# US 11,028,086 B2 · Pyrido-imidazo rifamycins

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- Number: US 11,028,086 B2
- Document ID: US11028086B2
- Status: Granted
- Kind: B2
- Application number: 16/718,634
- Filed: 2019-12-18
- Published: 2020-05-21
- Granted: 2021-06-08
- Earliest claimed: 2017-06-26
- Assignees: Biofer S.p.A.
- Applicants: Biofer S.p.A.
- Inventors: Egidio Marchi; Alessandro Lapini Sacchetti; Claudia Ori; Lisa Preti
- Web page: https://patentgrep.com/patent/US11028086B2

## CPC

- C07D 471/22: in which the condensed systems contains four or more hetero rings
- C07D 498/18: Bridged systems
- A61P 31/04: Antibacterial agents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel pyrido-imidazo rifamycins, characterized by a highly selective antibacterial activity and low absorption by oral route.

## Claims

### Claim 1

A compound of Formula (I) or pharmaceutically acceptable salts thereof
wherein
R and R1 may be H,
with the proviso that:
when
then R1═H and R2═CH3CO— or H;
when
then R═H and R2═CH3CO— or H;
when
then R1═H and R2═CH3CO— or H; and
when
then R═H and R2═CH3CO— or H;
wherein R3 and R4 are the same or different and selected from the group comprising hydrogen, linear or branched C1-C10 alkyl, optionally substituted with one or more substituents selected from aminoalkyl, alkoxy, phenoxy, or sulfo, and aryl, optionally mono- or disubstituted with C1-C4 alkyl or alkoxy groups, halogen, amino, nitro; or
R3 and R4 taken together with two consecutive carbon atoms of the pyridine core may form a phenyl ring, optionally substituted with C1-C4 alkyl, or a 5- or 6-membered heterocyclic ring, optionally substituted with C1-C4 alkyl,
R5 is selected from the group comprising hydrogen, hydroxy, linear or branched C1-C10 alkyl, optionally substituted with one or more substituents selected from aminoalkyl, alkoxy, phenoxy, or sulfo, and aryl optionally mono- or disubstituted with C1-C4 alkyl or alkoxy groups, halogen, amino, nitro.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein the aryl, optionally mono- or disubstituted with C1-C4 alkyl or alkoxy groups, halogen, amino, nitro, is selected from phenyl and benzyl.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein when R3 and R4 are taken together with two consecutive carbon atoms of the pyridine core to form a 5- or 6-membered heterocyclic ring, optionally substituted with C1-C4 alkyl, said 5- or 6-membered heterocyclic ring is selected from the group comprising pyrrolidine, piperidine, piperazine, and morpholine.

### Claim 4 (depends on 1)

A compound according to claim 1, selected from the group consisting of:
4′-[(4-methyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
4′-[(1-piperidinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
4′-[(N,N-dimethylamino)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
4′-[(4-carboxyamidopyridyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
5′-[(N,N-dimethylamino)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
5′-[(1-piperidinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
5′-[(N,N-dimethylamino)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
4′-[(4-methyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S;
25-desacetyl-5′-[(1-piperidinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
25-desacetyl-5′-[(N,N-dimethylamino)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
4′-[(N-morpholinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
5′-[(N-morpholinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
25-desacetyl-4′-[(N-morpholinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
25-desacetyl-5′-[(N-morpholinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
4′-[(N-propyl,N-butyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
5′-[(N-propyl,N-butyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
25-desacetyl-4′-[(N-propyl,N-butyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
25-desacetyl-5′-[(N-propyl,N-butyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
4′-[(N,N-dipentyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
5′-[(N,N-dipentyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
25-desacetyl-4′-[(N,N-dipentyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
25-desacetyl-5′-[(N,N-dipentyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
4′-[(4-ethyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
5′-[(4-ethyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
25-desacetyl-4′-[(4-ethyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
25-desacetyl-5′-[(4-ethyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
4′-[(4-propyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
5′-[(4-propyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV;
25-desacetyl-4′-[(4-propyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV; and
25-desacetyl-5′-[(4-propyl-1-piperazinyl)iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV; or pharmaceutically acceptable salts thereof.

### Claim 5

A compound selected from the group consisting of 4′-[(alkyloxy-iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin and 4′-[N-alkyliminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV.

### Claim 6 (depends on 5)

A compound according to claim 5, selected from the group consisting of 4′-(N-methoxy)-iminomethyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV and 4′-(N-isopropyl)-iminomethyl]-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV.

### Claim 7

The compound: 4′-hydroxymethyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S or SV, or pharmaceutically acceptable salts thereof.

### Claim 8

The compound: 4′-formyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S or SV, e or pharmaceutically acceptable salts thereof.

### Claim 9 (depends on 1)

A compound according to claim 1, for use as a medicament.

### Claim 10 (depends on 9)

A compound according to claim 9, for use in the treatment of a gastrointestinal tract disease or in a skin, eye, vaginal or dental infection.

### Claim 11 (depends on 9)

A compound according to claim 9, for use in the treatment dry mastitis, in vaginal diseases in cows, in intestinal diseases in pets, or as auxinic therapy in animal husbandry.

### Claim 12 (depends on 10)

The compound according to claim 10, wherein the gastrointestinal tract disease is selected from the group consisting of diseases due to dismicrobism, IBD, Crohn's disease, diverticulosis, and traveler's diarrhea.

### Claim 13 (depends on 10)

The compound according to claim 10, wherein the skin, eye, vaginal or dental infection is an infection requiring a chronic treatment.

### Claim 14 (depends on 11)

The compound according to claim 11, wherein the animal husbandry is husbandry of chickens, turkeys, ducks, or rabbits.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising at least one compound of Formula (I) according to claim 1, together with at least one pharmaceutically acceptable excipient.

### Claim 16 (depends on 15)

A pharmaceutical composition according to claim 15, suitable to be administered topically.

### Claim 17 (depends on 16)

The pharmaceutical composition according to claim 16, wherein the composition is suitable to be administered in the form of a solid, liquid or gel.

### Claim 18 (depends on 1)

A process for producing a compound of Formula (I) according to claim 1 when R and R1 may be H,
or
comprising the steps of:
reacting Rifamycin O with 2-amino-4-hydroxymethylpyridine to obtain 4′-hydroxymethyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S or SV;
oxidizing in liquid phase 4′-hydroxymethyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S or SV with a suitable oxidant to obtain 4′-formyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S or SV; and
reacting 4′-formyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S or SV with a hydrazine of Formula (II) NH2—N(R3)(R4), wherein R3 and R4 are as defined in Formula (I), to obtain the corresponding hydrazone.

### Claim 19 (depends on 18)

The process according to claim 18, wherein from about 1 to about 6 molar equivalents of 2-amino-4-hydroxymethylpyridine are used per mole of Rifamycin O and/or from about 1 to about 6 molar equivalents of hydrazine are used per mole of 4′-formyl-4-desoxypyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin S or SV.

### Claim 20 (depends on 18)

The process according to claim 18, wherein the solvent used is an organic solvent selected from an aliphatic alkanol containing 1 to 4 carbon atoms, alone or in a mixture with water, or with DMF, or in a short-chain halogenated solvent.

### Claim 21 (depends on 18)

The process according to claim 18, wherein the reaction temperature may vary from the temperature of 10° C. to the solvent boiling point and/or the reaction time may vary from a few minutes to 24 h.

### Claim 22 (depends on 18)

The process according to claim 18, wherein the obtained compound of Formula (I) is oxidized by treatment with a suitable oxidant.

### Claim 23 (depends on 18)

The process according to claim 18,
wherein the step of oxidizing in liquid phase is in an aprotic solvent, and
wherein the oxidant is manganese dioxide.

### Claim 24 (depends on 20)

The process according to claim 20, wherein the short-chain halogenated solvent is dichloromethane.

### Claim 25 (depends on 21)

The process according to claim 21, wherein the reaction temperature may vary from the temperature of 10° C. to a temperature not above 80° C. and/or the reaction time may vary from a few minutes to 24 h.

### Claim 26 (depends on 22)

The process according to claim 22, wherein the oxidant is manganese dioxide.

### Claim 27 (depends on 1)

A process for producing a compound of Formula (I) according to claim 1 when R and R1 may be H,
or comprising the steps of:
comprising the steps of:
reacting a hydrazine of Formula (II) NH2—N(R3)(R4), wherein R3 and R4 are as defined in Formula (I), with 2-amino-4-formylpyridine or with 2-amino-5-formylpyridine to obtain the corresponding hydrazone; and
reacting the obtained hydrazone with Rifamycin O, 3-iodorifamycin S, 3-bromorifamycin S, or 25-desacetyl-25-hydroxyrifamycin S.

### Claim 28 (depends on 27)

The process according to claim 27, wherein from about 1 to about 6 moles of the obtained hydrazone are used per mole of Rifamycin O or 3-iodo/bromo rifamycin S.