ZA200500172B - Nucleoside derivatives for treating hepatitis C virus infection - Google Patents

Description

ADENOSINE A2A RECEPTOR ANTAGONISTS FOR TREATING RESTLESS LEGS SYNDROME OR

RELATED DISORDERS

FIELD OF THE INVENTION

The present invention relates to methods of treating restless legs syndrome or related disorders. The method of treatment is preferably by administering a pharmaceutical agent containing a therapeutically effective amount of an adenosine A,, receptor antagonist. More preferably the adenosine A, receptor antagonist is a xanthine derivative.

Most preferably, the adenosine A; receptor antagonist is a xanthine derivative described in detail herein.

BACKGROUND OF THE INVENTION

Restless Legs Syndrome

Restless legs syndrome (RLS) is a distinctive but often misdiagnosed sensorimotor disorder. The general incidence of RLS is high and is the seventh most frequently diagnosed musculoskeletal disorder out of 103 diagnoses relating to these conditions [Arch. Intern. Med., 161, 483- 484 (2001)]. RLS is also characterized as a sleep disorder and is frequently diagnosed as a cause of insomnia [Sleep

Med., 2, 367-369 (2001); and Sleep, 23, 237-241 (2000}].

Although RLS was first described in the 17% century, the classic features that define the syndrome were first presented in 1945 [The London practice of Physick. London:

Bassett et al. Eds. (1962); and Acta Med. Scand. Suppl., 158, 1-123 (1945)]. Despite the number of years since RLS was first appreciated as a medical indication, diagnosis and treatment remain sub-optimal. Even though it may affect up to 10% of the US population, it is often unrecognized or misdiagnosed. In some cases, a cause can pe found, such as iron-deficiency anemia, and the RLS can be cured. In general, however, motor restlessness is poorly diagnosed and treated [IJCP, 55, 320-322 (2001)].

Although the etiology of RLS is unknown, the primary anatomic localization of abnormal functioning in RLS is possibly in spinal system [Disord., 13(suppl 2), 294 (1998)]. Several new diagnostic tools may aid in identifying RLS [J. Neurol., 249, 164-170 (2002); and Clin.

Neurophys., 113, 571-578 (2002)].

The features associated with RLS include dysesthesias deep in the limb that compel the person to move in order to relieve the sensation and that are engendered and exacerbated by rest, primarily in the evening and at night [HealthNews, Greene, June, 10 (2001)]. In 1995, the

International RLS Study Group published the primary and associated features of this disorder [Mov. Dis., 10, 634- 642 (1995)]. For recent reviews, see, Latorre & Irr (2001) http: //www.emedicine.com/NEURO/topic509.htm; 2001 Medical

Bulletin, Restless Legs Syndrome Foundation, Inc.; and Am.

J. Med. Sci., 319, 397-403 (2000). Additional criteria of

RLS include involuntary, rhythmic retraction movements occurring especially at night, and especially during sleep stages I and II; and sleep disturbance results in daytime fatigue.

Although RLS occurs as a component of several diseases, it is not indicative of these diseases [Sleep, 23, 361-367 (2000); Arch. Neurol., 59, 421-424 (2002); J.

Neurol. Sci., 196, 33-36 (2002); and J. Neurol. Neurosurg. psych., 72, 555 (2002)].

According to the Restless Legs Syndrome Foundation (www.rls.org), adults with RLS will typically have all four of the following primary features. First, the bothersome, but usually not painful, sensations deep in the legs produce an irresistible urge to move. Second, symptoms are worse or exclusively present when the afflicted individual is at rest, and the sensations are typically lessened by } voluntary movement of the affected extremity. Third, symptoms are worse in the evening and at night, especially , when the individual lies down. Fourth, movements of the toes, feet, or legs (known as restlessness) are typically seen when the afflicted individual is sitting or lying down in the evening. This restlessness may be seen as fidgetiness or nervousness.

The dysesthesias and accompanying urge to move occur most commonly during the evening or early part of the night (between 6 pm and 4 am) [Sleep, 22, 901-912 (1999); and

Mov. Disord., 14, 102-110 (1999)]. Patients are less bothered by symptoms during the daytime and, even if severely affected, often obtain some relief near dawn. The symptoms progress over time in about two thirds of RLS patients and may be severe enough to be disabling, disrupting sleep and impacting on a patient’s life and well-being.

Adults with RLS almost always describe these uncomfortable sensations or parenthesis, which most commonly occur in the legs, as being like an electric current, water moving, or insects crawling or as tingling, aching, or grabbing. A wide variety of other descriptions have been offered, and some patients cannot describe the sensations at all except as an urge to move the leg [Neurol., 47, 1435-1441 (1996)].

In a significant minority of individuals with RLS (perhaps 20% to 30%), similar sensations occur in the arms, } usually in more severely affected patients later in the clinical course of their disorder [Eur. Neurol., 45, 67-74

(2001); and Eur. Neurol., 44, 133-138 (2000)])]. Even less frequently, these sensations occur in the trunk or elsewhere. The sensations are not generally described as . painful, but if asked directly, a minority (perhaps 20%) of patients will describe the sensations as painful. . The unpleasant limb sensations of RLS are precipitated by rest or inactivity such as lying in bed, riding in a car or airplane or sitting in a theater. Some patients describe increasing discomfort and involuntary limb jerking if they remain still. There is an urge to move the legs because relief is often gained after moving. To relieve the urge to move, patients typically walk around, although they may attempt to obtain relief through performing a wide variety of movements such as rocking, shaking, stretching, marching in place, pacing, or bending. Some patients obtain relief simply from standing.

These varied movements that patients select to reduce their symptoms are under voluntary control and can be suppressed on command. Suppression may greatly increase the patient's discomfort, however, and few severely affected individuals are capable of stifling their restless movements for more than a brief period when they are symptomatic. In rare cases, the movements may occur as the dominant symptoms with only very limited awareness of the urge to move. ) In most cases, the cause of RLS is unknown. Such idiopathic disease can be familial and, if so, is transmitted in an autosomal dominant fashion. Progressive decrease in age at onset with subsequent generations has been described in some families. Patients with familial

RLS tend to have an earlier age at onset and slower progression. Despite the use of dopaminergic agents to

~ treat RLS, the genes involved in dopaminergic neurotransmission were found to have no influence on RLS [Neurol., 57, 1304-1306 (2001)]. . Associated features of RLS

RLS symptoms can cause difficulty in falling and . staying asleep resulting in abnormal tiredness during waking hours. Chronic sleep deprivation and its resultant daytime sleepiness can affect the patient's ability to work, participate in social activities, and partake in recreational pastimes and can cause mood swings, which can affect their personal relationships.

RLS may be the result of another condition, which, when present, worsens the underlying RLS. This is called secondary RLS. During pregnancy, particularly during the last few months, up to 15% of women develop RLS. After delivery, their symptoms often vanish. Other causes include the following. Deficiency of iron, folate, B-12 or magnesium. Iron, folate and B-12 deficiencies can result in anemia. Magnesium deficiency is rare except in the presence of unusual diets. RLS can be the initial symptom of iron deficiency. Polyneuropathy can also lead to RLS.

Polyneuropathy can be caused by alcohol abuse, amyloidosis, diabetes mellitus, lumbosacral radiculopathy, Lyme disease, rheumatoid arthritis, uremia or vitamin B-12 deficiency.

Gastric surgery, which can lead to mal-absorption of foods.

Chronic obstructive pulmonary disease (COPD) which can lead to changes in blood chemistry such as acidosis or alkalosis, low oxygen saturation, or retention of carbon dioxide. These changes in the blood chemistry can, in turn, irritate the peripheral nerves and result in RLS. ] Chronic venous insufficiency or varicose veins. Intake of certain drugs such as alcohol, caffeine, anticonvulsants,

antidepressants, beta blockers, lithium or certain major tranquilizing agents. Abrupt withdrawal from certain drugs such as vasodilators, sedatives or antidepressants. . Myelopathy or myelitis. Hypothyroidism or hyperthyroidism.

Hypoparathyroidism or hyperparathyroidism. Acute . intermittent porphrya. Liver failure. Cancer.

Though RLS is diagnosed most often in people in their middle years, many individuals with RLS, particularly those with primary RLS, can trace their symptoms back to childhood. These symptoms may have been called growing pains or the children may have been thought to be hyperactive because they had difficulty sitting quietly.

No laboratory test exists that can confirm a diagnosis of RLS. However, a thorough physical examination, including the results of necessary laboratory tests, can reveal temporary disorders, such as iron deficiency, that may be associated with RLS. Some patients will require an overnight testing of sleep to determine other causes of their sleep disturbance.

Treatment

If an underlying iron or vitamin deficiency is found to be the cause of a patient's restless legs, supplementing with iron, vitamin B12, or folate (as indicated) may be sufficient to relieve the symptoms. Current recommendations include checking a serum ferritin level (to evaluate iron-storage status) and supplementing with iron if the ferritin level is less than 50 pg/L. Patients with varicose veins have been found to benefit from use of sclerosing agents. Those with uremia may have relief after kidney transplantation or correction of anemia with i erythropoietin.

The use of some medications seems to worsen the symptoms of RLS. These drugs include calcium-channel blockers, most antinausea medications, some cold and . allergy medications, major tranquilizers, phenytoin, and most antidepressants. . Unfortunately, in many cases, the symptoms of RLS either initially do not resolve with the treatment of underlying disorders and the implementation of lifestyle changes or, over time, progress so that relief is insufficient with these methods. In either case, the use of medications may become necessary.

No drugs have been approved by the U.S. Food and Drug

Administration for the treatment of RLS, but several drugs have undergone clinical studies in RLS and have been approved for other conditions. These medications fall into four main classes—dopaminergic agents, sedatives, pain relievers, and anticonvulsants. Each drug or class of drugs has its own benefits, limitations, and side-effect profile. The choice of medication is dependent upon the timing and severity of symptoms. Generally, treatment begins with a low dose taken an hour or two before bedtime.

If tolerance to one drug develops, another class of drugs may be substituted.

Dopaminergic agents

The primary and first-line treatment for RLS is with a dopaminergic agent [Expert Opin. Investig. Drugs, 11, 501- 514 (2002); Neurol., 58(Suppl. 1), S87-5S92 (2002); and

Danek et al. In Neurological Disorders: Course and

Treatment Academic Press, pp. 819-823 (1996)]. Involvement of altered activity of dopaminergic diencephalic spinal ] neurons that originate in All region [Brain Res., 342, 340- 351 (1985)].

Although dopaminergic agents are used to treat

Parkinson's disease, RLS is not a form of Parkinson’s disease [J. Neurol. Sci., 196, 33-36 (2002)]. All of these . drugs should be started at low doses and increased very slowly to decrease potential side effects. Due to the . disabling side effects associated with long-term dopaminergic activation, chronic use of this class of drugs in RLS has not been adopted.

A variety of dopaminergic agents have been described for treating RLS. These include carbidopa, levodopa, carbidopa with levodopa (Sinemet), ropinerole, pramipexole, cabergoline, entacapone and, Piribedil [Mov. Dis., 17, 421 (2002); Mov. Dis., 16, 579-581 (2001); Eur. Neurol., 46 (suppl 1), 24-26 (2001); US Patent Nos. 6,194,445; 6,114,326; 6,001,861; 5,945,424; and US patent application no. 2001/0029262].

Dopaminergic agents can cause the side effect known as augmentation or rebound. Augmentation comprises an earlier onset of symptoms in the evening than before treatment, appearance of symptoms during the day, involvement of other body parts and an increased severity of symptoms. The only recourse is to stop taking the drug. Other side effects include nausea, dizziness, somnolence, insomnia, constipation, postural hypotension, asthenia and hallucination.

Sedatives

Sedative agents are most effective for relieving the nighttime symptoms of RLS. They are used either at bedtime in addition to a dopaminergic agent or for individuals who have primarily nighttime symptoms. The most commonly used } sedative is clonazepam (Klonopin). Other suggested

) medications such as anti-histamines and NKl-receptor antagonists may function via their sedative effect.

Pain relievers . Pain-relieving drugs are used most often for people with severe relentless symptoms of RLS. Some examples of . medications in this category include codeine, Darvon or

Darvocet (propoxyphene); Dolophine (methadone); Percocet (oxycodone) ; Ultram (tramadol); and Vicodin (hydrocodone).

Opioids have been found to be the most effective at relieving symptoms, and relief has been found with intrathecal delivery of morphine or bupivacaine [Acta

Anaesthesiol. Scand., 46, 114-117 (2002)]}. Opioids are potent suppressors of RLS and PLMS, but the risks of abuse and addiction limit their use. Side effects and adverse reactions include dizziness, sedation, nausea, vomiting, constipation, hallucination and headache.

Anticonvulsants

These drugs are particularly effective for some, but not all, patients with marked daytime symptoms, particularly people who have pain syndromes associated with their RLS. Gabapentin (Neurontin) is the anticonvulsant that has shown the most promise in treating the symptoms of

RLS [Neurol., 57, 1717-1719 (2001)].

Other Therapies

Other suggested treatments include transcutaneous electrical nerve stimulation, conditioning therapy, and various procedures to reduce incompetent veins, but none of these ancillary treatments has been clearly established to be effective [Health Technol. Assess., 1, 1-135 (1997);

Sleep, 19, 442-444 (1996); and Dermatol. Surg., 21, 328-332 (1995)1.

N In particular, the Edinburgh vein study found that most lower-limb symptoms (including RLS) probably have a nonvenous cause and surgical intervention (i.e., . sclerotherapy or “vein stripping”) is unlikely to alleviate the symptoms [Brit. Med. J., 318, 353-35 (1999)]. One group advocates medical therapy for what they call “hypotonic phlebopathy” (a mild form of venous insufficiency), but their clinical description coincides with the symptoms of RLS almost perfectly [Minerva

Cardioangiol., 48, 277-285 (2000)].

Additional pharmaceutical agents have been proposed to treat RLS. These include SHT antagonists; «, antagonists such as Mirtazapine; NKl-receptor antagonists; anti- histamines; and an herbal extract of Valeriana [Neurol., 53, 1154 (1999); US Patent Nos. 6,346,283; 6,329,401; 6,319,927; 6,281,207; 6,214,837; and US patent application nos. 2002/0035057; 2001/0034320; 2002/0010201].

Mirtazapine, however, may cause RLS [Psych. Clin. Neurosci., 56, 209-210 (2002) 1].

Children

Recent literature also points toward an association between RLS and symptoms of attention-deficit hyperactivity disorder [Sleep, 25, 213-218 (2002)]. A few case reports and one case series have assessed treatment specific to children. These case reports have indicated individual responses to strict limit-setting in enforcing the child's sleep schedule, restricting caffeine consumption, and using medications such as clonazepam, carbidopa/levodopa, pergolide, or clonidine [Picchietti In Wilson, ed. Sleep thief: restless legs syndrome. Orange Park, FL: Galaxy

Books pp. 82-94 (1996); Pediatr. Neurol., 22, 182-186

; (2000) ; Sleep Res., 22, 70 (1993); Pediatr Neurol., 11, 241-245 (1994); and Sleep, 22, 297-300 (1999).

Benzodiazepines, anticonvulsants, alpha-adrenergic . agents, and opioids have been extensively used in children with disorders other than RLS, as has chronic use of : levodopa for dopa-responsive dystonia (J. Am. Acad. Child

Adolesc. Psych., 33, 424-426 (1994); and Neurol., 41, 174- 181 (1991)]. An open-label trial of pergolide in the treatment of RLS in five children with RLS found that not only the sleep parameters, but also the children’s scores of attention and impulsivity, improved [Pediatr. Neurol., 22, 182-186 (2000)].

PLMS

About 80% of patients with RLS have unilateral or bilateral periodic limb movements of sleep (PLMS), also called nocturnal myoclonus. Patients without RLS also experience PLMS. These movements are stereotyped, repetitive, slow flexion of the limbs (legs alone or legs more than arms) during the early stages of sleep. The movements occur semirhythmically at intervals of 5 to 60 seconds and last about 1.5 to 2.5 seconds. In the lower limbs, repetitive dorsi flexion of the big toe with fanning of the small toes is seen, along with flexion of the ankles, knees and thighs. Arm movements usually consist of the flexion of the forearm in combination with the wrist.

There can be night-to-night variability in the number of movements.

PLMS can occur while patients are awake and are called dyskinesias. Such dyskinesias are uncommon but can occur in up to 50% or RLS patients. } PLMS increases with age. Thirty five percent or more of people aged 65 and older experience PLMS. PLMS also occurs in younger people, though less commonly. Men and women are equally affected. The exact cause of PLMS is still unknown. The underlying mechanisms probably involve factors in the nervous system, although studies have not revealed any consistent abnormalities. : PLMS are not considered medically serious. They can, however, be implicated as a contributing factor in chronic insomnia and/or daytime fatigue because they may cause awakenings during the night. Occasionally, PLMS may be an indicator of a serious medical condition such as kidney disease, diabetes or anemia.

A number of medications have been shown to be effective in treating PLMS, but treatment is only necessary when PLMS are accompanied by restless legs (RLS), insomnia or daytime fatigue.

Adenosine Ax Receptors

Adenosine is known to act via four major receptor subtypes, A;, Aza, As, A;, which have been characterized according to their primary sequences (Pharmacol. Rev., 46, 143-156 (1994)]. Adenosine A, receptors are abundant in the caudate-putamen, nucleus accumbens, and olfactory tubercle in several species [Brain Res., 519, 333-337 (1990)]. A variety of Ap receptor antagonists have been synthesized (US Patent Nos. 6,262,106; 6,222,035; 6,197,788; 5,756,735; 5,703,085; 5,670,498; 5,565,460; and 5,484,920).

In the caudate-putamen, adenosine A,, receptors are localized on several neurons and have been shown to modulate the neurotransmission of y-aminobutyric acid (GABA), acetylcholine and glutamate [J. Neurochem., 66, : 1882-1888 (1996); J. Neurosci., 16, 605-611 (1996);

Neuroscience, 100, 53-62 (2000); Trends Pharmacol. Sci., 18, 338-344 (1997); and Biosci. Biotechnol. Biochem., 65, 1447- 1457 (2001)]. These actions of the A, receptor contribute } to the control of motor behavior since A, receptor agonists inhibit locomotor activity and induce catalepsy in rodents . [Adv. Neurol., 80, 121-123 (1999); and Psychopharmacology, 147, 90-95 (1999)]. In contrast, adenosine A;, receptor antagonists prevent the motor disturbances of dopamine D; receptor null mice [J. Neurosci., 20, 5848-5852 (2000)].

A,, receptor antagonists have been evaluated in parkinsonian monkeys and found to be effective at treating symptoms of Parkinson’s disease [Ann. Neurol., 43, 507-513 (1998) ; NeuroReport, 9, 2857-2860 (1998); and Exp. Neurol., 162, 321-327 (2000)]. It was demonstrated that the adenosine Aza receptor antagonist KW-6002 exhibits antiparkinsonian activity without producing hyperactivity and provoking dyskinesia [Neurology, 52, 1673-1677 (1999)].

More recently, the neuroprotective effect of an adenosine A, receptor antagonist KW-6002 has been demonstrated in MPTP-induced dopaminergic neurodegeneration (J. Neurochem., 80, 262-270 (2002); and J. Neurosci., 21,

RC143 (1-6) (2001)].

SUMMARY OF THE INVENTION

The present invention relates to methods of treating restless legs syndrome or related disorders by administering a pharmaceutical agent containing a therapeutically effective amount of an adenosine Aj, receptor antagonist to a patient in need thereof. The present invention also relates to use of an adenosine A; receptor antagonist for manufacturing a therapeutic agent for treatment of restless legs syndrome as well as to therapeutic agents for restless legs syndrome comprising an adenosine A,, receptor antagonist.

Preferably the adenosine A,, receptor antagonist is a xanthine derivative or a pharmaceutically acceptable salt thereof. More preferably, the adenosine A, receptor - antagonist is a xanthine derivative or a pharmaceutically acceptable salt thereof described in detail herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the following (1) to (26) . (1) A method of treating restless legs syndrome, comprising administrating an effective amount of at least one adenosine A; receptor antagonist to a patient in need thereof. (2) The method of treating restless legs syndrome according to the above (1) wherein the adenosine Aon receptor antagonist is a xanthine derivative or a pharmaceutically acceptable salt thereof. (3) The method of treating restless legs syndrome according to the above (2) wherein the xanthine derivative is represented by the following formula (I):

X2

Rt 3

Yrs R

PO San

Xi | N

R2 (I) wherein R}, R?, and R® independently represent hydrogen, lower alkyl, lower alkenyl, or lower alkynyl; R' represents cycloalkyl, -(CH;)o-R® (in which R® represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; and n is an integer of 0 to 4) or "4 : N\ vz } Y2 {in which Y! and Y¥® independently represent hydrogen, halogen or lower alkyl; and Z represents substituted or unsubstituted aryl, or

R¢ O fc H,)m (0) (in which R® represents hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, nitro or amino; and m represents an integer of 1 to 3)}; and x! and X? independently represent O or S. (4) The method of treating restless legs syndrome according to the above (2) wherein the xanthine derivative is represented by the following formula (I-A):

Oo Ra

Rta / H

AN

7 N\

A N N Z2

R2a H (I-A) wherein R!® and R?®* independently represent methyl or ethyl;

R®® represents hydrogen or lower alkyl; and 2° represents

“ R7 re - - R9

R10 (in which at least one of R’, R® and R® represents lower alkyl or lower alkoxy and the others represent hydrogen; R*’ represents hydrogen or lower alkyl) or

R6 O {CH m

Oo (in which R® and m have the same meanings as defined above, respectively). (5) The method of treating restless legs syndrome according to the above (2) wherein the xanthine derivative is represented by the following formula (I-B):

Q R3b

Rb / Y1

N

/ N\\ b 2

R2b Y (I-B) wherein R' and R?® independently represent hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R*® represents hydrogen or lower alkyl; ZP represents substituted or unsubstituted naphthyl, or

RS O

T(CH,m 0)

(in which R® and m have the same meanings as defined above, respectively); and Y' and Y? have the same meanings as defined above, respectively. (6) The method of treating restless legs syndrome according to the above (2) wherein the xanthine derivative is (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine. (7) The method of treating restless legs syndrome according to the above (1) wherein the adenosine Aj, receptor antagonist is a compound represented by the formula (II):

NHQ?

N A N~ Nr 1

R13 ANA

R12 (IN) wherein R'' represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; R*? represents hydrogen, halogen, lower alkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; R!? represents hydrogen, halogen or X?r!* (in which X? represents O or S; and R represents substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, or substituted or unsubstituted aralkyl); and Q°® represents hydrogen or 3,4-dimethoxybenzyl {e.g. 5-amino-7- (4-benzoylpiperazinyl)-2-(2- furyl) [1,2,4]triazolo(1,5- clpyrimidine}, or a pharmaceutically acceptable salt thereof. (8) The method of treating restless legs syndrome according to the above (1) wherein the adenosine BA,

receptor antagonist is a compound represented by the formula (III):

Ha’ ~n-N

RE. yg RS re ON 16 N

RNIN mR n3 (1) wherein R!® represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R'® represents hydrogen, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; m3 and n3 are independently an integer of 0 to 4; Q® represents hydrogen or 3,4- dimethoxybenzyl; R?° represents hydrogen, halogen, hydroxy, or substituted or unsubstituted lower alkyl; R!’ represents hydroxy, hydroxy-substituted lower alkyl, substituted or unsubstituted lower alkoxy, or imidazo({l,2-a]pyridyl; and

R!® and R! independently represent hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted aryl; or R'® and R!? are combined together with an adjacent carbon atom to form a substituted or unsubstituted cycloalkyl {e.g. 5-amino-2-(2-furyl)-7-(4-(2-hydroxy-2- methylpropyl)piperazinyl) [1,2,4]triazolo[1,5-c]pyrimidine}, or a pharmaceutically acceptable salt thereof. (9) The method of treating restless legs syndrome according to the above (1) wherein the adenosine Aj, receptor antagonist is a compound represented by the formula (IV):

NH, ~n-N z*

AU

R21 N N

(IV) : wherein Zz! represents 0 or S; and R?! represents Ph- (CHz) nsY* (in which Ph represents phenyl unsubstituted or substituted with halogen or lower alkyl; Y? is a single bond, O or S; and n4 is an integer of 0 to 5) {e.g. 7-amino-2-(2-furyl)- 5-phenoxy[1l,2,4)-triazolo[1,5-alpyrimidine}, or a pharmaceutically acceptable salt thereof. (10) The method of treating restless legs syndrome according to the above (1) wherein the adenosine Aza receptor antagonist is a compound represented by the formula (V): bai

NNN oa : R23x5 Ay Je)” R

Vv) wherein R?? represents hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkanoyl; R?? represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heterocyclic group; R%* represents a substituted or unsubstituted heterocyclic group: x? represents a single bond, O, S, S(O), S(0)2 or NR®*® (in which R?® represents hydrogen, or substituted or unsubstituted lower alkyl); and

A represents N or CR?*® (in which R?® represents hydrogen, or substituted or unsubstituted lower alkyl), or a pharmaceutically acceptable salt thereof. . (11) The method of treating restless legs syndrome according to the above (1) wherein the adenosine Aja : receptor antagonist is a compound represented by the formula (VI):

Y®

R28. JL -N

N™ 'N YR?

As a ‘B.. (VI) wherein R?’ represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; Y¢ represents 0, S or NR?° (in which R?® represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl); R2® represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or a substituted or unsubstituted heterocyclic group; and B and the adjacent two carbon atoms are combined to form a substituted or unsubstituted carbon ring or heterocyclic ring, or a pharmaceutically acceptable salt thereof. (12) The method of treating restless legs syndrome according to the above (1) wherein the adenosine Aja receptor antagonist is a compound represented by the formula (VII):

R3

OL

R30. Js w” NTN

R33 (VII) wherein R%*® represents substituted or unsubstituted lower alkyl, or substituted or unsubstituted aryl; W represents

CH,CH,, CH=CH or CC; rR represents hydrogen, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted amino, or a substituted or unsubstituted heterocyclic group; R3? represents hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted hetercaryl, or substituted or unsubstituted lower alkenyl; and R*? represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted lower alkynyl {e.g. 4-[6- amino-8-(3- fluorophenyl)-9-methyl-9H-2-fluorenyl]-2- methyl-3-butyn-2-0l}, or a pharmaceutically acceptable salt thereof. : (13) The method of treating restless legs syndrome according to the above (1) wherein the adenosine Apa receptor antagonist is a compound represented by the formula (VIII):

R35

R41 R400 R36

R37

R42 a : R39

R43 N= —2R

- (VIII) wherein R®® represents hydrogen or lower alkyl; R** and R*’ independently represent hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted aryl; and R*®, R*?, R*", R%, R*? and R*’ independently represent hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group, or a pharmaceutically acceptable salt thereof. (14) The method of treating restless legs syndrome according to the above (1) wherein the adenosine A; receptor antagonist is a compound represented by the formula (IX): " R49

R

XOX N=

NN N—\ (IX) wherein Xx° represents CH or N; R* represents lower alkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; R*° represents substituted or unsubstituted lower alkyl, or a substituted or unsubstituted heterocyclic group; and R‘® represents hydroxy, halogen, or substituted or unsubstituted lower alkyl {e.g. 3-(2- (thiazol-2-ylmethyl) -3-oxo0-2,3-dihydropyridazin-6-yl]-

2-phenylpyrazolo{l,5-a)lpyridine}, or a pharmaceutically acceptable salt thereof. (15) The method of treating restless legs syndrome according to the above (1) wherein the adenosine A; receptor antagonist is a compound represented by the formula (X):

RY RY a0

R \ PY

N~ “RY

R®1 (X) wherein X'° represents O or S; R*’ and R‘® independently represent hydrogen, lower alkyl, aryl, hydroxy, alkoxy, cyano or nitro, or together form a carbonyl, oxime, imino or hydrazone group; R*’ represents lower alkyl or aryl; and

R%%, R°! and R®*? independently represent hydroxy, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, nitro, cyano or alkoxy {e.g. (2R)-2-(1- hydroxy-2-propylamino)thieno(3,2-d]l pyrimidin-4-yl 2- thienylmethanone}, or a pharmaceutically acceptable salt thereof. (16) The method of treating restless legs syndrome according to the above (1) wherein the adenosine Aj, receptor antagonist is a compound represented by the ] formula (XI):

* R53 wr

PN S—Ar

R54 N

R5% : (XI) wherein RS? represents hydrogen, hydroxy, halogen, substituted or unsubstituted amino, or substituted or unsubstituted lower alkyl; R** represents hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted lower alkynyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower alkoxy; R°° represents substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Ar represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Q' and Ww independently represent N or CH {e.g. 5-[6-amino-8-(3- fluorophenyl) -9H-9-purinyl] -1-methyl-1,2-dihydro-2- pyrimidine}, or a pharmaceutically acceptable salt thereof. (17) The method of treating restless legs syndrome according to the above (1) wherein the adenosine Aza receptor antagonist is a compound represented by the formula NH, (XII):

PN

NZ N-N ye

R—X'N XX N

N= (xu) wherein R®¢ represents substituted or unsubstituted aryl, substituted or unsubstituted cycloalkenyl, or substituted

] or unsubstituted heteroaryl; X'? represents a single bond or

C(0); and R®’ represents substituted or unsubstituted lower alkyl, or a pharmaceutically acceptable salt thereof. (18) The method of treating restless legs syndrome according to the above (1) wherein the adenosine Az, : receptor antagonist is a compound represented by the formula (XIII):

Raa 2 ~ R59

R62. J 1 eo

N X R

RE! (XIII) wherein A!® represents a single bond, -S-, -N(R®?)- (in which

R®? represents hydrogen or lower alkyl), -(CH;),-, -CH=CH-, -

CC- or -0O-; X' and Y'® independently represents N or CH;

R*® represents hydrogen, substituted or unsubstituted lower alkyl, lower alkenyl, lower alkynyl, halogen, cyano or cycloalkyl; R®’ represents hydrogen, halogen, cyano, nitro, substituted or unsubstituted lower alkyl, lower alkenyl, or substituted or unsubstituted aryl; R°® represents lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R®* and R®? independently represent hydrogen, or substituted or unsubstituted aryl, or a pharmaceutically acceptable salt thereof. (19) The method of treating restless legs syndrome according to the above (1) wherein the adenosine A;, receptor antagonist is a compound represented by the formula (XIV):

R6°

R96 y@os a

RS’ NNN

R8 : (XIV) wherein R®® represents substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R®® and R®’ independently represent hydrogen, cyano or S(O).phenyl; R®® represents hydrogen, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted amino; and R®® represents substituted or unsubstituted amino {e.g. 2-(4,5-dihydro-furan-2-yl)-7-m- tolyl-[1,2,4]triazolo[1,5-al0yridine-5-ylamine}, or a pharmaceutically acceptable salt thereof. (20) The method of treating restless legs syndrome according to the above (1) wherein the adenosine A; receptor antagonist is a compound represented by the formula (XV):

R’0 N Als

A

RS

(XV) wherein A'® represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; B® represents substituted or unsubstituted heteroaryl; R®’ and R”° independently represent hydrogen, or substituted or } unsubstituted amino, or a pharmaceutically acceptable salt thereof.

(21) The method of treating restless legs syndrome according to the above (1) wherein the adenosine Aj receptor antagonist is a compound represented by the . formula (XVI):

H,N.__N._R™

R’1 1X R73

R’2 (XVI) wherein R’* represents cyano, carboxy, or substituted or unsubstituted carbamoyl; R’? represents hydrogen, hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Rand R’* independently represent substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group, or a pharmaceutically acceptable salt thereof. (22) The method of treating restless legs syndrome according to the above (1) wherein the adenosine Aj receptor antagonist is a compound represented by the formula (XVII):

R75

R76 N a

Bes J—R £78 x17 (XVII) wherein R’® represents hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy, benzyloxy or OCF;; R’ and R”’ independently represent hydroxy, halogen, lower alkyl or lower alkoxy; R’® represents hydrogen, halogen, lower alkyl, lower alkenyl, carboxy, lower alkanoyl, lower alkoxycarbonyl, (CH;)n1,-OH (in which nl17 is an integer of 0 to 4), substituted or unsubstituted phenyl, 2,3-dihydro-1H- indolyl, azepan-1-yl or 1,4-oxazepan-4-yl; R’’ represents : substituted or unsubstituted phenyl; and X'’ represents O, S or 2H {e.g. 4-hydroxymethyl-N- (4-methoxy-7-phenyl- benzothiazol-2-yl)benzamide}, or a pharmaceutically acceptable salt thereof. (23) The method of treating restless legs syndrome according to the above (1) wherein the adenosine Aj, receptor antagonist is (-)-(11S,2'R)-a-2-piperidinyl-2,8- bis (trifluoromethyl) -4-quinolinemethanol or a pharmaceutically acceptable salt thereof. (24) Use of the adenosine A,, receptor antagonist described in any one of the above (1) to (23) for manufacturing a therapeutic agent for restless legs syndrome. (25) A therapeutic agent for restless legs syndrome comprising the adenosine A,a receptor antagonist described in any one of the above (1) to (23). (26) A method of treating nocturnal myoclonus, comprising administrating an effective amount of the adenosine A, receptor antagonist described in any one of the above (1) to (23) to a patient in need thereof.

The adenosine A, receptor antagonist used in the method of the present invention is not limited as long as it has A.x receptor antagonistic activity. A,x receptor antagonistic activity includes activity to inhibit, . suppress or cause the cessation of at least one adenosine-mediated biological activity by, e.g., binding to } adenosine A,n receptors, or interfering with or preventing the binding of adenosine to the receptor. Examples of the adenosine A,;, receptor antagonist include compounds disclosed in US 5,484,920, US 5,703,085, WO 92/06976, WO . 94/01114, US 5,565,460, WO 98/42711, WO 00/17201, WO 99/43678, WO 99/26627, WO 01/92264, WO 99/35147, WO : 00/13682, WO 00/13681, WO 00/69464, WO 01/40230, WO 01/02409, WO 01/02400, EP 1054012, WO 01/62233, WO 01/17999,

WO 01/80893, WO 02/14282, WO 01/97786, or the like. More specifically, examples include compounds represented by the above-described formula (I), (I-A), (I-B), or (II) to (XViI), (-)-(11s,2’'R)-o-2-piperidinyl-2,8- bis(trifluoromethyl) -4-quinolinemethanol, and pharmaceutically acceptable salts thereof.

A preferred adenosine A;, receptor antagonist used in the method of the present invention is (E)-8-(3,4- dimethoxystyryl)-1,3-diethyl-7-methylxanthine (hereinafter referred to Compound A) shown below.

OCH; 0] CHy ey Cen

PY |; 0” °N N

C2Hs

In the definition of each group of formulas (I), (I-

A), (I-B), and (II) to (XVII), the lower alkyl and the lower alkyl moiety of the lower alkoxy, hydroxy-substituted lower alkyl, lower alkanoyl, and lower alkoxycarbonyl include straight-chain or branched alkyl groups having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, : butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl and octyl. The lower alkenyl includes straight-chain or branched alkenyl groups having 2 to 8

) carbon atoms, such as vinyl, allyl, methacryl, crotyl, 3- butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl, 5-hexenyl, 2- heptenyl and 2-octenyl. The lower alkynyl includes . straight-chain or branched alkynyl groups having 2 to 8 carbon atoms, such as ethynyl, propargyl, 2-butynyl, 3- butynyl, 2-pentynyl, 4-pentynyl, 2-hexynyl, 5-hexynyl, 4- methyl-2-pentynyl, 2-heptynyl and 2-octynyl. The cycloalkyl includes cycloalkyl groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The cycloalkenyl includes cycloalkenyl groups having 4 to 8 carbon atoms, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. The aryl includes those having 6 to 14 carbon atoms, such as phenyl and naphthyl.

The aralkyl includes those having 7 to 15 carbon atoms, such as benzyl, phenethyl, benzhydryl and naphthylmethyl.

Examples of the heteroaryl are furyl, thienyl, pyrrolyl, pyranyl, thiopyranyl, pyridyl, thiazolyl, imidazolyl, pyrimidyl, pyridazinyl, pyridazinoyl, triazinyl, indolyl, quinolyl, purinyl and benzothiazolyl. Examples of the heterocyclic group are pyrrolidinyl, piperidino, piperidinyl, piperazinyl, morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, homopiperidino, homopiperidinyl, homopiperazinyl, tetrahydropyridinyl, tetrahydroguinolinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolidinyl, thiazolidinyl and oxazolidinyl in addition to groups listed as examples of the heteroaryl. The halogen includes fluorine, chlorine, bromine and iodine. The carbon ring formed by combining B and the adjacent two carbons include those having 4 to 8 carbon atoms and at least one double bond, such as cyclobutene, cyclopentene, cyclohexene,

cycloheptene and cyclooctene. Examples of the heterocyclic ring formed by combining B and the adjacent two carbons are pyrrole, pyrane, thiopyrane, pyridine, thiazole, imidazole, pyrimidine, triazine, indole, quinoline, benzothiazole, pyrroline, tetrahydropyridine, tetrahydropyrazine, : tetrahydroquinoline and tetrahydroisoquinoline.

The substituted lower alkyl, the substituted lower alkoxy, the substituted lower alkanoyl and the substituted lower alkenyl each have, for example, 1 to 3 independently selected substituents. Examples of the substituents are hydroxy, substituted or unsubstituted lower alkoxy, halogen, nitro, amino, lower alkylamino, di(lower alkyl) amino, trifluoromethyl, trifluoromethoxy, benzyloxy, phenyl and phenoxy. The lower alkyl and the alkyl moiety of the lower alkoxy, lower alkylamino and di (lower alkyl)amino have the same meaning as the lower alkyl defined above.

The halogen has the same meaning as the halogen defined above. Examples of the substituent of the substituted lower alkoxy are hydroxy, lower alkoxy, halogen, amino, azide, carboxy and lower alkoxycarbonyl. The lower alkyl moiety of the lower alkoxy and lower alkoxycarbonyl has the same meaning as the lower alkyl defined above, and the halogen has the same meaning as the halogen defined above.

The substituted aryl, the substituted naphthyl, the substituted phenyl, the substituted aralkyl, the substituted heterocyclic ring, the substituted heteroaryl, the substituted cycloalkyl, the substituted cycloalkenyl, the substituted carbon ring formed by combining B and the adjacent two carbons, and the substituted heterocyclic ring formed by combining B and the adjacent two carbons each have, for example, 1 to 4 independently selected substituents. Examples of the substituents are lower

Claims (4)

1. ; PCT/US2003/026644 " CLAIMS 1 A substance or composition for use in a method of treating restless legs syndrome, said substance or composition comprising at least one adenosine Aj, receptor antagonist, and said method comprising administrating an effective amount of said substance or composition to a patient in need thereof.
2. 2 A substance or composition for use in a method of . treatment according to claim 1 wherein the adenosine Apa receptor antagonist is a xanthine derivative or a pharmaceutically acceptable salt thereof.
3. 3 A substance or composition for use in a method of treatment according to claim 2 wherein the xanthine derivative is represented by the following formula (I): x2 iN rs N PO Wan Xi | N R2 (1) wherein R!, R?, and R® independently represent hydrogen, lower alkyl, lower alkenyl, or lower alkynyl; R! represents cycloalkyl, -(CH;),-R° (in which R’ represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group; and n is an integer of 0 to 4) or 4 NN ~s Y2 47 AMENDED SHEET

   J PCT/US2003/026644 " {in which Y! and Y? independently represent hydrogen, halogen or lower alkyl; and Z represents substituted or unsubstituted aryl, or Ré O (CHM Oo (in which R® represents hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, nitro or amino; and m represents an integer of 1 to 3)}; and X! and x? independently represent O or S.
4. 4 A substance or composition for use in a method of treatment according to claim 2 wherein the xanthine derivative is represented by the following formula (I-A): 0) Ria Ra J H RN rt 77 A N~ TN a R2a H (I-A) wherein R!® and R®® independently represent methyl or ethyl; R3?® represents hydrogen or lower alkyl; and Z*® represents R7 Rs R10 (in which at least one of R’, R® and R® represents lower alkyl or lower alkoxy and the others represent hydrogen; RYO represents hydrogen or lower alkyl) or 48 AMENDED SHEET y PCT/US2003/026644 BE Ré Ow ( CH,)m 0 (in which R® and m have the same meanings as defined above, respectively). A substance or composition for use in a method of treatment according to claim 2 wherein the xanthine derivative is (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7- methylxanthine. 6 Use of the adenosine Aja receptor antagonist described in any one of claims 1 to 5 for manufacturing a therapeutic agent for restless legs syndrome. 7 A therapeutic agent for restless legs syndrome comprising the adenosine Aj, receptor antagonist described in any one of claims 1 to 5. 8 Use of the adenosine Aj, receptor antagonist described in any one of claims 1 to 5 in the manufacture of a medicament for treating nocturnal myoclonus. 9 A substance or composition for use in a method of treating nocturnal myoclonus, said substance or composition comprising the adenosine Aj, receptor antagonist described in any one of claims 1 to 5, and said method comprising administering an effective amount of said substance or composition to a patient in need thereof.

   A substance or composition for use in a method of treatment according to any one of claims 1 to 5 or 9, substantially as herein described and illustrated. 11 Use according to claim 6, substantially as herein described and illustrated. 12 An agent according to claim 7 or claim 8, substantially as herein described and illustrated. 49 AMENDED SHEET

   : PCT/US2003/026644 " 13 A substance or composition for a new use in a method of treatment, a new use of an adenosine Aj, receptor antagonist described in any one of claims 1 to 5, or a new agent, substantially as herein described. 50 : AMENDED SHEET