# US 2010/0168129 A1 · Drugs with anticholestatic activity

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- Number: US 2010/0168129 A1
- Document ID: US20100168129A1
- Status: Published application
- Kind: A1
- Application number: 12/452,674
- Filed: 2008-07-17
- Published: 2010-07-01
- Earliest claimed: 2007-07-17
- Inventors: Mario Brufani; Luciano Cellai; Barbara Bartolini; Ilaria Medici; Bianca Maria Lagrasta
- Web page: https://patentgrep.com/patent/US20100168129A1

## CPC

- C07D 498/08: Bridged systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

New compounds belonging to the structural formula (I) are described. in which R1, R2, A, Y and X are specified in the description, useful in the treatment of cholestasis and substantially devoid of antibacterial activity. The synthesis process of said compounds, the pharmaceutical compositions containing them and their use in therapy are also described.

## Claims

### Claim at position 1

1-15. (canceled)

### Claim 16

A compound of formula (I)
where
R1 and R2 are chosen from —OH or —OCH3, otherwise R1 and R2 taken together form a —O—C(CH3)2—O— group,
the ring A is chosen from:
Y is chosen from H and —CO—CH3,
X is chosen from CH2, O, S, NH, NR3, N—COR3,
where R3 denotes:
a) a linear or branched alkyl group having 1 to 9 carbon atoms,
b) a (CH2)n—R4 chain, where n is 0 to 8 and R4 is chosen from OH, NH2, halogen, a cycloalkyl, aryl or heterocyclic group, with the proviso that when n is 1, R4 is not phenyl, or
c) a (CH2)m—Z—(CH2)nCH3 chain, where m+n is 1 to 8, and Z denotes —O—, —S—, —NH—, —N(R5), where R5 is a linear or branched alkyl having 1 to 9 carbon atoms.

### Claim 17 (depends on 16)

The compound according to claim 16, wherein X is NR3.

### Claim 18 (depends on 17)

The compound according to claim 17, wherein R3 is:
a) a linear or branched alkyl having 1 to 4 carbon atoms,
b) a (CH2)n—R4 chain, where n is 0 and R4 is chosen from cyclohexyl, phenyl, piperidino, morpholino and thiomorpholino, or
c) a (CH2)m—Z—(CH2)n—CH3 chain, where m+n is 1 to 5, and Z denotes —O—, —S—, —NH—, —NR5—, where R5 is a linear or branched alkyl having 1 to 9 carbon atoms.

### Claim 19 (depends on 16)

The compound according to claim 16, chosen from:
3-(4′-methyl-1′-piperazinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin SV
3-(4′-methyl-1′-piperazinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin SV
3-(4′-methyl-1′-piperazinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin S
3-(4′-methyl-1′-piperazinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin S
3-(4′-ethyl-1′-piperazinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin SV
3-(4′-ethyl-1′-piperazinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin SV
3-(4′-ethyl-1′-piperazinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin S
3-(4′-ethyl-1′-piperazinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin S
3-(1′-piperidinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin SV
3-(1′-piperidinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin SV
3-(1′-piperidinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin S
3-(1′-piperidinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin S
3-(4′-phenyl-1′-piperazinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin SV
3-(4′-phenyl-1′-piperazinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin SV
3-(4′-phenyl-1′-piperazinyl-iminomethyl)-16,17,18,19,28,29-hexahydro-rifamycin S
3-(4′-phenyl-1′-piperazinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin S
3-[4′-(2-ethoxyethyl)-1′-piperazinyl-iminomethyl]-16,17,18,19,28,29-hexahydrorifamycin SV
3-[4′-(2-ethoxyethyl)-1′-piperazinyl-iminomethyl]-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin SV
3-[4′-(2-ethoxyethyl)-1′-piperazinyl-iminomethyl]-16,17,18,19,28,29-hexahydrorifamycin S
3-[4′-(2-ethoxyethyl)-1′-piperazinyl-iminomethyl]-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin S
3-(1′-morpholinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin SV
3-(1′-morpholinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin SV
3-(1′-morpholinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin S
3-(1′-morpholinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin S
3-(1′-thiomorpholinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin SV
3-(1′-thiomorpholinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin SV
3-(1′-thiomorpholinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin S
3-(1′-thiomorpholinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin S
3-(4′-isopropyl-1′-piperazinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin SV
3-(4′-isopropyl-1′-piperazinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin SV
3-(4′-isopropyl-1′-piperazinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin S
3-(4′-isopropyl-1′-piperazinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin S
3-(4′-cyclohexyl-1′-piperazinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin SV
3-(4′-cyclohexyl-1′-piperazinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin SV
3-(4′-cyclohexyl-1′-piperazinyl-iminomethyl)-16,17,18,19,28,29-hexahydrorifamycin S
3-(4′-cyclohexyl-1′-piperazinyl-iminomethyl)-21,23-O-isopropylidene-16,17,18,19,28,29-hexahydrorifamycin S
3-(4′-methyl-1′-piperazinyl-iminomethyl)-16,17,18,19,28,29-hexahydro-25-desacetylrifamycin SV
3-[4′-(2-hydroxyethyl)-1′-piperazinyl-iminomethyl]-16,17,18,19,28,29-hexahydrorifamycin SV

### Claim 20

Method for the treatment of cholestasis and diseases related thereto comprising the administration of a compound of formula (I)
where
R1 and R2 are chosen from —OH or —OCH3, otherwise R1 and R2 taken together form a —O—C(CH3)2—O— group,
the ring A is chosen from:
Y is chosen from H and —CO—CH3,
X is chosen from CH2, O, S, NH, NR3, N—COR3,
where R3 denotes:
a) a linear or branched alkyl group having 1 to 9 carbon atoms,
b) a (CH2)n—R4 chain, where n is 0 to 8, and R4 is chosen from OH, NH2, halogen, a cycloalkyl, aryl or heterocyclic group,
c) a (CH2)m—Z—(CH2)nCH3 chain, where m+n is 1 to 8, and Z denotes —O—, —S—, —NH—, —N(R5), where R5 is a linear or branched alkyl having 1 to 9 carbon atoms.

### Claim 21 (depends on 20)

The method according to claim 20, wherein said diseases related to cholestasis are obstructive cholestasis, drug-induced cholestasis, Dubin-Johson Syndrome, sitosterolemia and in general all disorders of hepatobiliary transport.

### Claim 22 (depends on 16)

A pharmaceutical composition comprising at least one compound of formula (I) according to claim 16 and at least one pharmaceutically acceptable excipient.

### Claim 23 (depends on 22)

The pharmaceutical composition according to claim 22 comprising at least one dosage unit comprising 60 mg to 4000 mg of the compound of formula (I).

### Claim 24 (depends on 22)

The pharmaceutical composition according to claim 22 in the form of a tablet, capsule, powder, granule, pill, liquid solution, suspension, emulsion, syrup, elixir, suppository, ointment, cream, lotion, gel, paste, transdermal formulation, medicated membrane or patch.

### Claim 25 (depends on 16)

A process for preparing the compound of formula (I) according to claim 16 comprising the following steps:
(i) reduction of the double bonds in positions 16,17,18,19,28,29 of rifamycin S or SV; and
(ii) addition of the group
in position 3 of the product obtained in (i), where X has the meanings indicated in claim 16.

### Claim 26 (depends on 25)

The process according to claim 25, wherein step (i) takes place by catalytic hydrogenation.

### Claim 27 (depends on 16, 25)

The process according to claim 25, wherein step (ii) takes place by treating the product of (i) with formaldehyde and a primary amine in the presence of an oxidizing agent, and then with a hydrazine of formula:
where X has the meanings as above defined in claim 16.

### Claim 28 (depends on 25)

The process according to claim 25 for obtaining the compound of formula (I) having Y═H, comprising the use of C25—O-desacetylrifamycin S or SV as the starting product.