HK1145151A - 1-amino-alkylcyclohexane derivatives for the treatment of cochlear tinnitus - Google Patents

Description

1-amino-alkylcyclohexane derivatives for the treatment of cochlear tinnitus

Technical Field

The present invention relates to the treatment of an individual afflicted with cochlear tinnitus comprising administering to said individual an effective amount of a 1-amino-alkylcyclohexane derivative.

Background

Tinnitus (tinnitius) is commonly referred to as "ringing in the ear" -a sound sensation produced in the absence of an exogenous acoustic signal. Tinnitus is defined as "acoustic sensation in the cochlea produced solely by activity in the nervous system without any corresponding mechanical, vibratory activity, i.e., tinnitus resembling the sensation of an auditory illusion" (Jastreboff et al, J Am Acad Audio 2000; 11 (3): 162-. Tinnitus is often associated with reduced sound tolerance (i.e. hyperacusis).

The pathophysiology of subjective tinnitus remains unclear, and the clear pathogenesis of tinnitus has not been established. Tinnitus can be caused by a number of environmental and physical triggers. Among these factors, acute acoustic trauma, occupational noise, and entertainment music are most often mentioned. In general, tinnitus appears to be a result of neuronal dysfunction in the auditory pathway. This dysfunction is erroneously perceived by the higher auditory center as a sound, which can lead to a change in function within the auditory nervous system. Inappropriate functional changes in cortical architecture may lead to a shift in the balance between excitatory and inhibitory neurotransmission and may lead to more severe tinnitus. In any case, potential dysfunction in the auditory pathway and auditory cortex is associated with the activity of the prefrontal cortex and limbic system.

In most cases (95%), sensory tinnitus is completely subjective in nature, e.g., there is no physical source of an identifiable acoustic signal and therefore cannot be heard externally. A physical examination is performed to exclude objective tinnitus (e.g., the patient's perception of sound is caused by a genuine source of acoustic waves, such as sound from turbulence in blood vessels reaching the cochlea). Tinnitus may be classified according to the duration of the tinnitus and the degree of tinnitus expression (e.g., the severity or disturbance of the tinnitus) (McCombe et al, Clin Otolarynggol 2001; 26 (5): 388. sup. -. 393 and Davis et al, epidemic of Tinnitus. in: Tyler R, edition. Tinnitus handbook. san Diego: Single Publishing Group; 2000.p. 1-23). Tinnitus can be a serious affliction to the patient with social and psychological complications in terms of its effects.

It has also been suggested to further divide the tinnitus into two groups, depending on the tinnitus perceived by the affected individuals: peripheral tinnitus and central tinnitus. It is speculated that peripheral (or cochlear) tinnitus originates from the peripheral nervous system and cochlea, and central tinnitus originates from the auditory cortex.

The physiology of the cochlea provides some help in understanding the causes of those forms of disease associated with the cochlea. Two rows of hair cells are found in the cochlea. The Outer Hair Cells (OHC) actively contract in the presence of sound, increasing the incoming low oscillation signal, modulating the response of the Inner Hair Cells (IHC). Noise exposure, including frequent, repeated, or even a single "blast trauma", can damage cochlear hair cells, particularly their delicate cilia. OHCs are more sensitive to noise, ototoxic drugs, trauma, etc. because they require a greater amount of oxygen than IHCs. Impaired OHC can lead to a reduction in auditory system dynamic range and impaired frequency selectivity due to loss of amplification of activity. Uncontrolled contractions of an impaired OHC stimulate IHC and nerve action potentials (which are translated into sound by the brain). IHC injury leads to abnormal ciliary deviation, which causes depolarization of the cells, leads to uncontrolled release of neurotransmitters and again triggers a sound sensation without a real source of sound (Baguley, Br Med Bull. 2002; 63: 195-.

Over time, higher levels of auditory pathways may be involved and tinnitus perception may no longer be dependent on cochlear pathology. A large central amplification (central amplification) triggered by pathological cognitive aggregation occurs. Presumably, an amplification feedback mechanism was established between the peripheral system and the CNS cognitive domain (Zenner, Ziel. Dtsch Arztebl.2001; 37: 2361-.

Although a number of afferent, mainly glutamatergic, nerve fibers are produced by IHC (Furness et al, J Neurosci.2003 Dec 10; 23 (36): 11296-11304), OHC is the main target for efferent nerve fibers and acetylcholine, the main efferent neurotransmitter in the cochlea (Dallos et al, J Neurosci.1997 Mar 15; 17 (6): 2212-2226). It is believed that excess glutamate in cochlear neurons can lead to tinnitus. Thus, several methods for treating tinnitus have been established through the use of NMDA receptor blockers, such as acamprosate or caroverine. Studies of these substances have shown little success, probably because the therapeutic target is primarily an afferent part of the auditory system, with only a slight effect on efferent neurotransmission.

Maison et al (J Neurosci.2002Dec 15; 22 (24): 10838-.

However, to date, there has been no recognized specific Tinnitus treatment that can reproducibly reduce Tinnitus and the Tinnitus-induced affliction beyond the placebo effect (Dobie, Laryngososcope 1999; 109 (8): 1202-. Thus, there is a need for a drug product that is effective in treating or preventing tinnitus.

It has been discovered that 1-amino-alkylcyclohexanes, such as neramexane (also known as 1-amino-1, 3, 3, 5, 5-pentamethylcyclohexane), can be used to treat a variety of diseases, particularly neurological diseases including alzheimer's disease and neuropathic pain. 1-amino-alkylcyclohexanes, such as neramexane, are disclosed in detail in U.S. patent nos. 6,034,134 and 6,071,966, the subject matter of which is incorporated herein by reference. It is believed that the therapeutic effect of 1-amino-alkylcyclohexanes, such as neramexane, is related to the effect of inhibiting excessive glutamate at the neuronal N-methyl-D-aspartate (NMDA) receptor, and for this reason this compound falls into the category of NMDA antagonists, or NMDA receptor antagonists. Neramexane has also been disclosed to exhibit α 9/α 10 nicotinic receptor antagonist activity (Plazas et al, Eur J Pharmacol, 2007Jul 2; 566 (1-3): 11-19).

US patent No.6,034,134 discloses that 1-amino-alkylcyclohexanes can be used for the treatment of tinnitus due to their NMDA receptor antagonist activity.

The inventors have found that 1-amino-alkylcyclohexanes such as neramexane are effective in the treatment of cochlear tinnitus.

Summary of The Invention

The present invention relates to a 1-amino-alkylcyclohexane derivative for the treatment or prevention of cochlear tinnitus in a subject in need thereof.

In another aspect the present invention relates to the use of a 1-amino-alkylcyclohexane derivative for the manufacture of a medicament for the treatment or prevention of cochlear tinnitus in a subject in need thereof. The 1-amino-alkylcyclohexane derivative may be neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate.

In another aspect of the invention, the treatment is performed within three (3) to twelve (12) months of onset of tinnitus (e.g., treatment within three (3) to twelve months (including three (3) to eight (8) months) after the first appearance of tinnitus). The 1-amino-alkylcyclohexane derivative may be neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate.

In another aspect of this treatment of the present invention, the individual is afflicted with tinnitus associated with hearing loss or tinnitus associated with mild hearing loss.

In another aspect the present invention relates to 1-amino-alkylcyclohexane derivatives for the treatment or prevention of tinnitus associated with hearing loss or mild hearing loss, and the use of a 1-amino-alkylcyclohexane derivative for the manufacture of a medicament for the treatment or prevention of cochlear tinnitus in a subject in need thereof.

In another aspect, the invention relates to a 1-amino-alkylcyclohexane derivative for the treatment or prevention of tinnitus, wherein the treatment is carried out within three to twelve months of the onset of tinnitus (subacute tinnitus), or wherein the treatment is carried out within three to eight months of the onset of tinnitus, and the use of a 1-amino-alkylcyclohexane derivative for the manufacture of a medicament for the treatment or prevention of tinnitus, wherein the treatment is carried out within three to twelve months of the onset of tinnitus, or wherein the treatment is carried out within three to eight months of the onset of tinnitus.

In another aspect, the invention relates to a 1-amino-alkylcyclohexane derivative (e.g. neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate) in an immediate release or modified release formulation for the treatment of cochlear tinnitus.

Another aspect of the invention relates to a derivative or use as defined above, wherein a 1-amino-alkylcyclohexane derivative (e.g. neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) and at least one further drug which has been shown to be effective in the treatment of tinnitus are administered to said individual.

Another aspect of the invention relates to a derivative or use as defined above, wherein a 1-amino-alkylcyclohexane derivative (e.g. neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) and at least one further drug selected from the group consisting of antidepressants or anxiolytics (such as selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), 5-hydroxytryptamine-noradrenaline reuptake inhibitors (SNRIs), noradrenergic and specific 5-hydroxytryptamine antidepressants (NASSAs), noradrenaline (noradrenaline)) reuptake inhibitors (NRIs), noradrenaline-dopamine reuptake inhibitors, or 5-hydroxytryptamine 1A agonists), dopamine antagonists, alpha 2 delta ligands, and NK1 antagonists are administered to said individual.

Another aspect of the invention relates to a 1-amino-alkylcyclohexane derivative (e.g. neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate) in combination with other tinnitus therapies and optionally at least one pharmaceutically acceptable carrier or excipient.

Another aspect of the invention relates to a 1-amino-alkylcyclohexane derivative (e.g. neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate) in combination with an additional agent selected from an antidepressant or anxiolytic agent (e.g. selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), 5-hydroxytryptamine-noradrenaline reuptake inhibitors (SNRIs), noradrenergic and specific 5-hydroxytryptake inhibitors (NASSAs), noradrenaline (noradrenaline)) reuptake inhibitors (NRIs), noradrenaline-dopamine reuptake inhibitors, or 5-hydroxytryptamine 1A agonists), a dopamine antagonist, an alpha 2 delta ligand, and an NK1 antagonist, and optionally at least one pharmaceutically acceptable carrier or excipient.

Another aspect of the invention relates to 1-amino-alkylcyclohexane derivatives (e.g. neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate) for the treatment or prevention of tinnitus in combination with a further drug selected from the group consisting of antidepressants or anxiolytics (e.g. selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), 5-hydroxytryptamine-noradrenaline reuptake inhibitors (SNRIs), noradrenergic and specific 5-hydroxytryptamine antidepressants (NASSAs), noradrenaline (noradrenaline)) reuptake inhibitors (NRIs), noradrenaline-dopamine reuptake inhibitors, or 5-hydroxytryptamine 1A agonists), dopamine antagonists, alpha 2 delta ligands and NK1 antagonists, and optionally at least one pharmaceutically acceptable carrier or excipient.

The present invention also relates to a method of treating or preventing cochlear tinnitus in a subject in need thereof comprising administering an effective amount of a 1-amino-alkylcyclohexane derivative, or a pharmaceutically acceptable salt thereof (e.g., neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate), in a pharmaceutically acceptable carrier.

Another aspect of the invention relates to such a method wherein the treatment is performed within three to twelve months of onset of tinnitus.

Another aspect of the invention relates to such a method wherein the treatment is performed within three to eight months of onset of tinnitus.

Another aspect of the invention relates to such a method wherein the tinnitus is associated with hearing loss, including mild hearing loss.

Another aspect of the invention relates to a method wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) is administered at about 5mg to about 150mg per day, or wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) is administered at from about 5mg to about 100mg per day, or wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) is administered at about 5mg to about 75mg per day, or wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) is administered at about 50mg per day, or wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) is administered at about 75mg per day.

Another aspect of the invention relates to a method wherein the 1-amino-alkylcyclohexane derivative (e.g. neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) is administered once daily, twice daily (b.i.d.) or three times daily.

Another aspect of the invention relates to a method wherein the 1-amino-alkylcyclohexane derivative (e.g. neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) is administered twice daily (b.i.d.).

Another aspect of the invention relates to a method wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) is administered in an immediate release formulation.

Another aspect of the invention relates to a method wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) is administered in a modified release formulation.

The invention also relates to a method of treating or preventing cochlear tinnitus in a subject in need thereof comprising administering an effective amount of a 1-amino-alkylcyclohexane derivative, or a pharmaceutically acceptable salt thereof (e.g., neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate), and other drugs which have been shown to be effective in treating or preventing tinnitus.

Another aspect of the invention relates to a method of treating or preventing tinnitus, such as cochlear tinnitus, in a subject in need thereof comprising administering an effective amount of a 1-amino-alkylcyclohexane derivative, or a pharmaceutically acceptable salt thereof (e.g., neramexane, or a pharmaceutically acceptable salt thereof, such as neramexane mesylate), and an additional agent selected from the group consisting of antidepressants or anxiolytics (such as selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), 5-hydroxytryptamine-norepinephrine reuptake inhibitors (SNRIs), noradrenergic and specific 5-hydroxytryptake inhibitors (NASSAs), noradrenaline (noradrenaline)) reuptake inhibitors (NRIs), noradrenaline-dopamine reuptake inhibitors, or 5-hydroxytryptamine 1A agonists), dopamine antagonists, alpha 2 delta ligands, beta-agonists, and pharmaceutically acceptable salts thereof, And NK1 antagonists.

Another aspect of the invention relates to a method wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) and the other drug are administered in combination.

Another aspect of the invention relates to a method wherein the 1-amino-alkylcyclohexane derivative (e.g., neramexane or a pharmaceutically acceptable salt thereof, such as neramexane mesylate) and the other drug are administered as a single formulation.

The invention also relates to a method of treating tinnitus in a subject in need thereof comprising administering an effective amount of a 1-amino-alkylcyclohexane derivative, or a pharmaceutically acceptable salt thereof (e.g., neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate), in a pharmaceutically acceptable carrier, wherein the treatment is performed within three to twelve months of onset of tinnitus.

Another aspect of the invention relates to such a method wherein the treatment is performed within three to eight months of onset of tinnitus.

The invention also relates to a method of treating or preventing tinnitus associated with hearing loss, including mild hearing loss, in a subject in need thereof, comprising administering an effective amount of a 1-amino-alkylcyclohexane derivative, or a pharmaceutically acceptable salt thereof (e.g., neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate), in a pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for the treatment or prevention of cochlear tinnitus comprising a therapeutically effective amount of a 1-amino-alkylcyclohexane derivative, or a pharmaceutically acceptable salt thereof (e.g. neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate), and at least one pharmaceutically acceptable carrier or excipient.

The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a 1-amino-alkylcyclohexane derivative, or a pharmaceutically acceptable salt thereof (e.g. neramexane or a pharmaceutically acceptable salt thereof such as neramexane mesylate), in combination with an additional pharmaceutical agent which has been shown to be effective in the treatment or prevention of tinnitus, and optionally at least one pharmaceutically acceptable carrier or excipient.

Brief description of the drawings

FIG. 1 shows the Tinnitus study data for neramexane, which indicates that the 50mg dose group compared to placebo indicates Tinnitus-Change in Fragebox (TBF-12) (i.e. German version of Tinnitus Handicap Inventory or THI) score.

Detailed description of the invention

The term "tinnitus" as used herein includes, without limitation, all manifestations of subjective and objective tinnitus and (tinnitus of) acute, subacute and chronic forms. It also includes cochlear tinnitus as well as tinnitus associated with hearing loss or mild hearing loss.

The term "cochlear tinnitus" as used herein refers to tinnitus in the frequency range of hearing loss. The term cochlear tinnitus includes motor tintus, cochlear motor tintus or hair cell tinnitus. Cochlear tinnitus may be caused by toxic drugs (e.g., loop diuretics such as furosemide, aminoglycosides such as gentamicin) or loud exposure (e.g., acoustic trauma, chronic occupational noise).

The term "subacute tinnitus" as used herein includes tinnitus that lasts for a period of three (3) to twelve (12) months.

The term "hearing loss" (or "hearing impairment") as used herein refers to a complete or partial loss of the ability to perceive sound or to distinguish between different sounds. Hearing loss is clinically diagnosed by an increased hearing threshold level on a pure audiogram. The threshold level in decibels (dB) for the left/right ear can be calculated as the average of the actual numbers at different frequencies on a pure audiogram, i.e., as the average threshold level of hearing level at 0.25, 0.5, 1, 2, and 4 kHz. There are many different degrees of hearing loss. Hearing loss is defined herein as "mild hearing loss" (or "mild hearing impairment") if the hearing threshold level is within 20-40 decibels (dB). Noise-induced tinnitus associated with hearing loss may be caused by acute or chronic conditions. Prolonged exposure to excessive noise is a more common cause of noise-induced tinnitus associated with hearing loss; however, such tinnitus associated with hearing loss may also be caused by loud sounds. Sensorineural tinnitus associated with hearing loss is due to sensory dullness in the inner ear or impairment of auditory nervous system function. Sensorineural tinnitus associated with hearing loss may be caused by abnormalities of hair cells on the cochlea kel pedicle (Corti) apparatus.

In the present invention, the term "subject" includes mammals including animals and humans.

The term 1-amino-alkylcyclohexane derivative is used herein to describe a 1-amino-alkylcyclohexane compound or a compound derived from a 1-amino-alkylcyclohexane, for example a pharmaceutically acceptable salt of a 1-amino-alkylcyclohexane. The 1-amino-alkylcyclohexane derivative may also be referred to as a "1-aminocyclohexane derivative".

The 1-amino-alkylcyclohexane derivatives according to the invention can be represented by the general formula (I):

wherein R is- (CH)₂)_n-(CR⁶R⁷)_m-NR⁸R⁹

Wherein n + m is 0, 1, or 2

Wherein R is¹To R⁷Independently selected from hydrogen and C_1-6Alkyl, wherein R⁸And R⁹Independently selected from hydrogen and C_1-6Group consisting of alkyl radicals or together represent lower-alkylene- (CH)₂)_x-wherein x is 2 to 5 inclusive, and optical isomers, enantiomers, hydrates, and pharmaceutically acceptable salts thereof.

Non-limiting examples of 1-amino-alkylcyclohexanes for use according to the present invention include:

1-amino-1, 3, 5-trimethylcyclohexane,

1-amino-1 (trans), 3 (trans), 5-trimethylcyclohexane,

1-amino-1 (cis), 3 (cis), 5-trimethylcyclohexane,

1-amino-1, 3, 3, 5-tetramethylcyclohexane,

1-amino-1, 3, 3, 5, 5-pentamethylcyclohexane (neramexane),

1-amino-1, 3, 5, 5-tetramethyl-3-ethylcyclohexane,

1-amino-1, 5, 5-trimethyl-3, 3-diethylcyclohexane,

1-amino-1, 5, 5-trimethyl-cis-3-ethylcyclohexane,

1-amino- (1S, 5S) cis-3-ethyl-1, 5, 5-trimethylcyclohexane,

1-amino-1, 5, 5-trimethyl-trans-3-ethylcyclohexane,

1-amino- (1R, 5S) trans-3-ethyl-1, 5, 5-trimethylcyclohexane,

1-amino-1-ethyl-3, 3, 5, 5-tetramethylcyclohexane,

1-amino-1-propyl-3, 3, 5, 5-tetramethylcyclohexane,

n-methyl-1-amino-1, 3, 3, 5, 5-pentamethylcyclohexane,

n-ethyl-1-amino-1, 3, 3, 5, 5-pentamethyl-cyclohexane,

n- (1, 3, 3, 5, 5-pentamethylcyclohexyl) pyrrolidine,

3, 3, 5, 5-tetramethylcyclohexylmethylamine,

1 amino-1, 3, 3, 5 (trans) -tetramethylcyclohexane (axial amino),

3-propyl-1, 3, 5, 5-tetramethylcyclohexylamine hemihydrate,

1-amino-1, 3, 5, 5-tetramethyl-3-ethylcyclohexane,

1-amino-1, 3, 5-trimethylcyclohexane,

1-amino-1, 3-dimethyl-3-propylcyclohexane,

1-amino-1, 3 (trans), 5 (trans) -trimethyl-3 (cis) -propylcyclohexane,

1-amino-1, 3-dimethyl-3-ethylcyclohexane,

1-amino-1, 3, 3-trimethylcyclohexane,

cis-3-ethyl-1 (trans) -3 (trans) -5-trimethylcyclohexylamine,

1-amino-1, 3 (trans) -dimethylcyclohexane,

1, 3, 3-trimethyl-5, 5-dipropylcyclohexylamine,

1-amino-1-methyl-3 (trans) -propylcyclohexane,

1-methyl-3 (cis) -propylcyclohexylamine,

1-amino-1-methyl-3 (trans) -ethylcyclohexane,

1-amino-1, 3, 3-trimethyl-5 (cis) -ethylcyclohexane,

1-amino-1, 3, 3-trimethyl-5 (trans) -ethylcyclohexane,

cis-3-propyl-1, 5, 5-trimethylcyclohexylamine,

trans-3-propyl-1, 5, 5-trimethylcyclohexylamine,

n-ethyl-1, 3, 3, 5, 5-pentamethylcyclohexylamine,

n-methyl-1-amino-1, 3, 3, 5-pentamethylcyclohexane,

1-amino-1-methylcyclohexane,

n, N-dimethyl-1-amino-1, 3, 3, 5, 5-pentamethylcyclohexane,

2- (3, 3, 5, 5-tetramethylcyclohexyl) ethylamine,

2-methyl-1- (3, 3, 5, 5-tetramethylcyclohexyl) propyl-2-amine,

2- (1, 3, 3, 5, 5-pentamethylcyclohexyl) -ethylamine hemihydrate,

n- (1, 3, 3, 5, 5-pentamethylcyclohexyl) -pyrrolidine,

1-amino-1, 3 (trans), 5 (trans) -trimethylcyclohexane,

1-amino-1, 3 (cis), 5 (cis) -trimethylcyclohexane,

1-amino- (1R, 5S) trans-5-ethyl-1, 3, 3-trimethylcyclohexane,

1-amino- (1S, 5S) cis-5-ethyl-1, 3, 3-trimethylcyclohexane,

1-amino-1, 5, 5-trimethyl-3 (cis) -isopropyl-cyclohexane,

1-amino-1, 5, 5-trimethyl-3 (trans) -isopropyl-cyclohexane,

1-amino-1-methyl-3 (cis) -ethyl-cyclohexane,

1-amino-1-methyl-3 (cis) -methyl-cyclohexane,

1-amino-5, 5-diethyl-1, 3, 3-trimethyl-cyclohexane,

1-amino-1, 3, 3, 5, 5-pentamethylcyclohexane,

1-amino-1, 5, 5-trimethyl-3, 3-diethylcyclohexane,

1-amino-1-ethyl-3, 3, 5, 5-tetramethylcyclohexane,

n-ethyl-1-amino-1, 3, 3, 5, 5-pentamethylcyclohexane,

n- (1, 3, 5-trimethylcyclohexyl) pyrrolidine or piperidine,

n- [1, 3 (trans), 5 (trans) -trimethylcyclohexyl ] pyrrolidine or piperidine,

n- [1, 3 (cis), 5 (cis) -trimethylcyclohexyl ] pyrrolidine or piperidine,

n- (1, 3, 3, 5-tetramethylcyclohexyl) pyrrolidine or piperidine,

n- (1, 3, 3, 5, 5-pentamethylcyclohexyl) pyrrolidine or piperidine,

n- (1, 3, 5, 5-tetramethyl-3-ethylcyclohexyl) pyrrolidine or piperidine,

n- (1, 5, 5-trimethyl-3, 3-diethylcyclohexyl) pyrrolidine or piperidine,

n- (1, 3, 3-trimethyl-cis-5-ethylcyclohexyl) pyrrolidine or piperidine,

n- [ (1S, 5S) cis-5-ethyl-1, 3, 3-trimethylcyclohexyl ] pyrrolidine or piperidine,

n- (1, 3, 3-trimethyl-trans-5-ethylcyclohexyl) pyrrolidine or piperidine,

n- [ (1R, 5S) trans-5-ethyl, 3, 3-trimethylcyclohexyl ] pyrrolidine or piperidine,

n- (1-ethyl-3, 3, 5, 5-tetramethylcyclohexyl) pyrrolidine or piperidine,

n- (1-propyl-3, 3, 5, 5-tetramethylcyclohexyl) pyrrolidine or piperidine,

n- (1, 3, 3, 5, 5-pentamethylcyclohexyl) pyrrolidine,

and optical isomers, diastereomers, enantiomers, hydrates, pharmaceutically acceptable salts thereof, and mixtures thereof.

1-amino-alkylcyclohexane derivatives (e.g. neramexane, 1-amino-1, 3, 3, 5, 5-pentamethylcyclohexane) are disclosed in U.S. Pat. Nos. 6,034,134 and 6,071,966. 1-amino-alkylcyclohexane derivatives (e.g., neramexane) in the form of any one of a pharmaceutically acceptable salt, solvate, isomer, conjugate and prodrug are useful according to the present invention, and any 1-amino-alkylcyclohexane derivative (e.g., neramexane) referred to in this specification should be understood to also refer to such salts, solvates, isomers, conjugates and prodrugs.

The term antidepressant or anxiolytic (e.g., selective 5-hydroxytryptamine reuptake inhibitor (SSRIs), 5-hydroxytryptamine-noradrenaline reuptake inhibitor (SNRIs), noradrenergic and specific 5-hydroxytryptamine antidepressant (NASSAs), noradrenaline (noradrenaline)) reuptake inhibitor (NRIs), noradrenaline-dopamine reuptake inhibitor, or 5-hydroxytryptamine 1A agonist) as used herein includes: fluoxetine, fluvoxamine paroxetine, citalopram, escitalopram, sertraline, bupropion, desipramine, reboxetine, viloxazine, amitazapine, milnacipran, nefazodone, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, atomoxetine, buspirone and pharmaceutically acceptable salts thereof.

The term dopamine antagonist as used herein includes trans-1- {4- [2- [4- (2, 3-dichlorophenyl) -piperazin-1-yl ] -ethyl ] -cyclohexyl } -3, 3-dimethyl-urea and pharmaceutically acceptable salts thereof.

The term α 2 δ ligand as used herein includes gabapentin, pregabalin, phenibut, pregabalin, preg,PF-2393296And, andPF-293765and pharmaceutically acceptable salts thereof.

The term NK1 antagonist as used herein includes aprepitant, fosaprepitant, vatipitant, casopiptan (I) (casopitant)、AV-608、dilopetineAnd, andLY-686017and pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts include, but are not limited to, acid addition salts such as those formed with hydrochloric, methanesulfonic, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, tartaric, citric, benzoic, carbonic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, p-aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acids. All of these salts (or other similar salts) can be prepared by conventional methods. The nature of the salt is not critical if it is non-toxic and does not significantly interfere with the desired pharmacological activity.

The term "analog" or "derivative" is used herein in the conventional pharmaceutical sense to refer to a molecule that is structurally similar to a reference molecule (e.g., neramexane), but which has been modified in an oriented and controlled manner such that one or more particular substituents on the reference molecule are replaced by additional substituents, thereby producing a molecule that is structurally similar to the reference molecule. The synthesis and screening of analogs (e.g., using structural and/or biochemical analysis) to identify slightly modified versions of known compounds that may have improved or biased properties (e.g., higher potency and/or selectivity for a particular targeted type of receptor, ability to penetrate the mammalian blood brain barrier more, fewer side effects, etc.)) is a known drug design approach in the field of pharmaceutical chemistry.

The term "treating" as used herein means alleviating or alleviating at least one symptom of a disease in a subject. Within the meaning of the present invention, the term "treatment" also means preventing, delaying onset (i.e. the period before clinical manifestation of the disease) and/or reducing the risk of development or worsening of the disease.

The term "therapeutically effective" with respect to a dose or amount refers to an amount of a compound or pharmaceutical composition sufficient to produce the desired activity when administered to a mammal in need thereof.

The phrase "pharmaceutically acceptable" as used in connection with the compositions of the present invention means that the molecular entities and other ingredients of such compositions are physiologically tolerable and do not typically produce adverse reactions upon administration to a mammal (e.g., a human). Generally, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or a state government or listed in the u.s. pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

Pharmaceutical compositions for use in the present inventionThe term "carrier" refers to a diluent, excipient, or vehicle with which the active compound (e.g., neramexane) is administered. The pharmaceutical carrier can be a sterile liquid, such as water, saline solution, aqueous dextrose solution, aqueous glycerol solution, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Gennaro in "Remington's pharmaceutical sciences" 20^thSuitable drug carriers are described in the edition.

The term "about" or "approximately" generally means within 20%, alternatively within 10%, including within 5%, of a given value or range. Alternatively, the term "about" means within about one log (i.e., one order of magnitude), including within 2-fold of a given value, especially in biological systems.

In conjunction with the methods of the present invention, the present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a 1-amino-alkylcyclohexane derivative (e.g., neramexane). The compositions of the present invention may further comprise a carrier or excipient (both pharmaceutically acceptable). The composition may be prepared for once daily administration, twice daily administration or three times daily administration.

The active ingredients (e.g., neramexane, such as neramexane mesylate) or compositions of the invention can be used to treat at least one of the above conditions, wherein the medicament is suitably or appropriately prepared for specific administration (e.g., once daily, twice daily, or three times daily) as disclosed herein. The package insert and/or the patient notification contain corresponding information for this purpose.

The active ingredients (e.g., neramexane, such as neramexane mesylate) or compositions of the invention can be used for the manufacture of medicaments for the treatment of at least one of the above conditions, wherein the medicaments are suitable or suitably formulated for specific administration (e.g., once daily, twice daily, or three times daily) as disclosed herein. The package insert and/or the patient notification contain corresponding information for this purpose.

According to the present invention, the dosage form of the 1-amino-alkylcyclohexane derivative (e.g. neramexane) may be the following solid, semisolid or liquid formulation.

The 1-amino-alkylcyclohexane derivatives of the invention (e.g., neramexane) can be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. In another embodiment for administration to a pediatric subject, the 1-amino-alkylcyclohexane derivative may be formulated as a scented liquid (e.g., a mint flavor). The 1-amino-alkylcyclohexane derivatives of the present invention may be administered orally in the form of capsules, tablets, etc., or in semisolid or liquid preparations (see Remington's Pharmaceutical Sciences, 20)^thEdition，by A.R.Gennaro)。

For oral administration in the form of tablets or capsules, the 1-amino-alkylcyclohexane derivatives of the invention (e.g. neramexane) may be admixed with non-toxic pharmaceutically acceptable excipients such as binders (e.g. pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, etc.); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), coloring agents, and combinations of flavoring agents, gelatin, sweetening agents, natural or synthetic gums (e.g., acacia, tragacanth or alginate), buffer salts, carboxymethylcellulose, polyethylene glycol, waxes, and the like.

The tablets may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talc, titanium dioxide, and the like. In addition, the tablets may be coated with a polymer dissolved in a volatile organic solvent or mixture of organic solvents. In particular embodiments, neramexane is formulated as an Immediate Release (IR) or Modified Release (MR) tablet. Immediate release solid dosage forms release most or all of the active ingredient over a short period of time, such as 60 minutes or less, and may allow rapid drug absorption (immediate release formulations of 1-amino-alkylcyclohexanes, such as neramexane, are disclosed in published US applications nos. 2006/0002999 and 2006/0198884, the subject matter of which is incorporated herein by reference). Modified release solid oral dosage forms allow for the sustained release of the active ingredient over an extended period of time in an effort to maintain therapeutically effective plasma levels over a similar extended time interval and/or to modify other pharmacokinetic properties of the active ingredient (neramexane modified release formulations are disclosed in published US application No.2007/0141148, the subject matter of which is incorporated herein by reference). For example, neramexane mesylate can be prepared in a modified release dosage form (including modified release tablets) to provide a 50mg dose of neramexane mesylate.

In the case of soft gelatin capsules, the 1-amino-alkylcyclohexane derivatives of the invention (e.g. neramexane) may be mixed, for example, with vegetable oils or polyethylene glycols. Hard gelatin capsules may contain granules of the active ingredient using excipients as described above for tablets, such as lactose, sucrose, sorbitol, mannitol, starches (e.g. potato, corn or amylopectin), cellulose derivatives or gelatin. Liquid or semi-solid drugs can also be filled into hard gelatin capsules.

The 1-amino-alkylcyclohexane derivatives of the invention (e.g. neramexane) can also be incorporated into microspheres or microcapsules made of, for example, polyglycolic acid/lactic acid (PGLA) (see, for example, u.s. patent nos. 5,814,344; 5,100,669 and 4,849,222; PCT application nos. WO95/11010 and WO 93/07861). Biocompatible polymers, including, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acids, polyaminocaprolactones, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polynitrile acrylates, and crosslinked or amphiphilic block copolymers of hydrogels, may be used to achieve controlled release of drugs.

Formulations of the 1-amino-alkylcyclohexane derivatives of the invention in semi-solid or liquid form may also be used. The 1-amino-alkylcyclohexane derivative (e.g. neramexane) may constitute from 0.1 to 99% by weight of the formulation, more particularly from 0.5 to 20% by weight of the formulation for injection, and from 0.2 to 50% by weight of the formulation suitable for oral administration.

In one embodiment of the invention, the 1-amino-alkylcyclohexane derivative (e.g. neramexane) is administered in a modified release formulation. Modified release dosage forms provide a means to improve patient compliance and ensure effective and safe treatment by reducing the incidence of adverse drug reactions. Modified release dosage forms can be used to prolong the pharmacological effect after administration and reduce the variation in plasma concentration of the drug over the dosage interval, as compared to immediate release solid dosage forms, thereby eliminating or reducing spikes.

A modified release dosage form may comprise a core coated with or containing a drug. The core is then coated with a modified release polymer (release modifying polymer) in which the drug is dispersed. The modified release polymer gradually decomposes and releases the drug over time. Thus, when the composition is exposed to an aqueous environment, i.e., the gastrointestinal tract, the outermost layer of the composition is effectively moderated to regulate the diffusion of the drug through the coating layer. The net rate of diffusion of the drug depends primarily on the ability of the gastric fluid to penetrate the coating or matrix and the solubility of the drug itself.

In another embodiment of the invention, the 1-amino-alkylcyclohexane derivative (e.g., neramexane) is formulated as an oral liquid formulation. Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Formulations for oral administration may be suitably formulated to provide controlled or delayed release of the active compound. Oral liquid formulations of 1-amino-alkylcyclohexanes, such as neramexane, are described in PCT international application No. PCT/US2004/037026, the subject matter of which is incorporated herein by reference.

For oral administration in liquid form, the 1-amino-alkylcyclohexane derivatives of the invention (e.g. neramexane) may be combined with non-toxic pharmaceutically acceptable inert carriers (e.g. ethanol, glycerol, water), suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (e.g. almond oil, oily esters, ethanol or fractionated vegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid), and the like. Stabilizers such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage form. For example, the solution may contain about 0.2% to about 20% by weight neramexane, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Such liquid formulations may optionally contain coloring agents, flavoring agents, saccharin, and carboxymethylcellulose or other excipients as thickeners.

In another embodiment, a therapeutically effective amount of a 1-amino-alkylcyclohexane derivative (e.g., neramexane) is administered as an oral solution comprising a preservative, a sweetener, a solubilizing agent, and a solvent. The oral solution may include one or more buffers, flavoring agents, or other excipients. In another embodiment, mint or other flavoring agents are added to the neramexane derivative oral liquid formulation.

For administration by inhalation, the 1-amino-alkylcyclohexane derivatives of the invention (e.g., neramexane) are conveniently delivered in pressurized packs or as a spray in a nebulizer, using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for delivering a metered amount. For example, capsules and cartridges, e.g., gelatin capsules and cartridges, containing a powder mixture of the compound and a suitable powder base such as lactose or starch for use in an inhaler or insufflator may be prepared.

Solutions for parenteral administration by injection may be prepared, for example, as aqueous solutions of water-soluble pharmaceutically acceptable salts of the active ingredients at concentrations of from about 0.5% to about 10% by weight. These solutions may also contain stabilizers and/or buffers and may be conveniently presented in ampoules of various dosage units.

The formulations of the invention may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), intradermal (i.d.), or intradermal injection (i.d.), by direct injection, e.g., by bolus injection or continuous intravenous drip. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with a preservative. In addition, the active ingredient may be presented as a powder which is reconstituted with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

The invention also provides a pharmaceutical pack or kit comprising one or more containers containing a 1-amino-alkylcyclohexane derivative, such as neramexane, and optionally further formulation ingredients. In one embodiment, neramexane is provided as an oral solution (2mg/ml) and a2 teaspoon capacity syringe (dose KORC) is used) To administer the drug. Each oral syringe has a blue hatch measurement mark (blue hatch marks), the line on the right of the syringe (tip down) representing tsp units and the line on the left representing ml units.

The optimal therapeutically effective amount can be determined experimentally, taking into account the precise mode of administration employed for the drug administration, the indication to which the administration is directed, the (circumstances) to which the subject is concerned (e.g., body weight, health, age, sex, etc.), and the preferences and experience of the attending physician or veterinarian.

The dosage units for rectal administration may be solutions or suspensions, or may be in the form of suppositories or retention enemas containing neramexane mixed with a neutral fat base, or gelatin rectal capsules containing the active substance in admixture with vegetable or paraffin oils.

Toxicity and therapeutic efficacy of the compositions of the present invention can be determined by standard pharmaceutical procedures performed on experimental animals, e.g., by measuring LD50 (the dose lethal to 50% of the population) and ED50 (the dose therapeutically effective in 50% of the population). The dose ratio of therapeutic and toxic effects is the therapeutic index, which can be expressed as the ratio LD50/ED 50. Preferred are compositions that exhibit a large therapeutic index.

The appropriate daily dosage of the active compounds of the invention for use in human therapy is about 0.01-10mg/kg body weight for oral administration and 0.001-10mg/kg body weight for parenteral administration. For example, for an adult human, a suitable daily dosage of neramexane (e.g., neramexane mesylate) is from about 5mg to about 150mg per day, such as from about 5mg to about 120mg, from about 5mg to about 100mg, or from about 5mg to about 75mg, or from about 5mg to about 50mg per day, such as 25mg or 37.5mg or 50mg per day. For example, the daily dosage can be adjusted according to body weight, such as 50 mg/day for a patient with a body weight of 90kg or more, or 75 mg/day for a patient with a body weight of 90kg or more. Equimolar amounts of other pharmaceutically acceptable salts, solvates, isomers, conjugates, prodrugs or derivatives thereof, such as neramexane hydrochloride, are also suitable. For pediatric patients of ages 4-14, neramexane (e.g., neramexane mesylate) can be administered in an oral liquid dosage form at a dosage of about 0.5 mg/day up to 10 mg/day.

The daily doses administered as referred to herein may be administered, for example, once, twice or three times daily, in one or two metered units each. Thus, a suitable dose per dosage unit may be a daily dose divided (e.g., evenly divided) into several parts per day for the number of dosage units given per day, such that a suitable dose per dosage unit is generally about equal to the daily dose or one-half, one-third, one-fourth, or one-sixth of the daily dose. The amount of each dosage unit can therefore be calculated as per the daily dosage described herein. Depending on the chosen dosing regimen, for example, a daily dose of 5mg may be considered as providing a dose per dosage unit (e.g., dosage units of about 5mg, 2.5mg, 1.67mg, 1.25mg, and 0.83 mg). A dosage of 150mg per day corresponds accordingly to a dosage of each dosage unit (e.g., 150mg, 75mg, 50mg, 37.5mg, and 25mg) of the corresponding dosing regimen.

The duration of treatment may be short term, e.g., a few weeks (e.g., 8-14 weeks), or long term until deemed unnecessary by the attending physician.

The 1-amino-alkylcyclohexane derivatives of the invention (e.g. neramexane) may be administered as monotherapy or in combination with other drugs for the treatment of tinnitus.

The term "combination" for active ingredients is used herein to define a single pharmaceutical composition (formulation) containing two active agents (e.g., a composition comprising a 1-amino-alkylcyclohexane derivative such as neramexane and other tinnitus treating drugs) or two separate pharmaceutical compositions each comprising one active agent administered in combination (e.g., a composition comprising a 1-amino-alkylcyclohexane derivative such as neramexane or other tinnitus treating drugs).

In the meaning of the present invention, the term "co-administration" means that the 1-amino-alkylcyclohexane derivative, such as neramexane, and a second active ingredient (e.g. other agents for the treatment of cochlear tinnitus) are administered simultaneously in one composition, or simultaneously or sequentially in different compositions. However, for sequential administration to be considered "combined", separate administration of the 1-amino-alkylcyclohexane derivative, e.g. neramexane, and the second active ingredient must be carried out at intervals which still produce the beneficial effect of treating cochlear tinnitus in a mammal.

Exemplary formulation examples

The active ingredients can be processed into tablets, coated tablets, capsules, drip solutions (lip solutions), suppositories, injections, and infusion preparations, etc. with the aid of commonly used solvents, adjuvants, and carriers, and can be applied to medical treatment by oral, rectal, parenteral, and other routes. Tablets suitable for oral administration may be prepared by conventional tableting techniques. The following examples are given for illustrative purposes only and are not intended to be limiting.

Formulation example 1: neramexane mesylate immediate release tablet

The following table gives the compositions of neramexane immediate release tablets at doses of 12.5, 25.0, 37.5, and 50.0mg, including the active ingredient, coating agent, and other excipients.

TABLE 1-12.5mg Neramexane mesylate film-coated tablets

Composition (I)	Amount [ mg ]]	Function of
			Neramexane mesylate	12.50	Active pharmaceutical ingredient
Microcrystalline cellulose	103.25	Adhesive agent
			Croscarmellose sodium	6.25	Disintegrating agent
Silicon dioxide (colloid)	1.25	Glidants
			Talc	1.25	Glidants
Magnesium stearate	0.50	Lubricant agent
			Weight of the tablet core	125.00
Coating materials (HPMC), Opadry or Sepifilm	5.00	Coating film
			Coating weight	5.00
Total weight of coated tablets	130.00

TABLE 2-25.0mg Neramexane mesylate film-coated tablets

Composition (I)	Amount [ mg ]]	Function of
			Neramexane mesylate	25.00	Active pharmaceutical ingredient
Microcrystalline cellulose	206.50	Adhesive agent
			Croscarmellose sodium	12.5	Disintegrating agent

Composition (I)	Amount [ mg ]]	Function of
			Silicon dioxide (colloid)	2.50	Glidants
Talc	2.50	Glidants
			Magnesium stearate	1.00	Lubricant agent
Weight of the tablet core	250.00
			Coating materials (HPMC), Opadry or Sepifilm	10.00	Coating film
Coating weight	10.00
			Total weight of coated tablets	260.00

TABLE 3-37.5mg Neramexane mesylate film-coated tablets

Composition (I)	Amount [ mg ]]	Function of
			Neramexane mesylate	37.50	Active pharmaceutical ingredient
Microcrystalline cellulose	309.75	Adhesive agent
			Croscarmellose sodium	18.75	Disintegrating agent
Silicon dioxide (colloid)	3.75	Glidants
			Talc	3.75	Glidants
Magnesium stearate	1.50	Lubricant agent
			Weight of the tablet core	375.00
Coating materials (HPMC), Opadry or Sepifilm	15.00	Coating film
			Coating weight	15.00

Composition (I)	Amount [ mg ]]	Function of
			Total weight of coated tablets	390.00

TABLE 4-50.0mg Neramexane mesylate film-coated tablets

Composition (I)	Amount [ mg ]]	Function of
			Neramexane mesylate	50.00	Active pharmaceutical ingredient
Microcrystalline cellulose	413.00	Adhesive agent
			Croscarmellose sodium	25.00	Disintegrating agent
Silicon dioxide (colloid)	5.00	Glidants
			Talc	5.00	Glidants
Magnesium stearate	2.00	Lubricant agent
			Weight of the tablet core	500.00
Coating materials (HPMC), Opadry or Sepifilm	20.00	Coating film
			Coating weight	20.00
Total weight of coated tablets	520.00

The following examples illustrate the invention without limiting its scope.

Example 1:double-blind placebo-controlled trial of Neramexane for the treatment of tinnitus

The purpose of this trial plan was to conduct a clinical trial to evaluate the effectiveness of neramexane in treating tinnitus. The primary objective of this study was to compare the effectiveness, tolerability and safety of three different doses (25, 50 or 75 mg/day) of neramexane mesylate with placebo in subjects with at least moderate subjective tinnitus.

Design of research

The effectiveness of neramexane was evaluated in double-blind, multicenter, randomized, placebo-controlled, parallel-group studies in subjects afflicted with at least moderate tinnitus. Approximately 100 patients (patients who met the specified inclusion criteria and did not meet any of the specified exclusion criteria) were randomized into each of 4 double-blind treatment groups (25, 50, 75 mg/day neramexane mesylate or placebo), resulting in a total of approximately 400 patients.

The 16-week double-blind treatment period consisted of a 4-week upward escalating dose period and a 12-week fixed-dose treatment period with no change in maintenance administered twice daily. However, if tolerability is poor, the investigator may consider reducing the dose in an amount of 25 mg/day (or placebo, respectively). After the treatment period, there was a 4-week follow-up period without active treatment and concomitant treatment limitations. Overall, the study included seven study visits: screening, baseline, visits at the end of weeks 4,8, 12, 16, and 20.

The scheduled visits for each patient were evaluated as follows:

visit 1 (screening): after signing the consent, the subjects were subjected to physical examination and clinical laboratory tests. Patients eligible for the study were evaluated by examining inclusion/exclusion criteria. An initial tinnitus interview was conducted. The subject also completed Tinnitus-Fragebogen (TBF-12) (i.e. Tinnitus Handdicap Inventory) or THI (Newman CW et al, Tinnitus Handdicap Inventory progression of Tinnitus disorder Development, Arch ocular prosthetic Heart Surg 1996; 122 (2): 143. minus 148; Newman CW et al. Psychometric adevaluation of the Tinniting Handycap Inventory (THI) for evaluating Tinnitus tumor output. jam Acdiol 1998; 9 (2): 153. minus 160. German and revision 25 item 12 of clause 25 (Greimel et al KV--Fragebogen(TBF-12).Manual.Frankfurt am Main：Swets &Zeitlinger b.v.; 2000) hospital anxiety-Depression Scale-Depression sub-Scale (HADS-D) questionnaire and Hearing hypersensitivity: (berempfindlichkeit-Fragenbogen) Questionnaire (if applicable).

Visit 2 (baseline): the subjects were asked for adverse events and changes to concomitant medication/disease and these events and changes were recorded. Subject eligibility for the study was assessed on the basis of review of the inclusion/exclusion criteria. Review of the trial program and concomitant medications allowed and prohibited was made by the subject. An initial tinnitus interview was conducted. The subject also completed TBF-12, HADS-D questionnaire andquestionnaire (if applicable). Subjects were enrolled in the study and dispensed the study medication (placebo or neramexane) as follows.

Visit 3 (week 4): this visit was made at the end of the 4 week upward escalating dose period. The subjects were asked for adverse events and changes associated with drug treatment/disease and these events and changes were recorded. Follow-up tinnitus interviews were conducted. The subject also completed TBF-12, HADS-D questionnaire andquestionnaire (if applicable). Medication compliance was assessed and the next 4 weeks of medication were dispensed as described below.

Visit 4 (week 8): this visit was made at the end of the first 4-week fixed-dose double-blind treatment period. The subjects were asked for adverse events and changes with drug treatment/disease and these changes were recorded. Blood samples were collected to determine the predose concentration of neramexane. Follow-up tinnitus interviews were conducted. The subject also completed TBF-12, HADS-D questionnaire andquestionnaire (if applicable). Evaluating a drug treatmentTreatment compliance and dispensing of the next 4 weeks of medication as follows.

Visit 5 (week 12): this visit was made at the end of the second 4-week fixed-dose double-blind treatment period. The subjects were asked for adverse events and changes with drug treatment/disease and these changes were recorded. Follow-up tinnitus interviews were conducted. The subject also completed TBF-12, HADS-D questionnaire andquestionnaire (if applicable). Medication compliance was assessed and the next 4 weeks of medication were dispensed as described below.

Visit 6 (week 16, end of treatment): this visit was made at the end of the 12-week fixed-dose double-blind treatment period. The subjects were asked for adverse events and changes with drug treatment/disease and these changes were recorded. Clinical laboratory evaluations were performed. Follow-up tinnitus interview was conducted with subjects completing TBF-12, HADS-D questionnaires andquestionnaire (if applicable). Pure tone audiometry (air conduction) was also performed.

Visit 7 (week 20): this visit was made at the end of a 4-week follow-up period after the last drug dose study. A review of concomitant medications since the last visit and the incidence of adverse events was made by the subject. Follow-up tinnitus interview was conducted with subjects completing TBF-12, HADS-D questionnaires andquestionnaire (if applicable).

Administration of Neramexane

Neramexane mesylate immediate release tablets (12.5mg and 25mg) and corresponding placebo tablets were administered as film coated tablets.

The medication dispensed from visit 2 to visit 5 was provided in the form of blister boxes (blisters). Each blister pack contains 4 blister cards (blister cards) and 1 preparation blister card for 4 treatment weeks. The blister card is determined by the treatment week. Daily medications in the blister card are determined daily. Study medication on each study day consisted of 4 separate tablets. One blister card contains 32 tablets (7 x 4 tablets, 4 tablets per day, and 4 preps for 1 day use). One medication package for each patient consisted of 5 boxes. The 2 nd box was added as a preliminary drug to the 1 st box (escalating dose period up), and the 2 nd box was dispensed only if the subject lost one blister card in the 1 st or entire box.

Study medication was dispensed at visit 2 (baseline, day 0). Each patient will receive a blister pack containing 5 blister cards (including a preparation blister card) of double blind study medication (i.e., 32 tablets). On the day beginning after dispensing study medication, subjects were instructed to take 2 tablets at a time, 2 times per day (4 tablets/day) until they returned for the next study visit (visit 3). Certain placebo tablets are incorporated into the dosing regimen to ensure that those subjects who are assigned to take the active drug are rendered unaware (blinding) during the upward escalating dose period. 25. Administration of the target dose of 50, or 75 mg/day fixed maintenance began at the time of double-blind treatment beginning at week five and continued throughout the study. At each subsequent visit (corresponding to visits 3, 4, and 5 at the end of weeks 4,8, and 12), the patient received another blister cassette containing 5 blister cards (containing double-blind medications for use during the interventional treatment period until the next study visit) for 4 weeks of use. The dosing regimen is shown in table 5.

Throughout the double-blind treatment period, patients should adhere to 2 × 2 tablets of medication daily at constant 12-hour intervals. If the patient had taken the morning dose of study medication on the days of visit 4 and visit 6 (weeks 8 and 16), no scheduled blood sampling was performed. The investigator must re-dispense a sufficient amount of study medication. The patient should adhere to 2 x 2 tablets of medication each day at constant 12 hour intervals, returning to the Neramexane pre-blood-collection dose over the time window of visit 4 and visit 6.

TABLE 5 administration of Neramexane mesylate

(xx/xx) refer to the morning/evening dose in mg, respectively

If the tolerability is poor, the investigator can consider the 25mg/d dose reduction by omitting the larger tablet in the morning, which constitutes an effective dose reduction only in the 75mg/d and 50mg/d neramexane mesylate groups. After omitting the morning dose of the larger tablet (25mg or placebo, respectively), these patients could proceed with the study according to the schedule, but only take one smaller tablet (12.5mg or placebo, respectively) for the morning dose and 2 different sized tablets (12.5mg, 25mg or placebo, respectively) for the evening dose. The dose was allowed to remain stable until the end of the study.

Subjects should be instructed to take study medication at a convenient but stable point in time throughout the course of the study, if possible at a constant 12 hour dosing interval (e.g., 6:00h and 18:00h or 8:00h and 20:00 h). At each study visit, the investigator asked the time point of study medication intake the day before. At the end of weeks 4,8, 12, and 16 (or after premature termination), patients should return to the study site and simultaneously bring their blister packs containing 5 blister cards back to assess medication compliance.

Therapeutic effect

Main results

The change in TBF-12 total score from baseline (visit 2) to endpoint visit (visit 6, i.e. week 16) is the primary efficacy endpoint (primary efficacy endpoint) in this study.

Secondary outcome

TBF-12 Total score on all Baseline post visit except for endpoint visit (value and Absolute Baseline Change)

Change (value and absolute change) of TBF-12 total score from week 16 to week 20.

TBF-12 factor scores on all post baseline visits (values and absolute baseline changes, including change from week 16 to week 20).

-auditory hypersensitivity questionnaire(“berempfindlichkeys-Fragebogen "), values and absolute baseline changes, including week 16 to week 20 changes, total score and factor score on all post-baseline visits (if hyperacusis present).

-change in clinical global impression: item 27 of the follow-up tinnitus interview was summarized after dividing the response into two parts comparing any improvement (values 1, 2, 3) to no improvement (values 4, 5, 6, 7) and comparing significant improvement (values 1, 2) to no significant improvement (values 3, 4, 5, 6, 7).

Total fraction of HADS-D and depression and anxiety scale on all post-baseline visits (value and absolute baseline change, and change from week 16 to week 20).

Tinnitus interview values on all post-baseline visits (initial and follow-up); absolute baseline changes and week 16 to week 20 changes for items 8, 9, 10, 19, 20, 21, 24, 25 and 26 of the follow-up interview.

Data analysis

All efficacy analyses were performed in the ITT population using the Last Observation Carried Forward (LOCF) method. For sensitivity, per-protocol set analysis and analysis of the observed cases were also performed. All statistical tests used to test primary efficacy (confirmatory tests) and secondary efficacy criteria (exploratory tests), as well as all other statistical tests used for exploratory analysis, were two-sided hypothesis tests performed at a 5% level of significance. Standard descriptive statistics were also performed for all variables.

The change from baseline (visit 2) to week 16 of TBF-12 total score was analyzed using a two-way ANCOVA model (with treatment groups and study center as factors and baseline as covariate).

As far as secondary efficacy parameters are concerned, the neramexane to placebo comparison is carried out, if appropriate, by a visit using a two-way ANCOVA (with the treatment group and the study centre as factors and the baseline value of the corresponding efficacy parameter as covariate).

This clinical study showed satisfactory results in terms of efficacy and safety. In addition, subgroup analysis showed that subjects classified by the respective investigators as suffering from cochlear tinnitus (i.e., tinnitus in the frequency range of sensory neurohearing loss and tinnitus at the 3 to 12dB sensory level in the patient) had a good effect on treatment with neramexane. Figure 1 shows the amount of change in TBF-12 score at the end of treatment for the 50mg dose group compared to placebo. In the same trial, patients treated within three (3) to eight (8) months of tinnitus onset (table 6) and patients with mild hearing loss (table 7) showed better effects on neramexane (tinnitus treatment) than the general study population (table 8). In particular, in the 50mg dose group, the improvement was significantly higher in patients who started tinnitus within three to eight months prior to treatment or patients who showed mild hearing loss (individual group-1.9 point difference) and reached statistical significance in post-hoc analysis (p ═ 0.019 and 0.024), whereas the difference from placebo was only 0.8 point in the total study population and did not reach statistical significance (p ═ 0.098).

Treatment with a daily dose monotherapy of neramexane of 50 or 75mg resulted in a weaker benefit in patients with clinical symptoms of anxiety or depression at baseline (shown as a total score of 10 points or more in the Hospital Anxiety Depression Scale (HADS)) compared to such treatment in patients scoring below 10 points at baseline (table 9). Since anxiety and depression are common medical problems in tinnitus patients (Reynolds et al, clin. otolaryngol., 2004, 29, 628-634), the combination of antidepressants and anxiolytics with neramexane may provide additional benefit for the treatment of these tinnitus subpopulations.

These findings indicate that neramexane is effective in treating subjects with tinnitus generated prior to the cochlear neutral and focal stages, and therefore neramexane can be used to treat patients with cochlear tinnitus.

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The scope of the invention is not intended to be limited by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will be apparent to those skilled in the art. Such modifications are intended to fall within the scope of the appended claims.

All patents, applications, publications, experimental methods, literature, and other materials cited herein are hereby incorporated by reference.

Claims (24)

1. A 1-amino-alkylcyclohexane derivative for the treatment or prevention of cochlear tinnitus.

Use of a 1-amino-alkylcyclohexane derivative for the manufacture of a medicament for the treatment or prevention of cochlear tinnitus.

3. The derivative/use according to claim 1 or 2, wherein treatment is performed within three to twelve months of onset of tinnitus, or wherein treatment is performed within three to eight months of onset of tinnitus.

4. The derivative/use according to any of the preceding claims, wherein the tinnitus is associated with hearing loss, or wherein the tinnitus is associated with mild hearing loss.

5. A 1-amino-alkylcyclohexane derivative for the treatment or prevention of tinnitus associated with hearing loss or mild hearing loss.

Use of a 1-amino-alkylcyclohexane derivative for the manufacture of a medicament for the treatment or prevention of tinnitus associated with hearing loss or mild hearing loss.

7. A 1-amino-alkylcyclohexane derivative for the treatment or prevention of tinnitus, wherein treatment is effected within three to twelve months of onset of tinnitus, or wherein treatment is effected within three to eight months of onset of tinnitus.

Use of a 1-amino-alkylcyclohexane derivative for the manufacture of a medicament for the treatment or prevention of tinnitus, wherein treatment occurs within three to twelve months of onset of tinnitus, or wherein treatment occurs within three to eight months of onset of tinnitus.

9. The derivative/use according to any of the preceding claims, wherein the 1-amino-alkylcyclohexane derivative is neramexane or a pharmaceutically acceptable salt thereof.

10. The derivative/use according to claim 9, wherein the 1-amino-alkylcyclohexane derivative is neramexane mesylate.

11. The derivative/use according to claim 10, wherein neramexane mesylate is administered at about 5mg to about 150mg per day, or neramexane mesylate is administered at about 5mg to about 100mg per day, or wherein neramexane mesylate is administered at about 5mg to about 75mg per day, or wherein neramexane mesylate is administered at about 50mg per day, or wherein neramexane mesylate is administered at about 75mg per day.

12. The derivative/use according to any of claims 9 to 11, wherein neramexane or a pharmaceutically acceptable salt thereof is administered once daily, twice daily (b.i.d.), or three times daily.

13. The derivative/use according to claim 12, wherein neramexane or a pharmaceutically acceptable salt thereof is administered twice daily.

14. The derivative/use according to any of claims 9 to 13, wherein neramexane or a pharmaceutically acceptable salt thereof is administered in an immediate release formulation or in a modified release formulation.

15. The derivative/use according to any of the preceding claims, wherein an additional drug which has been shown to be effective in the treatment or prevention of tinnitus, and optionally at least one pharmaceutically acceptable carrier or excipient, is administered.

16. The derivative/use according to any of the preceding claims, wherein an additional drug selected from the group consisting of antidepressants or anxiolytics, dopamine antagonists, a2 delta ligand, and NK1 antagonists is administered, and optionally at least one pharmaceutically acceptable carrier or excipient.

17. The derivative/use according to claim 16, wherein the antidepressant or anxiolytic is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), a 5-hydroxytryptamine-noradrenaline reuptake inhibitor (SNRI), a noradrenergic and specific 5-hydroxytryptamine antidepressant (NASSA), a noradrenaline (noradrenaline) reuptake inhibitor (NRI), a noradrenaline-dopamine reuptake inhibitor, or a 5-hydroxytryptamine 1A agonist.

18. The derivative/use according to any of claims 15 to 17, wherein the 1-amino-alkylcyclohexane derivative is neramexane or a pharmaceutically acceptable salt thereof.

19. The derivative/use according to any of claims 15 to 18, wherein neramexane or a pharmaceutically acceptable salt thereof is administered in combination with another drug.

20. The derivative/use according to any of claims 15 to 18, wherein neramexane or a pharmaceutically acceptable salt thereof and the other pharmaceutical agent are administered in the form of a single formulation.

21. A pharmaceutical composition comprising a 1-amino-alkylcyclohexane derivative, or a pharmaceutically acceptable salt thereof, in combination with an additional drug selected from an antidepressant or anxiolytic, a dopamine antagonist, an a2 delta ligand, and an NK1 antagonist.

22. The pharmaceutical composition of claim 21, wherein the antidepressant or anxiolytic is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), a 5-hydroxytryptamine-noradrenaline reuptake inhibitor (SNRI), a noradrenergic and specific 5-hydroxytryptamine antidepressant (NASSA), a noradrenaline (noradrenaline) reuptake inhibitor (NRI), a noradrenaline-dopamine reuptake inhibitor, or a 5-hydroxytryptamine 1A agonist.

23. The pharmaceutical composition as claimed in claim 21 or 22, wherein the 1-amino-alkylcyclohexane derivative is neramexane or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition according to any one of claims 21 to 23 for the treatment or prevention of tinnitus.