CN112745279A

CN112745279A - Methazolamide and analogs thereof and application thereof in treatment of normal-pressure hydrocephalus

Info

Publication number: CN112745279A
Application number: CN202011093500.6A
Authority: CN
Inventors: 虞英民; 谢齐昂; 赵志良; 沈杞容; 朱金梁; 胡秀波; 金玉坤; 沈文忠; 刘东华; 宣艳红; 刘锐; 李福高; 徐承智
Original assignee: Hangzhou Aoyipollen Pharmaceutical Co ltd
Current assignee: Hangzhou Aoyipollen Pharmaceutical Co ltd
Priority date: 2019-10-31
Filing date: 2020-10-13
Publication date: 2021-05-04

Abstract

The invention discloses methazolamide and analogs thereof and application thereof in the treatment of normal-pressure hydrocephalus, and discloses a compound of a general formula (I) for treating normal-pressure hydrocephalus:

wherein R is selected from substituted or unsubstituted straight chain alkyl groups.

Description

Methazolamide and analogs thereof and application thereof in treatment of normal-pressure hydrocephalus

Technical Field

The present disclosure relates to the field of medicine, and more particularly to the field of treatment of normal pressure hydrocephalus.

Background

Normal Pressure Hydrocephalus (NPH) refers to the clinical manifestation of three symptoms of gait disorder, cognitive disorder and urinary incontinence, the manifestation of the disease of a patient is progressive development of different degrees, the imaging examination has ventricular enlargement, and the measurement of cerebrospinal pressure is 70-200 mmH₂O(1 mmH₂O ═ 0.0098 kPa).

Normal pressure hydrocephalus is clinically divided into two categories. One type is secondary NPH (sNPH), which is often secondary to diseases with clear pathogenesis, such as craniocerebral trauma, subarachnoid hemorrhage, intracranial infection, encephalitis and the like. One category is idiopathic nph (iinph) with no clear etiology in the clinic.

The classic clinical manifestations of iinph are the triple signs of gait disorders, cognitive disorders and urinary incontinence, with gait disorders being the most common and cognitive disorders and urinary incontinence also having varying degrees of morbidity, with about half of the patients having the triple signs at the same time. In addition to the triple, patients with iNPH may also be associated with other clinical manifestations, such as headache, dizziness, vertigo, prolonged sleep time, Parkinson's tremor, and sexual dysfunction, but these symptoms are not specific. In addition, iNPH patients are also associated with other diseases, such as cerebrovascular diseases, diabetes, Parkinson's disease, Alzheimer's disease, etc

According to the epidemiological survey data of Norway, the prevalence rate of suspected iNPH is about 21.9/10 ten thousand, the prevalence rate is about 5.5/10 ten thousand, and the average of the Japanese population over 61 years old "possible iNPH prevalence rate based on MRI image support" is 1.1%. Currently, no iNPH epidemiological data exist in China, and according to the international epidemiological survey data, about 200 million normal pressure hydrocephalus patients are presumed not to be identified and treated in time in China, so that the life quality of the old is seriously affected.

NPH has no ideal method for clinical treatment at present. There are two modalities of non-surgical and surgical treatment routinely available. The non-operative treatment is suitable for early-stage patients or patients with mild disease and slow development, and aims to reduce secretion of cerebrospinal fluid or increase water discharge of organisms by mainly adopting diuretics such as furosemide, mannitol, dihydrocholrush and the like, but at present, the non-operative treatment is only empirical medication, no guidance is recommended, no medicine instruction is listed, and the non-operative treatment is clear in medicine indication, and the diuretic is not suitable for long-term medication because adverse reactions such as electrolyte disorder, hyperuricemia, hyperglycemia, hyperlipidemia and the like can occur after long-term use. The operation treatment is suitable for the cases with higher ventricular pressure (more than or equal to 250mm water column) or failure through non-operation treatment. Severe hydrocephalus such as head circumference over 50 cm, cerebral cortex atrophy thickness below 1 cm, with severe dysfunction and deformity, can also be treated by operation, but has poor curative effect. The operation modes mainly comprise three operation modes of (1) obstruction removing operation, (2) cerebrospinal fluid formation reducing operation and (3) cerebrospinal fluid shunt operation. The complications of surgical treatment are common, mainly including blockage of shunt system, infection, excessive or insufficient shunt, fissure ventricular syndrome and the like.

Because most of NPH patients are seen in the elderly over 60 years old, many patients have co-morbidities, the side effects of the operation are considered, and most of patients resist the operation, the study on the effectiveness and the safety of non-operation drug treatment is imperative.

Disclosure of Invention

In one aspect, the disclosure relates to compounds of formula (I) for use in treating normal pressure hydrocephalus:

In another aspect, the disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (i) and a pharmaceutically acceptable adjuvant.

In another aspect, the disclosure relates to the use of a compound of formula (i) in the manufacture of a medicament for the treatment of normal pressure hydrocephalus.

In another aspect, the disclosure relates to the use of a pharmaceutical composition comprising a compound of formula (i) and a pharmaceutically acceptable adjuvant for the treatment of normal pressure hydrocephalus.

Drawings

FIG. 1 shows an MRI image of the head of a patient before methazolamide is administered to a case in one embodiment of the present disclosure;

FIG. 2 shows an MRI image of a patient's head three months after a case takes methazolamide in an embodiment of the present disclosure;

FIG. 3 shows a CT image of the head of a patient after taking methazolamide in one case of the disclosed embodiment;

fig. 4 shows a head CT image of a patient seven months after taking methazolamide in one case in an embodiment of the present disclosure.

Detailed description of the invention

In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments can be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.

Unless otherwise required by the disclosure, throughout the specification and the appended claims, the words "comprise", "comprising", and "have" are to be construed in an open, inclusive sense, i.e., "including but not limited to".

Reference throughout the specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that a particular reference element, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment, and furthermore, particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

Definition of

In the present disclosure, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms, preferably alkyl groups containing 1 to 3 carbon atoms.

In the present disclosure, the term "straight chain alkyl" refers to a saturated aliphatic hydrocarbon group, including straight chain groups of 1 to 6 carbon atoms, preferably alkyl groups containing 1 to 3 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl.

In the present disclosure, the term "substituted or unsubstituted" means that any one or more hydrogen atoms on a particular atom are substituted or unsubstituted with a substituent, as long as the valence of the particular atom is normal and the substituted compound is stable.

In the present disclosure, the term "pharmaceutically acceptable excipients" refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations; is a substance which has been reasonably evaluated in terms of safety in addition to the active ingredient and is contained in a pharmaceutical preparation.

In the present disclosure, the term "therapeutically effective amount" refers to an amount sufficient to perform a treatment when administered to an individual for the treatment of normal pressure hydrocephalus. The "therapeutically effective amount" will vary depending on the particular condition, disease, disorder or condition being treated and its severity, as well as the age, weight, physical condition and responsiveness of the individual being treated. Thus, one or more of these parameters may be used to select and adjust a therapeutically effective amount of methazolamide. Furthermore, the amount may also be determined using pharmacological methods known in the art, such as dose response curves.

In the present disclosure, the term "injection" refers to a pharmaceutical dosage form, which is prepared into a concentrated (diluted) solution or a lyophilized powder for injection for subcutaneous, intramuscular, and intravenous injection by one or more injection preparation processes of dissolving, concentrating, diluting, filling, sterilizing, etc.

In the present disclosure, the term "capsule" refers to a solid preparation prepared by preparing a drug or a combination of a drug and related excipients into granules, pellets or powder suitable for filling by related preparation means, and filling the granules, pellets or powder into a hollow hard capsule or an elastic soft capsule, wherein the materials constituting the hollow hard capsule shell or the elastic soft capsule shell are gelatin, glycerol, water and other medicinal materials, but the proportions of the components are different and the preparation method is different.

In the present disclosure, the term "granule" refers to a granular preparation prepared by mixing a drug with appropriate excipients, and can be generally divided into soluble granules, suspension granules and effervescent granules, and if the particle size is in the range of 105 to 500 microns, it is also called fine granule.

In the present disclosure, the term "tablet" refers to a tablet-like preparation made of a drug and suitable excipients by formulation techniques.

In the present disclosure, the term "CT" refers to scanning a certain thickness of a layer of a human body with an X-ray beam, receiving the X-ray transmitted through the layer by a detector, converting the X-ray into visible light, converting the visible light into an electrical signal by photoelectric conversion, converting the electrical signal into a digital signal by an analog/digital converter (analog/digital converter), and inputting the digital signal to a computer for processing.

In this disclosure, the term "bid" refers to the common mode of administration in prescription, abbreviated twice daily.

In the present disclosure, the term "MRI" refers to magnetic resonance imaging, which is a type of tomographic imaging that obtains electromagnetic signals from a human body using a magnetic resonance phenomenon and reconstructs human body information.

In the present disclosure, the term "methazolamide" refers to the compounds of formula (I) wherein R is methyl.

Detailed Description

In certain embodiments, the substituted or unsubstituted straight chain alkyl group can be a substituted or unsubstituted C1-4 alkyl group.

In certain embodiments, the substituted or unsubstituted straight chain alkyl can be methyl.

In another aspect, the disclosure relates to a pharmaceutical composition comprising a compound of formula (i) and a pharmaceutically acceptable excipient.

In certain embodiments, the pharmaceutical composition further comprises a potassium supplement.

In certain embodiments, illustrative examples of potassium supplements that can be used in the present disclosure include, but are not limited to, potassium chloride, potassium carbonate, dipotassium hydrogen phosphate, potassium citrate, potassium gluconate, potassium lactate, potassium glycerophosphate, and potassium sulfate.

In certain embodiments, the pharmaceutical compositions of the present disclosure can be formulated into injections, capsules, granules, and tablets.

In another aspect, the disclosure relates to the use of a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (i) and a pharmaceutically acceptable adjuvant for the treatment of normal pressure hydrocephalus.

In certain embodiments, illustrative examples of dosage forms that can be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, injections, capsules, granules, and tablets.

In another aspect, the disclosure relates to a method of treating normal pressure hydrocephalus comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (i).

In certain embodiments, the subject is a mammal.

In certain embodiments, the mammal is a human.

Hereinafter, the present disclosure will be explained in detail by the following examples in order to better understand various aspects of the present application and advantages thereof. It should be understood, however, that the following examples are not limiting and are merely illustrative of certain embodiments of the present disclosure.

Examples

Example 1: patient 1, female, 67 years old.

Disease states and treatment procedures: the patient is diagnosed with unstable walking for 5 years and memory disorder and fecal incontinence for more than 2 years, the patient is diagnosed with hydrocephalus by head MRI, the tablet containing methazolamide with effective treatment amount is orally taken 50mgbid after the diagnosis, the patient condition is gradually relieved after the medicine is taken for three months, the mental state is good, the patient can communicate with family members by using a mobile phone and a computer, the logical thinking ability and judgment ability are improved, the patient can consult the condition (the patient is a surgeon) and still cannot walk, but the muscle strength of the limbs is normal, and the stool is normal. The head MRI was reviewed as shown in fig. 1 and 2 below, wherein fig. 1 shows the head MRI image of the patient before the case of example 1 took methazolamide, and fig. 2 shows the head MRI image of the patient three months after the case of example 1 took methazolamide 50 mgbid.

As can be seen from a comparison of FIGS. 1 and 2, the patients who took tablets containing a therapeutically effective amount of methazolamide had a significantly reduced number of collateral ventricular leucosis in their lateral ventricle than before.

Example 2: patient 2, male, 80 years old.

Disease states and treatment procedures: chief complaints about 80 years old, weakness of both lower limbs, and memory decline for more than 1 month, were found to fall to stairs and complain about headache. Performing head CT to indicate extensive subarachnoid hemorrhage, performing emergency head CTA examination to indicate right middle cerebral aneurysm, and performing emergency treatment to indicate subarachnoid hemorrhage; intracranial aneurysms; coronary heart disease; after coronary artery stent operation, the patient has limb weakness and slow reaction after the operation, and the examination of the skull CT indicates that the change after the aneurysm operation, the subarachnoid hemorrhage is reduced compared with the former, the right frontotemporal lobe and the island lobe can be seen into sheet low-density shadow, and the patient can be consulted by a neurological consultation center to be admitted into the hospital with hydrocephalus. The diagnosis of the head CT is hydrocephalus, old cerebral infarction, the clinical diagnosis is NPH, 25mgbid tablets containing methazolamide with effective treatment amount are orally taken after hospital admission, the weakness of both lower limbs of a patient is obviously improved after 1 week, the original lower limb can not move autonomously, the walking can be improved to be capable of walking by self, and the walking is still unstable. The cognitive function of a patient is improved after 1 month of treatment, the treatment scheme is changed into the mode that methazolamide is orally taken at 50mgbid, when the patient takes about 3 months, because the patient stops taking the potassium tablet orally by himself or herself, the potassium is supplemented by potassium chloride sustained-release tablets, the disease condition is further improved and is stable all the time, the patient can walk by himself, and the family members and the patient are satisfied. The head CT reexamination after 7 months of treatment suggests that hydrocephalus is relieved earlier. The patient has no adverse reaction. The CT images are shown in figures 3 and 4 in detail, wherein figure 3 shows the CT image of the head of the patient before methazolamide is taken in the case of example 2, and figure 4 shows the CT image of the head of the patient after methazolamide is taken in the case of example 2 for seven months at 50 mgbid.

Example 3: patient 3, female, 82 years old.

Disease states and treatment procedures: the main statement "the calculated force for hypomnesis is 3 and a half months worse". At 28 out-patient visits on 12 months in 2017, the tablets containing a therapeutically effective amount of methazolamide are taken initially, 25mg bid for the first 2 weeks, and then 50mg bid is added to the tablets containing a therapeutically effective amount of methazolamide taken orally. The traditional Chinese medicine is taken for a long time, the head CT is rechecked after the doctor visits in 2018 and 02-06 days, hydrocephalus is reduced, and the medicine is taken in the outpatient clinic all the time at present, so that the condition of the patient is stable. After 1 year and half of taking the tablets containing the methazolamide with the effective treatment amount, the cognitive impairment is recovered well, the state of illness is stable all the time, and no obvious side effect appears for more than one year.

Example 4: patient 4, male, 73 years old.

Disease states and treatment procedures: the diagnosis is mainly described as "abnormal gait, urinary incontinence for 2 years, aggravated in 1 month". The symptoms of the patient do not involve the upper limbs, do not have tremor of the limbs, and do not have obvious hypomnesis and unconsciousness disorder. Hydrocephalus is diagnosed. The oral administration of 50mgbid tablets containing a therapeutically effective amount of methazolamide was started two weeks after the visit. After one month, the standing is stable, the body balance is improved, and the person does not topple forward or fall down.

Example 5: patient 5, male, 66 years old.

Disease states and treatment procedures: the main remarks are that the patient can see a doctor for 3 years with slow response and unstable walking. The patients have no urinary incontinence, slightly reduced cognitive function, no speech and limb movement disorder, no limb tremor, no bradykinesia, no hallucinations and no mental symptoms. In emergency treatment, head magnetic resonance indicates that ventricles of brain and aqueducts of midbrain on both sides are enlarged to receive and admit hydrocephalus. The patient has no fever since the disease, the general state is good, the diet is good, and the defecation is normal. The patient orally takes 50mgbid tablets containing methazolamide with a therapeutically effective dose, the tablets are reduced to 25mgbid after one week, the symptoms are obviously improved, the walking speed is increased faster than before, and the reaction is sensitive than before.

Wherein the tablet containing methazolamide in a therapeutically effective amount is provided by Hangzhou Australian medicine industry Co.

To sum up: after the tablets of methazolamide with the effective treatment amount are taken, the symptoms of the normal-pressure hydrocephalus of the cases are all improved, and the living state and the life quality of the cases are improved to a great extent.

In the present disclosure, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions.

From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications or improvements may be made by those skilled in the art without departing from the spirit and scope of the disclosure, and that such modifications or improvements are intended to be within the scope of the appended claims.

Claims

1. A compound of formula (I) for use in the treatment of normal pressure hydrocephalus:

2. The compound of claim 1, wherein the linear alkyl group is selected from substituted or unsubstituted C1-4 alkyl.

3. A compound according to claim 1 or 2 wherein the straight chain alkyl group is methyl.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 3 and a pharmaceutically acceptable adjuvant.

5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition further comprises a potassium supplement.

6. The pharmaceutical composition of claim 5, wherein the potassium supplement is selected from potassium chloride, potassium carbonate, dipotassium hydrogen phosphate, potassium citrate, potassium gluconate, potassium lactate, potassium glycerophosphate, potassium sulfate, or mixtures thereof.

7. The pharmaceutical composition of any one of claims 4 to 6, wherein the pharmaceutical composition is an injection, a capsule, a granule, or a tablet.

8. Use of a compound according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of normal pressure hydrocephalus.

9. Use of a pharmaceutical composition according to any one of claims 4 to 7 for the treatment of normal pressure hydrocephalus.

10. A method of treating normotensive hydrocephalus comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 3.

11. The method of claim 10, wherein the subject is a mammal.

12. The method of claim 11, wherein the mammal is a human.