# US 9,751,894 B2 · Cephem compounds, their production and use

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- Number: US 9,751,894 B2
- Document ID: US9751894B2
- Status: Granted
- Kind: B2
- Application number: 15/369,181
- Filed: 2016-12-05
- Published: 2017-06-15
- Granted: 2017-09-05
- Earliest claimed: 2015-12-10
- Assignees: Naeja-Rgm Pharmaceuticals Inc.
- Applicants: Naeja-Rgm Pharmaceuticals Inc.
- Inventors: Samarendra Nath Maiti; Dai Quoc Nguyen; Andhe V. N. Reddy; Judy Yip; Chan Minh Ha; Rong Ling; Rudong Shan; Madhava Reddy Madala
- Web page: https://patentgrep.com/patent/US9751894B2

## CPC

- C07D 501/56: with the 7-amino radical acylated by carboxylic acids containing hetero rings
- A61K 31/423: condensed with carbocyclic rings
- A61K 31/428: condensed with carbocyclic rings
- A61K 31/546: containing further heterocyclic rings, e.g. cephalothin
- A61K 31/69: Boron compounds
- A61P 31/04: Antibacterial agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 501/04: from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

Cephem compounds, pharmaceutically acceptable salts thereof, and methods of using same, wherein the compound has a bicyclic nitrogen-containing aromatic heterocyclic ring as the quaternary ammoniomethyl group at the 3-position and one or both of a terminal amidine residue (substituted or unsubstituted) attached to an aryl or a 5- or 6-membered heteroaryl group (substituted or unsubstituted) which is further attached through a spacer to the free N-atom of the quaternary nitrogen-containing bicyclic ring at the 3-side chain, or a terminal guanidine residue attached to an aryl or a 5- or 6-membered heteroaryl group (substituted or unsubstituted) which is further attached through a spacer to the free N-atom of the quaternary nitrogen-containing bicyclic ring at the 3-side chain.

## Claims

### Claim 1

A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein in the formula (I),
(i) A is defined by the formula (Ia):
Where X is N, C(H), C(F) or C(Cl);
(ii) B is defined as hydrogen, methyl, ethyl or represented by the formula (Ib)
wherein, R1 and R2 is independently hydrogen or lower alkyl; or
wherein R1 and R2 together may form a 3 to 6-membered spiro ring system; and
m is 0 or 1
(iii) C represents a quaternized bicyclic nitrogen containing aromatic heterocyclic ring represented by the formulae (Ic) to (Iz)
(iv) D represents CH2, CH2CH2 or CH2CO
(v) E represents a substituted benzene ring or a substituted 5- or 6-membered aromatic heterocyclic ring having at least one heteroatom selected from O, S and N, wherein the heteroaromatic ring includes pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, and thienyl;
(vi) F is substituted amidine or substituted guanidine; and
(vii) G is hydrogen, methyl, ethyl, C3-6 alkyl, C3-6 cycloalkyl or a substituted 5- or 6-membered aliphatic or a substituted 5- or 6-membered aromatic heterocyclic ring, wherein the heterocyclic ring is substituted with at least 1-2 hetero atoms selected from N, O, and S (αor β).

### Claim 2 (depends on 1)

A compound as recited in claim 1, where E is selected from a substituted aryl or a 5- and 6-membered aromatic heterocyclic rings

### Claim 3 (depends on 2)

A compound as recited in claim 2, wherein the optional substituents include chloro, fluoro, cyano, hydroxy, amino, carboxy, acetyl, methoxy, ethoxy, trifluoromethyl, pyrrolidinyloxy, and piperidinyloxy.

### Claim 4 (depends on 1)

A compound as recited in claim 1, wherein the preferred examples of “-C-D-E-F” include the following organic residues

### Claim 5 (depends on 1)

The compound of formula (I) as recited in claim 1, which is selected from the following group of compounds:

### Claim 6 (depends on 1)

A method of treating a bacterial infection comprising administering to a mammal in need thereof an antibacterially effective amount of a compound as recited in claim 1.

### Claim 7 (depends on 1)

A pharmaceutical composition containing as an active ingredient, at least one compound as recited in claim 1.

### Claim 8 (depends on 1)

A method of treating a bacterial infection comprising administering to a mammal in need thereof a combination of (i) an antibacterially effective amount of a compound as recited in claim 1, and (ii) a therapeutically effective amount of a β-lactamase inhibitor selected from the group consisting of:

### Claim 9 (depends on 1)

A pharmaceutical composition containing as an active ingredient at least (i) one compound as recited in claim 1 and (ii) a therapeutically effective amount of a β-lactamase inhibitor selected from the group consisting of:

### Claim 10 (depends on 8)

The method as recited in claim 8, wherein (i) and (ii) are administered simultaneously, sequentially, or separated in time.

### Claim 11 (depends on 9)

The pharmaceutical composition as recited in claim 9, wherein the ratio of the weight of (i) to the weight of (ii) is in the range of from about 1:20 to about 20:1.

### Claim 12 (depends on 1)

A process for preparing a compound of formula (I) as recited in claim 1, the process comprising one of the following processes:
Process I wherein the intermediate VIII (q =0, Y =chloride) is coupled with intermediate (IX) to provide the intermediate (X) followed by removal of protecting groups to provide the compound of formula (I)
or
Process II wherein the intermediate VIII (q =1, Y =iodide) is coupled with intermediate (IX) and subsequently reducing the sulfoxide to sulfide providing the intermediate (XI) by removal of the protecting groups provides the compound of formula (I)