Compounds useful as potassium channel openers

Abstract

The present invention discloses novel compounds which are useful as potassium channel openers, in particular as openers of the Kv7.4 potassium channel. The novel compounds are compounds according to formula I, ##STR00001##
wherein n=0 or 1, RL is a substituent selected from the group consisting of unsubstituted or substituted cycloalkyl groups, in particular bicycloalkyl groups, unsubstituted or substituted phenyl groups, unsubstituted or substituted thienyl groups or cyclopentathienyl groups, and unsubstituted or substituted indanyl groups, which optionally contain heteroatoms, and RR is a substituent selected from the group consisting of unsubstituted or substituted phenyl groups or unsubstituted or substituted benzyl groups, which optionally contain heteroatoms, or a stereoisomer, a tautomer, a prodrug or a salt, preferably pharmaceutically acceptable salt thereof.

Claims

1. A compound of formula I ##STR00007## wherein n=0, RL is a substituent selected from the group consisting of unsubstituted bicycloalkyl groups, and substituted thienyl groups, wherein said thienyl groups are substituted with at least one F-atom or Cl-atom, and RR is a substituted benzyl group, wherein said benzyl group comprises at least one substituent being SF.sub.5, or a stereoisomer, a tautomer, a prodrug or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein said bicycloalkyl groups selected as substituent RL comprise 5 to 10 C-atoms.

3. The compound according to claim 1, wherein said thienyl groups are substituted with at least one Cl-atom.

4. The compound according to claim 1, wherein said bicycloalkyl groups selected as substituent RL comprise 6 to 8 C-atoms.

5. The compound according to claim 1, wherein the compound is (1R,2R,4S)-rel-N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, or (1S,2S,4R)—N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide.

6. The compound according to claim 1, wherein the compound is 5-Chloro-N-(4-(pentafluorosulfanyl)benzyl)thiophene-2-carboxamide or 5-Fluoro-N-(4-(pentafluorosulfanyl)benzyl)thiophene-2-carboxamide.

7. A pharmaceutically acceptable salt of the compound according to claim 1.

8. A pharmaceutical composition or medicament, comprising: at least one compound according to claim 1, and a pharmaceutically acceptable carrier or diluent.

9. A method of using the compound according to claim 1, comprising administering to a subject a pharmaceutically effective amount of the compound of claim 1 for use as a pharmaceutical composition or a medicament.

10. The method according to claim 9, wherein said use is for treating a disorder associated with aberrant potassium channel activity in mammals.

11. The method according to claim 10, wherein the disorder to be treated is an inner ear hearing loss after damage or loss of sensory hair cells in an organ of Corti.

12. The method according to claim 9, wherein said use is for prophylaxis of an inner ear hearing loss.

Description

(1) In this context the drawings show

(2) FIG. 1: Schematic illustration of the experimental design to investigate otoprotective compounds in an ototoxic drug-induced hearing loss model in vivo.

(3) FIG. 2: Quantitative analysis of CAP responses on day 0. (A) CAP-threshold loss after pretreatment with ACOU001. (B) Otoprotection after local application of ACOU001 and kanamycin/furosemide in comparison to the treatment with the ototoxic drug alone.

(4) FIG. 3: Quantitative analysis of CAP responses at different observation time point. Otoprotection 7 days (A) and 21 days (B) after treatment with ACOU001 and kanamycin/furosemide in comparison to the treatment with the ototoxic drug alone.

(5) The typical workflow of the in vivo experiments is shown in FIG. 1. All animals received care in accordance with the standards described by the German law on Protecting Animals' (Tierschutzgesetz) and with the European Directive 2010/63/EU for the protection of animals used for experimental purposes. Experiments were approved by the local authorities (Application HN03/15).

(6) All procedures were performed under anesthesia using a mixture of Fentanyl, Midazolam and Medetomidine. During surgery and measurements animals were kept on a 37° C. heating pad. For repeated recording of the Compound Action Potential (CAP) of the auditory nerve, guinea pigs were bilaterally implanted with a permanent gold electrode at the round window (RW) niche connected to a miniature plug on the skull. Audiograms were determined between 0.5 and 45.6 kHz, at a resolution of 8 steps per octave. An automated threshold search algorithm was applied.

(7) After a baseline audiogram was measured, animals were pretreated with an ion channel activator, in this case with ACOU001, via local application to the middle ear. ACOU001 (internal designation of the applicant) is 5-Chloro-N-(4-(pentafluorosulfanyl)benzyl)thiophene-2-carboxamide.

(8) The chemical structure of this compound ACOU001 is as follows:

(9) ##STR00003##

(10) The solution containing ACOU001 was removed after 2 hours and the middle ear rinsed and dried out before CAP recordings were performed to assess threshold shifts. Guinea pigs were then deafened by local application to the middle ear using a mixture of 200 mg/ml kanamycin, 50 mg/ml furosemide and 100 μM ACOU001. CAP response thresholds were compared to ears which were exposed to the ototoxic agent alone. CAP recordings were performed 7, 14 and 21 days after this treatment. After the final measurement on day 21, animals were sacrificed, cochleae fixed by perfusion with 4% paraformaldehyde and prepared for immunohistological analysis to quantify hair cell (HC) protection.

(11) The results obtained from this set of experiments are shown in FIGS. 2 and 3. Compared to the baseline CAP-thresholds in untreated ears (FIG. 2A, (middle) broken line), pretreatment with the compound ACOU001 ((upper) solid line) lead to a small, most likely conductive, hearing loss ((lower) dotdashed line: difference between upper and middle line). This conductive hearings loss might be explained by remaining fluid in the middle ear after local application. The remaining fluid impairs middle ear transmission at low frequencies (FIG. 2A, black triangles).

(12) Exposure to kanamycin and furosemide (FIG. 2B, (upper) broken line) revealed severe pancochlear hearing loss. In contrast, application of ACOU001 together with the ototoxic drug ((middle) solid line) caused a significant reduction of hearing loss of 25 dB SPL (SPL: Sound Pressure Level) in mid to high frequencies (5-11 kHz) compared to the ototoxic drug alone (lower dotdashed line).

(13) Seven days after administration of kanamycin and furosemide, profound hearing loss was recorded and remained permanent in the entire frequency range (PTS: Permanent Threshold Shift) over a duration of 21 days (FIG. 3A/B, upper broken line). CAP curves after treatment with kanamycin/furosemide plus ACOU001 also shifted to higher threshold levels after seven days but ameliorated after 21 days (FIG. 3A/B, middle solid line). In comparison to the one deafened animal, a significant reduction of hearing loss (25-40 dB SPL) at all frequencies was recorded after 21 days of co-treatment with the aminoglycoside kanamycin plus ACOU001 (FIG. 3B, lower dotdashed line).

(14) Similar significant results (with hearing protections (reduction of hearing loss) of at least 20-30 dB SPL) are obtained during in vivo experiments with the compounds (1R,2R,4S)-rel-N-(3-(pentafluorosulfanyhbenzypicyclo[2.2.1]heptane-2-carboxamide

(15) ##STR00004## (1S,2S,4R)—N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide

(16) ##STR00005## N-(2,6-dimethyl-4-(pyrrolidin-1-yl)phenyl)-2-(5-chloro-thiophene-2-yl)acetamide

(17) ##STR00006##