Field of the Invention This invention relates to a new use of compounds that are angiotensin II (Ang II) receptor agonists, more particularly selective agonists of the Ang II type 2 receptor (hereinafter the AT2 receptor), and especially agonists that bind selectively to that receptor, for therapeutic treatment or prevention of peripheral neuropathy, including diabetic neuropathy.

Background of the invention

Peripheral neuropathy (PN) is damage to or disease affecting nerves which may impair sensation, movement, gland or organ function, or other aspect of health, depending on the type of nerve affected. Common causes include systemic diseases (e.g. diabetes) vitamin deficiency, medication (e.g. chemotherapy) radiation and several other causes. Diabetic neuropathies are nerve damaging disorders associated with diabetes mellitus (DM). The diabetic neuropathies are a heterogeneous group of disorders with diverse clinical manifestations. The early recognition and appropriate management of neuropathy in the patient with diabetes is important.

DM is the leading known cause of neuropathy in developed countries, and neuropathy is the most common complication and a great source of morbidity and mortality in diabetes patients. Globally, diabetic neuropathy affects approximately 132 million people as of 2010 or approx. 2% of the population in Western countries.

People with diabetes can, over time, develop nerve damage throughout the body. Some people with nerve damage have no symptoms. Others may have symptoms such as pain, tingling, or numbness— loss of feeling— in the hands, arms, feet, and legs. Nerve problems can occur in every organ system, including the digestive tract, heart, and sex organs. Diabetic neuropathy can be classified as peripheral, autonomic, proximal, or focal. Each affects different parts of the body in various ways.

About 60 to 70 percent of people with diabetes have some form of neuropathy, and in approx. 1/3 of these the neuropathy is painful. People with diabetes can develop nerve problems at any time, but risk rises with age and longer duration of diabetes. The highest rates of neuropathy are among people who have had diabetes for at least 25 years. Nerve damage is likely due to a combination of factors including, but not limited to, those listed below:

• metabolic factors, such as high blood glucose, long duration of diabetes, abnormal blood fat levels, and possibly low levels of insulin

• neurovascular factors, leading to damage to the blood vessels that carry oxygen and nutrients to nerves

• medication, e.g. chemotherapy

• autoimmune factors that cause inflammation in nerves

· mechanical injury to nerves, such as carpal tunnel syndrome

• inherited traits that increase susceptibility to nerve disease

• lifestyle factors, such as smoking or alcohol use.

Symptoms depend on the type of neuropathy and which nerves are affected. Some people with nerve damage have no symptoms at all. For others, the first symptom is often numbness, tingling, or pain in the feet. Symptoms are often minor at first, and because most nerve damage occurs over several years, mild cases may go unnoticed for a long time. Symptoms can involve the sensory, motor, and autonomic— or involuntary— nervous systems. In some people, mainly those with focal neuropathy, the onset of pain may be sudden and severe.

Other symptoms of nerve damage may include: pain in the legs, hands, arms, and fingers; wasting of the muscles of the feet or hands; indigestion, nausea, or vomiting; diarrhoea or constipation; dizziness or faintness due to a drop in blood pressure after standing or sitting up; problems with urination; erectile dysfunction in men or vaginal dryness in women; and weakness. Symptoms that are not due to neuropathy, but often accompany it, include weight loss and depression.

Foot ulcers and amputation, which are consequences of diabetic neuropathy and/or peripheral arterial disease (PAD), are common and represent major causes of morbidity and mortality in people with diabetes.

Clinical guidelines recommend pain relief in painful diabetic neuropathy through the use of antidepressants such as amitriptyline and duloxetine, the γ-aminobutyric acid analogues gabapentin and pregabalin, opioids and topical agents such as capsaicin. Small molecule angiotensin II type 2 receptor antagonists have also been proposed as analgesics for neuropathic pain. (Smith M., ef a/., Pain Med. 14:692-705).

Specific treatment for the underlying nerve damage, other than improved glycemic control, is currently not available. The development of new treatment strategies and so- called disease-modifying agents for peripheral neuropathy is therefore important.

The RAS is a key regulator of blood pressure homeostasis. Renin, a protease, cleaves its only known substrate (angiotensinogen) to form angiotensin I, which in turn serves as substrate to angiotensin converting enzyme (ACE) to form Ang II. The endogenous hormone Ang II is a linear octapeptide (Asp^Arg^Va^-Tyi^-lle^His^Pro^Phe ⁸ ), and is an active component of the RAS.

Several studies in adult individuals appear to demonstrate that, in the modulation of the response following Ang II stimulation, activation of the AT2 receptor has opposing effects to those mediated by the AT1 receptor. The AT2 receptor has also been shown to be involved in apoptosis and inhibition of cell proliferation (de Gasparo M et al. Pharmacol Rev 2000; 52:415-472). The expected pharmacological effects of agonism of the AT2 receptor are described in general in de Gasparo M et al., 2000. It is not mentioned that agonism of the AT2 receptor may be used to treat or prevent peripheral neuropathy.

AT2 receptor agonists have also been described in the prior art, for instance in international patent application WO 2002/096883. However, the use of those compounds in the treatment of diabetic neuropathy or peripheral neuropathy is not mentioned. International patent application WO 2015/189342 discloses the use of angiotensin II type 2 receptor agonists for the treatment of pain.

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

Disclosure of the Invention

According to a first aspect of the invention, there is provided a method for treating or preventing one or more conditions or symptoms associated with peripheral neuropathy in a subject suffering from peripheral neuropathy, comprising administering to the subject a therapeutically effective amount of an AT2 receptor agonist or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the one or more conditions or symptoms are selected from the group consisting of numbness or insensitivity to pain or temperature, cramps, extreme sensitivity to touch, loss of balance and coordination, blood pressure abnormalities, constipation, gastroparesis, difficulty with swallowing, diarrhoea, weight loss, urinary tract infections, urinary incontinence, decreased sexual response, profuse sweating, reduced responsiveness of the pupils of the eye to changes in light, weakness in the legs, inability to focus the eye, double vision and paralysis on one side of the face. According to a second aspect of the invention, there is provided an AT2 receptor agonist, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in treating or preventing one or more conditions or symptoms associated with peripheral neuropathy in a subject suffering from peripheral neuropathy. Said one or more conditions or symptoms are as defined above in respect of the first aspect of the invention.

According to a third aspect of the invention, there is provided a method for preventing peripheral neuropathy in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of an AT2 receptor agonist or a pharmaceutically acceptable salt, solvate or prodrug thereof.

According to a fourth aspect of the invention, there is provided an AT2 receptor agonist, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in preventing peripheral neuropathy. According to another aspect of the invention, there is provided the use of an AT2 receptor agonist, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for preventing peripheral neuropathy or for treating or preventing one or more conditions or symptoms associated with peripheral neuropathy, wherein said conditions or symptoms are as defined above in respect of the first aspect of the invention.

The methods and uses of the first, second, third and fourth aspects of the invention are hereinafter referred to as the "methods of the invention". AT2 receptor agonists may also be referred to herein as the "compounds of the invention".

Compounds that are useful in the first, second, third and fourth aspects of the invention are agonists of Ang II receptor, more particularly, are agonists of the AT2 receptor, and, especially, are selective agonists of that sub-receptor, in particular non-peptide selective agonists. In some embodiments, the useful compounds are those that fully and those that partially activate the AT2 receptor and those compounds that can stimulate or activate the AT2 receptor. In some embodiments, the compounds of the invention (i.e. the AT2 receptor agonist) may be defined as any compound that can stimulate or activate the AT2 receptor. For the avoidance of doubt, the methods of the invention may involve more than one AT2 receptor agonists, through preferably they involve only one such compound (and/or salts, solvates and prodrugs thereof). In some embodiments, the compound of the invention is an AT2 receptor specific agonist and binds selectively to the AT2 receptor. In some embodiments, the compound of invention is a non-peptide AT2 receptor specific agonist that binds selectively to the AT2 receptor. A particular compound that may be mentioned in this respect is N-Butyloxycarbonyl-3-(4- imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamid e (Compound 21 or, in short, C21 or C-21 ). Pharmaceutically acceptable salts, solvates and prodrugs of C21 are also useful for the therapeutic treatment and prevention of peripheral neuropathy. C21 is an example of a compound that bind selectively to the AT2 receptor.

Pharmaceutically-acceptable salts include, but are not limited to, acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo or by freeze-drying). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. For the avoidance of doubt, other pharmaceutically acceptable derivatives of compounds of the invention are included within the scope of the invention (e.g. solvates, prodrugs etc).

In embodiments in which the method of the invention involves N-Butyloxycarbonyl-3-(4- imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamid e, said compound may be provided in the form of a pharmaceutically-acceptable salt, in particular a HCI salt thereof. As used herein, a "prodrug" is a composition that undergoes an in vivo modification when administered to a subject, wherein the product of the in vivo modification is a therapeutically effective compound. Prodrugs of compounds may be prepared by, for example, preparing a given compound as an ester. Thus, for example, an esterified form of the compound may be administered to a subject and may be de-esterified in vivo thereby releasing a therapeutically effective compound. Alternatively, some compounds may be prepared as prodrugs by adding short polypeptides (e.g., 1-6 amino acids) to the compound. Such prodrugs when administered to a subject may be cleaved (by, e.g., trypsin or other peptidases/proteases) thereby releasing a therapeutically effective compound. Formation of prodrugs is not limited by the specific examples described herein. Other ways of preparing therapeutically effective compounds as prodrugs are known.

Compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.

Compounds of the invention also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.

The compound N-Butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso- butylthiophene-2-sulfonamide (C21 ) with the structure provided in Fig. 5, may be made in accordance with techniques well known to those skilled in the art, for example as described in international patent application WO 2002/096883, and all of its content is hereby incorporated by reference. The compounds of the invention are useful because they possess pharmacological activity. In particular, the compounds of the invention are agonists of Ang II receptor, more particularly, they are agonists of the AT2 receptor, and, especially, are selective agonists of that sub-receptor. Compounds of the invention have the advantage that they bind selectively to, and exhibit agonist activity at, the AT2 receptor. By compounds that "bind selectively" to the AT2 receptor, we include that the affinity ratio for the relevant compound (AT2:AT1 ) is at least 100:1 , preferably at least 1000:1 , more preferably at least 10000:1 , and even more preferably at least 25000:1.

Binding affinities may be determined by methods known to those skilled in the art, for example the assays described in WO 2002/096883. Other embodiments and advantages will be more fully apparent from the following disclosure. It should be appreciated that the invention may be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

As used in the description of the embodiments of the invention, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also, as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items.

Furthermore, the term "about," as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, refers to variations of 20%, 10%, 5%, 1 %, 0.5%, or even 0.1 % of the specified amount.

When a range is employed (e.g., a range from x to y) it is it meant that the measurable value is a range from about x to about y, or any range therein, such as about xi to about

It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. Unless otherwise defined, all terms, including technical and scientific terms used in the description, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. "Effective amount" or dosage as used herein refers to an amount of a compound, composition and/or formulation that is sufficient to produce a desired effect, which can be a therapeutic and/or beneficial effect. The effective amount or dosage will vary with the age, general condition of the subject, the severity of the condition being treated, the particular agent administered, the duration of the treatment, the nature of any concurrent treatment, the pharmaceutically acceptable carrier used, and like factors within the knowledge and expertise of those skilled in the art. As appropriate, an "effective amount" or dosage in any individual case can be determined by one of skill in the art by reference to the pertinent texts and literature and/or by using routine experimentation. A "therapeutically effective" amount as used herein is an amount that is sufficient to treat (as defined herein) the subject. Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject. As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, inhibiting the progress of a disease or disorder or a symptom thereof as described herein, or delaying, eliminating or reducing the incidence or onset of a disorder or disease or a symptom thereof as described herein, as compared to that which would occur in the absence of the measure taken. The terms "prophylaxis" or "prophylactic use" and "prophylactic treatment" as used herein, refer to any medical or public health procedure whose purpose is to prevent the disease herein disclosed. As used herein, the terms "prevent", "prevention" and "preventing" refer to the reduction in the risk of acquiring or developing a given condition, or the reduction or inhibition of the recurrence or said condition in a subject who is not ill. These terms may also refer to the reduction in the risk of developing a symptom of the disease or condition.

A "subject in need" of the methods of the invention can be a subject known to have or suspected of having peripheral neuropathy. We also include subjects that have an increased susceptibility to peripheral neuropathy, but who do not yet have symptoms of peripheral neuropathy (such as diabetic patients who do not yet have symptoms of peripheral diabetic neuropathy). The term "increased likelihood" in this context refers to a subject that has a likelihood of suffering from said disease that is at least 10% higher than that for the average population.

Thus, the methods of the invention are particularly suited to the treatment or prevention of peripheral neuropathy in patients that are not suffering from pain associated with peripheral neuropathy. For example, the compounds of the invention (e.g., AT2 receptor agonists, particularly C21 ) may be useful in the treatment or prevention of peripheral neuropathy (such as peripheral diabetic neuropathy or chemotherapy-induced peripheral neuropathy) in the absence of associated pain.

As used herein the term "concomitant administration" or "combination administration" of a compound, therapeutic agent or known drug with an AT2 receptor agonist as part of a method of the invention means administration of a known medication or drug and, in addition, the one or more AT2 receptor agonists at such time that both the known drug and the one or more AT2 receptor agonists will have a therapeutic effect. In some cases, this therapeutic effect will be synergistic. Such concomitant administration can involve concurrent (i.e., at the same time, in parallel at the same time), prior, or subsequent administration (e.g., sequential) of the known drug with respect to the administration of the AT2 receptor agonist. Such concomitant or combination administration may also refer to administration of an AT2 receptor agonist through different administrative routes separately (e.g., at least about 2 or more hours apart), sequentially (e.g., within about 2 hours, e.g., about 15 sec, 30 sec, 45 sec, 1 min, 2, min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 1 1 min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20 min, 21 min, 22 min, 23 min, 24 min, 25 min, 26 min, 27 min, 28 min, 29 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min, 60 min, 65 min, 70 min, 75 min, 80 min, 85 min, 90 min, 95 min, 100 min, 105 min, 110 min, 1 15 min, and the like, and any range or value therein) and/or in parallel at the same time (e.g., concurrently) in order to achieve effective amount or dosage. A person of skill in the art, would have no difficulty determining the appropriate timing, sequence and dosages of administration for particular drugs and compounds of the present invention.

In addition, in some embodiments, the AT2 receptor agonist will be used, either alone or in combination with one or more other therapeutic medications as described herein (including one or more other AT2 receptor agonists), or their pharmaceutically acceptable salts, solvates or prodrugs, for manufacturing a medicament for the purpose of providing treatment or prophylaxis for peripheral neuropathy. All patents, patent applications and publications referred to herein are incorporated by reference in their entirety. In the event of conflicting terminology, the present specification is controlling. Further, the embodiments described in one aspect of the present invention are not limited to the aspect described. The embodiments may also be applied to a different aspect of the invention as long as the embodiments do not prevent these aspects of the invention from operating for their intended purpose.

Current guidance for the treatment of diabetic neuropathy from the U.S. Department of Health and Human Services, National Institutes of Health is to maintain safe glucose levels via treatment with pharmaceuticals and control of diet and exercise.

Chemotherapy-induced peripheral neuropathy often causes severe peripheral neurotoxicity and pain. Several mechanisms are involved in the pathophysiology; including the formation of reactive oxygen species. Preferential sites are sensory neurons, Schwann cells and neuronal and glial cells in the spinal cord. For the present, treatment of chemotherapy-induced peripheral neuropathy relies on reducing or discontinuing the offending agent, and treating the neuropathic pain using a variety of drugs. No single agent, however, is regarded as effective in larger populations and a huge medical need remains.

It has now been found that compounds of the invention (e.g., AT2 receptor agonists, particularly C21 ) are useful in the treatment and prevention of peripheral neuropathy. The gradual degradation of nerve functions that result from e.g. diabetes or from chemotherapy is based on a number of pathophysiological processes that can be targeted using the compounds of the invention. Thus, particular examples of peripheral neuropathy that may be mentioned include peripheral diabetic neuropathy and chemotherapy-induced peripheral neuropathy.

Diabetic neuropathy (including peripheral diabetic neuropathy) is generally classified as a microvascular disease. Vascular and neural diseases are closely related and intertwined. Blood vessels depend on normal nerve function, and nerves depend on adequate blood flow. The first pathological change in the small blood vessels is narrowing of the blood vessels. As the disease progresses, neuronal dysfunction correlates closely with the development of blood vessel abnormalities, such as capillary basement membrane thickening and endothelial hyperplasia, which contribute to diminished oxygen tension and hypoxia. Neuronal ischemia is a well-established characteristic of diabetic neuropathy. Thus, small blood vessel dysfunction occurs early in diabetes, parallels the progression of neural dysfunction, and may be sufficient to support the severity of structural, functional, and clinical changes observed in diabetic neuropathy. Diabetic neuropathy can be classified as peripheral, autonomic, proximal, or focal.

As discussed by Gongalves et al. (Nature reviews | Neurology Volume 13 | March 2017 | 135) an increased blood velocity in jeopardized capillaries may prevent efficient oxygen extraction, causing hypoxia. The resulting low oxygen tension, in turn, upregulates the expression of hypoxia-inducible-factor l alpha (HIF-1a) and NF-kappaB, which increase oxidative stress and inflammation resulting in a loss of trophic support for nerve cells.

The compounds of the invention are particularly suited to use in methods of treating or preventing peripheral diabetic neuropathy. Peripheral diabetic neuropathy

Symptoms vary according to the class of sensory fibers involved. The most common early symptoms are induced by the involvement of small fibers and include pain and dysesthesias (unpleasant sensations of burning and tingling). The involvement of large fibers may cause numbness and loss of protective sensation (LOPS). LOPS indicates the presence of distal sensorimotor polyneuropathy and is a risk factor for diabetic foot ulceration. The following clinical tests may be used to assess small and large-fiber function and protective sensation:

1. Small-fiber function: pinprick and temperature sensation

2. Large-fiber function: vibration perception, 10-g monofilament, and ankle reflexes 3. Protective sensation: 10-g monofilament.

To confirm that a drug has neuroprotective effects, subjective symptoms and objective measurements of nerve function, using electrophysiological examinations, need to be recorded in placebo-controlled clinical trials of sufficient size and length.

Electrodiagnostic tests measure the electrical activity of muscles and nerves to determine if there is nerve damage, the extent of the damage and potentially the cause of the damage. Examples of such objective evaluations are electromyography and nerve conduction velocity testing. Electromyogram (EMG) detects any signs of blocking or slowing down of responses to nerve stimulation. The test provides information about the muscle itself and shows how well it receives stimulation from the nerve.

Nerve conduction velocity test (NEV), also called a nerve conduction study, measures how quickly electrical impulses move along a nerve. A healthy nerve conducts signals with greater speed and strength than a damaged nerve. The speed of nerve conduction is influenced by the myelin sheath— the insulating coating that surrounds the nerve. This test is used to diagnose nerve damage or dysfunction and can differentiate injury to the nerve fiber (axon) from injury to the myelin sheath surrounding the nerve, which is useful in diagnostic and therapeutic strategies.

The American Diabetes Association recently published guidelines for patient management:

• All patients should be assessed for diabetic peripheral neuropathy starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes and at least annually thereafter.

• Assessment for distal symmetric polyneuropathy should include a careful history and assessment of either temperature or pinprick sensation (small-fiber function) and vibration sensation using a 128-Hz tuning fork (for large-fiber function).

· All patients should have annual 10-g monofilament testing to identify feet at risk for ulceration and amputation.

Peripheral neuropathy, the most common type of diabetic neuropathy, causes pain or loss of feeling in the toes, feet, legs, hands, and arms. Peripheral neuropathy, also called distal symmetric neuropathy or sensorimotor neuropathy, is nerve damage in the arms and legs. Feet and legs are likely to be affected before hands and arms. Many people with diabetes have signs of neuropathy that a doctor could note but feel no symptoms themselves. Symptoms of peripheral neuropathy may include

• numbness or insensitivity to pain or temperature

· a tingling, burning, or prickling sensation

• sharp pains or cramps

• extreme sensitivity to touch, even light touch

• loss of balance and coordination Thus, the methods of the invention are particularly suited to the treatment or prevention of peripheral neuropathy in patients that are not suffering from pain associated with peripheral neuropathy. For example, the compounds of the invention (e.g., AT2 receptor agonists, particularly C21 ) may be useful in the treatment or prevention of peripheral neuropathy (such as peripheral diabetic neuropathy or chemotherapy-induced peripheral neuropathy) in the absence of associated pain.

Peripheral neuropathy generally affects some or all of the sensory nerves, the motor nerves and the autonomic nerves. Peripheral neuropathy may cause muscle weakness and loss of reflexes, especially at the ankle, leading to changes in the way a person walks. Foot deformities, such as hammertoes and the collapse of the midfoot, may occur. Blisters and sores may appear on numb areas of the foot because pressure or injury goes unnoticed. If an infection occurs and is not treated promptly, the infection may spread to the bone, and the foot may then have to be amputated. Many amputations are preventable if minor problems are caught and treated in time. Compounds of the invention may also be useful in preventing or treating foot ulcers, and/or preventing the need for amputation of all or part of the foot, particularly where the foot ulcers or amputation is associated with diabetic neuropathy.

Methods of treating or preventing peripheral neuropathy, as disclosed herein, including peripheral diabetic neuropathy and chemotherapy-induced peripheral neuropathy, may include methods of treating or preventing conditions and symptoms associated with peripheral neuropathy, such as those conditions and symptoms described herein, in particular numbness or insensitivity to pain or temperature, cramps, extreme sensitivity to touch, loss of balance and coordination, blood pressure abnormalities, constipation, gastroparesis, difficulty with swallowing, diarrhoea, weight loss, urinary tract infections, urinary incontinence, decreased sexual response, profuse sweating, reduced responsiveness of the pupils of the eye to changes in light, weakness in the legs, inability to focus the eye, double vision and paralysis on one side of the face, called Bell's palsy. Data on a beneficial effect of C21 in a model of spinal cord injury has already been published (Namsolleck et al. Neurobiology of Disease 51 (2013) 177-191 ). The proposed explanation is that C21 stimulates healing processes in the body. One such example is the ability to regenerate nerve fibers as demonstrated in that paper. One important aspect is that an AT2R antagonist, EMA401 , has reduced pain in postherpetic subjects. However, it has surprisingly been found that animals treated with C21 (an AT2 receptor agonist) do not show any signs of C21 -induced pain or abnormal behaviour. Surprisingly, healthy human volunteers exposed to very high C21 doses, with plasma concentrations well above the expected therapeutic range, have not reported any symptoms indicating that C21 causes pain. In fact, a few reports of mild headache in the Phase I program was not dose-related and as frequently seen among placebo-treated subjects. The fact that subjects were fasting and no coffee allowed remains the most plausible explanation for this mild headache.

Angiotensin II receptor agonists have now been shown to enhance microvascular blood flow in muscles accompanied by an increased interstitial oxygen saturation. It has now been demonstrated that direct activation of AT2 receptors with C21 (Compound 21 ) potently increases muscle microvascular perfusion and oxygenation, via an angiotensin II type-2 receptor-dependent, NO-mediated mechanism. Angiotensin II receptor agonists have also been shown to improve nutrient blood flow to organ areas in models characterized by poor perfusion (as demonstrated by increased expression of hypoxia inducible factor (HIF-1a)).

The combination of these effects, and others, makes angiotensin II receptor agonists (particularly AT2 receptor agonists) viable candidate drugs for the treatment or prevention of peripheral neuropathy in particular diabetic neuropathy. In an embodiment of the invention, AT2 receptor agonists may be useful in minimizing the reduction in sensory perception and/or motor functions, for example reductions which are due to or arise as a consequence of peripheral neuropathy in the subject. AT2 receptor agonists may also facilitate the retention or improvement of sensory perception and/or motor functions in a subject that is suffering from peripheral neuropathy or that may be susceptible to peripheral neuropathy.

The compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, or via inhalation or pulmonary route, or any combination thereof, in a pharmaceutically acceptable dosage form, in solution, in suspension, including nanosuspensions, or in liposome formulation. Preferred routes of administration are nasal, oral, parenteral and via inhalation. Oral administration is the most preferred route. Additional methods of administration include, but are not limited to, intraarterial, intramuscular, intraperitoneal, intraportal, intradermal, epidural, intrathecal administration, or any combination thereof. In one embodiment, there is provided a method of preventing peripheral neuropathy, or a method of treating or preventing one or more conditions or symptoms associated with peripheral neuropathy, comprising administrating a therapeutically effective amount of an angiotensin II receptor agonist (e.g., an AT2 receptor agonist or other compound that stimulates an AT2 receptor in particular non-peptide agonists), or a pharmaceutically acceptable salt, solvate or prodrug thereof, through a combination of administrative routes, either separately, sequentially or in parallel at the same time (e.g., concurrently), preferably via inhalation and orally, in order to achieve effective amount or dosage, to a patient in need of such a therapy. Similar embodiments of the second and fourth aspects of the invention which involve a combination of administrative routes, either separately, sequentially or in parallel at the same time are also envisaged.

In a further embodiment, there is provided a method of preventing peripheral neuropathy, or a method of treating or preventing one or more conditions or symptoms associated with peripheral neuropathy, comprising administrating a therapeutically effective amount of the compound N-Butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso- butylthiophene-2-sulfonamide (C21 ), or a pharmaceutically acceptable salt, solvate or prodrug thereof, through a combination of administrative routes, either separately, sequentially or in parallel at the same time (e.g., concurrently), preferably orally, in order to achieve effective dosage, to a patient in need of such a therapy. Similar embodiments of the second and fourth aspects of the invention which involve a combination of administrative routes, either separately, sequentially or in parallel at the same time are also envisaged. In embodiments in which the methods of the invention involve the administration of more than one pharmaceutically active compound to the subject in need thereof (e.g. where the subject is administered more than one AT2 receptor agonist, the pharmaceutically active compounds may be administered alone (e.g., separately), and/or sequentially, and/or in parallel at the same time (e.g., concurrently), using different administrative routes, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, or via inhalation, and the like. Administration through inhalation is preferably done by using a nebulizer, thus delivering the compound of the invention (e.g., an AT2 receptor agonist or other compound that stimulates an AT2 receptor, or a pharmaceutically acceptable salt, solvate or prodrug thereof) to the small lung tissue including the alveoli and bronchioles, preferably without causing irritation or cough in the treated subject.

Preferably, administration of a therapeutically effective amount of a compound of the invention (or a pharmaceutically acceptable salt, solvate or prodrug thereof) is performed by a combination of administrative routes, either separately (e.g., about 2 or more hours apart from one another), sequentially (e.g., within about 2 hours of one another), or in parallel at the same time (e.g., concurrently), including via inhalation and orally, achieving an effective dosage.

In some embodiments, there is provided a method of preventing peripheral neuropathy, or a method of treating or preventing one or more conditions or symptoms associated with peripheral neuropathy, comprising administering a therapeutically effective amount of a compound of the invention (e.g., an AT2 receptor agonist or other compound that stimulates an AT2 receptor, or a pharmaceutically acceptable salt, solvate or prodrug thereof), through a combination of administrative routes, either separately, sequentially, or in parallel at the same time, preferably via inhalation and orally, in order to achieve effective amount or dosage, to a patient in need of such a therapy. In some embodiments, there is provided a method of preventing peripheral neuropathy, or a method of treating or preventing one or more conditions or symptoms associated with peripheral neuropathy, comprising administering a therapeutically effective amount of the compound N-Butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso- butylthiophene-2-sulfonamide (C21 ), or a pharmaceutically acceptable salt, solvate or prodrug thereof, through a combination of administrative routes, either separately, sequentially, or in parallel at the same time, preferably via inhalation and orally, in order to achieve effective dosage, to a patient in need of such a therapy.

Such combinations of administrative routes, preferably via inhalation and orally, may be presented as separate formulations of the compound of invention that are optimized for each administrative route.

Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.

Depending upon the patient to be treated and the route of administration, the AT2 receptor agonist (or pharmaceutically acceptable salt, solvate or prodrug thereof) may be administered at varying doses. Although doses will vary from patient to patient, suitable daily doses are in the range of about 0.1 to about 1000 mg (e.g., 0.1 , 0.5, 1 , 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 mg, and the like, or any range or value therein) per patient, administered in single or multiple doses. More preferred daily doses are in the range of about 0.1 to about 250 mg (e.g., 0.2, 0.3, 0.4, 0.5, 1 , 1.5, 2, 2.5, 3, 3.5, 4. 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 mg, and the like, or any range or value therein) per patient. A particularly preferred daily dose is in the range of from about 0.3 to about 100 mg per patient.

Individual doses of the AT2 receptor agonist may be in the range 0.1 to 100 mg (e.g., 0.3, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg, and the like, or any range or values therein).

In any event, the physician, or the skilled person, will be able to determine the actual dosage, which will be most suitable for an individual patient, which is likely to vary with the condition that is to be treated, as well as the age, weight, sex and response of the particular patient to be treated. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

According to a fifth aspect of the invention there is thus provided a pharmaceutical formulation comprising a compound of the invention (e.g., an AT2 receptor agonist or other compound that stimulates an AT2 receptor, or a pharmaceutically acceptable salt, solvate or prodrug thereof), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, for use in the treatment or prevention of peripheral neuropathy. AT2 receptor agonists disclosed herein may also be administered in combination with other AT2 agonists that are known in the art, as well as in combination with AT1 receptor antagonists that are known in the art, and/or in combination with an inhibitor of angiotensin converting enzyme (ACE). Thus, according to a sixth aspect of the invention, there is provided a combination comprising (i) AT2 receptor agonist, or pharmaceutically acceptable salt, solvate or prodrug thereof, and (ii) AT1 receptor antagonist and/or an inhibitor of angiotensin converting enzyme (ACE), for use in the therapeutic treatment or prevention of peripheral neuropathy. Non-limiting but illustrative examples of AT1 receptor antagonists that can be used according to the embodiments include azilsartan, candesartan, eprosartan, fimasartan, irbesartan, losartan, milfasartan, olmesartan, pomisartan, pratosartan, ripiasartan, saprisartan, tasosartan, telmisartan, valsartan and/or combinations thereof. Non-limiting but illustrative examples of ACE inhibitors that can be used according to the embodiments include captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, fosinopril, moexipril, cilazapril, spirapril, temocapril, alacepril, ceronapril, delepril, moveltipril, and/or combinations thereof.

In treatment regimens which involve the administration of an AT2 receptor agonist in conjunction with a second agent (i.e. either an AT1 receptor antagonist or an angiotensin converting enzyme (ACE) inhibitor (or both) as described herein), the AT2 receptor agonist may be administered separately, sequentially and/or concurrently with the second agent (or agents).

In an embodiment of the sixth aspect of the invention, the AT2 receptor agonist is provided in the same composition as the AT1 receptor antagonist and/or the angiotensin converting enzyme (ACE) inhibitor. Alternatively, the AT2 receptor agonist may be provided in a separate composition from the AT1 receptor antagonist. Similarly, the AT2 receptor agonist may be provided in a separate composition from the angiotensin converting enzyme (ACE) inhibitor.

Thus, in one embodiment there is provided a combination comprising:

(A) an AT2 receptor agonist and/or a compound that stimulates AT2 receptors, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and

(B) an AT1 receptor antagonist, and/or an ACE inhibitor,

wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, for use in the therapeutic treatment or prevention of peripheral neuropathy.

Such combination products provide for the administration of an AT2 receptor agonist and/or a compound that stimulates an AT2 receptor (as defined herein), in conjunction with an AT1 receptor antagonist and/or an ACE inhibitor, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises an AT2 receptor agonist or a compound that stimulates an AT2 receptor (e.g., an AT2 receptor agonist, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as disclosed herein), and at least one formulation comprises an AT1 receptor antagonist and/or an ACE inhibitor, or may be presented (i.e., formulated) as a combined preparation (i.e., presented as a single formulation an AT2 receptor agonist and/or a compound that stimulates an AT2 receptor together with either an AT1 receptor antagonist or an ACE inhibitor, or both an AT1 receptor antagonist and an ACE inhibitor).

Thus, there is further provided:

(1 ) a pharmaceutical formulation comprising an AT2 receptor agonist and/or a compound that stimulates an AT2 receptor (e.g., an AT2 receptor agonist, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as disclosed herein) and an AT1 receptor antagonist and/or an ACE inhibitor in admixture with a pharmaceutically-acceptable adjuvant, diluent and/or carrier, for use in the therapeutic treatment or prevention of peripheral neuropathy; and

(2) a kit of parts comprising components:

(a) a pharmaceutical formulation comprising an AT2 receptor agonist and/or a compound capable of stimulating AT2 receptors (e.g., an AT2 receptor agonist, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as disclosed herein), in admixture with a pharmaceutically-acceptable adjuvant, diluent and/or carrier; and

(b) a pharmaceutical formulation including an AT1 receptor antagonist, and/or an ACE inhibitor, in admixture with a pharmaceutically-acceptable adjuvant, diluent and/or carrier,

which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other, for use in the therapeutic treatment or prevention of peripheral neuropathy.

When the method of the invention involves the administration of both an AT1 receptor antagonist and an angiotensin converting enzyme inhibitor, said substances may be provided in the same composition as the AT2 receptor agonist in order to improve patient compliance. Conversely, it may be advantageous to administer one or more of the components separately from the others, e.g. in order to minimize the likelihood of the pharmaceutical substances interacting detrimentally with each other following administration. Thus, when the method involves the administration of both an AT1 receptor antagonist and an angiotensin converting enzyme inhibitor to the patient, it is preferred that the AT1 receptor antagonist and the angiotensin converting enzyme (ACE) inhibitor are provided in separate compositions from one another and/or from the AT2receptor agonist.

The benefits of using the AT2 receptor agonists (pharmaceutically acceptable salts, solvates or prodrugs thereof) disclosed herein, preferably via a combination of administrative routes, separately, and/or sequentially, and/or in parallel at the same time is to produce a tailored treatment for the patient in need of the therapy, with the possibility of preventing and/or reducing side effects, and also tune the correct dosage levels of a therapeutically effective amount of an AT2 receptor agonist.

The methods of the invention disclosed herein may also have the advantage that the AT2 receptor agonist may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties than compounds known in the prior art as being useful in the treatment or prevention of peripheral neuropathy. Such effects may be evaluated clinically, objectively and/or subjectively by a health care professional, a treatment subject or an observer. Subjects suitable to be treated with formulations disclosed herein include, but are not limited to, mammalian subjects. In some embodiments, the subject can be a human subject.

Figures

The following drawings are provided to illustrate various aspects of the present inventive concept and are not intended to limit the scope of the present invention unless specified herein. Figure 1. C21 increases microvascular blood flow (MBF) and tissue oxygenation without increasing microvascular flow velocity (MFV). Effects of C-21 on muscle microvascular recruitment and oxygenation. Each rat received a continuous intravenous infusion of C-21 or saline (Control) for 120 min. A: Microvascular Blood Volume; B: Microvascular Flow Velocity; C: Microvascular Blood Flow; D. muscle oxygenation. n=5 each. ^* P<0.02, ^** P<0.03, # P<0.001 (ANOVA). Figure 2. Expression of Hypoxia Inducible Factor-1 alpha in a model of poor perfusion - C21 reduces the expression of HIF-1 alpha without any reduction of the high blood pressure. Figure 3. Model system used to study effect of C21 treatment on tactile sensitivity.

Figure 4. Effect of C21 treatment on tactile sensitivity measured by Von Frey test. - 1 day (A) and 7 days (B) after Vincristine injection. Figure 5. Structure of N-Butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-iso- butylthiophene-2-sulfonamide (C21)

Examples Methods:

Animal Preparations and Experimental Protocols:

Overnight-fasted adult male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA) weighing 250 - 380 g were studied. Prior to the study rats were fed standard laboratory chow and water ad libitum and housed at 22 ± 2°C on a 12 hr light- dark cycle. Rats were anesthetized with thiobutabarbital 180 mg/kg i.p. (Inactin®, SigmaAldrich, St. Louis, MO), placed in a supine position on a heating pad to ensure euthermia and intubated to maintain a patent airway. The carotid artery and the jugular vein were cannulated with polyethylene tubing (PE-50, Fisher Scientific, Newark, DE) for arterial blood pressure monitoring, arterial blood sampling and various infusions.

After a 30-45 min baseline period to ensure hemodynamic stability and a stable level of anesthesia, baseline microvascular parameters, including microvascular blood volume (MBV), microvascular flow velocity (MFV) and microvascular blood flow (MBF), were determined on the proximal adductor muscle group (adductor magnus and semimembranosus) of the right hindlimb using contrast-enhanced ultrasound (CEU) with microbubbles as the contrast agent (Definiiy, Lantheus Medical Imaging), as previously described. Rats then received various intravenous infusions. C-21 (300 ng/kg/min, Vicore Pharma AB, Gothenburg, Sweden) was infused for 120 min (0 - 120 min) in the presence or absence of AT ₂ R (And II type-2 receptor) antagonist PD (50 μg/kg/min) or NO synthase (NOS) inhibitor Λ/G-nitro-L-arginine methyl ester (L- NAME; 50 μ9/Ι<9/ιτπη, Sigma Aldrich, Louis, MO). PD and L-NAME infusion were started 30 min before the commencement of C-21 infusion. At the dose selected PD potently restricts MBV in muscle and L-NAME raises mean arterial blood pressure (MAP) by 20- 30 mm Hg above the baseline without affecting the heart rate. We chose to infuse C-21 at 300 ng/kg/min as at this dose C-21 lowers MAP in spontaneously hypertensive rats (SHR) but not in normotensive rats.

Microvascular parameters were determined at various time points using CEU. Throughout the study, MAP was monitored via a sensor connected to the arterial catheter (Harvard Apparatus, Holliston, MA and AD Instruments, Inc., Colorado Springs, CO). During the insulin clamp, arterial blood glucose was determined every 10 min using an Accu-Chek Advantage glucometer (Roche Diagnostics, Indianapolis, IN), and 30% dextrose (30% wt/vol) was infused at a variable rate to maintain blood glucose within 10% of basal, by the Animal Care and Use Committee of the University of Virginia.

Measurement of muscle interstitial oxygen saturation

Muscle interstitial oxygen saturation was measured using a fiber-optic oxygen measurement system (OXYMICRO, World Precision Instruments), based on the effect of dynamic luminescence quenching by molecular oxygen. Briefly, a needle housing the fibro-optic oxygen microsensor was inserted into the right hindlimb skeletal muscle and the glass fiber with its oxygen sensitive tip inside the needle was extended into muscle interstitium by carefully pressing the syringe plunger. Measurements were taken every 10 sec, and 30 min average values were calculated. Statistical Analysis:

All data are presented as mean ± SEM. A P-value of < 0.05 was considered statistically significant.

C-21 recruits skeletal muscle microvasculature via AT2RS and this action is mediated through NO production

As shown in Figure 1 , C-21 significantly increased muscle microvascular recruitment by increasing MBV within the first 30 min and this effect lasted for the entire 120 min infusion period (P<0.02) but MFV was not affected. As MBF is the product of MBV and MFV, the increase in MBV led to a two-fold increase in muscle MBF (P<0.03). These were associated with a significant, progressive increase in muscle oxygenation (P<0.0002). The increases in MBV, MBF and muscle oxygenation induced by C-21 were all blocked by either PD or L-NAME, suggesting that these effects were mediated via both AT2R and NO biosynthesis. Neither MAP nor blood glucose levels changed significantly during C-21 infusion (see Table above). As expected, L-NAME co-infusion raised MAP by 20-30 mmHg (P=0.01 ). In this study, it was demonstrated that direct activation of AT ₂ RS with C-21 potently increases muscle microvascular perfusion and oxygenation, via an AT ₂ R-dependent, NO-mediated mechanism.

Thus, with the recent findings that nutrient blood flow needs to be provided to the compromised nerve without any increase in flow velocity to effectively oxygenate the nerve, AT2R agonism holds therapeutic potential in the prevention and treatment of peripheral neuropathy.

C21 was administered to pregnant hypertensive rats to evaluate effects on various components of the renin-angiotensin system in placental vessels. Figure 2 presents the expression of HIF-1alpha in placenta, which was reduced to control levels in animals treated with C21.

Prevention of sensory neuropathy

Animal experiments demonstrate that an AT2R agonist, C21 , is capable of preventing the sensory neuropathy induced by vincristine (100 μg/kg/day, i.p.), one of the first line therapies for lymphoma.

C21 treatment was started one day before vincristine administration (see Figure 3), and functional assessment as well as other investigations were performed on Day 7. Vincristine markedly induced allodynia (hypersensitivity) in control animals, and C21 treatment significantly improved the function back to baseline values. (Figure 4)

In a further morphological analysis of the sciatic nerve, the vincristine-induced decrease of myelinated fibers was totally prevented by C21 , an effect that was not seen after administration of an AT1 receptor blocker, candesartan. C21 thus has the potential to prevent neuropathy induced by chemotherapy. Possible mechanisms behind the neuroprotective effects of C21 remains to be clarified. The neuroregenerative action seen in other models, together with maintained microcirculation, providing nutrient blood and oxygen supply to the nerve, may have key importance. Treatment with C21 is expected to reduce the need for dose-reduction and/or cessation of effective chemotherapy treatment (like vincristine) due to neuropathic side-effects in patients in need of such chemotherapy. A reduced need for drugs to manage the pain (analgesics, opioids, gabapentin, pregabalin, etc.) is expected to result.

Long-term therapy with C21 is expected to reduce the incidence and the severity of neuropathy in diabetic patients - measured both as fewer reported subjective sym ptoms (paresthesiae, numbness, sensory deficits, muscle strength loss, and degree of neuropathic pain) and reduced rate of deterioration in repeated objective electrophysiological measurements. Again, a reduction in the usage of analgesics to manage symptoms is expected to result.

C21 use across larger populations is expected to reduce the number of cases of diabetic wounds on legs and feet and thus reduce the risk of, and need for, amputations. The neuroprotective action of C21 , together with favorable microvascular effects, providing nutrient blood flow and oxygen to vulnerable areas, is expected to support, and in some cases restore, nerve function and facilitate wound healing. From a health-care perspective, the costly management of 'the diabetic foot' can be expected to see a change in trend.