TW200819123A - Methods of treatment using alpha-2-delta-1 selective compounds - Google Patents

Abstract

The invention is directed to a method of treating a disorder or condition using an alpha-2-delta ligand with high affinity and selectivity for the alpha-2-delta-1 calcium channel subunit subtype. Administration of the alpha-2-delta-1 selective ligand, or a pharmaceutically acceptable salt, to a mammal, including a human, avoids or reduces the adverse effects compared to the administration of an alpha-2-delta non-selective ligand.

Description

200819123 IX. Description of the Invention: [Technical Field of the Invention] The present invention relates to the treatment of a condition or a condition by administering a selective ligand of an α-2-δ-1 subunit of a preferred calcium ion channel membrane protein. method. Such ligands are useful in the treatment of CNS and pain related conditions and conditions and may avoid or reduce the adverse effects associated with administration of non-selective alpha-2-delta ligands. [Prior Art] The voltage gated mother ion channel is composed of pore-forming α-1 (α!) subunits and auxiliary α-2-δ, β and γ (α^δ, β and γ, respectively) proteins. The combination is formed (Catterall WA (2000) Annul. Rev. Cell Dev. Biol. 16:521-5 5 5). It is known that α2δ proteins regulate the calcium ion channel density and voltage-dependent kinetics of these calcium channels (Felix R. et al. (1997) J. Neurosci 17: 6884-6891; Klugbauer et al. (1999) J Neurosci 19: 684-691; Hobom Μ et al. (2000) Eur J. Neurosci 12: 1217-1226; AQinNlA (2002) Mol. Pharmacol. 62: 485-496). The φ α2δ protein is encoded by a single gene and then translated into a2 and δ units. The α2 subunit is a highly thiolated extracellular protein and is linked to the membrane-anchored protein δ via a disulfide bond (Wang Μ. et al. (1999) Biochem. J. 〆 342:313-320; Marais E. et al. 2001) Mol. Pharmacol. 59: 1243-1248; and Gong HC et al. (2001) J. Membr. Biol. 184:3 5-43). Molecular colonization of the α2δ subunit has revealed four α2δ subtypes among multiple species (Qin Ν. et al. (2002) Mol. Pharmacol. 62: 485-496). See also WO 00/20450, which refers to α2δ·1, α2δ-2, α2δ-3, and α2δ-4 as α2δ-Α, α2δ-Β, respectively. The α2δ·1 unit 121934.doc 200819123 The Genbank accession number includes: M76559 (human); U73483, U73484, U73485, U73486 and U73487 (mouse); M86621 (rat); and AF077665 (pig). See also Brown and N. Gee. (1998) J. Biol. Chem. 273: 25458-25465. The registration number of α2δ-2 subunits includes: AJ251368, AJ251367.1, Abolll30.1, ΝΜ-006030.1, AF040709, AF042792, AF042793 (human); AF247139, NM-02063.2, AF247141, AB093246.1, ΑΚ044603·1 (small Rats; and AF486277.1 and ΝΜ175592.2 (rat). The non-selective α2δ ligand binds with high affinity to both subtypes of the calcium ion channel α2δ subtype. For example, Gabapentin, 1-aminomethyl-cyclohexyl-acetic acid (Neurontin®) is considered to be an antiepileptic drug that binds to α2δ-1 and α2δ-2 with high affinity. In addition, Pregabalin, S_(+)3-aminomethyl-5-mercapto-hexanoic acid (LyHca®), also binds to the α2δ-1 and α2δ-2 subtypes with high affinity. Both gabapentin and pregabalin are regarded as non-selective α2δ ligands (Gong HC· et al. (2001) several Membr, Biol 184: 35-43). [Invention] The present invention relates to the treatment of mammals including humans. A method of treating a condition or condition comprising administering to the mammal a therapeutically effective amount of an alpha-2·δ-1 (α2δ-1) selective ligand or a pharmaceutically acceptable salt thereof, wherein the disorder Or the condition is selected from the group consisting of pain, muscle fiber pain, epilepsy, restless legs, hot flashes, affective disorders, and sleep disorders. As shown below, administration of an α2δ-1 selective ligand can avoid or reduce one or more adverse reactions associated with administration of an α2δ non-selective ligand, such as 121934.doc 200819123 Good response includes (but not Limited to) sedation, dizziness, movement disorders and fatigue. The avoidance or reduction of adverse reactions following administration of the aj-1 selective ligand is due to the high binding affinity of the aj-l selective ligand to the calcium ion channel subunit subtype. [Embodiment] The present invention relates to a method of treating a condition or condition in a mammal comprising a human comprising administering to the mammal a therapeutically effective amount of an alpha-2·δ_1(α2δ_1) selective ligand or A pharmaceutically acceptable salt. These ligands are useful in the treatment of central nervous system (CNS) and pain related disorders and conditions and can avoid or reduce the adverse effects associated with administration of alpha beta non-selective ligands. Such CNS and pain related conditions include, but are not limited to, pain, muscle fiber pain, epilepsy, restless legs, hot flashes, affective disorders, and sleep disorders. Such adverse reactions include, but are not limited to, sedation, dizziness, movement disorders, and strength. As described in NS Gee et al., J. Biol. Chem., 1996, 271: 5879-5776, the degree of binding to the αβ subunit can be determined using a radioligand binding assay using [3Η] gabapentin and from a pig brain. The aj subunit of the organization is measured. "ad-l selective" ligand means a selective ligand, or a pharmaceutically acceptable salt thereof, wherein the ligand or salt is replaced by [3h]-gabapentin combined with a secondary unit Effectively, at least 3 fold times the effectiveness of [3Η]-gabapentin combined with the unit of α2δ_2&; such as the binding inhibition value of [3h]-gabapentin by binding the compound to the aj-l unit (Κ〇 is determined by comparing the ligand substitution with the Ki of the subunit in combination with Bapit. Therefore, for the purpose of the present invention, 121934.doc 200819123 is selective for ligand replacement and α2δ- The ratio of the K! value of the [3h]· Heding of the first unit to the ratio of the [3h]_gabapentin combined with the compound substitution and the aj_2 subunit. The method for determining the Ki values is in the art. It is known and described herein. Therefore, the Ki of [3H]-gabapentin combined with the test unit can be substituted with the compound and the [3Ημ gabapentin] & comparison from the test compound identified "Μ choice Ligand. For the purposes of the present invention, one or more aj 1 remote ligands can be identified from the aj ligand. The α_2_§·ι ligand can be included or generally disclosed in the following references. Their compounds: US 4024175, ΕΡ

0641330, including 3-methylgabapentin; US 5,563,175, WO 97/33858, WO 97/33859, WO/99/31057, WO 99/31074, WO 97/29101, WO 02/085839, including [(lR, 5R, 6S)-6-(aminomethyl)bicyclo[3·2·〇]heptyl]acetic acid; WO 99/31075, including 3-(1-aminoindenyl-cyclohexylmethyl)-4Η-[ 1,2,4]oxadiazol-5-one and C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine; w〇99/21824, including (38, 48)-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid; WO 01/90052, WO 01/28978, including (la, 3a, 5a) (3-amino- Mercapto-bicyclo[3,2.0]heptan-3-yl)-acetic acid; WO 98/17627, WO 00/76958, including (3S,5R)-3-aminoindolyl-5-methyl-octanoic acid; WO 03/082807, including (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid; WO 04/039367, including (2S , 4S)-4-(3-fluorobenzyl)proline and (2S,4S)-4-(3-chlorophenoxy)proline; EP 1178034, EP 121934.doc 200819123 1201240, WO 99/ 31074, WO 03/000642, WO 02/22568,

WO 02/30871, WO 02/30881, WO 02/100392, WO 02/100347, WO 02/42414, WO 02/32736; WO 02/28881; US 10/935,826 (publication 20050059654); US 10/640,515 ( Publication No. 20040092522); WO 04/054566; US 10/401,060 (Publication No. 20030195251) and US Pat. No. 10/949,908 (Publication No. 20050124668); or a pharmaceutically acceptable salt, ester or solvate thereof, The disclosures are hereby incorporated by reference in their entirety in each of the in the the the the the the the the the the

Wherein X is a carboxylic acid or carboxylic acid bioisostere; η is 0, 1 or 2;

Ri, Rla, R2, R2a, R3, R3a, R4 and ampule are "independently selected from fluorene and CV C6 alkyl, or R1 and R2, or R2 and R3 together form one or two selected from the group consisting of CrG alkyl. a substituent-substituted c3-C7 cycloalkyl ring; or a pharmaceutically acceptable salt or solvate thereof. In the formula (1), suitably, R1, Rla, R2a, R3a, R4 and R4a are hydrazine and R2 and R3 is independently selected from the group consisting of hydrazine and methyl, or Rla, R2a, R3a & "ruthenium", and R1 and R2 or R2 together with R3 form a C^C which is optionally substituted with one or two methyl substituents: 7 cycloalkyl ring. A suitable carboxylic acid bioisosteric system is selected from the group consisting of 121934.doc 200819123 tetrazolyl and oxadiazolone. Preferably, hydrazine is a carboxylic acid. In formula 3(), R', Rla, R2a, R3a, R4 and the ruler "is Η and R2 and R are independently selected from fluorene and methyl" or Rla, R2a, R3a & R4a are Η, and RWr2 or R2 and rl form a C4_C5m base ring, or when it is well-being,

Rl, RU, β, ^, RmH and R2 and R, a cyclopentyl ring, or when 11 is 1 'Rl, RU, V and R' are Η and R is a HRi, π, 0, R3a , U r3 forms a ring

Butyl ring, or when n is 2, R!, Rla, r2, R2a, r3, R3a, r4 and r4, h, or n are 〇' R丨, Rla, R2a, R3a, RjR4mR, R3 form a cyclopentane Base ring. The α2δ ligand also includes those described by the following formula (n):

Wherein: η is 0 or 1, R1 is hydrogen or Cl.C6 alkyl; r2 is hydrogen or alkyl; y is hydrogen or C--C6 alkyl; R4 is hydrogen or Cl_C6 alkyl; R5 is hydrogen or a base And R is hydrogen or CKC6 alkyl; or a pharmaceutically acceptable salt thereof, j3〇m' 酉 animal or solvate. In the embodiment, the ligand is a compound of formula (II) wherein ri is ◦C6 alkyl, R2 is methyl, R3-R6 is hydrogen and n is. In another embodiment, the <RTIgt;[theta]θ ligand is a compound of formula (II) wherein Ri is methyl, ethyl, propyl or n-butyl, R is fluorenyl, R3-R6 is hydrogen and nao or 1. When Μ is 121934.doc -11 - 200819123 methyl, R3-R6 is hydrogen and η is 〇, and R1 is suitably ethyl, n-propyl or n-butyl. When R2 is a methyl group, R and R6 are hydrogen and ^ is 1, and R1 is suitably a methyl group or a n-propyl group. The compound of formula (II) is suitably in the 3S, 5R configuration. The α-2-δ ligand also includes: [(1R,5R,6S)_6·(aminomethyl)bicyclo][3.2.0]hept-6-yl]acetic acid, 3·(1-aminoindole) -cyclohexylmethyl)_4Η·[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazolylmethyl)-cycloheptylmethane, (3S, 4S )-(i-aminomethyl_3,4-dimethyl-cyclopentylacetic acid, (1α, 3α, 5α) (3-amino-methyl-bicyclo[3·2·〇]g_3· Acetate, (3S,; 5R)-3-aminomethyl·5-methyl-octanoic acid, (3S,5R)_3•amino-5·methyl-heptanoic acid, (3S,5R)- 3-amino-5-methyl-decanoic acid, (38,511)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline and 2!5,48)_4-(3_fluorogangyl)proline and its pharmaceutically acceptable salts and solvates. For the purposes of the present invention, aj non-selective ligands include gabapentin (3S) , 5R)-3-feylmethylcyclopropyl-5-methyl-hexanoic acid, and the s_(+) enantiomer of pregabalin% aminomethyl-5-mercapto-hexanoic acid ( LyHca8). For the purpose of the present invention, ajq selective ligand, (3S, 4R, 5R)_3·amino-4,5-dimethyloctanoic acid, hereinafter referred to as "the" is described. Compound a ,,.

Selectivity was determined by calculating the binding affinity Ki value from the gabapentin bound to the calcium ion channel subunit membrane protein prepared from recombinant human α2δ-1 cells and recombinant human α2δ-2 cells. Substitution of [3H]-gabapentin 121934.doc -12- 200819123 The & value of binding to recombinant porcine ad-l and recombinant human add cell membrane corresponds to the binding affinity of the abalone ligand. The ratio of the respective K values of the two recombinant cell membrane proteins corresponds to the binding selectivity to ajq. The selectivity of the selective ligand to the aW-1 subtype is at least 30 times, 40 times, 50 times, 1 time, 500 times or 1000 times the selectivity of binding to the ^2 unit. The average & values of Compound A for recombinant ο^δ-ΐ and recombinant human cell membranes were 35 nM and 1670 nM, respectively, indicating a 48-fold selectivity for aj-l subunits. This method of administration is only required to administer a therapeutically effective amount of a selective ligand or a pharmaceutically acceptable salt thereof for the treatment of one or more of the conditions or conditions described herein. The therapeutically effective amount should generally be from about 1 mg to about 300 mg per kg of subject weight. A typical dose for a normal-weight adult subject should be from about 10 mg to about 5000 mg per day. In a clinical setting, a regulatory agency such as the US Food and Drug Administration ("FDA" may require a specific therapeutically effective amount. 9 In determining how to construct a method according to the invention for treating one or more of the conditions mentioned herein Or an effective amount or a therapeutically effective amount of the aj-1 selective ligand or a pharmaceutically acceptable salt thereof, the physician or veterinarian should generally - in view of the experience of the physician or veterinarian, public clinical research, examination The age, sex, weight and general condition of the person, the type and extent of the condition or condition being treated, and the subject's use of other medications, if any, take into account many factors. Dosages may fall within the ranges or concentrations stated above, or may vary outside of their range, i.e., below or above, depending on the needs of the individual subject and the severity of the condition being treated 121,934. Doc -13- 200819123 Depending on the specific treatment formulation used, it is determined that the appropriate dosage for a particular condition 2 is within the skill of a medical or veterinary technique. It can be initiated with a smaller dose of ajq ligand, which is the optimal dose for a particular subject. Thereafter, the dose can be increased slightly, and the sputum is increased until the final effect is reached in this case. For convenience, if necessary, the total daily dose can be divided into several parts and administered in the same day. 乂 乂 实 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她 她Methods of illness or condition: pain, such as acute pain, chronic pain, pain caused by soft tissue and peripheral injuries (such as acute trauma); also known as complex regional pain syndromes that reflect sympathetic dystrophy, herpes zoster Neuralgia, occipital neuralgia, trigeminal neuralgia, segmental neuralgia or intercostal neuralgia and other neuralgia; musculoskeletal pain, such as pain associated with stress, sprains and trauma (such as broken bones); central god (four) systemic pain , such as pain associated with spinal pain, spinal pain associated with spinal cord or brain stem injury; lower back pain, sciatica, toothache, myofascial pain syndrome • group, vulvar incision pain , gout pain, and pain caused by burns; deep and visceral pain, such as angina, muscle pain, eye pain, sedative pain, oral pain (such as toothache); abdominal pain and gynecological pain, such as dysmenorrhea , pain and pain associated with endometriosis; body-induced pain; associated with nerve damage and nerve root damage, such as associated with peripheral neurological disorders such as nerve compression, brachial plexus tears, and peripheral neuropathy Pain's pain associated with amputation#, second and neuralgia, neuroma or vasculitis; diabetic neuropathy, chemotherapy-induced neuropathy, acute cancer therapy, neuralgia and belt (4) meridian pain; atypical musculoskeletal pain and spider Omentum 121934.doc -14· 200819123 inflammation; occipital neuralgia, Α Α > restless group related hyperalgesia, idiopathic pain, pain with legs, pain associated with gallstones, cancer-related Neuralgia and non-God disease / i ^ ^ wide k A,,, two pain, phantom limb pain, temporomandibular pain and maxillary sinus pain:, and gastrointestinal disorders (such as ulcerative colitis, indigestion, = & Sex Mumps) related pain; postoperative m-mark pain and non-god, 'two 14 pain' such as pain associated with joint pain, myalgia, vasculitis and muscle fiber pain, #士,人/匕έ向向The therapeutic mammalian administration: a ligand, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt, and a method for treating a mammal selected from the group consisting of the following diseases A method of a disorder or condition of the group: an affective disorder, such as depression, or more specifically, a sexual disorder, such as a single-intermittent or recurrent f-depression depression, a severe unipolar recurrent severe depressive episode, And anti-depressive depression; seasonal affective disorder, conduct disorder and schizophrenic behavior, obsessive-compulsive disorder, stress-related physical illness and anxiety (such as generalized anxiety disorder, social anxiety disorder); stress disorder, including post-traumatic stress And acute stress disorder, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of a Αδ-ι ligand or a pharmaceutically acceptable salt thereof. See Diagnostic and Statistical manual 〇f Memal Dis〇rders, Fourth Edition (DSM-IV), American Psychiatric Association...

Association), Washington, D.C., May 1194, p. 435-page 436. Another preferred embodiment relates to a method of treating a condition or condition in a mammal selected from the group consisting of: a sleep disorder, such as insomnia (eg, primary insomnia, including psychophysiological insomnia) And idiopathic 121934.doc -15- 200819123 including leg restlessness syndrome secondary to insomnia

φ The method comprises administering to a mammal in need of such treatment a therapeutically effective amount of a ligand or a pharmaceutically acceptable salt thereof. Insomnia; secondary insomnia, including legs: symptoms, insomnia secondary to anxiety, muscle fiber pain and insomnia secondary to neuralgia, and, disease, REM sleep disorder, sleep breathing ^ another better The embodiments are directed to a method of treating a condition or condition selected from the group consisting of muscle fiber pain (FM). Muscle fiber pain is a chronic syndrome characterized by widespread pain, non-energy restorative sleep, mood disturbance, and fatigue. Usually with! ^^ Related syndromes include large bowel dysfunction and migraine. The success of treating FM with a single pharmacological agent was not significant and the results of clinical trials were disappointing. Based on the current understanding of the mechanisms and pathways involved in FM, the letter will require a variety of agents for the main symptoms of pain, sleep disturbances, mood disturbances and fatigue. Patients with muscle fiber pain are often sensitive to side effects of medications, which may be related to the disease

• Physiologically relevant features (Barkhuizen A, Rational and Targeted - pharmacologic treatment of fibromyalgia. Rheum Dis Clin N

Am 2002; 28: 261-290; Leventhal LJ. Management of fibromyalgia, Ann Intern Med 1999; 131:850-8) 〇 Although FM is a complex condition with multiple aspects, this complexity can be fully assessed (Yunus MB , A comprehensive medical evaluation 121934.doc -16· 200819123 of patients with fibromyalgia syndrome, Rheum Dis N Am 20〇2; 28:201417). The diagnosis of FM is usually recommended by the American College of Rheumatology classification criteria (Bennett RM, The rational management of fibromyalgia patients. Rheum Dis Clin N Am 2002; 28; 181-199; Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, etc., The American College of

Rheumatology 1990 criteria for the classification of fibromyalgia: Report of the Multicenter Criteria Committee. Arthritis Rheum 1990; 33: 160-72). Assessment, management, and pharmacological treatment of muscle fiber pain have been reviewed (Barkhuizen A, Rational and Targeted pharmacologic treatment of fibromyalgia. Rheum Dis Clin N Am 2002 ; Buskila D, Fibomyalgia, chronic fatigue syndrome and myofaoial pain syndrome. Current opinions in Rheumatology 2001; 13:117-127; Leventhal LJ,

Ann Intern Med 1999; 13 1:850-8; Bennett RM, The rational management of fibromyalgia patients. Rheum Dis. Clin N Am 2002; 28: 181-199 ί Yunus MB, A comprehensive medical evaluation of patients with Fibromyalgia syndrome, Rheum Dis N Am 2002; 28:201-217) Another preferred embodiment relates to a method of treating a condition or condition selected from the group consisting of epilepsy. Epilepsy is an intermittent disturbance of consciousness that can cause generalized paralysis during the period. The etiology of the condition is unknown, usually hereditary, 121934.doc -17- 200819123 and its symptoms are characterized by special sensation, smell or sensation, called "aura of consciousness" and the usual "aura". The term "epilepsy" is a group of transient episodes (seizures) associated with loss of mind or cognitive impairment, usually not always characterized by physical activity (痉挛) and sometimes autonomic hyperactivity, and Collective names for chronic sacral neurological disorders associated with abnormalities and excessive EKG disorders. Seizures in mammals, including humans, are classified based on the clinical manifestations of the attack and the EKG pattern. The type of seizure is often used to treat epilepsy. Types are classified, including gran mal (systemic tonic-k), absence epilepsy (small seizures), cortical local epilepsy, temporal lobe (psychomotor) epilepsy, and usually in adolescents A further embodiment of pediatric epilepsy. Another preferred embodiment relates to a method of treating a condition or condition selected from the group consisting of a restless leg syndrome (RLS). The restless leg syndrome is about 10% to 15 invasive. % of the general population and often unrecognized and misdiagnosed as common / paralyzed conditions. It is mainly clinically diagnosed and rarely requires multiple types of sleep assessment. It is primary and can be treated. The legs are not chronic, and the symptoms are exacerbated with age, and the most disabling feature is sleep-type insomnia. The feeling of discomfort of the legs is a characteristic (action) disorder, which is worse during periods of inactivity or rest during sitting or lying down. Individuals affected by RLS narrate these feelings as pulling and pulling Pulling, peristalsis, tingling and tingling, and sometimes it is a painful feeling that usually has an irresistible load on the moving leg. Sudden muscle twitching can also occur. The activity can temporarily relieve discomfort. Symptoms can also prevent falling asleep (sleeping insomnia 121934.doc 200819123). A variety of etiology of RLS have been proposed, including pregnancy, polyneuropathy and drug withdrawal. However, the common theme seems to be with the blood to the spinal nerve roots. = attenuation of inflammation of the relevant central nervous system. Changes in nerve conduction have also been reported, suggesting abnormalities in spinal cord function. Another preferred embodiment relates to a treatment selected from the group consisting of hot flashes A method of illness or condition. Hot flashes occur in male and female mammals, including humans. Females with low estrogen levels are prone to hot flashes. This deficiency can be attributed to radiation therapy that prematurely induces menopause. Or may be caused by treatment with a specific drug such as anti-estrogen therapy or certain drugs (such as Tambuxifen (Nolvadex). In addition, hot flashes may be menopause or postmenopausal, medical and cancer. With regard to men, androgen deprivation can be the cause of hot flashes. Similarly, hormonal imbalance can be induced by drugs (such as LUpron (LeUpr〇iide) and Zoledex). G〇serelin is induced by radiation. For example, surgery on both sides of a sputum adenoid or testicular cancer can also cause hot flashes in men. The above methods are also collectively referred to herein, the method of the present invention. π, another preferred embodiment relates to a method of treating a condition or condition selected from the methods of the invention, comprising administering to a mammal comprising a human a therapeutically effective amount of a cxj-1 ligand or a pharmaceutically thereof thereof An acceptable salt wherein at least one adverse reaction is avoided or reduced. Another embodiment relates to a method of providing neuroprotection for brain damage caused by stroke, cardiac arrest, Alzheimer's disease, and other related conditions. Another embodiment relates to any one of the above methods, wherein an αβ-Ι ligand or a pharmaceutically acceptable salt thereof is administered to a mammal comprising a human or a pharmaceutically acceptable salt thereof for use in the treatment of the above method Any two or more of the comorbid conditions and conditions mentioned in any of them. Another embodiment relates to any one of the methods for the treatment described above (any of the methods of the invention) comprising administering to a mammal comprising a human aj-l selective ligand, wherein the The ligand is (38,411,511> 3-amino-4,5-dimethyloctanoic acid or a pharmaceutically acceptable salt thereof. Another embodiment relates to avoiding or reducing adverse reactions of mammals including humans. Included is the administration of aj-l selective ligand or a pharmaceutically acceptable salt thereof. Terms, adverse reactions include, but are not limited to, dizziness, fatigue, movement disorders, sedation, somnolence, fatigue, nystagmus , weight gain, vomiting, peripheral edema, indigestion, tremor, nervousness, forgetfulness, inhibition, convulsions, myalgia, rhinitis, diplopia, amblyopia, discomfort, high blood pressure, flatulence, most often described as being by the body Purple healing, joint pain, dizziness, increased exercise, reduced or absent reflexes, hyperreflexia, hostility, and visual abnormalities caused by trauma-induced contusion. The term "avoid" as used herein means the selective coordination of α2δβ1. Body Mammals do not produce an adverse reaction. The term "π reduction" as used herein means that the frequency or incidence of one or more adverse reactions has been reduced by at least 10%. Another embodiment relates to about 10 mg to 5000 per day. An amount of α2δ_1 selective ligand of mg. Another embodiment relates to α2δ_丨 selectivity of a liquid or solid dosage form of 121934.doc -20- 200819123 ligand. Contains (Xj-l selective Administration of a dosage form of a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof can be administered orally, parenterally, subcutaneously, intravenously, intramuscularly, intramuscularly, intravitally, by nasal mu Intraluminal or intravesical instillation, intraocular, intraarterial, intralesional, intraventricular, or by administration to the epidermis, sublingual or mucosal. Another κ application is related to a selective coordination of aj·1 Pharmaceutical composition of a pharmaceutically acceptable carrier. The term, pharmaceutically acceptable means refers to the pharmacological and toxicological point of view regarding composition, formulation, stability, safety and bioavailability. Said that they are acceptable to mammals including humans. Sexual and/or Substance A pharmaceutical composition of an alpha beta-1 ligand or a pharmaceutically acceptable salt thereof is prepared by formulating the active compound together with a pharmaceutical carrier in unit dosage form. Some examples of unit dosage forms For lozenges, capsules, pills, powders, aqueous and non-aqueous oral solutions and suspensions, transdermal solutions and parenteral solutions, which are packaged in a container containing one or greater number of unit doses and which can be subdivided into individual doses. Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as crace and sucrose; starches such as corn starch and horse starch starch; cellulose derivatives such as sodium carboxymethylcellulose, Ethyl cellulose, decyl cellulose and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, eucalyptus oil, corn oil and cocoa Oil; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline and phosphate buffer solution; and commonly used in pharmaceutical formulations Other compatible materials in the 121934.doc -21. 200819123 quality. The composition to be used in the present invention may also contain other components such as a coloring agent 'flavoring agent and/or a preservative. These materials, if any, are usually used in relatively small amounts. The compositions, if desired, may also contain other therapeutic agents which are conventionally used to treat the condition or condition being treated.

The percentage of active ingredient in the above compositions may vary over a wide range, but for practical purposes it is preferably present at a concentration of at least 10% in the solid composition and at least 2% in the original liquid composition. Most desirable, and the mouthpieces are those compositions in which a higher proportion of active ingredient is present, e.g., up to about 95% of the active ingredient. The ad-i ligand or a pharmaceutically acceptable salt thereof can be administered in any form. Preferably, the administration is in unit dosage form. The unit dosage form of the ligand to be used in the present invention or a pharmaceutically acceptable salt thereof may also be included; the condition or condition in which the ligand is or the condition to which the aj-1 ligand is administered Or other treatments in the treatment of a condition or condition secondary to the disease: Portions Some of the compounds used in the methods of the present invention are capable of further forming pharmaceutically acceptable salts, including but not limited to, acid addition salts and/or base addition salts. These acid addition salts are formed from basic compounds which are formed from acidic compounds. All such forms are within the scope of the compounds which are suitable for use in the methods of the invention. The pharmaceutically acceptable acid addition salts of the test compounds suitable for use in the process of the invention include the following non-toxic salts: inorganic acids such as hydrochloric acid, acid breaker, dish acid, sulfuric acid, hydrogen acid, Hydrogen acid, hydrogen sulphuric acid, sub-121934.doc -22- 200819123 sulphuric acid and its analogues; and organic acids, such as aliphatic monocarboxylic acids and diweiric acid, phenyl substituted succinic acid, hydroxy succinic acid , burnt diacid, aromatic acid, aliphatic rhein and aromatic sulfonic acid. Therefore, the salts include sulfates, pyrosulfates, hydrogen sulfates, sulfites, bisulfites, nitrates, acid salts, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates. Salt, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, octoate, isobutyrate, oxalate, malonate, succinate, octanedioate, Sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, mercaptobenzoate, dinitrobenzoate, neighbor Phthalate, besylate, tosylate, phenylacetate, citrate, lactate, malate, tartrate, guanidinium and the like. Also included are salts of amino acids such as arginine and its analogs, and gluconate, galacturonate (see, for example, Berge SM, pharmaceutical Salts ", J. 〇f pharma. Sci , 1977; 66:1) 0 _ an acid addition salt of a basic compound suitable for use in the process of the invention is obtained by contacting a compound of the free form with a desired amount of the desired acid in a taro manner to produce a non-sulfonium salt. To prepare. The compound of the free form can be regenerated by contacting the thus formed acid addition salt with a base in a conventional manner and isolating the free base form of the compound. The free base form of the compound prepared according to the process of the invention and its individual acid addition salt forms differ slightly in certain physical properties such as solubility, crystal structure, hygroscopicity and the like, but otherwise free base forms The compounds and their individual acid addition salt forms are equivalent for the purposes of the present invention. 121934.doc -23- 200819123 A pharmaceutically acceptable addition salt of an acidic compound suitable for use in the method of the invention can be obtained by reacting a compound of the free acid form with a non-toxic metal cation (such as a metal cation or an alkaline earth metal cation) Or an amine (especially an organic amine) is contacted to prepare. Examples of suitable metal cations include sodium cation (Na+), potassium cation^+^ magnesium cation (9)^+^ calcium cation^^) and the like. Examples of suitable amines are N,N,-dibenzylethylenediamine, chloroprocaine, oxime, diethanolamine, dicyclohexylamine, ethylenediamine, N-methyl reduced glucosamine And procaine (see, for example, Berge, supra, 1977). The base addition salt of an acidic compound suitable for use in the process of the invention can be obtained by freely reacting the compound in free acid form with a sufficient amount of the desired base. Contact to produce salt to make a shave. The free acid form of the compound can be contacted with the acid by conventional means, and the free acid of the compound can be isolated to be suitable for use in the free acid form of the compound of the present invention and its individual salt forms such as Some of the physical properties of solubility, crystal structure, hygroscopicity, and the like are slightly different 'but in other respects such salts and individual free acids are equivalent for the purposes of the present invention. The grasses suitable for use in the method of the present invention may be in the form of an unsolvated form and a glutenated form (including a hydrated form) in the presence of blood ii = (r hydrated form) and non-solvent. The forms are equivalent and are intended to be within the scope of the invention. It is suitable for some of the methods of the present invention, and the center of each of the one or more solids may exist in the r configuration or the s configuration. Any diastereomeric or diastereomeric forms of the further salts can be obtained by the use of a ligand or a pharmaceutically acceptable method thereof, 121934.doc -24-200819123, enantiomeric or epimeric forms, and mixtures thereof. In addition, certain forms of compounds suitable for use in the process of the present invention exist, such as the entgegen (E) isomer rren(z) isomer of the alkene. The method of the present invention may use any of the ligands, or any of its pharmaceutically acceptable salts, in the cis, trans, omnidirectional, and reverse directions.

Wgegen (8) or Zusammen (z) isomers, and mixtures thereof.

Certain compounds which are in the process of the invention may exist in two or more overlapping isomeric forms. The tautomeric forms of such compounds can be exchanged, for example, by dilute alcoholization/deanolization or the like. The method of the present invention may use any tautomeric form of the __! ligand or a pharmaceutically acceptable salt thereof, and mixtures thereof. For the preparation of pharmaceutical compositions from the ligands of the invention, the pharmaceutically acceptable carrier can be either solid or liquid. Solid form preparations include powders, preparations, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances which can also act as diluents, flavoring agents, binders, preservatives, lozenge disintegrating agents or encapsulating materials. In the powder, the carrier is a fine powdery solid mixed with the finely divided active component. 3 In a tablet, the active ingredient is mixed with the carrier having the necessary adhesive properties in a suitable ratio and compacted to the desired shape and size. The powders and lozenges preferably contain from 5% or 10% to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, strontium, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, carboxymethylcellulose, and sputum. , cocoa butter and the like. The term "formulation" is intended to include a formulation of an active compound with an encapsulating material as a carrier, the encapsulating material providing an active component (with or without other carriers) loaded therein. a capsule surrounding the agent, the carrier thereby being associated with the active ingredient. Similarly, a flat gel and a buccal agent are included. Lozenges, powders, capsules, pills, cachets and buccal preparations can be used as suitable A solid dosage form for oral administration. For the preparation of a suppository, a low melting wax such as a mixture of a fatty acid glyceride or a cocoa butter is first melted' and the active ingredient is homogenized by stirring.

Dispersed in it. The molten homogeneous mixture is then poured into a mold of suitable size, allowed to cool, and thereby solidified. Liquid form preparations include solutions, m floats and emulsions such as water or water, alcohol solutions. For parenteral injection, the liquid preparation can be formulated as a solution in an aqueous solution of polyethylene glycol. Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding suitable coloring, flavoring, stabilizing and thickening agents as needed. An aqueous suspension suitable for oral administration can be obtained by using a fine powdery active component with a viscous material such as a day, or a synthetic gum, a resin, a methylcellulose, a sodium methacrylate, and a suspension agent thereof. It is prepared by dispersing in water together. It also includes a liquid form preparation intended for use in a buffer: solid solution. The liquid forms include solution, suspension 2: agent, #嶋 active component, may contain Coloring agents, flavoring agents, buffers, artificial and natural sweeteners, dispersing agents, months!: ~solvents and their analogues. " Containing a good early dosage form. In this form, the preparation is subdivided into fields. Unit dosage of the active ingredient of the unit. The unit dosage form can be a package of 121934.doc -26 - 200819123, which contains discrete quantities of preparations such as packaged tablets, capsules and powders in vials or ampoules. The unit dosage form can be a single capsule, lozenge, lozenge or buccal preparation, or it can be any such dosage form in a sealed form. Depending on the particular application and the effectiveness of the active ingredient, the unit dosage formulation Active component The quantity can be varied or adjusted within the range of O.i 111 § to 1 g. Medical use

: The drug can be administered 3 times a day, for example, in the form of a capsule of 100 mg 4 300 mg. If desired, the composition may also contain other compatible therapeutic agents. The compound used in the pharmaceutical method of the present invention in a therapeutic use is administered at an initial dose of from about 1 mg/kg to about 100 mg/kg per day. A daily dose range of from about 1 mg/kg to about 100 mg/kg is preferred. However, the dosage will vary depending on the needs of the patient, the severity of the condition being treated, and the compound employed. Determining the appropriate dosage for the dosage regimen is within the skill range of the art. The treatment is initiated with a smaller dose that is less than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect is achieved in these circumstances. For convenience, the total sputum dose can be divided into several portions and administered portion by day during the day if necessary. The term "treating" as used herein refers to a process of preventing or preventing the progression or prevention of a condition or condition to which the term is applied, or preventing one or more symptoms of the condition or condition. . As used herein, the term "treatment" refers to the treatment behavior, where "treating" is defined as just above. 0 treatment "utilization should be understood when describing the invention and using Used interchangeably. In the embodiment, the term ''uses,',,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The treatment includes mammals of humans to treat a disease or a disease as described herein. The phrase "low carbon alkyl, means a direct bond or a branched bond having (1) carbon atoms. 'and it includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, r-butyl, non-Zeng-butyl-n-pentyl, n-hexyl and Its similar group.

The term "alkyl group" as used herein, unless otherwise specified, includes a valence hydrocarbon group having a linear, branched or cyclic moiety or a combination thereof. Examples of &quot;hide&quot; include, but are not limited to, ) methyl, ethyl, propyl, isopropyl, butyl 'isobutyl, second τ and tributyl, pentyl, hexyl, heptyl, ethyl butyl, j propyl, ring Butyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and the like. The mountain is not otherwise specified, otherwise the cycloalkyl group is a saturated monovalent carbocyclic group containing 3 to 7 carbons. Select _ | ^ ^ propyl, hydrazine, J, pentyl, cyclohexyl and cycloheptyl. In the 施K example, the present invention relates to the selective coordination of α2δ-1 into S, 4R, 5R)-3-Amino-4,5-dimercaptooctanoic acid (hereinafter referred to as &quot;Chemical A&quot;) or a pharmaceutically acceptable salt thereof for treatment; the chemical & Prepared by the following method: W+((R)-3·methyl-hexyl)-4·phenyloxazolidinone is produced under _ 3 ' 'under nitrogen, to anhydrous tetrahydrofuran (THF) ) (150 mL) Anthraquinone copper (1) dimethyl sulfide complex (13 34 g, 64.87 mmol) was added with emulsified propyl magnesium 2 Μ ether solution (64.87 mL, 129.7 121934.doc -28-200819123 mmol) and stirred. 20 minutes. (R)-3-but-2-enyl-4-phenyl-oxazole bite-2·one (15.0) added to THF (60 mL) at -15 °C for 15 min. g, 64·87 mmol) and allowed to slowly warm to room temperature over 4 hours. The mixture was cooled to 0 ° C and quenched with saturated ammonium chloride solution. The suspension was extracted into diethyl ether. After washing, it was washed with brine and dried with EtOAc EtOAc EtOAc (EtOAc). (m5 6H) 1.2(m, 3H) 1.6(s? 1H) 2.0(m? 1H) 2.7(dd, J=16.1,8·5 Hz, 1H) 3.0 (dd, J=15.9, 5·4 Hz, 1H) 4.3 (dd, J=8.9, 3.8 Hz, 1H) 4·7 (t, J=8.9 Hz, 1H) 5.4 (dd, J=8.8, 3.9 Hz, 1H) 5.4 (dd, J=8.8, 3.9 Hz, 1H) 7.3 (m, 5 H). MS, m/z (relative intensity)·· 276[M+1H, 100%]. (R)-3-((2R,3R)-2,3- Dimethyl-hexyl)-4-phenyl-oxazole -2- ketone was added via cannula to a solution of sodium bis(trimethyldecane) guanamine (16.2 g, 88·3 mmol) in 1 M THF at -78 °C (R)-3-((R)- A solution of 3-methyl-hexyl)-4-phenyl-oxazolidine-2-one (18.7 g, 67.9 mmol) in 70 mL of dry THF. The resulting solution was stirred at -78 ° C for 30 minutes. Iododecane (48.2 g, 339.5 mmol) was added and stirring was continued at -78 °C for 4 hours. The reaction was quenched with saturated ammonium sulphate solution, extracted into CH.sub.2 C.sub.2 and washed with &lt The solution was dried over MgSO4, EtOAc (EtOAc) MS, m/z (relative intensity): 4 NMR (400 MHz, CDCI3) δ ppm 0.8 (t5 J=7.0 Hz? 3 H) 0.9 (d? J = 6.6 Hz5 3 H) 1.0 (d, J=6.8 Hz , 3 H) 1.0 (d, J=8.5 Hz, 1 Η) 1·1 (m, 1 H) 121934.doc -29- 200819123 1.4 (m,1 Η) 1·7 (m,1 Η) 3.7 ( m,1 Η) 4·2 (dd,J=8.8, 3·4 Ηζ,1 Η) 4·6 (t, J=8.7 Ηζ, 1 Η) 5.4 (dd, J=8.7, 3·3 Ηζ, 1 Η) 7·2 (m, 2 Η) 7.3 (m, 3 Η). MS, m/z (relative intensity): 290 [M+1H, 100% (4S, 5R)-4,5-diphenyl-oxazolidine-2-one is equipped with an overhead stirrer, thermocouple And a 5 L round bottom flask with a distillation head fed with 550 g (2.579 mo)) (lR, 2S)-diphenyl-2-aminoethanol, 45 7 g (3·868 mo, 1.5 equivalents) of diphenyl carbonate Ester, 18 g (〇.258 mo 〇·1 equivalent) of NaOEt and 3·5 L of toluene in 1 mL of EtOH. The reaction was heated until the internal temperature reached 90 C and the EtO Ή steaming started. The reaction was refluxed until the internal temperature reached 110 ° C (7 hours). For each 500 mL of solvent removed via a distillation head, 500 mL of toluene was added to the reaction. A total of approximately 1.6 L of solvent was removed. The reaction was allowed to cool to room temperature and then was taken on a 3 L thick fritted funnel at 2 psig N2. Nitrogen gas was blown overnight through a cake to obtain 580 g (94% yield) of the title compound··1HNMR (DMSO) 7·090-6.985 (m, 6H), 6·930-6·877 (m, 4H), 5 ·900 (d,1Η, J = 8-301),5·206 (d5 1H,J=8.301) 〇(4S,5R)-3-((E)_2-methyl-hex-2-enyl fluorenyl -4,5-Diphenyl-oxazolidine-2-one (Alternative A) A reflux condenser was fitted to a 20 L jacketed reactor. The reactor was fed with 1100 g (4.597 mol) of (4S,5R)-4,5-diphenyloxan-2-one, 884 g (6.896 mol) of (E)-2-mercapto-2- Pentenoic acid, 1705 g (6.896 mol) EEDQ, 48 g (1.149 mol) LiCl and 16 L EtOAc. The reaction mixture was heated to 65 ° C for 200 minutes. The reaction mixture was allowed to cool to room 121934.doc -30-200819123 and extracted 3 times with a 3·5 L 1 N HCl aliquot. The combined aqueous extracts were filtered to give a white solid. The recovered white solid was further added to the organic layer. The distillation head was fitted to a 2 L reactor and the organic layer was distilled to successively remove: 13.5 L EtOAc, then 5 L heptane was added to the reactor; 5 L EtOAc / heptane, then 5 B Heptane was added to the reactor; and 2·7 L of EtOAc/heptane, followed by the addition of 2.7 [heptane] to the reactor. The contents of the reactor were cooled to 25 ° C and the resulting mixture was filtered under 5 psig of nitrogen while washing with 4 L of heptane. The wet cake was dried overnight under a pressure of nitrogen to give 1521 g of the title compound: 111 </ RTI> </ RTI> 411 (01^0) 7.12 - 6.94 (m, 8H), 6.834 (dd, 2H, J = 7.8135 1.709), 6.060 ( d,1H, J=8.057),6.050 (td,1H,:Γ=7·447,1.221), 5.795 (d,1H, J=8.057),2.119-2.064 (m,2H),1·778 (d , 3H, J = 0.997), 1_394 (m, 2H), 0.874 (t, 3H, J = 7.324); analytical calculations: C, 75·62; Η, 6·63; N, 4.01. Found: C, 75·26 ; Η, 6.72; N, 3.95 〇(4S,5R)-3-(2-(E)-methyl-hex-2-enyl)-4,5- Diphenyl-oxazolidine-2-one (alternative B) in 溶液C under a solution of (E)-2-methyl-2-hexenoic acid (6.0 g, 47 mmol) in 250 mL THF 16.3 mL (117 mmol) of triethylamine was added followed by 5.8 mL (47 mmol) of trimethylacetamidine chloride to give a thick suspension. The mixture was stirred at 0 ° C for 1 hour, at which time 2.0 g (47 mmol) of a gasified chain was added in one portion, followed by 1 〇〇g (42 mm 〇l) (4S, 5R)-4,5 in 4 batches. - Diphenyl-2-oxazolidinone. Stirring was maintained throughout the addition of solids. The resulting mixture was stirred at 0 C for 1 hour, then was stirred at ambient temperature for 129. s. The residue was partitioned between EtOAc / water. To the residue was added 1 mL of methyl tertiary butyl ether (MTBE) and the mixture was carefully warmed under vortex. The warm syrup was filtered to give the title compound: NMR (CDC13) δ 7.12 (m, 3 Η), 7.07 (m, 3 Η), 6.94 (m, 2Η), 6.84 (m, 2Η), 6.17 (m, ιΗ), 5·89 (d, /=7·8 Hz, 1H), 5·68 (d, J=7.8 Hz, 1Η) ), 2·18 (m, 2H), 1.92 (s, 3H), 1.50 (m, 2H), 0·96 (t5 / = 7.6 Hz, 3H) 〇 (48, 5 magic -3- (( 2,, and 3,3,3-didecyl-hexyl)-4,5-diphenyl-oxan-2-indole, equipped with an addition funnel, mechanical stirrer, and nitrogen inlet to 22 L 4 neck On a round bottom flask, the system was purged with nitrogen for 1 hour. THF (6 L) was fed to the flask, followed by 1236 g (6.01 mol) of CuBr.S(CH3)2 and 364 g (8.59 mol) of UCl. The reaction was stirred at ambient temperature for 15 minutes. The solution was allowed to cool to -35 °C and the internal temperature of the reaction mixture was maintained at _25 ° (:3:3. The solution was stirred for 1 hour after the completion of the addition of CHsMgCl. (4S,5R)-3-((E)-2-methyl-hex-2-enyl)- 4,5 was added as a solid in one portion. - Diphenyl acetophenone-2-one (1.0 0 Kg, 2·86 mol) and the reaction was stirred at -40 ° C for 4 hours. The reaction mixture was transferred to another equipment equipped with a mechanical stirrer, a transfer tube, a vacuum line and cooled in an ice water bath over 2 hours. 4 L 1··1 acetic acid··THF solution in a 22 L flask. Stir the stopped solution for 30 minutes and then 4 L in saturated NH4C1 aqueous solution 2 Μ 121934.doc -32- 200819123 NH4〇H and 2 L water dilution. The two phase mixture was stirred for 15 minutes and the phases were separated. The organic phase was washed 4 times with an aliquot of 4 L 2 M NH 4 〇H solution. No blue was observed in the wash or organic phase. The organic phase was diluted with 8 L of water and the THF was distilled off until the internal temperature of the distillation pot reached % π. The suspension was cooled to ambient temperature and filtered. The solid was washed with 4 L of water and suction dried to afford 868.2 g of milky white This product was recrystallized from 2 L of 95:5 heptane: toluene to give the title compound: NMR (CDC13) 7·12-6.85 (m) , 10H), 5.90 (d, lH, J = 8.06Hz), 5.72 (d, lH, J = 7.81), 3.83_ 3·76 (m, 1H), 1.9 5-1.89 (m,1H),1.35-1.31 (m,1H), 1.11 (d,3H,J = 6.84), 1.10-0.95 (m,3H),0·92 (d,3H,J=6.59) , 〇·76 (t, 3H, J=7.20) MS (APCI) Μ+1=366·2. (2R,3R)-2,3-Dimercapto-hexan-1-ol A solution of LAH (95.9 mL, 95.9 mmol) in 1 M THF was added to THF (300 mL) at -78 ° C under nitrogen. (R)-3-((2R,3R)-2,3 -.monomethyl-hexanyl)-4 -benyl-σ 嗤 bite-2 -嗣 and disturbed at the temperature Mix for 3 hours. Water was added dropwise to stop the excess LAH and the solution was poured into a mixture of ice and diethyl ether. The mixture was extracted into diethyl ether, washed with water and dried over EtOAc. The solution was concentrated and then an excess of hexane was added. The resulting white precipitate was filtered and washed with hexane. The filtrate was concentrated to give the title compound (5.05 g, 1% yield): NMR (400 MHz, CDC13) δ ppm 0.9 (m, 9 H) l. 〇 (d, 1 = 6.8 Hz, 1 H) 1.1 (m5 1 H) 1·2 (m5 3 Η) 1·6 (m, 2 H) 3.4 (m. 1 Η) 3.6 (m5 1 H) 〇(2R,3R)-2,3- Dimethyl-hexanal 121934.doc -33- 200819123 Pyridinium chlorochromate (27.35 g, 126·9 mm〇1) and neutral alumina (96 g per gram of chlorochromic acid) under helium The pyridinium 3·5 g) was stirred in anhydrous dichloromethane for 25 hours. (2R,3R)_2,3-dimethylhexanol (5·〇g, 38·46 mm〇1) added to dichloromethane (6 mL) and the obtained dark slurry was Stir under chamber μ for 3 hours. The slurry was passed through a small amount of silica dioxide dissolved in excess dichloromethane. Evaporation of the solvent gave the title compound (4.1 g, 84% yield): NMM 400 MHz, CDC 13) δ ppm 0.8 (m, 3 φ H) 〇·9 (d, J=6·6 Hz, 3 H) 1.0 (d, J = 6.6 Hz, 3 Η) 1·2 (m, 4 H) U (m, 1 Η) 2·2 (m, 1 H) 9.6 (s, 1H). (S) N-(l-ethyl), amine oxalate! 985, 41, 3455] 20 g (166 mmol) anhydrous magnesium sulfate, 60 mL dichloromethane, 9.63 g (80 mmol) (S A mixture of a-methylbenzylamine and 11 g (80 mmol) of anisaldehyde was stirred at room temperature under nitrogen overnight. The mixture was filtered through a pad of anhydrous MgS04 washed with 14 mL of EtOAc. The filtrate was cooled under nitrogen • to 0 C and 20_8 g (121 mmol) was added to make 85% m-chloroperbenzoic acid (slightly exothermic) of the slurry in 40 mL of dichloromethane. Stirring was continued for 1, 5 hours, at which time the cooling bath was removed and stirring was continued for 2.5 hours. The mixture was filtered and the solid was washed with 50 mL of dichloromethane. The filtrate was washed with 100 mL of 0.5 Μ sodium sulfite, 100 mL of 〇·5 Μ potassium carbonate, 1 〇〇 mL, water, dried over anhydrous sodium sulfate, filtered and removed by rotary evaporation (bath temperature &lt; 3 〇 ° C) Solvent. The residue was dissolved in 100 ml of dry ethanol, then cooled to EtOAc and EtOAc (EtOAc) The mixture was stirred overnight at ambient temperature. Dioxane methane (150 mL) was added to precipitate excess hydroxylamine hydrochloride 121934.doc -34 - 200819123 and allowed to stand for 2 hours, then filtered and concentrated. The resulting oil was dissolved in 50 ml of water and washed twice with 50 mL of diethyl ether. The aqueous layer was poured into 5 mL of saturated sodium bicarbonate to give a solution of pH 7-8 (and more sodium bicarbonate was added if necessary) to give a white solid, which was extracted four times with 5 〇 mL of diethyl ether. The squamous layer was combined and washed with brine, dried over anhydrous sodium sulfate, and filtered, and then filtered and evaporated to </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The resulting white solid was collected by filtration and dried <RTI ID=0.0> MS (ion mode: APCI) m/z = 179 [M+H]. ! H-NMR (CD3〇D) 7.5-7.4 (m, 5H), 4.51-4.46 (q,1H,J=4.2),1·66·1·64 (d, 3H, J=4.2). [[(2R,3R)-dimethylhexyl (hexylidine)]-2-(S)·methylbenzylamine]v-oxide [Overton,/· C/rew· jPer/τίιι 2&gt;aiis· 2 1991, 1041] (2R,3R)-2,3-dimethylhexanal (3 33 g, 26·4 mmol), 6.00 g (26.4 mmol) (S)-N in 40 mL of di-methane - (1·Phenylethylamine oxalate and 4·0 mL (29 mmol) of triethylamine were stirred overnight at room temperature. The reaction solution was washed with 25 mL of saturated sodium bicarbonate solution and 25 mL of brine. Drying over anhydrous sodium sulfate, filtered and EtOAc EtOAc EtOAc EtOAc. +H].h-NMR (CDC13) 7.43-7.24 (m, 5H),6·60-6·55 (m,1H),5.00-4.93 (m,1H),3·09-3·02 (m , 1H),1·79-1·76 (m,3H),1.63-1.57 (m,1H),1·37·0·77 (m, llH)〇3-(8)-[1·(Κ ), 2-(Κ)·dimethylpentyl]-2-(S)-l-phenethyl buck bite-6-嗣121934.doc -35- 200819123 will be 50 at 0 °C [2-(R),3_(R)-Dimethylhexylene]-2-(S)-methylbenzylamine N-oxide in mL dichloromethane (4·30 g, ι 74 1^11 〇1) 63 mg (0.17 mmol) of zinc triflate was treated with 7·6 mL (35 mmol) of 1-(t-butyldimethylsilyloxy)-1-methoxy-ethylene, stirred for 5 minutes and then The cooling bath was removed. Stirring was continued overnight at ambient temperature. The solution was washed with water and brine, concentrated to an oil, and then dissolved in 45 mL THF. 2 N aqueous hydrochloric acid (45 mL) was added and the mixture was (9) It was heated for 2 hours. The cooled mixture was diluted with 50 mL of EtOAc. EtOAc evaporated. Chromatography with hexanes gave an oil which crystallised from 20 ml of hot <RTI ID=0.0></RTI> </RTI> </RTI> <RTIgt; W-NMR (CDCls) 7.35-7.24 (m? 5H)5 4.03-3.98 (q5 1H? J=4.2)? 3.38- 3.32 (m,1H), 2.40-2.34 (dd,1H,:ί=4· 5 and 11.1), 2·08-2·02 (dd. 1H, J=5.2 and 11.1), 1.63-0.77 (m, 18H). (3S,4R,5R)-3-Amino-4,5-dimethyloctanoic acid 3-(8)-[1-(11),2-(11)-dimethylindenyl]-2-( 8) Small phenethyl]isoxanthine-5-one (2.26 g, 7.8 mmol) was hydrogenated with 0. 8 g of 20% palladium on carbon in 100 mL of ethanol for 17.8 hours. The mixture was filtered and concentrated to a white solid. crystalljjjjjjjjjjjj MS (ion mode: APCI) m/z = 188 [M+H]. 1H-NMR (CD3OD) 3·47·3·42 (m, 1H), 2.45-2.40 (dd, 1Η, j=2〇 and ΐ〇·5), 2.24-2.20 (dd, 1Η, J = 6.5 and 10·5), 1·63, 1·〇2 (m, 6H), 0.96-0.88 (m, 12H) 〇121934.doc -36-200819123 The following description of the present invention is provided by way of example and not limitation. The following methods, results and overviews are presented as α2δ-1 selective ligands, compound Α and α2δ non-selective ligands, (3S,5R)-3-aminomethyl-6-cyclopropyl-5- Examples of in vitro receptor binding and behavioral effects of thiol-hexanoic acid (hereinafter referred to as "Compound B") (as described in WO 00/076958) 〇

Method Receptor Binding: The previously constructed 293 cells stably expressing recombinant porcine α2δ-1 and human α2δ-2 subunits (Gong HC et al., (2001) J. Membr. Biol. 184: 35-43) at T -75 flasks were grown under normal cell culture conditions (RPMI-1640 medium containing 10% FBS, 200 pg G418 and 1% penicillin/streptomycin at 37 ° C, 5% CO 2 ) The cells were collected at this point until 90% confluence was reached. The cells were suspended in ice-cold 5 mM Tris/5 mM EDTA buffer containing PMSF (0.1 mM) and protease inhibitor cocktail (Roche), pH 7·4 (ΤΕ buffer) and allowed to stand on ice for 30 minutes. . Using 20 pulses by ultrasonic treatment, the cells were disrupted by 40-50 cycles and then centrifuged at 3000 xg for 10 minutes. The supernatant was transferred to a new tube and centrifuged at 50,000 xg for 30 minutes 121934.doc -37-200819123. The resulting pellet was resuspended in 10 mM HEPES buffer (pH 7.4) and homogenized, followed by storage at -80 °C. The protein concentration is measured by well-known methods. The [3H]-gabapentin SPA binding assay was performed in a Costar 3632 96-well, bottom transparent assay plate using wheat germ agglutinin coated polyethylene toluene proximity assay (SPA) beads (Amersham Biosciences). Α-2-δ-l or α2δ-2 membrane proteins (10-20 pg protein per well) and SPA beads (0.5 mg per well) with 30 nM [3H]-gabapentin (60 Ci/mmol; by Pfizer Global Research and Development Michigan Labs synthesis) was mixed in 10 mM HEPES/10 mM MgS04 assay buffer (pH adjusted to 7.4 using KOH). The final pore volume was 200 μΐ and non-specific binding was determined in the presence of 10 μΜ unlabeled (cold) pregabalin. A mixture containing membrane proteins and SPA beads and [3H]-gabapentin was incubated overnight (16-20 hours) at room temperature and the plates were then counted on a Wallace Trilux 1450 Microbeta scintillation counter. The curve fitting and IC5G values were calculated using the 4 parameters of the GraphPad Prism 4·0 software, and the Ki values were determined using the previously determined KD values of α2δ-1 (KD=41 nM) and (χ2δ-2). The Kd value (KD = 146 ιιΜ) and the equation of Cheng and Prussoff (Biochem Pharmacol (1973) 22 (23): 3099-3 108) were determined. Behavioral test animals: Male, C57BL/6J mice (Jackson Laboratories, Bar Harbor, Maine) was used for vogel clash, motor activity, and accelerated rod testing. Animals aged 5 weeks were accepted and acclimated to the experimental equipment for 1 week prior to testing. 121934.doc -38 - 200819123 3 weeks old male DBA/2J mice (jackson Laboratories, Bar

Harbor, Maine) to assess anticonvulsant activity. The mice were placed in a temperature/humidity controlled room in each of the isolation chambers 5 for 12 hours, 12 hours, and dark time (6: 〇〇 AM on). Food and water were freely available. All procedures were performed in accordance with the laboratory animal management and use guidelines, approved by the PGRD Animal Use Committee.

Vogel device: 10 test device consists of 12 modular operating chambers (Coulboum

Instruments). The front and back sides of the test chambers are made of transparent Plexiglas. Cover the front door to reduce distraction from the inside of the test chamber. The back faces the wall, away from the flow of the test room (fl〇w 〇f traffic) and is not covered for observation. All chambers have a stainless steel grid and are measured at 7x7x12 inches. Each test chamber was made through a transparent plexiglas and the internal chamber was measured to be 6.75χ3·5χ1·5吋. Reduced chamber space limits animal activity and directs behavior to the side of the chamber, above the floor • I.5吋 opening. A modular optical meter installed at the opening is used to measure foraging. The water bottle is connected to the outside of the cage and the drinking water pipe extends through the module into the opening. The fortified system consists of a mixture of evaporated milk: water 1:! Introduce the ^ beam so that it traverses between the two glass rods located adjacent the top end of the drinking water pipe. Each time the animal is eating a drinking water pipe, the beam is interrupted and the foraging is automatically recorded. Use (Coulboum Instruments) to program a universal electric shocker to deliver an electric shock between the clam-shaped ground and the drinking water pipe for a leap second, but terminate immediately when the contact between the animal and the drinking water pipe is interrupted.

Vogel program: I21934.doc -39- 200819123 After 24 hours of water shortage on the first day, the test subjects were placed in the test chamber and allowed to drink without penalty for a 1 minute training period. Request for money During the training period, 1〇〇·ΐ5〇 times, ., 1 Λ χ person is allowed to be private. Subjects who completed the training criteria prior to training a 1-point bundle in 10 minutes were removed from the test chamber. This is used to limit the food intake of all subjects to their total daily consumption, scoop 25/〇. Mice that failed to complete 1 or more foraging were excluded from the 4 study. Immediately after the first-day training period, the mice were returned to their original cages and continued to be dehydrated. All mice were then fasted overnight after testing. On the second test day, the mice were dosed with vehicle or test compound and tested after 30 minutes. During the 1 minute test period, mice received a light shock (0.4 mA) for every 10 food intakes [fixed ratio (FR) 10 time course]. Therefore, there is a conflict situation. · The mouse has the action of drinking water. The machine is suppressed by electric shock. Accepting a lower number of shock events reflects anxiety-related behavior. Standard anti-anxiety drugs resulted in a significant increase in the number of shock events relative to the concurrent vehicle control group and produced an anxiolytic-like effect. The group mean SEM (N=12/group) was calculated and all data were analyzed using the Anova 〇n Ranks/Dunn method compared to the parallel vehicle control group. Anticonvulsant activity (DBA/2J mice) Prior to the anticonvulsant test, the mice were placed on a 4 inch square wire mesh suspended 12 to 18 inches from the table by steel bars. The square was slowly inverted by 180 degrees and the mice were observed for 30 seconds. Any mouse that fell from the wire mesh was rated as a motor disorder. By placing individual mice in a closed acrylic plastic chamber (height 21_cm, diameter about 3〇_121934.doc -40·200819123 cm) with a tweeter (4-cm diameter) in the center of the top cover Start the anticonvuls test. An audio signal generator (pr〇tek model B-810) is used to generate a continuous sinusoidal tone that is linearly scanned every 1 millisecond at a frequency between 8 kHz and 16 kHz. During stimulation, the average sound pressure level on the ground of the chamber was approximately 10 0 dB. Mice were placed in the chamber and allowed to acclimate to the environment for 1 minute. DBA/2J mice in the vehicle treatment group responded to sound stimuli (applied until a strong stretch, or for a maximum of 60 seconds), wherein the characteristic seizure process consisted of the following: running around, followed by clonic seizures, And later stretched straight, and finally the breath stopped and 90% or more of the mice died. In vehicle-treated mice, the entire process from onset to respiratory arrest lasts for about 10 seconds to 15 seconds. Exercise activity: The LMA test uses the 16-Beam Digiscan Animal Activity Monitor (Accuscan).

Electronic, Colombus, OH). Each chamber consisted of a Plexigias box with a Plexiglas insert measuring i6 x 16 leaves, which divided the chamber into four quarters each of 7.5 x 7.5. Two mice were placed in a diagonal quadrant for testing (turning on the light) and the infrared beam detection activity was located on the periphery of the chamber. The entire test chamber is enclosed in a sound reduction chamber to reduce noise outside the test period. All mice were fasted overnight before the test day. On the test day, 3 minutes before the test, the mice received the vehicle or the test compound and recorded the total distance (cm) for 5 hours in 5 minute intervals. Data were reported as group mean SEM (N=10/group) and subjected to one-way variable analysis (One Way Anova)/Dunnett's or Anova on Ranks/Dunn's, for comparison with parallel vehicle groups for statistical purposes. Analysis (if 121934.doc -41 - 200819123 is appropriate). Accelerated Rotating Bar: The test equipment consists of four programmable SmanR〇d8 chambers, Instruments, C〇lumbus, 〇H). Each chamber is %(10)(8)

Cm(w)x30(d) and equipped with a raft attached horizontally to the center above the lattice ground: (10) Rotating rod. The rod spans the chamber to a width of 11 em and a diameter of 3 cm. Concentrate the 》 to make the rod accelerate at a rate of 转 25 rev / sec in seconds to Μ • ah's maximum speed ‘after which the rod decelerates to the stop position in the last 5 seconds. One (10) (four) „ between 67 seconds 1 riding test, the mouse tail directly suspended above the buckle for 3 seconds while starting the cycle, then gently lower it to the rotating rod”], the mouse must be placed on the pole Or fall to the bottom of the test chamber. Two infrared (IR) beams connected to the programmable timer are present two centimeters above the floor of the test chamber. The mouse dropped from the rod interrupted the ir beam and caused the timer to automatically turn off to record the fall latency (seconds). One day after the test, the mouse must complete 2 of 6 consecutive training tests, and _ '曰 is greater than 10 seconds. Animals that completed the training criteria were fasted overnight. The second day test consisted of the average of 3 consecutive tests on the rod following the 30 minute pretreatment time. Data are reported as group mean ± SEM (N = l2 / group) and subject to - single factor variable analysis / Dunnett's or An〇va 〇n Ranks / Dunn's compared to the parallel vehicle group for statistical analysis (if appropriate). Compound: Compound A and Compound B were each dissolved in sterile physiological saline and delivered to each dose in a total volume of 5 Torr at a dose of 3-30 μg/mouse. Vehicle control mice received 5 pL of sterile physiological saline. A 27 g steel needle corrected to 3 121934.doc -42 - 200819123 mm / wood was attached to a 25-speak Hamilton syringe for intraventricular (ICV) administration. The mouse was held down by hand and the injection site was determined by positioning the rigid halide on the top of the head with a needle tip. The needle was inserted 1 cm from the anterior side of the anterior and 2 mm from the posterior portion of the anterior portion. The needle was inserted through the skull and into the ventricle and administered with a rapid injection of the drug or vehicle. Results Receptor binding revealed that Compound A replaced [3H]-gabapentin bound with a membrane protein prepared from recombinant pigs in a medium to high affinity, while Compound a was replaced with a membrane prepared from recombinant human α2δ_2 cells with very low affinity. Protein-bound [3Η]-gabapentin. Replacement [3Η]_gabapentin binds to recombinant pigs and [3Η]-gabapentin binds to recombinant human Μ·: cell membranes with & values of 35 nM and 1670 nM, respectively. The selectivity to α2δ-1 is 48 times more selective for the α2δ-2 site. In comparison, the non-selective compound (compound Β) was substituted for the Ki value of 32.8 ηΜ for the recombinant porcine aj-1 cell membrane and the Ki value for the recombinant human α2δ-2 cell membrane 34·9 Μ 置换 [3η] ]_Gabapentin. The Κ value for gabapentin was determined to be 75 η Μ (recombinant porcine α2δ-1 cell membrane), and 114 η Μ (recombinant human aj-2 cell membrane) (all values in this section are average). Behavioral testing Compound A was compared to compound b in a Vogel conflict test, a sound-induced tonic attack and a motor activity and a rotational rod adverse reaction model. In the Vogel Clash Test, the effects of ICV administration on C57BL/6J mice following 3 minutes of pretreatment with Compound A and Compound b are shown in Tables 121934.doc-43-200819123 1 and Table 2, respectively. Table 1. Effect of Compound A in Vogc 4 Conflict Test Treatment Group 1 (μg/mouse) a Pathway Average Number of Shocks b Vehicle - ICV 1ϋ.8 ± 1.1 Compound A 3 ICV 23.6 ± 4.8 Compound A 10 ICV 33 · 3 soil 5·3* compound A 30 ICV 43·4±3·0* &amp; administered in 5 gL volume b data as mean zfcSEM N=12/group*=p&lt;0.05AnovaonRanks/Dunn's, with parallel Media comparison

Table 2. The effect of compound hydrazine in Vogel's f-test. Treatment group dose (μg/mouse) a Pathway average number of shocks b Vehicle - ICV 9·9 Soil 1·0 Compound B 0.3 ICV 12.5±2.7 Compound B 1 ICV 16.9 soil 2·4 compound B 3 ICV 31.2±8·2* aH5pL volume administration 匕 data as mean soil SEM N=12/group*=ρ&lt;0·05 Anova on Ranks/Dunn's, with parallel media sword Comparison of _____ cxj-l selective ligands, Compound a (330 μg/mouse) SV〇gel conflict produced a dose-dependent anxiolytic-like effect, which was reflected as an average shock event compared with the parallel vehicle control group. Increase (Table 1). The mean control SEM of the vehicle control group was 10.8±1·1. Statistically significant was observed at 10 μg/mouse and 30 μg/mouse (mean SEM = 33.3 ± 5·3 and 43·4 ± 3 〇 (differential)). The non-selective compound, compound Β (0.33 μg/mouse), produced a dose-dependent anxiolytic-like effect in the Vogel conflict model, which was reflected as an increase in the average shock event compared to the vehicle control group (Table 2). ). The vehicle control group was flat 121934.doc • 44- 200819123 The mean soil SEM was 9·9±ΐ·〇. The minimum effective dose (MED) of Compound b was 3 μg/mouse, and the reaction amount at this dose was 31.2 ± 8.2. Therefore, both compounds showed an anxiolytic-like effect. Following the pretreatment with Compound A and Compound B for 2 hours, the effects of ICV administration on DBA/2J mice on the prevention of paroxysmal onset of seizures are shown in Tables 3 and 4, respectively.

Table 3. Effect of Compound A on prevention of paroxysmal onset of seizures in the treatment group. Treatment group dose (μg/mouse) a Pathway protected number / number of tests ED50 (pg) [95% confidence interval] b Vehicle - ICV 0/10 6·6[4·2 to 10.3] Compound A 3 ICV 2/10 Compound A 10 ICV 5/10 Compound A 30 ICV 10/10 aW5pL Volume administration b Probability by Litchfield JT, Wilcoxon F method Unit analysis (Probit analysis) N=10/group Table 4. Compound Β effect on prevention of paroxysmal onset of seizures in treatment group dose (micrograms/mouse) a pathway protected number / number of tests ΕΒ 50 (μΕ) [ 95% confidence region f^]b vehicle - ICV 0/10 11·3 [5·7 to 22.1] Compound Β 3 ICV 1/10 Compound Β 10 ICV 5/10 Compound Β 30 ICV 8/10 aWl0pL Volume administration b. Litchfield JT, Wilcoxon F method for probability unit analysis N=10/group of compound A (3-30 μg/mouse) to produce DBA/2J mice from strong straight hair 121934.doc -45- 200819123 The dose-dependent increase in protection. The ED50 value of Compound A was determined to be 6.6 pg ICV; the 95% confidence interval was [4.2 to 10.3]. Similarly, Compound B (3 - 3 0 μg/mouse) produced a dose-dependent increase in the protection of DBA/2J mice from tonic attack. The ED50 value of Compound B was determined to be 11.3 ICV; the 95% confidence interval was [5·7 to 22.1]. The effects of ICV administration on the activity and accelerated rod activity of 'C57BL/6:M, mice after 30 minutes of pretreatment with compound hydrazine and compound hydrazine are shown in Tables 5 and 6, Tables 7 and 8, respectively. in. Table 5. Effect of Compound A on Exercise Activity (Adverse Reactions) Treatment Group Dose (μg/mouse) a Pathway Average Travel Distance (cm)b Vehicle - ICV 2,386.9 Soil 273·5 Compound A 3 ICV 2,634.7±266.8 Compound A 10 ICV 2, 214.0 ± 179.2 Compound A 30 ICV 2, 444.3 ± 318.7 & 5 mL volumetric administration according to the average: tSEM N = 10 / group * = ρ &lt; 0 · 05 ANOVA / causal, compared with parallel media Table 6. Effect of Compound Β on Exercise Activity 不良: Adverse Reactions) Treatment Group Dose (μg/mouse) a Pathway Average Travel Distance (cm)b Vehicle - ICV 2,336.5±294.9 Compound Β 1 ICV 3,052·9 士 463.5 Compound Β 3 ICV 2,070.2士328.7 CompoundΒ 10 ICV 699·9±158.9* Compound Β 30 ICV 368.0 Soil 66·3* Volumetric administration data is the average value ztSEM N=10/group*=ρ&lt;〇·05 ANOVA/cause, In summary, compared with the vehicle, the average distance traveled by mice administered with increasing doses (3-3 μg/small 121934.doc -46-200819123 murine icv) of sputum b was reduced relative to vehicle. To 84.3%. Statistical significance was observed in gram/mouse and 3 〇 micrograms/mouse. MED &amp; 0 μg/mouse of Compound B. Compound a (3_3 〇 microgram/mouse ' ICV) had no effect on the average travel distance over the entire test dose range. Therefore, adverse reactions to the movement of mice which are finely divided, such as selective ligands, are avoided. Because it is insoluble at higher concentrations, (iv) higher doses are detected. When the average dive (seconds) b 54^±4.0 4Γΐ±4Υ 4g〇±2.6~ 423±42 treatment group dose (microgram ΛΙ

Vehicle Compound A Compound A Compound A Treatment Group Dose (μg/mouse) a Pathway Average Reagent - ICV 1 v -__一) 43 ·7 ±4·2 -~- Compound B 3 ~ ICV 33.0士3.0 ~^ Compound B To ~^ ICV 31.6±3.3* ^ Compound B 30 ~^ ICV 20.2±1.8* ^-- 5 Data as mean zbSEM N=12/group^匕0.05 ANOVA/cause, compared with the media The mean drop-down of mice administered Compound B with increasing doses (3_3 μg/cm), ICV, compared to vehicle, resulted in a dose-dependent decrease. A statistical significance of 121934.doc -47 - 200819123 was observed under 10 μg/mouse and 3 μg/mouse, which reduced the average descent time by 24.5% to 53.8% compared with the vehicle. The Med of Compound 3 was 1 μg/mouse. The compound Α did not have a statistically significant effect on the mean drop potential over the entire dose range. Therefore, it was shown that administration of the a4-l selective ligand has an improved adverse reaction profile. The frequency or incidence (percentage) of one or more adverse reactions following the subsequent administration of the αβ-1 selective ligand may be reduced by at least 1% or more. The compound Α is an αβ-Ι selective ligand. In the substitutional [3η]-gabapentin _ competitive binding study, the compound Α inhibits the recombinant porcine αβ-Ι protein with 35 ηΜ binding, and its binding inhibition with recombinant human ajj protein is 48 times that of the former. 1670 nM. In contrast, non-selective α2δ ligands such as compound b showed similar binding affinities for an (Ki = 32.8 nM) and a2 § 2 (Ki = 34 9 nM). In the behavioral tests, both compound a and compound B produced anti-anxiety-like effects in the C57BL/6J mouse v〇gel conflict model following ICV administration and produced anticonvulsant activity in the mouse DBA/2 sound-induced seizure model. . # In contrast, Compound B has significant activity in two behavioral models commonly used to assess potential adverse effects, accelerated rods and locomotor activity at doses required for anti-anxiety and anticonvulsant activity, while Compound A These are not. There is no significant effect in the good reaction model. - In summary, these data show a compound that prefers δδ-1 protein, a modified/zero window of the compound ,, which exhibits a robust resistance to reduced motor and motion control adverse reactions when compared to non-selective ligands. Anxiety-like effect. Although the form of the invention disclosed herein constitutes the prior preferred embodiment 121934.doc -48-200819123. It is not intended herein to refer to all possible forms or ramifications of the invention. It is to be understood that the terminology used herein is for the purpose of description and description All numerical ranges recited in the specification, including one or more endpoints, include the endpoints and all values in between. All references cited herein are incorporated herein by reference.

121934.doc -49-

Claims (1)

200819123 X. Patent application scope · 1. A kind of α-2·δ-1 selective ligand or t “way, which is used for the manufacture of a medicament for treating a disease including a 'learnably acceptable salt” In the case of a mammal or a mammal, the condition is selected from the group consisting of epilepsy, hyperactivity of the legs, pain in the legs, pain in the muscle fibers, and pain, ..., lake red, affective disorder, and sleep disorders. 2. For the application of the application item, (3S, 4R, 5R) · 3 · Amino dimethyl = 2, such as a selective ligand for the salt of repair. Toray or its pharmaceutically acceptable 3. If requested It is expected that the selectivity of the selective ligand to the α-2-δ-fold and the 4:=/-time unit is as high as "1". -7; 500^4 1000^—Under single t W selective ligand binding pair: early selectivity (10) selection of cut units 5. Use of claim 1 6. Use of claim 1 · Use as claimed in item 1. 8. Use of claim 7 9. Use case 1 and social anxiety. Where the pain condition is neuralgia. 'The sleep disorder is insomnia. 'The condition is hot flashes. Among them, the hot redness is induced by surgery or drugs. , wherein the affective disorder is selected from systemic anxiety I 0 · such as gray sputum, use 'where the condition is epilepsy. II. If the application of jg 1 j is requested, wherein the condition is a sign of restlessness in the leg 12 • If jg 1 is requested, the condition is muscle fiber pain. 121934.doc 200819123 13. The use according to claim 1, wherein the α-2-δ-Ι selective coordination system is administered in an amount of from 10 mg to 5 mg per day. 14. The use of claim 1, wherein the agent is for oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal instillation, by implantation, by intraluminal Or intravesical instillation, intraocular, intraarterial, intralesional, transdermal, or by administration to the mucosa for administration.雩 15. The use of the claimed item, wherein the selective coordination system is present in a pharmaceutical composition W comprising the ligand and a pharmaceutically acceptable carrier. 16. The use of claim 15, wherein the pharmaceutical composition is in a liquid or solid dosage form. I21934.doc 200819123 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula·· 121934.doc