# US 10,246,478 B2 · Polyene macrolide derivative

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- Number: US 10,246,478 B2
- Document ID: US10246478B2
- Status: Granted
- Kind: B2
- Application number: 15/315,646
- Filed: 2015-06-12
- Published: 2017-07-06
- Granted: 2019-04-02
- Earliest claimed: 2014-06-12
- Assignees: Shionogi & Co., Ltd.
- Applicants: Shionogi & Co., Ltd.
- Inventors: Keisuke Miyazaki; Kenji Takaya; Takafumi Ohara; Hideki Sugimoto; Manabu Fujitani; Yuki Ogata; Naoyuki Suzuki
- Web page: https://patentgrep.com/patent/US10246478B2

## CPC

- C07H 17/08: Hetero rings containing eight or more ring members, e.g. erythromycins
- A61P 31/10: Antimycotics
- C07H 1/00: Processes for the preparation of sugar derivatives
- C07H 23/00: Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12 (esters with inorganic acids C07H11/00)
- 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

The present invention is the following Amphotericin B derivative: wherein each symbol is defined in description. The compound of the present invention has 16th position (X) is urea structure, cyclic structure, hydroxyalkyl or substituted monoalkylcarbamoyl. The compound of the present invention has antifungal activity.

## Claims

### Claim 1

A compound represented by formula (I):
wherein X is a group of formula (II):
or —N(RF)—CO—X1,
wherein in formula (II) Ring C is substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted non-aromatic carbocycle, substituted or unsubstituted aromatic heterocycle or substituted or unsubstituted non-aromatic heterocycle;
wherein RF is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; and
X1 is any one of following groups (III)-(VI):
wherein in formula (I) L, J1 and V1 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted amino or substituted or unsubstituted alkyloxy;
J2 and V2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
or J1 and J2 and/or V1 and V2 may be taken together to form oxo;
wherein in formula (III) or (IV) Ra1 and Rb1 are each independently, hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted amino, formyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, sulfo, cyano, substituted or unsubstituted ureido, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyl ammonium, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylphosphonyl, substituted or unsubstituted dialkynylphosphonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclylamino, substituted or unsubstituted non-aromatic carbocyclylamino, substituted or unsubstituted aromatic heterocyclylamino, substituted or unsubstituted non-aromatic heterocyclylamino, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl or substituted or unsubstituted non-aromatic heterocyclylsulfonyl;
Ra2 and Rb2 are each independently hydrogen, halogen, hydroxy, carboxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxyalkyl, substituted or unsubstituted non-aromatic heterocyclyloxyalkenyl or substituted or unsubstituted non-aromatic heterocyclyloxyalkynyl;
Ra3 and Rb3 are each independently, hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxyalkyl, substituted or unsubstituted non-aromatic heterocyclyloxyalkenyl or substituted or unsubstituted non-aromatic heterocyclyloxyalkynyl;
or Ra2 and Ra3 and/or Rb2 and Rb3 are each independently may be taken together to form oxo, substituted or unsubstituted imino or thioxo, or may be taken together with neighboring atoms to form substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle;
Ra4, Rb4 and Rc4 are each independently, hydrogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl or substituted or unsubstituted non-aromatic carbocyclyl;
Rb5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
wherein in formula (V) or (VI) Ring A and Ring B are each independently, substituted or unsubstituted nitrogen-containing aromatic heterocycle or substituted or unsubstituted nitrogen-containing non-aromatic heterocycle;
wherein in formula (III) T is a bond, —N(Ra5)— or —O—;
wherein the Ra5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl or substituted or unsubstituted alkynylcarbonyl;
wherein in formula (III) or (IV) m and n are each independently an integer of 0 to 10;
wherein in formula (I) Y is any one of following groups:
wherein in formula (VII) RA is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
RB and RC are each independently hydrogen, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
or RB and RC may be taken together to form oxo, substituted or unsubstituted imino or thioxo, or may be taken together with neighboring atoms to form substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle;
wherein in formula (VII) or (VIII) RD is hydrogen, hydroxy, carboxy, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted amidino, substituted or unsubstituted guanidino, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl or substituted or unsubstituted non-aromatic heterocyclyl;
wherein in formula (VIII) RE is hydrogen, hydroxy or substituted or unsubstituted amino;
wherein in formula (VII) q is an integer of 0 to 10;
provided that the following compounds are excluded:
the compounds which X is either of following groups; and Y is —NH2;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, wherein J1, L and V1 are hydroxy; and J2 and V2 are hydrogen.

### Claim 3 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, wherein X is a group of formula: —N(RF)—CO—X1; X1 is a group represented by formula (III); and T is a bond.

### Claim 4 (depends on 3)

The compound or its pharmaceutically acceptable salt according to claim 3, wherein Ra1 is halogen, hydroxy, carboxy, substituted or unsubstituted amino, substituted or unsubstituted aromatic heterocyclylamino, substituted or unsubstituted non-aromatic heterocyclylamino, substituted or unsubstituted alkylammonium, carbamoyl, sulfamoyl, sulfo, cyano, substituted or unsubstituted ureido, guanidino, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted alkyiphosphonyl, substituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl or substituted or unsubstituted non-aromatic heterocyclyl;
wherein said substituted or unsubstituted amino is selected from unsubstituted amino, hydroxyamino, sulfamoylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylsulfonylamino, substituted or unsubstituted non-aromatic carbocyclylcarbonylamino, substituted or unsubstituted aromatic carbocyclylcarbonylamino, substituted or unsubstituted aromatic heterocyclylcarbonylamino and substituted or unsubstituted non-aromatic heterocyclylcarbonylamino;
wherein said substituted or unsubstituted ureido is selected from ureido, substituted or unsubstituted alkylureido, substituted or unsubstituted aromatic heterocyclylureido and substituted or unsubstituted aromatic heterocyclylureido;
wherein said substituted sulfamoyl is substituted or unsubstituted aromatic heterocyclylsulfamoyl.

### Claim 5 (depends on 3)

The compound or its pharmaceutically acceptable salt according to claim 3,
wherein Ra2 are each independently hydrogen, halogen, hydroxy, carboxy, amino, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic heterocyclyloxyalkyl or substituted or unsubstituted alkylcarbonyl;
Ra3 are each independently, hydrogen, halogen, substituted or unsubstituted alkyl or substituted or unsubstituted non-aromatic heterocyclyloxyalkyl;
or Ra2 and Ra3 may be taken together to form oxo, or may be taken together with neighboring atoms to form non-aromatic carbocycle or non-aromatic heterocycle.

### Claim 6 (depends on 3)

The compound or its pharmaceutically acceptable salt according to claim 3, wherein Ra4 is hydrogen, hydroxy, amino, substituted or unsubstituted alkyl or substituted or unsubstituted non-aromatic carbocyclyl.

### Claim 7 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, wherein X is a group of formula: —N(RF)—CO—X1; X1 is a group represented by formula (III); and T is —N(Ra5)— or —O—.

### Claim 8 (depends on 7)

The compound or its pharmaceutically acceptable salt according to claim 7, wherein Ra1 is hydroxy, carboxy, substituted amino, substituted or unsubstituted aromatic heterocyclylamino, formyl, carbamoyl, cyano, guanidino, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, or substituted ureido;
wherein said substituted amino is hydroxyamino or substituted or unsubstituted alkylamino;
wherein said substituted ureido is substituted or unsubstituted aromatic heterocyclylureido.

### Claim 9 (depends on 7)

The compound or its pharmaceutically acceptable salt according to claim 7, wherein Ra2 are each independently hydrogen, hydroxy or substituted or unsubstituted alkyl;
Ra3 are each independently hydrogen or substituted or unsubstituted alkyl;
or Ra2 and Ra3 may be taken together to form oxo or thioxo, or may be taken together with neighboring atoms to form substituted or unsubstituted non-aromatic carbocycle.

### Claim 10 (depends on 7)

The compound or its pharmaceutically acceptable salt according to claim 7, wherein Ra4 is hydrogen.

### Claim 11 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, wherein X is a group of formula: —N(RF)—CO—X hu 1 ; and X 1 is a group represented by formula (IV).

### Claim 12 (depends on 11)

The compound or its pharmaceutically acceptable salt according to claim 11, wherein Rb1 is hydroxy.

### Claim 13 (depends on 11)

The compound or its pharmaceutically acceptable salt according to claim 11, wherein n is 1 or 2; Rb2 are each independently hydrogen or hydroxy; and Rb3 is hydrogen.

### Claim 14 (depends on 11)

The compound or its pharmaceutically acceptable salt according to claim 11, wherein Rb4 is hydrogen; and Rb5 is hydrogen or substituted or unsubstituted alkyl.

### Claim 15 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, wherein X is —N(RF)—CO—X1; and X1 is a group represented by formula (V).

### Claim 16 (depends on 15)

The compound or its pharmaceutically acceptable salt according to claim 15, wherein ring A is substituted or unsubstituted nitrogen-containing non-aromatic heterocycle.

### Claim 17 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, wherein X is a group of formula: —N(RF)—CO—X 1; X1 is a group represented by formula (VI).

### Claim 18 (depends on 17)

The compound or its pharmaceutically acceptable salt according to claim 17, wherein ring B is substituted or unsubstituted nitrogen-containing non-aromatic heterocycle.

### Claim 19 (depends on 17)

The compound or its pharmaceutically acceptable salt according to claim 17, wherein Rc4 is hydrogen.

### Claim 20 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, wherein RF is hydrogen.

### Claim 21 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, wherein X is a group represented by formula (II); and said group is represent by formula (IX):
wherein ring D and ring E are each independently substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted non-aromatic carbocycle, substituted or unsubstituted aromatic heterocycle or substituted or unsubstituted non-aromatic heterocycle; and
Z is a bond, alkylene, —O—, —S—or —N(H)—.

### Claim 22 (depends on 21)

The compound or its pharmaceutically acceptable salt according to claim 21, wherein ring D is substituted or unsubstituted aromatic heterocycle; and ring E is substituted or unsubstituted aromatic carbocycle or substituted or unsubstituted aromatic heterocycle.

### Claim 23 (depends on 21)

The compound or its pharmaceutically acceptable salt according to claim 21, wherein Z is a bond.

### Claim 24 (depends on 21)

The compound or its pharmaceutically acceptable salt according to claim 21, wherein the substituent(s) on ring E is/are alkylamino.

### Claim 25 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, wherein RA are each independently hydrogen or substituted or unsubstituted alkyl; RB are each independently hydrogen or hydroxy or substituted or unsubstituted amino; RC are each independently hydrogen or hydroxy or substituted or unsubstituted amino; or RB and RC may be taken together to form oxo, substituted or unsubstituted imino, hydroxyimino or cyanoimino;
RD is hydrogen, hydroxy, carboxy, substituted or unsubstituted amino, carbamoyl, guanidine, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl or substituted or unsubstituted non-aromatic heterocyclyl;
RE is amino;
wherein said substituted or unsubstituted amino is unsubstituted amino or substituted or unsubstituted alkylamino;
wherein said substituted or unsubstituted imino is unsubstituted imino, hydroxyimino or cyanoimino.

### Claim 26 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, wherein Y is NH2.

### Claim 27 (depends on 2)

The compound or its pharmaceutically acceptable salt according to claim 2, wherein X is a group of formula: —N(RF)—CO—X1 , wherein X1 is a group represented by formula (III);
T is —N(H)—; Ra1 is carboxy, carbamoyl or substituted amino; Ra2 is each independently hydrogen or hydroxy; and Ra3 and Ra4 are hydrogen; m is 2; and Y is NH2.

### Claim 28 (depends on 1)

A pharmaceutical composition containing the compound or its pharmaceutically acceptable salt according to claim 1.

### Claim 29 (depends on 28)

A pharmaceutical composition of claim 28 having antifungal activity.

### Claim 30

A compound represented by formula (X), (XI), (XVI) or (XVII):
or its pharmaceutically acceptable salt.

### Claim 31 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1,

### Claim 32 (depends on 31)

A pharmaceutical composition comprising the compound according to claim 31, or its pharmaceutically acceptable salt.

### Claim 33 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, said compound being:

### Claim 34 (depends on 33)

A pharmaceutical composition comprising the compound according to claim 33, or its pharmaceutically acceptable salt.

### Claim 35 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, said compound being:

### Claim 36 (depends on 35)

A pharmaceutical composition comprising the compound according to claim 35, or its pharmaceutically acceptable salt.

### Claim 37 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, said compound being:

### Claim 38 (depends on 37)

A pharmaceutical composition comprising the compound according to claim 37, or its pharmaceutically acceptable salt.

### Claim 39 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, said compound being:

### Claim 40 (depends on 39)

A pharmaceutical composition comprising the compound according to claim 39, or its pharmaceutically acceptable salt.

### Claim 41 (depends on 1)

The compound or its pharmaceutically acceptable salt according to claim 1, said compound being:

### Claim 42 (depends on 21)

A pharmaceutical composition comprising the compound according to claim 21, or its pharmaceutically acceptable salt.