HK1179625A - Prophylactic or therapeutic medication for inner ear disorders - Google Patents

Description

Prophylactic or therapeutic agent for inner ear disorder

Technical Field

The present invention relates to a pharmaceutical for preventing or treating inner ear disorders, which contains a compound having an aldose reductase inhibitory activity as an active ingredient.

Background

Inner ear disorders are disorders that frequently cause inner ear heavy hearing, inner ear tinnitus and inner ear vertigo due to disorders occurring in the inner ear. Auditory ossicles develop as a result of aging, disease, genetic factors, or noise. It was estimated at 2009 that about 14% of adults in the united states (3800 ten thousand) had some degree of inner ear sexual overhearing. Tinnitus internalis is a phenomenon in which sound is perceived without a sound source from the outside. Among the aural vertigo, severe rotary vertigo is often observed, which is accompanied by nausea, vomiting and tinnitus. At present, no effective therapeutic agent is available for auditory ossification, tinnitus and vertigo.

For the treatment of inner ear disorders, administration of a steroid agent, administration of a blood flow improver (e.g., disodium adenosine triphosphate) or a metabolic accelerator (e.g., mecobalamin) for the purpose of improving inner ear circulatory disorders, administration of a diuretic (e.g., isosorbide) for the purpose of improving endolymphatic edema, hyperbaric oxygen therapy, astraganic ganglion blocking therapy, and the like are performed. However, the existing treatment means are limited at present, and cannot be said to be sufficient for the treatment of inner ear disorders.

The spirohydantoin derivative represented by the general formula (I) is a compound having an inhibitory activity against Aldose Reductase (AR) (non-patent document 1). The use of this compound as a diabetic complication (patent document 1), a circulatory organ system disease (patent document 2), various diseases accompanied by aging as a Maillard Reaction (Maillard Reaction) inhibitor (patent document 3), simple diabetic retinopathy (patent document 4), diabetic keratopathy (patent document 5), diabetic maculopathy (patent document 6), severe diabetic retinopathy (patent document 7), cardiac dysfunction or myocardial disorder (patent document 8), acute renal insufficiency (patent document 9), cerebral ischemia during brain attack or cerebral ischemia reperfusion disorder (patent document 10), and a protective agent for the retinal nerve or optic nerve (patent document 11) is described in each document. However, there has been no report on the use of inner ear disorders. In addition, there is no report on the use of other aldose reductase inhibitors for inner ear disorders.

Documents of the prior art

Patent document

Patent document 1: japanese laid-open patent publication No. 61-200991

Patent document 2: japanese laid-open patent publication No. 4-173791

Patent document 3: japanese laid-open patent publication No. 6-135968

Patent document 4: japanese laid-open patent publication No. 7-242547

Patent document 5: japanese laid-open patent publication No. 8-231549

Patent document 6: international publication No. 2005/072066

Patent document 7: international publication No. 2005/079792

Patent document 8: international publication No. 2006/090699

Patent document 9: international publication No. 2007/069727

Patent document 10: international publication No. 2007/097301

Patent document 11: international publication No. 2008/093691

Non-patent document

Non-patent document 1: arzneim. -Forsch./Drug Res.,44,344-

Disclosure of Invention

Problems to be solved by the invention

As described above, there is a strong clinical need for establishing a therapeutic method with high efficacy and safety for the prevention or treatment of inner ear disorders. Particularly, in view of safety, there is a strong demand for the development of drug therapies that can be taken for a long period of time. The present invention has been made in view of such a background, and an object thereof is to provide a prophylactic or therapeutic agent for inner ear disorders.

Means for solving the problems

Therefore, the inventors of the present invention evaluated the effect of the spirocyclic hydantoin derivative represented by the general formula (I) on inner ear disorders. As a result, it was found that the compound is effective for the dysfunction of Auditory Brainstem Response (ABR) and hair cell loss inside the cochlear. That is, according to the present invention, a prophylactic or therapeutic agent for inner ear disorders comprising a spirocyclic hydantoin derivative represented by general formula (I) as an active ingredient can be provided.

(wherein X represents a halogen atom or a hydrogen atom, R¹And R²Simultaneously or separately represent a hydrogen atom or C which may have a substituent_1-6An alkyl group. )

The spirocyclic hydantoin derivative represented by the general formula (I) is preferably (2S,4S) -6-fluoro-2 ',5' -dioxaspiro [ chroman-4, 4' -imidazoline ] -2-carboxamide (hereinafter referred to as fidarestat).

Specifically, inner ear disorders can be enumerated by inner ear heavy hearing, inner ear tinnitus, and inner ear vertigo. Examples of the inner ear hearing include perceptual hearing, mixed hearing, and the like.

In addition, the compounds of the present invention can be administered in combination with other drugs for inner ear disorders. Among them, as other drugs used for inner ear disorders, steroid drugs, anticholinergic drugs, antihistamine drugs, antiviral drugs, leukotriene receptor antagonists, anticoagulants, vasodilators, thrombolytics, vitamin B derivatives, and ear circulation improvers can be cited, and 1 or more of them can be combined.

ADVANTAGEOUS EFFECTS OF INVENTION

According to the present invention, a medicine for preventing or treating an inner ear disorder can be provided. In addition, as a preferred embodiment of the present invention, a highly safe medication that can be taken for a long time can be provided.

Drawings

Fig. 1 shows the effect of prophylactic administration of fidarestat on the increase in Auditory Brainstem Response (ABR) threshold after 1 week in a mouse strong sound model.

Fig. 2 shows the effect of prophylactic administration of fidarestat on the increase in Auditory Brainstem Response (ABR) threshold after 2 weeks in a mouse strong sound model.

Figure 3 shows the effect of therapeutic administration of fidarestat, Prednisolone (Prednisolone), or both on the increase in the Auditory Brainstem Response (ABR) threshold after 1 week in a mouse model of robust sound.

Figure 4 shows the effect of therapeutic administration of fidarestat, prednisolone, or both on an increase in the Auditory Brainstem Response (ABR) threshold after 2 weeks in a mouse model of strong voice.

Fig. 5 shows the inhibitory effect of fidarestat on the increase in the outer hair cell shedding rate inside the cochlea.

Fig. 6 shows the inhibitory effect of fidarestat on the disappearance of outer hair cells caused by gentamicin loading.

Detailed Description

The present invention will be described in more detail below. The active ingredient of the medicine of the present invention is a spirocyclic hydantoin derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof. These compounds are known compounds and can be produced by the synthetic method described in Japanese patent laid-open No. 63-057588 and the like.

In the formula, X represents a halogen atom or a hydrogen atom, and is preferably a halogen atom such as a fluorine atom. In the formula¹And R²Simultaneously or separately represent a hydrogen atom or C which may have a substituent_1-6Alkyl groups, preferably hydrogen atoms. Further, the above-mentioned C_1-6Among alkyl groups, C is preferred_1-3An alkyl group. Among these compounds, X is particularly preferably a fluorine atom or R¹And R²A compound which is a hydrogen atom.

The pharmaceutically acceptable salts of the spirohydantoin derivatives are preferred in view of their use as pharmaceutically acceptable salts. Specifically, pharmacologically acceptable inorganic and organic base salts such as sodium, lithium, potassium, magnesium, ammonium, quaternary ammonium salts, diethylamine and diethanolamine can be cited. These salts can be easily obtained by treating a spirocyclic hydantoin derivative represented by general formula (I) with a base, for example.

In addition, 4 stereoisomers are present in the above spirohydantoin derivatives, and the present invention also provides their isomers and racemates as mixtures thereof. Among these, (2S,4S) -6-fluoro-2 ',5' -dioxaspiro [ chroman-4, 4' -imidazoline ] -2-carboxamide (common name: fidarestat) is preferred.

The medicine of the present invention is a medicine for preventing or treating inner ear disorders, and specific examples of the inner ear disorders include inner ear heavy hearing, inner ear tinnitus, and inner ear vertigo. Inner ear disorder means that the inner ear is disturbed for some reason. The inner ear is located in the deepest part of the ear, and the inner ear of mammals is composed of the cochlea, the vestibule, and the semicircular canals. The cause of inner ear disorders includes circulatory disorders, metabolic disorders, inflammation (infection), and the like. The hair cells were detached, denatured, and edema due to abnormal circulation of lymph fluid in the inner ear were observed on the tissues. Since organs responsible for sense of hearing and sense of balance are present in the inner ear, when the inner ear is impaired, symptoms and observations such as heavy hearing, tinnitus, vertigo, eye shake, shaking, ear pain, sense of ear closure, increase in spontaneous sound, or hyperacusis are accompanied.

Heavy hearing occurs due to age, disease, genetic factors, or noise. Depending on the cause of the disorder, a distinction can be made between conductive and perceptual re-listening and a mixed re-listening of both concurrent conductive and perceptual re-listening. Conductive hearing occurs when an organ transmitting vibration is inflamed due to trauma of the outer ear or middle ear. Perceptual heavy listening occurs for the following reasons: it was judged that the cochlea of the inner ear in which sound is vibrating is impaired, the function of sensory cells is decreased, and the nerve is impaired when signals are transmitted from the sensory cells to the brain. In addition, it also occurs in cases where there is a reduction in hair cells inside the cochlea due to some cause of nerve damage or aging. Thus, inner ear hearing is typically either sensorineural hearing or mixed hearing.

Examples of the sensorineural hearing include sudden hearing, viral hearing, drug hearing due to side effects of antibiotics, anticancer agents, diuretics, etc., which have not been clearly defined, noisy hearing due to strong noise over a long period of time, sound trauma due to pop sounds, gunshot sounds, earphones with increased sound volume, etc., hearing due to Meniere's Disease, and elderly hearing due to aging.

In the present invention, the inner ear hearing is not limited to the cause of occurrence, and means a phenomenon in which sound cannot be heard well due to hearing deterioration caused by the inner ear being impaired, and includes perceptual hearing and mixed hearing. Further, inner ear tinnitus refers to a phenomenon in which sound is perceived despite no sound source from the outside. Tinnitus is often accompanied by sexual hearing in the inner ear, and the protection of the inner ear from sexual hearing in the inner ear is also helpful for the prevention of tinnitus.

The pharmaceutical composition of the present invention has a protective effect on hair cells of the inner ear, and therefore, is considered to have an effect of reducing vertigo caused by the inner ear. Among the aural vertigo, severe rotational vertigo is frequently observed, and nausea, vomiting and tinnitus are often accompanied. Benign paroxysmal positional vertigo, meniere's disease and the like are also included in the auditory vertigo. The organ responsible for hearing (cochlea) and the organ responsible for balanced sensation associated with vertigo (vestibule of inner ear) are originally differentiated from the same organ and are in the same position or very close to each other, and thus easily affect each other. Therefore, besides the symptoms of heavy hearing, inner ear disorders are often accompanied by tinnitus and vertigo. Therefore, it is considered that the improvement of inner ear disorder is effective for hearing stress, tinnitus and vertigo.

The dose of the compound represented by the general formula (I) as an active ingredient of the medicine of the present invention varies depending on the symptoms, age, administration method, dosage form, etc., and generally, 0.1mg to 450mg, preferably 1mg to 300mg, is administered to 1 adult patient per 1 day, or 1 day in several divided doses.

The pharmaceutical composition of the present invention can be formulated by a conventional formulation technique, for example, as a tablet, capsule, powder, granule, liquid, syrup, injection or ear drop. The formulated medicine can be administered orally or non-orally.

In the case of a solid preparation, a pharmacologically acceptable excipient, for example, starch, lactose, purified white sugar, glucose, crystalline cellulose, carboxyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, calcium phosphate, magnesium stearate, gum arabic and the like can be used in the preparation, and a lubricant, a binder, a disintegrating agent, a coating agent, a coloring agent and the like can be blended as necessary. In addition, in the case of a liquid formulation, a stabilizer, a cosolvent, a suspending agent, an emulsifier, a buffer, a preservative, and the like can be used.

In addition, the medicament of the present invention can be administered in combination with other medicaments or therapies for inner ear disorders. Examples of the other drugs that can be combined include a steroid drug, an anticholinergic drug, an antihistamine drug, an antiviral drug, a leukotriene receptor antagonist, an anticoagulant, a vasodilator, a thrombolytic drug, vitamin B and its derivative, or an inner ear circulation-improving drug, and 1 or more of them can be combined. The other drugs for inner ear disorders are administered mainly for the purpose of improving blood circulation in the inner ear. If the medicine of the present invention is combined with another medicine for inner ear disorders, the effect of each agent can be enhanced. In particular, steroid drugs are clinically limited in dosage or administration time due to problems of side effects. The combination with the drug of the present invention has a great advantage in terms of safety and efficacy, such as the ability to release the steroid drug from the early stage.

Examples of the other therapies that can be combined include hyperbaric oxygen therapy and stellate ganglion blocking therapy. Hyperbaric oxygen therapy is a therapy in which oxygen is delivered to the whole body by inhaling oxygen in an atmosphere of a pressure higher than atmospheric pressure, and aims to improve the blood flow. The stellate ganglion blocking therapy is a treatment method in which the function of the sympathetic nerve is temporarily paralyzed by blocking the stellate ganglion to increase the parasympathetic nerve function.

When the medicine of the present invention is administered in combination with another medicine for inner ear disorders, the active ingredient thereof may be contained in each preparation as a plurality of preparations or may be contained in the same preparation as 1 preparation. The combined medicine is a medicine to be administered in combination with a plurality of medicines or active ingredients thereof. The plurality of medicines or active ingredients thereof are preferably administered to the patient substantially simultaneously. When a plurality of active ingredients to be administered are contained in each preparation as a plurality of preparations, the administration is not limited to the case where these plurality of preparations are administered simultaneously. Since each preparation is usually administered according to the original administration method, they are administered the same number of times, and sometimes different numbers of times.

Examples of modes of administering the above-described medicine of the present invention in combination with other medicines for inner ear disorders include:

(1) administration of a single formulation comprising both the medicament of the invention and the other medicament;

(2) 2 or more preparations prepared by separately preparing the drug of the present invention and other drugs are administered simultaneously by the same route of administration;

(3) 2 or more preparations prepared by separately formulating the drug of the present invention and other drugs are administered with a time difference in the same administration route;

(4) 2 or more preparations prepared by separately formulating the drug of the present invention and other drugs are administered simultaneously by different routes of administration;

(5) 2 or more preparations prepared by separately formulating the drug of the present invention and other drugs are administered with time differences by different administration routes;

(6) 2 or more preparations prepared by separately formulating the drug of the present invention and other drugs are administered by the same route at different administration intervals; and

(7) the 2 or more preparations prepared by separately formulating the drug of the present invention and other drugs are administered by different routes and at different intervals.

The amount of other drugs used for inner ear disorders varies depending on the drug. The steroid drug is usually administered in an amount of 0.1mg to 500mg 1 time or several times per 1 day. Anticholinergic agents, antihistamines, antiviral agents, leukotriene receptor antagonists, anticoagulants, vasodilators, thrombolytics, vitamin B derivatives and inner ear circulation improvers are preferably administered in accordance with the usual usage and amounts prescribed in the respective agents.

The spirocyclic hydantoin derivative represented by general formula (I) which is an active ingredient of the pharmaceutical composition of the present invention is a compound having an Aldose Reductase (AR) inhibitory activity, and therefore shows a correlation between the AR inhibitory activity and the effect of preventing or treating inner ear disorders. Examples of the compound having an aldose reductase inhibitory activity include Ranirestat (Ranirestat) (AS-3201), ARI-809 (CP-744809), Epalrestat (Epalrestat), Zopolrestat (Zopolrestat), Zenarestat (Zenarestat), Tolrestat (Tolrestat), Imirestat (Imirestat), Ponalrestat (Ponalrestat), voglibose (Voglistat), [5- (3-thienyl) tetrazol-1-yl ] acetic acid monohydrate (TAT), M-160209, SG-210, and NZ-314. It can be inferred that these compounds also have a preventive or therapeutic effect on inner ear disorders.

Examples

The present invention will be described more specifically with reference to examples. In the following examples, fidarestat was selected from among the compounds of the general formula (I) and tested. These are not intended to limit the present invention and may be changed within a range not departing from the gist of the present invention.

1. Evaluation of inner ear disorders in mouse Strong Sound model

Test method

The evaluation was carried out using a mouse model of strong sound. This is a model of inner ear disorders caused by exposure to loud sounds, prepared by loading a B6 mouse (Slc, female, experiment started at 8 weeks of age) with a loud sound (128 dB SPL (sound pressure level) for 4 hours before the loud sound load, measuring an auditory brainstem response (ABR: auditory brainstem response) threshold (pre value), measuring ABR after 1 and 2 weeks of 4 hours after the load, regarding the preventive experiment, after measuring the ABR threshold after 2 weeks, the inner ear was extirpated and fixed in such a way as to enable pathological evaluation of the shedding of 2 hair cells called inner hair cells and outer hair cells inside the cochlea, the shedding of hair cells was represented by inner hair cells (inner hair cells, representing inner hair cells arranged in 1 row as IHC) and outer hair cells (outer hair cells, representing inner hair cells arranged in 3 row as ohouter hair cells, 1 from the inner side as ohouter hair cells, respectively, 2. 3) pathological evaluation. The tests were performed by analysis of variance (Fisher test was used as post hoc test).

(1) Prophylactic agent administration

Animals were divided into 2 groups of strong voice group (control group, n = 10) and strong voice + fidarestat 32mg/kg/day administration group (fidarestat administration group, n = 10), ABR was performed in 10 groups, and pathological evaluation was performed in 5 groups. Wherein fidarestat is administered with mixed baits from 2 days before a strong sound load to 2 weeks after the sound load.

(2) Administration of therapeutic agents

Animals were divided into 5 groups of a loud speaker group (control group, n = 6), a loud speaker + fidarestat 8mg/kg/day administration group, a 32mg/kg/day administration group (fidarestat administration group, n = 6), a loud speaker + prednisolone 1mg/kg/day administration group (prednisolone administration group, n = 6), and a loud speaker + prednisolone 1mg/kg/day administration group (combination administration group, n = 6), and 6 cases of each group were subjected to ABR. Wherein fidarestat is administered with mixed baits from a strong sound load to 2 weeks. Prednisolone was administered orally 1 time after a strong sound load.

Results

(1) Effect on increase of Auditory Brainstem Response (ABR) threshold

Fidarestat significantly inhibited the increase in Auditory Brainstem Response (ABR) threshold observed with a strong sound load after both 1 and 2 weeks of the strong sound load (fig. 1-4). That is, fidarestat showed both prophylactic and therapeutic effects against an increase in ABR threshold caused by a strong sound load. In addition, among the therapeutic effects, the same effect as that of the prednisolone 1mg/kg/day administration was observed in the fidarestat 32mg/kg/day administration group, and a more significant inhibitory effect was observed in the combined administration group than in the prednisolone administration group.

(2) Effect on increasing hair cell shedding rate inside cochlea

Fidarestat significantly inhibited the increase in shedding rate of outer hair cells observed after 2 weeks of strong sound load (fig. 5).

Investigation of

The effect of fidarestat on inner ear disorders was studied using a powerful acoustic model of mice that is commonly used in the evaluation of efficacy against inner ear disorders. The auditory disorder model is an inflammatory model involving free radicals, active oxygen, and phospholipase a2, and the effectiveness of steroid drugs is known. Fidarestat confirmed a significant protective effect on both the increase in the Auditory Brainstem Response (ABR) threshold observed after a powerful sound and the increase in the shedding rate of outer hair cells inside the cochlea. In addition, the effects of intra-cochlear pathologies and the effects of auditory function are consistent results. Having such protective action on the inner ear, fidarestat was shown to be effective for inner ear disorders such as inner ear hearing loss, inner ear vertigo, and inner ear tinnitus. And the effect is comparable to that of prednisolone, which is a steroid agent commonly used in inner ear disorders. Moreover, when fidarestat and prednisolone were used in combination, the effect was more enhanced than in the case of separate administration. The detachment method has been a problem in terms of clinical side effects with respect to steroid drugs such as prednisolone, but from the results of this experiment, fidarestat is also considered to be useful as a maintenance therapy agent after detachment of the steroid drug. As described above, fidarestat is effective for the prevention or treatment of inner ear disorders.

2. Evaluation of inner ear disorders in gentamicin-loaded outer hair cell disappearance model

Test method

After the cochlea is removed from the 3-5 day old SD rat, the lateral wall is uncovered (latex wall), the basal helix coreti (Corti) was collected. After culturing the organ of Corti late, the cells were cultured for 48 hours in a culture medium supplemented with gentamicin (35. mu.g) and with fidarestat at each concentration (0, 0.05, 0.1, 0.2, 0.5, 1, 2. mu.M). After incubation, fixation with 4% paraformaldehyde was performed. Wherein the culture medium is Dulbecco's modified eagles medium (DMEM solution) containing 10% fetal bovine serum (total bovine serum), HEPES (250 mM) and penicillin G (30U/l) at 37 deg.C and 5% CO₂And culturing under the condition of 95% humidity.

Test results

The rate of outer hair cell disappearance by gentamicin loading was 50% in the control group, but the rate of disappearance was 25% at 0.5 μ M or more, although significant inhibition was observed from 0.1 μ M in the fidarestat-administered group (fig. 6). That is, over 0.5. mu.M 75% of the outer hair cells survived.

Investigation of

The effect of fidarestat on the pharmacological inner ear disorder was studied using the gentamicin loaded outer hair cell disappearance model that is common in the evaluation of effectiveness against the pharmacological inner ear disorder. As a result, fidarestat suppressed hair cell shedding due to gentamicin load from a low concentration, and confirmed its effectiveness. That is, fidarestat is effective for the prevention or treatment of pharmaceutical inner ear disorders caused by side effects such as antibiotics, anticancer agents, or diuretics. As described above, the effectiveness was confirmed not only for the powerful acoustic inner ear disorder but also for the pharmacological inner ear disorder, and therefore fidarestat is considered to be effective for any cause of inner ear disorder.

Claims (6)

1. A medicament for preventing or treating inner ear disorders, characterized by:

which comprises a spirohydantoin derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient,

wherein X represents a halogen atom or a hydrogen atom, R¹And R²At the same time or separatelyIs not hydrogen atom or C which may have a substituent_1-6An alkyl group.

2. The medicament of claim 1, wherein:

the spirohydantoin derivative shown in the general formula (I) is (2S,4S) -6-fluoro-2 ',5' -dioxaspiro [ chroman-4, 4' -imidazoline ] -2-formamide.

3. The medicament of claim 1 or 2, wherein:

the inner ear disorder is selected from the group consisting of inner ear hearing loss, inner ear tinnitus, and inner ear vertigo.

4. The medicament of claim 3, wherein:

the inner ear hearing is a sensorineural hearing or a mixed hearing.

5. The medicament according to any one of claims 1 to 4, wherein:

it is combined with other medicines for inner ear disorder.

6. The medicament of claim 5, wherein:

the other medicine for inner ear disorder is at least 1 selected from the group consisting of steroid drugs, anticholinergic drugs, antihistamine drugs, antiviral drugs, leukotriene receptor antagonists, anticoagulants, vasodilators, thrombolytics, vitamin B derivatives and inner ear circulation improvers.