HK1072893A - New treatments for restless legs syndrome - Google Patents

Description

Novel therapy for restless legs syndrome

Technical Field

The present invention relates to the use of heterocyclic amines and substituted phenylazacycloalkanes and pharmaceutically acceptable salts thereof for the treatment of restless legs syndrome.

Background

Restless Legs Syndrome (RLS) is a sensorimotor neurological disorder with paresthesia, sleep disturbance and, in most cases, periodic limb movements in sleep (PLMS).

There appear to be two forms of RLS: idiopathic and uremic forms. Both of these forms are referred to herein as RLS. The RLS is characterized by: (1) the desire to move the legs, usually accompanied by paresthesia/dysesthesia, (2) restlessness of movement, (3) worsening or only existing of symptoms at rest (i.e. lying, sitting), at least partial or temporary relief by activity, and (4) worsening of symptoms at night or in the evening. RLS is fully described in the references cited in U.S. Pat. Nos. 6,001,861 and 6,114,326, which are incorporated herein by reference. These 4 minimum criteria have allowed clinical diagnosis according to the international RLS research group. RLS is considered by some to be a sleep disorder in which the patient experiences leg discomfort sensations described as crawling, tingling, pulling or pain. One or both legs may be affected. These sensations occur when the RLS patient lies down or sits for extended periods of time, such as sitting at a table, driving a car, or watching a movie. RLS symptoms worsen with relaxation and reduced activity. RLS patients tend to be more painful at night and night.

Sensory and motor symptoms of RLS often result in severe sleep disturbance, prolonged sleep latency, reduced total sleep time or reduced or absent slow wave sleep, and reduced sleep efficiency. RLS patients often sleep best towards the end of the night or in the early morning. Due to less sleep at night, RLS patients may feel sleepy occasionally or regularly during the day. Almost all RLS patients exhibit periodic leg activity (PLM), which occurs during Sleep (PLMs), and while awake. The number of PLMs and related parameters are considered to be a marker of RLS severity, as PLM is often associated with nocturnal arousals and, if present at wake time, may prevent a patient from falling asleep. Therefore, polysomnography is often required to evaluate the efficacy of drug treatments.

Problems while sleeping and awake lead to the possibility that RLS patients may experience difficulties in work, social life and recreational activities. RLS is fairly common and always annoying. In the past, it has been called "crazy leg". RLS sensations are described as pulling, traction, crawling, peristalsis, drilling, tingling, needling, stinging and sometimes painful sensations, which are often accompanied by an inability to resist the urge of the active leg. A sudden muscle reflex may occur.

Various agents have been used to treat RLS. Although it has been reported to use a so-called Restex manufactured by Roche pharmaceuticals, Germany^*There is currently no substance approved for this indication in the united states based on levodopa.

Over the years, various treatments for RLS have been proposed. The general treatment falls into four categories: anticonvulsants, benzodiazepines *, opioids, and dopaminergic agents.

Anticonvulsant agents. Several anticonvulsants have been tested for the treatment of RLS. Anticonvulsants appear to act by reducing sensory disturbances (unpleasant sensations) and impulses to exercise. These drugs are particularly effective in some, but not all, patients with significant daytime symptoms, especially those with RLS accompanied by pain syndrome. Gabapentin (Neurontin) is an anticonvulsant drug that appears to hold promise for the treatment of RLS symptoms. Possible side effects of gabapentin include dizziness, lethargy, fatigue, increased appetite and instability. The sedative properties of gabapentin may affect the ability to operate heavy machinery, including motor vehicles.

Benzodiazepines *. Several benzodiazepines *, including clonazepam (Klonopin), nitrazepam, lorazepam and temazepam, have been used to treat RLS and sometimes to improve the quality of nocturnal sleep. Benzodiazepine * is a central nervous system inhibitor that does not completely inhibit RLS sensation and leg activity, but allows the patient to gain more sleep despite problems. Some drugs in this group cause daytime sleepiness.

Opioids are narcotic analgesics and relaxants that can inhibit RLS and PLMS in certain people, particularly in patients with severe and restless symptoms of RLS. Some examples of such drugs include codeine, propoxyphene (Darvon or Darvocet), oxycodone (Percocet, Tylox, Roxiprin), pentazocine (Talwin), hydrocodone (Vicodin), and methadone.

Ekbom mentions the therapeutic effect of opioids in the initial description of RLS. This effect has recently been further confirmed in open clinical trials, see Trzepacz PT, VioletteEJ, sateria MJ (1984.) Response to opioids in three patients with restless leg syndrome opioid symptoms, Am j. 141: 993-99, and Hening WA, and periodicnovements in sleep in stress trees syndrome; treatment of patients with psychotics (periodic movement in sleep of restless legs syndrome: treatment with opioids.) Neurology; 36: 1363-1366(1986). In these studies, it was found that RLS can be reversed by naloxone, an opioid receptor antagonist. Opioids are potent inhibitors of RLS and PLMS, but they carry risks of abuse and risk of addiction limits. Side effects and adverse reactions include dizziness, sedation, nausea, vomiting, constipation, hallucinations and headache. But in severe cases, particularly those undergoing hemodialysis, opiates may be an alternative treatment.

Dopaminergic drugs have produced certain interesting results. Dopaminergic agents are drugs commonly used in the treatment of parkinson's disease, and in some cases appear to provide some short-term relief for certain RLS patients. RLS is not a form of parkinson's disease, but a different neuropathy. Several studies have shown that L-dopa administered with a peripheral carboxylase inhibitor in a 10: 1 ratio is effective in treating RLS. See, for example, the following articles: brodeur C, Montplaivir J, Marinier R, Godbout R., "Treatment of RLS and PMS with L-dopa: a double-blind controlled study (treatment of RLS and PMS with L-dopa: double blind control study), "Neurology (Neurology); 35: 1845-Montplaiiri J, Godbout R, Poirier G, Bedardm.A, "Restless legs syndrome and periodic movements in sleep: physiopathiology and treatment with L-dopa (Restless legs syndrome and periodic movements in sleep: pathophysiology and treatment with L-dopa, "Clinical Neuropharmacology"; 9: 456-463 (1986); Von Scheele C, "Levodopain restriction legs)," Lancet (Lancet), "2: 426-427(1986). Akpinar S.," restriction legrodyne treatment with dopachy drugs "; 10: 69-79 (1987).

A control trial recorded using Polysomnography (PSG) in a double blind trial design also showed that L-dopa given twice during the night significantly reduced RLS and PLMS throughout the night at bedtime. Brodeur C, Montplaivir J, Marinier R, GodboutR, "Treatment of RLS and PMS with L-dopa: a double-blind controlled study (treatment of RLS and PMS with L-dopa: double blind control study), "Neurology (Neurology); 35: 1845-1848(1988). In most cases, 100mg l-dopa in combination with the 10mg decarboxylase inhibitor carbidopa completely inhibited RLS, although PLMS rebound (potentiation) is often observed during the last phase of the night. Montplacir J, godpout R, poinier G, bedard m.a., clinical neuropharmacology (clinical neuropharmacology); 9: 456-463(1986). Two major side effects commonly seen in patients treated with L-dopa are: 1) daytime symptoms rebound when patients receive treatment only at night; and 2) a single dose of L-dopa at bedtime reduces PLMS in the first third of the night, but causes these movements to rebound in the latter third of the night, at which time L-dopa is no longer effective. Similarly, the same study indicates that severely ill patients may experience paresthesia and restlessness anew during the day when L-dopa treatment is repeated at midnight.

The D2 receptor agonist bromocriptine is also used for RLS treatment. Walters, AS; hening, WA; chokroverty, S; Gidr-Franck, S.A double blue random amplified cross over tertiary of bromocriptine and placebo in restriction less syndrome Ann neuron; 198824: 455-458. After a dose of 7.5mg administered 1-3 hours prior to sleep, subjective improvement in restlessness and paresthesia was better reported in 5 of 6 patients compared to placebo. The reported side effects were transient nasal stuffiness and dizziness in one patient.

The dopamine D1/D2 agonist pergolide (half-life 7-16 hours) in combination with low doses of L-dopa can lead to clinical improvement in patients who do not respond to L-dopa administration alone, but can also cause several important side effects, such as orthostatic hypotension and gastrointestinal problems.

Internet RLS site, http: // www.rls.org, the following is for dopaminergic drug therapy. Note that internet sites may be updated at any time, and the following citation is reproduced in 3 months 1999. "dopaminergic agents are the major and first-line treatments of RLS that act in the central nervous system by increasing the levels of dopamine, a chemical substance that is naturally produced by the body and that regulates the transmission of information between cells of the nervous system. "but then the station raises such a warning: "the most commonly used dopaminergic agent is carbidopa-levodopa (Sinemet)^*(ii) a DuPont-Merck). Using Sinemet^*Has the advantages that the drug has the longest time to market and is the least expensive dopaminergic agent. However, Sinemet^*It does have a very important drawback: up to 85% of people who take this drug to treat RLS experience a phenomenon known as potentiation. "this site provides another description of augmentation. "the strengthening effect is such that: general dosage of Sinemet^*Get you symptom relief, so you can sleep at night, but it occurs earlier in the day (in the afternoon or even in the morning)Abnormal sensation, need for activity, and restlessness (usually increased intensity). If this happens, you may try to increase your Sinemet^*Doses were to treat these daytime symptoms, but that would be the wrong approach. If reinforcement does occur, increase Sinemet^*The dose of (a) will only worsen rather than improve your symptoms. Most RLS patients with booster effects must be treated with another drug. "

"albeit Sinemet^*Indeed, it works well for many people with minimal side effects (mainly gastrointestinal upset, nausea, vomiting and headache), but every person who is taking this drug to treat RLS needs to be clearly aware of the possibility of producing a potentiation. Another consideration you should understand is due to protein interference with Sinemet^*You should avoid taking high protein food immediately before taking the drug. "

The internet site continues to discuss other possible treatments.

"A newer drug pergolide mesylate (Permax)^*) Showing great potential for treating RLS. Recent studies have shown that this drug is associated with Sinemet^*Is equally effective and has a much lower probability of causing strengthening (Permax)^*10% and Sinemet^*80%) of the total weight. Permax^*Has the disadvantage that it is more than Sinemet^*More expensive and less durable than it is, and thus less familiar to physicians in developing such drugs. The major side effects are dizziness, nausea and nasal congestion. "

"Bromopiptin methanesulfonate (Parlodel)^*) Is another dopaminergic agent useful in the treatment of RLS. The results of the study on the effectiveness of bromocriptine are mixed, although good results were reported by individual patients. "

“Permax^*And Parlodel^*Are dopamine receptor agonists, meaning that they act at the dopamine binding site, while Sinemet^*Increase normal dopamine production of body. Other research suggestionsBy Permax^*(pergolide) treated patients will develop tolerance to the drug.

Considering the problems presented in all possible treatments described above, there is fairly no optimal effective treatment for RLS. RLS patients turning to the Internet and seeing the above annotations will be stuck with numerous possible treatments, such as iron supplements, melatonin, Prozac^*、Sinement^*、Klonopin^*Clonazepam, all of the above drugs and drug classes, and even electrical stimulation of the legs or feet prior to bedtime. See: http: // www.rls.org. On the internet, one can find that there is no good treatment regime for RLS, and medical books list more than 15 different treatments or regimes, but none of them is very effective. The following quotes from RLS patients are posted on the internet RLS site: "I feel as if there are worms crawling and crawling in my legs. I need to twist my legs to make these sensations disappear. Sometimes, in the evening, i want to not stop moving my legs while i are driving or sitting to watch movies or television. I just want to strike the leg with a hammer. "http: // www.rls.org.

Physicians may currently attempt to use levodopa in combination with a dopa decarboxylase inhibitor (DDCI) such as carbidopa. Controlled studies on levodopa have demonstrated beneficial effects on subjective RLS symptoms and sleep quality, as demonstrated by polysomnography studies. Since conventional release formulations generally do not maintain therapeutic effect over the night, sustained release formulations have been attempted. Although many RLS patients exhibit excellent responses to levodopa, there is increasing evidence that shorter duration of action and intensification of symptoms may be a factor limiting levodopa therapy.

Recent patent literature has proposed new therapies that are available and useful, but they have not yet been widely prescribed, see U.S. Pat. No. 6,114,326, which discloses the use of Cabergoline (Cabergoline), a synthetic ergoline derivative and dopamine agonist, by itself or in combination with levodopa, to treat RLS. In U.S.6,001,861, the use of pramipexole (pramipexole), a dopamine D3/D2 agonist, for the treatment of RLS is disclosed.

Potentiation is described above and includes the development of RLS symptoms earlier in the evening than before treatment, the appearance of symptoms during the day, involvement of other parts of the body (i.e. arms) or increased severity of symptoms. In view of the problem of potentiation, alternative treatment options for RLS are of great interest, particularly for patients with severe RLS. The choice of which possible RLS treatment is a problem for any treating physician, since the possible known therapies show serious drawbacks. Here we provide novel compounds that can be used in the treatment of RLS.

Summary of The Invention

The present invention provides methods of treating Restless Legs Syndrome (RLS) using heterocyclic amines, substituted phenylazacycloalkanes, and pharmaceutically acceptable salts thereof. The invention also provides the use of heterocyclic amines, substituted phenylazacycloalkanes and pharmaceutically acceptable salts thereof for the preparation of medicaments for the treatment of RLS.

In one aspect, the invention provides a method of treating RLS in a patient suffering therefrom and in need thereof, comprising administering a heterocyclic amine of structural formula I or a pharmaceutically acceptable salt thereof,

formula I

Or a heterocyclic amine of structural formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of RLS, wherein:

R₁、R₂and R₃Independently is

a) The presence of hydrogen in the presence of hydrogen,

b)C_1-6alkyl radical, C_3-5Alkenyl or C_3-5An alkynyl group,

c)C_3-7cycloalkyl radical, C_4-10Cycloalkyl-or phenyl-substituted C_1-6Alkyl, or

d)R₁And R₂Form C by bonding_3-7Cyclic amines, which may contain additional heteroatoms and/or unsaturation;

x is

a) The presence of hydrogen in the presence of hydrogen,

b)C_1-6an alkyl group, a carboxyl group,

c) the halogen(s) are selected from the group consisting of,

d) a hydroxyl group(s),

e) alkoxy radical, or

f) The cyano group(s),

g) an amide (carboxamide),

h) carboxyl group, or

i) An alkoxycarbonyl group;

a is

a)CH、CH₂CH-halogen, CHCH₃、C＝O、C＝S、C-SCH₃、C＝NH、C-NH₂、C-NHCH₃、C-NHCOOCH₃Or a C-NHCN group, or a combination thereof,

b)SO₂or is or

c)N；

B is

a)CH₂CH, CH-halogen or C ═ O,

b) n, NH or N-CH₃Or is or

c)O；

n is 0 or 1; while

D is

a)CH、CH₂CH-halogen or C ═ O,

b) o, or

c) N, NH or N-CH₃。

Preferred compounds of formula I for use in the present invention include (R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5, 1-ij ] -quinolin-2 (1H) -one, (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -thione and pharmaceutically acceptable salts of any of the compounds.

In another aspect of the invention, there is provided a method of treating RLS in a patient suffering therefrom and in need thereof, comprising administering a substituted phenylazacycloalkane of structural formula II or a pharmaceutically acceptable salt thereof

Formula II

Or a substituted phenylazacycloalkane of structural formula II or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of RLS, wherein:

n is 0 to 3;

R¹and R²Independently H (provided that only one group at a time is H), -OH (provided that R is⁴Not hydrogen), CN, CH₂CN, 2-or 4-CF₃、CH₂CF₃、CH₂CHF₂、CH＝CF₂、(CH₂)₂CF₃Vinyl, 2-propenyl, OSO₂CH₃、OSO₂CF₃、SSO₂CF₃、COR⁴、COOR⁴、CON(R⁴)₂、SO_xCH₃(wherein x is 0-2), SO_xCF₃、O(CH₂)_xCF₃、SO₂N(R⁴)₂、CH＝NOR⁴、COCOOR⁴、COCOON(R⁴)₂、C_1-8Alkyl radical, C_3-8Cycloalkyl radical, CH₂OR⁴、CH₂(R⁴)₂、NR⁴SO₂CF₃、NO₂Halogen, phenyl in position 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine;

R³is hydrogen, CF₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, - (CH)₂)_m-R⁵(wherein m is 1-8), CH₂SCH₃Or C combined with said nitrogen atom and one of its adjacent carbon atoms to form a cyclic structure₄-C₈An alkyl group;

R⁴independently of each other is hydrogen, CF₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, - (CH)₂)_m-R⁵Wherein m is 1 to 8;

R⁵is phenyl, phenyl (by CN, CF)₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl substitution), 2-thiophenyl, 3-thiophenyl, -NR⁶CONR⁶R⁷or-CONR⁶R⁷；

R⁶And R⁷Independently of one another is hydrogen, C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl methyl, C₂-C₈Alkenyl or C₂-C₈An alkynyl group; while

With the proviso thatIs when R¹Is 2-CN or 4-CN, R is H, R₃When n is n-Pr and n is 1 or 3, the compound is a pure enantiomer.

Preferred compounds of formula II for use in the present invention include those wherein R is¹A compound which is CN; wherein R is²Is H and R³A compound which is n-propyl; wherein R is¹is-OSO₂CF₃A compound of (1); wherein R is¹Is SO₂CH₃A compound of (1); wherein R is²Is H and R³Is C_1-8A compound of an alkyl group; a compound wherein n is 2; wherein R is¹Is 3-OH, R²Is H, R³Is n-propyl, and R⁴Is C_1-8A compound of an alkyl group; and compounds wherein n is 0.

Particularly preferred compounds of formula II include (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrochloride, (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrobromide and (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine (2E) -2-butenedioate (1: 1).

Detailed Description

The present invention provides the use of two classes of compounds having dopamine receptor activity for the treatment of RLS or for the manufacture of a medicament for the treatment of RLS.

One class of compounds useful in the treatment of RLS in the present invention are those compounds generally or specifically disclosed in U.S. Pat. Nos. 5,273,975 and 5,436,240, or pharmaceutically acceptable salts thereof. These compounds are collectively referred to as heterocyclic amines and are structurally represented by formula I, wherein:

R₁、R₂and R₃Independently is

a) The presence of hydrogen in the presence of hydrogen,

b)C_1-6alkyl radical, C_3-5Alkenyl or C_3-5An alkynyl group,

c)C_3-7cycloalkyl radical, C_4-10Cycloalkyl-or phenyl-substituted C_1-6Alkyl, or

d)R₁And R₂Form C by bonding_3-7Cyclic amines, which may contain additional heteroatoms and/or unsaturation;

x is

a) The presence of hydrogen in the presence of hydrogen,

b)C_1-6an alkyl group, a carboxyl group,

c) the halogen(s) are selected from the group consisting of,

d) a hydroxyl group(s),

e) an alkoxy group,

f) the cyano group(s),

g) the acid amide,

h) carboxyl group, or

i) An alkoxycarbonyl group;

a is

a)CH、CH₂CH-halogen, CHCH₃、C＝O、C＝S、C-SCH₃、C＝NH、C-NH₂、C-NHCH₃、C-NHCOOCH₃Or a C-NHCN group, or a combination thereof,

b)SO₂or is or

c)N；

B is

a)CH₂CH, CH-halogen or C ═ O, or

b) N, NH or N-CH₃，

c)O；

n is 0 or 1; while

D is

a)CH、CH₂CH-halogen or C ═ O,

b) o, or

c) N, NH or N-CH₃。

Illustrative advantages for use with the inventionSelected compounds of formula I include those wherein D is N or NH and N is 0; wherein A is CH or CH₂、CHCH₃、C＝O、C＝S、C-SCH₃、C＝NH、C-NH₂、C-NHCH₃、C-NHCOOCH₃Or a compound of C-NHCN; and compounds wherein a is CH or C ═ O.

Particularly suitable compounds of formula I in the present invention are compounds of formula Ia,

formula Ia

The compound of formula Ia is named (R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5, 1-ij ] -quinolin-2 (1H) -one (unconverted CAS Name) or (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -one (generated by ACD/Name software).

Another particularly suitable compound of formula I in the present invention is the maleate salt of a compound of formula Ia, and is represented by formula Ib:

formula Ib

The compound of formula Ib is named (R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5, 1-ij ] -quinolin-2 (1H) one (Z) -2-butenedioate (1: 1) or (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -one maleate.

Another group of compounds within the scope of general formula I shown above are selected heterocyclic amine compounds, wherein a is C ═ S; most preferably (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione, i.e. a compound of formula Ic, also referred to herein as formula VIII,

formula Ic or formula VIII

And pharmaceutically acceptable salts thereof. Preferably (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij)]Quinoline-2 (1H) -thione (IX) is present as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts are preferred over the corresponding free amines because of their better water solubility and crystallinity. Pharmaceutically acceptable salts include salts of inorganic and organic acids. Preferred pharmaceutically acceptable salts include the salts of the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, citric acid, methanesulfonic acid, CH₃-(CH₂)_n1-COOH (wherein n is₁0-4), HOOC- (CH)₂)n₁-COOH (wherein n is as defined above), HOOC-CH ═ CH-COOH, Φ -COOH. For other acceptable salts, see int.j.pharm., 33, 201-217 (1986). More preferably (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij)]Quinoline-2 (1H) -thiones exist as the maleate salt, i.e. (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij)]Quinoline-2 (1H) -thione maleate. The maleate salt is represented below as formula Id or formula IX.

Of the formula Id or IX

Heterocyclic amines, methods for their preparation and methods for preparing pharmaceuticals from them are disclosed in U.S. Pat. Nos. 5,273,975 and 5,436,240, which are incorporated herein by reference. Although U.S. Pat. No.5,273,975 discloses and claims (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione generally, it has no examples to include this compound nor specifically describes it. (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione (VIII) is preferably prepared from the corresponding non-thio analog (5R) - (methylamino) -5, 6-dihydro-4H-imidazo (4, 5, 1-ij) quinoline- (2H) -one (VII). A preferred method for the preparation of (5R) - (methylamino) -5, 6-dihydro-4H-imidazo (4, 5, 1-ij) quinolin- (2H) -one (VII) is illustrated in preparation example 1 and examples 1-6 and is illustrated in FIG. A. Example 7 illustrates a preferred method for converting (5R) - (methylamino) -5, 6-dihydro-4H-imidazo (4, 5, 1-ij) quinolin- (2H) -one (VII) to (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -thione (VIII). A preferred method for converting (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione (VIII) to (5R) -5- (methylamino) -5, 6 dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione maleate (IX) is illustrated in example 8.

Another class of compounds useful in the present invention are those compounds, or pharmaceutically acceptable salts thereof, disclosed generally or specifically in U.S. Pat. Nos. 5,594,024 and 5,462,947, both of which are incorporated herein by reference. These compounds are collectively referred to as substituted phenylazacycloalkanes, and their structures are represented by formula II, wherein:

n is 0 to 3;

R¹and R²Independently H (provided that only one group at a time is H), -OH (provided that R is⁴Not hydrogen), CN, CH₂CN, 2-or 4-CF₃、CH₂CF₃、CH₂CHF₂、CH＝CF₂、(CH₂)₂CF₃Vinyl, 2-propenyl, OSO₂CH₃、OSO₂CF₃、SSO₂CF₃、COR⁴、COOR⁴、CON(R⁴)₂、SO_xCH₃(wherein x is 0-2), SO_xCF₃、O(CH₂)_xCF₃、SO₂N(R⁴)₂、CH＝NOR⁴、COCOOR⁴、COCOON(R⁴)₂、C_1-8Alkyl radical, C_3-8Cycloalkyl radical, CH₂OR₄、CH₂(R⁴)₂、NR⁴SO₂CF₃、NO₂Halogen, phenyl in position 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole,Tetrazole or pyridine;

R³is hydrogen, CF₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, - (CH)₂)_m-R⁵(wherein m is 1-8), CH₂SCH₃Or C combined with said nitrogen atom and one of its adjacent carbon atoms to form a cyclic structure₄-C₈An alkyl group;

R⁴independently of each other is hydrogen, CF₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, - (CH)₂)_m-R⁵Wherein m is 1 to 8;

R⁵is phenyl, phenyl (by CN, CF)₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl substitution), 2-thiophenyl, 3-thiophenyl, -NR⁶CONR⁶R⁷or-CONR⁶R⁷；

R⁶And R⁷Independently of one another is hydrogen, C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl methyl, C₂-C₈Alkenyl or C₂-C₈An alkynyl group; while

With the proviso that when R¹Is 2-CN or 4-CN, R²Is H, R³When n is n-Pr and n is 1 or 3, the compound is a pure enantiomer.

Also useful in the present invention are pharmaceutically acceptable salts of the compounds of formula II above.

Preferred compounds of formula II for use in the present invention include: wherein R is¹A compound which is CN; wherein R is²Is H and R³A compound which is n-propyl; wherein R is¹is-OSO₂CF₃A compound of (1); wherein R is¹Is SO₂CH₃A compound of (1); wherein R is²Is H and R³Is C_1-8A compound of an alkyl group; a compound wherein n is 2; wherein R is¹Is 3-OH, R is H, R₃Is n-propyl and R⁴Is C_1-8A compound of an alkyl group; and compounds in which n is 0.

Particularly suitable compounds of formula II in the present invention are (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrochloride (unconverted CAS Name) or OSU6162 or (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrochloride (produced by ACD/Name software) and represented by formula IIa:

formula IIa

Another particularly suitable compound of formula II in the present invention is (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrobromide (unconverted CAS Name) or (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrobromide (produced by ACD/Name software) and represented by formula IIb:

formula IIb

Another particularly suitable compound of formula II in the present invention is (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine (2E) -2-butenedioate (1: 1) (unconverted CAS name) or (S) -OSU6162, and is represented by formula IIc:

formula IIc

Such substituted phenylazacycloalkanes, processes for their preparation, and methods for preparing pharmaceuticals from them are disclosed in U.S. Pat. Nos. 5,462,947 and 5,594,024, which are incorporated herein by reference.

Conventional pharmaceutical preparations of heterocyclic amines and substituted phenylazacycloalkanes may be employed, for example, the preparations consist essentially of an inert pharmaceutical carrier and an effective dose of the active substance; for example, the formulations are in the form of conventional tablets or coated tablets, capsules, lozenges, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal patches and the like. Tablets are preferred.

An effective dosage range for a compound of formula I is about 0.1-50 mg/day. More specifically, an effective dose of a compound of formula I wherein a is C ═ O ranges from 1 to 50 mg/day, typically in excess of 1mg, preferably 4 to 10 mg/day, per administration to the patient per time and day. For compounds of formula I wherein a is C ═ S, an effective dose range is 0.4 to 10 mg/day, and typically more than 0.4mg, preferably 1.6 to 10 mg/day, is administered to the patient each time and daily.

An effective dosage range for a compound of formula II is about 10-100 mg/day, typically more than 10mg, preferably 15-40mg, most preferably 20-30mg per day per time and day of administration to the patient.

Although the above dosage levels for the heterocyclic amines and substituted phenylazacycloalkanes are expressed as mg/day and they are generally administered once or twice daily, surprisingly they may be administered at these dosages on a less than daily basis. While these drugs may be administered once daily or twice daily, for some patients they may be administered only three times per week, twice per week or even once per week. For less than daily dosing, the size and dosage of the tablet may vary, and the mg of drug administered to each patient may actually be the mg/day dose suggested above. When administered on a daily or less frequent schedule, the daily doses described herein will only be for the day of administration.

Patients with milder forms of the disease are expected to require less medication. Patients with more severe forms of the disease and patients already treated with other dopaminergic agents may expect to require more medication. If the patient does not experience intolerable side effects, the dosage should be adjusted to obtain the maximum therapeutic effect. The dosage should be gradually increased. The precise dosage of the heterocyclic amine compounds and phenylazacycloalkanes is determined by the treating physician by evaluating factors such as the stage of progression of the condition, the weight and age of the patient, whether and to what extent other drugs, such as L-dopa or levodopa, are administered, and other factors which are generally evaluated by the physician prior to determining the dosage of CNS drug to be administered to the patient.

Definition and contract

The following definitions and explanations pertain to the terms used throughout this document, including the specification and claims.

Definition of

Chromatography (column and flash chromatography) refers to the purification/separation of compounds, expressed as (carrier, eluent). It will be appreciated that appropriate fractions are collected and concentrated to give the target compound.

CMR refers to C-13 magnetic resonance spectroscopy, and chemical shifts in ppm (δ) are reported in the low magnetic field of TMS.

IR refers to infrared spectrum.

HPLC refers to high pressure liquid chromatography.

MS refers to mass spectra, expressed as m/e, m/z or mass/charge units. [ M + H ]]⁺Refers to the cation of the parent compound bearing a hydrogen atom. EI refers to electron collisions. CI refers to chemical ionization. FAB refers to fast atom bombardment.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, and chemical shifts in ppm (δ) are reported in the low magnetic field of tetramethylsilane.

Pharmaceutically acceptable refers to properties and/or substances that are acceptable to the patient from a pharmacological/toxicological point of view, and to the pharmaceutical chemist from a physical/chemical point of view, with respect to composition, formulation, stability, patient acceptance and bioavailability.

RLS means restless legs syndrome

Brine refers to saturated aqueous sodium chloride solution.

Solubility of the solid in the solvent, and the ratio of solid to solvent is weight/volume (wt/v).

For the solvent pair, the ratio of the solvents used is volume/volume ratio (v/v).

Temperatures are expressed in degrees celsius.

TLC refers to thin layer chromatography.

-phi means phenyl (C)₆H₅)。

[α]_D ²⁵The optical rotation angle (specific optical rotation) of plane polarized light using sodium D system (589A) was determined at 25 ℃.

Examples

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The examples and figure a detailed below describe how to prepare various compounds and/or perform various methods of the invention. The examples and figures are to be understood as illustrative only and not limiting in any way to the foregoing. Those skilled in the art will quickly recognize appropriate variations of the method with respect to the reactants and reaction conditions and techniques.

Preparation example 1 (R) -naproxen chloride

R-naproxen (can.j. chem., 72(1), 142-5(1994), 260g), dichloromethane (3.33kg) and DMF (8.2ml) were added to the reactor. Oxalyl chloride (191.8g) was slowly added to the mixture. After addition of oxalyl chloride, the slurry was stirred at 5-10 ° and then slowly warmed to 20-25 °. The resulting mixture was concentrated to remove dichloromethane, branched octane was added to this concentrate and the mixture was concentrated again. More branched octane was added to this concentrate and the mixture was cooled to 0 ° and stirred until crystalline. The crystal slurry was filtered, the crystalline cake was washed with octane and dried at 20-25 ° to give the title compound.

The filtrate from the first step was concentrated, branched octane was added and the mixture was cooled and stirred to give the title compound in a second round of yield. The crystal slurry was filtered, the crystal cake was washed with branched octane and dried at 20-25 ℃.

Example 11-benzyl-4H-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -one (II)

A mixture of 4H-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -one (I, J. heterocyclic Chem., 19, 837-49(1982), 1.0g, 5.8mmol) in DMF (10ml) was cooled to 0 ℃ and treated with potassium tert-butoxide (1.98M, 3.2ml, 6.3mmol) in THF, maintaining the reaction temperature at 0 ℃.

The resulting mixture was stirred at 0 ° for 10 minutes. Benzyl bromide (0.73ml, 6.1mmol) was then added while maintaining the reaction temperature at 0 °. After 1 hour, the mixture was partitioned with methyl tert-butyl ether (MTBE) and water and then washed several times with water.

The MTBE phase was concentrated under reduced pressure. The concentrate was cooled to 0 °, filtered and washed twice with 0 ° MTBE. The product was dried at 50 ℃ under reduced pressure with a nitrogen purge to give the title compound, CMR (CDCl)₃100MHz)153.78, 136.44, 128.69, 127.67, 127.60, 126.73, 125.86, 122.90, 122.78, 121.28, 116.92, 116.17, 108.36, 44.95, and 42.37 δ.

Example 2 (5R, 6R) -1-benzyl-5-bromo-6-hydroxy-5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -one (III)

1-benzyl-4H-imidazo [4, 5, 1-ij)]Quinolin-2 (1H) -one (II, example 1, 240g), acetonitrile (1.086kg), water (227ml) and fluoroboric acid (48.5%, 13.4g) were mixed and cooled to 0-5 ℃. Dibromantin (163.5g) was slurried in acetonitrile and added to the reaction mixture. The reaction was carried out at 0-5 ℃ for about 3 hours. After the reaction was complete, methyl t-butyl ether was added over about 45 minutes, maintaining the reaction temperature in the tank below 10 °. The slurry was cooled to-10 to-15 deg.C, stirred for 1 hour, and then filtered. The product was washed with pre-cooled methyl tert-butyl ether and dried with 40 ° nitrogen to give the title compound, CMR (CDCl)₃)156.0, 137.8, 130.5, 129.6, 129.3, 129.1, 126.6, 123.6, 122.5, 119.6, 110.4, 69.9, 49.6, 47.7, 46.9 and 43.8 delta.

Example 3 (5S, 6S) -1-benzyl-5-bromo-2-oxo-1, 2, 5, 6-tetrahydro-4H-imidazo [4, 5, 1-ij ] quinolin-6-yl (2R) - (6-methoxy-2-naphthyl) propanoate (IVA) and (5R, 6R) -1-benzyl-5-bromo-2-oxo-1, 2, 5, 6-tetrahydro-4H-imidazo [4, 5, 1-ij ] quinolin-6-yl (2R) - (6-methoxy-2-naphthyl) propanoate (IVB)

Mixing (5R, 6R) -1-benzyl-5-bromo-6-hydroxy-5, 6-dihydro-4H-imidazo [4, 5, 1-ij)]Quinolin-2 (1H) -one (III, example 2, 143g), dichloromethane (3,136g), N-methylmorpholine (100.2g) and 4-dimethylaminopyridine (497mg) were added to the reactor and the mixture was cooled to 0-5 ℃. (R) -naproxen chloride (preparation 1, 118.5g) dissolved in methylene chloride (694ml) was added to the reactor over about 1 hour, and the mixture was stirred at 0-5 ℃ to complete the reaction. Additional naproxen chloride was added to complete the reaction, if necessary. A solution of potassium carbonate diluted with water was added to the mixture. The aqueous phase was extracted with dichloromethane and the combined dichloromethane phases were washed with water. The washed mixture was concentrated by vacuum distillation and the solvent was exchanged with ethyl acetate. The concentrate was cooled to-10 ° and stirred. The slurry was filtered and the crystal cake was washed with pre-cooled methyl tert-butyl etherDrying at 50 ℃ gave the title compound, (5S, 6S) -1-benzyl-5-bromo-2-oxo-1, 2, 5, 6-tetrahydro-4H-imidazo [4, 5, 1-ij) as a solid]Quinolin-6-yl (2R) -2- (6-methoxy-2-naphthyl) propanoate (IVA), CMR (CDCl)₃) δ 173.2, 157.8, 153.4, 136.1, 134.6, 133.7, 129.2, 128.8, 127.8, 127.8, 127.6, 127.2, 125.9, 125.9, 125.6, 121.5, 121.4, 119.1, 113.2, 109.0, 105, 105.6, 69.2, 55.3, 45.4, 45.2, 42.5, 41.7 and 18.3.

Example 4 (5R, 6R) -1-benzyl-5-hydroxy-6- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -one (V)

(5S, 6S) -1-benzyl-5-bromo-2-oxo-1, 2, 5, 6-tetrahydro-4H-imidazo [4, 5, 1-ij) is reacted in acetonitrile (1,297g)]Quinolin-6-yl (2R) -2- (6-methoxy-2-naphthyl) propionate (IVA, example 3, 110g) was slurried. After addition of aqueous methylamine (40 wt%, 327g), the reaction was carried out at about 30 ℃ for about 12 hours. After completion of the reaction, the mixture was concentrated and ethyl acetate was added. Dilute hydrochloric acid was added to prepare a water soluble salt of the title compound. The by-product (R-naproxen formamide impurity) was insoluble in water and remained in the ethyl acetate phase. Further extraction and washing was performed to better separate the (naproxen acetamide) impurity while minimizing the loss of the target product. Sodium hydroxide solution was then added to the aqueous phase and the hydrochloride salt of the title compound was converted to the free base. The free base is less soluble in water and is extracted into ethyl acetate. The product mixture was concentrated and the solvent was exchanged with ethyl acetate to remove water. Crystallization was accomplished by adding branched octane and cooling the mixture. The resulting slurry was filtered, washed and dried at 50 ℃ to give the title compound, CMR (CDCl)₃) δ 153.7, 136.3, 128.7, 127.8, 127.7, 125.7, 121.3, 119.9, 118.6, 107.5, 66.2, 60.1, 45.1, 42.6 and 34.0.

Example 5 (7aS, 8aR) -4-benzyl-8-methyl-7, 7a, 8, 8 a-Tetrahydrocycloazepino (azireno) [2, 3c ] imidazo [4, 5, 1-ij ] quinolin-5 (4H) -one (VI)

To prevent the reaction of n-butyllithium with water, distillation is usedMixing (5R, 6R) -1-benzyl-5-hydroxy-6- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij)]Quinolin-2 (1H) -one (V, example 4, 70g) and THF (1,389g) were concentrated to remove any water. The mixture was cooled to about-10 deg., and n-butyllithium was added to prepare the lithium salt of the starting material, while n-butane byproduct was formed in the exothermic reaction. Benzenesulfonyl chloride was added slowly to prepare the benzenesulfonate in an exothermic reaction. The reaction mixture was warmed to 20-25 ℃ to complete the reaction. An aqueous potassium carbonate solution was added to scavenge benzenesulfonic acid, and the mixture was stirred to crystallize. Water was added to complete the crystallization, the slurry was stirred, cooled and filtered. The crystal cake was washed with water, then branched octane and dried at 40-50 ℃ to give the title compound, CMR (CDCl)₃) δ 154.1, 136.3, 128.6, 127.9, 127.6, 124.3, 120.7, 119.7, 107.4, 46.7, 44.9, 40.7, 38.1 and 37.6.

Example 6 (5R) - (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -one (VII)

A mixture of (7aS, 8aR) -4-benzyl-8-methyl-7, 7a, 8, 8a tetrahydrocycloazepino (azireno) [2, 3-c ] imidazo [4, 5, 1-ij ] quinolin-5 (4H) -one (VI, example 5, 40g) tert-amyl alcohol (42.4g) and anhydrous ammonia (1,200g) was treated with lithium at-33 ℃. After the lithium addition was complete, the reaction mixture turned from a yellow slurry to a dark blue mixture. The dark blue mixture was stirred for 30-60 minutes and then quenched by the addition of water. The cooling water is removed from the condenser and the ammonia is evaporated. The residue was dissolved in methanol. The mixture was then concentrated to dryness to give the title compound, which was transferred to the next step without isolation.

Example 7 (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione (VIII)

Heating (5R) - (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-i) under a nitrogen atmosphere in a 125 ℃ oil bathj]Mixture of quinolin-2 (1H) -one (VII, example 6, 15.0g, 73.8mmol) and tetraphosphorus decasulfide (36.1g, 81.2mmol) in pyridine (300 mL). The reaction was stirred for 5 hours. The mixture was cooled to 20-25 ° and pyridine was removed under reduced pressure. Sodium hydroxide (2.2N, 200mL) was added, followed by a vigorous reaction. Additional sodium hydroxide (1N) was added until a solution was formed. The solution was saturated with sodium chloride and extracted with dichloromethane (2.5L, portions). The organic phase was absorbed into silica (40g) and purified by column chromatography (silica, 225 g; methanol/dichloromethane, 3.5-5.0/96.5-95). The appropriate fractions were collected and concentrated. Recrystallize this material from methanol/ethyl acetate/hexane to give the title compound, mp ═ 210-; IR (drift) 2940, 2907, 2884, 1483, 1458, 1391, 1366, 1354, 1254, 1239, 1229, 895, 762, 734 and 630cm^-1；NMR(300MHz，CDCl₃) δ 7.12, 7.03, 7.00, 4.30, 3.96, 3.30-3.50, 3.15, 2.88 and 2.57; MS (EI) M/z 219 (M)⁺) 190, 189, 187, 186, 164, 163, 155, 145; for C₁₁H₁₃N₃S(MH⁺) Hrms (fab) calculated 220.0908, found 220.0904.

Example 8 (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione maleate (IX)

A solution of maleic acid (0.317g, 2.36mmol) in a minimum amount of methanol (. about.1 mL) was added to (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij)]Mixture of quinoline-2 (1H) -thione (VIII, example 7, 0.493g, 2.25mmol) in dichloromethane. The resulting solid was collected by filtration to give the title compound; mp 195-196 °; [ alpha ] to]²⁵D ═ 60 ° (c0.93, methanol); IR (drift) 3140, 3112.3060, 2969, 1627, 1619, 1568, 1481, 1455, 1398, 1389, 1361, 1220, 868 and 747cm^-1；NMR(300MHz，CD₃OD) delta 7.20-7.30, 7.10-7.20, 6.26, 4.49, 4.31, 4.05-4.20, 3.28 and 2.83；CMR(100MHz，DMSO-d₆+CD₃OD) δ 170.4, 169.4, 136.6, 131.1, 130.9, 125.1, 122.1, 116.2, 109.6, 53.9, 43.1, 31.9 and 27.2; ms (esi) m/z 220.1(MH +).

FIG. A

Graph A-continuation

Wherein R is_N1Is phenyl, and R_XIs the bromine, and the bromine is the bromine,

graph A-continuation

Claims (36)

1. A method for treating Restless Legs Syndrome (RLS) in a patient suffering from RLS, the method comprising administering an effective amount of a compound selected from the group consisting of a heterocyclic amine, a substituted phenylazacycloalkane, and a pharmaceutically acceptable salt of any of the compounds.

2. The method of claim 1, wherein the compound is a heterocyclic amine.

3. The method of claim 1, wherein the compound is a heterocyclic amine of formula I or a pharmaceutically acceptable salt thereof,

formula I

Wherein:

R₁、R₂and R₃Independently is

a) The presence of hydrogen in the presence of hydrogen,

b)C_1-6alkyl radical, C_3-5Alkenyl or C_3-5An alkynyl group,

c)C_3-7cycloalkyl radical, C_4-10Cycloalkyl-or phenyl-substituted C_1-6Alkyl, or

d)R₁And R₂Form C by bonding_3-7Cyclic amines, which may contain additional heteroatoms and/or unsaturation;

x is

a) The presence of hydrogen in the presence of hydrogen,

b)C_1-6an alkyl group, a carboxyl group,

c) the halogen(s) are selected from the group consisting of,

d) a hydroxyl group(s),

e) an alkoxy group,

f) the cyano group(s),

g) the acid amide,

h) carboxyl group, or

i) An alkoxycarbonyl group;

a is

a)CH、CH₂CH-halogen, CHCH₃、C＝O、C＝S、C-SCH₃、C＝NH、C-NH₂、C-NHCH₃、C-NHCOOCH₃Or a C-NHCN group, or a combination thereof,

b)SO₂or is or

c)N；

B is

a)CH₂CH, CH-halogen or C ═ O, or

b) N, NH or N-CH₃；

c)O；

n is 0 or 1; while

D is

a)CH、CH₂CH-halogen or C ═ O,

b)O，

c) n, NH or N-CH₃。

4. The method of claim 3, wherein D is N or NH and N is 0.

5. The method of claim 3, wherein A is CH, CH₂、CHCH₃、C＝O、C＝S、C-SCH₃、C＝NH、C-NH₂、C-NHCH₃、C-NHCOOCH₃Or C-NHCN.

6. The method of claim 3, wherein A is CH, C ═ O, or C ═ S.

7. The method of claim 3, wherein the dose of the compound is about 0.1-50 mg/day.

8. The method of claim 6, wherein A is C ═ O and the compound is (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinolin-2 (1H) -one or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the compound is (R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5, 1-ij ] -quinolin-2 (1H) one (Z) -2-butenedioic acid salt (1: 1).

10. The method of claim 9, wherein the dose of the compound is about 1-50 mg/day.

11. The method of claim 9, wherein the dose of the compound is about 4-10 mg/day.

12. The method of claim 6, wherein A is C ═ S and the compound is (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione or a pharmaceutically acceptable salt thereof.

13. The method of claim 12, wherein said compound is (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione maleate.

14. The method of claim 13, wherein the dose of the compound is 0.1-50 mg/day.

15. The method of claim 13, wherein the dose of the compound is 0.4-10 mg/day.

16. The method of claim 1, wherein said compound is a substituted phenylazacycloalkane.

17. The method of claim 1, wherein the compound is a substituted phenylazacycloalkane of formula II,

formula II

Wherein:

n is 0 to 3;

R¹and R²Independently H (provided that only one group at a time is H), -OH (provided that R is⁴Not hydrogen), CN, CH₂CN, 2-or 4-CF₃、CH₂CF₃、CH₂CHF₂、CH＝CF₂、(CH₂)₂CF₃Vinyl, 2-propenyl, OSO₂CH₃、OSO₂CF₃、SSO₂CF₃、COR⁴、COOR⁴、CON(R⁴)₂、SO_xCH₃(wherein x is 0-2), SO_xCF₃、O(CH₂)_xCF₃、SO₂N(R⁴)₂、CH＝NOR⁴、COCOOR⁴、COCOON(R⁴)₂、C_1-8Alkyl radical, C_3-8Cycloalkyl radical, CH₂OR⁴、CH₂(R⁴)₂、NR⁴SO₂CF₃、NO₂Halogen, phenyl in position 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine;

R³is hydrogen, CF₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, - (CH)₂)_m-R⁵(wherein m is 1-8), CH₂SCH₃Or C combined with said nitrogen atom and one of its adjacent carbon atoms to form a cyclic structure₄-C₈An alkyl group;

R⁴independently of each other is hydrogen, CF₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl, 3, 3, 3-trifluoropropyl, 4, 4, 4-trifluorobutyl, - (CH)₂)_m-R⁵Wherein m is 1 to 8;

R⁵is phenyl, phenyl (by CN, CF)₃、CH₂CF₃、C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl-methyl, C₂-C₈Alkenyl radical, C₂-C₈Alkynyl substitution), 2-thiophenyl, 3-thiophenyl, -NR⁶CONR⁶R⁷or-CONR⁶R⁷；

R⁶And R⁷Independently of one another is hydrogen, C₁-C₈Alkyl radical, C₃-C₈Cycloalkyl radical, C₄-C₉Cycloalkyl methyl, C₂-C₈Alkenyl or C₂-C₈An alkynyl group; while

With the proviso that when R¹Is 2-CN or 4-CN, R²Is H, R³When n is n-Pr and n is 1 or 3, theThe compound is a pure enantiomer.

18. The method of claim 17, wherein the dose of the compound is 10-100 mg/day.

19. The method of claim 17, wherein R¹Is CN.

20. The method of claim 17, wherein R²Is H and R³Is n-propyl.

21. The method of claim 17, wherein R¹is-OSO₂CF₃。

22. The method of claim 17, wherein R¹is-SO₂CH₃And n is 2.

23. The method of claim 17, wherein R²Is H and R³Is C_1-8An alkyl group.

24. The method of claim 17, wherein n is 2.

25. The method of claim 17, wherein R¹Is 3-OH, R²Is H, R³Is n-propyl, and R⁴Is C_1-8An alkyl group.

The method of claim 17, wherein n is 0.

27. The method of claim 22, wherein the compound is (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine or a pharmaceutically acceptable salt thereof.

28. The method of claim 27, wherein the compound is (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrochloride.

29. The method of claim 28, wherein the dose of the compound is 10-100 mg/day.

30. The method of claim 28, wherein the dose of the compound is 20-30 mg/day.

31. The method of claim 27, wherein the compound is (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrobromide.

32. The method of claim 27, wherein the compound used is (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine (2E) -2-butenedioate (1: 1).

33. Use of a compound selected from heterocyclic amines of formula I and substituted phenylazacycloalkanes of formula II, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and management of such a condition in a patient suffering from or susceptible to Restless Legs Syndrome (RLS).

34. The use of claim 33, wherein the compound is (5R) -5, 6-dihydro-5- (methylamino) -4H-imidazo [4, 5, 1-ij ] -quinolin-2 (1H) one (Z) -2-butenedioate (1: 1).

35. The use of claim 33, wherein the compound is (5R) -5- (methylamino) -5, 6-dihydro-4H-imidazo [4, 5, 1-ij ] quinoline-2 (1H) -thione maleate.

36. The use of claim 33, wherein the compound is (3S) -3- [3- (methylsulfonyl) phenyl ] -1-propylpiperidine hydrochloride.