# US 2014/0155357 A1 · Substituted tetracycline compounds

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- Number: US 2014/0155357 A1
- Document ID: US20140155357A1
- Status: Published application
- Kind: A1
- Application number: 13/918,197
- Filed: 2013-06-14
- Published: 2014-06-05
- Earliest claimed: 2004-10-25
- Inventors: Paul Abato; Haregewein Assefa; Joel Berniac; Beena Bhatia; Todd Bowser; Jackson Chen; Mark Grier; Laura Honeyman; Mohamed Y. Ismail; Mark L. Nelson; Kwasi Ohemeng; Jingwen Pan
- Web page: https://patentgrep.com/patent/US20140155357A1

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 1/10: Laxatives
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 33/06: Antimalarials
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 237/26: of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
- C07C 251/48: with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
- C07C 255/59: the carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C 259/10: having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
- C07C 271/18: to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
- C07C 271/22: to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
- C07C 271/24: with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07D 207/335: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 207/337: Radicals 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 211/70: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 213/30: Oxygen atoms
- C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
- C07D 213/61: Halogen atoms or nitro radicals
- C07D 213/73: Unsubstituted amino or imino radicals
- C07D 213/74: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- C07D 213/84: Nitriles
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 241/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 261/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 263/32: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 277/28: Radicals substituted by nitrogen atoms
- C07D 277/30: Radicals 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 295/096: with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- 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 295/192: from aromatic carboxylic acids
- C07D 307/46: Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
- C07D 307/52: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 307/54: Radicals 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 309/14: Nitrogen atoms not forming part of a nitro radical
- C07D 333/20: by nitrogen atoms (nitro, nitroso radicals C07D333/12)
- C07D 333/24: Radicals 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 333/38: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 487/04: Ortho-condensed systems
- C07C 2601/02: with a three-membered ring
- C07C 2603/46: 1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention pertains, at least in part, to novel substituted tetracycline compounds. These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for tetracycline compounds such as blocking tetracycline efflux and modulation of gene expression.

## Claims

### Claim at position 1

1-33. (canceled)

### Claim 34

A tetracycline compound of Formula (III):
wherein
R9 is R′—O—N═CR″—, R′—OC(═O)—, R9aR9bNC(═O)—, methoxycarbonyl substituted alkynyl, pyrazinyl, alkylaminocarbonylalkyl, methoxymethyl, methoxymethyl substituted alkynyl, dimethylaminocarbonyl, cyclopropyl, methyl, amino substituted pyridinyl, alkoxyalkyl, alkylcarbonyl, arylcarbonyl, pyrimidinyl, alkoxycarbonyl substituted alkynyl, oxazolyl, pyrazolyl, carboxylate, halogen, piperidinylcarbonyl, alkyoxyalkyl substituted alkynyl, pyridinyl, thiazolyl, substituted or unsubstituted arylthiocarbonyl, cyano, deuterated alkylaminoalkyl, pyrrolidonylcarbonyl, carboxylatecarbonyl, alkylcarbonyl substituted phenyl, cyano substituted pyridinyl, aminocarbonyl substituted phenyl, dialkylaminomethyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted furanyl, alkylcarbonylamino substituted pyridinyl, dialkylamino substituted phenyl, carboxylate substituted phenyl, azepanylcarbonyl, or piperazinylcarbonyl;
R10 is hydrogen or alkenyl;
R′ is unsubstituted alkyl, amino substituted alkyl, methoxy substituted alkyl, halogen substituted alkyl;
R″ is alkyl;
R9a is hydrogen or alkyl;
R9b is alkyl, hydroxyl, alkoxy, hydroxyalkyl, alkoxyalkyl, alkylcarbonylaminoalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aryl, cycloalkyl or aminoalkyl; and pharmaceutically acceptable salts, esters and prodrugs thereof, provided that when R9 is halogen, then R10 is alkenyl.

### Claim at position 3

35-65. (canceled)

### Claim 66 (depends on 34)

The compound of claim 34, wherein R9 is methoxycarbonyl substituted alkynyl, pyrazinyl, methoxymethyl, cyclopropyl, methyl, methoxymethyl substituted alkynyl, amino substituted pyridinyl, alkylcarbonyl, arylcarbonyl, pyrimidinyl, oxazolyl, pyrazolyl, carboxylate, pyridinyl, thiazolyl, substituted or unsubstituted thiophenyl, piperidinylcarbonyl, dialkylaminomethyl, cyano, substituted or unsubstituted arylthiocarbonyl, deuterated alkylaminoalkyl, substituted furanyl, isoxolazolyl, cyano substituted pyridinyl, alkylcarbonylamino substituted pyridinyl, dialkylamino substituted phenyl, pyrrolidonylcarbonyl, azepanylcarbonyl, carboxylatecarbonyl, alkylcarbonyl substituted phenyl, aminocarbonyl substituted phenyl, carboxylate substituted phenyl or piperazinylcarbonyl.

### Claim at position 5

67-78. (canceled)

### Claim 79 (depends on 34)

The tetracycline compound of claim 34, wherein said compound is:

### Claim at position 7

80-258. (canceled)

### Claim 259 (depends on 34)

A method for treating a tetracycline responsive state in a subject, comprising administering to said subject an effective amount of a tetracycline compound of claim 34, such that said subject is treated.

### Claim 260 (depends on 259)

The method of claim 259, wherein said tetracycline responsive state is malaria.

### Claim 261 (depends on 259)

The method of claim 259, wherein said tetracycline responsive state is a bacterial infection, a viral infection, or a parasitic infection.

### Claim at position 11

262-265. (canceled)

### Claim 266 (depends on 259)

The method of claim 259, wherein said tetracycline associated state is multiple sclerosis.

### Claim 267 (depends on 259)

The method of claim 259, wherein said subject is a human.

### Claim 268 (depends on 259)

The method of claim 259, wherein said tetracycline compound is administered with a pharmaceutically acceptable carrier.

### Claim 269 (depends on 34)

A pharmaceutical composition comprising a therapeutically effective amount of a tetracycline compound of claim 34 and a pharmaceutically acceptable carrier.

### Claim 270 (depends on 79)

The tetracycline compound of claim 79, wherein said compound is:

### Claim 271 (depends on 259)

The method of claim 259, wherein the tetracycline compound is:

### Claim 272 (depends on 269)

The pharmaceutical composition of claim 269, wherein the tetracycline compound is: