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WO2004037266A1 - Compounds for the treatment of cough - Google Patents

Compounds for the treatment of cough Download PDF

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Publication number
WO2004037266A1
WO2004037266A1 PCT/EP2003/011759 EP0311759W WO2004037266A1 WO 2004037266 A1 WO2004037266 A1 WO 2004037266A1 EP 0311759 W EP0311759 W EP 0311759W WO 2004037266 A1 WO2004037266 A1 WO 2004037266A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
methyl
hydrogen
alkyl
cough
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2003/011759
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French (fr)
Inventor
Christine Charman
John R. Fozard
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Novartis Pharma GmbH Austria
Novartis AG
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Novartis Pharma GmbH Austria
Novartis AG
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Priority to AU2003274067A priority Critical patent/AU2003274067A1/en
Publication of WO2004037266A1 publication Critical patent/WO2004037266A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents

Definitions

  • This invention relates to organic compounds and, in particular to their use as pharmaceuticals.
  • the invention provides, in one aspect, use of a compound of formula I
  • R 1 is phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, C ⁇ -C -alkyl, trifluoromethyl, hydroxy and C ⁇ -C -alkoxy, R 2 is hydrogen or C ⁇ -C7-alkyl,
  • R 3 is hydrogen, C ⁇ -C 7 -alkyl or phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, C ⁇ -C7-alkyl, trifluoromethyl, hydroxy and C 1 -C7- alkoxy,
  • R 4 is phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, Ci-Cyalkyl, trifluoromethyl, hydroxy and Ci-Cyalkoxy; or is naphthyl, 1H- indol-3-yl or l-C ⁇ -C7-alkyl-indol-3-yl,
  • R 5 and R 6 are each independently of the other hydrogen or C ⁇ -C 7 -alkyl, at least one of R 5 and R 6 being hydrogen, and R 7 is C 3 -C8-cycloalkyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl.
  • the invention provides, in another aspect, a method of treating cough, in a subject, particularly a human subject, in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula I as hereinbefore defined.
  • Treatment of cough in accordance with the invention may be symptomatic.
  • Cough to be treated in accordance with the invention includes conditions associated with an action that occurs as the result of irritation of the throat, larynx and airways. It takes the form of a noisy expulsion of air, and its function is to clear the airways of the substances causing the irritation anything from particles of dust to smoke, chemicals, and virus-laden mucus. Cough may be due to one or more underlying diseases including chronic obstructive pulmonary disease (COPD), upper respiratory tract infections (UR ⁇ ), postnasal drip, acute viral infection, asthma, lung cancer, interstitial lung disease, gastroesophageal reflux disease (GERD), angiotensin converting enzyme-induced cough and heart failure.
  • COPD chronic obstructive pulmonary disease
  • UR ⁇ upper respiratory tract infections
  • postnasal drip postnasal drip
  • acute viral infection asthma
  • lung cancer interstitial lung disease
  • gastroesophageal reflux disease GEF
  • angiotensin converting enzyme-induced cough and heart failure angiotensin converting enzyme-
  • C ⁇ -C7-alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably C ⁇ -C 4 alkyl, especially methyl or ethyl, and more especially methyl.
  • Halogen is, for example, fluorine, chlorine, bromine or iodine.
  • Halophenyl is, for example, (fluoro-, chloro-, bromo- or iodo-)phenyl, preferably fluorophenyl or chlorophenyl, especially 4-fluorophenyl or 4-chlorophenyl, and more especially 4-chlorophenyl.
  • Dihalophenyl is, for example, dichlorophenyl, difluorophenyl or chlorofluorophenyl, preferably dichlorophenyl or difluorophenyl, especially 3,4-dichlorophenyl or 3,4- difluorophenyl, and more especially 3,4-dichlorophenyl.
  • Trihalophenyl is, for example, trifluorophenyl or trichlorophenyl.
  • l-C ⁇ -C7-alkyl-indol-3-yl is, for example, l-methyl-indol-3-yl.
  • C 3 -C 8 -Cycloalkyl - and analogously C5-C7-cycloalkyl - is in each case a cycloalkyl radical having the number of ring carbon atoms indicated.
  • C.-Cs-Cycloalkyl is therefore, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably cyclohexyl.
  • D-Azacycloheptan-2-on-3-yl corresponds to the following group
  • the compounds of formula I may be of formula IA
  • Compounds of formula IA are usually preferred for use in accordance with the invention.
  • Compounds of formula I having a basic group may, for example, form acid addition salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates.
  • suitable mineral acids such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates.
  • corresponding salts with bases are also possible, for example corresponding alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or organic amines, for example ammonium salts.
  • the invention relates preferably to the use of compounds of formula I wherein
  • R 1 is phenyl, 3,5-bistrifluoromethyl-phenyl or 3,4,5-trimethoxyphenyl,
  • R 2 is hydrogen or C ⁇ -C7-alkyl
  • R 3 is hydrogen or phenyl
  • R 4 is phenyl, halo-phenyl, dihalo-phenyl, trihalo-phenyl, 2-naphthyl, lH-indol-3-yl or 1-C ⁇ -
  • R 5 and R 6 are each independently of the other hydrogen or C ⁇ -C7-alkyl, at least one of R 5 and R 6 being hydrogen, and
  • R 7 is C5-C7cycloalkyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl.
  • the invention relates especially to the use of compounds of formula I wherein
  • R 1 is 3,5-bistrifluoromethyl-phenyl
  • R 2 is hydrogen, methyl or ethyl
  • R 3 is hydrogen or phenyl
  • R 4 is phenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichloro-phenyl, 3,4-difluoro-phenyl, 3- fluoro-4-chloro-phenyl, 3,4,5-trifluoro-phenyl, 2-naphthyl, lH-indol-3-yl or 1 -methyl -indol-
  • R 5 and R 6 are each independently of the other hydrogen or methyl, at least one of R s and R 6 being hydrogen, and
  • R 7 is cyclohexyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl.
  • the invention relates more especially to the use of compounds of formula I wherein
  • R 1 is 3,5-bistrifluoromethyl-phenyl
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen or phenyl
  • R 4 is phenyl, 4-chlorophenyl, 3,4-dichloro-phenyl, 2-naphthyl, lH-indol-3-yl or 1 -methyl - indol-3-yl,
  • R 5 and R 6 are hydrogen
  • R 7 is cyclohexyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl. Special mention should be made of each of the following sub-groups of a group of compounds of formula I:
  • the invention relates most importantly to the use of (4R)-4-[N'-methyl-N'-(3,5-bistrifluoro- methylbenzoyl)amino]-4-(3,4-dichlorobenzyl)-but-2-enoic acid N-[(R)-epsilon-caprolactam- 3-yl]-amide, i.e. a compound of formula II
  • the compounds of formula I in free or pharmaceutically acceptable salt form, may be prepared as described in WO 98/07694 or WO 01/85696. As mentioned therein, they may be in the form of their hydrates and/or may include other solvents, for example solvents which may have been used for the crystallisation of compounds in solid form.
  • the compounds of formula I may be obtained in the form of mixtures of stereoisomers, for example mixtures of diastereoisomers or mixtures of enantiomers, such as racemates, or possibly also in the form of pure stereoisomers.
  • Mixtures of diastereoisomers obtainable in accordance with the process or by some other method can be separated in customary manner into mixtures of enantiomers, for example racemates, or into individual diastereoisomers, for example on the basis of the physico-chemical differences between the constituents in known manner by fractional crystallisation, distillation and/or chromatography.
  • the more active isomer is isolated.
  • Mixtures of enantiomers, especially racemates, obtainable in accordance with the process or by some other method can be separated into the individual enantiomers by known methods, for example by recrystallisation from an optically active solvent, with the aid of microorganisms, by chromatography and/or by reaction with an optically active auxiliary compound, for example a base, acid or alcohol, to form mixtures of diastereoisomeric salts or functional derivatives, such as esters, separation thereof and freeing of the desired enantio- mer.
  • an optically active auxiliary compound for example a base, acid or alcohol
  • compounds of formula I in free form or in pharmaceutically acceptable salt form, may be administered by any appropriate route, for example orally, e.g. in tablet, capsule or liquid form, parenterally, for example in the form of an injectable solution or suspension, or intranasally, for example in the form of an aerosol or other atomisable formulation using an appropriate intranasal delivery device, e.g. a nasal spray such as those known in the art, or by inhalation. Oral administration is however preferred.
  • the compound of formula I in free or salt form may be administered in a pharmaceutical composition together with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition may be as described in WO 98/07694, for example dry powders, tablets, capsules, liquids, injection solutions, infusion solutions or inhalation suspensions as described in Examples A to E of WO 98/07694, or may be prepared using other formulating ingredients and techniques known in the art.
  • the dosage of the compound of formula I in free or salt form can depend on various factors, such as the activity and duration of action of the active ingredient, the severity of the condition to be treated, the mode of administration, the species, sex, ethnic origin, age and weight of the subject and/or its individual condition.
  • the daily dose for administration for example oral administration, to a warm-blooded animal, particularly a human being, weighing about 75 kg is estimated to be from approximately 1 mg to approximately 1000 mg, especially from approximately 5 mg to approximately 200 mg. That dose may be administered, for example, in a single dose or in several part doses of, for example, from 5 to 200 mg.
  • the suitability of a compound of formula I for the treatment of cough may be tested by determining the inhibitory effect of a compound of formula I on cough induced by release of endogenous neuropeptides in guinea pigs.
  • Unanaesthetised, unrestrained male Dunkin Hartley guinea pigs 250-500 g are placed individually in a transparent plastic whole body plethysmograph (Buxco, USA) and baseline airway function measured for 2 minutes.
  • the guinea pigs are exposed to a nebulised (DeVilbiss ultrasonic, USA) aqueous solution of citric acid (0.6 M) for 10 minutes.
  • the compound of formula I (0.3, 3.0 or 10.0 mg/kg) or vehicle (2% dimethylsulfoxide (DMSO), 1:5 CREMOPHOR El ⁇ saline) are dosed orally 2 hours prior to the 10 minute citric acid (0.6 M) challenge. Animals are not selected but rather randomly assigned to different groups. Each drug treatment group is further sub-divided into different groups for the different doses. All experiments have appropriate time matched controls. Values are given as means + s.e. mean. For statistical differences the data is analysed using ANONA and post-hoc Tukey's test, with a P value ⁇ 0.05 taken as significant.
  • Cough is measured as follows: the plethysmograph chamber is fitted with a microphone and connected to both an external speaker and a computer. The animals are continuously watched by an observer who counts the number of coughs. The criteria for cough are the characteristic high sound with the mouth open, which is readily distinguished from a sneeze. During cough there is a quick large abdominal movement which is detected as a transient increase in airflow over and above the normal flow.
  • Cough is measured using this method during the 10 minutes exposure and for a further 5 minutes following exposure.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The use of a compound of Formula (I) in free form or in the form of a pharmaceutically acceptable salt for the preparation of a medicament for the treatment of a cough, wherein R1, R2, R3, R4, R5, R6 and R7 have the meanings as indicated in the specification.

Description

COMPOUNDS FOR THE TREATMENT OF COUGH
This invention relates to organic compounds and, in particular to their use as pharmaceuticals.
The invention provides, in one aspect, use of a compound of formula I
Figure imgf000002_0001
in free form or in the form of a pharmaceutically acceptable salt for the preparation of a medicament for the treatment of a cough, wherein
R1 is phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, Cι-C -alkyl, trifluoromethyl, hydroxy and Cι-C -alkoxy, R2 is hydrogen or Cι-C7-alkyl,
R3 is hydrogen, Cι-C7-alkyl or phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, Cι-C7-alkyl, trifluoromethyl, hydroxy and C1-C7- alkoxy,
R4 is phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, Ci-Cyalkyl, trifluoromethyl, hydroxy and Ci-Cyalkoxy; or is naphthyl, 1H- indol-3-yl or l-Cι-C7-alkyl-indol-3-yl,
R5 and R6 are each independently of the other hydrogen or Cι-C7-alkyl, at least one of R5 and R6 being hydrogen, and R7 is C3-C8-cycloalkyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl.
The invention provides, in another aspect, a method of treating cough, in a subject, particularly a human subject, in need of such treatment, which comprises administering to said subject an effective amount of a compound of formula I as hereinbefore defined.
Treatment of cough in accordance with the invention may be symptomatic.
Cough to be treated in accordance with the invention includes conditions associated with an action that occurs as the result of irritation of the throat, larynx and airways. It takes the form of a noisy expulsion of air, and its function is to clear the airways of the substances causing the irritation anything from particles of dust to smoke, chemicals, and virus-laden mucus. Cough may be due to one or more underlying diseases including chronic obstructive pulmonary disease (COPD), upper respiratory tract infections (URΗ), postnasal drip, acute viral infection, asthma, lung cancer, interstitial lung disease, gastroesophageal reflux disease (GERD), angiotensin converting enzyme-induced cough and heart failure. The compounds of the formula I are effective in treating cough including non-productive cough, also known as dry cough, particularly non-productive cough associated with COPD or acute viral infection.
The general terms used hereinabove and hereinbelow preferably have the following meanings:
Cι-C7-alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably Cι-C4alkyl, especially methyl or ethyl, and more especially methyl.
Halogen is, for example, fluorine, chlorine, bromine or iodine.
Halophenyl is, for example, (fluoro-, chloro-, bromo- or iodo-)phenyl, preferably fluorophenyl or chlorophenyl, especially 4-fluorophenyl or 4-chlorophenyl, and more especially 4-chlorophenyl.
Dihalophenyl is, for example, dichlorophenyl, difluorophenyl or chlorofluorophenyl, preferably dichlorophenyl or difluorophenyl, especially 3,4-dichlorophenyl or 3,4- difluorophenyl, and more especially 3,4-dichlorophenyl.
Trihalophenyl is, for example, trifluorophenyl or trichlorophenyl.
l-Cι-C7-alkyl-indol-3-yl is, for example, l-methyl-indol-3-yl.
C3-C8-Cycloalkyl - and analogously C5-C7-cycloalkyl - is in each case a cycloalkyl radical having the number of ring carbon atoms indicated. C.-Cs-Cycloalkyl is therefore, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably cyclohexyl. D-Azacycloheptan-2-on-3-yl corresponds to the following group
Figure imgf000004_0001
which is derived from D(+)-epsilon-caprolactam (amino-)substituted in the 3-position [ « D- 3-amino-epsilon-caprolactam = (R)-3-amino-hexahydro-2-azepinone]. Analogously, L-aza- cycloheptan-2-on-3-yl corresponds to the group
Figure imgf000004_0002
which is derived from L(-)-epsilon-caprolactam (amino-)substituted in the 3-position [« L-3- amino-epsilon-caprolactam = (S)-3-amino-hexahydro-2-azepinone].
The compounds of formula I may be of formula IA
Figure imgf000004_0003
where * denotes the R configuration, or of formula IB
Figure imgf000004_0004
where * denotes the S configuration, where R1, R2, R3, R4, R5, R6 and R7 are as hereinbefore defined.
Compounds of formula IA are usually preferred for use in accordance with the invention. Compounds of formula I having a basic group may, for example, form acid addition salts with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates. Where the compounds of formula I contain an acid group, corresponding salts with bases are also possible, for example corresponding alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or organic amines, for example ammonium salts.
The invention relates preferably to the use of compounds of formula I wherein
R1 is phenyl, 3,5-bistrifluoromethyl-phenyl or 3,4,5-trimethoxyphenyl,
R2 is hydrogen or Cι-C7-alkyl,
R3 is hydrogen or phenyl,
R4 is phenyl, halo-phenyl, dihalo-phenyl, trihalo-phenyl, 2-naphthyl, lH-indol-3-yl or 1-Cι-
C7-alkyl-indol-3-yl,
R5 and R6 are each independently of the other hydrogen or Cι-C7-alkyl, at least one of R5 and R6 being hydrogen, and
R7 is C5-C7cycloalkyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl.
The invention relates especially to the use of compounds of formula I wherein
R1 is 3,5-bistrifluoromethyl-phenyl,
R2 is hydrogen, methyl or ethyl,
R3 is hydrogen or phenyl,
R4 is phenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichloro-phenyl, 3,4-difluoro-phenyl, 3- fluoro-4-chloro-phenyl, 3,4,5-trifluoro-phenyl, 2-naphthyl, lH-indol-3-yl or 1 -methyl -indol-
3-yl,
R5 and R6 are each independently of the other hydrogen or methyl, at least one of Rs and R6 being hydrogen, and
R7 is cyclohexyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl.
The invention relates more especially to the use of compounds of formula I wherein
R1 is 3,5-bistrifluoromethyl-phenyl,
R2 is hydrogen or methyl,
R3 is hydrogen or phenyl,
R4 is phenyl, 4-chlorophenyl, 3,4-dichloro-phenyl, 2-naphthyl, lH-indol-3-yl or 1 -methyl - indol-3-yl,
R5 and R6 are hydrogen, and
R7 is cyclohexyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl. Special mention should be made of each of the following sub-groups of a group of compounds of formula I:
(1) compounds of formula I wherein R7 is D-azacycloheptan-2-on-3-yl; (2) compounds of formula I wherein R5 and R6 are hydrogen; (3) compounds of formula I wherein R1 is phenyl, 3,5-bistrifluoromethyl-phenyl or 3,4,5-trimethoxyphenyl; (4) compounds of formula I in free form, that is to say not in the form of a salt.
Specific examples of compounds of formula I include:
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(l-methyl-indol-3-yl)-pent-2- enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(l-methyl-indol-3-yl)-pent-2- enoic acid N-[(S)-epsilon-caprolactam-3-yl]-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(l-methyl-indol-3-yl)-pent-2- enoic acid N-cyclohexyl-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(l-methyl-indol-3-yl)-2- methyl-pent-2-enoic acid N-cyclohexyl-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(l-methyl-indol-3-yl)-2- methyl-pent-2-enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide, (4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(l-methyl-indol-3-yl)-2- methyl-pent-2-enoic acid N-[(S)-epsilon-caprolactam-3-yl]- amide,
(4R)-(N'-methyl-N'-benzoyl-amino)-5-(l-methyl-indol-3-yl)-2-methyl-pent-2-enoic acid N- [(R)-epsilon-caprolactam-3-yl]-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(naphth-2-yl)-pent-2-enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide,
(4R)-(N'-methyl-N'-benzoyl)-amino-5-(naphth-2-yl)-pent-2-enoic acid N-[(R)-epsilon- caprolactam-3-yl]-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(naphth-2-yl)-2-methyl-pent- 2-enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide,
(4R)-[N'-methyl-N'-(3,4,5-trimethoxy-benzoyl)-amino]-5-(naphth-2-yl)-2-methyl-pent-2- enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(naphth-2-yl)-2-methyl-pent- 2-enoic acid N-[(S)-epsilon-caprolactam-3-yl]-amide, (4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(naphth-2-yl)-2-methyl-pent-
2-enoic acid N-cyclohexyl-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(l-methyl-indol-3-yl)-pent-2- enoic acid N-[(S)-epsilon-caprolactam-3-yl]-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(4-chlorobenzyl)-but-2-enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(4-chlorobenzyl)-but-2-enoic acid N-[(S)-epsilon-caprolactam-3-yl]-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(4-chlorobenzyl)-but-2-enoic acid N-cyclohexyl-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(3,4-dichlorobenzyl)-but-2- enoic acid N-cyclohexyl-amide,
(4R)-[N,-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(3,4-difluorobenzyl)-but-2- enoic acid N-cyclohexyl-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chlorophenyl)-2-methyl- pent-2-enoic acid N-cyclohexylamide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chlorophenyl)-2-methyl- pent-2-enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(4-chlorobenzyl)-2-methyl- but-2-enoic acid [(S)-epsilon-caprolactam-3-yl]-amide,
(4R)-[N'-ethyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chlorophenyl)-pent-2-enoic acid N-[(S)-epsilon-caprolactam-3-yl]-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chlorophenyl)-3-methyl- pent-2-enoic acid N-cyclohexyl-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(4-chlorobenzyl)-3-methyl- but-2-enoic acid [(R)-epsilon-caprolactam-3-yl]-amide,
(4R)-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(4-chlorobenzyl)-but-2-enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide,
(4R)-4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(3,4-dichlorobenzyl)-but-2- enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide,
(4R)- and (4S)-4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(3-fluoro-4- chlorobenzyl)-but-2-enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide,
(4R)- and (4S)-4-[N,-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(3,4- difluorobenzyl)-but-2-enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide, (4R)- and (4S)-4-[N,-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(3,4- dibromobenzyl)-but-2-enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide,
(4R)- and (4S)-4-[N'-methyl-N,-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(3,4,5- trifluorobenzyl)-but-2-enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide,
(4R)- and (4S)-4-[N,-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-4-(4-fluorobenzyl)- but-2-enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide,
(4R)- and (4S)-[N'-(3,5-bistrifluoromethyl-benzoyl)-N'-methyl-amino]-5,5-diphenyl-pent-2- enoic acid N-[(S)-epsilon-caprolactam-3-yl]-amide,
(4S)-4-[N'-methyl-N'-(3,5-bistrifluoromethylbenzoyl)amino]-4-(3,4-dichlorobenzyl)-but-2- enoic acid N-[(R)-epsilon-caprolactam-3-yl]-amide,
(4R)-4-[N'-methyl-N'-(3,5-bistrifluoromethylbenzoyl)amino]-4-(3,4-dichlorobenzyl)-but-2- enoic acid N-[(S)-epsilon-caprolactam-3-yl]-amide, and
(4S)-4-[N'-methyl-N'-(3,5-bistrifluoromethylbenzoyl)amino]-4-(3,4-dichlorobenzyl)-but-2- enoic acid N-[(S)-epsilon-caprolactam-3-yl]-amide.
The invention relates most importantly to the use of (4R)-4-[N'-methyl-N'-(3,5-bistrifluoro- methylbenzoyl)amino]-4-(3,4-dichlorobenzyl)-but-2-enoic acid N-[(R)-epsilon-caprolactam- 3-yl]-amide, i.e. a compound of formula II
Figure imgf000008_0001
The compounds of formula I, in free or pharmaceutically acceptable salt form, may be prepared as described in WO 98/07694 or WO 01/85696. As mentioned therein, they may be in the form of their hydrates and/or may include other solvents, for example solvents which may have been used for the crystallisation of compounds in solid form.
Depending upon the nature of the variables and the corresponding number of centres of asymmetry and also upon the starting materials and procedures chosen, the compounds of formula I may be obtained in the form of mixtures of stereoisomers, for example mixtures of diastereoisomers or mixtures of enantiomers, such as racemates, or possibly also in the form of pure stereoisomers. Mixtures of diastereoisomers obtainable in accordance with the process or by some other method can be separated in customary manner into mixtures of enantiomers, for example racemates, or into individual diastereoisomers, for example on the basis of the physico-chemical differences between the constituents in known manner by fractional crystallisation, distillation and/or chromatography. Advantageously the more active isomer is isolated.
Mixtures of enantiomers, especially racemates, obtainable in accordance with the process or by some other method can be separated into the individual enantiomers by known methods, for example by recrystallisation from an optically active solvent, with the aid of microorganisms, by chromatography and/or by reaction with an optically active auxiliary compound, for example a base, acid or alcohol, to form mixtures of diastereoisomeric salts or functional derivatives, such as esters, separation thereof and freeing of the desired enantio- mer. Advantageously the more active enantiomer is isolated.
In the treatment of disorders in accordance with the invention, compounds of formula I, in free form or in pharmaceutically acceptable salt form, may be administered by any appropriate route, for example orally, e.g. in tablet, capsule or liquid form, parenterally, for example in the form of an injectable solution or suspension, or intranasally, for example in the form of an aerosol or other atomisable formulation using an appropriate intranasal delivery device, e.g. a nasal spray such as those known in the art, or by inhalation. Oral administration is however preferred.
The compound of formula I in free or salt form may be administered in a pharmaceutical composition together with a pharmaceutically acceptable diluent or carrier. Such compositions may be as described in WO 98/07694, for example dry powders, tablets, capsules, liquids, injection solutions, infusion solutions or inhalation suspensions as described in Examples A to E of WO 98/07694, or may be prepared using other formulating ingredients and techniques known in the art.
The dosage of the compound of formula I in free or salt form can depend on various factors, such as the activity and duration of action of the active ingredient, the severity of the condition to be treated, the mode of administration, the species, sex, ethnic origin, age and weight of the subject and/or its individual condition. In a normal case the daily dose for administration, for example oral administration, to a warm-blooded animal, particularly a human being, weighing about 75 kg is estimated to be from approximately 1 mg to approximately 1000 mg, especially from approximately 5 mg to approximately 200 mg. That dose may be administered, for example, in a single dose or in several part doses of, for example, from 5 to 200 mg.
The suitability of a compound of formula I for the treatment of cough, for example nonproductive cough, may be tested by determining the inhibitory effect of a compound of formula I on cough induced by release of endogenous neuropeptides in guinea pigs. Unanaesthetised, unrestrained male Dunkin Hartley guinea pigs (250-500 g) are placed individually in a transparent plastic whole body plethysmograph (Buxco, USA) and baseline airway function measured for 2 minutes. The guinea pigs are exposed to a nebulised (DeVilbiss ultrasonic, USA) aqueous solution of citric acid (0.6 M) for 10 minutes.
The compound of formula I (0.3, 3.0 or 10.0 mg/kg) or vehicle (2% dimethylsulfoxide (DMSO), 1:5 CREMOPHOR ElΛsaline) are dosed orally 2 hours prior to the 10 minute citric acid (0.6 M) challenge. Animals are not selected but rather randomly assigned to different groups. Each drug treatment group is further sub-divided into different groups for the different doses. All experiments have appropriate time matched controls. Values are given as means + s.e. mean. For statistical differences the data is analysed using ANONA and post-hoc Tukey's test, with a P value < 0.05 taken as significant.
Cough is measured as follows: the plethysmograph chamber is fitted with a microphone and connected to both an external speaker and a computer. The animals are continuously watched by an observer who counts the number of coughs. The criteria for cough are the characteristic high sound with the mouth open, which is readily distinguished from a sneeze. During cough there is a quick large abdominal movement which is detected as a transient increase in airflow over and above the normal flow.
Cough is measured using this method during the 10 minutes exposure and for a further 5 minutes following exposure.
Exposure of animals pre-treated with the vehicle (0.9% saline) for 0.6 M citric acid results in a cough response. Oral administration of (4R)-4-[Ν'-methyl-Ν'-(3,5-bistrifluoro- methylbenzoyl)amino]-4-(3,4-dichlorobenzyl)-but-2-enoic acid N-[(R)-epsilon-caprolactam- 3-yl]-amide (0.3, 3 or 10 mg/kg, p.o. -2h) significantly (P < 0.05) inhibits cough by 62 + 11, 63 ± 8 and 86 ± 4%, respectively compared with vehicle (2% DMSO, 1:5 CREMOPHOR EL®:0.9% saline)-treated animals.

Claims

1. The use of a compound of formula I
Figure imgf000012_0001
in free form or in the form of a pharmaceutically acceptable salt for the preparation of a medicament for the treatment of cough, wherein
R1 is phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, Cι-C7-alkyl, trifluoromethyl, hydroxy and Cι-C7-alkoxy, R2 is hydrogen or Cι-C7-alkyl,
R3 is hydrogen, G-C7-alkyl or phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, G-C7-alkyl, trifluoromethyl, hydroxy and C1-C7- alkoxy,
R4 is phenyl that is unsubstituted or is substituted by 1, 2 or 3 substituents selected from the group halogen, G-C7-alkyl, trifluoromethyl, hydroxy and Cι-C7-alkoxy; or is naphthyl, 1H- indol-3-yl or l-Cι-C7-alkyl-indol-3-yl,
R5 and R6 are each independently of the other hydrogen or Cι-C7-alkyl, at least one of R5 and R6 being hydrogen, and R7 is C3-C8-cycloalkyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl.
2. Use according to claim 1, in which the compound of formula I is of formula IA
Figure imgf000012_0002
where * denotes the R configuration and R1, R2, R3, R4, R5, R6 and R7 are as defined in claim 1.
3. Use according to claim 1 or 2, in which
R1 is phenyl, 3,5-bistrifluoromethyl-phenyl or 3,4,5-trimethoxyphenyl,
R2 is hydrogen or G-C7-alkyl,
R3 is hydrogen or phenyl, R4 is phenyl, halo-phenyl, dihalo-phenyl, trihalo-phenyl, 2-naphthyl, lH-indol-3-yl or 1-G-
C7-alkyl-indol-3-yl,
R5 and R6 are each independently of the other hydrogen or Cι-C7-alkyl, at least one of R5 and R6 being hydrogen, and
R7 is Cs-C7cycloalkyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl.
4. Use according to claim 1 or 2, in which R1 is 3,5-bistrifluoromethyl-phenyl,
R2 is hydrogen, methyl or ethyl,
R3 is hydrogen or phenyl,
R4 is phenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichloro-phenyl, 3,4-difluoro-phenyl, 3- fluoro-4-chloro-phenyl, 3,4,5-trifluoro-phenyl, 2-naphthyl, lH-indol-3-yl or 1-methyl-indol-
3-yl,
RJ and R6 are each independently of the other hydrogen or methyl, at least one of R5 and R6 being hydrogen, and
R7 is cyclohexyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl.
5. Use according to claim 1 or 2, in which R1 is 3,5-bistrifluoromethyl-phenyl,
R2 is hydrogen or methyl,
R3 is hydrogen or phenyl,
R4 is phenyl, 4-chlorophenyl, 3,4-dichloro-phenyl, 2-naphthyl, lH-indol-3-yl or 1-methyl- indol-3-yl,
R5 and R6 are hydrogen, and
R7 is cyclohexyl, D-azacycloheptan-2-on-3-yl or L-azacycloheptan-2-on-3-yl.
6. Use according to claim 1, in which the compound of formula I is a compound of formula
Figure imgf000013_0001
7. Use according to any one of claims 1 to 6, in which the cough is a productive cough.
8. Use according to any one of claims 1 to 6, in which the cough is a non-productive cough.
9. Use according to claim 8, in which the cough is associated with chronic obstructive pulmonary disease or acute viral infection.
10. Use according to claim 8, in which the cough is associated with asthma.
PCT/EP2003/011759 2002-10-24 2003-10-23 Compounds for the treatment of cough Ceased WO2004037266A1 (en)

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Publication number Priority date Publication date Assignee Title
WO2006045820A1 (en) * 2004-10-27 2006-05-04 Laboratori Guidotti S.P.A. Pharmaceutical compositions based on nk2 antagonists for pediatric use
EA012264B1 (en) * 2004-10-27 2009-08-28 Лаборатори Гуидотти С.П.А. Pharmaceutical compositions based on nk2 antagonists for pediatric use
US7727955B2 (en) 2004-10-27 2010-06-01 Laboratori Guidotti S.P.A. Pharmaceutical compositions based on NK2 antagonists for pediatric use
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