# US 5,891,878 A · Quinolones and their therapeutic use

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- Number: US 5,891,878 A
- Document ID: US5891878A
- Status: Granted
- Kind: A
- Application number: 08/691,338
- Filed: 1996-08-02
- Granted: 1999-04-06
- Earliest claimed: 1995-08-02
- Assignees: Chiroscience Limited
- Inventors: Steven Colin Beasley; John Gary Montana; Hazel John Dyke; Alan Findlay Haughan; Karen Ann Runcie; David Thomas Manallack; George Martin Buckley; Robert James Maxey; Hannah Jayne Kendall; Andrew Douglas Baxter
- Web page: https://patentgrep.com/patent/US5891878A

## CPC

- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/12: Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/16: Anti-Parkinson drugs
- 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 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

1-Alkyl-substituted-quinolone-3-carboxamides have therapeutic utility via inhibition of Phosphodiesterase IV esterase and/or Tumour Necrosis Factor activity. The compounds of the invention have the general formula (I): ##STR1## The compounds of the invention encompassed by formula (I) include enantiomers, diastereoisomers and mixtures, including racemic mixtures.

## Claims

### Claim 1

A method for treating a disease state capable of being modulated by inhibition of production of phosphodiesterase IV or tumour necrosis factor, wherein the disease state is a pathological condition selected from the group consisting of asthma, chronic bronchitis, adult respiratory distress syndrome, psoriasis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses of the eye, rheumatoid arthritis, gouty arthritis, and other arthritic conditions, atopic eczema, keratosis, ulcerative colitis, Crohn's disease, multi-infarct dementia, senile dementia, memory impairment associated with Parkinson's Disease, depression, tardive dyskinesia, gastroprotection and intermittent claudication, and wherein said method comprises the administration of a compound of formula (I) ##STR9## in which: R.sup.1 is C.sub.1-6 alkyl, C.sub.1-6 cycloalkylalkyl, C.sub.1-6 heterocycloalkyl, C.sub.1-6 arylalkyl or C.sub.1-6 heteroarylalkyl, any of which is optionally substituted by one or more substitutents selected from the group consisting of halo, C.sub.1-6 alkoxy, hydroxy, CN, CO.sub.2 H, CO.sub.2 C.sub.1-6 alkyl esters, CONHC.sub.1-6 alkyl amides, C.sub.1-6 alkyl, NR.sup.9 R.sup.10 and SO.sub.2 NR.sup.11 R.sup.12,
R.sup.3 is phenyl, pyridyl, thienyl, furyl, pyrazinyl, pyridazinyl, pyrimidinyl, or C.sub.3-10 cycloalkyl, to any of which is optionally fused a second, carboxylic or heterocyclic ring, and wherein the, or each, ring is optionally substituted at any available position by one or more substitutents selected from the group consisting of halogens, C.sub.1-6 alkoxy, OH, CN, COOH, CO.sub.2 C.sub.1-6 alkyl esters, CONHC.sub.1-6 alkyl amides, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, NR.sup.9 R.sup.10, SO.sub.2 NR.sup.11 R.sup.12, aryl, heteroaryl, cycloalkyl and heterocyclo;
Y is O or S;
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are the same or different and are each II, halo, C.sub.1-6 alkoxy, hydroxy, CN, CO.sub.2 H, CO.sub.2 C.sub.1-6 alkyl esters, CONHC.sub.1-6 alkyl amides, NR.sup.9 R.sup.10 or C.sup.1-6 alkyl, in which alkyl may be optionally substituted by halo, C.sub.1-6 alkoxy, hydroxy, CN, CO.sub.2 H, CO.sub.2 C.sub.1-6 alkyl esters, CONHC.sub.1-6 alkyl amides, NR.sup.9 R.sup.10 or SO.sub.2 NR.sup.11 R.sup.12, or any two adjacent groups R.sup.4 -R.sup.7 and the C atoms to which they are attached form a 5 or 6-membered ring containing 0, 1 or 2 heteroatoms;
either R.sup.9 and R.sup.10 are the same or different and are each H, C.sub.1-6 alkyl, aryl, heteroaryl, COCF.sub.3, SO.sub.2 CF.sub.3, cycloalkyl, C.sub.1-6 alkylcarbonyl, arylcarbonyl, C.sub.1-6 alkoxycarbonyl, arylsulphonyl or C.sub.1-6 alkylsulphonyl; or NR.sup.9 R.sup.10 is a 5 or 6-membered ring such as pyrrolidine, piperidine, morpholine, or piperazine ring;
R.sup.11 and R.sup.12 are the same or different and are each H, C.sub.1-6 alkyl or cycloalkyl; and
n=0-3;
with the proviso that when R.sup.3 is substituted cyclohexyl and n=1, the substitutents do not include COOH (or esters thereof);
wherein the compound is in the form of a racemate, an enantiomer or a mixture of enantiomers;
or a pharmaceutically-acceptable salt, solvate, hydrate or combination thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein R.sup.1 is not cycloalkylalkyl.

### Claim 3 (depends on 2)

The method of claim 2, wherein Y is O.

### Claim 4 (depends on 3)

The method of claim 3, wherein R.sup.3 is phenyl, thienyl, furyl or cycloalkyl, no two of R.sup.4 -R.sup.7 form a ring, and neither R.sup.9 nor R.sup.10 is aryl, heteroaryl, COCF.sub.3 or SO.sub.2 CF.sub.3.

### Claim 5 (depends on 3)

The method of claim 3, wherein R.sup.3 is pyridyl, no two of R.sup.4 -R.sup.7 form a ring, and neither R.sup.9 nor R.sup.10 is aryl, heteroaryl, COCF.sub.3 or SO.sub.2 CF.sub.3.

### Claim 6 (depends on 1)

The method of claim 1, wherein n=0-2.

### Claim 7 (depends on 1)

The method of claim 1, wherein R.sup.3 is pyridyl, phenyl, pyrindanyl, indanyl or tetralinyl.

### Claim 8 (depends on 1)

The method of claim 1, wherein R.sup.1 is alkyl.

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of
1-Ethyl-1,4-dihydro-4-oxo-N-›2-(4-pyridyl)ethyl!-6-(trifluoromethyl)-3-quin olinecarboxamide
1-Ethyl-1,4-dihydro-4-oxo-N-›2-(3-pyridyl)ethyl!-6-(trifluoromethyl)-3-quin olinecarboxamide
1-Ethyl-1,4-dihydro-4-oxo-N-(3-pyridylmethyl)-6-(trifluoromethyl)-3-quinoli necarboxamide
N-(2-Chlorobenzyl)-1-ethyl-1,4-dihydro-4-oxo-6-(trifluoromethyl)-3-quinolin ecarboxamide
1-Ethyl-1,4-dihydro-4-oxo-N-(2-pyridylmethyl)-6-(trifluoromethyl)-3-quinoli necarboxamide
N-›2-(2-Chlorophenyl)ethyl!-1-ethyl-1,4-dihydro-4-oxo-6-(trifluoromethyl)-3 -quinolinecarboxamide
1-Ethyl-1,4-dihydro-4-oxo-N-(4-pyridylmethyl)-6-(trifluoromethyl)-3-quinoli necarboxamide
1-Ethyl-1,4-dihydro-4-oxo-N-›2-(2-pyridyl)ethyl!-6-(trifluoromethyl)-3-quin olinecarboxamide
1-Ethyl-1,4-dihydro-4-oxo-N-›2-(phenyl)ethyl!-6-(trifluoromethyl)-3-quinoli necarboxamide
N-Benzyl-1-ethyl-1,4-dihydro-4-oxo-6-(trifluoromethyl)-3-quinolinecarboxami de
1-Ethyl-1,4-dihydro-4-oxo-N-(2-pyridylmethyl)-6-(trifluoromethyl)-3-quinoli necarboxamide hydrochloride
1-Ethyl-1,4-dihydro-4-oxo-N-›2-(3-pyridyl)ethyl!-6-(trifluoromethyl)-3-quin olinecarboxamide hydrochloride
1-Ethyl-1,4-dihydro-4-oxo-N-›3-(phenyl)propyl!-6-(trifluoromethyl)-3-quinol inecarboxamide
5-Ethyl-5,8-dihydro-N-(1-indanyl)-8-oxo-1,3-dioxolo›4,5-g!quinoline-7-carbo xamide
5-Ethyl-5,8-dihydro-8-oxo-N-(1-tetralinyl)-1,3-dioxolo›4,5-g!quinoline-7-ca rboxamide
5-Ethyl-5,8-dihydro-8-oxo-N-›2-(phenyl)ethyl!-1,3-dioxolo›4,5-g!quinoline-7 -carboxamide
5-Ethyl-5,8-dihydro-N-(2-indanyl)-8-oxo-1,3-dioxolo›4,5-g!quinoline-7-carbo xamide
5-Ethyl-5,8-dihydro-8-oxo-N-(2-tetralinyl)-1,3-dioxolo›4,5-g!-quinoline-7-c arboxamide
5-Ethyl-5,8-dihydro-N-›2-(3,4-dimethoxyphenyl)ethyl!-8-oxo-1,3-dioxolo›4,5- g!quinoline-7-carboxamide
5-Ethyl-5,8-dihydro-8-oxo-N-›2-(2-pyridyl)ethyl!-1,3-dioxolo›4,5-g!quinolin e-7-carboxamide
5-Ethyl-5,8-dihydro-8-oxo-N-›2-(4-pyridyl)ethyl!-1,3-dioxolo›4,5-g!quinolin e-7-carboxamide and
1-Ethyl-1,4-dihydro-4-oxo-N-›2-(4-pyridyl)ethyl!-7-(trifluoromethyl)-3-quin olinecarboxamide.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of
1-Ethyl-1,4-dihydro4-oxo-N-›2-(4-pyridyl)ethyl!-3-quinolinecarboxamide
5-Ethyl-5,8-dihydro-8-oxo-N-›2-(4-pyridyl)ethyl!-1,3-dioxolo›4,5-g!quinolin e-7-carboxamidehydrochloride
5-Ethyl-5,8-dihydro-N-(4-methoxyphenylmethyl)-8-oxo-1,3-dioxolo›4,5-g!quino line-7-carboxamide
1-Ethyl-1,4-dihydro-N-›1-(5,6-dimethoxy)indanyl!4-oxo-6-(trifluoromethyl)-3 -quinolinecarboxamide
5-Ethyl-5,8-dihydro-N-›1-(5,6-dimethoxy)indanyl!-8-oxo-1,3-dioxolo ›4,5-g!quinoline-7-carboxamide
5-Ethyl-5,8-dihydro-N-›2-(2,3-dimethoxyphenyl)ethyl!-8-oxo-1,3-dioxolo›4,5- g!quinoline-7-carboxamide
5-Ethyl-5,8-dihydro-8-oxo-N-›5-(5,6,7,8-tetrahydroquinoline)!-1,3-dioxolo›4 ,5-g!quinoline-7-carboxamide
1-Ethyl-1,4-dihydro-6,7-dimethoxy-4-oxo-N-›2-(4-pyridyl)ethyl!-3-quinolinec arboxamide
1-Ethyl-1,4-dihydro-4-oxo-6-methyl-N-›2-(4-pyridyl)ethyl!-3-quinolinecarbox amide
1-Ethyl-1,4-dihydro-4-oxo-6-methyl-N-›2-(4-pyridyl)ethyl!-3-quinolinecarbox amide hydrochloride
6-Fluoro-1,4-dihydro-4-oxo-N-›2-(4-pyridyl)ethyl!-1-›(4-pyridyl)methyl!-3-q uinolinecarboxamide
6-Fluoro-1,4-dihydro-4-oxo-N-›2-(4-pyridyl)ethyl!-1-›(4-pyridyl)methyl!-3-q uinolinecarboxamide dihydrochloride
1-Ethyl-1,4-dihydro-4-oxo-N-›pyrindan-7-yl!-6-(trifluoromethyl)-3-quinoline carboxamide
1-Ethyl-1,4-dihydro-N-›2-(2-methoxyphenyl)ethyl!-4-oxo-6-(trifluoromethyl)- 3-quinolinecarboxamide
1-Ethyl-1,4-dihydro-N-›2-(3-methoxyphenyl)ethyl!-4-oxo-6-(trifluoromethyl)- 3-quinolinecarboxamide
1-Ethyl-1,4-dihydro-N-›2-(4-methoxyphenyl)ethyl!-4-oxo-6-(trifluoromethyl)- 3-quinolinecarboxamide
1-Ethyl-1,4-dihydro-4-oxo-N-›pyrindan-7-yl!-6-(trifluoromethyl)-3-quinoline carboxamide hydrochloride
1-Ethyl-1,4-dihydro-N-›2-(3,4-dimethoxyphenyl)ethyl!-4-oxo-6-(trifluorometh yl)-3-quinolinecarboxamide
1-Ethyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-N-›2-(4-pyridyl)ethyl!-3-quino linecarboxamide
1-Ethyl-1,4-dihydro-N-›2-(4-pyridyl)ethyl!-4-thiocarbonyl-6-(trifluoromethy l)-3-quinolinecarboxamide
1-Ethyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-N-›2-(4-pyridyl)ethyl!-3-quinol inecarboxamide
1-Ethyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-N-›2-(4-pyridyl)ethyl!-3-quinol inecarboxamide hydrochloride
1-Ethyl-1,4-dihydro-N-›1-(5-methoxy)indanyl!-4-oxo-6-(trifluoromethyl)-3-qu inolinecarboxamide
1,4-Dihydro-4-oxo-1-n-propyl-N-›2-(4-pyridyl)ethyl!-6-(trifluoromethyl)-3-q uinolinecarboxamide
1,4-Dihydro-4-oxo-1-n-propyl-N-›2-(4-pyridyl)ethyl!-6-(trifluoromethyl)-3-q uinolinecarboxamide hydrochloride and
N-›1-(5-Acetamido)indanyl!-1-ethyl-1,4-dihydro-4-oxo-6-(trifluoromethyl)-3- quinolinecarboxamide.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound is in the form of an enantiomer, or mixture of enantiomers.

### Claim 12 (depends on 1)

The method of claim 1, with the further provisos that the compound is not one wherein:
(i) R.sup.3 --(CH.sub.2).sub.n -- is benzyl, pyridyl or furyl, Y is O, R.sup.1 alkyl R.sup.4, R.sup.7 and R.sup.8 are H, and R.sup.5 and R.sup.6 together are --OCH.sub.2 O--; and
(ii) R.sup.3 is phenyl, pyridyl or furyl, R.sup.1 is alkyl or arylalkyl, Y is O, and, while the other two are H, two of R.sup.4 -R.sup.7 and the C atoms to which they are attached form a furan ring.