HK1082410A

HK1082410A - Pregabalin derivatives for the treatment of fibromyalgia and other disorders

Info

Publication number: HK1082410A
Application number: HK06102784.0A
Authority: HK
Inventors: D．J．多莱; C．P．小泰勒; A．J．索普; D．J．伍斯特罗
Original assignee: 沃尼尔．朗伯有限责任公司
Priority date: 2002-12-13
Filing date: 2003-12-03
Publication date: 2006-06-09

Description

Pregabalin derivatives for the treatment of fibromyalgia and other diseases

Background

The present invention relates to the use of certain α 2 δ ligands in the treatment of fibromyalgia and other central nervous system disorders. Fibromyalgia (FM) is a chronic syndrome characterized primarily by widespread pain, bradypsychia, mood disorders, and fatigue. The main symptoms of fibromyalgia include pain, sleep, mood disorders and fatigue. Syndromes commonly associated with fibromyalgia include irritable bowel syndrome and migraine headaches, among others. The success of using a single active agent to treat fibromyalgia has been described as appropriate, and clinical trial results have been disappointing. Based on the current understanding of the mechanisms and pathways involved in fibromyalgia, a variety of active agents are thought to be needed for the main symptoms of pain, sleep disturbances, mood disorders, and fatigue. Patients with fibromyalgia are often susceptible to side effects of drugs, a feature that may be related to the pathophysiology of the disease (BarkhuizenA, "Rational and targeted drug therapy for fibromyalgia" (Rational and targeted pharmacological treatment of fibromyalgia.) - [ national rheumatism in America (Rheum Dis Clin N Am) 2002; 28: 261-.

Although fibromyalgia is a complex disease with multiple aspects, this complexity can be well evaluated (Yunus MB, "comprehensive medical evaluation of patients with fibromyalgia syndrome" -American national clinical rheumatism (Rheum Dis Clin N Am) 2002; 28: 201-. The diagnosis of FM is usually based on The 1990 recommendations of The American College of Rheumatology classification (Bennett RM, "rational control of fibromyalgia patients" (The organizational management of fibromyalgia patents.) - "American national clinical rheumatism (Rheum Dis Clin N Am) 2002; 28: 181-199; Wolfe F, Smythe HA, YunusMB, Bennett RM, Bombardier C, Goldenberg DL et al," 1990 standards of The American College of Rheumatology classification for fibromyalgia ": multicenter Standard Committee Report" (The American College of Rheumatology Criteria for The classification of The fibromyalgia: Report of The multicenter Critical Committee.) (Arthrois Rheumatology 1990; 33: 1990; 33: 1990-72). Evaluation, control and drug therapy of Fibromyalgia (Barkhuizen A, "Rational and targeted drug therapy of Fibromyalgia" (Rational and targeted pharmacological treatment of Fibromyalgia.) - "national clinical rheumatism in N Am 2002; Bukila D," Fibromyalgia, chronic fatigue syndrome and myofascial pain syndrome "(fibrous and muscular pain syndrome) — recent Rheumatology opinion (Current opinions in Rheumatology) 2001; 13: 117. sup. 127; Leventhal LJ.," control of Fibromyalgia "(Management of Fibromyalgia of International medicine years 1999 (Ann. sup. N. 131; Interheaven. sup. RM-8; national medicine of rheumatalgia; Benzyphi. sup. 199; national rheumatism of Fibromyalgia; radial of women # 181. sup. 35; American tissue of rheumatalgia; radial pain # 199; national rheumatism of Yun. sup. gral # 181; national rheumatism of Yu. sup. TM.), "comprehensive medical evaluation of patients with fibromyalgia syndrome" (A comprehensive medical evaluation of properties with fibromyalgia syndrome) — national clinical rheumatism in America (Rheum Dis Clin N Am) 2002; 28: 201-217).

Restless Leg Syndrome (RLS) is characterized by the following minimum diagnostic criteria: (a) the need to move to the extremes, often associated with paresthesia/dysesthesia; (b) exercise and restlessness; (c) worsening of symptoms in a quiescent state due to at least temporary reduction in activity; and (d) worsening of evening or night symptoms. Other features commonly observed in RLS include sleep disorders, periodic limb movements in sleep and similar involuntary movements upon waking, idiopathic forms of normal neurological examination results, a trend of symptoms worsening in middle to old years, and in some cases, familial history implications of dominant genetic patterns of chromosomes. See Walters AS; "better definition of restless leg Syndrome-International research Group on restless leg Syndrome" (aware a beta definition of The stress Legs Syndrome-The International stress Legs Syndrome Group) & movement disorders (Mov disorders.) (1995)10 (5): 634-42. See also Bhatia M and Bhowmik D; "maintenance of Restless legs syndrome in hemodialysis patients" (Restless legs syndrome innainmenace haemolysis patents) "renal dialysis Transplant (NephrolDial Transplant) (2003) 18: 217. restless leg syndrome can be a primary disease but also secondary diseases related to, for example, renal insufficiency, genetics, pregnancy, poliomyelitis, infectious diseases, vitamin deficiency, different types of anemia, diabetes and certain drugs (e.g. prochlorperazine, lithium and mianserin).

Gabapentin, pregabalin and other α 2 δ ligands, including 4H- [1, 2, 4] oxadiazol-5-one, C- [1- (1H-tetrazol-5-ylmethyl) -cycloheptyl ] -methylamine, (3S, 4S) - (1-aminomethyl-3, 4-dimethyl-cyclopentyl) -acetic acid, (1a, 3a, 5a) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid and (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid and pharmaceutically acceptable salts and solvates thereof are described in U.S. Pat. nos. 4,024,175, US4,087,544, US6,306,910, WO 9924, WO0190052, WO0128978, EP0641330, WO 1769827 and WO 0076958. The entire contents of the above patents and applications are incorporated herein by reference.

The compounds used in the process of the invention are mono-and disubstituted 3-propyl gamma-aminobutyric acid. The compounds used in the methods of the invention described below are disclosed in U.S. patent application Ser. No. US10/009,938, filed on 10.12.2001, and U.S. patent application Ser. No. US10/324,929, filed on 20.12.2002, and their various uses are disclosed. The applications US10/009,938 and US10/324,929 are incorporated herein by reference in their entirety.

Summary of The Invention

The present invention relates to a method of treating diseases in a mammal, including a human, comprising the step of administering to said mammal a therapeutically effective amount of a compound of formula 1:

wherein:

R¹is hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms or phenyl;

R²is a linear or branched alkyl group of 4 to 8 carbon atoms, a linear or branched alkenyl group of 2 to 8 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms, an alkoxy group of 1 to 6 carbon atoms, -alkylcycloalkyl-alkylalkoxy, -alkyloh, -alkylphenyl, -alkylphenoxy or-substituted phenyl; and wherein said disorder is selected from the group consisting of OCD, phobias, PTSD, restless leg syndrome, premenstrual dysphoric disorder, hot flashes, and fibromyalgia. This process is also referred to hereinafter as "the process of the invention".

The present invention also relates to a method of treatment of a disease in a mammal, including a human, comprising the step of administering to said mammal a therapeutically effective amount of the compound (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid or a pharmaceutically acceptable salt thereof, wherein said disease is selected from the group consisting of OCD, phobia, PTSD, restless legs syndrome, premenstrual dysphoric disorder, hot flashes and fibromyalgia. The compound (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid is hereinafter also referred to as "Compound A".

The present invention also relates to a method of treating fibromyalgia and concomitant disorders in a mammal, including a human, comprising the step of administering to said mammal a therapeutically effective amount of a compound of formula 1 as described above, wherein said concomitant disorder is selected from migraine, temporomandibular joint dysfunction, autonomic dysfunction, endocrine dysfunction, dizziness, intolerance to cold, chemical sensitivity, dry symptoms, cognitive dysfunction, general anxiety disorder, premenstrual dysphoric disorder, irritable bowel syndrome, functional abdominal pain, neuropathic pain, somatoform disorder, OCD, phobia, and PTSD.

The present invention also relates to a method for the treatment of fibromyalgia and concomitant diseases in mammals, including humans, comprising the step of administering to said mammal a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof, wherein said concomitant diseases are selected from the group consisting of the above-mentioned concomitant diseases.

The present invention also relates to a method of increasing slow wave sleep in a human subject treated with an active agent that reduces slow wave sleep, comprising administering to a human subject in need of such treatment:

(a) a compound of formula 1 as described above or a pharmaceutically acceptable salt thereof; and

(b) human growth hormone or a human growth hormone secretagogue or a pharmaceutically acceptable salt thereof;

wherein the amounts of active agents "a" and "b" are selected such that the combination is effective to increase slow wave sleep.

(a) a compound A; and

The present invention also relates to a method of increasing slow wave sleep in a human subject comprising administering to a human subject in need of such treatment:

(a) compound a or a pharmaceutically acceptable salt thereof; and

A more specific embodiment of the invention relates to any of the above methods for increasing slow wave sleep, wherein the human growth hormone secretagogue used is 2-amino-N- [2- (3 a-benzyl-2-methyl-3-oxo-2, 3, 3a, 4, 6, 7-hexahydro-pyrazolo [4, 3-c ] pyridin-5-yl) -1-benzyloxymethyl-2-oxo-ethyl ] -2-methyl-propionamide.

The present invention also relates to any one of the above methods of increasing slow wave sleep in a human subject treated with an active agent that decreases slow wave sleep, comprising the step of administering to such human subject an amount of a compound of formula 1 as described above, or a pharmaceutically acceptable salt thereof, effective to increase slow wave sleep.

The present invention relates in one embodiment to any one of the above methods wherein the disease treated is a phobia selected from the group consisting of field phobia, field phobia without a history of panic disorder, specific phobia, and social phobia.

In another embodiment, the present invention relates to any one of the above methods wherein the compound administered is compound a or a pharmaceutically acceptable salt thereof and wherein the disease treated is OCD, PTSD or phobia.

In another embodiment the present invention relates to any one of the above methods wherein the compound administered is compound a or a pharmaceutically acceptable salt thereof and wherein the disease treated is a phobia selected from the group consisting of field phobia and specific phobia.

In another embodiment, the present invention relates to any one of the above methods wherein the compound administered is compound a or a pharmaceutically acceptable salt thereof and wherein the disease treated is fibromyalgia.

In another embodiment, the present invention relates to any one of the above methods, wherein the compound administered is selected from the group consisting of: 3-aminomethyl-5-methylheptanoic acid; (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid; 3-aminomethyl-5-methyl-octanoic acid; 3-aminomethyl-4, 5-dimethyl-hexanoic acid; (3S, 4S) -3-aminomethyl-4, 5-dimethyl-hexanoic acid; (3R, 4R) -3-aminomethyl-4, 5-dimethyl-hexanoic acid MP; 3-aminomethyl-4-isopropyl-hexanoic acid; 3-aminomethyl-4-isopropyl-heptanoic acid; (3S, 5S) -3-aminomethyl-6-fluoro-5-methyl-hexanoic acid; (3S, 5S) -3-aminomethyl-7-fluoro-5-methyl-heptanoic acid; (3S, 5S) -3-aminomethyl-7, 7, 7-trifluoro-5-methylheptanoic acid; (3S, 5R) -3-aminomethyl-8, 8, 8-trifluoro-5-methyl-octanoic acid; (3S, 5S) -3-aminomethyl-5, 6-dimethyl-heptanoic acid; (3R, 4R, 5R) -3-aminomethyl-4, 5-dimethyl-heptanoic acid; and (3R, 4R, 5R) -3-aminomethyl-4, 5-dimethyl-octanoic acid; or a pharmaceutically acceptable salt thereof; and wherein the disease is selected from the group consisting of OCD, agoraphobia without a history of panic disorder, specific phobia, social phobia, PTSD, and fibromyalgia. The compounds directly listed in the above process are hereinafter also referred to as "group a compounds".

In another embodiment, the present invention relates to any one of the above methods, wherein the disease treated is OCD or PTSD and the compound administered is a group a compound or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to any one of the above methods, wherein the disorder treated is fibromyalgia and the compound or salt administered is a group a compound or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention relates to any one of the above methods wherein the disease treated is fibromyalgia and wherein the compound administered is compound a or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention relates to any of the above methods of treating fibromyalgia and associated disorders, wherein said associated disorder is generalized anxiety disorder, anxious dysthymia, irritable bowel syndrome, functional abdominal pain, neuropathic pain, somatoform disorder or migraine.

The invention also relates to methods of treating a disease or condition in a mammal selected from the group consisting of: acute pain, chronic pain, pain caused by soft tissue and peripheral injury, such as acute trauma; complex regional pain syndrome, also known as reflex sympathetic dystrophy; postherpetic neuralgia, occipital neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, and other neuralgia; pain associated with osteoarthritis and rheumatoid arthritis; musculoskeletal pain, such as pain associated with strain, sprain and trauma, such as bone fracture; spinal pain, central nervous system pain, such as pain resulting from spinal cord or brainstem injury; low back pain, sciatica, dental pain, myofascial pain syndrome, vulvar incisional pain, gouty pain and pain due to burns; deep and visceral pain, such as cardiac pain; muscle pain; eye pain; inflammatory pain; orofacial pain, such as dental pain; abdominal pain; and gynecological pain, such as dysmenorrhea, childbirth pain, and pain associated with endometriosis; somatic pain; pain associated with nerve and nerve root damage, such as pain associated with peripheral nerve disorders, e.g., nerve involvement and brachial plexus avulsion; pain associated with amputation, trigeminal neuralgia, neuroma or vasculitis; diabetic neuropathy, chemotherapy-induced neuropathy, acute herpes and postherpetic neuralgia; atypical facial pain, neuropathic low back pain and arachnoiditis, trigeminal neuralgia, occipital neuralgia, segmental or intercostal neuralgia, HIV-associated neuralgia, cancer-associated neuropathic pain, diabetic-associated neuropathic pain and arachnoiditis, trigeminal neuralgia, occipital neuralgia, segmental or intercostal neuralgia, HIV-associated neuralgia and AIDS-associated neuralgia and other neuralgias; allodynia, hyperalgesia, causalgia, idiopathic pain, pain resulting from chemotherapy; occipital neuralgia, psychogenic pain, avulsion of the brachial plexus, pain associated with restless leg syndrome; pain associated with gallstones; pain due to chronic alcoholism or hypothyroidism or uremia or vitamin deficiency; neuropathic and non-neuropathic pain associated with cancer, commonly referred to as cancer pain; pseudolimb pain, functional abdominal pain, headaches including migraine with aura, migraine without aura and other vascular headaches, acute or chronic tension headaches, sinus headaches and cluster headaches; temporomandibular and maxillary sinus pain; pain due to ankylosing spondylitis and gout; pain due to increased bladder contractions; pain associated with Gastrointestinal (GI) diseases, diseases caused by helicobacter pylori and GI tract diseases such as gastritis, proctitis, gastroduodenal ulcer, peptic ulcer, dyspepsia, diseases associated with neuronal control of the viscera, ulcerative colitis, chronic pancreatitis, crohn's disease, and emesis; postoperative pain, scar pain and chronic non-neuropathic pain such as HIV-associated pain, anthralgia and myalgia; vasculitis; and fibromyalgia; the method comprises the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula 1, compound a, or a pharmaceutically acceptable salt thereof.

The invention also relates to methods of treating a disease or condition in a mammal selected from the group consisting of: affective disorders such as depression, or more specifically depression, for example major depressive disorder, major unipolar recurrent major depressive episode, dysthymic disorder, depressive neurosis and functional depression, melancholic depression including anorexia, weight loss, insomnia, early morning walking or depression of psychomotor activity, atypical depression (or reactive depression) including increased appetite, hypersomnia, agitation or irritability; for the treatment of depression; seasonal affective disorder and pediatric depression; premenstrual syndrome, premenstrual dysthymic disorder, hot flashes, bipolar disorders or manic depressive disorders such as bipolar I disorder, bipolar II disorder and disorders of the thoraco-around gland; seasonal affective disorder, conduct disorder and disruptive behavior disorder; stress-related somatic and anxiety disorders such as childhood anxiety disorder, panic disorder with or without agoraphobia, phobias, agoraphobia and specific phobias including without a history of panic disorder (e.g., specific animal phobias), social anxiety disorder, social phobia, Obsessive Compulsive Disorder (OCD), autism, and related disorders including mental retardation in general, affective disorders related to psychotic disorders such as acute mania and depression related to bipolar psychotic disorder, affective disorders related to schizophrenia, behavioral disorders related to mental development, autism, behavioral disorders and disruptive behavior disorders, borderline personality disorder, anxious psychotic episodes, and anxiety related to psychosis; stress disorders including post-traumatic stress disorder (PTSD) and acute stress disorder; and general anxiety disorders; the method comprises the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula 1, compound a, or a pharmaceutically acceptable salt thereof.

It will be appreciated that the compounds used in the methods of the invention may be used in combination with other antidepressants or anxiolytics for the treatment of depression or anxiety. Suitable classes of antidepressants include norepinephrine reuptake inhibitors, selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRIs), Corticotropin Releasing Factor (CRF) antagonists, alpha-adrenoceptor antagonists, and atypical antidepressants. Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Examples of suitable tertiary amine tricyclics include amitriptyline, clomipramine, doxepin, imipramine and trimipramine and pharmaceutically acceptable salts thereof. Examples of suitable secondary amine tricyclics include amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof. Suitable selective 5-hydroxytryptamine reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine and sertraline and pharmaceutically acceptable salts thereof. Suitable monoamine oxidase inhibitors include isocarboxazid, phenelzine, tranylcypromine and selegiline and pharmaceutically acceptable salts thereof. Suitable reversible inhibitors of monoamine oxidase include moclobemide and pharmaceutically acceptable salts thereof. Suitable 5-hydroxytryptamine and norepinephrine reuptake inhibitors for use in the present invention include venlafaxine and pharmaceutically acceptable salts thereof. Suitable CRF antagonists include those described in International patent applications WO94/13643, WO94/13644, WO94/13661, WO94/13676 and WO 94/13677. Suitable atypical antidepressants include bupropion, lithium, nefazodone, trazodone and viloxazine and pharmaceutically acceptable salts thereof. Suitable classes of anxiolytic agents include benzodiazepine * class and 5-HTIA agonists or antagonists, especially 5-HTIA partial agonists and Corticotropin Releasing Factor (CRF) antagonists. Suitable benzodiazepines * include alprazolam, clonazepam *, clonazepam, chlordiazepoxide, diazepam, halazepam, lorazepam, oxazepam and pramazepam, and pharmaceutically acceptable salts thereof. Suitable 5-HTIA receptor agonists or antagonists include in particular the 5-HTIA receptor partial agonists buspirone, fluoroxingchun, gepirone and ethametiprone and pharmaceutically acceptable salts thereof.

The invention also relates to methods of treating a disease or condition in a mammal selected from the group consisting of: sleep disorders such as insomnia (e.g., primary insomnia, including psychophysiological and idiopathic insomnia; secondary insomnia, including secondary insomnia of restless leg syndrome, insomnia associated with premenopausal and/or postmenopausal, Parkinson's disease or another chronic disease and temporary insomnia); sleep disorders, sleep deprivation, REM sleep disorders, sleep apnea, hypersomnia, parasomnia, sleep cycle disorders, jet lag, narcolepsy, sleep disorders associated with shift work or irregular work schedules, lack of sleep quality due to decreased slow wave sleep due to medications or other causes; and other sleep disorders; the method comprises the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula 1, compound a, or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of increasing slow wave sleep and increasing growth hormone secretion in a human subject in a mammal, comprising the step of administering to a human subject in need of such treatment a therapeutically effective amount of a compound of formula 1, compound a or a pharmaceutically acceptable salt thereof.

The invention also relates to a method of treating a disease or condition in a mammal, including a human, selected from the group consisting of: respiratory diseases, particularly those associated with hypersecretion of mucus, such as chronic airway obstructive disease, bronchopneumonia, chronic bronchitis, cystic fibrosis, adult respiratory distress syndrome, and bronchospasm; cough, pertussis, Angiotensin Converting Enzyme (ACE) -induced cough, tuberculosis, allergies such as eczema and rhinitis; contact dermatitis, atopic dermatitis, urticaria and eczematoid dermatitis; itch, itch associated with hemodialysis; inflammatory diseases such as inflammatory bowel disease, psoriasis, osteoarthritis, cartilage damage (e.g. due to physical activity or osteoarthritis), rheumatoid arthritis, psoriatic arthritis, asthma, pruritus and sunburn; and hypersensitivity diseases such as poison lacquer; comprising the step of administering to a human subject in need of such treatment a therapeutically effective amount of a compound of formula 1, compound a, or a pharmaceutically acceptable salt thereof.

Other more specific embodiments of the invention include any of the above methods wherein the compound of formula 1, compound a, or a pharmaceutically acceptable salt thereof, is administered to a human to treat any two or more diseases or conditions in combination selected from those involved in any of the above methods.

Another more specific embodiment of this invention is directed to any of the above methods of treating fibromyalgia wherein a compound of formula 1, compound a, or a pharmaceutically acceptable salt thereof, is administered to a human to treat fibromyalgia and the accompanying generalized anxiety disorder.

Another more specific embodiment of the present invention relates to any of the above methods wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof is administered to a human for the treatment of major depressive disorder and associated irritable bowel syndrome.

Another more specific embodiment of this invention relates to any of the above methods wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof, is administered to a human to treat major depressive disorder and concomitant functional abdominal pain.

Another more specific embodiment of this invention relates to any of the foregoing methods wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof, is administered to a human for the treatment of major depressive disorder and associated neuropathic pain.

Another more specific embodiment of this invention relates to any of the above methods wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof is administered to a human for the treatment of fibromyalgia and associated premenstrual dysphoric disorder.

Another more specific embodiment of this invention relates to any of the above methods wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof, is administered to a human to treat major depressive disorder and concomitant dysthymic disorder.

Another more specific embodiment of this invention relates to any of the above methods wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof is administered to a human to treat major depressive disorder and concomitant fibromyalgia.

Another more specific embodiment of this invention relates to any of the above methods wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof is administered to a human to treat dysthymia and concomitant fibromyalgia.

Another more specific embodiment of the present invention relates to any of the above methods, wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof, is administered to a human for the treatment of dysthymia and concomitant somatoform disorders selected from the group consisting of somatization disorders, transmutation disorders, somatoform disorders, hypochondriasis, somatoform pain disorders, undifferentiated somatoform disorders and somatoform disorders not otherwise specified. See, Diagnostic and Statistical Manual of mental disorders 4 th edition (DSM-IV), American Psychiatric Association, Washington, D.C., May 1194, pp.435-436.

Another more specific embodiment of this invention relates to any of the above methods wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof, is administered to a human for the treatment of fibromyalgia and associated irritable bowel syndrome.

Another more specific embodiment of this invention relates to any of the above methods wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof, is administered to a human to treat fibromyalgia and the attendant functional abdominal pain.

Another more specific embodiment of this invention relates to any of the above methods wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof, is administered to a human for the treatment of fibromyalgia and associated neuropathic pain.

Another more specific embodiment of this invention relates to any of the above methods wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof, is administered to a human for the treatment of generalized anxiety disorder and associated premenstrual dysphoric disorder.

Another more specific embodiment of this invention relates to any of the above methods wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof, is administered to a human for the treatment of general anxiety disorder and concomitant dysthymia.

Another more specific embodiment of this invention relates to any of the above methods wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof, is administered to a human for the treatment of general anxiety disorder and concomitant fibromyalgia.

Another more specific embodiment of this invention relates to any of the above methods, wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof, is administered to a human for the treatment of general anxiety disorders and concomitant somatoform disorders selected from the group consisting of somatization disorders, transition form disorders, hypochondriasis, somatoform pain disorders (or simply "painful disorders"), somatoform disorders, undifferentiated somatoform disorders and somatoform disorders not otherwise specified. See, for example, Diagnostic and statistical guidelines for psychosis (Diagnostic and statistical manual of Mental Disorders) 4 th edition (DSM-IV), American Psychiatric Association, Washington, D.C., May 1194, pp.435-436.

Another more specific embodiment of this invention relates to any of the above methods, wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof, is administered to a human for the treatment of fibromyalgia and associated somatoform disorders selected from the group consisting of somatization disorders, conversion disorders, hypochondriasis, somatoform pain disorders (or simply "painful disorders"), somatoform disorders, undifferentiated somatoform disorders and somatoform disorders not otherwise specified. See, for example, Diagnostic and statistical guidelines for psychosis (Diagnostic and statistical manual of Mental Disorders) 4 th edition (DSM-IV), American Psychiatric Association, Washington, D.C., May 1194, pp.435-436.

Another more specific embodiment of the present invention relates to any of the above methods, wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof is administered to a human for the treatment of major depressive disorder and one or more accompanying physical symptoms selected from the group consisting of anorexia, sleep disorders (e.g., insomnia, interrupted sleep, early wakefulness, tiredness arousal), loss of libido, restlessness, fatigue, constipation, dyspepsia, palpitation, pain and aches (e.g., headache, neck pain, back pain, limb pain, joint pain, abdominal pain), dizziness, nausea, heartburn, nervousness, tremor, sensations of causalgia and tingling, morning stiffness, abdominal symptoms (e.g., abdominal pain, abdominal distension, snoring, diarrhea) and symptoms associated with general anxiety (e.g., excessive anxiety and annoyance occurring for many days rather than for at least 6 months (expectation of anxiety and annoyance), A large number of situations and activities of concern, difficulty in controlling annoyances, etc.). See, Diagnostic and statistical guidelines for psychosis (Diagnostic and statistical manual of Mental Disorders) 4 th edition (DSM-IV), American Psychiatric Association, Washington, D.C., May 1194, pp.435-436 and 445-469. The entire contents of this reference are incorporated herein by reference.

Another more specific embodiment of the present invention relates to any of the above methods, wherein a compound of formula 1, compound a or a pharmaceutically acceptable salt thereof, is administered to a human to treat major depressive disorder and one or more accompanying somatic symptoms selected from the group consisting of fatigue, headache, neck pain, back pain, limb pain, joint pain, abdominal distension, gurgling, neuropathic diarrhea, and symptoms associated with generalized anxiety disorder (e.g., excessive anxiety and distress occurring for a number of days rather than at least 6 months) (anxious expectations), see "Diagnostic and Statistical guidelines for psychosis" (Diagnostic and Statistical manual of neurological Disorders) 4 th edition (DSM-IV), American Psychiatric Association, washingingd.c., May 1194, pp.435-436 and 469.

Another more specific embodiment of the present invention relates to any of the above methods, wherein the compound of formula 1, compound a or a pharmaceutically acceptable salt thereof is administered to a human for the treatment of general anxiety disorder and one or more accompanying physical symptoms selected from the group consisting of anorexia, sleep disorders (e.g., insomnia, interrupted sleep, early wakefulness, tiredness arousal), loss of libido, restlessness, fatigue, constipation, dyspepsia, palpitation, pain and pain (e.g., headache, neck pain, back pain, limb pain, joint pain, abdominal pain), dizziness, nausea, heartburn, tremor, sensations of causalgia and tingling, morning stiffness, abdominal symptoms (e.g., abdominal pain, abdominal distension, gurgling, diarrhea) and symptoms associated with severe anxiety (e.g., sadness, lacrimation, loss of interest, fear, helplessness, despair, fatigue, low self-esteem, low-quality, loss of interest, fear, helplessness, despair-feeling, fatigue, low self-being, loss of interest, loss of the body, obsessive-compulsive concepts, suicidal thoughts, fatigue, impaired memory and concentration, loss of power, volvulus, decreased appetite, increased appetite).

The invention also relates to methods of treating a disease or condition in a mammal selected from the group consisting of: sleep disorders such as insomnia (e.g., primary insomnia, including psychophysiological and idiopathic insomnia; secondary insomnia, including restless leg syndrome, Parkinson's disease, or another chronic disease secondary insomnia and temporary insomnia); sleep disorders, sleep deprivation, REM sleep disorders, sleep apnea, hypersomnia, parasomnia, sleep cycle disorders, jet lag, narcolepsy, sleep disorders associated with shift work or irregular work schedules, lack of sleep quality due to decreased slow wave sleep due to medications or other causes; and other sleep disorders; the method comprises the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula 1, compound a, or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of increasing slow wave sleep in a human subject, the method comprising the step of administering to a human subject in need of such treatment a therapeutically effective amount of a compound of formula 1, compound a, or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method for increasing growth hormone secretion in a human subject, the method comprising the step of administering to a human subject in need of such treatment a therapeutically effective amount of a compound of formula 1, compound a or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating irritable bowel syndrome in a mammal, preferably a human, comprising the step of administering to a human subject in need of such treatment a therapeutically effective amount of a compound of formula 1, compound a or a pharmaceutically acceptable salt thereof.

Another more specific embodiment of the invention relates to any of the above methods, wherein the disease is restless leg syndrome and wherein the restless leg syndrome is a secondary syndrome associated with another disease or condition including, but not limited to, renal insufficiency, genetics, pregnancy, poliomyelitis, infectious diseases, vitamin deficiency, anemia of a different type, diabetes, certain drugs (e.g., prochlorperazine, lithium, and mianserin).

Another more specific embodiment of the present invention relates to any of the above methods, wherein the disease is restless legs syndrome and wherein the restless legs syndrome is secondary syndrome associated with certain medications including, but not limited to prochlorperazine, lithium and mianserin,

Another more specific embodiment of the present invention relates to a method of treating a disease in a mammal, including a human, comprising the step of administering to said mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein said compound is compound a and wherein said disease is selected from the group consisting of restless legs syndrome, premenstrual dysphoric disorder and hot flashes.

Another more specific embodiment of this invention relates to a method of treating restless legs syndrome in a mammal, including a human, which method comprises the step of administering to said mammal a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, wherein said compound is compound a.

Another more specific embodiment of the present invention relates to a method of treating a disease in a mammal, including a human, comprising the step of administering to said mammal a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein said compound is a group a compound and wherein said disease is selected from the group consisting of restless legs syndrome, premenstrual dysphoric disorder and hot flashes.

The invention also relates to methods of treating a disease or condition in a mammal selected from the group consisting of: dyskinesias such as primary dyskinesia, akinesia, dyskinesias (e.g., familial paroxysmal dyskinesia, tardive dyskinesia, tremor, chorea, myoclonus, tics and other dyskinesias); spasticity, including muscle spasticity, periodic limb movement disorder, hypotonia with paralysis; tourette's syndrome; scott syndrome; paralysis (e.g., bell's palsy, cerebral palsy, birth injury palsy, upper limb palsy, wasting palsy, ischemic palsy, progressive bulbar palsy, and other palsy); akinesia-rigidity syndrome; extrapyramidal movement disorders such as drug-induced movement disorders, for example neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and drug-induced postural tremor; restless leg syndrome and dyskinesias associated with Parkinson's disease or Huntington's chorea; the method comprises the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula 1, compound a, or a pharmaceutically acceptable salt thereof.

A particular embodiment of the present invention relates to any of the above methods using compounds of formula 1, wherein the compounds or salts used in such methods are such compounds: wherein R is¹Is hydrogen and R²Is a straight or branched chain alkyl of 4 to 8 carbon atoms.

A further embodiment of the present invention relates to any of the above methods, wherein the compound or salt used in the method is selected from the group consisting of:

3-aminomethyl-5-methyl-nonanoic acid;

3-aminomethyl-5-methyl-decanoic acid;

3-aminomethyl-5-methyl-undecanoic acid;

3-aminomethyl-5-methyl-dodecanoic acid;

3-aminomethyl-5-methyl-tridecanoic acid;

3-aminomethyl-5-cyclopropyl-hexanoic acid;

3-aminomethyl-5-cyclobutyl-hexanoic acid;

3-aminomethyl-5-trifluoromethyl-hexanoic acid;

3-aminomethyl-5- (2-chloro-phenyl) -hexanoic acid;

3-aminomethyl-5- (3-chloro-phenyl) -hexanoic acid;

3-aminomethyl-5- (4-chloro-phenyl) -hexanoic acid;

3-aminomethyl-5- (2-methoxyphenyl) -hexanoic acid;

3-aminomethyl-5- (3-methoxyphenyl) -hexanoic acid;

3-aminomethyl-5- (4-methoxyphenyl) -hexanoic acid;

3-aminomethyl-5- (phenylmethyl) -hexanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-decanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-undecanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-dodecanoic acid;

(3S, 5R) -3-aminomethyl-5, 9-dimethyl-decanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-5, 7-dimethyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5, 10-dimethyl-undecanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8-fluoro-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-9-fluoro-5-methyl-nonanoic acid;

(3S, 5S) -3-aminomethyl-5-methoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-ethoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-propoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-isopropoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-tert-butoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-fluoromethoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-fluoro-ethoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3, 3, 3-trifluoro-propoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-phenoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-propoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-isopropoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-fluoro-ethoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (3, 3, 3-trifluoro-propoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-phenoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl 6- (4-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl 6- (3-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl 6- (2-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl 6- (4-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl 6- (3-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl 6- (2-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-6-benzyloxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-7-hydroxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-methoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7-propoxy-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-isopropoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-fluoro-ethoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (3, 3, 3-trifluoro-propoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-7-benzyloxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7-phenoxy-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (4-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (3-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (4-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (3-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (4-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (3-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (4-trifluoromethyl-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (3-trifluoromethyl-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (2-trifluoromethyl-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (4-nitro-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (3-nitro-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (2-nitro-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-phenyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-fluoro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-fluoro-phenyl) -5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-7-phenyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-hept-6-enoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-oct-7-enoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-non-8-enoic acid;

(E) - (3S, 5S) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(Z) - (3S, 5S) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(Z) - (3S, 5S) -3-aminomethyl-5-methyl-non-6-enoic acid;

(E) - (3S, 5S) -3-aminomethyl-5-methyl-non-6-enoic acid;

(E) - (3S, 5R) -3-aminomethyl-5-methyl-non-7-enoic acid;

(Z) - (3S, 5R) -3-aminomethyl-5-methyl-non-7-enoic acid;

(Z) - (3S, 5R) -3-aminomethyl-5-methyl-dec-7-enoic acid;

(E) - (3S, 5R) -3-aminomethyl-5-methyl-undec-7-enoic acid;

(3S, 5S) -3-aminomethyl-5, 6, 6-trimethyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-cyclopropyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-cyclobutyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-8-phenyl-octanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-phenyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-7-phenyl-heptanoic acid;

3-aminomethyl-5-methylheptanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid;

3-aminomethyl-5-methyl-octanoic acid;

3-aminomethyl-4, 5-dimethyl-hexanoic acid;

(3S, 4S) 3-aminomethyl-4, 5-dimethyl-hexanoic acid;

(3S, 4R) 3-aminomethyl-4, 5-dimethyl-hexanoic acid;

3-aminomethyl-4-isopropyl-hexanoic acid;

3-aminomethyl-4-isopropyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-6-fluoro-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-7-fluoro-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7, 7, 7-trifluoro-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-8, 8, 8-trifluoro-5-methyl-octanoic acid;

(3S, 5S) -3-aminomethyl-5, 6-dimethyl-heptanoic acid;

(3R, 4R, 5R) -3-aminomethyl-4, 5-dimethyl-heptanoic acid; and

(3R, 4R, 5R) -3-aminomethyl-4, 5-dimethyl-octanoic acid.

In particular (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid as active agent for the treatment of the following diseases: fibromyalgia; fibromyalgia and one or more associated diseases; and/or Obsessive Compulsive Disorder (OCD), post traumatic stress syndrome (PTSD), agoraphobia without a history of panic disorder, specific phobia, social phobia, restless leg syndrome, premenstrual dysphoric disorder, and/or hot flashes.

The term "lower alkyl" is a straight or branched chain alkyl of 1 to 4 carbons.

Unless otherwise indicated, the term "alkyl" is a straight or branched chain hydrocarbon group of 1 to 6 carbons, including, but not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, t-butyl, pentyl.

The phenyl group of the compound of formula 1 may be unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of hydroxy, carboxy, alkoxycarbonyl, halogen, CF₃Nitro, alkyl and alkoxy. Preferred substituents are halogens.

Since amino acids are amphoteric, when R is hydrogen, pharmaceutically compatible salts can be salts of suitable inorganic or organic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, citric acid, malic acid, salicylic acid, malonic acid, maleic acid, succinic acid, methanesulfonic acid, and ascorbic acid. The corresponding hydroxides or carbonates are used as starting materials for salification with alkali metals or alkaline earth metals, for example sodium, potassium, magnesium or calcium. Salts can also be prepared using quaternary ammonium ions, such as tetramethylammonium ion. The carboxyl group of the amino acid can be esterified in a known manner.

Certain compounds used in the methods of the present invention may exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Certain compounds used in the process of the invention carry one or more chiral centers and each center may exist in the R (D) or S (L) configuration. The present invention includes all enantiomeric and epimeric forms and suitable mixtures thereof.

One beneficial aspect of using the compounds of the present invention in the treatment of fibromyalgia is that they are not addictive. In these methods, the compounds may be combined with other active agents, including antidepressants and/or anxiolytics.

Detailed Description

The compounds of formula 1 are prepared as described below and described in U.S. patent application No. US10/009,938, filed on 10.12.2001, and U.S. patent application No. US10/324,929, filed on 20.12.2002. In the following schemeAnd in discussion, R¹And R²As defined above.

The following examples are provided to illustrate the present invention and are not intended to limit the scope of the present invention. General synthetic schemes

Method 1

a)LiAlH₄；

b) Pyridinium dichromate;

c) triethyl phosphonoacetate, NaH;

d) nitromethane DBU;

e) h2 Pd/C; HCl; iii ion exchange chromatography.

Method 2

X ═ OEt or a chiral oxazolidine adjuvant.

a) Triethyl phosphonoacetate, NaH;

b) i.NaOH, ii.pivaloyl chloride, Et₃N、XH；

c)R¹MgBr、CuBr₂DMS；

d)NaHMDS、BrCH₂CO₂tBu；

e)R＝tBu i.LiOH、H₂O₂；ii.BH₃，iii.TsCl、ET₃N，iv.NaN₃、DMSO；

f)R＝Eti.LiOH、H₂O₂；ii.BH₃，iii.PTSA、THF；iv HBr EtOH，

v.NaN₃ DMSO；

g)i.H₂Pd/C; hcl, iii ion exchange chromatography.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

Synthesis of example 1: 3-aminomethyl-5-methylheptanoic acid

a)PDC、CH₂Cl₂；

b) NaH, triethylphosphonoacetate;

c)DBU、CH₃NO₂；

d)H₂、10％Pd/C；

e)6N HCl, reflux, ion exchange resin (Dowex50 WX8, strong acid). 3-methyl-1-pentanal 11

To a stirred solution of pyridinium dichromate (112.17g, 298.1mmol) in 500mL of dichloromethane was added 3-methyl-1-pentanol 10(15g, 146.79 mmol). After stirring for 2.5 hours, 400mL of diethyl ether were added and stirring continued for an additional 5 minutes. The filtrate from the mixture was concentrated to a small volume and passed through a Florisil column. The compound was eluted with petroleum ether and further subjected to silica gel column chromatography using 10% ether in petroleum ether as eluent to give 11(6.5g, 44%).

¹H-NMR(CDCl₃)δ9.72，(d，-CHO)，2.38(dd，1H，-CH₂CHO)，2.19(dd，1H，-CH₂CHO)，1.95(m，1H，C₂H₅(CH₃)CHCH₂-), 1.4-1.0(m), 0.9-0.8(m), 5-methyl-2-heptanoic acid ethyl ester 12

Sodium hydride (60% dispersion, 2.4g, 65mmol) was washed with hexane and suspended in 60mL of dimethoxyethane. While cooling in an ice-water bath, triethyl phosphonoacetate was slowly added, accounting for 5 minutes. The reaction was stirred at 0 ℃ for 15 minutes and a solution of 3-methyl-1-pentanal 11(6.5g, 65mmol) in 20mL of methoxyethane was added. After refluxing overnight, the concentrate was concentrated, water and hexane were added, the organic phase was separated and a portion of the aqueous phase was decanted. The solution was washed twice with brine and dried over magnesium sulfate. Evaporation of the solvent gave 12(6.75g, 61%).

¹H-NMR(CDCl₃)δ6.89(m，1H，-CH₂CH：CHCOOEt)，5.77(d，1H，-CH₂CH：CHCOOEt)，4.16(q，2H，-COOCH₂CH₃) 2.15 and 1.98 (one multiplet per 1H, -CH₂CH：CHCOOEt)，1.48(m，1H，C₂H₅(CH₃)CHCH₂) 1.30-1.10(m), and 0.83.

5-methyl-3-nitromethylheptanoic acid ethyl ester 13

A solution of ethyl 5-methyl-2-heptanoate 12(6.75g, 39.70mmol), DBU (6.0g, 39.7mmol), nitromethane (21.97g, 359.9mmol) in 80mL of acetonitrile was stirred at room temperature under nitrogen overnight. The mixture was concentrated to an oil. The oil solution in ether was washed with 1n hcl, brine. The system was evaporated to give a light oil, which was chromatographed and dried. The system was evaporated to give an oil which was chromatographed using 5% to 10% diethyl ether in petroleum ether to give 13(3.6g, 42%).

¹H-NMR(CDCl₃)δ4.49-4.39(m)，4.12-4.07(m)，3.61(m)，2.36(m)，1.36-1.18(m)，0.86-0.79.

3-aminomethyl-5-methylheptanoic acid (example 1)

Ethyl 5-methyl-3-nitromethylheptanoate 13(3.6g) was hydrogenated in ethanol in the presence of 20% Pd/C and evaporated to give 14.6 equivalents of 30mL hydrochloric acid were added and refluxed overnight. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene. The aqueous solution of the residue was washed on Dowex50 WX8-100 ion exchange resin which had been washed to neutral pH with HPLC grade water. By usingEluting the column with water until the eluate is neutral pH, and eluting with 0.5N.NH₄The OH solution was eluted to give a fraction containing 3-aminomethyl-5-methylheptanoic acid. Fractions were combined and further subjected to C₁₈The column is subjected to chromatography. The compound was eluted with 40% water in methanol and crystallized from methanol-ether to give 630mg of example 1.¹H-NMR(CD₃OD)δ2.83(m，1H)，2.75(m，1H)，2.35(m，1H)，2.15(m，1H)，1.95(1H，bs)，1.38(1H，m)，1.3-1.15(m，2H)，1.14-0.95(m，2H).0.80(m，2CH₃) MS molecular ion found (M +1)174 and other ions were 156, 139 and 102. To C₉H₁₉NO₂Calculated analytical values: c, 62.39; h11.05; and N8.08. Measurement value: c, 62.00; h10.83; and (7) N7.98.

The following examples can be prepared in a similar manner:

3-aminomethyl-5-methyl-heptanoic acid;

3-aminomethyl-5-methyl-octanoic acid;

3-aminomethyl-5-methyl-nonanoic acid;

3-aminomethyl-5-methyl-decanoic acid;

3-aminomethyl-5-methyl-undecanoic acid;

3-aminomethyl-5-methyl-dodecanoic acid;

3-aminomethyl-5-methyl-tridecanoic acid;

3-aminomethyl-5-cyclopropyl-hexanoic acid;

3-aminomethyl-5-cyclobutyl-hexanoic acid;

3-aminomethyl-5-trifluoromethyl-hexanoic acid;

3-aminomethyl-5- (2-chloro-phenyl) -hexanoic acid;

3-aminomethyl-5- (3-chloro-phenyl) -hexanoic acid;

3-aminomethyl-5- (4-chloro-phenyl) -hexanoic acid;

3-aminomethyl-5- (2-methoxyphenyl) -hexanoic acid;

3-aminomethyl-5- (3-methoxyphenyl) -hexanoic acid;

3-aminomethyl-5- (4-methoxy-phenyl) -hexanoic acid; and

3-aminomethyl-5- (phenylmethyl) -hexanoic acid.

Synthesis of example 2: (3R, 4S) 3-aminomethyl-4, 5-dimethyl-hexanoic acid

Example 2

Reagents and conditions:

a) (R) - (-) -4-phenyl-2-oxazolidinone, (CH)₃)₃CCOCl、Et₃N、LiCl、THF、-20-23℃；

b)MeMgCl、CuBrSMe₂、THF、-35℃；

c)NaHMDS、BrCH₂CO₂tBu、THF、-78℃--40℃；

d)LiOH、H₂O₂、THF、H₂O、25℃；

e)BH₃SMe₂、THF、0-25℃；

f) pTsCl, pyridine, 25 ℃;

g)NaN₃、DMSO、60℃；

h) raney nickel, MeOH, H₂；

i)3MHCl, reflux, ion exchange resin (Dowex50 WX8, strong acid).

[ R- (E) ]3- (4-methyl-pent-2-enoyl) -4-phenyl-oxazolidin-2-one 16

Trimethylacetyl chloride (7.8g, 0.065mol) was added to acid 14(6.9g, 0.06mol) and triethylamine (18g, 0.187mol) in THF (200mL) at-20 ℃. After 1 hour, lithium chloride (2.35g, 0.55mol) and (R) - (-) -4-phenyl-2-oxazolidinone (8.15g, 0.05mol) were added and the thick suspension was warmed to room temperature. After 20 hours, the suspension was filtered and the filtrate was concentrated. The resulting solid was recrystallized from hexane/ethyl acetate (5: 1) to give oxazolidinone 16 as a white solid (8.83g, 68%).¹H NMR(CDCl₃) δ 7.35(m, 5H), 7.18(dd, 1H, J ═ 15.4 and 1.2Hz), 7.02(dd, 1H, J ═ 15.4 and 6.8Hz), 5.45(dd, 1H, J ═ 8.8 and 3.9Hz), 4.68(t, 1H, J ═ 8.8Hz), 4.22(dd, 1H, J ═ 8.8 and 3.9Hz), 2.50(m, 1H), 1.04(d, 1H, J ═ 1.4Hz), 1.02(d,

1H, J ═ 1.4 Hz.) MS, m/z (relative intensity): 260[ M + H, 100% ] (3R, 3R) 3- (3, 4-dimethyl-pentanoyl) -4-phenyl-oxazolidin-2-one 17

To copper (I) bromide-dimethyl sulfide complex (dimethyl sulfide complex) in THF (45mL) at-20 ℃ was added methyl magnesium chloride (as a 3M solution in THF). After 20 minutes, oxazolidinone 16(3.69g, 0.014mol) in THF (20mL) was added dropwise over 10 minutes. After 2.5 hours, the reaction was quenched by addition of saturated aqueous ammonium chloride solution. The resulting layers were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with 1M hydrochloric acid and then with 5% aqueous sodium hydroxide solution. The organic phase was dried (MgSO)₄) And concentrated to give oxazolidinone 17 as a white solid (3.39g, 88%).¹H NMR(CDCl₃)δ

7.30(m, 1H), 5.40(dd, 1H, J ═ 8.8 and 3.7Hz), 4.63(t, 1H, J ═ 8.8Hz), 4.21(dd, 1H, J ═ 8.8 and 3.7Hz), 2.85(dd, 1H, J ═ 16.1 and 5.6Hz), 2.8(dd, 1H, J ═ 16.1 and 8.5Hz), 1.90(m, 1H), 1.56(m, 2H), 0.83(d, 3H, J ═ 6.8Hz), 0.78(d, 3H, J ═ 6.8Hz), 0.75(d, 3H, J ═ 6.8Hz), MS, m/z (relative intensity): 276[ M + H, 100% ] [3R- (3R (R), 4S) ] -4, 5-dimethyl-3- (2-oxo-4-phenyl-oxazolidine-3-carbonyl) -hexanoic acid tert-butyl ester 18

Sodium bis (trimethylsilyl) amide (14.4mL, 0.014mol of a 1M solution in THF) was added to oxazolidinone 17(3.37g, 0.012mol) in THF (35mL) at-78 ℃. After 35 minutes, tert-butyl bromoacetate (3.5g, 0.018mol) was added and the solution was immediately warmed to-40 ℃. After 3 hours, the reaction was quenched by addition of saturated aqueous ammonium chloride solution. The resulting layers were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with 1M hydrochloric acid and then with 5% aqueous sodium hydroxide solution. The organic phase was dried (MgSO)₄) And concentrated. Flash chromatography (9: 1-5: 1 hexanes/ethyl acetate gradient) afforded ester 18(3.81g, 82%) as a white solid.¹H NMR(CDCl₃) δ 7.35(m, 5H), 5.37(dd, 1H, J ═ 8.4 and 3.1Hz), 4.67(t, 1H, J ═ 8.7Hz), 4.41(dt, 1H, J ═ 12.0 and 3.5Hz), 4.25(dd, 1H, J ═ 8.68 and 3.1Hz), 2.65(dd, 1H, J ═ 16.9 and 12.0Hz), 2.25(dd, 1H, J ═ 16.9 and 3.5Hz), 1.6(m, 1H), 1.45(m, 1H), 1.23(s, 9H), 1.02(d, 1H, J ═ 6.5Hz), 0.93(d, 1H, J ═ 6.7Hz), 0.80(d, 1H, J ═ 7.7 Hz), 0.80(m, 1H, J ═ 7.0 (MS/z): 429[ M-H + CH₃CN，100％]，388[M-H，20％](3R, 4S) -2- (1, 2-dimethyl-propyl) -succinic acid 4-tert-butyl ester 19

To oxazolidinone 18(3.62g, 9.3mmol) in THF (54 mL)/water (15mL) was added a pre-mix solution of lithium hydroxide (20mL of a 0.8M aqueous solution, 0.016mol)/H₂O₂(5.76mL of a 30% aqueous solution). After 7 hours, the solution was diluted with water and sodium bisulfite (. about.10 g) was added. After stirring for a further 0.5 h, the two layers were separated and the aqueous phase was extracted with diethyl ether. The aqueous phase was made acidic with 1M hydrochloric acid (pH2) and extracted with diethyl ether. The combined organic phases were dried (MgSO)₄) And concentrated. Flash chromatography (5: 1 hexanes/ethyl acetate) afforded acid 19(2.1g, 95%) as a colorless oil.

¹H NMR(CDCl₃) δ 3.0(m, 1H), 2.55(dd, 1H, J ═ 16.6 and 11.2Hz), 2.27(dd, 1H, J ═ 16.6 and 3.4Hz), 1.70(m, 1H), 1.53(m, 1H), 1.45(m, 1H), 1.43(s, 9H), 0.95(d, 1H, J ═ 6.8Hz), 0.90(d, 1H, J ═ 6.6Hz), 0.83(d, 1H, J ═ 6.8Hz) MS, m/z (relative intensity): 243[ M-H, 100%]Tert-butyl (3R, 4S) -3-hydroxymethyl-4, 5-dimethyl-hexanoate 20

Borane-methyl sulfide complex (16mL, 0.032mol of a 2M solution in THF) was added to a stirred solution of acid 19(1.96g, 8mmol) in THF (20mL) at 0 deg.C. After 20 hours, methanol was added to terminate foaming and the solution was concentrated. Flash chromatography (5: 1 hexanes/ethyl acetate gradient) afforded alcohol 20(1.29g, 70%) as a colorless oil.¹HNMR(CDCl₃) δ 3.62(m, 1H), 2.32(m, 1H), 2.14(m, 1H), 1.6(m, 1H), 1.45(s, 9H), 1.35(m, 1H), 0.93(d, 1H, J ═ 6.8Hz), 0.86(d, 1H, J ═ 6.8Hz), 0.77(d, 1H, J ═ 6.9Hz). 175[ M-tBu, 100%]Tert-butyl (3R, 4S) -4, 5-dimethyl-3- (toluene-4-sulfonyloxymethyl) -hexanoate 21

P-toluenesulfonyl chloride (847mg, 4.4mmol) was added to alcohol 6(850mg, 3.7mmol), DMAP (10mg, 0.08mmol) and triethylamine (1.23mL, 8.88mmol) in CH at 0 deg.C₂Cl₂(20mL) and allowed to warm to room temperature. After 15 hours, the solution was washed with 1N hydrochloric acid and then with brine. The combined organic phases were dried (MgSO)₄) And concentrated. Flash chromatography (100-92% hexane/ethyl acetate gradient) afforded tosylate 7(1.22g, 86%) as a thick gum.

¹H NMR

(CDCl₃)δ7.80(d，2H，J＝8.2Hz)，7.25(d，2H，J＝8.2Hz)，3.92(m，1H)，2.38

(s，3H)，2.20(m，2H)，1.95(m，1H)，1.40(m，1H)，1.32(s，9H)，1.27(m，1H)，0.78

(d，1H，J＝6.6Hz)，0.73(d，1H，J＝6.6Hz)，0.63(d，1H，J＝7.1Hz).MS，m/z

(relative intensity): 311[ 85% ], 198[ 100% ], 157[ 95% ], (3R, 4S) -3-azidomethyl-4, 5-dimethyl-hexanoic acid tert-butyl ester 22

A solution of tosylate 21(1.19g, 3.1mmol) and sodium azide (402mg, 6.2mmol) in DMSO (15mL) was warmed to 60 ℃ for 2.5 h. Water (100rnL) was added and the solution was extracted with ether. The combined organic phases were dried (MgSO)₄) And concentrated. Flash chromatography (9: 1 hexanes/ethyl acetate) afforded azide 22(628mg, 80%) as a colorless oil.

¹H NMR(CDCl₃) δ 3.4(dd, 1H, J ═ 12.21 and 6.11Hz), 3.3(dd, 1H, J ═ 21.11 and 6.59Hz), 2.30(dd, 1H, J ═ 15.14 and 3.66Hz), 2.25(m, 1H), 2.05(dd, 1H, J ═ 15.14 and 9.04Hz), 1.55(m, 1H), 1.45(s, 9H), 1.35(m, 1H), 0.95(d, 1H, J ═ 6.59Hz), 0.90(d, 1H, J ═ 6.83Hz), 0.80(d, 1H, J ═ 7.08Hz), MS (m/z): (relative intensity): 228[ M-N₂，35％]，172[M-N₂-tBu，100％]Tert-butyl (3R, 4S) -3-aminomethyl-4, 5-dimethyl-hexanoate 23 and [4R- [4R (S) ]]]-4- (1, 2-dimethyl-propyl) -pyrrolidin-2-one 24

Azide 8(640mg, 2.5mmol) and Raney nickel (1g) in methanol (50mL) were shaken under hydrogen for 4 hours. The solution was filtered and the filtrate was concentrated to give a mixture of amine 23 and lactam 24, which was used in the next step without further purification. (3R, 4S) -3-aminomethyl-4, 5-dimethyl-hexanoic acid (example 2)

A solution of amine 23 and lactam 24(500mg) in 3M hydrochloric acid was heated to reflux for 9 hours and then stirred at room temperature for 15 hours. The solution was concentrated and the resulting solid was subjected to purification including ion exchange chromatography in sequence (Dowex50 WX8, strong acid) to form the oxalate, which was then further purified by ion exchange chromatography (Dowex50 WX8, strong acid) to afford example 2(343mg) as a white solid.¹H NMR(D₂O) δ 2.87(m, 2H), 2.22(dd, 1H, J ═ 15.4 and 3.4Hz), 2.12(m, 1H), 1.93(dd, 1H, J ═ 15.4 and 9.5Hz), 1.38(m, 1H), 1.12(m, 1H), 0.77(d, 1H, J ═ 6.6Hz), 0.74(d, 1H, J ═ 6.6Hz), 0.70(d, 1H, J ═ 6.8Hz) MS, m/z (relative intensity): 174[ M + H, 100%].

The following examples can be prepared in a similar manner:

3-aminomethyl-4, 5-dimethyl-hexanoic acid;

(3R, 4S) -3-aminomethyl-4, 5-dimethyl-hexanoic acid MP;

(3S, 4S) -3-aminomethyl-4, 5-dimethyl-hexanoic acid;

(3R, 4R) -3-aminomethyl-4, 5-dimethyl-hexanoic acid MP;

3-aminomethyl-4-isopropyl-hexanoic acid;

3-aminomethyl-4-isopropyl-heptanoic acid;

3-aminomethyl-4-isopropyl-octanoic acid;

3-aminomethyl-4-isopropyl-nonanoic acid;

3-aminomethyl-4-isopropyl-decanoic acid; and

3-aminomethyl-4-phenyl-5-methyl-hexanoic acid.

Method 3

Wherein

R₃OMe or H

R₄＝Me，Et

n is 0 to 2

The compound of structure 30 can be prepared from the compound of structure 29 by treating with an aqueous solution of an acid such as hydrochloric acid at room temperature-reflux temperature. Alternatively, it can be prepared by reacting trifluoroacetic acid with, for example, CH₂Cl₂Or EtOAc, etc. from the compound of structure 32. Compound 32 can be prepared by base mediated hydrolysis of a Boc protected lactam, such as compound 31, where compound 31 itself can be prepared from the compound of structure 29 by treatment with di-tert-butyl dicarbonate in a solvent such as THF and the like. For example, treatment of Boc-lactam 31 with aqueous sodium hydroxide solution can produce acid 32.

Compounds of structure 29 can be prepared from compounds of structure 28(n ═ 0) by treatment with sodium or lithium metal in ammonia. The reaction is preferably carried out in ammonia using sodium metal. On the other hand, compounds of structure 29 can be prepared from compounds of structure 28 (n-1 or 2) by treating with ceric ammonium nitrate (ceric ammonium nitrate) in a mixture of acetonitrile and water. Other methods for removing substituted alkoxybenzyl groups from nitrogen are known in the literature and are described in Green' Protective groups in organic Synthesis, Wiley, 2ed, 1991 and may be used.

The compounds of structure 28 can be prepared from compounds of structure 27 (where LG is a leaving group, such as halide or alkyl sulfonate, preferably iodide can be used) by reactions well known in the art to form carbon-carbon bonds. Several methods exist in the literature for coupling organohalides or Organic alkyl sulfonates with organometallic reagents in the presence of various metal salts, which are summarized in Integrated Organic Synthesis (Comprehensive Organic Synthesis) volume 3: 413, they may be used. For example, compounds of structure 28 can be prepared from compounds of structure 27 (wherein LG is an iodide) by treating with a suitable secondary halide (chloride or iodide) in a solvent such as tetrahydrofuran in the presence of magnesium metal, iodine, and copper dimethyl sulfide bromide. Alternatively, El Marini, Synthesis (Synthesis), 1992: 1104, or a combination thereof. Thus, compounds of structure 28 can be prepared from compounds of structure 27 (where LG is an iodide) by treatment with a suitable methyl-substituted secondary halide, such as iodide, in magnesium, iodine, and a solvent such as tetrahydrofuran in the presence of lithium tetrachlorocuprate.

The compounds of structure 27 incorporate a suitable leaving group that can undergo nucleophilic substitution with a suitable nucleophile. Examples of such leaving groups include: halides, such as chloride, bromide or iodide; and sulfonic acid esters such as methanesulfonate, toluenesulfonate, trifluoromethanesulfonate, nosylate and the like.

Compounds of structure 27 (where LG ═ iodide) can be prepared from compounds of structure 26 by treatment with iodine, triphenylphosphine and imidazole in solvents such as toluene and the like.

The compound of structure 26 can be prepared from the compound of structure 25 by treating with a metal borohydride, such as sodium borohydride, in a solvent such as tetrahydrofuran or DME.

Can be prepared according to the general protocol described by Zonetic et al, journal of organic chemistry (J.org.chem.), 1980; 45: 810-814 or Nielsen et al, J.Org.chem., 1990; 33: 71-77, compound 25 is prepared in a similar manner using a suitable benzylamine such as, but not limited to, benzylamine, 4-methoxybenzylamine or 2, 4-dimethoxybenzylamine.

Alternatively, the compound of structure 26 can be treated with sodium metal and ammonia to provide 4-hydroxymethyl-pyrrolidone, which can be iodinated to provide 4-iodomethyl-pyrrolidone. The 4-iodomethyl-pyrrolidone can then be coupled with an organometallic reagent following the above procedure while avoiding the lactam nitrogen being protected as follows.

A method similar to that described above for the lactam of structure 33 can be used (see general methods for preparation of Nielsen et al, J. org. chem., 1990; 33: 71-77), thereby establishing a fixed stereochemistry at C3 of the final amino acid.

Compounds that can be prepared in this manner include:

3-aminomethyl-5-methyl-6-phenyl-hexanoic acid;

3-aminomethyl-6- (4-chloro-phenyl) -5-methyl-hexanoic acid;

3-aminomethyl-6- (3-chloro-phenyl) -5-methyl-hexanoic acid;

3-aminomethyl-6- (2-chloro-phenyl) -5-methyl-hexanoic acid;

3-aminomethyl-6- (4-fluoro-phenyl) -5-methyl-hexanoic acid;

3-aminomethyl-6- (3-fluoro-phenyl) -5-methyl-hexanoic acid;

3-aminomethyl-6- (2-fluoro-phenyl) -5-methyl-hexanoic acid;

3-aminomethyl-5-methyl-7-phenyl-heptanoic acid;

3-aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;

3-aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;

3-aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;

3-aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid;

3-aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;

3-aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

(3S) -3-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

(3S) -3-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

(3S) -3-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

(3S) -3-aminomethyl-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-5-methyl-octanoic acid;

(3S) -3-aminomethyl-5-methyl-nonanoic acid;

(3S) -3-aminomethyl-5-methyl-decanoic acid;

(3S) -3-aminomethyl-5-methyl-undecanoic acid;

(3S) -3-aminomethyl-5, 7-dimethyl-octanoic acid;

(3S) -3-aminomethyl-5, 8-dimethyl-nonanoic acid;

(3S) -3-aminomethyl-5, 9-dimethyl-decanoic acid;

(3S) -3-aminomethyl-5, 6-dimethyl-heptanoic acid;

(3S) -3-aminomethyl-5, 6, 6-trimethyl-heptanoic acid;

(3S) -3-aminomethyl-5-cyclopropyl-hexanoic acid;

(3S) -3-aminomethyl-6-fluoro-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-7-fluoro-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-8-fluoro-5-methyl-octanoic acid;

(3S) -3-aminomethyl-7, 7, 7-trifluoro-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-8, 8, 8-trifluoro-5-methyl-octanoic acid;

(3S) -3-aminomethyl-5-methyl-hept-6-enoic acid;

(3S) -3-aminomethyl-5-methyl-oct-7-enoic acid;

(3S) -3-aminomethyl-5-methyl-non-8-enoic acid;

(E) - (3S) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(Z) - (3S) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(E) - (3S) -3-aminomethyl-5-methyl-non-6-enoic acid;

(Z) - (3S) -3-aminomethyl-5-methyl-non-6-enoic acid;

(E) - (3S) -3-aminomethyl-5-methyl-non-7-enoic acid;

(Z) - (3S) -3-aminomethyl-5-methyl-non-7-enoic acid;

(E) - (3S) -3-aminomethyl-5-methyl-dec-7-enoic acid;

(Z) - (3S) -3-aminomethyl-5-methyl-dec-7-enoic acid;

3-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

3-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

3-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

3-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

3-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

3-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

3-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

3-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

3-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

3-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

3-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

3-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

3-aminomethyl-5-methyl-heptanoic acid;

3-aminomethyl-5-methyl-octanoic acid;

3-aminomethyl-5-methyl-nonanoic acid;

3-aminomethyl-5-methyl-decanoic acid;

3-aminomethyl-5-methyl-undecanoic acid;

3-aminomethyl-5, 7-dimethyl-octanoic acid;

3-aminomethyl-5, 8-dimethyl-nonanoic acid;

3-aminomethyl-5, 9-dimethyl-decanoic acid;

3-aminomethyl-5, 6-dimethyl-heptanoic acid;

3-aminomethyl-5, 6, 6-trimethyl-heptanoic acid;

3-aminomethyl-5-cyclopropyl-hexanoic acid;

3-aminomethyl-6-fluoro-5-methyl-hexanoic acid;

3-aminomethyl-7-fluoro-5-methyl-heptanoic acid;

3-aminomethyl-8-fluoro-5-methyl-octanoic acid;

3-aminomethyl-7, 7, 7-trifluoro-5-methyl-heptanoic acid;

3-aminomethyl-8, 8, 8-trifluoro-5-methyl-octanoic acid;

3-aminomethyl-5-methyl-hept-6-enoic acid;

3-aminomethyl-5-methyl-oct-7-enoic acid;

3-aminomethyl-5-methyl-non-8-enoic acid;

(E) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(Z) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(E) -3-aminomethyl-5-methyl-non-6-enoic acid;

(Z) -3-aminomethyl-5-methyl-non-6-enoic acid;

(E) -3-aminomethyl-5-methyl-non-7-enoic acid;

(Z) -3-aminomethyl-5-methyl-non-7-enoic acid;

(E) -3-aminomethyl-5-methyl-dec-7-enoic acid; and

(Z) -3-aminomethyl-5-methyl-dec-7-enoic acid.

Method 4

The compound of structure 40 can be prepared from the compound of structure 39 by treatment with diethylaminosulfur trifluoride at-78 deg.C to room temperature and in a solvent such as dichloromethane. Other methods of fluorinating alcohols are known and can be found in Wilkinson in "review of chemistry" (chem.rev.) 1992; 92: 505- > 519 is typically used. The compound of structure 40 can be converted to the essential γ -amino acid as described in method 3 above.

A compound of structure 39 can be prepared from a compound of structure 38 by: treatment with osmium tetroxide and sodium periodate in a solvent such as THF and water and reduction of the resulting intermediate with sodium borohydride in a solvent such as ethanol.

The compounds of structures 38 and 34 can be prepared from the compound of structure 33 according to the principles described in method 3.

An alternative method of synthesizing alcohol 39(n ═ 0) involves treating the compound of structure 36 with a metal borohydride, such as sodium borohydride, in a solvent such as tetrahydrofuran or DME to give the compound of structure 37, which can be fluorinated in a manner similar to the preparation of the compound of structure 40. Compounds of structure 36 can be prepared from compounds of structure 35 by treatment with sodium chloride or lithium chloride in aqueous DMSO at room temperature-reflux temperature. The reaction is preferably carried out using sodium chloride in aqueous DMSO at reflux. Compounds of structure 35 are prepared from compounds of structure 34 by treating with an appropriate diester of methylmalonic acid, such as dimethyl methylmalonate, and the like, and sodium hydride in a solvent such as DMSO or THF, and the like. The reaction is preferably carried out by the following steps: NaH is added to a solution of dimethyl methylmalonate in DMSO, followed by the addition of lactam 34 (where LG is preferably iodide or as defined in method 3) pre-dissolved in DMSO.

Compounds 39 and 37 can be converted to free amino acids with hydroxyl groups by the methods described above.

The following compounds can be prepared in this manner:

(3S) -3-aminomethyl-6-fluoro-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-7-fluoro-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-8-fluoro-5-methyl-octanoic acid;

(3S) -3-aminomethyl-9-fluoro-5-methyl-nonanoic acid;

(3S) -3-aminomethyl-7-hydroxy-5-methyl-heptanoic acid; and

(3S) -3-aminomethyl-6-hydroxy-5-methyl-hexanoic acid.

Method 5

Compounds of structure 41 can be prepared from compounds of structure 39 by treating with a suitable alkyl iodide (or alkyl sulfonate) such as methyl iodide and the like and a base such as n-butyl lithium or sodium hydride and the like in a solvent such as DMSO or THF and the like. The reaction is preferably carried out by the following steps: NaH is added to a solution of alcohol in DMSO, followed by the addition of alkyl iodide and heating of the reaction mixture at room temperature-reflux temperature. The compound of structure 41 is converted to a γ -amino acid as described above.

On the other hand, compounds of structure 41 can be derived from compounds of structure 42 (where LG ═ iodide, bromide, or sulfonate as described in the example of method 3) by treating the appropriate alkoxy anion in a solvent such as DMSO or THF. The compound of structure 42 can also be used as a substrate for carbon-carbon bond formation as outlined in method 3.

Compounds that can be prepared in this manner include:

(3S) -3-aminomethyl-7-hydroxy-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7-methoxy-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7-ethoxy-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7-propoxy-heptanoic acid;

(3S) -3-aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (2-fluoro-ethoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (3, 3, 3-trifluoro-propoxy) -heptanoic acid;

(3S) -3-aminomethyl-6-hydroxy-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6-methoxy-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6-ethoxy-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-5-methyl-6-propoxy-hexanoic acid;

(3S) -3-aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (2-fluoro-ethoxy) -5-methyl-hexanoic acid; and

(3S) -3-aminomethyl-5-methyl-6- (3, 3, 3-trifluoro-propoxy) -hexanoic acid.

Method 6

Can be as described above and by Hoekstra et al Organic Process Research and Development 1997; 1: 26-38 from a compound of structure 45, a compound of structure 53 is prepared.

The compound of structure 45 can be prepared from the compound of structure 44 by treating with a solution of chromium trioxide in water/sulfuric acid. Hudlicky, Oxidation in Organic Chemistry, ACS journal 186, ACS 1990: 77 by an alternative method of cleaving the alkene at 44.

Compounds of structure 44 (wherein R is R) can be prepared from (S) -citronellyl bromide by reactions well known in the art to form carbon-carbon bonds and as described in method 3₂Alkyl, branched alkyl, cyclopentyl, alkyl-cycloalkyl). Halides substituted with alkoxy anions in (S) -citronellyl bromide, where R ═ alkoxy or phenoxy ethers (and suitable substituents thereof as in formula 1), may also be used to form compounds of structure 44. On the other hand, ethers may be obtained by treating (S) -citronellol with a base, such as sodium hydride, and treating the resulting alkoxide with a suitable alkyl halide to provide compounds of structure 44. In another approach, (S) -citronellyl bromide (or a suitable sulfonate ester such as, but not limited to, (S) -3, 7-dimethyl-oct-6-enyl methanesulfonate) can be reduced to (R) -2, 6-dimethyl-oct-2-ene using a suitable metal borohydride or using an aluminum hydride species such as LAH.

One skilled in the art will appreciate that the appropriate selection of R-or S-citronellol or R-or S-citronellyl bromide can produce the requisite isomer at the final amino acid C5.

Compounds that can be prepared in this manner include:

(3S, 5S) -3-aminomethyl-7-methoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7-propoxy-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-isopropoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-fluoro-ethoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7-benzyloxy-5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7-phenoxy-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (4-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (3-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (4-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (3-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (4-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (3-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-7- (2-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (4-nitro-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (3-nitro-phenoxy) -heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-7- (2-nitro-phenoxy) -heptanoic acid;

(3S, 5R) -3-aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;

(3S, SR) -3-aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-decanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-undecanoic acid;

(3S, 5R) -3-aminomethyl-5, 9-dimethyl-decanoic acid;

(3S, 5S) -3-aminomethyl-7-fluoro-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-8-fluoro-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-8, 8, 8-trifluoro-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-7-phenyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid; and

(3S, 5R) -3-aminomethyl-5, 10-dimethyl-undecanoic acid.

Method 7

Can be carried out by a process such as CH₂Cl₂Compounds of structure 58 are prepared from compounds of structure 57 by treating with boron trifluoride diethyl etherate and triethylsilane in such solvents. On the other hand, canThe use of Meyers, journal of organic chemistry (j.org.chem.) 1993; 58: 36-42, whereby a compound of structure 57 is treated with sodium cyanoborohydride and 3% HCl in methanol in a solvent such as THF/methanol.

Can be determined according to Koot in Tetrahedron letters 1992; 33: 7969 procedures in 7972A compound of structure 57 is prepared from a compound of structure 56 by treatment with dimethylamine in a solvent such as DMF.

A compound of structure 56 can be prepared from a compound of structure 54 by: the appropriate primary halide 55 (iodide, bromide or chloride) is treated with tBuLi under standard transmetallation conditions and the resulting organometallic reagent is treated with an appropriate copper salt such as, but not limited to, copper bromide or copper iodide. The resulting organocuprate is added to a lactam in a solvent such as THF (see Koot et al, J. org. chem., 1992; 57: 1059-1061 for the preparation of chiral lactam 54). This method is described by Koot in Tetrahedron letters 1992; 33: 7969 the process of 7972 is typical.

One skilled in the art will appreciate that appropriate selection of the R-or S-primary halide 55 will yield the requisite isomer at the final amino acid C5.

Compounds that can be prepared in this manner include:

(3S, 5S) -3-aminomethyl-5-methoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-ethoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-propoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-isopropoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-tert-butoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-fluoromethoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-fluoro-ethoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3, 3, 3-trifluoro-propoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-phenoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-chloro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-fluoro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-methoxy-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (4-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (3-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5- (2-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-propoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-isopropoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-fluoro-ethoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6- (3, 3, 3-trifluoro-propoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-phenoxy-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl 6- (4-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl 6- (3-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl 6- (2-trifluoromethyl-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl 6- (4-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl 6- (3-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl 6- (2-nitro-phenoxy) -hexanoic acid;

(3S, 5S) -3-aminomethyl-6-benzyloxy-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-decanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-undecanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-dodecanoic acid;

(3S, 5R) -3-aminomethyl-5, 7-dimethyl-octanoic acid;

(3S, 5R) -3-aminomethyl-5, 9-dimethyl-decanoic acid;

(3S, 5R) -3-aminomethyl-5, 10-dimethyl-undecanoic acid;

(3S, 5S) -3-aminomethyl-5, 6-dimethyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5, 6, 6-trimethyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-cyclopropyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6-fluoro-5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-7-fluoro-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-8-fluoro-5-methyl-octanoic acid;

(3S, 5S) -3-aminomethyl-7, 7, 7-trifluoro-5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-8, 8, 8-trifluoro-5-methyl-octanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-6-phenyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-chloro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (4-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-methoxy-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (3-fluoro-phenyl) -5-methyl-hexanoic acid;

(3S, 5S) -3-aminomethyl-6- (2-fluoro-phenyl) -5-methyl-hexanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-7-phenyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-chloro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-methoxy-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (4-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (3-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5R) -3-aminomethyl-7- (2-fluoro-phenyl) -5-methyl-heptanoic acid;

(3S, 5S) -3-aminomethyl-5-methyl-hept-6-enoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-oct-7-enoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-non-8-enoic acid;

(E) - (3S, 5S) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(Z) - (3S, 5S) -3-aminomethyl-5-methyl-oct-6-enoic acid;

(Z) - (3S, 5S) -3-aminomethyl-5-methyl-non-6-enoic acid;

(E) - (3S, 5S) -3-aminomethyl-5-methyl-non-6-enoic acid;

(E) - (3S, 5R) -3-aminomethyl-5-methyl-non-7-enoic acid;

(Z) - (3S, 5R) -3-aminomethyl-5-methyl-non-7-enoic acid;

(Z) - (3S, 5R) -3-aminomethyl-5-methyl-dec-7-enoic acid; and

(E) - (3S, 5R) -3-aminomethyl-5-methyl-undec-7-enoic acid.

Method 8

This can be done by the methods described in Mitsunobu, Synthesis (Synthesis) 1981: treating the compound of structure 59 with an appropriately substituted phenol (including phenol itself) under the conditions described in 1 to prepare the compound of structure 60.

The compound of structure 59 can be prepared from the compound of structure 39 by treating with metallic sodium or lithium or the like in ammonia. The reaction is preferably carried out using metallic sodium in ammonia.

Direct hydrolysis of compound 60 can yield the desired amino acid and means of hydrolysis of the lactam protected by Boc can be used.

Compounds that can be prepared in this manner include:

(3S) -3-aminomethyl-5-methyl-7-phenoxy-heptanoic acid;

(3S) -3-aminomethyl-7- (4-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (3-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (2-chloro-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (4-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (3-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (2-fluoro-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (4-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (3-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-7- (2-methoxy-phenoxy) -5-methyl-heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (4-trifluoromethyl-phenoxy) -heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (3-trifluoromethyl-phenoxy) -heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (2-trifluoromethyl-phenoxy) -heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (4-nitro-phenoxy) -heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (3-nitro-phenoxy) -heptanoic acid;

(3S) -3-aminomethyl-5-methyl-7- (2-nitro-phenoxy) -heptanoic acid;

(3S) -3-aminomethyl-6- (3-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (2-chloro-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (4-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (3-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (2-fluoro-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (4-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (3-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-6- (2-methoxy-phenoxy) -5-methyl-hexanoic acid;

(3S) -3-aminomethyl-5-methyl 6- (4-trifluoromethyl-phenoxy) -hexanoic acid;

(3S) -3-aminomethyl-5-methyl 6- (3-trifluoromethyl-phenoxy) -hexanoic acid;

(3S) -3-aminomethyl-5-methyl 6- (2-trifluoromethyl-phenoxy) -hexanoic acid;

(3S) -3-aminomethyl-5-methyl 6- (4-nitro-phenoxy) -hexanoic acid;

(3S) -3-aminomethyl-5-methyl 6- (3-nitro-phenoxy) -hexanoic acid;

(3S) -3-aminomethyl-5-methyl 6- (2-nitro-phenoxy) -hexanoic acid;

(3S) -3-aminomethyl-5-methyl-6-phenoxy-hexanoic acid; and

(3S) -3-aminomethyl-6- (4-chloro-phenoxy) -5-methyl-hexanoic acid.

Method 9

Synthesis of C-4 substituted analogs

Compounds of structure 64 can be prepared from compounds of structure 63 by treating 63 with hydrogen at 50psi in the presence of a catalyst such as raney nickel and a base such as triethylamine in an organic solvent such as methanol. The resulting product is then treated with an aqueous acid solution such as 6N HCl at room temperature-reflux temperature. The resulting mixture may be subjected to ion exchange chromatography to isolate product 64.

Compounds of structure 63 can be prepared from compounds of structure 62B by treating with a suitable base such as, but not limited to, sodium hydride, n-butyl lithium, and the like, and an alkylating agent such as tert-butyl bromoacetate or benzyl bromoacetate in a solvent such as DMSO or THF. The reaction was carried out by treating a solution of the compound of structure 62B in THF with sodium hydride and alkylating the resulting anion with tert-butyl bromoacetate.

Compounds of structure 62B can be prepared from compounds of structure 62A by treating with sodium chloride in a solvent such as aqueous DMSO at a temperature of 50 ℃ to reflux.

Compounds of structure 62A may be prepared from compounds of structure 61 by the following steps: treatment with a suitable alkyl metal halide, such as an alkyl lithium reagent or an organomagnesium halide, in a solvent such as THF or diethyl ether in the presence of a copper salt such as, but not limited to, copper iodide, copper bromide, dimethyl sulfide. Alternatively, the reaction may be carried out by treating the nitrile with an alkyl magnesium chloride in a solvent such as diethyl ether at or below room temperature.

Compounds such as 61 can be prepared according to procedures well known in the literature for condensation between isobutyraldehyde and methylcyanoacetate.

The method 10 comprises the following steps: c-4 substitution

Double branched 3-substituted GABA analogs can be prepared from azide 71 in two steps: the lactam obtained is obtained by hydrogenation of azide 71 in the presence of a noble metal catalyst, such as 5% palladium on carbon, and hydrolysis with a strong acid, such as 6N HCl, under reflux. The final product 72 can then be isolated using ion exchange chromatography.

Compound 71 can be prepared in two steps: the lactone, such as 70, is treated with HBr in a solvent such as ethanol at a temperature such as 0 deg.C and the resulting bromide is reacted with sodium azide at a temperature of 10 deg.C to 80 deg.C in a solvent such as dimethyl sulfoxide.

Lactone 70 can be prepared in two steps: by oxidizing a compound such as sodium periodate, such as 69, with an oxidizing agent in methanol in the presence of a catalytic amount of ruthenium trichloride in a solvent such as acetonitrile at a temperature of 0 ℃ to 100 ℃ and subsequently treating the resulting compound with potassium carbonate at a temperature of 25 ℃ to 70 ℃ and then with an acid such as p-toluenesulfonic acid in a solvent such as THF or an aqueous acid such as aqueous HCl at ambient temperature and at reflux.

Compounds such as 69 can be prepared by the following steps: compounds such as 68 are reduced with a hydride reducing agent such as lithium aluminum hydride in a solvent such as diethyl ether or THF and the resulting alcohol is reacted with an acylating agent such as acetic anhydride in the presence of a base such as triethylamine or pyridine.

The compounds of structure 68 can be prepared from compounds such as 67 by reaction with hydrogen at about 50psi in a solvent such as ethanol in the presence of a noble metal catalyst such as 5% palladium on carbon. Compounds of general formula 67 can be prepared by reacting a compound of structure 66 with an ethanol solution saturated with hydrogen bromide. Compounds such as 66 can be prepared from compounds such as 65 by treating a compound such as a ketone with a strong base such as lithium diisopropylamine at a temperature such as-78 ℃ and in a solvent such as THF and reacting the resulting anion with a compound such as benzyl bromide or benzyl iodide. Optically active forms of compounds of structure 66 (R ═ H or lower alkyl) (Davies, J.org.chem., 1999; 64 (23): 8501-.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

Example 3: synthesis of 3-aminomethyl-5-methyl-octanoic acid

1-benzyl-4-hydroxymethyl-pyrrolidin-2-one 74

Sodium borohydride (8.0g, 0.211mol) was added to a solution of methyl-1-benzyl-5-oxo-3-pyrrolidinecarboxylate 73 (see Zonetic et al, J.org.chem., 1980; general Synthesis procedure of 45: 810-814) (32.0g, 0.137mol) in 1, 2-dimethoxyethane (600mL) and refluxed for 19 hours. The reaction was cooled to room temperature and 200mL of water was added. The reaction was quenched with 1M citric acid and concentrated under reduced pressure. The residue was extracted with dichloromethane, dried over magnesium sulphate and evaporated to dryness to give 17.47g of 62% alcohol 74 as a clear oil.

¹H NMR(CDCl₃) δ 7.30(m, 5H), 4.38(d, 1H, J ═ 14.7), 4.46(d, 1H, J ═ 14.7), 3.56(m, 2H), 3.36(m, 1H), 3.10(m, 1H), 2.52(m, 2H), 2.26(m, 1H). MS, m/z (relative intensity): 207[ M +2H, 66%]IR (KBr)3345, 2946, 2866, 1651, 1445, 1025, 737, and 698cm^-1.

1-benzyl-4-iodomethyl-pyrrolidin-2-one 75

To the alcoholic lactam 74(11.18g, 0.056mol) in 210mL of toluene was added sequentially triphenylphosphine (20.0g, 0.076mol), imidazole (10.8g, 0.159mol) and iodine (19.0g, 0.075 mol). After stirring the suspension for 1.5 hours, the supernatant was poured into another flask. The viscous yellow residue was washed twice with diethyl ether and the solutions were combined. The solvent was evaporated and the residue was chromatographed on silica gel, eluting with 1: 1 acetone/hexane to give 7.92g, 46% iodolactam 75 as a yellow oil.¹H NMR(CDCl₃) δ 7.25(m, 5H), 4.38(d, 1H, J ═ 14.6), 4.46(d, 1H, J ═ 14.6), 3.38(dd, 1H, J ═ 7.8 and 2.2), 3.20(dd, 1H, J ═ 5.6 and 4.4), 3.12(dd, 1H, J ═ 7.3 and 2.4), 2.96(dd, 1H, J ═ 5.8 and 4.4), 2.60(m, 2H), 2.22(dd, 1H, J ═ 10.5 and 9.7), MS, m/z (relative strength): 224[ M-H-Bn, 94% ]]，317[M+2H，64％]IR 3027, 2917, 1688, 1438, 1267, and 701cm^-1.

1-benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76

To a suspension of magnesium powder (0.50g, 0.021mol) in 15mL dry THF under a nitrogen atmosphere was added iodine crystals and 2-bromopentane (2.88g, 0.019 mol). After the cooled exothermic reaction was periodically taken in an ice bath, the reaction was stirred at room temperature for 2 hours. 8ml of Li were added at 0 deg.C₂CuCl₄(from 84mg LiCl and 134mg CuCl₂Prepared in 10mL of dry THF), followed by dropwise addition of 1-benzyl-4-iodomethyl-pyrrolidin-2-one 75 in 15mL of dry THF and maintaining the resulting suspension under stirring at 0 ℃ for 3 hours. Stirring was continued at room temperature for 1 hour, after which time it was quenched with saturated ammonium chloride solution. Water was added to dissolve the precipitate formed and the solution was then extracted with ether and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel 1: 1 acetone/hexane to give 1.13g, 69% of 1-benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76.¹H NMR(CDCl₃) Δ 7.30(m, 5H), 4.44(m, 2H), 3.32(m, 1H), 2.86(m, 1H), 2.56(m, 1H), 2.40(m, 1H), 2.10(m, 1H), 1.30(m, 6H), 1.10(m, 1H), 0.90 "m, 6H. MS, m/z (relative to

Strength): 261[ M +2H, 100%]，301[M-H+CH₃CN，82％]，260[M+H，72％].

4- (2-methyl-pentyl) -pyrrolidin-2-one 77

A250 mL 3-necked flask equipped with a dry ice condenser was cooled to-78 ℃. Ammonia (80mL) was condensed into the flask and 1-benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76(1.67g, 0.006mol) in 15mL THF was added. Freshly cut sodium beads were added until a dark blue color persisted. The cooling bath was removed and the reaction was stirred under reflux (-33 ℃) for 1 hour. The reaction was quenched with ammonium chloride and excess ammonia was evaporated. The resulting residue was diluted with water, extracted with dichloromethane and dried over magnesium sulfate. Evaporation of the solvent followed by chromatography on silica gel eluting with 1: 1 acetone/hexane afforded 0.94g, 86% 4- (2-methyl-pentyl) -pyrrolidin-2-one 77.¹H NMR(CDCl₃) δ 6.25(br, 1H), 3.44(m, 1H), 2.95(m, 1H), 2.54(m, 1H), 2.40(m, 1H), 1.98(m, 1H), 1.30(m, 6H), 0.80(m, 6H). MS, m/z (relative intensity): 212[ M +2H + CH₃CN，100％]，171[M+2H，72％]，170[M+1H，65％].

3-aminomethyl-5-methyl-octanoic acid (example 3)

4- (2-methyl-pentyl) -pyrrolidin-2-one 77(0.94g, 0.007mol) was dissolved in 70mL of 6N HCl and refluxed for 20 hours. The solution was evaporated in vacuo and the aqueous solution of the residue was put on a Dowex50 WX8-100 (strong acid) ion exchange resin which had been washed with HPLC grade water. The column was first eluted with water until the eluent was at constant pH and then eluted with 5% ammonium hydroxide solution. The ammonium hydroxide fraction was evaporated and azeotroped with toluene. The white solid was washed with acetone, filtered and dried in a vacuum oven for 24 hours to give 0.61g, 59% of the amino acid.

¹H NMR(CD₃OD) δ 3.00(m, 1H), 2.85(m, 1H), 2.48(m, 1H), 2.30(m, 1H), 2.14(brm, 1H), 1.60(brm, 1H), 1.38(m, 4H), 1.18(m, 2H), 0.60(m, 6H) MS, m/z (relative intensity): 188[ M + H, 100%].

Example 4: synthesis of 3-aminomethyl-5, 7-dimethyl-octanoic acid

Example 4

1- (4-methoxy-benzyl) -5-oxo-pyrrolidine-3-carboxylic acid methyl ester 79

4-methoxybenzylamine (42g, 0.306mol) in methanol (40mL) at 0 ℃ was added to dimethyl itaconate (48g, 0.306mol) in methanol (13 mL). The solution was stirred at room temperature for 4 days. 1N HCl was added to the solution followed by diethyl ether. The layers were separated and the aqueous phase was extracted with ether. The combined organic phases were dried (MgSO)₄). Upon filtration of the desiccant, the desired material 79 precipitated from the solution was collected and dried in vacuo. 23.26g, 29%. MS, m/z (relative intensity): 264[ M + H, 100%]To C₁₄H₁₇N₁O₄Calculated analytical values: c, 63.87; h, 6.51; n, 5.32. Measurement value: c, 63.96; h, 6.55; and N, 5.29.

4-hydroxymethyl-1- (4-methoxy-benzyl) -pyrrolidin-2-one 80

Reacting NaBH at room temperature₄(15g, 0.081mol) were added portionwise to 79 in ethanol (600 mL). After 4.5 hours, water (. about.200 mL) was carefully added to the reaction and the solution was stirred at room temperature overnight. The resulting solid was removed by filtration and the filtrate was concentrated to give alcohol 80 as an oil. 15.33g, 81%. MS, m/z (relative intensity): 235[ M + H, 100%]. 4-iodomethyl-1- (4-methoxy-benzyl) -pyrrolidin-2-one 81

To the alcohol 80 in PhMe (12.9g, 0.055mol) was added triphenylphosphine (20g, 0.077mol), imidazole (10.8g, 0.16mol) and iodine (19g, 0.075 mol). The suspension was stirred at room temperature for 5 hours. Saturated aqueous sodium thiosulfate was added and the layers were separated. The aqueous phase was extracted with ether and the combined organic phases were washed with brine, dried (MgSO)₄) And concentrated. Flash chromatography of the residue (6: 1-4: 1 toluene/acetone) afforded iodide 81 as an oil. 11.9g, 63%. MS, m/z (relative intensity): 346[ M + H, 100%].4- (2, 4-dimethyl-pentyl) -1- (4-methoxy-benzyl) -pyrrolidin-2-one 82

Using a procedure analogous to the preparation of 1-benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76 gives 4- (2, 4-dimethyl-pentyl) -1- (4-methoxy-benzyl) -pyrrolidin-2-one as an oil. 1.22g, 29%. MS, m/z (relative intensity): 304[ M + H, 100% ]. 4- (2, 4-dimethyl-pentyl) -pyrrolidin-2-one 83

To lactam (1.17g, 3.86mmol) in MeCN (20mL) at 0 deg.C was added H₂Ceric ammonium nitrate (4.2g, 7.7mmol) in O (10 mL). After 50 minutes, a further portion of ceric ammonium nitrate (2.1g, 3.86mmol) was added and after 1 hour the mixture was adsorbed on silica gel and flash chromatographed to give an oil. MS, m/z (relative intensity): 183[ M + H, 100%]。

3-aminomethyl-5, 7-dimethyl-octanoic acid (example 4)

The amino acid was obtained as a solid using a procedure analogous to the preparation of 3-aminomethyl-5-methyl-octanoic acid (example 3). MS, m/z (relative intensity): 202[ M + H, 100% ].

Example 5: synthesis of (S) -3-aminomethyl-5-methyl-octanoic acid

Example 5

(S) -4-hydroxymethyl-1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 84

To ester 33(49g, 0.198mol) in EtOH (600mL) was added sodium borohydride (22g, 0.595 mol). After 7 hours, 1M citric acid was carefully added and after the foam had stopped to evolve, water was added to stop the reaction completely. Ethanol was removed under reduced pressure and ethyl acetate was added. The resulting two layers were separated, the aqueous phase was extracted with EtOAc and the combined organic phases were dried (MgSO)₄) And concentrated to obtain heavy oil. MS, m/z (relative intensity): [ M + H, 100%]。

(S) -4-iodomethyl-1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 85

Using a procedure similar to iodination of compound 80 gave iodide 85 as an oil. 35.2g, 56%. To C₁₃H₁₆I₁N₁O₁Calculated analytical values: c, 47.43; h, 4.90; n, 4.25. measurement: c, 47.41; h, 4.83; and N, 4.17.

4- (2-methyl-pentyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 86

Using a procedure similar to that used to prepare 1-benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76 gives 2.71g, 81.0% 86 as an oil. MS, m/z (relative intensity): 274[ M +1H, 100%]，315[M+H+CH₃CN，65％]。

(S) -4- (2-methyl-pentyl) -pyrrolidin-2-one 87

Using a procedure similar to that for preparation of 4- (2-methyl-pentyl) -pyrrolidin-2-one 77 gives 1.14g, 72.8% 87 as an oil. MS, m/z (relative intensity): 170[ M +1H, 10%]，211[M+1H+CH₃CN，90％]。

Example 5: (S) -3-aminomethyl-5-methyl-octanoic acid

Similar procedure as for the preparation of 3-aminomethyl-5-methyl-octanoic acid (example 3) was used to give 0.88g of amino acid (example 5), 74.3%.

¹H NMR(CD₃OD)δ2.95(m，1H)，2.80(m，1H)，2.40(m，1H)，2.25(m，1H)，2.05(brm，1H)，1.50(brm，1H)，1.30(m，4H)，1.10(m，2H)，0.90(m，6H).

MS, m/z (relative intensity): 188[ M +1H, 100%]，186[M-1H，100％]，229[M+1H+CH₃CN，30％].

Example 6: synthesis of (S) -3-aminomethyl-7-methoxy-5-methyl-heptanoic acid

(S) -4- (2-methyl-pent-4-enyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 88

Using a procedure analogous to that for preparation of 1-benzyl-4- (2-methyl-pentyl) -pyrrolidin-2-one 76 gives adduct 88 as an oil. 6g, 74%. MS, m/z (relative intensity): 272[ M + H, 100% ].

(S) -4- (4-hydroxy-2-methyl-butyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 89

Mixing OsO₄(2mL of a 4% solution in t-BuOH) was added to the solution in THF/H₂Olefin 88(5.8g, 0.021mol) in O (3: 1, 100 mL). After 1 hour, sodium periodate (11.4g, 0.053mol) was added. After 2 hours, the suspension was filtered and washed with dichloromethaneThe solid was washed with an alkane. The filtrate was concentrated and the residue was azeotroped with toluene. The residue was dissolved in ethanol and sodium borohydride (2.5g) was added. The suspension was stirred at room temperature overnight. 1N citric acid was added and the mixture was diluted with ether. The resulting two layers were separated and the aqueous phase was extracted with ether and the combined organic phases were dried (MgSO₄) And concentrated. The residue was flash chromatographed (1: 1 hexane/EtOAc) to give an oil. 4.2g, 73%. MS, MS, m/z (relative intensity): 276[ M + H, 100%]. (S) -4- (4-methoxy-2-methyl-butyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 90

To alcohol 89(2g, 7.66mmol) in DMSO (60mL) at room temperature was added NaH (368mg, 60% in oil). After 30 min, methyl iodide (1.08g, 7.66mmol) was added and the solution was stirred at room temperature overnight at which time the reaction was diluted with water (500 mL). The solution was extracted with ether and the combined organic extracts were dried (MgSO)₄) And concentrated. Flash chromatography of the residue (90% -50% hexane/acetone) afforded product 90 as an oil (1.1g, 52%). MS M/z290 (M + H, 100%).

(S) -4- (4-methoxy-2-methyl-butyl) -pyrrolidin-2-one 91

Using a procedure analogous to that for preparation of 4- (2-methyl-pentyl) -pyrrolidin-2-one 77 gives lactam 91 as an oil. MS, m/z (relative intensity): 186[ M + H, 100% ].

Example 6: (S) -3-aminomethyl-7-methoxy-5-methyl-heptanoic acid

The procedure was carried out in a similar manner to synthetic example 3. The resulting amino acid isolated from ion exchange chromatography was recrystallized from methanol/ethyl acetate to give example 6 as a white solid. MSm/z 204(M + H, 100%). To C₁₀H₂₁N₁O₃Calculated analytical values: c, 59.09; h, 10.41; and N, 6.89. Measurement value: c, 58.71; h, 10.21; n, 6.67.

Example 7: synthesis of (S) -3-aminomethyl-6-fluoro-5-methyl-hexanoic acid

Example 7

2-methyl-2- [ (S) -5-oxo-1- ((S) -1-phenyl-ethyl) -pyrrolidin-3-ylmethyl ] -malonic acid dimethyl ester 92

To dimethyl methylmalonate (1.06g, 7.29mmol) in DMSO (7mL) at room temperature was added NaH (291mg of a 60% dispersion in oil). After cessation of foaming, lactam 85(2g, 7.29mol) in DMSO (5mL) was added. After 1 hour, water was added and the aqueous solution was extracted with ether. Drying the combined organic extracts (MgSO)₄) And concentrated. Flash chromatography (1: 1 hexane/acetone) of the residue afforded the product as an oil (1.7g, 81%). MS M/z348(M + H, 100%).

2-methyl-3- [ (S) -5-oxo-1- ((S) -1-phenyl-ethyl) -pyrrolidin-3-yl ] -propionic acid methyl ester 93

Ester 92(483mg, 1.4mmol), NaCl (104mg, 1.8mmol), water (105. mu.L) and DMSO (5mL) were heated to reflux for 2 h. The solution was cooled to room temperature, water was added and the aqueous solution was extracted with ether. Drying the combined organic extracts (MgSO)₄) And concentrated. Flash chromatography (80% -66% hexane/acetone) of the residue afforded an oil (160mg, 40%). MSm/z 290(M + H, 100%).

(S) -4- (3-hydroxy-2-methyl-propyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 37

To ester 93(4.82g, 0.017mol) in EtOH (100mL) was added NaBH₄(3.7g, 0.10mol) and the mixture was heated to reflux for 2.5 hours. The solution was cooled to 0 ℃ and 1M citric acid was carefully added followed by water. The solution was concentrated to half the volume added and extracted with ether. Drying the combined organic extracts (MgSO)₄) And concentrated. Flash chromatography (1: 1 hexane/acetone) of the residue afforded the product as an oil (2.6g, 59%). MS M/z 262(M + H, 100%).

(S) -4- (3-fluoro-2-methyl-propyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 94

At-78 ℃ in CH₂Cl₂DAST (1g, 6.2mmol) in (20mL) was added in CH₂Cl₂Alcohol 37 in (10 mL). After 1 hour at-78 ℃, the solution was warmed to room temperature. After 7 hours, the solution was carefully quenched with saturated aqueous sodium bicarbonate and the two layers were separated. The organic phase was dried (MgSO)₄) And concentrated. Flash chromatography of the residue (90% -66% hexane/acetone) afforded the product as an oil (600mg, 37%). MS M/z 264(M + H, 100%). (S) -4- (3-fluoro-2-methyl-propyl) -1-pyrrolidin-2-one 95

Similar procedure as used for the preparation of 4- (2-methyl-pentyl) -pyrrolidin-2-one 77 was used to give the lactam as an oil (242mg, 68%). MS M/z 159(M, 100%).

Example 7(S) -3-aminomethyl-6-fluoro-5-methyl-hexanoic acid

The procedure was carried out analogously to Synthesis example 3. The resulting amino acid isolated from ion exchange chromatography was recrystallized from methanol/ethyl acetate to give example 7 as a white solid. MS M/z 177(M, 100%). To C₈H₁₆F₁N₁O₂：0.02H₂Calculated analytical values of O: c, 54.11; h, 9.10; and N, 7.89. Measurement value: c, 53.75; h, 9.24; and N, 7.72.

Example 8: synthesis of (S) -3-aminomethyl-6-methoxy-5-methyl-hexanoic acid

Example 8

(S) -4- (3-methoxy-2-methyl-propyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 96

Using a procedure analogous to that for preparation of (S) -4- (4-methoxy-2-methyl-butyl) -1- ((S) -1-phenyl-ethyl) -pyrrolidin-2-one 90 gave ether 96 as an oil (90mg, 37%). MS M/z 276(M + H, 100%).

(S) -4- (3-methoxy-2-methyl-propyl) -pyrrolidin-2-one 97

Using a procedure analogous to preparation of 4- (2-methyl-pentyl) -pyrrolidin-2-one 77 gave ether 97 as an oil (760mg, 93%). MS M/z 171(M + H, 100%).

Example 8(S) -3-aminomethyl-6-methoxy-5-methyl-hexanoic acid

The procedure was carried out analogously to Synthesis example 3. The resulting amino acid isolated from ion exchange chromatography was recrystallized from methanol/ethyl acetate to give example 8 as a white solid. MS M/z 190(M + H, 100%). To C₉H₁₉N₁O₃Calculated analytical values: c, 57.12; h, 10.12; measurement value: c, 57.04; h, 10.37; and N, 7.30. The second batch precipitated from the mother liquor (via)¹H NMR confirmed the 1: 5 ratio of the C5 isomers). MS M/z 190(M + H, 100%).

Example 9: synthesis of (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid hydrochloride

(R) -2, 6-dimethyl-non-2-ene 98

To (S) -citronellyl bromide (50g, 0.228mol) in THF (800mL) at 0 deg.C was added LiCI (4.3g), followed by CuCl₂(6.8 g). After 30 minutes, methylmagnesium chloride (152mL of 3M in THF, Aldrich) was added and the solution warmed to room temperature. After 10 hours, the solution was cooled to 0 ℃ and saturated aqueous ammonium chloride solution was carefully added. The resulting layers were separated and the aqueous phase was extracted with diethyl ether. The combined organic phases were dried (MgSO)₄) And concentrated to an oil. 32.6 g; 93 percent. Used without further purification.

(R) -4-methyl-heptanoic acid 99

CrO was added to alkene 98(20g, 0.13mol) in acetone (433mL) over 50 minutes₃(39g, 0.39mol) in H₂SO₄(33mL)/H₂Solution in O (146 mL). After 6 hours, a certain amount of hydrogen peroxide is added₂SO₄(22mL)/H₂CrO in O (100mL)₃(26g, 0.26 mol). After 12 hours, the solution was diluted with brine and extracted with ether. The combined organic phases were dried (MgSO)₄) And concentrated. Flash chromatography (gradient 6: 1-2: 1 hexanes/EtOAc) afforded product 99 as an oil. 12.1 g; MS, m/z (relative intensity): 143[ M-H, 100%]。

(4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one 100

To the acid 99(19g, 0.132mol) and triethylamine (49.9g, 0.494mol) in THF (500mL) at 0 deg.C was added trimethylacetyl chloride (20g, 0.17 mol). After 1 hour, LiCl (7.1g, 0.17mol) was added followed by oxazolidinone (30g, 0.17 mol). The mixture was warmed to room temperature and after 16 hours, the filtrate was filtered off by filtration and the solution was concentrated under reduced pressure. Flash chromatography (7: 1 hexanes/EtOAc) afforded product 100 as an oil. 31.5 g; 79 percent. [ alpha ] to]_D5.5(c 1 in CHCl)₃In (1). MS, m/z (relative intensity): 304[ M + H, 100%]。

(3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester 101

To oxazolidinone 100(12.1g, 0.04mol) in THF (200mL) at-50 ℃ was added NaHMDS (48mL of a 1M solution in THP). After 30 min, tert-butyl bromoacetate (15.6g, 0.08mol) was added. The solution was stirred at-50 ℃ for 4 hours and then warmed to room temperature. After 16 hours, a saturated aqueous solution of ammonium chloride was added and the two layers were separated. The aqueous phase was extracted with diethyl ether and the combined organic phases were dried (MgSO)₄) And concentrated. Flash chromatography (9: hexanes/EtOAc) afforded product 101 as a white solid. 12g of a mixture; 72 percent. [ alpha ] to]_D30.2(c1 in CHCl)₃In (1).¹³C NMR(100MHz；CDCl₃)176.47，171.24，152.72，133.63，128.87，125.86，80.85，78.88，55.34，39.98，38.77，38.15，37.58，30.60，28.23，20.38，20.13，14.50，14.28.

(S) -2- ((R) -2-methyl-pentyl) -succinic acid 4-tert-butyl ester 102

At 0 ℃ in H₂O (73mL) and ester 101(10.8g, 0.025mol) in THF (244mL) were added LiOH (51.2mL of a 0.8M solution) and H₂O₂(14.6mL of a 30% solution). After 4 hours, an additional 12.8mL LiOH (0.8M solution) and 3.65mL H were added₂O₂(30% solution). After 30 minutes, sodium bisulfite (7g), sodium sulfite (13g) and water (60mL) were added followed by hexane (100mL) and ether (100 mL). The layers were separated and the aqueous layer was extracted with ether. The combined organic phases were concentrated to an oil, which was dissolved in heptane (300 mL). The resulting solid was removed by filtration and the filtrate was dried (MgSO₄) And concentrated to give an oil (6g, 93%) which was used without further purification. MS, m/z (relative intensity): 257[ M + H, 100%]。

(3S, 5R) -3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 103

To acid 102(3.68g, 0.014mol) in THF (100mL) at 0 deg.C was added BH₃.Me₂(36mL of a 2M solution in THF, Aldrich) at which time the solution was warmed to room temperature. After 15 hours, ice was carefully added to the solution (to control foaming) followed by brine. The solution was extracted with ether and the combined organic phases were dried (MgSO)₄) And concentrated under reduced pressure. Flash chromatography (4: 1 hexanes/EtOAc) afforded alcohol 103 as an oil (2.0g, 59%).¹³CNMR(100MHz；CDCl₃)173.56，

80.85, 65.91, 39.74, 39.20, 38.90, 35.65, 29.99, 28.31, 20.18, 19.99, 14.56.(3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -octanoic acid tert-butyl ester 104

To room temperature in CH₂Cl₂To alcohol 103(1.98g, 8.1mmol) in (40mL) was added triethylamine (2.4g, 0.024mol), DMAP (20mg) and tosyl chloride (2.3g, 0.012 mol). After 14 hours, 1N HCl was added and the layers were separated. The aqueous phase was extracted with diethyl ether and the combined organic phases were dried (MgSO)₄) And concentrated. Flash chromatography (95% hexanes/EtOAc) afforded tosylate 104 as an oil (2.94g, 91%).¹³C NMR(100MHz；CDCl₃)171.60，144.92，133.07，130.02，128.12，80.80，72.15，39.73，38.09，37.89，32.67，29.71，28.22，21.83，20.10，19.54，14.49.

(3S, 5R) -3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105

Tosylate 104(2.92g, 7.3mmol) and sodium azide (1.43g, 0.02mol) were warmed to-50 ℃ in DMSO (30 mL). After 2 hours, the solution was cooled to room temperature and diluted with water. The solution was extracted with ether and the combined organic phases were dried (MgSO)₄) And concentrated to an oil. 1.54g, 79%. Further purification by flash chromatography (95% hexanes/EtOAc) afforded an oil. [ alpha ] to]_D-8.3(c1 in CHCl)₃In (1).

¹³C NMR(100MHz；CDCl₃)172.01, 80.73, 54.89, 39.73, 39.46, 39.00, 33.40, 29.85, 28.30, 20.15, 19.82, 14.52.(S) -4- ((R) -2-methyl-pentyl) -pyrrolidin-2-one 107 and (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid tert-butyl ester 106

The nitride 105 was treated with 5% Pd/C and shaken under hydrogen for 20 hours, at which time 200mg of 5% Pd/C was added. After 6 hours, the filtrate was concentrated to give an oil, which was obtained by¹H NMR found a mixture of primary amine 106 and lactam 107 (1.75g), which was used without further purification.

Example 9(3S, 5R) -3-aminomethyl-5-methyl-octanoic acid hydrochloride

With 3N HCl (40mL)) A mixture of primary amine 106 and lactam 107 (1.74g) was treated and the solution warmed to 50 ℃ for 4 hours and then cooled to room temperature. After 12 h, the solution was concentrated and the residue was recrystallized from ethyl acetate to give the amino acid as a white solid, 605 mg. MS, m/z (relative intensity): 188[ M + H, 100%]. To C₁₀H₂₁N₁O₂：H₁Cl₁Calculated analytical values: c, 53.68; h, 9.91; and N, 6.26. Measurement value: c, 53.83; h, 10.12; and N, 6.07.

Example 10: synthesis of (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid

Methanesulfonic acid (S) -3, 7-dimethyl-oct-6-enyl ester 108

At 0 ℃ in CH₂Cl₂S- (-) -citronellol (42.8g, 0.274mol) and triethylamine (91mL, 0.657mol) in (800mL) were added to CH₂Cl₂Methanesulfonyl chloride (26mL, 0.329mol) (200 mL). After 2 hours at 0 ℃, the solution was washed with 1N HCl, then brine. The organic phase was dried (MgSO)₄) And concentrated to give an oil (60.5g, 94%), which was used without further purification.

¹H NMR(400MHz；CDCl₃)5.05(1H，m)，4.2(2H，m)，2.95(3H，s)，1.98(2H，m)，1.75(1H，m)，1.6(3H，s)，1.5(4H，m)，1.35(2H，m)，1.2(1H，m)，0.91(3H，d，J＝6.5Hz).

(R) -2, 6-dimethyl-oct-2-ene 109

To olefin 108(60g, 0.256mol) in THF (1L) at 0 deg.C was added lithium aluminum hydride (3.8g, 0.128 mol). After 7 hours, a further 3.8g of lithium aluminium hydride were added and the solution was warmed to room temperature. After 18 hours, a further 3.8g of lithium aluminium hydride are added. After an additional 21 hours, the reaction was carefully quenched with 1N citric acid and the solution was further diluted with brine. Separating the two phases obtained andthe organic phase was dried (MgSO)₄) And concentrated to give an oil which was used without further purification. MS, m/z (relative intensity): 139[ M-H, 100%]。

(R) -4-methyl-hexanoic acid 110

Using a procedure analogous to the synthesis of (R) -4-methyl-heptanoic acid 99 gave the acid as an oil (9.3g, 56%). MS, m/z (relative intensity): 129[ M-H, 100% ]. (4R, 5S) -4-methyl-3- ((R) -4-methyl-hexanoyl) -5-phenyl-oxazolidin-2-one 111

Using a procedure analogous to the synthesis of (4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one 100 gave oxazolidinone 111 as an oil (35.7g, 95%). MS, m/z (relative intensity): 290[ M + H, 100% ].

(3S, 5R) -5-methyl-3- [1- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl) -formyl ] -heptanoic acid tert-butyl ester 112

Using a procedure analogous to the synthesis of tert-butyl (3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoate 101 gave 112 as an oil (7.48 g; 31%).

(S) -2- ((R) -2-methyl-butyl) -succinic acid 4-tert-butyl ester 113

At 0 ℃ in H₂O (53mL) and ester 112 in THF (176mL) (7.26g, 0.018mol) LiOH (37mL of a 0.8M solution) and H were added₂O₂(10.57mL of a 30% solution) and allowed to warm to room temperature. After 2 hours, sodium bisulfite (7g), sodium sulfite (13g), and water (60mL) were added, followed by hexane (100mL) and ether (100 mL). The layers were separated and the aqueous layer was extracted with ether. The combined organic phases were concentrated to an oil, which was dissolved in heptane (200 mL). The resulting solid was removed by filtration and the filtrate was dried (MgSO₄) And concentrated to give an oil (4.4g) which was used without further purification.

(3S, 5R) -3-hydroxymethyl-5-methyl-heptanoic acid tert-butyl ester 114

Use and preparationA similar procedure for (3S, 5R) -3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 103 gave alcohol 114 as an oil (2.68g, 69%). MS, m/z (relative intensity): 216[ 89% ]]，174[M-(CH₃)₃C，100％]。

(3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -heptanoic acid tert-butyl ester 115

At 0 ℃ in CH₂Cl₂To alcohol 114(2.53g, 0.011mmol) in (140mL) was added pyridine (2.6g, 0.033mol), DMAP (100mg) and tosyl chloride (3.15g, 0.016mol) and the solution was warmed to room temperature for 3.5 hours at which time DMAP and TsCl (3.15g) were added. After 14 hours, 1N HCl was added and the layers were separated. The organic phase is washed with brine and then dried (MgSO)₄) And concentrated. Flash chromatography (95% -86% hexanes/EtOAc) afforded tosylate 115 as an oil (1.53g, 36%).

¹³C NMR(100MHz；CDCl₃)130.03，128.12，72.18，37.89，37.71，32.67，31.49，29.88，28.22，21.83，19.07，11.37.

(3S, 5R) -3-azidomethyl-5-methyl-heptanoic acid tert-butyl ester 116

Using a procedure analogous to the preparation of tert-butyl (3S, 5R) -3-azidomethyl-5-methyl-octanoate 105 gives 0.956g, 97% oil. MS, m/z (relative intensity): 216[ 89% ]]，228[M-N₂，80％]。

(S) -4- ((R) -2-methyl-butyl) -pyrrolidin-2-one 118 and (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid tert-butyl ester 117

Azide 106 was treated with 5% Pd/C (90mg) in THF (20mL) and shaken under hydrogen for 36 h. The catalyst was removed by filtration and the resulting oil was used without further purification.

Example 10(3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid

Treatment of amine 117 with lactam 118 with 6N HClThe mixture was warmed to 50 ℃ for 17 hours, then cooled to room temperature and concentrated. The obtained oil was subjected to ion exchange chromatography using 5% ammonium hydroxide (Dowex, strong acid resin) to obtain a cream-like solid, which was recrystallized from methanol/ethyl acetate to obtain (3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid of example 10. MS, m/z (relative intensity): 174[ M + H, 100%]. To C₁₉H₁₉N₁O₂Calculated analytical values: c, 62.39; h, 11.05; and N, 8.08. Measurement value: c, 62.23; h, 11.33; and N, 7.89.

Example 11: synthesis of (3S, 5S) -3-aminomethyl-5-methyl-octanoic acid

Example 11

(S) -2, 6-dimethyl-non-2-ene 119

Adding CuCl₂(5.36g, 39.7mmol) and LiCl (3.36, 80.0mmol) were stirred together in dry THF (40mL) for 15 min. The resulting solution was added to 3.0M methylmagnesium chloride in THF (168mL) at 0 ℃ under nitrogen and stirred at that temperature for 15 minutes. To the reaction suspension was slowly added (R) - (-) -citronellyl bromide (55.16g, 251.8mmol) in TE (100mL) and stirred at 0 ℃ for 2.5 hours. The system was warmed to room temperature and stirring continued for an additional 1 hour. The mixture was cooled to 0 ℃ and quenched with saturated ammonium chloride solution. The suspension was then extracted into ether, washed with water and MgSO₄And (5) drying. The solution was concentrated under reduced pressure to give 36.3g, 94% of (S) -2, 6-dimethyl-non-2-ene as an oil. MS, m/z (relative intensity): 153[ M-1H, 100%]，194[M-1H+CH₃CN，45％]。

(S) -4-methyl-heptanoic acid 120

To (S) -2, 6-dimethyl-non-2-ene 119(39.0g, 253.2mmol) in acetone (1L) at 0 deg.C was added dropwise Jones reagent (2.7M, 600mL) over 1.5 hours and the temperature was kept stirring for 18 hours. The reaction mixture was poured into saturated Na₂SO₄The solution was dissolved and extracted into ether. The system was washed with brine and concentrated in vacuo. The oily residue was dissolved in methanol (70mL) and 1M NaOH (700mL) and then stirred for 30 min. By CH₂Cl₂The aqueous solution was washed, acidified with 10% HCl and extracted into CH₂Cl₂. With MgSO₄The solution was dried and concentrated to dryness to give 24.22g, 66% of (S) -4-methyl-heptanoic acid as an oil. MS, m/z (relative intensity): 143[ M-1H, 100%]。

(4R, 5S) -4-methyl-3- ((S) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one 121

Using a procedure analogous to the preparation of (4R, 5S) -4-methyl-3- ((R) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one 100, (4R, 5S) -4-methyl-3- ((S) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one 1216.2g, 80.0% was obtained as an oil. MS, m/z (relative intensity): 304[ M +1H, 100%]，355[M-1H+CH₃CN，60％]。

(3S, 5S) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoic acid tert-butyl ester 122

1.6M n-BuLi in hexane (18.0mL, 30.1mmol) was added dropwise to a solution of diisopropylamine (4.6mL, 32.6mmol) in dry THF (50mL) at-5 deg.C under nitrogen, maintaining the temperature below 0 deg.C during the addition. The mixture was kept stirring at-5 ℃ for 20 minutes and then cooled to-78 ℃. 121(7.6g, 25.1mmol) in dry THF (12mL) was added to the LDA solution and stirred at-78 deg.C for 30 min. Tert-butylbromoacetate (4.8mL, 32.6mmol) was added to the reaction and stirring was continued for 2h at-78 ℃. The system was warmed to room temperature and then stirred for an additional 18 hours. With saturated NaH₂PO₄The solution quenched the reaction, extracted into ethyl acetate and MgSO₄And (5) drying. Concentrating the solution to obtain a solidThe residue was dissolved in hot hexane. The hexane solution was cooled to room temperature and thereafter cooled in an ice bath. The resulting precipitate was collected and allowed to air dry to give 122 as a fluffy white solid. 4.3g, 41%. MS, m/z (relative intensity): 362[ M-C (CH)₃)₃+1H，100％]，418[M+1H，20％]。

(S) -2- ((S) -2-methyl-pentyl) -succinic acid 4-tert-butyl ester and (3S, 5S) -3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 123

To the ester 122(7.26g, 0.018mol) in THF (203.0mL) and water (61.0mL) at 0 deg.C was added H₂O₂(12.2mL) and LiOH (0.8M, 42.7 mL). The resulting solution was stirred at 0 ℃ for 4 hours. To the reaction system were added sodium hydrogen sulfite (7g), sodium sulfite (13g) and water (60 mL). A mixture of 1: 1 diethyl ether/hexane (200mL) was then added and the aqueous phase was separated. The aqueous phase was extracted with diethyl ether and the organic phase was concentrated to MgSO₄The combined organic extracts were dried and concentrated in vacuo. The residue was dissolved in heptane and kept stirring for 5 minutes. The resulting precipitate was filtered and the filtrate was concentrated to dryness to give an oil.

(3S, 5S) -3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 123

Following a procedure analogous to the preparation of tert-butyl (3S, 5R) -3-hydroxymethyl-5-methyl-octanoate 103 gave 1234.0g, 76.0%. MS, m/z (relative intensity): 230230[ M-C (CH)₃)₃+1H+CH₃CN，100％]，189[M-C(CH₃)₃+1H，70％]。

(3S, 5S) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -octanoic acid tert-butyl ester 124

Following a procedure analogous to the preparation of (3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -octanoic acid tert-butyl ester 104 gives 6.9g of 124. MS, m/z (relative intensity): 343[ M-C (CH)₃)₃+1H，70％]，384[M-C(CH₃)₃+1H+CH₃CN，100％]. (3S, 5S) -3-azidomethyl-5-methyl-heptanoic acid tert-butyl ester 125

According to the same systemA similar procedure to that for the preparation of tert-butyl (3S, 5R) -3-azidomethyl-5-methyl-octanoate 105 gave 2.9g, 66% 125 as an oil. MS, m/z (relative intensity): 212[ M-C (CH)₃)₃-1H，45％]。

(3S, 5S) -3-aminomethyl-5-methyl-octanoic acid tert-butyl ester 126

A mixture of 125(2.8g, 10.4mmol) and 10% Pd/C (1.0g) in methanol (50.0mL) was hydrogenated at 41PSI for 96 hours. The solution was filtered to give 1.7g of crude 126, which was used in the next step without further purification. MS, m/z (relative intensity): 244[ M +1H, 100%]，285[M+1H+CH₃CN，25％]。

Example 11(3S, 5S) -3-aminomethyl-5-methyl-octanoic acid

Example 11 was obtained following a procedure analogous to the preparation of example 10(3S, 5R) -3-aminomethyl-5-methyl-heptanoic acid. 380mg, 29.0%.

¹H NMR(CD₃OD) δ 2.90(dd, J ═ 3.9, 8.8Hz, 1H), 2.80(dd, J ═ 7.6, 5.1Hz, 1H), 2.40(dd, J ═ 3.2, 12.51Hz, 1H), 2.20(dd, J ═ 8.8, 6.8Hz, 1H), 2.05(m, 1H), 1.55(m, 1H), 1.30(m, 3H), 1.10(m, 2H), 0.85(m, 6H); MS, m/z (relative intensity): 187[ M +1H, 100%]，211[M+1H+CH₃CN，30％].

Example 12: synthesis of (3S, 5S) -3-aminomethyl-5-methyl-heptanoic acid

Example 12

(S) -2, 6-dimethyl-oct-2-ene 127

(R) - (-) -citronellyl bromide (49.1g, 224.2mmol) was added dropwise to a 1.0M solution of LAH in THF (336mL, 336mmol) at 0 deg.C over a 45 minute period. Stirring was continued for a further 4 hours at 0 ℃. The reaction was slowly stopped with saturated ammonium chloride solution, followed by addition of bEther (100 mL). The resulting white slurry was filtered and MgSO₄The filtrate was dried. The solution was concentrated under reduced pressure to give 26.2g, 83% 127 as an oil. MS, m/z (relative intensity): 180[ M +1H + CH ]₃CN，100％]，139[M-1H，90％]。

(S) -4-methyl-hexanoic acid 128

Using a procedure similar to that used to prepare compound 120 gave 15.9g of 128 as an oil. MS, m/z (relative intensity): 129[ M-1H, 100%]，170[M+1H+CH₃CN，100％]。

(4R, 5S) -4-methyl-3- ((S) -4-methyl-hexanoyl) -5-phenyl-oxazolidin-2-one 129

Using a procedure analogous to that used for the preparation of (4R, 5S) -4-methyl-3- ((S) -4-methyl-heptanoyl) -5-phenyl-oxazolidin-2-one 121 gave 35.0g of crude (4R, 5S) -4-methyl-3- ((S) -4-methyl-hexanoyl) -5-phenyl-oxazolidin-2-one 129 as an oil. It was used in the next step without further purification. MS, m/z (relative intensity): 290[ M +1H, 100%]，331[M+1H+CH₃CN，20％]。

(3S, 5S) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -heptanoic acid tert-butyl ester 130

Using a procedure analogous to that used for the preparation of tert-butyl (3S, 5S) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoate 122 gave 4.6.0g, 25.4% of 130 as a white solid. MS, m/z (relative intensity): 348[ M-C (CH)₃)₃+1H，100％]，443[M-1H+CH₃CN，100％]，402[M-1H，55％]，404[M+1H，45％]. (3S, 5S) -3-hydroxymethyl-5-methyl-heptanoic acid tert-butyl ester 131

Using a procedure analogous to that used to prepare tert-butyl (3S, 5S) -3-hydroxymethyl-5-methyl-octanoate 123 gave 1.2g, 52.1% of 131 as an oil. MS, m/z (relative intensity): 175[ M-C (CH)₃)₃+1H，100％]，173[M-C(CH₃)₃-1H，100％]，216[M-C(CH₃)₃+1H+CH₃CN，95％]。

(3S, 5S) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -heptanoic acid tert-butyl ester 132

Using a procedure analogous to that used to prepare (3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -octanoic acid tert-butyl ester 104 gives 2.1g of 132 as an oil. The product was used in the next step without further purification. MS, m/z (relative intensity): 329[ M-C (CH)₃)₃+1H，85％]，370[M-C(CH₃)₃+1H+CH₃CN，65％]。

(3S, 5S) -3-azidomethyl-5-methyl-heptanoic acid tert-butyl ester 133

Using a procedure analogous to that used for the preparation of (3S, 5R) -3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105 gives 0.76g, 54.0% of 133 as an oil. The product was used in the next step without further purification. MS, m/z (relative intensity): 198[ M-C (CH)₃)₃-1H，100％]。

(3S, 5S) -3-aminomethyl-5-methyl-heptanoic acid tert-butyl ester 134

Using a procedure analogous to that used to prepare tert-butyl (3S, 5S) -3-aminomethyl-5-methyl-octanoate 126 gives 0.62g of 134 as an oil. The product was used in the next step without further purification. MS, m/z (relative intensity): 230[ M +1H, 100%]，271[M+1H+CH₃CN，45％]。

Example 12(3S, 5S) -3-aminomethyl-5-methyl-heptanoic acid

Using a procedure analogous to that used to prepare example 11, (3S, 5S) -3-aminomethyl-5-methyl-heptanoic acid (0.3g, 65.1%) was obtained as a white solid.

¹H NMR(CD₃OD) δ 2.80-3.00(m, 2H), 2.40(m, 1H), 2.20(dd, J ═ 8.2, 7.1Hz, 1H), 2.05(m, 1H), 1.30-1.50(m, 3H), 1.00-1.20(m, 2H), 0.9(m, 6H); MS, m/z (relative intensity): 187[ M +1H, 100%]，211[M+1H+CH₃CN，30％]MS, m/z (relative intensity): 174[ M +1H, 100%]，172[M-1H，100％]，215[M+1H+CH₃CN，20％].

Example 13: synthesis of (3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid hydrochloride

(R) -4-methyl-octanoic acid 136

Lithium chloride (0.39g, 9.12mmol) and copper (I) chloride (0.61g, 4.56mmol) were combined in 45mL THF at ambient temperature and stirred for 15 minutes, then cooled to 0 deg.C at which time ethylmagnesium bromide (1M solution in THF, 45mL, 45mmol) was added. (S) -citronellyl bromide (5.0g, 22.8mmol) was added dropwise and the solution was slowly warmed to ambient temperature while stirring overnight. By careful addition of saturated NH₄Cl (aq) stop the reaction and Et₂O and saturated NH₄Cl (aq) was stirred together for 30 min. The phases were separated and the organic phase was dried (MgSO₄) And concentrated. The crude product was used without purification.

To a solution of alkene 135(3.8g, 22.8mmol) in 50mL of acetone at 0 deg.C was added Jones' reagent (in H)₂SO₄Medium 2.7M (aq), 40mL, 108mmol) and the solution was slowly warmed to ambient temperature while stirring overnight. The mixture was partitioned between Et₂O and H₂Between O, the phases were separated and the organic phase was washed with brine, dried (MgSO)₄) And concentrated. The residue was purified by flash chromatography (8: 1 hexanes: EtOAc) to give 2.14g (59%) of acid 136 as a colorless oil: LRMS: mlz 156.9.9 (M +);¹H NMR(CDCl₃): δ 2.33(m, 2H), 1.66(m, 1H), 1.43(m, 2H), 1.23(m, 5H), 1.10(m, 1H), 0.86(m, 6H). By combining 26.7g of CrO₃、23ml H₂SO₄With combined use of H₂O diluted to 100mL the jones reagent was made into a 2.7M solution.

(4R, 5S) -4-methyl-3- ((R) -4-methyl-octanoyl) -5-phenyl-oxazolidin-2-one 137

To a solution of 25mL CH at 0 deg.C₂Cl₂To 136(2.14g, 13.5mmol) was added 3 drops of DMF followed by oxalyl chloride (1.42mL, 16.2mmol), resulting in vigorous evolution of gas. The solution was warmed directly to ambient temperature, stirred for 30 minutes and concentrated. To a solution of oxazolidinone (2.64g, 14.9mmol) in 40mL THF at-78 deg.C was simultaneously added n-butyllithium (1.6M solution in hexane, 9.3mL, 14.9mmol) dropwise. The mixture was stirred for 10 minutes at which time the acid chloride in 10mL THF was added dropwise. The reaction was stirred at-78 ℃ for 30 minutes, then warmed directly to ambient temperature and saturated NH was used₄The Cl quenched. The mixture was partitioned between Et₂O and saturated NH₄Between Cl (aq), separate the phases and dry the organic phase (MgSO)₄) And concentrated to give 3.2g of oxazolidinone 137 as a colorless oil. LRMS: m/z 318.2(M +);¹H NMR(CDCl₃): δ 7.34(m, 5H), 5.64(d, J ═ 7.3Hz, 1H), 4.73 (quintuple, J ═ 6.8Hz, 1H), 2.96(m, 1H), 2.86(m, 1H), 1.66(m, 1H), 1.47(m, 2H), 1.26(m, 5H), 1.13(m, 1H), 0.88(m, 9H).

The crude product was used without purification.

(3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -nonanoic acid tert-butyl ester 138

To a solution of diisopropylamine (1.8mL, 12.6mmol) in 30mL THF at-78 deg.C was added n-butyllithium (1.6M solution in hexane, 7.6mL, 12.1mmol) and the mixture was stirred for 10 minutes at which time oxazolidinone 137(3.2g, 10.1mmol) in 10mL THF was added dropwise. The solution was stirred for 30 min, t-butyl bromoacetate (1.8mL, 12.1mmol) was added dropwise rapidly at-50 ℃ and the mixture was slowly warmed to 10 ℃ over 3 h. The mixture was partitioned between Et₂O and saturated NH₄Between Cl (aq), separate the phases and dry the organic phase (MgSO)₄) And concentrated. The residue was purified by flash chromatography (16: 1-8: 1 hexane)Alkane: EtOAc) to give 2.65g (61%) of ester 138 as a colorless crystalline solid. mp is 84-86 ℃. [ alpha ] to]_D23+17.1(c＝1.00，CHCl₃)；¹H NMR(CDCl₃): δ 7.34(m, 5H), 5.62(d, J ═ 7.3Hz, 1H), 4.73 (quintuple, J ═ 6.8Hz, 1H), 4.29(m, 1H), 2.67(dd, J ═ 9.8, 16.4Hz, 1H), 2.40(dd, J ═ 5.1, 16.4Hz, 1H), 1.69(m, 1H), 1.38(s, 9H), 1.28(m, 7H), 1.08(m, 1H), 0.88(m, 9H);¹³C NMR(CDCl₃) δ 176.45, 171.22, 152.71, 133.64, 128.86, 125.86, 80.83, 78.87, 55.33, 40.02, 38.21, 37.59, 36.31, 30.86, 29.29, 28.22, 23.14, 20.41, 14.36, 14.26. To C₂₅H₃₇NO₅Calculated analytical values: c, 69.58; h, 8.64; and N, 3.25. Measurement value: c, 69.37; h, 8.68; and N, 3.05.

(S) -2- ((R) -2-methyl-hexyl) -succinic acid 4-tert-butyl ester 139

To a solution of ester 138(2.65g, 6.14mmol) in 20mL THF at 0 deg.C was added pre-cooled (0 deg.C) LiOH monohydrate (1.0g, 23.8mmol) and hydrogen peroxide (30 wt% aq, 5.0mL) in 10mL H₂Solution in O. The mixture was stirred vigorously for 90 minutes, then warmed to ambient temperature and stirred for 90 minutes. By adding 100mL of 10% NaHSO at 0 deg.C₃Quench the reaction (aq) and use Et₂And (4) extracting. The phases were separated and the organic phase was washed with brine, dried (MgSO)₄) And concentrated. The crude acid 139 was used without further purification.

(3S, 5R) -3-hydroxymethyl-5-methyl-nonanoic acid tert-butyl ester 140

To a solution of crude acid 139 (6.14mmol) in 30mL THF at 0 deg.C was added borane-dimethyl sulfide complex (2.0M solution in THF, 4.6mL, 9.2mmol) and the mixture was slowly warmed to ambient temperature overnight. Additional BH3-DMS was added until the acid consumption was complete (ca. 5 mL). The reaction was quenched by addition of MeOH and then partitioned in Et₂O and saturated NaHCO₃(aqueous solution). The phases were separated and the organic phase was washed with brine, dried (MgSO)₄) And concentrated to give alcohol 140.LRMS：m/z 226.1；¹H NMR(CDCl₃): δ 3.63(dd, J ═ 11.0, 4.2Hz, 1H), 3.42(dd, J ═ 11.0, 6.8Hz, 1H), 2.30(dd, J ═ 14.9, 7.6Hz, 1H), 2.20(dd, J ═ 14.9, 5.6Hz, 1H), 2.03(m, 2H), 1.42(s, 9H), 1.24(m, 6H), 1.02(m, 2H), 0.85(m, 6H). The crude product was used without purification.

(3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -nonanoic acid tert-butyl ester 141

To a solution of 30mL CH at 0 deg.C₂Cl₂To alcohol 140(6.14mmol) in (1.8mL, 13mmol) was added DMAP (0.1g), p-toluenesulfonyl chloride (1.37g, 7.2mmol) and triethylamine (1.8 mL). Immediately after addition the mixture was warmed to ambient temperature and stirred overnight and the reaction did not go to completion. The mixture was partitioned between Et₂Between O and 1N HCl (aq), the phases are separated and washed with saturated NaHCO₃The organic phase was washed (aqueous solution) and dried (MgSO)₄) And concentrated to give tosylate 141. The product was used without further purification.

(3S, 5R) -3-azidomethyl-5-methyl-nonanoic acid tert-butyl ester 142

Azide 142 was obtained as a colorless oil following a procedure analogous to the preparation of tert-butyl (3S, 5R) -3-azidomethyl-5-methyl-octanoate 105.

¹H NMR(CDCl₃)：δ3.31(dd，J＝12.2，4.2Hz，1H)，3.19(dd，J＝12.2，5.9Hz，1H)，2.22(m，1H)，2.10(m，1H)，1.39(s，9H)，1.21(m，8H)，1.00(m，2H)，0.81(m，6H).

Example 13(3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid hydrochloride

Azide 142(1.0g) in the Presence of 20% Pd/C, EtOH and 45psi H₂Hydrogenation for 15 hours gave crude amino ester 143, which was concentrated and used without purification, 6mL of 6N HCl (aq) was added to amino ester 143 and the mixture was heated to reflux for 90 minutes, cooled and concentrated. From EtOAc: recrystallization from hexane gave 0.38g (45% from Symbio)Nitride) (3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid hydrochloride, (HCl salt) as a colorless crystalline solid, and also obtained a second crop of 82mg (10% from azide). MP 146-. LRMS: m/z 200.1(M +);¹H NMR(CDCl₃): δ 2.87(dd, J ═ 13.2, 5.4Hz, 1H), 2.79(dd, J ═ 13.2, 7.3Hz, 1H), 2.29(d, J ═ 6.8Hz, 2H), 2.08(m, 1H), 1.31(m, 1H), 1.09(m, 7HO, 0.92(m, 1H), 0.68(m, 6H), pair C₁₁H₂₄NO₂Analytical values calculated for Cl: c, 55.57; h, 10.17; and N, 5.89. Measurement value: c, 55.69; h, 10.10; and N, 5.86.

Example 14: synthesis of (3S, 5S) -3-aminomethyl-5-methyl-nonanoic acid

(S) -acid 145 was prepared from (R) -citronellyl bromide following the procedure outlined above for (R) -4-methyl-octanoic acid 136. The yield is almost the same and¹h NMR spectra with (R) -acid enantiomers¹The H NMR spectrum was the same. LRMS: m/z 158.9(M + 1).

Oxazolidinone 146 was prepared from acid 145 as described above for (4R, 5S) -4-methyl-3- ((R) -4-methyl-octanoyl) -5-phenyl-oxazolidin-2-one 137. LRMS: m/z290.1 (M-27);¹H NMR(CDCl₃): δ 7.38(m, 3H), 7.28(m, 2H), 5.64(d, J ═ 7.1Hz, 1H), 4.74 (quintuple, J ═ 6.8Hz, 1H), 2.92(m, 2H), 1.71(m, 1H), 1.42(m, 7H), 1.18(m, 1H), 0.88(m, 9H).

Tert-butyl ester 147 was prepared from oxazolidinone 146 as described above for compound 138. LRMS: m/z 348.1 (M-83).

Preparation of oxazolidinone 14 from tert-butyl ester 147 as described above for tert-butyl (3S, 5R) -3-hydroxymethyl-5-methyl-nonanoate 1409。 LRMS：m/z156.9(M-100)；¹H NMR(CDCl₃)：δ3.60(dd，J＝11.0，4.6Hz，1H)，3.45(dd，J＝11.0，6.8Hz，1H)，2.24(m，2H)，2.04(m，2H)，1.42(s，9H)，1.17-1.38(m，7H)，1.11(m，1H)，0.84(m，6H).

Example 14: (3S, 5S) -3-aminomethyl-5-methyl-nonanoic acid

(3S, 5S) -3-aminomethyl-5-methyl-nonanoic acid is obtained from 149 as described above for (3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid hydrochloride. The crude hydrochloride salt thus obtained was purified by ion exchange chromatography using Dowex50 WX850-100 mesh H-type resin, using 10% NH₄OH was used as eluent to give the free base. With Et₂O the waxy solid was washed twice and dried to give an amorphous white solid, mp144-146 ℃. LRMS: m/z 172.0 (M-28);¹H MR(CDCl₃)：δ2.76(d，J＝5.9Hz，2H)，2.14(m，1H)，1.96(m，2H)，1.25(m，1H)，1.12(m，6H)，0.96(m，2H)，0.66(m，6H).

example 15: synthesis of (3S, 5R) -3-aminomethyl-5-methyl-decanoic acid

(R) -2, 6-Dimethylundec-2-ene 153

Using a procedure analogous to that for preparation of (S) -2, 6-dimethyl-non-2-ene 119 gave 153 as a colorless oil (20.16g, 98%).¹H NMR(400MHz，CDCl₃)δ5.10-5.06(m，1H)，2.10-1.89(m，2H)，1.66(s，3H)，1.58(s，3H)，1.34-1.23(m，4H)，1.15-1.06(m，2H)，0.88-0.81(m，11H).

(R) -4-methylnonanoic acid 154

(R) -2, 6-Dimethylundec-2-ene 153(10.03g, 55.03mmol) was dissolved in acetone (270mL) and cooled to 0 deg.C. Dropwise adding Jones reagent (CrO)₃/H₂SO₄) (2.7M, 120mL) and the reaction was warmed to room temperature over 18 hours. The reaction was poured into water/Na₂SO₄(200mL) and the aqueous layer was extracted with ethyl acetate (4X 100 mL). With MgSO₄The combined organic layers were dried, filtered and rotary evaporated to an oil. Dissolving the crude oil in CH₂Cl₂(400mL) and cooled to-78 ℃. Ozone was bubbled through the reaction to a blue color to remove trace impurities (6E) (3S) -3, 7-dimethylocta-1, 6-diene. Dimethyl sulfide (5mL) was added and the reaction was stirred at room temperature for 2 hours. The solvent was removed and the crude material was chromatographed on silica gel, eluting with 20% EtOAc in hexanes to give an oil. The oil was dissolved in ether (100mL) and extracted with 10% NaOH (2X 25 mL). The aqueous layers were combined and extracted with ether (50 mL). The aqueous layer was cooled to 0 ℃ and acidified with HCl. The acidified layer was extracted with EtOAc (3X 100mL) and MgSO₄The combined extracts were dried, filtered and rotary evaporated to give 154 as an oil (6.86g, 54%).¹H NMR(400MHz，CDCl₃)δ2.40-2.25(m，4H)，1.70-1.62(m，2H)，1.47-1.11(m，8H)，0.87-0.84(m，6H)；[α]_D-11.4(c1 in CHCl)₃In (1).

(4R, 5S) -4-methyl-3- ((R) -4-methyl-nonanoyl) -5-phenyl-oxazolidin-2-one 155

Compound 154(6.504g, 37.76mmol) was dissolved in THF (95mL) and cooled to 0 ℃. Triethylamine (19.74mL, 141.6mmol) was added dropwise followed by trimethylacetyl chloride (6.98mL, 56.64 mmol). The thick white suspension was stirred at 0 ℃ for 90 minutes. LiCl (1.86g, 41.54mmol), (4R) -4-methyl-5-phenyl-1, 3-oxazolidin-2-one (6.824g, 38.51mmol) and THF (70mL) were added and the reaction was allowed to warm to room temperature overnight. The solvent was evaporated. The solid was dissolved in EtOAc, filtered off and washed thoroughly with EtOAc. The filtrate was washed with water (2X 50mL) and brine. With MgSO₄The combined organic layers were dried, filtered and rotary evaporated. Chromatography of the crude material on silica gel eluting with 10% EtOAc in hexanes afforded 155 as an oil (10.974g, 88%). ¹H NMR(400MHz，CDCl₃) δ 7.44-7.35(m, 3H), 7.31-7.26(m, 2H), 5.66(d, J ═ 7.33Hz, 1H), 4.76 (quintuple, J ═ 7.03Hz, 1H), 3.04-2.96(m, 1H), 2.93-2.86(m, 1H), 1.74-1.66(m, 1H), 1.52-1.47(m, 1H), 1.46-1.36(m, 2H), 1.27-1.16(m, 2H), 0.92-0.87(m, 8H); [ alpha ] to]_D+34.1(c1 in CHCl)₃In (1).

(3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -decanoic acid tert-butyl ester 156

Obtained according to a procedure analogous to the preparation of tert-butyl (3S, 5S) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -octanoate 122 was (3S, 5R) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyloxazolidine-3-carbonyl) -decanoate tert-butyl ester 156 as an oil (0.668g, 90%).

¹H NMR(400MHz，CDCl₃) δ 7.41-7.28(m, 5H), 5.63(d, J ═ 7.33Hz, 1H), 4.74 (quintuple, J ═ 6.84Hz, 1H), 4.33-4.26(m, 1H), 2.68(dd, J ═ 16.4, 9.77Hz, 1H), 2.41(dd, J ═ 16.6, 4.88Hz, 1H), 1.68 (quintuple, J ═ 6.6Hz, 1H), 1.50-1.32(m, 10H), 1.28-1.21(m, 1H), 1.15-1.08(m, 1H), 0.90-0.86(m, 9H); MS (APCI) M/z348 (M)⁺-97，100％)；[α]_D+18.8(c1 in CHCl)₃In (1).

(S) -2- ((R) -2-methyl-heptyl) -succinic acid 4-tert-butyl ester 157

Compound 156(5.608b, 12.59mmol) was dissolved in THF/H₂O (60mL/14mL) and cooled to 0 ℃. Combine LiOH (1N, 18.89mL) and H₂O₂(35%, 4.45mL, 50.4mmol) and then added dropwise to the reaction maintaining T < 5 ℃. The reaction was stirred at 0 ℃ for 4 hours and Na was added₂SO₃(6.3g) quenched and added dropwise to 50mL H₂NaHSO in O₃(3.4 g). The reaction was stirred for 15 minutes and the layers were separated. The aqueous layer was extracted with EtOAc (3X 100mL) and MgSO₄The combined extracts were dried, filtered and rotary evaporated to an oil. Dissolving the crude materialIn EtOAc (10mL) and added dropwise to heptane (250 mL). The suspension was stirred for 20 minutes and the solid was filtered and washed with heptane. With 60 ℃ H₂The filtrate was washed with O (100mL), MgSO₄Dried, filtered and rotary evaporated to 157 as an oil (3.52 g). The temperature was taken directly to the next step.

(3S, 5R) -3-hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 158

Compound 157(3.52g, 12.3mmol) was dissolved in anhydrous THF (123mL) and cooled to 0 ℃. Borane dimethylsulfide complex (10M, 3.69mL) was added dropwise and then the reaction was warmed to room temperature and stirred for 1 hour. The reaction was cooled to 0 ℃ and quenched with dropwise addition of methanol MeOH (20 mL). The reaction was stirred for 18 hours and the solvent was rotary evaporated. Chromatography of the crude material on silica gel eluting with 20% EtOAc in hexanes afforded 158(2.28g, 68%) as an oil.

¹H NMR(400MHz，CDCl₃)δ3.65-3.59(m，1H)，3.43(dd，J＝11.1，6.96Hz，1H)，2.31(dd，J＝14.9，7.57Hz，1H)，2.21(dd，J＝15.1，5.62Hz，1H)，2.06-2.02(m，1H)，1.43(s，9H)，1.40-1.25(m，4H)，1.07-1.13(m，1H)，1.03-0.96(m，1H)，0.86-0.84(m，6H)；MS(APCI)m/z 216(M⁺-56，100％).

(3S, 5R) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -decanoic acid tert-butyl ester 159

Compound 158(2.27g, 8.33mmol) is dissolved in CH₂Cl₂(30mL) and cooled to 0 ℃. Tosyl chloride (1.91g, 10.0mmol) and the catalyst DMAP were added, followed by dropwise addition of triethylamine (2.55mL, 18.33 mmol). The reaction was then stirred at 0 ℃ for 18 hours. The solvent was rotary evaporated (removed under reduced pressure) and the crude material was washed with EtOAc and filtered. The solid was washed with EtOAc and the filtrate was washed with 0.5N HCl (20mL), brine (30mL), MgSO₄Dried, filtered and rotary evaporated. Chromatography of the oil on silica gel with a gradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes afforded 159(3.399g, 96%) as an oilA compound (I) is provided.¹H NMR(400MHz，

CDCl₃)δ7.75(d，J＝8.30Hz，2H)，7.31(d，J＝8.30Hz，2H)，3.99(dd，J＝9.65，3.54Hz，1H)，3.89(dd，J＝9.52，5.37Hz，1H)，2.42(s，3H)，2.28(dd，J＝14.7，6.23Hz，1H)，2.19-2.14(m，1H)，2.10(dd，J＝14.9，6.35Hz，1H)，1.38(s，9H)，1.31-1.17(m，3H)，1.08-0.81(m，2H)，0.79-0.76(m，6H)；[α]_D10.1(c1 in CHCl)₃In (1).

(3S, 5R) -3-azidomethyl-5-methyl-decanoic acid tert-butyl ester 160

Compound 159(3.01g, 7.05mmol), sodium azide (1.26g, 19.40mmol) and DMSO (12mL) were combined and heated to 60 ℃ for 3 hours. To the reaction was added EtOAc and filtered. The solid was washed with EtOAc (100mL) and the filtrate was rotary evaporated. The crude product was chromatographed on silica gel 160 as an oil, eluting with 5% EtOAc in hexanes (1.86g, 89%). (3S, 5R) -3-aminomethyl-5-methyl-decanoic acid tert-butyl ester 161

A solution of compound 160(1.86g, 6.25mmol) in THF (50mL) was shaken under hydrogen atmosphere and pressure over 5% Pd/C for 8h with three hydrogen purges. The catalyst was filtered off and the filtrate was evaporated. The crude product was chromatographed on silica gel eluting with methanol to give 161 as an oil (1.21g, 71%).

¹H NMR(400MHz，CDCl₃)δ2.70(dd，J＝12.9，4.40Hz，1H)，2.54(dd，J＝12.7，6.59Hz，1H)，2.26(dd，J＝14.5，6.96，1H)，2.12(dd，J＝14.5，6.47Hz，1H)，1.91(m，1H)，1.91(m，1H)，1.43(s，12H)，1.39-1.25(m，4H)，1.14-1.07(m，1H)，1.03-0.97(m，1H)，0.86-0.82(m，6H).

Example 15(3S, 5R) -3-aminomethyl-5-methyl-decanoic acid

Compound 161(1.20g, 4.44mmol) was heated to 50 ℃ for 4h in 3N HCl (30 mL). The solvent was evaporated and the oil washed with toluene and evaporated. The crude material was passed through an ion exchange column (Dowex50 WX8-100, strong acid), with water and then 0.5N NH₄OH is eluted. (3S, 5R) -3-aminomethyl-5-methyl-decanoic acid was isolated as a white solid (0.725g, 75%). mp-174-175 ℃;¹H NMR(400MHz，CDCl₃)δ2.83(dd，J＝12.69，4.88Hz，1H)，2.70(dd，J＝13.1，7.45Hz，1H)，2.08(d，J＝6.59Hz，2H)，1.98(m，1H)，1.28-1.20(m，1H)，1.19-1.09(m，2H)，0.99-0.91(m，2H)，0.66(m，6H)；MS(APCI)m/z 215(M⁺，10％)，174(M⁺-41，100％)；[α]_D-5.7(c1.025 at H)₂In O).

Example 16: synthesis of (3S, 5S) -3-aminomethyl-5-methyl-decanoic acid

(S) -2, 6-dimethyl-undec-2-ene 162

In N₂The n-propylmagnesium chloride/ether solution (2.0M, 228mL) was cooled to-20 ℃ in a gas atmosphere. Combined LiCl (3.87g, 91.25mmol) and CuCl₂(6.13g, 45.63mmol) and distilled THF (456mL) and stirred for 30 min. Introducing Li through a conduit₂CuCl₄The solution was added to the Grignard reagent and the resulting solution was stirred at-20 ℃ for 30 minutes. R- (-) -citronellyl bromide (50g, 228.1mmol) was dissolved in THF (60mL) and added dropwise to the Grignard reagent. The reaction was stirred at 0 ℃ for 1 hour. The reaction was cooled to-40 ℃ and NH was added dropwise₄Cl saturated, 200mL) to stop the reaction. The layers were separated and the aqueous layer was extracted with ether (3X 100 mL). With MgSO₄The combined organic layers were dried, filtered and rotary evaporated to an oil. Chromatography on silica gel eluting with hexanes afforded 162 as a colorless oil (9.15g, 22%). ¹H NMR(400MHz，CDCl₃)δ5.10-5.06(m，1H)，2.10-1.89(m，2H)，1.66(s，3H)，1.58(s，3H)，1.34-1.23(m，4H)，1.15-1.06(m，2H)，0.88-0.81(m，11H).

(S) -4-methylnonanoic acid 163

Compound 162(7.97g, 43.7mmol) was dissolved in acetone (214mL) and cooled to 0 ℃. Dropwise adding Jones reagent (CrO)₃/H₂SO₄) (2.7M, 95mL) and the reaction was allowed to warm to room temperature over 18 hours. The reaction was poured into water/Na₂SO₄(200mL) and the aqueous layer was extracted with ethyl acetate (4X 100 mL). With MgSO₄The combined organic layers were dried, filtered and rotary evaporated to an oil. Chromatography on silica gel eluting with hexanes afforded 163 as an oil (5.56g, 74%).

¹H NMR(400MHz，CDCl₃) δ 2.40-2.25(m, 4H), 1.70-1.62(m, 2H), 1.47-1.11(m, 8H), 0.87-0.84(m, 6H); MS APCI M/z 170.9(M-1, 100%) (4R, 5S) -4-methyl-3- ((S) -4-methyl-nonanoyl) -5-phenyl-oxazolidin-2-one 164

Using a procedure similar to that used to prepare compound 155, but using (S) -4-methylnonanoic acid 163(5.56g, 32.27mmol) as the reactant, 164 was obtained as an oil (10.70g 100%).¹H NMR(400MHz，CDCl₃) δ 7.42-7.34(m, 3H), 7.28(d, J ═ 6.59Hz, 2H), 5.64(d, J ═ 7.33Hz, 1H), 4.74(quin, J ═ 6.78Hz, 1H), 2.94-2.85(m, 2H), 1.73-1.67(m, 1H), 1.47-1.43(m, 1H), 1.39-1.22(m, 7H), 0.90-0.84(m, 8H). (3S, 5S) -5-methyl-3- ((4R, 5S) -4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl) -decanoic acid tert-butyl ester 165

Using a procedure similar to that used to prepare compound 156 gave 165 as a solid (4.25g, 61%). MS (APCI) M/z 446 (M)⁺+1，10％)，390(M⁺-55, 100%, - (tBu). (S) -2- ((S) -2-methyl-heptyl) -succinic acid 4-tert-butyl ester 166

Using a procedure similar to that used to prepare compound 157, but using ester 165(8.42g, 18.89mmol) as the reactant gave 166 as an oil (5.81 g). This material was used in the next step. MS (APCI) M/z 285(M-1, 100%).

(3S, 5S) -3-hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 167

A procedure similar to that used to prepare compound 158 was used, except that (S) -2- ((S) -2-methyl-heptyl) -succinic acid 4-tert-butyl ester 166(5.78g, 20.18mmol) was used as the reactant to give 167 as an oil (4.18g, 76%).¹H NMR(400MHz，CDCl₃)δ3.64-3.58(m，1H)，3.84-3.42(m，1H)，2.28-2.20(m，1H)，2.09-2.02(m，1H)，1.43(s，9H)，1.26-1.18(m，8H)，1.11-1.04(m，2H)，0.87-0.83(m，6H)；MS(APCI)m/z 217(M⁺-55，50％，-tBu).

(3S, 5S) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -decanoic acid tert-butyl ester 168

Using a procedure similar to that used to prepare compound 159, but using (3S, 5S) -3-hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 167(4.164g, 15.29mmol) as the reactant gave 168 as an oil (4.17g, 64%).

¹H NMR(400MHz，CDCl₃)δ7.75(d，J＝8.30Hz，2H)，7.31(d，J＝8.30Hz，2H)，3.97(dd，J＝9.52，4.15Hz，1H)，3.90(dd，J＝9.52，5.13Hz，1H)，2.42(s，3H)，2.28，2.19-2.13(m，2H)，1.37(s，9H)，1.27-1.01(m，11H)，0.85(t，J＝7.08Hz，3H)，0.76(d，J＝6.35Hz，3H).

(3S, 5S) -3-azidomethyl-5-methyl-decanoic acid tert-butyl ester 169

Using a procedure similar to that used to prepare compound 160, but using (3S, 5S) -5-methyl-3- (toluene-4-sulfonyloxymethyl) -decanoic acid tert-butyl ester 168(4.155g, 9.74mmol) as the reactant gave 169 as an oil (2.77g, 96%). MS (APCI) M/z 270 (M)⁺-27，30％，-N₂)，214(M⁺-87，100％，-tBu，-N₂) (3S, 5S) -3-aminomethyl-5-methyl-decanoic acid tert-butyl ester 170

Using a procedure similar to that used to prepare compound 161, but using (3S, 5S) -3-azidomethyl-5-methyl-decanoic acid tert-butyl ester 169(2.50g, 8.405mmol) as the reactant gave 170 as an oil (1.648g, 72%). MS (APCI) M/z272 (M)⁺+1，100％).

Example 14(3S, 5S) -3-aminomethyl-5-methyl-decanoic acid

Using a procedure similar to that used in example 15, but using tert-butyl (3S, 5S) -3- (aminomethyl) -5-methyldecanoate 170(1.6g, 6.00mmol) as the reactant, example 16 was obtained as a white solid (72%). MS (APCI) M/z272 (M)⁺+1，

mp＝174-175℃；¹H NMR(400MHz，CD₃OD)δ2.91(dd，J＝12.9，3.91Hz，1H)，2.83(dd，J＝12.7，7.57Hz，1H)，2.43(dd，J＝15.6，3.17Hz，1H)，2.19(dd，J＝15.6，8.80 Hz，1H)，2.08-2.04(m，1H)，1.53(m，1H)，1.38-1.27(m，7H)，1.78-1.03(m，2H)，0.90-0.86(m，6H)，0.66(m，6H)；MS(APCI)m/z 216(M⁺+1，100％)，214(M^-1，100％)；[α]_D+21.4(c1 in MeOH).

Example 17: synthesis of (3R, 4R) -3-aminomethyl-4, 5-dimethyl-hexanoic acid

Example 17

(S) -2-benzyl-3-methyl-butan-1-ol 172

Reference documents: JACS 1997; 119: 6510. amide 171.

Large Scale procedure for the Synthesis of (S) -2-benzyl-3-methylbutyl acetate 173 from 171

N-butyllithium (in hexane) at-78 deg.C10M, 100mL, 1000mmol, 3.9 equiv.) was added to a solution of diisopropylamine (108.9g, 150.9mL, 1.076mol, 4.20 equiv.) in THF (600 mL). The resulting solution was stirred for 10 minutes and warmed to 0 ℃ and held at that temperature for 10 minutes. Borane-ammonia complex (31.65g, 1.025mmol and 4.0 equiv.) was added in one portion and the suspension was stirred at 0 ℃ for 15 minutes and at 23 ℃ for 15 minutes and then cooled to 0 ℃. A solution of amide 171(86g, 256.41mmol, 1 eq.) in THF was added to the cold hydride over 3 minutes via a catheter. The reaction was stirred overnight at 23 ℃ and then cooled to 0 ℃. The excess hydride was cooled by slow addition of 3N HCl (700 mL). The reaction mixture was then diluted with aqueous HCl (3N, 200mL) and brine and then extracted with ether (4X 15 mL). The ether solution was concentrated to a small volume and 200mL of 2N NaOH was added and stirred at 23 ℃ for 2.5 hours. Additional ether was added and the layers were separated. The combined organic layers were washed with salt and dried over sodium sulfate. Flash chromatography (petroleum ether-25% diethyl ether-TEA) of the residue afforded alcohol 172, 50 g. NMR (CDCl)₃)δ7.35-7.16(m，5H，C₆H₅)，3.55(app.t，2H，-CH₂OH)，2.71(dd，1H，ArCH₂CH-)，2.52(dd，1H，ArCH₂CH)，1.87(m，1H，CHCH(Me)，1.67(m，1H，CH(Me)₂)，0.98(d，3H，CH₃) And 0.96(d, 3H, CH)₃).

A3.3 g sample was saved for characterization and the remainder was immediately acetylated at room temperature (triethylamine 50mL, DMAP 4.6g, acetic anhydride 32mL) overnight. After completion of the procedure, chromatography on silica gel, eluting with petroleum ether and then 10% in petroleum ether afforded 62g of 173. NMR (CDCl)₃)δ7.30-7.14(m，5H，C₆H₅)，3.98(m，2H，-CH₂OAc)，2.71(dd，1H，ArCH₂CH-)，2.51(dd，1H，ArCH₂CH)，1.99(s，3H，CH₃C ═ O), 1.82(m, 1H, chch (me) and ch (me)₂)，0.97(d，3H，CH₃) And 0.95(d, 3H, CH)₃).

(S) -acetoxymethyl-4-methyl-pentanoic acid 174 and (S) -4-isopropyl-dihydro-furan-2-one 175

Acetate 173(15g, 68.18mmol) was dissolved in CH₃CN (150mL), carbon tetrachloride (150mL) and HPLC grade water (300mL) with stirring. Sodium periodate (262.50g, 1220mmol) was added followed by ruthenium chloride (650mg, 3.136 mmol). After stirring overnight, the system was diluted with ether and water and filtered through a pad of celite. The organic portion was separated and the aqueous phase was further extracted with ether. After drying over magnesium sulfate, the solvent was evaporated. To the residue was added potassium carbonate (42g) and refluxed overnight in methanol (250mL) and cooled to room temperature. After evaporation, water was added to dissolve the solids and concentrated HCl was added to bring the pH to 2. Chloroform was added and extracted overnight. The organic phase was separated and the aqueous phase was further extracted with chloroform. The combined organic extracts were dried, evaporated and the product was purified with a silica gel column and the compound was eluted with 20% diethyl ether in dichloromethane. Fractions were monitored by tlc and I₂KI solution detection of spots. The fractions were combined to give 4.6g of lactone 175.

NMR(CDCl₃)δ4.38(dd，1H，CH_aH_bO)，3.93(app.t，1H，CH_aH_bO)，2.54(dd，1H，CH_cH_dC ═ O), 2.23(m, 2H, chch (me), and CH_cH_dC＝O)，1.60(m，1H，CH(Me)₂)，0.92(d，3H，CH₃) And 0.85(d, 3H, CH)₃).

(3R, 4R) -3-benzyl-4-isopropyl-dihydro-furan-2-one 176

Lithium bis (trimethylsilyl) amide (1.0M solution in THF, 92mL, 92mmol) was added to a solution of (S) - β - (2-propyl) - γ -butyrolactone 175(11.68g, 91.25mmol) in dry 100mL THF at-78 deg.C under an argon atmosphere and 3-5 minutes. The system was stirred for 1 hour and a solution of benzyl iodide (21.87g, 100.37mmol) in dry THF was added quickly. Stirring was continued for 1.5 h and quenched at-78 ℃ by addition of aqueous salt solution followed by addition of ethyl acetate. The organic phase was separated and the aqueous phase was further extracted with ether. Chromatography on silica gel eluting first with 5% dichloromethane in petroleum ether and finally with 10% ether in petroleum ether afforded the desired compound 11.6g, 58%.

NMR(CDCl₃)δ7.19(m，5H，C₆H₅)，4.02(app.t，1H，CH_aH_bO)，3.87(dd，1H，CH_aH_bO)，2.98(d，2H，ArCH₂)，2.57(q，1H，BnCHC＝O)，2.05(m，1H，CHCH(Me)₂，1.55(m，1H，CH(Me)₂)，0.81(d，3H，CH₃) And 0.72(d, 3H, CH)₃).

(2R, 3R) -2-benzyl-3-bromomethyl-4-methyl-pentanoic acid ethyl ester 177

Lactone 176(6.5g, 29.8mmol) was dissolved in absolute ethanol (80mL) and cooled with an ice bath. Anhydrous HBr was bubbled through the solution for 1 hour and stirred at room temperature overnight while maintaining the reaction system in a dry gas environment. The system was poured onto an ice-cooled mixture of petroleum ether and brine. The organic phase was separated and the aqueous phase was further extracted with petroleum ether. The combined organic solutions were washed repeatedly with cold water and dried. The solvent was evaporated in vacuo to give 7.0g of crude compound. NMR (CDCl)₃)δ7.27(m，5H，C₆H₅)，4.02(m，2H，CH₃CH₂O)，3.70(dd，1H，CH_aH_bBr)，3.55(dd，1H，CH_aH_bBr)，2.97(m，2H，ArCH₂)，2.83(q，1H，BnCHC＝O)，2.11(m，1H，CHCH(Me)₂，1.97(m，1H，CH(Me)₂)，1.10(t，3H，CH₃CH₂O)，0.96(d，3H，CH₃) And 0.93(d, 3H, CH)₃).

(2R, 3R) -2-benzyl-3, 4-dimethyl-pentanoic acid ethyl ester 178

Bromide ester 177(7.25g, about 80% pure) in ethanol (100mL) containing triethylamine (3.2mL) was hydrogenated in the presence of 20% Pd/C (1.0g) overnight. The system was filtered through a pad of celite and the filter cake was washed with ethanol. The solvent was evaporated and the residue was dissolved in diethyl ether, whereupon the solid (Et) was isolated₃Hcl) under reduced pressure. The solids were removed by filtration. The filtrate was concentrated and the procedure was repeated to remove all hydrochloride salts. Subjecting the product to silica gel column chromatography withPetroleum ether elution afforded 3.35g of the desired debrominated compound.

NMR(CDCl₃)δ7.21(m，5H，C₆H₅)，3.95(m，2H，CH₃CH₂O)，2.85(m，2H，ArCH₂)，2.64(q，1H，BnCHC＝O)，1.85(m，1H，CHCH(Me)₂，1.62(m，1H，CH(Me)₂)，1.05(t，3H，CH₃CH₂O)，0.95(d，3H，CH₃)0.84(d，3H，CH₃) And 0.82(d, 3H, CH)₃).

MS yields 290(M + CH)₃CN), 249(M +1) and others at 203. Further elution with diethyl ether gave the lactone (2.25g) carried over from the previous step.

Acetic acid (2R, 3R) -2-benzyl-3, 4-dimethyl-pentyl ester 179

Ethyl ester 178(3.20g, 12.85mmol) was dissolved in dry diethyl ether and cooled with an ice bath under an inert atmosphere. Lithium aluminium hydride (500mg, 13.15mmol) was added and the suspension was stirred at room temperature overnight. Excess LAH was removed by careful addition of ethyl acetate while the reaction was stirred in an ice bath. Saturated sodium sulfate was carefully added to solidify the alumina which separated as a white precipitate at room temperature. The reaction mixture was diluted with dichloromethane and dried by adding anhydrous sodium sulfate. After filtration, the solution was concentrated to give 3.0g of oil.

This material (3.0g) was dissolved in dichloromethane (30mL) and triethylamine (2.5mL), and DMAP (200mg) and acetic anhydride (1.5mL) were added. The system was stirred at room temperature for 3 hours and diluted with ether. The ether solution was washed with water, 1N HCl, saturated sodium bicarbonate, brine and dried. The solution was concentrated in vacuo to give 1793.16g of an acetoxy compound.

NMR(CDCl₃)δ7.19(m，5H，C₆H₅)，4.03(m，2H，CH₃CH₂O)，2.69(m，2H，ArCH₂)，2.09(m，1H，BnCHCH₂O)，2.02(s，3H，CH₃C＝O)，1.68(m，1H，CH₃CHCH(Me)₂，1.23(m，1H，CH(Me)₂)，0.87(d，3H，CH₃)，0.84(d，3H，CH₃) And 0.81(d, 3H, CH)₃).

(R) -4- ((R) -1, 2-dimethyl-propyl) -dihydro-furan-2-one 180

To a solution of aromatic 179(5.0g, 20.16mmol) in HPLC grade acetonitrile (60mL), carbon tetrachloride (60mL) and water (120mL) was added sodium periodate (86.24g, 403.32mmol, 20 equiv.), followed by RuCl₃(414mg, 10 mol%). The mixture was stirred vigorously at room temperature overnight and diluted with dichloromethane (400 mL). The mixture was filtered through a pad of celite to remove solid precipitate. The organic portion was separated and the aqueous phase was further extracted with dichloromethane. After concentration of the combined organic fractions, the residue was dissolved in ether and passed through a Florisil column. The compound was eluted with 3% methanol in ether, evaporated to a paste, which was dissolved in methanol (100 mL). Potassium carbonate (8.0g) was added and the mixture was refluxed for 6 hours. The solvent was evaporated and the solid residue was dissolved in water. The pH was adjusted to 2 by careful addition of concentrated HCl while cooling with an ice water bath and stirring. Chloroform (200mL) was added to the solution and stirred as such at room temperature overnight. The organic phase was separated and the aqueous portion was further extracted with chloroform. After drying, the solvent was evaporated to give 1805.0g of lactone. NMR (CDCl)₃)δ4.36(app.t，1H，CH_aH_bO)，3.85(app.t，1H，CH_aH_bO)，2.46(m，2H，CH_cH_dC＝O)，2.13(m，2H，CHCH₂C＝O)，1.60(m，1H，CH(Me)₂)，1.35(m，1H，CH₃CHCH(Me)₂)，0.86(d，3H，CH₃) And 0.72(t, 3H, CH)₃).

(3R, 4R) -3-bromomethyl-4, 5-dimethyl-hexanoic acid ethyl ester 181

Lactone 180(5.0g) was dissolved in absolute ethanol (25mL) and purged with argon. When cooled with an ice-water bath, anhydrous HBr was allowed to foam through the mixture for 45 minutes and was stable at room temperature overnight. The mixture was poured into ice-brine and hexane. The organic phase was separated and the aqueous phase was further extracted with hexane. The combined organic extracts were dried and evaporated. Flash chromatography using 10% diethyl ether in petroleum ether was performed to give 1813.54g of bromo ester.

NMR(CDCl₃)δ4.14(q，2H，CH₃H₂O)，3.60(dd，1H，CH_aH_bBr)，3.41(dd，1H，CH_cH_b Br)，2.54(dd，1H，CH_aH_bC＝O)，2.44(dd，1H，CH_aH_bC＝O)，2.22(m，1H，O＝CCH₂CHCH₂Br)，1.67(m，1H，CHCH₃CH(Me)₂，1.37(m，1H，CH(Me)₂)，1.26(t，3H，CH₃CH₂O)，0.94(d，3H，CHCH₃CH(Me)₂，0.81(d，3H，((CH₃)₂)CHCH₃CH) and 0.79(d, 3H, ((CH)₃)₂)CHCH₃CH).

(3R, 4R) -3-azidomethyl-4, 5-dimethyl-hexanoic acid ethyl ester 182 and example 17(3R, 4R) -3-aminomethyl-4, 5-dimethyl-hexanoic acid

Bromide ester 181(3.54g, 13.34mmol), sodium azide (1.04g, 16.13mmol) in anhydrous DMF (8.0mL) was stirred at room temperature overnight. Water (16mL) and hexane were added, the organic portion was separated and the aqueous portion was further extracted with hexane. The system was dried and evaporated to give 3.0g of azidoester.

NMR(CDCl₃)δ4.14(q，2H，CH₃H₂O)，3.48(dd，1H，CH_aH_bN₃)，3.21(dd，1H，CH_cH_b N₃)，2.34(m 2H，CH_aH_bC＝O)，2.20(m，1H，O＝CCH₂CHCH₂N₃)，1.60(m，1H，CHCH₃CH(Me)₂Hydrogenation of the compound (HPL, 66480 x 100). The crude hydrogenated product was dissolved in 6N HCl and refluxed overnight. The solvent was evaporated in vacuo and the residue was azeotroped with toluene. The crude product was further purified by ion exchange column chromatography (Dowex50Wb X8-100), washed with HPLC grade water to neutral eluent, followed by 0.5N NH₄The OH solution elutes the compound. The product is separated from methanolMedium crystallization gave 720 mg. NMR (CD)₃OD)δ3.04(dd，1H，CH_aH_bNH₂)，2.82(dd，1H，CH_cH_b NH₂)，2.52(dd，1H，CH_aH_bC＝O)，2.40(dd，1H，CH_aH_bC＝O)，2.07(m，1H，O＝CCH₂CHCH₂NH₂)，1.67(m，1H，CHCH₃CH(Me)₂，1.35(m，1H，CH(Me)₂)，0.97(d，3H，CHCH₃CH(Me)₂，0.88(d，3H，((CH₃)₂)CHCH₃CH) and 0.83(d, 3H, ((CH)₃)₂)CHCH₃CH).[α]x-5.3(C, MeOH, 1.9mg/mL) vs. C₉H₁₉NO₂Calculated analytical values: c62.39, H11.05, N8.08. Measurement value: c62.01, H11.35, N7.88. MS confirmed ion at 215(M + CH)₃CN)、197(M+Na⁺)、174(M+H⁺). Hypersil BDS C by reverse phase HPLC₁₈50/50 CH with 5 micron and mobile phase containing 0.1% TFA₃Analysis of the derivative by CN-water gave 99.93% purity with a retention time of 8.21 minutes.

Examples 18 to 20: synthesis of 3-aminomethyl-4-isopropyl-heptanoic acid

Example 18R ═ nPr

Example 19R ═ nBu

Example 20R Et

2-cyano-4-methyl-2-pentenoic acid methyl ester 61

A solution of isobutyraldehyde (30.0g, 416mmol), methyl-cyano-acetate (20.6g, 208mmol), ammonium hydroxide (3.2g, 41.6mmol) and acetic acid (5.0g, 83.2mmol) in 500mL of tolueneWarm to reflux in a dean-stark trap for 12 hours. The mixture was cooled to room temperature and saturated NaHSO was used₃(3X 100mL), saturated NaHCO₃(3X 100mL) and 100mL saline. With Na₂SO₄The organic layer was dried and the solvent was evaporated. The remaining oil was distilled under high vacuum (0.5mm Hg, b.p. ═ 115 ℃ f.) to give 28.8g of methyl 2-cyano-4-methyl-2-pentenoate 61 as an oil (90% yield).

2-cyano-3-isopropyl-hexanoic acid methyl ester 183

2.0M propylmagnesium chloride in Et₂A solution in O (9.8mL, 19.6mmol) was added to a solution of 2-cyano-4-methyl-2-pentenoic acid (3.0g, 19.6mmol) in 50mL THF and the system was cooled to-40 deg.C with an IPA/dry ice bath under an argon atmosphere. The solution was stirred for 4 hours and saturated KH was added by adding 50mL₂PO₄The reaction was quenched. THF was evaporated and the remaining oil was submitted to 50% CH₂Cl₂Medium pressure silica gel chromatography in hexane. Yield 1.9g (50%) of methyl 2-cyano-3-isopropyl-hexanoate as an oil.

2-cyano-2- (1-isopropyl-butyl) -succinic acid 4-tert-butyl ester 1-methyl ester 184

A solution of methyl 2-cyano-3-isopropyl-hexanoate (1.9g, 9.6mmol) in 10mL THF was added to a slurry of NaH (washed with hexane, 0.23g, 9.6mmol) in 20mL THF, and the system was cooled with ice-water under an argon atmosphere. The solution was stirred for 10 min and tert-butyl bromoacetate (2.1g, 10.6mmol) was added. The solution was warmed to room temperature. After 12 hours, KH was saturated by adding 50mL₂PO₄The reaction was quenched and THF was evaporated. Extract the organic product into Et₂O (3X 50mL) over MgSO₄The combined organic layers were dried. The solvent was evaporated and the remaining oil was taken up in 25% hexane/CH₂Cl₂Medium pressure silica gel chromatography. The yield of 4-tert-butyl 2-cyano-2- (1-isopropyl-butyl) -succinate 1-methyl ester was 1.3g (42%) as an oil.

3-cyano-4-isopropyl-heptanoic acid tert-butyl ester 185

2-cyano-2- (1-isopropyl-butyl) -succinic acid 4-tert-butyl ester 1-methyl ester (1.3g, 4.2mmol), NaCl (0.25g, 4.2mmol) and H₂A mixture of O (0.15g, 8.3mmol) in 25mL of LDMSO was warmed to 130 ℃ for 12 hours. The mixture was cooled to room temperature and diluted with 100mL brine. The organic product was extracted into Et₂O (3X 50 mL). Combine the organic layers and consume 50mL of H₂O and 50mL brine. With Na₂SO₄Drying and evaporation of the solvent gave 0.8g (75% yield) of tert-butyl 3-cyano-4-isopropyl-heptanoate as an oil. 4- (1-isopropyl-butyl) -2-pyrrolidone 186

3-cyano-4-isopropyl-heptanoic acid tert-butyl ester (0.8g, 3.2mmol) in 50psi H₂Reduction in MeOH with TEA and Ra Ni in ambient. When absorbing the theoretical amount of H₂In time, the catalyst was removed by filtration and the solvent was evaporated to give 0.6g (yield 100%) of 4- (1-isopropyl-butyl) -2-pyrrolidone as an oil.

Example 18: 3-aminomethyl-4-isopropyl-heptanoic acid

4- (1-isopropyl-butyl) -2-pyrrolidone (0.6g, 2.3mmol) was refluxed in 50mL6.0M HCl at moderate temperature for 12 h. The solution was cooled to room temperature and filtered through celite. The filtrate was evaporated and the remaining solid was recrystallized from MeOH/EtOAc. Yield 0.035g (6% yield) of 3-aminomethyl-4-isopropyl-heptanoic acid as hydrochloride,

mp 160-170℃.¹H NMR(CD₃OD)δ0.9(m，9H)，1.30(m，5H)，1.78(m，1H)，2.30(m，2H)，2.45(m，1H)，2.95(m，2H).MS(APCI，CH₃CN，H₂O)201(M⁺，100％).

example 19: 3-aminomethyl-4-isopropyl-octanoic acid

Prepared according to the procedure of example 18. Yield 0.13g (15%) of 3-aminomethyl-4-isopropyl-octanoic acid. mp 160-.¹H NMR(CD₃OD)δ0.9(m，9H)，1.30(m，7H)，1.78(m，1H)，2.30(m，1H)，2.45(m，2H)，2.95(m，2H).MS(APCI，CH₃CN，H₂O)198(M-17，100％)，216(M⁺，50％).

Example 20: 3-aminomethyl-4-isopropyl-hexanoic acid

Prepared according to the procedure of example 18. Yield 0.11g (42%) of 3-aminomethyl-4-isopropyl-hexanoic acid. mp is 170 and 180 ℃.¹H NMR(CD₃OD)δ0.9(m，9H)，1.18(m，1H)，1.39(m，3H)，1.78(m，1H)，2.30(m，1H)，2.45(m，1H)，2.95(m，2H).MS(APCI，CH₃CN，H₂O)188(M⁺，100％).

Example 21

(i)MeO₂CCH＝PPh₃、THF、40℃；(ii)MeNO₂DBU; (iii) raney nickel, H₂、MeOH；(iv)Pd-C、MeOH、H₂；(v)6N HCl

Synthesis of unsaturated ester 188

(S) - (-) -citronellal 187(2.0mL, 11.03mmol) was stirred in dry tetrahydrofuran (30mL) at 40 ℃ with methyltriphenylphosphinylidenoacetate (3.69g, 11.03 mmol). After 8 hours, the mixture was cooled to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was stirred with n-pentane (50 mL). After 1 hour, the solid was removed by filtration and the solvent was removed in vacuo to give an oil which was purified by flash chromatography (silica gel, ethyl acetate: heptane 1: 9) to give 2.05g (88%) of 188 as a clear oil.

¹H NMR(400MHz)(CDCl₃)δ0.90(3H，d，J＝6Hz)；1.12-1.40(2H，m)；1.60(3H，s)；1.62(1H，m)；1.68(3H，s)；2.01(3H，m)；2.21(1H，m)；3.73(3H，s)；5.08(1H，m)；5.82(1H，d，J＝16Hz)；6.94(1H，m).MS(CI⁺)(m/z)：211(MH⁺75%), 179 (78%), 151 (100%). IR (film) (cm)^-1)v：1271，1436，1728，2917.

Synthesis of Nitro ester 189

Ester 188(2.02g, 9.6mmol) was reacted with 1, 8-diazabicyclo [5, 4, 0]]Undec-7-ene (1.44mL, 9.6mmol) was dissolved in nitromethane (25mL) and stirred at room temperature. After 23 h, the mixture was diluted with ether (150mL) and washed with water (50mL) and then 2N HCl (50 mL). The organic phase was collected and filtered (MgSO)₄) And the solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate: heptane 3: 7) to give 2.26g (87%) of 189 as a clear oil. Note that it and all subsequent compounds are equimolar mixtures of 2 diastereomers.¹H NMR(400MHz)(CDCl₃) δ 0.90(2 × 3H, each d, J ═ 6 Hz); 1.09-1.58(10H, m); 1.602(6H, s); 1.685(6H, s); 1.94(4H, m); 2.42(4H, m); 2.66(2H, m); 3.70(6H, s); 4.42(4H, m); 5.07(2H, m) MS (CI)⁺)(m/z)：272(MH⁺90%, 240 (100%), 151 (100%). IR (film) (cm)^-1)v：1554，1739，2918.

Synthesis of lactam 191

Nitro ester 189(2.09g, 7.7mmol) was dissolved in methanol (75mL) and shaken on Raney nickel (catalyst, prewashed with water and then with methanol) at 35 ℃ under a hydrogen atmosphere (39 psi). After 17 hours, the mixture was filtered through celite. The solvent was removed in vacuo to give an oil.¹H NMR confirmed that part of the double bonds were reduced, and thus it was used without further purification. A sample of partially reduced product (440mg, 2.1mmol) was dissolved in methanol (40mL) and shaken over 5% Pd-C under hydrogen. After 18 hours, the catalyst was removed by filtration through celite to give 442mg (99% from partially reduced material) as a clear oil which did not require purification. Note that this material and all subsequent compounds are equimolar mixtures of 2 diastereomers.¹H NMR(400MHz)(CDCl₃)δ：0.88(18H，m)；1.04-1.58(20H，m)；1.96(2H，m)；2.40(2H，m)；2.58(2H，m)；2.98(2H，m)；(3.45(2H，m)，5.82(2H，brs).MS(CI⁺)(m/z)：212(MH⁺，100％).

Synthesis of example 21

Lactam 191(428mg, 2.0mmol) was heated to reflux in 6N HCl (20 mL). After 5 hours, the mixture was cooled to room temperature and washed with dichloromethane (2X 10 mL). The aqueous phase was collected and the solvent was removed in vacuo. The residue was dissolved in water (10mL) and lyophilized to give 382mg (71%) of example 34 as a white solid. Note that the compound is an equimolar mixture of 2 diastereomers.¹H NMR(400MHz)(d₆-DMSO)δ0.82(18H，m)；0.95-1.55(20H，m)；2.05-2.45(6H，m)；2.75(4H，m)；7.98(6H，br s).MS(CI⁺)(m/z)：230([MH-HCl]⁺，90％)，212(100％).

Microanalysis: c₁₃H₂₈NO₂Calculated Cl: c58.74; h10.62; and N5.27.

Measurement value: c58.46; h10.50; and (4) N5.33.

The opposite C5-stereochemistry to example 21 can be obtained by those skilled in the art using (R) - (+) -citronellal.

The compounds of the present invention may be prepared and administered in a variety of oral and parenteral dosage forms. Thus, the compounds of the invention may be administered by injection, i.e. intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally or intraperitoneally. In addition, the compounds of the present invention may be administered by inhalation, for example intranasally. In addition, the compounds of the present invention may be administered transdermally. The following dosage forms may include a compound of formula 1 or a corresponding pharmaceutically acceptable salt of a compound of formula 1 as an active ingredient, as will be apparent to those skilled in the art.

For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid dosage forms include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may act as diluents, flavouring agents, binders, preservatives, tablet disintegrating agents or an encapsulating material.

In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.

In tablets, the active ingredient is mixed with a carrier having the necessary binding characteristics in suitable proportions and compacted in the shape and size desired.

Powders and tablets preferably contain 5 or 10 to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparing" is intended to encompass formulating the active compound as an encapsulating material for making capsules, wherein the active ingredient is centrally surrounded, and hence in intimate contact, with a carrier, with or without other carriers. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

To prepare suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is homogeneously dispersed therein by stirring. The molten homogeneous mixture is then poured into a plastic film of conventional size, allowed to cool and thereby solidify.

Liquid formulations include solutions, suspensions and emulsions, for example, water or aqueous propylene glycol solutions. For parenteral injection, the liquid formulation may be formulated as a solution in the form of an aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be prepared by dispersing the active ingredient in a finely divided form in water containing viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.

Also included are solid dosage forms which are converted immediately prior to use to liquid dosage forms for oral administration. Such liquid dosage forms include solutions, suspensions and emulsions. These formulations may include active ingredients and coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The pharmaceutical preparation is preferably in unit dosage form. In such dosage forms, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation containing discrete quantities of the preparation, such as tablets in bags, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be a capsule, cachet, or lozenge itself or it can be the packaged form of an appropriate number of any of these dosage forms.

The amount of active ingredient in a unit dosage form may vary or be adjusted between 0.1mg and 1g depending on the particular application or efficacy of the active ingredient. In medical applications, for example, 100 or 300mg of the capsule is administered 3 times per day. Other compatible therapeutic agents may also be included in the composition, if desired.

In therapeutic applications, the compounds used in the methods of the invention are initially administered in a dose of about 0.01mg to about 100 mg/kg/day. A daily dosage range of about 0.01mg to about 100mg/kg is preferred. However, the dosage may vary with the needs of the patient, the severity of the condition being treated and the compound being used. It is within the skill of the art to determine the appropriate dosage for a particular situation. Generally, treatment is initiated with smaller doses than the optimal dose of the compound. Thereafter, small doses are escalated until the optimal effect in this situation is reached. For convenience, the total daily dose may be divided and administered in portions on the day, if desired.

The compounds of the illustrative examples prepared according to the invention were tested as described in example 22.

Example 22

Rat paw pad tactile allodynia model generated by acid pre-injection in calf muscle

Patients with fibromyalgia syndrome (FMS) typically exhibit widespread chronic musculoskeletal pain, often accompanied by tactile allodynia (pain that is in response to a relatively light tactile stimulus that is generally non-painful). A rat model of persistent mechanical allodynia consistent with muscle tenderness found in these patients has been developed. Multiple injections of acidified saline into the gastrocnemius Muscle of rats produced long-lasting allodynia (conveniently measured at the paw pad), which was considered centrally mediated (Sluka K, Kalra A, Moore S.: unilateral intramuscular injection of acidic saline produced bilateral long-lasting hyperalgesia.) - (Muscle Nerve 2001; 24: 37-46; Sluka K, Rohlwing J, Bussey R et al: "reversal of Chronic myalgia induced by repeated injection of acid by administering mu-and delta-rather than kappa-opioid receptor agonists via the spinal column" (hormone induced muscular pain reversal assay J.) - (Pharma) experiment J2002-50). This model was used to evaluate the ability of the compounds of the present invention to inhibit allodynia.

Allodynia was induced as described by Sluka et al (Sluka K, Kalra A, Moore S. "unilateral intramuscular injection of acidic saline produced bilateral long-lasting hyperalgesia" (Unilateralin injections of acidic saline product a bilateral, long-lasting hyperalgesia.) -. musculus Nerve (Muscle Nerve) 2001; 24: 37-46) with minor modifications. On day 0, male Sprague-Dawley rats (-200 g body weight) in the dark cycle were placed in suspended wire-bottom cages and acclimatized for 0.5 hours. The baseline paw withdrawal thresholds (bending forces of 2.0, 3.6, 5.5, 8.5, 15.1 and 28.8g) were determined for the right paw by Von Frey monofilament using the Dixon voltammetry (Dixon W. "effective analysis of experimental observations" ("effective analysis of experimental observations") - "Ann Rev Pharmacol Toxicol) 1980; 20: 441-62). Von Frey hairs were applied to the plantar surface for 6 seconds and paw withdrawal during this time period was considered a positive reaction. After evaluation, the right gastrocnemius muscle was shaved, wiped with alcohol and injected with 0.1mL of 0.9% NaCl solution acidified to pH4 with HCl. Injections were repeated on day 5. Animals were controlled on days 6, 7 and 8 with a dynamic plantar tactile meter (Ugo Basile, Comerio-varee, Italy) to facilitate the induction of allodynia. To screen rats for the development of allodynia, 15.1g Von Frey hairs were applied to the ipsilateral paw on day 11. Positive responders from this test were included in the compound evaluation study. On day 12 (day of peak allodynia), animals were divided into treatment groups and then the ipsilateral paw withdrawal threshold was determined in order to establish allodynia (decline in paw withdrawal threshold) compared to baseline values. Rats were then given orally 10mL/kg vehicle (0.5% hydroxypropyl-methylcellulose/0.2% Tween 80) or the indicated dose of the compound of the invention. Paw withdrawal thresholds were re-evaluated with Von Frey hair 2, 5, 8 and 24 hours after dosing in a blind fashion and time-course experiment 2 hours after dosing for dose response studies. Inhibition of allodynia in each animal was determined by dividing the increase in post-treatment paw withdrawal threshold by the difference between baseline and pre-treatment paw withdrawal values. This score is then converted to percent inhibition by multiplying by 100.

In this manner, the ability of one or more of the compounds described above to reduce allodynia in a dose-dependent manner is assessed and the lowest effective dose is determined. To determine the time period of inhibition, allodynia was monitored at various time points after the lowest effective dose of the compound of the invention.

In this manner, it was evaluated whether administration of one or more of the above compounds would reduce footpad tactile allodynia caused by prior injections of acidic saline. The duration of efficacy was also determined. The results make it possible to evaluate the compounds of the invention for the treatment of allodynia associated with fibromyalgia syndrome.

Claims

1. A method of treatment of a disease in a mammal, including a human, comprising the step of administering to said mammal a therapeutically effective amount of a compound of formula 1:

wherein:

R¹is hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms or phenyl; and is

R²Of 4 to 8 carbon atomsStraight or branched chain alkyl, straight or branched chain alkenyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxy of 1 to 6 carbon atoms, -alkylcycloalkyl, -alkylalkoxy, -alkylOH, -alkylphenyl, -alkylphenoxy or-substituted phenyl; and wherein said disorder is selected from the group consisting of OCD, phobias, PTSD, restless leg syndrome, premenstrual dysphoric disorder, hot flashes, and fibromyalgia.

2. A method for the treatment of a disease in a mammal, including a human, comprising the step of administering to said mammal a therapeutically effective amount of the compound (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid or a pharmaceutically acceptable salt thereof, wherein said disease is selected from the group consisting of OCD, phobias, PTSD, restless leg syndrome, premenstrual dysphoric disorder, hot flashes and fibromyalgia.

3. The method of claim 2, wherein the disorder is selected from the group consisting of restless legs syndrome, premenstrual dysphoric disorder, hot flashes, and fibromyalgia.

4. The method of claim 2, wherein the disorder is fibromyalgia.

5. The method of claim 1 or 2, wherein the disorder is selected from the group consisting of restless leg syndrome, premenstrual dysphoric disorder, hot flashes, and fibromyalgia.

6. The method of claim 1 or 2, wherein the disease is selected from the group consisting of OCD, PTSD, and phobias; and wherein said phobia is selected from the group consisting of field phobia and specific phobia.

7. A method of treatment of fibromyalgia and concomitant diseases in a mammal, including a human, comprising the step of administering to said mammal a therapeutically effective amount of a compound of formula 1:

wherein:

R²Is a straight or branched chain alkyl of 4 to 8 carbon atoms, a straight or branched chain alkenyl of 2 to 8 carbon atoms, a cycloalkyl of 3 to 7 carbon atoms, an alkoxy of 1 to 6 carbon atoms, -alkylcycloalkyl, -alkylalkoxy, -alkylOH, -alkylphenyl, -alkylphenoxy or-substituted phenyl; and wherein said concomitant disorder is selected from the group consisting of migraine, temporomandibular joint dysfunction, autonomic dysfunction, endocrine dysfunction, dizziness, cold intolerance, chemical sensitivity, sjogren's symptoms, cognitive dysfunction, generalized anxiety disorder, premenstrual dysphoric disorder, irritable bowel syndrome, functional abdominal pain, neuropathic pain, somatoform disorder, OCD, phobia, and PTSD.

8. A method of treatment of fibromyalgia and concomitant disorders in a mammal, including a human, comprising the step of administering to said mammal a therapeutically effective amount of the compound (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid or a pharmaceutically acceptable salt thereof, wherein said concomitant disorder is selected from migraine, temporomandibular joint dysfunction, autonomic nerve dysfunction, endocrine dysfunction, dizziness, intolerance of cold, chemical sensitivity, dry symptoms, cognitive dysfunction, generalized anxiety disorder, premenstrual dysphoric disorder, irritable bowel syndrome, functional somatic colic, neuropathic pain, formal disorders, OCD, phobia and PTSD.

9. The method of claim 7 or 8, wherein the compound administered is selected from the group consisting of:

(3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-decanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-undecanoic acid; and

(3S, 5R) -3-aminomethyl-5-methyl-dodecanoic acid;

or a pharmaceutically acceptable salt thereof.

10. The method of claim 8, wherein the concomitant disease is generalized anxiety disorder, premenstrual dysphoric disorder, somatoform disorder, irritable bowel syndrome, functional abdominal pain, neuropathic pain, or migraine.

11. A method of increasing slow wave sleep in a human subject treated with an active agent that reduces slow wave sleep, comprising administering to a human subject in need of such treatment:

(a) a compound of formula 1 as claimed in claim 1 or a pharmaceutically acceptable salt thereof; and

12. A method of increasing slow wave sleep in a human subject treated with an active agent that reduces slow wave sleep, comprising administering to a human subject in need of such treatment:

(a) the compound (3S, 5R) -3-aminomethyl-5-methyl-octanoic acid or a pharmaceutically acceptable salt thereof; and

13. A method of increasing slow wave sleep in a human subject comprising administering to a human subject in need of such treatment:

14. A method of increasing slow wave sleep in a human subject comprising administering to a human subject in need of such treatment:

15. The method of claim 1, 7, 11 or 13, wherein the compound is selected from the group consisting of:

(3S, 5R) -3-aminomethyl-5-methyl-nonanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-decanoic acid;

(3S, 5R) -3-aminomethyl-5-methyl-undecanoic acid; and

(3S, 5R) -3-aminomethyl-5-methyl-dodecanoic acid;

or a pharmaceutically acceptable salt thereof.