, or —NO2;
f. with T being selected from
—OH, —F, —Cl, —Br, I, —CCH, —CN, —N3, —OCH3, —OCF3, —NH2, —NHCH3, —N(CH3)2, —CH3, —CH2—CH3, —CF3 or —NO2,
—(CH2)m—C(═O)ORa, —(CH2)m—S(O2)ORa, with m being selected from 0, 1 or 2, with Ra being
hydrogen,
a substituted or unsubstituted C1-C16 alkyl, a substituted or unsubstituted C2-C16 alkenyl, a substituted or unsubstituted C2-C16 alkynyl, or a C1-C16 haloalkyl, or a substituted or unsubstituted C3-C10 cycloalkyl or a substituted or unsubstituted C3-C10 halo cycloalkyl;
g. with D1, D4 and D5 being each independently from each other from
wherein
each R8 being —H, or with each R8 being selected independently from each other from —H, —CH3, —CH2CH3, and
V being O;
h. wherein the compounds of formulae (2a) is disclaimed:
wherein R1 is H or CO(NH2), R2′ is CO(NH2) or CN, R3′ is H or OCH3.

### Claim 2 (depends on 1)

The compound according to claim 1 having formulae 21
wherein X1, BC, R8, R11n, R10n and T have the meaning as recited in claim 1.

### Claim 3 (depends on 1)

The compound according to claim 1 having formulae 25
wherein X1, BC, R8, R11, R10 and T have the meaning as recited in claim 1 and E is
with n of R1n being 0 or 1, and
with each R1 independently from any other R1 being selected from —OH or —CH3.

### Claim 4

A compound selected from the group consisting of:

### Claim 5 (depends on 1)

The compound of claim 1, wherein E is
with n of R1n being 0 or 1, and
with each R1 independently from any other R1 being selected from —OH or —CH3.

### Claim 6 (depends on 1)

The compound of claim 1, wherein E is selected from the group consisting of
with m of R9m being 0, and
with each T being selected independently from each other from —C(CH3)2, —NH, —S or —O,
with T′ being selected from —O, —S or —NH,
with T″ being ═N,
with R5 and R6 being selected independently from each other from —H, —F or —CH3,
with R6′ being selected from —OH, —OCH3, —OCH2CH3 or —CH3, and
with R7 being ═O.

### Claim 7 (depends on 1)

The compound of claim 1, wherein
R2 and R3 is selected independently from each other from —H, —F, —CN, —CH3, —CH2CH3, —OCH3, —OCH2CH3, —OCH2CH2CH3, —OCH(CH3)2, —OCF3, —CH2CF3, —CHFCF3, —CF2CF3, —CHF2, —CH2F or —CF3;
Z is H and Y is CN or —C(═O)NH2;
each R8 is selected independently from each other from H or CH3;
M is an unsubstituted C1-C8 alkyl;
m is 0 or 1;
q is 0 or 1; and
each Ra, Rb or Rc are selected independently from each other from a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted C1-C8 haloalkyl, a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle.

### Claim 8 (depends on 1)

The compound of claim 1, wherein
n of R1n is 0, 1, 2 or 3;
M is an unsubstituted C1-C8 alkyl;
m is 0 or 1;
q is 0 or 1; and
each Ra, Rb or Rc are selected independently from each other from a substituted or unsubstituted C1-C8 alkyl, a substituted or unsubstituted C1-C8 alkoxy, a substituted or unsubstituted C2-C8 alkenyl, a substituted or unsubstituted C2-C8 alkynyl, a substituted or unsubstituted C1-C8 haloalkyl, a substituted or unsubstituted C4-C10 heterocycle or a substituted or unsubstituted C4-C10 halo heterocycle.

### Claim 9 (depends on 1)

The compound of claim 1, wherein
n of R10n being 1 or 2; and
with each R10 independently from any other R10 being selected from —OH, —OCH3.

### Claim 10 (depends on 1)

The compound of claim 1, wherein n of R11n is
2 and each R11 independently from any other R11 is —OH, or —OCH3,
1 and R11 is —OH, or
1 and R11 is —OCH3.

### Claim 11 (depends on 1)

The compound according to claim 1 wherein T is —CO2H.

### Claim 12 (depends on 1)

The compound of claim 1, wherein the compound is used to treat a bacterial infection by Salmonella enteritidis, Pseudomonas aeruginosa, Staphylococcus auereus, Escherichia coli, Bacillus sbutillis, Micrococcus luteus, Bacillus megaterium, or Myobacterium phlei.

### Claim 13

A compound selected from the group consisting of:

### Claim 14

A compound selected from the group consisting of: